KR101820637B1 - Anti-myostatin antibodies, polypeptides containing variant fc regions, and methods of use - Google Patents

Abstract

This specification provides anti-myostatin antibodies and methods of making and using them. A nucleic acid encoding said anti-myostatin antibody and a host cell comprising said nucleic acid. This specification also provides polypeptides containing variant Fc regions and methods of making and using the same. A nucleic acid encoding said polypeptide and a host cell comprising said nucleic acid.

Description

ANTI-MYOSTATIN ANTIBODIES, POLYPEPTIDES CONTAINING VARIANT FC REGIONS, AND METHODS OF USE [0001] The present invention relates to anti-myostatin antibodies, polypeptides containing variant Fc regions,

The present invention relates to anti-myostatin antibodies and methods of use thereof. The invention also relates to polypeptides containing variant Fc regions and methods of use thereof.

Myostatin (also referred to as growth differentiation factor-8 (GDF8)) is a secreted protein and is a member of the protein with the transforming growth factor-beta (TGF-beta) phase. Members of the phase have growth-regulating and morphogenetic properties (see, for example, NPL 1, NPL 2 and PTL 1). Myostatin is mainly expressed in developmental and adult skeletal muscles and functions as a negative regulator of muscle growth. Systemic overexpression of myostatin in adult mice induces muscle wasting (see, for example, NPL 3), whereas in other words, myostatin knockout mice have a muscle mass two to three times greater than their wild- (See, for example, NPL 4). ≪ / RTI >

Like other members of the TGF-beta family, myostatin is synthesized as a large precursor protein containing the N-terminal propeptide domain and the C-terminal domain considered as the active molecule (e.g., NPL 5; PTL 2 Please refer. The two molecules of the myostatin precursor are covalently bound through a single disulfide bond present in the C-terminal growth factor domain. The active mature myostatin (the disulfide-linked homodimer consisting of the C-terminal growth factor domain) is liberated from the myostatin precursor through a multistage proteolytic processing. In the first step of the myostatin activation pathway, a peptide bond between the N-terminal propeptide domain and the C-terminal growth factor domain, Arg266-Asp267, is detected in both of the two chains of the homodimeric precursor, And is cleaved by a converting enzyme. However, the three peptides generated (two propeptides and one mature myostatin (i. E., The disulfide-linked homodimer consisting of the growth factor domain) remain bound and the "latent myostatin" Lt; RTI ID = 0.0 > non-covalent < / RTI > The mature myostatin can then be liberated from latent myostatin through degradation of the propeptide. Members of bone morphogenetic protein 1 (BMP1) of metalloproteinase cleave a single peptide bond, Arg98-Asp99, in the propeptide and simultaneously release mature, active myostatin, homodimers (e. See NPL 6). Moreover, the latent myostatin can also be activated in vitro by dissolving the complex by acid or heat treatment (see, for example, NPL 7).

Myostatin exerts its effect through the transmembrane serine / threonine kinase heterodimer receptor, and its activation stimulates the receptor phosphorylation transfer response to stimulate serine / threonine kinase activity. The myostatin pathway binds to the active receptor type IIB (ActRIIB) with high affinity and then phosphorylation transfer reaction of the low affinity receptor, actibin-type kinase 4 (ALK4) or actibin-type kinase 5 (ALK5) And activating myostatin dimer. In addition, the proteins Smad2 and Smad3 were subsequently activated and complexed with Smad4, and subsequently found to be translocated to the nucleus for activation of target gene transcription. ActRIIB has been shown to be able to mediate the effect of myostatin in vivo because expression of the dominant negative form of ActRIIB in mice imitates myostatin gene knockout (see, for example, NPL 8).

(MD) (including duchenne muscular dystrophy), amyotrophic lateral sclerosis (ALS), muscular dystrophy, traumatic atrophy, weakness, COPD, myopenia, and cancer or Cachexia resulting from other diseases, as well as kidney disease, heart failure or disease, and liver disease are associated with muscle wasting (i. E., Muscle tissue loss or impaired function). Patients will benefit from increased muscle mass and / or muscle strength; Currently available therapies for these diseases are limited. Thus, because of its role as a negative regulator of skeletal muscle growth, myostatin is a desirable target for the therapeutic or prophylactic intervention for such diseases or conditions, or for monitoring the progression of such diseases or conditions have. In particular, agents that inhibit the activity of myostatin can be therapeutically beneficial.

Inhibition of myostatin expression induces both hypertrophy and hypertrophy (NPL 4). Myostatin modulates myocardial regeneration after miostatin damage and deficiency accelerates muscle regeneration in myostatin-deficient mice (see, for example, NPL 9). For example, the anti-myostatin (GDF8) antibodies described in PTL 3, PTL 4, PTL 5, PTL 6 and PTL 7, and PTL 8, PTL 9 and PTL 10 bind to myostatin and inhibit both in vitro and in vivo Lt; RTI ID = 0.0 > myostatin < / RTI > activity associated with negative regulation of skeletal muscle mass, for example. The myostatin-neutralizing antibody is used to determine the body weight, skeletal muscle mass, and muscle size of the skeletal muscle of wild-type mice (see, for example, NPL 10) and mdx mice (see, for example, NPL 11; NPL 12) And strength. However, all of these prior art antibodies are specific for mature myostatin, but not specific for latent myostatin, and strategies described for inhibition of the myostatin activity include those associated with mature myostatin, Lt; / RTI > were used.

Antibodies are attracting attention as drugs because they are very stable in the body and have few side effects (see, for example, NPL 13 and NPL 14). Nearly all therapeutic antibodies currently on the market are antibodies to the human IgG1 subclass. One of the known functions of IgG class antibodies is antibody-dependent cell-mediated cytotoxicity (hereinafter referred to as ADCC activity) (see, for example, NPL 15). In the case of an antibody exhibiting ADCC activity, the antibody Fc region may be an antibody-binding receptor Fc gamma receptor present on the surface of effector cells, such as killer cells, natural killer cells, and activated macrophages, Gt; Fc < / RTI > gamma R).

In humans, the Fc gamma RIa (CD64A), Fc gamma RIIa (CD32A), Fc gamma RIIb (CD32B), Fc gamma RIIIa (CD16A) and Fc gamma RIIIb (CD16B) Have also been reported (see, for example, NPL 16). Fc gamma RIa, Fc gamma RIIa and Fc gamma RIIIa are referred to as activated Fc gamma R because they have immunologically active functions and Fc gamma RIIb are referred to as inhibitory Fc gamma R because they have immunosuppressive function See NPL 17).

In the binding between the Fc region and the Fc gamma R, a plurality of amino acid residues in the antibody hinge region and the CH2 domain and a sugar chain attached to the Asn of the 297th position (EU numbering) bonded to the CH2 domain were significant See NPL 18, NPL 19 and NPL 20 for more information). Various mutants with Fc gamma R-binding properties have been studied so far, with antibodies mutated predominantly to such sites; Fc region variants with higher binding activity for activated Fc gamma R were obtained (see, for example, PTL 11, PTL 12, PTL 13 and PTL 14).

When activated Fc gamma R cross-links with the immune complex, it phosphorylates the immunoreceptor tyrosine-based activation motif (ITAM) contained in the intracellular domain or the FcR common gamma-chain (interacting partner) Activating SYK and triggering an activation signal cascade triggers an inflammatory immune response (see, for example, NPL 21).

Fc gamma RIIb is the only Fc gamma R expressed on B cells (see, for example, NPL 22). It has been reported that the interaction of the antibody Fc region with Fc gamma RIIb inhibits the primary immune response of B cells (see, for example, NPL 23). Furthermore, it has been reported that B cell activation and antibody production by B cells are inhibited when Fc gamma RIIb and B cell receptor (BCR) on B cells cross-link through blood immunocomplexes (for example, NPL 24 ). In the immunosuppressive signaling mediated by BCR and Fc gamma RIIb, an immunoreceptor tyrosine-based inhibitory motive (ITIM) contained in the intracellular domain of Fc gamma RIIb is required (see, for example, NPL 25 and NPL 26 Please. When ITIM is phosphorylated upon signal transduction, SH2-containing inositol polyphosphate 5-phosphatase (SHIP) is recruited, delivery of other activated Fc gamma R signal cascades is inhibited, and inflammatory immune responses are suppressed (for example, NPL 27 ). Furthermore, it has been reported that aggregation of Fc gamma RIIb alone transiently inhibits calcium influx due to BCR cross-linking and B cell proliferation in a BCR-independent manner without inducing apoptosis of IgM-producing B cells See NPL 28 for more information).

Fc gamma RIIb is also expressed on dendritic cells, macrophages, activated neutrophils, mast cells, and basophils. Fc gamma RIIb inhibits the function of activated Fc gamma R, e.g., the release of phagocytic and inflammatory cytokines in such cells and inhibits inflammatory immune responses (see, for example, NPL 17).

The importance of the immunosuppressive function of Fc gamma RIIb has so far been demonstrated through studies using Fc gamma RIIb knockout mice. In Fc gamma RIIb knockout mice, humoral immunity is not adequately regulated (see, for example, NPL 29), sensitivity to collagen-induced arthritis (CIA) increases (see, for example, NPL 30) There are reports of symptoms such as lupus-like symptoms and Goodpasture's syndrome-like symptoms (see, for example, NPL 31).

In addition, regulatory imperfections in Fc gamma RIIb have been reported to be associated with human autoimmune diseases. For example, the relationship between the genetic polymorphisms in the transmembrane region and the promoter region of Fc gamma RIIb and the incidence of systemic lupus erythematosus (SLE) (e.g. NPL 32, NPL 33, NPL 34, NPL 35 and NPL 36 , And a reduction in the expression of Fc gamma RIIb on the B cell surface in SLE patients (see, for example, NPL 37 and NPL 38).

From the mouse model and clinical discovery itself, Fc gamma RIIb is considered to play an autoimmune and inflammatory disease inhibitory role, especially through involvement with B cells, which is a promising target molecule for the inhibition of autoimmune diseases and inflammatory diseases.

IgG1, which is mainly used as a commercially available therapeutic antibody, is known to bind not only to Fc gamma RIIb but also strongly to activated Fc gamma R (see, for example, NPL 39). By using an Fc gamma RIIb binding with enhanced Fc gamma RIIb binding, or an improved Fc gamma RIIb-binding selectivity relative to activated Fc gamma R, it may be possible to develop therapeutic antibodies with greater immunosuppressive properties relative to the case of IgGl have. For example, it has been proposed that the use of antibodies with variable regions that bind Fc and BCR with increased Fc gamma RIIb binding can inhibit B cell activation (see, for example, NPL 40). IgE bound to B-cell receptors and cross-linked Fc gamma RIIb on B cells inhibits the differentiation of B cells into plasma cells, resulting in the inhibition of IgE production; In human PBMC-transplanted mice, it has been reported that human IgG and IgM concentrations are maintained while human IgE levels are reduced (see, for example, NPL 41). In addition to IgE, when CD79b, a constituent molecule of the Fc gamma RIIB and B-cell receptor complex, is cross-linked by antibodies, it has been reported that B cell proliferation is inhibited in vitro and alleviates arthritic symptoms in a collagen arthritis model See NPL 42).

In addition to B cells, cross-linking of Fc Epsilon RI and Fc gamma RIIb on mast cells using a molecule fused to the Fc portion of IgE in which the Fc portion of IgG with increased Fc gamma RIIb binding binds IgE receptor Fc Epsilon RI Has been reported to cause phosphorylation of Fc gamma RIIb, thereby inhibiting Fc epsilon RI-dependent calcium entry. This suggests that inhibition of degranulation through Fc gamma RIIb stimulation is possible by increasing Fc gamma RIIb binding (see, for example, NPL 43).

Correspondingly, antibodies with Fc with improved Fc gamma RIIb-binding activity are proposed as promising therapeutics for inflammatory diseases such as autoimmune diseases.

Furthermore, it has been reported that the activation of macrophages and dendritic cells via toll-type receptor 4 due to LPS stimulation is inhibited in the presence of antibody-antigen immunoconjugates, suggesting that this effect is also the action of immune complexes via Fc gamma RIIb (See, for example, NPL 44 and NPL 45). Thus, the use of antibodies with increased Fc gamma RIIb binding is expected to enable the enhancement of TLR-mediated activated signal-inhibitory action; Thus, such antibodies have been proposed as promising therapeutic agents for inflammatory diseases such as autoimmune diseases.

In addition, mutants with increased Fc gamma RIIb binding have been suggested to be therapeutic agents for inflammatory diseases, such as autoimmune diseases, as well as a promising therapeutic for cancer. To date, Fc gamma RIIb has been found to play an important role in the agonistic activity of the agonist antibody to the anti-TNF receptor phase. Specifically, it has been proposed that the interaction activity of the antibody against CD40, DR4, DR5, CD30 and CD137 contained in the TNF receptor is required to interact with Fc gamma RIIb (for example, NPL 46, NPL 47, NPL 48, NPL 49 , NPL 50, NPL 51 and NPL 52). NPL 46 shows that the use of antibodies with increased Fc gamma RIIb binding augments the anti-tumor effect of anti-CD40 antibodies. Correspondingly, an antibody with an increased Fc gamma RIIb is expected to have the effect of enhancing the agonistic activity of an agonist antibody, including an antibody to the anti-TNF receptor phase.

In addition, cell proliferation is inhibited when an antibody that recognizes a type of receptor tyrosine kinase (RTK) Kit and cross-links with Fc gamma RIIb and Kit on Kit-expressing cells is used. Similar effects have been reported even when the Kit is constitutively activated and has mutations that cause tumor formation (see, for example, NPL 53). Thus, the use of antibodies with increased Fc gamma RIIb binding is expected to increase the inhibitory effect on cells expressing RTKs with constitutively activated mutations.

Antibodies with Fc with improved Fc gamma RIIb-binding activity have been reported (see, for example, NPL 40). In this document, Fc gamma RIIb-binding activity has been improved by altering the antibody Fc region, such as S267E / L328F, G236D / S267E and S239D / S267E. Among them, the antibody introduced with the S267E / L328F mutation binds most strongly to Fc gamma RIIb and has the same level of Fc gamma RIa and Fc gamma RIIa H as in the case of native IgG1, And the residue is His). However, another report suggests that the alteration may result in the same level of Fc gamma RIIb binding (which results in the Fc gamma RIIb-binding selectivity of the Fc gamma RIIa R form, where the residue at position 131 of Fc gamma RIIa is Arg) (Meaning that it is not improved compared to type-R Fc gamma RIIa) (see, for example, NPL 15).

It is believed that only Fc gamma RIIa binding is enhanced and Fc gamma RIIb binding is not increased, affecting cells such as platelets that express Fc gamma RIIa but not Fc gamma RIIb (see, for example, NPL 17 ). For example, a group of patients receiving a bevacizumab, an antibody to VEGF, is known to have an increased risk of thromboembolism (see, for example, NPL 54). Furthermore, thromboembolism was observed in a similar manner in clinical development studies of antibodies to CD40 ligand, and the clinical study was discontinued (see, for example, NPL 55). In both cases of these antibodies, a later study using animal models suggested that the administered antibody would aggregate platelets and form blood clots via Fc gamma RIIa on the platelets (for example, NPL 56 and NPL 57 Please refer. In systemic lupus erythematosus, an autoimmune disease, platelets are activated via an Fc gamma RIIa-dependent mechanism and platelet activation has been reported to correlate with severity of symptoms (see, for example, NPL 58). Administration of an antibody with increased Fc gamma RIIa binding in such patients, who are already at high risk of developing thromboembolism, will increase the risk of developing thromboembolism and is therefore extremely dangerous.

Furthermore, it has been reported that antibodies with increased Fc gamma RIIa binding augment macrophage-mediated antibody-dependent cellular activity (ADCP) (see, for example, NPL 59). When the antigen bound by the antibody is predated by macrophages, the antibody itself is also considered to be predated simultaneously. When an antibody is administered as a drug, a peptide fragment derived from the administered antibody appears to be also provided as an antigen, thereby increasing the risk of producing an antibody (anti-therapeutic antibody) against the therapeutic antibody. More specifically, the increase in Fc gamma RIIa binding will increase the risk of antibody production to the therapeutic antibody, which will significantly decrease its value as a drug. Furthermore, Fc gamma RIIb on dendritic cells contributes to peripheral immune tolerance by inhibiting dendritic cell activation caused by an immune complex formed between antigen and antibody, or by inhibiting antigen delivery to T cells through an activated Fc gamma receptor (For example, see NPL 60). Since Fc gamma RIIa is also expressed on dendritic cells, when an antibody with Fc having an increased selective binding to Fc gamma RIIb is used as the agent, an antigen is released by dendritic cells or the like due to the increased selective binding to Fc gamma RIIb And the risk of the generation of the anti-drug antibody can be relatively reduced. Such antibodies may also be useful with respect to the above.

More specifically, the drug value will be significantly reduced when the Fc gamma RIIa binding is increased, which leads to an increased risk of thrombus formation through platelet aggregation and an increased risk of anti-therapeutic antibody production due to increased immunogenicity do.

From the above viewpoint, the above-mentioned Fc variants with increased Fc gamma RIIb binding exhibit significantly increased R-type Fc gamma RIIa binding compared to the case of native IgG1. Thus, its value as a medicament for patients with R-type Fc gamma RIIa is significantly reduced. The H and R forms of Fc gamma RIIa are observed at about the same frequency in white and black (see, for example, NPL 61 and NPL 62). Thus, when the Fc variant is used in the treatment of an autoimmune disease, the number of patients that can be safely used, but who can benefit from it as a medicament will be limited.

Furthermore, dendritic cells have been reported to be mature in dendritic cells where the interaction between Fc gamma RIIb deficient dendritic cells or Fc gamma RIIb and the antibody Fc portion is inhibited by anti-Fc gamma RIIb antibodies (see, for example, NPL 63 and NPL 64). The report suggests that Fc gamma RIIb actively suppresses the maturation of dendritic cells in normal conditions without inflammation and no activation. In addition to Fc gamma RIIb, Fc gamma RIIa is expressed on dendritic cell surfaces; Thus, although binding to the inhibitory Fc gamma RIIb is increased and binding to the activated Fc gamma R, e. G., Fc gamma RIIa is also increased, the maturation of dendritic cells may eventually be promoted. More specifically, improving the ratio of Fc gamma RIIb-binding activity to Fc gamma RIIb-binding activity as well as Fc gamma RIIa-binding activity is considered important in providing antibodies having immunosuppressive action.

Thus, when considering the generation of agents that utilize the Fc gamma RIIb binding-mediated immunosuppressive action, Fc variants with an association to both the Fc gamma RIIa H and R allotypes, as well as having enhanced Fc gamma RIIb-binding activity And the binding is maintained at a level similar to that of native IgG1 or attenuated to the lower level.

On the other hand, some cases have been reported in which amino acid changes are introduced into the Fc region to increase Fc gamma RIIb-binding selectivity (see, for example, NPL 65). However, as reported in this document, all variants with improved Fc gamma RIIb selectivity showed decreased Fc gamma RIIb binding compared to native IgG1. Thus, it would be difficult for these mutants to actually induce Fc gamma RIIb-mediated immunosuppressive responses more strongly than IgG1.

Furthermore, since Fc gamma RIIb plays an important role in the above-mentioned agent antibody, it is expected that increasing its binding activity will increase agonist activity. However, if the Fc gamma RIIa binding is similarly increased, unintended activities such as ADCC activity and ADCP activity will appear, which may cause side effects. Also from the above viewpoint, it may be desirable to be able to selectively increase the Fc gamma RIIb-binding activity.

The above results show that in the production of therapeutic antibodies for the treatment of autoimmune diseases and cancer using Fc gamma RIIb, the binding activity to both Fc gamma RIIa allotypes is maintained or reduced compared to the case of natural IgG, It is important that the RIIb binding be increased. However, Fc gamma RIIb shares 93% sequence identity in the extracellular region with that of Fc gamma RIIa, one of the activated Fc gamma Rs, and they are structurally very similar. There are allotype, H type and R type of Fc gamma RIIa (here, the amino acid at position 131 is His (H type) or Arg (R type)), which react differently from the above antibodies See NPL 66 for more information). Thus, a difficult problem could be the generation of Fc region variants with increased selective Fc gamma RIIb binding compared to each allotype of Fc gamma RIIa, which distinguishes very homologous sequences between Fc gamma RIIa and Fc gamma RIIb It is accompanied. Despite these difficulties, a number of Fc region variants with selective binding activity against Fc gamma RIIb have been identified to some extent by performing a comprehensive amino acid deformation assay in the Fc region compared to Fc gamma RIIa (e.g., PTL 16, PTL 17, PTL 18, PTL 19 and PTL 20).

There is some report on Fc region variants with binding selectivity for Fc gamma RIIb in relation to human Fc gamma R, while there are reports about Fc region variants with binding selectivity for Fc gamma RIIb in relation to monkey Fc gamma R There is no report. Due to the absence of such Fc variants, the effect of Fc variants selectively binding to Fc gamma RIIb has not yet been thoroughly tested in monkeys.

Apart from this, it has been reported that by modifying the charge of an amino acid residue that may be exposed on the surface of the antibody to increase or decrease the isoelectric point (pI) of the antibody, the half-life of the antibody in the blood can be regulated See PTL 21 and PTL 22). Indicating that the plasma half-life of the antibody can be extended by reducing the pI of the antibody or vice versa.

In addition, it has been reported that integration of antigens into cells can be promoted, particularly by modifying the charge of a specified amino acid residue in its CH3 domain to increase the pI of the antibody (see, for example, NPL 23). It has also been reported that modifying the charge of the amino acid residues in the constant region (mainly the CH1 domain) of the antibody to reduce the pI can prolong the half-life of the antibody in plasma (see, for example, NPL 24).

Citation list

[Patent Literature]

[PTL 1]

U.S. Patent No. 5,827,733

[PTL 2]

WO 1994/021681

[PTL 3]

U.S. Patent No. 6,096,506

[PTL 4]

U.S. Patent No. 7,261,893

[PTL 5]

U.S. Patent No. 7,320,789

[PTL 6]

U.S. Patent No. 7,807,159

[PTL 7]

U.S. Patent No. 7,888,486

[PTL 8]

WO 2005/094446

[PTL 9]

WO 2007/047112

[PTL 10]

WO 2010/070094

[PTL 11]

WO 2000/042072

[PTL 12]

WO 2006/019447

[PTL 13]

WO 2004/099249

[PTL 14]

WO 2004/029207

[PTL 15]

US Application No. US2009 / 0136485

[PTL 16]

WO 2012/115241

[PTL 17]

WO 2013/047752

[PTL 18]

WO 2013/125667

[PTL 19]

WO 2014/030728

[PTL 20]

WO 2014/163101

[PTL 21]

WO 2007/114319

[PTL 22]

WO 2009/041643

[PTL 23]

WO 2014/145159

[PTL 24]

WO 2012/016227

[Non-Patent Document]

[NPL 1]

Kingsley et al., Genes Dev. 8 (2): 133-146 (1994)

[NPL 2]

Hoodless et al., Curr. Top. Microbiol. Immunol. 228: 235-272 (1998)

[NPL 3]

Zimmers et al., Science 296 (5572): 1486-1488 (2002)

[NPL 4]

McPherron et al., Nature 387 (6628): 83-90 (1997)

[NPL 5]

McPherron and Lee, Proc. Natl. Acad. Sci. USA 94 (23): 12457-12461 (1997)

[NPL 6]

Szlama et al., FEBS J 280 (16): 3822-3839 (2013)

[NPL 7]

Lee, PloS One 3 (2): e1628 (2008)

[NPL 8]

Lee, Proc. Natl. Acad. Sci. USA 98 (16): 9306-9311 (2001)

[NPL 9]

McCroskery et al., J Cell Sci. 118 (15): 3531-3541 (2005)

[NPL 10]

Whittemore et al., Biochem. Biophys. Res. Commun. 300 (4): 965-971 (2003)

[NPL 11]

Bogdanovich et al., Nature 420 (6914): 418-421 (2002)

[NPL 12]

Wagner., Ann. Neurol. 52 (6): 832-836 (2002)

[NPL 13]

Reichert et al., Nat. Biotechnol. 23: 1073-1078 (2005)

[NPL 14]

Pavlou et al., Eur. J. Pharm. Biopharm. 59: 389-396 (2005)

[NPL 15]

Clark et al., Chem. Immunol. 65: 88-110 (1997)

[NPL 16]

Jefferis et al., Immunol. Lett. 82: 57-65 (2002)

[NPL 17]

Smith et al., Nat. Rev. Immunol. 10: 328-343 (2010)

[NPL 18]

Radaev et al., J. Biol. Chem. 276: 16478-16483 (2001)

[NPL 19]

Greenwood et al., Eur. J. Immunol. 23: 1098-1104 (1993)

[NPL 20]

Morgan et al., Immunology 86: 319-324 (1995)

[NPL 21]

Nimmerjahn et al., Nat. Rev. Immunol. 8: 34-47 (2008)

[NPL 22]

Amigorena et al., Eur. J. Immunol. 19: 1379-1385 (1989)

[NPL 23] Sinclair, J. Exp. Med. 129: 1183-1201 (1969)

[NPL 24]

Heyman, Immunol. Lett. 88: 157-161 (2003)

[NPL 25]

Amigorena et al., Science 256: 1808-1812 (1992)

[NPL 26]

Muta et al., Nature 368: 70-73 (1994)

[NPL 27]

Ravetch, Science 290: 84-89 (2000)

[NPL 28]

Fournier et al., J. Immunol. 181: 5350-5359 (2008)

[NPL 29]

J. Immunol. 163: 618-622 (1999)

[NPL 30]

Yuasa et al., J. Exp. Med. 189: 187-194 (1999)

[NPL 31]

Nakamura et al., J. Exp. Med. 191: 899-906 (2000)

[NPL 32]

Blank, Hum. Genet. 117: 220-227 (2005)

[NPL 33]

Olferiev et al., J. Biol. Chem. 282: 1738-1746 (2007)

[NPL 34]

Chen et al., Arthritis Rheum. 54: 3908-3917 (2006)

[NPL 35]

Floto et al., Nat. Med. 11: 1056-1058 (2005)

[NPL 36]

Li et al., J. Immunol. 176: 5321-5328 (2006)

[NPL 37]

Mackay et al., J. Exp. Med. 203: 2157-2164 (2006)

[NPL 38]

Yang et al., J. Immunol. 178: 3272-3280 (2007)

[NPL 39]

Bruhns et al., Blood 113: 3716-3725 (2009)

[NPL 40]

Chu et al., Mol. Immunol. 45: 3926-3933 (2008)

[NPL 41]

Chu et al., J. Allergy Clin. Immunol. 129: 1102-1115 (2012)

[NPL 42]

Data et al., Arthritis Rheum. 62: 1933-1943 (2010)

[NPL 43]

Cemerski et al., Immunol. Lett. 143: 34-43 (2012)

[NPL 44]

Wenink et al., J. Immunol. 183: 4509-4520 (2009)

[NPL 45]

Zhang et al., J. Immunol. 182: 554-562 (2009)

[NPL 46]

Ravetch, Science 333: 1030-1034 (2011)

[NPL 47]

Wilson et al., Cancer Cell 19: 101-113 (2011)

[NPL 48]

Kohrt et al., J. Clin. Invest. 122: 1066-1075 (2012)

[NPL 49]

Xu et al., J. Immunol. 171: 562-568 (2003)

[NPL 50]

Zhang et al., Blood 108: 705-710 (2006)

[NPL 51]

Chuntharapai et al., J. Immunol. 166: 4891-4898 (2001)

[NPL 52]

Ravetch et al., Proc. Natl. Acad. Sci. USA 109: 10966-10971 (2012)

[NPL 53]

Malbec et al., Immunol. Lett. 143: 28-33 (2012)

[NPL 54]

Scappaticci et al., J. Natl. Cancer. Inst. 99: 1232-1239 (2007)

[NPL 55]

Arthritis Rheum. 48: 719-727 (2003)

[NPL 56]

Meyer et al., J. Thromb. Haemost. 7: 171-181 (2008)

[NPL 57]

Robles-Carrillo et al., J. Immunol. 185: 1577-1583 (2010)

[NPL 58]

Duffau et al., Sci. Transl. Med. 2: 47ra63 (2010)

[NPL 59]

Richards et al., Mol. Cancer Ther. 7: 2517-2527 (2008)

[NPL 60]

Desai et al., J. Immunol. 178: 6217-6226 (2007)

[NPL 61]

Salmon et al., J. Clin. Invest. 97: 1348-1354 (1996)

[NPL 62]

Manger et al., Arthritis Rheum. 41: 1181-1189 (1998)

[NPL 63]

Boruchov et al., J. Clin. Invest. 115: 2914-2923 (2005)

[NPL 64]

Dhodapkar et al., Proc. Natl. Acad. Sci. USA 102: 2910-2915 (2005)

[NPL 65]

Armor et al., Mol. Immunol. 40: 585-593 (2003)

[NPL 66]

Warmerdam et al., J. Exp. Med. 172: 19-25 (1990)

It is an object of the present invention to provide anti-myostatin antibodies, polypeptides containing variant Fc regions, and methods of use thereof.

The present invention provides anti-myostatin antibodies and methods of use thereof. The present invention also provides proteins containing variant Fc regions and methods of use thereof.

In some embodiments, the isolated anti-myostatin antibody of the invention binds to latent myostatin. In a further embodiment, the antibody binds to an epitope in the fragment consisting of amino acids 21-100 of the myostatin propeptide (SEQ ID NO: 78). In some embodiments, the isolated anti-myostatin antibody of the invention inhibits the activation of myostatin. In a further embodiment, the antibody blocks the release of mature myostatin from latent myostatin. In a further embodiment, the antibody blocks proteolytic release of mature myostatin. In a further embodiment, the antibody blocks spontaneous release of mature myostatin. In a further embodiment, the antibody does not bind to mature myostatin. In a further embodiment, the antibody binds to the same epitope as the antibody set forth in Table 13. In a further embodiment, the antibody binds to the same epitope as the antibody comprising the VH and VL pairs set forth in Table 13. In a further embodiment, the antibody binds to the same epitope as the antibody described in Table 2a. In a further embodiment, the antibody binds to the same epitope as the antibody comprising the VH and VL pairs set forth in Table 2a. In a further embodiment, the antibody binds to the same epitope as the antibody described in Table 11a. In a further embodiment, the antibody binds to the same epitope as the antibody comprising the VH and VL pairs set forth in Table 11a. In a further embodiment, the antibody binds to the same epitope as the antibody described in Tables 2a, 11a or 13. In a further embodiment, the antibody binds to the same epitope as the antibody comprising the VH and VL pairs set forth in Table 2a, 11a or 13.

In some embodiments, the isolated anti-myostatin antibody of the invention binds latent myostatin to a higher affinity at neutral pH than at an acidic pH. In some embodiments, the anti-myostatin antibody binds to latent myostatin with a higher affinity at pH 7.4 than at pH 5.8. In some embodiments, the isolated anti-myostatin antibody of the invention binds to a polypeptide fragment consisting of amino acids 21-100 of myostatin propeptide (SEQ ID NO: 78) with a higher affinity at pH 7.4 than at pH 5.8 . In some embodiments, the antibody binds to the same myostatin epitope as the antibody described in Table 13 with a higher affinity at neutral pH than at an acidic pH. In an additional embodiment, the anti-myostatin antibody binds to the same epitope as the antibody set forth in Table 13 with a higher affinity at pH 7.4 than at pH 5.8. In a further embodiment, the antibody binds to the same epitope as the antibody comprising the VH and VL pairs set forth in Table 13 with a higher affinity at pH 7.4 than at pH 5.8. In some embodiments, the antibody binds to the same myostatin epitope as the antibody described in Table 2a with a higher affinity at neutral pH than at an acidic pH. In some embodiments, the antibody binds to the same myostatin epitope as the antibody described in Table 2a with a higher affinity at pH 7.4 than at pH 5.8. In an additional embodiment, the antibody binds to the same epitope as the antibody comprising the VH and VL pairs set forth in Table 2a with a higher affinity at pH 7.4 than at pH 5.8. In an additional embodiment, the anti-myostatin antibody binds to the same myostatin epitope as the antibody described in Table 11a with a higher affinity at neutral pH than at an acidic pH. In a further embodiment, the antibody binds to the same myostatin epitope as the antibody described in Table 11a with a higher affinity at pH 7.4 than at pH 5.8. In an additional embodiment, the antibody binds to the same epitope as the antibody comprising the VH and VL pairs set forth in Table 11a with a higher affinity at pH 7.4 than at pH 5.8. In a further embodiment, the anti-myostatin antibody binds to the same myostatin epitope as the antibody described in Tables 2a, 11a or 13 with a higher affinity at neutral pH than at an acidic pH. In a further embodiment, the antibody binds to the same myostatin epitope as the antibody described in Table 2a, 11a or 13 with a higher affinity at pH 7.4 than at pH 5.8. In a further embodiment, the antibody binds to the same epitope as the antibody comprising the VH and VL pairs described in Tables 2a, 11a or 13 with a higher affinity at pH 7.4 than at pH 5.8.

In some embodiments, the isolated anti-myostatin antibody of the present invention competes with the antibody provided herein for latent myostatin binding. In some embodiments, the isolated anti-myostatin antibody of the invention competes against the antibody described in Table 13 for latent myostatin binding. In some embodiments, the isolated anti-myostatin antibody of the present invention competes for latent myostatin binding with antibodies comprising the VH and VL pairs set forth in Table 13. In some embodiments, the antibody competes against the antibody described in Table 2a for latent myostatin binding. In some embodiments, the isolated anti-myostatin antibodies of the invention compete for latent myostatin binding with antibodies comprising the VH and VL pairs set forth in Table 2a. In some embodiments, the antibody competes against the antibody described in Table 11a for latent myostatin binding. In some embodiments, the isolated anti-myostatin antibodies of the invention compete for latent myostatin binding with antibodies comprising the VH and VL pairs set forth in Table 11a. In an additional embodiment, the anti-myostatin antibody competes against the antibody described in Table 2a, 11a or 13 for latent myostatin binding. In an additional embodiment, the anti-myostatin antibody competes against latent myostatin binding with an antibody comprising the VH and VL pairs set forth in Table 2a, 11a or 13. In a further embodiment, the anti-myostatin antibody binds latent myostatin to a higher affinity at neutral pH than at an acidic pH. In a further embodiment, the anti-myostatin antibody binds to latent myostatin with a higher affinity at pH 7.4 than at pH 5.8. In a further embodiment, the anti-myostatin antibody binds to a polypeptide fragment consisting of the amino acids 21-100 of the myostatin pro peptide (SEQ ID NO: 78) with a higher affinity at pH 7.4 than at pH 5.8. Methods for assessing the ability of an antibody to compete with a reference antibody for latent myostatin binding are described herein and are known in the art.

In some embodiments, the isolated anti-myostatin antibody of the invention is a monoclonal antibody. In some embodiments, the isolated anti-myostatin antibody of the invention is a human, humanized, or chimeric antibody. In some embodiments, the isolated anti-myostatin antibody of the invention is an antibody fragment that binds myostatin. In some embodiments, the isolated anti-myostatin antibody of the invention is an antibody fragment that binds latent myostatin. In some embodiments, the isolated anti-myostatin antibody of the invention is an antibody fragment that binds to a polypeptide fragment comprising the amino acids 21-100 of the myostatin propeptide (SEQ ID NO: 78). In some embodiments, the isolated anti-myostatin antibody of the invention is a full length IgG antibody.

In some embodiments, anti-myostatin antibodies of the invention include:

(a) an HVR comprising an amino acid sequence GVPAX ₁ SX ₂ GGDX ₃ wherein X ₁ is Y or H, X ₂ is T or H, and X ₃ is L or K (SEQ ID NO: 128) H3, (ii) HVR-L3 comprising the amino acid sequence AGGYGGGX ₁ YA wherein X ₁ is L or R (SEQ ID NO: 131), and (iii) amino acid sequence IISX ₁ AGX ₂ X ₃ YX ₄ X ₅ X ₆ WAKX ₇ wherein X ₁ is Y or H, X ₂ is S or K, X ₃ is T, M or K, X ₄ is Y or K, X ₅ is A, M or E , X ₆ is S or E, X ₇ is G or K) (comprising SEQ ID NO: 127) HVR-H2;

(ii) an HVR-H1 comprising (i) an amino acid sequence X ₁ X ₂ DIS wherein X ₁ is S or H and X ₂ is Y, T, D or E (SEQ ID NO: 126) ) Amino acid sequence IISX ₁ AGX ₂ X ₃ YX ₄ X ₅ X ₆ WAKX ₇ wherein X ₁ is Y or H, X ₂ is S or K, X ₃ is T, M or K, X ₄ is Y Or K, and X ₅ is A, M or E, X ₆ is S or E and X ₇ is G or K) (SEQ ID NO: 127), and (iii) amino acid sequence GVPAX ₁ HVR-H3 comprising SX ₂ GGDX ₃ wherein X ₁ is Y or H, X ₂ is T or H and X ₃ is L or K (SEQ ID NO: 128);

(c) an HVR-H1 comprising (i) an amino acid sequence X ₁ X ₂ DIS wherein X ₁ is S or H and X ₂ is Y, T, D or E (SEQ ID NO: 126) ) Amino acid sequence IISX ₁ AGX ₂ X ₃ YX ₄ X ₅ X ₆ WAKX ₇ wherein X ₁ is Y or H, X ₂ is S or K, X ₃ is T, M or K, X ₄ is Y or K, and, X ₅ is a, and M or E, X ₆ is S or E, and, X ₇ is G or K a) (SEQ ID NO: 127), HVR-H2, (iii) the amino acid sequence GVPAX ₁ SX containing HVR-H3 comprising ₂ GGDX ₃ wherein X ₁ is Y or H, X ₂ is T or H and X ₃ is L or K (SEQ ID NO: 128), (iv) an amino acid sequence X ₁ X ₂ SQX ₃ VX ₄ X ₅ X ₆ NWLS where X ₁ is Q or T, X ₂ is S or T, X ₃ is S or E, X ₄ is Y or F, X ₅ is D or H, and X ₆ is N, D, A, or E) (SEQ ID NO: 129); (v) HVR-L2 comprising the amino acid sequence WAX ₁ TLAX ₂ (wherein X ₁ is S or E and X ₂ is S, Y, F or W) (SEQ ID NO: 130); And (vi) HVR-L3 comprising the amino acid sequence AGGYGGGX ₁ YA (wherein X ₁ is L or R) (SEQ ID NO: 131);

(i) amino acid sequence X ₁ X ₂ SQX ₃ VX ₄ X ₅ X ₆ NWLS wherein X ₁ is Q or T, X ₂ is S or T, X ₃ is S or E, X ₄ is Y or F, and, X ₅ is D or H, X ₆ is N, D, or E is a) (containing SEQ ID NO: 129) HVR-L1; (ii) HVR-L2 comprising the amino acid sequence WAX ₁ TLAX ₂ (wherein X ₁ is S or E and X ₂ is S, Y, F, or W) (SEQ ID NO: 130); And (iii) HVR-L3 comprising the amino acid sequence AGGYGGGX ₁ YA (wherein X ₁ is L or R) (SEQ ID NO: 131). In some embodiments, the antibody of (b) comprises a heavy chain variable domain framework FR1 comprising an amino acid sequence of any one of SEQ ID NOs: 132-134; FR2 comprising an amino acid sequence of any one of SEQ ID NOS: 135-136; FR3 comprising the amino acid sequence of SEQ ID NO: 137; And FR4 comprising the amino acid sequence of SEQ ID NO: 138. In some embodiments, the antibody of (d) comprises a light chain variable domain framework FR1 comprising the amino acid sequence of SEQ ID NO: 139; FR2 comprising an amino acid sequence of any one of SEQ ID NOS: 140-141; FR3 comprising the amino acid sequence of any one of SEQ ID NOS: 142-143; And FR4 comprising the amino acid sequence of SEQ ID NO: 144.

In some embodiments, the isolated anti-myostatin antibody of the invention comprises (a) an amino acid sequence GVPAX ₁ SX ₂ GGDX ₃ wherein X ₁ is Y or H, X ₂ is T or H, X ₃ is L or K) comprising the amino acid sequence AGGYGGGX ₁ YA (wherein X ₁ is L or R) (SEQ ID NO: 131), and (b) HVR- c) amino acid sequence IISX ₁ AGX ₂ X ₃ YX ₄ X ₅ X ₆ WAKX ₇ wherein X ₁ is Y or H, X ₂ is S or K, X ₃ is T, M or K, X ₄ is and Y or K, and X ₅ is a, M or E, X ₆ comprises a HVR-H2 comprising the S or E, X ₇ is G or K) (SEQ ID NO: 127).

In some embodiments, the isolated anti-myostatin antibody of the invention comprises (a) an amino acid sequence X ₁ X ₂ DIS where X ₁ is S or H and X ₂ is Y, T, D or E, (SEQ ID NO: 126), (b) amino acid sequence IISX ₁ AGX ₂ X ₃ YX ₄ X ₅ X ₆ WAKX ₇ wherein X ₁ is Y or H, X ₂ is S or K, X ₃ is T, M or K, X ₄ is Y or K, X ₅ is A, M or E, X ₆ is S or E, and X ₇ is G or K (SEQ ID NO: 127) (C) amino acid sequence GVPAX ₁ SX ₂ GGDX ₃ wherein X ₁ is Y or H, X ₂ is T or H, and X ₃ is L or K (SEQ ID NO: 128) HVR-H3 < / RTI > In a further embodiment, the antibody comprises a heavy chain variable domain framework FR1 comprising an amino acid sequence of any one of SEQ ID NOS: 132-134; FR2 comprising an amino acid sequence of any one of SEQ ID NOS: 135-136; FR3 comprising the amino acid sequence of SEQ ID NO: 137; And FR4 comprising the amino acid sequence of SEQ ID NO: 138. In a further embodiment, the antibody comprises (a) an amino acid sequence X ₁ X ₂ SQX ₃ VX ₄ X ₅ X ₆ NWLS, wherein X ₁ is Q or T, X ₂ is S or T, X ₃ is S Or E; X ₄ is Y or F; X ₅ is D or H; and X ₆ is N, D, A or E) (SEQ ID NO: 129); (b) HVR-L2 comprising the amino acid sequence WAX ₁ TLAX ₂ , wherein X ₁ is S or E and X ₂ is S, Y, F, or W (SEQ ID NO: 130); And (c) HVR-L3 comprising the amino acid sequence AGGYGGGX ₁ YA, wherein X ₁ is L or R (SEQ ID NO: 131).

In some embodiments, the isolated anti-myostatin antibody of the invention comprises (a) an amino acid sequence X ₁ X ₂ SQX ₃ VX ₄ X ₅ X ₆ NWLS, wherein X ₁ is Q or T, X ₂ is S Or T, X ₃ is S or E, X ₄ is Y or F, X ₅ is D or H, and X ₆ is N, D, A or E) (SEQ ID NO: 129) L1; (b) HVR-L2 comprising the amino acid sequence WAX ₁ TLAX ₂ , wherein X ₁ is S or E and X ₂ is S, Y, F, or W (SEQ ID NO: 130); And (c) HVR-L3 comprising the amino acid sequence AGGYGGGX ₁ YA, wherein X ₁ is L or R (SEQ ID NO: 131). In a further embodiment, the antibody comprises a light chain variable domain framework FR1 comprising the amino acid sequence of SEQ ID NO: 139; FR2 comprising an amino acid sequence of any one of SEQ ID NOS: 140-141; FR3 comprising the amino acid sequence of any one of SEQ ID NOS: 142-143; And FR4 comprising the amino acid sequence of SEQ ID NO: 144.

In some embodiments, the isolated anti-myostatin antibody of the invention comprises a heavy chain variable domain framework FR1 comprising an amino acid sequence of any one of SEQ ID NOs: 132-134; FR2 comprising an amino acid sequence of any one of SEQ ID NOS: 135-136; FR3 comprising the amino acid sequence of SEQ ID NO: 137; And FR4 comprising the amino acid sequence of SEQ ID NO: 138. In some embodiments, the isolated anti-myostatin antibody of the invention comprises a light chain variable domain framework FR1 comprising the amino acid sequence of SEQ ID NO: 139; FR2 comprising an amino acid sequence of any one of SEQ ID NOS: 140-141; FR3 comprising the amino acid sequence of any one of SEQ ID NOS: 142-143; And FR4 comprising the amino acid sequence of SEQ ID NO: 144.

In some embodiments, the isolated anti-myostatin antibody of the invention comprises (a) at least 95% sequence identity to an amino acid sequence of any one of SEQ ID NOS: 13, 16-30, 32-34, and 86-95 VH sequence; (b) a VL sequence having at least 95% sequence identity to the amino acid sequence of any one of SEQ ID NOS: 15, 31, 35-38, and 96-99; Or (c) the VH sequence as in (a) and the VL sequence as in (b). In a further embodiment, the antibody comprises (a) a VH sequence of any one of SEQ ID NOS: 13, 16-30, 32-34 and 86-95. In a further embodiment, the antibody comprises a VL sequence of any one of SEQ ID NOS: 15, 31, 35-38, and 96-99. In some embodiments, the antibody comprises a VH sequence of any one of SEQ ID NOS: 13, 16-30, 32-34, and 86-95. In a further embodiment, the antibody comprises a VH sequence of any one of SEQ ID NOS: 13, 16-30, 32-34 and 86-95; And SEQ ID NOs: 15, 31, 35-38, and 96-99.

The present invention also provides an isolated nucleic acid encoding the anti-myostatin antibody of the invention. The present invention also provides a host cell comprising the nucleic acid of the present invention. The present invention also provides a method of producing an antibody comprising culturing a host cell of the invention to produce an antibody.

In some aspects, the present invention provides a method of producing an antibody comprising: (a) culturing a host cell of the invention to produce an antibody; Or (b) immunizing an animal with a polypeptide, wherein the polypeptide is administered at a dose of 21 to 100 times the myostatin propeptide (SEQ ID NO: 78) Lt; RTI ID = 0.0 > amino acid < / RTI >

The present invention also provides a method for producing an anti-myostatin antibody. In some embodiments, the method comprises immunizing an animal with a polypeptide, wherein the polypeptide comprises a region corresponding to an amino acid at positions 21 to 100 of the myostatin propeptide (SEQ ID NO: 78) do.

The present invention also provides a pharmaceutical formulation comprising an anti-myostatin antibody of the invention and a pharmaceutically acceptable carrier.

The anti-myostatin antibody of the present invention may be for use as a medicine. In some embodiments, the antibody comprises (a) treatment of muscle wasting disease; (b) an increase in muscle tissue mass; (c) increased muscle tissue strength; Or (d) for the manufacture of a medicament for the reduction of body fat accumulation. In some embodiments, the anti-myostatin antibody of the invention may be for use in the treatment of muscle wasting disease. The anti-myostatin antibody of the present invention may be for use in increasing muscle tissue mass. The anti-myostatin antibody of the present invention may be for use in increasing muscle tissue strength. The anti-myostatin antibody of the present invention may be for use in reducing body fat accumulation.

In some embodiments, the anti-myostatin antibody provided herein comprises (a) treatment of muscle wasting disease; (b) an increase in muscle tissue mass; (c) increased muscle tissue strength; Or (d) reduce body fat accumulation.

The anti-myostatin antibody of the present invention can be used in the manufacture of medicaments. In some embodiments, the antibody comprises (a) treatment of muscle wasting disease; (b) an increase in muscle tissue mass; (c) increased muscle tissue strength; Or (d) for the manufacture of a medicament for the reduction of body fat accumulation. In some embodiments, the agent is for the treatment of muscle wasting disease. In some embodiments, the agent is for an increase in muscle tissue mass. In some embodiments, the agent is for an increase in muscle tissue strength. In some embodiments, the agent is for the reduction of body fat accumulation.

The present invention also provides a method of treating an individual having muscle wasting disease. In some embodiments, the method comprises administering to the subject an effective amount of an anti-myostatin antibody of the invention. The present invention also provides a method for increasing the mass of muscle tissue in an individual. In some embodiments, the method comprises increasing the mass of the muscle tissue by administering to the subject an effective amount of an anti-myostatin antibody of the invention. The present invention also provides a method of increasing the strength of muscle tissue in an individual. In some embodiments, the method comprises increasing the intensity of muscle tissue by administering to the subject an effective amount of an anti-myostatin antibody of the invention. The present invention also provides a method of reducing body fat accumulation in an individual. In some embodiments, the method comprises administering to the subject an effective amount of an anti-myostatin antibody of the invention to reduce body fat accumulation.

The present invention provides polypeptides comprising a variant Fc region and methods of making and using the same.

In one embodiment, the invention provides Fc gamma RIIB-binding polypeptides comprising variant Fc regions and methods of use thereof. In some embodiments, a variant Fc region having an enhanced Fc gamma RIIb-binding activity of the invention comprises at least one amino acid change in the parent Fc region. In a further embodiment, the ratio of [KD value of parent Fc region to monkey Fc gamma RIIb] / [KD value of variant Fc region to monkey Fc gamma RIIb] is at least 2.0. In a further embodiment, the ratio of [KD value of parent Fc region to monkey Fc gamma RIIIa] / [KD value of variant Fc region to monkey Fc gamma RIIIa] is 0.5 or less. In a further embodiment, the ratio of [KD value of parent Fc region to human Fc gamma RIIb] / [KD value of variant Fc region to human Fc gamma RIIb] is at least 2.0. In a further embodiment, the ratio of [KD value of parent Fc region to human Fc gamma RIIIa] / [KD value of variant Fc region to human Fc gamma RIIIa] is 0.5 or less. In a further embodiment, the ratio of [KD value of parent Fc region to human Fc gamma RIIa (H form)] / [KD value of mutant Fc region to human Fc gamma RIIa (H form)] is 5.0 or less. In a further embodiment, the ratio of [KD value of parent Fc region to human Fc gamma RIIa (R form)] / [KD value of mutant Fc region to human Fc gamma RIIa (R form)] is 5.0 or less. In another embodiment, the KD value of the variant Fc region for the monkey Fc gamma RIIb is 1.0 x 10 < ^-6 > M or less. In another embodiment, the KD value of the variant Fc region for the monkey Fc gamma RIIIa is 5.0 x 10 < ^-7 > M or higher. In another embodiment, the KD value of the variant Fc region for human Fc gamma RIIb is 2.0 x 10 < ^-6 > M or less. In another embodiment, the KD value of the variant Fc region for human Fc gamma RIIIa is greater than 1.0 x 10 < ^-6 > M. In another embodiment, the KD value of the variant Fc region for human Fc gamma RIIa (Form H) is 1.0 x 10 < ^-7 > M or greater. In another embodiment, the KD value of the variant Fc region for the human Fc gamma RIIa (R form) is greater than or equal to 2.0 x 10 < ^-7 > M.

In some embodiments, the variant Fc region of the invention having increased Fc gamma RIIb-binding activity is selected from the group consisting of 231, 232, 233, 234, 235, 236, 237, 238, 239, 264, 266, 267, At least one amino acid change in at least one position selected from the group consisting of SEQ ID NOs: 268, 271, 295, 298, 325, 326, 327, 328, 330, 331, 332, 334,

In a further embodiment, the variant Fc region having increased Fc gamma RIIb-binding activity comprises (a) one amino acid change at position 236, and (b) (i) 231,232, 233, 234, 235, 237, 238, 239, 264, 266, 267, 268, 271, 295, 298, 325, 326, 327, 328, 330, 331, 332, 334 and 396; (ii) positions 231, 232, 235, 239, 268, 295, 298, 326, 330, and 396; And (iii) at least one amino acid change in at least one position selected from the group consisting of positions 268, 295, 326, and 330.

In a further embodiment, the variant Fc region with increased Fc gamma RIIb-binding activity comprises (a) one amino acid change at position 236, and (b) 231, 232, 233, 234, 235 At least one of the positions selected from the group consisting of 237, 238, 239, 264, 266, 267, 268, 271, 295, 298, 325, 326, 327, 328, 330, 331, 332, 334, And at least two amino acid modifications including one amino acid modification.

In a further embodiment, the variant Fc region with increased Fc gamma RIIb-binding activity comprises (a) one amino acid change at position 236, and (b) 231, 232, 235, 239, 268 , 295, 298, 326, 330, and 396. In another embodiment, the at least one amino acid modification comprises at least one amino acid change in at least one position selected from the group consisting of:

In a further embodiment, the variant Fc region with increased Fc gamma RIIb-binding activity comprises (a) one amino acid change at position 236, and (b) 268, 295, 326, and 330 At least one amino acid change comprising at least one amino acid change in at least one position selected from the group consisting of SEQ ID NO:

In some embodiments, the variant Fc region of the present invention having enhanced Fc gamma RIIb-binding activity is selected from the group consisting of (a) Asp, Glu, Phe, Gly, His, Ile, Lys, Leu, Met, Asn, Pro, Gln, Arg, Ser, Thr, Val, Trp, Tyr; (b) Ala, Asp, Glu, Phe, Gly, His, Ile, Lys, Leu, Met, Asn, Gln, Arg, Ser, Thr, Val, Trp, Tyr at position 232; (c) Asp at position 233; (d) Trp, Tyr at position 234; (e) Trp at position 235; (f) Ala, Asp, Glu, His, Ile, Leu, Met, Asn, Gln, Ser, Thr, Val at position 236; (g) Asp at position 237, Tyr; (h) Glu, Ile, Met, Gln, Tyr at position 238; (i) Ile, Leu, Asn, Pro, Val at position 239; (j) Ile at position 264; (k) Phe at position 266; (l) Ala, His, Leu at position 267; (m) Asp at position 268, Glu; (n) Asp, Glu, Gly at position 271; (o) Leu at position 295; (p) Leu at position 298; (q) Glu, Phe, Ile, Leu at position 325; (r) Thr at position 326; (s) Ile, Asn at position 327; (t) Thr at position 328; (u) Lys, Arg at position 330; (v) Glu at position 331; (w) Asp at position 332; (x) Asp, Ile, Met, Val, Tyr at position 334; And (y) at least one selected from the group consisting of Ala, Asp, Glu, Phe, Gly, His, Ile, Lys, Leu, Met, Asn, Gln, Arg, Ser, Thr, Val, Trp and Tyr at position 396 ≪ / RTI >

In a further embodiment, the variant Fc region having the increased Fc gamma RIIb-binding activity is selected from the group consisting of (a) Gly, Thr at position 231; (b) Asp at position 232; (c) Trp at position 235; (d) Asn, Thr at position 236; (e) Val at position 239; (f) Asp at position 268, Glu; (g) Leu at position 295; (h) Leu at position 298; (i) Thr at position 326; (j) at least one amino acid selected from the group consisting of Lys, Arg at position 330, and Lys and Met at position 396 (k).

In another embodiment, the invention provides polypeptides comprising an isoelectric point (pI) -increated variant Fc region and methods of use thereof. In some embodiments, a polypeptide comprising a variant Fc region having increased pi has at least two amino acid changes in the parent Fc region. In a further embodiment, the amino acid alterations increase the isoelectric point (pI) of the mutant Fc region, respectively, as compared to the case of the parent Fc region. In a further embodiment, the amino acid can be exposed on the surface of the variant Fc region. In a further embodiment, the polypeptide comprises said variant Fc region and an antigen-binding domain. In a further embodiment, the antigen-binding activity of the antigen-binding domain varies with ion concentration conditions. In a further embodiment, variant Fc regions with increased pI of the present invention are selected from the group consisting of 285, 311, 312, 315, 318, 333, 335, 337, 341, 342, 343, 384, 385, 388, 390, 399, 400, 401, 402, 413, 420, 422, and 431. In a further embodiment, the variant Fc region having the increased pI comprises Arg or Lys at each of the selected positions.

In some embodiments, variant Fc regions of the invention comprise the amino acid alterations set forth in Tables 14-30.

In some embodiments, the polypeptide comprises a variant Fc region of the invention. In a further embodiment, the parent Fc region is derived from human IgG1. In a further embodiment, the polypeptide is an antibody. In a further embodiment, the polypeptide is an Fc fusion protein.

The present invention provides a polypeptide comprising the amino acid sequence of any one of SEQ ID NOS: 229-381.

The present invention also provides an isolated nucleic acid encoding a polypeptide comprising a variant Fc region of the invention. The present invention also provides a host cell comprising the nucleic acid of the present invention. The present invention also provides a method for producing a polypeptide comprising a variant Fc region comprising culturing a host cell of the invention to produce a polypeptide.

The present invention also provides a pharmaceutical formulation comprising a polypeptide comprising a variant Fc region of the invention and a pharmaceutically acceptable carrier.

Figure 1 illustrates the inhibition of proteolytic activation of latent myostatin by an anti-latent myostatin antibody, as described in Example 3. The activity of active myostatin released from latent myostatin by BMP1 protease was measured in the presence of anti-latent myostatin antibody using HEK blue analysis.
Figure 2 illustrates the inhibition of spontaneous activation of latent myostatin by an anti-latent myostatin antibody, as described in Example 4. The activity of the active myostatin released from latent myostatin by 37 ° C incubation was measured in the presence of anti-latent myostatin antibody using HEK blue assay.
Figure 3 illustrates the binding of anti-latent myostatin antibodies to the propeptide domain, as described in Example 5.
Figure 4 illustrates Western blot analysis for myostatin propeptide, as described in Example 6. Proteolytic cleavage of myostatin propeptide by BMP1 was evaluated in the presence and absence of anti-latent myostatin antibody.
Figures 5A-5C are graphs showing the effect of anti-latent (anti-human) antibodies against human latent myostatin (A), cynomolgus monkey latent myostatin (B) and mouse latent myostatin 0.0 > BIACORE (R) < / RTI > sensorgram of the myostatin antibody MST1032-G1m.
Figure 6a illustrates the in vivo efficacy of anti-latent myostatin antibodies and anti-mature myostatin antibodies against muscle mass and fat mass, as described in Example 8. SCID mice were administered an anti-latent myostatin antibody (MST1032-G1m; described as MST1032 in the figure) or an anti-mature myostatin antibody (41C1E4) Were measured.
Figure 6b illustrates the in vivo efficacy of anti-latent myostatin antibodies and anti-mature myostatin antibodies to muscle mass and fat mass, as described in Example 8. SCID mice were dosed with anti-latent myostatin antibody (MST1032-G1m, described as MST1032 in the figure) or anti-mature myostatin antibody (41C1E4) and the total body fat mass from day 0 to day 14 Were measured.
Figure 6C illustrates the in vivo efficacy of anti-latent myostatin antibodies and anti-mature myostatin antibodies against muscle mass and fat mass, as described in Example 8. SCID mice were administered an anti-latent myostatin antibody (MST1032-G1m, described as MST1032 in the figure) or an anti-mature myostatin antibody (41C1E4), and the gastrocnemius and quadriceps mass were measured.
Figure 7a illustrates a comparison of in vivo efficacy between a plurality of anti-myostatin antibodies, as described in Example 9. SCID mice were administered an anti-latent myostatin antibody (MST1032-G1m, described as MST1032 in the figure) or an anti-mature myostatin antibody (41C1E4, REGN, OGD, or MYO-029) Body weight was measured.
Figure 7b illustrates a comparison of in vivo efficacy between a number of anti-myostatin antibodies, as described in Example 9. SCID mice were administered an anti-latent myostatin antibody (MST1032-G1m, described as MST1032 in the figure) or an anti-mature myostatin antibody (41C1E4, REGN, OGD, or MYO-029) Respectively.
Figure 7C illustrates a comparison of in vivo efficacy between a number of anti-myostatin antibodies, as described in Example 9. SCID mice were administered an anti-latent myostatin antibody (MST1032-G1m, described as MST1032 in the figure) or an anti-mature myostatin antibody (41C1E4, REGN, OGD, or MYO-029) The change in total body fat mass was measured from day 14 to day 14.
Figure 8 illustrates inhibition of proteolytic and spontaneous activation of latent myostatin by humanized anti-latent myostatin antibody, as described in Example 10. [ The activity of the active myostatin released from latent myostatin by BMP1 protease (proteolytic) or without BMP1 (spontaneous) by incubation at 37 [deg.] C was measured using HEK blue assay using an anti-latent myostatin antibody Lt; / RTI >
Figure 9 illustrates a Biacore (TM) sensorgram of histidine substituted variants of an anti-latent myostatin antibody, as described in Example 11. The antibody / antigen complex was dissociated at pH 7.4 and then further dissociated at pH 5.8 (indicated by arrows) to evaluate the pH-dependent interaction. The antibodies tested in this experiment were Ab001 (black solid line curve), Ab002 (black short dashed curve), Ab003 (black dotted curve), Ab004 (gray short dashed curve), Ab005 - dashed curve), and Ab007 (black long-dashed curve).
Figure 10 illustrates the inhibition of proteolytic and spontaneous activation of latent myostatin by pH-dependent anti-latent myostatin antibodies, as described in Example 13. The activity of the active myostatin released from latent myostatin by BMP1 protease (proteolytic) or without BMP1 (spontaneous) by incubation at 37 [deg.] C was measured using HEK blue assay using an anti-latent myostatin antibody Lt; / RTI > The antibodies MS1032LO01-SG1, MS1032LO02-SG1, MS1032LO03-SG1, and MS1032LO04-SG1 are listed in the figure as MSLO-01, MSLO-02, MSLO-03, and MSLO-04, respectively. Inhibition of protein degradation and spontaneous activation of latent myostatin comparable to MS1032LO00-SG1 was achieved by MS1032LO01-SG1, MS1032LO02-SG1, MS1032LO03-SG1, and MS1032LO04-SG1.
Figures 11A-11F illustrate Biacore (TM) sensorgrams of pH-dependent anti-latent myostatin antibodies, as described in Example 14. The kinetic parameters of MST1032-SG1 (A), MS1032LO00-SG1 (B), MS1032LO01-SG1 (C), MS1032LO02-SG1 (D), MS1032LO03-SG1 (E), and MS1032LO04- And acidic pH.
Figure 12 illustrates the time course of plasma myostatin concentration after intravenous administration of anti-myostatin antibody in mice, as described in Example 15. The effect of Fc gamma R-mediated cell uptake of the antibody / antigen complex on in vivo myostatin clearance was evaluated by measuring the effect of anti-myostatin antibody (MS1032LO00-SG1) with Fc gamma R binding and Fc gamma R binding Anti-myostatin antibody (MS1032LO00-F760).
Figure 13 illustrates the time course of plasma myostatin concentration following intravenous administration of anti-myostatin antibody in mice, as described in Example 16. The effect of pH-dependent binding of anti-myostatin antibody on in vivo myostatin clearance was assessed using a pH-dependent anti-myostatin antibody (MS1032LO01-SG1 or MS1032LO01-F760) and a non-pH- Statin antibody (MS1032LO00-SG1 or MS1032LO00-F760).
Figures 14A-14E illustrate the in vivo efficacy of pH-dependent and non-pH-dependent anti-latent myostatin antibodies, as described in Example 17. dependent anti-latent myostatin antibody (MS1032LO00-SG1; depicted as MSLO0 in the figure) in the presence of a pH-dependent anti-latent myostatin antibody (MS1032LO01-SG1; (A), total body mass (B), quadriceps mass (C), gastrocnemius mass (D), and grip strength (E) were measured.
Figure 15 illustrates the binding activity of the anti-latent myostatin antibody MST1032 to latent myostatin and GDF11, as described in Example 19.
Figure 16 illustrates the inhibitory activity of the anti-latent myostatin antibody MST1032 on proteolytic and spontaneous activation of GDF11, as described in Example 20. The activity of active GDF11 released by BMP1 protease (proteolytic) or 37 [deg.] C incubation (spontaneous) without BMP1 was measured in the presence of anti-latent myostatin antibody using HEK blue assay.
Figure 17 illustrates the inhibition of proteolytic activation of latent myostatin by an anti-latent myostatin antibody, as described in Example 22. The activity of active myostatin released from latent myostatin by BMP1 protease was measured in the presence of anti-latent myostatin antibody using HEK blue assay.
FIG. 18 illustrates the time course of plasma myostatin concentration after intravenous administration of anti-latent myostatin antibody in mice, as described in Example 23. FIG. The effect of pH dependence on in vivo myostatin clearance was compared to that of non-pH dependent anti-latent myostatin antibody (MS1032LO00-SG1) and different pH-dependent anti-latent myostatin antibodies (MS1032LO01-SG1, MS1032LO06 -SG1, MS1032LO11-SG1, MS1032LO18-SG1, MS1032LO19-SG1, MS1032LO21-SG1 and MS1032LO25-SG1).
Figures 19A and 19B illustrate the time course of plasma myostatin concentration after intravenous administration of anti-latent myostatin antibody in cynomolgus monkeys, as described in Example 24. (A) The effect of pH dependence and Fc engineering on in vivo myostatin clearance was evaluated using a non-pH-dependent anti-latent myostatin antibody (MS1032LO00-SG1) and a pH-dependent anti- Were compared by comparing statistin antibodies (MS1032LO06-SG1012, MS1032LO06-SG1016, MS1032LO06-SG1029, MS1032LO06-SG1031, MS1032LO06-SG1033, MS1032LO06-SG1034). (B) The effect of Fc engineering on in vivo myostatin clearance was compared to that of anti-latent myostatin antibodies (MS1032LO19-SG1079, MS1032LO19-SG1071, MS1032LO19-SG1080, MS1032LO19- SG1074, MS1032LO19- SG1081, and MS1032LO19- SG1077).
Figure 20A illustrates the in vivo efficacy of an anti-latent myostatin antibody (MS1032 variant) on lipid body weight (LBM), grip strength and body fat mass, as described in Example 25, with Figures 20b to 20i . MS1032LO06-SG1, MS1032LO11-SG1, and MS1032LO18-SG1 were administered to Scid mice and the fat-free body weight (FIG. 20a) was measured.
Figure 20b shows the in vivo efficacy of an anti-latent myostatin antibody (MS1032 variant) on lipid body weight (LBM), grip strength and body fat mass as described in Example 25, with Figures 20a, 20c- For example. MS1032LO06-SG1, MS1032LO19-SG1, and MS1032LO25-SG1 were administered to Scid mice and the fat-free body weight (FIG. 20b) was measured.
Figure 20C is a graph showing the effect of an anti-latent myostatin antibody (MS1032 variant) on in vivo body fat (LBM), grip strength and body fat mass as described in Example 25 with Figures 20a and 20b, 20d- Illustrate efficacy. MS1032LO01-SG, MS1032LO06-SG1, and MS1032LO11-SG1 were administered to Scid mice and the fat-free body weight (FIG. 20c) was measured.
Figure 20d is a graphical representation of the effect of an anti-latent myostatin antibody (MS1032 variant) on in vivo body fat (LBM), grip strength and body fat mass, as described in Example 25 with Figures 20a to 20c, 20e to 20i Illustrate efficacy. MS1032LO06-SG1, MS1032LO11-SG1 and MS1032LO18-SG1 were administered to Scid mice and the grip strength (Figure 20d) was measured.
20E is a graph showing the effect of an anti-latent myostatin antibody (MS1032 variant) on in vivo body fat (LBM), grip strength and body fat mass, as described in Example 25, with Figs. 20a to 20d, 20f to 20i Illustrate efficacy. MS1032LO06-SG1, MS1032LO19-SG1, and MS1032LO25-SG1 were administered to Scid mice and the grip strength (Figure 20e) was measured.
Figure 20f shows the effect of an anti-latent myostatin antibody (MS1032 variant) on in vivo body fat (LBM), grip strength and body fat mass as described in Example 25, with Figures 20a to 20e, 20g to 20i Illustrate efficacy. MS1032LO01-SG, MS1032LO06-SG1, and MS1032LO11-SG1 were administered to Scid mice and the grip strength (Figure 20f) was measured.
Figure 20g shows the effect of an anti-latent myostatin antibody (MS1032 variant) on in vivo body fat (LBM), grip strength and body fat mass, as described in Example 25, with Figures 20a to 20f, 20h and 20i Illustrate efficacy. MS1032LO06-SG1, MS1032LO11-SG1, and MS1032LO18-SG1 were administered to Scid mice and body fat mass (Figure 20g) was measured.
Figure 20h shows the in vivo efficacy of an anti-latent myostatin antibody (MS1032 variant) on lipid body weight (LBM), grip strength and body fat mass as described in Example 25, with Figures 20a to 20g, For example. MS1032LO06-SG1, MS1032LO19-SG1, and MS1032LO25-SG1 were administered to Scid mice and body mass (FIG. 20h) was measured.
Figure 20i illustrates the in vivo efficacy of an anti-latent myostatin antibody (MS1032 variant) on lean body mass (LBM), grip strength and body fat mass, as described in Example 25, with Figures 20a to 20h . MS1032LO01-SG1, MS1032LO06-SG, and MS1032LO11-SG1 were administered to Scid mice and body fat mass (Fig. 20i) was measured.
Figure 21 illustrates the inhibitory activity against latent myostatin activation by an anti-latent myostatin antibody, as described in Example 26. The amount of mature myostatin released from latent myostatin by BMP1 protease was measured in the presence of anti-latent myostatin antibodies (MST1032, MST1504, MST1538, MST1551, MST1558, MST1572, and MST1573).
Figure 22A illustrates a construct of a latent myostatin fragment of 100 amino acids each designed for the epitope mapping of anti-latent myostatin antibodies, as described in Example 26.
Figure 22B illustrates a Western Blotting assay for a GST-tagged human latent myostatin fragment (GST-hMSTN) by an anti-GST antibody, as described in Example 26. Each lane indicates: 1, GST-hMSTN 1-100 aa; 2, GST-hMSTN 21-120aa; 3, GST-hMSTN 41-140aa; 4, GST-hMSTN 61-160aa; 5, GST-hMSTN 81-180aa; 6, GST-hMSTN 101-200aa; 7, GST-hMSTN 121-220aa; 8, GST-hMSTN 141-241aa; 9, GST control group.
Figure 22C is a graph showing the effect of a Western blot on the GST tagged human latent myostatin fragment (GST-hMSTN) by anti-latent myostatin antibodies (MST1032, MST1538, MST1572, and MST1573) The lining analysis is illustrated. Each lane indicates: 1, GST-hMSTN 1-100 aa; 2, GST-hMSTN 21-120aa; 3, GST-hMSTN 41-140aa; 4, GST-hMSTN 61-160aa; 5, GST-hMSTN 81-180aa; 6, GST-hMSTN 101-200aa; 7, GST-hMSTN 121-220aa; 8, GST-hMSTN 141-241aa; 9, GST control group; 10, human latent myostatin (100 ng).
Figure 22d illustrates the summarized results and the deduced epitope location of the Western Blotting assay for anti-latent myostatin antibodies (MST1032, MST1538, MST1572, and MST1573) as described in Example 26. [
Figure 23 illustrates the alignment of amino acid sequences of Cynomolgus (Cyno) Fc gamma RIIa1, Fc gamma RIIa2, Fc gamma RIIa3, Fc gamma RIIb, human Fc gamma RIIaH, Fc gamma RIIaR, and Fc gamma RIIb. The rectangular regions refer to the putative residues interacting with the Fc domain.
24 shows the time course of total myostatin concentration in plasma after intravenous administration of anti-myostatin antibody with Fc gamma RIIb-enhanced Fc variants in all human Fc gamma R transgenic mice, as described in Example 28 The process is illustrated. The effect of Fc gamma RIIb-enhanced Fc variants on antigen removal via human Fc gamma RIIb was evaluated.
Figure 25 illustrates the time course of antibody concentration following intravenous administration of an anti-myostatin antibody with Fc gamma RIIb-enhanced Fc variants in all human Fc gamma R transgenic mice, as described in Example 28. The effect of Fc gamma RIIb-enhanced Fc variants on antibody pharmacokinetics was evaluated.
26A and 26B illustrate the time course of plasma myostatin concentration after intravenous administration of an anti-latent myostatin antibody in a sinomorphous monkey, as described in Example 29. [ (A) The effect of pH dependence and Fc engineering on in vivo myostatin clearance was assessed using a non-pH dependent anti-latent antibody (MS1032LO00-SG1) and a pH-dependent anti-latent myostatin (MS1032LO06-SG1012, MS1032LO06-SG1016, MS1032LO06-SG1029, MS1032LO06-SG1031, MS1032LO06-SG1033, MS1032LO06-SG1034). (B) The effect of Fc engineering on in vivo myostatin clearance was compared to that of anti-latent myostatin antibodies (MS1032LO19-SG1079, MS1032LO19-SG1071, MS1032LO19-SG1080, MS1032LO19- SG1074, MS1032LO19- SG1081, and MS1032LO19- SG1077).
Figure 27A illustrates the time course of total myostatin concentration in plasma after intravenous administration of an anti-myostatin antibody with pI-increased Fc variants in human FcRn transgenic mice, as described in Example 30. The effect of pi-elevated Fc variants on antigen removal was evaluated.
Figure 27B illustrates the time course of antibody concentration in plasma after intravenous administration of an anti-myostatin antibody with pI-increased Fc variants in human FcRn transgenic mice, as described in Example 30. The effect of pi-enhanced Fc variants on antibody pharmacokinetics was evaluated.
Figure 28A illustrates the time course of total myostatin concentration in plasma after intravenous administration of anti-myostatin antibody with pi-enhanced Fc variants in human FcRn transgenic mice, as described in Example 30. The effect of pi-elevated Fc variants on antigen removal was evaluated. In this assay, excess human normal immunoglobulin was co-administered with the anti-myostatin antibody to mimic the situation of human plasma.
Figure 28B illustrates the time course of antibody concentration in plasma after intravenous administration of anti-myostatin antibody with pi-enhanced Fc variants in human FcRn transgenic mice, as described in Example 30. The effect of pi-enhanced Fc variants on antibody pharmacokinetics was evaluated. In this assay, excess human normal immunoglobulin was co-administered with the anti-myostatin antibody to mimic the situation of human plasma.
29 shows the time course of total myostatin concentration in plasma after intravenous administration of anti-myostatin antibody with Fc gamma RIIb-enhanced Fc variants in human Fc gamma RIIb transgenic mice, as described in Example 31 . The effect of Fc gamma RIIb-enhanced Fc variants on antigen removal via human Fc gamma RIIb was evaluated.
Figure 30 illustrates the time course of antibody concentration in plasma after intravenous administration of anti-myostatin antibody with Fc gamma RIIb-enhanced Fc variants in human Fc gamma RIIb transgenic mice, as described in Example 31 . The effect of Fc gamma RIIb-enhanced Fc variants on antibody pharmacokinetics was evaluated.
Figure 31 illustrates the results of cell imaging analysis of anti-myostatin antibodies with Fc gamma RIIb-enhanced Fc variants, as described in Example 33. Each antibody complexed with fluorescence-labeled myostatin and the intracellular uptake of the antigen-antibody complex into cells expressing human Fc gamma RIIb was measured.

The techniques and procedures described or referenced herein are generally well understood by those skilled in the art and are routinely used using conventional methods, for example, the widely used methods described in the following references: Sambrook et al., Molecular Cloning: A Laboratory Manual (2001) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; Current Protocols in Molecular Biology (F. M. Ausubel, et al., Eds., (2003)); PCR: A Practical Approach (M.J. MacPherson, B. D. Hames and G. R. Taylor eds. (1995)), Harlow and Lane, eds. (1988) Antibodies, A Laboratory Manual, and Animal Cell Culture (R. I. Freshney, eds. (1987)); Oligonucleotide Synthesis (M. J. Gait, ed., 1984); Methods in Molecular Biology, Humana Press; Cell Biology: A Laboratory Notebook (J. E. Cellis, ed., 1998) Academic Press; Animal Cell Culture (R. I. Freshney), ed., 1987); Introduction to Cell and Tissue Culture (J. P. Mather and P.E. Roberts, 1998) Plenum Press; Cell and Tissue Culture: Laboratory Procedures (A. Doyle, J. B. Griffiths, and D. G. Newell, eds., 1993-8) J. Wiley and Sons; Handbook of Experimental Immunology (D.M. Weir and C.C. Blackwell, eds.); Gene Transfer Vectors for Mammalian Cells (J.M. Miller and M. P. Calos, eds., 1987); PCR: The Polymerase Chain Reaction, (Mullis et al., Eds., 1994); Current Protocols in Immunology (J. E. Coligan et al., Eds., 1991); Short Protocols in Molecular Biology (Wiley and Sons, 1999); Immunobiology (C.A. Janeway and P. Travers, 1997); Antibodies (P. Finch, 1997); Antibodies: A Practical Approach (D. Catty., Ed., IRL Press, 1988-1989); Monoclonal Antibodies: A Practical Approach (P. Shepherd and C. Dean, eds., Oxford University Press, 2000); Using Antibodies: A Laboratory Manual (E. Harlow and D. Lane, Cold Spring Harbor Laboratory Press, 1999); The Antibodies (M. Zanetti and J. D. Capra, eds., Harwood Academic Publishers, 1995); And Cancer: Principles and Practice of Oncology (V.T. DeVita et al., Eds., J. B. Lippincott Company, 1993).

I. Definition

Unless otherwise defined, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. , John Wiley & John Wiley & Sons (New York, NY 1994), and Singleton et al., Dictionary of Microbiology and Molecular Biology 2nd ed. &Amp; Sons (New York, NY 1992) provide general guidance to many of the terms used in the present application to those skilled in the art. All references cited herein, including patent applications and publications, are incorporated by reference in their entirety.

To interpret this specification, the following definitions shall apply and whenever appropriate, terms used in the singular will also include the plural and vice versa. The terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting. In the event that any of the definitions presented below conflict with any document cited herein by reference, the definitions given below shall govern.

"Receptor human framework" for purposes of the present invention includes a light chain variable domain (VL) framework or a heavy chain variable domain (VH) framework derived from a human immunoglobulin framework or human common framework, ≪ / RTI > A "receptor " human framework derived from a human immunoglobulin framework or human common framework may contain the same amino acid sequence or may contain amino acid sequence changes. In some embodiments, the number of amino acid changes is 10 or less, 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, 4 or less, 3 or less or 2 or less. In some embodiments, the VL receptor human framework is consistent with a VL human immunoglobulin framework sequence or a human common framework sequence.

"Affinity" refers to the strength of the total sum of non-covalent interactions between a molecule (e.g., an antibody) and a single binding site of its binding partner (e.g., an antigen). Unless otherwise indicated, as used herein, "binding affinity" refers to the unique binding affinity that reflects a 1: 1 interaction between members of a binding pair (eg, an antibody and an antigen). The affinity of the molecule X for its relative Y can generally be expressed by the dissociation constant (Kd). The affinity may be measured by conventional methods known in the art, such as those described herein. Specific and exemplary embodiments for measuring binding affinity are described below.

An "affinity matured" antibody refers to an antibody that has altered one or more modifications in one or more hypervariable regions (HVRs), such as ameliorating the affinity of the antibody to an antigen, do.

The terms "anti-myostatin antibody" and "antibody binding to myostatin" are intended to mean that the antibody binds to myostatin in an affinity sufficient to be useful as a diagnostic agent and / ≪ / RTI > In one embodiment, the degree of binding of an anti-myostatin antibody to an unrelated, non-myostatin protein is determined by, for example, determining the binding of the antibody to myostatin as measured by radioimmunoassay (RIA) ≪ / RTI > In certain embodiments, antibodies that bind to my Oh statin is 1 μM or less, 100 nM or less, 10 nM or less, 1 nM or less, 0.1 nM or less, 0.01 nM or less, or 0.001 nM or less (e.g., 10 ^-8 M or less , For example, 10 ^-8 M to 10 ^-13 M, for example 10 ^-9 M to 10 ^-13 M) dissociation constants (Kd). In some embodiments, the anti-myostatin antibody binds to an epitope of myostatin that is conserved between myostatins from different species.

As used herein, the term " antibody "is used in its broadest sense and includes various antibody constructs such as, but not limited to, monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e. G. Bispecific antibodies) Binding fragment thereof.

"Antibody fragments" refers to molecules other than whole antibodies that comprise a portion of the complete antibody that binds to the antigen to which the whole antibody binds. Examples of antibody fragments include, but are not limited to, Fv, Fab, Fab ', Fab'-SH, F (ab') ₂ ; Diabody; Linear antibodies; Single chain antibody molecules (e. G. ScFv); And multispecific antibodies formed from antibody fragments.

As an " antibody that binds to the same epitope "as a reference antibody refers to an antibody that blocks binding of the reference antibody to an antigen in a competition analysis and / or, conversely, a reference antibody that blocks binding of the antibody to an antigen in a competition assay do. An exemplary competition analysis is provided herein.

The term "chimeric" antibody refers to an antibody derived from a different source or species wherein the remainder of the heavy chain and / or light chain is derived from a different source or species, while a portion of the heavy and / or light chain is derived from a particular source or species.

"Class" of an antibody refers to a type of constant domain or constant region possessed by its heavy chain. Of the antibody to five major classes, namely, and the IgA, IgD, IgE, IgG and IgM is present, a number of which are subclasses (isotypes), e.g., _{IgG 1, IgG 2, IgG 3} , IgG 4, IgA 1 , and IgA < / RTI > ₂ . The heavy chain constant domains corresponding to these different classes of immunoglobulins are referred to as alpha, delta, epsilon, gamma and mu, respectively.

The term "cytotoxic agent" as used herein refers to a substance that inhibits or prevents cellular function and / or causes cell death or cell destruction. Cytotoxic agents include, but are not limited to, radioactive isotopes (such as At ²¹¹ , I ¹³¹ , I ¹²⁵ , Y ⁹⁰ , Re ¹⁸⁶ , Re ¹⁸⁸ , Sm ¹⁵³ , Bi ²¹² , P ³² , Pb ²¹² , ; A chemotherapeutic agent or a drug (e.g., methotrexate, adriamycin, vinca alkaloid (vincristine, vinblastine, etoposide), doxorubicin, melphalan, mitomycin C, chlorambucil, daunorubicin, ; Growth inhibitors; Enzymes and fragments thereof, such as nucleic acid degrading enzymes; Antibiotic; Toxins, including fragments and / or variants thereof, such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin; And various antitumor or anticancer agents described below.

"Effector function" refers to biological activities that can result from the Fc region of the antibody (which varies with the antibody isotype). Examples of antibody effector functions include C1q binding and complement dependent cytotoxicity (CDC); Fc receptor binding; Antibody-dependent cell-mediated cytotoxicity (ADCC); Food; Down regulation of cell surface receptors (e. G., B cell receptors); And B cell activation.

An "effective amount" of an agonist, e. G., A pharmaceutical formulation, refers to an amount effective to achieve the desired therapeutic or prophylactic result for the required dosage and time.

The term "epitope" includes any determinant that can be bound by an antibody. An epitope is a region of the antigen that is bound by an antibody that targets the antigen, and includes specific amino acids that are in direct contact with the antibody. Epitopic determinants can include chemically active surface groups of molecules such as amino acids, sugar chains, phosphoryl or sulfonyl groups, and can have specific three dimensional structural features and / or specific charge characteristics. In general, antibodies specific for a particular target antigen will preferentially recognize an epitope on the target antigen in a complex mixture of proteins and / or macromolecules.

"Fc receptor" or "FcR" describes a receptor that binds to the Fc region of an antibody. In some embodiments, the FcR is a native human FcR. In some embodiments, FcR comprises binding to an IgG antibody (gamma receptor) and includes receptors for Fc gamma RI, Fc gamma RII, and Fc gamma RIII subclasses, including allelic variants and, optionally, do. The Fc gamma RII receptor includes Fc gamma RIIA ("activation receptor") and Fc gamma RIIB ("inhibitory receptor") having similar amino acid sequences that differ primarily in the cytoplasmic domain. Activated receptor Fc gamma RIIA contains an immunoreceptor tyrosine-based activation motif (ITAM) in its cytoplasmic domain. Inhibitory receptor Fc gamma RIIB contains an immunoreceptor tyrosine-based inhibitory motive (ITIM) in its cytoplasmic domain (see, for example, Daeron, Annu. Rev. Immunol. 15: 203-234 ). FcR is described, for example, in Ravetch and Kinet, Annu. Rev. Immunol. 9: 457-92 (1991); Capel et al., Immunomethods 4: 25-34 (1994); And de Haas et al., J. Lab. Clin. Med. 126: 330-41 (1995). Other FcRs, including those identified later, are included in the term "FcR" herein.

The term "Fc receptor" or "FcR" also refers to the transfer of maternal IgG to the fetus (Guyer et al., J. Immunol. 117: 587 (1976)) and Kim et al., J. Immunol. 24: 249 (1994)) and a neonatal receptor, FcRn, which is responsible for the regulation of immunoglobulin homeostasis. Methods of measuring binding to FcRn are known (see, for example, Ghetie and Ward., Immunol. Today 18 (12): 592-598 (1997); Ghetie et al., Nature Biotechnology 15 See Hinton et al., J. Biol. Chem. 279 (8): 6213-6216 (2004); WO 2004/92219 (Hinton et al. ). The binding of the human FcRn in vivo and the serum half-life of the human FcRn high affinity binding polypeptide can be determined, for example, by using transgenic mice or transfected human cell lines expressing human FcRn, or primate administered with such polypeptides with variant Fc regions . ≪ / RTI > WO 2000/42072 (Presta) discloses antibody variants with improved or decreased binding to FcR. See also, for example, Shields et al., J. Biol. Chem. 9 (2): 6591-6604 (2001).

