US20160120952A1

US20160120952A1 - Therapeutic agents comprising elastin-like peptides

Info

Publication number: US20160120952A1
Application number: US14/919,328
Authority: US
Inventors: Ashutosh Chilkoti
Original assignee: Duke University
Current assignee: Duke University
Priority date: 2008-06-27
Filing date: 2015-10-21
Publication date: 2016-05-05
Also published as: WO2009158704A3; CA2953975C; EP3412300A1; US10596230B2; JP2011526303A; EP2307038A2; US8178495B2; US20100022455A1; JP2015218177A; EP2307038A4; CN105727261A; US20190091297A1; US20200282022A1; CN102131516B; US20130079277A1; CA2726894A1; JP2019085420A; EP4074327A1; EP2926825A1; US9821036B2

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_01 US_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 ELP 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 W in 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 vivo 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 β-turn structure. Exemplary peptide sequences suitable for creating a β-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, Ca-methyl amino acids, Na-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 entrety, 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.

Glucaqon-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^E-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 deivative 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 et 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 β 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 et 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 et 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 et al., 1993, Diabetologia 36: 741-4, Creutzfeldt et 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, gastrointestional 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), Arg²⁶Lys³⁶-GLP-1(7-37), Arg³⁴Lys³⁶-GLP-1(7-37), Arg²⁶Lys³⁹-GLP-1(7-39), Arg³⁴Lys⁴⁰-GLP-1(7-40), Arg^26,34Lys^36,39-GLP-I (7-39), Arg^26,34Lys^36,40-GLP-1(7-40), Gly⁸Arg²⁶-GLP-1(7-37); Gly⁸Arg³⁴-GLP-1(7-37); Gly⁸Lys³⁸-GLP-1(7-37); Gly⁸Arg^26,34Lys³⁶-GLP-1(7-37), Gly⁸Arg^26,34Lys³⁹-GLP-1(7-39), Gly⁸Arg^26,34Lys⁴⁰-GLP-1(7-40), Gly⁸Arg²⁶Lys³⁶-GLP-1(7-37), Gly⁸Arg³⁴Lys³⁶-GLP-1(7-37), Gly⁸Arg²⁶Lys³⁹-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, June 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:

(SEQ ID NO: 18)

HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPSKKKKKK-NH2

(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. 10-14, 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, FEMS 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 proline 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 WO08/019368, 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, H4IIe 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 et 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 recombinaint 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 NS, 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 Q250C; 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 sequences—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

