CN117651718A

CN117651718A - Antigen binding proteins that specifically bind PRAME

Info

Publication number: CN117651718A
Application number: CN202280032801.9A
Authority: CN
Inventors: G·普索拉; M·霍夫曼; M·赫特; S·邦克; F·翁弗多尔本; F·斯彻沃贝尔; D·毛雷尔; M·贾沃斯基; C·瓦格纳; F·斯彻沃尔; H·舒斯特
Original assignee: Immatics Biotechnologies GmbH
Current assignee: Immatics Biotechnologies GmbH
Priority date: 2021-05-05
Filing date: 2022-05-04
Publication date: 2024-03-05

Abstract

The present invention relates to antigen binding proteins directed against antigens derived from PRAME proteins. The invention particularly provides antigen binding proteins specific for the tumor-expressed antigen PRAME, wherein the tumor antigen comprises or consists of SEQ ID No. 50 and is in a complex with Major Histocompatibility Complex (MHC) proteins. The antigen binding proteins of the invention particularly comprise Complementarity Determining Regions (CDRs) of novel engineered T Cell Receptors (TCRs) that specifically bind to the PRAME peptide. The antigen binding proteins of the invention are useful in the diagnosis, treatment and prevention of PRAME expressing cancerous diseases. Nucleic acids encoding the antigen binding proteins of the invention, vectors comprising the nucleic acids, recombinant cells expressing the antigen binding proteins, and pharmaceutical compositions comprising the antigen binding proteins of the invention are also provided.

Description

Antigen binding proteins that specifically bind PRAME

PRAME refers to an "antigen preferentially expressed in melanoma" and belongs to a family of germ-line encoded antigens known as cancer-testis antigens. Cancer-testis antigens are targets for immunotherapeutic intervention. PRAME is expressed in a variety of solid tumors and in leukemias and lymphomas. Peptide SLLQHLIGL (SEQ ID NO: 50), also known as PRAME-004, corresponds to amino acids 425-433 of the full length PRAME protein (SEQ ID NO: 328), and is presented on the cell surface as a complex with MHC molecules, in particular HLA-A.02 (Kessler et al, J Exp Med.2001, 1 month; 193 (1): 73-88). Peptide epitopes presented by MHC molecules can be bound by TCRs.

Despite the advances that have been made in the development of molecular targeted drugs for cancer therapies, there remains a need in the art for the development of new anticancer agents that specifically target cancer cells rather than molecules that are highly characteristic of normal tissue cells. Because PRAME-004 peptide is specifically expressed on tumors, it is a target for T cell-based immunotherapy.

WO 2018/172533 discloses TCRs, including TCR R11P3D3, which bind to PRAME-004 peptide in complex with MHC protein complexes, and the use of said TCRs in the diagnosis, treatment and prevention of (over) expressing PRAME cancerous diseases. However, these TCRs are not engineered in the CDR regions to bind to target antigens with increased affinity.

Native TCRs are usually found in low affinity (K _D =300 μm to 1 μm) to MHC-presented antigens, so binding to MHC-presented cancer autoantigens with an affinity above 10 μm is rarely observed, in contrast to viral foreign antigens to which TCRs are known to have a binding affinity in the range of 1-10 μm (Aleksic et al 2012,Eur J Immunol.2012 months; 42 (12):3174-9). Part of this phenomenon is explained by the occurrence in the thymusThe T cells in culture are negatively selected on the self peptide-MHC ligand such that T cells with too high affinity for such self peptide-MHC are eliminated (tolerance induction). This low affinity of TCR for cancer autoantigens may be one possible explanation for tumor immune escape (Aleksic et al, 2012,Eur J Immunol.2012, 12 months; 42 (12): 3174-9). Thus, it seems a desirable strategy to design TCR variants that bind to cancer autoantigens with higher affinity for use as antigen recognition constructs in Adoptive Cell Therapy (ACT). Furthermore, engineering of high affinity TCR variants that can be expressed as soluble proteins would be desirable for targeting cancer autoantigens with soluble therapeutic agents (i.e., through the use of bispecific molecules) (Hickman et al, month 2016,J Biomol Screen.2016; 21 (8): 769-85).

However, increasing the affinity of TCRs may also increase the risk of side effects. As mentioned above, in nature, high affinity TCRs against tumor-associated antigens (which are self-proteins) are excluded by thymus selection to avoid recognition of self-peptides presented on normal tissues by cross-reactivity. Thus, simply increasing the affinity of a TCR for its target sequence may also increase the affinity for similar non-cancer specific peptides and thus increase the risk of cross-reactivity and unwanted cytotoxic effects on healthy tissue. For engineered TCRs targeting MAGE-A3, this has been painly found to be not just a theoretical risk. In particular, the previously disclosed results have shown lethal toxicity in two patients infused with T cells engineered to express a MAGE-A3 targeted TCR that cross-reacted with peptides from the myoglobin (tin), even though cross-reactivity was not predicted in preclinical studies (Linette GP et al Blood 2013;122:863-71; cameron BJ et al Sci. Transl. Med.2013; 5:197-103). These patients show that TCR-engineered T cells may have severe and unpredictable off-target and organ-specific toxicity.

Thus, there is an unmet medical need to develop and provide antigen binding proteins that bind to their targets with higher affinity, thereby allowing even targeting tumor cells or cell lines with reduced expression of target antigenic peptides, while maintaining a high safety profile due to low or reduced cross-reactivity with potential off-target peptides (also referred to as "analogue peptides" or "SimPep"). Such antigen binding proteins should ideally also have good metabolic and/or pharmacokinetic profiles and should be suitable for manufacture on a large scale compatible with industrial practice.

Thus, the inventors will engineer antigen binding proteins specific for PRAME-004 peptides comprising CDR variants derived from the parent TCR R11P3D 3. The antigen binding proteins provided herein have increased binding affinity to peptide-MHC complexes and increased stability, such as reduced aggregation during expression and/or purification, and/or increased solubility, thereby making them more suitable for medical use.

Furthermore, the antigen binding proteins of the invention, in particular bispecific T cell engagement receptorsExert high cytotoxicity against PRAME-004 positive tumor cells (e.g. cell lines Hs695T and U2OS cells), with half maximal effective concentration (EC ₅₀ ) Between 1 and 1000 pM. EC (EC) ₅₀ A100-fold, preferably more than 1000-fold, higher comparison to PRAME-004-negative tumor cells (e.g.cell line T98G) indicates an increased safety of the antigen binding proteins of the invention.

Furthermore, the inventors demonstrated significant tumor growth inhibition of the antigen binding proteins of the invention at low doses in a therapeutic in vivo mouse model.

In summary, the surprising findings of the inventors provide, inter alia, the following advantages over the prior art: providing an antigen binding molecule having (i) increased affinity for its target peptide while maintaining high tumor selectivity; (ii) Increased specificity/reduced cross-reactivity, resulting in reduced off-target and extra-tumor cytotoxicity and an overall improved safety profile; (iii) increased stability; (iv) Improved expression yield and solubility, suitable for large-scale production; and (v) reduced immunogenicity.

Disclosure of Invention

In a first aspect, the present invention relates to an antigen binding protein which specifically binds to a PRAME antigenic peptide comprising or consisting of the amino acid sequence SLLQHLIGL of SEQ ID No. 50 and which is in a complex with a Major Histocompatibility Complex (MHC) protein, said antigen binding protein comprising

(a) A first polypeptide comprising a variable domain V comprising Complementarity Determining Regions (CDRs) CDRa1, CDRa2 and CDRa3 _A Wherein

The CDRa1 comprises or consists of: the amino acid sequence VKEFQD (SEQ ID NO: 16) or the amino acid sequence differing from SEQ ID NO:16 by one, two or three amino acid mutations, preferably amino acid substitutions, and

the CDRa3 comprises or consists of: amino acid sequence ALYNNLDMR (SEQ ID NO: 33)

Or ALYNNYDMR (SEQ ID NO: 34) or an amino acid sequence which differs from SEQ ID NO:33 or SEQ ID NO:34 by one, two or three, preferably one or two, amino acid mutations, preferably amino acid substitutions, and

(b) A second polypeptide comprising a variable domain V comprising CDRb1, CDRb2 and CDRb3 _B Wherein

The CDRb1 comprises or consists of: the amino acid sequence SGSNS (SEQ ID NO: 10) or the amino acid sequence which differs from SEQ ID NO:10 by one or two amino acid mutations, preferably amino acid substitutions, and

the CDRb3 comprises or consists of: amino acid sequence ASSX ₁ GX ₂ X ₃ DX ₄ QY(SEQ ID NO:

327 X), wherein X ₁ Is P, A or T, X ₂ Is A or S, X ₃ Is T or I, and X ₄ Is K or A, or is identical to SEQ ID

NO 327 is distinguished by one, two or three amino acid mutations, preferably amino acid substitutions.

In a second aspect, the invention relates to an isolated nucleic acid comprising a sequence encoding the antigen binding protein of the first aspect of the invention.

In a third aspect, the invention relates to a vector comprising a nucleic acid of the second aspect of the invention.

In a fourth aspect, the invention relates to a host cell comprising the antigen binding protein of the first aspect, the nucleic acid of the second aspect or the vector of the third aspect of the invention.

In a fifth aspect, the invention relates to a pharmaceutical composition comprising an antigen binding protein of the first aspect, a nucleic acid of the second aspect, a vector of the third aspect or a host cell of the fourth aspect, and a pharmaceutically acceptable carrier.

In a sixth aspect, the present invention relates to a method of producing an antigen binding protein of the first aspect of the invention, the method comprising

(a) Providing a host cell, wherein the host cell,

(b) Providing a genetic construct comprising a coding sequence encoding an antigen binding protein of the first aspect of the invention,

(c) Introducing the genetic construct into the host cell, and

(d) Expressing the genetic construct by the host cell.

In a seventh aspect, the invention provides an antigen binding protein of the first aspect, a nucleic acid of the second aspect, a vector of the third aspect, a host cell of the fourth aspect or a pharmaceutical composition of the fifth aspect for use in medicine, in particular for use in the diagnosis, prevention and/or treatment of a proliferative disease.

Definition of the definition

“PRAME"OR"Antigens preferentially expressed in melanoma"antigen originally identified as being overexpressed in melanoma (Ikeda et al Immunity.1997, month 2; 6 (2): 199-208); it is also known as CT130, MAPE, OIP-4 and has Uniprot accession number P78395 (available at 1.11.2019). The protein functions as a repressor of retinoic acid receptor signaling (Epping et al, cell.2005, 9, 23; 122 (6): 835-47). PRAME belongs to a germ line encoded antigen called cancer-testis antigenA family. Cancer-testis antigens are attractive targets for immunotherapeutic intervention because they are expressed limited or no in normal adult tissues. PRAME is expressed in a variety of solid tumors and in leukemias and lymphomas (Doolan et al, breast Cancer Res treat.2008, 5 months; 109 (2): 359-65; epping et al, cancer res.2006, 11 months; 66 (22): 10639-42; ercolak et al, breast Cancer Res treat.2008, 5 months; 109 (2): 359-65; matsushita et al, leuk lymphoma.2003, 44 (3): 439-44; mitsuhashi et al, int.j hemalol.4; 100 (1): 88-95; proto 201queire et al, leuk res.2006, 30 (11): 1333-9; szczepanski et al, oral Oncol.3, 2,: 49 (2): 144-51; van Baren et al, br Haatol.1998, 5-6; 1379). PRAME targeted therapies of the invention may be particularly suitable for the treatment of cancers including, but not limited to, acute myeloid leukemia, breast cancer, cholangiocellular carcinoma, biliary cancer, glioblastoma, hepatocellular carcinoma, head and neck squamous cell carcinoma, melanoma, non-hodgkin lymphoma, non-small cell lung adenocarcinoma, non-small cell lung carcinoma, squamous cell non-small cell lung carcinoma, ovarian cancer, esophageal cancer, renal cell carcinoma, small cell lung carcinoma, bladder cancer, uterine and endometrial cancer, chronic lymphocytic leukemia, colorectal cancer, osteosarcoma and synovial sarcoma, preferably breast cancer, cholangiocellular carcinoma, hepatocellular carcinoma, head and neck squamous cell carcinoma, squamous cell non-small cell lung carcinoma, ovarian cancer, esophageal cancer, renal cell carcinoma, small cell lung carcinoma, bladder cancer, uterine and endometrial cancer, and synovial sarcoma.

“PRAME antigenic peptides"comprises or consists of amino acid sequence SLLQHLIGL (SEQ ID NO: 50) which corresponds to amino acids 425-433 of the full length PRAME protein of the amino acid sequence of SEQ ID NO:328, as accessible (e.g.as available at 2019, month 1, 11) under Uniprot accession number P78395. PRAME derived peptides comprising or consisting of the amino acid sequence SLLQHLIGL (SEQ ID NO: 50) are also referred to herein as PRAME-004.PRAME-004 peptides are peptide epitopes derived from tumor-associated or tumor-specific proteins and are presented on the cell surface by Major Histocompatibility Complex (MHC) molecules. More particularly, PRAThe ME-004-derived peptides are presented on the cell surface as complexes with HLA-A.times.02. Med.2001, 1 month 1 day; 193 (1):73-88). In the context of the present invention, the terms "PRAME antigenic peptide", "PRAME peptide" or "PRAME-004" are used interchangeably and refer to a peptide comprising or consisting of the amino acid sequence SLLQHLIGL (SEQ ID NO: 50). Preferably, the PRAME peptide consists of the amino acid sequence SLLQHLIGL. Where the PRAME peptide comprises other amino acids than amino acid sequence SLLQHLIGL, the total length of the PRAME peptide is preferably no more than 12 amino acids.

The term "as used herein"Antigens"OR"Target antigen"refers to a molecule or portion or complex of a molecule capable of being bound by an antigen binding site, such as found in an antibody, TCR, and/or other antigen binding protein of the invention. In the present case, the antigen is a PRAME peptide comprising or consisting of the amino acid sequence SLLQHLIGL of SEQ ID No. 50, more preferably a PRAME peptide comprising or consisting of the amino acid sequence SLLQHLIGL of SEQ ID No. 50 in a complex with an MHC protein (such as an HLA protein, e.g. HLA-a-02).

“Domain'Any region of a protein may be defined, typically based on sequence homology, and is often associated with a particular structural or functional entity.

In the context of the present invention, the term "Immunoglobulin (Ig) domains"refers to a protein domain consisting of a 2-layer sandwich of 7-9 antiparallel beta strands arranged in two beta sheets with greek key topology. Ig domains are probably the most commonly used "building blocks" in naturally occurring proteins. Proteins containing Ig domains are included in the immunoglobulin superfamily, including, for example, antibodies, T Cell Receptors (TCRs), and cell adhesion molecules. Examples of Ig domains are the variable and constant domains of antibodies and TCRs.

In the case of the present invention, V _α Refers to the variable domain of the TCR alpha chain.

In the case of the present invention, V _β Refers to the variable domain of the TCR β chain.

In the case of the present invention, V _γ Refers to the variable domain of the TCR gamma chain.

In the case of the present invention, V _δ Refers to the variable domain of the TCR delta chain.

In the case of the present invention, V _A Refers to a variable domain comprising TCR-derived CDRs, in particular, a chain-derived CDR1a, CDR3a and optionally CDR2 a. The sequences surrounding the CDRs, i.e. the framework sequences, may be derived from the variable domains of the TCR, i.e. the variable domains of the TCR alpha, beta, gamma or delta chains, or from the variable domains of the antibody, preferably from the variable domains of the TCR alpha chain.

In the case of the present invention, V _B Refers to a variable domain comprising TCR-derived CDRs, in particular, beta-chain derived CDR1b, CDR3b and optionally CDR2 b. The sequences surrounding the CDRs, i.e. the framework sequences, may be derived from the variable domains of the TCR, i.e. the variable domains of the TCR alpha, beta, gamma or delta chains, or from the variable domains of the antibody, preferably from the variable domains of the TCR beta chain.

In the case of the present invention, V _L Refers to the variable domain of an antibody light chain.

In the case of the present invention, V _H Refers to the variable domain of an antibody heavy chain.

In the case of the present invention, C _L Refers to the constant domain of the antibody light chain.

In the case of the present invention, C _H1 、C _H2 And C _H3 Refers to the constant domain of an antibody heavy chain, in particular an IgG heavy chain.

The term'Epitope(s)"also known as an antigenic determinant is a portion of an antigen that is recognized by the immune system. As used herein, the term epitope includes the terms "structural epitope" and "functional epitope". "Structural epitopes"are those amino acids in an antigen (e.g., peptide-MHC complex) that are covered by an antigen binding protein when the antigen binding protein binds to the antigen. Typically, the antigen is at any atom of the amino acid of the antigen binding proteinAll amino acids within are considered to be covered. Structural epitopes of antigens can be determined by methods known in the art, including X-ray crystallography or NMR analysis. The structural epitope of an antibody typically comprises 20 to 30 amino acids. The structural epitope of the TCR typically comprises 20 to 30 amino acids. "Functional epitopes"is a subset of those amino acids forming a structural epitope and comprises amino acids in an antigen that are critical for the formation of an interface with the antigen binding protein of the invention or functional fragment thereof (either by direct formation of non-covalent interactions such as H-bonds, salt bridges, aromatic ring stacking or hydrophobic interactions, or by indirect stabilization of the binding conformation of the antigen) and is determined, for example, by mutation scanning. In the context of the present invention, a functional epitope is also referred to as a "binding motif". Typically, the functional epitope in an antigen bound by an antibody comprises between 4 and 6 amino acids. Typically, the functional epitope of the peptide-MHC complex comprises between 2 and 6 or 7 amino acids of the peptide and between 2 and 7 amino acids of the MHC molecule. Since peptides presented by MHC I typically have a length of between 8 amino acids and 10 amino acids, only a subset of the amino acids of each given peptide are part of the functional epitope of the peptide-MHC complex. The epitopes bound by the antigen binding proteins of the invention, in particular functional epitopes, comprise or consist of the amino acids in the antigen required to form a binding interface. In the context of the present invention, the functional epitope (i.e. binding motif) comprises at least amino acids 3, 5 and 7, preferably none of amino acids 1 and 4 of the PRAME-004 antigenic peptide of SEQ ID NO: 50.

“Major histocompatibility complex"(MHC) is a group of cell surface proteins necessary for the adaptive immune system to recognize foreign molecules in vertebrates and subsequently determine histocompatibility. The main function of MHC molecules is to bind to antigens derived from pathogens and display them on the cell surface for proper T cell recognition. Human MHC is also known as HLA (human leukocyte antigen) complex (or HLA alone). The MHC gene family is divided into three subgroups: class I, class II and class III. Complexes of peptides with MHC class I are recognized by CD8 positive T cells carrying the appropriate T Cell Receptor (TCR), while complexes of peptides with MHC class II molecules are attenuated by CD4 positive helper T carrying the appropriate TCRAnd (5) cell identification. Since both CD8 and CD4 dependent responses combine and synergistically promote anti-tumor effects, the identification and characterization of tumor-associated antigens and corresponding T cell receptors is of great importance in the development of cancer immunotherapy (e.g. vaccines) and cell therapies. The HLA-A gene is located on the short arm of chromosome 6 and encodes the larger component alpha chain of HLA-A. Variation of HLA-A alpha chains is critical for HLa function. This variation promotes genetic diversity in the population. Because each HLA has a different affinity for certain structural peptides, a larger class of HLA means that a larger class of antigen is "presented" on the cell surface. In the context of the present disclosure, the MHC class I HLA protein may be an HLA-a, HLA-B or HLA-C protein, suitably an HLA-a protein, for example HLA-a x 02. In an MHC class I-dependent immune response, peptides must not only be able to bind to certain MHC class I molecules expressed by tumor cells, they must then also be recognized by T cells carrying specific T Cell Receptors (TCRs).

Herein "Antigenic peptides in complexes with MHC proteins"refers to antigenic peptides that are non-covalently bound to MHC molecules. In particular, antigenic peptides are localized to the "peptide binding groove" formed by MHC molecules. Complexes of MHC molecules with antigenic peptides are also referred to herein as "peptide-MHC complexes" or "pMHC complexes". In the case of PRAME antigenic peptides, the complex is also referred to as "PRAME antigenic peptide-MHC complex" or "PRAME-004: MHC complex".

“HLA-A*02"means a specific HLA allele, wherein the letter a means an allele and the prefix" ×02 prefix "means A2 serotype.

Terms herein"antigen binding proteins"refers to a polypeptide comprising an antigen binding site capable of specifically binding to an antigen. The antigen binding proteins of the invention comprise TCR-derived CDRs, in particular variable domain V comprising TCR-derived CDRa1, CDRa3 and optionally CDRa2 _A And variable domain V comprising TCR-derived CDRb1, CDRb3 and optionally CDRb2 _B . In particular embodiments, the entire V _A Domain and/or whole V _B The domain is of TCR origin and is therefore V _α And V _β Or V _γ And V _δ A domain. In the context of the present specification, the term antigen binding protein includes a plurality of TCR and antibody formats, as defined below. In one example, the antigen binding protein comprises TCR-derived CDRs, in particular TCR-derived CDRa1, CDRa3, CDRb1, CDRb3 and optionally CDRa2 and CDRb2 as defined in the claims, which have been grafted onto the antibody heavy and light chains. In another example, the entire TCR source V _α Domain and/or whole TCR-derived V _β The domains are grafted onto the heavy and light chains of the antibody. Those skilled in the art understand that such constructs represent hybrid antigen binding proteins that will have the antigen specificity of a TCR from which CDRs or variable domains are derived, but will have the overall structure of an antibody and thus may be referred to as an "antibody". The term antigen binding protein also includes bispecific or multispecific antigen binding proteins. Except for V comprising a TCR-derived CDRa1, CDRa3, CDRb1, CDRb3 and optionally CDRa2 and CDRb2 as defined in the claims _A And V _B In addition, such bispecific or multispecific antigen-binding proteins further comprise at least one further variable domain and optionally a constant domain, wherein the variable domain and/or constant domain may be derived from an antibody or TCR. Also, it is understood by those skilled in the art that such constructs comprising elements of both antibodies and TCRs represent heterozygous forms, and may be referred to as "bispecific TCRs", "bispecific antibodies" or "bispecific TCR-antibody molecules", depending on the composition of the antigen binding protein, as well as on the opinion and/or focus of those skilled in the art. In some embodiments, the antigen binding proteins of the invention comprise a V comprising a TCR-derived CDRa1, CDRa3, CDRb1, CDRb3 and optionally CDRa2 and CDRb2 as defined in the claims _A And V _B And also contain and V _A Or V _B Additional domains fused directly or indirectly. Such antigen binding proteins may be referred to as "TCR fusion proteins". Examples of additional domains contained in "TCR fusion proteins" are listed below. In a preferred embodiment, the antigen binding protein is a bispecific TCR-antibody molecule as defined below, more preferably as followsBispecific T cell engagement receptor as defined hereinIn such embodiments, the antigen binding protein comprises two different antigen binding sites and is capable of binding specifically to two different antigens simultaneously, as is known, for example, from bispecific antibodies.

In one embodiment, the antigen binding proteins of the present disclosure specifically bind to a PRAME antigenic peptide comprising or consisting of the amino acid sequence SLLQHLIGL of SEQ ID No. 50 and in a complex with a Major Histocompatibility Complex (MHC) protein comprising

The CDRA1 comprises the amino acid sequence VKEFQD (SEQ ID NO: 16) or an amino acid sequence which differs from SEQ ID NO:16 by at most one, at most two or at most three amino acid substitutions, and

The CDRA3 comprises an amino acid sequence of ALYNNLDMR (SEQ ID NO: 33) or ALYNNYDMR (SEQ ID NO: 34), or differs from SEQ ID NO:33 or SEQ ID NO:34 by at most one, at most two or at most three amino acid substitutions, and

the CDRA2 comprises the amino acid sequence FGPYGKE (SEQ ID NO: 32) or an amino acid sequence which differs from SEQ ID NO:32 by at most one, at most two or at least three amino acid substitutions, and

The CDRB1 comprises the amino acid sequence SGSNS (SEQ ID NO: 10) or an amino acid sequence which differs from SEQ ID NO:10 by at most one or at most two amino acid substitutions, and

the CDRb3 comprises an amino acid sequence ASSX ₁ GX ₂ X ₃ DX ₄ QY (SEQ ID NO: 327), wherein X ₁ Is P, A or T, X ₂ Is A or S, X ₃ Is T or I, and X ₄ Is K or A, or an amino acid sequence which differs from SEQ ID NO 327 by at most one, at most two or at most three amino acid substitutions, and

the CDRb2 comprises the amino acid sequence FQNTAV (SEQ ID NO: 36) or a CDRb2 amino acid sequence differing from SEQ ID NO:36 by at most one, at most two, at most three, at most four, at most five or at most six amino acid substitutions.

In one embodiment, the antigen binding proteins of the present disclosure comprise

CDRA1 comprising SEQ ID NO. 16,

CDRA2 comprising SEQ ID NO. 32,

CDRA3 comprising SEQ ID NO. 33,

CDRB1 comprising SEQ ID NO. 10,

CDRB2 comprising SEQ ID NO. 36

CDRB3 comprising SEQ ID NO 327.

CDRA1 comprising SEQ ID NO. 16,

CDRA2 comprising SEQ ID NO. 32,

CDRA3 comprising SEQ ID NO. 34,

CDRB1 comprising SEQ ID NO. 10,

CDRB2 comprising SEQ ID NO. 36

CDRB3 comprising SEQ ID NO 327.

In one embodiment, the amino acid substitution is a conservative amino acid substitution.

"herein"At least one of"refers to one or more specified objects, such as 1, 2, 3, 4, 5, or 6 or more specified objects. For example, at least one binding site herein refers to 1, 2, 3, 4, 5, or 6 or more binding sites.

In the context of the present invention, the term "Bispecific'By antigen binding protein is meant that has at least two binding valences and binding specificities for two different antigens, and thus comprises at least two antigen binding sites. The term'Binding value"means The number of binding sites in an antigen binding protein, e.g. a bivalent antigen binding protein, refers to an antigen binding protein having two binding sites. The binding sites may bind to the same or different targets, i.e. the bivalent antigen binding protein may be monospecific, i.e. bind to one target, or bispecific, i.e. bind to two different targets. The antigen binding molecules of the invention comprise at least one antigen binding site comprising TCR-derived CDRs. In a preferred embodiment, the antigen binding molecules of the invention comprise at least one TCR-derived antigen binding site.

The term "as used herein"TCR"is intended to include conventional/native TCRs and engineered TCRs, particularly functional TCR fragments, single chain TCRs and bispecific or multispecific TCRs.

“Native TCR"refers to a wild-type TCR that can be isolated from nature. TCRs having the same type of domain and domain arrangement as native TCRs and comprising TCR-derived CDRs and framework regions can also be referred to as "TCRs"Conventional TCR". Native/conventional TCRs are heterodimeric cell surface proteins of the immunoglobulin superfamily, which are associated with invariant proteins of the CD3 complex involved in mediating signal transduction. Native heterodimeric TCRs exist in αβ and γδ forms that are structurally similar but have different positions and possible functions. The extracellular portions of native heterodimeric δ1δ0 and γδtcrs contain two polypeptides, each of which has a membrane-proximal constant domain (also referred to as a constant region) and a membrane-distal variable domain (also referred to as a variable region). In the context of the present invention, such TCRs are also referred to as full length TCRs. The native αδ2 heterodimeric TCR has an α chain and a β chain. The alpha chain comprises variable (V), junction (J) and constant (C) regions, and the beta chain comprises V, J and C regions and typically also comprises a short diversity (D) region between the variable and junction regions, but this diversity region is typically considered to be part of the junction region. The constant regions of the TCR alpha and beta chains are referred to as TRAC and TRBC (Lefranc, (2001), curr Protoc Immunol Appendix 1:appdix 10), respectively. In the context of the present invention, the constant regions of the TCR alpha and beta chains (TRAC and TRBC) comprise Transmembrane (TM) regions. Each of the constant and variable regions (or domains) includes an intrachain disulfide bond. The variable domain contains A highly polymorphic loop similar to the Complementarity Determining Regions (CDRs) of an antibody.

Each TCR variable domain comprises three "embedded in a framework sequence"TCR complementarity determining region"(CDR), one is a hypervariable region called CDR 3. In the case of the present invention, CDRa1, CDRa2 and CDRa3 represent alpha chain CDRs and CDRb1, CDRb2 and CDRb3 represent beta chain CDRs. There are several types of alpha chain variable domains and several types of beta chain variable domains, distinguished by their framework, CDR1 and CDR2 sequences, and by the partially defined CDR3 sequences. The alpha chain variable domain types are referred to by unique TRAV numbering in IMGT nomenclature, the beta chain variable domain types are referred to by unique TRBV numbering in IMGT nomenclature (Folch and Lefranc, (2000), exp Clin Immunogenet (1): 42-54; scaviner and Lefranc, (2000), exp Clin Immunogenet (2): 83-96; lefranc and Lefranc, (2001), "T cell Receptor Factsbook", academic Press). Additional information about antibodies and TCR genes can be found in international ImMunoGeneTics informationLefranc M-P et al (Nucleic Acids Res.2015, 1 month; 43 (Database issue): D413-22; andhttp://www.imgt.org/) Is a kind of medium. In TCRs, the CDR1 and CDR3 amino acid residues are contacted with the antigenic peptide, while the CDR2 amino acid residues are predominantly contacted with the HLA molecule (Stadinski et al, J Immunol.2014, 6, 15; 192 (12): 6071-6082; cole et al, J Biol chem.2014, 1, 10; 289 (2): 628-38). The antigen specificity of a TCR is thus defined by CDR3 and CDR1 sequences. CDR2 sequences are not required for determination of antigen specificity, but may play a role in the overall affinity of the TCR for peptide-MHC complex.

“TCR frame region"(FR) refers to the amino acid sequence inserted between CDRs, i.e., refers to those portions of the variable domain that are conserved to some extent between different TCRs. The α, β, γ and δ chain variable domains each have four FRs, designated herein as FR1-a, FR2-a, FR3-a, FR4-a (for the α or γ chain), and FR1-b, FR2-b, FR3-b, FR4-b (for the β or δ chain), respectively. Thus, the alpha chain or gamma chain variable domain can beDescribed as (FR 1-a) - (CDRa 1) - (FR 2-a) - (CDRa 2) - (FR 3-a) - (CDRa 3) - (FR 4-a), and the β -or δ -chain variable domain may be described as (FR 1-b) - (CDRb 1) - (FR 2-b) - (CDRb 2) - (FR 3-b) - (CDRb 3) - (FR 4-b). In the context of the present invention, the CDR/FR sequences in the variable domains of the alpha, beta, gamma or delta chains are determined based on the IMGT definition (Lefranc et al, dev. Comp. Immunol.,2003,27 (1): 55-77; www. IMGT. Org). Thus, when related to TCR or TCR-derived domains, CDR/FR amino acid positions are expressed according to the IMGT definition. Preferably, variable domain V _α The IMGT positions of CDR/FR amino acid positions are given in analogy to the IMGT numbering of TRAV24 x 01, and/or variable domain V _β The IMGT positions of the CDR/FR amino acid positions of (2) are given in analogy to the IMGT numbers of TRBV 12-3.times.01.

In the context of the present invention, the term "Alpha/beta TCR/CD3 complex"refers to a T cell receptor complex as present on the surface of a T cell. Most T cells express an α/β TCR, which consists of disulfide-bonded α and β chains, which typically bind to the complex surface of antigenic peptides presented by MHC. The TCR itself does not emit a signal, but is constitutively associated with CD3, a protein complex designated T cell co-receptor and containing an intracellular signaling motif (Birnbaum et al; PNAS volume 11, 49; 17576-17581,2014). The α/β TCR is non-covalently coupled to this conserved multi-subunit signaling device, which comprises CD3 epsilon gamma, CD3 epsilon delta, and CD3 zeta dimers that together form the α/β TCR/CD3 complex.

“CD3"is a protein complex and consists of four distinct chains. In mammals, the complex contains a CD3 gamma chain, a CD3 delta chain, and two CD3 epsilon chains. In T lymphocytes, these chains associate with TCR and ζ chains to generate activation signals.

In particular, engineered TCRs (and thus the term "TCR" as used in the context of the present invention) include functional TCR fragments, stable mature TCRs, affinity mature TCRs, single chain TCRs, chimeric, humanized, bispecific and multispecific TCRs. " Functional TCR fragments"fragments comprising (a) native or conventional TCRs which retain the TCR from which they were derived in binding to target antigenAnd (b) a recombinant/engineered antigen binding protein comprising TCR-derived CDR sequences, in particular CDR1, CDR3 and optionally CDR2 sequences. Because binding to the target antigen is defined by these CDR sequences, the antigen binding proteins comprising them retain the ability of the TCR from which the CDRs are derived to bind to the target antigen. Those skilled in the art will appreciate that CDRs must be interspersed with Framework Regions (FR), but that the particular amino acid sequence is not critical for target antigen specificity. The variable domains comprising TCR-derived CDRs and antibody-derived FRs can thus be regarded as "functional TCR fragments". Other examples of functional TCR fragments include single variable domains, e.g. V _α 、V _β 、V _δ 、V _γ Or fragments of alpha, beta, delta, gamma chains, e.g. "V _α -C _α "or" V _β -C _β "or a portion thereof. Such segments may additionally comprise a corresponding hinge region. "as used herein"Single chain TCR (scTCR)"means a TCR wherein the variable domain of the TCR is located on a single polypeptide. Typically, the variable domains in sctcrs are separated by a linker, wherein the linker typically comprises 10 to 30 amino acids, such as 25 amino acids.

"herein"Chimeric TCR'Refers to a TCR wherein the TCR chain comprises a series from a plurality of species. Preferably, in the context of the present invention, a TCR may comprise an alpha chain comprising a human alpha chain variable region, e.g. a murine constant region of a murine TCR alpha chain. "Bispecific TCR"including bispecific TCR-antibody molecules, particularly scTCR-F _ab Or T cell engagement receptorAs defined below.

The term "as used herein"Antibodies to"is intended to include both conventional/natural antibodies and engineered antibodies, particularly functional antibody fragments, single chain antibodies, single domain antibodies, bispecific or multispecific antibodies.

“Natural antibody"refers to a wild-type antibody that can be isolated from nature. Has a phase with natural antibodiesAntibodies of the same type and arrangement of domains and comprising antibody-derived CDR and FR sequences may also be referred to as "Conventional antibodies". In natural/conventional antibodies, two heavy chains are linked to each other by disulfide bonds, and each heavy chain is linked to a light chain by disulfide bonds. There are two types of light chains, namely Lanbuda (lambda) and Kapa (kappa). There are five major heavy chain classes (or isotypes) that determine the functional activity of an antibody molecule: igM, igD, igG, igA and IgE. Each chain contains a different domain (also referred to as a region). The light chain comprises two domains, i.e. the variable domains (V _L ) And constant domain (C _L ). The heavy chain comprises four or five domains, depending on the antibody isotype; i.e. the variable domain (V) _H ) And three or four constant domains (C _H1 、C _H2 And C _H3 And optionally C _H4 Collectively referred to as C _H ). Light chain (V) _L ) And heavy chain (V) _H ) The variable domains of both determine the binding recognition and specificity to the antigen. Light chain (C) _L ) And heavy chain (C) _H ) Conferring important biological properties such as antibody chain association, secretion, trans-placental mobility, complement fixation and F _c Receptors (F) _c R) is a combination of two or more of the above.

The specificity of an antibody exists in the structural complementarity between the binding site of the antibody and the epitope. The binding site of the antibody is derived mainly from "Antibody complementarity determining region'(CDR) or hypervariable region residues. Occasionally, residues from non-hypervariable regions or Framework Regions (FR) affect the overall domain structure and thus the binding site. CDRs refer to amino acid sequences that together define the binding affinity and specificity of the native Fv region of the native antibody binding site. The light and heavy chains of antibodies each have three CDRs, designated CDR1-L, CDR2-L, CDR-L and CDR1-H, CDR2-H, CDR3-H, respectively. Thus, an antibody antigen binding site comprises six CDRs, including sets of CDRs from each of the heavy and light chain V regions. " Antibody framework regions"(FR) refers to the amino acid sequence inserted between CDRs, i.e., refers to those portions of the antibody light and heavy chain variable regions that are relatively conserved between different antibodies of a single species. Light chain and heavy chain of antibodiesEach has four FRs, designated FR1-L, FR2-L, FR-L, FR-L and FR1-H, FR2-H, FR3-H, FR-H, respectively. Thus, the light chain variable domain may be described as (FR 1-L) - (CDR 1-L) - (FR 2-L) - (CDR 2-L) - (FR 3-L) - (CDR 3-L) - (FR 4-L), and the heavy chain variable domain may be described as (FR 1-H) - (CDR 1-H) - (FR 2-H) - (CDR 2-H) - (FR 3-H) - (CDR 3-H) - (FR 4-H). As used herein, a "human framework region" is a framework region that is substantially identical (about 85% or more, particularly 90%, 95%, 97%, 99% or 100%) to the framework region of a naturally occurring human antibody. In the context of the present invention, the CDR/FR definitions in the antibody light or heavy chain variable domains are determined based on the IMGT definition (Lefranc et al, dev. Comp. Immunol.,2003,27 (1): 55-77; www. IMGT. Org). Thus, the amino acid sequences of CDR1, CDR2 and CDR3 and the amino acid sequences of FR1, FR2, FR3 and FR4 of a given variable chain are expressed according to the IMGT definition.

Engineered antibody forms include functional antibody fragments, single chain antibodies, single domain antibodies, and chimeric, humanized, bispecific or multispecific antibodies. Engineered antibody forms also include constructs in which TCR-derived CDRs (possibly comprising additional 3,2 or 1N-terminal and/or C-terminal framework residues) or the entire TCR-derived variable domain are grafted onto an antibody heavy or light chain. More particularly, CDRa1, CDRa3 and optionally CDRa2 can be grafted into a variable heavy chain amino acid sequence, and CDRb1, CDRb3 and optionally CDRb2 can be grafted into a variable light chain amino acid sequence, or vice versa. As another example, the light chain variable domain of an antibody may be replaced by the alpha chain variable domain of a TCR, and the heavy chain variable domain may be replaced by the beta chain variable domain of a TCR, or vice versa. " Functional antibody fragments"refers to the portion of a full length antibody that retains the ability to bind to its target antigen, and in particular to the antigen binding or variable regions of a full length antibody. Examples of functional antibody fragments include Fv, fab, F (ab ') 2, fab', dsFv, (dsFv) 2, scFv, sc (Fv) 2 and diabodies. The functional antibody fragment may also be a single domain antibody, such as a heavy chain antibody. The term "Fab" refers to an antibody fragment having a molecular weight of about 50,000 daltons and antigen binding activity, wherein upon passage through an eggIn fragments obtained by treating IgG with a protease (e.g., papain), about half of the N-terminal side of the H chain and the entire L chain are bound together via disulfide bonds. Fv fragments are the N-terminal part of antibody Fab fragments and consist of a variable part of one light chain and one heavy chain.

As used herein, the "form" of an antigen binding protein specifies a defined spatial arrangement of domains, in particular variable domains and optionally constant domains. Important features of such antigen binding protein forms are the number of polypeptide chains (single chain, double chain or multiple chain), the type and length of the linker connecting the different domains, the number of variable domains (and thus the number of binding valences), the number of different variable domains (and thus the number of specificities for different antigens, e.g. bispecific, multispecific), and the order and orientation (e.g. cross, parallel) of the variable domains.

Many different bispecific and multispecific forms are described in the art of antibody contexts, and as will be appreciated by those skilled in the art, such bispecific and multispecific forms can be used in the context of the present invention by substituting in these forms the variable domains described in the context of the present invention for antibody domains. Such forms include, for example, diabodies, cross-double variable domain (CODV) and Double Variable Domain (DVD) proteins. An overview of different bispecific antibody formats and the manner in which they are produced is disclosed, for example, in Brinkmann u. And Kontermann e.e.mabs.2017, 2-3 months; 9 (2) 182-212. DVD formats are disclosed, for example, in the following scientific papers (Wu C et al Nat Biotechnol 2007;25:1290-7;PMID:17934452;Wu C. Et al MAbs 2009;1:339-47; lacy SE et al MAbs 2015;7:605-19;PMID:25764208;Craig RB et al PLoS One 2012;7:e46778;PMID:23056448;Piccione EC et al MAbs 2015). CODV is disclosed, for example, in ontouha SC et al arthoritis rheomol.2015 for 10 months; 67 (10) 2661-72 or, for example, WO 2012/135345, WO 2016/116626. Diabodies are described, for example, in the following documents: holliger P et al Protein Eng 1996;9:299-305; PMID 8736497; atwell JL et al Mol Immunol 1996;33:1301-12; PMID 9171890; kontermann RE, nat Biotechnol 1997;15:629-31; PMID 9219263; kontermann RE et al Immunotechnology 1997;3:137-44; PMID 9237098; cochlovus B et al Cancer Res 2000;60:4336-41; PMID 10969772; deNardo DG et al Cancer Biother Radiopharm 2001;16:525-35; PMID 11789029.

“Diabodies"refers to a bivalent molecule consisting of two chains, each chain comprising two variable domains from the same or different antibodies. If the antibodies are different, one antibody (comprising V _LX And V _HX The variable domain of antibody X) is located on two different polypeptide chains, and the other antibody (comprising V) _LY And V _HY The variable domains of antibody Y) of (c) are also located on two different polypeptide chains. The domains dimerize in a head-to-tail orientation. Both strands may have configuration V _HX -L _Db1 -V _LY And V _HY -L _Db2 -V _LX Or V _LX -L _Db1 -V _HY And V _LY -L _Db2 -V _HX Or V _HX -L _Db1 -V _HY And V _LY -L _Db2 -V _LX Or V _LX -L _Db1 -V _LY And V _HY -L _Db2 -V _HX . To allow the domains to dimerize head to tail, both strands contain linkers, i.e., L _Db1 And L _Db2 The linkers separate the variable domains and may be the same or different. The linker is preferably a short linker. Short linkers are typically between 2 and 12, 3 and 13, such as 3, 4, 5, 6, 7, 8, 9 amino acids in length, for example 4, 5 (Brinkmann U. And Kontermann E.E.MAbs.2017, month 2-3; 9 (2): 182-212) or 8 amino acids in length, such as "GGGS" of SEQ ID NO:290, "GGGGS" of SEQ ID NO:286 or "GGGSGGGG" of SEQ ID NO: 214.

In'Dual variable domain immunoglobulins ”(DVD-Ig ^TM ) In the "form, the target binding variable domain of monoclonal antibody Y (domain V _LY And V _HY ) In general with conventional antibody X (comprising domain V _LX And V _HX ) Fusion, wherein the light chain of conventional antibody X thus comprises an additional light chain variable domain (V _LY ) And the heavy chain of conventional antibody X comprises an additional heavy chain variable domain (V _HY ). DVD-Ig as described in the art ^TM Usually consisting of two polypeptide chains, one comprising V _HY -L ₁ -V _HX -L ₂ -C _H1 -C _H2 -C _H3 Heavy chain of (A) and a chain comprising V _LY -L ₃ -V _LX -L ₄ The light chain of CL, or a chain comprising V _HX -L ₁ -V _HY -L ₂ -C _H1 -C _H2 -C _H3 Heavy chain of (A) and a chain comprising V _LX -L ₃ -V _LY -L ₄ -C _L Is a light chain of (c). Domain V _HY /V _LY And V _HX /V _LX Thus paired in parallel. Connection joint L ₁ And L ₃ Preferably between 5 and 20 amino acids, such as 5 to 15 amino acids, and/or the linker L ₂ And L ₄ May be present or absent.

As described in the art "Cross double variable domainsThe "(CODV) form represents a form in which the variable domain of antibody X (V _LX And V _HX ) Variable domain of antibody Y (V _LY And V _HY ) Connected in a manner that allows cross pairing of the variable domains.

In the case of the present invention, in the CODV-Ig form, the polypeptide chain has, for example, configuration V _HX -L ₁ -V _HY -L ₂ -C _H1 -C _H2 -C _H3 And V _LY -L ₃ -V _LX -L ₄ -C _L Or V _HY -L ₁ -V _HX -L ₂ -C _H1 -C _H2 -C _H3 And V _LX -L ₃ -V _LY -L ₄ -C _L Or V _HX -L ₃ -V _HY -L ₄ -C _H1 -C _H2 -C _H3 And V _LY -L ₁ -V _LX -L ₂ -C _L Or V _HY -L ₃ -V _HX -L ₄ -C _H1 -C _H2 -C _H3 And V _LX -L ₁ -V _LY -L ₂ -C _L . Joint (L) ₁ To L ₄ ) Typically of different lengths, they may also be hologlycine linkers or serine-glycine linkers. To allow cross-pairing, one chain (heavy or light) typically contains a longer linker than the other. For example, in the CODV configuration listed above, L ₁ Is 3 to 12 amino acid residues in length, L ₂ Is 3 to 14 amino acid residues in length, L ₃ Is 1 to 8 amino acid residues in length, and L ₄ Is 1 to 3 amino acid residues in length, or L ₁ Is 5 to 10 amino acid residues in length, L ₂ Is 5 to 8 amino acid residues in length, L ₃ Is 1 to 5 amino acid residues in length, and L ₄ Is 1 to 2 amino acid residues in length, or L ₁ Is 7 amino acid residues in length, L ₂ Is 5 amino acid residues in length, L ₃ Is 1 amino acid residue in length, and L ₄ Is 2 amino acid residues in length.

The term'Humanized antibodies"refers to antibodies that are of wholly or partially non-human origin and that have been modified by substitution of certain amino acids, particularly in the framework regions of the heavy and light chains, to avoid or minimize the immune response in humans. The constant domain of humanized antibodies is predominantly human C _H And C _L A domain. Various methods for humanization of antibody sequences are known in the art; see, e.g., almagro and Franson (2008) Front biosci.13:1619-1633 for reviews.

As will be appreciated by those skilled in the art, the structure of antibodies, particularly the structure of the antibody heavy and light chain variable domains, is similar to that of TCR alpha, beta, gamma or delta chain variable domains, thereby facilitating grafting of CDRs as defined in the context of the present invention into antibodies (including conventional antibodies, bispecific antibodies or multispecific antibodies).

Knowing the amino acid sequence of the CDRs of an antibody, TCR or antigen-binding protein of the invention, one skilled in the art can readily determine framework regions, such as TCR framework regions or antibody framework regions. In the case where no CDR is indicated, one skilled in the art can first determine the CDR amino acid sequence based on the IMGT definition of the TCR or the IMGT definition of the antibody, and then determine the amino acid sequence of the framework region.

Bispecific TCR-antibody formats

In a preferred embodiment, the antigen binding protein of the invention is a bispecific molecule, in particular a bispecific TCR-antibody molecule, i.e. an antigen binding protein comprising at least two antigen binding sites, one derived from an antibody and the other derived from a TCR or comprising at least TCR-derived CDRs, in particular CDR1a, CDR3a, CDR1b, CDR3b and optionally CDR2a and CDR2b. The antigen binding site derived from an antibody comprises a variable domain V _L And V _H 。

In such bispecific TCR-antibody molecules, the variable domains may be arranged, for example, as described for the different bispecific antibody formats discussed above. Techniques for producing such bispecific antibodies are also disclosed in the prior art cited above, and the skilled artisan can thereby readily use the CDRs or variable domains as defined herein to generate and produce the antigen binding proteins of the invention in the forms disclosed herein. In addition, other forms are possible, such as the following: wherein on each chain the variable domains are separated by a constant domain that mediates dimerization, such that in the final molecule, two antigen binding sites are located on either side of the constant domain of dimerization. Those skilled in the art are well able to select an appropriate linker to ensure folding in the desired conformation.

In a most preferred embodiment, the antigen binding proteins of the invention are bispecific T cell engagement receptorsWhich is a soluble F-containing antigen binding site comprising a TCR antigen binding site and an antibody antigen binding site _c Is described. The antibody antigen binding site is formed by the heavy and light chain variable domains of an antibody and is also referred to as a "recruiter" because it binds effector cells, e.g., T cells, and recruits the cells to a tumor.Comprising two polypeptide chains, wherein the antigen binding site is formed by variable domains positioned in a cross orientation on different polypeptide chains.

In the context of the present application, "At least 85% identical to the reference sequence"is a sequence having 85% or more, in particular 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity over the entire length to the entire length of the reference sequence. Proteins consisting of amino acid sequences that are "at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identical" to a reference sequence may comprise mutations, such as deletions, insertions and/or substitutions, as compared to the reference sequence. In the case of substitution, a protein consisting of an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to a reference sequence may correspond to a homologous sequence derived from another species different from the reference sequence.

In the context of the present application, "Percent identity"can be calculated using global alignment (i.e., comparing two sequences over their entire lengths). Methods for comparing identity of two or more sequences are well known in the art. For example, a "needle" program can be used that uses a Needleman-Wunsch global alignment algorithm (Needleman and Wunsch,1970J. Mol. Biol. 48:443-453) to find the optimal alignment (including gaps) of two sequences, taking into account the entire length of the two sequences. needle programs are available, for example, on the ebi.ac.uk web site and are further described in the following publications (EMBOSS: the European Molecular Biology Open Software Suite (2000) Rice, P.longden, I.and Bleasby, A.trends in Genetics 16, (6) pages 276-277). According to the invention, the percentage identity between two polypeptides is calculated using the EMBOSS: needle (global) program, wherein the "vacancy open" parameter is equal to 10.0, the "vacancy extended" parameter is equal to 0.5, and the Blosum62 matrix is used.

“Amino acid substitutions"may be conservative or non-conservative". Preferably, the substitution is a conservative substitution, whereinOne amino acid is substituted for another amino acid having similar structural and/or chemical properties.

In one embodiment, conservative substitutions may include those described by Dayhoff under "The Atlas of Protein Sequence and structure, volume 5", natl.biomedical Research, the contents of which are incorporated by reference in their entirety. For example, in one aspect, amino acids belonging to one of the following groups may be interchanged, thereby constituting a conservative exchange: group 1: alanine (a), proline (P), glycine (G), asparagine (N), serine (S), threonine (T); group 2: cysteine (C), serine (S), tyrosine (Y), threonine (T); group 3: valine (V), isoleucine (I), leucine (L), methionine (M), alanine (a), phenylalanine (F); group 4: lysine (K), arginine (R), histidine (H); group 5: phenylalanine (F), tyrosine (Y), tryptophan (W), histidine (H); group 6: aspartic acid (D), glutamic acid (E). In one aspect, the conservative amino acid substitution may be selected from the following: t→ A, G → A, A → I, T → V, A → M, T → I, A → V, T →G and/or T→S.

In another embodiment, conservative amino acid substitutions may include substitution of another amino acid with the same class of amino acids, e.g., (1) non-polar: ala, val, leu, ile, pro, met, phe, trp; (2) uncharged polarity: gly, ser, thr, cys, tyr, asn, gln; (3) acidity: asp, glu; and (4) alkaline: lys, arg, his. Other conservative amino acid substitutions may also be made as follows: (1) aromatic: phe, tyr, his; (2) proton donor: asn, gln, lys, arg, his, trp; and (3) proton acceptor: glu, asp, thr, ser, tyr, asn, gln (see, e.g., U.S. patent No. 10,106,805, the contents of which are incorporated by reference in their entirety).

In another embodiment, conservative substitutions may be made according to table 1. Methods for predicting tolerance to protein modifications can be found, for example, in Guo et al, proc.Natl.Acad.Sci., USA,101 (25): 9205-9210 (2004), the contents of which are incorporated by reference in their entirety.

Table 1: conservative amino acid substitutions

In another embodiment, conservative substitutions may be those shown under the heading "conservative substitutions" in table 2. If such substitutions result in a change in biological activity, more substantial changes can be introduced, designated as "exemplary substitutions" in Table 2, and the products can be screened if desired.

Table 2: amino acid substitutions

The antigen binding proteins of the invention may be of any length, i.e. may comprise any number of amino acids, provided that they retain their biological activity, e.g. the ability to specifically bind to their target antigens, detect diseased cells in a host, or treat or prevent diseases in a host, etc.

The antigen binding proteins of the invention may comprise synthetic amino acids in place of one or more naturally occurring amino acids. Such synthetic amino acids are known in the art and may include, for example, aminocyclohexane carboxylic acid, norleucine, α -amino-N-decanoic acid, homoserine, S-acetylaminomethyl-cysteine, trans-3-hydroxyproline and trans-4-hydroxyproline, 4-aminophenylalanine, 4-nitrophenylalanine, 4-chlorophenylalanine, 4-carboxyphenylalanine, β -phenylserine β -hydroxyphenylalanine, phenylglycine, α -naphthylalanine, cyclohexylalanine, cyclohexylglycine, indoline-2-carboxylic acid, 1,2,3, 4-tetrahydroisoquinoline-3-carboxylic acid, aminomalonic acid monoamide, N ' -benzyl-N ' -methyl-lysine, N ' -dibenzyl-lysine, 6-hydroxylysine, ornithine, α -aminocyclopentane carboxylic acid, α -aminocyclohexane carboxylic acid, α - (2-amino-2-norbornane) -carboxylic acid, α, γ -diaminobutyric acid, α, β -diaminopropionic acid, homophenylalanine and α -tert-butylglycine.

In one embodiment, the antigen binding proteins of the invention may be glycosylated, amidated, carboxylated, phosphorylated, esterified, N-acylated, cyclized via, for example, a disulfide bridge, or converted to an acid addition salt and/or optionally dimerized or multimerized, or conjugated.

In another embodiment, the antigen binding proteins of the invention are in the form of salts, e.g., pharmaceutically acceptable salts. Suitable pharmaceutically acceptable acid addition salts may include those derived from: inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid, and sulfuric acid; and organic acids such as tartaric acid, acetic acid, citric acid, malic acid, lactic acid, fumaric acid, benzoic acid, glycolic acid, gluconic acid, succinic acid, and arylsulfonic acid, for example, p-toluenesulfonic acid.

"herein"Covalent attachment"for example, refers to disulfide bridges or peptide linkages or covalent linkages via a linker or linker sequence (e.g., a polypeptide linker).

The term "as used herein"Joint"refers to one or more amino acid residues inserted between domains or between a domain and an agent that provide sufficient flexibility to the domain or element, e.g., to allow the variable domains of the antigen binding proteins of the invention to fold correctly to form antigen binding sites, e.g., in cross-pairing (in CODV format or in some diabody format) or in parallel pairing configuration (e.g., in DVD format) of the antigen binding proteins.

In some embodiments, a linker consisting of 0 amino acids means that the linker is absent. At the amino acid sequence level, linkers are inserted at the transition between the variable domains or between the variable domain and the constant domain (or dimerization domain), respectively. Transitions between domains can be identified because the general size of the antibody domain as well as the TCR domain is well understood. The exact location of the domain transition can be determined by locating peptide stretches that do not form secondary structural elements (such as beta sheets or alpha helices), as confirmed by experimental data or as can be assumed by modeling or techniques of secondary structure prediction. The term linker as used in the context of the present invention includes but is not limited toNot limited to being referred to as L ₁ 、L ₂ 、L ₃ 、L ₄ 、L ₅ And L ₆ Is a joint of a metal wire.

The linker being e.g. L, provided that it is not otherwise provided in the corresponding context ₁ 、L ₂ 、L ₃ 、L ₄ 、L ₅ And L ₆ May be at least 1 to 30 amino acids in length. In some embodiments, a linker such as L ₁ 、L ₂ 、L ₃ 、L ₄ 、L ₅ And L ₆ Can be 2-25, 2-20 or 3-18 amino acids in length. In some embodiments, a linker such as L ₁ 、L ₂ 、L ₃ 、L ₄ 、L ₅ And L ₆ May be a peptide of no more than 14, 13, 12, 11, 10, 9, 8, 7, 6 or 5 amino acids in length. In other embodiments, a linker such as L ₁ 、L ₂ 、L ₃ 、L ₄ 、L ₅ And L ₆ Can be 5-25, 5-15, 4-11, 10-20 or 20-30 amino acids in length. In other embodiments, a linker such as L ₁ 、L ₂ 、L ₃ 、L ₄ 、L ₅ And L ₆ May be about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 amino acids in length. In particular embodiments, a linker such as L ₁ 、L ₂ 、L ₃ 、L ₄ 、L ₅ And L ₆ May be less than 24, less than 20, less than 16, less than 12, less than 10, for example 5 to 24, 10 to 24 or 5-10 amino acid residues in length. In some embodiments, the linker is equal to 1 or more amino acid residues in length, such as more than 1, more than 2, more than 5, more than 10, more than 20 amino acid residues in length, and more than 22 amino acid residues in length.

Exemplary linkers such as L ₁ 、L ₂ 、L ₃ 、L ₄ 、L ₅ And L ₆ Comprising or consisting of an amino acid sequence selected from the group consisting of: GGGS (SEQ ID NO: 290), GGGGS (SEQ ID NO: 286), GGGAS (SEQ ID NO: 287), GGGSGGGG (SEQ ID NO: 214), GGGGSGGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 61), GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 70), GGSGG (SEQ ID NO: 226), GGGGSGGGGSGGGGS (SEQ ID NO: 280), GGGGSAAA (SEQ ID NO: 358), in particular GGGSGGGG (SEQ ID NO: 214), GGGGSGGGGSGGGGSGGGGGGGGGGS (SEQ ID NO: 70) and GGGGSGGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 61).

The term "as used in the context of the present invention" _c F domain"cover natural F _c And F _c Variants, and include monomeric, dimeric and multimeric F _c Domains, whether digested from intact antibodies or produced by other means.

The term "as used herein" _c Natural F"refers to a molecule comprising the sequence of a non-antigen binding fragment derived from digestion of an antibody or produced by other means, which molecule is in monomeric, dimeric or multimeric form and may contain a hinge region. Natural F _c Particularly of human origin, and may be of any antibody class, but IgG1 and IgG2 are preferred. Natural F _c The molecule is made up of monomeric polypeptides that can be linked into dimeric or multimeric forms by covalent (i.e., disulfide bonds) and non-covalent associations. Natural F _c The number of intermolecular disulfide bonds between the monomer subunits of the molecule ranges from 1 to 4, depending on the class (e.g., igG, igA, and IgE) or subclass (e.g., igG1, igG2, igG3, igAl, and IgGA 2). Natural F _c An example of this is disulfide-bonded dimer resulting from papain digestion of IgG. Natural F _c An example of an amino acid sequence is SEQ ID NO. 329.

The term "as used herein" _c F variants"means from natural F _c Modification but still comprises salvage receptor F _c Rn (New F) _c Receptor) or a sequence of binding sites. Exemplary F _c Variants and their interactions with salvage receptors are known in the art. Thus, the term "F _c Variants "may comprise variants derived from non-human natural F _c A humanized molecule or sequence. In addition, natural F _c Comprises a region that can be removed because the region provides an undesirable structural feature or biological activity of the antigen binding proteins of the invention. Thus, the first and second substrates are bonded together,the term "F _c Variants "comprise molecules or sequences that lack one or more native F _c A site or residue, or one or more F _c The site or residue has been modified, said F _c Site or residue influence or involvement: (1) disulfide bond formation, (2) incompatibility with the selected host cell, (3) N-terminal heterogeneity upon expression in the selected host cell, (4) glycosylation, (5) interaction with complement, (6) interaction with F other than a salvage receptor _c Binding of a receptor, or (7) Antibody Dependent Cellular Cytotoxicity (ADCC).

In one embodiment, the Fc domain is a human IgG Fc domain, preferably derived from human IgG1, igG2, igG3 or IgG4, preferably IgG1 or IgG2, more preferably IgG1.

In some embodiments, the antigen binding protein comprises two F' s _c Domain (F) _c1 And F _c2 For example as used in the examplesForm), the two F _c The domains have the same antibody isotype or isotype subclass. Thus, in some embodiments, F _c1 And F _c2 Both belong to the IgG1 subclass, or to the IgG2 subclass, or to the IgG3 subclass, or to the IgG4 subclass. In a preferred embodiment, F _c1 And F _c2 Both belong to the IgG1 subclass, or to the IgG2 subclass, more preferably to the IgG1 subclass.

In some embodiments, F _c The region also comprises an RF and/or "knob-to-hole" mutation, as defined below.

“RF mutation"generally means F _c Amino acids HY in the CH3 domain of the domain are mutated to RF, as described in mutations H435R and Y436F in the CH3 domain, as described in Jendeberg, L.et al (1997,J.Immunological Meth., 201:25-34), and are described as advantageous for purification purposes because they eliminate binding to protein A. In which the antigen binding protein comprises two F _C In the case of domains, the RF mutation may be located at one or both F _c In domains, preferably located at one F _c Domain.

“Pestle and mortar structure"technique" refers to the mutations T366S, L368A and Y407V, in particular T366S (mortar) and T366W (pestle), both located at C _H3 -C _H3 In the interface to promote heteromultimer formation, has been described in patents US 5731168 and US 8216805, notably, which are incorporated herein by reference. Those knob-to-socket structural mutations may be further stabilized by introducing additional cysteine amino acid substitutions Y349C and S354C.

"pestle" mutations are present, for example, in F of SEQ ID NO:149 _c In the amino acid sequence, and "mortar" mutations are present, for example, in F of SEQ ID NO. 150 _c Amino acid sequence.

In some embodiments, F of one polypeptide _c Domain (e.g. F _c1 ) At C thereof _H3 The domain comprising the amino acid substitution T366W (pestle), and F of another polypeptide _c Domain (e.g. F _c2 ) At C thereof _H3 The domain comprises the amino acid substitutions T366S, L368A and Y407V (mortar) or vice versa.

In some embodiments, F of one polypeptide _c Domain (e.g. F _c1 ) At C thereof _H3 The domain comprises or further comprises the amino acid substitution S354C, and F of another polypeptide _c Domain (e.g. F _c2 ) At C thereof _H3 The domain comprises or also comprises the amino acid substitution Y349C or vice versa.

Thus, in some embodiments, F of one polypeptide _c Domain (e.g. F _c1 ) At C thereof _H3 The domain comprises amino acid substitutions S354C and T366W (pestle), and F of another polypeptide _c Domain (e.g. F _c2 ) At C thereof _H3 The domains comprise amino acid substitutions Y349C, T366S, L368A and Y407V (mortar) or vice versa.

This set of amino acid substitutions can be further extended by including the amino acid substitution K409A on one polypeptide and F405K in another polypeptide, e.g., wei et al (Structural basis of a novel heterodimeric F) _c forbispecific antibody production, oncotarget.2017). Thus, in some embodiments, F of one polypeptide _c Domain (e.g. F _c1 ) At C thereof _H3 The domain comprises or further comprises the amino acid substitution K409A, and F of another polypeptide _c Domain (e.g. F _c2 ) At C thereof _H3 The domain comprises or also comprises the amino acid substitution F405K, or vice versa.

In some cases, the artificially introduced cysteine bridge may improve the stability of the antigen binding protein, optimally without interfering with the binding characteristics of the antigen binding protein. Such cysteine bridges may further improve heterodimerization.

Other amino acid substitutions, such as charged pair substitutions, have been described in the art, e.g. EP 2 970 484, for improving heterodimerization of the resulting protein.

Thus, in one embodiment, F of a polypeptide _c Domain (e.g. F _c1 ) Comprises or further comprises the charge pair substitution E356K, E356R, D R or D356K and D399K or D399R, and F of another polypeptide _c Domain (e.g. F _c2 ) Comprising or also comprising charge pair substitutions R409D, R409E, K E or K409D and N392D, N392E, K392E or K392D, or vice versa.

In another embodiment, F is present on one or both polypeptide chains, preferably on both polypeptide chains _c The domain may comprise inhibition F _c Gamma receptor (F) _c yR) one or more changes in binding. Such changes may include L234A, L235A.

In another embodiment, F is present on one or both polypeptide chains, preferably on both polypeptide chains _c The domain may comprise an N297Q mutation to remove F _c N-glycosylation sites within the moiety, such mutations eliminate F _c -gamma-receptor interactions.

“Hinge”、“Hinge region"OR"Hinge domain"generally means that the heavy chain is located at C _H1 Domain and C _H2 Flexible portions between domains. It is about 25 amino acids in length and is divided into "upper hinge", "and"Middle hinges "or" core hinges "and" lower hinges ". "hinge subdomain" refers to an upper hinge, a middle (or core) hinge, or a lower hinge. The amino acid sequences of the hinges of the IgG1, igG2, igG3 and IgG4 molecules are shown below:

IgG1：E ₂₁₆ PKSCDKTHTCPPCPAPELLG(SEQ ID NO:330)

IgG2：E ₂₁₆ RKCCVECPPCPAPPVAGP(SEQ ID NO:331)

IgG3：ELKTPLGDTTHTCPRCPEPKSCDTPPPCPRCPE ₂₁₆ PKSCDTPPPCPRCPAPELLG(SEQ ID NO:332)

IgG4：E ₂₁₆ SKYGPPCPSCPAPEFLG(SEQ ID NO:333)。

In the case of the present invention, it is mentioned F _c Amino acid positions in the domain, which amino acid positions or residues are indicated according to the EU numbering system, as described, for example, in Edelman, g.m. et al, proc.Natl.Acad.USA,63,78-85 (1969).

At the moment to be composed of a hinge, C _H2 And C _H3 F consisting of domains or parts thereof _c In the case of partial incorporation into antigen binding proteins, more particularly into bispecific antigen binding proteins, the formation of a protein consisting of F _c :F _c -gamma receptor (F) _c γr) interactions cause problems of non-specific immobilization of these molecules. F (F) _c γr consists of different cell surface molecules (F _c γRI、F _c γRIIa、F _c γRIIb、F _c γriii) with different affinities to the F of IgG molecules _c Partially displayed epitopes bind. Thus, non-specific (i.e. not induced by either of the two binding domains of the bispecific molecule) immobilization is disadvantageous due to the following: i) The effect on the pharmacokinetics of the molecule, and ii) the off-target activation of immune effector cells, a variety of F have been identified _c Variants and mutations can eliminate F _c γr binds. In this case Morgan et al 1995, immunology (The N-terminal end of The C) _H2 domain of chimeric human IgG1 anti-HLA-DR is necessary for C1q,F _c yRI and F _c yrii binding) discloses residues 233-236 of human IgG1 and the corresponding sequence derived from human IgG2 (i.e., residue 2 33P, 234V and 235A and wherein no amino acid is present at position 236), resulting in elimination of F _c Gamma RI binding, elimination of C1q binding and reduction of F _c γriii binding. EP1075496 discloses a composition having F _c Antibodies and other F-containing antibodies that vary in region (e.g., one or more of 233P, 234V, 235A, and have no residues in position 236 or 236G, and 327G, 330S, and 331S) _c Wherein the recombinant antibody is capable of binding to the target molecule without triggering significant complement-dependent lysis or cell-mediated destruction of the target.

Thus, in some embodiments, F _c The region comprises or further comprises one or more amino acids or deletions selected from the group consisting of: 233P, 234V, 235A, 236 (no residue) or G, 327G, 330S, 331S, preferably F _c The region comprises or further comprises amino acids 233P, 234V, 235A, 236 (no residues) or G and one or more amino acids selected from 327G, 330S, 331S, most preferably F _c The region comprises or also comprises amino acids 233P, 234V, 235A, 236 (no residues) and 331S.

In one other embodiment, F _c The domain comprises or further comprises the amino acid substitutions N297Q, N297G or N297A, preferably N297Q.

Amino acid substitutions "N297Q", "N297G" or "N297A" refer to the elimination of F at position 297 _c Amino acid substitutions at the native N-glycosylation site within the domain. The amino acid substitution further prevents F _c Gamma-receptor interactions and reduce variability of the final protein product (i.e. antigen binding protein of the invention) due to sugar residues as described, for example, in Tao, MH and Morrison, SL (J immunol.10, 15, 1989; 143 (8): 2595-601).

In one other embodiment, especially in the absence of a light chain, F _c The domain comprises or further comprises the amino acid substitution C220S. Amino acid substitution "C220S" deletions form C _H1 -C _L Disulfide-bonded cysteines.

In some embodiments, F _c The domain comprises or further comprises at least two additional cysteine residues, e.g. S354C and Y349C or L242C and K334C, wherein S354C is located in one polyF of peptide _c Domain (e.g. F _c1 ) In (C) and Y349C is at F of another polypeptide _c Domain (e.g. F _c2 ) To form heterodimers, and/or wherein L242C and K334C are located at the same F _c Domain, i.e.F located in one or both polypeptides _c1 Or F _c2 To form a intra-domain C-C bond.

The antigen binding proteins of the present disclosure may be synthetic, recombinant, isolated, engineered, and/or purified.

“Purified (3)"means that when referring to a polypeptide (e.g., an antigen binding protein of the invention) or nucleotide sequence (e.g., encoding an antigen binding protein or functional fragment thereof as described herein), there is a molecule as shown, but essentially no other biological macromolecule of the same type. The term "purified" as used herein particularly means that at least 75%, 85%, 95% or 98% by weight of the same type of biomacromolecule is present.

Purified nucleic acid molecule encoding a particular polypeptide means that the nucleic acid molecule is substantially free of other nucleic acid molecules not encoding the subject polypeptide; however, the molecule may include some additional bases or moieties that do not adversely affect the essential characteristics of the composition.

The term'Separated from each other"means altered or removed from a natural state. For example, a nucleic acid or peptide naturally occurring in a living animal is not "isolated," but the same nucleic acid or peptide, partially or completely isolated from coexisting materials in its natural state, is "isolated. The isolated nucleic acid or protein may be present in a substantially purified form, or may be present in a non-natural environment (such as, for example, a host cell). The isolated antigen binding protein is substantially free of other antigen binding proteins having different antigen specificities (e.g., an antigen binding protein that specifically binds PRAME is substantially free of antigen binding proteins that specifically bind antigens other than PRAME). In addition, the isolated antigen binding protein may be substantially free of other cellular material and/or chemicals.

“Recombination"molecules" have been obtained by recombinant meansA molecule that is produced, expressed, produced or isolated. Recombinant molecules do not exist in nature.

The term'Gene"means a DNA sequence encoding or corresponding to a particular amino acid sequence comprising all or part of one or more proteins or enzymes, and may or may not include regulatory DNA sequences, such as promoter sequences, that determine, for example, the conditions under which the gene is expressed. Some genes (not structural genes) may be transcribed from DNA to RNA but are not translated into amino acid sequences. Other genes may function as regulators of structural genes or as regulators of DNA transcription. In particular, the term gene may be intended for genomic sequences encoding proteins, i.e. sequences comprising regulatory, promoter, intron and exon sequences.

In the context of the present invention, "Affinity for"defined by the equilibrium binding between an antigen binding protein and its antigen (i.e.the PRAME-004 peptide according to SEQ ID NO:50 in a complex with an MHC protein). Affinity can be achieved, for example, at half maximum effective concentration (EC ₅₀ ) Or equilibrium dissociation constant (K) _D ) To represent. In the context of the present invention, high affinity means K at.ltoreq.100 nM,.ltoreq.50 nM,.ltoreq.10 nM or.ltoreq.5 nM _D And (5) combining.

“ _D K"is the equilibrium dissociation constant between an antigen binding protein and its antigen, i.e., k _off /k _on Is a ratio of (2). K (K) _D And affinity are inversely related. K (K) _D The value is related to the concentration of antigen binding protein, and K _D The lower the value, the higher the affinity of the antigen binding protein. Affinity, i.e. K _D The values may be assessed experimentally by a variety of known methods, such as measuring association and dissociation rates with Surface Plasmon Resonance (SPR) or Biological Layer Interferometry (BLI), as described in more detail below in section "antigen binding protein". K (K) _D Preferably by Biological Layer Interferometry (BLI). More preferably, the antigen binding protein is K with a PRAME antigenic peptide _D Is determined by BLI at a temperature of between 20 ℃ and 35 ℃, preferably 25 ℃ to 32 ℃, more preferably about 30 ℃ and a pH of 6.5 to 8.0, preferably 7.0 to 7.6. Even more preferably, the antigenK binding proteins to PRAME antigenic peptides _D Is determined by BLI at a temperature of between 20 ℃ and 35 ℃, preferably 25 ℃ to 32 ℃, more preferably about 30 ℃, a pH of 6.5 to 8.0, preferably 7.0 to 7.6, and a salt concentration of 100 to 200mM, preferably 120 to 175mM, more preferably about 140 mM. Most preferably, the antigen binding protein is K with the PRAME antigenic peptide _D Was determined by BLI in a buffer comprising or consisting of PBS, 0.05% Tween-20 and 0.1% BSA at 30 ℃. In such measurements, the concentration of antigen binding protein is typically between 1.56-500nM, depending on the affinity of the interaction measured. In comparing the K of antigen binding proteins to two different peptides (e.g., target peptide and potentially off-target peptide/analog) _D If the two peptides have similar HLA binding strength, the loading conditions of the peptide-HLA are the same for both measurements and the range of antigen binding protein concentrations is selected with consideration of the expected affinity.

“Half maximum effective concentration"also referred to as" EC ₅₀ By "(generally refers to the concentration of a molecule that induces a half of the response between baseline and maximum after a specified exposure time. EC (EC) ₅₀ Negatively correlated with affinity, EC ₅₀ The lower the value, the higher the molecular affinity. In one example, "EC ₅₀ "refers to the concentration of an antigen binding protein of the invention that induces a half of the response between baseline and maximum after a specified exposure time, and more specifically, to the concentration of an antigen binding protein of the invention that induces a half of the response between baseline and maximum after a specified exposure time. EC (EC) ₅₀ The values may be assessed experimentally by a variety of known methods using, for example, binding assays, such as ELISA or flow cytometry, or functional assays, such as IFN- γ release assays or Lactate Dehydrogenase (LDH) release assays.

