# Patent

## Title
Therapeutic agents comprising insulin and elastin-like peptides

## 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 persistence in the body, solubility, and bioavailability.

## Background
PRIORITY
This application claims priority to U.S. application Ser. No. 13/445,979, filed Apr. 13, 2012, which is a continuation of U.S. application Ser. No. 12/493,912, filed Jun. 29, 2009 (now U.S. Pat. No. 8,178,495), which claims priority to U.S. Provisional Application No. 61/076,221, filed Jun. 27, 2008, which are hereby incorporated by reference in their entireties.


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—04US_SubSeqList.txt, date recorded: Nov. 6, 2012, 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 persistence 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 proteinaceous 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, persistence, 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 proteinaceous 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.
FIGS. 2A-B illustrate an exendin-4/ELP fusion. 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).
FIGS. 3A-B illustrate exendin-4 constructs having an N-terminal Tev cleavage site. 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).
FIGS. 4A-B illustrate an exendin-4 construct with a DsbA leader sequence. 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.
FIGS. 5A-B illustrate a GLP-1/ELP fusion. 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).
FIGS. 6A-B illustrate a GLP-1/ELP fusion. 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).
FIGS. 7A-B illustrate a Factor VII/ELP fusion. 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).
FIGS. 8A-B illustrate an insulin/ELP fusion. 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 T1/2 of 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 T1/2 of about 12.9 hours when administered by i.v. to rats, and a T1/2 of 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 subcutaneously.
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, Cα-methyl amino acids; Nα-methyl amino acids, and amino acid analogs in general.
Selection of X is independent in each ELP structural unit (e.g., for each structural unit defined herein having a guest residue X). For example, X may be independently selected for each structural unit as an amino acid having a positively charged side chain, an amino acid having a negatively charged side chain, or an amino acid having a neutral side chain, including in some embodiments, a hydrophobic side chain.
In still other embodiments, the ELP component(s) may include polymeric or oligomeric repeats of the pentapeptides VPGXG (SEQ ID NO:3), IPGXG (SEQ ID NO:5) or LPGXG (SEQ ID NO:7), or a combination thereof, where X is as defined above.
In each embodiment, the structural units, or in some cases polymeric or oligomeric repeats, of the ELP sequences may be separated by one or more amino acid residues that do not eliminate the overall effect of the molecule, that is, in imparting certain improvements to the therapeutic component as described. In certain embodiments, such one or more amino acids also do not eliminate or substantially affect the phase transition properties of the ELP component (relative to the deletion of such one or more amino acids).
In each repeat, X is independently selected. The structure of the resulting ELP components may be described using the notation ELPk [XiYj-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+M2X2 where X is the MW of the fusion protein, and M0=116.21; M1=−1.7499; M2=0.010349.
While the Tt of the ELP component, and therefore of the ELP component coupled to a therapeutic component, is affected by the identity and hydrophobicity of the guest residue, X, additional properties of the molecule may also be affected. Such properties include, but are not limited to solubility, bioavailability, persistence, and half-life of the molecule.
As described in PCT/US2007/077767 (published as WO 2008/030968), which is hereby incorporated by reference in its entirety, the ELP-coupled therapeutic component can retain the therapeutic component's biological activity. Additionally, ELPs themselves can exhibit long half-lives. Therefore, ELP components in accordance with the present invention substantially increase (e.g. by greater than 10%, 20%, 30%, 50%, 100%, 200%, 500% or more, in specific embodiments) the half-life of the therapeutic component when conjugated thereto. Such half-life (or in some embodiments persistence or rate of clearance) is determined in comparison to the half-life of the free (unconjugated or unfused) form of the therapeutic component. Furthermore, ELPs may target high blood content organs, when administered in vivo, and thus, can partition in the body, to provide a predetermined desired corporeal distribution among various organs or regions of the body, or a desired selectivity or targeting of a therapeutic agent. In sum, the therapeutic agents contemplated by the invention are administered or generated in vivo as active compositions having extended half-lives (e.g., circulatory half-life), among other potential benefits described herein.
The invention thus provides various agents for therapeutic (in vivo) application, where the therapeutic component is biologically active. Such therapeutic components include those listed in Table 1 (e.g., full length or functional portions or functional analogs thereof), as well as GLP-1 receptor agonists such as GLP-1 or exendin-4, insulin, or Factor VII/VIIa, and functional analogs thereof. The structure and activity of such therapeutic components are described in detail below. In some forms of the therapeutic agent, the coupling of the therapeutic component to the ELP component is effected by direct covalent bonding or indirect (through appropriate spacer groups) bonding (as described elsewhere herein). Further, the therapeutic component(s) and the ELP component(s) can be structurally arranged in any suitable manner involving such direct or indirect covalent bonding, relative to one another.
Glucagon-Like Peptide (GLP)-1 Receptor Agonists
In certain embodiments of the invention, the therapeutic agent comprises an ELP component fused or conjugated to a GLP-1 receptor agonist, such as GLP-1, exendin-4, or functional analogs thereof.
Human GLP-1 is a 37 amino acid residue peptide originating from preproglucagon which is synthesized in the L-cells in the distal ileum, in the pancreas, and in the brain. Processing of preproglucagon to give GLP-1 (7-36)amide, GLP-1 (7-37) and GLP-2 occurs mainly in the L-cells. A simple system is used to describe fragments and analogs of this peptide. For example, Gly8-GLP-1 (7-37) designates a fragment of GLP-1 formally derived from GLP-1 by deleting the amino acid residues Nos. 1 to 6 and substituting the naturally occurring amino acid residue in position 8 (Ala) by Gly. Similarly, Lys34 (Nε-tetradecanoyl)-GLP-1(7-37) designates GLP-1 (7-37) wherein the ε-amino group of the Lys residue in position 34 has been tetradecanoylated. Where reference in this text is made to C-terminally extended GLP-1 analogues, the amino acid residue in position 38 is Arg unless otherwise indicated, the optional amino acid residue in position 39 is also Arg unless otherwise indicated and the optional amino acid residue in position 40 is Asp unless otherwise indicated. Also, if a C-terminally extended analogue extends to position 41, 42, 43, 44 or 45, the amino acid sequence of this extension is as in the corresponding sequence in human preproglucagon unless otherwise indicated.
The parent peptide of GLP-1, proglucagon (PG), has several cleavage sites that produce various peptide products dependent on the tissue of origin including glucagon (PG[32-62]) and GLP-1[7-36]NH2 (PG[72-107]) in the pancreas, and GLP-1[7-37] (PG[78-108]) and GLP-1[7-36]NH2 (PG[78-107]) in the L cells of the intestine where GLP-1[7-36]NH2 (78-107 PG) is the major product. The GLP-1 component in accordance with the invention may be any biologically active product or derivative of proglocagon, or functional analog thereof, including: GLP-1 (1-35), GLP-1(1-36), GLP-1 (1-36)amide, GLP-1 (1-37), GLP-1 (1-38), GLP-1 (1-39), GLP-1 (1-40), GLP-1 (1-41), GLP-1 (7-35), GLP-1 (7-36), GLP-1 (7-36)amide, GLP-1 (7-37), GLP-1 (7-38), GLP-1 (7-39), GLP-1 (7-40) and GLP-1 (7-41), or a analog of the foregoing. Generally, the GLP-1 component in some embodiments may be expressed as GLP-1 (A-B), where A is an integer from 1 to 7 and B is an integer from 38 to 45, optionally with one or more amino acid substitutions as defined below.
As an overview, after processing in the intestinal L-cells, GLP-1 is released into the circulation, most notably in response to a meal. The plasma concentration of GLP-1 rises from a fasting level of approximately 15 pmol/L to a peak postprandial level of 40 pmol/L. For a given rise in plasma glucose concentration, the increase in plasma insulin is approximately threefold greater when glucose is administered orally compared with intravenously (Kreymann 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 at al., 1993, Dig Dis Sci 38: 665-73) and may enhance peripheral glucose disposal (D'Alessio at al., 1994, J. Clin Invest 93: 2293-6).
A combination of actions gives GLP-1 unique therapeutic advantages over other agents currently used to treat non-insulin-dependent diabetes mellitus (NIDDM). First, a single subcutaneous dose of GLP-1 can completely normalize post prandial glucose levels in patients with NIDDM (Gutniak at 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 at al., 1996, Diabetes Care 19:580-6).
GLP-1 is, however, metabolically unstable, having a plasma half-life (t1/2) 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]NH2 has the following amino acid sequence: HAEGTFTSDVSSYLEGQAAKEFIAWLVKGR (SEQ ID NO: 13), which may be employed as the GLP-1 component in accordance with the invention. Alternatively, the GLP-1 component may contain glycine (G) at the second position, giving, for example, the sequence HGEGTFTSDVSSYLEGQAAKEFIAWLVKGR (SEQ ID NO: 17). The GLP-1 component may be a biologically active fragment of GLP-1, for example, as disclosed in US 2007/0041951, which is hereby incorporated by reference in its entirety. Other fragments and modified sequences of GLP-1 are known in the art (U.S. Pat. No. 5,614,492; U.S. Pat. No. 5,545,618; European Patent Application, Publication No. EP 0658568 A1; WO 93/25579, which are hereby incorporated by reference in their entireties). Such fragments and modified sequences may be used in connection with the present invention, as well as those described below.
Certain structural and functional analogs of GLP-1 have been isolated from the venom of the Gila monster lizards (Heloderma suspectum and Heloderma horridum) and have shown clinical utility. Such molecules find use in accordance with the present invention. In particular, exendin-4 is a 39 amino acid residue peptide isolated from the venom of Heloderma suspectum and shares approximately 52% homology with human GLP-1. Exendin-4 is a potent GLP-1 receptor agonist that stimulates insulin release, thereby lowering blood glucose levels. Exendin-4 has the following amino acid sequence: HGEGTFTSDLSKQMEEEAVRLFEWLKNGGPSSGAPPPS (SEQ ID NO: 14). A synthetic version of exendin-4 known as exenatide (marketed as Byetta®) has been approved for the treatment of Type-2 Diabetes. Although exenatide is structurally analogous to native GLP-1, it has a longer half-life after injection.
While exenatide has the ability to lower blood glucose levels on its own, it can also be combined with other medications such as metformin, a thiozolidinedione, a sulfonylureas, and/or insulin to improve glucose control. Exenatide is administered by injection subcutaneously twice per day using a pre-filled pen device. Typical human responses to exenatide include improvements in the initial rapid release of endogenous insulin, an increase in β-cell growth and replication, suppression of pancreatic glucagon release, delayed gastric emptying, and reduced appetite—all of which function to lower blood glucose. Unlike sulfonylureas and meglitinides, exenatide increases insulin synthesis and secretion in the presence of glucose only, thus lessening the risk of hypoglycemia. Despite the therapeutic utility of exenatide, it has certain undesirable traits, including the requirement of twice daily injections, gastrointestinal side effects, and similar to native GLP-1, a relatively short half-life (i.e. approximately 2 hr).
Various functional analogs of GLP-1 and exendin-4 are, known, and which find use in accordance with the invention. These include liraglutide (Novo Nordisk, WO98/008871), R1583/taspoglutide (Roche, WO00/034331), CJC-1131 (ConjuChem, WO00/069911), ZP-10/AVE0010 (Zealand Pharma, Sanofi-Aventis, WO01/004156), and LY548806 (Eli Lilly, WO03/018516).
Liraglutide, also known as NN2211, is a GLP-1 receptor agonist analog that has been designed for once-daily injection (Harder et al., 2004, Diabetes Care 27: 1915-21). Liraglutide has been tested in patients with type-2 diabetes in a number of studies and has been shown to be effective over a variety of durations. In one study, treatment with liraglutide improved glycemic control, improved β-cell function, and reduced endogenous glucose release in patients with type-2 diabetes after one week of treatment (Degn et al., 2004, Diabetes 53: 1187-94). In a similar study, eight weeks of 0.6-mg liraglutide therapy significantly improved glycemic control without increasing weight in subjects with type 2 diabetes compared with those on placebo (Harder et al., 2004, Diabetes Care 27: 1915-21).
Thus, in certain embodiments, the GLP-1 receptor agonist in accordance with the invention is as described in WO98/008871, which is hereby incorporated by reference in its entirety. The GLP-1 receptor agonist may have at least one lipophilic substituent, in addition to one, two, or more amino acid substitutions with respect to native GLP-1. For example, the lipophilic substituent may be an acyl group selected from CH3(CH2)nCO—, wherein n is an integer from 4 to 38, such as an integer from 4 to 24. The lipophilic substituent may be an acyl group of a straight-chain or branched alkyl or fatty acid (for example, as described in WO98/008871, which description is hereby incorporated by reference).
In certain embodiments, the GLP-1 component is Arg26-GLP-1 (7-37), Arg34-GLP-1(7-37), Lys36-GLP-1 (7-37), Arg26,34Lys36-GLP-I (7-37), Arg26,34Lys38-GLP-I (7-38), Arg28,34Lys39-GLP-1 (7-39), Arg26,34Lys40-GLP-1(7-40), Arg26Lys36-GLP-1(7-37), Arg34Lys36-GLP-1(7-37), Arg26Lys39-GLP-1(7-39), Arg34Lys40-GLP-1(7-40), Arg26,34Lys36,39-GLP-I (7-39), Arg26,34Lys36,40-GLP-1(7-40), Gly8Arg26-GLP-1(7-37); Gly8Arg34-GLP-1(7-37); Gly8Lys38-GLP-1(7-37); Gly8Arg26,34Lys36-GLP-1(7-37), Gly8Arg26,34Lys39-GLP-1(7-39), Gly8Arg26,34Lys40-GLP-1(7-40), Gly8Arg26Lys36-GLP-1(7-37), Gly8Arg34Lys36-GLP-1(7-37), Gly8Arg26Lys39-GLP-1(7-39); Gly8Arg34Lys40-GLP-1(7-40), Gly8Arg28,34Lys36,39-GLP-1(7-39) and Gly8Arg26,34Lys35,40-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 [Aib8,35]hGLP-1(7-36)NH2 (e.g. taspoglutide), wherein Aib is alpha-aminoisobutyric acid.
CJC-1131 is a GLP-1 analog that consists of a DPP-IV-resistant form of GLP-1 joined to a reactive chemical linker group that allows GLP-1 to form a covalent and irreversible bond with serum albumin following subcutaneous injection (Kim et al., 2003, Diabetes 52: 751-9). In a 12-week, randomized, double-blind, placebo-controlled multicenter study, CJC-1131 and metformin treatment was effective in reducing fasting blood glucose levels in type 2 diabetes patients (Ratner et al., Abstract No. 10-OR, Jun. 10-14, 2005, 65th American Diabetes Association Meeting, San Francisco, Calif.).
Thus, in certain embodiments, the GLP-1 receptor agonist is as described in WO00/069911, which is hereby incorporated by reference in its entirety. In some embodiments, the GLP-1 receptor agonist is modified with a reactive group which reacts with amino groups, hydroxyl groups or thiol groups on blood components to form a stable covalent bond. In certain embodiments, the GLP-1 receptor agonist is modified with a reactive group selected from the group consisting of succinimidyl and maleimido groups. In certain exemplary embodiments, the GLP-1 receptor agonist has the sequence/structure: D-Ala8Lys37-(2-(2-(2-maleimidopropionamido(ethoxy)ethoxy)acetamide))-GLP-1(7-37) (e.g. CJC-1131).
AVE0010, also known as ZP-10, is a GLP-1 receptor agonist that may be employed in connection with the invention. In a recent double-blind study, patients treated with once daily dosing of AVE0010 demonstrated significant reductions in HbA1c levels (Ratner et al., Abstract No. 433-P, 68th American Diabetes Association Meeting, San Francisco, Calif.). At the conclusion of the study, the percentages of patients with HbA1c<7% ranged from 47-69% for once daily dosing compared to 32% for placebo. In addition, AVE0010 treated patients showed dose-dependent reductions in weight and post-prandial plasma glucose.
Thus, in certain embodiments, the GLP-1 receptor agonist is as described in WO01/004156, which is hereby incorporated by reference in its entirety. For example, the GLP-1 receptor agonist may have the sequence: HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPSKKKKKK-NH2 (SEQ ID NO: 18) (e.g. AVE0010).
LY548806 is a GLP-1 derivative designed to be resistant to proteolysis by dipeptidase-peptidyl IV (DPP-IV) (Jackson et al., Abstract No. 562, Jun. 10-14, 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 at 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 at 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 His7 of 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, at 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 at 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 at 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 HbA1c. 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 praline with lysine at position 28 and the substitution of lysine with praline at position 29 of the insulin B chain. Although these modifications do not alter receptor binding, they help to block the formation of insulin dimers and hexamers, allowing for larger amounts of active monomeric insulin to be available for postprandial injections.
In another embodiment, the insulin may contain an A and/or B chain of aspart (also known as Novolog, Novo Nordisk). Insulin aspart is designed with the single replacement of the amino acid praline by aspartic acid at position 28 of the human insulin B chain. This modification helps block the formation for insulin hexamers, creating a faster acting insulin.
In yet another embodiment, the insulin may contain an A and/or B chain of glulisine (also known as Apidra, Sanofi-Aventis). Insulin glulisine is a short acting analog created by substitution of asparagine at position 3 by lysine and lysine at position 29 by glutamine of human insulin B chain. Insulin glulisine has more rapid onset of action and shorter duration of action compared to regular human insulin.
In another embodiment, the insulin may contain an A and/or B chain of glargine (also known as Lantus, Sanofi-Aventis). Insulin glargine differs from human insulin in that the amino acid asparagine at position 21 of the A chain is replaced by glycine and two arginines are added to the C-terminus of the B-chain. Compared with bedtime neutral protamine Hagedorn (NPH) insulin (an intermediate acting insulin), insulin glargine is associated with less nocturnal hypoglycemia in patients with type 2 diabetes.
In yet another embodiment, the insulin may contain an A and/or B chain from detemir (also known as Levemir, Novo Nordisk). Insulin detemir is a soluble (at neutral pH) long-acting insulin analog, in which the amino acid threonine at B30 is removed and a 14-carbon, myristoyl fatty acid is acetylated to the epsilon-amino group of LysB29. After subcutaneous injection, detemir dissociates, thereby exposing the free fatty acid which enables reversible binding to albumin molecules. So at steady state, the concentration of free unbound insulin is greatly reduced resulting in stable plasma glucose levels.
In some embodiments, the insulin may be a single-chain insulin analog (SIA) (e.g. as described in U.S. Pat. No. 6,630,438 and WO08/019,368, which are hereby incorporated by reference in their entirety). Single-chain insulin analogs encompass a group of structurally-related proteins wherein the A and B chains are covalently linked by a polypeptide linker. The polypeptide linker connects the C-terminus of the B chain to the N-terminus of the A chain. The linker may be of any length so long as the linker provides the structural conformation necessary for the SIA to have a glucose uptake and insulin receptor binding effect. In some embodiments, the linker is about 5-18 amino acids in length. In other embodiments, the linker is about 9-15 amino acids in length. In certain embodiments, the linker is about 12 amino acids long. In certain exemplary embodiments, the linker has the sequence KDDNPNLPRLVR (SEQ ID NO.: 20) or GAGSSSRRAPQT (SEQ ID NO.: 21). However, it should be understood that many variations of this sequence are possible such as in the length (both addition and deletion) and substitutions of amino acids without substantially compromising the effectiveness of the produced SIA in glucose uptake and insulin receptor binding activities. For example, several different amino acid residues may be added or removed from either end without substantially decreasing the activity of the produced SIA.
An exemplary single-chain insulin analog currently in clinical development is albulin (Duttaroy et al., 2005, Diabetes 54: 251-8). Albulin can be produced in yeast or in mammalian cells. It consists of the B and A chain of human insulin (100% identity to native human insulin) linked together by a dodecapeptide linker and fused to the NH2 terminals 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 NH2 terminus of mature HSA, contained within a pSAC35 vector for expression in yeast. In accordance with the present invention, the HSA component of abulia may be replaced with an ELP component as described herein.
Thus, in one aspect, the present invention provides therapeutic agents comprising an elastin-like peptide (ELP) and an insulin or functional analog thereof. For example, in certain embodiments, the insulin is a mammalian insulin, such as human insulin or porcine insulin. In accordance with the invention, the ELP component may be coupled (e.g., via recombinant fusion or chemical conjugation) to the insulin A chain, or B chain, or both. The insulin may comprise each of chains A, B, and C (SEQ ID NOS: 51 and 52), or may contain a processed form, containing only chains A and B. In some embodiments, chains A and B are connected by a short linking peptide, to create a single chain insulin. The insulin may be a functional analog of human insulin, including functional fragments truncated at the N-terminus and/or C-terminus (of either or both of chains A and B) by from 1 to 10 amino acids, including by 1, 2, 3, or about 5 amino acids. Functional analogs may contain from 1 to 10 amino acid insertions, deletions, and/or substitutions (collectively) with respect to the native sequence (e.g., SEQ ID NOS 15 and 16), and in each case retaining the activity of the peptide. For example, functional analogs may have 1, 2, 3, 4, or 5 amino acid insertions, deletions, and/or substitutions (collectively) with respect to the native sequence (which may contain chains A and B, or chains A, B, and C). Such activity may be confirmed or assayed using any available assay, including those described herein. In these or other embodiments, the insulin component has at least about 75%, 80%, 85%, 90%, 95%, or 98% identity with each of the native sequences for chains A and B (SEQ ID NOS:15 and 16). The determination of sequence identity between two sequences (e.g., between a native sequence and a functional analog) can be accomplished using any alignment tool, including Tatusova et al., Blast 2 sequences—a new tool for comparing protein and nucleotide sequences, FEMS Microbiol Lett. 174:247-250 (1999). The insulin component may contain additional chemical modifications known in the art.
In another aspect, the present invention provides methods for the treatment or prevention of diabetes, including type I and II diabetes. The method comprises administering an effective amount of the therapeutic agent comprising an elastin-like peptide (ELP) component and an insulin (or functional analog thereof) component to a patient in need thereof. Generally, the patient may be a human or non-human animal (e.g., dog, cat, cow, or horse) patient. Preferably, the patient is human.
To characterize the in vitro binding properties of an insulin analog or an ELP-containing insulin analog, competition binding assays may be performed in various cell lines that express the insulin receptor (Jehle et al., 1996, Diabetologia 39: 421-432). For example, competition binding assays using CHO cells overexpressing the human insulin receptor may be employed. Insulin can also bind to the IGF-1 receptor with a lower affinity than the insulin receptor. To determine the binding affinity of an ELP-containing insulin analog, a competition binding assay can be performed using 125I-labeled IGF-1 in L6 cells.
The activities of insulin include stimulation of peripheral glucose disposal and inhibition of hepatic glucose production. The ability of an ELP-containing insulin analog to mediate these biological activities can be assayed in vitro using known methodologies. For example, the effect of an ELP-containing analog on glucose uptake in 3T3-L1 adipocytes can be measured and compared with that of insulin. Pretreatment of the cells with a biologically active analog will generally produce a dose-dependent increase in 2-deoxyglucose uptake. The ability of an ELP-containing insulin analog to regulate glucose production may be measured in any number of cells types, for example, H4Ile hepatoma cells. In this assay, pretreatment with a biologically active analog will generally result in a dose-dependent inhibition of the amount of glucose released.
Factor VII (VIIa)
In certain embodiments, the invention provides therapeutic agents comprising an ELP component coupled (e.g., via fusion or conjugation) to a Factor VII/VIIa. Coagulation is the biological process of blood clot formation involving many different serine proteases as well as their essential cofactors and inhibitors. It is initiated by exposure of Factor VII (FVII) and Factor VIIa (FVIIa) to its membrane bound cofactor, tissue factor (TF), resulting in production of Factor Xa (FXa) and more FVIIa. The process is propagated upon production of Factor IXa (FIXa) and additional FXa that, upon binding with their respective cofactors FVIIIa and FVa, form platelet bound complexes, ultimately resulting in the formation of thrombin and a fibrin clot. Thrombin also serves to further amplify coagulation by activation of cofactors such as FV and FVII and zymogens such as Factor XI. Moreover, thrombin activates platelets leading to platelet aggregation, which is necessary for the formation of a hemostatic plug.
Factor VII circulates in the blood in a zymogen form, and is converted to its active form, Factor VIIa, by either factor IXa, factor Xa, factor XIIa, or thrombin by minor proteolysis. Factor VIIa is a two-chain, 50 kilodalton (kDa) plasma serine protease. The active form of the enzyme comprises a heavy chain (254 amino acid residues) containing a catalytic domain and a light chain (152 residues) containing 2 epidermal growth factor (EGF)-like domains. The mature factor VII/VIIa that circulates, in plasma is composed of 406 amino acid residues (SEQ ID NO: 33). The light and heavy chains are held together by a disulfide bond.
As noted above, Factor VIIa is generated by proteolysis of a single peptide bond from its single chain zymogen, Factor VII, which is present at approximately 0.5 μg/ml in plasma. The conversion of zymogen Factor VII into the activated two-chain molecule occurs by cleavage of an internal peptide bond. In human Factor VII, the cleavage site is at Arg152-Ile153 (Hagen et al., 1986, PNAS USA 83:2412-6).
“Factor VII/VIIa” as used in this application means a product consisting of either the unactivated form (factor VII) or the activated form (factor VIIa) or mixtures thereof. “Factor VII/VIIa” within the above definition includes proteins that have an amino acid sequence of native human factor VII/VIIa. It also includes proteins with a slightly modified amino acid sequence, for instance, a modified N-terminal end including N-terminal amino acid deletions or additions so long as those proteins substantially retain the activity of factor VIIa. “Factor VII” within the above definition also includes natural allelic variations that may exist and occur from one individual to another. Also, degree and location of glycosylation or other post-translation modifications may vary depending on the chosen host cells and the nature of the host cellular environment.
In the presence of calcium ions, Factor VIIa binds with high affinity to TF. TF is a 263 amino acid residue glycoprotein composed of a 219 residue extracellular domain, a single transmembrane domain, and a short cytoplasmic domain (Morrissey et al., 1987, Cell 50: 129-35). The TF extracellular domain is composed of two fibronectin type III domains of about 105 amino acids each. The binding of FVIIa is mediated entirely by the TF extracellular domain (Muller at 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.TM NovoSevenTM 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 NovoSevenTM” FDA reference number 96-0597. Moreover, the half-life of recombinant FVIIa is shorter in pediatric patients ( ̃1.3 hours), suggesting that higher doses of recombinant FVIIa may be required in this population (Roberts at al., 2004, Blood 104: 3858-64). Accordingly, relatively high doses and frequent administration are necessary to reach and sustain the desired therapeutic or prophylactic effect. As a consequence, adequate dose regulation is difficult to obtain and the need of frequent intravenous administrations imposes restrictions on the patient's way of living.
A molecule with a longer circulation half-life would decrease the number of necessary administrations. Given the frequent injections associated with currently available FVIIa therapy and the potential for obtaining more optimal therapeutic FVIIa levels with concomitant enhanced therapeutic effect, there is a clear need for improved FVII or FVIIa-like molecules with a longer half-life in vivo.
Recombinant human coagulation factor VIIa (rFVIIa, NovoSeven; Novo Nordisk A/S, Copenhagen, Denmark) has proven to be efficacious for the treatment of bleeding episodes in hemophilia patients with inhibitors. A small fraction of patients may be refractory to rFVIIa treatment and could potentially benefit from genetically modified FVIIa molecules with increased potencies. To this end, FVIIa analogs with increased intrinsic activity have been investigated that exhibit superior hemostatic profiles in vitro (see e.g. WO02/077218 or WO05/074975, which are hereby incorporated by reference in their entirety, and Tranholm at 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 Microbial 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 InnovinTM (Dade, Miami, Fla.) prothrombin time reagent (recombinant human tissue factor with phospholipids and CaCl2). Clot formation is detected optically and time to clotting measured. Clotting time (seconds) is compared to the mean clotting time of FVII-deficient plasma alone and plotted as the fractional clotting time versus FVIIa analog concentration.
Therapeutic Proteins
The present invention further provides therapeutic agents comprising an ELP component and at least one therapeutic protein selected from Table 1. The ELP component and therapeutic protein may be coupled by recombinant fusion or chemical conjugation as described herein. Such therapeutic proteins are listed in Table 1 by protein name and GeneSeq Accession No. The amino acid sequence of each Therapeutic Protein, which is known in the art, is hereby incorporated by reference for each Therapeutic Protein listed in Table 1. Such therapeutic proteins are further described in US patent or PCT publications that are also listed in Table 1, and such US patent and PCT publications are hereby incorporated by reference, especially with respect to the structure of such therapeutic proteins and described functional analogs.
Table 1 further describes the biological activity of each listed Therapeutic Protein, as well as an exemplary assay for determining the activity of functional analogs or agents of the invention (e.g., fusion with an ELP component). Generally, functional analogs of therapeutic proteins listed in Table 1 may include functional fragments truncated at the N-terminus and/or C-terminus by from 1 to 10 amino acids, including by 1, 2, 3, 4 or about 5 amino acids. Functional analogs may contain from 1 to 10 amino acid insertions, deletions, and/or substitutions (collectively) with respect to the base sequence (e.g., as listed in Table 1), and in each case retaining the full or partial biological activity (as listed in Table 1) of the therapeutic protein. For example, functional analogs may have 1, 2, 3, 4, or 5 amino acid insertions, deletions, and/or substitutions (collectively) with respect to the base sequence. Such activity may be confirmed or assayed using any available assay, including those described in the Table. In these or other embodiments, the therapeutic protein has at least about 75%, 80%, 85%, 90%, 95%, or 98% identity with the corresponding base sequence. The molecules may further comprise additional chemical modifications known for each in the art.
In some embodiments, the therapeutic protein (e.g., as selected from Table 1) has a size of less than about 25 kDa, or less than about 10 kDa, or less than about 5 kDa, and the corresponding therapeutic agent of the invention (e.g., comprising the ELP component) has a molecular weight of less than about 60 kDa, 55 kDa, 50 kDa, or 40 kDa.
Table 1 further lists preferred indications for each therapeutic protein, for which the corresponding therapeutic agent finds use, such as in a method for treatment or prevention related to such indication.












TABLE 1







PCT/Patent







Reference



Exemplary
(the patents



Identifier
and



(the sequences
publications



listed in this
listed in this



column are each
column are

Exemplary Activity Assay



hereby
each hereby

(the publications listed in this column


Therapeutic
incorporated by
incorporated

are each hereby incorporated by


Protein X
reference)
by reference)
Biological Activity
reference)
Preferred Indication Y







BMP-1
GeneSeq
WO8800205
BMP1 belongs to the transforming growth
BMP-1 activity can be determined using
Induction of Cartilage,



Acession P80618

factor-beta (TGFB) superfamily. Bone
the following assays known in the art: Nat
Tissue and Bone Growth,





morphogenic proteins induce cartilage
Genet. 2001 Jan; 27(1): 84-8; Eur J
and Diabetes





and bone formation, play important role
Biochem 1996 Apr 1; 237(1): 295-302; J





in nephrogesis, and play an important
Biol Chem, Vol. 274, Issue 16, 10897-10902,





role in the development of many organs,
Apr. 16, 1999; and Hogan, B. L. M.





including lung, heart, teeth, gut, skin, and
(1996) Genes Dev. 10, 1580-1594.





particularly the kidney.


BMP-2
GeneSeq
WO8800205
BMP-2 belongs to the transforming
BMP-2 activity can be determined using the
Induction of Cartilage,



Accession P80619

growth factor-beta (TGFB) superfamily.
following assays known in the art: Nat
Tissue and Bone Growth,





Bone morphogenic protein induces bone
Genet. 2001 Jan; 27(1): 84-8; Eur J
and Diabetes





formation.
Biochem 1996 Apr 1; 237(1): 295-302; J Biol






Chem, Vol. 274, Issue 16, 10897-10902,






Apr. 16, 1999; and Hogan, B. L. M. (1996)






Genes Dev. 10, 1580-1594.


BMP-2B
GeneSeq
U.S. Pat. No. 5,631,142
BMP-2b belongs to the transforming
BMP-2b activity can be determined using
Induction of Cartilage,



Accession W24850

growth factor-beta (TGFB) superfamily.
the following assays known in the art: Nat
Tissue and Bone Growth,





Bone morphogenic protein induces bone
Genet. 2001 Jan; 27(1): 84-8; Eur J
and Diabetes





formation.
Biochem 1996 Apr 1; 237(1): 295-302; I Biol






Cbcre, Vol. 274, Issue 16, 10897-10902,






Apr. 16, 1999; and Hogan, B. L. M. (1996)






Genes Dev. 10, 1580-1594.


BMP-4
GeneSeq
WO0020591
BMP-4 belongs to the transforming
BMP-4 activity can be determined using the
Induction of Cartilage,



Accession

growth factor-beta (TGFB) superfamily.
following assays known in the art: Nat
Tissue and Bone Growth,



B02796

Bone morphogenic protein induces bone
Genet. 2001 Jan; 27(1): 84-8; Eur J
and Diabetes





formation.
Biochem 1996 Apr 1; 237(1): 295-302; J






Biol Chem, Vol. 274, Issue 16, 10897-10902,






Apr. 16, 1999; and Hogan, B. L. M.






(1996) Genes Dev. 10, 1580-1594.


BMP-5
GeneSeq
WO0020591
BMP-5 belongs to the transforming
BMP-5 activity can be determined using the
Induction of Cartilage,



Accession

growth factor-beta (TGFB) superfamily.
following assays known in the art: Nat
Tissue and Bone Growth,



B02797

Bone morphogenic protein induces bone
Genet. 2001 Jan; 27(1): 84-8; Eur J
and Diabetes





formation.
Biochem 1996 Apr 1; 237(1): 295-302; J






Biol Chem, Vol. 274, Issue 16, 10897-10902,






Apr. 16, 1999; and Hogan, B. L. M.






(1996) Genes Dev. 10, 1580-1594.


BMP-6
GeneSeq
U.S. Pat. No. 5,187,076
BMP-6 belongs to the transforming
BMP-6 activity can be determined using the
Induction of Cartilage,



Accession

growth factor-beta (TGFB) superfamily.
following assays known in the art: Nat
Tissue and Bone Growth,



R32904

Bone morphogenic protein induces bone
Genet. 2001 Jan; 27(1): 84-8; Eur J
and Diabetes





formation.
Biochem 1996 Apr 1; 237(1): 295-302; J






Biol Chem, Vol. 274, Issue 16, 10897-10902,






Apr. 16, 1999; and Hogan, B. L. M.






(1996) Genes Dev. 10, 1580-1594.


Osteogenic
GeneSeq
WO973462
OP-1 belongs to the transforming growth
OP-1 activity can be determined using the
Induction of Cartilage,


Protein-1; OP-1;
Accession

factor-beta (TGFB) superfamily. Bone
following assays known in the art: Nat
Tissue and Bone Growth,


BMP-7
W34783

morphogenic protein induces bone
Genet. 2001 Jan; 27(1): 84-8; Eur J
and Diabetes





formation.
Biochem 1996 Apr 1; 237(1): 295-302; J






Biol Chem, Vol. 274, Issue 16, 10897-10902,






Apr. 16, 1999; and Hogan, B. L. M.






(1996) Genes Dev. 10, 1580-1594.


