US20130085104A1

US20130085104A1 - Therapeutic agents comprising elastin-like peptides

Info

Publication number: US20130085104A1
Application number: US13/524,807
Authority: US
Inventors: Ashutosh Chilkoti
Original assignee: Duke University
Current assignee: Duke University
Priority date: 2008-06-27
Filing date: 2012-06-15
Publication date: 2013-04-04
Also published as: EP2926825A1; CN105727261A; US20190091297A1; US10596230B2; EP2307038A4; JP2015218177A; CN102131516A; WO2009158704A2; EP3412300A1; CA2953975C; WO2009158704A3; US20130079277A1; CA2953975A1; JP2017088627A; US8178495B2; EP2307038A2; EP4074327A1; US20130085099A1; US9200083B2; US20200282022A1

Abstract

The present invention provides therapeutic agents and compositions comprising elastin-like peptides (ELPs) and therapeutic proteins. In some embodiments, the therapeutic protein is a GLP-1 receptor agonist, insulin, or Factor VII/VIIa, including functional analogs. The present invention further provides encoding polynucleotides, as well as methods of making and using the therapeutic agents. The therapeutic agents have improvements in relation to their use as therapeutics, including, inter alia, one or more of half-life, clearance and/or persistance in the body, solubility, and bioavailability.

Description

PRIORITY

This application claims priority to U.S. Provisional Application. No. 61/076,221, filed Jun. 27, 2008, which is hereby incorporated by reference in its entirety.

FIELD OF THE INVENTION

This application discloses therapeutic agents comprising elastin-like-peptides, and is related to PCT/US2007/077767 (published as WO 2008/030968 on Mar. 13, 2008) having an International Filing Date of Sep. 6, 2007. This application is also related to PCT/US2006/048572 (published as WO 2007/073486 on Jun. 28, 2007) having an International Filing Date of Dec. 20, 2006. WO 2008/030968 and WO 2007/073486 are each hereby incorporated by reference in their entireties.

DESCRIPTION OF THE TEXT FILE SUBMITTED ELECTRONICALLY

The contents of the text file submitted electronically herewith are incorporated herein by reference in their entirety: A computer readable format copy of the Sequence Listing (filename: PHAS_—010_—01US_SeqList_ST25.txt, date recorded: Jun. 26, 2009, file size 50 kb).

BACKGROUND OF THE INVENTION

Therapeutic proteins or peptides in their native state or when recombinantly produced can be labile molecules exhibiting, inter alia, short periods of serum stability, serum half-life (i.e., circulatory half-life), or limited persistance in the body. Such molecules can also be extremely labile when formulated, such as when formulated in aqueous solutions.
In some instances, polyethylene glycol (PEG) conjugated to a proteinaceous molecule results in a longer-acting, sustained activity of the molecule. PEG attachment, however, can often substantially reduce or even destroy the protein's therapeutic activity. Therapeutic proteins and/or peptides have also been stabilized by fusion to certain proteins that are capable of extending serum half-life. For example, in some instances, therapeutic proteins fused to albumin, transferrin, and antibody fragments exhibit extended serum, half-life when compared to the therapeutic protein in the unfused state. See U.S. Pat. No. 7,238,667 (particularly with respect to albumin conjugates), U.S. Pat. No. 7,176,278 (particularly with respect to transferrin conjugates), and U.S. Pat. No. 5,766,883, which are each hereby incorporated by reference in their entireties.
There remains a need in the art for more stable, longer acting, and/or effective proteinaceous molecules.

SUMMARY OF THE INVENTION

The present invention provides therapeutic agents comprising an elastin-like peptide (ELP) component and a therapeutic proteinacious component. The ELP component contains structural peptide units, which may be repeating units, structurally related to, or derived from, sequences of the elastin protein. Such ELP components provide certain therapeutic advantages to the therapeutic agent, such as comparatively better stability, solubility, bioavailability, half-life, persistance, and/or biological action of the therapeutic proteinaceous component. Such properties may be determined, for example, with respect to the therapeutic component's unfused or unconjugated counterpart. In some embodiments, the BP components may undergo a reversible inverse phase transition, which may impart additional practical and/or therapeutic advantages. The invention further provides polynucleotides encoding the therapeutic agents of the invention, as well as methods of treatment or prophylaxis for certain biological conditions.
In a first aspect, the invention provides a therapeutic agent comprising an elastin-like peptide (ELP) component and a therapeutic proteinacious component, as well as pharmaceutical compositions containing the same for delivery to a subject or patient in need. The therapeutic component may be selected from active portions of the therapeutic proteins listed in Table 1, or functional analogs thereof. In certain embodiments, the therapeutic component is a GLP-1 receptor agonist, such as GLP-1, exendin-4, or a functional analog thereof. Such therapeutic components are generally effective for, among other things, increasing insulin secretion from the pancreas in a glucose-dependent manner. In other embodiments, the therapeutic component is an insulin or functional analog thereof, which is generally effective for promoting glucose uptake from the blood and storage within cells. In still other embodiments, the therapeutic component is a Factor VII/VIIa or functional analog thereof, which is generally effective for promoting coagulation by activation of Factor X or Factor IX.
The ELP and therapeutic components may be covalently coupled by various means, including chemical coupling (e.g., conjugation) and recombinant fusion technology. In addition, the number of ELP or therapeutic components per molecule, and their respective positions within the molecule, may vary as needed. The therapeutic agent may further include one or more spacer or linker moieties, which in addition to providing the desired functional independence of the ELP and therapeutic components, may optionally provide for additional functionalities, such as a protease-sensitive feature to allow for proteolytic release or activation of the therapeutic component. The therapeutic agent may further include one or more targeting components such as, for example, a peptide or protein to target the therapeutic agent to a particular cell type, e.g., a cancer cell, or to a particular organ.
In a second aspect, the invention provides polynucleotides, such polynucleotides comprising a nucleotide sequence encoding a therapeutic agent of the invention. For example, the nucleotide sequence encodes an ELP fusion with a functional portion of at least one therapeutic protein listed in Table 1 (or functional analog thereof). In certain embodiments, the therapeutic component is a GLP-1 receptor agonist (including GLP-1 and exendin-4), insulin, Factor VII/VIIa, or functional analog thereof. Such polynucleotides may further comprise additional control element(s) operably linked to the nucleotide sequence, such as promoter elements and/or other transcription or expression-related signals. The polynucleotide may be inserted into various vectors, which may be useful for production of the therapeutic agent in host cells, including, for example, bacterial and eukaryotic host cells.
In a third aspect, the invention provides a method for treating or preventing a disease; disorder, or condition in a subject, such as in a mammalian patient, including a human patient. The method comprises administering an effective amount of the therapeutic agent of the invention (or pharmaceutical composition containing the same) to a subject or patient in need thereof. For example, the patient may be in need of an agent having a biological activity or preferred indication listed in Table 1. In certain embodiments employing a GLP-1 receptor agonist/ELP compound or employing an insulin/ELP compound, the invention provides a method for treating one or more disorders including type 1 or type 2 diabetes, hyperglycemia, and impaired glucose tolerance. In certain other embodiments employing Factor VII/VIIa/ELP compound, the invention provides a method for treating one or more disorders including hemophilia, post-surgical bleeding, anticoagulation-induced bleeding, thrombocytopenia, factor VII deficiency, factor XI deficiency, and intracranial hemorrhage.
Various other aspects, features and embodiments of the invention will be more fully apparent from the following disclosure and appended claims.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 depicts plasmid pET24d-ELP1-90, encoding an ELP component with a 10 unit VPGXG (SEQ ID NO: 3) repeat motif, where guest position X is V, G, and A in the ratio of 5:3:2. This motif is repeated eight times with a final C-terminal 10-unit repeat where X is V, G, A, and Win the ratio 4:3:2:1. This ELP component is represented generally as [(VPGXG)₁₀]₉.

FIG. 2A depicts plasmid pET24d-Ex-4 ELP1-90 encoding an ELP component with VPGXG (SEQ ID NO: 3) repeat motif (as in FIG. 1) cloned in frame with an N-terminal exendin-4 component. FIG. 2B depicts the nucleotide and amino acid sequence of the exendin-4/ELP fusion (SEQ ID NOS: 23 and 24). Primer sequences are indicated (SEQ ID NOS:35-40).

FIG. 3A depicts the nucleotide and amino acid sequence of an exendin-4 construct having an N-terminal Tev (Tobacco Etch Virus cysteine protease) cleavage site (SEQ ID NOS: 25 and 26). Primer sequences are indicated (SEQ ID NOS:38, 41, 42). FIG. 3B also depicts the nucleotide and amino acid sequence of an exendin-4 construct having an N-terminal Tev cleavage site, but with an additional sequence N-terminal to the Tev cleavage site to provide a better target for the protease (SEQ ID NOS: 27 and 28). Primer sequences are indicated (SEQ ID NOS:38, 43, 44).

FIG. 4A depicts the nucleotide and amino acid sequence of an exendin-4/ELP fusion as in FIGS. 1-3, but with a DsbA leader sequence to direct secretion into the periplasmic space (SEQ ID NOS: 29 and 30). Primer sequences are indicated (SEQ ID NOS:38, 45, 46). FIG. 4B depicts plasmid pET24d-DsbA-Ex-4 ELP1-90 encoding the fusion of FIG. 4A.

FIG. 5A depicts pPB0868, which encodes GLP-1(A8G,7-37)ELP1-90. FIG. 5B depicts the nucleotide and amino acid sequence of the encoded fusion protein (SEQ ID NOS: 53 and 54, respectively).

FIG. 6A depicts pPB1022, which encodes GLP-1(A8G,7-37)ELP1-120. FIG. 6B depicts the nucleotide and amino acid sequence of the encoded fusion protein (SEQ ID NOS: 55 and 56, respectively).

FIG. 7A depicts pPB0788, which encodes Factor VII-ELP1-90. FIG. 7B depicts the nucleotide and amino acid sequence of the encoded fusion protein (SEQ ID NOS: 57 and 58, respectively).

FIG. 8A depicts the nucleotide and amino acid sequence of an insulin (B, C, and A chains) having the ELP component cloned in frame (SEQ ID NOS: 31 and 32). Primer sequences are indicated (SEQ ID NOS: 47 and 48). FIG. 8B depicts plasmid pET24d Insulin-ELP1-90 expressing the insulin/ELP fusion of FIG. 8A.

FIG. 9 is a Western blot for FVII-ELP1-90 from transient transfection of Freestyle HEK293, detected with mouse anti-human FVII monoclonal antibody. Lanes are: (1) culture media; (2) FVII ELP1-90 after purification by phase transition; and FVII control.

FIG. 10 is an SDS-PAGE showing recombinant production of an Exendin-4/ELP4-60 fusion. Lanes are: (M) Protein markers; (1) Exendin-4 ELP4-60 from total lysate; (2) Exendin-4 ELP4-60 from insoluble lysate; (3) Exendin-4 ELP4-60 from soluble lysate; (4) Exendin-4 ELP4-60 from 1st transition (equal volume); (5) Exendin-4 ELP4-60 from 2nd transition (concentrated); (6) Exendin-4 ELP4-60 from 3rd transition (concentrated).

FIG. 11 shows the activation of Factor X by FactorVIIa-ELP1-90, and by Factor VIIa as a comparison. As shown, FactorVIIa-ELP retains full activity.

FIG. 12 shows that Factor VIIa-ELP1-90 has a long PK when administered by i.v. in rats. FactorVIIa has a T_1/2of about 690 min. as compared to about 45-60 min. for Factor VIIa.

FIG. 13 shows the high in vitro activity of GLP1-ELP and Exendin-4-ELP, when compared to the activity of Exendin peptide.

FIG. 14 shows that GLP1-ELP has a T_1/2of about 12.9 hours when administered by i.v. to rats, and a T_1/2of about 8.6 hours when administered subcutaneously (SQ).

FIG. 15 shows that GLP-1 ELP has a long half-life in rabbits of about 20 hours when administered i.v., and about 24 hours when administered sub-cutaneously.

FIG. 16 shows sustained glycemic control in diabetic mice with GLP-1-ELP.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides therapeutic agents comprising an elastin-like peptide (ELP) (“the ELP component”) and a therapeutic component. The therapeutic component may be selected from Table 1 (e.g., selected from a Therapeutic Protein, or functional portion or functional analog thereof, listed in Table 1). In certain embodiments, the therapeutic component is a GLP-1 receptor agonist, such as GLP-1 or exendin-4, or may be insulin, Factor VII/VIIa, or functional analog thereof. The ELP component contains structural units related to, or derived from, sequences of the elastin protein, which provides certain therapeutic advantages, such as comparatively better persistence, stability, solubility, bioavailability, half-life, and/or biological action of the therapeutic component. Such properties may be determined with respect to, for example, an unfused or unconjugated counterpart of the therapeutic component. The invention further provides polynucleotides encoding the therapeutic agents of the invention, as well as methods of treatment or prophylaxis for certain biological conditions, including the preferred indications listed in Table 1, and including diabetes (e.g., Type I and Type II), hyperglycemia, bleeding, hemophilia, and hemorrhage, among others.
For ease of reference in the ensuing discussion, set out below are definitions of some terms appearing in the discussion.
As used herein, the term “therapeutic agent” or “therapeutic component” refers to an agent or component capable of inducing a biological effect in viva and/or in vitro. The biological effect may be useful for treating and/or preventing a condition, disorder, or disease in a subject or patient.
As used herein, the term “coupled” means that the specified components are either directly covalently bonded to one another (e.g., via chemical conjugation or recombinant fusion technology), or indirectly covalently joined to one another (e.g., via chemical conjugation or recombinant fusion technology) through an intervening moiety or moieties, such as a bridge, spacer, or linker.
As used herein, “half-life” (which generally refers to in vivo half-life or circulatory half-life) is the period of time that is required for a 50% diminution of bioactivity of the active agent to occur. Such term is to be contrasted with “persistence,” which is the overall temporal duration of the active agent in the body, and “rate of clearance” as being a dynamically changing variable that may or may not be correlative with the numerical values of half-life and persistence.
The term “functional analog” refers to a protein that is an active analog (e.g., either chemical or protein analog), derivative, fragment, truncation isoform or the like of a native protein. For example, the functional analog may be a functional analog of a therapeutic protein listed in Table 1, or may be a functional analog of a GLP-1 receptor agonist (e.g., GLP-1, exendin), insulin, or Factor VII/VIIa. A polypeptide is active when it retains some or all of the biological activity of the corresponding native polypeptide, as determined in vivo or in one or more indicative in vitro assays. Exemplary activity assays for certain therapeutic proteins, which are determinative of activity, are listed Table 1. Further, such biological activities and assays for GLP-1 receptor agonists, insulin, and Factor VII/VIIa, which are determinative of whether a given molecule is a “functional analog,” are described in detail elsewhere herein.
As used herein, the term “native,” as used in reference to an amino acid sequence, indicates that the amino acid sequence is found in a naturally-occurring protein.
As used herein, the term “spacer” refers to any moiety, peptide or other chemical entity, that may be interposed between the ELP component and the therapeutic component. For example, the spacer may be a divalent group that is covalently bonded at one terminus to the ELP component, and covalently bonded at the other terminus to the therapeutic component. The therapeutic agents may therefore be open to the inclusion of additional chemical structure that does not preclude the efficacy of the agent for its intended purpose. The spacer may, for example, be a protease-sensitive spacer moiety that is provided to control the pharmacokinetics of the agent, or the spacer may be a protease-resistant moiety.
The therapeutic component and the ELP component may be coupled with one another in any suitable covalent manner, including chemical coupling and recombinant technology, such that the therapeutic agent is efficacious for its intended purpose, and such that the presence of the ELP component enhances the therapeutic component in some functional, therapeutic or physiological aspect. For example, the ELP-coupled therapeutic component may be enhanced in, e.g., its bioavailability, bio-unavailability, therapeutically effective dose, biological action, formulation compatibility, resistance to proteolysis or other degradative modality, solubility, half-life or other measure of persistence in the body subsequent to administration, rate of clearance from the body subsequent to administration, etc. Such enhancement may be determined, for example, in relation to a corresponding unconjugated or unfused counterpart therapeutic (e.g., determined relative to native GLP-1, exendin, insulin, or Factor VII/VIIa, or a therapeutic protein listed in Table 1).
In some embodiments, the therapeutic agent of the invention circulates or exists in the body in a soluble form, and escapes filtration by the kidney thereby persisting in the body in an active form. In some embodiments, the therapeutic agents of the invention have a molecular weight of less than the generally recognized cut-off for filtration through the kidney, such as less than about 60 kD, or in some embodiments less than about 55, 50, 45, 40, 30, or 20 kDa, and persist in the body by at least 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 20-fold, or 100-fold longer than an uncoupled (e.g., unfused or unconjugated) therapeutic counterpart.
The number of ELP and/or therapeutic components per molecule, and their respective positions within the molecule, may vary among embodiments of the invention. For example, in embodiments where the agent is a recombinant fusion, at least one ELP component may be placed at one or both of the N-terminus and the C-terminus. Where the ELP component is at both the N-terminus and C-terminus of the fusion, the ELP components will flank the therapeutic component. Alternatively, the therapeutic component may be positioned at either or both of the N-terminus and C-terminus. Where the therapeutic component is at both the N-terminus and C-terminus, the therapeutic component will flank the ELP component. In a further embodiment, different therapeutic components are positioned at the N-terminus and C-terminus of the molecule. As discussed in detail herein, in certain embodiments, such therapeutic component(s) may be released by proteolysis of a spacer moiety separating the ELP and therapeutic components. In certain embodiments, the therapeutic component may be inactive in the fused state, and becoming active upon proteolytic release from the ELP component(s). Alternatively, the therapeutic component remains active in the fused state, making proteolytic processing of the therapeutic agent unnecessary for biological activity.
When prepared as recombinant fusions, the therapeutic agent can be prepared by known recombinant expression techniques. For example, to recombinantly produce the therapeutic agent, a nucleic acid sequence encoding the chimeric gene is operatively linked to a suitable promoter sequence such that the nucleic acid sequence encoding such fusion protein will be transcribed and/or translated into the desired fusion protein in the host cells. Preferred promoters are those useful for expression in E. coli, such as the T7 promoter. Any commonly used expression system may be used, including eukaryotic or prokaryotic systems. Specific examples include yeast (e.g., Saccharomyces spp., Pichia spp.), baculovirus, mammalian, and bacterial systems, such as E. coli, and Caulobacter.
The various aspects and embodiments of the invention are described in greater detail in the following sections.

Elastin-Like Peptide (ELP) Component

The therapeutic agent of the invention may comprise one or more ELP components. The ELP components comprise or consist of structural peptide units or sequences that are related to, or derived from, the elastin protein. Such sequences are useful for improving the properties of therapeutic proteins, such as those listed in Table 1, as well as GLP-1 receptor agonists (e.g., GLP-1 or exendin-4), insulin, and Factor VII/VIIa in one or more of bioavailability, therapeutically effective dose, biological action, formulation compatibility, resistance to proteolysis, solubility, half-life or other measure of persistence in the body subsequent to administration, and/or rate of clearance from the body.
The ELP component is constructed from structural units of from three to about twenty amino acids, or in some embodiments, from four to ten amino acids, such as five or six amino acids. The length of the individual structural units, in a particular ELP component, may vary or may be uniform. In certain embodiments, the ELP component is constructed of a polytetra-, polypenta-, polyhexa-, polyhepta-, polyocta, and polynonapeptide motif of repeating structural units. Exemplary structural units include units defined by SEQ ID NOS: 1-12 (below), which may be employed as repeating structural units, including tandem-repeating units, or may be employed in some combination, to create an ELP effective for improving the properties of the therapeutic component. Thus, the ELP component may comprise or consist essentially of structural unit(s) selected from SEQ ID NOS: 1-12, as defined below.
The ELP component, comprising such structural units, may be of varying sizes. For example, the ELP component may comprise or consist essentially of from about 10 to about 500 structural units, or in certain embodiments about 15 to about 150 structural units, or in certain embodiments from about 20 to about 100 structural units, or from about 50 to about 90 structural units, including one or a combination of units defined by SEQ ID NOS: 1-12. Thus, the ELP component may have a length of from about 50 to about 2000 amino acid residues, or from about 100 to about 600 amino acid residues, or from about 200 to about 500 amino acid residues, or from about 200 to about 400 amino acid residues.
In some embodiments, the ELP component, or in some cases the therapeutic agent, has a size of less than about 65 kDa, or less than about 60 kDa, or less than about 55 kDa, or less than about 50 kDa, or less than about 40 kDa, or less than about 30 or 25 kDa. Three major blood proteins, Human Serum Albumin (HSA), Transferrin (Tf) and IgG, or the Fc portion of IgGs in their glycosylated form, have been exploited to extend the half-lives of proteins and peptides for improved therapeutic use. These molecules are 585, 679 and 480 amino acids in length giving molecular weights of about 66, 77, and ˜75 kDa (including glycosylations), respectively. They are each globular and relatively compact. The half life of these molecules is determined by a number of factors, including charge distribution, rescue of molecules by the neonatal Fc receptor (FcRn) (HSA and Fc) or cycling of Tf through the Tf receptor (TfR), and their size which prevents filtering through the kidney glomerulus. HSA is slightly below the generally regarded cut-off for filtration through the kidney (˜70 kDa) but its charge distribution helps prevent this. It would be anticipated that, in order to achieve half-life extension of the same order as that achieved with HSA, Tf and Fc, a protein of at least this molecular weight range would be required or desirable, i.e. having over 550 amino acids and being over 65 kDa. However, an ELP with a small number of amino acids relative to HSA, Tf and Fc (e.g., in the range of about 300 to 400) and around 30 to 40 kDa may have a half life that matches and/or exceeds that of HSA, Tf, and Fc.
In some embodiments, the ELP component in the untransitioned state may have an extended, relatively unstructured and non-globular form, and thus such molecules may have a large expanded structure in comparison to HSA, Tf and Fc, so as to escape kidney filtration. In such embodiments, the therapeutic agents of the invention have a molecular weight of less than the generally recognized cut-off for filtration through the kidney, such as less than about 60 kD, or in some embodiments less than about 55, 50, 45, 40, 30, or 25 kDa, and persist in the body by at least 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 20-fold, or 100-fold longer than an uncoupled (e.g., unfused or unconjugated) therapeutic counterpart.
In certain embodiments, the ELP component undergoes a reversible inverse phase transition. That is, the ELP components are structurally disordered and highly soluble in water below a transition temperature (Tt), but exhibit a sharp (2-3° C. range) disorder-to-order phase transition when the temperature is raised above the Tt, leading to desolvation and aggregation of the ELP components. For example, the ELP forms insoluble polymers, when reaching sufficient size, which can be readily removed and isolated from solution by centrifugation. Such phase transition is reversible, and isolated insoluble ELPs can be completely resolubilized in buffer solution when the temperature is returned below the Tt of the ELPs. Thus, the therapeutic agents of the invention can, in some embodiments, be separated from other contaminating proteins to high purity using inverse transition cycling procedures, e.g., utilizing the temperature-dependent solubility of the therapeutic agent, or salt addition to the medium. Successive inverse phase transition cycles can be used to obtain a high degree of purity. In addition to temperature and ionic strength, other environmental variables useful for modulating the inverse transition of the therapeutic agents include pH, the addition of inorganic and organic solutes and solvents, side-chain ionization or chemical modification, and pressure.
In certain embodiments, the ELP component does not undergo a reversible inverse phase transition, or does not undergo such a transition at a biologically relevant Tt, and thus the improvements in the biological and/or physiological properties of the molecule (as described elsewhere herein), may be entirely or substantially independent of any phase transition properties. Nevertheless, such phase transition properties may impart additional practical advantages, for example, in relation to the recovery and purification of such molecules.
In certain embodiments, the ELP component(s) may be formed of structural units, including but not limited to:

- (a) the tetrapeptide Val-Pro-Gly-Gly, or VPGG (SEQ ID NO: 1);
- (b) the tetrapeptide Ile-Pro-Gly-Gly, or IPGG (SEQ ID NO: 2);
- (c) the pentapeptide Val-Pro-Gly-X-Gly (SEQ ID NO: 3), or VPGXG, where X is any natural or non-natural amino acid residue, and where X optionally varies among polymeric or oligomeric repeats;
- (d) the pentapeptide Ala-Val-Gly-Val-Pro, or AVGVP (SEQ ID NO: 4);
- (e) the pentapeptide Ile-Pro-Gly-X-Gly, or IPGXG (SEQ ID NO: 5), where X is any natural or non-natural amino acid residue, and where X optionally varies among polymeric or oligomeric repeats;
- (e) the pentapeptide Ile-Pro-Gly-Val-Gly, or IPGVG (SEQ ID NO: 6);
- (f) the pentapeptide Leu-Pro-Gly-X-Gly, or LPGXG (SEQ ID NO: 7), where X is any natural or non-natural amino acid residue, and where X optionally varies among polymeric or oligomeric repeats;
- (g) the pentapeptide Leu-Pro-Gly-Val-Gly, or LPGVG (SEQ ID NO: 8);
- (h) the hexapeptide Val-Ala-Pro-Gly-Val-Gly, or VAPGVG (SEQ ID NO: 9);
- (I) the octapeptide Gly-Val-Gly-Val-Pro-Gly-Val-Gly, or GVGVPGVG (SEQ ID NO: 10);
- (J) the nonapeptide Val-Pro-Gly-Phe-Gly-Val-Gly-Ala-Gly, or VPGFGVGAG (SEQ ID NO: 11); and

(K) the nonapeptides Val-Pro-Gly-Val-Gly-Val-Pro-Gly-Gly, or VPGVGVPGG (SEQ ID NO: 12).
Such structural units defined by SEQ ID NOS:1-12 may form structural repeat units, or may be used in combination to form an ELP component in accordance with the invention. In some embodiments, the ELP component is formed entirely (or almost entirely) of one or a combination of (e.g., 2, 3 or 4) structural units selected from SEQ ID NOS: 1-12. In other embodiments, at least 75%, or at least 80%, or at least 90% of the ELP component is formed from one or a combination of structural units selected from SEQ ID NOS: 1-12, and which may be present as repeating units.
In certain embodiments, the ELP component(s) contain repeat units, including tandem repeating units, of the pentapeptide Val-Pro-Gly-X-Gly (SEQ ID NO:3), where X is as defined above, and where the percentage of Val-Pro-Gly-X-Gly (SEQ ID NO:3) pentapeptide units taken with respect to the entire ELP component (which may comprise structural units other than VPGXG (SEQ ID NO:3)) is greater than about 75%, or greater than about 85%, or greater than about 95% of the ELP component. The ELP component may contain motifs having a 5 to 15-unit repeat (e.g. about 10-unit repeat) of the pentapeptide of SEQ ID NO: 3, with the guest residue X varying among at least 2 or at least 3 of the units. The guest residues may be independently selected, such as from the amino acids V, I, L, A, G, and W (and may be selected so as to retain a desired inverse phase transition property). The repeat motif itself may be repeated, for example, from about 5 to about 12 times, such as about 8 to 10 times, to create an exemplary ELP component. The ELP component as described in this paragraph may of course be constructed from any one of the structural units defined by SEQ ID NOS: 1-12, or a combination thereof.
In some embodiments, the ELP component may include a 6-turn structure. Exemplary peptide sequences suitable for creating a 6-turn structure are described in International Patent Application PCT/US96/05186, which is hereby incorporated by reference in its entirety. For example, the fourth residue (X) in the elastin pentapeptide sequence, VPGXG (SEQ ID NO:3), can be altered without eliminating the formation of a β-turn. Alternatively, the ELP component may lack a β-turn, or otherwise have a different conformation and/or folding character.
In certain embodiments, the ELP components include polymeric or oligomeric repeats of the pentapeptide VPGXG (SEQ ID NO: 3), where the guest residue X is any amino acid. X may be a naturally occurring or non-naturally occurring amino acid. In some embodiments, X is selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine and valine. In some embodiments, X is a natural amino acid other than proline or cysteine.
The guest residue X (e.g., with respect to SEQ ID NO: 3, or other ELP structural unit) may be a non-classical (non-genetically encoded) amino acid. Examples of non-classical amino acids include: D-isomers of the common amino acids, 2, 4-diaminobutyric acid, α-amino isobutyric acid, A-aminobutyric acid. Abu, 2-amino butyric acid, γ-Abu, ε-Ahx, 6-amino hexanoic acid. Aib, 2-amino isobutyric acid, 3-amino propionic acid, ornithine, norleucine, norvaline, hydroxyproline, sarcosine, citrulline, homocitrulline, cysteic acid, t-butylglycine, t-butylalanine, phenylglycine, cyclohexylalanine, β-alanine, fluoro-amino acids, designer amino acids such as β-methyl amino acids, Cα-methyl amino acids, Nα-methyl amino acids, and amino acid analogs in general.
Selection of X is independent in each ELP structural unit (e.g., for each structural unit defined herein having a guest residue X). For example, X may be independently selected for each structural unit as an amino acid having a positively charged side chain, an amino acid having a negatively charged side chain, or an amino acid having a neutral side chain, including in some embodiments, a hydrophobic side chain.
In still other embodiments, the ELP component(s) may include polymeric or oligomeric repeats of the pentapeptides VPGXG (SEQ ID NO:3), IPGXG (SEQ ID NO:5) or LPGXG (SEQ ID NO:7), or a combination thereof, where X is as defined above.
In each embodiment, the structural units, or in some cases polymeric or oligomeric repeats, of the ELP sequences may be separated by one or more amino acid residues that do not eliminate the overall effect of the molecule, that is, in imparting certain improvements to the therapeutic component as described. In certain embodiments, such one or more amino acids also do not eliminate or substantially affect the phase transition properties of the ELP component (relative to the deletion of such one or more amino acids).
In each repeat. X is independently selected. The structure of the resulting ELP components may be described using the notation ELPk [X_iY_j-n], where k designates a particular ELP repeat unit, the bracketed capital letters are single letter amino acid codes and their corresponding subscripts designate the relative ratio of each guest residue X in the structural units (where applicable), and n describes the total length of the ELP in number of the structural repeats. For example, ELP1 [V₅A₂G₃-10] designates an ELP component containing 10 repeating units of the pentapeptide VPGXG (SEQ ID NO:3), where X is valine, alanine, and glycine at a relative ratio of 5:2:3; ELP1 [K₁V₂F₁-4] designates an ELP component containing 4 repeating units of the pentapeptide VPGXG (SEQ ID NO:3), where X is lysine, valine, and phenylalanine at a relative ratio of 1:2:1; ELP1 [K₁V₇F₁-9] designates a polypeptide containing 9 repeating units of the pentapeptide VPGXG (SEQ ID NO:3), where X is lysine, valine, and phenylalanine at a relative ratio of 1:7:1; ELP1 [V-5] designates a polypeptide containing 5 repeating units of the pentapeptide VPGXG (SEQ ID NO:3), where X is exclusively valine; ELP1 [V-20] designates a polypeptide containing 20 repeating units of the pentapeptide VPGXG (SEQ ID NO:3), where X is exclusively valine; ELP2 [5] designates a polypeptide containing 5 repeating units of the pentapeptide AVGVP (SEQ ID NO:4); ELP3 [V-5] designates a polypeptide containing 5 repeating units of the pentapeptide IPGXG (SEQ ID NO:5), where X is exclusively valine; ELP4 [V-5] designates a polypeptide containing 5 repeating units of the pentapeptide LPGXG (SEQ ID NO:7), where X is exclusively valine. Such ELP components as described in this paragraph may be used in connection with the present invention to increase the therapeutic properties of the therapeutic component.
Further, the Tt is a function of the hydrophobicity of the guest residue. Thus, by varying the identity of the guest residue(s) and their mole fraction(s), ELPs can be synthesized that exhibit an inverse transition over a 0-100° C. range. Thus, the Tt at a given ELP length may be decreased by incorporating a larger fraction of hydrophobic guest residues in the ELP sequence. Examples of suitable hydrophobic guest residues include valine, leucine, isoleucine, phenyalanine, tryptophan and methionine. Tyrosine, which is moderately hydrophobic, may also be used. Conversely, the Tt may be increased by incorporating residues, such as those selected from the group consisting of: glutamic acid, cysteine, lysine, aspartate, alanine, asparagine, serine, threonine, glycine, arginine, and glutamine; preferably selected from alanine, serine, threonine and glutamic acid.
The ELP component in some embodiments is selected or designed to provide a Tt ranging from about 10 to about 80° C., such as from about 35 to about 60° C., or from about 38 to about 45° C. In some embodiments, the Tt is greater than about 40° C. or greater than about 42° C., or greater than about 45° C., or greater than about 50° C. The transition temperature, in some embodiments, is above the body temperature of the subject or patient (e.g., >37° C.) thereby remaining soluble in vivo, or in other embodiments, the Tt is below the body temperature (e.g., <37° C.) to provide alternative advantages, such as in vivo formation of a drug depot for sustained release of the therapeutic agent.
The Tt of the ELP component can be modified by varying ELP chain length, as the Tt generally increases with decreasing MW. For polypeptides having a molecular weight >100,000, the hydrophobicity scale developed by Urry et al. (PCT/US96/05186, which is hereby incorporated by reference in its entirety) is preferred for predicting the approximate Tt of a specific ELP sequence. However, in some embodiments, ELP component length can be kept relatively small, while maintaining a target Tt, by incorporating a larger fraction of hydrophobic guest residues (e.g., amino acid residues having hydrophobic side chains) in the ELP sequence. For polypeptides having a molecular weight <100,000, the Tt may be predicted or determined by the following quadratic function: Tt=M₀+M₁X+M₂X²where X is the MW of the fusion protein, and M₀=116.21; M₁=−1.7499; M₂=0.010349.
While the Tt of the ELP component, and therefore of the ELP component coupled to a therapeutic component, is affected by the identity and hydrophobicity of the guest residue, X, additional properties of the molecule may also be affected. Such properties include, but are not limited to solubility, bioavailability, persistence, and half-life of the molecule.
As described in PCT/US2007/077767 (published as WO 2008/030968), which is hereby incorporated by reference in its entirety, the ELP-coupled therapeutic component can retain the therapeutic component's biological activity. Additionally, ELPs themselves can exhibit long half-lives. Therefore, ELP components in accordance with the present invention substantially increase (e.g. by greater than 10%, 20%, 30%, 50%, 100%, 200%, 500% or more, in specific embodiments) the half-life of the therapeutic component when conjugated thereto. Such half-life (or in some embodiments persistance or rate of clearance) is determined in comparison to the half-life of the free (unconjugated or unfused) form of the therapeutic component. Furthermore, ELPs may target high blood content organs, when administered in vivo, and thus, can partition in the body, to provide a predetermined desired corporeal distribution among various organs or regions of the body, or a desired selectivity or targeting of a therapeutic agent. In sum, the therapeutic agents contemplated by the invention are administered or generated in vivo as active compositions having extended half-lives (e.g., circulatory half-life), among other potential benefits described herein.
The invention thus provides various agents for therapeutic (in vivo) application, where the therapeutic component is biologically active. Such therapeutic components include those listed in Table 1 (e.g., full length or functional portions or functional analogs thereof), as well as GLP-1 receptor agonists such as GLP-1 or exendin-4, insulin, or Factor VII/VIIa, and functional analogs thereof. The structure and activity of such therapeutic components are described in detail below. In some forms of the therapeutic agent, the coupling of the therapeutic component to the ELP component is effected by direct covalent bonding or indirect (through appropriate spacer groups) bonding (as described elsewhere herein). Further, the therapeutic component(s) and the ELP component(s) can be structurally arranged in any suitable manner involving such direct or indirect covalent bonding, relative to one another.