The term "Fc region" is used herein to define the C-terminal region of an immunoglobulin heavy chain that contains at least a portion of a constant region. The term includes a unique sequence Fc region and a variant Fc region. In one embodiment, the human IgG heavy chain Fc region extends from Cys226, or from Pro 230 to the carboxyl-terminus of the heavy chain. However, the C-terminal lysine (Lys447) or glycine-lysine (residues 446-447) of the Fc region may or may not be present. Unless otherwise specified herein, the numbering of amino acid residues in the Fc region or constant region is described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. The EU numbering system (also referred to as the EU index) as disclosed in the Public Health Service, National Institutes of Health, Bethesda, MD, 1991.

The term "Fc region-containing antibody" refers to an antibody comprising an Fc region. Terminus lysine (residue 447 according to the EU numbering system) or C-terminal glycine-lysine (residue 446-447) of the Fc region can be used, for example, in the purification of the antibody or in recombinant engineering of the nucleic acid encoding the antibody . Correspondingly, a composition comprising an antibody having an Fc region according to the present invention may comprise an antibody having G446-K447, no G446 and no K447, and all G446-K447 removed, or a mixture of the three types of antibodies . ≪ / RTI >

"Framework" or "FR" refers to a variable domain residue other than a hypervariable region (HVR) residue. FRs of a variable domain generally consist of four FR domains, FR1, FR2, FR3 and FR4. Correspondingly, the HVR and FR sequences are generally present in the VH (or VL) sequence as follows: FR1-H1 (L1) -FR2-H2 (L2) -FR3-H3 (L3) -FR4.

The terms "full-length antibody "," complete antibody "and" whole antibody "refer herein to an antibody having a structure substantially similar to a native antibody structure or having a heavy chain containing an Fc region as defined herein .

"Functional Fc region" has "effector function" of the unique sequence Fc region. Exemplary "effector functions" include Clq binding; CDC; Fc receptor binding; ADCC; Food; Down regulation of cell surface receptors (e. G., B cell receptors; BCR), and the like. Such effector functions generally require an Fc region that binds to a binding domain (e. G., An antibody variable domain) and may be assessed using a variety of assays, for example as disclosed in the definition herein.

The terms "host cell," "host cell line," and "host cell culture" are used interchangeably and refer to a cell into which an exogenous nucleic acid has been introduced, including progeny of such cells. Host cells include "transformants" and "transformed cells" and include descendants derived therefrom, regardless of the number of primary transformed cells and passages. The offspring may contain mutations, although the mother cells and the nucleic acid content may not be perfectly consistent. Included are mutant progeny that have the same function or biological activity as selected or selected in the initially transformed cells.

A "human antibody" is one having an amino acid sequence corresponding to the amino acid sequence of an antibody derived from a non-human source produced by human or human cells or using a human antibody repertoire or other human antibody-encoding sequence. The definition of the human antibody specifically excludes humanized antibodies comprising non-human antigen-binding moieties.

"Human common framework" is a framework that represents the most commonly occurring amino acid residues in the selection of human immunoglobulin VL or VH framework sequences. Generally, the selection of human immunoglobulin VL or VH sequences is from a subgroup of variable domain sequences. Generally, subgroups of such sequences are described in Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, NIH Publication 91-3242, Bethesda MD (1991), vol. 1-3]. In one embodiment, the subgroup for VL is a subgroup kappa I such as in Kabat et al. In one embodiment, the subgroup for the VH is a subgroup III such as in Kabat et al.

A "humanized" antibody refers to a chimeric antibody comprising an amino acid residue from a non-human HVR and an amino acid residue from a human FR. In some embodiments, the humanized antibody will comprise substantially all of at least one and typically two variable domains, wherein all or substantially all of said HVRs (e. G., CDRs) And all or substantially all of the FRs correspond to those of a human antibody. The humanized antibody may optionally comprise at least a portion of the antibody constant region derived from the human antibody. An antibody, e. G., A "humanized form," of a non-human antibody refers to an antibody that has undergone humanization.

The term "hypervariable region" or "HVR ", as used herein, refers to a region where the sequence is a highly modified (" complementarity determining region "or" CDR ") and / or forms a structurally defined ring Refers to the respective regions of the antibody variable domain that contain and / or contain antigen-contacting residues ("antigen-contacting portions"). Generally, the antibody comprises six HVRs: three of VH (H1, H2, H43) and three of VL (L1, L2, L3). Exemplary HVRs herein include (a) amino acid residues 26-32 (L1), 50-52 (L2), 91-96 (L3), 26-32 (H1), 53-55 Highly modified rings (Chothia and Lesk, J. MoI. Biol. 196: 901-917 (1987)) present in 101 (H3)); (b) is present at amino acid residues 24-34 (L1), 50-56 (L2), 89-97 (L3), 31-35b (H1), 50-65 (H2), and 95-102 CDR (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, NIH, Bethesda, MD (1991)); (c) amino acid residues 27c-36 (L1), 46-55 (L2), 89-96 (L3), 30-35b (H1), 47-58 (H2), and 93-101 Antigen contacts (MacCallum et al., J. Mol. Biol. 262: 732-745 (1996)); And (d) a combination of (a), (b), and / or (c) such as HVR amino acid residues 46-56 (L2), 47-56 (L2), 48-56 56 (L2), 26-35 (H1), 26-35b (H1), 49-65 (H2), 93-102 (H3), and 94-102 (H3).

Unless otherwise indicated, the HVR residues and other residues (e.g. FR residues) in the variable domains are numbered according to Kabat et al. Herein.

An "immunoconjugate" is an antibody conjugated to one or more heterologous molecule (s), including but not limited to cytotoxic agents.

An "individual" or "subject" is a mammal. Mammals include, but are not limited to, domestic animals (e.g., cows, sheep, cats, dogs and horses), primates (e.g., human and non-human primates such as monkeys), rabbits and rodents ). In some embodiments, the subject or subject is a human.

An "isolated" antibody is isolated from a component of its natural environment. In some embodiments, the antibody is conjugated to an antibody as determined by, for example, electrophoresis (e.g., SDS-PAGE, isoelectric point electrophoresis (IEF), capillary electrophoresis) or chromatography Gt; 95% < / RTI > or 99% pure. For a review of methods for evaluating antibody purity, see, for example, Flatman et al., J. Chromatogr. B 848: 79-87 (2007).

An "isolated" nucleic acid refers to a nucleic acid molecule isolated from a component of its natural environment. Isolated nucleic acids include nucleic acid molecules contained in a cell that normally contains the nucleic acid molecule but the nucleic acid molecule is present at a chromosomal site other than the chromosome or at its natural chromosomal location.

Refers to one or more nucleic acid molecules (or fragments thereof) encoding an antibody heavy chain and a light chain, wherein the nucleic acid molecule (s) as described above in a single vector or in a separate vector, , Wherein such nucleic acid molecule (s) are present at one or more of the host cells.

The term "monoclonal antibody" as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., individual antibodies comprising the population, for example, contain a natural mutation or a monoclonal antibody preparation Of the same and / or the same epitope, except for the possible variant antibodies (such variants as described above generally present in minor amounts) that arise during the manufacture of the antibody. In contrast to polyclonal antibody preparations which typically comprise different antibodies to different determinants (epitopes), each monoclonal antibody of the monoclonal antibody preparation is directed to a single determinant on the antigen. Thus, the term "monoclonal" refers to the character of the antibody as being obtained from a substantially homogeneous population of antibodies and is not to be construed as requiring production of the antibody by any particular method. For example, monoclonal antibodies used in accordance with the present invention may be used in a variety of techniques, including but not limited to, hybridoma methods, recombinant DNA methods, phage-display methods, and transforms containing part or all of the human immunoglobulin locus , And other exemplary methods for producing such monoclonal antibodies and methods as described above are described herein.

"Naked antibody" refers to an antibody that is not conjugated to a heterologous moiety (e. G., A cytotoxic moiety) or a radioactive label. The naked antibody may be present in a pharmaceutical formulation.

"Natural antibody" refers to a natural immunoglobulin molecule having a variety of structures. For example, a native IgG antibody is a heterotetrameric glycoprotein of about 150,000 daltons consisting of two identical light chains and two identical heavy chains disulfide-linked. From the N-terminus to the C-terminus, each heavy chain has a variable domain (VH) (also referred to as a variable domain or heavy chain variable domain) followed by three constant domains (CH1, CH2 and CH3). Similarly, from N- to C-terminus, each light chain has a variable region (VL) (also referred to as a variable light or light chain variable domain) followed by an invariant light (CL) domain. The light chain of an antibody can be assigned to one of two types (called kappa (kappa) and lambda (lambda)), based on the amino acid sequence of its constant domain.

The "intrinsic sequence Fc region" includes the amino acid sequence corresponding to the amino acid sequence of the Fc region found in nature. The native sequence human Fc region comprises a native sequence human IgGl Fc region (non-A and A allotype); A native sequence human IgG2 Fc region; A native sequence human IgG3 Fc region; And native sequence human IgG4 Fc regions as well as native variants thereof.

The term "package insert" refers to a description that is typically included in a commercial package of a therapeutic product, and may include indications, usage, dosage, administration, combination therapy, contraindication, and / .

The "percent amino acid sequence match (%)" with respect to the reference polypeptide sequence means that after aligning the sequence and the introduced gap (if necessary) to achieve the maximum sequence match percent, any conservative substitution And is defined as the percentage of the amino acid residues in the candidate sequence corresponding to the amino acid residues in the reference polypeptide sequence. Alignment to measure percent amino acid sequence identity can be determined in a variety of ways within the skill of the art, e. G., Publicly available computer software such as BLAST, BLAST-2, ALIGN, Megalign (DNASTAR) Or GENETYX TM (Genetyx Co., Ltd.)). ≪ / RTI > Those of skill in the art can determine any parameters necessary to align the sequence, e.g., any operation necessary to achieve maximum alignment over the entire length of the sequences being compared. The ALIGN-2 sequence comparison computer program is copyrighted by Genentech, Inc., and the source code is registered with the US copyright office (Washington DC, USA 20559) under the user's document (registered under US Copyright Registration No. TXU510087) ). ≪ / RTI > The ALIGN-2 program is publicly available from Genentech Corporation of South San Francisco, CA or may be compiled from source code. The ALIGN-2 program must be compiled for use on a Unix execution system including Digital UNIX (UNIX) V4.0D. All sequence comparison parameters are specified by the ALIGN-2 program and do not change.

In a situation where ALIGN-2 is used for amino acid sequence comparison, the given amino acid sequence B of a given amino acid sequence A is substituted for the amino acid sequence conformity% (which, on the other hand, to the given amino acid sequence B , Said sequence B, or a given amino acid sequence A that has or comprises a constant amino acid sequence identity to said sequence B) is calculated as follows: 100 x fraction X / Y; Wherein X is the number of amino acid residues recorded as matching congruence by the program in the alignment of the sequence alignment program ALIGN-2 of A and B and Y is the total number of amino acid residues in B. If the length of the amino acid sequence A is not equal to the length of the amino acid sequence B, it will be understood that the% amino acid sequence match of A with respect to B is not equal to the% amino acid sequence match% of B with respect to A. Unless specifically stated otherwise, all amino acid sequence% values used herein are obtained as described in the immediately preceding paragraph using the ALIGN-2 computer program.

The term "pharmaceutical formulation" refers to an agent present in a form such that the biological activity of the active ingredient contained in the formulation is effective and does not contain additional ingredients that are not unacceptably toxic to the subject to whom the formulation is administered do.

"Pharmaceutically acceptable carrier" refers to a component in a pharmaceutical formulation that, in addition to the active ingredient, is non-toxic to the subject. Pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers or preservatives.

The term " myostatin ", as used herein, refers to any natural source of mRNA from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats) Statins. ≪ / RTI > Unless otherwise indicated, the term " myostatin "refers to a human myostatin protein having the amino acid sequence shown in SEQ ID NO: 1 and containing the terminal propeptide domain of human myostatin as shown in SEQ ID NO: 75 or 78 do. The term includes "full-length " unmodified myostatin, as well as any form of myostatin produced by processing in cells. The term also encompasses naturally occurring variants of myostatin, such as, for example, fused or allelic variants. The amino acid sequence of an exemplary human myostatin (promyostatin) is shown in SEQ ID NO: 1. The amino acid sequence of an exemplary C-terminal growth factor domain of human myostatin is shown in SEQ ID NO: 2. The amino acid sequence of an exemplary N-terminal propeptide domain of human myostatin is shown in SEQ ID NO: 75 or 78. The active mature myostatin is a disulfide-linked homodimer consisting of two C-terminal growth factor domains. Inactive latent myostatin is a non-covalent-conjugated complex of two propeptides and mature myostatin. As disclosed herein, an antibody of the invention binds to the inert latent myostatin, but does not bind to the mature active myostatin homodimer. In some embodiments, the antibody of the invention binds to an epitope in a fragment consisting of amino acids 21-100 of the myostatin propeptide (SEQ ID NO: 78), but does not bind to the mature active myostatin homodimer. The amino acid sequences of the exemplary synomolcus monkey and mouse myostatin (promyostatin) are shown in SEQ ID NOS: 3 and 5, respectively. The amino acid sequences of exemplary C-terminal growth factor domains of Cynomolgus monkey and murine myostatin are shown in SEQ ID NOS: 4 and 6, respectively. The amino acid sequences of exemplary N-terminal propeptide domains of cinomolcus monkey and murine myostatin are shown in SEQ ID NO: 76 or 79, and 77 or 80, respectively. GDF-11 (BMP-11) is a molecule closely related to myostatin, both of which are members of the TGF-beta phase. Similar to myostatin, GDF11 is first synthesized as a precursor polypeptide and then digested with an N-terminal pro-domain and a C-terminal mature GDF11. The amino acid sequence of human GDF11 (precursor) is shown in SEQ ID NO: 81. The amino acid sequence of the C-terminal mature human GDF11 is shown in SEQ ID NO: 82. The amino acid sequence of the N-terminal pro domain of human GDF11 is shown in SEQ ID NO: 83 or 84. The amino acid sequences of SEQ ID NOS: 1, 3, 5, 78, 79, 80, 81, and 84 include signal sequences. Their amino acids 1 to 24 correspond to the above and they are removed during processing in the cells.

As used herein, "treatment" (and grammatical variations thereof, for example, "treating" or "treating") refers to a clinical intervention intended to alter the natural course of an individual being treated, For prevention, or during a clinical pathology process. Preferred effects of the treatment include, but are not limited to, preventing the occurrence or recurrence of the disease, alleviating the symptoms, reducing any direct or indirect pathological consequences of the disease, preventing metastasis, reducing the rate of disease progression, , And a sedated or improved prognosis. In some embodiments, the antibodies of the invention are used to delay the onset of disease or slow the progression of the disease.

The term "variable region" or "variable domain" refers to the heavy or light chain domain of the antibody involved in the antigen binding of the antibody. The variable domains of the heavy and light chains of the native antibody (VH and VL, respectively) generally have a similar structure, wherein each domain comprises four conserved framework regions (FR) and three hypervariable regions (HVR) (See, for example, Kindt et al., Kuby Immunology, 6 ^th ed., WH Freeman and Co., page 91 (2007)). A single VH or VL domain may be sufficient to confer antigen-binding specificity. Furthermore, antibodies that bind to a particular antigen can be isolated using the VH or VL domains from an antibody that binds to the antigen, respectively, to select a library of complementary VL or VL domains. See, e.g., Portolano et al., J. Immunol. 150: 880-887 (1993); See Clarkson et al., Nature 352: 624-628 (1991).

A "variant Fc region" comprises an amino acid sequence that differs from the amino acid sequence of the native sequence Fc region by at least one amino acid modification (alteration), preferably by one or more amino acid substitution (s). Preferably, the variant Fc region comprises at least one amino acid substitution relative to the native sequence Fc region or relative to the Fc region of the parent polypeptide, e. G., The native sequence Fc region, or from about 1 to about 10 in the Fc region of the parent polypeptide Amino acid substitution, and preferably from about 1 to about 5 amino acid substitutions. In the present invention, the variant Fc region is preferably at least about 80% homologous to the Fc region of the native sequence Fc region and / or the Fc region of the parent polypeptide, and most preferably at least about 90% homologous to the Fc region of the parent polypeptide, Will have at least about 95% homology with the above.

The term "vector, " as used herein, refers to a nucleic acid molecule capable of propagating another nucleic acid that binds to the vector. The term includes vectors as self-replicating nucleic acid constructs as well as vectors integrated into the genome of the host cell into which the vector is introduced. Some vectors may direct expression of the nucleic acid to which the vector is operatively linked. Such vectors are referred to herein as "expression vectors. &Quot;

II. Composition and method

In one aspect, the invention is based in part on anti-myostatin antibodies and uses thereof. In some embodiments, antibodies are provided that bind to myostatin. The antibodies of the invention are useful, for example, for the diagnosis or treatment of muscle wasting disease.

In another aspect, the invention is based, in part, on polypeptides comprising a variant Fc region and uses thereof. In one embodiment, there is provided a polypeptide comprising a variant Fc region having increased Fc gamma RIIb-binding activity. In another embodiment, there is provided a polypeptide comprising a variant Fc region having an increased pi. In certain embodiments, the polypeptide of the invention is an antibody. Polypeptides comprising the variant Fc region of the present invention are useful, for example, for the diagnosis or treatment of diseases.

A. Exemplary anti-Fc < RTI ID = 0.0 > Myostatin  Antibodies and Polypeptide

In one embodiment, the invention provides isolated antibodies that bind to myostatin. In some embodiments, the anti-myostatin antibody of the invention binds to latent myostatin. In a further embodiment, the anti-myostatin antibody of the invention is administered in combination with a myostatin polypeptide (human: SEQ ID NO: 75 or 78; cynomolgus monkey: SEQ ID NO: 76 or 79; mouse: SEQ ID NO: 77 or 80) . In a further embodiment, the antibody binds to an epitope in the fragment consisting of the amino acids 21-100 of the myostatin propeptide (SEQ ID NO: 78). The propeptide is contained in latent myostatin as one of the components as described above. In some embodiments, the anti-myostatin antibody of the invention inhibits the activation of myostatin. In some embodiments, the anti-myostatin antibody blocks the release of mature myostatin from latent myostatin. Mature myostatin has been reported to be released from latent myostatin via proteolytic and non-proteolytic processes. The anti-myostatin antibody of the present invention can block proteolytic and / or non-proteolytic release of mature myostatin from latent myostatin. In some embodiments, the anti-myostatin antibody blocks proteolytic cleavage of latent myostatin. In some embodiments, the anti-myostatin antibody blocks the protease's access to latent myostatin (particularly the proteolytic cleavage site of latent myostatin (Arg98-Asp99)). In a further embodiment the protease is selected from the group consisting of BMP1 / TLD and a metalloprotease such as BMP1, TED, tolloid-type protein-1 (TLL-1), or tolloid- Lt; / RTI > In another embodiment, the anti-myostatin antibody blocks the non-proteolytic release of mature myostatin from latent myostatin. Non-protein degradative release as used herein refers to spontaneous release of mature myostatin from latent myostatin, which is not accompanied by proteolytic cleavage of latent myostatin. Such non-proteolytic release includes, for example, the release of mature myostatin by incubating latent myostatin at 37 ° C in the absence of a protease cleaving the latent myostatin. In some embodiments, the anti-myostatin antibody of the invention does not bind to mature myostatin. In some embodiments, the anti-myostatin antibody binds to the same epitope as the antibody described in Table 2a. In some embodiments, the anti-myostatin antibody competes against the antibody described in Table 2a for latent myostatin binding. In a further embodiment, anti-myostatin antibodies compete for latent myostatin binding with antibodies comprising the VH and VL pairs described in Table 2a. In some embodiments, the anti-myostatin antibody competes for fragment binding consisting of the antibody described in Table 2a and amino acids 21-100 of the myostatin pro peptide (SEQ ID NO: 78). In a further embodiment, the anti-myostatin antibody binds to the same epitope as the antibody set forth in Table 11a or 13. In some embodiments, the anti-myostatin antibody competes against the antibody described in Table 11a or 13 for latent myostatin binding. In some embodiments, the anti-myostatin antibody competes for fragment binding consisting of the antibody described in Table 11a or 13 and the amino acid 21-100 of the myostatin propeptide (SEQ ID NO: 78). In some embodiments, the anti-myostatin antibody of the invention binds to latent myostatin and inhibits the activation of myostatin. In a further embodiment, the antibody comprises (a) blocking the release of mature myostatin from latent myostatin; (b) block the proteolytic release of mature myostatin; (c) block spontaneous release of mature myostatin; Or (d) does not bind to mature myostatin; Or an amino acid 21-100 of myostatin propeptide (SEQ ID NO: 78). In a further embodiment, the antibody competes or binds to the same epitope as the antibody, with respect to latent myostatin binding to an antibody comprising the VH and VL pairs set forth in Table 2a, 11a or 13. In a further embodiment, the antibody binds to latent myostatin with greater affinity at neutral pH (e.g., pH 7.4) than at an acidic pH (e.g., pH 5.8). In a further embodiment, the antibody comprises (a) a monoclonal antibody, (b) a human, humanized or chimeric antibody; (c) a full-length IgG antibody, or (d) an antibody fragment that binds to a latent myostatin or myostatin propeptide.

In another embodiment, the anti-myostatin antibody of the invention does not bind to GDF11. In some embodiments, the anti-myostatin antibody of the invention does not inhibit the activation of GDF11. In some embodiments, the anti-myostatin antibody does not block the release of mature GDF11 from latent GDF11. The anti-myostatin antibody of the present invention does not block proteolytic or non-proteolytic release of mature GDF11 from latent GDF11. In some embodiments, the anti-myostatin antibody does not block proteolytic cleavage of latent GDF11. In some embodiments, the anti-myostatin antibody does not block the protease access to latent GDF11 (particularly the proteolytic cleavage site of latent GDF11). In a further embodiment the protease is selected from the group consisting of BMP1 / TLD and a metalloprotease such as BMP1, TED, tolloid-type protein-1 (TLL-1), or tolloid- Lt; / RTI > Non-protein degradative release as used herein refers to spontaneous release of mature GDF11 from latent GDF11, which is not accompanied by proteolytic cleavage of latent GDF11. Such non-proteolytic release includes, for example, the release of mature GDF11 by incubating latent GDF11 in the absence of protease digesting the latent GDF11 at 37 < 0 > C. Most of the known anti-myostatin antibodies to date have not been specific to myostatin. These antibodies have high affinity for other members of the TGF-beta phase, such as GDF11, and neutralize their biological activity. GDF11 plays an important role during embryogenesis and is responsible for the homeostatic transformation of the central skeleton. Homozygous GDF11 knockout mice are fatal before and after delivery, and mice bearing one wild-type copy of the GDF11 gene are capable of growth but have skeletal malformations. Although GDF11 plays an important role during embryogenesis, antagonists that inhibit GDF11 have the theoretical safety risk that can appear as toxic in treated patients or as reproductive toxicity, for example, in fertile women. Thus, there is a need for a particular inhibition of the myostatin activity in the treatment of myostatin-related disorders, particularly in fertile women, where it is desirable to increase muscle mass, size, strength, etc.

In another aspect, the invention provides an anti-myostatin antibody that exhibits pH-dependent binding properties. As used herein, the expression "pH-dependent binding" means that the antibody exhibits "reduced binding to myostatin at an acid pH compared to binding at neutral pH" , The two expressions can be used interchangeably). For example, "antibodies having pH-dependent binding properties " include antibodies that bind to myostatin with a higher affinity at neutral pH than at acidic pH. In some embodiments, the antibodies of the present invention have at least 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 400, 1000, 10,000 times higher affinity to myostatin. In some embodiments, the antibody binds to myostatin (e.g., latent myostatin or proteostomastatin) with a higher affinity at pH 7.4 than at pH 5.8. In a further embodiment the antibody is at least 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75 , 80, 85, 90, 95, 100, 200, 400, 1000, 10,000 times higher affinity to myostatin.

When the antigen is a soluble protein, binding of the antibody to the antigen may produce an extended half-life of the antigen in the plasma (i.e., a reduced clearance of the antigen from plasma) because the antibody is less than the antigen itself Because it can have a longer half-life in plasma and act as a carrier for the antigen. This is due to recirculation of the antigen-antibody complex by FcRn through intracellular endosomal pathways (Roopenian, Nat. Rev. Immunol. 7 (9): 715-725 (2007)). However, antibodies that have pH-dependent binding properties that bind to the antigen in the extracellular environment, while releasing the antigen into the acidic endosomal compartment after entering the cell, exhibit antigen neutralization and clearance as compared to counterparts that bind in a pH- (Igawa et al., Nature Biotechnol. 28 (11): 1203-1207 (2010)); Devanaboyina et al., MAbs 5 (6): 851-859 2013)]; WO 2009/125825).

For purposes of this specification, the "affinity" of an antibody to myostatin is indicated by the KD of the antibody. The KD of the antibody refers to the equilibrium dissociation constant of the antibody-antigen interaction. The greater the KD value for the binding of the antibody to its antigen, the weaker its binding affinity for that particular antigen. Correspondingly, as used herein, the expression " higher affinity at neutral pH than at acidic pH "(or equivalent expression as" pH-dependent binding ") refers to the binding of an antibody that binds to myostatin at acidic pH KD is greater than the KD of the antibody binding to myostatin at neutral pH. For example, in the context of the present invention, an antibody is a neutral pH at an acidic pH where the KD of the antibody binding to myostatin is at least two times greater than the KD of the antibody binding to myostatin at neutral pH Lt; RTI ID = 0.0 > myostatin < / RTI > Thus, the present invention provides a method of inhibiting the binding of myostatin to the myostatin at a neutral pH by at least 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, , 75, 80, 85, 90, 95, 100, 200, 400, 1000, 10,000 times greater KD. In another embodiment, the KD value of the antibody at neutral pH can be 10 ^-7 M, 10 ^-8 M, 10 ^-9 M, 10 ^-10 M, 10 ^-11 M, 10 ^-12 M or lower. In another embodiment, the KD value of the antibody at acidic pH may be 10 ^-9 M, 10 ^-8 M, 10 ^-7 M, 10 ^-6 M or higher.

In a further embodiment, the antibody has a higher affinity at neutral pH than at acidic pH when the KD of the antibody binding to myostatin at pH 5.8 is at least two-fold greater than the KD of the antibody binding to myostatin at pH 7.4 It is considered to bind to myostatin (for example, latent myostatin or the protease myostatin) on Mars. In some embodiments, the provided antibodies are at least 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65 Bind to myostatin at pH 5.8 with KD greater than 70, 75, 80, 85, 90, 95, 100, 200, 400, In another embodiment, the KD value of the antibody at pH 7.4 can be 10 ^-7 M, 10 ^-8 M, 10 ^-9 M, 10 ^-10 M, 10 ^-11 M, 10 ^-12 M or lower. In another embodiment, the KD value of the antibody at pH 5.8 may be 10 ^-9 M, 10 ^-8 M, 10 ^-7 M, 10 ^-6 M or higher.

The binding properties of the antibody to a particular antigen may also be indicated by the kd of the antibody. The kd of the antibody refers to the dissociation rate constant of the antibody against the specific antigen and is expressed by the reciprocal of the second (i.e., seconds ^-1 ). An increase in the kd value means a weaker binding of the antibody to its antigen. Thus, the present invention includes antibodies that bind to myostatin at a higher kd value at acidic pH than at neutral pH. The present invention is directed to a method of inhibiting myostatin binding to at least 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75 , 80, 85, 90, 95, 100, 200, 400, 1000, 10000 times greater kd for binding to myostatin at acidic pH. In another embodiment, the antibody of the kd value at neutral pH was ^{10 -2 ℓ / s, 10 -3} ℓ / s, 10 -4 ℓ / s, 10 -5 ℓ / s, 10 -6 ℓ / s or less . In another embodiment, the kd value of the antibody at an acidic pH may be 10 ^-3 L / s, 10 ^-2 L / s, 10 ^-1 L / s. The present invention also includes an antibody that binds to myostatin (e.g., latent myostatin or theprotein myostatin) at a higher kd value at pH 5.8 than at pH 7.4. The present invention is directed to a method of inhibiting myostatin binding to at least 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 400, 1000, 10000 times more kd to the myostatin at pH 5.8. In another embodiment, kd value of the antibody at pH 7.4 is ^{10 -2 ℓ / s, 10 -3} ℓ / s, 10 -4 ℓ / s, 10 -5 ℓ / s, 10 -6 ℓ / s or less . In another embodiment, the kd value of the antibody at pH 5.8 may be 10 ^-3 L / s, 10 ^-2 L / s, 10 ^-1 L / s.

In some cases, "reduced binding to myostatin at acidic pH compared to binding at neutral pH" may be attributed to the KD value of antibody binding to myostatin at acidic pH versus the KD value of antibody binding to myostatin at neutral pH KD ratio (or vice versa). For example, an antibody is considered to exhibit "reduced binding to myostatin at acidic pH compared to binding at neutral pH " for the purposes of the present invention when the antibody exhibits an acid / neutral KD ratio of at least 2 . In some embodiments, the pH 5.8 / pH 7.4 KD ratio for the anti-myostatin antibody of the invention is greater than 2. In some exemplary embodiments, the acid / neutral KD ratio for an antibody of the invention is 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70 , 75, 80, 85, 90, 95, 100, 200, 400, 1000, 10,000 or more. In another embodiment, the KD value of the antibody at neutral pH can be 10 ^-7 M, 10 ^-8 M, 10 ^-9 M, 10 ^-10 M, 10 ^-11 M, 10 ^-12 M or lower. In another embodiment, the KD value of the antibody at acidic pH may be 10 ^-9 M, 10 ^-8 M, 10 ^-7 M, 10 ^-6 M or higher. In further instances, the antibody is capable of inhibiting myostatin (e.g., latent myostatin) at an acidic pH compared to binding at neutral pH if the antibody exhibits a pH 5.8 / pH 7.4 KD ratio of at least 2 Bond ".< / RTI > In some exemplary embodiments, the pH 5.8 / pH 7.4 KD ratio for the antibody is 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, , 80, 85, 90, 95, 100, 200, 400, 1000, 10,000 or more. In another embodiment, the KD value of the antibody at pH 7.4 can be 10 ^-7 M, 10 ^-8 M, 10 ^-9 M, 10 ^-10 M, 10 ^-11 M, 10 ^-12 M or lower. In another embodiment, the KD value of the antibody at pH 5.8 may be 10 ^-9 M, 10 ^-8 M, 10 ^-7 M, 10 ^-6 M or higher.

In some cases, "reduced binding to myostatin at acidic pH compared to binding at neutral pH" may be attributed to the kd value of antibody binding to myostatin at acidic pH versus the kd value of antibody binding to myostatin at neutral pH kd ratio (or vice versa). For example, an antibody may be considered to exhibit "reduced binding to myostatin at acidic pH compared to binding at neutral pH " for the purposes of the present invention when the antibody exhibits an acidic / neutral kd ratio of at least 2 . In some exemplary embodiments, the pH 5.8 / pH 7.4 kd ratio for an antibody of the invention is greater than 2. In some exemplary embodiments, the acid / neutral kd ratio for an antibody of the invention is 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, , 75, 80, 85, 90, 95, 100, 200, 400, 1000, 10,000 or more. In another embodiment, the antibody of the kd value at neutral pH was ^{10 -2 ℓ / s, 10 -3} ℓ / s, 10 -4 ℓ / s, 10 -5 ℓ / s, 10 -6 ℓ / s or less . In another embodiment, the kd value of the antibody at an acidic pH may be 10 ^-3 L / s, 10 ^-2 L / s, 10 ^-1 L / s. In some exemplary embodiments, the pH 5.8 / pH 7.4 kd ratio for an antibody of the invention is 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, , 70, 75, 80, 85, 90, 95, 100, 200, 400, 1000, 10,000 or more. In another embodiment, kd value of the antibody at pH 7.4 is ^{10 -2 ℓ / s, 10 -3} ℓ / s, 10 -4 ℓ / s, 10 -5 ℓ / s, 10 -6 ℓ / s or less . In another embodiment, the kd value of the antibody at pH 5.8 may be 10 ^-3 L / s, 10 ^-2 L / s, 10 ^-1 L / s.

As used herein, the expression "acidic pH" means a pH of 4.0 to 6.5. The expression "acidic pH" is intended to refer to any of the following: 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, , 6.2, 6.3, 6.4, and 6.5. In certain embodiments, the "acidic pH" is 5.8.

As used herein, the expression "neutral pH" means a pH of 6.7 to about 10.0. The term "neutral pH" is used to refer to any of the following: 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, , 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, and 10.0. In certain embodiments, the "neutral pH" is 7.4.

KD values and kd values as shown herein can be measured using a surface plasmon resonance-based biosensor to characterize antibody-antigen interactions (see, e. G., Example 7 herein) ). KD value and kd value can be measured at 25 캜 or 37 캜.

In some embodiments, the anti-myostatin antibody of the invention binds to myostatin from more than one species. In a further embodiment, the anti-myostatin antibody binds to myostatin from human and non-human animals. In a further embodiment, the anti-myostatin antibody binds to myostatin from humans, mice, and monkeys (e.g., cynomolgus, rhesus monkey, spiny monkey, chimpanzee or baboon).

In some embodiments, the anti-myostatin antibody of the invention binds to latent myostatin from more than one species. In a further embodiment, the anti-myostatin antibody binds to latent myostatin from human and non-human animals. In a further embodiment, the anti-myostatin antibody binds to latent myostatin from humans, mice, and monkeys.

In some embodiments, the anti-myostatin antibody of the invention binds to the protease myostatin from more than one species. In a further embodiment, the anti-myostatin antibody binds to the protease myostatin from human and non-human animals. In a further embodiment, the anti-myostatin antibody binds to the protease myostatin from humans, mice, and monkeys.

In a further aspect, the invention provides an anti-myostatin antibody that forms an immunoconjugate (i.e., an antigen-antibody complex) with myostatin. In some embodiments, two or more anti-myostatin antibodies bind to two or more myostatin molecules to form an immune complex. This is possible because the antibody has two antigen-binding sites and myostatin is present as a homodimer containing two myostatin molecules. The anti-myostatin antibody may bind to the same epitope on the myostatin molecule or may bind to a different epitope on the myostatin molecule, much like a bispecific antibody. Generally speaking, when two or more antibodies form an immunoconjugate with two or more antigens, the resulting immunoconjugate is strongly bound to the Fc receptor present on the cell surface due to the binding activity effect through the Fc region of the antibody in the complex And then can be absorbed into the cells with high efficiency. Thus, the above-mentioned anti-myostatin antibody, which is capable of forming an immunoconjugate containing two or more anti-myostatin antibodies and two or more myostatin molecules, has a strong binding to the Fc receptor due to the binding activity effect , It is possible to induce a rapid clearance of myostatin from plasma in the living body.

Furthermore, it is believed that antibodies with pH-dependent binding properties have superior properties for antigen neutralization and clearance compared to their counterparts that bind in a pH-independent manner (Igawa et al., Nature Biotech. 28 (11): 1203-1207 (2010); Devanaboyina et al., Mabs 5 (6): 851-859 (2013); WO 2009/125825). Thus, antibodies that have both of these two properties, that is, antibodies that form an immune complex that has two or more antibodies with pH-dependent binding properties and that have two or more antigens, are highly sensitive to the highly accelerated removal of antigen from plasma It is expected to have more excellent properties (WO 2013/081143).

In another aspect, the invention provides a kit comprising: (a) HVR-H1 comprising an amino acid sequence of any one of SEQ ID NOs: 55-57, 114-115, 126; (b) HVR-H2 comprising the amino acid sequence of any one of SEQ ID NOS: 58-60, 116-120, and 127; (c) HVR-H3 comprising the amino acid sequence of any one of SEQ ID NOS: 61-64, 121, and 128; (d) HVR-L1 comprising the amino acid sequence of any one of SEQ ID NOS: 65-69, 122-124, and 129; (e) HVR-L2 comprising an amino acid sequence of any one of SEQ ID NOS: 70-72, 125, and 130; And (f) an anti-myostatin antibody comprising at least 1, 2, 3, 4, 5 or 6 HVRs selected from HVR-L3 comprising the amino acid sequence of any one of SEQ ID NOs: do.

In another aspect, the invention provides a kit comprising: (a) HVR-H1 comprising an amino acid sequence of any one of SEQ ID NOs: 55-57; (b) HVR-H2 comprising the amino acid sequence of any one of SEQ ID NOs: 58-60; (c) HVR-H3 comprising the amino acid sequence of any one of SEQ ID NOs: 61-64; (d) HVR-L1 comprising the amino acid sequence of any one of SEQ ID NOs: 65-69; (e) HVR-L2 comprising the amino acid sequence of any one of SEQ ID NOS: 70-72; And (f) at least 1, 2, 3, 4, 5 or 6 HVRs selected from HVR-L3 comprising the amino acid sequence of any one of SEQ ID NOs: 73-74.

In one aspect, the invention provides a kit comprising: (a) HVR-H1 comprising the amino acid sequence of any one of SEQ ID NOs: 114-115; (b) HVR-H2 comprising the amino acid sequence of any one of SEQ ID NOs: 116-120; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 121; (d) HVR-L1 comprising the amino acid sequence of any one of SEQ ID NOs: 122-124; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 125; And (f) at least one, two, three, four, five or six highly modified regions (HVR) selected from HVR-L3 comprising the amino acid sequence of any one of SEQ ID NOs: Lt; / RTI >

In another aspect, the invention provides a kit comprising: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 114; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 58; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 63; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 122; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 71; And (f) at least 1, 2, 3, 4, 5 or 6 HVRs selected from HVR-L3 comprising the amino acid sequence of SEQ ID NO: 74. In another aspect, the invention provides a kit comprising: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 114; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 58; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 63; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 123; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 71; And (f) at least 1, 2, 3, 4, 5 or 6 HVRs selected from HVR-L3 comprising the amino acid sequence of SEQ ID NO: 74.

In another aspect, the invention provides a kit comprising: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 126; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 127; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 128; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 129; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 130; And (f) at least 1, 2, 3, 4, 5 or 6 HVRs selected from HVR-L3 comprising the amino acid sequence of SEQ ID NO: 131.

In one aspect, the invention provides a kit comprising: (a) HVR-H1 comprising the amino acid sequence of any one of SEQ ID NOs: 55-57, 114-115, 126; (b) HVR-H2 comprising the amino acid sequence of any one of SEQ ID NOS: 58-60, 116-120, and 127; (c) at least one, at least two or three VH HVR sequences selected from HVR-H3 comprising the amino acid sequence of any one of SEQ ID NOS: 61-64, 121, and 128. In one embodiment, the antibody comprises HVR-H3 comprising an amino acid sequence of any one of SEQ ID NOs: 61-64, 121, In another embodiment, the antibody comprises HVR-H3 comprising an amino acid sequence of any one of SEQ ID NOs: 61-64, 121, 128 and HVR-L3 comprising an amino acid sequence of any of SEQ ID NOs: 73-74, 131 . In a further embodiment, the antibody comprises HVR-H3 comprising an amino acid sequence of any one of SEQ ID NOs: 61-64, 121, 128, HVR-L3 comprising an amino acid sequence of any of SEQ ID NOs: 73-74, 131 , And HVR-H2 comprising the amino acid sequence of any one of SEQ ID NOS: 58-60, 116-120, and 127. In a further embodiment, the antibody comprises (a) HVR-H1 comprising the amino acid sequence of any one of SEQ ID NOs: 55-57, 114-115, 126; (b) HVR-H2 comprising the amino acid sequence of any one of SEQ ID NOS: 58-60, 116-120, and 127; And (c) HVR-H3 comprising an amino acid sequence of any one of SEQ ID NOS: 61-64, 121, and 128.

In one embodiment, the invention provides a kit comprising: (a) HVR-H1 comprising the amino acid sequence of any one of SEQ ID NOs: 55-57; (b) HVR-H2 comprising the amino acid sequence of any one of SEQ ID NOs: 58-60; And (c) at least one, at least two or three VH HVR sequences selected from HVR-H3 comprising the amino acid sequence of any one of SEQ ID NOs: 61-64. In one embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of any one of SEQ ID NOs: 61-64. In another embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of any one of SEQ ID NOs: 61-64 and HVR-L3 comprising the amino acid sequence of any of SEQ ID NOs: 73-74. In a further embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of any one of SEQ ID NOs: 61-64, HVR-L3 comprising the amino acid sequence of any one of SEQ ID NOs: 73-74, Gt; HVR-H2 < / RTI > comprising an amino acid sequence of any one of SEQ ID NOs: In a further embodiment, the antibody comprises (a) HVR-H1 comprising the amino acid sequence of any one of SEQ ID NOs: 55-57; (b) HVR-H2 comprising the amino acid sequence of any one of SEQ ID NOs: 58-60; And (c) HVR-H3 comprising the amino acid sequence of any one of SEQ ID NOs: 61-64.

In another aspect, the invention provides a kit comprising: (a) HVR-H1 comprising the amino acid sequence of any one of SEQ ID NOs: 114-115; (b) HVR-H2 comprising the amino acid sequence of any one of SEQ ID NOs: 116-120; And (c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 121. In another aspect, the invention provides an antibody comprising at least one, at least two, or three VH HVR sequences selected from HVR- In one embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO: 121. In another embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO: 121 and HVR-L3 comprising the amino acid sequence of any of SEQ ID NOs: 73-74. In a further embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO: 121, HVR-L3 comprising the amino acid sequence of any one of SEQ ID NOs: 73-74, and any one of SEQ ID NOs: 116-120 RTI ID = 0.0 > HVR-H2 < / RTI > comprising an amino acid sequence. In a further embodiment, the antibody comprises (a) HVR-H1 comprising the amino acid sequence of any one of SEQ ID NOs: 114-115; (b) HVR-H2 comprising the amino acid sequence of any one of SEQ ID NOs: 116-120; And (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 121.

In another aspect, the invention provides a kit comprising: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 114; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 58; And (c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 63. In another aspect, the invention provides an antibody comprising at least one, at least two, or three VH HVR sequences selected from HVR- In one embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO: 63. In another embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO: 63 and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 74. In a further embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO: 63, HVR-L3 comprising the amino acid sequence of SEQ ID NO: 74, and HVR-H2 comprising the amino acid sequence of SEQ ID NO: 58 do. In a further embodiment, the antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 114; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 58; And (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 63.

In another aspect, the invention provides a kit comprising: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 126; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 127; And (c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 128. The present invention further provides an antibody comprising at least one, at least two or three VH HVR sequences selected from HVR-H3 comprising the amino acid sequence of SEQ ID NO: In one embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO: 128. In another embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO: 128 and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 131. In a further embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO: 128, HVR-L3 comprising the amino acid sequence of SEQ ID NO: 131, and HVR-H2 comprising the amino acid sequence of SEQ ID NO: 127 do. In a further embodiment, the antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 126; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 127; And (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 128.

In another aspect, the invention provides a kit comprising: (a) HVR-L1 comprising an amino acid sequence of any one of SEQ ID NOs: 65-69, 122-124, 129; (b) HVR-L2 comprising the amino acid sequence of any one of SEQ ID NOS: 70-72, 125, and 130; And (c) at least one, at least two or three VL HVR sequences selected from HVR-L3 comprising the amino acid sequence of any one of SEQ ID NOs: 73-74, 131. In one embodiment, the antibody comprises (a) HVR-L1 comprising the amino acid sequence of any one of SEQ ID NOs: 65-69, 122-124, 129; (b) HVR-L2 comprising the amino acid sequence of any one of SEQ ID NOS: 70-72, 125, and 130; And (c) HVR-L3 comprising an amino acid sequence of any one of SEQ ID NOs: 73-74, 131.

In another aspect, the invention provides a kit comprising: (a) HVR-L1 comprising an amino acid sequence of any one of SEQ ID NOs: 65-69; (b) HVR-L2 comprising the amino acid sequence of any one of SEQ ID NOs: 70-72; And (c) at least one, at least two or three VL HVR sequences selected from HVR-L3 comprising the amino acid sequence of any one of SEQ ID NOs: 73-74. In one embodiment, the antibody comprises (a) HVR-L1 comprising the amino acid sequence of any one of SEQ ID NOs: 65-69; (b) HVR-L2 comprising the amino acid sequence of any one of SEQ ID NOs: 70-72; And (c) HVR-L3 comprising an amino acid sequence of any one of SEQ ID NOs: 73-74.

In another aspect, the invention provides a kit comprising: (a) HVR-L1 comprising the amino acid sequence of any one of SEQ ID NOs: 122-124; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 125; And (c) at least one, at least two or three VL HVR sequences selected from HVR-L3 comprising the amino acid sequence of any one of SEQ ID NOs: 73-74. In one embodiment, the antibody comprises (a) an HVR-L1 comprising the amino acid sequence of any one of SEQ ID NOs: 122-124; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 125; And (c) HVR-L3 comprising an amino acid sequence of any one of SEQ ID NOs: 73-74.

In another aspect, the invention provides a kit comprising: (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 122; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 71; And (c) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 74. In another aspect, the invention provides an antibody comprising at least one, at least two or three VL HVR sequences selected from HVR-L3 comprising the amino acid sequence of SEQ ID NO: In one embodiment, the antibody comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 122; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 71; And (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 74. In another embodiment, the invention provides a kit comprising: (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 123; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 71; And (c) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 74. In another aspect, the invention provides an antibody comprising at least one, at least two or three VL HVR sequences selected from HVR-L3 comprising the amino acid sequence of SEQ ID NO: In one embodiment, the antibody comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 123; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 71; And (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 74.

In another aspect, the invention provides a kit comprising: (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 129; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 130; And (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 131. The present invention also provides an antibody comprising at least one, at least two or three VL HVR sequences selected from HVR-L3 comprising the amino acid sequence of SEQ ID NO: In one embodiment, the antibody comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 129; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 130; And (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 131.

In another aspect, an antibody of the invention comprises: (a) (i) HVR-H1 comprising an amino acid sequence of any one of SEQ ID NOs: 55-57, 114, 115, 126; (ii) HVR-H2 comprising the amino acid sequence of any one of SEQ ID NOS: 58-60, 116-120, and 127; And (iii) a VH domain comprising at least one, at least two, or all three VH HVR sequences selected from HVR-H3 comprising the amino acid sequence of any one of SEQ ID NOS: 61-64, 121, And (b) (i) HVR-L1 comprising the amino acid sequence of any one of SEQ ID NOs: 65-69, 122-124, and 129; (ii) HVR-L2 comprising the amino acid sequence of any one of SEQ ID NOS: 70-72, 125, and 130; And (iii) a VL domain comprising at least one, at least two, or all three VL HVR sequences selected from HVR-L3 comprising an amino acid sequence of any one of SEQ ID NOs: 73-74, 131.

In another embodiment, an antibody of the invention comprises: (a) (i) HVR-H1 comprising an amino acid sequence of any one of SEQ ID NOs: 55-57; (ii) HVR-H2 comprising the amino acid sequence of any one of SEQ ID NOS: 58-60; And (iii) a VH domain comprising at least one, at least two, or all three VH HVR sequences selected from HVR-H3 comprising the amino acid sequence of any one of SEQ ID NOs: 61-64; And (b) (i) HVR-L1 comprising the amino acid sequence of any one of SEQ ID NOs: 65-69; (ii) HVR-L2 comprising the amino acid sequence of any one of SEQ ID NOS: 70-72; And (iii) a VL domain comprising at least one, at least two, or all three VL HVR sequences selected from HVR-L3 comprising the amino acid sequence of any of SEQ ID NOs: 73-74.

In another embodiment, an antibody of the invention comprises: (a) (i) HVR-H1 comprising the amino acid sequence of any one of SEQ ID NOs: 114-115; (ii) HVR-H2 comprising the amino acid sequence of any one of SEQ ID NOs: 116-120; And (iii) a VH domain comprising at least one, at least two, or all three VH HVR sequences selected from HVR-H3 comprising the amino acid sequence of SEQ ID NO: 121; And (b) (i) HVR-L1 comprising the amino acid sequence of any one of SEQ ID NOs: 122-124; (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 125; And (iii) a VL domain comprising at least one, at least two, or all three VL HVR sequences selected from HVR-L3 comprising the amino acid sequence of any of SEQ ID NOs: 73-74. In another aspect, an antibody of the invention comprises: (a) (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 114; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 58; And (iii) a VH domain comprising at least one, at least two, or all three VH HVR sequences selected from HVR-H3 comprising the amino acid sequence of SEQ ID NO: 63; And (b) (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 122; (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 71; And (iii) a VL domain comprising at least one, at least two, or all three VL HVR sequences selected from HVR-L3 comprising the amino acid sequence of SEQ ID NO: 74. In another aspect, an antibody of the invention comprises: (a) (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 114; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 58; And (iii) a VH domain comprising at least one, at least two, or all three VH HVR sequences selected from HVR-H3 comprising the amino acid sequence of SEQ ID NO: 63; And (b) (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 123; (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 71; And (iii) a VL domain comprising at least one, at least two, or all three VL HVR sequences selected from HVR-L3 comprising the amino acid sequence of SEQ ID NO: 74.

In another aspect, an antibody of the invention comprises: (a) (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 126; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 127; And (iii) a VH domain comprising at least one, at least two, or all three VH HVR sequences selected from HVR-H3 comprising the amino acid sequence of SEQ ID NO: 128; And (b) (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 129; (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 130; And (iii) a VL domain comprising at least one, at least two, or all three VL HVR sequences selected from HVR-L3 comprising the amino acid sequence of SEQ ID NO: 131.

In another aspect, the invention provides a kit comprising: (a) HVR-H1 comprising an amino acid sequence of any one of SEQ ID NOs: 55-57, 114-115, 126; (b) HVR-H2 comprising the amino acid sequence of any one of SEQ ID NOS: 58-60, 116-120, and 127; (c) HVR-H3 comprising the amino acid sequence of any one of SEQ ID NOS: 61-64, 121, and 128; (d) HVR-L1 comprising the amino acid sequence of any one of SEQ ID NOS: 65-69, 122-124, and 129; (e) HVR-L2 comprising an amino acid sequence of any one of SEQ ID NOS: 70-72, 125, and 130; And (f) an HVR-L3 comprising an amino acid sequence of any one of SEQ ID NOS: 73-74 and 131.

In another aspect, the invention provides a kit comprising: (a) HVR-H1 comprising an amino acid sequence of any one of SEQ ID NOs: 55-57, 114-115; (b) HVR-H2 comprising the amino acid sequence of any one of SEQ ID NOS: 58-60, 116-120; (c) HVR-H3 comprising the amino acid sequence of any one of SEQ ID NOs: 61-64, 121; (d) HVR-L1 comprising the amino acid sequence of any one of SEQ ID NOS: 65-69, 122-124; (e) HVR-L2 comprising an amino acid sequence of any one of SEQ ID NOS: 70-72, 125; And (f) an HVR-L3 comprising an amino acid sequence of any one of SEQ ID NOs: 73-74.

In another aspect, the invention provides a kit comprising: (a) HVR-H1 comprising the amino acid sequence of any one of SEQ ID NOs: 114-115; (b) HVR-H2 comprising the amino acid sequence of any one of SEQ ID NOs: 116-120; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 121; (d) HVR-L1 comprising the amino acid sequence of any one of SEQ ID NOs: 122-124; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 125; And (f) an HVR-L3 comprising an amino acid sequence of any one of SEQ ID NOs: 73-74. In another aspect, the invention provides a kit comprising: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 114; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 58; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 63; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 122; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 71; And (f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 74. In another aspect, the invention provides a kit comprising: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 114; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 58; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 63; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 123; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 71; And (f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 74.

In another aspect, the invention provides a kit comprising: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 126; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 127; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 128; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 129; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 130; And (f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 131.

In some embodiments, any one or more amino acids of the anti-myostatin antibody as provided above are substituted at the following HVR positions: (a) position 1 and 2 in HVR-H1 (SEQ ID NO: 55) ; (b) positions 4, 7, 8, 10, 11, 12 and 16 in HVR-H2 (SEQ ID NO: 58); (c) positions 5, 7 and 11 in HVR-H3 (SEQ ID NO: 61); (d) positions 1, 2, 5, 7, 8 and 9 in HVR-L1 (SEQ ID NO: 65); (e) positions 3 and 7 in HVR-L2 (SEQ ID NO: 70); And (f) position 8 of HVR-L3 (SEQ ID NO: 73).

In some embodiments, the at least one amino acid substitution of an anti-myostatin antibody is a conservative substitution as provided herein. In some embodiments, any one or more of the following substitutions may be made in any combination: (a) in HVR-H1 (SEQ ID NO: 55), S1H; Y2T, D, or E; (b) in HVR-H2 (SEQ ID NO: 58), Y4H; S7K; T8M or K; Y10K; A11M or E; S12E; G16K; (c) HVR-H3 (SEQ ID NO: 61), Y5H; T7H; L11K; (d) In HVR-L1 (SEQ ID NO: 65), Q1T; S2T; S5E; Y7F; D8H; N9D or A or E; (e) HVR-L2 (SEQ ID NO: 70), S3E; S7Y, F or W; And (f) HVR-L3 (SEQ ID NO: 73), L8R.

126, 127, 128, 129, 130, and 131 for HVR-H1, HVR-H2, HVR-H3, HVR-L1, HVR- Are included by the common sequence.

In any of the above embodiments, the anti-myostatin antibody can be humanized. In one embodiment, the anti-myostatin antibody comprises an HVR as in any of the above embodiments and further comprises a receptor human framework, such as a human immunoglobulin framework or human common framework do. In another embodiment, the anti-myostatin antibody comprises an HVR as in any of the embodiments above, and further comprises a VH or VL comprising a FR sequence. In a further embodiment, the anti-myostatin antibody comprises the following heavy and / or light chain variable domain FR sequences: In the case of the heavy chain variable domain, the FR1 comprises an amino acid sequence of any one of SEQ ID NOS: 132-134 Wherein FR2 comprises the amino acid sequence of any one of SEQ ID NOS: 135-136, FR3 comprises the amino acid sequence of SEQ ID NO: 137, and FR4 comprises the amino acid sequence of SEQ ID NO: 138. In the case of the light chain variable domain, FR1 comprises the amino acid sequence of SEQ ID NO: 139, FR2 comprises the amino acid sequence of any one of SEQ ID NOs: 140-141, FR3 comprises the amino acid sequence of any one of SEQ ID NOs: 142-143 And FR4 comprises the amino acid sequence of SEQ ID NO: 144.

In one aspect, the invention provides a kit comprising: (a) HVR-H1 comprising the amino acid sequence of any one of SEQ ID NOs: 157-162; (b) HVR-H2 comprising the amino acid sequence of any one of SEQ ID NOS: 163-168; (c) HVR-H3 comprising the amino acid sequence of any one of SEQ ID NOs: 169-174; (d) HVR-L1 comprising the amino acid sequence of any one of SEQ ID NOs: 175-180; (e) HVR-L2 comprising the amino acid sequence of any one of SEQ ID NOs: 181-186; And (f) at least 1, 2, 3, 4, 5 or 6 HVRs selected from HVR-L3 comprising the amino acid sequence of any one of SEQ ID NOs: 187-192.

In one aspect, the invention provides a kit comprising: (a) HVR-H1 comprising the amino acid sequence of any one of SEQ ID NOs: 157-162; (b) HVR-H2 comprising the amino acid sequence of any one of SEQ ID NOS: 163-168; And (c) at least one, at least two, or three VH HVR sequences selected from HVR-H3 comprising the amino acid sequence of any one of SEQ ID NOs: 169-174. In one embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of any one of SEQ ID NOS: 169-174. In another embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of any one of SEQ ID NOs: 169-174 and HVR-L3 comprising the amino acid sequence of any one of SEQ ID NOs: 187-192. In a further embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of any one of SEQ ID NOs: 169-174, HVR-L3 comprising the amino acid sequence of any one of SEQ ID NOs: 187-192, and SEQ ID NO: Gt; HVR-H2 < / RTI > comprising an amino acid sequence of any one of SEQ ID NOs. In a further embodiment, the antibody comprises (a) HVR-H1 comprising the amino acid sequence of any one of SEQ ID NOs: 157-162; (b) HVR-H2 comprising the amino acid sequence of any one of SEQ ID NOS: 163-168; And (c) HVR-H3 comprising the amino acid sequence of any one of SEQ ID NOs: 169-174.

In another aspect, the invention provides a kit comprising: (a) HVR-L1 comprising an amino acid sequence of any one of SEQ ID NOs: 175-180; (b) HVR-L2 comprising the amino acid sequence of any one of SEQ ID NOS: 181-186; And (c) at least one, at least two or three VL HVR sequences selected from HVR-L3 comprising an amino acid sequence of any one of SEQ ID NOs: 187-192. In one embodiment, the antibody comprises (a) HVR-L1 comprising the amino acid sequence of any one of SEQ ID NOs: 175-180; (b) HVR-L2 comprising the amino acid sequence of any one of SEQ ID NOS: 181-186; And (c) HVR-L3 comprising an amino acid sequence of any one of SEQ ID NOs: 187-192.

In another embodiment, an antibody of the invention comprises: (a) (i) HVR-H1 comprising the amino acid sequence of any one of SEQ ID NOs: 157-162; (ii) HVR-H2 comprising the amino acid sequence of any one of SEQ ID NOS: 163-168; And (iii) a VH domain comprising at least one, at least two, or all three VH HVR sequences selected from HVR-H3 comprising the amino acid sequence of any one of SEQ ID NOs: 169-174; And (b) (i) HVR-L1 comprising the amino acid sequence of any one of SEQ ID NOs: 175-180; (ii) HVR-L2 comprising the amino acid sequence of any one of SEQ ID NOS: 181-186; And (iii) a VL domain comprising at least one, at least two, or all three VL HVR sequences selected from HVR-L3 comprising an amino acid sequence of any one of SEQ ID NOs: 187-192.

In another aspect, the invention provides a kit comprising: (a) HVR-H1 comprising an amino acid sequence of any one of SEQ ID NOs: 157-162; (b) HVR-H2 comprising the amino acid sequence of any one of SEQ ID NOS: 163-168; (c) HVR-H3 comprising the amino acid sequence of any one of SEQ ID NOs: 169-174; (d) HVR-L1 comprising the amino acid sequence of any one of SEQ ID NOs: 175-180; (e) HVR-L2 comprising the amino acid sequence of any one of SEQ ID NOs: 181-186; And (f) an HVR-L3 comprising an amino acid sequence of any one of SEQ ID NOs: 187-192.

In another embodiment, the anti-myostatin antibody has at least 90%, 91%, 92%, 93%, 94%, or 90% identity to the amino acid sequence of any of SEQ ID NOS: 13, 16-30, 32-34, , 95%, 96%, 97%, 98%, 99%, or 100% sequence identity. In some embodiments, a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% For example, conservative substitutions), insertions or deletions, but the anti-myostatin antibody comprising the sequence retains the ability to bind to myostatin. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted and / or deleted in any one of SEQ ID NOS: 13, 16-30, 32-34, and 86-95. In some embodiments, substitutions, insertions or deletions occur in the region outside the HVR (i.e., in the FR). Optionally, the anti-myostatin antibody comprises a VH sequence of any one of SEQ ID NOS: 13, 16-30, 32-34 and 86-95, including post-translational modifications of the sequence. In a particular embodiment, the VH comprises (a) HVR-H1 comprising the amino acid sequence of any one of SEQ ID NOs: 55-57, 114-115, 126; (b) HVR-H2 comprising the amino acid sequence of any one of SEQ ID NOS: 58-60, 116-120, and 127; And (c) one, two or three HVRs selected from HVR-H3 comprising an amino acid sequence of any one of SEQ ID NOs: 61-64, 121, Post-translational modifications include, without limitation, modification of glutamine or glutamate in the N-terminus of the heavy or light chain to pyroglutamic acid by pyroglutamylation.

In another embodiment, the anti-myostatin antibody comprises at least 90%, 91%, 92%, 93%, 94%, 95% or more of the amino acid sequence of any one of SEQ ID NOS: 13, 16-30, 32, , 96%, 97%, 98%, 99%, or 100% sequence identity. In some embodiments, a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% For example, conservative substitutions), insertions or deletions, but the anti-myostatin antibody comprising the sequence retains the ability to bind to myostatin. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted and / or deleted in any one of SEQ ID NOS: 13, 16-30, 32, 33, In some embodiments, substitutions, insertions or deletions occur in the region outside the HVR (i.e., in the FR). Optionally, the anti-myostatin antibody comprises a VH sequence of any one of SEQ ID NOS: 13, 16-30, 32, 33 and 34, including post-translational modifications of the sequence. In certain embodiments, the VH comprises (a) HVR-H1 comprising the amino acid sequence of any one of SEQ ID NOs: 55-57; (b) HVR-H2 comprising the amino acid sequence of any one of SEQ ID NOs: 58-60; And (c) one, two or three HVRs selected from HVR-H3 comprising the amino acid sequence of any one of SEQ ID NOs: 61-64. Post-translational modifications include, without limitation, modification of glutamine or glutamate in the N-terminus of the heavy or light chain to pyroglutamic acid by pyroglutamylation.

In another embodiment, the anti-myostatin antibody comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% %, 99%, or 100% sequence identity. In some embodiments, a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% For example, conservative substitutions), insertions or deletions, but the anti-myostatin antibody comprising the sequence retains the ability to bind to myostatin. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted and / or deleted in any one of SEQ ID NOs: 86-95. In some embodiments, substitutions, insertions or deletions occur in the region outside the HVR (i.e., in the FR). Optionally, the anti-myostatin antibody comprises a VH sequence of any one of SEQ ID NOs: 86-95, including post-translational modifications of the sequence. In a particular embodiment, the VH comprises (a) HVR-H1 comprising the amino acid sequence of any one of SEQ ID NOs: 57, 114-115, 126; (b) HVR-H2 comprising the amino acid sequence of any one of SEQ ID NOs: 58, 116-120, 127; And (c) one, two, or three HVRs selected from HVR-H3 comprising the amino acid sequence of any one of SEQ ID NOs: 63, 121, Post-translational modifications include, without limitation, modification of glutamine or glutamate in the N-terminus of the heavy or light chain to pyroglutamic acid by pyroglutamylation.

In another embodiment, the anti-myostatin antibody comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% Or a VH sequence with 100% sequence identity. In some embodiments, a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% For example, conservative substitutions), insertions or deletions, but the anti-myostatin antibody comprising the sequence retains the ability to bind to myostatin. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted and / or deleted in SEQ ID NO: 86. In some embodiments, substitutions, insertions or deletions occur in the region outside the HVR (i.e., in the FR). Optionally, the anti-myostatin antibody comprises the VH sequence of SEQ ID NO: 86, including post-translational modifications of the sequence. In a particular embodiment, the VH comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 114; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 58; And (c) one, two or three HVRs selected from HVR-H3 comprising the amino acid sequence of SEQ ID NO: 63. Post-translational modifications include, without limitation, modification of glutamine or glutamate in the N-terminus of the heavy or light chain to pyroglutamic acid by pyroglutamylation. In another embodiment, the anti-myostatin antibody comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% Or a VH sequence with 100% sequence identity. In some embodiments, a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% For example, conservative substitutions), insertions or deletions, but the anti-myostatin antibody comprising the sequence retains the ability to bind to myostatin. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted and / or deleted in SEQ ID NO: 92. In some embodiments, substitutions, insertions or deletions occur in the region outside the HVR (i.e., in the FR). Optionally, the anti-myostatin antibody comprises the VH sequence of SEQ ID NO: 92, including post-translational modifications of the sequence. In a particular embodiment, the VH comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 114; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 58; And (c) one, two or three HVRs selected from HVR-H3 comprising the amino acid sequence of SEQ ID NO: 63. Post-translational modifications include, without limitation, modification of glutamine or glutamate in the N-terminus of the heavy or light chain to pyroglutamic acid by pyroglutamylation.

In another embodiment, there is provided an anti-myostatin antibody, wherein said antibody has at least 90%, 91%, 92%, 90%, 90%, 90% 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity. In some embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% For example, conservative substitutions), insertions or deletions, but the anti-myostatin antibody comprising the sequence retains the ability to bind to myostatin. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted and / or deleted in any one of SEQ ID NOS: 15, 31, 35-58, and 96-99. In some embodiments, substitutions, insertions or deletions occur in the region outside the HVR (i.e., in the FR). Optionally, the anti-myostatin antibody comprises a VL sequence of any one of SEQ ID NOS: 15, 31, 35-38 and 96-99, including post-translational modifications of the sequence. In a particular embodiment, the VL comprises (a) HVR-L1 comprising the amino acid sequence of any one of SEQ ID NOs: 65-69, 122-124, 129; (b) HVR-L2 comprising the amino acid sequence of any one of SEQ ID NOS: 70-72, 125, and 130; And (c) one, two or three HVRs selected from HVR-L3 comprising the amino acid sequence of any one of SEQ ID NOs: 73-74, 131. Post-translational modifications include, without limitation, modification of glutamine or glutamate in the N-terminus of the heavy or light chain to pyroglutamic acid by pyroglutamylation.

In another embodiment, there is provided an anti-myostatin antibody, wherein said antibody comprises at least 90%, 91%, 92%, 90%, 90%, 90% 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity. In some embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% For example, conservative substitutions), insertions or deletions, but the anti-myostatin antibody comprising the sequence retains the ability to bind to myostatin. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted and / or deleted in any one of SEQ ID NOS: 15, 31, 35, 36, 37 and 58. In some embodiments, substitutions, insertions or deletions occur in the region outside the HVR (i.e., in the FR). Optionally, the anti-myostatin antibody comprises a VL sequence of any one of SEQ ID NOS: 15, 31, 35, 36, 37 and 38, including post-translational modifications of the sequence. In a particular embodiment, the VL comprises (a) HVR-L1 comprising the amino acid sequence of any one of SEQ ID NOs: 65-69; (b) HVR-L2 comprising the amino acid sequence of any one of SEQ ID NOs: 70-72; And (c) one, two or three HVRs selected from HVR-L3 comprising the amino acid sequence of any one of SEQ ID NOs: 73-74. Post-translational modifications include, without limitation, modification of glutamine or glutamate in the N-terminus of the heavy or light chain to pyroglutamic acid by pyroglutamylation.

In another embodiment, there is provided an anti-myostatin antibody, wherein said antibody comprises at least 90%, 91%, 92%, 93%, 94%, 95% or more of the amino acid sequence of any one of SEQ ID NOs: 96-99. , 96%, 97%, 98%, 99%, or 100% sequence identity. In some embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% For example, conservative substitutions), insertions or deletions, but the anti-myostatin antibody comprising the sequence retains the ability to bind to myostatin. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted and / or deleted in any one of SEQ ID NOs: 96-99. In some embodiments, substitution, insertion or deletion occurs in the region outside the HVR. Optionally, the anti-myostatin antibody comprises a VL sequence of any one of SEQ ID NOs: 96-99, including post-translational modifications of the sequence. In certain embodiments, the VL comprises (a) HVR-L1 comprising the amino acid sequence of any one of SEQ ID NOs: 122-124, 129; (b) HVR-L2 comprising the amino acid sequence of any one of SEQ ID NOS: 71, 125, and 130; And (c) one, two or three HVRs selected from HVR-L3 comprising the amino acid sequence of any one of SEQ ID NOs: 74 and 131. Post-translational modifications include, without limitation, modification of glutamine or glutamate in the N-terminus of the heavy or light chain to pyroglutamic acid by pyroglutamylation.

In another embodiment, there is provided an anti-myostatin antibody, wherein said antibody comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96% %, 98%, 99%, or 100% sequence identity. In some embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% For example, conservative substitutions), insertions or deletions, but the anti-myostatin antibody comprising the sequence retains the ability to bind to myostatin. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted and / or deleted in SEQ ID NO: 96. In some embodiments, substitution, insertion or deletion occurs in the region outside the HVR. Optionally, the anti-myostatin antibody comprises the VL sequence of SEQ ID NO: 96, including post-translational modifications of the sequence. In a particular embodiment, the VL comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 122; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 71; And (c) one, two or three HVRs selected from HVR-L3 comprising the amino acid sequence of SEQ ID NO: 74. Post-translational modifications include, without limitation, modification of glutamine or glutamate in the N-terminus of the heavy or light chain to pyroglutamic acid by pyroglutamylation. In another aspect, there is provided an anti-myostatin antibody, wherein said antibody comprises an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96% %, 98%, 99%, or 100% sequence identity. In some embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% For example, conservative substitutions), insertions or deletions, but the anti-myostatin antibody comprising the sequence retains the ability to bind to myostatin. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted and / or deleted in SEQ ID NO: 97. In some embodiments, substitution, insertion or deletion occurs in the region outside the HVR. Optionally, the anti-myostatin antibody comprises the VL sequence of SEQ ID NO: 97, including post-translational modifications of the sequence. In a particular embodiment, the VL comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 123; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 71; And (c) one, two or three HVRs selected from HVR-L3 comprising the amino acid sequence of SEQ ID NO: 74. Post-translational modifications include, without limitation, modification of glutamine or glutamate in the N-terminus of the heavy or light chain to pyroglutamic acid by pyroglutamylation.

In another aspect, there is provided an anti-myostatin antibody, wherein said antibody comprises a VH as in any one of the provided embodiments and a VL as in any of the provided embodiments. In one embodiment, the antibody comprises a VH and VL sequence of any one of SEQ ID NOS: 13, 16-30, 32-34 and 86-95 and any one of SEQ ID NOs: 15, 31, 35-38, and 96-99 , And post-translational modifications of these sequences. In one embodiment, the antibody comprises a VH and VL sequence of any one of SEQ ID NOS: 13, 16-30, and 32-34 and SEQ ID NOS: 15, 31, and 35-38, Post-transformation. In one embodiment, the antibody comprises a VH and VL sequence of any one of SEQ ID NOs: 86-95 and SEQ ID NOs: 96-99, respectively, and a post-translational modification of these sequences. Post-translational modifications include, without limitation, modification of glutamine or glutamate in the N-terminus of the heavy or light chain to pyroglutamic acid by pyroglutamylation.

In another aspect, there is provided an anti-myostatin antibody, wherein said antibody comprises a VH as in any one of the provided embodiments and a VL as in any of the provided embodiments. In one embodiment, the antibody comprises the VH and VL sequences of SEQ ID NO: 86 and SEQ ID NO: 96, respectively, and the post-translational modifications of these sequences. In one embodiment, the antibody comprises the VH and VL sequences of SEQ ID NO: 92 and SEQ ID NO: 97, respectively, and post-translational modifications of these sequences. Post-translational modifications include, without limitation, modification of glutamine or glutamate in the N-terminus of the heavy or light chain to pyroglutamic acid by pyroglutamylation.

In another embodiment, the anti-myostatin antibody comprises at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% or more of the amino acid sequence of any one of SEQ ID NO: , 98%, 99%, or 100% sequence identity. In some embodiments, a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% For example, conservative substitutions), insertions or deletions, but the anti-myostatin antibody comprising the sequence retains the ability to bind to myostatin. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted and / or deleted in any one of SEQ ID NOS: 12, 145-150. In some embodiments, substitutions, insertions or deletions occur in the region outside the HVR (i.e., in the FR). Optionally, the anti-myostatin antibody comprises a VH sequence of any one of SEQ ID NOS: 12, 145-150, including post-translational modifications of the sequence. In a particular embodiment, the VH comprises (a) HVR-H1 comprising the amino acid sequence of any one of SEQ ID NOS: 55, 157-162; (b) HVR-H2 comprising the amino acid sequence of any one of SEQ ID NOS: 58, 163-168; And (c) one, two or three HVRs selected from HVR-H3 comprising the amino acid sequence of any one of SEQ ID NOs: 61, 169-174. Post-translational modifications include, without limitation, modification of glutamine or glutamate in the N-terminus of the heavy or light chain to pyroglutamic acid by pyroglutamylation.

In another aspect, there is provided an anti-myostatin antibody, wherein said antibody comprises at least 90%, 91%, 92%, 93%, 94%, 94% (VL) having 95%, 96%, 97%, 98%, 99%, or 100% sequence correspondence. In some embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% For example, conservative substitutions), insertions or deletions, but the anti-myostatin antibody comprising the sequence retains the ability to bind to myostatin. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted and / or deleted in any one of SEQ ID NOS: 14, 151-156. In some embodiments, substitutions, insertions or deletions occur in the region outside the HVR (i.e., in the FR). Optionally, the anti-myostatin antibody comprises a VL sequence of any one of SEQ ID NOs: 14 and 151-156, including post-translational modifications of the sequence. In a specific embodiment, the VH comprises (a) HVR-L1 comprising the amino acid sequence of any one of SEQ ID NO: 65, 175-180; (b) HVR-L2 comprising an amino acid sequence of any one of SEQ ID NOS: 70, 181-186; And (c) one, two or three HVRs selected from HVR-L3 comprising the amino acid sequence of any one of SEQ ID NOs: 73, 187-192. Post-translational modifications include, without limitation, modification of glutamine or glutamate in the N-terminus of the heavy or light chain to pyroglutamic acid by pyroglutamylation.

In another aspect, there is provided an anti-myostatin antibody, wherein said antibody comprises a VH as in any one of the provided embodiments and a VL as in any of the provided embodiments. In one embodiment, the antibody comprises a VH and VL sequence of any one of SEQ ID NO: 12, 145-150 and SEQ ID NO: 14, 151-156, respectively, and a post-translational modification of these sequences. Post-translational modifications include, without limitation, modification of glutamine or glutamate in the N-terminus of the heavy or light chain to pyroglutamic acid by pyroglutamylation.

In some embodiments, an anti-myostatin antibody of the invention comprises a VH as in any one of the above provided embodiments, and a VH of SEQ ID NO: 7, 9, 11, 193, 195-198, 227, 228, 229-381 And a heavy chain constant region comprising any one of the amino acid sequences. In some embodiments, an anti-myostatin antibody of the invention comprises a light chain constant region comprising a VL as in any one of the provided embodiments and a sequence of amino acids of any of SEQ ID NOs: 8 and 10.

In a further aspect, the invention provides an antibody that binds to the same epitope as the anti-myostatin antibody provided herein. In a further aspect, the invention provides an antibody that binds to the same epitope as the antibody described in Table 2a. In a further aspect, the invention provides an antibody that binds to the same epitope as the antibody described in Tables 11a or 13. In some embodiments, an antibody is provided that binds to an epitope in a fragment of a myostatin propeptide consisting of amino acids 21-100 of SEQ ID NO: 78. On the other hand, the antibody may comprise an amino acid sequence selected from the group consisting of amino acids 21-80, 41-100, 21-60, 41-80, 61-100, 21-40, 41-60, 61-80, Binds to the statin propeptide fragment.

In a further aspect of the invention, the anti-myostatin antibody according to any one of the above embodiments is a monoclonal antibody and comprises a chimeric, humanized or human antibody. In one embodiment, the anti-myostatin antibody is an antibody fragment, such as an Fv, Fab, Fab ', scFv, diabody, or F (ab') ₂ fragment. In another embodiment, the antibody is a full-length IgG antibody, such as a complete IgG1 or IgG4 antibody or another antibody class or isotype as defined herein.

In a further aspect, the anti-myostatin antibody according to any one of the above embodiments may comprise either alone or in combination with any of the features as described in the following sections 1-7.

1. Antibody affinity

In certain embodiments, the antibodies provided herein are 1 μM or less, 100 nM or less, 10 nM or less, 1 nM or less, 0.1 nM or less, 0.01 nM or less, or 0.001 nM or less (e.g., 10 ^-8 M or less, e.g. (10 ^-8 M to 10 ^-13 M, for example 10 ^-9 M to 10 ^-13 M) dissociation constants (Kd).

In one embodiment, Kd is measured by radiolabeled antigen binding assay (RIA). In one embodiment, the RIA is performed with a Fab version of the antibody of interest and its antigen. For example, the binding affinity of a Fab in a solution of an antigen can be measured by equilibrating the Fab with a minimum concentration of ( ¹²⁵ I) -labeled antigen in the presence of a series of titrated, unlabeled antigens, followed by anti-Fab antibody- (See, for example, Chen et al., J. Mol. Biol. 293: 865-881 (1999)). To establish the conditions of the assay, a MICROTITER 占 multi-well plate (Thermo Scientific) was added to 5 占 퐂 / ml 50 mM sodium carbonate (pH 9.6) (Cappel Labs) and subsequently blocked with 2% (w / v) bovine serum albumin in PBS for 2 to 5 hours at room temperature (approximately 23 ° C). In a non-adsorptive plate (Nunc # 269620), 100 pM or 26 pM [ ¹²⁵ I] -antigen is mixed with serial dilutions of the Fab of interest (Presta et al., Cancer Res. 57: 4593- 4599 (1997)], consistent with the evaluation of the anti-VEGF antibody, Fab-12. Followed by culturing the Fab of interest overnight; The culture may be continued for a longer period of time (e.g., about 65 hours) to reach equilibrium. Thereafter, the mixture is transferred to the capture plate for incubation (for example, for 1 hour) at room temperature. The solution is then removed and the plate is washed 8 times with 0.1% Polysorbate 20 (Tween-20 (TM)) in PBS. When the plate was dried, 150 [mu] l / well scintillant (MICROSCINT-20) (trademark); Packard) is added and the plate is counted on a TOPCOUNT (trademark) gamma counter (Packard) for 10 minutes. The concentration of each Fab providing less than 20% of the maximal binding is selected for use in competitive binding assays.

According to another embodiment, Kd is measured using Biacore (TM) surface plasmon resonance analysis. Analysis using, for example, Biacore (TM) -2000 or Biacore (TM) -3000 (Biacore (TM), Piscataway, NJ) RU) at 25 < 0 > C using antigen CM5 chip. In one embodiment, a carboxymethylated dextran biosensor chip (CM5, Biacore (TM)) is coupled to the N-ethyl-N '- (3-dimethylaminopropyl) Carbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS). The antigen is diluted to 5 μg / ml (about 0.2 μM) with 10 mM sodium acetate pH 4.8 and then injected at a flow rate of 5 μl / min to achieve a coupled protein of approximately 10 response units (RU). Following antigen injection, 1 M ethanolamine is injected to block unreacted groups. For kinetic measurements, two-fold serial dilutions of Fab (0.78 nM to 500 nM) were incubated with 0.05% Polysorbate 20 (Tween-20 ™) surfactant at 25 ° C. at a flow rate of approximately 25 μl / min in PBS (PBST). The binding rate kon and dissociation rate koff are calculated by fitting the binding and dissociation sensorgrams simultaneously using a simple one-to-one Langmuir binding model (Biacore (TM) evaluation software version 3.2). The parallel dissociation constant (Kd) is calculated as a ratio of k _off / k _on . See, for example, Chen et al., J. Mol. Biol. 293: 865-881 (1999). If it exceeds ^1, the spectrometer the coupling speed, for example, ^stop-the combined rate of 10 ⁶ M ^-1 s by the surface plasmon resonance analysis flow (stop-flow) equipped spectrophotometer (Aviv Instruments ( In PBS, pH 7.2, in the presence of increasing concentrations of antigen as measured in an 8000-series SLM-AMINCO (trademark) spectrophotometer (ThermoSpectronic) with a stir cuvette Can be measured using a fluorescence quenching technique to measure the increase or decrease of the fluorescence emission intensity (excitation = 295 nm; emission = 340 nm, 16 nm pass band) of the antigen antibody (Fab type) at 25 ° C.

2. Antibody fragments

In some embodiments, the antibody provided herein is an antibody fragment. Antibody fragments include, but are not limited to, Fab, Fab ', Fab'-SH, F (ab') ₂ , Fv and scFv fragments, and other fragments described below. For a review of some antibody fragments, see Hudson et al. Nat. Med. 9: 129-134 (2003). For a review of the scFv fragment, see, for example, Pluckthun, in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., (Springer-Verlag, New York), pp. 269-315 (1994); WO 1993/16185; And U.S. Patent No. 5,571,894 and U.S. Patent No. 5,587,458. For a discussion of Fab and F (ab ') ₂ fragments that contain an exogenous receptor binding epitope residues and have increased in vivo half life, see U.S. Patent No. 5,869,046.

A diabody is an antibody fragment having two antigen-binding sites that can be bivalent or bispecific. For example EP 404,097; WO 1993/01161; Hudson et al., Nat. Med. 9: 129-134 (2003); And Hollinger et al., Proc. Natl. Acad. Sci. USA 90: 6444-6448 (1993). Triabodies and tetrabodies are also described in Hudson et al., Nat. Med. 9: 129-134 (2003).

A single-domain antibody is an antibody fragment comprising part or all of the heavy chain variable domain of the antibody or a portion or all of the light chain variable domain. In some embodiments, the single-domain antibody is a human single-domain antibody (see Domantis, Inc., Waltham, MA; see, for example, U.S. Patent No. 6,248,516 B1).

Antibody fragments may be produced by various techniques, for example, by production by recombinant host cells (e. G., E. coli or phage) as well as proteolytic cleavage of whole antibodies, such as, but not limited to, those described herein have.

3. Chimeric  And humanized antibodies

In some embodiments, the antibody provided herein is a chimeric antibody. Some chimeric antibodies are described, for example, in U.S. Patent Nos. 4,816,567; And Morrison et al., Proc. Natl. Acad. Sci. USA 81: 6851-6855 (1984). In one example, the chimeric antibody comprises a non-human variable region (e. G., A variable region derived from a mouse, rat, hamster, rabbit, or non-human primate, such as a monkey) and a human constant region. In a further example, chimeric antibodies are "class-converted" antibodies in which the class or subclass is changed from the case of the parent antibody. Chimeric antibodies include their antigen-binding fragments.

In some embodiments, the chimeric antibody is a humanized antibody. Typically, non-human antibodies are humanized to reduce immunogenicity to humans while maintaining the specificity and affinity of the parent-human antibody. Generally, humanized antibodies include one or more variable domains in which the HVR, e.g., a CDR (or portion thereof) is derived from a non-human antibody and the FR (or portion thereof) is derived from a human antibody sequence. The human antibody will optionally also comprise at least a portion of a human constant region. In some embodiments, some FR residues in the humanized antibody are compared to corresponding residues from a non-human antibody (e. G., An antibody from which the HVR residue is derived) to restore or improve antibody specificity or affinity .

Humanized antibodies and methods for their preparation are described, for example, in Almagro, Front. Biosci. 13: 1619-1633 (2008), for example, Riechmann et al., Nature 332: 323-329 (1988); Queen et al., Proc. Nat'l Acad. Sci. USA 86: 10029-10033 (1989); U.S. Patent No. 5,821,337, U.S. Patent No. 7,527,791, U.S. Patent No. 6,982,321 and U.S. Patent No. 7,087,409; (Kashmiri et al., Methods 36: 25-34 (2005)) (describing specificity determining region (SDR) grafting); Padlan, Mol. Immunol. 28: 489-498 (1991)] (describe "peeling"); Dall'Acqua et al., Methods 36: 43-60 (2005)) (describing "FR shuffling"); And Osbourn et al., Methods 36: 61-68 (2005) and Klimka et al., Br. J. Cancer, 83: 252-260 (2000)) (describing an "induction selection" approach to FR shuffling).

Human framework regions that can be used for humanization include, but are not limited to, selected framework regions (see, for example, Sims et al. J. Immunol. 151: 2296 (1993) ; A framework region (e. G., Carter et al., Proc. Natl. Acad. Sci. USA 89: 4285 (1992)) derived from a common sequence of human subclasses of certain subgroups of light or heavy chain variable regions See Presta et al. J. Immunol. 151: 2623 (1993)); Human maturation (somatic mutation) framework regions or human germline family framework regions (see, for example, Almagro and Fransson, Front. Biosci. 13: 1619-1633 (2008)); And a framework region derived from the selected FR library (see, for example, Baca et al., J. Biol. Chem. 272: 10678-10684 (1997) and Rosok et al., J. Biol. Chem. 271: 22611-22618 (1996)).

4. Human Antibody

In some embodiments, the antibody provided herein is a human antibody. Human antibodies can be generated using a variety of techniques known in the art. Human antibodies are generally described in van Dijk and van de Winkel, Curr. Opin. Pharmacol. 5: 368-374 (2001) and Lonberg, Curr. Opin. Immunol. 20: 450-459 (2008).

Human antibodies can be produced by administering an immunogen to a transgenic animal that has been modified to produce a complete human antibody or a complete antibody having a human variable region in response to an antigen challenge. Such animals typically contain some or all of the human immunoglobulin locus, wherein the locus replaces the endogenous immunoglobulin locus or is chromosomally present or is randomly integrated into the chromosome of the animal. In such transgenic mice, the endogenous immunoglobulin locus was generally inactivated. For a review of methods for obtaining human antibodies from transgenic animals, see Lonberg, Nat. Biotech. 23: 1117-1125 (2005). Also, for example, U.S. Patent No. 6,075,181 and U.S. Patent No. 6,150,584, which describe XENOMOUSE (trademark) technology; U.S. Patent No. 5,770,429, which describes HUMAB (TM) technology; See U.S. Patent No. 7,041,870, which describes K-M Mouse (TM) technology, and U.S. Patent Application Publication No. 2007/0061900, which describes VELOCIMOUSE (TM) technology. The human variable region from the complete antibody produced by such an animal can be further modified, for example, by association with a different human constant region.