Antigen binding proteins

The antigen binding proteins of the invention are engineered from a scaffold sequence into which a plurality of mutations are introduced. The antigen binding proteins of the invention have a profile that is particularly suitable for therapeutic use. Typically, the identification of such antigen binding proteins is not straightforward and typically has a high loss rate.

In the first case, the skilled person is required to identify a suitable starting or scaffold sequence. For the present invention, this is the following TCR: good affinity for target peptide-HLA complexes, e.g., 200 μΜ or greater; high target specificity levels, e.g., relatively weak or no binding to alternative peptide-HLA complexes; which can be refolded and purified in high yield. Given the degeneracy of TCR recognition, it is difficult for even one skilled in the art to determine whether a particular stent TCR sequence has a specific profile that qualifies it for engineering for therapeutic use (Wooldridge et al, J Biol chem.2012, 1/6; 287 (2): 1 168-77).

A particularly important step is the conversion of the TCR into a soluble form that can be stably expressed. Naturally occurring TCRs are membrane bound and are expressed only as complexes with CD 3. In addition to antibodies expressed in a conventional manner as single chain variable fragment (scFv) molecules, the corresponding single chain T cell receptor variable domain (scTv) constructs tend to aggregate and misfold (Richman et al Mol immunol.2009, month 2; 46 (5): 902-16.Doi:10.1016/j. Molimu. 2008.09.021.Epub, month 10, month 29). This step is necessary to produce the active biological substance, but may also be critical for other engineering steps as described below. The process of scTv conversion and production of stable and soluble molecules typically involves engineering one or more specific mutations (including but not limited to substitutions, insertions and/or deletions) in the framework region and/or one or more CDRs onto the TCR initiation sequence to increase expression and stability of scTv. Each TCR herein has a different set of mutations, depending on the combination of variable domains and the composition of CDR 3. Specific mutations and/or combinations of mutations that produce significant increases in solubility and stability are unpredictable and high loss rates exist. In many cases, it may not be possible to achieve a significant increase in solubility and stability with a given TCR starting sequence.

The next challenge is to engineer TCRs to have higher affinity for target antigens while retaining desirable characteristics such as specificity and yield. TCRs, as they exist in nature, have a weak affinity (low micromolar range) for target antigens, and TCRs directed against cancer antigens typically have weaker antigen recognition than virus-specific TCRs (Aleksic et al Eur J immunol.2012, 12; 42 (12): 3174-9). This weak affinity down-regulated binding to HLA on cancer cells means that therapeutic TCRs for cancer immunotherapy generally need to be engineered to increase their affinity for the target antigen, thereby generating a more potent response. Such an increase in affinity is necessary for soluble TCR-based agents. In such cases, antigen binding affinities in the nanomolar to picomolar range, as well as binding half-lives of several hours, are desirable. Affinity maturation processes typically involve engineering specific mutations in one or more CDRs and/or combinations of mutations (including but not limited to substitutions, insertions, and/or deletions) in one or more CDRs onto the starting TCR sequence to increase the intensity of antigen recognition. In order to produce a significant increase in affinity of a given TCR for a given target, one skilled in the art may have to engineer a combination of mutations in the CDRs from a large library of possible alternatives. Specific mutations and/or combinations of mutations that produce a significant increase in affinity are unpredictable and high loss rates exist. In many cases, it may not be possible to achieve a significant increase in affinity with a given TCR starting sequence.

The affinity maturation process must also take into account the necessity to maintain TCR antigen specificity. Increasing the affinity of TCRs for their target antigens carries a significant risk of revealing cross-reactivity with other unintended targets due to the inherent degeneracy of TCR antigen recognition (wooldge et al, J Biol chem.2012, 1 month 6; 287 (2): 1 168-77; wilson et al, mol lmmunol.2004, 2 months; 40 (14-15): 1047-55; zhao et al, J immunol.2007, 11 months 1; 179 (9): 5845-54). At natural levels of affinity, recognition of cross-reactive antigens may be too low to react. If cross-reactive antigens are displayed on normal healthy cells, there is a high probability of off-target binding in vivo, which can be manifested as clinical toxicity. Thus, in addition to increasing antigen binding strength, the skilled person must also engineer mutations in one or more CDRs and/or combinations of mutations in one or more CDRs that allow the TCR to retain high specificity for the target antigen and thus show a good safety profile in preclinical testing. Also, suitable mutations and/or combinations of mutations are unpredictable. The loss rate at this stage is even higher and in many cases may not be achievable at all from a given TCR starting sequence. Despite the above difficulties, the inventors have identified antigen binding proteins comprising TCR-derived CDRs which have particularly high affinity (low nanomolar range) and high degree of antigen specificity.

Using TCR R11P3D3 as disclosed in WO 2018/172533 (which is incorporated herein by reference) as a starting point, the inventors have designed, generated and tested variants of the variable α and variable β domains of R11P3D3 in the form of a single chain TCR (scTCR); optionally conjugated to Fab fragments and in the form ofForm of the invention. In this way, the inventors identified different CDRs, in particular CDRa1, CDRa3, CDRb1 and CDRb3 and optionally CDRa2 and CDRb2, which are associated with the antigen binding proteins of the invention binding their targets (i.e. PRAME-004 peptides in complex with MHC proteins) with high affinity and high specificity.

The inventors designed bispecificMolecules, single chain TCRs (sctcrs), and bispecific scTCR-Fab molecules. All constructs bound specifically to peptide-MHC complexes comprising PRAME-004 peptides. The bispecific constructs disclosed in the examples further bind to effector cells, in particular T cells, via antibody-derived "recruiters". The inventors thus demonstrated that the CDRs can be used in single chain TCR constructs as well as in bispecific TCR-antibody molecules, and that the identified CDRs can be used to generate different antigen binding proteins with high affinity and high specificity to PRAME-004 peptides in complex with MHC proteins.

Thus, in a first aspect, the present invention relates to an antigen binding protein that specifically binds to a PRAME antigenic peptide comprising the amino acid sequence S of SEQ ID No. 50LLQHLIGL or consists thereof and is in complex with a Major Histocompatibility Complex (MHC) protein comprising a variable domain V comprising Complementarity Determining Regions (CDRs) CDRA1, CDRA2 and CDRA3 _A Wherein

-the CDRa1 comprises or consists of: the amino acid sequence of VKEFQD (SEQ ID NO: 16) or with

SEQ ID NO. 16 differs by one, two or three amino acid mutations, preferably amino acid substitutions, and

-the CDRa3 comprises or consists of: ALYNNLDMR (SEQ ID NO: 33) or ALYNNYDMR

(SEQ ID NO: 34) or one from SEQ ID NO:33 or SEQ ID NO:34,

Amino acid sequences of two or three, preferably one or two amino acid mutations, preferably amino acid substitutions, and variable domains V containing CDRb1, CDRb2 and CDRb3 _B Wherein

-the CDRb1 comprises or consists of: amino acid sequence of SGSN (SEQ ID NO: 10) or amino acid sequence of SGSN

SEQ ID NO. 10 differs by one, two or three, preferably one or two amino acid mutations, preferably amino acid substitutions, and

-the CDRb3 comprises or consists of: ASSX (automatic service X) ₁ GX ₂ X ₃ DX ₄ The amino acid sequence of QY (SEQ ID NO: 327), wherein X ₁ Is P, A or T, preferably P, X ₂ Is A or S, preferably A, X ₃ Is T or I, and X ₄ T, K or A, preferably K or A, more preferably K, or an amino acid sequence which differs from SEQ ID NO 327 by one, two or three amino acid mutations, preferably amino acid substitutions.

The specificity of the antigen binding protein is determined by the amino acid sequences CDRa1, CDRa3, CDRb1 and CDRb3 and is independent of the amino acid sequences of CDRa2 and CDRb 2.

In some embodiments, the CDRa2 comprises or consists of: the amino acid sequence of SEQ ID NO. 32 or the amino acid sequence which differs from SEQ ID NO. 32 by one, two or three amino acid mutations, preferably amino acid substitutions, and/or CDRB2 comprises or consists of the following: the amino acid sequence of SEQ ID NO. 36 or an amino acid sequence differing from SEQ ID NO. 36 by one, two, three, four, five or six, preferably NO more than five, more preferably NO more than four, even more preferably NO more than three amino acid mutations, preferably amino acid substitutions.

In some embodiments, the antigen binding protein comprises CDRa1, CDRb1 and optionally CDRa2 and CDRb2 as defined above, the CDRa3 comprises or consists of: the amino acid sequence of SEQ ID NO. 33 or the amino acid sequence which differs from SEQ ID NO. 33 by one, two or three, preferably one or two amino acid mutations, preferably amino acid substitutions, and the CDRB3 comprises or consists of: ASSX (automatic service X) ₁ GX ₂ X ₃ DX ₄ The amino acid sequence of QY (SEQ ID NO: 327), wherein X ₁ Is P, A or T, preferably P, X ₂ Is A or S, preferably A, X ₃ Is T or I, and X ₄ T, K or A, preferably K or A, more preferably K, or an amino acid sequence which differs from SEQ ID NO 327 by one, two or three amino acid mutations, preferably amino acid substitutions.

In some embodiments, the antigen binding protein comprises CDRa1, CDRb1 and optionally CDRa2 and CDRb2 as defined above, the CDRa3 comprises or consists of: the amino acid sequence of SEQ ID NO. 34 or the amino acid sequence which differs from SEQ ID NO. 34 by one, two or three, preferably one or two amino acid mutations, preferably amino acid substitutions, and the CDRB3 comprises or consists of: ASSX (automatic service X) ₁ GX ₂ X ₃ DX ₄ The amino acid sequence of QY (SEQ ID NO: 327), wherein X ₁ Is P, A or T, preferably P, X ₂ Is A or S, preferably A, X ₃ Is T or I, and X ₄ T, K or A, more preferably K or A, preferably K, or an amino acid sequence which differs from SEQ ID NO 327 by one, two or three amino acid mutations, preferably amino acid substitutions.

In a preferred embodiment, the CDRB3 comprises or consists ofThe composition is as follows: ASSPGX ₂ X ₃ DX ₄ The amino acid sequence of QY (SEQ ID NO: 364), wherein X ₂ Is A or S, preferably A, X ₃ Is T or I, and X ₄ Is T, K or A, preferably K or A, more preferably K, or an amino acid sequence which differs from SEQ ID NO. 364 by one, two or three amino acid mutations, preferably amino acid substitutions.

In a preferred embodiment, the CDRb3 comprises or consists of: ASSPGX ₂ TDX ₄ The amino acid sequence of QY (SEQ ID NO: 363), wherein X ₂ Is A or S, preferably A, and X ₄ T, K or A, preferably K or A, more preferably K, or an amino acid sequence which differs from SEQ ID NO 363 by one, two or three amino acid mutations, preferably amino acid substitutions.

In other preferred embodiments, the CDRb3 comprises or consists of: ASSPGAX ₃ DX ₄ The amino acid sequence of QY (SEQ ID NO: 365), wherein X ₃ Is T or I, preferably I, and X ₄ Is K or A, preferably K, or an amino acid sequence which differs from SEQ ID NO. 365 by one, two or three amino acid mutations, preferably amino acid substitutions.

In some embodiments, the antigen binding protein comprises CDRa1, CDRb1 and optionally CDRa2 and CDRb2 as defined above, the CDRa3 comprises or consists of: the amino acid sequence of SEQ ID NO. 33 or the amino acid sequence which differs from SEQ ID NO. 33 by one, two or three, preferably one or two amino acid mutations, preferably amino acid substitutions, and the CDRB3 comprises or consists of: the amino acid sequence of SEQ ID NO. 48 or the amino acid sequence which differs from SEQ ID NO. 48 by one, two, three or four, preferably one, two or three, more preferably one or two amino acid mutations, preferably amino acid substitutions.

In some embodiments, the antigen binding protein comprises CDRa1, CDRb1 and optionally CDRa2 and CDRb2 as defined above, the CDRa3 comprises or consists of: the amino acid sequence of SEQ ID NO. 33 or the amino acid sequence which differs from SEQ ID NO. 33 by one, two or three, preferably one or two amino acid mutations, preferably amino acid substitutions, and the CDRB3 comprises or consists of: the amino acid sequence of SEQ ID NO. 48, or SEQ ID NO. 283, or SEQ ID NO. 281, or SEQ ID NO. 297, or the amino acid sequence differing from SEQ ID NO. 48, SEQ ID NO. 297, SEQ ID NO. 281 or SEQ ID NO. 283 by one, two or three, preferably one or two amino acid mutations, preferably amino acid substitutions.

In a preferred embodiment, CDRA1, CDRA3, CDRB1, CDRB3 and optionally CDRA2 and CDRB2 differ from SEQ ID NO. 16, SEQ ID NO. 33 or 34, SEQ ID NO. 10, SEQ ID NO. 327, SEQ ID NO. 32 and SEQ ID NO. 36, respectively, by NO more than two, preferably NO more than one amino acid mutation, preferably an amino acid substitution. In a preferred embodiment, the amino acid substitutions in the CDRs are conservative substitutions.

Variable domain V _A And variable domain V _B Together forming an antigen binding site that binds to PRAME-004 antigenic peptides complexed with MHC proteins. Hereinafter, this antigen binding site is sometimes also referred to as "first antigen binding site".

CDRa1, CDRa2 and CDRa3 are derived from a TCR a chain variable domain, and CDRb1, CDRb2 and CDRb3 are derived from a TCR β chain variable domain.

With respect to CDR, V _A And V _B Also comprises a Framework Region (FR). FR sequences may be TCR-derived, i.e., derived from TCR alpha, beta, gamma, or delta chain variable domains, or may be derived from antibody variable domains. In one example, V _A FR sequences comprising antibody light chain variable domains and can therefore be described as (FR 1-L) - (CDRA 1) - (FR 2-L) - (CDRA 2) - (FR 3-L) - (CDRA 3) - (FR 4-L), and V _B The FR sequence comprising the antibody heavy chain variable domain and can therefore be described as (FR 1-H) - (CDRb 1) - (FR 2-H) - (CDRb 2) - (FR 3-H) - (CDRb 3) - (FR 4-H). Preferably V _A FR sequences comprising an alpha chain variable domain or a gamma chain variable domain, preferably an alpha chain variable domain and can therefore be described as (FR 1-a) - (CDRa 1) - (FR 2-a) - (CDRa 2) - (FR 3-a) - (CDRa 3) - (FR 4-a), and V _B FR sequences comprising a β chain variable domain or a δ chain variable domain, preferably a β chain variable domain, and And thus can be described as (FR 1-b) - (CDRb 1) - (FR 2-b) - (CDRb 2) - (FR 3-b) - (CDRb 3) - (FR 4-b). Throughout V _A In the case where the domain is derived from a TCR alpha chain, V _A May also be referred to as V _α . Throughout V _B In the case where the domain is derived from a TCR β chain, V _B May also be referred to as V _β 。

In some embodiments of the present invention, in some embodiments,

according to IMGT, the position 27 of CDRA1 is V or is substituted by an amino acid selected from L, I, M, F, A, T, N, Q, H, E, D and S, in particular from T, N, S and I,

according to IMGT, the position 28 of CDRA1 is K or is substituted by an amino acid selected from R, Q, H, N, A, V, S, G, L, I and T, in particular from R, A and S,

according to IMGT, the position 38 of CDRa1 is D or is substituted by an amino acid selected from E, N, Q, H, K and R, in particular N,

according to IMGT, the position 64 of CDRA2 is K or is substituted by an amino acid selected from R, Q, H, N, T, V, A, L, I, M and F, in particular from R, T and V,

according to IMGT, the position 114 of CDRA3 is L or Y or is substituted by an amino acid selected from M, W, H, Q, A, I, K, R, V, D, E, F and N, in particular from H, Q, A, I, K, R, V, D, E, F and N, more in particular from H, Q, A and I,

according to IMGT, the position 56 of CDRb2 is F or is substituted by an amino acid selected from Y, M, L, W, H, V, I and A, in particular from Y, M and L,

According to IMGT, the position 57 of CDRb2 is Q or is substituted with an amino acid selected from N, R, D, E, Q, H, K and K, in particular N, provided that when the amino acid at position 63 is T or S, the amino acid at position 57 is not N,

according to IMGT, the position 58 of CDRb2 is N or is substituted by an amino acid selected from Q, H, D, K, R, S and T, in particular S,

according to IMGT, position 63 of CDRb2 is T or is substituted with an amino acid selected from S, V, A, D, Q and E, in particular from S and E, provided that when the amino acid at position 57 is N, the amino acid at position 63 is not T or S,

according to IMGT, the position 64 of CDRb2 is A or is substituted by an amino acid selected from V, L, I, S, G and T, in particular T,

according to IMGT, the position 65 of CDRb2 is V or is substituted by an amino acid selected from L, I, M, A, T, F and S, in particular from I, L and T,

according to IMGT, position 108 of CDRb3 is P, A or T or is substituted with an amino acid selected from V, L, I, S, G, R, K, N and Q, in particular from R and S, provided that when the amino acid at position 110 is T or S, the amino acid at position 108 is not N,

according to IMGT, CDRb3 is a or S or is substituted with an amino acid selected from V, L, I, G, T and C, in particular T, provided that when the amino acid at position 108 is N, the amino acid at position 110 is not T or S,

-according to IMGT, position 113 of CDRb3 is T or I or is substituted by an amino acid selected from V, L, I, G and T, and

according to IMGT, position 115 of CDRb3 is T, K or a or is substituted with an amino acid selected from G, L, I, V, R, Q, N, Y, H, E and F, in particular from L, I, V, R, Q, N, Y, H, E and F, more in particular from L, I, V and R.

In some embodiments of the present invention, in some embodiments,

CDRA1 comprises the amino acid sequence X ₁ X ₂ EFQX ₃ (SEQ ID NO: 334) or consisting thereof, wherein X ₁ V, T, N, I or S, preferably V; t or N, most preferably V, X ₂ K, R, S or A, more preferably K or R, most preferably K, and X ₃ Is D or N, preferably D,

CDRA2 comprises the amino acid sequence FGPYGX ₁ E (SEQ ID NO: 335) or consists thereof, wherein X ₁ K, R, T or V, preferably K or R, most preferably K,

CDRA3 comprises the amino acid sequence ALYNNX ₁ DMR (SEQ ID NO: 336) or consists thereof, wherein X ₁ L, Y, H, Q, A, I, K, R, V, D, E, F or N, preferably L, Y, H, Q, A, I, K or R, more preferably L, Y, H, Q or A, most preferably L or Y,

CDRB1 preferably comprises or consists of the amino acid sequence SEQ ID NO. 10,

CDRb2 comprises the amino acid sequence X ₁ X ₂ X ₃ X ₄ X ₅ X ₆ Or consist of, wherein X ₁ F, Y, M or L, preferably F or Y, most preferably F, X ₂ Is Q or N, preferably Q (if X ₂ Is N, then X ₃ Also N), X ₃ Is N or S, preferably N, X ₄ Is T, S or E, preferably T or S, most preferably T (if X ₄ S is then X ₂ Q), X ₅ Is A or T, preferably A, and X ₆ Is V, I, L or T, preferably V or I, most preferably V (SEQ ID NO: 337), more preferably CDRB2 comprises the amino acid sequence X ₁ QX ₃ TX ₅ X ₆ (SEQ ID NO: 359) or consists thereof, wherein X ₁ F, Y, M or L, preferably F or Y, most preferably F, X ₃ Is N or S, preferably N, X ₅ Is A or T, preferably A, and X ₆ Is V, I, L or T, preferably V or I, most preferably V, and

CDRb3 comprises the amino acid sequence ASSX ₁ GX ₂ X ₃ DX ₄ QY (SEQ ID NO: 338) or consists thereof, wherein X ₁ P, R, A, T or S, preferably P, T or A, most preferably P, X ₂ Is A or S, preferably A, X ₃ Is T or I, preferably T, and X ₄ K, A, L, I, V, R, Q, N, Y, T, H, E or F, preferably K, A, L, I, V, R, Q, N or Y, more preferably K, A, L, I, V or R, most preferably K or A.

In some embodiments of the present invention, in some embodiments,

-CDRa1 comprises or consists of an amino acid sequence selected from the group consisting of: SEQ ID NO. 16, SEQ ID NO. 17, SEQ ID NO. 18, SEQ ID NO. 19, SEQ ID NO. 20, SEQ ID NO. 21, SEQ ID NO. 22, SEQ ID NO. 19

NO 23, SEQ ID NO 24, SEQ ID NO 25, SEQ ID NO 26, SEQ ID NO 27 and SEQ ID NO 28,

-CDRa2 comprises or consists of an amino acid sequence selected from the group consisting of: SEQ ID NO. 32, SEQ ID NO. 30, SEQ ID NO. 31 and SEQ ID NO. 29,

-CDRa3 comprises or consists of an amino acid sequence selected from the group consisting of: SEQ ID NO. 33, SEQ ID NO. 34, SEQ ID NO. 227, SEQ ID NO. 233, SEQ ID NO. 219, SEQ ID NO. 229, SEQ ID NO. 231, SEQ ID NO. 235, SEQ ID NO. 237, SEQ ID NO. 221, SEQ ID NO. 223, SEQ ID NO. 225 and SEQ ID NO. 9,

CDRB1 comprises or consists of the amino acid sequence SEQ ID NO. 10,

-CDRb2 comprises or consists of an amino acid sequence selected from the group consisting of: SEQ ID NO. 36, SEQ ID NO. 37, SEQ ID NO. 38, SEQ ID NO. 39, SEQ ID NO. 40, SEQ ID NO. 41, SEQ ID NO. 42, SEQ ID NO. 39

NO 43, SEQ ID NO 44 and SEQ ID NO 35, and/or

-CDRb3 comprises or consists of an amino acid sequence selected from the group consisting of: 46, 47, 48, 49, 239, 241, 243, 245, 247, 249, 251, 253, 255, 257, 259, 261, 263,

SEQ ID NO:265、SEQ ID NO:267、SEQ ID NO:273、SEQ ID NO:275、SEQ ID NO:277、

SEQ ID NO:279、SEQ ID NO:281、SEQ ID NO:283、SEQ ID NO:292、SEQ ID NO:293、

294, 297, 298, 301, 302 and 271 and 269.

Preferably, the antigen binding protein comprises CDRA1 of SEQ ID NO. 16, CDRA3 of SEQ ID NO. 34, CDRB1 of SEQ ID NO. 10, CDRB3 of SEQ ID NO. 48 or 292, and optionally CDRA2 of SEQ ID NO. 32 and CDRB2 of SEQ ID NO. 36.

In a preferred example, the antigen binding protein comprises CDRA1 of SEQ ID NO. 16, CDRA3 of SEQ ID NO. 34, CDRB1 of SEQ ID NO. 10, and CDRB3 of SEQ ID NO. 48, and optionally CDRA2 of SEQ ID NO. 32 and CDRB2 of SEQ ID NO. 36. Thus, the antigen binding protein may comprise CDRA1 of SEQ ID NO. 16, CDRA3 of SEQ ID NO. 34, CDRB1 of SEQ ID NO. 10, CDRB3 of SEQ ID NO. 48, CDRA2 of SEQ ID NO. 32, and CDRB2 of SEQ ID NO. 36.

In another preferred example, the antigen binding protein comprises CDRA1 of SEQ ID NO. 16, CDRA3 of SEQ ID NO. 34, CDRB1 of SEQ ID NO. 10, and CDRB3 of SEQ ID NO. 292, and optionally CDRA2 of SEQ ID NO. 32 and CDRB2 of SEQ ID NO. 36. Thus, the antigen binding protein may comprise CDRA1 of SEQ ID NO. 16, CDRA3 of SEQ ID NO. 34, CDRB1 of SEQ ID NO. 10, CDRB3 of SEQ ID NO. 292, CDRA2 of SEQ ID NO. 32, and CDRB2 of SEQ ID NO. 36.

Preferably, the antigen binding protein comprises CDRA1 of SEQ ID NO. 16, CDRA 33, 34 or 9, CDRA1 of SEQ ID NO. 10, 48, 49, 47, 281, 292, 294, 297, 298, 301 or 283, and optionally CDRA2 of SEQ ID NO. 32 and CDRB2 of SEQ ID NO. 36, without modification.

In some embodiments, the PRAME antigenic peptide consists of SEQ ID NO. 50.

In some embodiments, the antigen binding protein specifically binds to the amino acid sequence of SEQ ID NO. 50 as a complex with an MHC protein.

In some embodiments, the MHC protein is an MHC class I HLA protein, such as HLA-A, HLA-B or HLA-C, preferably HLA-A, more preferably HLA-A.times.02.

In a preferred embodiment, the antigen binding protein specifically binds to a structural epitope of the PRAME-004 antigenic peptide of SEQ ID NO. 50. In a more preferred embodiment, the antigen binding protein specifically binds to a functional epitope of the PRAME-004 antigenic peptide of SEQ ID NO. 50.

The inventors performed experiments to identify residues in PRAME-004 that are associated with binding of the antigen binding proteins of the invention (fig. 5, table 4, table 10, table 12, table 16). As a result, the inventors can identify amino acid positions 3, 5, 6, 7 and 8 of SEQ ID No. 50 as being associated with binding. The amino acid at position 3 is strongly recognized by the antigen binding proteins of the invention. The amino acid at position 5 is also strongly recognized. The most strongly recognized is the amino acid at position 7. The amino acids at positions 6 and 8 make a minor contribution. Positions 3, 5 and 7, and optionally 6 and 8 of SEQ ID NO. 50 are also referred to herein as the "binding motif" of PRAME-004. The person skilled in the art knows that the exact epitope or functional epitope determination may vary slightly depending on the method used and the cut-off value chosen.

In some embodiments, the antigen binding protein specifically binds to a functional epitope comprising or consisting of 3, 4 or 5 amino acid positions selected from positions 3, 5, 6, 7 and 8, in particular positions 3, 5 and 7 of SEQ ID No. 50. In some embodiments, the antigen binding protein specifically binds to a functional epitope comprising amino acid positions 3, 5 and 7 of SEQ ID NO. 50. In some embodiments, the antigen binding protein specifically binds to a functional epitope consisting of amino acid positions 3, 5 and 7, or 3, 5, 6 and 7, or 3, 5, 7 and 8, or 3, 5, 6, 7 and 8 of SEQ ID NO:50, preferably amino acid positions 1 and 4 other than SEQ ID NO: 50. In other words, the antigen binding protein specifically binds to amino acid positions 3, 5 and 7 and optionally 6 and/or 8, preferably not 1 or 4 of SEQ ID No. 50, preferably in a complex with an MHC protein, in particular an HLA protein, more particularly HLA-a, even more particularly HLA-a x 02. In one embodiment, the antigen binding proteins of the present disclosure specifically bind to a functional epitope comprising at least 3 amino acid positions selected from positions 3, 5, 6, 7 and 8 of SEQ ID NO. 50, provided that the antigen binding protein does not bind to amino acid positions 1 and 4 of SEQ ID NO. 50. In one embodiment, the antigen binding protein specifically binds to a functional epitope comprising or consisting of at least 6 or 7 amino acid positions selected from positions 1, 3, 4, 5, 6, 7 and 8 of SEQ ID No. 50.

The amino acid sequence according to SEQ ID NO. 50, wherein at least one position is substituted, is referred to as "PRAME variant sequence" in the context of the present specification. In particular, one position is substituted with alanine (SEQ ID NOS: 318-324). Peptides having a PRAME variant sequence are also referred to herein as PRAME variant peptides. In one embodiment, the antigen binding proteins of the invention bind to PRAME variant peptidesAnd at least one of positions 1, 3, 4, 5, 6, 7 and 8, in particular one of positions 3, 5, 6, 7 and 8, more in particular one of positions 3, 5 and 7, is substituted with alanine in the PRAME variant peptide in a complex with an MHC protein compared to K bound to a PRAME antigenic peptide of SEQ ID No. 50 _D The PRAME variant peptides have reduced affinity, in particular K _D The increase is more than or equal to 2 times, more than or equal to 5 times, more than or equal to 10 times, more than or equal to 20 times or more than or equal to 30 times. Preferably, K _D Is determined as specified in the definition section above.

In the antigen binding proteins, particularly bispecific antigen binding proteins, more particularlyIn form, the CDR amino acid sequences identified by the inventors increase the binding affinity, stability and specificity of the antigen binding proteins, particularly compared to reference proteins.

"herein"Reference proteins"refers to a protein that is compared to the antigen binding proteins of the invention. The comparison of the antigen binding proteins of the invention with a reference protein is performed under similar, preferably identical experimental conditions, preferably in parallel. Such a reference protein may be an antigen binding protein comprising CDRs of a parent/wild type TCR R11P3D3, which parent/wild type TCR R11P3D3 is disclosed in WO 2018/172533. The reference protein is preferably in the same form as the antigen binding protein to be compared. Where the antigen binding protein is scTCR, a suitable reference protein is scTCR R R11P3D3SD (SEQ ID NO: 6) comprising the variable domain of TCR R11P3D3, including stabilizing mutations. For example, the reference protein may be a CDR comprising TCR R11P3D3 as described hereinAlternatively, the reference protein is an antigen binding protein, e.gWhich comprises the CDRs of "CDR 6". C of "CDR6DR is CDRA1 of amino acid sequence DRGSQS (SEQ ID NO: 339), CDRA2 of amino acid sequence IYSNGD (SEQ ID NO: 340), CDRA3 of amino acid sequence AAVIDNDQGGILT (SEQ ID NO: 341), CDRB1 of amino acid sequence PGHRA (SEQ ID NO: 342), CDRB2 of amino acid sequence YVHGEE (SEQ ID NO: 343) and CDRB3 of amino acid sequence ASSPWDSPNVQY (SEQ ID NO: 344). The reference protein may be CDR6 (TPP-1109) comprising a first polypeptide chain comprising or consisting of SEQ ID NO 153 and a second polypeptide chain comprising or consisting of SEQ ID NO 154. TPP-1109 contains UCHT1 (V17) recruiters corresponding to SEQ ID NOs 108 and 109. Furthermore, the reference protein may be a CDR6 scTCR having a polypeptide chain comprising or consisting of SEQ ID NO. 357. The inventors show in the examples that CDR6 is comprised, in particular + ->The antigen binding proteins of the CDRs of TPP-1109 bind to amino acids at positions 5, 6, 7 and 8, but not positions 2 and 3 of the PRAME-004 antigenic peptide (Table 16). Thus, an antigen binding protein comprising the CDRs of CDR6 does not bind to amino acid 3 of the PRAME-004 antigenic peptide, but instead is strongly bound/recognized by the antigen binding proteins of the invention.

Affinity for

The antigen binding proteins of the invention comprise CDR sequences selected to provide increased affinity for the PRAME-004: MHC complex (FIG. 2, table 3). As can be seen from the examples (Table 4, table 8, table 10, table 12, table 15 and Table 16), the antigen binding proteins of the invention have a high affinity, in particular a K of 50nM, 10nM, 5nM or 3nM _D Binding to PRAME-004: MHC complex.

Thus, in one embodiment, the antigen binding proteins of the invention have increased affinity, particularly as compared to a reference protein.

In one embodiment, the antigen binding proteins of the invention are expressed in the following K _D PRAME peptide and HLA molecule comprising or consisting of the amino acid sequence of SEQ ID NO 50Complex binding, preferably HLA-A x 02, of said K _D Less than or equal to 100nM, less than or equal to 50nM, less than or equal to 10nM, preferably less than or equal to 5nM, more preferably less than or equal to 3nM, e.g., 10pM to 100nM, 10pM to 50nM, 10pM to 10nM, 10pM to 5nM, 10pM to 3nM.

In one example, the antigen binding protein of the invention is a scTCR-Fab and is expressed in the following K _D Binding to a complex of a PRAME peptide comprising or consisting of the amino acid sequence of SEQ ID No. 50 with an HLA molecule, preferably HLA-a-02, said K _D Less than or equal to 100nM, less than or equal to 50nM, less than or equal to 40nM, less than or equal to 30nM, less than or equal to 20nM, less than or equal to 15nM, preferably less than or equal to 15nM, e.g., 10pM to 100nM, 10pM to 50nM, 10pM to 20nM, 5nM to 20nM.

In one other example, the antigen binding protein of the invention is TCER and is expressed in K as follows _D Binding to a complex of a PRAME peptide comprising or consisting of the amino acid sequence of SEQ ID No. 50 with an HLA molecule, preferably HLA-a-02, said K _D Less than or equal to 100nM, less than or equal to 50nM, less than or equal to 10nM, preferably less than or equal to 5nM, more preferably less than or equal to 3nM, e.g., 10pM to 100nM, 10pM to 50nM, 10pM to 10nM, 10pM to 5nM, 10pM to 3nM.

For measuring affinity, e.g. K _D Methods of (2) are known to those skilled in the art and include, for example, surface Plasmon Resonance (SPR) and biological layer interferometry. For determining K _D Also described in the examples section. As known to those skilled in the art, the experimental conditions, such as the buffers used, the protein concentration, used in those experiments can significantly affect the results.

Thus, in one example, the antigen binding proteins of the invention are expressed, for example, asAnd analyzed for its binding affinity to HLA-A x 02:prame-004 monomers. Typically, measurements are made, for example, on an Octet RED384 system, typically using manufacturer recommended settings. Briefly, binding kinetics are typically measured at 30℃and an oscillation rate of, for example, 1000rpm using, for example, PBS, 0.05% Tween-20, 0.1% BSA as buffer. Loading of peptide-HLA complexes, in particular HLA-A 02/PRAME-004 complexes, onto a biosensor such as HIS1KAfter which->Is a continuous dilution of (a).

As disclosed herein, the antigen binding proteins of the invention bind specifically to a complex comprising or consisting of the amino acid sequence of SEQ ID No. 50, a PRAME antigenic peptide and an HLA molecule, preferably HLA-a x 02. If the antigen binding protein is a TCR expressed on a T cell, binding of the antigen binding protein to the complex may elicit an immune response upon binding. Thus, in one embodiment, the antigen binding proteins of the invention induce an immune response, preferably wherein the immune response is characterized by an increase in interferon gamma (ifnγ) levels.

Yield rate

The inventors have demonstrated in the examples (Table 5, table 6, table 7, table 9, table 11 and Table 14) that antigen binding proteins have high yields of end products, in particular yields of ≡1mg/l, ≡1.5mg/l, ≡2mg/l, ≡5mg/l, ≡10mg/l, ≡15mg/l, ≡20mg/l, ≡30mg/l, ≡40mg/l, ≡50mg/l, ≡60mg/l.

The inventors demonstrated in the examples (table 5, table 6, table 7, table 9, table 11 and table 14) that the antigen binding proteins have high final product yields, in particular increased yields compared to the reference protein, more in particular increased yields compared to antigen binding proteins comprising CDRs of "CDR6" expressed under the same conditions.

In one example, the antigen binding protein is scTCR-Fab (as described in example 2) and the product yield is ≡8mg/l, ≡10mg/l, ≡15mg/l, ≡20mg/l, ≡30mg/l, ≡40mg/l,. Gtoreq.50 mg/l,. Gtoreq.60 mg/l,. Gtoreq.70 mg/l, such as 8mg/l to 85mg/l, 10mg/l to 85mg/l, 14mg/l to 85mg/l, 50mg/l to 85mg/l.

In one further, the antigen binding protein is TCER comprising VL and VH of the recruiter UCHT1V17 and the product yield is ≡10mg/l, ≡12mg/l, ≡15mg/l, ≡16mg/l, ≡17mg/l, ≡18mg/l, preferably ≡15mg/l, such as from 10mg/l to 30mg/l, from 15mg/l to 25mg/l, from 15mg/l to 30mg/l, preferably from 15mg/l to 30mg/l.

The final product yield is typically determined 10-11 days after transfection. Methods for measuring the yield of the product are known to those skilled in the art. Exemplary procedures are described in the examples section.

Thus, in one embodiment, the antigen binding proteins of the invention have improved yields, particularly when expressed under the same conditions as the reference protein.

Stability of

The inventors demonstrated in the examples (table 5, table 6, table 7, table 9, table 11 and table 14) that antigen binding proteins have high stability.

In the context of the present invention, the term "Stability of"refers to physical stability and can be assessed qualitatively and/or quantitatively using various analytical techniques described in the art and reviewed in, for example, the following documents: peptide and Protein Drug Delivery,247-301, vincent Lee, editions, marcel Dekker, inc., new York, N.Y., pubs. (1991) and Jones, A.Adv.drug Delivery Rev.10:29-90 (1993). To measure stability, samples comprising the antigen binding proteins of the invention may be tested in a stability study, wherein the sample is exposed to stress conditions for a selected period of time, after which the chemical and physical stability is quantitatively and optionally qualitatively analyzed using appropriate analytical techniques. In the context of the present invention, those methods specifically refer to evaluating aggregate formation (e.g., using Size Exclusion Chromatography (SEC)), by measuring turbidity (e.g., by Dynamic Light Scattering (DLS) or photoresistance method (LO)) and/or by visual inspection (e.g., by determining color and clarity). The sample is considered stable in the presence of only low aggregation as defined below.

In the context of the present invention, improved stability refers, for example, to increased physical stability upon exposure to thermal stress. Thus, the newly developed antigen binding proteins of the invention can withstand stress conditions, especially thermal stress, better than the reference protein.

“Low aggregation"for example, means that a sample comprising an antigen binding protein has been exposed to stress conditions (e.g., 40℃in a buffer such as PBSThe temperature of (2) is continued for 14 days) the monomer content is 80% > or more, 85% > or more, 90% > or more, 94% > or more, 95% > or more, 96% > or more, 97% > or more, 98% > or more, 99% or more, such as 94% to 99%, 95% to 99%, 96% to 99%, 97% to 99% of the monomer content, typically when measured by SEC such as SEC-HPLC in a buffer such as PBS. For SEC, in the case of the present invention, the difference of 1%, 2%, 3%, 4%, preferably 1% or 2%, more preferably 1% of the monomer content under the test conditions is considered to be significantly different, depending on the column used, the operating pressure and the speed of the buffer. In other words, when the monomer content of the reference antigen binding protein is 96% and the monomer content of the antigen binding protein of the invention is 97% when measured under the same conditions, the monomer content of the antigen binding protein of the invention is significantly different from the reference antigen binding protein and thus significantly increased.

The inventors confirmed (Table 5, table 6, table 7, table 9, table 11 and Table 14) that the antigen binding proteins were stable, in particular with monomer contents of ≡80%,. Gtoreq.85%,. Gtoreq.90%,. Gtoreq.92%,. Gtoreq.94%,. Gtoreq.95%,. Gtoreq.97% after 14 days in a buffer such as PBS at 40 ℃.

In one embodiment, the antigen binding proteins of the invention are stable or have improved stability when exposed to stress conditions for a certain period of time, such as 14 days at a temperature of 40 ℃, in particular compared to a reference protein.

In one embodiment, the antigen binding proteins of the invention exhibit no or only low aggregation or reduced aggregation when exposed to stress conditions for a certain period of time, such as 14 days at a temperature of 40 ℃, in particular compared to a reference protein.

Specificity (specificity)

The inventors demonstrated in the examples (fig. 3-6, table 3, table 4, table 8, table 13, table 15) that the antigen binding proteins of the invention bind to the target antigen with high specificity, i.e. PRAME antigenic peptides comprising SEQ ID NO:50 in a complex with MHC proteins, preferably in a complex with HLA-A-02.

As described above, the inventors identified that amino acid positions 3, 5, 6, 7 and 8, particularly 3, 5 and 7, of SEQ ID NO. 50 are associated with binding of the antigen binding proteins of the invention to the PRAME-004 antigenic peptide (i.e., to the "binding motif" of the PRAME-004 antigenic peptide). The inventors identified potential off-target peptides that are, for example, similar to the sequence and/or motif of PRAME-004, and thus have an increased risk of binding to antigen binding proteins that bind to PRAME-004.

In the context of the present invention, "herein"Similar peptides"refers to a potentially off-target peptide, i.e., a peptide that may potentially be bound by an antigen binding protein of the invention based on its biochemical/biophysical characteristics (including but not limited to homologous sequences or similar motifs). The analogous peptides typically comprise 8 to 11 amino acids in length. In the context of the present invention, the analogous peptide is typically presented by MHC. Furthermore, in the context of the present invention, similar peptides include peptides comprising or consisting of an amino acid sequence similar to that of the PRAME-004 antigenic peptide, more particularly peptides comprising epitopes in which some or all of the amino acids have the same and/or similar biochemical/biophysical characteristics as the amino acids constituting the epitope of the PRAME-004 peptide, as compared to the epitope of the PRAME-004 antigenic peptide. In some examples, the analogous peptides studied in the context of the present invention are databases of HLA-A x 02 binding peptides presented from tumor and normal tissues using similarity scores in the binding-associated sites of PRAME-004 and requirements for at least one detection of normal tissuesDatabase) is selected. Binding of antigen binding proteins to similar peptides presented by MHC proteins may lead to adverse reactions. Such adverse effects may be "extra-neoplastic" side effects, such as cross-reactivity of specific TCRs with similar peptides in healthy tissues, as reported in the following documents: lowdell et al, cytotherapy, published 12.4.2018.

In particular, in the case of the present invention, the following peptides are analogous peptides: TMED9-001 (SEQ ID NO: 51), CAT-001 (SEQ ID NO: 52), DDX60L-001 (SEQ ID NO: 53), LRRC70-001 (SEQ ID NO: 54), PTPLB-001 (SEQ ID NO: 55), HDAC5-001 (SEQ ID NO: 56), VPS13B-002 (SEQ ID NO: 57), ZNF318-001 (SEQ ID NO: 58), CCDC51-001 (SEQ ID NO: 59), IFT17-003 (SEQ ID NO: 60), DIAPH1-004 (SEQ ID NO: 62), FADS2-001 (SEQ ID NO: 63), FRYL-003 (SEQ ID NO: 64), GIMAP8-001 (SEQ ID NO: 65), HSF1-001 (SEQ ID NO: 66), KNT-001 (SEQ ID NO: 67), MAU-001 (SEQ ID NO: 68), 4-001 (SEQ ID NO: 69), ZNF318-001 (SEQ ID NO: 71), MYO 1-001 (SEQ ID NO: 59), FADS2-001 (SEQ ID NO: 75), FADS2-001 (SEQ ID NO: 63), FRYL-003 (SEQ ID NO: 64), GIMAP8-001 (SEQ ID NO: 68), GIMAP 1-001 (SEQ ID NO: 68), and HSF1-001 (SEQ ID NO: 68) FARSA-001 (SEQ ID NO: 306), FAOX 15B-003 (SEQ ID NO: 304), FAM114A2-002 (SEQ ID NO: 305), GPR56-002 (SEQ ID NO: 307), IGHD-002 (SEQ ID NO: 308), NOMAP-3-0972 (SEQ ID NO: 309), NOMAP-3-1265 (SEQ ID NO: 310), NOMAP-3-1408 (SEQ ID NO: 311), NOMAP-3-1587 (SEQ ID NO: 312), NOMAP-3-1768 (SEQ ID NO: 313), NOMAP-5-0765 (SEQ ID NO: 314), PDCD10-004 (SEQ ID NO: 315), TSN-001 (SEQ ID NO: 316), ARMC9-002 (SEQ ID NO: 187), CLI-001 (SEQ ID NO: 188), G1-001 (SEQ ID NO: 190), COPS7A-001 (SEQ ID NO: 192), EIF-194), T2-07NO: 202 (SEQ ID NO: 196), NOMAP-5-0765 (SEQ ID NO: 314), PDCD 10-002 (SEQ ID NO: 007), SPAM 10-002 (SEQ ID NO:200, SEQ ID NO: 001 (SEQ ID NO: 200) TGM2-002 (SEQ ID NO: 210) and TPR-004 (SEQ ID NO: 212).

The term'Specificity (specificity)"generally refers to the ability of an antigen binding protein to distinguish a target peptide from a similar peptide as described above. In other words, the antigen binding proteins bind with high affinity to the PRAME-004:MHC complex, in particular K _D Below 100nM, below 50nM, below 10nM, preferably below 5nM, but does not bind significantly to the analogous peptide MHC complex.

It will be appreciated by those skilled in the art that some of the similar peptides will not bind to the antigen binding proteins of the invention to a detectable extent, e.g., no binding signal or functional response beyond background levels will be detected, where "background levels" refers to binding signals or functional responses observed for non-homologous, "non-similar" peptides or in the absence of peptides.

For other similar peptides, very low binding can be detected, but no significant binding can be detected. The latter of these analogous peptides can also be described as "potentially related" analogous peptides. Expression "No significant binding”、“Not significantly combine"means an antigen binding protein:

1) With K binding to PRAME-004 peptide MHC complex _D Compared with the prior art, the K which is more than or equal to 25 times, more than or equal to 30 times, more than or equal to 40 times, more than or equal to 50 times, more than or equal to 75 times or more than or equal to 100 times is increased _D Binding (e.g., to a similar peptide: MHC complex);

2) Shows a significantly reduced "functional response" (e.g. to a similar peptide: MHC complex) compared to the functional response to PRAME-004 peptide: MHC complex; or alternatively

3) The detection of MHC multimers with labeled similar peptides was shown to be significantly reduced compared to the detection of MHC multimers with PRAME-004 peptides.

Affinity, in particular K _D Preferably measured using Biological Layer Interferometry (BLI), as described in the examples section. With K binding to PRAME-004 peptide MHC complex _D In contrast, K binding to analogous peptide MHC complexes _D The increase in (2) can also be expressed as two K _D Is a ratio of (2). For example, if bound to the PRAME-004 peptide, MHC complex K _D In contrast, K binding to analogous peptide MHC complexes _D Increase by 100 times, then K _D The ratio "peptide-like/PRAME-004" was 100. Those skilled in the art will appreciate that if binding is too weak, affinity for the analogous peptide, MHC complex, may not be measured.

“Functional reaction"refers to a response measured in a functional assay, e.g., in an activation assay (e.g., IFN-gamma release assay) or in a cytotoxicity assay (e.g., LDH release assay), as described in the experimental section below. IFN-gamma release assay measures IFN-gamma release from T cells exposed to a specific peptide, MHC complex. LDH release assay measures LDH released from target cells that express a peptide MHC complex on their surface and are killed by T cells that specifically bind to the peptide MHC complex. The binding may be directly via a TCR expressed on the T cell, or Is indirectly via a soluble bispecific molecule that binds to the peptide MHC complex and to a T cell (i.e., recruits the T cell). If combined with EC bound to PRAME-004 peptide MHC complex ₅₀ In contrast, EC ₅₀ The functional response in IFN-gamma release assay is considered to be significantly reduced by increasing the number of the functional response by not less than 25, not less than 30, not less than 40, not less than 50, not less than 75 or not less than 100 times, preferably not less than 200, not less than 300, not less than 500 or not less than 1000 times. If combined with EC bound to PRAME-004 peptide MHC complex ₅₀ In contrast, EC ₅₀ An increase of 25 or more, 30 or more, 40 or more, 50 or more, 75 or more, or 100 or more, preferably 200 or more, 300 or 500 or more, or 1000 or more, is considered to be a significant decrease in functional response in the LDH release assay.

Specifically, detection with labeled analogous peptide: MHC multimer refers to staining with analogous peptide: MHC tetramer, wherein antigen binding proteins are expressed on the surface of cells, preferably yeast cells (example 1.1 and example 1.2). If the number of positive (i.e.stained) cells is 5%, 3% or 1% of the total number of cells, or if the number of positive cells is 10%, 5% or 2.5% of positive cells stained with PRAME-004 peptide: MHC tetramer, or if EC ₅₀ The reduction is more than or equal to 50 times, more than or equal to 75 times, more than or equal to 100 times, more than or equal to 150 times, and more than or equal to 200 times, and the detection is considered to be obviously reduced.

The antigen binding proteins of the invention are engineered to have high affinity for the target peptide while avoiding binding to similar peptides. This is an important advantage of the antigen binding proteins of the invention, as binding to similar peptides increases the risk of side effects when present on normal tissues. Thus, the fact that the antigen binding proteins of the invention bind to similar peptides with only low affinity makes them promising anti-cancer therapies in terms of safety.

The inventors demonstrated that antigen binding proteins, in particular, by LDH release assayThe molecule caused cell lysis of T2 cells loaded with the target peptide PRAME-004 (table 17). The inventors further confirmed that antigen binding proteins, in particular +.>The molecule causes cell lysis of the PRAME positive tumor cell line, whereas the PRAME negative tumor cell line is not subject to +.>Effects of molecular co-incubation (FIGS. 7-9). These in vitro experiments further demonstrate the safety of the antigen binding proteins of the invention and document that cytotoxic effects have high selectivity for PRAME positive tumor tissue. Thus, the molecules of the present invention exhibit a beneficial safety profile.

In some embodiments, the antigen binding proteins of the invention do not bind significantly to at least 1, at least 2, at least 3, at least 4, at least 5, at least 10, at least 20, or all analogous peptides selected from the group consisting of: TMED9-001, CAT-001, DDX60L-001, LRRC70-001, PTPLB-001, HDAC5-001, VPS13B-002, ZNF318-001, CCDC51-001, IFT17-003, DIAPH1-004, FADS2-001, FRYL-003, GIMAP8-001, HSF1-001, KNT-001, MAU-001, MCM4-001, MPPE1-001, MYO1B-002, PRR12-001, PTRF-003, RASGRP1-001, SMARCD1-001, TGM2-001, VAV1-001, VIM-009, FARSA-001, ALOX15B-003, FAM114A2-002, GPR56-002, IGHD-002, NODS 3-0972, NOMAP-3-1265, NOMAP 3-1408, NOMAP 3-1587, MAP-3-8, MAU-075, MAP-65, PDCP 1-5, EXT 10, PROM 2-009, CAP 2-001, TGM2-002, VAV1-001, VIM-009, FARSA-3-0972, FARSA 15B-003, FARSA-114A-2-002, FAMAP-3-5, CLMC-3-5, and, CAPE-5-6-7, the analogue peptide is in complex with MHC.

In a preferred embodiment, the antigen binding proteins of the invention do not bind significantly to IFT17-003 in a complex with MHC.

In some embodiments, the antigen binding proteins of the invention exhibit a significantly reduced functional response to at least 1, at least 2, at least 3, at least 4, at least 5, at least 10, at least 20, or all similar peptides selected from the group consisting of: TMED9-001, CAT-001, DDX60L-001, LRRC70-001, PTPLB-001, HDAC5-001, VPS13B-002, ZNF318-001, CCDC51-001, IFT17-003, DIAPH1-004, FADS2-001, FRYL-003, GIMAP8-001, HSF1-001, KNT-001, MAU-001, MCM4-001, MPPE1-001, MYO1B-002, PRR12-001, PTRF-003, RASGRP1-001, SMARCD1-001, TGM2-001, VAV1-001, VIM-009, FARSA-001, ALOX15B-003, FAM114A2-002, GPR56-002, IGHD-002, NODS 3-0972, NOMAP-3-1265, NOMAP 3-1408, NOMAP 3-1587, MAP-3-8, MAU-075, MAP-65, PDCP 1-5, EXT 10, PROM 2-009, CAP 2-001, TGM2-002, VAV1-001, VIM-009, FARSA-3-0972, FARSA 15B-003, FARSA-114A-2-002, FAMAP-3-5, CLMC-3-5, and, CAPE-5-6-7, the analogue peptide is in complex with MHC. In a preferred embodiment, the antigen binding proteins of the invention exhibit a significantly reduced functional response to IFT17-003 in complex with MHC compared to the functional response to the PRAME-004 peptide, MHC complex.

In some embodiments, the antigen binding proteins of the invention, particularly soluble bispecific antigen binding proteins, more particularlyA form of an antigen binding protein that binds to at least 1, at least 2, at least 3, at least 4, at least 5, at least 10, at least 15, or all like peptides selected from the group consisting of: TMED9-001, CAT-001, DDX60L-001, LRRC70-001, PTPLB-001, HDAC5-001, VPS13B-002, ZNF318-001, CCDC51-001, IFT17-003, DIAPH1-004, FADS2-001, FRYL-003, GIMAP8-001, HSF1-001, KNT-001, MAU-001, MCM4-001, MPPE1-001, MYO1B-002, PRR12-001, PTRF-003, RASGRP1-001, SMARCD1-001, TGM2-001, VAV1-001, VIM-009, FARSA-001, ALOX15B-003, FAM114A2-002, GPR56-002, IGHD-002, NODS 3-0972, NOMAP-3-1265, NOMAP 3-1408, NOMAP 3-1587, MAP-3-8, MAU-075, MAP-65, PDCP 1-5, EXT 10, PROM 2-009, CAP 2-001, TGM2-002, VAV1-001, VIM-009, FARSA-3-0972, FARSA 15B-003, FARSA-114A-2-002, FAMAP-3-5, CLMC-3-5, and, CAPE-5-6-7, in particular selected from the following: GIMAP8-001, MYO1B-002, SMARCD1-001, VIM-009, FARSA-001, ALOX15B-003, FAM114A2-002, GPR56-002, IGHD-002, NOM AP-3-0972, NOMAP-3-1265, NOMAP-3-1408, NOMAP-3-1587, NOMAP-3-1768, NOMAP-5-0765, PDCD10-004, TSN-001, and/or selected from the group consisting of: ARMC9-002, CLI-001, COPG1-001, COPS7A-001, EIF-009, EXT2-006, LMNA-001, PKM-005, PSMB3-002, RPL-007, SPATS2L-003, SYNE1-002, TGM2-002 and TPR-004, in complex with MHC, and K binding to PRAME-004 peptide: MHC complex _D In contrast, the bound K _D The increase is more than or equal to 25 times, more than or equal to 30 times, more than or equal to 40 times, more than or equal to 50 times, more than or equal to 75 times or more than or equal to 100 times. In a preferred embodiment, the antigen binding proteins of the invention, in particular soluble bispecific antigen binding proteins, more in particular +.>Form of antigen binding protein, IFT17-003 bound to complex with MHC, and PRAME-004 peptide bound to K of MHC complex _D In contrast, the bound K _D The increase is more than or equal to 25 times, more than or equal to 30 times, more than or equal to 40 times, more than or equal to 50 times, more than or equal to 75 times or more than or equal to 100 times.

In some embodiments, the antigen binding proteins of the invention, particularly when expressed on the surface of cells, more particularly yeast cells, exhibit significantly reduced detection with a labeled analog peptide, MHC multimer, as compared to detection with a PRAME-004 peptide, MHC multimer, comprising an analog peptide selected from the group consisting of: TMED9-001, CAT-001, DDX60L-001, LRRC70-001, PTPLB-001, HDAC5-001, VPS13B-002, ZNF318-001, CCDC51-001, IFT17-003, DIAPH1-004, FADS2-001, FRYL-003, GIMAP8-001, HSF1-001, KNT-001, MAU-001, MCM4-001, MPPE1-001, MYO1B-002, PRR12-001, PTRF-003, RASGRP1-001, SMARCD1-001, TGM2-001, VAV1-001, VIM-009, FARSA-001, ALOX15B-003, FAM114A2-002, GPR56-002, IGHD-002, NODS 3-0972, NOMAP-3-1265, NOMAP 3-1408, NOMAP 3-1587, MAP-3-8, MAU-075, MAP-65, PDCP 1-5, EXT 10, PROM 2-009, CAP 2-001, TGM2-002, VAV1-001, VIM-009, FARSA-3-0972, FARSA 15B-003, FARSA-114A-2-002, FAMAP-3-5, CLMC-3-5, and, CAPE-5-6-7, in particular selected from the following: TMED9-001, CAT-001, DDX60L-001, LRRC70-001, PTPLB-001, HDAC5-001, VPS13B-002, ZNF318-001, CCDC51-001, IFT17-003, DIAPH1-004, FADS2-001, FRYL-003, GIMAP8-001, HSF1-001, KNT-001, MAU-001, MCM4-001, MPPE1-001, MYO1B-002, PRR12-001, PTRF-003, RASGRP1-001, SMARCD1-001, TGM2-001 and VAV1-001, more particularly IFT17-003 in a complex with MHC.

The antigen binding proteins of the invention have a high safety profile.

"herein"Security profile"refers to the ability to distinguish tumor cells, particularly tumor cells presenting PRAME-004: mhc complex, from healthy cells. This capability is typically represented by an indication of a security window.

"herein"Security window"OR"Treatment window"means a parameter that compares the concentration of compound required to induce a degree of cytotoxicity against tumor cells, particularly tumor cells presenting PRAME-004:mhc complex, such as 10%, 50%, 90% or 100% cytotoxicity, to the concentration required to induce cytotoxicity against healthy cells, preferably to a similar degree, more preferably to the same degree. For example, if the concentration of antigen binding protein required to induce 90% cytotoxicity against a tumor cell line is 1pM and the concentration required to induce 90% cytotoxicity against, for example, healthy cells is 1000pM, the safety window is 1000 because the concentration of cytotoxicity required against a tumor cell line is 1000-fold lower than the concentration required for healthy cells.

In some embodiments, the safety window comparison induces half maximal (50%) cytotoxicity (EC ₅₀ ) The desired concentration of compound and induction of half maximal (50%) cytotoxicity against healthy cells (EC ₅₀ ) The desired compound concentration. Thus, if for antigen binding proteins, EC against tumor cell lines ₅₀ EC of 1pM and directed against e.g. healthy cells ₅₀ 1000pM, the safety window is 1000 because of EC against tumor cell lines ₅₀ 1000-fold lower than healthy cells.

In a preferred embodiment, the antigen binding proteins of the invention are characterized by a safety window of ∈100, ∈500, ∈1000, ∈2000, ∈3000, ∈4000, ∈5000, ∈6000, ∈8000, > 10000, such as between 500 and 10000, preferably between 1000 and 10000.

By "cells presenting PRAME-004: MHC complexes" herein is meant cells presenting PRAME antigenic peptides as complexes with MHC molecules on the surface, wherein the copy number of the PRAME-004: MHC complexes can be determined by methods known to the person skilled in the art. In a preferred embodiment, the cells presenting PRAME-004:mhc complexes are tumor cells, wherein the tumor is preferably a cancer as defined in section "methods of treatment and uses" below. In the case of the present invention, the complex is over-presented on the cell surface of the cells presenting the PRAME-004:mhc complex, compared to the level of the PRAME-004:mhc complex on the cell surface in normal (healthy) tissue (also referred to as "healthy cells"). " Excessive transition RenderingBy "is meant that the PRAME-004:mhc complex is present at a level of at least 1.2 times, preferably at least 2 times, and more preferably between 5 and 10 times the level of presence in healthy tissue, preferably in healthy tissue or cells.

In one embodiment, the PRAME-004:mhc complex copy number of cells presenting PRAME-004:mhc complex is more than 50, more than 80, more than 100, more than 120, more than 150, more than 300, more than 400, more than 600, more than 800, more than 1000, more than 1500, more than 2000, preferably the PRAME-004:mhc copy number is 50 to 2000, such as 80 to 2000, such as 100 to 2000, e.g. 120 to 2000.

"herein"Copy number"refers to the amount of PRAME-004:mhc complex as defined in the context of the present invention present on the cell surface of a cell (e.g. a PRAME-004:mhc presenting cell, e.g. a cancer cell, or a healthy cell). The copy number of the protein can be determined by a variety of methods known in the art, including FACS analysis of diseased cells with a fluorescently labeled antigen binding protein.

"herein"Healthy cells"orNormal tissue cellsRefers to cells that are not tumor cells, preferably healthy cells herein refers to cells surrounding the PRAME-004:MHC presenting cell, In particular cells of tissue surrounding tumor cells presenting PRAME-004:mhc complexes. However, in some cases, healthy cells may also express and present PRAME-004:mhc complexes on their surface. Generally, in the context of the present invention, in healthy cells, the PRAME-004:MHC complex is present in lower amounts (copy number) than in tumor cells, as will be appreciated by those skilled in the art. Thus, in one embodiment, the healthy cells have a PRAME-004:mhc complex copy number of less than 50, less than 20, less than 10, preferably less than 10 PRAME-004:mhc complex copy numbers, preferably PRAME-004:mhc complex copy numbers between 0 and 10.

The healthy cells are preferably selected from: astrocytes, GABA neurons, cardiomyocytes, cardiac microvascular endothelial cells, chondrocytes, aortic endothelial cells, coronary endothelial cells, dermal microvascular endothelial cells, mesenchymal stem cells, nasal epithelial cells, peripheral blood mononuclear cells, pulmonary artery smooth muscle cells, pulmonary fibroblasts, epidermal keratinocytes, renal cortical epithelial cells and tracheal smooth muscle cells, preferably astrocytes, in particular iPSC-derived astrocytes, cardiomyocytes, in particular iPSC-derived cardiomyocytes, aortic endothelial cells, mesenchymal stem cells and tracheal smooth muscle cells.

In a preferred embodiment, the concentration of the antigen binding protein of the invention required to achieve at least 90%, preferably 100% cytotoxicity in tumor cells, in particular tumor cells presenting PRAME-004:mhc complex, is at least 100-fold, at least 500-fold, at least 1000-fold, at least 5000-fold or at least 10000-fold lower than the concentration required to achieve at least 10%, at least 50%, at least 90% or 100% cytotoxicity in healthy cells selected from the group consisting of: astrocytes, GABA neurons, cardiomyocytes, cardiac microvascular endothelial cells, chondrocytes, aortic endothelial cells, coronary endothelial cells, dermal microvascular endothelial cells, mesenchymal stem cells, nasal epithelial cells, peripheral blood mononuclear cells, pulmonary artery smooth muscle cells, lung fibroblasts, epidermal keratinocytes, renal cortical epithelial cells and tracheal smooth muscle cells, preferably astrocytes, in particular iPSC-derived astrocytes, cardiomyocytes, in particular iPSC-derived astrocytes, iPSC-derived cardiomyocytes, aortic endothelial cells, mesenchymal stem cells and tracheal smooth muscle cells.

The inventors demonstrate that CDRs as defined in the claims can be used in antigen binding proteins having different forms. For example, in the experimental section, the inventors are in These CDRs are used in molecular neutralization single chain TCR constructs, such as bispecific TCRs comprising a scTCR fused to a Fab fragment (scTCR-Fab).

Thus, one skilled in the art will appreciate from these experiments that in fact CDRs as described herein can be used in different antigen binding proteins of the invention.

In one embodiment, the epitope and binding characteristics are conserved when the form of the antigen binding protein is altered.

In some embodiments, the antigen binding protein is a TCR or an antibody. Those skilled in the art will appreciate that where the antigen binding protein is an antibody, the "antibody" comprises at least the CDR1, CDR3 and optionally CDR2 sequences of TCR origin as defined in the claims, and thus is not a natural or conventional antibody. However, an antigen binding protein that is unreasonably such as TCR-derived CDRs and antibody-derived framework regions and antibody-derived constant domains will have the overall structure of a conventional antibody, and may be referred to as an "antibody.

In some embodiments, the antigen binding protein is bispecific, particularly a bispecific TCR, bispecific antibody, or bispecific TCR-antibody molecule. Those skilled in the art will appreciate that also in the case where the antigen binding protein is a bispecific "antibody", one of the antigen binding sites comprises CDR1, CDR3 and optionally CDR2 sequences of TCR origin as defined in the claims, while the other antigen binding site may be entirely of antibody origin.

In one embodiment, the antigen binding protein is of human origin, which is understood to be produced from a human antigen locus and thus comprises human sequences, in particular human TCR or antibody sequences.

In one embodiment, the antigen binding protein is characterized as an affinity matured antigen binding protein capable of specifically binding to PRAME-004 antigenic peptides, in particular PRAME-004:mhc complex, with a higher affinity than the parent molecule, in particular TCR R11P3D3.

In some embodiments, the antigen binding protein comprises a polypeptide comprising V _A Is a first polypeptide chain of (C) and contains V _B Is a second polypeptide chain of (a).

In some embodiments, the first polypeptide and the second polypeptide, and thus V _A And V _B Positioned on a single polypeptide chain. Such a single chain construct may be a single chain TCR (scTCR), a single chain antibody or a single chain bispecific antigen-binding protein, in particular a single chain bispecific antibody, a single chain bispecific TCR or a single chain bispecific TCR-antibody molecule. An example of a single chain TCR (scTCR) is the construct used in example 1, which may also be referred to as a single chain TCR variable domain ("scTv") molecule. An example of a single chain "antibody" would be an scFv in which CDRs have been replaced by TCR-derived CDRs. An example of a single chain bispecific antibody would be a diabody, wherein one binding site is of antibody origin and the other binding site is of TCR origin or comprises at least TCR-derived CDRs. As discussed above, such hybrid antigen binding proteins may alternatively be referred to as single chain bispecific TCRs or single chain bispecific TCR-antibody molecules.

Frame area

The inventors of the present invention have additionally found that specific mutations in the framework region of the antigen binding protein have an advantageous effect compared to the parent TCR R11P3D 3.

At V _A Among the advantageous mutations are:

N20K, which removes naturally occurring possible N-glycosylation sites,

W44K, which is equal to V _B In (2) improving the pairing, affinity and stability of variable domains, and

-a52F, V55Y, K T and G93D, which increase the stability of the antigen binding protein.

At V _B Among the advantageous mutations are:

A84D, A84E, A Q, A84N, A S, preferably A84D, which increases the affinity for the peptide-MC complex,

-Q44E, which is in combination with V _A W44K combinations of (a) to improve pairing, affinity and stability of variable domains, and

-M46P and R48Q, which increase the stability of the antigen binding protein.

The mutations are represented according to IMGT nomenclature.

Thus, the antigen binding proteins of the invention preferably comprise V _A N20K, W, K, A, F, V, 55, Y, K T and G93D (V with R11P3D3 _α Compare), preferably all, and V _B In A84D, Q, E, M P and R48Q (with R11P3D 3V _β Compare), preferably all.

The antigen binding proteins of the invention may also comprise V _A L2M, L I and Q14K (with R11P3D 3V _α Compare) one or more of V _B E11L, E K and R22H (with R11P3D 3V _β Compare) one or more of the following.

Thus, the antigen binding proteins of the invention preferably comprise V _A One or more, preferably all, of the following amino acids 20K, 44K, 52F, 55Y, 92T and 93D, and V _B One or more, preferably all, of 84D, 44E, 46P and 48Q of (b).

The antigen binding proteins of the invention may also comprise V _A One or more of the following amino acids 2M, 39I and 14K and V _B One or more of 11L or 11K and 22H.

In one embodiment, V _A Also comprising one or more, preferably all, of the frame regions selected from the group consisting of: FR1-a, FR2-a, FR3-a and FR4-a, wherein

-FR1-a comprises or consists of: the amino acid sequence of SEQ ID NO. 345 or SEQ ID NO. 346, or at least 85%, 90% or 95% identical to SEQ ID NO. 345, preferably an amino acid sequence comprising K or N at position 20, more preferably K and/or L or M at position 2;

-FR2-a comprises or consists of: the amino acid sequence of SEQ ID NO 347 or SEQ ID NO 348, or an amino acid sequence which is at least 85%, 90% or 95% identical to SEQ ID NO 347, preferably comprises L, I or M, more preferably L or I, A or D at position 47, more preferably A, K or W at position 44, preferably K, F or A at position 52, preferably F and/or Y or V, preferably Y at position 55;

-FR3-a comprises or consists of: the amino acid sequence of SEQ ID NO. 349, or an amino acid sequence which is at least 85%, 90% or 95% identical to SEQ ID NO. 349, preferably comprises T or K at position 92, preferably T and/or D or G, preferably D at position 93;

-FR4-a comprises or consists of: the amino acid sequence of SEQ ID NO. 350 or an amino acid sequence at least 85%, 90% or 95% identical to SEQ ID NO. 350; and is also provided with

V _B Also comprising one or more, preferably all, of the frame regions selected from the group consisting of: FR1-b, FR2-b, FR3-b and FR4-b, wherein

-FR1-b comprises or consists of: the amino acid sequence of SEQ ID NO:351 or SEQ ID NO:352, or at least 85%, 90% or 95% identical to SEQ ID NO:351, preferably an amino acid sequence comprising H or N at position 10, more preferably H, E, L or K at position 11, preferably E and/or R or H at position 22;

-FR2-b comprises or consists of: the amino acid sequence of SEQ ID NO. 353, or an amino acid sequence which is at least 85%, 90% or 95% identical to SEQ ID NO. 353, preferably comprises R or K at position 43, more preferably R, E or Q at position 44, preferably E, M or P at position 46, more preferably P and/or R or Q at position 48, more preferably Q;

-FR3-b comprises or consists of: the amino acid sequence of SEQ ID NO:354 or SEQ ID NO:355, or at least 85%, 90% or 95% identical to SEQ ID NO:354, preferably comprises an amino acid sequence of D, A, E, R, K, Q, N or S, more preferably D, A, E, Q, N or S, more preferably D or A, even more preferably D, at position 84; and is also provided with

-FR4-b comprises or consists of: the amino acid sequence of SEQ ID NO. 356 or an amino acid sequence at least 85%, 90% or 95% identical to SEQ ID NO. 356.

Consider a variant of an antigen binding protein as described herein and use the expression "as defined in the definition section above"At least 85% identical to the reference sequence"explicitly mentioned. For example, the amino acid sequences of FR1-a, FR2-a, FR3-a, FR4-a, FR1-b, FR2-b, FR3-b and FR4-b can be distinguished from the reference sequences SEQ ID NO:345, SEQ ID NO:346, SEQ ID NO:347, SEQ ID NO:348, SEQ ID NO:349, SEQ ID NO:350, SEQ ID NO:351, SEQ ID NO:352, SEQ ID NO:353, SEQ ID NO:354, SEQ ID NO:355 or SEQ ID NO:356 by at least one amino acid substitution, in particular at least one conservative amino acid substitution and/or substitution with a canonical residue, as appropriate. In particular, as the case may be, V _A And V _B The sequences FR1-a, FR2-a, FR3-a and FR4-a, FR1-b, FR2-b, FR3-b and FR4-b can differ from the reference sequences SEQ ID NO:345, SEQ ID NO:346, SEQ ID NO:347, SEQ ID NO:348, SEQ ID NO:349, SEQ ID NO:350, SEQ ID NO:351, SEQ ID NO:352, SEQ ID NO:353, SEQ ID NO:354, SEQ ID NO:355 or SEQ ID NO:356 by only conservative amino acid substitutions.

Modifications and variations can be made in the amino acid sequence of the antigen binding proteins of the invention and in the corresponding DNA sequence, respectively, and still result in a functional antigen binding protein or polypeptide having the desired characteristics. Can be at V _A And/or V _B In particular in the framework regions or in the CDRs.

Compared with TCR R11P3D3, V _A And V _B Preferably comprising an amino acid substitution at position 44 according to IMGT numbering. In embodiments where the antigen binding protein is a TCR, these substitutions improve pairing of the chains (i.e., pairing of the alpha and beta chains or pairing of the gamma and delta chains). At V _A Or V _B The amino acid present at position 44 in (a) may be substituted with an amino acid selected from the group consisting of: q, R, D, E, K, L, W and V. Preferably V _A Substitutions W44K and V in (a) _B Q44E in SEQ, respectively present inIn ID No. 347, SEQ ID No. 348 (FR 2-a) and SEQ ID No. 353 (FR 2-b) and results in amino acid pair v _A 44K/v _B 44E. Other suitable combinations are: v _A 44Q/v _B 44Q、v _A 44D/v _B 44R、 _vA 44R/v _B 44D、 _vA 44E/v _B 44K、v _A 44D/v _B 44K、v _A 44K/v _B 44D、v _A 44R/v _B 44E；v _A 44E/v _B 44R、v _A 44L/v _B 44W、v _A 44W/v _B 44L、v _A 44V/v _B 44W and v _A 44W/v _B 44V。

Additional substitutions and descriptions may be found in U.S. patent application No. 2018-0162922, the contents of which are incorporated herein by reference in their entirety.

Variable domains

In one embodiment, V _A An amino acid sequence comprising or consisting of a TCR-derived variable domain contained in a polypeptide comprising: 100, 103, 105, 106, 111, 122, 124, 126, 128, 151, 155, 156, 157, 158, 159, 166, 167, 169, 171, 173, 175, 177, 178, 179, 180, 181, 183, 189, 191, 193, 195, 197, 199, 201, 203, 205, 207, 209, 211, 213, 215, 217, 285, 291, 295, 299, or 303, and V _B An amino acid sequence comprising or consisting of a TCR-derived variable domain contained in a polypeptide comprising: 101, 102, 104, 107, 110, 119, 121, 131, 133, 143, 152, 153, 160, 161, 162, 163, 164, 165, 168, 170, 172, 174, 176, 182, 184, 185, 186, 216, 218, 220, 222, 224, 228, 230, 232, 234, 236, 238, 240, 242, 244, 246, 248, 250, 252, 254, 256, 258, 260, 262, 264, 266, 268, 270, 272, 274, 276, 278, 282, 284, 296, or 300. The person skilled in the art is fully able to distinguish the amino acid sequences of TCR-derived variable domains within the polypeptide sequences of SEQ ID NOs mentioned above.