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

BMP-1	GeneSeq	WO8800205	BMP1 belongs to the transforming growth	BMP-1 activity can be determined	Induction of Cartilage, Tissue
	Acession		factor-beta (TGFB) superfamily. Bone	using the following assays known in	and Bone Growth, and Diabetes
	P80618		morphogenic proteins induce cartilage and	the art: Nat Genet. 2001 January;
			bone formation, play important role in	27(1): 84-8; Eur J Biochem 1996
			nephrogesis, and play an important role in	Apr. 1; 237(1): 295-302; J Biol
			the development of many organs, including	Chem, Vol. 274, Issue 16, 10897-
			lung, heart, teeth, gut, skin, and	10902, Apr. 16, 1999; and Hogan,
			particularly the kidney.	B. L. M. (1996) Genes Dev.
				10, 1580-1594.
BMP-2	GeneSeq	WO8800205	BMP-2 belongs to the transforming growth	BMP-2 activity can be determined	Induction of Cartilage, Tissue
	Accession		factor-beta (TGFB) superfamily. Bone	using the following assays known in	and Bone Growth, and Diabetes
	P80619		morphogenic protein induces bone	the art: Nat Genet. 2001 January;
			formation.	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-2B	GeneSeq	U.S. Pat. No.	BMP-2b belongs to the transforming growth	BMP-2b activity can be determined	Induction of Cartilage, Tissue
	Accession	5,631,142	factor-beta (TGFB) superfamily. Bone	using the following assays known in	and Bone Growth, and Diabetes
	W24850		morphogenic protein induces bone	the art: Nat Genet. 2001 January;
			formation.	27(1): 84-8; Eur J 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 growth	BMP-4 activity can be determined	Induction of Cartilage, Tissue
	Accession		factor-beta (TGFB) superfamily. Bone	using the following assays known in	and Bone Growth, and Diabetes
	B02796		morphogenic protein induces bone	the art: Nat Genet. 2001 January;
			formation.	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-5	GeneSeq	WO0020591	BMP-5 belongs to the transforming growth	BMP-5 activity can be determined	Induction of Cartilage, Tissue
	Accession		factor-beta (TGFB) superfamily. Bone	using the following assays known in	and Bone Growth, and Diabetes
	B02797		morphogenic protein induces bone	the art: Nat Genet. 2001 January;
			formation.	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-6	GeneSeq	U.S. Pat. No.	BMP-6 belongs to the transforming growth	BMP-6 activity can be determined	Induction of Cartilage, Tissue
	Accession	5,187,076	factor-beta (TGFB) superfamily. Bone	using the following assays known in	and Bone Growth, and Diabetes
	R32904		morphogenic protein induces bone	the art: Nat Genet. 2001 January;
			formation.	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.
Osteo-	GeneSeq	WO973462	OP-1 belongs to the transforming growth	OP-1 activity can be determined	Induction of Cartilage, Tissue
genic	Accession		factor-beta (TGFB) superfamily. Bone	using the following assays known in	and Bone Growth, and Diabetes
Protein-1;	W34783		morphogenic protein induces bone	the art: Nat Genet. 2001 January;
OP-1;			formation.	27(1): 84-8; Eur J Biochem 1996
BMP-7				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.
Osteo-	GeneSeq	WO9406399	OP-2 belongs to the transforming growth	OP-2 activity can be determined	Induction of Cartilage, Tissue
genic	Accession		factor-beta (TGFB) superfamily. Bone	using the following assays known in	and Bone Growth, and Diabetes
Protein-2	R57973		morphogenic protein induces bone	the art: Nat Genet. 2001 January;
			formation.	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.
GDP-1	GeneSeq	WO9406449	Members of the TGF-beta	The effect of GDF-1 on signaling	Developmental disorders,
	Accession		family of proteins	can be assayed by treating Primary	Induction of Cartilage, Tissue
	R60961		initiate cell signaling by binding to	BAECs transferred with a construct	and Bone Growth, and Diabetes
			heteromeric receptor complexes of type I	called p3TP-Lux, containing a TGF-
			(TbetaRI) and type II (TbetaRII)	beta responsive promoter fused to a
			serine/threonine kinase receptors (reviewed	reporter gene, and measuring
			by Massague, J. et al. (1994) Trends Cell	luciferase gene expression (Wrana et
			Biol. 4: 172 178; Miyazono, K. et al. (1994)	al., 1994, Nature 370: 341-347).
			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 growth	BMP-9 activity can be determined	Induction of Cartilage, Tissue
	Accession		factor-beta (TGFB) superfamily. Bone	using the following assays known in	and Bone Growth, and Diabetes
	R86903		morphogenic protein induces bone	the art: Nat Genet. 2001 January;
			formation.	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-10	GeneSeq	WO9426893	BMP-10 belongs to the transforming growth	BMP-10 activity can be determined	Induction of Cartilage, Tissue
	Accession		factor-beta (TGFB) superfamily. Bone	using the following assays known in	and Bone Growth, and Diabetes
	R66202		morphogenic protein induces bone	the art: Nat Genet. 2001 January;
			formation.	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-12	GeneSeq	WO9516035	BMP-12 belongs to the transforming growth	BMP-12 activity can be determined	Induction of Cartilage, Tissue
	Accession		factor-beta (TGFB) superfamily. Bone	using the following assays known in	and Bone Growth, and Diabetes
	R78734		morphogenic protein induces bone	the art: Nat Genet. 2001 January;
			formation.	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-15	GeneSeq	W09636710	BMP-15 belongs to the transforming growth	BMP-15 activity can be determined	Induction of Cartilage, Tissue
	Accession		factor-beta (TGFB) superfamily. Bone	using the following assays known in	and Bone Growth, and Diabetes
	W11261		morphogenic protein induces bone	the art: Nat Genet. 2001 January;
			formation.	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-17	GeneSeq	WO9929718	BMP-17 belongs to the transforming growth	BMP-17 activity can be determined	Induction of Cartilage, Tissue
	Accession		factor-beta (TGFB) superfamily. Bone	using the following assays known in	and Bone Growth, and Diabetes
	Y17870		morphogenic protein induces bone	the art: Nat Genet. 2001 January;
			formation.	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-18	GeneSeq	WO9929718	BMP-18 belongs to the transforming growth	BMP-18 activity can be determined	Induction of Cartilage, Tissue
	Accession		factor-beta (TGFB) superfamily. Bone	using the following assays known in	and Bone Growth, and Diabetes
	Y17871		morphogenic protein induces bone	the art: Nat Genet. 2001 January;
			formation.	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.
Inhibin	GeneSeq	WO0020591	The inhibin beta A subunit joins the alpha	Tumor suppressor activity of inhibin	Tumor suppression.
alpha	Accession		subunit to form a pituitary FSH secretion	can be determined using assays
	B02806		inhibitor. Inhibin has been shown to	known in the art: Matzuk et al.,
			regulate gonadal stromal cell proliferation	Nature 1992 Nov. 26: 360
			negatively and to have tumour-suppressor	(6402); 313-9.
			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	GeneSeq	WO0020591	The inhibin beta A subunit joins the alpha	Tumor suppressor activity of inhibin	Tumor suppression.
beta	Accession		subunit to form a pituitary FSH secretion	can be determined using assays
	H02808		inhibitor. Inhibin has been shown to	known in the art: Matzuk et al.,
			regulate gonadal stromal cell proliferation	Nature 1992 Nov. 26: 360
			negatively and to have tumour-suppressor	(6402); 313-9.
			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	GeneSeq	WO9849296	Cerebus is believed to be involved in the	BMP activity, in the presence of the	BMP Antagonist useful for
Protein	Accession		inhibition of BMP activity	antagonist Cerebus, can be	Osteosarcoma, abnormal bone
	W86032			determined using the following	growth.
				assays known in the art: 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	GeneSeq	WO9614579	Soluble BMP receptor kinase protein-3 is	BMP activity, in the presence of the	BMP Antagonist useful for
BMP	Accession		involved in the binding of BMPs. Soluble	soluble antagonist BMP receptor	Osteosarcoma, abnormal bone
Receptor	R95227		BMP receptor kinase protein-3 is useful as	kinase protein-3, can be determined	growth.
Kinase			an antagonist for the inhibition of BMP	using the following assays known in
Protein-3			activity.	the art: 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.
BMP	GeneSeq	WO9741250	BMPs belong to the transforming growth	BMP activity, in the presence of the	Bone formation or
Pro-	Accession		factor-beta (TGFB) superfamily. Bone	Furin, can be determined using the	Regeneration Abnormalities
cessing	W36099		morphogenic protein induces bone	following assays known in the art:
Enzyme			formation.	Nat Genet. 2001 January; 27(1): 84-8;
Furin				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-	GeneSeq	WO9216228	Members of the TGF-beta	The effect of TGF betas on signaling	Useful for treating cancer and
beta 1	Accession		family of proteins	can be assayed by treating Primary	to promote wound healing.
	R29657		initiate cell signaling by binding to	BAECs transfected with a construct
			heteromeric receptor complexes of type I	called p3TP-Lux, containing a TGF-
			(TbetaRI) and type II (TbetaRII)	beta responsive promoter fused to a
			serine/threonine kinase receptors (reviewed	reporter gene, and measuring
			by Massague, J. et al. (1994) Trends Cell	luciferase gene expression (Wrana et
			Biol. 4: 172 178; Miyazono, K. et al. (1994)	al., 1994, Nature 370: 341-347).
			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-	GeneSeq	EP542679	Members of the TGF-beta	The effect of TGF betas on signaling	Useful for treating cancer and
beta 2	Accession		family of proteins	can be assayed by treating Primary	to promote wound healing.
	R39659		initiate cell signaling by binding to	BAECs transfected with a construct
			heteromeric receptor complexes of type I	called p3TP-Lux, containing a TGF-
			(TbetaRI) and type II (TbetaRII)	beta responsive promoter fused to a
			serine/threonine kinase receptors (reviewed	reporter gene, and measuring
			by Massague, J. et al. (1994) Trends Cell	luciferase gene expression (Wrana et
			Biol. 4: 172 178; Miyazono, K. et al. (1994)	al., 1994, Nature 370: 341-347).
			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-	GeneSeq	WO0015798	Members of the TGF-beta	The effect of TGF betas on signaling	Useful for treating cancer and
beta 9	Accession		family of proteins	can be assayed by treating Primary	to promote wound healing.
	Y70654		initiate cell signaling by binding to	BAECs transfected with a construct
			heteromeric receptor complexes of type I	called p3TP-Lux, containing a TGF-
			(TbetaRI) and type II (TbetaRII)	beta responsive promoter fused to a
			serine/threonine kinase receptors (reviewed	reporter gene, and measuring
			by Massague, J. et al. (1994) Trends Cell	luciferase gene expression (Wrana et
			Biol. 4: 172 178; Miyazono, K. et al. (1994)	al., 1994, Nature 370: 341-347).
			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		GB2305921	Members of the TGF-beta	The effect of TGF betas on signaling	Useful for control of fibrosis,
beta			family of proteins	in the presence of an anti-TGF beta	immune, and inflammatory
family			initiate cell signaling by binding to	antibody, can be assayed by treating	disease.
anti-			heteromeric receptor complexes of type I	Primary BAECs transfected with a
bodies			(TbetaRI) and type II (TbetaRII)	construct called p3TP-Lux,
			serine/threonine kinase receptors (reviewed	containing a TGF-beta responsive
			by Massague, J. et al. (1994) Trends Cell	promoter fused to a reporter
			Biol. 4: 172 178; Miyazono, K. et al. (1994)	gene, and measuring luciferase gene
			Adv. Immunol. 55: 181-220). Activation of	expression (Wrana et al., 1994,
			this heteromeric receptor complex occurs	Nature 370: 341-347).
			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	GeneSeq	WO0012551	Members of the TGF-beta	The effect of TGF betas on signaling	Useful for inhibiting tissue or
TGF beta	Accession		family of proteins	in the presence of a TGF beta	tumor growth.
binding	Y70552		initiate cell signaling by binding to	binding protein, can be assayed by
protein			heteromeric receptor complexes of type I	treating Primary BAECs transfected
II			(TbetaRI) and type II (TbetaRII)	with a construct called p3TP-Lux,
			serine/threonine kinase receptors (reviewed	containing a TGF-beta responsive
			by Massague, J. et al. (1994) Trends Cell	promoter fused to a reporter gene,
			Biol. 4: 172 178; Miyazono, K. et al. (1994)	and measuring luciferase gene
			Adv. Immunol 55: 181-220). Activation of	expression (Wrana et al., 1994,
			this heteromeric receptor complex occurs	Nature 370: 341-347).
			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	The effect of TGF betas on signaling	Bone formation or
	Accession		family of proteins	can be assayed by treating Primary	Regeneration Abnormalities
	W36100		initiate cell signaling by binding to	BAECs transfected with a construct
			heteromeric receptor complexes of type I	called p3TP-Lux, containing a TGF-
			(TbetaRI) and type II (TbetaRII)	beta responsive promoter fused to a
			serine/threonine kinase receptors (reviewed	reporter gene, and measuring
			by Massague, J. et al. (1994) Trends Cell	luciferase gene expression (Wrana et
			Biol. 4: 172 178; Miyazono, K. et al. (1994)	al., 1994, Nature 370: 341-347).
			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	GeneSeq	WO9837195	BMPs are involved in the induction of bone	BMP activity, in the presence of b57	BMP Antagonist useful for
Protein	Accession		formation. Specific antagonists are useful is	protein, can be determined using the	Osteosarcoma, abnormal bone
	W69293		preventing this activity from occurring.	following assays known in the art:	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, 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	Type II diabetes and
	Accession		mouse FIZZI and FIZZ3/Resistin genes. The	II diabetes can be determined using	Syndrome X.
	W69293		characteristic feature of this family is the C-	assays known in the art: Pontoglio
			terminal stretch of 10 cys residues with	et al., J Clin Invest 1998 May 15;
			identical spacing. The mouse homolog of	101(10): 2215-22.
			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	Lactose intolerance.
	Accession		binding proteins characterized by an affinity	to bind lactose can be determined
	W11841		for beta-galactoside containing	using assays known in the art:
			glycoconjugates.	Wada, et al., J Biol Chem 1997
				Feb. 28; 272(9): 6078-86.
APM-I;	GeneSeq	W00026363	ACPR30 gene is exclusively expressed in	Ability of ACRP30 polypeptides to	Obesity, Metabolic disorders,
ACRP-30;	Accession		adipose tissue. ACRP30 is thought to	influence obesity and fat oxidation	Lipid Metabolism; Hormone
Famoxin	Y71035		increase fatty acid oxidation by muscle	can be determined using assays	Secretion.
			tissue.	known in the art: Fruebis et al.,
				Proc Nat'l Acad Sci USA 2001
				Feb. 13; 98(4): 2005-10.
ACRP-30	GeneSeq	WO0063376	ACPR30 gene is exclusively expressed in	Ability of ACRP30 homologue polypeptides to	Obesity, Metabolic disorders,
Homologue;	Accession		adipose tissue. ACRP30 is thought to	influence obesity and fat oxidation	Lipid Metabolism; Hormone
Complement	B30234		increase fatty acid oxidation by muscle	can be determined using assays	Secretion.
Component			tissue.	known in the art: Fruebis et al.,
Clq C				Proc Nat'l 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	Diabetes mellitus; Regulation
	Accession		secretion and insulin activity, and therefore	type II diabetes can be determined	of Insulin secretory response;
	Y79567		may be useful in the treatment of type II	using assays known in the art:	Insulin mediated glucose
			diabetes.	Pontoglio et al., J Clin Invest 1998	transport disorders.
				May 15; 101(10): 2215-22.
Calpain-10b	GeneSeq	WO0023603	Calpain is believed to play a role in insulin	Ability of Calpain-10 to influence	Diabetes mellitus; Regulation
	Accession		secretion and insulin activity, and therefore	type II diabetes can be determined	of Insulin secretory response;
	Y79568		may be useful in the treatment of type II	using assays known in the art:	Insulin mediated glucose
			diabetes.	Pontoglio et al., J Clin Invest 1998	transport disorders.
				May 15; 101(10): 2215-22.
Calpain-10c	GeneSeq	WO0023603	Calpain is believed to play a role in insulin	Ability of Calpain-10 to influence	Diabetes mellitus; Regulation
	Accession		secretion and insulin activity, and therefore	type II diabetes can be determined	of Insulin secretory response;
	Y79569		may be useful in the treatment of type II	using assays known in the art:	Insulin mediated glucose
			diabetes.	Pontoglio et al., J Clin Invest 1998	transport disorders.
				May 15; 101(10): 2215-22.
PDGF-D	GeneSeq	WO0027879	Vascular Endothelial Growth Factor.	Proliferation assay using NR6R-	Wound Healing; Atherosclermis.
	Accession			3T3 cells (Rizzino 1988 Cancer
	Y71130			Res. 48: 4266).
FasL	GeneSeq	WO9936079	Activities associated with apoptosis and	Activity can be determined using	Apoptosis-related disorders;
	Accession		immune system functions.	Apoptosis assays known in the art:	Autoimmune disorders; Graft
	Y28594			Walczak et al. (1996) EMBOJ 16:	v-Host disorders.
				5386-5397.
Chondro	GeneSeq	W00029579	Chondromodulin proteins are cartilage	Ability of Chondromodulin-like	Antianglogenic agent;
modulin-	Accession		proteins thought to confer resistance to	protein to inhibit vascularization	Osteoblast proliferation
like	Y71262		anglogeneis, and thus are useful as anti-	can be determined using assays	stimulator; prevents
protein			angiogenic agents that may have utility in	known in the art: Hirakie et al.,	vascularization of cartilage
			combating cancer.	J Biol Chem 1997 Dec. 19;	tissue; Useful to treat cancer.
				272(51): 32419-26.
Patched	GeneSeq	U.S. Pat. No.	Patched is a tumour-suppressor	Ability of soluble Patched to bind	Receptor for Hedgehog
	Accession	5,837,538	receptor for Sonic hedgehog (shh), which	to and inhibit the activities of shh	cellular proliferation signaling
	W72969		is a protein that controls developmental	can be determined using assays	molecule. This receptor is
			patterning and growth.	known in the art: Stone et al.,	useful as a means of
				Nature 1996 Nov. 14;	preventing cellular
				384(6605): 129-34.	proliferation via the shh
					signaling pathway, thus useful
					for cancers.
Patched-2	GeneSeq	WO9953058	Patched is a tumour-suppressor	Ability of soluble Patched to bind	Receptor for Hedgehog
	Accession		receptor for Sonic hedgehog (shh), which	to and inhibit the activities of shh	cellular proliferation signaling
	Y43261		is a protein that controls developmental	can be determined using assays	molecule. This receptor is
			patterning and growth.	known in the art: Stone et al.,	useful as a means of
				Nature 1996 Nov. 14;	preventing cellular
				384(6605): 129-34.	proliferation via the shh
					signaling pathway, thus useful
					for cancers.
Maspin;	GeneSeq	WO9405804	Maspin is a member of the serpin family of	The inhibitory effects cf Maspin	Tumor suppressor which is
Protease	Accession		serine protease inhibitors that is thought to	and other protease inhibitors can be	down-regulated in breast
Inhibitor	R50938		suppress tumor metastasis.	assayed using methods known in	cancers. The maspin protein
5				the art such as a labeled protease	has tumour suppressing and
				substrate, for example, Universal	invasion suppressing activity.
				Protease Substrate (casein,
				resorufin-labeled): Roche
				Molecular Biochemicals, Cat. No.
				1080733.
Endostatin	GeneSeq	WO0064946	Endostatin is believed to inhibit effects of	The inhibitory effects of endostatin	Anti-angiogenic activity.
	Accession		capillary endothelial cell proliferation.	can be assayed using assays	Useful in the prevention and/or
	B28399			disclosed by Cao et al. (1996) J.	treatment of cancers.
				Biol. Chem. 271 29461-29467.
aFGF;	GeneSeq	EP298723	Fibroblast Growth Factor	Proliferation assay using NR6R-	Promotion of growth and
FGF-1	Accession			3T3 cells (Rizzino 1988 Cancer	proliferation of cells, such as
	P94037			Res. 48: 4266); Examples 23 and	epithelial cells and
				39 disclosed herein.	keratinocytes. Antagonists
					may be useful as anti-cancer
					agents.
bFGF;	GeneSeq	FR2642086	Fibroblast Growth Factor	Proliferation assay using NR6R-	Promotion of growth and
FGF-2	Accession			3T3 cells (Rizzino 1988 Cancer	proliferation of cells, such as
	R06685			Res. 48: 4266); Examples 23 and	epithelial cells and
				39 disclosed herein.	keratinocytes. Antagonists
					may be useful as anti-cancer
					agents.
FGF-3;	GeneSeq	WO9503831	Fibroblast Growth Factor	Proliferation assay using NR6R-	Promotion of growth and
INT-2	Accession			3T3 cells (Rizzino 1988 Cancer	proliferation of cells, such as
	R07824			Res. 48: 4266); Examples 23 and	epithelial cells and
				39 disclosed herein.	keratinocytes. Antagonists
					may be useful as anti-cancer
					agents.
FGF-4;	GeneSeq	WO9503831	Fibroblast Growth Factor	Proliferation assay using NR6R-	Promotion of growth and
HST-1;	Accession			3T3 cells (Rizzino 1988 Cancer	proliferation of cells, such as
HBGF-4	R07825			Res. 48: 4266); Examples 23 and	epithelial cells and
				39 disclosed herein.	keratinocytes. Antagonists
					may be useful as anti-cancer
					agents.
FGF-5	GeneSeq	WO9730155	Fibroblast Growth Factor	Proliferation assay using NR6R-	Promotion of growth and
	Accession			3T3 cells (Rizzino 1988 Cancer	proliferation of cells, such as
	W22600			Res. 48: 4266); Examples 23 and	epithelial cells and
				39 disclosed herein.	keratinocytes. Antagonists
					may be useful as anti-cancer
					agents.
FGF-6;	GeneSeq	EP613946	Fibroblast Growth Factor	Proliferation assay using NR6R-	Promotion of growth and
Heparin	Accession			3T3 cells (Rizzino 1988 Cancer	proliferation of cells, such as
binding	R58555			Res. 48: 4266); Examples 23 and	epithelial cells and
secreted				39 disclosed herein.	keratinocytes. Antagonists
trans-					may be useful as anti-cancer
forming					agents.
factor-2
FGF-8	GeneSeq	WO9524928	Fibroblast Growth Factor	Proliferation assay using NR6R-	Promotion of growth and
	Accession			3T3 cells (Rizzino 1988 Cancer	proliferation of cells, such as
	R80783			Res. 48: 4266); Examples 23 and	epithelial cells and
				39 disclosed herein.	keratinocytes. Antagonists
					may be useful as anti-cancer
					agents.
FGF-9;	GeneSeq	WO9503831	Fibroblast Growth Factor	Proliferation assay using NR6R-	Promotion of growth and
Gila	Accession			3T3 cells (Rizzino 1988 Cancer	proliferation of cells, such as
activating	R70822			Res. 48: 4266); Examples 23 and	epithelial cells and
factor				39 disclosed herein.	keratinocytes. Antagonists
					may be useful as anti-cancer
					agents.
FGF-12;	GeneSeq	WO9635708	Fibroblast Growth Factor	Proliferation assay using NR6R-	Promotion of growth and
Fibroblast	Accession			3T3 cells (Rizzino 1988 Cancer	proliferation of cells, such as
growth	W06309			Res. 48: 4266); Examples 23 and	epithelial cells and
factor				39 disclosed herein.	keratinocytes. Antagonists
homologous					may be useful as anti-cancer
factor-1					agents.
FGF-15	GeneSeq	WO9927100	Fibroblast Growth Factor	Proliferation assay using NR6R-	Promotion of growth and
	Accession			3T3 cells (Rizzino 1988 Cancer	proliferation of cells, such as
	Y08582			Res. 48: 4266); Examples 23 and	epithelial cells and
				39 disclosed herein.	keratinocytes. Antagonists
					may be useful as anti-cancer
					agents.
FGF-16	GeneSeq	WO9918128	Fibroblast Growth Factor	Proliferation assay using NR6R-	Promotion of growth and
	Accession			3T3 cells (Rizzino 1988 Cancer	proliferation of cells, such as
	Y05474			Res. 48: 4266); Examples 23 and	epithelial cells and
				39 disclosed herein.	keratinocytes. Antagonists
					may be useful as anti-cancer
					agents.
FGF-18	GeneSeq	WO9927100	Fibroblast Growth Factor	Proliferation assay using NR6R-	Promotion of growth and
	Accession			3T3 cells (Rizzino 1988 Cancer	proliferation of cells, such as
	Y08590			Res. 48: 4266); Examples 23 and	epithelial cells and
				39 disclosed herein.	keratinocytes. Antagonists
					may be useful as anti-cancer
					agents.
fit-3	GeneSeq	EP627487	Stem Cell Progenitor	Chemokine activities can be	Promotion of immune cell
ligand	Accession			determined using assays known in	growth and/or differentiation.
	R67541			the art: Methods in Molecular
				Biology, 2000, vol. 138:
				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	VEGF activity can be determined	Promotion of growth and
	Accession		proliferation of endothelial cells.	using assays known in the art, such	proliferation of cells, such as
	Y69417			as those disclosed in International	vascular endothelial cells.
				Publication No. WO0045835, for	Antagonists may be useful as
				example.	anti-angiogenic agents, and
					may be applicable for cancer.
VEGB-121	GeneSeq	WO0071713	Promotes the growth and/or	VEGF activity can be determined	Promotion of growth and
	Accession		proliferation of endothelial cells.	using assays known in the art, such	proliferation of cells, such as
	B50432			as those disclosed in International	vascular endothelial cells.
				Publication No. WO0045835, for	Antagonists may be useful as
				example.	anti-angiogenic agents, and
					may be applicable for cancer.
VEGF-138	GeneSeq	WO9940197	Promotes the growth and/or	VEGF activity can be determined	Promotion of growth and
	Accession		proliferation of endothelial cells.	using assays known in the art, such	proliferation of cells, such as
	Y43483			as those disclosed in International	vascular endothelial cells.
				Publication No. WO0045835, for	Antagonists may be useful as
				example.	anti-angiogenic agents, and
					may be applicable for cancer.
VEGF-145	GeneSeq	WO0013702	Promotes the growth and/or	VEGF activity can be determined	Promotion of growth and
	Accession		proliferation of endothelial cells.	using assays known in the art, such	proliferation of cells, such as
	Y69413			as those disclosed in International	vascular endothelial cells.
				Publication No. WO0045835, for	Antagonists may be useful as
				example.	anti-angiogenic agents, and
					may be applicable for cancer.
VEGF-162	GeneSeq	W09940197	Promotes the growth and/or	VEGF activity can be determined	Promotion of growth and
	Accession		proliferation of endothelial cells.	using assays known in the art, such	proliferation of cells, such as
	Y43484			as those disclosed in International	vascular endothelial cells.
				Publication No. WO0045835, for	Antagonists may be useful as
				example.	anti-angiogenic agents, and
					may be applicable for cancer.
VEGF-165	GeneSeq	WO0013702	Promotes the growth and/or	VEGF activity can be determined	Promotion of growth and
	Accession		proliferation of endothelial cells.	using assays known in the art, such	proliferation of cells, such as
	Y69414			as those disclosed in International	vascular endothelial cells.
				Publication No. WO0045835, for	Antagonists may be useful as
				example.	anti-angiogenic agents, and
					may be applicable for cancer.
VEGF-182	GeneSeq	W09940197	Promotes the growth and/or	VEGF activity can be determined	Promotion of growth and
	Accession		proliferation of endothelial cells.	using assays known in the art, such	proliferation of cells, such as
	Y43483			as those disclosed in International	vascular endothelial cells.
				Publication No. WO0045835, for	Antagonists may be useful as
				example.	anti-angiogenic agents, and
					may be applicable for cancer.
VEGF-189	GeneSeq	WO0013702	Promotes the growth and/or	VEGF activity can be determined	Promotion of growth and
	Accession		proliferation of endothelial cells.	using assays known in the art, such	proliferation of cells, such as
	Y69415			as those disclosed in International	vascular endothelial cells.
				Publication No. WO0045835, for	Antagonists may be useful as
				example.	anti-angiogenic agents, and
					may be applicable for cancer.
VEGF-206	GeneSeq	W00013702	Promotes the growth and/or	VEGF activity can be determined	Promotion of growth and
	Accession		proliferation of endothelial cells.	using assays known in the art, such	proliferation of cells, such as
	Y69416			as those disclosed in International	vascular endothelial cells.
				Publication No. WO0045835, for	Antagonists may be useful as
				example.	anti-angiogenic agents, and
					may be applicable for cancer.
VEGF-D	GeneSeq	WO9807832	Promotes the growth and/or	VEGF activity can be determined	Promotion of growth and
	Accession		proliferation of endothelial cells.	using assays known in the art, such	proliferation of cells, such as
	W53240			as those disclosed in International	vascular endothelial cells.
				Publication No. WO0045835, for	Antagonists may be useful as
				example.	anti-angiogenic agents, and
					may be applicable for cancer.
VEGF-E;	GeneSeq	W09947677	Promotes the growth and/or	VEGF activity can be determined	Promotion of growth and
VEGF-X	Accession		proliferation of endothelial cells.	using assays known in the art, such	proliferation of cells, such as
	Y33679			as those disclosed in International	vascular endothelial cells.
				Publication No. WO0045835, for	Antagonists may be useful as
				example.	anti-angiogenic agents, and
					may be applicable for cancer.
VEGF	GeneSeq	WO9831794	Receptor for VEGF polypeptides	VEGF activity, in the presence of	VEGF Receptor. Fusion
Receptor;	Accession			flk-1 polypeptides, can be	protein with the extracellular
KDR;	W69679			determined using assays known in	domain is useful as an anti-
flk-1				the art, such as those disclosed in	angiogenic agent. Antagonists
				International Publication No.	may be useful in the promotion
				WO0045835, for example.	of angiogenesis.
Soluble	GeneSeq	U.S. Pat. No.	Receptor for VEGF polypeptides	VEGF activity, in the presence of	VEGF Receptor. Fusion
VEGF	Accession	5,712,380		VEGF Receptor polypeptides, can	protein with the extracellular
Receptor	W47037			be determined using assays known in	domain is useful as an anti-
				the art, such as those disclosed in	angiogenic agent. Antagonists
				International Publication No.	may be useful in the promotion
				WO0045835, for example.	of angiogenesis.
flt-1	GeneSeq	WO0021560	Receptor for VEGF polypeptides	VEGF activity, in the presence of	VEGF Receptor. Fusion
	Accession			flt-1 polypeptides, can be	protein with the extracellular
	Y70751			determined using assays known in	domain is useful as an anti-
				the art, such as those disclosed in	angiogenic agent. Antagonists
				International Publication No.	may be useful in the promotion
				WO0045835, for example.	of angiogenesis.
VEGF R-3;	GeneSeq	WO0058511	Receptor for VEGF polypeptides	VEGF activity, in the presence of	VEGF Receptor. Fusion
flt-4	Accession			flt-4 polypeptides, can be	protein with the extracellular
	B29047			determined using assays known in	domain is useful as an anti-
				the art, such as those disclosed in	angiogenic agent. Antagonists
				International Publication No.	may be useful in the promotion
				WO0045835, for example.	of angiogenesis.
Neuro-	GeneSeq	WO9929858	Vascular Endothelial Growth Factor	VEGF activity can be determined	Promotion of growth and
pilin-1	Accession			using assays known in the art, such	proliferation of cells, such as
	Y06319			as those disclosed in International	vascular endothelial cells.
				Publication No. WO0045835, for	Antagonists may be useful as
				example.	anti-angiogenic agents, and
					may be applicable for cancer.
Neuro-	GeneSeq	WO9929858	Vascular Endothelial Growth Factor	VEGF activity can be determined	Promotion of growth and
pilin-2	Accession			using assays known in the art, such	proliferation of cells, such as
	Y03618			as those disclosed in International	vascular endothelial cells.
				Publication No. WO0045835, for	Antagonists may be useful as
				example.	anti-angiogenic agents, and
					may be applicable for cancer.
Human	GeneSeq	W09730085	Troponins are contractile proteins that are	Ability of soluble Troponins to	Anti-angiogenesis
fast	Accession		thought to inhibit angiogenesis. High levels	inhibit anglogenesis can be
twitch	W22597		may contribute to the difficulty encountered	determined using assays known in
skeletal			in revascularizing the ischemic myocardium	the art: . Proc Natl Acad Sci USA
muscle			after cardiovascular injury.	1999 Mar. 16; 96(6): 2645-50.
troponin C
Human	GeneSeq	W09730085	Troponins are contractile proteins that are	Ability of soluble Troponins to	Anti-angiogenesis
fast	Accession		thought to inhibit angiogenesis. High levels	inhibit anglogenesis can be
twitch	W18054		may contribute to the difficulty encountered	determined using assays known in
skeletal			in revascularizing the ischemic myocardium	the art: . Proc Natl Acad Sci USA
muscle			after cardiovascular injury.	1999 Mar. 16; 96(6): 2645-50.
troponin I
Human fast	GeneSeq	W09730085	Troponins are contractile proteins that are	Ability of soluble Troponins to	Anti-angiogenesis
twitch	Accession		thought to inhibit angiogenesis. High levels	inhibit anglogenesis can be
skeletal	W22599		may contribute to the difficulty encountered	determined using assays known in
muscle			in revascularizing the ischemic myocardium	the art: . Proc Natl Acad Sci USA
troponin T			after cardiovascular injury.	1999 Mar. 16; 96(6): 2645-50.
fragment.	GeneSeq	W09719955	Troponins are contractile proteins that are	Ability of soluble Troponins to	Anti-angiogenesis
myo-	Accession		thought to inhibit angiogenesis. High levels	inhibit anglogenesis can be
fibrillar	W18053		may contribute to the difficulty encountered	determined using assays known in
protein			in revascularizing the ischemic myocardium	the art: . Proc Natl Acad Sci USA
troponin I			after cardiovascular injury.	1999 Mar. 16; 96(6): 2645-50.
myo-	GeneSeq	W09719955	Troponins are contractile proteins that are	Ability of soluble Troponins to	Anti-angiogenesis
fibrillar	Accession		thought to inhibit angiogenesis. High levels	inhibit anglogenesis can be
protein	W18054		may contribute to the difficulty encountered	determined using assays known in
troponin I			in revascularizing the ischemic myocardium	the art: . Proc Natl Acad Sci USA
			after cardiovascular injury.	1999 Mar. 16; 96(6): 2645-50.
Troponin	GeneSeq	WO9933874	Troponins are contractile proteins that are	Ability of soluble Troponins to	Anti-angiogenesis
peptides	Accessions		thought to inhibit angiogenesis. High levels	inhibit anglogenesis can be
	Y29581,		may contribute to the difficulty encountered	determined using assays known in
	Y29582,		in revascularizing the ischemic myocardium	the art: . Proc Natl Acad Sci USA
	Y29583,		after cardiovascular injury.	1999 Mar. 16; 96(6): 2645-50.
	Y29584,
	Y29585,
	and
	Y29586
Human fast	GeneSeq	WO0054770	Troponins are contractile proteins that are	Ability of soluble Troponins to	Anti-angiogenesis
twitch	Accession		thought to inhibit angiogenesis. High levels	inhibit anglogenesis can be
skeletal	B00134		may contribute to the difficulty encountered	determined using assays known in
muscle			in revascularizing the ischemic myocardium	the art: . Proc Natl Acad Sci USA
Troponin			after cardiovascular injury.	1999 Mar. 16; 96(6): 2645-50.
subunit C
Human fast	GeneSeq	WO0054770	Troponins are contractile proteins that are	Ability of soluble Troponins to	Anti-angiogenesis
twitch	Accession		thought to inhibit angiogenesis. High levels	inhibit anglogenesis can be
skeletal	B00135		may contribute to the difficulty encountered	determined using assays known in
muscle			in revascularizing the ischemic myocardium	the art: . Proc Natl Acad Sci USA
Troponin			after cardiovascular injury.	1999 Mar. 16; 96(6): 2645-50.
subunit I
Protein
Human fast	GeneSeq	WO0054770	Troponins are contractile proteins that are	Ability of soluble Troponins to	Anti-angiogenesis
twitch	Accession		thought to inhibit angiogenesis. High levels	inhibit anglogenesis can be
skeletal	B00136		may contribute to the difficulty encountered	determined using assays known in
muscle			in revascularizing the ischemic myocardium	the art: . Proc Natl Acad Sci USA
Troponin			after cardiovascular injury.	1999 Mar. 16; 96(6): 2645-50.
subunit T
Activator	GeneSeq	WO9013648	PAIs are believed to play a role	Methods that measure plasminogen	Anti-angiogenesis; blood-
In-	Accession		in cancer, and cardiovascular disease	activator inhibitor (PAI) activity	clotting disorders.
hibitor-1;	R08411		and blood-clotting disorders.	are known in the art, for example,
PAI-1				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.
Plasmin-	GeneSeq	DE3722673	PAIs are believed to play a role	Methods that measure plasminogen	Anti-angiogenesis; blood-
ogen	Accession		in cancer, and cardiovascular disease	activator inhibitor (PAI) activity	clotting disorders.
Activator	P94160		and blood-clotting disorders.	are known in the art, for example,
In-				assay the ability of PAI to inhibit
hibitor-2;				tissue plasminogen activator (tPA)
PAI-2				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	GeneSeq	WO9102057	PAIs are believed to play a role	Methods that measure plasminogen	Anti-angiogenesis; blood-
In-	Accession		in cancer, and cardiovascular disease	activator inhibitor (PAI) activity	clotting disorders.