Human antibodies can also be prepared by hybridoma-based methods. Human myeloma and mouse-human xenogeneic myeloma cell lines for the production of human monoclonal antibodies have been described (see, for example, Kozbor J. Immunol., 133: 3001 (1984); Brodeur et al., Monoclonal Antibody Production Techniques and Applications, pp. 51-63 (Marcel Dekker, Inc., New York, 1987) and Boerner et al., J. Immunol. 147: 86 (1991)). Human antibodies produced through human B-cell hybridoma technology are also described in Li et al., Proc. Natl. Acad. Sci. USA 103: 3557-3562 (2006). Additional methods are described, for example, in U.S. Patent No. 7,189,826 (which describes the generation of monoclonal human IgM antibodies from hybridoma cell lines) and the method described in Ni, Xiandai Mianyixue 26 (4): 265-268 (2006) -Human hybridomas). ≪ / RTI > Human hybridoma technology (Trioma technology) is also described in Vollmers and Brandlein, Histology and Histopathology 20 (3): 927-937 (2005) and Vollmers and Brandlein, Methods and Findings in Experimental and Clinical Pharmacology 27 3): 185-191 (2005).

Human antibodies can also be generated by isolating Fv clone variable domain sequences selected from among human-derived phage display libraries. The variable domain sequence as described above can then be combined with the desired human constant domain. Techniques for selecting human antibodies from antibody libraries are described below.

5. Library - Derived  Antibody

The antibodies of the invention can be isolated by screening combinatorial libraries for antibodies having the desired activity or activities. For example, various methods are known in the art for generating a phage display library and screening such libraries for antibodies with the desired binding properties. Such methods are described, for example, in Hoogenboom et al. in Methods in Molecular Biology 178: 1-37 (2000); Reviewed in O'Brien et al., Ed., Human Press, Totowa, NJ, 2001, for example McCafferty et al., Nature 348: 552-554; Clackson et al., Nature 352: 624-628 (1991); Marks et al., J. Mol. Biol. 222: 581-597 (1992); (Lo, ed., Human Press, Totowa, N.J., 2003); < RTI ID = 0.0 > Marks and Bradbury, in Methods in Molecular Biology 248: 161-175; Sidhu et al., J. Mol. Biol. 338 (2): 299-310 (2004); Lee et al., J. Mol. Biol. 340 (5): 1073-1093 (2004); Fellouse, Proc. Natl. Acad. Sci. USA 101 (34): 12467-12472 (2004); And Lee et al., J. Immunol. Methods 284 (1-2): 119-132 (2004).

In some phage display methods, repertoires of the VH and VL genes were cloned separately by polymerase chain reaction (PCR) and randomly recombined in a phage library, followed by PCR as described in Winter et al., Ann. Rev. Immunol. 12: 433-455 (1994). ≪ / RTI > Phages typically represent antibody fragments as short chain Fv (scFv) fragments or as Fab fragments. The library from the immunized source provides a high-affinity antibody to the immunogen without the need to make a hybridoma. On the one hand, a single source of antibody can be obtained by cloning a naïve repertoire (e. G. From humans) into a wide variety of non-human immunoglobulins, without any immunization as described in Griffiths et al., EMBO J, 12: 725-734 (1993) Self and also to the self antigen. Finally, the naive library can also be constructed synthetically by cloning non-rearranged V-gene segments from stem cells, encoding highly variable CDR3 regions using PCR primer-containing random sequences, and achieving rearrangement in vitro (Described in Hoogenboom and Winter, J. Mol. Biol. 227: 381-388 (1992)). Patent publications describing human antibody phage libraries are described, for example, in U.S. Patent No. 5,750,373, and U.S. Patent Publications 2005/0079574, 2005/0119455, 2005/0266000, 2007/0117126, 2007/0160598, 2007/0237764, 2007/0292936 , And 2009/0002360.

Antibodies or antibody fragments isolated from human antibody libraries are referred to herein as human antibodies or human antibody fragments.

6. Multispecific antibodies

In some embodiments, the antibodies provided herein are multispecific antibodies, e. G. Bispecific antibodies. A multispecific antibody is a monoclonal antibody having binding specificity for at least two different sites. In some embodiments, one of the binding specificities is for myostatin and the other is for any other antigen. In some embodiments, bispecific antibodies may bind to two different epitopes of myostatin. Bispecific antibodies can also be used to localize cytotoxic agents to cells expressing myostatin. Bispecific antibodies can be prepared as whole-length antibodies or antibody fragments.

Techniques for the preparation of multispecific antibodies include recombinant co-expression of two immunoglobulin heavy-chain pairs with different specificity (Milstein and Cuello, Nature 305: 537 (1983), WO 1993/08829, (See, for example, Traunecker et al., EMBO J. 10: 3655 (1991)), and "hole in handle" engineering (see, for example, U.S. Patent No. 5,731,168). Manipulation of electrostatic steering effects for the production of antibody Fc-heterodimeric molecules (WO 2009 / 089004A1); Cross-linking of two or more antibodies or fragments (see, for example, U.S. Patent No. 4,676,980 and Brennan et al., Science, 229: 81 (1985)); The use of leucine zippers for the production of bispecific antibodies (see, e.g., Kostelny et al., J. Immunol. 148 (5): 1547-1553 (1992)); The use of the "diabody" technique for the production of bispecific antibody fragments (see, for example, Hollinger et al., Proc. Natl. Acad. Sci. USA 90: 6444-6448 (1993)); And the use of short chain Fv (sFv) dimers (see, for example, Gruber et al., J. Immunol. 152: 5368 (1994)); And for example, Tutt et al., J. Immunol. 147: 60 (1991), which is herein incorporated by reference in its entirety.

Engineered antibodies, such as "Octopus antibodies ", having three or more functional antigen binding sites are also included herein (see, e.g., US 2006 / 0025576A1).

The antibody or fragment herein also includes "dual-acting FAb" or "DAF ", which includes an antigen binding site that binds to another, different antigen as well as myostatin (see, for example, US 2008/0069820 ).

7. Antibody variants

In some embodiments, amino acid sequence variants of the antibodies provided herein are contemplated. For example, it may be desirable to improve the binding affinity and / or other biological properties of the antibody. Amino acid sequence variants of the antibody may be prepared by introducing suitable modifications into the nucleotide sequence encoding the antibody, or by peptide synthesis. Such modifications include, for example, deletion from the amino acid sequence of the antibody, and / or insertion into the sequence and / or substitution of the residue in the sequence. Any combination of deletion, insertion and substitution can be performed to arrive at the final structure as long as the final structure has the desired properties, such as antigen-binding.

a. Substitution, insertion and deletion mutants

In some embodiments, antibody variants having one or more amino acid substitutions are provided. Interesting sites for substitutional mutagenesis include HVR and FR. Conservative substitutions are shown in Table 1 under the heading "Preferred substitutions ". More substantial changes are provided in Table 1, under the heading "Exemplary Substitutions ", and as further described below with reference to the amino acid side chain classes. Amino acid substitutions can be introduced into the antibody of interest and the product can be screened for the desired activity, e. G., Maintained / improved antigen binding, reduced immunogenicity, or improved ADCC or CDC.

[Table 1]

Amino acids may also be classified according to their common side chain properties: (1) hydrophobicity: norleucine, Met, Ala, Val, Leu, Ile; (2) Neutral hydrophilic: Cys, Ser, Thr, Asn, Gln; (3) Acid: Asp, Glu; (4) Basicity: His, Lys, Arg; (5) Residues affecting chain orientation: Gly, Pro; (6) Aromatic: Trp, Tyr, Phe. Non-conservative substitutions will involve exchanging members of one of these groups for members of another group.

One type of substitutional variant involves displacing one or more highly variable region residues of a parent antibody (e. G., A humanized or human antibody). Generally, the resulting variant (s) selected for further study has a modification (e. G., Improvement) of some biological properties (e. G. Increased affinity, reduced immunogenicity) relative to the parent antibody /, Or substantially retain some of the biological properties of the parent antibody. Exemplary substitution variants are affinity matured antibodies, which can be conveniently generated using, for example, phage display-substrate affinity maturation techniques, e. G., Those disclosed in the present invention. Briefly, one or more HVR residues are mutated and variant antibodies are displayed on the digestion and screened for a particular biological activity (e. G., Binding affinity).

Alterations (e. G., Substitution) can be performed in the HVR, e. G. To improve antibody affinity. Such modifications may be referred to as HVR "hot spots ", i.e. residues encoded by codons that undergo mutations at high frequency during somatic cell maturation (e.g., Chowdhury, Methods Mol. Biol. 207: 179-196 ), And / or residues contacting the antigen, wherein the resulting modified VH or VL is tested for binding affinity. Affinity maturation by fabrication and re-selection from secondary libraries is described, for example, in Hoogenboom et al. in Methods in Molecular Biology 178: 1-37 (2002)) (O'Brien et al., ed., Human Press, Totowa, NJ, (2001)). In some embodiments of affinity maturation, diversity is introduced into the variable genes selected for maturation by any of a variety of methods (e. G., Error inducing PCR, chain shuffling, or oligonucleotide-directed mutagenesis) . Subsequently, a secondary library is created. The library is then screened to identify any antibody variants with the desired affinity. Another method of introducing diversity involves an HVR-directed approach in which multiple HVR residues (e.g., 4 to 6 residues at a time) are randomized. HVR residues involved in antigen binding can be specifically identified using, for example, alanine injection mutagenesis or modeling. In particular, CDR-H3 and CDR-L3 are often targeted.

In some embodiments, substitution, insertion, or deletion can occur within one or more HVRs, so long as such changes do not substantially reduce the ability of the antibody to bind to the antigen. For example, conservative modifications (e. G. Conservative substitutions as provided herein) that do not substantially reduce binding affinity can be performed in the HVR. Such modifications may be, for example, outside the antigen-contacting residues in the HVR. In some embodiments of the variant VH and VL sequences provided above, each HVR is unaltered or contains 1, 2, or 3 amino acid substitutions.

Methods useful for identifying residues or regions of antibodies that can be targeted for mutagenesis are referred to as "alanine transduction" as described in Cunningham and Wells, Science 244: 1081-1085 (1989). In this method, residues or groups of target residues (e.g., charged residues such as arg, asp, his, lys, and glu) are identified and compared to determine if the interaction of the antigen and antibody is affected Are replaced by neutral or negatively charged amino acids (such as alanine or polyalanine) for measurement. Additional substitutions can be introduced at the amino acid positions to demonstrate functional sensitivity to initial displacement. Alternatively, or in addition, the crystal structure of the antigen-antibody complex can be analyzed to identify the points of contact between the antibody and the antigen. Such contacting residues and neighboring residues can be targeted or removed as replacement candidates. Variants may be screened to determine if the variants contain the desired properties.

Amino acid sequence insertions include sequential insertion of single or multiple amino acid residues as well as amino- and / or carboxy-terminal fusions ranging in length from one residue to a polypeptide containing more than 100 residues. Examples of terminal insertions include antibodies having an N-terminal methionyl residue. Other insertional variants of the antibody molecule include fusion to the N- or C-terminus of the antibody to an enzyme (e.g., for ADEPT) or to a polypeptide that increases the serum half-life of the antibody.

b. Glycosylation variant

In some embodiments, the antibody provided herein is modified to increase or decrease the degree to which the antibody is glycosylated. Addition or deletion of the glycosylation site to the antibody may conveniently be accomplished by altering the amino acid sequence so that one or more glycosylation sites are created or removed.

If the antibody comprises an Fc region, the carbohydrate attached thereto may be altered. Intrinsic antibodies produced by mammalian cells typically contain a branched, double-tactile oligosaccharide that is typically attached by an N-bond to Asn297 of the CH2 domain of the Fc region (see, e. G., Wright et al . TIBTECH 15: refer to 26-32 (1997)). The oligosaccharides include fucose attached to GlcNAc in the "stem" of the double tactical oligosaccharide structure as well as various carbohydrates such as mannose, N-acetylglucosamine (GlcNAc), galactose, and sialic acid can do. In some embodiments, modification of the oligosaccharide in an antibody of the invention may be performed to produce antibody variants with some improved properties.

In one embodiment, antibody variants having carbohydrate structures attached (directly or indirectly) to the Fc region are provided. For example, the amount of fucose in such antibodies may be between 1% and 80%, between 1% and 65%, between 5% and 65%, or between 20% and 40%. The amount of fucose can be determined by comparing the amount of fucose with that of all sugar structures (e. G., Complexes, hybrids and high mannose structures) attached to Asn 297 as measured by MALDI-TOF mass spectrometry as described, for example, in WO 2008/077546. Is calculated by calculating the average amount of fucose in the sugar chains in Asn297. Asn297 refers to the asparagine residue located approximately 297 of the Fc region (Eu numbering of Fc region residues); Asn297 may also be located at about ± 3 amino acids upstream or downstream of position 297, i.e. at positions 294-300 due to small sequence variation in the antibody. Such fucosylation variants may have improved ADCC function. For example, U.S. Publication No. US 2003/0157108 (Presta, L.); US 2004/0093621 (Kyowa Hakko Kogyo Co., Ltd). Examples of publications related to "fusucosylated" or "fucose-deficient" antibody variants are described in US 2003/0157108; WO 2000/61739; WO 2001/29246; US 2003/0115614; US 2002/0164328; US 2004/0093621; US 2004/0132140; US 2004/0110704; US 2004/0110282; US 2004/0109865; WO 2003/085119; WO 2003/084570; WO 2005/035586; WO 2005/035778; WO 2005/053742; WO 2002/031140; Okazaki et al., J. Mol. Biol. 336: 1239-1249 (2004); Yamane-Ohnuki et al., Biotech. Bioeng. 87: 614 (2004). An example of a cell line capable of producing a fucosylated antibody is a protein fucosylated deficient Lec13 CHO cell (Ripka et al., Arch. Biochem. Biophys. 249: 533-545 (1986) Such as the alpha-1,6-fucosyltransferase gene, FUT8, knockout CHO cells (see, for example, WO 01/057108 A1, (Kanda et al., Biotechnol. Bioeng. 94 (4): 680-688 (2006)), and WO < RTI ID = 0.0 > 2003/085107).

Bisected oligosaccharides, such as double-tactile oligosaccharides attached to the Fc region of an antibody, additionally provide antibody variants bisected by GlcNAc. Such antibody variants may have reduced fucosylation and / or improved ADCC function. Examples of such antibody variants are described, for example, in WO 2003/011878 (Jean-Mairet et al.); U.S. Patent No. 6,602,684 (Umana et al.); And US 2005/0123546 (Umana et al.). Also provided are antibody variants having at least one galactose residue in an oligosaccharide attached to said Fc region. Such antibody variants may have improved CDC function. Such antibody variants are described, for example, in WO 1997/30087 (Patel et al.); WO 1998/58964 (Raju, S.); and WO 1999/22764 (Rajesh).

c. Fc region variants

In some embodiments, one or more amino acid modifications can be introduced into the Fc region of an antibody provided herein to generate Fc region variants. The Fc region variant may comprise a human Fc region sequence (e.g., a human IgG1, IgG2, IgG3 or IgG4 Fc region) comprising an amino acid modification (e.g., substitution) at one or more amino acid positions.

In some embodiments, the invention contemplates that some (but not all) effector functions, such as antibody variants, may be used in combination with other agents, such as antibodies, in which the half-life of the antibody is important in vivo, but some effector functions (e.g. complement and ADCC) are desirable candidates for unnecessary or deleterious uses ). ≪ / RTI > In vitro and / or in vivo cytotoxicity assays can be performed to confirm reduction / depletion of CDC and / or ADCC activity. For example, Fc receptor (FcR) binding assays can be performed to ensure that antibodies do not have Fc gamma R binding (and therefore do not have ADCC activity) but retain FcRn binding ability. Primary cells mediating ADCC, NK cells, express only Fc gamma RIII, whereas mononuclear cells express Fc gamma RI, Fc gamma RII and Fc gamma RIII. FcR expression on hematopoietic cells has been described in Ravetch and Kinet, Annu. Rev. Immunol . 9: 457-492 (1991). Non-limiting examples of in vitro assays for assessing ADCC activity of molecules of interest are described in U.S. Patent No. 5,500,362 (e.g., Hellstrom et < RTI ID = 0.0 > al . Proc . Nat'l Acad . Sci . USA 83: 7059-7063 (1986)) and Hellstrom, I et al . , Proc . Nat'l Acad. Sci . USA 82: 1499-1502 (1985); See U.S. Patent No. 5,821,337 (Bruggemann et al . , J. Exp . Med . 166: 1351-1361 (1987)). Alternatively, non-radioactive assay methods may be used (e.g., ACTI (trademark) non-radioactive cytotoxicity assay (CellTechnology, Inc., Mountain View, CA) ; And the CytoTox 96 (TM) non-radioactive cytotoxicity assay (Promega, Madison, Wis.). Effector cells useful in such assays include peripheral blood mononuclear cells (PBMC) and natural killer (NK) cells. Alternatively, or additionally, the ADCC activity of the molecule of interest can be measured in vivo, for example, in Clynes et al . Proc. Nat'l Acad . Sci . USA 95: 652-656 (1998). The C1q binding assay can also be performed to confirm that the antibody can not bind to C1q and therefore lacks CDC activity. See for example the C1q and C3c binding ELISAs of WO 2006/029879 and WO 2005/100402. To assess complement activation, CDC assays may be performed (see, for example, Gazzano-Santoro et al . , J. Immunol . Methods 202: 163 (1996); Cragg et al . , Blood 101: 1045-1052 (2003); And Cragg, Blood 103: 2738-2743 (2004)). FcRn binding and in vivo elimination / half-life measurements can also be performed using methods known in the art (see, for example, Petkova et al . , Int'l . Immunol . 18 (12): 1759-1769 (2006)).

Antibodies with reduced effector function include those with substitutions of one or more of Fc region residues 238, 265, 269, 270, 297, 327 and 329 (US Pat. No. 6,737,056). Such Fc mutants include the so-called "DANA" Fc mutants with substitutions of residues 265 and 297 to alanine, with Fc mutants having substitutions at two or more of amino acid positions 265, 269, 270, 297 and 327 U.S. Patent No. 7,332,581).

Several antibody variants with improved or reduced binding to FcR have been disclosed (see, for example, U.S. Patent No. 6,737,056; WO 2004/056312, and Shields et al., J. Biol. Chem. ): 6591-6604 (2001)).

In some embodiments, the antibody variant comprises an Fc region having one or more amino acid substitutions that improve ADCC, for example, substitutions at positions 298, 333 and / or 334 (EU numbering of residues) of said Fc region.

In some embodiments, for example, U.S. Patent No. 6,194,551, WO 99/51642, and Idusogie et al . J. Immunol . 164: 4178-4184 (2000)], in the Fc region, to produce altered (i.e., improved or reduced) C1q binding and / or complement dependent cytotoxicity (CDC).

Increased half-life and neonatal Fc receptor (FcRn) (responsible for delivery of parent IgG to fetus) (Guyer et al. , J. Immunol . 117: 587 (1976) and Kim et al. , J Immunol. 24: 249 (1994)) are disclosed in US2005 / 0014934 (Hinton et al.). The antibodies comprise the Fc region having one or more substitutions that improve the binding of the Fc region to FcRn. Such Fc variants may have Fc region residues 238, 256, 265, 272, 286, 303, 305, 307, 311, 312, 317, 340, 356, 360, 362, 376, 378, 380, 382, 413, 424, and 434, e.g., substitutions at Fc region residue 434 (U. S. Patent No. 7,371, 826). Also see Duncan, Nature 322: 738-40 (1988) on other examples of Fc region variants; U.S. Patent No. 5,648,260 and U.S. Patent No. 5,624,821; And WO 94/29351.

d. Cysteine engineered antibody variants

In some embodiments, it may be desirable to generate a "thio MAb" in which one or more residues of a cysteine engineered antibody, e. G., An antibody, is substituted with a cysteine residue. In certain embodiments, the substituted residue is present at an accessible site of the antibody. By displacing the residue with a cysteine, a reactive thiol group is located at an accessible site of the antibody, and using it, the antibody is conjugated to another moiety, such as a drug moiety or linker-drug moiety, as further disclosed herein An immunoconjugate can be generated. In some embodiments, any one or more of the following residues may be substituted with cysteine: V205 of the light chain (Kabat numbering); A118 of the heavy chain (EU numbering); And S400 (EU numbering) of the heavy chain Fc region. Cysteine engineered antibodies can be generated, for example, as disclosed in U.S. Patent No. 7,521,541.

e. Antibody derivative

In some embodiments, the antibodies provided herein can be further modified to include additional non-proteinaceous moieties known in the art and readily available. Suitable moieties for the derivatization of the antibody include, but are not limited to, water soluble polymers. Non-limiting examples of water soluble polymers include, but are not limited to, polyethylene glycol (PEG), copolymers of ethylene glycol / propylene glycol, carboxymethylcellulose, dextran, polyvinyl alcohol, polyvinylpyrrolidone, Propylene glycol (propylene glycol), polyoxyethylene (propylene glycol), polyoxyethylene (polyoxypropylene), polyoxyethylene (polyoxyethylene) Homopolymers, polypropylene oxide / ethylene oxide copolymers, polyoxyethylated polyols (e.g., glycerol), polyvinyl alcohol, and mixtures thereof. Polyethylene glycol propionaldehyde may have advantages in manufacturing due to its water stability. The polymer may have any molecular weight and may be branched or unbranched. The number of polymers attached to the antibody can vary and, if more than one polymer is attached, these polymers can be the same or different molecules. In general, the number and / or type of polymers used in the derivatization should be limited, including the specific nature of the antibody to which it is to be improved, whether the antibody derivative is to be used in therapy under defined conditions, Can be determined by reference.

In another embodiment, there is provided a conjugate of an antibody and a non-proteinaceous moiety that can be selectively heated by exposure to radiation. In one embodiment, the non-proteinaceous moiety is a carbon nanotube (Kam et al. , Proc. Natl. Acad. Sci. USA 102: 11600-11605 (2005)). The radiation may have any wavelength and includes, but is not limited to, a wavelength that is not harmful to normal cells but heats the non-proteinaceous moiety to a temperature at which it kills cells close to the antibody-non-proteinaceous moiety.

8. Variant Fc region

In one aspect, the invention provides an isolated polypeptide comprising a variant Fc region having increased Fc gamma RIIb-binding activity. In some embodiments, the polypeptide is an antibody. In some embodiments, the polypeptide is an Fc fusion protein. In some embodiments, the variant Fc region comprises at least one amino acid residue change (e.g., substitution) relative to a corresponding sequence in a native or reference variant sequence (sometimes collectively referred to herein as the "parent" Fc region) . In some embodiments, the variant Fc region of the invention has increased binding activity to monkey Fc gamma RIIb relative to the parent Fc region. In a particular embodiment, the monkey Fc gamma RIIb is Cynomolgus monkey Fc gamma RIIb (SEQ ID NO: 223).

In some embodiments, the ratio of [KD value of parent Fc region to monkey Fc gamma RIIb] / [KD value of variant Fc region to monkey Fc gamma RIIb] is at least 2.0, at least 3.0, at least 4.0, at least 5.0, at least 6.0 Or more, 7.0 or more, 8.0 or more, 9.0 or more, 10 or more, 15 or more, 20 or more, 25 or more, 30 or more, 40 or more or 50 or more. In a further embodiment, the variant Fc region has reduced binding activity to monkey Fc gamma RIIIa. In some embodiments, the ratio of [KD value of parent Fc region to monkey Fc gamma RIIIa] / [KD value of variant Fc region to monkey Fc gamma RIIIa] is less than 0.50, less than 0.40, less than 0.30, less than 0.20, less than 0.10 Or less, 0.09 or less, 0.08 or less, 0.07 or less, 0.06 or less, 0.05 or less, 0.04 or less, 0.03 or less, 0.02 or less, or 0.01 or less. In some embodiments, the monkey Fc gamma RIIb has the sequence of SEQ ID NO: 223 (Cynomolgus monkey). In some embodiments, the monkey Fc gamma RIIIa has the sequence of SEQ ID NO: 224 (Cynomolgus monkey).

In a further embodiment, the variant Fc region has increased binding activity to human Fc gamma RIIb. In some embodiments, the ratio of [KD value of parent Fc region to human Fc gamma RIIb] / KD value of mutant Fc region to human Fc gamma RIIb is at least 2.0, at least 3.0, at least 4.0, at least 5.0, at least 6.0 Or more, 7.0 or more, 8.0 or more, 9.0 or more, 10 or more, 15 or more, 20 or more, 25 or more, 30 or more, 40 or more or 50 or more. In a further embodiment, the variant Fc region has reduced binding activity to human Fc gamma RIIIa. In some embodiments, the ratio of [KD value of parent Fc region to human Fc gamma RIIIa] / [KD value of variant Fc region to human Fc gamma RIIIa] is less than 0.50, less than 0.40, less than 0.30, less than 0.20, less than 0.10 Or less, 0.09 or less, 0.08 or less, 0.07 or less, 0.06 or less, 0.05 or less, 0.04 or less, 0.03 or less, 0.02 or less, or 0.01 or less. In some embodiments, the human Fc gamma RIIb has the sequence of SEQ ID NO: 212, 213 or 214. In some embodiments, the human Fc gamma RIIIa has the sequence of SEQ ID NO: 215, 216, 217 or 218.

In a further embodiment, the variant Fc region has reduced binding activity for human Fc gamma RIIa (H form) than for human Fc gamma RIIb. In some embodiments, the ratio of [KD value of parent Fc region to human Fc gamma RIIa (H form)] / [KD value of variant Fc region to human Fc gamma RIIa (H form)] is 5.0 or less, 4.0 or less , 3.0 or less, 2.0 or less, 1.0 or less, 0.9 or less, 0.8 or less, 0.7 or less, 0.6 or less, 0.5 or less, 0.4 or less, 0.3 or less, 0.2 or less or 0.1 or less. In a further embodiment, the variant Fc region has reduced binding activity for human Fc gamma RIIa (R form) than for human Fc gamma RIIb. In some embodiments, the ratio of [KD value of parent Fc region to human Fc gamma RIIa (R form)] / [KD value of variant Fc region to human Fc gamma RIIa (R form)] is 5.0 or less, 4.0 or less , 3.0 or less, 2.0 or less, 1.0 or less, 0.9 or less, 0.8 or less, 0.7 or less, 0.6 or less, 0.5 or less, 0.4 or less, 0.3 or less, 0.2 or less or 0.1 or less. In some embodiments, the human Fc gamma RIIa (H form) has the sequence of SEQ ID NO: 211. In some embodiments, the human Fc gamma RIIa (R form) has the sequence of SEQ ID NO: 210.

In some embodiments, the ratio of [KD value of parent Fc region to monkey Fc gamma RIIa] / [KD value of variant Fc region to monkey Fc gamma RIIa] is at least 2.0, at least 3.0, at least 4.0, at least 5.0, at least 6.0 Or more, 7.0 or more, 8.0 or more, 9.0 or more, 10 or more, 15 or more, 20 or more, 25 or more, 30 or more, 40 or more or 50 or more. In some embodiments, the monkey Fc gamma RIIa is selected from the group consisting of the monkey Fc gamma RIIa1 (e.g., cynomolgus Fc gamma RIIa1 (SEQ ID NO: 220)), the monkey Fc gamma RIIa2 (e.g. cynomolgus Fc gamma RIIa2 ), And the monkey Fc gamma RIIa3 (e.g., cynomolgus Fc gamma RIIa3 (SEQ ID NO: 222)).

In another embodiment, the KD value of the monkey variant Fc region for Fc gamma RIIb is 1.0x10 ^-6 M or less, 9.0x10 ^-7 M or less, 8.0x10 ^-7 M or less, 7.0x10 ^-7 M or less, 6.0x10 ^{- 7} M or less, it can be not more than 5.0x10 ^-7 M or less, 4.0x10 ^-7 M or less, 3.0x10 ^-7 M or less, 2.0x10 ^-7 M, alternatively no more than 1.0x10 ^-7 M. In another embodiment, the Fc monkey KD value of the variant Fc region of the gamma RIIIa is 5.0x10 ^-7 M or more, more than 6.0x10 ^-7 M, 7.0x10 ^-7 M or more, more than 8.0x10 ^-7 M, 9.0x10 ^{- 7} M or more, more than 1.0x10 ^-6 M, 2.0x10 ^-6 M or more, more than 3.0x10 ^-6 M, 4.0x10 ^-6 or more M, 5.0x10 ^-6 or more M, 6.0x10 ^-6 or more M, 7.0x10 ^-6 M or more, 8.0 x 10 ^-6 M or more, 9.0 x 10 ^-6 M or more, or 1.0 x 10 ^-5 M or more. In another embodiment, KD value of the variant Fc region to human Fc gamma RIIb is 2.0x10 ^-6 M or less, 1.0x10 ^-6 M or less, 9.0x10 ^-7 M or less, 8.0x10 ^-7 M or less, 7.0x10 ^{- 7} M or less, it can be not more than 6.0x10 ^-7 M or less, 5.0x10 ^-7 M or less, 4.0x10 ^-7 M or less, 3.0x10 ^-7 M or less, 2.0x10 ^-7 M, alternatively no more than 1.0x10 ^-7 M. In another embodiment, KD value of the variant Fc region to human Fc gamma RIIIa is more than 1.0x10 ^-6 M, 2.0x10 ^-6 M or more, more than 3.0x10 ^-6 M, 4.0x10 ^-6 M or more, 5.0x10 ^- more than ⁶ M, 6.0x10 least ^-6 M, 7.0x10 ^-6 M or more, 8.0x10 least ^-6 M, 9.0x10 least ^-6 M, 1.0x10 ^-5 or more M, 2.0x10 ^-5 or more M, 3.0x10 ^-5 M or more, 4.0 x 10 ^-5 M or more, or 5.0 x 10 ^-5 M or more. In another embodiment, the human Fc gamma KD value of the variant Fc region for RIIa (H-type) is 1.0x10 ^-7 M or more, more than 2.0x10 ^-7 M, 3.0x10 ^-7 M or more, more than 4.0x10 ^-7 M , 5.0x10 least ^-7 M, 6.0x10 ^-7 M or more, 7.0x10 ^-7 M or more, 8.0x10 ^-7 M or more, 9.0x10 ^-7 M or more, 1.0x10 least ^-6 M, 2.0x10 ^-6 M or more, 3.0 x 10 ^-6 M or more, 4.0 x 10 ^-6 M or more, or 5.0 x 10 ^-6 M or more. In another embodiment, the human Fc gamma KD value of the variant Fc region for RIIa (R-type) is 2.0x10 ^-7 M or more, more than 3.0x10 ^-7 M, 4.0x10 ^-7 M or more, more than 5.0x10 ^-7 M , 6.0x10 least ^-7 M, 7.0x10 ^-7 M or more, 8.0x10 ^-7 M or more, 9.0x10 ^-7 M or more, 1.0x10 least ^-6 M, 2.0x10 ^-6 or more M, 3.0x10 ^-6 M or more, 4.0 x 10 ^-6 M or more, or 5.0 x 10 ^-6 M or more.

In another embodiment, the KD value of the monkey variant Fc region for Fc gamma RIIa is 1.0x10 ^-6 M or less, 9.0x10 ^-7 M or less, 8.0x10 ^-7 M or less, 7.0x10 ^-7 M or less, 6.0x10 ^{- 7} M or less, it can be not more than 5.0x10 ^-7 M or less, 4.0x10 ^-7 M or less, 3.0x10 ^-7 M or less, 2.0x10 ^-7 M, alternatively no more than 1.0x10 ^-7 M. In some embodiments, monkey Fc gamma RIIa can be selected from any one of monkey Fc gamma RIIa1, monkey Fc gamma RIIa2, and monkey Fc gamma RIIa3.

When developing drugs for the treatment of human disease, an assessment of its efficacy and safety in monkeys is important because of its biological proximity to humans. From the above viewpoint, the drug to be developed may desirably have cross-reactivity to both human and monkey in the target binding activity.

Refers to a receptor capable of binding to the Fc region of an IgG1, IgG2, IgG3, and IgG4 monoclonal antibody, wherein the Fc gamma receptor gene (referred to herein as the Fc gamma receptor, Fc gamma R or FcgR) ≪ RTI ID = 0.0 > and / or < / RTI > In humans, Fc gamma RI (CD64), which includes homologous Fc gamma RIa, Fc gamma RIb and Fc gamma RIc, Fc gamma RII (CD32), including homologous Fc gamma RIIa (including allotype H131 (H type) and R131 (type R)), Fc gamma RIIb (including Fc gamma RIIb-1 and Fc gamma RIIb- ); And Fc gamma RIII (CD16) including homologous Fc gamma RIIIa (including allotypes V158 and F158), and Fc gamma RIIIb (including allotype Fc gamma RIIIb-NA1 and Fc gamma RIIIb-NA2) Human Fc gamma R, Fc gamma R isotype or allotype. Fc gamma RIIb1 and Fc gamma RIIb2 have been reported as a joining variant of human Fc gamma RIIb. Also, an eukaryotic variant termed Fc gamma RIIb3 has been reported (J Exp Med, 1989, 170: 1369-1385). In addition to these joining variants, human Fc gamma RIIb contains all of the joining variants (NP_001002273.1, NP_001002274.1, NP_001002275.1, NP_001177757.1, and NP_003992.3) registered with the NCBI. Furthermore, human Fc gamma RIIb has been shown to be effective in all of the previously reported genetic polymorphisms as well as in Fc gamma RIIb (Arthritis Rheum. 48: 3242-3252 (2003); Kono et al., Hum. 14: 2881-2892 (2005); and Kyogoju et al., Arthritis Rheum. 46: 1242-1254 (2002)) and all subsequently reported genetic polymorphisms.

In Fc gamma RIIa, there are two allotypes, one of which is histidine (H-form) at position 131 of Fc gamma RIIa and the other of which is substituted by arginine at position 131 (R form) (Warrmerdam, J. Exp. Med. 172: 19-25 (1990)).

The Fc gamma R can be derived from any organism, including, but not limited to, human, mouse, rat, rabbit and monkey-derived Fc gamma. The mouse Fc gamma R is an Fc gamma R homologue of Fc gamma RI (CD64), Fc gamma RII (CD32), Fc gamma RIII (CD16) and Fc gamma RIII- But are not limited to these. Unless otherwise specified, the term "monkey Fc gamma R" or its variants refers to the Cynomorphous Fc gamma RIIa1 (SEQ ID NO: 220), Fc gamma RIIa2 (SEQ ID NO: 221), Fc gamma RIIa3 (SEQ ID NO: 222) RIIb (SEQ ID NO: 223) or Fc gamma RIIIaS (SEQ ID NO: 224).

The polynucleotide sequence of human Fc gamma RI is set forth in SEQ ID NO: 199 (NM_000566.3); The polynucleotide sequence of human Fc gamma RIIa is presented in SEQ ID NO: 200 (BC020823.1) or SEQ ID NO: 201 (NM_001136219.1); The polynucleotide sequence of human Fc gamma RIIb is presented in SEQ ID NO: 202 (BC146678.1) or SEQ ID NO: 203 (NM_004001.3); The polynucleotide sequence of human Fc gamma RIIIa is presented in SEQ ID NO: 204 (BC033578.1) or SEQ ID NO: 205 (NM_001127593.1); The polynucleotide sequence of human Fc gamma RIIIb is set forth in SEQ ID NO: 206 (BC128562.1).

The amino acid sequence of human Fc gamma RI is set forth in SEQ ID NO: 207 (NP_000557.1); The amino acid sequence of human Fc gamma RIIa is set forth in SEQ ID NO: 208 (AAH20823.1), SEQ ID NO: 209, SEQ ID NO: 210 or SEQ ID NO: 211; The amino acid sequence of human Fc gamma RIIb is set forth in SEQ ID NO: 212 (AAI46679.1), SEQ ID NO: 213 or SEQ ID NO: 214; The amino acid sequence of human Fc gamma RIIIa is set forth in SEQ ID NO: 215 (AAH33678.1), SEQ ID NO: 216, SEQ ID NO: 217 or SEQ ID NO: 218; The amino acid sequence of human Fc gamma RIIIb is set forth in SEQ ID NO: 219 (AAI28563.1).

The amino acid sequence of synomolcus monkey Fc gamma RIIa is presented in SEQ ID NO: 220 (Fc gamma RIIa1), SEQ ID NO: 221 (Fc gamma RIIa2) or SEQ ID NO: 222 (Fc gamma RIIa3); The amino acid sequence of Cynomolgus Fc gamma RIIb is set forth in SEQ ID NO: 223; The amino acid sequence of Cynomolgus monkey Fc gamma RIIIa is set forth in SEQ ID NO: 224.

In one aspect, the invention provides a polypeptide comprising a variant Fc region having increased Fc gamma RIIb-binding activity relative to a corresponding reference Fc gamma RIIb-binding polypeptide. In a further aspect, the polypeptides of the present invention are characterized by having an amino acid sequence at 231, 232, 233, 234, 235, 236, 237, 238, 239, 264, 266, 267, 268, 271, 295, 298, 325, 326 , 327, 328, 330, 331, 332, 334, and 396. In one embodiment, In some embodiments, the Fc gamma RIIb has the sequence of the synomolgus monkey Fc gamma RIIb (SEQ ID NO: 223). In some embodiments, the Fc gamma RIIb has the sequence of human Fc gamma RIIb (SEQ ID NO: 212, 213, or 214).

(A) one amino acid change at position 236, and (b) 231, 232, 233, 234, 235, 236, 237, 238, 239, 264, 266, At least two amino acids comprising at least one amino acid change in at least one position selected from the group consisting of SEQ ID NOs: 267, 268, 271, 295, 298, 325, 326, 327, 328, 330, 331, 332, 334, Lt; RTI ID = 0.0 > Fc < / RTI > gamma RIIb-binding activity. In some embodiments, the Fc gamma RIIb has the sequence of the synomolgus monkey Fc gamma RIIb (SEQ ID NO: 223). In some embodiments, the Fc gamma RIIb has the sequence of human Fc gamma RIIb (SEQ ID NO: 212, 213, or 214).

In one aspect, the invention provides a polypeptide comprising a variant Fc region having increased Fc gamma RIIb-binding activity comprising an amino acid change at position 236 according to EU numbering.

In one embodiment, the present invention provides a polypeptide comprising (a) one amino acid modification at position 236, and (b) at least one amino acid modification at position 231, 232, 235, 239, 268, 295, 298, 326, 330, A variant Fc region having an increased Fc gamma RIIb-binding activity comprising at least two amino acid modifications comprising at least one amino acid alteration in at least one position selected from the group consisting of: In a further embodiment, the variant Fc region comprises an amino acid alteration of at least one position selected from the group consisting of 231, 232, 235, 239, 268, 295, 298, 326, 330, and 396 according to EU numbering . In a further embodiment, said variant Fc region comprises an amino acid alteration of at least one position selected from the group consisting of 268, 295, 326 and 330 according to EU numbering. In some embodiments, the Fc gamma RIIb has the sequence of the synomolgus monkey Fc gamma RIIb (SEQ ID NO: 223). In some embodiments, the Fc gamma RIIb has the sequence of human Fc gamma RIIb (SEQ ID NO: 212, 213, or 214).

In another aspect, the invention provides a polypeptide comprising a variant Fc region having an increased Fc gamma RIIb-binding activity comprising an amino acid alteration according to any of the following (1) to (37) according to EU numbering : (1) positions 231, 236, 239, 268 and 330; (2) positions 231, 236, 239, 268, 295 and 330; (3) positions 231, 236, 268 and 330; (4) positions 231, 236, 268, 295 and 330; (5) 232, 236, 239, 268, 295 and 330 positions; (6) 232, 236, 268, 295 and 330 positions; (7) 232, 236, 268 and 330 positions; (8) positions 235, 236, 268, 295, 326 and 330; (9) positions 235, 236, 268, 295 and 330; (10) positions 235, 236, 268 and 330; (11) positions 235, 236, 268, 330, and 396; (12) positions 235, 236, 268 and 396; (13) positions 236, 239, 268, 295, 298 and 330; (14) positions 236, 239, 268, 295, 326 and 330; (15) positions 236, 239, 268, 295 and 330; (16) positions 236, 239, 268, 298 and 330; (17) positions 236, 239, 268, 326 and 330; (18) positions 236, 239, 268 and 330; (19) positions 236, 239, 268, 330 and 396; (20) positions 236, 239, 268 and 396; (21) positions 236 and 268; (22) positions 236, 268 and 295; (23) positions 236, 268, 295, 298 and 330; (24) positions 236, 268, 295, 326 and 330; (25) positions 236, 268, 295, 326, 330, and 396; (26) positions 236, 268, 295 and 330; (27) positions 236, 268, 295, 330 and 396; (28) positions 236, 268, 298 and 330; (29) positions 236, 268, 298 and 396; (30) positions 236, 268, 326 and 330; (31) positions 236, 268, 326, 330, and 396; (32) positions 236, 268 and 330; (33) positions 236, 268, 330, and 396; (34) positions 236, 268 and 396; (35) positions 236 and 295; (36) positions 236, 330 and 396; And (37) positions 236 and 396. In some embodiments, the Fc gamma RIIb has the sequence of the synomolgus monkey Fc gamma RIIb (SEQ ID NO: 223). In some embodiments, the Fc gamma RIIb has the sequence of human Fc gamma RIIb (SEQ ID NO: 212, 213, or 214).

In a further embodiment, the variant Fc region having the increased Fc gamma RIIb-binding activity is selected from the group consisting of (a) Asp, Glu, Phe, Gly, His, Ile, Lys, Leu, Met , Asn, Pro, Gln, Arg, Ser, Thr, Val, Trp, Tyr; (b) Ala, Asp, Glu, Phe, Gly, His, Ile, Lys, Leu, Met, Asn, Gln, Arg, Ser, Thr, Val, Trp, Tyr at position 232; (c) Asp at position 233; (d) Trp, Tyr at position 234; (e) Trp at position 235; (f) Ala, Asp, Glu, His, Ile, Leu, Met, Asn, Gln, Ser, Thr, Val at position 236; (g) Asp at position 237, Tyr; (h) Glu, Ile, Met, Gln, Tyr at position 238; (i) Ile, Leu, Asn, Pro, Val at position 239; (j) Ile at position 264; (k) Phe at position 266; (l) Ala, His, Leu at position 267; (m) Asp at position 268, Glu; (n) Asp, Glu, Gly at position 271; (o) Leu at position 295; (p) Leu at position 298; (q) Glu, Phe, Ile, Leu at position 325; (r) Thr at position 326; (s) Ile, Asn at position 327; (t) Thr at position 328; (u) Lys, Arg at position 330; (v) Glu at position 331; (w) Asp at position 332; (x) Asp, Ile, Met, Val, Tyr at position 334; And (y) at least one selected from the group consisting of Ala, Asp, Glu, Phe, Gly, His, Ile, Lys, Leu, Met, Asn, Gln, Arg, Ser, Thr, Val, Trp and Tyr at position 396 ≪ / RTI > In some embodiments, the Fc gamma RIIb has the sequence of the synomolgus monkey Fc gamma RIIb (SEQ ID NO: 223). In some embodiments, the Fc gamma RIIb has the sequence of human Fc gamma RIIb (SEQ ID NO: 212, 213, or 214).

In a further embodiment, the variant Fc region having the increased Fc gamma RIIb-binding activity is selected from the group consisting of (a) Gly, Thr at position 231; (b) Asp at position 232; (c) Trp at position 235; (d) Asn, Thr at position 236; (e) Val at position 239; (f) Asp at position 268, Glu; (g) Leu at position 295; (h) Leu at position 298; (i) Thr at position 326; (j) Lys, Arg at position 330; And (k) at least one amino acid change (e.g., substitution) selected from the group consisting of Lys and Met at position 396. In a further embodiment, the variant Fc region having the increased Fc gamma RIIb-binding activity has Asn at position 236, Glu at position 268, Lys at position 330, and Met at position 396, according to EU numbering (E. G., Substitution). In a further embodiment, the variant Fc region having the increased Fc gamma RIIb-binding activity is selected from the group consisting of Asn at position 236, Asp at position 268, and amino acid modification of Lys at position 330 Lt; / RTI > substitution). In a further embodiment, the variant Fc region having the increased Fc gamma RIIb-binding activity is selected from Asn at position 236, Asp at position 268, Leu at position 295, and Lys at position 330 according to EU numbering (E. G., Substitution). In a further embodiment, the variant Fc region having the increased Fc gamma RIIb-binding activity is selected from the group consisting of Thr at position 236, Asp at position 268, and amino acid modification of Lys at position 330 Lt; / RTI > substitution). In a further embodiment, the variant Fc region having the increased Fc gamma RIIb-binding activity has Asn at position 236, Asp at position 268, Leu at position 295, Thr at position 326, And amino acid alterations (e. G., Substitution) of Lys at position < RTI ID = 0.0 > 330. < / RTI > In a further embodiment, the variant Fc region having the increased Fc gamma RIIb-binding activity is selected from the group consisting of Trp at position 235, Asn at position 236, Asp at position 268, Leu at position 295, Thr at position 326, and amino acid modification (e.g., substitution) of Lys at position 330.

In one aspect, the invention provides a polypeptide comprising a variant Fc region having an increased Fc gamma RIIb-binding activity comprising an amino acid change at position 238 according to EU numbering.

In one embodiment, the present invention provides an enhanced Fc gamma RIIb-1 mutant comprising at least one amino acid change in at least one position selected from the group consisting of 234, 238, 250, 264, 267, 307, and 330 according to EU numbering. A variant Fc region having a binding activity. In a further embodiment, the polypeptide comprises an amino acid modification of at least one position selected from the group consisting of 234, 250, 264, 267, 307 and 330 according to EU numbering. In some embodiments, the Fc gamma RIIb has the sequence of the synomolgus monkey Fc gamma RIIb (SEQ ID NO: 223). In some embodiments, the Fc gamma RIIb has the sequence of human Fc gamma RIIb (SEQ ID NO: 212, 213, or 214).

In another aspect, the invention provides a polypeptide comprising a variant Fc region having an increased Fc gamma RIIb-binding activity comprising an amino acid alteration according to EU Numbering, comprising any one of the following (1) to (9) (1) positions 234, 238, 250, 307 and 330; (2) positions 234, 238, 250, 264, 307 and 330; (3) positions 234, 238, 250, 264, 267, 307 and 330; (4) positions 234, 238, 250, 267, 307 and 330; (5) positions 238, 250, 264, 307 and 330; (6) positions 238, 250, 264, 267, 307 and 330; (7) positions 238, 250, 267, 307 and 330; (8) positions 238, 250 and 307; And (9) positions 238, 250, 307 and 330. In some embodiments, the Fc gamma RIIb has the sequence of the synomolgus monkey Fc gamma RIIb (SEQ ID NO: 223). In some embodiments, the Fc gamma RIIb has the sequence of human Fc gamma RIIb (SEQ ID NO: 212, 213, or 214).

In a further embodiment, the variant Fc region having the increased Fc gamma RIIb-binding activity is selected from the group consisting of: (a) Tyr at position 234; (b) Asp at position 238; (c) Val at position 250; (d) Ile at position 264; (e) Ala at position 267; (f) Pro at position 307; And (g) Lys at position 330. In another embodiment of the invention, In a further embodiment, the variant Fc region having the increased Fc gamma RIIb-binding activity comprises an amino acid alteration (e. G., Substitution) of Asp at position 238 according to EU numbering. In a further embodiment, the variant Fc region having the increased Fc gamma RIIb-binding activity is selected from the group consisting of Asp at position 238, Val at position 250, and amino acid at position 307, according to EU numbering Lt; / RTI > substitution). In a further embodiment, the variant Fc region having the increased Fc gamma RIIb-binding activity is selected from Asp at position 238, Val at position 250, Pro at position 307, and Lys at position 330 in accordance with EU numbering (E. G., Substitution). In a further embodiment, the variant Fc region having the increased Fc gamma RIIb-binding activity is selected from the group consisting of Asp at position 238, Val at position 250, Ile at position 264, Pro at position 307, And amino acid alterations (e. G., Substitution) of Lys at position < RTI ID = 0.0 > 330. < / RTI > In a further embodiment, the variant Fc region having the increased Fc gamma RIIb-binding activity is selected from the group consisting of Asp at position 238, Val at position 250, Ala at position 267, Pro at position 307, And amino acid alterations (e. G., Substitution) of Lys at position < RTI ID = 0.0 > 330. < / RTI > In a further embodiment, the variant Fc region having the increased Fc gamma RIIb-binding activity is selected from the group consisting of Tyr at position 234, Asp at position 238, Val at position 250, Pro at position 307, And amino acid alterations (e. G., Substitution) of Lys at position < RTI ID = 0.0 > 330. < / RTI > In a further embodiment, the variant Fc region having the increased Fc gamma RIIb-binding activity is selected from the group consisting of Tyr at position 234, Asp at position 238, Val at position 250, Ala at position 267, Pro at position 307, and amino acid modification (e.g., substitution) of Lys at position 330. In a further embodiment, the variant Fc region having the increased Fc gamma RIIb-binding activity is selected from the group consisting of Asp at position 238, Val at position 250, Ile at position 264, Ala at position 267, Pro at position 307, and amino acid modification (e.g., substitution) of Lys at position 330. In a further embodiment, the variant Fc region having the increased Fc gamma RIIb-binding activity is selected from the group consisting of Tyr at position 234, Asp at position 238, Val at position 250, Ile at position 264, Pro at position 307, and amino acid modification (e.g., substitution) of Lys at position 330. In a further embodiment, the variant Fc region having the increased Fc gamma RIIb-binding activity is selected from the group consisting of Tyr at position 234, Asp at position 238, Val at position 250, Ile at position 264, Ala at position 267, Pro at position 307, and amino acid modification (e.g., substitution) of Lys at position 330. In some embodiments, the Fc gamma RIIb has the sequence of the synomolgus monkey Fc gamma RIIb (SEQ ID NO: 223). In some embodiments, the Fc gamma RIIb has the sequence of human Fc gamma RIIb (SEQ ID NO: 212, 213, or 214).

In another aspect, the invention provides an isolated polypeptide comprising a variant Fc region having an increased isoelectric point (pI). In some embodiments, the variant Fc region described herein comprises at least two amino acid changes in the parent Fc region. In some embodiments, the amino acid alterations each increase the isoelectric point (pi) of the variant Fc region relative to the case of the parent Fc region. This is based on the discovery that removal of the antigen from the plasma can be facilitated by the antibody having an increased pi by, for example, modification of at least two amino acid residues upon administration of the antibody in vivo.

In the present invention, pi may be a theoretical or experimentally measured pi. The value of the pi may be measured, for example, by isoelectric focusing known to those skilled in the art. The value of the theoretical pI can be calculated using, for example, gene and amino acid sequence analysis software (Genetyx, etc.).

In one embodiment, the pI is at least 0.01, 0.03, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5 or more, at least 0.6, 0.7, 0.8, 0.9 or more, at least 1.0, 1.1 , 1.2, 1.3, 1.4, 1.5 or more, or at least 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 3.0 or more.

In some embodiments, the amino acid can be exposed on the surface of the variant Fc region for increased pi. In the present invention, the amino acid that can be exposed on the surface is generally referred to as an amino acid residue located on the surface of the polypeptide constituting the variant Fc region. The amino acid residue located on the surface of the polypeptide refers to an amino acid residue having a side chain that can be contacted with a solvent molecule (usually a water molecule in general). However, the side chain need not necessarily be in complete contact with the solvent molecule, and even if a portion of the side chain is in contact with the solvent molecule, the amino acid is defined as the "amino acid residue located on the surface ". The amino acid residues located on the surface of the polypeptide also include amino acid residues located close to the surface whereby the side chains are, in part, electrically charged from another amino acid residue in contact with the solvent molecule. Skilled artisans may use, for example, commercially available software to produce a homology model of a polypeptide. On the one hand, methods known to those skilled in the art, for example X-ray crystallography, can be used. Amino acid residues that can be exposed on the surface are measured using coordinates from a three-dimensional model, for example, using a computer program such as the Insight II program (Accelrys). Surface-exposed regions can be measured using techniques known in the art (see, for example, Lee and Richards (J. Mol. Biol. 55: 379-400 (1971); Connolly The surface-exposed regions can be measured using software suitable for protein modeling and three-dimensional structural information. [0033] Software available for the above purposes (e.g., For example, SYBYL biopolymer module software (Tripos Associates). If the operation requires a user input size parameter, the "size" Further, a method of measuring surface-exposed areas using software for personal computers is described in Pacios, Comput. Chem. 18 (4): 377-386 (1994), J. Mol. Model. 1: 46-53 (1995). Based on such information as described above, suitable amino acid residues located on the surface of the polypeptide making up the variant Fc region can be selected.

In some embodiments, the polypeptide comprises both the variant Fc region and the antigen-binding domain. In a further embodiment, the antigen is a soluble antigen. In one embodiment, the antigen is present in a subject's biological fluid (e.g., plasma, interstitial fluid, lymph fluid, ascites, pleural fluid). The antigen may also be a membrane antigen.

In a further embodiment, the antigen-binding activity of the antigen-binding domain varies with ion concentration conditions. In one embodiment, the ion concentration is not particularly limited and is referred to as hydrogen ion concentration (pH) or metal ion concentration. In the present specification, the metal ions include metal elements other than hydrogen, such as alkaline metals and copper group elements, Group II elements such as alkaline earth metals and zinc group elements, group III elements excluding boron, carbon and silicon Refers to an element of Group IV element, Group VIII element, for example, elements belonging to the A group of the iron and platinum group elements, V, VI and VII, and metal elements such as antimony, bismuth and polonium. In the present invention, metal ions include calcium ions as described, for example, in WO 2012/073992 and WO 2013/125667. In one embodiment, "ion concentration condition" may be a condition that focuses on the difference in biological aspects of the antigen-binding domain between a low ion concentration and a high ion concentration. Furthermore, the expression "antigen-binding activity of the antigen-binding domain varies with ionic conditions" means that the antigen-binding activity of the antigen-binding domain varies between low and high ionic concentrations (such antigen- The binding domain is referred to herein as the "ion concentration-dependent antigen-binding domain"). The antigen-binding activity of the antigen-binding domain under high ionic concentration conditions can be higher (stronger) or lower (weaker) than under low ionic concentration conditions. In one embodiment, an ion-concentration-dependent antigen-binding domain (e. G., A pH-dependent antigen-binding domain or a calcium ion concentration-dependent antigen-binding domain) is described, for example, in WO 2009/125825, WO 2012/073992 and Can be obtained by the known methods described in WO 2013/046722.

In the present invention, the antigen-binding activity of the antigen-binding domain under high calcium ion concentration conditions can be higher than under low calcium ion concentration conditions. The high calcium ion concentration is not particularly limited, but may be any concentration selected from 100 μM to 10 mM, 200 μM to 5 mM, 400 μM to 3 mM, 200 μM to 2 mM, 400 μM to 1 mM, or 500 μM to 2.5 mM And it is preferable that the concentration is close to plasma (blood) concentration of calcium ion in vivo. On the other hand, the low calcium ion concentration may be a concentration selected from 0.1 μM to 30 μM, 0.2 μM to 20 μM, 0.5 μM to 10 μM, 1 μM to 5 μM, or 2 μM to 4 μM, Which is close to the concentration of calcium ions in the initial endosome.

In one embodiment, the ratio between antigen-binding activities under low calcium ion concentration conditions and high calcium ion concentration conditions is not limited, but the dissociation constant (KD) under low calcium ion concentration conditions versus the KD under high calcium ion concentration conditions Ratio, that is, KD (low calcium ion concentration condition) / KD (high calcium ion concentration condition) is 2 or more, 10 or more, or 40 or more. The upper limit of the ratio may be 400, 1000 or 10000 as long as the antigen-binding domain can be generated by techniques known to those skilled in the art. On the other hand, for example, a dissociation rate constant (kd) can be used in place of the KD. In this case, the ratio of kd under the condition of low calcium ion concentration to the amount of kd under the condition of high calcium ion concentration, that is, kd (low calcium ion concentration condition) / kd (high calcium ion concentration condition) is 2 or more, 30 or more. The upper limit of the ratio may be 50, 100, or 200 as long as the antigen-binding domain can be generated based on the conventional technical knowledge of those skilled in the art.

In the present invention, the antigen-binding activity of the antigen-binding domain under low hydrogen ion concentration (neutral pH) may be higher than under high hydrogen ion concentration (acidic pH). The acidic pH may be selected, for example, from pH 4.0 to pH 6.5, or from pH 4.5 to pH 6.5, or from pH 5.0 to pH 6.5, or from pH 5.5 to pH 6.5, Is close to the in vivo pH in the living body. The acidic pH may also be pH 5.8 or pH 6.0. In certain embodiments, the acidic pH is pH 5.8. On the other hand, the neutral pH may be selected, for example, from pH 6.7 to pH 10.0, pH 6.7 to pH 9.5, pH 7.0 to pH 9.0, or pH 7.0 to pH 8.0, (Blood) is close to the pH in vivo. The neutral pH may also be, for example, pH 7.4 or pH 7.0. In certain embodiments, the neutral pH is pH 7.4.

In one embodiment, the ratio between antigen-binding activities under acid pH conditions and neutral pH conditions is not limited, but the ratio of KD under dissociation constants (KD) to neutral pH conditions under acidic pH conditions, i.e., KD (acid pH conditions ) / KD (neutral pH condition) is 2 or more, 10 or more, or 40 or more. The upper limit of the ratio may be 400, 1000 or 10000 as long as the antigen-binding domain can be generated by techniques known to those skilled in the art. On the other hand, for example, a dissociation rate constant (kd) can be used in place of the KD. In this case, the ratio of kd under acid pH conditions to kd under neutral pH conditions, that is, kd (acidic pH condition) / kd (neutral pH condition) is 2 or more, 5 or more, 10 or more or 30 or more. The upper limit of the ratio may be 50, 100, or 200 as long as the antigen-binding domain can be generated based on the conventional technical knowledge of those skilled in the art.

In one embodiment, for example, at least one amino acid residue is substituted with an amino acid residue having a side chain pKa of 4.0 to 8.0 and / or an amino acid residue having a side chain pKa of 4.0 to 8.0 as described in WO 2009/125825 One amino acid is inserted into the antigen-binding domain. The amino acid can be substituted and / or inserted at any site as long as the antigen-binding activity of the antigen-binding domain is weaker under acidic pH conditions than under neutral pH conditions prior to displacement or insertion. Where the antigen-binding domain has a variable region or CDR, the region may be in the variable region or CDR. The number of substituted or inserted amino acids can be suitably determined by those skilled in the art; The number may be more than one. An antigen-binding activity of the antigen-binding domain can be changed according to the hydrogen ion concentration condition using an amino acid having a side chain pKa of 4.0 to 8.0. Such amino acids include, for example, natural amino acids such as His (H) and Glu (E), and unnatural amino acids such as histidine analogues (US2009 / 0035836), m-NO2-Tyr (pKa 7.45) , 3,5-Br2-Tyr (pKa 7.21), and 3,5-I2-Tyr (pKa 7.38) (Heyl et al., Bioorg. Med. Chem. 11 (17): 3761-3768 2003). Amino acids having a side chain pKa of 6.0 to 7.0 can also be used, including for example His (H).

In another embodiment, a preferred antigen-binding domain is described in the variant Fc region with increased pi, which can be obtained by the methods described in Japanese Patent Application JP2015-021371 and JP2015-185254.

In some embodiments, the variant Fc region with increased pi is selected from the group consisting of 285, 311, 312, 315, 318, 333, 335, 337, 341, 342, 343, 384, 385, 388, 390, 399, 400, 401, 402, 413, 420, 422, and 431.

In a further embodiment, the variant Fc region having the increased pI comprises at least two of at least two selected from the group consisting of 311, 341, 343, 384, 399, 400, 401, 402, and 413 Includes two amino acid changes.

In another aspect, the invention provides a polypeptide comprising a variant Fc region having an increased pI comprising an amino acid modification of any one of the following (1) to (10): (1) Positions 311 and 341; (2) positions 311 and 343; (3) positions 311, 343, and 413; (4) positions 311, 384, and 413; (5) positions 311 and 399; (6) positions 311 and 401; (7) positions 311 and 413; (8) positions 400 and 413; (9) positions 401 and 413; And (10) positions 401 and 413.

Methods of increasing the pI of a protein include, for example, reducing the number of amino acids having negatively charged side chains (e.g., aspartic acid and glutamic acid) at neutral pH conditions and / or reducing the number of amino acids having positively charged side chains For example, arginine, lysine and histidine). An amino acid having a negatively charged side chain has a negative charge represented by -1 under pH conditions sufficiently higher than its side chain pKa, which is a well-known theory to those skilled in the art. For example, the theoretical pKa for the side chain of aspartic acid is 3.9, and the side chain has a negative charge represented as -1 in a neutral pH condition (for example, a solution at pH 7.0). In other words, an amino acid having a positively charged side chain has a positive charge represented by +1 under pH conditions sufficiently lower than its side chain pKa. For example, the theoretical pKa for the side chain of arginine is 12.5, and the side chain has a positive charge represented by +1 in neutral pH conditions (e.g., a solution at pH 7.0). On the other hand, an amino acid having a side chain having no charge in a neutral pH condition (for example, a solution of pH 7.0) contains 15 types of natural amino acids, namely alanine, cysteine, phenylalanine, glycine, isoleucine, leucine, methionine, asparagine, Proline, glutamine, serine, threonine, valine, tryptophan, and tyrosine. Of course, the amino acid that increases the pI may be an unnatural amino acid.

From the above, as a method for increasing the pI of a protein under neutral pH conditions (for example, a solution having a pH of 7.0), for example, a method of replacing aspartic acid or glutamic acid (the side chain thereof has a negative charge of -1) Charge changes of +1 to the protein of interest can be conferred by substituting amino acids with uncharged side chains. Furthermore, the charge modification of +1 can be imparted to the protein by substituting arginine or lysine (the side chain of which has a positive charge of +1) instead of an amino acid having a side chain with no charge, for example. Furthermore, the charge modification of +2 can be imparted to the protein at a time by substituting arginine or lysine (the side chain of which has a positive charge of +1) instead of aspartic acid or glutamic acid (whose side chain has a negative charge of -1) can do. On the other hand, in order to increase the pI of a protein, an amino acid having an uncharged side chain and / or an amino acid having a positively charged side chain is added to or inserted into the amino acid sequence of the protein, Amino acids with side chains and / or amino acids with negatively charged side chains which are preferably present in the amino acid sequence of the protein can be deleted. For example, the N-terminal and C-terminal amino acid residues of the protein may have a backbone-derived charge (NH ₃ ⁺ of the N-terminal amino group and COO ^- of the C-terminal carbonyl group) in addition to its side chain- . Thus, the pI of a protein may also be increased by performing some addition, deletion, substitution, or insertion of the backbone-derived functional group.

Substitution of the amino acid for increasing the pI may be carried out, for example, by substitution of an amino acid having a side chain having no charge instead of an amino acid having a negatively charged side chain, substitution of an amino acid having a positively charged side chain in place of the amino acid having a side chain having no charge And substitution of amino acids with positively charged side chains instead of amino acids with negatively charged side chains in the amino acid sequence of the parent Fc region, either alone or in a suitable combination.

The insertion or addition of an amino acid to increase the pI may be carried out by, for example, inserting or adding an amino acid having a side chain having no charge, and / or inserting or adding an amino acid having a positively charged side chain in the amino acid sequence of the parent Fc region , Which are carried out singly or in suitable combinations.

Deletion of the amino acid to increase the pI includes, for example, deletion of an amino acid having a side chain with no charge and / or deletion of an amino acid having a negatively charged side chain in the amino acid sequence of the parent Fc region, Or in a suitable combination.

In one embodiment, natural amino acids for increasing pi can be classified as follows: (a) an amino acid with a negatively charged side chain may be Glu (E) or Asp (D); (b) amino acids having side chains that do not have a charge are Ala, Asn, Cys, Gln, GI, His, ), Met (M), Phe (F), Pro (P), Ser (S), Thr (T), Trp (W), Tyr (Y), or Val And (c) the amino acid having a positively charged side chain may be His (H), Lys (K), or Arg (R). In one embodiment, the amino acid insertions or substitutions after modification are Lys (K) or Arg (R).

In another aspect, the invention provides isolated polypeptides comprising a variant Fc region having increased Fc gamma RIIb-binding activity and increased pi. In some embodiments, the variant Fc region described herein comprises at least two amino acid changes in the parent Fc region.

In one aspect, the present invention relates to a method and apparatus for (a) subjecting EU numbers to 231, 232, 233, 234, 235, 236, 237, 238, 239, 264, 266, 267, 268, 271, 295, 298, 325, At least one amino acid change in at least one position selected from the group consisting of SEQ ID NOS: 326, 327, 328, 330, 331, 332, 334 and 396; and (b) 285, 311, 312, 315, 318 At least two of at least two positions selected from the group consisting of SEQ ID NOs: 333, 335, 337, 341, 342, 343, 384, 385, 388, 390, 399, 400, 401, 402, 413, There is provided a polypeptide comprising a variant Fc region having increased Fc gamma RIIb-binding activity and increased pI comprising at least three amino acid modifications including amino acid modifications.

In one aspect, the present invention relates to a method for the detection of (a) at least one of at least one position selected from the group consisting of 231, 232, 235, 236, 239, 268, 295, 298, 326, 330, And (b) at least two amino acid changes in at least two positions selected from the group consisting of 311, 341, 343, 384, 399, 400, 401, 402 and 413 according to EU numbering There is provided a polypeptide comprising a variant Fc region having increased Fc gamma RIIb-binding activity and increased pi, comprising three amino acid modifications.

In another aspect, the invention provides a polypeptide comprising a variant Fc region having an increased Fc gamma RIIb-binding activity and an increased pi, comprising an amino acid modification of any one of (1) to (9) (1) 235, 236, 268, 295, 311, 326, 330 and 343 positions according to EU numbering; (2) positions 236, 268, 295, 311, 326, 330, and 343; (3) positions 236, 268, 295, 311, 330, and 413; (4) positions 236, 268, 311, 330, 396 and 399; (5) positions 236, 268, 311, 330, and 343; (6) positions 236, 268, 311, 330, 343, and 413; (7) positions 236, 268, 311, 330, 384, and 413; (8) positions 236, 268, 311, 330 and 413; And (9) positions 236, 268, 330, 396, 400, and 413. In some embodiments, the Fc gamma RIIb has the sequence of the synomolgus monkey Fc gamma RIIb (SEQ ID NO: 223). In some embodiments, the Fc gamma RIIb has the sequence of human Fc gamma RIIb (SEQ ID NO: 212, 213, or 214).

(A) at least one amino acid change in at least one position selected from the group consisting of 234, 238, 250, 264, 267, 307 and 330 according to EU numbering; and (b) 382, 343, 384, 385, 388, 390, 399, 400, 401, 402, 413, 420, 422, and 314, 315, 318, 333, 335, 337, 341, 342, 431, comprising at least three amino acid modifications comprising at least two amino acid modifications of at least two positions selected from the group consisting of SEQ ID NO: 431, SEQ ID NO: 431, SEQ ID NO: Lt; / RTI > In a further embodiment, the polypeptide comprises at least two amino acid changes in at least two positions selected from the group consisting of 311, 341, 343, 384, 399, 400, 401, 402 and 413 according to EU numbering . In some embodiments, the Fc gamma RIIb has the sequence of the synomolgus monkey Fc gamma RIIb (SEQ ID NO: 223). In some embodiments, the Fc gamma RIIb has the sequence of human Fc gamma RIIb (SEQ ID NO: 212, 213, or 214).

In another aspect, the invention provides a polypeptide comprising a variant Fc region having an increased Fc gamma RIIb-binding activity and an increased pi, comprising an amino acid modification of any one of (1) to (16) (1) 234, 238, 250, 264, 307, 311, 330 and 343 positions according to EU numbering; (2) positions 234, 238, 250, 264, 307, 311, 330, and 413; (3) positions 234, 238, 250, 264, 267, 307, 311, 330, and 343; (4) positions 234, 238, 250, 264, 267, 307, 311, 330 and 413; (5) positions 234, 238, 250, 267, 307, 311, 330, and 343; (6) positions 234, 238, 250, 267, 307, 311, 330, and 413; (7) positions 234, 238, 250, 307, 311, 330, and 343; (8) positions 234, 238, 250, 307, 311, 330 and 413; (9) positions 238, 250, 264, 267, 307, 311, 330 and 343; (10) 238, 250, 264, 267, 307, 311, 330 and 413; (11) positions 238, 250, 264, 307, 311, 330 and 343; (12) positions 238, 250, 264, 307, 311, 330 and 413; (13) positions 238, 250, 267, 307, 311, 330, and 343; (14) positions 238, 250, 267, 307, 311, 330, and 413; (15) positions 238, 250, 307, 311, 330 and 343; And (16) positions 238, 250, 307, 311, 330, and 413.

In a further embodiment, the variant Fc region comprises an amino acid alteration selected from any single alteration, a combination of single alterations, or a combination change described in Tables 14 to 30. [

In some embodiments, the polypeptide comprises a variant Fc region of the invention. In a further embodiment, the polypeptide is an antibody heavy chain constant region. In a further embodiment, the polypeptide is an antibody heavy chain. In a further embodiment, the polypeptide is an antibody. In a further embodiment, the polypeptide is an Fc fusion protein.

In a further embodiment, the invention provides a polypeptide comprising the amino acid sequence of any one of SEQ ID NOS: 229-381.

As used herein, "parent Fc region" refers to the Fc region prior to the introduction of the amino acid alteration (s) described herein. A preferred example of the parent Fc region comprises an Fc region derived from a native antibody. Antibodies include, for example, IgA (IgA1, IgA2), IgD, IgE, IgG (IgG1, IgG2, IgG3, IgG4), and IgM. Antibodies can be derived from humans or monkeys (e.g., cynomolgus, rhesus monkey, spiny monkey, chimpanzee or baboon monkey). Natural antibodies may also include natural mutations. Multiple allotype sequences of IgG due to genetic polymorphisms are described in "Sequences of proteins of immunological interest" 91-3242, and any of them can be used in the present invention. In particular, in the case of human IgG1, the amino acid sequence at positions 356 to 358 (EU numbering) may be DEL or EEM. Preferred examples of the parent Fc region include an Fc region derived from a heavy chain constant region of human IgG1 (SEQ ID NO: 195), human IgG2 (SEQ ID NO: 196), human IgG3 (SEQ ID NO: 197) and human IgG4 do. Another preferred example of the parent Fc region is an Fc region derived from the heavy chain constant region SG1 (SEQ ID NO: 9). Furthermore, the parent Fc region may be an Fc region generated by adding an amino acid alteration (s) other than the amino acid alteration (s) described herein to an Fc region derived from the native antibody.

In addition, amino acid modifications performed for other purposes (s) may be incorporated into the variant Fc regions described herein. For example, amino acid substitutions that improve FcRn-binding activity (Hinton et al., J. Immunol. 176 (1): 346-356 (2006); Dall'Acqua et al., J. Biol Immunol. 18 (12): 1759-1769 (2006)]; Zalevsky et al., Nat. Biotechnol. And WO 2009/086320), and amino acid substitutions (WO 2009/041613) to improve antibody heteromorphism or stability (WO 2006/053441; WO 2006/053301; WO 2006/053301; and WO 2009/086320) . On the other hand, polypeptides having the antigenic clearance promoting properties described in WO 2011/122011, WO 2012/132067, WO 2013/046704 or WO 2013/046704 or WO 2013/180201, polypeptides specifically binding to the target tissues described in WO 2013/180200 , Polypeptides having the property of repeated binding to a plurality of antigen molecules described in WO 2009/125825, WO 2012/073992 or WO 2013/047752 can be combined with the variant Fc regions described herein. On the other hand, for the purpose of conferring binding ability to other antigens, the amino acid modifications disclosed in EP1752471 and EP1772465 can be linked to the CH3 of the variant Fc region described herein. On the other hand, for the purpose of increasing plasma retention, an amino acid change (WO 2012/016227) that reduces the pI of the constant region can be coupled to the variant Fc region described herein. On the one hand, amino acid modifications (WO 2014/145159) that increase the pI of the constant region can be coupled to the variant Fc region described herein for the purpose of promoting uptake into the cell. On the other hand, for the purpose of promoting the removal of target molecules from plasma, amino acid changes (Japanese Patent Applications JP2015-021371 and JP2015-185254) that increase the pI of the constant region can be incorporated into the variant Fc region described herein. In one embodiment, such modifications may include substitution of at least one position selected from the group consisting of, for example, 311, 343, 384, 399, 400 and 413 according to EU numbering. In a further embodiment, such substitution may be the substitution of an amino acid by Lys or Arg at each position.

Amino acid modifications that increase human FcRn-binding activity at acidic pH can also be conjugated to the variant Fc regions described herein. Specifically, such a modification may be made, for example, by substituting Leu for Met at position 428 and for substitution of Ser for Asn at position 434 according to EU numbering (Zalevsky et al., Nat. Biotechnol. -159 (2010)); Substitution of Ala in place of Asn at position 434 (Deng et al., Metab. Dispos. 38 (4): 600-605 (2010)); Substitution of Tyr for Met at position 252, substitution of Thr for Ser at position 254, and substitution of Glu for Thr at position 256 (Dall'Acqua et al., J. Biol. Chem. 281: 23514- 23524 (2006)); Substitution of Gln for Thr at position 250 and substitution of Leu for Met at position 428 (Hinton et al., J. Immunol.176 (1): 346-356 (2006)); 89 (2): 283-290 (2011)], and WO 2010/106180, WO 2010/045193, WO 2009 / 0548492, WO 2008/022152, WO 2006/050166, WO 2006/053301, WO 2006/031370, WO 2005/123780, WO 2005/047327, WO 2005/037867, WO 2004/035752, or WO 2002/060919 Such modifications include, for example, at least one selected from the group consisting of substitution of Leu for Met at position 428, substitution of Ala for Asn at position 434, and substitution of Thr for Tyr at position 436 These modifications may additionally include the substitution of Arg for Gln at position 438 and / or the substitution of Glu for Ser at position 440 (Japanese Patent Applications JP2015-021371 and JP2015-185254 ).

Two or more polypeptides comprising the variant Fc region described herein can be included in a molecule, wherein two polypeptides comprising the variant Fc region bind very similarly to the antibody. The type of the antibody is not limited, and IgA (IgA1, IgA2), IgD, IgE, IgG (IgG1, IgG2, IgG3, IgG4), IgM and the like can be used.

The two linked polypeptides comprising a variant Fc region may comprise a polypeptide comprising a variant Fc region (hereinafter referred to as the homologous variant Fc region) into which the same amino acid alteration (s) has been introduced, or a different amino acid alteration Or variant Fc regions in which the amino acid alteration (s) are introduced only in one of the Fc regions (hereinafter referred to as " variant Fc region "Quot; heterologous polypeptide "). One of the preferred amino acid modifications is a change in the ring structure from positions 233 to 239 (EU numbering) in the CH2 domain of the Fc region associated with binding to Fc gamma RIIb and Fc gamma RIIa. Preferably, one modification is introduced into the ring structure of one CH2 domain of the Fc gamma RIIb-binding activity and / or Fc region that enhances selectivity, and another modification is carried out in CH2 of another Fc region that destabilizes the ring structure Is introduced into the ring structure of the domain. Examples of amino acid modifications capable of destabilizing the ring structure of the CH2 domain may be substitution of another amino acid of at least one amino acid selected from amino acids 235, 236, 237, 238 and 239. Specifically, the amino acid at position 235 is changed to Asp, Gln, Glu, or Thr, the amino acid at position 236 is changed to Asn, the amino acid at position 237 is substituted with Phe or Trp And the amino acid at position 238 is changed to Glu, Gly or Asn and the amino acid at position 239 is changed to Asp or Glu.

For binding of heterologous polypeptides comprising a variant Fc region, the homologous polypeptides comprising the Fc region may be introduced into the variant Fc region by introducing electrostatic repulsion at the interface of the CH2 or CH3 domain of the variant Fc region, as described in WO 2006/106905 A technique for suppressing unintended coupling can be applied.

Examples of amino acid residues that contact at the interface of the CH2 or CH3 domain of the Fc region include residues at position 356 (EU numbering), residues at position 439 (EU numbering), positions at position 357 (EU numbering) Residues at position 370 (EU numbering), residues at position 399 (EU numbering), and residues at position 409 (EU numbering).

More specifically, for example, one to three pairs of amino acid residues selected from (1) to (3) shown below can generate an Fc region having the same charge: (1) 356 and 439 in the CH3 domain Amino acid residue at the EU numbering position); (2) amino acid residues at positions 357 and 370 (EU numbering) in the CH3 domain; And (3) amino acid residues at positions 399 and 409 (EU numbering) in the CH3 domain.

Furthermore, a heterologous polypeptide comprising the variant Fc region may be generated, wherein one to three of the amino acid residues selected from (1) to (3) shown above are identical in the CH3 domain of the first Fc region The pair of amino acid residues selected from among the first Fc regions mentioned above also have the same charge among the CH3 domains of the second Fc region except that the charges in the first and second Fc regions are opposite.

In the above-mentioned Fc region, for example, a negatively charged amino acid residue is preferably selected from glutamic acid (E) and aspartic acid (D), and the positively charged amino acid residue is preferably selected from lysine (K) Arginine (R) and histidine (H).

Other known techniques may be used in addition to binding of heterologous polypeptides comprising the variant Fc region. Specifically, the technique described above is used to replace an amino acid side chain present in one of the Fc regions with a larger side chain (meaning "handle") and to remove the amino acid side chain present in the Fc region from a smaller (Hole; "void") and inserting the handle into the hole. This can promote efficient binding between Fc-region-containing polypeptides having amino acid sequences that differ from each other (WO 1996/027011; Ridgway et al., Prot. Eng. 9: 617-621 (1996); Merchant et al., Nat. Biotech., 16, 677-681 (1998)).

In addition, other known techniques may also be used for heterologous binding of polypeptides comprising the variant Fc region. Binding of the polypeptide comprising the Fc region can be efficiently induced using strand-exchange engineered domain CH3 heterodimers (Davis et al., Prot. Eng. Des. &Amp; -202 (2010)). The technique can also be used to efficiently induce binding between Fc region-containing polypeptides having different amino acid sequences.

In addition, a heterodimeric antibody generation technique (described in WO 2011/028952) using the binding of antibodies CHl and CL and the binding of VH and VL can also be used.

As in the methods described in WO 2008/119353 and WO 2011/131746, two types of homodimeric antibodies are first generated, the antibodies are incubated under reducing conditions to dissociate them, A technique for generating antibodies can be used.

Strop, J. Mol. Biol. Such as Lys, Arg, Glu, and Asp, as in the methods described in US Pat. No. 4,302,214 (2012), by introducing a heterodimeric antibody into the CH3 domain by introducing electrostatic repulsion into the CH3 domain It is also possible to use the technique of generating.

Furthermore, it is also possible to use techniques to generate heterodimeric antibodies by modifying the CH2 and CH3 domains, such as in the method described in WO 2012/058768.

In order to produce a polypeptide containing a heterologous variant Fc region, when two polypeptides comprising a variant Fc region having a different amino acid sequence are simultaneously expressed, the polypeptide comprising the homologous variant Fc region is usually expressed as an impurity . In such a case, the polypeptide containing the heterologous variant Fc region can be efficiently obtained by isolating and purifying from the polypeptide comprising the homologous variant Fc region using known techniques. By introducing an amino acid change into the variable region of the two types of antibody heavy chains to produce isoelectric point differences between the homodimerized antibody and the heterodimerized antibody, the isomerized antibody Have been reported (WO 2007/114325). By preparing a heterodimeric antibody comprising two types of heavy chains derived from mouse IgG2a binding to protein A and from rat IgG2b not binding to protein A, the heterodimeric antibody Have been reported (WO 1998/050431 and WO 1995/033844).

Furthermore, the heterodimeric antibody can be produced by replacing the amino acid residues 435 and 436 (EU numbering) located in the protein A binding site of the antibody heavy chain with an amino acid such as Tyr or His to produce a different protein A binding affinity , And can be efficiently purified using protein A chromatography.

In the present invention, the amino acid modification means either substitution, deletion, addition, insertion and modification, or a combination thereof. In the present invention, amino acid changes can be referred to as amino acid mutations.

Upon substitution of an amino acid residue, substitution with a different amino acid residue can be carried out for the purpose of altering aspects such as (a) to (c) described below: (a) a polypeptide in a sheet- Backbone structure; (b) electric charge or hydrophobicity of the target site; Or (c) the size of the side chain.

Amino acid residues are grouped into the following groups based on their general side chain properties: (1) hydrophobicity: norleucine, Met, Ala, Val, Leu, and Ile; (2) neutral hydrophilic: Cys, Ser, Thr, Asn, and Gln; (3) Acid: Asp, and Glu; (4) Basicity: His, Lys, and Arg; (5) residues affecting chain orientation: Gly, and Pro; (6) Aromatic: Trp, Tyr, and Phe.

Amino acid modifications are made by a variety of methods known to those skilled in the art. Such a method can be performed by a site-directed mutagenesis method (Hashimoto-Gotoh et al., Gene 152: 271-275 (1995); Zoller, Meth. Enzymol. 100: 468-500 (1983) ; Kramer et al., Nucleic Acids Res. 12: 9441-9456 (1984)); Kramer and Fritz, Methods Enzymol. 154: 350-367 (1987); And Kunkel, Proc. Natl. Acad. Sci. USA 82: 488-492 (1985)), PCR mutagenesis methods, and cassette mutagenesis methods.

The number of amino acid changes introduced into the Fc region is not limited. In some embodiments, the above may be 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18,

Amino acid modifications include post-translational modifications. Specific post-translational modifications may be addition or deletion of sugar chain. For example, the amino acid residue 297 (EU numbering) of the IgG1 constant region can be sugar chain-modified. The sugar chain structure for such modification is not limited. For example, sialic acid can be added to the sugar chain of the Fc region (MAbs 2010 Sep-Oct, 2 (5): 519-527). Generally, antibodies expressed in eukaryotic cells include glycosylation in the constant region. For example, it is known to add some types of sugar chains to antibodies expressed in cells, such as eukaryotic cells transformed with expression vectors containing DNA encoding the native antibody-producing cells or antibodies of mammals have.

The eukaryotic cells shown here include yeast and animal cells. For example, CHO cells and HEK293 cells are typical animal cells used for transformation by expression vectors containing antibody-encoding DNA. On the other hand, constant regions without glycosylation are also encompassed by the present invention. Non-glycosylated antibodies of the constant region can be obtained by expressing the antibody-encoding gene in prokaryotic cells such as Escherichia coli.

Furthermore, the polypeptides comprising the variant Fc regions of the invention can be chemically modified into a variety of molecules, such as polyethylene glycol (PEG) and cytotoxic agents. Such chemical modification methods of polypeptides have been established in the art.

In one aspect, the invention provides an isolated polypeptide comprising a variant Fc region having increased Fc gamma RIIb-binding activity. In some embodiments, the polypeptide is an antibody. In some embodiments, the polypeptide is an Fc fusion protein. In some embodiments, the antibody is a chimeric antibody or a humanized antibody. The origin of the antibody is not particularly limited, and examples include human antibodies, mouse antibodies, rat antibodies, and rabbit antibodies. In some embodiments, the polypeptide is an Fc fusion protein.

The protein binding motif of an Fc fusion protein comprising variable regions and variant Fc regions of an antibody comprising the variant Fc regions provided herein can recognize any antigen. Examples of antigens that can be bound by such antibodies and fusion proteins include, but are not limited to, but are not limited to, ligands (cytokines, chemokines, etc.), receptors, cancer antigens, MHC antigens, differentiating antigens, immunoglobulins, ≪ / RTI >

Examples of cytokines that can be recombinantly fused with a polypeptide comprising a variant Fc region bound and / or introduced by an antibody or fusion protein comprising a variant Fc region of the invention include, but are not limited to, interleukins 1 to 18, (EGF, FGF, IGF, NGF, PDGF, TGF, HGF, etc.), factor (G-CSF, M-CSF, GM-CSF etc.), interferon (IFN-alpha, IFN-beta, IFN- , Tumor necrosis factor (TNF-alpha and TNF-beta), lymphotoxin, erythropoietin, leptin, SCF, TPO, MCAF and BMP.

Examples of a chemokine that can be recombinantly fused with a polypeptide comprising a variant Fc region bound and / or initiated by an antibody or fusion protein comprising the variant Fc region of the invention include, but are not limited to CC chemokines, For example, CCL1 to CCL28, CXC chemokines such as CXCL1 to CXCL17, CKemokines such as XCL1 to XCL2, and CX3C chemokines such as CX3CL1.