Osteogenic
GeneSeq
WO9406399
OP-2 belongs to the transforming growth
OP-2 activity can be determined using the
Induction of Cartilage,


Protein-2
Accession R57973

factor-beta (TGFB) superfamily. Bone
following assays known in the art: Nat
Tissue and Bone Growth,





morphogenic protein induces bone
Genet. 2001 Jan; 27(1): 84-8; Eur J
and Diabetes





formation.
Biochem 1996 Apr 1; 237(1): 295-302; J






Biol Chem, Vol. 274, Issue 16, 10897-10902,






Apr. 16, 1999; and Hogan, B. L. M.






(1996) Genes Dev. 10, 1580-1594.


GDP-1
GeneSeq
WO9406449
Members of the TGF-beta family of
The effect of GDF-1 on signaling can be
Developmental disorders,



Accession

proteins initiate cell signaling by binding
assayed by treating Primary BAECs
Induction of Cartilage,



R60961

to heteromeric receptor complexes of
transferred with a construct called p3TP-
Tissue and Bone Growth,





type I (TbetaRI) and type II (TbetaRII)
Lux, containing a TGF-beta responsive
and Diabetes





serine/threonine kinase receptors
promoter fused to a reporter gene, and





(reviewed by Massague, J. et al. (1994)
measuring luciferase gene expression





Trends Cell Biol. 4: 172 178; Miyazono, K.
(Wrana et al., 1994, Nature 370: 341-347).





et al. (1994) Adv. Immunol. 55: 181-220).





Activation of this heteromeric receptor





complex occurs when TGF-beta binds to





TbetaRII, which then recruits and





phosphorylates TbetaRI. Activated





TbetaRI then propagates the signal to





downstream targets (Chen, F. and





Weinberg, R. A. (1995) PNA892: 1565-1569;





Wrana, J. L. et al. (1994) Nature





370: 341 347).


BMP-9
GeneSeq
WO9533830
BMP-9 belongs to the transforming
BMP-9 activity can be determined using the
Induction of Cartilage,



Accession

growth factor-beta (TGFB) superfamily.
following assays known in the art: Nat
Tissue and Bone Growth,



R86903

Bone morphogenic protein induces bone
Genet. 2001 Jan; 27(1): 84-8; Eur J
and Diabetes





formation.
Biochem 1996 Apr 1; 237(1): 295-302; J






Biol Chem, Vol. 274, Issue 16, 10897-10902,






Apr. 16, 1999; and Hogan, B. L. M.






(1996) Genes Dev. 10, 1580-1594.


BMP-10
GeneSeq
WO9426893
BMP-10 belongs to the transforming
BMP-10 activity can be determined using
Induction of Cartilage,



Accession R66202

growth factor-beta (TGFB) superfamily.
the following assays known in the art: Nat
Tissue and Bone Growth,





Bone morphogenic protein induces bone
Genet. 2001 Jan; 27(1): 84-8; Eur J
and Diabetes





formation.
Biochem 1996 Apr 1; 237(1): 295-302; J






Biol Chem, Vol. 274, Issue 16, 10897-10902,






Apr. 16, 1999; and Hogan, B. L. M.






(1996) Genes Dev. 10, 1580-1594.


BMP-12
GeneSeq
WO9516035
BMP-12 belongs to the transforming
BMP-12 activity can be determined using
Induction of Cartilage,



Accession R78734

growth factor-beta (TGFB) superfamily.
the following assays known in the art: Nat
Tissue and Bone Growth,





Bone morphogenic protein induces bone
Genet. 2001 Jan; 27(1): 84-8; Eur J
and Diabetes





formation.
Biochem 1996 Apr 1; 237(1): 295-302; J






Biol Chem, Vol. 274, Issue 16, 10897-10902,






Apr. 16, 1999; and Hogan, B. L. M.






(1996) Genes Dev. 10, 1580-1594.


BMP-15
GeneSeq
W09636710
BMP-15 belongs to the transforming
BMP-15 activity can be determined using
Induction of Cartilage,



Accession W11261

growth factor-beta (TGFB) superfamily.
the following assays known in the art: Nat
Tissue and Bone Growth,





Bone morphogenic protein induces bone
Genet. 2001 Jan; 27(1): 84-8; Eur J
and Diabetes





formation.
Biochem 1996 Apr 1; 237(1): 295-302; J






Biol Chem, Vol. 274, Issue 16, 10897-10902,






Apr. 16, 1999; and Hogan, B. L. M.






(1996) Genes Dev. 10, 1580-1594.


BMP-17
GeneSeq
WO9929718
BMP-17 belongs to the transforming
BMP-17 activity can be determined using
Induction of Cartilage,



Accession Y17870

growth factor-beta (TGFB) superfamily.
the following assays known in the art: Nat
Tissue and Bone Growth,





Bone morphogenic protein induces bone
Genet. 2001 Jan; 27(1): 84-8; Eur J
and Diabetes





formation.
Biochem 1996 Apr 1; 237(1): 295-302; J






Biol Chem, Vol. 274, Issue 16, 10897-10902,






Apr. 16, 1999; and Hogan, B. L. M.






(1996) Genes Dev. 10, 1580-1594.


BMP-18
GeneSeq
WO9929718
BMP-18 belongs to the transforming
BMP-18 activity can be determined using
Induction of Cartilage,



Accession Y17871

growth factor-beta (TGFB) superfamily.
the following assays known in the art: Nat
Tissue and Bone Growth,





Bone morphogenic protein induces bone
Genet. 2001 Jan; 27(1): 84-8; Eur J
and Diabetes





formation.
Biochem 1996 Apr 1; 237(1): 295-302; J






Biol Chem, Vol. 274, Issue 16, 10897-10902,






Apr. 16, 1999; and Hogan, B. L. M.






(1996) Genes Dev. 10, 1580-1594.


Inhibin alpha
GeneSeq
WO0020591
The inhibin beta A subunit joins the alpha
Tumor suppressor activity of inhibin can be
Tumor suppression.



Accession B02806

subunit to form a pituitary FSH secretion
determined using assays known in the art:





inhibitor. Inhibin has been shown to
Matzuk et al., Nature 1992 Nov. 26: 360





regulate gonadal stromal cell proliferation
(6402); 313-9.





negatively and to have tumour-





suppressor activity. In addition, serum





levels of inhibin have been shown to





reflect the size of granulosa-cell tumors





and can therefore be used as a marker





for primary as well as recurrent disease.


Inhibin beta
GeneSeq
WO0020591
The inhibin beta A subunit joins the alpha
Tumor suppressor activity of inhibin can be
Tumor suppression.



Accession

subunit to form a pituitary FSH secretion
determined using assays known in the art:



H02808

inhibitor. Inhibin has been shown to
Matzuk et al., Nature 1992 Nov. 26: 360





regulate gonadal stromal cell proliferation
(6402); 313-9.





negatively and to have tumour-





suppressor activity. In addition, serum





levels of inhibin have been shown to





reflect the size of granulosa-cell tumors





and can therefore be used as a marker





for primary as well as recurrent disease.


Cerebus Protein
GeneSeq
WO9849296
Cerebus is believed to be involved in the
BMP activity, in the presence of the
BMP Antagonist useful for



Accession

inhibition of BMP activity
antagonist Cerebus, can be determined
Osteosarcoma, abnormal



W86032


using the following assays known in the art:
bone growth.






Nat Genet. 2001 Jan; 27(1): 84-8; Eur J






Biochem 1996 Apr 1; 237(1): 295-302; J






Biol Chem, Vol. 274, Issue 16, 10897-10902,






Apr. 16, 1999; and Hogan, B. L. M.






(1996) Genes Dev. 10, 1580-1594.


Soluble BMP
GeneSeq
WO9614579
Soluble BMP receptor kinase protein-3 is
BMP activity, in the presence of the soluble
BMP Antagonist useful for


Receptor Kinase
Accession

involved in the binding of BMPs. Soluble
antagonist BMP receptor kinase protein-3,
Osteosarcoma, abnormal


Protein-3
R95227

BMP receptor kinase protein-3 is useful
can be determined using the following
bone growth.





as an antagonist for the inhibition of BMP
assays known in the art: Nat Genet. 2001





activity.
Jan; 27(1): 84-8; Eur J Biochem 1996 Apr 1;






237(1): 295-302; J Biol Chem, Vol. 274,






Issue 16, 10897-10902, Apr. 16, 1999; and






Hogan, B. L. M. (1996) Genes Dev. 10,






1580-1594.


BMP Processing
GeneSeq
WO9741250
BMPs belong to the transforming growth
BMP activity, in the presence of the Furin,
Bone formation or


Enzyme Furin
Accession

factor-beta (TGFB) superfamily. Bone
can be determined using the following
Regeneration



W36099

morphogenic protein induces bone
assays known in the art: Nat Genet. 2001
Abnormalities





formation.
Jan; 27(1): 84-8; Eur J Biochem 1996 Apr 1;






237(1): 295-302; J Biol Chem, Vol. 274,






Issue 16, 10897-10902, Apr. 16, 1999; and






Hogan, B. L. M. (1996) Genes Dev. 10,






1580-1594.


TGF-beta 1
GeneSeq
WO9216228
Members of the TGF-beta family of
The effect of TGF betas on signaling can
Useful for treating cancer



Accession

proteins initiate cell signaling by binding
be assayed by treating Primary BAECs
and to promote wound



R29657

to heteromeric receptor complexes of
transfected with a construct called p3TP-
healing.





type I (TbetaRI) and type II (TbetaRII)
Lux, containing a TGF-beta responsive





serine/threonine kinase receptors
promoter fused to a reporter gene, and





(reviewed by Massague, J. et al. (1994)
measuring luciferase gene expression





Trends Cell Biol. 4: 172 178; Miyazono, K.
(Wrana et al., 1994, Nature 370: 341-347).





et al. (1994) Adv. Immunol. 55: 181-220).





Activation of this heteromeric receptor





complex occurs when TGF-beta. binds to





TbetaRII, which then recruits and





phosphorylates TbetaRI. Activated





TbetaRI then propagates the signal to





downstream targets (Chen, F. and





Weinberg. R. A. (1995) PNA892: 1565-1569;





Wrana, J. L. et al. (1994) Nature





370: 341.


TGF-beta 2
GeneSeq
EP542679
Members of the TGF-beta family of
The effect of TGF betas on signaling can
Useful for treating cancer



Accession

proteins initiate cell signaling by binding
be assayed by treating Primary BAECs
and to promote wound



R39659

to heteromeric receptor complexes of
transfected with a construct called p3TP-
healing.





type I (TbetaRI) and type II (TbetaRII)
Lux, containing a TGF-beta responsive





serine/threonine kinase receptors
promoter fused to a reporter gene, and





(reviewed by Massague, J. et al. (1994)
measuring luciferase gene expression





Trends Cell Biol. 4: 172 178; Miyazono, K.
(Wrana et al., 1994, Nature 370: 341-347).





et al. (1994) Adv. Immunol. 55: 181-220).





Activation of this heteromeric receptor





complex occurs when TGF-beta. binds to





TbetaRII, which then recruits and





phosphorylates TbetaRI. Activated





TbetaRI then propagates the signal to





downstream targets (Chen, F. and





Weinberg. R. A. (1995) PNA892: 1565-1569;





Wrana, J. L. et al. (1994) Nature





370: 341.


ZTGF-beta 9
GeneSeq
WO0015798
Members of the TGF-beta family of
The effect of TGF betas on signaling can
Useful for treating cancer



Accession

proteins initiate cell signaling by binding
be assayed by treating Primary BAECs
and to promote wound



Y70654

to heteromeric receptor complexes of
transfected with a construct called p3TP-
healing.





type I (TbetaRI) and type II (TbetaRII)
Lux, containing a TGF-beta responsive





serine/threonine kinase receptors
promoter fused to a reporter gene, and





(reviewed by Massague, J. et al. (1994)
measuring luciferase gene expression





Trends Cell Biol. 4: 172 178; Miyazono, K.
(Wrana et al., 1994, Nature 370: 341-347).





et al. (1994) Adv. Immunol. 55: 181-220).





Activation of this heteromeric receptor





complex occurs when TGF-beta. binds to





TbetaRII, which then recruits and





phosphorylates TbetaRI. Activated





TbetaRI then propagates the signal to





downstream targets (Chen, F. and





Weinberg. R. A. (1995) PNA892: 1565-1569;





Wrana, J. L. et al. (1994) Nature





370: 341.


Anti-TGF beta

GB2305921
Members of the TGF-beta family of
The effect of TGF betas on signaling in the
Useful for control of


family antibodies


proteins initiate cell signaling by binding
presence of an anti-TGF beta antibody, can
fibrosis, immune, and





to heteromeric receptor complexes of
be assayed by treating Primary BAECs
inflammatory disease.





type I (TbetaRI) and type II (TbetaRII)
transfected with a construct called p3TP-





serine/threonine kinase receptors
Lux, containing a TGF-beta responsive





(reviewed by Massague, J. et al. (1994)
promoter fused to a reporter gene, and





Trends Cell Biol. 4: 172 178; Miyazono, K.
measuring luciferase gene expression





et al. (1994) Adv. Immunol. 55: 181-220).
(Wrana et al., 1994, Nature 370: 341-347).





Activation of this heteromeric receptor





complex occurs when TGF-beta. binds to





TbetaRII, which then recruits and





phosphorylates TbetaRI. Activated





TbetaRI then propagates the signal to





downstream targets (Chen, F. and





Weinberg. R. A. (1995) PNA892: 1565-1569;





Wrana, J. L. et al. (1994) Nature





370: 341.


Latent TGF beta
GeneSeq
WO0012551
Members of the TGF-beta family of
The effect of TGF betas on signaling in the
Useful for inhibiting tissue


binding protein II
Accession

proteins initiate cell signaling by binding
presence of a TGF beta binding protein,
or tumor growth.



Y70552

to heteromeric receptor complexes of
can be assayed by treating Primary BAECs





type I (TbetaRI) and type II (TbetaRII)
transfected with a construct called p3TP-





serine/threonine kinase receptors
Lux, containing a TGF-beta responsive





(reviewed by Massague, J. et al. (1994)
promoter fused to a reporter gene, and





Trends Cell Biol. 4: 172 178; Miyazono, K.
measuring luciferase gene expression





et al. (1994) Adv. Immunol. 55: 181-220).
(Wrana et al., 1994, Nature 370: 341-347).





Activation of this heteromeric receptor





complex occurs when TGF-beta. binds to





TbetaRII, which then recruits and





phosphorylates TbetaRI. Activated





TbetaRI then propagates the signal to





downstream targets (Chen, F. and





Weinberg. R. A. (1995) PNA892: 1565-1569;





Wrana, J. L. et al. (1994) Nature





370: 341.


MP52
GeneSeq
WO9741250
Members of the TGF-beta family of
The effect of TGF betas on signaling can
Bone formation or



Accession

proteins initiate cell signaling by binding
be assayed by treating Primary BAECs
Regeneration



W36100

to heteromeric receptor complexes of
transfected with a construct called p3TP-
Abnormalities





type I (TbetaRI) and type II (TbetaRII)
Lux, containing a TGF-beta responsive





serine/threonine kinase receptors
promoter fused to a reporter gene, and





(reviewed by Massague, J. et al. (1994)
measuring luciferase gene expression





Trends Cell Biol. 4: 172 178; Miyazono, K.
(Wrana et al., 1994, Nature 370: 341-347).





et al. (1994) Adv. Immunol. 55: 181-220).





Activation of this heteromeric receptor





complex occurs when TGF-beta. binds to





TbetaRII, which then recruits and





phosphorylates TbetaRI. Activated





TbetaRI then propagates the signal to





downstream targets (Chen, F. and





Weinberg. R. A. (1995) PNA892: 1565-1569;





Wrana, J. L. et al. (1994) Nature





370: 341.


b57 Protein
GeneSeq
WO9837195
BMPs are involved in the induction of
BMP activity, in the presence of b57
BMP Antagonist useful for



Accession

bone formation. Specific antagonists are
protein, can be determined using the
Osteosarcoma, abnormal



W69293

useful is preventing this activity from
following assays known in the art: Nat
bone growth.





occurring.
Genet. 2001 Jan; 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 gcne belongs to the family defined by
Ability of resistin to influence type II
Type II diabetes and



Accession

mouse FIZZI and FIZZ3/Resistin genes.
diabetes can be determined using assays
Syndrome X.



W69293

The characteristic feature of this family is
known in the art: Pontoglio et al., J Clin





the C-terminal stretch of 10 cys residues
Invest 1998 May 15; 101(10): 2215-22.





with identical spacing. The mouse





homolog of this protein is secreted by





adipocytes, may be the hormone





potantially linking obesity to type II





diabetes.


Galectin-4
GeneSeq
WO9703190
Galectins are a family of carbohydrate-
Ability of Galectin-4 polypeptides to bind
Lactose intolerance.



Accession

binding proteins characterized by an
lactose can be determined using assays



W11841

affinity for beta-galactoside containing
known in the art: Wada, et al., J Biol Chem





glycoconjugates.
1997 Feb 28; 272(9): 6078-86.


APM-I; ACRP-30;
GeneSeq
W00026363
ACPR30 gene is exclusively expressed in
Ability of ACRP30 polypeptides to
Obesity, Metabolic


Famoxin
Accession

adipose tissue. ACRP30 is thought to
influence obesity and fat oxidation can be
disorders, Lipid



Y71035

increase fatty acid oxidation by muscle
determined using assays known in the art:
Metabolism; Hormone





tissue.
Fruebis et al., Proc Nat'l Acad Sci USA
Secretion.






2001 Feb 13; 98(4): 2005-10.


ACRP-30
GeneSeq
WO0063376
ACPR30 gene is exclusively expressed in
Ability of ACRP30 homologue
Obesity, Metabolic


Homologue;
Accession

adipose tissue. ACRP30 is thought to
polypeptides to influence obesity and fat
disorders, Lipid


Complement
B30234

increase fatty acid oxidation by muscle
oxidation can be determined using assays
Metabolism; Hormone


Component Clq C


tissue.
known in the art: Fruebis et al., Proc Nat'l
Secretion.






Acad Sci USA 2001 Feb 13; 98(4): 2005-10.


Calpain-10a
GeneSeq
WO0023603
Calpain is believed to play a role in insulin
Ability of Calpain-10 to influence type II
Diabetes mellitus;



Accession

secretion and insulin activity, and
diabetes can be determined using assays
Regulation of Insulin



Y79567

therefore may be useful in the treatment
known in the art: Pontoglio et al., J Clin
secretory response;





of type II diabetes.
Invest 1998 May 15; 101(10): 2215-22.
Insulin mediated glucose







transport disorders.


Calpain-10b
GeneSeq
WO0023603
Calpain is believed to play a role in insulin
Ability of Calpain-10 to influence type II
Diabetes mellitus;



Accession

secretion and insulin activity, and
diabetes can be determined using assays
Regulation of Insulin



Y79568

therefore may be useful in the treatment
known in the art: Pontoglio et al., J Clin
secretory response;





of type II diabetes.
Invest 1998 May 15; 101(10): 2215-22.
Insulin mediated glucose







transport disorders.


Calpain-10c
GeneSeq
WO0023603
Calpain is believed to play a role in insulin
Ability of Calpain-10 to influence type II
Diabetes mellitus;



Accession

secretion and insulin activity, and
diabetes can be determined using assays
Regulation of Insulin



Y79569

therefore may be useful in the treatment
known in the art: Pontoglio et al., J Clin
secretory response;





of type II diabetes.
Invest 1998 May 15; 101(10): 2215-22.
Insulin mediated glucose







transport disorders.


PDGF-D
GeneSeq
WO0027879
Vascular Endothelial Growth Factor.
Proliferation assay using NR6R-3T3 cells
Wound Healing;



Accession


(Rizzino 1988 Cancer Res. 48: 4266).
Atherosclermis.



Y71130


FasL
GeneSeq
WO9936079
Activities associated with apoptosis and
Activity can be determined using
Apoptosis-related



Accession

immune system functions.
Apoptosis assays known in the art:
disorders; Autoimmune



Y28594


Walczak et al. (1996) EMBOJ 16: 5386-5397.
disorders; Graft v-Host







disorders.


Chondro modulin-
GeneSeq
W00029579
Chondromodulin proteins are cartilage
Ability of Chondromodulin-like protein to
Antianglogenic agent;


like protein
Accession

proteins thought to confer resistance to
inhibit vascularization can be determined
Osteoblast proliferation



Y71262

anglogeneis, and thus are useful as anti-
using assays known in the art: Hirakie et
stimulator; prevents





angiogenic agents that may have utility in
al., J Biol Chem 1997 Dec 19;
vascularization of cartilage





combating cancer.
272(51): 32419-26.
tissue; Useful to treat







cancer.


Patched
GeneSeq
U.S. Pat. No. 5,837,538
Patched is a tumour-suppressor receptor
Ability of soluble Patched to bind to and
Receptor for Hedgehog



Accession

for Sonic hedgehog (shh), which is a
inhibit the activities of shh can be
cellular proliferation



W72969

protein that controls developmental
determined using assays known in the art:
signaling molecule. This





patterning and growth.
Stone et al., Nature 1996 Nov 14;
receptor is useful as a






384(6605): 129-34.
means of preventing







cellular proliferation via the







shh signaling pathway,







thus useful for cancers.


Patched-2
GeneSeq
WO9953058
Patched is a tumour-suppressor receptor
Ability of soluble Patched to bind to and
Receptor for Hedgehog



Accession

for Sonic hedgehog (shh), which is a
inhibit the activities of shh can be
cellular proliferation



Y43261

protein that controls developmental
determined using assays known in the art:
signaling molecule. This





patterning and growth.
Stone et al., Nature 1996 Nov 14;
receptor is useful as a






384(6605): 129-34.
means of preventing







cellular proliferation via the







shh signaling pathway,







thus useful for cancers.


Maspin; Protease
GeneSeq
WO9405804
Maspin is a member of the serpin family of
The inhibitory effects cf Maspin and other
Tumor suppressor which is


Inhibitor 5
Accession

serine protease inhibitors that is thought
protease inhibitors can be assayed using
down-regulated in breast



R50938

to suppress tumor metastasis.
methods known in the art such as a
cancers. The maspin






labeled protease substrate, for example,
protein has tumour






Universal Protease Substrate (casein,
suppressing and invasion






resorufin-labeled): Roche Molecular
suppressing activity.






Biochemicals, Cat. No. 1080733.


Endostatin
GeneSeq
WO0064946
Endostatin is believed to inhibit effects of
The inhibitory effects of endostatin can be
Anti-angiogenic activity.



Accession

capillary endothelial cell proliferation.
assayed using assays disclosed by Cao et
Useful in the prevention



B28399


al. (1996) J. Biol. Chem. 271 29461-29467.
and/or treatment of







cancers.


aFGF; FGF-1
GeneSeq
EP298723
Fibroblast Growth Factor
Proliferation assay using NR6R-3T3 cells
Promotion of growth and



Accession


(Rizzino 1988 Cancer Res. 48: 4266);
proliferation of cells, such



P94037


Examples 23 and 39 disclosed herein.
as epithelial cells and







keratinocytes. Antagonists







may be useful as anti-







cancer agents.


bFGF; FGF-2
GeneSeq
FR2642086
Fibroblast Growth Factor
Proliferation assay using NR6R-3T3 cells
Promotion of growth and



Accession


(Rizzino 1988 Cancer Res. 48: 4266);
proliferation of cells, such



R06685


Examples 23 and 39 disclosed herein.
as epithelial cells and







keratinocytes. Antagonists







may be useful as anti-







cancer agents.


FGF-3; INT-2
GeneSeq
WO9503831
Fibroblast Growth Factor
Proliferation assay using NR6R-3T3 cells
Promotion of growth and



Accession


(Rizzino 1988 Cancer Res. 48: 4266);
proliferation of cells, such



R07824


Examples 23 and 39 disclosed herein.
as epithelial cells and







keratinocytes. Antagonists







may be useful as anti-







cancer agents.


FGF-4; HST-1;
GeneSeq
WO9503831
Fibroblast Growth Factor
Proliferation assay using NR6R-3T3 cells
Promotion of growth and


HBGF-4
Accession


(Rizzino 1988 Cancer Res. 48: 4266);
proliferation of cells, such



R07825


Examples 23 and 39 disclosed herein.
as epithelial cells and







keratinocytes. Antagonists







may be useful as anti-







cancer agents.


FGF-5
GeneSeq
WO9730155
Fibroblast Growth Factor
Proliferation assay using NR6R-3T3 cells
Promotion of growth and



Accession


(Rizzino 1988 Cancer Res. 48: 4266);
proliferation of cells, such



W22600


Examples 23 and 39 disclosed herein.
as epithelial cells and







keratinocytes. Antagonists







may be useful as anti-







cancer agents.


FGF-6; Heparin
GeneSeq
EP613946
Fibroblast Growth Factor
Proliferation assay using NR6R-3T3 cells
Promotion of growth and


binding secreted
Accession


(Rizzino 1988 Cancer Res. 48: 4266);
proliferation of cells, such


transforming
R58555


Examples 23 and 39 disclosed herein.
as epithelial cells and


factor-2




keratinocytes. Antagonists







may be useful as anti-







cancer agents.


FGF-8
GeneSeq
WO9524928
Fibroblast Growth Factor
Proliferation assay using NR6R-3T3 cells
Promotion of growth and



Accession


(Rizzino 1988 Cancer Res. 48: 4266);
proliferation of cells, such



R80783


Examples 23 and 39 disclosed herein.
as epithelial cells and







keratinocytes. Antagonists







may be useful as anti-







cancer agents.


FGF-9; Gila
GeneSeq
WO9503831
Fibroblast Growth Factor
Proliferation assay using NR6R-3T3 cells
Promotion of growth and


activating factor
Accession


(Rizzino 1988 Cancer Res. 48: 4266);
proliferation of cells, such



R70822


Examples 23 and 39 disclosed herein.
as epithelial cells and







keratinocytes. Antagonists







may be useful as anti-







cancer agents.


FGF-12;
GeneSeq
WO9635708
Fibroblast Growth Factor
Proliferation assay using NR6R-3T3 cells
Promotion of growth and


Fibroblast growth
Accession


(Rizzino 1988 Cancer Res. 48: 4266);
proliferation of cells, such


factor homologous
W06309


Examples 23 and 39 disclosed herein.
as epithelial cells and


factor-1




keratinocytes. Antagonists







may be useful as anti-







cancer agents.


FGF-15
GeneSeq
WO9927100
Fibroblast Growth Factor
Proliferation assay using NR6R-3T3 cells
Promotion of growth and



Accession


(Rizzino 1988 Cancer Res. 48: 4266);
proliferation of cells, such



Y08582


Examples 23 and 39 disclosed herein.
as epithelial cells and







keratinocytes. Antagonists







may be useful as anti-







cancer agents.


FGF-16
GeneSeq
WO9918128
Fibroblast Growth Factor
Proliferation assay using NR6R-3T3 cells
Promotion of growth and



Accession


(Rizzino 1988 Cancer Res. 48: 4266);
proliferation of cells, such



Y05474


Examples 23 and 39 disclosed herein.
as epithelial cells and







keratinocytes. Antagonists







may be useful as anti-







cancer agents.


FGF-18
GeneSeq
WO9927100
Fibroblast Growth Factor
Proliferation assay using NR6R-3T3 cells
Promotion of growth and



Accession


(Rizzino 1988 Cancer Res. 48: 4266);
proliferation of cells, such



Y08590


Examples 23 and 39 disclosed herein.
as epithelial cells and







keratinocytes. Antagonists







may be useful as anti-







cancer agents.


fit-3 ligand
GeneSeq
EP627487
Stem Cell Progenitor
Chemokine activities can be determined
Promotion of immune cell



Accession


using assays known in the art: Methods in
growth and/or



R67541


Molecular Biology, 2000, vol. 138:
differentiation.






Chemokine Protocols. Edited by: A. E. I. Proudfoot,






T. N. C. Wells, and C. A. Power.






© Humana Press Inc., Totowa, NJ.


VEGF-110
GeneSeq
WO0013702
Promotes the growth and/or proliferation
VEGF activity can be determined using
Promotion of growth and



Accession

of endothelial cells.
assays known in the art, such as those
proliferation of cells, such



Y69417


disclosed in International Publication No.
as vascular endothelial






WO0045835, for example.
cells. Antagonists may be







useful as anti-angiogenic







agents, and may be







applicable for cancer.


VEGB-121
GeneSeq
WO0071713
Promotes the growth and/or proliferation
VEGF activity can be determined using
Promotion of growth and



Accession

of endothelial cells.
assays known in the art, such as those
proliferation of cells, such



B50432


disclosed in International Publication No.
as vascular endothelial






WO0045835, for example.
cells. Antagonists may be







useful as anti-angiogenic







agents, and may be







applicable for cancer.


VEGF-138
GeneSeq
WO9940197
Promotes the growth and/or proliferation
VEGF activity can be determined using
Promotion of growth and



Accession

of endothelial cells.
assays known in the art, such as those
proliferation of cells, such



Y43483


disclosed in International Publication No.
as vascular endothelial






WO0045835, for example.
cells. Antagonists may be







useful as anti-angiogenic







agents, and may be







applicable for cancer.


VEGF-145
GeneSeq
WO0013702
Promotes the growth and/or proliferation
VEGF activity can be determined using
Promotion of growth and



Accession

of endothelial cells.
assays known in the art, such as those
proliferation of cells, such



Y69413


disclosed in International Publication No.
as vascular endothelial






WO0045835, for example.
cells. Antagonists may be







useful as anti-angiogenic







agents, and may be







applicable for cancer.


VEGF-162
GeneSeq
W09940197
Promotes the growth and/or proliferation
VEGF activity can be determined using
Promotion of growth and



Accession

of endothelial cells.
assays known in the art, such as those
proliferation of cells, such



Y43484


disclosed in International Publication No.
as vascular endothelial






WO0045835, for example.
cells. Antagonists may be







useful as anti-angiogenic







agents, and may be







applicable for cancer.


VEGF-165
GeneSeq
WO0013702
Promotes the growth and/or proliferation
VEGF activity can be determined using
Promotion of growth and



Accession

of endothelial cells.
assays known in the art, such as those
proliferation of cells, such



Y69414


disclosed in International Publication No.
as vascular endothelial






WO0045835, for example.
cells. Antagonists may be







useful as anti-angiogenic







agents, and may be







applicable for cancer.


VEGF-182
GeneSeq
W09940197
Promotes the growth and/or proliferation
VEGF activity can be determined using
Promotion of growth and



Accession

of endothelial cells.
assays known in the art, such as those
proliferation of cells, such



Y43483


disclosed in International Publication No.
as vascular endothelial






WO0045835, for example.
cells. Antagonists may be







useful as anti-angiogenic







agents, and may be







applicable for cancer.


VEGF-189
GeneSeq
WO0013702
Promotes the growth and/or proliferation
VEGF activity can be determined using
Promotion of growth and



Accession

of endothelial cells.
assays known in the art, such as those
proliferation of cells, such



Y69415


disclosed in International Publication No.
as vascular endothelial






WO0045835, for example.
cells. Antagonists may be







useful as anti-angiogenic







agents, and may be







applicable for cancer.


VEGF-206
GeneSeq
W00013702
Promotes the growth and/or proliferation
VEGF activity can be determined using
Promotion of growth and



Accession

of endothelial cells.
assays known in the art, such as those
proliferation of cells, such



Y69416


disclosed in International Publication No.
as vascular endothelial






WO0045835, for example.
cells. Antagonists may be







useful as anti-angiogenic







agents, and may be







applicable for cancer.


VEGF-D
GeneSeq
WO9807832
Promotes the growth and/or proliferation
VEGF activity can be determined using
Promotion of growth and



Accession

of endothelial cells.
assays known in the art, such as those
proliferation of cells, such



W53240


disclosed in International Publication No.
as vascular endothelial






WO0045835, for example.
cells. Antagonists may be







useful as anti-angiogenic







agents, and may be







applicable for cancer.


VEGF-E; VEGF-X
GeneSeq
W09947677
Promotes the growth and/or proliferation
VEGF activity can be determined using
Promotion of growth and



Accession

of endothelial cells.
assays known in the art, such as those
proliferation of cells, such



Y33679


disclosed in International Publication No.
as vascular endothelial






WO0045835, for example.
cells. Antagonists may be







useful as anti-angiogenic







agents, and may be







applicable for cancer.


VEGF Receptor;
GeneSeq
WO9831794
Receptor for VEGF polypeptides
VEGF activity, in the presence of flk-1
VEGF Receptor. Fusion


KDR; flk-1
Accession


polypeptides, can be determined using
protein with the



W69679


assays known in the art, such as those
extracellular domain is






disclosed in International Publication No.
useful as an anti-






WO0045835, for example.
angiogenic agent.







Antagonists may be useful







in the promotion of







angiogenesis.


Soluble VEGF
GeneSeq
U.S. Pat. No. 5,712,380
Receptor for VEGF polypeptides
VEGF activity, in the presence of VEGF
VEGF Receptor. Fusion


Receptor
Accession


Receptor polypeptides, can be determined
protein with the



W47037


using assays known in the art, such as
extracellular domain is






those disclosed in International
useful as an anti-






Publication No. WO0045835, for example.
angiogenic agent.







Antagonists may be useful







in the promotion of







angiogenesis.


flt-1
GeneSeq
WO0021560
Receptor for VEGF polypeptides
VEGF activity, in the presence of flt-1
VEGF Receptor. Fusion



Accession


polypeptides, can be determined using
protein with the



Y70751


assays known in the art, such as those
extracellular domain is






disclosed in International Publication No.
useful as an anti-






WO0045835, for example.
angiogenic agent.







Antagonists may be useful







in the promotion of







angiogenesis.


VEGF R-3; flt-4
GeneSeq
WO0058511
Receptor for VEGF polypeptides
VEGF activity, in the presence of flt-4
VEGF Receptor. Fusion



Accession


polypeptides, can be determined using
protein with the



B29047


assays known in the art, such as those
extracellular domain is






disclosed in International Publication No.
useful as an anti-






WO0045835, for example.
angiogenic agent.







Antagonists may be useful







in the promotion of







angiogenesis.


Neuropilin-1
GeneSeq
WO9929858
Vascular Endothelial Growth Factor
VEGF activity can be determined using
Promotion of growth and



Accession


assays known in the art, such as those
proliferation of cells, such



Y06319


disclosed in International Publication No.
as vascular endothelial






WO0045835, for example.
cells. Antagonists may be







useful as anti-angiogenic







agents, and may be







applicable for cancer.


Neuropilin-2
GeneSeq
WO9929858
Vascular Endothelial Growth Factor
VEGF activity can be determined using
Promotion of growth and



Accession


assays known in the art, such as those
proliferation of cells, such



Y03618


disclosed in International Publication No.
as vascular endothelial






WO0045835, for example.
cells. Antagonists may be







useful as anti-angiogenic







agents, and may be







applicable for cancer.


Human fast twitch
GeneSeq
W09730085
Troponins are contractile proteins that are
Ability of soluble Troponins to inhibit
Anti-angiogenesis


skeletal muscle
Accession

thought to inhibit angiogencsis. High
anglogenesis can be determined using


troponin C
W22597

levels may contribute to the difficulty
assays known in the art:. Proc Natl Acad





encountered in revascularizing the
Sci USA 1999 Mar 16; 96(6): 2645-50.





ischemic myocardium after cardiovascular





injury.


Human fast twitch
GeneSeq
W09730085
Troponins are contractile proteins that are
Ability of soluble Troponins to inhibit
Anti-angiogenesis


skeletal muscle
Accession

thought to inhibit angiogencsis. High
anglogenesis can be determined using


troponin I
W18054

levels may contribute to the difficulty
assays known in the art:. Proc Natl Acad





encountered in revascularizing the
Sci USA 1999 Mar 16; 96(6): 2645-50.





ischemic myocardium after cardiovascular





injury.