hibitor-2;	R10921		and blood-clotting disorders.	are known in the art, for example,
PAI-2				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	GeneSeq	WO9105048	PAIs are believed to play a role	Methods that measure plasminogen	Anti-angiogenesis; blood-
PAI-1	Accessions		in cancer, and cardiovascular disease	activator inhibitor (PAI) activity	clotting disorders.
mutants	R11755,		and blood-clotting disorders.	are known in the art, for example,
	R11756,			assay the ability of PAI to inhibit
	R11757,			tissue plasminogen activator (tPA)
	R11758,			or urokinase (uPA): J Biochem
	R11759,			Biophys Methods 2000 Sep. 11; 45(2):
	R11760,			127-40, Breast Cancer Res
	R11761,			Treat 1996; 41(2): 141-6. Methods
	R11762			that measure anti-angiogenesis
	and			activity are known in the art, for
	R11763			example, Proc Natl Acad Sci USA
				1999 Mar. 16; 96(6): 2645-50.
CXCR3;	GeneSeq	WO0018431	Chemokines are a family of related	Chemokine activities can be	Soluble CXCR3 polypeptides
CXC	Accession		small, secreted proteins	determined using assays known in	may be useful for inhibiting
	Y79372		involved in biological processes	the art: Methods in Molecular	chemokine activities and viral
			ranging from hematopoiesis,	Biology, 2000, vol. 138:	infection.
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ.
			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	GeneSeq	WO9737005	Chemokines are a family of related	Chemokine activities can be	Immune disorders.
Rantes	Accession		small, secreted proteins	determined using assays known in
	W38129		involved in biological processes	the art: Methods in Molecular
			ranging from hematopoiesis,	Biology, 2000, vol. 138:
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ.
			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	Chemokine activities can be	Immune disorders.
	Accession		small, secreted proteins	determined using assays known in
	Y05299		involved in biological processes	the art: Methods in Molecular
			ranging from hematopoiesis,	Biology, 2000, vol. 138:
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ.
			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	Chemokine activities can be	Immune disorders.
	Accession		small, secreted proteins	determined using assays known in
	R73914		involved in biological processes	the art: Methods in Molecular
			ranging from hematopoiesis,	Biology, 2000, vol. 138:
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ.
			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	Chemokine activities can be	Immune disorders.
	Accession		small, secreted proteins	determined using assays known in
	Y26176		involved in biological processes	the art: Methods in Molecular
			ranging from hematopoiesis,	Biology, 2000, vol. 138:
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ.
			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	GeneSeq	WO9519436	Chemokines are a family of related	Chemokine activities can be	Soluble MCP-1 Receptor
receptor	Accession		small, secreted proteins	determined using assays known in	polypeptides may be useful for
	R79165		involved in biological processes	the art: Methods in Molecular	inhibiting chemokine activities
			ranging from hematopoiesis,	Biology, 2000, vol. 138:	and viral infection.
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ.
			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	Chemokine activities can be	Immune disorders.
	Accession		small, secreted proteins	determined using assays known in
	R73915		involved in biological processes	the art: Methods in Molecular
			ranging from hematopoiesis,	Biology, 2000, vol. 138:
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ.
			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	GeneSeq	W09809171	Chemokines are a family of related	Chemokine activities can be	Soluble MCP-4 Receptor
receptor	Accession		small, secreted proteins	determined using assays known in	polypeptides may be useful for
	W56689		involved in biological processes	the art: Methods in Molecular	inhibiting chemokine activities
			ranging from hematopoiesis,	Biology, 2000, vol. 138:	and viral infection.
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ.
			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	U.S. Pat. No.	Chemokines are a family of related	Chemokine activities can be	Soluble RANTES Receptor
receptor	Accession	5,652,133	small, secreted proteins	determined using assays known in	polypeptides may be useful for
	W29588		involved in biological processes	the art: Methods in Molecular	inhibiting chemokine activities
			ranging from hematopoiesis,	Biology, 2000, vol. 138:	and viral infection.
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ.
			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	GeneSeq	WO9854317	Chemokines are a family of related	Chemokine activities can be	Soluble CCR5 polypeptides
variant	Accession		small, secreted proteins	determined using assays known in	may be useful for inhibiting
	W88238		involved in biological processes	the art: Methods in Molecular	chemokine activities and viral
			ranging from hematopoiesis,	Biology, 2000, vol. 138:	infection.
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ.
			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.	Chemokines are a family of related	Chemokine activities can be	Soluble CCR7 polypeptides
	Accession	6,153,441	small, secreted proteins	determined using assays known in	may be useful for inhibiting
	B50859		involved in biological processes	the art: Methods in Molecular	chemokine activities and viral
			ranging from hematopoiesis,	Biology, 2000, vol. 138:	infection.
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ.
			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	Chemokine activities can be	Immune disorders.
	Accession		small, secreted proteins	determined using assays known in
	W23345		involved in biological processes	the art: Methods in Molecular
			ranging from hematopoiesis,	Biology, 2000, vol. 138:
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ.
			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	Chemokine activities can be	Immune disorders.
	Accession		small, secreted proteins	determined using assays known in
	W10099		involved in biological processes	the art: Methods in Molecular
			ranging from hematopoiesis,	Biology, 2000, vol. 138:
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ.
			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.
Neuro-	GeneSeq	U.S. Pat. No.	Neurotactin may play a role in chemotactic	Chemotactic leukocyte migration	Immune disorders.
tactin	Accessions	6,013,257	leukocyte migration and brain inflammation	assays are known in the art, for
	Y77537,	WO9742224	processes.	example: J. Immunol. Methods 33,
	W34307,			((1980)); Nature 1997 Jun. 5;
	Y53259,			387(6633): 611-7.
	and,
	Y77539
Human	GeneSeq	U.S. Pat. No.	Chemokines are a family of related	chemokine activities can be	Immune disorders.
CKbeta-9	Accession	6,153,441	small, secreted proteins	determined using assays known in
	B50860		involved in biological processes	the art: Methods in Molecular
			ranging from hematopoiesis,	Biology, 2000, vol. 138:
			angiogenesis, and leukocyte trafficking.	chemokine Protocols. Edited by:
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ.
			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.
Lympho-	GeneSeq	WO0073320	Chemokines are a family of related	chemokine activities can be	Immune disorders.
tactin	Accession		small, secreted proteins involved in	determined using assays known in
	B50052		biological processes ranging from	the art: Methods in Molecular
			hematopoiesis, angiogenesis, and	Biology, 2000, vol. 138:
			leukocyte trafficking.	Chemokine Protocols. Edited by:
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ.
			rejection, viral infection, and tumor biology.
			The chemokines exert their effects by acting
			on a family of seven transmembrane G.
MIP-3	GeneSeq	WO9801557	Chemokines are a family of related	chemokine activities can be	Immune disorders.
alpha	Accession		small, secreted proteins involved in	determined using assays known in
	W44398		biological processes ranging from	the art: Methods in Molecular
			hematopoiesis, angiogenesis, and	Biology, 2000, vol. 138:
			leukocyte trafficking.	Chemokine Protocols. Edited by:
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ.
			rejection, viral infection, and tumor biology.
			The chemokines exert their effects by acting
			on a family of seven transmembrane G.
MIP-3	GeneSeq	WO9801557	Chemokines are a family of related	Chemokine activities can be	Immune disorders.
beta	Accession		small, secreted proteins involved in	determined using assays known in
	W44399		biological processes ranging from	the art: Methods in Molecular
			hematopoiesis, angiogenesis, and	Biology, 2000, vol. 138:
			leukocyte trafficking.	Chemokine Protocols. Edited by:
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ.
			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	Chemokine activities can be	Immune disorders.
	Accession		small, secreted proteins involved in	determined using assays known in
	R70798		biological processes ranging from	the art: Methods in Molecular
			hematopoiesis, angiogenesis, and	Biology, 2000, vol. 138:
			leukocyte trafficking.	Chemokine Protocols. Edited by:
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ.
			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	Chemokine activities can be	Hematopoietic growth factors.
Inhib-	Accession		small, secreted proteins involved in	determined using assays known in
itory	R11553		biological processes ranging from	the art: Methods in Molecular
Factor			hematopoiesis, angiogenesis, and	Biology, 2000, vol. 138:
			leukocyte trafficking.	Chemokine Protocols. Edited by:
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ.
			rejection, viral infection, and tumor biology.
			The chemokines exert their effects by acting
			on a family of seven transmembrane G.
thrombo-	GeneSeq	WO9521920	Thrombopoietin is involved in the	Thrombopoietin (TPO) can be	Hematopoietic growth factors.
poietin	Accession		regulation of the growth and	assayed to determine regulation of
	R79905		differentiation of	growth and differentiation of
			megakaryocytes and preceptors thereof.	megakaryocytes. Mol Cell Biol
				2001 April; 21(8): 2659-70; Exp
				Hematol
2001 January; 29(1): 51-8
				and within.
c-kit	GeneSeq	EP992579 and	C-kit ligan is thought to stimulate the	Chemokine activities can be	Hematopoietic growth factors.
ligand;	Accession	EP676470	proliferation of mast cells, and is able to	determined using assays known in
SCF; Mast	Y53284,		augment the proliferation of both myeloid	the art: Methods in Molecular
cell	R83978		and lymphoid hematopoietic progenitors in	Biology, 2000, vol. 138:
growth	and		bone marrow culture. C-kit ligand is also	Chemokine Protocols. Edited by:
factor;	R83977		though to act synergistically with other	A. E. I. Proudfoot, T. N. C. Wells,
MGF;			cytokines.	and C. A. Power. Humana Press
Fibro-				Inc., Totowa, NJ.
sarcoma-
derived
stem cell
factor
Platelet	GeneSeq	WO0066736	Vascular Endothelial Growth Factor	VEGF activity can be determined	Promotion of growth and
derived	Accession			using assays known in the art, such	proliferation of cells, such as
growth	B48653			as those disclosed in International	vascular endothelial cells.
factor				Publication No. WO0045835, for	Antagonists may be useful as
				example.	anti-angiogenic agents, and
					may be applicable for cancer.
Melanoma	GeneSeq	WO9503328	Melanoma inhibiting protein has melanoma-	Tumor suppressor activity of	Cancer; melanoma
inhibiting	Accession		inhibiting activity and can be used to treat	melanoma inhibiting protein can be
protein	R69811		cancer (melanoma, glioblastoma,	determined using assays known in
			neuroblastoma, small cell lung cancer,	the art: Matzuk et al., Nature 1992
			neuroectodermal tumors) or as an	Nov. 26; 360(6402): 313-9.
			immunosuppressant (it inhibits IL-2 or
			phytohaemagglutinin induced proliferation
			of peripheral blood lymphocytes.
Glioma-	GeneSeq	EP399816	Vascular Endothelial Growth Factor	VEGF activity can be determined	Promotion of growth and
derived	Accession			using assays known in the art, such	proliferation of cells, such as
growth	R08120			as those disclosed in International	vascular endothelial cells.
factor				Publication No. WO0045835, for	Antagonists may be useful as
				example.	anti-angiogenic agents, and
					may be applicable for cancer.
Platelet	GeneSeq	EP682110	Vascular Endothelial Growth Factor	VEGF activity can be determined	Promotion of growth and
derived	Accession			using assays known in the art, such	proliferation of cells, such as
growth	R84759			as those disclosed in International	vascular endothelial cells.
factor				Publication No. WO0045835, for	Antagonists may be useful as
pre-				example.	anti-angiogenic agents, and
cursor A					may be applicable for cancer.
Platelet	GeneSeq	EP682110	Vascular Endothelial Growth Factor	VEGF activity can be determined	Promotion of growth and
derived	Accession			using assays known in the art, such	proliferation of cells, such as
growth	R84760			as those disclosed in International	vascular endothelial cells.
factor				Publication No. WO0045835, for	Antagonists may be useful as
pre-				example.	anti-angiogenic agents, and
cursor B					may be applicable for cancer.
Platelet	GeneSeq	EP282317	Vascular Endothelial Growth Factor	VEGF activity can be determined	Promotion of growth and
derived	Accession			using assays known in the art, such	proliferation of cells, such as
growth	P80595			as those disclosed in International	vascular endothelial cells.
factor	and			Publication No. WO0045835, for	Antagonists may be useful as
Bv-sis	P80596			example.	anti-angiogenic agents, and
					may be applicable for cancer.
Placental	GeneSeq	WO9206194	Vascular Endothelial Growth Factor	VEGF activity can be determined	Promotion of growth and
Growth	Accessions			using assays known in the art, such	proliferation of cells, such as
Factor	R23059			as those disclosed in International	vascular endothelial cells.
	and			Publication No. WO0045835, for	Antagonists may be useful as
	R23060			example.	anti-angiogenic agents, and
					may be applicable for cancer.
Placental	GeneSeq	DE19748734	Vascular Endothelial Growth Factor	VEGF activity can be determined	Promotion of growth and
Growth	Accession			using assays known in the art, such	proliferation of cells, such as
Factor-2	Y08289			as those disclosed in International	vascular endothelial cells.
				Publication No. WO0045835, for	Antagonists may be useful as
				example.	anti-angiogenic agents, and
					may be applicable for cancer.
Thrombo-	GeneSeq	WO0000612	Thrombopoietin is involved in the	Thrombopoietin (TPO) can be	Thrombocytopenia, cancer.
poietin	Accession		regulation of the growth and	assayed to determine regulation of
deriv-	Y77244		differentiation of	growth and differentiation of
ative1			megakaryocytes and preceptors thereof.	megakaryocytes. Mol Cell Biol
				2001 April; 21(8): 2659-70; Exp
				Hematol
2001 January; 29(1): 51-8
				and within.
Thrombo-	GeneSeq	WO0000612	Thrombopoietin is involved in the	Thrombopoietin (TPO) can be	Thrombocytopenia, cancer.
poietin	Accession		regulation of the growth and	assayed to determine regulation of
deriv-	Y77255		differentiation of	growth and differentiation of
ative2			megakaryocytes and preceptors thereof.	megakaryocytes. Mol Cell Biol
				2001 April; 21(8): 2659-70; Exp
				Hematol
2001 January; 29(1): 51-8
				and within.
Thrombo-	GeneSeq	WO0000612	Thrombopoietin is involved in the	Thrombopoietin (TPO) can be	Thrombocytopenia, cancer.
poietin	Accession		regulation of the growth and	assayed to determine regulation of
deriv-	Y77262		differentiation of	growth and differentiation of
ative3			megakaryocytes and preceptors thereof.	megakaryocytes. Mol Cell Biol
				2001 April; 21(8): 2659-70; Exp
				Hematol
2001 January; 29(1): 51-8
				and within.
Thrombo-	GeneSeq	WO0000612	Thrombopoietin is involved in the	Thrombopoietin (TPO) can be	Thrombocytopenia, cancer.
poietin	Accession		regulation of the growth and	assayed to determine regulation of
deriv-	Y77267		differentiation of	growth and differentiation of
ative4			megakaryocytes and preceptors thereof.	megakaryocytes. Mol Cell Biol
				2001 April; 21(8): 2659-70; Exp
				Hematol
2001 January; 29(1): 51-8
				and within.
Thrombo-	GeneSeq	WO0000612	Thrombopoietin is involved in the	Thrombopoietin (TPO) can be	Thrombocytopenia, cancer.
poietin	Accession		regulation of the growth and	assayed to determine regulation of
deriv-	Y77246		differentiation of	growth and differentiation of
ative5			megakaryocytes and preceptors thereof.	megakaryocytes. Mol Cell Biol
				2001 April; 21(8): 2659-70; Exp
				Hematol
2001 January; 29(1): 51-8
				and within.
Thrombo-	GeneSeq	WO0000612	Thrombopoietin is involved in the	Thrombopoietin (TPO) can be	Thrombocytopenia, cancer.
poietin	Accession		regulation of the growth and	assayed to determine regulation of
deriv-	Y77253		differentiation of	growth and differentiation of
ative6			megakaryocytes and preceptors thereof.	megakaryocytes. Mol Cell Biol
				2001 April; 21(8): 2659-70; Exp
				Hematol
2001 January; 29(1): 51-8
				and within.
Thrombo-	GeneSeq	WO0000612	Thrombopoietin is involved in the	Thrombopoietin (TPO) can be	Thrombocytopenia, cancer.
poietin	Accession		regulation of the growth and	assayed to determine regulation of
deriv-	Y77256		differentiation of	growth and differentiation of
ative7			megakaryocytes and preceptors thereof.	megakaryocytes. Mol Cell Biol
				2001 April; 21(8): 2659-70; Exp
				Hematol
2001 January; 29(1): 51-8
				and within.
Fract-	GeneSeq	U.S. Pat. No.	Fractalkine is believed to play a role in	Fractalkine activity can be	Immune disorders.
alkine	Accession	6,043,086	chemotactic leukocyte migration and	determined using Chemotactic
	Y53255		neurological disorders.	leukocyte migration 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	Chemokine activities can be	Immune disorders.
	Accession		small, secreted proteins	determined using assays known in
	W23345		involved in biological processes	the art: Methods in Molecular
			ranging from hematopoiesis,	Biology, 2000, vol. 138:
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ.
			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.	Chemokines are a family of related	Chemokine activities can be	Soluble CCR7 polypeptides
	Accession	6,153,441	small, secreted proteins	determined using assays known in	may be useful for inhibiting
	B50859		involved in biological processes	the art: Methods in Molecular	chemokine activities and viral
			ranging from hematopoiesis,	Biology, 2000, vol. 138:	infection.
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ.
			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	GeneSeq	EP414151	Nerve Growth Factor	Proliferation assay using NR6R-	Neurological disorders, cancer
Growth	Accession			3T3 cells (Rizzino 1988 Cancer
Factor-	R11474			Res. 48: 4266)
beta
Nerve	GeneSeq	EP859056	Nerve Growth Factor	Proliferation assay using NR6R	Neurological disorders, cancer
Growth	Accession			3T3 cells (Rizzino 1988 Cancer
Factor-	W69725			Res. 48: 4266
beta2
Neuro-	GeneSeq	WO9821234	Neurotrophins regulate neuronal	Trk tyrosine kinase activation assays	Neurological disorders, cancer
trophin-3	Accession		cell survival and synaptic	known in the art can be used to
	W8889		plasticity.	assay for neurotrophin activity, for
				example, Proc Natl Acad Sci USA
				2001 Mar. 13; 98(6): 3555-3560.
Neuro-	GeneSeq	WO9325684	Neurotrophins regulate neuronal	Trk tyrosine kinase activation assays	Neurological disorders, cancer
trophin-3	Accession		cell survival and synaptic	known in the art can be used to
	R47100		plasticity.	assay for neurotrophin activity, for
				example, Proc Natl Acad Sci USA
				2001 Mar. 13; 98(6): 3555-3560.
Neuro-	GeneSeq	WO9325684	Neurotrophins regulate neuronal	Trk tyrosine kinase activation assays	Neurological disorders, cancer
trophin-4a	Accession		cell survival and synaptic	known in the art can be used to
	R47101		plasticity.	assay for neurotrophin activity, for
				example, Proc Natl Acad Sci USA
				2001 Mar. 13; 98(6): 3555-3560.
				13; 98(6): 3555-3560
Neuro-	GeneSeq	WO9325684	Neurotrophins regulate neuronal	Trk tyrosine kinase activation assays	Neurological disorders, cancer
trophin-4b	Accession		cell survival and synaptic	known in the art can be used to
	R47102		plasticity. tyrosine kinases.	assay for neurotrophin activity, for
				example, Proc Natl Acad Sci USA
				2001 Mar. 13; 98(6): 3555-3560.
Neuro-	GeneSeq	WO9325684	Neurotrophins regulate neuronal	Trk tyrosine kinase activation assays	Neurological disorders, cancer
trophin-4c	Accession		cell survival and synaptic	known in the art can be used to
	R47103		plasticity. tyrosine kinases.	assay for neurotrophin activity, for
				example, Proc Natl Acad Sci USA
				2001 Mar. 13; 98(6): 3555-3560.
Neuro-	GeneSeq	WO9325684	Neurotrophins regulate neuronal	Trk tyrosine kinase activation assays	Neurological disorders, cancer
trophin-4d	Accession		cell survival and synaptic	known in the art can be used to
	R47102		plasticity. tyrosine kinases.	assay for neurotrophin activity, for
				example, Proc Natl Acad Sci USA
				2001 Mar. 13; 98(6): 3555-3560.
Platelet-	GeneSeq	U.S. Pat. No.	Vascular Endothelial Growth Factor	VEGF activity can be determined	Promotion of growth and
Derived	Accession	5,219,739		using assays known in the art, such	proliferation of cells, such as
Growth	R38918			as those disclosed in International	vascular endothelial cells.
Factor				Publication No. W00045835, for	Hematopoietic and immune
A chain				example.	disorders. Antagonists may be
					useful as anti-angiogenic
					agents, and may be applicable
					for cancer
Platelet-	GeneSeq	U.S. Pat. No.	Vascular Endothelial Growth Factor	VEGF activity can be determined	Promotion of growth and
Derived	Accession	5,219,739		using assays known in the art, such	proliferation of cells, such as
Growth	R38919			as those disclosed in International	vascular endothelial cells.
Factor				Publication No. W00045835, for	Hematopoietic and immune
B chain				example.	disorders. Antagonists may be
					useful as anti-angiogenic
					agents, and may be applicable
					for cancer
Stromal	GeneSeq	WO9948528	Stromal Growth Factor	Proliferation assay using NR6R-	Hematopoietic, immune
Derived	Accession			3T3 cells (Rizzino 1988 Cancer	disorders, cancer
Factor-1	Y39995			Res. 48: 4266)
alpha
Stromal	GeneSeq	CA2117953	Stromal Growth Factor	Proliferation assay using NR6R-	Hematopoietic, immune
Derived	Accession			3T3 cells (Rizzino 1988 Cancer	disorders, cancer
Factor-1	R75420			Res. 48: 4266)
beta
Tarc	GeneSeq	WO9711969	Chemotactic for T lymphocytes. May	Chemotactic leukocyte migration	Antiinflammatory. Immune
	Accession		play a role in T-cell development.	assays are known in the art, for	disorders, cancer
	W14917		Thought to bind CCR8 and CCR4	example: J. Immunol. Methods 33
				((1980))
Pro-	GeneSeq	WO9521625	Prolactin is involved in immune cell	Immune coil proliferation and	Reproductive system
lactin	Accession		proliferation and apoptosis.	suppression of apoptosis by	disorders, cancer.
	R78691			prolactin can be assayed by methods
				well-known in the art, for example,
				Buckley, A R and Buckley D J, Ann
				N Y Acad Sci 2000; 917: 522-33,
				and within.
Pro-	GeneSeq	U.S. Pat. No.	Prolactin is involved in immune cell	Immune coil proliferation and	Reproductive system
lactin2	Accession	5,955,346	proliferation and apoptosis.	suppression of apoptosis by	disorders, cancer.
	Y31764			prolactin can be assayed by methods
				well-known in the art, for example,
				Buckley, A R and Buckley D J, Ann
				NY Acad Sci 2000; 917: 522-33,
				and within.
Follicle	GeneSeq	EP974359	FSH stimulates secretion of interleukin-1 by	FSH activities can be determined	Reproductive system
stimu-	Accession		cells isolated from women in the follicular	using assays known in the art; J	disorders, cancer.
lating	Y54160		phase	Gend Specif Med 1999 November-
hormone				December; 2(6): 30-4; Mol Cell
Alpha				Endocrinol. 1997 Nov. 15;
subunit				134(2): 109-18.
Follicle	GeneSeq	EP974359	FSH stimulates secretion of interleukin-1 by	FSH activities can be determined	Reproductive system
stimu-	Accession		cells isolated from women in the follicular	using assays known in the art; J	disorders, cancer.
lating	Y54161		phase	Gend Specif Med 1999 November-
hormone				December; 2(6): 30-4; Mol Cell
Beta				Endocrinol. 1997 Nov. 15;
subunit				134(2): 109-18.
Sub-	GeneSeq	WO0054053	Substance P is associated with	Immuneregulation and bone	diabetes mellitus,
stance P	Accession		immunoregulation.	marrow, cell proliferation by	hypertension, cancer
(tachy-	B23027			substance P can be assayed by
kinin)				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 M A and Dabrowski
				Z J. J Cell Biochem 2001; 81(3)499-506.
Ocytocin	GeneSeq	WO0053755	Oxytocin is involved in the induction of	Oxytocin and prostaglandin E(2)	inflammatory disorders
(Neuro-	Accession		prostaglandin (E2) release as well as an	release and Ocytocin (Ca2+)	immunologic disorders,
physin I)	B24085		increased amount of calcium release by	increase can be assayed by methods	cancer
	and		smooth muscle cells.	well-known in the art, for example,
	B24086			Pavan et al., AM J Obset Gynecol
				2000 July; 183(1): 76-82 and
				Holda et al., Cell Calcium 1996
				July; 20(1): 43 51.
Vaso-	GeneSeq	WO0053755	Vasopressinis believed to have a direct	Vasopressin activity can be	inflammatory disorders
pressin	Accession		antidiuretic action on the kidney, and it is	determined using assays known in	immunologic disorders,
(Neuro-	B24085		thought to cause vasoconstriction of the	the art, for example, Endocr Regul	cancer
physin	and		peripheral vessels.	1996 March; 30(1): 13-17.
II)	B24086
IL-1	GeneSeq	EP165654	Interleukins are a group of multifunctional	Interleukin activity can be	inflammatory disorders,
	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	immunologic disorders,
	P60326		monocytes, and macrophages. Known	the art: Matthews et al., in	cancer
			functions include stimulating	Lymphokines and Interferens: A
			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and Orencole &
			of neutrophils and T lymphocytes,	Dinarclio (1989) Cytokine 1, 14-20.
			and/or inhibition of interferons.
IL-1	GeneSeq	EP456332	Interleukins are a group of multifunctional	Interleukin activity can be	inflammatory disorders,
mature	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	immunologic disorders,
	R14855		monocytes, and macrophages. Known	the art: Matthews et al., in	cancer
			functions include stimulating	Lymphokines and Interferens: A
			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and Orencole &
			of neutrophils and T lymphocytes,	Dinarclio (1989) Cytokine 1, 14-20.
			and/or inhibition of interferons.
IL-1	GeneSeq	WO9922763	Interleukins are a group of multifunctional	Interleukin activity can be	inflammatory disorders,
beta	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	immunologic disorders,
	Y08322		monocytes, and macrophages. Known	the art: Matthews et al., in	cancer
			functions include stimulating	Lymphokines and Interferens: A
			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and Orencole &
			of neutrophils and T lymphocytes,	Dinarclio (1989) Cytokine 1, 14-20.
			and/or inhibition of interferons.
IL-3	GeneSeq	WO8806161	Interleukins are a group of multifunctional	Interleukin activity can be	inflammatory disorders,
variants	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	immunologic disorders,
	P80382,		monocytes, and macrophages. Known	the art: Matthews et al., in	cancer
	P80383,		functions include stimulating	Lymphokines and Interferens: A
	P80384,		proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
	and		T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
	P80381		and lymphocytes), chemotaxis	1987, pp. 221-225; and Kitamura
			of neutrophils and T lymphocytes,	et al (1989) J Cell Physiol.
			and/or inhibition of interferons.	140 323-334.
IL-4	GeneSeq	WO8702990	Interleukins are a group of multifunctional	Interleukin activity can be	inflammatory disorders,
	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	immunologic disorders,
	P70615		monocytes, and macrophages. Known	the art: Matthews et al., in	cancer
			functions include stimulating	Lymphokines and Interferens: A
			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and Siegel &
			of neutrophils and T lymphocytes,	Mostowski (1990) J Immunol
			and/or inhibition of interferons.	Methods 132, 287-295.
IL-4	GeneSeq	WO9747744	Interleukins are a group of multifunctional	Interleukin activity can be	inflammatory disorders,
muteins	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	immunologic disorders,
	W52151		monocytes, and macrophages. Known	the art: Matthews et al., in	cancer
	W52152		functions include stimulating	Lymphokines and Interferens: A
	W52153		proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
	W52154		T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
	W52155		and lymphocytes), chemotaxis	1987, pp. 221-225; and Siegel &
	W52156		of neutrophils and T lymphocytes,	Mostowski (1990) J Immunol
	W52157		and/or inhibition of interferons.	Methods 132, 287-295.
	W52158
	W52159
	W52160
	W52161
	W52162
	W52163
	W52164
	and
	W52165
IL-1	GeneSeq	EP324447	Interleukins are a group of multifunctional	Interleukin activity can be	inflammatory disorders,
alpha	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	immunologic disorders,
	P90108		monocytes, and macrophages. Known	the art: Matthews et al., in	cancer
			functions include stimulating	Lymphokines and Interferens: A
			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and Orencole &
			of neutrophils and T lymphocytes,	Dinarello (1989) Cytokine 1, 14-20.
			and/or inhibition of interferons.
IL-3	GeneSeq	WO9307171	Interleukins are a group of multifunctional	Interleukin activity can be	inflammatory disorders,
variants	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	immunologic disorders,
	R38561,		monocytes, and macrophages. Known	the art: Matthews et al., in	cancer
	R38562,		functions include stimulating	Lymphokines and Interferens: A
	R38563,		proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
	R38564,		T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
	R38565,		and lymphocytes), chemotaxis	1987, pp. 221-225; and Aarden
	R38566,		of neutrophils and T lymphocytes,	et al (1987) Eur. J. Immunol 17,
	R38567,		and/or inhibition of interferons.	1411-16.
	R38568,
	R38569,
	R38570,
	R38571,
	and
	R38572
IL-6	GeneSeq	WO9402512	Interleukins are a group of multifunctional	Interleukin activity can be	inflammatory disorders,
	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	immunologic disorders,
	R45717		monocytes, and macrophages. Known	the art: Matthews et al., in	cancer
	and		functions include stimulating	Lymphokines and Interferens: A
	R45718		proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and Aarden
			of neutrophils and T lymphocytes,	et al (1987) Eur. J. Immunol 17,
			and/or inhibition of interferons.	1411-16.
IL-13	GeneSeq	WO9404680	Interleukins are a group of multifunctional	Interleukin activity can be	inflammatory disorders,
	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	immunologic disorders,
	R48624		monocytes, and macrophages. Known	the art: Matthews et al., in	cancer
			functions include stimulating	Lymphokines and Interferens: A
			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and Boutelier
			of neutrophils and T lymphocytes,	et al (1995) J. Immunol. Methods
			and/or inhibition of interferons.	181, 29.
IL-4	GeneSeq	DE4137333	Interleukins are a group of multifunctional	Interleukin activity can be	inflammatory disorders,
mutein	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	immunologic disorders,
	R47182		monocytes, and macrophages. Known	the art: Matthews et al., in	cancer
			functions include stimulating	Lymphokines and Interferens: A
			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and Siegel &
			of neutrophils and T lymphocytes,	Mostowski (1990) J Immunol
			and/or inhibition of interferons.	Methods 132, 287-295.
IL-4	GeneSeq	DE4137333	Interleukins are a group of multifunctional	Interleukin activity can be	inflammatory disorders,
mutein	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	immunologic disorders,
Y124X	R47183		monocytes, and macrophages. Known	the art: Matthews et al., in	cancer
			functions include stimulating	Lymphokines and Interferens: A
			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and Siegel &
			of neutrophils and T lymphocytes,	Mostowski (1990) J Immunol
			and/or inhibition of interferons.	Methods 132, 287-295.
IL-4	GeneSeq	DE4137333	Interleukins are a group of multifunctional	Interleukin activity can be	inflammatory disorders,
mutein	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	immunologic disorders,
Y124G	R47184		monocytes, and macrophages. Known	the art: Matthews et al., in	cancer
			functions include stimulating	Lymphokines and Interferens: A
			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and Siegel &
			of neutrophils and T lymphocytes,	Mostowski (1990) J Immunol
			and/or inhibition of interferons.	Methods 132, 287-295.
Human	GeneSeq	WO9317698	Interleukins are a group of multifunctional	Interleukin activity can be	inflammatory disorders,
Inter-	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	immunologic disorders,
leukin-10	R41664		monocytes, and macrophages. Known	the art: Matthews et al., in	cancer
(precursor)			functions include stimulating	Lymphokines and Interferens: A
			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and Thompson-
			of neutrophils and T lymphocytes,	Snipes et al (1991) J. Exp. Med.
			and/or inhibition of interferons.	173, 507-510.
Human	GeneSeq	WO9318783-A	Interleukins are a group of multifunctional	Interleukin activity can be	inflammatory disorders,
Inter-	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	immunologic disorders,
leukin-10	R42642		monocytes, and macrophages. Known	the art: Matthews et al., in	cancer
			functions include stimulating	Lymphokines and Interferens: A
			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and Thompson-
			of neutrophils and T lymphocytes,	Snipes et al (1991) J. Exp. Med.
			and/or inhibition of interferons.	173, 507-510.
Human	GeneSeq	EP569042	Interleukins are a group of multifunctional	Interleukin activity can be	inflammatory disorders,
inter-	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	immunologic disorders,
leukin-1	R42447		monocytes, and macrophages. Known	the art: Matthews et al., in	cancer
beta			functions include stimulating	Lymphokines and Interferens: A
precursor.			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and Orencole &
			of neutrophils and T lymphocytes,	Dinarello (1989) Cytokine 1, 14-20.
			and/or inhibition of interferons.
Inter-	GeneSeq	EP578278	Interleukins are a group of multifunctional	Interleukin activity can be	inflammatory disorders,
leukin-	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	immunologic disorders,
1alpha	R45364		monocytes, and macrophages. Known	the art: Matthews et al., in	cancer
			functions include stimulating	Lymphokines and Interferens: A
			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225.
			of neutrophils and T lymphocytes,
			and/or inhibition of interferons.
Human	GeneSeq	JP04063595	Interleukins are a group of multifunctional	Interleukin activity can be	inflammatory disorders,
inter-	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	immunologic disorders,
leukin-3	R22814		monocytes, and macrophages. Known	the art: Matthews et al., in	cancer
variant			functions include stimulating	Lymphokines and Interferens: A
			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and Kitamura
			of neutrophils and T lymphocytes,	et al (1989) J Cell Physiol. 140
			and/or inhibition of interferons.	323-334.
IL-1i	GeneSeq	EP541920	Interleukins are a group of multifunctional	Interleukin activity can be	inflammatory disorders,
fragments	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	immunologic disorders,
	R35484		monocytes, and macrophages. Known	the art: Matthews et al., in	cancer
	and		functions include stimulating	Lymphokines and Interferens: A
	R35485		proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and
			of neutrophils and T lymphocytes,	Orencole & Dinarclio (1989)
			and/or inhibition of interferons.	Cytokine 1, 14-20.
IL-1	GeneSeq	EPS541920	Interleukins are a group of multifunctional	Interleukin activity can be	inflammatory disorders,
inhibitor	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	immunologic disorders,
(IL-Ii)	R35486		monocytes, and macrophages. Known	the art: Matthews et al., in	cancer
	and		functions include stimulating	Lymphokines and Interferens: A
	R35484		proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and
			of neutrophils and T lymphocytes,	Orencole & Dinarelio (1989)
			and/or inhibition of interferons.	Cytokine 1, 14-20.
ICE 22 kD	GeneSeq	EP533350	Interleukins are a group of multifunctional	Interleukin activity can be	inflammatory disorders,