In one embodiment of the present invention, in one embodiment,

-V _A comprises or consists of: the amino acid sequence of SEQ ID NO. 132, or an amino acid sequence which is at least 85%, 90% or 95% identical to SEQ ID NO. 132, preferably comprises CDRA1 of SEQ ID NO. 16, CDRA2 of SEQ ID NO. 32 and CDRA3 of SEQ ID NO. 33, SEQ ID NO. 34 or SEQ ID NO. 9, and further optionally comprises K or N, preferably K, L, M or I, preferably L or I, K or W, preferably K, at position 39, at position 44, F or A, preferably F, Y or V, preferably Y, at position 55, T or K, preferably T and/or D or G, preferably D, at position 93, at position 20; and is also provided with

-V _B Comprising or consisting of: the amino acid sequence of SEQ ID NO 134, or CDRb3 which is at least 85%, 90% or 95% identical to SEQ ID NO 134, preferably comprises the amino acid sequence of CDRb1 of SEQ ID NO 10, CDRb2 of SEQ ID NO 36 and CDRb2 of SEQ ID NO 48, SEQ ID NO 49, SEQ ID NO 47, SEQ ID NO 281, SEQ ID NO 292, SEQ ID NO 294, SEQ ID NO 297, SEQ ID NO 298, SEQ ID NO 301 or SEQ ID NO 283, and further optionally comprises E, L or K, preferably E, R or H at position 22, E or Q at position 44, preferably E, P or M at position 46, preferably P, Q or R at position 48, preferably Q and/or D, A, E, R, K, Q, N or S, more preferably D, A, E, Q, N or S, preferably D or A.

Preferably, the method comprises the steps of,

-V _A comprising or consisting of: the amino acid sequence of SEQ ID NO. 132, or at least 85%, 90% or 95% identical to SEQ ID NO. 132, comprising CDRA1 of SEQ ID NO. 16, CDRA2 of SEQ ID NO. 32 and CDRA3 of SEQ ID NO. 33, SEQ ID NO. 34 or SEQ ID NO. 9, and further optionally comprising an amino acid sequence of K or N, preferably K, L, M or I, preferably L or I, K or W at position 39, preferably K, F or A, preferably F, Y or V at position 55, preferably Y, T or K at position 92, preferably T and/or D or G, preferably D at position 93 at position 20; and is also provided with

-V _B Comprising or consisting of: the amino acid sequence of SEQ ID NO. 134, or at least 85%, 90% or 95% identical to SEQ ID NO. 134, comprises CDRB1 of SEQ ID NO. 10, CDRB2 of SEQ ID NO. 36 and SEQ ID48, 49, 47, 281, 292, 294, 297, 298, 301 or 283 CDRB3 and further optionally comprises an amino acid sequence of E, L or K, preferably E, R or H at position 22, E or Q at position 44, preferably E, P or M at position 46, preferably P, Q or R at position 48, preferably Q and/or D, A, E, R, K, Q, N or S, preferably D, A, E, Q, N or S, more preferably D or A at position 84.

In a preferred embodiment of the present invention, in a preferred embodiment,

-V _A comprising or consisting of the amino acid sequence of SEQ ID NO. 132, SEQ ID NO. 129, SEQ ID NO. 137 or SEQ ID NO. 142, and

-V _B comprises or consists of the amino acid sequences of SEQ ID NO. 134, SEQ ID NO. 130, SEQ ID NO. 135, SEQ ID NO. 136, SEQ ID NO. 138, SEQ ID NO. 139, SEQ ID NO. 140, SEQ ID NO. 141, SEQ ID NO. 144, SEQ ID NO. 145, SEQ ID NO. 146, SEQ ID NO. 147 or SEQ ID NO. 148.

It is particularly preferred that the composition,

-V _A comprising or consisting of the amino acid sequence of SEQ ID NO. 132, and V _B An amino acid sequence comprising or consisting of SEQ ID NO. 134;

-V _A comprising or consisting of the amino acid sequence of SEQ ID NO. 132, and V _B Comprising or consisting of the amino acid sequence of SEQ ID NO. 135;

-V _A comprising or consisting of the amino acid sequence of SEQ ID NO. 132, and V _B Comprising or consisting of the amino acid sequence of SEQ ID NO. 140;

-V _A comprising or consisting of the amino acid sequence of SEQ ID NO. 132, and V _B Comprising or consisting of the amino acid sequence of SEQ ID NO. 136;

-V _A comprises or consists of the amino acid sequence of SEQ ID NO 137, and V _B An amino acid sequence comprising or consisting of SEQ ID NO. 134;

-V _A Comprising the amino acid sequence of SEQ ID NO. 137Or consist of it, and V _B Comprising or consisting of the amino acid sequence of SEQ ID NO. 135; or alternatively

-V _A Comprises or consists of the amino acid sequence of SEQ ID NO 137, and V _B Comprising or consisting of the amino acid sequence of SEQ ID NO. 134.

Most preferably V _A Comprising or consisting of the amino acid sequence of SEQ ID NO. 132, and V _B Comprising or consisting of the amino acid sequence of SEQ ID NO. 134, 135 or 140, in particular SEQ ID NO. 135. Thus V _A May comprise or consist of the amino acid sequence of SEQ ID NO. 132, and V _B May comprise or consist of the amino acid sequence of SEQ ID NO: 135. Alternatively, V _A May comprise or consist of the amino acid sequence of SEQ ID NO. 132, and V _B May comprise or consist of the amino acid sequence of SEQ ID NO. 140.

Consider a variant of an antigen binding protein as described herein and use the expression "as defined in the definition section above"At least 85% identical to the reference sequence"explicitly mentioned. For example, V _A And V _B Can differ from the reference sequences of SEQ ID NO. 132 and SEQ ID NO. 134, respectively, by at least one amino acid substitution, in particular at least one conservative amino acid substitution and/or substitution with canonical residues. In particular V _A And V _B Can differ from the reference sequences of SEQ ID NO. 132 and SEQ ID NO. 134, respectively, only by conservative amino acid substitutions.

Modifications and variations can be made in the amino acid sequence of the antigen binding proteins of the invention and in the corresponding DNA sequence, respectively, and still result in a functional antigen binding protein or polypeptide having the desired characteristics.

In one embodiment, the antigen binding proteins of the invention further comprise one or more of the following:

(i) One or more additional antigen binding sites;

(ii) A transmembrane region, optionally comprising a cytoplasmic signaling region;

(iii) A diagnostic agent;

(iv) A therapeutic agent; or alternatively

(v) PK adjustment part.

Where elements (i) to (v) listed above are polypeptides fused to an antigen binding protein of the invention, the antigen binding protein may also be referred to as a "TCR fusion protein".

The further antigen binding site is preferably of antibody origin.

In the context of the present invention, "Transmembrane region"may be, for example, a TCR alpha or beta transmembrane domain.

“Cytoplasmic signaling region"may be, for example, a TCR alpha or beta intracellular domain.

"herein"Diagnostic agents"refers to a detectable molecule or substance, such as a fluorescent molecule, a radioactive molecule, or any other label known in the art that provides a signal (directly or indirectly).

“Fluorescent molecules"is known in the art and includes Fluorescein Isothiocyanate (FITC), phycoerythrin (PE), fluorophores for blue lasers (e.g., perCP, PE-Cy7, PE-Cy5, FL3 and APC or Cy5, FL 4), fluorophores for red, violet or UV lasers (e.g., pacific blue, pacific orange).

“Radioactive molecules"including but not limited to radioactive atoms for scintigraphy studies, such as I ¹²³ 、I ¹²⁴ 、In ¹¹¹ 、Re ¹⁸⁶ 、Re ¹⁸⁸ 、Tc ⁹⁹ . The antigen binding proteins of the invention may also comprise spin labels for Nuclear Magnetic Resonance (NMR) imaging (also known as magnetic resonance imaging, MRI), such as iodine-123, indium-111, fluorine-19, carbon-13, nitrogen-15, oxygen-17, gadolinium, manganese or iron.

Such diagnostic agents may be directly coupled (i.e., physically linked) to the antigen binding protein, or may be indirectly linked.

"herein"Therapeutic agent"refers to agents having therapeutic effects. The terms therapeutic agent and drug are used interchangeably herein. In one embodiment, the therapeutic agent may be a growth inhibitor, such as a cytotoxic agent or radioisotope.

Can be used indiscriminately "Growth inhibitors"or" antiproliferative agent "refers to a compound or composition that inhibits the growth of cells, particularly tumor cells, in vitro or in vivo.

The term "as used herein"Cytotoxic agents"means a substance that inhibits or prevents cellular function and/or causes cellular destruction. The term'Cytotoxic agents"is intended to include chemotherapeutic agents, enzymes, antibiotics and toxins (e.g., small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, including fragments and/or variants thereof) as well as various antineoplastic or anticancer agents disclosed below. In some embodiments, the cytotoxic agent is a taxane, a vinca, a taxane, a maytansinoid or a maytansinoid analog (e.g., DM1 or DM 4), a small drug, a tomaymycin or a pyrrolobenzodiazepine derivative, a candidiasis derivative, a leptomycin derivative, an auristatin or a dolastatin analog, a prodrug, a topoisomerase II inhibitor, a DNA alkylating agent, an anti-tubulin agent, CC-1065 or a CC-1065 analog.

Terminology"radioisotope"Intended to include radioisotopes suitable for the treatment of cancer, e.g., at ²¹¹ 、Bi ²¹² 、Er ¹⁶⁹ 、I ¹³¹ 、I ¹²⁵ 、Y ⁹⁰ 、In ¹¹¹ 、P ³² 、Re ¹⁸⁶ 、Re ¹⁸⁸ 、Sm ¹⁵³ 、Sr ⁸⁹ And a radioisotope of Lu. Such radioisotopes typically emit primarily beta radiation. In one embodiment, the radioisotope is an alpha emitter isotope, more precisely thorium 227, which emits alpha radiation.

In some embodiments, the antigen binding proteins of the invention are covalently attached to at least one growth inhibitor directly or via a cleavable or non-cleavable linker. An antigen binding protein attached to such at least one growth inhibitor may also be referred to as a conjugate. The cleavable linker facilitates release of the cytotoxic agent or growth inhibitory agent from the antigen binding protein in the cell. For example, an acid labile linker, a peptidase sensitive linker, an esterase labile linker, a photolabile linker, or a disulfide containing linker may be used (see, e.g., U.S. Pat. No. 5,208,020). The linker may also be a "non-cleavable linker" (e.g., an SMCC linker), which may in some cases lead to better tolerability.

The preparation of such conjugates (e.g., immunoconjugates) is described in application WO 2004/091668 or Hudecz, f., methods mol. Biol.298:209-223 (2005) and Kirin et al, inorg chem.44 (15): 5405-5415 (2005), the contents of which are incorporated herein by reference in their entirety and can be transferred by one skilled in the art into the preparation of antigen binding proteins of the invention attached to such at least one growth inhibitor.

Alternatively, fusion proteins comprising an antigen binding protein of the invention and a cytotoxic or growth inhibitory polypeptide may be prepared by recombinant techniques or peptide synthesis. The length of DNA may comprise corresponding regions encoding the two portions of the conjugate, adjacent to each other or separated by a region encoding a linker peptide that does not disrupt the desired properties of the conjugate.

The antigen binding proteins of the invention may also be used in dependent enzyme mediated prodrug therapies by conjugating the polypeptide to a prodrug activating enzyme that converts a precursor (e.g., a peptide-based chemotherapeutic agent, see WO 81/01145) to an active anticancer agent (see, e.g., WO 88/07378 and U.S. patent No. 4,975,278).

"herein"PK adjustment part"refers to the moiety that modulates the pharmacokinetics of an antigen binding protein of the invention. Thus, the moiety in particular modulates the in vivo half-life and distribution of the antigen binding proteins of the invention. In a preferred embodiment, the PK modulating moiety extends the half-life of the antigen binding protein. PK modulating moieties include, but are not limited to, PEG (Dozier et al, (2015) Int J Mol Sci.Oct 28;16 (10): 25831-64 and Jevsivar et al, (2010) Biotechnol J.Jan;5 (1): 113-28), PAS (Schlapchy et al, (2013) Protein Eng Des Sel.Aug;26 (8): 489-501), albumin (Dennis et al, (2002) J Biol chem.Sep 20;277 (38): 35035-43), antibodies and/or F of unstructured polypeptides _c Part (Schellenberger et al, (2009) Nat Biotechnol. Dec;27 (12): 1186-90).

In one embodiment, the antigen binding proteins of the invention further comprise one or more of the following: enzymes, cytokines (e.g., human IL-2, IL-7, or IL-15), nanocarriers, or nucleic acids.

2 nd antigen binding site

In a preferred embodiment, the antigen binding protein further comprises an antibody light chain variable domain (V _L ) And antibody heavy chain variable domains (V _H ). Variable domain V _L And variable domain V _H Together forming an antigen binding site. Hereinafter, this antigen binding site is sometimes also referred to as "second antigen binding site". From V _L And V _H The antigen binding site formed preferably binds to an antigen of an effector cell, which may also be referred to as a "recruiter" because it recruits effector cells to the tumor. In the context of the present invention, "effector cells" refer to T cells or natural killer cells (NK cells).

In a preferred embodiment, V _L And V _H Binding to an antigen selected from the group consisting of: CD2, CD3 (e.g., CD3 gamma, CD3 delta, and CD3 epsilon chain), CD4, CD5, CD7, CD8, CD10, CD11b, CD11c, CD14, CD16, CD18, CD22, CD25, CD28, CD32a, CD32b, CD33, CD41b, CD42a, CD42b, CD44, CD45RA, CD49, CD55, CD56, CD61, CD64, CD68, CD90, CD94, CD95, CD117, CD123, CD125, CD134, CD137, CD152, CD163, CD193, CD203c, CD235a, CD278, CD279, CD287, nkp, NKG2D, GITR, F _c εRI, TCRα/β, TCRγ/δ, HLA-DR, and 4-1BB or combinations thereof, and/or V _L And V _H Binds to effector cells. By "combination thereof" is meant a complex of two or more of the antigens, such as a tcra/βcd3 complex. Preferably, the antigen is CD3, a tcra/βcd3 complex or CD28, more preferably CD3 or a tcra/βcd3 complex.

For the targeting of the TCR-CD3 complex, V derived from the CD 3-specific humanized antibody hUCHT1 (Zhu et al Identification of heavy chain residues in a humanized anti-CD3 antibody important for efficient antigen binding and T cell activation.J Immunol,1995,155,1903-1910) can be used _H And V _L Domains, in particular from UCHT1 variants UCHT1-V17, UCHT1-V17opt, UCHT1-V21 or UCHT1-V23, preferably from UCHT1-V17 _H And V _L Domain, more preferably V comprising or consisting of SEQ ID NO 109 _H And V comprising or consisting of SEQ ID NO 108 _L . Alternatively, V derived from antibody BMA031 (which targets the TCR alpha/beta CD3 complex) and its humanized forms (Shearman et al, construction, expression and characterization of humanized antibodies directed against the human alpha/beta T cell receptor, J Immunol,1991,147,4366-73) may be used _H And V _L Domains, in particular V derived from BMA031 variant BMA031 (V36) or BMA031 (V10), preferably from BMA031 (V36) _H And V _L Domains, more preferably V comprising or consisting of SEQ ID NO 112 or SEQ ID NO 114 (A02) or SEQ ID NO 115 (D01) or SEQ ID NO 116 (A02_H2) or SEQ ID NO 117 (D01_H2) _H And V comprising or consisting of SEQ ID NO 113 _L . As a further alternative, V derived from the CD3 epsilon specific antibody H2C (described in EP2 1 55 783) may be used _H And V _L Domains, in particular V comprising or consisting of SEQ ID NO 118 or SEQ ID NO 123 (N100D) or SEQ ID NO 125 (N100E) or SEQ ID NO 127 (S101A) _H And V comprising or consisting of SEQ ID NO 120 _L . All positions and CDR definitions conform to the Kabat numbering scheme.

In some embodiments, V _H And V _L Together with TCR alpha/beta CD3 complex and

V _H Included

heavy chain complementarity determining region 1 (HCDR 1) comprising the amino acid sequence of SEQ ID NO. 381 (SYVMH),

-HCDR2 comprising yinpyridvtkyx ₁ X ₂ KFX ₃ The amino acid sequence of G (SEQ ID NO: 382) wherein X ₁ Is A or N; x is X ₂ Is E or Q; and/or X ₃ Is Q or K

-HCDR3

Heavy chain framework regions (HFR) 1-4; and is also provided with

V _L Included

Light chain complementarity determining region 1 (LCDR 1) comprising the amino acid sequence of SEQ ID NO:383 (SATSSVSYMH),

LCDR2 comprising the amino acid sequence of SEQ ID NO:384 (DTSKLAS), an

-LCDR3，

Wherein the method comprises the steps of

-at least one amino acid of HCDR1 comprising the amino acid sequence of SEQ ID No. 1 and/or at least one amino acid of HCDR2 comprising the amino acid sequence of SEQ ID No. 2 (not positively charged) is substituted by a positively charged amino acid; and/or

-at least one amino acid of LCDR1 comprising the amino acid sequence of SEQ ID No. 3 and/or at least one amino acid of LCDR2 comprising the amino acid sequence of SEQ ID No. 4 (non-positively charged) is substituted with a positively charged amino acid; and/or

HFR3 comprises a tyrosine (Y) residue at position 90 according to Kabat numbering.

Preferably, the antigen binding polypeptide comprises

Positively charged amino acids in the heavy chain:

r, K or H at position 31;

r, K or H at position 53; and/or

-R or K at position 54; and/or

Positively charged amino acids in the light chain

-R or K at position 31; and/or

R or K at position 56.

In some embodiments, V _H Comprising a sequence selected from the group consisting of: 112, 114 to 117 and 366 to 376, and V _L Comprising a sequence selected from the group consisting of: SEQ ID NOS 113 and 377 to 380. Preferably V _H Comprises or consists of the amino acid sequence of SEQ ID NO 112 or 114 to 117, and V _L Comprising or consisting of the amino acid sequence of SEQ ID NO. 113 or 378, preferably 113.

“CD28"expressed on T cells" and can provide the costimulatory signals required for T cell activation. CD28 in T cell proliferation and survival, cytokine production and T helper cell type 2 developmentHas important function.

“CD134"also referred to as Ox40.CD134/OX40 is expressed 24 to 72 hours post activation and can be used to define a second co-stimulatory molecule.

“4-1BB"capable of binding to 4-1BB ligand on Antigen Presenting Cells (APCs), thereby generating a costimulatory signal for T cells.

“CD5"is another example of a receptor found primarily on T cells, CD5 is also found at low levels on B cells.

“CD95”Is another example of a receptor that modulates T cell function, and is also known as the Fas receptor, which mediates apoptosis signaling through Fas ligands expressed on other cell surfaces. CD95 has been reported to regulate the TCR/CD3 driven signaling pathway in resting T lymphocytes.

“NK cell-specific receptor molecules"is, for example, CD16 (a low affinity F _c Receptors) and NKG2D.

Examples of receptor molecules present on the surface of both T cells and Natural Killer (NK) cells are CD2 and other members of the CD2 superfamily. CD2 is able to act as a costimulatory molecule for T cells and NK cells.

Bispecific and multispecific antigen-binding proteins

Thus, the antigen binding proteins of the invention preferably comprise V forming a first antigen binding site specific for the PRAME-004:MHC complex _A And V _B And forming a second antigen binding site capable of binding to effector cells, preferably T cells _L And V _H 。V _A 、V _B 、V _L And V _H May be located on a single polypeptide chain or on several polypeptide chains, preferably on two polypeptide chains. With respect to V _A 、V _B 、V _L And V _H The antigen binding proteins of the invention may or may not comprise a dimerization domain, preferably a constant immunoglobulin domain.

In some embodiments, V _A 、V _B 、V _L And V _H Positioned on both polypeptide chains. Preferably, each polypeptide chain comprises two variable domains. Preferably, one polypeptide chain comprises V _A And the other polypeptide chain comprises V _B . Preferably, comprises V _A Comprising V _L And V _H One of them and contains V _B Comprising V _L And V _H Another of which is a member of the group. It is also possible to include V _A Comprising V _L And V _H Both and contain V _B Does not comprise V _L And V _H Either one of these, or vice versa. Another possibility is that one polypeptide chain comprises V _A One polypeptide chain comprising V _B And the third polypeptide chain comprises V _L And V _H 。

In a preferred embodiment, the antigen binding protein comprises a first polypeptide chain and a second polypeptide chain, wherein

The first polypeptide chain is represented by formula [ Ia ]:

V ₁ -L ₁ -D ₁ -L ₂ -V ₂ -L ₃ -D ₂ [Ia]，

and the second polypeptide chain is represented by formula [ IIa ]

V ₃ -L ₄ -D ₃ -L ₅ -V ₄ -L ₆ -D ₄ [IIa]，

Wherein the method comprises the steps of

-V ₁ 、V ₂ 、V ₃ And V ₄ Is a variable domain, one of which is V _A ，V ₁ To V ₄ One of them is V _B One is V _L And one is V _H ；

-D ₁ 、D ₂ 、D ₃ And D ₄ Is a dimerization domain and may be present or absent, wherein D ₁ And D ₃ D (D) ₂ And D ₄ Specifically bind to each other, and D ₁ And D ₃ Or D ₂ And D ₄ At least one pair of which is present; and is also provided with

-L ₁ 、L ₂ 、L ₃ 、L ₄ 、L ₅ And L ₆ Is a linker, wherein L ₁ And L ₄ Is present and L ₂ 、L ₃ 、L ₅ And L ₆ May be present or absent.

Preferably V ₁ And V ₂ One of them is V _A ，V ₃ And V ₄ One of them is V _B And one of the remaining two variable domains is V _L And the other is V _H In other words, V _A And V _B Is positioned on different polypeptide chains, and V _L And V _H Positioned on different polypeptide chains.

The dimerization domain is preferably a heterodimerization domain that mediates heterodimerization of a first polypeptide chain with a second polypeptide chain, but does not mediate homodimerization of two first polypeptide chains or two second polypeptide chains. In a preferred embodiment, a pair of dimerization domains (e.g., D ₁ And D ₃ And/or D ₂ And D ₄ ) Comprising immunoglobulin constant domains, e.g. C of antibody origin _L And C _H1 Or C _L -F _c And C _H1 -F _c Or TCR derived C _α And C _β Or a pair of C _H3 Domain or a pair of F _c Domain, wherein C _H3 And F _c The domain preferably comprises an introduced mutation that forces heterodimerization, such as a knob-to-hole mutation.

In an even more preferred embodiment, the antigen binding protein comprises a first polypeptide chain and a second polypeptide chain, wherein the first polypeptide chain is represented by formula [ Ib ]:

V ₁ -L ₁ -V ₂ -L ₃ -D ₂ [Ib]，

and the second polypeptide chain is represented by formula [ IIb ]:

V ₃ -L ₄ -V ₄ -L ₆ -D ₄ [IIb]，

wherein the method comprises the steps of

-V ₁ 、V ₂ 、V ₃ 、V ₄ Is a variable domain, one of which is V _A One is V _B One is V _L And one is V _H ；

-D ₂ And D ₄ Is a dimerization domain, preferably F, that specifically binds to each other _c A domain; and is also provided with

-L ₁ 、L ₃ 、L ₄ And L ₆ Is a linker, wherein L ₃ And L ₆ May be present or absent.

As described for formula Ia and formula IIa, preferably V _A And V _B Positioned on different polypeptide chains and V _L And V _H Positioned on different polypeptide chains, and the dimerization domain is a heterodimerization domain.

In a preferred embodiment, D ₂ And D ₄ Is a pair F _c Domain F _c1 And F _c2 Specifically D ₂ Is F _c1 And D is ₄ Is F _c2 Wherein F _c1 And F _c2 Are identical or different, preferably different, and preferably contain mutations that force heterodimerization. In one embodiment, F _c1 Comprising or consisting of the amino acid sequence SEQ ID NO 150 (mortar), and F _c2 Comprising or consisting of the amino acid sequence SEQ ID NO 149 (pestle) or vice versa. In particular, at F _c1 Positioned to contain V _L On the polypeptide chain and F _c2 Positioned to contain V _H F when in the polypeptide chain of (C) _c1 Comprises or consists of the amino acid sequence SEQ ID NO 149 (pestle), and F _c2 Comprises or consists of the amino acid sequence SEQ ID NO 150 (mortar), and is shown in F _c1 Positioned to contain V _H On the polypeptide chain and F _c2 Positioned to contain V _L F when in the polypeptide chain of (C) _c1 Comprising or consisting of the amino acid sequence SEQ ID NO 150 (mortar), and F _c2 Comprising or consisting of the amino acid sequence SEQ ID NO 149 (pestle).

It will be appreciated by those skilled in the art that in an antigen binding protein comprising a first polypeptide chain and a second polypeptide chain represented by formula Ia and formula IIa or formula Ib and formula IIb, respectively, V _A And V _B And V is equal to _L And V _H Can be in parallel orientation, e.gIn DVD form, or in cross-orientation, as in CODV form.

In formula Ia and formula IIa or formula Ib and formula IIb, V _A 、V _B 、V _L And V _H May have the following orientations:

(1)V ₁ is V _H ，V ₂ Is V _B ，V ₃ Is V _A And V is ₄ Is V _L ；

(2)V ₁ Is V _B ，V ₂ Is V _H ，V ₃ Is V _L The method comprises the steps of carrying out a first treatment on the surface of the And V is ₄ Is V _A ；

(3)V ₁ Is V _B ，V ₂ Is V _L ，V ₃ Is V _H And V is ₄ Is V _A ；

(4)V ₁ Is V _L ，V ₂ Is V _B ，V ₃ Is V _A And V is ₄ Is V _H ；

(5)V ₁ Is V _H ，V ₂ Is V _B ，V ₃ Is V _L And V is ₄ Is V _A ；

(6)V ₁ Is V _B ，V ₂ Is V _H ；V ₃ Is V _A And V is ₄ Is V _L ；

(7)V ₁ Is V _L ，V ₂ Is V _B ，V ₃ Is V _H And V is ₄ Is V _A ；

(8)V ₁ Is V _B ，V ₂ Is V _L ，V ₃ Is V _A And V is ₄ Is V _H ；

(9)V ₁ Is V _H ，V ₂ Is V _L ，V ₃ Is V _A And V is ₄ Is V _B ；

(10)V ₁ Is V _L ，V ₂ Is V _H ，V ₃ Is V _A And V is ₄ Is V _B ；

(11)V ₁ Is V _H ，V ₂ Is V _L ，V ₃ Is V _B And V is ₄ Is V _A The method comprises the steps of carrying out a first treatment on the surface of the Or alternatively

(12)V ₁ Is V _L ，V ₂ Is V _H ，V ₃ Is V _B And V is ₄ Is V _A 。

Preferably V _A 、V _B 、V _L And V _H Having the orientation described in (1) - (8), i.e.V _A And V _B Positioned on different polypeptide chains and V _L And V _H Positioned on different polypeptide chains. More preferably V _A 、V _B 、V _L And V _H Having the orientations described in (1) - (4), i.e.V _A And V _B And V is equal to _L And V _H With a cross orientation.

Joint L ₁ 、L ₂ 、L ₃ 、L ₄ 、L ₅ Defined in the article section "definition" above. In some embodiments, certain linker lengths may be preferred for a particular format. However, knowledge about the length of the linker and its amino acid sequence is well within the knowledge in the art, and multiple linkers and one linker, different forms of amino acid sequences are part of the state of the art and are disclosed in the disclosure cited above.

Particularly preferably, the antigen binding proteins of the invention are in the form ofForm of the invention. At->In a form of embodiment, the antigen binding protein comprises a polypeptide of formula [ IIa ]]And [ IIb ]]A first polypeptide chain and a second polypeptide chain as defined above, wherein ∈10 >

-V ₁ Is V _H ，V ₂ Is V _B ，V ₃ Is V _A And V is ₄ Is V _L ；

V ₁ Is V _B ，V ₂ Is V _H ，V ₃ Is V _L The method comprises the steps of carrying out a first treatment on the surface of the And V is ₄ Is V _A ；

V ₁ Is V _B ，V ₂ Is V _L ，V ₃ Is V _H And V is ₄ Is V _A The method comprises the steps of carrying out a first treatment on the surface of the Or alternatively

V ₁ Is V _L ，V ₂ Is V _B ，V ₃ Is V _A And V is ₄ Is V _H ；

-L ₃ And L ₆ Absence of;

-L ₁ and L ₄ Preferably comprising or consisting of the amino acid sequence of SEQ ID NO. 214; and is also provided with

-D ₂ And D ₄ Is a pair F _c Domain F _c1 And F _c2 Wherein F _c1 And F _c2 Is different and comprises mutations that force heterodimerization, preferably "knob and hole structure" mutations.

In a preferred embodiment of the present invention, in a preferred embodiment,

-V _L comprising or consisting of the amino acid sequence SEQ ID NO 108 and V _H Comprising or consisting of the amino acid sequence SEQ ID NO 109, or

-V _L Comprising or consisting of the amino acid sequence SEQ ID NO 113 and V _H Comprising or consisting of the amino acid sequences SEQ ID NO 112, SEQ ID NO 114, SEQ ID NO 115, SEQ ID NO 116 or SEQ ID NO 117, or

-V _L Comprising or consisting of the amino acid sequence SEQ ID NO 120 and V _H Comprising or consisting of the amino acid sequences SEQ ID NO. 118, SEQ ID NO. 123, SEQ ID NO. 125 or SEQ ID NO. 127.

In a particularly preferred embodiment, the antigen binding protein comprises a first polypeptide chain selected from the group consisting of: 100, 103, 105, 106, 111, 122, 126, 128, 151, 155, 156, 157, 158, 159, 166, 167, 169, 171, 173, 175, 177, 178, 179, 180, 181, 183, 189, 191, 193, 195, 197, 199, 201, 203, 205, 207, 209, 211, 213, 215, 217, 285, 291, 295, 299 and 303, and a second polypeptide chain selected from the group consisting of: 101, 102, 104, 107, 110, 119, 121, 131, 133, 143, 152, 160, 161, 162, 163, 164, 165, 168, 170, 172, 174, 176, 182, 184, 185, 186, 216, 218, 220, 222, 224, 228, 230, 232, 234, 236, 238, 240, 242, 244, 246, 248, 250, 252, 254, 256, 258, 260, 262, 264, 266, 268, 270, 272, 274, 276, 278, 282, 284, 296, or 300.

In an even more preferred embodiment, the antigen binding protein comprises a first polypeptide chain selected from the group consisting of: 100, 103, 105, 151, 156, 158, 166, 167, 175, 178, 180, 183, 193, 285, 291, 295, 299, and 303, more preferably selected from the group consisting of SEQ ID NOs 100, 103, 105, 167, 183, 193, 285, 291, 295, 299, and 303, and a second polypeptide chain selected from the group consisting of: 101, 102, 104, 160, 161, 162, 163, 164, 165, 170, 172, 174, 176, 182, 185, 186, 284, 296 or 300, more preferably selected from the group consisting of SEQ ID NOs 101, 102, 104, 160, 162, 176, 186, 284, 296 or 300.

In a most preferred embodiment, the antigen binding protein comprises

The first polypeptide chain of SEQ ID NO. 100 and the second polypeptide chain of SEQ ID NO. 101, or the first polypeptide chain of SEQ ID NO. 103 and the second polypeptide chain of SEQ ID NO. 102, or the first polypeptide chain of SEQ ID NO. 105 and the second polypeptide chain of SEQ ID NO. 104, or the first polypeptide chain of SEQ ID NO. 167 and the second polypeptide chain of SEQ ID NO. 160, or the first polypeptide chain of SEQ ID NO. 183 and the second polypeptide chain of SEQ ID NO. 176, or the first polypeptide chain of SEQ ID NO. 193 and the second polypeptide chain of SEQ ID NO. 186, or the first polypeptide chain of SEQ ID NO. 285 and the second polypeptide chain of SEQ ID NO. 284, or the second polypeptide chain of SEQ ID NO. 291 and the second polypeptide chain of SEQ ID NO. 284, or the second polypeptide chain of SEQ ID NO. 295 and the second polypeptide chain of SEQ ID NO. 186, or the first polypeptide chain of SEQ ID NO. 296 and the second polypeptide chain of SEQ ID NO. 162, or the second polypeptide chain of SEQ ID NO. 162 and/or 162, either-the first polypeptide chain of SEQ ID NO. 158 and the second polypeptide chain of SEQ ID NO. 284, either-the first polypeptide chain of SEQ ID NO. 158 and the second polypeptide chain of SEQ ID NO. 300, or-the first polypeptide chain of SEQ ID NO. 303 and the second polypeptide chain of SEQ ID NO. 161, or-the first polypeptide chain of SEQ ID NO. 303 and the second polypeptide chain of SEQ ID NO. 163, or-the first polypeptide chain of SEQ ID NO. 291 and the second polypeptide chain of SEQ ID NO. 164, or-the first polypeptide chain of SEQ ID NO. 291 and the second polypeptide chain of SEQ ID NO. 170, or-the first polypeptide chain of SEQ ID NO. 291 and the second polypeptide chain of SEQ ID NO. 172, or-the first polypeptide chain of SEQ ID NO. 166 and the second polypeptide chain of SEQ ID NO. 170, or-the first polypeptide chain of SEQ ID NO. 166 and the second polypeptide chain of SEQ ID NO. 172, or-the first polypeptide chain of SEQ ID NO. 182 and the second polypeptide chain of SEQ ID NO. 182, or-the second polypeptide chain of SEQ ID NO. 172, or-the first polypeptide chain of SEQ ID NO. 166 and the second polypeptide chain of SEQ ID NO. 182 and the second polypeptide chain of NO. 182 and 182, or-first polypeptide chain of SEQ ID NO. 182 and NO. 182, or-a first polypeptide chain of SEQ ID NO. 180 and a second polypeptide chain of SEQ ID NO. 186;

In particular, it is a combination of two or more of the above-mentioned

-a first polypeptide chain of SEQ ID NO. 100 and a second polypeptide chain of SEQ ID NO. 101, or-a first polypeptide chain of SEQ ID NO. 103 and a second polypeptide chain of SEQ ID NO. 102, or-a first polypeptide chain of SEQ ID NO. 105 and a second polypeptide chain of SEQ ID NO. 104, or-a first polypeptide chain of SEQ ID NO. 158 and a second polypeptide chain of SEQ ID NO. 300, or-a first polypeptide chain of SEQ ID NO. 167 and a second polypeptide chain of SEQ ID NO. 160, or-a first polypeptide chain of SEQ ID NO. 183 and a second polypeptide chain of SEQ ID NO. 176, or-a first polypeptide chain of SEQ ID NO. 193 and a second polypeptide chain of SEQ ID NO. 186, or-a first polypeptide chain of SEQ ID NO. 285 and a second polypeptide chain of SEQ ID NO. 284, or-a first polypeptide chain of SEQ ID NO. 291 and a second polypeptide chain of SEQ ID NO. 164, or

-a first polypeptide chain of SEQ ID NO 291 and a second polypeptide chain of SEQ ID NO 284, or

-a first polypeptide chain of SEQ ID NO:295 and a second polypeptide chain of SEQ ID NO:186, or

-a first polypeptide chain of SEQ ID NO:295 and a second polypeptide chain of SEQ ID NO:296, or

-a first polypeptide chain of SEQ ID NO:299 and a second polypeptide chain of SEQ ID NO:162, or

-a first polypeptide chain of SEQ ID NO:285 and a second polypeptide chain of SEQ ID NO:300, or

-a first polypeptide chain of SEQ ID NO:303 and a second polypeptide chain of SEQ ID NO:162, or

-a first polypeptide chain of SEQ ID No. 291 and a second polypeptide chain of SEQ ID No. 300;

even more particularly

-a first polypeptide chain of SEQ ID NO. 158 and a second polypeptide chain of SEQ ID NO. 300, or

-a first polypeptide chain of SEQ ID NO. 291 and a second polypeptide chain of SEQ ID NO. 164.

Thus, in a most preferred embodiment, the antigen binding protein may comprise a first polypeptide chain of SEQ ID NO. 158 and a second polypeptide chain of SEQ ID NO. 300.

scTCR

In some embodiments, the first polypeptide and the second polypeptide, and thus V _A And V _B Positioned on a single polypeptide chain. In such embodiments, the antigen binding proteins of the invention may be described as single chain TCRs. However, depending on the FR sequence and constant domain contained in the antigen binding protein, it may also be referred to as a single chain antibody or single chain TCR-antibody molecule, as discussed above.

The scTCR may comprise a variable domain derived from a first TCR or comprising at least a CDR derived from the first TCR, a variable domain derived from a second TCR or comprising at least a CDR derived from the second TCR, and a constant domain of the first or second TCR; in other words, a single chain TCR comprises a variable domain derived from one TCR (e.g. derived from an alpha chain or a gamma chain) and the entire chain (e.g. a beta chain or a delta chain) of another TCR, or vice versa. Furthermore, the scTCR may optionally comprise one or more linkers, preferably peptide linkers, which join the domains together. Also provided are scTCRs of the invention which are fused to a human cytokine such as IL-2, IL-7 or IL-15.

In one embodiment, the single chain TCR is in one of the single chain forms selected from: v (V) _A -L _t -V _B 、V _B -L _t -V _A 、V _A -C _α -L _t -V _B 、V _A -C _β -L _t -V _B 、V _A -L _t -V _B -C _β 、V _A -L _t -V _B -C _α 、V _A -C _α -L _t -V _B -C _β 、V _A -C _b -L _t -V _B -C _α Preferably V _A -L _t -V _B 、V _B -L _t -V _A Wherein V is _A Is a first variable domain as defined above, and wherein V _B Is a second variable domain as defined above, C _α And C _β TCR alpha and beta constant domains, respectively present or absent, and L _t Is present or absent and is as defined in the definition section above.

In a particular embodiment, the antigen binding protein of the invention is a scTCR comprising the amino acid sequence of any one of SEQ ID NOS: 79-87 or 89-92, or an amino acid sequence at least 85% identical to SEQ ID NOS: 79-87 or 89-92, preferably the amino acid sequence of SEQ ID NO: 87.

scTCR-Fab

The single chain TCR may comprise a C-terminal linked or N-terminal linked further variable domain, in particular V as described above _L And/or V _H 。

In one embodiment, such another variable domain may be via a linker L _k And (5) connection. In one preferenceIn embodiments, linker L _k hinge-C being a linker or amino acid sequence SEQ ID NO:360 as defined above _H1 Sequence.

In a particular embodiment, the antigen binding protein of the invention is a scTCR-Fab comprising a polypeptide comprising V _A 、V _B And V _L Or V _H Preferably V _H Is a first polypeptide chain of (2) and contains V _L And V _H Another of (a), preferably V _L Is a second polypeptide chain of (a). Preferably, the scTCR-Fab comprises a first polypeptide chain comprising or consisting of: the amino acid sequence of any one of SEQ ID NOs 94-98 or an amino acid sequence at least 85% identical to SEQ ID NOs 94-98, said second polypeptide chain comprising or consisting of: the amino acid sequence of any one of SEQ ID NO. 93 or an amino acid sequence at least 85% identical to SEQ ID NO. 93.

Full length TCR

In another embodiment, the antigen binding proteins of the invention comprise two polypeptide chains, wherein V _A Contained in the (full length) TCR alpha or gamma chain, and V _B Contained in the (full length) TCR β or δ chain. In such embodiments, the antigen binding protein preferably has the structure of a conventional αβ TCR or γδ TCR as described above. In one embodiment, the TCR is an αβ TCR and comprises an α chain constant domain (TRAC) sequence according to SEQ ID No. 361 and a β chain constant domain (TRBC 1 or TRBC 2) sequence according to SEQ ID No. 362.

In one embodiment, the TCR constant domain sequence may be derived from any suitable species, such as any mammal, e.g., human, rat, monkey, rabbit, donkey, or mouse, preferably human. In some preferred embodiments, the TCR constant domain sequence may be slightly modified, for example by introducing a heterologous sequence, preferably a mouse sequence, which may increase TCR expression and stability. Moreover, other stabilizing mutations as known in the state of the art (e.g. WO 2018/104407, PCT/EP2018/069151, WO 2011/044186, WO 2014/018863) may be introduced, such as substitution of unfavorable amino acids in the variable region and/or introduction of disulfide bridges between TCR C domains and removal of unpaired cysteines.

In particular, the TCR constant domain sequence may be modified by truncation or substitution to delete the native disulfide bond between Cys4 of exon 2 of TRAC and Cys2 of exon 2 of TRBC1 or TRBC 2. One or more alpha and/or beta chain constant domain sequences may also be modified by substituting Thr 48 of TRAC and Ser57 of TRBC1 or TRBC2 with a cysteine residue that forms a disulfide bond between the alpha and beta constant domains of the TCR. TRBC1 or TRBC2 may additionally comprise a cysteine to alanine mutation at position 75 of the constant domain, and an asparagine to aspartic acid mutation at position 89 of the constant domain. The constant domain may additionally or alternatively contain other mutations, substitutions or deletions relative to the native TRAC and/or TRBC1/2 sequence. The terms TRAC and TRBC1/2 encompass natural polymorphic variants such as N to K at position 4 of TRAC (Bragado et al Int immunol.1994, month 2; 6 (2): 223-30).

The invention also includes particles displaying antigen binding proteins, particularly TCRs, and including the particles in a library of particles. Such particles include, but are not limited to, phage, yeast, ribosomes, or mammalian cells. Methods of generating such particles and libraries are known in the art (see, e.g., WO 2004/044004; WO 01/48145, chervin et al (2008) J.Immuno. Methods 339.2:175-184).

Nucleic acids, vectors and recombinant host cells

In a second aspect, the invention relates to an isolated nucleic acid comprising or consisting of a sequence encoding the antigen binding protein of the first aspect of the invention.

In the context of the present invention, the term "nucleic acid" refers to a single-or double-stranded oligomer or polymer of deoxyribonucleotide or ribonucleotide bases, or both. The nucleotide monomers consist of nucleobases, five carbon sugars (such as, but not limited to, ribose or 2' -deoxyribose), and one to three phosphate groups. Typically, nucleic acids are formed via phosphodiester bonds between individual nucleotide monomers, in the context of the present invention the term nucleic acid includes, but is not limited to, ribonucleic acid (RNA) and deoxyribonucleic acid (DNA) molecules, but also includes synthetic forms comprising other linked nucleic acids (e.g., peptide nucleic acids, as described in Nielsen et al (Science 254:1497-1500, 1991). Typically, a nucleic acid is a single-or double-stranded molecule and is composed of naturally occurring nucleotides. The depiction of a single strand of nucleic acid also defines the sequence of the (at least part of) complementary strand. The nucleic acid may be single-stranded or double-stranded, or may contain portions of both double-stranded and single-stranded sequences. An exemplary double stranded nucleic acid molecule may have a 3 'or 5' single stranded overhang and thus need not or is not assumed to be fully double stranded throughout its length. The term nucleic acid encompasses a chromosome or a segment of a chromosome, a vector (e.g., an expression vector), an expression cassette, naked DNA or RNA polymers, primers, probes, cDNA, genomic DNA, recombinant DNA, cRNA, mRNA, tRNA, microrna (miRNA), or small interfering RNA (siRNA). The nucleic acid may be, for example, single-stranded, double-stranded or triple-stranded, and is not limited to any particular length. Unless otherwise indicated, a particular nucleic acid sequence comprises or encodes a complementary sequence in addition to any explicitly indicated sequence.

The nucleic acid may be present in whole cells, in cell lysates, or may be in partially purified or substantially pure form. Nucleic acids are "isolated" or "become substantially pure" when other cellular components or other contaminants (e.g., other cellular nucleic acids or proteins) are removed by standard techniques for purification.

The nucleic acid molecules of the present disclosure can be obtained using standard molecular biology techniques, including, but not limited to, methods of amplification and reverse transcription of RNA. Once the DNA fragments encoding, for example, variable strands are obtained, these DNA fragments can be further manipulated by standard recombinant DNA techniques, for example, to convert the variable region genes into full-length genes. In these manipulations, a DNA fragment encoding a variant is operably linked to another DNA molecule or to a fragment encoding another protein (e.g., a constant region or flexible linker). The term "operably linked" as used in this context is intended to mean that the two DNA fragments are joined in a functional manner, e.g. such that the amino acid sequences encoded by the two DNA fragments remain in frame or such that the protein is expressed under the control of a desired promoter. The isolated DNA encoding a variable region (e.g., a variable alpha region and/or a variable beta region) can be converted to a full-length gene by operably linking the DNA encoding the variable region to another DNA molecule encoding a constant region. The sequences of human constant region genes (e.g., for TCRs or antibodies) are known in the art, and DNA fragments encompassing these regions can be obtained by standard PCR amplification.

Typically, the nucleic acid is a DNA or RNA molecule, which may be included in a suitable vector.

The first polypeptide and the second polypeptide described herein may be encoded on one nucleic acid molecule or two separate nucleic acid molecules.

Thus, also provided herein are expression vectors and host cells for producing the antigen binding proteins or functional fragments thereof described herein.

The term'Carrier body”、“Cloning vector"He"Expression vector"refers to a vehicle by which a DNA or RNA sequence (e.g., a foreign gene) can be introduced into a host cell to transform the host and facilitate expression (e.g., transcription and translation) of the introduced sequence.

A variety of expression vectors may be employed to express polynucleotides encoding antigen binding proteins or functional fragments thereof. Both viral-based and non-viral expression vectors can be used to produce the antigen binding proteins described herein, or functional fragments thereof, in mammalian host cells. Non-viral vectors and systems include a variety of plasmids, cosmids, episomes, artificial chromosomes, phage, or viral vectors.

Such vectors may comprise regulatory elements (e.g., promoters, enhancers, terminators, etc.) to cause or direct expression of the polypeptide upon administration to a subject. Examples of promoters and enhancers used in expression vectors for animal cells include SV40 early promoter and enhancer (Mizukami T. Et al 1987), moloney (Moloney) mouse leukemia virus LTR promoter and enhancer (Kuwana Y et al 1987), antibody heavy chain promoter (Mason JO et al 1985) and enhancer (Gillies SD et al 1983), and the like.

For example, non-viral vectors useful for expression of the polynucleotides and polypeptides described herein in mammalian (e.g., human or non-human) cells include all suitable vectors known in the art for expressing proteins. Other examples of plasmids include replicative plasmids comprising an origin of replication, or integrative plasmids, such as for example pUC, pcDNA, pBR and the like.

The term "viral vector" refers to a nucleic acid vector construct comprising at least one element of viral origin and having the ability to be packaged into viral vector particles and encoding at least an exogenous nucleic acid. The vector and/or particle may be used for the purpose of transferring the nucleic acid of interest into a cell in vitro or in vivo. Various forms of viral vectors are known in the art. Useful viral vectors include vectors based on: retrovirus, lentivirus, adenovirus, adeno-associated virus, herpes virus, SV 40-based vectors, papilloma virus, EB virus, vaccinia virus vectors, and Simplex Forest Virus (SFV). Recombinant viruses can be produced by techniques known in the art, such as by transfection of packaging cells or by transient transfection with helper plasmids or viruses. Typical examples of viral packaging cells include PA317 cells, psiCRIP cells, gpenv+ cells, 293 cells, and the like. Detailed protocols for the generation of such replication-defective recombinant viruses can be found, for example, in the following documents: WO 95/14785, WO 96/22378, US 5,882,877, US 6,013,516, US 4,861,719, US 5,278,056 and WO 94/19478.

The nucleic acids encoding the first polypeptide and the second polypeptide described herein may be present in the same vector or in separate vectors. The first polypeptide and the second polypeptide described herein may be present in the same vector or in separate vectors.

In a fourth aspect, the invention relates to a host cell comprising the antigen binding protein of the first aspect, the nucleic acid of the second aspect or the vector of the third aspect of the invention. Host cells may be transfected, infected or transformed with a nucleic acid and/or vector according to the invention.

The term'Transformation"means that a" foreign "(i.e., extrinsic) gene, DNA orThe RNA sequence is introduced into a host cell such that the host cell will express the introduced gene or sequence to produce the desired substance, typically an antigen binding protein or functional fragment thereof as described herein. Host cells that receive and express introduced DNA or RNA have been "Transformation”。

The nucleic acids of the invention may be used to produce the recombinant antigen-binding proteins of the invention in a suitable expression system. The term'Expression system"means a host cell and compatible vector under suitable conditions, for example for expressing a protein encoded by foreign DNA carried by and introduced into the host cell.

Common expression systems include E.coli (E.coli) host cells and plasmid vectors, insect host cells and baculovirus vectors, and mammalian host cells and vectors. Other examples of host cells include, but are not limited to, prokaryotic cells (e.g., bacteria) and eukaryotic cells (e.g., yeast cells, mammalian cells, insect cells, plant cells, etc.). Specific examples include E.coli, kluyveromyces (Kluyveromyces) or Saccharomyces (Saccharomyces) yeast, mammalian cell lines (e.g., green monkey kidney cells (Vero cells), CHO cells, 3T3 cells, COS cells, HEK cells, etc.), primary or established mammalian cell cultures (e.g., produced from primordial lymphocytes, fibroblasts, embryonic cells, epithelial cells, neural cells, adipocytes, etc.). Examples also include mouse SP2/0-Ag14 cells (ATCC CRL 1581), mouse P3X63-Ag8.653 cells (ATCC CRL 1580), CHO cells in which the dihydrofolate reductase gene is deficient (Urlaub G et al; 1980), rat YB2/3HL.P2.G11.16Ag.20 cells (ATCC CRL 1662), and the like. In some embodiments, YB2/0 cells may be preferred because the ADCC activity of the chimeric or humanized antibody is enhanced when expressed in the cells.

In accordance with the above, in one embodiment the invention relates to a host cell comprising an antigen binding protein of the invention, or a nucleic acid encoding an antigen binding protein of the invention, or a vector encoding an antigen binding protein of the invention, as defined above, wherein the host cell is preferably a) a lymphocyte, such as a T lymphocyte or a T lymphocyte progenitor, e.g. a CD4 or CD8 positive T cell, or b) a cell for recombinant expression, such as a Chinese Hamster Ovary (CHO) cell.

In particular, for the expression of some antigen binding proteins of the invention, in particular antigen binding proteins comprising two polypeptides that are not linked, the expression vector may be of the type in which the gene encoding the heavy chain of the antibody and the gene encoding the light chain of the antibody are present on separate vectors, or of the type in which both genes are present on the same vector (tandem type). As regards the ease of construction of the antigen binding protein expression vector, ease of introduction into animal cells and balance between the expression levels of the antibody H chain and L chain in animal cells, a tandem humanized antibody expression vector is preferred (Shitara K et al J Immunol methods.1994, 1/3; 167 (1-2): 271-8). Examples of tandem humanized antibody expression vectors include pKANTEX93 (WO 97/10354), pEE18, and the like.

In one embodiment, such recombinant host cells may be used to produce at least one antigen binding protein of the invention.

Pharmaceutical composition

In a fifth aspect, the invention relates to a pharmaceutical composition comprising an antigen binding protein of the invention, a nucleic acid of the invention, a vector of the invention or a host cell of the invention and a pharmaceutically acceptable carrier.

The antigen binding proteins of the invention have been shown to be capable of achieving cytotoxicity against tumor cells. Thus, the antigen binding proteins of the invention are useful for destroying tumor cells in a patient. The immune response in the patient may be induced by direct administration of the antigen binding protein to the patient, desirably in combination with an agent (i.e., adjuvant) that enhances immunogenicity. Immune responses derived from such therapeutic vaccination can be expected to be highly specific for tumor cells, since peptide SLLQHLIGL (SEQ ID NO: 50) is not presented or over-presented on normal tissue in comparable copy numbers, thereby preventing the risk of undesired autoimmune responses against normal tissue cells in patients.

The invention also relates to an antigen binding protein according to the invention for use as a medicament. The invention also relates to a pharmaceutical composition of the invention for use as a medicament.

The term "as used herein"Pharmaceutical composition"OR"Therapeutic compositionsBy "is meant a compound or composition that is capable of inducing a desired therapeutic effect when properly administered to a subject.

In some embodiments, the subject may also be referred to as a patient.

Such therapeutic or pharmaceutical compositions may comprise a therapeutically effective amount of an antigen binding protein of the invention or an antigen binding protein further comprising a therapeutic agent, admixed with a pharmaceutically or physiologically acceptable formulation selected for suitability to the mode of administration.

The antigen binding proteins of the invention will typically be supplied as part of a sterile pharmaceutical composition which will typically include a pharmaceutically acceptable carrier and/or a pharmaceutically acceptable carrier diluent.

“Pharmaceutical compositions"OR"Pharmaceutically acceptable"refers to molecular entities and compositions that do not produce adverse, allergic or other untoward reactions when administered to a mammal, particularly a human, as the case may be. Pharmaceutically acceptable carrier or excipient refers to any type of nontoxic solid, semisolid or liquid filler, diluent, encapsulating material or formulation aid.

“Pharmaceutically acceptable carriers or excipients"may also be referred to as"Pharmaceutically acceptable diluents"OR"Pharmaceutical agents Upper acceptable vehicle", and may include physiologically compatible solvents, compatibilizers, stabilizers, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. Thus, in one embodiment, the carrier is an aqueous carrier.

In another aspect, the aqueous carrier, when combined with the antigen binding proteins described herein, is capable of imparting improved properties, e.g., improved solubility, efficacy, and/or improved immunotherapy.

The form, route of administration, dosage and regimen of the pharmaceutical composition will naturally depend on the condition to be treated, the severity of the disease, the age, weight and sex of the patient, etc. The pharmaceutical composition may be in any suitable form (depending on the desired method of administration to the patient). It may be provided in unit dosage form, will typically be provided in a sealed container, and may be provided as part of a kit. Such a kit will typically (but not necessarily) include instructions for use. Which may comprise a plurality of said unit dosage forms.

Empirical considerations (such as biological half-life) will generally aid in the determination of the dosage. The frequency of administration can be determined and adjusted during the course of treatment and is based on reducing the number of cancer cells, maintaining a reduction in cancer cells, reducing proliferation of cancer cells, or killing cancer cells. Alternatively, a sustained continuous release formulation of the antigen binding protein may be appropriate. Various formulations and devices for achieving sustained release are known in the art.

In one embodiment, the dose of antigen binding protein in an individual that has been administered one or more administrations can be determined empirically. Increasing doses of antigen binding protein are administered to an individual. To assess the efficacy of antigen binding proteins, markers of cancer cell status can be tracked. These include direct measurement of cancer cell proliferation and cell death by FACS, other imaging techniques; improvement in health as assessed by such measurements, or improvement in quality of life or prolongation of survival as measured by accepted tests. It will be apparent to those skilled in the art that the dosage will vary depending on the individual, the disease state, and the past and concurrent treatments used.

In particular, the pharmaceutical composition contains a vehicle that is pharmaceutically acceptable for a formulation that can be injected. In particular, these may be isotonic sterile saline solutions (monosodium or disodium phosphate, sodium chloride, potassium chloride, calcium chloride or magnesium chloride, etc. or mixtures of such salts), or dry, in particular freeze-dried, compositions which, after addition (as the case may be) of sterile water or physiological saline, allow the constitution of injectable solutions.

The dosage for administration may be adjusted according to a number of parameters, in particular according to the mode of administration used, the relevant pathology, or alternatively the desired duration of treatment.

For the preparation of a pharmaceutical composition, an effective amount of the antigen binding protein of the invention may be dissolved or dispersed in a pharmaceutically acceptable carrier or aqueous medium.

Pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations comprising sesame oil, peanut oil or aqueous propylene glycol; sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and fluid to the extent that easy injectability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.

Solutions of the active compound as the free base or pharmacologically acceptable salt may be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof, and in oils. Under ordinary conditions of storage and use, these formulations contain preservatives to prevent microbial growth.

The antigen binding proteins of the invention may be formulated as compositions in neutral or salt form. Pharmaceutically acceptable salts include acid addition salts (formed with the free amino groups of the protein) formed with inorganic acids (such as, for example, hydrochloric or phosphoric acid) or organic acids (such as acetic, oxalic, tartaric, mandelic, and the like). Salts with free carboxyl groups may also be derived from inorganic bases (such as, for example, sodium, potassium, ammonium, calcium or ferric hydroxides) and organic bases (such as isopropylamine, trimethylamine, glycine, histidine, procaine, and the like).

Sterile injectable solutions are prepared by the following procedure: the active compound is incorporated in the desired amount into an appropriate solvent optionally containing the various other ingredients listed above, followed by filter sterilization. Typically, the dispersion is prepared by: the various sterilized active ingredients are incorporated into a sterile vehicle which contains the basic dispersion medium and the other required ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

Also contemplated is the preparation of more concentrated or highly concentrated solutions for direct injection, wherein the use of DMSO as solvent is contemplated to result in extremely rapid penetration, delivering high concentrations of active agents to small tumor areas.

After formulation, the solution will be administered in a manner compatible with the dosage formulation and in an amount such as is therapeutically effective. The formulations are readily administered in a variety of dosage forms, such as the types of injectable solutions described above, but drug delivery capsules and the like may also be employed.

Method for producing antigen binding proteins

(a) Providing a host cell, wherein the host cell,

(b) Providing a genetic construct comprising a coding sequence encoding said antigen binding protein,

(c) Introducing the genetic construct into the host cell, and

(d) Expressing the gene construct by the host cell, and optionally

(e) Selecting cells expressing and/or secreting said antigen binding protein.

In one embodiment, the method further comprises isolating and purifying the antigen binding protein from the host cell, and optionally, reconstituting the antigen binding protein in a T cell. The person skilled in the art is fully capable of selecting suitable host cells for expression of the antigen binding protein.

The antigen binding proteins of the invention may be produced by any technique known in the art, such as, but not limited to, any chemical, biological, genetic or enzymatic technique, alone or in combination.

The antigen binding proteins of the invention are suitably isolated from the culture medium by antibody purification procedures such as, for example, protein a-sepharose, hydroxyapatite chromatography, gel electrophoresis, dialysis or affinity chromatography.

In one embodiment, recovering the expressed antigen binding protein or polypeptide herein refers to performing protein a chromatography, kappa selection chromatography and/or size exclusion chromatography, preferably protein a chromatography and/or size exclusion chromatography, more preferably protein a chromatography and size exclusion chromatography.

Knowing the amino acid sequence of the desired sequence, one skilled in the art can produce the antigen binding proteins of the invention by standard techniques for producing polypeptides. For example, the antigen binding proteins may be synthesized using well known solid phase methods, particularly using commercially available peptide synthesis equipment (such as manufactured by Applied Biosystems of foster, california) and following the manufacturer's instructions. Alternatively, the antibodies and antigen binding proteins of the invention may be produced by recombinant DNA and gene transfection techniques well known in the art (see Morrison SL. et al (1984) and patent documents US5,202,238 and US5,204,244). For example, fragments may be obtained as DNA expression products after the following process: the DNA sequence encoding the desired (poly) peptide is incorporated into an expression vector and such vector is introduced into a suitable eukaryotic or prokaryotic host which will express the desired polypeptide, from which it can then be isolated using well known techniques.

In one example, i.e. inIn the case of (a), the DNA sequences encoding VH and VL and variable α (vα) and variable β (vβ), as well as encoding the linker, may be obtained by, for example, gene synthesis. The resulting DNA sequences can be cloned in frame into the coding hinge region, derived from e.g. human IgG4[ accession numbers: k01316]And IgG1[ accession number: p01857]CH of (2) ₂ And CH (CH) ₃ Expression vector for domainsAnd may be further engineered. The engineering of the knob-to-socket mutations to incorporate CH stabilization with and without additional interchain disulfide bonds can be performed according to the method described by Reiter et al (Stabilization of the Fv Fragments in Recombinant Immunotoxins by Disulfide Bonds Engineered into Conserved Framework regions. Biochemistry,1994,33,5451-5459) ₃ A domain; to remove CH ₂ An N glycosylation site (e.g., an N297Q mutation); to introduce F _c Silent mutation or to stabilize the introduction of additional disulfide bonds into V respectively _L And V _H Is a kind of medium.

Methods for producing humanized antibodies based on conventional recombinant DNA and gene transfection techniques are well known in the art (see, e.g., riechmann l. 1988;Neuberger MS. Et al 1985) and can be readily applied to the production of antigen binding proteins.

In one example, the vector used to express the recombinant antigen-binding proteins of the invention is designed as a monocistronic pUC19 derivative, for example, under the control of a HCMV-derived promoter element. Amplification of plasmid DNA, for example, in E.coli according to standard culture methods, followed by the use of commercially available kits (Macherey&Nagel) for purification. According to the manufacturer's instructions (ExpiCHO ^TM A system; thermo Fisher Scientific) purified plasmid DNA is used for transient transfection of e.g.CHO-S cells. Culturing transfected CHO cells, e.g., at, e.g., 32℃to 37℃for 6-14 days, and receiving ExpiCHO ^TM One to two feeds of the feed solution.

By, for example, filtration (0.22 μm), for example, with SartoclearLaboratory filter aids (Sartorius) to clarify conditioned cell supernatants. Using for example +.>Pure 25L FPLC system (GE life sciences) to purify bispecific antigen binding proteins, the system was equipped to perform affinity chromatography and size exclusion chromatography in tandem. According toStandard affinity chromatography protocols affinity chromatography is performed on, for example, protein a or protein L columns (GE lives). For example, size exclusion chromatography is performed directly after elution from the affinity column (pH 2.8) using, for example, a Superdex 200pg 16/600 column (GE Life sciences) according to standard protocols to obtain high purity monomeric proteins. The calculated extinction coefficient is used on, for example, a NanoDrop system (Thermo Scientific) to determine protein concentration from the predicted protein sequence. The concentration was adjusted by using a Vivaspin device (Sartorius), if necessary. Finally, the purified molecules are stored at a concentration of about 1mg/mL in, for example, phosphate buffered saline at a temperature of 2 ℃ to 8 ℃.

The mass of the purified bispecific antigen binding protein is determined by e.g. HPLC-SEC on a MabPac SEC-1 column (5 μm,7.8X300 mM) which is run in a Vanquish UHPLC system in e.g. 50mM sodium phosphate pH 6.8 containing 300mM NaCl.

Therapeutic methods and uses

In a seventh aspect, the invention provides an antigen binding protein of the first aspect, a nucleic acid of the second aspect, a vector of the third aspect, a host cell of the fourth aspect or a pharmaceutical composition of the fifth aspect for use in medicine, in particular for use in the diagnosis, prevention and/or treatment of a proliferative disease. Preferably, for therapeutic use (i.e. prophylaxis and/or treatment), the antigen binding protein comprises a first antigen binding site (i.e. a peptide consisting of V _A And V _B Formed antigen binding site) and a second antigen binding site (i.e., formed by V) _L And V _H The antigen binding site formed). The inventors have shown in the in vitro experimental part of several bispecific compounds of the invention, the cytotoxic activity of those constructs against PRAME positive cancer cell lines such as Hs695T and U2 OS. The inventors have additionally demonstrated that the cytotoxic activity is highly specific and limited to PRAME positive cells, as the bispecific antigen binding protein induces only marginally lysis in cell lines that do not present the peptide PRAME-004.

Thus, the antigen binding proteins of the invention, in particular the bispecificSpecific antigen binding proteins, e.g.Can be used for treating cancer. The antigen binding proteins of the invention may be used for therapeutic purposes in humans and/or non-human mammals. In one embodiment, the antigen binding proteins of the invention can bind to tumor cells and reduce the growth of and/or kill tumor cells presenting peptide SLLQHLIGL (SEQ ID NO: 50) on the surface of MHC complex. It is to be understood that the antigen binding protein is administered at a concentration that promotes binding under physiological (e.g., in vivo) conditions. In another embodiment, the antigen binding proteins may be used in immunotherapy against tumor cells of different tissues (e.g., lung, breast, ovary, or kidney). In another embodiment, the antigen binding protein alone may bind to and reduce the growth of and/or kill tumor cells.

Accordingly, the present invention relates to a method of treating or preventing a proliferative disease or disorder, said method comprising administering to a subject in need thereof a therapeutically effective amount of an antigen binding protein, nucleic acid or vector, host cell or pharmaceutical composition according to the invention as defined in the section "antigen binding protein", "nucleic acid" or "pharmaceutical composition".

In a particular embodiment, the invention relates to a method of treating a subject suffering from a proliferative disease, said method comprising administering to said subject T cells expressing on the cell surface an antigen binding protein of the invention.

In another embodiment, the invention relates to a method of eliciting an immune response in a subject suffering from a proliferative disease, said method comprising administering to said subject a composition comprising T cells expressing on the cell surface an antigen recognizing construct of the invention.

In one embodiment, the immune response mentioned in the method is a cytotoxic T cell response.

In one embodiment, the antigen binding protein of the invention, the nucleic acid of the invention or the vector of the invention, the host cell of the invention or the pharmaceutical composition of the invention is for use in the diagnosis, prevention and/or treatment of a proliferative disease.

The invention also relates to the use of an antigen binding protein, nucleic acid or vector, host cell or pharmaceutical composition according to the invention for the manufacture of a medicament for the treatment or prevention of a proliferative disease or disorder in a subject.

In one embodiment, the invention relates to a method of eliciting an immune response in a patient suffering from a cancer presenting a peptide consisting of or comprising the amino acid sequence of SLLQHLIGL (SEQ ID NO: 50) in complex with an MHC protein, the method comprising administering to the patient an antigen binding protein of the disclosure, wherein the cancer is selected from the group consisting of: acute myeloid leukemia, breast cancer, cholangiocellular carcinoma, gall bladder cancer, glioblastoma, hepatocellular carcinoma, head and neck squamous cell carcinoma, melanoma, non-hodgkin lymphoma, non-small cell lung cancer adenocarcinoma, non-small cell lung cancer, squamous cell non-small cell lung cancer, ovarian cancer, esophageal cancer, renal cell carcinoma, small cell lung cancer, bladder cancer, uterine and endometrial cancer, osteosarcoma, chronic lymphocytic leukemia, colorectal cancer, and synovial sarcoma.

In one embodiment, the invention relates to the use of an antigen binding protein, nucleic acid or vector, host cell or pharmaceutical composition according to the invention for treating or preventing a disease or disorder in a subject.

The term'A subject"OR"Individual body"interchangeably used and may be, for example, a human or non-human mammal, preferably a human.

In the context of the present invention, the term "Treatment of"OR"Treatment of"refers to therapeutic use (i.e., for a subject suffering from a given disease) and means reversing, alleviating, inhibiting the progression of one or more symptoms of such disorder or condition. Thus, treatment refers not only to treatment that results in complete cure of the disease, but also to treatment that slows disease progression and/or prolongs survival of the subject.

“Prevention of"means a prophylactic use (i.e., on a subject susceptible to a given disease))。

In one embodiment, "Disease of the human body"OR"Barrier formation"is any condition that would benefit from treatment with the antigen binding proteins of the invention. In one embodiment, this includes chronic and acute disorders or diseases, including those pathological conditions that predispose a subject to the disorder. The term'In need of treatment"refers to subjects already suffering from a disorder and those subjects to be prevented from the disorder.

In a particular embodiment, the antigen binding proteins of the invention are bispecific, more particularlyAs described herein.

“Proliferative diseases", such as cancer, involves deregulated and/or inappropriate proliferation of cells.

Thus, in one embodiment, the proliferative disorder is cancer.

In another embodiment, the cancer is a cancer in which PRAME antigens are overexpressed, mutated, and/or presented with MHC-associated PRAME-derived tumor-associated antigens.

Thus, a particularly preferred cancer is PRAME positive cancer.

In the case of the present invention, related peptides such as, for example, PRAME-004 peptide are found in all cancers if guided by NCI>98% of the presentation, the cancer is considered"PRAME" positive "". In all other indications mentioned herein, a biopsy may be performed, as it is standard in the treatment of these cancers and may be based onAnd related methods for identifying the peptides (according to WO 03/100432; WO 2005/076009; WO 2011/128448; WO 2016/107740, US 7,811,828, US 9,791,444 and US2016/0187351, the contents of each of which are hereby incorporated by reference in their entirety). In one embodiment, the cancer is readily determined (i.e., diagnosed), for example, by using the antigen binding proteins of the invention. Using antigens Methods of binding proteins to identify cancers that express antigens are known to those of skill in the art. It should be understood that the terms "cancer" and "cancer" are not used interchangeably herein, as cancer (cancer) is a special type of cancer that is newly developed in the skin or in tissues lining or covering body organs.

In one embodiment, as PRAME"Positive" presentation of target peptideIs selected from the group consisting of: acute myeloid leukemia, breast cancer, cholangiocellular carcinoma, biliary cancer, glioblastoma, hepatocellular carcinoma, head and neck squamous cell carcinoma, melanoma, non-hodgkin lymphoma, non-small cell lung cancer adenocarcinoma, non-small cell lung cancer, squamous cell non-small cell lung cancer, ovarian cancer, esophageal cancer, renal cell carcinoma, small cell lung cancer, bladder cancer, uterine and endometrial cancer, osteosarcoma, chronic lymphocytic leukemia, colorectal cancer and synovial sarcoma, preferably breast cancer, cholangiocarcinoma, hepatocellular carcinoma, head and neck squamous cell carcinoma, squamous cell non-small cell lung cancer, ovarian cancer, esophageal cancer, renal cell carcinoma, small cell lung cancer, bladder cancer, uterine and endometrial cancer, and synovial sarcoma.

In one embodiment, wherein the cancer is a cancer in which PRAME antigen is overexpressed, mutated, and/or presented with a PRAME-derived tumor-associated antigen associated with MHC, the cancer is readily determined, e.g., by use of an antigen binding protein of the invention. Methods for using antigen binding proteins to identify cancers that express antigens are known to those of skill in the art.

Documents providing guidelines for Cancer therapy include Cancer, principles and Practice of Oncology, 4 th edition, deVita et al, editors J.B. Lippincott Co., philadelphia, pa. (1993). The appropriate treatment is selected based on the particular type of cancer and other factors such as the general health of the patient, as is well known in the relevant arts. In treating cancer patients, the antigen binding proteins of the invention may be used alone or may be added to treatment regimens with other antineoplastic agents.

Thus, in some embodiments, the antigen binding protein may be administered concurrently with, before or after, a variety of drugs and treatments (such as, for example, chemotherapeutic agents, non-chemotherapeutic agents, antineoplastic agents, and/or radiation) that are widely used in cancer treatment.

In one embodiment, the invention relates to a method of treating a patient suffering from a cancer comprising or consisting of the amino acid sequence of SLLQHLIGL (SEQ ID NO: 50) presenting as a complex with an MHC protein, comprising administering to the patient an antigen binding protein of the disclosure, wherein the cancer is selected from the group consisting of acute myeloid leukemia, breast cancer, cholangiocarcinoma, gall bladder cancer, glioblastoma, hepatocellular carcinoma, head and neck squamous cell carcinoma, melanoma, non-Hodgkin's lymphoma, non-small cell lung carcinoma adenocarcinoma, non-small cell lung carcinoma, squamous cell non-small cell lung carcinoma, ovarian cancer, esophageal cancer, renal cell carcinoma, small cell lung carcinoma, bladder cancer, uterine and endometrial cancer, osteosarcoma, chronic lymphocytic leukemia, colorectal cancer, and synovial sarcoma.

"herein"Diagnosis of"refers to medical diagnosis and refers to determining which disease or condition accounts for the symptoms and signs of an individual.

Antigen binding proteins or pharmaceutical compositions thereof "Therapeutically effective amount ofBy "is meant an amount of antigen binding protein sufficient to treat the proliferative disease at a reasonable benefit/risk ratio applicable to any medical treatment. However, it will be appreciated that the total daily dose of the antigen binding protein, nucleic acid or vector, host cell or pharmaceutical composition of the invention will be determined by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient will depend on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the particular antigen binding protein employed; the particular composition employed, the age, weight, general health, sex and diet of the patient; the time of administration, route of administration and rate of excretion of the particular polypeptide employed; duration of treatment; a medicament for use in combination or simultaneously with the particular polypeptide employed; and similar factors well known in the medical arts. For example, as is well known in the art, to be less than desirable to achieve The levels of those required for therapeutic effect begin the dosage of the compound and gradually increase the dosage until the desired effect is achieved.

In one embodiment, the efficacy of treatment with an antigen binding protein of the invention is determined in vivo, e.g., in a mouse cancer model, and by measuring, e.g., the change in tumor volume between the treatment group and the control group.

The pharmaceutical compositions, vectors, nucleic acids and cells of the invention may be provided in substantially pure form, e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% pure.

The antigen binding protein of the invention, the nucleic acid of the invention or the vector of the invention, the host cell of the invention or the pharmaceutical composition of the invention may be administered by any feasible method.

As disclosed herein, in some embodiments, a host cell as defined above is used in a medical use or method of treatment as described herein. In the same embodiment, the host cell is preferably a) a lymphocyte, such as a T lymphocyte or a T lymphocyte progenitor, e.g. a CD4 or CD8 positive T cell, most preferably a T cell.

Thus, the host cells of the invention, preferably T cells, may be used as an active ingredient of a therapeutic composition. Accordingly, the present invention also provides a method of killing target cells of a patient that abnormally express a polypeptide comprising peptide SLLQHLIGL (SEQ ID NO: 50), comprising administering to the patient an effective amount of a host cell, preferably a T cell. In the case of this method, the host cell preferably elicits an immune response once administered to the subject.