Human fast twitch
GeneSeq
W09730085
Troponins are contractile proteins that are
Ability of soluble Troponins to inhibit
Anti-angiogenesis


skeletal muscle
Accession

thought to inhibit angiogencsis. High
anglogenesis can be determined using


troponin T
W22599

levels may contribute to the difficulty
assays known in the art:. Proc Natl Acad





encountered in revascularizing the
Sci USA 1999 Mar 16; 96(6): 2645-50.





ischemic myocardium after cardiovascular





injury.


fragment.
GeneSeq
W09719955
Troponins are contractile proteins that are
Ability of soluble Troponins to inhibit
Anti-angiogenesis


myofibrillar protein
Accession

thought to inhibit angiogencsis. High
anglogenesis can be determined using


troponin I
W18053

levels may contribute to the difficulty
assays known in the art:. Proc Natl Acad





encountered in revascularizing the
Sci USA 1999 Mar 16; 96(6): 2645-50.





ischemic myocardium after cardiovascular





injury.


myofibrillar protein
GeneSeq
W09719955
Troponins are contractile proteins that are
Ability of soluble Troponins to inhibit
Anti-angiogenesis


troponin I
Accession

thought to inhibit angiogencsis. High
anglogenesis can be determined using



W18054

levels may contribute to the difficulty
assays known in the art:. Proc Natl Acad





encountered in revascularizing the
Sci USA 1999 Mar 16; 96(6): 2645-50.





ischemic myocardium after cardiovascular





injury.


Troponin peptides
GeneSeq
WO9933874
Troponins are contractile proteins that are
Ability of soluble Troponins to inhibit
Anti-angiogenesis



Accessions

thought to inhibit angiogencsis. High
anglogenesis can be determined using



Y29581, Y29582,

levels may contribute to the difficulty
assays known in the art:. Proc Natl Acad



Y29583, Y29584,

encountered in revascularizing the
Sci USA 1999 Mar 16; 96(6): 2645-50.



Y29585, and

ischemic myocardium after cardiovascular



Y29586

injury.


Human fast twitch
GeneSeq
WO0054770
Troponins are contractile proteins that are
Ability of soluble Troponins to inhibit
Anti-angiogenesis


skeletal muscle
Accession

thought to inhibit angiogencsis. High
anglogenesis can be determined using


Troponin subunit C
B00134

levels may contribute to the difficulty
assays known in the art:. Proc Natl Acad





encountered in revascularizing the
Sci USA 1999 Mar 16; 96(6): 2645-50.





ischemic myocardium after cardiovascular





injury.


Human fast twitch
GeneSeq
WO0054770
Troponins are contractile proteins that are
Ability of soluble Troponins to inhibit
Anti-angiogenesis


skeletal muscle
Accession

thought to inhibit angiogencsis. High
anglogenesis can be determined using


Troponin subunit I
B00135

levels may contribute to the difficulty
assays known in the art:. Proc Natl Acad


Protein


encountered in revascularizing the
Sci USA 1999 Mar 16; 96(6): 2645-50.





ischemic myocardium after cardiovascular





injury.


Human fast twitch
GeneSeq
WO0054770
Troponins are contractile proteins that are
Ability of soluble Troponins to inhibit
Anti-angiogenesis


skeletal muscle
Accession

thought to inhibit angiogencsis. High
anglogenesis can be determined using


Troponin subunit T
B00136

levels may contribute to the difficulty
assays known in the art:. Proc Natl Acad





encountered in revascularizing the
Sci USA 1999 Mar 16; 96(6): 2645-50.





ischemic myocardium after cardiovascular





injury.


Activator Inbibitor-
GeneSeq
WO9013648
PAIs are believed to play a role in cancer,
Methods that measure plasminogen
Anti-angiogenesis; blood-


1; PAI-1
Accession

and cardiovascular disease and blood-
activator inhibitor (PAI) activity are known
clotting disorders.



R08411

clotting disorders.
in the art, for example, assay the ability of






PAI to inhibit tissue plasminogen activator






(tPA) or urokinase (uPA): J Biochem






Biophys Methods 2000 Sep 11; 45(2): 127-40,






Breast Cancer Res Treat






1996; 41(2): 141-6. Methods that measure






anti-angiogenesis activity are known in the






art, for example, Proc Natl Acad Sci USA






1999 Mar 16; 96(6): 2645-50.


Plasminogen
GeneSeq
DE3722673
PAIs are believed to play a role in cancer,
Methods that measure plasminogen
Anti-angiogenesis; blood-


Activator Inhibitor-
Accession

and cardiovascular disease and blood-
activator inhibitor (PAI) activity are known
clotting disorders.


2; PAI-2
P94160

clotting disorders.
in the art, for example, assay the ability of






PAI to inhibit tissue plasminogen activator






(tPA) or urokinase (uPA): J Biochem






Biophys Methods 2000 Sep 11; 45(2): 127-40,






Breast Cancer Res Treat






1996; 41(2): 141-6. Methods that measure






anti-angiogenesis activity are known in the






art, for example, Proc Natl Acad Sci USA






1999 Mar 16; 96(6): 2645-50.


Activator Inhibitor-
GeneSeq
WO9102057
PAIs are believed to play a role in cancer,
Methods that measure plasminogen
Anti-angiogenesis; blood-


2; PAI-2
Accession

and cardiovascular disease and blood-
activator inhibitor (PAI) activity are known
clotting disorders.



R10921

clotting disorders.
in the art, for example, assay the ability of






PAI to inhibit tissue plasminogen activator






(tPA) or urokinase (uPA): J Biochem






Biophys Methods 2000 Sep 11; 45(2): 127-40,






Breast Cancer Res Treat






1996; 41(2): 141-6. Methods that measure






anti-angiogenesis activity are known in the






art, for example, Proc Natl Acad Sci USA






1999 Mar 16; 96(6): 2645-50.


Human PAI-1
GeneSeq
WO9105048
PAIs are believed to play a role in cancer,
Methods that measure plasminogen
Anti-angiogenesis; blood-


mutants
Accessions

and cardiovascular disease and blood-
activator inhibitor (PAI) activity are known
clotting disorders.



R11755, R11756,

clotting disorders.
in the art, for example, assay the ability of



R11757, R11758,


PAI to inhibit tissue plasminogen activator



R11759, R11760,


(tPA) or urokinase (uPA): J Biochem



R11761, R11762


Biophys Methods 2000 Sep 11; 45(2): 127-40,



and R11763


Breast Cancer Res Treat






1996; 41(2): 141-6. Methods that measure






anti-angiogenesis activity are known in the






art, for example, Proc Natl Acad Sci USA






1999 Mar 16; 96(6): 2645-50.


CXCR3; CXC
GeneSeq
WO0018431
Chemokines are a family of related small,
Chemokine activities can be determined
Soluble CXCR3



Accession

secreted proteins involved in biological
using assays known in the art: Methods in
polypeptides may be useful



Y79372

processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:
for inhibiting chemokine





angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,
activities and viral infection.





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ.





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Modified Rantes
GeneSeq
WO9737005
Chemokines are a family of related small,
Chemokine activities can be determined
Immune disorders.



Accession

secreted proteins involved in biological
using assays known in the art: Methods in



W38129

processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:





angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ.





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


RANTES
GeneSeq
EP905240
Chemokines are a family of related small,
Chemokine activities can be determined
Immune disorders.



Accession

secreted proteins involved in biological
using assays known in the art: Methods in



Y05299

processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:





angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ.





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


MCI-Ia
GeneSeq
WO9509232
Chemokines are a family of related small,
Chemokine activities can be determined
Immune disorders.



Accession

secreted proteins involved in biological
using assays known in the art: Methods in



R73914

processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:





angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ.





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


MCP-Ib
GeneSeq
WO9929728
Chemokines are a family of related small,
Chemokine activities can be determined
Immune disorders.



Accession

secreted proteins involved in biological
using assays known in the art: Methods in



Y26176

processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:





angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ.





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


MCP-I receptor
GeneSeq
WO9519436
Chemokines are a family of related small,
Chemokine activities can be determined
Soluble MCP-1 Receptor



Accession

secreted proteins involved in biological
using assays known in the art: Methods in
polypeptides may be useful



R79165

processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:
for inhibiting chemokine





angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,
activities and viral infection.





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ.





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


MCP-3
GeneSeq
W09509232
Chemokines are a family of related small,
Chemokine activities can be determined
Immune disorders.



Accession

secreted proteins involved in biological
using assays known in the art: Methods in



R73915

processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:





angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ.





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


MCP-4 receptor
GeneSeq
W09809171
Chemokines are a family of related small,
Chemokine activities can be determined
Soluble MCP-4 Receptor



Accession

secreted proteins involved in biological
using assays known in the art: Methods in
polypeptides may be useful



W56689

processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:
for inhibiting chemokine





angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,
activities and viral infection.





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ.





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


RANTES receptor
GeneSeq
U.S. Pat. No. 5,652,133
Chemokines are a family of related small,
Chemokine activities can be determined
Soluble RANTES Receptor



Accession

secreted proteins involved in biological
using assays known in the art: Methods in
polypeptides may be useful



W29588

processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:
for inhibiting chemokine





angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,
activities and viral infection.





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ.





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


CCR5 variant
GeneSeq
WO9854317
Chemokines are a family of related small,
Chemokine activities can be determined
Soluble CCR5 polypeptides



Accession

secreted proteins involved in biological
using assays known in the art: Methods in
may be useful for inhibiting



W88238

processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:
chemokine activities and





angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,
viral infection.





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ.





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


CCR7
GeneSeq
U.S. Pat. No. 6,153,441
Chemokines are a family of related small,
Chemokine activities can be determined
Soluble CCR7 polypeptides



Accession

secreted proteins involved in biological
using assays known in the art: Methods in
may be useful for inhibiting



B50859

processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:
chemokine activities and





angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,
viral infection.





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ.





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


CXC3
GeneSeq
WO9727299
Chemokines are a family of related small,
Chemokine activities can be determined
Immune disorders.



Accession

secreted proteins involved in biological
using assays known in the art: Methods in



W23345

processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:





angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ.





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Eotaxin
GeneSeq
WO9700960
Chemokines are a family of related small,
Chemokine activities can be determined
Immune disorders.



Accession

secreted proteins involved in biological
using assays known in the art: Methods in



W10099

processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:





angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ.





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Neurotactin
GeneSeq
U.S. Pat. No. 6,013,257
Neurotactin may play a role in
Chemotactic leukocyte migration assays
Immune disorders.



Accessions
WO9742224
chemotactic leukocyte migration and brain
are known in the art, for example: J.



Y77537, W34307,

inflammation processes.
Immunol. Methods 33, ((1980)); Nature



Y53259, and,


1997 Jun 5; 387(6633): 611-7.



Y77539


Human CKbeta-9
GeneSeq
U.S. Pat. No. 6,153,441
Chemokines are a family of related small,
Chemokine activities can be determined
Immune disorders.



Accession

secreted proteins involved in biological
using assays known in the art: Methods in



B50860

processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:





angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ.





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Lymphotactin
GeneSeq
WO0073320
Chemokines are a family of related small,
Chemokine activities can be determined
Immune disorders.



Accession

secreted proteins involved in biological
using assays known in the art: Methods in



B50052

processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:





angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ.





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G.


MIP-3 alpha
GeneSeq
WO9801557
Chemokines are a family of related small,
Chemokine activities can be determined
Immune disorders.



Accession

secreted proteins involved in biological
using assays known in the art: Methods in



W44398

processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:





angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ.





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G.


MIP-3 beta
GeneSeq
WO9801557
Chemokines are a family of related small,
Chemokine activities can be determined
Immune disorders.



Accession

secreted proteins involved in biological
using assays known in the art: Methods in



W44399

processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:





angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ.





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G.


MIP-Gamma
GeneSeq
WO9504158
Chemokines are a family of related small,
Chemokine activities can be determined
Immune disorders.



Accession

secreted proteins involved in biological
using assays known in the art: Methods in



R70798

processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:





angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ.





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G.


Stem Cell
GeneSeq
WO9104274
Chemokines are a family of related small,
Chemokine activities can be determined
Hematopoietic growth


Inhibitory
Accession

secreted proteins involved in biological
using assays known in the art: Methods in
factors.


Factor
R11553

processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:





angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ.





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G.


thrombopoietin
GeneSeq
WO9521920
Thrombopoietin is involved in the
Thrombopoietin (TPO) can be assayed to
Hematopoietic growth



Accession

regulation of the growth and differentiation
determine regulation of growth and
factors.



R79905

of megakaryocytes and preceptors
differentiation of megakaryocytes. Mol





thereof.
Cell Biol 2001 Apr; 21(8): 2659-70; Exp






Hematol 2001 Jan; 29(1): 51-8 and within.


c-kit ligand;
GeneSeq
EP992579 and
C-kit ligan is thought to stimulate the
Chemokine activities can be determined
Hematopoietic growth


SCF; Mast cell
Accession
EP676470
proliferation of mast cells, and is able to
using assays known in the art: Methods in
factors.


growth factor;
Y53284, R83978

augment the proliferation of both myeloid
Molecular Biology, 2000, vol. 138:


MGF;
and R83977

and lymphoid hematopoietic progenitors in
Chemokine Protocols. Edited by: A. E. I. Proudfoot,


Fibrosarcoma-


bone marrow culture. C-kit ligand is also
T. N. C. Wells, and C. A. Power.


derived stem


though to act synergistically with other
© Humana Press Inc., Totowa, NJ.


cell factor


cytokines.


Platelet derived
GeneSeq
WO0066736
Vascular Endothelial Growth Factor
VEGF activity can be determined using
Promotion of growth and


growth factor
Accession B48653


assays known in the art, such as those
proliferation of cells, such






disclosed in International Publication No.
as vascular endothelial






WO0045835, for example.
cells. Antagonists may be







useful as anti-angiogenic







agents, and may be







applicable for cancer.


Melanoma
GeneSeq
WO9503328
Melanoma inhibiting protein has
Tumor suppressor activity of melanoma
Cancer; melanoma


inhibiting protein
Accession R69811

melanoma-inhibiting activity and can be
inhibiting protein can be determined using





used to treat cancer (melanoma,
assays known in the art: Matzuk et al.,





glioblastoma, neuroblastoma, small cell
Nature 1992 Nov 26; 360(6402): 313-9.





lung cancer, neuroectodermal tumors) or





as an immunosuppressant (it inhibits IL-2





or phytohaemagglutinin induced





proliferation of peripheral blood





lymphocytes.


Glioma-derived
GeneSeq
EP399816
Vascular Endothelial Growth Factor
VEGF activity can be determined using
Promotion of growth and


growth factor
Accession R08120


assays known in the art, such as those
proliferation of cells, such






disclosed in International Publication No.
as vascular endothelial






WO0045835, for example.
cells. Antagonists may be







useful as anti-angiogenic







agents, and may be







applicable for cancer.


Platelet derived
GeneSeq
EP682110
Vascular Endothelial Growth Factor
VEGF activity can be determined using
Promotion of growth and


growth factor
Accession R84759


assays known in the art, such as those
proliferation of cells, such


precursor A



disclosed in International Publication No.
as vascular endothelial






WO0045835, for example.
cells. Antagonists may be







useful as anti-angiogenic







agents, and may be







applicable for cancer.


Platelet derived
GeneSeq
EP682110
Vascular Endothelial Growth Factor
VEGF activity can be determined using
Promotion of growth and


growth factor
Accession R84760


assays known in the art, such as those
proliferation of cells, such


precursor B



disclosed in International Publication No.
as vascular endothelial






WO0045835, for example.
cells. Antagonists may be







useful as anti-angiogenic







agents, and may be







applicable for cancer.


Platelet derived
GeneSeq
EP282317
Vascular Endothelial Growth Factor
VEGF activity can be determined using
Promotion of growth and


growth factor Bvsis
Accession P80595


assays known in the art, such as those
proliferation of cells, such



and P80596


disclosed in International Publication No.
as vascular endothelial






WO0045835, for example.
cells. Antagonists may be







useful as anti-angiogenic







agents, and may be







applicable for cancer.


Placental Growth
GeneSeq
WO9206194
Vascular Endothelial Growth Factor
VEGF activity can be determined using
Promotion of growth and


Factor
Accessions


assays known in the art, such as those
proliferation of cells, such



R23059 and


disclosed in International Publication No.
as vascular endothelial



R23060


WO0045835, for example.
cells. Antagonists may be







useful as anti-angiogenic







agents, and may be







applicable for cancer.


Placental Growth
GeneSeq
DE19748734
Vascular Endothelial Growth Factor
VEGF activity can be determined using
Promotion of growth and


Factor-2
Accession Y08289


assays known in the art, such as those
proliferation of cells, such






disclosed in International Publication No.
as vascular endothelial






WO0045835, for example.
cells. Antagonists may be







useful as anti-angiogenic







agents, and may be







applicable for cancer.


Thrombopoietin
GeneSeq
WO0000612
Thrombopoietin is involved in the
Thrombopoietin (TPO) can be assayed to
Thrombocytopenia, cancer.


derivative1
Accession Y77244

regulation of the growth and differentiation
determine regulation of growth and





of megakaryocytes and preceptors
differentiation of megakaryocytes. Mol





thereof.
Cell Biol 2001 Apr; 21(8): 2659-70; Exp






Hematol 2001 Jan; 29(1): 51-8 and within.


Thrombopoietin
GeneSeq
WO0000612
Thrombopoietin is involved in the
Thrombopoietin (TPO) can be assayed to
Thrombocytopenia, cancer.


derivative2
Accession Y77255

regulation of the growth and differentiation
determine regulation of growth and





of megakaryocytes and preceptors
differentiation of megakaryocytes. Mol





thereof.
Cell Biol 2001 Apr; 21(8): 2659-70; Exp






Hematol 2001 Jan; 29(1): 51-8 and within.


Thrombopoietin
GeneSeq
WO0000612
Thrombopoietin is involved in the
Thrombopoietin (TPO) can be assayed to
Thrombocytopenia, cancer.


derivative3
Accession Y77262

regulation of the growth and differentiation
determine regulation of growth and





of megakaryocytes and preceptors
differentiation of megakaryocytes. Mol





thereof.
Cell Biol 2001 Apr; 21(8): 2659-70; Exp






Hematol 2001 Jan; 29(1): 51-8 and within.


Thrombopoietin
GeneSeq
WO0000612
Thrombopoietin is involved in the
Thrombopoietin (TPO) can be assayed to
Thrombocytopenia, cancer.


derivative4
Accession Y77267

regulation of the growth and differentiation
determine regulation of growth and





of megakaryocytes and preceptors
differentiation of megakaryocytes. Mol





thereof.
Cell Biol 2001 Apr; 21(8): 2659-70; Exp






Hematol 2001 Jan; 29(1): 51-8 and within.


Thrombopoietin
GeneSeq
WO0000612
Thrombopoietin is involved in the
Thrombopoietin (TPO) can be assayed to
Thrombocytopenia, cancer.


derivative5
Accession Y77246

regulation of the growth and differentiation
determine regulation of growth and





of megakaryocytes and preceptors
differentiation of megakaryocytes. Mol





thereof.
Cell Biol 2001 Apr; 21(8): 2659-70; Exp






Hematol 2001 Jan; 29(1): 51-8 and within.


Thrombopoietin
GeneSeq
WO0000612
Thrombopoietin is involved in the
Thrombopoietin (TPO) can be assayed to
Thrombocytopenia, cancer.


derivative6
Accession Y77253

regulation of the growth and differentiation
determine regulation of growth and





of megakaryocytes and preceptors
differentiation of megakaryocytes. Mol





thereof.
Cell Biol 2001 Apr; 21(8): 2659-70; Exp






Hematol 2001 Jan; 29(1): 51-8 and within.


Thrombopoietin
GeneSeq
WO0000612
Thrombopoietin is involved in the
Thrombopoietin (TPO) can be assayed to
Thrombocytopenia, cancer.


derivative7
Accession Y77256

regulation of the growth and differentiation
determine regulation of growth and





of megakaryocytes and preceptors
differentiation of megakaryocytes. Mol





thereof.
Cell Biol 2001 Apr; 21(8): 2659-70; Exp






Hematol 2001 Jan; 29(1): 51-8 and within.


Fractalkine
GeneSeq
U.S. Pat. No. 6,043,086
Fractalkine is believed to play a role in
Fractalkine activity can be determined
Immune disorders.



Accession Y53255

chemotactic leukocyte migration and
using Chemotactic leukocyte migration





neurological disorders.
assays known in the art, for example: J.






Immunol. Methods 33, ((1980)); Nature






1997 Jun 5; 387(6633): 611-7.


CXC3
GeneSeq
WO9757599
Chemokines are a family of related small,
Chemokine activities can be determined
Immune disorders.



Accession

secreted proteins involved in biological
using assays known in the art: Methods in



W23345

processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:





angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ.





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


CCR7
GeneSeq
U.S. Pat. No. 6,153,441
Chemokines are a family of related small,
Chemokine activities can be determined
Soluble CCR7 polypeptides



Accession B50859

secreted proteins involved in biological
using assays known in the art: Methods in
may be useful for inhibiting





processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:
chemokine activities and





angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,
viral infection.





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ.





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Nerve Growth
GeneSeq
EP414151
Nerve Growth Factor
Proliferation assay using NR6R-3T3 cells
Neurological disorders,


Factor-beta
Accession R11474


(Rizzino 1988 Cancer Res. 48: 4266)
cancer


Nerve Growth
GeneSeq
EP859056
Nerve Growth Factor
Proliferation assay using NR6R 3T3 cells
Neurological disorders,


Factor-beta2
Accession


(Rizzino 1988 Cancer Res. 48: 4266
cancer



W69725


Neurotrophin-3
GeneSeq
WO9821234
Neurotrophins regulate neuronal cell
Trk tyrosine kinase activation assays
Neurological disorders,



Accession

survival and synaptic plasticity.
known in the art can be used to assay for
cancer



W8889


neurotrophin activity, for example, Proc






Natl Acad Sci USA 2001 Mar






13; 98(6): 3555-3560.


Neurotrophin-3
GeneSeq
WO9325684
Neurotrophins regulate neuronal cell
Trk tyrosine kinase activation assays
Neurological disorders,



Accession R47100

survival and synaptic plasticity.
known in the art can be used to assay for
cancer






neurotrophin activity, for example, Proc






Natl Acad Sci USA 2001 Mar






13; 98(6): 3555-3560.


Neurotrophin-4a
GeneSeq
WO9325684
Neurotrophins regulate neuronal cell
Trk tyrosine kinase activation assays
Neurological disorders,



Accession R47101

survival and synaptic plasticity.
known in the art can be used to assay for
cancer






neurotrophin activity, for example, Proc






Natl Acad Sci USA 2001 Mar






13; 98(6): 3555-3560. 13; 98(6): 3555-3560


Neurotrophin-4b
GeneSeq
WO9325684
Neurotrophins regulate neuronal cell
Trk tyrosine kinase activation assays
Neurological disorders,



Accession R47102

survival and synaptic plasticity.
known in the art can be used to assay for
cancer





tyrosine kinases.
neurotrophin activity, for example, Proc






Natl Acad Sci USA 2001 Mar






13; 98(6): 3555-3560.


Neurotrophin-4c
GeneSeq
WO9325684
Neurotrophins regulate neuronal cell
Trk tyrosine kinase activation assays
Neurological disorders,



Accession R47103

survival and synaptic plasticity.
known in the art can be used to assay for
cancer





tyrosine kinases.
neurotrophin activity, for example, Proc






Natl Acad Sci USA 2001 Mar






13; 98(6): 3555-3560.


Neurotrophin-4d
GeneSeq
WO9325684
Neurotrophins regulate neuronal cell
Trk tyrosine kinase activation assays
Neurological disorders,



Accession R47102

survival and synaptic plasticity.
known in the art can be used to assay for
cancer





tyrosine kinases.
neurotrophin activity, for example, Proc






Natl Acad Sci USA 2001 Mar






13; 98(6): 3555-3560.


Platelet-Derived
GeneSeq
U.S. Pat. No. 5,219,739
Vascular Endothelial Growth Factor
VEGF activity can be determined using
Promotion of growth and


Growth Factor
Accession R38918


assays known in the art, such as those
proliferation of cells, such


A chain



disclosed in International Publication No.
as vascular endothelial






W00045835, for example.
cells. Hematopoietic and







immune disorders.







Antagonists may be useful







as anti-angiogenic agents,







and may be applicable for







cancer


Platelet-Derived
GeneSeq
U.S. Pat. No. 5,219,739
Vascular Endothelial Growth Factor
VEGF activity can be determined using
Promotion of growth and


Growth Factor
Accession R38919


assays known in the art, such as those
proliferation of cells, such


B chain



disclosed in International Publication No.
as vascular endothelial






W00045835, for example.
cells. Hematopoietic and







immune disorders.







Antagonists may be useful







as anti-angiogenic agents,







and may be applicable for







cancer


Stromal Derived
GeneSeq
WO9948528
Stromal Growth Factor
Proliferation assay using NR6R-3T3 cells
Hematopoietic, immune


Factor-1 alpha
Accession


(Rizzino 1988 Cancer Res. 48: 4266)
disorders, cancer



Y39995


Stromal Derived
GeneSeq
CA2117953
Stromal Growth Factor
Proliferation assay using NR6R-3T3 cells
Hematopoietic, immune


Factor-1 beta
Accession


(Rizzino 1988 Cancer Res. 48: 4266)
disorders, cancer



R75420


Tarc
GeneSeq
WO9711969
Chemotactic for T lymphocytes. May play
Chemotactic leukocyte migration assays
Antiinflammatory. Immune



Accession

a role in T-cell development. Thought to
are known in the art, for example: J.
disorders, cancer



W14917

bind CCR8 and CCR4
Immunol. Methods 33 ((1980))


Prolactin
GeneSeq
WO9521625
Prolactin is involved in immune cell
Immune coil proliferation and suppression
Reproductive system



Accession R78691

proliferation and apoptosis.
of apoptosis by prolactin can be assayed
disorders, cancer.






by methods well-known in the art, for






example, Buckley, AR and Buckley DJ,






Ann N Y Acad Sci 2000; 917: 522-33, and






within.


Prolactin2
GeneSeq
U.S. Pat. No. 5,955,346
Prolactin is involved in immune cell
Immune coil proliferation and suppression
Reproductive system



Accession

proliferation and apoptosis.
of apoptosis by prolactin can be assayed
disorders, cancer.



Y31764


by methods well-known in the art, for






example, Buckley, AR and Buckley DJ,






Ann N Y Acad Sci 2000; 917: 522-33, and






within.


Follicle stimulating
GeneSeq
EP974359
FSH stimulates secretion of interleukin-1
FSH activities can be determined using
Reproductive system


hormone Alpha
Accession

by cells isolated from women in the
assays known in the art; J Gend Specif
disorders, cancer.


subunit
Y54160

follicular phase
Med 1999 Nov-Dec; 2(6): 30-4; Mol Cell






Endocrinol. 1997 Nov 15; 134(2): 109-18.


Follicle stimulating
GeneSeq
EP974359
FSH stimulates secretion of interleukin-1
FSH activities can be determined using
Reproductive system


hormone Beta
Accession

by cells isolated from women in the
assays known in the art; J Gend Specif
disorders, cancer.


subunit
Y54161

follicular phase
Med 1999 Nov-Dec; 2(6): 30-4; Mol Cell






Endocrinol. 1997 Nov 15; 134(2): 109-18.


Substance P
GeneSeq
WO0054053
Substance P is associated with
Immuneregulation and bone marrow, cell
diabetes mellitus,


(tachykinin)
Accession

immunoregulation.
proliferation by substance P can be
hypertension, cancer



B23027


assayed by methods well-known in the art,






for example, Lai et al. Proc Natl Acad Sci






USA 2001 Mar 27; 98(7): 3970-5; Jallat-






Daloz et al. Allergy Asthma Proc 2001 Jan-






Feb; 22(1): 17-23; Kahler et al. Exp Lung






Res 2001 Jan-Feb; 27(1): 25-46; and






Adamus MA and Dabrowski ZJ. J Cell






Biochem 2001; 81(3)499-506.


Ocytocin
GeneSeq
WO0053755
Oxytocin is involved in the induction of
Oxytocin and prostaglandin E(2) release
inflammatory disorders


(Neurophysin I)
Accession

prostaglandin (E2) release as well as an
and Ocytocin (Ca2+) increase can be
immunologic disorders,



B24085 and

increased amount of calcium release by
assayed by methods well-known in the art,
cancer



B24086

smooth muscle cells.
for example, Pavan et al., AM J Obset






Gynecol 2000 Jul; 183(1): 76-82 and Holda






et al., Cell Calcium 1996 Jul; 20(1): 43 51.


Vasopressin
GeneSeq
WO0053755
Vasopressinis believed to have a direct
Vasopressin activity can be determined
inflammatory disorders


(Neurophysin II)
Accession

antidiuretic action on the kidney, and it is
using assays known in the art, for example,
immunologic disorders,



B24085 and

thought to cause vasoconstriction of the
Endocr Regul 1996 Mar; 30(I): 13-17.
cancer



B24086

peripheral vessels.


IL-1
GeneSeq
EP165654
Interleukins are a group of multifunctional
Interleukin activity can be determined using
inflammatory disorders,



Accession

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al., in
immunologic disorders,



P60326

monocytes, and macrophages. Known
Lymphokines and Interferens: A Practical
cancer





functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,





of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225; and





cells, eosinophils, and lymphocytes),
Orencole & Dinarclio (1989) Cytokine 1,





chemotaxis of neutrophils and T
14-20.





lymphocytes, and/or inhibition of





interferons.


IL-1 mature
GeneSeq
EP456332
Interleukins are a group of multifunctional
Interleukin activity can be determined using
inflammatory disorders,



Accession

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al., in
immunologic disorders,



R14855

monocytes, and macrophages. Known
Lymphokines and Interferens: A Practical
cancer





functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,





of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225; and





cells, eosinophils, and lymphocytes),
Orencole & Dinarclio (1989) Cytokine 1,





chemotaxis of neutrophils and T
14-20.





lymphocytes, and/or inhibition of





interferons.


IL-1 beta
GeneSeq
WO9922763
Interleukins are a group of multifunctional
Interleukin activity can be determined using
inflammatory disorders,



Accession

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al., in
immunologic disorders,



Y08322

monocytes, and macrophages. Known
Lymphokines and Interferens: A Practical
cancer





functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,





of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225; and





cells, eosinophils, and lymphocytes),
Orencole & Dinarclio (1989) Cytokine 1,





chemotaxis of neutrophils and T
14-20.





lymphocytes, and/or inhibition of





interferons.


IL-3 variants
GeneSeq
WO8806161
Interleukins are a group of multifunctional
Interleukin activity can be determined using
inflammatory disorders,



Accession

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al., in
immunologic disorders,



P80382, P80383,

monocytes, and macrophages. Known
Lymphokines and Interferens: A Practical
cancer



P80384, and

functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,



P80381

of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225; and





cells, eosinophils, and lymphocytes),
Kitamura et al (1989) J Cell Physiol. 140





chemotaxis of neutrophils and T
323-334.





lymphocytes, and/or inhibition of





interferons.


IL-4
GeneSeq
WO8702990
Interleukins are a group of multifunctional
Interleukin activity can be determined using
inflammatory disorders,



Accession

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al., in
immunologic disorders,



P70615

monocytes, and macrophages. Known
Lymphokines and Interferens: A Practical
cancer





functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,





of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225; and





cells, eosinophils, and lymphocytes),
Siegel & Mostowski (1990) J Immunol





chemotaxis of neutrophils and T
Methods 132, 287-295.





lymphocytes, and/or inhibition of





interferons.


IL-4 muteins
GeneSeq
WO9747744
Interleukins are a group of multifunctional
Interleukin activity can be determined using
inflammatory disorders,



Accession

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al., in
immunologic disorders,



W52151

monocytes, and macrophages. Known
Lymphokines and Interferens: A Practical
cancer



W52152

functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,



W52153

of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225; and



W52154

cells, eosinophils, and lymphocytes),
Siegel & Mostowski (1990) J Immunol



W52155

chemotaxis of neutrophils and T
Methods 132, 287-295.



W52156

lymphocytes, and/or inhibition of



W52157

interferons.



W52158



W52159



W52160



W52161



W52162



W52163



W52164



and W52165


IL-1 alpha
GeneSeq
EP324447
Interleukins are a group of multifunctional
Interleukin activity can be determined using
inflammatory disorders,



Accession

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al., in
immunologic disorders,



P90108

monocytes, and macrophages. Known
Lymphokines and Interferens: A Practical
cancer





functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,





of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225; and





cells, eosinophils, and lymphocytes),
Orencole & Dinarello (1989) Cytokine 1,





chemotaxis of neutrophils and T
14-20.





lymphocytes, and/or inhibition of





interferons.


IL-3 variants
GeneSeq
WO9307171
Interleukins are a group of multifunctional
Interleukin activity can be determined using
inflammatory disorders,



Accession

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al., in
immunologic disorders,



R38561, R38562,

monocytes, and macrophages. Known
Lymphokines and Interferens: A Practical
cancer



R38563, R38564,

functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,



R38565, R38566,

of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225; and



R38567, R38568,

cells, eosinophils, and lymphocytes),
Aarden et al (1987) Eur. J. Immunol 17,



R38569, R38570,

chemotaxis of neutrophils and T
1411-16.



R38571, and

lymphocytes, and/or inhibition of



R38572

interferons.


IL-6
GeneSeq
WO9402512
Interleukins are a group of multifunctional
Interleukin activity can be determined using
inflammatory disorders,



Accession

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al., in
immunologic disorders,



R45717 and

monocytes, and macrophages. Known
Lymphokines and Interferens: A Practical
cancer



R45718

functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,





of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225; and





cells, eosinophils, and lymphocytes),
Aarden et al (1987) Eur. J. Immunol 17,





chemotaxis of neutrophils and T
1411-16.





lymphocytes, and/or inhibition of





interferons.


IL-13
GeneSeq
WO9404680
Interleukins are a group of multifunctional
Interleukin activity can be determined using
inflammatory disorders,



Accession

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al., in
immunologic disorders,



R48624

monocytes, and macrophages. Known
Lymphokines and Interferens: A Practical
cancer





functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,





of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225; and





cells, eosinophils, and lymphocytes),
Boutelier et al (1995) J. Immunol. Methods





chemotaxis of neutrophils and T
181, 29.





lymphocytes, and/or inhibition of





interferons.


IL-4 mutein
GeneSeq
DE4137333
Interleukins are a group of multifunctional
Interleukin activity can be determined using
inflammatory disorders,



Accession

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al., in
immunologic disorders,



R47182

monocytes, and macrophages. Known
Lymphokines and Interferens: A Practical
cancer





functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,





of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225; and





cells, eosinophils, and lymphocytes),
Siegel & Mostowski (1990) J Immunol





chemotaxis of neutrophils and T
Methods 132, 287-295.





lymphocytes, and/or inhibition of





interferons.


IL-4 mutein
GeneSeq
DE4137333
Interleukins are a group of multifunctional
Interleukin activity can be determined using
inflammatory disorders,


Y124X
Accession

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al., in
immunologic disorders,



R47183

monocytes, and macrophages. Known
Lymphokines and Interferens: A Practical
cancer





functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,





of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225; and





cells, eosinophils, and lymphocytes),
Siegel & Mostowski (1990) J Immunol





chemotaxis of neutrophils and T
Methods 132, 287-295.





lymphocytes, and/or inhibition of





interferons.