subunit.	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	immunologic disorders,
	R33780		monocytes, and macrophages. Known	the art: Matthews et al., in	cancer
			functions include stimulating	Lymphokines and Interferens: A
			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225.
			of neutrophils and T lymphocytes,
			and/or inhibition of interferons.
ICE 20 kD	GeneSeq	EP533350	Interleukins are a group of multifunctional	Interleukin activity can be	inflammatory disorders,
subunit.	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	immunologic disorders,
	R33781		monocytes, and macrophages. Known	the art: Matthews et al., in	cancer
			functions include stimulating	Lymphokines and Interferens: A
			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225.
			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	inflammatory disorders,
subunit	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	immunologic disorders,
	R33782		monocytes, and macrophages. Known	the art: Matthews et al., in	cancer
			functions include stimulating	Lymphokines and Interferens: A
			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225.
			of neutrophils and T lymphocytes,
			and/or inhibition of interferons.
Human	GeneSeq	WO9317698	Interleukins are a group of multifunctional	Interleukin activity can be	inflammatory disorders,
Inter-	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	immunologic disorders,
leukin-10	R41664		monocytes, and macrophages. Known	the art: Matthews et al., in	cancer
(precursor)			functions include stimulating	Lymphokines and Interferens: A
			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and Thompson-
			of neutrophils and T lymphocytes,	Snipes et al (1991) J. Exp. Med.
			and/or inhibition of interferons.	173, 507-510.
Human	GeneSeq	WO9318783	Interleukins are a group of multifunctional	Interleukin activity can be	inflammatory disorders,
Inter-	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	immunologic disorders,
leukin-10	R42642		monocytes, and macrophages. Known	the art: Matthews et al., in	cancer
			functions include stimulating	Lymphokines and Interferens: A
			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and Thompson-
			of neutrophils and T lymphocytes,	Snipes et al (1991) J. Exp. Med.
			and/or inhibition of interferons.	173, 507-510.
Human	GeneSeq	EP569042	Interleukins are a group of multifunctional	Interleukin activity can be	inflammatory disorders,
Inter-	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	immunologic disorders,
leukin-1	R42447		monocytes, and macrophages. Known	the art: Matthews et al., in	cancer
beta			functions include stimulating	Lymphokines and Interferens: A
precursor			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and Kitamura
			of neutrophils and T lymphocytes,	et al (1989) J Cell Physiol. 140
			and/or inhibition of interferons.	323-334.
Human	GeneSeq	WO9403492	Interleukins are a group of multifunctional	Interleukin activity can be	inflammatory disorders,
inter-	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	immunologic disorders,
leukin-6	R49041		monocytes, and macrophages. Known	the art: Matthews et al., in	cancer
			functions include stimulating	Lymphokines and Interferens: A
			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and Aarden et al
			of neutrophils and T lymphocytes,	(1987) Eur. J. Immunol 17, 1411-16.
			and/or inhibition of interferons.
Mutant	GeneSeq	WO9411402	Interleukins are a group of multifunctional	Interleukin activity can be	inflammatory disorders,
Inter-	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	immunologic disorders,
leukin 6	R54990		monocytes, and macrophages. Known	the art: Matthews et al., in	cancer
S176R			functions include stimulating	Lymphokines and Interferens: A
			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and Aarden et al
			of neutrophils and T lymphocytes,	(1987) Eur. J. Immunol 17, 1411-16.
			and/or inhibition of interferons.
Inter-	GeneSeq	JP06145063	Interleukins are a group of multifunctional	Interleukin activity can be	inflammatory disorders,
leukin 6	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	immunologic disorders,
	R55256		monocytes, and macrophages. Known	the art: Matthews et al., in	cancer
			functions include stimulating	Lymphokines and Interferens: A
			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and Aarden et al
			of neutrophils and T lymphocytes,	(1987) Eur. J. Immunol 17, 1411-16.
			and/or inhibition of interferons.
Inter-	GeneSeq	JP06100595	Interleukins are a group of multifunctional	Interleukin activity can be	Soluble IL-8
leukin 8	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	receptor polypeptides
(IL-8)	R53932		monocytes, and macrophages. Known	the art: Matthews et al., in	may be useful for inhibiting
receptor			functions include stimulating	Lymphokines and Interferens: A	interleukin activities.
			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and Holmes et al
			of neutrophils and T lymphocytes,	(1991) Science 253, 1278-80.
			and/or inhibition of interferons.
Human	GeneSeq	U.S. Pat. No.	Interleukins are a group of multifunctional	Interleukin activity can be	inflammatory disorders,
inter-	Accession	5,328,988	cytokines synthesized by lymphocytes,	determined using assays known in	immunologic disorders,
leukin-7	R59919		monocytes, and macrophages. Known	the art: Matthews et al., in	cancer
			functions include stimulating	Lymphokines and Interferens: A
			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and Park et al
			of neutrophils and T lymphocytes,	(1990) J. Exp. Med. 171, 1073-79.
			and/or inhibition of interferons.
IL-3	GeneSeq	WO9521254	Interleukins are a group of multifunctional	Interleukin activity can be	inflammatory disorders,
containing	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	immunologic disorders,
fusion	R79342		monocytes, and macrophages. Known	the art: Matthews et al., in	cancer
protein.	and		functions include stimulating	Lymphokines and Interferens: A
	R79344		proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and Kitamura
			of neutrophils and T lymphocytes,	et al (1989) J Cell Physiol. 140 323-
			and/or inhibition of interferons.	334.
IL-3	GeneSeq	ZA9402636	Interleukins are a group of multifunctional	Interleukin activity can be	inflammatory disorders,
mutant	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	immunologic disorders,
proteins	R79254,		monocytes, and macrophages. Known	the art: Matthews et al., in	cancer
	R79255,		functions include stimulating	Lymphokines and Interferens: A
	R79256,		proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
	R79257,		T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
	R79258,		and lymphocytes), chemotaxis	1987, pp. 221-225; and Giri et al
	R79259,		of neutrophils and T lymphocytes,	(1994) EMBO J. 13 2822-2830.
	R79260,		and/or inhibition of interferons.
	R79261,
	R79262,
	R79263,
	R79264,
	R79265,
	R79266,
	R79267,
	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	inflammatory disorders,
subunit.	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	immunologic disorders,
	R63018		monocytes, and macrophages. Known	the art: Matthews et al., in	cancer
			functions include stimulating	Lymphokines and Interferens: A
			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225.
			of neutrophils and T lymphocytes,
			and/or inhibition of interferons.
AGF	GeneSeq	WO9429344	Interleukins are a group of multifunctional	Interleukin activity can be	inflammatory disorders,
	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	immunologic disorders,
	R64240		monocytes, and macrophages. Known	the art: Matthews et al., in	cancer
			functions include stimulating	Lymphokines and Interferens: A
			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225.
			of neutrophils and T lymphocytes,
			and/or inhibition of interferons.
Human	GeneSeq	WO9519786	Interleukins are a group of multifunctional	Interleukin activity can be	inflammatory disorders,
inter-	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	immunologic disorders,
laukin-12	R79187		monocytes, and macrophages. Known	the art: Matthews et al., in	cancer
40 kD			functions include stimulating	Lymphokines and Interferens: A
subunit			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and Hori et al
			of neutrophils and T lymphocytes,	(1987), Blood 70, 1069-1078.
			and/or inhibition of interferons.
Human	GeneSeq	WO9530695	Interleukins are a group of multifunctional	Interleukin activity can be	Soluble IL-8
inter-	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	receptor polypeptides
leukin-15	R90843		monocytes, and macrophages. Known	the art: Matthews et al., in	may be useful for inhibiting
receptor			functions include stimulating	Lymphokines and Interferens: A	interleukin activities.
from			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
clone P1			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and Giri et al
			of neutrophils and T lymphocytes,	(1994) EMBO J. 13 2822-2830.
			and/or inhibition of interferons.
Human	GeneSeq	WO9604306	Interleukins are a group of multifunctional	Interleukin activity can be	inflammatory disorders,
inter-	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	immunologic disorders,
leukin-7	R92796		monocytes, and macrophages. Known	the art: Matthews et al., in	cancer
			functions include stimulating	Lymphokines and Interferens: A
			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and Park et al
			of neutrophils and T lymphocytes,	(1990) J. Exp. Med. 171, 1073-79.
			and/or inhibition of interferons.
inter-	GeneSeq	WO9604306	Interleukins are a group of multifunctional	Interleukin activity can be	inflammatory disorders,
leukin-9	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	immunologic disorders,
	R92797		monocytes, and macrophages. Known	the art: Matthews et al., in	cancer
			functions include stimulating	Lymphokines and Interferens: A
			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and Yang et al
			of neutrophils and T lymphocytes,	(1989) Blood 74, 1880-84.
			and/or inhibition of interferons.
inter-	GeneSeq	WO9604306	Interleukins are a group of multifunctional	Interleukin activity can be	inflammatory disorders,
leukin-3	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	immunologic disorders,
	R92801		monocytes, and macrophages. Known	the art: Matthews et al., in	cancer
			functions include stimulating	Lymphokines and Interferens: A
			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and Kitamura
			of neutrophils and T lymphocytes,	et al (1989) J Cell Physiol. 140
			and/or inhibition of interferons.	323-334.
Human	GeneSeq	WO9604306	Interleukins are a group of multifunctional	Interleukin activity can be	inflammatory disorders,
inter-	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	immunologic disorders,
leukin-5	R92802		monocytes, and macrophages. Known	the art: Matthews et al., in	cancer
			functions include stimulating	Lymphokines and Interferens: A
			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and Kitamura
			of neutrophils and T lymphocytes,	et al (1989) J Cell Physiol. 140
			and/or inhibition of interferons.	323-334.
Recomb-	GeneSeq	DEI9617202	Interleukins are a group of multifunctional	Interleukin activity can be	inflammatory disorders,
inant	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	immunologic disorders,
inter-	W33373		monocytes, and macrophages. Known	the art: Matthews et al., in	cancer
leukin-16			functions include stimulating	Lymphokines and Interferens: A
			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and Lim et al
			of neutrophils and T lymphocytes,	(1996) J. Immunol. 156, 2566-70.
			and/or inhibition of interferons.
Human	GeneSeq	DE19617202	Interleukins are a group of multifunctional	Interleukin activity can be	inflammatory disorders,
IL-16	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	immunologic disorders,
protein	W33234		monocytes, and macrophages. Known	the art: Matthews et al., in	cancer
			functions include stimulating	Lymphokines and Interferens: A
			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and Lim et al
			of neutrophils and T lymphocytes,	(1996) J. Immunol. 156, 2566-70.
			and/or inhibition of interferons.
ThrI 17	GeneSeq	WO9708321	Interleukins are a group of multifunctional	Interleukin activity can be	inflammatory disorders,
human	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	immunologic disorders,
inter-	W27521		monocytes, and macrophages. Known	the art: Matthews et al., in	cancer
leukin
9			functions include stimulating	Lymphokines and Interferens: A
			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225.
			of neutrophils and T lymphocytes,
			and/or inhibition of interferons.
MetI 17	GeneSeq	WO9708321	Interleukins are a group of multifunctional	Interleukin activity can be	inflammatory disorders,
human	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	immunologic disorders,
inter-	W27522		monocytes, and macrophages. Known	the art: Matthews et al., in	cancer
leukin
9			functions include stimulating	Lymphokines and Interferens: A
			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and Yang et al
			of neutrophils and T lymphocytes,	(1989) Blood 74, 1880-84.
			and/or inhibition of interferons.
Human	GeneSeq	EP86-4585	Interleukins are a group of multifunctional	Interleukin activity can be	inflammatory disorders,
intra-	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	immunologic disorders,
cellular	W77158		monocytes, and macrophages. Known	the art: Matthews et al., in	cancer
IL-1			functions include stimulating	Lymphokines and Interferens: A
receptor			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
antagonist.			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and Orencole &
			of neutrophils and T lymphocytes,	Dinarello (1989) Cytokine 1, 14-20.
			and/or inhibition of interferons.
Human	GeneSeq	EP864585	Interleukins are a group of multifunctional	Interleukin activity can be	inflammatory disorders,
inter-	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	immunologic disorders,
leukin-18	W77158		monocytes, and macrophages. Known	the art: Matthews et al., in	cancer
protein			functions include stimulating	Lymphokines and Interferens: A
(IL-18)			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and USHIO et al
			of neutrophils and T lymphocytes,	(1996) J. Immunol. 156, 4274-79.
			and/or inhibition of interferons.
Human	GeneSeq	EP861663	Interleukins are a group of multifunctional	Interleukin activity can be	inflammatory disorders,
inter-	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	immunologic disorders,
leukin-18	W77077		monocytes, and macrophages. Known	the art: Matthews et al., in	cancer
			functions include stimulating	Lymphokines and Interferens: A
			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and USHIO et al
			of neutrophils and T lymphocytes,	(1996) J. Immunol. 156, 4274-79.
			and/or inhibition of interferons.
Human	GeneSeq	EP861663	Interleukins are a group of multifunctional	Interleukin activity can be	inflammatory disorders,
inter-	Accessions		cytokines synthesized by lymphocytes,	determined using assays known in	immunologic disorders,
leukin 18	W77083,		monocytes, and macrophages. Known	the art: Matthews et al., in	cancer
deriv-	W77084,		functions include stimulating	Lymphokines and Interferons: A
atives	W77085,		proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
	W77086,		T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
	W77087,		and lymphocytes), chemotaxis	1987, pp. 221-225; and Ushio et al
	W77088,		of neutrophils and T lymphocytes,	(1996) J. Immunol, 156, 4274-79.
	and		and/or inhibition of interferons.
	W77089
Inter-	GeneSeq	WO9827997	Interleukins are a group of multifunctional	Interleukin activity can be	inflammatory disorders,
leukin-9	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	immunologic disorders,
(IL-9)	W68158		monocytes, and macrophages. Known	the art: Matthews et al., in	cancer
mature			functions include stimulating	Lymphokines and Interferons: A
protein			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
(Thr117			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
version).			and lymphocytes), chemotaxis	1987, pp. 221-225; and Yang et al
			of neutrophils and T lymphocytes,	(1989) Blood 74, 1880-84.
			and/or inhibition of interferons.
IL-9	GenSeq	WO9827997	Interleukins are a group of multifunctional	Interleukin activity can be	inflammatory disorders,
mature	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	immunologic disorders,
protein	W68157		monocytes, and macrophages. Known	the art: Matthews et al., in	cancer
variant			functions include stimulating	Lymphokines and Interferons: A
(Met117			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
version)			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and Yang et al
			of neutrophils and T lymphocytes,	(1989) Blood 74, 1880-84.
			and/or inhibition of interferons.
Human	GeneSeq	WO9824904	Interleukins are a group of multifunctional	Interleukin activity can be	inflammatory disorders,
IL-9	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	immunologic disorders,
receptor	W64058		monocytes, and macrophages. Known	the art: Matthews et al., in	cancer
protein			functions include stimulating	Lymphokines and Interferons: A
variant #3.			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and Yang et al
			of neutrophils and T lymphocytes,	(1989) Blood 74, 1880-84.
			and/or inhibition of interferons.
Human	GenSeq	WO9824904	Interleukins are a group of multifunctional	Interleukin activity can be	Soluble IL-9
IL-9	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	receptor polypeptides
receptor	W64060		monocytes, and macrophages. Known	the art: Matthews et al., in	may be useful for inhibiting
protein			functions include stimulating	Lymphokines and Interferons: A	interleukin activities.
variant			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
fragment			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and Yang et al
			of neutrophils and T lymphocytes,	(1989) Blood 74, 1880-84.
			and/or inhibition of interferons.
Human	GeneSeq	WO9824904	Interleukins are a group of multifunctional	Interleukin activity can be	Soluble IL-9
IL-9	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	receptor polypeptides
receptor	W64061		monocytes, and macrophages. Known	the art: Matthews et al., in	may be useful for inhibiting
protein			functions include stimulating	Lymphokines and Interferons: A	interleukin activities.
variant #3.			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and Yang et al
			of neutrophils and T lymphocytes,	(1989) Blood 74, 1880-84.
			and/or inhibition of interferons.
Human	GeneSeq	WO9817689	Interleukins are a group of multifunctional	Interleukin activity can be	inflammatory disorders,
Inter-	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	immunologic disorders,
leukin-12	W51311		monocytes, and macrophages. Known	the art: Matthews et al., in	cancer
p40			functions include stimulating	Lymphokines and Interferons: A
protein			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and Hori et al
			of neutrophils and T lymphocytes,	(1987), Blood 70, 1069-1078.
			and/or inhibition of interferons.
Human	GeneSeq	WO9817689	Interleukins are a group of multifunctional	Interleukin activity can be	inflammatory disorders,
inter-	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	immunologic disorders,
leukin-12	W51312		monocytes, and macrophages. Known	the art: Matthews et al., in	cancer
p35			functions include stimulating	Lymphokines and Interferons: A
protein			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and Hori et al
			of neutrophils and T lymphocytes,	(1987), Blood 70, 1069-1078.
			and/or inhibition of interferons.
Human	GeneSeq	DE19649233-	Interleukins are a group of multifunctional	Interleukin activity can be	inflammatory disorders,
protein	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	immunologic disorders,
with	W63753		monocytes, and macrophages. Known	the art: Matthews et al., in	cancer
IL-16			functions include stimulating	Lymphokines and Interferons: A
activity			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and Lim et al
			of neutrophils and T lymphocytes,	(1996) J. Immunol. 156, 2566-70.
			and/or inhibition of interferons.
Human	GeneSeq	DE19649233-	Interleukins are a group of multifunctional	Interleukin activity can be	inflammatory disorders,
protein	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	immunologic disorders,
with	W59425		monocytes, and macrophages. Known	the art: Matthews et al., in	cancer
IL-16			functions include stimulating	Lymphokines and Interferons: A
activity			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and Lim et al
			of neutrophils and T lymphocytes,	(1996) J. Immunol. 156, 2566-70.
			and/or inhibition of interferons.
Human	GeneSeq	U.S. Pat. No.	Interleukins are a group of multifunctional	Interleukin activity can be	inflammatory disorders,
inter-	Accession	5,747,024	cytokines synthesized by lymphocytes,	determined using assays known in	immunologic disorders,
leukin-	W53878		monocytes, and macrophages. Known	the art: Matthews et al., in	cancer
15			functions include stimulating	Lymphokines and Interferons: A
			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and Giri et al
			of neutrophils and T lymphocytes,	(1994) EMBO J. 13 2822-2830.
			and/or inhibition of interferons.
Human	GeneSeq	WO9747744	Interleukins are a group of multifunctional	Interleukin activity can be	inflammatory disorders,
wild-type	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	immunologic disorders,
inter-	W52149		monocytes, and macrophages. Known	the art: Matthews et al., in	cancer
leukin-4			functions include stimulating	Lymphokines and Interferons: A
(hIL-4)			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
protein			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and Siegel &
			of neutrophils and T lymphocytes,	Mostowski (1990) J Immunol
			and/or inhibition of interferons.	Methods 132, 287-295.
inter-	GeneSeq	WO9747744	Interleukins are a group of multifunctional	Interleukin activity can be	inflammatory disorders,
leukin-4	Accessions		cytokines synthesized by lymphocytes,	determined using assays known in	immunologic disorders,
muteins	W52150,		monocytes, and macrophages. Known	the art: Matthews et al., in	cancer
	W52151,		functions include stimulating	Lymphokines and Interferons: A
	W52153,		proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
	W52154,		T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
	W52155,		and lymphocytes), chemotaxis	1987, pp. 221-225; and Siegel &
	W52156,		of neutrophils and T lymphocytes,	Mostowski (1990) J Immunol
	W52157,		and/or inhibition of interferons.	Methods 132, 287-295.
	W52158,
	W52159,
	W52160,
	W52161,
	W52162,
	W52163,
	W52164,
	W52165,
	W52166,
	and
	W52167
Human	GeneSeq	WO9935268	Interleukins are a group of multifunctional	Interleukin activity can be	inflammatory disorders,
inter-	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	immunologic disorders,
leukin 1	Y28408		monocytes, and macrophages. Known	the art: Matthews et al., in	cancer
delta			functions include stimulating	Lymphokines and Interferons: A
			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and Orencole &
			of neutrophils and T lymphocytes,	Dinarello (1989) Cytokine 1, 14-20.
			and/or inhibition of interferons.
Human	GeneSeq	WO9935268	Interleukins are a group of multifunctional	Interleukin activity can be	inflammatory disorders,
inter-	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	immunologic disorders,
leukin-1	Y24395		monocytes, and macrophages. Known	the art: Matthews et al., in	cancer
receptor			functions include stimulating	Lymphokines and Interferons: A
antagonist			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
beta			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and Orencole &
			of neutrophils and T lymphocytes,	Dinarello (1989) Cytokine 1, 14-20.
			and/or inhibition of interferons.
Human	GeneSeq	WO9932632	Interleukins are a group of multifunctional	Interleukin activity can be	inflammatory disorders,
EDIRF II	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	immunologic disorders,
protein	Y22199		monocytes, and macrophages. Known	the art: Matthews et al., in	cancer
sequence			functions include stimulating	Lymphokines and Interferons: A
			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225.
			of neutrophils and T lymphocytes,
			and/or inhibition of interferons.
Human	GeneSeq	WO9932632	Interleukins are a group of multifunctional	Interleukin activity can be	inflammatory disorders,
EDIRF I	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	immunologic disorders,
protein	Y22197		monocytes, and macrophages. Known	the art: Matthews et al., in	cancer
sequence			functions include stimulating	Lymphokines and Interferons: A
			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225.
			of neutrophils and T lymphocytes,
			and/or inhibition of interferons.
Human	GeneSeq	WO9919480	Interleukins are a group of multifunctional	Interleukin activity can be	Soluble IL-1RD10
IL-1RD10	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	receptor polypeptides
protein	Y14131		monocytes, and macrophages. Known	the art: Matthews et al., in	may be useful for inhibiting
sequence			functions include stimulating	Lymphokines and Interferons: A	interleukin activites.
			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and Orencole &
			of neutrophils and T lymphocytes,	Dinarello (1989) Cytokine 1, 14-20.
			and/or inhibition of interferons.
Human	GeneSeq	WO9919480	Interleukins are a group of multifunctional	Interleukin activity can be	Soluble IL-1RD10
IL-1RD9	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	receptor polypeptides
	Y14122		monocytes, and macrophages. Known	the art: Matthews et al., in	may be useful for inhibiting
			functions include stimulating	Lymphokines and Interferons: A	interleukin activites.
			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and Orencole &
			of neutrophils and T lymphocytes,	Dinarello (1989) Cytokine 1, 14-20.
			and/or inhibition of interferons.
Human	GeneSeq	WO9919491	Interleukins are a group of multifunctional	Interleukin activity can be	inflammatory disorders,
DNAX	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	immunologic disorders,
inter-	Y09196		monocytes, and macrophages. Known	the art: Matthews et al., in	cancer
leukin-40			functions include stimulating	Lymphokines and Interferons: A
			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225.
			of neutrophils and T lymphocytes,
			and/or inhibition of interferons.
(DIL-40)	GeneSeq	WO9919491	Interleukins are a group of multifunctional	Interleukin activity can be	inflammatory disorders,
alternative	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	immunologic disorders,
sequence	Y09197		monocytes, and macrophages. Known	the art: Matthews et al., in	cancer
			functions include stimulating	Lymphokines and Interferons: A
			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225.
			of neutrophils and T lymphocytes,
			and/or inhibition of interferons.
IL-11	GeneSeq	WO9405318	Interleukins are a group of multifunctional	Interleukin activity can be	inflammatory disorders,
	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	immunologic disorders,
	R50176		monocytes, and macrophages. Known	the art: Matthews et al., in	cancer
			functions include stimulating	Lymphokines and Interferons: A
			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and Lu et al
			of neutrophils and T lymphocytes,	(1994) J immunol. Methods 173, 19.
			and/or inhibition of interferons.
Human	GeneSeq	EP566410	Interleukins are a group of multifunctional	Interleukin activity can be	inflammatory disorders,
adipo-	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	immunologic disorders,
genesis	R43260		monocytes, and macrophages. Known	the art: Matthews et al., in	cancer
inhibitory			functions include stimulating	Lymphokines and Interferons: A
factor			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225.
			of neutrophils and T lymphocytes,
			and/or inhibition of interferons.
IL-11	GeneSeq	JP08127539	Interleukins are a group of multifunctional	Interleukin activity can be	inflammatory disorders,
	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	immunologic disorders,
	W02202		monocytes, and macrophages. Known	the art: Matthews et al., in	cancer
			functions include stimulating	Lymphokines and Interferons: A
			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and Lu et al
			of neutrophils and T lymphocytes,	(1994) J immunol. Methods 173, 19.
			and/or inhibition of interferons.
IL-14	GeneSeq	WO9416074	Interleukins are a group of multifunctional	Interleukin activity can be	inflammatory disorders,
	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	immunologic disorders,
	R55800		monocytes, and macrophages. Known	the art: Matthews et al., in	cancer
			functions include stimulating	Lymphokines and Interferons: A
			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and Ambrus et al
			of neutrophils and T lymphocytes,	(1993) PNAS 90, 63330-34.
			and/or inhibition of interferons.
IL-17	GeneSeq	U.S. Pat. No.	Interleukins are a group of multifunctional	Interleukin activity can be	Soluble IL-17
receptor	Accession	6,072,033	cytokines synthesized by lymphocytes,	determined using assays known in	receptor polypeptides
	B03807		monocytes, and macrophages. Known	the art: Matthews et al., in	may be useful for inhibiting
			functions include stimulating	Lymphokines and Interferons: A	interleukin activities.
			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and Yao et al
			of neutrophils and T lymphocytes,	(1995) J. Immunol. 155, 5483-86.
			and/or inhibition of interferons.
IL-17	GeneSeq	WO9518826	Interleukins are a group of multifunctional	Interleukin activity can be	inflammatory disorders,
	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	immunologic disorders,
	R76573		monocytes, and macrophages. Known	the art: Matthews et al., in	cancer
			functions include stimulating	Lymphokines and Interferons: A
			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and Yao et al
			of neutrophils and T lymphocytes,	(1995) J. Immunol. 155, 5483-86.
			and/or inhibition of interferons.
CTLA-8	GeneSeq	WO9704097	Interleukins are a group of multifunctional	Interleukin activity can be	inflammatory disorders,
	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	immunologic disorders,
	W13651		monocytes, and macrophages. Known	the art: Matthews et al., in	cancer
			functions include stimulating	Lymphokines and Interferons: A
			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225.
			of neutrophils and T lymphocytes,
			and/or inhibition of interferons.
IL-19	GeneSeq	WO9808870	Interleukins are a group of multifunctional	Interleukin activity can be	inflammatory disorders,
	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	immunologic disorders,
	W37935		monocytes, and macrophages. Known	the art: Matthews et al., in	cancer
			functions include stimulating	Lymphokines and Interferons: A
			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and Gallagher et
			of neutrophils and T lymphocytes,	al (2000) Genes Immun. 1, 442-50.
			and/or inhibition of interferons.
IL-21	GeneSeq	WO0024758	Interleukins are a group of multifunctional	Interleukin activity can be	inflammatory disorders,
(TIF)	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	immunologic disorders,
	Y92879		monocytes, and macrophages. Known	the art: Matthews et al., in	cancer
			functions include stimulating	Lymphokines and Interferons: A
			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and Parrish-
			of neutrophils and T lymphocytes,	Novak et al (2000) Nature 408,
			and/or inhibition of interferons.	57-63.
IL-8	GeneSeq	WO9306229	Interleukins are a group of multifunctional	Interleukin activity can be	Soluble IL-8
receptor	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	receptor polypeptides
	R33420		monocytes, and macrophages. Known	the art: Matthews et al., in	may be useful for inhibiting
			functions include stimulating	Lymphokines and Interferons: A	interleukin activities.
			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and Holmes et al
			of neutrophils and T lymphocytes,	(1991) Science 253, 1278-80..
			and/or inhibition of interferons.
Human	GeneSeq	U.S. Pat. No.	Interleukins are a group of multifunctional	Interleukin activity can be	Soluble type II interleukin-1
type II	Accession	5,464,937	cytokines synthesized by lymphocytes,	determined using assays known in	receptor polypeptides
inter-	R85480		monocytes, and macrophages. Known	the art: Matthews et al., in	may be useful for inhibiting
leukin-1			functions include stimulating	Lymphokines and Interferons: A	interleukin activities.
receptor			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and Orencole &
			of neutrophils and T lymphocytes,	Dinarello (1989) Cytokine 1, 14-20.
			and/or inhibition of interferons.
Human	GeneSeq	EP638644	Interleukins are a group of multifunctional	Interleukin activity can be	Soluble IL-12
inter-	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	receptor polypeptides
leukin-12	R69632		monocytes, and macrophages. Known	the art: Matthews et al., in	may be useful for inhibiting
receptor			functions include stimulating	Lymphokines and Interferons: A	interleukin activities.
			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and Hori et al
			of neutrophils and T lymphocytes,	(1987), Blood 70, 1069-1078.
			and/or inhibition of interferons.
Inter-	GeneSeq	U.S. Pat. No.	Interleukins are a group of multifunctional	Interleukin activity can be	Soluble IL-8
leukin 8	Accession	5,440,021	cytokines synthesized by lymphocytes,	determined using assays known in	receptor B polypeptides
receptor	R80758		monocytes, and macrophages. Known	the art: Matthews et al., in	may be useful for inhibiting
B			functions include stimulating	Lymphokines and Interferons: A	interleukin activities.
			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and Holmes et al
			of neutrophils and T lymphocytes,	(1991) Science 253, 1278-80.
			and/or inhibition of interferons.
Human	GeneSeq	JP08103276	Interleukins are a group of multifunctional	Interleukin activity can be	Soluble IL-8
IL-8	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	receptor A polypeptides
receptor	B09989		monocytes, and macrophages. Known	the art: Matthews et al., in	may be useful for inhibiting
protein			functions include stimulating	Lymphokines and Interferons: A	interleukin activities.
hIL8RA			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and Holmes et al
			of neutrophils and T lymphocytes,	(1991) Science 253, 1278-80.
			and/or inhibition of interferons.
Human	GeneSeq	JP08103276	Interleukins are a group of multifunctional	Interleukin activity can be	Soluble IL-8
IL-8	Accession		cytokines synthesized by lymphocytes,	determined using asays known in	receptor polypeptides
receptor	B09990		monocytes, and macrophages. Known	the art: Matthews et al., in	may be useful for inhibiting
protein			functions include stimulating	Lymphokines and Interferons: A	interleukin activities.
hIL8R			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and Holmes et al
			of neutrophils and T lymphocytes,	(1991) Science 253, 1278-80.
			and/or inhibition of interferons.
Inter-	GeneSeq	WO9621732-	Interleukins are a group of multifunctional	Interleukin activity can be	Soluble IL-2
leukin-2	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	receptor polypeptides
receptor	R97569		monocytes, and macrophages. Known	the art: Matthews et al., in	may be useful for inhibiting
associated			functions include stimulating	Lymphokines and Interferons: A	interleukin activities.
protein			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
p43			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and Gillis et al
			of neutrophils and T lymphocytes,	(1978) J. Immunol. 120, 2027.
			and/or inhibition of interferons.
Human	GeneSeq	WO9629408	Interleukins are a group of multifunctional	Interleukin activity can be	Soluble IL-17
inter-	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	receptor polypeptides
leukin-17	W04185		monocytes, and macrophages. Known	the art: Matthews et al., in	may be useful for inhibiting
receptor			functions include stimulating	Lymphokines and Interferons: A	interleukin activities.
			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and Yao et al
			of neutrophils and T lymphocytes,	(1995) J. Immunol. 155, 5483-86.
			and/or inhibition of interferons.
Human	GeneSeq	WO9619574	Interleukins are a group of multifunctional	Interleukin activity can be	Soluble IL-11
inter-	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	receptor polypeptides
leukin-11	R99090		monocytes, and macrophages. Known	the art: Matthews et al., in	may be useful for inhibiting
receptor			functions include stimulating	Lymphokines and Interferons: A	interleukin activities.
			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and Lu et al
			of neutrophils and T lymphocytes,	(1994) J immunol. Methods 173, 19.
			and/or inhibition of interferons.