Examples of receptors that can be recombinantly fused with a polypeptide comprising a variant Fc region bound and / or introduced by an antibody or fusion protein comprising a variant Fc region of the invention include, but are not limited to, a receptor, A tyrosine kinase-type receptor, a serine / threonine kinase-type receptor, a TNF receptor, a G protein-coupled receptor, a GPI anchor-type receptor, a tyrosine phosphatase-type receptor, an adhesion factor, and a hormone Receptor < / RTI > The receptors belonging to these receptors and their properties are described in Cooke, ed. New Comprehesive Biochemistry Vol. 18B "Hormones and their Actions Part II" pp. 1-46 (1988) Elsevier Science Publishers BV; Patthy (Cell 61 (1): 13-14 (1990)); Ullrich (Cell 61 (2): 203-212 (1990)); Massague (Cell 69 (6): 1067-1070 (1992)); Miyajima et al. (Annu. Rev. Immunol. 10: 295-331 (1992)); Taga et al. (FASEB J. 6: 3387-3396 (1992)); Fantl et al. (Annu Rev. Biochem 62: 453-481 (1993)); Smith et al. (Cell 76 (6): 959-962 (1994)); And Flower (Biochim. Biophys. Acta 1422 (3): 207-234 (1999)).

Examples of specific receptors belonging to the above mentioned receptor family include human or mouse erythropoietin (EPO) receptors (Jones et al., Blood 76 (1): 31-35 (1990); D'Andrea (G-CSF) receptor (Fukunaga et al., Proc. Natl. Acad. Sci.), Cell 57 (2): 277-285 USA 87 (22): 8702-8706 (1990)), mG-CSFR (Fukunaga et al., Cell 61 (2): 341-350 (1990)), human or mouse thrombopoietin ) Receptor (Skoda et al., EMBO J. 12 (7): 2645-7), which is incorporated herein by reference in its entirety (see, for example, Vigon et al., Proc. Natl. Acad. Sci. USA 89 (12): 5640-5644 (Ullrich et al., Nature 313 (6005): 756-761 (1985)), human or mouse Flt-3 ligand receptors (Small et al. (PDGF) receptor (Gronwald et al., Proc. Natl. Acad. Sci. USA 91 (2): 459-463 (1994)]) or human platelet-derived growth factor Acad Sci USA 85 (10 (Uze et al., Cell 60 (2): 225-234 (1990)); Novick et < RTI ID = 0.0 > al Human or mouse leptin receptor, human or mouse growth hormone (GH) receptor, human or mouse interleukin (IL) -10 receptor, human or mouse insulin-like Growth factor (IGF) -1 receptor, a human or mouse leukemia inhibitory factor (LIF) receptor, and a human or mouse cyclic neurotrophin receptor (CNTF) receptor.

Cancer antigens are antigens expressed as cells become malignant and are also referred to as tumor-specific antigens. The abnormal sugar chain appearing on the cell surface or protein molecule when the cell becomes cancerous is also a cancer antigen, which is also referred to as a sugar chain cancer antigen. Examples of cancer antigens that can be bound by antibodies or fusion proteins containing a variant Fc region of the invention include, but are not limited to, GPC3 (a receptor belonging to the GPI anchor type receptor family mentioned above and also expressed in many cancers including liver cancer) As well as EpCAM (expressed in a number of cancers including lung cancer) (Linnenbach et al., ≪ RTI ID = 0.0 > CA 19-9, CA15-3, and sialyl SSEA-1 (SLX).

MHC antigens are roughly classified as MHC class I antigens and MHC class II antigens. MHC class I antigens include HLA-A, -B, -C, -E, -F, -G, and -H, and MHC class II antigens include HLA-DR, -DQ, and -DP.

Examples of differentiation antigens that can be recombinantly fused with a polypeptide comprising a variant Fc region bound and / or introduced by an antibody or fusion protein comprising a variant Fc region of the invention include but are not limited to CD1, CD2, CD4, CD20, CD20, CD30, CD30, CD30, CD30, CD30, CD30, CD30, CD30, CD49, CD49b, CD49b, CD49c, CD49d, CD49e, CD49f, CD51, CD54, CD55, CD56, CD57, CD58, CD61, CD62E, CD62L, CD62P, CD64, CD69, CD71, CD73, CD95, CD102, CD106, CD122, CD126, and CDw130.

Immunoglobulins include IgA, IgM, IgD, IgG and IgE. The immunoconjugate comprises at least one of the components of the immunoglobulin.

Other examples of antigens that can be recombinantly fused with a polypeptide comprising a variant Fc region bound and / or introduced by an antibody or fusion protein comprising a variant Fc region of the invention include, but are not limited to 17-IA, 4- 1BB, 4Dc, 6-keto-PGF1a, 8-iso-PGF2a, 8-oxo-dG, A1 adenosine receptor, A33, ACE, ACE-2, Actibin, Activin A, Activin AB, TIBIN C, ACTIBIN RIA, ACTIBINE RIA ALK-2, ACTIBINE RIB ALK-4, ACTIBINE RIIA, ACTIBINE RIIB, ADAM, ADAM10, ADAM12, ADAM15, ADAM17 / TACE, ADAM8, ADAM9, ADAMTS, ADAMTS4, ADAMTS5 , Adrenaline, aFGF, ALCAM, ALK, ALK-1, ALK-7, alpha-1-antitrypsin, alpha-V / beta-1 antagonist, ANG, Ang, APAF-1, APE, APJ, APP, APRIL , AR, ARC, ART, aldethamine, anti-Id, ASPARTIC, atrial sodium natriuretic peptide, av / b3 integrin, Axl, b2M, B7-1, B7-2, B7- BACE, BACE, BACE, BAC, BFF, BAFF-R, Bag-1, BAK, Bax, BCA-1, BMP-2, BMP-3, BMP-4, BMP-2b, BMP-5, BMP-6 2, BMPR-1, BMP-7 (OP-1), BMP-8 (BMP-8a, OP- BPDE, DNA, BTC, Complement Factor 3 (C3), C3a, C4, BMPR-II, and BMPR-II (BRK-3) Cancer antigens (CEA), cancer-associated antigens, cathepsin A, cathepsin B, cathepsin C / DPPI, cathepsin D, cathepsin E, catechin D, carnitine, C5, C5a, C10, CA125, CAD- Catechin H, Cathepsin L, Cathepsin O, Cathepsin S, Cathepsin V, Cathepsin X / Z / P, CBL, CCI, CCK2, CCL, CCL1, CCL11, CCL12, CCL13, CCL14, CCL15, CCL16, CCL17, CCL18, CCL19, CCL2, CCL20, CCL21, CCL22, CCL23, CCL24, CCL25, CCL26, CCL27, CCL28, CCL3, CCL4, CCL5, CCL6, CCL7, CCL8, CCL9 / 10, CCR, CCR1, CCR10, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CD1, CD2, CD3, CD3E, CD4, CD5, CD6, CD7, CD8, CD10, CD11a, CD11b, CD11c, CD13, CD18, CD19, CD20, CD21, CD22, CD 23, CD25, CD27L, CD28, CD29, CD30, CD30L, CD32, CD33 (p67 protein), CD34, CD38, CD40, CD40L, CD44, CD45, CD46, CD49a, CD52, CD54, CD55, CD56, CD66e, CD74, CD80 (B7-1), CD89, CD95, CD123, CD137, CD138, CD140a, CD146, CD147, CD148, CD152, CD164, CEACAM5, CFTR, cGMP, CINC, botulinum toxin, clostridium perprene CTX-4, CX3CL1, CX3CR1, CXCL, CXCL1, CXCL2, CTX-1, CTL-1, , CXCL3, CXCL4, CXCL5, CXCL6, CXCL7, CXCL8, CXCL9, CXCL10, CXCL11, CXCL12, CXCL13, CXCL14, CXCL15, CXCL16, CXCR, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, , DCC, DcR3, DC-SIGN, complement regulator (decelerating factor), des (1-3) -IGF-I (brain IGF-1), Dhh, digoxin, DNAM-1, Dnase, Dpp, DPPIV / CD26 Ept, Ept, EAF, ErbB-1, EMA, EMMPRIN, ENA, Endothelin receptor, Encephalinase, eNOS, Eot, Eotaxin 1, EpCAM, Ephrin B2 / EphB4, EPO, ERCC, E-cell FGF, FGF, FGF-19, FGF-2, FGF3, FGF-1, factor IIa, Factor VII, Factor VIIIc, factor IX, fibroblast activation protein (FAP), Fas, FcRl, FEN- 8, FGFR, FGFR-3, fibrin, FL, FLIP, Flt-3, Flt-4, follicle stimulating hormone, fractalcain, FZD1, FZD2, FZD3, FZD4, FZD5, FZD6, FZD7, FZD8, FZD9, FZD10, G250 GDF-1, GDF-3 (Vgr-2), GDF-5 (BMP-14, CDMP-1), GDF-6 (BMP-13, CDMP), GCP-2, GCP-2, GCSF, GD2, GD3, GDF, GFR-1, GFR-alpha 1, GFR-2, GDF-7 (BMP-12, CDMP-3), GDF8 (myostatin), GDF-9, GDF- GpR-alpha2, GFR-alpha3, GITR, glucagon, Glut4, glycoprotein IIb / IIIa (GPIIb / IIIa), GM-CSF, gp130, gp72, GRO, growth hormone releasing hormone, (HGF), Hep B gp120, heparanase, Her2, Her2 / neu (ErbB-2), and hepatocyte growth factor (HGF) Herb (ErbB-3), Her4 (ErbB-4), Herpes simplex virus (HSV) gB glycoprotein, HSV gD glycoprotein, HGFA, Human giant cell virus (HCMV), including human melanoma-associated antigen (HMW-MAA), HIV gp120, HIV IIIB gp 120 V3 loop, HLA, HLA-DR, HM1.24, HMFG PEM, HRG, Hrk, , Human growth hormone (HGH), HVEM, I-309, IAP, ICAM, ICAM-1, ICAM-3, ICE, ICOS, IFNg, Ig, IgA receptor, IgE, IGF, IGF binding protein, IGF- , IGF-I, IGF-II, IL, IL-1, IL-1R, IL-2, IL-2R, IL-4, IL-4R, IL-5, IL- , IL-8, IL-9, IL-10, IL-12, IL-13, IL-15, IL-18, IL-18R, IL-23, interferon Gamma, inhivin, iNOS, insulin A chain, insulin B chain, insulin-like growth factor 1, integrin alpha 2, integrin alpha 3, integrin alpha 4, integrin alpha 4 / beta 1, integrin alpha 4 / beta 7, 5 (alpha V), Integrin Alpha 5 / Beta 1, Integrin Alpha 5 / Beta 3, Integrin Alpha 6, Integrin Beta 1, Integrin Beta 2, Interferon gamma, IP-10, I-TAC, JE, Crane 5, Carrick Crane 6, Knife Crane 11, Calicrain 12, Calicrain 14, Calicrain 15, Calicrain L1, Calicrain L2, Calicrain L3, Calicrain L4, KC, KDR, Keratinocyte Growth Factor (KGF), Laminin 5, LAMP, LAP, LFA-1, LFA-3, Lfo, LIF-L, LEF-1, LBP, , LIGHT, lipoprotein, LIX, LKN, Lptn, L-selectin, LT-a, LT-b, LTB4, LTBP-1, lung surface, progesterone, lymphotoxin beta receptor, Mac-1, MAdCAM, MAG, MAP2, MGC, MCC-2, MCP, M-CSF, MDC, Mer, metalloprotease, MGDF receptor, MGMT, MHC (HLA-DR), MIF, MIG, MIP, MIP- MMP-1, MMP-10, MMP-11, MMP-12, MMP-13, MMP-14, MMP-15, MMP-2, MMP- MMP-9, MPIF, Mpo, MSK, MSP, mucin (Muc1), MUC18, mullerian-inhibiting substance, Mug, MuSK, NAIP, NAP, NCAD, N-cadherin, NCA90, NCAM, Tropin-3, -4, or -6, neurin, nerve growth factor (NGF), NGF PARG, PARP, PBR, PTH, PGF, PADPr, PTH, PGF, PGF, PGF, PGF, PGF, PGF, PGF, PGF, PGF, RG, NGF-beta, nNOS, NO, NOS, Npn, NRG-3, NT, NTN, OB, OGG1, OPG, OPN, OSM, OX40L, OX40R, PGF, PCAD, P-cadherin, PCNA, PDGF, PDK-1, PECAM, PEM, PF4, PGE, PGF, PGI2, PGJ2, PIN, PLA2, placental alkaline phosphatase (PSMA), PTEN, PTHrp, Ptk, PTN, R51, RANK, RANKL, RANTES, Lelaxin A chain, Lelaxin B chain, (RSV), RSV Fgp, Ret, rheumatoid factor, RLIP76, RPA2, RSK, S100, SCF / KL, SDF-1, SERINE, Serum albumin, sFRP-3, Shh, SIGIRR, SK- 1, SLAM, SLPI, SMAC, SMDF, SMOH, SOD, SPARC, Stat, STEAP, STEAP-II, TACE, TACI, TAG-72 TGF-beta, TGF-beta, < RTI ID = 0.0 > TGF-beta, < / RTI > TGF-beta RII, TGF-beta RIIb, TGF-beta RIII, TGF-beta1, TGF-beta2, TGF-beta3, TGF-beta4 and TGF- TNF-alpha beta, TNF-beta2, TNFc, TNF, TGF-beta, TIMP, TIMP, TMPO, TMPRSS2, TMPR, TMPRSS2, Thymus-stimulating hormone, TNFRSF10A (TRAIL R1 Apo-2, DR4), TNFRSF10B (TRAIL R2 DR5, KILLER, TRICK-2A, TRICK-B), TNFRSF10C (TRAIL R3 DcR1, LIT, TRID) TNFRSFl4 (HVEM ATAR, HveA, LIGHT R), TNFRSFl3 (BAFF R), TNFRSFl4 (HVEM ATAR, HveA, LIGHT R), TNFRSFl 1 (RANK ODFR, TRANCE R) , TR2), TNFRSF16 (NGFR p75NTR), TNFRSF17 (BCMA), TNFRSF18 (GITR AITR), TNFRSF19 (TROY TAJ, TRADE), TNFRSF19L (RELT), TNFRSF1A (TNF RI CD120a, p55-60) , p75-80), TNFRSF26 (TNFRH3), TNFRSF3 (LTbR TNF RIII, TNFCR), TNFRSF4 (OX40 ACT35, TXGP1 R), TNFRSF5 (CD40 p50), TNFRSF6 (Fas Apo-1, APT1, CD95), TNFRSF6B DcR3 M68, TR6), TNFRSF7 (DR3 Apo-3, LARD, TR-3), TNFRSF2 (DcTRAIL R2 TNFRH2), TNFRST23 (DcTRAIL R1 TNFRH1), TNFRSF25 , TNFSF10 (TRAIL Apo-2 ligand, TL2), TNFSF11 (TRANCE / RANK ligand ODF, OPG ligand), TNFSF12 (TWEAK Apo-3 ligand, DR3 ligand), TNFSF13 (APRIL TALL2), TNFSF13B (TNF-a coenetin, DIF, TNFSF2), TNFSF15 (TL1A / VEGI), TNFSF18 (GITR ligand AITR ligand, TL6), TNFSF14 (LIGHT HVEM ligand, LTg) TNFSF1B (TNF-b LTa, TNFSF1), TNFSF3 (LTb TNFC, p33), TNFSF4 (OX40 ligand gp34, TXGP1), TNFSF5 (CD40 ligand CD154, gp39, HIGM1, IMD3, TRAP), TNFSF6 (Fas ligand Apo-1 ligand , APT1 ligand), TNFSF7 (CD27 ligand CD70), TNFSF8 (CD30 ligand CD153), TNFSF9 (4-1BB ligand CD137 ligand), TP-1, t-PA, Tpo, TRAIL, TRAIL, TRAIL- R2, TRANCE, transferrin receptor, TRF, Trk, TROP-2, TSG, TSLP, tumor associated antigen CA125, VEFGR-1 (flt-1), VEGF-2, VEFGR-1 (flt-1), VEGF , VEGFR, VEGFR-3 (flt-4), VEGI, VIM, viral antigen, VLA, VLA-1, VLA-4, VNR integrin, von Willebrand factor, WIF-1, WNT1, WNT2, WNT2B / , WNT3A, WNT4, WNT5A, WNT5B, WNT6, WNT7A, WNT7B, WNT8A, WNT8B, WNT9A, WNT9B, WNT10A, WNT10B, WNT11, WNT16, XCL1, XCL2, XCR1, XCR1, XEDAR, XIAP, XPD, HMGB1, Beta, CD81, CD97, CD98, DDR1, DKK1, EREG, Hsp90, IL-17 / IL-17R, IL-20 / IL-20R, oxidized LDL, PCSK9, precalcine, RON, TMEM16F, SOD1, Granin A, Chromogranin B, tau, VAP1, high molecular weight kininogen, IL-31, IL-31R, Nav1.1, Nav1.2, Nav1.3, Nav1.4, Nav1.5, Nav1. C4a, C4b, C5, C5a, C5b, C6, C3, C4, C8, C7, C8, C9, factor B, factor D, factor H, propeldine, sclerostin, fibrinogen, fibrin, prothrombin, Factor VIIIa Factor IX Factor IXa Factor X Factor Xa Factor XI Factor XIa Factor XII Factor XIIa Factor XIII Factor XI 1, PAI-2, GPC3, sidecane-1, sidecane-2, sidecane-3, paclitaxel, XIIIa, TFPI, antithrombin III, EPCR, thrombomodulin, TAPI, tPA, plasminogen, , Sidecane-4, LPA, and S1P; And receptors for hormones and growth factors.

As discussed herein, one or more amino acid residue changes are allowed in an amino acid sequence that constitutes a variable region as long as it retains its antigen-binding activity. There is no particular restriction on the site of alteration and the number of amino acids altered when changing the amino acid sequence of the variable region. For example, the amino acids present in the CDRs and / or FRs can be suitably modified. When the amino acid in the variable region is altered, the binding activity is preferably maintained without particular limitations; For example, the binding activity may be greater than 50%, greater than 80%, and greater than 100% as compared to before change. Furthermore, the binding activity can be increased by amino acid modification. For example, the binding activity may be 2-, 5-, or 10-fold higher than before the change. Modification of the amino acid sequence may be at least one of amino acid residue substitution, addition, deletion and modification.

For example, modification of the N-terminal glutamine of the variable region to pyroglutamate by pyroglutamylation is a well known variant to those skilled in the art. Thus, where the heavy chain N terminus is glutamine, the antibody described herein may comprise a variable region in which the glutamine is modified to pyroglutamic acid.

The antibody variable regions described herein may have any sequence, and the region may be of any origin, such as a mouse antibody, a rat antibody, a rabbit antibody, a goat antibody, a camel antibody, by humanization of these non-human antibodies The resulting humanized antibody, and the antibody variable region of a human antibody. Furthermore, these antibodies may have various amino acid substitutions introduced into their variable regions to improve their antigen binding, pharmacokinetics, stability and immunogenicity. The variable region can bind repeatedly to the antigen due to its pH dependency in antigen binding (WO 2009/125825).

The kappa chain and the lambda chain are present in the antibody light chain constant region, any of the above being acceptable. Furthermore, these chains may have some amino acid modifications, for example substitution, deletion, addition and / or insertion.

Furthermore, the polypeptide comprising the variant Fc region described herein can be made into an Fc fusion protein by linking it to another protein, such as a physiologically active peptide. Such a fusion protein may be a multimer of at least two polypeptides comprising the variant Fc region. Examples of such other proteins include, but are not limited to, receptors, adhesion molecules, ligands and enzymes.

Examples of Fc fusion proteins include proteins fused to an Fc region for a receptor that binds to a target molecule, such as a TNFR-Fc fusion protein, an IL1R-Fc fusion protein, a VEGFR-Fc fusion protein, and a CTLA4-Fc fusion protein (Dumont et al., BioDrugs. 20 (3): 151-60 (2006))). Furthermore, the protein to be fused may be selected from other molecules having target binding activity, such as scFvs (WO 2005/037989), single-domain antibodies (WO 2004/058821; WO 2003/002609), antibody- , 7: 653-658 (2006)]; Current Opinion in Biotechnology 18: 1-10 (2007); Nygren et al., Curr. Such as DARPins (WO 2002/020565), Affibody (WO 1995/001937), Avicel (US Pat. Avimer (WO 2004/044011; WO 2005/040229), and Adnectin (WO 2002/032925). Furthermore, the antibody and Fc fusion protein can be multispecific and can bind to multiple types of target molecules or epitopes.

B. Recombinant Methods and Compositions

Antibodies can be generated, for example, using recombinant methods and compositions as disclosed in U.S. Patent No. 4,816,567. In one embodiment, an isolated nucleic acid encoding the anti-myostatin antibody disclosed herein is provided. In another embodiment, provided is an isolated nucleic acid encoding a variant Fc region described herein or a polypeptide comprising a parent Fc region. Such a nucleic acid may encode an amino acid sequence comprising the VL of the antibody (e.g., the light and / or heavy chain of the antibody) and / or an amino acid sequence comprising the VH. In a further embodiment, one or more vectors (e. G., Expression vectors) comprising such nucleic acids are provided. In a further embodiment, a host cell comprising such a nucleic acid is provided. In one such embodiment, the host cell comprises (1) a vector comprising a nucleic acid encoding an amino acid sequence comprising the VL of the antibody and an amino acid sequence comprising the VH of the antibody, or (2) a VL (E. G., Transformed with these vectors) a first vector comprising a nucleic acid encoding an amino acid sequence comprising the VH of the antibody and a second vector comprising a nucleic acid encoding an amino acid sequence comprising the VH of the antibody. In one embodiment, the host cell is a eukaryote, for example, a Chinese hamster ovary (CHO) cell or a lymphoid cell (eg, Y0, NS0, and Sp20 cells). In one embodiment, there is provided a method of producing an anti-myostatin antibody, wherein said method comprises contacting a host cell comprising a nucleic acid encoding said antibody, as provided above, under conditions suitable for expression of the antibody And optionally recovering the antibody from the host cell (or host cell culture medium). In another embodiment, there is provided a method of producing a polypeptide comprising a variant Fc region or a parent Fc region, wherein the method comprises contacting a polypeptide, e. G. An antibody, as provided above under conditions suitable for expression of the polypeptide , Culturing a host cell comprising the nucleic acid (s) encoding the Fc region or variant Fc region, and optionally recovering the polypeptide from the host cell (or host cell culture medium).

For recombinant production of the anti-myostatin antibody, the nucleic acid encoding the antibody, for example as described above, is isolated and inserted into one or more vectors for further cloning and / or expression in host cells. For recombinant production of the Fc region, the nucleic acid encoding the Fc region is isolated and inserted into one or more vectors for further cloning and / or expression in the host cell. Such nucleic acids can be readily isolated and sequenced using conventional procedures (e. G., By using oligonucleotide probes that are capable of specifically binding to the genes encoding the heavy and light chains of the antibody).

Suitable host cells for cloning or expression of the antibody-encoding vector include the prokaryotic or eukaryotic cells disclosed herein. For example, antibodies can be produced in bacteria, particularly where glycosylation and Fc effector function are not required. For the expression of antibody fragments and polypeptides in bacteria, see, for example, U.S. Patent No. 5,648,237, U.S. Patent No. 5,789,199, and U.S. Patent No. 5,840,523. (Also see Charlton, Methods in Molecular Biology, Vol. 248, BKC Lo, ed., Humana Press, Totowa, NJ, (2003), pp. 245-254, which describes the expression of antibody fragments in Escherichia coli ]). After expression, the antibody can be isolated from the bacterial cell paste in the solution fraction and further purified.

In addition to prokaryotes, eukaryotic microbes, such as fibrous fungi or yeast, e.g., fungal and yeast strains that produce antibodies with a " humanized "glycosylation pathway that has a partial or complete human glycosylation pattern, Suitable cloning or expression hosts. Gerngross, Nat. Biotech. 22: 1409-1414 (2004); And Li et al., Nat. Biotech. 24: 210-215 (2006).

Suitable host cells for expression of glycosylated antibodies are also derived from multicellular organisms (invertebrates and vertebrates). Examples of invertebrate cells are plant and insect cells. Especially Spodoptera For the transfection of frugiperda cells, a number of baculovirus strains which can be used with insect cells have been identified.

Plant cell cultures can also be used as hosts. See, for example, U.S. Patent Nos. 5,959,177, 6,040,498, 6,420,548, 7,125,978, and 6,417,429 (PLANTIBODIES ) Technology).

Vertebrate cells can also be used as hosts. For example, mammalian cell lines suitable for propagation in suspension may be useful. Another example of a useful mammalian host cell line is the monkey kidney CV1 strain transformed by SV40 (COS-7); Human embryonic kidney lines (such as 293 or 293 cells as described in Graham et al., J. Gen. Virol. 36: 59 (1977)); Baby hamster kidney cells (BHK); Mouse Sertoli cells (for example TM4 cells as described in Mather, Biol. Reprod. 23: 243-252 (1980)); Monkey kidney cells (CV1); African green monkey kidney cells (VERO-76); Human cervical carcinoma cells (HELA); (MDCK), human lung cells (W138), human hepatocytes (Hep G2), mouse breast tumors (MMT 060562) such as those described in Mather et al., Annals NY Acad. Other useful mammalian host cell lines are Chinese hamster ovary (CHO) cells, such as DHFR ^- CHO cells (see, for example, And myeloma cell lines such as Y0, NS0, and Sp2 / O. Some mammals suitable for antibody production include, but are not limited to, For review of host cell lines, see, for example, Yazaki and Wu, Methods in Molecular Biology, Vol. 248 (BKCLo, ed.), Humana Press, Totowa, NJ, pp. 255-268 (2003) ].

Antibodies with pH-dependent properties can be obtained using selection and / or mutagenesis methods, for example, as described in WO 2009/125825. The screening method may include any process that identifies an antibody having pH-dependent binding properties in a population of antibodies specific for a particular antigen. In some embodiments, the screening method can comprise measuring one or more binding parameters (e. G., KD or kd) of the individual antibodies in the initial antibody population in both acidic and neutral pH. The binding parameters of the antibody can be measured using, for example, surface plasmon resonance, or any other assay that allows quantitative or qualitative assessment of the binding properties of the antibody to a particular antigen. In some embodiments, the screening method may comprise identifying an antibody that binds to the antigen with an acid / neutral KD ratio of two or more. In a further embodiment, the screening method may include identifying an antibody that binds to the antigen at a pH of 5.8 / pH 7.4 KD ratio of 2 or more. On the other hand, the screening method may include identifying an antibody that binds to the antigen with an acid / neutral kd ratio of two or more. In a further embodiment, the screening method may comprise identifying an antibody that binds to the antigen at a pH of 5.8 / pH 7.4 kd ratio of 2 or more.

In another embodiment, the mutagenesis method can include incorporating deletion, substitution or addition of heavy chain and / or light chain amino acids of the antibody to increase the pH-dependent binding of the antibody to the antigen. In some embodiments, the mutagenesis can be carried out in one or more variable domains of the antibody, for example in one or more HVRs (e. G., CDRs). For example, the mutagenesis may involve substitution by another amino acid of an amino acid in one or more HVRs (e.g., CDRs) of the antibody. In some embodiments, the mutagenesis can comprise displacing one or more amino acids in at least one HVR (e. G., A CDR) of the antibody with histidine. In some embodiments, "increased pH-dependent binding" means that the mutated version of the antibody has a greater acid / neutral KD ratio than the original "parent" (i.e., less pH- Indicating a greater acid / neutral kd ratio. In some embodiments, the mutated version of the antibody has an acid / neutral KD ratio of at least 2. In some embodiments, the mutated version of the antibody has a KD 5.8 / pH 7.4 KD ratio of at least 2. On the other hand, the mutated version of the antibody has an acid / neutral kd ratio of 2 or more. In a further embodiment, the mutated version of the antibody has a pH of 5.8 / pH 7.4 kd ratio of at least 2.

Polyclonal antibodies are preferably generated in animals by multiple subcutaneous (sc) or intraperitoneal (ip) injections of the relevant antigen and adjuvant. A biologically active agent or a derivatizing agent, for example maleimido benzoyl sulfosuccinimide ester, to a protein which is immunogenic in the species to which the relevant antigen is to be immunized, for example, keyhole limpet hemocyanin, serum albumin, (Via a cysteine residue), N-hydroxysuccinimide (via a lysine residue), glutaraldehyde, succinic anhydride, SOCl ₂ , or R ¹ N = C = NR where R and R ¹ are different alkyl groups Lt; / RTI > may be useful).

An animal, usually a non-human mammal, is contacted with, for example, 100 μg or 5 μg of protein or conjugate (for rabbit or mouse, respectively) with 3 volumes of Freund's complete adjuvant, To an antigen, an immunogen conjugate or a derivative thereof. One month later the animal is boosted by subcutaneous injection at multiple sites at 1/5 to 1/10 of the original amount of peptide or conjugate in the Freund's complete adjuvant. After 7 to 14 days, the animal is drawn and serum is analyzed for antibody titer. The animals are inoculated additionally to the stationary station. Preferably, the animal is boosted with a conjugate conjugated to the same antigen but through different proteins and / or different crosslinking reagents. The conjugates can also be prepared as recombinant cell cultures as protein fusions. Also, flocculants such as alum are suitably used to increase the immune response.

Monoclonal antibodies are obtained from a population of substantially homogeneous antibodies, that is, individual antibodies comprising the population can be assayed for possible natural mutations and / or post-translational modifications (e. G., Isomerization, amidation) Except for the same. Thus, the modifier "monoclonal " indicates that the characteristics of the antibody are not a mixture of different antibodies.

For example, the monoclonal antibody can be prepared using the hybridoma method first described in Kohler et al., Nature 256 (5517): 495-497 (1975). In the hybridoma method, a mouse or other suitable host animal, e. G. A hamster, is immunized as described herein above to generate or produce an antibody that will specifically bind to the protein used for said immunization Induce lymphocytes that can. On the other hand, lymphocytes may be immunized in vitro.

The immunizing agent will typically comprise an antigenic protein or a fusion variant thereof. In general, peripheral blood lymphocytes (PBL) are used when cells of human origin are required, or spleen cells or lymph node cells are used when a non-human mammalian source is needed. The lymphocytes are then fused with an immortalized cell line using a suitable fusing agent, such as polyethylene glycol, to form hybridoma cells (Goding, Monoclonal Antibodies: Principles and Practice, Academic Press (1986), pp. 59 -103]).

Immortalized cell lines are usually transformed mammalian cells, especially myeloma cells, of rodent, bovine and human origin. Usually, a rat or mouse myeloma cell line is used. The hybridoma cells thus prepared are preferably seeded and grown in a suitable culture medium containing one or more substances that inhibit the growth or survival of the unmixed, apoptotic cells. For example, if the said myeloma cells are free of hypoxanthine guanine phosphoribosyl transferase (HGPRT or HPRT) enzyme, the culture medium for said hybridoma typically comprises hypoxanthine, aminopterin and thymidine (HAT Medium (which is a substance that prevents the growth of HGPRT-deficient cells).

Preferred immortalized myeloma cells efficiently fuse, support stable high-level production of antibodies by the selected antibody-producing cells, and are sensitive to media such as HAT medium. Of these, mouse myeloma cell lines such as MOPC-21 and MPC-11 mouse tumors (available from the Salk Institute Cell Distribution Center, San Diego, CA) and SP-2 Derivatives, such as X63-Ag8-653 (available from the American Type Culture Collection, Manassas, Va., USA). Human myeloma and mouse-human heteromyeloma cell lines have also been described for the production of human monoclonal antibodies (Kozbor et al., J. Immunol. 133 (6): 3001-3005 (1984); Brodeur et al. , Monoclonal Antibody Production Techniques and Applications, Marcel Dekker, Inc., New York, pp. 51-63 (1987)).

The culture medium in which hybridoma cells are grown is analyzed for the production of monoclonal antibodies against the antigen. Preferably, the binding specificity of the monoclonal antibody produced by the hybridoma cells is determined by immunoprecipitation or by in vitro binding assays such as radioimmunoassay (RIA) or enzyme-linked immunosorbant assay (ELISA) do. Such techniques and analyzes are known in the art. For example, binding affinity can be measured by Munson's Scatchard assay (Anal. Biochem. 107 (1): 220-239 (1980)).

After identifying hybridoma cells that produce antibodies of the desired specificity, affinity, and / or activity, the clones may be subcloned by limiting dilution procedures and grown by standard methods (Goding) . Suitable culture media for this purpose include, for example, D-MEM or RPMI-1640 medium. In addition, the hybridoma cells can be grown in vivo as tumors in mammals.

The monoclonal antibody secreted by the subclone is suitably recovered from the culture medium, the pluripotent or serum by a conventional immunoglobulin purification procedure such as protein A-sepharose, hydroxyapatite chromatography, gel electrophoresis, Dialysis, or affinity chromatography.

Antibodies can be generated by immunizing a suitable host animal against the antigen. In one embodiment, the antigen is a polypeptide comprising full-length myostatin. In one embodiment, the antigen is a polypeptide comprising latent myostatin. In one embodiment, the antigen is a polypeptide comprising a myostatin propeptide. In one embodiment, the antigen is a polypeptide comprising a region corresponding to the amino acid at position 21 to 100 of the myostatin propeptide (SEQ ID NO: 78). In one embodiment, the antigen is selected from the group consisting of 21-80, 41-100, 21-60, 41-80, 61-100, 21-40, 41-60, 61- 80, or 81-100. The invention also encompasses antibodies produced by immunizing an animal against the antigen. The antibody may include any one or combination of the features described in the "Exemplary anti-myostatin antibody ".

Fc region can be obtained by partially digesting an IgG1, IgG2, IgG3, IgG4 monoclonal antibody or the like with a protease such as pepsin, and then re-eluting the fraction adsorbed on the protein A column. The protease is not particularly limited as long as Fab and F (ab ') 2 can cleave the whole-length antibody to be produced in a limited manner by suitably setting enzyme reaction conditions such as pH, including pepsin and papain do.

Still further, the present invention provides a method of producing a polypeptide comprising a variant Fc region having increased Fc gamma RIIb-binding activity relative to a polypeptide comprising a parent Fc region, said method comprising at least one amino acid change Into the parent Fc region. In some embodiments, the resulting polypeptide is an antibody. In some embodiments, the antibody is a chimeric antibody, or a humanized antibody. In some embodiments, the resulting polypeptide is an Fc fusion protein.

In some embodiments, the generating method comprises the steps of: (a) producing a polypeptide comprising a parent Fc region; (b) introducing at least one amino acid change into the parent Fc region of the polypeptide; (c) measuring the monkey Fc gamma RIIb-binding activity of the polypeptide comprising the parent Fc region and the Fc region of step (b); (d) a polypeptide comprising a variant Fc region having increased monkey Fc gamma RIIb-binding activity relative to a polypeptide comprising said parent Fc region is selected.

In some embodiments, the generating method comprises the steps of: (a) producing a polypeptide comprising a parent Fc region; (b) introducing at least one amino acid change into the parent Fc region of the polypeptide; (c) measuring the monkey Fc gamma RIIIa- binding activity of the polypeptide comprising the parent Fc region and the Fc region of step (b); (d) a polypeptide comprising a variant Fc region having reduced monkey Fc gamma RIIIa- binding activity relative to a polypeptide comprising said parent Fc region is selected.

In some embodiments, the generating method comprises the steps of: (a) producing a polypeptide comprising a parent Fc region; (b) introducing at least one amino acid change into the parent Fc region of the polypeptide; (c) measuring the human Fc gamma RIIb-binding activity of the polypeptide comprising the parent Fc region and the polypeptide comprising the Fc region of step (b); (d) a polypeptide comprising a variant Fc region having increased human Fc gamma RIIb-binding activity relative to a polypeptide comprising said parent Fc region is selected.

In some embodiments, the generating method comprises the steps of: (a) producing a polypeptide comprising a parent Fc region; (b) introducing at least one amino acid change into the parent Fc region of the polypeptide; (c) measuring the human Fc gamma RIIIa- binding activity of the polypeptide comprising the parent Fc region and the Fc region of step (b); (d) a polypeptide comprising a variant Fc region having reduced human Fc gamma RIIIa- binding activity relative to a polypeptide comprising said parent Fc region is selected.

In some embodiments, the generating method comprises the steps of: (a) producing a polypeptide comprising a parent Fc region; (b) introducing at least one amino acid change into the parent Fc region of the polypeptide; (c) measuring the human Fc gamma RIIa (H form) -binding activity of the polypeptide comprising the parent Fc region and the Fc region of step (b); (d) a polypeptide comprising a variant Fc region having reduced human Fc gamma RIIa (H form) -binding activity relative to a polypeptide comprising said parent Fc region is selected.

In some embodiments, the generating method comprises the steps of: (a) producing a polypeptide comprising a parent Fc region; (b) introducing at least one amino acid change into the parent Fc region of the polypeptide; (c) measuring the human Fc gamma RIIa (R form) -binding activity of the polypeptide comprising the parent Fc region and the Fc region of step (b); (d) a polypeptide comprising a variant Fc region having reduced human Fc gamma RIIa (R form) -binding activity relative to a polypeptide comprising said parent Fc region is selected.

In one embodiment, in the above-mentioned production method of a polypeptide comprising a variant Fc region having an increased Fc gamma RIIb-binding activity, in the above-mentioned generation method, 231, 232, 233, 234, 235, 236, 237, 238 At least one amino acid of at least one position selected from the group consisting of SEQ ID NOs: 239, 264, 266, 267, 268, 271, 295, 298, 325, 326, 327, 328, 330, 331, 332, 334, Is changed. In some embodiments, the Fc gamma RIIb has the sequence of the synomolgus monkey Fc gamma RIIb (SEQ ID NO: 223). In some embodiments, the Fc gamma RIIb has the sequence of human Fc gamma RIIb (SEQ ID NO: 212, 213, or 214).

In another embodiment, at position 236, one amino acid is altered in the above-mentioned production method of a polypeptide comprising a variant Fc region having increased Fc gamma RIIb-binding activity.

In another embodiment, in the above-mentioned production method of a polypeptide comprising a variant Fc region having an increased Fc gamma RIIb-binding activity, (a) one amino acid change at position 236, and (b) ) 231, 232, 233, 234, 235, 237, 238, 239, 264, 266, 267, 268, 271, 295, 298, 325, 326, 327, 328, 330, 331, 332, At least two amino acids comprising at least one amino acid change in at least one position selected from the group consisting of SEQ ID NOs: In some embodiments, the Fc gamma RIIb has the sequence of the synomolgus monkey Fc gamma RIIb (SEQ ID NO: 223). In some embodiments, the Fc gamma RIIb has the sequence of human Fc gamma RIIb (SEQ ID NO: 212, 213, or 214).

In another embodiment, in the above-mentioned production method of a polypeptide comprising a variant Fc region having an increased Fc gamma RIIb-binding activity, (a) one amino acid change at position 236, and (b) ) At least two amino acids comprising at least one amino acid change in at least one position selected from the group consisting of 231, 232, 235, 239, 268, 295, 298, 326, 330, In some embodiments, the Fc gamma RIIb has the sequence of the synomolgus monkey Fc gamma RIIb (SEQ ID NO: 223). In some embodiments, the Fc gamma RIIb has the sequence of human Fc gamma RIIb (SEQ ID NO: 212, 213, or 214).

In another embodiment, in the above-mentioned production method of a polypeptide comprising a variant Fc region having an increased Fc gamma RIIb-binding activity, (a) one amino acid change at position 236, and b) at least two amino acids comprising at least one amino acid change in at least one position selected from the group consisting of 268, 295, 298, 326 and 330 are altered. In some embodiments, the Fc gamma RIIb has the sequence of the synomolgus monkey Fc gamma RIIb (SEQ ID NO: 223). In some embodiments, the Fc gamma RIIb has the sequence of human Fc gamma RIIb (SEQ ID NO: 212, 213, or 214).

In another embodiment, in the above-mentioned production method of a polypeptide comprising a variant Fc region having an increased Fc gamma RIIb-binding activity, in the above-mentioned production method, at any one of the following positions (1) to (37) according to EU numbering, (1) positions 231, 236, 239, 268 and 330; (2) positions 231, 236, 239, 268, 295 and 330; (3) positions 231, 236, 268 and 330; (4) positions 231, 236, 268, 295 and 330; (5) 232, 236, 239, 268, 295 and 330 positions; (6) 232, 236, 268, 295 and 330 positions; (7) 232, 236, 268 and 330 positions; (8) positions 235, 236, 268, 295, 326 and 330; (9) positions 235, 236, 268, 295 and 330; (10) positions 235, 236, 268 and 330; (11) positions 235, 236, 268, 330, and 396; (12) positions 235, 236, 268 and 396; (13) positions 236, 239, 268, 295, 298 and 330; (14) positions 236, 239, 268, 295, 326 and 330; (15) positions 236, 239, 268, 295 and 330; (16) positions 236, 239, 268, 298 and 330; (17) positions 236, 239, 268, 326 and 330; (18) positions 236, 239, 268 and 330; (19) positions 236, 239, 268, 330 and 396; (20) positions 236, 239, 268 and 396; (21) positions 236 and 268; (22) positions 236, 268 and 295; (23) positions 236, 268, 295, 298 and 330; (24) positions 236, 268, 295, 326 and 330; (25) positions 236, 268, 295, 326, 330, and 396; (26) positions 236, 268, 295 and 330; (27) positions 236, 268, 295, 330 and 396; (28) positions 236, 268, 298 and 330; (29) positions 236, 268, 298 and 396; (30) positions 236, 268, 326 and 330; (31) positions 236, 268, 326, 330, and 396; (32) positions 236, 268 and 330; (33) positions 236, 268, 330, and 396; (34) positions 236, 268 and 396; (35) positions 236 and 295; (36) positions 236, 330 and 396; And (37) positions 236 and 396. In some embodiments, the Fc gamma RIIb has the sequence of the synomolgus monkey Fc gamma RIIb (SEQ ID NO: 223). In some embodiments, the Fc gamma RIIb has the sequence of human Fc gamma RIIb (SEQ ID NO: 212, 213, or 214).

In a further embodiment, in the above-mentioned production method of a polypeptide comprising a variant Fc region having an increased Fc gamma RIIb-binding activity, the amino acid alteration is (a) 231 Asp, Glu, Phe, Gly, His, Ile, Lys, Leu, Met, Asn, Pro, Gln, Arg, Ser, Thr, Val, Trp, Tyr in position; (b) Ala, Asp, Glu, Phe, Gly, His, Ile, Lys, Leu, Met, Asn, Gln, Arg, Ser, Thr, Val, Trp, Tyr at position 232; (c) Asp at position 233; (d) Trp, Tyr at position 234; (e) Trp at position 235; (f) Ala, Asp, Glu, His, Ile, Leu, Met, Asn, Gln, Ser, Thr, Val at position 236; (g) Asp at position 237, Tyr; (h) Glu, Ile, Met, Gln, Tyr at position 238; (i) Ile, Leu, Asn, Pro, Val at position 239; (j) Ile at position 264; (k) Phe at position 266; (l) Ala, His, Leu at position 267; (m) Asp at position 268, Glu; (n) Asp, Glu, Gly at position 271; (o) Leu at position 295; (p) Leu at position 298; (q) Glu, Phe, Ile, Leu at position 325; (r) Thr at position 326; (s) Ile, Asn at position 327; (t) Thr at position 328; (u) Lys, Arg at position 330; (v) Glu at position 331; (w) Asp at position 332; (x) Asp, Ile, Met, Val, Tyr at position 334; And (y) Ala, Asp, Glu, Phe, Gly, His, Ile, Lys, Leu, Met, Asn, Gln, Arg, Ser, Thr, Val, Trp and Tyr at position 396. In some embodiments, the Fc gamma RIIb has the sequence of the synomolgus monkey Fc gamma RIIb (SEQ ID NO: 223). In some embodiments, the Fc gamma RIIb has the sequence of human Fc gamma RIIb (SEQ ID NO: 212, 213, or 214).

In a further embodiment, in the above-mentioned production method of a polypeptide comprising a variant Fc region having an increased Fc gamma RIIb-binding activity, the amino acid alteration is (a) 231 Position of Gly, Thr; (b) Asp at position 232; (c) Trp at position 235; (d) Asn, Thr at position 236; (e) Val at position 239; (f) Asp at position 268, Glu; (g) Leu at position 295; (h) Leu at position 298; (i) Thr at position 326; (j) Lys, Arg at position 330; And (k) Lys at position 396, Met. In some embodiments, the Fc gamma RIIb has the sequence of the synomolgus monkey Fc gamma RIIb (SEQ ID NO: 223). In some embodiments, the Fc gamma RIIb has the sequence of human Fc gamma RIIb (SEQ ID NO: 212, 213, or 214).

In a further embodiment, in the above-mentioned method of production of a polypeptide comprising a variant Fc region having an increased Fc gamma RIIb-binding activity, the amino acid alteration comprises Asn at position 236, Glu at position 268 , Lys at position 330, and Met at position 396. In a further embodiment, in the above-mentioned method of production of a polypeptide comprising a variant Fc region having an increased Fc gamma RIIb-binding activity, the amino acid alteration comprises Asn at position 236, Asp at position 268 , And Lys at position 330. In a further embodiment, in the above-mentioned method of production of a polypeptide comprising a variant Fc region having an increased Fc gamma RIIb-binding activity, the amino acid alteration comprises Asn at position 236, Asp at position 268 Leu at position 295, and Lys at position 330. In a further embodiment, in the above-mentioned method of production of a polypeptide comprising a variant Fc region having an increased Fc gamma RIIb-binding activity, the amino acid alteration is selected from the group consisting of Thr at position 236, Asp at position 268 , And Lys at position 330. In a further embodiment, in the above-mentioned method of production of a polypeptide comprising a variant Fc region having an increased Fc gamma RIIb-binding activity, the amino acid alteration comprises Asn at position 236, Asp at position 268 Leu at position 295, Thr at position 326, and Lys at position 330. In a further embodiment, in the above-mentioned method of production of a polypeptide comprising a variant Fc region having an increased Fc gamma RIIb-binding activity, the amino acid alteration comprises Trp at position 235, Asn at position 236 Asp at position 268, Leu at position 295, Thr at position 326, and Lys at position 330.

In one embodiment, in the above-mentioned method of production of a polypeptide comprising a variant Fc region having increased Fc gamma RIIb-binding activity, as described above in accordance with EU numbering 234, 238, 250, 264, 267, 307, and 330 At least one amino acid in at least one position selected from the group consisting of SEQ ID NO: In some embodiments, the Fc gamma RIIb has the sequence of the synomolgus monkey Fc gamma RIIb (SEQ ID NO: 223). In some embodiments, the Fc gamma RIIb has the sequence of human Fc gamma RIIb (SEQ ID NO: 212, 213, or 214).

In another embodiment, in the above-mentioned method of production of a polypeptide comprising a variant Fc region having increased Fc gamma RIIb-binding activity, one amino acid is altered at position 238.

In another embodiment, in the above-mentioned generation method of a polypeptide comprising a variant Fc region having an increased Fc gamma RIIb-binding activity, (a) one amino acid change at position 238 and (b) ) At least two amino acids comprising at least one amino acid change in at least one position selected from the group consisting of 234, 250, 264, 267, 307 and 330 are modified. In some embodiments, the Fc gamma RIIb has the sequence of the synomolgus monkey Fc gamma RIIb (SEQ ID NO: 223). In some embodiments, the Fc gamma RIIb has the sequence of human Fc gamma RIIb (SEQ ID NO: 212, 213, or 214).

In another embodiment, in the above-mentioned production method of a polypeptide comprising a variant Fc region having an increased Fc gamma RIIb-binding activity, in the above-mentioned production method, at any one of the following positions (1) to (9) according to EU numbering, (1) positions 234, 238, 250, 307, and 330; (2) positions 234, 238, 250, 264, 307 and 330; (3) positions 234, 238, 250, 264, 267, 307 and 330; (4) positions 234, 238, 250, 267, 307 and 330; (5) positions 238, 250, 264, 307 and 330; (6) positions 238, 250, 264, 267, 307 and 330; (7) positions 238, 250, 267, 307 and 330; (8) positions 238, 250 and 307; And (9) positions 238, 250, 307 and 330.

In a further embodiment, in the above-mentioned production method of a polypeptide comprising a variant Fc region having an increased Fc gamma RIIb-binding activity, the amino acid modification is carried out at each position in accordance with EU numbering: (a) Location of Tyr; (b) Asp at position 238; (c) Val at position 250; (d) Ile at position 264; (e) Ala at position 267; (f) Pro at position 307; And (g) Lys at position 330. In a further embodiment, in the above-mentioned production method of a polypeptide comprising a variant Fc region having increased Fc gamma RIIb-binding activity, the amino acid modification is Asp at position 238, according to EU numbering. In a further embodiment, in the above-mentioned method of production of a polypeptide comprising a variant Fc region having an increased Fc gamma RIIb-binding activity, the amino acid alteration comprises Asp at position 238, Val at position 250, , And Pro at position 307. In a further embodiment, in the above-mentioned method of production of a polypeptide comprising a variant Fc region having an increased Fc gamma RIIb-binding activity, the amino acid alteration comprises Asp at position 238, Val at position 250, Pro at position 307, and Lys at position 330. In a further embodiment, in the above-mentioned method of production of a polypeptide comprising a variant Fc region having an increased Fc gamma RIIb-binding activity, the amino acid alteration comprises Asp at position 238, Val at position 250, , Ile at position 264, Pro at position 307, and Lys at position 330. In a further embodiment, in the above-mentioned method of production of a polypeptide comprising a variant Fc region having an increased Fc gamma RIIb-binding activity, the amino acid alteration comprises Asp at position 238, Val at position 250, Ala at position 267, Pro at position 307, and Lys at position 330. In a further embodiment, in the above-mentioned production method of a polypeptide comprising a variant Fc region having an increased Fc gamma RIIb-binding activity, the amino acid alteration is selected from the group consisting of Tyr at position 234, Asp at position 238 , Val at position 250, Pro at position 307, and Lys at position 330. In a further embodiment, in the above-mentioned production method of a polypeptide comprising a variant Fc region having an increased Fc gamma RIIb-binding activity, the amino acid alteration is selected from the group consisting of Tyr at position 234, Asp at position 238 Val at position 250, Ala at position 267, Pro at position 307, and Lys at position 330. In a further embodiment, in the above-mentioned method of production of a polypeptide comprising a variant Fc region having an increased Fc gamma RIIb-binding activity, the amino acid alteration comprises Asp at position 238, Val at position 250, Ile at position 264, Ala at position 267, Pro at position 307, and Lys at position 330. In a further embodiment, in the above-mentioned production method of a polypeptide comprising a variant Fc region having an increased Fc gamma RIIb-binding activity, the amino acid alteration is selected from the group consisting of Tyr at position 234, Asp at position 238 Val at position 250, Ile at position 264, Pro at position 307, and Lys at position 330. In a further embodiment, in the above-mentioned production method of a polypeptide comprising a variant Fc region having an increased Fc gamma RIIb-binding activity, the amino acid alteration is selected from the group consisting of Tyr at position 234, Asp at position 238 Val at position 250, Ile at position 264, Ala at position 267, Pro at position 307, and Lys at position 330. In some embodiments, the Fc gamma RIIb has the sequence of the synomolgus monkey Fc gamma RIIb (SEQ ID NO: 223). In some embodiments, the Fc gamma RIIb has the sequence of human Fc gamma RIIb (SEQ ID NO: 212, 213, or 214).

Still further, the invention provides a method of producing a polypeptide comprising a variant Fc region having increased pI compared to a polypeptide comprising a parent Fc region, said method comprising the step of altering at least two amino acid changes in said parent Fc region .

In some embodiments, the method for producing a polypeptide comprising the variant Fc region provided herein comprises the steps of: (a) preparing a polypeptide comprising a parent Fc region; (b) introducing at least two amino acid modifications into the parent Fc region of the polypeptide; (c) measuring the pI of the polypeptide comprising the parent Fc region and the polypeptide comprising the Fc region of step (b); (d) selecting a polypeptide comprising a variant Fc region having an increased pI relative to a corresponding polypeptide comprising said parent Fc region.

311, 312, 315, 318, 333, 335, 337, 341, 342, 337, 341, 342, At least two amino acids in at least two positions selected from the group consisting of SEQ ID NOs: 343, 384, 385, 388, 390, 399, 400, 401, 402, 413, 420, 422, In a further embodiment, the resulting polypeptide comprises a variant Fc region having an increased pi, which is identified as 311, 341, 343, 384, 399, 400, 401, 402, and 413 At least two amino acid changes in at least two positions selected from the group consisting of SEQ ID NOs.

In another embodiment, in any of the following positions (1) to (10), the amino acid is changed in the above-mentioned production method of a polypeptide comprising a mutant Fc region having an increased pI: according to EU numbering, (1) positions 311 and 341; (2) positions 311 and 343; (3) positions 311, 343, and 413; (4) positions 311, 384, and 413; (5) positions 311 and 399; (6) positions 311 and 401; (7) positions 311 and 413; (8) positions 400 and 413; (9) positions 401 and 413; And (10) positions 402 and 413.

In a further embodiment, in the above-mentioned production method of a polypeptide comprising a variant Fc region having an increased pI, the amino acid alteration is Arg at position 400 and Lys at position 413 according to EU numbering. In a further embodiment, in the above-mentioned production method of a polypeptide comprising a variant Fc region having increased pi, the amino acid alteration is Arg at position 311 and Lys at position 413 according to EU numbering. In a further embodiment, in the above-mentioned production method of a polypeptide comprising a variant Fc region having increased pi, the amino acid alteration is Arg at position 311 and Arg at position 399 according to EU numbering. In a further embodiment, in the above-mentioned production method of a polypeptide comprising a variant Fc region having an increased pI, the amino acid modification is Arg at position 311 and Arg at position 343 according to EU numbering. In a further embodiment, in the above-mentioned production method of a polypeptide comprising a variant Fc region having increased pi, the amino acid alteration is Arg at position 311 and Arg at position 413 according to EU numbering. In a further embodiment, in the above-mentioned method of production of a polypeptide comprising a variant Fc region having increased pi, the amino acid alteration is selected from Arg at position 311, Arg at position 343, and position 413 according to EU numbering Of Arg. In a further embodiment, in the above-mentioned production method of a polypeptide comprising a variant Fc region having increased pi, the amino acid alteration is selected from Arg at position 311, Arg at position 384, and Arg at position 413 Of Arg.

In a further aspect, in the above-mentioned production method of a polypeptide comprising a variant Fc region with increased pi, the amino acid alteration is selected from Lys and Arg at each position.

In a further aspect, the amino acid alteration in the above-mentioned production methods is selected from any single alteration, a combination of single alterations, and the combination alterations described in Tables 14 to 30. [

Optionally, when the polypeptide comprising the variant Fc region further comprises an antigen-binding domain, the above-mentioned method of production of the polypeptide may comprise the following additional steps: (e) mouse, rat, rabbit Evaluating the pharmacokinetics of antigens in plasma after administration of a polypeptide comprising said parent Fc region and a polypeptide comprising said variant Fc region in an animal, such as a dog, a monkey, and a human; (f) a polypeptide comprising a variant Fc region in which the ability to remove an antigen from plasma is increased compared to a polypeptide comprising the parent Fc region is selected.

Polypeptides comprising variant Fc regions produced by any of the above-mentioned methods and any of the methods known in the art are encompassed by the present invention.

C. Analysis

The anti-myostatin antibodies provided herein can be identified, screened, or characterized for their physical / chemical properties and / or biological activity by various assays known in the art.

The variant Fc regions provided herein can be identified, screened, or characterized for their physical / chemical properties and / or biological activity by various assays known in the art.

1. Combination and other analyzes

In one embodiment, the antibodies of the invention are tested for their antigen binding activity by known methods, such as ELISA, Western blot, Biacore (TM), and the like. In one embodiment, a polypeptide comprising a variant Fc region of the invention is tested for its Fc receptor binding activity by a known method, such as Biacore (R), for example.

In another aspect, competitive assays can be used to identify antibodies that compete with any of the anti-myostatin antibodies described herein for binding to myostatin. In some embodiments, such competitive antibodies as described above inhibit binding of the reference antibody to myostatin by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% %, 60%, 65%, 70%, 75% or more. In some instances, binding is inhibited by at least 80%, 85%, 90%, 95% or more. In some embodiments, such competitive antibodies may be derived from the same epitope bound by the anti-myostatin antibody described herein (e. G., The anti-myostatin antibody described in Tables 2a, Linear or stereostructured epitope). In a further embodiment, the reference antibody has the VH and VL pairs set forth in Tables 2a, 11a or 13. Detailed illustrative methods for mapping antibody-binding epitopes are described in Morris (1996) "Epitope Mapping Protocols ", in Methods in Molecular Biology, Vol. 66 (Humana Press, Totowa, NJ).

In an exemplary competition assay, a labeled first antibody that binds an immobilized latent myostatin or myostatin propeptide to myostatin and an ability to compete with the first antibody for binding to the myostatin Lt; / RTI > in a solution containing a second unlabeled antibody to be tested. The second antibody may be present in the hybridoma supernatant. As a control, immobilized myostatin is incubated in a solution containing the labeled first antibody but not the second unlabeled antibody. After incubation under conditions permitting the binding of the first antibody to the myostatin, the excess unbound antibody is removed and the amount of label bound to immobilized myostatin is determined. If the amount of label bound to immobilized myostatin is substantially reduced in the test sample as compared to the control sample, this implies that the second antibody competes with the first antibody for binding to the myostatin (See, for example, Harlow and Lane (1988) Antibodies: A Laboratory Manual ch.14 (Cold Spring Harbor Laboratory, Cold Spring Harbor, NY)).

Assays for measuring binding activity of polypeptides containing one or more Fc gamma R and variant Fc regions for members are described herein or otherwise known in the art. Such binding assays include, but are not limited to, Biacore (TM) assays (using surface plasmon resonance (SPR) phenomena), amplified luminescent proximity uniformity assay (ALPHA) screening, ELISA, and fluorescence activated cell sorting FACS (Lazar et al., Proc. Natl. Acad. Sci. USA (2006) 103 (11): 4005-4010).

In one embodiment, using the ViaCore (TM) assay, it is determined whether the binding activity of a polypeptide comprising a variant Fc region is increased, maintained, or decreased with respect to a particular Fc gamma R and members, For example, the method and reagent (for example, protein A, protein L, protein A / G, protein G, anti-lambda chain antibody, anti-carboxychiral antibody, antigenic peptide (Antigenic protein) interacting with the polypeptide comprising the Fc region of the variant immobilized or captured on the sensor chip as an analyte], can be assessed by observing whether there is a decrease or increase in the value of the dissociation constant (KD) have. The change in binding activity may also be compared by comparing changes in resonance unit (RU) values on the sensorgram before and after interaction with the captured polypeptide comprising the variant Fc region in one or more of the Fc gamma R's as an analyte Can be measured. On the other hand, Fc gamma R can be immobilized or captured on the sensor chip, and the polypeptide comprising the variant Fc region is used as an analyte.

In the Biacore (registered trademark) analysis, one of the materials (ligand) is immobilized on the gold foil on the sensor chip when observing the interaction, and the total reflection occurs on the back surface of the sensor chip , A part of the reduced reflection intensity is formed in the reflected light portion (SPR signal). When observing the interaction, the other one (analyte) of the materials is allowed to flow on the surface of the sensor chip, and when the ligand binds to the analyte, the mass of the immobilized ligand molecule increases and the The refractive index of the solvent changes. The position of the SPR signal shifts as a result of this refractive index change (on the other hand, the signal position is returned when the coupling is dissociated). The Biacore (TM) system refers to the above-mentioned movement amount or, more specifically, to the time variable of mass by plotting the mass change on the surface of the sensor chip on the coordinate as measurement data (sensorgram). The amount of analyte bound to the ligand captured on the surface of the sensor chip is measured from the sensorgram. Kinetic parameters such as binding rate constant (ka) and dissociation rate constant (kd) are measured from the curves of the sensorgrams and the dissociation constant (KD) is measured from the ratio of these constants. In the Biacore (registered trademark) method, a method of measuring inhibition is preferably used. Examples of such inhibition measurement methods are described in Lazar et al., Proc. Natl. Acad. Sci. USA 103 (11): 4005-4010 (2006).

ALPHA screening is performed by the ALPHA technique using two beads, a donor and a receptor, based on the following principle. The luminescent signal is detected only when the molecule bound to the donor bead is physically interacting with the molecule bound to the acceptor bead, and the two beads are located very close to each other. The laser-excited photosensitizer in the donor bead converts the ambient oxygen to an excited-state singlet oxygen. Singlet oxygen is dispersed around the donor bead and when it reaches the adjacent acceptor bead a chemiluminescent reaction is induced in the bead and ultimately light is emitted. When the molecule bound to the donor bead does not interact with the molecule bound to the acceptor bead, the chemiluminescent reaction does not occur because the singlet oxygen generated by the donor bead does not reach the acceptor bead.

For example, a biotinylated polypeptide complex binds to the donor bead and an Fc gamma receptor tagged with glutathione S transferase (GST) binds to the acceptor bead. In the absence of a competitive polypeptide complex comprising a variant Fc region, a polypeptide complex comprising a parent Fc region interacts with the Fc gamma receptor to produce a 520 to 620 nm signal. A polypeptide complex comprising an untagged variant Fc region competes with a polypeptide complex comprising a parent Fc region for interaction with said Fc gamma receptor. Relative binding activity can be measured by quantitatively analyzing the fluorescence reduction observed as a result of the competition. It is known to biotinylate a polypeptide complex such as an antibody using sulfo-NHS-biotin or the like. Expressing the Fc gamma receptor and GST in a cell carrying a fusion gene produced by infecting a polynucleotide encoding the Fc gamma receptor with a polynucleotide encoding GST in an expression vector and performing purification using a glutathione column, Is suitably employed as a method of tagging the Fc gamma receptor with GST. The obtained signal is preferably processed into a single-site (for example, using a non-linear regression analysis using software such as GRAPHPAD PRISM (GraphPad, San Diego, USA) Analyze by adapting to competitive model.

The variant Fc region with reduced Fc gamma R-binding activity has a substantially weaker binding activity than the parent Fc region when performing analysis using a substantially equivalent amount of the corresponding parent Fc region and variant Fc region, Refers to the Fc region that binds gamma R. Furthermore, variant Fc regions with increased Fc gamma R-binding activity are substantially more potent than the corresponding parent Fc region when conducting assays using substantially equal amounts of parent Fc region and variant Fc region Quot; refers to an Fc region that binds to Fc gamma R as active. The variant Fc region with retained Fc gamma R-binding activity is equivalent to or homologous to the parent Fc region when performing analysis using polypeptides containing substantially equivalent amounts of the corresponding parent Fc region and variant Fc region, Refers to an Fc region that binds to Fc gamma R with very little different binding activity.

Whether the binding activity of the Fc region for the various Fc gamma Rs has been increased or decreased is determined from the increase or decrease of the binding amount of various Fc gamma Rs to the Fc region (which was measured according to the above mentioned measurement method) . Here, the binding amounts of the various Fc gamma Rs to the Fc region are determined by comparing the difference in the RU value of the sensorgrams before and after the interaction between the Fc region and the various Fc gamma R as the analyte, And the RU value of the sensorgram changed before and after the capture of the sensorgram.

In the present invention, the augmented Fc gamma RIIb-binding activity is preferably determined, for example, by measuring the KD value of the parent Fc region against Fc gamma RIIb / [Fc gamma RIIb The KD value of the mutant Fc region to the mutant Fc region is preferably at least 2.0, at least 3.0, at least 4.0, at least 5.0, at least 6.0, at least 7.0, at least 8.0, at least 9.0, at least 10, at least 15, at least 20, Means at least 30, at least 35, at least 40, at least 45, or even at least 50, at least 55, at least 60, at least 65, at least 70, at least 75, at least 80, at least 85, at least 90, at least 95, do.

The KD value (mol / L) of the variant Fc region described herein for Fc gamma RIIb is preferably less than that of the parent Fc region for Fc gamma RIIb, for example less than or equal to 2.0x10 < ^-6 & ^-6 M or less, 9.0x10 ^-7 M or less, 8.0x10 ^-7 M or less, 7.0x10 ^-7 M or less, 6.0x10 ^-7 M or less, 5.0x10 ^-7 M or less, 4.0x10 ^-7 M or less, 3.0x10 ^{- 7} M or less, 2.0x10 ^-7 M or less, 1.0x10 ^-7 M or less, 9.0x10 ^-8 M or less, 8.0x10 ^-8 M or less, 7.0x10 ^-8 M or less, 6.0x10 ^-8 M or less, 5.0x10 ^-8 M or less.

Furthermore, the variant Fc region with increased binding selectivity for Fc gamma RIIb relative to Fc gamma RIIa is (a) increased in Fc gamma RIIb-binding activity and maintained or reduced in Fc gamma RIIa-binding activity; (b) Fc gamma RIIb-binding activity is increased and Fc gamma RIIa-binding activity is also increased, but the degree of increase in Fc gamma RIIa-binding activity is lower than that of Fc gamma RIIb-binding activity; Or (c) refers to an Fc region where the Fc gamma RIIb-binding activity is reduced and the Fc gamma RIIa-binding activity is also reduced, but the degree of decrease in Fc gamma RIIb-binding activity is less than the degree of decrease in Fc gamma RIIa- binding activity . Whether the variant Fc region has improved binding selectivity for Fc gamma RIIb rather than for Fc gamma RIIa can be determined, for example, by comparing the ratio of the KD value for the Fc gamma RIIa to the KD value for the Fc gamma RIIb of the variant Fc region [KD value of mutant Fc region against Fc gamma RIIa] / [KD value of mutant Fc region against Fc gamma RIIb]) was calculated from the KD value of Fc gamma RIIa versus Fc gamma RIIa KD (Ratio of [KD value of parent Fc region to Fc gamma RIIa] / [KD value of parent Fc region to Fc gamma RIIb]) (this was measured according to the example mentioned above) . Specifically, when the KD ratio for the variant Fc region is greater than for the parent Fc region, the variant Fc region has improved binding selectivity to Fc gamma RIIb rather than to Fc gamma RIIa relative to the parent Fc region . In particular, in humans, the Fc gamma RIIb-binding activity is more potent than Fc gamma RIIa (H) because the amino acid sequence of Fc gamma RIIb shares a higher correspondence with Fc gamma RIIa (type R) than Fc gamma RIIa (R type) than Fc gamma RIIa (type R). Thus, finding amino acid alterations (s) that can increase binding selectivity for human Fc gamma RIIb compared to human Fc gamma RIIa (R form) increases binding selectivity for Fc gamma RIIb in humans compared to Fc gamma RIIa It is important to do.

Where the variant Fc region of the invention has a higher binding activity for Fc gamma RIIb and has a lower binding activity for Fc gamma RIII (e.g., Fc gamma RIIIa or Fc gamma RIIIb), the variant Fc region may be Fc gamma RIIb-specificity.

2. Activity analysis

In one embodiment, an assay is provided to identify an anti-myostatin antibody having biological activity. Biological activities include, for example, inhibiting the activation of myostatin, blocking the release of mature myostatin from latent myostatin, inhibiting proteolytic cleavage of latent myostatin, Blocking access to orthostat, and the like. It also provides an antibody having such a biological activity in vivo and / or ex vivo. In some embodiments, the antibodies of the invention are tested for such biological activity.

In some embodiments, whether the test antibody inhibits the cleavage of latent myostatin is determined by contacting the protease capable of cleaving latent myostatin with the latent myostatin in the presence or absence of the test antibody (Myostatin) using methods known in the art, such as electrophoresis, chromatography, immunoblot analysis, enzyme-linked immunosorbant assay (ELISA), or mass spectrometry (See, for example, Thies et al., Growth Factors 18 (4): 251-259 (2001)). When a reduced amount of the cleavage product of the latent myostatin (e.g., human myostatin propeptide) is detected in the presence (or subsequent to contact with the antibody) of the test antibody, Is identified as an antibody capable of inhibiting myostatin cleavage. In some embodiments, whether the test antibody blocks protease access to latent myostatin is determined by a method for detecting protein interactions between the protease and latent myostatin, such as ELISA or VIA Core (Registered trademark). If a reduced interaction between the protease and latent myostatin is detected in the presence (or subsequent to contacting the antibody) of the test antibody, the test antibody will block access to the latent myostatin of the protease Lt; / RTI >

In some embodiments, the ability of the test antibody to block the release of mature myostatin from latent myostatin can be assessed using mature myostatin activity, for example, binding activity to the myostatin receptor, Lt; RTI ID = 0.0 > (e. G., ActRIIb). Cells useful for such assays may be cells expressing an endogenous myostatin receptor, for example a L6 muscle cell, or a myostatin receptor such as an actin receptor, such as the actin II type receptor [Thies et < RTI ID = 0.0 > al.]). ≪ / RTI > Binding of myostatin to the myostatin receptor can be detected using receptor binding assays. The myostatin mediated signal transduction can be tested in the signal transduction pathway, for example, by examining the phosphorylation of the Smad polypeptide, by examining the expression of the myostatin regulated gene, including the reporter gene, It can be detected at an arbitrary level by measuring proliferation. When reduced mature myostatin activity is detected in the presence of (or in contact with) the test antibody, the test antibody is identified as an antibody capable of blocking the release of mature myostatin from latent myostatin do.

The inhibition of myostatin activation can also be detected and / or measured using the methods illustrated and exemplified in the Examples. Using these or other suitable types of assays, test antibodies can be screened for those that can inhibit the activation of myostatin. In some embodiments, the inhibition of myostatin activation is at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, or at least 5% And a reduction of more than 40%. In some embodiments, this refers to inhibition of myostatin activation by at least 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% .

In another embodiment, an assay for the identification of anti-myostatin antibodies that form an immunoconjugate (i. E., An antigen-antibody complex) with myostatin is provided. It also provides an antibody having such a biological activity in vivo and / or ex vivo.

In some embodiments, the antibodies of the invention are tested for such biological activity.

In some embodiments, the formation of immune complexes is assessed by methods such as size exclusion (gel filtration) chromatography, ultracentrifugation, light scattering, electron microscopy, or mass spectrometry (Mol. Immunol. 39: 77-84 (2002), Mol. Immunol. 47: 357-364 (2009)). These methods use the property that the immunocomplex is an antibody alone, or a molecule larger than an antigen alone. When a large complex containing two or more antibodies and two or more antigens (e.g., myostatin molecules) is detected in the presence of test antibodies and antigens, the test antibody may comprise two or more antibodies and two or more myostatin Lt; RTI ID = 0.0 > a < / RTI > molecule. In another embodiment, the formation of an immune complex is detected by ELISA, FACS, or SPR (surface plasmon resonance; e.g., using Biacore (TM)) (Shields et al., J. Biol. Chem. Suzuki et al., J. Immunol. 184 (4), pp. 276 (9): 6591-6604 (2001); Singh et al., J. Immunol. Methods 50: 109-114 : 1968-1976 (2010)]; Luo et al., MAbs 1 (5): 491-504 (2009)). These methods utilize the property that an immunoconjugate containing two or more antibodies and two or more antigens can bind more strongly to an Fc receptor or complement component than to an antibody or antigen alone. When the increased binding to the Fc receptor or complement component is detected in the presence of both the test antibody and the antigen as compared to in the presence of the antibody alone, the test antibody may be an immunizing agent comprising two or more antibodies and two or more myostatin molecules Lt; RTI ID = 0.0 > complex. ≪ / RTI > In another embodiment, the formation of an immunocomplex is evaluated by administering a test antibody to an animal (e.g., a mouse) and measuring the clearance of the antigen from the plasma. As described above, antibodies that form an immunoconjugate containing two or more antibodies together with two or more antigens are expected to accelerate the removal of antigen from plasma. Thus, when accelerated removal of myostatin from plasma is observed in test antibody-administered mice as compared to a reference antibody-administered mouse, the test antibody is more efficient than two or more antibodies and more than two Is identified as an antibody capable of forming an immunoconjugate containing a myostatin molecule.

D. Immunoconjugates

In some embodiments, the present invention is directed to a composition comprising at least one cytotoxic agent, such as a chemotherapeutic agent or drug, a growth inhibitory agent, a toxin (e.g., a protein toxin, a bacterial, fungal, enzymatic active toxin of plant or animal origin, ), Or an anti-myostatin antibody as described herein conjugated to a radioactive isotope.

In some embodiments, the present invention is directed to a composition comprising at least one cytotoxic agent, such as a chemotherapeutic agent or drug, a growth inhibitory agent, a toxin (e.g., a protein toxin, a bacterial, fungal, enzymatic active toxin of plant or animal origin, ), Or a variant Fc region of the present invention conjugated to a radioactive isotope.

In one embodiment, the immunoconjugate is an antibody wherein the antibody comprises one or more drugs, such as, but not limited to, maytansinoids (see U.S. Patent No. 5,208,020, U.S. Patent No. 5,416,064 and EP 0 425 235 B1); Auristatin, such as the monomethylauristatin drug moieties DE and DF (MMAE and MMAF) (U.S. Pat. No. 5,635,483, U.S. Pat. No. 5,780,588, and U.S. Pat. No. 7,498,298); Dolastatin; Calicheamicin or derivatives thereof (U.S. Patent No. 5,712,374, U.S. Patent No. 5,714,586, U.S. Patent No. 5,739,116, U.S. Patent No. 5,767,285, U.S. Patent No. 5,770,701, U.S. Patent No. 5,770,710, U.S. Patent No. 5,773,001, and See, for example, U.S. Patent No. 5,877,296; Hinman et al., Cancer Res 53: 3336-3342 (1993); and Lode et al., Cancer Res. 58: 2925-2928 (1998) ; Anthracyclines such as daunomycin or doxorubicin (Kratz et al., Current Med. Chem. 13: 477-523 (2006); Jeffrey et al., Bioorganic & Natl. Acad. Sci. USA 97: 829-821 (2005)), as described in the literature [Torgov et al., Bioconj. Chem. 16: 717-721 (2000); Dubowchik et al., Bioorg. &Amp; Med. Chem. Letters 12: 1529-1532 (2002); King et al., J. Med. Chem. 45: 4336-4343 ) And U.S. Patent No. 6,630,579; Methotrexate; Bindeseo; Taxanes such as docetaxel, paclitaxel, laurotaxel, teflon shell, and hortata taxol; Tricothecene; And an antibody-drug conjugate (ADC) conjugated to a drug comprising CC1065.

In another embodiment, the immunoconjugate is an enzyme active toxin or a fragment thereof, such as, but not limited to, diphtheria A chain, unbound active fragment of diphtheria toxin, exotoxin A chain (from Pseudomonas aeruginosa), lysine A chain, (PAPI, PAPII and PAP-S), momordica carantia inhibitors, curcumin, corticosteroids, cortisone, An antibody as described herein conjugated to catechin, a saponin orophylline inhibitor, gelonin, mitogellin, resorcinosine, penomycin, enomycin and tricothecene.

In another embodiment, the immunoconjugate comprises an antibody as described herein that is conjugated to a radioactive atom to form a radioactive conjugate. A variety of radioactive isotopes can be used to generate radioactive conjugates. For example, radioisotopes At ²¹¹ , I ¹³¹ , I ¹²⁵ , Y ⁹⁰ , Re ¹⁸⁶ , Re ¹⁸⁸ , Sm ¹⁵³ , Bi ²¹² , P ³² , Pb ²¹² , and Lu. When the radioactive conjugate is used for detection, the conjugate may be labeled with radioactive atoms for scintillography studies, such as tc99m or I123, or spin markers for nuclear magnetic resonance (NMR) imaging (also known as magnetic resonance imaging, mri) For example, iodine-123, iodine-131, indium-111, fluorine-19, carbon-13, nitrogen-15, oxygen-17, gadolinium, manganese or iron.

Antibodies and cytotoxic agents may be conjugated to various bi-functional protein coupling agents such as N-succinimidyl-3- (2-pyridyldithio) propionate (SPDP), succinimidyl- Maleimidomethyl) cyclohexane-1-carboxylate (SMCC), iminothiolane (IT), bi-functional derivatives of imidoesters (such as dimethyladipimidate HCl), active esters Diazonium derivatives such as bis- (diazomethyl) imidazolidine, imidylsubstituted), aldehydes such as glutaraldehyde, bis-azido compounds such as bis (p-azidobenzoyl) hexanediamine, (e.g., p-diazonium benzoyl) -ethylenediamine), diisocyanates (e.g., toluene 2,6-diisocyanate), and bis-active fluorine compounds such as 1,5-difluoro-2,4- Nitrobenzene). ≪ / RTI > For example, ricin immunotoxins can be prepared as described in Vitetta et al., Science 238: 1098 (1987). Carbon-14-labeled 1-isothiocyanatobenzyl-3-methyldiethylenetriamine pentaacetic acid (MX-DTPA) is an exemplary chelating agent for conjugation of radionuclides to the antibody. See WO 1994/11026. The linker may be a "cleavable linker" that promotes the release of a cytotoxic drug in a cell. For example, acid-labile linkers, peptidase-sensitive linkers, photo-labile linkers, dimethyl linkers or disulfide-containing linkers (Chari et al., Cancer Res. 52: 127-131 (1992); U.S. Patent No. 5,208,020) can be used.

The immunoconjugate or ADC may be a cross-linking reagent such as, but not limited to, BMPS, EMCS, GMBS, HBVS, LC-SMCC, MBS, MPBH, SBAP, SIA, SIAB, SMCC, SMPB, SMPH, SMBO, Sulfo-KMUS, Sulfo-MBS, Sulfo-SIB, Sulfo-SMCC, and Sulfo-SMPB, and SVSB (succinimidyl-4- (vinylsulfonyl) benzoate), such as those commercially available from Pierce Biotechnology, (Pierce Biotechnology, Inc., Rockville, Ill., USA) is expressly contemplated in the present invention.

E. Methods and compositions for diagnosis and detection

In some embodiments, any one of the anti-myostatin antibodies provided herein is useful for detecting the presence of myostatin in a biological sample. The term "detecting " as used herein includes quantitative or qualitative detection. In some embodiments, the biological sample can be a cell or tissue, such as serum, whole blood, plasma, biopsy sample, tissue sample, cell suspension, saliva, sputum, mouthwash, cerebrospinal fluid, amniotic fluid, , Lymph, urine, sweat, leakage, gastric juice, synovial fluid, peritoneal fluid, lens secretion or mucus.

In one embodiment, there is provided an anti-myostatin antibody for use in a diagnostic or detection method. In a further aspect, there is provided a method of detecting the presence of latent myostatin or myostatin propeptide in a biological sample. In some embodiments, the method comprises contacting the biological sample with an anti-myostatin antibody as described herein under conditions that allow binding of the anti-myostatin antibody to myostatin, Lt; RTI ID = 0.0 > myostatin < / RTI > antibody and myostatin. Such methods may be in vitro or in vivo methods. In one embodiment, an anti-myostatin antibody is used to select a subject eligible for therapy with an anti-myostatin antibody, for example, if myostatin is a biomarker for patient selection.

Exemplary diseases that may be diagnosed using the antibodies of the invention include, but are not limited to, muscular dystrophy (MD) (including duchenne muscular dystrophy), amyotrophic lateral sclerosis (ALS), muscular dystrophy, tracheal dystrophy, wrist tunnel syndrome, Type 2 diabetes, impaired glucose tolerance, metabolic syndrome (including syndrome X), insulin resistance (including trauma, such as hip or nitrogen < RTI ID = 0.0 > Osteoarthritis, and metabolic bone disease (including low bone mass, premature gonadal dysfunction, and osteoarthritis), osteoporosis, osteoarthritis, and metabolic bone disease (including, for example, Androgen deprivation, vitamin D deficiency, secondary hyperparathyroidism, malnutrition and anorexia nervosa).

In some embodiments, a labeled anti-myostatin antibody is provided. Markers include, but are not limited to, moieties or moieties that are indirectly detected, e. G., Through enzyme reactions or molecular interactions, as well as markers or moieties that are directly detected (e.g., fluorescent, colorimetric, electron- For example enzymes or ligands. Exemplary labels include, but are not limited to, radioactive isotopes ³² P, ¹⁴ C, ¹²⁵ I, ³ H and ¹³¹ I, fluorescent moieties such as rare earth chelates or fluororesins and derivatives thereof, rhodamine and derivatives thereof, Luciferase, such as firefly luciferase and bacterial luciferase (U.S. Patent No. 4,737,456), luciferin, 2,3-dihydropthalazineion, horseradish peroxidase (HRP ), Alkaline phosphatase, -galactosidase, glucoamylase, lysozyme, saccharide oxidase such as glucose oxidase, galactose oxidase, and glucose-6-phosphate dehydrogenase, heterocyclic oxidase, For example, free radicals and xanthines (coupled with dye precursors using hydrogen peroxide, such as enzymes that oxidize HRP), lactoperoxidase, or microperoxidase, biotin / avidin, , It comprises a bacteriophage cover, stable free radicals and the like.

F. Pharmaceutical Formulation

The pharmaceutical formulations of anti-myostatin antibodies as described herein can be prepared by mixing such an antibody having the desired degree of purity with one or more optional pharmaceutically acceptable carriers (see Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980)) to form lyophilized formulations or aqueous solutions.

A pharmaceutical formulation of a polypeptide comprising a variant Fc region as described herein can be prepared by mixing a polypeptide as described above having the desired degree of purity with a pharmaceutically acceptable carrier in one or more optional pharmaceutically acceptable carriers, By weight.

Pharmaceutically acceptable carriers are generally non-toxic to the recipient at the dosages and concentrations employed, such carriers including, but not limited to, buffers such as phosphate, citrate and other organic acids; Antioxidants including ascorbic acid and methionine; (For example, octadecyldimethylbenzylammonium chloride, hexamethonium chloride, benzalkonium chloride, benzethonium chloride, phenol, butyl or benzyl alcohol, alkyl parabens such as methyl or propyl paraben, Cyclohexanol; 3-pentanol; and m-cresol); Low molecular weight (less than about 10 residues) polypeptides; Proteins, such as serum albumin, gelatin, or immunoglobulins; Hydrophilic polymers such as polyvinylpyrrolidone; Amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; Monosaccharides, daisaccharides, and other carbohydrates such as glucose, mannose, or dextrin; Chelating agents such as EDTA; Sugars such as sucrose, mannitol, trehalose or sorbitol; Salt-forming counter ions, such as sodium; Metal complexes (e. G., Zn-protein complexes); And / or non-ionic surfactants such as polyethylene glycol (PEG). Exemplary pharmaceutically acceptable carriers in the present invention include interstitial drug dispersants such as soluble neutral-active hyaruronidase glycoprotein (sHASEGP) such as human soluble PH-20 hyaruronidase glycoprotein, For example, rHuPH20 (HYLENEX (registered trademark), Baxter International, Inc.). Some exemplary sHASEGPs including rHuPH20 and methods of use are disclosed in U.S. Patent Nos. 2005/0260186 and 2006/0104968. In one embodiment, the sHASEGP is used in combination with one or more additional glycosaminoglycanases, such as a chondroitinase.

Exemplary lyophilized formulations are disclosed in U.S. Patent No. 6,267,958. Aqueous antibody formulations include those disclosed in U. S. Patent No. 6,171, 586 and WO 2006/044908, the latter formulation comprising a histidine-acetate buffer.

The formulations of the present invention may also contain more than one active ingredient required for the particular indication being treated, preferably those having complementarity that do not adversely affect each other. Such active ingredients are suitably present together in an amount effective for the intended purpose.

The active ingredient may be incorporated into microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) Or in each hydroxymethylcellulose or gelatin-microcapsule and poly- (methylmethacrylate) microcapsule in a large emulsion. Such techniques are described in Remington ' s Pharmaceutical Sciences, 16th edition, Osol, A. (ed.) (1980).

A sustained-release preparation may be prepared. Suitable examples of sustained-release preparations include semipermeable substrates of solid hydrophobic polymers containing the antibody, wherein the substrate is in the form of a molded article, e.g., a film or microcapsule.

Formulations used for in vivo administration are generally sterile. Sterilization can be easily performed, for example, by filtration through a sterile filter membrane.

G. Therapeutic Methods and Compositions

Any of the anti-myostatin antibodies provided herein may be used in therapy. Likewise, any of the polypeptides comprising the variant Fc regions provided herein can be used in a method of treatment.