In one aspect, a TCR-elicited immune response or T cell response may refer to proliferation and activation of effector functions induced by a peptide such as SLLQHLIGL (SEQ ID NO: 50) in vitro or in vivo. For MHC class I restricted cytotoxic T cells, for example, effector function may be peptide pulsed, peptide precursor pulsed or lysis of naturally peptide-presenting target cells; secretion of cytokines, preferably interferon-gamma, TNF-alpha or IL-2, induced by the peptide; secretion of effector molecules, such as granzymes or perforins, induced by peptides; or degranulation.

Thus, a host cell as defined above may be from a subject (autologous) or from another individual: preferably, the other individual is healthy.

“Healthy and healthyBy "is meant that the subject is generally in good health, preferably has an active immune system, and more preferably does not suffer from any disease that can be readily tested and detected.

In a specific example, the host cell is a T cell. Thus, in the case of the present invention, T cells are typically collected from a subject by apheresis when T cells as defined above are used as a drug. The T cells are then genetically engineered to express the antigen binding proteins of the invention on their cell surfaces, and then the genetically engineered T cells are expanded and then reinfused into a subject. In this example, the antigen binding protein is preferably a TCR.

In another approach, the host cell may be a stem cell, such as a mesenchymal stem cell, and is engineered to express the antigen binding protein of the invention. In this example, the antigen binding protein is a soluble protein as defined above, such as an antibody, scTCR, or diabody.

Thus, a host cell has been transfected, infected or transformed with a nucleic acid and/or vector according to the invention as described above in the section "nucleic acid, vector and recombinant host cell".

When transfecting a host cell to express an antigen binding protein of the invention, preferably the cell comprises an expression vector capable of expressing the antigen binding protein. The host cell may be referred to as an activated host cell.

Protocols for this so-called adoptive transfer of T cells are well known in the art. An overview can be found in: gattioni et al and Morgan et al (Gattineni, L. Et al, nat. Rev. Immunol.6 (2006): 383-393; morgan, R.A. et al, science 314 (2006): 126-129).

Various other methods can be used to generate T cells in vitro. For example, autologous tumor infiltrating lymphocytes may be used in the generation of CTLs. Plabanski et al (Plabanski, M. Et al, eur. J Immunol 25 (1995): 1783-1787) utilized autologous peripheral blood lymphocytes (PLB) in the preparation of T cells. Likewise, B cells can be used in the production of autologous T cells.

Allogeneic cells may also be used in the preparation of T cells, and the method is described in detail in US6805861, which is incorporated herein by reference.

Host cells expressing the antigen binding proteins of the invention against peptide SLLQHLIGL (SEQ ID NO: 50) can be used in therapy. Thus, a further aspect of the invention provides an activated host cell obtainable by the foregoing method of the invention.

Activated host cells produced by the above method can specifically recognize cells that abnormally express a polypeptide comprising peptide SLLQHLIGL (SEQ ID NO: 50).

By "aberrant expression", the inventors also mean that the polypeptide is overexpressed compared to the level of expression in normal (healthy) tissue, or that the gene is silenced in the tissue from which the tumor is derived, but expressed in the tumor. By "over-expression", the inventors mean that the polypeptide is present at a level that is at least 1.2 times the level present in normal tissue; preferably at least 2 times, and more preferably at least 5 times or 10 times the level present in normal tissue.

In one aspect, a host cell, particularly a T cell, recognizes the cell by interaction (e.g., binding) via its antigen binding protein, particularly its TCR, with the PRAME-004 complex. Host cells can be used in a method of killing target cells of a patient that abnormally express a polypeptide comprising peptide SLLQHLIGL (SEQ ID NO: 50), wherein an effective amount of the activated host cells is administered to the patient. T cells administered to a patient may be derived from the patient and activated as described above (i.e., they are autologous T cells). Alternatively, the T cells are not from the patient, but from another individual. Of course, it is preferred if the individual is a healthy individual. By "healthy individual" the inventors mean that the individual is generally in good health, preferably has an active immune system, and more preferably is not suffering from any disease that can be easily tested and detected.

In vivo, the target cells of CD8 positive T cells according to the invention may be tumor cells (which sometimes express MHC class II) and/or stromal cells surrounding a tumor (tumor cells) (which sometimes also express MHC class II) (Dengjel, J. Et al, clin Cancer Res 12 (2006): 4163-4170).

Diagnostic use

PRAME is expressed on the surface of PRAME expressing cancers as defined above. The antigen PRAME constitutes a cancer marker and thus has the potential to be used to indicate the effectiveness of anti-cancer therapies or to detect disease recurrence.

Thus, in a further aspect, the present invention provides an antigen binding protein of the first aspect, a nucleic acid of the second aspect, a vector of the third aspect, a host cell of the fourth aspect or a pharmaceutical composition of the fifth aspect for use as a diagnostic agent, in particular as an in vivo diagnostic agent. In a preferred embodiment, the diagnostic agent is for diagnosing a proliferative disease. In a more preferred embodiment, the diagnostic agent is used for diagnosing cancers comprising or consisting of the amino acid sequence of SLLQHLIGL (SEQ ID NO: 50) presenting in a complex with MHC proteins, preferably wherein the cancer is selected from acute myeloid leukemia, breast cancer, cholangiocellular carcinoma, biliary cancer, glioblastoma, hepatocellular carcinoma, head and neck squamous cell carcinoma, melanoma, non-Hodgkin's lymphoma, non-small cell lung cancer adenocarcinoma, non-small cell lung cancer, squamous cell non-small cell lung cancer, ovarian cancer, esophageal cancer, renal cell carcinoma, small cell lung cancer, bladder cancer, uterine and endometrial cancer, osteosarcoma, chronic lymphocytic leukemia, colorectal cancer and synovial sarcoma.

Those skilled in the art will appreciate that for diagnostic purposes, the antigen binding protein comprises V _A And V _B But preferably does not contain V _L And V _H 。

In one embodiment, the antigen binding proteins of the invention are used as components of an assay in the context of therapies targeting PRAME expressing tumors to determine patient treatmentSensitivity of the therapeutic agent, monitoring the effectiveness of the anti-cancer therapy or detecting recurrence of the disease after treatment. In particular, as defined herein comprises V _A And V _B The antigen binding proteins of the domains are used as components of diagnostic assays, wherein bispecific antigen binding proteins are used as components of therapeutic agents.

Thus, another object of the present invention relates to an antigen binding protein according to the present invention for use in the in vivo detection of PRAME expression in a subject, or for use in the ex vivo or in vitro detection of PRAME expression in a biological sample of a subject. The detection may be intended in particular for

a) Diagnosing the presence of cancer in a subject, or

b) Determining the sensitivity of a patient suffering from cancer to a PRAME-targeted therapeutic, or

c) Monitoring the effectiveness of anti-PRAME cancer therapies or detecting cancer recurrence following anti-pame cancer therapies, particularly for therapies using dual specificity according to the invention; by detecting the expression of the surface protein PRAME on tumor cells.

In one embodiment, the antigen binding protein is intended for in vitro or ex vivo use.

Kit for detecting a substance in a sample

Finally, the invention also provides a kit comprising at least one antigen binding protein of the invention.

In one embodiment, the kit comprises

a) At least one antigen binding protein of the invention as defined above in the section "antigen binding protein",

b) Optionally packaging material

c) Optionally a label or package insert contained within the packaging material that indicates that the antigen binding protein is effective for treating cancer or for use in cancer treatment.

In related embodiments, at least one antigen binding protein of the invention is contained in single-and/or multi-chamber pre-filled syringes (e.g., liquid syringes and freeze syringes).

In one embodiment, the invention encompasses a kit for producing a single dose administration unit.

Thus, in one embodiment, at least one antigen binding protein of the invention as mentioned in a) of the kit of the invention is a dried antigen binding protein of the invention contained in a first container. The kit also contains a second container with an aqueous formulation.

Thus, in one embodiment, the kit comprises

a) A first container comprising at least one dried antigen binding protein of the invention as defined above in section "antigen binding protein",

b) A second container comprising an aqueous formulation;

c) Optionally packaging material

d) Optionally a label or package insert contained within the packaging material that indicates that the antigen binding protein is effective for treating cancer or for use in cancer treatment.

The aqueous formulation is typically one comprising a pharmaceutically acceptable carrier as defined above in section "pharmaceutical composition".

In related embodiments, the "first container" and "second" container refer to the chambers of a multi-chamber prefilled syringe (e.g., a freeze syringe).

Throughout this application, the term "And/or"is a grammatical conjunctive term that should be construed to cover one or more situations in which it is connected. For example, the phrase "such native sequence proteins can be prepared using standard recombinant and/or synthetic methods" indicates that native sequence proteins can be prepared using standard recombinant and synthetic methods, or native sequence proteins can be prepared using standard recombinant methods, or native sequence proteins can be prepared using synthetic methods.

Furthermore, throughout this application, the term "Included"should be construed to cover all explicitly mentioned features as well as optional, additional, unspecified features. As used herein, the term "IncludedThe use of "also discloses embodiments in which no other features than those specifically mentioned are present (i.e."Is composed of … …”)。

In addition, the indefinite article'One/one (a)'Or'One/one (an)"does not exclude a plurality/plurality". The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage.

The invention will now be described in more detail with reference to the following figures and examples. All documents and patent documents cited herein are hereby incorporated by reference. While the invention has been illustrated and described in detail in the foregoing description, the embodiments are to be considered as illustrative or exemplary and not restrictive.

Drawings

Fig. 1: the TCR was converted to a stable scTCR via yeast surface display. The ScTCR molecules displayed on the surface of transformed saccharomyces cerevisiae (Saccharomyces cerevisiae) EBY100 were stained with anti-Myc-FITC antibodies to determine expression levels, and PE-tagged HLA-A 02/PRAME-004 tetramers to study functional binding. The unmodified scTCR R11P3D3 (left panel, SEQ ID NO: 5) was compared to an R11P1D3 stable scTCR variant (right panel, SEQ ID NO: 6) carrying nine stable framework mutations and three single point mutations in the CDRs, which resulted from selection of the scTCR library.

Fig. 2: affinity maturation of scTCR CDR1 alpha via yeast surface display. Stable scTCRs containing unmodified and mature CDR 1. Alpha. Were stained with HLA-A 02/PRAME-004 monomers at a concentration of 10 nM. Contrast staining was performed with a mixture of HLA-A 02/SimPep tetramers, each tetramer applied at a concentration of 10nM, containing peptides with high sequence similarity to PRAME-004 (SEQ ID NO: 50) (SEQ ID NOs: 51 to 59). The stable scTCR R11P3D3SD (SEQ ID NO: 6) (SEQ ID NO:13; bottom right panel) with unmodified alpha chain CDR1 sequence SSNFYN was compared to scTCR variants comprising affinity matured alpha chain CDR1 sequence VKEFQD, NKEFQD, TREFQD, NREFQD, TSEFQD, TKEFQD, VREFQD, TAEFQD, VSEFQD, VAEFQD, IKEFQN, VREFQN and TAEFQN (SEQ ID NO 16 to 28), respectively. SSNFYN (SEQ ID NO 13) is the corresponding CDRa1 sequence of stable scTCR R11P3D3 SD.

Fig. 3: binding of high affinity scTCR yeast clones to similar peptides. Yeast clones carrying stable scTCRs with mature CDRs (SEQ ID NOS: 79 to 87 and 89 to 92) were stained with 100nM of HLA-A.02 monomer containing the PRAME-004 target peptide or one of 7 analogous peptides (SEQ ID NOS: 52 to 56 and 58 to 59).

Fig. 4: binding of high affinity scTCR yeast clones to similar peptides. Yeast clones carrying stable scTCRs with mature CDRs (SEQ ID NOS: 79 to 87 and 89 to 92) were stained with 100nM of HLA-A.02 monomer containing the PRAME-004 target peptide or one of 19 analogous peptides (SEQ ID NOS 51, 57, 60, 62 to 69 and 71 to 78). R16p1c10_cdr6_sctcr (SEQ ID NO 357) was added as a reference, but only the binding of this clone to PRAME-004 and IFT17-003 (SEQ ID NO 60) was assessed.

Fig. 5: binding motifs were determined using high affinity scTCR yeast clones. Yeast clones carrying stable scTCRs with mature CDRs (SEQ ID NOS: 79, 80, 82, 83 and 85 to 87) were stained with PRAME-004 and with PRAME-004 peptide variants containing alanine substitutions (SEQ ID NOS 318 to 324) with HLA-A.times.02 applied at concentrations of 10nM, 3nM, 1nM and 0.3 nM.

Fig. 6: similar peptide screens for soluble scTCR-Fab molecules. Binding to 14 like peptides (SEQ ID NOs: 187, 188, 190, 192, 194, 196, 198, 200, 202, 204, 206, 208, 210 and 212) was analyzed using biolayer interferometry at a concentration of scTCR-Fab of 1 μm at HLA-A x 02. The upper curve in each figure represents scTCR-Fab bound to the target HLA-A.times.02/PRAME-004 monomer.

Fig. 7:in vitro cytotoxicity of molecules against target positive and target negative tumor cell lines. PBMCs from healthy HLA-A-02 positive donors were gradually increased by a ratio of 1:10 with the target positive tumor cell line Hs695T (+) or the target negative but HLA-A-02 positive tumor cell line T98G (∈) respectively>Incubating in the presence of concentration. The released LDH pair was measured after 48 hours of co-cultivation>The induced cytotoxicity was quantified. The results of the experiments evaluating TPP-93 and TPP-79 are shown in the upper and lower panels, respectively.

Fig. 8:in vitro cytotoxicity of molecule TPP-105 against target positive and target negative tumor cell lines. PBMCs from healthy HLA-A-02 positive donors were incubated with target positive tumor cell line Hs695T (+) or target negative but HLA-A-02 positive tumor cell line T98G (≡) at a ratio of 1:10 in the presence of increasing concentrations of TPP-105, respectively. The released LDH pair was measured after 48 hours of co-cultivation>The induced cytotoxicity was quantified.

Fig. 9:summary of cytotoxicity data for groove (Slot) III molecules. Calculation of EC of dose-response curves obtained in LDH release assays using nonlinear 4-point curve fitting ₅₀ Values. For each evaluation +.>Molecules depicting EC calculated against target positive tumor cell line Hs695T (+), U2OS (≡), and target negative but HLA-A x 02 positive tumor cell line T98G () ₅₀ Values. Thus, each symbol represents one assay using PBMCs derived from various HLA-A 02 positive donors. For TPP-871/T98G, EC ₅₀ Is an estimate because TPP-871 does not recognize T98G.

Fig. 10:cell III variants were cytotoxic to T2 cells loaded with different concentrations of target peptide in vitro. Cytotoxicity was determined by quantifying LDH released into the supernatant. Human PBMC were used as effector cells with an E:T ratio of 5:1. The readout was performed after 48 h.

Fig. 11: for the selectedNormal tissue cell safety analysis of groove III variants. Compared to cytotoxicity against PRAME-004 positive Hs695T tumor cells, the evaluation of the response against 5 different normal tissue cell types expressing HLA-A-02 was made by>Mediated cytotoxicity. PBMCs from healthy HLA-A-02+ donors were co-cultured with normal tissue cells or Hs695T tumor cells (in triplicate) in a 1:1 mixture of the corresponding normal tissue cell culture medium (4, 10a or 13 a) with T cell culture medium (LDH-AM) or in T cell culture medium alone at a ratio of 10:1. After 48 hours, the release of LDH was measured (LDH-Glo ^TM Kit, promega) to evaluate lysis of normal tissue cells and Hs695T cells.

Fig. 12: for the selectedNormal tissue cell safety analysis of groove IV variants. Evaluating +.10 different normal tissue cell types for expression of HLA-A.times.02 compared to cytotoxicity against PRAME-004 positive Hs695T tumor cells>Mediated cytotoxicity. PBMCs from healthy HLA-A-02+ donors were co-cultured with normal tissue cells or Hs695T tumor cells (in triplicate) in a 1:1 mixture of the corresponding normal tissue cell culture medium (3, 4, 8a, 10a, 13a or 16 a) with T cell culture medium (LDH-AM) or in T cell culture medium alone at a ratio of 10:1. After 48 hours, by measuring LDH Release (LDH-Glo) ^TM Kit, promega) to evaluate lysis of normal tissue cells and Hs695T cells.

Fig. 13: for the selectedNormal tissue cell safety analysis of groove IV variants. Evaluating +.f. for 6 different normal tissue cell types expressing HLA-A.times.02 compared to cytotoxicity against PRAME-004 positive Hs695T tumor cells>Mediated cytotoxicity. PBMCs from healthy HLA-A-02+ donors were co-cultured with normal tissue cells or Hs695T tumor cells (in triplicate) in a 1:1 mixture of the corresponding normal tissue cell culture medium (10 a, 13a or 16 a) with T cell culture medium (LDH-AM) at a ratio of 10:1. After 48 hours, the release of LDH was measured (LDH-Glo ^TM Kit, promega) to evaluate lysis of normal tissue cells and Hs695T cells.

Examples

Example 1: single chain TCR (scTCR form)

Example 1.1: stabilization of scTCR production

For the present invention, the TCR R11P3D3 (SEQ ID NO:1 and 2, full length) was converted to a single chain TCR construct (scTCR R11P3D3, SEQ ID NO: 5) using the variable alpha (SEQ ID NO: 3) and beta (SEQ ID NO: 4) domains and the appropriate glycine-serine linker sequence (SEQ ID NO: 61). For TCR maturation via yeast surface display, DNA of the corresponding sequence was synthesized and transformed into saccharomyces cerevisiae EBY100 along with a pCT 302-based yeast display vector (Boder and Wittrup, methods enzymol.2000; 328:430-44). The fusion protein (SEQ ID NO: 325) obtained after homologous recombination in yeast contains a leader peptide (SE)Q ID NO: 88) (Boder and Wittrup, nat Biotechnol.1997, month 6; 15 553-7), the protein of interest, scTCR R11P3D3 (SEQ ID NO: 5) or variants thereof, and additional peptide tags (FLAG and Myc (SEQ ID NO 99 and 288)) for determining the expression level of the fusion protein. Libraries of scTCR variants were generated via PCR using degenerate primers, and transformation of yeast cells was performed as described in WO 2018/091396, and resulted in up to 10 ⁹ Individual yeast clones/libraries.

The selection procedure for yeast clones carrying the mutant scTCR variant with improved binding to PRAME-004 in the case of HLA-A.02 was essentially as described in Smith et al (Methods Mol biol.2015; 1319:95-141). The most promising candidates were selected using expression as determined by Myc tag-FITC staining, in particular functional binding as determined via HLA-A x 02/PRAME-004 tetramer staining (fig. 1). The scTCR transformation by yeast surface display reveals nine framework mutations combined with three single point CDR mutations, resulting in a stable scTCR R11P3D3SD (SEQ ID NO: 6) showing improved expression and HLA-A.times.02/PRAME-004 tetramer binding.

Example 1.2: affinity maturation, binding motif and specificity assessment of stable scTCR

To generate scTCR molecules with higher binding affinity to HLA-A.times.02/PRAME-004, all CDRs were matured individually using the previously identified stable scTCR R11P3D3SD (SEQ ID NO: 6). CDR residues were randomized by using degenerate DNA oligo primers essentially as described previously (Smith et al Methods Mol biol.2015; 1319:95-141). The resulting DNA library was transformed as described in example 1.

For the selection of affinity-enhanced and specific R11P3D3SD scTCR variants, each round of selection used decreasing concentrations of HLA-A 02/PRAME-004 tetramer or monomer. After four rounds of selection, a single scTCR clone was isolated and sequenced to yield multiple affinity matured CDR sequences. As exemplarily shown for sctcrs with mature CDRa1 sequences (SEQ ID NOs: 16 to 28, fig. 2), significant improvements in HLA-A 02/PRAME-004 monomer binding can also be shown for sctcrs with mature CDRa2 and CDRb2 (SEQ ID NOs 29 to 32 and 35 to 45, table 3). The selectivity of HLA-A 02/PRAME-004 binding was preserved during maturation, as confirmed by low binding of scTCR to a mixture of HLA-A 02 tetramers containing peptides (analogue peptide or SimPep) with high sequence similarity to PRAME-004 peptide (SEQ ID NO: 50). All selected scTCR maturation variants showed significant staining with a 10nM concentration of HLA-A.02/PRAME-004 monomer, whereas the immature stable scTCR R11P3D3SD as reference showed no staining (FIG. 2 and Table 3). Furthermore, binding of the mature scTCR to a mixture of similar peptides (applied in high affinity form of the HLA-A.02 tetramer at a concentration of 10 nM) failed to detect or only showed low signal compared to HLA-A.02/PRAME-004 monomer binding, confirming the ability of the mature variants of scTCR to bind the PRAME-004 target peptide in a highly specific manner.

Table 3: binding data of yeast-borne scTCR to mutant CDR 2. Stable scTCRs containing unmodified and mature CDR 2. Alpha. And CDR 2. Beta. Were stained with 10nM HLA-A.times.02/PRAME-004 monomer and counterstained with a mixture of HLA-A.times.02 tetramers, each tetramer applied at a concentration of 10nM, containing peptides (like peptide or SimPep, SEQ ID NO:51 to 59) with high sequence similarity to PRAME-004 (SEQ ID NO: 50). * : corresponding CDRs from R11P3D3SD_scTCR (SEQ ID NO: 6)

To further enhance the affinity of scTCR clones, the mature CDRs identified in the CDR libraries described above were systematically combined in one DNA library and transformed into saccharomyces cerevisiae EBY100, as described in example 1.1. This library was selected using HLA-A 02/PRAME-004 monomers and sctcrs from single yeast clones were sequenced and analyzed for their binding to HLA-A 02 monomers containing PRAME-004 target peptide or one peptide from the group of 26 peptides (analogous peptides) sharing sequence similarity to PRAME-004 (SEQ ID NOs: 51-60, 62 to 69 and 71 to 78). All selected high affinity scTCR variants (SEQ ID NOs 79 to 87 and 89 to 92) bind strongly to HLA-A 02/PRAME-004 monomers, which bind EC ₅₀ Values are in the low nanomolar or subnanomolar range (table 4), as calculated by nonlinear 4-point curve fitting. Except that SMARCD1-001 (SEQ ID NO: 76) elicited a slightly above background binding signal (fig. 4, except that in the case of HLA-A x 02 monomer applied at 100nM concentration, none of the scTCR variants (SEQ ID NOs 79 to 87 and 89 to 92) exhibited a high binding specificity to the CDR mutations of the combination with the data presented in fig. 3, fig. 4, table 4) that demonstrated NO above background level binding to any of the similar peptides (SEQ ID NOs: 51-60, 62 to 69 and 71 to 78), the binding characteristics were superior to the reference scTCR (r16p1c10_cdr 6_sctcr, SEQ ID NO 357) that showed a strong binding to IFT17-003 (SEQ ID NO 60) at a level indistinguishable from PRAME-004 binding.

A further examination of the functional epitopes on the target peptides in the case of HLA-A x 02 presentation of a set of selected high affinity sctcrs from yeast surface display, termed binding motifs. This was solved by evaluation of binding of scTCR-bearing yeast cells to the corresponding PRAME-004 peptide variants in the case of HLA-A.times.02 by single alanine substitutions at positions 1, 3, 4, 5, 6, 7 and 8 in the PRAME-004 target peptides (SEQ ID NO 318 to 324). Yeast cells harboring high affinity scTCRs were stained with four concentrations (10 nM, 3nM, 1nM, 0.3 nM) of HLA-A-a.02 monomer with PRAME-004 or the corresponding alanine-substituted peptide, and the broad binding motif of all scTCR variants with strong recognition at positions 3, 5 and 7 was revealed as confirmed by the lack of staining signals at all tested monomer concentrations. For positions 6 and 8 of the PRAME-004 peptide, contributions to the binding motif can be assumed, since alanine substitutions at these positions significantly reduce the staining signal, even if this is observed with a lower stringency than positions 3, 5 and 7. For positions 1 and 4 of the PRAME-004 peptide, only the edge contribution or no contribution to the binding motif could be determined, as alanine substitution resulted in a staining intensity almost comparable to that observed with the PRAME-004 target peptide (fig. 5 and table 4).

For further analysis, five scTCR clones, namely, R111P3D3SDA7_A02_scTCR (SEQ ID NO: 79), R111P3D3SDA7_A09_scTCR (SEQ ID NO: 82), R11P3D3SDA7_A10_scTCR (SEQ ID NO: 83), R11P3D3SDA7_B03_scTCR (SEQ ID NO: 85) and R11P3D3SDA7_B06_scTCR (SEQ ID NO: 87), were subjected to conversion to scTCR-Fab bispecific forms to determine other protein characteristics (see examples below).

Example 2: production and characterization of soluble scTCR-Fab molecules

TCRs consisting of vα and vβ domains were designed, generated and tested in single chain (scTCR) format coupled to Fab fragments of humanized UCHT1 antibodies (tables 5 and 18). The vector for recombinant protein expression was designed as a monocistronic pUC19 derivative under the control of a promoter element of HCMV origin. Plasmid DNA was amplified in E.coli according to standard culture methods and subsequently purified using commercially available kits (Macherey & Nagel). Transient transfection of CHO cells was performed using purified plasmid DNA. Transfected CHO cells were cultured at 32℃to 37℃for 10-11 days.

Using Sartoclear by filtration (0.22 μm)Laboratory filter aids (Sartorius) to clarify conditioned cell supernatants. Use->Pure 25L FPLC systems (GE life sciences) purify bispecific molecules, which are equipped for affinity chromatography and size exclusion chromatography in tandem. Affinity chromatography was performed on protein L columns (GE lives) according to standard affinity chromatography protocols. According to standard protocols, size exclusion chromatography was performed directly after elution from the affinity column (pH 2.8) using a Superdex 200 pg 16/600 column (GELifesciences) to obtain high purity monomeric protein. The calculated extinction coefficient is used on the NanoDrop system (Thermo Scientific) to determine protein concentration from the predicted protein sequence. The concentration was adjusted by using a Vivaspin device (Sartorius), if necessary. Finally, the purified molecules were stored at a concentration of about 1 mg/mL at a temperature of 2-8deg.C In phosphate buffered saline. The final product yield was calculated after purification and formulation was completed.

The mass of the purified bispecific molecule was determined by HPLC-SEC on a MabPac SEC-1 column (5 μm,4X300 mM) run in a Vanquish uHPLC system in 50 mM sodium phosphate pH6.8 containing 300 mM NaCl.

Stress stability testing was performed by incubating molecules formulated in PBS for up to two weeks at 40 ℃. Integrity, aggregate content, and monomer recovery were analyzed by HPLC-SEC analysis as described above.

Table 5: summary of productivity and stress stability data obtained for scTCR-Fab molecules.

The binding affinity of scTCR-Fab molecule TPP-70-TPP-74 to HLA-A.times.02 monomer containing PRAME-004 target peptide was analyzed by biolayer interferometry. Measurements were made on the Octet RED384 system using manufacturer recommended settings. The assay was run at a sensor offset of 3 mm and a collection rate of 5 Hz. Binding kinetics were measured at 30℃and at an oscillation rate of 1000 rpm using PBS, 0.05% Tween-20, 0.1% BSA as buffer. His-tagged HLA-A 02/PRAME-004 monomers were loaded onto the HIS1K biosensor prior to analysis of serial dilutions of scTCR-Fab molecules. Data evaluation was performed using Octet data analysis HT software. For scTCR-Fab molecules, a strong binding affinity was determined, K _D Values ranged from 4 nM to 12 nM (table 4). In addition, scTCR-Fab variants were screened for binding to 14 similar peptides (SEQ ID NOs: 187, 188, 190, 192, 194, 196, 198, 200, 202, 204, 206, 208, 210 and 212). Screening with similar peptides was performed by biolayer interferometry essentially as described above, which analyzed scTCR-Fab molecules at high concentrations of 1. Mu.M to allow detection of weak binding signals. Neither mature scTCR variant showed binding to any of the analogue peptides tested (figure 6). Use of scTCR from TPP-74 to generate a peptide with alternative forms, such asA bispecific molecule in the form.

Example 3: t cell engagement receptorForm of the invention

Example 3.1: is bispecific in nature Generation and characterization of soluble scTCR forms

For the followingConstruction of the molecule, the DNA sequences encoding VH and VL derived from hUCHT1 (Var 17), a novel humanized form of anti-CD 3 antibody UCHT1, BMA031 (V36), a humanized antibody that binds to the TCR/CD3 complex, or anti-CD 3 antibody ID4, and the sequences encoding vα and vβ and the corresponding linkers, were obtained by genetic synthesis. The resulting DNA sequence was cloned in frame to encode a DNA sequence derived from human IgG1[ accession No.: p01857]The hinge region, CH2 and CH3 domains. The CH2 and CH3 domains are engineered to contain different mutations (including the N297Q mutation) to eliminate binding to fcγ receptors and complement, and to incorporate a knob-to-socket structure into the CH3 domain with additional interchain disulfide stabilization. The +. >Production, purification and characterization of the molecules (Table 6, table 18).

Table 6: for the followingSummary of the productivity and stress stability data obtained for the molecules.

Regarding killing of HLA-A 02 positive tumor cell lines presenting PRAME-004 target peptides on the cell surface (e.g. Hs 695T), evaluation in LDH release assayFunctionality of the molecule. In addition, HLA-A.02 positive but PRAME-004 negative tumor cell lines (e.g.T98G) were evaluated to characterize +.>Nonspecific or off-target activity of the variants. Tumor cell lines were added at increasing +.10 to PBMC from healthy HLA-A.02 positive donors at a ratio of 1:10>Co-incubation in the presence of concentration. The released LDH pair was measured after 48 hours of co-cultivation>The induced cytotoxicity was quantified. Calculation of EC of dose-response curves using nonlinear 4-point curve fitting ₅₀ Values. Represents 3->The results of the molecules (tables 6, 18) are shown in fig. 7 and 8. The results confirm that all 3 +.>The molecules are both functional and induce T cell mediated cytotoxicity in a strictly PRAME-004 dependent manner.

Example 3.2: groove I

Construction using VH and VL domains derived from hUCHT1 (Var 17) or BMA031 (V36) and vα and vβ as described above (example 3.1) A molecule. The +.>Production, purification and characterization of the molecules (tables 7, 18).

Table 7: for tank ISummary of the productivity and stress stability data obtained for the molecules. />

Analysis via biological layer interferometryBinding affinity of groove I variants TPP-106, TPP-108-TPP-129 to target peptide-HLA complex (HLA-A. Times.02/PRAME-004). Measurements were made on an Octet RED384 system as described above. Determination of strong binding affinity, K _D Values ranged from 3nM to 10nM (Table 8). These data show the additional affinity improvement effect of TCR mutations bA84D and aN114Y, while mutation bT115L/K, bL11E, bP 3546M, bQ R, aN K does not appear to affect binding affinity. Furthermore, the binding affinities of three selected analogue peptides used as potential off-target peptides in the case of HLA-A x 02 were determined and K was calculated compared to the binding of the target peptide-HLa _D A window. The strongest +.A.about.of the analogous peptide was observed for GIMAP8-001>Binding, its K _D The window ranges from 26 times to 168 times. More than 25 times K _D The window already provides a good therapeutic window.

Table 8:groove I variantsHLA-A 02/PRAME-004 binding K _D Value of K for three selected analogous peptides used as potential off-target peptides _D Windows, as measured via biological layer interferometry. / >

Example 3.3: groove II

Construction of other Using VH and VL domains derived from BMA031 (V36) or ID4 and V.alpha.and V.beta.as described above (example 3.1)A molecule. The corresponding +.>Production, purification and characterization of molecules (table 9, table 18), all ID 4-based molecules were purified using MAbSelect SuRE columns (GE life sciences).

Table 9: for tank IISummary of the productivity and stress stability data obtained for the molecules.

Analysis via biological layer interferometryTank II variants TPP-207-TPP-222 and TPP-227-TPP-230 bind affinity to target peptide-HLA complex (HLA-a×02/PRAME-004). Measurements were made on an Octet RED384 system as described above. Determination of strong binding affinity, K _D Values ranged from 1nM to 7nM (Table 10). For the same TCR variant in combination with the ID4 recruiter (i.e., the same V) when compared to the combination with the BMA031 (V36) recruiter _A And V _B ) Higher binding affinity was observed (TPP-219-TPP-222 compared to TPP-211-TPP-214). Such as for +.>Molecular observations (example 3.2), it is possible to do this for the +.>The variants confirm the affinity improving effect of the TCR mutations bA84D and aN114Y, whereas no effect on affinity was found again for the mutation bT115L/K, bP46M, bQ R, aN K.

For the selectedMolecular evaluation of TCR binding motifs. To determine the binding motif, affinity was measured for target peptide-HLA complexes (HLA-a 02/PRAME-004) and for complexes with PRAME-004 variants carrying alanine substitutions at peptide positions 1, 3, 4, 5, 6, 7 or 8. Affinity measurements were performed on the Octet RED384 or HTX systems as described above. If a reduction of binding affinity or signal (measured for the highest concentration analyzed) of at least 2-fold is detected for the alanine-substituted peptide variant, then the PRAME-004 position is considered part of the TCR binding motif. All->Variants all showed a broad binding motif identifying at least four peptide PRAME-004 positions (table 10).

Table 10:tank II variants K binding to HLA-A.times.02/PRAME-004 _D Value and K according to PRAME-004 peptide variants substituted with Ala _D The binding motif of the window is determined as measured via biolayer interferometry. For the A5 peptide, K _D The window is set as100-fold, since no binding to very low binding prevents affinity determination. />

Example 3.4: groove IIa

Based on the previousData for variant generation (example 3.3), new variants were generated carrying systematic substitutions of selected TCR amino acid positions, which positive effects on protein properties or binding properties could be detected in previous experiments. The corresponding +.A is performed as outlined in example 3.3 >Production, purification and characterization of the molecules (tables 11 and 18). The productivity and stress stability data are summarized in table 11.

Table 11: for the groove IIaSummary of the productivity and stress stability data obtained for the molecules. />

Analysis via biological layer interferometryBinding affinity of groove IIa variants TPP-235-TPP-250, TPP-252-TPP-268, TPP-270-TPP-277, TPP-279 to target peptide-HLA complex (HLA-A.times.02/PRAME-004). Measurements were made on an Octet RED384 or HTX system as described above. Finding a strong binding affinity, K thereof _D Values ranged from 2nM to 15nM (Table 12). For position bA84, amino acid substitutions show that bA84D is the most preferred substitution. At position aN114, alternative amino acid substitutions were found with affinities comparable to aN114Y, such as A, H, I and L. Alternatives to bT115K/L with comparable affinities were identified and included R, A, I and V. Introduction of the mutation bA110S slightly reduced the affinity of the corresponding variant.

For the selectedVariant assessment binding motif. To determine the binding motif, affinity was measured as described above for target peptide-HLA complexes (HLA-a 02/PRAME-004) and for complexes with PRAME-004 variants carrying alanine substitutions at peptide positions 1, 3, 4, 5, 6, 7 or 8. If a reduction of binding affinity or signal (measured for the highest concentration analyzed) of at least 2-fold is detected for the alanine-substituted peptide variant, then the PRAME-004 position is considered part of the TCR binding motif. All tested +. >Variants all showed broad binding motifs that recognized at least three peptide positions (table 12).

In addition to binding motifs, the selected material was further analyzed by biolayer interferometryBinding specificity of tank II and IIa variants to a set of 16 similar peptides potentially useful as off-target peptides. Measurements were made on an Octet HTX system substantially as described above. For the analysis, peptide-HLA complexes comprising PRAME-004 target peptide, individual peptides of a group of similar peptides or control peptides were loaded onto the HIS1K biosensor and were loaded at a height of 1. Mu.M>Concentration analysis->Binding of variants. For the selected +.>Variants, the response signal at the end of the 5min association period was used to calculate the relative binding signal of the similar peptide compared to the PRAME-004 target peptide (table 13). Under these conditions, even binding events with very low affinity will be detected, which can be described as not significant (e.g., with K binding to the PRAME-004 peptide: MHC complex _D In contrast, combine with K _D The increase is more than or equal to 25 times, more than or equal to 30 times, more than or equal to 40 times, more than or equal to 50 times, more than or equal to 75 times or more than or equal to 100 times). Of the 16 analyzed analog peptides, 11 peptides did not show any choice +.>Any combination of variants. Binding with lower signal than PRAME-004 was detected for five out of 16 similar peptides and was directed against +. >Groove III variants are analyzed in more detail for four of these peptides, e.g., to measure K compared to the PRAME-004 target peptide _D A window.

Table 12:tank II variants K binding to HLA-A.times.02/PRAME-004 _D Value and K according to PRAME-004 peptide variants substituted with Ala _D The binding motif of the window is determined as measured via biolayer interferometry. For the A5 peptide, K _D The window was set at 100-fold because no binding to low binding prevented affinity determination.

Table 13: selected isThe relative binding signals of the groove II and IIa variants to the similar peptides (as a percentage of the signal detected for the PRAME-004 target peptide) were measured via biolayer interferometry. />

Example 3.5: groove III

Construction of other variants using VH and VL domains derived from BMA031 (V36) or modified variants thereof (a 02 and D01) or ID4 and vα and vβ as described above (example 3.1)Production of additional +.sup.10 based on UCHT1-V17 recruitment antibody (TPP-1109)>The molecules are used as references. DNA constructs encoding the corresponding molecules were generated as outlined above. CHO-S cells were transfected by electroporation (MaxCyte) using the resulting plasmid for +.>Transient expression and production of variants (tables 14 and 18). Purification, formulation and initial characterization of the molecules were performed as outlined above in example 3.3.

Table 14: for groove III Summary of the productivity and stress stability data obtained for the molecules.

Assessment in LDH Release assayThe molecules were related to the efficacy of killing HLA-A-02 positive tumor cell lines presenting different levels of PRAME-004 target peptides on the cell surface. In addition, HLA-A.02 positive but PRAME-004 negative tumor cell lines (e.g.T98G) were evaluated to characterize +.>Nonspecific or off-target activity of the variants. Tumor cell lines were combined with PBMC effectors derived from healthy HLA-A 02 positive donors at a ratio of 1:10 and at increasing +.>Co-incubation in the presence of concentration. The released LDH pair was measured after 48 hours of co-cultivation>The induced cytotoxicity was quantified. Calculation of EC of dose-response curves using nonlinear 4-point curve fitting ₅₀ Values. EC of two PRAME-004 positive tumor cell lines (Hs 695T and U2 OS) and PRAME-004 negative tumor cell line (T98G) were determined with different PBMC donors in different experiments ₅₀ Values, and are graphically summarized in fig. 9.

Analysis via biological layer interferometryTank III variants TPP-214, TPP-222, TPP-230, TPP-666, TPP-669, TPP-871, TPP-872, TPP-876, TPP-879, TPP-891, TPP-894 binding affinity to target peptide-HLA complex (HLA-A. Times.02/PRAME-004). Measurements were performed on an Octet HTX system at 30 ℃. Assays were run on HIS1K biosensor in 16 channel mode with PBS, 0.05% tween-20, 0.1% bsa as assay buffer at a sensor offset of 3mm and a collection rate of 5 Hz. The following sequence of measurement steps was repeated to measure Has binding affinity: regeneration (5 s,10mM glycine, pH 1.5)/neutralization (5 s, assay buffer; one regeneration cycle consisted of four regenerations/neutralization replicates), baseline (60 s, assay buffer), loading (120 s, 10. Mu.g/ml peptide-HLA), baseline (120 s, assay buffer), association (300 s,in the range of 100nM to 1.56nM or 50nM to 0.78nM, assay buffer as reference), dissociation (300 s, assay buffer). Data evaluation was performed using Octet data analysis HT software. Reference sensor subtraction was performed to subtract potential dissociation of peptide-HLA loaded onto the biosensor (via the biosensor loaded with peptide-HLA measured in buffer). The data traces were aligned with the baseline (average of last 5 s), the dissociation steps were corrected for step-to-step, savitzky-Golay filtration was applied and the curves were globally fitted using a 1:1 binding model (Rmax was disconnected by the sensor). Finding a strong binding affinity, K thereof _D Values ranged from 2nM to 5nM (Table 15). In addition, the binding affinities of four previously identified potential off-target peptides were determined and K was calculated compared to target peptide-HLA binding _D A window. Measurements were performed on an Octet RED384 or HTX system at 30 ℃. Assays were run on HIS1K biosensor in 16 channel mode with PBS, 0.05% tween-20, 0.1% bsa as assay buffer at a sensor offset of 3mm and a collection rate of 5 Hz. The following sequence of assay steps was repeated to measure all binding affinities: regeneration (5 s,10mM glycine, pH 1.5)/neutralization (5 s, assay buffer; one regeneration cycle consisted of four regenerations/neutralization replicates), baseline (60 s, assay buffer), loading (120 s, 10. Mu.g/ml peptide-HLA), baseline (120 s, assay buffer), association (300 s, >In the range of 500nM to 7.81nM, assay buffer as reference), dissociation (300 s, assay buffer). Data evaluation was performed using Octet data analysis HT software. Reference sensor subtraction to subtract potential dissociation of peptide-HLA loaded onto biosensor(via a biosensor loaded with the corresponding peptide-HLA measured in buffer). The data traces were aligned with the baseline (average of last 5 s), the dissociation steps were corrected for step-to-step, savitzky-Golay filtration was applied and the curves were globally fitted using a 1:1 binding model (Rmax was disconnected by the sensor). In general, all variants were found to bind significantly weaker to potential off-target peptides than to target peptides, which showed a window of at least 60-fold to even no binding at all. NOMAP-3-1408 was not selected for K _D It was determined, but it showed a comparable relative binding signal to VIM-009 (table 13). For VIM-009, the least measured K _D Window is>100 times (Table 15). Thus, binding to VIM-009 is irrelevant, and affinity determination for NOMAP-3-1408 binding is considered unnecessary based on the comparable binding signals of NOMAP-3-1408 and VIM-009. For one interaction, 50 times K is calculated _D A window. However, for this interaction, as well as for several other, the value of Rmax calculated by the fitting algorithm is too low, so that the interaction is assumed to be weaker than the calculated value, and therefore the window is larger. The corresponding interactions are shown in table 15. To further analyze the specificity of the different variants, the binding motif was determined for positions 1, 3, 4, 5, 6, 7, 8 by measuring affinity to the target peptide-HLA complex as well as to alanine substituted variants. Measurements were performed on an Octet HTX system at 30 ℃. Assays were run on HIS1K biosensor at 3mm sensor offset and 5Hz acquisition rate in 16 channel or 8 channel mode using PBS, 0.05% tween-20, 0.1% bsa as assay buffer. The following sequence of assay steps was repeated to measure all binding affinities: regeneration (5 s,10mM glycine, pH 1.5)/neutralization (5 s, assay buffer; one regeneration cycle consisted of four regenerations/neutralization replicates), baseline (60 s, assay buffer), loading (120 s, 10. Mu.g/ml peptide-HLA), baseline (120 s, assay buffer), association (150 s, frisbee>In the range of 400 nM to 6.25 nM, assay buffer as reference), dissociation (300 s, assay buffer). Analysis of HT software Using Octet data for data And (5) evaluating. Reference sensor subtraction was performed to subtract potential dissociation of the peptide-HLA loaded onto the biosensor (via the biosensor loaded with the corresponding peptide-HLA measured in buffer). The data traces were aligned with the baseline (average of last 5 s), the dissociation steps were corrected for step-to-step, savitzky-Golay filtration was applied and the curve was globally fitted using a 1:1 binding model (Rmax was disconnected by the sensor). For at least a 2-fold decrease in affinity or binding signal (measured for the highest concentration analyzed), the position is considered part of the binding motif. All tested +.>Variants all showed broad binding motifs that recognized at least four and up to all analyzed peptide positions (table 16). A positive effect of bA84, aN114L and bA110S/bT115A on the binding motif was observed, consistent with previous data. For comparison, analysis of alternative targeting PRAME-004 +.>Binding motif of reference molecule (TPP-1109). This->The positions 5-8 of the peptide are recognized and thus binding is limited to this peptide stretch, whereby +.>The positions identified by the groove III variants are more evenly distributed throughout the peptide.

Further characterization ofTank III variants TPP-214, TPP-222, TPP-230, TPP-666, TPP-669, TPP-871, TPP-872, TPP-876, TPP-879, TPP-891, TPP-894 ability to kill T2 cells loaded with different levels of target peptide. After loading T2 cells 2 h with corresponding concentrations of PRAME-004, peptide-loaded T2 cells were loaded with human PBMC at increasing concentrations of +. >Co-culture 48h in the presence of variants. The level of LDH released into the supernatant was quantified using the CytoTox 96 nonradioactive cytotoxicity assay kit (Promega). All->Variants all showed potent killing of PRAME-004 loaded T2 cells with sub-picomolar EC at peptide loading concentration of 10 nM ₅₀ Values (fig. 10, table 17). For decreasing PRAME-004 loading levels, EC ₅₀ The value increases. However, even at the very low PRAME-004 loading concentration of 10 pM, all +.>Variants all induced killing, except for TPP-214. Table 15: measured by biological layer interferometryK binding of groove III variants to HLA-A.times.02/PRAME-004 _D Value and K of four selected off-target peptides _D A window. />

¹ Expected K _D The window is higher than the values given in the table (the calculated Rmax values for these interactions are too low due to the overall low binding signal). Table 16: measured by biological layer interferometryK binding of groove III variants to HLA-A.times.02/PRAME-004 _D Value and Ala substituted peptide variants K _D Windows were used for binding motif determination. For position 5, for K _D The window gives a threshold of 100. The identification of this location is at least 100 times.

Table 17:cell III variants were cytotoxic to PRAME-004 loaded T2 cells in vitro. T2 cells were co-cultured with human PBMC at a 5:1 E:T ratio for 48h. The PRAME-004 loading concentration is indicated. Computing Ec in a platform (top) using nonlinear 4-point curve fitting ₅₀ Values and cytotoxicity level.

¹ High variability within replicates does not allow reliable EC ₅₀ And (5) calculating.

Table 18 bispecific molecules

In Table 18, the term "alpha chain" is meant to include V in addition to TPP-70, TPP-71, TPP-72, TPP-73 and TPP74 _α I.e. a polypeptide chain derived from the variable domain of the TCR alpha chain. The term "beta strand" is meant to encompass V _β I.e. a polypeptide chain derived from the variable domain of the TCR β chain. For TPP-70, TPP-71, TPP-72, TPP-73 and TPP74, the "alpha chain" does not comprise any TCR-derived variable domains, but the "beta chain" comprises two TCR-derived variable domains, one derived from a TCR alpha chain and one derived from a TCR beta chain.

Example 3.6: for the selected Safety assessment of groove III candidates

In the use of astroidsCell and cardiomyocyte (derived from induced pluripotent stem cells) and evaluation in killing experiments of aortic endothelial cells, mesenchymal stem cells and airway smooth muscle cellsSecurity profiles for molecules TPP-230, TPP-666, TPP-871 and TPP-891 (table 14-table 18). FIG. 11 shows that the above normal cell types (all expressing HLA-A02) are increasing +.>Results of co-cultivation in the presence of concentration. The cells were co-cultured in a 1:1 mixture of the corresponding normal tissue cell culture medium and T cell culture medium or in T cell culture medium alone (LDH-AM). After 48h of co-culture, the supernatant was harvested and purified by LDH-Glo ^TM Kit (Promega) to measure LDH release to evaluate +.>Induced normal tissue cell lysis. For determining the security window, will +.>The molecules were co-incubated with the PRAME-004 positive tumor cell line Hs695T in the same setup in a corresponding 1:1 mixture of normal tissue cell culture medium and T cell culture medium, after which LDH release was assessed.

As shown in FIG. 11, even at the highest of 100nMAt this concentration, no cytotoxicity against normal tissue cells was observed with TPP-230 and TPP-871. For TPP-666 and TPP-891, at 100nM +.>Some normal tissue cell lysis was observed at the concentration, but no lysis was detected at 10 nM. In +.>Normal tissue cell lysis at 100nM concentration indicates a safety window of 1,000-fold (TPP-666 and TPP-891) or higher (TPP-230 and TPP-871) when the molecules showed significant lysis at 100pM and some molecules even when compared to Hs695T tumor cells that showed lysis at 10pM concentration.

Example 3.7: tank IV

Construction of other variants using VH and VL domains derived from BMA031 (V36) or modified variants thereof (a 02 and D01) or ID4 and vα and vβ as described above (example 3.1)DNA constructs encoding the corresponding molecules were generated as outlined above. CHO-S cells were transfected by electroporation (MaxCyte) using the resulting plasmid for +. >Transient expression and production of variants (tables 20 and 18). Purification, formulation and initial characterization of the molecules were performed as outlined above in example 3.3.

Table 20: for tank IVSummary of the productivity and stress stability data obtained for the molecules.

In Table 20, the term "alpha chain" is meant to include V _α I.e. a polypeptide chain derived from the variable domain of the TCR alpha chain. The term "beta strand" is meant to encompass V _β I.e. a polypeptide chain derived from the variable domain of the TCR β chain.

Assessment in LDH Release assayThe molecules were related to the efficacy of killing HLA-A-02 positive tumor cell lines presenting different levels of PRAME-004 target peptides on the cell surface. In addition, HLA-A.02 positive but PRAME-004 negative tumor cell lines (e.g.T98G) were evaluated to characterize +.>Nonspecific or off-target activity of the variants. Tumor cell lines were combined with PBMC effectors derived from healthy HLA-A 02 positive donors at a ratio of 1:10 and at increasing +.>Co-incubation in the presence of concentration. The released LDH pair was measured after 48 hours of co-cultivation>The induced cytotoxicity was quantified. Calculation of EC of dose-response curves using nonlinear 4-point curve fitting ₅₀ Values. EC of PRAME-004 positive tumor cell line U2OS and PRAME-004 negative tumor cell line (T98G) were determined in different experiments using different PBMC donors ₅₀ Values, and are summarized in table 21.

Table 21: for tank IVSummary of LDH release assay data obtained by the molecules.

Analysis via biological layer interferometryTank IV variants TPP-1292, TPP-1294 to TPP-1298, TPP-1300 to TPP-1309, TPP-1333, TPP-1334 and target peptide-HLA complex (HLA-A. Times.02/PRAME-0)04 Is used for the binding affinity of the substrate). Measurements were performed on an Octet HTX system at 30 ℃. Assays were run on HIS1K biosensor in 16 channel mode with PBS, 0.05% tween-20, 0.1% bsa as assay buffer at a sensor offset of 3mm and a collection rate of 5 Hz. The following sequence of assay steps was repeated to measure all binding affinities: regeneration (5 s,10mM glycine, pH 1.5)/neutralization (5 s, assay buffer; one regeneration cycle consisted of four regenerations/neutralization replicates), baseline (60 s, assay buffer), loading (120 s, 10. Mu.g/ml peptide-HLA), baseline (120 s, assay buffer), association (300 s,>in the range of 100nM to 1.56nM or 50nM to 0.78nM, assay buffer as reference), dissociation (300 s, assay buffer). Data evaluation was performed using Octet data analysis HT software. Reference sensor subtraction was performed to subtract potential dissociation of peptide-HLA loaded onto the biosensor (via the biosensor loaded with peptide-HLA measured in buffer). The data traces were aligned with the baseline (average of last 5 s), the dissociation steps were corrected for step-to-step, savitzky-Golay filtration was applied and the curves were globally fitted using a 1:1 binding model (Rmax was disconnected by the sensor). Finding a strong binding affinity, K thereof _D Values ranged from 2nM to 15nM (Table 22). In addition, the binding affinities of two previously identified potential off-target peptides were determined and K was calculated compared to target peptide-HLA binding _D A window. Measurements were performed on an Octet RED384 or HTX system at 30 ℃. Assays were run on HIS1K biosensor in 16 channel mode with PBS, 0.05% tween-20, 0.1% bsa as assay buffer at a sensor offset of 3mm and a collection rate of 5 Hz. The following sequence of assay steps was repeated to measure all binding affinities: regeneration (5 s,10mM glycine, pH 1.5)/neutralization (5 s, assay buffer; one regeneration cycle consisted of four regenerations/neutralization replicates), baseline (60 s, assay buffer), loading (120 s, 10. Mu.g/ml peptide-HLA), baseline (120 s, assay buffer), association (300 s,>in the range of 500nM to 7.81nM, assay buffer as reference), dissociation (300 s, assay buffer). Data evaluation was performed using Octet data analysis HT software. Reference sensor subtraction was performed to subtract potential dissociation of the peptide-HLA loaded onto the biosensor (via the biosensor loaded with the corresponding peptide-HLA measured in buffer). The data traces were aligned with the baseline (average of last 5 s), the dissociation steps were corrected for step-to-step, savitzky-Golay filtration was applied and the curves were globally fitted using a 1:1 binding model (Rmax was disconnected by the sensor). In general, all variants were found to bind significantly weaker to potential off-target peptides than to target peptides, which showed a window of at least 10-fold to even no binding at all. The corresponding interactions are shown in table 22. To further analyze the specificity of variants TPP-1294, TPP-1295, TPP-1298, TPP-1333, TPP-1334, binding motifs were determined by measuring affinity to the target peptide-HLA complex and to alanine substituted variants for positions 1, 3, 4, 5, 6, 7, 8. Measurements were performed on an Octet HTX system at 30 ℃. Assays were run on HIS1K biosensor at 3mm sensor offset and 5Hz acquisition rate in 16 channel or 8 channel mode using PBS, 0.05% tween-20, 0.1% bsa as assay buffer. The following sequence of assay steps was repeated to measure all binding affinities: regeneration (5 s,10mM glycine, pH 1.5)/neutralization (5 s, assay buffer; one regeneration cycle consisted of four regenerations/neutralization replicates), baseline (60 s, assay buffer), loading (120 s, 10. Mu.g/ml peptide-HLA), baseline (120 s, assay buffer), association (150 s, >In the range of 400nM to 6.25nM, assay buffer as reference), dissociation (300 s, assay buffer). Data evaluation was performed using Octet data analysis HT software. Reference sensor subtraction was performed to subtract potential dissociation of the peptide-HLA loaded onto the biosensor (via the biosensor loaded with the corresponding peptide-HLA measured in buffer). Aligning the data trace with the baseline (average of last 5 s), performing inter-step calibration for the dissociation stepJust, savitzky-Golay filtration was applied and the curve was globally fitted using a 1:1 binding model (Rmax was disconnected by the sensor). For at least a 2-fold decrease in affinity or binding signal (measured for the highest concentration analyzed), the position is considered part of the binding motif. All tested +.>Variants all showed broad binding motifs that recognized at least five and up to all analyzed peptide positions (table 23).

Table 22: measured by biological layer interferometryTank IV variant K binding to HLA-A.times.02/PRAME-004 _D Value and K of two selected off-target peptides _D A window. />

Table 23: measured by biological layer interferometryTank IV variant K binding to HLA-A.times.02/PRAME-004 _D Value and Ala substituted peptide variants K _D Windows were used for binding motif determination. For position 5, for K _D The window gives a threshold of 100. The identification of this location is at least 100 times.

Example 3.8: for the selected Safety assessment of tank IV candidates

Evaluation in killing experiments using the following cellsSecurity profiles for molecules TPP-1294, TPP-1295, TPP-1298, TPP-1333 and TPP-1334 (tables 18 and 20-23): astrocytes, gammA-Aminobutyric acid neurons and cardiomyocytes (derived from induced pluripotent stem cells; iHA, iHN and iHCM, respectively), pulmonary fibroblasts (HPF), cardiac microvascular endothelial cells (HCMEC), dermal microvascular endothelial cells (HDMEC), aortic endothelial cells (HAoEC), coronary smooth muscle cells (HCASMC), renal cortical epithelial cells (HRCEpC) and tracheal smooth muscle cells (HTSMC). In addition, the bridging molecule TPP-891 was tested with other molecules TPP-214 and TPP-669 from earlier slots. FIGS. 12 and 13 show that the ratio of the normal cell types above (all expressing HLA-A.times.02) to PBMC effector cells from healthy HLA-A.times.02+ donors (target cells: effector cells) is increasing at 1:10 (target cells: effector cells)>Results of co-cultivation in the presence of concentration. The cells were co-cultured in a 1:1 mixture of the corresponding normal tissue cell culture medium and T cell culture medium or in T cell culture medium alone (LDH-AM). After 48h of co-culture, the supernatant was harvested and purified by LDH-Glo ^TM Kit (Promega) to measure LDH release to evaluate +.>Induced normal tissue cell lysis. For determining the security window, will +.>The molecules were co-incubated with the PRAME-004 positive tumor cell line Hs695T in the same setup in a corresponding 1:1 mixture of normal tissue cell culture medium and T cell culture medium, after which LDH release was assessed.

As shown in fig. 12 and 13, up to a concentration of 10nM for any of the molecules testedNo cytotoxicity against normal tissue cells was observed. At a concentration of 100nM, only the bridging and reference molecules TPP-891, TPP-669 and TPP-214 showed some increased cytotoxicity levels above background. The only exception was TPP-1294 in iPSC-derived astrocytes, which had elevated cytotoxicity only at 100 nM. In +.>Normal tissue cell lysis at 100nM concentration indicates a safety window of 1,000-fold (TPP-1294) or higher (TPP-1295, TPP-1298, TPP-1334 and TPP-1335) when the molecules show significant lysis at 100pM and some molecules even compared to Hs695T tumor cells that show lysis at 10pM concentration.

Example 4: detection of PRAME peptides on primary tissues by mass spectrometry

For identification and relative quantification of HLA ligands by mass spectrometry, HLA molecules from shock-frozen (shock-frezen) tissue samples were purified and HLA-related peptides were isolated. The isolated peptides were separated and the sequences were identified by an on-line nanoelectrospray ionization (nanoESI) liquid chromatography-mass spectrometry (LC-MS) experiment. Since the peptides are directly identified as ligands for HLA molecules of the primary tumor, these results provide direct evidence of the natural processing and presentation of the identified peptides on primary cancer tissues. The collected LC-MS data was then processed and quantified using a proprietary label-free quantitative data analysis pipeline that incorporated the algorithm used for: sequence identification, spectral clustering, ion counting, retention time alignment, charge state deconvolution and normalization. The resulting target detection frequencies are depicted in table 19 below.

Table 19: frequency of peptide detection in tumor samples. The target detection frequency is shown as + (> 0%), ++ (> 10%), ++ (> 30%), or++ + ++. (> 50%).

Clause of (b)

1. An antigen binding protein that specifically binds to a PRAME antigenic peptide comprising or consisting of the amino acid sequence SLLQHLIGL of SEQ ID No. 50 and in a complex with a Major Histocompatibility Complex (MHC) protein, said antigen binding protein comprising

the CDRa3 comprises or consists of: ALYNNLDMR (SEQ ID NO: 33) or ALYNNYDMR (SEQ ID NO: 34) or an amino acid sequence which differs from SEQ ID NO:33 or SEQ ID NO:34 by one, two or three, preferably one or two amino acid mutations, preferably amino acid substitutions, and

the CDRb3 comprises or consists of: amino acid sequence ASSX ₁ GX ₂ X ₃ DX ₄ QY (SEQ ID NO: 327), wherein X ₁ Is P, A or T, X ₂ Is A or S, X ₃ Is T or I, and X ₄ Is K or A, or an amino acid sequence which differs from SEQ ID NO 327 by one, two or three amino acid mutations, preferably amino acid substitutions.

2. The antigen binding protein of clause 1, wherein

(a) The CDRa2 comprises or consists of: amino acid sequence FGPYGKE (SEQ ID NO: 32) or an amino acid sequence which differs from SEQ ID NO:32 by one, two or three amino acid mutations, preferably amino acid substitutions, and/or

(b) The CDRb2 comprises or consists of: the amino acid sequence FQNTAV (SEQ ID NO: 36) or the CDRB2 amino acid sequence which differs from SEQ ID NO:36 by one, two, three, four, five or six amino acid mutations, preferably amino acid substitutions.

3. The antigen binding protein of clause 1 or 2, wherein

-according to IMGT, position 113 of CDRb3 is T or I or is substituted by an amino acid selected from V, L and G, and

4. The antigen binding protein of any one of clauses 1 to 3, wherein the antigen binding protein specifically binds to the amino acid sequence of SEQ ID No. 50 in a complex with an MHC protein, in particular an HLA protein, more particularly HLA-a, even more particularly HLA-a x 02.

5. The antigen binding protein according to any one of clauses 1 to 4, wherein the antigen binding protein specifically binds to or consists of at least 3, 4 or 5 amino acid positions selected from positions 3, 5, 6, 7 and 8, in particular 3, 5 and 7 of SEQ ID No. 50, preferably to a functional epitope consisting of amino acid positions 3, 5 and 7, or 3, 5, 6 and 7, or 3, 5, 7 and 8, or 3, 5, 6, 7 and 8 of SEQ ID No. 50, but preferably not amino acid positions 1 and 4 of SEQ ID No. 50.

6. The antigen binding protein of any one of clauses 1 to 4, wherein the antigen binding protein specifically binds to a functional epitope comprising or consisting of at least 6 or 7 amino acid positions selected from positions 1, 3, 4, 5, 6, 7 and 8 of SEQ ID No. 50.

7. The antigen binding protein of any one of clauses 1 to 6, wherein the antigen binding protein binds to a complex of the PRAME antigenic peptide with an MHC protein, in particular an HLA protein, more particularly HLA-a, even more particularly HLA-a x 02, with a KD as follows: less than or equal to 100nM, less than or equal to 50nM, less than or equal to 10nM, preferably less than or equal to 5nM.

8. The antigen binding protein of any one of clauses 1 to 7, wherein the antigen binding protein does not significantly bind to at least 1, at least 2, at least 3, at least 4, at least 5, at least 10, at least 20, or all analogous peptides selected from the group consisting of: TMED9-001 (SEQ ID NO: 51), CAT-001 (SEQ ID NO: 52), DDX60L-001 (SEQ ID NO: 53), LRRC70-001 (SEQ ID NO: 54), PTPLB-001 (SEQ ID NO: 55), HDAC5-001 (SEQ ID NO: 56), VPS13B-002 (SEQ ID NO: 57), ZNF318-001 (SEQ ID NO: 58), CCDC51-001 (SEQ ID NO: 59), IFT17-003 (SEQ ID NO: 60), DIAPH1-004 (SEQ ID NO: 62), FADS2-001 (SEQ ID NO: 63), FRYL-003 (SEQ ID NO: 64), GIMAP8-001 (SEQ ID NO: 65), HSF1-001 (SEQ ID NO: 66), KNT-001 (SEQ ID NO: 67), MAU-001 (SEQ ID NO: 68), 4-001 (SEQ ID NO: 69), ZNF318-001 (SEQ ID NO: 71), MYO 1-001 (SEQ ID NO: 59), FADS2-001 (SEQ ID NO: 75), FADS2-001 (SEQ ID NO: 63), FRYL-003 (SEQ ID NO: 64), GIMAP8-001 (SEQ ID NO: 68), GIMAP 1-001 (SEQ ID NO: 68), and HSF1-001 (SEQ ID NO: 68) FARSA-001 (SEQ ID NO: 306), FAOX 15B-003 (SEQ ID NO: 304), FAM114A2-002 (SEQ ID NO: 305), GPR56-002 (SEQ ID NO: 307), IGHD-002 (SEQ ID NO: 308), NOMAP-3-0972 (SEQ ID NO: 309), NOMAP-3-1265 (SEQ ID NO: 310), NOMAP-3-1408 (SEQ ID NO: 311), NOMAP-3-1587 (SEQ ID NO: 312), NOMAP-3-1768 (SEQ ID NO: 313), NOMAP-5-0765 (SEQ ID NO: 314), PDCD10-004 (SEQ ID NO: 315), TSN-001 (SEQ ID NO: 316), ARMC9-002 (SEQ ID NO: 187), CLI-001 (SEQ ID NO: 188), G1-001 (SEQ ID NO: 190), COPS7A-001 (SEQ ID NO: 192), EIF-194), T2-07NO: 202 (SEQ ID NO: 196), NOMAP-5-0765 (SEQ ID NO: 314), PDCD 10-002 (SEQ ID NO: 007), SPAM 10-002 (SEQ ID NO:200, SEQ ID NO: 001 (SEQ ID NO: 200) TGM2-002 (SEQ ID NO: 210) and TPR-004 (SEQ ID NO: 212), said analogous peptides being in complex with MHC proteins, preferably said antigen binding proteins not significantly binding to IFT17-003 (SEQ ID NO: 60) being in complex with MHC proteins.

9. The antigen binding protein of any one of clauses 1 to 8, wherein the antigen binding protein has multi-specificity, e.g. tetra-specific, tri-specific or bispecific, preferably bispecific, in particular the antigen binding protein is a bispecific TCR, bispecific antibody or bispecific TCR-antibody molecule.

10. The antigen binding protein of any one of clauses 1 to 9, wherein the first polypeptide and the second polypeptide are comprised in a single polypeptide chain or in two polypeptide chains, preferably wherein V _A Contained in the first polypeptide chain and V _B Included in the second polypeptide chain.

11. The antigen binding protein of any one of clauses 1 to 10, wherein V _A Also comprising one or more, preferably all, of the frame regions selected from the group consisting of: FR1-a, FR2-a, FR3-a and FR4-a, wherein

-FR1-a comprises or consists of: the amino acid sequence of SEQ ID NO. 345 or SEQ ID NO. 346, or an amino acid sequence which is at least 85%, 90% or 95% identical to SEQ ID NO. 345, preferably comprises K or N at position 20, more preferably K and/or L or M at position 2, more preferably L;

-FR3-a comprises or consists of: the amino acid sequence of SEQ ID NO. 349, or an amino acid sequence which is at least 85%, 90% or 95% identical to SEQ ID NO. 349, preferably comprises T or K at position 92, more preferably T and/or D or G, preferably D at position 93;

12. The antigen binding protein of any one of clauses 1 to 11, wherein

-V _A Comprising or consisting of: the amino acid sequence of SEQ ID NO. 132, or at least 85%, 90% or 95% identical to SEQ ID NO. 132, preferably comprisesAn amino acid sequence comprising CDRa1 of SEQ ID No. 16, CDRa2 of SEQ ID No. 32 and CDRa3 of SEQ ID No. 33, SEQ ID No. 34 or SEQ ID No. 9, and further comprising K or N, preferably K, L, M or I, preferably L or I, preferably K or W at position 39, preferably K, F or a, preferably F at position 52, Y or V at position 55, preferably Y, T or K at position 92, preferably T and/or D or G, preferably D at position 93 at position 20; and is also provided with

-V _B Comprising or consisting of: the amino acid sequence of SEQ ID NO 134, or CDRB1 of SEQ ID NO 134, CDRB2 of SEQ ID NO 36 and CDRB3 of SEQ ID NO 48, SEQ ID NO 49, SEQ ID NO 47, SEQ ID NO 281, SEQ ID NO 292, SEQ ID NO 294, SEQ ID NO 297, SEQ ID NO 298, SEQ ID NO 301 or SEQ ID NO 283, and further amino acid sequences of E, L or K, preferably E, R or H at position 22, E or Q at position 44, preferably E, P or M at position 46, preferably P, Q or R at position 48, preferably Q and/or D, A, E, Q, N or S, preferably D or A at position 84, are at least 85%, 90% or 95% identical to the amino acid sequence of SEQ ID NO 134.

13. The antigen binding protein of any one of clauses 1 to 12, wherein

14. The antigen binding protein of any one of clauses 1 to 13, further comprising one or more of the following:

(i) One or more additional antigen binding sites;

(iii) A diagnostic agent;

(iv) A therapeutic agent; and

(v) PK adjustment part.

15. The antigen binding protein of any one of clauses 1 to 14, further comprising an antibody light chain variable domain (V _L ) And antibody heavy chain variable domains (V _H )。

16. The antigen binding protein of clause 15, wherein VL and VH bind to an antigen selected from the group consisting of: CD2, CD3, in particular CD3 gamma, CD3 delta and/or CD3 epsilon, CD4, CD5, CD7, CD8, CD10, CD11b, CD11c, CD14, CD16, CD18, CD22, CD25, CD28, CD32a, CD32b, CD33, CD41b, CD42a, CD42b, CD44, CD45RA, CD49, CD55, CD56, CD61, CD64, CD68, CD90, CD94, CD95, CD117, CD123, CD125, CD134, CD137, CD152, CD163, CD193, CD203c, CD235a, CD278, CD279, CD287, nkp, NKG2D, GITR, fc epsilon RI, tcra/beta and gamma/delta, HLA-DR and 4-1BB or combinations thereof, and/or binds to effector cells, in particular T cells or natural killer cells (NK cells).

17. The antigen binding protein of clause 15 or 16, wherein the antigen binding protein comprises a first polypeptide chain and a second polypeptide chain,

wherein the method comprises the steps of

The first polypeptide chain is represented by formula [ Ia ]:

V ₁ -L ₁ -D ₁ -L ₂ -V ₂ -L ₃ -D ₂ [Ia]，

and the second polypeptide chain is represented by formula [ IIa ]

V ₃ -L ₄ -D ₃ -L ₅ -V ₄ -L ₆ -D ₄ [IIa]，

Wherein the method comprises the steps of

-V ₁ 、V ₂ 、V ₃ And V ₄ Is a variable domain, wherein V ₁ To V ₄ One of them is V _A One is V _B One is V _L And one is V _H ；

18. The antigen binding protein of any one of clauses 15 to 17, wherein the antigen binding protein comprises a first polypeptide chain and a second polypeptide chain,

wherein the method comprises the steps of

The first polypeptide chain is represented by formula [ Ib ]:

V ₁ -L ₁ -V ₂ -L ₃ -D ₂ [Ib]，

and the second polypeptide chain is represented by formula [ IIb ]:

V ₃ -L ₄ -V ₄ -L ₆ -D ₄ [IIb]，

wherein the method comprises the steps of

-V ₁ 、V ₂ 、V ₃ 、V ₄ Is a variable domain, preferably wherein V ₁ And V ₂ One of them is V _A ，V ₃ And V ₄ One of them is V _B And one of the remaining two variable domains is V _L And the other is V _H ；

-D ₂ And D ₄ Is a dimerization domain, preferably F _c A domain; and is also provided with

19. The antigen binding protein of clause 17 or 18, wherein

(1)V ₁ Is V _H ，V ₂ Is V _B ，V ₃ Is V _A And V is ₄ Is V _L ；

(2)V ₁ Is V _B ，V ₂ Is V _H ，V ₃ Is V _L And V is ₄ Is V _A ；

(3)V ₁ Is V _B ，V ₂ Is V _L ，V ₃ Is V _H And V is ₄ Is V _A ；

(4)V ₁ Is V _L ，V ₂ Is V _B ，V ₃ Is V _A And V is ₄ Is V _H ；

(5)V ₁ Is V _H ，V ₂ Is V _B ，V ₃ Is V _L And V is ₄ Is V _A ；

(6)V ₁ Is V _B ，V ₂ Is V _H ，V ₃ Is V _A And V is ₄ Is V _L ；

(7)V ₁ Is V _L ，V ₂ Is V _B ，V ₃ Is V _H And V is ₄ Is V _A ；

(8)V ₁ Is V _B ，V ₂ Is V _L ，V ₃ Is V _A And V is ₄ Is V _H ；

(9)V ₁ Is V _H ，V ₂ Is V _L ，V ₃ Is V _A And V is ₄ Is V _B ；

(10)V ₁ Is V _L ，V ₂ Is V _H ，V ₃ Is V _A And V is ₄ Is V _B ；

(12)V ₁ Is V _L ，V ₂ Is V _H ，V ₃ Is V _B And V is ₄ Is V _A 。

20. The antigen binding protein of any one of clauses 1-19, comprising

-a first polypeptide chain selected from the group consisting of: 100, 103, 105, 106, 111, 122, 126, 128, 151, 155, 156, 157, 158, 159, 166, 167, 169, 171, 173, 175, 177, 178, 179, 180, 181, 183, 189, 191, 193, 195, 197, 199, 201, 203, 205, 207, 209, 211, 213, 215, 217, 285, 291, 295, 299 and 303

-a second polypeptide chain selected from the group consisting of: 101, 102, 104, 107, 110, 119, 121, 131, 133, 143, 152, 160, 161, 162, 163, 164, 165, 168, 170, 172, 174, 176, 182, 184, 185, 186, 216, 218, 220, 222, 224, 228, 230, 232, 234, 236, 238, 240, 242, 244, 246, 248, 250, 252, 254, 256, 258, 260, 262, 264, 266, 268, 270, 272, 274, 276, 278, 282, 284, 296, or 300.

21. The antigen binding protein of any one of clauses 1 to 13, wherein V _A Included in the TCR alpha chain or gamma chain; and/or V _B Included in the TCR β chain or the δ chain.

22. An isolated nucleic acid comprising a sequence encoding the antigen binding protein of any one of clauses 1-21.

23. A vector comprising the nucleic acid of clause 22.

24. A host cell comprising the antigen binding protein of any one of clauses 1-21, or the nucleic acid of clause 22, or the vector of clause 23.

25. The host cell of clause 24, wherein the host cell is

Lymphocytes, preferably T lymphocytes or T lymphocyte progenitors, e.g.CD 4 or CD8 positive T cells, or

Cells for recombinant expression, such as Chinese Hamster Ovary (CHO) cells or yeast cells.

26. A pharmaceutical composition comprising the antigen binding protein of any one of clauses 1-21, the nucleic acid of clause 22, the vector of clause 23, or the host cell of clause 24 or 25, and a pharmaceutically acceptable carrier.