Human	GeneSeq	WO9623067	Interleukins are a group of multifunctional	Interleukin activity can be	Inflammatory disorders,
inter-	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	immunologic disorders,
leukin-1	W01911		monocytes, and macrophages. Known	the art: Matthews et al., in	cancer
receptor			functions include stimulating	Lymphokines and Interferons: A
accessory			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
protein			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and Orencole &
			of neutrophils and T lymphocytes,	Dinarello (1989) Cytokine 1, 14-
			and/or inhibition of interferons.	20.
AGF	GeneSeq	U.S. Pat. No.	Interleukins are a group of multifunctional	Interleukin activity can be	Inflammatory disorders,
Protein	Accession	5,488,032	cytokines synthesized by lymphocytes,	determined using assays known in	immunologic disorders,
	R92749		monocytes, and macrophages. Known	the art: Matthews et al., in	cancer
			functions include stimulating	Lymphokines and Interferons: A
			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225.
			of neutrophils and T lymphocytes,
			and/or inhibition of interferons.
Human	GeneSeq	W09607739	Interleukins are a group of multifunctional	Interleukin activity can be	Soluble IL-type-3
inter-	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	receptor polypeptides
leukin-1	R91064		monocytes, and macrophages. Known	the art: Matthews et al., in	may be useful for inhibiting
type-3			functions include stimulating	Lymphokines and Interferons: A	interleukin activities
receptor			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and Orencole &
			of neutrophils and T lymphocytes,	Dinarello (1989) Cytokine 1, 14-
			and/or inhibition of interferons.	20.
Human	GeneSeq	WO9720926	Interleukins are a group of multifunctional	Interleukin activity can be	Soluble IL-13 beta
inter-	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	receptor polypeptides
leukin-13	W24972		monocytes, and macrophages. Known	the art: Matthews et al., in	may be useful for inhibiting
beta			functions include stimulating	Lymphokines and Interferons: A	interleukin activities.
receptor			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and Boutelier et al
			of neutrophils and T lymphocytes,	(1995) J. Immunol. Methods 181, 29.
			and/or inhibition of interferons.
Human	GeneSeq	WO9720926	Interleukins are a group of multifunctional	Interleukin activity can be	Soluble IL-13 alpha
inter-	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	receptor polypeptides
leukin-13	W24973		monocytes, and macrophages. Known	the art: Matthews et al., in	may be useful for inhibiting
alpha			functions include stimulating	Lymphokines and Interferons: A	interleukin activities.
receptor			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and Boutelier et al
			of neutrophils and T lymphocytes,	(1995) J. Immunol. Methods 181, 29.
			and/or inhibition of interferons.
Human	GeneSeq	U.S. Pat. No.	Interleukins are a group of multifunctional	Interleukin activity can be	Soluble IL-4
inter-	Accession	5,599,905	cytokines synthesized by lymphocytes,	determined using assays known in	receptor polypeptides
leukin-4	W13499		monocytes, and macrophages. Known	the art: Matthews et al., in	may be useful for inhibiting
receptor			functions include stimulating	Lymphokines and Interferons: A	interleukin activities.
			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and Siegel &
			of neutrophils and T lymphocytes,	Mostowski (1990) J Immunol
			and/or inhibition of interferons.	Methods 132, 287-295.
Human	GeneSeq	EP759466	Interleukins are a group of multifunctional	Interleukin activity can be	Soluble IL-12 beta-2
inter-	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	receptor polypeptides
leukin-12	W12771		monocytes, and macrophages. Known	the art: Matthews et al., in	may be useful for inhibiting
beta-2			functions include stimulating	Lymphokines and Interferons: A	interleukin activities.
receptor			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and Hori et al
			of neutrophils and T lymphocytes,	(1987), Blood 70, 1069-1078.
			and/or inhibition of interferons.
Human	GeneSeq	EP759466	Interleukins are a group of multifunctional	Interleukin activity can be	Soluble IL-12 beta-1
inter-	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	receptor polypeptides
leukin-12	W12772		monocytes, and macrophages. Known	the art: Matthews et al., in	may be useful for inhibiting
beta-1			functions include stimulating	Lymphokines and Interferons: A	interleukin activities.
receptor.			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and Hori et al
			of neutrophils and T lymphocytes,	(1987), Blood 70, 1069-1078.
			and/or inhibition of interferons.
Human IL-9	GeneSeq	WO9824904	Interleukins are a group of multifunctional	Interleukin activity can be	Soluble IL-9 receptor
receptor	Accessions		cytokines synthesized by lymphocytes,	determined using assays known in	polypeptides may be useful for
protein	W64055,		monocytes, and macrophages. Known	the art: Matthews et al., in	inhibiting interleukin
	W64056,		functions include stimulating	Lymphokines and Interferons: A	activities.
	and		proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
	W64057		T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and Yang et al
			of neutrophils and T lymphocytes,	(1989), Blood 74, 1880-84..
			and/or inhibition of interferons.
IL-10	GeneSeq	U.S. Pat. No.	Interleukins are a group of multifunctional	Interleukin activity can be	Soluble IL-10
receptor	Accession	5,716,804	cytokines synthesized by lymphocytes,	determined using assays known in	receptor polypeptides
	W41804		monocytes, and macrophages. Known	the art: Matthews et al., in	may be useful for inhibiting
			functions include stimulating	Lymphokines and Interferons: A	interleukin activities.
			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and Thompson-
			of neutrophils and T lymphocytes,	Snipes et al (1991) J. Exp. Med.
			and/or inhibition of interferons.	173, 507-510.
Human IL-6	GeneSeq	JP11196867	Interleukins are a group of multifunctional	Interleukin activity can be	Soluble IL-6
receptor	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	receptor polypeptides
	Y30938		monocytes, and macrophages. Known	the art: Matthews et al., in	may be useful for inhibiting
			functions include stimulating	Lymphokines and Interferons: A	interleukin activities.
			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and Aarden et al
			of neutrophils and T lymphocytes,	(1987) Eur. J. Immunol 17, 1411-16.
			and/or inhibition of interferons.
Il-17	GeneSeq	U.S. Pat. No.	Interleukins are a group of multifunctional	Interleukin activity can be	Soluble IL-17
receptor	Accession	6,096,305	cytokines synthesized by lymphocytes,	determined using assays known in	receptor polypeptides
	Y97181		monocytes, and macrophages. Known	the art: Matthews et al., in	may be useful for inhibiting
			functions include stimulating	Lymphokines and Interferons: A	interleukin activities.
			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and Yao et al
			of neutrophils and T lymphocytes,	(1995) J. Immunol. 155, 5483-86.
			and/or inhibition of interferons.
Il-17	GeneSeq	U.S. Pat. No.	Interleukins are a group of multifunctional	Interleukin activity can be	Soluble IL-17
receptor	Accession	6,100,235	cytokines synthesized by lymphocytes,	determined using assays known in	receptor polypeptides
	Y97131		monocytes, and macrophages. Known	the art: Matthews et al., in	may be useful for inhibiting
			functions include stimulating	Lymphokines and Interferons: A	interleukin activities.
			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and Yao et al
			of neutrophils and T lymphocytes,	(1995) J. Immunol. 155, 5483-86.
			and/or inhibition of interferons.
Human	GeneSeq	EP509826	Interleukins are a group of multifunctional	Interleukin activity can be	Soluble IL-3
inter-	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	receptor polypeptides
leukin-3	R25300		monocytes, and macrophages. Known	the art: Matthews et al., in	may be useful for inhibiting
receptor			functions include stimulating	Lymphokines and Interferons: A	interleukin activities.
			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and Kitamura et al
			of neutrophils and T lymphocytes,	(1989) J Cell Physiol. 140 323-334.
			and/or inhibition of interferons.
Human	GeneSeq	WO9102063	Interleukins are a group of multifunctional	Interleukin activity can be	Soluble GM-CSF
GM-CSF	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	receptor polypeptides
receptor	R10919		monocytes, and macrophages. Known	the art: Matthews et al., in	may be useful for inhibiting
			functions include stimulating	Lymphokines and Interferons: A	interleukin activities.
			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225.
			of neutrophils and T lymphocytes,
			and/or inhibition of interferons.
Human	GeneSeq	EP492214	Interleukins are a group of multifunctional	Interleukin activity can be	Soluble IL-5
IL-5	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	receptor alpha polypeptides
receptor	R25064		monocytes, and macrophages. Known	the art: Matthews et al., in	may be useful for inhibiting
alpha			functions include stimulating	Lymphokines and Interferons: A	interleukin activities.
chain			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and Kitamura et al
			of neutrophils and T lymphocytes,	(1989) J Cell Physiol. 140, 323-334.
			and/or inhibition of interferons.
Il-5	GeneSeq	WO9847923	Interleukins are a group of multifunctional	Interleukin activity can be	Soluble IL-5
receptor	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	receptor polypeptides
	W82842		monocytes, and macrophages. Known	the art: Matthews et al., in	may be useful for inhibiting
			functions include stimulating	Lymphokines and Interferons: A	interleukin activities.
			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and Kitamura et al
			of neutrophils and T lymphocytes,	(1989) J Cell Physiol. 140, 323-334.
			and/or inhibition of interferons.
Il-6	GeneSeq	JP05091892	Interleukins are a group of multifunctional	Interleukin activity can be	Soluble IL-6
receptor	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	receptor polypeptides
	R37215		monocytes, and macrophages. Known	the art: Matthews et al., in	may be useful for inhibiting
			functions include stimulating	Lymphokines and Interferons: A	interleukin activities.
			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and Aarden et al
			of neutrophils and T lymphocytes,	(1987) Eur. J. Immunol 17, 1411-16.
			and/or inhibition of interferons.
Human	GeneSeq	AU8928720	Interleukins are a group of multifunctional	Interleukin activity can be	Soluble B cell stimulating
B cell	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	factor-2 receptor polypeptides
stimu-	P90525		monocytes, and macrophages. Known	the art: Matthews et al., in	may be useful for inhibiting
lating			functions include stimulating	Lymphokines and Interferons: A	interleukin activities.
factor-2			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
receptor			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225.
			of neutrophils and T lymphocytes,
			and/or inhibition of interferons.
IL-7	GeneSeq	EP403114	Interleukins are a group of multifunctional	Interleukin activity can be	Soluble IL-7
receptor	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	receptor polypeptides
clone	R08330		monocytes, and macrophages. Known	the art: Matthews et al., in	may be useful for inhibiting
			functions include stimulating	Lymphokines and Interferons: A	interleukin activities.
			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and Park et al
			of neutrophils and T lymphocytes,	(1990) J. Exp. Med. 171, 1073-79.
			and/or inhibition of interferons.
EPO	GeneSeq	WO9008822	EPO Receptor is involved in the	EPO Receptor activity can be	Inflammatory disorders,
receptor;	Accession		proliferation and differentiation of	determined using assays known in	immunologic disorders,
EPOR	R06512		erythroblasts.	the art, such as, J Biol Chem 2001	cancer, erythroblast
				Mar. 23; 276(12: 8995-9002; JAK2	proliferation and
				protein tyrosine kinase activity:	differentiation
				Blood 1994 Sep. 1; 84(5): 1501-7
				and Mol Cell Biol. 1994
				October; 14(10: 6506-14.
IL-15	GeneSeq	WO9530695	Interleukins are a group of multifunctional	Interleukin activity can be	Soluble IL-15
receptor	Accession		cytokines synthesized by lymphocytes,	determined using assays known in	receptor polypeptides
	R90843		monocytes, and macrophages. Known	the art: Matthews et al., in	may be useful for inhibiting
			functions include stimulating	Lymphokines and Interferons: A	interleukin activities.
			proliferation of immune cells (e.g.,	Practical Approach, Clemens et al.,
			T helper cells, B cells, eosinophils,	eds, IRL Press, Washington, D.C.
			and lymphocytes), chemotaxis	1987, pp. 221-225; and Giri et al
			of neutrophils and T lymphocytes,	(1994) EMBO J. 13 2822-2830.
			and/or inhibition of interferons.
CD137;	GeneSeq	WO9507984	Activities associated with apoptosis, NF-kB	Apoptosis activity, NF-kB	Soluble 4-1BB
4-1BB	Accession		activation, and co-stimulation of immune	activation, and B and T cell co-	receptor polypeptides
Receptor	R70977		cells such as T and B cells.	stimulation can be determined using	may be useful for inhibiting
Protein				assays known in the art: Moore et	apoptosis, NF-kB activation,
				al., 1999, Science, 285(5425): 260-3;	and/or co-stimulation of immune
				Song H Y et al., 1997 Proc Natl	cells such as B and T cells.
				Acad Sci USA 94(18): 9792-6;
				Epsevik and Nissen-Meyer, 1986, J.
				Immunol. Methods.
BCMA	GeneSeq	WO0068378	Activities associated with apoptosis, NF-kB	Apoptosis activity, NF-kB	Soluble BCMA
	Accession		activation, and co-stimulation of immune	activation, and B and T cell co-	receptor polypeptides
	Y71979		cells such as T and B cells.	stimulation can be determined using	may be useful for inhibiting
				assays known in the art: Moore et	apoptosis, NF-kB activation,
				al., 1999, Science, 285(5425): 260-3;	and/or co-stimulation of immune
				Song H Y et al., 1997 Proc Natl	cells such as B and T cells.
				Acad Sci USA 94(18): 9792-6;
				Epsevik and Nissen-Meyer, 1986, J.
				Immunol. Methods.
CD27	GeneSeq	WO9201049	Activities associated with apoptosis, NF-kB	Apoptosis activity, NF-kB	Soluble CD27 polypeptides
	Accession		activation, and co-stimulation of immune	activation, and B and T cell co-	may be useful for inhibiting
	R20814		cells such as T and B cells.	stimulation can be determined using	apoptosis, NF-kB activation,
				assays known in the art: Moore et	and/or co-stimulation of immune
				al., 1999, Science, 285(5425): 260-3;	cells such as B and T cells.
				Song H Y et al., 1997 Proc Natl
				Acad Sci USA 94(18): 9792-6;
				Epsevik and Nissen-Meyer, 1986, J.
				Immunol. Methods.
CD30	GeneSeq	DE4200043	Activities associated with apoptosis, NF-kB	Apoptosis activity, NF-kB	Soluble CD30 polypeptides
	Accession		activation, and co-stimulation of immune	activation, and B and T cell co-	may be useful for inhibiting
	R35478		cells such as T and B cells.	stimulation can be determined using	apoptosis, NF-kB activation,
				assays known in the art:	and/or co-stimulation of immune
				Moore et al., 1999, Science, 285(5425):	cells such as B and T cells.
				260-3; Song H Y et al.,
				1997 Proc Natl Acad Sci USA
				94(18): 9792-6; Epsevik and
				Nissen-Meyer, 1986, J. Immunol.
				Methods.
CD40	GeneSeq	WO9945944	Activities associated with apoptosis, NF-kB	Apoptosis activity, NF-kB	Soluble CD40 polypeptides
	Accession		activation, and co-stimulation of immune	activation, and B and T cell co-	may be useful for inhibiting
	Y33499		cells such as T and B cells.	stimulation can be determined using	apoptosis, NF-kB activation,
				assays known in the art: Moore et	and/or co-stimulation of immune
				al., 1999, Science 285(5425): 260-3;	cells such as B and T cells.
				Song H Y et al., 1997 Proc Natl
				Acad Sci USA 94(18): 9792-6;
				Epsevik and Nissen-Meyer, 1986, J.
				Immunol. Methods.
EDAR	Genbank		Activities associated with apoptosis, NF-kB	Apoptosis activity, NF-kB	Immune Disorders,
	Accession		activation, and co-stimulation of immune	activation, and B and T cell co-	Lymphomas, X-linked
	AAD50077		cells such as T and B cells.	stimulation can be determined using	hypohidrotic ectodermal
				assays known in the art: Moore et	dysplasia
				al., 1999, Science, 285(5425): 260-3;
				Song H Y et al., 1997 Proc Natl
				Acad Sci USA 94(18): 9792-6;
				Epsevik and Nissen-Meyer, 1986, J.
				Immunol. Methods.
OX40;	GeneSeq	WO9512673	Activities associated with apoptosis, NF-kB	Apoptosis activity, NF-kB	Immune Disorders,
ACT-4	Accession		activation, and co-stimulation of immune	activation, and B and T cell co-	Lymphomas,
	R74737		cells such as T and B cells.	stimulation can be determined using	T cell disorders
				assays known in the art: Moore et
				al., 1999, Science, 285(5425): 260-3;
				Song H Y 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, NF-kB	Apoptosis activity, NF-kB	Soluble TACI
	Accession		activation, and co-stimulation of immune	activation, and B and T cell co-	receptor polypeptides
	W75783		cells such as T and B cells.	stimulation can be determined using	may be useful for inhibiting
				assays known in the art: Moore et	apoptosis, NF-kB activation,
				al., 1999, Science, 285(5425): 260-3;	and/or co-stimulation of immune
				Song H Y et al., 1997 Proc Natl	cells such as B and T cells.
				Acad Sci USA 94(18): 9792-6;
				Epsevik and Nissen-Meyer, 1986, J.
				Immunol. Methods.
TNF-R	GeneSeq	AU9058976	Activities associates with apoptosis, NF-kB	Apoptosis activity, NF-kB	Soluble TNF-R
	Accession		activation, and co-stimulation of immune	activation, and B and T cell co-	receptor polypeptides
	R10986		cells such as T and B cells.	stimulation can be determined using	may be useful for inhibiting
				assays known in the art: Moore et	apoptosis, NF-kB activation,
				al., 1999, Science, 285(5425): 260-3;	and/or co-stimulation of immune
				Song H Y et al., 1997 Proc Natl	cells such as B and T cells.
				Acad Sci USA 94(18): 9792-6;
				Epsevik and Nissen-Meyer, 1986, J.
				Immunol. Methods.
TNF-RII;	GeneSeq	EP418014	Activities associated with apoptosis, NF-kB	Apoptosis activity, NF-kB	Soluble TNFR-II
TNF	Accession		activation, and co-stimulation of immune	activation, and B and T cell co-	receptor polypeptides
p75	R11141		cells such as T and B cells.	stimulation can be determined using	may be useful for inhibiting
receptor;				assays known in the art: Moore et	apoptosis, NF-kB activation,
Death				al., 1999, Science, 285(5425): 260-3;	and/or co-stimulation of immune
Receptor				Song H Y et al., 1997 Proc Natl	cells such as B and T cells.
				Acad Sci USA 94(18)9792-6;
				Epsevik and Nissen-Meyer, 1986, J.
				Immunol. Methods.
hAPO-4;	GeneSeq	WO9911791	Activities associated with apoptosis, NF-kB	Apoptosis activity, NF-kB	Immune Disorders,
TROY	Accession		activation, and co-stimulation of immune	activation, and B and T cell co-	Cancers
	W93581		cells such as T and B cells.	stimulation can be determined using
				assays known in the art: Moore et
				al., 1999, Science, 285(5425): 260-3;
				Song H Y 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, NF-kB	Apoptosis activity, NF-kB	Inflammatory disorders,
precursor	Accession		activation, and co-stimulation of immune	activation, and B and T cell co-	immunologic disorders,
	P60074		cells such as T and B cells.	stimulation can be determined using	cancer
				assays known in the art: Moore et
				al., 1999, Science, 285(5425): 260-3;
				Song H Y et al., 1997 Proc Natl
				Acad Sci USA 94(18): 9792-6;
				Epsevik and Nissen-Meyer, 1986, J.
				Immunol. Methods.
Human	GeneSeq	EP619372	Activities associated with apoptosis, NF-kB	Apoptosis activity, NF-kB	Inflammatory disorders,
TNF-alpha	Accession		activation, and co-stimulation of immune	activation, and B and T cell co-	immunologic disorders,
	R62463		cells such as T and B cells	stimulation can be determined using	cancer
				assays known in the art: Moore et
				al., 1999, Science, 285(5425): 260-3;
				Song H Y et al., 1997 Proc Natl
				Acad Sci USA 94(18): 9792-6;
				Epsevik and Nissen-Meyer, 1986, J.
				Immunol. Methods.
Human	GeneSeq	EP563714	Activities associated with apoptosis, NF-kB	Apoptosis activity, NF-kB	Inflammatory disorders,
TNF-alpha	Accession		activation, and co-stimulation of immune	activation, and B and T cell co-	immunologic disorders,
	R42679		cells such as T and B cells.	stimulation can be determined using	cancer
				assays known in the art: Moore et
				al., 1999, Science, 285(5425): 260-3;
				Song H Y et al., 1997 Proc Natl
				Acad Sci USA 94(18): 9792-6;
				Epsevik and Nissen-Meyer, 1986, J.
				Immunol. Methods.
Human	GeneSeq	WO0064479	Activities associated with apoptosis, NF-kB	Apoptosis activity, NF-kB	Inflammatory disorders,
TNF-beta	Accession		activation, and co-stimulation of immune	activation, and B and T cell co-	immunologic disorders,
(LT-alpha)	B37799		cells such as T and B cells.	stimulation can be determined using	cancer
				assays known in the art: Moore et
				al., 1999, Science, 285(5425): 260-3;
				Song H Y 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, NF-kB	Apoptosis activity, NF-kB	Inflammatory disorders,
	Accession		activation, and co-stimulation of immune	activation, and B and T cell co-	immunologic disorders,
	P70107		cells such as T and B cells.	stimulation can be determined using	cancer
				assays known in the art: Moore et
				al., 1999, Science, 285(5425): 260-3;
				Song H Y 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, NF-kB	Apoptosis activity, NF-kB	Inflammatory disorders,
	Accession		activation, and co-stimulation of immune	activation, and B and T cell co-	immunologic disorders,
	R56869		cells such as T and B cells.	stimulation can be determined using	cancer
				assays known in the art: Moore et
				al., 1999, Science, 285(5425): 260-3;
				Song H Y 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, NF-kB	Apoptosis activity, NF-kB	Inflammatory disorders,
	Accession		activation, and co-stimulation of immune	activation, and B and T cell co-	immunologic disorders,
	W83195		cells such as T and B cells.	stimulation can be determined using	cancer,
				assays known in the art: Moore et	loss of bone mass
				al., 1999, Science, 285(5425): 260-3;
				Song H Y 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, NF-kB	Apoptosis activity, NF-kB	Inflammatory disorders,
	Accession		activation, and co-stimulation of immune	activation, and B and T cell co-	immunologic disorders,
	W98071		cells such as T and B cells.	stimulation can be determined using	cancer
				assays known in the art: Moore, et
				al., 1999, Science, 285(5425): 260-3;
				Song H Y 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, NF-kB	Apoptosis activity, NF-kB	Inflammatory disorders,
	Accession		activation, and co-stimulation of immune	activation, and B and T cell co-	immunologic disorders,
	W95041		cells such as T and B cells.	stimulation can be determined using	cancer
				assays known in the art: Moore et
				al., 1999, Science, 285(5425): 260-3;
				Song H Y 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, NF-kB	Apoptosis activity, NF-kB	Inflammatory disorders,
	Accession		activation, and co-stimulation of immune	activation, and B and T cell co-	immunologic disorders,
	R50121		cells such as T and B cells.	stimulation can be determined using	cancer
				assays known in the art: Moore et
				al., 1999, Science, 285(5425): 260-3;
				Song H Y et al., 1997 Proc Natl
				Acad Sci USA 94(18): 9792-6;
				Epsevik and Nissen-Meyer, 1986, J.
				Immunol. Methods.
CD30	GeneSeq	WO9324135	Activities associated with apoptosis, NF-kB	Apoptosis activity, NF-kB	Inflammatory disorders,
ligand	Accession		activation, and co-stimulation of immune	activation, and B and T cell co-	immunologic disorders,
	R45007		cells such as T and B cells.	stimulation can be determined using	cancer
				assays known in the art: Moore et
				al., 1999, Science, 285(5425): 260-3;
				Song H Y 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, NF-kB	Apoptosis activity, NF-kB	Inflammatory disorders,
	Accession		activation, and co-stimulation of immune	activation, and B and T cell co-	immunologic disorders,
	R85486		cells such as T and B cells.	stimulation can be determined using	cancer
				assays known in the art: Moore, et
				al., 1999, Science, 285(5425): 260-3;
				Song H Y et al., 1997 Proc Natl
				Acad Sci USA 94(18): 9792-6;
				Epsevik and Nissen-Meyer, 1986, J.
				Immunol. Methods.
4-1BB	GeneSeq	U.S. Pat. No.	Activities associated with apoptosis, NF-kB	Apoptosis activity, NF-kB	Inflammatory disorders,
ligand	Accession	5,674,704	activation, and co-stimulation of immune	activation, and B and T cell co-	immunologic disorders,
	W26657		cells such as T and B cells.	stimulation can be determined using	cancer
				assays known in the art: Moore et
				al., 1999, Science, 285(5425): 260-3;
				Song H Y et al, 1997 Proc Natl
				Acad Sci USA 94(18): 9792-6;
				Epsevik and Nissen-Meyer, 1986, J.
				Immunol. Methods.
FAS	GeneSeq	WO0058465	Activities associated with apoptosis, NF-kB	Apoptosis activity, NF-kB	Soluble DcR3 polypeptides
Ligand	Accession		activation, and co-stimulation of immune	activation, and B and T cell co-	may be useful for inhibiting
Inhibitory	B19335		cells such as T and B cells.	stimulation can be determined using	apoptosis, NF-kB activation,
Protein				assays known in the art: Moore et	and/or co-stimulation of immune
(DcR3)				al., 1999, Science, 285(5425): 260-3;	cells such as B and T cells.
				Song H Y et al., 1997 Proc Natl
				Acad Sci USA 94(18): 9792-6;
				Epsevik and Nissen-Meyer, 1986, J.
				Immunol. Methods
OX40L	GeneSeq	WO9521915	Activities associated with apoptosis, NF-kB	Apoptosis activity, NF-kB	Inflammatory disorders,
	Accession		activation, and co-stimulation of immune	activation, and B and T cell co-	immunologic disorders,
	R79903		cells such as T and B cells.	stimulation can be determined using	cancer
				assays known in the art: Moore et
				al., 1999, Science, 285(5425): 260-3;
				Song H Y 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	HIV protease activities are known in	HIV, inflammatory disorders,
inhibitor	Accessions		function/binding of HIV	the art: HIV protease assays:	immunologic disorders,
peptides	R12435,			EP0387231. One can modify the	cancer, viral infections
	R12436,			assay to look for inhibition using
	R12437,			any of the disclosed protease
	R12438,			inhibitor polypeptides.
	R12439,
	R12440,
	and
	R1244
Retro-	GeneSeq	EP387231	Peptides that inhibit the	HIV protease activities are known in	HIV, inflammatory disorders,
viral	Accessions		function/binding of HIV	the art: HIV protease assays:	immunologic disorders,
protease	R06660,			EP0387231. One can modify the	cancer, viral infections
inhibitors	R06661,			assay to look for inhibition using
	R06662,			any of the disclosed protease
	R06663,			inhibitor polypeptides.
	R06664,
	R06665,
	R06666,
	R06667,
	R06668,
	R06669,
	R06670,
	R06671,
	R06672,
	R06673,
	R06674,
	R06675,
	and
	R06676
HIV	GeneSeq	WO9301828	Peptides that inhibit the	HIV protease activities are known in the	HIV, inflammatory disorders,
protease	Accessions		function/binding of HIV	art. HIV protease assays EP0387231.	immunologic disorders,
inhibiting	R59293,			One can modify the assay to look for	cancer, viral infections
peptides	R59294,			inhibition using any of the disclosed
	R59295,			protease inhibitor polypeptides.
	R59296,
	R59297,
	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	GeneSeq	DE4412174	Peptides that inhibit the	HIV protease activities are known in the	HIV, inflammatory disorders,
protease	Accessions		function/binding of HIV	art: HIV protease assays: EP0387231.	immunologic disorders,
hinibitors	R86326,			One can modify the assay to look for	cancer, viral infections
	R86327,			inhibition using any of the disclosed
	R86328,			protease inhibitor polypeptides.
	R86329,
	R86330,
	R86331,
	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	GeneSeq	WO9959615	Peptides that inhibit the	HIV protease activities are known in	HIV, inflammatory disorders,
Inhibitor	Accession		function/binding of HIV	the art: HIV protease assays:	immunologic disorders,
Peptide	Y89687			EP0387231. One can modify the	cancer, viral infections
				assay to look for inhibition using
				any of the disclosed protease
				inhibitor polypeptides.
HIV	GenSeq	WO9948513	Peptides that inhibit the	HIV Protease activities are known	HIV, inflammatory disorders,
Inhibitor	Accession		function/binding of HIV	in the art; HIV protease assays:	immunologic disorders,
Peptide	Y31955			EP0387231. One can modify the	cancer, viral infections
				assay to look for inhibition using
				any of the disclosed protease
				inhibitor polypeptides.
HIV	www.sciencex-		Peptides that inhibit the	HIV protease activities are known	HIV, inflammatory disorders,
Inhibitor	press.org;		function/binding of HIV	in the art: HIV protease assays:	immunologic disorders,
Peptide	Published			EP0387231. One can modify the	cancer, viral infections
	online 12			assay to look for inhibition using
	Jan. 2001;			any of the disclosed protease
	10.1126/sci-			inhibitor polypeptides.
	ence.1057453
Human	GeneSeq	WO9509232	Chemokines are a family of related	Chemokine activities can be	Immune disorders, particularly
monocyte	Accession		small, secreted proteins	determined using assays known in	useful for treating bacterial
chemo-	R73915		involved in biological processes	the art: Methods in Molecular	and/or viral menigitis
attractant			ranging from hematopoiesis,	Biology, 2000, vol. 138:
factor			angiogenesis, and leukocyte trafficking.	Chemokine Protocols, Edited by:
hMCP-3			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	WO9509232	Chemokines are a family of related	Chemokine activities can be	Immune disorders, particularly
monocyte	Accession		small, secreted proteins	determined using assays known in	useful for treating bacterial
chemo-	R73914		involved in biological processes	the art: Methods in Molecular	and/or viral menigitis
attractant			ranging from hematopoiesis,	Biology, 2000, vol. 138:
factor			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
hMCP-1			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	WO9429341	Chemokines are a family of related	Chemokine activities can be	Immune disorders,
gro-	Accessions		small, secreted proteins	determined using assays known in	inflammatory disorders,
beta	R66699		involved in biological processes	the art: Methods in Molecular	blood-related disorders,
chemokine	and		ranging from hematopoiesis,	Biology, 2000, vol. 138:	stem cell transplantation,
	W17671		angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:	cancer
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	WO9429341	Chemokines are a family of related	Chemokine activities can be	Immune disorders,
gro-	Accessions		small, secreted proteins	determined using assays known in	inflammatory disorders,
gamma	R66700		involved in biological processes	the art: Methods in Molecular	blood-related disorders,
chemokine	and		ranging from hematopoiesis,	Biology, 2000, vol. 138:	stem cell transplantation,
	W17672		angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:	cancer
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	WO9429341	Chemokines are a family of related	Chemokine activities can be	Immune disorders,
gro-	Accessions		small, secreted proteins	determined using assays known in	inflammatory disorders,
alpha	R66698 and		involved in biological processes	the art: Methods in Molecular	blood-related disorders,
chemokine	W18024		ranging from hematopoiesis,	Biology, 2000, vol. 138:	stem cell transplantation,
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:	cancer
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	Chemokine activities can be	Immune disorders, particularly
eosinophil-	Accession		small, secreted proteins	determined using assays known in	treatment of eosinophilia,
expressed	W05186		involved in biological processes	the art: Methods in Molecular	inflammation,
chemokine			ranging from hematopoiesis,	Biology, 2000, vol. 138:	allergies, asthma, leukaemia
(EEC)			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:	and lymphoma
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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.
Chemo-	GeneSeq	WO9613587	Chemokines are a family of related	Chemokine activities can be	Cancer and blood-related
kine-like	Accessions		small, secreted proteins	determined using assasys known in	disorders, particularly
protein	R92318		involved in biological processes	the art: Methods in Molecular	myelosuppression
PF4-414	and		ranging from hematopoiesis,	Biology, 2000, vol. 138:
Full-	R99809		angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
Length			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
and			similarly diverse range of pathologies	and C. A. Power. Humana Press
Mature			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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.
Chemo-	GeneSeq	WO9613587	Chemokines are a family of related	Chemokine activities can be	Cancer and blood-related
kine-like	Accession		small, secreted proteins	determined using assays known in	disorders, particularly
protein	R99812		involved in biological processes	the art: Methods in Molecular	myelosuppression
IL-8M3			ranging from hematopoiesis,	Biology, 2000, vol. 138:
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ; and Holmes et al
			rejection, viral infection, and tumor	(1991) Science 253, 1278-80.
			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	Chemokine activities can be	Cancer and blood-related
inter-	Accession		small, secreted proteins	determined using assays known in	disorders, particularly
leukin-8	R99814		involved in biological processes	the art: Methods in Molecular	myelosuppression
(IL-8)			ranging from hematopoiesis,	Biology, 2000, vol. 138:
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ; and Holmes et al
			rejection, viral infection, and tumor	(1991) Science 253, 1278-80.
			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.
Chemo-	GeneSeq	WO9613587	Chemokines are a family of related	Chemokine activities can be	Cancer and blood-related
kine-like	Accessions		small, secreted proteins	determined using assays known in	disorders, particularly
protein	R99815		involved in biological processes	the art: Methods in Molecular	myelosuppression
IL-8M1	and		ranging from hematopoiesis,	Biology, 2000, vol. 138:
Full-	R99803		angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
Length			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
and			similarly diverse range of pathologies	and C. A. Power. Humana Press
Mature			including inflammation, allergy, tissue	Inc., Totowa, NJ; and Holmes et al
			rejection, viral infection, and tumor	(1991) Science 253, 1278-80.
			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.
Chemo-	GeneSeq	WO9613587	Chemokines are a family of related	Chemokine activities can be	Cancer and blood-related
kine-like	Accessions		small, secreted proteins	determined using assays known in	disorders, particularly
protein	R99816		involved in biological processes	the art: Methods in Molecular	myelosuppression.
IL - 8M8	and		ranging from hematopoiesis,	Biology, 2000, vol. 138:
Full-	R99805		angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
Length			Members of this family are involved in a	A. E. I. Proudfoot; T. N. C. Wells,
and			similarly diverse range of pathologies	and C. A. Power. Humana Press
Mature			including inflammation, allergy, tissue	Inc., Totowa, NJ; and Holmes et al
			rejection, viral infection, and tumor	(1991) Science 253, 1278-80.
			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.
Chemo-	GeneSeq	WO9613587	Chemokines are a family of related	Chemokine activities can be	Cancer and blood-related
kine-like	Accessions		small, secreted proteins	determined using assays known in	disorders, particularly
protein	R99817		involved in biological processes	the art: Methods in Molecular	myelosuppression.
IL - 8M8	and		ranging from hematopoiesis,	Biology, 2000, vol. 138:
Full-	R99806		angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
Length			Members of this family are involved in a	A. E. I. Proudfoot; T. N. C. Wells,
and			similarly diverse range of pathologies	and C. A. Power. Humana Press
Mature			including inflammation, allergy, tissue	Inc., Totowa, NJ; and Holmes et al
			rejection, viral infection, and tumor	(1991) Science 253, 1278-80.
			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.
Chemo-	GeneSeq	WO9613587	Chemokines are a family of related	Chemokine activities can be	Cancer and blood-related
kine-like	Accessions		small, secreted proteins	determined using assays known in	disorders, particularly
protein	R99818		involved in biological processes	the art: Methods in Molecular	myelosuppression.
IL - 8M8	and		ranging from hematopoiesis,	Biology, 2000, vol. 138:
Full-	R99804		angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
Length			Members of this family are involved in a	A. E. I. Proudfoot; T. N. C. Wells,