IL-4 mutein
GeneSeq
DE4137333
Interleukins are a group of multifunctional
Interleukin activity can be determined using
inflammatory disorders,


Y124G
Accession

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al., in
immunologic disorders,



R47184

monocytes, and macrophages. Known
Lymphokines and Interferens: A Practical
cancer





functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,





of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225; and





cells, eosinophils, and lymphocytes),
Siegel & Mostowski (1990) J Immunol





chemotaxis of neutrophils and T
Methods 132, 287-295.





lymphocytes, and/or inhibition of





interferons.


Human
GeneSeq
WO9317698
Interleukins are a group of multifunctional
Interleukin activity can be determined using
inflammatory disorders,


Interleukin-10
Accession

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al., in
immunologic disorders,


(precursor)
R41664

monocytes, and macrophages. Known
Lymphokines and Interferens: A Practical
cancer





functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,





of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225; and





cells, eosinophils, and lymphocytes),
Thompson-Snipes et al (1991) J. Exp. Med.





chemotaxis of neutrophils and T
173, 507-510.





lymphocytes, and/or inhibition of





interferons.


Human
GeneSeq
WO9318783-A
Interleukins are a group of multifunctional
Interleukin activity can be determined using
inflammatory disorders,


Interleukin-10
Accession

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al., in
immunologic disorders,



R42642

monocytes, and macrophages. Known
Lymphokines and Interferens: A Practical
cancer





functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,





of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225; and





cells, eosinophils, and lymphocytes),
Thompson-Snipes et al (1991) J. Exp. Med.





chemotaxis of neutrophils and T
173, 507-510.





lymphocytes, and/or inhibition of





interferons.


Human
GeneSeq
EP569042
Interleukins are a group of multifunctional
Interleukin activity can be determined using
inflammatory disorders,


interleukin-1
Accession

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al., in
immunologic disorders,


beta precursor.
R42447

monocytes, and macrophages. Known
Lymphokines and Interferens: A Practical
cancer





functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,





of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225; and





cells, eosinophils, and lymphocytes),
Orencole & Dinarello (1989) Cytokine 1,





chemotaxis of neutrophils and T
14-20.





lymphocytes, and/or inhibition of





interferons.


Interleukin-
GeneSeq
EP578278
Interleukins are a group of multifunctional
Interleukin activity can be determined using
inflammatory disorders,


1alpha
Accession

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al., in
immunologic disorders,



R45364

monocytes, and macrophages. Known
Lymphokines and Interferens: A Practical
cancer





functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,





of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225.





cells, eosinophils, and lymphocytes),





chemotaxis of neutrophils and T





lymphocytes, and/or inhibition of





interferons.


Human
GeneSeq
JP04063595
Interleukins are a group of multifunctional
Interleukin activity can be determined using
inflammatory disorders,


interleukin-3
Accession

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al., in
immunologic disorders,


variant
R22814

monocytes, and macrophages. Known
Lymphokines and Interferens: A Practical
cancer





functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,





of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225; and





cells, eosinophils, and lymphocytes),
Kitamura et al (1989) J Cell Physiol. 140





chemotaxis of neutrophils and T
323-334.





lymphocytes, and/or inhibition of





interferons.


IL-1i fragments
GeneSeq
EP541920
Interleukins are a group of multifunctional
Interleukin activity can be determined using
inflammatory disorders,



Accession

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al., in
immunologic disorders,



R35484 and

monocytes, and macrophages. Known
Lymphokines and Interferens: A Practical
cancer



R35485

functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,





of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225; and





cells, eosinophils, and lymphocytes),
Orencole & Dinarclio (1989) Cytokine 1,





chemotaxis of neutrophils and T
14-20.





lymphocytes, and/or inhibition of





interferons.


IL-1 inhibitor
GeneSeq
EPS541920
Interleukins are a group of multifunctional
Interleukin activity can be determined using
inflammatory disorders,


(IL-li)
Accession

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al., in
immunologic disorders,



R35486 and

monocytes, and macrophages. Known
Lymphokines and Interferens: A Practical
cancer



R35484

functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,





of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225; and





cells, eosinophils, and lymphocytes),
Orencole & Dinarclio (1989) Cytokine 1,





chemotaxis of neutrophils and T
14-20.





lymphocytes, and/or inhibition of





interferons.


ICE 22 kD subunit.
GeneSeq
EP533350
Interleukins are a group of multifunctional
Interleukin activity can be determined using
inflammatory disorders,



Accession

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al., in
immunologic disorders,



R33780

monocytes, and macrophages. Known
Lymphokines and Interferens: A Practical
cancer





functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,





of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225.





cells, eosinophils, and lymphocytes),





chemotaxis of neutrophils and T





lymphocytes, and/or inhibition of





interferons.


ICE 20 kD subunit.
GeneSeq
EP533350
Interleukins are a group of multifunctional
Interleukin activity can be determined using
inflammatory disorders,



Accession

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al., in
immunologic disorders,



R33781

monocytes, and macrophages. Known
Lymphokines and Interferens: A Practical
cancer





functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,





of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225.





cells, eosinophils, and lymphocytes),





chemotaxis of neutrophils and T





lymphocytes, and/or inhibition of





interferons.


ICE 10 kD
GeneSeq
EP533350
Interleukins are a group of multifunctional
Interleukin activity can be determined using
inflammatory disorders,


subunit
Accession

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al., in
immunologic disorders,



R33782

monocytes, and macrophages. Known
Lymphokines and Interferens: A Practical
cancer





functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,





of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225.





cells, eosinophils, and lymphocytes),





chemotaxis of neutrophils and T





lymphocytes, and/or inhibition of





interferons.


Human
GeneSeq
WO9317698
Interleukins are a group of multifunctional
Interleukin activity can be determined using
inflammatory disorders,


Interleukin-10
Accession

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al., in
immunologic disorders,


(precursor)
R41664

monocytes, and macrophages. Known
Lymphokines and Interferens: A Practical
cancer





functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,





of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225; and





cells, eosinophils, and lymphocytes),
Thompson-Snipes et al (1991) J. Exp. Med.





chemotaxis of neutrophils and T
173, 507-510.





lymphocytes, and/or inhibition of





interferons.


Human
GeneSeq
WO9318783
Interleukins are a group of multifunctional
Interleukin activity can be determined using
inflammatory disorders,


Interleukin-10
Accession

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al., in
immunologic disorders,



R42642

monocytes, and macrophages. Known
Lymphokines and Interferens: A Practical
cancer





functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,





of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225; and





cells, eosinophils, and lymphocytes),
Thompson-Snipes et al (1991) J. Exp. Med.





chemotaxis of neutrophils and T
173, 507-510.





lymphocytes, and/or inhibition of





interferons.


Human
GeneSeq
EP569042
Interleukins are a group of multifunctional
Interleukin activity can be determined using
inflammatory disorders,


Interleukin-1
Accession

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al., in
immunologic disorders,


beta precursor
R42447

monocytes, and macrophages. Known
Lymphokines and Interferens: A Practical
cancer





functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,





of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225; and





cells, eosinophils, and lymphocytes),
Kitamura et al (1989) J Cell Physiol. 140





chemotaxis of neutrophils and T
323-334.





lymphocytes, and/or inhibition of





interferons.


Human
GeneSeq
WO9403492
Interleukins are a group of multifunctional
Interleukin activity can be determined using
inflammatory disorders,


interleukin-6
Accession

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al., in
immunologic disorders,



R49041

monocytes, and macrophages. Known
Lymphokines and Interferens: A Practical
cancer





functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,





of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225; and





cells, eosinophils, and lymphocytes),
Aarden et al (1987) Eur. J. Immunol 17,





chemotaxis of neutrophils and T
1411-16.





lymphocytes, and/or inhibition of





interferons.


Mutant Interleukin 6
GeneSeq
WO9411402
Interleukins are a group of multifunctional
Interleukin activity can be determined using
inflammatory disorders,


S176R
Accession

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al., in
immunologic disorders,



R54990

monocytes, and macrophages. Known
Lymphokines and Interferens: A Practical
cancer





functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,





of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225; and





cells, eosinophils, and lymphocytes),
Aarden et al (1987) Eur. J. Immunol 17,





chemotaxis of neutrophils and T
1411-16.





lymphocytes, and/or inhibition of





interferons.


Interleukin 6
GeneSeq
JP06145063
Interleukins are a group of multifunctional
Interleukin activity can be determined using
inflammatory disorders,



Accession

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al., in
immunologic disorders,



R55256

monocytes, and macrophages. Known
Lymphokines and Interferens: A Practical
cancer





functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,





of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225; and





cells, eosinophils, and lymphocytes),
Aarden et al (1987) Eur. J. Immunol 17,





chemotaxis of neutrophils and T
1411-16.





lymphocytes, and/or inhibition of





interferons.


Interleukin 8
GeneSeq
JP06100595
Interleukins are a group of multifunctional
Interleukin activity can be determined using
Soluble IL-8 receptor


(IL-8) receptor
Accession

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al., in
polypeptides may be useful



R53932

monocytes, and macrophages. Known
Lymphokines and Interferens: A Practical
for inhibiting interleukin





functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,
activities.





of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225; and





cells, eosinophils, and lymphocytes),
Holmes et al (1991) Science 253, 1278-80.





chemotaxis of neutrophils and T





lymphocytes, and/or inhibition of





interferons.


Human
GeneSeq
U.S. Pat. No. 5,328,988
Interleukins are a group of multifunctional
Interleukin activity can be determined using
inflammatory disorders,


interleukin-7
Accession

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al., in
immunologic disorders,



R59919

monocytes, and macrophages. Known
Lymphokines and Interferens: A Practical
cancer





functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,





of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225; and





cells, eosinophils, and lymphocytes),
Park et al (1990) J. Exp. Med. 171, 1073-79.





chemotaxis of neutrophils and T





lymphocytes, and/or inhibition of





interferons.


IL-3 containing
GeneSeq
WO9521254
Interleukins are a group of multifunctional
Interleukin activity can be determined using
inflammatory disorders,


fusion protein.
Accession

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al., in
immunologic disorders,



R79342 and

monocytes, and macrophages. Known
Lymphokines and Interferens: A Practical
cancer



R79344

functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,





of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225; and





cells, eosinophils, and lymphocytes),
Kitamura et al (1989) J Cell Physiol. 140





chemotaxis of neutrophils and T
323-334.





lymphocytes, and/or inhibition of





interferons.


IL-3 mutant
GeneSeq
ZA9402636
Interleukins are a group of multifunctional
Interleukin activity can be determined using
inflammatory disorders,


proteins
Accession

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al., in
immunologic disorders,



R79254, R79255,

monocytes, and macrophages. Known
Lymphokines and Interferens: A Practical
cancer



R79256, R79257,

functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,



R79258, R79259,

of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225; and



R79260, R79261,

cells, eosinophils, and lymphocytes),
Giri et al (1994) EMBO J. 13 2822-2830.



R79262, R79263,

chemotaxis of neutrophils and T



R79264, R79265,

lymphocytes, and/or inhibition of



R79266, R79267,

interferons.



R79268, R79269,



R79270, R79271,



R79272, R79273,



R79274, R79275,



R79276, R79277,



R79278, R79279,



R79280, R79281,



R79282, R79283,



R79284, and



R79285


IL-12 p40
GeneSeq
AU9466072
Interleukins are a group of multifunctional
Interleukin activity can be determined using
inflammatory disorders,


subunit.
Accession

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al., in
immunologic disorders,



R63018

monocytes, and macrophages. Known
Lymphokines and Interferens: A Practical
cancer





functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,





of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225.





cells, eosinophils, and lymphocytes),





chemotaxis of neutrophils and T





lymphocytes, and/or inhibition of





interferons.


AGF
GeneSeq
WO9429344
Interleukins are a group of multifunctional
Interleukin activity can be determined using
inflammatory disorders,



Accession

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al., in
immunologic disorders,



R64240

monocytes, and macrophages. Known
Lymphokines and Interferens: A Practical
cancer





functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,





of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225.





cells, eosinophils, and lymphocytes),





chemotaxis of neutrophils and T





lymphocytes, and/or inhibition of





interferons.


Human
GeneSeq
WO9519786
Interleukins are a group of multifunctional
Interleukin activity can be determined using
inflammatory disorders,


interlaukin-12 40 kD
Accession

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al., in
immunologic disorders,


subunit
R79187

monocytes, and macrophages. Known
Lymphokines and Interferens: A Practical
cancer





functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,





of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225; and





cells, eosinophils, and lymphocytes),
Hori et al (1987), Blood 70, 1069-1078.





chemotaxis of neutrophils and T





lymphocytes, and/or inhibition of





interferons.


Human
GeneSeq
WO9530695
Interleukins are a group of multifunctional
Interleukin activity can be determined using
Soluble IL-8 receptor


interleukin-15
Accession

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al., in
polypeptides may be useful


receptor from
R90843

monocytes, and macrophages. Known
Lymphokines and Interferens: A Practical
for inhibiting interleukin


clone P1


functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,
activities.





of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225; and





cells, eosinophils, and lymphocytes),
Giri et al (1994) EMBO J. 13 2822-2830.





chemotaxis of neutrophils and T





lymphocytes, and/or inhibition of





interferons.


Human
GeneSeq
WO9604306
Interleukins are a group of multifunctional
Interleukin activity can be determined using
inflammatory disorders,


interleukin-7
Accession

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al., in
immunologic disorders,



R92796

monocytes, and macrophages. Known
Lymphokines and Interferens: A Practical
cancer





functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,





of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225; and





cells, eosinophils, and lymphocytes),
Park et al (1990) J. Exp. Med. 171, 1073-79.





chemotaxis of neutrophils and T





lymphocytes, and/or inhibition of





interferons.


interleukin-9
GeneSeq
WO9604306
Interleukins are a group of multifunctional
Interleukin activity can be determined using
inflammatory disorders,



Accession

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al., in
immunologic disorders,



R92797

monocytes, and macrophages. Known
Lymphokines and Interferens: A Practical
cancer





functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,





of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225; and





cells, eosinophils, and lymphocytes),
Yang et al (1989) Blood 74, 1880-84.





chemotaxis of neutrophils and T





lymphocytes, and/or inhibition of





interferons.


interleukin-3
GeneSeq
WO9604306
Interleukins are a group of multifunctional
Interleukin activity can be determined using
inflammatory disorders,



Accession

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al., in
immunologic disorders,



R92801

monocytes, and macrophages. Known
Lymphokines and Interferens: A Practical
cancer





functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,





of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225; and





cells, eosinophils, and lymphocytes),
Kitamura et al (1989) J Cell Physiol. 140





chemotaxis of neutrophils and T
323-334.





lymphocytes, and/or inhibition of





interferons.


Human
GeneSeq
WO9604306
Interleukins are a group of multifunctional
Interleukin activity can be determined using
inflammatory disorders,


interleukin-5
Accession

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al., in
immunologic disorders,



R92802

monocytes, and macrophages. Known
Lymphokines and Interferens: A Practical
cancer





functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,





of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225; and





cells, eosinophils, and lymphocytes),
Kitamura et al (1989) J Cell Physiol. 140





chemotaxis of neutrophils and T
323-334.





lymphocytes, and/or inhibition of





interferons.


Recombinant
GeneSeq
DE19617202
Interleukins are a group of multifunctional
Interleukin activity can be determined using
inflammatory disorders,


interleukin-16
Accession

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al., in
immunologic disorders,



W33373

monocytes, and macrophages. Known
Lymphokines and Interferens: A Practical
cancer





functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,





of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225; and





cells, eosinophils, and lymphocytes),
Lim et al (1996) J. Immunol. 156, 2566-70.





chemotaxis of neutrophils and T





lymphocytes, and/or inhibition of





interferons.


Human IL-16
GeneSeq
DE19617202
Interleukins are a group of multifunctional
Interleukin activity can be determined using
inflammatory disorders,


protein
Accession

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al., in
immunologic disorders,



W33234

monocytes, and macrophages. Known
Lymphokines and Interferens: A Practical
cancer





functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,





of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225; and





cells, eosinophils, and lymphocytes),
Lim et al (1996) J. Immunol. 156, 2566-70.





chemotaxis of neutrophils and T





lymphocytes, and/or inhibition of





interferons.


Thrl 17 human
GeneSeq
WO9708321
Interleukins are a group of multifunctional
Interleukin activity can be determined using
inflammatory disorders,


interleukin 9
Accession

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al., in
immunologic disorders,



W27521

monocytes, and macrophages. Known
Lymphokines and Interferens: A Practical
cancer





functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,





of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225.





cells, eosinophils, and lymphocytes),





chemotaxis of neutrophils and T





lymphocytes, and/or inhibition of





interferons.


Metl 17 human
GeneSeq
WO9708321
Interleukins are a group of multifunctional
Interleukin activity can be determined using
inflammatory disorders,


interleukin 9
Accession

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al., in
immunologic disorders,



W27522

monocytes, and macrophages. Known
Lymphokines and Interferens: A Practical
cancer





functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,





of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225; and





cells, eosinophils, and lymphocytes),
Yang et al (1989) Blood 74, 1880-84.





chemotaxis of neutrophils and T





lymphocytes, and/or inhibition of





interferons.


Human
GeneSeq
EP86-4585
Interleukins are a group of multifunctional
Interleukin activity can be determined using
inflammatory disorders,


intracellular IL-1
Accession

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al., in
immunologic disorders,


receptor
W77158

monocytes, and macrophages. Known
Lymphokines and Interferens: A Practical
cancer


antagonist.


functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,





of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225; and





cells, eosinophils, and lymphocytes),
Orencole & Dinarello (1989) Cytokine 1,





chemotaxis of neutrophils and T
14-20.





lymphocytes, and/or inhibition of





interferons.


Human
GeneSeq
EP864585
Interleukins are a group of multifunctional
Interleukin activity can be determined using
inflammatory disorders,


interleukin-18
Accession

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al., in
immunologic disorders,


protein (IL-18)
W77158

monocytes, and macrophages. Known
Lymphokines and Interferens: A Practical
cancer





functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,





of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225; and





cells, eosinophils, and lymphocytes),
USHIO et al (1996) J. Immunol. 156, 4274-79.





chemotaxis of neutrophils and T





lymphocytes, and/or inhibition of





interferons.


Human
GeneSeq
EP861663
Interleukins are a group of multifunctional
Interleukin activity can be determined using
inflammatory disorders,


interleukin-18
Accession

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al., in
immunologic disorders,



W77077

monocytes, and macrophages. Known
Lymphokines and Interferens: A Practical
cancer





functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,





of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225; and





cells, eosinophils, and lymphocytes),
USHIO et al (1996) J. Immunol. 156, 4274-79.





chemotaxis of neutrophils and T





lymphocytes, and/or inhibition of





interferons.


Human interleukin
GeneSeq
EP861663
Interleukins are a group of multifunctional
Interleukin activity can be determined using
inflammatory disorders,


18 derivatives
Accessions

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al.,
immunologic disorders,



W77083,

monocytes, and macrophages. Known
in Lymphokines and Interferons: A Practical
cancer



W77084,

functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,



W77085,

of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225; and



W77086,

cells, eosinophils, and lymphocytes),
Ushio et al (1996) J. Immunol, 156, 4274-79.



W77087,

chemotaxis of neutrophils and T



W77088, and

lymphocytes, and/or inhibition of



W77089

interferons.


Interleukin-9
GeneSeq
WO9827997
Interleukins are a group of multifunctional
Interleukin activity can be determined using
inflammatory disorders,


(IL-9) mature
Accession

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al.,
immunologic disorders,


protein (Thr117
W68158

monocytes, and macrophages. Known
in Lymphokines and Interferons: A Practical
cancer


version).


functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,





of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225; and





cells, eosinophils, and lymphocytes),
Yang et al (1989) Blood 74, 1880-84.





chemotaxis of neutrophils and T





lymphocytes, and/or inhibition of





interferons.


IL-9 mature
GenSeq Accession
WO9827997
Interleukins are a group of multifunctional
Interleukin activity can be determined using
inflammatory disorders,


protein variant
W68157

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al.,
immunologic disorders,


(Met117 version)


monocytes, and macrophages. Known
in Lymphokines and Interferons: A Practical
cancer





functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,





of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225; and





cells, eosinophils, and lymphocytes),
Yang et al (1989) Blood 74, 1880-84.





chemotaxis of neutrophils and T





lymphocytes, and/or inhibition of





interferons.


Human IL-9
GeneSeq
WO9824904
Interleukins are a group of multifunctional
Interleukin activity can be determined using
inflammatory disorders,


receptor protein
Accession

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al.,
immunologic disorders,


variant #3.
W64058

monocytes, and macrophages. Known
in Lymphokines and Interferons: A Practical
cancer





functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,





of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225; and





cells, eosinophils, and lymphocytes),
Yang et al (1989) Blood 74, 1880-84.





chemotaxis of neutrophils and T





lymphocytes, and/or inhibition of





interferons.


Human IL-9
GenSeq Accession
WO9824904
Interleukins are a group of multifunctional
Interleukin activity can be determined using
Soluble IL-9 receptor


receptor protein
W64060

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al.,
polypeptides may be useful


variant fragment


monocytes, and macrophages. Known
in Lymphokines and Interferons: A Practical
for inhibiting interleukin





functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,
activities.





of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225; and





cells, eosinophils, and lymphocytes),
Yang et al (1989) Blood 74, 1880-84.





chemotaxis of neutrophils and T





lymphocytes, and/or inhibition of





interferons.


Human IL-9
GeneSeq
WO9824904
Interleukins are a group of multifunctional
Interleukin activity can be determined using
Soluble IL-9 receptor


receptor protein
Accession

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al.,
polypeptides may be useful


variant #3.
W64061

monocytes, and macrophages. Known
in Lymphokines and Interferons: A Practical
for inhibiting interleukin





functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,
activities.





of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225; and





cells, eosinophils, and lymphocytes),
Yang et al (1989) Blood 74, 1880-84.





chemotaxis of neutrophils and T





lymphocytes, and/or inhibition of





interferons.


Human
GeneSeq
WO9817689
Interleukins are a group of multifunctional
Interleukin activity can be determined using
inflammatory disorders,


Interleukin-12 p40
Accession

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al.,
immunologic disorders,


protein
W51311

monocytes, and macrophages. Known
in Lymphokines and Interferons: A Practical
cancer





functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,





of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225; and





cells, eosinophils, and lymphocytes),
Hori et al (1987), Blood 70, 1069-1078.





chemotaxis of neutrophils and T





lymphocytes, and/or inhibition of





interferons.


Human
GeneSeq
WO9817689
Interleukins are a group of multifunctional
Interleukin activity can be determined using
inflammatory disorders,


Interleukin-12 p35
Accession

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al.,
immunologic disorders,


protein
W51312

monocytes, and macrophages. Known
in Lymphokines and Interferons: A Practical
cancer





functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,





of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225; and





cells, eosinophils, and lymphocytes),
Hori et al (1987), Blood 70, 1069-1078.





chemotaxis of neutrophils and T





lymphocytes, and/or inhibition of





interferons.


Human protein
GeneSeq
DE19649233-
Interleukins are a group of multifunctional
Interleukin activity can be determined using
inflammatory disorders,


with IL-16 activity
Accession

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al.,
immunologic disorders,



W63753

monocytes, and macrophages. Known
in Lymphokines and Interferons: A Practical
cancer





functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,





of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225; and





cells, eosinophils, and lymphocytes),
Lim et al (1996) J. Immunol. 156, 2566-70.





chemotaxis of neutrophils and T





lymphocytes, and/or inhibition of





interferons.


Human protein
GeneSeq
DE19649233-
Interleukins are a group of multifunctional
Interleukin activity can be determined using
inflammatory disorders,


with IL-16 activity
Accession

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al.,
immunologic disorders,



W59425

monocytes, and macrophages. Known
in Lymphokines and Interferons: A Practical
cancer





functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,





of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225; and





cells, eosinophils, and lymphocytes),
Lim et al (1996) J. Immunol. 156, 2566-70.





chemotaxis of neutrophils and T





lymphocytes, and/or inhibition of





interferons.


Human
GeneSeq
U.S. Pat. No. 5,747,024
Interleukins are a group of multifunctional
Interleukin activity can be determined using
inflammatory disorders,


interleukin-15
Accession

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al.,
immunologic disorders,



W53878

monocytes, and macrophages. Known
in Lymphokines and Interferons: A Practical
cancer





functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,





of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225; and





cells, eosinophils, and lymphocytes),
Giri et al (1994) EMBO J. 13 2822-2830.





chemotaxis of neutrophils and T





lymphocytes, and/or inhibition of





interferons.


Human wild-type
GeneSeq
WO9747744
Interleukins are a group of multifunctional
Interleukin activity can be determined using
inflammatory disorders,


interleukin-4 (hIL-
Accession

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al.,
immunologic disorders,


4) protein
W52149

monocytes, and macrophages. Known
in Lymphokines and Interferons: A Practical
cancer





functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,





of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225; and





cells, eosinophils, and lymphocytes),
Siegel & Mostowski (1990) J Immunol





chemotaxis of neutrophils and T
Methods 132, 287-295.





lymphocytes, and/or inhibition of





interferons.


interleukin-4
GeneSeq
WO9747744
Interleukins are a group of multifunctional
Interleukin activity can be determined using
inflammatory disorders,


muteins
Accessions

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al.,
immunologic disorders,



W52150,

monocytes, and macrophages. Known
in Lymphokines and Interferons: A Practical
cancer



W52151,

functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,



W52153,

of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225; and



W52154,

cells, eosinophils, and lymphocytes),
Siegel & Mostowski (1990) J Immunol



W52155,

chemotaxis of neutrophils and T
Methods 132, 287-295.



W52156,

lymphocytes, and/or inhibition of



W52157,

interferons.



W52158,



W52159,



W52160,



W52161,



W52162,



W52163,



W52164,



W52165,



W52166, and



W52167


Human interleukin
GeneSeq
WO9935268
Interleukins are a group of multifunctional
Interleukin activity can be determined using
inflammatory disorders,


1 delta
Accession

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al.,
immunologic disorders,



Y28408

monocytes, and macrophages. Known
in Lymphokines and Interferons: A Practical
cancer





functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,





of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225; and





cells, eosinophils, and lymphocytes),
Orencole & Dinarello (1989) Cytokine 1,





chemotaxis of neutrophils and T
14-20.





lymphocytes, and/or inhibition of





interferons.


Human
GeneSeq
WO9935268
Interleukins are a group of multifunctional
Interleukin activity can be determined using
inflammatory disorders,


interleukin-1
Accession

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al.,
immunologic disorders,


receptor
Y24395

monocytes, and macrophages. Known
in Lymphokines and Interferons: A Practical
cancer


antagonist beta


functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,





of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225; and





cells, eosinophils, and lymphocytes),
Orencole & Dinarello (1989) Cytokine 1,





chemotaxis of neutrophils and T
14-20.





lymphocytes, and/or inhibition of





interferons.


Human EDIRF II
GeneSeq
WO9932632
Interleukins are a group of multifunctional
Interleukin activity can be determined using
inflammatory disorders,


protein sequence
Accession

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al.,
immunologic disorders,



Y22199

monocytes, and macrophages. Known
in Lymphokines and Interferons: A Practical
cancer





functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,





of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225.





cells, eosinophils, and lymphocytes),





chemotaxis of neutrophils and T





lymphocytes, and/or inhibition of





interferons.


Human EDIRF I
GeneSeq
WO9932632
Interleukins are a group of multifunctional
Interleukin activity can be determined using
inflammatory disorders,


protein sequence
Accession

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al.,
immunologic disorders,



Y22197

monocytes, and macrophages. Known
in Lymphokines and Interferons: A Practical
cancer





functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,





of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225.





cells, eosinophils, and lymphocytes),





chemotaxis of neutrophils and T





lymphocytes, and/or inhibition of





interferons.


Human IL-1RD10
GeneSeq
WO9919480
Interleukins are a group of multifunctional
Interleukin activity can be determined using
Soluble IL-1RD10 receptor


protein sequence
Accession

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al.,
polypeptides may be useful



Y14131

monocytes, and macrophages. Known
in Lymphokines and Interferons: A Practical
for inhibiting interleukin





functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,
activites.





of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225; and





cells, eosinophils, and lymphocytes),
Orencole & Dinarello (1989) Cytokine 1,





chemotaxis of neutrophils and T
14-20.





lymphocytes, and/or inhibition of





interferons.


Human IL-1RD9
GeneSeq
WO9919480
Interleukins are a group of multifunctional
Interleukin activity can be determined using
Soluble IL-1RD10 receptor



Accession

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al.,
polypeptides may be useful



Y14122

monocytes, and macrophages. Known
in Lymphokines and Interferons: A Practical
for inhibiting interleukin





functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,
activites.





of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225; and





cells, eosinophils, and lymphocytes),
Orencole & Dinarello (1989) Cytokine 1,





chemotaxis of neutrophils and T
14-20.





lymphocytes, and/or inhibition of





interferons.


Human DNAX
GeneSeq
WO9919491
Interleukins are a group of multifunctional
Interleukin activity can be determined using
inflammatory disorders,


interleukin-40
Accession

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al.,
immunologic disorders,



Y09196

monocytes, and macrophages. Known
in Lymphokines and Interferons: A Practical
cancer





functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,





of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225.





cells, eosinophils, and lymphocytes),





chemotaxis of neutrophils and T





lymphocytes, and/or inhibition of





interferons.


(DIL-40)
GeneSeq
WO9919491
Interleukins are a group of multifunctional
Interleukin activity can be determined using
inflammatory disorders,


alternative
Accession

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al.,
immunologic disorders,


sequence
Y09197

monocytes, and macrophages. Known
in Lymphokines and Interferons: A Practical
cancer





functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,





of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225.





cells, eosinophils, and lymphocytes),





chemotaxis of neutrophils and T





lymphocytes, and/or inhibition of





interferons.


IL-11
GeneSeq
WO9405318
Interleukins are a group of multifunctional
Interleukin activity can be determined using
inflammatory disorders,



Accession

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al.,
immunologic disorders,



R50176

monocytes, and macrophages. Known
in Lymphokines and Interferons: A Practical
cancer





functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,





of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225; and





cells, eosinophils, and lymphocytes),
Lu et al (1994) J immunol. Methods 173,





chemotaxis of neutrophils and T
19.





lymphocytes, and/or inhibition of





interferons.


Human
GeneSeq
EP566410
Interleukins are a group of multifunctional
Interleukin activity can be determined using
inflammatory disorders,


adipogenesis
Accession

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al.,
immunologic disorders,


inhibitory factor
R43260

monocytes, and macrophages. Known
in Lymphokines and Interferons: A Practical
cancer





functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,





of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225.





cells, eosinophils, and lymphocytes),





chemotaxis of neutrophils and T





lymphocytes, and/or inhibition of





interferons.


IL-11
GeneSeq
JP08127539
Interleukins are a group of multifunctional
Interleukin activity can be determined using
inflammatory disorders,



Accession

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al.,
immunologic disorders,



W02202

monocytes, and macrophages. Known
in Lymphokines and Interferons: A Practical
cancer





functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,





of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225; and





cells, eosinophils, and lymphocytes),
Lu et al (1994) J immunol. Methods 173,





chemotaxis of neutrophils and T
19.





lymphocytes, and/or inhibition of





interferons.


IL-14
GeneSeq
WO9416074
Interleukins are a group of multifunctional
Interleukin activity can be determined using
inflammatory disorders,



Accession

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al.,
immunologic disorders,



R55800

monocytes, and macrophages. Known
in Lymphokines and Interferons: A Practical
cancer





functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,





of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225; and





cells, eosinophils, and lymphocytes),
Ambrus et al (1993) PNAS 90, 63330-34.





chemotaxis of neutrophils and T





lymphocytes, and/or inhibition of





interferons.


IL-17 receptor
GeneSeq
U.S. Pat. No. 6,072,033
Interleukins are a group of multifunctional
Interleukin activity can be determined using
Soluble IL-17 receptor



Accession

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al.,
polypeptides may be useful



B03807

monocytes, and macrophages. Known
in Lymphokines and Interferons: A Practical
for inhibiting interleukin





functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,
activities.





of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225; and





cells, eosinophils, and lymphocytes),
Yao et al (1995) J. Immunol. 155, 5483-86.





chemotaxis of neutrophils and T





lymphocytes, and/or inhibition of





interferons.


IL-17
GeneSeq
WO9518826
Interleukins are a group of multifunctional
Interleukin activity can be determined using
inflammatory disorders,



Accession

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al.,
immunologic disorders,



R76573

monocytes, and macrophages. Known
in Lymphokines and Interferons: A Practical
cancer





functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,





of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225; and





cells, eosinophils, and lymphocytes),
Yao et al (1995) J. Immunol. 155, 5483-86.





chemotaxis of neutrophils and T





lymphocytes, and/or inhibition of





interferons.


CTLA-8
GeneSeq
WO9704097
Interleukins are a group of multifunctional
Interleukin activity can be determined using
inflammatory disorders,



Accession

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al.,
immunologic disorders,



W13651

monocytes, and macrophages. Known
in Lymphokines and Interferons: A Practical
cancer





functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,





of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225.





cells, eosinophils, and lymphocytes),





chemotaxis of neutrophils and T





lymphocytes, and/or inhibition of





interferons.


IL-19
GeneSeq
WO9808870
Interleukins are a group of multifunctional
Interleukin activity can be determined using
inflammatory disorders,



Accession

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al.,
immunologic disorders,



W37935

monocytes, and macrophages. Known
in Lymphokines and Interferons: A Practical
cancer





functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,





of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225; and





cells, eosinophils, and lymphocytes),
Gallagher et al (2000) Genes Immun. 1,





chemotaxis of neutrophils and T
442-50.





lymphocytes, and/or inhibition of





interferons.


IL-21 (TIF)
GeneSeq
WO0024758
Interleukins are a group of multifunctional
Interleukin activity can be determined using
inflammatory disorders,



Accession

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al.,
immunologic disorders,



Y92879

monocytes, and macrophages. Known
in Lymphokines and Interferons: A Practical
cancer





functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,





of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225; and





cells, eosinophils, and lymphocytes),
Parrish-Novak et al (2000) Nature 408, 57-63.





chemotaxis of neutrophils and T





lymphocytes, and/or inhibition of





interferons.


IL-8 receptor
GeneSeq
WO9306229
Interleukins are a group of multifunctional
Interleukin activity can be determined using
Soluble IL-8 receptor



Accession

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al.,
polypeptides may be useful



R33420

monocytes, and macrophages. Known
in Lymphokines and Interferons: A Practical
for inhibiting interleukin





functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,
activities.





of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225; and





cells, eosinophils, and lymphocytes),
Holmes et al (1991) Science 253, 1278-80..





chemotaxis of neutrophils and T





lymphocytes, and/or inhibition of





interferons.


Human type II
GeneSeq
U.S. Pat. No. 5,464,937
Interleukins are a group of multifunctional
Interleukin activity can be determined using
Soluble type II interleukin-1


interleukin-1
Accession

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al.,
receptor polypeptides may


receptor
R85480

monocytes, and macrophages. Known
in Lymphokines and Interferons: A Practical
be useful for inhibiting





functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,
interleukin activities.





of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225; and





cells, eosinophils, and lymphocytes),
Orencole & Dinarello (1989) Cytokine 1,





chemotaxis of neutrophils and T
14-20.





lymphocytes, and/or inhibition of





interferons.