27. A method of producing an antigen binding protein according to any one of clauses 1 to 21, the method comprising

a. Providing a host cell, wherein the host cell,

b. providing a genetic construct comprising a coding sequence encoding an antigen binding protein according to any one of clauses 1 to 21,

c. introducing the genetic construct into the host cell, and

d. expressing the genetic construct by the host cell.

28. The method of clause 27, further comprising isolating and purifying the antigen binding protein from the host cell, and optionally, reconstituting the antigen binding protein in a T cell.

29. The antigen binding protein of any one of clauses 1 to 21, the nucleic acid of clause 22, the vector of clause 23, the host cell of clause 24 or 25, or the pharmaceutical composition of clause 26, for use in medicine.

29. The antigen binding protein according to any one of clauses 1 to 21, the nucleic acid according to clause 22 or the vector according to clause 23, the host cell according to clause 24 or 25 or the pharmaceutical composition according to clause 26, for use in the diagnosis, prevention and/or treatment of a proliferative disease, such as cancer, wherein the cancer is selected from acute myeloid leukemia, breast cancer, cholangiocellular carcinoma, biliary cancer, glioblastoma, hepatocellular carcinoma, head and neck squamous cell carcinoma, melanoma, non-hodgkin lymphoma, non-small cell lung cancer adenocarcinoma, non-small cell lung cancer, squamous cell non-small cell lung cancer, ovarian cancer, esophageal cancer, renal cell carcinoma, small cell lung cancer, bladder cancer, uterine and endometrial cancer, osteosarcoma, chronic lymphocytic leukemia, colorectal cancer and synovial sarcoma.

Sequence listing

<110> imatikex biotechnology Co., ltd

<120> antigen binding proteins that specifically bind PRAME

<130> 1017-29 PCT

<150> EP21172351.5

<151> 2021-05-05

<150> US63/184,689

<151> 2021-05-05

<160> 384

<170> patent In version 3.5

<210> 1

<211> 251

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 1

Ile Leu Asn Val Glu Gln Ser Pro Gln Ser Leu His Val Gln Glu Gly

1 5 10 15

Asp Ser Thr Asn Phe Thr Cys Ser Phe Pro Ser Ser Asn Phe Tyr Ala

20 25 30

Leu His Trp Tyr Arg Trp Glu Thr Ala Lys Ser Pro Glu Ala Leu Phe

35 40 45

Val Met Thr Leu Asn Gly Asp Glu Lys Lys Lys Gly Arg Ile Ser Ala

50 55 60

Thr Leu Asn Thr Lys Glu Gly Tyr Ser Tyr Leu Tyr Ile Lys Gly Ser

65 70 75 80

Gln Pro Glu Asp Ser Ala Thr Tyr Leu Cys Ala Leu Tyr Asn Asn Asn

85 90 95

Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro Asn Ile

100 105 110

Gln Asn Pro Asp Pro Ala Val Tyr Gln Leu Arg Asp Ser Lys Ser Ser

115 120 125

Asp Lys Ser Val Cys Leu Phe Thr Asp Phe Asp Ser Gln Thr Asn Val

130 135 140

Ser Gln Ser Lys Asp Ser Asp Val Tyr Ile Thr Asp Lys Thr Val Leu

145 150 155 160

Asp Met Arg Ser Met Asp Phe Lys Ser Asn Ser Ala Val Ala Trp Ser

165 170 175

Asn Lys Ser Asp Phe Ala Cys Ala Asn Ala Phe Asn Asn Ser Ile Ile

180 185 190

Pro Glu Asp Thr Phe Phe Pro Ser Pro Glu Ser Ser Cys Asp Val Lys

195 200 205

Leu Val Glu Lys Ser Phe Glu Thr Asp Thr Asn Leu Asn Phe Gln Asn

210 215 220

Leu Ser Val Ile Gly Phe Arg Ile Leu Leu Leu Lys Val Ala Gly Phe

225 230 235 240

Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser

245 250

<210> 2

<211> 290

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 2

Gly Val Ile Gln Ser Pro Arg His Glu Val Thr Glu Met Gly Gln Glu

1 5 10 15

Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His Asn Ser Leu Phe Trp

20 25 30

Tyr Arg Gln Thr Met Met Arg Gly Leu Glu Leu Leu Ile Tyr Phe Asn

35 40 45

Asn Asn Val Pro Ile Asp Asp Ser Gly Met Pro Glu Asp Arg Phe Ser

50 55 60

Ala Lys Met Pro Asn Ala Ser Phe Ser Thr Leu Lys Ile Gln Pro Ser

65 70 75 80

Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala Ser Ser Pro Gly Ser

85 90 95

Thr Asp Thr Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val Leu Glu

100 105 110

Asp Leu Lys Asn Val Phe Pro Pro Glu Val Ala Val Phe Glu Pro Ser

115 120 125

Glu Ala Glu Ile Ser His Thr Gln Lys Ala Thr Leu Val Cys Leu Ala

130 135 140

Thr Gly Phe Tyr Pro Asp His Val Glu Leu Ser Trp Trp Val Asn Gly

145 150 155 160

Lys Glu Val His Ser Gly Val Ser Thr Asp Pro Gln Pro Leu Lys Glu

165 170 175

Gln Pro Ala Leu Asn Asp Ser Arg Tyr Cys Leu Ser Ser Arg Leu Arg

180 185 190

Val Ser Ala Thr Phe Trp Gln Asn Pro Arg Asn His Phe Arg Cys Gln

195 200 205

Val Gln Phe Tyr Gly Leu Ser Glu Asn Asp Glu Trp Thr Gln Asp Arg

210 215 220

Ala Lys Pro Val Thr Gln Ile Val Ser Ala Glu Ala Trp Gly Arg Ala

225 230 235 240

Asp Cys Gly Phe Thr Ser Glu Ser Tyr Gln Gln Gly Val Leu Ser Ala

245 250 255

Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala Val

260 265 270

Leu Val Ser Ala Leu Val Leu Met Ala Met Val Lys Arg Lys Asp Ser

275 280 285

Arg Gly

290

<210> 3

<211> 110

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 3

Ile Leu Asn Val Glu Gln Ser Pro Gln Ser Leu His Val Gln Glu Gly

1 5 10 15

Asp Ser Thr Asn Phe Thr Cys Ser Phe Pro Ser Ser Asn Phe Tyr Ala

20 25 30

Leu His Trp Tyr Arg Trp Glu Thr Ala Lys Ser Pro Glu Ala Leu Phe

35 40 45

Val Met Thr Leu Asn Gly Asp Glu Lys Lys Lys Gly Arg Ile Ser Ala

50 55 60

Thr Leu Asn Thr Lys Glu Gly Tyr Ser Tyr Leu Tyr Ile Lys Gly Ser

65 70 75 80

Gln Pro Glu Asp Ser Ala Thr Tyr Leu Cys Ala Leu Tyr Asn Asn Asn

85 90 95

Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro

100 105 110

<210> 4

<211> 111

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 4

Gly Val Ile Gln Ser Pro Arg His Glu Val Thr Glu Met Gly Gln Glu

1 5 10 15

Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His Asn Ser Leu Phe Trp

20 25 30

Tyr Arg Gln Thr Met Met Arg Gly Leu Glu Leu Leu Ile Tyr Phe Asn

35 40 45

Asn Asn Val Pro Ile Asp Asp Ser Gly Met Pro Glu Asp Arg Phe Ser

50 55 60

Ala Lys Met Pro Asn Ala Ser Phe Ser Thr Leu Lys Ile Gln Pro Ser

65 70 75 80

Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala Ser Ser Pro Gly Ser

85 90 95

Thr Asp Thr Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val Leu

100 105 110

<210> 5

<211> 246

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 5

Ile Leu Asn Val Glu Gln Ser Pro Gln Ser Leu His Val Gln Glu Gly

1 5 10 15

Asp Ser Thr Asn Phe Thr Cys Ser Phe Pro Ser Ser Asn Phe Tyr Ala

20 25 30

Leu His Trp Tyr Arg Trp Glu Thr Ala Lys Ser Pro Glu Ala Leu Phe

35 40 45

Val Met Thr Leu Asn Gly Asp Glu Lys Lys Lys Gly Arg Ile Ser Ala

50 55 60

Thr Leu Asn Thr Lys Glu Gly Tyr Ser Tyr Leu Tyr Ile Lys Gly Ser

65 70 75 80

Gln Pro Glu Asp Ser Ala Thr Tyr Leu Cys Ala Leu Tyr Asn Asn Asn

85 90 95

Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro Gly Gly

100 105 110

Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

115 120 125

Gly Ser Gly Gly Gly Gly Ser Gly Val Ile Gln Ser Pro Arg His Glu

130 135 140

Val Thr Glu Met Gly Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser

145 150 155 160

Gly His Asn Ser Leu Phe Trp Tyr Arg Gln Thr Met Met Arg Gly Leu

165 170 175

Glu Leu Leu Ile Tyr Phe Asn Asn Asn Val Pro Ile Asp Asp Ser Gly

180 185 190

Met Pro Glu Asp Arg Phe Ser Ala Lys Met Pro Asn Ala Ser Phe Ser

195 200 205

Thr Leu Lys Ile Gln Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe

210 215 220

Cys Ala Ser Ser Pro Gly Ser Thr Asp Thr Gln Tyr Phe Gly Pro Gly

225 230 235 240

Thr Arg Leu Thr Val Leu

245

<210> 6

<211> 246

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 6

Ile Leu Asn Val Glu Gln Ser Pro Gln Ser Leu His Val Gln Glu Gly

1 5 10 15

Asp Ser Thr Asn Phe Thr Cys Ser Phe Pro Ser Ser Asn Phe Tyr Asn

20 25 30

Leu His Trp Tyr Arg Lys Glu Thr Ala Lys Ser Pro Glu Phe Leu Phe

35 40 45

Tyr Met Thr Ser Asn Gly Asp Glu Lys Lys Lys Gly Arg Ile Ser Ala

50 55 60

Thr Leu Asn Thr Lys Glu Gly Tyr Ser Tyr Leu Tyr Ile Thr Asp Ser

65 70 75 80

Gln Pro Glu Asp Ser Ala Thr Tyr Leu Cys Ala Leu Tyr Asn Asn Asn

85 90 95

Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro Gly Gly

100 105 110

Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

115 120 125

Gly Ser Gly Gly Gly Gly Ser Gly Val Ile Gln Ser Pro Arg His Leu

130 135 140

Val Thr Glu Met Gly Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser

145 150 155 160

Gly His Asn Ser Leu Phe Trp Tyr Arg Glu Thr Pro Met Gln Gly Leu

165 170 175

Glu Leu Leu Ile Tyr Phe Asn Asn Asn Glu Pro Ile Asp Asp Ser Gly

180 185 190

Met Pro Glu Asp Arg Phe Ser Ala Lys Met Pro Asn Ala Ser Phe Ser

195 200 205

Thr Leu Lys Ile Gln Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe

210 215 220

Cys Ala Ser Ser Pro Gly Ser Thr Asp Thr Gln Tyr Phe Gly Pro Gly

225 230 235 240

Thr Arg Leu Thr Val Leu

245

<210> 7

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 7

Ser Ser Asn Phe Tyr Ala

1 5

<210> 8

<211> 7

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 8

Met Thr Leu Asn Gly Asp Glu

1 5

<210> 9

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 9

Ala Leu Tyr Asn Asn Asn Asp Met Arg

1 5

<210> 10

<211> 5

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 10

Ser Gly His Asn Ser

1 5

<210> 11

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 11

Phe Asn Asn Asn Val Pro

1 5

<210> 12

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 12

Ala Ser Ser Pro Gly Ser Thr Asp Thr Gln Tyr

1 5 10

<210> 13

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 13

Ser Ser Asn Phe Tyr Asn

1 5

<210> 14

<211> 7

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 14

Met Thr Ser Asn Gly Asp Glu

1 5

<210> 15

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 15

Phe Asn Asn Asn Glu Pro

1 5

<210> 16

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 16

Val Lys Glu Phe Gln Asp

1 5

<210> 17

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 17

Asn Lys Glu Phe Gln Asp

1 5

<210> 18

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 18

Thr Arg Glu Phe Gln Asp

1 5

<210> 19

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 19

Asn Arg Glu Phe Gln Asp

1 5

<210> 20

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 20

Thr Ser Glu Phe Gln Asp

1 5

<210> 21

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 21

Thr Lys Glu Phe Gln Asp

1 5

<210> 22

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 22

Val Arg Glu Phe Gln Asp

1 5

<210> 23

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 23

Thr Ala Glu Phe Gln Asp

1 5

<210> 24

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 24

Val Ser Glu Phe Gln Asp

1 5

<210> 25

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 25

Val Ala Glu Phe Gln Asp

1 5

<210> 26

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 26

Ile Lys Glu Phe Gln Asn

1 5

<210> 27

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 27

Val Arg Glu Phe Gln Asn

1 5

<210> 28

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 28

Thr Ala Glu Phe Gln Asn

1 5

<210> 29

<211> 7

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 29

Phe Gly Pro Tyr Gly Val Glu

1 5

<210> 30

<211> 7

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 30

Phe Gly Pro Tyr Gly Arg Glu

1 5

<210> 31

<211> 7

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 31

Phe Gly Pro Tyr Gly Thr Glu

1 5

<210> 32

<211> 7

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 32

Phe Gly Pro Tyr Gly Lys Glu

1 5

<210> 33

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 33

Ala Leu Tyr Asn Asn Leu Asp Met Arg

1 5

<210> 34

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 34

Ala Leu Tyr Asn Asn Tyr Asp Met Arg

1 5

<210> 35

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 35

Tyr Gln Asn Thr Ala Ile

1 5

<210> 36

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 36

Phe Gln Asn Thr Ala Val

1 5

<210> 37

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 37

Tyr Gln Asn Thr Ala Val

1 5

<210> 38

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 38

Tyr Gln Asn Thr Ala Leu

1 5

<210> 39

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 39

Phe Gln Asn Thr Ala Thr

1 5

<210> 40

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 40

Met Gln Asn Ser Ala Val

1 5

<210> 41

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 41

Phe Gln Asn Thr Ala Leu

1 5

<210> 42

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 42

Met Gln Asn Thr Ala Ile

1 5

<210> 43

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 43

Leu Gln Asn Thr Ala Val

1 5

<210> 44

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 44

Met Gln Asn Thr Ala Val

1 5

<210> 45

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 45

Phe Asn Ser Glu Thr Val

1 5

<210> 46

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 46

Ala Ser Ser Pro Gly Ser Ile Asp Thr Gln Tyr

1 5 10

<210> 47

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 47

Ala Ser Ser Pro Gly Ala Thr Asp Thr Gln Tyr

1 5 10

<210> 48

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 48

Ala Ser Ser Pro Gly Ala Thr Asp Lys Gln Tyr

1 5 10

<210> 49

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 49

Ala Ser Ser Pro Gly Ser Thr Asp Ala Gln Tyr

1 5 10

<210> 50

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 50

Ser Leu Leu Gln His Leu Ile Gly Leu

1 5

<210> 51

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 51

Ser Ile Leu Gln Thr Leu Ile Leu Val

1 5

<210> 52

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 52

Ser Leu Ile Glu His Leu Gln Gly Leu

1 5

<210> 53

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 53

Ser Leu Ile Gln His Leu Glu Glu Ile

1 5

<210> 54

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 54

Ser Leu Leu Lys Asn Leu Ile Tyr Leu

1 5

<210> 55

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 55

Ser Leu Leu Asn His Leu Pro Tyr Leu

1 5

<210> 56

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 56

Ser Leu Leu Gln His Val Leu Leu Leu

1 5

<210> 57

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 57

Ser Leu Leu Gln Lys Gln Ile Met Leu

1 5

<210> 58

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 58

Ser Leu Ser Gln Glu Leu Val Gly Val

1 5

<210> 59

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 59

Ser Val Leu Gly Ala Leu Ile Gly Val

1 5

<210> 60

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 60

Phe Met Asn Pro His Leu Ile Ser Val

1 5

<210> 61

<211> 25

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 61

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly

1 5 10 15

Gly Gly Gly Ser Gly Gly Gly Gly Ser

20 25

<210> 62

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 62

Ser Ile Leu Gln His Leu Leu Leu Val

1 5

<210> 63

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 63

Leu Leu Leu Ala His Ile Ile Ala Leu

1 5

<210> 64

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 64

His Leu Leu Ser Lys Leu Ile Ser Val

1 5

<210> 65

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 65

Lys Leu Leu Lys Asn Leu Ile Gly Ile

1 5

<210> 66

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 66

Lys Leu Ile Gln Phe Leu Ile Ser Leu

1 5

<210> 67

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 67

Tyr Met Leu Glu His Val Ile Thr Leu

1 5

<210> 68

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 68

Ile Leu Leu Glu His Ile Ile Met Cys

1 5

<210> 69

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 69

Ser Ile Leu Glu His Gln Ile Gln Val

1 5

<210> 70

<211> 20

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 70

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly

1 5 10 15

Gly Gly Gly Ser

20

<210> 71

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 71

Ser Leu Leu Leu Lys Leu Ile Ala Val

1 5

<210> 72

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 72

Ser Leu Leu Asp Asn Met Ile Gly Val

1 5

<210> 73

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 73

Phe Leu Ile Gln His Leu Leu Gln Ala

1 5

<210> 74

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 74

Ser Leu Leu Asp Lys Ile Ile Gly Ala

1 5

<210> 75

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 75

Glu Leu Leu Gln Lys Val Ile Thr Leu

1 5

<210> 76

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 76

Ile Ile Ile Asn His Val Ile Ser Val

1 5

<210> 77

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 77

Phe Val Leu Gly His Phe Ile Leu Leu

1 5

<210> 78

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 78

Asn Leu Leu Pro His Ala Ile Asn Leu

1 5

<210> 79

<211> 246

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 79

Ile Leu Asn Val Glu Gln Ser Pro Gln Ser Leu His Val Gln Glu Gly

1 5 10 15

Asp Ser Thr Asn Phe Thr Cys Ser Phe Pro Thr Arg Glu Phe Gln Asp

20 25 30

Leu His Trp Tyr Arg Lys Glu Thr Ala Lys Ser Pro Glu Phe Leu Phe

35 40 45

Tyr Phe Gly Pro Tyr Gly Val Glu Lys Lys Lys Gly Arg Ile Ser Ala

50 55 60

Thr Leu Asn Thr Lys Glu Gly Tyr Ser Tyr Leu Tyr Ile Thr Asp Ser

65 70 75 80

Gln Pro Glu Asp Ser Ala Thr Tyr Leu Cys Ala Leu Tyr Asn Asn Asn

85 90 95

Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro Gly Gly

100 105 110

Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

115 120 125

Gly Ser Gly Gly Gly Gly Ser Gly Val Ile Gln Ser Pro Arg His Leu

130 135 140

Val Thr Glu Met Gly Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser

145 150 155 160

Gly His Asn Ser Leu Phe Trp Tyr Arg Glu Thr Pro Met Gln Gly Leu

165 170 175

Glu Leu Leu Ile Tyr Phe Gln Asn Thr Ala Val Ile Asp Asp Ser Gly

180 185 190

Met Pro Glu Asp Arg Phe Ser Ala Lys Met Pro Asn Ala Ser Phe Ser

195 200 205

Thr Leu Lys Ile Gln Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe

210 215 220

Cys Ala Ser Ser Pro Gly Ser Thr Asp Thr Gln Tyr Phe Gly Pro Gly

225 230 235 240

Thr Arg Leu Thr Val Leu

245

<210> 80

<211> 246

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 80

Ile Leu Asn Val Glu Gln Ser Pro Gln Ser Leu His Val Gln Glu Gly

1 5 10 15

Asp Ser Thr Asn Phe Thr Cys Ser Phe Pro Thr Lys Glu Phe Gln Asp

20 25 30

Leu His Trp Tyr Arg Lys Glu Thr Ala Lys Ser Pro Glu Phe Leu Phe

35 40 45

Tyr Phe Gly Pro Tyr Gly Val Glu Lys Lys Lys Gly Arg Ile Ser Ala

50 55 60

Thr Leu Asn Thr Lys Glu Gly Tyr Ser Tyr Leu Tyr Ile Thr Asp Ser

65 70 75 80

Gln Pro Glu Asp Ser Ala Thr Tyr Leu Cys Ala Leu Tyr Asn Asn Asn

85 90 95

Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro Gly Gly

100 105 110

Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

115 120 125

Gly Ser Gly Gly Gly Gly Ser Gly Val Ile Gln Ser Pro Arg His Leu

130 135 140

Val Thr Glu Met Gly Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser

145 150 155 160

Gly His Asn Ser Leu Phe Trp Tyr Arg Glu Thr Pro Met Gln Gly Leu

165 170 175

Glu Leu Leu Ile Tyr Phe Gln Asn Thr Ala Val Ile Asp Asp Ser Gly

180 185 190

Met Pro Glu Asp Arg Phe Ser Ala Lys Met Pro Asn Ala Ser Phe Ser

195 200 205

Thr Leu Lys Ile Gln Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe

210 215 220

Cys Ala Ser Ser Pro Gly Ala Thr Asp Thr Gln Tyr Phe Gly Pro Gly

225 230 235 240

Thr Arg Leu Thr Val Leu

245

<210> 81

<211> 246

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 81

Ile Leu Asn Val Glu Gln Ser Pro Gln Ser Leu His Val Gln Glu Gly

1 5 10 15

Asp Ser Thr Asn Phe Thr Cys Ser Phe Pro Thr Arg Glu Phe Gln Asp

20 25 30

Leu His Trp Tyr Arg Lys Glu Thr Ala Lys Ser Pro Glu Phe Leu Phe

35 40 45

Tyr Phe Gly Pro Tyr Gly Lys Glu Lys Lys Lys Gly Arg Ile Ser Ala

50 55 60

Thr Leu Asn Thr Lys Glu Gly Tyr Ser Tyr Leu Tyr Ile Thr Asp Ser

65 70 75 80

Gln Pro Glu Asp Ser Ala Thr Tyr Leu Cys Ala Leu Tyr Asn Asn Asn

85 90 95

Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro Gly Gly

100 105 110

Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

115 120 125

Gly Ser Gly Gly Gly Gly Ser Gly Val Ile Gln Ser Pro Arg His Leu

130 135 140

Val Thr Glu Met Gly Gln Glu Val Thr Leu His Cys Lys Pro Ile Ser

145 150 155 160

Gly His Asn Ser Leu Phe Trp Tyr Arg Glu Thr Pro Met Gln Gly Leu

165 170 175

Glu Leu Leu Ile Tyr Phe Gln Asn Thr Ala Val Ile Asp Asp Ser Gly

180 185 190

Met Pro Glu Asp Arg Phe Ser Ala Lys Met Pro Asn Ala Ser Phe Ser

195 200 205

Thr Leu Lys Ile Gln Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe

210 215 220

Cys Ala Ser Ser Pro Gly Ser Thr Asp Thr Gln Tyr Phe Gly Pro Gly

225 230 235 240

Thr Arg Leu Thr Val Leu

245

<210> 82

<211> 246

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 82

Ile Leu Asn Val Glu Gln Ser Pro Gln Ser Leu His Val Gln Glu Gly

1 5 10 15

Asp Ser Thr Asn Phe Thr Cys Ser Phe Pro Thr Lys Glu Phe Gln Asp

20 25 30

Leu His Trp Tyr Arg Lys Glu Thr Ala Lys Ser Pro Glu Phe Leu Phe

35 40 45

Tyr Phe Gly Pro Tyr Gly Arg Glu Lys Lys Lys Gly Arg Ile Ser Ala

50 55 60

Thr Leu Asn Thr Lys Glu Gly Tyr Ser Tyr Leu Tyr Ile Thr Asp Ser

65 70 75 80

Gln Pro Glu Asp Ser Ala Thr Tyr Leu Cys Ala Leu Tyr Asn Asn Asn

85 90 95

Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro Gly Gly

100 105 110

Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

115 120 125

Gly Ser Gly Gly Gly Gly Ser Gly Val Ile Gln Ser Pro Arg His Leu

130 135 140

Val Thr Glu Met Gly Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser

145 150 155 160

Gly His Asn Ser Leu Phe Trp Tyr Arg Glu Thr Pro Met Gln Gly Leu

165 170 175

Glu Leu Leu Ile Tyr Phe Gln Asn Thr Ala Val Ile Asp Asp Ser Gly

180 185 190

Met Pro Glu Asp Arg Phe Ser Ala Lys Met Pro Asn Ala Ser Phe Ser

195 200 205

Thr Leu Lys Ile Gln Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe

210 215 220

Cys Ala Ser Ser Pro Gly Ala Thr Asp Thr Gln Tyr Phe Gly Pro Gly

225 230 235 240

Thr Arg Leu Thr Val Leu

245

<210> 83

<211> 246

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 83

Ile Leu Asn Val Glu Gln Ser Pro Gln Ser Leu His Val Gln Glu Gly

1 5 10 15

Asp Ser Thr Asn Phe Thr Cys Ser Phe Pro Ser Ser Asn Phe Tyr Asn

20 25 30

Leu His Trp Tyr Arg Lys Glu Thr Ala Lys Ser Pro Glu Phe Leu Phe

35 40 45

Tyr Phe Gly Pro Tyr Gly Val Glu Lys Lys Lys Gly Arg Ile Ser Ala

50 55 60

Thr Leu Asn Thr Lys Glu Gly Tyr Ser Tyr Leu Tyr Ile Thr Asp Ser

65 70 75 80

Gln Pro Glu Asp Ser Ala Thr Tyr Leu Cys Ala Leu Tyr Asn Asn Asn

85 90 95

Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro Gly Gly

100 105 110

Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

115 120 125

Gly Ser Gly Gly Gly Gly Ser Gly Val Ile Gln Ser Pro Arg His Leu

130 135 140

Val Thr Glu Met Gly Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser

145 150 155 160

Gly His Asn Ser Leu Phe Trp Tyr Arg Glu Thr Pro Met Gln Gly Leu

165 170 175

Glu Leu Leu Ile Tyr Phe Asn Ser Glu Thr Val Ile Asp Asp Ser Gly

180 185 190

Met Pro Glu Asp Arg Phe Ser Ala Lys Met Pro Asn Ala Ser Phe Ser

195 200 205

Thr Leu Lys Ile Gln Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe

210 215 220

Cys Ala Ser Ser Pro Gly Ala Thr Asp Thr Gln Tyr Phe Gly Pro Gly

225 230 235 240

Thr Arg Leu Thr Val Leu

245

<210> 84

<211> 246

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 84

Ile Leu Asn Val Glu Gln Ser Pro Gln Ser Leu His Val Gln Glu Gly

1 5 10 15

Asp Ser Thr Asn Phe Thr Cys Ser Phe Pro Asn Lys Glu Phe Gln Asp

20 25 30

Leu His Trp Tyr Arg Lys Glu Thr Ala Lys Ser Pro Glu Phe Leu Phe

35 40 45

Tyr Phe Gly Pro Tyr Gly Val Glu Lys Lys Lys Gly Arg Ile Ser Ala

50 55 60

Thr Leu Asn Thr Lys Glu Gly Tyr Ser Tyr Leu Tyr Ile Thr Asp Ser

65 70 75 80

Gln Pro Glu Asp Ser Ala Thr Tyr Leu Cys Ala Leu Tyr Asn Asn Asn

85 90 95

Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro Gly Gly

100 105 110

Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

115 120 125

Gly Ser Gly Gly Gly Gly Ser Gly Val Ile Gln Ser Pro Arg His Leu

130 135 140

Val Thr Glu Met Gly Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser

145 150 155 160

Gly His Asn Ser Leu Phe Trp Tyr Arg Glu Thr Pro Met Gln Gly Leu

165 170 175

Glu Leu Leu Ile Tyr Tyr Gln Asn Thr Ala Val Ile Asp Asp Ser Gly

180 185 190

Met Pro Glu Asp Arg Phe Ser Ala Lys Met Pro Asn Ala Ser Phe Ser

195 200 205

Thr Leu Lys Ile Gln Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe

210 215 220

Cys Ala Ser Ser Pro Gly Ala Thr Asp Thr Gln Tyr Phe Gly Pro Gly

225 230 235 240

Thr Arg Leu Thr Val Leu

245

<210> 85

<211> 246

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 85

Ile Leu Asn Val Glu Gln Ser Pro Gln Ser Leu His Val Gln Glu Gly

1 5 10 15

Asp Ser Thr Asn Phe Thr Cys Ser Phe Pro Asn Lys Glu Phe Gln Asp

20 25 30

Leu His Trp Tyr Arg Lys Glu Thr Ala Lys Ser Pro Glu Phe Leu Phe

35 40 45

Tyr Phe Gly Pro Tyr Gly Thr Glu Lys Lys Lys Gly Arg Ile Ser Ala

50 55 60

Thr Leu Asn Thr Lys Glu Gly Tyr Ser Tyr Leu Tyr Ile Thr Asp Ser

65 70 75 80

Gln Pro Glu Asp Ser Ala Thr Tyr Leu Cys Ala Leu Tyr Asn Asn Asn

85 90 95

Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro Gly Gly

100 105 110

Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

115 120 125

Gly Ser Gly Gly Gly Gly Ser Gly Val Ile Gln Ser Pro Arg His Leu

130 135 140

Val Thr Glu Met Gly Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser

145 150 155 160

Gly His Asn Ser Leu Phe Trp Tyr Arg Glu Thr Pro Met Gln Gly Leu

165 170 175

Glu Leu Leu Ile Tyr Phe Gln Asn Thr Ala Val Ile Asp Asp Ser Gly

180 185 190

Met Pro Glu Asp Arg Phe Ser Ala Lys Met Pro Asn Ala Ser Phe Ser

195 200 205

Thr Leu Lys Ile Gln Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe

210 215 220

Cys Ala Ser Ser Pro Gly Ser Thr Asp Thr Gln Tyr Phe Gly Pro Gly

225 230 235 240

Thr Arg Leu Thr Val Leu

245

<210> 86

<211> 246

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 86

Ile Leu Asn Val Glu Gln Ser Pro Gln Ser Leu His Val Gln Glu Gly

1 5 10 15

Asp Ser Thr Asn Phe Thr Cys Ser Phe Pro Ser Ser Asn Phe Tyr Asn

20 25 30

Leu His Trp Tyr Arg Lys Glu Thr Ala Lys Ser Pro Glu Phe Leu Phe

35 40 45

Tyr Phe Gly Pro Tyr Gly Lys Glu Lys Lys Lys Gly Arg Ile Ser Ala

50 55 60

Thr Leu Asn Thr Lys Glu Gly Tyr Ser Tyr Leu Tyr Ile Thr Asp Ser

65 70 75 80

Gln Pro Glu Asp Ser Ala Thr Tyr Leu Cys Ala Leu Tyr Asn Asn Asn

85 90 95

Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro Gly Gly

100 105 110

Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

115 120 125

Gly Ser Gly Gly Gly Gly Ser Gly Val Ile Gln Ser Pro Arg His Leu

130 135 140

Val Thr Glu Met Gly Gln Glu Val Thr Leu His Cys Lys Pro Ile Ser

145 150 155 160

Gly His Asn Ser Leu Phe Trp Tyr Arg Glu Thr Pro Met Gln Gly Leu

165 170 175

Glu Leu Leu Ile Tyr Tyr Gln Asn Thr Ala Ile Ile Asp Asp Ser Gly

180 185 190

Met Pro Glu Asp Arg Phe Ser Ala Lys Met Pro Asn Ala Ser Phe Ser

195 200 205

Thr Leu Lys Ile Gln Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe

210 215 220

Cys Ala Ser Ser Pro Gly Ser Thr Asp Thr Gln Tyr Phe Gly Pro Gly

225 230 235 240

Thr Arg Leu Thr Val Leu

245

<210> 87

<211> 246

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 87

Ile Leu Asn Val Glu Gln Ser Pro Gln Ser Leu His Val Gln Glu Gly

1 5 10 15

Asp Ser Thr Asn Phe Thr Cys Ser Phe Pro Val Lys Glu Phe Gln Asp

20 25 30

Leu His Trp Tyr Arg Lys Glu Thr Ala Lys Ser Pro Glu Phe Leu Phe

35 40 45

Tyr Phe Gly Pro Tyr Gly Lys Glu Lys Lys Lys Gly Arg Ile Ser Ala

50 55 60

Thr Leu Asn Thr Lys Glu Gly Tyr Ser Tyr Leu Tyr Ile Thr Asp Ser

65 70 75 80

Gln Pro Glu Asp Ser Ala Thr Tyr Leu Cys Ala Leu Tyr Asn Asn Asn

85 90 95

Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro Gly Gly

100 105 110

Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

115 120 125

Gly Ser Gly Gly Gly Gly Ser Gly Val Ile Gln Ser Pro Arg His Leu

130 135 140

Val Thr Glu Met Gly Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser

145 150 155 160

Gly His Asn Ser Leu Phe Trp Tyr Arg Glu Thr Pro Met Gln Gly Leu

165 170 175

Glu Leu Leu Ile Tyr Phe Gln Asn Thr Ala Val Ile Asp Asp Ser Gly

180 185 190

Met Pro Glu Asp Arg Phe Ser Ala Lys Met Pro Asn Ala Ser Phe Ser

195 200 205

Thr Leu Lys Ile Gln Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe

210 215 220

Cys Ala Ser Ser Pro Gly Ala Thr Asp Thr Gln Tyr Phe Gly Pro Gly

225 230 235 240

Thr Arg Leu Thr Val Leu

245

<210> 88

<211> 87

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 88

Met Gln Leu Leu Arg Cys Phe Ser Ile Phe Ser Val Ile Ala Ser Val

1 5 10 15

Leu Ala Gln Glu Leu Thr Thr Ile Cys Glu Gln Ile Pro Ser Pro Thr

20 25 30

Leu Glu Ser Thr Pro Tyr Ser Leu Ser Thr Thr Thr Ile Leu Ala Asn

35 40 45

Gly Lys Ala Met Gln Gly Val Phe Glu Tyr Tyr Lys Ser Val Thr Phe

50 55 60

Val Ser Asn Cys Gly Ser His Pro Ser Thr Thr Ser Lys Gly Ser Pro

65 70 75 80

Ile Asn Thr Gln Tyr Val Phe

85

<210> 89

<211> 246

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 89

Ile Leu Asn Val Glu Gln Ser Pro Gln Ser Leu His Val Gln Glu Gly

1 5 10 15

Asp Ser Thr Asn Phe Thr Cys Ser Phe Pro Val Lys Glu Phe Gln Asp

20 25 30

Leu His Trp Tyr Arg Lys Glu Thr Ala Lys Ser Pro Glu Phe Leu Phe

35 40 45

Tyr Phe Gly Pro Tyr Gly Lys Glu Lys Lys Lys Gly Arg Ile Ser Ala

50 55 60

Thr Leu Asn Thr Lys Glu Gly Tyr Ser Tyr Leu Tyr Ile Thr Asp Ser

65 70 75 80

Gln Pro Glu Asp Ser Ala Thr Tyr Leu Cys Ala Leu Tyr Asn Asn Asn

85 90 95

Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro Gly Gly

100 105 110

Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

115 120 125

Gly Ser Gly Gly Gly Gly Ser Gly Val Ile Gln Ser Pro Arg Asn Leu

130 135 140

Val Thr Glu Met Gly Gln Glu Val Thr Leu His Cys Lys Pro Ile Ser

145 150 155 160

Gly His Asn Ser Leu Phe Trp Tyr Arg Glu Thr Pro Met Gln Gly Leu

165 170 175

Glu Leu Leu Ile Tyr Phe Asn Ser Glu Thr Val Ile Asp Asp Ser Gly

180 185 190

Met Pro Glu Asp Arg Phe Ser Ala Lys Met Pro Asn Ala Ser Phe Ser

195 200 205

Thr Leu Lys Ile Gln Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe

210 215 220

Cys Ala Ser Ser Pro Gly Ser Thr Asp Thr Gln Tyr Phe Gly Pro Gly

225 230 235 240

Thr Arg Leu Thr Val Leu

245

<210> 90

<211> 246

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 90

Ile Leu Asn Val Glu Gln Ser Pro Gln Ser Leu His Val Gln Glu Gly

1 5 10 15

Asp Ser Thr Asn Phe Thr Cys Ser Phe Pro Asn Lys Glu Phe Gln Asp

20 25 30

Leu His Trp Tyr Arg Lys Glu Thr Asp Lys Ser Pro Glu Phe Leu Phe

35 40 45

Tyr Phe Gly Pro Tyr Gly Arg Glu Lys Lys Lys Gly Arg Ile Ser Ala

50 55 60

Thr Leu Asn Thr Lys Glu Gly Tyr Ser Tyr Leu Tyr Ile Thr Asp Ser

65 70 75 80

Gln Pro Glu Asp Ser Ala Thr Tyr Leu Cys Ala Leu Tyr Asn Asn Asn

85 90 95

Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro Gly Gly

100 105 110

Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

115 120 125

Gly Ser Gly Gly Gly Gly Ser Gly Val Ile Gln Ser Pro Arg His Leu

130 135 140

Val Thr Glu Met Gly Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser

145 150 155 160

Gly His Asn Ser Leu Phe Trp Tyr Lys Glu Thr Pro Met Gln Gly Leu

165 170 175

Glu Leu Leu Ile Tyr Tyr Gln Asn Thr Ala Val Ile Asp Asp Ser Gly

180 185 190

Met Pro Glu Asp Arg Phe Ser Ala Lys Met Pro Asn Ala Ser Phe Ser

195 200 205

Thr Leu Lys Ile Gln Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe

210 215 220

Cys Ala Ser Ser Pro Gly Ala Thr Asp Thr Gln Tyr Phe Gly Pro Gly

225 230 235 240

Thr Arg Leu Thr Val Leu

245

<210> 91

<211> 246

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 91

Ile Leu Asn Val Glu Gln Ser Pro Gln Ser Leu His Val Gln Glu Gly

1 5 10 15

Asp Ser Thr Asn Phe Thr Cys Ser Phe Pro Thr Arg Glu Phe Gln Asp

20 25 30

Leu His Trp Tyr Arg Lys Glu Thr Ala Lys Ser Pro Glu Phe Leu Phe

35 40 45

Tyr Phe Gly Pro Tyr Gly Thr Glu Lys Lys Lys Gly Arg Ile Ser Ala

50 55 60

Thr Leu Asn Thr Lys Glu Gly Tyr Ser Tyr Leu Tyr Ile Thr Asp Ser

65 70 75 80

Gln Pro Glu Asp Ser Ala Thr Tyr Leu Cys Ala Leu Tyr Asn Asn Asn

85 90 95

Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro Gly Gly

100 105 110

Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

115 120 125

Gly Ser Gly Gly Gly Gly Ser Gly Val Ile Gln Ser Pro Arg His Leu

130 135 140

Val Thr Glu Met Gly Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser

145 150 155 160

Gly His Asn Ser Leu Phe Trp Tyr Arg Glu Thr Pro Met Gln Gly Leu

165 170 175

Glu Leu Leu Ile Tyr Tyr Gln Asn Thr Ala Val Ile Asp Asp Ser Gly

180 185 190

Met Pro Glu Asp Arg Phe Ser Ala Lys Met Pro Asn Ala Ser Phe Ser

195 200 205

Thr Leu Lys Ile Gln Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe

210 215 220

Cys Ala Ser Ser Ser Gly Ala Thr Asp Thr Gln Tyr Phe Gly Pro Gly

225 230 235 240

Thr Arg Leu Thr Val Leu

245

<210> 92

<211> 246

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 92

Ile Leu Asn Val Glu Gln Ser Pro Gln Ser Leu His Val Gln Glu Gly

1 5 10 15

Asp Ser Thr Asn Phe Thr Cys Ser Phe Pro Thr Lys Glu Phe Gln Asp

20 25 30

Met His Trp Tyr Arg Lys Glu Thr Ala Lys Ser Pro Glu Phe Leu Phe

35 40 45

Tyr Phe Gly Pro Tyr Gly Val Glu Lys Lys Lys Gly Arg Ile Ser Ala

50 55 60

Thr Leu Asn Thr Lys Glu Gly Tyr Ser Tyr Leu Tyr Ile Thr Asp Ser

65 70 75 80

Gln Pro Glu Asp Ser Ala Thr Tyr Leu Cys Ala Leu Tyr Asn Asn Asn

85 90 95

Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro Gly Gly

100 105 110

Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

115 120 125

Gly Ser Gly Gly Gly Gly Ser Gly Val Ile Gln Ser Pro Arg His Leu

130 135 140

Val Thr Glu Met Gly Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser

145 150 155 160

Gly His Asn Ser Leu Phe Trp Tyr Arg Glu Thr Pro Met Gln Gly Leu

165 170 175

Glu Leu Leu Ile Tyr Phe Gln Asn Thr Ala Val Ile Asp Asp Ser Gly

180 185 190

Met Pro Glu Asp Arg Phe Ser Ala Lys Met Pro Asn Ala Ser Phe Ser

195 200 205

Thr Leu Lys Ile Gln Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe

210 215 220

Cys Ala Ser Ser Pro Gly Ser Thr Asp Thr Gln Tyr Phe Gly Pro Gly

225 230 235 240

Thr Arg Leu Thr Val Leu

245

<210> 93

<211> 214

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 93

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Arg Asn Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Gln Thr Leu Pro Trp

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala

100 105 110

Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly

115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala

130 135 140

Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln

145 150 155 160

Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser

165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr

180 185 190

Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser

195 200 205

Phe Asn Arg Gly Glu Cys

210

<210> 94

<211> 487

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 94

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr

20 25 30

Thr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Ala Gln Lys Phe

50 55 60

Gln Asp Arg Val Thr Leu Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp

100 105 110

Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro

115 120 125

Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr

130 135 140

Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr

145 150 155 160

Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro

165 170 175

Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr

180 185 190

Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn

195 200 205

His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser

210 215 220

Cys Asp Lys Thr His Thr Ser Pro Pro Ser Pro Ala Pro Pro Val Ala

225 230 235 240

Gly Ile Leu Asn Val Glu Gln Ser Pro Gln Ser Leu His Val Gln Glu

245 250 255

Gly Asp Ser Thr Asn Phe Thr Cys Ser Phe Pro Thr Arg Glu Phe Gln

260 265 270

Asp Leu His Trp Tyr Arg Lys Glu Thr Ala Lys Ser Pro Glu Phe Leu

275 280 285

Phe Tyr Phe Gly Pro Tyr Gly Val Glu Lys Lys Lys Gly Arg Ile Ser

290 295 300

Ala Thr Leu Asn Thr Lys Glu Gly Tyr Ser Tyr Leu Tyr Ile Thr Asp

305 310 315 320

Ser Gln Pro Glu Asp Ser Ala Thr Tyr Leu Cys Ala Leu Tyr Asn Asn

325 330 335

Asn Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro Gly

340 345 350

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

355 360 365

Gly Gly Ser Gly Gly Gly Gly Ser Gly Val Ile Gln Ser Pro Arg His

370 375 380

Leu Val Thr Glu Met Gly Gln Glu Val Thr Leu Arg Cys Lys Pro Ile

385 390 395 400

Ser Gly His Asn Ser Leu Phe Trp Tyr Arg Glu Thr Pro Met Gln Gly

405 410 415

Leu Glu Leu Leu Ile Tyr Phe Gln Asn Thr Ala Val Ile Asp Asp Ser

420 425 430

Gly Met Pro Glu Asp Arg Phe Ser Ala Lys Met Pro Asn Ala Ser Phe

435 440 445

Ser Thr Leu Lys Ile Gln Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr

450 455 460

Phe Cys Ala Ser Ser Pro Gly Ser Thr Asp Thr Gln Tyr Phe Gly Pro

465 470 475 480

Gly Thr Arg Leu Thr Val Leu

485

<210> 95

<211> 487

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 95

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr

20 25 30

Thr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Ala Gln Lys Phe

50 55 60

Gln Asp Arg Val Thr Leu Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp

100 105 110

Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro

115 120 125

Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr

130 135 140

Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr

145 150 155 160

Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro

165 170 175

Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr

180 185 190

Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn

195 200 205

His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser

210 215 220

Cys Asp Lys Thr His Thr Ser Pro Pro Ser Pro Ala Pro Pro Val Ala

225 230 235 240

Gly Ile Leu Asn Val Glu Gln Ser Pro Gln Ser Leu His Val Gln Glu

245 250 255

Gly Asp Ser Thr Asn Phe Thr Cys Ser Phe Pro Thr Lys Glu Phe Gln

260 265 270

Asp Leu His Trp Tyr Arg Lys Glu Thr Ala Lys Ser Pro Glu Phe Leu

275 280 285

Phe Tyr Phe Gly Pro Tyr Gly Arg Glu Lys Lys Lys Gly Arg Ile Ser

290 295 300

Ala Thr Leu Asn Thr Lys Glu Gly Tyr Ser Tyr Leu Tyr Ile Thr Asp

305 310 315 320

Ser Gln Pro Glu Asp Ser Ala Thr Tyr Leu Cys Ala Leu Tyr Asn Asn

325 330 335

Asn Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro Gly

340 345 350

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

355 360 365

Gly Gly Ser Gly Gly Gly Gly Ser Gly Val Ile Gln Ser Pro Arg His

370 375 380

Leu Val Thr Glu Met Gly Gln Glu Val Thr Leu Arg Cys Lys Pro Ile

385 390 395 400

Ser Gly His Asn Ser Leu Phe Trp Tyr Arg Glu Thr Pro Met Gln Gly

405 410 415

Leu Glu Leu Leu Ile Tyr Phe Gln Asn Thr Ala Val Ile Asp Asp Ser

420 425 430

Gly Met Pro Glu Asp Arg Phe Ser Ala Lys Met Pro Asn Ala Ser Phe

435 440 445

Ser Thr Leu Lys Ile Gln Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr

450 455 460

Phe Cys Ala Ser Ser Pro Gly Ala Thr Asp Thr Gln Tyr Phe Gly Pro

465 470 475 480

Gly Thr Arg Leu Thr Val Leu

485

<210> 96

<211> 487

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 96

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr

20 25 30

Thr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Ala Gln Lys Phe

50 55 60

Gln Asp Arg Val Thr Leu Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp

100 105 110

Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro

115 120 125

Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr

130 135 140

Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr

145 150 155 160

Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro

165 170 175

Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr

180 185 190

Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn

195 200 205

His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser

210 215 220

Cys Asp Lys Thr His Thr Ser Pro Pro Ser Pro Ala Pro Pro Val Ala

225 230 235 240

Gly Ile Leu Asn Val Glu Gln Ser Pro Gln Ser Leu His Val Gln Glu

245 250 255

Gly Asp Ser Thr Asn Phe Thr Cys Ser Phe Pro Ser Ser Asn Phe Tyr

260 265 270

Asn Leu His Trp Tyr Arg Lys Glu Thr Ala Lys Ser Pro Glu Phe Leu

275 280 285

Phe Tyr Phe Gly Pro Tyr Gly Val Glu Lys Lys Lys Gly Arg Ile Ser

290 295 300

Ala Thr Leu Asn Thr Lys Glu Gly Tyr Ser Tyr Leu Tyr Ile Thr Asp

305 310 315 320

Ser Gln Pro Glu Asp Ser Ala Thr Tyr Leu Cys Ala Leu Tyr Asn Asn

325 330 335

Asn Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro Gly

340 345 350

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

355 360 365

Gly Gly Ser Gly Gly Gly Gly Ser Gly Val Ile Gln Ser Pro Arg His

370 375 380

Leu Val Thr Glu Met Gly Gln Glu Val Thr Leu Arg Cys Lys Pro Ile

385 390 395 400

Ser Gly His Asn Ser Leu Phe Trp Tyr Arg Glu Thr Pro Met Gln Gly

405 410 415

Leu Glu Leu Leu Ile Tyr Phe Asn Ser Glu Thr Val Ile Asp Asp Ser

420 425 430

Gly Met Pro Glu Asp Arg Phe Ser Ala Lys Met Pro Asn Ala Ser Phe

435 440 445

Ser Thr Leu Lys Ile Gln Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr

450 455 460

Phe Cys Ala Ser Ser Pro Gly Ala Thr Asp Thr Gln Tyr Phe Gly Pro

465 470 475 480

Gly Thr Arg Leu Thr Val Leu

485

<210> 97

<211> 487

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 97

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr

20 25 30

Thr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Ala Gln Lys Phe

50 55 60

Gln Asp Arg Val Thr Leu Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp

100 105 110

Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro

115 120 125

Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr

130 135 140

Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr

145 150 155 160

Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro

165 170 175

Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr

180 185 190

Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn

195 200 205

His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser

210 215 220

Cys Asp Lys Thr His Thr Ser Pro Pro Ser Pro Ala Pro Pro Val Ala

225 230 235 240

Gly Ile Leu Asn Val Glu Gln Ser Pro Gln Ser Leu His Val Gln Glu

245 250 255

Gly Asp Ser Thr Asn Phe Thr Cys Ser Phe Pro Asn Lys Glu Phe Gln

260 265 270

Asp Leu His Trp Tyr Arg Lys Glu Thr Ala Lys Ser Pro Glu Phe Leu

275 280 285

Phe Tyr Phe Gly Pro Tyr Gly Thr Glu Lys Lys Lys Gly Arg Ile Ser

290 295 300

Ala Thr Leu Asn Thr Lys Glu Gly Tyr Ser Tyr Leu Tyr Ile Thr Asp

305 310 315 320

Ser Gln Pro Glu Asp Ser Ala Thr Tyr Leu Cys Ala Leu Tyr Asn Asn

325 330 335

Asn Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro Gly

340 345 350

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

355 360 365

Gly Gly Ser Gly Gly Gly Gly Ser Gly Val Ile Gln Ser Pro Arg His

370 375 380

Leu Val Thr Glu Met Gly Gln Glu Val Thr Leu Arg Cys Lys Pro Ile

385 390 395 400

Ser Gly His Asn Ser Leu Phe Trp Tyr Arg Glu Thr Pro Met Gln Gly

405 410 415

Leu Glu Leu Leu Ile Tyr Phe Gln Asn Thr Ala Val Ile Asp Asp Ser

420 425 430

Gly Met Pro Glu Asp Arg Phe Ser Ala Lys Met Pro Asn Ala Ser Phe

435 440 445

Ser Thr Leu Lys Ile Gln Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr

450 455 460

Phe Cys Ala Ser Ser Pro Gly Ser Thr Asp Thr Gln Tyr Phe Gly Pro

465 470 475 480

Gly Thr Arg Leu Thr Val Leu

485

<210> 98

<211> 487

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 98

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr

20 25 30

Thr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Ala Gln Lys Phe

50 55 60

Gln Asp Arg Val Thr Leu Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp

100 105 110

Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro

115 120 125

Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr

130 135 140

Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr

145 150 155 160

Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro

165 170 175

Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr

180 185 190

Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn

195 200 205

His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser

210 215 220

Cys Asp Lys Thr His Thr Ser Pro Pro Ser Pro Ala Pro Pro Val Ala

225 230 235 240

Gly Ile Leu Asn Val Glu Gln Ser Pro Gln Ser Leu His Val Gln Glu

245 250 255

Gly Asp Ser Thr Asn Phe Thr Cys Ser Phe Pro Val Lys Glu Phe Gln

260 265 270

Asp Leu His Trp Tyr Arg Lys Glu Thr Ala Lys Ser Pro Glu Phe Leu

275 280 285

Phe Tyr Phe Gly Pro Tyr Gly Lys Glu Lys Lys Lys Gly Arg Ile Ser

290 295 300

Ala Thr Leu Asn Thr Lys Glu Gly Tyr Ser Tyr Leu Tyr Ile Thr Asp

305 310 315 320

Ser Gln Pro Glu Asp Ser Ala Thr Tyr Leu Cys Ala Leu Tyr Asn Asn

325 330 335

Asn Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro Gly

340 345 350

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

355 360 365

Gly Gly Ser Gly Gly Gly Gly Ser Gly Val Ile Gln Ser Pro Arg His

370 375 380

Leu Val Thr Glu Met Gly Gln Glu Val Thr Leu Arg Cys Lys Pro Ile

385 390 395 400

Ser Gly His Asn Ser Leu Phe Trp Tyr Arg Glu Thr Pro Met Gln Gly

405 410 415

Leu Glu Leu Leu Ile Tyr Phe Gln Asn Thr Ala Val Ile Asp Asp Ser

420 425 430

Gly Met Pro Glu Asp Arg Phe Ser Ala Lys Met Pro Asn Ala Ser Phe

435 440 445

Ser Thr Leu Lys Ile Gln Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr

450 455 460

Phe Cys Ala Ser Ser Pro Gly Ala Thr Asp Thr Gln Tyr Phe Gly Pro

465 470 475 480

Gly Thr Arg Leu Thr Val Leu

485

<210> 99

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 99

Asp Tyr Lys Asp Asp Asp Asp Lys

1 5

<210> 100

<211> 454

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 100

Ile Leu Asn Val Glu Gln Ser Pro Gln Ser Leu His Val Gln Glu Gly

1 5 10 15

Asp Ser Thr Asn Phe Thr Cys Ser Phe Pro Val Lys Glu Phe Gln Asp

20 25 30

Leu His Trp Tyr Arg Lys Glu Thr Ala Lys Ser Pro Glu Phe Leu Phe

35 40 45

Tyr Phe Gly Pro Tyr Gly Lys Glu Lys Lys Lys Gly Arg Ile Ser Ala

50 55 60

Thr Leu Asn Thr Lys Glu Gly Tyr Ser Tyr Leu Tyr Ile Thr Asp Ser

65 70 75 80

Gln Pro Glu Asp Ser Ala Thr Tyr Leu Cys Ala Leu Tyr Asn Asn Asn

85 90 95

Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro Gly Gly

100 105 110

Gly Ser Gly Gly Gly Gly Asp Ile Gln Met Thr Gln Ser Pro Ser Ser

115 120 125

Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser

130 135 140

Gln Asp Ile Arg Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys

145 150 155 160

Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Leu His Ser Gly Val

165 170 175

Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr

180 185 190

Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln

195 200 205

Gly Gln Thr Leu Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile

210 215 220

Lys Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro

225 230 235 240

Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

245 250 255

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

260 265 270

Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val

275 280 285

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

290 295 300

Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

305 310 315 320

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala

325 330 335

Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

340 345 350

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr

355 360 365

Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser

370 375 380

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

385 390 395 400

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

405 410 415

Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe

420 425 430

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

435 440 445

Ser Leu Ser Leu Ser Pro

450

<210> 101

<211> 470

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 101

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr

20 25 30

Thr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Ala Gln Lys Phe

50 55 60

Gln Asp Arg Val Thr Leu Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp

100 105 110

Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Ser Gly Gly

115 120 125

Gly Gly Gly Val Ile Gln Ser Pro Arg His Leu Val Thr Glu Met Gly

130 135 140

Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His Asn Ser Leu

145 150 155 160

Phe Trp Tyr Arg Glu Thr Pro Met Gln Gly Leu Glu Leu Leu Ile Tyr

165 170 175

Phe Gln Asn Thr Ala Val Ile Asp Asp Ser Gly Met Pro Glu Asp Arg

180 185 190

Phe Ser Ala Lys Met Pro Asn Ala Ser Phe Ser Thr Leu Lys Ile Gln

195 200 205

Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala Ser Ser Pro

210 215 220

Gly Ala Thr Asp Thr Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val

225 230 235 240

Leu Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro

245 250 255

Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

260 265 270

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

275 280 285

Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val

290 295 300

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

305 310 315 320

Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

325 330 335

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala

340 345 350

Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

355 360 365

Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr

370 375 380

Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser

385 390 395 400

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

405 410 415

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val

420 425 430

Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe

435 440 445

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

450 455 460

Ser Leu Ser Leu Ser Pro

465 470

<210> 102

<211> 454

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 102

Gln Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Ser Ala Thr Ser Ser Val Ser Tyr Met

20 25 30

His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr

35 40 45

Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser

50 55 60

Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu

65 70 75 80

Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr

85 90 95

Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Ser Gly Gly

100 105 110

Gly Gly Gly Val Ile Gln Ser Pro Arg His Leu Val Thr Glu Met Gly

115 120 125

Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His Asn Ser Leu

130 135 140

Phe Trp Tyr Arg Glu Thr Pro Met Gln Gly Leu Glu Leu Leu Ile Tyr

145 150 155 160

Phe Gln Asn Thr Ala Val Ile Asp Asp Ser Gly Met Pro Glu Asp Arg

165 170 175

Phe Ser Ala Lys Met Pro Asn Ala Ser Phe Ser Thr Leu Lys Ile Gln

180 185 190

Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala Ser Ser Pro

195 200 205

Gly Ala Thr Asp Thr Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val

210 215 220

Leu Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro

225 230 235 240

Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

245 250 255

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

260 265 270

Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val

275 280 285

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

290 295 300

Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

305 310 315 320

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala

325 330 335

Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

340 345 350

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr

355 360 365

Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser

370 375 380

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

385 390 395 400

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

405 410 415

Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe

420 425 430

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

435 440 445

Ser Leu Ser Leu Ser Pro

450

<210> 103

<211> 467

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 103

Ile Leu Asn Val Glu Gln Ser Pro Gln Ser Leu His Val Gln Glu Gly

1 5 10 15

Asp Ser Thr Asn Phe Thr Cys Ser Phe Pro Val Lys Glu Phe Gln Asp

20 25 30

Leu His Trp Tyr Arg Lys Glu Thr Ala Lys Ser Pro Glu Phe Leu Phe

35 40 45

Tyr Phe Gly Pro Tyr Gly Lys Glu Lys Lys Lys Gly Arg Ile Ser Ala

50 55 60

Thr Leu Asn Thr Lys Glu Gly Tyr Ser Tyr Leu Tyr Ile Thr Asp Ser

65 70 75 80

Gln Pro Glu Asp Ser Ala Thr Tyr Leu Cys Ala Leu Tyr Asn Asn Asn

85 90 95

Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro Gly Gly

100 105 110

Gly Ser Gly Gly Gly Gly Glu Val Gln Leu Val Gln Ser Gly Ala Glu

115 120 125

Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly

130 135 140

Tyr Lys Phe Thr Ser Tyr Val Met His Trp Val Arg Gln Ala Pro Gly

145 150 155 160

Gln Gly Leu Glu Trp Met Gly Tyr Ile Asn Pro Tyr Asn Asp Val Thr

165 170 175

Lys Tyr Ala Glu Lys Phe Gln Gly Arg Val Thr Leu Thr Ser Asp Thr

180 185 190

Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp

195 200 205

Thr Ala Val His Tyr Cys Ala Arg Gly Ser Tyr Tyr Asp Tyr Glu Gly

210 215 220

Phe Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Glu Pro

225 230 235 240

Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Pro

245 250 255

Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr

260 265 270

Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val

275 280 285

Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val

290 295 300

Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gln Ser

305 310 315 320

Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu

325 330 335

Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala

340 345 350

Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro

355 360 365

Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln

370 375 380

Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala

385 390 395 400

Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr

405 410 415

Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu

420 425 430

Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser

435 440 445

Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser

450 455 460

Leu Ser Pro

465

<210> 104

<211> 457

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 104

Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly

1 5 10 15

Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser Gly

20 25 30

Tyr Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly

35 40 45

Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro Ala Arg Phe

50 55 60

Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val

65 70 75 80

Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Ala Leu Trp Tyr Ser Asn

85 90 95

Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly Gly

100 105 110

Ser Gly Gly Gly Gly Gly Val Ile Gln Ser Pro Arg His Leu Val Thr

115 120 125

Glu Met Gly Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His

130 135 140

Asn Ser Leu Phe Trp Tyr Arg Glu Thr Pro Met Gln Gly Leu Glu Leu

145 150 155 160

Leu Ile Tyr Phe Gln Asn Thr Ala Val Ile Asp Asp Ser Gly Met Pro

165 170 175

Glu Asp Arg Phe Ser Ala Lys Met Pro Asn Ala Ser Phe Ser Thr Leu

180 185 190

Lys Ile Gln Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala

195 200 205

Ser Ser Pro Gly Ala Thr Asp Thr Gln Tyr Phe Gly Pro Gly Thr Arg

210 215 220

Leu Thr Val Leu Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro

225 230 235 240

Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro

245 250 255

Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr

260 265 270

Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn

275 280 285

Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg

290 295 300

Glu Glu Gln Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val

305 310 315 320

Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser

325 330 335

Asn Lys Ala Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys

340 345 350

Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp

355 360 365

Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe

370 375 380

Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu

385 390 395 400

Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe

405 410 415

Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly

420 425 430

Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr

435 440 445

Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455

<210> 105

<211> 472

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 105

Ile Leu Asn Val Glu Gln Ser Pro Gln Ser Leu His Val Gln Glu Gly

1 5 10 15

Asp Ser Thr Asn Phe Thr Cys Ser Phe Pro Val Lys Glu Phe Gln Asp

20 25 30

Leu His Trp Tyr Arg Lys Glu Thr Ala Lys Ser Pro Glu Phe Leu Phe

35 40 45

Tyr Phe Gly Pro Tyr Gly Lys Glu Lys Lys Lys Gly Arg Ile Ser Ala

50 55 60

Thr Leu Asn Thr Lys Glu Gly Tyr Ser Tyr Leu Tyr Ile Thr Asp Ser

65 70 75 80

Gln Pro Glu Asp Ser Ala Thr Tyr Leu Cys Ala Leu Tyr Asn Asn Asn

85 90 95

Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro Gly Gly

100 105 110

Gly Ser Gly Gly Gly Gly Glu Val Gln Leu Val Glu Ser Gly Gly Gly

115 120 125

Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly

130 135 140

Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly

145 150 155 160

Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr

165 170 175

Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg

180 185 190

Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr

195 200 205

Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe Gly Asn

210 215 220

Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr

225 230 235 240

Val Ser Ser Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro

245 250 255

Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro

260 265 270

Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys

275 280 285

Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp

290 295 300

Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu

305 310 315 320

Glu Gln Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu

325 330 335

His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn

340 345 350

Lys Ala Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly

355 360 365

Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu

370 375 380

Leu Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr

385 390 395 400

Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn

405 410 415

Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe

420 425 430

Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn

435 440 445

Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr

450 455 460

Gln Lys Ser Leu Ser Leu Ser Pro

465 470

<210> 106

<211> 454

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 106

Ile Met Asn Val Glu Gln Ser Pro Gln Ser Leu His Val Gln Glu Gly

1 5 10 15

Asp Ser Thr Asn Phe Thr Cys Ser Phe Pro Val Lys Glu Phe Gln Asp

20 25 30

Leu His Trp Tyr Arg Lys Glu Thr Ala Lys Ser Pro Glu Phe Leu Phe

35 40 45

Tyr Phe Gly Pro Tyr Gly Lys Glu Lys Lys Lys Gly Arg Ile Ser Ala

50 55 60

Thr Leu Asn Thr Lys Glu Gly Tyr Ser Tyr Leu Tyr Ile Thr Asp Ser

65 70 75 80

Gln Pro Glu Asp Ser Ala Thr Tyr Leu Cys Ala Leu Tyr Asn Asn Asn

85 90 95

Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro Gly Gly

100 105 110

Gly Ser Gly Gly Gly Gly Asp Ile Gln Met Thr Gln Ser Pro Ser Ser

115 120 125

Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser

130 135 140

Gln Asp Ile Arg Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys

145 150 155 160

Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Leu His Ser Gly Val

165 170 175

Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr

180 185 190

Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln

195 200 205

Gly Gln Thr Leu Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile

210 215 220

Lys Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro

225 230 235 240

Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

245 250 255

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

260 265 270

Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val

275 280 285

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

290 295 300

Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

305 310 315 320

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala

325 330 335

Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

340 345 350

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr

355 360 365

Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser

370 375 380

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

385 390 395 400

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

405 410 415

Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe

420 425 430

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

435 440 445

Ser Leu Ser Leu Ser Pro

450

<210> 107

<211> 470

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 107

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr

20 25 30

Thr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Ala Gln Lys Phe

50 55 60

Gln Asp Arg Val Thr Leu Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp

100 105 110

Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Ser Gly Gly

115 120 125

Gly Gly Gly Val Ile Gln Ser Pro Arg His Leu Val Thr Glu Met Gly

130 135 140

Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His Asn Ser Leu

145 150 155 160

Phe Trp Tyr Arg Glu Thr Pro Met Gln Gly Leu Glu Leu Leu Ile Tyr

165 170 175

Phe Gln Asn Thr Ala Val Ile Asp Asp Ser Gly Met Pro Glu Asp Arg

180 185 190

Phe Ser Ala Lys Met Pro Asn Asp Ser Phe Ser Thr Leu Lys Ile Gln

195 200 205

Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala Ser Ser Pro

210 215 220

Gly Ala Thr Asp Thr Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val

225 230 235 240

Leu Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro

245 250 255

Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

260 265 270

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

275 280 285

Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val

290 295 300

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

305 310 315 320

Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

325 330 335

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala

340 345 350

Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

355 360 365

Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr

370 375 380

Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser

385 390 395 400

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

405 410 415

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val

420 425 430

Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe

435 440 445

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

450 455 460

Ser Leu Ser Leu Ser Pro

465 470

<210> 108

<211> 107

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 108

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Arg Asn Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Gln Thr Leu Pro Trp

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 109

<211> 122

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 109

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr

20 25 30

Thr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Ala Gln Lys Phe

50 55 60

Gln Asp Arg Val Thr Leu Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp

100 105 110

Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 110

<211> 454

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 110

Gln Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Ser Ala Thr Ser Ser Val Ser Tyr Met

20 25 30

His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr

35 40 45

Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser

50 55 60

Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu

65 70 75 80

Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr

85 90 95

Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Ser Gly Gly

100 105 110

Gly Gly Gly Val Ile Gln Ser Pro Arg His Leu Val Thr Glu Met Gly

115 120 125

Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His Asn Ser Leu

130 135 140

Phe Trp Tyr Arg Glu Thr Pro Met Gln Gly Leu Glu Leu Leu Ile Tyr

145 150 155 160

Phe Gln Asn Thr Ala Val Ile Asp Asp Ser Gly Met Pro Glu Asp Arg

165 170 175

Phe Ser Ala Lys Met Pro Asn Asp Ser Phe Ser Thr Leu Lys Ile Gln

180 185 190

Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala Ser Ser Pro

195 200 205

Gly Ala Thr Asp Thr Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val

210 215 220

Leu Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro

225 230 235 240

Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

245 250 255

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

260 265 270

Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val

275 280 285

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

290 295 300

Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

305 310 315 320

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala

325 330 335

Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

340 345 350

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr

355 360 365

Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser

370 375 380

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

385 390 395 400

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

405 410 415

Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe

420 425 430

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

435 440 445

Ser Leu Ser Leu Ser Pro

450

<210> 111

<211> 467

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 111

Ile Met Asn Val Glu Gln Ser Pro Gln Ser Leu His Val Gln Glu Gly

1 5 10 15

Asp Ser Thr Asn Phe Thr Cys Ser Phe Pro Val Lys Glu Phe Gln Asp

20 25 30

Leu His Trp Tyr Arg Lys Glu Thr Ala Lys Ser Pro Glu Phe Leu Phe

35 40 45

Tyr Phe Gly Pro Tyr Gly Lys Glu Lys Lys Lys Gly Arg Ile Ser Ala

50 55 60

Thr Leu Asn Thr Lys Glu Gly Tyr Ser Tyr Leu Tyr Ile Thr Asp Ser

65 70 75 80

Gln Pro Glu Asp Ser Ala Thr Tyr Leu Cys Ala Leu Tyr Asn Asn Asn

85 90 95

Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro Gly Gly

100 105 110

Gly Ser Gly Gly Gly Gly Glu Val Gln Leu Val Gln Ser Gly Ala Glu

115 120 125

Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly

130 135 140

Tyr Lys Phe Thr Ser Tyr Val Met His Trp Val Arg Gln Ala Pro Gly

145 150 155 160

Gln Gly Leu Glu Trp Met Gly Tyr Ile Asn Pro Tyr Asn Asp Val Thr

165 170 175

Lys Tyr Ala Glu Lys Phe Gln Gly Arg Val Thr Leu Thr Ser Asp Thr

180 185 190

Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp

195 200 205

Thr Ala Val His Tyr Cys Ala Arg Gly Ser Tyr Tyr Asp Tyr Glu Gly

210 215 220

Phe Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Glu Pro

225 230 235 240

Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Pro

245 250 255

Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr

260 265 270

Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val

275 280 285

Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val

290 295 300

Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gln Ser

305 310 315 320

Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu

325 330 335

Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala

340 345 350

Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro

355 360 365

Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln

370 375 380

Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala

385 390 395 400

Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr

405 410 415

Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu

420 425 430

Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser

435 440 445

Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser

450 455 460

Leu Ser Pro

465

<210> 112

<211> 120

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 112

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Lys Phe Thr Ser Tyr

20 25 30

Val Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Tyr Ile Asn Pro Tyr Asn Asp Val Thr Lys Tyr Ala Glu Lys Phe

50 55 60

Gln Gly Arg Val Thr Leu Thr Ser Asp Thr Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val His Tyr Cys

85 90 95

Ala Arg Gly Ser Tyr Tyr Asp Tyr Glu Gly Phe Val Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 113

<211> 106

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 113

Gln Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Ser Ala Thr Ser Ser Val Ser Tyr Met

20 25 30

His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr

35 40 45

Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser

50 55 60

Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu

65 70 75 80

Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr

85 90 95

Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 114

<211> 120

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 114

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Lys Phe Thr Arg Tyr

20 25 30

Val Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Tyr Ile Asn Pro Tyr Asn Asp Val Thr Lys Tyr Ala Glu Lys Phe

50 55 60

Gln Gly Arg Val Thr Leu Thr Ser Asp Thr Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val His Tyr Cys

85 90 95

Ala Arg Gly Ser Tyr Tyr Asp Tyr Glu Gly Phe Val Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 115

<211> 120

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 115

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Lys Phe Thr Ser Tyr

20 25 30

Val Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Tyr Ile Asn Pro Arg Asn Asp Val Thr Lys Tyr Ala Glu Lys Phe

50 55 60

Gln Gly Arg Val Thr Leu Thr Ser Asp Thr Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val His Tyr Cys

85 90 95

Ala Arg Gly Ser Tyr Tyr Asp Tyr Glu Gly Phe Val Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 116

<211> 120

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 116

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Lys Phe Thr Arg Tyr

20 25 30

Val Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Tyr Ile Asn Pro Tyr Asn Asp Val Thr Lys Tyr Ala Glu Lys Phe

50 55 60

Gln Gly Arg Val Thr Leu Thr Ser Asp Thr Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gly Ser Tyr Tyr Asp Tyr Glu Gly Phe Val Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 117

<211> 120

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 117

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Lys Phe Thr Ser Tyr

20 25 30

Val Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Tyr Ile Asn Pro Arg Asn Asp Val Thr Lys Tyr Ala Glu Lys Phe

50 55 60

Gln Gly Arg Val Thr Leu Thr Ser Asp Thr Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gly Ser Tyr Tyr Asp Tyr Glu Gly Phe Val Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 118