In one embodiment, an anti-myostatin antibody is provided for use as a medicament. In a further aspect, there is provided an anti-myostatin antibody for use in the treatment of muscle wasting disease. In some embodiments, anti-myostatin antibodies are provided for use in a therapeutic method. In some embodiments, the invention provides an anti-myostatin antibody for use in a method of treatment of said individual, comprising administering to said subject an amount of said anti-myostatin antibody to an individual having a muscle wasting disease. In one embodiment, the method also comprises administering to said subject an effective amount of at least one additional therapeutic agent. In a further embodiment, the invention provides an anti-myostatin antibody for use in increasing muscle mass. In some embodiments, the present invention provides a method for increasing the mass of muscle tissue in an individual, comprising administering to the individual an effective amount of the anti-myostatin antibody to increase the mass of the muscle tissue. - myostatin antibody. In a further embodiment, the invention provides an anti-myostatin antibody for use in increasing muscle tissue strength. In some embodiments, the present invention provides a method for increasing the intensity of muscle tissue in a subject, comprising administering to the subject an effective amount of the anti-myostatin antibody to increase the strength of the muscle tissue. - myostatin antibody. In a further embodiment, the present invention provides an anti-myostatin antibody for use in reducing body fat accumulation. In some embodiments, the invention provides an anti-myostatin antibody for use in a method of reducing body fat accumulation in a subject, comprising administering to the subject an effective amount of the anti-myostatin antibody to reduce body fat accumulation Lt; / RTI > The "entity" according to any of the above embodiments is preferably a human.

The anti-myostatin antibody of the present invention may exhibit pH-dependent binding properties. In a further embodiment, the invention provides an anti-myostatin antibody for use in augmenting the clearance of myostatin from plasma. In some embodiments, the invention provides a method of increasing the clearance of myostatin from plasma in the subject, comprising administering to the subject an effective amount of the anti-myostatin antibody to increase the clearance of myostatin from plasma. 0.0 > anti-myostatin < / RTI > antibody for use in the method. In one embodiment, anti-myostatin antibodies with pH-dependent binding properties increase the clearance of myostatin from plasma, as compared to conventional anti-myostatin antibodies that do not have pH-dependent binding properties. In a further embodiment, an anti-myostatin antibody having a pH-dependent binding property between the binding at pH 5.8 and pH 7.4 is less potent than a conventional anti-myostatin antibody that does not have pH- Increases the clearance of myostatin. The "entity" according to any of the above embodiments is preferably a human.

In a further aspect, the invention provides the use of an anti-myostatin antibody in the manufacture or formulation of a medicament. In one embodiment, the agent is for treating muscle wasting disease. In a further embodiment, the medicament is for use in a method of treatment of the disease, comprising administering an effective amount of the medicament to a subject having a muscle wasting disease. In one embodiment, the method also comprises administering to said subject an effective amount of at least one additional therapeutic agent. In a further embodiment, the agent is for increasing the mass of the muscle tissue. In a further embodiment, the medicament is for use in a method for increasing the mass of muscle tissue in the subject, comprising administering to the subject an effective amount of the medicament to increase the mass of the muscle tissue. In a further embodiment, the agent is for increasing the strength of the muscle tissue. In a further embodiment, the agent is for use in a method of increasing the intensity of muscle tissue in the subject, comprising administering to the subject an effective amount of the agent to increase the strength of the muscle tissue. In a further embodiment, the medicament is for reducing body fat accumulation. In a further embodiment, the medicament is for use in a method for reducing body fat accumulation in a subject, comprising administering to the subject an effective amount of the medicament to reduce body fat accumulation. An "entity" in accordance with any of the above embodiments may be a human.

The anti-myostatin antibody of the present invention may exhibit pH-dependent binding properties. In a further embodiment, the agent is for increasing the clearance of myostatin from plasma. In a further embodiment, the medicament is for use in a method of increasing the clearance of myostatin from plasma in the subject, comprising administering to the subject an effective amount of the medicament to increase the clearance of myostatin from plasma. . In one embodiment, anti-myostatin antibodies with pH-dependent binding properties increase the clearance of myostatin from plasma, as compared to conventional anti-myostatin antibodies that do not have pH-dependent binding properties. In a further embodiment, the anti-myostatin antibody exhibits different pH-dependent binding characteristics between the binding at pH 5.8 and pH 7.4. The "entity" according to any of the above embodiments is preferably a human.

In another aspect, the invention provides a method of treating muscle wasting disease. In one embodiment, the method comprises administering an effective amount of the anti-myostatin antibody provided herein to an individual having such a muscle wasting disease. In one embodiment, the method also comprises administering to said subject an effective amount of at least one additional therapeutic agent. An "entity" in accordance with any of the above embodiments may be a human.

In another aspect, the invention provides a method of increasing muscle mass in an individual. In one embodiment, the method comprises administering to the subject an effective amount of an anti-myostatin antibody provided herein to increase the mass of the muscle tissue. In one embodiment, the "entity" is a human.

In another aspect, the invention provides a method of increasing muscle tissue strength in an individual. In one embodiment, the method comprises administering to the subject an effective amount of an anti-myostatin antibody provided herein to increase muscle tissue strength. In one embodiment, the "entity" is a human.

In another aspect, the present invention provides a method of reducing body fat accumulation in an individual. In one embodiment, the method comprises administering to the subject an effective amount of an anti-myostatin antibody provided herein to reduce body fat accumulation. In one embodiment, the "entity" is a human.

The anti-myostatin antibody of the present invention may exhibit pH-dependent binding properties. In a further embodiment, the invention provides a method of increasing the clearance of myostatin from plasma in an individual. In one embodiment, the method comprises administering to the subject an effective amount of the anti-myostatin antibody to increase the clearance of myostatin from plasma. In one embodiment, anti-myostatin antibodies with pH-dependent binding properties increase the clearance of myostatin from plasma, as compared to conventional anti-myostatin antibodies that do not have pH-dependent binding properties. In a further embodiment, the anti-myostatin antibody exhibits different pH-dependent binding characteristics between the binding at pH 5.8 and pH 7.4. In one embodiment, "entity" is a human.

In a further aspect, the invention provides a pharmaceutical formulation comprising any one of the anti-myostatin antibodies provided herein, for use, for example, in any of the above methods of treatment. In one embodiment, the pharmaceutical formulations comprise any one of the anti-myostatin antibodies provided herein and a pharmaceutically acceptable carrier. In another embodiment, the pharmaceutical formulations comprise any one of the anti-myostatin antibodies provided herein and at least one additional therapeutic agent.

In a further aspect, the pharmaceutical formulation is for the treatment of muscle wasting disease. In a further embodiment, the pharmaceutical formulation is for increasing the mass of the muscle tissue. In a further embodiment, the pharmaceutical formulation is for increasing the strength of the muscle tissue. In a further embodiment, the pharmaceutical formulation is for reducing body fat accumulation. The anti-myostatin antibody of the present invention may exhibit pH-dependent binding properties. In a further embodiment, the pharmaceutical formulation is for increasing the clearance of myostatin from plasma. In one embodiment, the pharmaceutical formulation is administered to a subject having a muscle wasting disease. The "entity" according to any of the above embodiments is preferably a human.

In a further aspect, the present invention provides a method for the manufacture of a pharmaceutical or pharmaceutical formulation, wherein any one of the anti-myostatin antibodies provided herein, for use in any of the above methods of treatment, RTI ID = 0.0 > acceptable < / RTI > In one embodiment, the method of manufacturing a pharmaceutical or pharmaceutical formulation further comprises adding at least one additional therapeutic agent to the pharmaceutical or pharmaceutical formulation.

In some embodiments, the muscle fatigue disease is selected from the group consisting of muscular dystrophy (including MD (including duodenal myositis), amyotrophic lateral sclerosis (ALS), muscular dystrophy, tracheal dystrophy, wrist tunnel syndrome, weakness, (Including syndromes X), insulin resistance (including trauma, such as resistance caused by hip or nitrogen imbalance), chronic inflammatory diseases such as diabetic retinopathy, diabetic retinopathy, diabetic retinopathy, diabetic retinopathy, Osteoarthritis, and metabolic bone disease (including low bone mass, early gonadal dysfunction, androgen deprivation, vitamin D deficiency, secondary osteoporosis, osteoarthritis, and osteoarthritis) Hyperparathyroidism, malnutrition and anorexia nervosa).

Any of the polypeptides comprising the variant Fc region provided herein can be used in a method of treatment. In a further aspect, the invention provides a pharmaceutical formulation comprising a polypeptide comprising any one of the polypeptides comprising a variant Fc region provided herein, for use, for example, in a therapeutic method. In one embodiment, the pharmaceutical formulations comprise a polypeptide comprising any one of the polypeptides comprising a variant Fc region provided herein and a pharmaceutically acceptable carrier. In another embodiment, the pharmaceutical formulations comprise a polypeptide comprising any one of the variant Fc regions provided herein and at least one additional therapeutic agent.

In one aspect, there is provided a polypeptide comprising a variant Fc region for use as a medicament. In a further aspect, there is provided a polypeptide comprising a variant Fc region for use in the treatment of a disease. In some embodiments, polypeptides comprising a variant Fc region for use in a therapeutic method are provided. In some embodiments, the present invention provides a method of treating a subject, comprising administering to a subject suffering from the disorder a therapeutically effective amount of a polynucleotide comprising a variant Fc region comprising an effective amount of a variant Fc region provided herein, Peptide. In one embodiment, the method also comprises administering to said subject an effective amount of at least one additional therapeutic agent. In one embodiment, "entity" is a human.

In a further aspect, the invention provides the use of a polypeptide comprising a variant Fc region in the manufacture or formulation of a medicament. In one embodiment, the medicament is for treating a disease. In some embodiments, the polypeptide is an antibody. In some embodiments, the polypeptide is an Fc fusion protein. In a further embodiment, the medicament is for use in a method for the treatment of a disease comprising administering an effective amount of the medicament to an individual having a disease to be treated. In one embodiment, the method also comprises administering to said subject an effective amount of at least one additional therapeutic agent. In one embodiment, the "entity" is a human.

In a further aspect, the invention provides a method of treating a disease. In one embodiment, the method comprises administering to a subject suffering from such a disease an effective amount of a polypeptide comprising a variant Fc region. In one embodiment, the method also comprises administering to said subject an effective amount of at least one additional therapeutic agent. In one embodiment, the "entity" is a human.

In a further aspect, the invention provides a pharmaceutical formulation comprising a polypeptide comprising a variant Fc region provided herein, for use in a therapeutic method, such as any of the methods of treatment described herein. In one embodiment, the pharmaceutical formulations comprise a polypeptide comprising a variant Fc region provided herein and a pharmaceutically acceptable carrier. In another embodiment, the pharmaceutical formulations comprise a polypeptide comprising a variant Fc region provided herein and at least one additional therapeutic agent.

In a further aspect, the pharmaceutical formulation is for treating a disease. In one embodiment, the pharmaceutical formulation is administered to a subject having a disease. In one embodiment, the "entity" is a human.

In a further embodiment, the invention provides a polypeptide comprising a variant Fc region for use in inhibiting activation of B cells, mast cells, dendritic cells and / or basophils. In some embodiments, the invention provides a method of treating a subject suffering from a B-cell, a mast cell, a dendritic cell, and / or a B-cell comprising administering to the subject a polypeptide comprising an effective amount of a variant Fc region There is provided a polypeptide comprising a variant Fc region for use in a method for inhibiting activation of cells, mast cells, dendritic cells and / or basophils. In one embodiment, the "entity" is a human.

In a further aspect, the invention provides the use of a polypeptide comprising a variant Fc region in the manufacture or formulation of a medicament. In some embodiments, the polypeptide is an antibody. In some embodiments, the polypeptide is an Fc fusion protein. In a further embodiment, the medicament is for inhibiting activation of B cells, mast cells, dendritic cells and / or basophils. In a further embodiment, the medicament is a B cell, a mast cell, a bovine cell, a mammal, a human, or a mammal, including a human, comprising administering to the individual an effective amount of the agent to inhibit activation of B cells, mast cells, dendritic cells, Dendritic cells and / or basophils. In one embodiment, the "entity" is a human.

In a further aspect, the invention provides a method of inhibiting the activation of B cells, mast cells, dendritic cells and / or basophils in an individual. In one embodiment, the method comprises administering to the subject a polypeptide comprising a variant Fc region in an amount effective to inhibit activation of B cells, mast cells, dendritic cells, and / or basophils. In one embodiment, the "entity" is a human.

In a further aspect, the invention provides a pharmaceutical formulation comprising a polypeptide comprising a variant Fc region. In a further embodiment, the pharmaceutical formulation is for inhibiting the activation of B cells, mast cells, dendritic cells and / or basophils.

The polypeptide comprising the variant Fc region of the present invention can inhibit the activation of B cells, mast cells, dendritic cells and / or basophils. While not wishing to be bound by theory, it is believed that the inhibited activation is the result of selective binding of the provided variant Fc region to Fc gamma RIIb without activation of Fc gamma R. As used herein, "B cell activation" includes proliferation, IgE production, IgM production, and IgA production. While not intending to be bound by theory, the inhibited activation of B cells inhibits IgM production of B cells by inhibiting IgE production of B cells and cross-linking with IgM by cross-linking Fc gamma RIIb with IgE, Is believed to be a result of the ability of the provided variant Fc region on the polypeptide comprising the variant Fc region of the invention to inhibit IgA production by cross-linking. In addition to the above, an inhibitory effect similar to that mentioned above is achieved by contacting Fc gamma RIIb with a molecule that is expressed on B cells and contains an ITAM domain within the cell or interacts with the ITAM domain, e.g., BCR, CD9 and CD79b Or indirectly by cross-linking. As used herein, "activation of mast cells" includes proliferation, activation by IgE, and degranulation. Without wishing to be bound by theory, it is believed that the inhibited activation of the mast cell can be induced by modulating Fc gamma RIIb expression on mast cells, including the ITAM domain or interacting with the ITAM domain, such as Fc epsilon RI, DAP12 and CD200R3 Is believed to be the result of the ability of the provided variant Fc region on a polypeptide comprising a variant Fc region of the invention to cross-link directly or indirectly with an IgE receptor molecule. As used herein, "activation of a basophil device" includes proliferation and degassing of a basophil. Without wishing to be bound by theory, it is believed that the inhibited activation of neutrophils can be accomplished by contacting the Fc gamma RIIb with an antibody that either directly or indirectly cross-links molecules on the cell membrane that contain or interact with the ITAM domain within the cell It is believed to be a result of the ability of the provided variant Fc region on a polypeptide comprising the variant Fc region of the invention. As used herein, "dendritic cell activation" includes the proliferation and degranulation of dendritic cells. Without wishing to be bound by theory, it is believed that the inhibited activation of the dendritic cells can be achieved by either directly or indirectly cross-linking Fc gamma RIIb with molecules on the cell membrane that contain or interact with the ITAM domain within the cell Is believed to be the result of the ability of the provided variant Fc region on a polypeptide comprising the variant Fc region of the invention.

In a further embodiment, the invention provides polypeptides comprising the variant Fc regions provided herein for use in the treatment of immunological inflammatory diseases. In some embodiments, the invention relates to a method of treating said immunologic inflammatory disease in said subject, comprising administering to said subject a polypeptide comprising an amount of a variant Fc region effective to treat immunological inflammatory disease Lt; RTI ID = 0.0 > Fc < / RTI > region. In one embodiment, the "entity" is a human.

In a further aspect, the invention provides the use of a polypeptide comprising the variant Fc region provided herein in the manufacture or preparation of a medicament. In some embodiments, the polypeptide is an antibody. In some embodiments, the polypeptide is an Fc fusion protein. In a further embodiment, the agent is for treating immunological inflammatory diseases. In a further embodiment, the medicament is for use in a method of treating the immunological inflammatory disease in a subject, comprising administering to the subject an amount of the medicament effective to treat an immunological inflammatory disease. An "entity" in accordance with any of the above embodiments may be a human.

In a further aspect, the present invention provides a method for treating an immunological inflammatory disease in an individual. In one embodiment, the method comprises administering to the subject a polypeptide comprising an amount of a variant Fc region effective to treat an immunological inflammatory disease. In one embodiment, "entity" is a human.

In a further aspect, the invention provides a pharmaceutical formulation comprising any one of said polypeptides comprising a variant Fc region provided herein. In a further embodiment, the pharmaceutical formulation is for treating immunological inflammatory diseases.

As described above, since the polypeptide comprising the variant Fc region of the present invention can inhibit the activation of B cells, mast cells, dendritic cells and / or neutrophils, consequently, the polypeptide comprising the variant Fc region of the present invention Administration of the peptides can treat or prevent immunological inflammatory diseases.

In some embodiments, the treated immunological inflammatory disease is selected from the group consisting of rheumatoid arthritis, autoimmune hepatitis, autoimmune thyroiditis, autoimmune thyroid disease, autoimmune adrenocortical disease, autoimmune hemolytic anemia, autoimmune thrombocytopenic purpura, Autoimmune thrombocytopenia, autoimmune receptor disease, autoimmune infertility, chronic active hepatitis, glomerulonephritis, interstitial pulmonary fibrosis, multiple sclerosis, Paget's disease, osteoporosis, autoimmune atrophy, autoimmune atrophic gastritis, autoimmune neutropenia, Inflammatory bowel disease, adult respiratory distress syndrome (ARDS), psoriasis, Crohn's disease, bassadoes disease, childhood diabetes, Addison's disease, myasthenia gravis, lens-induced uveitis , Systemic lupus erythematosus, allergic rhinitis, allergic dermatitis, ulcerative colitis, hypersensitivity, muscle regression, cachexia, whole body Ischemia-reperfusion injury, atherosclerosis, cerebral trauma, brain malaria, septicemia, diabetic retinopathy, diabetic retinopathy, diabetic retinopathy, diabetic retinopathy, scleroderma, scleroderma, Sjogren's syndrome, Behcet's disease, IgA neuropathy, hay fever, antiphospholipid antibody syndrome, septic shock, toxic shock syndrome, fever, pain due to staining, aplastic anemia, hemolytic anemia, idiopathic thrombocytopenia, Goodpasture's syndrome, Guilin-Barre syndrome, Hashimoto's thyroiditis, , Atopic dermatitis, chronic atopic gastritis, primary biliary cirrhosis, primary sclerosing cholangitis, autoimmune pancreatitis, aortic aneuritis syndrome, rapid progression, multiple sclerosis, multiple sclerosis, multiple sclerosis, Wegener's granulomatosis, nodular arteritis, mixed connective tissue disease, fibromyalgia, asthma, Glomerulonephritis, hypertrophic anemia, idiopathic thrombocytopenic purpura, primary hypothyroidism, idiopathic Addison's disease, Leukodystrophy, autoimmune optic neuropathy, idiopathic azoospermia, acute myelogenous leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic myelogenous leukemia, chronic myelogenous leukemia, chronic myelogenous leukemia, , Schizoaffective syndrome, Graves' disease, schizophrenia, schizoaffective syndrome, chronic myelogenous leukemia, chronic myelogenous leukemia, chronic myelogenous leukemia, chronic myelogenous leukemia, chronic myelogenous leukemia, chronic myelogenous leukemia, hypoglycemia, chronic urticaria, ankylosing spondylitis, Alzheimer's disease, dehydration-induced disease, amyotrophic lateral sclerosis, hypoparathyroidism, Dresler syndrome, Eaton-Lambert syndrome, herpes dermatitis, alopecia, progressive systemic sclerosis, CREST syndrome Esophageal dysfunction, scleroderma, and capillary vasculopathy), sarcoidosis, rheumatic fever, polymorphism The present invention relates to the use of a compound of formula (I) for the manufacture of a medicament for the treatment of endometriosis, myocarditis, myocarditis, endocarditis, endocarditis, hemorrhagic fever, rheumatoid arthritis, , Mycobacterium tuberculosis, Mycobacterium tuberculosis, Mycobacterium tuberculosis, Mycobacterium tuberculosis, Mycobacterium tuberculosis, myofascial fasciitis, Peltia syndrome, platelet nonresponsive purpura, graft rejection, mumps, cardiomyopathies, pyogenic arthritis, familial Mediterranean fever, Merkle-Wells syndrome and high-IgD syndrome.

In a further embodiment, the invention provides a polypeptide comprising a variant Fc region for use in treating or preventing an autoimmune disease caused by, or associated with, the production of an antibody (autoantibody) to an autoantigen to provide. In some embodiments, the invention provides a method of treating an autoimmune disease in a subject comprising administering to the subject a polypeptide comprising an amount of a variant Fc region effective to treat or prevent an autoimmune disease, There is provided a polypeptide comprising a variant Fc region for use in a method of treating or preventing an autoimmune disease caused by, or associated with, The "entity" according to any of the above embodiments is preferably a human.

In a further aspect, the invention provides the use of a polypeptide comprising the variant Fc region provided herein in the manufacture or preparation of a medicament. In some embodiments, the polypeptide is an antibody. In some embodiments, the polypeptide is an Fc fusion protein. In a further embodiment, the agent is for treating or preventing an autoimmune disease caused by, or associated with, the production of an antibody (autoantibody) to an autoantigen. In a further aspect, the medicament is administered to a subject by administering to the subject an amount of the medicament in an amount effective to treat or prevent an autoimmune disease, such as by the generation of an antibody (autoantibody) For the treatment or prevention of autoimmune diseases which may be associated with < RTI ID = 0.0 > a < / RTI > The "entity" according to any one of the above embodiments may preferably be a human.

In a further aspect, the invention provides a method for treating or preventing an autoimmune disease caused by, or associated with, the production of an antibody (autoantibody) to an autoantigen in an individual. In one embodiment, the method comprises administering to the subject a polypeptide comprising an amount of a variant Fc region effective to treat or prevent the autoimmune disease. In one embodiment, "entity" is a human.

In a further aspect, the invention provides a pharmaceutical formulation comprising any of the polypeptides comprising a variant Fc region provided herein. In a further embodiment, the pharmaceutical formulations are for the treatment or prevention of autoimmune diseases caused by, or associated with, the production of antibodies (autoantibodies) to autoantigens.

Polypeptides comprising variant Fc regions of the invention can be used to treat or prevent autoimmune diseases caused by, or associated with, the production of autoantibodies by inhibiting the production of antibodies (autoantibodies) to autoantigens have. It has been reported that the use of fusion molecules of the antibody Fc portion with AchR (an autoantigen of myasthenia gravis) inhibits the proliferation of B cells expressing AchR-recognized BCR and induces apoptosis (J. Neuroimmunol 227: 35 -43 (2010)). The use of a fusion protein formed between the variant Fc region of the invention and an antigen recognized by autoantibody allows cross-linking between Fc gamma RIIb and the BCR for the autoantigen on the B cell, And / or induce apoptosis of said B cells.

In some embodiments, the autoimmune disease that may be treated or prevented is selected from the group consisting of Guillain-Barre syndrome, myasthenia gravis, chronic atrophic gastritis, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, autoimmune pancreatitis, Hypothyroidism, idiopathic thrombocytopenic purpura, idiopathic thrombocytopenic purpura, Bassadoes disease, Hashimoto's thyroiditis, primary hypothyroidism, idiopathic Addison's disease, insulin-dependent diabetes mellitus, Acute epidermolysis bullosa, alopecia areata, amyotrophic lateral sclerosis, acute alopecia, Sartan's acute appendicitis, Harada disease, autoimmune optic neuropathy, autoimmune optic neuropathy, idiopathic hypersensitivity, Arteriosclerosis, obesity, habitual abortion, type II diabetes, hypoglycemia and chronic urticaria .

In a further embodiment, the invention provides a polypeptide comprising a variant Fc region for use in the treatment of a disease associated with a deficiency in a biologically essential protein. In some embodiments, the invention relates to a method of treating the disease in a subject, comprising administering to the subject a polypeptide comprising an amount of a variant Fc region effective to treat a disease associated with a deficiency of a biological essential protein And a variant Fc region for use in said polypeptide. The "entity" according to any of the above embodiments is preferably a human.

In a further aspect, the invention provides the use of a polypeptide comprising a variant Fc region in the manufacture or formulation of a medicament. In some embodiments, the polypeptide is an antibody. In some embodiments, the polypeptide is an Fc fusion protein. In a further embodiment, the medicament is for treating a disease associated with a deficiency of a biological essential protein. In a further embodiment, the agent is for use in a method of treating the disease in a subject, comprising administering to the subject an amount of the agent effective to treat a disease associated with a deficiency of a biologically essential protein. An "entity" in accordance with any of the above embodiments may be a human.

In a further aspect, the invention provides a method of treating a disease associated with a deficiency of a biologically essential protein in an individual. In one embodiment, the method comprises administering to the subject a polypeptide comprising an amount of a variant Fc region effective for the treatment of the disease. In one embodiment, "entity" is a human.

In a further aspect, the invention provides a pharmaceutical formulation comprising any of the polypeptides comprising a variant Fc region provided herein. In a further embodiment, the pharmaceutical formulation is for the treatment of a disease associated with a deficiency of a biological essential protein.

For diseases with a deficiency of a biologically essential protein, therapeutic methods are used in which the protein is administered and supplemented as a medicament. However, since the patient does not have the protein from the beginning, the patient recognizes the externally supplemented protein as an antibody that produces foreign substances and proteins. As a result, the protein is easily removed and the effect as a medicine is reduced. The use of a fusion protein comprising such a protein and the variant Fc region of the invention allows cross-linking between Fc gamma RIIb and a BCR that recognizes the protein on the B cell, It causes.

In some embodiments, the complementing protein is selected from the group consisting of Factor VIII, Factor IX, TPO, EPO, alpha-iduronidase, iduronate sulfatase, type A heparan N-sulfatase, type B alpha-N-acetylglucose Acetyltransferase, D-type N-acetylglucosamine 6-sulfatase, galactose 6-sulfatase, N-acetylgalactosamine 4-sulfatase, beta- Is selected from the group consisting of glucuronidase, croonidase, alpha-galactosidase, acid alpha-galactosidase, and glucocerebrosidase. These proteins can be supplemented for diseases such as, but not limited to, hemophilia, idiopathic thrombocytopenic purpura, renal anemia, and lysosomal diseases (mucopolysaccharidosis, Fabry disease, Pompe disease and Gaucher disease).

In a further embodiment, the invention provides polypeptides comprising a variant Fc region for use in the treatment of a viral infection. In some embodiments, the invention provides a method for treating a viral infection in a subject comprising administering to the subject a polypeptide comprising an amount of a variant Fc region effective to treat a viral infection, wherein the variant Fc region / RTI > The "entity" according to any of the above embodiments is preferably a human.

In a further aspect, the invention provides the use of a polypeptide comprising the variant Fc region provided herein in the manufacture or preparation of a medicament. In some embodiments, the polypeptide is an antibody. In some embodiments, the polypeptide is an Fc fusion protein. In a further embodiment, the agent is for treating a viral infection. In a further embodiment, the agent is for use in a method of treating the disease in a subject, comprising administering to the subject an amount of the agent effective to treat a viral infection. An "entity" in accordance with any of the above embodiments may be a human.

In a further aspect, the invention provides a method of treating a viral infection in an individual. In one embodiment, the method comprises administering to the subject a polypeptide comprising a variant Fc region in an amount effective to treat a viral infection. In one embodiment, "entity" is a human.

In a further aspect, the invention provides a pharmaceutical formulation comprising any of the polypeptides comprising a variant Fc region provided herein. In a further embodiment, the pharmaceutical formulation is for the treatment of a viral infection.

Anti-viral antibodies comprising a variant Fc region of the invention can inhibit antibody-dependent increases observed by conventional anti-viral antibodies. An antibody-dependent increase is a phenomenon in which the virus bound to the antibody is predated via activation of Fc gamma R to increase the infection of the virus with respect to the cells. The binding of anti-dengue-virus antibodies to Fc gamma RIIb has been reported to play an important role in the inhibition of antibody-dependent enhancement (Proc. Natl. Acad. Sci. USA 108: 12479-12484, (2011) ). The cross-linking of Fc gamma RIIb molecules by the immunoconjugate of anti-dengue-virus antibodies and dengue viruses inhibits Fc gamma R-mediated phagocytosis, resulting in the inhibition of antibody-dependent enhancement. Examples of such viruses include Dengue viruses (DENV1, DENV2, DENV3 and DENV4) and HIV (including but not limited to).

In a further embodiment, the invention provides polypeptides comprising a variant Fc region for use in the prevention or treatment of arteriosclerosis. In some embodiments, the invention provides a method for preventing or treating atherosclerosis in a subject, comprising administering to the subject a polypeptide comprising an amount of a variant Fc region effective to prevent or treat arteriosclerosis And a variant Fc region. In some embodiments, the polypeptide is an antibody. In some embodiments, the polypeptide is an Fc fusion protein. The "entity" according to any of the above embodiments is preferably a human.

In a further aspect, the invention provides the use of a polypeptide comprising the variant Fc region provided herein in the manufacture or preparation of a medicament. In some embodiments, the polypeptide is an antibody. In some embodiments, the polypeptide is an Fc fusion protein. In a further embodiment, the agent is for the prevention or treatment of atherosclerosis. In a further embodiment, the medicament is for use in a method of preventing or treating the disease in a subject, comprising administering to the subject an amount of the medicament effective to prevent or treat arteriosclerosis. An "entity" in accordance with any of the above embodiments may be a human.

In a further aspect, the invention provides a method of preventing or treating arteriosclerosis in a subject. In one embodiment, the method comprises administering to the subject a polypeptide comprising a variant Fc region in an amount effective to prevent or treat arteriosclerosis. In one embodiment, "entity" is a human.

In a further aspect, the invention provides a pharmaceutical formulation comprising any of the polypeptides comprising a variant Fc region provided herein. In some embodiments, the polypeptide is an antibody. In some embodiments, the polypeptide is an Fc fusion protein. In a further embodiment, the pharmaceutical formulation is for the prevention or treatment of arteriosclerosis.

Antibodies to the cause of oxidative LDL, i. E. Arteriosclerosis, comprising a variant Fc region of the invention can prevent Fc gamma RIIa-dependent attachment of inflammatory cells. The anti-oxidized LDL antibody inhibits the interaction between oxidized LDL and CD36, while the anti-oxidized LDL antibody binds to endothelial cells and mononuclear cells secrete Fc gamma IIa-dependent or Fc gamma in a RI- (Immunol. Lett. 108: 52-61, (2007)). The use of an antibody comprising a variant Fc region of the invention can inhibit Fc gamma RIIa-dependent binding by an Fc gamma RIIb-mediated inhibitory signal and inhibit mononuclear cell adhesion.

In a further embodiment, the invention provides polypeptides comprising a variant Fc region for use in the prevention or treatment of cancer. In some embodiments, the present invention provides a method for preventing or treating cancer in a subject, comprising administering to the subject a polypeptide comprising an amount of a variant Fc region effective to prevent or treat cancer, Fc region of the polypeptide. The "entity" according to any of the above embodiments is preferably a human.

In a further aspect, the invention provides the use of a polypeptide comprising the variant Fc region provided herein in the manufacture or preparation of a medicament. In some embodiments, the polypeptide is an antibody. In some embodiments, the polypeptide is an Fc fusion protein. In a further embodiment, the agent is for the prevention or treatment of cancer. In a further embodiment, the medicament is for use in a method for preventing or treating cancer in a subject, comprising administering to the subject an amount of the medicament effective to prevent or treat cancer. An "entity" in accordance with any of the above embodiments may be a human.

In a further aspect, the invention provides a method of preventing or treating cancer in an individual. In one embodiment, the method comprises administering to the subject a polypeptide comprising a variant Fc region in an amount effective to prevent or treat cancer. In some embodiments, the polypeptide is an antibody. In some embodiments, the polypeptide is an Fc fusion protein. In one embodiment, "entity" is a human.

In a further aspect, the invention provides a pharmaceutical formulation comprising any of the polypeptides comprising a variant Fc region provided herein. In some embodiments, the polypeptide is an antibody. In some embodiments, the polypeptide is an Fc fusion protein. In a further embodiment, the pharmaceutical formulation is for the prophylaxis or treatment of cancer.

As described above, it is known that the increase of Fc gamma RIIb binding increases the agonistic activity of the agonist antibody and increases the antitumor effect of the antibody. Accordingly, an agent antibody comprising the variant Fc region of the present invention is useful for the treatment or prevention of cancer. Specifically, the variant Fc region of the present invention can be used in combination with, for example, a receptor with a TNF receptor, such as CD120a, CD120b, lymphotoxin beta receptor, CD134, CD40, FAS, TNFRSF6B, CD27, CD30, CD137, TNFRSF10A, TNFRSF10B, TNFRSF10, RANK, osteoprotegerin, TNFRSF12A, TNFRSF13B, TNFRSF13C, TNFRSF14, nerve growth factor receptor, TNFRSF17, TNFRSF18, TNFRSF19, TNFRSF21, TNFRSF25 and the ectodysplasia A2 receptor, Treatment or prophylaxis. Furthermore, the agonist activity is also increased for antibodies to other molecules that exhibit agonistic activity through interaction with Fc gamma RIIb. In addition, by incorporating the variant Fc region of the present invention into an antibody against a receptor tyrosine kinase (RTK), for example, a kit that inhibits cell proliferation upon crosslinking with Fc gamma RIIb, the inhibitory effect of the antibody on cell proliferation Can be increased.

In some embodiments, the present invention provides a method of treating cancer, including, but not limited to, small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, and squamous cell carcinoma of the lung, colon, rectal, colon, breast, liver, stomach, pancreatic, Cancer of the ovary, thyroid cancer, cholangiocarcinoma, peritoneal cancer, mesothelioma, squamous cell carcinoma, cervical cancer, endometrial cancer, bladder cancer, esophageal cancer, head and neck cancer, nasopharyngeal carcinoma, salivary cancer, thymoma, skin cancer, basal cell tumor, malignant melanoma, (Including acute myelogenous leukemia, acute myelogenous leukemia, acute promyelocytic leukemia, acute myeloid mononuclear leukemia and acute mononuclear leukemia), chronic myelogenous leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, Chronic lymphocytic leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma (bucket lymphoma, chronic lymphocytic leukemia, bacterial sarcoma, mantle cell lymphoma, follicular lymphoma, diffuse large cell lymphoma, Lymphoma, hairy leukemia plasmacytoma, peripheral T-cell lymphoma, and adult T cell leukemia / lymphoma), Langerhans cell histiocytosis, multiple myeloma, myelodysplastic syndrome, brain tumor (glioma, astrocytoma, glioblastoma, Including neuroblastoma, retinoblastoma, osteosarcoma, Kaposi sarcoma, Ewing's sarcoma, angiosarcoma, and angiocellular carcinoma.

Antibodies that have been modified to have increased binding activity for Fc gamma R, including Fc gamma RIIb, by modification of at least one amino acid residue are described in, for example, WO 2013/047752, WO 2013/125667, WO 2014/030728, or WO 2014 / 163101, < / RTI >

Without wishing to be bound by any particular theory, it is believed that an antibody having increased Fc gamma R-binding activity under neutral pH conditions is rapidly absorbed into the cell along with its antigen complexed with the antibody, resulting in the antibody being administered in vivo The removal of the antigen from the plasma may be promoted.

Antibodies that have been modified to have increased pi by deformation of at least one amino acid residue that may be exposed on the antibody surface are described, for example, in WO 2007/114319, WO 2009/041643, WO 2014/145159, or WO 2012/016227 Or as suggested, can facilitate antigen removal from plasma.

While not wishing to be bound by any particular theory, it is believed that the pH of the biological fluid (e.g., plasma) is in the neutral pH range. In biological fluids, the net positive charge of the pi-enhanced antibody is increased due to the increased pi, so that the antibody has a physico-chemical Coulomb interaction on the endothelial cell surface with a net negative charge relative to the antibody without increased pi Is pulled more strongly by. This means that the absorption into the cell of the antibody complexed with the antigen is increased through the non-specific binding as described above, which increases antigen elimination from the plasma. This phenomenon is expected to occur normally in vivo, regardless of cell type, tissue type, or organ type.

In this specification, the increase in antigen removal from plasma means that the rate of antigen removal from plasma, for example, is increased as compared to the case where a polypeptide comprising the corresponding Fc region not modified as described above is administered. The increase in antigen removal from the plasma can be assessed, for example, by measuring the concentration of antigen in plasma. Various methods for measuring antigen concentration in plasma are known in the art.

In a further embodiment, the invention provides a polypeptide comprising a variant Fc region for use in promoting the removal of an antigen from plasma. In some embodiments, the invention provides a method of promoting the removal of an antigen from plasma in a subject, comprising administering to the subject a polypeptide comprising an amount of a variant Fc region effective to promote the removal of the antigen from plasma And a variant Fc region for use in said polypeptide. In these embodiments, it may be preferred that the polypeptide further comprises an antigen-binding domain. The "entity" according to any of the above embodiments is preferably a human.

In a further aspect, the invention provides the use of a polypeptide comprising the variant Fc region provided herein in the manufacture or preparation of a medicament. In some embodiments, the polypeptide is an antibody. In some embodiments, the polypeptide is an Fc fusion protein. In a further embodiment, the agent is for promoting the removal of antigen from plasma. In a further embodiment, the medicament is for use in a method for promoting the removal of an antigen from plasma in the subject, comprising administering to the subject an amount of the medicament effective to promote the removal of the antigen from the plasma. In these embodiments, it may be preferred that the polypeptide further comprises an antigen-binding domain. An "entity" in accordance with any of the above embodiments may be a human.

In a further aspect, the invention provides a method of promoting the removal of an antigen from a plasma in an individual. In one embodiment, the method comprises administering to the subject a polypeptide comprising an amount of a variant Fc region effective to promote the removal of the antigen from plasma. In this embodiment, it may be preferred that the polypeptide further comprises an antigen-binding domain. In one embodiment, "entity" is a human.

In a further aspect, the invention provides a pharmaceutical formulation comprising any of the polypeptides comprising a variant Fc region provided herein. In a further embodiment, the pharmaceutical formulation is for promoting the removal of antigen from plasma. In this embodiment, it may be preferred that the polypeptide further comprises an antigen-binding domain.

In one embodiment, an antibody having a variant Fc region of the invention, as compared to before the amino acid modification, is capable of reducing antigen removal from the plasma, for example, at least 1.1-fold, 1.25-fold , 1.5-fold, 1.75-fold, 2.0-fold, 2.25-fold, 2.5-fold, 2.75-fold, 3.0-fold, 3.25-fold, 3.5- fold, 3.75-fold, 4.0-fold, 4.25- Fold, 7.0-fold, 7.5-fold, 8.0-fold, 8.5-fold, 9.0-fold, 9.5-fold, or 10.0- Increase by more than double.

In a further aspect, the invention encompasses mixing any of the polypeptides comprising a variant Fc region provided herein for use, for example, in any of the above methods of treatment with a pharmaceutically acceptable carrier Or a pharmaceutically acceptable salt thereof. In one embodiment, the method of manufacturing a pharmaceutical or pharmaceutical formulation further comprises adding at least one additional therapeutic agent to the pharmaceutical or pharmaceutical formulation.

The antibodies of the invention may be used in therapy alone or in combination with other agents. For example, the antibodies of the invention may be co-administered with at least one additional therapeutic agent.

Likewise, the polypeptides comprising the variant Fc regions of the invention can be used in therapy alone or in combination with other agents. For example, a polypeptide comprising a variant Fc region of the invention can be co-administered with at least one additional therapeutic agent.

Such combined treatment regimens as shown above may be used in combination with simultaneous administration wherein two or more therapeutic agents are included in the same or separate formulations and separate administration wherein the administration of a polypeptide or antibody comprising the variant Fc region of the invention Which may occur prior to, concurrent with, and / or following administration of the additional therapeutic or therapeutic agents). In one embodiment, administration of the anti-myostatin antibody and administration of the additional therapeutic agent are within about one month of each other, or within about 1, 2 or 3 weeks, or about 1, 2, 3, 4, 5, It occurs within six days.

In another embodiment, administration of the polypeptide comprising the variant Fc region and administration of the additional therapeutic agent is within about 1 month of each other, or within about 1, 2 or 3 weeks, or about 1, 2, 3, 4, 5 , Or within six days.

An antibody or polypeptide (and any additional therapeutic agent) comprising a variant Fc region of the invention may be administered by any suitable means, such as parenteral, intrapulmonary, and intranasal, and if desired localized, by intralesional administration . Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. Administration may be by any suitable route, e. G. Injection, e. G. Intravenous or subcutaneous injection, depending in part on whether the administration is short or chronic. The present invention contemplates various dosing schedules, including single or multiple doses, single doses, and pulse injections, at various time points, without limitation.

Antibodies or polypeptides comprising the variant Fc regions of the invention may be formulated, administered and administered in a manner consistent with good medical practice. Factors to be considered in this context include the particular disease being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disease, the delivery site of the agent, the method of administration, the schedule of administration, and other factors known to healthcare practitioners do. The antibody optionally is formulated, although not required, with one or more agents currently used to prevent or treat the disease in question. The effective amount of such other agents will vary according to the amount of antibody present in the formulation, the type of disease or therapeutic agent, and other factors discussed above. They may be administered at the same doses as described herein and according to the route of administration, or at a dosage of about 1 to 99% of the dosages disclosed herein, or at any dose determined to be experimentally / clinically appropriate, .

For the prevention or treatment of disease, a suitable dose of the antibody of the present invention (when used alone or in combination with one or more other therapeutic agents) will depend on the type of disease being treated, the type of antibody, the variant Fc region, Type, the severity and course of the disease, whether the antibody or polypeptide comprising the variant Fc region is used for prophylactic or therapeutic purposes, a prior therapy, the clinical history of the patient, and the variant Fc region , And the judgment of the attending physician. The antibody or polypeptide comprising the variant Fc region of the present invention is suitably administered to the patient at one time or over a series of treatments. Depending on the type and severity of the disease, an antibody of from about 1 [mu] g / kg to 15 mg / kg (e.g., 0.1 mg / kg to 10 mg / kg) Whether by continuous infusion, may be an initial candidate dose for administration to the patient. Any typical daily dosage may range from about 1 [mu] g / kg to 100 mg / kg or more, depending on the factors mentioned above. For repeated administrations over several days, according to the above conditions, the treatment can generally be continued until the desired inhibition of the disease symptoms occurs. One exemplary dosage of an antibody or polypeptide comprising said variant Fc region will range from about 0.05 mg / kg to about 10 mg / kg. Thus, one or more doses of about 0.5 mg / kg, 2.0 mg / kg, 4.0 mg / kg or 10 mg / kg (or any combination thereof) may be administered to the patient. Such a dose may be administered intermittently, e. G. Every week or every three weeks (e. G., An antibody or polypeptide comprising the mutant Fc region of about 2 to about 20 times, RTI ID = 0.0 > a < / RTI > One or more lower doses may be administered following the initial higher loading dose. The progress of the therapy is readily monitored by conventional techniques and assays.

It is contemplated that any of the above formulations and methods of treatment may be performed in place of or in addition to the anti-myostatin antibody using the immunoconjugates of the invention.

Likewise, it is contemplated that any of the above formulations and methods of treatment may be performed in place of, or in addition to, the polypeptides comprising the variant Fc regions provided herein using the immunoconjugates of the invention.

H. Products

In another aspect of the present invention, there is provided an article containing a substance useful for the treatment, prevention and / or diagnosis of the above-mentioned diseases. The article of manufacture comprises a container and a label or package insert on or associated with the container. Suitable containers include, for example, bottles, vials, syringes, IV solution bags, and the like. The container may be formed from a variety of materials, such as glass or plastic. The container may hold the composition alone or in combination with another composition that is effective for the treatment, prevention and / or diagnosis of a condition and may have a sterile access port (e.g., the container may be an intravenous solution bag or a hypodermic needle It can be a vial having a cap that can be pierced). At least one active agent in the composition is an antibody of the invention. The label or package insert indicates that the composition is used for treatment of a selected condition. Moreover, the article of manufacture comprises: (a) a first container containing the composition, wherein the composition comprises an antibody of the invention; And (b) a second container containing the composition, wherein said composition comprises an additional cytotoxic agent or other therapeutic agent. In the above embodiments of the present invention, the product may further comprise a package insert indicating that the composition can be used to treat a particular condition. Alternatively, or additionally, the article of manufacture may comprise a second (or third) container comprising a pharmaceutically acceptable buffer, such as a BWFI, phosphate-buffered saline, Ringer's solution and dextrose solution, May be further included. The article may further comprise other materials which may be desirable from a commercial and user standpoint, such as other buffers, diluents, filters, needles and syringes.

It is contemplated that any of the articles of manufacture may comprise an immunoconjugate of the invention in place of or in addition to the anti-myostatin antibody.

[Example]

The following are examples of methods and compositions of the present invention. It is contemplated that various other embodiments may be practiced as long as the general substrate is provided above.

[Example 1]

Human, poem Nomolgus  Monkey and mouse Myostatin Latency  And mature forms of expression and purification

Human laxative myostatin (also described herein as a human myostatin latent form) (SEQ ID NO: 1) was transformed into FreeStyle 293-F cells (FS293-F cells) (Thermo Fisher) , Carlsbad, Calif.). The clarified medium containing the expressed human myostatin latent form was acidified to pH 6.8, diluted with 1/2 volume of milli-Q water and applied to a Q-Sepharose FF anion exchange column (Zihealthcare, Uppsala, Sweden) Respectively. The pass-through fraction was adjusted to pH 5.0 and applied to an SP-Sepharose cation exchange column (GE Healthcare, Uppsala, Sweden) followed by a NaCl gradient. Fractions containing the human myostatin latent form were collected and subsequently added to a Superdex x200 gel filtration column (Gly Healthcare, Uppsala, Sweden) equilibrated with 1xPBS. Fractions containing the human myostatin latent form were then pooled and stored at -80 [deg.] C.

The human mature myostatin (also described herein as the human myostatin mature form) (SEQ ID NO: 2) was purified from the purified human myostatin latent form. The human myostatin latent form was acidified by the addition of 0.1% trifluoroacetic acid (TFA) and applied to a Vydac 214TP C4 reversed-phase column (Grace, Deerfield, Ill., USA) CH ₃ CN gradient. Fractions containing human mature myostatin were pooled, dried and stored at -80 [deg.] C. For reconstitution, human mature myostatin was dissolved in 4 mM HCl.

Both miostatin latent and mature forms of expression and purification from synomolgus monkeys (Cynomolgus or Cyno) (SEQ ID NOS: 3 and 4, respectively) and mice (SEQ ID NOS: 5 and 6, respectively) Exactly the same way. The mature form of the homologous form of homology between human, synonym and mouse was 100% identical, and thus any mature myostatin, regardless of species, was used as mature myostatin in all necessary experiments.

[Example 2]

term- Latency Myostatin  Identification of antibodies

Anti-latent myostatin antibodies were prepared, selected and analyzed as follows.

12-16 week old NZW rabbits were intradermally immunized with mouse latent myostatin and / or human latent myostatin (50-100 μg / dose / rabbit). The dose was repeated three to four times over a period of one month. One week after the final immunization, spleen and blood were collected from the immunized rabbits. The antigen-specific B-cells were stained with labeled antigen and classified into FCM cell sorter (FACS aria III, BD) and plated at 25,000 cells / well EL4 cells / well in 96- (European collection of cell cultures) and 20-fold diluted rabbit T-cell purification medium and cultured for 7-12 days. EL4 cells were treated with mitomycin C (Sigma) for 2 hours and washed 3 times in advance. The rabbit T-cell purification medium was prepared by culturing rabbit thymocytes in RPMI-1640 containing phytohemagglutinin-M (Roche), phorbol 12-myristate 13-acetate (Sigma) and 2% FBS . After incubation, the B-cell culture supernatant was collected for further analysis and the pellets were stored at low temperature.

ELISA assays were used to test the specificity of the antibodies in the B-cell culture supernatant. Streptavidin (GeneScript) was coated onto 384-well Maxisorp (Knock) at 50 nM in PBS for 1 hour at room temperature. The plates were then blocked with 5-fold diluted Blocking One (Nacalai Tesque). Human or mouse latent myostatin was labeled with NHS-PEG4-biotin (PIERCE) and added to the blocked ELISA plate, incubated for 1 hour and washed with tris-buffered brine (0.05% Tween-20 TBS-T). B-cell culture supernatant was added to the ELISA plate, incubated for 1 hour, and washed with TBS-T. Binding was detected by goat anti-rabbit IgG-horseradish peroxidase (BETHYL) and then ABTS (KPL) was added.

A total of 17,818 B-cell lines were screened for binding specificity for mouse and / or human latent myostatin, and 299 cell lines were selected and selected from MST0255-287, 630-632, 677-759, 910, 932-1048, 1050 -1055, 1057-1066, 1068, 1070-1073, 1075-1110, 1113-1119. RNA was purified from the corresponding cell pellet using the ZR-96 Quick-RNA kit (ZYMO RESEARCH).

The DNA encoding the variable regions of the heavy chain and the light chain of each selected cell line was amplified by reverse transcription PCR, and the heavy chain constant region G1m sequence (SEQ ID NO: 50 (amino acid sequence is shown in SEQ ID NO: 7)) and the light chain constant region k0MTC or k0MC SEQ ID NO: 53 or 194 (amino acid sequence (both identical) is shown in SEQ ID NO: 8. Recombinant antibodies were prepared from the Freestyle FS293-F cells and 293 pectin The recombinant antibody was purified with Protein A (Gly Healthcare) and incubated with D-PBS or His buffer (20 mM histidine, 150 mM NaCl, < RTI ID = 0.0 & pH 6.0). If necessary, size exclusion chromatography may be further performed to remove high molecular weight and / or low molecular weight components It was going.

[Example 3]

term- Latency Myostatin  Characterization of antibodies HEK blue  analysis( BMP1  Activation))

Reporter gene analysis was used to assess the biological activity of active myostatin in vitro. HEK-Blue (TM) TGF-beta cells (Invivogen) expressing the Smad3 / 4-binding element (SBE) -induced SEAP reporter gene are used to monitor the activation of actin type 1 and type 2 receptors Allowing detection of biologically active myostatin. The active myostatin stimulates the production of SEAP secreted into the cell supernatant. The amount of the secreted SEAP is then assessed using QUANTIBlue (trademark) (Invivogen).

HEK-Blue (trademark) TGF-beta cells were treated with 10% fetal bovine serum, 50 μg / ml streptomycin, 50 U / ml penicillin, 100 μg / ml normocin (Gibco) supplemented with streptavidin, streptomycin, styrosidine, 200 [mu] g / ml HygroGold (TM) and 100 [mu] g / ml Zeocin (TM). During the functional analysis, cells were exchanged for assay media (DMEM with 0.1% bovine serum albumin, streptomycin, penicillin and normocine (TM)) and seeded in 96-well plates. Human, cynomolgus, or mouse latency myostatin was incubated with recombinant human BMP1 (R & D Systems) and anti-latent antibody overnight at 37 < 0 > C. The sample mixture was transferred to the cells. After 24-hour incubation, the cell supernatant was mixed with QuantiBlue (trademark) and optical density at 620 nm was measured in a colorimetric plate reader. As shown in FIG. 1, mAb MST1032-G1m (see Table 2a for amino acid and nucleotide sequences), as reflected by the reduced concentration of secreted SEAP, is expressed in human, cynomolgus and mouse latent myostatin Lt; RTI ID = 0.0 > protease-mediated < / RTI > MST1032-G1m exhibited almost comparable inhibitory activity against human, cynomolgus and mouse latent myostatin.

[Table 2a]

[Table 2b]

[Example 4]

term- Latency Myostatin  Characterization of antibodies HEK blue  Analysis (voluntary activation)

Human, cynomolgus, or mouse latent myostatin was incubated with the anti-latent myostatin antibody overnight at 37 ° C and the sample mixture was transferred to HEK-Blue (trademark) TGF-beta cells. After 24-hour incubation, the cell supernatants were mixed with QuantiBlue (trademark) and optical density at 620 nm was measured in a colorimetric plate reader. As shown in Figure 2, a glass from its latent form of active myostatin was detected after incubation at 37 占 폚. In the presence of mAb MST1032-G1m, myostatin activation was inhibited, thus lower SEAP levels were detected in the cell supernatants. MST1032-G1m inhibited the spontaneous activation of latent myostatin and showed almost comparable inhibitory activity against human, cinomolgus and mouse latent myostatin.

[Example 5]

term- Latency Myostatin  Characterization of antibodies (ELISA)

An uncoated ELISA plate (NUNC-IMMUNO plate McSysop surface, Nalge Nunc International) was coated with 20 μl of 50 nM streptavidin (GenScript) at room temperature for 1 hour Lt; / RTI > Plates were then washed three times with PBST and blocked with 50 [mu] l of 20% blocking source (Nacalai Tesque). The next day, each well of each plate was incubated with biotinylated mature myostatin, human or mouse biotinylated latent myostatin, or biotinylated recombinant mouse myostatin propeptide-Fc chimeric protein (R & D Systems) 0.0 > nM / well / 20 < / RTI > After washing, 20 [mu] l of antibody samples were added to the wells and the plates were left for 1 hour. The plate was washed and 20 μl of anti-human IgG-horseradish peroxidase (HRP) (Abcam) diluted in HEPES-buffered saline was added and the plate was left for an additional 1 hour . The plate was then washed again, then 50 ul ABTS (KPL) was added to each well, and the plate was incubated for 1 hour. Signals were detected at 405 nm in a colorimetric plate reader. The results of the above bonding experiment are shown in Fig. MST1032-G1m bound latent myostatin (i.e., a non-covalent complex of mature myostatin and a propeptide) and a propeptide but did not bind to mature myostatin. These results show that MST1032-G1 m specifically binds to the myostatin propeptide (e. G., The propeptide moiety), but not to the active myostatin (e. G., The mature region).

[Example 6]

term- Latency Myostatin  Characterization of antibodies Western Blot )

Mouse latent myostatin was incubated with recombinant human BMP1 (R & D Systems) in the presence or absence of MST1032-G1m overnight at 37 < 0 > C. The sample was then mixed with 4x reduced SDS-PAGE sample buffer (Wako) and heated at 95 ° C for 5 minutes and then loaded for SDS gel electrophoresis. Protein was transferred to the membrane by the Trans-Blot® Turbo ™ delivery system (Bio-rad). Myostatin propeptide was detected using an anti-mouse GDF8 propeptide antibody (R & D Systems), which was then detected by anti-Yang IgG-HRP (Santa Cruz). The membrane was incubated with the ECL substrate and imaged using an ImageQuant LAS 4000 (GE Healthcare). As shown in Fig. 4, proteolytic cleavage by BMP1 was inhibited by MST1032-G1m.

[Example 7]

term- Latency Myostatin  Characterization of antibodies Via core (Registered trademark))

The kinetic parameters of the anti-latent myostatin antibody against human, Cynomolgus monkey (Shino) and mouse latent myostatin were measured at 37 < 0 > C using Biacore (TM) T200 equipment (Gly Healthcare) Lt; / RTI > at pH 7.4. Pro A / G (Pierce) was immobilized on all flow cells of the CM4 chip using an amine coupling kit (Gly Healthcare). Anti-latent myostatin antibodies and assays were prepared in ACES pH 7.4 (20 mM ACES, 150 mM NaCl, 1.2 mM CaCl ₂ , 0.05% Tween 20, 0.005% NaN ₃ ). Antibodies were captured on the sensor surface by proA / G. The level of antibody capture was typically between 150 and 220 resonant units (RU). Subsequently, human, synonymous or mouse latent myostatin was injected at 3.125 to 50 nM prepared by two-fold serial dilutions and then dissociated. The sensor surface was regenerated with 25 mM NaOH. Dynamic parameters were measured by treating the data using Biacore (TM) T200 evaluation software, version 2.0 (GE Healthcare) and fitting to a 1: 1 binding model. The sensorgram is shown in Fig. The binding rate (ka), dissociation rate (kd) and binding affinity (KD) are listed in Table 3. The kinetic parameters of MST1032-G1m for human, sino and mouse latent myostatin were comparable.

[Table 3]

[Example 8]

Anti-muscle < RTI ID = 0.0 > Latency Myostatin  Antibody In vivo  efficacy

The in vivo efficacy of mAb MST1032-G1m was evaluated in mice. The anti-mature myostatin antibody 41C1E4 (as described in U.S. Patent No. 7,632,499) was used as a positive control in this study. In order to avoid potential immune modulation due to mouse anti-human antibody responses, in vivo studies were performed in immunodeficient-severely complex immunodeficient (SCID) mice. A 5-week-old SCID (CB-17 SCID) mouse (Charles River Laboratories Japan, Inc., Kanagawa, Japan) was administered intravenously once per week for 2 weeks Monoclonal antibody or vehicle (PBS). At day 0, 7 and 14, the total fat-free body weight and lipid mass of the mice were evaluated by nuclear magnetic resonance (NMR) (Min spec LF-50, Bruker Bio Spin, Kanagawa, Japan) . The animals were anesthetized on day 14, and gastrocnemius and quadriceps were excised and weighed.

Statistical significance was measured by ANOVA, Student's t-test and Dunnett's with JMP9 software (SAS, Inc.). A p value of less than 0.05 was considered significant.

The results of the above experiment are shown in Figs. 6A to 6C. Both of the two antibodies (MST1032-G1m and 41C1E4) increased the fat-body weight in a dose-dependent manner and MST1032-G1m significantly reduced fat mass compared to the vehicle (PBS) group at 14 days upon administration at 40 mg / .

After two weeks of treatment, the antibodies administered at 10 mg / kg and 40 mg / kg produced a significant increment in the wet weight of gastrocnemius and quadriceps compared to the vehicle group.

[Example 9]

variety Myostatin  Of related antibodies In vivo  Comparison of efficacy

All experimental setups for the above comparison were the same as in Example 8. A variety of myostatin-related antibodies, 41C1E4, REGN, OGD and MYO-029 were tested in 5-week-old SCID mice for two weeks. REGN, OGD and MYO-029 are anti-mature myostatin antibodies described as H4H1657N2 in WO 2011/150008, as OGD1.0.0 in WO 2013/186719, and as MYO-029 in WO 2004/037861, respectively. These antibodies were administered intravenously once a week. Lipid body weight and fat mass were examined by systemic NMR scanning at days 0 and 14. The grip strength was measured on the 14th day using an earthing force tester (for example, GPM-100B, MELQUEST Ltd., Toyama, Japan). As shown in the results provided in Figures 7a to 7c, the lean body mass was increased (P > 0.05) by the antibodies except MYO-029. The grip strength of the MST1032-G1m-administered group was significantly increased (P < 0.05) at 10 mg / kg compared to the vehicle (PBS) group. 41C1E4 and REGN also significantly increased grip compared to vehicle (PBS). Total body fat mass tended to be reduced by MST1032-G1m at 10 mg / kg. The lipid-lowering effect of MST1032-G1m was stronger than that of other anti-mature myostatin antibodies.

[Example 10]

Anti-potential Myostatin  Humanization of antibodies

The amino acid residues of the antibody variable region are numbered according to Kabat (Kabat et al., Sequence of proteins of immunological interest, 5 ^th Ed., Public Health Service, National Institutes of Health, Bethesda, MD (1991)).

The variable regions of the heavy and light chains for the humanized MST0132 antibody were designed. Some of the humanized MST1032 antibodies contain reverse mutations in the framework region. The designed heavy and light chain variable region polynucleotides were synthesized by Zen Script, each having a heavy chain constant region SG1 sequence (SEQ ID NO: 52 (amino acid sequence shown in SEQ ID NO: 9)) and a light chain constant region SK1 sequence No. 54 (amino acid sequence shown in SEQ ID NO: 10)). Humanized antibodies were transiently expressed in FS293-F cells and HEK blue assay and Biacore (TM) assay were performed as described above. As shown in Figure 8 and Table 4, compared to Figures 1 and 2, the humanized antibody (MS1032LO00-SG1) showed comparable inhibitory activity and affinity for chimeric antibodies (MST1032-G1m).

[Table 4]

[Example 11]

pH - Dependence of anti- Latency Myostatin  Generation of antibodies

To generate pH-dependent anti-latent myostatin antibodies, histidine scanning mutagenesis was performed on all CDRs of mAb MS1032LO00-SG1. Each amino acid in the CDRs was amplified by using an In-Fusion HD Cloning Kit (Glontech Inc. or Takara Bio Company) according to the manufacturer's instructions. . &Lt; / RTI &gt; After confirming each mutant through a correctly mutated sequence analysis, the mutants were transiently expressed and purified by the method described above. All histidine-substituted variants were evaluated by the modified Biacore (TM) assay compared to the case described above. Briefly, an additional dissociation step at pH 5.8 was integrated into the Biacore (TM) assay immediately after the dissociation step at pH 7.4. This is to evaluate the pH-dependent dissociation between the antibody (Ab) and the antigen (Ag) from the complex formed at pH 7.4, contrary to the corresponding dissociation at pH 5.8. The dissociation rate at pH 5.8 buffer was determined by processing and fitting the data using Scrubber 2.0 (BioLogic Software) curve fitting software.

As shown in Figure 9, the parent antibody (Ab001) did not show a decrease in inhibitory response at pH 5.8 compared to the pH 7.4 dissociation step. Many of the single-histidine substitutions produced a modest to strong decrease in binding response at pH 5.8 compared to the pH 7.4 dissociation step. The dissociation rates at pH 5.8 for each of the single-histidine substituted variants are shown in Table 5. As shown in Table 5, Ab002 exhibited the fastest Ab / Ag complex dissociation rate at pH 5.8, which is more than 200 times faster than the parent antibody (Ab001). Antibodies with these combinations of mutations were then generated in the CDRs. The CDR sequences of the antibodies containing these various mutations are shown in Table 6.

[Table 5]

[Table 6]

[Example 12]

pH - Dependence of anti- Latency Myostatin  Improve the affinity of antibodies

In order to identify mutations that improve affinity and / or in vitro inhibitory activity at pH 7.4, more than 500 variants were selected for each of the heavy and light chains, using at least one variant produced in Example 11 as a template Respectively. These variants had their respective amino acids in the CDR replaced by 18 different amino acids, except for the original amino acids and cysteine. The binding capacity of variants to human latent myostatin was evaluated at 37 [deg.] C under pH 7.4 using Biacore (R) 4000 instrument (Gly Healthcare). Culture supernatants containing mutants expressed in FS293-F cells were prepared with ACES pH 7.4 buffer containing 10 mg / ml BSA and 0.1 mg / ml carboxymethyldextran (CMD). Each antibody was captured on the flow cell until the capture level reached around 200 RU. 25 nM human latent myostatin was then injected onto the flow cell. An additional dissociation step at pH 5.8 was integrated into the Biacore (TM) assay immediately after the dissociation step at pH 7.4. This additional dissociation step assesses the pH-dependent dissociation between the antibody (Ab) and the antigen (Ag) from the complex formed at pH 7.4. The flow cell surface was regenerated with 25 mM NaOH. Dynamic parameters were measured using the ViaCore (R) 4000 evaluation software, version 2.0 (GE Healthcare). Analysis of additional dissociation at pH 5.8 was performed using scrubber 2 (BioLogic Software).

Variants with improved affinity and / or in vitro inhibitory activity at pH 7.4 were selected and combined with mutations that improved the pH dependency identified in Example 11. [ Following the combination of these mutations, four variants (MS1032LO01, 02, 03 and 04) were selected and SG1 or F760 (SEQ ID NO: 11) for BIAcore (TM) binding kinetic analysis, in vitro and / And 51). SG1 and F760 are both human heavy chain constant regions. The binding affinity of SG1 to human Fc gamma R is comparable to that of the native IgGl constant region, but in the case of F760 it is eliminated by Fc variant (also described herein as silent Fc). Amino acid and nucleotide sequences of the four anti-myostatin variants are shown in Table 2a.

[Example 13]

pH - dependent MS1032 variant of  Characterization HEK blue  analysis( BMP1  And spontaneous activation))

All experimental setups were the same as in Examples 3 and 4. As shown in Figure 10, all variants showed inhibitory activity against human latent myostatin comparable to MS1032LO00-SG1.

[Example 14]

pH - dependent MS1032 variant of  Characterization Via core (Registered trademark))

All experimental setups were the same as in Example 7, except that measurements were also performed in ACES pH 5.8 buffer in addition to ACES pH 7.4 conditions. Some antibodies were measured only against human latent myostatin. Antibody capture levels were targeted at 185 RU and 18.5 RU for binding activity and affinity analysis, respectively. Dynamic parameters were measured using a 1: 1 binding fit with Biacore (TM) T200 evaluation software, version 2.0 (GE Healthcare). The sensorgrams of all antibodies to human latent myostatin with binding activity conditions are shown in FIG. 11, and ka, kd and KD calculated from different conditions are listed in Tables 7-10. Under these binding activity conditions, all antibodies except MS1032LO00-SG1 showed a faster dissociation rate under acidic pH than at neutral pH. Under these affinity conditions, all antibodies except MS1032LO00-SG1 showed weak interaction with latent myostatin at acidic pH, and therefore no kinetic parameters were determined.

[Table 7]

[Table 8]

[Table 9]

[Table 10]

[Example 15]

From the mouse Fc  Gamma R bound and removed Fc  Gamma R Having a bond Between antibodies  Comparison of Plasma Total Myostatin Concentration

C.B -17 SCID  Using the mouse In vivo  exam

The accumulation of endogenous myostatin was evaluated in vivo in the administration of anti-latent myostatin antibody in C.B-17 SCID mice (In Vivos, Singapore). Anti-latent myostatin antibody (3 mg / ml) was administered intravenously in a single dose of 10 ml / kg. Blood was collected at 5 minutes, 7 hours, 1 day, 2 days, 3 days, 7 days, 14 days, 21 days, and 28 days after administration. The collected blood was immediately centrifuged at 14,000 rpm for 10 minutes at 4 DEG C to separate the plasma. The separated plasma was stored at -80 ° C. or lower until measurement. The anti-latent myostatin antibodies used were MS1032LO00-SG1 and MS1032LO00-F760.

Electrochemiluminescence (ECL) in plasma by total Myostatin  Measurement of concentration

The concentration of total myostatin in mouse plasma was measured by ECL. The anti-mature myostatin-immobilized plates were incubated with anti-mature myostatin antibody RK35 (described in WO 2009/058346) on a MULTI-ARRAY 96-well plate (Meso Scale Discovery) ) And cultured overnight at &lt; RTI ID = 0.0 &gt; 4 C. &lt; / RTI &gt; Mature myostatin curve curves and mouse plasma samples were prepared 40 times or more diluted. The samples were mixed in acidic solution (0.2 M glycine-HCl, pH 2.5) to dissociate mature myostatin from its binding protein (e.g., a propeptide). Subsequently, the samples were added to an anti-mature myostatin-immobilized plate and bound for 1 hour at room temperature and then washed. Subsequently, the anti-mature myostatin antibody RK22 (as described in WO 2009/058346) labeled with SULFO TAG was added and the plate was incubated at room temperature for 1 hour and washed. Read buffer T (x4) (meso scale discovery) was immediately added to the plate and the signal was detected by SECTOR Imager 2400 (Meso Scale Discovery). The mature myostatin concentration was calculated based on the response of the calibration curve using the analysis software SOFTmax PRO (Molecular Devices). The time course of the total myostatin concentration in plasma after intravenous administration of the anti-latent myostatin antibody measured by the above method is shown in Fig.

In vivo Myostatin  For accumulation Fc  Effect of gamma R binding

After 28 days of administration of the antibody MS1032LO00-F760, the plasma total myostatin concentration was 248 times greater than the plasma total myostatin concentration at 5 minutes. In contrast, after administration of MS1032LO00-SG1, the plasma total myostatin concentration at day 28 was 37 times greater than the plasma total myostatin concentration at 5 minutes. A difference of approximately seven times the plasma total myostatin concentration on day 28 was observed between MS1032L00-F760 (silent Fc) and MS1032LO00-SG1 due to Fc gamma R binding. In human soluble IL-6R (hsIL-6R), the difference in plasma hsIL-6R concentration was not so significant between anti-hsIL-6R antibody-F760 (silent Fc) and -SG1 as described in WO 2013/125667. Since hsIL-6R is a monomeric antigen, the antibody-hsIL-6R complex contains only 1 Fc. Thus, the results in WO 2013/125667 suggested that the antibody-antigen complex with 1 Fc did not bind Fc gamma R in vivo sufficiently to accelerate the uptake of immune complexes by the cells. On the other hand, in the case of a multispecific antigen (e.g., myostatin), the antibody can make a large immune complex, and the antibody-antigen complex contains more than two Fc. Thus, significant differences between plasma antigen concentrations can be observed between F760 and SB1 due to strong binding activity binding to Fc gamma. The results suggest that MST1032 can form large immune complexes containing more than two antibodies with myostatin.

[Example 16]

In mice, non- pH  Dependent anti- Latency Myostatin  Antibodies and pH - Dependence of anti- incubation Comparison of Plasma Total Myostatin Levels between Streptomycostatin Antibodies

C.B -17 SCID  Using the mouse In vivo  exam

The in vivo accumulation of endogenous mouse myostatin was assessed following administration of the anti-latent myostatin antibody in C.B-17 SCID mice (Invivo, Singapore) as described in Example 15. [ The anti-latent myostatin antibodies used were MS1032LO01-SG1 and MS1032LO01-F760.

Total of plasma by ECL Myostatin  Measurement of concentration

The concentration of total myostatin in mouse plasma was measured by ECL as described in Example 15. [ The time course of plasma total myostatin concentration after intravenous administration of the anti-latent myostatin antibody as measured by the above method is shown in FIG.

In vivo Myostatin  For accumulation pH - dependency Myostatin  Effect of binding

pH-dependent anti-latent myostatin antibodies (MS1032LO01-SG1 and MS1032LO01-F760) were tested in vivo and a comparison of plasma total myostatin levels was performed. The results of measuring the total myostatin concentration after administration of MS1032LO00-SG1 and MS1032LO00-F760 described in Example 15 are also shown in Fig. MS1032LO00 is a non-pH-dependent antibody and MS1032LO01 is a pH-dependent antibody. As shown in Figure 13, the total myostatin concentration after administration of MS1032LO01-F760 was reduced compared to MS1032LO00-F760 due to pH-dependent binding. Moreover, the total myostatin concentration after administration of MS1032LO01-SG1 was significantly reduced compared to the case of MS1032LO00-SG1 due to increased cell uptake by pH-dependent binding and Fc gamma R binding. MS1032LO01-SG1 is expected to have excellent properties to increase the clearance of myostatin from plasma as a "sweeping antibody ".

[Example 17]

pH - Dependence of anti- Latency Myostatin  Antibody In vivo  effect

All experimental setups were the same as in Example 8. As shown in Fig. 14, MS1032LO00-SG1 (non-cleaved antibody) and MS1032LO01-SG1 (indwelling antibody) were administered intravenously to SCID mice at doses of 0.2, 1 and 5 mg / kg, Dose-dependently. MS1032LO01-SG1 significantly increased the quadriceps wet weight and grip strength at 1 and 5 mg / kg compared to the vehicle group (PBS) and significantly increased the lean body weight and gastrocnemius wet weight at 5 mg / kg. MS1032LO01-SG1 also significantly reduced fat mass compared to vehicle group (PBS) at 1 and 5 mg / kg. MS1032LO00-SG1 did not show an increase in lean body mass at 0.2 mg / kg. On the other hand, MS1032LO01-SG1 significantly increased fat-free body weight, quadriceps wet weight, gastrocnemius wet weight and grip strength at 0.2 mg / kg. Thus, pH-dependent binding antibodies exhibit greater muscle mass growth and muscle strength improvement compared to non-pH-dependent binding antibodies.

[Example 18]

Human and mouse Latency GDF11  Expression and purification

Human GDF11 (also referred to herein as flag-hGDF11, human latent GDF11, hGDF11, or human GDF11, described herein as SEQ ID NO: 85) with flag-tag on the N-terminal single- Lt; / RTI &gt; The clarification medium expressing the flag-hGDF11 was applied to a column packed with an anti-Flag M2 affinity resin (Sigma) and eluted with a flag peptide (Sigma). The fractions containing the flag-hGDF11 were pooled and subsequently added to a Superdex 200 gel filtration column (Gly Healthcare) equilibrated in 1xPBS. Fractions containing the flag-hGDF11 were then pooled and stored at -80 [deg.] C.

[Example 19]

term- Latency Myostatin  Characterization of antibodies (ELISA)

Uncoated ELISA plates (nunc-Immunoplate McSysop surface, Flying Knot International) were coated with 20 [mu] l of 50 nM Streptavidin (GenScript) at room temperature for 2 hours. Plates were then washed three times with PBST and blocked with 50 [mu] l of 20% blocking source (Nacalai Tesque). The next day, each well of the plate was incubated with 2 nM / well / 20 μl of biotinylated human latent myostatin or 20 nM / well / 20 μl of biotinylated human latent GDF11 for 2 hours. After washing, 20 [mu] l of antibody samples were added to the wells and the plates were left for 1 hour. The plate was washed and 20 [mu] l of anti-human IgG-horseradish peroxidase (HRP) diluted in HEPES-buffered saline (Abbe cam) was added and the plate was left for an additional hour. The plate was washed again, then 50 ul of ABTS (KPL) was added to each well, and the plate was incubated for 1 hour. Signals were detected at 405 nm in a colorimetric plate reader. The results of the above bonding experiment are shown in Fig. MST1032-G1m bound latent myostatin (i.e., a non-covalent complex of mature myostatin and a propeptide), but not hGDF11. These results show that MST1032-G1m binds specifically to the myostatin, but not hGDF11.

[Example 20]

term- Latency Myostatin  Characterization of antibodies HKE blue  analysis( BMP1  And spontaneous activation))

Reporter gene analysis was used to assess the biological activity of active GDF11 in vitro. HEK-Blue (trademark) TGF-beta cells (Invivogen) expressing the Smad3 / 4-binding element (SBE) -induced SEAP reporter gene are activated by monitoring the activation of actin type 1 and type 2 receptors, . &Lt; / RTI &gt; Active GDF11 stimulates the production and secretion of SEAP into cell supernatants. The amount of the secreted SEAP is then assessed using Quantib Blue (Invibogen).

HEK-Blue (trademark) TGF-beta cells were cultured in RPMI 1640 medium supplemented with 10% fetal bovine serum, 50 μg / ml streptomycin, 50 U / ml penicillin, 100 μg / ml normocin (trademark), 30 μg / ml blasticidin , 200 μg / ml Hygro Gold (TM) and 100 μg / ml Zeocin (TM) supplemented with DMEM medium (Gibco). During the functional analysis, cells were exchanged for assay media (DMEM with 0.1% bovine serum albumin, streptomycin, penicillin and normocine (TM)) and seeded in 96-well plates. Human GDF11 was incubated overnight at 37 占 in the presence and absence of recombinant human BMP1 (Calbiochem) and anti-latent antibody (MST1032-G1m). The sample mixture was transferred to the cells. After 24-hour incubation, the cell supernatant was mixed with QuantiBlue (trademark) and optical density at 620 nm was measured in a colorimetric plate reader. As shown in FIG. 16, MST1032-G1m did not prevent protease-mediated or spontaneous activation of human GDF11 and therefore did not inhibit the secretion of SEAP.

[Example 21]

MS1032 mutant to increase swallowing effect of  Additional optimization

As a pH-dependent antibody, MS1032LO01-SG1 exhibited superior efficacy in mice and therefore could be used to introduce mutations into the antibody CDRs, such as to increase pH dependence, increase uptake into cells, increase stability, Additional optimizations were performed by exchanging work areas. More than 1000 variants were evaluated in the ViaCore (TM) and / or HEK blue assay as described above and MS1032LO06-SG1, MS1032LO07-SG1, MS1032LO10-SG1, MS1032LO11-SG1, MS1032LO12- SG1, MS1032LO18- MS1032LO19-SG1, MS1032LO21-SG1, MS1032LO23-SG1, MS1032LO24-SG1, MS1032LO25-SG1, and MS1032LO26-SG1. The amino acid and nucleotide sequences of the antibodies thus generated are shown in Table 11.

[Table 11a]

[Table 11b]

The affinity of the MS1032 variant binding to human, cynomolgus monkey (syno) or mouse latent myostatin at pH 7.4 and pH 5.8 was measured at 37 ° C using Biacore (TM) T200 equipment (Ziehl Healthcare) And the effect of pH on antigen binding was evaluated. Pro A / G (Pierce) was immobilized on all flow cells of the CM4 chip using an amine coupling kit (Gly Healthcare). All antibodies and analytes were prepared in ACES pH 7.4 or pH 5.8 buffer containing 20 mM ACES, 150 mM NaCl, 1.2 mM CaCl ₂ , 0.05% Tween 20, 0.005% NaN ₃ . Each antibody was captured on the sensor surface by proA / G. The level of antibody capture was typically between 130 and 240 resonant units (RU). Human, sino or mouse latent myostatin was injected at 3.125 to 50 nM prepared by two-fold serial dilutions and then dissociated. The sensor surface was regenerated with 10 mM glycine HCl pH 1.5 in each cycle. The binding affinities were measured by treating the data using a Biacore (R) T200 evaluation software, version 2.0 (GE Healthcare) and fitting it to a 1: 1 binding model.

The affinity (KD) of MST1032 variants for human, cynomolgus monkey (syno) and mouse latent myostatin at pH 7.4 and pH 5.8 are shown in Table 12. Table 12: All variants showed a KD ratio of 5 or more (KD at pH 5.8) / (KD at pH 7.4), indicating pH dependent binding to latent myostatin.

[Table 12]

[Example 22]

HEK blue  Additional optimized variants in the assay field  Evaluation of neutralization activity

We have shown that MS1032LO06-SG1, MS1032LO0-SG1, MS1032LO10-SG1, MS1032LO11-SG1, MS1032LO12-SG1, MS1032LO18-SG1, MS1032LO19-SG1, MS1032LO21- SG1, MS1032LO21- -SG1 and MS1032LO25-SG1. &Lt; / RTI &gt; As shown in Fig. 17, all the mutants showed activity comparable to MS1032LO01-SG1.

[Example 23]

In mice, non- pH  Dependent anti- Latency Myostatin  Antibodies and different pH - dependence anti-latency Myostatin Antibody between  Plasma gun Myostatin  Concentration comparison

C.B-17 SCID  Using the mouse In vivo  exam

The accumulation of endogenous myostatin was assessed in vivo upon administration of anti-latent myostatin antibody in C.B-17 SCID mice (Invivo, Singapore). Anti-latent myostatin antibody (3 mg / ml) was administered intravenously in a single dose of 10 ml / kg. Blood was collected at 5 minutes, 7 hours, 1 day, 2 days, 3 days, 7 days, 14 days, 21 days, and 28 days after administration. The collected blood was immediately centrifuged at 14,000 rpm for 10 minutes at 4 DEG C to separate the plasma. The separated plasma was stored at -80 ° C. or lower until measurement. The tested anti-latent myostatin antibodies were MS1032LO00-SG1, MS1032LO01-SG1, MS1032LO06-SG1, MS1032LO11-SG1, MS1032LO18-SG1, MS1032LO19-SG1, MS1032LO21-SG1 and MS1032LO25-SG1.

Electrochemiluminescence (ECL) in plasma by total Myostatin  Measurement of concentration

The concentration of total myostatin in mouse plasma was measured by ECL. The anti-mature myostatin-immobilized plate was prepared by dispensing the anti-mature myostatin antibody RK35 (as described in WO 2009/058346) on a multi-array 96-well streptavidin plate (Mesoscalve Discovery) And incubated in blocking buffer for 2 hours at room temperature. Mature myostatin curve curves and mouse plasma samples were prepared 40 times or more diluted. The samples were mixed in acidic solution (0.2 M glycine-HCl, pH 2.5) to dissociate mature myostatin from its binding protein (e.g., a propeptide). Subsequently, the samples were added to an anti-mature myostatin-immobilized plate and bound for 1 hour at room temperature and then washed. Subsequently, the sulfated-tagged anti-mature myostatin antibody RK22 (as described in WO 2009/058346) was added and the plate was incubated at room temperature for 1 hour and washed. Read buffer T (x4) (meso scale discovery) was immediately applied to the plate and the signal was detected by sector imager 2400 (Meso Scale Discovery). The mature myostatin concentration was calculated based on the response of the calibration curve using the analysis software Soft Max Pro (Molecular Devices). The time course of the total myostatin concentration in plasma after intravenous administration of the anti-latent myostatin antibody measured by the above method is shown in Fig.

In vivo  In the study, Myostatin  For accumulation pH - dependency Myos Effect of tartine binding

The effect of pH-dependence on the accumulation of myostatin in mice was compared to that of non-pH-dependent anti-latent myostatin antibody (MS1032LO00-SG1) and different pH-dependent anti-latent myostatin antibody (MS1032LO01-SG1, MS1032LO06-SG1, MS1032LO11-SG1, MS1032LO18-SG1, MS1032LO19-SG1, MS1032LO21-SG1 and MS1032LO25-SG1. The introduction of pH-dependent significantly promotes myostatin clearance from SCID mouse plasma. As shown in Figure 18, the pH-dependent anti-latent myostatin antibodies (MS1032LO01-SG1, MS1032LO0-SG1, MS1032LO11-SG1, MS1032LO18-SG1, MS1032LO19- SG1, MS1032LO21- SG1 and MS1032LO25- To less myostatin accumulation than non-pH-dependent anti-latent myostatin antibody (MS1032LO00-SG1).

[Example 24]

Sinomorphous Non-pH-dependent anti- latent myostatin antibodies and anti- latent antibodies with both pH- and Fc engineering in monkeys Myostatin Comparison of plasma total myostatin concentrations between antibodies

Sinomolgus  Using a monkey In vivo  exam

The accumulation of endogenous myostatin was measured in 2-4-year-old Filipino monkeys (Sinomolgus monkeys) of Cambodia (Shin Nippon Biomedical Laboratories Ltd., Japan) Statins were evaluated in vivo upon administration of the antibody. A dose level of 30 mg / kg was injected into the levator vein of the forearm using a disposable syringe, extension tube, intrinsic needle, and infusion pump. The rate of administration was 30 minutes per body. Blood was administered 5 minutes, 7 hours and 1, 2, 3, 7, 14, 21, 28, 35, 42, 49 and 56 days before or 5 minutes and 2, 4 and 7 hours 1, 2, 3, 7, 14, 21, 28, 35, 42, 49 and 56 days. Blood was collected from the femoral vein with a syringe containing sodium heparin. The blood was immediately cooled on ice and plasma was obtained by centrifugation at 1700 x g for 10 minutes at 4 [deg.] C. The plasma samples were stored in a cryogenic freezer (acceptable range: -70 ° C or less) until measurement. The anti-latent myostatin antibody used was the MS1032LO00-SG1, MS1032LO06-SG1012, MS1032LO06-SG1016, MS1032LO06-SG1029, MS1032LO06-SG1031, MS1032LO06-SG1033, and MS1032LO06- SG1034 (here SG1012, SG1016, SG1029, SG1031 , SG1033, and SG1034 are heavy chain constant regions made on the basis of SG1 as described below.

SG1079, SG1071, SG1080, SG1074, SG1081, and SG1077 have the following characteristics: anti-latent myostatin antibodies MS1032LO19-SG1079, MS1032LO19-SG1071, MS1032LO19-SG1080, MS1032LO19-SG1074, MS1032LO19- , A dose level of 2 mg / kg was administered intravenously into the ipsilateral or vein of the forearm using a disposable syringe and an intrinsic needle. Blood was collected 5 minutes before, 2, 4, and 7 hours and 1, 2, 3, 7, and 14 days before initiation of administration and at the end of administration. The blood was treated as described above. Plasma samples were stored in a cryogenic freezer (acceptable range: below -70 ° C) until measurement.

Electrochemiluminescence (ECL) in plasma by total Myostatin  Measurement of concentration

The concentration of total myostatin in monkey plasma was measured by ECL as described in Example 23. [ The time course of total myostatin concentration in plasma after intravenous administration of the anti-latent myostatin antibody measured by the above method is shown in Fig.

Among monkey plasma using electrochemiluminescence (ECL) ADA  Measure

The biotinylated drug was coated onto a multi-array 96-well streptavidin plate (Mesoscale Discovery) and incubated in a low crossbreak buffer (Candor) for 2 hours at room temperature. A monkey plasma sample was diluted 20-fold in a low crossbuffer before adding it to the plate. Samples were incubated overnight at 4 ° C. The next day, the plate was washed three times with washing buffer before addition of the sulfotaglated anti-monkey IgG secondary antibody (Thermofisher Scientific). After incubation at room temperature for 1 hour, the plate was washed three times with washing buffer. Read buffer T (x4) (meso scale discovery) was immediately applied to the plate and the signal was detected using sector imager 2400 (Meso Scale Discovery).

In vivo  From a monkey Myostatin  For accumulation pH - dependency and Fc  The Effects of Engineering

In Cynomolgus monkeys, administration of a non-pH-dependent antibody (MS1032LO00-SG1) produced at least a 60-fold increase in myostatin concentration from baseline at 28 days. On day 28, the pH-dependent anti-latent myostatin antibodies MS1032LO06-SG1012 and MS1032LO06-SG1033 produced 3-fold and 8-fold increases from baseline, respectively. The strong withdrawal was mainly due to an increase in affinity for the synomolgus monkey Fc gamma RIIb. On day 28, the pH-dependent anti-latent myostatin antibodies MS1032LO06-SG1029, MS1032LO06-SG1031 and MS1032LO06-SG1034 were able to clear antigen below baseline. The reason for the strong clearing of MS1032LO06-SG1029, MS1032LO06-SG1031 and MS1032LO06-SG1034 is due to the increase in non-specific uptake in cells due to the increase of positively charged clusters of antibodies and the increased binding of Fc gamma R-mediated It is an increase in cell uptake.