and			similarly diverse range of pathologies	and C. A. Power. Humana Press
Mature			including inflammation, allergy, tissue	Inc., Totowa, NJ; and Holmes et al
			rejection, viral infection, and tumor	(1991) Science 253, 1278-80.
			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.
Chemo-	GeneSeq	WO9613587	Chemokines are a family of related	Chemokine activities can be	Cancer and blood-related
kine-like	Accessions		small, secreted proteins	determined using assays known in	disorders, particularly
protein	R99819		involved in biological processes	the art: Methods in Molecular	myelosuppression.
IL - 8M8	and		ranging from hematopoiesis,	Biology, 2000, vol. 138:
Full-	R99807		angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
Length			Members of this family are involved in a	A. E. I. Proudfoot; T. N. C. Wells,
and			similarly diverse range of pathologies	and C. A. Power. Humana Press
Mature			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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.
Chemo-	GeneSeq	WO9613587	Chemokines are a family of related	Chemokine activities can be	Cancer and blood-related
kine-like	Accessions		small, secreted proteins	determined using assays known in	disorders, particularly
protein	R99822 and		involved in biological processes	the art: Methods in Molecular	myelosuppression.
IL - 8M8	R9807		ranging from hematopoiesis,	Biology, 2000, vol. 138:
Full-			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
Length			Members of this family are involved in a	A. E. I. Proudfoot; T. N. C. Wells,
and			similarly diverse range of pathologies	and C. A. Power. Humana Press
Mature			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	WO9622374	Chemokines are a family of related	Chemokine activities can be	Immune disorders
foetal	Accession		small, secreted proteins	determined using assays known in
spleen	R98499		involved in biological processes	the art: Methods in Molecular
expressed			ranging from hematopoiesis,	Biology, 2000, vol. 138:
chemokine,			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
FSEC			Members of this family are involved in a	A. E. I. Proudfoot; T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	GeneSeq	WO9616979	Chemokines are a family of related	Chemokine activities can be	Inflammation of the liver
expressed	Accession		small, secreted proteins	determined using assasys known in
chemokine-1	R95689		involved in biological processes	the art: Methods in Molecular
(LVEC-1)			ranging from hematopoiesis,	Biology, 2000, vol. 138:
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
			Members of this family are involved in a	A. E. I. Proudfoot; T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	GeneSeq	WO9616979	Chemokines are a family of related	Chemokine activities can be	Inflammation of the liver
expressed	Accession		small, secreted proteins	determined using assasys known in
chemokine-2	R95690		involved in biological processes	the art: Methods in Molecular
(LVEC-2)			ranging from hematopoiesis,	Biology, 2000, vol. 138:
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
			Members of this family are involved in a	A. E. I. Proudfoot; T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	Chemokine activities can be	Inflammation, particularly of
expressed	Accession		small, secreted proteins	determined using assasys known in	the liver
chemokine	R95691		involved in biological processes	the art: Methods in Molecular
(PGEC)			ranging from hematopoiesis,	Biology, 2000, vol. 138:
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
			Members of this family are involved in a	A. E. I. Proudfoot; T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	Chemokine activities can be	Inflammation, angiogenesis,
expressed	Accession		small, secreted proteins	determined using assasys known in	tumorigenesis,
chemokine	R97664		involved in biological processes	the art: Methods in Molecular	musculoskeletal disorders
(ADEC)			ranging from hematopoiesis,	Biology, 2000, vol. 138:
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
			Members of this family are involved in a	A. E. I. Proudfoot; T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	Chemokine activities can be	Immune disorders,
chemokineCC-	Accession		small, secreted proteins	determined using assays known in	cell migration,
2	W38170		involved in biological processes	the art: Methods in Molecular	proliferation, and
			ranging from hematopoiesis,	Biology, 2000, vol. 138;	differentiation disorders
			angiogenesis, and leukocyte trafficking.	Chemokine protocols. Edited by:
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc. Totowa, NJ
			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	Chemokine activities can be	Immune disorders,
chemokine	Accession		small, secreted proteins	determined using assays known in	cell migration,
HCC-1	W38171		involved in biological processes	the art: Methods in molecular	proliferation, and
			ranging from hematopoiesis,	Biology 2000, vol. 138:	differentiation disorders
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells
			similarly diverse range of pathologies	and C. A. Power Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	Chemokine activities can be	Immune disorders,
chemokine	Accession		small, secreted proteins	determined using assays known in	cell migration,
CC-3	W38172		involved in biological processes	the art: Methods in molecular	proliferation and
			ranging from hematopiesis,	Biology, 2000, vol. 138:	differentiation disorders
			anglogenesis, and leukocyte trafficking.	Chemokine Protocols, Edited by
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	Chemokine activities can be	Immune disorders,
beta-	Accession		small, secreted proteins	determined using assays known in	vascular disorders,
chemokine	W27271		involved in biological processes	the art: Methods in molecular	cancer
designated			ranging from hematopoiesis,	Biology, 2000, vol. 138:
PTEC			anglogenesis, and leukocyte trafficking.	Chemokine Protocols, Edited by
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	WO9727299	Chemokines are a family of related	Chemokine activities can be	Immune disorders,
CX3C	Accession		small, secreted proteins	determined using assays known in	inflammatory diseases,
111 amino	W23344		involved in biological processes	the art: Methods in molecular	abnormal proliferation,
acid			ranging from hematopoiesis,	Biology, 2000, vol. 138:	regeneration,
chemokine			anglogenesis, and leukocyte trafficking.	Chemokine Protocols, Edited by	degeneration, and
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,	atrophy
			similarly diverse range of pathologies	and C. A. Power Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	WO9721812	Chemokines are a family of related	Chemokine activities can be	Abnormal physiology and
CCF18	Accession		small, secreted proteins	determined using assays known in	development disorders,
chemokine	W25942		involved in biological processes	the art: Methods in molecular	can also be used as an
			ranging from hematopoiesis,	Biology, 2000, vol. 138:	anti-viral agent
			anglogenesis, and leukocyte trafficking.	Chemokine Protocols, Edited by
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	WO9725427	Chemokines are a family of related	Chemokine activities can be	Chemotaxis, blood-related
beta-	Accession		small, secreted proteins	determined using assays known in	disorders, viral infection,
chemokine	W26655		involved in biological processes	the art: Methods in molecular	HIV, wound healing, cancer
H1305			ranging from hematopoiesis,	Biology, 2000, vol. 138:
(MCP-2)			anglogenesis, and leukocyte trafficking.	Chemokine Protocols, Edited by
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	Chemokine activities can be	Inflammatory and
eosino-	Accession		small, secreted proteins	determined using assays known in	immune disorders
cyte CC	W14990		involved in biological processes	the art: Methods in molecular
type			ranging from hematopoiesis,	Biology, 2000, vol. 138:
chemokine			anglogenesis, and leukocyte trafficking.	Chemokine Protocols, Edited by
eotaxin			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	WO9711969	Chemokines are a family of related	Chemokine activities can be	Inflammatory and immune
thymus	Accession		small, secreted proteins	determined using assays known in	disorders
and	W14018		involved in biological processes	the art: Methods in molecular
activation			ranging from hematopoiesis,	Biology, 2000, vol. 138:
regulated			anglogenesis, and leukocyte trafficking.	Chemokine Protocols, Edited by
cytokine			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
(TARC)			similarly diverse range of pathologies	and C. A. Power Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	Chemokine activities can be	Cancer,
chemokine	Accession		small, secreted proteins	determined using assays known in	wound healing,
beta-	W16315		involved in biological processes	the art: Methods in molecular	immune disorders
8 short			ranging from hematopoiesis,	Biology, 2000, vol. 138:
forms			anglogenesis, and leukocyte trafficking.	Chemokine Protocols, Edited by
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	Chemokine activities can be	Inflammatory diseases,
derived	Accession		small, secreted proteins	determined using assays known in	wound healin,
chemokine,	W20058		involved in biological processes	the art: Methods in Molecular	angiogenesis
MDC			ranging from hematopoiesis,	Biology, 2000, vol. 138:
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	Chemokine activities can be	Inflammatory and
chemokine	Accession		small, secreted proteins	determined using assays known in	immune diseases
ZSIG-35	W30565		involved in biological processes	the art: Methods in Molecular
			ranging from hematopoiesis,	Biology, 2000, vol. 138:
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	GeneSeq	WO98328658	Chemokines are a family of related	Chemokine activities can be	Immune and
CC	Accesssion		small, secreted proteins involved in	determined using assays known in	inflammatory disorders,
chemokine	W69990		biological processes ranging from	the art: Methods in Molecular	abnormal proliferation,
“ILINCK”			hematopoiesis, angiogenesis, and	Biology, 2000, vol. 138:	regeneration,
			leukocyte trafficking.	Chemokine Protocols. Edited by:	generation and
				A. E. I. Proudfoot, T. N. C. Wells,	atrophy disorders
				and C. A. Power. Humana Press
				Inc., Totowa, NJ
Primate	GeneSeq	WO9832858	Chemokines are a family of related	Chemokine activities can be	Immune and
CXC	Accession		small, secreted proteins	determined using assays known in	inflammatory disorders,
chemokine	W69989		involved in biological processes	the art: Methods in Molecular	abnormal proliferation,
“IBICK”			ranging from hematopoiesis,	Biology, 2000, vol. 138:	regeneration,
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Editd by.	generation and
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,	atrophy disorders
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	WO9831809	Chemokines are a family of related	Chemokine activities can be	Immune,
CC-type	Accession		small, secreted proteins	determined using assays known in	inflammatory, and
chemokine	W69163		involved in biological processes	the art: Methods in Molecular	infectious disorders,
protein			ranging from hematopoiesis,	Biology, 2000, vol. 138:	cancer
designated			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
SLC			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
(secondary			similarly diverse range of pathologies	and C. A. Power. Humana Press
lymphoid			including inflammation, allergy, tissue	Inc., Totowa, NJ
chemokine)			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	WO9826071	Chemokines are a family of related	Chemokine activities can be	Cancer and
CC	Accession		small, secreted proteins	determined using assays known in	infectious diseases,
chemokine	W62542		involved in biological processes	the art: Methods in Molecular	particularly
ELC			ranging from hematopoiesis,	Biology, 2000, vol. 138:	herpes virus
protein			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	Wo9823750	Chemokines are a family of related	Chemokine activities can be	Abnormal proliferation,
DVic-1	Accession		small, secreted proteins	determined using assays known in	regeneration,
C-C	W60649		involved in biological processes	the art: Methods in Molecular	degeneration, and
chemokine			ranging from hematopoiesis,	Biology, 2000, vol. 138:	atrophy disorders,
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:	including cancer
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	WO9823750	Chemokines are a family of related	Chemokine activities can be	Immune disorders,
C-C	Accession		small, secreted proteins	determined using assays known in	cell proliferation
chemokine	W60650		involved in biological processes	the art: Methods in Molecular	disorders, cancer
DGWCC			ranging from hematopoiesis,	Biology, 2000, vol. 138:
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	WO9824907	Chemokines are a family of related	Chemokine activities can be	Immune disorders,
STCP-1	Accession		small, secreted proteins	determined using assays known in	particularly T cell
	W62783		involved in biological processes	the art: Methods in Molecular	related disorders,
			ranging from hematopoiesis,	Biology, 2000, vol. 138:	viral infection, and
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:	inflammation,
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,	especially joint
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	GeneSeq	WO9821330	Chemokines are a family of related	Chemokine activities can be	Immune and
protein	Accession		small, secreted proteins	determined using assays known in	inflammatory disorders,
	W61279		involved in biological processes	the art: Methods in Molecular	angiogenesis, cancer,
			ranging from hematopoiesis,	Biology, 2000, vol. 138:	and proliferation
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:	disorders, particularly
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,	myeloproliferative
			similarly diverse range of pathologies	and C. A. Power. Humana Press	diseases
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	Chemokine activities can be	Cancer and
Chr19Kine	Acession		small, secreted proteins	determined using assays known in	degenerative
protein	W50887		involved in biological processes	the art: Methods in Molecular	disorders
			ranging from hematopoiesis,	Biology, 2000, vol. 138:
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols, Edited by:
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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.	Chemokines are a family of related	Chemokine activities can be	Immune,
T cell	Accession	5,780,268	small, secreted proteins	determined using assays known in	inflammatory, and
mixed	W58703		involved in biological processes	the art: Mehtods of Molecular	infectious disorders,
lymphocyte			ranging from hematopoiesis,	Biology, 2000, vol. 138:	cancer
reaction			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
expressed			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
chemokine			similarly diverse range of pathologies	and C. A. Power Humana Press
(TMEC)			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	W09814581	Chemokines are a family of related	Chemokine activities can be	Cancer and
6CKine	Accession		small, secreted proteins	determined using assays known in	degenerative
protein	W50885		involved in biological processes	the art: Mehtods of Molecular	disorders
			ranging from hematopoiesis,	Biology, 2000, vol. 138:
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	WO9817800	Chemokines are a family of related	Chemokine activities can be	Immune,
liver	Accession		small, secreted proteins	determined using assays known in	inflammatory, and
and	W57475		involved in biological processes	the art: Mehtods of Molecular	infectious disorders,
activation			ranging from hematopoiesis,	Biology, 2000, vol. 138:	cancer
regulated			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
chemokine			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
(LARC)			similarly diverse range of pathologies	and C. A. Power Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	Infectious diseases,
peptide	Accession		small, secreted proteins	determined using assays known in	particularly HIV
	W29538		involved in biological processes	the art: Mehtods of Molecular
			ranging from hematopoiesis,	Biology, 2000, vol. 138:
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	Infectious diseases,
8-68	Accession		small, secreted proteins	determined using assays known in	particularly HIV
	W29529		involved in biological processes	the art: Mehtods of Molecular
			ranging from hematopoiesis,	Biology, 2000, vol. 138:
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	Infectious diseases,
9-68	Accession		small, secreted proteins	determined using assays known in	particularly HIV
	W29528		involved in biological processes	the art: Mehtods of Molecular
			ranging from hematopoiesis,	Biology, 2000, vol. 138:
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	Abnormal proliferation,
chemokine	Accession		small, secreted proteins	determined using assays known in	regeneration,
protein	W59433		involved in biological processes	the art: Mehtods of Molecular	degeneration or
331D5			ranging from hematopoiesis,	Biology, 2000, vol. 138:	atrophy, including cancer
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	Abnormal proliferation,
chemokine	Accession		small, secreted proteins	determined using assays known in	regeneration,
protein	W59430		involved in biological processes	the art: Mehtods of Molecular	degeneration or
61164			ranging from hematopoiesis,	Biology, 2000, vol. 138:	atrophy, including cancer
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	Immune,
MCP-4	Accession		small, secreted proteins	determined using assays known in	Inflammatory, and
	W56690		involved in biological processes	the art: Mehtods of Molecular	infectious diseases
			ranging from hematopoiesis,	Biology, 2000, vol. 138:
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	FR2751658	Chemokines are a family of related	Chemokine activities can be	HIV infections
stromal	Accession		small, secreted proteins	determined using assays known in
cell-	W50766		involved in biological processes	the art: Methods in Molecular
derived			ranging from hematopoiesis,	Biology, 2000, vol. 138:
chemokine,			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
SDF-1			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	Chemokine activities can be	Immune and
expressed	Accession		small, secreted proteins	determined using assays known in	inflammatory
chemokine	W44397		involved in biological processes	the art: Methods in Molecular	disorders
(TECK)			ranging from hematopoiesis,	Biology, 2000, vol. 138:
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	Chemokine activities can be	Immune and inflammatory
chemokine	Accession		small, secreted proteins	determined using assays known in	disorders
MIP-	W44398		involved in biological processes	the art: Methods in Molecular
3alpha			ranging from hematopoiesis,	Biology, 2000, vol. 138:
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	Chemokine activities can be	Immune and
chemokine	Accession		small, secreted proteins	determined using assays known in	inflammatory
MIP-	W44399		involved in biological processes	the art: Methods in Molecular	disorders
3beta			ranging from hematopoiesis,	Biology, 2000, vol. 138:
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	WO9802459	Chemokines are a family of related	Chemokine activities can be	Immune disorders, respiratory
monocyte	Accession		small, secreted proteins	determined using assays known in	disorders, cancer
chemotactic	W42072		involved in biological processes	the art: Methods in Molecular
proprotein			ranging from hematopoiesis,	Biology, 2000, vol. 138:
(MCPP)			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
sequence			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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.	Chemokines are a family of related	Chemokine activities can be	Immune, and
derived	Accessions	5,688,927/	small, secreted proteins	determined using assays known in	inflammatory
chemokine	W40811	U.S. Pat. No.	involved in biological processes	the art: Methods in Molecular	disorders,
(MDC)	and	5,932,703	ranging from hematopoiesis,	Biology, 2000, vol. 138:	cancer
	Y24414		angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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.	Chemokines are a family of related	Chemokine activities can be	Immune and
derived	Accession	5,932,703	small, secreted proteins	determined using assays known in	inflammatory
chemokine	Y24416		involved in biological processes	the art: Methods in Molecular	disorders
analogue			ranging from hematopoiesis,	Biology, 2000, vol. 138:
MDC-eyfy			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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.	Chemokines are a family of related	Chemokine activities can be	Immune and
derived	Accession	5,932,703	small, secreted proteins	determined using assays known in	inflammatory
chemokine	Y24413		involved in biological processes	the art: Methods in Molecular	disorders
analogue			ranging from hematopoiesis,	Biology, 2000, vol. 138:
MDC			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
(n + 1)			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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.	Chemokines are a family of related	Chemokine activities can be	Immune and
derived	Accession	5,932,703	small, secreted proteins	determined using assays known in	inflammatory
chemokine	Y24415		involved in biological processes	the art: Methods in Molecular	disorders
analogue			ranging from hematopoiesis,	Biology, 2000, vol. 138:
MDC-yl			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	JP11243960	Chemokines are a family of related	Chemokine activities can be	Allergic diseases
type CC	Accession		small, secreted proteins	determined using assays known in	and HIV
chemokine	Y43178		involved in biological processes	the art: Methods in Molecular	infection
eotaxin
3			ranging from hematopoiesis,	Biology, 2000, vol. 138:
protein			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
sequence			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	WO9946392	Chemokines are a family of related	Chemokine activities can be	Cancer and immune disorders,
MCP-3 and	Acession		small, secreted proteins	determined using assays known in	particularly HIV infection
human	Y29893		involved in biological processes	the art: Methods in Molecular
Muc-1			ranging from hematopoiesis,	Biology, 2000, vol. 138:
core			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
epitope			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
(VNT)			similarly diverse range of pathologies	and C. A. Power. Humana Press
fusion			including inflammation, allergy, tissue	Inc., Totowa, NJ
protein			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	WO9946392	Chemokines are a family of related	Chemokine activities can be	Cancer and immune disorders,
IP-10 and	Accession		small, secreted proteins	determined using assays known in	particularly HIV infection
human	Y29894		involved in biological processes	the art: Methods in Molecular
Muc-1			ranging from hematopoiesis,	Biology, 2000, vol. 138:
core			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
epitope			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
(VNT)			similarly diverse range of pathologies	and C. A. Power. Humana Press
fusion			including inflammation, allergy, tissue	Inc., Totowa, NJ
protein			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	W09946392	Chemokines are a family of related	Chemokine activities can be	Cancer and immune disorders,
IP-10 and	Accession		small, secreted proteins	determined using assays known in	particularly HIV infection
HIV-1	Y29897		involved in biological processes	the art: Methods in Molecular
gp
120			ranging from hematopoiesis,	Biology, 2000, vol. 138:
hyper-			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
variable			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
region			similarly diverse range of pathologies	and C. A. Power. Humana Press
fusion			including inflammation, allergy, tissue	Inc., Totowa, NJ
protein			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	WO9936540	Chemokines are a family of related	chemokine activities can be	Breast disease, including
mammary	Accessions		small, secreted proteins	determined using assays known in	cancer
associated	Y29092 and		involved in biological processes	the art: Methods in Molecular
chemokine	Y29093		ranging from hematopoiesis,	Biology, 2000, vol. 138:
(MACK)			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
protein			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
Full-			similarly diverse range of pathologies	and C. A. Power. Humana Press
Length			including inflammation, allergy, tissue	Inc., Totowa, NJ
and			rejection, viral infection, and tumor
Mature			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	GeneSeq	WO9933990	Chemokines are a family of related	Chemokine activities can be	Inflammation due to stimuli
protein	Accession		small, secreted proteins	determined using assays known in	such as heart attacks and
	Y28290		involved in biological processes	the art: Methods in Molecular	stroke, infection, physical
			ranging from hematopoiesis,	Biology, 2000, vol. 138:	trauma, UV or ionizing
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:	radiation, burns, frostbite or
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,	corrosive chemicals
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	WO9928473	Chemokines are a family of related	Chemokine activities can be	HIV infection and cancer,
Lkn-1	Accessions	and	small, secreted proteins	determined using assays known in	particularly leukemia
Full-	Y17280,	WO9928472	involved in biological processes	the art: Methods in Molecular
Length	Y17274,		ranging from hematopoiesis,	Biology, 2000, vol. 138:
and	Y17281,		angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
Mature	and		Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
protein	Y17275		similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	Chemokine activities can be	Inhibit or stimulate
modified	Accession		small, secreted proteins	determined using assays known in	angiogenesis, inhibit the
chemokine	Y05818		involved in biological processes	the art: Methods in Molecular	binding of HIV
met-			ranging from hematopoiesis,	Biology, 2000, vol. 138:
hSDF-1			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
alpha			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	Chemokine activities can be	Inhibit or stimulate
modified	Accession		small, secreted proteins	determined using assays known in	angiogenesis, inhibit the
chemokine	Y05819		involved in biological processes	the art: Methods in Molecular	binding of HIV,
met-			ranging from hematopoiesis,	Biology, 2000, vol. 138:	antiinflammatory;
hSDF-1			angiogenesis, and leukocyte trafficking.	chemokine Protocols. Edited by:	immunosuppressant
beta			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	Chemokine activities can be	Inhibit or stimulate
modified	Accession		small, secreted proteins	determined using assays known in	angiogenesis, inhibit the
chemokine	Y05820		involved in biological processes	the art: Methods in Molecular	binding of HIV,
GroHEK/			ranging from hematopoiesis,	Biology, 2000, vol. 138:	antiinflammatory;
hSDF-			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:	immunosuppressant
1alpha			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	Chemokine activities can be	Inhibit or stimulate
modified	Accession		small, secreted proteins	determined using assays known in	angiogenesis, inhibit the
chemokine	Y05821		involved in biological processes	the art: Methods in Molecular	binding of HIV,
GroHEK/			ranging from hematopoiesis,	Biology, 2000, vol. 138:	antiinflammatory;
hSDF-			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:	immunosuppressant
1beta.			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	Chemokine activities can be	Increase or enhance an
Eotaxin	Accession		small, secreted proteins	determined using assays known in	inflammatory response, an
	Y14230		involved in biological processes	the art: Methods in Molecular	immune response
			ranging from hematopoiesis,	Bilogy, 2000, vol. 138:	orhaematopoietic cell-
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:	associated activity; treat a
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,	vascular indication; Cancer;
			similarly diverse range of pathologies	and C. A. Power. Humana Press	enhance wound healing, to
			including inflammation, allergy, tissue	Inc., Totowa, NJ	prevent or treat asthma,
			rejection, viral infection, and tumor		organ transplant rejction,
			biology. The chemokines exert their		rheumatoid arthritis
			effects by acting on a family of seven		or allergy
			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	Chemokine activities can be	Immune disorders, Vascular
hMCP1a	Accession		small, secreted proteins	determined using assays known in	disorders, Wound healing,
	Y14225		involved in biological processes	the art: Methods in Molecular	cancer, prevent organ
			ranging from hematopoiesis,	Bilogy, 2000, vol. 138:	transplant rejection, Increase
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:	or enhance an inflammatory
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,	response,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	Chemokine activities can be	Immune disorders, Vascular
hMCP1b	Accession		small, secreted proteins	determined using assays known in	disorders, Wound healing,
	Y14226		involved in biological processes	the art: Methods in Molecular	cancer, prevent organ
			ranging from hematopoiesis,	Bilogy, 2000, vol. 138:	transplant rejection, Increase
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:	or enhance an inflammatory
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,	response,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	Chemokine activities can be	Immune disorders, Vascular
hSDF1b	Accession		small, secreted proteins	determined using assays known in	disorders, Wound healing,
	Y14228		involved in biological processes	the art: Methods in Molecular	cancer, prevent organ
			ranging from hematopoiesis,	Bilogy, 2000, vol. 138:	transplant rejection, Increase
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:	or enhance an inflammatory
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,	response,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	Chemokine activities can be	Immune disorders, Vascular
hIL-8	Accession		small, secreted proteins	determined using assays known in	disorders, Wound healing,
	Y14229		involved in biological processes	the art: Methods in Molecular	cancer, prevent organ
			ranging from hematopoiesis,	Bilogy, 2000, vol. 138:	transplant rejection, Increase
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:	or enhance an inflammatory
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,	response,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ; and Holmes et al
			rejection, viral infection, and tumor	(1991) Science 253, 1278-80.
			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	Chemokine activities can be	Immune disorders, Vascular
hMCP1	Accession		small, secreted proteins	determined using assays known in	disorders, Wound healing,
	Y14222		involved in biological processes	the art: Methods in Molecular	cancer, prevent organ
			ranging from hematopoiesis,	Bilogy, 2000, vol. 138:	transplant rejection, Increase
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:	or enhance an inflammatory
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,	response,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	Chemokine activities can be	Immune disorders, Vascular
hMCP2	Accession		small, secreted proteins	determined using assays known in	disorders, Wound healing,
	Y14223		involved in biological processes	the art: Methods in Molecular	cancer, prevent organ
			ranging from hematopoiesis,	Bilogy, 2000, vol. 138:	transplant rejection, Increase
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:	or enhance an inflammatory
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,	response,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	Chemokine activities can be	Immune disorders, Vascular
hMCP3	Accession		small, secreted proteins	determined using assays known	disorders, Wound healing,
	Y14224		involved in biological processes	in the art: Methods in Molecular	cancer, prevent organ
			ranging from hematopoiesis,	Bilogy, 2000, vol. 138:	transplant rejection, Increase
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:	or enhance an inflammatory
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,	response,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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.
C-C	GeneSeq	EP905240	Chemokines are a family of related	Chemokine activities can be	Inflammatory, Immune and
chemokine,	Accession		small, secreted proteins involved in	determined using assays known in	infectious diseases; pulmonary
MCP2	Y05300		biological processes ranging from	the art: Methods in Molecular	diseases and skin
			hematopoiesis, angiogenesis, and	Bilogy, 2000, vol. 138:	disorders; tumours, and
			leukocyte trafficking.	Chemokine Protocols. Edited by:	angiogenesis-and
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,	haematopoiesis-related
			similarly diverse range of pathologies	and C. A. Power. Humana Press	diseases
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	Chemokine activities can be	Inflammatory, Immune and
monocyte	Accession		small, secreted proteins involved in	determined using assays known in	infectious diseases; pulmonary
chemotactic	Y07233		biological processes ranging from	the art: Methods in Molecular	diseases and skin disorders;
protein 2			hematopoiesis, angiogenesis, and	Bilogy, 2000, vol. 138:	tumours, and angiogenesis-
			leukocyte trafficking.	Chemokine Protocols. Edited by:	and haematopoiesis-related
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,	diseases
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	Chemokines activities can be	Inflammatory, immune and
monocyte	Accession		small, secreted proteins	determined using assays known in	infectious diseases; pulmonry
chemotactic	Y07234		involved in biological processes	the art: Methods in Molecular	diseases and skin disorders;
protein 2			ranging from hematopoiesis,	Biology, 2000, vol. 138:	tumours, and angiogenesis-and
(6-76)			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:	haematopoiesis-related
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,	diseases
			similarly diverse range of pathologies	and C. A. Power, Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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.
Truncated	GeneSeq	EP905241;	Chemokines are a family of related	Chemokines activities can be	Inflammatory, immune and
RANTES	Accessions	EP906954	small, secreted proteins	determined using assays known in	infectious diseases; pulmonry
protein	Y07236		involved in biological processes	the art: Methods in Molecular	diseases and skin disorders;
(3-68)	and		ranging from hematopoiesis,	Biology, 2000, vol. 138:	tumours, and angiogenesis-and
	Y07232		angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:	haematopoiesis-related
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,	diseases
			similarly diverse range of pathologies	and C. A. Power, Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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.
Wild type	GeneSeq	EP905241	Chemokines are a family of related	Chemokines activities can be	Inflammatory, immune and
monocyte	Accession		small, secreted proteins	determined using assays known in	infectious diseases; pulmonry
chemotactic	Y07237		involved in biological processes	the art: Methods in Molecular	diseases and skin disorders;
protein 2			ranging from hematopoiesis,	Biology, 2000, vol. 138:	tumours, and angiogenesis-and
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:	haematopoiesis-related
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,	diseases
			similarly diverse range of pathologies	and C. A. Power, Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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.
Truncated	GeneSeq	EP905241	Chemokines are a family of related	Chemokines activities can be	Inflammatory, immune and
monocyte	Accession		small, secreted proteins	determined using assays known in	infectious diseases; pulmonry
chemotactic	Y07238		involved in biological processes	the art: Methods in Molecular	diseases and skin disorders;
protein			ranging from hematopoiesis,	Biology, 2000, vol. 138:	tumours, and angiogenesis-and
2 (6-76)			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:	haematopoiesis-related
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,	diseases
			similarly diverse range of pathologies	and C. A. Power, Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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 partial	GeneSeq	EP897980	Chemokines are a family of related	Chemokines activities can be	Soluble CXCR4B receptor