<211> 125

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 118

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr

20 25 30

Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp

50 55 60

Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr

65 70 75 80

Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr

85 90 95

Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp

100 105 110

Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120 125

<210> 119

<211> 470

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 119

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr

20 25 30

Thr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Ala Gln Lys Phe

50 55 60

Gln Asp Arg Val Thr Leu Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp

100 105 110

Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Ser Gly Gly

115 120 125

Gly Gly Gly Val Ile Gln Ser Pro Arg His Leu Val Thr Glu Met Gly

130 135 140

Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His Asn Ser Leu

145 150 155 160

Phe Trp Tyr Arg Glu Thr Pro Met Gln Gly Leu Glu Leu Leu Ile Tyr

165 170 175

Phe Gln Asn Thr Ala Val Ile Asp Asp Ser Gly Met Pro Glu Asp Arg

180 185 190

Phe Ser Ala Lys Met Pro Asn Asp Ser Phe Ser Thr Leu Lys Ile Gln

195 200 205

Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala Ser Ser Pro

210 215 220

Gly Ala Thr Asp Leu Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val

225 230 235 240

Leu Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro

245 250 255

Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

260 265 270

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

275 280 285

Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val

290 295 300

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

305 310 315 320

Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

325 330 335

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala

340 345 350

Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

355 360 365

Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr

370 375 380

Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser

385 390 395 400

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

405 410 415

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val

420 425 430

Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe

435 440 445

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

450 455 460

Ser Leu Ser Leu Ser Pro

465 470

<210> 120

<211> 109

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 120

Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly

1 5 10 15

Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser Gly

20 25 30

Tyr Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly

35 40 45

Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro Ala Arg Phe

50 55 60

Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val

65 70 75 80

Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Ala Leu Trp Tyr Ser Asn

85 90 95

Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105

<210> 121

<211> 470

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 121

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr

20 25 30

Thr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Ala Gln Lys Phe

50 55 60

Gln Asp Arg Val Thr Leu Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp

100 105 110

Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Ser Gly Gly

115 120 125

Gly Gly Gly Val Ile Gln Ser Pro Arg His Glu Val Thr Glu Met Gly

130 135 140

Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His Asn Ser Leu

145 150 155 160

Phe Trp Tyr Arg Glu Thr Pro Met Gln Gly Leu Glu Leu Leu Ile Tyr

165 170 175

Phe Gln Asn Thr Ala Val Ile Asp Asp Ser Gly Met Pro Glu Asp Arg

180 185 190

Phe Ser Ala Lys Met Pro Asn Asp Ser Phe Ser Thr Leu Lys Ile Gln

195 200 205

Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala Ser Ser Pro

210 215 220

Gly Ala Thr Asp Leu Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val

225 230 235 240

Leu Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro

245 250 255

Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

260 265 270

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

275 280 285

Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val

290 295 300

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

305 310 315 320

Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

325 330 335

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala

340 345 350

Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

355 360 365

Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr

370 375 380

Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser

385 390 395 400

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

405 410 415

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val

420 425 430

Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe

435 440 445

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

450 455 460

Ser Leu Ser Leu Ser Pro

465 470

<210> 122

<211> 454

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 122

Ile Leu Asn Val Glu Gln Ser Pro Gln Ser Leu His Val Gln Glu Gly

1 5 10 15

Asp Ser Thr Lys Phe Thr Cys Ser Phe Pro Val Lys Glu Phe Gln Asp

20 25 30

Leu His Trp Tyr Arg Lys Glu Thr Ala Lys Ser Pro Glu Phe Leu Phe

35 40 45

Tyr Phe Gly Pro Tyr Gly Lys Glu Lys Lys Lys Gly Arg Ile Ser Ala

50 55 60

Thr Leu Asn Thr Lys Glu Gly Tyr Ser Tyr Leu Tyr Ile Thr Asp Ser

65 70 75 80

Gln Pro Glu Asp Ser Ala Thr Tyr Leu Cys Ala Leu Tyr Asn Asn Asn

85 90 95

Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro Gly Gly

100 105 110

Gly Ser Gly Gly Gly Gly Asp Ile Gln Met Thr Gln Ser Pro Ser Ser

115 120 125

Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser

130 135 140

Gln Asp Ile Arg Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys

145 150 155 160

Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Leu His Ser Gly Val

165 170 175

Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr

180 185 190

Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln

195 200 205

Gly Gln Thr Leu Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile

210 215 220

Lys Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro

225 230 235 240

Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

245 250 255

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

260 265 270

Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val

275 280 285

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

290 295 300

Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

305 310 315 320

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala

325 330 335

Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

340 345 350

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr

355 360 365

Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser

370 375 380

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

385 390 395 400

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

405 410 415

Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe

420 425 430

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

435 440 445

Ser Leu Ser Leu Ser Pro

450

<210> 123

<211> 125

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 123

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr

20 25 30

Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp

50 55 60

Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr

65 70 75 80

Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr

85 90 95

Tyr Cys Val Arg His Gly Asn Phe Gly Asp Ser Tyr Ile Ser Tyr Trp

100 105 110

Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120 125

<210> 124

<211> 454

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 124

Ile Met Asn Val Glu Gln Ser Pro Gln Ser Leu His Val Gln Glu Gly

1 5 10 15

Asp Ser Thr Asn Phe Thr Cys Ser Phe Pro Val Lys Glu Phe Gln Asp

20 25 30

Leu His Trp Tyr Arg Lys Glu Thr Ala Lys Ser Pro Glu Phe Leu Phe

35 40 45

Tyr Phe Gly Pro Tyr Gly Lys Glu Lys Lys Lys Gly Arg Ile Ser Ala

50 55 60

Thr Leu Asn Thr Lys Glu Gly Tyr Ser Tyr Leu Tyr Ile Thr Asp Ser

65 70 75 80

Gln Pro Glu Asp Ser Ala Thr Tyr Leu Cys Ala Leu Tyr Asn Asn Asn

85 90 95

Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro Gly Gly

100 105 110

Gly Ser Gly Gly Gly Gly Asp Ile Gln Met Thr Gln Ser Pro Ser Ser

115 120 125

Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser

130 135 140

Gln Asp Ile Arg Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys

145 150 155 160

Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Leu His Ser Gly Val

165 170 175

Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr

180 185 190

Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln

195 200 205

Gly Gln Thr Leu Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile

210 215 220

Lys Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro

225 230 235 240

Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

245 250 255

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

260 265 270

Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val

275 280 285

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

290 295 300

Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

305 310 315 320

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala

325 330 335

Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

340 345 350

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr

355 360 365

Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser

370 375 380

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

385 390 395 400

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

405 410 415

Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe

420 425 430

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

435 440 445

Ser Leu Ser Leu Ser Pro

450

<210> 125

<211> 125

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 125

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr

20 25 30

Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp

50 55 60

Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr

65 70 75 80

Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr

85 90 95

Tyr Cys Val Arg His Gly Asn Phe Gly Glu Ser Tyr Ile Ser Tyr Trp

100 105 110

Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120 125

<210> 126

<211> 454

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 126

Ile Leu Asn Val Glu Gln Ser Pro Gln Ser Leu His Val Gln Glu Gly

1 5 10 15

Asp Ser Thr Asn Phe Thr Cys Ser Phe Pro Val Lys Glu Phe Gln Asp

20 25 30

Leu His Trp Tyr Arg Lys Glu Thr Ala Lys Ser Pro Glu Phe Leu Phe

35 40 45

Tyr Phe Gly Pro Tyr Gly Lys Glu Lys Lys Lys Gly Arg Ile Ser Ala

50 55 60

Thr Leu Asn Thr Lys Glu Gly Tyr Ser Tyr Leu Tyr Ile Thr Asp Ser

65 70 75 80

Gln Pro Glu Asp Ser Ala Thr Tyr Leu Cys Ala Leu Tyr Asn Asn Tyr

85 90 95

Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro Gly Gly

100 105 110

Gly Ser Gly Gly Gly Gly Asp Ile Gln Met Thr Gln Ser Pro Ser Ser

115 120 125

Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser

130 135 140

Gln Asp Ile Arg Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys

145 150 155 160

Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Leu His Ser Gly Val

165 170 175

Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr

180 185 190

Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln

195 200 205

Gly Gln Thr Leu Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile

210 215 220

Lys Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro

225 230 235 240

Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

245 250 255

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

260 265 270

Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val

275 280 285

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

290 295 300

Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

305 310 315 320

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala

325 330 335

Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

340 345 350

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr

355 360 365

Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser

370 375 380

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

385 390 395 400

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

405 410 415

Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe

420 425 430

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

435 440 445

Ser Leu Ser Leu Ser Pro

450

<210> 127

<211> 125

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 127

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr

20 25 30

Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp

50 55 60

Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr

65 70 75 80

Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr

85 90 95

Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ala Tyr Ile Ser Tyr Trp

100 105 110

Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120 125

<210> 128

<211> 454

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 128

Ile Met Asn Val Glu Gln Ser Pro Gln Ser Leu His Val Gln Glu Gly

1 5 10 15

Asp Ser Thr Asn Phe Thr Cys Ser Phe Pro Val Lys Glu Phe Gln Asp

20 25 30

Leu His Trp Tyr Arg Lys Glu Thr Ala Lys Ser Pro Glu Phe Leu Phe

35 40 45

Tyr Phe Gly Pro Tyr Gly Lys Glu Lys Lys Lys Gly Arg Ile Ser Ala

50 55 60

Thr Leu Asn Thr Lys Glu Gly Tyr Ser Tyr Leu Tyr Ile Thr Asp Ser

65 70 75 80

Gln Pro Glu Asp Ser Ala Thr Tyr Leu Cys Ala Leu Tyr Asn Asn Tyr

85 90 95

Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro Gly Gly

100 105 110

Gly Ser Gly Gly Gly Gly Asp Ile Gln Met Thr Gln Ser Pro Ser Ser

115 120 125

Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser

130 135 140

Gln Asp Ile Arg Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys

145 150 155 160

Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Leu His Ser Gly Val

165 170 175

Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr

180 185 190

Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln

195 200 205

Gly Gln Thr Leu Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile

210 215 220

Lys Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro

225 230 235 240

Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

245 250 255

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

260 265 270

Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val

275 280 285

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

290 295 300

Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

305 310 315 320

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala

325 330 335

Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

340 345 350

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr

355 360 365

Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser

370 375 380

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

385 390 395 400

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

405 410 415

Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe

420 425 430

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

435 440 445

Ser Leu Ser Leu Ser Pro

450

<210> 129

<211> 110

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 129

Ile Leu Asn Val Glu Gln Ser Pro Gln Ser Leu His Val Gln Glu Gly

1 5 10 15

Asp Ser Thr Asn Phe Thr Cys Ser Phe Pro Val Lys Glu Phe Gln Asp

20 25 30

Leu His Trp Tyr Arg Lys Glu Thr Ala Lys Ser Pro Glu Phe Leu Phe

35 40 45

Tyr Phe Gly Pro Tyr Gly Lys Glu Lys Lys Lys Gly Arg Ile Ser Ala

50 55 60

Thr Leu Asn Thr Lys Glu Gly Tyr Ser Tyr Leu Tyr Ile Thr Asp Ser

65 70 75 80

Gln Pro Glu Asp Ser Ala Thr Tyr Leu Cys Ala Leu Tyr Asn Asn Asn

85 90 95

Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro

100 105 110

<210> 130

<211> 111

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 130

Gly Val Ile Gln Ser Pro Arg His Leu Val Thr Glu Met Gly Gln Glu

1 5 10 15

Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His Asn Ser Leu Phe Trp

20 25 30

Tyr Arg Glu Thr Pro Met Gln Gly Leu Glu Leu Leu Ile Tyr Phe Gln

35 40 45

Asn Thr Ala Val Ile Asp Asp Ser Gly Met Pro Glu Asp Arg Phe Ser

50 55 60

Ala Lys Met Pro Asn Ala Ser Phe Ser Thr Leu Lys Ile Gln Pro Ser

65 70 75 80

Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala Ser Ser Pro Gly Ala

85 90 95

Thr Asp Thr Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val Leu

100 105 110

<210> 131

<211> 470

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 131

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr

20 25 30

Thr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Ala Gln Lys Phe

50 55 60

Gln Asp Arg Val Thr Leu Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp

100 105 110

Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Ser Gly Gly

115 120 125

Gly Gly Gly Val Ile Gln Ser Pro Arg His Glu Val Thr Glu Met Gly

130 135 140

Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His Asn Ser Leu

145 150 155 160

Phe Trp Tyr Arg Glu Thr Pro Met Gln Gly Leu Glu Leu Leu Ile Tyr

165 170 175

Phe Gln Asn Thr Ala Val Ile Asp Asp Ser Gly Met Pro Glu Asp Arg

180 185 190

Phe Ser Ala Lys Met Pro Asn Asp Ser Phe Ser Thr Leu Lys Ile Gln

195 200 205

Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala Ser Ser Pro

210 215 220

Gly Ala Thr Asp Lys Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val

225 230 235 240

Leu Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro

245 250 255

Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

260 265 270

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

275 280 285

Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val

290 295 300

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

305 310 315 320

Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

325 330 335

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala

340 345 350

Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

355 360 365

Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr

370 375 380

Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser

385 390 395 400

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

405 410 415

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val

420 425 430

Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe

435 440 445

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

450 455 460

Ser Leu Ser Leu Ser Pro

465 470

<210> 132

<211> 110

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 132

Ile Leu Asn Val Glu Gln Ser Pro Gln Ser Leu His Val Gln Glu Gly

1 5 10 15

Asp Ser Thr Lys Phe Thr Cys Ser Phe Pro Val Lys Glu Phe Gln Asp

20 25 30

Leu His Trp Tyr Arg Lys Glu Thr Ala Lys Ser Pro Glu Phe Leu Phe

35 40 45

Tyr Phe Gly Pro Tyr Gly Lys Glu Lys Lys Lys Gly Arg Ile Ser Ala

50 55 60

Thr Leu Asn Thr Lys Glu Gly Tyr Ser Tyr Leu Tyr Ile Thr Asp Ser

65 70 75 80

Gln Pro Glu Asp Ser Ala Thr Tyr Leu Cys Ala Leu Tyr Asn Asn Tyr

85 90 95

Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro

100 105 110

<210> 133

<211> 470

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 133

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr

20 25 30

Thr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Ala Gln Lys Phe

50 55 60

Gln Asp Arg Val Thr Leu Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp

100 105 110

Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Ser Gly Gly

115 120 125

Gly Gly Gly Val Ile Gln Ser Pro Arg His Glu Val Thr Glu Met Gly

130 135 140

Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His Asn Ser Leu

145 150 155 160

Phe Trp Tyr Arg Glu Thr Met Met Gln Gly Leu Glu Leu Leu Ile Tyr

165 170 175

Phe Gln Asn Thr Ala Val Ile Asp Asp Ser Gly Met Pro Glu Asp Arg

180 185 190

Phe Ser Ala Lys Met Pro Asn Asp Ser Phe Ser Thr Leu Lys Ile Gln

195 200 205

Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala Ser Ser Pro

210 215 220

Gly Ala Thr Asp Leu Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val

225 230 235 240

Leu Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro

245 250 255

Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

260 265 270

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

275 280 285

Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val

290 295 300

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

305 310 315 320

Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

325 330 335

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala

340 345 350

Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

355 360 365

Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr

370 375 380

Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser

385 390 395 400

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

405 410 415

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val

420 425 430

Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe

435 440 445

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

450 455 460

Ser Leu Ser Leu Ser Pro

465 470

<210> 134

<211> 111

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 134

Gly Val Ile Gln Ser Pro Arg His Glu Val Thr Glu Met Gly Gln Glu

1 5 10 15

Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His Asn Ser Leu Phe Trp

20 25 30

Tyr Arg Glu Thr Pro Met Gln Gly Leu Glu Leu Leu Ile Tyr Phe Gln

35 40 45

Asn Thr Ala Val Ile Asp Asp Ser Gly Met Pro Glu Asp Arg Phe Ser

50 55 60

Ala Lys Met Pro Asn Asp Ser Phe Ser Thr Leu Lys Ile Gln Pro Ser

65 70 75 80

Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala Ser Ser Pro Gly Ala

85 90 95

Thr Asp Lys Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val Leu

100 105 110

<210> 135

<211> 111

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 135

Gly Val Ile Gln Ser Pro Arg His Glu Val Thr Glu Met Gly Gln Glu

1 5 10 15

Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His Asn Ser Leu Phe Trp

20 25 30

Tyr Arg Glu Thr Pro Met Gln Gly Leu Glu Leu Leu Ile Tyr Phe Gln

35 40 45

Asn Thr Ala Val Ile Asp Asp Ser Gly Met Pro Glu Asp Arg Phe Ser

50 55 60

Ala Lys Met Pro Asn Ala Ser Phe Ser Thr Leu Lys Ile Gln Pro Ser

65 70 75 80

Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala Ser Ser Pro Gly Ala

85 90 95

Thr Asp Lys Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val Leu

100 105 110

<210> 136

<211> 111

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 136

Gly Val Ile Gln Ser Pro Arg His Glu Val Thr Glu Met Gly Gln Glu

1 5 10 15

Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His Asn Ser Leu Phe Trp

20 25 30

Tyr Arg Glu Thr Pro Met Gln Gly Leu Glu Leu Leu Ile Tyr Phe Gln

35 40 45

Asn Thr Ala Val Ile Asp Asp Ser Gly Met Pro Glu Asp Arg Phe Ser

50 55 60

Ala Lys Met Pro Asn Asp Ser Phe Ser Thr Leu Lys Ile Gln Pro Ser

65 70 75 80

Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala Ser Ser Pro Gly Ser

85 90 95

Thr Asp Ala Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val Leu

100 105 110

<210> 137

<211> 110

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 137

Ile Leu Asn Val Glu Gln Ser Pro Gln Ser Leu His Val Gln Glu Gly

1 5 10 15

Asp Ser Thr Lys Phe Thr Cys Ser Phe Pro Val Lys Glu Phe Gln Asp

20 25 30

Leu His Trp Tyr Arg Lys Glu Thr Ala Lys Ser Pro Glu Phe Leu Phe

35 40 45

Tyr Phe Gly Pro Tyr Gly Lys Glu Lys Lys Lys Gly Arg Ile Ser Ala

50 55 60

Thr Leu Asn Thr Lys Glu Gly Tyr Ser Tyr Leu Tyr Ile Thr Asp Ser

65 70 75 80

Gln Pro Glu Asp Ser Ala Thr Tyr Leu Cys Ala Leu Tyr Asn Asn Leu

85 90 95

Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro

100 105 110

<210> 138

<211> 111

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 138

Gly Val Ile Gln Ser Pro Arg His Glu Val Thr Glu Met Gly Gln Glu

1 5 10 15

Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His Asn Ser Leu Phe Trp

20 25 30

Tyr Arg Glu Thr Pro Met Gln Gly Leu Glu Leu Leu Ile Tyr Phe Gln

35 40 45

Asn Thr Ala Val Ile Asp Asp Ser Gly Met Pro Glu Asp Arg Phe Ser

50 55 60

Ala Lys Met Pro Asn Asp Ser Phe Ser Thr Leu Lys Ile Gln Pro Ser

65 70 75 80

Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala Ser Ser Ala Gly Ala

85 90 95

Thr Asp Lys Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val Leu

100 105 110

<210> 139

<211> 111

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 139

Gly Val Ile Gln Ser Pro Arg His Glu Val Thr Glu Met Gly Gln Glu

1 5 10 15

Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His Asn Ser Leu Phe Trp

20 25 30

Tyr Arg Glu Thr Pro Met Gln Gly Leu Glu Leu Leu Ile Tyr Phe Gln

35 40 45

Asn Thr Ala Val Ile Asp Asp Ser Gly Met Pro Glu Asp Arg Phe Ser

50 55 60

Ala Lys Met Pro Asn Asp Ser Phe Ser Thr Leu Lys Ile Gln Pro Ser

65 70 75 80

Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala Ser Ser Pro Gly Ala

85 90 95

Ile Asp Lys Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val Leu

100 105 110

<210> 140

<211> 111

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 140

Gly Val Ile Gln Ser Pro Arg His Glu Val Thr Glu Met Gly Gln Glu

1 5 10 15

Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His Asn Ser Leu Phe Trp

20 25 30

Tyr Arg Glu Thr Pro Met Gln Gly Leu Glu Leu Leu Ile Tyr Phe Gln

35 40 45

Asn Thr Ala Val Ile Asp Asp Ser Gly Met Pro Glu Asp Arg Phe Ser

50 55 60

Ala Lys Met Pro Asn Asp Ser Phe Ser Thr Leu Lys Ile Gln Pro Ser

65 70 75 80

Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala Ser Ser Ala Gly Ser

85 90 95

Thr Asp Ala Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val Leu

100 105 110

<210> 141

<211> 111

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 141

Gly Val Ile Gln Ser Pro Arg His Glu Val Thr Glu Met Gly Gln Glu

1 5 10 15

Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His Asn Ser Leu Phe Trp

20 25 30

Tyr Arg Glu Thr Pro Met Gln Gly Leu Glu Leu Leu Ile Tyr Phe Gln

35 40 45

Asn Thr Ala Val Ile Asp Asp Ser Gly Met Pro Glu Asp Arg Phe Ser

50 55 60

Ala Lys Met Pro Asn Asp Ser Phe Ser Thr Leu Lys Ile Gln Pro Ser

65 70 75 80

Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala Ser Ser Pro Gly Ser

85 90 95

Ile Asp Ala Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val Leu

100 105 110

<210> 142

<211> 110

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 142

Ile Leu Asn Val Glu Gln Ser Pro Gln Ser Leu His Val Gln Glu Gly

1 5 10 15

Asp Ser Thr Lys Phe Thr Cys Ser Phe Pro Val Lys Glu Phe Gln Asp

20 25 30

Ile His Trp Tyr Arg Lys Glu Thr Ala Lys Ser Pro Glu Phe Leu Phe

35 40 45

Tyr Phe Gly Pro Tyr Gly Lys Glu Lys Lys Lys Gly Arg Ile Ser Ala

50 55 60

Thr Leu Asn Thr Lys Glu Gly Tyr Ser Tyr Leu Tyr Ile Thr Asp Ser

65 70 75 80

Gln Pro Glu Asp Ser Ala Thr Tyr Leu Cys Ala Leu Tyr Asn Asn Tyr

85 90 95

Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro

100 105 110

<210> 143

<211> 470

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 143

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr

20 25 30

Thr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Ala Gln Lys Phe

50 55 60

Gln Asp Arg Val Thr Leu Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp

100 105 110

Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Ser Gly Gly

115 120 125

Gly Gly Gly Val Ile Gln Ser Pro Arg His Glu Val Thr Glu Met Gly

130 135 140

Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His Asn Ser Leu

145 150 155 160

Phe Trp Tyr Arg Glu Thr Met Met Arg Gly Leu Glu Leu Leu Ile Tyr

165 170 175

Phe Gln Asn Thr Ala Val Ile Asp Asp Ser Gly Met Pro Glu Asp Arg

180 185 190

Phe Ser Ala Lys Met Pro Asn Asp Ser Phe Ser Thr Leu Lys Ile Gln

195 200 205

Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala Ser Ser Pro

210 215 220

Gly Ala Thr Asp Leu Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val

225 230 235 240

Leu Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro

245 250 255

Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

260 265 270

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

275 280 285

Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val

290 295 300

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

305 310 315 320

Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

325 330 335

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala

340 345 350

Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

355 360 365

Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr

370 375 380

Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser

385 390 395 400

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

405 410 415

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val

420 425 430

Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe

435 440 445

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

450 455 460

Ser Leu Ser Leu Ser Pro

465 470

<210> 144

<211> 111

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 144

Gly Val Ile Gln Ser Pro Arg His Glu Val Thr Glu Met Gly Gln Glu

1 5 10 15

Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His Asn Ser Leu Phe Trp

20 25 30

Tyr Arg Glu Thr Pro Met Gln Gly Leu Glu Leu Leu Ile Tyr Phe Gln

35 40 45

Asn Thr Ala Val Ile Asp Asp Ser Gly Met Pro Glu Asp Arg Phe Ser

50 55 60

Ala Lys Met Pro Asn Ala Ser Phe Ser Thr Leu Lys Ile Gln Pro Ser

65 70 75 80

Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala Ser Ser Ala Gly Ala

85 90 95

Thr Asp Lys Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val Leu

100 105 110

<210> 145

<211> 111

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 145

Gly Val Ile Gln Ser Pro Arg His Glu Val Thr Glu Met Gly Gln Glu

1 5 10 15

Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His Asn Ser Leu Phe Trp

20 25 30

Tyr Arg Glu Thr Pro Met Gln Gly Leu Glu Leu Leu Ile Tyr Phe Gln

35 40 45

Asn Thr Ala Val Ile Asp Asp Ser Gly Met Pro Glu Asp Arg Phe Ser

50 55 60

Ala Lys Met Pro Asn Ala Ser Phe Ser Thr Leu Lys Ile Gln Pro Ser

65 70 75 80

Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala Ser Ser Thr Gly Ala

85 90 95

Thr Asp Lys Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val Leu

100 105 110

<210> 146

<211> 111

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 146

Gly Val Ile Gln Ser Pro Arg His Glu Val Thr Glu Met Gly Gln Glu

1 5 10 15

Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His Asn Ser Leu Phe Trp

20 25 30

Tyr Arg Glu Thr Pro Met Gln Gly Leu Glu Leu Leu Ile Tyr Phe Gln

35 40 45

Asn Thr Ala Val Ile Asp Asp Ser Gly Met Pro Glu Asp Arg Phe Ser

50 55 60

Ala Lys Met Pro Asn Ala Ser Phe Ser Thr Leu Lys Ile Gln Pro Ser

65 70 75 80

Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala Ser Ser Pro Gly Ala

85 90 95

Ile Asp Lys Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val Leu

100 105 110

<210> 147

<211> 111

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 147

Gly Val Ile Gln Ser Pro Arg His Glu Val Thr Glu Met Gly Gln Glu

1 5 10 15

Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His Asn Ser Leu Phe Trp

20 25 30

Tyr Arg Glu Thr Pro Met Gln Gly Leu Glu Leu Leu Ile Tyr Phe Gln

35 40 45

Asn Thr Ala Val Ile Asp Asp Ser Gly Met Pro Glu Asp Arg Phe Ser

50 55 60

Ala Lys Met Pro Asn Ala Ser Phe Ser Thr Leu Lys Ile Gln Pro Ser

65 70 75 80

Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala Ser Ser Ala Gly Ala

85 90 95

Ile Asp Lys Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val Leu

100 105 110

<210> 148

<211> 111

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 148

Gly Val Ile Gln Ser Pro Arg His Glu Val Thr Glu Met Gly Gln Glu

1 5 10 15

Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His Asn Ser Leu Phe Trp

20 25 30

Tyr Arg Glu Thr Pro Met Gln Gly Leu Glu Leu Leu Ile Tyr Phe Gln

35 40 45

Asn Thr Ala Val Ile Asp Asp Ser Gly Met Pro Glu Asp Arg Phe Ser

50 55 60

Ala Lys Met Pro Asn Ala Ser Phe Ser Thr Leu Lys Ile Gln Pro Ser

65 70 75 80

Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala Ser Ser Thr Gly Ala

85 90 95

Ile Asp Lys Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val Leu

100 105 110

<210> 149

<211> 229

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 149

Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala

1 5 10 15

Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys

20 25 30

Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val

35 40 45

Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp

50 55 60

Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr

65 70 75 80

Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp

85 90 95

Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu

100 105 110

Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg

115 120 125

Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys

130 135 140

Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp

145 150 155 160

Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys

165 170 175

Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser

180 185 190

Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser

195 200 205

Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser

210 215 220

Leu Ser Leu Ser Pro

225

<210> 150

<211> 229

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 150

Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala

1 5 10 15

Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys

20 25 30

Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val

35 40 45

Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp

50 55 60

Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr

65 70 75 80

Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp

85 90 95

Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu

100 105 110

Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg

115 120 125

Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys

130 135 140

Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp

145 150 155 160

Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys

165 170 175

Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser

180 185 190

Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser

195 200 205

Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser

210 215 220

Leu Ser Leu Ser Pro

225

<210> 151

<211> 467

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 151

Ile Leu Asn Val Glu Gln Ser Pro Gln Ser Leu His Val Gln Glu Gly

1 5 10 15

Asp Ser Thr Lys Phe Thr Cys Ser Phe Pro Val Lys Glu Phe Gln Asp

20 25 30

Leu His Trp Tyr Arg Lys Glu Thr Ala Lys Ser Pro Glu Phe Leu Phe

35 40 45

Tyr Phe Gly Pro Tyr Gly Lys Glu Lys Lys Lys Gly Arg Ile Ser Ala

50 55 60

Thr Leu Asn Thr Lys Glu Gly Tyr Ser Tyr Leu Tyr Ile Thr Asp Ser

65 70 75 80

Gln Pro Glu Asp Ser Ala Thr Tyr Leu Cys Ala Leu Tyr Asn Asn Tyr

85 90 95

Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro Gly Gly

100 105 110

Gly Ser Gly Gly Gly Gly Glu Val Gln Leu Val Gln Ser Gly Ala Glu

115 120 125

Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly

130 135 140

Tyr Lys Phe Thr Arg Tyr Val Met His Trp Val Arg Gln Ala Pro Gly

145 150 155 160

Gln Gly Leu Glu Trp Met Gly Tyr Ile Asn Pro Tyr Asn Asp Val Thr

165 170 175

Lys Tyr Ala Glu Lys Phe Gln Gly Arg Val Thr Leu Thr Ser Asp Thr

180 185 190

Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp

195 200 205

Thr Ala Val Tyr Tyr Cys Ala Arg Gly Ser Tyr Tyr Asp Tyr Glu Gly

210 215 220

Phe Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Glu Pro

225 230 235 240

Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Pro

245 250 255

Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr

260 265 270

Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val

275 280 285

Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val

290 295 300

Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gln Ser

305 310 315 320

Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu

325 330 335

Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala

340 345 350

Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro

355 360 365

Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln

370 375 380

Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala

385 390 395 400

Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr

405 410 415

Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu

420 425 430

Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser

435 440 445

Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser

450 455 460

Leu Ser Pro

465

<210> 152

<211> 454

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 152

Gln Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Ser Ala Thr Ser Ser Val Ser Tyr Met

20 25 30

His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr

35 40 45

Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser

50 55 60

Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu

65 70 75 80

Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr

85 90 95

Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Ser Gly Gly

100 105 110

Gly Gly Gly Val Ile Gln Ser Pro Arg His Glu Val Thr Glu Met Gly

115 120 125

Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His Asn Ser Leu

130 135 140

Phe Trp Tyr Arg Glu Thr Pro Met Gln Gly Leu Glu Leu Leu Ile Tyr

145 150 155 160

Phe Gln Asn Thr Ala Val Ile Asp Asp Ser Gly Met Pro Glu Asp Arg

165 170 175

Phe Ser Ala Lys Met Pro Asn Asp Ser Phe Ser Thr Leu Lys Ile Gln

180 185 190

Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala Ser Ser Pro

195 200 205

Gly Ala Thr Asp Leu Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val

210 215 220

Leu Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro

225 230 235 240

Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

245 250 255

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

260 265 270

Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val

275 280 285

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

290 295 300

Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

305 310 315 320

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala

325 330 335

Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

340 345 350

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr

355 360 365

Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser

370 375 380

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

385 390 395 400

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

405 410 415

Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe

420 425 430

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

435 440 445

Ser Leu Ser Leu Ser Pro

450

<210> 153

<211> 479

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 153

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr

20 25 30

Thr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Ala Gln Lys Phe

50 55 60

Gln Asp Arg Val Thr Leu Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp

100 105 110

Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Ser Gly Gly

115 120 125

Gly Gly Lys Ala Gly Val Thr Gln Thr Pro Arg Tyr Leu Ile Lys Thr

130 135 140

Arg Gly Gln Gln Val Thr Leu Ser Cys Ser Pro Ile Pro Gly His Arg

145 150 155 160

Ala Val Ser Trp Tyr Gln Gln Thr Pro Gly Gln Gly Leu Gln Phe Leu

165 170 175

Phe Glu Tyr Val His Gly Glu Glu Arg Asn Lys Gly Asn Phe Pro Gly

180 185 190

Arg Phe Ser Gly Arg Gln Phe Ser Asn Ser Ser Ser Glu Met Asn Ile

195 200 205

Ser Asn Leu Glu Leu Gly Asp Ser Ala Leu Tyr Leu Cys Ala Ser Ser

210 215 220

Pro Trp Asp Ser Pro Asn Val Gln Tyr Phe Gly Pro Gly Thr Arg Leu

225 230 235 240

Thr Val Thr Glu Asp Leu Lys Asn Glu Pro Lys Ser Ser Asp Lys Thr

245 250 255

His Thr Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val

260 265 270

Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr

275 280 285

Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu

290 295 300

Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys

305 310 315 320

Thr Lys Pro Arg Glu Glu Gln Tyr Gln Ser Thr Tyr Arg Val Val Ser

325 330 335

Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys

340 345 350

Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser Ile Glu Lys Thr Ile

355 360 365

Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro

370 375 380

Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Ser Cys Ala

385 390 395 400

Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn

405 410 415

Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser

420 425 430

Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg

435 440 445

Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu

450 455 460

His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

465 470 475

<210> 154

<211> 463

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 154

Gln Lys Glu Val Glu Gln Asn Ser Gly Pro Leu Ser Val Pro Glu Gly

1 5 10 15

Ala Ile Ala Ser Leu Asn Cys Thr Tyr Ser Asp Arg Gly Ser Gln Ser

20 25 30

Phe Phe Trp Tyr Arg Gln Tyr Ser Gly Lys Ser Pro Glu Leu Ile Met

35 40 45

Ser Ile Tyr Ser Asn Gly Asp Lys Glu Asp Gly Arg Phe Thr Ala Gln

50 55 60

Leu Asn Lys Ala Ser Gln Tyr Val Ser Leu Leu Ile Arg Asp Ser Gln

65 70 75 80

Pro Ser Asp Ser Ala Thr Tyr Leu Cys Ala Ala Val Ile Asp Asn Asp

85 90 95

Gln Gly Gly Ile Leu Thr Phe Gly Thr Gly Thr Arg Leu Thr Ile Ile

100 105 110

Pro Asn Ile Gln Asn Gly Gly Gly Ser Gly Gly Gly Gly Asp Ile Gln

115 120 125

Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val

130 135 140

Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Arg Asn Tyr Leu Asn Trp

145 150 155 160

Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr

165 170 175

Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser

180 185 190

Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile

195 200 205

Ala Thr Tyr Phe Cys Gln Gln Gly Gln Thr Leu Pro Trp Thr Phe Gly

210 215 220

Gln Gly Thr Lys Val Glu Ile Lys Glu Pro Lys Ser Ser Asp Lys Thr

225 230 235 240

His Thr Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val

245 250 255

Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr

260 265 270

Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu

275 280 285

Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys

290 295 300

Thr Lys Pro Arg Glu Glu Gln Tyr Gln Ser Thr Tyr Arg Val Val Ser

305 310 315 320

Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys

325 330 335

Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser Ile Glu Lys Thr Ile

340 345 350

Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro

355 360 365

Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys Leu

370 375 380

Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn

385 390 395 400

Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser

405 410 415

Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg

420 425 430

Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu

435 440 445

His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

450 455 460

<210> 155

<211> 467

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 155

Ile Leu Asn Val Glu Gln Ser Pro Gln Ser Leu His Val Gln Glu Gly

1 5 10 15

Asp Ser Thr Asn Phe Thr Cys Ser Phe Pro Val Lys Glu Phe Gln Asp

20 25 30

Leu His Trp Tyr Arg Lys Glu Thr Ala Lys Ser Pro Glu Phe Leu Phe

35 40 45

Tyr Phe Gly Pro Tyr Gly Lys Glu Lys Lys Lys Gly Arg Ile Ser Ala

50 55 60

Thr Leu Asn Thr Lys Glu Gly Tyr Ser Tyr Leu Tyr Ile Thr Asp Ser

65 70 75 80

Gln Pro Glu Asp Ser Ala Thr Tyr Leu Cys Ala Leu Tyr Asn Asn Tyr

85 90 95

Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro Gly Gly

100 105 110

Gly Ser Gly Gly Gly Gly Glu Val Gln Leu Val Gln Ser Gly Ala Glu

115 120 125

Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly

130 135 140

Tyr Lys Phe Thr Ser Tyr Val Met His Trp Val Arg Gln Ala Pro Gly

145 150 155 160

Gln Gly Leu Glu Trp Met Gly Tyr Ile Asn Pro Tyr Asn Asp Val Thr

165 170 175

Lys Tyr Ala Glu Lys Phe Gln Gly Arg Val Thr Leu Thr Ser Asp Thr

180 185 190

Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp

195 200 205

Thr Ala Val His Tyr Cys Ala Arg Gly Ser Tyr Tyr Asp Tyr Glu Gly

210 215 220

Phe Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Glu Pro

225 230 235 240

Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Pro

245 250 255

Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr

260 265 270

Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val

275 280 285

Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val

290 295 300

Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gln Ser

305 310 315 320

Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu

325 330 335

Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala

340 345 350

Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro

355 360 365

Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln

370 375 380

Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala

385 390 395 400

Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr

405 410 415

Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu

420 425 430

Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser

435 440 445

Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser

450 455 460

Leu Ser Pro

465

<210> 156

<211> 467

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 156

Ile Leu Asn Val Glu Gln Ser Pro Gln Ser Leu His Val Gln Glu Gly

1 5 10 15

Asp Ser Thr Lys Phe Thr Cys Ser Phe Pro Val Lys Glu Phe Gln Asp

20 25 30

Leu His Trp Tyr Arg Lys Glu Thr Ala Lys Ser Pro Glu Phe Leu Phe

35 40 45

Tyr Phe Gly Pro Tyr Gly Lys Glu Lys Lys Lys Gly Arg Ile Ser Ala

50 55 60

Thr Leu Asn Thr Lys Glu Gly Tyr Ser Tyr Leu Tyr Ile Thr Asp Ser

65 70 75 80

Gln Pro Glu Asp Ser Ala Thr Tyr Leu Cys Ala Leu Tyr Asn Asn Leu

85 90 95

Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro Gly Gly

100 105 110

Gly Ser Gly Gly Gly Gly Glu Val Gln Leu Val Gln Ser Gly Ala Glu

115 120 125

Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly

130 135 140

Tyr Lys Phe Thr Ser Tyr Val Met His Trp Val Arg Gln Ala Pro Gly

145 150 155 160

Gln Gly Leu Glu Trp Met Gly Tyr Ile Asn Pro Arg Asn Asp Val Thr

165 170 175

Lys Tyr Ala Glu Lys Phe Gln Gly Arg Val Thr Leu Thr Ser Asp Thr

180 185 190

Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp

195 200 205

Thr Ala Val Tyr Tyr Cys Ala Arg Gly Ser Tyr Tyr Asp Tyr Glu Gly

210 215 220

Phe Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Glu Pro

225 230 235 240

Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Pro

245 250 255

Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr

260 265 270

Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val

275 280 285

Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val

290 295 300

Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gln Ser

305 310 315 320

Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu

325 330 335

Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala

340 345 350

Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro

355 360 365

Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln

370 375 380

Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala

385 390 395 400

Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr

405 410 415

Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu

420 425 430

Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser

435 440 445

Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser

450 455 460

Leu Ser Pro

465

<210> 157

<211> 467

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 157

Ile Leu Asn Val Glu Gln Ser Pro Gln Ser Leu His Val Gln Glu Gly

1 5 10 15

Asp Ser Thr Lys Phe Thr Cys Ser Phe Pro Val Lys Glu Phe Gln Asp

20 25 30

Leu His Trp Tyr Arg Lys Glu Thr Ala Lys Ser Pro Glu Phe Leu Phe

35 40 45

Tyr Phe Gly Pro Tyr Gly Lys Glu Lys Lys Lys Gly Arg Ile Ser Ala

50 55 60

Thr Leu Asn Thr Lys Glu Gly Tyr Ser Tyr Leu Tyr Ile Thr Asp Ser

65 70 75 80

Gln Pro Glu Asp Ser Ala Thr Tyr Leu Cys Ala Leu Tyr Asn Asn Asn

85 90 95

Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro Gly Gly

100 105 110

Gly Ser Gly Gly Gly Gly Glu Val Gln Leu Val Gln Ser Gly Ala Glu

115 120 125

Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly

130 135 140

Tyr Lys Phe Thr Ser Tyr Val Met His Trp Val Arg Gln Ala Pro Gly

145 150 155 160

Gln Gly Leu Glu Trp Met Gly Tyr Ile Asn Pro Tyr Asn Asp Val Thr

165 170 175

Lys Tyr Ala Glu Lys Phe Gln Gly Arg Val Thr Leu Thr Ser Asp Thr

180 185 190

Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp

195 200 205

Thr Ala Val His Tyr Cys Ala Arg Gly Ser Tyr Tyr Asp Tyr Glu Gly

210 215 220

Phe Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Glu Pro

225 230 235 240

Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Pro

245 250 255

Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr

260 265 270

Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val

275 280 285

Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val

290 295 300

Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gln Ser

305 310 315 320

Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu

325 330 335

Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala

340 345 350

Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro

355 360 365

Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln

370 375 380

Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala

385 390 395 400

Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr

405 410 415

Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu

420 425 430

Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser

435 440 445

Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser

450 455 460

Leu Ser Pro

465

<210> 158

<211> 467

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 158

Ile Leu Asn Val Glu Gln Ser Pro Gln Ser Leu His Val Gln Glu Gly

1 5 10 15

Asp Ser Thr Lys Phe Thr Cys Ser Phe Pro Val Lys Glu Phe Gln Asp

20 25 30

Leu His Trp Tyr Arg Lys Glu Thr Ala Lys Ser Pro Glu Phe Leu Phe

35 40 45

Tyr Phe Gly Pro Tyr Gly Lys Glu Lys Lys Lys Gly Arg Ile Ser Ala

50 55 60

Thr Leu Asn Thr Lys Glu Gly Tyr Ser Tyr Leu Tyr Ile Thr Asp Ser

65 70 75 80

Gln Pro Glu Asp Ser Ala Thr Tyr Leu Cys Ala Leu Tyr Asn Asn Tyr

85 90 95

Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro Gly Gly

100 105 110

Gly Ser Gly Gly Gly Gly Glu Val Gln Leu Val Gln Ser Gly Ala Glu

115 120 125

Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly

130 135 140

Tyr Lys Phe Thr Ser Tyr Val Met His Trp Val Arg Gln Ala Pro Gly

145 150 155 160

Gln Gly Leu Glu Trp Met Gly Tyr Ile Asn Pro Arg Asn Asp Val Thr

165 170 175

Lys Tyr Ala Glu Lys Phe Gln Gly Arg Val Thr Leu Thr Ser Asp Thr

180 185 190

Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp

195 200 205

Thr Ala Val Tyr Tyr Cys Ala Arg Gly Ser Tyr Tyr Asp Tyr Glu Gly

210 215 220

Phe Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Glu Pro

225 230 235 240

Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Pro

245 250 255

Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr

260 265 270

Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val

275 280 285

Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val

290 295 300

Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gln Ser

305 310 315 320

Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu

325 330 335

Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala

340 345 350

Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro

355 360 365

Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln

370 375 380

Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala

385 390 395 400

Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr

405 410 415

Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu

420 425 430

Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser

435 440 445

Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser

450 455 460

Leu Ser Pro

465

<210> 159

<211> 467

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 159

Ile Leu Asn Val Glu Gln Ser Pro Gln Ser Leu His Val Gln Glu Gly

1 5 10 15

Asp Ser Thr Lys Phe Thr Cys Ser Phe Pro Val Lys Glu Phe Gln Asp

20 25 30

Leu His Trp Tyr Arg Lys Glu Thr Ala Lys Ser Pro Glu Phe Leu Phe

35 40 45

Tyr Phe Gly Pro Tyr Gly Lys Glu Lys Lys Lys Gly Arg Ile Ser Ala

50 55 60

Thr Leu Asn Thr Lys Glu Gly Tyr Ser Tyr Leu Tyr Ile Thr Asp Ser

65 70 75 80

Gln Pro Glu Asp Ser Ala Thr Tyr Leu Cys Ala Leu Tyr Asn Asn Tyr

85 90 95

Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro Gly Gly

100 105 110

Gly Ser Gly Gly Gly Gly Glu Val Gln Leu Val Gln Ser Gly Ala Glu

115 120 125

Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly

130 135 140

Tyr Lys Phe Thr Ser Tyr Val Met His Trp Val Arg Gln Ala Pro Gly

145 150 155 160

Gln Gly Leu Glu Trp Met Gly Tyr Ile Asn Pro Tyr Asn Asp Val Thr

165 170 175

Lys Tyr Ala Glu Lys Phe Gln Gly Arg Val Thr Leu Thr Ser Asp Thr

180 185 190

Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp

195 200 205

Thr Ala Val His Tyr Cys Ala Arg Gly Ser Tyr Tyr Asp Tyr Glu Gly

210 215 220

Phe Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Glu Pro

225 230 235 240

Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Pro

245 250 255

Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr

260 265 270

Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val

275 280 285

Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val

290 295 300

Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gln Ser

305 310 315 320

Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu

325 330 335

Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala

340 345 350

Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro

355 360 365

Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln

370 375 380

Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala

385 390 395 400

Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr

405 410 415

Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu

420 425 430

Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser

435 440 445

Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser

450 455 460

Leu Ser Pro

465

<210> 160

<211> 454

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 160

Gln Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Ser Ala Thr Ser Ser Val Ser Tyr Met

20 25 30

His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr

35 40 45

Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser

50 55 60

Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu

65 70 75 80

Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr

85 90 95

Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Ser Gly Gly

100 105 110

Gly Gly Gly Val Ile Gln Ser Pro Arg His Glu Val Thr Glu Met Gly

115 120 125

Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His Asn Ser Leu

130 135 140

Phe Trp Tyr Arg Glu Thr Pro Met Gln Gly Leu Glu Leu Leu Ile Tyr

145 150 155 160

Phe Gln Asn Thr Ala Val Ile Asp Asp Ser Gly Met Pro Glu Asp Arg

165 170 175

Phe Ser Ala Lys Met Pro Asn Asp Ser Phe Ser Thr Leu Lys Ile Gln

180 185 190

Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala Ser Ser Pro

195 200 205

Gly Ala Thr Asp Lys Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val

210 215 220

Leu Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro

225 230 235 240

Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

245 250 255

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

260 265 270

Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val

275 280 285

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

290 295 300

Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

305 310 315 320

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala

325 330 335

Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

340 345 350

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr

355 360 365

Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser

370 375 380

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

385 390 395 400

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

405 410 415

Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe

420 425 430

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

435 440 445

Ser Leu Ser Leu Ser Pro

450

<210> 161

<211> 454

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 161

Gln Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Ser Ala Thr Ser Ser Val Ser Tyr Met

20 25 30

His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr

35 40 45

Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser

50 55 60

Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu

65 70 75 80

Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr

85 90 95

Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Ser Gly Gly

100 105 110

Gly Gly Gly Val Ile Gln Ser Pro Arg His Glu Val Thr Glu Met Gly

115 120 125

Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His Asn Ser Leu

130 135 140

Phe Trp Tyr Arg Glu Thr Pro Met Gln Gly Leu Glu Leu Leu Ile Tyr

145 150 155 160

Phe Gln Asn Thr Ala Val Ile Asp Asp Ser Gly Met Pro Glu Asp Arg

165 170 175

Phe Ser Ala Lys Met Pro Asn Asp Ser Phe Ser Thr Leu Lys Ile Gln

180 185 190

Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala Ser Ser Ala

195 200 205

Gly Ala Thr Asp Lys Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val

210 215 220

Leu Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro

225 230 235 240

Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

245 250 255

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

260 265 270

Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val

275 280 285

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

290 295 300

Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

305 310 315 320

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala

325 330 335

Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

340 345 350

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr

355 360 365

Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser

370 375 380

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

385 390 395 400

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

405 410 415

Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe

420 425 430

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

435 440 445

Ser Leu Ser Leu Ser Pro

450

<210> 162

<211> 454

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 162

Gln Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Ser Ala Thr Ser Ser Val Ser Tyr Met

20 25 30

His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr

35 40 45

Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser

50 55 60

Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu

65 70 75 80

Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr

85 90 95

Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Ser Gly Gly

100 105 110

Gly Gly Gly Val Ile Gln Ser Pro Arg His Glu Val Thr Glu Met Gly

115 120 125

Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His Asn Ser Leu

130 135 140

Phe Trp Tyr Arg Glu Thr Pro Met Gln Gly Leu Glu Leu Leu Ile Tyr

145 150 155 160

Phe Gln Asn Thr Ala Val Ile Asp Asp Ser Gly Met Pro Glu Asp Arg

165 170 175

Phe Ser Ala Lys Met Pro Asn Asp Ser Phe Ser Thr Leu Lys Ile Gln

180 185 190

Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala Ser Ser Pro

195 200 205

Gly Ala Thr Asp Lys Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val

210 215 220

Leu Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro

225 230 235 240

Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

245 250 255

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

260 265 270

Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val

275 280 285

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

290 295 300

Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

305 310 315 320

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala

325 330 335

Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

340 345 350

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr

355 360 365

Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser

370 375 380

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

385 390 395 400

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

405 410 415

Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe

420 425 430

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

435 440 445

Ser Leu Ser Leu Ser Pro

450

<210> 163

<211> 454

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 163

Gln Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Ser Ala Thr Ser Ser Val Ser Tyr Met

20 25 30

His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr

35 40 45

Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser

50 55 60

Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu

65 70 75 80

Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr

85 90 95

Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Ser Gly Gly

100 105 110

Gly Gly Gly Val Ile Gln Ser Pro Arg His Glu Val Thr Glu Met Gly

115 120 125

Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His Asn Ser Leu

130 135 140

Phe Trp Tyr Arg Glu Thr Pro Met Gln Gly Leu Glu Leu Leu Ile Tyr

145 150 155 160

Phe Gln Asn Thr Ala Val Ile Asp Asp Ser Gly Met Pro Glu Asp Arg

165 170 175

Phe Ser Ala Lys Met Pro Asn Asp Ser Phe Ser Thr Leu Lys Ile Gln

180 185 190

Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala Ser Ser Pro

195 200 205

Gly Ala Ile Asp Lys Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val

210 215 220

Leu Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro

225 230 235 240

Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

245 250 255

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

260 265 270

Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val

275 280 285

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

290 295 300

Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

305 310 315 320

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala

325 330 335

Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

340 345 350

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr

355 360 365

Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser

370 375 380

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

385 390 395 400

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

405 410 415

Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe

420 425 430

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

435 440 445

Ser Leu Ser Leu Ser Pro

450

<210> 164

<211> 454

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 164

Gln Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Ser Ala Thr Ser Ser Val Ser Tyr Met

20 25 30

His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr

35 40 45

Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser

50 55 60

Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu

65 70 75 80

Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr

85 90 95

Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Ser Gly Gly

100 105 110

Gly Gly Gly Val Ile Gln Ser Pro Arg His Glu Val Thr Glu Met Gly

115 120 125

Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His Asn Ser Leu

130 135 140

Phe Trp Tyr Arg Glu Thr Pro Met Gln Gly Leu Glu Leu Leu Ile Tyr

145 150 155 160

Phe Gln Asn Thr Ala Val Ile Asp Asp Ser Gly Met Pro Glu Asp Arg

165 170 175

Phe Ser Ala Lys Met Pro Asn Asp Ser Phe Ser Thr Leu Lys Ile Gln

180 185 190

Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala Ser Ser Ala

195 200 205

Gly Ser Thr Asp Ala Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val

210 215 220

Leu Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro

225 230 235 240

Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

245 250 255

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

260 265 270

Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val

275 280 285

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

290 295 300

Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

305 310 315 320

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala

325 330 335

Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

340 345 350

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr

355 360 365

Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser

370 375 380

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

385 390 395 400

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

405 410 415

Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe

420 425 430

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

435 440 445

Ser Leu Ser Leu Ser Pro

450

<210> 165

<211> 454

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 165

Gln Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Ser Ala Thr Ser Ser Val Ser Tyr Met

20 25 30

His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr

35 40 45

Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser

50 55 60

Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu

65 70 75 80

Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr

85 90 95

Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Ser Gly Gly

100 105 110

Gly Gly Gly Val Ile Gln Ser Pro Arg His Glu Val Thr Glu Met Gly

115 120 125

Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His Asn Ser Leu

130 135 140

Phe Trp Tyr Arg Glu Thr Pro Met Gln Gly Leu Glu Leu Leu Ile Tyr

145 150 155 160

Phe Gln Asn Thr Ala Val Ile Asp Asp Ser Gly Met Pro Glu Asp Arg

165 170 175

Phe Ser Ala Lys Met Pro Asn Asp Ser Phe Ser Thr Leu Lys Ile Gln

180 185 190

Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala Ser Ser Pro

195 200 205

Gly Ser Ile Asp Ala Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val

210 215 220

Leu Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro

225 230 235 240

Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

245 250 255

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

260 265 270

Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val

275 280 285

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

290 295 300

Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

305 310 315 320

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala

325 330 335

Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

340 345 350

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr

355 360 365

Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser

370 375 380

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

385 390 395 400

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

405 410 415

Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe

420 425 430

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

435 440 445

Ser Leu Ser Leu Ser Pro

450

<210> 166

<211> 467

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 166

Ile Leu Asn Val Glu Gln Ser Pro Gln Ser Leu His Val Gln Glu Gly

1 5 10 15

Asp Ser Thr Lys Phe Thr Cys Ser Phe Pro Val Lys Glu Phe Gln Asp

20 25 30

Ile His Trp Tyr Arg Lys Glu Thr Ala Lys Ser Pro Glu Phe Leu Phe

35 40 45

Tyr Phe Gly Pro Tyr Gly Lys Glu Lys Lys Lys Gly Arg Ile Ser Ala

50 55 60

Thr Leu Asn Thr Lys Glu Gly Tyr Ser Tyr Leu Tyr Ile Thr Asp Ser

65 70 75 80

Gln Pro Glu Asp Ser Ala Thr Tyr Leu Cys Ala Leu Tyr Asn Asn Tyr

85 90 95

Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro Gly Gly

100 105 110

Gly Ser Gly Gly Gly Gly Glu Val Gln Leu Val Gln Ser Gly Ala Glu

115 120 125

Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly

130 135 140

Tyr Lys Phe Thr Ser Tyr Val Met His Trp Val Arg Gln Ala Pro Gly

145 150 155 160

Gln Gly Leu Glu Trp Met Gly Tyr Ile Asn Pro Arg Asn Asp Val Thr

165 170 175

Lys Tyr Ala Glu Lys Phe Gln Gly Arg Val Thr Leu Thr Ser Asp Thr

180 185 190

Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp

195 200 205

Thr Ala Val His Tyr Cys Ala Arg Gly Ser Tyr Tyr Asp Tyr Glu Gly

210 215 220

Phe Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Glu Pro

225 230 235 240

Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Pro

245 250 255

Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr

260 265 270

Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val

275 280 285

Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val

290 295 300

Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gln Ser

305 310 315 320

Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu

325 330 335

Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala

340 345 350

Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro

355 360 365

Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln

370 375 380

Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala

385 390 395 400

Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr

405 410 415

Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu

420 425 430

Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser

435 440 445

Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser

450 455 460

Leu Ser Pro

465

<210> 167

<211> 467

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 167

Ile Leu Asn Val Glu Gln Ser Pro Gln Ser Leu His Val Gln Glu Gly

1 5 10 15

Asp Ser Thr Lys Phe Thr Cys Ser Phe Pro Val Lys Glu Phe Gln Asp

20 25 30

Leu His Trp Tyr Arg Lys Glu Thr Ala Lys Ser Pro Glu Phe Leu Phe

35 40 45

Tyr Phe Gly Pro Tyr Gly Lys Glu Lys Lys Lys Gly Arg Ile Ser Ala

50 55 60

Thr Leu Asn Thr Lys Glu Gly Tyr Ser Tyr Leu Tyr Ile Thr Asp Ser

65 70 75 80

Gln Pro Glu Asp Ser Ala Thr Tyr Leu Cys Ala Leu Tyr Asn Asn Tyr

85 90 95

Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro Gly Gly

100 105 110

Gly Ser Gly Gly Gly Gly Glu Val Gln Leu Val Gln Ser Gly Ala Glu

115 120 125

Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly

130 135 140

Tyr Lys Phe Thr Ser Tyr Val Met His Trp Val Arg Gln Ala Pro Gly

145 150 155 160

Gln Gly Leu Glu Trp Met Gly Tyr Ile Asn Pro Tyr Asn Asp Val Thr

165 170 175

Lys Tyr Ala Glu Lys Phe Gln Gly Arg Val Thr Leu Thr Ser Asp Thr

180 185 190

Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp

195 200 205

Thr Ala Val His Tyr Cys Ala Arg Gly Ser Tyr Tyr Asp Tyr Glu Gly

210 215 220

Phe Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Glu Pro

225 230 235 240

Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Pro

245 250 255

Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr

260 265 270

Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val

275 280 285

Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val

290 295 300

Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gln Ser

305 310 315 320

Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu

325 330 335

Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala

340 345 350

Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro

355 360 365

Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln

370 375 380

Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala

385 390 395 400

Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr

405 410 415

Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu

420 425 430

Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser

435 440 445

Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser

450 455 460

Leu Ser Pro

465

<210> 168

<211> 454

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 168

Gln Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Ser Ala Thr Ser Ser Val Ser Tyr Met

20 25 30

His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr

35 40 45

Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser

50 55 60

Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu

65 70 75 80

Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr

85 90 95

Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Ser Gly Gly

100 105 110

Gly Gly Gly Val Ile Gln Ser Pro Arg His Glu Val Thr Glu Met Gly

115 120 125

Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His Asn Ser Leu

130 135 140

Phe Trp Tyr Arg Glu Thr Met Met Arg Gly Leu Glu Leu Leu Ile Tyr

145 150 155 160

Phe Gln Asn Thr Ala Val Ile Asp Asp Ser Gly Met Pro Glu Asp Arg

165 170 175

Phe Ser Ala Lys Met Pro Asn Asp Ser Phe Ser Thr Leu Lys Ile Gln

180 185 190

Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala Ser Ser Pro

195 200 205

Gly Ala Thr Asp Lys Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val

210 215 220

Leu Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro

225 230 235 240

Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

245 250 255

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

260 265 270

Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val

275 280 285

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

290 295 300

Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

305 310 315 320

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala

325 330 335

Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

340 345 350

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr

355 360 365

Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser

370 375 380

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

385 390 395 400

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

405 410 415

Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe

420 425 430

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

435 440 445

Ser Leu Ser Leu Ser Pro

450

<210> 169

<211> 467

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 169

Ile Leu Asn Val Glu Gln Ser Pro Gln Ser Leu His Val Gln Glu Gly

1 5 10 15

Asp Ser Thr Asn Phe Thr Cys Ser Phe Pro Val Lys Glu Phe Gln Asp

20 25 30

Leu His Trp Tyr Arg Lys Glu Thr Ala Lys Ser Pro Glu Phe Leu Phe

35 40 45

Tyr Phe Gly Pro Tyr Gly Lys Glu Lys Lys Lys Gly Arg Ile Ser Ala

50 55 60

Thr Leu Asn Thr Lys Glu Gly Tyr Ser Tyr Leu Tyr Ile Thr Asp Ser

65 70 75 80

Gln Pro Glu Asp Ser Ala Thr Tyr Leu Cys Ala Leu Tyr Asn Asn Asn

85 90 95

Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro Gly Gly

100 105 110

Gly Ser Gly Gly Gly Gly Glu Val Gln Leu Val Gln Ser Gly Ala Glu

115 120 125

Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly

130 135 140

Tyr Lys Phe Thr Ser Tyr Val Met His Trp Val Arg Gln Ala Pro Gly

145 150 155 160

Gln Gly Leu Glu Trp Met Gly Tyr Ile Asn Pro Tyr Asn Asp Val Thr

165 170 175

Lys Tyr Ala Glu Lys Phe Gln Gly Arg Val Thr Leu Thr Ser Asp Thr

180 185 190

Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp

195 200 205

Thr Ala Val His Tyr Cys Ala Arg Gly Ser Tyr Tyr Asp Tyr Glu Gly

210 215 220

Phe Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Glu Pro

225 230 235 240

Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Pro

245 250 255

Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr

260 265 270

Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val

275 280 285

Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val

290 295 300

Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gln Ser

305 310 315 320

Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu

325 330 335

Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala

340 345 350

Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro

355 360 365

Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln

370 375 380

Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala

385 390 395 400

Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr

405 410 415

Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu

420 425 430

Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser

435 440 445

Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser

450 455 460

Leu Ser Pro

465

<210> 170

<211> 454

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 170

Gln Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Ser Ala Thr Ser Ser Val Ser Tyr Met

20 25 30

His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr

35 40 45

Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser

50 55 60

Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu

65 70 75 80

Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr

85 90 95

Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Ser Gly Gly

100 105 110

Gly Gly Gly Val Ile Gln Ser Pro Arg His Glu Val Thr Glu Met Gly

115 120 125

Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His Asn Ser Leu

130 135 140

Phe Trp Tyr Arg Glu Thr Pro Met Gln Gly Leu Glu Leu Leu Ile Tyr

145 150 155 160

Phe Gln Asn Thr Ala Val Ile Asp Asp Ser Gly Met Pro Glu Asp Arg

165 170 175

Phe Ser Ala Lys Met Pro Asn Ala Ser Phe Ser Thr Leu Lys Ile Gln

180 185 190

Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala Ser Ser Ala

195 200 205

Gly Ala Thr Asp Lys Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val

210 215 220

Leu Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro

225 230 235 240

Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

245 250 255

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

260 265 270

Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val

275 280 285

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

290 295 300

Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

305 310 315 320

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala

325 330 335

Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

340 345 350

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr

355 360 365

Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser

370 375 380

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

385 390 395 400

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

405 410 415

Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe

420 425 430

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

435 440 445

Ser Leu Ser Leu Ser Pro

450

<210> 171

<211> 467

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 171

Ile Leu Asn Val Glu Gln Ser Pro Gln Ser Leu His Val Gln Glu Gly

1 5 10 15

Asp Ser Thr Asn Phe Thr Cys Ser Phe Pro Val Lys Glu Phe Gln Asp

20 25 30

Leu His Trp Tyr Arg Lys Glu Thr Ala Lys Ser Pro Glu Phe Leu Phe

35 40 45

Tyr Phe Gly Pro Tyr Gly Lys Glu Lys Lys Lys Gly Arg Ile Ser Ala

50 55 60

Thr Leu Asn Thr Lys Glu Gly Tyr Ser Tyr Leu Tyr Ile Thr Asp Ser

65 70 75 80

Gln Pro Glu Asp Ser Ala Thr Tyr Leu Cys Ala Leu Tyr Asn Asn Tyr

85 90 95

Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro Gly Gly

100 105 110

Gly Ser Gly Gly Gly Gly Glu Val Gln Leu Val Gln Ser Gly Ala Glu

115 120 125

Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly

130 135 140

Tyr Lys Phe Thr Ser Tyr Val Met His Trp Val Arg Gln Ala Pro Gly

145 150 155 160

Gln Gly Leu Glu Trp Met Gly Tyr Ile Asn Pro Tyr Asn Asp Val Thr

165 170 175

Lys Tyr Ala Glu Lys Phe Gln Gly Arg Val Thr Leu Thr Ser Asp Thr

180 185 190

Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp

195 200 205

Thr Ala Val His Tyr Cys Ala Arg Gly Ser Tyr Tyr Asp Tyr Glu Gly

210 215 220

Phe Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Glu Pro

225 230 235 240

Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Pro

245 250 255

Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr

260 265 270

Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val

275 280 285

Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val

290 295 300

Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gln Ser

305 310 315 320

Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu

325 330 335

Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala

340 345 350

Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro

355 360 365

Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln

370 375 380

Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala

385 390 395 400

Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr

405 410 415

Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu

420 425 430

Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser

435 440 445

Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser

450 455 460

Leu Ser Pro

465

<210> 172

<211> 454

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 172

Gln Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Ser Ala Thr Ser Ser Val Ser Tyr Met

20 25 30

His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr

35 40 45

Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser

50 55 60

Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu

65 70 75 80

Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr

85 90 95

Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Ser Gly Gly

100 105 110

Gly Gly Gly Val Ile Gln Ser Pro Arg His Glu Val Thr Glu Met Gly

115 120 125

Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His Asn Ser Leu

130 135 140

Phe Trp Tyr Arg Glu Thr Pro Met Gln Gly Leu Glu Leu Leu Ile Tyr

145 150 155 160

Phe Gln Asn Thr Ala Val Ile Asp Asp Ser Gly Met Pro Glu Asp Arg

165 170 175

Phe Ser Ala Lys Met Pro Asn Ala Ser Phe Ser Thr Leu Lys Ile Gln

180 185 190

Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala Ser Ser Thr

195 200 205

Gly Ala Thr Asp Lys Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val

210 215 220

Leu Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro

225 230 235 240

Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

245 250 255

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

260 265 270

Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val

275 280 285

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

290 295 300

Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

305 310 315 320

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala

325 330 335

Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

340 345 350

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr

355 360 365

Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser

370 375 380

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

385 390 395 400

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

405 410 415

Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe

420 425 430

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

435 440 445

Ser Leu Ser Leu Ser Pro

450

<210> 173

<211> 467

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 173

Ile Leu Asn Val Glu Gln Ser Pro Gln Ser Leu His Val Gln Glu Gly

1 5 10 15

Asp Ser Thr Lys Phe Thr Cys Ser Phe Pro Val Lys Glu Phe Gln Asp

20 25 30

Leu His Trp Tyr Arg Lys Glu Thr Ala Lys Ser Pro Glu Phe Leu Phe

35 40 45

Tyr Phe Gly Pro Tyr Gly Lys Glu Lys Lys Lys Gly Arg Ile Ser Ala

50 55 60

Thr Leu Asn Thr Lys Glu Gly Tyr Ser Tyr Leu Tyr Ile Thr Asp Ser

65 70 75 80

Gln Pro Glu Asp Ser Ala Thr Tyr Leu Cys Ala Leu Tyr Asn Asn Asn

85 90 95

Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro Gly Gly

100 105 110

Gly Ser Gly Gly Gly Gly Glu Val Gln Leu Val Gln Ser Gly Ala Glu

115 120 125

Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly

130 135 140

Tyr Lys Phe Thr Ser Tyr Val Met His Trp Val Arg Gln Ala Pro Gly

145 150 155 160

Gln Gly Leu Glu Trp Met Gly Tyr Ile Asn Pro Tyr Asn Asp Val Thr

165 170 175

Lys Tyr Ala Glu Lys Phe Gln Gly Arg Val Thr Leu Thr Ser Asp Thr

180 185 190

Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp

195 200 205

Thr Ala Val His Tyr Cys Ala Arg Gly Ser Tyr Tyr Asp Tyr Glu Gly

210 215 220

Phe Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Glu Pro

225 230 235 240

Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Pro

245 250 255

Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr

260 265 270

Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val

275 280 285

Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val

290 295 300

Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gln Ser

305 310 315 320

Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu

325 330 335

Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala

340 345 350

Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro

355 360 365

Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln

370 375 380

Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala

385 390 395 400

Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr

405 410 415

Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu

420 425 430

Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser

435 440 445

Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser

450 455 460

Leu Ser Pro

465

<210> 174

<211> 454

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 174

Gln Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Ser Ala Thr Ser Ser Val Ser Tyr Met

20 25 30

His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr

35 40 45

Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser

50 55 60

Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu

65 70 75 80

Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr

85 90 95

Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Ser Gly Gly

100 105 110

Gly Gly Gly Val Ile Gln Ser Pro Arg His Glu Val Thr Glu Met Gly

115 120 125

Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His Asn Ser Leu

130 135 140

Phe Trp Tyr Arg Glu Thr Pro Met Gln Gly Leu Glu Leu Leu Ile Tyr

145 150 155 160

Phe Gln Asn Thr Ala Val Ile Asp Asp Ser Gly Met Pro Glu Asp Arg

165 170 175

Phe Ser Ala Lys Met Pro Asn Ala Ser Phe Ser Thr Leu Lys Ile Gln

180 185 190

Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala Ser Ser Pro

195 200 205

Gly Ala Ile Asp Lys Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val

210 215 220

Leu Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro

225 230 235 240

Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

245 250 255

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

260 265 270

Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val

275 280 285

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

290 295 300

Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

305 310 315 320

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala

325 330 335

Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

340 345 350

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr

355 360 365

Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser

370 375 380

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

385 390 395 400

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

405 410 415

Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe

420 425 430

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

435 440 445

Ser Leu Ser Leu Ser Pro

450

<210> 175

<211> 472

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 175

Ile Leu Asn Val Glu Gln Ser Pro Gln Ser Leu His Val Gln Glu Gly

1 5 10 15

Asp Ser Thr Lys Phe Thr Cys Ser Phe Pro Val Lys Glu Phe Gln Asp

20 25 30

Leu His Trp Tyr Arg Lys Glu Thr Ala Lys Ser Pro Glu Phe Leu Phe

35 40 45

Tyr Phe Gly Pro Tyr Gly Lys Glu Lys Lys Lys Gly Arg Ile Ser Ala

50 55 60

Thr Leu Asn Thr Lys Glu Gly Tyr Ser Tyr Leu Tyr Ile Thr Asp Ser

65 70 75 80

Gln Pro Glu Asp Ser Ala Thr Tyr Leu Cys Ala Leu Tyr Asn Asn Tyr

85 90 95

Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro Gly Gly

100 105 110

Gly Ser Gly Gly Gly Gly Glu Val Gln Leu Val Glu Ser Gly Gly Gly

115 120 125

Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly

130 135 140

Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly

145 150 155 160

Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr

165 170 175

Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg

180 185 190

Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr

195 200 205

Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe Gly Asp

210 215 220

Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr

225 230 235 240

Val Ser Ser Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro

245 250 255

Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro

260 265 270

Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys

275 280 285

Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp

290 295 300

Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu

305 310 315 320

Glu Gln Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu

325 330 335

His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn

340 345 350

Lys Ala Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly

355 360 365

Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu

370 375 380

Leu Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr

385 390 395 400

Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn

405 410 415

Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe

420 425 430

Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn

435 440 445

Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr

450 455 460

Gln Lys Ser Leu Ser Leu Ser Pro

465 470

<210> 176

<211> 457

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 176

Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly

1 5 10 15

Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser Gly

20 25 30

Tyr Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly

35 40 45

Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro Ala Arg Phe

50 55 60

Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val

65 70 75 80

Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Ala Leu Trp Tyr Ser Asn

85 90 95

Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly Gly

100 105 110

Ser Gly Gly Gly Gly Gly Val Ile Gln Ser Pro Arg His Glu Val Thr

115 120 125

Glu Met Gly Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His

130 135 140

Asn Ser Leu Phe Trp Tyr Arg Glu Thr Pro Met Gln Gly Leu Glu Leu

145 150 155 160

Leu Ile Tyr Phe Gln Asn Thr Ala Val Ile Asp Asp Ser Gly Met Pro

165 170 175

Glu Asp Arg Phe Ser Ala Lys Met Pro Asn Asp Ser Phe Ser Thr Leu

180 185 190

Lys Ile Gln Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala

195 200 205

Ser Ser Pro Gly Ala Thr Asp Lys Gln Tyr Phe Gly Pro Gly Thr Arg

210 215 220

Leu Thr Val Leu Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro

225 230 235 240

Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro

245 250 255

Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr

260 265 270

Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn

275 280 285

Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg

290 295 300

Glu Glu Gln Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val

305 310 315 320

Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser

325 330 335

Asn Lys Ala Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys

340 345 350

Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp

355 360 365

Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe

370 375 380

Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu

385 390 395 400

Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe

405 410 415

Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly

420 425 430

Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr

435 440 445

Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455

<210> 177

<211> 472

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 177

Ile Leu Asn Val Glu Gln Ser Pro Gln Ser Leu His Val Gln Glu Gly

1 5 10 15

Asp Ser Thr Asn Phe Thr Cys Ser Phe Pro Val Lys Glu Phe Gln Asp

20 25 30

Leu His Trp Tyr Arg Lys Glu Thr Ala Lys Ser Pro Glu Phe Leu Phe

35 40 45

Tyr Phe Gly Pro Tyr Gly Lys Glu Lys Lys Lys Gly Arg Ile Ser Ala

50 55 60

Thr Leu Asn Thr Lys Glu Gly Tyr Ser Tyr Leu Tyr Ile Thr Asp Ser

65 70 75 80

Gln Pro Glu Asp Ser Ala Thr Tyr Leu Cys Ala Leu Tyr Asn Asn Asn

85 90 95

Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro Gly Gly

100 105 110

Gly Ser Gly Gly Gly Gly Glu Val Gln Leu Val Glu Ser Gly Gly Gly

115 120 125

Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly

130 135 140

Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly

145 150 155 160

Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr

165 170 175

Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg

180 185 190

Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr

195 200 205

Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe Gly Asn

210 215 220

Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr

225 230 235 240

Val Ser Ser Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro

245 250 255

Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro

260 265 270

Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys

275 280 285

Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp

290 295 300

Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu

305 310 315 320

Glu Gln Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu

325 330 335

His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn

340 345 350

Lys Ala Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly

355 360 365

Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu

370 375 380

Leu Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr

385 390 395 400

Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn

405 410 415

Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe

420 425 430

Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn

435 440 445

Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr

450 455 460

Gln Lys Ser Leu Ser Leu Ser Pro

465 470

<210> 178

<211> 472

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 178

Ile Leu Asn Val Glu Gln Ser Pro Gln Ser Leu His Val Gln Glu Gly

1 5 10 15

Asp Ser Thr Lys Phe Thr Cys Ser Phe Pro Val Lys Glu Phe Gln Asp

20 25 30

Leu His Trp Tyr Arg Lys Glu Thr Ala Lys Ser Pro Glu Phe Leu Phe

35 40 45

Tyr Phe Gly Pro Tyr Gly Lys Glu Lys Lys Lys Gly Arg Ile Ser Ala

50 55 60

Thr Leu Asn Thr Lys Glu Gly Tyr Ser Tyr Leu Tyr Ile Thr Asp Ser

65 70 75 80

Gln Pro Glu Asp Ser Ala Thr Tyr Leu Cys Ala Leu Tyr Asn Asn Tyr

85 90 95

Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro Gly Gly

100 105 110

Gly Ser Gly Gly Gly Gly Glu Val Gln Leu Val Glu Ser Gly Gly Gly

115 120 125

Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly

130 135 140

Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly

145 150 155 160

Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr

165 170 175

Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg

180 185 190

Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr

195 200 205

Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe Gly Glu

210 215 220

Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr

225 230 235 240

Val Ser Ser Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro

245 250 255

Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro

260 265 270

Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys

275 280 285

Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp

290 295 300

Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu

305 310 315 320

Glu Gln Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu

325 330 335

His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn

340 345 350

Lys Ala Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly

355 360 365

Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu

370 375 380

Leu Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr

385 390 395 400

Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn

405 410 415

Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe

420 425 430

Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn

435 440 445

Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr

450 455 460

Gln Lys Ser Leu Ser Leu Ser Pro

465 470

<210> 179

<211> 472

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 179

Ile Leu Asn Val Glu Gln Ser Pro Gln Ser Leu His Val Gln Glu Gly

1 5 10 15

Asp Ser Thr Asn Phe Thr Cys Ser Phe Pro Val Lys Glu Phe Gln Asp

20 25 30

Leu His Trp Tyr Arg Lys Glu Thr Ala Lys Ser Pro Glu Phe Leu Phe

35 40 45

Tyr Phe Gly Pro Tyr Gly Lys Glu Lys Lys Lys Gly Arg Ile Ser Ala

50 55 60

Thr Leu Asn Thr Lys Glu Gly Tyr Ser Tyr Leu Tyr Ile Thr Asp Ser

65 70 75 80

Gln Pro Glu Asp Ser Ala Thr Tyr Leu Cys Ala Leu Tyr Asn Asn Tyr

85 90 95

Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro Gly Gly

100 105 110

Gly Ser Gly Gly Gly Gly Glu Val Gln Leu Val Glu Ser Gly Gly Gly

115 120 125

Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly

130 135 140

Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly

145 150 155 160

Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr

165 170 175

Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg

180 185 190

Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr

195 200 205

Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe Gly Asn

210 215 220

Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr

225 230 235 240

Val Ser Ser Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro

245 250 255

Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro

260 265 270

Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys

275 280 285

Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp

290 295 300

Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu

305 310 315 320

Glu Gln Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu

325 330 335

His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn

340 345 350

Lys Ala Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly

355 360 365

Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu

370 375 380

Leu Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr

385 390 395 400

Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn

405 410 415

Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe

420 425 430

Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn

435 440 445

Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr

450 455 460

Gln Lys Ser Leu Ser Leu Ser Pro

465 470

<210> 180

<211> 472

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 180

Ile Leu Asn Val Glu Gln Ser Pro Gln Ser Leu His Val Gln Glu Gly

1 5 10 15

Asp Ser Thr Lys Phe Thr Cys Ser Phe Pro Val Lys Glu Phe Gln Asp

20 25 30

Leu His Trp Tyr Arg Lys Glu Thr Ala Lys Ser Pro Glu Phe Leu Phe

35 40 45

Tyr Phe Gly Pro Tyr Gly Lys Glu Lys Lys Lys Gly Arg Ile Ser Ala

50 55 60

Thr Leu Asn Thr Lys Glu Gly Tyr Ser Tyr Leu Tyr Ile Thr Asp Ser

65 70 75 80

Gln Pro Glu Asp Ser Ala Thr Tyr Leu Cys Ala Leu Tyr Asn Asn Tyr

85 90 95

Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro Gly Gly

100 105 110

Gly Ser Gly Gly Gly Gly Glu Val Gln Leu Val Glu Ser Gly Gly Gly

115 120 125

Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly

130 135 140

Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly

145 150 155 160

Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr

165 170 175

Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg

180 185 190

Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr

195 200 205

Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe Gly Asn

210 215 220

Ala Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr

225 230 235 240

Val Ser Ser Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro

245 250 255

Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro

260 265 270

Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys

275 280 285

Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp

290 295 300

Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu

305 310 315 320

Glu Gln Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu

325 330 335

His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn

340 345 350

Lys Ala Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly

355 360 365

Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu

370 375 380

Leu Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr

385 390 395 400

Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn

405 410 415

Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe

420 425 430

Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn

435 440 445

Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr

450 455 460

Gln Lys Ser Leu Ser Leu Ser Pro

465 470

<210> 181

<211> 472

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 181

Ile Leu Asn Val Glu Gln Ser Pro Gln Ser Leu His Val Gln Glu Gly

1 5 10 15

Asp Ser Thr Lys Phe Thr Cys Ser Phe Pro Val Lys Glu Phe Gln Asp

20 25 30

Leu His Trp Tyr Arg Lys Glu Thr Ala Lys Ser Pro Glu Phe Leu Phe

35 40 45

Tyr Phe Gly Pro Tyr Gly Lys Glu Lys Lys Lys Gly Arg Ile Ser Ala

50 55 60

Thr Leu Asn Thr Lys Glu Gly Tyr Ser Tyr Leu Tyr Ile Thr Asp Ser

65 70 75 80

Gln Pro Glu Asp Ser Ala Thr Tyr Leu Cys Ala Leu Tyr Asn Asn Asn

85 90 95

Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro Gly Gly

100 105 110

Gly Ser Gly Gly Gly Gly Glu Val Gln Leu Val Glu Ser Gly Gly Gly

115 120 125

Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly

130 135 140

Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly

145 150 155 160

Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr

165 170 175

Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg

180 185 190

Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr

195 200 205

Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe Gly Asn

210 215 220

Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr

225 230 235 240

Val Ser Ser Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro

245 250 255

Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro

260 265 270

Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys

275 280 285

Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp

290 295 300

Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu

305 310 315 320

Glu Gln Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu

325 330 335

His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn

340 345 350

Lys Ala Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly

355 360 365

Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu

370 375 380

Leu Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr

385 390 395 400

Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn

405 410 415

Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe

420 425 430

Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn

435 440 445

Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr

450 455 460

Gln Lys Ser Leu Ser Leu Ser Pro

465 470

<210> 182

<211> 454

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 182

Gln Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Ser Ala Thr Ser Ser Val Ser Tyr Met