Administration of pH-dependent anti-latent myostatin antibodies MS1032LO19-SG1079, MS1032LO19-SG1071, MS1032LO19-SG1080, MS1032LO19-SG1074, MS1032LO19-SG1081 and MS1032LO19- SG1077 inhibited myostatin concentration in synomolgus monkeys from day 1 (&Lt; 0.25 ng / ml). On day 14, the concentration of myostatin increased above the detection limit for MS1032LO19-SG1079 and MS1032LO19-SG1071, whereas for MS1032LO19-SG1080, MS1032LO19-SG1074, MS1032LO19-SG1081 and MS1032LO19- SG1077, It remained below the limit. Milder inhibition of MS1032LO19-SG1079 and MS1032LO19-SG1071 could be due to differences in pI mutations.

The data could be achieved by a mutation that increases the binding of myostatin from the plasma to binding to Fc gamma RIIb, or by a complex mutation that increases the positivity of the antibody and increases binding to Fc gamma RIIb. It was anticipated that a strong sweep of myostatin could be achieved in humans by complex mutations that increase the positivity of the antibody and increase binding to Fc gamma RIIb.

[Example 25]

Additional optimized variants in mice of In vivo  efficacy

The in vivo efficacy was evaluated in Scid mice using MS1032LO06-SG1, MS1032LO11-SG1, MS1032LO18-SG1, MS1032LO19-SG1, and MS1032LO25-SG1 as described in Example 8. Three independent studies were performed and MS1032LO01 was used as a control.

The results of these experiments are shown in Figs. 20A to 20I. All of the antibodies (MS1032LO06-SG1, MS1032LO11-SG1, MS1032LO18-SG1, MS1032LO19-SG1, and MS1032LO25-SG1) showed a dose-dependent increase in body fat gain as well as lean body mass (LBM). The antibodies also showed a dose-dependent decrease in body fat mass.

[Example 26]

term- Latency Myostatin  Antibody Epitope  Mapping

Additional anti-human latent myostatin antibodies were generated for mapping of their corresponding binding epitopes. Two NZW rabbits were immunized and harvested as described in Example 2. The identified 1760 antibody-producing B-cell line was further screened for its ability to block BMPl mediated activation of human latent myostatin. Briefly, B-cell supernatants containing secreted antibodies were incubated with human latent myostatin overnight at 37 占 폚 in the presence of recombinant human BMP1 (R & D Systems). 50 [mu] l of the reaction mixture was then transferred to a meso-scale discovery multi-array 96-well plate coated with the anti-mature myostatin antibody RK35 (as described in WO 2009/058346). After incubation for 1 hour at room temperature with shaking, the plate was incubated with the biotinylated anti-mature myostatin antibody RK22 (as described in WO 2009/058346) followed by sulfot-tagged streptavidin. The read buffer T (x4) (meso scale discovery) was then added to the plate and the ECL signal was detected by sector imager 2400 (Meso Scale Discovery). Ninety-four weeks showing different levels of neutralizing activity were selected for downstream analysis (MST1495-MST1588). The variable regions of these selected strains were cloned as described in Example 2 except that the expression vector with the heavy chain constant region F1332m sequence (SEQ ID NO: 193) was used.

The inhibitory activity against human latent myostatin activation is shown in Table 13 with the sequence identifiers for the amino acid sequences of the seven anti-latent myostatin antibodies (MST1032, MST1504, MST1538, MST1551, MST1558, MST1572, and MST1573; ) Was further evaluated. As shown in Figure 21, all of the antibodies were able to inhibit BMPl mediated activation of human latent myostatin in a dose-dependent manner.

[Table 13]

Four antibodies that work well in Western blotting were selected for epitope mapping. A fragment of the N-terminal propeptide encoding the region of the human latent myostatin was cloned into the pGEX4.1 vector to generate a GST-tagged propeptide fragment of 100 amino acids, wherein the 80 amino acids are duplicated 22a). Protein expression was induced in BL21 water-soluble cells transformed with the Overnight Express Autoinduction System (Merck Millipore) and proteins were digested with BugBuster protein extraction reagent (Novagen) ). &Lt; / RTI &gt; The expression of the desired protein fragments at about 37 kDa was confirmed by Western blotting analysis as described in Example 6 (anti-GST antibody (Abcam)) (Figure 22b). As shown in Figure 22c, when tested with anti-human latent myostatin antibodies, all four antibodies were able to induce latent myostatin activation, but they recognized different epitopes on human latent myostatin. The MST1032 antibody was able to detect the first 5 fragments and no band was detected after removal of amino acids 81-100 (SEQ ID NO: 78). Both the MST1538 and MST1572 antibodies bind only to the first three fragments and no band was detected in the absence of amino acids 41-60 of SEQ ID NO: 78. Only antibody MST1573 binds strongly to the first two fragments, suggesting that its epitope is within amino acids 21-40 of SEQ ID NO: 78 (Fig. 22D).

[Example 27]

New Fc  gamma RIIb - Increased Fc  Mutant of  Development

In this example, Fc engineering to increase the myostatin clearance is illustrated.

It has been demonstrated in WO 2013/125667 that the clearance of a soluble antigen can be increased by administration of an antigen-binding molecule comprising an Fc domain exhibiting increased affinity for Fc gamma RIIb. Furthermore, Fc variants which may exhibit increased binding to human Fc gamma RIIb are exemplified in WO &lt; RTI ID = 0.0 &gt; 2012/125241 &lt; / RTI &gt; and WO 2014/030728. It has also been demonstrated that these Fc variants can exhibit selectively increased binding to human Fc gamma RIIb and reduced binding to other active Fc gamma Rs. This selective increase in Fc gamma RIIb binding may be beneficial not only in reducing the clearance of soluble antigens but also in reducing undesirable effector function and the risk of an immune response.

For the development of antibody drugs, efficacy, pharmacokinetics and safety should be evaluated in non-human animals in which the drug is pharmacologically active. If the drug is only active in humans, another approach should be considered, for example the use of surrogate antibodies (Int. J. Tox. 28: 230-253 (2009)). However, it may not be easy to accurately predict the effect of the interaction between the Fc region and the Fc gamma R in humans using the substitution antibody because the expression pattern and / or function of Fc gamma R in non-human animals This is not always the same as in humans. The Fc region of the antibody drug has cross-reactivity to non-human animals, particularly Cynomolgus monkeys with an expression pattern and function of Fc gamma R close to that of humans, and thus the results obtained in non- It may be desirable to be able to extrapolate.

Thus, Fc variants exhibiting cross-reactivity to human and Sino Fc gamma R have been developed in this study.

Humans and monkeys Fc  Existing for Gamma R Fc  gamma RIIb - Increased Fc  Mutant of  Affinity measurement

The heavy chain gene of the human Fc gamma RIIb enhanced mutant disclosed herein as "Fc gamma RIIb augmented" means "having enhanced Fc gamma RIIb-binding activity" disclosed in WO 2012/115241, Position of Pro was replaced with Asp in the heavy chain of MS1032LO06-SG1, which was named M103205H795-SG1 (VH, SEQ ID NO: 86; CH, SEQ ID NO: 9). The resulting heavy chain is referred to as M103205H795-MY009 (VH, SEQ ID NO: 86; CH, SEQ ID NO: 252). As antibody light chain, M103202L889-SK1 (VL, SEQ ID NO: 96; CL, SEQ ID NO: 10) was used. The recombinant antibody was expressed according to the method shown in Example 34.

The extracellular domain of Fc gamma R was prepared in the following manner. The synthesis of genes for the extracellular domain of human Fc gamma R was performed in a manner known to those skilled in the art based on the information registered in NCBI. Specifically, Fc gamma RIIa is based on the sequence of NCBI storage # NM_001136219.1, Fc gamma RIIb is based on NM_004001.3, and Fc gamma RIIIa is based on NM_001127593.1. The allotypes of Fc gamma RIIa and Fc gamma RIIIa are designated as Fc gamma RIIa (J. Exp. Med. 172: 19-25 (1990)) and Fc gamma RIIIa (J. Clin. Invest. ): 1059-1070 (1997)). &Lt; / RTI &gt; The synthesis of the gene for the extracellular domain of the synomolcus monkey Fc gamma R was performed by cloning the cDNA of each Fc gamma R from the cynomolgus monkey using methods known to those skilled in the art. The amino acid sequence of the extracellular domain of the prepared Fc gamma R is shown in the sequence listing: SEQ ID NO: 210 for human Fc gamma RIIaR, SEQ ID NO: 211 for human Fc gamma RIIaH, SEQ ID NO: 214 for human Fc gamma RIIb , SEQ ID NO: 217 for human Fc gamma RIIIaF, SEQ ID NO: 218 for human Fc gamma RIIIaV, SEQ ID NO: 220 for syno Fc gamma RIIa1, SEQ ID NO: 221 for syno Fc gamma RIIa2, SEQ ID NO: 222 for syno Fc gamma RIIa3, SEQ ID NO: 223 for Sino Fc gamma RIIb, SEQ ID NO: 224 for Sino Fc gamma RIIIaS). His-tag was then added to their C-terminus and each gene obtained was inserted into an expression vector designed for mammalian cell expression. The expression vector was introduced into Freestyle 293 cells (Invitrogen) derived from human dendritic cells to express the target protein. After incubation, the resulting culture supernatant was filtered and purified in principle by the following four steps. (Superdex 200) as the first step, affinity chromatography on His-tag HP as the second step, cation exchange chromatography using SP Sepharose FF as the first step and gel filtration column chromatography (Superdex 200) As a third step, and sterile filtration as a fourth step. The absorbance of the purified protein at 280 nm was measured using a spectrophotometer and the concentration of the purified protein was measured using the extinction coefficient calculated by the method of PACE (Protein Science 4: 2411-2423 (1995))) .

A kinetic analysis of the interaction between these antibodies and Fc gamma R was performed using Biacore TM T200 or Biacore (TM) 4000 (GE Healthcare). HBS-EP + (Gly Healthcare) was used as the running buffer and the measurement temperature was set at 25 占 폚. The chip generated by immobilizing protein A, protein A / G or mouse anti-human IgG kappa light chain (BD biosciences) on series S sensor chip CM4 or CM5 (gli Healthcare) by an amine-coupling method Respectively. The antibody of interest was captured on the chip, interacted with each Fc gamma R diluted with the performance buffer, and the binding to the antibody was measured. After this measurement, the antibodies captured on the chip were washed by reacting the chip with 10 mM glycine-HCl, pH 1.5 and 25 mM NaOH to be repeatedly used and regenerated. The sensorgrams obtained as a result of the measurement were analyzed by a 1: 1 Langmuir binding model using Biacore (TM) evaluation software to calculate the binding rate constant ka (L / mol / s) and the dissociation rate constant kd (1 / s), and the dissociation constant KD (mol / L) was calculated from these values. Because binding of MS1032LO06-MY009 to human Fc gamma RIIaH, human Fc gamma RIIIaV, and syno Fc gamma RIIIaS was weak, kinetic parameters such as KD could not be calculated from the above-mentioned assays. With respect to such interactions, the KD values were calculated using the following 1: 1 binding model described in the Biacore (R) T100 Software Handbook BR1006-48 Edition AE.

Req = CxRmax / (KD + C) + RI where Req is the steady state versus concentration of the analyte Is the plot of the binding level, C is the concentration, RI is the bulk refractive index contribution in the sample, and Rmax is the analyte binding ability of the surface. When rearranging the above equation, KD can be expressed as Equation 2: KD = C x Rmax / (Req - RI) - C. KD can be calculated by substituting the values of Rmax, RI, and C into Equation 1 or Equation 2. From the current measurement conditions, RI = 0, C = 2 μmol / L can be used. Furthermore, the Rmax value obtained by entirely matching the obtained sensorgram as a result of analyzing the interaction between each Fc gamma R and IgG1 using the above 1: 1 Langmuir binding model is divided by the amount of captured SG1, Was multiplied by the amount of MY009 captured and the resulting value was used as Rmax. The calculation is based on the assumption that the limiting amount of each Fc gamma R that can be bound by SG1 remains unchanged for all mutants generated by introducing a mutation at Sg1 and that Rmax is proportional to the amount of antibody bound on the chip . Req was defined as the binding amount of each Fc gamma R for each variant on the sensor chip observed during the measurement.

Table 14 shows the results of kinetic analysis of SG1 and MY009 for human and syno Fc gamma R. The KD value in gray colored cells was calculated using Equation 2 because the affinity was too weak to be accurately measured by kinetic analysis. The KD multiple value was calculated by dividing the KD value of SG1 by the KD value of the mutant for each Fc gamma R. [

As shown in Table 14, the human Fc gamma RIIb-enhanced mutant MY009 does not exhibit an increased binding to syno Fc gamma RIIb but exhibits an increased binding to human Fc gamma RIIb. His affinity for Sino Fc gamma RIIb was reduced by a factor of 0.4 compared to SG1 suggesting that the human Fc gamma RIIb-enhanced mutant MY009 does not have cross-reactivity to Sino Fc gamma R.

Human and Shino Fc  gamma RIIb  New &lt; RTI ID = 0.0 &gt; Fc Mutant  Development

Ideally, the novel Fc variants should have selectively increased binding to both human and Sino Fc gamma RIIb and reduced binding to other active Fc gamma R. However, since the putative Fc binding residues in Sino Fc gamma RIIb are perfectly identical to any of the allotypes of Sino Fc gamma RIIa (Figure 23), it is possible to achieve a selective increase in synovial Fc gamma RIIb binding compared to Sino Fc gamma RIIa It is theoretically impossible to do. Thus, the novel Fc variants should have selectively increased binding to human Fc gamma RIIb, syno Fc gamma RIIb, and syno Fc gamma RIIa.

The results of a comprehensive mutagenesis study performed in WO 2012/115241 were used to obtain novel Fc variants that exhibit selectively enhanced binding to both human and syno Fc gamma RIIb. In this comprehensive mutagenesis study, a comprehensive mutation was introduced at all positions of the Fc gamma R binding region of the IgG1 antibody and the binding to each Fc gamma R was comprehensively analyzed as shown in the following procedure.

[Table 14]

The variable region of the glypicane 3 antibody comprising the CDR of GpH7, an anti-glypican 3 antibody with improved plasma kinetics as disclosed in WO 2009/041062, was used as the antibody heavy chain variable region (GpH7: SEQ ID NO: 225). Similarly, for the antibody light chain, GpL16-k0 (SEQ ID NO: 226) of the glypedicane 3 antibody with improved plasma kinetics as disclosed in WO 2009/041062 was used. Furthermore, the K439E mutation used B3 (SEQ ID NO: 228) introduced into G1d (SEQ ID NO: 227) generated by removing the C-terminal Gly and Lys of IgG1 as the antibody H chain constant region. The heavy chain prepared by fusing GpH7 and B3 is called GpH7-B3 (VH, SEQ ID NO: 225; CH, SEQ ID NO: 228).

With respect to GpH7-B3, the amino acid residues believed to be related to the Fc gamma R bond and the surrounding amino acid residues (position 234-239, 265-271, 295, 296, 298, 300 and 324-337 according to EU numbering) Were replaced with 18 amino acid residues except for the original amino acid residue and Cys, respectively. These Fc variants are referred to as B3 variants. B3 variants were expressed and the binding of the protein-A purified antibody to each Fc gamma R (Fc gamma RIIa H form, Fc gamma RIIa R form, Fc gamma RIIb and Fc gamma RIIIaF) was comprehensively evaluated as follows. Analysis of the interaction between each altered antibody and the Fc gamma receptor produced as described above was performed using the ViaCore (R) T100 (Gly Healthcare), ViaCore (TM) T200 (Gly Healthcare) A100, &lt; / RTI &gt; or ViaCore (R) 4000). HBS-EP + (Gly Healthcare) was used as the running buffer and the measurement temperature was set at 25 ° C. (Thermosynthetic), Protein A / G (Thermo Scientific) or Protein L (ACTIGEN) or Bio Vision (Thermo Scientific) to the Series S sensor chip CM4 or CM5 Bio Vision) was immobilized on a chip. After capturing the antibody of interest on the sensor chip, the Fc gamma receptor diluted with the performance buffer was allowed to interact and the amount bound to the antibody was measured. However, since the amount of the bound Fc gamma receptor changes depending on the amount of the captured antibody, the amount of the bound Fc gamma receptor is divided by the amount of each of the captured antibodies to obtain corrected values, Respectively. Further, the antibody captured on the chip was washed with 10 mM glycine-HCl, pH 1.5, and the chip was repeatedly regenerated and used. The value of the Fc gamma R binding amount of each B3 variant was compared with that of the parent B3 antibody (having the sequence of native human IgG1 at positions 234 to 239, 265 to 271, 295, 296, 298, 300 and 324 to 337 according to EU numbering Antibody) by the value of the Fc gamma R binding amount. The value obtained by multiplying the value by 100 was used as an indicator of the relative Fc gamma R-binding activity of each variant.

Table 15 shows binding profiles of promising substitutions selected on the basis of the following criteria (greater than 40% for human Fc gamma RIIb, less than 100% for human Fc gamma RIIaR and Fc gamma RIIaH, as compared to the case of parent B3 antibody, Less than 100% for human Fc gamma RIIIaF).

[Table 15]

In the next step, the cross-reactivity of these substitutions to the Sino Fc gamma R was evaluated. These 16 mutants were introduced into M103205H795-SG1. The mutants were expressed using M103202L889-SK1 as a light chain and their affinity for Sino Fc gamma RIIa1, IIa2, IIa3, IIb, IIIaS was analyzed.

Table 16 shows the binding profiles of these 16 variants to the syno-Fc gamma R. &lt; tb &gt; &lt; TABLE &gt; The value of the Fc gamma R binding amount was obtained by dividing the amount of bound Fc gamma R by the amount of each captured antibody. The value was further standardized using a value for SG1 as 100.

[Table 16]

Of the 16 selected Fc variants, only MY001 retained the binding to syno Fc gamma RIIb at 85% over SG1. In addition, MY001 showed reduced binding to syno Fc gamma RIIIaS and retained its binding to syno Fc gamma RIIa1, IIa2 and IIa3. As a result, the G236N mutation is a unique substitution exhibiting a similar binding profile for both human and syno Fc gamma R.

G236N substitution shows cross-reactivity to both human and syno Fc gamma R, but its affinity for Fc gamma RIIb is lower than SG1 (75% for human Fc gamma RIIb and 85% for syno Fc gamma RIIb, respectively) . To increase its affinity for Fc gamma RIIb, additional substitutions were evaluated. Specifically, the results of a comprehensive mutagenesis study showing increased binding to human Fc gamma RIIb, decreased binding to human Fc gamma RIIIa and increased selectivity for human Fc gamma RIIb compared to human Fc gamma RIIa (Table 17)

[Table 17]

Of these substitutions, L234W and L234Y were selected to increase selectivity for human Fc gamma RIIb relative to human Fc gamma RIIa. G236A, G236S, A330R, A330K and P331E were also selected to reduce binding to human Fc gamma RIIIa. All other substitutions were selected to increase binding to human Fc gamma RIIb. The cross-reactivity of the selected substitutions to the Sino Fc gamma R was evaluated. In addition, three substitutions, P396M, V264I and E233D, were also evaluated. The substitutions were introduced into M103205H795-SG1 and the mutants were expressed using M103202L889-SK1 as a light chain.

Table 18 shows the kinetic analysis of selected substitutions including G236N for both human and syno Fc gamma R. Specifically, the substitution was introduced into M103205H795-SG1. The mutants were expressed using M103202L889-SK1 as a light chain and their affinity for Sino Fc gamma RIIa1, IIa2, IIa3, IIb, IIIaS was analyzed. The KD values in gray colored cells were calculated using [Equation 2] because their affinity was too weak to be accurately measured by kinetic analysis. The KD multiple value was calculated by dividing the KD value of SG1 by the KD value of the mutant for each Fc gamma R. [

G236N showed binding affinity for syno Fc gamma RIIa1, syno Fc gamma RIIa2, syno Fc gamma RIIa3 and syno Fc gamma RIIb comparable to SG1. The affinity for human Fc gamma RIIb is reduced by a factor of 0.6, but the affinity for human Fc gamma RIIaH and human Fc gamma RIIaR is reduced by 0.2 and 0.1 fold, respectively, Indicating high selectivity. Furthermore, its affinity for Sino Fc gamma RIIIaS and human Fc gamma RIIIaV is 0.03 and 0.04, respectively, which can be beneficial for the elimination of ADCC activity. Based on the above results, G236N showed almost ideal cross-reactivity to human and syno Fc gamma R, but its affinity for both human and syno Fc gamma RIIb should be increased.

Of the additional substitutions that were evaluated, S298L, G236A, P331E, E233D, K334Y, K334M, L235W, S239V, K334I, L234W, K328T, Q295L, K334V, K326T, P396M, I332D, H268E, P271G, S267A, Lt; RTI ID = 0.0 &gt; RIIb. &Lt; / RTI &gt; Specifically, H268D showed the greatest effect (7 fold for human Fc gamma RIIb and 5.3 fold for syno Fc gamma RIIb). Regarding the reduction effect on Fc gamma RIIIa binding, G236S, A330K, and G236D showed less than 0.5-fold affinity compared to SG1.

To increase the affinity of MY001 for human and Sino Fc gamma RIIb, the combinations of substitutions listed in Table 18 were evaluated. Specifically, the substitution was introduced into M103205H795-SG1. The mutants were expressed as light chains using M103202L889-SK1 and their affinity was analyzed. Table 19 shows the results of kinetic analysis for human and syno Fc gamma R. The KD values in gray colored cells were calculated using Equation 2 because their affinity was too weak to be accurately measured by kinetic analysis. The KD multiple value was calculated by dividing the KD value of SG1 by the KD value of the mutant for each Fc gamma R. [

[Table 18]

[Table 19]

All of the mutants inhibited the affinity for human Fc gamma RIIIaV by less than 0.26 times as compared to SG1 and by less than 0.42 times as compared to Sino Fc gamma RIIIaS. Furthermore, mutants except MY047, MY051, and MY141 have successfully demonstrated an enhanced binding to both human and Sino Fc gamma RIIb relative to MY001 and their human Fc gamma RIIa binding was maintained at less than 2-fold relative to SG1. Among these, MY201, MY210, MY206, MY144, MY103, MY212, MY105, MY205, MY109, MY107, MY209, MY101, MY518, MY198 and MY197 were increased more than 4-fold over both human and Sino Fc gamma RIIb Lt; / RTI &gt; In particular, MY205, MY209, MY198, and MY197 showed over 7 fold increased binding for both human and syno Fc gamma RIIb binding.

Substitution at position 396 in the CH3 domain is illustrated in WO2014030728 as increasing the affinity for human Fc gamma RIIb. A comprehensive mutagenesis was introduced at position 396 of M103205H795-MY052 (containing G236N / H268E / P396M substitution). The resulting mutants were expressed using M103202L889-SK1 as a light chain and their affinity for human and Sino Fc gamma R was evaluated (Table 20). The value of the KD multiple was calculated by dividing the KD value of SG1 by the KD value of the mutant for each Fc gamma R.

Of the substitutions tested, P396I, P396K and P396L maintained human Fc gamma RIIb binding by more than 5-fold over SG1 and only P396L substitution increased affinity for human Fc gamma RIIb relative to MY052. For binding to Sino Fc gamma RIIb, parent MY052 showed the highest affinity, 3.9 fold increase from SG1.

Since G236N exhibited the ideal cross-reactivity to human and Sino Fc gamma R, other substitutions at position 236, which were not evaluated in the preceding examples, were tested. Specifically, Asn in M103205H795-MY201 was replaced with Met, His, Val, Gln, Leu, Thr, and Ile. The resulting mutants were expressed using M103202L889-SK1 as light chain and their affinity for human and syno Fc gamma R was evaluated (Table 21). The KD values in gray colored cells were calculated using Equation 2 because their affinity was too weak to be accurately measured by kinetic analysis. The KD multiple value was calculated by dividing the KD value of SG1 by the KD value of the mutant for each Fc gamma R. [

[Table 20]

[Table 21]

[Table 22]

All of the above variants showed reduced affinity for both human and synonymous Fc gamma RIIb compared to parent MY201, but MY265 (generated by substituting Asn for Thr at position 236 of MY201) with human Fc 2.1 fold increase in gamma RIIb and 3.1 fold increase in syno Fc gamma RIIb. MY265 also maintained reduced binding to both human and syno Fc gamma RIIIa. G236T increased the affinity for human Fc gamma RIIaH and Fc gamma RIIaR by more than 2.5-fold compared to SG1, but is the second beneficial substitution at position 236.

To improve the selectivity and affinity of MY265 for human Fc gamma RIIb, extensive mutagenesis studies into positions 231 and 232 were performed. Specifically, positions 231 and 232 of M103205H795-MY265 were replaced with 18 amino acid residues except for the original amino acid and Cys. The resulting mutants were expressed using M103202L889-SK1 as light chain and their affinity for human and syno Fc gamma R was assessed (Table 22). The value of the KD multiple was calculated by dividing the KD value of SG1 by the KD value of the mutant for each Fc gamma R.

The addition of A231T, A231M, A231V, A231G, A231F, A231I, A231L, A231, A231W, P232V, P232Y, P232F, P232M, P232I, P232W and P232L in relation to affinity for Fc gamma RIIb, Fc gamma RIIb. In particular, the addition of A231T and A231G reduced human Fc gamma RIIaR binding relative to MY265.

The combination of the substitutions not evaluated in the preceding embodiments was evaluated. The substitutions found to be tested and found to be promising were combined and introduced into M103205H795-SG1. The resulting mutants were expressed using M103202L889-SK1 as a light chain and their affinity for human and syno Fc gamma R was evaluated. Table 23 shows the above results and the KD values of gray colored cells were calculated using [Equation 2] because their affinity was too weak to be accurately measured by kinetic analysis. The KD multiple value was calculated by dividing the KD value of SG1 by the KD value of the mutant for each Fc gamma R. [ Values for MY209 selected as promising mutants in Table 19 are again shown for comparison.

Of the mutants tested, only MY213 showed a higher binding affinity for both human and syno Fc gamma RIIb relative to MY209. However, the affinity of MY213 for human Fc gamma RIIaH and human Fc gamma RIIaR is higher than that for MY209.

[Table 23A]

[Table 23B]

[Table 24]

[Example 28]

All humans Fc  Gamma R Transgenic  From the mouse Fc  gamma RIIb - Increased Fc  Mutant To  Evaluation of myostatin clearance to be used

The clearance effect of myostatin by the Fc gamma RIIb-enhanced Fc variants prepared in Example 27 was evaluated in mice in which all mouse Fc gamma R was deleted and human Fc gamma R encoded as transgene was inserted into the mouse genome (Proc. Natl. Acad. Sci., 2012, 109, 6181). All mouse Fc gamma R in the mouse is replaced with human to allow the affinity enhancement effect on the clearance of soluble antigens to human Fc gamma RIIb to be evaluated in mice. In addition, the pI-increasing substitution was also evaluated with the Fc gamma RIIb-enhanced Fc variants produced in Example 27.

Tested  Mutant of  Manufacturing and Profiles

The eight antibodies tested and their binding profiles are summarized in Table 24. The heavy chain, MS103205H795-PK2, was prepared by introducing pI-increasing substitution (S400R / D413K) in MS103205H795-MY101. MS103205H795-MY351, MS103205H795-MY344, and MS103205H795-MY335 were introduced by introducing another pI-increasing substitution (Q311R / D413K) in MS103205H795-MY201, MS103205H795-MY205 and MS103205H795-MY265, respectively. All of the MS1032LO06 variants were expressed as M103202L889-SK1 as light chain according to the method shown in Example 27 and their affinity for human and syno Fc gamma R was evaluated using the method of Example 27. [

Based on the SPR analysis summarized in Table 24, it was determined that the pI-increasing substitution did not affect Fc gamma R binding of Fc gamma RIIb-enhanced Fc variants. MY101 and PK2 (produced by introducing S400R / D413K into MY101) exhibited human Fc gamma RIIb binding increased 9 and 8-fold, respectively. The affinity of MY101 and PK2 for human Fc gamma RIIa remained comparable to SG1. With respect to other human and Sino Fc gamma R, they exhibited nearly identical binding profiles. Similarly, MY351 showed a similar binding profile as parent MY201, MY344 showed a similar binding profile to parent MY205, and MY335 showed similar binding profile to parent MY265 (Table 21). These results imply that the pI-increasing substitution, either S400R / D413K and Q311R / D413K, does not affect the affinity for human and Sino Fc gamma R.

All humans Fc  Gamma R Transgenic  PK studies in mice

All humans Fc  Gamma R Transgenic  Using the mouse In vivo  exam

The removal of myostatin and anti-latent myostatin antibodies was assessed in vivo in all human Fc gamma R transgenic mice upon co-administration of anti-latent myostatin antibody and human latent myostatin ( 24 and 25). Anti-latent myostatin antibody (0.3 mg / ml) and latent myostatin (0.05 mg / ml) were administered to the jugular vein in a single dose of 10 ml / kg. Anti-drug antibodies were inhibited by administering anti-CD antibody (1 mg / ml) to the jugular vein at a dose of 10 ml / kg three times (every 10 days). Blood was collected at 5 minutes, 15 minutes, 1 hour, 4 hours, 7 hours, 1 day, 2 days, 7 days, 14 days, 21 days, and 28 days after administration. The collected blood was immediately centrifuged at 15,000 rpm for 5 minutes at 4 &lt; 0 &gt; C to separate plasma. The separated plasma was stored at -20 캜 or lower until measurement. The anti-latent myostatin antibodies used were MS1032LO06-SG1, MS1032LO06-MY101, MS1032LO06-PK2, MS1032LO06-MY201, MS1032LO06-MY351, MS1032LO06-MY205, MS1032LO06-MY344 and MS1032LO06-MY335.

Electrochemiluminescence (ECL) in plasma by total Myostatin  Measurement of concentration

The concentration of total myostatin in mouse plasma was measured by ECL. Anti-mature myostatin antibody-immobilized plates were prepared by dispensing the anti-mature myostatin antibody RK35 (WO 2009058346) on multi-array 96-well plates (Mesoscale Discovery) and incubated overnight at 4 ° C. Mature myostatin curve curves and murine plasma samples were prepared that were at least 4 times diluted. The samples were mixed in acidic solution (0.2 M glycine-HCl, pH 2.5) to dissociate mature myostatin from its binding protein (e.g., a propeptide). Subsequently, the samples were added to an anti-mature myostatin-immobilized plate and bound for 1 hour at room temperature and then washed. The biotin-tagged anti-mature myostatin antibody RK22 (WO 2009/058346) was then added and the plate was incubated at room temperature for 1 hour and then washed. Subsequently, the sulfotaglabeled streptavidin (meso scale discovery) was added and the plate was incubated at room temperature for 1 hour and then washed. Read buffer T (x4) (meso scale discovery) was immediately applied to the plate and the signal was detected by sector imager 2400 (Meso Scale Discovery). The mature myostatin concentration was calculated based on the response of the calibration curve using the analysis software Soft Max Pro (Molecular Devices). The time course of the total myostatin concentration in plasma after intravenous administration of the anti-latent myostatin antibody measured by the above method is shown in Fig.

High Performance Liquid Chromatography - Electrospray Tandem Mass Spectrometry (LC / ESI - MS / MS Measurement of anti-latent myostatin antibody concentration in plasma

The anti-latent myostatin antibody concentration in mouse plasma was measured by LC / ESI-MS / MS. The concentrations of the calibration standards were 1.56 25, 3.125, 6.25, 12.5, 25, 50, 100 and 200 μg / ml in mouse plasma. 3 [mu] l of the calibration standards and plasma samples were added to 50 [mu] l Ab-Capture Mag (ProteNova) and incubated for 2 hours at room temperature. Thereafter, the magnetic beads were recovered from the sample and washed twice with 0.2 ml of 10 mmol / L PBS with 0.05% Tween 20. Subsequently, the magnetic beads were washed with 10 mmol / L PBS to ensure removal of tween 20. After washing, the magnetic beads were suspended in 25 μl of 7.5 mol / L urea, 8 mmol / L dithiothreitol and 1 μg / mL lysozyme (chicken egg white) in 50 mmol / L ammonium bicarbonate, Samples were incubated at 56 DEG C for 45 minutes. Subsequently, 2 占 퐇 of 500 mmol / L iodoacetamide was added and the sample was incubated in a dark room at 37 占 폚 for 30 minutes. Then, 150 μl of 0.67 μg / ml of biochemical lysylendopeptidase (wako) was added to 50 mmol / L ammonium bicarbonate to perform lysylendopeptidase cleavage, and the sample was incubated at 37 ° C. for 3 hours Lt; / RTI &gt; Subsequently, trypsin cleavage was performed by adding 10 [mu] l of 10 [mu] g / ml sequencing grade modified trypsin (Promega) to 50 mmol / L ammonium bicarbonate. Samples were cut under mixing overnight at 37 占 and quenched by addition of 5 占 퐇 of 10% trifluoroacetic acid. 50 [mu] l of cut samples were analyzed by LC / ESI-MS / MS. LC / ESI-MS / MS was performed using a Xevo TQ-S triple quadrupole instrument (Waters) equipped with 2D I-class UPLC (Waters). The anti-latent myostatin antibody-specific peptide YAFGQGTK and lysozyme specific peptide GTDVQAWIR (as an internal standard) were monitored by the above selected reaction monitoring (SRM). (M / z 637.3) for [M + 2H] 2+ (m / z 436.2) for the anti-latent myostatin antibody and [M + 2H] 2+ z 523.3) to the y8 ion (m / z 545.3). An internal calibration curve was created by weighing (1 / x or 1 / x2) linear regression using the plotted peak area against concentration. Mouse plasma concentrations were calculated from the calibration curves using the analysis software Masslynx Ver.4.1 (Waters). The time course of antibody concentration in plasma after intravenous administration of anti-latent myostatin antibody and latent myostatin measured by the above method is shown in Fig.

In vivo Myostatin  For concentration pI  And Fc  Effect of gamma R binding

The plasma total myostatin concentration at 7 hours after administration of MS1032LO06-SG1 was reduced by 5-fold compared to the plasma total myostatin concentration at 5 minutes. In contrast, plasma total myostatin levels at 7 hours after administration of MS1032LO06-MY101, MS1032LO06-MY201, and MS1032LO06-MY205 were 28 to 200 fold lower than plasma total myostatin levels at 5 minutes. Furthermore, plasma total myostatin concentrations at 7 hours after administration of MS1032LO06-PK2, MS1032LO06-MY351, MS1032LO06-MY344, and MS1032LO06-MY335 were reduced by 361 to 419 times compared to plasma total myostatin concentrations at 5 minutes . On the other hand, the difference in the concentration of each antibody at each sampling time was within approximately 2-fold compared to MS1032LO06-SG1, and the pI variant did not increase antibody clearance from plasma. Both the human Fc gamma RIIb binding-enhanced antibody and the pI-increasing substitution increased the removal of myostatin, but the antibody was not.

High pI variants have more positive charge in plasma. Since the positive charge interacts with the cell surface of the negative charge, the antigen-antibody immunoconjugate of the high pI variant closer to the cell surface increased cell uptake of the antigen-antibody immunoconjugate of the high pI variant.

[Example 29]

From a monkey Fc  gamma RIIb - Increased Fc  Mutant To  using Myostatin Clear run Evaluation of

The effect of the increased binding of the Fc variants developed in Example 27 on synoyl Fc gamma RIIb for myostatin monohydrate was evaluated in synomorphic monkeys. The complex effect with pI-increasing substitution was also evaluated.

Tested  Mutant of  Manufacturing and Profiles

The 14 antibodies tested and their binding profiles are summarized in Table 25. Fc variants with increased binding to FcRn at acidic pH have been reported to improve antibody half-life in vivo (J. Biol. Chem. 2006 281: 23514-23524 (2006); Nat. Biotechnol 28: 157-159 (2010), Clin Pharm. &Amp; Thera. 89 (2): 283-290 (2011)). To improve antibody half-life without binding to rheumatic agents, we conjugated these substitutions with Fc gamma RIIb-enhanced and pi-enhanced Fc variants.

MS103205H795-SG1029, MS103205H795-SG1031, MS103205H795-SG1033, MS103205H795-SG1034 and MS103205H795-SG1034 were introduced into the MS103205H795-SG1012, MS103205H795-SG1012, MS103205H795-SG1029, MS103205H795-SG1031, MS103205H795-SG1033, MS103205H795-SG1034, N434A substitution in MS103205H795-MY101, MS103205 H795-MY344, MS103205H795-MY351, MS103205H795-MY201, . MS103205H795-SG1016 by introducing pI-incremental substitution (Q311R / D399K) into MS103205H795-SG1012. MS103240H795-SG1071 and MS103240H795-SG1079 were introduced into MS103240 H795-MY344 (MS103240H795: VH, SEQ ID NO: 92) with M428L / N434A / Y436T / Q438R / S440E substitutions and N434A / Q438R / S440E substitutions, respectively.

MS103240H795-SG1074 and MS103240H795-SG1077 were introduced into MS103240H795-MY209 and MS103240H795-MY518, respectively, with pI-increasing substituted Q311R / P343R and M428L / N434A / Y436T / Q438R / S440E substitutions. MS103240H795-SG1080 and MS103240H795-SG1081, pI-increasing substituted Q311R / P343R and N434A / Q438R / S440E substitutions, respectively, in MS103240H795-MY209 and MS103240H795-MY518. MS103240H795-SG1071 was prepared by introducing pI-incrementally substituted Q311R / D413K and M428L / N434A / Y436T / Q438R / S440E substitutions into MS103240H795-MY205. MS103240H795-SG1079 was prepared by introducing pI-incrementally substituted Q311R / D413K and N434A / Q438R / S440E substitutions into MS103240H795-MY205. These MS1032LO06 mutants and MS1032LO19 mutants were expressed as light chains according to the method shown in Example 34 as M103202L889-SK1 and M103202L1045-SK1 (M103202L1045: VL, SEQ ID NO: 97), respectively, and their affinity for human and syno Fc gamma R And evaluated using the method of Example 27. [ In this example, the KD multiple value for each Fc variant was calculated by dividing the KD value of parent SG1 by the KD value of the mutant for each Fc gamma R. For example, the KD multiple values for MS1032LO06-SG1012 and MS1032LO19-SG1071 were calculated by dividing the KD values of MS1032LO06-SG1 and MS1032LO19-SG1 by the KD values of MS1032LO06-SG1012 and MS1032LO19-SG1071, respectively.

[Table 25]

The results of the SPR analysis are summarized in Table 25. Of these mutants, SG1012, SG1016, SG1074 and SG1080 show the strongest affinity for human Fc gamma RIIb (which has a tenfold increased affinity for human Fc gamma RIIb relative to SG1).

29.2. PK studies in monkeys

Sinomolgus  Using a monkey In vivo  exam

The accumulation of endogenous myostatin was assessed in vivo by the administration of an anti-latent myostatin antibody in 2-4 year old Filipino monkeys (Sinomolgus monkeys) (Shin Nippon Biomedical, Levatoris, Ltd., Japan) Respectively. A dose level of 30 mg / kg was injected into the levator vein of the forearm using a disposable syringe, extension tube, intrinsic needle, and infusion pump. The rate of administration was 30 minutes per body. Blood was administered 5 minutes, 7 hours and 1, 2, 3, 7, 14, 21, 28, 35, 42, 49 and 56 days before or 5 minutes and 2, 4 and 7 hours 1, 2, 3, 7, 14, 21, 28, 35, 42, 49 and 56 days. Blood was collected from the femoral vein with a syringe containing sodium heparin. The blood was immediately cooled on ice and plasma was obtained by centrifugation at 1700 x g for 10 minutes at 4 [deg.] C. The plasma samples were stored in a cryogenic freezer (acceptable range: -70 ° C or less) until measurement. The anti-latent myostatin antibody used was the MS1032LO00-SG1, MS1032LO06-SG1012, MS1032LO06-SG1016, MS1032LO06-SG1029, MS1032LO06-SG1031, MS1032LO06-SG1033, and MS1032LO06- SG1034 (here SG1012, SG1016, SG1029, SG1031 , SG1033, and SG1034 are heavy chain constant regions made based on SG1 as described below.

SG1079, SG1071, SG1080, SG1074, SG1081, and SG1077 have the following characteristics: anti-latent myostatin antibodies MS1032LO19-SG1079, MS1032LO19-SG1071, MS1032LO19-SG1080, MS1032LO19-SG1074, MS1032LO19- , The dose level of 2 mg / kg was administered in the ipsilateral vein or vein of the forearm using a disposable syringe and an intrinsic needle. Blood was collected 5 minutes before, 2, 4, and 7 hours and 1, 2, 3, 7, and 14 days before initiation of administration and at the end of administration. The blood was treated as described above. Plasma samples were stored in a cryogenic freezer (acceptable range: below -70 ° C) until measurement.

Electrochemiluminescence (ECL) in plasma by total Myostatin  Measurement of concentration

The concentration of total myostatin in monkey plasma was measured by ECL as described in Example 23. [ The time course of the total myostatin concentration in plasma after intravenous administration of the anti-latent myostatin antibody measured by the above method is shown in Fig.

Among monkey plasma using electrochemiluminescence (ECL) ADA  Measure

The biotinylated drug was coated onto a multi-array 96-well streptavidin plate (Mesoscale Discovery) and incubated in a low crossbuffer (Candid) at room temperature for 2 hours. A monkey plasma sample was diluted 20-fold in a low crossbuffer before adding it to the plate. Samples were incubated overnight at 4 ° C. The next day, the plate was washed three times with washing buffer before addition of the sulfotaglated anti-monkey IgG secondary antibody (Thermofisher Scientific). After incubation at room temperature for 1 hour, the plate was washed three times with washing buffer. Read buffer T (x4) (meso scale discovery) was immediately applied to the plate and the signal was detected using sector imager 2400 (Meso Scale Discovery).

In vivo  From a monkey Myostatin  For accumulation pH - dependency and Fc  The Effects of Engineering

In Cynomolgus monkeys, administration of a non-pH-dependent antibody (MS1032LO00-SG1) produced at least a 60-fold increase in myostatin concentration from baseline at 28 days. On day 28, the pH-dependent anti-latent myostatin antibodies MS1032LO06-SG1012 and MS1032LO06-SG1033 produced 3-fold and 8-fold increases from baseline, respectively. The strong withdrawal was mainly due to an increase in affinity for the synomolgus monkey Fc gamma RIIb. On day 28, the pH-dependent anti-latent myostatin antibodies MS1032LO06-SG1029, MS1032LO06-SG1031 and MS1032LO06-SG1034 were able to clear antigen below baseline. The reason for the strong clearing of MS1032LO06-SG1029, MS1032LO06-SG1031 and MS1032LO06-SG1034 is due to the increase in non-specific uptake in cells due to the increase of positively charged clusters of antibodies and the increased binding of Fc gamma R-mediated It is an increase in cell uptake.

Administration of pH-dependent anti-latent myostatin antibodies MS1032LO19-SG1079, MS1032LO19-SG1071, MS1032LO19-SG1080, MS1032LO19-SG1074, MS1032LO19-SG1081 and MS1032LO19- SG1077 inhibited myostatin concentration in synomolgus monkeys from day 1 (&Lt; 0.25 ng / ml). On day 14, the concentration of the increased myostatin increased above the detection limit for MS1032LO19-SG1079 and MS1032LO19-SG1071, while for MS1032LO19-SG1080, MS1032LO19-SG1074, MS1032LO19-SG1081 and MS1032LO19- SG1077, Remained below the detection limit. Milder inhibition of MS1032LO19-SG1079 and MS1032LO19-SG1071 could be due to differences in pI mutations.

The data could be achieved by a complex mutation that increases the binding of Fc gamma RIIb to mutants or antibodies that increase binding to Fc gamma RIIb and increases binding to Fc gamma RIIb. Strong cleavage of myostatin could be achieved in humans by complex mutations that increase the positivity of the antibody and increase binding to Fc gamma RIIb.

[Example 30]

Myostatin Clearance  To increase pI - Increased  Selection of substitutions

In order to increase the clearance of myostatin, the pI increased substitution in the Fc portion of the antibody was evaluated in this example. The method of adding an amino acid substitution to the antibody constant region to increase the pI is not particularly limited, but can be carried out, for example, by the method described in WO 2014/145159. As in the case of the variable region, the amino acid substitutions introduced into the constant region preferably increase negatively charged amino acids (such as aspartic acid and glutamic acid, for example, arginine and lysine) while increasing positively charged amino acids Lt; / RTI &gt; Furthermore, an amino acid substitution can be introduced at any position in the antibody constant region, and the substitution can be a single amino acid substitution or a combination of multiple amino acid substitutions. Although not particularly limited, the introduction site for amino acid substitution is preferably a position at which the amino acid side chain can be exposed on the surface of the antibody molecule. Particularly preferred examples include a method of introducing a combination of multiple amino acid substitutions at such positions that can be exposed on the surface of the antibody molecule. On the one hand, the multiple amino acid substitutions introduced herein are preferably such that the substitutions are structurally close to each other. Furthermore, although there are no particular limitations, the multiple amino acid substitutions introduced herein are preferably substitutions for positively charged amino acids, thus preferably producing a state in which a plurality of positive charges are present at structurally close positions .

Tested  Mutant of  Manufacturing and Profiles

The antibodies tested are summarized in Table 26. Heavy chain, MS103205H795-SG141, and pI-increasing substituted Q311R / D399R to MS103205H795-SG1. Other heavy chain variants were also prepared by introducing each substitution shown in Table 26 into MS103205H795-SG1. All of the MS1032LO06 variants were expressed as M103202L889-SK1 as light chain according to the method shown in Example 34. [

ViaCore &lt; (R) &gt;  using pI - Increased Fc  Mutant of  mouse Fc  gamma RII - bond analysis

With respect to the resulting Fc region variant-containing antibody, binding analysis between the soluble mouse Fc gamma RII and the antigen-antibody complex was performed using Biacore (R) T200 (Gly Healthcare). Soluble mouse Fc gamma RII was produced in the form of His-tagged molecules by methods known to those skilled in the art. The appropriate amount of anti-His antibody was immobilized on the sensor chip CM5 (Gyalthcare) by the amine coupling method using the His capture kit (GE Healthcare) to capture the mouse Fc gamma RII. Antibody-antigen complexes and running buffer (as reference solution) were then injected to allow interaction with the captured mouse Fc gamma RII on the sensor chip. 150 mM NaCl, 1.2 mM CaCl ₂ , and 0.05% (w / v) Tween 20 were used as performance buffers at pH 7.4 and 20 mM N- (2-acetamido) Buffer was also used to dilute the soluble mouse Fc gamma RII. To regenerate the sensor chip, 10 mM glycine-HCl was used at pH 1.5. All measurements were performed at 25 ° C. The analysis was performed based on the binding (RU) calculated from the sensorgram obtained by the above measurement, and shows the relative value when binding amount of SG1 is limited to 1.00. To calculate these parameters, the ViaCore (R) T100 evaluation software (ZihealthCare) was used.

The SPR analysis results are summarized in Table 26. Several Fc variants have been shown to have increased affinity for immobilized mouse Fc gamma RII on the Biacore (TM) sensor chip.

While not intending to be bound by any particular theory, the above results can be described as follows. The Biacore (TM) sensor chip is known to be negatively charged, and the charged state can be regarded as resembling a cell membrane surface. More specifically, the affinity of an antigen-antibody complex for immobilized mouse Fc gamma RII on a negatively charged Biacore (R) sensor chip is such that the antigen-antibody complex is present on a similarly negatively charged membrane surface Lt; RTI ID = 0.0 &gt; Fc &lt; / RTI &gt; gamma RII.

[Table 26]

Here, an antibody produced by introducing a pI-increasing deformation into the Fc region is an antibody that is more positive in the charge of the Fc region than that before the introduction of the strain. Thus, the Coulombic interaction between the Fc region (positive charge) and the sensor chip surface (negative charge) can be considered to be enhanced by the pI-increasing amino acid modification. Moreover, such effects are expected to occur similarly on the same negatively charged cell membrane surface; Therefore, it is expected that the above-mentioned effect shows an effect of accelerating the rate of absorption into cells in vivo.

Of the pI increased Fc variants with two amino acid substitutions from SG1, the antigen-antibody complexes produced by SG141, P1499m, P1501m and P1540m exhibit the highest binding to human Fc gamma RIIb. Amino acid substitutions on Q311R / D399R, Q311R / P343R, Q311R / D413R and D401R / D413K are presumed to have a strong charge effect on binding to human Fc gamma RIIb on the sensor chip.

pI - Increased Fc  Mutant of  Cell absorption

To assess the rate of cellular uptake into human Fc gamma RIIb-expressing cell lines, the following assay was performed. MDCK (Madin-Dalby dog kidney) cell lines that constitutively express human Fc gamma RIIb were generated by known methods. These cells were used to evaluate the intracellular uptake of antigen-antibody complexes.

Specifically, human potential myostatin (antigen) was labeled using pHrodoRed (Life Technologies) according to established protocols, and the antigen-antibody complex was incubated with an antibody concentration of 10 mg / ml and an antigen concentration of 2.5 mg / Culture solution. The culture solution containing the antigen-antibody complex was added to a culture plate of the aforementioned MDCK cells (constitutively expressing human Fc gamma RIIb), incubated for 1 hour, and then the fluorescence intensity of the antigen absorbed into the cell Was quantitatively analyzed using an InCell Analyzer 6000 (Jihealthcare). The amount of the absorbed antigen was expressed as a relative value to the SG1 value (considered as 1.00).

The results of quantitative analysis of the cell uptake are summarized in Table 26. Strong fluorescence from the antigen in the cells was observed in a number of Fc variants.

While not intending to be bound by any particular theory, the above results can be described as follows.

The antigen and antibody added to the cell culture solution form an antigen-antibody complex in the culture solution. The antigen-antibody complex binds to human Fc gamma RIIb expressed on the cell membrane through the antibody Fc region and absorbs the cell in a receptor-dependent manner. The antibodies used in this experiment bind to the antigen in a pH-dependent manner; Thus, the antibody can be dissociated from the antigen in the endosomes (acid pH conditions) inside the cell. Since the dissociated antigen is labeled with pHrodoRed as described above, it fluoresces in the endosome. Thus, it is believed that the intense fluorescence intensity within the cell indicates that absorption of the antigen-antibody complex into the cell occurs more rapidly or in greater amounts.

Of the pI increased Fc variants with two amino acid substitutions from SG1, the antigen-antibody complexes produced by SG141, P1375m, P1378m, P1499m, P1524m, P1525m, P1532m, P1533m, P1540m, P1541m and P1543m, Exhibit strong antigen uptake. Amino acid substitutions on the Q311R / D399R, Q311R / D413K, S400R / D413K, Q311R / P343R, Q311R / G341R, Q311R / G341K, Q311R / D401R, Q311R / D401K, D401R / D413K, D401K / D413K and G402K / Lt; RTI ID = 0.0 &gt; antibody &lt; / RTI &gt;

human FcRn Transgenic  PK studies in mice

human FcRn Transgenic  Using the mouse In vivo  exam

The removal of myostatin and the anti-latent myostatin antibody was performed in a human FcRn transgenic mouse in which the mouse FcRn had been replaced with human FcRn and the co-administration of the anti-latent myostatin antibody and latent myostatin Lt; / RTI &gt; The anti-latent myostatin antibody (0.1 mg / ml) and mouse latent myostatin (0.05 mg / ml) were injected into the jugular vein at a single dose of 10 mg / kg in experimental PK-2 . (100 mg / ml) were incubated with the experimental PK-1 antibody (10 mg / ml) and incubated overnight at 37 &lt; RTI ID = 0.0 &gt; 4 (described in FIG. 28) into the jugular vein in a single dose of 10 mg / kg. Blood was collected at 5 minutes, 15 minutes, 1 hour, 4 hours, 7 hours, 1 day, 2 days, 7 days, 14 days, 21 days, and 28 days after administration in experimental PK-2. Blood was collected at 5 minutes, 1 hour, 4 hours, 7 hours, 1 day, 7 days, 14 days, 21 days and 30 days after administration in experimental PK-4. The collected blood was immediately centrifuged at 15,000 rpm for 5 minutes at 4 DEG C to isolate the plasma. The separated plasma was stored at -20 캜 or lower until measurement. The anti-latent myostatin antibody used was MS1032LO06-SG1, MS1032LO06-P1375m, MS1032LO06-P1378m and MS1032LO06-P1383m in Experiment PK-2 and MS1032LO06-P1375m and MS1032LO06-P1499m in Experiment PK-4.

Electrochemiluminescence (ECL) in plasma by total Myostatin  Measurement of concentration

The concentration of total myostatin in mouse plasma was determined by ECL as described in Example 28 (Ravetch PK). The time course of total myostatin concentration in plasma after intravenous administration of anti-latent myostatin antibody and latent myostatin measured by this method is shown in Figures 27a and 28a.

enzyme- Combined  Immunoassay analysis (ELISA) Latency Myostatin  Measurement of antibody concentration

The concentration of anti-latent myostatin antibody in mouse plasma was measured by ELISA in experimental PK-2. An anti-human IgG (gamma-chain specific) F (ab ') 2 antibody fragment (Sigma) was dispensed onto a Nunc-ImmunoPlate MaxiSorp (Flying Knife International) and allowed to stand overnight at 4 ° C Anti-human IgG-immobilized plates were prepared. A black curve sample with a plasma concentration of 2.5, 1.25, 0.625, 0.313, 0.156, 0.078 and 0.039 μg / ml, and a mouse plasma sample diluted 100 times or more were prepared. The samples were then dispensed onto anti-human IgG-immobilized plates and allowed to stand at room temperature for 1 hour. Subsequently, a goat anti-human IgG (gamma-chain specific) biotin conjugate (Southern Biotech) was added and reacted at room temperature for 1 hour. Subsequently, Streptavidin-poly HRP80 (Stereospecific Detection Technologies) was added and reacted at room temperature for 1 hour. The color reaction was performed using a TMB One Component HRP Microwell substrate Microwell Substrate) (BioFX levoratriz). After the reaction was stopped with 1 N sulfuric acid (Showa Chemical), the absorbance at 450 nm was measured by a microplate reader. Mouse plasma concentrations were calculated from the absorbance of the calibration curves using the software Soft Max Pro (Molecular Devices). The time course of antibody concentration in plasma after intravenous administration of anti-latent myostatin antibody and latent myostatin measured by this method is shown in Figure 27B.

The concentration of anti-latent myostatin antibody in mouse plasma was measured by Gyrolab Bioaffy (trademark) CD (Gyros) in Experiment PK-4. The biotinylated anti-human IgG Fc antibody was flowed onto a streptavidin bead column in the microstructure of the CD. Plasma concentrations of 0.5, 1, 2, 4, 8, 16 and 32 μg / ml spiked plasma concentrations of human normal immunoglobulin (CSL Bering AG) 5 mg / ml and mouse latent myostatin 200 μg / And mouse plasma samples diluted 25 times or more with plasma concentrations of 200 [mu] g / ml of mouse latent myostatin were spiked. The samples were then added to the CD and allowed to flow onto the bead column. Subsequently, an Alexa-labeled goat anti-human IgG polyclonal antibody (BETHYL) was added to the CD and allowed to flow onto the bead column. Mouse plasma concentrations were calculated from the response of the calibration curve using the Gyrolab evaluation program described above. The time course of antibody concentration in plasma after intravenous administration of anti-latent myostatin antibody and latent myostatin measured by this method is shown in Figure 28B.

In vivo Myostatin  For concentration pI  effect

The plasma total myostatin concentration at 7 hours after administration of MS1032LO06-SG1 was 12 times lower than the plasma total myostatin concentration at 5 minutes in the above experiment PK-2. In contrast, the plasma total myostatin concentration at 7 hours after administration of MS1032LO06-P1375m, MS1032LO06-P1378m and MS1032LO06-P1383m was 26-67 times higher than the plasma total myostatin concentration at 5 minutes in Experiment PK-2 Respectively. The antibody concentrations of MS1032LO06-P1378m and MS1032LO06-P1383m decreased by more than 3-fold compared to the case of MS1032LO06-SG1, but the difference in MS1032LO06-P1375m concentration at each sampling time compared to the case of MS1032LO06- Times. The pI variants with amino acid substitutions on Q311R / D413K showed increased myostatin clearance from plasma without increasing antibody removal from plasma.

Furthermore, after administration of MS1032LO06-P1499m, the total myostatin and antibody concentrations were assessed by co-administration of human normal immunoglobulin to mimic human plasma. The plasma total myostatin concentration at 7 hours after administration of MS1032LO06-P1375m and MS1032LO06-P1499m was 3.4 to 5.3 times lower than the plasma total myostatin concentration at 5 minutes, and in MS1032LO06-P1499m in experiment PK-4 The total myostatin concentration and antibody concentration at the time of sampling was 1.5 times less than that of MS1032LO06-P1375m. The pI variants with amino acid substitutions on Q311R / P343R also showed increased myostatin removal from plasma without increasing antibody removal from plasma.

High pI variants have more positive charge in plasma. Since the positive charge interacts with the cell surface of the negative charge, the antigen-antibody immunoconjugate complex of the high pI variant gathered closer to the cell surface and increased the cell uptake of the high-pI variant antigen-antibody immunoconjugate.

[Example 31]

Fc  gamma RIIb - Increased Fc  Mutant Wow  together pI - Increased  substitution

The effect of myostatin clearance by Fc gamma RIIb-enhanced Fc variants in combination with other pi-increasing substitutions was evaluated in human Fc gamma RIIb transgenic mice. Human Fc gamma RIIb transgenic mice are tested for their ability to express all exons of the human FCGR2B gene by standard techniques (see, e.g., J. Immunol., 2015 Oct 1; 195 (7): 3198-205) The BAC (bacterial artificial chromosome) vector was generated by microinjection of C57BL / 6N into the nucleus of embryos. Mouse Fc gamma RIIb deficient mice were generated using Zinc Tongue Nuclease (ZFN) designed to target exon 1. The humanized Fc gamma RIIb mice were established by crossing human Fc gamma RIIb transgenic mice with mouse Fc gamma RIIb KO mice. Using the mouse, the combined effects of increased affinity for human Fc gamma RIIb and increased pI for clearance of soluble antigens can be assessed.

Tested  Mutant of  Manufacturing and Profiles

The seven antibodies tested and their binding profiles are summarized in Table 27. The respective pI-increasing substituted Q311R / D413R, Q311R / P343R, Q311R / P343R / D413R, Q311R / N384R / D413R into MS103205H795-MY201 were introduced into the heavy chain MS103205H795-MY352, MS103205H795-PK55, MS103205H795-PK56, MS103205H795- . All MS1032LO06 variants were expressed as M103202L889-SK1 as light chain according to the method shown in Example 30 and their affinity for human and Syno Fc gamma R was evaluated using the method of Example 27. [

[Table 27]

Based on the SPR analysis summarized in Table 27, it was confirmed that the pI-increasing substitution did not affect Fc gamma R binding of Fc gamma RIIb-enhanced Fc variants. MY201 and MY351 (prepared by introducing Q311R / D413K into MY201) show human Fc gamma RIIb binding increased 6-fold and 5-fold, respectively. With respect to other human and Sino Fc gamma R, they exhibit almost the same binding profile. Similarly, MY352, PK55, PK56 and PK57 showed similar binding profiles as parent MY201 (Table 27). These results imply that none of the pI-increasing substitutions have an effect on the affinity for human and synonymous Fc gamma R.

human Fc  gamma RIIb Transgenic  PK studies in mice

human Fc  gamma RIIb Transgenic  Using the mouse In vivo  exam

The removal of myostatin and the anti-latent myostatin antibody was performed in human Fc gamma RIIb transgenic mice in which the mouse Fc gamma RII was replaced with human Fc gamma RIIb, an anti-latent myostatin antibody, 0.0 &gt; co-administered &lt; / RTI &gt; The anti-latent myostatin antibody (0.3 mg / ml) and latent myostatin (0.05 mg / ml) were administered into the jugular vein in a single dose of 10 mg / kg. Blood was collected at 5 minutes, 1 hour, 4 hours, 7 hours, 1 day, 7 days, 14 days, 21 days, and 28 days after administration. The collected blood was immediately centrifuged at 15,000 rpm for 5 minutes at 4 DEG C to isolate the plasma. The separated plasma was stored at -20 캜 or lower until measurement. The anti-latent myostatin antibodies used were MS1032LO06-SG1, MS1032LO06-MY351, MS1032LO06-MY352, MS1032LO06-PK55, MS1032LO06-PK56 and MS1032LO06-PK57.

Total of plasma by electrochemiluminescence Myostatin  Measurement of concentration

The concentration of total myostatin in mouse plasma was measured by electrochemiluminescence (ECL) as described in Example 28. [ The time course of total myostatin concentration in plasma after intravenous administration of anti-latent myostatin antibody and latent myostatin measured by this method is shown in Fig.

enzyme- Combined  Immunoassay analysis (ELISA) Latency Myostatin  Measurement of antibody concentration

The concentration of anti-latent myostatin antibody in mouse plasma was measured by ELISA. Human IgG (gamma-chain specific) F (ab ') 2 antibody fragments (Sigma) were dispensed onto nunk-immunoprecipitate (Flying Nunc International) and allowed to stand overnight at 4 ° C for anti-human IgG- Lt; / RTI &gt; A black curve sample with a plasma concentration of 2.5, 1.25, 0.625, 0.313, 0.156, 0.078 and 0.039 μg / ml, and a mouse plasma sample diluted 100 times or more were prepared. The samples were then dispensed onto anti-human IgG-immobilized plates and allowed to stand at room temperature for 1 hour. Subsequently, a goat anti-human IgG (gamma-chain specific) biotin conjugate (Southern Biotech) was added and reacted at room temperature for 1 hour. Subsequently, Streptavidin-poly HRP80 (Stereospecific Detection Technologies) was added and reacted at room temperature for 1 hour. The color development reaction was carried out using TMB One Component HRP Microwell Substrate (BioFX levoratolyz) as a substrate Respectively. After the reaction was stopped with 1 N sulfuric acid (Showa Chemical), the absorbance at 450 nm was measured by a microplate reader. Mouse plasma concentrations were calculated from the absorbance of the calibration curves using the software Soft Max Pro (Molecular Devices). The time course of antibody concentration in plasma after intravenous administration of anti-latent myostatin antibody and latent myostatin measured by this method is shown in Fig.

In vivo Myostatin  For concentration pI  And Fc  Effect of gamma R binding

After the administration of MS1032LO06-MY201, the plasma total myostatin concentration at 7 hours was 8 times lower than the plasma total myostatin concentration at 5 minutes. In contrast, the plasma total myostatin concentration at 7 hours after administration of MS1032LO06-PK57 was 376 times lower than the plasma total myostatin concentration at 5 minutes. Other high pI variants showed a similar increase in myostatin removal from plasma. The antibody concentration of the high pI variant at day 28 was 2 to 3 fold lower than the antibody concentration of MS1032LO06-SG1, and the pI variant showed a slight increase in antibody removal from plasma.

High pI variants have more positive charge in plasma. Since the positive charge interacts with the cell surface of the negative charge, the antigen-antibody immunoconjugate of the high pI variant became closer to the cell surface and increased the cell uptake of the antigen-antibody immunoconjugate of the high pI variant.

[Example 32]

human Fc  gamma RIIb - Increased Fc  Mutant of  Development

Human Fc gamma RIIb-enhanced Fc variants with anti-myostatin variable regions were prepared and their affinity for human Fc gamma R was assessed. Specifically, human Fc gamma RIIb-enhanced Fc variants were prepared by introducing substitutions into MS103240H795-SG1 (VH, SEQ ID NO: 92; CH, SEQ ID NO: 9) with T250V / T307P substitution. In addition, substitution (Q311R / D413K or Q311R / P343R) was also introduced. The mutant was expressed using M103202L1045-SK1 as a light chain and its affinity for human Fc gamma R was analyzed according to the method shown in Example 34. [ Table 28 shows the results of kinetic analysis for human and syno Fc gamma R. The KD values in gray colored cells were calculated using Equation 2 because their affinity was too weak to be accurately measured by kinetic analysis.

All the mutants evaluated showed reduced binding to human Fc gamma RIIaR, Fc gamma RIIaH, Fc gamma RIIIaV and increased affinity for human Fc gamma RIIb compared to SG1. The affinity for human Fc gamma RIIb varies from 4.1 fold to 30.5 fold increase over SG1. The affinity for human Fc gamma RIIaR was 0.02-fold to 0.22-fold. The affinities for human Fc gamma RIIaH and human Fc gamma RIIIaV were 0.04 and 0.012, respectively. The substitution (T250V / T307P) was found not to affect the binding profile for human Fc gamma R by comparing the affinity of MY009 (P238D) and MY214 (P238D / T250V / T307P). On the other hand, the pI-increasing substitution pair (Q311R / D413K and Q311R / P343R) all reduced the binding affinity by about 0.5-fold compared to mutants not containing the pI-increasing substitution. For example, T114 showed a 30.5-fold higher affinity for human Fc gamma RIIb, but only 16.1-fold and 14.5-fold increases, respectively, with Q311R / D413K (TT33) and Q311R / P343R (TT32).

Furthermore, the substitutions used in Example 29 to improve antibody half-life and reduce binding to rheumatic factors were introduced into human Fc gamma RIIb-enhanced Fc variants and their affinity for human Fc gamma R (Table 29). In the SPR analysis, all data were obtained using mouse anti-human IgG kappa light chain for capture of the antibody of interest. Table 30 shows the results and KD values in gray colored cells were calculated using [Equation 2] because their affinity was too weak to be accurately measured by kinetic analysis.

[Table 28]

[Table 29]

[Table 30]

SG1 and TT33 were re-evaluated in this measurement, in which the capture method is different from the case of Table 28. &lt; tb &gt; &lt; TABLE &gt; As a result, the "KD multiple" value of TT33 was consistent with that obtained in Table 28 (16.1 times in Table 28 and 15.7 times in Table 30 for human Fc gamma RIIb). TT92 and TT93 (prepared by introducing N434A / Q438R / S440E and M428L / N434A / Y436T / Q438R / S440E to TT33) exhibited binding profiles comparable to TT33. Similarly, TT90 and TT91 derived from TT32, TT72 and TT73 derived from TT31, TT70 and TT71 derived from TT30, TT68 and TT69 derived from TT21, and TT66 and TT67 derived from TT20 are shown in Table 28 Lt; RTI ID = 0.0 &gt; profile. &Lt; / RTI &gt; These results indicate that the improvement in antibody half-life and the substitution for reduction of binding to rheumatic factors do not affect the binding profile of human Fc gamma RIIb-enhanced mutants to human Fc gamma R.

[Example 33]

Fc  gamma RIIb - Increased Fc  Mutant of  Cell imaging analysis

To assess the intracellular absorption of the antigen-antibody complex formed by the antibody described in Example 32, the cell imaging assay described in Example 30 was performed. In order to avoid signal saturation, the antigen-antibody complex was formed in the culture solution with an antibody concentration of 1.25 mg / ml and an antigen concentration of 0.34 mg / ml in this Example.

The results of the analysis are shown in Fig. By increasing the binding affinity for human Fc gamma RIIb, the cell uptake of antigen-antibody complexes was increased. In the case of TT14 in which the binding affinity for human Fc gamma RIIb was increased 30-fold compared to SG1, the intracellular antigen fluorescence intensity was increased 7.5-fold in the case of SG1.

The pI-increasing substitutions (Q311R / D413K and Q311R / P343R) reduced the binding affinity for human Fc gamma RIIb by about 0.5-fold compared to mutants not containing the pI-increasing substitution, Cellular uptake of the mutant antibody antibody complexes was increased compared to Fc mutants without pI increased substitution. TT33 shows a 36-fold increase in antigen antibody uptake into the cell compared to SG1, whereas its parent TT14 shows a 7.5-fold increase in cell uptake. Furthermore, TT33 exhibits cellular uptake of antigen-antibody complexes comparable to intracellularly as compared to SG1071, SG1074, SG1077, SG1079, SG1089 and SG1081, which exhibit strong clearing in synonyms monkeys. These results suggest that the combination of Fc gamma RIIb-enhanced Fc variants and pI-enhanced substitutions is a powerful tool for antigen clearance.

[Example 34]

Preparation of antibody expression vectors; And expression and purification of antibodies

Synthesis of a full-length gene encoding the nucleotide sequence of the H chain and L chain of the antibody variable region was carried out by assemble PCR or the like using a method known to those skilled in the art. Introduction of amino acid substitutions was carried out by methods known to those skilled in the art using PCR and the like. The obtained plasmid fragment was inserted into an animal cell expression vector to generate an H-chain expression vector and an L-chain expression vector. The nucleotide sequence of the obtained expression vector was determined by a method known to a person skilled in the art. The resulting plasmid was transiently introduced into HEK293H cell line or Freestyle 293 cell (Invitrogen) derived from human embryonic kidney cancer cells (Invitrogen) for antibody expression. The obtained culture supernatant was collected and then passed through a 0.22 μm MILLEX®-GV filter (Millipore) or a 0.45 μm Millex®-GV filter (Millipore) to obtain a culture supernatant Respectively. Antibodies were notified to the person skilled in the art using the rProtein A Sepharose Fast Flow (Gly Healthcare) or Protein G Sepharose 4 Fast Flow (Gly Healthcare) from the obtained culture supernatant. Lt; / RTI &gt; For comparison of the purified antibodies, their absorbance at 280 nm was measured using a spectrophotometer. From the obtained values, the antibody concentration was calculated using the extinction coefficient calculated by a method such as PACE (Protein Sci. 4: 2411-2423 (1995)).

Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, the above description and examples should not be construed as limiting the scope of the invention. The disclosures of all patents and scientific references cited herein are expressly incorporated by reference in their entirety.