Glucagon-Like Peptide (GLP)-1 Receptor Agonists

In certain embodiments of the invention, the therapeutic agent comprises an ELP component fused or conjugated to a GLP-1 receptor agonist, such as GLP-1, exendin-4, or functional, analogs thereof.
Human GLP-1 is a 37 amino acid residue peptide originating from preproglucagon which is synthesized in the L-cells in the distal ileum, in the pancreas, and in the brain. Processing of preproglucagon to give GLP-1 (7-36)amide, GLP-1 (7-37) and GLP-2 occurs mainly in the L-cells. A simple system is used to describe fragments and analogs of this peptide. For example, Gly⁸-GLP-1 (7-37) designates a fragment of GLP-1 formally derived from GLP-1 by deleting the amino acid residues Nos. 1 to 6 and substituting the naturally occurring amino acid residue in position 8 (Ala) by Gly. Similarly, Lys³⁴(N^ε-tetradecanoyl)-GLP-1(7-37) designates GLP-1 (7-37) wherein the ε-amino group of the Lys residue in position 34 has been tetradecanoylated. Where reference in this text is made to C-terminally extended GLP-1 analogues, the amino acid residue in position 38 is Arg unless otherwise indicated, the optional amino acid residue in position 39 is also Arg unless otherwise indicated and the optional amino acid residue in position 40 is Asp unless otherwise indicated. Also, if a C-terminally extended analogue extends to position 41, 42, 43, 44 or 45, the amino acid sequence of this extension is as in the corresponding sequence in human preproglucagon unless otherwise indicated.
The parent peptide of GLP-1, proglucagon (PG), has several cleavage sites that produce various peptide products dependent on the tissue of origin including glucagon (PG[32-62]) and GLP-1[7-36]NH₂(PG[72-107]) in the pancreas, and GLP-1[7-37] (PG[78-108]) and GLP-1[7-36]NH₂(PG [78-107]) in the L cells of the intestine where GLP-1[7-36]NH₂(78-107 PG) is the major product. The GLP-1 component in accordance with the invention may be any biologically active product or derivative of proglocagon, or functional analog thereof, including: GLP-1 (1-35), GLP-1(1-36), GLP-1 (1-36)amide, GLP-1 (1-37), GLP-1 (1-38), GLP-1 (1-39), GLP-1 (1-40), GLP-1 (1-41), GLP-1 (7-35), GLP-1 (7-36), GLP-1 (7-36)amide, GLP-1 (7-37), GLP-1 (7-38), GLP-1 (7-39), GLP-1 (7-40) and GLP-1 (7-41), or a analog of the foregoing. Generally, the GLP-1 component in some embodiments may be expressed as GLP-1 (A-B), where A is an integer from 1 to 7 and B is an integer from 38 to 45, optionally with one or more amino acid substitutions as defined below.
As an overview, after processing in the intestinal L-cells, GLP-1 is released into the circulation, most notably in response to a meal. The plasma concentration of GLP-1 rises from a fasting level of approximately 15 pmol/L to a peak postprandial level of 40 pmol/L. For a given rise in plasma glucose concentration, the increase in, plasma insulin is approximately threefold greater when glucose is administered orally compared with intravenously (Kreymann at al., 1987, Lancet 2(8571): 1300-4). This alimentary enhancement of insulin release, known as the incretin effect, is primarily humoral and GLP-1 is now thought to be the most potent physiological incretin in humans. GLP-1 mediates insulin production via binding to the GLP-1 receptor, known to be expressed in pancreatic 13 cells. In addition to the insulinotropic effect, GLP-1 suppresses glucagon secretion, delays gastric emptying (Wettergen et al., 1993, Dig Dis Sci 38: 665-73) and may enhance peripheral glucose disposal (D'Alessio at al., 1994, J. Clin Invest 93: 2293-6).
A combination of actions gives GLP-1 unique therapeutic advantages over other agents currently used to treat non-insulin-dependent diabetes mellitus (NIDDM). First, a single subcutaneous dose of GLP-1 can completely normalize post prandial glucose levels in patients with NIDDM (Gutniak et al., 1994, Diabetes Care 17: 1039-44). This effect may be mediated both by increased insulin release and by a reduction in glucagon secretion. Second, intravenous infusion of GLP-1 can delay postprandial gastric emptying in patients with NIDDM (Williams et al., 1996, J. Clin Endo Metab 81: 327-32). Third, unlike sulphonylureas, the insulinotropic action of GLP-1 is dependent on plasma glucose concentration (Holz at al., 1993, Nature 361:362-5). Thus, the loss of GLP-1-mediated insulin release at low plasma glucose concentration protects against severe hypoglycemia.
When given to healthy subjects, GLP-1 potently influences glycemic levels as well as insulin and glucagon concentrations (Orskov, 1992, Diabetologia 35:701-11), effects which are glucose dependent (Weir et al., 1989, Diabetes 38: 338-342). Moreover, it is also effective in patients with diabetes (Gutniak, M., 1992, N. Engl J. Med. 226: 1316-22), normalizing blood glucose levels in type 2 diabetic subjects and improving glycemic control in type 1 patients (Nauck at al., 1993, Diabetologia 36: 741-4, Creutzfeldt at al., 1996, Diabetes Care 19:580-6).
GLP-1 is, however, metabolically unstable, having a plasma half-life (t_1/2) of only 1-2 minutes in vivo. Moreover, exogenously administered GLP-1 is also rapidly degraded (Deacon et al., 1995, Diabetes 44: 1126-31). This metabolic instability has limited the therapeutic potential of native GLP-1.
GLP-1[7-36]NH₂has the following amino acid sequence: HAEGTFTSDVSSYLEGQAAKEFIAWLVKGR (SEQ ID NO: 13), which may be employed as the GLP-1 component in accordance with the invention. Alternatively, the GLP-1 component may contain glycine (G) at, the second position, giving, for example, the sequence HGEGTFTSDVSSYLEGQAAKEFIAWLVKGR (SEQ ID NO: 17). The GLP-1 component may be a biologically active fragment of GLP-1, for example, as disclosed in US 2007/0041951, which is hereby incorporated by reference in its entirety. Other fragments and modified sequences of GLP-1 are known in the art (U.S. Pat. No. 5,614,492; U.S. Pat. No. 5,545,618; European Patent Application, Publication No. EP 0658568 A1; WO 93/25579, which are hereby incorporated by reference in their entireties). Such fragments and modified sequences may be used in connection with the present invention, as well as those described below.
Certain structural and functional analogs of GLP-1 have been isolated from the venom of the Gila monster lizards (Heloderma suspectum and Heloderma horridum) and have shown clinical utility. Such molecules find use in accordance with the present invention. In particular, exendin-4 is a 39 amino acid residue peptide isolated from the venom of Heloderma suspectum and shares approximately 52% homology with human GLP-1. Exendin-4 is a potent GLP-1 receptor agonist that stimulates insulin release, thereby lowering blood glucose levels. Exendin-4 has the following amino acid sequence: HGEGTFTSDLSKQMEEEAVRLFEWLKNGGPSSGAPPPS (SEQ ID NO: 14). A synthetic version of exendin-4 known as exenatide (marketed as Byetta®) has been approved for the treatment of Type-2 Diabetes. Although exenatide is structurally analogous to native GLP-1, it has a longer half-life after injection.
While exenatide has the ability to lower blood glucose levels on its own, it can also be combined with other medications such as metformin, a thiozolidinedione, a sulfonylureas, and/or insulin to improve glucose control. Exenatide is administered by injection subcutaneously twice per day using a pre-filled pen device. Typical human responses to exenatide include improvements in the initial rapid release of endogenous insulin, an increase in β-cell growth and replication, suppression of pancreatic glucagon release, delayed gastric emptying, and reduced appetite—all of which function to lower blood glucose. Unlike sulfonylureas and meglitinides, exenatide increases insulin synthesis and secretion in the presence of glucose only, thus lessening the risk of hypoglycemia. Despite the therapeutic utility of exenatide, it has certain undesirable traits, including the requirement of twice daily injections, gastrointestinal side effects, and similar to native GLP-1, a relatively short half-life (i.e. approximately 2 hr).
Various functional analogs of GLP-1 and exendin-4 are known, and which find use in accordance with the invention. These include liraglutide (Novo Nordisk, WO98/008871), R1583/taspoglutide (Roche, WO00/034331), CJC-1131 (ConjuChem, WO00/069911), ZP-10/AVE0010 (Zealand Pharma, Sanofi-Aventis, WO01/004156), and LY548806 (Eli Lilly, WO03/018516).
Liraglutide, also known as NN2211, is a GLP-1 receptor agonist analog that has been designed for once-daily injection (Harder et al., 2004, Diabetes Care 27: 1915-21). Liraglutide has been tested in patients with type-2 diabetes in a number of studies and has been shown to be effective over a variety of durations. In one study, treatment with liraglutide improved glycemic control, improved β-cell function, and reduced endogenous glucose release in patients with type-2 diabetes after one week of treatment (Degn et al., 2004, Diabetes 53: 1187-94). In a similar study, eight weeks of 0.6-mg liraglutide therapy significantly improved glycemic control without increasing weight in subjects with type 2 diabetes compared with those on placebo (Harder et al., 2004, Diabetes Care 27: 1915-21).
Thus, in certain embodiments, the GLP-1 receptor agonist in accordance with the invention is as described in WO98/008871, which is hereby incorporated by reference in its entirety. The GLP-1 receptor agonist may have at least one lipophilic substituent, in addition to one, two, or more amino acid substitutions with respect to native GLP-1. For example, the lipophilic substituent may be an acyl group selected from CH₃(CH₂)_nCO—, wherein n is an integer from 4 to 38, such as an integer from 4 to 24. The lipophilic substituent may be an acyl group of a straight-chain or branched alkyl or fatty acid (for example, as described in WO98/008871, which description is hereby incorporated by reference).
In certain embodiments, the GLP-1 component is Arg²⁶-GLP-1 (7-37), Arg³⁴-GLP-1(7-37), Lys³⁶-GLP-1 (7-37), Arg^26,34Lys³⁶-GLP-I (7-37), Arg^26,34Lys³⁸-GLP-I (7-38), Arg^28,34Lys³⁹-GLP-1 (7-39), Arg^26,34Lys⁴⁰-GLP-1(7-40), AreLys³⁶-GLP-1(7-37), Arg³⁴Lys³⁶-GLP-1(7-37), AreLys³⁶-GLP-1(7-39), Arg³⁴Lys⁴⁰-GLP-1(7-40), Arg^26,34Lys^38,39-GLP-I (7-39), Arg^26,34Lys^36,40-GLP-1(7-40), Gly⁸Arg²⁶-GLP-1(7-37); Gly⁶Arg³⁴-GLP-1(7-37); Gly⁸Lys³⁸-GLP-1(7-37); Gly⁸Arg^26,34Lys³⁶-GLP-1(7-37), Gly⁸Arg^26,34Lys³⁶-GLP-1(7-39), Gly⁸Arg^26,34Lys⁴⁰-GLP-1(7-40), Gly⁸Arg²⁶Lys³⁶-GLP-1(7-37), Gly⁸Arg³⁴Lys³⁶-GLP-1(7-37), Gly⁸Arg²⁶Lys³⁶-GLP-1(7-39); Gly⁸Arg³⁴Lys⁴⁰-GLP-1 (7-40), Gly⁸Arg^28,34Lys^36,39-GLP-1 (7-39) and Gly⁸Arg^26,34Lys^35,40-GLP-1(7-40), each optionally having a lipophilic substituent. For example, the GLP-1 receptor agonist may have the sequence/structure Arg³⁴Lys²⁶-(N-ε-(γ-Glu(N-α-hexadecanoyl)))-GLP-I(7-37).
Taspoglutide, also known as R1583 or BIM 51077, is a GLP-1 receptor agonist that has been shown to improve glycemic control and lower body weight in subjects with type 2 diabetes mellitus treated with metformin (Abstract No. A-1604, Jun. 7, 2008, 68th American Diabetes Association Meeting, San Francisco, Calif.).
Thus, in certain embodiments, the GLP-1 receptor agonist is as described in WO00/034331, which is hereby incorporated by reference in its entirety. In certain exemplary embodiments, the GLP-1 receptor agonist has the sequence [Aib^8,35]hGLP-1(7-36)NH₂(e.g. taspoglutide), wherein Aib is alpha-aminoisobutyric acid.
CJC-1131 is a GLP-1 analog that consists of a DPP-IV-resistant form of GLP-1 joined to a reactive chemical linker group that allows GLP-1 to form a covalent and irreversible bond with serum albumin following subcutaneous injection (Kim et al., 2003, Diabetes 52: 751-9). In a 12-week, randomized, double-blind, placebo-controlled multicenter study, CJC-1131 and metformin treatment was effective in reducing fasting blood glucose levels in type 2 diabetes patients (Ratner et al., Abstract No. 10-OR, Jun. 10-14th, 2005, 65th American Diabetes Association Meeting, San Francisco, Calif.).
Thus, in certain embodiments, the GLP-1 receptor agonist is as described in WO00/069911, which is hereby incorporated by reference in its entirety. In some embodiments, the GLP-1 receptor agonist is modified with a reactive group which reacts with amino groups, hydroxyl groups or thiol groups on blood components to form a stable covalent bond. In certain embodiments, the GLP-1 receptor agonist is modified with a reactive group selected from the group consisting of succinimidyl and maleimido groups. In certain exemplary embodiments, the GLP-1 receptor agonist has the sequence/structure: D-Ala⁸Lys³⁷-(2-(2-(2-maleimidopropionamido(ethoxy)ethoxy)acetamide))-GLP-1(7-37) (e.g. CJC-1131).
AVE0010, also known as ZP-10, is a GLP-1 receptor agonist that may be employed in connection with the invention. In a recent double-blind study, patients treated with once daily dosing of AVE0010 demonstrated significant reductions in HbA1c levels (Ratner et al., Abstract No. 433-P, 68th American Diabetes Association Meeting, San Francisco, Calif.). At the conclusion of the study, the percentages of patients with HbA1c <7% ranged from 47-69% for once daily dosing compared to 32% for placebo. In addition, AVE0010 treated patients showed dose-dependent reductions in weight and post-prandial plasma glucose.
Thus, in certain embodiments, the GLP-1 receptor agonist is as described in WO01/004156, which is hereby incorporated by reference in its entirety. For example, the GLP-1 receptor agonist may have the sequence: HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPSKKKKKK-NH2 (SEQ ID NO: 18) (e.g. AVE0010).
LY548806 is a GLP-1 derivative designed to be resistant to proteolysis by dipeptidase-peptidyl IV (DPP-IV) (Jackson et al., Abstract No, 562, Jun. 10-14th, 2005, 65th American Diabetes Association Meeting, San Francisco, Calif.). In an animal model of hyperglycemia, LY548806 has been shown to produce a significant lowering of blood glucose levels during the hyperglycemic phase (Saha et al., 2006, J. Pharm. Exp. Ther. 316: 1159-64). Moreover, LY548806 was shown to produce a significant increase in insulin levels consistent with its known mechanism of action, namely stimulation of insulin release in the presence of hyperglycemia.
Thus, in certain embodiments, the GLP-1 receptor agonist is as described in WO03/018516, which is hereby incorporated by reference in its entirety. In some embodiments, the therapeutic agents of the present invention comprise GLP-1 analogs wherein the backbone for such analogs or fragments contains an amino acid other than alanine at position 8 (position 8 analogs). The backbone may also include L-histidine, D-histidine, or modified forms of histidine such as desamino-histidine, 2-amino-histidine, β-hydroxy-histidine, homohistidine, α-fluoromethyl-histidine, or α-methyl-histidine at position 7. In some embodiments, these position 8 analogs may contain one or more additional changes at positions 12, 16, 18, 19, 20, 22, 25, 27, 30, 33, and 37 compared to the corresponding amino acid of native GLP-1. In other embodiments, these position 8 analogs may contain one or more additional changes at positions 16, 18, 22, 25 and 33 compared to the corresponding amino acid of native GLP-1. In certain exemplary embodiments, the GLP-1 receptor agonist has the sequence: HVEGTFTSDVSSYLEEQAAKEFIAWLIKGRG-OH (SEQ ID NO: 19) (e.g. LY548806).
Thus, the present invention provides therapeutic agents comprising an elastin-like peptide (ELP) and a GLP-1 receptor agonist. For example, in certain embodiments, the GLP-1 receptor agonist is GLP-1 (SEQ ID NO:13, 17, or 59) or a functional analog thereof. In other embodiments, the GLP-1 receptor agonist is exendin-4 (SEQ ID NO:14) or a functional analog thereof. Such functional analogs of GLP-1 or exendin-4 include functional fragments truncated at the C-terminus by from 1 to 10 amino acids, including by 1, 2, 3, or up to about 5 amino acids (with respect to SEQ ID NOS: 13, 14, 17, or 59). Such functional analogs may contain from 1 to 10 amino acid insertions, deletions, and/or substitutions (collectively) with respect to the native sequence (e.g., SEQ ID NOS 13, 14, and 59), and in each case retaining the activity of the peptide. For example, the functional analog of GLP-1 or exendin-4 may have from 1 to about 3, 4, or 5 insertions, deletions and/or substitutions (collectively) with respect to SEQ ID NOS: 13, 59 and 14, and in each case retaining the activity of the peptide. Such activity may be confirmed or assayed using any available assay, including those described herein. In these or other embodiments, the GLP-1 receptor agonist component has at least about 50%, 75%, 80%, 85%, 90%, or 95% identity with the native sequence (SEQ ID NOS: 13, 59, and 14). The determination of sequence identity between two sequences (e.g., between a native sequence and a functional analog) can be accomplished using any alignment tool, including Tatusova et al., Blast 2 sequences—a new tool for comparing protein and nucleotide sequences, FENS Microbiol Lett. 174:247-250 (1999). Such functional analogs may further comprise additional chemical modifications, such as those described in this section and/or others known in the art.
In certain embodiments, the GLP1-ELP fusion has a sequence exemplified herein as SEQ ID NOS: 54 and 56. When processed, the mature form of such fusion protein will begin with the His⁷of GLP.
In another aspect, the present invention provides methods for the treatment or prevention of type 2 diabetes, impaired glucose tolerance, type 1 diabetes, hyperglycemia, obesity, binge eating, bulimia, hypertension, syndrome X, dyslipidemia, cognitive disorders, atheroschlerosis, non-fatty liver disease, myocardial infarction, coronary heart disease and other cardiovascular disorders. The method comprises administering the therapeutic agent comprising the elastin-like peptide (ELP) and the GLP-1 receptor agonist (as described above) to a patient in need of such treatment. In these or other embodiments, the present invention provides methods for decreasing food intake, decreasing β-cell apoptosis, increasing β-cell function and β-cell mass, and/or for restoring glucose sensitivity to β-cells. Generally, the patient may be a human or non-human animal patient (e.g., dog, cat, cow, or horse). Preferably, the patient is human.
The treatment with a ELP/GLP-1 receptor agonist compound according to the present invention may also be combined with one or more pharmacologically active substances, e.g. selected from antidiabetic agents, antiobesity agents, appetite regulating agents, antihypertensive agents, agents for the treatment and/or prevention of complications resulting from or associated with diabetes and agents for the treatment and/or prevention of complications and disorders resulting from or associated with obesity. In the present context, the expression “antidiabetic agent” includes compounds for the treatment and/or prophylaxis of insulin resistance and diseases wherein insulin resistance is the pathophysiological mechanism.
The ability of a GLP-1 or exendin-4 analog, or an GLP-1 receptor agonist/ELP compound, to bind the GLP-1 receptor may be determined by standard methods, for example, by receptor-binding activity screening procedures which involve providing appropriate cells that express the GLP-1 receptor on their surface, for example, insulinoma cell lines such as RINmSF cells or INS-1 cells. In addition to measuring specific binding of tracer to membrane using radioimmunoassay methods, cAMP activity or glucose dependent insulin production can also be measured. In one method, a polynucleotide encoding the GLP-1 receptor is employed to transfect cells to thereby express the GLP-1 receptor protein. Thus, these methods may be employed for testing or confirming whether a suspected GLP-1 receptor agonist is active. An exemplary assay is described in greater detail herein.
In addition, known methods can be used to measure or predict the level of biologically activity of a GLP-1 receptor agonist or GLP-1 receptor agonist/ELP in vivo (See e.g. Siegel, et al., 1999, Regul Pept 79(2-3): 93-102). In particular, GLP-1 receptor agonists or GLP-1 receptor agonist/ELP compounds can be assessed for their ability to induce the production of insulin in vivo using a variety of known assays for measuring GLP-1 activity. For example, an ELP/GLP-1 receptor agonist compound can be introduced into a cell, such as an immortalized β-cell, and the resulting cell can be contacted with glucose. If the cell produces insulin in response to the glucose, then the modified GLP-1 is generally considered biologically active in vivo (Fehmann et al., 1992, Endocrinology 130: 159-166). An exemplary assay is described in greater detail herein.
The ability of an GLP-1 receptor agonist/ELP compound to enhance β-cell proliferation, inhibit β-cell apoptosis, and regulate islet growth may also be measured using known assays. Pancreatic β-cell proliferation may be assessed by ³H-tymidine or BrdU incorporation assays (See e.g. Buteau et al., 2003, Diabetes 52: 124-32), wherein pancreatic β-cells such as INS(832/13) cells are contacted with an ELP/GLP-1 receptor agonist compound and analyzed for increases in ³H-thymidine or BrdU incorporation. The antiapoptotic activity of an ELP/GLP-1 receptor agonist compound can be measured in cultured insulin-secreting cells and/or in animal models where diabetes occurs as a consequence of an excessive rate of beta-cell apoptosis (See e.g. Bulotta et al., 2004, Cell Biochem Biophys 40(3 suppl): 65-78).
In addition to GLP-1, other peptides of this family, such as those derived from processing of the pro-glucagon gene, such as GLP-2, GIP, and oxyntomodulin, could be conjugated or fused to the ELP component (as described herein) to enhance the therapeutic potential.

Insulin

In other embodiments, the present invention provides a therapeutic agent comprising an ELP component coupled to insulin (e.g., via fusion or conjugation). Insulin injections, e.g. of human insulin, can be used to treat diabetes. The insulin-making cells of the body are called β-cells, and they are found in the pancreas gland. These cells clump together to form the “islets of Langerhans”, named for the German medical student who described them.
The synthesis of insulin begins at the translation of the insulin gene, which resides on chromosome 11. During translation, two introns are spliced out of the mRNA product, which encodes a protein of 110 amino acids in length. This primary translation product is called preproinsulin and is inactive. It contains a signal peptide of 24 amino acids in length, which is required for the protein to cross the cell membrane.
Once the preproinsulin reaches the endoplasmic reticulum, a protease cleaves off the signal peptide to create proinsulin. Proinsulin consists of three domains: an amino-terminal B chain, a carboxyl-terminal A chain, and a connecting peptide in the middle known as the C-peptide. Insulin is composed of two chains of amino acids named chain A (21 amino acids—GIVEQCCASVCSLYQLENYCN) (SEQ ID NO: 15) and chain B (30 amino acids FVNQHLCGSHLVEALYLVCGERGFFYTPKA) (SEQ ID NO: 16) that are linked together by two disulfide bridges. There is a 3rd disulfide bridge within the A chain that links the 6th and 11th residues of the A chain together. In most species, the length and amino acid compositions of chains A and B are similar, and the positions of the three disulfide bonds are highly conserved. For this reason, pig insulin can replace deficient human insulin levels in diabetes patients. Today, porcine insulin has largely been replaced by the mass production of human proinsulin by bacteria (recombinant insulin).
Insulin molecules have a tendency to form dimers in solution, and in the presence of zinc ions, insulin dimers associate into hexamers. Whereas monomers of insulin readily diffuse through the blood and have a rapid effect, hexamers diffuse slowly and have a delayed onset of action. In the design of recombinant insulin, the structure of insulin can be modified in a way that reduces the tendency of the insulin molecule to form dimers and hexamers but that does not interrupt binding to the insulin receptor. In this way, a range of preparations are made, varying from short acting to long acting.
Within the endoplasmic reticulum, proinsulin is exposed to several specific peptidases that remove the C-peptide and generate the mature and active form of insulin. In the Golgi apparatus, insulin and free C-peptide are packaged into secretory granules, which accumulate in the cytoplasm of the β-cells. Exocytosis of the granules is triggered by the entry of glucose into the beta cells. The secretion of insulin has a broad impact on metabolism.
There are two phases of insulin release in response to a rise in glucose. The first is an immediate release of insulin. This is attributable to the release of preformed insulin, which is stored in secretory granules. After a short delay, there is a second, more prolonged release of newly synthesized insulin.
Once released, insulin is active for a only a brief time before it is degraded by enzymes. Insulinase found in the liver and kidneys breaks down insulin circulating in the plasma, and as a result, insulin has a half-life of only about 6 minutes. This short duration of action results in rapid changes in the circulating levels of insulin.
Insulin analogs have been developed with improved therapeutic properties (Owens et al., 2001, Lancet 358: 739-46; Vajo et al., 2001, Endocr Rev 22: 706-17), and such analogs may be employed in connection with the present invention. Various strategies, including elongation of the COOH-terminal end of the insulin B-chain and engineering of fatty acid-acylated insulins with substantial affinity for albumin are used to generate longer-acting insulin analogs. However, in vivo treatments with available longer-acting insulin compounds still result in a high frequency of hypo- and hyperglycemic excursions and modest reduction in HbA_1c. Accordingly, development of a truly long-acting and stable human insulin analog still remains an important task.
Functional analogs of insulin that may be employed in accordance with the invention include rapid acting analogs such as lispro, aspart and glulisine, which are absorbed rapidly (<30 minutes) after subcutaneous injection, peak at one hour, and have a relatively short duration of action (3 to 4 hours). In addition, two long acting insulin analogs have been developed: glargine and detemir, and which may be employed in connection with the invention. The long acting insulin analogs have an onset of action of approximately two hours and reach a plateau of biological action at 4 to 6 hours, and may last up to 24 hours.
Thus, in one embodiment, the insulin component may contain the A and/or B chain of lispro (also known as Humalog, Eli Lilly). Insulin lispro differs from human insulin by the substitution of proline with lysine at position 28 and the substitution of lysine with proline at position 29 of the insulin B chain. Although these modifications do not alter receptor binding, they help to block the formation of insulin dimers and hexamers, allowing for larger amounts of active monomeric insulin to be available for postprandial injections.
In another embodiment, the insulin may contain an A and/or B chain of aspart (also known as Novolog, Novo Nordisk). Insulin aspart is designed with the single replacement of the amino acid praline by aspartic acid at position 28 of the human insulin B chain. This modification helps block the formation for insulin hexamers, creating a faster acting insulin.
In yet another embodiment, the insulin may contain an A and/or B chain of glulisine (also known as Apidra, Sanofi-Aventis). Insulin glulisine is a short acting analog created by substitution of asparagine at position 3 by lysine and lysine at position 29 by glutamine of human insulin B chain. Insulin glulisine has more rapid onset of action and shorter duration of action compared to regular human insulin.
In another embodiment, the insulin may contain an A and/or B chain of glargine (also known as Lantus, Sanofi-Aventis). Insulin glargine differs from human insulin in that the amino acid asparagine at position 21 of the A chain is replaced by glycine and two arginines are added to the C-terminus of the B-chain. Compared with bedtime neutral protamine Hagedorn (NPH) insulin (an intermediate acting insulin), insulin glargine is associated with less nocturnal hypoglycemia in patients with type 2 diabetes.
In yet another embodiment, the insulin may contain an A and/or B chain from detemir (also known as Levemir, Novo Nordisk). Insulin detemir is a soluble (at neutral pH) long-acting insulin analog, in which the amino acid threonine at B30 is removed and a 14-carbon, myristoyl fatty acid is acetylated to the epsilon-amino group of LysB29. After subcutaneous injection, detemir dissociates, thereby exposing the free fatty acid which enables reversible binding to albumin molecules. So at steady state, the concentration of free unbound insulin is greatly reduced resulting in stable plasma glucose levels.
In some embodiments, the insulin may be a single-chain insulin analog (SIA) (e.g. as described in U.S. Pat. No. 6,630,438 and WO08/019,368, which are hereby incorporated by reference in their entirety). Single-chain insulin analogs encompass a group of structurally-related proteins wherein the A and B chains are covalently linked by a polypeptide linker. The polypeptide linker connects the C-terminus of the B chain to the N-terminus of the A chain. The linker may be of any length so long as the linker provides the structural conformation necessary for the SIA to have a glucose uptake and insulin receptor binding effect. In some embodiments, the linker is about 5-18 amino acids in length. In other embodiments, the linker is about 9-15 amino acids in length. In certain embodiments, the linker is about 12 amino acids long. In certain exemplary embodiments, the linker has the sequence KDDNPNLPRLVR (SEQ ID NO.: 20) or GAGSSSRRAPQT (SEQ ID NO.: 21). However, it should be understood that many variations of this sequence are possible such as in the length (both addition and deletion) and substitutions of amino acids without substantially compromising the effectiveness of the produced SIA in glucose uptake and insulin receptor binding activities. For example, several different amino acid residues may be added or removed from either end without substantially decreasing the activity of the produced SIA.
An exemplary single-chain insulin analog currently in clinical development is albulin (Duttaroy et al., 2005, Diabetes 54: 251-8). Albulin can be produced in yeast or in mammalian cells. It consists of the B and A chain of human insulin (100% identity to native human insulin) linked together by a dodecapeptide linker and fused to the NH₂terminals of the native human serum albumin. For expression and purification of albulin, Duttaroy et al. constructed a synthetic gene construct encoding a single-chain insulin containing the B- and A-chain of mature human insulin linked together by a dodecapeptide linker using four overlapping primers and PCR amplification. The resulting PCR product was ligated in-frame between the signal peptide of human serum albumin (HSA) and the NH₂terminus of mature HSA, contained within a pSAC35 vector for expression in yeast. In accordance with the present invention, the HSA component of abulin may be replaced with an ELP component as described herein.
Thus, in one aspect, the present invention provides therapeutic agents comprising an elastin-like peptide (ELP) and an insulin or functional analog thereof. For example, in certain embodiments, the insulin is a mammalian insulin, such as human insulin or porcine insulin. In accordance with the invention, the ELP component may be coupled (e.g., via recombinant fusion or chemical conjugation) to the insulin A chain, or B chain, or both. The insulin may comprise each of chains A, B, and C (SEQ ID NOS: 51 and 52), or may contain a processed form, containing only chains A and B. In some embodiments, chains A and B are connected by a short linking peptide, to create a single chain insulin. The insulin may be a functional analog of human insulin, including functional fragments truncated at the N-terminus and/or C-terminus (of either or both of chains A and B) by from 1 to 10 amino acids, including by 1, 2, 3, or about 5 amino acids. Functional analogs may contain from 1 to 10 amino acid insertions, deletions, and/or substitutions (collectively) with respect to the native sequence (e.g., SEQ ID NOS 15 and 16), and in each case retaining the activity of the peptide. For example, functional analogs may have 1, 2, 3, 4, or 5 amino acid insertions, deletions, and/or substitutions (collectively) with respect to the native sequence (which may contain chains A and B, or chains A, B, and C). Such activity may be confirmed or assayed using any available assay, including those described herein. In these or other embodiments, the insulin component has at least about 75%, 80%, 85%, 90%, 95%, or 98% identity with each of the native sequences for chains A and B (SEQ ID NOS:15 and 16). The determination of sequence identity between two sequences (e.g., between a native sequence and a functional analog) can be accomplished using any alignment tool, including Tatusova et al., Blast 2 sequences—a new tool for comparing protein and nucleotide sequences, FEMS Microbiol Lett. 174:247-250 (1999). The insulin component may contain additional chemical modifications known in the art.
In another aspect, the present invention provides methods for the treatment or prevention of diabetes, including type I and II diabetes. The method comprises administering an effective amount of the therapeutic agent comprising an elastin-like peptide (ELP) component and an insulin (or functional analog thereof) component to a patient in need thereof. Generally, the patient may be a human or non-human animal (e.g., dog, cat, cow, or horse) patient. Preferably, the patient is human.
To characterize the in vitro binding properties of an insulin analog or an ELP-containing insulin analog, competition binding assays may be performed in various cell lines that express the insulin receptor (Jehle et al., 1996, Diabetologia 39: 421-432). For example, competition binding assays using CHO cells overexpressing the human insulin receptor may be employed. Insulin can also bind to the IGF-1 receptor with a lower affinity than the insulin receptor. To determine the binding affinity of an ELP-containing insulin analog, a competition binding assay can be performed using ¹²⁵I-labeled IGF-1 in L6 cells.
The activities of insulin include stimulation of peripheral glucose disposal and inhibition of hepatic glucose production. The ability of an ELP-containing insulin analog to mediate these biological activities can be assayed in vitro using known methodologies. For example, the effect of an ELP-containing analog on glucose uptake in 3T3-L1 adipocytes can be measured and compared with that of insulin. Pretreatment of the cells with a biologically active analog will generally produce a dose-dependent increase in 2-deoxyglucose uptake. The ability of an ELP-containing insulin analog to regulate glucose production may be measured in any number of cells types, for example, H4Ile hepatoma cells. In this assay, pretreatment with a biologically active analog will generally result in a dose-dependent inhibition of the amount of glucose released.
Factor VII (VIIa)
In certain embodiments, the invention provides therapeutic agents comprising an ELP component coupled (e.g., via fusion or conjugation) to a Factor VII/VIIa. Coagulation is the biological process of blood clot formation involving many different serine proteases as well as their essential cofactors and inhibitors. It is initiated by exposure of Factor VII (FVII) and Factor VIIa (FVIIa) to its membrane bound cofactor, tissue factor (TF), resulting in production of Factor Xa (FXa) and more FVIIa. The process is propagated upon production of Factor IXa (FIXa) and additional FXa that, upon binding with their respective cofactors FVIIIa and FVa, form platelet bound complexes, ultimately resulting in the formation of thrombin and a fibrin clot. Thrombin also serves to further amplify coagulation by activation of cofactors such as FV and FVII and zymogens such as Factor XI. Moreover, thrombin activates platelets leading to platelet aggregation, which is necessary for the formation of a hemostatic plug.
Factor VII circulates in the blood in a zymogen form, and is converted to its active form, Factor VIIa, by either factor IXa, factor Xa, factor XIIa, or thrombin by minor proteolysis. Factor VIIa is a two-chain, 50 kilodalton (kDa) plasma serine protease. The active form of the enzyme comprises a heavy chain (254 amino acid residues) containing a catalytic domain and a light chain (152 residues) containing 2 epidermal growth factor (EGF)-like domains. The mature factor VII/VIIa that circulates in plasma is composed of 406 amino acid residues (SEQ ID NO: 33). The light and heavy chains are held together by a disulfide bond.
As noted above, Factor VIIa is generated by proteolysis of a single peptide bond from its single chain zymogen, Factor VII, which is present at approximately 0.5 μg/ml in plasma. The conversion of zymogen Factor VII into the activated two-chain molecule occurs by cleavage of an internal peptide bond. In human Factor VII, the cleavage site is at Arg152-Ile153 (Hagen et al., 1986, PNAS USA 83: 2412-6).
“Factor VII/VIIa” as used in this application means a product consisting of either the unactivated form (factor VII) or the activated form (factor VIIa) or mixtures thereof. “Factor VII/VIIa” within the above definition includes proteins that have an amino acid sequence of native human factor VII/VIIa. It also includes proteins with a slightly modified amino acid sequence, for instance, a modified N-terminal end including N-terminal amino acid deletions or additions so long as those proteins substantially retain the activity of factor VIIa. “Factor VII” within the above definition also includes natural allelic variations that may exist and occur from one individual to another. Also, degree and location of glycosylation or other post-translation modifications may vary depending on the chosen host cells and the nature of the host cellular environment.
In the presence of calcium ions, Factor VIIa binds with high affinity to TF. TF is a 263 amino acid residue glycoprotein composed of a 219 residue extracellular domain, a single transmembrane domain, and a short cytoplasmic domain (Morrissey et al., 1987, Cell 50: 129-35). The TF extracellular domain is composed of two fibronectin type III domains of about 105 amino acids each. The binding of FVIIa is mediated entirely by the TF extracellular domain (Muller et al., 1994, Biochem. 33:10864-70). Residues in the area of amino acids 16-26 and 129-147 contribute to the binding of FVIIa as well as the coagulant function of the molecule. Residues Lys20, Trp45, Asp58, Tyr94, and Phe140 make a large contribution (1 kcal/mol) to the free energy (ΔG) of binding to FVIIa.
TF is expressed constitutively on cells separated from plasma by the vascular endothelium. Its expression on endothelial cells and monocytes is induced by exposure to inflammatory cytokines or bacterial lipopolysaccharides (Drake et al., 1989, J. Cell Biol. 109: 389). Upon tissue injury, the exposed extracellular domain of TF forms a high affinity, calcium dependent complex with FVII. Once bound to TF, FVII can be activated by peptide bond cleavage to yield serine protease FVIIa. The enzyme that catalyzes this step in vivo has not been elucidated, but in vitro FXa, thrombin, TF:FVIIa and FIXa can catalyze this cleavage. FVIIa has only weak activity upon its physiological substrates FX and FIX whereas the TF:FVIIa complex rapidly activates FX and FIX.
The TF:FVIIa complex constitutes the primary initiator of the extrinsic pathway of blood coagulation. The complex initiates the extrinsic pathway by activation of FX to Factor Xa (FXa), FIX to Factor IXa (FIXa), and additional FVII to FVIIa. The action of TF:FVIIa leads ultimately to the conversion of prothrombin to thrombin, which carries out many biological functions. Among the most important activities of thrombin is the conversion of fibrinogen to fibrin, which polymerizes to form a clot. The TF:FVIIa complex also participates as a secondary factor in extending the physiological effects of the contact activation system.
The initiation and subsequent regulation of coagulation is complex, since maintenance of hemostasis is crucial for survival. There is an exquisite balance between hemostasis (normal clot formation and dissolution) and thrombosis (pathogenic clot formation). Serious clinical conditions involving aberrations in coagulation include deep vein thrombosis, myocardial infarction, pulmonary embolism, stroke and disseminated intravascular coagulation (in sepsis). There are also many bleeding coagulopathies where there is insufficient clot formation. These include hemophilia A (FVIII deficiency) or hemophilia B (FIX deficiency), where procoagulant therapy is required. The challenge in this therapeutic area is to operate in the narrow window between too much and too little coagulation.
The use of exogenous FVIIa as a therapeutic agent has been shown to induce hemostasis in patients with hemophilia A and B (Hedner, 2001, Seminars Hematol. 38 (suppl. 12): 43-7; Hedner, 2004, Seminars Hematol. 41 (suppl. 1): 35-9). It also has been used to treat bleeding in patients with liver disease, anticoagulation-induced bleeding, surgery, thrombocytopenia, thrombasthenia, Bemard-Soulier syndrome, von Willebrand disease, and other bleeding disorders (See e.g. Roberts at al., 2004, Blood 104: 3858-64).
Commercial preparations of human recombinant FVIIa are sold as NovoSeven.™ NovoSeven™ is indicated for the treatment of bleeding episodes in hemophilia A or B patients and is the only recombinant FVIIa effective for bleeding episodes currently available. A circulating recombinant FVIIa half-life of 2.3 hours was reported in “Summary Basis for Approval for NovoSeven™” FDA reference number 96-0597. Moreover, the half-life of recombinant FVIIa is shorter in pediatric patients (˜1.3 hours), suggesting that higher doses of recombinant FVIIa may be required in this population (Roberts et al., 2004, Blood 104: 3858-64). Accordingly, relatively high doses and frequent administration are necessary to reach and sustain the desired therapeutic or prophylactic effect. As a consequence, adequate dose regulation is difficult to obtain and the need of frequent intravenous administrations imposes restrictions on the patient's way of living.
A molecule with a longer circulation half-life would decrease the number of necessary administrations. Given the frequent injections associated with currently available FVIIa therapy and the potential for obtaining more optimal therapeutic FVIIa levels with concomitant enhanced therapeutic effect, there is a clear need for improved FVII or FVIIa-like molecules with a longer half-life in vivo.
Recombinant human coagulation factor VIIa (rFVIIa, NovoSeven; Novo Nordisk A/S, Copenhagen, Denmark) has proven to be efficacious for the treatment of bleeding episodes in hemophilia patients with inhibitors. A small fraction of patients may be refractory to rFVIIa treatment and could potentially benefit from genetically modified FVIIa molecules with increased potencies. To this end, FVIIa analogs with increased intrinsic activity have been investigated that exhibit superior hemostatic profiles in vitro (see e.g. WO02/077218 or WO05/074975, which are hereby incorporated by reference in their entirety, and Tranholm et al., 2003, Blood 102(10): 3615-20, which is also incorporated by reference). These analogs may also be used as more efficacious hemostatic agents in other indications where efficacy of rFVIIa has been observed, including in thrombocytopenia and trauma.
Thus, in some embodiments, the Factor VIIa analog that may be used in accordance with the invention is as described in WO02/077218 or WO05/074975. For example, the FVIIa analog may have a glutamine substituted for methionine at position 298 (i.e. M298Q-FVIIa). In certain exemplary embodiments, the FVIIa analog contains two additional mutations, valine at position 158 replaced by aspartic acid and glutamic acid at position 296 replaced by valine (i.e. V158D/E296V/M298Q-FVIIa). Additionally or alternatively, the Factor VIIa analog may have an alanine residue substitution for lysine at position 337 (i.e. V158D/E296V/M298Q/K337A-FVIIa). In still other embodiments, the Factor VIIa analog has a substitution or insertion selected from Q2500; P406C; and 407C, wherein a cysteine has also been introduced in the C-terminal sequence (see, e.g. U.S. Pat. No. 7,235,638, which is hereby incorporated by reference in its entirety). The Factor VIIa analog may further comprise a substitution or insertion at one or more of positions 247, 260, 393, 396, and/or 405.
In these or other embodiments, the Factor VIIa analog comprises a substitution relative to the sequence of native Factor VIIa selected from: (a) a substitution of Lys157 with an amino acid selected from the group consisting of Gly, Val, Ser, Thr, Asp, and Glu; (b) a substitution of Lys337 with an amino acid selected from the group consisting of Ala, Gly, Val, Ser, Thr, Gln, Asp, and Glu; (c) a substitution of Asp334 with any amino acid other than Ala or Asn; and (d) a substitution of Ser336 with any amino acid other than Ala or Cys (see e.g. U.S. Pat. No. 7,176,288, which is hereby incorporated by reference in its entirety). Additionally or alternatively, the Factor VIIa analog comprises a substitution of the Leu at position 305 of Factor VII with an amino acid residue selected from the group consisting of Val, Ile, Met, Phe, Trp, Pro, Gly, Ser, Thr, Cys, Tyr, Asn, Glu, Lys, Arg, His, Asp and Gln (see e.g. U.S. Pat. No. 6,905,683, which is hereby incorporated by reference in its entirety).
Thus, in one aspect, the present invention provides therapeutic agents comprising an elastin-like peptide (ELP) and a Factor VII/VIIa, or functional analog thereof. For example, in certain embodiments, the Factor VII/VIIa is human Factor VII/VIIa (e.g., SEQ ID NO: 33). The Factor VII/VIIa may be a functional analog of human Factor VII/VIIa, including functional fragments truncated at the N-terminus and/or C-terminus by from 1 to 10 amino acids, including by 1, 2, 3, or about 5 amino acids. Functional analogs may contain from 1 to 10 amino acid insertions, deletions, and/or substitutions (collectively) with respect to the native sequence (e.g., SEQ ID NO: 33), and in each case retaining the activity of the peptide. For example, such analogs may have from 1 to about 5 amino acid insertions, deletions, and/or substitutions (collectively) with respect to the native full length sequence, or with respect to one or both of the heavy and light chains. Such activity may be confirmed or assayed using any available assay, including those described herein. In these or other embodiments, the Factor VII/VIIa component has at least about 75%, 80%, 85%, 90%, 95%, or 98% identity with the native sequence (SEQ ID NO:33). The determination of sequence identity between two sequences (e.g., between a native sequence and a functional analog) can be accomplished using any alignment tool, including Tatusova et al., Blast 2 sequence—a new tool for comparing protein and nucleotide sequences, FEMS Microbiol Lett. 174:247-250 (1999).
in exemplary embodiments, the FactorVII-ELP fusion has the amino acid sequence of SEQ ID NO:58. SEQ ID NO:58 further comprises a TEV protease cleavage site between the FactorVII and ELP sequences, which may be beneficial for removing the ELP sequence post expression where desired. However, in accordance with the invention, the tev sequence may be entirely removed, or replaced with another linking sequence as disclosed herein.
In another aspect, the present invention provides methods for the treatment or prevention of bleeding-related disorders. The method comprises administering an effective amount of the therapeutic agent comprising an elastin-like peptide (ELP) and a Factor VII/VIIa or functional analog thereof to a patient in need. In certain embodiments, the bleeding-related disorder is one or more of hemophilia (A or B), post-surgical bleeding, anticoagulation-induced bleeding, thrombocytopenia, Factor VII deficiency, Factor XI deficiency, bleeding in patients with liver disease, thrombasthenia, Bemard-Soulier syndrome, von Willebrand disease, and intracranial hemorrhage. Generally, the patient is a human or non-human animal (e.g., dog, cat, cow, or horse) patient. Preferably, the patient is human.
To characterize the in vitro binding properties of a suspected Factor VII/VIIa analog, or an ELP-containing Factor VIIa analog, TF binding assays can be performed as described previously (See, e.g., Chaing et al., 1994, Blood 83(12): 3524-35). Briefly, recombinant human TF can be coated onto Immulon II plates in carbonate antigen buffer overnight at 4° C. BSA is also coated onto the plates for use as a control. ELP-containing Factor VIIa analogs may be added at various concentrations in TBS-T buffer. After several washes, monospecific polyclonal rabbit anti-human FVIIa sera is added and incubated for approximately an hour at room temperature. Next, goat anti-rabbit IgG conjugated to alkaline phosphatase is added, followed by the alkaline phosphatase substrate PNPP, which is used for detection. After subtraction of background, the absorbance at ˜405 nm is taken to be directly proportional to the degree of Factor VIIa binding to the immobilized TF. These values can then be compared to control plasma containing Factor VIIa.
The clotting ability of a Factor VII/VIIa analog or an ELP-containing Factor VIIa analog can be measured in human FVII deficient plasma. In this assay, the ELP-containing Factor VIIa analog diluted to varying concentrations directly into FVII deficient plasma. In a coagulometer, one part plasma a FVIIa analog can be mixed with 2 parts Innovin™ (Dade, Miami, Fla.) prothrombin time reagent (recombinant human tissue factor with phospholipids and CaCl₂). Clot formation is detected optically and time to clotting measured. Clotting time (seconds) is compared to the mean clotting time of FVII-deficient plasma alone and plotted as the fractional clotting time versus FVIIa analog concentration.

Therapeutic Proteins

The present invention further provides therapeutic agents comprising an ELP component and at least one therapeutic protein selected from Table 1. The ELP component and therapeutic protein may be coupled by recombinant fusion or chemical conjugation as described herein. Such therapeutic proteins are listed in Table 1 by protein name and GeneSeq Accession No. The amino acid sequence of each Therapeutic Protein, which is known in the art, is hereby incorporated by reference for each Therapeutic Protein listed in Table 1. Such therapeutic proteins are further described in US patent or PCT publications that are also listed in Table 1, and such US patent and PCT publications are hereby incorporated by reference, especially with respect to the structure of such therapeutic proteins and described functional analogs.
Table 1 further describes the biological activity of each listed Therapeutic Protein, as well as an exemplary assay for determining the activity of functional analogs or agents of the invention (e.g., fusion with an ELP component). Generally, functional analogs of therapeutic proteins listed in Table 1 may include functional fragments truncated at the N-terminus and/or C-terminus by from 1 to 10 amino acids, including by 1, 2, 3, 4 or about 5 amino acids. Functional analogs may contain from 1 to 10 amino acid insertions, deletions, and/or substitutions (collectively) with respect to the base sequence (e.g., as listed in Table 1), and in each case retaining the full or partial biological activity (as listed in Table 1) of the therapeutic protein. For example, functional analogs may have 1, 2, 3, 4, or 5 amino acid insertions, deletions, and/or substitutions (collectively) with respect to the base sequence. Such activity may be confirmed or assayed using any available assay, including those described in the Table. In these or other embodiments, the therapeutic protein has at least about 75%, 80%, 85%, 90%, 95%, or 98% identity with the corresponding base sequence. The molecules may further comprise additional chemical modifications known for each in the art.
In some embodiments, the therapeutic protein (e.g., as selected from Table 1) has a size of less than about 25 kDa, or less than about 10 kDa, or less than about 5 kDa, and the corresponding therapeutic agent of the invention (e.g., comprising the ELP component) has a molecular weight of less than about 60 kDa, 55 kDa, 50 kDa, or 40 kDa.
Table 1 further lists preferred indications for each therapeutic protein, for which the corresponding therapeutic agent finds use, such as in a method for treatment or prevention related to such indication.

TABLE 1

		PCT/Patent
		Reference
	Exemplary	(the patents
	Identifier	and
	(the sequences	publications
	listed in this	listed in this
	column are each	column are		Exemplary Activity Assay
	hereby	each hereby		(the publications listed in this column
Therapeutic	incorporated by	incorporated		are each hereby incorporated by
Protein X	reference)	by reference)	Biological Activity	reference)	Preferred Indication Y