20 25 30

His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr

35 40 45

Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser

50 55 60

Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu

65 70 75 80

Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr

85 90 95

Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Ser Gly Gly

100 105 110

Gly Gly Gly Val Ile Gln Ser Pro Arg His Glu Val Thr Glu Met Gly

115 120 125

Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His Asn Ser Leu

130 135 140

Phe Trp Tyr Arg Glu Thr Pro Met Gln Gly Leu Glu Leu Leu Ile Tyr

145 150 155 160

Phe Gln Asn Thr Ala Val Ile Asp Asp Ser Gly Met Pro Glu Asp Arg

165 170 175

Phe Ser Ala Lys Met Pro Asn Ala Ser Phe Ser Thr Leu Lys Ile Gln

180 185 190

Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala Ser Ser Ala

195 200 205

Gly Ala Ile Asp Lys Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val

210 215 220

Leu Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro

225 230 235 240

Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

245 250 255

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

260 265 270

Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val

275 280 285

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

290 295 300

Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

305 310 315 320

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala

325 330 335

Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

340 345 350

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr

355 360 365

Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser

370 375 380

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

385 390 395 400

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

405 410 415

Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe

420 425 430

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

435 440 445

Ser Leu Ser Leu Ser Pro

450

<210> 183

<211> 472

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 183

Ile Leu Asn Val Glu Gln Ser Pro Gln Ser Leu His Val Gln Glu Gly

1 5 10 15

Asp Ser Thr Lys Phe Thr Cys Ser Phe Pro Val Lys Glu Phe Gln Asp

20 25 30

Leu His Trp Tyr Arg Lys Glu Thr Ala Lys Ser Pro Glu Phe Leu Phe

35 40 45

Tyr Phe Gly Pro Tyr Gly Lys Glu Lys Lys Lys Gly Arg Ile Ser Ala

50 55 60

Thr Leu Asn Thr Lys Glu Gly Tyr Ser Tyr Leu Tyr Ile Thr Asp Ser

65 70 75 80

Gln Pro Glu Asp Ser Ala Thr Tyr Leu Cys Ala Leu Tyr Asn Asn Tyr

85 90 95

Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro Gly Gly

100 105 110

Gly Ser Gly Gly Gly Gly Glu Val Gln Leu Val Glu Ser Gly Gly Gly

115 120 125

Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly

130 135 140

Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly

145 150 155 160

Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr

165 170 175

Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg

180 185 190

Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr

195 200 205

Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe Gly Asn

210 215 220

Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr

225 230 235 240

Val Ser Ser Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro

245 250 255

Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro

260 265 270

Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys

275 280 285

Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp

290 295 300

Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu

305 310 315 320

Glu Gln Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu

325 330 335

His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn

340 345 350

Lys Ala Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly

355 360 365

Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu

370 375 380

Leu Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr

385 390 395 400

Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn

405 410 415

Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe

420 425 430

Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn

435 440 445

Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr

450 455 460

Gln Lys Ser Leu Ser Leu Ser Pro

465 470

<210> 184

<211> 454

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 184

Gln Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Ser Ala Thr Ser Ser Val Ser Tyr Met

20 25 30

His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr

35 40 45

Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser

50 55 60

Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu

65 70 75 80

Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr

85 90 95

Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Ser Gly Gly

100 105 110

Gly Gly Gly Val Ile Gln Ser Pro Arg His Glu Val Thr Glu Met Gly

115 120 125

Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His Asn Ser Leu

130 135 140

Phe Trp Tyr Arg Glu Thr Pro Met Gln Gly Leu Glu Leu Leu Ile Tyr

145 150 155 160

Phe Gln Asn Thr Ala Val Ile Asp Asp Ser Gly Met Pro Glu Asp Arg

165 170 175

Phe Ser Ala Lys Met Pro Asn Ala Ser Phe Ser Thr Leu Lys Ile Gln

180 185 190

Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala Ser Ser Pro

195 200 205

Gly Ala Thr Asp Lys Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val

210 215 220

Leu Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro

225 230 235 240

Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

245 250 255

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

260 265 270

Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val

275 280 285

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

290 295 300

Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

305 310 315 320

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala

325 330 335

Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

340 345 350

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr

355 360 365

Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser

370 375 380

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

385 390 395 400

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

405 410 415

Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe

420 425 430

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

435 440 445

Ser Leu Ser Leu Ser Pro

450

<210> 185

<211> 454

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 185

Gln Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Ser Ala Thr Ser Ser Val Ser Tyr Met

20 25 30

His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr

35 40 45

Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser

50 55 60

Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu

65 70 75 80

Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr

85 90 95

Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Ser Gly Gly

100 105 110

Gly Gly Gly Val Ile Gln Ser Pro Arg His Glu Val Thr Glu Met Gly

115 120 125

Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His Asn Ser Leu

130 135 140

Phe Trp Tyr Arg Glu Thr Pro Met Gln Gly Leu Glu Leu Leu Ile Tyr

145 150 155 160

Phe Gln Asn Thr Ala Val Ile Asp Asp Ser Gly Met Pro Glu Asp Arg

165 170 175

Phe Ser Ala Lys Met Pro Asn Ala Ser Phe Ser Thr Leu Lys Ile Gln

180 185 190

Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala Ser Ser Thr

195 200 205

Gly Ala Ile Asp Lys Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val

210 215 220

Leu Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro

225 230 235 240

Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

245 250 255

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

260 265 270

Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val

275 280 285

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

290 295 300

Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

305 310 315 320

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala

325 330 335

Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

340 345 350

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr

355 360 365

Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser

370 375 380

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

385 390 395 400

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

405 410 415

Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe

420 425 430

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

435 440 445

Ser Leu Ser Leu Ser Pro

450

<210> 186

<211> 457

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 186

Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly

1 5 10 15

Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser Gly

20 25 30

Tyr Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly

35 40 45

Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro Ala Arg Phe

50 55 60

Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val

65 70 75 80

Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Ala Leu Trp Tyr Ser Asn

85 90 95

Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly Gly

100 105 110

Ser Gly Gly Gly Gly Gly Val Ile Gln Ser Pro Arg His Glu Val Thr

115 120 125

Glu Met Gly Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His

130 135 140

Asn Ser Leu Phe Trp Tyr Arg Glu Thr Pro Met Gln Gly Leu Glu Leu

145 150 155 160

Leu Ile Tyr Phe Gln Asn Thr Ala Val Ile Asp Asp Ser Gly Met Pro

165 170 175

Glu Asp Arg Phe Ser Ala Lys Met Pro Asn Ala Ser Phe Ser Thr Leu

180 185 190

Lys Ile Gln Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala

195 200 205

Ser Ser Pro Gly Ala Thr Asp Lys Gln Tyr Phe Gly Pro Gly Thr Arg

210 215 220

Leu Thr Val Leu Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro

225 230 235 240

Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro

245 250 255

Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr

260 265 270

Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn

275 280 285

Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg

290 295 300

Glu Glu Gln Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val

305 310 315 320

Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser

325 330 335

Asn Lys Ala Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys

340 345 350

Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp

355 360 365

Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe

370 375 380

Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu

385 390 395 400

Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe

405 410 415

Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly

420 425 430

Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr

435 440 445

Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455

<210> 187

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 187

Ser Leu Ala Glu Gly Arg Leu Tyr Leu

1 5

<210> 188

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 188

Asn Leu Leu Pro Lys Leu His Ile Val

1 5

<210> 189

<211> 472

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 189

Ile Leu Asn Val Glu Gln Ser Pro Gln Ser Leu His Val Gln Glu Gly

1 5 10 15

Asp Ser Thr Asn Phe Thr Cys Ser Phe Pro Val Lys Glu Phe Gln Asp

20 25 30

Leu His Trp Tyr Arg Lys Glu Thr Ala Lys Ser Pro Glu Phe Leu Phe

35 40 45

Tyr Phe Gly Pro Tyr Gly Lys Glu Lys Lys Lys Gly Arg Ile Ser Ala

50 55 60

Thr Leu Asn Thr Lys Glu Gly Tyr Ser Tyr Leu Tyr Ile Thr Asp Ser

65 70 75 80

Gln Pro Glu Asp Ser Ala Thr Tyr Leu Cys Ala Leu Tyr Asn Asn Tyr

85 90 95

Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro Gly Gly

100 105 110

Gly Ser Gly Gly Gly Gly Glu Val Gln Leu Val Glu Ser Gly Gly Gly

115 120 125

Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly

130 135 140

Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly

145 150 155 160

Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr

165 170 175

Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg

180 185 190

Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr

195 200 205

Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe Gly Asn

210 215 220

Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr

225 230 235 240

Val Ser Ser Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro

245 250 255

Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro

260 265 270

Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys

275 280 285

Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp

290 295 300

Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu

305 310 315 320

Glu Gln Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu

325 330 335

His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn

340 345 350

Lys Ala Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly

355 360 365

Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu

370 375 380

Leu Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr

385 390 395 400

Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn

405 410 415

Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe

420 425 430

Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn

435 440 445

Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr

450 455 460

Gln Lys Ser Leu Ser Leu Ser Pro

465 470

<210> 190

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 190

Ala Ile Val Asp Lys Val Pro Ser Val

1 5

<210> 191

<211> 472

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 191

Ile Leu Asn Val Glu Gln Ser Pro Gln Ser Leu His Val Gln Glu Gly

1 5 10 15

Asp Ser Thr Lys Phe Thr Cys Ser Phe Pro Val Lys Glu Phe Gln Asp

20 25 30

Leu His Trp Tyr Arg Lys Glu Thr Ala Lys Ser Pro Glu Phe Leu Phe

35 40 45

Tyr Phe Gly Pro Tyr Gly Lys Glu Lys Lys Lys Gly Arg Ile Ser Ala

50 55 60

Thr Leu Asn Thr Lys Glu Gly Tyr Ser Tyr Leu Tyr Ile Thr Asp Ser

65 70 75 80

Gln Pro Glu Asp Ser Ala Thr Tyr Leu Cys Ala Leu Tyr Asn Asn Asn

85 90 95

Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro Gly Gly

100 105 110

Gly Ser Gly Gly Gly Gly Glu Val Gln Leu Val Glu Ser Gly Gly Gly

115 120 125

Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly

130 135 140

Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly

145 150 155 160

Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr

165 170 175

Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg

180 185 190

Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr

195 200 205

Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe Gly Asn

210 215 220

Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr

225 230 235 240

Val Ser Ser Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro

245 250 255

Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro

260 265 270

Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys

275 280 285

Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp

290 295 300

Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu

305 310 315 320

Glu Gln Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu

325 330 335

His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn

340 345 350

Lys Ala Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly

355 360 365

Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu

370 375 380

Leu Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr

385 390 395 400

Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn

405 410 415

Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe

420 425 430

Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn

435 440 445

Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr

450 455 460

Gln Lys Ser Leu Ser Leu Ser Pro

465 470

<210> 192

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 192

Ala Leu Ala Thr Leu Ile His Gln Val

1 5

<210> 193

<211> 472

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 193

Ile Leu Asn Val Glu Gln Ser Pro Gln Ser Leu His Val Gln Glu Gly

1 5 10 15

Asp Ser Thr Lys Phe Thr Cys Ser Phe Pro Val Lys Glu Phe Gln Asp

20 25 30

Leu His Trp Tyr Arg Lys Glu Thr Ala Lys Ser Pro Glu Phe Leu Phe

35 40 45

Tyr Phe Gly Pro Tyr Gly Lys Glu Lys Lys Lys Gly Arg Ile Ser Ala

50 55 60

Thr Leu Asn Thr Lys Glu Gly Tyr Ser Tyr Leu Tyr Ile Thr Asp Ser

65 70 75 80

Gln Pro Glu Asp Ser Ala Thr Tyr Leu Cys Ala Leu Tyr Asn Asn Tyr

85 90 95

Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro Gly Gly

100 105 110

Gly Ser Gly Gly Gly Gly Glu Val Gln Leu Val Glu Ser Gly Gly Gly

115 120 125

Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly

130 135 140

Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly

145 150 155 160

Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr

165 170 175

Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg

180 185 190

Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr

195 200 205

Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe Gly Asn

210 215 220

Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr

225 230 235 240

Val Ser Ser Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro

245 250 255

Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro

260 265 270

Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys

275 280 285

Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp

290 295 300

Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu

305 310 315 320

Glu Gln Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu

325 330 335

His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn

340 345 350

Lys Ala Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly

355 360 365

Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu

370 375 380

Leu Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr

385 390 395 400

Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn

405 410 415

Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe

420 425 430

Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn

435 440 445

Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr

450 455 460

Gln Lys Ser Leu Ser Leu Ser Pro

465 470

<210> 194

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 194

Ser Leu Asp Gln Pro Thr Gln Thr Val

1 5

<210> 195

<211> 467

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 195

Ile Leu Asn Val Glu Gln Ser Pro Gln Ser Leu His Val Gln Glu Gly

1 5 10 15

Asp Ser Thr Asn Phe Thr Cys Ser Phe Pro Val Lys Glu Phe Gln Asp

20 25 30

Leu His Trp Tyr Arg Lys Glu Thr Ala Lys Ser Pro Glu Phe Leu Phe

35 40 45

Tyr Phe Gly Pro Tyr Gly Lys Glu Lys Lys Lys Gly Arg Ile Ser Ala

50 55 60

Thr Leu Asn Thr Lys Glu Gly Tyr Ser Tyr Leu Tyr Ile Thr Asp Ser

65 70 75 80

Gln Pro Glu Asp Ser Ala Thr Tyr Leu Cys Ala Leu Tyr Asn Asn Ala

85 90 95

Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro Gly Gly

100 105 110

Gly Ser Gly Gly Gly Gly Glu Val Gln Leu Val Gln Ser Gly Ala Glu

115 120 125

Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly

130 135 140

Tyr Lys Phe Thr Ser Tyr Val Met His Trp Val Arg Gln Ala Pro Gly

145 150 155 160

Gln Gly Leu Glu Trp Met Gly Tyr Ile Asn Pro Tyr Asn Asp Val Thr

165 170 175

Lys Tyr Ala Glu Lys Phe Gln Gly Arg Val Thr Leu Thr Ser Asp Thr

180 185 190

Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp

195 200 205

Thr Ala Val His Tyr Cys Ala Arg Gly Ser Tyr Tyr Asp Tyr Glu Gly

210 215 220

Phe Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Glu Pro

225 230 235 240

Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Pro

245 250 255

Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr

260 265 270

Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val

275 280 285

Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val

290 295 300

Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gln Ser

305 310 315 320

Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu

325 330 335

Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala

340 345 350

Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro

355 360 365

Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln

370 375 380

Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala

385 390 395 400

Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr

405 410 415

Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu

420 425 430

Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser

435 440 445

Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser

450 455 460

Leu Ser Pro

465

<210> 196

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 196

Ser Leu Phe Arg Val Ile Thr Glu Val

1 5

<210> 197

<211> 467

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 197

Ile Leu Asn Val Glu Gln Ser Pro Gln Ser Leu His Val Gln Glu Gly

1 5 10 15

Asp Ser Thr Asn Phe Thr Cys Ser Phe Pro Val Lys Glu Phe Gln Asp

20 25 30

Leu His Trp Tyr Arg Lys Glu Thr Ala Lys Ser Pro Glu Phe Leu Phe

35 40 45

Tyr Phe Gly Pro Tyr Gly Lys Glu Lys Lys Lys Gly Arg Ile Ser Ala

50 55 60

Thr Leu Asn Thr Lys Glu Gly Tyr Ser Tyr Leu Tyr Ile Thr Asp Ser

65 70 75 80

Gln Pro Glu Asp Ser Ala Thr Tyr Leu Cys Ala Leu Tyr Asn Asn Asp

85 90 95

Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro Gly Gly

100 105 110

Gly Ser Gly Gly Gly Gly Glu Val Gln Leu Val Gln Ser Gly Ala Glu

115 120 125

Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly

130 135 140

Tyr Lys Phe Thr Ser Tyr Val Met His Trp Val Arg Gln Ala Pro Gly

145 150 155 160

Gln Gly Leu Glu Trp Met Gly Tyr Ile Asn Pro Tyr Asn Asp Val Thr

165 170 175

Lys Tyr Ala Glu Lys Phe Gln Gly Arg Val Thr Leu Thr Ser Asp Thr

180 185 190

Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp

195 200 205

Thr Ala Val His Tyr Cys Ala Arg Gly Ser Tyr Tyr Asp Tyr Glu Gly

210 215 220

Phe Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Glu Pro

225 230 235 240

Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Pro

245 250 255

Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr

260 265 270

Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val

275 280 285

Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val

290 295 300

Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gln Ser

305 310 315 320

Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu

325 330 335

Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala

340 345 350

Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro

355 360 365

Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln

370 375 380

Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala

385 390 395 400

Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr

405 410 415

Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu

420 425 430

Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser

435 440 445

Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser

450 455 460

Leu Ser Pro

465

<210> 198

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 198

Arg Leu Ala Val Tyr Ile Asp Arg Val

1 5

<210> 199

<211> 467

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 199

Ile Leu Asn Val Glu Gln Ser Pro Gln Ser Leu His Val Gln Glu Gly

1 5 10 15

Asp Ser Thr Asn Phe Thr Cys Ser Phe Pro Val Lys Glu Phe Gln Asp

20 25 30

Leu His Trp Tyr Arg Lys Glu Thr Ala Lys Ser Pro Glu Phe Leu Phe

35 40 45

Tyr Phe Gly Pro Tyr Gly Lys Glu Lys Lys Lys Gly Arg Ile Ser Ala

50 55 60

Thr Leu Asn Thr Lys Glu Gly Tyr Ser Tyr Leu Tyr Ile Thr Asp Ser

65 70 75 80

Gln Pro Glu Asp Ser Ala Thr Tyr Leu Cys Ala Leu Tyr Asn Asn Glu

85 90 95

Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro Gly Gly

100 105 110

Gly Ser Gly Gly Gly Gly Glu Val Gln Leu Val Gln Ser Gly Ala Glu

115 120 125

Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly

130 135 140

Tyr Lys Phe Thr Ser Tyr Val Met His Trp Val Arg Gln Ala Pro Gly

145 150 155 160

Gln Gly Leu Glu Trp Met Gly Tyr Ile Asn Pro Tyr Asn Asp Val Thr

165 170 175

Lys Tyr Ala Glu Lys Phe Gln Gly Arg Val Thr Leu Thr Ser Asp Thr

180 185 190

Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp

195 200 205

Thr Ala Val His Tyr Cys Ala Arg Gly Ser Tyr Tyr Asp Tyr Glu Gly

210 215 220

Phe Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Glu Pro

225 230 235 240

Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Pro

245 250 255

Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr

260 265 270

Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val

275 280 285

Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val

290 295 300

Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gln Ser

305 310 315 320

Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu

325 330 335

Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala

340 345 350

Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro

355 360 365

Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln

370 375 380

Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala

385 390 395 400

Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr

405 410 415

Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu

420 425 430

Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser

435 440 445

Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser

450 455 460

Leu Ser Pro

465

<210> 200

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 200

Pro Ile Leu Tyr Arg Pro Val Ala Val

1 5

<210> 201

<211> 467

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 201

Ile Leu Asn Val Glu Gln Ser Pro Gln Ser Leu His Val Gln Glu Gly

1 5 10 15

Asp Ser Thr Asn Phe Thr Cys Ser Phe Pro Val Lys Glu Phe Gln Asp

20 25 30

Leu His Trp Tyr Arg Lys Glu Thr Ala Lys Ser Pro Glu Phe Leu Phe

35 40 45

Tyr Phe Gly Pro Tyr Gly Lys Glu Lys Lys Lys Gly Arg Ile Ser Ala

50 55 60

Thr Leu Asn Thr Lys Glu Gly Tyr Ser Tyr Leu Tyr Ile Thr Asp Ser

65 70 75 80

Gln Pro Glu Asp Ser Ala Thr Tyr Leu Cys Ala Leu Tyr Asn Asn Phe

85 90 95

Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro Gly Gly

100 105 110

Gly Ser Gly Gly Gly Gly Glu Val Gln Leu Val Gln Ser Gly Ala Glu

115 120 125

Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly

130 135 140

Tyr Lys Phe Thr Ser Tyr Val Met His Trp Val Arg Gln Ala Pro Gly

145 150 155 160

Gln Gly Leu Glu Trp Met Gly Tyr Ile Asn Pro Tyr Asn Asp Val Thr

165 170 175

Lys Tyr Ala Glu Lys Phe Gln Gly Arg Val Thr Leu Thr Ser Asp Thr

180 185 190

Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp

195 200 205

Thr Ala Val His Tyr Cys Ala Arg Gly Ser Tyr Tyr Asp Tyr Glu Gly

210 215 220

Phe Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Glu Pro

225 230 235 240

Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Pro

245 250 255

Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr

260 265 270

Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val

275 280 285

Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val

290 295 300

Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gln Ser

305 310 315 320

Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu

325 330 335

Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala

340 345 350

Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro

355 360 365

Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln

370 375 380

Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala

385 390 395 400

Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr

405 410 415

Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu

420 425 430

Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser

435 440 445

Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser

450 455 460

Leu Ser Pro

465

<210> 202

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 202

Gly Leu Ala Thr Asp Val Gln Thr Val

1 5

<210> 203

<211> 467

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 203

Ile Leu Asn Val Glu Gln Ser Pro Gln Ser Leu His Val Gln Glu Gly

1 5 10 15

Asp Ser Thr Asn Phe Thr Cys Ser Phe Pro Val Lys Glu Phe Gln Asp

20 25 30

Leu His Trp Tyr Arg Lys Glu Thr Ala Lys Ser Pro Glu Phe Leu Phe

35 40 45

Tyr Phe Gly Pro Tyr Gly Lys Glu Lys Lys Lys Gly Arg Ile Ser Ala

50 55 60

Thr Leu Asn Thr Lys Glu Gly Tyr Ser Tyr Leu Tyr Ile Thr Asp Ser

65 70 75 80

Gln Pro Glu Asp Ser Ala Thr Tyr Leu Cys Ala Leu Tyr Asn Asn His

85 90 95

Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro Gly Gly

100 105 110

Gly Ser Gly Gly Gly Gly Glu Val Gln Leu Val Gln Ser Gly Ala Glu

115 120 125

Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly

130 135 140

Tyr Lys Phe Thr Ser Tyr Val Met His Trp Val Arg Gln Ala Pro Gly

145 150 155 160

Gln Gly Leu Glu Trp Met Gly Tyr Ile Asn Pro Tyr Asn Asp Val Thr

165 170 175

Lys Tyr Ala Glu Lys Phe Gln Gly Arg Val Thr Leu Thr Ser Asp Thr

180 185 190

Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp

195 200 205

Thr Ala Val His Tyr Cys Ala Arg Gly Ser Tyr Tyr Asp Tyr Glu Gly

210 215 220

Phe Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Glu Pro

225 230 235 240

Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Pro

245 250 255

Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr

260 265 270

Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val

275 280 285

Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val

290 295 300

Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gln Ser

305 310 315 320

Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu

325 330 335

Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala

340 345 350

Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro

355 360 365

Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln

370 375 380

Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala

385 390 395 400

Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr

405 410 415

Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu

420 425 430

Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser

435 440 445

Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser

450 455 460

Leu Ser Pro

465

<210> 204

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 204

Lys Ile Tyr Glu Gly Gln Val Glu Val

1 5

<210> 205

<211> 467

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 205

Ile Leu Asn Val Glu Gln Ser Pro Gln Ser Leu His Val Gln Glu Gly

1 5 10 15

Asp Ser Thr Asn Phe Thr Cys Ser Phe Pro Val Lys Glu Phe Gln Asp

20 25 30

Leu His Trp Tyr Arg Lys Glu Thr Ala Lys Ser Pro Glu Phe Leu Phe

35 40 45

Tyr Phe Gly Pro Tyr Gly Lys Glu Lys Lys Lys Gly Arg Ile Ser Ala

50 55 60

Thr Leu Asn Thr Lys Glu Gly Tyr Ser Tyr Leu Tyr Ile Thr Asp Ser

65 70 75 80

Gln Pro Glu Asp Ser Ala Thr Tyr Leu Cys Ala Leu Tyr Asn Asn Ile

85 90 95

Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro Gly Gly

100 105 110

Gly Ser Gly Gly Gly Gly Glu Val Gln Leu Val Gln Ser Gly Ala Glu

115 120 125

Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly

130 135 140

Tyr Lys Phe Thr Ser Tyr Val Met His Trp Val Arg Gln Ala Pro Gly

145 150 155 160

Gln Gly Leu Glu Trp Met Gly Tyr Ile Asn Pro Tyr Asn Asp Val Thr

165 170 175

Lys Tyr Ala Glu Lys Phe Gln Gly Arg Val Thr Leu Thr Ser Asp Thr

180 185 190

Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp

195 200 205

Thr Ala Val His Tyr Cys Ala Arg Gly Ser Tyr Tyr Asp Tyr Glu Gly

210 215 220

Phe Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Glu Pro

225 230 235 240

Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Pro

245 250 255

Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr

260 265 270

Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val

275 280 285

Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val

290 295 300

Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gln Ser

305 310 315 320

Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu

325 330 335

Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala

340 345 350

Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro

355 360 365

Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln

370 375 380

Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala

385 390 395 400

Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr

405 410 415

Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu

420 425 430

Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser

435 440 445

Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser

450 455 460

Leu Ser Pro

465

<210> 206

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 206

Asn Leu Cys Pro Thr Arg Ile Glu Val

1 5

<210> 207

<211> 467

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 207

Ile Leu Asn Val Glu Gln Ser Pro Gln Ser Leu His Val Gln Glu Gly

1 5 10 15

Asp Ser Thr Asn Phe Thr Cys Ser Phe Pro Val Lys Glu Phe Gln Asp

20 25 30

Leu His Trp Tyr Arg Lys Glu Thr Ala Lys Ser Pro Glu Phe Leu Phe

35 40 45

Tyr Phe Gly Pro Tyr Gly Lys Glu Lys Lys Lys Gly Arg Ile Ser Ala

50 55 60

Thr Leu Asn Thr Lys Glu Gly Tyr Ser Tyr Leu Tyr Ile Thr Asp Ser

65 70 75 80

Gln Pro Glu Asp Ser Ala Thr Tyr Leu Cys Ala Leu Tyr Asn Asn Leu

85 90 95

Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro Gly Gly

100 105 110

Gly Ser Gly Gly Gly Gly Glu Val Gln Leu Val Gln Ser Gly Ala Glu

115 120 125

Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly

130 135 140

Tyr Lys Phe Thr Ser Tyr Val Met His Trp Val Arg Gln Ala Pro Gly

145 150 155 160

Gln Gly Leu Glu Trp Met Gly Tyr Ile Asn Pro Tyr Asn Asp Val Thr

165 170 175

Lys Tyr Ala Glu Lys Phe Gln Gly Arg Val Thr Leu Thr Ser Asp Thr

180 185 190

Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp

195 200 205

Thr Ala Val His Tyr Cys Ala Arg Gly Ser Tyr Tyr Asp Tyr Glu Gly

210 215 220

Phe Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Glu Pro

225 230 235 240

Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Pro

245 250 255

Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr

260 265 270

Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val

275 280 285

Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val

290 295 300

Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gln Ser

305 310 315 320

Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu

325 330 335

Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala

340 345 350

Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro

355 360 365

Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln

370 375 380

Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala

385 390 395 400

Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr

405 410 415

Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu

420 425 430

Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser

435 440 445

Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser

450 455 460

Leu Ser Pro

465

<210> 208

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 208

Phe Leu Leu Gln His Gln Thr Phe Leu

1 5

<210> 209

<211> 467

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 209

Ile Leu Asn Val Glu Gln Ser Pro Gln Ser Leu His Val Gln Glu Gly

1 5 10 15

Asp Ser Thr Asn Phe Thr Cys Ser Phe Pro Val Lys Glu Phe Gln Asp

20 25 30

Leu His Trp Tyr Arg Lys Glu Thr Ala Lys Ser Pro Glu Phe Leu Phe

35 40 45

Tyr Phe Gly Pro Tyr Gly Lys Glu Lys Lys Lys Gly Arg Ile Ser Ala

50 55 60

Thr Leu Asn Thr Lys Glu Gly Tyr Ser Tyr Leu Tyr Ile Thr Asp Ser

65 70 75 80

Gln Pro Glu Asp Ser Ala Thr Tyr Leu Cys Ala Leu Tyr Asn Asn Lys

85 90 95

Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro Gly Gly

100 105 110

Gly Ser Gly Gly Gly Gly Glu Val Gln Leu Val Gln Ser Gly Ala Glu

115 120 125

Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly

130 135 140

Tyr Lys Phe Thr Ser Tyr Val Met His Trp Val Arg Gln Ala Pro Gly

145 150 155 160

Gln Gly Leu Glu Trp Met Gly Tyr Ile Asn Pro Tyr Asn Asp Val Thr

165 170 175

Lys Tyr Ala Glu Lys Phe Gln Gly Arg Val Thr Leu Thr Ser Asp Thr

180 185 190

Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp

195 200 205

Thr Ala Val His Tyr Cys Ala Arg Gly Ser Tyr Tyr Asp Tyr Glu Gly

210 215 220

Phe Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Glu Pro

225 230 235 240

Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Pro

245 250 255

Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr

260 265 270

Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val

275 280 285

Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val

290 295 300

Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gln Ser

305 310 315 320

Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu

325 330 335

Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala

340 345 350

Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro

355 360 365

Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln

370 375 380

Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala

385 390 395 400

Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr

405 410 415

Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu

420 425 430

Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser

435 440 445

Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser

450 455 460

Leu Ser Pro

465

<210> 210

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 210

Leu Leu Ala Glu Arg Asp Leu Tyr Leu

1 5

<210> 211

<211> 467

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 211

Ile Leu Asn Val Glu Gln Ser Pro Gln Ser Leu His Val Gln Glu Gly

1 5 10 15

Asp Ser Thr Asn Phe Thr Cys Ser Phe Pro Val Lys Glu Phe Gln Asp

20 25 30

Leu His Trp Tyr Arg Lys Glu Thr Ala Lys Ser Pro Glu Phe Leu Phe

35 40 45

Tyr Phe Gly Pro Tyr Gly Lys Glu Lys Lys Lys Gly Arg Ile Ser Ala

50 55 60

Thr Leu Asn Thr Lys Glu Gly Tyr Ser Tyr Leu Tyr Ile Thr Asp Ser

65 70 75 80

Gln Pro Glu Asp Ser Ala Thr Tyr Leu Cys Ala Leu Tyr Asn Asn Gln

85 90 95

Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro Gly Gly

100 105 110

Gly Ser Gly Gly Gly Gly Glu Val Gln Leu Val Gln Ser Gly Ala Glu

115 120 125

Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly

130 135 140

Tyr Lys Phe Thr Ser Tyr Val Met His Trp Val Arg Gln Ala Pro Gly

145 150 155 160

Gln Gly Leu Glu Trp Met Gly Tyr Ile Asn Pro Tyr Asn Asp Val Thr

165 170 175

Lys Tyr Ala Glu Lys Phe Gln Gly Arg Val Thr Leu Thr Ser Asp Thr

180 185 190

Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp

195 200 205

Thr Ala Val His Tyr Cys Ala Arg Gly Ser Tyr Tyr Asp Tyr Glu Gly

210 215 220

Phe Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Glu Pro

225 230 235 240

Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Pro

245 250 255

Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr

260 265 270

Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val

275 280 285

Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val

290 295 300

Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gln Ser

305 310 315 320

Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu

325 330 335

Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala

340 345 350

Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro

355 360 365

Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln

370 375 380

Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala

385 390 395 400

Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr

405 410 415

Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu

420 425 430

Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser

435 440 445

Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser

450 455 460

Leu Ser Pro

465

<210> 212

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 212

Glu Leu Asp Val Arg Ile Thr Ala Leu

1 5

<210> 213

<211> 467

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 213

Ile Leu Asn Val Glu Gln Ser Pro Gln Ser Leu His Val Gln Glu Gly

1 5 10 15

Asp Ser Thr Asn Phe Thr Cys Ser Phe Pro Val Lys Glu Phe Gln Asp

20 25 30

Leu His Trp Tyr Arg Lys Glu Thr Ala Lys Ser Pro Glu Phe Leu Phe

35 40 45

Tyr Phe Gly Pro Tyr Gly Lys Glu Lys Lys Lys Gly Arg Ile Ser Ala

50 55 60

Thr Leu Asn Thr Lys Glu Gly Tyr Ser Tyr Leu Tyr Ile Thr Asp Ser

65 70 75 80

Gln Pro Glu Asp Ser Ala Thr Tyr Leu Cys Ala Leu Tyr Asn Asn Arg

85 90 95

Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro Gly Gly

100 105 110

Gly Ser Gly Gly Gly Gly Glu Val Gln Leu Val Gln Ser Gly Ala Glu

115 120 125

Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly

130 135 140

Tyr Lys Phe Thr Ser Tyr Val Met His Trp Val Arg Gln Ala Pro Gly

145 150 155 160

Gln Gly Leu Glu Trp Met Gly Tyr Ile Asn Pro Tyr Asn Asp Val Thr

165 170 175

Lys Tyr Ala Glu Lys Phe Gln Gly Arg Val Thr Leu Thr Ser Asp Thr

180 185 190

Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp

195 200 205

Thr Ala Val His Tyr Cys Ala Arg Gly Ser Tyr Tyr Asp Tyr Glu Gly

210 215 220

Phe Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Glu Pro

225 230 235 240

Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Pro

245 250 255

Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr

260 265 270

Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val

275 280 285

Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val

290 295 300

Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gln Ser

305 310 315 320

Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu

325 330 335

Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala

340 345 350

Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro

355 360 365

Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln

370 375 380

Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala

385 390 395 400

Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr

405 410 415

Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu

420 425 430

Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser

435 440 445

Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser

450 455 460

Leu Ser Pro

465

<210> 214

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 214

Gly Gly Gly Ser Gly Gly Gly Gly

1 5

<210> 215

<211> 467

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 215

Ile Leu Asn Val Glu Gln Ser Pro Gln Ser Leu His Val Gln Glu Gly

1 5 10 15

Asp Ser Thr Asn Phe Thr Cys Ser Phe Pro Val Lys Glu Phe Gln Asp

20 25 30

Leu His Trp Tyr Arg Lys Glu Thr Ala Lys Ser Pro Glu Phe Leu Phe

35 40 45

Tyr Phe Gly Pro Tyr Gly Lys Glu Lys Lys Lys Gly Arg Ile Ser Ala

50 55 60

Thr Leu Asn Thr Lys Glu Gly Tyr Ser Tyr Leu Tyr Ile Thr Asp Ser

65 70 75 80

Gln Pro Glu Asp Ser Ala Thr Tyr Leu Cys Ala Leu Tyr Asn Asn Val

85 90 95

Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro Gly Gly

100 105 110

Gly Ser Gly Gly Gly Gly Glu Val Gln Leu Val Gln Ser Gly Ala Glu

115 120 125

Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly

130 135 140

Tyr Lys Phe Thr Ser Tyr Val Met His Trp Val Arg Gln Ala Pro Gly

145 150 155 160

Gln Gly Leu Glu Trp Met Gly Tyr Ile Asn Pro Tyr Asn Asp Val Thr

165 170 175

Lys Tyr Ala Glu Lys Phe Gln Gly Arg Val Thr Leu Thr Ser Asp Thr

180 185 190

Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp

195 200 205

Thr Ala Val His Tyr Cys Ala Arg Gly Ser Tyr Tyr Asp Tyr Glu Gly

210 215 220

Phe Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Glu Pro

225 230 235 240

Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Pro

245 250 255

Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr

260 265 270

Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val

275 280 285

Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val

290 295 300

Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gln Ser

305 310 315 320

Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu

325 330 335

Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala

340 345 350

Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro

355 360 365

Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln

370 375 380

Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala

385 390 395 400

Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr

405 410 415

Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu

420 425 430

Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser

435 440 445

Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser

450 455 460

Leu Ser Pro

465

<210> 216

<211> 454

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 216

Gln Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Ser Ala Thr Ser Ser Val Ser Tyr Met

20 25 30

His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr

35 40 45

Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser

50 55 60

Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu

65 70 75 80

Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr

85 90 95

Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Ser Gly Gly

100 105 110

Gly Gly Gly Val Ile Gln Ser Pro Arg His Glu Val Thr Glu Met Gly

115 120 125

Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His Asn Ser Leu

130 135 140

Phe Trp Tyr Arg Glu Thr Pro Met Gln Gly Leu Glu Leu Leu Ile Tyr

145 150 155 160

Phe Gln Asn Thr Ala Val Ile Asp Asp Ser Gly Met Pro Glu Asp Arg

165 170 175

Phe Ser Ala Lys Met Pro Asn Glu Ser Phe Ser Thr Leu Lys Ile Gln

180 185 190

Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala Ser Ser Pro

195 200 205

Gly Ala Thr Asp Lys Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val

210 215 220

Leu Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro

225 230 235 240

Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

245 250 255

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

260 265 270

Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val

275 280 285

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

290 295 300

Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

305 310 315 320

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala

325 330 335

Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

340 345 350

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr

355 360 365

Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser

370 375 380

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

385 390 395 400

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

405 410 415

Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe

420 425 430

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

435 440 445

Ser Leu Ser Leu Ser Pro

450

<210> 217

<211> 467

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 217

Ile Leu Asn Val Glu Gln Ser Pro Gln Ser Leu His Val Gln Glu Gly

1 5 10 15

Asp Ser Thr Asn Phe Thr Cys Ser Phe Pro Val Lys Glu Phe Gln Asp

20 25 30

Leu His Trp Tyr Arg Lys Glu Thr Ala Lys Ser Pro Glu Phe Leu Phe

35 40 45

Tyr Phe Gly Pro Tyr Gly Lys Glu Lys Lys Lys Gly Arg Ile Ser Ala

50 55 60

Thr Leu Asn Thr Lys Glu Gly Tyr Ser Tyr Leu Tyr Ile Thr Asp Ser

65 70 75 80

Gln Pro Glu Asp Ser Ala Thr Tyr Leu Cys Ala Leu Tyr Asn Asn Tyr

85 90 95

Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro Gly Gly

100 105 110

Gly Ser Gly Gly Gly Gly Glu Val Gln Leu Val Gln Ser Gly Ala Glu

115 120 125

Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly

130 135 140

Tyr Lys Phe Thr Ser Tyr Val Met His Trp Val Arg Gln Ala Pro Gly

145 150 155 160

Gln Gly Leu Glu Trp Met Gly Tyr Ile Asn Pro Tyr Asn Asp Val Thr

165 170 175

Lys Tyr Ala Glu Lys Phe Gln Gly Arg Val Thr Leu Thr Ser Asp Thr

180 185 190

Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp

195 200 205

Thr Ala Val His Tyr Cys Ala Arg Gly Ser Tyr Tyr Asp Tyr Glu Gly

210 215 220

Phe Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Glu Pro

225 230 235 240

Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Pro

245 250 255

Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr

260 265 270

Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val

275 280 285

Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val

290 295 300

Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gln Ser

305 310 315 320

Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu

325 330 335

Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala

340 345 350

Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro

355 360 365

Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln

370 375 380

Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala

385 390 395 400

Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr

405 410 415

Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu

420 425 430

Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser

435 440 445

Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser

450 455 460

Leu Ser Pro

465

<210> 218

<211> 454

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 218

Gln Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Ser Ala Thr Ser Ser Val Ser Tyr Met

20 25 30

His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr

35 40 45

Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser

50 55 60

Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu

65 70 75 80

Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr

85 90 95

Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Ser Gly Gly

100 105 110

Gly Gly Gly Val Ile Gln Ser Pro Arg His Glu Val Thr Glu Met Gly

115 120 125

Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His Asn Ser Leu

130 135 140

Phe Trp Tyr Arg Glu Thr Pro Met Gln Gly Leu Glu Leu Leu Ile Tyr

145 150 155 160

Phe Gln Asn Thr Ala Val Ile Asp Asp Ser Gly Met Pro Glu Asp Arg

165 170 175

Phe Ser Ala Lys Met Pro Asn Arg Ser Phe Ser Thr Leu Lys Ile Gln

180 185 190

Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala Ser Ser Pro

195 200 205

Gly Ala Thr Asp Lys Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val

210 215 220

Leu Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro

225 230 235 240

Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

245 250 255

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

260 265 270

Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val

275 280 285

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

290 295 300

Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

305 310 315 320

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala

325 330 335

Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

340 345 350

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr

355 360 365

Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser

370 375 380

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

385 390 395 400

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

405 410 415

Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe

420 425 430

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

435 440 445

Ser Leu Ser Leu Ser Pro

450

<210> 219

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 219

Ala Leu Tyr Asn Asn Ala Asp Met Arg

1 5

<210> 220

<211> 454

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 220

Gln Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Ser Ala Thr Ser Ser Val Ser Tyr Met

20 25 30

His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr

35 40 45

Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser

50 55 60

Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu

65 70 75 80

Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr

85 90 95

Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Ser Gly Gly

100 105 110

Gly Gly Gly Val Ile Gln Ser Pro Arg His Glu Val Thr Glu Met Gly

115 120 125

Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His Asn Ser Leu

130 135 140

Phe Trp Tyr Arg Glu Thr Pro Met Gln Gly Leu Glu Leu Leu Ile Tyr

145 150 155 160

Phe Gln Asn Thr Ala Val Ile Asp Asp Ser Gly Met Pro Glu Asp Arg

165 170 175

Phe Ser Ala Lys Met Pro Asn Lys Ser Phe Ser Thr Leu Lys Ile Gln

180 185 190

Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala Ser Ser Pro

195 200 205

Gly Ala Thr Asp Lys Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val

210 215 220

Leu Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro

225 230 235 240

Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

245 250 255

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

260 265 270

Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val

275 280 285

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

290 295 300

Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

305 310 315 320

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala

325 330 335

Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

340 345 350

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr

355 360 365

Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser

370 375 380

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

385 390 395 400

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

405 410 415

Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe

420 425 430

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

435 440 445

Ser Leu Ser Leu Ser Pro

450

<210> 221

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 221

Ala Leu Tyr Asn Asn Asp Asp Met Arg

1 5

<210> 222

<211> 454

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 222

Gln Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Ser Ala Thr Ser Ser Val Ser Tyr Met

20 25 30

His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr

35 40 45

Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser

50 55 60

Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu

65 70 75 80

Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr

85 90 95

Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Ser Gly Gly

100 105 110

Gly Gly Gly Val Ile Gln Ser Pro Arg His Glu Val Thr Glu Met Gly

115 120 125

Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His Asn Ser Leu

130 135 140

Phe Trp Tyr Arg Glu Thr Pro Met Gln Gly Leu Glu Leu Leu Ile Tyr

145 150 155 160

Phe Gln Asn Thr Ala Val Ile Asp Asp Ser Gly Met Pro Glu Asp Arg

165 170 175

Phe Ser Ala Lys Met Pro Asn Gln Ser Phe Ser Thr Leu Lys Ile Gln

180 185 190

Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala Ser Ser Pro

195 200 205

Gly Ala Thr Asp Lys Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val

210 215 220

Leu Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro

225 230 235 240

Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

245 250 255

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

260 265 270

Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val

275 280 285

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

290 295 300

Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

305 310 315 320

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala

325 330 335

Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

340 345 350

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr

355 360 365

Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser

370 375 380

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

385 390 395 400

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

405 410 415

Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe

420 425 430

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

435 440 445

Ser Leu Ser Leu Ser Pro

450

<210> 223

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 223

Ala Leu Tyr Asn Asn Glu Asp Met Arg

1 5

<210> 224

<211> 454

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 224

Gln Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Ser Ala Thr Ser Ser Val Ser Tyr Met

20 25 30

His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr

35 40 45

Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser

50 55 60

Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu

65 70 75 80

Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr

85 90 95

Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Ser Gly Gly

100 105 110

Gly Gly Gly Val Ile Gln Ser Pro Arg His Glu Val Thr Glu Met Gly

115 120 125

Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His Asn Ser Leu

130 135 140

Phe Trp Tyr Arg Glu Thr Pro Met Gln Gly Leu Glu Leu Leu Ile Tyr

145 150 155 160

Phe Gln Asn Thr Ala Val Ile Asp Asp Ser Gly Met Pro Glu Asp Arg

165 170 175

Phe Ser Ala Lys Met Pro Asn Asn Ser Phe Ser Thr Leu Lys Ile Gln

180 185 190

Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala Ser Ser Pro

195 200 205

Gly Ala Thr Asp Lys Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val

210 215 220

Leu Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro

225 230 235 240

Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

245 250 255

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

260 265 270

Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val

275 280 285

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

290 295 300

Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

305 310 315 320

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala

325 330 335

Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

340 345 350

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr

355 360 365

Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser

370 375 380

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

385 390 395 400

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

405 410 415

Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe

420 425 430

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

435 440 445

Ser Leu Ser Leu Ser Pro

450

<210> 225

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 225

Ala Leu Tyr Asn Asn Phe Asp Met Arg

1 5

<210> 226

<211> 454

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 226

Gln Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Ser Ala Thr Ser Ser Val Ser Tyr Met

20 25 30

His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr

35 40 45

Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser

50 55 60

Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu

65 70 75 80

Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr

85 90 95

Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Ser Gly Gly

100 105 110

Gly Gly Gly Val Ile Gln Ser Pro Arg His Glu Val Thr Glu Met Gly

115 120 125

Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His Asn Ser Leu

130 135 140

Phe Trp Tyr Arg Glu Thr Pro Met Gln Gly Leu Glu Leu Leu Ile Tyr

145 150 155 160

Phe Gln Asn Thr Ala Val Ile Asp Asp Ser Gly Met Pro Glu Asp Arg

165 170 175

Phe Ser Ala Lys Met Pro Asn Tyr Ser Phe Ser Thr Leu Lys Ile Gln

180 185 190

Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala Ser Ser Pro

195 200 205

Gly Ala Thr Asp Lys Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val

210 215 220

Leu Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro

225 230 235 240

Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

245 250 255

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

260 265 270

Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val

275 280 285

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

290 295 300

Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

305 310 315 320

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala

325 330 335

Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

340 345 350

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr

355 360 365

Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser

370 375 380

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

385 390 395 400

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

405 410 415

Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe

420 425 430

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

435 440 445

Ser Leu Ser Leu Ser Pro

450

<210> 227

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 227

Ala Leu Tyr Asn Asn His Asp Met Arg

1 5

<210> 228

<211> 454

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 228

Gln Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Ser Ala Thr Ser Ser Val Ser Tyr Met

20 25 30

His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr

35 40 45

Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser

50 55 60

Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu

65 70 75 80

Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr

85 90 95

Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Ser Gly Gly

100 105 110

Gly Gly Gly Val Ile Gln Ser Pro Arg His Glu Val Thr Glu Met Gly

115 120 125

Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His Asn Ser Leu

130 135 140

Phe Trp Tyr Arg Glu Thr Pro Met Gln Gly Leu Glu Leu Leu Ile Tyr

145 150 155 160

Phe Gln Asn Thr Ala Val Ile Asp Asp Ser Gly Met Pro Glu Asp Arg

165 170 175

Phe Ser Ala Lys Met Pro Asn Ser Ser Phe Ser Thr Leu Lys Ile Gln

180 185 190

Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala Ser Ser Pro

195 200 205

Gly Ala Thr Asp Lys Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val

210 215 220

Leu Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro

225 230 235 240

Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

245 250 255

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

260 265 270

Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val

275 280 285

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

290 295 300

Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

305 310 315 320

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala

325 330 335

Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

340 345 350

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr

355 360 365

Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser

370 375 380

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

385 390 395 400

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

405 410 415

Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe

420 425 430

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

435 440 445

Ser Leu Ser Leu Ser Pro

450

<210> 229

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 229

Ala Leu Tyr Asn Asn Ile Asp Met Arg

1 5

<210> 230

<211> 454

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 230

Gln Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Ser Ala Thr Ser Ser Val Ser Tyr Met

20 25 30

His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr

35 40 45

Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser

50 55 60

Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu

65 70 75 80

Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr

85 90 95

Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Ser Gly Gly

100 105 110

Gly Gly Gly Val Ile Gln Ser Pro Arg His Glu Val Thr Glu Met Gly

115 120 125

Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His Asn Ser Leu

130 135 140

Phe Trp Tyr Arg Glu Thr Pro Met Gln Gly Leu Glu Leu Leu Ile Tyr

145 150 155 160

Phe Gln Asn Thr Ala Val Ile Asp Asp Ser Gly Met Pro Glu Asp Arg

165 170 175

Phe Ser Ala Lys Met Pro Asn Asp Ser Phe Ser Thr Leu Lys Ile Gln

180 185 190

Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala Ser Ser Pro

195 200 205

Gly Ala Thr Asp Arg Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val

210 215 220

Leu Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro

225 230 235 240

Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

245 250 255

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

260 265 270

Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val

275 280 285

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

290 295 300

Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

305 310 315 320

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala

325 330 335

Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

340 345 350

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr

355 360 365

Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser

370 375 380

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

385 390 395 400

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

405 410 415

Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe

420 425 430

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

435 440 445

Ser Leu Ser Leu Ser Pro

450

<210> 231

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 231

Ala Leu Tyr Asn Asn Lys Asp Met Arg

1 5

<210> 232

<211> 454

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 232

Gln Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Ser Ala Thr Ser Ser Val Ser Tyr Met

20 25 30

His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr

35 40 45

Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser

50 55 60

Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu

65 70 75 80

Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr

85 90 95

Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Ser Gly Gly

100 105 110

Gly Gly Gly Val Ile Gln Ser Pro Arg His Glu Val Thr Glu Met Gly

115 120 125

Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His Asn Ser Leu

130 135 140

Phe Trp Tyr Arg Glu Thr Pro Met Gln Gly Leu Glu Leu Leu Ile Tyr

145 150 155 160

Phe Gln Asn Thr Ala Val Ile Asp Asp Ser Gly Met Pro Glu Asp Arg

165 170 175

Phe Ser Ala Lys Met Pro Asn Asp Ser Phe Ser Thr Leu Lys Ile Gln

180 185 190

Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala Ser Ser Pro

195 200 205

Gly Ala Thr Asp His Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val

210 215 220

Leu Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro

225 230 235 240

Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

245 250 255

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

260 265 270

Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val

275 280 285

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

290 295 300

Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

305 310 315 320

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala

325 330 335

Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

340 345 350

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr

355 360 365

Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser

370 375 380

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

385 390 395 400

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

405 410 415

Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe

420 425 430

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

435 440 445

Ser Leu Ser Leu Ser Pro

450

<210> 233

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 233

Ala Leu Tyr Asn Asn Gln Asp Met Arg

1 5

<210> 234

<211> 454

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 234

Gln Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Ser Ala Thr Ser Ser Val Ser Tyr Met

20 25 30

His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr

35 40 45

Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser

50 55 60

Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu

65 70 75 80

Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr

85 90 95

Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Ser Gly Gly

100 105 110

Gly Gly Gly Val Ile Gln Ser Pro Arg His Glu Val Thr Glu Met Gly

115 120 125

Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His Asn Ser Leu

130 135 140

Phe Trp Tyr Arg Glu Thr Pro Met Gln Gly Leu Glu Leu Leu Ile Tyr

145 150 155 160

Phe Gln Asn Thr Ala Val Ile Asp Asp Ser Gly Met Pro Glu Asp Arg

165 170 175

Phe Ser Ala Lys Met Pro Asn Asp Ser Phe Ser Thr Leu Lys Ile Gln

180 185 190

Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala Ser Ser Pro

195 200 205

Gly Ala Thr Asp Glu Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val

210 215 220

Leu Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro

225 230 235 240

Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

245 250 255

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

260 265 270

Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val

275 280 285

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

290 295 300

Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

305 310 315 320

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala

325 330 335

Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

340 345 350

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr

355 360 365

Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser

370 375 380

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

385 390 395 400

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

405 410 415

Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe

420 425 430

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

435 440 445

Ser Leu Ser Leu Ser Pro

450

<210> 235

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 235

Ala Leu Tyr Asn Asn Arg Asp Met Arg

1 5

<210> 236

<211> 454

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 236

Gln Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Ser Ala Thr Ser Ser Val Ser Tyr Met

20 25 30

His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr

35 40 45

Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser

50 55 60

Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu

65 70 75 80

Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr

85 90 95

Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Ser Gly Gly

100 105 110

Gly Gly Gly Val Ile Gln Ser Pro Arg His Glu Val Thr Glu Met Gly

115 120 125

Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His Asn Ser Leu

130 135 140

Phe Trp Tyr Arg Glu Thr Pro Met Gln Gly Leu Glu Leu Leu Ile Tyr

145 150 155 160

Phe Gln Asn Thr Ala Val Ile Asp Asp Ser Gly Met Pro Glu Asp Arg

165 170 175

Phe Ser Ala Lys Met Pro Asn Asp Ser Phe Ser Thr Leu Lys Ile Gln

180 185 190

Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala Ser Ser Pro

195 200 205

Gly Ala Thr Asp Ala Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val

210 215 220

Leu Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro

225 230 235 240

Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

245 250 255

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

260 265 270

Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val

275 280 285

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

290 295 300

Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

305 310 315 320

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala

325 330 335

Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

340 345 350

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr

355 360 365

Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser

370 375 380

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

385 390 395 400

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

405 410 415

Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe

420 425 430

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

435 440 445

Ser Leu Ser Leu Ser Pro

450

<210> 237

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 237

Ala Leu Tyr Asn Asn Val Asp Met Arg

1 5

<210> 238

<211> 454

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 238

Gln Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Ser Ala Thr Ser Ser Val Ser Tyr Met

20 25 30

His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr

35 40 45

Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser

50 55 60

Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu

65 70 75 80

Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr

85 90 95

Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Ser Gly Gly

100 105 110

Gly Gly Gly Val Ile Gln Ser Pro Arg His Glu Val Thr Glu Met Gly

115 120 125

Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His Asn Ser Leu

130 135 140

Phe Trp Tyr Arg Glu Thr Pro Met Gln Gly Leu Glu Leu Leu Ile Tyr

145 150 155 160

Phe Gln Asn Thr Ala Val Ile Asp Asp Ser Gly Met Pro Glu Asp Arg

165 170 175

Phe Ser Ala Lys Met Pro Asn Asp Ser Phe Ser Thr Leu Lys Ile Gln

180 185 190

Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala Ser Ser Pro

195 200 205

Gly Ala Thr Asp Gln Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val

210 215 220

Leu Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro

225 230 235 240

Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

245 250 255

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

260 265 270

Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val

275 280 285

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

290 295 300

Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

305 310 315 320

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala

325 330 335

Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

340 345 350

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr

355 360 365

Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser

370 375 380

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

385 390 395 400

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

405 410 415

Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe

420 425 430

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

435 440 445

Ser Leu Ser Leu Ser Pro

450

<210> 239

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 239

Ala Ser Ser Pro Gly Ala Thr Asp Leu Gln Tyr

1 5 10

<210> 240

<211> 454

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 240

Gln Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Ser Ala Thr Ser Ser Val Ser Tyr Met

20 25 30

His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr

35 40 45

Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser

50 55 60

Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu

65 70 75 80

Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr

85 90 95

Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Ser Gly Gly

100 105 110

Gly Gly Gly Val Ile Gln Ser Pro Arg His Glu Val Thr Glu Met Gly

115 120 125

Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His Asn Ser Leu

130 135 140

Phe Trp Tyr Arg Glu Thr Pro Met Gln Gly Leu Glu Leu Leu Ile Tyr

145 150 155 160

Phe Gln Asn Thr Ala Val Ile Asp Asp Ser Gly Met Pro Glu Asp Arg

165 170 175

Phe Ser Ala Lys Met Pro Asn Asp Ser Phe Ser Thr Leu Lys Ile Gln

180 185 190

Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala Ser Ser Pro

195 200 205

Gly Ala Thr Asp Asn Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val

210 215 220

Leu Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro

225 230 235 240

Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

245 250 255

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

260 265 270

Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val

275 280 285

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

290 295 300

Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

305 310 315 320

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala

325 330 335

Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

340 345 350

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr

355 360 365

Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser

370 375 380

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

385 390 395 400

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

405 410 415

Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe

420 425 430

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

435 440 445

Ser Leu Ser Leu Ser Pro

450

<210> 241

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 241

Ala Ser Ser Pro Gly Ala Thr Asp Arg Gln Tyr

1 5 10

<210> 242

<211> 454

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 242

Gln Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Ser Ala Thr Ser Ser Val Ser Tyr Met

20 25 30

His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr

35 40 45

Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser

50 55 60

Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu

65 70 75 80

Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr

85 90 95

Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Ser Gly Gly

100 105 110

Gly Gly Gly Val Ile Gln Ser Pro Arg His Glu Val Thr Glu Met Gly

115 120 125

Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His Asn Ser Leu

130 135 140

Phe Trp Tyr Arg Glu Thr Pro Met Gln Gly Leu Glu Leu Leu Ile Tyr

145 150 155 160

Phe Gln Asn Thr Ala Val Ile Asp Asp Ser Gly Met Pro Glu Asp Arg

165 170 175

Phe Ser Ala Lys Met Pro Asn Asp Ser Phe Ser Thr Leu Lys Ile Gln

180 185 190

Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala Ser Ser Pro

195 200 205

Gly Ala Thr Asp Phe Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val

210 215 220

Leu Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro

225 230 235 240

Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

245 250 255

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

260 265 270

Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val

275 280 285

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

290 295 300

Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

305 310 315 320

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala

325 330 335

Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

340 345 350

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr

355 360 365

Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser

370 375 380

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

385 390 395 400

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

405 410 415

Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe

420 425 430

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

435 440 445

Ser Leu Ser Leu Ser Pro

450

<210> 243

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 243

Ala Ser Ser Pro Gly Ala Thr Asp His Gln Tyr

1 5 10

<210> 244

<211> 454

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 244

Gln Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Ser Ala Thr Ser Ser Val Ser Tyr Met

20 25 30

His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr

35 40 45

Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser

50 55 60

Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu

65 70 75 80

Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr

85 90 95

Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Ser Gly Gly

100 105 110

Gly Gly Gly Val Ile Gln Ser Pro Arg His Glu Val Thr Glu Met Gly

115 120 125

Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His Asn Ser Leu

130 135 140

Phe Trp Tyr Arg Glu Thr Pro Met Gln Gly Leu Glu Leu Leu Ile Tyr

145 150 155 160

Phe Gln Asn Thr Ala Val Ile Asp Asp Ser Gly Met Pro Glu Asp Arg

165 170 175

Phe Ser Ala Lys Met Pro Asn Asp Ser Phe Ser Thr Leu Lys Ile Gln

180 185 190

Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala Ser Ser Pro

195 200 205

Gly Ala Thr Asp Tyr Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val

210 215 220

Leu Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro

225 230 235 240

Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

245 250 255

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

260 265 270

Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val

275 280 285

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

290 295 300

Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

305 310 315 320

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala

325 330 335

Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

340 345 350

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr

355 360 365

Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser

370 375 380

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

385 390 395 400

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

405 410 415

Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe

420 425 430

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

435 440 445

Ser Leu Ser Leu Ser Pro

450

<210> 245

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 245

Ala Ser Ser Pro Gly Ala Thr Asp Glu Gln Tyr

1 5 10

<210> 246

<211> 454

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 246

Gln Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Ser Ala Thr Ser Ser Val Ser Tyr Met

20 25 30

His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr

35 40 45

Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser

50 55 60

Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu

65 70 75 80

Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr

85 90 95

Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Ser Gly Gly

100 105 110

Gly Gly Gly Val Ile Gln Ser Pro Arg His Glu Val Thr Glu Met Gly

115 120 125

Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His Asn Ser Leu

130 135 140

Phe Trp Tyr Arg Glu Thr Pro Met Gln Gly Leu Glu Leu Leu Ile Tyr

145 150 155 160

Phe Gln Asn Thr Ala Val Ile Asp Asp Ser Gly Met Pro Glu Asp Arg

165 170 175

Phe Ser Ala Lys Met Pro Asn Asp Ser Phe Ser Thr Leu Lys Ile Gln

180 185 190

Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala Ser Ser Pro

195 200 205

Gly Ala Thr Asp Ile Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val

210 215 220

Leu Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro

225 230 235 240

Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

245 250 255

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

260 265 270

Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val

275 280 285

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

290 295 300

Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

305 310 315 320

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala

325 330 335

Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

340 345 350

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr

355 360 365

Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser

370 375 380

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

385 390 395 400

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

405 410 415

Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe

420 425 430

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

435 440 445

Ser Leu Ser Leu Ser Pro

450

<210> 247

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 247

Ala Ser Ser Pro Gly Ala Thr Asp Ala Gln Tyr

1 5 10

<210> 248

<211> 454

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 248

Gln Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Ser Ala Thr Ser Ser Val Ser Tyr Met

20 25 30

His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr

35 40 45

Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser

50 55 60

Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu

65 70 75 80

Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr

85 90 95

Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Ser Gly Gly

100 105 110

Gly Gly Gly Val Ile Gln Ser Pro Arg His Glu Val Thr Glu Met Gly

115 120 125

Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His Asn Ser Leu

130 135 140

Phe Trp Tyr Arg Glu Thr Pro Met Gln Gly Leu Glu Leu Leu Ile Tyr

145 150 155 160

Phe Gln Asn Thr Ala Val Ile Asp Asp Ser Gly Met Pro Glu Asp Arg

165 170 175

Phe Ser Ala Lys Met Pro Asn Asp Ser Phe Ser Thr Leu Lys Ile Gln

180 185 190

Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala Ser Ser Pro

195 200 205

Gly Ala Thr Asp Val Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val

210 215 220

Leu Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro

225 230 235 240

Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

245 250 255

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

260 265 270

Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val

275 280 285

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

290 295 300

Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

305 310 315 320

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala

325 330 335

Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

340 345 350

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr

355 360 365

Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser

370 375 380

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

385 390 395 400

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

405 410 415

Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe

420 425 430

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

435 440 445

Ser Leu Ser Leu Ser Pro

450

<210> 249

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 249

Ala Ser Ser Pro Gly Ala Thr Asp Gln Gln Tyr

1 5 10

<210> 250

<211> 454

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 250

Gln Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Ser Ala Thr Ser Ser Val Ser Tyr Met

20 25 30

His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr

35 40 45

Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser

50 55 60

Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu

65 70 75 80

Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr

85 90 95

Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Ser Gly Gly

100 105 110

Gly Gly Gly Val Ile Gln Ser Pro Arg His Glu Val Thr Glu Met Gly

115 120 125

Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His Asn Ser Leu

130 135 140

Phe Trp Tyr Arg Glu Thr Pro Met Gln Gly Leu Glu Leu Leu Ile Tyr

145 150 155 160

Phe Gln Asn Thr Ala Val Ile Asp Asp Ser Gly Met Pro Glu Asp Arg

165 170 175

Phe Ser Ala Lys Met Pro Asn Asp Ser Phe Ser Thr Leu Lys Ile Gln

180 185 190

Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala Ser Ser Pro

195 200 205

Gly Ser Thr Asp Arg Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val

210 215 220

Leu Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro

225 230 235 240

Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

245 250 255

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

260 265 270

Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val

275 280 285

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

290 295 300

Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

305 310 315 320

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala

325 330 335

Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

340 345 350

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr

355 360 365

Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser

370 375 380

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

385 390 395 400

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

405 410 415

Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe

420 425 430

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

435 440 445

Ser Leu Ser Leu Ser Pro

450

<210> 251

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 251

Ala Ser Ser Pro Gly Ala Thr Asp Asn Gln Tyr

1 5 10

<210> 252

<211> 454

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 252

Gln Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Ser Ala Thr Ser Ser Val Ser Tyr Met

20 25 30

His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr

35 40 45

Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser

50 55 60

Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu

65 70 75 80

Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr

85 90 95

Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Ser Gly Gly

100 105 110

Gly Gly Gly Val Ile Gln Ser Pro Arg His Glu Val Thr Glu Met Gly

115 120 125

Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His Asn Ser Leu

130 135 140

Phe Trp Tyr Arg Glu Thr Pro Met Gln Gly Leu Glu Leu Leu Ile Tyr

145 150 155 160

Phe Gln Asn Thr Ala Val Ile Asp Asp Ser Gly Met Pro Glu Asp Arg

165 170 175

Phe Ser Ala Lys Met Pro Asn Asp Ser Phe Ser Thr Leu Lys Ile Gln

180 185 190

Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala Ser Ser Pro

195 200 205

Gly Ser Thr Asp His Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val

210 215 220

Leu Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro

225 230 235 240

Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

245 250 255

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

260 265 270

Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val

275 280 285

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

290 295 300

Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

305 310 315 320

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala

325 330 335

Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

340 345 350

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr

355 360 365

Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser

370 375 380

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

385 390 395 400

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

405 410 415

Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe

420 425 430

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

435 440 445

Ser Leu Ser Leu Ser Pro

450

<210> 253

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 253

Ala Ser Ser Pro Gly Ala Thr Asp Phe Gln Tyr

1 5 10

<210> 254

<211> 454

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 254

Gln Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Ser Ala Thr Ser Ser Val Ser Tyr Met

20 25 30

His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr

35 40 45

Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser

50 55 60

Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu

65 70 75 80

Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr

85 90 95

Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Ser Gly Gly

100 105 110

Gly Gly Gly Val Ile Gln Ser Pro Arg His Glu Val Thr Glu Met Gly

115 120 125

Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His Asn Ser Leu

130 135 140

Phe Trp Tyr Arg Glu Thr Pro Met Gln Gly Leu Glu Leu Leu Ile Tyr

145 150 155 160

Phe Gln Asn Thr Ala Val Ile Asp Asp Ser Gly Met Pro Glu Asp Arg

165 170 175

Phe Ser Ala Lys Met Pro Asn Asp Ser Phe Ser Thr Leu Lys Ile Gln

180 185 190

Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala Ser Ser Pro

195 200 205

Gly Ser Thr Asp Glu Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val

210 215 220

Leu Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro

225 230 235 240

Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

245 250 255

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

260 265 270

Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val

275 280 285

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

290 295 300

Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

305 310 315 320

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala

325 330 335

Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

340 345 350

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr

355 360 365

Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser

370 375 380

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

385 390 395 400

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

405 410 415

Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe

420 425 430

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

435 440 445

Ser Leu Ser Leu Ser Pro

450

<210> 255

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 255

Ala Ser Ser Pro Gly Ala Thr Asp Tyr Gln Tyr

1 5 10

<210> 256

<211> 454

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 256

Gln Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Ser Ala Thr Ser Ser Val Ser Tyr Met

20 25 30

His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr

35 40 45

Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser

50 55 60

Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu

65 70 75 80

Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr

85 90 95

Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Ser Gly Gly

100 105 110

Gly Gly Gly Val Ile Gln Ser Pro Arg His Glu Val Thr Glu Met Gly

115 120 125

Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His Asn Ser Leu

130 135 140

Phe Trp Tyr Arg Glu Thr Pro Met Gln Gly Leu Glu Leu Leu Ile Tyr

145 150 155 160

Phe Gln Asn Thr Ala Val Ile Asp Asp Ser Gly Met Pro Glu Asp Arg

165 170 175

Phe Ser Ala Lys Met Pro Asn Asp Ser Phe Ser Thr Leu Lys Ile Gln

180 185 190

Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala Ser Ser Pro

195 200 205

Gly Ser Thr Asp Ala Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val

210 215 220

Leu Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro

225 230 235 240

Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

245 250 255

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

260 265 270

Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val

275 280 285

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

290 295 300

Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

305 310 315 320

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala

325 330 335

Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

340 345 350

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr

355 360 365

Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser

370 375 380

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

385 390 395 400

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

405 410 415

Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe

420 425 430

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

435 440 445

Ser Leu Ser Leu Ser Pro

450

<210> 257

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 257

Ala Ser Ser Pro Gly Ala Thr Asp Ile Gln Tyr

1 5 10

<210> 258

<211> 454

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 258

Gln Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Ser Ala Thr Ser Ser Val Ser Tyr Met

20 25 30

His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr

35 40 45

Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser

50 55 60

Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu

65 70 75 80

Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr

85 90 95

Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Ser Gly Gly

100 105 110

Gly Gly Gly Val Ile Gln Ser Pro Arg His Glu Val Thr Glu Met Gly

115 120 125

Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His Asn Ser Leu

130 135 140

Phe Trp Tyr Arg Glu Thr Pro Met Gln Gly Leu Glu Leu Leu Ile Tyr

145 150 155 160

Phe Gln Asn Thr Ala Val Ile Asp Asp Ser Gly Met Pro Glu Asp Arg

165 170 175

Phe Ser Ala Lys Met Pro Asn Asp Ser Phe Ser Thr Leu Lys Ile Gln

180 185 190

Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala Ser Ser Pro

195 200 205

Gly Ser Thr Asp Gln Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val

210 215 220

Leu Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro

225 230 235 240

Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

245 250 255

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

260 265 270

Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val

275 280 285

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

290 295 300

Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

305 310 315 320

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala

325 330 335

Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

340 345 350

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr

355 360 365

Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser

370 375 380

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

385 390 395 400

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

405 410 415

Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe

420 425 430

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

435 440 445

Ser Leu Ser Leu Ser Pro

450

<210> 259

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 259

Ala Ser Ser Pro Gly Ala Thr Asp Val Gln Tyr

1 5 10

<210> 260

<211> 454

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 260

Gln Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Ser Ala Thr Ser Ser Val Ser Tyr Met

20 25 30

His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr

35 40 45

Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser

50 55 60

Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu

65 70 75 80

Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr

85 90 95

Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Ser Gly Gly

100 105 110

Gly Gly Gly Val Ile Gln Ser Pro Arg His Glu Val Thr Glu Met Gly

115 120 125

Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His Asn Ser Leu

130 135 140

Phe Trp Tyr Arg Glu Thr Pro Met Gln Gly Leu Glu Leu Leu Ile Tyr

145 150 155 160

Phe Gln Asn Thr Ala Val Ile Asp Asp Ser Gly Met Pro Glu Asp Arg

165 170 175

Phe Ser Ala Lys Met Pro Asn Asp Ser Phe Ser Thr Leu Lys Ile Gln

180 185 190

Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala Ser Ser Pro

195 200 205

Gly Ser Thr Asp Asn Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val

210 215 220

Leu Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro

225 230 235 240

Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

245 250 255

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

260 265 270

Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val

275 280 285

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

290 295 300

Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

305 310 315 320

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala

325 330 335

Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

340 345 350

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr

355 360 365

Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser

370 375 380

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

385 390 395 400

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

405 410 415

Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe

420 425 430

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

435 440 445

Ser Leu Ser Leu Ser Pro

450

<210> 261

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 261

Ala Ser Ser Pro Gly Ser Thr Asp Arg Gln Tyr

1 5 10

<210> 262

<211> 454

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 262

Gln Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Ser Ala Thr Ser Ser Val Ser Tyr Met