                         SEQUENCE LISTING <110> CHUGAI SEIYAKU KABUSHIKI KAISHA   <120> ANTI-MYOSTATIN ANTIBODIES, POLYPEPTIDES CONTAINING VARIANT Fc        REGIONS, AND METHODS OF USE <130> C1-A1518P <140> PCT / JP2016 / 087487 <141> 2016-12-16 <150> JP 2015-247070 <151> 2015-12-18 <160> 381 <170> PatentIn version 3.5 <210> 1 <211> 375 <212> PRT <213> Homo sapiens <400> 1 Met Gln Lys Leu Gln Leu Cys Val Tyr Ile Tyr Leu Phe Met Leu Ile 1 5 10 15 Val Ala Gly Pro Val Asp Leu Asn Glu Asn Ser Glu Gln Lys Glu Asn             20 25 30 Val Glu Lys Glu Gly Leu Cys Asn Ala Cys Thr Trp Arg Gln Asn Thr         35 40 45 Lys Ser Ser Arg Ile Glu Ala Ile Lys Ile Gln Ile Leu Ser Lys Leu     50 55 60 Arg Leu Glu Thr Ala Pro Asn Ile Ser Lys Asp Val Ile Arg Gln Leu 65 70 75 80 Leu Pro Lys Ala Pro Pro Leu Arg Glu Leu Ile Asp Gln Tyr Asp Val                 85 90 95 Gln Arg Asp Asp Ser Ser Asp Gly Ser Leu Glu Asp Asp Asp Tyr His             100 105 110 Ala Thr Thr Glu Thr Ile Ile Thr Met Pro Thr Glu Ser Asp Phe Leu         115 120 125 Met Gln Val Asp Gly Lys Pro Lys Cys Cys Phe Phe Lys Phe Ser Ser     130 135 140 Lys Ile Gln Tyr Asn Lys Val Val Lys Ala Gln Leu Trp Ile Tyr Leu 145 150 155 160 Arg Pro Val Glu Thr Pro Thr Thr Val Phe Val Gln Ile Leu Arg Leu                 165 170 175 Ile Lys Pro Met Lys Asp Gly Thr Arg Tyr Thr Gly Ile Arg Ser Leu             180 185 190 Lys Leu Asp Met Asn Pro Gly Thr Gly Ile Trp Gln Ser Ile Asp Val         195 200 205 Lys Thr Val Leu Gln Asn Trp Leu Lys Gln Pro Glu Ser Asn Leu Gly     210 215 220 Ile Glu Ile Lys Ala Leu Asp Glu Asn Gly His Asp Leu Ala Val Thr 225 230 235 240 Phe Pro Gly Pro Gly Glu Asp Gly Leu Asn Pro Phe Leu Glu Val Lys                 245 250 255 Val Thr Asp Thr Pro Lys Arg Ser Arg Arg Asp Phe Gly Leu Asp Cys             260 265 270 Asp Glu His Ser Thr Glu Ser Arg Cys Cys Arg Tyr Pro Leu Thr Val         275 280 285 Asp Phe Glu Ala Phe Gly Trp Asp Trp Ile Ile Ala Pro Lys Arg Tyr     290 295 300 Lys Ala Asn Tyr Cys Ser Gly Glu Cys Glu Phe Val Phe Leu Gln Lys 305 310 315 320 Tyr Pro His Thr His Leu Val His Gln Ala Asn Pro Arg Gly Ser Ala                 325 330 335 Gly Pro Cys Cys Thr Pro Thr Lys Met Ser Pro Ile Asn Met Leu Tyr             340 345 350 Phe Asn Gly Lys Glu Gln Ile Ile Tyr Gly Lys Ile Pro Ala Met Val         355 360 365 Val Asp Arg Cys Gly Cys Ser     370 375 <210> 2 <211> 109 <212> PRT <213> Homo sapiens <400> 2 Asp Phe Gly Leu Asp Cys Asp Glu His Ser Thr Glu Ser Arg Cys Cys 1 5 10 15 Arg Tyr Pro Leu Thr Val Asp Phe Glu Ala Phe Gly Trp Asp Trp Ile             20 25 30 Ile Ala Pro Lys Arg Tyr Lys Ala Asn Tyr Cys Ser Gly Glu Cys Glu         35 40 45 Phe Val Phe Leu Gln Lys Tyr Pro His Thr His Leu Val His Gln Ala     50 55 60 Asn Pro Arg Gly Ser Ala Gly Pro Cys Cys Thr Pro Thr Lys Met Ser 65 70 75 80 Pro Ile Asn Met Leu Tyr Phe Asn Gly Lys Glu Gln Ile Ile Tyr Gly                 85 90 95 Lys Ile Pro Ala Met Val Val Asp Arg Cys Gly Cys Ser             100 105 <210> 3 <211> 375 <212> PRT <213> Macaca fascicularis <400> 3 Met Gln Lys Leu Gln Leu Cys Val Tyr Ile Tyr Leu Phe Met Leu Ile 1 5 10 15 Val Ala Gly Pro Val Asp Leu Asn Glu Asn Ser Glu Gln Lys Glu Asn             20 25 30 Val Glu Lys Glu Gly Leu Cys Asn Ala Cys Thr Trp Arg Gln Asn Thr         35 40 45 Lys Ser Ser Arg Ile Glu Ala Ile Lys Ile Gln Ile Leu Ser Lys Leu     50 55 60 Arg Leu Glu Thr Ala Pro Asn Ile Ser Lys Asp Ala Ile Arg Gln Leu 65 70 75 80 Leu Pro Lys Ala Pro Pro Leu Arg Glu Leu Ile Asp Gln Tyr Asp Val                 85 90 95 Gln Arg Asp Asp Ser Ser Asp Gly Ser Leu Glu Asp Asp Asp Tyr His             100 105 110 Ala Thr Thr Glu Thr Ile Ile Thr Met Pro Thr Glu Ser Asp Phe Leu         115 120 125 Met Gln Val Asp Gly Lys Pro Lys Cys Cys Phe Phe Lys Phe Ser Ser     130 135 140 Lys Ile Gln Tyr Asn Lys Val Val Lys Ala Gln Leu Trp Ile Tyr Leu 145 150 155 160 Arg Pro Val Glu Thr Pro Thr Thr Val Phe Val Gln Ile Leu Arg Leu                 165 170 175 Ile Lys Pro Met Lys Asp Gly Thr Arg Tyr Thr Gly Ile Arg Ser Leu             180 185 190 Lys Leu Asp Met Asn Pro Gly Thr Gly Ile Trp Gln Ser Ile Asp Val         195 200 205 Lys Thr Val Leu Gln Asn Trp Leu Lys Gln Pro Glu Ser Asn Leu Gly     210 215 220 Ile Glu Ile Lys Ala Leu Asp Glu Asn Gly His Asp Leu Ala Val Thr 225 230 235 240 Phe Pro Gly Pro Gly Glu Asp Gly Leu Asn Pro Phe Leu Glu Val Lys                 245 250 255 Val Thr Asp Thr Pro Lys Arg Ser Arg Arg Asp Phe Gly Leu Asp Cys             260 265 270 Asp Glu His Ser Thr Glu Ser Arg Cys Cys Arg Tyr Pro Leu Thr Val         275 280 285 Asp Phe Glu Ala Phe Gly Trp Asp Trp Ile Ile Ala Pro Lys Arg Tyr     290 295 300 Lys Ala Asn Tyr Cys Ser Gly Glu Cys Glu Phe Val Phe Leu Gln Lys 305 310 315 320 Tyr Pro His Thr His Leu Val His Gln Ala Asn Pro Arg Gly Ser Ala                 325 330 335 Gly Pro Cys Cys Thr Pro Thr Lys Met Ser Pro Ile Asn Met Leu Tyr             340 345 350 Phe Asn Gly Lys Glu Gln Ile Ile Tyr Gly Lys Ile Pro Ala Met Val         355 360 365 Val Asp Arg Cys Gly Cys Ser     370 375 <210> 4 <211> 109 <212> PRT <213> Macaca fascicularis <400> 4 Asp Phe Gly Leu Asp Cys Asp Glu His Ser Thr Glu Ser Arg Cys Cys 1 5 10 15 Arg Tyr Pro Leu Thr Val Asp Phe Glu Ala Phe Gly Trp Asp Trp Ile             20 25 30 Ile Ala Pro Lys Arg Tyr Lys Ala Asn Tyr Cys Ser Gly Glu Cys Glu         35 40 45 Phe Val Phe Leu Gln Lys Tyr Pro His Thr His Leu Val His Gln Ala     50 55 60 Asn Pro Arg Gly Ser Ala Gly Pro Cys Cys Thr Pro Thr Lys Met Ser 65 70 75 80 Pro Ile Asn Met Leu Tyr Phe Asn Gly Lys Glu Gln Ile Ile Tyr Gly                 85 90 95 Lys Ile Pro Ala Met Val Val Asp Arg Cys Gly Cys Ser             100 105 <210> 5 <211> 376 <212> PRT <213> Mus musculus <400> 5 Met Met Gln Lys Leu Gln Met Tyr Val Tyr Ile Tyr Leu Phe Met Leu 1 5 10 15 Ile Ala Ala Gly Pro Val Asp Leu Asn Glu Gly Ser Glu Arg Glu Glu             20 25 30 Asn Val Glu Lys Glu Gly Leu Cys Asn Ala Cys Ala Trp Arg Gln Asn         35 40 45 Thr Arg Tyr Ser Arg Ile Glu Ala Ile Lys Ile Gln Ile Leu Ser Lys     50 55 60 Leu Arg Leu Glu Thr Ala Pro Asn Ile Ser Lys Asp Ala Ile Arg Gln 65 70 75 80 Leu Leu Pro Arg Ala Pro Pro Leu Arg Glu Leu Ile Asp Gln Tyr Asp                 85 90 95 Val Gln Arg Asp Asp Ser Ser Asp Gly Ser Leu Glu Asp Asp Asp Tyr             100 105 110 His Ala Thr Thr Glu Thr Ile Ile Thr Met Pro Thr Glu Ser Asp Phe         115 120 125 Leu Met Gln Ala Asp Gly Lys Pro Lys Cys Cys Phe Phe Lys Phe Ser     130 135 140 Ser Lys Ile Gln Tyr Asn Lys Val Val Lys Ala Gln Leu Trp Ile Tyr 145 150 155 160 Leu Arg Pro Val Lys Thr Pro Thr Thr Val Phe Val Gln Ile Leu Arg                 165 170 175 Leu Ile Lys Pro Met Lys Asp Gly Thr Arg Tyr Thr Gly Ile Arg Ser             180 185 190 Leu Lys Leu Asp Met Ser Pro Gly Thr Gly Ile Trp Gln Ser Ile Asp         195 200 205 Val Lys Thr Val Leu Gln Asn Trp Leu Lys Gln Pro Glu Ser Asn Leu     210 215 220 Gly Ile Glu Ile Lys Ala Leu Asp Glu Asn Gly His Asp Leu Ala Val 225 230 235 240 Thr Phe Pro Gly Pro Gly Glu Asp Gly Leu Asn Pro Phe Leu Glu Val                 245 250 255 Lys Val Thr Asp Thr Pro Lys Arg Ser Arg Arg Asp Phe Gly Leu Asp             260 265 270 Cys Asp Glu His Ser Thr Glu Ser Arg Cys Cys Arg Tyr Pro Leu Thr         275 280 285 Val Asp Phe Glu Ala Phe Gly Trp Asp Trp Ile Ile Ala Pro Lys Arg     290 295 300 Tyr Lys Ala Asn Tyr Cys Ser Gly Glu Cys Glu Phe Val Phe Leu Gln 305 310 315 320 Lys Tyr Pro His Thr His Leu Val His Gln Ala Asn Pro Arg Gly Ser                 325 330 335 Ala Gly Pro Cys Cys Thr Pro Thr Lys Met Ser Pro Ile Asn Met Leu             340 345 350 Tyr Phe Asn Gly Lys Glu Gln Ile Ile Tyr Gly Lys Ile Pro Ala Met         355 360 365 Val Val Asp Arg Cys Gly Cys Ser     370 375 <210> 6 <211> 109 <212> PRT <213> Mus musculus <400> 6 Asp Phe Gly Leu Asp Cys Asp Glu His Ser Thr Glu Ser Arg Cys Cys 1 5 10 15 Arg Tyr Pro Leu Thr Val Asp Phe Glu Ala Phe Gly Trp Asp Trp Ile             20 25 30 Ile Ala Pro Lys Arg Tyr Lys Ala Asn Tyr Cys Ser Gly Glu Cys Glu         35 40 45 Phe Val Phe Leu Gln Lys Tyr Pro His Thr His Leu Val His Gln Ala     50 55 60 Asn Pro Arg Gly Ser Ala Gly Pro Cys Cys Thr Pro Thr Lys Met Ser 65 70 75 80 Pro Ile Asn Met Leu Tyr Phe Asn Gly Lys Glu Gln Ile Ile Tyr Gly                 85 90 95 Lys Ile Pro Ala Met Val Val Asp Arg Cys Gly Cys Ser             100 105 <210> 7 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 7 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu             180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 305 310 315 320 Gln Lys Ser Leu Ser Leu Ser Pro                 325 <210> 8 <211> 107 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 8 Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 1 5 10 15 Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe             20 25 30 Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln         35 40 45 Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Cys     50 55 60 Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 65 70 75 80 Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser                 85 90 95 Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys             100 105 <210> 9 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 9 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu             180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 305 310 315 320 Gln Lys Ser Leu Ser Leu Ser Pro                 325 <210> 10 <211> 107 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 10 Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 1 5 10 15 Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe             20 25 30 Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln         35 40 45 Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser     50 55 60 Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 65 70 75 80 Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser                 85 90 95 Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys             100 105 <210> 11 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 11 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Arg Gly Gly Pro Lys Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu             180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu 225 230 235 240 Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 305 310 315 320 Gln Lys Ser Leu Ser Leu Ser Pro                 325 <210> 12 <211> 116 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 12 Gln Ser Leu Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Gly Ser 1 5 10 15 Leu Thr Val Thr Cys Arg Val Ser Gly Ile Asp Leu Ser Ser Tyr Asp             20 25 30 Ile Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly         35 40 45 Ile Ile Ser Tyr Ala Gly Ser Thr Tyr Tyr Ala Ser Trp Ala Lys Gly     50 55 60 Arg Phe Thr Ile Ser Lys Thr Ser Thr Thr Val Asp Leu Lys Met Thr 65 70 75 80 Ser Leu Thr Thr Glu Asp Thr Ala Thr Tyr Phe Cys Ala Arg Gly Val                 85 90 95 Pro Ala Tyr Ser Thr Gly Gly Asp Leu Trp Gly Pro Gly Thr Leu Val             100 105 110 Thr Val Ser Ser         115 <210> 13 <211> 119 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 13 Gln Val Thr Leu Lys Glu Ser Gly Pro Val Leu Val Lys Pro Thr Glu 1 5 10 15 Thr Leu Thr Leu Thr Cys Thr Val Ser Gly Ile Asp Leu Ser Ser Tyr             20 25 30 Asp Ile Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val         35 40 45 Gly Ile Ile Ser Tyr Ala Gly Ser Thr Tyr Tyr Ala Ser Trp Ala Lys     50 55 60 Gly Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val Val Leu 65 70 75 80 Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr Cys Ala                 85 90 95 Arg Gly Val Pro Ala Tyr Ser Thr Gly Gly Asp Leu Trp Gly Gln Gly             100 105 110 Thr Leu Val Thr Val Ser Ser         115 <210> 14 <211> 110 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 14 Ala Gln Val Leu Thr Gln Thr Ala Ser Ser Val Ala Ala Val Gly 1 5 10 15 Gly Thr Val Thr Ile Asn Cys Gln Ser Ser Gln Ser Val Tyr Asp Asn             20 25 30 Asn Trp Leu Ser Trp Phe Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu         35 40 45 Leu Ile Tyr Trp Ala Ser Thr Leu Ala Ser Gly Val Ser Ser Arg Phe     50 55 60 Lys Gly Ser Gly Ser Gly Thr Gln Phe Thr Leu Thr Ile Ser Asp Leu 65 70 75 80 Glu Cys Asp Ala Ala Thr Tyr Tyr Cys Ala Gly Gly Tyr Gly Gly                 85 90 95 Gly Leu Tyr Ala Phe Gly Gly Gly Thr Lys Val Glu Ile Lys             100 105 110 <210> 15 <211> 110 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 15 Asp Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Gln Ser Ser Gln Ser Val Tyr Asp Asn             20 25 30 Asn Trp Leu Ser Trp Phe Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu         35 40 45 Leu Ile Tyr Trp Ala Ser Thr Leu Ala Ser Gly Val Ser Ser Arg Phe     50 55 60 Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu 65 70 75 80 Gln Pro Glu Asp Ala Ala Thr Tyr Tyr Cys Ala Gly Gly Tyr Gly Gly                 85 90 95 Gly Leu Tyr Ala Phe Gly Gln Gly Thr Lys Val Glu Ile Lys             100 105 110 <210> 16 <211> 119 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 16 Gln Val Thr Leu Lys Glu Ser Gly Pro Val Leu Val Lys Pro Thr Glu 1 5 10 15 Thr Leu Thr Leu Thr Cys Thr Val Ser Gly Ile Asp Leu Ser His Tyr             20 25 30 Asp Ile Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val         35 40 45 Gly Ile Ile Ser Tyr Ala Gly Ser Thr Tyr Tyr Ala Ser Trp Ala Lys     50 55 60 Gly Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val Val Leu 65 70 75 80 Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr Cys Ala                 85 90 95 Arg Gly Val Pro Ala Tyr Ser Thr Gly Gly Asp Leu Trp Gly Gln Gly             100 105 110 Thr Leu Val Thr Val Ser Ser         115 <210> 17 <211> 119 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 17 Gln Val Thr Leu Lys Glu Ser Gly Pro Val Leu Val Lys Pro Thr Glu 1 5 10 15 Thr Leu Thr Leu Thr Cys Thr Val Ser Gly Ile Asp Leu Ser Ser Tyr             20 25 30 Asp Ile Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val         35 40 45 Gly Ile Ile Ser His Ala Gly Ser Thr Tyr Tyr Ala Ser Trp Ala Lys     50 55 60 Gly Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val Val Leu 65 70 75 80 Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr Cys Ala                 85 90 95 Arg Gly Val Pro Ala Tyr Ser Thr Gly Gly Asp Leu Trp Gly Gln Gly             100 105 110 Thr Leu Val Thr Val Ser Ser         115 <210> 18 <211> 119 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 18 Gln Val Thr Leu Lys Glu Ser Gly Pro Val Leu Val Lys Pro Thr Glu 1 5 10 15 Thr Leu Thr Leu Thr Cys Thr Val Ser Gly Ile Asp Leu Ser Ser Tyr             20 25 30 Asp Ile Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val         35 40 45 Gly Ile Ile Ser Tyr Ala Gly Ser Thr Tyr Tyr Ala Ser Trp Ala Lys     50 55 60 Gly Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val Val Leu 65 70 75 80 Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr Cys Ala                 85 90 95 Arg Gly Val Pro Ala His Ser Thr Gly Gly Asp Leu Trp Gly Gln Gly             100 105 110 Thr Leu Val Thr Val Ser Ser         115 <210> 19 <211> 119 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 19 Gln Val Thr Leu Lys Glu Ser Gly Pro Val Leu Val Lys Pro Thr Glu 1 5 10 15 Thr Leu Thr Leu Thr Cys Thr Val Ser Gly Ile Asp Leu Ser Ser Tyr             20 25 30 Asp Ile Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val         35 40 45 Gly Ile Ile Ser Tyr Ala Gly Ser Thr Tyr Tyr Ala Ser Trp Ala Lys     50 55 60 Gly Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val Val Leu 65 70 75 80 Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr Cys Ala                 85 90 95 Arg Gly Val Pro Ala Tyr Ser His Gly Gly Asp Leu Trp Gly Gln Gly             100 105 110 Thr Leu Val Thr Val Ser Ser         115 <210> 20 <211> 119 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 20 Gln Val Thr Leu Lys Glu Ser Gly Pro Val Leu Val Lys Pro Thr Glu 1 5 10 15 Thr Leu Thr Leu Thr Cys Thr Val Ser Gly Ile Asp Leu Ser His Tyr             20 25 30 Asp Ile Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val         35 40 45 Gly Ile Ile Ser His Ala Gly Ser Thr Tyr Tyr Ala Ser Trp Ala Lys     50 55 60 Gly Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val Val Leu 65 70 75 80 Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr Cys Ala                 85 90 95 Arg Gly Val Pro Ala Tyr Ser Thr Gly Gly Asp Leu Trp Gly Gln Gly             100 105 110 Thr Leu Val Thr Val Ser Ser         115 <210> 21 <211> 119 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 21 Gln Val Thr Leu Lys Glu Ser Gly Pro Val Leu Val Lys Pro Thr Glu 1 5 10 15 Thr Leu Thr Leu Thr Cys Thr Val Ser Gly Ile Asp Leu Ser Ser Tyr             20 25 30 Asp Ile Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val         35 40 45 Gly Ile Ile Ser His Ala Gly Ser Thr Tyr Tyr Ala Ser Trp Ala Lys     50 55 60 Gly Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val Val Leu 65 70 75 80 Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr Cys Ala                 85 90 95 Arg Gly Val Pro Ala His Ser Thr Gly Gly Asp Leu Trp Gly Gln Gly             100 105 110 Thr Leu Val Thr Val Ser Ser         115 <210> 22 <211> 119 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 22 Gln Val Thr Leu Lys Glu Ser Gly Pro Val Leu Val Lys Pro Thr Glu 1 5 10 15 Thr Leu Thr Leu Thr Cys Thr Val Ser Gly Ile Asp Leu Ser His Tyr             20 25 30 Asp Ile Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val         35 40 45 Gly Ile Ile Ser Tyr Ala Gly Ser Thr Tyr Tyr Ala Ser Trp Ala Lys     50 55 60 Gly Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val Val Leu 65 70 75 80 Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr Cys Ala                 85 90 95 Arg Gly Val Pro Ala His Ser Thr Gly Gly Asp Leu Trp Gly Gln Gly             100 105 110 Thr Leu Val Thr Val Ser Ser         115 <210> 23 <211> 119 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 23 Gln Val Thr Leu Lys Glu Ser Gly Pro Val Leu Val Lys Pro Thr Glu 1 5 10 15 Thr Leu Thr Leu Thr Cys Thr Val Ser Gly Ile Asp Leu Ser His Tyr             20 25 30 Asp Ile Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val         35 40 45 Gly Ile Ile Ser His Ala Gly Ser Thr Tyr Tyr Ala Ser Trp Ala Lys     50 55 60 Gly Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val Val Leu 65 70 75 80 Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr Cys Ala                 85 90 95 Arg Gly Val Pro Ala His Ser Thr Gly Gly Asp Leu Trp Gly Gln Gly             100 105 110 Thr Leu Val Thr Val Ser Ser         115 <210> 24 <211> 119 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 24 Gln Val Thr Leu Lys Glu Ser Gly Pro Val Leu Val Lys Pro Thr Glu 1 5 10 15 Thr Leu Thr Leu Thr Cys Thr Val Ser Gly Ile Asp Leu Ser His Tyr             20 25 30 Asp Ile Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val         35 40 45 Gly Ile Ile Ser Tyr Ala Gly Ser Thr Tyr Tyr Ala Ser Trp Ala Lys     50 55 60 Gly Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val Val Leu 65 70 75 80 Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr Cys Ala                 85 90 95 Arg Gly Val Pro Ala Tyr Ser His Gly Gly Asp Leu Trp Gly Gln Gly             100 105 110 Thr Leu Val Thr Val Ser Ser         115 <210> 25 <211> 119 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 25 Gln Val Thr Leu Lys Glu Ser Gly Pro Val Leu Val Lys Pro Thr Glu 1 5 10 15 Thr Leu Thr Leu Thr Cys Thr Val Ser Gly Ile Asp Leu Ser Ser Tyr             20 25 30 Asp Ile Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val         35 40 45 Gly Ile Ile Ser His Ala Gly Ser Thr Tyr Tyr Ala Ser Trp Ala Lys     50 55 60 Gly Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val Val Leu 65 70 75 80 Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr Cys Ala                 85 90 95 Arg Gly Val Pro Ala Tyr Ser His Gly Gly Asp Leu Trp Gly Gln Gly             100 105 110 Thr Leu Val Thr Val Ser Ser         115 <210> 26 <211> 119 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 26 Gln Val Thr Leu Lys Glu Ser Gly Pro Val Leu Val Lys Pro Thr Glu 1 5 10 15 Thr Leu Thr Leu Thr Cys Thr Val Ser Gly Ile Asp Leu Ser Ser Tyr             20 25 30 Asp Ile Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val         35 40 45 Gly Ile Ile Ser Tyr Ala Gly Ser Thr Tyr Tyr Ala Ser Trp Ala Lys     50 55 60 Gly Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val Val Leu 65 70 75 80 Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr Cys Ala                 85 90 95 Arg Gly Val Pro Ala His Ser His Gly Asp Leu Trp Gly Gln Gly             100 105 110 Thr Leu Val Thr Val Ser Ser         115 <210> 27 <211> 119 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 27 Gln Val Thr Leu Lys Glu Ser Gly Pro Val Leu Val Lys Pro Thr Glu 1 5 10 15 Thr Leu Thr Leu Thr Cys Thr Val Ser Gly Ile Asp Leu Ser His Tyr             20 25 30 Asp Ile Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val         35 40 45 Gly Ile Ile Ser His Ala Gly Ser Thr Tyr Tyr Ala Ser Trp Ala Lys     50 55 60 Gly Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val Val Leu 65 70 75 80 Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr Cys Ala                 85 90 95 Arg Gly Val Pro Ala Tyr Ser His Gly Gly Asp Leu Trp Gly Gln Gly             100 105 110 Thr Leu Val Thr Val Ser Ser         115 <210> 28 <211> 119 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 28 Gln Val Thr Leu Lys Glu Ser Gly Pro Val Leu Val Lys Pro Thr Glu 1 5 10 15 Thr Leu Thr Leu Thr Cys Thr Val Ser Gly Ile Asp Leu Ser Ser Tyr             20 25 30 Asp Ile Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val         35 40 45 Gly Ile Ile Ser His Ala Gly Ser Thr Tyr Tyr Ala Ser Trp Ala Lys     50 55 60 Gly Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val Val Leu 65 70 75 80 Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr Cys Ala                 85 90 95 Arg Gly Val Pro Ala His Ser His Gly Asp Leu Trp Gly Gln Gly             100 105 110 Thr Leu Val Thr Val Ser Ser         115 <210> 29 <211> 119 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 29 Gln Val Thr Leu Lys Glu Ser Gly Pro Val Leu Val Lys Pro Thr Glu 1 5 10 15 Thr Leu Thr Leu Thr Cys Thr Val Ser Gly Ile Asp Leu Ser His Tyr             20 25 30 Asp Ile Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val         35 40 45 Gly Ile Ile Ser Tyr Ala Gly Ser Thr Tyr Tyr Ala Ser Trp Ala Lys     50 55 60 Gly Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val Val Leu 65 70 75 80 Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr Cys Ala                 85 90 95 Arg Gly Val Pro Ala His Ser His Gly Asp Leu Trp Gly Gln Gly             100 105 110 Thr Leu Val Thr Val Ser Ser         115 <210> 30 <211> 119 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 30 Gln Val Thr Leu Lys Glu Ser Gly Pro Val Leu Val Lys Pro Thr Glu 1 5 10 15 Thr Leu Thr Leu Thr Cys Thr Val Ser Gly Ile Asp Leu Ser His Tyr             20 25 30 Asp Ile Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val         35 40 45 Gly Ile Ile Ser His Ala Gly Ser Thr Tyr Tyr Ala Ser Trp Ala Lys     50 55 60 Gly Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val Val Leu 65 70 75 80 Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr Cys Ala                 85 90 95 Arg Gly Val Pro Ala His Ser His Gly Asp Leu Trp Gly Gln Gly             100 105 110 Thr Leu Val Thr Val Ser Ser         115 <210> 31 <211> 110 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 31 Asp Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Gln Ser Ser Gln Ser Val Tyr His Asn             20 25 30 Asn Trp Leu Ser Trp Phe Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu         35 40 45 Leu Ile Tyr Trp Ala Ser Thr Leu Ala Ser Gly Val Ser Ser Arg Phe     50 55 60 Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu 65 70 75 80 Gln Pro Glu Asp Ala Ala Thr Tyr Tyr Cys Ala Gly Gly Tyr Gly Gly                 85 90 95 Gly Leu Tyr Ala Phe Gly Gln Gly Thr Lys Val Glu Ile Lys             100 105 110 <210> 32 <211> 119 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 32 Gln Val Thr Leu Lys Glu Ser Gly Pro Val Leu Val Lys Pro Thr Glu 1 5 10 15 Thr Leu Thr Leu Thr Cys Thr Val Ser Gly Ile Asp Leu Ser His Thr             20 25 30 Asp Ile Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val         35 40 45 Gly Ile Ile Ser Tyr Ala Gly Ser Thr Tyr Tyr Ala Ser Trp Ala Lys     50 55 60 Gly Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val Val Leu 65 70 75 80 Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr Cys Ala                 85 90 95 Arg Gly Val Pro Ala Tyr Ser His Gly Gly Asp Leu Trp Gly Gln Gly             100 105 110 Thr Leu Val Thr Val Ser Ser         115 <210> 33 <211> 119 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 33 Gln Val Thr Leu Lys Glu Ser Gly Pro Val Leu Val Lys Pro Thr Glu 1 5 10 15 Thr Leu Thr Leu Thr Cys Thr Val Ser Gly Ile Asp Leu Ser His Thr             20 25 30 Asp Ile Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val         35 40 45 Gly Ile Ile Ser Tyr Ala Gly Ser Thr Tyr Tyr Met Ser Trp Ala Lys     50 55 60 Gly Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val Val Leu 65 70 75 80 Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr Cys Ala                 85 90 95 Arg Gly Val Pro Ala Tyr Ser His Gly Gly Asp Leu Trp Gly Gln Gly             100 105 110 Thr Leu Val Thr Val Ser Ser         115 <210> 34 <211> 119 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 34 Gln Val Thr Leu Lys Glu Ser Gly Pro Val Leu Val Lys Pro Thr Glu 1 5 10 15 Thr Leu Thr Leu Thr Cys Thr Val Ser Gly Ile Asp Leu Ser His Tyr             20 25 30 Asp Ile Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val         35 40 45 Gly Ile Ile Ser Tyr Ala Gly Ser Thr Tyr Tyr Ala Ser Trp Ala Lys     50 55 60 Gly Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val Val Leu 65 70 75 80 Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr Cys Ala                 85 90 95 Arg Gly Val Pro Ala Tyr Ser His Gly Gly Asp Leu Trp Gly Gln Gly             100 105 110 Thr Leu Val Thr Val Ser Ser         115 <210> 35 <211> 110 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 35 Asp Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Thr Ser Ser Gln Ser Val Tyr His Asn             20 25 30 Asn Trp Leu Ser Trp Phe Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu         35 40 45 Leu Ile Tyr Trp Ala Ser Thr Leu Ala Tyr Gly Val Ser Ser Phe     50 55 60 Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu 65 70 75 80 Gln Pro Glu Asp Ala Ala Thr Tyr Tyr Cys Ala Gly Gly Tyr Gly Gly                 85 90 95 Gly Arg Tyr Ala Phe Gly Gln Gly Thr Lys Val Glu Ile Lys             100 105 110 <210> 36 <211> 110 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 36 Asp Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Gln Ser Ser Gln Ser Val Tyr His Asn             20 25 30 Asn Trp Leu Ser Trp Phe Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu         35 40 45 Leu Ile Tyr Trp Ala Ser Thr Leu Ala Phe Gly Val Pro Ser Arg Phe     50 55 60 Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu 65 70 75 80 Gln Pro Glu Asp Ala Ala Thr Tyr Tyr Cys Ala Gly Gly Tyr Gly Gly                 85 90 95 Gly Leu Tyr Ala Phe Gly Gln Gly Thr Lys Val Glu Ile Lys             100 105 110 <210> 37 <211> 110 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 37 Asp Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Gln Thr Ser Gln Ser Val Tyr His Asp             20 25 30 Asn Trp Leu Ser Trp Phe Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu         35 40 45 Leu Ile Tyr Trp Ala Ser Thr Leu Ala Ser Gly Val Ser Ser Arg Phe     50 55 60 Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu 65 70 75 80 Gln Pro Glu Asp Ala Ala Thr Tyr Tyr Cys Ala Gly Gly Tyr Gly Gly                 85 90 95 Gly Arg Tyr Ala Phe Gly Gln Gly Thr Lys Val Glu Ile Lys             100 105 110 <210> 38 <211> 110 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 38 Asp Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Thr Ser Ser Gln Ser Val Tyr His Asp             20 25 30 Asn Trp Leu Ser Trp Phe Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu         35 40 45 Leu Ile Tyr Trp Ala Ser Thr Leu Ala Tyr Gly Val Ser Ser Phe     50 55 60 Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu 65 70 75 80 Gln Pro Glu Asp Ala Ala Thr Tyr Tyr Cys Ala Gly Gly Tyr Gly Gly                 85 90 95 Gly Leu Tyr Ala Phe Gly Gln Gly Thr Lys Val Glu Ile Lys             100 105 110 <210> 39 <211> 348 <212> DNA <213> Artificial sequence <220> An artificially synthesized sequence <400> 39 cagtcgctgg aggagtccgg gggtcgcctg gtaacgcctg gaggatccct gacagtcacc 60 tgcagagtct ctggaatcga cctcagtagt tacgacatca gctgggtccg ccaggctcca 120 gggaaggggc tggagtggat cggaatcatt agttatgctg gtagcacata ctacgcgagc 180 tgggcaaaag gccgattcac catctccaaa acctcgacca cggtggatct gaaaatgacc 240 agtctgacaa ccgaggacac ggccacctat ttctgtgcca gaggtgtgcc tgcttatagt 300 actggtggtg acttgtgggg cccaggcacc ctggtcaccg tctcctcc 348 <210> 40 <211> 357 <212> DNA <213> Artificial sequence <220> An artificially synthesized sequence <400> 40 caggtgacac tgaaagaaag cggccccgtg ctggtgaagc caaccgagac actgactctg 60 acctgcacag tgagtgggat cgacctgagc agctacgaca tctcctgggt gcggcaggca 120 cccggaaagg gcctggaatg ggtcggcatc attagctacg ccgggagcac atactatgcc 180 agctgggcta aaggaagact gactatctcc aaggacacct ctaaaaacca ggtggtcctg 240 actatgacca atatggaccc cgtggataca gcaacttact attgtgccag gggcgtccct 300 gcttactcta ccggagggga tctgtgggga cagggaaccc tggtgacagt ctctagt 357 <210> 41 <211> 330 <212> DNA <213> Artificial sequence <220> An artificially synthesized sequence <400> 41 gcgcaagtgc tgacccagac tgcatcatcc gtgtctgcag ctgtgggagg cacagtcacc 60 atcaattgcc agtccagtca gagtgtttat gataacaact ggttatcctg gtttcagcag 120 aaaccagggc agcctcccaa gctcctgatc tattgggcat ccactctggc atctggggtc 180 ccatcgcggt tcaaaggcag tggatctggg acacagttca ctctcaccat cagcgacctg 240 gagtgtgacg atgctgccac ttactactgt gcaggcggtt atggtggtgg tctgtatgct 300 ttcggcggag ggaccaaggt ggagatcaaa 330 <210> 42 <211> 330 <212> DNA <213> Artificial sequence <220> An artificially synthesized sequence <400> 42 gacattgtga tgactcagtc tcctgccact ctgtcactga gccctggcga gcgagcaacc 60 ctgtcttgcc agagcagcca gtccgtgtac gacaacaatt ggctgagctg gttccagcag 120 aagccagggc agccccctaa actgctgatc tattgggcat caacactggc cagcggcgtc 180 ccctccagat tctccggatc tggcagtggg actgacttta ccctgaccat cagcagcctc 240 cagcccgagg atgccgctac ctactattgt gctggcgggt acggaggcgg gctgtatgca 300 tttggacagg gcacaaaggt ggaaatcaaa 330 <210> 43 <211> 357 <212> DNA <213> Artificial sequence <220> An artificially synthesized sequence <400> 43 caggtgacac tgaaagaaag cggccccgtg ctggtgaagc caaccgagac actgactctg 60 acctgcacag tgagtgggat cgacctgagc cacaccgaca tctcctgggt gcggcaggca 120 cccggaaagg gcctggaatg ggtcggcatc attagctacg ccgggagcac atactatgcc 180 agctgggcta aaggaagact gactatctcc aaggacacct ctaaaaacca ggtggtcctg 240 actatgacca atatggaccc cgtggataca gcaacttact attgtgccag gggcgtccct 300 gcttactctc acggagggga tctgtgggga cagggaaccc tggtgacagt ctctagt 357 <210> 44 <211> 357 <212> DNA <213> Artificial sequence <220> An artificially synthesized sequence <400> 44 caggtgacac tgaaagaaag cggccccgtg ctggtgaagc caaccgagac actgactctg 60 acctgcacag tgagtgggat cgacctgagc cacaccgaca tctcctgggt gcggcaggca 120 cccggaaagg gcctggaatg ggtcggcatc attagctacg ccgggagcac atactatatg 180 agctgggcta aaggaagact gactatctcc aaggacacct ctaaaaacca ggtggtcctg 240 actatgacca atatggaccc cgtggataca gcaacttact attgtgccag gggcgtccct 300 gcttactctc acggagggga tctgtgggga cagggaaccc tggtgacagt ctctagt 357 <210> 45 <211> 357 <212> DNA <213> Artificial sequence <220> An artificially synthesized sequence <400> 45 caggtgacac tgaaagaaag cggccccgtg ctggtgaagc caaccgagac actgactctg 60 acctgcacag tgagtgggat cgacctgagc cactacgaca tctcctgggt gcggcaggca 120 cccggaaagg gcctggaatg ggtcggcatc attagctacg ccgggagcac atactatgcc 180 agctgggcta aaggaagact gactatctcc aaggacacct ctaaaaacca ggtggtcctg 240 actatgacca atatggaccc cgtggataca gcaacttact attgtgccag gggcgtccct 300 gcttactctc acggagggga tctgtgggga cagggaaccc tggtgacagt ctctagt 357 <210> 46 <211> 330 <212> DNA <213> Artificial sequence <220> An artificially synthesized sequence <400> 46 gacattgtga tgactcagtc tcctgccact ctgtcactga gccctggcga gcgagcaacc 60 ctgtcttgca ccagcagcca gtccgtgtac cacaacaatt ggctgagctg gttccagcag 120 aagccagggc agccccctaa actgctgatc tattgggcat caacactggc ctacggcgtc 180 ccctccagat tctccggatc tggcagtggg actgacttta ccctgaccat cagcagcctc 240 cagcccgagg atgccgctac ctactattgt gctggcgggt acggaggcgg gcggtatgca 300 tttggacagg gcacaaaggt ggaaatcaaa 330 <210> 47 <211> 330 <212> DNA <213> Artificial sequence <220> An artificially synthesized sequence <400> 47 gacattgtga tgactcagtc tcctgccact ctgtcactga gccctggcga gcgagcaacc 60 ctgtcttgcc agagcagcca gtccgtgtac cacaacaatt ggctgagctg gttccagcag 120 aagccagggc agccccctaa actgctgatc tattgggcat caacactggc cttcggcgtc 180 ccctccagat tctccggatc tggcagtggg actgacttta ccctgaccat cagcagcctc 240 cagcccgagg atgccgctac ctactattgt gctggcgggt acggaggcgg gctgtatgca 300 tttggacagg gcacaaaggt ggaaatcaaa 330 <210> 48 <211> 330 <212> DNA <213> Artificial sequence <220> An artificially synthesized sequence <400> 48 gacattgtga tgactcagtc tcctgccact ctgtcactga gccctggcga gcgagcaacc 60 ctgtcttgcc agaccagcca gtccgtgtac cacgacaatt ggctgagctg gttccagcag 120 aagccagggc agccccctaa actgctgatc tattgggcat caacactggc cagcggcgtc 180 ccctccagat tctccggatc tggcagtggg actgacttta ccctgaccat cagcagcctc 240 cagcccgagg atgccgctac ctactattgt gctggcgggt acggaggcgg gcggtatgca 300 tttggacagg gcacaaaggt ggaaatcaaa 330 <210> 49 <211> 330 <212> DNA <213> Artificial sequence <220> An artificially synthesized sequence <400> 49 gacattgtga tgactcagtc tcctgccact ctgtcactga gccctggcga gcgagcaacc 60 ctgtcttgca ccagcagcca gtccgtgtac cacgacaatt ggctgagctg gttccagcag 120 aagccagggc agccccctaa actgctgatc tattgggcat caacactggc ctacggcgtc 180 ccctccagat tctccggatc tggcagtggg actgacttta ccctgaccat cagcagcctc 240 cagcccgagg atgccgctac ctactattgt gctggcgggt acggaggcgg gctgtatgca 300 tttggacagg gcacaaaggt ggaaatcaaa 330 <210> 50 <211> 987 <212> DNA <213> Artificial sequence <220> An artificially synthesized sequence <400> 50 gcttccacca agggcccatc ggtcttcccc ctggcaccct cctccaagtc cacctctggg 60 ggcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 120 tggaactcag gcgccctgac ctccggcgtg cacaccttcc cggctgtcct acagtcctca 180 ggactctact ccctctcctc cgtggtgacc gtgccctcct cgtccttggg cacccagacc 240 tacatctgca acgtgaatca caagccctcc aacaccaagg tggacaagaa agttgagccc 300 aaatcttgtg acaaaactca cacatgccca ccgtgcccag cacctgaact cctgggggga 360 ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 420 gaggtcacat gcgtggtggt ggacgtgtcc cacgaagacc ctgaggtcaa gttcaactgg 480 tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacaac 540 tccacgtacc gtgtggtctc cgtcctcacc gtcctgcacc aggactggct gaatggcaag 600 gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 660 aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccgggaggaa 720 atgaccaaga accaggtctc cctgacctgc ctggtcaaag gcttctatcc ctccgacatc 780 gccgtggagt gggagtccaa tgggcagccg gagaacaact acaagaccac gcctcccgtg 840 ctggactccg acggctcctt cttcctctac tccaagctca ccgtggacaa gtccaggtgg 900 cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 960 cagaagtcgc tctccctgtc tccgtag 987 <210> 51 <211> 984 <212> DNA <213> Artificial sequence <220> An artificially synthesized sequence <400> 51 gctagcacca agggcccatc ggtcttcccc ctggcaccct cctccaagag cacctctggg 60 ggcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 120 tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 180 ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacccagacc 240 tacatctgca acgtgaatca caagcccagc aacaccaagg tggacaagaa agttgagccc 300 aaatcttgtg acaaaactca cacatgccca ccgtgcccag cacctgaact ccggggggga 360 ccgaaagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 420 gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 480 tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacaac 540 agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 600 gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 660 aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccgggatgag 720 ctgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 780 gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg 840 ctggactccg acggctcctt cttcctctac agcaagctca ccgtggacaa gagcaggtgg 900 cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 960 cagaagagcc tctccctgtc tccg 984 <210> 52 <211> 987 <212> DNA <213> Artificial sequence <220> An artificially synthesized sequence <400> 52 gcttccacca agggcccatc ggtcttcccc ctggcaccct cctccaagtc gacctctggg 60 ggcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 120 tggaactcag gcgccctgac cagtggcgtg cacaccttcc cggctgtcct acagtcctca 180 ggactctact ccctcagtag tgtggtgacc gtgccctcca gtagtttggg cacccagacc 240 tacatctgca acgtgaatca caagcccagt aacaccaagg tggacaagaa agttgagccc 300 aaatcttgtg acaaaactca cacatgccca ccgtgcccag cacctgagct cctgggggga 360 ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 420 gaggtcacat gcgtggtggt ggacgtgagt cacgaagacc ctgaggtcaa gttcaactgg 480 tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacaac 540 agtacgtacc gtgtggtcag tgtcctcacc gtcctgcacc aggactggct gaatggcaag 600 gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 660 aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccgggaggag 720 atgaccaaga accaggtcag tctgacctgc ctggtcaaag gcttctatcc cagtgacatc 780 gccgtggagt gggagagtaa tgggcagccg gagaacaact acaagaccac gcctcccgtg 840 ctggactccg acggctcctt cttcctctac agtaagctca ccgtggacaa gagtaggtgg 900 cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 960 cagaagagtc tctccctgtc tccgtga 987 <210> 53 <211> 324 <212> DNA <213> Artificial sequence <220> An artificially synthesized sequence <400> 53 cgtacggtgg ctgcaccatc tgtcttcatc ttcccgccat ctgatgagca gttgaaatct 60 ggaactgcct ctgttgtgtg cctgctgaat aacttctatc ccagagaggc caaagtacag 120 tggaaggtgg ataacgccct ccaatcgggt aactcccagg agagtgtcac agagcaggac 180 tccaaggact gcacctactc cctctcctcc accctgacgc tgtccaaagc agactacgag 240 aaacacaaag tctacgcctg cgaagtcacc catcagggcc tgtcctcgcc cgtcacaaag 300 tccttcaaca ggggagagtg ttga 324 <210> 54 <211> 324 <212> DNA <213> Artificial sequence <220> An artificially synthesized sequence <400> 54 cgtacggtgg ctgcaccatc tgtcttcatc ttcccgccat ctgatgagca gttgaaatct 60 ggtaccgcct ctgttgtgtg cctgctgaat aacttctatc ccagagaggc caaagtacag 120 tggaaggtgg ataacgccct ccaatcgggt aactcccagg agagtgtcac agagcaggac 180 agtaaggaca gtacctacag tctcagtagt accctgacgc tgtccaaagc agactacgag 240 aaacacaaag tctacgcctg cgaagtcacc catcagggcc tgtcctcgcc cgtcacaaag 300 tccttcaaca ggggagagtg ttga 324 <210> 55 <211> 5 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 55 Ser Tyr Asp Ile Ser 1 5 <210> 56 <211> 5 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 56 His Tyr Asp Ile Ser 1 5 <210> 57 <211> 5 <212> PRT <213> Artificial Sequence <220> An artificially synthesized sequence <400> 57 His Thr Asp Ile Ser 1 5 <210> 58 <211> 16 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 58 Ile Ile Ser Tyr Ala Gly Ser Thr Tyr Tyr Ala Ser Trp Ala Lys Gly 1 5 10 15 <210> 59 <211> 16 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 59 Ile Ile Ser His Ala Gly Ser Thr Tyr Tyr Ala Ser Trp Ala Lys Gly 1 5 10 15 <210> 60 <211> 16 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 60 Ile Ile Ser Tyr Ala Gly Ser Thr Tyr Tyr Met Ser Trp Ala Lys Gly 1 5 10 15 <210> 61 <211> 11 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 61 Gly Val Pro Ala Tyr Ser Thr Gly Gly Asp Leu 1 5 10 <210> 62 <211> 11 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 62 Gly Val Pro Ala His Ser Thr Gly Gly Asp Leu 1 5 10 <210> 63 <211> 11 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 63 Gly Val Pro Ala Tyr Ser His Gly Gly Asp Leu 1 5 10 <210> 64 <211> 11 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 64 Gly Val Pro Ala His Ser His Gly Gly Asp Leu 1 5 10 <210> 65 <211> 13 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 65 Gln Ser Ser Gln Ser Val Tyr Asp Asn Asn Trp Leu Ser 1 5 10 <210> 66 <211> 13 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 66 Gln Ser Ser Gln Ser Val Tyr His Asn Asn Trp Leu Ser 1 5 10 <210> 67 <211> 13 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 67 Thr Ser Ser Gln Ser Val Tyr His Asn Asn Trp Ser Ser 1 5 10 <210> 68 <211> 13 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 68 Gln Thr Ser Gln Ser Val Tyr His Asp Asn Trp Leu Ser 1 5 10 <210> 69 <211> 13 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 69 Thr Ser Ser Gln Ser Val Tyr His Asp Asn Trp Leu Ser 1 5 10 <210> 70 <211> 7 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 70 Trp Ala Ser Thr Leu Ala Ser 1 5 <210> 71 <211> 7 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 71 Trp Ala Ser Thr Leu Ala Tyr 1 5 <210> 72 <211> 7 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 72 Trp Ala Ser Thr Leu Ala Phe 1 5 <210> 73 <211> 10 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 73 Ala Gly Gly Tyr Gly Gly Gly Leu Tyr Ala 1 5 10 <210> 74 <211> 10 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 74 Ala Gly Gly Tyr Gly Gly Gly Arg Tyr Ala 1 5 10 <210> 75 <211> 242 <212> PRT <213> Homo sapiens <400> 75 Glu Asn Ser Glu Gln Lys Glu Asn Val Glu Lys Glu Gly Leu Cys Asn 1 5 10 15 Ala Cys Thr Trp Arg Gln Asn Thr Lys Ser Ser Arg Ile Glu Ala Ile             20 25 30 Lys Ile Gln Ile Leu Ser Lys Leu Arg Leu Glu Thr Ala Pro Asn Ile         35 40 45 Ser Lys Asp Val Ile Arg Gln Leu Leu Pro Lys Ala Pro Pro Leu Arg     50 55 60 Glu Leu Ile Asp Gln Tyr Asp Val Gln Arg Asp Asp Ser Ser Asp Gly 65 70 75 80 Ser Leu Glu Asp Asp Asp Tyr His Ala Thr Thr Glu Thr Ile Ile Thr                 85 90 95 Met Pro Thr Glu Ser Asp Phe Leu Met Gln Val Asp Gly Lys Pro Lys             100 105 110 Cys Cys Phe Phe Lys Phe Ser Ser Lys Ile Gln Tyr Asn Lys Val Val         115 120 125 Lys Ala Gln Leu Trp Ile Tyr Leu Arg Pro Val Glu Thr Pro Thr Thr     130 135 140 Val Phe Val Gln Ile Leu Arg Leu Ile Lys Pro Met Lys Asp Gly Thr 145 150 155 160 Arg Tyr Thr Gly Ile Arg Ser Leu Lys Leu Asp Met Asn Pro Gly Thr                 165 170 175 Gly Ile Trp Gln Ser Ile Asp Val Lys Thr Val Leu Gln Asn Trp Leu             180 185 190 Lys Gln Pro Glu Ser Asn Leu Gly Ile Glu Ile Lys Ala Leu Asp Glu         195 200 205 Asn Gly His Asp Leu Ala Val Thr Phe Pro Gly Pro Gly Glu Asp Gly     210 215 220 Leu Asn Pro Phe Leu Glu Val Lys Val Thr Asp Thr Pro Lys Arg Ser 225 230 235 240 Arg Arg          <210> 76 <211> 242 <212> PRT <213> Macaca fascicularis <400> 76 Glu Asn Ser Glu Gln Lys Glu Asn Val Glu Lys Glu Gly Leu Cys Asn 1 5 10 15 Ala Cys Thr Trp Arg Gln Asn Thr Lys Ser Ser Arg Ile Glu Ala Ile             20 25 30 Lys Ile Gln Ile Leu Ser Lys Leu Arg Leu Glu Thr Ala Pro Asn Ile         35 40 45 Ser Lys Asp Ala Ile Arg Gln Leu Leu Pro Lys Ala Pro Pro Leu Arg     50 55 60 Glu Leu Ile Asp Gln Tyr Asp Val Gln Arg Asp Asp Ser Ser Asp Gly 65 70 75 80 Ser Leu Glu Asp Asp Asp Tyr His Ala Thr Thr Glu Thr Ile Ile Thr                 85 90 95 Met Pro Thr Glu Ser Asp Phe Leu Met Gln Val Asp Gly Lys Pro Lys             100 105 110 Cys Cys Phe Phe Lys Phe Ser Ser Lys Ile Gln Tyr Asn Lys Val Val         115 120 125 Lys Ala Gln Leu Trp Ile Tyr Leu Arg Pro Val Glu Thr Pro Thr Thr     130 135 140 Val Phe Val Gln Ile Leu Arg Leu Ile Lys Pro Met Lys Asp Gly Thr 145 150 155 160 Arg Tyr Thr Gly Ile Arg Ser Leu Lys Leu Asp Met Asn Pro Gly Thr                 165 170 175 Gly Ile Trp Gln Ser Ile Asp Val Lys Thr Val Leu Gln Asn Trp Leu             180 185 190 Lys Gln Pro Glu Ser Asn Leu Gly Ile Glu Ile Lys Ala Leu Asp Glu         195 200 205 Asn Gly His Asp Leu Ala Val Thr Phe Pro Gly Pro Gly Glu Asp Gly     210 215 220 Leu Asn Pro Phe Leu Glu Val Lys Val Thr Asp Thr Pro Lys Arg Ser 225 230 235 240 Arg Arg          <210> 77 <211> 242 <212> PRT <213> Mus musculus <400> 77 Glu Gly Ser Glu Arg Glu Glu Asn Val Glu Lys Glu Gly Leu Cys Asn 1 5 10 15 Ala Cys Ala Trp Arg Gln Asn Thr Arg Tyr Ser Arg Ile Glu Ala Ile             20 25 30 Lys Ile Gln Ile Leu Ser Lys Leu Arg Leu Glu Thr Ala Pro Asn Ile         35 40 45 Ser Lys Asp Ala Ile Arg Gln Leu Leu Pro Arg Ala Pro Pro Leu Arg     50 55 60 Glu Leu Ile Asp Gln Tyr Asp Val Gln Arg Asp Asp Ser Ser Asp Gly 65 70 75 80 Ser Leu Glu Asp Asp Asp Tyr His Ala Thr Thr Glu Thr Ile Ile Thr                 85 90 95 Met Pro Thr Glu Ser Asp Phe Leu Met Gln Ala Asp Gly Lys Pro Lys             100 105 110 Cys Cys Phe Phe Lys Phe Ser Ser Lys Ile Gln Tyr Asn Lys Val Val         115 120 125 Lys Ala Gln Leu Trp Ile Tyr Leu Arg Pro Val Lys Thr Pro Thr Thr     130 135 140 Val Phe Val Gln Ile Leu Arg Leu Ile Lys Pro Met Lys Asp Gly Thr 145 150 155 160 Arg Tyr Thr Gly Ile Arg Ser Leu Lys Leu Asp Met Ser Pro Gly Thr                 165 170 175 Gly Ile Trp Gln Ser Ile Asp Val Lys Thr Val Leu Gln Asn Trp Leu             180 185 190 Lys Gln Pro Glu Ser Asn Leu Gly Ile Glu Ile Lys Ala Leu Asp Glu         195 200 205 Asn Gly His Asp Leu Ala Val Thr Phe Pro Gly Pro Gly Glu Asp Gly     210 215 220 Leu Asn Pro Phe Leu Glu Val Lys Val Thr Asp Thr Pro Lys Arg Ser 225 230 235 240 Arg Arg          <210> 78 <211> 266 <212> PRT <213> Homo sapiens <400> 78 Met Gln Lys Leu Gln Leu Cys Val Tyr Ile Tyr Leu Phe Met Leu Ile 1 5 10 15 Val Ala Gly Pro Val Asp Leu Asn Glu Asn Ser Glu Gln Lys Glu Asn             20 25 30 Val Glu Lys Glu Gly Leu Cys Asn Ala Cys Thr Trp Arg Gln Asn Thr         35 40 45 Lys Ser Ser Arg Ile Glu Ala Ile Lys Ile Gln Ile Leu Ser Lys Leu     50 55 60 Arg Leu Glu Thr Ala Pro Asn Ile Ser Lys Asp Val Ile Arg Gln Leu 65 70 75 80 Leu Pro Lys Ala Pro Pro Leu Arg Glu Leu Ile Asp Gln Tyr Asp Val                 85 90 95 Gln Arg Asp Asp Ser Ser Asp Gly Ser Leu Glu Asp Asp Asp Tyr His             100 105 110 Ala Thr Thr Glu Thr Ile Ile Thr Met Pro Thr Glu Ser Asp Phe Leu         115 120 125 Met Gln Val Asp Gly Lys Pro Lys Cys Cys Phe Phe Lys Phe Ser Ser     130 135 140 Lys Ile Gln Tyr Asn Lys Val Val Lys Ala Gln Leu Trp Ile Tyr Leu 145 150 155 160 Arg Pro Val Glu Thr Pro Thr Thr Val Phe Val Gln Ile Leu Arg Leu                 165 170 175 Ile Lys Pro Met Lys Asp Gly Thr Arg Tyr Thr Gly Ile Arg Ser Leu             180 185 190 Lys Leu Asp Met Asn Pro Gly Thr Gly Ile Trp Gln Ser Ile Asp Val         195 200 205 Lys Thr Val Leu Gln Asn Trp Leu Lys Gln Pro Glu Ser Asn Leu Gly     210 215 220 Ile Glu Ile Lys Ala Leu Asp Glu Asn Gly His Asp Leu Ala Val Thr 225 230 235 240 Phe Pro Gly Pro Gly Glu Asp Gly Leu Asn Pro Phe Leu Glu Val Lys                 245 250 255 Val Thr Asp Thr Pro Lys Arg Ser Arg Arg             260 265 <210> 79 <211> 266 <212> PRT <213> Macaca fascicularis <400> 79 Met Gln Lys Leu Gln Leu Cys Val Tyr Ile Tyr Leu Phe Met Leu Ile 1 5 10 15 Val Ala Gly Pro Val Asp Leu Asn Glu Asn Ser Glu Gln Lys Glu Asn             20 25 30 Val Glu Lys Glu Gly Leu Cys Asn Ala Cys Thr Trp Arg Gln Asn Thr         35 40 45 Lys Ser Ser Arg Ile Glu Ala Ile Lys Ile Gln Ile Leu Ser Lys Leu     50 55 60 Arg Leu Glu Thr Ala Pro Asn Ile Ser Lys Asp Ala Ile Arg Gln Leu 65 70 75 80 Leu Pro Lys Ala Pro Pro Leu Arg Glu Leu Ile Asp Gln Tyr Asp Val                 85 90 95 Gln Arg Asp Asp Ser Ser Asp Gly Ser Leu Glu Asp Asp Asp Tyr His             100 105 110 Ala Thr Thr Glu Thr Ile Ile Thr Met Pro Thr Glu Ser Asp Phe Leu         115 120 125 Met Gln Val Asp Gly Lys Pro Lys Cys Cys Phe Phe Lys Phe Ser Ser     130 135 140 Lys Ile Gln Tyr Asn Lys Val Val Lys Ala Gln Leu Trp Ile Tyr Leu 145 150 155 160 Arg Pro Val Glu Thr Pro Thr Thr Val Phe Val Gln Ile Leu Arg Leu                 165 170 175 Ile Lys Pro Met Lys Asp Gly Thr Arg Tyr Thr Gly Ile Arg Ser Leu             180 185 190 Lys Leu Asp Met Asn Pro Gly Thr Gly Ile Trp Gln Ser Ile Asp Val         195 200 205 Lys Thr Val Leu Gln Asn Trp Leu Lys Gln Pro Glu Ser Asn Leu Gly     210 215 220 Ile Glu Ile Lys Ala Leu Asp Glu Asn Gly His Asp Leu Ala Val Thr 225 230 235 240 Phe Pro Gly Pro Gly Glu Asp Gly Leu Asn Pro Phe Leu Glu Val Lys                 245 250 255 Val Thr Asp Thr Pro Lys Arg Ser Arg Arg             260 265 <210> 80 <211> 267 <212> PRT <213> Mus musculus <400> 80 Met Met Gln Lys Leu Gln Met Tyr Val Tyr Ile Tyr Leu Phe Met Leu 1 5 10 15 Ile Ala Ala Gly Pro Val Asp Leu Asn Glu Gly Ser Glu Arg Glu Glu             20 25 30 Asn Val Glu Lys Glu Gly Leu Cys Asn Ala Cys Ala Trp Arg Gln Asn         35 40 45 Thr Arg Tyr Ser Arg Ile Glu Ala Ile Lys Ile Gln Ile Leu Ser Lys     50 55 60 Leu Arg Leu Glu Thr Ala Pro Asn Ile Ser Lys Asp Ala Ile Arg Gln 65 70 75 80 Leu Leu Pro Arg Ala Pro Pro Leu Arg Glu Leu Ile Asp Gln Tyr Asp                 85 90 95 Val Gln Arg Asp Asp Ser Ser Asp Gly Ser Leu Glu Asp Asp Asp Tyr             100 105 110 His Ala Thr Thr Glu Thr Ile Ile Thr Met Pro Thr Glu Ser Asp Phe         115 120 125 Leu Met Gln Ala Asp Gly Lys Pro Lys Cys Cys Phe Phe Lys Phe Ser     130 135 140 Ser Lys Ile Gln Tyr Asn Lys Val Val Lys Ala Gln Leu Trp Ile Tyr 145 150 155 160 Leu Arg Pro Val Lys Thr Pro Thr Thr Val Phe Val Gln Ile Leu Arg                 165 170 175 Leu Ile Lys Pro Met Lys Asp Gly Thr Arg Tyr Thr Gly Ile Arg Ser             180 185 190 Leu Lys Leu Asp Met Ser Pro Gly Thr Gly Ile Trp Gln Ser Ile Asp         195 200 205 Val Lys Thr Val Leu Gln Asn Trp Leu Lys Gln Pro Glu Ser Asn Leu     210 215 220 Gly Ile Glu Ile Lys Ala Leu Asp Glu Asn Gly His Asp Leu Ala Val 225 230 235 240 Thr Phe Pro Gly Pro Gly Glu Asp Gly Leu Asn Pro Phe Leu Glu Val                 245 250 255 Lys Val Thr Asp Thr Pro Lys Arg Ser Ser Arg             260 265 <210> 81 <211> 407 <212> PRT <213> Homo sapiens <400> 81 Met Val Leu Ala Leu Leu Leu Leu 1 5 10 15 Glu Leu Arg Pro Gly Glu Ala Ala Glu Gly Pro Ala Ala Ala Ala             20 25 30 Ala Ala Ala Ala Ala Ala Ala Gly Val Gly Gly Glu Arg Ser         35 40 45 Ser Arg Pro Ala Pro Ser Val Ala Pro Glu Pro Asp Gly Cys Pro Val     50 55 60 Cys Val Trp Arg Gln His Ser Arg Glu Leu Arg Leu Glu Ser Ile Lys 65 70 75 80 Ser Gln Ile Leu Ser Lys Leu Arg Leu Lys Glu Ala Pro Asn Ile Ser                 85 90 95 Arg Glu Val Val Lys Gln Leu Leu Pro Lys Ala Pro Pro Leu Gln Gln             100 105 110 Ile Leu Asp Leu His Asp Phe Gln Gly Asp Ala Leu Gln Pro Glu Asp         115 120 125 Phe Leu Glu Glu Asp Glu Tyr His Ala Thr Thr Glu Thr Val Ile Ser     130 135 140 Met Ala Gln Glu Thr Asp Pro Ala Val Gln Thr Asp Gly Ser Pro Leu 145 150 155 160 Cys Cys His Phe His Phe Ser Pro Lys Val Met Phe Thr Lys Val Leu                 165 170 175 Lys Ala Gln Leu Trp Val Tyr Leu Arg Pro Val Pro Arg Pro Ala Thr             180 185 190 Val Tyr Leu Gln Ile Leu Arg Leu Lys Pro Leu Thr Gly Glu Gly Thr         195 200 205 Ala Gly Gly Gly Gly Gly Gly Arg Arg His Ile Arg Ile Arg Ser Leu     210 215 220 Lys Ile Glu Leu His Ser Arg Gly His Trp Gln Ser Ile Asp Phe 225 230 235 240 Lys Gln Val Leu His Ser Trp Phe Arg Gln Pro Gln Ser Asn Trp Gly                 245 250 255 Ile Glu Ile Asn Ala Phe Asp Pro Ser Gly Thr Asp Leu Ala Val Thr             260 265 270 Ser Leu Gly Pro Gly Ala Glu Gly Leu His Pro Phe Met Glu Leu Arg         275 280 285 Val Leu Glu Asn Thr Lys Arg Ser Arg Arg Asn Leu Gly Leu Asp Cys     290 295 300 Asp Glu His Ser Ser Glu Ser Arg Cys Cys Arg Tyr Pro Leu Thr Val 305 310 315 320 Asp Phe Glu Ala Phe Gly Trp Asp Trp Ile Ile Ala Pro Lys Arg Tyr                 325 330 335 Lys Ala Asn Tyr Cys Ser Gly Gln Cys Glu Tyr Met Phe Met Gln Lys             340 345 350 Tyr Pro His Thr His Leu Val Gln Gln Ala Asn Pro Arg Gly Ser Ala         355 360 365 Gly Pro Cys Cys Thr Pro Thr Lys Met Ser Pro Ile Asn Met Leu Tyr     370 375 380 Phe Asn Asp Lys Gln Gln Ile Ile Tyr Gly Lys Ile Pro Gly Met Val 385 390 395 400 Val Asp Arg Cys Gly Cys Ser                 405 <210> 82 <211> 109 <212> PRT <213> Homo sapiens <400> 82 Asn Leu Gly Leu Asp Cys Asp Glu His Ser Ser Glu Ser Arg Cys Cys 1 5 10 15 Arg Tyr Pro Leu Thr Val Asp Phe Glu Ala Phe Gly Trp Asp Trp Ile             20 25 30 Ile Ala Pro Lys Arg Tyr Lys Ala Asn Tyr Cys Ser Gly Gln Cys Glu         35 40 45 Tyr Met Phe Met Gln Lys Tyr Pro His Thr His Leu Val Gln Gln Ala     50 55 60 Asn Pro Arg Gly Ser Ala Gly Pro Cys Cys Thr Pro Thr Lys Met Ser 65 70 75 80 Pro Ile Asn Met Leu Tyr Phe Asn Asp Lys Gln Gln Ile Ile Tyr Gly                 85 90 95 Lys Ile Pro Gly Met Val Val Asp Arg Cys Gly Cys Ser             100 105 <210> 83 <211> 274 <212> PRT <213> Homo sapiens <400> 83 Ala Glu Gly Pro Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala 1 5 10 15 Ala Gly Val Gly Gly Glu Arg Ser Ser Arg Pro Ala Pro Ser Val Ala             20 25 30 Pro Glu Pro Asp Gly Cys Pro Val Cys Val Trp Arg Gln His Ser Arg         35 40 45 Glu Leu Arg Leu Glu Ser Ile Lys Ser Gln Ile Leu Ser Lys Leu Arg     50 55 60 Leu Lys Glu Ala Pro Asn Ile Ser Arg Glu Val Val Lys Gln Leu Leu 65 70 75 80 Pro Lys Ala Pro Pro Leu Gln Gln Ile Leu Asp Leu His Asp Phe Gln                 85 90 95 Gly Asp Ala Leu Gln Pro Glu Asp Phe Leu Glu Glu Asp Glu Tyr His             100 105 110 Ala Thr Thr Glu Thr Val Ile Ser Met Ala Gln Glu Thr Asp Pro Ala         115 120 125 Val Gln Thr Asp Gly Ser Pro Leu Cys Cys His Phe His Phe Ser Pro     130 135 140 Lys Val Met Phe Thr Lys Val Leu Lys Ala Gln Leu Trp Val Tyr Leu 145 150 155 160 Arg Pro Val Arg Pro Ala Thr Val Tyr Leu Gln Ile Leu Arg Leu                 165 170 175 Lys Pro Leu Thr Gly Gly Gly Thr Ala Gly Gly Gly Gly Gly Gly Gly Arg             180 185 190 Arg His Ile Arg Ile Arg Ser Leu Lys Ile Glu Leu His Ser Arg Ser         195 200 205 Gly His Trp Gln Ser Ile Asp Phe Lys Gln Val Leu His Ser Trp Phe     210 215 220 Arg Gln Pro Gln Ser Asn Trp Gly Ile Glu Ile Asn Ala Phe Asp Pro 225 230 235 240 Ser Gly Thr Asp Leu Ala Val Thr Ser Leu Gly Pro Gly Ala Glu Gly                 245 250 255 Leu His Pro Phe Met Glu Leu Arg Val Leu Glu Asn Thr Lys Arg Ser             260 265 270 Arg Arg          <210> 84 <211> 298 <212> PRT <213> Homo sapiens <400> 84 Met Val Leu Ala Leu Leu Leu Leu 1 5 10 15 Glu Leu Arg Pro Gly Glu Ala Ala Glu Gly Pro Ala Ala Ala Ala             20 25 30 Ala Ala Ala Ala Ala Ala Ala Gly Val Gly Gly Glu Arg Ser         35 40 45 Ser Arg Pro Ala Pro Ser Val Ala Pro Glu Pro Asp Gly Cys Pro Val     50 55 60 Cys Val Trp Arg Gln His Ser Arg Glu Leu Arg Leu Glu Ser Ile Lys 65 70 75 80 Ser Gln Ile Leu Ser Lys Leu Arg Leu Lys Glu Ala Pro Asn Ile Ser                 85 90 95 Arg Glu Val Val Lys Gln Leu Leu Pro Lys Ala Pro Pro Leu Gln Gln             100 105 110 Ile Leu Asp Leu His Asp Phe Gln Gly Asp Ala Leu Gln Pro Glu Asp         115 120 125 Phe Leu Glu Glu Asp Glu Tyr His Ala Thr Thr Glu Thr Val Ile Ser     130 135 140 Met Ala Gln Glu Thr Asp Pro Ala Val Gln Thr Asp Gly Ser Pro Leu 145 150 155 160 Cys Cys His Phe His Phe Ser Pro Lys Val Met Phe Thr Lys Val Leu                 165 170 175 Lys Ala Gln Leu Trp Val Tyr Leu Arg Pro Val Pro Arg Pro Ala Thr             180 185 190 Val Tyr Leu Gln Ile Leu Arg Leu Lys Pro Leu Thr Gly Glu Gly Thr         195 200 205 Ala Gly Gly Gly Gly Gly Gly Arg Arg His Ile Arg Ile Arg Ser Leu     210 215 220 Lys Ile Glu Leu His Ser Arg Gly His Trp Gln Ser Ile Asp Phe 225 230 235 240 Lys Gln Val Leu His Ser Trp Phe Arg Gln Pro Gln Ser Asn Trp Gly                 245 250 255 Ile Glu Ile Asn Ala Phe Asp Pro Ser Gly Thr Asp Leu Ala Val Thr             260 265 270 Ser Leu Gly Pro Gly Ala Glu Gly Leu His Pro Phe Met Glu Leu Arg         275 280 285 Val Leu Glu Asn Thr Lys Arg Ser Arg Arg     290 295 <210> 85 <211> 409 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 85 Met Lys Trp Val Thr Phe Leu Leu Leu Leu Phe Ile Ser Gly Ser Ala 1 5 10 15 Phe Ser Asp Tyr Lys Asp Asp Asp Asp Lys Ala Glu Gly Pro Ala Ala             20 25 30 Ala Ala Ala Ala Ala Ala Ala Ala Ala Gly Val Gly Gly Glu         35 40 45 Arg Ser Ser Arg Pro Ala Pro Ser Val Ala Pro Glu Pro Asp Gly Cys     50 55 60 Pro Val Cys Val Trp Arg Gln His Ser Arg Glu Leu Arg Leu Glu Ser 65 70 75 80 Ile Lys Ser Gln Ile Leu Ser Lys Leu Arg Leu Lys Glu Ala Pro Asn                 85 90 95 Ile Ser Arg Glu Val Val Lys Gln Leu Leu Pro Lys Ala Pro Pro Leu             100 105 110 Gln Gln Ile Leu Asp Leu His Asp Phe Gln Gly Asp Ala Leu Gln Pro         115 120 125 Glu Asp Phe Leu Glu Glu Asp Glu Tyr His Ala Thr Thr Glu Thr Val     130 135 140 Ile Ser Met Ala Gln Glu Thr Asp Pro Ala Val Gln Thr Asp Gly Ser 145 150 155 160 Pro Leu Cys Cys His Phe His Phe Ser Pro Lys Val Met Phe Thr Lys                 165 170 175 Val Leu Lys Ala Gln Leu Trp Val Tyr Leu Arg Pro Val Val Pro Arg Pro             180 185 190 Ala Thr Val Tyr Leu Gln Ile Leu Arg Leu Lys Pro Leu Thr Gly Glu         195 200 205 Gly Thr Ala Gly Gly Gly Gly Gly Gly Arg Arg His Ile Arg Ile Arg     210 215 220 Ser Leu Lys Ile Glu Leu His Ser Arg Ser Gly His Trp Gln Ser Ile 225 230 235 240 Asp Phe Lys Gln Val Leu His Ser Trp Phe Arg Gln Pro Gln Ser Asn                 245 250 255 Trp Gly Ile Glu Ile Asn Ala Phe Asp Pro Ser Gly Thr Asp Leu Ala             260 265 270 Val Thr Ser Leu Gly Pro Gly Ala Glu Gly Leu His Pro Phe Met Glu         275 280 285 Leu Arg Val Leu Glu Asn Thr Lys Arg Ser Arg Arg Asn Leu Gly Leu     290 295 300 Asp Cys Asp Glu His Ser Ser Glu Ser Arg Cys Cys Arg Tyr Pro Leu 305 310 315 320 Thr Val Asp Phe Glu Ala Phe Gly Trp Asp Trp Ile Ile Ala Pro Lys                 325 330 335 Arg Tyr Lys Ala Asn Tyr Cys Ser Gly Gln Cys Glu Tyr Met Phe Met             340 345 350 Gln Lys Tyr Pro His Thr His Leu Val Gln Gln Ala Asn Pro Arg Gly         355 360 365 Ser Ala Gly Pro Cys Cys Thr Pro Thr Lys Met Ser Pro Ile Asn Met     370 375 380 Leu Tyr Phe Asn Asp Lys Gln Gln Ile Ile Tyr Gly Lys Ile Pro Gly 385 390 395 400 Met Val Val Asp Arg Cys Gly Cys Ser                 405 <210> 86 <211> 119 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 86 Gln Val Thr Leu Lys Glu Ser Gly Pro Val Leu Val Lys Pro Thr Glu 1 5 10 15 Thr Leu Thr Leu Thr Cys Thr Val Ser Gly Ile Asp Leu Ser His Asp             20 25 30 Asp Ile Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val         35 40 45 Gly Ile Ile Ser Tyr Ala Gly Ser Thr Tyr Tyr Ala Ser Trp Ala Lys     50 55 60 Gly Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val Val Leu 65 70 75 80 Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr Cys Ala                 85 90 95 Arg Gly Val Pro Ala Tyr Ser His Gly Gly Asp Leu Trp Gly Gln Gly             100 105 110 Thr Leu Val Thr Val Ser Ser         115 <210> 87 <211> 119 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 87 Gln Val Thr Leu Lys Glu Ser Gly Pro Val Leu Val Lys Pro Thr Glu 1 5 10 15 Thr Leu Thr Leu Thr Cys Thr Val Ser Gly Ile Asp Leu Ser His Asp             20 25 30 Asp Ile Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val         35 40 45 Gly Ile Ile Ser Tyr Ala Gly Ser Met Tyr Tyr Ala Ser Trp Ala Lys     50 55 60 Gly Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val Val Leu 65 70 75 80 Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr Cys Ala                 85 90 95 Arg Gly Val Pro Ala Tyr Ser His Gly Gly Asp Lys Trp Gly Gln Gly             100 105 110 Thr Leu Val Thr Val Ser Ser         115 <210> 88 <211> 119 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 88 Gln Val Thr Leu Lys Glu Ser Gly Pro Val Leu Val Lys Pro Thr Glu 1 5 10 15 Thr Leu Thr Leu Thr Cys Thr Val Ser Gly Ile Asp Leu Ser His Thr             20 25 30 Asp Ile Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val         35 40 45 Gly Ile Ile Ser Tyr Ala Gly Lys Thr Tyr Tyr Ala Ser Trp Ala Lys     50 55 60 Lys Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val Val Leu 65 70 75 80 Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr Cys Ala                 85 90 95 Arg Gly Val Pro Ala Tyr Ser His Gly Gly Asp Leu Trp Gly Gln Gly             100 105 110 Thr Leu Val Thr Val Ser Ser         115 <210> 89 <211> 119 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 89 Gln Val Thr Leu Lys Glu Ser Gly Pro Val Leu Val Lys Pro Thr Glu 1 5 10 15 Thr Leu Thr Leu Thr Cys Thr Val Ser Gly Ile Asp Leu Ser His Thr             20 25 30 Asp Ile Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val         35 40 45 Gly Ile Ile Ser Tyr Ala Gly Lys Lys Tyr Tyr Ala Ser Trp Ala Lys     50 55 60 Gly Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val Val Leu 65 70 75 80 Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr Cys Ala                 85 90 95 Arg Gly Val Pro Ala Tyr Ser His Gly Gly Asp Leu Trp Gly Gln Gly             100 105 110 Thr Leu Val Thr Val Ser Ser         115 <210> 90 <211> 119 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 90 Gln Val Thr Leu Lys Glu Ser Gly Pro Val Leu Val Lys Pro Thr Glu 1 5 10 15 Thr Leu Thr Leu Thr Cys Thr Val Ser Gly Ile Asp Leu Ser His Thr             20 25 30 Asp Ile Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val         35 40 45 Gly Ile Ile Ser Tyr Ala Gly Ser Lys Tyr Lys Ala Ser Trp Ala Lys     50 55 60 Gly Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val Val Leu 65 70 75 80 Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr Cys Ala                 85 90 95 Arg Gly Val Pro Ala Tyr Ser His Gly Gly Asp Leu Trp Gly Gln Gly             100 105 110 Thr Leu Val Thr Val Ser Ser         115 <210> 91 <211> 119 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 91 Gln Val Thr Leu Lys Glu Ser Gly Pro Val Leu Val Lys Pro Thr Glu 1 5 10 15 Thr Leu Thr Leu Thr Cys Thr Val Ser Gly Ile Asp Leu Ser His Asp             20 25 30 Asp Ile Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val         35 40 45 Gly Ile Ile Ser Tyr Ala Gly Lys Lys Tyr Tyr Ala Ser Trp Ala Lys     50 55 60 Gly Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val Val Leu 65 70 75 80 Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr Cys Ala                 85 90 95 Arg Gly Val Pro Ala Tyr Ser His Gly Gly Asp Leu Trp Gly Gln Gly             100 105 110 Thr Leu Val Thr Val Ser Ser         115 <210> 92 <211> 119 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 92 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ile Asp Leu Ser His Asp             20 25 30 Asp Ile Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val         35 40 45 Ser Ile Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Se     50 55 60 Gly Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val Val Leu 65 70 75 80 Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr Cys Ala                 85 90 95 Arg Gly Val Pro Ala Tyr Ser His Gly Gly Asp Leu Trp Gly Gln Gly             100 105 110 Thr Leu Val Thr Val Ser Ser         115 <210> 93 <211> 119 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 93 Gln Val Thr Leu Lys Glu Ser Gly Pro Val Leu Val Lys Pro Thr Glu 1 5 10 15 Thr Leu Thr Leu Thr Cys Lys Val Ser Gly Ile Asp Leu Ser His Asp             20 25 30 Asp Ile Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val         35 40 45 Ser Ile Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Se     50 55 60 Gly Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val Val Leu 65 70 75 80 Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr Cys Ala                 85 90 95 Arg Gly Val Pro Ala Tyr Ser His Gly Gly Asp Leu Trp Gly Gln Gly             100 105 110 Thr Leu Val Thr Val Ser Ser         115 <210> 94 <211> 119 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 94 Gln Val Thr Leu Lys Glu Ser Gly Pro Val Leu Val Lys Pro Thr Glu 1 5 10 15 Thr Leu Thr Leu Thr Cys Lys Val Ser Gly Ile Asp Leu Ser His Glu             20 25 30 Asp Ile Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val         35 40 45 Ser Ile Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Se     50 55 60 Gly Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val Val Leu 65 70 75 80 Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr Cys Ala                 85 90 95 Arg Gly Val Pro Ala Tyr Ser His Gly Gly Asp Leu Trp Gly Gln Gly             100 105 110 Thr Leu Val Thr Val Ser Ser         115 <210> 95 <211> 119 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 95 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ile Asp Leu Ser His Glu             20 25 30 Asp Ile Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val         35 40 45 Ser Ile Ile Ser Tyr Ala Gly Ser Lys Tyr Tyr Ala Ser Trp Ala Lys     50 55 60 Gly Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val Val Leu 65 70 75 80 Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr Cys Ala                 85 90 95 Arg Gly Val Pro Ala Tyr Ser His Gly Gly Asp Leu Trp Gly Gln Gly             100 105 110 Thr Leu Val Thr Val Ser Ser         115 <210> 96 <211> 110 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 96 Asp Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Thr Ser Ser Gln Ser Val Tyr His Ala             20 25 30 Asn Trp Leu Ser Trp Phe Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu         35 40 45 Leu Ile Tyr Trp Ala Ser Thr Leu Ala Tyr Gly Val Ser Ser Phe     50 55 60 Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu 65 70 75 80 Gln Pro Glu Asp Ala Ala Thr Tyr Tyr Cys Ala Gly Gly Tyr Gly Gly                 85 90 95 Gly Arg Tyr Ala Phe Gly Gln Gly Thr Lys Val Glu Ile Lys             100 105 110 <210> 97 <211> 110 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 97 Asp Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Thr Thr Ser Gln Ser Val Tyr His Glu             20 25 30 Asn Trp Leu Ser Trp Phe Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu         35 40 45 Leu Ile Tyr Trp Ala Ser Thr Leu Ala Tyr Gly Val Ser Ser Phe     50 55 60 Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu 65 70 75 80 Gln Pro Glu Asp Ala Ala Thr Tyr Tyr Cys Ala Gly Gly Tyr Gly Gly                 85 90 95 Gly Arg Tyr Ala Phe Gly Gln Gly Thr Lys Val Glu Ile Lys             100 105 110 <210> 98 <211> 110 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 98 Asp Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Thr Ser Ser Gln Ser Val Phe His Glu             20 25 30 Asn Trp Leu Ser Trp Phe Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu         35 40 45 Leu Ile Tyr Trp Ala Ser Thr Leu Ala Trp Gly Val Ser Ser Arg Phe     50 55 60 Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu 65 70 75 80 Gln Pro Glu Asp Ala Ala Thr Tyr Tyr Cys Ala Gly Gly Tyr Gly Gly                 85 90 95 Gly Arg Tyr Ala Phe Gly Gln Gly Thr Lys Val Glu Ile Lys             100 105 110 <210> 99 <211> 110 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 99 Asp Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Thr Thr Ser Gln Ser Val Tyr His Glu             20 25 30 Asn Trp Leu Ser Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu         35 40 45 Leu Ile Tyr Trp Ala Ser Thr Leu Ala Tyr Gly Val Ser Ser Phe     50 55 60 Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu 65 70 75 80 Gln Pro Glu Asp Val Ala Thr Tyr Tyr Cys Ala Gly Gly Tyr Gly Gly                 85 90 95 Gly Arg Tyr Ala Phe Gly Gln Gly Thr Lys Val Glu Ile Lys             100 105 110 <210> 100 <211> 357 <212> DNA <213> Artificial sequence <220> An artificially synthesized sequence <400> 100 caggtgacac tgaaagaaag cggccccgtg ctggtgaagc caaccgagac actgactctg 60 acctgcacag tgagtgggat cgacctgagc cacgacgaca tctcctgggt gcggcaggca 120 cccggaaagg gcctggaatg ggtcggcatc attagctacg ccgggagcac atactatgcc 180 agctgggcta aaggaagact gactatctcc aaggacacct ctaaaaacca ggtggtcctg 240 actatgacca atatggaccc cgtggataca gcaacttact attgtgccag gggcgtccct 300 gcttactctc acggagggga tctgtgggga cagggaaccc tggtgacagt ctctagt 357 <210> 101 <211> 357 <212> DNA <213> Artificial sequence <220> An artificially synthesized sequence <400> 101 caggtgacac tgaaagaaag cggccccgtg ctggtgaagc caaccgagac actgactctg 60 acctgcacag tgagtgggat cgacctgagc cacgacgaca tctcctgggt gcggcaggca 120 cccggaaagg gcctggaatg ggtcggcatc attagctacg ccgggagcat gtactatgcc 180 agctgggcta aaggaagact gactatctcc aaggacacct ctaaaaacca ggtggtcctg 240 actatgacca atatggaccc cgtggataca gcaacttact attgtgccag gggcgtccct 300 gcttactctc acggagggga taagtgggga cagggaaccc tggtgacagt ctctagt 357 <210> 102 <211> 357 <212> DNA <213> Artificial sequence <220> An artificially synthesized sequence <400> 102 caggtgacac tgaaagaaag cggccccgtg ctggtgaagc caaccgagac actgactctg 60 acctgcacag tgagtgggat cgacctgagc cacaccgaca tctcctgggt gcggcaggca 120 cccggaaagg gcctggaatg ggtcggcatc attagctacg ccgggaagac atactatgcc 180 agctgggcta aaaaaagact gactatctcc aaggacacct ctaaaaacca ggtggtcctg 240 actatgacca atatggaccc cgtggataca gcaacttact attgtgccag gggcgtccct 300 gcttactctc acggagggga tctgtgggga cagggaaccc tggtgacagt ctctagt 357 <210> 103 <211> 357 <212> DNA <213> Artificial sequence <220> An artificially synthesized sequence <400> 103 caggtgacac tgaaagaaag cggccccgtg ctggtgaagc caaccgagac actgactctg 60 acctgcacag tgagtgggat cgacctgagc cacaccgaca tctcctgggt gcggcaggca 120 cccggaaagg gcctggaatg ggtcggcatc attagctacg ccgggaagaa atactatgcc 180 agctgggcta aaggaagact gactatctcc aaggacacct ctaaaaacca ggtggtcctg 240 actatgacca atatggaccc cgtggataca gcaacttact attgtgccag gggcgtccct 300 gcttactctc acggagggga tctgtgggga cagggaaccc tggtgacagt ctctagt 357 <210> 104 <211> 357 <212> DNA <213> Artificial sequence <220> An artificially synthesized sequence <400> 104 caggtgacac tgaaagaaag cggccccgtg ctggtgaagc caaccgagac actgactctg 60 acctgcacag tgagtgggat cgacctgagc cacaccgaca tctcctgggt gcggcaggca 120 cccggaaagg gcctggaatg ggtcggcatc attagctacg ccgggagcaa atacaaggcc 180 agctgggcta aaggaagact gactatctcc aaggacacct ctaaaaacca ggtggtcctg 240 actatgacca atatggaccc cgtggataca gcaacttact attgtgccag gggcgtccct 300 gcttactctc acggagggga tctgtgggga cagggaaccc tggtgacagt ctctagt 357 <210> 105 <211> 357 <212> DNA <213> Artificial sequence <220> An artificially synthesized sequence <400> 105 caggtgacac tgaaagaaag cggccccgtg ctggtgaagc caaccgagac actgactctg 60 acctgcacag tgagtgggat cgacctgagc cacgacgaca tctcctgggt gcggcaggca 120 cccggaaagg gcctggaatg ggtcggcatc attagctacg ccgggaagaa atactatgcc 180 agctgggcta aaggaagact gactatctcc aaggacacct ctaaaaacca ggtggtcctg 240 actatgacca atatggaccc cgtggataca gcaacttact attgtgccag gggcgtccct 300 gcttactctc acggagggga tctgtgggga cagggaaccc tggtgacagt ctctagt 357 <210> 106 <211> 357 <212> DNA <213> Artificial sequence <220> An artificially synthesized sequence <400> 106 caggtgcagc tggtcgaatc tggaggagga ctggtgcagc caggagggtc actgcgactg 60 agctgtgccg tgtccgggat cgacctgtca cacgacgata ttagctgggt gagacaggca 120 cccgggaagg gactggaatg ggtctctatc attagttacg ccggcagcac ctactatgcc 180 tcttgggcta aaggcaggct gaccatttct aaggacacaa gtaaaaacca ggtggtcctg 240 accatgacaa atatggaccc cgtggatact gcaacctact attgcgcccg gggcgtccct 300 gcttatagcc acggcggcga tctgtgggga caggggacac tggtgactgt cagctcc 357 <210> 107 <211> 357 <212> DNA <213> Artificial sequence <220> An artificially synthesized sequence <400> 107 caggtgacac tgaaagaaag cggccccgtg ctggtgaagc caaccgagac actgactctg 60 acctgcaaag tgagtgggat cgacctgagc cacgacgaca tctcctgggt gcggcaggca 120 cccggaaagg gcctggaatg ggtctccatc attagctacg ccgggagcac atactatgcc 180 agctgggcta aaggaagact gactatctcc aaggacacct ctaaaaacca ggtggtcctg 240 actatgacca atatggaccc cgtggataca gcaacttact attgtgccag gggcgtccct 300 gcttactctc acggagggga tctgtgggga cagggaaccc tggtgacagt ctctagt 357 <210> 108 <211> 357 <212> DNA <213> Artificial sequence <220> An artificially synthesized sequence <400> 108 caggtgacac tgaaagaaag cggccccgtg ctggtgaagc caaccgagac actgactctg 60 acctgcaaag tgagtgggat cgacctgagc cacgaggaca tctcctgggt gcggcaggca 120 cccggaaagg gcctggaatg ggtctccatc attagctacg ccgggagcac atactatgcc 180 agctgggcta aaggaagact gactatctcc aaggacacct ctaaaaacca ggtggtcctg 240 actatgacca atatggaccc cgtggataca gcaacttact attgtgccag gggcgtccct 300 gcttactctc acggagggga tctgtgggga cagggaaccc tggtgacagt ctctagt 357 <210> 109 <211> 357 <212> DNA <213> Artificial sequence <220> An artificially synthesized sequence <400> 109 caggtgcagc tggtcgaatc tggaggagga ctggtgcagc caggagggtc actgcgactg 60 agctgtgccg tgtccgggat cgacctgtca cacgaggata ttagctgggt gagacaggca 120 cccgggaagg gactggaatg ggtctctatc attagttacg ccggcagcaa gtactatgcc 180 tcttgggcta aaggcaggct gaccatttct aaggacacaa gtaaaaacca ggtggtcctg 240 accatgacaa atatggaccc cgtggatact gcaacctact attgcgcccg gggcgtccct 300 gcttatagcc acggcggcga tctgtgggga caggggacac tggtgactgt cagctcc 357 <210> 110 <211> 330 <212> DNA <213> Artificial sequence <220> An artificially synthesized sequence <400> 110 gacattgtga tgactcagtc tcctgccact ctgtcactga gccctggcga gcgagcaacc 60 ctgtcttgca ccagcagcca gtccgtgtac cacgccaatt ggctgagctg gttccagcag 120 aagccagggc agccccctaa actgctgatc tattgggcat caacactggc ctacggcgtc 180 ccctccagat tctccggatc tggcagtggg actgacttta ccctgaccat cagcagcctc 240 cagcccgagg atgccgctac ctactattgt gctggcgggt acggaggcgg gcggtatgca 300 tttggacagg gcacaaaggt ggaaatcaaa 330 <210> 111 <211> 330 <212> DNA <213> Artificial sequence <220> An artificially synthesized sequence <400> 111 gacattgtga tgactcagtc tcctgccact ctgtcactga gccctggcga gcgagcaacc 60 ctgtcttgca ccaccagcca gtccgtgtac cacgagaatt ggctgagctg gttccagcag 120 aagccagggc agccccctaa actgctgatc tattgggcat caacactggc ctacggcgtc 180 ccctccagat tctccggatc tggcagtggg actgacttta ccctgaccat cagcagcctc 240 cagcccgagg atgccgctac ctactattgt gctggcgggt acggaggcgg gcggtatgca 300 tttggacagg gcacaaaggt ggaaatcaaa 330 <210> 112 <211> 330 <212> DNA <213> Artificial sequence <220> An artificially synthesized sequence <400> 112 gacattgtga tgactcagtc tcctgccact ctgtcactga gccctggcga gcgagcaacc 60 ctgtcttgca ccagcagcca gtccgtgttc cacgagaatt ggctgagctg gttccagcag 120 aagccagggc agccccctaa actgctgatc tattgggcat caacactggc ctggggcgtc 180 ccctccagat tctccggatc tggcagtggg actgacttta ccctgaccat cagcagcctc 240 cagcccgagg atgccgctac ctactattgt gctggcgggt acggaggcgg gcggtatgca 300 tttggacagg gcacaaaggt ggaaatcaaa 330 <210> 113 <211> 330 <212> DNA <213> Artificial sequence <220> An artificially synthesized sequence <400> 113 gacattgtga tgactcagtc tcctgccact ctgtcactga gccctggcga gcgagcaacc 60 ctgtcttgca ccaccagcca gtccgtgtac cacgagaatt ggctgagctg gtaccagcag 120 aagccagggc agccccctaa actgctgatc tattgggcat caacactggc ctacggcgtc 180 ccctccagat tctccggatc tggcagtggg actgacttta ccctgaccat cagcagcctc 240 cagcccgagg atgtcgctac ctactattgt gctggcgggt acggaggcgg gcggtatgca 300 tttggacagg gcacaaaggt ggaaatcaaa 330 <210> 114 <211> 5 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 114 His Asp Asp Ile Ser 1 5 <210> 115 <211> 5 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 115 His Glu Asp Ile Ser 1 5 <210> 116 <211> 16 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 116 Ile Ile Ser Tyr Ala Gly Ser Met Tyr Tyr Ala Ser Trp Ala Lys Gly 1 5 10 15 <210> 117 <211> 16 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 117 Ile Ile Ser Tyr Ala Gly Lys Thr Tyr Tyr Ala Ser Trp Ala Lys Lys 1 5 10 15 <210> 118 <211> 16 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 118 Ile Ile Ser Tyr Ala Gly Lys Lys Tyr Tyr Ala Ser Trp Ala Lys Gly 1 5 10 15 <210> 119 <211> 16 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 119 Ile Ile Ser Tyr Ala Gly Ser Lys Tyr Lys Ala Ser Trp Ala Lys Gly 1 5 10 15 <210> 120 <211> 16 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 120 Ile Ile Ser Tyr Ala Gly Ser Lys Tyr Tyr Ala Ser Trp Ala Lys Gly 1 5 10 15 <210> 121 <211> 11 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 121 Gly Val Pro Ala Tyr Ser His Gly Gly Asp Lys 1 5 10 <210> 122 <211> 13 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 122 Thr Ser Ser Gln Ser Val Tyr His Ala Asn Trp Leu Ser 1 5 10 <210> 123 <211> 13 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 123 Thr Thr Ser Gln Ser Val Tyr His Glu Asn Trp Leu Ser 1 5 10 <210> 124 <211> 13 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 124 Thr Ser Ser Gln Ser Val Phe His Glu Asn Trp Leu Ser 1 5 10 <210> 125 <211> 7 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 125 Trp Ala Ser Thr Leu Ala Trp 1 5 <210> 126 <211> 5 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <220> <221> misc_feature <222> (1) <223> Xaa is Ser or His <220> <221> misc_feature <222> (2) (2) &Lt; 223 > Xaa is Tyr, Thr, Asp or Glu <400> 126 Xaa Xaa Asp Ile Ser 1 5 <210> 127 <211> 16 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <220> <221> misc_feature <222> (4) (4) <223> Xaa is Tyr or His <220> <221> misc_feature <222> (7) (7) <223> Xaa is Ser or Lys <220> <221> misc_feature &Lt; 222 > (8) &Lt; 223 > Xaa is Thr, Met or Lys <220> <221> misc_feature &Lt; 222 > (10) <223> Xaa is Tyr or Lys <220> <221> misc_feature &Lt; 222 > (11) <223> Xaa is Ala, Met or Glu <220> <221> misc_feature (12). (12) <223> Xaa is Ser or Glu <220> <221> misc_feature &Lt; 222 > (16) <223> Xaa is Gly or Lys <400> 127 Ile Ile Ser Xaa Ala Gly Xaa Xaa Tyr Xaa Xaa Xaa Trp Ala Lys Xaa 1 5 10 15 <210> 128 <211> 11 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <220> <221> misc_feature &Lt; 222 > (5) <223> Xaa is Tyr or His <220> <221> misc_feature <222> (7) (7) <223> Xaa is Thr or His <220> <221> misc_feature &Lt; 222 > (11) <223> Xaa is Leu or Lys <400> 128 Gly Val Pro Ala Xaa Ser Xaa Gly Gly Asp Xaa 1 5 10 <210> 129 <211> 13 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <220> <221> misc_feature <222> (1) <223> Xaa is Gln or Thr <220> <221> misc_feature <222> (2) (2) <223> Xaa is Ser or Thr <220> <221> misc_feature &Lt; 222 > (5) <223> Xaa is Ser or Glu <220> <221> misc_feature <222> (7) (7) &Lt; 223 > Xaa is Tyr or Phe <220> <221> misc_feature &Lt; 222 > (8) <223> Xaa is Asp or His <220> <221> misc_feature &Lt; 222 > (9) <223> Xaa is Asn, Asp, Ala or Glu <400> 129 Xaa Xaa Ser Gln Xaa Val Xaa Xaa Xaa Asn Trp Leu Ser 1 5 10 <210> 130 <211> 7 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <220> <221> misc_feature &Lt; 222 > (3) <223> Xaa is Ser or Glu <220> <221> misc_feature <222> (7) (7) &Lt; 223 > Xaa is Ser, Tyr, Phe or Trp <400> 130 Trp Ala Xaa Thr Leu Ala Xaa 1 5 <210> 131 <211> 10 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <220> <221> misc_feature &Lt; 222 > (8) <223> Xaa is Leu or Arg <400> 131 Ala Gly Gly Tyr Gly Gly Gly Xaa Tyr Ala 1 5 10 <210> 132 <211> 30 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 132 Gln Val Thr Leu Lys Glu Ser Gly Pro Val Leu Val Lys Pro Thr Glu 1 5 10 15 Thr Leu Thr Leu Thr Cys Thr Val Ser Gly Ile Asp Leu Ser             20 25 30 <210> 133 <211> 30 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 133 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ile Asp Leu Ser             20 25 30 <210> 134 <211> 30 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 134 Gln Val Thr Leu Lys Glu Ser Gly Pro Val Leu Val Lys Pro Thr Glu 1 5 10 15 Thr Leu Thr Leu Thr Cys Lys Val Ser Gly Ile Asp Leu Ser             20 25 30 <210> 135 <211> 14 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 135 Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Gly 1 5 10 <210> 136 <211> 14 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 136 Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser 1 5 10 <210> 137 <211> 32 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 137 Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val Val Leu Thr 1 5 10 15 Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr Cys Ala Arg             20 25 30 <210> 138 <211> 11 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 138 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 1 5 10 <210> 139 <211> 23 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 139 Asp Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys             20 <210> 140 <211> 15 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 140 Trp Phe Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr 1 5 10 15 <210> 141 <211> 15 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 141 Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr 1 5 10 15 <210> 142 <211> 32 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 142 Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 1 5 10 15 Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Ala Ala Thr Tyr Tyr Cys             20 25 30 <210> 143 <211> 32 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 143 Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 1 5 10 15 Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Val Ala Thr Tyr Tyr Cys             20 25 30 <210> 144 <211> 10 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 144 Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 1 5 10 <210> 145 <211> 121 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 145 Gln Ser Val Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr Pro 1 5 10 15 Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Arg Tyr Tyr             20 25 30 Val Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly         35 40 45 Ile Ile Tyr Thr Gly Gly Asn Thr Asn Tyr Ala Ser Trp Ala Lys Gly     50 55 60 Arg Phe Thr Ile Ser Lys Ala Ser Thr Thr Val Asp Leu Lys Met Thr 65 70 75 80 Gly Pro Thr Thr Glu Asp Thr Ala Thr Tyr Phe Cys Ala Gly Phe Leu                 85 90 95 Asp Tyr Ser His Tyr Thr Thr Gly Gly Tyr Tyr Leu Asp Leu Trp Gly             100 105 110 Pro Gly Thr Leu Val Thr Val Ser Ser         115 120 <210> 146 <211> 119 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 146 Gln Ser Leu Glu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly Thr 1 5 10 15 Leu Thr Leu Thr Cys Lys Ala Ser Gly Ile Asp Phe Ser Ser Tyr Tyr             20 25 30 Tyr Met Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile         35 40 45 Ala Cys Ile Tyr Ala Gly Ile Ser Gly Ser Thr Tyr Tyr Ala Ser Trp     50 55 60 Ala Lys Gly Arg Phe Thr Ile Ser Lys Thr Ser Ser Thr Thr Val Thr 65 70 75 80 Leu Gln Met Thr Ser Leu Thr Ala Ala Asp Thr Ala Thr Tyr Phe Cys                 85 90 95 Ala Arg Asp Pro Tyr His Phe Asp Tyr Gly Ser Leu Trp Gly Pro Gly             100 105 110 Thr Leu Val Thr Val Ser Ser         115 <210> 147 <211> 116 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 147 Gln Ser Leu Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr Pro 1 5 10 15 Leu Thr Leu Thr Cys Thr Val Ser Gly Ile Asp Leu Ser Arg Tyr Trp             20 25 30 Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly         35 40 45 Ile Ile Ser Ser Gly Gly Thr Thr Tyr Tyr Ala Ser Trp Ala Lys Gly     50 55 60 Arg Phe Thr Ile Ser Lys Thr Ser Thr Thr Val Asp Leu Lys Ile Thr 65 70 75 80 Ser Pro Thr Thr Glu Asp Thr Ala Thr Tyr Phe Cys Ala Arg Asp Ser                 85 90 95 Arg Tyr Gly Ala Ala Arg Leu Asp Leu Trp Gly Gln Gly Thr Leu Val             100 105 110 Thr Val Ser Ser         115 <210> 148 <211> 109 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 148 Gln Ser Val Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr Pro 1 5 10 15 Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Ser Tyr Ile             20 25 30 Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly         35 40 45 Phe Ile Tyr Val Ser Gly Ser Thr Tyr Tyr Ala Ser Trp Ala Lys Gly     50 55 60 Arg Phe Thr Ile Ser Arg Thr Ser Thr Thr Val Asp Leu Arg Ile Thr 65 70 75 80 Ser Pro Thr Thr Glu Asp Thr Ala Thr Tyr Phe Cys Val Arg Thr Trp                 85 90 95 Asp Leu Trp Gly Pro Gly Thr Leu Val Thr Val Ser Ser             100 105 <210> 149 <211> 115 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 149 Gln Ser Val Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr Pro 1 5 10 15 Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Ser Tyr Ala             20 25 30 Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly         35 40 45 Ile Ile Tyr Gly Val Gly Ser Thr Tyr Tyr Ala Ser Trp Ala Lys Gly     50 55 60 Arg Phe Thr Ile Ser Lys Thr Ser Thr Thr Val Asp Leu Lys Ile Ala 65 70 75 80 Ser Pro Thr Thr Glu Asp Thr Ala Thr Tyr Phe Cys Ala Arg Asp Asp                 85 90 95 Tyr Gly Trp Gly Tyr Thr Asn Leu Trp Gly Pro Gly Thr Leu Val Thr             100 105 110 Val Ser Ser         115 <210> 150 <211> 117 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 150 Gln Ser Val Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr Pro 1 5 10 15 Leu Thr Leu Thr Cys Thr Val Ser Gly Ile Asp Leu Ser Ser Ser Ser             20 25 30 Met Ile Trp Val Arg Gln Ala Pro Gly Glu Gly Leu Lys Tyr Ile Gly         35 40 45 Phe Ile Ser Lys Ser Gly Tyr Thr Tyr Tyr Ala Ser Trp Ala Lys Gly     50 55 60 Arg Phe Thr Ile Ser Lys Thr Ser Thr Thr Val Asp Leu Lys Ile Thr 65 70 75 80 Ser Pro Thr Thr Glu Asp Thr Ala Thr Tyr Phe Cys Ala Arg Gly Gly                 85 90 95 Tyr Ser Gly Asp Trp Asp Tyr Phe Thr Leu Trp Gly Pro Gly Thr Leu             100 105 110 Val Thr Val Ser Ser         115 <210> 151 <211> 112 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 151 Gln Val Leu Thr Gln Thr Pro Ser Ser Val Ala Val Val Gly Gly 1 5 10 15 Thr Val Thr Ile Asn Cys Gln Ala Ser Gln Ser Val Tyr Asn Asn Lys             20 25 30 Asn Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu         35 40 45 Ile Tyr Tyr Ala Ser Thr Leu Pro Ser Gly Val Ser Ser Arg Phe Lys     50 55 60 Gly Ser Gly Ser Gly Thr Gln Phe Thr Leu Thr Ile Ser Gly Val Gln 65 70 75 80 Cys Asp Asp Ala Thr Tyr Tyr Cys Gln Gly Glu Phe Ser Cys Gly                 85 90 95 Ser Ala Asp Cys Thr Ala Phe Gly Gly Gly Thr Lys Val Glu Ile Lys             100 105 110 <210> 152 <211> 112 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 152 Ala Leu Val Met Thr Gln Thr Pro Ala Ser Val Ser Ala Ala Val Gly 1 5 10 15 Gly Thr Val Thr Ile Asn Cys Gln Ala Ser Gln Ser Val Tyr Gly Gly             20 25 30 Asn Glu Leu Ser Trp Tyr Gln Gln Glu Pro Gly Gln Pro Pro Lys Leu         35 40 45 Leu Ile Tyr Ser Ala Ser Lys Leu Ala Ser Gly Val Ser Ser Arg Phe     50 55 60 Lys Gly Ser Gly Ser Gly Thr Gln Phe Thr Leu Thr Ile Ser Gly Val 65 70 75 80 Gln Cys Asp Asp Ala Ala Ala Tyr Tyr Cys Ala Gly Tyr Arg Thr Tyr                 85 90 95 Ser Asp Asp Asn Ala Phe Gly Gly Gly Thr Lys Val Glu Ile Lys             100 105 110 <210> 153 <211> 112 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 153 Gln Val Leu Thr Gln Thr Pro Ala Ser Val Ser Ala Ala Val Gly Gly 1 5 10 15 Thr Val Thr Ile Asn Cys Gln Ser Ser Gln Ser Val Ala Gly Asn Asp             20 25 30 Asn Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu         35 40 45 Ile Tyr Tyr Ala Ser Asn Leu Ala Ser Gly Val Ser Ser Arg Phe Lys     50 55 60 Gly Ser Gly Ser Gly Thr Arg Phe Thr Leu Thr Ile Ser Asp Val Gln 65 70 75 80 Cys Asp Asp Ala Thr Tyr Tyr Cys Leu Gly Asn Tyr Asp Cys Ser                 85 90 95 Ser Ala Asp Cys Asp Ala Phe Gly Gly Gly Thr Lys Val Glu Ile Lys             100 105 110 <210> 154 <211> 109 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 154 Gln Val Leu Thr Gln Thr Ser Ser Thr Ser Ala Val Val Gly Gly 1 5 10 15 Thr Val Thr Ile Asn Cys Gln Ser Ser Gln Ser Val Tyr Asp Asn Asn             20 25 30 Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Arg Leu         35 40 45 Ile Tyr Gly Ala Ser Thr Leu Asp Ser Gly Val Ser Ser Arg Phe Lys     50 55 60 Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Asp Leu Glu 65 70 75 80 Cys Asp Asp Ala Thr Tyr Tyr Cys Gln Gly Gly Tyr Ser Gly Asn                 85 90 95 Ile Tyr Pro Phe Gly Gly Gly Thr Lys Val Glu Ile Lys             100 105 <210> 155 <211> 111 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 155 Gln Val Leu Thr Gln Thr Pro Ser Ser Val Ser Ala Ala Val Gly Gly 1 5 10 15 Thr Val Thr Ile Asn Cys Gln Ser Ser Gln Ser Val Tyr Asn Asn Asn             20 25 30 Tyr Leu Ala Trp Phe Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu         35 40 45 Ile Tyr Asp Ala Ser Lys Leu Ala Ser Gly Val Ser Ser Arg Phe Lys     50 55 60 Gly Ser Gly Ser Gly Thr Gln Phe Thr Leu Thr Ile Ser Gly Val Gln 65 70 75 80 Cys Asp Asp Ala Ala Thr Tyr Tyr Cys Gln Gly Ser Tyr Tyr Ser Ser                 85 90 95 Gly Trp Tyr Arg Ala Phe Gly Gly Gly Thr Lys Val Glu Ile Lys             100 105 110 <210> 156 <211> 114 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 156 Ala Asp Ile Val Met Thr Gln Thr Pro Ala Ser Val Glu Ala Ala Val 1 5 10 15 Gly Gly Thr Val Thr Ile Lys Cys Gln Ala Ser Glu Ser Ile Gly Asn             20 25 30 Ala Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu         35 40 45 Ile Tyr Gly Ala Phe Asn Leu Glu Ser Gly Val Ser Ser Arg Phe Arg     50 55 60 Gly Ser Gly Ser Gly Thr Glu Tyr Thr Leu Thr Ile Ser Asp Leu Glu 65 70 75 80 Cys Asp Asp Ala Thr Tyr Tyr Cys Gln Gly Tyr Phe Trp Ser Ser                 85 90 95 Ser Thr Ile Tyr Ala Phe Trp Ala Phe Gly Gly Gly Thr Lys Val Glu             100 105 110 Ile Lys          <210> 157 <211> 5 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 157 Arg Tyr Tyr Val Ser 1 5 <210> 158 <211> 6 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 158 Ser Tyr Tyr Tyr Met Cys 1 5 <210> 159 <211> 5 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 159 Arg Tyr Trp Met Ser 1 5 <210> 160 <211> 5 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 160 Ser Tyr Ile Met Gly 1 5 <210> 161 <211> 5 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 161 Ser Tyr Ala Met Ser 1 5 <210> 162 <211> 5 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 162 Ser Ser Ser Met Ile 1 5 <210> 163 <211> 16 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 163 Ile Ile Tyr Thr Gly Gly Asn Thr Asn Tyr Ala Ser Trp Ala Lys Gly 1 5 10 15 <210> 164 <211> 18 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 164 Cys Ile Tyr Ala Gly Ile Ser Gly Ser Thr Tyr Tyr Ala Ser Trp Ala 1 5 10 15 Lys Gly          <210> 165 <211> 16 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 165 Ile Ile Ser Ser Gly Gly Thr Thr Tyr Tyr Ala Ser Trp Ala Lys Gly 1 5 10 15 <210> 166 <211> 16 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 166 Phe Ile Tyr Val Ser Gly Ser Thr Tyr Tyr Ala Ser Trp Ala Lys Gly 1 5 10 15 <210> 167 <211> 16 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 167 Ile Ile Tyr Gly Val Gly Ser Thr Tyr Tyr Ala Ser Trp Ala Lys Gly 1 5 10 15 <210> 168 <211> 16 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 168 Phe Ile Ser Lys Ser Gly Tyr Thr Tyr Tyr Ala Ser Trp Ala Lys Gly 1 5 10 15 <210> 169 <211> 16 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 169 Phe Leu Asp Tyr Ser His Tyr Thr Thr Gly Gly Tyr Tyr Leu Asp Leu 1 5 10 15 <210> 170 <211> 10 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 170 Asp Pro Tyr His Phe Asp Tyr Gly Ser Leu 1 5 10 <210> 171 <211> 11 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 171 Asp Ser Arg Tyr Gly Ala Ala Arg Leu Asp Leu 1 5 10 <210> 172 <211> 4 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 172 Thr Trp Asp Leu One <210> 173 <211> 10 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 173 Asp Asp Tyr Gly Trp Gly Tyr Thr Asn Leu 1 5 10 <210> 174 <211> 12 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 174 Gly Gly Tyr Ser Gly Asp Trp Asp Tyr Phe Thr Leu 1 5 10 <210> 175 <211> 13 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 175 Gln Ala Ser Gln Ser Val Tyr Asn Asn Lys Asn Leu Ala 1 5 10 <210> 176 <211> 13 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 176 Gln Ala Ser Gln Ser Val Tyr Gly Gly Asn Glu Leu Ser 1 5 10 <210> 177 <211> 13 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 177 Gln Ser Ser Gln Ser Val Ala Gly Asn Asp Asn Leu Ala 1 5 10 <210> 178 <211> 13 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 178 Gln Ser Ser Gln Ser Val Tyr Asp Asn Asn Trp Leu Ala 1 5 10 <210> 179 <211> 13 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 179 Gln Ser Ser Gln Ser Val Tyr Asn Asn Asn Tyr Leu Ala 1 5 10 <210> 180 <211> 11 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 180 Gln Ala Ser Glu Ser Ile Gly Asn Ala Leu Ala 1 5 10 <210> 181 <211> 7 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 181 Tyr Ala Ser Thr Leu Pro Ser 1 5 <210> 182 <211> 7 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 182 Ser Ala Ser Lys Leu Ala Ser 1 5 <210> 183 <211> 7 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 183 Tyr Ala Ser Asn Leu Ala Ser 1 5 <210> 184 <211> 7 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 184 Gly Ala Ser Thr Leu Asp Ser 1 5 <210> 185 <211> 7 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 185 Asp Ala Ser Lys Leu Ala Ser 1 5 <210> 186 <211> 7 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 186 Gly Ala Phe Asn Leu Glu Ser 1 5 <210> 187 <211> 13 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 187 Gln Gly Glu Phe Ser Cys Gly Ser Ala Asp Cys Thr Ala 1 5 10 <210> 188 <211> 12 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 188 Ala Gly Tyr Arg Thr Tyr Ser Asp Asp Asp Asn Ala 1 5 10 <210> 189 <211> 13 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 189 Leu Gly Asn Tyr Asp Cys Ser Ser Ala Asp Cys Asp Ala 1 5 10 <210> 190 <211> 10 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 190 Gln Gly Gly Tyr Ser Gly Asn Ile Tyr Pro 1 5 10 <210> 191 <211> 12 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 191 Gln Gly Ser Tyr Tyr Ser Ser Gly Trp Tyr Arg Ala 1 5 10 <210> 192 <211> 15 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 192 Gln Gly Tyr Phe Trp Ser Ser Ser Thr Ile Tyr Ala Phe Trp Ala 1 5 10 15 <210> 193 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 193 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Arg Arg Gly Pro Lys Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu             180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 305 310 315 320 Gln Lys Ser Leu Ser Leu Ser Pro                 325 <210> 194 <211> 324 <212> DNA <213> Artificial sequence <220> An artificially synthesized sequence <400> 194 cgtacggtgg ctgcaccatc tgtcttcatc ttcccgccat ctgatgagca gttgaaatct 60 ggaactgcct ctgttgtgtg cctgctgaat aacttctatc ccagagaggc caaagtacag 120 tggaaggtgg ataacgccct ccaatcgggt aactcccagg agagtgtcac agagcaggac 180 agtaaggact gcacctacag tctcagtagt accctgacgc tgtccaaagc agactacgag 240 aaacacaaag tctacgcctg cgaagtcacc catcagggcc tgtcctcgcc cgtcacaaag 300 tccttcaaca ggggagagtg ttga 324 <210> 195 <211> 330 <212> PRT <213> Homo sapiens <400> 195 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu             180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu 225 230 235 240 Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 305 310 315 320 Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys                 325 330 <210> 196 <211> 326 <212> PRT <213> Homo sapiens <400> 196 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg 1 5 10 15 Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Asn Phe Gly Thr Gln Thr 65 70 75 80 Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro             100 105 110 Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp         115 120 125 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp     130 135 140 Val Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly 145 150 155 160 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn                 165 170 175 Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp             180 185 190 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro         195 200 205 Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu     210 215 220 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn 225 230 235 240 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile                 245 250 255 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr             260 265 270 Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys         275 280 285 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys     290 295 300 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 305 310 315 320 Ser Leu Ser Pro Gly Lys                 325 <210> 197 <211> 377 <212> PRT <213> Homo sapiens <400> 197 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Thr Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Arg Val Glu Leu Lys Thr Pro Leu Gly Asp Thr Thr His Thr Cys Pro             100 105 110 Arg Cys Pro Glu Pro Lys Ser Cys Asp Thr Pro Pro Pro Cys Pro Arg         115 120 125 Cys Pro Glu Pro Lys Ser Cys Asp Thr Pro Pro Pro Cys Pro Arg Cys     130 135 140 Pro Glu Pro Lys Ser Cys Asp Thr Pro Pro Pro Cys Pro Arg Cys Pro 145 150 155 160 Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys                 165 170 175 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val             180 185 190 Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln Phe Lys Trp Tyr         195 200 205 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu     210 215 220 Gln Tyr Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Leu His 225 230 235 240 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys                 245 250 255 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln             260 265 270 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met         275 280 285 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro     290 295 300 Ser Asp Ile Ala Val Glu Trp Glu Ser Ser Gly Gln Pro Glu Asn Asn 305 310 315 320 Tyr Asn Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu                 325 330 335 Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Ile             340 345 350 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn Arg Phe Thr Gln         355 360 365 Lys Ser Leu Ser Leu Ser Pro Gly Lys     370 375 <210> 198 <211> 327 <212> PRT <213> Homo sapiens <400> 198 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg 1 5 10 15 Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Lys Thr 65 70 75 80 Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro Ala Pro             100 105 110 Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys         115 120 125 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val     130 135 140 Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp 145 150 155 160 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe                 165 170 175 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp             180 185 190 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu         195 200 205 Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg     210 215 220 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys 225 230 235 240 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp                 245 250 255 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys             260 265 270 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser         275 280 285 Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser     290 295 300 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 305 310 315 320 Leu Ser Leu Ser Leu Gly Lys                 325 <210> 199 <211> 1125 <212> DNA <213> Homo sapiens <400> 199 atgtggttct tgacaactct gctcctttgg gttccagttg atgggcaagt ggacaccaca 60 aaggcagtga tcactttgca gcctccatgg gtcagcgtgt tccaagagga aaccgtaacc 120 ttgcactgtg aggtgctcca tctgcctggg agcagctcta cacagtggtt tctcaatggc 180 acagccactc agacctcgac ccccagctac agaatcacct ctgccagtgt caatgacagt 240 ggtgaataca ggtgccagag aggtctctca gggcgaagtg accccataca gctggaaatc 300 cacagaggct ggctactact gcaggtctcc agcagagtct tcacggaagg agaacctctg 360 gccttgaggt gtcatgcgtg gaaggataag ctggtgaca atgtgcttta ctatcgaaat 420 ggcaaagcct ttaagttttt ccactggaat tctaacctca ccattctgaa aaccaacata 480 agtcacaatg gcacctacca ttgctcaggc atgggaaagc atcgctacac atcagcagga 540 atatctgtca ctgtgaaaga gctatttcca gctccagtgc tgaatgcatc tgtgacatcc 600 ccactcctgg aggggaatct ggtcaccctg agctgtgaaa caaagttgct cttgcagagg 660 cctggtttgc agctttactt ctccttctac atgggagag agaccctgcg aggcaggaac 720 acatcctctg aataccaaat actaactgct agaagagaag actctgggtt atactggtgc 780 gaggctgcca cagaggatgg aaatgtcctt aagcgcagcc ctgagttgga gcttcaagtg 840 cttggcctcc agttaccaac tcctgtctgg tttcatgtcc ttttctatct ggcagtggga 900 ataatgtttt tagtgaacac tgttctctgg gtgacaatac gtaaagaact gaaaagaaag 960 aaaaagtggg atttagaaat ctctttggat tctggtcatg agaagaaggt aatttccagc 1020 cttcaagaag acagacattt agaagaagag ctgaaatgtc aggaacaaaa agaagaacag 1080 ctgcaggaag gggtgcaccg gaaggagccc cagggggcca cgtag 1125 <210> 200 <211> 951 <212> DNA <213> Homo sapiens <400> 200 atgactatgg agacccaaat gtctcagaat gtatgtccca gaaacctgtg gctgcttcaa 60 ccattgacag ttttgctgct gctggcttct gcagacagtc aagctgctcc cccaaaggct 120 gtgctgaaac ttgagccccc gtggatcaac gtgctccagg aggactctgt gactctgaca 180 tgccaggggg ctcgcagccc tgagagcgac tccattcagt ggttccacaa tgggaatctc 240 attcccaccc acacgcagcc cagctacagg ttcaaggcca acaacaatga cagcggggag 300 tacacgtgcc agactggcca gaccagcctc agcgaccctg tgcatctgac tgtgctttcc 360 gaatggctgg tgctccagac ccctcacctg gagttccagg agggagaaac catcatgctg 420 aggtgccaca gctggaagga caagcctctg gtcaaggtca cattcttcca gaatggaaaa 480 tcccagaaat tctcccattt ggatcccacc ttctccatcc cacaagcaaa ccacagtcac 540 agtggtgatt accactgcac aggaaacata ggctacacgc tgttctcatc caagcctgtg 600 accatcactg tccaagtgcc cagcatgggc agctcttcac caatgggggt cattgtggct 660 gtggtcattg cgactgctgt agcagccatt gttgctgctg tagtggcctt gatctactgc 720 aggaaaaagc ggatttcagc caattccact gatcctgtga aggctgccca atttgagcca 780 cctggacgtc aaatgattgc catcagaaag agacaacttg aagaaaccaa caatgactat 840 gaaacagctg acggcggcta catgactctg aaccccaggg cacctactga cgatgataaa 900 aacatctacc tgactcttcc tcccaacgac catgtcaaca gtaataacta a 951 <210> 201 <211> 954 <212> DNA <213> Homo sapiens <400> 201 atgactatgg agacccaaat gtctcagaat gtatgtccca gaaacctgtg gctgcttcaa 60 ccattgacag ttttgctgct gctggcttct gcagacagtc aagctgcagc tcccccaaag 120 gctgtgctga aacttgagcc cccgtggatc aacgtgctcc aggaggactc tgtgactctg 180 acatgccagg gggctcgcag ccctgagagc gactccattc agtggttcca caatgggaat 240 ctcattccca cccacacgca gcccagctac aggttcaagg ccaacaacaa tgacagcggg 300 gagtacacgt gccagactgg ccagaccagc ctcagcgacc ctgtgcatct gactgtgctt 360 tccgaatggc tggtgctcca gacccctcac ctggagttcc aggagggaga aaccatcatg 420 ctgaggtgcc acagctggaa ggacaagcct ctggtcaagg tcacattctt ccagaatgga 480 aaatcccaga aattctccca tttggatccc accttctcca tcccacaagc aaaccacagt 540 cacagtggtg attaccactg cacaggaaac ataggctaca cgctgttctc atccaagcct 600 gtgaccatca ctgtccaagt gcccagcatg ggcagctctt caccaatggg gatcattgtg 660 gctgtggtca ttgcgactgc tgtagcagcc attgttgctg ctgtagtggc cttgatctac 720 tgcaggaaaa agcggatttc agccaattcc actgatcctg tgaaggctgc ccaatttgag 780 ccacctggac gtcaaatgat tgccatcaga aagagacaac ttgaagaaac caacaatgac 840 tatgaaacag ctgacggcgg ctacatgact ctgaacccca gggcacctac tgacgatgat 900 aaaaacatct acctgactct tcctcccaac gaccatgtca acagtaataa ctaa 954 <210> 202 <211> 876 <212> DNA <213> Homo sapiens <400> 202 atgggaatcc tgtcattctt acctgtcctt gccactgaga gtgactgggc tgactgcaag 60 tccccccagc cttggggtca tatgcttctg tggacagctg tgctattcct ggctcctgtt 120 gctgggacac ctgcagctcc cccaaaggct gtgctgaaac tcgagcccca gtggatcaac 180 gtgctccagg aggactctgt gactctgaca tgccggggga ctcacagccc tgagagcgac 240 tccattcagt ggttccacaa tgggaatctc attcccaccc acacgcagcc cagctacagg 300 ttcaaggcca acaacaatga cagcggggag tacacgtgcc agactggcca gaccagcctc 360 agcgaccctg tgcatctgac tgtgctttct gagtggctgg tgctccagac ccctcacctg 420 gagttccagg agggagaaac catcgtgctg aggtgccaca gctggaagga caagcctctg 480 gtcaaggtca cattcttcca gaatggaaaa tccaagaaat tttcccgttc ggatcccaac 540 ttctccatcc cacaagcaaa ccacagtcac agtggtgatt accactgcac aggaaacata 600 ggctacacgc tgtactcatc caagcctgtg accatcactg tccaagctcc cagctcttca 660 ccgatgggga tcattgtggc tgtggtcact gggattgctg tagcggccat tgttgctgct 720 gtagtggcct tgatctactg caggaaaaag cggatttcag ccaatcccac taatcctgat 780 gaggctgaca aagttggggc tgagaacaca atcacctatt cacttctcat gcacccggat 840 gctctggaag agcctgatga ccagaaccgt atttag 876 <210> 203 <211> 933 <212> DNA <213> Homo sapiens <400> 203 atgggaatcc tgtcattctt acctgtcctt gccactgaga gtgactgggc tgactgcaag 60 tccccccagc cttggggtca tatgcttctg tggacagctg tgctattcct ggctcctgtt 120 gctgggacac ctgcagctcc cccaaaggct gtgctgaaac tcgagcccca gtggatcaac 180 gtgctccagg aggactctgt gactctgaca tgccggggga ctcacagccc tgagagcgac 240 tccattcagt ggttccacaa tgggaatctc attcccaccc acacgcagcc cagctacagg 300 ttcaaggcca acaacaatga cagcggggag tacacgtgcc agactggcca gaccagcctc 360 agcgaccctg tgcatctgac tgtgctttct gagtggctgg tgctccagac ccctcacctg 420 gagttccagg agggagaaac catcgtgctg aggtgccaca gctggaagga caagcctctg 480 gtcaaggtca cattcttcca gaatggaaaa tccaagaaat tttcccgttc ggatcccaac 540 ttctccatcc cacaagcaaa ccacagtcac agtggtgatt accactgcac aggaaacata 600 ggctacacgc tgtactcatc caagcctgtg accatcactg tccaagctcc cagctcttca 660 ccgatgggga tcattgtggc tgtggtcact gggattgctg tagcggccat tgttgctgct 720 gtagtggcct tgatctactg caggaaaaag cggatttcag ctctcccagg ataccctgag 780 tgcagggaaa tgggagagac cctccctgag aaaccagcca atcccactaa tcctgatgag 840 gctgacaaag ttggggctga gaacacaatc acctattcac ttctcatgca cccggatgct 900 ctggaagagc ctgatgacca gaaccgtatt tag 933 <210> 204 <211> 765 <212> DNA <213> Homo sapiens <400> 204 atgtggcagc tgctcctccc aactgctctg ctacttctag tttcagctgg catgcggact 60 gaagatctcc caaaggctgt ggtgttcctg gagcctcaat ggtacagggt gctcgagaag 120 gacagtgtga ctctgaagtg ccagggagcc tactcccctg aggacaattc cacacagtgg 180 tttcacaatg agagcctcat ctcaagccag gcctcgagct acttcattga cgctgccaca 240 gttgacgaca gtggagagta caggtgccag acaaacctct ccaccctcag tgacccggtg 300 cagctagaag tccatatcgg ctggctgttg ctccaggccc ctcggtgggt gttcaaggag 360 gaagacccta ttcacctgag gtgtcacagc tggaagaaca ctgctctgca taaggtcaca 420 tatttacaga atggcaaagg caggaagtat tttcatcata attctgactt ctacattcca 480 aaagccacac tcaaagacag cggctcctac ttctgcaggg ggcttgttgg gagtaaaaat 540 gtgtcttcag agactgtgaa catcaccatc actcaaggtt tgtcagtgtc aaccatctca 600 tcattctttc cacctgggta ccaagtctct ttctgcttgg tgatggtact cctttttgca 660 gtggacacag gactatattt ctctgtgaag acaaacattc gaagctcaac aagagactgg 720 aaggaccata aatttaaatg gagaaaggac cctcaagaca aatga 765 <210> 205 <211> 765 <212> DNA <213> Homo sapiens <400> 205 atgtggcagc tgctcctccc aactgctctg ctacttctag tttcagctgg catgcggact 60 gaagatctcc caaaggctgt ggtgttcctg gagcctcaat ggtacagggt gctcgagaag 120 gacagtgtga ctctgaagtg ccagggagcc tactcccctg aggacaattc cacacagtgg 180 tttcacaatg agagcctcat ctcaagccag gcctcgagct acttcattga cgctgccaca 240 gtcgacgaca gtggagagta caggtgccag acaaacctct ccaccctcag tgacccggtg 300 cagctagaag tccatatcgg ctggctgttg ctccaggccc ctcggtgggt gttcaaggag 360 gaagacccta ttcacctgag gtgtcacagc tggaagaaca ctgctctgca taaggtcaca 420 tatttacaga atggcaaagg caggaagtat tttcatcata attctgactt ctacattcca 480 aaagccacac tcaaagacag cggctcctac ttctgcaggg ggctttttgg gagtaaaaat 540 gtgtcttcag agactgtgaa catcaccatc actcaaggtt tggcagtgtc aaccatctca 600 tcattctttc cacctgggta ccaagtctct ttctgcttgg tgatggtact cctttttgca 660 gtggacacag gactatattt ctctgtgaag acaaacattc gaagctcaac aagagactgg 720 aaggaccata aatttaaatg gagaaaggac cctcaagaca aatga 765 <210> 206 <211> 702 <212> DNA <213> Homo sapiens <400> 206 atgtggcagc tgctcctccc aactgctctg ctacttctag tttcagctgg catgcggact 60 gaagatctcc caaaggctgt ggtgttcctg gagcctcaat ggtacagcgt gcttgagaag 120 gacagtgtga ctctgaagtg ccagggagcc tactcccctg aggacaattc cacacagtgg 180 tttcacaatg agagcctcat ctcaagccag gcctcgagct acttcattga cgctgccaca 240 gtcaacgaca gtggagagta caggtgccag acaaacctct ccaccctcag tgacccggtg 300 cagctagaag tccatatcgg ctggctgttg ctccaggccc ctcggtgggt gttcaaggag 360 gaagacccta ttcacctgag gtgtcacagc tggaagaaca ctgctctgca taaggtcaca 420 tatttacaga atggcaaaga caggaagtat tttcatcata attctgactt ccacattcca 480 aaagccacac tcaaagatag cggctcctac ttctgcaggg ggcttgttgg gagtaaaaat 540 gtgtcttcag agactgtgaa catcaccatc actcaaggtt tggcagtgtc aaccatctca 600 tcattctctc cacctgggta ccaagtctct ttctgcttgg tgatggtact cctttttgca 660 gtggacacag gactatattt ctctgtgaag acaaacattt ga 702 <210> 207 <211> 374 <212> PRT <213> Homo sapiens <400> 207 Met Trp Phe Leu Thr Thr Leu Leu Leu Trp Val Pro Val Asp Gly Gln 1 5 10 15 Val Asp Thr Thr Lys Ala Val Ile Thr Leu Gln Pro Pro Trp Val Ser             20 25 30 Val Phe Gln Glu Glu Thr Val Thr Leu His Cys Glu Val Leu His Leu         35 40 45 Pro Gly Ser Ser Ser Thr Gln Trp Phe Leu Asn Gly Thr Ala Thr Gln     50 55 60 Thr Ser Thr Pro Ser Tyr Arg Ile Thr Ser Ala Ser Val Asn Ser Ser 65 70 75 80 Gly Glu Tyr Arg Cys Gln Arg Gly Leu Ser Gly Arg Ser Asp Pro Ile                 85 90 95 Gln Leu Glu Ile His Arg Gly Trp Leu Leu Leu Gln Val Ser Ser Arg             100 105 110 Val Phe Thr Glu Gly Glu Pro Leu Ala Leu Arg Cys His Ala Trp Lys         115 120 125 Asp Lys Leu Val Tyr Asn Val Leu Tyr Tyr Arg Asn Gly Lys Ala Phe     130 135 140 Lys Phe Phe His Trp Asn Ser Asn Leu Thr Ile Leu Lys Thr Asn Ile 145 150 155 160 Ser His Asn Gly Thr Tyr His Cys Ser Gly Met Gly Lys His Arg Tyr                 165 170 175 Thr Ser Ala Gly Ile Ser Val Thr Val Lys Glu Leu Phe Pro Ala Pro             180 185 190 Val Leu Asn Ala Ser Val Thr Ser Pro Leu Leu Glu Gly Asn Leu Val         195 200 205 Thr Leu Ser Cys Glu Thr Lys Leu Leu Leu Gln Arg Pro Gly Leu Gln     210 215 220 Leu Tyr Phe Ser Phe Tyr Met Gly Ser Lys Thr Leu Arg Gly Arg Asn 225 230 235 240 Thr Ser Ser Glu Tyr Gln Ile Leu Thr Ala Arg Arg Glu Asp Ser Gly                 245 250 255 Leu Tyr Trp Cys Glu Ala Ala Thr Glu Asp Gly Asn Val Leu Lys Arg             260 265 270 Ser Pro Glu Leu Glu Leu Gln Val Leu Gly Leu Gln Leu Pro Thr Pro         275 280 285 Val Trp Phe His Val Leu Phe Tyr Leu Ala Val Gly Ile Met Phe Leu     290 295 300 Val Asn Thr Val Leu Trp Val Thr Ile Arg Lys Glu Leu Lys Arg Lys 305 310 315 320 Lys Lys Trp Asp Leu Glu Ile Ser Leu Asp Ser Gly His Glu Lys Lys                 325 330 335 Val Ile Ser Ser Leu Gln Glu Asp Arg His Leu Glu Glu Glu Leu Lys             340 345 350 Cys Gln Glu Gln Lys Glu Glu Glu Leu Gln Glu Gly Val His Arg Lys         355 360 365 Glu Pro Gln Gly Ala Thr     370 <210> 208 <211> 316 <212> PRT <213> Homo sapiens <400> 208 Met Thr Met Glu Thr Gln Met Ser Gln Asn Val Cys Pro Arg Asn Leu 1 5 10 15 Trp Leu Leu Gln Pro Leu Thr Val Leu Leu Leu Leu Ala Ser Ala Asp             20 25 30 Ser Gln Ala Ala Pro Pro Lys Ala Val Leu Lys Leu Glu Pro Pro Trp         35 40 45 Ile Asn Val Leu Gln Glu Asp Ser Val Thr Leu Thr Cys Gln Gly Ala     50 55 60 Arg Ser Pro Glu Ser Asp Ser Ile Gln Trp Phe His Asn Gly Asn Leu 65 70 75 80 Ile Pro Thr His Thr Gln Pro Ser Tyr Arg Phe Lys Ala Asn Asn Asn                 85 90 95 Asp Ser Gly Glu Tyr Thr Cys Gln Thr Gly Gln Thr Ser Leu Ser Asp             100 105 110 Pro Val His Leu Thr Val Leu Ser Glu Trp Leu Val Leu Gln Thr Pro         115 120 125 His Leu Glu Phe Gln Glu Gly Glu Thr Ile Met Leu Arg Cys His Ser     130 135 140 Trp Lys Asp Lys Pro Leu Val Lys Val Thr Phe Phe Gln Asn Gly Lys 145 150 155 160 Ser Gln Lys Phe Ser His Leu Asp Pro Thr Phe Ser Ile Pro Gln Ala                 165 170 175 Asn His Ser His Ser Gly Asp Tyr His Cys Thr Gly Asn Ile Gly Tyr             180 185 190 Thr Leu Phe Ser Ser Lys Pro Val Thr Ile Thr Val Gln Val Ser Ser         195 200 205 Met Gly Ser Ser Ser Pro Met Gly Val Ile Val Ala Val Val Ile Ala     210 215 220 Thr Ala Val Ala Ala Ile Val Ala Ala Val Ala Leu Ile Tyr Cys 225 230 235 240 Arg Lys Lys Arg Ile Ser Ala Asn Ser Thr Asp Pro Val Lys Ala Ala                 245 250 255 Gln Phe Glu Pro Pro Gly Arg Gln Met Ile Ala Ile Arg Lys Arg Gln             260 265 270 Leu Glu Glu Thr Asn Asn Asp Tyr Glu Thr Ala Asp Gly Gly Tyr Met         275 280 285 Thr Leu Asn Pro Arg Ala Pro Thr Asp Asp Asp Lys Asn Ile Tyr Leu     290 295 300 Thr Leu Pro Pro Asn Asp His Val Asn Ser Asn Asn 305 310 315 <210> 209 <211> 317 <212> PRT <213> Homo sapiens <400> 209 Met Thr Met Glu Thr Gln Met Ser Gln Asn Val Cys Pro Arg Asn Leu 1 5 10 15 Trp Leu Leu Gln Pro Leu Thr Val Leu Leu Leu Leu Ala Ser Ala Asp             20 25 30 Ser Gln Ala Ala Pro Pro Lys Ala Val Leu Lys Leu Glu Pro Pro         35 40 45 Trp Ile Asn Val Leu Gln Glu Asp Ser Val Thr Leu Thr Cys Gln Gly     50 55 60 Ala Arg Ser Pro Glu Ser Asp Ser Ile Gln Trp Phe His Asn Gly Asn 65 70 75 80 Leu Ile Pro Thr His Thr Gln Pro Ser Tyr Arg Phe Lys Ala Asn Asn                 85 90 95 Asn Asp Ser Gly Glu Tyr Thr Cys Gln Thr Gly Gln Thr Ser Leu Ser             100 105 110 Asp Pro Val His Leu Thr Val Leu Ser Glu Trp Leu Val Leu Gln Thr         115 120 125 Pro His Leu Glu Phe Gln Glu Gly Glu Thr Ile Met Leu Arg Cys His     130 135 140 Ser Trp Lys Asp Lys Pro Leu Val Lys Val Thr Phe Phe Gln Asn Gly 145 150 155 160 Lys Ser Gln Lys Phe Ser His Leu Asp Pro Thr Phe Ser Ile Pro Gln                 165 170 175 Ala Asn His Ser Ser Gly Asp Tyr His Cys Thr Gly Asn Ile Gly             180 185 190 Tyr Thr Leu Phe Ser Ser Lys Pro Val Thr Ile Thr Val Gln Val Pro         195 200 205 Ser Met Gly Ser Ser Ser Pro Met Gly Ile Ile Val Ala Val Val Ile     210 215 220 Ala Thr Ala Val Ala Ala Ile Val Ala Ala Val Ala Leu Ile Tyr 225 230 235 240 Cys Arg Lys Lys Arg Ile Ser Ala Asn Ser Thr Asp Pro Val Lys Ala                 245 250 255 Ala Gln Phe Glu Pro Pro Gly Arg Gln Met Ile Ala Ile Arg Lys Arg             260 265 270 Gln Leu Glu Glu Thr Asn Asn Asp Tyr Glu Thr Ala Asp Gly Gly Tyr         275 280 285 Met Thr Leu Asn Pro Arg Ala Pro Thr Asp Asp Asp Lys Asn Ile Tyr     290 295 300 Leu Thr Leu Pro Pro Asn Asp His Val Asn Ser Asn Asn 305 310 315 <210> 210 <211> 218 <212> PRT <213> Homo sapiens <400> 210 Met Thr Met Glu Thr Gln Met Ser Gln Asn Val Cys Pro Arg Asn Leu 1 5 10 15 Trp Leu Leu Gln Pro Leu Thr Val Leu Leu Leu Leu Ala Ser Ala Asp             20 25 30 Ser Gln Ala Ala Pro Pro Lys Ala Val Leu Lys Leu Glu Pro Pro         35 40 45 Trp Ile Asn Val Leu Gln Glu Asp Ser Val Thr Leu Thr Cys Gln Gly     50 55 60 Ala Arg Ser Pro Glu Ser Asp Ser Ile Gln Trp Phe His Asn Gly Asn 65 70 75 80 Leu Ile Pro Thr His Thr Gln Pro Ser Tyr Arg Phe Lys Ala Asn Asn                 85 90 95 Asn Asp Ser Gly Glu Tyr Thr Cys Gln Thr Gly Gln Thr Ser Leu Ser             100 105 110 Asp Pro Val His Leu Thr Val Leu Ser Glu Trp Leu Val Leu Gln Thr         115 120 125 Pro His Leu Glu Phe Gln Glu Gly Glu Thr Ile Met Leu Arg Cys His     130 135 140 Ser Trp Lys Asp Lys Pro Leu Val Lys Val Thr Phe Phe Gln Asn Gly 145 150 155 160 Lys Ser Gln Lys Phe Ser Arg Leu Asp Pro Thr Phe Ser Ile Pro Gln                 165 170 175 Ala Asn His Ser Ser Gly Asp Tyr His Cys Thr Gly Asn Ile Gly             180 185 190 Tyr Thr Leu Phe Ser Ser Lys Pro Val Thr Ile Thr Val Gln Val Pro         195 200 205 Ser Met Gly Ser Ser Ser Pro Gly Ile     210 215 <210> 211 <211> 218 <212> PRT <213> Homo sapiens <400> 211 Met Thr Met Glu Thr Gln Met Ser Gln Asn Val Cys Pro Arg Asn Leu 1 5 10 15 Trp Leu Leu Gln Pro Leu Thr Val Leu Leu Leu Leu Ala Ser Ala Asp             20 25 30 Ser Gln Ala Ala Pro Pro Lys Ala Val Leu Lys Leu Glu Pro Pro         35 40 45 Trp Ile Asn Val Leu Gln Glu Asp Ser Val Thr Leu Thr Cys Gln Gly     50 55 60 Ala Arg Ser Pro Glu Ser Asp Ser Ile Gln Trp Phe His Asn Gly Asn 65 70 75 80 Leu Ile Pro Thr His Thr Gln Pro Ser Tyr Arg Phe Lys Ala Asn Asn                 85 90 95 Asn Asp Ser Gly Glu Tyr Thr Cys Gln Thr Gly Gln Thr Ser Leu Ser             100 105 110 Asp Pro Val His Leu Thr Val Leu Ser Glu Trp Leu Val Leu Gln Thr         115 120 125 Pro His Leu Glu Phe Gln Glu Gly Glu Thr Ile Met Leu Arg Cys His     130 135 140 Ser Trp Lys Asp Lys Pro Leu Val Lys Val Thr Phe Phe Gln Asn Gly 145 150 155 160 Lys Ser Gln Lys Phe Ser His Leu Asp Pro Thr Phe Ser Ile Pro Gln                 165 170 175 Ala Asn His Ser Ser Gly Asp Tyr His Cys Thr Gly Asn Ile Gly             180 185 190 Tyr Thr Leu Phe Ser Ser Lys Pro Val Thr Ile Thr Val Gln Val Pro         195 200 205 Ser Met Gly Ser Ser Ser Pro Gly Ile     210 215 <210> 212 <211> 291 <212> PRT <213> Homo sapiens <400> 212 Met Gly Ile Leu Ser Phe Leu Pro Val Leu Ala Thr Glu Ser Asp Trp 1 5 10 15 Ala Asp Cys Lys Ser Pro Gln Pro Trp Gly His Met Leu Leu Trp Thr             20 25 30 Ala Val Leu Phe Leu Ala Pro Ala Gla Thr Pro Ala Ala Pro Pro         35 40 45 Lys Ala Val Leu Lys Leu Glu Pro Gln Trp Ile Asn Val Leu Gln Glu     50 55 60 Asp Ser Val Thr Leu Thr Cys Arg Gly Thr His Ser Pro Glu Ser Asp 65 70 75 80 Ser Ile Gln Trp Phe His Asn Gly Asn Leu Ile Pro Thr His Thr Gln                 85 90 95 Pro Ser Tyr Arg Phe Lys Ala Asn Asn Asn Asp Ser Gly Glu Tyr Thr             100 105 110 Cys Gln Thr Gly Gln Thr Ser Leu Ser Asp Pro Val His Leu Thr Val         115 120 125 Leu Ser Glu Trp Leu Val Leu Gln Thr Pro His Leu Glu Phe Gln Glu     130 135 140 Gly Glu Thr Ile Val Leu Arg Cys His Ser Trp Lys Asp Lys Pro Leu 145 150 155 160 Val Lys Val Thr Phe Phe Gln Asn Gly Lys Ser Lys Lys Phe Ser Arg                 165 170 175 Ser Asp Pro Asn Phe Ser Ile Pro Gln Ala Asn His Ser His Ser Gly             180 185 190 Asp Tyr His Cys Thr Gly Asn Ile Gly Tyr Thr Leu Tyr Ser Ser Lys         195 200 205 Pro Val Thr Ile Thr Val Gln Ala Pro Ser Ser Ser Pro Met Gly Ile     210 215 220 Ile Val Ala Val Val Thr Gly Ile Ala Val Ala Ile Val Ala Ala 225 230 235 240 Val Val Ala Leu Ile Tyr Cys Arg Lys Lys Arg Ile Ser Ala Asn Pro                 245 250 255 Thr Asn Pro Asp Glu Ala Asp Lys Val Gly Ala Glu Asn Thr Ile Thr             260 265 270 Tyr Ser Leu Leu Met His Pro Asp Ala Leu Glu Glu Pro Asp Asp Gln         275 280 285 Asn Arg Ile     290 <210> 213 <211> 310 <212> PRT <213> Homo sapiens <400> 213 Met Gly Ile Leu Ser Phe Leu Pro Val Leu Ala Thr Glu Ser Asp Trp 1 5 10 15 Ala Asp Cys Lys Ser Pro Gln Pro Trp Gly His Met Leu Leu Trp Thr             20 25 30 Ala Val Leu Phe Leu Ala Pro Ala Gla Thr Pro Ala Ala Pro Pro         35 40 45 Lys Ala Val Leu Lys Leu Glu Pro Gln Trp Ile Asn Val Leu Gln Glu     50 55 60 Asp Ser Val Thr Leu Thr Cys Arg Gly Thr His Ser Pro Glu Ser Asp 65 70 75 80 Ser Ile Gln Trp Phe His Asn Gly Asn Leu Ile Pro Thr His Thr Gln                 85 90 95 Pro Ser Tyr Arg Phe Lys Ala Asn Asn Asn Asp Ser Gly Glu Tyr Thr             100 105 110 Cys Gln Thr Gly Gln Thr Ser Leu Ser Asp Pro Val His Leu Thr Val         115 120 125 Leu Ser Glu Trp Leu Val Leu Gln Thr Pro His Leu Glu Phe Gln Glu     130 135 140 Gly Glu Thr Ile Val Leu Arg Cys His Ser Trp Lys Asp Lys Pro Leu 145 150 155 160 Val Lys Val Thr Phe Phe Gln Asn Gly Lys Ser Lys Lys Phe Ser Arg                 165 170 175 Ser Asp Pro Asn Phe Ser Ile Pro Gln Ala Asn His Ser His Ser Gly             180 185 190 Asp Tyr His Cys Thr Gly Asn Ile Gly Tyr Thr Leu Tyr Ser Ser Lys         195 200 205 Pro Val Thr Ile Thr Val Gln Ala Pro Ser Ser Ser Pro Met Gly Ile     210 215 220 Ile Val Ala Val Val Thr Gly Ile Ala Val Ala Ile Val Ala Ala 225 230 235 240 Val Val Ala Leu Ile Tyr Cys Arg Lys Lys Arg Ile Ser Ala Leu Pro                 245 250 255 Gly Tyr Pro Glu Cys Arg Glu Met Gly Glu Thr Leu Pro Glu Lys Pro             260 265 270 Ala Asn Pro Thr Asn Pro Asp Glu Ala Asp Lys Val Gly Ala Glu Asn         275 280 285 Thr Ile Thr Ser Leu Leu Met His Pro Asp Ala Leu Glu Glu Pro     290 295 300 Asp Asp Gln Asn Arg Ile 305 310 <210> 214 <211> 217 <212> PRT <213> Homo sapiens <400> 214 Met Gly Ile Leu Ser Phe Leu Pro Val Leu Ala Thr Glu Ser Asp Trp 1 5 10 15 Ala Asp Cys Lys Ser Pro Gln Pro Trp Gly His Met Leu Leu Trp Thr             20 25 30 Ala Val Leu Phe Leu Ala Pro Ala Gla Thr Pro Ala Ala Pro Pro         35 40 45 Lys Ala Val Leu Lys Leu Glu Pro Gln Trp Ile Asn Val Leu Gln Glu     50 55 60 Asp Ser Val Thr Leu Thr Cys Arg Gly Thr His Ser Pro Glu Ser Asp 65 70 75 80 Ser Ile Gln Trp Phe His Asn Gly Asn Leu Ile Pro Thr His Thr Gln                 85 90 95 Pro Ser Tyr Arg Phe Lys Ala Asn Asn Asn Asp Ser Gly Glu Tyr Thr             100 105 110 Cys Gln Thr Gly Gln Thr Ser Leu Ser Asp Pro Val His Leu Thr Val         115 120 125 Leu Ser Glu Trp Leu Val Leu Gln Thr Pro His Leu Glu Phe Gln Glu     130 135 140 Gly Glu Thr Ile Val Leu Arg Cys His Ser Trp Lys Asp Lys Pro Leu 145 150 155 160 Val Lys Val Thr Phe Phe Gln Asn Gly Lys Ser Lys Lys Phe Ser Arg                 165 170 175 Ser Asp Pro Asn Phe Ser Ile Pro Gln Ala Asn His Ser His Ser Gly             180 185 190 Asp Tyr His Cys Thr Gly Asn Ile Gly Tyr Thr Leu Tyr Ser Ser Lys         195 200 205 Pro Val Thr Ile Thr Val Gln Ala Pro     210 215 <210> 215 <211> 254 <212> PRT <213> Homo sapiens <400> 215 Met Trp Gln Leu Leu Leu Pro Thr Ala Leu Leu Leu Leu Val Ser Ala 1 5 10 15 Gly Met Arg Thr Glu Asp Leu Pro Lys Ala Val Val Phe Leu Glu Pro             20 25 30 Gln Trp Tyr Arg Val Leu Glu Lys Asp Ser Val Thr Leu Lys Cys Gln         35 40 45 Gly Ala Tyr Ser Pro Glu Asp Asn Ser Thr Gln Trp Phe His Asn Glu     50 55 60 Ser Leu Ile Ser Ser Gln Ala Ser Ser Tyr Phe Ile Asp Ala Ala Thr 65 70 75 80 Val Asp Asp Ser Gly Glu Tyr Arg Cys Gln Thr Asn Leu Ser Thr Leu                 85 90 95 Ser Asp Pro Val Gln Leu Glu Val His Ile Gly Trp Leu Leu Leu Gln             100 105 110 Ala Pro Arg Trp Val Phe Lys Glu Glu Asp Pro Ile His Leu Arg Cys         115 120 125 His Ser Trp Lys Asn Thr Ala Leu His Lys Val Thr Tyr Leu Gln Asn     130 135 140 Gly Lys Gly Arg Lys Tyr Phe His His Asn Ser Asp Phe Tyr Ile Pro 145 150 155 160 Lys Ala Thr Leu Lys Asp Ser Gly Ser Tyr Phe Cys Arg Gly Leu Val                 165 170 175 Gly Ser Lys Asn Val Ser Ser Glu Thr Val Asn Ile Thr Ile Thr Gln             180 185 190 Gly Leu Ser Val Ser Thr Ile Ser Ser Phe Phe Pro Pro Gly Tyr Gln         195 200 205 Val Ser Phe Cys Leu Val Met Val Leu Leu Phe Ala Val Asp Thr Gly     210 215 220 Leu Tyr Phe Ser Val Lys Thr Asn Ile Arg Ser Ser Thr Arg Asp Trp 225 230 235 240 Lys Asp His Lys Phe Lys Trp Arg Lys Asp Pro Gln Asp Lys                 245 250 <210> 216 <211> 254 <212> PRT <213> Homo sapiens <400> 216 Met Trp Gln Leu Leu Leu Pro Thr Ala Leu Leu Leu Leu Val Ser Ala 1 5 10 15 Gly Met Arg Thr Glu Asp Leu Pro Lys Ala Val Val Phe Leu Glu Pro             20 25 30 Gln Trp Tyr Arg Val Leu Glu Lys Asp Ser Val Thr Leu Lys Cys Gln         35 40 45 Gly Ala Tyr Ser Pro Glu Asp Asn Ser Thr Gln Trp Phe His Asn Glu     50 55 60 Ser Leu Ile Ser Ser Gln Ala Ser Ser Tyr Phe Ile Asp Ala Ala Thr 65 70 75 80 Val Asp Asp Ser Gly Glu Tyr Arg Cys Gln Thr Asn Leu Ser Thr Leu                 85 90 95 Ser Asp Pro Val Gln Leu Glu Val His Ile Gly Trp Leu Leu Leu Gln             100 105 110 Ala Pro Arg Trp Val Phe Lys Glu Glu Asp Pro Ile His Leu Arg Cys         115 120 125 His Ser Trp Lys Asn Thr Ala Leu His Lys Val Thr Tyr Leu Gln Asn     130 135 140 Gly Lys Gly Arg Lys Tyr Phe His His Asn Ser Asp Phe Tyr Ile Pro 145 150 155 160 Lys Ala Thr Leu Lys Asp Ser Gly Ser Tyr Phe Cys Arg Gly Leu Phe                 165 170 175 Gly Ser Lys Asn Val Ser Ser Glu Thr Val Asn Ile Thr Ile Thr Gln             180 185 190 Gly Leu Ala Val Ser Thr Ile Ser Ser Phe Phe Pro Pro Gly Tyr Gln         195 200 205 Val Ser Phe Cys Leu Val Met Val Leu Leu Phe Ala Val Asp Thr Gly     210 215 220 Leu Tyr Phe Ser Val Lys Thr Asn Ile Arg Ser Ser Thr Arg Asp Trp 225 230 235 240 Lys Asp His Lys Phe Lys Trp Arg Lys Asp Pro Gln Asp Lys                 245 250 <210> 217 <211> 208 <212> PRT <213> Homo sapiens <400> 217 Met Trp Gln Leu Leu Leu Pro Thr Ala Leu Leu Leu Leu Val Ser Ala 1 5 10 15 Gly Met Arg Thr Glu Asp Leu Pro Lys Ala Val Val Phe Leu Glu Pro             20 25 30 Gln Trp Tyr Arg Val Leu Glu Lys Asp Ser Val Thr Leu Lys Cys Gln         35 40 45 Gly Ala Tyr Ser Pro Glu Asp Asn Ser Thr Gln Trp Phe His Asn Glu     50 55 60 Ser Leu Ile Ser Ser Gln Ala Ser Ser Tyr Phe Ile Asp Ala Ala Thr 65 70 75 80 Val Asp Asp Ser Gly Glu Tyr Arg Cys Gln Thr Asn Leu Ser Thr Leu                 85 90 95 Ser Asp Pro Val Gln Leu Glu Val His Ile Gly Trp Leu Leu Leu Gln             100 105 110 Ala Pro Arg Trp Val Phe Lys Glu Glu Asp Pro Ile His Leu Arg Cys         115 120 125 His Ser Trp Lys Asn Thr Ala Leu His Lys Val Thr Tyr Leu Gln Asn     130 135 140 Gly Lys Gly Arg Lys Tyr Phe His His Asn Ser Asp Phe Tyr Ile Pro 145 150 155 160 Lys Ala Thr Leu Lys Asp Ser Gly Ser Tyr Phe Cys Arg Gly Leu Phe                 165 170 175 Gly Ser Lys Asn Val Ser Ser Glu Thr Val Asn Ile Thr Ile Thr Gln             180 185 190 Gly Leu Ala Val Ser Thr Ile Ser Ser Phe Phe Pro Pro Gly Tyr Gln         195 200 205 <210> 218 <211> 208 <212> PRT <213> Homo sapiens <400> 218 Met Trp Gln Leu Leu Leu Pro Thr Ala Leu Leu Leu Leu Val Ser Ala 1 5 10 15 Gly Met Arg Thr Glu Asp Leu Pro Lys Ala Val Val Phe Leu Glu Pro             20 25 30 Gln Trp Tyr Arg Val Leu Glu Lys Asp Ser Val Thr Leu Lys Cys Gln         35 40 45 Gly Ala Tyr Ser Pro Glu Asp Asn Ser Thr Gln Trp Phe His Asn Glu     50 55 60 Ser Leu Ile Ser Ser Gln Ala Ser Ser Tyr Phe Ile Asp Ala Ala Thr 65 70 75 80 Val Asp Asp Ser Gly Glu Tyr Arg Cys Gln Thr Asn Leu Ser Thr Leu                 85 90 95 Ser Asp Pro Val Gln Leu Glu Val His Ile Gly Trp Leu Leu Leu Gln             100 105 110 Ala Pro Arg Trp Val Phe Lys Glu Glu Asp Pro Ile His Leu Arg Cys         115 120 125 His Ser Trp Lys Asn Thr Ala Leu His Lys Val Thr Tyr Leu Gln Asn     130 135 140 Gly Lys Gly Arg Lys Tyr Phe His His Asn Ser Asp Phe Tyr Ile Pro 145 150 155 160 Lys Ala Thr Leu Lys Asp Ser Gly Ser Tyr Phe Cys Arg Gly Leu Val                 165 170 175 Gly Ser Lys Asn Val Ser Ser Glu Thr Val Asn Ile Thr Ile Thr Gln             180 185 190 Gly Leu Ala Val Ser Thr Ile Ser Ser Phe Phe Pro Pro Gly Tyr Gln         195 200 205 <210> 219 <211> 233 <212> PRT <213> Homo sapiens <400> 219 Met Trp Gln Leu Leu Leu Pro Thr Ala Leu Leu Leu Leu Val Ser Ala 1 5 10 15 Gly Met Arg Thr Glu Asp Leu Pro Lys Ala Val Val Phe Leu Glu Pro             20 25 30 Gln Trp Tyr Ser Val Leu Glu Lys Asp Ser Val Thr Leu Lys Cys Gln         35 40 45 Gly Ala Tyr Ser Pro Glu Asp Asn Ser Thr Gln Trp Phe His Asn Glu     50 55 60 Ser Leu Ile Ser Ser Gln Ala Ser Ser Tyr Phe Ile Asp Ala Ala Thr 65 70 75 80 Val Asn Asp Ser Gly Glu Tyr Arg Cys Gln Thr Asn Leu Ser Thr Leu                 85 90 95 Ser Asp Pro Val Gln Leu Glu Val His Ile Gly Trp Leu Leu Leu Gln             100 105 110 Ala Pro Arg Trp Val Phe Lys Glu Glu Asp Pro Ile His Leu Arg Cys         115 120 125 His Ser Trp Lys Asn Thr Ala Leu His Lys Val Thr Tyr Leu Gln Asn     130 135 140 Gly Lys Asp Arg Lys Tyr Phe His His Asn Ser Asp Phe His Ile Pro 145 150 155 160 Lys Ala Thr Leu Lys Asp Ser Gly Ser Tyr Phe Cys Arg Gly Leu Val                 165 170 175 Gly Ser Lys Asn Val Ser Ser Glu Thr Val Asn Ile Thr Ile Thr Gln             180 185 190 Gly Leu Ala Val Ser Thr Ile Ser Ser Phe Ser Pro Pro Gly Tyr Gln         195 200 205 Val Ser Phe Cys Leu Val Met Val Leu Leu Phe Ala Val Asp Thr Gly     210 215 220 Leu Tyr Phe Ser Val Lys Thr Asn Ile 225 230 <210> 220 <211> 211 <212> PRT <213> Macaca fascicularis <400> 220 Met Ser Gln Asn Val Cys Pro Gly Asn Leu Trp Leu Leu Gln Pro Leu 1 5 10 15 Thr Val Leu Leu Leu Leu Ala Ser Ala Asp Ser Gln Thr Ala Pro Pro             20 25 30 Lys Ala Val Leu Lys Leu Glu Pro Pro Trp Ile Asn Val Leu Arg Glu         35 40 45 Asp Ser Val Thr Leu Thr Cys Gly Gly Ala His Ser Pro Asp Ser Asp     50 55 60 Ser Thr Gln Trp Phe His Asn Gly Asn Leu Ile Pro Thr His Thr Gln 65 70 75 80 Pro Ser Tyr Arg Phe Lys Ala Asn Asn Asn Asp Ser Gly Glu Tyr Arg                 85 90 95 Cys Gln Thr Gly Arg Thr Ser Leu Ser Asp Pro Val His Leu Thr Val             100 105 110 Leu Ser Glu Trp Leu Ala Leu Gln Thr Pro His Leu Glu Phe Arg Glu         115 120 125 Gly Glu Thr Ile Met Leu Arg Cys His Ser Trp Lys Asp Lys Pro Leu     130 135 140 Ile Lys Val Thr Phe Phe Gln Asn Gly Ile Ala Lys Lys Phe Ser His 145 150 155 160 Met Asp Pro Asn Phe Ser Ile Pro Arg Ala Asn His Ser His Ser Gly                 165 170 175 Asp Tyr His Cys Thr Gly Asn Ile Gly Tyr Thr Pro Tyr Ser Ser Lys             180 185 190 Pro Val Thr Ile Thr Val Gln Val Pro Ser Val Gly Ser Ser Ser Pro         195 200 205 Met Gly Ile     210 <210> 221 <211> 211 <212> PRT <213> Macaca fascicularis <400> 221 Met Ser Gln Asn Val Cys Pro Gly Asn Leu Trp Leu Leu Gln Pro Leu 1 5 10 15 Thr Val Leu Leu Leu Leu Ala Ser Ala Asp Ser Gln Thr Ala Pro Pro             20 25 30 Lys Ala Val Leu Lys Leu Glu Pro Pro Trp Ile Asn Val Leu Arg Glu         35 40 45 Asp Ser Val Thr Leu Thr Cys Gly Gly Ala His Ser Pro Asp Ser Asp     50 55 60 Ser Thr Gln Trp Phe His Asn Gly Asn Leu Ile Pro Thr His Thr Gln 65 70 75 80 Pro Ser Tyr Arg Phe Lys Ala Asn Asn Asn Asp Ser Gly Glu Tyr Arg                 85 90 95 Cys Gln Thr Gly Arg Thr Ser Leu Ser Asp Pro Val His Leu Thr Val             100 105 110 Leu Ser Glu Trp Leu Ala Leu Gln Thr Thr His Leu Glu Phe Arg Glu         115 120 125 Gly Glu Thr Ile Met Leu Arg Cys His Ser Trp Lys Asp Lys Pro Leu     130 135 140 Ile Lys Val Ala Phe Phe Gln Asn Gly Lys Ser Lys Asn Phe Ser His 145 150 155 160 Met Asn Pro Asn Phe Ser Ile Pro Gln Ala Asn His Ser His Ser Gly                 165 170 175 Asp Tyr His Cys Thr Gly Asn Ile Gly Tyr Thr Pro Tyr Ser Ser Lys             180 185 190 Pro Val Thr Ile Thr Val Gln Val Pro Ser Val Gly Ser Ser Ser Pro         195 200 205 Met Gly Ile     210 <210> 222 <211> 211 <212> PRT <213> Macaca fascicularis <400> 222 Met Ser Gln Asn Val Cys Pro Gly Asn Leu Trp Leu Leu Gln Pro Leu 1 5 10 15 Thr Val Leu Leu Leu Leu Ala Ser Ala Asp Ser Gln Thr Ala Pro Pro             20 25 30 Lys Ala Val Leu Lys Leu Glu Pro Pro Trp Ile Asn Val Leu Arg Glu         35 40 45 Asp Ser Val Thr Leu Thr Cys Gly Gly Ala His Ser Pro Asp Ser Asp     50 55 60 Ser Thr Gln Trp Phe His Asn Gly Asn Leu Ile Pro Thr His Thr Gln 65 70 75 80 Pro Ser Tyr Arg Phe Lys Ala Asn Asn Asn Asp Ser Gly Glu Tyr Arg                 85 90 95 Cys Gln Thr Gly Arg Thr Ser Leu Ser Asp Pro Val His Leu Thr Val             100 105 110 Leu Ser Glu Trp Leu Ala Leu Gln Thr Thr His Leu Glu Phe Arg Glu         115 120 125 Gly Glu Thr Ile Met Leu Arg Cys His Ser Trp Lys Asp Lys Pro Leu     130 135 140 Ile Lys Val Ala Phe Phe Gln Asn Gly Ile Ser Lys Lys Phe Ser Pro 145 150 155 160 Met Asn Pro Asn Phe Ser Ile Pro Arg Ala Asn His Ser His Ser Gly                 165 170 175 Asp Tyr His Cys Thr Gly Asn Ile Gly Tyr Thr Pro Tyr Ser Ser Lys             180 185 190 Pro Val Thr Ile Thr Val Gln Val Pro Ser Val Gly Ser Ser Ser Pro         195 200 205 Met Gly Ile     210 <210> 223 <211> 217 <212> PRT <213> Macaca fascicularis <400> 223 Met Gly Ile Leu Ser Phe Leu Pro Val Leu Ala Thr Glu Ser Asp Trp 1 5 10 15 Ala Asp Cys Lys Ser Ser Gln Pro Trp Gly His Met Leu Leu Trp Thr             20 25 30 Ala Val Leu Phe Leu Ala Pro Ala Gla Thr Pro Ala Ala Pro Pro         35 40 45 Lys Ala Val Leu Lys Leu Glu Pro Pro Trp Ile Asn Val Leu Arg Glu     50 55 60 Asp Ser Val Thr Leu Thr Cys Gly Gly Ala His Ser Pro Asp Ser Asp 65 70 75 80 Ser Thr Gln Trp Phe His Asn Gly Asn Leu Ile Pro Thr His Thr Gln                 85 90 95 Pro Ser Tyr Arg Phe Lys Ala Asn Asn Asn Asp Ser Gly Glu Tyr Arg             100 105 110 Cys Gln Thr Gly Arg Thr Ser Leu Ser Asp Pro Val His Leu Thr Val         115 120 125 Leu Ser Glu Trp Leu Ala Leu Gln Thr Pro His Leu Glu Phe Arg Glu     130 135 140 Gly Glu Thr Ile Met Leu Arg Cys His Ser Trp Lys Asp Lys Pro Leu 145 150 155 160 Ile Lys Val Thr Phe Phe Gln Asn Gly Ile Ser Lys Lys Phe Ser His                 165 170 175 Met Asn Pro Asn Phe Ser Ile Pro Gln Ala Asn His Ser His Ser Gly             180 185 190 Asp Tyr His Cys Thr Gly Asn Ile Gly Tyr Thr Pro Tyr Ser Ser Lys         195 200 205 Pro Val Thr Ile Thr Val Gln Val Pro     210 215 <210> 224 <211> 208 <212> PRT <213> Macaca fascicularis <400> 224 Met Trp Gln Leu Leu Leu Pro Thr Ala Leu Leu Leu Leu Val Ser Ala 1 5 10 15 Gly Met Arg Ala Glu Asp Leu Pro Lys Ala Val Val Phe Leu Glu Pro             20 25 30 Gln Trp Tyr Arg Val Leu Glu Lys Asp Ser Val Thr Leu Lys Cys Gln         35 40 45 Gly Ala Tyr Ser Pro Glu Asp Asn Ser Thr Arg Trp Phe His Asn Glu     50 55 60 Ser Leu Ile Ser Ser Gln Thr Ser Ser Tyr Phe Ile Ala Ala Ala Arg 65 70 75 80 Val Asn Asn Ser Gly Glu Tyr Arg Cys Gln Thr Ser Leu Ser Thr Leu                 85 90 95 Ser Asp Pro Val Gln Leu Glu Val His Ile Gly Trp Leu Leu Leu Gln             100 105 110 Ala Pro Arg Trp Val Phe Lys Glu Glu Glu Ser Ile His Leu Arg Cys         115 120 125 His Ser Trp Lys Asn Thr Leu Leu His Lys Val Thr Tyr Leu Gln Asn     130 135 140 Gly Lys Gly Arg Lys Tyr Phe His Gln Asn Ser Asp Phe Tyr Ile Pro 145 150 155 160 Lys Ala Thr Leu Lys Asp Ser Gly Ser Tyr Phe Cys Arg Gly Leu Ile                 165 170 175 Gly Ser Lys Asn Val Ser Ser Glu Thr Val Asn Ile Thr Ile Thr Gln             180 185 190 Asp Leu Ala Val Ser Ser Ser Ser Phe Phe Pro Pro Gly Tyr Gln         195 200 205 <210> 225 <211> 115 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 225 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Thr Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr             20 25 30 Glu Met His Trp Ile Arg Gln Pro Pro Gly Glu Gly Leu Glu Trp Ile         35 40 45 Gly Ala Ile Asp Pro Lys Thr Gly Asp Thr Ala Tyr Ser Glu Ser Phe     50 55 60 Gln Asp Arg Val Thr Leu Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Thr Arg Phe Tyr Ser Tyr Thr Tyr Trp Gly Gln Gly Thr Leu Val Thr             100 105 110 Val Ser Ser         115 <210> 226 <211> 219 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 226 Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly 1 5 10 15 Glu Pro Ala Ser Ile Ser Cys Gln Ala Ser Glu Ser Leu Val His Ser             20 25 30 Asn Arg Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser         35 40 45 Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro     50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Ser Gln Asn                 85 90 95 Thr His Val Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Glu             100 105 110 Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu         115 120 125 Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe     130 135 140 Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln 145 150 155 160 Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser                 165 170 175 Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu             180 185 190 Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser         195 200 205 Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys     210 215 <210> 227 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 227 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu             180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu 225 230 235 240 Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 305 310 315 320 Gln Lys Ser Leu Ser Leu Ser Pro                 325 <210> 228 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 228 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu             180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu 225 230 235 240 Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 305 310 315 320 Gln Glu Ser Leu Ser Leu Ser Pro                 325 <210> 229 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 229 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Asn Gly Pro Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ser Glu Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu             180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Met Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 305 310 315 320 Gln Lys Ser Leu Ser Leu Ser Pro                 325 <210> 230 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 230 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Asn Gly Pro Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ser Glu Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu             180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Met Val Leu Asp Arg Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Lys Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 305 310 315 320 Gln Lys Ser Leu Ser Leu Ser Pro                 325 <210> 231 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 231 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Asn Gly Pro Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ser Asp Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu             180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 305 310 315 320 Gln Lys Ser Leu Ser Leu Ser Pro                 325 <210> 232 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 232 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Asn Gly Pro Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ser Asp Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Lys Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 305 310 315 320 Gln Lys Ser Leu Ser Leu Ser Pro                 325 <210> 233 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 233 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Asn Gly Pro Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ser Asp Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Leu Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu             180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 305 310 315 320 Gln Lys Ser Leu Ser Leu Ser Pro                 325 <210> 234 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 234 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Asn Gly Pro Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ser Asp Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Leu Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Lys Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 305 310 315 320 Gln Lys Ser Leu Ser Leu Ser Pro                 325 <210> 235 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 235 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Thr Gly Pro Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ser Asp Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Lys Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 305 310 315 320 Gln Lys Ser Leu Ser Leu Ser Pro                 325 <210> 236 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 236 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Asn Gly Pro Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ser Glu Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu             180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Met Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Ala His Tyr Thr 305 310 315 320 Gln Lys Ser Leu Ser Leu Ser Pro                 325 <210> 237 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 237 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Asn Gly Pro Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ser Glu Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Met Val Leu Arg Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Ala His Tyr Thr 305 310 315 320 Gln Lys Ser Leu Ser Leu Ser Pro                 325 <210> 238 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 238 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Asn Gly Pro Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ser Asp Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Leu Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Lys Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Ala His Tyr Thr 305 310 315 320 Gln Lys Ser Leu Ser Leu Ser Pro                 325 <210> 239 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 239 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Asn Gly Pro Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ser Asp Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Lys Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Ala His Tyr Thr 305 310 315 320 Gln Lys Ser Leu Ser Leu Ser Pro                 325 <210> 240 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 240 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Asn Gly Pro Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ser Asp Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu             180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Ala His Tyr Thr 305 310 315 320 Gln Lys Ser Leu Ser Leu Ser Pro                 325 <210> 241 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 241 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Thr Gly Pro Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ser Asp Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Lys Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Ala His Tyr Thr 305 310 315 320 Gln Lys Ser Leu Ser Leu Ser Pro                 325 <210> 242 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 242 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Asn Gly Pro Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ser Asp Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Leu Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Lys Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Ala His Thr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 243 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 243 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Asn Gly Pro Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ser Asp Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Leu Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Thr Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Arg Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Ala His Thr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 244 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 244 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Trp Asn Gly Pro Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ser Asp Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Leu Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Thr Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Arg Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Ala His Thr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 245 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 245 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Asn Gly Pro Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ser Asp Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Leu Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Lys Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Ala His Tyr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 246 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 246 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Asn Gly Pro Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ser Asp Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Leu Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Thr Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Arg Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Ala His Tyr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 247 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 247 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Trp Asn Gly Pro Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ser Asp Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Leu Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Thr Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Arg Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Ala His Tyr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 248 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 248 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Asn Gly Pro Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ser Asp Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Arg Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 305 310 315 320 Gln Lys Ser Leu Ser Leu Ser Pro                 325 <210> 249 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 249 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Asn Gly Pro Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ser Asp Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Arg Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 305 310 315 320 Gln Lys Ser Leu Ser Leu Ser Pro                 325 <210> 250 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 250 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Asn Gly Pro Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ser Asp Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Arg Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Arg Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 305 310 315 320 Gln Lys Ser Leu Ser Leu Ser Pro                 325 <210> 251 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 251 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Asn Gly Pro Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ser Asp Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Arg Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Arg Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 305 310 315 320 Gln Lys Ser Leu Ser Leu Ser Pro                 325 <210> 252 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 252 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu             180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 305 310 315 320 Gln Lys Ser Leu Ser Leu Ser Pro                 325 <210> 253 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 253 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 305 310 315 320 Gln Lys Ser Leu Ser Leu Ser Pro                 325 <210> 254 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 254 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 305 310 315 320 Gln Lys Ser Leu Ser Leu Ser Pro                 325 <210> 255 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 255 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Ile Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 305 310 315 320 Gln Lys Ser Leu Ser Leu Ser Pro                 325 <210> 256 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 256 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ala His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 305 310 315 320 Gln Lys Ser Leu Ser Leu Ser Pro                 325 <210> 257 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 257 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Tyr Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 305 310 315 320 Gln Lys Ser Leu Ser Leu Ser Pro                 325 <210> 258 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 258 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Tyr Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ala His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 305 310 315 320 Gln Lys Ser Leu Ser Leu Ser Pro                 325 <210> 259 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 259 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Ile Asp Val Ala His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 305 310 315 320 Gln Lys Ser Leu Ser Leu Ser Pro                 325 <210> 260 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 260 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Tyr Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Ile Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 305 310 315 320 Gln Lys Ser Leu Ser Leu Ser Pro                 325 <210> 261 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 261 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Tyr Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Ile Asp Val Ala His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 305 310 315 320 Gln Lys Ser Leu Ser Leu Ser Pro                 325 <210> 262 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 262 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Arg Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 305 310 315 320 Gln Lys Ser Leu Ser Leu Ser Pro                 325 <210> 263 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 263 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Lys Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 305 310 315 320 Gln Lys Ser Leu Ser Leu Ser Pro                 325 <210> 264 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 264 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Ile Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Arg Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 305 310 315 320 Gln Lys Ser Leu Ser Leu Ser Pro                 325 <210> 265 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 265 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Ile Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Lys Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 305 310 315 320 Gln Lys Ser Leu Ser Leu Ser Pro                 325 <210> 266 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 266 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ala His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Arg Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 305 310 315 320 Gln Lys Ser Leu Ser Leu Ser Pro                 325 <210> 267 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 267 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ala His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Lys Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 305 310 315 320 Gln Lys Ser Leu Ser Leu Ser Pro                 325 <210> 268 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 268 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Tyr Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Arg Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 305 310 315 320 Gln Lys Ser Leu Ser Leu Ser Pro                 325 <210> 269 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 269 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Tyr Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Lys Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 305 310 315 320 Gln Lys Ser Leu Ser Leu Ser Pro                 325 <210> 270 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 270 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Tyr Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ala His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Arg Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 305 310 315 320 Gln Lys Ser Leu Ser Leu Ser Pro                 325 <210> 271 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 271 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Tyr Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ala His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Lys Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 305 310 315 320 Gln Lys Ser Leu Ser Leu Ser Pro                 325 <210> 272 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 272 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Ile Asp Val Ala His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Arg Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 305 310 315 320 Gln Lys Ser Leu Ser Leu Ser Pro                 325 <210> 273 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 273 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Ile Asp Val Ala His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Lys Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 305 310 315 320 Gln Lys Ser Leu Ser Leu Ser Pro                 325 <210> 274 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 274 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Tyr Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Ile Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Arg Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 305 310 315 320 Gln Lys Ser Leu Ser Leu Ser Pro                 325 <210> 275 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 275 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Tyr Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Ile Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Lys Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 305 310 315 320 Gln Lys Ser Leu Ser Leu Ser Pro                 325 <210> 276 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 276 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Tyr Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Ile Asp Val Ala His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Arg Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 305 310 315 320 Gln Lys Ser Leu Ser Leu Ser Pro                 325 <210> 277 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 277 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Tyr Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Ile Asp Val Ala His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Lys Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 305 310 315 320 Gln Lys Ser Leu Ser Leu Ser Pro                 325 <210> 278 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 278 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu             180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Ala His Tyr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 279 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 279 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Ala His Tyr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 280 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 280 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Ala His Tyr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 281 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 281 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Ile Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Ala His Tyr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 282 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 282 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ala His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Ala His Tyr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 283 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 283 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Tyr Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Ala His Tyr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 284 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 284 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Tyr Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ala His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Ala His Tyr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 285 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 285 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Ile Asp Val Ala His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Ala His Tyr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 286 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 286 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Tyr Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Ile Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Ala His Tyr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 287 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 287 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Tyr Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Ile Asp Val Ala His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Ala His Tyr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 288 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 288 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Arg Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Ala His Tyr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 289 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 289 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Lys Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Ala His Tyr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 290 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 290 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Ile Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Arg Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Ala His Tyr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 291 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 291 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Ile Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Lys Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Ala His Tyr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 292 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 292 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ala His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Arg Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Ala His Tyr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 293 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 293 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ala His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Lys Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Ala His Tyr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 294 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 294 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Tyr Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Arg Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Ala His Tyr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 295 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 295 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Tyr Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Lys Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Ala His Tyr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 296 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 296 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Tyr Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ala His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Arg Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Ala His Tyr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 297 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 297 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Tyr Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ala His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Lys Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Ala His Tyr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 298 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 298 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Ile Asp Val Ala His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Arg Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Ala His Tyr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 299 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 299 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Ile Asp Val Ala His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Lys Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Ala His Tyr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 300 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 300 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Tyr Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Ile Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Arg Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Ala His Tyr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 301 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 301 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Tyr Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Ile Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Lys Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Ala His Tyr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 302 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 302 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Tyr Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Ile Asp Val Ala His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Arg Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Ala His Tyr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 303 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 303 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Tyr Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Ile Asp Val Ala His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Lys Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Ala His Tyr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 304 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 304 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu             180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Ala His Thr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 305 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 305 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Ala His Thr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 306 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 306 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Ala His Thr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 307 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 307 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Ile Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Ala His Thr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 308 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 308 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ala His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Ala His Thr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 309 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 309 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Tyr Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Ala His Thr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 310 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 310 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Tyr Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ala His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Ala His Thr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 311 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 311 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Ile Asp Val Ala His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Ala His Thr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 312 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 312 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Tyr Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Ile Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Ala His Thr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 313 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 313 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Tyr Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Ile Asp Val Ala His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Ala His Thr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 314 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 314 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Arg Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Ala His Thr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 315 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 315 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Lys Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Ala His Thr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 316 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 316 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Ile Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Arg Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Ala His Thr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 317 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 317 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Ile Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Lys Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Ala His Thr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 318 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 318 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ala His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Arg Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Ala His Thr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 319 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 319 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ala His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Lys Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Ala His Thr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 320 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 320 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Tyr Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Arg Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Ala His Thr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 321 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 321 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Tyr Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Lys Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Ala His Thr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 322 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 322 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Tyr Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ala His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Arg Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Ala His Thr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 323 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 323 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Tyr Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ala His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Lys Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Ala His Thr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 324 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 324 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Ile Asp Val Ala His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Arg Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Ala His Thr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 325 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 325 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Ile Asp Val Ala His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Lys Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Ala His Thr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 326 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 326 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Tyr Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Ile Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Arg Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Ala His Thr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 327 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 327 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Tyr Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Ile Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Lys Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Ala His Thr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 328 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 328 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Tyr Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Ile Asp Val Ala His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Arg Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Ala His Thr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 329 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 329 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Tyr Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Ile Asp Val Ala His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Lys Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Ala His Thr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 330 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 330 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu             180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Ala His Thr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 331 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 331 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Ala His Thr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 332 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 332 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Ala His Thr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 333 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 333 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Ile Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Ala His Thr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 334 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 334 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ala His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Ala His Thr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 335 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 335 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Tyr Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Ala His Thr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 336 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 336 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Tyr Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ala His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Ala His Thr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 337 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 337 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Ile Asp Val Ala His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Ala His Thr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 338 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 338 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Tyr Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Ile Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Ala His Thr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 339 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 339 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Tyr Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Ile Asp Val Ala His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Ala His Thr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 340 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 340 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Arg Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Ala His Thr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 341 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 341 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Lys Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Ala His Thr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 342 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 342 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Ile Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Arg Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Ala His Thr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 343 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 343 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Ile Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Lys Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Ala His Thr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 344 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 344 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ala His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Arg Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Ala His Thr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 345 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 345 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ala His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Lys Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Ala His Thr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 346 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 346 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Tyr Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Arg Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Ala His Thr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 347 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 347 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Tyr Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Lys Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Ala His Thr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 348 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 348 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Tyr Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ala His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Arg Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Ala His Thr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 349 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 349 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Tyr Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ala His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Lys Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Ala His Thr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 350 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 350 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Ile Asp Val Ala His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Arg Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Ala His Thr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 351 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 351 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Ile Asp Val Ala His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Lys Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Ala His Thr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 352 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 352 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Tyr Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Ile Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Arg Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Ala His Thr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 353 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 353 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Tyr Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Ile Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Lys Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Ala His Thr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 354 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 354 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Tyr Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Ile Asp Val Ala His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Arg Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Ala His Thr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 355 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 355 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Tyr Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Ile Asp Val Ala His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Lys Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Ala His Thr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 356 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 356 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu             180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Ala His Tyr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 357 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 357 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Ala His Tyr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 358 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 358 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Ala His Tyr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 359 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 359 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Ile Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Ala His Tyr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 360 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 360 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ala His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Ala His Tyr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 361 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 361 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Tyr Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Ala His Tyr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 362 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 362 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Tyr Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ala His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Ala His Tyr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 363 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 363 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Ile Asp Val Ala His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Ala His Tyr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 364 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 364 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Tyr Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Ile Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Ala His Tyr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 365 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 365 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Tyr Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Ile Asp Val Ala His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Ala His Tyr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 366 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 366 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Arg Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Ala His Tyr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 367 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 367 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Lys Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Ala His Tyr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 368 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 368 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Ile Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Arg Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Ala His Tyr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 369 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 369 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Ile Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Lys Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Ala His Tyr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 370 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 370 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ala His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Arg Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Ala His Tyr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 371 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 371 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ala His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Lys Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Ala His Tyr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 372 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 372 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Tyr Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Arg Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Ala His Tyr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 373 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 373 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Tyr Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Lys Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Ala His Tyr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 374 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 374 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Tyr Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ala His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Arg Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Ala His Tyr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 375 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 375 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Tyr Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Val Asp Val Ala His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Lys Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Ala His Tyr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 376 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 376 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Ile Asp Val Ala His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Arg Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Ala His Tyr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 377 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 377 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Ile Asp Val Ala His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Lys Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Ala His Tyr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 378 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 378 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Tyr Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Ile Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Arg Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Ala His Tyr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 379 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 379 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Tyr Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Ile Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Lys Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Ala His Tyr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 380 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 380 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Tyr Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Ile Asp Val Ala His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Arg Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Ala His Tyr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325 <210> 381 <211> 328 <212> PRT <213> Artificial sequence <220> An artificially synthesized sequence <400> 381 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr             20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser         35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser     50 55 60 Leu Ser Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys                 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys             100 105 110 Pro Ala Pro Glu Tyr Leu Gly Gly Asp Ser Val Phe Leu Phe Pro Pro         115 120 125 Lys Pro Lys Asp Val Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys     130 135 140 Val Val Ile Asp Val Ala His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu                 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Val Leu             180 185 190 His Arg Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn         195 200 205 Lys Ala Leu Pro Lys Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly     210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr                 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn             260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe         275 280 285 Leu Tyr Ser Lys Leu Thr Val Lys Lys Ser Arg Trp Gln Gln Gly Asn     290 295 300 Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Ala His Tyr Thr 305 310 315 320 Arg Lys Glu Leu Ser Leu Ser Pro                 325