BMP-1	GeneSeq	WO8800205	BMP1 belongs to the transforming growth	BMP-1 activity can be determined using	Induction of Cartilage,
	Acession P80618		factor-beta (TGFB) superfamily. Bone	the following assays known in the art: Nat	Tissue and Bone Growth,
			morphogenic proteins induce cartilage	Genet. 2001 January; 27(1): 84-8; Eur J	and Diabetes
			and bone formation, play important role	Biochem 1996 Apr. 1; 237(1): 295-302; J
			in nephrogesis, and play an important	Biol Chem, Vol. 274, Issue 16, 10897-10902,
			role in the development of many organs,	Apr. 16, 1999; and Hogan, B. L. M.
			including lung, heart, teeth, gut, skin, and	(1996) Genes Dev. 10, 1580-1594.
			particularly the kidney.
BMP-2	GeneSeq	WO8800205	BMP-2 belongs to the transforming	BMP-2 activity can be determined using the	Induction of Cartilage,
	Accession P80619		growth factor-beta (TGFB) superfamily.	following assays known in the art: Nat	Tissue and Bone Growth,
			Bone morphogenic protein induces bone	Genet. 2001 January; 27(1): 84-8; Eur J	and Diabetes
			formation.	Biochem 1996 Apr. 1; 237(1): 295-302; J Biol
				Chem, Vol. 274, Issue 16, 10897-10902,
				Apr. 16, 1999; and Hogan, B. L. M. (1996)
				Genes Dev. 10, 1580-1594.
BMP-2B	GeneSeq	U.S. Pat. No. 5,631,142	BMP-2b belongs to the transforming	BMP-2b activity can be determined using	Induction of Cartilage,
	Accession W24850		growth factor-beta (TGFB) superfamily.	the following assays known in the art: Nat	Tissue and Bone Growth,
			Bone morphogenic protein induces bone	Genet. 2001 January; 27(1): 84-8; Eur J	and Diabetes
			formation.	Biochem 1996 Apr. 1; 237(1): 295-302; I Biol
				Cbcre, Vol. 274, Issue 16, 10897-10902,
				Apr. 16, 1999; and Hogan, B. L. M. (1996)
				Genes Dev. 10, 1580-1594.
BMP-4	GeneSeq	WO0020591	BMP-4 belongs to the transforming	BMP-4 activity can be determined using the	Induction of Cartilage,
	Accession		growth factor-beta (TGFB) superfamily.	following assays known in the art: Nat	Tissue and Bone Growth,
	B02796		Bone morphogenic protein induces bone	Genet. 2001 January; 27(1): 84-8; Eur J	and Diabetes
			formation.	Biochem 1996 Apr. 1; 237(1): 295-302; J
				Biol Chem, Vol. 274, Issue 16, 10897-10902,
				Apr. 16, 1999; and Hogan, B. L. M.
				(1996) Genes Dev. 10, 1580-1594.
BMP-5	GeneSeq	WO0020591	BMP-5 belongs to the transforming	BMP-5 activity can be determined using the	Induction of Cartilage,
	Accession		growth factor-beta (TGFB) superfamily.	following assays known in the art: Nat	Tissue and Bone Growth,
	B02797		Bone morphogenic protein induces bone	Genet. 2001 January; 27(1): 84-8; Eur J	and Diabetes
			formation.	Biochem 1996 Apr. 1; 237(1): 295-302; J
				Biol Chem, Vol. 274, Issue 16, 10897-10902,
				Apr. 16, 1999; and Hogan, B. L. M.
				(1996) Genes Dev. 10, 1580-1594.
BMP-6	GeneSeq	U.S. Pat. No. 5,187,076	BMP-6 belongs to the transforming	BMP-6 activity can be determined using the	Induction of Cartilage,
	Accession		growth factor-beta (TGFB) superfamily.	following assays known in the art: Nat	Tissue and Bone Growth,
	R32904		Bone morphogenic protein induces bone	Genet. 2001 January; 27(1): 84-8; Eur J	and Diabetes
			formation.	Biochem 1996 Apr. 1; 237(1): 295-302; J
				Biol Chem, Vol. 274, Issue 16, 10897-10902,
				Apr. 16, 1999; and Hogan, B. L. M.
				(1996) Genes Dev. 10, 1580-1594.
Osteogenic	GeneSeq	WO973462	OP-1 belongs to the transforming growth	OP-1 activity can be determined using the	Induction of Cartilage,
Protein-1; OP-1;	Accession		factor-beta (TGFB) superfamily. Bone	following assays known in the art: Nat	Tissue and Bone Growth,
BMP-7	W34783		morphogenic protein induces bone	Genet. 2001 January; 27(1): 84-8; Eur J	and Diabetes
			formation.	Biochem 1996 Apr. 1; 237(1): 295-302; J
				Biol Chem, Vol. 274, Issue 16, 10897-10902,
				Apr. 16, 1999; and Hogan, B. L. M.
				(1996) Genes Dev. 10, 1580-1594.
Osteogenic	GeneSeq	WO9406399	OP-2 belongs to the transforming growth	OP-2 activity can be determined using the	Induction of Cartilage,
Protein-2	Accession R57973		factor-beta (TGFB) superfamily. Bone	following assays known in the art: Nat	Tissue and Bone Growth,
			morphogenic protein induces bone	Genet. 2001 January; 27(1): 84-8; Eur J	and Diabetes
			formation.	Biochem 1996 Apr. 1; 237(1): 295-302; J
				Biol Chem, Vol. 274, Issue 16, 10897-10902,
				Apr. 16, 1999; and Hogan, B. L. M.
				(1996) Genes Dev. 10, 1580-1594.
GDP-1	GeneSeq	WO9406449	Members of the TGF-beta family of	The effect of GDF-1 on signaling can be	Developmental disorders,
	Accession		proteins initiate cell signaling by binding	assayed by treating Primary BAECs	Induction of Cartilage,
	R60961		to heteromeric receptor complexes of	transferred with a construct called p3TP-	Tissue and Bone Growth,
			type I (TbetaRI) and type II (TbetaRII)	Lux, containing a TGF-beta responsive	and Diabetes
			serine/threonine kinase receptors	promoter fused to a reporter gene, and
			(reviewed by Massague, J. et al. (1994)	measuring luciferase gene expression
			Trends Cell Biol. 4: 172 178; Miyazono, K.	(Wrana et al., 1994, Nature 370: 341-347).
			et al. (1994) Adv. Immunol. 55: 181-220).
			Activation of this heteromeric receptor
			complex occurs when TGF-beta binds to
			TbetaRII, which then recruits and
			phosphorylates TbetaRI. Activated
			TbetaRI then propagates the signal to
			downstream targets (Chen, F. and
			Weinberg, R. A. (1995) PNA892: 1565-1569;
			Wrana, J. L. et al. (1994) Nature
			370: 341 347).
BMP-9	GeneSeq	WO9533830	BMP-9 belongs to the transforming	BMP-9 activity can be determined using the	Induction of Cartilage,
	Accession		growth factor-beta (TGFB) superfamily.	following assays known in the art: Nat	Tissue and Bone Growth,
	R86903		Bone morphogenic protein induces bone	Genet. 2001 January; 27(1): 84-8; Eur J	and Diabetes
			formation.	Biochem 1996 Apr. 1; 237(1): 295-302; J
				Biol Chem, Vol. 274, Issue 16, 10897-10902,
				Apr. 16, 1999; and Hogan, B. L. M.
				(1996) Genes Dev. 10, 1580-1594.
BMP-10	GeneSeq	WO9426893	BMP-10 belongs to the transforming	BMP-10 activity can be determined using	Induction of Cartilage,
	Accession R66202		growth factor-beta (TGFB) superfamily.	the following assays known in the art: Nat	Tissue and Bone Growth,
			Bone morphogenic protein induces bone	Genet. 2001 January; 27(1): 84-8; Eur J	and Diabetes
			formation.	Biochem 1996 Apr. 1; 237(1): 295-302; J
				Biol Chem, Vol. 274, Issue 16, 10897-10902,
				Apr. 16, 1999; and Hogan, B. L. M.
				(1996) Genes Dev. 10, 1580-1594.
BMP-12	GeneSeq	WO9516035	BMP-12 belongs to the transforming	BMP-12 activity can be determined using	Induction of Cartilage,
	Accession R78734		growth factor-beta (TGFB) superfamily.	the following assays known in the art: Nat	Tissue and Bone Growth,
			Bone morphogenic protein induces bone	Genet. 2001 January; 27(1): 84-8; Eur J	and Diabetes
			formation.	Biochem 1996 Apr. 1; 237(1): 295-302; J
				Biol Chem, Vol. 274, Issue 16, 10897-10902,
				Apr. 16, 1999; and Hogan, B. L. M.
				(1996) Genes Dev. 10, 1580-1594.
BMP-15	GeneSeq	W09636710	BMP-15 belongs to the transforming	BMP-15 activity can be determined using	Induction of Cartilage,
	Accession W11261		growth factor-beta (TGFB) superfamily.	the following assays known in the art: Nat	Tissue and Bone Growth,
			Bone morphogenic protein induces bone	Genet. 2001 January; 27(1): 84-8; Eur J	and Diabetes
			formation.	Biochem 1996 Apr. 1; 237(1): 295-302; J
				Biol Chem, Vol. 274, Issue 16, 10897-10902,
				Apr. 16, 1999; and Hogan, B. L. M.
				(1996) Genes Dev. 10, 1580-1594.
BMP-17	GeneSeq	WO9929718	BMP-17 belongs to the transforming	BMP-17 activity can be determined using	Induction of Cartilage,
	Accession Y17870		growth factor-beta (TGFB) superfamily.	the following assays known in the art: Nat	Tissue and Bone Growth,
			Bone morphogenic protein induces bone	Genet. 2001 January; 27(1): 84-8; Eur J	and Diabetes
			formation.	Biochem 1996 Apr. 1; 237(1): 295-302; J
				Biol Chem, Vol. 274, Issue 16, 10897-10902,
				Apr. 16, 1999; and Hogan, B. L. M.
				(1996) Genes Dev. 10, 1580-1594.
BMP-18	GeneSeq	WO9929718	BMP-18 belongs to the transforming	BMP-18 activity can be determined using	Induction of Cartilage,
	Accession Y17871		growth factor-beta (TGFB) superfamily.	the following assays known in the art: Nat	Tissue and Bone Growth,
			Bone morphogenic protein induces bone	Genet. 2001 January; 27(1): 84-8; Eur J	and Diabetes
			formation.	Biochem 1996 Apr. 1; 237(1): 295-302; J
				Biol Chem, Vol. 274, Issue 16, 10897-10902,
				Apr. 16, 1999; and Hogan, B. L. M.
				(1996) Genes Dev. 10, 1580-1594.
Inhibin alpha	GeneSeq	WO0020591	The inhibin beta A subunit joins the alpha	Tumor suppressor activity of inhibin can be	Tumor suppression.
	Accession B02806		subunit to form a pituitary FSH secretion	determined using assays known in the art:
			inhibitor. Inhibin has been shown to	Matzuk et al., Nature 1992 Nov. 26: 360
			regulate gonadal stromal cell proliferation	(6402); 313-9.
			negatively and to have tumour-
			suppressor activity. In addition, serum
			levels of inhibin have been shown to
			reflect the size of granulosa-cell tumors
			and can therefore be used as a marker
			for primary as well as recurrent disease.
Inhibin beta	GeneSeq	WO0020591	The inhibin beta A subunit joins the alpha	Tumor suppressor activity of inhibin can be	Tumor suppression.
	Accession		subunit to form a pituitary FSH secretion	determined using assays known in the art:
	H02808		inhibitor. Inhibin has been shown to	Matzuk et al., Nature 1992 Nov. 26: 360
			regulate gonadal stromal cell proliferation	(6402); 313-9.
			negatively and to have tumour-
			suppressor activity. In addition, serum
			levels of inhibin have been shown to
			reflect the size of granulosa-cell tumors
			and can therefore be used as a marker
			for primary as well as recurrent disease.
Cerebus Protein	GeneSeq	WO9849296	Cerebus is believed to be involved in the	BMP activity, in the presence of the	BMP Antagonist useful for
	Accession		inhibition of BMP activity	antagonist Cerebus, can be determined	Osteosarcoma, abnormal
	W86032			using the following assays known in the art:	bone growth.
				Nat Genet. 2001 January; 27(1): 84-8; Eur J
				Biochem 1996 Apr. 1; 237(1): 295-302; J
				Biol Chem, Vol. 274, Issue 16, 10897-10902,
				Apr. 16, 1999; and Hogan, B. L. M.
				(1996) Genes Dev. 10, 1580-1594.
Soluble BMP	GeneSeq	WO9614579	Soluble BMP receptor kinase protein-3 is	BMP activity, in the presence of the soluble	BMP Antagonist useful for
Receptor Kinase	Accession		involved in the binding of BMPs. Soluble	antagonist BMP receptor kinase protein-3,	Osteosarcoma, abnormal
Protein-3	R95227		BMP receptor kinase protein-3 is useful	can be determined using the following	bone growth.
			as an antagonist for the inhibition of BMP	assays known in the art: Nat Genet. 2001
			activity.	Jan; 27(1): 84-8; Eur J Biochem 1996 Apr. 1;
				237(1): 295-302; J Biol Chem, Vol. 274,
				Issue 16, 10897-10902, Apr. 16, 1999; and
				Hogan, B. L. M. (1996) Genes Dev. 10,
				1580-1594.
BMP Processing	GeneSeq	WO9741250	BMPs belong to the transforming growth	BMP activity, in the presence of the Furin,	Bone formation or
Enzyme Furin	Accession		factor-beta (TGFB) superfamily. Bone	can be determined using the following	Regeneration
	W36099		morphogenic protein induces bone	assays known in the art: Nat Genet. 2001	Abnormalities
			formation.	Jan; 27(1): 84-8; Eur J Biochem 1996 Apr. 1;
				237(1): 295-302; J Biol Chem, Vol. 274,
				Issue 16, 10897-10902, Apr. 16, 1999; and
				Hogan, B. L. M. (1996) Genes Dev. 10,
				1580-1594.
TGF-beta 1	GeneSeq	WO9216228	Members of the TGF-beta family of	The effect of TGF betas on signaling can	Useful for treating cancer
	Accession		proteins initiate cell signaling by binding	be assayed by treating Primary BAECs	and to promote wound
	R29657		to heteromeric receptor complexes of	transfected with a construct called p3TP-	healing.
			type I (TbetaRI) and type II (TbetaRII)	Lux, containing a TGF-beta responsive
			serine/threonine kinase receptors	promoter fused to a reporter gene, and
			(reviewed by Massague, J. et al. (1994)	measuring luciferase gene expression
			Trends Cell Biol. 4: 172 178; Miyazono, K.	(Wrana et al., 1994, Nature 370: 341-347).
			et al. (1994) Adv. Immunol. 55: 181-220).
			Activation of this heteromeric receptor
			complex occurs when TGF-beta. binds to
			TbetaRII, which then recruits and
			phosphorylates TbetaRI. Activated
			TbetaRI then propagates the signal to
			downstream targets (Chen, F. and
			Weinberg. R. A. (1995) PNA892: 1565-1569;
			Wrana, J. L. et al. (1994) Nature
			370: 341.
TGF-beta 2	GeneSeq	EP542679	Members of the TGF-beta family of	The effect of TGF betas on signaling can	Useful for treating cancer
	Accession		proteins initiate cell signaling by binding	be assayed by treating Primary BAECs	and to promote wound
	R39659		to heteromeric receptor complexes of	transfected with a construct called p3TP-	healing.
			type I (TbetaRI) and type II (TbetaRII)	Lux, containing a TGF-beta responsive
			serine/threonine kinase receptors	promoter fused to a reporter gene, and
			(reviewed by Massague, J. et al. (1994)	measuring luciferase gene expression
			Trends Cell Biol. 4: 172 178; Miyazono, K.	(Wrana et al., 1994, Nature 370: 341-347).
			et al. (1994) Adv. Immunol. 55: 181-220).
			Activation of this heteromeric receptor
			complex occurs when TGF-beta. binds to
			TbetaRII, which then recruits and
			phosphorylates TbetaRI. Activated
			TbetaRI then propagates the signal to
			downstream targets (Chen, F. and
			Weinberg. R. A. (1995) PNA892: 1565-1569;
			Wrana, J. L. et al. (1994) Nature
			370: 341.
ZTGF-beta 9	GeneSeq	WO0015798	Members of the TGF-beta family of	The effect of TGF betas on signaling can	Useful for treating cancer
	Accession		proteins initiate cell signaling by binding	be assayed by treating Primary BAECs	and to promote wound
	Y70654		to heteromeric receptor complexes of	transfected with a construct called p3TP-	healing.
			type I (TbetaRI) and type II (TbetaRII)	Lux, containing a TGF-beta responsive
			serine/threonine kinase receptors	promoter fused to a reporter gene, and
			(reviewed by Massague, J. et al. (1994)	measuring luciferase gene expression
			Trends Cell Biol. 4: 172 178; Miyazono, K.	(Wrana et al., 1994, Nature 370: 341-347).
			et al. (1994) Adv. Immunol. 55: 181-220).
			Activation of this heteromeric receptor
			complex occurs when TGF-beta. binds to
			TbetaRII, which then recruits and
			phosphorylates TbetaRI. Activated
			TbetaRI then propagates the signal to
			downstream targets (Chen, F. and
			Weinberg. R. A. (1995) PNA892: 1565-1569;
			Wrana, J. L. et al. (1994) Nature
			370: 341.
Anti-TGF beta		GB2305921	Members of the TGF-beta family of	The effect of TGF betas on signaling in the	Useful for control of
family antibodies			proteins initiate cell signaling by binding	presence of an anti-TGF beta antibody, can	fibrosis, immune, and
			to heteromeric receptor complexes of	be assayed by treating Primary BAECs	inflammatory disease.
			type I (TbetaRI) and type II (TbetaRII)	transfected with a construct called p3TP-
			serine/threonine kinase receptors	Lux, containing a TGF-beta responsive
			(reviewed by Massague, J. et al. (1994)	promoter fused to a reporter gene, and
			Trends Cell Biol. 4: 172 178; Miyazono, K.	measuring luciferase gene expression
			et al. (1994) Adv. Immunol. 55: 181-220).	(Wrana et al., 1994, Nature 370: 341-347).
			Activation of this heteromeric receptor
			complex occurs when TGF-beta. binds to
			TbetaRII, which then recruits and
			phosphorylates TbetaRI. Activated
			TbetaRI then propagates the signal to
			downstream targets (Chen, F. and
			Weinberg. R. A. (1995) PNA892: 1565-1569;
			Wrana, J. L. et al. (1994) Nature
			370: 341.
Latent TGF beta	GeneSeq	WO0012551	Members of the TGF-beta family of	The effect of TGF betas on signaling in the	Useful for inhibiting tissue
binding protein II	Accession		proteins initiate cell signaling by binding	presence of a TGF beta binding protein,	or tumor growth.
	Y70552		to heteromeric receptor complexes of	can be assayed by treating Primary BAECs
			type I (TbetaRI) and type II (TbetaRII)	transfected with a construct called p3TP-
			serine/threonine kinase receptors	Lux, containing a TGF-beta responsive
			(reviewed by Massague, J. et al. (1994)	promoter fused to a reporter gene, and
			Trends Cell Biol. 4: 172 178; Miyazono, K.	measuring luciferase gene expression
			et al. (1994) Adv. Immunol. 55: 181-220).	(Wrana et al., 1994, Nature 370: 341-347).
			Activation of this heteromeric receptor
			complex occurs when TGF-beta. binds to
			TbetaRII, which then recruits and
			phosphorylates TbetaRI. Activated
			TbetaRI then propagates the signal to
			downstream targets (Chen, F. and
			Weinberg. R. A. (1995) PNA892: 1565-1569;
			Wrana, J. L. et al. (1994) Nature
			370: 341.
MP52	GeneSeq	WO9741250	Members of the TGF-beta family of	The effect of TGF betas on signaling can	Bone formation or
	Accession		proteins initiate cell signaling by binding	be assayed by treating Primary BAECs	Regeneration
	W36100		to heteromeric receptor complexes of	transfected with a construct called p3TP-	Abnormalities
			type I (TbetaRI) and type II (TbetaRII)	Lux, containing a TGF-beta responsive
			serine/threonine kinase receptors	promoter fused to a reporter gene, and
			(reviewed by Massague, J. et al. (1994)	measuring luciferase gene expression
			Trends Cell Biol. 4: 172 178; Miyazono, K.	(Wrana et al., 1994, Nature 370: 341-347).
			et al. (1994) Adv. Immunol. 55: 181-220).
			Activation of this heteromeric receptor
			complex occurs when TGF-beta. binds to
			TbetaRII, which then recruits and
			phosphorylates TbetaRI. Activated
			TbetaRI then propagates the signal to
			downstream targets (Chen, F. and
			Weinberg. R. A. (1995) PNA892: 1565-1569;
			Wrana, J. L. et al. (1994) Nature
			370: 341.
b57 Protein	GeneSeq	WO9837195	BMPs are involved in the induction of	BMP activity, in the presence of b57	BMP Antagonist useful for
	Accession		bone formation. Specific antagonists are	protein, can be determined using the	Osteosarcoma, abnormal
	W69293		useful is preventing this activity from	following assays known in the art: Nat	bone growth.
			occurring.	Genet. 2001 January; 27(1): 84-8; Eur J
				Biochem 1996 Apr. 1; 237(1): 295-302; J
				Biol Chem, Vol. 274, Issue 16, 1089-10902,
				Apr. 16, 1999; and Hogan, B. L. M.
				(1996) Genes Deve. 10, 1580-1594.
Resistin	GeneSeq	WO0064920	This gene belongs to the family defined by	Ability of resistin to influence type II	Type II diabetes and
	Accession		mouse FIZZI and FIZZ3/Resistin genes.	diabetes can be determined using assays	Syndrome X.
	W69293		The characteristic feature of this family is	known in the art: Pontoglio et al., J Clin
			the C-terminal stretch of 10 cys residues	Invest 1998 May 15; 101(10): 2215-22.
			with identical spacing. The mouse
			homolog of this protein is secreted by
			adipocytes, may be the hormone
			potantially linking obesity to type II
			diabetes.
Galectin-4	GeneSeq	WO9703190	Galectins are a family of carbohydrate-	Ability of Galectin-4 polypeptides to bind	Lactose intolerance.
	Accession		binding proteins characterized by an	lactose can be determined using assays
	W11841		affinity for beta-galactoside containing	known in the art: Wada, et al., J Biol Chem
			glycoconjugates.	1997 Feb 28; 272(9): 6078-86.
APM-I; ACRP-30;	GeneSeq	W00026363	ACPR30 gene is exclusively expressed in	Ability of ACRP30 polypeptides to	Obesity, Metabolic
Famoxin	Accession		adipose tissue. ACRP30 is thought to	influence obesity and fat oxidation can be	disorders, Lipid
	Y71035		increase fatty acid oxidation by muscle	determined using assays known in the art:	Metabolism; Hormone
			tissue.	Fruebis et al., Proc Nat'l Acad Sci USA	Secretion.
				2001 Feb 13; 98(4): 2005-10.
ACRP-30	GeneSeq	WO0063376	ACPR30 gene is exclusively expressed in	Ability of ACRP30 homologue	Obesity, Metabolic
Homologue;	Accession		adipose tissue. ACRP30 is thought to	polypeptides to influence obesity and fat	disorders, Lipid
Complement	B30234		increase fatty acid oxidation by muscle	oxidation can be determined using assays	Metabolism; Hormone
Component Clq C			tissue.	known in the art: Fruebis et al., Proc Nat'l	Secretion.
				Acad Sci USA 2001 Feb 13; 98(4): 2005-10.
Calpain-10a	GeneSeq	WO0023603	Calpain is believed to play a role in insulin	Ability of Calpain-10 to influence type II	Diabetes mellitus;
	Accession		secretion and insulin activity, and	diabetes can be determined using assays	Regulation of Insulin
	Y79567		therefore may be useful in the treatment	known in the art: Pontoglio et al., J Clin	secretory response;
			of type II diabetes.	Invest 1998 May 15; 101(10): 2215-22.	Insulin mediated glucose
					transport disorders.
Calpain-10b	GeneSeq	WO0023603	Calpain is believed to play a role in insulin	Ability of Calpain-10 to influence type II	Diabetes mellitus;
	Accession		secretion and insulin activity, and	diabetes can be determined using assays	Regulation of Insulin
	Y79568		therefore may be useful in the treatment	known in the art: Pontoglio et al., J Clin	secretory response;
			of type II diabetes.	Invest 1998 May 15; 101(10): 2215-22.	Insulin mediated glucose
					transport disorders.
Calpain-10c	GeneSeq	WO0023603	Calpain is believed to play a role in insulin	Ability of Calpain-10 to influence type II	Diabetes mellitus;
	Accession		secretion and insulin activity, and	diabetes can be determined using assays	Regulation of Insulin
	Y79569		therefore may be useful in the treatment	known in the art: Pontoglio et al., J Clin	secretory response;
			of type II diabetes.	Invest 1998 May 15; 101(10): 2215-22.	Insulin mediated glucose
					transport disorders.
PDGF-D	GeneSeq	WO0027879	Vascular Endothelial Growth Factor.	Proliferation assay using NR6R-3T3 cells	Wound Healing;
	Accession			(Rizzino 1988 Cancer Res. 48: 4266).	Atherosclermis.
	Y71130
FasL	GeneSeq	WO9936079	Activities associated with apoptosis and	Activity can be determined using	Apoptosis-related
	Accession		immune system functions.	Apoptosis assays known in the art:	disorders; Autoimmune
	Y28594			Walczak et al. (1996) EMBOJ 16: 5386-5397.	disorders; Graft v-Host
					disorders.
Chondro modulin-	GeneSeq	W00029579	Chondromodulin proteins are cartilage	Ability of Chondromodulin-like protein to	Antianglogenic agent;
like protein	Accession		proteins thought to confer resistance to	inhibit vascularization can be determined	Osteoblast proliferation
	Y71262		anglogeneis, and thus are useful as anti-	using assays known in the art: Hirakie et	stimulator; prevents
			angiogenic agents that may have utility in	al., J Biol Chem 1997 Dec 19;	vascularization of cartilage
			combating cancer.	272(51): 32419-26.	tissue; Useful to treat
					cancer.
Patched	GeneSeq	U.S. Pat. No. 5,837,538	Patched is a tumour-suppressor receptor	Ability of soluble Patched to bind to and	Receptor for Hedgehog
	Accession		for Sonic hedgehog (shh), which is a	inhibit the activities of shh can be	cellular proliferation
	W72969		protein that controls developmental	determined using assays known in the art:	signaling molecule. This
			patterning and growth.	Stone et al., Nature 1996 Nov 14;	receptor is useful as a
				384(6605): 129-34.	means of preventing
					cellular proliferation via the
					shh signaling pathway,
					thus useful for cancers.
Patched-2	GeneSeq	WO9953058	Patched is a tumour-suppressor receptor	Ability of soluble Patched to bind to and	Receptor for Hedgehog
	Accession		for Sonic hedgehog (shh), which is a	inhibit the activities of shh can be	cellular proliferation
	Y43261		protein that controls developmental	determined using assays known in the art:	signaling molecule. This
			patterning and growth.	Stone et al., Nature 1996 Nov 14;	receptor is useful as a
				384(6605): 129-34.	means of preventing
					cellular proliferation via the
					shh signaling pathway,
					thus useful for cancers.
Maspin; Protease	GeneSeq	WO9405804	Maspin is a member of the serpin family of	The inhibitory effects cf Maspin and other	Tumor suppressor which is
Inhibitor 5	Accession		serine protease inhibitors that is thought	protease inhibitors can be assayed using	down-regulated in breast
	R50938		to suppress tumor metastasis.	methods known in the art such as a	cancers. The maspin
				labeled protease substrate, for example,	protein has tumour
				Universal Protease Substrate (casein,	suppressing and invasion
				resorufin-labeled): Roche Molecular	suppressing activity.
				Biochemicals, Cat. No. 1080733.
Endostatin	GeneSeq	WO0064946	Endostatin is believed to inhibit effects of	The inhibitory effects of endostatin can be	Anti-angiogenic activity.
	Accession		capillary endothelial cell proliferation.	assayed using assays disclosed by Cao et	Useful in the prevention
	B28399			al. (1996) J. Biol. Chem. 271 29461-29467.	and/or treatment of
					cancers.
aFGF; FGF-1	GeneSeq	EP298723	Fibroblast Growth Factor	Proliferation assay using NR6R-3T3 cells	Promotion of growth and
	Accession			(Rizzino 1988 Cancer Res. 48: 4266);	proliferation of cells, such
	P94037			Examples 23 and 39 disclosed herein.	as epithelial cells and
					keratinocytes. Antagonists
					may be useful as anti-
					cancer agents.
bFGF; FGF-2	GeneSeq	FR2642086	Fibroblast Growth Factor	Proliferation assay using NR6R-3T3 cells	Promotion of growth and
	Accession			(Rizzino 1988 Cancer Res. 48: 4266);	proliferation of cells, such
	R06685			Examples 23 and 39 disclosed herein.	as epithelial cells and
					keratinocytes. Antagonists
					may be useful as anti-
					cancer agents.
FGF-3; INT-2	GeneSeq	WO9503831	Fibroblast Growth Factor	Proliferation assay using NR6R-3T3 cells	Promotion of growth and
	Accession			(Rizzino 1988 Cancer Res. 48: 4266);	proliferation of cells, such
	R07824			Examples 23 and 39 disclosed herein.	as epithelial cells and
					keratinocytes. Antagonists
					may be useful as anti-
					cancer agents.
FGF-4; HST-1;	GeneSeq	WO9503831	Fibroblast Growth Factor	Proliferation assay using NR6R-3T3 cells	Promotion of growth and
HBGF-4	Accession			(Rizzino 1988 Cancer Res. 48: 4266);	proliferation of cells, such
	R07825			Examples 23 and 39 disclosed herein.	as epithelial cells and
					keratinocytes. Antagonists
					may be useful as anti-
					cancer agents.
FGF-5	GeneSeq	WO9730155	Fibroblast Growth Factor	Proliferation assay using NR6R-3T3 cells	Promotion of growth and
	Accession			(Rizzino 1988 Cancer Res. 48: 4266);	proliferation of cells, such
	W22600			Examples 23 and 39 disclosed herein.	as epithelial cells and
					keratinocytes. Antagonists
					may be useful as anti-
					cancer agents.
FGF-6; Heparin	GeneSeq	EP613946	Fibroblast Growth Factor	Proliferation assay using NR6R-3T3 cells	Promotion of growth and
binding secreted	Accession			(Rizzino 1988 Cancer Res. 48: 4266);	proliferation of cells, such
transforming	R58555			Examples 23 and 39 disclosed herein.	as epithelial cells and
factor-2					keratinocytes. Antagonists
					may be useful as anti-
					cancer agents.
FGF-8	GeneSeq	WO9524928	Fibroblast Growth Factor	Proliferation assay using NR6R-3T3 cells	Promotion of growth and
	Accession			(Rizzino 1988 Cancer Res. 48: 4266);	proliferation of cells, such
	R80783			Examples 23 and 39 disclosed herein.	as epithelial cells and
					keratinocytes. Antagonists
					may be useful as anti-
					cancer agents.
FGF-9; Gila	GeneSeq	WO9503831	Fibroblast Growth Factor	Proliferation assay using NR6R-3T3 cells	Promotion of growth and
activating factor	Accession			(Rizzino 1988 Cancer Res. 48: 4266);	proliferation of cells, such
	R70822			Examples 23 and 39 disclosed herein.	as epithelial cells and
					keratinocytes. Antagonists
					may be useful as anti-
					cancer agents.
FGF-12;	GeneSeq	WO9635708	Fibroblast Growth Factor	Proliferation assay using NR6R-3T3 cells	Promotion of growth and
Fibroblast growth	Accession			(Rizzino 1988 Cancer Res. 48: 4266);	proliferation of cells, such
factor homologous	W06309			Examples 23 and 39 disclosed herein.	as epithelial cells and
factor-1					keratinocytes. Antagonists
					may be useful as anti-
					cancer agents.
FGF-15	GeneSeq	WO9927100	Fibroblast Growth Factor	Proliferation assay using NR6R-3T3 cells	Promotion of growth and
	Accession			(Rizzino 1988 Cancer Res. 48: 4266);	proliferation of cells, such
	Y08582			Examples 23 and 39 disclosed herein.	as epithelial cells and
					keratinocytes. Antagonists
					may be useful as anti-
					cancer agents.
FGF-16	GeneSeq	WO9918128	Fibroblast Growth Factor	Proliferation assay using NR6R-3T3 cells	Promotion of growth and
	Accession			(Rizzino 1988 Cancer Res. 48: 4266);	proliferation of cells, such
	Y05474			Examples 23 and 39 disclosed herein.	as epithelial cells and
					keratinocytes. Antagonists
					may be useful as anti-
					cancer agents.
FGF-18	GeneSeq	WO9927100	Fibroblast Growth Factor	Proliferation assay using NR6R-3T3 cells	Promotion of growth and
	Accession			(Rizzino 1988 Cancer Res. 48: 4266);	proliferation of cells, such
	Y08590			Examples 23 and 39 disclosed herein.	as epithelial cells and
					keratinocytes. Antagonists
					may be useful as anti-
					cancer agents.
fit-3 ligand	GeneSeq	EP627487	Stem Cell Progenitor	Chemokine activities can be determined	Promotion of immune cell
	Accession			using assays known in the art: Methods in	growth and/or
	R67541			Molecular Biology, 2000, vol. 138:	differentiation.
				Chemokine Protocols. Edited by: A. E. I. Proudfoot,
				T. N. C. Wells, and C. A. Power.
				© Humana Press Inc., Totowa, NJ.
VEGF-110	GeneSeq	WO0013702	Promotes the growth and/or proliferation	VEGF activity can be determined using	Promotion of growth and
	Accession		of endothelial cells.	assays known in the art, such as those	proliferation of cells, such
	Y69417			disclosed in International Publication No.	as vascular endothelial
				WO0045835, for example.	cells. Antagonists may be
					useful as anti-angiogenic
					agents, and may be
					applicable for cancer.
VEGB-121	GeneSeq	WO0071713	Promotes the growth and/or proliferation	VEGF activity can be determined using	Promotion of growth and
	Accession		of endothelial cells.	assays known in the art, such as those	proliferation of cells, such
	B50432			disclosed in International Publication No.	as vascular endothelial
				WO0045835, for example.	cells. Antagonists may be
					useful as anti-angiogenic
					agents, and may be
					applicable for cancer.
VEGF-138	GeneSeq	WO9940197	Promotes the growth and/or proliferation	VEGF activity can be determined using	Promotion of growth and
	Accession		of endothelial cells.	assays known in the art, such as those	proliferation of cells, such
	Y43483			disclosed in International Publication No.	as vascular endothelial
				WO0045835, for example.	cells. Antagonists may be
					useful as anti-angiogenic
					agents, and may be
					applicable for cancer.
VEGF-145	GeneSeq	WO0013702	Promotes the growth and/or proliferation	VEGF activity can be determined using	Promotion of growth and
	Accession		of endothelial cells.	assays known in the art, such as those	proliferation of cells, such
	Y69413			disclosed in International Publication No.	as vascular endothelial
				WO0045835, for example.	cells. Antagonists may be
					useful as anti-angiogenic
					agents, and may be
					applicable for cancer.
VEGF-162	GeneSeq	W09940197	Promotes the growth and/or proliferation	VEGF activity can be determined using	Promotion of growth and
	Accession		of endothelial cells.	assays known in the art, such as those	proliferation of cells, such
	Y43484			disclosed in International Publication No.	as vascular endothelial
				WO0045835, for example.	cells. Antagonists may be
					useful as anti-angiogenic
					agents, and may be
					applicable for cancer.
VEGF-165	GeneSeq	WO0013702	Promotes the growth and/or proliferation	VEGF activity can be determined using	Promotion of growth and
	Accession		of endothelial cells.	assays known in the art, such as those	proliferation of cells, such
	Y69414			disclosed in International Publication No.	as vascular endothelial
				WO0045835, for example.	cells. Antagonists may be
					useful as anti-angiogenic
					agents, and may be
					applicable for cancer.
VEGF-182	GeneSeq	W09940197	Promotes the growth and/or proliferation	VEGF activity can be determined using	Promotion of growth and
	Accession		of endothelial cells.	assays known in the art, such as those	proliferation of cells, such
	Y43483			disclosed in International Publication No.	as vascular endothelial
				WO0045835, for example.	cells. Antagonists may be
					useful as anti-angiogenic
					agents, and may be
					applicable for cancer.
VEGF-189	GeneSeq	WO0013702	Promotes the growth and/or proliferation	VEGF activity can be determined using	Promotion of growth and
	Accession		of endothelial cells.	assays known in the art, such as those	proliferation of cells, such
	Y69415			disclosed in International Publication No.	as vascular endothelial
				WO0045835, for example.	cells. Antagonists may be
					useful as anti-angiogenic
					agents, and may be
					applicable for cancer.
VEGF-206	GeneSeq	W00013702	Promotes the growth and/or proliferation	VEGF activity can be determined using	Promotion of growth and
	Accession		of endothelial cells.	assays known in the art, such as those	proliferation of cells, such
	Y69416			disclosed in International Publication No.	as vascular endothelial
				WO0045835, for example.	cells. Antagonists may be
					useful as anti-angiogenic
					agents, and may be
					applicable for cancer.
VEGF-D	GeneSeq	WO9807832	Promotes the growth and/or proliferation	VEGF activity can be determined using	Promotion of growth and
	Accession		of endothelial cells.	assays known in the art, such as those	proliferation of cells, such
	W53240			disclosed in International Publication No.	as vascular endothelial
				WO0045835, for example.	cells. Antagonists may be
					useful as anti-angiogenic
					agents, and may be
					applicable for cancer.
VEGF-E; VEGF-X	GeneSeq	W09947677	Promotes the growth and/or proliferation	VEGF activity can be determined using	Promotion of growth and
	Accession		of endothelial cells.	assays known in the art, such as those	proliferation of cells, such
	Y33679			disclosed in International Publication No.	as vascular endothelial
				WO0045835, for example.	cells. Antagonists may be
					useful as anti-angiogenic
					agents, and may be
					applicable for cancer.
VEGF Receptor;	GeneSeq	WO9831794	Receptor for VEGF polypeptides	VEGF activity, in the presence of flk-1	VEGF Receptor. Fusion
KDR; flk-1	Accession			polypeptides, can be determined using	protein with the
	W69679			assays known in the art, such as those	extracellular domain is
				disclosed in International Publication No.	useful as an anti-
				WO0045835, for example.	angiogenic agent.
					Antagonists may be useful
					in the promotion of
					angiogenesis.
Soluble VEGF	GeneSeq	U.S. Pat. No. 5,712,380	Receptor for VEGF polypeptides	VEGF activity, in the presence of VEGF	VEGF Receptor. Fusion
Receptor	Accession			Receptor polypeptides, can be determined	protein with the
	W47037			using assays known in the art, such as	extracellular domain is
				those disclosed in International	useful as an anti-
				Publication No. WO0045835, for example.	angiogenic agent.
					Antagonists may be useful
					in the promotion of
					angiogenesis.
flt-1	GeneSeq	WO0021560	Receptor for VEGF polypeptides	VEGF activity, in the presence of flt-1	VEGF Receptor. Fusion
	Accession			polypeptides, can be determined using	protein with the
	Y70751			assays known in the art, such as those	extracellular domain is
				disclosed in International Publication No.	useful as an anti-
				WO0045835, for example.	angiogenic agent.
					Antagonists may be useful
					in the promotion of
					angiogenesis.
VEGF R-3; flt-4	GeneSeq	WO0058511	Receptor for VEGF polypeptides	VEGF activity, in the presence of flt-4	VEGF Receptor. Fusion
	Accession			polypeptides, can be determined using	protein with the
	B29047			assays known in the art, such as those	extracellular domain is
				disclosed in International Publication No.	useful as an anti-
				WO0045835, for example.	angiogenic agent.
					Antagonists may be useful
					in the promotion of
					angiogenesis.
Neuropilin-1	GeneSeq	WO9929858	Vascular Endothelial Growth Factor	VEGF activity can be determined using	Promotion of growth and
	Accession			assays known in the art, such as those	proliferation of cells, such
	Y06319			disclosed in International Publication No.	as vascular endothelial
				WO0045835, for example.	cells. Antagonists may be
					useful as anti-angiogenic
					agents, and may be
					applicable for cancer.
Neuropilin-2	GeneSeq	WO9929858	Vascular Endothelial Growth Factor	VEGF activity can be determined using	Promotion of growth and
	Accession			assays known in the art, such as those	proliferation of cells, such
	Y03618			disclosed in International Publication No.	as vascular endothelial
				WO0045835, for example.	cells. Antagonists may be
					useful as anti-angiogenic
					agents, and may be
					applicable for cancer.
Human fast twitch	GeneSeq	W09730085	Troponins are contractile proteins that are	Ability of soluble Troponins to inhibit	Anti-angiogenesis
skeletal muscle	Accession		thought to inhibit angiogencsis. High	anglogenesis can be determined using
troponin C	W22597		levels may contribute to the difficulty	assays known in the art:. Proc Natl Acad
			encountered in revascularizing the	Sci USA 1999 Mar 16; 96(6): 2645-50.
			ischemic myocardium after cardiovascular
			injury.
Human fast twitch	GeneSeq	W09730085	Troponins are contractile proteins that are	Ability of soluble Troponins to inhibit	Anti-angiogenesis
skeletal muscle	Accession		thought to inhibit angiogencsis. High	anglogenesis can be determined using
troponin I	W18054		levels may contribute to the difficulty	assays known in the art:. Proc Natl Acad
			encountered in revascularizing the	Sci USA 1999 Mar 16; 96(6): 2645-50.
			ischemic myocardium after cardiovascular
			injury.
Human fast twitch	GeneSeq	W09730085	Troponins are contractile proteins that are	Ability of soluble Troponins to inhibit	Anti-angiogenesis
skeletal muscle	Accession		thought to inhibit angiogencsis. High	anglogenesis can be determined using
troponin T	W22599		levels may contribute to the difficulty	assays known in the art:. Proc Natl Acad
			encountered in revascularizing the	Sci USA 1999 Mar 16; 96(6): 2645-50.
			ischemic myocardium after cardiovascular
			injury.
fragment.	GeneSeq	W09719955	Troponins are contractile proteins that are	Ability of soluble Troponins to inhibit	Anti-angiogenesis
myofibrillar protein	Accession		thought to inhibit angiogencsis. High	anglogenesis can be determined using
troponin I	W18053		levels may contribute to the difficulty	assays known in the art:. Proc Natl Acad
			encountered in revascularizing the	Sci USA 1999 Mar 16; 96(6): 2645-50.
			ischemic myocardium after cardiovascular
			injury.
myofibrillar protein	GeneSeq	W09719955	Troponins are contractile proteins that are	Ability of soluble Troponins to inhibit	Anti-angiogenesis
troponin I	Accession		thought to inhibit angiogencsis. High	anglogenesis can be determined using
	W18054		levels may contribute to the difficulty	assays known in the art:. Proc Natl Acad
			encountered in revascularizing the	Sci USA 1999 Mar 16; 96(6): 2645-50.
			ischemic myocardium after cardiovascular
			injury.
Troponin peptides	GeneSeq	WO9933874	Troponins are contractile proteins that are	Ability of soluble Troponins to inhibit	Anti-angiogenesis
	Accessions		thought to inhibit angiogencsis. High	anglogenesis can be determined using
	Y29581, Y29582,		levels may contribute to the difficulty	assays known in the art:. Proc Natl Acad
	Y29583, Y29584,		encountered in revascularizing the	Sci USA 1999 Mar 16; 96(6): 2645-50.
	Y29585, and		ischemic myocardium after cardiovascular
	Y29586		injury.
Human fast twitch	GeneSeq	WO0054770	Troponins are contractile proteins that are	Ability of soluble Troponins to inhibit	Anti-angiogenesis
skeletal muscle	Accession		thought to inhibit angiogencsis. High	anglogenesis can be determined using
Troponin subunit C	B00134		levels may contribute to the difficulty	assays known in the art:. Proc Natl Acad
			encountered in revascularizing the	Sci USA 1999 Mar 16; 96(6): 2645-50.
			ischemic myocardium after cardiovascular
			injury.
Human fast twitch	GeneSeq	WO0054770	Troponins are contractile proteins that are	Ability of soluble Troponins to inhibit	Anti-angiogenesis
skeletal muscle	Accession		thought to inhibit angiogencsis. High	anglogenesis can be determined using
Troponin subunit I	B00135		levels may contribute to the difficulty	assays known in the art:. Proc Natl Acad
Protein			encountered in revascularizing the	Sci USA 1999 Mar 16; 96(6): 2645-50.
			ischemic myocardium after cardiovascular
			injury.
Human fast twitch	GeneSeq	WO0054770	Troponins are contractile proteins that are	Ability of soluble Troponins to inhibit	Anti-angiogenesis
skeletal muscle	Accession		thought to inhibit angiogencsis. High	anglogenesis can be determined using
Troponin subunit T	B00136		levels may contribute to the difficulty	assays known in the art:. Proc Natl Acad
			encountered in revascularizing the	Sci USA 1999 Mar 16; 96(6): 2645-50.
			ischemic myocardium after cardiovascular
			injury.
Activator Inbibitor-	GeneSeq	WO9013648	PAIs are believed to play a role in cancer,	Methods that measure plasminogen	Anti-angiogenesis; blood-
1; PAI-1	Accession		and cardiovascular disease and blood-	activator inhibitor (PAI) activity are known	clotting disorders.
	R08411		clotting disorders.	in the art, for example, assay the ability of
				PAI to inhibit tissue plasminogen activator
				(tPA) or urokinase (uPA): J Biochem
				Biophys Methods 2000 Sep 11; 45(2): 127-40,
				Breast Cancer Res Treat
				1996; 41(2): 141-6. Methods that measure
				anti-angiogenesis activity are known in the
				art, for example, Proc Natl Acad Sci USA
				1999 Mar 16; 96(6): 2645-50.
Plasminogen	GeneSeq	DE3722673	PAIs are believed to play a role in cancer,	Methods that measure plasminogen	Anti-angiogenesis; blood-
Activator Inhibitor-	Accession		and cardiovascular disease and blood-	activator inhibitor (PAI) activity are known	clotting disorders.
2; PAI-2	P94160		clotting disorders.	in the art, for example, assay the ability of
				PAI to inhibit tissue plasminogen activator
				(tPA) or urokinase (uPA): J Biochem
				Biophys Methods 2000 Sep 11; 45(2): 127-40,
				Breast Cancer Res Treat
				1996; 41(2): 141-6. Methods that measure
				anti-angiogenesis activity are known in the
				art, for example, Proc Natl Acad Sci USA
				1999 Mar 16; 96(6): 2645-50.
Activator Inhibitor-	GeneSeq	WO9102057	PAIs are believed to play a role in cancer,	Methods that measure plasminogen	Anti-angiogenesis; blood-
2; PAI-2	Accession		and cardiovascular disease and blood-	activator inhibitor (PAI) activity are known	clotting disorders.
	R10921		clotting disorders.	in the art, for example, assay the ability of
				PAI to inhibit tissue plasminogen activator
				(tPA) or urokinase (uPA): J Biochem
				Biophys Methods 2000 Sep 11; 45(2): 127-40,
				Breast Cancer Res Treat
				1996; 41(2): 141-6. Methods that measure
				anti-angiogenesis activity are known in the
				art, for example, Proc Natl Acad Sci USA
				1999 Mar 16; 96(6): 2645-50.
Human PAI-1	GeneSeq	WO9105048	PAIs are believed to play a role in cancer,	Methods that measure plasminogen	Anti-angiogenesis; blood-
mutants	Accessions		and cardiovascular disease and blood-	activator inhibitor (PAI) activity are known	clotting disorders.
	R11755, R11756,		clotting disorders.	in the art, for example, assay the ability of
	R11757, R11758,			PAI to inhibit tissue plasminogen activator
	R11759, R11760,			(tPA) or urokinase (uPA): J Biochem
	R11761, R11762			Biophys Methods 2000 Sep 11; 45(2): 127-40,
	and R11763			Breast Cancer Res Treat
				1996; 41(2): 141-6. Methods that measure
				anti-angiogenesis activity are known in the
				art, for example, Proc Natl Acad Sci USA
				1999 Mar 16; 96(6): 2645-50.
CXCR3; CXC	GeneSeq	WO0018431	Chemokines are a family of related small,	Chemokine activities can be determined	Soluble CXCR3
	Accession		secreted proteins involved in biological	using assays known in the art: Methods in	polypeptides may be useful
	Y79372		processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:	for inhibiting chemokine
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,	activities and viral infection.
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ.
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Modified Rantes	GeneSeq	WO9737005	Chemokines are a family of related small,	Chemokine activities can be determined	Immune disorders.
	Accession		secreted proteins involved in biological	using assays known in the art: Methods in
	W38129		processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ.
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
RANTES	GeneSeq	EP905240	Chemokines are a family of related small,	Chemokine activities can be determined	Immune disorders.
	Accession		secreted proteins involved in biological	using assays known in the art: Methods in
	Y05299		processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ.
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
MCI-Ia	GeneSeq	WO9509232	Chemokines are a family of related small,	Chemokine activities can be determined	Immune disorders.
	Accession		secreted proteins involved in biological	using assays known in the art: Methods in
	R73914		processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ.
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
MCP-Ib	GeneSeq	WO9929728	Chemokines are a family of related small,	Chemokine activities can be determined	Immune disorders.
	Accession		secreted proteins involved in biological	using assays known in the art: Methods in
	Y26176		processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ.
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
MCP-I receptor	GeneSeq	WO9519436	Chemokines are a family of related small,	Chemokine activities can be determined	Soluble MCP-1 Receptor
	Accession		secreted proteins involved in biological	using assays known in the art: Methods in	polypeptides may be useful
	R79165		processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:	for inhibiting chemokine
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,	activities and viral infection.
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ.
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
MCP-3	GeneSeq	W09509232	Chemokines are a family of related small,	Chemokine activities can be determined	Immune disorders.
	Accession		secreted proteins involved in biological	using assays known in the art: Methods in
	R73915		processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ.
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
MCP-4 receptor	GeneSeq	W09809171	Chemokines are a family of related small,	Chemokine activities can be determined	Soluble MCP-4 Receptor
	Accession		secreted proteins involved in biological	using assays known in the art: Methods in	polypeptides may be useful
	W56689		processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:	for inhibiting chemokine
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,	activities and viral infection.
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ.
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
RANTES receptor	GeneSeq	U.S. Pat. No. 5,652,133	Chemokines are a family of related small,	Chemokine activities can be determined	Soluble RANTES Receptor
	Accession		secreted proteins involved in biological	using assays known in the art: Methods in	polypeptides may be useful
	W29588		processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:	for inhibiting chemokine
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,	activities and viral infection.
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ.
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
CCR5 variant	GeneSeq	WO9854317	Chemokines are a family of related small,	Chemokine activities can be determined	Soluble CCR5 polypeptides
	Accession		secreted proteins involved in biological	using assays known in the art: Methods in	may be useful for inhibiting
	W88238		processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:	chemokine activities and
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,	viral infection.
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ.
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
CCR7	GeneSeq	U.S. Pat. No. 6,153,441	Chemokines are a family of related small,	Chemokine activities can be determined	Soluble CCR7 polypeptides
	Accession		secreted proteins involved in biological	using assays known in the art: Methods in	may be useful for inhibiting
	B50859		processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:	chemokine activities and
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,	viral infection.
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ.
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
CXC3	GeneSeq	WO9727299	Chemokines are a family of related small,	Chemokine activities can be determined	Immune disorders.
	Accession		secreted proteins involved in biological	using assays known in the art: Methods in
	W23345		processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ.
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Eotaxin	GeneSeq	WO9700960	Chemokines are a family of related small,	Chemokine activities can be determined	Immune disorders.
	Accession		secreted proteins involved in biological	using assays known in the art: Methods in
	W10099		processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ.
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Neurotactin	GeneSeq	U.S. Pat. No. 6,013,257	Neurotactin may play a role in	Chemotactic leukocyte migration assays	Immune disorders.
	Accessions	WO9742224	chemotactic leukocyte migration and brain	are known in the art, for example: J.
	Y77537, W34307,		inflammation processes.	Immunol. Methods 33, ((1980)); Nature
	Y53259, and,			1997 Jun 5; 387(6633): 611-7.
	Y77539
Human CKbeta-9	GeneSeq	U.S. Pat. No. 6,153,441	Chemokines are a family of related small,	Chemokine activities can be determined	Immune disorders.
	Accession		secreted proteins involved in biological	using assays known in the art: Methods in
	B50860		processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ.
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Lymphotactin	GeneSeq	WO0073320	Chemokines are a family of related small,	Chemokine activities can be determined	Immune disorders.
	Accession		secreted proteins involved in biological	using assays known in the art: Methods in
	B50052		processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ.
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G.
MIP-3 alpha	GeneSeq	WO9801557	Chemokines are a family of related small,	Chemokine activities can be determined	Immune disorders.
	Accession		secreted proteins involved in biological	using assays known in the art: Methods in
	W44398		processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ.
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G.
MIP-3 beta	GeneSeq	WO9801557	Chemokines are a family of related small,	Chemokine activities can be determined	Immune disorders.
	Accession		secreted proteins involved in biological	using assays known in the art: Methods in
	W44399		processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ.
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G.
MIP-Gamma	GeneSeq	WO9504158	Chemokines are a family of related small,	Chemokine activities can be determined	Immune disorders.
	Accession		secreted proteins involved in biological	using assays known in the art: Methods in
	R70798		processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ.
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G.
Stem Cell	GeneSeq	WO9104274	Chemokines are a family of related small,	Chemokine activities can be determined	Hematopoietic growth
Inhibitory	Accession		secreted proteins involved in biological	using assays known in the art: Methods in	factors.
Factor	R11553		processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ.
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G.
thrombopoietin	GeneSeq	WO9521920	Thrombopoietin is involved in the	Thrombopoietin (TPO) can be assayed to	Hematopoietic growth
	Accession		regulation of the growth and differentiation	determine regulation of growth and	factors.
	R79905		of megakaryocytes and preceptors	differentiation of megakaryocytes. Mol
			thereof.	Cell Biol 2001 Apr; 21(8): 2659-70; Exp
				Hematol
2001 January; 29(1): 51-8 and within.
c-kit ligand;	GeneSeq	EP992579 and	C-kit ligan is thought to stimulate the	Chemokine activities can be determined	Hematopoietic growth
SCF; Mast cell	Accession	EP676470	proliferation of mast cells, and is able to	using assays known in the art: Methods in	factors.
growth factor;	Y53284, R83978		augment the proliferation of both myeloid	Molecular Biology, 2000, vol. 138:
MGF;	and R83977		and lymphoid hematopoietic progenitors in	Chemokine Protocols. Edited by: A. E. I. Proudfoot,
Fibrosarcoma-			bone marrow culture. C-kit ligand is also	T. N. C. Wells, and C. A. Power.
derived stem			though to act synergistically with other	© Humana Press Inc., Totowa, NJ.
cell factor			cytokines.
Platelet derived	GeneSeq	WO0066736	Vascular Endothelial Growth Factor	VEGF activity can be determined using	Promotion of growth and
growth factor	Accession B48653			assays known in the art, such as those	proliferation of cells, such
				disclosed in International Publication No.	as vascular endothelial
				WO0045835, for example.	cells. Antagonists may be
					useful as anti-angiogenic
					agents, and may be
					applicable for cancer.
Melanoma	GeneSeq	WO9503328	Melanoma inhibiting protein has	Tumor suppressor activity of melanoma	Cancer; melanoma
inhibiting protein	Accession R69811		melanoma-inhibiting activity and can be	inhibiting protein can be determined using
			used to treat cancer (melanoma,	assays known in the art: Matzuk et al.,
			glioblastoma, neuroblastoma, small cell	Nature 1992 Nov 26; 360(6402): 313-9.
			lung cancer, neuroectodermal tumors) or
			as an immunosuppressant (it inhibits IL-2
			or phytohaemagglutinin induced
			proliferation of peripheral blood
			lymphocytes.
Glioma-derived	GeneSeq	EP399816	Vascular Endothelial Growth Factor	VEGF activity can be determined using	Promotion of growth and
growth factor	Accession R08120			assays known in the art, such as those	proliferation of cells, such
				disclosed in International Publication No.	as vascular endothelial
				WO0045835, for example.	cells. Antagonists may be
					useful as anti-angiogenic
					agents, and may be
					applicable for cancer.
Platelet derived	GeneSeq	EP682110	Vascular Endothelial Growth Factor	VEGF activity can be determined using	Promotion of growth and
growth factor	Accession R84759			assays known in the art, such as those	proliferation of cells, such
precursor A				disclosed in International Publication No.	as vascular endothelial
				WO0045835, for example.	cells. Antagonists may be
					useful as anti-angiogenic
					agents, and may be
					applicable for cancer.
Platelet derived	GeneSeq	EP682110	Vascular Endothelial Growth Factor	VEGF activity can be determined using	Promotion of growth and
growth factor	Accession R84760			assays known in the art, such as those	proliferation of cells, such
precursor B				disclosed in International Publication No.	as vascular endothelial
				WO0045835, for example.	cells. Antagonists may be
					useful as anti-angiogenic
					agents, and may be
					applicable for cancer.
Platelet derived	GeneSeq	EP282317	Vascular Endothelial Growth Factor	VEGF activity can be determined using	Promotion of growth and
growth factor Bvsis	Accession P80595			assays known in the art, such as those	proliferation of cells, such
	and P80596			disclosed in International Publication No.	as vascular endothelial
				WO0045835, for example.	cells. Antagonists may be
					useful as anti-angiogenic
					agents, and may be
					applicable for cancer.
Placental Growth	GeneSeq	WO9206194	Vascular Endothelial Growth Factor	VEGF activity can be determined using	Promotion of growth and
Factor	Accessions			assays known in the art, such as those	proliferation of cells, such
	R23059 and			disclosed in International Publication No.	as vascular endothelial
	R23060			WO0045835, for example.	cells. Antagonists may be
					useful as anti-angiogenic
					agents, and may be
					applicable for cancer.
Placental Growth	GeneSeq	DE19748734	Vascular Endothelial Growth Factor	VEGF activity can be determined using	Promotion of growth and
Factor-2	Accession Y08289			assays known in the art, such as those	proliferation of cells, such
				disclosed in International Publication No.	as vascular endothelial
				WO0045835, for example.	cells. Antagonists may be
					useful as anti-angiogenic
					agents, and may be
					applicable for cancer.
Thrombopoietin	GeneSeq	WO0000612	Thrombopoietin is involved in the	Thrombopoietin (TPO) can be assayed to	Thrombocytopenia, cancer.
derivative1	Accession Y77244		regulation of the growth and differentiation	determine regulation of growth and
			of megakaryocytes and preceptors	differentiation of megakaryocytes. Mol
			thereof.	Cell Biol 2001 Apr; 21(8): 2659-70; Exp
				Hematol
2001 January; 29(1): 51-8 and within.
Thrombopoietin	GeneSeq	WO0000612	Thrombopoietin is involved in the	Thrombopoietin (TPO) can be assayed to	Thrombocytopenia, cancer.
derivative2	Accession Y77255		regulation of the growth and differentiation	determine regulation of growth and
			of megakaryocytes and preceptors	differentiation of megakaryocytes. Mol
			thereof.	Cell Biol 2001 Apr; 21(8): 2659-70; Exp
				Hematol
2001 January; 29(1): 51-8 and within.
Thrombopoietin	GeneSeq	WO0000612	Thrombopoietin is involved in the	Thrombopoietin (TPO) can be assayed to	Thrombocytopenia, cancer.
derivative3	Accession Y77262		regulation of the growth and differentiation	determine regulation of growth and
			of megakaryocytes and preceptors	differentiation of megakaryocytes. Mol
			thereof.	Cell Biol 2001 Apr; 21(8): 2659-70; Exp
				Hematol
2001 January; 29(1): 51-8 and within.
Thrombopoietin	GeneSeq	WO0000612	Thrombopoietin is involved in the	Thrombopoietin (TPO) can be assayed to	Thrombocytopenia, cancer.
derivative4	Accession Y77267		regulation of the growth and differentiation	determine regulation of growth and
			of megakaryocytes and preceptors	differentiation of megakaryocytes. Mol
			thereof.	Cell Biol 2001 Apr; 21(8): 2659-70; Exp
				Hematol
2001 January; 29(1): 51-8 and within.
Thrombopoietin	GeneSeq	WO0000612	Thrombopoietin is involved in the	Thrombopoietin (TPO) can be assayed to	Thrombocytopenia, cancer.
derivative5	Accession Y77246		regulation of the growth and differentiation	determine regulation of growth and
			of megakaryocytes and preceptors	differentiation of megakaryocytes. Mol
			thereof.	Cell Biol 2001 Apr; 21(8): 2659-70; Exp
				Hematol
2001 January; 29(1): 51-8 and within.
Thrombopoietin	GeneSeq	WO0000612	Thrombopoietin is involved in the	Thrombopoietin (TPO) can be assayed to	Thrombocytopenia, cancer.
derivative6	Accession Y77253		regulation of the growth and differentiation	determine regulation of growth and
			of megakaryocytes and preceptors	differentiation of megakaryocytes. Mol
			thereof.	Cell Biol 2001 Apr; 21(8): 2659-70; Exp
				Hematol
2001 January; 29(1): 51-8 and within.
Thrombopoietin	GeneSeq	WO0000612	Thrombopoietin is involved in the	Thrombopoietin (TPO) can be assayed to	Thrombocytopenia, cancer.
derivative7	Accession Y77256		regulation of the growth and differentiation	determine regulation of growth and
			of megakaryocytes and preceptors	differentiation of megakaryocytes. Mol
			thereof.	Cell Biol 2001 Apr; 21(8): 2659-70; Exp
				Hematol
2001 January; 29(1): 51-8 and within.
Fractalkine	GeneSeq	U.S. Pat. No. 6,043,086	Fractalkine is believed to play a role in	Fractalkine activity can be determined	Immune disorders.
	Accession Y53255		chemotactic leukocyte migration and	using Chemotactic leukocyte migration
			neurological disorders.	assays known in the art, for example: J.
				Immunol. Methods 33, ((1980)); Nature
				1997 Jun 5; 387(6633): 611-7.
CXC3	GeneSeq	WO9757599	Chemokines are a family of related small,	Chemokine activities can be determined	Immune disorders.
	Accession		secreted proteins involved in biological	using assays known in the art: Methods in
	W23345		processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ.
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
CCR7	GeneSeq	U.S. Pat. No. 6,153,441	Chemokines are a family of related small,	Chemokine activities can be determined	Soluble CCR7 polypeptides
	Accession B50859		secreted proteins involved in biological	using assays known in the art: Methods in	may be useful for inhibiting
			processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:	chemokine activities and
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,	viral infection.
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ.
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Nerve Growth	GeneSeq	EP414151	Nerve Growth Factor	Proliferation assay using NR6R-3T3 cells	Neurological disorders,
Factor-beta	Accession R11474			(Rizzino 1988 Cancer Res. 48: 4266)	cancer
Nerve Growth	GeneSeq	EP859056	Nerve Growth Factor	Proliferation assay using NR6R 3T3 cells	Neurological disorders,
Factor-beta2	Accession			(Rizzino 1988 Cancer Res. 48: 4266	cancer
	W69725
Neurotrophin-3	GeneSeq	WO9821234	Neurotrophins regulate neuronal cell	Trk tyrosine kinase activation assays	Neurological disorders,
	Accession		survival and synaptic plasticity.	known in the art can be used to assay for	cancer
	W8889			neurotrophin activity, for example, Proc
				Natl Acad Sci USA 2001 Mar
				13; 98(6): 3555-3560.
Neurotrophin-3	GeneSeq	WO9325684	Neurotrophins regulate neuronal cell	Trk tyrosine kinase activation assays	Neurological disorders,
	Accession R47100		survival and synaptic plasticity.	known in the art can be used to assay for	cancer
				neurotrophin activity, for example, Proc
				Natl Acad Sci USA 2001 Mar
				13; 98(6): 3555-3560.
Neurotrophin-4a	GeneSeq	WO9325684	Neurotrophins regulate neuronal cell	Trk tyrosine kinase activation assays	Neurological disorders,
	Accession R47101		survival and synaptic plasticity.	known in the art can be used to assay for	cancer
				neurotrophin activity, for example, Proc
				Natl Acad Sci USA 2001 Mar
				13; 98(6): 3555-3560. 13; 98(6): 3555-3560
Neurotrophin-4b	GeneSeq	WO9325684	Neurotrophins regulate neuronal cell	Trk tyrosine kinase activation assays	Neurological disorders,
	Accession R47102		survival and synaptic plasticity.	known in the art can be used to assay for	cancer
			tyrosine kinases.	neurotrophin activity, for example, Proc
				Natl Acad Sci USA 2001 Mar
				13; 98(6): 3555-3560.
Neurotrophin-4c	GeneSeq	WO9325684	Neurotrophins regulate neuronal cell	Trk tyrosine kinase activation assays	Neurological disorders,
	Accession R47103		survival and synaptic plasticity.	known in the art can be used to assay for	cancer
			tyrosine kinases.	neurotrophin activity, for example, Proc
				Natl Acad Sci USA 2001 Mar
				13; 98(6): 3555-3560.
Neurotrophin-4d	GeneSeq	WO9325684	Neurotrophins regulate neuronal cell	Trk tyrosine kinase activation assays	Neurological disorders,
	Accession R47102		survival and synaptic plasticity.	known in the art can be used to assay for	cancer
			tyrosine kinases.	neurotrophin activity, for example, Proc
				Natl Acad Sci USA 2001 Mar
				13; 98(6): 3555-3560.
Platelet-Derived	GeneSeq	U.S. Pat. No. 5,219,739	Vascular Endothelial Growth Factor	VEGF activity can be determined using	Promotion of growth and
Growth Factor	Accession R38918			assays known in the art, such as those	proliferation of cells, such
A chain				disclosed in International Publication No.	as vascular endothelial
				W00045835, for example.	cells. Hematopoietic and
					immune disorders.
					Antagonists may be useful
					as anti-angiogenic agents,
					and may be applicable for
					cancer
Platelet-Derived	GeneSeq	U.S. Pat. No. 5,219,739	Vascular Endothelial Growth Factor	VEGF activity can be determined using	Promotion of growth and
Growth Factor	Accession R38919			assays known in the art, such as those	proliferation of cells, such
B chain				disclosed in International Publication No.	as vascular endothelial
				W00045835, for example.	cells. Hematopoietic and
					immune disorders.
					Antagonists may be useful
					as anti-angiogenic agents,
					and may be applicable for
					cancer
Stromal Derived	GeneSeq	WO9948528	Stromal Growth Factor	Proliferation assay using NR6R-3T3 cells	Hematopoietic, immune
Factor-1 alpha	Accession			(Rizzino 1988 Cancer Res. 48: 4266)	disorders, cancer
	Y39995
Stromal Derived	GeneSeq	CA2117953	Stromal Growth Factor	Proliferation assay using NR6R-3T3 cells	Hematopoietic, immune
Factor-1 beta	Accession			(Rizzino 1988 Cancer Res. 48: 4266)	disorders, cancer
	R75420
Tarc	GeneSeq	WO9711969	Chemotactic for T lymphocytes. May play	Chemotactic leukocyte migration assays	Antiinflammatory. Immune
	Accession		a role in T-cell development. Thought to	are known in the art, for example: J.	disorders, cancer
	W14917		bind CCR8 and CCR4	Immunol. Methods 33 ((1980))
Prolactin	GeneSeq	WO9521625	Prolactin is involved in immune cell	Immune coil proliferation and suppression	Reproductive system
	Accession R78691		proliferation and apoptosis.	of apoptosis by prolactin can be assayed	disorders, cancer.
				by methods well-known in the art, for
				example, Buckley, AR and Buckley DJ,
				Ann N Y Acad Sci 2000; 917: 522-33, and
				within.
Prolactin2	GeneSeq	U.S. Pat. No. 5,955,346	Prolactin is involved in immune cell	Immune coil proliferation and suppression	Reproductive system
	Accession		proliferation and apoptosis.	of apoptosis by prolactin can be assayed	disorders, cancer.
	Y31764			by methods well-known in the art, for
				example, Buckley, AR and Buckley DJ,
				Ann N Y Acad Sci 2000; 917: 522-33, and
				within.
Follicle stimulating	GeneSeq	EP974359	FSH stimulates secretion of interleukin-1	FSH activities can be determined using	Reproductive system
hormone Alpha	Accession		by cells isolated from women in the	assays known in the art; J Gend Specif	disorders, cancer.
subunit	Y54160		follicular phase	Med 1999 Nov-Dec; 2(6): 30-4; Mol Cell
				Endocrinol. 1997 Nov 15; 134(2): 109-18.
Follicle stimulating	GeneSeq	EP974359	FSH stimulates secretion of interleukin-1	FSH activities can be determined using	Reproductive system
hormone Beta	Accession		by cells isolated from women in the	assays known in the art; J Gend Specif	disorders, cancer.
subunit	Y54161		follicular phase	Med 1999 Nov-Dec; 2(6): 30-4; Mol Cell
				Endocrinol. 1997 Nov 15; 134(2): 109-18.
Substance P	GeneSeq	WO0054053	Substance P is associated with	Immuneregulation and bone marrow, cell	diabetes mellitus,
(tachykinin)	Accession		immunoregulation.	proliferation by substance P can be	hypertension, cancer
	B23027			assayed by methods well-known in the art,
				for example, Lai et al. Proc Natl Acad Sci
				USA
2001 Mar. 27; 98(7): 3970-5; Jallat-
				Daloz et al. Allergy Asthma Proc 2001 January
				February; 22(1): 17-23; Kahler et al. Exp Lung
				Res
2001 January-February; 27(1): 25-46; and
				Adamus MA and Dabrowski ZJ. J Cell
				Biochem
2001; 81(3)499-506.
Ocytocin	GeneSeq	WO0053755	Oxytocin is involved in the induction of	Oxytocin and prostaglandin E(2) release	inflammatory disorders
(Neurophysin I)	Accession		prostaglandin (E2) release as well as an	and Ocytocin (Ca2+) increase can be	immunologic disorders,
	B24085 and		increased amount of calcium release by	assayed by methods well-known in the art,	cancer
	B24086		smooth muscle cells.	for example, Pavan et al., AM J Obset
				Gynecol 2000 July; 183(1): 76-82 and Holda
				et al., Cell Calcium 1996 Jul; 20(1): 43 51.
Vasopressin	GeneSeq	WO0053755	Vasopressinis believed to have a direct	Vasopressin activity can be determined	inflammatory disorders
(Neurophysin II)	Accession		antidiuretic action on the kidney, and it is	using assays known in the art, for example,	immunologic disorders,
	B24085 and		thought to cause vasoconstriction of the	Endocr Regul 1996 Mar; 30(I): 13-17.	cancer
	B24086		peripheral vessels.
IL-1	GeneSeq	EP165654	Interleukins are a group of multifunctional	Interleukin activity can be determined using	inflammatory disorders,
	Accession		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al., in	immunologic disorders,
	P60326		monocytes, and macrophages. Known	Lymphokines and Interferens: A Practical	cancer
			functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,
			of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225; and
			cells, eosinophils, and lymphocytes),	Orencole & Dinarclio (1989) Cytokine 1,
			chemotaxis of neutrophils and T	14-20.
			lymphocytes, and/or inhibition of
			interferons.
IL-1 mature	GeneSeq	EP456332	Interleukins are a group of multifunctional	Interleukin activity can be determined using	inflammatory disorders,
	Accession		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al., in	immunologic disorders,
	R14855		monocytes, and macrophages. Known	Lymphokines and Interferens: A Practical	cancer
			functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,
			of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225; and
			cells, eosinophils, and lymphocytes),	Orencole & Dinarclio (1989) Cytokine 1,
			chemotaxis of neutrophils and T	14-20.
			lymphocytes, and/or inhibition of
			interferons.
IL-1 beta	GeneSeq	WO9922763	Interleukins are a group of multifunctional	Interleukin activity can be determined using	inflammatory disorders,
	Accession		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al., in	immunologic disorders,
	Y08322		monocytes, and macrophages. Known	Lymphokines and Interferens: A Practical	cancer
			functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,
			of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225; and
			cells, eosinophils, and lymphocytes),	Orencole & Dinarclio (1989) Cytokine 1,
			chemotaxis of neutrophils and T	14-20.
			lymphocytes, and/or inhibition of
			interferons.
IL-3 variants	GeneSeq	WO8806161	Interleukins are a group of multifunctional	Interleukin activity can be determined using	inflammatory disorders,
	Accession		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al., in	immunologic disorders,
	P80382, P80383,		monocytes, and macrophages. Known	Lymphokines and Interferens: A Practical	cancer
	P80384, and		functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,
	P80381		of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225; and
			cells, eosinophils, and lymphocytes),	Kitamura et al (1989) J Cell Physiol. 140
			chemotaxis of neutrophils and T	323-334.
			lymphocytes, and/or inhibition of
			interferons.
IL-4	GeneSeq	WO8702990	Interleukins are a group of multifunctional	Interleukin activity can be determined using	inflammatory disorders,
	Accession		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al., in	immunologic disorders,
	P70615		monocytes, and macrophages. Known	Lymphokines and Interferens: A Practical	cancer
			functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,
			of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225; and
			cells, eosinophils, and lymphocytes),	Siegel & Mostowski (1990) J Immunol
			chemotaxis of neutrophils and T	Methods 132, 287-295.
			lymphocytes, and/or inhibition of
			interferons.
IL-4 muteins	GeneSeq	WO9747744	Interleukins are a group of multifunctional	Interleukin activity can be determined using	inflammatory disorders,
	Accession		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al., in	immunologic disorders,
	W52151		monocytes, and macrophages. Known	Lymphokines and Interferens: A Practical	cancer
	W52152		functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,
	W52153		of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225; and
	W52154		cells, eosinophils, and lymphocytes),	Siegel & Mostowski (1990) J Immunol
	W52155		chemotaxis of neutrophils and T	Methods 132, 287-295.
	W52156		lymphocytes, and/or inhibition of
	W52157		interferons.
	W52158
	W52159
	W52160
	W52161
	W52162
	W52163
	W52164
	and W52165
IL-1 alpha	GeneSeq	EP324447	Interleukins are a group of multifunctional	Interleukin activity can be determined using	inflammatory disorders,
	Accession		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al., in	immunologic disorders,
	P90108		monocytes, and macrophages. Known	Lymphokines and Interferens: A Practical	cancer
			functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,
			of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225; and
			cells, eosinophils, and lymphocytes),	Orencole & Dinarello (1989) Cytokine 1,
			chemotaxis of neutrophils and T	14-20.
			lymphocytes, and/or inhibition of
			interferons.
IL-3 variants	GeneSeq	WO9307171	Interleukins are a group of multifunctional	Interleukin activity can be determined using	inflammatory disorders,
	Accession		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al., in	immunologic disorders,
	R38561, R38562,		monocytes, and macrophages. Known	Lymphokines and Interferens: A Practical	cancer
	R38563, R38564,		functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,
	R38565, R38566,		of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225; and
	R38567, R38568,		cells, eosinophils, and lymphocytes),	Aarden et al (1987) Eur. J. Immunol 17,
	R38569, R38570,		chemotaxis of neutrophils and T	1411-16.
	R38571, and		lymphocytes, and/or inhibition of
	R38572		interferons.
IL-6	GeneSeq	WO9402512	Interleukins are a group of multifunctional	Interleukin activity can be determined using	inflammatory disorders,
	Accession		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al., in	immunologic disorders,
	R45717 and		monocytes, and macrophages. Known	Lymphokines and Interferens: A Practical	cancer
	R45718		functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,
			of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225; and
			cells, eosinophils, and lymphocytes),	Aarden et al (1987) Eur. J. Immunol 17,
			chemotaxis of neutrophils and T	1411-16.
			lymphocytes, and/or inhibition of
			interferons.
IL-13	GeneSeq	WO9404680	Interleukins are a group of multifunctional	Interleukin activity can be determined using	inflammatory disorders,
	Accession		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al., in	immunologic disorders,
	R48624		monocytes, and macrophages. Known	Lymphokines and Interferens: A Practical	cancer
			functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,
			of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225; and
			cells, eosinophils, and lymphocytes),	Boutelier et al (1995) J. Immunol. Methods
			chemotaxis of neutrophils and T	181, 29.
			lymphocytes, and/or inhibition of
			interferons.
IL-4 mutein	GeneSeq	DE4137333	Interleukins are a group of multifunctional	Interleukin activity can be determined using	inflammatory disorders,
	Accession		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al., in	immunologic disorders,
	R47182		monocytes, and macrophages. Known	Lymphokines and Interferens: A Practical	cancer
			functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,
			of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225; and
			cells, eosinophils, and lymphocytes),	Siegel & Mostowski (1990) J Immunol
			chemotaxis of neutrophils and T	Methods 132, 287-295.
			lymphocytes, and/or inhibition of
			interferons.
IL-4 mutein	GeneSeq	DE4137333	Interleukins are a group of multifunctional	Interleukin activity can be determined using	inflammatory disorders,
Y124X	Accession		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al., in	immunologic disorders,
	R47183		monocytes, and macrophages. Known	Lymphokines and Interferens: A Practical	cancer
			functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,
			of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225; and
			cells, eosinophils, and lymphocytes),	Siegel & Mostowski (1990) J Immunol
			chemotaxis of neutrophils and T	Methods 132, 287-295.
			lymphocytes, and/or inhibition of
			interferons.
IL-4 mutein	GeneSeq	DE4137333	Interleukins are a group of multifunctional	Interleukin activity can be determined using	inflammatory disorders,
Y124G	Accession		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al., in	immunologic disorders,
	R47184		monocytes, and macrophages. Known	Lymphokines and Interferens: A Practical	cancer
			functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,
			of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225; and
			cells, eosinophils, and lymphocytes),	Siegel & Mostowski (1990) J Immunol
			chemotaxis of neutrophils and T	Methods 132, 287-295.
			lymphocytes, and/or inhibition of
			interferons.
Human	GeneSeq	WO9317698	Interleukins are a group of multifunctional	Interleukin activity can be determined using	inflammatory disorders,
Interleukin-10	Accession		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al., in	immunologic disorders,
(precursor)	R41664		monocytes, and macrophages. Known	Lymphokines and Interferens: A Practical	cancer
			functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,
			of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225; and
			cells, eosinophils, and lymphocytes),	Thompson-Snipes et al (1991) J. Exp. Med.
			chemotaxis of neutrophils and T	173, 507-510.
			lymphocytes, and/or inhibition of
			interferons.
Human	GeneSeq	WO9318783-A	Interleukins are a group of multifunctional	Interleukin activity can be determined using	inflammatory disorders,
Interleukin-10	Accession		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al., in	immunologic disorders,
	R42642		monocytes, and macrophages. Known	Lymphokines and Interferens: A Practical	cancer
			functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,
			of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225; and
			cells, eosinophils, and lymphocytes),	Thompson-Snipes et al (1991) J. Exp. Med.
			chemotaxis of neutrophils and T	173, 507-510.
			lymphocytes, and/or inhibition of
			interferons.
Human	GeneSeq	EP569042	Interleukins are a group of multifunctional	Interleukin activity can be determined using	inflammatory disorders,
interleukin-1	Accession		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al., in	immunologic disorders,
beta precursor.	R42447		monocytes, and macrophages. Known	Lymphokines and Interferens: A Practical	cancer
			functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,
			of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225; and
			cells, eosinophils, and lymphocytes),	Orencole & Dinarello (1989) Cytokine 1,
			chemotaxis of neutrophils and T	14-20.
			lymphocytes, and/or inhibition of
			interferons.
Interleukin-	GeneSeq	EP578278	Interleukins are a group of multifunctional	Interleukin activity can be determined using	inflammatory disorders,
1alpha	Accession		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al., in	immunologic disorders,
	R45364		monocytes, and macrophages. Known	Lymphokines and Interferens: A Practical	cancer
			functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,
			of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225.
			cells, eosinophils, and lymphocytes),
			chemotaxis of neutrophils and T
			lymphocytes, and/or inhibition of
			interferons.
Human	GeneSeq	JP04063595	Interleukins are a group of multifunctional	Interleukin activity can be determined using	inflammatory disorders,
interleukin-3	Accession		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al., in	immunologic disorders,
variant	R22814		monocytes, and macrophages. Known	Lymphokines and Interferens: A Practical	cancer
			functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,
			of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225; and
			cells, eosinophils, and lymphocytes),	Kitamura et al (1989) J Cell Physiol. 140
			chemotaxis of neutrophils and T	323-334.
			lymphocytes, and/or inhibition of
			interferons.
IL-1i fragments	GeneSeq	EP541920	Interleukins are a group of multifunctional	Interleukin activity can be determined using	inflammatory disorders,
	Accession		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al., in	immunologic disorders,
	R35484 and		monocytes, and macrophages. Known	Lymphokines and Interferens: A Practical	cancer
	R35485		functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,
			of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225; and
			cells, eosinophils, and lymphocytes),	Orencole & Dinarclio (1989) Cytokine 1,
			chemotaxis of neutrophils and T	14-20.
			lymphocytes, and/or inhibition of
			interferons.
IL-1 inhibitor	GeneSeq	EPS541920	Interleukins are a group of multifunctional	Interleukin activity can be determined using	inflammatory disorders,
(IL-li)	Accession		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al., in	immunologic disorders,
	R35486 and		monocytes, and macrophages. Known	Lymphokines and Interferens: A Practical	cancer
	R35484		functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,
			of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225; and
			cells, eosinophils, and lymphocytes),	Orencole & Dinarclio (1989) Cytokine 1,
			chemotaxis of neutrophils and T	14-20.
			lymphocytes, and/or inhibition of
			interferons.
ICE 22 kD subunit.	GeneSeq	EP533350	Interleukins are a group of multifunctional	Interleukin activity can be determined using	inflammatory disorders,
	Accession		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al., in	immunologic disorders,
	R33780		monocytes, and macrophages. Known	Lymphokines and Interferens: A Practical	cancer
			functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,
			of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225.
			cells, eosinophils, and lymphocytes),
			chemotaxis of neutrophils and T
			lymphocytes, and/or inhibition of
			interferons.
ICE 20 kD subunit.	GeneSeq	EP533350	Interleukins are a group of multifunctional	Interleukin activity can be determined using	inflammatory disorders,
	Accession		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al., in	immunologic disorders,
	R33781		monocytes, and macrophages. Known	Lymphokines and Interferens: A Practical	cancer
			functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,
			of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225.
			cells, eosinophils, and lymphocytes),
			chemotaxis of neutrophils and T
			lymphocytes, and/or inhibition of
			interferons.
ICE 10 kD	GeneSeq	EP533350	Interleukins are a group of multifunctional	Interleukin activity can be determined using	inflammatory disorders,
subunit	Accession		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al., in	immunologic disorders,
	R33782		monocytes, and macrophages. Known	Lymphokines and Interferens: A Practical	cancer
			functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,
			of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225.
			cells, eosinophils, and lymphocytes),
			chemotaxis of neutrophils and T
			lymphocytes, and/or inhibition of
			interferons.
Human	GeneSeq	WO9317698	Interleukins are a group of multifunctional	Interleukin activity can be determined using	inflammatory disorders,
Interleukin-10	Accession		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al., in	immunologic disorders,
(precursor)	R41664		monocytes, and macrophages. Known	Lymphokines and Interferens: A Practical	cancer
			functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,
			of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225; and