Human
GeneSeq
EP638644
Interleukins are a group of multifunctional
Interleukin activity can be determined using
Soluble IL-12 receptor


interleukin-12
Accession

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al.,
polypeptides may be useful


receptor
R69632

monocytes, and macrophages. Known
in Lymphokines and Interferons: A Practical
for inhibiting interleukin





functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,
activities.





of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225; and





cells, eosinophils, and lymphocytes),
Hori et al (1987), Blood 70, 1069-1078.





chemotaxis of neutrophils and T





lymphocytes, and/or inhibition of





interferons.


Interleukin 8
GeneSeq
U.S. Pat. No. 5,440,021
Interleukins are a group of multifunctional
Interleukin activity can be determined using
Soluble IL-8 receptor B


receptor B
Accession

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al.,
polypeptides may be useful



R80758

monocytes, and macrophages. Known
in Lymphokines and Interferons: A Practical
for inhibiting interleukin





functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,
activities.





of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225; and





cells, eosinophils, and lymphocytes),
Holmes et al (1991) Science 253, 1278-80.





chemotaxis of neutrophils and T





lymphocytes, and/or inhibition of





interferons.


Human IL-8
GeneSeq
JP08103276
Interleukins are a group of multifunctional
Interleukin activity can be determined using
Soluble IL-8 receptor A


receptor protein
Accession B09989

cytokines synthesized by lymphocytes,
assays known in the art: Matthews et al.,
polypeptides may be useful


hIL8RA


monocytes, and macrophages. Known
in Lymphokines and Interferons: A Practical
for inhibiting interleukin





functions include stimulating proliferation
Approach, Clemens et al., eds, IRL Press,
activities.





of immune cells (e.g., T helper cells, B
Washington, D.C. 1987, pp. 221-225; and





cells, eosinophils, and lymphocytes),
Holmes et al (1991) Science 253, 1278-80.





chemotaxis of neutrophils and T





lymphocytes, and/or inhibition of





interferons.


Human IL-8
GeneSeq
JP08103276
Interleukins are a group of multifunctional
Interleukin activity can be determined
Soluble IL-8 receptor


receptor protein
Accession B09990

cytokines synthesized by lymphocytes,
using asays known in the art: Matthews et
polypeptides may be


hIL8R


monocytes, and macrophages. Known
al., in Lymphokines and Interferons: A
useful for inhibiting





functions include stimulating proliferation
Practical Approach, Clemens et al., eds,
interleukin activities.





of immune cells (e.g., T helper cells, B
IRL Press, Washington, D.C. 1987, pp.





cells, eosinophils, and lymphocytes),
221-225; and Holmes et al (1991) Science





chemotaxis of neutrophils and T
253, 1278-80.





lymphocytes, and/or inhibition of





interferons.


Interleukin-2
GeneSeq
WO9621732-
Interleukins are a group of multifunctional
Interleukin activity can be determined
Soluble IL-2 receptor


receptor
Accession

cytokines synthesized by lymphocytes,
using assays known in the art: Matthews
polypeptides may be


associated protein
R97569

monocytes, and macrophages. Known
et al., in Lymphokines and Interferons: A
useful for inhibiting


p43


functions include stimulating proliferation
Practical Approach, Clemens et al., eds,
interleukin activities.





of immune cells (e.g., T helper cells, B
IRL Press, Washington, D.C. 1987, pp.





cells, eosinophils, and lymphocytes),
221-225; and Gillis et al (1978) J.





chemotaxis of neutrophils and T
Immunol. 120, 2027.





lymphocytes, and/or inhibition of





interferons.


Human
GeneSeq
WO9629408
Interleukins are a group of multifunctional
Interleukin activity can be determined
Soluble IL-17 receptor


interleukin-17
Accession

cytokines synthesized by lymphocytes,
using assays known in the art: Matthews
polypeptides may be


receptor
W04185

monocytes, and macrophages. Known
et al., in Lymphokines and Interferons: A
useful for inhibiting





functions include stimulating proliferation
Practical Approach, Clemens et al., eds,
interleukin activities.





of immune cells (e.g., T helper cells, B
IRL Press, Washington, D.C. 1987, pp.





cells, eosinophils, and lymphocytes),
221-225; and Yao et al (1995) J. Immunol.





chemotaxis of neutrophils and T
155, 5483-86.





lymphocytes, and/or inhibition of





interferons.


Human
GeneSeq
WO9619574
Interleukins are a group of multifunctional
Interleukin activity can be determined
Soluble IL-11 receptor


interleukin-11
Accession

cytokines synthesized by lymphocytes,
using assays known in the art: Matthews
polypeptides may be


receptor
R99090

monocytes, and macrophages. Known
et al., in Lymphokines and Interferons: A
useful for inhibiting





functions include stimulating proliferation
Practical Approach, Clemens et al., eds,
interleukin activities.





of immune cells (e.g., T helper cells, B
IRL Press, Washington, D.C. 1987, pp.





cells, eosinophils, and lymphocytes),
221-225; and Lu et al (1994) J immunol.





chemotaxis of neutrophils and T
Methods 173, 19.





lymphocytes, and/or inhibition of





interferons.


Human
GeneSeq
WO9623067
Interleukins are a group of multifunctional
Interleukin activity can be determined
Inflammatory disorders,


interleukin-1
Accession

cytokines synthesized by lymphocytes,
using assays known in the art: Matthews
immunologic disorders,


receptor
W01911

monocytes, and macrophages. Known
et al., in Lymphokines and Interferons: A
cancer


accessory protein


functions include stimulating proliferation
Practical Approach, Clemens et al., eds,





of immune cells (e.g., T helper cells, B
IRL Press, Washington, D.C. 1987, pp.





cells, eosinophils, and lymphocytes),
221-225; and Orencole & Dinarello (1989)





chemotaxis of neutrophils and T
Cytokine 1, 14-20.





lymphocytes, and/or inhibition of





interferons.


AGF Protein
GeneSeq
U.S. Pat. No. 5,488,032
Interleukins are a group of multifunctional
Interleukin activity can be determined
Inflammatory disorders,



Accession

cytokines synthesized by lymphocytes,
using assays known in the art: Matthews
immunologic disorders,



R92749

monocytes, and macrophages. Known
et al., in Lymphokines and Interferons: A
cancer





functions include stimulating proliferation
Practical Approach, Clemens et al., eds,





of immune cells (e.g., T helper cells, B
IRL Press, Washington, D.C. 1987, pp.





cells, eosinophils, and lymphocytes),
221-225.





chemotaxis of neutrophils and T





lymphocytes, and/or inhibition of





interferons.


Human
GeneSeq
W09607739
Interleukins are a group of multifunctional
Interleukin activity can be determined
Soluble IL-type-3 receptor


interleukin-1 type-
Accession

cytokines synthesized by lymphocytes,
using assays known in the art: Matthews
polypeptides may be


3 receptor
R91064

monocytes, and macrophages. Known
et al., in Lymphokines and Interferons: A
useful for inhibiting





functions include stimulating proliferation
Practical Approach, Clemens et al., eds,
interleukin activities





of immune cells (e.g., T helper cells, B
IRL Press, Washington, D.C. 1987, pp.





cells, eosinophils, and lymphocytes),
221-225; and Orencole & Dinarello (1989)





chemotaxis of neutrophils and T
Cytokine 1, 14-20.





lymphocytes, and/or inhibition of





interferons.


Human
GeneSeq
WO9720926
Interleukins are a group of multifunctional
Interleukin activity can be determined
Soluble IL-13 beta


interleukin-13 beta
Accession

cytokines synthesized by lymphocytes,
using assays known in the art: Matthews
receptor polypeptides may


receptor
W24972

monocytes, and macrophages. Known
et al., in Lymphokines and Interferons: A
be useful for inhibiting





functions include stimulating proliferation
Practical Approach, Clemens et al., eds,
interleukin activities.





of immune cells (e.g., T helper cells, B
IRL Press, Washington, D.C. 1987, pp.





cells, eosinophils, and lymphocytes),
221-225; and Boutelier et al (1995) J.





chemotaxis of neutrophils and T
Immunol. Methods 181, 29.





lymphocytes, and/or inhibition of





interferons.


Human
GeneSeq
WO9720926
Interleukins are a group of multifunctional
Interleukin activity can be determined
Soluble IL-13 alpha


interleukin-13
Accession

cytokines synthesized by lymphocytes,
using assays known in the art: Matthews
receptor polypeptides may


alpha receptor
W24973

monocytes, and macrophages. Known
et al., in Lymphokines and Interferons: A
be useful for inhibiting





functions include stimulating proliferation
Practical Approach, Clemens et al., eds,
interleukin activities.





of immune cells (e.g., T helper cells, B
IRL Press, Washington, D.C. 1987, pp.





cells, eosinophils, and lymphocytes),
221-225; and Boutelier et al (1995) J.





chemotaxis of neutrophils and T
Immunol. Methods 181, 29.





lymphocytes, and/or inhibition of





interferons.


Human
GeneSeq
U.S. Pat. No. 5,599,905
Interleukins are a group of multifunctional
Interleukin activity can be determined
Soluble IL-4 receptor


interleukin-4
Accession

cytokines synthesized by lymphocytes,
using assays known in the art: Matthews
polypeptides may be


receptor
W13499

monocytes, and macrophages. Known
et al., in Lymphokines and Interferons: A
useful for inhibiting





functions include stimulating proliferation
Practical Approach, Clemens et al., eds,
interleukin activities.





of immune cells (e.g., T helper cells, B
IRL Press, Washington, D.C. 1987, pp.





cells, eosinophils, and lymphocytes),
221-225; and Siegel & Mostowski (1990) J





chemotaxis of neutrophils and T
Immunol Methods 132, 287-295.





lymphocytes, and/or inhibition of





interferons.


Human
GeneSeq
EP759466
Interleukins are a group of multifunctional
Interleukin activity can be determined
Soluble IL-12 beta-2


interleukin-12
Accession

cytokines synthesized by lymphocytes,
using assays known in the art: Matthews
receptor polypeptides may


beta-2 receptor
W12771

monocytes, and macrophages. Known
et al., in Lymphokines and Interferons: A
be useful for inhibiting





functions include stimulating proliferation
Practical Approach, Clemens et al., eds,
interleukin activities.





of immune cells (e.g., T helper cells, B
IRL Press, Washington, D.C. 1987, pp.





cells, eosinophils, and lymphocytes),
221-225; and Hori et al (1987), Blood 70,





chemotaxis of neutrophils and T
1069-1078.





lymphocytes, and/or inhibition of





interferons.


Human
GeneSeq
EP759466
Interleukins are a group of multifunctional
Interleukin activity can be determined
Soluble IL-12 beta-1


interleukin-12
Accession

cytokines synthesized by lymphocytes,
using assays known in the art: Matthews
receptor polypeptides may


beta-1 receptor.
W12772

monocytes, and macrophages. Known
et al., in Lymphokines and Interferons: A
be useful for inhibiting





functions include stimulating proliferation
Practical Approach, Clemens et al., eds,
interleukin activities.





of immune cells (e.g., T helper cells, B
IRL Press, Washington, D.C. 1987, pp.





cells, eosinophils, and lymphocytes),
221-225; and Hori et al (1987), Blood 70,





chemotaxis of neutrophils and T
1069-1078.





lymphocytes, and/or inhibition of





interferons.


Human IL-9
GeneSeq
WO9824904
Interleukins are a group of multifunctional
Interleukin activity can be determined
Soluble IL-9 receptor


receptor protein
Accessions

cytokines synthesized by lymphocytes,
using assays known in the art: Matthews
polypeptides may be



W64055, W64056,

monocytes, and macrophages. Known
et al., in Lymphokines and Interferons: A
useful for inhibiting



and W64057

functions include stimulating proliferation
Practical Approach, Clemens et al., eds,
interleukin activities.





of immune cells (e.g., T helper cells, B
IRL Press, Washington, D.C. 1987, pp.





cells, eosinophils, and lymphocytes),
221-225; and Yang et al (1989), Blood 74,





chemotaxis of neutrophils and T
1880-84..





lymphocytes, and/or inhibition of





interferons.


IL-10 receptor
GeneSeq
U.S. Pat. No. 5,716,804
Interleukins are a group of multifunctional
Interleukin activity can be determined
Soluble IL-10 receptor



Accession

cytokines synthesized by lymphocytes,
using assays known in the art: Matthews
polypeptides may be



W41804

monocytes, and macrophages. Known
et al., in Lymphokines and Interferons: A
useful for inhibiting





functions include stimulating proliferation
Practical Approach, Clemens et al., eds,
interleukin activities.





of immune cells (e.g., T helper cells, B
IRL Press, Washington, D.C. 1987, pp.





cells, eosinophils, and lymphocytes),
221-225; and Thompson-Snipes et al





chemotaxis of neutrophils and T
(1991) J. Exp. Med. 173, 507-510.





lymphocytes, and/or inhibition of





interferons.


Human IL-6
GeneSeq
JP11196867
Interleukins are a group of multifunctional
Interleukin activity can be determined
Soluble IL-6 receptor


receptor
Accession Y30938

cytokines synthesized by lymphocytes,
using assays known in the art: Matthews
polypeptides may be





monocytes, and macrophages. Known
et al., in Lymphokines and Interferons: A
useful for inhibiting





functions include stimulating proliferation
Practical Approach, Clemens et al., eds,
interleukin activities.





of immune cells (e.g., T helper cells, B
IRL Press, Washington, D.C. 1987, pp.





cells, eosinophils, and lymphocytes),
221-225; and Aarden et al (1987) Eur. J.





chemotaxis of neutrophils and T
Immunol 17, 1411-16.





lymphocytes, and/or inhibition of





interferons.


Il-17 receptor
GeneSeq
U.S. Pat. No. 6,096,305
Interleukins are a group of multifunctional
Interleukin activity can be determined
Soluble IL-17 receptor



Accession Y97181

cytokines synthesized by lymphocytes,
using assays known in the art: Matthews
polypeptides may be





monocytes, and macrophages. Known
et al., in Lymphokines and Interferons: A
useful for inhibiting





functions include stimulating proliferation
Practical Approach, Clemens et al., eds,
interleukin activities.





of immune cells (e.g., T helper cells, B
IRL Press, Washington, D.C. 1987, pp.





cells, eosinophils, and lymphocytes),
221-225; and Yao et al (1995) J. Immunol.





chemotaxis of neutrophils and T
155, 5483-86.





lymphocytes, and/or inhibition of





interferons.


Il-17 receptor
GeneSeq
U.S. Pat. No. 6,100,235
Interleukins are a group of multifunctional
Interleukin activity can be determined
Soluble IL-17 receptor



Accession Y97131

cytokines synthesized by lymphocytes,
using assays known in the art: Matthews
polypeptides may be





monocytes, and macrophages. Known
et al., in Lymphokines and Interferons: A
useful for inhibiting





functions include stimulating proliferation
Practical Approach, Clemens et al., eds,
interleukin activities.





of immune cells (e.g., T helper cells, B
IRL Press, Washington, D.C. 1987, pp.





cells, eosinophils, and lymphocytes),
221-225; and Yao et al (1995) J. Immunol.





chemotaxis of neutrophils and T
155, 5483-86.





lymphocytes, and/or inhibition of





interferons.


Human
GeneSeq
EP509826
Interleukins are a group of multifunctional
Interleukin activity can be determined
Soluble IL-3 receptor


interleukin-3
Accession

cytokines synthesized by lymphocytes,
using assays known in the art: Matthews
polypeptides may be


receptor
R25300

monocytes, and macrophages. Known
et al., in Lymphokines and Interferons: A
useful for inhibiting





functions include stimulating proliferation
Practical Approach, Clemens et al., eds,
interleukin activities.





of immune cells (e.g., T helper cells, B
IRL Press, Washington, D.C. 1987, pp.





cells, eosinophils, and lymphocytes),
221-225; and Kitamura et al (1989) J Cell





chemotaxis of neutrophils and T
Physiol. 140 323-334.





lymphocytes, and/or inhibition of





interferons.


Human GM-CSF
GeneSeq
WO9102063
Interleukins are a group of multifunctional
Interleukin activity can be determined
Soluble GM-CSF receptor


receptor
Accession

cytokines synthesized by lymphocytes,
using assays known in the art: Matthews
polypeptides may be



R10919

monocytes, and macrophages. Known
et al., in Lymphokines and Interferons: A
useful for inhibiting





functions include stimulating proliferation
Practical Approach, Clemens et al., eds,
interleukin activities.





of immune cells (e.g., T helper cells, B
IRL Press, Washington, D.C. 1987, pp.





cells, eosinophils, and lymphocytes),
221-225.





chemotaxis of neutrophils and T





lymphocytes, and/or inhibition of





interferons.


Human IL-5
GeneSeq
EP492214
Interleukins are a group of multifunctional
Interleukin activity can be determined
Soluble IL-5 receptor


receptor alpha
Accession

cytokines synthesized by lymphocytes,
using assays known in the art: Matthews
alpha polypeptides may be


chain
R25064

monocytes, and macrophages. Known
et al., in Lymphokines and Interferons: A
useful for inhibiting





functions include stimulating proliferation
Practical Approach, Clemens et al., eds,
interleukin activities.





of immune cells (e.g., T helper cells, B
IRL Press, Washington, D.C. 1987, pp.





cells, eosinophils, and lymphocytes),
221-225; and Kitamura et al (1989) J Cell





chemotaxis of neutrophils and T
Physiol. 140, 323-334.





lymphocytes, and/or inhibition of





interferons.


II-5 receptor
GeneSeq
WO9847923
Interleukins are a group of multifunctional
Interleukin activity can be determined
Soluble IL-5 receptor



Accession

cytokines synthesized by lymphocytes,
using assays known in the art: Matthews
polypeptides may be



W82842

monocytes, and macrophages. Known
et al., in Lymphokines and Interferons: A
useful for inhibiting





functions include stimulating proliferation
Practical Approach, Clemens et al., eds,
interleukin activities.





of immune cells (e.g., T helper cells, B
IRL Press, Washington, D.C. 1987, pp.





cells, eosinophils, and lymphocytes),
221-225; and Kitamura et al (1989) J Cell





chemotaxis of neutrophils and T
Physiol. 140, 323-334.





lymphocytes, and/or inhibition of





interferons.


II-6 receptor
GeneSeq
JP05091892
Interleukins are a group of multifunctional
Interleukin activity can be determined
Soluble IL-6 receptor



Accession

cytokines synthesized by lymphocytes,
using assays known in the art: Matthews
polypeptides may be



R37215

monocytes, and macrophages. Known
et al., in Lymphokines and Interferons: A
useful for inhibiting





functions include stimulating proliferation
Practical Approach, Clemens et al., eds,
interleukin activities.





of immune cells (e.g., T helper cells, B
IRL Press, Washington, D.C. 1987, pp.





cells, eosinophils, and lymphocytes),
221-225; and Aarden et al (1987) Eur. J.





chemotaxis of neutrophils and T
Immunol 17, 1411-16.





lymphocytes, and/or inhibition of





interferons.


Human B cell
GeneSeq
AU8928720
Interleukins are a group of multifunctional
Interleukin activity can be determined
Soluble B cell stimulating


stimulating factor-
Accession P90525

cytokines synthesized by lymphocytes,
using assays known in the art: Matthews
factor-2 receptor


2 receptor


monocytes, and macrophages. Known
et al., in Lymphokines and Interferons: A
polypeptides may be





functions include stimulating proliferation
Practical Approach, Clemens et al., eds,
useful for inhibiting





of immune cells (e.g., T helper cells, B
IRL Press, Washington, D.C. 1987, pp.
interleukin activities.





cells, eosinophils, and lymphocytes),
221-225.





chemotaxis of neutrophils and T





lymphocytes, and/or inhibition of





interferons.


IL-7 receptor
GeneSeq
EP403114
Interleukins are a group of multifunctional
Interleukin activity can be determined
Soluble IL-7 receptor


clone
Accession

cytokines synthesized by lymphocytes,
using assays known in the art: Matthews
polypeptides may be



R08330

monocytes, and macrophages. Known
et al., in Lymphokines and Interferons: A
useful for inhibiting





functions include stimulating proliferation
Practical Approach, Clemens et al., eds,
interleukin activities.





of immune cells (e.g., T helper cells, B
IRL Press, Washington, D.C. 1987, pp.





cells, eosinophils, and lymphocytes),
221-225; and Park et al (1990) J. Exp.





chemotaxis of neutrophils and T
Med. 171, 1073-79.





lymphocytes, and/or inhibition of





interferons.


EPO receptor;
GeneSeq
WO9008822
EPO Receptor is involved in the
EPO Receptor activity can be determined
Inflammatory disorders,


EPOR
Accession

proliferation and differentiation of
using assays known in the art, such as, J
immunologic disorders,



R06512

erythroblasts.
Biol Chem 2001 Mar 23; 276(12: 8995-9002;
cancer, erythroblast






JAK2 protein tyrosine kinase
proliferation and






activity: Blood 1994 Sep 1; 84(5): 1501-7
differentiation






and Mol Cell Biol. 1994 Oct; 14(10: 6506-14.


IL-15 receptor
GeneSeq
WO9530695
Interleukins are a group of multifunctional
Interleukin activity can be determined
Soluble IL-15 receptor



Accession

cytokines synthesized by lymphocytes,
using assays known in the art: Matthews
polypeptides may be



R90843

monocytes, and macrophages. Known
et al., in Lymphokines and Interferons: A
useful for inhibiting





functions include stimulating proliferation
Practical Approach, Clemens et al., eds,
interleukin activities.





of immune cells (e.g., T helper cells, B
IRL Press, Washington, D.C. 1987, pp.





cells, eosinophils, and lymphocytes),
221-225; and Giri et al (1994) EMBO J. 13





chemotaxis of neutrophils and T
2822-2830.





lymphocytes, and/or inhibition of





interferons.


CD137; 4-1BB
GeneSeq
WO9507984
Activities associated with apoptosis, NF-
Apoptosis activity, NF-kB activation, and B
Soluble 4-1BB receptor


Receptor Protein
Accession

kB activation, and co-stimulation of
and T cell co-stimulation can be
polypeptides may be



R70977

immune cells such as T and B cells.
determined using assays known in the art:
useful for inhibiting






Moore et al., 1999, Science,
apoptosis, NF-kB






285(5425): 260-3; Song HY et al., 1997
activation, and/or co-






Proc Natl Acad Sci USA 94(18): 9792-6;
stimulation of immune






Epsevik and Nissen-Meyer, 1986, J.
cells such as B and T






Immunol. Methods.
cells.


BCMA
GeneSeq
WO0068378
Activities associated with apoptosis, NF-
Apoptosis activity, NF-kB activation, and B
Soluble BCMA receptor



Accession Y71979

kB activation, and co-stimulation of
and T cell co-stimulation can be
polypeptides may be





immune cells such as T and B cells.
determined using assays known in the art:
useful for inhibiting






Moore et al., 1999, Science,
apoptosis, NF-kB






285(5425): 260-3; Song HY et al., 1997
activation, and/or co-






Proc Natl Acad Sci USA 94(18): 9792-6;
stimulation of immune






Epsevik and Nissen-Meyer, 1986, J.
cells such as B and T






Immunol. Methods.
cells.


CD27
GeneSeq
WO9201049
Activities associated with apoptosis, NF-
Apoptosis activity, NF-kB activation, and B
Soluble CD27



Accession

kB activation, and co-stimulation of
and T cell co-stimulation can be
polypeptides may be



R20814

immune cells such as T and B cells.
determined using assays known in the art:
useful for inhibiting






Moore et al., 1999, Science,
apoptosis, NF-kB






285(5425): 260-3; Song HY et al., 1997
activation, and/or co-






Proc Natl Acad Sci USA 94(18): 9792-6;
stimulation of immune






Epsevik and Nissen-Meyer, 1986, J.
cells such as B and T






Immunol. Methods.
cells.


CD30
GeneSeq
DE4200043
Activities associated with apoptosis, NF-
Apoptosis activity, NF-kB activation, and B
Soluble CD30



Accession

kB activation, and co-stimulation of
and T cell co-stimulation can be
polypeptides may be



R35478

immune cells such as T and B cells.
determined using assays known in the art:
useful for inhibiting






Moore et al., 1999, Science,
apoptosis, NF-kB






285(5425): 260-3; Song HY et al., 1997
activation, and/or co-






Proc Natl Acad Sci USA 94(18): 9792-6;
stimulation of immune






Epsevik and Nissen-Meyer, 1986, J.
cells such as B and T






Immunol. Methods.
cells.


CD40
GeneSeq
WO9945944
Activities associated with apoptosis,
Apoptosis activity, NF-kB activation, and B
Soluble CD40



Accession

NF-kB activation, and co-stimulation of
and T cell co-stimulation can be
polypeptides may be



Y33499

immune cells such as T and B cells.
determined using assays known in the art:
useful for inhibiting






Moore et al., 1999, Science
apoptosis, NF-kB






285(5425): 260-3; Song HY et al., 1997
activation, and/or co-






Proc Natl Acad Sci USA 94(18): 9792-6;
stimulation of immune






Epsevik and Nissen-Meyer, 1986, J.
cells such as B and T






Immunol. Methods.
cells.


EDAR
Genbank

Activities associated with apoptosis,
Apoptosis activity, NF-kB activation, and B
Immune Disorders,



Accession

NF-kB activation, and co-stimulation of
and T cell co-stimulation can be
Lymphomas, X-linked



AAD50077

immune cells such as T and B cells.
determined using assays known in the art:
hypohidrotic ectodermal






Moore et al., 1999, Science,
dysplasia






285(5425): 260-3; Song HY et al., 1997






Proc Natl Acad Sci USA 94(18): 9792-6;






Epsevik and Nissen-Meyer, 1986, J.






Immunol. Methods.


OX40; ACT-4
GeneSeq
WO9512673
Activities associated with apoptosis,
Apoptosis activity, NF-kB activation, and B
Immune Disorders,



Accession R74737

NF-kB activation, and co-stimulation of
and T cell co-stimulation can be
Lymphomas, T cell





immune cells such as T and B cells.
determined using assays known in the art:
disorders






Moore et al., 1999, Science,






285(5425): 260-3; Song HY et al., 1997






Proc Natl Acad Sci USA 94(18): 9792-6;






Epsevik and Nissen-Meyer, 1986, J.






Immunol. Methods.


TACI
GeneSeq
WO9839361
Activities associated with apoptosis,
Apoptosis activity, NF-kB activation, and B
Soluble TACI receptor



Accession

NF-kB activation, and co-stimulation of
and T cell co-stimulation can be
polypeptides may be



W75783

immune cells such as T and B cells.
determined using assays known in the art:
useful for inhibiting






Moore et al., 1999, Science,
apoptosis, NF-kB






285(5425): 260-3; Song HY et al., 1997
activation, and/or co-






Proc Natl Acad Sci USA 94(18): 9792-6;
stimulation of immune






Epsevik and Nissen-Meyer, 1986, J.
cells such as B and T






Immunol. Methods.
cells.


TNF-R
GeneSeq
AU9058976
Activities associates with apoptosis,
Apoptosis activity, NF-kB activation, and B
Soluble TNF-R receptor



Accession R10986

NF-kB activation, and co-stimulation of
and T cell co-stimulation can be
polypeptides may be





immune cells such as T and B cells.
determined using assays known in the art:
useful for inhibiting






Moore et al., 1999, Science,
apoptosis, NF-kB






285(5425): 260-3; Song HY et al., 1997
activation, and/or co-






Proc Natl Acad Sci USA 94(18): 9792-6;
stimulation of immune






Epsevik and Nissen-Meyer, 1986, J.
cells such as B and T






Immunol. Methods.
cells.


TNF-RII; TNF
GeneSeq
EP418014
Activities associated with apoptosis,
Apoptosis activity, NF-kB activation, and B
Soluble TNFR-II receptor


p75 receptor;
Accession R11141

NF-kB activation, and co-stimulation of
and T cell co-stimulation can be
polypeptides may be


Death Receptor


immune cells such as T and B cells.
determined using assays known in the art:
useful for inhibiting






Moore et al., 1999, Science,
apoptosis, NF-kB






285(5425): 260-3; Song HY et al., 1997
activation, and/or co-






Proc Natl Acad Sci USA 94(18)9792-6;
stimulation of immune






Epsevik and Nissen-Meyer, 1986, J.
cells such as B and T






Immunol. Methods.
cells.


hAPO-4; TROY
GeneSeq
WO9911791
Activities associated with apoptosis,
Apoptosis activity, NF-kB activation, and B
Immune Disorders,



Accession

NF-kB activation, and co-stimulation of
and T cell co-stimulation can be
Cancers



W93581

immune cells such as T and B cells.
determined using assays known in the art:






Moore et al., 1999, Science,






285(5425): 260-3; Song HY et al., 1997






Proc Natl Acad Sci USA 94(18): 9792-6;






Epsevik and Nissen-Meyer, 1986, J.






Immunol. Methods.


TNF-alpha
GeneSeq
EP205038
Activities associated with apoptosis,
Apoptosis activity, NF-kB activation, and B
Inflammatory disorders,


precursor
Accession P60074

NF-kB activation, and co-stimulation of
and T cell co-stimulation can be
immunologic disorders,





immune cells such as T and B cells.
determined using assays known in the art:
cancer






Moore et al., 1999, Science,






285(5425): 260-3; Song HY et al., 1997






Proc Natl Acad Sci USA 94(18): 9792-6;






Epsevik and Nissen-Meyer, 1986, J.






Immunol. Methods.


Human TNF-
GeneSeq
EP619372
Activities associated with apoptosis,
Apoptosis activity, NF-kB activation, and B
Inflammatory disorders,


alpha
Accession R62463

NF-kB activation, and co-stimulation of
and T cell co-stimulation can be
immunologic disorders,





immune cells such as T and B cells
determined using assays known in the art:
cancer






Moore et al., 1999, Science,






285(5425): 260-3; Song HY et al., 1997






Proc Natl Acad Sci USA 94(18): 9792-6;






Epsevik and Nissen-Meyer, 1986, J.






Immunol. Methods.


Human TNF-
GeneSeq
EP563714
Activities associated with apoptosis,
Apoptosis activity, NF-kB activation, and B
Inflammatory disorders,


alpha
Accession R42679

NF-kB activation, and co-stimulation of
and T cell co-stimulation can be
immunologic disorders,





immune cells such as T and B cells.
determined using assays known in the art:
cancer






Moore et al., 1999, Science,






285(5425): 260-3; Song HY et al., 1997






Proc Natl Acad Sci USA 94(18): 9792-6;






Epsevik and Nissen-Meyer, 1986, J.






Immunol. Methods.


Human TNF-
GeneSeq
WO0064479
Activities associated with apoptosis,
Apoptosis activity, NF-kB activation, and B
Inflammatory disorders,


beta (LT-alpha)
Accession B37799

NF-kB activation, and co-stimulation of
and T cell co-stimulation can be
immunologic disorders,





immune cells such as T and B cells.
determined using assays known in the art:
cancer






Moore et al., 1999, Science,






285(5425): 260-3; Song HY et al., 1997






Proc Natl Acad Sci USA 94(18): 9792-6;






Epsevik and Nissen-Meyer, 1986, J.






Immunol. Methods.


LT-alpha
GeneSeq
EP250000
Activities associated with apoptosis,
Apoptosis activity, NF-kB activation, and B
Inflammatory disorders,



Accession P70107

NF-kB activation, and co-stimulation of
and T cell co-stimulation can be
immunologic disorders,





immune cells such as T and B cells.
determined using assays known in the art:
cancer






Moore et al., 1999, Science,






285(5425): 260-3; Song HY et al., 1997






Proc Natl Acad Sci USA 94(18): 9792-6;






Epsevik and Nissen-Meyer, 1986, J.






Immunol. Methods.


LT-beta
GeneSeq
WO9413808
Activities associated with apoptosis,
Apoptosis activity, NF-kB activation, and B
Inflammatory disorders,



Accession R56869

NF-kB activation, and co-stimulation of
and T cell co-stimulation can be
immunologic disorders,





immune cells such as T and B cells.
determined using assays known in the art:
cancer






Moore et al., 1999, Science,






285(5425): 260-3; Song HY et al., 1997






Proc Natl Acad Sci USA 94(18)9792-6;






Epsevik and Nissen-Meyer, 1986, J.






Immunol. Methods.


OPGL
GeneSeq
WO9846751
Activities associated with apoptosis,
Apoptosis activity, NF-kB activation, and B
Inflammatory disorders,



Accession

NF-kB activation, and co-stimulation of
and T cell co-stimulation can be
immunologic disorders,



W83195

immune cells such as T and B cells.
determined using assays known in the art:
cancer, loss of bone mass






Moore et al., 1999, Science,






285(5425): 260-3; Song HY et al., 1997






Proc Natl Acad Sci USA 94(18)9792-6;






Epsevik and Nissen-Meyer, 1986, J.






Immunol. Methods.


FasL
GeneSeq
WO9903999
Activities associated with apoptosis,
Apoptosis activity, NF-kB activation, and B
Inflammatory disorders,



Accession

NF-kB activation, and co-stimulation of
and T cell co-stimulation can be
immunologic disorders,



W98071

immune cells such as T and B cells.
determined using assays known in the art:
cancer






Moore, et al., 1999, Science,






285(5425): 260-3; Song HY et al., 1997






Proc Natl Acad Sci USA 94(18)9792-6;






Epsevik and Nissen-Meyer, 1986, J.






Immunol. Methods.


FasL
GeneSeq
WO9903998
Activities associated with apoptosis,
Apoptosis activity, NF-kB activation, and B
Inflammatory disorders,



Accession

NF-kB activation, and co-stimulation of
and T cell co-stimulation can be
imunologic disorders,



W95041

immune cells such as T and B cells.
determined using assays known in the art:
cancer






Moore et al., 1999, Science,






285(5425): 260-3; Song HY et al., 1997






Proc Natl Acad Sci USA 94(18): 9792-6;






Epsevik and Nissen-Meyer, 1986, J.






Immunol. Methods.


CD27L
GeneSeq
WO9405691
Activities associated with apoptosis,
Apoptosis activity, NF-kB activation, and B
Inflammatory disorders,



Accession R50121

NF-kB activation, and co-stimulation of
and T cell co-stimulation can be
immunologic disorders,





immune cells such as T and B cells.
determined using assays known in the art:
cancer






Moore et al., 1999, Science,






285(5425): 260-3; Song HY et al., 1997






Proc Natl Acad Sci USA 94(18): 9792-6;






Epsevik and Nissen-Meyer, 1986, J.






Immunol. Methods.


CD30 ligand
GeneSeq
WO9324135
Activities associated with apoptosis,
Apoptosis activity, NF-kB activation, and B
Inflammatory disorders,



Accession R45007

NF-kB activation, and co-stimulation of
and T cell co-stimulation can be
immunologic disorders,





immune cells such as T and B cells.
determined using assays known in the art:
cancer






Moore et al., 1999, Science,






285(5425): 260-3; Song HY et al., 1997






Proc Natl Acad Sci USA 94(18): 9792-6;






Epsevik and Nissen-Meyer, 1986, J.






Immunol. Methods.


CD40L
GeneSeq
WO9529935
Activities associated with apoptosis,
Apoptosis activity, NF-kB activation, and B
Inflammatory disorders,



Accession R85486

NF-kB activation, and co-stimulation of
and T cell co-stimulation can be
immunologic disorders,





immune cells such as T and B cells.
determined using assays known in the art:
cancer






Moore, et al., 1999, Science,






285(5425): 260-3; Song HY et al., 1997






Proc Natl Acad Sci USA 94(18): 9792-6;






Epsevik and Nissen-Meyer, 1986, J.