20 25 30

His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr

35 40 45

Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser

50 55 60

Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu

65 70 75 80

Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr

85 90 95

Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Ser Gly Gly

100 105 110

Gly Gly Gly Val Ile Gln Ser Pro Arg His Glu Val Thr Glu Met Gly

115 120 125

Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His Asn Ser Leu

130 135 140

Phe Trp Tyr Arg Glu Thr Pro Met Gln Gly Leu Glu Leu Leu Ile Tyr

145 150 155 160

Phe Gln Asn Thr Ala Val Ile Asp Asp Ser Gly Met Pro Glu Asp Arg

165 170 175

Phe Ser Ala Lys Met Pro Asn Asp Ser Phe Ser Thr Leu Lys Ile Gln

180 185 190

Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala Ser Ser Pro

195 200 205

Gly Ser Thr Asp Phe Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val

210 215 220

Leu Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro

225 230 235 240

Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

245 250 255

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

260 265 270

Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val

275 280 285

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

290 295 300

Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

305 310 315 320

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala

325 330 335

Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

340 345 350

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr

355 360 365

Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser

370 375 380

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

385 390 395 400

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

405 410 415

Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe

420 425 430

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

435 440 445

Ser Leu Ser Leu Ser Pro

450

<210> 263

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 263

Ala Ser Ser Pro Gly Ser Thr Asp His Gln Tyr

1 5 10

<210> 264

<211> 454

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 264

Gln Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Ser Ala Thr Ser Ser Val Ser Tyr Met

20 25 30

His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr

35 40 45

Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser

50 55 60

Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu

65 70 75 80

Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr

85 90 95

Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Ser Gly Gly

100 105 110

Gly Gly Gly Val Ile Gln Ser Pro Arg His Glu Val Thr Glu Met Gly

115 120 125

Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His Asn Ser Leu

130 135 140

Phe Trp Tyr Arg Glu Thr Pro Met Gln Gly Leu Glu Leu Leu Ile Tyr

145 150 155 160

Phe Gln Asn Thr Ala Val Ile Asp Asp Ser Gly Met Pro Glu Asp Arg

165 170 175

Phe Ser Ala Lys Met Pro Asn Asp Ser Phe Ser Thr Leu Lys Ile Gln

180 185 190

Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala Ser Ser Pro

195 200 205

Gly Ser Thr Asp Tyr Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val

210 215 220

Leu Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro

225 230 235 240

Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

245 250 255

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

260 265 270

Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val

275 280 285

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

290 295 300

Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

305 310 315 320

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala

325 330 335

Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

340 345 350

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr

355 360 365

Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser

370 375 380

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

385 390 395 400

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

405 410 415

Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe

420 425 430

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

435 440 445

Ser Leu Ser Leu Ser Pro

450

<210> 265

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 265

Ala Ser Ser Pro Gly Ser Thr Asp Glu Gln Tyr

1 5 10

<210> 266

<211> 454

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 266

Gln Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Ser Ala Thr Ser Ser Val Ser Tyr Met

20 25 30

His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr

35 40 45

Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser

50 55 60

Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu

65 70 75 80

Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr

85 90 95

Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Ser Gly Gly

100 105 110

Gly Gly Gly Val Ile Gln Ser Pro Arg His Glu Val Thr Glu Met Gly

115 120 125

Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His Asn Ser Leu

130 135 140

Phe Trp Tyr Arg Glu Thr Pro Met Gln Gly Leu Glu Leu Leu Ile Tyr

145 150 155 160

Phe Gln Asn Thr Ala Val Ile Asp Asp Ser Gly Met Pro Glu Asp Arg

165 170 175

Phe Ser Ala Lys Met Pro Asn Asp Ser Phe Ser Thr Leu Lys Ile Gln

180 185 190

Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala Ser Ser Pro

195 200 205

Gly Ser Thr Asp Ile Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val

210 215 220

Leu Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro

225 230 235 240

Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

245 250 255

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

260 265 270

Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val

275 280 285

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

290 295 300

Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

305 310 315 320

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala

325 330 335

Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

340 345 350

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr

355 360 365

Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser

370 375 380

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

385 390 395 400

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

405 410 415

Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe

420 425 430

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

435 440 445

Ser Leu Ser Leu Ser Pro

450

<210> 267

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 267

Ala Ser Ser Pro Gly Ser Thr Asp Gln Gln Tyr

1 5 10

<210> 268

<211> 454

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 268

Gln Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Ser Ala Thr Ser Ser Val Ser Tyr Met

20 25 30

His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr

35 40 45

Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser

50 55 60

Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu

65 70 75 80

Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr

85 90 95

Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Ser Gly Gly

100 105 110

Gly Gly Gly Val Ile Gln Ser Pro Arg His Glu Val Thr Glu Met Gly

115 120 125

Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His Asn Ser Leu

130 135 140

Phe Trp Tyr Arg Glu Thr Pro Met Gln Gly Leu Glu Leu Leu Ile Tyr

145 150 155 160

Phe Gln Asn Thr Ala Val Ile Asp Asp Ser Gly Met Pro Glu Asp Arg

165 170 175

Phe Ser Ala Lys Met Pro Asn Asp Ser Phe Ser Thr Leu Lys Ile Gln

180 185 190

Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala Ser Ser Pro

195 200 205

Gly Ser Thr Asp Val Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val

210 215 220

Leu Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro

225 230 235 240

Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

245 250 255

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

260 265 270

Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val

275 280 285

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

290 295 300

Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

305 310 315 320

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala

325 330 335

Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

340 345 350

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr

355 360 365

Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser

370 375 380

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

385 390 395 400

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

405 410 415

Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe

420 425 430

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

435 440 445

Ser Leu Ser Leu Ser Pro

450

<210> 269

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 269

Ala Ser Ser Pro Gly Ser Thr Asp Asn Gln Tyr

1 5 10

<210> 270

<211> 457

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 270

Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly

1 5 10 15

Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser Gly

20 25 30

Tyr Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly

35 40 45

Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro Ala Arg Phe

50 55 60

Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val

65 70 75 80

Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Ala Leu Trp Tyr Ser Asn

85 90 95

Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly Gly

100 105 110

Ser Gly Gly Gly Gly Gly Val Ile Gln Ser Pro Arg His Glu Val Thr

115 120 125

Glu Met Gly Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His

130 135 140

Asn Ser Leu Phe Trp Tyr Arg Glu Thr Pro Met Gln Gly Leu Glu Leu

145 150 155 160

Leu Ile Tyr Phe Gln Asn Thr Ala Val Ile Asp Asp Ser Gly Met Pro

165 170 175

Glu Asp Arg Phe Ser Ala Lys Met Pro Asn Glu Ser Phe Ser Thr Leu

180 185 190

Lys Ile Gln Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala

195 200 205

Ser Ser Pro Gly Ala Thr Asp Lys Gln Tyr Phe Gly Pro Gly Thr Arg

210 215 220

Leu Thr Val Leu Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro

225 230 235 240

Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro

245 250 255

Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr

260 265 270

Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn

275 280 285

Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg

290 295 300

Glu Glu Gln Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val

305 310 315 320

Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser

325 330 335

Asn Lys Ala Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys

340 345 350

Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp

355 360 365

Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe

370 375 380

Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu

385 390 395 400

Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe

405 410 415

Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly

420 425 430

Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr

435 440 445

Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455

<210> 271

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 271

Ala Ser Ser Pro Gly Ser Thr Asp Phe Gln Tyr

1 5 10

<210> 272

<211> 457

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 272

Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly

1 5 10 15

Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser Gly

20 25 30

Tyr Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly

35 40 45

Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro Ala Arg Phe

50 55 60

Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val

65 70 75 80

Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Ala Leu Trp Tyr Ser Asn

85 90 95

Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly Gly

100 105 110

Ser Gly Gly Gly Gly Gly Val Ile Gln Ser Pro Arg His Glu Val Thr

115 120 125

Glu Met Gly Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His

130 135 140

Asn Ser Leu Phe Trp Tyr Arg Glu Thr Pro Met Gln Gly Leu Glu Leu

145 150 155 160

Leu Ile Tyr Phe Gln Asn Thr Ala Val Ile Asp Asp Ser Gly Met Pro

165 170 175

Glu Asp Arg Phe Ser Ala Lys Met Pro Asn Arg Ser Phe Ser Thr Leu

180 185 190

Lys Ile Gln Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala

195 200 205

Ser Ser Pro Gly Ala Thr Asp Lys Gln Tyr Phe Gly Pro Gly Thr Arg

210 215 220

Leu Thr Val Leu Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro

225 230 235 240

Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro

245 250 255

Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr

260 265 270

Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn

275 280 285

Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg

290 295 300

Glu Glu Gln Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val

305 310 315 320

Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser

325 330 335

Asn Lys Ala Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys

340 345 350

Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp

355 360 365

Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe

370 375 380

Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu

385 390 395 400

Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe

405 410 415

Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly

420 425 430

Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr

435 440 445

Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455

<210> 273

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 273

Ala Ser Ser Pro Gly Ser Thr Asp Tyr Gln Tyr

1 5 10

<210> 274

<211> 457

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 274

Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly

1 5 10 15

Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser Gly

20 25 30

Tyr Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly

35 40 45

Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro Ala Arg Phe

50 55 60

Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val

65 70 75 80

Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Ala Leu Trp Tyr Ser Asn

85 90 95

Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly Gly

100 105 110

Ser Gly Gly Gly Gly Gly Val Ile Gln Ser Pro Arg His Glu Val Thr

115 120 125

Glu Met Gly Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His

130 135 140

Asn Ser Leu Phe Trp Tyr Arg Glu Thr Pro Met Gln Gly Leu Glu Leu

145 150 155 160

Leu Ile Tyr Phe Gln Asn Thr Ala Val Ile Asp Asp Ser Gly Met Pro

165 170 175

Glu Asp Arg Phe Ser Ala Lys Met Pro Asn Lys Ser Phe Ser Thr Leu

180 185 190

Lys Ile Gln Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala

195 200 205

Ser Ser Pro Gly Ala Thr Asp Lys Gln Tyr Phe Gly Pro Gly Thr Arg

210 215 220

Leu Thr Val Leu Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro

225 230 235 240

Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro

245 250 255

Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr

260 265 270

Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn

275 280 285

Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg

290 295 300

Glu Glu Gln Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val

305 310 315 320

Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser

325 330 335

Asn Lys Ala Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys

340 345 350

Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp

355 360 365

Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe

370 375 380

Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu

385 390 395 400

Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe

405 410 415

Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly

420 425 430

Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr

435 440 445

Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455

<210> 275

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 275

Ala Ser Ser Pro Gly Ser Thr Asp Ile Gln Tyr

1 5 10

<210> 276

<211> 457

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 276

Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly

1 5 10 15

Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser Gly

20 25 30

Tyr Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly

35 40 45

Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro Ala Arg Phe

50 55 60

Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val

65 70 75 80

Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Ala Leu Trp Tyr Ser Asn

85 90 95

Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly Gly

100 105 110

Ser Gly Gly Gly Gly Gly Val Ile Gln Ser Pro Arg His Glu Val Thr

115 120 125

Glu Met Gly Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His

130 135 140

Asn Ser Leu Phe Trp Tyr Arg Glu Thr Pro Met Gln Gly Leu Glu Leu

145 150 155 160

Leu Ile Tyr Phe Gln Asn Thr Ala Val Ile Asp Asp Ser Gly Met Pro

165 170 175

Glu Asp Arg Phe Ser Ala Lys Met Pro Asn Gln Ser Phe Ser Thr Leu

180 185 190

Lys Ile Gln Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala

195 200 205

Ser Ser Pro Gly Ala Thr Asp Lys Gln Tyr Phe Gly Pro Gly Thr Arg

210 215 220

Leu Thr Val Leu Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro

225 230 235 240

Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro

245 250 255

Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr

260 265 270

Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn

275 280 285

Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg

290 295 300

Glu Glu Gln Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val

305 310 315 320

Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser

325 330 335

Asn Lys Ala Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys

340 345 350

Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp

355 360 365

Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe

370 375 380

Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu

385 390 395 400

Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe

405 410 415

Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly

420 425 430

Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr

435 440 445

Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455

<210> 277

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 277

Ala Ser Ser Pro Gly Ser Thr Asp Val Gln Tyr

1 5 10

<210> 278

<211> 457

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 278

Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly

1 5 10 15

Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser Gly

20 25 30

Tyr Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly

35 40 45

Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro Ala Arg Phe

50 55 60

Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val

65 70 75 80

Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Ala Leu Trp Tyr Ser Asn

85 90 95

Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly Gly

100 105 110

Ser Gly Gly Gly Gly Gly Val Ile Gln Ser Pro Arg His Glu Val Thr

115 120 125

Glu Met Gly Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His

130 135 140

Asn Ser Leu Phe Trp Tyr Arg Glu Thr Pro Met Gln Gly Leu Glu Leu

145 150 155 160

Leu Ile Tyr Phe Gln Asn Thr Ala Val Ile Asp Asp Ser Gly Met Pro

165 170 175

Glu Asp Arg Phe Ser Ala Lys Met Pro Asn Asn Ser Phe Ser Thr Leu

180 185 190

Lys Ile Gln Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala

195 200 205

Ser Ser Pro Gly Ala Thr Asp Lys Gln Tyr Phe Gly Pro Gly Thr Arg

210 215 220

Leu Thr Val Leu Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro

225 230 235 240

Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro

245 250 255

Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr

260 265 270

Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn

275 280 285

Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg

290 295 300

Glu Glu Gln Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val

305 310 315 320

Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser

325 330 335

Asn Lys Ala Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys

340 345 350

Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp

355 360 365

Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe

370 375 380

Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu

385 390 395 400

Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe

405 410 415

Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly

420 425 430

Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr

435 440 445

Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455

<210> 279

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 279

Ala Ser Ser Ser Gly Ala Thr Asp Val Gln Tyr

1 5 10

<210> 280

<211> 457

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 280

Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly

1 5 10 15

Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser Gly

20 25 30

Tyr Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly

35 40 45

Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro Ala Arg Phe

50 55 60

Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val

65 70 75 80

Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Ala Leu Trp Tyr Ser Asn

85 90 95

Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly Gly

100 105 110

Ser Gly Gly Gly Gly Gly Val Ile Gln Ser Pro Arg His Glu Val Thr

115 120 125

Glu Met Gly Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His

130 135 140

Asn Ser Leu Phe Trp Tyr Arg Glu Thr Pro Met Gln Gly Leu Glu Leu

145 150 155 160

Leu Ile Tyr Phe Gln Asn Thr Ala Val Ile Asp Asp Ser Gly Met Pro

165 170 175

Glu Asp Arg Phe Ser Ala Lys Met Pro Asn Tyr Ser Phe Ser Thr Leu

180 185 190

Lys Ile Gln Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala

195 200 205

Ser Ser Pro Gly Ala Thr Asp Lys Gln Tyr Phe Gly Pro Gly Thr Arg

210 215 220

Leu Thr Val Leu Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro

225 230 235 240

Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro

245 250 255

Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr

260 265 270

Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn

275 280 285

Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg

290 295 300

Glu Glu Gln Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val

305 310 315 320

Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser

325 330 335

Asn Lys Ala Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys

340 345 350

Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp

355 360 365

Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe

370 375 380

Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu

385 390 395 400

Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe

405 410 415

Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly

420 425 430

Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr

435 440 445

Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455

<210> 281

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 281

Ala Ser Ser Ala Gly Ala Thr Asp Lys Gln Tyr

1 5 10

<210> 282

<211> 457

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 282

Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly

1 5 10 15

Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser Gly

20 25 30

Tyr Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly

35 40 45

Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro Ala Arg Phe

50 55 60

Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val

65 70 75 80

Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Ala Leu Trp Tyr Ser Asn

85 90 95

Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly Gly

100 105 110

Ser Gly Gly Gly Gly Gly Val Ile Gln Ser Pro Arg His Glu Val Thr

115 120 125

Glu Met Gly Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His

130 135 140

Asn Ser Leu Phe Trp Tyr Arg Glu Thr Pro Met Gln Gly Leu Glu Leu

145 150 155 160

Leu Ile Tyr Phe Gln Asn Thr Ala Val Ile Asp Asp Ser Gly Met Pro

165 170 175

Glu Asp Arg Phe Ser Ala Lys Met Pro Asn Ser Ser Phe Ser Thr Leu

180 185 190

Lys Ile Gln Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala

195 200 205

Ser Ser Pro Gly Ala Thr Asp Lys Gln Tyr Phe Gly Pro Gly Thr Arg

210 215 220

Leu Thr Val Leu Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro

225 230 235 240

Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro

245 250 255

Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr

260 265 270

Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn

275 280 285

Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg

290 295 300

Glu Glu Gln Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val

305 310 315 320

Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser

325 330 335

Asn Lys Ala Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys

340 345 350

Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp

355 360 365

Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe

370 375 380

Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu

385 390 395 400

Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe

405 410 415

Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly

420 425 430

Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr

435 440 445

Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455

<210> 283

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 283

Ala Ser Ser Pro Gly Ala Ile Asp Lys Gln Tyr

1 5 10

<210> 284

<211> 454

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 284

Gln Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Ser Ala Thr Ser Ser Val Ser Tyr Met

20 25 30

His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr

35 40 45

Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser

50 55 60

Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu

65 70 75 80

Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr

85 90 95

Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Ser Gly Gly

100 105 110

Gly Gly Gly Val Ile Gln Ser Pro Arg His Glu Val Thr Glu Met Gly

115 120 125

Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His Asn Ser Leu

130 135 140

Phe Trp Tyr Arg Glu Thr Pro Met Gln Gly Leu Glu Leu Leu Ile Tyr

145 150 155 160

Phe Gln Asn Thr Ala Val Ile Asp Asp Ser Gly Met Pro Glu Asp Arg

165 170 175

Phe Ser Ala Lys Met Pro Asn Asp Ser Phe Ser Thr Leu Lys Ile Gln

180 185 190

Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala Ser Ser Pro

195 200 205

Gly Ser Thr Asp Ala Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val

210 215 220

Leu Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro

225 230 235 240

Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

245 250 255

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

260 265 270

Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val

275 280 285

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

290 295 300

Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

305 310 315 320

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala

325 330 335

Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

340 345 350

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr

355 360 365

Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser

370 375 380

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

385 390 395 400

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

405 410 415

Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe

420 425 430

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

435 440 445

Ser Leu Ser Leu Ser Pro

450

<210> 285

<211> 467

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 285

Ile Leu Asn Val Glu Gln Ser Pro Gln Ser Leu His Val Gln Glu Gly

1 5 10 15

Asp Ser Thr Lys Phe Thr Cys Ser Phe Pro Val Lys Glu Phe Gln Asp

20 25 30

Leu His Trp Tyr Arg Lys Glu Thr Ala Lys Ser Pro Glu Phe Leu Phe

35 40 45

Tyr Phe Gly Pro Tyr Gly Lys Glu Lys Lys Lys Gly Arg Ile Ser Ala

50 55 60

Thr Leu Asn Thr Lys Glu Gly Tyr Ser Tyr Leu Tyr Ile Thr Asp Ser

65 70 75 80

Gln Pro Glu Asp Ser Ala Thr Tyr Leu Cys Ala Leu Tyr Asn Asn Tyr

85 90 95

Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro Gly Gly

100 105 110

Gly Ser Gly Gly Gly Gly Glu Val Gln Leu Val Gln Ser Gly Ala Glu

115 120 125

Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly

130 135 140

Tyr Lys Phe Thr Arg Tyr Val Met His Trp Val Arg Gln Ala Pro Gly

145 150 155 160

Gln Gly Leu Glu Trp Met Gly Tyr Ile Asn Pro Tyr Asn Asp Val Thr

165 170 175

Lys Tyr Ala Glu Lys Phe Gln Gly Arg Val Thr Leu Thr Ser Asp Thr

180 185 190

Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp

195 200 205

Thr Ala Val His Tyr Cys Ala Arg Gly Ser Tyr Tyr Asp Tyr Glu Gly

210 215 220

Phe Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Glu Pro

225 230 235 240

Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Pro

245 250 255

Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr

260 265 270

Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val

275 280 285

Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val

290 295 300

Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gln Ser

305 310 315 320

Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu

325 330 335

Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala

340 345 350

Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro

355 360 365

Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln

370 375 380

Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala

385 390 395 400

Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr

405 410 415

Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu

420 425 430

Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser

435 440 445

Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser

450 455 460

Leu Ser Pro

465

<210> 286

<211> 5

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 286

Gly Gly Gly Gly Ser

1 5

<210> 287

<211> 5

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 287

Gly Gly Gly Ala Ser

1 5

<210> 288

<211> 10

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 288

Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu

1 5 10

<210> 289

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 289

Ala Ala Ala Gly Gly Ser Gly Gly

1 5

<210> 290

<211> 4

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 290

Gly Gly Gly Ser

1

<210> 291

<211> 467

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 291

Ile Leu Asn Val Glu Gln Ser Pro Gln Ser Leu His Val Gln Glu Gly

1 5 10 15

Asp Ser Thr Lys Phe Thr Cys Ser Phe Pro Val Lys Glu Phe Gln Asp

20 25 30

Leu His Trp Tyr Arg Lys Glu Thr Ala Lys Ser Pro Glu Phe Leu Phe

35 40 45

Tyr Phe Gly Pro Tyr Gly Lys Glu Lys Lys Lys Gly Arg Ile Ser Ala

50 55 60

Thr Leu Asn Thr Lys Glu Gly Tyr Ser Tyr Leu Tyr Ile Thr Asp Ser

65 70 75 80

Gln Pro Glu Asp Ser Ala Thr Tyr Leu Cys Ala Leu Tyr Asn Asn Tyr

85 90 95

Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro Gly Gly

100 105 110

Gly Ser Gly Gly Gly Gly Glu Val Gln Leu Val Gln Ser Gly Ala Glu

115 120 125

Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly

130 135 140

Tyr Lys Phe Thr Ser Tyr Val Met His Trp Val Arg Gln Ala Pro Gly

145 150 155 160

Gln Gly Leu Glu Trp Met Gly Tyr Ile Asn Pro Arg Asn Asp Val Thr

165 170 175

Lys Tyr Ala Glu Lys Phe Gln Gly Arg Val Thr Leu Thr Ser Asp Thr

180 185 190

Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp

195 200 205

Thr Ala Val His Tyr Cys Ala Arg Gly Ser Tyr Tyr Asp Tyr Glu Gly

210 215 220

Phe Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Glu Pro

225 230 235 240

Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Pro

245 250 255

Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr

260 265 270

Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val

275 280 285

Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val

290 295 300

Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gln Ser

305 310 315 320

Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu

325 330 335

Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala

340 345 350

Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro

355 360 365

Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln

370 375 380

Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala

385 390 395 400

Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr

405 410 415

Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu

420 425 430

Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser

435 440 445

Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser

450 455 460

Leu Ser Pro

465

<210> 292

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 292

Ala Ser Ser Ala Gly Ser Thr Asp Ala Gln Tyr

1 5 10

<210> 293

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 293

Ala Ser Ser Arg Gly Ser Thr Asp Ala Gln Tyr

1 5 10

<210> 294

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 294

Ala Ser Ser Pro Gly Ser Ile Asp Ala Gln Tyr

1 5 10

<210> 295

<211> 472

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 295

Ile Leu Asn Val Glu Gln Ser Pro Gln Ser Leu His Val Gln Glu Gly

1 5 10 15

Asp Ser Thr Lys Phe Thr Cys Ser Phe Pro Val Lys Glu Phe Gln Asp

20 25 30

Leu His Trp Tyr Arg Lys Glu Thr Ala Lys Ser Pro Glu Phe Leu Phe

35 40 45

Tyr Phe Gly Pro Tyr Gly Lys Glu Lys Lys Lys Gly Arg Ile Ser Ala

50 55 60

Thr Leu Asn Thr Lys Glu Gly Tyr Ser Tyr Leu Tyr Ile Thr Asp Ser

65 70 75 80

Gln Pro Glu Asp Ser Ala Thr Tyr Leu Cys Ala Leu Tyr Asn Asn Leu

85 90 95

Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro Gly Gly

100 105 110

Gly Ser Gly Gly Gly Gly Glu Val Gln Leu Val Glu Ser Gly Gly Gly

115 120 125

Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly

130 135 140

Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly

145 150 155 160

Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr

165 170 175

Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg

180 185 190

Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr

195 200 205

Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe Gly Asn

210 215 220

Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr

225 230 235 240

Val Ser Ser Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro

245 250 255

Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro

260 265 270

Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys

275 280 285

Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp

290 295 300

Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu

305 310 315 320

Glu Gln Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu

325 330 335

His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn

340 345 350

Lys Ala Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly

355 360 365

Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu

370 375 380

Leu Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr

385 390 395 400

Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn

405 410 415

Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe

420 425 430

Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn

435 440 445

Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr

450 455 460

Gln Lys Ser Leu Ser Leu Ser Pro

465 470

<210> 296

<211> 457

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 296

Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly

1 5 10 15

Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser Gly

20 25 30

Tyr Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly

35 40 45

Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro Ala Arg Phe

50 55 60

Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val

65 70 75 80

Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Ala Leu Trp Tyr Ser Asn

85 90 95

Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly Gly

100 105 110

Ser Gly Gly Gly Gly Gly Val Ile Gln Ser Pro Arg His Glu Val Thr

115 120 125

Glu Met Gly Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His

130 135 140

Asn Ser Leu Phe Trp Tyr Arg Glu Thr Pro Met Gln Gly Leu Glu Leu

145 150 155 160

Leu Ile Tyr Phe Gln Asn Thr Ala Val Ile Asp Asp Ser Gly Met Pro

165 170 175

Glu Asp Arg Phe Ser Ala Lys Met Pro Asn Asp Ser Phe Ser Thr Leu

180 185 190

Lys Ile Gln Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala

195 200 205

Ser Ser Pro Gly Ala Thr Asp Lys Gln Tyr Phe Gly Pro Gly Thr Arg

210 215 220

Leu Thr Val Leu Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro

225 230 235 240

Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro

245 250 255

Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr

260 265 270

Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn

275 280 285

Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg

290 295 300

Glu Glu Gln Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val

305 310 315 320

Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser

325 330 335

Asn Lys Ala Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys

340 345 350

Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp

355 360 365

Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe

370 375 380

Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu

385 390 395 400

Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe

405 410 415

Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly

420 425 430

Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr

435 440 445

Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455

<210> 297

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 297

Ala Ser Ser Thr Gly Ala Thr Asp Lys Gln Tyr

1 5 10

<210> 298

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 298

Ala Ser Ser Ala Gly Ala Ile Asp Lys Gln Tyr

1 5 10

<210> 299

<211> 467

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 299

Ile Leu Asn Val Glu Gln Ser Pro Gln Ser Leu His Val Gln Glu Gly

1 5 10 15

Asp Ser Thr Lys Phe Thr Cys Ser Phe Pro Val Lys Glu Phe Gln Asp

20 25 30

Leu His Trp Tyr Arg Lys Glu Thr Ala Lys Ser Pro Glu Phe Leu Phe

35 40 45

Tyr Phe Gly Pro Tyr Gly Lys Glu Lys Lys Lys Gly Arg Ile Ser Ala

50 55 60

Thr Leu Asn Thr Lys Glu Gly Tyr Ser Tyr Leu Tyr Ile Thr Asp Ser

65 70 75 80

Gln Pro Glu Asp Ser Ala Thr Tyr Leu Cys Ala Leu Tyr Asn Asn Leu

85 90 95

Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro Gly Gly

100 105 110

Gly Ser Gly Gly Gly Gly Glu Val Gln Leu Val Gln Ser Gly Ala Glu

115 120 125

Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly

130 135 140

Tyr Lys Phe Thr Arg Tyr Val Met His Trp Val Arg Gln Ala Pro Gly

145 150 155 160

Gln Gly Leu Glu Trp Met Gly Tyr Ile Asn Pro Tyr Asn Asp Val Thr

165 170 175

Lys Tyr Ala Glu Lys Phe Gln Gly Arg Val Thr Leu Thr Ser Asp Thr

180 185 190

Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp

195 200 205

Thr Ala Val His Tyr Cys Ala Arg Gly Ser Tyr Tyr Asp Tyr Glu Gly

210 215 220

Phe Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Glu Pro

225 230 235 240

Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Pro

245 250 255

Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr

260 265 270

Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val

275 280 285

Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val

290 295 300

Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gln Ser

305 310 315 320

Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu

325 330 335

Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala

340 345 350

Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro

355 360 365

Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln

370 375 380

Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala

385 390 395 400

Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr

405 410 415

Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu

420 425 430

Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser

435 440 445

Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser

450 455 460

Leu Ser Pro

465

<210> 300

<211> 454

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 300

Gln Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Ser Ala Thr Ser Ser Val Ser Tyr Met

20 25 30

His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr

35 40 45

Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser

50 55 60

Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu

65 70 75 80

Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr

85 90 95

Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Ser Gly Gly

100 105 110

Gly Gly Gly Val Ile Gln Ser Pro Arg His Glu Val Thr Glu Met Gly

115 120 125

Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His Asn Ser Leu

130 135 140

Phe Trp Tyr Arg Glu Thr Pro Met Gln Gly Leu Glu Leu Leu Ile Tyr

145 150 155 160

Phe Gln Asn Thr Ala Val Ile Asp Asp Ser Gly Met Pro Glu Asp Arg

165 170 175

Phe Ser Ala Lys Met Pro Asn Ala Ser Phe Ser Thr Leu Lys Ile Gln

180 185 190

Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala Ser Ser Pro

195 200 205

Gly Ala Thr Asp Lys Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val

210 215 220

Leu Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro

225 230 235 240

Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

245 250 255

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

260 265 270

Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val

275 280 285

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

290 295 300

Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

305 310 315 320

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala

325 330 335

Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

340 345 350

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr

355 360 365

Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser

370 375 380

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

385 390 395 400

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

405 410 415

Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe

420 425 430

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

435 440 445

Ser Leu Ser Leu Ser Pro

450

<210> 301

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 301

Ala Ser Ser Thr Gly Ala Ile Asp Lys Gln Tyr

1 5 10

<210> 302

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 302

Ala Ser Ser Ser Gly Ala Thr Asp Thr Gln Tyr

1 5 10

<210> 303

<211> 467

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 303

Ile Leu Asn Val Glu Gln Ser Pro Gln Ser Leu His Val Gln Glu Gly

1 5 10 15

Asp Ser Thr Lys Phe Thr Cys Ser Phe Pro Val Lys Glu Phe Gln Asp

20 25 30

Leu His Trp Tyr Arg Lys Glu Thr Ala Lys Ser Pro Glu Phe Leu Phe

35 40 45

Tyr Phe Gly Pro Tyr Gly Lys Glu Lys Lys Lys Gly Arg Ile Ser Ala

50 55 60

Thr Leu Asn Thr Lys Glu Gly Tyr Ser Tyr Leu Tyr Ile Thr Asp Ser

65 70 75 80

Gln Pro Glu Asp Ser Ala Thr Tyr Leu Cys Ala Leu Tyr Asn Asn Leu

85 90 95

Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro Gly Gly

100 105 110

Gly Ser Gly Gly Gly Gly Glu Val Gln Leu Val Gln Ser Gly Ala Glu

115 120 125

Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly

130 135 140

Tyr Lys Phe Thr Ser Tyr Val Met His Trp Val Arg Gln Ala Pro Gly

145 150 155 160

Gln Gly Leu Glu Trp Met Gly Tyr Ile Asn Pro Arg Asn Asp Val Thr

165 170 175

Lys Tyr Ala Glu Lys Phe Gln Gly Arg Val Thr Leu Thr Ser Asp Thr

180 185 190

Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp

195 200 205

Thr Ala Val His Tyr Cys Ala Arg Gly Ser Tyr Tyr Asp Tyr Glu Gly

210 215 220

Phe Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Glu Pro

225 230 235 240

Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Pro

245 250 255

Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr

260 265 270

Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val

275 280 285

Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val

290 295 300

Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gln Ser

305 310 315 320

Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu

325 330 335

Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala

340 345 350

Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro

355 360 365

Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln

370 375 380

Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala

385 390 395 400

Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr

405 410 415

Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu

420 425 430

Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser

435 440 445

Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser

450 455 460

Leu Ser Pro

465

<210> 304

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 304

His Leu Leu Pro Glu Val Phe Thr Leu

1 5

<210> 305

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 305

Asp Val Leu Asn Pro Leu Ile Thr Ala

1 5

<210> 306

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 306

Leu Thr Leu Gly His Leu Met Gly Val

1 5

<210> 307

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 307

Phe Leu Leu Ser Glu Pro Val Ala Leu

1 5

<210> 308

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 308

Leu Leu Thr Pro Ala Val Gln Asp Leu

1 5

<210> 309

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 309

Tyr Leu Gln Ala Ser Tyr Thr Tyr Leu

1 5

<210> 310

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 310

Phe Leu Asp Thr Ile Lys Ser Asn Leu

1 5

<210> 311

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 311

Ser Leu Leu Val His Asn Val Ser Val

1 5

<210> 312

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 312

Thr Leu Gln Glu Phe Leu Lys Leu Ala

1 5

<210> 313

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 313

Phe Leu Ile Thr Gln Leu Lys Met Leu

1 5

<210> 314

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 314

Val Leu Asp Ser Val Lys Leu Glu Ala

1 5

<210> 315

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 315

Ile Leu Gln Thr Phe Lys Thr Val Ala

1 5

<210> 316

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 316

Ile Leu Ala Ser Glu Leu Ser Arg Leu

1 5

<210> 317

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 317

Ser Leu Asn Leu Arg Glu Thr Asn Leu

1 5

<210> 318

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 318

Ala Leu Leu Gln His Leu Ile Gly Leu

1 5

<210> 319

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 319

Ser Leu Ala Gln His Leu Ile Gly Leu

1 5

<210> 320

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 320

Ser Leu Leu Ala His Leu Ile Gly Leu

1 5

<210> 321

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 321

Ser Leu Leu Gln Ala Leu Ile Gly Leu

1 5

<210> 322

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 322

Ser Leu Leu Gln His Ala Ile Gly Leu

1 5

<210> 323

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 323

Ser Leu Leu Gln His Leu Ala Gly Leu

1 5

<210> 324

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 324

Ser Leu Leu Gln His Leu Ile Ala Leu

1 5

<210> 325

<211> 369

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 325

Met Gln Leu Leu Arg Cys Phe Ser Ile Phe Ser Val Ile Ala Ser Val

1 5 10 15

Leu Ala Gln Glu Leu Thr Thr Ile Cys Glu Gln Ile Pro Ser Pro Thr

20 25 30

Leu Glu Ser Thr Pro Tyr Ser Leu Ser Thr Thr Thr Ile Leu Ala Asn

35 40 45

Gly Lys Ala Met Gln Gly Val Phe Glu Tyr Tyr Lys Ser Val Thr Phe

50 55 60

Val Ser Asn Cys Gly Ser His Pro Ser Thr Thr Ser Lys Gly Ser Pro

65 70 75 80

Ile Asn Thr Gln Tyr Val Phe Gly Gly Gly Gly Ser Asp Tyr Lys Asp

85 90 95

Asp Asp Asp Lys Gly Gly Gly Ala Ser Ile Leu Asn Val Glu Gln Ser

100 105 110

Pro Gln Ser Leu His Val Gln Glu Gly Asp Ser Thr Asn Phe Thr Cys

115 120 125

Ser Phe Pro Ser Ser Asn Phe Tyr Ala Leu His Trp Tyr Arg Trp Glu

130 135 140

Thr Ala Lys Ser Pro Glu Ala Leu Phe Val Met Thr Leu Asn Gly Asp

145 150 155 160

Glu Lys Lys Lys Gly Arg Ile Ser Ala Thr Leu Asn Thr Lys Glu Gly

165 170 175

Tyr Ser Tyr Leu Tyr Ile Lys Gly Ser Gln Pro Glu Asp Ser Ala Thr

180 185 190

Tyr Leu Cys Ala Leu Tyr Asn Asn Asn Asp Met Arg Phe Gly Ala Gly

195 200 205

Thr Arg Leu Thr Val Lys Pro Gly Gly Gly Gly Ser Gly Gly Gly Gly

210 215 220

Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser

225 230 235 240

Gly Val Ile Gln Ser Pro Arg His Glu Val Thr Glu Met Gly Gln Glu

245 250 255

Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His Asn Ser Leu Phe Trp

260 265 270

Tyr Arg Gln Thr Met Met Arg Gly Leu Glu Leu Leu Ile Tyr Phe Asn

275 280 285

Asn Asn Val Pro Ile Asp Asp Ser Gly Met Pro Glu Asp Arg Phe Ser

290 295 300

Ala Lys Met Pro Asn Ala Ser Phe Ser Thr Leu Lys Ile Gln Pro Ser

305 310 315 320

Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala Ser Ser Pro Gly Ser

325 330 335

Thr Asp Thr Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val Leu Ala

340 345 350

Ala Ala Gly Gly Ser Gly Gly Glu Gln Lys Leu Ile Ser Glu Glu Asp

355 360 365

Leu

<210> 326

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<220>

<221> X1

<222> (6)..(6)

<223> X1 is L or Y

<400> 326

Ala Leu Tyr Asn Asn Xaa Asp Met Arg

1 5

<210> 327

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<220>

<221> X1

<222> (4)..(4)

<223> X1 is P, A or T

<220>

<221> X2

<222> (6)..(6)

<223> X2 is A or S

<220>

<221> X3

<222> (7)..(7)

<223> X3 is T or I

<220>

<221> X4

<222> (9)..(9)

<223> X4 is K or A

<400> 327

Ala Ser Ser Xaa Gly Xaa Xaa Asp Xaa Gln Tyr

1 5 10

<210> 328

<211> 509

<212> PRT

<213> Homo sapiens (Homo sapiens)

<400> 328

Met Glu Arg Arg Arg Leu Trp Gly Ser Ile Gln Ser Arg Tyr Ile Ser

1 5 10 15

Met Ser Val Trp Thr Ser Pro Arg Arg Leu Val Glu Leu Ala Gly Gln

20 25 30

Ser Leu Leu Lys Asp Glu Ala Leu Ala Ile Ala Ala Leu Glu Leu Leu

35 40 45

Pro Arg Glu Leu Phe Pro Pro Leu Phe Met Ala Ala Phe Asp Gly Arg

50 55 60

His Ser Gln Thr Leu Lys Ala Met Val Gln Ala Trp Pro Phe Thr Cys

65 70 75 80

Leu Pro Leu Gly Val Leu Met Lys Gly Gln His Leu His Leu Glu Thr

85 90 95

Phe Lys Ala Val Leu Asp Gly Leu Asp Val Leu Leu Ala Gln Glu Val

100 105 110

Arg Pro Arg Arg Trp Lys Leu Gln Val Leu Asp Leu Arg Lys Asn Ser

115 120 125

His Gln Asp Phe Trp Thr Val Trp Ser Gly Asn Arg Ala Ser Leu Tyr

130 135 140

Ser Phe Pro Glu Pro Glu Ala Ala Gln Pro Met Thr Lys Lys Arg Lys

145 150 155 160

Val Asp Gly Leu Ser Thr Glu Ala Glu Gln Pro Phe Ile Pro Val Glu

165 170 175

Val Leu Val Asp Leu Phe Leu Lys Glu Gly Ala Cys Asp Glu Leu Phe

180 185 190

Ser Tyr Leu Ile Glu Lys Val Lys Arg Lys Lys Asn Val Leu Arg Leu

195 200 205

Cys Cys Lys Lys Leu Lys Ile Phe Ala Met Pro Met Gln Asp Ile Lys

210 215 220

Met Ile Leu Lys Met Val Gln Leu Asp Ser Ile Glu Asp Leu Glu Val

225 230 235 240

Thr Cys Thr Trp Lys Leu Pro Thr Leu Ala Lys Phe Ser Pro Tyr Leu

245 250 255

Gly Gln Met Ile Asn Leu Arg Arg Leu Leu Leu Ser His Ile His Ala

260 265 270

Ser Ser Tyr Ile Ser Pro Glu Lys Glu Glu Gln Tyr Ile Ala Gln Phe

275 280 285

Thr Ser Gln Phe Leu Ser Leu Gln Cys Leu Gln Ala Leu Tyr Val Asp

290 295 300

Ser Leu Phe Phe Leu Arg Gly Arg Leu Asp Gln Leu Leu Arg His Val

305 310 315 320

Met Asn Pro Leu Glu Thr Leu Ser Ile Thr Asn Cys Arg Leu Ser Glu

325 330 335

Gly Asp Val Met His Leu Ser Gln Ser Pro Ser Val Ser Gln Leu Ser

340 345 350

Val Leu Ser Leu Ser Gly Val Met Leu Thr Asp Val Ser Pro Glu Pro

355 360 365

Leu Gln Ala Leu Leu Glu Arg Ala Ser Ala Thr Leu Gln Asp Leu Val

370 375 380

Phe Asp Glu Cys Gly Ile Thr Asp Asp Gln Leu Leu Ala Leu Leu Pro

385 390 395 400

Ser Leu Ser His Cys Ser Gln Leu Thr Thr Leu Ser Phe Tyr Gly Asn

405 410 415

Ser Ile Ser Ile Ser Ala Leu Gln Ser Leu Leu Gln His Leu Ile Gly

420 425 430

Leu Ser Asn Leu Thr His Val Leu Tyr Pro Val Pro Leu Glu Ser Tyr

435 440 445

Glu Asp Ile His Gly Thr Leu His Leu Glu Arg Leu Ala Tyr Leu His

450 455 460

Ala Arg Leu Arg Glu Leu Leu Cys Glu Leu Gly Arg Pro Ser Met Val

465 470 475 480

Trp Leu Ser Ala Asn Pro Cys Pro His Cys Gly Asp Arg Thr Phe Tyr

485 490 495

Asp Pro Glu Pro Ile Leu Cys Pro Cys Phe Met Pro Asn

500 505

<210> 329

<211> 232

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 329

Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala

1 5 10 15

Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

20 25 30

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

35 40 45

Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val

50 55 60

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

65 70 75 80

Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

85 90 95

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala

100 105 110

Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

115 120 125

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr

130 135 140

Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser

145 150 155 160

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

165 170 175

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

180 185 190

Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe

195 200 205

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

210 215 220

Ser Leu Ser Leu Ser Pro Gly Lys

225 230

<210> 330

<211> 21

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 330

Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala

1 5 10 15

Pro Glu Leu Leu Gly

20

<210> 331

<211> 19

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 331

Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val

1 5 10 15

Ala Gly Pro

<210> 332

<211> 53

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 332

Glu Leu Lys Thr Pro Leu Gly Asp Thr Thr His Thr Cys Pro Arg Cys

1 5 10 15

Pro Glu Pro Lys Ser Cys Asp Thr Pro Pro Pro Cys Pro Arg Cys Pro

20 25 30

Glu Pro Lys Ser Cys Asp Thr Pro Pro Pro Cys Pro Arg Cys Pro Ala

35 40 45

Pro Glu Leu Leu Gly

50

<210> 333

<211> 18

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 333

Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro Ala Pro Glu Phe

1 5 10 15

Leu Gly

<210> 334

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<220>

<221> X1

<222> (1)..(1)

<223> X1 is V, T, N, I or S, preferably V; t or N, most preferably V,

<220>

<221> X2

<222> (2)..(2)

<223> X2 is K, R, S or A, more preferably K or R, most preferably K

<220>

<221> X3

<222> (6)..(6)

<223> X3 is D or N, preferably D

<400> 334

Xaa Xaa Glu Phe Gln Xaa

1 5

<210> 335

<211> 7

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<220>

<221> X1

<222> (6)..(6)

<223> X1 is K, R, T or V, preferably K or R, most preferably K

<400> 335

Phe Gly Pro Tyr Gly Xaa Glu

1 5

<210> 336

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<220>

<221> X1

<222> (6)..(6)

<223> X1 is L, Y, H, Q, A, I, K, R, V, D, E, F or N, preferably L, Y,

H. Q, A, I, K or R, more preferably L, Y, H, Q or a,

most preferably L or Y

<400> 336

Ala Leu Tyr Asn Asn Xaa Asp Met Arg

1 5

<210> 337

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<220>

<221> X1

<222> (1)..(1)

<223> X1 is F, Y, M or L, preferably F or Y, most preferably F

<220>

<221> X2

<222> (2)..(2)

<223> X2 is Q or N, preferably Q (if X2 is N, then X3 is also N)

<220>

<221> X3

<222> (3)..(3)

<223> X3 is N or S, preferably N

<220>

<221> X4

<222> (4)..(4)

<223> X4 is T, S or E, preferably T or S, most preferably T (if X4 is

S, then X2 is Q)

<220>

<221> X5

<222> (5)..(5)

<223> X5 is A or T, preferably A

<220>

<221> X6

<222> (6)..(6)

<223> X6 is V, I, L or T, preferably V or I, most preferably V

<400> 337

Xaa Xaa Xaa Xaa Xaa Xaa

1 5

<210> 338

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<220>

<221> X1

<222> (4)..(4)

<223> X1 is P, R, A, T or S, preferably P, T or A, most preferably P

<220>

<221> X2

<222> (6)..(6)

<223> X2 is A or S, preferably A

<220>

<221> X3

<222> (7)..(7)

<223> X3 is T or I, preferably T

<220>

<221> X4

<222> (9)..(9)

<223> X4 is K, A, L, I, V, R, Q, N, Y, T, H, E or F, preferably K, A,

L, I, V, R, Q, N or Y, more preferably K, A, L, I, V or R,

most preferably K or A

<400> 338

Ala Ser Ser Xaa Gly Xaa Xaa Asp Xaa Gln Tyr

1 5 10

<210> 339

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 339

Asp Arg Gly Ser Gln Ser

1 5

<210> 340

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 340

Ile Tyr Ser Asn Gly Asp

1 5

<210> 341

<211> 13

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 341

Ala Ala Val Ile Asp Asn Asp Gln Gly Gly Ile Leu Thr

1 5 10

<210> 342

<211> 5

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 342

Pro Gly His Arg Ala

1 5

<210> 343

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 343

Tyr Val His Gly Glu Glu

1 5

<210> 344

<211> 12

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 344

Ala Ser Ser Pro Trp Asp Ser Pro Asn Val Gln Tyr

1 5 10

<210> 345

<211> 26

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 345

Ile Leu Asn Val Glu Gln Ser Pro Gln Ser Leu His Val Gln Glu Gly

1 5 10 15

Asp Ser Thr Lys Phe Thr Cys Ser Phe Pro

20 25

<210> 346

<211> 26

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 346

Ile Leu Asn Val Glu Gln Ser Pro Gln Ser Leu His Val Gln Glu Gly

1 5 10 15

Asp Ser Thr Asn Phe Thr Cys Ser Phe Pro

20 25

<210> 347

<211> 17

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 347

Leu His Trp Tyr Arg Lys Glu Thr Ala Lys Ser Pro Glu Phe Leu Phe

1 5 10 15

Tyr

<210> 348

<211> 17

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 348

Ile His Trp Tyr Arg Lys Glu Thr Ala Lys Ser Pro Glu Phe Leu Phe

1 5 10 15

Tyr

<210> 349

<211> 34

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 349

Lys Lys Lys Gly Arg Ile Ser Ala Thr Leu Asn Thr Lys Glu Gly Tyr

1 5 10 15

Ser Tyr Leu Tyr Ile Thr Asp Ser Gln Pro Glu Asp Ser Ala Thr Tyr

20 25 30

Leu Cys

<210> 350

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 350

Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro

1 5 10

<210> 351

<211> 24

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 351

Gly Val Ile Gln Ser Pro Arg His Glu Val Thr Glu Met Gly Gln Glu

1 5 10 15

Val Thr Leu Arg Cys Lys Pro Ile

20

<210> 352

<211> 24

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 352

Gly Val Ile Gln Ser Pro Arg His Leu Val Thr Glu Met Gly Gln Glu

1 5 10 15

Val Thr Leu Arg Cys Lys Pro Ile

20

<210> 353

<211> 17

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 353

Leu Phe Trp Tyr Arg Glu Thr Pro Met Gln Gly Leu Glu Leu Leu Ile

1 5 10 15

Tyr

<210> 354

<211> 38

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 354

Ile Asp Asp Ser Gly Met Pro Glu Asp Arg Phe Ser Ala Lys Met Pro

1 5 10 15

Asn Asp Ser Phe Ser Thr Leu Lys Ile Gln Pro Ser Glu Pro Arg Asp

20 25 30

Ser Ala Val Tyr Phe Cys

35

<210> 355

<211> 38

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 355

Ile Asp Asp Ser Gly Met Pro Glu Asp Arg Phe Ser Ala Lys Met Pro

1 5 10 15

Asn Ala Ser Phe Ser Thr Leu Lys Ile Gln Pro Ser Glu Pro Arg Asp

20 25 30

Ser Ala Val Tyr Phe Cys

35

<210> 356

<211> 10

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 356

Phe Gly Pro Gly Thr Arg Leu Thr Val Leu

1 5 10

<210> 357

<211> 258

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 357

Gln Lys Glu Val Glu Gln Asn Ser Gly Pro Leu Ser Val Pro Glu Gly

1 5 10 15

Ala Ile Ala Ser Leu Asn Cys Thr Tyr Ser Asp Arg Gly Ser Gln Ser

20 25 30

Phe Phe Trp Tyr Arg Gln Tyr Ser Gly Lys Ser Pro Glu Leu Ile Met

35 40 45

Ser Ile Tyr Ser Asn Gly Asp Lys Glu Asp Gly Arg Phe Thr Ala Gln

50 55 60

Leu Asn Lys Ala Ser Gln Tyr Val Ser Leu Leu Ile Arg Asp Ser Gln

65 70 75 80

Pro Ser Asp Ser Ala Thr Tyr Leu Cys Ala Ala Val Ile Asp Asn Asp

85 90 95

Gln Gly Gly Ile Leu Thr Phe Gly Thr Gly Thr Arg Leu Thr Ile Ile

100 105 110

Pro Asn Ile Gln Asn Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly

115 120 125

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Val

130 135 140

Thr Gln Thr Pro Arg Tyr Leu Ile Lys Thr Arg Gly Gln Gln Val Thr

145 150 155 160

Leu Ser Cys Ser Pro Ile Pro Gly His Arg Ala Val Ser Trp Tyr Gln

165 170 175

Gln Thr Pro Gly Gln Gly Leu Gln Phe Leu Phe Glu Tyr Val His Gly

180 185 190

Glu Glu Arg Asn Lys Gly Asn Phe Pro Gly Arg Phe Ser Gly Arg Gln

195 200 205

Phe Ser Asn Ser Ser Ser Glu Met Asn Ile Ser Asn Leu Glu Leu Gly

210 215 220

Asp Ser Ala Leu Tyr Leu Cys Ala Ser Ser Pro Trp Asp Ser Pro Asn

225 230 235 240

Val Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val Thr Glu Asp Leu

245 250 255

Lys Asn

<210> 358

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 358

Gly Gly Gly Gly Ser Ala Ala Ala

1 5

<210> 359

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<220>

<221> X1

<222> (1)..(1)

<223> X1 is F, Y, M or L, preferably F or Y, most preferably F

<220>

<221> X3

<222> (3)..(3)

<223> X3 is N or S, preferably N

<220>

<221> X5

<222> (5)..(5)

<223> X5 is A or T, preferably A

<220>

<221> X6

<222> (6)..(6)

<223> X6 is V, I, L or T, preferably V or I, most preferably V

<400> 359

Xaa Gln Xaa Thr Xaa Xaa

1 5

<210> 360

<211> 119

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<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 Pro 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 Ser Pro Pro Ser

100 105 110

Pro Ala Pro Pro Val Ala Gly

115

<210> 361

<211> 141

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 361

Asn Ile Gln Asn Pro Asp Pro Ala Val Tyr Gln Leu Arg Asp Ser Lys

1 5 10 15

Ser Ser Asp Lys Ser Val Cys Leu Phe Thr Asp Phe Asp Ser Gln Thr

20 25 30

Asn Val Ser Gln Ser Lys Asp Ser Asp Val Tyr Ile Thr Asp Lys Thr

35 40 45

Val Leu Asp Met Arg Ser Met Asp Phe Lys Ser Asn Ser Ala Val Ala

50 55 60

Trp Ser Asn Lys Ser Asp Phe Ala Cys Ala Asn Ala Phe Asn Asn Ser

65 70 75 80

Ile Ile Pro Glu Asp Thr Phe Phe Pro Ser Pro Glu Ser Ser Cys Asp

85 90 95

Val Lys Leu Val Glu Lys Ser Phe Glu Thr Asp Thr Asn Leu Asn Phe

100 105 110

Gln Asn Leu Ser Val Ile Gly Phe Arg Ile Leu Leu Leu Lys Val Ala

115 120 125

Gly Phe Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser

130 135 140

<210> 362

<211> 179

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 362

Glu Asp Leu Lys Asn Val Phe Pro Pro Glu Val Ala Val Phe Glu Pro

1 5 10 15

Ser Glu Ala Glu Ile Ser His Thr Gln Lys Ala Thr Leu Val Cys Leu

20 25 30

Ala Thr Gly Phe Tyr Pro Asp His Val Glu Leu Ser Trp Trp Val Asn

35 40 45

Gly Lys Glu Val His Ser Gly Val Ser Thr Asp Pro Gln Pro Leu Lys

50 55 60

Glu Gln Pro Ala Leu Asn Asp Ser Arg Tyr Cys Leu Ser Ser Arg Leu

65 70 75 80

Arg Val Ser Ala Thr Phe Trp Gln Asn Pro Arg Asn His Phe Arg Cys

85 90 95

Gln Val Gln Phe Tyr Gly Leu Ser Glu Asn Asp Glu Trp Thr Gln Asp

100 105 110

Arg Ala Lys Pro Val Thr Gln Ile Val Ser Ala Glu Ala Trp Gly Arg

115 120 125

Ala Asp Cys Gly Phe Thr Ser Glu Ser Tyr Gln Gln Gly Val Leu Ser

130 135 140

Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala

145 150 155 160

Val Leu Val Ser Ala Leu Val Leu Met Ala Met Val Lys Arg Lys Asp

165 170 175

Ser Arg Gly

<210> 363

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<220>

<221> X2

<222> (6)..(6)

<223> X2 is A or S, preferably A

<220>

<221> X4

<222> (9)..(9)

<223> X4 is T, K or A, preferably K or A, more preferably K

<400> 363

Ala Ser Ser Pro Gly Xaa Thr Asp Xaa Gln Tyr

1 5 10

<210> 364

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<220>

<221> X2

<222> (6)..(6)

<223> X2 is A or S, preferably A

<220>

<221> X3

<222> (7)..(7)

<223> X3 is T or I

<220>

<221> X4

<222> (9)..(9)

<223> X4 is T, K or A, preferably K or A, more preferably K

<400> 364

Ala Ser Ser Pro Gly Xaa Xaa Asp Xaa Gln Tyr

1 5 10

<210> 365

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<220>

<221> X3

<222> (7)..(7)

<223> X3 is T or I, preferably I

<220>

<221> X4

<222> (9)..(9)

<223> X4 is K or A, preferably K

<400> 365

Ala Ser Ser Pro Gly Ala Xaa Asp Xaa Gln Tyr

1 5 10

<210> 366

<211> 120

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 366

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Lys Phe Thr Ser Tyr

20 25 30

Val Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Tyr Ile Asn Pro Tyr Asn Asp Val Thr Lys Tyr Ala Glu Lys Phe

50 55 60

Gln Gly Arg Val Thr Leu Thr Ser Asp Thr Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gly Ser Tyr Tyr Asp Tyr Glu Gly Phe Val Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 367

<211> 120

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 367

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Lys Phe Thr Ser Tyr

20 25 30

Val Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Tyr Ile Asn Pro Tyr Lys Asp Val Thr Lys Tyr Ala Glu Lys Phe

50 55 60

Gln Gly Arg Val Thr Leu Thr Ser Asp Thr Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val His Tyr Cys

85 90 95

Ala Arg Gly Ser Tyr Tyr Asp Tyr Glu Gly Phe Val Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 368

<211> 120

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 368

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Lys Phe Thr Ser Tyr

20 25 30

Val Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Tyr Ile Asn Pro Tyr Lys Asp Val Thr Lys Tyr Ala Glu Lys Phe

50 55 60

Gln Gly Arg Val Thr Leu Thr Ser Asp Thr Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gly Ser Tyr Tyr Asp Tyr Glu Gly Phe Val Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 369

<211> 120

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 369

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Lys Phe Thr Ser Tyr

20 25 30

Val Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Tyr Ile Asn Pro Tyr Arg Asp Val Thr Lys Tyr Ala Glu Lys Phe

50 55 60

Gln Gly Arg Val Thr Leu Thr Ser Asp Thr Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val His Tyr Cys

85 90 95

Ala Arg Gly Ser Tyr Tyr Asp Tyr Glu Gly Phe Val Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 370

<211> 120

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 370

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Lys Phe Thr Ser Tyr

20 25 30

Val Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Tyr Ile Asn Pro Tyr Arg Asp Val Thr Lys Tyr Ala Glu Lys Phe

50 55 60

Gln Gly Arg Val Thr Leu Thr Ser Asp Thr Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gly Ser Tyr Tyr Asp Tyr Glu Gly Phe Val Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 371

<211> 120

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 371

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Lys Phe Thr His Tyr

20 25 30

Val Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Tyr Ile Asn Pro Tyr Asn Asp Val Thr Lys Tyr Ala Glu Lys Phe

50 55 60

Gln Gly Arg Val Thr Leu Thr Ser Asp Thr Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val His Tyr Cys

85 90 95

Ala Arg Gly Ser Tyr Tyr Asp Tyr Glu Gly Phe Val Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 372

<211> 120

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 372

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Lys Phe Thr Lys Tyr

20 25 30

Val Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Tyr Ile Asn Pro Tyr Asn Asp Val Thr Lys Tyr Ala Glu Lys Phe

50 55 60

Gln Gly Arg Val Thr Leu Thr Ser Asp Thr Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val His Tyr Cys

85 90 95

Ala Arg Gly Ser Tyr Tyr Asp Tyr Glu Gly Phe Val Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 373

<211> 120

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 373

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Lys Phe Lys Ser Tyr

20 25 30

Val Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Tyr Ile Asn Pro Tyr Asn Asp Val Thr Lys Tyr Ala Glu Lys Phe

50 55 60

Gln Gly Arg Val Thr Leu Thr Ser Asp Thr Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val His Tyr Cys

85 90 95

Ala Arg Gly Ser Tyr Tyr Asp Tyr Glu Gly Phe Val Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 374

<211> 120

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 374

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Lys Phe Arg Ser Tyr

20 25 30

Val Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Tyr Ile Asn Pro Tyr Asn Asp Val Thr Lys Tyr Ala Glu Lys Phe

50 55 60

Gln Gly Arg Val Thr Leu Thr Ser Asp Thr Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val His Tyr Cys

85 90 95

Ala Arg Gly Ser Tyr Tyr Asp Tyr Glu Gly Phe Val Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 375

<211> 120

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 375

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Lys Phe Thr Ser Tyr

20 25 30

Val Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Tyr Ile Asn Pro His Asn Asp Val Thr Lys Tyr Ala Glu Lys Phe

50 55 60

Gln Gly Arg Val Thr Leu Thr Ser Asp Thr Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val His Tyr Cys

85 90 95

Ala Arg Gly Ser Tyr Tyr Asp Tyr Glu Gly Phe Val Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 376

<211> 120

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 376

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Lys Phe Thr Ser Tyr

20 25 30

Val Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Tyr Ile Asn Pro Lys Asn Asp Val Thr Lys Tyr Ala Glu Lys Phe

50 55 60

Gln Gly Arg Val Thr Leu Thr Ser Asp Thr Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val His Tyr Cys

85 90 95

Ala Arg Gly Ser Tyr Tyr Asp Tyr Glu Gly Phe Val Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 377

<211> 106

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 377

Gln Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Ser Ala Thr Ser Ser Val Lys Tyr Met

20 25 30

His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr

35 40 45

Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser

50 55 60

Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu

65 70 75 80

Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr

85 90 95

Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 378

<211> 106

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 378

Gln Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Ser Ala Thr Ser Ser Val Arg Tyr Met

20 25 30

His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr

35 40 45

Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser

50 55 60

Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu

65 70 75 80

Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr

85 90 95

Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 379

<211> 106

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 379

Gln Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Ser Ala Thr Ser Ser Val Ser Tyr Met

20 25 30

His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr

35 40 45

Asp Thr Ser Lys Leu Ala Lys Gly Val Pro Ser Arg Phe Ser Gly Ser

50 55 60

Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu

65 70 75 80

Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr

85 90 95

Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 380

<211> 106

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 380

Gln Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Ser Ala Thr Ser Ser Val Ser Tyr Met

20 25 30

His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr

35 40 45

Asp Thr Ser Lys Leu Ala Arg Gly Val Pro Ser Arg Phe Ser Gly Ser

50 55 60

Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu

65 70 75 80

Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr

85 90 95

Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 381

<211> 5

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 381

Ser Tyr Val Met His

1 5

<210> 382

<211> 17

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<220>

<221> X1

<222> (12)..(12)

<223> X1 is A or N

<220>

<221> X2

<222> (13)..(13)

<223> X2 is E or Q

<220>

<221> X3

<222> (16)..(16)

<223> X3 is Q or K

<400> 382

Tyr Ile Asn Pro Tyr Asn Asp Val Thr Lys Tyr Xaa Xaa Lys Phe Xaa

1 5 10 15

Gly

<210> 383

<211> 10

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 383

Ser Ala Thr Ser Ser Val Ser Tyr Met His

1 5 10

<210> 384

<211> 7

<212> PRT

<213> artificial sequence

<220>

<223> modified or unmodified human sequences

<400> 384

Asp Thr Ser Lys Leu Ala Ser

1 5

Claims

the CDRa3 comprises or consists of: ALYNNLDMR (SEQ ID NO: 33) or ALYNNYDMR (SEQ ID NO: 34) or an amino acid sequence which differs from SEQ ID NO:34 by one, two or three, preferably one or two amino acid mutations, preferably amino acid substitutions, and

optionally the CDRa2 comprises or consists of: amino acid sequence FGPYGKE (SEQ ID NO:

32 Or an amino acid sequence which differs from SEQ ID NO. 32 by one, two or three amino acid mutations, preferably amino acid substitutions, and

327 X), wherein X ₁ Is P, A or T, X ₂ Is A or S, X ₃ Is T or I, andand X is ₄ Is K or A, or an amino acid sequence which differs from SEQ ID NO 327 by one, two or three amino acid mutations, preferably amino acid substitutions, and

optionally the CDRb2 comprises or consists of: the amino acid sequence FQNTAV (SEQ ID NO: 36) or the CDRB2 amino acid sequence which differs from SEQ ID NO:36 by one, two, three, four, five or six amino acid mutations, preferably amino acid substitutions.

2. The antigen binding protein according to claim 1, wherein the antigen binding protein specifically binds to or consists of at least 3, 4 or 5 amino acid positions selected from positions 3, 5, 6, 7 and 8, in particular 3, 5 and 7 of SEQ ID No. 50, preferably to or consists of amino acid positions 3, 5 and 7, or 3, 5, 6 and 7, or 3, 5, 7 and 8, or 3, 5, 6, 7 and 8, but preferably not amino acid positions 1 and 4 of SEQ ID No. 50, or

Specifically binds to a functional epitope comprising or consisting of at least 6 or 7 amino acid positions selected from positions 1, 3, 4, 5, 6, 7 and 8 of SEQ ID No. 50.

3. The antigen binding protein of claim 1 or 2, wherein the antigen binding protein does not significantly bind to at least 1, at least 2, at least 3, at least 4, at least 5, at least 10, at least 20, or all analogous peptides selected from the group consisting of: TMED9-001 (SEQ ID NO: 51), CAT-001 (SEQ ID NO: 52), DDX60L-001 (SEQ ID NO: 53), LRRC70-001 (SEQ ID NO: 54), PTPLB-001 (SEQ ID NO: 55), HDAC5-001 (SEQ ID NO: 56), VPS13B-002 (SEQ ID NO: 57), ZNF318-001 (SEQ ID NO: 58), CCDC51-001 (SEQ ID NO: 59), IFT17-003 (SEQ ID NO: 60), DIAPH1-004 (SEQ ID NO: 62), FADS2-001 (SEQ ID NO: 63), FRYL-003 (SEQ ID NO: 64), GIMAP8-001 (SEQ ID NO: 65), HSF1-001 (SEQ ID NO: 66), KNT-001 (SEQ ID NO: 67), MAU-001 (SEQ ID NO: 68), 4-001 (SEQ ID NO: 69), ZNF318-001 (SEQ ID NO: 71), MYO 1-001 (SEQ ID NO: 59), FADS2-001 (SEQ ID NO: 75), FADS2-001 (SEQ ID NO: 63), FRYL-003 (SEQ ID NO: 64), GIMAP8-001 (SEQ ID NO: 68), GIMAP 1-001 (SEQ ID NO: 68), and HSF1-001 (SEQ ID NO: 68) FARSA-001 (SEQ ID NO: 306), FAOX 15B-003 (SEQ ID NO: 304), FAM114A2-002 (SEQ ID NO: 305), GPR56-002 (SEQ ID NO: 307), IGHD-002 (SEQ ID NO: 308), NOMAP-3-0972 (SEQ ID NO: 309), NOMAP-3-1265 (SEQ ID NO: 310), NOMAP-3-1408 (SEQ ID NO: 311), NOMAP-3-1587 (SEQ ID NO: 312), NOMAP-3-1768 (SEQ ID NO: 313), NOMAP-5-0765 (SEQ ID NO: 314), PDCD10-004 (SEQ ID NO: 315), TSN-001 (SEQ ID NO: 316), ARMC9-002 (SEQ ID NO: 187), CLI-001 (SEQ ID NO: 188), G1-001 (SEQ ID NO: 190), COPS7A-001 (SEQ ID NO: 192), EIF-194), T2-07NO: 202 (SEQ ID NO: 196), NOMAP-5-0765 (SEQ ID NO: 314), PDCD 10-002 (SEQ ID NO: 007), SPAM 10-002 (SEQ ID NO:200, SEQ ID NO: 001 (SEQ ID NO: 200) TGM2-002 (SEQ ID NO: 210) and TPR-004 (SEQ ID NO: 212), said analogous peptides being in complex with MHC proteins, preferably said antigen binding proteins not significantly binding to IFT17-003 (SEQ ID NO: 60) being in complex with MHC proteins.

4. An antigen binding protein as claimed in any one of claims 1 to 3 wherein the antigen binding protein has multi-specificity, such as tetra-specific, tri-specific or bispecific, preferably bispecific, in particular the antigen binding protein is a bispecific TCR, bispecific antibody or bispecific TCR-antibody molecule.

5. The antigen binding protein of any one of claims 1 to 4, wherein

-said first polypeptide and said second polypeptide are comprised in a single polypeptide chain or in two polypeptide chains, preferably wherein V _A Contained in the first polypeptide chain and V _B Included in the second polypeptide chain; and/or

-said variable domain V _A Is V _α Or V _γ Domain, and the variable domain V _B Is V _β Or V _δ A domain.

6. The antigen binding protein of any one of claims 1 to 5, wherein V _A Also comprising one or more, preferably all, of the frame regions selected from the group consisting of: FR1-a, FR2-a, FR3-a and FR4-a, wherein

-FR3-b comprises or consists of: the amino acid sequence of SEQ ID NO:354 or 355, or at least 85%, 90% or 95% identical to SEQ ID NO:354, preferably comprises D, A, E, R, K, Q, N or S, more preferably D, A, E, Q, N or S, more preferably D or A, at position 84,

Even more preferably the amino acid sequence of D; and is also provided with

7. The antigen binding protein of any one of claims 1 to 6, wherein

-V _A Comprising or consisting of: the amino acid sequence of SEQ ID NO. 132, or a sequence identical to SEQ ID NO:

132 are at least 85%, 90% or 95% identical, preferably comprising CDRa1 of SEQ ID No. 16, SEQ ID NO:

32 and CDRA2 of SEQ ID NO. 33, SEQ ID NO. 34 or CDRA3 of SEQ ID NO. 9, and further an amino acid sequence of K or N, preferably K, L, M or I, preferably L or I, K or W, preferably K, F or A, preferably F, Y or V, preferably Y, T or K, preferably T, at position 92, and/or D or G, preferably D, at position 39, preferably at position 44, preferably K, F or A, preferably F, at position 52, Y or V, preferably at position 55, preferably T or K, preferably T and/or D, preferably at position 93, particularly V _A Comprising SEQ ID NO. 132, SEQ ID NO. 129, SEQ ID NO. 137 or SEQ ID NO:

142, or consists of the amino acid sequence of seq id no; and is also provided with

-V _B Comprising or consisting of: the amino acid sequence of SEQ ID NO. 134, or a sequence identical to SEQ ID NO:

134 are at least 85%, 90% or 95% identical, preferably comprising CDRb1 of SEQ ID No. 10, SEQ ID NO:

36, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:47, SEQ ID NO:

281. 292, 294, 297, 298, 301 or 283 CDRB3, and further amino acid sequences E, L or K, preferably E, R or H at position 22, E or Q at position 44, preferably E, P or M at position 46, preferably P, Q or R at position 48, preferably Q and/or D, A, E, Q, N or S, preferably D or A at position 84, particularly V, at position 11, preferably E, R or H at position 22, preferably E, P or M at position 46, preferably P, Q or R at position 48 _B Comprises or consists of the amino acid sequences of SEQ ID NO. 134, SEQ ID NO. 130, SEQ ID NO. 135, SEQ ID NO. 136, SEQ ID NO. 138, SEQ ID NO. 139, SEQ ID NO. 140, SEQ ID NO. 141, SEQ ID NO. 144, SEQ ID NO. 145, SEQ ID NO. 146, SEQ ID NO. 147 or SEQ ID NO. 148.

8. The antigen binding protein of any one of claims 1 to 7, further comprising an antibody light chain variable domain (V _L ) And antibody heavy chain variable domains (V _H ) Wherein preferably wherein V _L And V _H Binding to an antigen selected from the group consisting of: CD2, CD3, in particular CD3 gamma, CD3 delta and/or CD3 epsilon, CD4, CD5, CD7, CD8, CD10, CD11b, CD11c, CD14, CD16, CD18, CD22, CD25, CD28, CD32a, CD32b, CD33, CD41b, CD42a, CD42b, CD44, CD45RA, CD49, CD55, CD56, CD61, CD64, CD68, CD90, CD94, CD95, CD117, CD123, CD125, CD134, CD137, CD152, CD163, CD193, CD203c, CD235a, CD278, CD279, CD287, nkp, NKG2D, GITR, fc epsilon RI, tcra/beta and gamma/delta, HLA-DR and 4-1BB or combinations thereof, and/or binds to effector cells, in particular T cells or natural killer cells.

9. The antigen binding protein of claim 8, wherein the antigen binding protein comprises a first polypeptide chain and a second polypeptide chain, and wherein

The first polypeptide chain is represented by formula [ Ia ]:

V ₁ -L ₁ -D ₁ -L ₂ -V ₂ -L ₃ -D ₂ [Ia]，

and the second polypeptide chain is represented by formula [ IIa ]

V ₃ -L ₄ -D ₃ -L ₅ -V ₄ -L ₆ -D ₄ [IIa]，

Wherein the method comprises the steps of

10. The antigen binding protein of any one of claims 1 to 9, comprising

-a first polypeptide chain selected from the group consisting of: SEQ ID NO. 100, 103, 105, 106, 111, 122, 126,

128、151、155、156、157、158、159、166、167、169、171、173、175、177、

178、179、180、181、183、189、191、193、195、197、199、201、203、205、

207. 209, 211, 213, 215, 217, 285, 291, 295, 299 and 303, and

-a second polypeptide chain selected from the group consisting of: SEQ ID NOS 101, 102, 104, 107, 110, 119, 121,

131、133、143、152、160、161、162、163、164、165、168、170、172、174、

176、182、184、185、186、216、218、220、222、224、228、230、232、234、

236、238、240、242、244、246、248、250、252、254、256、258、260、262、

264. 266, 268, 270, 272, 274, 276, 278, 282, 284, 296, or 300.

11. An isolated nucleic acid comprising a sequence encoding the antigen binding protein of any one of claims 1 to 10.

12. A vector comprising the nucleic acid of claim 11.

13. A host cell comprising an antigen binding protein according to any one of claims 1 to 10, or a nucleic acid according to claim 11, or a vector according to claim 12, preferably wherein the host cell is a lymphocyte, preferably a T lymphocyte or a T lymphocyte progenitor cell, or a cell for recombinant expression, such as a Chinese Hamster Ovary (CHO) cell or a yeast cell.

14. A pharmaceutical composition comprising the antigen binding protein of any one of claims 1 to 10, the nucleic acid of claim 11, the vector of claim 12 or the host cell of claim 13, and a pharmaceutically acceptable carrier.

15. A method of producing the antigen binding protein of any one of claims 1 to 10, the method comprising

a. Providing a host cell, wherein the host cell,

b. providing a genetic construct comprising a coding sequence encoding an antigen binding protein according to any one of claims 1 to 10,

c. introducing the genetic construct into the host cell, and

d. expressing the gene construct by the host cell,

e. optionally further comprising isolating and purifying the antigen binding protein from the host cell, and optionally,

reconstructing the antigen binding protein in T cells.

16. The antigen binding protein according to any one of claims 1 to 10, the nucleic acid according to claim 11, the vector according to claim 12, the host cell according to claim 13 or the pharmaceutical composition according to claim 14 for use in medicine, in particular for use in the diagnosis, prevention and/or treatment of proliferative diseases such as cancer, wherein the cancer is selected from acute myeloid leukemia, breast cancer, cholangiocellular carcinoma, biliary cancer, glioblastoma, hepatocellular carcinoma, head and neck squamous cell carcinoma, melanoma, non-hodgkin lymphoma, non-small cell lung cancer adenocarcinoma, non-small cell lung cancer, squamous cell non-small cell lung cancer, ovarian cancer, esophageal cancer, renal cell carcinoma, small cell lung cancer, bladder cancer, uterine and endometrial cancer, osteosarcoma, chronic lymphocytic leukemia, colorectal cancer and synovial sarcoma.