			cells, eosinophils, and lymphocytes),	Thompson-Snipes et al (1991) J. Exp. Med.
			chemotaxis of neutrophils and T	173, 507-510.
			lymphocytes, and/or inhibition of
			interferons.
Human	GeneSeq	WO9318783	Interleukins are a group of multifunctional	Interleukin activity can be determined using	inflammatory disorders,
Interleukin-10	Accession		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al., in	immunologic disorders,
	R42642		monocytes, and macrophages. Known	Lymphokines and Interferens: A Practical	cancer
			functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,
			of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225; and
			cells, eosinophils, and lymphocytes),	Thompson-Snipes et al (1991) J. Exp. Med.
			chemotaxis of neutrophils and T	173, 507-510.
			lymphocytes, and/or inhibition of
			interferons.
Human	GeneSeq	EP569042	Interleukins are a group of multifunctional	Interleukin activity can be determined using	inflammatory disorders,
Interleukin-1	Accession		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al., in	immunologic disorders,
beta precursor	R42447		monocytes, and macrophages. Known	Lymphokines and Interferens: A Practical	cancer
			functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,
			of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225; and
			cells, eosinophils, and lymphocytes),	Kitamura et al (1989) J Cell Physiol. 140
			chemotaxis of neutrophils and T	323-334.
			lymphocytes, and/or inhibition of
			interferons.
Human	GeneSeq	WO9403492	Interleukins are a group of multifunctional	Interleukin activity can be determined using	inflammatory disorders,
interleukin-6	Accession		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al., in	immunologic disorders,
	R49041		monocytes, and macrophages. Known	Lymphokines and Interferens: A Practical	cancer
			functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,
			of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225; and
			cells, eosinophils, and lymphocytes),	Aarden et al (1987) Eur. J. Immunol 17,
			chemotaxis of neutrophils and T	1411-16.
			lymphocytes, and/or inhibition of
			interferons.
Mutant Interleukin 6	GeneSeq	WO9411402	Interleukins are a group of multifunctional	Interleukin activity can be determined using	inflammatory disorders,
S176R	Accession		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al., in	immunologic disorders,
	R54990		monocytes, and macrophages. Known	Lymphokines and Interferens: A Practical	cancer
			functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,
			of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225; and
			cells, eosinophils, and lymphocytes),	Aarden et al (1987) Eur. J. Immunol 17,
			chemotaxis of neutrophils and T	1411-16.
			lymphocytes, and/or inhibition of
			interferons.
Interleukin 6	GeneSeq	JP06145063	Interleukins are a group of multifunctional	Interleukin activity can be determined using	inflammatory disorders,
	Accession		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al., in	immunologic disorders,
	R55256		monocytes, and macrophages. Known	Lymphokines and Interferens: A Practical	cancer
			functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,
			of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225; and
			cells, eosinophils, and lymphocytes),	Aarden et al (1987) Eur. J. Immunol 17,
			chemotaxis of neutrophils and T	1411-16.
			lymphocytes, and/or inhibition of
			interferons.
Interleukin 8	GeneSeq	JP06100595	Interleukins are a group of multifunctional	Interleukin activity can be determined using	Soluble IL-8 receptor
(IL-8) receptor	Accession		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al., in	polypeptides may be useful
	R53932		monocytes, and macrophages. Known	Lymphokines and Interferens: A Practical	for inhibiting interleukin
			functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,	activities.
			of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225; and
			cells, eosinophils, and lymphocytes),	Holmes et al (1991) Science 253, 1278-80.
			chemotaxis of neutrophils and T
			lymphocytes, and/or inhibition of
			interferons.
Human	GeneSeq	U.S. Pat. No. 5,328,988	Interleukins are a group of multifunctional	Interleukin activity can be determined using	inflammatory disorders,
interleukin-7	Accession		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al., in	immunologic disorders,
	R59919		monocytes, and macrophages. Known	Lymphokines and Interferens: A Practical	cancer
			functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,
			of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225; and
			cells, eosinophils, and lymphocytes),	Park et al (1990) J. Exp. Med. 171, 1073-79.
			chemotaxis of neutrophils and T
			lymphocytes, and/or inhibition of
			interferons.
IL-3 containing	GeneSeq	WO9521254	Interleukins are a group of multifunctional	Interleukin activity can be determined using	inflammatory disorders,
fusion protein.	Accession		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al., in	immunologic disorders,
	R79342 and		monocytes, and macrophages. Known	Lymphokines and Interferens: A Practical	cancer
	R79344		functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,
			of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225; and
			cells, eosinophils, and lymphocytes),	Kitamura et al (1989) J Cell Physiol. 140
			chemotaxis of neutrophils and T	323-334.
			lymphocytes, and/or inhibition of
			interferons.
IL-3 mutant	GeneSeq	ZA9402636	Interleukins are a group of multifunctional	Interleukin activity can be determined using	inflammatory disorders,
proteins	Accession		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al., in	immunologic disorders,
	R79254, R79255,		monocytes, and macrophages. Known	Lymphokines and Interferens: A Practical	cancer
	R79256, R79257,		functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,
	R79258, R79259,		of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225; and
	R79260, R79261,		cells, eosinophils, and lymphocytes),	Giri et al (1994) EMBO J. 13 2822-2830.
	R79262, R79263,		chemotaxis of neutrophils and T
	R79264, R79265,		lymphocytes, and/or inhibition of
	R79266, R79267,		interferons.
	R79268, R79269,
	R79270, R79271,
	R79272, R79273,
	R79274, R79275,
	R79276, R79277,
	R79278, R79279,
	R79280, R79281,
	R79282, R79283,
	R79284, and
	R79285
IL-12 p40	GeneSeq	AU9466072	Interleukins are a group of multifunctional	Interleukin activity can be determined using	inflammatory disorders,
subunit.	Accession		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al., in	immunologic disorders,
	R63018		monocytes, and macrophages. Known	Lymphokines and Interferens: A Practical	cancer
			functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,
			of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225.
			cells, eosinophils, and lymphocytes),
			chemotaxis of neutrophils and T
			lymphocytes, and/or inhibition of
			interferons.
AGF	GeneSeq	WO9429344	Interleukins are a group of multifunctional	Interleukin activity can be determined using	inflammatory disorders,
	Accession		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al., in	immunologic disorders,
	R64240		monocytes, and macrophages. Known	Lymphokines and Interferens: A Practical	cancer
			functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,
			of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225.
			cells, eosinophils, and lymphocytes),
			chemotaxis of neutrophils and T
			lymphocytes, and/or inhibition of
			interferons.
Human	GeneSeq	WO9519786	Interleukins are a group of multifunctional	Interleukin activity can be determined using	inflammatory disorders,
interlaukin-12 40 kD	Accession		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al., in	immunologic disorders,
subunit	R79187		monocytes, and macrophages. Known	Lymphokines and Interferens: A Practical	cancer
			functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,
			of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225; and
			cells, eosinophils, and lymphocytes),	Hori et al (1987), Blood 70, 1069-1078.
			chemotaxis of neutrophils and T
			lymphocytes, and/or inhibition of
			interferons.
Human	GeneSeq	WO9530695	Interleukins are a group of multifunctional	Interleukin activity can be determined using	Soluble IL-8 receptor
interleukin-15	Accession		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al., in	polypeptides may be useful
receptor from	R90843		monocytes, and macrophages. Known	Lymphokines and Interferens: A Practical	for inhibiting interleukin
clone P1			functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,	activities.
			of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225; and
			cells, eosinophils, and lymphocytes),	Giri et al (1994) EMBO J. 13 2822-2830.
			chemotaxis of neutrophils and T
			lymphocytes, and/or inhibition of
			interferons.
Human	GeneSeq	WO9604306	Interleukins are a group of multifunctional	Interleukin activity can be determined using	inflammatory disorders,
interleukin-7	Accession		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al., in	immunologic disorders,
	R92796		monocytes, and macrophages. Known	Lymphokines and Interferens: A Practical	cancer
			functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,
			of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225; and
			cells, eosinophils, and lymphocytes),	Park et al (1990) J. Exp. Med. 171, 1073-79.
			chemotaxis of neutrophils and T
			lymphocytes, and/or inhibition of
			interferons.
interleukin-9	GeneSeq	WO9604306	Interleukins are a group of multifunctional	Interleukin activity can be determined using	inflammatory disorders,
	Accession		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al., in	immunologic disorders,
	R92797		monocytes, and macrophages. Known	Lymphokines and Interferens: A Practical	cancer
			functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,
			of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225; and
			cells, eosinophils, and lymphocytes),	Yang et al (1989) Blood 74, 1880-84.
			chemotaxis of neutrophils and T
			lymphocytes, and/or inhibition of
			interferons.
interleukin-3	GeneSeq	WO9604306	Interleukins are a group of multifunctional	Interleukin activity can be determined using	inflammatory disorders,
	Accession		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al., in	immunologic disorders,
	R92801		monocytes, and macrophages. Known	Lymphokines and Interferens: A Practical	cancer
			functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,
			of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225; and
			cells, eosinophils, and lymphocytes),	Kitamura et al (1989) J Cell Physiol. 140
			chemotaxis of neutrophils and T	323-334.
			lymphocytes, and/or inhibition of
			interferons.
Human	GeneSeq	WO9604306	Interleukins are a group of multifunctional	Interleukin activity can be determined using	inflammatory disorders,
interleukin-5	Accession		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al., in	immunologic disorders,
	R92802		monocytes, and macrophages. Known	Lymphokines and Interferens: A Practical	cancer
			functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,
			of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225; and
			cells, eosinophils, and lymphocytes),	Kitamura et al (1989) J Cell Physiol. 140
			chemotaxis of neutrophils and T	323-334.
			lymphocytes, and/or inhibition of
			interferons.
Recombinant	GeneSeq	DE19617202	Interleukins are a group of multifunctional	Interleukin activity can be determined using	inflammatory disorders,
interleukin-16	Accession		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al., in	immunologic disorders,
	W33373		monocytes, and macrophages. Known	Lymphokines and Interferens: A Practical	cancer
			functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,
			of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225; and
			cells, eosinophils, and lymphocytes),	Lim et al (1996) J. Immunol. 156, 2566-70.
			chemotaxis of neutrophils and T
			lymphocytes, and/or inhibition of
			interferons.
Human IL-16	GeneSeq	DE19617202	Interleukins are a group of multifunctional	Interleukin activity can be determined using	inflammatory disorders,
protein	Accession		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al., in	immunologic disorders,
	W33234		monocytes, and macrophages. Known	Lymphokines and Interferens: A Practical	cancer
			functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,
			of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225; and
			cells, eosinophils, and lymphocytes),	Lim et al (1996) J. Immunol. 156, 2566-70.
			chemotaxis of neutrophils and T
			lymphocytes, and/or inhibition of
			interferons.
Thrl 17 human	GeneSeq	WO9708321	Interleukins are a group of multifunctional	Interleukin activity can be determined using	inflammatory disorders,
interleukin 9	Accession		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al., in	immunologic disorders,
	W27521		monocytes, and macrophages. Known	Lymphokines and Interferens: A Practical	cancer
			functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,
			of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225.
			cells, eosinophils, and lymphocytes),
			chemotaxis of neutrophils and T
			lymphocytes, and/or inhibition of
			interferons.
Metl 17 human	GeneSeq	WO9708321	Interleukins are a group of multifunctional	Interleukin activity can be determined using	inflammatory disorders,
interleukin 9	Accession		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al., in	immunologic disorders,
	W27522		monocytes, and macrophages. Known	Lymphokines and Interferens: A Practical	cancer
			functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,
			of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225; and
			cells, eosinophils, and lymphocytes),	Yang et al (1989) Blood 74, 1880-84.
			chemotaxis of neutrophils and T
			lymphocytes, and/or inhibition of
			interferons.
Human	GeneSeq	EP86-4585	Interleukins are a group of multifunctional	Interleukin activity can be determined using	inflammatory disorders,
intracellular IL-1	Accession		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al., in	immunologic disorders,
receptor	W77158		monocytes, and macrophages. Known	Lymphokines and Interferens: A Practical	cancer
antagonist.			functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,
			of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225; and
			cells, eosinophils, and lymphocytes),	Orencole & Dinarello (1989) Cytokine 1,
			chemotaxis of neutrophils and T	14-20.
			lymphocytes, and/or inhibition of
			interferons.
Human	GeneSeq	EP864585	Interleukins are a group of multifunctional	Interleukin activity can be determined using	inflammatory disorders,
interleukin-18	Accession		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al., in	immunologic disorders,
protein (IL-18)	W77158		monocytes, and macrophages. Known	Lymphokines and Interferens: A Practical	cancer
			functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,
			of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225; and
			cells, eosinophils, and lymphocytes),	USHIO et al (1996) J. Immunol. 156, 4274-79.
			chemotaxis of neutrophils and T
			lymphocytes, and/or inhibition of
			interferons.
Human	GeneSeq	EP861663	Interleukins are a group of multifunctional	Interleukin activity can be determined using	inflammatory disorders,
interleukin-18	Accession		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al., in	immunologic disorders,
	W77077		monocytes, and macrophages. Known	Lymphokines and Interferens: A Practical	cancer
			functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,
			of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225; and
			cells, eosinophils, and lymphocytes),	USHIO et al (1996) J. Immunol. 156, 4274-79.
			chemotaxis of neutrophils and T
			lymphocytes, and/or inhibition of
			interferons.
Human interleukin	GeneSeq	EP861663	Interleukins are a group of multifunctional	Interleukin activity can be determined using	inflammatory disorders,
18 derivatives	Accessions		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al.,	immunologic disorders,
	W77083,		monocytes, and macrophages. Known	in Lymphokines and Interferons: A Practical	cancer
	W77084,		functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,
	W77085,		of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225; and
	W77086,		cells, eosinophils, and lymphocytes),	Ushio et al (1996) J. Immunol, 156, 4274-79.
	W77087,		chemotaxis of neutrophils and T
	W77088, and		lymphocytes, and/or inhibition of
	W77089		interferons.
Interleukin-9	GeneSeq	WO9827997	Interleukins are a group of multifunctional	Interleukin activity can be determined using	inflammatory disorders,
(IL-9) mature	Accession		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al.,	immunologic disorders,
protein (Thr117	W68158		monocytes, and macrophages. Known	in Lymphokines and Interferons: A Practical	cancer
version).			functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,
			of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225; and
			cells, eosinophils, and lymphocytes),	Yang et al (1989) Blood 74, 1880-84.
			chemotaxis of neutrophils and T
			lymphocytes, and/or inhibition of
			interferons.
IL-9 mature	GenSeq Accession	WO9827997	Interleukins are a group of multifunctional	Interleukin activity can be determined using	inflammatory disorders,
protein variant	W68157		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al.,	immunologic disorders,
(Met117 version)			monocytes, and macrophages. Known	in Lymphokines and Interferons: A Practical	cancer
			functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,
			of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225; and
			cells, eosinophils, and lymphocytes),	Yang et al (1989) Blood 74, 1880-84.
			chemotaxis of neutrophils and T
			lymphocytes, and/or inhibition of
			interferons.
Human IL-9	GeneSeq	WO9824904	Interleukins are a group of multifunctional	Interleukin activity can be determined using	inflammatory disorders,
receptor protein	Accession		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al.,	immunologic disorders,
variant #3.	W64058		monocytes, and macrophages. Known	in Lymphokines and Interferons: A Practical	cancer
			functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,
			of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225; and
			cells, eosinophils, and lymphocytes),	Yang et al (1989) Blood 74, 1880-84.
			chemotaxis of neutrophils and T
			lymphocytes, and/or inhibition of
			interferons.
Human IL-9	GenSeq Accession	WO9824904	Interleukins are a group of multifunctional	Interleukin activity can be determined using	Soluble IL-9 receptor
receptor protein	W64060		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al.,	polypeptides may be useful
variant fragment			monocytes, and macrophages. Known	in Lymphokines and Interferons: A Practical	for inhibiting interleukin
			functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,	activities.
			of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225; and
			cells, eosinophils, and lymphocytes),	Yang et al (1989) Blood 74, 1880-84.
			chemotaxis of neutrophils and T
			lymphocytes, and/or inhibition of
			interferons.
Human IL-9	GeneSeq	WO9824904	Interleukins are a group of multifunctional	Interleukin activity can be determined using	Soluble IL-9 receptor
receptor protein	Accession		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al.,	polypeptides may be useful
variant #
3.	W64061		monocytes, and macrophages. Known	in Lymphokines and Interferons: A Practical	for inhibiting interleukin
			functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,	activities.
			of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225; and
			cells, eosinophils, and lymphocytes),	Yang et al (1989) Blood 74, 1880-84.
			chemotaxis of neutrophils and T
			lymphocytes, and/or inhibition of
			interferons.
Human	GeneSeq	WO9817689	Interleukins are a group of multifunctional	Interleukin activity can be determined using	inflammatory disorders,
Interleukin-12 p40	Accession		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al.,	immunologic disorders,
protein	W51311		monocytes, and macrophages. Known	in Lymphokines and Interferons: A Practical	cancer
			functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,
			of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225; and
			cells, eosinophils, and lymphocytes),	Hori et al (1987), Blood 70, 1069-1078.
			chemotaxis of neutrophils and T
			lymphocytes, and/or inhibition of
			interferons.
Human	GeneSeq	WO9817689	Interleukins are a group of multifunctional	Interleukin activity can be determined using	inflammatory disorders,
Interleukin-12 p35	Accession		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al.,	immunologic disorders,
protein	W51312		monocytes, and macrophages. Known	in Lymphokines and Interferons: A Practical	cancer
			functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,
			of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225; and
			cells, eosinophils, and lymphocytes),	Hori et al (1987), Blood 70, 1069-1078.
			chemotaxis of neutrophils and T
			lymphocytes, and/or inhibition of
			interferons.
Human protein	GeneSeq	DE19649233-	Interleukins are a group of multifunctional	Interleukin activity can be determined using	inflammatory disorders,
with IL-16 activity	Accession		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al.,	immunologic disorders,
	W63753		monocytes, and macrophages. Known	in Lymphokines and Interferons: A Practical	cancer
			functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,
			of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225; and
			cells, eosinophils, and lymphocytes),	Lim et al (1996) J. Immunol. 156, 2566-70.
			chemotaxis of neutrophils and T
			lymphocytes, and/or inhibition of
			interferons.
Human protein	GeneSeq	DE19649233-	Interleukins are a group of multifunctional	Interleukin activity can be determined using	inflammatory disorders,
with IL-16 activity	Accession		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al.,	immunologic disorders,
	W59425		monocytes, and macrophages. Known	in Lymphokines and Interferons: A Practical	cancer
			functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,
			of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225; and
			cells, eosinophils, and lymphocytes),	Lim et al (1996) J. Immunol. 156, 2566-70.
			chemotaxis of neutrophils and T
			lymphocytes, and/or inhibition of
			interferons.
Human	GeneSeq	U.S. Pat. No. 5,747,024	Interleukins are a group of multifunctional	Interleukin activity can be determined using	inflammatory disorders,
interleukin-15	Accession		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al.,	immunologic disorders,
	W53878		monocytes, and macrophages. Known	in Lymphokines and Interferons: A Practical	cancer
			functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,
			of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225; and
			cells, eosinophils, and lymphocytes),	Giri et al (1994) EMBO J. 13 2822-2830.
			chemotaxis of neutrophils and T
			lymphocytes, and/or inhibition of
			interferons.
Human wild-type	GeneSeq	WO9747744	Interleukins are a group of multifunctional	Interleukin activity can be determined using	inflammatory disorders,
interleukin-4 (hIL-	Accession		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al.,	immunologic disorders,
4) protein	W52149		monocytes, and macrophages. Known	in Lymphokines and Interferons: A Practical	cancer
			functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,
			of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225; and
			cells, eosinophils, and lymphocytes),	Siegel & Mostowski (1990) J Immunol
			chemotaxis of neutrophils and T	Methods 132, 287-295.
			lymphocytes, and/or inhibition of
			interferons.
interleukin-4	GeneSeq	WO9747744	Interleukins are a group of multifunctional	Interleukin activity can be determined using	inflammatory disorders,
muteins	Accessions		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al.,	immunologic disorders,
	W52150,		monocytes, and macrophages. Known	in Lymphokines and Interferons: A Practical	cancer
	W52151,		functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,
	W52153,		of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225; and
	W52154,		cells, eosinophils, and lymphocytes),	Siegel & Mostowski (1990) J Immunol
	W52155,		chemotaxis of neutrophils and T	Methods 132, 287-295.
	W52156,		lymphocytes, and/or inhibition of
	W52157,		interferons.
	W52158,
	W52159,
	W52160,
	W52161,
	W52162,
	W52163,
	W52164,
	W52165,
	W52166, and
	W52167
Human interleukin	GeneSeq	WO9935268	Interleukins are a group of multifunctional	Interleukin activity can be determined using	inflammatory disorders,
1 delta	Accession		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al.,	immunologic disorders,
	Y28408		monocytes, and macrophages. Known	in Lymphokines and Interferons: A Practical	cancer
			functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,
			of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225; and
			cells, eosinophils, and lymphocytes),	Orencole & Dinarello (1989) Cytokine 1,
			chemotaxis of neutrophils and T	14-20.
			lymphocytes, and/or inhibition of
			interferons.
Human	GeneSeq	WO9935268	Interleukins are a group of multifunctional	Interleukin activity can be determined using	inflammatory disorders,
interleukin-1	Accession		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al.,	immunologic disorders,
receptor	Y24395		monocytes, and macrophages. Known	in Lymphokines and Interferons: A Practical	cancer
antagonist beta			functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,
			of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225; and
			cells, eosinophils, and lymphocytes),	Orencole & Dinarello (1989) Cytokine 1,
			chemotaxis of neutrophils and T	14-20.
			lymphocytes, and/or inhibition of
			interferons.
Human EDIRF II	GeneSeq	WO9932632	Interleukins are a group of multifunctional	Interleukin activity can be determined using	inflammatory disorders,
protein sequence	Accession		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al.,	immunologic disorders,
	Y22199		monocytes, and macrophages. Known	in Lymphokines and Interferons: A Practical	cancer
			functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,
			of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225.
			cells, eosinophils, and lymphocytes),
			chemotaxis of neutrophils and T
			lymphocytes, and/or inhibition of
			interferons.
Human EDIRF I	GeneSeq	WO9932632	Interleukins are a group of multifunctional	Interleukin activity can be determined using	inflammatory disorders,
protein sequence	Accession		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al.,	immunologic disorders,
	Y22197		monocytes, and macrophages. Known	in Lymphokines and Interferons: A Practical	cancer
			functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,
			of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225.
			cells, eosinophils, and lymphocytes),
			chemotaxis of neutrophils and T
			lymphocytes, and/or inhibition of
			interferons.
Human IL-1RD10	GeneSeq	WO9919480	Interleukins are a group of multifunctional	Interleukin activity can be determined using	Soluble IL-1RD10 receptor
protein sequence	Accession		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al.,	polypeptides may be useful
	Y14131		monocytes, and macrophages. Known	in Lymphokines and Interferons: A Practical	for inhibiting interleukin
			functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,	activites.
			of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225; and
			cells, eosinophils, and lymphocytes),	Orencole & Dinarello (1989) Cytokine 1,
			chemotaxis of neutrophils and T	14-20.
			lymphocytes, and/or inhibition of
			interferons.
Human IL-1RD9	GeneSeq	WO9919480	Interleukins are a group of multifunctional	Interleukin activity can be determined using	Soluble IL-1RD10 receptor
	Accession		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al.,	polypeptides may be useful
	Y14122		monocytes, and macrophages. Known	in Lymphokines and Interferons: A Practical	for inhibiting interleukin
			functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,	activites.
			of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225; and
			cells, eosinophils, and lymphocytes),	Orencole & Dinarello (1989) Cytokine 1,
			chemotaxis of neutrophils and T	14-20.
			lymphocytes, and/or inhibition of
			interferons.
Human DNAX	GeneSeq	WO9919491	Interleukins are a group of multifunctional	Interleukin activity can be determined using	inflammatory disorders,
interleukin-40	Accession		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al.,	immunologic disorders,
	Y09196		monocytes, and macrophages. Known	in Lymphokines and Interferons: A Practical	cancer
			functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,
			of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225.
			cells, eosinophils, and lymphocytes),
			chemotaxis of neutrophils and T
			lymphocytes, and/or inhibition of
			interferons.
(DIL-40)	GeneSeq	WO9919491	Interleukins are a group of multifunctional	Interleukin activity can be determined using	inflammatory disorders,
alternative	Accession		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al.,	immunologic disorders,
sequence	Y09197		monocytes, and macrophages. Known	in Lymphokines and Interferons: A Practical	cancer
			functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,
			of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225.
			cells, eosinophils, and lymphocytes),
			chemotaxis of neutrophils and T
			lymphocytes, and/or inhibition of
			interferons.
IL-11	GeneSeq	WO9405318	Interleukins are a group of multifunctional	Interleukin activity can be determined using	inflammatory disorders,
	Accession		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al.,	immunologic disorders,
	R50176		monocytes, and macrophages. Known	in Lymphokines and Interferons: A Practical	cancer
			functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,
			of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225; and
			cells, eosinophils, and lymphocytes),	Lu et al (1994) J immunol. Methods 173,
			chemotaxis of neutrophils and T	19.
			lymphocytes, and/or inhibition of
			interferons.
Human	GeneSeq	EP566410	Interleukins are a group of multifunctional	Interleukin activity can be determined using	inflammatory disorders,
adipogenesis	Accession		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al.,	immunologic disorders,
inhibitory factor	R43260		monocytes, and macrophages. Known	in Lymphokines and Interferons: A Practical	cancer
			functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,
			of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225.
			cells, eosinophils, and lymphocytes),
			chemotaxis of neutrophils and T
			lymphocytes, and/or inhibition of
			interferons.
IL-11	GeneSeq	JP08127539	Interleukins are a group of multifunctional	Interleukin activity can be determined using	inflammatory disorders,
	Accession		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al.,	immunologic disorders,
	W02202		monocytes, and macrophages. Known	in Lymphokines and Interferons: A Practical	cancer
			functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,
			of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225; and
			cells, eosinophils, and lymphocytes),	Lu et al (1994) J immunol. Methods 173,
			chemotaxis of neutrophils and T	19.
			lymphocytes, and/or inhibition of
			interferons.
IL-14	GeneSeq	WO9416074	Interleukins are a group of multifunctional	Interleukin activity can be determined using	inflammatory disorders,
	Accession		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al.,	immunologic disorders,
	R55800		monocytes, and macrophages. Known	in Lymphokines and Interferons: A Practical	cancer
			functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,
			of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225; and
			cells, eosinophils, and lymphocytes),	Ambrus et al (1993) PNAS 90, 63330-34.
			chemotaxis of neutrophils and T
			lymphocytes, and/or inhibition of
			interferons.
IL-17 receptor	GeneSeq	U.S. Pat. No. 6,072,033	Interleukins are a group of multifunctional	Interleukin activity can be determined using	Soluble IL-17 receptor
	Accession		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al.,	polypeptides may be useful
	B03807		monocytes, and macrophages. Known	in Lymphokines and Interferons: A Practical	for inhibiting interleukin
			functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,	activities.
			of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225; and
			cells, eosinophils, and lymphocytes),	Yao et al (1995) J. Immunol. 155, 5483-86.
			chemotaxis of neutrophils and T
			lymphocytes, and/or inhibition of
			interferons.
IL-17	GeneSeq	WO9518826	Interleukins are a group of multifunctional	Interleukin activity can be determined using	inflammatory disorders,
	Accession		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al.,	immunologic disorders,
	R76573		monocytes, and macrophages. Known	in Lymphokines and Interferons: A Practical	cancer
			functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,
			of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225; and
			cells, eosinophils, and lymphocytes),	Yao et al (1995) J. Immunol. 155, 5483-86.
			chemotaxis of neutrophils and T
			lymphocytes, and/or inhibition of
			interferons.
CTLA-8	GeneSeq	WO9704097	Interleukins are a group of multifunctional	Interleukin activity can be determined using	inflammatory disorders,
	Accession		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al.,	immunologic disorders,
	W13651		monocytes, and macrophages. Known	in Lymphokines and Interferons: A Practical	cancer
			functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,
			of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225.
			cells, eosinophils, and lymphocytes),
			chemotaxis of neutrophils and T
			lymphocytes, and/or inhibition of
			interferons.
IL-19	GeneSeq	WO9808870	Interleukins are a group of multifunctional	Interleukin activity can be determined using	inflammatory disorders,
	Accession		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al.,	immunologic disorders,
	W37935		monocytes, and macrophages. Known	in Lymphokines and Interferons: A Practical	cancer
			functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,
			of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225; and
			cells, eosinophils, and lymphocytes),	Gallagher et al (2000) Genes Immun. 1,
			chemotaxis of neutrophils and T	442-50.
			lymphocytes, and/or inhibition of
			interferons.
IL-21 (TIF)	GeneSeq	WO0024758	Interleukins are a group of multifunctional	Interleukin activity can be determined using	inflammatory disorders,
	Accession		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al.,	immunologic disorders,
	Y92879		monocytes, and macrophages. Known	in Lymphokines and Interferons: A Practical	cancer
			functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,
			of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225; and
			cells, eosinophils, and lymphocytes),	Parrish-Novak et al (2000) Nature 408, 57-63.
			chemotaxis of neutrophils and T
			lymphocytes, and/or inhibition of
			interferons.
IL-8 receptor	GeneSeq	WO9306229	Interleukins are a group of multifunctional	Interleukin activity can be determined using	Soluble IL-8 receptor
	Accession		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al.,	polypeptides may be useful
	R33420		monocytes, and macrophages. Known	in Lymphokines and Interferons: A Practical	for inhibiting interleukin
			functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,	activities.
			of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225; and
			cells, eosinophils, and lymphocytes),	Holmes et al (1991) Science 253, 1278-80..
			chemotaxis of neutrophils and T
			lymphocytes, and/or inhibition of
			interferons.
Human type II	GeneSeq	U.S. Pat. No. 5,464,937	Interleukins are a group of multifunctional	Interleukin activity can be determined using	Soluble type II interleukin-1
interleukin-1	Accession		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al.,	receptor polypeptides may
receptor	R85480		monocytes, and macrophages. Known	in Lymphokines and Interferons: A Practical	be useful for inhibiting
			functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,	interleukin activities.
			of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225; and
			cells, eosinophils, and lymphocytes),	Orencole & Dinarello (1989) Cytokine 1,
			chemotaxis of neutrophils and T	14-20.
			lymphocytes, and/or inhibition of
			interferons.
Human	GeneSeq	EP638644	Interleukins are a group of multifunctional	Interleukin activity can be determined using	Soluble IL-12 receptor
interleukin-12	Accession		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al.,	polypeptides may be useful
receptor	R69632		monocytes, and macrophages. Known	in Lymphokines and Interferons: A Practical	for inhibiting interleukin
			functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,	activities.
			of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225; and
			cells, eosinophils, and lymphocytes),	Hori et al (1987), Blood 70, 1069-1078.
			chemotaxis of neutrophils and T
			lymphocytes, and/or inhibition of
			interferons.
Interleukin 8	GeneSeq	U.S. Pat. No. 5,440,021	Interleukins are a group of multifunctional	Interleukin activity can be determined using	Soluble IL-8 receptor B
receptor B	Accession		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al.,	polypeptides may be useful
	R80758		monocytes, and macrophages. Known	in Lymphokines and Interferons: A Practical	for inhibiting interleukin
			functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,	activities.
			of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225; and
			cells, eosinophils, and lymphocytes),	Holmes et al (1991) Science 253, 1278-80.
			chemotaxis of neutrophils and T
			lymphocytes, and/or inhibition of
			interferons.
Human IL-8	GeneSeq	JP08103276	Interleukins are a group of multifunctional	Interleukin activity can be determined using	Soluble IL-8 receptor A
receptor protein	Accession B09989		cytokines synthesized by lymphocytes,	assays known in the art: Matthews et al.,	polypeptides may be useful
hIL8RA			monocytes, and macrophages. Known	in Lymphokines and Interferons: A Practical	for inhibiting interleukin
			functions include stimulating proliferation	Approach, Clemens et al., eds, IRL Press,	activities.
			of immune cells (e.g., T helper cells, B	Washington, D.C. 1987, pp. 221-225; and
			cells, eosinophils, and lymphocytes),	Holmes et al (1991) Science 253, 1278-80.
			chemotaxis of neutrophils and T
			lymphocytes, and/or inhibition of
			interferons.
Human IL-8	GeneSeq	JP08103276	Interleukins are a group of multifunctional	Interleukin activity can be determined	Soluble IL-8 receptor
receptor protein	Accession B09990		cytokines synthesized by lymphocytes,	using asays known in the art: Matthews et	polypeptides may be
hIL8R			monocytes, and macrophages. Known	al., in Lymphokines and Interferons: A	useful for inhibiting
			functions include stimulating proliferation	Practical Approach, Clemens et al., eds,	interleukin activities.
			of immune cells (e.g., T helper cells, B	IRL Press, Washington, D.C. 1987, pp.
			cells, eosinophils, and lymphocytes),	221-225; and Holmes et al (1991) Science
			chemotaxis of neutrophils and T	253, 1278-80.
			lymphocytes, and/or inhibition of
			interferons.
Interleukin-2	GeneSeq	WO9621732-	Interleukins are a group of multifunctional	Interleukin activity can be determined	Soluble IL-2 receptor
receptor	Accession		cytokines synthesized by lymphocytes,	using assays known in the art: Matthews	polypeptides may be
associated protein	R97569		monocytes, and macrophages. Known	et al., in Lymphokines and Interferons: A	useful for inhibiting
p43			functions include stimulating proliferation	Practical Approach, Clemens et al., eds,	interleukin activities.
			of immune cells (e.g., T helper cells, B	IRL Press, Washington, D.C. 1987, pp.
			cells, eosinophils, and lymphocytes),	221-225; and Gillis et al (1978) J.
			chemotaxis of neutrophils and T	Immunol. 120, 2027.
			lymphocytes, and/or inhibition of
			interferons.
Human	GeneSeq	WO9629408	Interleukins are a group of multifunctional	Interleukin activity can be determined	Soluble IL-17 receptor
interleukin-17	Accession		cytokines synthesized by lymphocytes,	using assays known in the art: Matthews	polypeptides may be
receptor	W04185		monocytes, and macrophages. Known	et al., in Lymphokines and Interferons: A	useful for inhibiting
			functions include stimulating proliferation	Practical Approach, Clemens et al., eds,	interleukin activities.
			of immune cells (e.g., T helper cells, B	IRL Press, Washington, D.C. 1987, pp.
			cells, eosinophils, and lymphocytes),	221-225; and Yao et al (1995) J. Immunol.
			chemotaxis of neutrophils and T	155, 5483-86.
			lymphocytes, and/or inhibition of
			interferons.
Human	GeneSeq	WO9619574	Interleukins are a group of multifunctional	Interleukin activity can be determined	Soluble IL-11 receptor
interleukin-11	Accession		cytokines synthesized by lymphocytes,	using assays known in the art: Matthews	polypeptides may be
receptor	R99090		monocytes, and macrophages. Known	et al., in Lymphokines and Interferons: A	useful for inhibiting
			functions include stimulating proliferation	Practical Approach, Clemens et al., eds,	interleukin activities.
			of immune cells (e.g., T helper cells, B	IRL Press, Washington, D.C. 1987, pp.
			cells, eosinophils, and lymphocytes),	221-225; and Lu et al (1994) J immunol.
			chemotaxis of neutrophils and T	Methods 173, 19.
			lymphocytes, and/or inhibition of
			interferons.
Human	GeneSeq	WO9623067	Interleukins are a group of multifunctional	Interleukin activity can be determined	Inflammatory disorders,
interleukin-1	Accession		cytokines synthesized by lymphocytes,	using assays known in the art: Matthews	immunologic disorders,
receptor	W01911		monocytes, and macrophages. Known	et al., in Lymphokines and Interferons: A	cancer
accessory protein			functions include stimulating proliferation	Practical Approach, Clemens et al., eds,
			of immune cells (e.g., T helper cells, B	IRL Press, Washington, D.C. 1987, pp.
			cells, eosinophils, and lymphocytes),	221-225; and Orencole & Dinarello (1989)
			chemotaxis of neutrophils and T	Cytokine	1, 14-20.
			lymphocytes, and/or inhibition of
			interferons.
AGF Protein	GeneSeq	U.S. Pat. No. 5,488,032	Interleukins are a group of multifunctional	Interleukin activity can be determined	Inflammatory disorders,
	Accession		cytokines synthesized by lymphocytes,	using assays known in the art: Matthews	immunologic disorders,
	R92749		monocytes, and macrophages. Known	et al., in Lymphokines and Interferons: A	cancer
			functions include stimulating proliferation	Practical Approach, Clemens et al., eds,
			of immune cells (e.g., T helper cells, B	IRL Press, Washington, D.C. 1987, pp.
			cells, eosinophils, and lymphocytes),	221-225.
			chemotaxis of neutrophils and T
			lymphocytes, and/or inhibition of
			interferons.
Human	GeneSeq	W09607739	Interleukins are a group of multifunctional	Interleukin activity can be determined	Soluble IL-type-3 receptor
interleukin-1 type-	Accession		cytokines synthesized by lymphocytes,	using assays known in the art: Matthews	polypeptides may be
3 receptor	R91064		monocytes, and macrophages. Known	et al., in Lymphokines and Interferons: A	useful for inhibiting
			functions include stimulating proliferation	Practical Approach, Clemens et al., eds,	interleukin activities
			of immune cells (e.g., T helper cells, B	IRL Press, Washington, D.C. 1987, pp.
			cells, eosinophils, and lymphocytes),	221-225; and Orencole & Dinarello (1989)
			chemotaxis of neutrophils and T	Cytokine	1, 14-20.
			lymphocytes, and/or inhibition of
			interferons.
Human	GeneSeq	WO9720926	Interleukins are a group of multifunctional	Interleukin activity can be determined	Soluble IL-13 beta
interleukin-13 beta	Accession		cytokines synthesized by lymphocytes,	using assays known in the art: Matthews	receptor polypeptides may
receptor	W24972		monocytes, and macrophages. Known	et al., in Lymphokines and Interferons: A	be useful for inhibiting
			functions include stimulating proliferation	Practical Approach, Clemens et al., eds,	interleukin activities.
			of immune cells (e.g., T helper cells, B	IRL Press, Washington, D.C. 1987, pp.
			cells, eosinophils, and lymphocytes),	221-225; and Boutelier et al (1995) J.
			chemotaxis of neutrophils and T	Immunol. Methods 181, 29.
			lymphocytes, and/or inhibition of
			interferons.
Human	GeneSeq	WO9720926	Interleukins are a group of multifunctional	Interleukin activity can be determined	Soluble IL-13 alpha
interleukin-13	Accession		cytokines synthesized by lymphocytes,	using assays known in the art: Matthews	receptor polypeptides may
alpha receptor	W24973		monocytes, and macrophages. Known	et al., in Lymphokines and Interferons: A	be useful for inhibiting
			functions include stimulating proliferation	Practical Approach, Clemens et al., eds,	interleukin activities.
			of immune cells (e.g., T helper cells, B	IRL Press, Washington, D.C. 1987, pp.
			cells, eosinophils, and lymphocytes),	221-225; and Boutelier et al (1995) J.
			chemotaxis of neutrophils and T	Immunol. Methods 181, 29.
			lymphocytes, and/or inhibition of
			interferons.
Human	GeneSeq	U.S. Pat. No. 5,599,905	Interleukins are a group of multifunctional	Interleukin activity can be determined	Soluble IL-4 receptor
interleukin-4	Accession		cytokines synthesized by lymphocytes,	using assays known in the art: Matthews	polypeptides may be
receptor	W13499		monocytes, and macrophages. Known	et al., in Lymphokines and Interferons: A	useful for inhibiting
			functions include stimulating proliferation	Practical Approach, Clemens et al., eds,	interleukin activities.
			of immune cells (e.g., T helper cells, B	IRL Press, Washington, D.C. 1987, pp.
			cells, eosinophils, and lymphocytes),	221-225; and Siegel & Mostowski (1990) J
			chemotaxis of neutrophils and T	Immunol Methods 132, 287-295.
			lymphocytes, and/or inhibition of
			interferons.
Human	GeneSeq	EP759466	Interleukins are a group of multifunctional	Interleukin activity can be determined	Soluble IL-12 beta-2
interleukin-12	Accession		cytokines synthesized by lymphocytes,	using assays known in the art: Matthews	receptor polypeptides may
beta-2 receptor	W12771		monocytes, and macrophages. Known	et al., in Lymphokines and Interferons: A	be useful for inhibiting
			functions include stimulating proliferation	Practical Approach, Clemens et al., eds,	interleukin activities.
			of immune cells (e.g., T helper cells, B	IRL Press, Washington, D.C. 1987, pp.
			cells, eosinophils, and lymphocytes),	221-225; and Hori et al (1987), Blood 70,
			chemotaxis of neutrophils and T	1069-1078.
			lymphocytes, and/or inhibition of
			interferons.
Human	GeneSeq	EP759466	Interleukins are a group of multifunctional	Interleukin activity can be determined	Soluble IL-12 beta-1
interleukin-12	Accession		cytokines synthesized by lymphocytes,	using assays known in the art: Matthews	receptor polypeptides may
beta-1 receptor.	W12772		monocytes, and macrophages. Known	et al., in Lymphokines and Interferons: A	be useful for inhibiting
			functions include stimulating proliferation	Practical Approach, Clemens et al., eds,	interleukin activities.
			of immune cells (e.g., T helper cells, B	IRL Press, Washington, D.C. 1987, pp.
			cells, eosinophils, and lymphocytes),	221-225; and Hori et al (1987), Blood 70,
			chemotaxis of neutrophils and T	1069-1078.
			lymphocytes, and/or inhibition of
			interferons.
Human IL-9	GeneSeq	WO9824904	Interleukins are a group of multifunctional	Interleukin activity can be determined	Soluble IL-9 receptor
receptor protein	Accessions		cytokines synthesized by lymphocytes,	using assays known in the art: Matthews	polypeptides may be
	W64055, W64056,		monocytes, and macrophages. Known	et al., in Lymphokines and Interferons: A	useful for inhibiting
	and W64057		functions include stimulating proliferation	Practical Approach, Clemens et al., eds,	interleukin activities.
			of immune cells (e.g., T helper cells, B	IRL Press, Washington, D.C. 1987, pp.
			cells, eosinophils, and lymphocytes),	221-225; and Yang et al (1989), Blood 74,
			chemotaxis of neutrophils and T	1880-84..
			lymphocytes, and/or inhibition of
			interferons.
IL-10 receptor	GeneSeq	U.S. Pat. No. 5,716,804	Interleukins are a group of multifunctional	Interleukin activity can be determined	Soluble IL-10 receptor
	Accession		cytokines synthesized by lymphocytes,	using assays known in the art: Matthews	polypeptides may be
	W41804		monocytes, and macrophages. Known	et al., in Lymphokines and Interferons: A	useful for inhibiting
			functions include stimulating proliferation	Practical Approach, Clemens et al., eds,	interleukin activities.
			of immune cells (e.g., T helper cells, B	IRL Press, Washington, D.C. 1987, pp.
			cells, eosinophils, and lymphocytes),	221-225; and Thompson-Snipes et al
			chemotaxis of neutrophils and T	(1991) J. Exp. Med. 173, 507-510.
			lymphocytes, and/or inhibition of
			interferons.
Human IL-6	GeneSeq	JP11196867	Interleukins are a group of multifunctional	Interleukin activity can be determined	Soluble IL-6 receptor
receptor	Accession Y30938		cytokines synthesized by lymphocytes,	using assays known in the art: Matthews	polypeptides may be
			monocytes, and macrophages. Known	et al., in Lymphokines and Interferons: A	useful for inhibiting
			functions include stimulating proliferation	Practical Approach, Clemens et al., eds,	interleukin activities.
			of immune cells (e.g., T helper cells, B	IRL Press, Washington, D.C. 1987, pp.
			cells, eosinophils, and lymphocytes),	221-225; and Aarden et al (1987) Eur. J.
			chemotaxis of neutrophils and T	Immunol	17, 1411-16.
			lymphocytes, and/or inhibition of
			interferons.
Il-17 receptor	GeneSeq	U.S. Pat. No. 6,096,305	Interleukins are a group of multifunctional	Interleukin activity can be determined	Soluble IL-17 receptor
	Accession Y97181		cytokines synthesized by lymphocytes,	using assays known in the art: Matthews	polypeptides may be
			monocytes, and macrophages. Known	et al., in Lymphokines and Interferons: A	useful for inhibiting
			functions include stimulating proliferation	Practical Approach, Clemens et al., eds,	interleukin activities.
			of immune cells (e.g., T helper cells, B	IRL Press, Washington, D.C. 1987, pp.
			cells, eosinophils, and lymphocytes),	221-225; and Yao et al (1995) J. Immunol.
			chemotaxis of neutrophils and T	155, 5483-86.
			lymphocytes, and/or inhibition of
			interferons.
Il-17 receptor	GeneSeq	U.S. Pat. No. 6,100,235	Interleukins are a group of multifunctional	Interleukin activity can be determined	Soluble IL-17 receptor
	Accession Y97131		cytokines synthesized by lymphocytes,	using assays known in the art: Matthews	polypeptides may be
			monocytes, and macrophages. Known	et al., in Lymphokines and Interferons: A	useful for inhibiting
			functions include stimulating proliferation	Practical Approach, Clemens et al., eds,	interleukin activities.
			of immune cells (e.g., T helper cells, B	IRL Press, Washington, D.C. 1987, pp.
			cells, eosinophils, and lymphocytes),	221-225; and Yao et al (1995) J. Immunol.
			chemotaxis of neutrophils and T	155, 5483-86.
			lymphocytes, and/or inhibition of
			interferons.
Human	GeneSeq	EP509826	Interleukins are a group of multifunctional	Interleukin activity can be determined	Soluble IL-3 receptor
interleukin-3	Accession		cytokines synthesized by lymphocytes,	using assays known in the art: Matthews	polypeptides may be
receptor	R25300		monocytes, and macrophages. Known	et al., in Lymphokines and Interferons: A	useful for inhibiting
			functions include stimulating proliferation	Practical Approach, Clemens et al., eds,	interleukin activities.
			of immune cells (e.g., T helper cells, B	IRL Press, Washington, D.C. 1987, pp.
			cells, eosinophils, and lymphocytes),	221-225; and Kitamura et al (1989) J Cell
			chemotaxis of neutrophils and T	Physiol. 140 323-334.
			lymphocytes, and/or inhibition of
			interferons.
Human GM-CSF	GeneSeq	WO9102063	Interleukins are a group of multifunctional	Interleukin activity can be determined	Soluble GM-CSF receptor
receptor	Accession		cytokines synthesized by lymphocytes,	using assays known in the art: Matthews	polypeptides may be
	R10919		monocytes, and macrophages. Known	et al., in Lymphokines and Interferons: A	useful for inhibiting
			functions include stimulating proliferation	Practical Approach, Clemens et al., eds,	interleukin activities.
			of immune cells (e.g., T helper cells, B	IRL Press, Washington, D.C. 1987, pp.
			cells, eosinophils, and lymphocytes),	221-225.
			chemotaxis of neutrophils and T
			lymphocytes, and/or inhibition of
			interferons.
Human IL-5	GeneSeq	EP492214	Interleukins are a group of multifunctional	Interleukin activity can be determined	Soluble IL-5 receptor
receptor alpha	Accession		cytokines synthesized by lymphocytes,	using assays known in the art: Matthews	alpha polypeptides may be
chain	R25064		monocytes, and macrophages. Known	et al., in Lymphokines and Interferons: A	useful for inhibiting
			functions include stimulating proliferation	Practical Approach, Clemens et al., eds,	interleukin activities.
			of immune cells (e.g., T helper cells, B	IRL Press, Washington, D.C. 1987, pp.
			cells, eosinophils, and lymphocytes),	221-225; and Kitamura et al (1989) J Cell
			chemotaxis of neutrophils and T	Physiol. 140, 323-334.
			lymphocytes, and/or inhibition of
			interferons.
Il-5 receptor	GeneSeq	WO9847923	Interleukins are a group of multifunctional	Interleukin activity can be determined	Soluble IL-5 receptor
	Accession		cytokines synthesized by lymphocytes,	using assays known in the art: Matthews	polypeptides may be
	W82842		monocytes, and macrophages. Known	et al., in Lymphokines and Interferons: A	useful for inhibiting
			functions include stimulating proliferation	Practical Approach, Clemens et al., eds,	interleukin activities.
			of immune cells (e.g., T helper cells, B	IRL Press, Washington, D.C. 1987, pp.
			cells, eosinophils, and lymphocytes),	221-225; and Kitamura et al (1989) J Cell
			chemotaxis of neutrophils and T	Physiol. 140, 323-334.
			lymphocytes, and/or inhibition of
			interferons.
Il-6 receptor	GeneSeq	JP05091892	Interleukins are a group of multifunctional	Interleukin activity can be determined	Soluble IL-6 receptor
	Accession		cytokines synthesized by lymphocytes,	using assays known in the art: Matthews	polypeptides may be
	R37215		monocytes, and macrophages. Known	et al., in Lymphokines and Interferons: A	useful for inhibiting
			functions include stimulating proliferation	Practical Approach, Clemens et al., eds,	interleukin activities.
			of immune cells (e.g., T helper cells, B	IRL Press, Washington, D.C. 1987, pp.
			cells, eosinophils, and lymphocytes),	221-225; and Aarden et al (1987) Eur. J.
			chemotaxis of neutrophils and T	Immunol	17, 1411-16.
			lymphocytes, and/or inhibition of
			interferons.
Human B cell	GeneSeq	AU8928720	Interleukins are a group of multifunctional	Interleukin activity can be determined	Soluble B cell stimulating
stimulating factor-	Accession P90525		cytokines synthesized by lymphocytes,	using assays known in the art: Matthews	factor-2 receptor
2 receptor			monocytes, and macrophages. Known	et al., in Lymphokines and Interferons: A	polypeptides may be
			functions include stimulating proliferation	Practical Approach, Clemens et al., eds,	useful for inhibiting
			of immune cells (e.g., T helper cells, B	IRL Press, Washington, D.C. 1987, pp.	interleukin activities.
			cells, eosinophils, and lymphocytes),	221-225.
			chemotaxis of neutrophils and T
			lymphocytes, and/or inhibition of
			interferons.
IL-7 receptor	GeneSeq	EP403114	Interleukins are a group of multifunctional	Interleukin activity can be determined	Soluble IL-7 receptor
clone	Accession		cytokines synthesized by lymphocytes,	using assays known in the art: Matthews	polypeptides may be
	R08330		monocytes, and macrophages. Known	et al., in Lymphokines and Interferons: A	useful for inhibiting
			functions include stimulating proliferation	Practical Approach, Clemens et al., eds,	interleukin activities.
			of immune cells (e.g., T helper cells, B	IRL Press, Washington, D.C. 1987, pp.
			cells, eosinophils, and lymphocytes),	221-225; and Park et al (1990) J. Exp.
			chemotaxis of neutrophils and T	Med. 171, 1073-79.
			lymphocytes, and/or inhibition of
			interferons.
EPO receptor;	GeneSeq	WO9008822	EPO Receptor is involved in the	EPO Receptor activity can be determined	Inflammatory disorders,
EPOR	Accession		proliferation and differentiation of	using assays known in the art, such as, J	immunologic disorders,
	R06512		erythroblasts.	Biol Chem	2001 Mar 23; 276(12: 8995-9002;	cancer, erythroblast
				JAK2 protein tyrosine kinase	proliferation and
				activity: Blood 1994 Sep 1; 84(5): 1501-7	differentiation
				and Mol Cell Biol. 1994 Oct; 14(10: 6506-14.
IL-15 receptor	GeneSeq	WO9530695	Interleukins are a group of multifunctional	Interleukin activity can be determined	Soluble IL-15 receptor
	Accession		cytokines synthesized by lymphocytes,	using assays known in the art: Matthews	polypeptides may be
	R90843		monocytes, and macrophages. Known	et al., in Lymphokines and Interferons: A	useful for inhibiting
			functions include stimulating proliferation	Practical Approach, Clemens et al., eds,	interleukin activities.
			of immune cells (e.g., T helper cells, B	IRL Press, Washington, D.C. 1987, pp.
			cells, eosinophils, and lymphocytes),	221-225; and Giri et al (1994) EMBO J. 13
			chemotaxis of neutrophils and T	2822-2830.
			lymphocytes, and/or inhibition of
			interferons.
CD137; 4-1BB	GeneSeq	WO9507984	Activities associated with apoptosis, NF-	Apoptosis activity, NF-kB activation, and B	Soluble 4-1BB receptor
Receptor Protein	Accession		kB activation, and co-stimulation of	and T cell co-stimulation can be	polypeptides may be
	R70977		immune cells such as T and B cells.	determined using assays known in the art:	useful for inhibiting
				Moore et al., 1999, Science,	apoptosis, NF-kB
				285(5425): 260-3; Song HY et al., 1997	activation, and/or co-
				Proc Natl Acad Sci USA 94(18): 9792-6;	stimulation of immune
				Epsevik and Nissen-Meyer, 1986, J.	cells such as B and T
				Immunol. Methods.	cells.
BCMA	GeneSeq	WO0068378	Activities associated with apoptosis, NF-	Apoptosis activity, NF-kB activation, and B	Soluble BCMA receptor
	Accession Y71979		kB activation, and co-stimulation of	and T cell co-stimulation can be	polypeptides may be
			immune cells such as T and B cells.	determined using assays known in the art:	useful for inhibiting
				Moore et al., 1999, Science,	apoptosis, NF-kB
				285(5425): 260-3; Song HY et al., 1997	activation, and/or co-
				Proc Natl Acad Sci USA 94(18): 9792-6;	stimulation of immune
				Epsevik and Nissen-Meyer, 1986, J.	cells such as B and T
				Immunol. Methods.	cells.
CD27	GeneSeq	WO9201049	Activities associated with apoptosis, NF-	Apoptosis activity, NF-kB activation, and B	Soluble CD27
	Accession		kB activation, and co-stimulation of	and T cell co-stimulation can be	polypeptides may be
	R20814		immune cells such as T and B cells.	determined using assays known in the art:	useful for inhibiting
				Moore et al., 1999, Science,	apoptosis, NF-kB
				285(5425): 260-3; Song HY et al., 1997	activation, and/or co-
				Proc Natl Acad Sci USA 94(18): 9792-6;	stimulation of immune
				Epsevik and Nissen-Meyer, 1986, J.	cells such as B and T
				Immunol. Methods.	cells.
CD30	GeneSeq	DE4200043	Activities associated with apoptosis, NF-	Apoptosis activity, NF-kB activation, and B	Soluble CD30
	Accession		kB activation, and co-stimulation of	and T cell co-stimulation can be	polypeptides may be
	R35478		immune cells such as T and B cells.	determined using assays known in the art:	useful for inhibiting
				Moore et al., 1999, Science,	apoptosis, NF-kB
				285(5425): 260-3; Song HY et al., 1997	activation, and/or co-
				Proc Natl Acad Sci USA 94(18): 9792-6;	stimulation of immune
				Epsevik and Nissen-Meyer, 1986, J.	cells such as B and T
				Immunol. Methods.	cells.
CD40	GeneSeq	WO9945944	Activities associated with apoptosis,	Apoptosis activity, NF-kB activation, and B	Soluble CD40
	Accession		NF-kB activation, and co-stimulation of	and T cell co-stimulation can be	polypeptides may be
	Y33499		immune cells such as T and B cells.	determined using assays known in the art:	useful for inhibiting
				Moore et al., 1999, Science	apoptosis, NF-kB
				285(5425): 260-3; Song HY et al., 1997	activation, and/or co-
				Proc Natl Acad Sci USA 94(18): 9792-6;	stimulation of immune
				Epsevik and Nissen-Meyer, 1986, J.	cells such as B and T
				Immunol. Methods.	cells.
EDAR	Genbank		Activities associated with apoptosis,	Apoptosis activity, NF-kB activation, and B	Immune Disorders,
	Accession		NF-kB activation, and co-stimulation of	and T cell co-stimulation can be	Lymphomas, X-linked
	AAD50077		immune cells such as T and B cells.	determined using assays known in the art:	hypohidrotic ectodermal
				Moore et al., 1999, Science,	dysplasia
				285(5425): 260-3; Song HY et al., 1997
				Proc Natl Acad Sci USA 94(18): 9792-6;
				Epsevik and Nissen-Meyer, 1986, J.
				Immunol. Methods.
OX40; ACT-4	GeneSeq	WO9512673	Activities associated with apoptosis,	Apoptosis activity, NF-kB activation, and B	Immune Disorders,
	Accession R74737		NF-kB activation, and co-stimulation of	and T cell co-stimulation can be	Lymphomas, T cell
			immune cells such as T and B cells.	determined using assays known in the art:	disorders
				Moore et al., 1999, Science,
				285(5425): 260-3; Song HY et al., 1997
				Proc Natl Acad Sci USA 94(18): 9792-6;
				Epsevik and Nissen-Meyer, 1986, J.
				Immunol. Methods.
TACI	GeneSeq	WO9839361	Activities associated with apoptosis,	Apoptosis activity, NF-kB activation, and B	Soluble TACI receptor
	Accession		NF-kB activation, and co-stimulation of	and T cell co-stimulation can be	polypeptides may be
	W75783		immune cells such as T and B cells.	determined using assays known in the art:	useful for inhibiting
				Moore et al., 1999, Science,	apoptosis, NF-kB
				285(5425): 260-3; Song HY et al., 1997	activation, and/or co-
				Proc Natl Acad Sci USA 94(18): 9792-6;	stimulation of immune
				Epsevik and Nissen-Meyer, 1986, J.	cells such as B and T
				Immunol. Methods.	cells.
TNF-R	GeneSeq	AU9058976	Activities associates with apoptosis,	Apoptosis activity, NF-kB activation, and B	Soluble TNF-R receptor
	Accession R10986		NF-kB activation, and co-stimulation of	and T cell co-stimulation can be	polypeptides may be
			immune cells such as T and B cells.	determined using assays known in the art:	useful for inhibiting
				Moore et al., 1999, Science,	apoptosis, NF-kB
				285(5425): 260-3; Song HY et al., 1997	activation, and/or co-
				Proc Natl Acad Sci USA 94(18): 9792-6;	stimulation of immune
				Epsevik and Nissen-Meyer, 1986, J.	cells such as B and T
				Immunol. Methods.	cells.
TNF-RII; TNF	GeneSeq	EP418014	Activities associated with apoptosis,	Apoptosis activity, NF-kB activation, and B	Soluble TNFR-II receptor
p75 receptor;	Accession R11141		NF-kB activation, and co-stimulation of	and T cell co-stimulation can be	polypeptides may be
Death Receptor			immune cells such as T and B cells.	determined using assays known in the art:	useful for inhibiting
				Moore et al., 1999, Science,	apoptosis, NF-kB
				285(5425): 260-3; Song HY et al., 1997	activation, and/or co-
				Proc Natl Acad Sci USA 94(18)9792-6;	stimulation of immune
				Epsevik and Nissen-Meyer, 1986, J.	cells such as B and T
				Immunol. Methods.	cells.
hAPO-4; TROY	GeneSeq	WO9911791	Activities associated with apoptosis,	Apoptosis activity, NF-kB activation, and B	Immune Disorders,
	Accession		NF-kB activation, and co-stimulation of	and T cell co-stimulation can be	Cancers
	W93581		immune cells such as T and B cells.	determined using assays known in the art:
				Moore et al., 1999, Science,
				285(5425): 260-3; Song HY et al., 1997
				Proc Natl Acad Sci USA 94(18): 9792-6;
				Epsevik and Nissen-Meyer, 1986, J.
				Immunol. Methods.
TNF-alpha	GeneSeq	EP205038	Activities associated with apoptosis,	Apoptosis activity, NF-kB activation, and B	Inflammatory disorders,
precursor	Accession P60074		NF-kB activation, and co-stimulation of	and T cell co-stimulation can be	immunologic disorders,
			immune cells such as T and B cells.	determined using assays known in the art:	cancer
				Moore et al., 1999, Science,
				285(5425): 260-3; Song HY et al., 1997
				Proc Natl Acad Sci USA 94(18): 9792-6;
				Epsevik and Nissen-Meyer, 1986, J.
				Immunol. Methods.
Human TNF-	GeneSeq	EP619372	Activities associated with apoptosis,	Apoptosis activity, NF-kB activation, and B	Inflammatory disorders,
alpha	Accession R62463		NF-kB activation, and co-stimulation of	and T cell co-stimulation can be	immunologic disorders,
			immune cells such as T and B cells	determined using assays known in the art:	cancer
				Moore et al., 1999, Science,
				285(5425): 260-3; Song HY et al., 1997
				Proc Natl Acad Sci USA 94(18): 9792-6;
				Epsevik and Nissen-Meyer, 1986, J.
				Immunol. Methods.
Human TNF-	GeneSeq	EP563714	Activities associated with apoptosis,	Apoptosis activity, NF-kB activation, and B	Inflammatory disorders,
alpha	Accession R42679		NF-kB activation, and co-stimulation of	and T cell co-stimulation can be	immunologic disorders,
			immune cells such as T and B cells.	determined using assays known in the art:	cancer
				Moore et al., 1999, Science,
				285(5425): 260-3; Song HY et al., 1997
				Proc Natl Acad Sci USA 94(18): 9792-6;
				Epsevik and Nissen-Meyer, 1986, J.
				Immunol. Methods.
Human TNF-	GeneSeq	WO0064479	Activities associated with apoptosis,	Apoptosis activity, NF-kB activation, and B	Inflammatory disorders,
beta (LT-alpha)	Accession B37799		NF-kB activation, and co-stimulation of	and T cell co-stimulation can be	immunologic disorders,
			immune cells such as T and B cells.	determined using assays known in the art:	cancer
				Moore et al., 1999, Science,
				285(5425): 260-3; Song HY et al., 1997
				Proc Natl Acad Sci USA 94(18): 9792-6;
				Epsevik and Nissen-Meyer, 1986, J.
				Immunol. Methods.
LT-alpha	GeneSeq	EP250000	Activities associated with apoptosis,	Apoptosis activity, NF-kB activation, and B	Inflammatory disorders,
	Accession P70107		NF-kB activation, and co-stimulation of	and T cell co-stimulation can be	immunologic disorders,
			immune cells such as T and B cells.	determined using assays known in the art:	cancer
				Moore et al., 1999, Science,
				285(5425): 260-3; Song HY et al., 1997
				Proc Natl Acad Sci USA 94(18): 9792-6;
				Epsevik and Nissen-Meyer, 1986, J.
				Immunol. Methods.
LT-beta	GeneSeq	WO9413808	Activities associated with apoptosis,	Apoptosis activity, NF-kB activation, and B	Inflammatory disorders,
	Accession R56869		NF-kB activation, and co-stimulation of	and T cell co-stimulation can be	immunologic disorders,
			immune cells such as T and B cells.	determined using assays known in the art:	cancer
				Moore et al., 1999, Science,
				285(5425): 260-3; Song HY et al., 1997
				Proc Natl Acad Sci USA 94(18)9792-6;
				Epsevik and Nissen-Meyer, 1986, J.
				Immunol. Methods.
OPGL	GeneSeq	WO9846751	Activities associated with apoptosis,	Apoptosis activity, NF-kB activation, and B	Inflammatory disorders,
	Accession		NF-kB activation, and co-stimulation of	and T cell co-stimulation can be	immunologic disorders,
	W83195		immune cells such as T and B cells.	determined using assays known in the art:	cancer, loss of bone mass
				Moore et al., 1999, Science,
				285(5425): 260-3; Song HY et al., 1997
				Proc Natl Acad Sci USA 94(18)9792-6;
				Epsevik and Nissen-Meyer, 1986, J.
				Immunol. Methods.
FasL	GeneSeq	WO9903999	Activities associated with apoptosis,	Apoptosis activity, NF-kB activation, and B	Inflammatory disorders,
	Accession		NF-kB activation, and co-stimulation of	and T cell co-stimulation can be	immunologic disorders,
	W98071		immune cells such as T and B cells.	determined using assays known in the art:	cancer
				Moore, et al., 1999, Science,
				285(5425): 260-3; Song HY et al., 1997
				Proc Natl Acad Sci USA 94(18)9792-6;
				Epsevik and Nissen-Meyer, 1986, J.
				Immunol. Methods.
FasL	GeneSeq	WO9903998	Activities associated with apoptosis,	Apoptosis activity, NF-kB activation, and B	Inflammatory disorders,
	Accession		NF-kB activation, and co-stimulation of	and T cell co-stimulation can be	imunologic disorders,
	W95041		immune cells such as T and B cells.	determined using assays known in the art:	cancer
				Moore et al., 1999, Science,
				285(5425): 260-3; Song HY et al., 1997
				Proc Natl Acad Sci USA 94(18): 9792-6;
				Epsevik and Nissen-Meyer, 1986, J.
				Immunol. Methods.
CD27L	GeneSeq	WO9405691	Activities associated with apoptosis,	Apoptosis activity, NF-kB activation, and B	Inflammatory disorders,
	Accession R50121		NF-kB activation, and co-stimulation of	and T cell co-stimulation can be	immunologic disorders,
			immune cells such as T and B cells.	determined using assays known in the art:	cancer
				Moore et al., 1999, Science,
				285(5425): 260-3; Song HY et al., 1997
				Proc Natl Acad Sci USA 94(18): 9792-6;
				Epsevik and Nissen-Meyer, 1986, J.
				Immunol. Methods.
CD30 ligand	GeneSeq	WO9324135	Activities associated with apoptosis,	Apoptosis activity, NF-kB activation, and B	Inflammatory disorders,
	Accession R45007		NF-kB activation, and co-stimulation of	and T cell co-stimulation can be	immunologic disorders,
			immune cells such as T and B cells.	determined using assays known in the art:	cancer
				Moore et al., 1999, Science,
				285(5425): 260-3; Song HY et al., 1997
				Proc Natl Acad Sci USA 94(18): 9792-6;
				Epsevik and Nissen-Meyer, 1986, J.
				Immunol. Methods.
CD40L	GeneSeq	WO9529935	Activities associated with apoptosis,	Apoptosis activity, NF-kB activation, and B	Inflammatory disorders,
	Accession R85486		NF-kB activation, and co-stimulation of	and T cell co-stimulation can be	immunologic disorders,
			immune cells such as T and B cells.	determined using assays known in the art:	cancer
				Moore, et al., 1999, Science,
				285(5425): 260-3; Song HY et al., 1997
				Proc Natl Acad Sci USA 94(18): 9792-6;
				Epsevik and Nissen-Meyer, 1986, J.
				Immunol. Methods.
4-1BB ligand	GeneSeq	U.S. Pat. No. 5,674,704	Activities associated with apoptosis,	Apoptosis activity, NF-kB activation, and B	Inflammatory disorders,
	Accession		NF-kB activation, and co-stimulation of	and T cell co-stimulation can be	immunologic disorders,
	W26657		immune cells such as T and B cells.	determined using assays known in the art:	cancer
				Moore et al., 1999, Science,
				285(5425): 260-3; Song HY et al., 1997
				Proc Natl Acad Sci USA 94(18): 9792-6;
				Epsevik and Nissen-Meyer, 1986, J.
				Immunol. Methods.
FAS Ligand	GeneSeq	WO0058465	Activities associated with apoptosis,	Apoptosis activity, NF-kB activation, and B	Soluble DcR3
Inhibitory	Accession B19335		NF-kB activation, and co-stimulation of	and T cell co-stimulation can be	polypeptides may be
Protein (DcR3)			immune cells such as T and B cells.	determined using assays known in the art:	useful for inhibiting
				Moore et al., 1999, Science,	apoptosis, NF-kB
				285(5425): 260-3; Song HY et al., 1997	activation, and/or co-
				Proc Natl Acad Sci USA 94(18): 9792-6;	stimulation of immune
				Epsevik and Nissen-Meyer, 1986, J.	cells such as B and T
				Immunol. Methods	cells.
OX40L	GeneSeq	WO9521915	Activities associated with apoptosis,	Apoptosis activity, NF-kB activation, and B	Inflammatory disorders,
	Accession R79903		NF-kB activation, and co-stimulation of	and T cell co-stimulation can be	immunologic disorders,
			immune cells such as T and B cells.	determined using assays known in the art:	cancer
				Moore et al., 1999, Science,
				285(5425): 260-3; Song HY et al., 1997
				Proc Natl Acad Sci USA 94(18): 9792-6;
				Epsevik and Nissen-Meyer, 1986, J.
				Immunol. Methods.
Protease	GeneSeq	WO9106561	Peptides that inhibit the function/binding	HIV protease activities are known in the art:	HIV, inflammatory
inhibitor	Accessions		of HIV	HIV protease assays: EP0387231. One	disorders, immunologic
peptides	R12435, R12436,			can modify the assay to look for inhibition	disorders, cancer, viral
	R12437, R12438,			using any of the disclosed protease	infections
	R12439, R12440,			inhibitor polypeptides.
	and R1244
Retroviral	GeneSeq	EP387231	Peptides that inhibit the function/binding	HIV protease activities are known in the art:	HIV, inflammatory
protease	Accessions		of HIV	HIV protease assays: EP0387231. One	disorders, immunologic
inhibitors	R06660, R06661,			can modify the assay to look for inhibition	disorders, cancer, viral
	R06662, R06663,			using any of the disclosed protease	infections
	R06664, R06665,			inhibitor polypeptides.
	R06666, R06667,
	R06668, R06669,
	R06670, R06671,
	R06672, R06673,
	R06674, R06675,
	and R06676
HIV protease	GeneSeq	WO9301828	Peptides that inhibit the function/binding	HIV protease activities are known in the art:	HIV, inflammatory
inhibiting	Accessions		of HIV	HIV protease assays: EP0387231. One	disorders, immunologic
peptides	R59293, R59294,			can modify the assay to look for inhibition	disorders, cancer, viral
	R59295, R59296,			using any of the disclosed protease	infections
	R59297,			inhibitor polypeptides.
	R59298, R59299,
	R592300, R59301,
	R59302, R59301,
	R59302, R59303,
	R59304, R59305,
	R59306, R59307,
	R59308, R59309,
	R59310, R59311,
	R59312, R59313,
	R59314, R59315,
	R59316, R59317
	R59318, R59319,
	R59320, R59321,
	R59322, R59323,
	R59324, R59325,
	R59326, R59327,
	R59328, R59329,
	R59330, R59331,
	R59332, R59333,
	R59334, R59335,
	R59336, R59337,
	R59338, R59339,
	R59340, R59341,
	R59342, R59343,
	R59344, R59345,
	R59346, R59347,
	R59348, R59349,
	and R59350
HIV-1 protease	GeneSeq	DE4412174	Peptides that inhibit the function/binding	HIV protease activities are known in the art:	HIV, inflammatory
hinibitors	Accessions		of HIV	HIV protease assays: EP0387231. One	disorders, immunologic
	R86326, R86327,			can modify the assay to look for inhibition	disorders, cancer, viral
	R86328, R86329,			using any of the disclosed protease	infections
	R86330, R86331,			inhibitor polypeptides.
	R86332, R86333,
	R86334, R86335,
	R86336, R86337,
	R86338, R86339,
	R86340, R86341,
	R86342, R86343,
	R86344, R86345,
	R86346, R86347,
	R86348, R86349,
	R86350, R86351,
	R86352, R86353,
	R86354, R86355,
	R86356, R86357,
	R86358, R86359,
	R86360, R86361,
	R86362, R86363,
	R86364, R86365,
	R86366, R86367,
	R86368, R86369,
	R86370, and
	R86371
HIV Inhibitor	GeneSeq	WO9959615	Peptides that inhibit the function/binding	HIV protease activities are known in the art:	HIV, inflammatory
Peptide	Accession		of HIV	HIV protease assays: EP0387231. One	disorders, immunologic
	Y89687			can modify the assay to look for inhibition	disorders, cancer, viral
				using any of the disclosed protease	infections
				inhibitor polypeptides.
HIV Inhibitor	GenSeq	WO9948513	Peptides that inhibit the function/binding	HIV Protease activities are known in the	HIV, inflammatory
Peptide	Accession Y31955		of HIV	art; HIV protease assays: EP0387231.	disorders, immunologic
				One can modify the assay to look for	disorders, cancer, viral
				inhibition using any of the disclosed	infections.
				protease inhibitor polypeptides.
HIV Inhibitor	www.sciencexpress.org;		Peptides that inhibit the function/binding	HIV protease activities are known in the	HIV, inflammatory
Peptide	Published		of HIV	art: HIV protease assays: EP0387231.	disorders, immunologic
	online 12 Jan.			One can modify the assay to look for	disorders, cancer, viral
	2001;			inhibition using any of the disclosed	infections
	10.1126/science.1057453			protease inhibitor polypeptides.
Human monocyte	GeneSeq	WO9509232	Chemokines are a family of small,	Chemokine activities can be determined	Immune disorders,
chemoattractant	Accession		secreted proteins involved in biological	using assays known in the art: Methods in	particularly useful for
factor hMCP-3	R73915		processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:	treating bacterial and/or
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols, Edited by: A. E. I. Proudfoot,	viral menigitis
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to - 17
			receptors thus far identified.
Human monocyte	GeneSeq	WO9509232	Chemokines are a family of related small,	Chemokine activities can be determined	Immune disorders,
chemoattractant	Accession		secreted proteins involved in biological	using assays known in the art: Methods in	particularly useful for
factor hMCP-1	R73914		processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:	treating bacterial and/or
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,	viral menigitis
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to - 17
			receptors thus far identified.
Human gro-beta	GeneSeq	WO9429341	Chemokines are a family of small,	Chemokine activities can be determined	Immune disorders,
chemokine	Accessions		secreted proteins involved in biological	using assays known in the art: Methods in	inflammatory disorders,
	R66699 and		processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:	blood-related disorders,
	W17671		angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,	stem cell transplantation,
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.	cancer
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to - 17
			receptors thus far identified.
Human gro-	GeneSeq	WO9429341	Chemokines are a family of related small,	Chemokine activities can be determined	Immune disorders,
gamma	Accessions		secreted proteins involved in biological	using assays known in the art: Methods in	inflammatory disorders,
chemokine	R66700 and		processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:	blood-related disorders,
	W17672		angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,	stem cell transplantation,
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.	cancer
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to - 17
			receptors thus far identified
Human gro-alpha	GeneSeq	WO9429341	Chemokines are a family of related small,	Chemokine activities can be determined	Immune disorders,
chemokine	Accessions		secreted proteins involved in biological	using assays known in the art: Methods in	inflammatory disorders,
	R66698 and		processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:	blood-related disorders,
	W18024		angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,	stem cell transplantation,
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.	cancer
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to - 17
			receptors thus far identified
Human	GeneSeq	WO9632481	Chemokines are a family of related small,	Chemokine activities can be determined	Immune disorders,
eosinophil-	Accession		secreted proteins involved in biological	using assays known in the art: Methods in	particularly treatment of
expressed	W05186		processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:	eosinophilia, inflammation,
chemokine (EEC)			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,	allergies, asthma,
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.	leukaemia and lymphoma
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to - 17
			receptors thus far identified
Chemokine-like	GeneSeq	WO9613587	Chemokines are a family of related small,	Chemokine activities can be determined	Cancer and blood-related
protein PF4-414	Accessions		secreted proteins involved in biological	using assays known in the art: Methods in	disorders, particularly
Full-Length and	R92318 and		processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:	myelosuppression
Mature	R99809		angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to - 17
			receptors thus far identified
Chemokine-like	GeneSeq	WO9613587	Chemokines are a family of related small,	Chemokine activities can be determined	Cancer and blood-related
protein IL-8M3	Accession		secreted proteins involved in biological	using assays known in the art: Methods in	disorders, particularly
	R99812		processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:	myelosuppression
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ; and
			including inflammation, allergy, tissue	Holmes et al (1991) Science 253, 1278-80.
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to - 17
			receptors thus far identified
Human	GeneSeq	WO9613587	Chemokines are a family of related small,	Chemokine activities can be determined	Cancer and blood-related
interleukin-8 (IL-8)	Accession		secreted proteins involved in biological	using assays known in the art: Methods in	disorders, particularly
	R99814		processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:	myelosuppression
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ; and
			including inflammation, allergy, tissue	Holmes et al (1991) Science 253, 1278-80.
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to - 17
			receptors thus far identified
Chemokine-like	GeneSeq	WO9613587	Chemokines are a family of related small,	Chemokine activities can be determined	Cancer and blood-related
protein IL-8M1	Accessions		secreted proteins involved in biological	using assays known in the art: Methods in	disorders, particularly
Full-Length and	R99815 and		processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:	myelosuppression
Mature	R99803		angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ; and
			including inflammation, allergy, tissue	Holmes et al (1991) Science 253, 1278-80.
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to - 17
			receptors thus far identified
Chemokine-like	GeneSeq	WO9613587	Chemokines are a family of related small,	Chemokine activities can be determined	Cancer and blood-related
protein IL-8M8	Accessions		secreted proteins involved in biological	using assasys known in the art: Methods	disorders, particularly
Full-Length and	R99816 and		processes ranging from hematopoiesis,	in Molecular Biology, 2000, vol. 138:	myelosuppression.
Mature	R99805		angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot;
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ; and
			including inflammation, allergy, tissue	Holmes et al (1991) Science 253, 1278-80.
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Chemokine-like	GeneSeq	WO9613587	Chemokines are a family of related small,	Chemokine activities can be determined	Cancer and blood-related
protein IL-8M8	Accessions		secreted proteins involved in biological	using assasys known in the art: Methods in	disorders, particularly
Full-Length and	R99817 and		processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:	myelosuppression.
Mature	R99806		angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot;
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ; and
			including inflammation, allergy, tissue	Holmes et al (1991) Science 253, 1278-80.
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Chemokine-like	GeneSeq	WO9613587	Chemokines are a family of related small,	Chemokine activities can be determined	Cancer and blood-related
protein IL-8M8	Accessions		secreted proteins involved in biological	using assasys known in the art: Methods in	disorders, particularly
Full-Length and	R99818 and		processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:	myelosuppression.
Mature	R99804		angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot;
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ; and
			including inflammation, allergy, tissue	Holmes et al (1991) Science 253, 1278-80.