CXCR4B	Accession		small, secreted proteins	determined using assays known in	polypeptides may be useful for
protein	W97363		involved in biological processes	the art: Methods in Molecular	inhibiting chemokine activities
			ranging from hematopoiesis,	Biology, 2000, vol. 138:	and viral infection.
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power, Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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.
Interferon	GeneSeq	U.S. Pat. No.	Chemokines are a family of related	Chemokines activities can be	Angiogenesis, Cancer,
gamma-	Accession	5,871,723	small, secreted proteins	determined using assays known in	Inflammatory and Immune
inducible	W96709		involved in biological processes	the art: Methods in Molecular	disorders, Cardio-Vascular
protein			ranging from hematopoiesis,	Biology, 2000, vol. 138:	discorders, Musco-skeletal
(IP-10)			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:	disorders
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power, Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	GeneSeq	U.S. Pat. No.	Chemokines are a family of related	Chemokines activities can be	Angiogenesis, Cancer,
monokine	Accession	5,871,723	small, secreted proteins	determined using assays known in	Inflammatory and Immune
induced	W96710		involved in biological processes	the art: Methods in Molecular	disorders, Cardio-Vascular
by gamma-			ranging from hematopoiesis,	Biology, 2000, vol. 138:	discorders, Musco-skeletal
interferon			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:	disorders
(MIG)			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power, Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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.
Inter-	GeneSeq	U.S. Pat. No.	Chemokines are a family of related	Chemokines activities can be	Angiogenesis, Cancer,
leukin-8	Accession	5,871,723	small, secreted proteins	determined using assays known in	Inflammatory and Immune
(IL-8)	W96711		involved in biological processes	the art: Methods in Molecular	disorders, Cardio-Vascular
protein.			ranging from hematopoiesis,	Biology, 2000, vol. 138:	discorders, Musco-skeletal
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:	disorders
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power, Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ; and Holmes et al
			rejection, viral infection, and tumor	(1991) Science 253, 1278-80.
			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.
Epithelial	GeneSeq	U.S. Pat. No.	Chemokines are a family of related	Chemokines activities can be	Angiogenesis, Cancer,
neutrophil	Accession	5,871,723	small, secreted proteins	determined using assays known in	Inflammatory and Immune
activating	W96712		involved in biological processes	the art: Methods in Molecular	disorders, Cardio-Vascular
protein-78			ranging from hematopoiesis,	Biology, 2000, vol. 138:	discorders, Musco-skeletal
(ENA-78)			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:	disorders
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power, Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	GeneSeq	U.S. Pat. No.	Chemokines are a family of related	Chemokines activities can be	Angiogenesis, Cancer,
related	Accession	5,871,723	small, secreted proteins	determined using assays known in	Inflammatory and Immune
oncogene-	W96713		involved in biological processes	the art: Methods in Molecular	disorders, Cardio-Vascular
alpha			ranging from hematopoiesis,	Biology, 2000, vol. 138:	discorders, Musco-skeletal
(GRO-			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:	disorders
alpha).			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power, Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	GeneSeq	U.S. Pat. No.	Chemokines are a family of related	Chemokine activities can be	Angiogenesis, Cancer,
related	Accession	5,871,723	small, secreted proteins	determined using assays known in	Inflammatory and Immune
oncogene-	W96714		involved in biological processes	the art: Methods in Molecular	disorders, Cardio-Vascular
beta			ranging from hematopoiesis,	Biology, 2000, vol. 138:	disorders, Musco-skeletal
(GRO-			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:	disorders
beta).			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power, Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	GeneSeq	U.S. Pat. No.	Chemokines are a family of related	Chemokine activities can be	Angiogenesis, Cancer,
related	Accession	5,871,723	small, secreted proteins	determined using assays known in	Inflammatory and Immune
oncogene-	W96715		involved in biological processes	the art: Methods in Molecular	disorders, Cardio-Vascular
gamma			ranging from hematopoiesis,	Biology, 2000, vol. 138:	disorders, Musco-skeletal
(GRO-			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:	disorders
gamma)			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power, Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	GeneSeq	U.S. Pat. No.	Chemokines are a family of related	Chemokine activities can be	Angiogenesis, Cancer,
platelet	Accession	5,871,723	small, secreted proteins	determined using assays known in	Inflammatory and Immune
basic	W96716		involved in biological processes	the art: Methods in Molecular	disorders, Cardio-Vascular
protein			ranging from hematopoiesis,	Biology, 2000, vol. 138:	disorders, Musco-skeletal
(PBP)			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:	disorders
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power, Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	GeneSeq	U.S. Pat. No.	Chemokines are a family of related	Chemokine activities can be	Angiogenesis, Cancer,
tissue	Accession	5,871,723	small, secreted proteins	determined using assays known in	Inflammatory and Immune
activating	S96717		involved in biological processes	the art: Methods in Molecular	disorders, Cardio-Vascular
protein-III			ranging from hematopoiesis,	Biology, 2000, vol. 138:	disorders, Musco-skeletal
(CTAP-III)			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:	disorders
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power, Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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.	Chemokines are a family of related	Chemokine activities can be	Angiogenesis, Cancer,
thrombo-	Accession	5,871,723	small, secreted proteins	determined using assays known in	Inflammatory and Immune
globulin	W96718		involved in biological processes	the art: Methods in Molecular	disorders, Cardio-Vascular
protein			ranging from hematopoiesis,	Biology, 2000, vol. 138:	disorders, Musco-skeletal
(beta-TG)			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:	disorders
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power, Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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.	Chemokines are a family of related	Chemokine activities can be	Angiogenesis, Cancer,
activating	Accession	5,871,723	small, secreted proteins	determined using assays known in	Inflammatory and Immune
peptide-2	W96719		involved in biological processes	the art: Methods in Molecular	disorders, Cardio-Vascular
(NAP-2)			ranging from hematopoiesis,	Biology, 2000, vol. 138:	disorders, Musco-skeletal
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:	disorders
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power, Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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.	Chemokines are a family of related	Chemokine activities can be	Angiogenesis, Cancer,
chemotactic	Accession	5,871,723	small, secreted proteins	determined using assays known in	Inflammatory and Immune
protein-2	W96720		involved in biological processes	the art: Methods in Molecular	disorders, Cardio-Vascular
(GCP-2)			ranging from hematopoiesis,	Biology, 2000, vol. 138:	disorders, Musco-skeletal
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:	disorders
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power, Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	Chemokine activities can be	Immune disorders, viral,
chemokine	Accession		small, secreted proteins	determined using assays known in	parasitic, fungal or
MIG-beta	W90124		involved in biological processes	the art: Methods in Molecular	bacterial
protein			ranging from hematopoiesis,	Biology, 2000, vol. 138:	infections, Cancer;
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:	autoimmune diseases or
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,	transplant rejection
			similarly diverse range of pathologies	and C. A. Power, Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	WO9854326	Chemokines are a family of related	Chemokine activities can be	Immune disorders, cancer,
ZCHEMO-8	Accession		small, secreted proteins	determined using assays known in	myelopoietic disorders,
	W82716		involved in biological processes	the art: Methods in Molecular	autoimmune
			ranging from hematopoiesis,	Biology, 2000, vol. 138:	disorders and
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:	immunodeficiencies,
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,	Inflammatory and infectious
			similarly diverse range of pathologies	and C. A. Power, Humana Press	diseases, Vascular
			including inflammation, allergy, tissue	Inc., Totowa, NJ	disorders,
			rejection, viral infection, and tumor		wound 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	GeneSeq	WO9854326	Chemokines are a family of related	Chemokine activities can be	Immune disorders, cancer,
Act-2	Accession		small, secreted proteins	determined using assays known in	myelopoietic disorders,
protein	W82717		involved in biological processes	the art: Methods in Molecular	autoimmune
			ranging from hematopoiesis,	Biology, 2000, vol. 138:	disorders and
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:	immunodeficiencies,
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,	Inflammatory and infectious
			similarly diverse range of pathologies	and C. A. Power, Humana Press	diseases, Vascular
			including inflammation, allergy, tissue	Inc., Totowa, NJ	disorders,
			rejection, viral infection, and tumor		wound 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	GeneSeq	WO9854326	Chemokines are a family of related	Chemokine activities can be	Immune disorders, cancer,
SISD	Acession		small, secreted proteins	determined using assays known in	myelopoietic disorders,
protein	W82720		involved in biological processes	the art: Methods in Molecular	autoimmune
			ranging from hematopoiesis,	Biology, 2000, vol. 138:	disorders and
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols, Edited by:	immunodeficiencies,
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,	Inflammatory and infectious
			similarly diverse range of pathologies	and C. A. Power. Humana Press	diseases, Vascular
			including inflammation, allergy, tissue	Inc., Totowa, NJ	disorders,
			rejection, viral infection, and tumor		wound 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	GeneSeq	WO9854326	Chemokines are a family of related	Chemokine activities can be	Immune disorders, cancer,
M110	Accession		small, secreted proteins	determined using assays known in	myelopoietic disorders,
protein	W82721		involved in biological processes	the art: Mehtods of Molecular	autoimmune
			ranging from hematopoiesis,	Biology, 2000, vol. 138:	disorders and
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:	immunodeficiencies,
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,	Inflammatory and infectious
			similarly diverse range of pathologies	and C. A. Power Humana Press	diseases, Vascular
			including inflammation, allergy, tissue	Inc., Totowa, NJ	disorders,
			rejection, viral infection, and tumor		wound 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	GeneSeq	W09854326	Chemokines are a family of related	Chemokine activities can be	Immune disorders, cancer,
M11A	Accession		small, secreted proteins	determined using assays known in	myelopoietic disorders,
protein	W82722		involved in biological processes	the art: Mehtods of Molecular	autoimmune
			ranging from hematopoiesis,	Biology, 2000, vol. 138:	disorders and
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:	immunodeficiencies,
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,	Inflammatory and infectious
			similarly diverse range of pathologies	and C. A. Power Humana Press	diseases, Vascular
			including inflammation, allergy, tissue	Inc., Totowa, NJ	disorders,
			rejection, viral infection, and tumor		wound 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	GeneSeq	WO9854326	Chemokines are a family of related	Chemokine activities can be	Immune disorders, cancer,
CCC3	Accession		small, secreted proteins	determined using assays known in	myelopoietic disorders,
protein	W82723		involved in biological processes	the art: Mehtods of Molecular	autoimmune
			ranging from hematopoiesis,	Biology, 2000, vol. 138:	disorders and
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:	immunodeficiencies,
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,	Inflammatory and infectious
			similarly diverse range of pathologies	and C. A. Power Humana Press	diseases, Vascular
			including inflammation, allergy, tissue	Inc., Totowa, NJ	disorders,
			rejection, viral infection, and tumor		wound 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.
A human	GeneSeq	WO9856818	Chemokines are a family of related	Chemokine activities can be	Cancer, wound healing
L105	Accession		small, secreted proteins	determined using assays known in
chemokine	W87588		involved in biological processes	the art: Mehtods of Molecular
designated			ranging from hematopoiesis,	Biology, 2000, vol. 138:
huL105_3.			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	GeneSeq	WO9856818	Chemokines are a family of related	Chemokine activities can be	Cancer, wound healing
L105	Accession		small, secreted proteins	determined using assays known in
chemokine	W87589		involved in biological processes	the art: Mehtods of Molecular
designated			ranging from hematopoiesis,	Biology, 2000, vol. 138:
huL105_7.			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	WO9848828	Chemokines are a family of related	Chemokine activities can be	Infectious diseases,
mature	Accession		small, secreted proteins	determined using assays known in	sepsis
gro-alpha	W81498		involved in biological processes	the art: Mehtods of Molecular
poly-			ranging from hematopoiesis,	Biology, 2000, vol. 138:
peptide			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
used to			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
treat			similarly diverse range of pathologies	and C. A. Power Humana Press
sepsis			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	WO9848828	Chemokines are a family of related	Chemokine activities can be	Infectious diseases,
mature	Accession		small, secreted proteins	determined using assays known in	sepsis
gro-gamma	W81500		involved in biological processes	the art: Mehtods of Molecular
poly-			ranging from hematopoiesis,	Biology, 2000, vol. 138:
peptide			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
used to			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
treat			similarly diverse range of pathologies	and C. A. Power Humana Press
sepsis			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	WO0053635	Chemokines are a family of related	Chemokine activities can be	Inflammatory disorders,
thymus	Accessions		small, secreted proteins	determined using assays known in	cancer,
expressed	B19607		involved in biological processes	the art: Mehtods of Molecular	Immune and vascular
chemokine	and		ranging from hematopoiesis,	Biology, 2000, vol. 138:	disorders
TECK and	B19608		angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
TECK			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
variant			similarly diverse range of pathologies	and C. A. Power Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	Autoimmune disorders,
chemokine	Accession		small, secreted proteins	determined using assays known in	Immune, Vascular and
SDF1alpha	B15791		involved in biological processes	the art: Mehtods of Molecular	Inflammatory disorders
			ranging from hematopoiesis,	Biology, 2000, vol. 138:
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	Autoimmune disorders,
chemokine	Accession		small, secreted proteins	determined using assays known in	Immune, Vascular and
GROalpha	B15793		involved in biological processes	the art: Methods in Molecular	Inflammatory diorders
			ranging from hematopoiesis,	Biology, 2000, vol. 138:
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
			Members of this family are involved in a	A. E. I. Proudfoot; T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	Autoimmune disorders,
chemokine	Accession		small, secreted proteins	determined using assays known in	Immune, Vascular and
eotaxin	B15794		involved in biological processes	the art: Methods in Molecular	Inflammatory disorders
			ranging from hematopoiesis,	Biology, 2000, vol. 138:
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
			Members of this family are involved in a	A. E. I. Proudfoot; T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	Autoimmune disorders,
chemokine	Accession		small, secreted proteins	determined using assays known in	Immune, Vascular and
MIG	B15803		involved in biological processes	the art: Methods in Molecular	Inflammatory disorders
			ranging from hematopoiesis,	Biology, 2000, vol. 138:
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
			Members of this family are involved in a	A. E. I. Proudfoot; T. N. C. Wells,
			similarly diverse range of pathologies	and C.A Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	Autoimmune disorders,
chemokine	Accession		small, secreted proteins	determined using assays known in	Immune, Vascular and
PF4	B15804		involved in biological processes	the art: Methods in Molecular	Inflammatory disorders
			ranging from hematopoiesis,	Biology, 2000, vol. 138:
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
			Members of this family are involved in a	A. E. I. Proudfoot; T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	Autoimmune disorders,
chemokine	Accession		small, secreted proteins	determined using assays known in	Immune, Vascular and
I-309	B15805		involved in biological processes	the art: Methods in Molecular	Inflammatory disorders
			ranging from hematopoiesis,	Biology, 2000, vol. 138:
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
			Members of this family are involved in a	A. E. I. Proudfoot; T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	Autoimmune disorders,
chemokine	Accession		small, secreted proteins	determined using assays known in	Immune, Vascular and
HCC-1	B15806		involved in biological processes	the art: Methods in Molecular	Inflammatory disorders
			ranging from hematopoiesis,	Biology, 2000, vol. 138:
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
			Members of this family are involved in a	A. E. I. Proudfoot; T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	Autoimmune disorders,
chemokine	Accession		small, secreted proteins	determined using assays known in	Immune, Vascular and
C10	B15807		involved in biological processes	the art: Methods in Molecular	Inflammatory disorders
			ranging from hematopoiesis,	Biology, 2000, vol. 138:
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
			Members of this family are involved in a	A. E. I. Proudfoot; T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	Autoimmune disorders,
chemokine	Accession		small, secreted proteins	determined using assays known in	Immune, Vascular and
CCR-2	B15808		involved in biological processes	the art: Methods in Molecular	Inflammatory disorders
			ranging from hematopoiesis,	Biology, 2000, vol. 138:
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
			Members of this family are involved in a	A. E. I. Proudfoot; T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	Autoimmune disorders,
chemokine	Accession		small, secreted proteins	determined using assays known in	Immune, Vascular and
ENA-78	B15809		involved in biological processes	the art: Methods in Molecular	Inflammatory disorders
			ranging from hematopoiesis,	Biology, 2000, vol. 138:
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
			Members of this family are involved in a	A. E. I. Proudfoot; T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	Autoimmune disorders,
chemokine	Accession		small, secreted proteins	determined using assays known in	Immune, Vascular and
GRObeta	B15810		involved in biological processes	the art: Methods in Molecular	Inflammatory disorders
			ranging from hematopoiesis,	Biology, 2000, vol. 138:
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
			Members of this family are involved in a	A. E. I. Proudfoot; T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	Autoimmune disorders,
chemokine	Accession		small, secreted proteins	determined using assays known in	Immune, Vascular and
IP-10	B15811		involved in biological processes	the art: Methods in Molecular	Inflammatory disorders
			ranging from hematopoiesis,	Biology, 2000, vol. 138:
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	Autoimmune disorders,
chemokine	Accession		small, secreted proteins	determined using assays known in	Immune, Vascular and
SDF1beta	B15812		involved in biological processes	the art: Methods in Molecular	Inflammatory disorders
			ranging from hematopoiesis,	Biology, 2000, vol. 138:
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	Autoimmune disorders,
chemokine	Accession		small, secreted proteins	determined using assays known in	Immune, Vascular and
GRO alpha	B15813		involved in biological processes	the art: Methods in Molecular	Inflammatory disorders
			ranging from hematopoiesis,	Biology, 2000, vol. 138:
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	Autoimmune disorders,
chemokine	Accession		small, secreted proteins	determined using assays known in	Immune, Vascular and
MIP1beta	B15831		involved in biological processes	the art: Methods in Molecular	Inflammatory disorders
			ranging from hematopoiesis,	Biology, 2000, vol. 138:
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	GeneSeq	U.S. Pat. No.	Chemokines are a family of related	Chemokine activities can be	Cancer
C-C	Accession	6,096,300	small, secreted proteins	determined using assays known in
chemokine	B07939		involved in biological processes	the art: Methods in Molecular
designated			ranging from hematopoiesis,	Biology, 2000, vol. 138:
exodus			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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.	Chemokines are a family of related	Chemokine activities can be	Chemotaxis, Gene Therapy,
chemokine	Accession	6,084,071	small, secreted proteins	determined using assays known in	Wound healing
L105_7	Y96922		involved in biological processes	the art: Methods in Molecular
			ranging from hematopoiesis,	Biology, 2000, vol. 138:
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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.	Chemokines are a family of related	Chemokine activities can be	Chemotaxis, Gene Therapy,
chemokine	Accession	6,084,071	small, secreted proteins	determined using assays known in	Wound healing
L105_3	Y96923		involved in biological processes	the art: Methods in Molecular
			ranging from hematopoiesis,	Biology, 2000, vol. 138:
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	WO0038706	Chemokines are a family of related	Chemokine activities can be	Cancer, Vascular and Immune
secondary	Accession		small, secreted proteins	determined using assays known in	disorders
lymphoid	B01434		involved in biological processes	the art: Methods in Molecular
chemokine			ranging from hematopoiesis,	Biology, 2000, vol. 138:
(SLC)			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	WO0029439	Chemokines are a family of related	Chemokine activities can be	Immune and Inflammatory
non-ELR	Accession		small, secreted proteins	determined using assays known in	disorders, Cancer, Haemostatic
CXC	Y96310		involved in biological processes	the art: Methods in Molecular	and thrombolytic
chemokine			ranging from hematopoiesis,	Biology, 2000, vol. 138:	activity
H174			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	WO0029439	Chemokines are a family of related	Chemokine activities can be	Immune and Inflammatory
non-ELR	Accession		small, secreted proteins	determined using assays known in	disorders, Cancer, haemostatic
CXC	Y96311		involved in biological processes	the art: Methods in Molecular	and thrombolytic activity
chemokine			ranging from hematopoiesis,	Biology, 2000, vol. 138:
IP10			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	WO0029439	Chemokines are a family of related	Chemokine activities can be	Immune and Inflammatory
non-ELR	Accession		small, secreted proteins	determined using assays known in	disorders, Cancer, haemostatic
CXC	Y96313		involved in biological processes	the art: Methods in Molecular	and thrombolytic activity
chemokine			ranging from hematopoiesis,	Biology, 2000, vol. 138:
Mig			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	Chemokine activities can be	Cancer, wound healing,
chemokine	Accession		small, secreted proteins	determined using assays known in	inflammatory and
Ckbeta-7	Y96280		involved in biological processes	the art: Methods in Molecular	immunoregulatory
			ranging from hematopoiesis,	Biology, 2000, vol. 138:	disorders
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	Chemokine activities can be	Cancer, wound healing,
chemokine	Accession		small, secreted proteins	determined using assays known in	inflammatory and
MIP-1alpha	Y96281		involved in biological processes	the art: Methods in Molecular	immunoregulatory
			ranging from hematopoiesis,	Biology, 2000, vol. 138:	disorders
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	GenSeq	WO0028035	Chemokines are a family of related	Chemokine activities can be	Cancer, wound healing,
mature	Accession		small, secreted proteins	determined using assays known in	inflammatory and
chemokine	Y96282		involved in biological processes	the art: Methods in Molecular	immunoregulatory
Ckbeta-7			ranging from hematopoiesis,	Biology, 2000, vol. 138:	disorders
(optionally			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
truncated)			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	Chemokine activities can be	Soluble CXCR3 polypeptides
chemokine	Accession		small, secreted proteins	determined using assays known in	may be useful for inhibiting
receptor	Y79372		involved in biological processes	the art: Methods in Molecular	chemokine activities and viral
CXCR3			ranging from hematopoiesis,	Biology, 2000, vol. 138:	infection.
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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.	Chemokines are a family of related	Chemokine activities can be	Neurological disorders,
neuro-	Accession	6,043,086	small, secreted proteins	determined using assays known in	Immune and respiratory
tactin	Y53259		involved in biological processes	the art: Methods in Molecular	disorders
chemokine			ranging from hematopoiesis,	Biology, 2000, vol. 138:
like			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
domain			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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	JP11302298	Chemokines are a family of related	Chemokine activities can be	Cancer and infectious
CC type	Accession		small, secreted proteins	determined using assays known in	diseases
chemokine	Y57771		involved in biological processes	the art: Methods in Molecular
inter-			ranging from hematopoiesis,	Biology, 2000, vol. 138:
leukin C			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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.	Chemokines are a family of related	Chemokine activities can be	Cancer, Auto-immune and
CKbeta-9	Accession	6,153,441	small, secreted proteins	determined using assays known in	inflammatory disorders,
	B50860		involved in biological processes	the art: Methods in Molecular	Cardiovascular disorders
			ranging from hematopoiesis,	Biology, 2000, vol. 138:
			angiogenesis, and leukocyte trafficking.	Chemokine Protocols. Edited by:
			Members of this family are involved in a	A. E. I. Proudfoot, T. N. C. Wells,
			similarly diverse range of pathologies	and C. A. Power. Humana Press
			including inflammation, allergy, tissue	Inc., Totowa, NJ
			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
Prepro-	GeneSeq	WO9637608	Apoa-1 participates in the reverse	Lipid binding activity can be	Useful for cardiovascular
apolipo-	Accession		transport of cholesterol from tissues	determined using assays known in	disorders, cholesterol
protein	W08602		to the liver for excretion by	the art, such as, for example, the	disorders, and
“paris”			promoting cholesterol efflux	Cholesterol Efflux Assays of	Hyperlipidaemia
variant			from tissues and by acting as a	Takahaski et al., P.N.A.S., Vol. 96,
			cofactor for the lecithin cholesterol	Issue	20, 11358-11363, Sep.
			acyltransferase (lcat).	28, 1999.
Prepro-		5,721,114	Apoa-1 participates in the reverse	Lipid binding activity can be	Useful for cardiovascular
apolipo-			transport of cholesterol from tissues	determined using assays known in	disorders, cholesterol
protein			to the liver for excretion by	the art, such as, for example, the	disorders, and
“milano”			promoting cholesterol efflux	Cholesterol Efflux Assays of	Hyperlipidaemia
variant			from tissues and by acting as a	Takahaski et al., P.N.A.S., Vol. 96,
			cofactor for the lecithin cholesterol	Issue	20, 11358-11363, Sep.
			acyltransferase (lcat).	28, 1999.
Glyco-	GeneSeq	WO9628169	Naturally produced female	Glycodelin-A activity can be	Naturally derived
delin-A;	Accession		contraceptive that is removed	determined using the hemizona	contraceptive useful for the
Pro-	W00289		rapidly from the body	assay as described in Oehninger, S.,	prevention of pregnancy.
gesterone-			following 2-3 days production.	Coddington, C. C., Hodgen, G. D., and
associated			Uses include contraception	Seppala, M (1995) Fertil.
endometrial				Steril. 63, 377-383.
protein
NOGO-A	Genbank		NOGO polypeptides are potent	Inhibition of Neurite outgrowth.	NOGO-A polypeptide
	Accession		inhibitors of neurite growth.	Antagonists to NOGO polypeptides	antagonists are useful for the
	CAB99248			may promote the outgrowth of	promotion of neural growth,
				neurites, thus inducing	which could be useful in the
				regeneration of neurons.	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	Inhibition of Neurite outgrowth.	NOGO-B polypeptide
	Accession		inhibitors of neurite growth.	Antagonists to NOGO polypeptides	antagonists are useful for the
	CAB99249			may promote the outgrowth of	promotion of neural growth,
				neurites, thus inducing	which could be useful in the
				regeneration of neurons.	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	Inhibition of Neurite outgrowth.	NOGO-C polypeptide
	Accession		inhibitors of neurite growth.	Antagonists to NOGO polypeptides	antagonists are useful for the
	CAB99250			may promote the outgrowth of	promotion of neural growth,
				neurites, thus inducing	which could be useful in the
				regeneration of neurons.	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	Inhibition of Neurite outgrowth by	NOGO-66 receptor
Receptor	Accession		inhibitors of neurite growth,	mediating the biological effects of	polypeptides are useful for the
	AAG53612		and are thought to mediate	NOGO polypeptides. Soluble	promotion of neural growth,
			their effects through the NOGO-66	NOGO-66 receptor polypeptides	which could be useful in the
			Receptor.	may promote the outgrowth of	treatment of neural disorders
				neurites, thus inducing	and dysfunction due to
				regeneration of neurons.	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		U.S. Pat. No.	These antibodies are useful for the	Collapsin activity, which is thought	Useful for the promotion of
specific		5,416,197	promotion of neurite outgrowth	to inhibit the outgrowth of neurites,	neural growth, which could be
for				can be assayed in the presence of	useful in the treatment of
collapsin				antibodies specific for collapsing	neural disorders and
				using assays known in the art, such	dysfunction due to
				as, for example, the collapse assay	degenerative diseases or
				disclosed by Luo et al., Cell 1993	trauma.
				Oct. 22; 75(2): 217-27
Humanized		WO9845331	These agents have anti-inflammatory	VEGF activity can be determined	Promotion of growth and
Anti-			and anti-cancer applications	using assays known in the art, such	proliferation of cells, such as
VEGF				as those disclosed in International	vascular endothelial cells.
Antibodies,				Publication No. WO0045835, for	Antagonists may be useful as
and				example.	anti-angiogenic agents, and
fragments					may be applicable for cancer
thereof
Humanized		WO0029584	These agents have anti-inflammatory	VEGF activity can be determined	Promotion of growth and
Anti-			and anti-cancer applications	using assays known in the art, such	proliferation of cells, such as
VEGF				as those disclosed in International	vascular endothelial cells.
Antibodies,				Publication No. WO0045835, for	Antagonists may be useful as
and				example.	anti-angiogenic agents, and
fragments					may be applicable for cancer
thereof
Membrane	GeneSeq.	WO9963088	Cancer, Immune Disorders	These proteins can be used for	Activities can be determined
bound	Accession			linking bioactive molecules to cells	using assay known in the art,
proteins	Y66631-			and for modulating biological	such as, for example, the
	Y66765			activities of cells, using the	assays disclosed in
				polypeptides for specific targeting.	International Publication No.
				The polypeptide targeting can be	WO0121658.
				used to kill the target cells, e.g. for
				the treatment of cancers. These
				proteins are useful for the treatment
				of immune system disorders.
Secreted	GenSeq	WO0053756	Cancer, Immune Disorders	These proteins can be used for	Activities can be determined
and	Accession			linking bioactive molecules to cells	using assay known in the art,
Trans-	B44241-			and for modulating biological	such as, for example, the
membrane	B44334			activities of cells, using the	assays disclosed in
poly-				polypeptides for specific targeting.	International Publication No.
peptides				The polypeptide targeting can be	WO0121658
				used to kill the target cells, e.g. for
				the treatment of cancers. These
				proteins are useful for the treatment
				of immune system disorders.
Secreted	GeneSeq	WO9946281	Cancer, Immune Disorders	These proteins can be used for	Activities can be determined
and	Accession			linking bioactive molecules to cells	using assay known in the art,
Trans-	Y41685-			and for modulating biological	such as, for example, the
membrane	Y41774			activities of cells, using the	assays disclosed in
poly-				polypeptides for specific targeting.	International Publication No.
peptides				The polypeptide targeting can be	WO0121658
				used to kill the target cells, e.g. for
				the treatment of cancers. These
				proteins are 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 SV₄₀early 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-ELF 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-ELF 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, re/A1, lac[F′, proAB, /αcI^qZΔM15, Tn10 (Tet^r)] (Stratagene La Jolla, Calif.). pUC19 (NEB, Beverly, Mass.) was used as the cloning vector for the ELP construction (Meyer and Chilkoti, Nat. Biotechnol., 17(11):1112-5, 1999). Modified forms of pET15b and pET24d vectors (Novagen) were used to express ELP and ELP-fusion proteins in BL21 Star (DE3) strain (F⁻, ompT, hsdS_B(r_B ⁻m_B ⁻), gal, dcm, me131, (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] PfIMI/BgII fragment from pUC19-ELP1 [V₅A₂G₃-10] into pUC19-ELP1 [V₅A₂G₃-10] linearized with PfIMI 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] PfIMI/BgII fragments respectively into PfIMI digested pUC 19-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] Pf1M1/BgI1 fragment from pUC19-ELP1 [K₁V₂F₁-4] into pUC19-ELP1 [K₁V₂F₁-4] linearized with Pf/M1 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 [K₁V₂F₁-I6], 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 PfIMI and HindIII compatible ends. The ELP1 [K₁V₇F₁-9] DNA segment was than ligated into PfIM1/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 AVGVP.
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], pUC 19-ELP2 [60] and pUC 19-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 PfIM1/BgII 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 PfIMI. 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-SaII-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 PfIMI and BgII, 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 PfIMI and BgII, 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 PfIMI and BgII, 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 PfIMI and BgII, 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 PfIMI and BgII, 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 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-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