Claims (15)

(a) the VH sequence of SEQ ID NO: 86 and the VL sequence of SEQ ID NO: 96;
(b) a VH sequence of SEQ ID NO: 87 and a VL sequence of SEQ ID NO: 96;
(c) a VH sequence of SEQ ID NO: 88 and a VL sequence of SEQ ID NO: 96;
(d) a VH sequence of SEQ ID NO: 89 and a VL sequence of SEQ ID NO: 96;
(e) a VH sequence of SEQ ID NO: 90 and a VL sequence of SEQ ID NO: 96;
(f) a VH sequence of SEQ ID NO: 91 and a VL sequence of SEQ ID NO: 96;
(g) the VH sequence of SEQ ID NO: 92 and the VL sequence of SEQ ID NO: 97;
(h) the VH sequence of SEQ ID NO: 93 and the VL sequence of SEQ ID NO: 97;
(i) the VH sequence of SEQ ID NO: 94 and the VL sequence of SEQ ID NO: 97; or
(j) a VH sequence of SEQ ID NO: 95 and a VL sequence of SEQ ID NO: 97
Lt; RTI ID = 0.0 &gt; myostatin. &Lt; / RTI &gt; The method according to claim 1,
A heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 352, and a light chain constant region comprising the amino acid sequence of SEQ ID NO: 10. The method according to claim 1,
Antibodies that are full-length IgG antibodies. 3. The method of claim 2,
Antibodies that are full-length IgG antibodies. 5. An isolated nucleic acid encoding the antibody of any one of claims 1 to 4. A host cell comprising the nucleic acid of claim 5. A method for producing an anti-myostatin antibody, comprising culturing the host cell of claim 6 to produce an antibody. delete delete delete delete delete delete delete delete

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