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Chemokine-like	GeneSeq	WO9613587	Chemokines are a family of related small,	Chemokine activities can be determined	Cancer and blood-related
protein IL-8M8	Accessions		secreted proteins involved in biological	using assasys known in the art: Methods in	disorders, particularly
Full-Length and	R99819 and		processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:	myelosuppression.
Mature	R99807		angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot;
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Chemokine-like	GeneSeq	WO9613587	Chemokines are a family of related small,	Chemokine activities can be determined	Cancer and blood-related
protein IL-8M8	Accessions		secreted proteins involved in biological	using assasys known in the art: Methods in	disorders, particularly
Full-Length and	R99822 and R9807		processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:	myelosuppression.
Mature			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot;
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Human foetal	GeneSeq	WO9622374	Chemokines are a family of related small,	Chemokine activities can be determined	Immune disorders
spleen expressed	Accession R98499		secreted proteins involved in biological	using assasys known in the art: Methods in
chemokine, FSEC			processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot;
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Liver expressed	GeneSeq	WO9616979	Chemokines are a family of related small,	Chemokine activities can be determined	Inflammation of the liver
chemokine-	Accession R95689		secreted proteins involved in biological	using assasys known in the art: Methods in
1(LVEC-1)			processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot;
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Liver expressed	GeneSeq	WO9616979	Chemokines are a family of related small,	Chemokine activities can be determined	Inflammation of the liver
chemokine-	Accession R95690		secreted proteins involved in biological	using assasys known in the art: Methods in
2(LVEC-2)			processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot;
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Pituitary	GeneSeq	WO9616979	Chemokines are a family of related small,	Chemokine activities can be determined	Inflammation, particularly
expressed	Accession R95691		secreted proteins involved in biological	using assasys known in the art: Methods in	of the liver
chemokine			processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:
(PGEC)			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot;
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Adenoid-	GeneSeq	WO9617868	Chemokines are a family of related small,	Chemokine activities can be determined	Inflammation,
expressed	Accession R97664		secreted proteins involved in biological	using assasys known in the art: Methods in	angiogenesis,
chemokine			processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:	tumorigenesis,
(ADEC)			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot;	musculoskeletal disorders
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Human	GeneSeq	WO9741230	Chemokines are a family of related small,	Chemokine activities can be determined	Immune disorders, cell
chemokineCC-2	Accession		secreted proteins involved in biological	using assays known in the art: Methods in	migration, proliferation,
	W38170		processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138;	and differentiation
			angiogenesis, and leukocyte trafficking.	Chemokine protocols. Edited by: A. E. I. Proudfoot,	disorders
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarly diverse range of pathologies	© Humana Press Inc. Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Human	GeneSeq	WO9741230	Chemokines are a family of related small,	Chemokine activities can be determined	Immune disorders, cell
chemokine	Accession		secreted proteins involved in biological	using assays known in the art: Methods in	migration, proliferation,
HCC-1	W38171		processes ranging from hematopiesis,	molecular Biology 2000, vol. 138:	and differentiation
			anglogenesis and leukocyte trafficking.	Chemokine Protocols. Edited by A. E. I. Proudfoot,	disorders
			Members of this family are involved in a	T. N. C. Wells and C. A. Power
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Human	GeneSeq	WO9741230	Chemokines are a family of related small,	Chemokine activities can be determined	Immune disorders, cell
chemokine CC-3	Accession		secreted proteins involved in biological	using assays known in the art: Methods in	migration, proliferation and
	W38172		processes ranging from hemotopoiesis,	molecular Biology, 2000, vol. 138:	differentiation disorders
			anglogenesis, and leukocyte trafficking.	Chemokine Protocols, Edited by A. E. I. Proudfoot,
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Novel	GeneSeq	WO9739126	Chemokines are a family of related small,	Chemokine activities can be determined	Immune disorders,
betachemokine	Accession		secreted proteins involved in biological	using assays known in the art: Methods in	vascular disorders, cancer
designated PTEC	W27271		processes ranging from hemotopoiesis,	molecular Biology, 2000, vol. 138:
			anglogenesis, and leukocyte trafficking.	Chemokine Protocols, Edited by A. E. I. Proudfoot,
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Human CX3C	GeneSeq	WO9727299	Chemokines are a family of related small,	Chemokine activities can be determined	Immune disorders,
111 amino acid	Accession		secreted proteins involved in biological	using assays known in the art: Methods in	inflammatory diseases,
chemokine	W23344		processes ranging from hemotopoiesis,	molecular Biology, 2000, vol. 138:	abnormal proliferation,
			anglogenesis, and leukocyte trafficking.	Chemokine Protocols, Edited by A. E. I. Proudfoot,	regeneration,
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power	degeneration, and atrophy
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Human CCF18	GeneSeq	WO9721812	Chemokines are a family of related small,	Chemokine activities can be determined	Abnormal physiology and
chemokine	Accession		secreted proteins involved in biological	using assays known in the art: Methods in	development disorders,
	W25942		processes ranging from hemotopoiesis,	molecular Biology, 2000, vol. 138:	can also be used as an
			anglogenesis, and leukocyte trafficking.	Chemokine Protocols, Edited by A. E. I. Proudfoot,	anti-viral agent
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Human beta-	GeneSeq	WO9725427	Chemokines are a family of related small,	Chemokine activities can be determined	Chemotaxis, blood-related
chemokine	Accession		secreted proteins involved in biological	using assays known in the art: Methods in	disorders, viral infection,
H1305 (MCP-2)	W26655		processes ranging from hemotopoiesis,	molecular Biology, 2000, vol. 138:	HIV, wound healing,
			anglogenesis, and leukocyte trafficking.	Chemokine Protocols, Edited by A. E. I. Proudfoot,	cancer
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Human	GeneSeq	WO9712914	Chemokines are a family of related small,	Chemokine activities can be determined	Inflammatory and immune
eosinocyte CC	Accession		secreted proteins involved in biological	using assays known in the art: Methods in	disorders
type chemokine	W14990		processes ranging from hemotopoiesis,	molecular Biology, 2000, vol. 138:
eotaxin			anglogenesis, and leukocyte trafficking.	Chemokine Protocols, Edited by A. E. I. Proudfoot,
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Human thymus	GeneSeq	WO9711969	Chemokines are a family of related small,	Chemokine activities can be determined	Inflammatory and immune
and activation	Accession		secreted proteins involved in biological	using assays known in the art: Methods in	disorders
regulated	W14018		processes ranging from hemotopoiesis,	molecular Biology, 2000, vol. 138:
cytokine			anglogenesis, and leukocyte trafficking.	Chemokine Protocols, Edited by A. E. I. Proudfoot,
(TARC)			Members of this family are involved in a	T. N. C. Wells, and C. A. Power
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Human	GeneSeq	WO9712041	Chemokines are a family of related small,	Chemokine activities can be determined	Cancer, would healing,
chemokine beta-	Accession		secreted proteins involved in biological	using assays known in the art: Methods in	immune disorders
8 short forms	W16315		processes ranging from hemotopoiesis,	molecular Biology, 2000, vol. 138:
			anglogenesis, and leukocyte trafficking.	Chemokine Protocols, Edited by A. E. I. Proudfoot,
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Microphage	GeneSeq	WO9640923	Chemokines are a family of related small,	Chemokine activities can be determined	Inflammatory diseases,
derived	Accession		secreted proteins involved in biological	using assays known in the art: Methods in	wound healin,
chemokine, MDC	W20058		processes ranging from hermaatopoiesis,	Molecular Biology, 2000, vol. 138:	angiogenesis
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Human	GeneSeq	WO9844117	Chemokines are a family of related small,	Chemokine activities can be determined	Inflammatory and immune
chemokine ZSIG-	Accession		secreted proteins involved in biological	using assays known in the art: Methods in	diseases
35	W30565		processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Primate CC	GeneSeq	WO98328658	Chemokines are a family of related small,	Chemokine activities can be determined	Immune and inflammatory
chemokine	Accesssion		secreted proteins involved in biological	using assays known in the art: Methods in	disorders, abnormal
“ILINCK”	W69990		processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:	proliferation, regeneration,
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,	generation and atrophy
				T. N. C. Wells, and C. A. Power.	disorders
				© Humana Press Inc., Totowa, NJ
Primate CXC	GeneSeq	WO9832858	Chemokines are a family of related small,	Chemokine activities can be determined	Immune and inflammatory
chemokine	Accession		secreted proteins involved in biological	using assays known in the art: Methods in	disorders, abnormal
“IBICK”	W69989		processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:	proliferation, regeneration,
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Editd by: A. E. I. Proudfoot,	generation and atrophy
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.	disorders
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Human CC-type	GeneSeq	WO9831809	Chemokines are a family of related small,	Chemokine activities can be determined	Immune, inflammatory,
chemokine protein	Accession		secreted proteins involved in biological	using assays known in the art: Methods in	and infectious disorders,
designated SLC	W69163		processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:	cancer
(secondary			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,
lymphoid			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
chemokine)			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Human CC	GeneSeq	WO9826071	Chemokines are a family of related small,	Chemokine activities can be determined	Cancer and infectious
chemokine ELC	Accession		secreted proteins involved in biological	using assays known in the art: Methods in	diseases, particularly
protein	W62542		processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:	herpes virus
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Human DVic-1	GeneSeq	Wo9823750	Chemokines are a family of related small,	Chemokine activities can be determined	Abnormal proliferation,
C-C chemokine	Accession		secreted proteins involved in biological	using assays known in the art: Methods in	regeneration,
	W60649		processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:	degeneration, and atrophy
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,	disorders, including cancer
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Human C-C	GeneSeq	WO9823750	Chemokines are a family of related small,	Chemokine activities can be determined	Immune disorders, cell
chemokine	Accession		secreted proteins involved in biological	using assays known in the art: Methods in	proliferation disorders,
DGWCC	W60650		processes ranging from hematophoiesis,	Molecular Biology, 2000, vol. 138:	cancer
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identifed.
Human STCP-1	GeneSeq	WO9824907	Chemokines are a family of related small,	Chemokine activities can be determined	Immune disorders,
	Accession		secreted proteins involved in biological	using assays known in the art: Methods in	particularly T cell related
	W62783		processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:	disorders, viral infection,
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,	and inflammation,
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.	especially joint
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Exodua protein	GeneSeq	WO9821330	Chamokines are a family of related small,	Chemokine activities can be determined	Immune and inflammatory
	Accession		secreted proteins involved in biological	using assays known in the art: Methods in	disorders, angiogenesis,
	W61279		processes ranging from hematopoiesis,	Molecular Biology, 2000, vol.138:	cancer, and proliferation
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,	disorders, particularly
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.	myeloproliferative
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ	diseases
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Human	GeneSeq	WO9814581	Chemokines are a family of related small,	Chemokine activities can be determined	Cancer and degenerative
Chr19Kine	Acession		secreted proteins involved in biological	using assays known in the art: Methods in	disorders
protein	W50887		processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols, Edited by: A. E. I. Proudfoot,
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Human T cell	GeneSeq	U.S. Pat. No. 5,780,268	Chemokines are a family of related	Chemokine activities can be determined	Immune, inflammatory,
mixed	Accession		small, secreted proteins involved in	using assays known in the art: Mehtods of	and infectious disorders,
lymphocyte	W58703		biological processes ranging from	Molecular Biology, 2000, vol. 138:	cancer
reaction			hematopoiesis, angiogenesis, and	Chemokine Protocols. Edited by: A. E. I. Proudfoot,
expressed			leukocyte trafficking. Members of this	T. N. C. Wells, and C. A. Power
chemokine			family are involved in a similarly diverse	© Humana Press Inc., Totowa, NJ
(TMEC)			range of pathologies including
			inflammation, allergy, tissue rejection,
			viral infection, and tumor biology. The
			chemokines exert their effects by acting
			on a family of seven transmembrane G-
			protein-coupled receptors. Over 40
			human chemokines have been
			described, which bind to ~17 receptors
			thus far identified.
Human 6CKine	GeneSeq	W09814581	Chemokines are a family of related	Chemokine activities can be determined	Cancer and degenerative
protein	Accession		small, secreted proteins involved in	using assays known in the art: Mehtods of	disorders
	W50885		biological processes ranging from	Molecular Biology, 2000, vol. 138:
			hematopoiesis, angiogenesis, and	Chemokine Protocols. Edited by: A. E. I. Proudfoot,
			leukocyte trafficking. Members of this	T. N. C. Wells, and C. A. Power
			family are involved in a similarly diverse	© Humana Press Inc., Totowa, NJ
			range of pathologies including
			inflammation, allergy, tissue rejection,
			viral infection, and tumor biology. The
			chemokines exert their effects by acting
			on a family of seven transmembrane G-
			protein-coupled receptors. Over 40
			human chemokines have been
			described, which bind to ~17 receptors
			thus far identified.
human liver and	GeneSeq	WO9817800	Chemokines are a family of related	Chemokine activities can be determined	Immune, inflammatory,
activation	Accession		small, secreted proteins involved in	using assays known in the art: Mehtods of	and infectious disorders,
regulated	W57475		biological processes ranging from	Molecular Biology, 2000, vol. 138:	cancer
chemokine			hematopoiesis, angiogenesis, and	Chemokine Protocols. Edited by: A. E. I. Proudfoot,
(LARC)			leukocyte trafficking. Members of this	T. N. C. Wells, and C. A. Power
			family are involved in a similarly diverse	© Humana Press Inc., Totowa, NJ
			range of pathologies including
			inflammation, allergy, tissue rejection,
			viral infection, and tumor biology. The
			chemokines exert their effects by acting
			on a family of seven transmembrane G-
			protein-coupled receptors. Over 40
			human chemokines have been
			described, which bind to ~17 receptors
			thus far identified.
RANTES	GeneSeq	WO9744462	Chemokines are a family of related	Chemokine activities can be determined	Infectious diseases,
peptide	Accession		small, secreted proteins involved in	using assays known in the art: Mehtods of	particularly HIV
	W29538		biological processes ranging from	Molecular Biology, 2000, vol. 138:
			hematopoiesis, angiogenesis, and	Chemokine Protocols. Edited by: A. E. I. Proudfoot,
			leukocyte trafficking. Members of this	T. N. C. Wells, and C. A. Power
			family are involved in a similarly diverse	© Humana Press Inc., Totowa, NJ
			range of pathologies including
			inflammation, allergy, tissue rejection,
			viral infection, and tumor biology. The
			chemokines exert their effects by acting
			on a family of seven transmembrane G-
			protein-coupled receptors. Over 40
			human chemokines have been
			described, which bind to ~17 receptors
			thus far identified.
RANTES 8-68	GeneSeq	WO9744462	Chemokines are a family of related	Chemokine activities can be determined	Infectious diseases,
	Accession		small, secreted proteins involved in	using assays known in the art: Mehtods of	particularly HIV
	W29529		biological processes ranging from	Molecular Biology, 2000, vol. 138:
			hematopoiesis, angiogenesis, and	Chemokine Protocols. Edited by: A. E. I. Proudfoot,
			leukocyte trafficking. Members of this	T. N. C. Wells, and C. A. Power
			family are involved in a similarly diverse	© Humana Press Inc., Totowa, NJ
			range of pathologies including
			inflammation, allergy, tissue rejection,
			viral infection, and tumor biology. The
			chemokines exert their effects by acting
			on a family of seven transmembrane G-
			protein-coupled receptors. Over 40
			human chemokines have been
			described, which bind to ~17 receptors
			thus far identified.
RANTES 9-68	GeneSeq	WO9744462	Chemokines are a family of related	Chemokine activities can be determined	Infectious diseases,
	Accession		small, secreted proteins involved in	using assays known in the art: Mehtods of	particularly HIV
	W29528		biological processes ranging from	Molecular Biology, 2000, vol. 138:
			hematopoiesis, angiogenesis, and	Chemokine Protocols. Edited by: A. E. I. Proudfoot,
			leukocyte trafficking. Members of this	T. N. C. Wells, and C. A. Power
			family are involved in a similarly diverse	© Humana Press Inc., Totowa, NJ
			range of pathologies including
			inflammation, allergy, tissue rejection,
			viral infection, and tumor biology. The
			chemokines exert their effects by acting
			on a family of seven transmembrane G-
			protein-coupled receptors. Over 40
			human chemokines have been
			described, which bind to ~17 receptors
			thus far identified.
Human	GeneSeq	WO9811226	Chemokines are a family of related	Chemokine activities can be determined	Abnormal proliferation,
chemokine	Accession		small, secreted proteins involved in	using assays known in the art: Mehtods of	regeneration,
protein 331D5	W59433		biological processes ranging from	Molecular Biology, 2000, vol. 138:	degeneration or atrophy,
			hematopoiesis, angiogenesis, and	Chemokine Protocols. Edited by: A. E. I. Proudfoot,	including cancer
			leukocyte trafficking. Members of this	T. N. C. Wells, and C. A. Power
			family are involved in a similarly diverse	© Humana Press Inc., Totowa, NJ
			range of pathologies including
			inflammation, allergy, tissue rejection,
			viral infection, and tumor biology. The
			chemokines exert their effects by acting
			on a family of seven transmembrane G-
			protein-coupled receptors. Over 40
			human chemokines have been
			described, which bind to ~17 receptors
			thus far identified.
Human	GeneSeq	WO9811226	Chemokines are a family of related	Chemokine activities can be determined	Abnormal proliferation,
chemokine	Accession		small, secreted proteins involved in	using assays known in the art: Mehtods of	regeneration,
protein 61164	W59430		biological processes ranging from	Molecular Biology, 2000, vol. 138:	degeneration or atrophy,
			hematopoiesis, angiogenesis, and	Chemokine Protocols. Edited by: A. E. I. Proudfoot,	including cancer
			leukocyte trafficking. Members of this	T. N. C. Wells, and C. A. Power
			family are involved in a similarly diverse	© Humana Press Inc., Totowa, NJ
			range of pathologies including
			inflammation, allergy, tissue rejection,
			viral infection, and tumor biology. The
			chemokines exert their effects by acting
			on a family of seven transmembrane G-
			protein-coupled receptors. Over 40
			human chemokines have been
			described, which bind to ~17 receptors
			thus far identified.
Chemokine	GeneSeq	WO9809171	Chemokines are a family of related	Chemokine activities can be determined	Immune, Inflammatory,
MCP-4	Accession		small, secreted proteins involved in	using assays known in the art: Mehtods of	and infectious diseases
	W56690		biological processes ranging from	Molecular Biology, 2000, vol. 138:
			hematopoiesis, angiogenesis, and	Chemokine Protocols. Edited by: A. E. I. Proudfoot,
			leukocyte trafficking. Members of this	T. N. C. Wells, and C. A. Power
			family are involved in a similarly diverse	© Humana Press Inc., Totowa, NJ
			range of pathologies including
			inflammation, allergy, tissue rejection,
			viral infection, and tumor biology. The
			chemokines exert their effects by acting
			on a family of seven transmembrane G-
			protein-coupled receptors. Over 40
			human chemokines have been
			described, which bind to ~17 receptors
			thus far identified.
Human stromal	GeneSeq	FR2751658	Chemokines are a family of related small,	Chemokine activities can be determined	HIV infections
cell-derived	Accession		secreted proteins involved in biological	using assays known in the art: Methods in
chemokine, SDF-1	W50766		processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Thymus	GeneSeq	WO9801557	Chemokines are a family of related small,	Chemokine activities can be determined	Immune and inflammatory
expressed	Accession W44397		secreted proteins involved in biological	using assays known in the art: Methods in	disorders
chemokine			processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:
(TECK)			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Human	GeneSeq	WO9801557	Chemokines are a family of related small,	Chemokine activities can be determined	Immune and inflammatory
chemokine MIP-	Accession W44398		secreted proteins involved in biological	using assays known in the art: Methods in	disorders
3alpha			processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Human	GeneSeq	WO9801557	Chemokines are a family of related small,	Chemokine activities can be determined	Immune and inflammatory
chemokine MIP-	Accession W44399		secreted proteins involved in biological	using assays known in the art: Methods in	disorders
3beta			processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Human monocyte	GeneSeq	WO9802459	Chemokines are a family of related small,	Chemokine activities can be determined	Immune disorders,
chemotactic	Accession W42072		secreted proteins involved in biological	using assays known in the art: Methods in	respiratory disorders,
proprotein			processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:	cancer
(MCPP) sequence			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Macrophage-	GeneSeq	U.S. Pat. No. 5,688,927/	Chemokines are a family of related small,	Chemokine activities can be determined	Immune, and inflammatory
derived	Accessions	U.S. Pat. No. 5,932,703	secreted proteins involved in biological	using assays known in the art: Methods in	disorders, cancer
chemokine (MDC)	W40811 and		processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:
	Y24414		angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Macrophage	GeneSeq	U.S. Pat. No. 5,932,703	Chemokines are a family of related small,	Chemokine activities can be determined	Immune and inflammatory
derived	Accession Y24416		secreted proteins involved in biological	using assays known in the art: Methods in	disorders
chemokine			processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:
analogue MDC-			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,
eyfy			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Macrophage	GeneSeq	U.S. Pat. No. 5,932,703	Chemokines are a family of related small,	Chemokine activities can be determined	Immune and inflammatory
derived	Accession Y24413		secreted proteins involved in biological	using assays known in the art: Methods in	disorders
chemokine			processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:
analogue MDC			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,
(n + 1)			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Macrophage	GeneSeq	U.S. Pat. No. 5,932,703	Chemokines are a family of related small,	Chemokine activities can be determined	Immune and inflammatory
derived	Accession Y24415		secreted proteins involved in biological	using assays known in the art: Methods in	disorders
chemokine			processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:
analogue MDC-yl			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Human type CC	GeneSeq	JP11243960	Chemokines are a family of related small,	Chemokine activities can be determined	Allergic diseases and HIV
chemokine	Accession Y43178		secreted proteins involved in biological	using assays known in the art: Methods in	infection
eotaxin
3 protein			processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:
sequence			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Human MCP-3	GeneSeq	WO9946392	Chemokines are a family of related small,	Chemokine activities can be determined	Cancer and immune
and human Muc-1	Acession Y29893		secreted proteins involved in biological	using assays known in the art: Methods in	disorders, particularly HIV
core epitope			processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:	infection
(VNT) fusion			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,
protein			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarily diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Human IP-10 and	GeneSeq	WO9946392	Chemokines are a family of related small,	Chemokine activities can be determined	Cancer and immune
human Muc-1	Accession Y29894		secreted proteins involved in biological	using assays known in the art: Methods in	disorders, particularly HIV
core epitope			processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:	infection
(VNT) fusion			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,
protein			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarily diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Human IP-10 and	GeneSeq	W09946392	Chemokines are a family of related small,	Chemokine activities can be determined	Cancer and immune
HIV-1 gp 120	Accession Y29897		secreted proteins involved in biological	using assays known in the art: Methods in	disorders, particularly HIV
hypervariable			processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:	infection
region fusion			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,
protein			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarily diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Human mammary	GeneSeq	WO9936540	Chemokines are a family of related small,	Chemokine activities can be determined	Breast disease, including
associated	Accessions		secreted proteins involved in biological	using assays known in the art: Methods in	cancer
chemokine	Y29092 and		processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:
(MACK) protein	Y29093		angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,
Full-Length and			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
Mature			similarily diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Tim-1 protein	GeneSeq	WO9933990	Chemokines are a family of related small,	Chemokine activities can be determined	Inflammation due to stimuli
	Accession		secreted proteins involved in biological	using assays known in the art: Methods in	such as heart attacks and
	Y28290		processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:	stroke, infection, physical
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,	trauma, UV or ionizing
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.	radiation, burns, frostbite
			similarily diverse range of pathologies	© Humana Press Inc., Totowa, NJ	or corrosive chemicals
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Human Lkn-1 Full-	GeneSeq	WO9928473	Chemokines are a family of related small,	Chemokine activities can be determined	HIV infection and cancer,
Length and	Accessions	and	secreted proteins involved in biological	using assays known in the art: Methods in	particularly leukemia
Mature protein	Y17280, Y17274,	WO9928472	processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:
	Y17281, and		angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,
	Y17275		Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarily diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
N-terminal	GeneSeq	WO9920759	Chemokines are a family of related small,	Chemokine activities can be determined	Inhibit or stimulate
modified	Accession Y05818		secreted proteins involved in biological	using assays known in the art: Methods in	angiogenesis, inhibit the
chemokine met-			processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:	binding of HIV
hSDF-1 alpha			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarily diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
N-terminal	GeneSeq	WO9920759	Chemokines are a family of related small,	Chemokine activities can be determined	Inhibit or stimulate
modified	Accession Y05819		secreted proteins involved in biological	using assays known in the art: Methods in	angiogenesis, inhibit the
chemokine met-			processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:	binding of HIV,
hSDF-1 beta			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,	antiinflammatory;
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.	immunosuppressant
			similarily diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
N-terminal	GeneSeq	WO9920759	Chemokines are a family of related small,	Chemokine activities can be determined	Inhibit or stimulate
modified	Accession Y05820		secreted proteins involved in biological	using assays known in the art: Methods in	angiogenesis, inhibit the
chemokine			processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:	binding of HIV,
GroHEK/hSDF-			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,	antiinflammatory;
1alpha			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.	immunosuppressant
			similarily diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
N-terminal	GeneSeq	WO9920759	Chemokines are a family of related small,	Chemokine activities can be determined	Inhibit or stimulate
modified	Accession Y05821		secreted proteins involved in biological	using assays known in the art: Methods in	angiogenesis, inhibit the
chemokine			processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:	binding of HIV,
GroHEK/hSDF-			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,	antiinflammatory;
1beta.			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.	immunosuppressant
			similarily diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Chemokine	GeneSeq	WO9912968	Chemokines are a family of related small,	Chemokine activities can be determined	Increase or enhance an
Eotaxin	Accession		secreted proteins involved in biological	using assays known in the art: Methods in	inflammatory response, an
	Y14230		processes ranging from hematopoiesis,	Molecular Bilogy, 2000, vol. 138:	immune response
			agiogenesis, and leukocye trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,	orhaematopoietic cell-
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.	associated activity; treat a
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ	vascular indication;
			including inflammation, allergy, tissue		Cancer; enhance wound
			rejection, viralk infection, and tumor		healing, to prevent or treat
			biology. The chemokines exert their		asthma, organ transplant
			effects by acting on a family of seven		rejction, rheumatoid
			transmembrane G-protein-coupled		arthritis or allergy
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Chemokine	GeneSeq	WO9912968	Chemokines are a family of related small,	Chemokine activities can be determined	Immune disorders,
hMCP1a	Accession		secreted proteins involved in biological	using assays known in the art: Methods in	Vascular disorders,
	Y14225		processes ranging from hematopoiesis,	Molecular Bilogy, 2000, vol. 138:	Wound healing, cancer,
			agiogenesis, and leukocye trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,	prevent organ transplant
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.	rejection, Increase or
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ	enhance an inflammatory
			including inflammation, allergy, tissue		response,
			rejection, viralk infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Chemokine	GeneSeq	WO9912968	Chemokines are a family of related small,	Chemokine activities can be determined	Immune disorders,
hMCP1b	Accession		secreted proteins involved in biological	using assays known in the art: Methods in	Vascular disorders,
	Y14226		processes ranging from hematopoiesis,	Molecular Bilogy, 2000, vol. 138:	Wound healing, cancer,
			agiogenesis, and leukocye trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,	prevent organ transplant
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.	rejection, Increase or
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ	enhance an inflammatory
			including inflammation, allergy, tissue		response,
			rejection, viralk infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Chemokine	GeneSeq	WO9912968	Chemokines are a family of related small,	Chemokine activities can be determined	Immune disorders,
hSDF1b	Accession		secreted proteins involved in biological	using assays known in the art: Methods in	Vascular disorders,
	Y14228		processes ranging from hematopoiesis,	Molecular Bilogy, 2000, vol. 138:	Wound healing, cancer,
			agiogenesis, and leukocye trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,	prevent organ transplant
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.	rejection, Increase or
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ	enhance an inflammatory
			including inflammation, allergy, tissue		response,
			rejection, viralk infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Chemokine	GeneSeq	WO9912968	Chemokines are a family of related small,	Chemokine activities can be determined	Immune disorders,
hIL-8	Accession		secreted proteins involved in biological	using assays known in the art: Methods in	Vascular disorders,
	Y14229		processes ranging from hematopoiesis,	Molecular Bilogy, 2000, vol. 138:	Wound healing, cancer,
			agiogenesis, and leukocye trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,	prevent organ transplant
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.	rejection, Increase or
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ; and	enhance an inflammatory
			including inflammation, allergy, tissue	Holmes et al (1991) Science 253, 1278-80.	response,
			rejection, viralk infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Chemokine	GeneSeq	WO9912968	Chemokines are a family of related small,	Chemokine activities can be determined	Immune disorders,
hMCP1	Accession		secreted proteins involved in biological	using assays known in the art: Methods in	Vascular disorders,
	Y14222		processes ranging from hematopoiesis,	Molecular Bilogy, 2000, vol. 138:	Wound healing, cancer,
			agiogenesis, and leukocye trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,	prevent organ transplant
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.	rejection, Increase or
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ	enhance an inflammatory
			including inflammation, allergy, tissue		response,
			rejection, viralk infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Chemokine	GeneSeq	WO9912968	Chemokines are a family of related small,	Chemokine activities can be determined	Immune disorders,
hMCP2	Accession		secreted proteins involved in biological	using assays known in the art: Methods in	Vascular disorders,
	Y14223		processes ranging from hematopoiesis,	Molecular Bilogy, 2000, vol. 138:	Wound healing, cancer,
			agiogenesis, and leukocye trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,	prevent organ transplant
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.	rejection, Increase or
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ	enhance an inflammatory
			including inflammation, allergy, tissue		response,
			rejection, viralk infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Chemokine	GeneSeq	WO9912968	Chemokines are a family of related small,	Chemokine activities can be determined	Immune disorders,
hMCP3	Accession		secreted proteins involved in biological	using assays known in the art: Methods in	Vascular disorders,
	Y14224		processes ranging from hematopoiesis,	Molecular Bilogy, 2000, vol. 138:	Wound healing, cancer,
			agiogenesis, and leukocye trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,	prevent organ transplant
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.	rejection, Increase or
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ	enhance an inflammatory
			including inflammation, allergy, tissue		response,
			rejection, viralk infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
C-C chemokine,	GeneSeq	EP905240	Chemokines are a family of related small,	Chemokine activities can be determined	Inflammatory, Immune and
MCP2	Accession		secreted proteins involved in biological	using assays known in the art: Methods in	infectious diseases;
	Y05300		processes ranging from hematopoiesis,	Molecular Bilogy, 2000, vol. 138:	pulmonary diseases and
			agiogenesis, and leukocye trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,	skin disorders; tumours,
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.	and angiogenesis-and
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ	haematopoiesis-related
			including inflammation, allergy, tissue		diseases
			rejection, viralk infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Wild type	GeneSeq	EP906954	Chemokines are a family of related small,	Chemokine activities can be determined	Inflammatory, Immune and
monocyte	Accession		secreted proteins involved in biological	using assays known in the art: Methods in	infectious diseases;
chemotactic	Y07233		processes ranging from hematopoiesis,	Molecular Bilogy, 2000, vol. 138:	pulmonary diseases and
protein 2			agiogenesis, and leukocye trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,	skin disorders; tumours,
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.	and angiogenesis-and
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ	haematopoiesis-related
			including inflammation, allergy, tissue		diseases
			rejection, viralk infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Truncated	GeneSeq	EP906954	Chemokines are a family of related small,	Chemokines activities can be determined	Inflammatory, immune and
monocyte	Accession		secreted proteins involved in biological	using assays known in the art: Methods in	infectious diseases;
chemotactic	Y07234		processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:	pulmonry diseases and skin
protein 2 (6-76)			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,	disorders; tumours, and
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power,	angiogenesis-and
			similarly diverse range of pathologies	Humana Press Inc., Totowa, NJ	haematopoiesis-related
			including inflammation, allergy, tissue		diseases
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a fmaily of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Truncated	GeneSeq	EP905241;	Chemokines are a family of related small,	Chemokines activities can be determined	Inflammatory, immune and
RANTES	Accessions	EP906954	secreted proteins involved in biological	using assays known in the art: Methods in	infectious diseases;
protein (3-68)	Y07236 and		processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:	pulmonry diseases and skin
	Y07232		angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,	disorders; tumours, and
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power,	angiogenesis-and
			similarly diverse range of pathologies	Humana Press Inc., Totowa, NJ	haematopoiesis-related
			including inflammation, allergy, tissue		diseases
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a fmaily of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Wild type	GeneSeq	EP905241	Chemokines are a family of related small,	Chemokines activities can be determined	Inflammatory, immune and
monocyte	Accession		secreted proteins involved in biological	using assays known in the art: Methods in	infectious diseases;
chemotactic	Y07237		processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:	pulmonry diseases and skin
protein
2			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,	disorders; tumours, and
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power,	angiogenesis-and
			similarly diverse range of pathologies	Humana Press Inc., Totowa, NJ	haematopoiesis-related
			including inflammation, allergy, tissue		diseases
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a fmaily of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Truncated	GeneSeq	EP905241	Chemokines are a family of related small,	Chemokines activities can be determined	Inflammatory, immune and
monocyte	Accession		secreted proteins involved in biological	using assays known in the art: Methods in	infectious diseases;
chemotactic	Y07238		processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:	pulmonry diseases and skin
protein 2 (6-76)			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,	disorders; tumours, and
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power,	angiogenesis-and
			similarly diverse range of pathologies	Humana Press Inc., Totowa, NJ	haematopoiesis-related
			including inflammation, allergy, tissue		diseases
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a fmaily of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
A partial	GeneSeq	EP897980	Chemokines are a family of related small,	Chemokines activities can be determined	Soluble CXCR4B receptor
CXCR4B	Accession		secreted proteins involved in biological	using assays known in the art: Methods in	polypeptides may be useful
protein	W97363		processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:	for inhibiting chemokine
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,	activities and viral infection.
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power,
			similarly diverse range of pathologies	Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a fmaily of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Interferon	GeneSeq	U.S. Pat. No. 5,871,723	Chemokines are a family of related small,	Chemokines activities can be determined	Angiogenesis, Cancer,
gamma-	Accession		secreted proteins involved in biological	using assays known in the art: Methods in	Inflammatory and Immune
inducible	W96709		processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:	disorders, Cardio-Vascular
protein (IP-10)			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,	discorders, Musco-skeletal
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power,	disorders
			similarly diverse range of pathologies	Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a fmaily of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
A monokine	GeneSeq	U.S. Pat. No. 5,871,723	Chemokines are a family of related small,	Chemokines activities can be determined	Angiogenesis, Cancer,
induced by	Accession		secreted proteins involved in biological	using assays known in the art: Methods in	Inflammatory and Immune
gamma-	W96710		processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:	disorders, Cardio-Vascular
interferon			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,	discorders, Musco-skeletal
(MIG)			Members of this family are involved in a	T. N. C. Wells, and C. A. Power,	disorders
			similarly diverse range of pathologies	Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a fmaily of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Interleukin-8	GeneSeq	U.S. Pat. No. 5,871,723	Chemokines are a family of related small,	Chemokines activities can be determined	Angiogenesis, Cancer,
(IL-8) protein.	Accession		secreted proteins involved in biological	using assays known in the art: Methods in	Inflammatory and Immune
	W96711		processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:	disorders, Cardio-Vascular
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,	discorders, Musco-skeletal
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power,	disorders
			similarly diverse range of pathologies	Humana Press Inc., Totowa, NJ; and
			including inflammation, allergy, tissue	Holmes et al (1991) Science 253, 1278-80.
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a fmaily of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Epithelial	GeneSeq	U.S. Pat. No. 5,871,723	Chemokines are a family of related small,	Chemokines activities can be determined	Angiogenesis, Cancer,
neutrophil	Accession		secreted proteins involved in biological	using assays known in the art: Methods in	Inflammatory and Immune
activating	W96712		processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:	disorders, Cardio-Vascular
protein-78			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,	discorders, Musco-skeletal
(ENA-78)			Members of this family are involved in a	T. N. C. Wells, and C. A. Power,	disorders
			similarly diverse range of pathologies	Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a fmaily of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Growth related	GeneSeq	U.S. Pat. No. 5,871,723	Chemokines are a family of related small,	Chemokines activities can be determined	Angiogenesis, Cancer,
oncogene-alpha	Accession		secreted proteins involved in biological	using assays known in the art: Methods in	Inflammatory and Immune
(GRO-alpha).	W96713		processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:	disorders, Cardio-Vascular
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,	discorders, Musco-skeletal
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power,	disorders
			similarly diverse range of pathologies	Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a fmaily of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Growth related	GeneSeq	U.S. Pat. No. 5,871,723	Chemokines are a family of related small,	Chemokine activities can be determined	Angiogenesis, Cancer,
oncogene-beta	Accession		secreted proteins involved in biological	using assays known in the art: Methods in	Inflammatory and Immune
(GRO-beta).	W96714		processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:	disorders, Cardio-Vascular
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,	disorders, Musco-skeletal
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power,	disorders
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified
Growth related	GeneSeq	U.S. Pat. No. 5,871,723	Chemokines are a family of related small,	Chemokine activities can be determined	Angiogenesis, Cancer,
oncogene-gamma	Accession W96715		secreted proteins involved in biological	using assays known in the art: Methods in	Inflammatory and Immune
(GRO-gamma)			processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:	disorders, Cardio-Vascular
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,	disorders, Musco-skeletal
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power,	disorders
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
A platelet basic	GeneSeq	U.S. Pat. No. 5,871,723	Chemokines are a family of related small,	Chemokine activities can be determined	Angiogenesis, Cancer,
protein (PBP)	Accession W96716		secreted proteins involved in biological	using assays known in the art: Methods in	Inflammatory and Immune
			processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:	disorders, Cardio-Vascular
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,	disorders, Musco-skeletal
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power,	disorders
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Connective tissue	GeneSeqAccession	U.S. Pat. No. 5,871,723	Chemokines are a family of related small,	Chemokine activities can be determined	Angiogenesis, Cancer,
activating protein-	S96717		secreted proteins involved in biological	using assays known in the art: Methods in	Inflammatory and Immune
III (CTAP-III)			processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:	disorders, Cardio-Vascular
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,	disorders, Musco-skeletal
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power,	disorders
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Beta-	GeneSeq	U.S. Pat. No. 5,871,723	Chemokines are a family of related small,	Chemokine activities can be determined	Angiogenesis, Cancer,
thromboglobulin	Accession W96718		secreted proteins involved in biological	using assays known in the art: Methods in	Inflammatory and Immune
protein (beta-TG)			processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:	disorders, Cardio-Vascular
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,	disorders, Musco-skeletal
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power,	disorders
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Neutrophil	GeneSeq	U.S. Pat. No. 5,871,723	Chemokines are a family of related small,	Chemokine activities can be determined	Angiogenesis, Cancer,
activating peptide-	Accession W96719		secreted proteins involved in biological	using assays known in the art: Methods in	Inflammatory and Immune
2 (NAP-2)			processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:	disorders, Cardio-Vascular
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,	disorders, Musco-skeletal
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power,	disorders
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Granulocyte	GeneSeq	U.S. Pat. No. 5,871,723	Chemokines are a family of related small,	Chemokine activities can be determined	Angiogenesis, Cancer,
chemotactic	Accession W96720		secreted proteins involved in biological	using assays known in the art: Methods in	Inflammatory and Immune
protein-2 (GCP-2)			processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:	disorders, Cardio-Vascular
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,	disorders, Musco-skeletal
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power,	disorders
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Human	GeneSeq	EP887409	Chemokines are a family of related small,	Chemokine activities can be determined	Immune disorders, viral,
chemokine MIG-	Accession W90124		secreted proteins involved in biological	using assays known in the art: Methods in	parasitic, fungal or
beta protein			processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:	bacterial infections,
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,	Cancer; autoimmune
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power,	diseases or transplant
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ	rejection
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Human ZCHEMO-8	GeneSeq	WO9854326	Chemokines are a family of related small,	Chemokine activities can be determined	Immune disorders, cancer,
	Accession W82716		secreted proteins involved in biological	using assays known in the art: Methods in	myelopoietic disorders,
			processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:	autoimmune disorders and
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,	immunodeficiencies,
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power,	Inflammatory and
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ	infectious diseases,
			including inflammation, allergy, tissue		Vascular disorders, wound
			rejection, viral infection, and tumor		healing
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Human Act-2	GeneSeq	WO9854326	Chemokines are a family of related small,	Chemokine activities can be determined	Immune disorders, cancer,
protein	Accession W82717		secreted proteins involved in biological	using assays known in the art: Methods in	myelopoietic disorders,
			processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:	autoimmune disorders and
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,	immunodeficiencies,
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power,	Inflammatory and
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ	infectious diseases,
			including inflammation, allergy, tissue		Vascular disorders, wound
			rejection, viral infection, and tumor		healing
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Human SISD	GeneSeq	WO9854326	Chemokines are a family of related small,	Chemokine activities can be determined	Immune disorders, cancer,
protein	Acession		secreted proteins involved in biological	using assays known in the art: Methods in	myelopoietic disorders,
	W82720		processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:	autoimmune disorders and
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols, Edited by: A. E. I. Proudfoot,	immunodeficiencies,
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.	Inflammatory and
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ	infectious diseases,
			including inflammation, allergy, tissue		Vascular disorders, wound
			rejection, viral infection, and tumor		healing
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Human M110	GeneSeq	WO9854326	Chemokines are a family of related	Chemokine activities can be determined	Immune disorders, cancer,
protein	Accession		small, secreted proteins involved in	using assays known in the art: Mehtods of	myelopoietic disorders,
	W82721		biological processes ranging from	Molecular Biology, 2000, vol. 138:	autoimmune disorders and
			hematopoiesis, angiogenesis, and	Chemokine Protocols. Edited by: A. E. I. Proudfoot,	immunodeficiencies,
			leukocyte trafficking. Members of this	T. N. C. Wells, and C. A. Power	Inflammatory and
			family are involved in a similarly diverse	© Humana Press Inc., Totowa, NJ	infectious diseases,
			range of pathologies including		Vascular disorders, wound
			inflammation, allergy, tissue rejection,		healing
			viral infection, and tumor biology. The
			chemokines exert their effects by acting
			on a family of seven transmembrane G-
			protein-coupled receptors. Over 40
			human chemokines have been
			described, which bind to ~17 receptors
			thus far identified.
Human M11A	GeneSeq	W09854326	Chemokines are a family of related	Chemokine activities can be determined	Immune disorders, cancer,
protein	Accession		small, secreted proteins involved in	using assays known in the art: Mehtods of	myelopoietic disorders,
	W82722		biological processes ranging from	Molecular Biology, 2000, vol. 138:	autoimmune disorders and
			hematopoiesis, angiogenesis, and	Chemokine Protocols. Edited by: A. E. I. Proudfoot,	immunodeficiencies,
			leukocyte trafficking. Members of this	T. N. C. Wells, and C. A. Power	Inflammatory and
			family are involved in a similarly diverse	© Humana Press Inc., Totowa, NJ	infectious diseases,
			range of pathologies including		Vascular disorders, wound
			inflammation, allergy, tissue rejection,		healing
			viral infection, and tumor biology. The
			chemokines exert their effects by acting
			on a family of seven transmembrane G-
			protein-coupled receptors. Over 40
			human chemokines have been
			described, which bind to ~17 receptors
			thus far identified.
Human CCC3	GeneSeq	WO9854326	Chemokines are a family of related	Chemokine activities can be determined	Immune disorders, cancer,
protein	Accession		small, secreted proteins involved in	using assays known in the art: Mehtods of	myelopoietic disorders,
	W82723		biological processes ranging from	Molecular Biology, 2000, vol. 138:	autoimmune disorders and
			hematopoiesis, angiogenesis, and	Chemokine Protocols. Edited by: A. E. I. Proudfoot,	immunodeficiencies,
			leukocyte trafficking. Members of this	T. N. C. Wells, and C. A. Power	Inflammatory and
			family are involved in a similarly diverse	© Humana Press Inc., Totowa, NJ	infectious diseases,
			range of pathologies including		Vascular disorders, wound
			inflammation, allergy, tissue rejection,		healing
			viral infection, and tumor biology. The
			chemokines exert their effects by acting
			on a family of seven transmembrane G-
			protein-coupled receptors. Over 40
			human chemokines have been
			described, which bind to ~17 receptors
			thus far identified.
A human L105	GeneSeq	WO9856818	Chemokines are a family of related	Chemokine activities can be determined	Cancer, wound healing
chemokine	Accession		small, secreted proteins involved in	using assays known in the art: Mehtods of
designated	W87588		biological processes ranging from	Molecular Biology, 2000, vol. 138:
huL105_3.			hematopoiesis, angiogenesis, and	Chemokine Protocols. Edited by: A. E. I. Proudfoot,
			leukocyte trafficking. Members of this	T. N. C. Wells, and C. A. Power
			family are involved in a similarly diverse	© Humana Press Inc., Totowa, NJ
			range of pathologies including
			inflammation, allergy, tissue rejection,
			viral infection, and tumor biology. The
			chemokines exert their effects by acting
			on a family of seven transmembrane G-
			protein-coupled receptors. Over 40
			human chemokines have been
			described, which bind to ~17 receptors
			thus far identified.
A human L105	GeneSeq	WO9856818	Chemokines are a family of related	Chemokine activities can be determined	Cancer, wound healing
chemokine	Accession		small, secreted proteins involved in	using assays known in the art: Mehtods of
designated	W87589		biological processes ranging from	Molecular Biology, 2000, vol. 138:
huL105_7.			hematopoiesis, angiogenesis, and	Chemokine Protocols. Edited by: A. E. I. Proudfoot,
			leukocyte trafficking. Members of this	T. N. C. Wells, and C. A. Power
			family are involved in a similarly diverse	© Humana Press Inc., Totowa, NJ
			range of pathologies including
			inflammation, allergy, tissue rejection,
			viral infection, and tumor biology. The
			chemokines exert their effects by acting
			on a family of seven transmembrane G-
			protein-coupled receptors. Over 40
			human chemokines have been
			described, which bind to ~17 receptors
			thus far identified.
Human mature	GeneSeq	WO9848828	Chemokines are a family of related	Chemokine activities can be determined	Infectious diseases, sepsis
gro-alpha	Accession		small, secreted proteins involved in	using assays known in the art: Mehtods of
polypeptide	W81498		biological processes ranging from	Molecular Biology, 2000, vol. 138:
used to treat			hematopoiesis, angiogenesis, and	Chemokine Protocols. Edited by: A. E. I. Proudfoot,
sepsis			leukocyte trafficking. Members of this	T. N. C. Wells, and C. A. Power
			family are involved in a similarly diverse	© Humana Press Inc., Totowa, NJ
			range of pathologies including
			inflammation, allergy, tissue rejection,
			viral infection, and tumor biology. The
			chemokines exert their effects by acting
			on a family of seven transmembrane G-
			protein-coupled receptors. Over 40
			human chemokines have been
			described, which bind to ~17 receptors
			thus far identified.
Human mature	GeneSeq	WO9848828	Chemokines are a family of related	Chemokine activities can be determined	Infectious diseases, sepsis
gro-gamma	Accession		small, secreted proteins involved in	using assays known in the art: Mehtods of
polypeptide	W81500		biological processes ranging from	Molecular Biology, 2000, vol. 138:
used to treat			hematopoiesis, angiogenesis, and	Chemokine Protocols. Edited by: A. E. I. Proudfoot,
sepsis			leukocyte trafficking. Members of this	T. N. C. Wells, and C. A. Power
			family are involved in a similarly diverse	© Humana Press Inc., Totowa, NJ
			range of pathologies including
			inflammation, allergy, tissue rejection,
			viral infection, and tumor biology. The
			chemokines exert their effects by acting
			on a family of seven transmembrane G-
			protein-coupled receptors. Over 40
			human chemokines have been
			described, which bind to ~17 receptors
			thus far identified.
Human thymus	GeneSeq	WO0053635	Chemokines are a family of related	Chemokine activities can be determined	Inflammatory disorders,
expressed	Accessions		small, secreted proteins involved in	using assays known in the art: Mehtods of	cancer, Immune and
chemokine	B19607 and		biological processes ranging from	Molecular Biology, 2000, vol. 138:	vascular disorders
TECK and	B19608		hematopoiesis, angiogenesis, and	Chemokine Protocols. Edited by: A. E. I. Proudfoot,
TECK variant			leukocyte trafficking. Members of this	T. N. C. Wells, and C. A. Power
			family are involved in a similarly diverse	© Humana Press Inc., Totowa, NJ
			range of pathologies including
			inflammation, allergy, tissue rejection,
			viral infection, and tumor biology. The
			chemokines exert their effects by acting
			on a family of seven transmembrane G-
			protein-coupled receptors. Over 40
			human chemokines have been
			described, which bind to ~17 receptors
			thus far identified.
Human	GeneSeq	WO0042071	Chemokines are a family of related	Chemokine activities can be determined	Autoimmune disorders,
chemokine	Accession B15791		small, secreted proteins involved in	using assays known in the art: Mehtods of	Immune, Vascular and
SDF1alpha			biological processes ranging from	Molecular Biology, 2000, vol. 138:	Inflammatory disorders
			hematopoiesis, angiogenesis, and	Chemokine Protocols. Edited by: A. E. I. Proudfoot,
			leukocyte trafficking. Members of this	T. N. C. Wells, and C. A. Power
			family are involved in a similarly diverse	© Humana Press Inc., Totowa, NJ
			range of pathologies including
			inflammation, allergy, tissue rejection,
			viral infection, and tumor biology. The
			chemokines exert their effects by acting
			on a family of seven transmembrane G-
			protein-coupled receptors. Over 40
			human chemokines have been
			described, which bind to ~17 receptors
			thus far identified.
Human	GeneSeq	WO0042071	Chemokines are a family of related small,	Chemokine activities can be determined	Autoimmune disorders,
chemokine	Accession B15793		secreted proteins involved in biological	using assasys known in the art: Methods	Immune, Vascular and
GROalpha			processes ranging from hematopoiesis,	in Molecular Biology, 2000, vol. 138:	Inflammatory diorders
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot;
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Human	GeneSeq	WO0042071	Chemokines are a family of related small,	Chemokine activities can be determined	Autoimmune disorders,
chemokine	Accession B15794		secreted proteins involved in biological	using assasys known in the art: Methods in	Immune, Vascular and
eotaxin			processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:	Inflammatory disorders
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot;
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Human	GeneSeq	WO0042071	Chemokines are a family of related small,	Chemokine activities can be determined	Autoimmune disorders,
chemokine MIG	Accession B15803		secreted proteins involved in biological	using assasys known in the art: Methods in	Immune, Vascular and
			processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:	Inflammatory disorders
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot;
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Human	GeneSeq	WO0042071	Chemokines are a family of related small,	Chemokine activities can be determined	Autoimmune disorders,
chemokine PF4	Accession B15804		secreted proteins involved in biological	using assasys known in the art: Methods in	Immune, Vascular and
			processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:	Inflammatory disorders
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot;
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Human	GeneSeq	WO0042071	Chemokines are a family of related small,	Chemokine activities can be determined	Autoimmune disorders,
chemokine I-309	Accession B15805		secreted proteins involved in biological	using assasys known in the art: Methods in	Immune, Vascular and
			processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:	Inflammatory disorders
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot;
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Human	GeneSeq	WO0042071	Chemokines are a family of related small,	Chemokine activities can be determined	Autoimmune disorders,
chemokine HCC-1	Accession B15806		secreted proteins involved in biological	using assasys known in the art: Methods in	Immune, Vascular and
			processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:	Inflammatory disorders
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot;
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Human	GeneSeq	WO0042071	Chemokines are a family of related small,	Chemokine activities can be determined	Autoimmune disorders,
chemokine C10	Accession B15807		secreted proteins involved in biological	using assasys known in the art: Methods in	Immune, Vascular and
			processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:	Inflammatory disorders
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot;
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Human	GeneSeq	WO0042071	Chemokines are a family of related small,	Chemokine activities can be determined	Autoimmune disorders,
chemokine CCR-2	Accession B15808		secreted proteins involved in biological	using assasys known in the art: Methods in	Immune, Vascular and
			processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:	Inflammatory disorders
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot;
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Human	GeneSeq	WO0042071	Chemokines are a family of related small,	Chemokine activities can be determined	Autoimmune disorders,
chemokine ENA-	Accession B15809		secreted proteins involved in biological	using assasys known in the art: Methods in	Immune, Vascular and
78			processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:	Inflammatory disorders
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot;
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Human	GeneSeq	WO0042071	Chemokines are a family of related small,	Chemokine activities can be determined	Autoimmune disorders,
chemokine	Accession B15810		secreted proteins involved in biological	using assasys known in the art: Methods in	Immune, Vascular and
GRObeta			processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:	Inflammatory disorders
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot;
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Human	GeneSeq	WO0042071	Chemokines are a family of related small,	Chemokine activities can be determined	Autoimmune disorders,
chemokine IP-10	Accession B15811		secreted proteins involved in biological	using assays known in the art: Methods in	Immune, Vascular and
			processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:	Inflammatory disorders
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Human	GeneSeq	WO0042071	Chemokines are a family of related small,	Chemokine activities can be determined	Autoimmune disorders,
chemokine	Accession B15812		secreted proteins involved in biological	using assays known in the art: Methods in	Immune, Vascular and
SDF1beta			processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:	Inflammatory disorders
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Human	GeneSeq	WO0042071	Chemokines are a family of related small,	Chemokine activities can be determined	Autoimmune disorders,
chemokine GRO	Accession B15813		secreted proteins involved in biological	using assays known in the art: Methods in	Immune, Vascular and
alpha			processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:	Inflammatory disorders
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Human	GeneSeq	WO0042071	Chemokines are a family of related small,	Chemokine activities can be determined	Autoimmune disorders,
chemokine	Accession B15831		secreted proteins involved in biological	using assays known in the art: Methods in	Immune, Vascular and
MIP1beta			processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:	Inflammatory disorders
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
A human C-C	GeneSeq	U.S. Pat. No. 6,096,300	Chemokines are a family of related small,	Chemokine activities can be determined	Cancer
chemokine	Accession B07939		secreted proteins involved in biological	using assays known in the art: Methods in
designated			processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:
exodus			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Human	GeneSeq	U.S. Pat. No. 6,084,071	Chemokines are a family of related small,	Chemokine activities can be determined	Chemotaxis, Gene
chemokine	Accession Y96922		secreted proteins involved in biological	using assays known in the art: Methods in	Therapy, Wound healing
L105_7			processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Human	GeneSeq	U.S. Pat. No. 6,084,071	Chemokines are a family of related small,	Chemokine activities can be determined	Chemotaxis, Gene
chemokine	Accession Y96923		secreted proteins involved in biological	using assays known in the art: Methods in	Therapy, Wound healing
L105_3			processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Human secondary	GeneSeq	WO0038706	Chemokines are a family of related small,	Chemokine activities can be determined	Cancer, Vascular and
lymphoid	Accession B01434		secreted proteins involved in biological	using assays known in the art: Methods in	Immune disorders
chemokine (SLC)			processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Human non-ELR	GeneSeq	WO0029439	Chemokines are a family of related small,	Chemokine activities can be determined	Immune and Inflammatory
CXC chemokine	Accession Y96310		secreted proteins involved in biological	using assays known in the art: Methods in	disorders, Cancer,
H174			processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:	Haemostatic and
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,	thrombolytic activity
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Human non-ELR	GeneSeq	WO0029439	Chemokines are a family of related small,	Chemokine activities can be determined	Immune and Inflammatory
CXC chemokine	Accession Y96311		secreted proteins involved in biological	using assays known in the art: Methods in	disorders, Cancer,
IP10			processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:	haemostatic and
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,	thrombolytic activity
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ~17
			receptors thus far identified.
Human non-ELR	GeneSeq	WO0029439	Chemokines are a family of related small,	Chemokine activities can be determined	Immune and Inflammatory
CXC chemokine	Accession Y96313		secreted proteins involved in biological	using assays known in the art: Methods in	disorders, Cancer,
Mig			processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:	haemostatic and
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,	thrombolytic activity
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ^~17
			receptors thus far identified.
Human	GeneSeq	WO0028035	Chemokines are a family of related small,	Chemokine activities can be determined	Cancer, wound healing,
chemokine	Accession Y96280		secreted proteins involved in biological	using assays known in the art: Methods in	inflammatory and
Ckbeta-7			processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:	immunoregulatory
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,	disorders
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ^~17
			receptors thus far identified.
Human	GeneSeq	WO0028035	Chemokines are a family of related small,	Chemokine activities can be determined	Cancer, wound healing,
chemokine MIP-	Accession Y96281		secreted proteins involved in biological	using assays known in the art: Methods in	inflammatory and
1alpha			processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:	immunoregulatory
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,	disorders
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ^~17
			receptors thus far identified.
Human mature	GenSeq	WO0028035	Chemokines are a family of related small,	Chemokine activities can be determined	Cancer, wound healing,
chemokine	Accession Y96282		secreted proteins involved in biological	using assays known in the art: Methods in	inflammatory and
Ckbeta-7			processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:	immunoregulatory
(optionally			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,	disorders
truncated)			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ^~17
			receptors thus far identified.
Human	GeneSeq	WO0018431	Chemokines are a family of related small,	Chemokine activities can be determined	Soluble CXCR3
chemokine	Accession Y79372		secreted proteins involved in biological	using assays known in the art: Methods in	polypeptides may be
receptor CXCR3			processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:	useful for inhibiting
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,	chemokine activities and
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.	viral infection.
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ^~17
			receptors thus far identified.
Human	GeneSeq	U.S. Pat. No. 6,043,086	Chemokines are a family of related small,	Chemokine activities can be determined	Neurological disorders,
neurotactin	Accession Y53259		secreted proteins involved in biological	using assays known in the art: Methods in	Immune and respiratory
chemokine like			processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:	disorders
domain			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ^~17
			receptors thus far identified.
Human CC type	GeneSeq	JP11302298	Chemokines are a family of related small,	Chemokine activities can be determined	Cancer and infectious
chemokine	Accession Y57771		secreted proteins involved in biological	using assays known in the art: Methods in	diseases
interleukin C			processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ^~17
			receptors thus far identified
Human CKbeta-9	GeneSeq	U.S. Pat. No. 6,153,441	Chemokines are a family of related small,	Chemokine activities can be determined	Cancer, Auto-immune and
	Accession B50860		secreted proteins involved in biological	using assays known in the art: Methods in	inflammatory disorders,
			processes ranging from hematopoiesis,	Molecular Biology, 2000, vol. 138:	Cardiovascular disorders
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by: A. E. I. Proudfoot,
			Members of this family are involved in a	T. N. C. Wells, and C. A. Power.
			similarly diverse range of pathologies	© Humana Press Inc., Totowa, NJ
			including inflammation, allergy, tissue
			rejection, viral infection, and tumor
			biology. The chemokines exert their
			effects by acting on a family of seven
			transmembrane G-protein-coupled
			receptors. Over 40 human chemokines
			have been described, which bind to ^~17
			receptors thus far identified
Preproapolipoprotein	GeneSeq	WO9637608	Apoa-1 participates in the reverse	Lipid binding activity can be determined	Useful for cardiovascular
“paris” variant	Accession		transport of cholesterol from tissues to	using assays known in the art, such as, for	disorders, cholesterol
	W08602		the liver for excretion by promoting	example, the Cholesterol Efflux Assays of	disorders, and
			cholesterol efflux from tissues and by	Takahaski et al., P. N. A. S., Vol. 96, Issue	Hyperlipidaemia
			acting as a cofactor for the lecithin	20, 11358-11363, Sep. 28, 1999.
			cholesterol acyltransferase (Icat).
Preproapolipoprotein		5,721,114	Apoa-1 participates in the reverse	Lipid binding activity can be determined	Useful for cardiovascular
“milano”			transport of cholesterol from tissues to	using assays known in the art, such as, for	disorders, cholesterol
variant			the liver for excretion by promoting	example, the Cholesterol Efflux Assays of	disorders, and
			cholesterol efflux from tissues and by	Takahaski et al., P. N. A. S., Vol. 96, Issue	Hyperlipidaemia
			acting as a cofactor for the lecithin	20, 11358-11363, Sep. 28, 1999.
			cholesterol acyltransferase (Icat).
Glycodelin-A;	GeneSeq	WO9628169	Naturally produced female contraceptive	Glycodelin-A activity can be determined	Naturally derived
Progesterone-	Accession		that is removed rapidly from the body	using the hemizona assay as described in	contraceptive useful for
associated	W00289		following 2-3 days production. Uses	Oehninger, S., Coddington, C. C., Hodgen, G. D.,	the prevention of
endometrial			include contraception	and Seppala, M (1995) Fertil. Steril.	pregnancy.
protein				63, 377-383.
NOGO-A	Genbank		NOGO polypeptides are potent inhibitors	Inhibition of Neurite outgrowth.	NOGO-A polypeptide
	Accession		of neurite growth.	Antagonists to NOGO polypeptides may	antagonists are useful for
	CAB99248			promote the outgrowth of neurites, thus	the promotion of neural
				inducing regeneration of neurons.	growth, which could be
					useful in the treatment of
					neural disorders and
					dysfunction due to
					degenerative diseases or
					trauma; useful in the
					treatment of neoplastic
					diseases of the CNS;
					induce regeneration of
					neurons or to promote the
					structural plasticity of the
					CNS.
NOGO-B	Genbank		NOGO polypeptides are potent inhibitors	Inhibition of Neurite outgrowth.	NOGO-B polypeptide
	Accession		of neurite growth.	Antagonists to NOGO polypeptides may	antagonists are useful for
	CAB99249			promote the outgrowth of neurites, thus	the promotion of neural
				inducing regeneration of neurons.	growth, which could be
					useful in the treatment of
					neural disorders and
					dysfunction due to
					degenerative diseases or
					trauma; useful in the
					treatment of neoplastic
					diseases of the CNS;
					induce regeneration of
					neurons or to promote the
					structural plasticity of the
					CNS.
NOGO-C	Genbank		NOGO polypeptides are potent inhibitors	Inhibition of Neurite outgrowth.	NOGO-C polypeptide
	Accession		of neurite growth.	Antagonists to NOGO polypeptides may	antagonists are useful for
	CAB99250			promote the outgrowth of neurites, thus	the promotion of neural
				inducing regeneration of neurons.	growth, which could be
					useful in the treatment of
					neural disorders and
					dysfunction due to
					degenerative diseases or
					trauma; useful in the
					treatment of neoplastic
					diseases of the CNS;
					induce regeneration of
					neurons or to promote the
					structural plasticity of the
					CNS.
NOGO-66	Genbank		NOGO polypeptides are potent inhibitors	Inhibition of Neurite outgrowth by	NOGO-66 receptor
Receptor	Accession		of neurite growth, and are thought to	mediating the biological effects of NOGO	polypeptides are useful for
	AAG53612		mediate their effects through the NOGO-	polypeptides. Soluble NOGO-66 receptor	the promotion of neural
			66 Receptor.	polypeptides may promote the outgrowth	growth, which could be
				of neurites, thus inducing regeneration of	useful in the treatment of
				neurons.	neural disorders and
					dysfunction due to
					degenerative diseases or
					trauma; useful in the
					treatment of neoplastic
					diseases of the CNS;
					induce regeneration of
					neurons or to promote the
					structural plasticity of the
					CNS.
Antibodies specific		U.S. Pat. No. 5,416,197	These antibodies are useful for the	Collapsin activity, which is thought to	Useful for the promotion of
for collapsin			promotion of neurite outgrowth	inhibit the outgrowth of neurites, can be	neural growth, which could
				assayed in the presence of antibodies	be useful in the treatment
				specific for collapsing using assays known	of neural disorders and
				in the art, such as, for example, the	dysfunction due to
				collapse assay disclosed by Luo et al.,	degenerative diseases or
				Cell 1993 Oct 22; 75(2): 217-27	trauma.
Humanized Anti-		WO9845331	These agents have anti-inflammatory and	VEGF activity can be determined using	Promotion of growth and
VEGF Antibodies,			anti-cancer applications	assays known in the art, such as those	proliferation of cells, such
and fragments				disclosed in International Publication No.	as vascular endothelial
thereof				WO0045835, for example.	cells. Antagonists may be
					useful as anti-angiogenic
					agents, and may be
					applicable for cancer
Humanized Anti-		WO0029584	These agents have anti-inflammatory and	VEGF activity can be determined using	Promotion of growth and
VEGF Antibodies,			anti-cancer applications	assays known in the art, such as those	proliferation of cells, such
and fragments				disclosed in International Publication No.	as vascular endothelial
thereof				WO0045835, for example.	cells. Antagonists may be
					useful as anti-angiogenic
					agents, and may be
					applicable for cancer
Membrane bound	GeneSeq.	WO9963088	Cancer, Immune Disorders	These proteins can be used for linking	Activities can be
proteins	Accession			bioactive molecules to cells and for	determined using assay
	Y66631-Y66765			modulating biological activities of cells,	known in the art, suchas,
				using the polypeptides for specific	for example, the assays
				targeting. The polypeptide targeting can	disclosed in International
				be used to kill the target cells, e.g. for the	Publication No.
				treatment of cancers. These proteins are	WO0121658.
				useful for the treatment of immune system
				disorders.
Secreted and	GenSeq	WO0053756	Cancer, Immune Disorders	These proteins can be used for linking	Activities can be
Transmembrane	Accession			bioactive molecules to cells and for	determined using assay
polypeptides	B44241-B44334			modulating biological activities of cells,	known in the art, suchas,
				using the polypeptides for specific	for example, the assays
				targeting. The polypeptide targeting can	disclosed in International
				be used to kill the target cells, e.g. for the	Publication No.
				treatment of cancers. These proteins are	WO0121658
				useful for the treatment of immune system
				disorders.
Secreted and	GeneSeq	WO9946281	Cancer, Immune Disorders	These proteins can be used for linking	Activities can be
Transmembrane	Accession			bioactive molecules to cells and for	determined using assay
polypeptides	Y41685-Y41774			modulating biological activities of cells,	known in the art, suchas,
				using the polypeptides for specific	for example, the assays
				targeting. The polypeptide targeting can	disclosed in International
				be used to kill the target cells, e.g. for the	Publication No.
				treatment of cancers. These proteins are	WO0121658
				useful for the treatment of immune system
				disorders.