Immunol. Methods.


4-1BB ligand
GeneSeq
U.S. Pat. No. 5,674,704
Activities associated with apoptosis,
Apoptosis activity, NF-kB activation, and B
Inflammatory disorders,



Accession

NF-kB activation, and co-stimulation of
and T cell co-stimulation can be
immunologic disorders,



W26657

immune cells such as T and B cells.
determined using assays known in the art:
cancer






Moore et al., 1999, Science,






285(5425): 260-3; Song HY et al., 1997






Proc Natl Acad Sci USA 94(18): 9792-6;






Epsevik and Nissen-Meyer, 1986, J.






Immunol. Methods.


FAS Ligand
GeneSeq
WO0058465
Activities associated with apoptosis,
Apoptosis activity, NF-kB activation, and B
Soluble DcR3


Inhibitory
Accession B19335

NF-kB activation, and co-stimulation of
and T cell co-stimulation can be
polypeptides may be


Protein (DcR3)


immune cells such as T and B cells.
determined using assays known in the art:
useful for inhibiting






Moore et al., 1999, Science,
apoptosis, NF-kB






285(5425): 260-3; Song HY et al., 1997
activation, and/or co-






Proc Natl Acad Sci USA 94(18): 9792-6;
stimulation of immune






Epsevik and Nissen-Meyer, 1986, J.
cells such as B and T






Immunol. Methods
cells.


OX40L
GeneSeq
WO9521915
Activities associated with apoptosis,
Apoptosis activity, NF-kB activation, and B
Inflammatory disorders,



Accession R79903

NF-kB activation, and co-stimulation of
and T cell co-stimulation can be
immunologic disorders,





immune cells such as T and B cells.
determined using assays known in the art:
cancer






Moore et al., 1999, Science,






285(5425): 260-3; Song HY et al., 1997






Proc Natl Acad Sci USA 94(18): 9792-6;






Epsevik and Nissen-Meyer, 1986, J.






Immunol. Methods.


Protease
GeneSeq
WO9106561
Peptides that inhibit the function/binding
HIV protease activities are known in the art:
HIV, inflammatory


inhibitor
Accessions

of HIV
HIV protease assays: EP0387231. One
disorders, immunologic


peptides
R12435, R12436,


can modify the assay to look for inhibition
disorders, cancer, viral



R12437, R12438,


using any of the disclosed protease
infections



R12439, R12440,


inhibitor polypeptides.



and R1244


Retroviral
GeneSeq
EP387231
Peptides that inhibit the function/binding
HIV protease activities are known in the art:
HIV, inflammatory


protease
Accessions

of HIV
HIV protease assays: EP0387231. One
disorders, immunologic


inhibitors
R06660, R06661,


can modify the assay to look for inhibition
disorders, cancer, viral



R06662, R06663,


using any of the disclosed protease
infections



R06664, R06665,


inhibitor polypeptides.



R06666, R06667,



R06668, R06669,



R06670, R06671,



R06672, R06673,



R06674, R06675,



and R06676


HIV protease
GeneSeq
WO9301828
Peptides that inhibit the function/binding
HIV protease activities are known in the art:
HIV, inflammatory


inhibiting
Accessions

of HIV
HIV protease assays: EP0387231. One
disorders, immunologic


peptides
R59293, R59294,


can modify the assay to look for inhibition
disorders, cancer, viral



R59295, R59296,


using any of the disclosed protease
infections



R59297,


inhibitor polypeptides.



R59298, R59299,



R592300, R59301,



R59302, R59301,



R59302, R59303,



R59304, R59305,



R59306, R59307,



R59308, R59309,



R59310, R59311,



R59312, R59313,



R59314, R59315,



R59316, R59317



R59318, R59319,



R59320, R59321,



R59322, R59323,



R59324, R59325,



R59326, R59327,



R59328, R59329,



R59330, R59331,



R59332, R59333,



R59334, R59335,



R59336, R59337,



R59338, R59339,



R59340, R59341,



R59342, R59343,



R59344, R59345,



R59346, R59347,



R59348, R59349,



and R59350


HIV-1 protease
GeneSeq
DE4412174
Peptides that inhibit the function/binding
HIV protease activities are known in the art:
HIV, inflammatory


hinibitors
Accessions

of HIV
HIV protease assays: EP0387231. One
disorders, immunologic



R86326, R86327,


can modify the assay to look for inhibition
disorders, cancer, viral



R86328, R86329,


using any of the disclosed protease
infections



R86330, R86331,


inhibitor polypeptides.



R86332, R86333,



R86334, R86335,



R86336, R86337,



R86338, R86339,



R86340, R86341,



R86342, R86343,



R86344, R86345,



R86346, R86347,



R86348, R86349,



R86350, R86351,



R86352, R86353,



R86354, R86355,



R86356, R86357,



R86358, R86359,



R86360, R86361,



R86362, R86363,



R86364, R86365,



R86366, R86367,



R86368, R86369,



R86370, and



R86371


HIV Inhibitor
GeneSeq
WO9959615
Peptides that inhibit the function/binding
HIV protease activities are known in the art:
HIV, inflammatory


Peptide
Accession

of HIV
HIV protease assays: EP0387231. One
disorders, immunologic



Y89687


can modify the assay to look for inhibition
disorders, cancer, viral






using any of the disclosed protease
infections






inhibitor polypeptides.


HIV Inhibitor
GenSeq
WO9948513
Peptides that inhibit the function/binding
HIV Protease activities are known in the
HIV, inflammatory


Peptide
Accession Y31955

of HIV
art; HIV protease assays: EP0387231.
disorders, immunologic






One can modify the assay to look for
disorders, cancer, viral






inhibition using any of the disclosed
infections.






protease inhibitor polypeptides.


HIV Inhibitor
www.sciencexpress.org;

Peptides that inhibit the function/binding
HIV protease activities are known in the
HIV, inflammatory


Peptide
Published

of HIV
art: HIV protease assays: EP0387231.
disorders, immunologic



online 12 Jan.


One can modify the assay to look for
disorders, cancer, viral



2001;


inhibition using any of the disclosed
infections



10.1126/science.1057453


protease inhibitor polypeptides.


Human monocyte
GeneSeq
WO9509232
Chemokines are a family of small,
Chemokine activities can be determined
Immune disorders,


chemoattractant
Accession

secreted proteins involved in biological
using assays known in the art: Methods in
particularly useful for


factor hMCP-3
R73915

processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:
treating bacterial and/or





angiogenesis, and leukocyte trafficking.
Chemokine Protocols, Edited by: A. E. I. Proudfoot,
viral menigitis





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to - 17





receptors thus far identified.


Human monocyte
GeneSeq
WO9509232
Chemokines are a family of related small,
Chemokine activities can be determined
Immune disorders,


chemoattractant
Accession

secreted proteins involved in biological
using assays known in the art: Methods in
particularly useful for


factor hMCP-1
R73914

processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:
treating bacterial and/or





angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,
viral menigitis





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to - 17





receptors thus far identified.


Human gro-beta
GeneSeq
WO9429341
Chemokines are a family of small,
Chemokine activities can be determined
Immune disorders,


chemokine
Accessions

secreted proteins involved in biological
using assays known in the art: Methods in
inflammatory disorders,



R66699 and

processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:
blood-related disorders,



W17671

angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,
stem cell transplantation,





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.
cancer





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to - 17





receptors thus far identified.


Human gro-
GeneSeq
WO9429341
Chemokines are a family of related small,
Chemokine activities can be determined
Immune disorders,


gamma
Accessions

secreted proteins involved in biological
using assays known in the art: Methods in
inflammatory disorders,


chemokine
R66700 and

processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:
blood-related disorders,



W17672

angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,
stem cell transplantation,





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.
cancer





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to - 17





receptors thus far identified


Human gro-alpha
GeneSeq
WO9429341
Chemokines are a family of related small,
Chemokine activities can be determined
Immune disorders,


chemokine
Accessions

secreted proteins involved in biological
using assays known in the art: Methods in
inflammatory disorders,



R66698 and

processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:
blood-related disorders,



W18024

angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,
stem cell transplantation,





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.
cancer





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to - 17





receptors thus far identified


Human
GeneSeq
WO9632481
Chemokines are a family of related small,
Chemokine activities can be determined
Immune disorders,


eosinophil-
Accession

secreted proteins involved in biological
using assays known in the art: Methods in
particularly treatment of


expressed
W05186

processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:
eosinophilia, inflammation,


chemokine (EEC)


angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,
allergies, asthma,





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.
leukaemia and lymphoma





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to - 17





receptors thus far identified


Chemokine-like
GeneSeq
WO9613587
Chemokines are a family of related small,
Chemokine activities can be determined
Cancer and blood-related


protein PF4-414
Accessions

secreted proteins involved in biological
using assays known in the art: Methods in
disorders, particularly


Full-Length and
R92318 and

processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:
myelosuppression


Mature
R99809

angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to - 17





receptors thus far identified


Chemokine-like
GeneSeq
WO9613587
Chemokines are a family of related small,
Chemokine activities can be determined
Cancer and blood-related


protein IL-8M3
Accession

secreted proteins involved in biological
using assays known in the art: Methods in
disorders, particularly



R99812

processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:
myelosuppression





angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ; and





including inflammation, allergy, tissue
Holmes et al (1991) Science 253, 1278-80.





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to - 17





receptors thus far identified


Human
GeneSeq
WO9613587
Chemokines are a family of related small,
Chemokine activities can be determined
Cancer and blood-related


interleukin-8 (IL-8)
Accession

secreted proteins involved in biological
using assays known in the art: Methods in
disorders, particularly



R99814

processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:
myelosuppression





angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ; and





including inflammation, allergy, tissue
Holmes et al (1991) Science 253, 1278-80.





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to - 17





receptors thus far identified


Chemokine-like
GeneSeq
WO9613587
Chemokines are a family of related small,
Chemokine activities can be determined
Cancer and blood-related


protein IL-8M1
Accessions

secreted proteins involved in biological
using assays known in the art: Methods in
disorders, particularly


Full-Length and
R99815 and

processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:
myelosuppression


Mature
R99803

angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ; and





including inflammation, allergy, tissue
Holmes et al (1991) Science 253, 1278-80.





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to - 17





receptors thus far identified


Chemokine-like
GeneSeq
WO9613587
Chemokines are a family of related small,
Chemokine activities can be determined
Cancer and blood-related


protein IL-8M8
Accessions

secreted proteins involved in biological
using assasys known in the art: Methods
disorders, particularly


Full-Length and
R99816 and

processes ranging from hematopoiesis,
in Molecular Biology, 2000, vol. 138:
myelosuppression.


Mature
R99805

angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot;





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ; and





including inflammation, allergy, tissue
Holmes et al (1991) Science 253, 1278-80.





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Chemokine-like
GeneSeq
WO9613587
Chemokines are a family of related small,
Chemokine activities can be determined
Cancer and blood-related


protein IL-8M8
Accessions

secreted proteins involved in biological
using assasys known in the art: Methods in
disorders, particularly


Full-Length and
R99817 and

processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:
myelosuppression.


Mature
R99806

angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot;





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ; and





including inflammation, allergy, tissue
Holmes et al (1991) Science 253, 1278-80.





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Chemokine-like
GeneSeq
WO9613587
Chemokines are a family of related small,
Chemokine activities can be determined
Cancer and blood-related


protein IL-8M8
Accessions

secreted proteins involved in biological
using assasys known in the art: Methods in
disorders, particularly


Full-Length and
R99818 and

processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:
myelosuppression.


Mature
R99804

angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot;





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ; and





including inflammation, allergy, tissue
Holmes et al (1991) Science 253, 1278-80.





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Chemokine-like
GeneSeq
WO9613587
Chemokines are a family of related small,
Chemokine activities can be determined
Cancer and blood-related


protein IL-8M8
Accessions

secreted proteins involved in biological
using assasys known in the art: Methods in
disorders, particularly


Full-Length and
R99819 and

processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:
myelosuppression.


Mature
R99807

angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot;





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Chemokine-like
GeneSeq
WO9613587
Chemokines are a family of related small,
Chemokine activities can be determined
Cancer and blood-related


protein IL-8M8
Accessions

secreted proteins involved in biological
using assasys known in the art: Methods in
disorders, particularly


Full-Length and
R99822 and R9807

processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:
myelosuppression.


Mature


angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot;





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Human foetal
GeneSeq
WO9622374
Chemokines are a family of related small,
Chemokine activities can be determined
Immune disorders


spleen expressed
Accession R98499

secreted proteins involved in biological
using assasys known in the art: Methods in


chemokine, FSEC


processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:





angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot;





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Liver expressed
GeneSeq
WO9616979
Chemokines are a family of related small,
Chemokine activities can be determined
Inflammation of the liver


chemokine-
Accession R95689

secreted proteins involved in biological
using assasys known in the art: Methods in


1(LVEC-1)


processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:





angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot;





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Liver expressed
GeneSeq
WO9616979
Chemokines are a family of related small,
Chemokine activities can be determined
Inflammation of the liver


chemokine-
Accession R95690

secreted proteins involved in biological
using assasys known in the art: Methods in


2(LVEC-2)


processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:





angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot;





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Pituitary
GeneSeq
WO9616979
Chemokines are a family of related small,
Chemokine activities can be determined
Inflammation, particularly


expressed
Accession R95691

secreted proteins involved in biological
using assasys known in the art: Methods in
of the liver


chemokine


processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:


(PGEC)


angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot;





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Adenoid-
GeneSeq
WO9617868
Chemokines are a family of related small,
Chemokine activities can be determined
Inflammation,


expressed
Accession R97664

secreted proteins involved in biological
using assasys known in the art: Methods in
angiogenesis,


chemokine


processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:
tumorigenesis,


(ADEC)


angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot;
musculoskeletal disorders





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Human
GeneSeq
WO9741230
Chemokines are a family of related small,
Chemokine activities can be determined
Immune disorders, cell


chemokineCC-2
Accession

secreted proteins involved in biological
using assays known in the art: Methods in
migration, proliferation,



W38170

processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138;
and differentiation





angiogenesis, and leukocyte trafficking.
Chemokine protocols. Edited by: A. E. I. Proudfoot,
disorders





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarly diverse range of pathologies
© Humana Press Inc. Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Human
GeneSeq
WO9741230
Chemokines are a family of related small,
Chemokine activities can be determined
Immune disorders, cell


chemokine
Accession

secreted proteins involved in biological
using assays known in the art: Methods in
migration, proliferation,


HCC-1
W38171

processes ranging from hematopiesis,
molecular Biology 2000, vol. 138:
and differentiation





anglogenesis and leukocyte trafficking.
Chemokine Protocols. Edited by A. E. I. Proudfoot,
disorders





Members of this family are involved in a
T. N. C. Wells and C. A. Power





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Human
GeneSeq
WO9741230
Chemokines are a family of related small,
Chemokine activities can be determined
Immune disorders, cell


chemokine CC-3
Accession

secreted proteins involved in biological
using assays known in the art: Methods in
migration, proliferation and



W38172

processes ranging from hemotopoiesis,
molecular Biology, 2000, vol. 138:
differentiation disorders





anglogenesis, and leukocyte trafficking.
Chemokine Protocols, Edited by A. E. I. Proudfoot,





Members of this family are involved in a
T. N. C. Wells, and C. A. Power





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Novel
GeneSeq
WO9739126
Chemokines are a family of related small,
Chemokine activities can be determined
Immune disorders,


betachemokine
Accession

secreted proteins involved in biological
using assays known in the art: Methods in
vascular disorders, cancer


designated PTEC
W27271

processes ranging from hemotopoiesis,
molecular Biology, 2000, vol. 138:





anglogenesis, and leukocyte trafficking.
Chemokine Protocols, Edited by A. E. I. Proudfoot,





Members of this family are involved in a
T. N. C. Wells, and C. A. Power





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Human CX3C
GeneSeq
WO9727299
Chemokines are a family of related small,
Chemokine activities can be determined
Immune disorders,


111 amino acid
Accession

secreted proteins involved in biological
using assays known in the art: Methods in
inflammatory diseases,


chemokine
W23344

processes ranging from hemotopoiesis,
molecular Biology, 2000, vol. 138:
abnormal proliferation,





anglogenesis, and leukocyte trafficking.
Chemokine Protocols, Edited by A. E. I. Proudfoot,
regeneration,





Members of this family are involved in a
T. N. C. Wells, and C. A. Power
degeneration, and atrophy





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Human CCF18
GeneSeq
WO9721812
Chemokines are a family of related small,
Chemokine activities can be determined
Abnormal physiology and


chemokine
Accession

secreted proteins involved in biological
using assays known in the art: Methods in
development disorders,



W25942

processes ranging from hemotopoiesis,
molecular Biology, 2000, vol. 138:
can also be used as an





anglogenesis, and leukocyte trafficking.
Chemokine Protocols, Edited by A. E. I. Proudfoot,
anti-viral agent





Members of this family are involved in a
T. N. C. Wells, and C. A. Power





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Human beta-
GeneSeq
WO9725427
Chemokines are a family of related small,
Chemokine activities can be determined
Chemotaxis, blood-related


chemokine
Accession

secreted proteins involved in biological
using assays known in the art: Methods in
disorders, viral infection,


H1305 (MCP-2)
W26655

processes ranging from hemotopoiesis,
molecular Biology, 2000, vol. 138:
HIV, wound healing,





anglogenesis, and leukocyte trafficking.
Chemokine Protocols, Edited by A. E. I. Proudfoot,
cancer





Members of this family are involved in a
T. N. C. Wells, and C. A. Power





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Human
GeneSeq
WO9712914
Chemokines are a family of related small,
Chemokine activities can be determined
Inflammatory and immune


eosinocyte CC
Accession

secreted proteins involved in biological
using assays known in the art: Methods in
disorders


type chemokine
W14990

processes ranging from hemotopoiesis,
molecular Biology, 2000, vol. 138:


eotaxin


anglogenesis, and leukocyte trafficking.
Chemokine Protocols, Edited by A. E. I. Proudfoot,





Members of this family are involved in a
T. N. C. Wells, and C. A. Power





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Human thymus
GeneSeq
WO9711969
Chemokines are a family of related small,
Chemokine activities can be determined
Inflammatory and immune


and activation
Accession

secreted proteins involved in biological
using assays known in the art: Methods in
disorders


regulated
W14018

processes ranging from hemotopoiesis,
molecular Biology, 2000, vol. 138:


cytokine


anglogenesis, and leukocyte trafficking.
Chemokine Protocols, Edited by A. E. I. Proudfoot,


(TARC)


Members of this family are involved in a
T. N. C. Wells, and C. A. Power





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Human
GeneSeq
WO9712041
Chemokines are a family of related small,
Chemokine activities can be determined
Cancer, would healing,


chemokine beta-
Accession

secreted proteins involved in biological
using assays known in the art: Methods in
immune disorders


8 short forms
W16315

processes ranging from hemotopoiesis,
molecular Biology, 2000, vol. 138:





anglogenesis, and leukocyte trafficking.
Chemokine Protocols, Edited by A. E. I. Proudfoot,





Members of this family are involved in a
T. N. C. Wells, and C. A. Power





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Microphage
GeneSeq
WO9640923
Chemokines are a family of related small,
Chemokine activities can be determined
Inflammatory diseases,


derived
Accession

secreted proteins involved in biological
using assays known in the art: Methods in
wound healin,


chemokine, MDC
W20058

processes ranging from hermaatopoiesis,
Molecular Biology, 2000, vol. 138:
angiogenesis





angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Human
GeneSeq
WO9844117
Chemokines are a family of related small,
Chemokine activities can be determined
Inflammatory and immune


chemokine ZSIG-
Accession

secreted proteins involved in biological
using assays known in the art: Methods in
diseases


35
W30565

processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:





angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Primate CC
GeneSeq
WO98328658
Chemokines are a family of related small,
Chemokine activities can be determined
Immune and inflammatory


chemokine
Accesssion

secreted proteins involved in biological
using assays known in the art: Methods in
disorders, abnormal


“ILINCK”
W69990

processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:
proliferation, regeneration,





angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,
generation and atrophy






T. N. C. Wells, and C. A. Power.
disorders






© Humana Press Inc., Totowa, NJ


Primate CXC
GeneSeq
WO9832858
Chemokines are a family of related small,
Chemokine activities can be determined
Immune and inflammatory


chemokine
Accession

secreted proteins involved in biological
using assays known in the art: Methods in
disorders, abnormal


“IBICK”
W69989

processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:
proliferation, regeneration,





angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Editd by: A. E. I. Proudfoot,
generation and atrophy





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.
disorders





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Human CC-type
GeneSeq
WO9831809
Chemokines are a family of related small,
Chemokine activities can be determined
Immune, inflammatory,


chemokine protein
Accession

secreted proteins involved in biological
using assays known in the art: Methods in
and infectious disorders,


designated SLC
W69163

processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:
cancer


(secondary


angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,


lymphoid


Members of this family are involved in a
T. N. C. Wells, and C. A. Power.


chemokine)


similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Human CC
GeneSeq
WO9826071
Chemokines are a family of related small,
Chemokine activities can be determined
Cancer and infectious


chemokine ELC
Accession

secreted proteins involved in biological
using assays known in the art: Methods in
diseases, particularly


protein
W62542

processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:
herpes virus





angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Human DVic-1
GeneSeq
Wo9823750
Chemokines are a family of related small,
Chemokine activities can be determined
Abnormal proliferation,


C-C chemokine
Accession

secreted proteins involved in biological
using assays known in the art: Methods in
regeneration,



W60649

processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:
degeneration, and atrophy





angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,
disorders, including cancer





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Human C-C
GeneSeq
WO9823750
Chemokines are a family of related small,
Chemokine activities can be determined
Immune disorders, cell


chemokine
Accession

secreted proteins involved in biological
using assays known in the art: Methods in
proliferation disorders,


DGWCC
W60650

processes ranging from hematophoiesis,
Molecular Biology, 2000, vol. 138:
cancer





angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identifed.


Human STCP-1
GeneSeq
WO9824907
Chemokines are a family of related small,
Chemokine activities can be determined
Immune disorders,



Accession

secreted proteins involved in biological
using assays known in the art: Methods in
particularly T cell related



W62783

processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:
disorders, viral infection,





angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,
and inflammation,





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.
especially joint





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Exodua protein
GeneSeq
WO9821330
Chamokines are a family of related small,
Chemokine activities can be determined
Immune and inflammatory



Accession

secreted proteins involved in biological
using assays known in the art: Methods in
disorders, angiogenesis,



W61279

processes ranging from hematopoiesis,
Molecular Biology, 2000, vol.138:
cancer, and proliferation





angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,
disorders, particularly





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.
myeloproliferative





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ
diseases





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Human
GeneSeq
WO9814581
Chemokines are a family of related small,
Chemokine activities can be determined
Cancer and degenerative


Chr19Kine
Acession

secreted proteins involved in biological
using assays known in the art: Methods in
disorders


protein
W50887

processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:





angiogenesis, and leukocyte trafficking.
Chemokine Protocols, Edited by: A. E. I. Proudfoot,





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Human T cell
GeneSeq
U.S. Pat. No. 5,780,268
Chemokines are a family of related
Chemokine activities can be determined
Immune, inflammatory,


mixed
Accession

small, secreted proteins involved in
using assays known in the art: Mehtods of
and infectious disorders,


lymphocyte
W58703

biological processes ranging from
Molecular Biology, 2000, vol. 138:
cancer


reaction


hematopoiesis, angiogenesis, and
Chemokine Protocols. Edited by: A. E. I. Proudfoot,


expressed


leukocyte trafficking. Members of this
T. N. C. Wells, and C. A. Power


chemokine


family are involved in a similarly diverse
© Humana Press Inc., Totowa, NJ


(TMEC)


range of pathologies including





inflammation, allergy, tissue rejection,





viral infection, and tumor biology. The





chemokines exert their effects by acting





on a family of seven transmembrane G-





protein-coupled receptors. Over 40





human chemokines have been





described, which bind to ~17 receptors





thus far identified.


Human 6CKine
GeneSeq
W09814581
Chemokines are a family of related
Chemokine activities can be determined
Cancer and degenerative


protein
Accession

small, secreted proteins involved in
using assays known in the art: Mehtods of
disorders



W50885

biological processes ranging from
Molecular Biology, 2000, vol. 138:





hematopoiesis, angiogenesis, and
Chemokine Protocols. Edited by: A. E. I. Proudfoot,





leukocyte trafficking. Members of this
T. N. C. Wells, and C. A. Power





family are involved in a similarly diverse
© Humana Press Inc., Totowa, NJ





range of pathologies including





inflammation, allergy, tissue rejection,





viral infection, and tumor biology. The





chemokines exert their effects by acting





on a family of seven transmembrane G-





protein-coupled receptors. Over 40





human chemokines have been





described, which bind to ~17 receptors





thus far identified.


human liver and
GeneSeq
WO9817800
Chemokines are a family of related
Chemokine activities can be determined
Immune, inflammatory,


activation
Accession

small, secreted proteins involved in
using assays known in the art: Mehtods of
and infectious disorders,


regulated
W57475

biological processes ranging from
Molecular Biology, 2000, vol. 138:
cancer


chemokine


hematopoiesis, angiogenesis, and
Chemokine Protocols. Edited by: A. E. I. Proudfoot,


(LARC)


leukocyte trafficking. Members of this
T. N. C. Wells, and C. A. Power





family are involved in a similarly diverse
© Humana Press Inc., Totowa, NJ





range of pathologies including





inflammation, allergy, tissue rejection,





viral infection, and tumor biology. The





chemokines exert their effects by acting





on a family of seven transmembrane G-





protein-coupled receptors. Over 40





human chemokines have been





described, which bind to ~17 receptors





thus far identified.


RANTES
GeneSeq
WO9744462
Chemokines are a family of related
Chemokine activities can be determined
Infectious diseases,


peptide
Accession

small, secreted proteins involved in
using assays known in the art: Mehtods of
particularly HIV



W29538

biological processes ranging from
Molecular Biology, 2000, vol. 138:





hematopoiesis, angiogenesis, and
Chemokine Protocols. Edited by: A. E. I. Proudfoot,





leukocyte trafficking. Members of this
T. N. C. Wells, and C. A. Power





family are involved in a similarly diverse
© Humana Press Inc., Totowa, NJ





range of pathologies including





inflammation, allergy, tissue rejection,





viral infection, and tumor biology. The





chemokines exert their effects by acting





on a family of seven transmembrane G-





protein-coupled receptors. Over 40





human chemokines have been





described, which bind to ~17 receptors





thus far identified.


RANTES 8-68
GeneSeq
WO9744462
Chemokines are a family of related
Chemokine activities can be determined
Infectious diseases,



Accession

small, secreted proteins involved in
using assays known in the art: Mehtods of
particularly HIV



W29529

biological processes ranging from
Molecular Biology, 2000, vol. 138:





hematopoiesis, angiogenesis, and
Chemokine Protocols. Edited by: A. E. I. Proudfoot,





leukocyte trafficking. Members of this
T. N. C. Wells, and C. A. Power





family are involved in a similarly diverse
© Humana Press Inc., Totowa, NJ





range of pathologies including





inflammation, allergy, tissue rejection,





viral infection, and tumor biology. The





chemokines exert their effects by acting





on a family of seven transmembrane G-





protein-coupled receptors. Over 40





human chemokines have been





described, which bind to ~17 receptors





thus far identified.


RANTES 9-68
GeneSeq
WO9744462
Chemokines are a family of related
Chemokine activities can be determined
Infectious diseases,



Accession

small, secreted proteins involved in
using assays known in the art: Mehtods of
particularly HIV



W29528

biological processes ranging from
Molecular Biology, 2000, vol. 138:





hematopoiesis, angiogenesis, and
Chemokine Protocols. Edited by: A. E. I. Proudfoot,





leukocyte trafficking. Members of this
T. N. C. Wells, and C. A. Power





family are involved in a similarly diverse
© Humana Press Inc., Totowa, NJ





range of pathologies including





inflammation, allergy, tissue rejection,





viral infection, and tumor biology. The





chemokines exert their effects by acting





on a family of seven transmembrane G-





protein-coupled receptors. Over 40





human chemokines have been





described, which bind to ~17 receptors





thus far identified.


Human
GeneSeq
WO9811226
Chemokines are a family of related
Chemokine activities can be determined
Abnormal proliferation,


chemokine
Accession

small, secreted proteins involved in
using assays known in the art: Mehtods of
regeneration,


protein 331D5
W59433

biological processes ranging from
Molecular Biology, 2000, vol. 138:
degeneration or atrophy,





hematopoiesis, angiogenesis, and
Chemokine Protocols. Edited by: A. E. I. Proudfoot,
including cancer





leukocyte trafficking. Members of this
T. N. C. Wells, and C. A. Power





family are involved in a similarly diverse
© Humana Press Inc., Totowa, NJ





range of pathologies including





inflammation, allergy, tissue rejection,





viral infection, and tumor biology. The





chemokines exert their effects by acting





on a family of seven transmembrane G-





protein-coupled receptors. Over 40





human chemokines have been





described, which bind to ~17 receptors





thus far identified.


Human
GeneSeq
WO9811226
Chemokines are a family of related
Chemokine activities can be determined
Abnormal proliferation,


chemokine
Accession

small, secreted proteins involved in
using assays known in the art: Mehtods of
regeneration,


protein 61164
W59430

biological processes ranging from
Molecular Biology, 2000, vol. 138:
degeneration or atrophy,





hematopoiesis, angiogenesis, and
Chemokine Protocols. Edited by: A. E. I. Proudfoot,
including cancer





leukocyte trafficking. Members of this
T. N. C. Wells, and C. A. Power





family are involved in a similarly diverse
© Humana Press Inc., Totowa, NJ





range of pathologies including





inflammation, allergy, tissue rejection,





viral infection, and tumor biology. The





chemokines exert their effects by acting





on a family of seven transmembrane G-





protein-coupled receptors. Over 40





human chemokines have been





described, which bind to ~17 receptors





thus far identified.


Chemokine
GeneSeq
WO9809171
Chemokines are a family of related
Chemokine activities can be determined
Immune, Inflammatory,


MCP-4
Accession

small, secreted proteins involved in
using assays known in the art: Mehtods of
and infectious diseases



W56690

biological processes ranging from
Molecular Biology, 2000, vol. 138:





hematopoiesis, angiogenesis, and
Chemokine Protocols. Edited by: A. E. I. Proudfoot,





leukocyte trafficking. Members of this
T. N. C. Wells, and C. A. Power





family are involved in a similarly diverse
© Humana Press Inc., Totowa, NJ





range of pathologies including





inflammation, allergy, tissue rejection,





viral infection, and tumor biology. The





chemokines exert their effects by acting





on a family of seven transmembrane G-





protein-coupled receptors. Over 40





human chemokines have been





described, which bind to ~17 receptors





thus far identified.


Human stromal
GeneSeq
FR2751658
Chemokines are a family of related small,
Chemokine activities can be determined
HIV infections


cell-derived
Accession

secreted proteins involved in biological
using assays known in the art: Methods in


chemokine, SDF-1
W50766

processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:





angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Thymus
GeneSeq
WO9801557
Chemokines are a family of related small,
Chemokine activities can be determined
Immune and inflammatory


expressed
Accession W44397

secreted proteins involved in biological
using assays known in the art: Methods in
disorders


chemokine


processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:


(TECK)


angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Human
GeneSeq
WO9801557
Chemokines are a family of related small,
Chemokine activities can be determined
Immune and inflammatory


chemokine MIP-
Accession W44398

secreted proteins involved in biological
using assays known in the art: Methods in
disorders


3alpha


processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:





angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Human
GeneSeq
WO9801557
Chemokines are a family of related small,
Chemokine activities can be determined
Immune and inflammatory


chemokine MIP-
Accession W44399

secreted proteins involved in biological
using assays known in the art: Methods in
disorders


3beta


processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:





angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Human monocyte
GeneSeq
WO9802459
Chemokines are a family of related small,
Chemokine activities can be determined
Immune disorders,


chemotactic
Accession W42072

secreted proteins involved in biological
using assays known in the art: Methods in
respiratory disorders,


proprotein


processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:
cancer


(MCPP) sequence


angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Macrophage-
GeneSeq
U.S. Pat. No. 5,688,927/
Chemokines are a family of related small,
Chemokine activities can be determined
Immune, and inflammatory


derived
Accessions
U.S. Pat. No. 5,932,703
secreted proteins involved in biological
using assays known in the art: Methods in
disorders, cancer


chemokine (MDC)
W40811 and

processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:



Y24414

angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Macrophage
GeneSeq
U.S. Pat. No. 5,932,703
Chemokines are a family of related small,
Chemokine activities can be determined
Immune and inflammatory


derived
Accession Y24416

secreted proteins involved in biological
using assays known in the art: Methods in
disorders


chemokine


processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:


analogue MDC-


angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,


eyfy


Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Macrophage
GeneSeq
U.S. Pat. No. 5,932,703
Chemokines are a family of related small,
Chemokine activities can be determined
Immune and inflammatory


derived
Accession Y24413

secreted proteins involved in biological
using assays known in the art: Methods in
disorders


chemokine


processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:


analogue MDC


angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,


(n + 1)


Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Macrophage
GeneSeq
U.S. Pat. No. 5,932,703
Chemokines are a family of related small,
Chemokine activities can be determined
Immune and inflammatory


derived
Accession Y24415

secreted proteins involved in biological
using assays known in the art: Methods in
disorders


chemokine


processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:


analogue MDC-yl


angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Human type CC
GeneSeq
JP11243960
Chemokines are a family of related small,
Chemokine activities can be determined
Allergic diseases and HIV


chemokine
Accession Y43178

secreted proteins involved in biological
using assays known in the art: Methods in
infection


eotaxin 3 protein


processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:


sequence


angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Human MCP-3
GeneSeq
WO9946392
Chemokines are a family of related small,
Chemokine activities can be determined
Cancer and immune


and human Muc-1
Acession Y29893

secreted proteins involved in biological
using assays known in the art: Methods in
disorders, particularly HIV


core epitope


processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:
infection


(VNT) fusion


angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,


protein


Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarily diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Human IP-10 and
GeneSeq
WO9946392
Chemokines are a family of related small,
Chemokine activities can be determined
Cancer and immune


human Muc-1
Accession Y29894

secreted proteins involved in biological
using assays known in the art: Methods in
disorders, particularly HIV


core epitope


processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:
infection


(VNT) fusion


angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,


protein


Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarily diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Human IP-10 and
GeneSeq
W09946392
Chemokines are a family of related small,
Chemokine activities can be determined
Cancer and immune


HIV-1 gp 120
Accession Y29897

secreted proteins involved in biological
using assays known in the art: Methods in
disorders, particularly HIV


hypervariable


processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:
infection


region fusion


angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,


protein


Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarily diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Human mammary
GeneSeq
WO9936540
Chemokines are a family of related small,
Chemokine activities can be determined
Breast disease, including


associated
Accessions

secreted proteins involved in biological
using assays known in the art: Methods in
cancer


chemokine
Y29092 and

processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:


(MACK) protein
Y29093

angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,


Full-Length and


Members of this family are involved in a
T. N. C. Wells, and C. A. Power.