k₁	k₂	k_e	V_d	AUC	Cl_B
(hr⁻¹)	(hr⁻¹)	(hr⁻¹)	(μL)	(mg 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 in 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-[V₁A₆G₇-160]
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 8x with a final (C-terminal) 10-unit repeat where X is a V, G, A and Win 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, 6, 10}G_{2, 7, 9}A_{3, 8})₈(V_{1, 4, 5, 6}G_{2, 7, 9}A_{3, 8}W₁₀)].
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 contructs, 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 8x 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 T_1/2when 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 an insulin A chain and an insulin B chain joined by one or more disulfide bonds and produced by peptidase processing of proinsulin, wherein said insulin A chain is a recombinant fusion protein with an elastin-like peptide (ELP) comprising 120 repeats of VPGXG (SEQ ID NO: 3), where X is V, G, or A at a ratio of 5:3:2.

102. The therapeutic agent of claim 101, wherein the insulin A chain amino acid sequence is positioned at the N-terminal end of the ELP.

103. The therapeutic agent of claim 101, wherein the Insulin A chain is SEQ ID NO: 15.

104. The therapeutic agent of claim 101, wherein the Insulin B chain is SEQ ID NO: 16.

105. The therapeutic agent of claim 101, wherein the Insulin A chain is SEQ ID NO: 15 and the Insulin B chain is SEQ ID NO: 16.

106. The therapeutic agent of claim 101, wherein the insulin A chain sequence comprises an amino acid sequence having about 5 amino acid insertions, deletions, and/or substitutions relative to SEQ ID NO: 15 and the insulin B chain sequence comprises an amino acid sequence having about 1 to 10 amino acid insertions, deletions, and/or substitutions relative to SEQ ID NO: 16.

107. The therapeutic agent of claim 101, wherein the therapeutic agent is formulated with a pharmaceutically acceptable carrier and/or excipient.

108. The therapeutic agent of claim 107, wherein the therapeutic agent is formulated for parenteral administration.

109. A therapeutic agent comprising the amino acid sequences of SEQ ID NOs: 15 and 16 united by one or more disulfide bonds and produced by peptidase processing of proinsulin,

wherein the amino acid sequence of SEQ ID NO: 15 is a recombinant fusion protein with an elastin-like peptide (ELP) comprising 120 repeats of VPGXG (SEQ ID NO: 3), where each X is V, G, or A at a ratio of 5:3:2.

110. The therapeutic agent of claim 109, wherein the amino acid sequence of SEQ ID NO: 15 is positioned at the N-terminal side of the ELP.

111. The therapeutic agent of claim 109, wherein the therapeutic agent is formulated with a pharmaceutically acceptable carrier and/or excipient.

112. The therapeutic agent of claim 109 wherein the peptidase processing comprises trypsin processing and carboxypeptidase B processing.

113. The therapeutic agent of claim 111, wherein the therapeutic agent is formulated for parenteral administration.