Conjugation and Coupling.

The present invention provides therapeutic agents comprising an ELP component and a therapeutic component, such as therapeutic proteins listed in Table 1, as well as a GLP-1 receptor agonists, insulin, Factor VII/VIIa, and functional analogs as described. Such agents may be prepared by recombinant technology and/or chemical coupling (e.g., conjugation).
A recombinantly-produced ELP fusion protein, in accordance with certain embodiments of the invention, includes the ELP component and the therapeutic component associated with one another by genetic fusion. For example, the fusion protein may be generated by translation of a polynucleotide encoding the therapeutic component cloned in-frame with the ELP component (or vice versa). Such an ELP fusion protein may contain one or more copies of the therapeutic component attached to the N-terminus and/or the C-terminus of the ELP component. In some embodiments, the therapeutic proteinacious component is attached to both the N- and C-terminus of the ELP component and the fusion protein may contain one or more equivalents of the therapeutic component on either or both ends of the ELP component.
In certain embodiments, the ELP component and the therapeutic components can be fused using a linker peptide of various lengths to provide greater physical separation and allow more spatial mobility between the fused portions, and thus maximize the accessibility of the therapeutic component, for instance, for binding to its cognate receptor. The linker peptide may consist of amino acids that are flexible or more rigid. For example, a flexible linker may include amino acids having relatively small side chains, and which may be hydrophilic. Without limitation, the flexible linker may contain a stretch of glycine and/or serine residues. More rigid linkers may contain, for example, more sterically hindering amino acid side chains, such as (without limitation) tyrosine or histidine. The linker may be less than about 50, 40, 30, 20, 10, or 5 amino acid residues. The linker can be covalently linked to and between an ELP component and a therapeutic component, for example, via recombinant fusion.
The linker or peptide spacer may be protease-cleavable or non-cleavable. By way of example, cleavable peptide spacers include, without limitation, a peptide sequence recognized by proteases (in vitro or in vivo) of varying type, such as Tev, thrombin, factor Xa, plasmin (blood proteases), metalloproteases, cathepsins (e.g., GFLG, etc.), and proteases found in other corporeal compartments. In some embodiments employing cleavable linkers, the fusion protein (“the therapeutic agent”) may be inactive, less active, or less potent as a fusion, which is then activated upon cleavage of the spacer in vivo Alternatively, where the therapeutic agent is sufficiently active as a fusion, a non-cleavable spacer may be employed. The non-cleavable spacer may be of any suitable type, including, for example, non-cleavable spacer moieties having the formula [(Gly)n-Ser]m (SEQ ID NO.: 22) where n is from 1 to 4, inclusive, and m is from 1 to 4, inclusive. Alternatively, a short ELP sequence different than the backbone ELP could be employed instead of a linker or spacer, while accomplishing the necessary effect.
In still other embodiments, the therapeutic agent is a recombinant fusion having a therapeutic component flanked on each terminus by an ELP component. At least one of said ELP components may be attached via a cleavable spacer, such that the therapeutic component is inactive, but activated in vivo by proteolytic removal of a single ELP component. The resulting single ELP fusion being active, and having an enhanced half-life (or other property described herein) in vivo.
In other embodiments, the present invention provides chemical conjugates of the ELP component and the therapeutic component. The conjugates can be made by chemically coupling an ELP component to a therapeutic component by any number of methods well known in the art (See e.g. Nilsson et al., 2005, Ann Rev Biophys Bio Structure 34: 91-118). In some embodiments, the chemical conjugate can be formed by covalently linking the therapeutic component to the ELP component, directly or through a short or long linker moiety, through one or more functional groups on the therapeutic proteinacious component, e.g., amine, carboxyl, phenyl, thiol or hydroxyl groups, to form a covalent conjugate. Various conventional linkers can be used, e.g., diisocyanates, diisothiocyanates, carbodiimides, bis(hydroxysuccinimide) esters, maleimide-hydroxysuccinimide esters, glutaraldehyde and the like.
Non-peptide chemical spacers can additionally be of any suitable type, including for example, by functional linkers described in Bioconjugate Techniques, Greg T. Hermanson, published by Academic Press, Inc., 1995, and those specified in the Cross-Linking Reagents Technical Handbook, available from Pierce Biotechnology, Inc. (Rockford, Ill.), the disclosures of which are hereby incorporated by reference, in their respective entireties. Illustrative chemical spacers include homobifunctional linkers that can attach to amine groups of Lys, as well as heterobifunctional linkers that can attach to Cys at one terminus, and to Lys at the other terminus.
In certain embodiments, relatively small ELP components (e.g., ELP components of less than about 30 kDa, 25 kDa, 20 kDa, 15 kDa, or 10 kDa), that do not transition at room temperature (or human body temperature, e.g., Tt>37° C.), are chemically coupled or crosslinked. For example, two relatively small ELP components, having the same or different properties, may be chemically coupled. Such coupling, in some embodiments, may take place in vivo, by the addition of a single cysteine residue at or around the C-terminus of the ELP. Such ELP components may each be fused to one or more therapeutic components, so as to increase activity or avidity at the target.