Mature


similarily diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Tim-1 protein
GeneSeq
WO9933990
Chemokines are a family of related small,
Chemokine activities can be determined
Inflammation due to stimuli



Accession

secreted proteins involved in biological
using assays known in the art: Methods in
such as heart attacks and



Y28290

processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:
stroke, infection, physical





angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,
trauma, UV or ionizing





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.
radiation, burns, frostbite





similarily diverse range of pathologies
© Humana Press Inc., Totowa, NJ
or corrosive chemicals





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Human Lkn-1 Full-
GeneSeq
WO9928473
Chemokines are a family of related small,
Chemokine activities can be determined
HIV infection and cancer,


Length and
Accessions
and
secreted proteins involved in biological
using assays known in the art: Methods in
particularly leukemia


Mature protein
Y17280, Y17274,
WO9928472
processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:



Y17281, and

angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,



Y17275

Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarily diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


N-terminal
GeneSeq
WO9920759
Chemokines are a family of related small,
Chemokine activities can be determined
Inhibit or stimulate


modified
Accession Y05818

secreted proteins involved in biological
using assays known in the art: Methods in
angiogenesis, inhibit the


chemokine met-


processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:
binding of HIV


hSDF-1 alpha


angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarily diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


N-terminal
GeneSeq
WO9920759
Chemokines are a family of related small,
Chemokine activities can be determined
Inhibit or stimulate


modified
Accession Y05819

secreted proteins involved in biological
using assays known in the art: Methods in
angiogenesis, inhibit the


chemokine met-


processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:
binding of HIV,


hSDF-1 beta


angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,
antiinflammatory;





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.
immunosuppressant





similarily diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


N-terminal
GeneSeq
WO9920759
Chemokines are a family of related small,
Chemokine activities can be determined
Inhibit or stimulate


modified
Accession Y05820

secreted proteins involved in biological
using assays known in the art: Methods in
angiogenesis, inhibit the


chemokine


processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:
binding of HIV,


GroHEK/hSDF-


angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,
antiinflammatory;


1alpha


Members of this family are involved in a
T. N. C. Wells, and C. A. Power.
immunosuppressant





similarily diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


N-terminal
GeneSeq
WO9920759
Chemokines are a family of related small,
Chemokine activities can be determined
Inhibit or stimulate


modified
Accession Y05821

secreted proteins involved in biological
using assays known in the art: Methods in
angiogenesis, inhibit the


chemokine


processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:
binding of HIV,


GroHEK/hSDF-


angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,
antiinflammatory;


1beta.


Members of this family are involved in a
T. N. C. Wells, and C. A. Power.
immunosuppressant





similarily diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Chemokine
GeneSeq
WO9912968
Chemokines are a family of related small,
Chemokine activities can be determined
Increase or enhance an


Eotaxin
Accession

secreted proteins involved in biological
using assays known in the art: Methods in
inflammatory response, an



Y14230

processes ranging from hematopoiesis,
Molecular Bilogy, 2000, vol. 138:
immune response





agiogenesis, and leukocye trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,
orhaematopoietic cell-





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.
associated activity; treat a





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ
vascular indication;





including inflammation, allergy, tissue

Cancer; enhance wound





rejection, viralk infection, and tumor

healing, to prevent or treat





biology. The chemokines exert their

asthma, organ transplant





effects by acting on a family of seven

rejction, rheumatoid





transmembrane G-protein-coupled

arthritis or allergy





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Chemokine
GeneSeq
WO9912968
Chemokines are a family of related small,
Chemokine activities can be determined
Immune disorders,


hMCP1a
Accession

secreted proteins involved in biological
using assays known in the art: Methods in
Vascular disorders,



Y14225

processes ranging from hematopoiesis,
Molecular Bilogy, 2000, vol. 138:
Wound healing, cancer,





agiogenesis, and leukocye trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,
prevent organ transplant





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.
rejection, Increase or





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ
enhance an inflammatory





including inflammation, allergy, tissue

response,





rejection, viralk infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Chemokine
GeneSeq
WO9912968
Chemokines are a family of related small,
Chemokine activities can be determined
Immune disorders,


hMCP1b
Accession

secreted proteins involved in biological
using assays known in the art: Methods in
Vascular disorders,



Y14226

processes ranging from hematopoiesis,
Molecular Bilogy, 2000, vol. 138:
Wound healing, cancer,





agiogenesis, and leukocye trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,
prevent organ transplant





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.
rejection, Increase or





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ
enhance an inflammatory





including inflammation, allergy, tissue

response,





rejection, viralk infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Chemokine
GeneSeq
WO9912968
Chemokines are a family of related small,
Chemokine activities can be determined
Immune disorders,


hSDF1b
Accession

secreted proteins involved in biological
using assays known in the art: Methods in
Vascular disorders,



Y14228

processes ranging from hematopoiesis,
Molecular Bilogy, 2000, vol. 138:
Wound healing, cancer,





agiogenesis, and leukocye trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,
prevent organ transplant





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.
rejection, Increase or





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ
enhance an inflammatory





including inflammation, allergy, tissue

response,





rejection, viralk infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Chemokine
GeneSeq
WO9912968
Chemokines are a family of related small,
Chemokine activities can be determined
Immune disorders,


hIL-8
Accession

secreted proteins involved in biological
using assays known in the art: Methods in
Vascular disorders,



Y14229

processes ranging from hematopoiesis,
Molecular Bilogy, 2000, vol. 138:
Wound healing, cancer,





agiogenesis, and leukocye trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,
prevent organ transplant





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.
rejection, Increase or





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ; and
enhance an inflammatory





including inflammation, allergy, tissue
Holmes et al (1991) Science 253, 1278-80.
response,





rejection, viralk infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Chemokine
GeneSeq
WO9912968
Chemokines are a family of related small,
Chemokine activities can be determined
Immune disorders,


hMCP1
Accession

secreted proteins involved in biological
using assays known in the art: Methods in
Vascular disorders,



Y14222

processes ranging from hematopoiesis,
Molecular Bilogy, 2000, vol. 138:
Wound healing, cancer,





agiogenesis, and leukocye trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,
prevent organ transplant





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.
rejection, Increase or





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ
enhance an inflammatory





including inflammation, allergy, tissue

response,





rejection, viralk infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Chemokine
GeneSeq
WO9912968
Chemokines are a family of related small,
Chemokine activities can be determined
Immune disorders,


hMCP2
Accession

secreted proteins involved in biological
using assays known in the art: Methods in
Vascular disorders,



Y14223

processes ranging from hematopoiesis,
Molecular Bilogy, 2000, vol. 138:
Wound healing, cancer,





agiogenesis, and leukocye trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,
prevent organ transplant





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.
rejection, Increase or





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ
enhance an inflammatory





including inflammation, allergy, tissue

response,





rejection, viralk infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Chemokine
GeneSeq
WO9912968
Chemokines are a family of related small,
Chemokine activities can be determined
Immune disorders,


hMCP3
Accession

secreted proteins involved in biological
using assays known in the art: Methods in
Vascular disorders,



Y14224

processes ranging from hematopoiesis,
Molecular Bilogy, 2000, vol. 138:
Wound healing, cancer,





agiogenesis, and leukocye trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,
prevent organ transplant





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.
rejection, Increase or





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ
enhance an inflammatory





including inflammation, allergy, tissue

response,





rejection, viralk infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


C-C chemokine,
GeneSeq
EP905240
Chemokines are a family of related small,
Chemokine activities can be determined
Inflammatory, Immune and


MCP2
Accession

secreted proteins involved in biological
using assays known in the art: Methods in
infectious diseases;



Y05300

processes ranging from hematopoiesis,
Molecular Bilogy, 2000, vol. 138:
pulmonary diseases and





agiogenesis, and leukocye trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,
skin disorders; tumours,





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.
and angiogenesis-and





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ
haematopoiesis-related





including inflammation, allergy, tissue

diseases





rejection, viralk infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Wild type
GeneSeq
EP906954
Chemokines are a family of related small,
Chemokine activities can be determined
Inflammatory, Immune and


monocyte
Accession

secreted proteins involved in biological
using assays known in the art: Methods in
infectious diseases;


chemotactic
Y07233

processes ranging from hematopoiesis,
Molecular Bilogy, 2000, vol. 138:
pulmonary diseases and


protein 2


agiogenesis, and leukocye trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,
skin disorders; tumours,





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.
and angiogenesis-and





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ
haematopoiesis-related





including inflammation, allergy, tissue

diseases





rejection, viralk infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Truncated
GeneSeq
EP906954
Chemokines are a family of related small,
Chemokines activities can be determined
Inflammatory, immune and


monocyte
Accession

secreted proteins involved in biological
using assays known in the art: Methods in
infectious diseases;


chemotactic
Y07234

processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:
pulmonry diseases and skin


protein 2 (6-76)


angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,
disorders; tumours, and





Members of this family are involved in a
T. N. C. Wells, and C. A. Power,
angiogenesis-and





similarly diverse range of pathologies
Humana Press Inc., Totowa, NJ
haematopoiesis-related





including inflammation, allergy, tissue

diseases





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a fmaily of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Truncated
GeneSeq
EP905241;
Chemokines are a family of related small,
Chemokines activities can be determined
Inflammatory, immune and


RANTES
Accessions
EP906954
secreted proteins involved in biological
using assays known in the art: Methods in
infectious diseases;


protein (3-68)
Y07236 and

processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:
pulmonry diseases and skin



Y07232

angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,
disorders; tumours, and





Members of this family are involved in a
T. N. C. Wells, and C. A. Power,
angiogenesis-and





similarly diverse range of pathologies
Humana Press Inc., Totowa, NJ
haematopoiesis-related





including inflammation, allergy, tissue

diseases





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a fmaily of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Wild type
GeneSeq
EP905241
Chemokines are a family of related small,
Chemokines activities can be determined
Inflammatory, immune and


monocyte
Accession

secreted proteins involved in biological
using assays known in the art: Methods in
infectious diseases;


chemotactic
Y07237

processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:
pulmonry diseases and skin


protein 2


angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,
disorders; tumours, and





Members of this family are involved in a
T. N. C. Wells, and C. A. Power,
angiogenesis-and





similarly diverse range of pathologies
Humana Press Inc., Totowa, NJ
haematopoiesis-related





including inflammation, allergy, tissue

diseases





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a fmaily of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Truncated
GeneSeq
EP905241
Chemokines are a family of related small,
Chemokines activities can be determined
Inflammatory, immune and


monocyte
Accession

secreted proteins involved in biological
using assays known in the art: Methods in
infectious diseases;


chemotactic
Y07238

processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:
pulmonry diseases and skin


protein 2 (6-76)


angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,
disorders; tumours, and





Members of this family are involved in a
T. N. C. Wells, and C. A. Power,
angiogenesis-and





similarly diverse range of pathologies
Humana Press Inc., Totowa, NJ
haematopoiesis-related





including inflammation, allergy, tissue

diseases





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a fmaily of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


A partial
GeneSeq
EP897980
Chemokines are a family of related small,
Chemokines activities can be determined
Soluble CXCR4B receptor


CXCR4B
Accession

secreted proteins involved in biological
using assays known in the art: Methods in
polypeptides may be useful


protein
W97363

processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:
for inhibiting chemokine





angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,
activities and viral infection.





Members of this family are involved in a
T. N. C. Wells, and C. A. Power,





similarly diverse range of pathologies
Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a fmaily of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Interferon
GeneSeq
U.S. Pat. No. 5,871,723
Chemokines are a family of related small,
Chemokines activities can be determined
Angiogenesis, Cancer,


gamma-
Accession

secreted proteins involved in biological
using assays known in the art: Methods in
Inflammatory and Immune


inducible
W96709

processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:
disorders, Cardio-Vascular


protein (IP-10)


angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,
discorders, Musco-skeletal





Members of this family are involved in a
T. N. C. Wells, and C. A. Power,
disorders





similarly diverse range of pathologies
Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a fmaily of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


A monokine
GeneSeq
U.S. Pat. No. 5,871,723
Chemokines are a family of related small,
Chemokines activities can be determined
Angiogenesis, Cancer,


induced by
Accession

secreted proteins involved in biological
using assays known in the art: Methods in
Inflammatory and Immune


gamma-
W96710

processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:
disorders, Cardio-Vascular


interferon


angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,
discorders, Musco-skeletal


(MIG)


Members of this family are involved in a
T. N. C. Wells, and C. A. Power,
disorders





similarly diverse range of pathologies
Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a fmaily of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Interleukin-8
GeneSeq
U.S. Pat. No. 5,871,723
Chemokines are a family of related small,
Chemokines activities can be determined
Angiogenesis, Cancer,


(IL-8) protein.
Accession

secreted proteins involved in biological
using assays known in the art: Methods in
Inflammatory and Immune



W96711

processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:
disorders, Cardio-Vascular





angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,
discorders, Musco-skeletal





Members of this family are involved in a
T. N. C. Wells, and C. A. Power,
disorders





similarly diverse range of pathologies
Humana Press Inc., Totowa, NJ; and





including inflammation, allergy, tissue
Holmes et al (1991) Science 253, 1278-80.





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a fmaily of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Epithelial
GeneSeq
U.S. Pat. No. 5,871,723
Chemokines are a family of related small,
Chemokines activities can be determined
Angiogenesis, Cancer,


neutrophil
Accession

secreted proteins involved in biological
using assays known in the art: Methods in
Inflammatory and Immune


activating
W96712

processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:
disorders, Cardio-Vascular


protein-78


angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,
discorders, Musco-skeletal


(ENA-78)


Members of this family are involved in a
T. N. C. Wells, and C. A. Power,
disorders





similarly diverse range of pathologies
Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a fmaily of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Growth related
GeneSeq
U.S. Pat. No. 5,871,723
Chemokines are a family of related small,
Chemokines activities can be determined
Angiogenesis, Cancer,


oncogene-alpha
Accession

secreted proteins involved in biological
using assays known in the art: Methods in
Inflammatory and Immune


(GRO-alpha).
W96713

processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:
disorders, Cardio-Vascular





angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,
discorders, Musco-skeletal





Members of this family are involved in a
T. N. C. Wells, and C. A. Power,
disorders





similarly diverse range of pathologies
Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a fmaily of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Growth related
GeneSeq
U.S. Pat. No. 5,871,723
Chemokines are a family of related small,
Chemokine activities can be determined
Angiogenesis, Cancer,


oncogene-beta
Accession

secreted proteins involved in biological
using assays known in the art: Methods in
Inflammatory and Immune


(GRO-beta).
W96714

processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:
disorders, Cardio-Vascular





angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,
disorders, Musco-skeletal





Members of this family are involved in a
T. N. C. Wells, and C. A. Power,
disorders





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified


Growth related
GeneSeq
U.S. Pat. No. 5,871,723
Chemokines are a family of related small,
Chemokine activities can be determined
Angiogenesis, Cancer,


oncogene-gamma
Accession W96715

secreted proteins involved in biological
using assays known in the art: Methods in
Inflammatory and Immune


(GRO-gamma)


processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:
disorders, Cardio-Vascular





angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,
disorders, Musco-skeletal





Members of this family are involved in a
T. N. C. Wells, and C. A. Power,
disorders





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


A platelet basic
GeneSeq
U.S. Pat. No. 5,871,723
Chemokines are a family of related small,
Chemokine activities can be determined
Angiogenesis, Cancer,


protein (PBP)
Accession W96716

secreted proteins involved in biological
using assays known in the art: Methods in
Inflammatory and Immune





processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:
disorders, Cardio-Vascular





angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,
disorders, Musco-skeletal





Members of this family are involved in a
T. N. C. Wells, and C. A. Power,
disorders





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Connective tissue
GeneSeqAccession
U.S. Pat. No. 5,871,723
Chemokines are a family of related small,
Chemokine activities can be determined
Angiogenesis, Cancer,


activating protein-
S96717

secreted proteins involved in biological
using assays known in the art: Methods in
Inflammatory and Immune


III (CTAP-III)


processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:
disorders, Cardio-Vascular





angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,
disorders, Musco-skeletal





Members of this family are involved in a
T. N. C. Wells, and C. A. Power,
disorders





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Beta-
GeneSeq
U.S. Pat. No. 5,871,723
Chemokines are a family of related small,
Chemokine activities can be determined
Angiogenesis, Cancer,


thromboglobulin
Accession W96718

secreted proteins involved in biological
using assays known in the art: Methods in
Inflammatory and Immune


protein (beta-TG)


processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:
disorders, Cardio-Vascular





angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,
disorders, Musco-skeletal





Members of this family are involved in a
T. N. C. Wells, and C. A. Power,
disorders





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Neutrophil
GeneSeq
U.S. Pat. No. 5,871,723
Chemokines are a family of related small,
Chemokine activities can be determined
Angiogenesis, Cancer,


activating peptide-
Accession W96719

secreted proteins involved in biological
using assays known in the art: Methods in
Inflammatory and Immune


2 (NAP-2)


processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:
disorders, Cardio-Vascular





angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,
disorders, Musco-skeletal





Members of this family are involved in a
T. N. C. Wells, and C. A. Power,
disorders





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Granulocyte
GeneSeq
U.S. Pat. No. 5,871,723
Chemokines are a family of related small,
Chemokine activities can be determined
Angiogenesis, Cancer,


chemotactic
Accession W96720

secreted proteins involved in biological
using assays known in the art: Methods in
Inflammatory and Immune


protein-2 (GCP-2)


processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:
disorders, Cardio-Vascular





angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,
disorders, Musco-skeletal





Members of this family are involved in a
T. N. C. Wells, and C. A. Power,
disorders





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Human
GeneSeq
EP887409
Chemokines are a family of related small,
Chemokine activities can be determined
Immune disorders, viral,


chemokine MIG-
Accession W90124

secreted proteins involved in biological
using assays known in the art: Methods in
parasitic, fungal or


beta protein


processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:
bacterial infections,





angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,
Cancer; autoimmune





Members of this family are involved in a
T. N. C. Wells, and C. A. Power,
diseases or transplant





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ
rejection





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Human ZCHEMO-8
GeneSeq
WO9854326
Chemokines are a family of related small,
Chemokine activities can be determined
Immune disorders, cancer,



Accession W82716

secreted proteins involved in biological
using assays known in the art: Methods in
myelopoietic disorders,





processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:
autoimmune disorders and





angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,
immunodeficiencies,





Members of this family are involved in a
T. N. C. Wells, and C. A. Power,
Inflammatory and





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ
infectious diseases,





including inflammation, allergy, tissue

Vascular disorders, wound





rejection, viral infection, and tumor

healing





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Human Act-2
GeneSeq
WO9854326
Chemokines are a family of related small,
Chemokine activities can be determined
Immune disorders, cancer,


protein
Accession W82717

secreted proteins involved in biological
using assays known in the art: Methods in
myelopoietic disorders,





processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:
autoimmune disorders and





angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,
immunodeficiencies,





Members of this family are involved in a
T. N. C. Wells, and C. A. Power,
Inflammatory and





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ
infectious diseases,





including inflammation, allergy, tissue

Vascular disorders, wound





rejection, viral infection, and tumor

healing





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Human SISD
GeneSeq
WO9854326
Chemokines are a family of related small,
Chemokine activities can be determined
Immune disorders, cancer,


protein
Acession

secreted proteins involved in biological
using assays known in the art: Methods in
myelopoietic disorders,



W82720

processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:
autoimmune disorders and





angiogenesis, and leukocyte trafficking.
Chemokine Protocols, Edited by: A. E. I. Proudfoot,
immunodeficiencies,





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.
Inflammatory and





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ
infectious diseases,





including inflammation, allergy, tissue

Vascular disorders, wound





rejection, viral infection, and tumor

healing





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Human M110
GeneSeq
WO9854326
Chemokines are a family of related
Chemokine activities can be determined
Immune disorders, cancer,


protein
Accession

small, secreted proteins involved in
using assays known in the art: Mehtods of
myelopoietic disorders,



W82721

biological processes ranging from
Molecular Biology, 2000, vol. 138:
autoimmune disorders and





hematopoiesis, angiogenesis, and
Chemokine Protocols. Edited by: A. E. I. Proudfoot,
immunodeficiencies,





leukocyte trafficking. Members of this
T. N. C. Wells, and C. A. Power
Inflammatory and





family are involved in a similarly diverse
© Humana Press Inc., Totowa, NJ
infectious diseases,





range of pathologies including

Vascular disorders, wound





inflammation, allergy, tissue rejection,

healing





viral infection, and tumor biology. The





chemokines exert their effects by acting





on a family of seven transmembrane G-





protein-coupled receptors. Over 40





human chemokines have been





described, which bind to ~17 receptors





thus far identified.


Human M11A
GeneSeq
W09854326
Chemokines are a family of related
Chemokine activities can be determined
Immune disorders, cancer,


protein
Accession

small, secreted proteins involved in
using assays known in the art: Mehtods of
myelopoietic disorders,



W82722

biological processes ranging from
Molecular Biology, 2000, vol. 138:
autoimmune disorders and





hematopoiesis, angiogenesis, and
Chemokine Protocols. Edited by: A. E. I. Proudfoot,
immunodeficiencies,





leukocyte trafficking. Members of this
T. N. C. Wells, and C. A. Power
Inflammatory and





family are involved in a similarly diverse
© Humana Press Inc., Totowa, NJ
infectious diseases,





range of pathologies including

Vascular disorders, wound





inflammation, allergy, tissue rejection,

healing





viral infection, and tumor biology. The





chemokines exert their effects by acting





on a family of seven transmembrane G-





protein-coupled receptors. Over 40





human chemokines have been





described, which bind to ~17 receptors





thus far identified.


Human CCC3
GeneSeq
WO9854326
Chemokines are a family of related
Chemokine activities can be determined
Immune disorders, cancer,


protein
Accession

small, secreted proteins involved in
using assays known in the art: Mehtods of
myelopoietic disorders,



W82723

biological processes ranging from
Molecular Biology, 2000, vol. 138:
autoimmune disorders and





hematopoiesis, angiogenesis, and
Chemokine Protocols. Edited by: A. E. I. Proudfoot,
immunodeficiencies,





leukocyte trafficking. Members of this
T. N. C. Wells, and C. A. Power
Inflammatory and





family are involved in a similarly diverse
© Humana Press Inc., Totowa, NJ
infectious diseases,





range of pathologies including

Vascular disorders, wound





inflammation, allergy, tissue rejection,

healing





viral infection, and tumor biology. The





chemokines exert their effects by acting





on a family of seven transmembrane G-





protein-coupled receptors. Over 40





human chemokines have been





described, which bind to ~17 receptors





thus far identified.


A human L105
GeneSeq
WO9856818
Chemokines are a family of related
Chemokine activities can be determined
Cancer, wound healing


chemokine
Accession

small, secreted proteins involved in
using assays known in the art: Mehtods of


designated
W87588

biological processes ranging from
Molecular Biology, 2000, vol. 138:


huL105_3.


hematopoiesis, angiogenesis, and
Chemokine Protocols. Edited by: A. E. I. Proudfoot,





leukocyte trafficking. Members of this
T. N. C. Wells, and C. A. Power





family are involved in a similarly diverse
© Humana Press Inc., Totowa, NJ





range of pathologies including





inflammation, allergy, tissue rejection,





viral infection, and tumor biology. The





chemokines exert their effects by acting





on a family of seven transmembrane G-





protein-coupled receptors. Over 40





human chemokines have been





described, which bind to ~17 receptors





thus far identified.


A human L105
GeneSeq
WO9856818
Chemokines are a family of related
Chemokine activities can be determined
Cancer, wound healing


chemokine
Accession

small, secreted proteins involved in
using assays known in the art: Mehtods of


designated
W87589

biological processes ranging from
Molecular Biology, 2000, vol. 138:


huL105_7.


hematopoiesis, angiogenesis, and
Chemokine Protocols. Edited by: A. E. I. Proudfoot,





leukocyte trafficking. Members of this
T. N. C. Wells, and C. A. Power





family are involved in a similarly diverse
© Humana Press Inc., Totowa, NJ





range of pathologies including





inflammation, allergy, tissue rejection,





viral infection, and tumor biology. The





chemokines exert their effects by acting





on a family of seven transmembrane G-





protein-coupled receptors. Over 40





human chemokines have been





described, which bind to ~17 receptors





thus far identified.


Human mature
GeneSeq
WO9848828
Chemokines are a family of related
Chemokine activities can be determined
Infectious diseases, sepsis


gro-alpha
Accession

small, secreted proteins involved in
using assays known in the art: Mehtods of


polypeptide
W81498

biological processes ranging from
Molecular Biology, 2000, vol. 138:


used to treat


hematopoiesis, angiogenesis, and
Chemokine Protocols. Edited by: A. E. I. Proudfoot,


sepsis


leukocyte trafficking. Members of this
T. N. C. Wells, and C. A. Power





family are involved in a similarly diverse
© Humana Press Inc., Totowa, NJ





range of pathologies including





inflammation, allergy, tissue rejection,





viral infection, and tumor biology. The





chemokines exert their effects by acting





on a family of seven transmembrane G-





protein-coupled receptors. Over 40





human chemokines have been





described, which bind to ~17 receptors





thus far identified.


Human mature
GeneSeq
WO9848828
Chemokines are a family of related
Chemokine activities can be determined
Infectious diseases, sepsis


gro-gamma
Accession

small, secreted proteins involved in
using assays known in the art: Mehtods of


polypeptide
W81500

biological processes ranging from
Molecular Biology, 2000, vol. 138:


used to treat


hematopoiesis, angiogenesis, and
Chemokine Protocols. Edited by: A. E. I. Proudfoot,


sepsis


leukocyte trafficking. Members of this
T. N. C. Wells, and C. A. Power





family are involved in a similarly diverse
© Humana Press Inc., Totowa, NJ





range of pathologies including





inflammation, allergy, tissue rejection,





viral infection, and tumor biology. The





chemokines exert their effects by acting





on a family of seven transmembrane G-





protein-coupled receptors. Over 40





human chemokines have been





described, which bind to ~17 receptors





thus far identified.


Human thymus
GeneSeq
WO0053635
Chemokines are a family of related
Chemokine activities can be determined
Inflammatory disorders,


expressed
Accessions

small, secreted proteins involved in
using assays known in the art: Mehtods of
cancer, Immune and


chemokine
B19607 and

biological processes ranging from
Molecular Biology, 2000, vol. 138:
vascular disorders


TECK and
B19608

hematopoiesis, angiogenesis, and
Chemokine Protocols. Edited by: A. E. I. Proudfoot,


TECK variant


leukocyte trafficking. Members of this
T. N. C. Wells, and C. A. Power





family are involved in a similarly diverse
© Humana Press Inc., Totowa, NJ





range of pathologies including





inflammation, allergy, tissue rejection,





viral infection, and tumor biology. The





chemokines exert their effects by acting





on a family of seven transmembrane G-





protein-coupled receptors. Over 40





human chemokines have been





described, which bind to ~17 receptors





thus far identified.


Human
GeneSeq
WO0042071
Chemokines are a family of related
Chemokine activities can be determined
Autoimmune disorders,


chemokine
Accession B15791

small, secreted proteins involved in
using assays known in the art: Mehtods of
Immune, Vascular and


SDF1alpha


biological processes ranging from
Molecular Biology, 2000, vol. 138:
Inflammatory disorders





hematopoiesis, angiogenesis, and
Chemokine Protocols. Edited by: A. E. I. Proudfoot,





leukocyte trafficking. Members of this
T. N. C. Wells, and C. A. Power





family are involved in a similarly diverse
© Humana Press Inc., Totowa, NJ





range of pathologies including





inflammation, allergy, tissue rejection,





viral infection, and tumor biology. The





chemokines exert their effects by acting





on a family of seven transmembrane G-





protein-coupled receptors. Over 40





human chemokines have been





described, which bind to ~17 receptors





thus far identified.


Human
GeneSeq
WO0042071
Chemokines are a family of related small,
Chemokine activities can be determined
Autoimmune disorders,


chemokine
Accession B15793

secreted proteins involved in biological
using assasys known in the art: Methods
Immune, Vascular and


GROalpha


processes ranging from hematopoiesis,
in Molecular Biology, 2000, vol. 138:
Inflammatory diorders





angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot;





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Human
GeneSeq
WO0042071
Chemokines are a family of related small,
Chemokine activities can be determined
Autoimmune disorders,


chemokine
Accession B15794

secreted proteins involved in biological
using assasys known in the art: Methods in
Immune, Vascular and


eotaxin


processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:
Inflammatory disorders





angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot;





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Human
GeneSeq
WO0042071
Chemokines are a family of related small,
Chemokine activities can be determined
Autoimmune disorders,


chemokine MIG
Accession B15803

secreted proteins involved in biological
using assasys known in the art: Methods in
Immune, Vascular and





processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:
Inflammatory disorders





angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot;





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Human
GeneSeq
WO0042071
Chemokines are a family of related small,
Chemokine activities can be determined
Autoimmune disorders,


chemokine PF4
Accession B15804

secreted proteins involved in biological
using assasys known in the art: Methods in
Immune, Vascular and





processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:
Inflammatory disorders





angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot;





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Human
GeneSeq
WO0042071
Chemokines are a family of related small,
Chemokine activities can be determined
Autoimmune disorders,


chemokine I-309
Accession B15805

secreted proteins involved in biological
using assasys known in the art: Methods in
Immune, Vascular and





processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:
Inflammatory disorders





angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot;





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Human
GeneSeq
WO0042071
Chemokines are a family of related small,
Chemokine activities can be determined
Autoimmune disorders,


chemokine HCC-1
Accession B15806

secreted proteins involved in biological
using assasys known in the art: Methods in
Immune, Vascular and





processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:
Inflammatory disorders





angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot;





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Human
GeneSeq
WO0042071
Chemokines are a family of related small,
Chemokine activities can be determined
Autoimmune disorders,


chemokine C10
Accession B15807

secreted proteins involved in biological
using assasys known in the art: Methods in
Immune, Vascular and





processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:
Inflammatory disorders





angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot;





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Human
GeneSeq
WO0042071
Chemokines are a family of related small,
Chemokine activities can be determined
Autoimmune disorders,


chemokine CCR-2
Accession B15808

secreted proteins involved in biological
using assasys known in the art: Methods in
Immune, Vascular and





processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:
Inflammatory disorders





angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot;





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Human
GeneSeq
WO0042071
Chemokines are a family of related small,
Chemokine activities can be determined
Autoimmune disorders,


chemokine ENA-
Accession B15809

secreted proteins involved in biological
using assasys known in the art: Methods in
Immune, Vascular and


78


processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:
Inflammatory disorders





angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot;





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Human
GeneSeq
WO0042071
Chemokines are a family of related small,
Chemokine activities can be determined
Autoimmune disorders,


chemokine
Accession B15810

secreted proteins involved in biological
using assasys known in the art: Methods in
Immune, Vascular and


GRObeta


processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:
Inflammatory disorders





angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot;





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Human
GeneSeq
WO0042071
Chemokines are a family of related small,
Chemokine activities can be determined
Autoimmune disorders,


chemokine IP-10
Accession B15811

secreted proteins involved in biological
using assays known in the art: Methods in
Immune, Vascular and





processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:
Inflammatory disorders





angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Human
GeneSeq
WO0042071
Chemokines are a family of related small,
Chemokine activities can be determined
Autoimmune disorders,


chemokine
Accession B15812

secreted proteins involved in biological
using assays known in the art: Methods in
Immune, Vascular and


SDF1beta


processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:
Inflammatory disorders





angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Human
GeneSeq
WO0042071
Chemokines are a family of related small,
Chemokine activities can be determined
Autoimmune disorders,


chemokine GRO
Accession B15813

secreted proteins involved in biological
using assays known in the art: Methods in
Immune, Vascular and


alpha


processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:
Inflammatory disorders





angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Human
GeneSeq
WO0042071
Chemokines are a family of related small,
Chemokine activities can be determined
Autoimmune disorders,


chemokine
Accession B15831

secreted proteins involved in biological
using assays known in the art: Methods in
Immune, Vascular and


MIP1beta


processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:
Inflammatory disorders





angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


A human C-C
GeneSeq
U.S. Pat. No. 6,096,300
Chemokines are a family of related small,
Chemokine activities can be determined
Cancer


chemokine
Accession B07939

secreted proteins involved in biological
using assays known in the art: Methods in


designated


processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:


exodus


angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Human
GeneSeq
U.S. Pat. No. 6,084,071
Chemokines are a family of related small,
Chemokine activities can be determined
Chemotaxis, Gene


chemokine
Accession Y96922

secreted proteins involved in biological
using assays known in the art: Methods in
Therapy, Wound healing


L105_7


processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:





angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Human
GeneSeq
U.S. Pat. No. 6,084,071
Chemokines are a family of related small,
Chemokine activities can be determined
Chemotaxis, Gene


chemokine
Accession Y96923

secreted proteins involved in biological
using assays known in the art: Methods in
Therapy, Wound healing


L105_3


processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:





angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Human secondary
GeneSeq
WO0038706
Chemokines are a family of related small,
Chemokine activities can be determined
Cancer, Vascular and


lymphoid
Accession B01434

secreted proteins involved in biological
using assays known in the art: Methods in
Immune disorders


chemokine (SLC)


processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:





angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Human non-ELR
GeneSeq
WO0029439
Chemokines are a family of related small,
Chemokine activities can be determined
Immune and Inflammatory


CXC chemokine
Accession Y96310

secreted proteins involved in biological
using assays known in the art: Methods in
disorders, Cancer,


H174


processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:
Haemostatic and





angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,
thrombolytic activity





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Human non-ELR
GeneSeq
WO0029439
Chemokines are a family of related small,
Chemokine activities can be determined
Immune and Inflammatory


CXC chemokine
Accession Y96311

secreted proteins involved in biological
using assays known in the art: Methods in
disorders, Cancer,


IP10


processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:
haemostatic and





angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,
thrombolytic activity





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Human non-ELR
GeneSeq
WO0029439
Chemokines are a family of related small,
Chemokine activities can be determined
Immune and Inflammatory


CXC chemokine
Accession Y96313

secreted proteins involved in biological
using assays known in the art: Methods in
disorders, Cancer,


Mig


processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:
haemostatic and





angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,
thrombolytic activity





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Human
GeneSeq
WO0028035
Chemokines are a family of related small,
Chemokine activities can be determined
Cancer, wound healing,


chemokine
Accession Y96280

secreted proteins involved in biological
using assays known in the art: Methods in
inflammatory and


Ckbeta-7


processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:
immunoregulatory





angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,
disorders





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Human
GeneSeq
WO0028035
Chemokines are a family of related small,
Chemokine activities can be determined
Cancer, wound healing,


chemokine MIP-
Accession Y96281

secreted proteins involved in biological
using assays known in the art: Methods in
inflammatory and


1alpha


processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:
immunoregulatory





angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,
disorders





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Human mature
GenSeq
WO0028035
Chemokines are a family of related small,
Chemokine activities can be determined
Cancer, wound healing,


chemokine
Accession Y96282

secreted proteins involved in biological
using assays known in the art: Methods in
inflammatory and


Ckbeta-7


processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:
immunoregulatory


(optionally


angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,
disorders


truncated)


Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Human
GeneSeq
WO0018431
Chemokines are a family of related small,
Chemokine activities can be determined
Soluble CXCR3


chemokine
Accession Y79372

secreted proteins involved in biological
using assays known in the art: Methods in
polypeptides may be


receptor CXCR3


processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:
useful for inhibiting





angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,
chemokine activities and





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.
viral infection.