Polynucleotides, Vectors, and Host Cells

In another aspect, the invention provides polynucleotides comprising a nucleotide sequence encoding the therapeutic agent of the invention. Such polynucleotides further comprise, in addition to sequences encoding the ELP and therapeutic components, one or more expression control elements. For example, the polynucleotide, may comprise one or more promoters or transcriptional enhancers, ribosomal binding sites, transcription termination signals, and polyadenylation signals, as expression control elements. The polynucleotide may be inserted within any suitable vector, which may be contained within any suitable host cell for expression.
A vector comprising the polynucleotide can be introduced into a cell for expression of the therapeutic agent. The vector can remain episomal or become chromosomally integrated, as long as the insert encoding the therapeutic agent can be transcribed. Vectors can be constructed by standard recombinant DNA technology. Vectors can be plasmids, phages, cosmids, phagemids, viruses, or any other types known in the art, which are used for replication and expression in prokaryotic or eukaryotic cells. It will be appreciated by one of skill in the art that a wide variety of components known in the art (such as expression control elements) may be included in such vectors, including a wide variety of transcription signals, such as promoters and other sequences that regulate the binding of RNA polymerase onto the promoter. Any promoter known to be effective in the cells in which the vector will be expressed can be used to initiate expression of the therapeutic agent. Suitable promoters may be inducible or constitutive. Examples of suitable promoters include the SV40 early promoter region, the promoter contained in the 3′ long terminal repeat of Rous sarcoma virus, the HSV-1 (herpes simplex virus-1) thymidine kinase promoter, the regulatory sequences of the metallothionein gene, etc., as well as the following animal transcriptional control regions, which exhibit tissue specificity and have been utilized in transgenic animals: elastase I gene control region which is active in pancreatic acinar cells; insulin gene control region which is active in pancreatic beta cells, immunoglobulin gene control region which is active in lymphoid cells, mouse mammary tumor virus control region which is active in testicular, breast, lymphoid and mast cells, albumin gene control region which is active in liver, alpha-fetoprotein gene control region which is active in liver, alpha 1-antitrypsin gene control region which is active in the liver, beta-globin gene control region which is active in erythroid cells, myelin basic protein gene control region which is active in oligodendrocyte cells in the brain, myosin light chain-2 gene control region which is active in skeletal muscle, and gonadotropin releasing hormone gene control region which is active in the hypothalamus.

Pharmaceutical Compositions

The present invention further provides pharmaceutical compositions comprising the therapeutic agents of the invention (as described above) together with a pharmaceutically acceptable carrier or excipient. Such pharmaceutical compositions may be employed in the methods of treatment as described above, for each of the therapeutic proteins, e.g., the therapeutic proteins listed in Table 1, GLP-1 receptor agonists, insulin, and Factor VII/VIIa embodiments.
The therapeutic agents of the invention may overcome certain deficiencies of peptide agents when administered (e.g., parenterally), including in some embodiments, the limitation that such peptides may be easily metabolized by plasma proteases or cleared from circulation by kidney filtration. Traditionally, the oral route of administration of peptide agents may also be problematic, because in addition to proteolysis in the stomach, the high acidity of the stomach destroys such peptide agents before they reach their intended target tissue. Peptides and peptide fragments produced by the action of gastric and pancreatic enzymes are cleaved by exo and endopeptidases in the intestinal brush border membrane to yield di- and tripeptides, and even if proteolysis by pancreatic enzymes is avoided, polypeptides are subject to degradation by brush border peptidases. Any of the peptide agents that survive passage through the stomach are further subjected to metabolism in the intestinal mucosa where a penetration barrier prevents entry into the cells. In certain embodiments, the therapeutic agents of the invention may overcome such deficiencies, and provide compositional forms having enhanced efficacy, bioavailability, therapeutic half-life, persistence, degradation assistance, etc. The therapeutic agents of the invention thus include oral and parenteral dose forms, as well as various other dose forms, by which peptide agents can be utilized in a highly effective manner. For example, in some embodiments, such agents may achieve high mucosal absorption, and the concomitant ability to use lower doses to elicit an optimum therapeutic effect.
The therapeutic agents of the present invention may be administered in smaller doses and/or less frequently than unfused or unconjugated counterparts. While one of skill in the art can determine the desirable dose in each case, a suitable dose of the therapeutic agent for achievement of therapeutic benefit, may, for example, be in a range of about 1 microgram (μg) to about 100 milligrams (mg) per kilogram body weight of the recipient per day, preferably in a range of about 10 μg to about 50 mg per kilogram body weight per day and most preferably in a range of about 10 μg to about 50 mg per kilogram body weight per day. The desired dose may be presented as one dose or two or more sub-doses administered at appropriate intervals throughout the day. These sub-doses can be administered in unit dosage forms, for example, containing from about 10 μg to about 1000 mg, preferably from about 50 μg to about 500 mg, and most preferably from about 50 μg to about 250 mg of active ingredient per unit dosage form. Alternatively, if the condition of the recipient so requires, the doses may be administered as a continuous infusion.
The mode of administration and dosage forms will of course affect the therapeutic amount of the peptide active therapeutic agent that is desirable and efficacious for a given treatment application. For example, orally administered dosages can be at least twice, e.g., 2-10 times, the dosage levels used in parenteral administration methods.
The therapeutic agents of the invention may be administered per se as well as in various forms including pharmaceutically acceptable esters, salts, and other physiologically functional derivatives thereof. The present invention also contemplates pharmaceutical formulations, both for veterinary and for human medical use, which include therapeutic agents of the invention. In such pharmaceutical and medicament formulations, the therapeutic agents can be used together with one or more pharmaceutically acceptable carrier(s) therefore and optionally any other therapeutic ingredients. The carrier(s) must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the formulation and not unduly deleterious to the recipient thereof. The therapeutic agents are provided in an amount effective to achieve the desired pharmacological effect, as described above, and in a quantity appropriate to achieve the desired daily dose.
The formulations of the therapeutic agent include those suitable for, parenteral as well as non-parenteral administration, and specific administration modalities include oral, rectal, buccal, topical, nasal, ophthalmic, subcutaneous, intramuscular, intravenous, transdermal, intrathecal, intra-articular, intra-arterial, sub-arachnoid, bronchial, lymphatic, vaginal, and intra-uterine administration. Formulations suitable for oral and parenteral administration are preferred.
When the therapeutic agent is used in a formulation including a liquid solution, the formulation advantageously can be administered orally or parenterally. When the therapeutic agent is employed in a liquid suspension formulation or as a powder in a biocompatible carrier formulation, the formulation may be advantageously administered orally, rectally, or bronchially.
When the therapeutic agent is used directly in the form of a powdered solid, the active agent can be advantageously administered orally. Alternatively, it may be administered bronchially, via nebulization of the powder in a carrier gas, to form a gaseous dispersion of the powder which is inspired by the patient from a breathing circuit comprising a suitable nebulizer device.
The formulations comprising the therapeutic agent of the present invention may conveniently be presented in unit dosage forms and may be prepared by any of the methods well known in the art of pharmacy. Such methods generally include the step of bringing the therapeutic agents into association with a carrier which constitutes one or more accessory ingredients. Typically, the formulations are prepared by uniformly and intimately bringing the therapeutic agent into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product into dosage forms of the desired formulation.
Formulations suitable for oral administration may be presented as discrete units such as capsules, cachets, tablets, or lozenges, each containing a predetermined amount of the active ingredient as a powder or granules; or a suspension in an aqueous liquor or a non-aqueous liquid, such as a syrup, an elixir, an emulsion, or a draught.
A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine, with the therapeutic agent being in a free-flowing form such as a powder or granules which optionally is mixed with a binder, disintegrant, lubricant, inert diluent, surface active agent, or discharging agent. Molded tablets comprised of a mixture of the powdered peptide active therapeutic agent-ELP construct(s) with a suitable carrier may be made by molding in a suitable machine.
A syrup may be made by adding the peptide active therapeutic agent-ELP construct(s) to a concentrated aqueous solution of a sugar, for example sucrose, to which may also be added any accessory ingredient(s). Such accessory ingredient(s) may include flavorings, suitable preservative, agents to retard crystallization of the sugar, and agents to increase the solubility of any other ingredient, such as a polyhydroxy alcohol, for example glycerol or sorbitol.
Formulations suitable for parenteral administration conveniently comprise a sterile aqueous preparation of the therapeutic agent, which preferably is isotonic with the blood of the recipient (e.g., physiological saline solution). Such formulations may include suspending agents and thickening agents or other microparticulate systems which are designed to target the peptide active therapeutic agent to blood components or one or more organs. The formulations may be presented in unit-dose or multi-dose form.
Nasal spray formulations comprise purified aqueous solutions of the therapeutic agent with preservative agents and isotonic agents. Such formulations are preferably adjusted to a pH and isotonic state compatible with the nasal mucus membranes.
Formulations for rectal administration may be presented as a suppository with a suitable carrier such as cocoa butter, hydrogenated fats, or hydrogenated fatty carboxylic acid.
Topical formulations comprise the therapeutic agent dissolved or suspended in one or more media, such as mineral oil, petroleum, polyhydroxy alcohols, or other bases used for topical pharmaceutical formulations.
In addition to the aforementioned ingredients, the formulations of this invention may further include one or more accessory ingredient(s) selected from diluents, buffers, flavoring agents, disintegrants, surface active agents, thickeners, lubricants, preservatives (including antioxidants), and the like.
The features and advantages of the present invention are more fully shown with respect to the following non-limiting examples.

EXAMPLES

Example 1

Construction of Various ELP Component Constructs

Cloning steps were conducted in Escherichia coli strain XL1-Blue (rec A1, endA1, gyrA96, thi-1, hsdR17 (r_k ⁻, m_k+), supE44, relA1, lac[F′, proAB, /αcrl^qZΔM15, Tn10 (Tet′)] (Stratagene La Jolla, Calif.). pUC19 (NEB, Beverly, Mass.) was used as the cloning vector for the ELP construction (Meyer and Chilkoti, Nat. Biotechnot., 17(11):1112-5, 1999). Modified forms of pET15b and pET24d vectors (Novagen) were used to express ELP and ELF-fusion proteins in BL21 Star (DE3) strain (F⁻, ompT, hsdS_B(r_B ⁻m_B ⁻), gal, dcm, rne131, (DE3)) (Invitrogen Carlsbed, Calif.) or BLR(DE3) (F⁻, ompT, hsdS_B(r_B ⁻m_B ⁻) gal, dcm, Δ(srl-recA) 306::Tn10(TcR)(DE3)) (Novagen Madison, Wis.). Synthetic DNA oligos were purchased from Integrated DNA Technologies, Coralville, Iowa. All vector constructs were made using standard molecular biology protocols (e.g., Current Protocols in Molecular Biology, ed. Ausubel, et al., 1995).

Construction of ELP1 [V₅A₂G₃] Gene Series

The ELP1 [V₅A₂G₃] series designate polypeptides containing multiple repeating units of the pentapeptide VPGXG (SEQ ID NO: 3), where X is valine, alanine, and glycine at a relative ratio of 5:2:3.
The ELP1 [V₅A₂G₃] series monomer, ELP1 [V₅A₂G₃-10], was created by annealing four 5′ phosphorylated, PAGE purified synthetic oligos to form double stranded DNA with EcoRI and HindIII compatible ends (Meyer and Chilkoti, Nat. Biotechnol., 17(11):1112-5, 1999). The oligos were annealed in a 1 μM mixture of the four oligos in 50 μl IX ligase buffer (Invitrogen) to 95° C. in a heating block than the block was allowed to cool slowly to room temperature. The ELP1 [V₅A₂G₃-10]/EcoRI-HindIII DNA segment was ligated into a pUC19 vector digested with EcoRI and HindIII and CIAP dephosphorylated (Invitrogen) to form pUC19-ELP1 [V₅A₂G₃-10]. Building of the ELP1 [V₅A₂G₃] series library began by inserting ELP1 [V₅A₂G₃-10] PflMI/BglI fragment from pUC19-ELP1 [V₅A₂G₃-10] into pUC19-ELP1 [V₅A₂G₃-10] linearized with PflMI and dephosphorylated with CIAP to create pUC19-ELP1 [V₅A₂G₃-20]. pUC19-ELP1 [V₅A₂G₃-20] was then built up to pUC19-ELP1 [V₅A₂G₃-30] and pUC19-ELP1 [V₅A₂G₃-40] by ligating ELP1 [V₅A₂G₃-10] or ELP1 [V₅A₂G₃-20] PflMI/BglI fragments respectively into PflMI digested pUC19-ELP1 [V₅A₂G₃-20]. This procedure was used to expand the ELP1 [V₅A₂G₃] series to create pUC19-ELP1 [V₅A₂G₃-60], pUC19-ELP1 [V₅A₂G₃-90] and pUC19-ELP1 [V₅A₂G₃-180] genes.

Construction of ELP1 [K₁V₂F₁] Gene Series

The ELP1 [K₁V₂F₁] series designate polypeptides containing multiple repeating units of the pentapeptide VPGXG (SEQ ID NO: 3), where X is lysine, valine, and phenylalanine at a relative ratio of 1:2:1.
The ELP1 [K₁V₂F₁] series monomer, ELP1 [K₁V₂F₁-4], was created by annealing two 5′ phosphorylated, PAGE purified synthetic oligos to form double stranded DNA with EcoRI and HindIII compatible ends (Meyer and Chilkoti, 1999). The oligos were annealed in a 1 μM mixture of the four oligos in 50 μl 1× ligase buffer (Invitrogen) to 95° C. in a heating block then the block was allowed to cool slowly to room temperature. The ELP1 [K₁V₂F₁-4]/EcoRI-HindIII DNA segment was ligated into a pUC19 vector digested with EcoRI and HindIII and CIAP dephosphorylated (Invitrogen) to form pUC19-ELP1 [K₁V₂F₁-4]. Building of the ELP1 [K₁V₂F₁] series library began by inserting ELP1 [K₁V₂F₁-4] PflMI/Bgl1 fragment from pUC19-ELP1 [K₁V₂F₁-4] into pUC19-ELP1 [K₁V₂F₁-4] linearized with PflM1 and dephosphorylated with CIAP to create pUC19-ELP1 [K₁V₂F₁-8]. Using the same procedure the ELP1 [K₁V₂F₁] series was doubled at each ligation to form pUC19-ELP1 pUC19-ELP1 [K₁V₂F₁-32], pUC19-ELP1 [K₁V₂F₁-64] and pUC19-ELP1 [K₁V₂F₁-128].

Construction of ELP1 [K₁V₇F₁] Gene Series

The ELP1 [K₁V₇F₁] series designate polypeptides containing multiple repeating units of the pentapeptide VPGXG (SEQ ID NO: 3), where X is lysine, valine, and phenylalanine at a relative ratio of 1:7:1.
The ELP1 [K₁V₇F₁] series monomer, ELP1 [K₁V₇F₁-9], was created by annealing four 5′ phosphorylated, PAGE purified synthetic oligos to form double stranded DNA with PflMI and HindIII compatible ends. The ELP1 [K₁V₇F₁-9] DNA segment was than ligated into PflMI/HindIII dephosphorylated PUC19-ELP1 [V₅A₂G₃-180] vector thereby substituting ELP1 [V₅A₂G₃-180] for ELP1 [K₁V₇F₁-9] to create the pUC19-ELP1 [K₁V₇F₁-9] monomer. The ELP1 [K₁V₇F₁] series was expanded in the same manner as the ELP1 [K₁V₂F1] series to create pUC19-ELP1 [K₁V₇F₁-18], PUC19-ELP1 [K₁V₇F₁-36], pUC19-ELP1 [K₁V₇F₁-72] and pUC19-ELP1 [K₁V₇F₁-144].

Construction of ELP1 [V] Gene Series

The ELP1 [V] series designate polypeptides containing multiple repeating units of the pentapeptide VPGXG (SEQ ID NO: 3), where X is exclusively valine.
The ELP1 [V] series monomer, ELP1 [V-5], was created by annealing two 5′ phosphorylated, PAGE purified synthetic oligos to form double stranded DNA with EcoRI and HindIII compatible ends. The ELP1 [V-5] DNA segment was than ligated into EcoRI/HindIII dephosphorylated pUC19 vector to create the pUC19-ELP1 [V-5] monomer. The ELP1 [V] series was created in the same manner as the ELP1 [V₅A₂G₃] series, ultimately expanding pUC19-ELP1 [V-5] to pUC19-ELP1 [V-60] and pUC19-ELP1 [V-120].

Construction of ELP2 Gene Series

The ELP2 series designate polypeptides containing multiple repeating units of the pentapeptide AVG VP.
The ELP2 series monomer, ELP2 [5], was created by annealing two 5′ phosphorylated, PAGE purified synthetic oligos to form double stranded DNA with EcoRI and HindIII compatible ends. The ELP2 [5] DNA segment was than ligated into EcoRI/HindIII dephosphorylated pUC19 vector to create the pUC19-ELP2[5] monomer. The ELP2 series was expanded in the same manner as the ELP1 [K₁V₂F₁] series to create pUC19-ELP2[10], pUC19-ELP2 [30], pUC19-ELP2 [60] and pUC19-ELP2 [120];

Construction of ELP3 [V] Gene Series

The ELP3 [V] series designate polypeptides containing multiple repeating units of the pentapeptide IPGXG (SEQ ID NO: 5), where X is exclusively valine.
The ELP3 [V] series monomer, ELP3 [V-5], was created by annealing two 5′ phosphorylated, PAGE purified synthetic oligos to form double stranded DNA with PfLM1 amino terminal and GGC carboxyl terminal compatible ends due to the lack of a convenient carboxyl terminal restriction site but still enable seamless addition of the monomer. The ELP3 [V-5] DNA segment was then ligated into PflM1/BglI dephosphorylated pUC19-ELP4[V-5], thereby substituting ELP4 [V-5] for ELP3 [V-5] to create the pUC19-ELP3 [V-5] monomer. The ELP3 [V] series was expanded by ligating the annealed ELP3 oligos into pUC19-ELP3[V-5] digested with PflMI. Each ligation expands the ELP3 [V] series by 5 to create ELP3 [V-10], ELP3 [V-15], etc.

Construction of the ELP4 [V] Gene Series

The ELP4 [V] series designate polypeptides containing multiple repeating units of the pentapeptide LPGXG (SEQ ID NO: 7), where X is exclusively valine.
The ELP4 [V] series monomer, ELP4 [V-5], was created by annealing two 5′ phosphorylated, PAGE purified synthetic oligos to form double stranded DNA with EcoRI and HindIII compatible ends. The ELP4 [V-5] DNA segment was than ligated into EcoRI/HindIII dephosphorylated pUC19 vector to create the pUC19-ELP4[V-5] monomer. The ELP4 [V] series was expanded in the same manner as the ELP1 [K₁V₂F₁] series to create pUC19-ELP4[V-10], pUC19-ELP4[V-30], pUC19-ELP4[V-60] and pUC19-ELP4[V-120].
The ELP genes were also inserted into other vectors such as pET15b-SD0, pET15b-SD3, pET15b-SD5, pET15b-SD6, and pET24d-SD21. The pET vector series are available from Novagen, San Diego, Calif.
The pET15b-SD0 vector was formed by modifying the pET15b vector using SD0 double-stranded DNA segment containing the multicloning restriction site (SacI-NdeI-NcoI-XhoI-SnaBI-BamHI). The SD0 double-stranded DNA segment had XbaI and BamHI compatible ends and was ligated into XbaI/BamHI linearized and 5′-dephosphorylated pET15b to form the pet15b-SD0 vector.
The pET15b-SD3 vector was formed by modifying the pET15b-SD0 vector using SD3 double-stranded DNA segment containing a SfiI restriction site upstream of a hinge region-thrombin cleavage site followed by the multicloning site (NdeI-NcoI-XhoI-SnaBI-BamHI). The SD3 double-stranded DNA segment had SacI and NdeI compatible ends and was ligated into SacI/NdeI linearized and 5′-dephosphorylated pET15b-SD0 to form the pET15b-SD3 vector.
The pET15b-SD5 vector was formed by modifying the pET15b-SD3 vector using the SD5 double-stranded DNA segment containing a SfiI restriction site upstream of a thrombin cleavage site followed by a hinge and the multicloning site (NdeI-NcoI-XhoI-SnaBI-BamHI). The SD5 double-stranded DNA segment had SfiI and NdeI compatible ends and was ligated into SfiI/NdeI linearized and 5′-dephosphorylated pET15b-SD3 to form the pET15b-SD5 vector.
The pET15b-SD6 vector was formed by modifying the pET15b-SD3 vector using the SD6 double-stranded DNA segment containing a SfiI restriction site upstream of a linker region-TEV cleavage site followed by the multicloning site (NdeI-NcoI-XhoI-SnaBI-BamHI). The SD6 double-stranded DNA segment had SfiI and NheI compatible ends and was ligated into SfiI/NdeI linearized and 5′-dephosphorylated pET15b-SD3 to form the pET15b-SD6 vector.
The pET24d-SD21 vector was formed by modifying the pET24d vector using the SD21 double-stranded DNA segment with NcoI and NheI compatible ends. The SD21 double-stranded DNA segment was ligated into NcoI/NheI linearized and 5′ dephosphorylated pET24d to create the pET24d-SD21 vector, which contained a new multi-cloning site NcoI-SfiI-NheI-BamHI-EcoRI-SacI-SalI-HindIII-NotI-XhoI with two stop codons directly after the SfiI site for insertion and expression of ELP with the minimum number of extra amino acids.
The pUC19-ELP1 [V₅A₂G₃-60], pUC19-ELP1 [V₅A₂G₃-90], and pUC19-ELP1 [V₅A₂G₃-180] plasmids produced in XL1-Blue were digested with PflMI and BglI, and the ELP-containing fragments were ligated into the SfiI site of the pET15b-SD3 expression vector as described hereinabove to create pET15b-SD3-ELP1 [V₅A₂G₃-60], pET15b-SD5-ELP1 [V₅A₂G₃-90] and pET15b-SD5-ELP1 [V₅A₂G₃-180], respectively.
The pUC19-ELP1 [V₅A₂G₃-90], pUC19-ELP1 [V₅A₂G₃-180], pUC19-ELP1 [V-60] and pUC19-ELP1 [V-120] plasmids produced in XL1-Blue were digested with PflMI and BglI, and the ELP-containing fragments were ligated into the SfiI site of the pET15b-SD5 expression vector as described hereinabove to create pET15b-SD5-ELP1 [V₅A₂G₃-90], pET15b-SD5-ELP1 [V₅A₂G₃-180], pET15b-SD5-ELP1 [V-60] and pET15b-SD5-ELP1 [V-120], respectively.
The pUC19-ELP1 [V₅A₂G₃-90] plasmid produced in XL1-Blue was digested with PflMI and BglI, and the ELP-containing fragment was ligated into the SfiI site of the pET15b-SD6 expression vector as described hereinabove to create pET15b-SD6-ELP1 [V₅A₂G₃-90].
The pUC19-ELP1 [K₁V₂F₁-64], and pUC19-ELP1 [K₁V₂F₁-128] plasmids produced in XL1-Blue were digested with PflMI and BglI, and the ELP-containing fragments were ligated into the SfiI site of the pET24d-SD21 expression vector as described hereinabove to create pET24d-SD21-ELP1 [K₁V₂F₁-64] and pET24d-SD21-ELP1 [K₁V₂F₁-128], respectively.
The pUC19-ELP1 [K₁V₇F₁-72] and pUC19-ELP1 [K₁V₇F₁-144] plasmids produced in XL1-Blue were digested with PflMI and BglI, and the ELP-containing fragments were ligated into the SfiI site of the pET24d-SD21 expression vector as described hereinabove to create pET24d-SD21-ELP1 [K₁V₇F₁-72], pET24d-SD21-ELP1 [K₁V₇F₁-144], respectively.
The pUC19-ELP2[60] and pUC19-ELP2[120] plasmids produced in XL1-Blue were digested with NcoI and HindIII, and the ELP-containing fragments were ligated into the NcoI and HindIII sites of the pET24d-SD21 expression vector as described hereinabove to create pET24d-SD21-ELP2[60], pET24d-SD21-ELP2[120], respectively.
The pUC19-ELP4[V-60] and pUC19-ELP4[V-120] plasmids produced in XL1-Blue were digested with Neal and HindIII, and the ELP-containing fragments were ligated into the NcoI and HindIII sites of the pET24d-SD21 expression vector as described hereinabove to create pET24d-SD21-ELP4[V-60], pET24d-SD21-ELP4[V-120], respectively.

Example 2

Isolation and Purification of Fusion Proteins Containing Insulin A Peptide (InsA)

ELP-InsA fusion proteins included the following:
Insulin A peptide and ELP1 [V-60] polypeptide with an enterokinase protease cleavage site therebetween.
Insulin A peptide and ELP1 [V₅A₂G₃-90] polypeptide with an enterokinase protease cleavage site therebetween.
Insulin A peptide and ELP1 [V-120] polypeptide with an enterokinase protease cleavage site therebetween.
Insulin A peptide and ELP1 [V₅A₂G₃-180] polypeptide with an enterokinase protease cleavage site therebetween.
A single colony of E. coli strain BLR (DE3) (Novagen) containing the respective ELP-InsA fusion protein was inoculated into 5 ml CircleGrow (Q-BIOgene, San Diego, Calif.) supplemented with 100 μg/ml ampicillin (Sigma) and grown at 37° C. with shaking at 250 rpm for 5 hours. The 5 ml culture was then inoculated into a 500 ml culture and allowed to grow at 25° C. for 16 hours before inducing with 1 mM IPTG for 4 hours at 25° C. The culture was harvested and suspended in 40 ml 20 mM Tris-HCl pH 7.4, 50 mM NaCl, 1 mM DTT and 1 Complete EDTA free Protease inhibitor pellet (Roche, Indianapolis, Ind.). Cells were lysed by ultrasonic disruption on ice for 3 minutes, which consisted of 10 seconds bursts at 35% power separated by 30 second cooling down intervals. Cell debris was removed by centrifugation at 20,000 g, 4° C. for 30 minutes.
Inverse phase transition was induced by adding NaCl to the cell lysate at room temperature to achieve a final concentration of 1.0 M therein, followed by centrifugation at 20,000 g for 15 minutes at room temperature. The resulting pellet contained the respective ELP-InsA fusion protein and non-specifically NaCl precipitated proteins.
The pellet was re-suspended in 40 ml ice-cold ml 20 mM Tris-HCl pH 7.4, 50 mM NaCl, 1 mM DTT and re-centrifuged at 20,000 g, 4° C. for 15 minutes to remove the non-specifically NaCl precipitated proteins. The inverse transition cycle was repeated two additional times to increase the purity of the respective ELP-InsA fusion protein and reduce the final volume to 0.5 ml.

Example 3

Half-Life of ELP1

The pharmacokinetics of ELP1 were determined by intravenously administering [¹⁴C]ELP1 to nude mice (Balb/c nu/nu) bearing a leg/flank FaDu xenograft and collecting blood samples at various time intervals after administration. The blood pharmacokinetics exhibited a characteristic distribution and elimination response for large macromolecules, which was well described by a bi-exponential process.
The plasma concentration time-course curve was fit to the analytical solution of a two-compartment model to approximate both an elimination and distribution response. Certain pharmakinetic parameters are shown in Table 1 below. The distribution volume of the ELP (1.338 μl) was nearly identical to the hypothetical plasma volume of 1.363 μl (Barbee, R. W., et al., Am. J. Physio. 263(3) (1992) R728-R733), indicating that the ELP did not rapidly distribute or bind to specific organs and tissues directly after administration. The AUC is a measure of the cumulative exposure to ELP in the central compartment or the blood plasma. The body clearance is defined as the rate of ELP elimination in the body relative to its plasma concentration and is the summation of clearance through all organs including the kidney, liver and others.

TABLE 1

Pharmacokinetic parameters calculated for [¹⁴C]ELP1

					AUC (mg	Cl_B
	k₁(hr⁻¹)	k₂(hr⁻¹)	k_e(hr⁻¹)	V_d(μL)	ELP hr/ml)	(μL/hr)

ELP1-150	3.54	1.99	0.24	1,338	7.1	317

The mass transfer rate constants are from a standard two-compartment model (k₁; from central to peripheral compartment; k₂, from peripheral to central compartment; and k_e, elimination from central compartment). The distribution volume (V_d), central compartment concentration time-course area under the curve (AUC) and body clearance (Cl_B) are displayed. Data are shown as the mean values (n=5, except V_dand initial plasma concentration (C_O) was calculated from a similar cohort with n=3).

Example 4

Biodistribution of ELPs 1N Nude Mice

¹⁴C Labeled ELP1-150 and/or ¹⁴C Labeled ELP2-160
¹⁴C labeled ELP1-150 and/or ¹⁴C labeled ELP2-160 were administered to nude mice with a FaDu tumor (mean+/−SD, n=6). The tumor was heated post administration of the ELP in a water bath at 41.5° C. The distribution was highest to the organs with the highest blood content: liver, kidneys, spleen, and lungs.

¹⁴C Labeled ELP2-[V₁A₈G₇-160]

¹⁴C labeled ELP2-[V₁A₈G₇-160] (T_t>60° C.) was administered to nude mice for a plasma concentration of 15 μM. ELP concentrations were determined following 1 hour of heating (41° C.) of an implanted FaDu tumor, located in the right hind leg of the nude mouse. Data are shown as the mean, plus the 95% confidence interval. N=6.
ELP concentration was measured 1.5 hours following systemic administration of ¹⁴C labeled ELP2-[V₁A₈G₇-160]. The highest distribution is seen in organs with the highest blood content: liver, kidneys, spleen, and lungs.

Example 5

Exendin-4 ELP Fusion

The DNA sequence for Exendin-4 (Ex-4) (SEQ ID NO: 14) was reverse translated from the amino acid sequence using codons optimized for E. coli expression. The DNA sequence encoding Exendin-4 was constructed by annealing together synthetic oligonucleotides with overhanging 5′ and 3′ ends compatible with the restriction sites NdeI and XhoI in the plasmid pET24d-ELP1-90 (FIG. 1). This plasmid was digested with the restriction enzymes NdeI and XhoI and the annealed DNA sequence was ligated into the cut vector. Insertion was confirmed by restriction digest and DNA sequencing. The resulting plasmid was designated as pET24d-Ex-4 ELP1-90 (FIG. 2A), and the sequence of the resulting Exendin-4-ELP fusion shown in FIG. 2B. Primers for construction of the fusion are also indicated.
pET24d-Ex-4 ELP1-90 was used to transform the E. coli strain BRL (Invitrogen) and selected transformants were grown in media 3 (1.2% Tryptone Peptone, 2.4% yeast extract, 5 g/L casamino acids, 2% glycerol, 2.313 g Potassium phosphate dibasic/L, 12.541 g Potassium phosphate monobasic/L) in shake flasks. Production proceeded by autoinduction by inoculating 1 OD cells into 1 L of media 3 and allowing growth to proceed for 17 hr at 37° C. without addition of inducer. The product was recovered by collection of the cell pellet, sonicated to disrupt the cells and recovered by thermal and/or salt induced transition modulated by the ELP moiety (Improved Non-chromatographic Purification of a Recombinant Protein by Cationic Elastin-like Polypeptides, Dong Woo Lim, Kimberly Trabbic-Carlson, J. Andrew MacKay, and Ashutosh Chilkoti. Biomacromolecules 2007, 8, 1417-1424).
This example is with the ELP designated 1-90. This is based on the VPGXG (SEQ ID NO: 3) motif where X is a V, G or A in the ratio 5:3:2 in a 10 unit repeat, repeated 8× with a final (C-terminal) 10-unit repeat where X is a V, G, A and W in the ratio 4:3:2:1.
[(VPGXG)10]₉where the X residue in the ten sequential iterations of the repeat unit (numerical subscript) can be described as [(V_1,4,5,8,10G_2,7,9A_3,8)₈(V_1,4,5,6G_2,7,9A_3,8W₁₀)].
The ELP may be any combination of VPGXG (SEQ ID NO: 3) units where X is any of the 20 natural amino, acids, except proline, in any combination of repeat units of any length. In addition, the amino acid may be an unnatural amino acid for which the host strain has been engineered to accept an engineered tRNA for incorporation at specific codon (Wang L, Brock A, Herberich B, Schultz P G. Expanding the genetic code of Escherichia coli. [2001] Science 292, 498-500).
This construct was produced in the cytosol with an N-terminal methionine, which is normally removed by methionine aminopeptidase. Complete and accurate processing of the methionine, however, cannot be assumed; this enzyme may also remove the N-terminal histidine of the Exendin-4 moiety. This could result in a mixture of, unprocessed, processed and incorrectly processed products. Consequently, further constructs were developed to generate products with correctly processed N-termini.
Primers were designed to add a Tev protease (Tobacco Etch Virus cysteine protease) cleavage site between the N-terminal methionine and the histidine at the N-terminus of Exendin-4. This allows for removal of the methionine and the Tev recognition sequence to give the mature N-terminus of Exendin-4 (histidine). This can be done post-production or the Tev protease can be co-expressed to cleave the recognition sequence during production, for instance, as an intein (Ge, X., Yang, D. S. C., Trabbic-Carlson, K., Kim, B., Chilkoti, A. and Filipe, C. D. M. Self-Cleavable Stimulus Responsive Tags for Protein Purification without Chromatography. J. Am. Chem. Soc. 127, 11228-11229, 2005). The Tev Exendin-4 sequence is shown in FIG. 3A. FIG. 3B shows additional sequences added, labeled as “Linker Tev,” provide a better target for the Tev protease.
An alternative route to obtaining a correctly processed N-terminus for Ex-4 is to use a leader or signal sequence that directs the product to the periplasm and which is cleaved by a signal peptidase in the process. In this instance, a signal sequence, DsbA, that directs the transcript to the signal recognition particle for direct secretion of the polypeptide into the periplasm is given. (See FIG. 4A). The plasmid pET24d-DsbA-Ex-4 ELP1-90 is shown in FIG. 4B.
While this example illustrates the preparation of therapeutic agents with Exendin-4 sequences, such sequences can be replaced with GLP-1, insulin, Factor VII/VIIa, or other therapeutic protein listed in Table 1, generated in exactly or a similar manner as detailed for Exendin-4.

Example 6

GLP1-ELP Fusion Protein

The ELP plasmid constructs were used to prepare two GLP1-ELP fusion proteins, GLP1(A8G,7-37)ELP1-90 and GLP1(A8G,7-37)ELP1-120. The plasmid constructs, fusion-encoding nucleotide sequence, as well as the amino acid sequence of the resulting fusion proteins are shown in FIGS. 5 and 6.
Both constructs contain an N-terminal Tev protease site to allow processing to the mature form where His⁷of GLP1 is at the N-terminus. The processed fusion proteins have calculated molecular weights of about 39,536 and about 50,828, respectively.

Example 7

FVII ELP Fusion Protein

The coagulation factor VII (FVII) gene was modified by PCR from a cDNA clone (Oragene) to add restriction sites at the 5′ and 3′ ends for cloning into the ELP-containing vector. At the 5′ end an NheI site was added and at the 3′ end a NotI site was added. The DNA and amino acid sequences of the Factor VII gene are shown in the accompanying Sequence Listing as SEQ ID NOS: 34 and 33, respectively. The DNA sequences of the 5′ and 3′ primers used to PCR amplify the factor VII (FVII) gene were:

(SEQ ID NO.: 49)

	P13:	CTAGCTAGCATGGTCTCCCAGGCCCTC

(SEQ ID NO.: 50)

P14:

TATTCTTGCGGCCGCGGGAAATGGGGCTCGCAG

The resulting PCR fragment was digested with the restriction enzymes NheI and NotI and ligated into the plasmid pcDNA3.1+ELP1-90 previously digested with the restriction enzymes NheI and NotI (FIG. 7A).
The resulting plasmid, pcDNA3.1+FVII-ELP1-90, was transiently transfected into HEK293 cells and culture media harvested. The ELP fusion was purified by phase transition (FIGS. 9 and 10).
The nucleotide and amino acid sequences of the FactorVII-ELP fusion is shown in FIG. 7B. As shown, the FactorVII-ELP fusion protein contains a Tev protease linker between the FactorVII component and the ELP component. This linker is optional.

Example 8

Insulin ELP Fusion Protein

The cDNA for the human insulin gene is modified at the 5′ and 3′ ends for insertion in to pET24d-ELP1-90. The 5′ primer adds an N-terminal methionine for bacterial expression and an NdeI restriction enzyme site. The 3′ primer adds an XhoI restriction enzyme site. The PCR product and the plasmid are both digested with the restriction enzymes NdeI and XhoI and ligated together. The sequence of the insulin (Chains B, C, and A fused to ELP1 is shown in FIG. 8A.
Correct insertion is determined by restriction digest and DNA sequencing. The resulting plasmid, designated pET24d Insulin-ELP1-90, is shown in FIG. 8B.
The native insulin form is generated after recovery from E. coli by treatment with trypsin and carboxypeptidase B to remove the C-peptide chain.
For correct processing of the N-terminus of the B-chain similar modifications to those made for the Exendin-4 fusion (protease cleavage site, signal sequence) can be implemented (see Example 4). Alternatively, the first two residues can be Met-Arg, which can also be removed by trypsin digestion in production of the final material (R. M. Belagaje, S. G. Reams, S. C. Ly and W. F. Prouty, Increased production of low molecular weight recombinant proteins in Escherichia coli. Protein Sci. 6, 1953-1962, 1997).
Additional constructs would place the insulin cDNA at the 3′ end of the ELP for a C-terminal fusion, add linkers between the Insulin and ELP sequences, and/or use modified forms of insulin which have no C-peptide (single chain insulins as described) removing the need for additional processing.

Example 9

Synthesis of the ELP Gene for Conjugation

A gene encoding a 50 amino acid sequence was constructed from chemically-synthesized oligonucleotides using standard molecular biology protocols. The 50 amino acid sequence contained 10 repeats of the pentapeptide VPGXG (SEQ ID NO: 3), where the guest residues (V, G, and A in a 5:3:2 molar ratio) were selected to provide a Tt of 40° C. The gene was oligomerized end-to-end by standard molecular biology techniques, to produce an oligomeric ELP gene. Additionally a single 50 amino acid sequence was constructed containing the 10 repeat pentapeptide VPGXG (SEQ ID NO: 3) polypeptide where the guest residues were V, G, A and C in a 4:3:2:1 molar ratio. This sequence could be added at any cycle of the oligomerization process to introduce a single cysteine residue into the final construct at a chosen point along the length of the construct.
The example given here is with the ELP designated 1-90. This is based on the VPGXG (SEQ ID NO: 3) motif where X is a V, G or A in the ratio 5:3:2 in a 10-unit repeat, repeated 8× with a final (C-terminal) 10-unit repeat where X is a V, G, A and C in the ratio 4:3:2:1, i.e., [(VPGXG)10]9 (SEQ ID NO.: 3).
Alternatively, the residue could be one of either arginine, lysine, aspartic acid or glutamic acid. The purpose of these amino acids is to provide a reactive side chain for the chemical conjugation of, for example, insulin. In this particular case the use of an ELP would be to extend the circulating half-life of the therapeutic protein (e.g., insulin) to provide prolonged basal glucose control. Conjugated to an ELP that transitions at body temperature, the insulin would form a precipitated depot at the site of injection in a similar manner to Lantus® (Sanofi Aventis) but without the requirement for formulation in acidic (pH 4.0) conditions with m-cresol for a more tolerable injection.

Example 10

Potency and Half-Life of Factor VII-ELP

FIG. 11 shows the activation of Factor X by FactorVIIa-ELP1-90, and by Factor VIIa as a comparison. Factor VII-ELP was produced in HEK cells. Factor VIIa was derived from human plasma. As shown, FactorVIIa-ELP retains full activity.
When administered to rats by i.v., Factor VII-ELP demonstrated a half-life of about 690 minutes. In contrast, Factor VII demonstrated a half-life of 45-60 minutes. Half-life in this example was measured by sandwich ELISA for FactorVII. FIG. 12.
Also in contrast, the reported half-life for NovoSeven™ is 45 minutes, the reported half-life for FactorVIIa-albumin fusion is 263 minutes, and the reported half-life for Factor VIIa-PEG is 300 minutes in mice and 600 minutes in dog.

Example 11

GLP-1 (or Exendin-4) In Vitro Bioassay

Activation of the GLP-1 receptor (GLP1R) results in production of CAMP secondary messenger within the cell. Therefore, GLP-1 or Exendin-4 analogs and corresponding therapeutic agents may be tested by their ability to activate GLP1R on the cell surface and produce cAMP.
For this bioassay CHO cells transfected with cDNA coding for GLP1R are used. These cells respond to stimulation by GLP-1 and produce high levels of cAMP. Log phase growing cells are plated and increasing concentrations of test compounds (e.g., therapeutic agent of the invention, or GLP-1 or exendin-4 functional analog) are added to the cells. After an appropriate incubation period (usually 15-60 min) in physiological buffer at 37° C. the cAMP produced is measured using a CatchPoint cAMP assay kit from Molecular Devices (Sunnyvale, Calif.). The EC₅₀of each test compound as compared to GLP-1 peptide or Exendin-4 peptide (or as compared to an unfused or unconjugated counterpart of a therapeutic agent of the invention) is indicative of the changes in activity due to a specific modifications introduced into the peptide, or due to particular chemical or recombinant coupling to an ELP component.
As shown in FIG. 13, both GLP1-ELP (PB0868) and Exendin-4-ELP (PB 0859) maintain high activity in vitro, shown in comparison to Exendin alone. It is of note that the specific activity of Albugon® and Liraglutide® run 50-100 fold less than the exendin peptide.

Example 12

GLP-1 (or Exendin-4) In Vivo Bioassay

The activity of GLP-1 or Exendin analogues or corresponding therapeutic agents may be tested in animals. For this assay, normal or diabetic animals may be used. Diabetic animals with blood glucose concentration 300-500 mg/dl are injected with different doses of GLP-1 or Exendin analogues or corresponding therapeutic agent, and changes in blood glucose monitored with a glucometer. The drop in glucose at different times points post administration is compared to that resulting with standard amounts of GLP-1 or Exendin-4 peptide, or compared to an unfused or unconjugated counterpart of a therapeutic agent of the invention. Alternatively, the blood glucose excursion in normal or diabetic animals during specific time period after administration of exogenous glucose is compared to GLP-1 or Exendin-4 (or to unfused or unconjugated counterparts of therapeutic agents). In this way the activity of the analogues and fusion proteins can be compared to the natural peptides.
FIG. 14 shows the pharmacokinetics of GLP1-ELP1-120 in rats administered both by i.v. and subcutaneously. Three rats were used for each time point. The dose was ˜10 mg/kg. The T_1/2when administered by i.v. was about 12.9 hours. The T_1/2when administered subcutaneously was about 8.6 hours.
FIG. 15 shows the pharmacokinetics of GLP1-ELP1-120 in rabbits administered both by i.v. and subcutaneously. Three rabbits were used for each time point. The dose was −1 mg/kg. The T₁₂when administered by i.v. was about 20 hours. The T_1/2when administered subcutaneously was about 24 hours.
FIG. 16 shows the sustained glycemic control in diabetic mice with GLP1-ELP1-90.
All reference cited herein are hereby incorporated by reference in their entireties. While the invention has been has been described herein in reference to specific aspects, features and illustrative embodiments of the invention, it will be appreciated that the utility of the invention is not thus limited, but rather extends to and encompasses numerous other variations, modifications and alternative embodiments, as will suggest themselves to those of ordinary skill in the field of the present invention, based on the disclosure herein

Claims

1.-100. (canceled)

101. A therapeutic agent comprising a fusion protein with an elastin-like-peptide (ELP) and an amino acid sequence of a glucagon-like peptide (GLP)-1 receptor agonist, the ELP comprising at least 60 units of VPGXG, where X is an independently selected amino acid.

102. The therapeutic agent of claim 101, wherein the GLP-1 receptor agonist is glucagon-like peptide (GLP)-1, or a functional analog thereof.

103. The therapeutic agent of claim 102, wherein the GLP-1 has from 1 to 3 amino acid modifications independently selected from an insertion, a deletion, a truncation, and/or a substitution.

104. The therapeutic agent of claim 103, wherein the GLP-1 is GLP-1 (A-B), wherein A is an integer from 1 to 7 and B is an integer from 38 to 45.

105. The therapeutic agent of claim 101, wherein the GLP-1 receptor agonist is GLP-1 (7-37), or a functional analog thereof.

106. The therapeutic agent of claim 105, wherein the GLP-1 (7-37) has from 1 to 3 amino acid modifications independently selected from an insertion, a deletion, a truncation, and/or a substitution.

107. The therapeutic agent of claim 101, wherein the GLP-1 receptor agonist is GLP-1 (7-36), or a functional analog thereof.

108. The therapeutic agent of claim 107, wherein the GLP-1 (7-36) has from 1 to 3 amino acid modifications independently selected from an insertion, a deletion, a truncation, and/or a substitution.

109. The therapeutic agent of claim 101, wherein the GLP-1 receptor agonist is Exendin-4, or a functional analog thereof.

110. The therapeutic agent of claim 109, wherein the Exendin-4 has from 1 to 3 amino acid modifications independently selected from an insertion, a deletion, a truncation, and/or a substitution.

111. The therapeutic agent of claim 101, wherein the GLP-1 receptor agonist is derived from processing of a pro-glucagon gene

112. The therapeutic agent of claim 101, wherein the GLP-1 receptor agonist is a glucose-dependent insulinotropic polypeptide (GIP).

113. The therapeutic agent of claim 101, wherein the GLP-1 receptor agonist is an oxyntomodulin.

114. The therapeutic agent of claim 101, wherein the therapeutic agent further comprises a glucagon-like peptide (GLP)-2.

115. The therapeutic agent of claim 101, wherein the therapeutic component comprises at least one of GLP-1, GLP-1 (7-37), GLP-1 (7-36), Exendin-4, GIP, oxyntomodulin, and GLP-2.

116. The therapeutic agent of claim 101, wherein the X in VPGXG is V, G, or A at a ratio of 5:3:2.

117. The therapeutic agent of claim 116, wherein the ELP comprises 60 units of VPGXG.

118. The therapeutic agent of claim 116, wherein the ELP comprises 90 units of VPGXG.

119. The therapeutic agent of claim 116, wherein the ELP comprises 120 units of VPGXG.

120. The therapeutic agent of claim 116, wherein the ELP comprises 180 units of VPGXG.

121. The therapeutic agent of claim 101, wherein the X in VPGXG is X is K, V, or F at a ratio of 1:2:1.

122. The therapeutic agent of claim 101, wherein the X in VPGXG is K, V, or F at a ratio of 1:7:1.

123. The therapeutic agent of claim 101, wherein the X in VPGXG is V.

124. The therapeutic agent of claim 101, wherein the ELP component has a Tt greater than 37° C.

125. The therapeutic agent of claim 101, wherein the ELP component has a Tt of from about 35° C. to about 60° C.

126. A pharmaceutical composition comprising the therapeutic agent of claim 101, and a pharmaceutically acceptable carrier and/or excipient.