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Human
GeneSeq
U.S. Pat. No. 6,043,086
Chemokines are a family of related small,
Chemokine activities can be determined
Neurological disorders,


neurotactin
Accession Y53259

secreted proteins involved in biological
using assays known in the art: Methods in
Immune and respiratory


chemokine like


processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:
disorders


domain


angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified.


Human CC type
GeneSeq
JP11302298
Chemokines are a family of related small,
Chemokine activities can be determined
Cancer and infectious


chemokine
Accession Y57771

secreted proteins involved in biological
using assays known in the art: Methods in
diseases


interleukin C


processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:





angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified


Human CKbeta-9
GeneSeq
U.S. Pat. No. 6,153,441
Chemokines are a family of related small,
Chemokine activities can be determined
Cancer, Auto-immune and



Accession B50860

secreted proteins involved in biological
using assays known in the art: Methods in
inflammatory disorders,





processes ranging from hematopoiesis,
Molecular Biology, 2000, vol. 138:
Cardiovascular disorders





angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: A. E. I. Proudfoot,





Members of this family are involved in a
T. N. C. Wells, and C. A. Power.





similarly diverse range of pathologies
© Humana Press Inc., Totowa, NJ





including inflammation, allergy, tissue





rejection, viral infection, and tumor





biology. The chemokines exert their





effects by acting on a family of seven





transmembrane G-protein-coupled





receptors. Over 40 human chemokines





have been described, which bind to ~17





receptors thus far identified


Preproapolipoprotein
GeneSeq
WO9637608
Apoa-1 participates in the reverse
Lipid binding activity can be determined
Useful for cardiovascular


“paris” variant
Accession

transport of cholesterol from tissues to
using assays known in the art, such as, for
disorders, cholesterol



W08602

the liver for excretion by promoting
example, the Cholesterol Efflux Assays of
disorders, and





cholesterol efflux from tissues and by
Takahaski et al., P. N. A. S., Vol. 96, Issue
Hyperlipidaemia





acting as a cofactor for the lecithin
20, 11358-11363, Sep. 28, 1999.





cholesterol acyltransferase (Icat).


Preproapolipoprotein

5,721,114
Apoa-1 participates in the reverse
Lipid binding activity can be determined
Useful for cardiovascular


“milano”


transport of cholesterol from tissues to
using assays known in the art, such as, for
disorders, cholesterol


variant


the liver for excretion by promoting
example, the Cholesterol Efflux Assays of
disorders, and





cholesterol efflux from tissues and by
Takahaski et al., P. N. A. S., Vol. 96, Issue
Hyperlipidaemia





acting as a cofactor for the lecithin
20, 11358-11363, Sep. 28, 1999.





cholesterol acyltransferase (Icat).


Glycodelin-A;
GeneSeq
WO9628169
Naturally produced female contraceptive
Glycodelin-A activity can be determined
Naturally derived


Progesterone-
Accession

that is removed rapidly from the body
using the hemizona assay as described in
contraceptive useful for


associated
W00289

following 2-3 days production. Uses
Oehninger, S., Coddington, C. C., Hodgen, G. D.,
the prevention of


endometrial


include contraception
and Seppala, M (1995) Fertil. Steril.
pregnancy.


protein



63, 377-383.


NOGO-A
Genbank

NOGO polypeptides are potent inhibitors
Inhibition of Neurite outgrowth.
NOGO-A polypeptide



Accession

of neurite growth.
Antagonists to NOGO polypeptides may
antagonists are useful for



CAB99248


promote the outgrowth of neurites, thus
the promotion of neural






inducing regeneration of neurons.
growth, which could be







useful in the treatment of







neural disorders and







dysfunction due to







degenerative diseases or







trauma; useful in the







treatment of neoplastic







diseases of the CNS;







induce regeneration of







neurons or to promote the







structural plasticity of the







CNS.


NOGO-B
Genbank

NOGO polypeptides are potent inhibitors
Inhibition of Neurite outgrowth.
NOGO-B polypeptide



Accession

of neurite growth.
Antagonists to NOGO polypeptides may
antagonists are useful for



CAB99249


promote the outgrowth of neurites, thus
the promotion of neural






inducing regeneration of neurons.
growth, which could be







useful in the treatment of







neural disorders and







dysfunction due to







degenerative diseases or







trauma; useful in the







treatment of neoplastic







diseases of the CNS;







induce regeneration of







neurons or to promote the







structural plasticity of the







CNS.


NOGO-C
Genbank

NOGO polypeptides are potent inhibitors
Inhibition of Neurite outgrowth.
NOGO-C polypeptide



Accession

of neurite growth.
Antagonists to NOGO polypeptides may
antagonists are useful for



CAB99250


promote the outgrowth of neurites, thus
the promotion of neural






inducing regeneration of neurons.
growth, which could be







useful in the treatment of







neural disorders and







dysfunction due to







degenerative diseases or







trauma; useful in the







treatment of neoplastic







diseases of the CNS;







induce regeneration of







neurons or to promote the







structural plasticity of the







CNS.


NOGO-66
Genbank

NOGO polypeptides are potent inhibitors
Inhibition of Neurite outgrowth by
NOGO-66 receptor


Receptor
Accession

of neurite growth, and are thought to
mediating the biological effects of NOGO
polypeptides are useful for



AAG53612

mediate their effects through the NOGO-
polypeptides. Soluble NOGO-66 receptor
the promotion of neural





66 Receptor.
polypeptides may promote the outgrowth
growth, which could be






of neurites, thus inducing regeneration of
useful in the treatment of






neurons.
neural disorders and







dysfunction due to







degenerative diseases or







trauma; useful in the







treatment of neoplastic







diseases of the CNS;







induce regeneration of







neurons or to promote the







structural plasticity of the







CNS.


Antibodies specific

U.S. Pat. No. 5,416,197
These antibodies are useful for the
Collapsin activity, which is thought to
Useful for the promotion of


for collapsin


promotion of neurite outgrowth
inhibit the outgrowth of neurites, can be
neural growth, which could






assayed in the presence of antibodies
be useful in the treatment






specific for collapsing using assays known
of neural disorders and






in the art, such as, for example, the
dysfunction due to






collapse assay disclosed by Luo et al.,
degenerative diseases or






Cell 1993 Oct 22; 75(2): 217-27
trauma.


Humanized Anti-

WO9845331
These agents have anti-inflammatory and
VEGF activity can be determined using
Promotion of growth and


VEGF Antibodies,


anti-cancer applications
assays known in the art, such as those
proliferation of cells, such


and fragments



disclosed in International Publication No.
as vascular endothelial


thereof



WO0045835, for example.
cells. Antagonists may be







useful as anti-angiogenic







agents, and may be







applicable for cancer


Humanized Anti-

WO0029584
These agents have anti-inflammatory and
VEGF activity can be determined using
Promotion of growth and


VEGF Antibodies,


anti-cancer applications
assays known in the art, such as those
proliferation of cells, such


and fragments



disclosed in International Publication No.
as vascular endothelial


thereof



WO0045835, for example.
cells. Antagonists may be







useful as anti-angiogenic







agents, and may be







applicable for cancer


Membrane bound
GeneSeq.
WO9963088
Cancer, Immune Disorders
These proteins can be used for linking
Activities can be


proteins
Accession


bioactive molecules to cells and for
determined using assay



Y66631-Y66765


modulating biological activities of cells,
known in the art, suchas,






using the polypeptides for specific
for example, the assays






targeting. The polypeptide targeting can
disclosed in International






be used to kill the target cells, e.g. for the
Publication No.






treatment of cancers. These proteins are
WO0121658.






useful for the treatment of immune system






disorders.


Secreted and
GenSeq
WO0053756
Cancer, Immune Disorders
These proteins can be used for linking
Activities can be


Transmembrane
Accession


bioactive molecules to cells and for
determined using assay


polypeptides
B44241-B44334


modulating biological activities of cells,
known in the art, suchas,






using the polypeptides for specific
for example, the assays






targeting. The polypeptide targeting can
disclosed in International






be used to kill the target cells, e.g. for the
Publication No.






treatment of cancers. These proteins are
WO0121658






useful for the treatment of immune system






disorders.


Secreted and
GeneSeq
WO9946281
Cancer, Immune Disorders
These proteins can be used for linking
Activities can be


Transmembrane
Accession


bioactive molecules to cells and for
determined using assay


polypeptides
Y41685-Y41774


modulating biological activities of cells,
known in the art, suchas,






using the polypeptides for specific
for example, the assays






targeting. The polypeptide targeting can
disclosed in International






be used to kill the target cells, e.g. for the
Publication No.






treatment of cancers. These proteins are
WO0121658






useful for the treatment of immune system






disorders.









Conjugation and Coupling

The present invention provides therapeutic agents comprising an ELP component and a therapeutic component, such as therapeutic proteins listed in Table 1, as well as a GLP-1 receptor agonists, insulin, Factor VII/VIIa, and functional analogs as described. Such agents may be prepared by recombinant technology and/or chemical coupling (e.g., conjugation).
A recombinantly-produced ELP fusion protein, in accordance with certain embodiments of the invention, includes the ELP component and the therapeutic component associated with one another by genetic fusion. For example, the fusion protein may be generated by translation of a polynucleotide encoding the therapeutic component cloned in-frame with the ELP component (or vice versa). Such an ELP fusion protein may contain one or more copies of the therapeutic component attached to the N-terminus and/or the C-terminus of the ELP component. In some embodiments, the therapeutic proteinaceous 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, anon-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 proteinaceous component, e.g., amine, carboxyl, phenyl, thiol or hydroxyl groups, to form a covalent conjugate. Various conventional linkers can be used, e.g., diisocyanates, diisothiocyanates, carbodiimides, bis(hydroxysuccinimide) esters, maleimide-hydroxysuccinimide esters, glutaraldehyde and the like.
Non-peptide chemical spacers can additionally be of any suitable type, including for example, by functional linkers described in Bioconjugate Techniques, Greg. T. Hermanson, published by Academic Press, Inc., 1995, and those specified in the Cross-Linking Reagents Technical Handbook, available from Pierce Biotechnology, Inc. (Rockford, Ill.), the disclosures of which are hereby incorporated by reference, in their respective entireties. Illustrative chemical spacers include homobifunctional linkers that can attach to amine groups of Lys, as well as heterobifunctional linkers that can attach to Cys at one terminus, and to Lys at the other terminus.
In certain embodiments, relatively small ELP components (e.g., ELP components of less than about 30 kDa, 25 kDa, 20 kDa, 15 kDa, or 10 kDa), that do not transition at room temperature (or human body temperature, e.g., Tt>37° C.), are chemically coupled or crosslinked. For example, two relatively small ELP components, having the same or different properties, may be chemically coupled. Such coupling, in some embodiments, may take place in vivo, by the addition of a single cysteine residue at or around the C-terminus of the ELP. Such ELP components may each be fused to one or more therapeutic components, so as to increase activity or avidity at the target.
Polynucleotides, Vectors, and Host Cells
In another aspect, the invention provides polynucleotides comprising a nucleotide sequence encoding the therapeutic agent of the invention. Such polynucleotides further comprise, in addition to sequences encoding the ELP and therapeutic components, one or more expression control elements. For example, the polynucleotide, may comprise one or more promoters or transcriptional enhancers, ribosomal binding sites, transcription termination signals, and polyadenylation signals, as expression control elements. The polynucleotide may be inserted within any suitable vector, which may be contained within any suitable host cell for expression.
A vector comprising the polynucleotide can be introduced into a cell for expression of the therapeutic agent. The vector can remain episomal or become chromosomally integrated, as long as the insert encoding the therapeutic agent can be transcribed. Vectors can be constructed by standard recombinant DNA technology. Vectors can be plasmids, phages, cosmids, phagemids, viruses, or any other types known in the art, which are used for replication and expression in prokaryotic or eukaryotic cells. It will be appreciated by one of skill in the art that a wide variety of components known in the art (such as expression control elements) may be included in such vectors, including a wide variety of transcription signals, such as promoters and other sequences that regulate the binding of RNA polymerase onto the promoter. Any promoter known to be effective in the cells in which the vector will be expressed can be used to initiate expression of the therapeutic agent. Suitable promoters may be inducible or constitutive. Examples of suitable promoters include the SV40 early promoter region, the promoter contained in the 3′ long terminal repeat of Rous sarcoma virus, the HSV-1 (herpes simplex virus-1) thymidine kinase promoter, the regulatory sequences of the metallothionein gene, etc., as well as the following animal transcriptional control regions, which exhibit tissue specificity and have been utilized in transgenic animals: elastase I gene control region which is active in pancreatic acinar cells; insulin gene control region which is active in pancreatic beta cells, immunoglobulin gene control region which is active in lymphoid cells, mouse mammary tumor virus control region which is active in testicular, breast, lymphoid and mast cells, albumin gene control region which is active in liver, alpha-fetoprotein gene control region which is active in liver, alpha 1-antitrypsin gene control region which is active in the liver, beta-globin gene control region which is active in erythroid cells, myelin basic protein gene control region which is active in oligodendrocyte cells in the brain, myosin light chain-2 gene control region which is active in skeletal muscle, and gonadotropin releasing hormone gene control region which is active in the hypothalamus.
Pharmaceutical Compositions
The present invention further provides pharmaceutical compositions comprising the therapeutic agents of the invention (as described above) together with a pharmaceutically acceptable carrier or excipient. Such pharmaceutical compositions may be employed in the methods of treatment as described above, for each of the therapeutic proteins, e.g., the therapeutic proteins listed in Table 1, GLP-1 receptor agonists, insulin, and Factor VII/VIIa embodiments.
The therapeutic agents of the invention may overcome certain deficiencies of peptide agents when administered (e.g., parenterally), including in some embodiments, the limitation that such peptides may be easily metabolized by plasma proteases or cleared from circulation by kidney filtration. Traditionally, the oral route of administration of peptide agents may also be problematic, because in addition to proteolysis in the stomach, the high acidity of the stomach destroys such peptide agents before they reach their intended target tissue. Peptides and peptide fragments produced by the action of gastric and pancreatic enzymes are cleaved by exo and endopeptidases in the intestinal brush border membrane to yield di- and tripeptides, and even if proteolysis by pancreatic enzymes is avoided, polypeptides are subject to degradation by brush border peptidases. Any of the peptide agents that survive passage through the stomach are further subjected to metabolism in the intestinal mucosa where a penetration barrier prevents entry into the cells. In certain embodiments, the therapeutic agents of the invention may overcome such deficiencies, and provide compositional forms having enhanced efficacy, bioavailability, therapeutic half-life, persistence, degradation assistance, etc. The therapeutic agents of the invention thus include oral and parenteral dose forms, as well as various other dose forms, by, which peptide agents can be utilized in a highly effective manner. For example, in some embodiments, such agents may achieve high mucosal absorption, and the concomitant ability to use lower doses to elicit an optimum therapeutic effect.
The therapeutic agents of the present invention may be administered in smaller doses and/or less frequently than unfused or unconjugated counterparts. While one of skill in the art can determine the desirable dose in each case, a suitable dose of the therapeutic agent for achievement of therapeutic benefit, may, for example, be in a range of about 1 microgram (μg) to about 100 milligrams (mg) per kilogram body weight of the recipient per day, preferably in a range of about 10 μg to about 50 mg per kilogram body weight per day and most preferably in a range of about 10 μg to about 50 mg per kilogram body weight per day. The desired dose may be presented as one dose or two or more sub-doses administered at appropriate intervals throughout the day. These sub-doses can be administered in unit dosage forms, for example, containing from about 10 μg to about 1000 mg, preferably from about 50 μg to about 500 mg, and most preferably from about 50 μg to about 250 mg of active ingredient per unit dosage form. Alternatively, if the condition of the recipient so requires, the doses may be administered as a continuous infusion.
The mode of administration and dosage forms will of course affect the therapeutic amount of the peptide active therapeutic agent that is desirable and efficacious for a given treatment application. For example, orally administered dosages can be at least twice, e.g., 2-10 times, the dosage levels used in parenteral administration methods.
The therapeutic agents of the invention may be administered per se as well as in various forms including pharmaceutically acceptable esters, salts, and other physiologically functional derivatives thereof. The present invention also contemplates pharmaceutical formulations, both for veterinary and for human medical use, which include therapeutic agents of the invention. In such pharmaceutical and medicament formulations, the therapeutic agents can be used together with one or more pharmaceutically acceptable carrier(s) therefore and optionally any other therapeutic ingredients. The carrier(s) must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the formulation and not unduly deleterious to the recipient thereof. The therapeutic agents are provided in an amount effective to achieve the desired pharmacological effect, as described above, and in a quantity appropriate to achieve the desired daily dose.
The formulations of the therapeutic agent include those suitable for parenteral as well as non-parenteral administration, and specific administration modalities include oral, rectal, buccal, topical, nasal, ophthalmic, subcutaneous, intramuscular, intravenous, transdermal, intrathecal, intra-articular, intra-arterial, sub-arachnoid, bronchial, lymphatic, vaginal, and intra-uterine administration. Formulations suitable for oral and parenteral administration are preferred.
When the therapeutic agent is used in a formulation including a liquid solution, the formulation advantageously can be administered orally or parenterally. When the therapeutic agent is employed in a liquid suspension formulation or as a powder in a biocompatible carrier formulation, the formulation may be advantageously administered orally, rectally, or bronchially.
When the therapeutic agent is used directly in the form of a powdered solid, the active agent can be advantageously administered orally. Alternatively, it may be administered bronchially, via nebulization of the powder in a carrier gas, to form a gaseous dispersion of the powder which is inspired by the patient from a breathing circuit comprising a suitable nebulizer device.
The formulations comprising the therapeutic agent of the present invention may conveniently be presented in unit dosage forms and may be prepared by any of the methods well known in the art of pharmacy. Such methods generally include the step of bringing the therapeutic agents into association with a carrier which constitutes one or more accessory ingredients. Typically, the formulations are prepared by uniformly and intimately bringing the therapeutic agent into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product into dosage forms of the desired formulation.
Formulations suitable for oral administration may be presented as discrete units such as capsules, cachets, tablets, or lozenges, each containing a predetermined amount of the active ingredient as a powder or granules; or a suspension in an aqueous liquor or a non-aqueous liquid, such as a syrup, an elixir, an emulsion, or a draught.
A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine, with the therapeutic agent being in a free-flowing form such as a powder or granules which optionally is mixed with a binder, disintegrant, lubricant, inert diluent, surface active agent, or discharging agent. Molded tablets comprised of a mixture of the powdered peptide active therapeutic agent-ELP construct(s) with a suitable carrier may be made by molding in a suitable machine.
A syrup may be made by adding the peptide active therapeutic agent-ELP construct(s) to a concentrated aqueous solution of a sugar, for example sucrose, to which may also be added any accessory ingredient(s). Such accessory ingredient(s) may include flavorings, suitable preservative, agents to retard crystallization of the sugar, and agents to increase the solubility of any other ingredient, such as a polyhydroxy alcohol, for example glycerol or sorbitol.
Formulations suitable for parenteral administration conveniently comprise a sterile aqueous preparation of the therapeutic agent, which preferably is isotonic with the blood of the recipient (e.g., physiological saline solution). Such formulations may include suspending agents and thickening agents or other microparticulate systems which are designed to target the peptide active therapeutic agent to blood components or one or more organs. The formulations may be presented in unit-dose or multi-dose form.
Nasal spray formulations comprise purified aqueous solutions of the therapeutic agent with preservative agents and isotonic agents. Such formulations are preferably adjusted to a pH and isotonic state compatible with the nasal mucus membranes.
Formulations for rectal administration may be presented as a suppository with a suitable carrier such as cocoa butter, hydrogenated fats, or hydrogenated fatty carboxylic acid.
Topical formulations comprise the therapeutic agent dissolved or suspended in one or more media, such as mineral oil, petroleum, polyhydroxy alcohols, or other bases used for topical pharmaceutical formulations.
In addition to the aforementioned ingredients, the formulations of this invention may further include one or more accessory ingredient(s) selected from diluents, buffers, flavoring agents, disintegrants, surface active agents, thickeners, lubricants, preservatives (including antioxidants), and the like.
The features and advantages of the present invention are more fully shown with respect to the following non-limiting examples.
EXAMPLES
Example 1
Construction of Various ELP Component Constructs
Cloning steps were conducted in Escherichia coli strain XL1-Blue (rec A1, endA1, gyrA96, thi-1, hsdR17 (rk−, mk+), supE44, relA1, lac[F′, proAB, /αclqZΔM15, Tn10 (Tetr)] (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, hsdSB (rB− mB−), gal, dcm, rne131, (DE3)) (Invitrogen Carlsbed, Calif.) or BLR(DE3) (F−, ompT, hsdSB (rB− mB−), 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 1× ligase buffer (Invitrogen) to 95° C. in a heating block than the block was allowed to cool slowly to room temperature. The ELP1 [V5A2G3-10]/EcoRI-HindIII DNA segment was ligated into a pUC19 vector digested with EcoRI and HindIII and CIAP dephosphorylated (Invitrogen) to form pUC19-ELP1 [V5A2G3-10]. Building of the ELP1 [V5A2G3] series library began by inserting ELP1 [V5A2G3-10] PflMI/BglI fragment from pUC19-ELP1 [V5A2G3-10] into pUC19-ELP1 [V5A2G3-10] linearized with PflMI and dephosphorylated with CIAP to create pUC19-ELP1 [V5A2G3-20]. pUC19-ELP1 [V5A2G3-20] was then built up to pUC19-ELP1 [V5A2G3-30] and pUC19-ELP1 [V5A2G3-40] by ligating ELP1 [V5A2G3-10] or ELP1 [V5A2G3-20] PflMI/BglI fragments respectively into PflMI digested 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] PflM1/Bgl1 fragment from pUC19-ELP1 [K1 V2F1-4] into pUC19-ELP1 [K1V2F1-4] linearized with PflM1 and dephosphorylated with CIAP to create pUC19-ELP1 [K1V2F1-8]. Using the same procedure the ELP1 [K1V2F1] series was doubled at each ligation to form pUC19-ELP1 [K1V2F1-I6], pUC19-ELP1 [K1V2F1-32], pUC19-ELP1 [K1 V2F1-64] and pUC19-ELP1 [K1V2F1-128].
Construction of ELP1 [K1V7F1I Gene Series
The ELP1 [K1V7F1] series designate polypeptides containing multiple repeating units of the pentapeptide VPGXG (SEQ ID NO: 3), where X is lysine, valine, and phenylalanine at a relative ratio of 1:7:1.
The ELP1 [K1V7F1] series monomer, ELP1 [K1V7F1-9], was created by annealing four 5′ phosphorylated, PAGE purified synthetic oligos to form double stranded DNA with PflMI and HindIII compatible ends. The ELP1 [K1V7F1-9] DNA segment was than ligated into PflM1/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], pUC19-ELP2 [60] and pUC19-ELP2 [120].
Construction of ELP3 [V] Gene Series
The ELP3 [V] series designate polypeptides containing multiple repeating units of the pentapeptide IPGXG (SEQ ID NO: 5), where X is exclusively valine.
The ELP3 [V] series monomer, ELP3 [V-5], was created by annealing two 5′ phosphorylated, PAGE purified synthetic oligos to form double stranded DNA with PfLM1 amino terminal and GGC carboxyl terminal compatible ends due to the lack of a convenient carboxyl terminal restriction site but still enable seamless addition of the monomer. The ELP3 [V-5] DNA segment was then ligated into PflM1/BglI dephosphorylated pUC19-ELP4[V-5], thereby substituting ELP4 [V-5] for ELP3 [V-5] to create the pUC19-ELP3 [V-5] monomer. The ELP3 [V] series was expanded by ligating the annealed ELP3 oligos into pUC19-ELP3[V-5] digested with PflMI. Each ligation expands the ELP3 [V] series by 5 to create ELP3 [V-10], ELP3 [V-15], etc.
Construction of the ELP4 [V] Gene Series
The ELP4 [V] series designate polypeptides containing multiple repeating units of the pentapeptide LPGXG (SEQ ID NO: 7), where X is exclusively valine.
The ELP4 [V] series monomer, ELP4 [V-5], was created by annealing two 5′ phosphorylated, PAGE purified synthetic oligos to form double stranded DNA with EcoRI and HindIII compatible ends. The ELP4 [V-5] DNA segment was than ligated into EcoRI/HindIII dephosphorylated pUC19 vector to create the pUC19-ELP4[V-5] monomer. The ELP4 [V] series was expanded in the same manner as the ELP1 [K1V2F1] series to create pUC19-ELP4[V-10], pUC19-ELP4[V-30], pUC19-ELP4[V-60] and pUC19-ELP4[V-120].
The ELP genes were also inserted into other vectors such as pET15b-SD0, pET15b-SD3, pET15b-SD5, pET15b-SD6, and pET24d-SD21. The pET vector series are available from Novagen, San Diego, Calif.
The pET15b-SD0 vector was formed by modifying the pET15b vector using SD0 double-stranded DNA segment containing the multicloning restriction site (SacI-NdeI-NcoI-XhoI-SnaBI-BamHI). The SD0 double-stranded DNA segment had XbaI and BamHI compatible ends and was ligated into XbaI/BamHI linearized and 5′-dephosphorylated pET15b to form the pet15b-SD0 vector.
The pET15b-SD3 vector was formed by modifying the pET15b-SD0 vector using SD3 double-stranded DNA segment containing a SfiI restriction site upstream of a hinge region-thrombin cleavage site followed by the multicloning site (NdeI-NcoI-XhoI-SnaBI-BamHI). The SD3 double-stranded DNA segment had SacI and NdeI compatible ends and was ligated into SacI/NdeI linearized and 5′-dephosphorylated pET15b-SD0 to form the pET15b-SD3 vector.
The pET15b-SD5 vector was formed by modifying the pET15b-SD3 vector using the SD5 double-stranded DNA segment containing a SfiI restriction site upstream of a thrombin cleavage site followed by a hinge and the multicloning site (NdeI-NcoI-XhoI-SnaBI-BamHI). The SD5 double-stranded DNA segment had SfiI and NdeI compatible ends and was ligated into SfiI/NdeI linearized and 5′-dephosphorylated pET15b-SD3 to form the pET15b-SD5 vector.
The pET15b-SD6 vector was formed by modifying the pET15b-SD3 vector using the SD6 double-stranded DNA segment containing a SfiI restriction site upstream of a linker region-TEV cleavage site followed by the multicloning site (NdeI-NcoI-XhoI-BnaBI-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 Doted into NcoI/NheI linearized and 5′ dephosphorylated pET24d to create the pET24d-SD21 vector, which contained a new multicloning site NcoI-SfiI-NheI-BamHI-EcoRI-SacI-SalI-HindIII-NotI-XhoI with two stop codons directly after the SfiI site for insertion and expression of ELP with the minimum number of extra amino acids.
The pUC19-ELP1 [V5A2G3-60], pUC19-ELP1 [V5A2G3-90], and pUC19-ELP1 [V5A2G3-180] plasmids produced in XL1-Blue were digested with PflMI and BglI, and the ELP-containing fragments were ligated into the SfiI site of the pET15b-SD3 expression vector as described hereinabove to create pET15b-SD3-ELP1 [V5A2G3-60], pET15b-SD5-ELP1 [V5A2G3-90] and pET15b-SD5-ELP1 [V5A2G3-180], respectively.
The pUC19-ELP1 [V5A2G3-90], pUC19-ELP1 [V5A2G3-180], pUC19-ELP1 [V-60] and pUC19-ELP1 [V-120] plasmids produced in XL1-Blue were digested with PflMI and BglI, and the ELP-containing fragments were ligated into the SfiI site of the pET15b-SD5 expression vector as described hereinabove to create pET15b-SD5-ELP1 [V5A2G3-90], pET15b-SD5-ELP1 [V5A2G3-180], pET15b-SD5-ELP1 [V-60] and pET15b-SD5-ELP1 [V-120], respectively.
The pUC19-ELP1 [V5A2G3-90] plasmid produced in XL1-Blue was digested with PflMI and BglI, and the ELP-containing fragment was ligated into the SfiI site of the pET15b-SD6 expression vector as described hereinabove to create pET15b-SD6-ELP1 [V5A2G3-90].
The pUC19-ELP1 [K1V2F1-64], and pUC19-ELP1 [K1V2F1-128] plasmids produced in XL1-Blue were digested with PflMI and BglI, and the ELP-containing fragments were ligated into the SfiI site of the pET24d-SD21 expression vector as described hereinabove to create pET24d-SD21-ELP1 [K1V2F1-64] and pET24d-SD21-ELP1 [K1V2F1-128], respectively.
The pUC19-ELP1 [K1V7F1-72] and pUC19-ELP1 [K1V7F1-144] plasmids produced in XL1-Blue were digested with PflMI and BglI, and the ELP-containing fragments were ligated into the SfiI site of the pET24d-SD21 expression vector as described hereinabove to create pET24d-SD21-ELP1 [K1V7F1-72], pET24d-SD21-ELP1 [K1V7F1-144], respectively.
The pUC19-ELP2[60] and pUC19-ELP2[120] plasmids produced in XL1-Blue were digested with NcoI and HindIII, and the ELP-containing fragments were ligated into the NcoI and HindIII sites of the pET24d-SD21 expression vector as described hereinabove to create pET24d-SD21-ELP2[60], pET24d-SD21-ELP2[120], respectively.
The pUC19-ELP4[V-60] and pUC19-ELP4[V-120] plasmids produced in XL1-Blue were digested with 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 or 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
ke
Vd
AUC (mg
ClB



(hr−1)
(hr−1)
(hr−1)
(μL)
ELP hr/ml)
(μL/hr)

















ELP1-150
3.54
1.99
0.24
1,338
7.1
317









The mass transfer rate constants are from a standard two-compartment model (k1; from central to peripheral compartment; k2, from peripheral to central compartment; and ke, elimination from central compartment). The distribution volume (Vd), central compartment concentration time-course area under the curve (AUC) and body clearance (ClB) are displayed. Data are shown as the mean values (n=5, except Vd and initial plasma concentration (CO) 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-[V1A8G7-160]
14C labeled ELP2-[V1A8G7-160] (Tt>60° C.) was administered to nude mice for a plasma concentration of 15 μM. ELP concentrations were determined following 1 hour of heating (41° C.) of an implanted FaDu tumor, located in the right hind leg of the nude mouse. Data are shown as the mean, plus the 95% confidence interval. N=6.
ELP concentration was measured 1.5 hours following systemic administration of 14C labeled ELP2-[V1A8G7-160]. The highest distribution is seen in, organs with the highest blood content: liver, kidneys, spleen, and lungs.
Example 5
Exendin-4 ELP Fusion
The DNA sequence for Exendin-4 (Ex-4) (SEQ ID NO: 14) was reverse translated from the amino acid sequence using codons optimized for E. coli expression. The DNA sequence encoding Exendin-4 was constructed by annealing together synthetic oligonucleotides with overhanging 5′ and 3′ ends compatible with the restriction sites NdeI and XhoI in the plasmid pET24d-ELP1-90 (FIG. 1). This plasmid was digested with the restriction enzymes NdeI and XhoI and the annealed DNA sequence was ligated into the cut vector. Insertion was confirmed by restriction digest and DNA sequencing. The resulting plasmid was designated as pET24d-Ex-4 ELP1-90 (FIG. 2A), and the sequence of the resulting Exendin-4-ELP fusion shown in FIG. 2B. Primers for construction of the fusion are also indicated.
pET24d-Ex-4 ELP1-90 was used to transform the E. coli strain BRL (Invitrogen) and selected transformants were grown in media 3 (1.2% Tryptone Peptone, 2.4% yeast extract, 5 g/L casamino acids, 2% glycerol, 2.313 g Potassium phosphate dibasic/L, 12.541 g Potassium phosphate monobasic/L) in shake flasks. Production proceeded by autoinduction by inoculating 1 OD cells into 1 L of media 3 and allowing growth to proceed for 17 hr at 37° C. without addition of inducer. The product was recovered by collection of the cell pellet, sonicated to disrupt the cells and recovered by thermal and/or salt induced transition modulated by the ELP moiety (Improved Non-chromatographic Purification of a Recombinant Protein by Cationic Elastin-like Polypeptides, Dong Woo Lim, Kimberly Trabbic-Carlson, J. Andrew MacKay, and Ashutosh Chilkoti. Biomacromolecules 2007, 8, 1417-1424).
This example is with the ELP designated 1-90. This is based on the VPGXG (SEQ ID NO: 3) motif where X is a V, G or A in the ratio 5:3:2 in a 10 unit repeat, repeated 8× with a final (C-terminal) 10-unit repeat where X is a V, G, A and W in the ratio 4:3:2:1.
[(VPGXG)10]9 where the X residue in the ten sequential iterations of the repeat unit (numerical subscript) can be described as [(V1, 4, 5, 6, 10G2, 7, 9A3, 8)8 (V1, 4, 5, 6G2, 7, 9A3, 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 His7 of GLP1 is at the N-terminus. The processed fusion proteins have calculated molecular weights of about 39,536 and about 50,828, respectively.
Example 7
FVII ELP Fusion Protein
The coagulation factor VII (FVII) gene was modified by PCR from a cDNA clone (Oragene) to add restriction sites at the 5′ and 3′ ends for cloning into the ELP-containing vector. At the 5′ end an NheI site was added and at the 3′ end a NotI site was added. The DNA and amino acid sequences of the Factor VII gene are shown in the accompanying Sequence Listing as SEQ ID NOS: 34 and 33, respectively. The DNA sequences of the 5′ and 3′ primers used to PCR amplify the factor VII (FVII) gene were:









(SEQ ID NO.: 49)










P13:
CTAGCTAGCATGGTCTCCCAGGCCCTC



 









(SEQ ID NO.: 50)










P14:
TATTCTTGCGGCCGCGGGAAATGGGGCTCGCAG






The resulting PCR fragment was digested with the restriction enzymes NheI and NotI and ligated into the plasmid pcDNA3.1+ ELP1-90 previously digested with the restriction enzymes NheI and NotI (FIG. 7A).
The resulting plasmid, pcDNA3.1+ FVII-ELP1-90, was transiently transfected into HEK293 cells and culture media harvested. The ELP fusion was purified by phase transition (FIGS. 9 and 10).
The nucleotide and amino acid sequences of the FactorVII-ELP fusion is shown in FIG. 7B. As shown, the FactorVII-ELP fusion protein contains a Tev protease linker between the FactorVII component and the ELP component. This linker is optional.
Example 8
Insulin ELP Fusion Protein
The cDNA for the human insulin gene is modified at the 5′ and 3′ ends for insertion in to pET24d-ELP1-90. The 5′ primer adds an N-terminal methionine for bacterial expression and an NdeI restriction enzyme site. The 3′ primer adds an XhoI restriction enzyme site. The PCR product and the plasmid are both digested with the restriction enzymes NdeI and XhoI and ligated together. The sequence of the insulin (Chains B, C, and A fused to ELP1 is shown in FIG. 8A.
Correct insertion is determined by restriction digest and DNA sequencing. The resulting plasmid, designated pET24d Insulin-ELP1-90, is shown in FIG. 8B.
The native insulin form is generated after recovery from E. coli by treatment with trypsin and carboxypeptidase B to remove the C-peptide chain.
For correct processing of the N-terminus of the B-chain similar modifications to those made for the Exendin-4 fusion (protease cleavage site, signal sequence) can be implemented (see Example 4). Alternatively, the first two residues can be Met-Arg, which can also be removed by trypsin digestion in production of the final material (R. M. Belagaje, S. G. Reams, S. C. Ly and W. F. Prouty, Increased production of low molecular weight recombinant proteins in Escherichia coli. Protein Sci. 6, 1953-1962, 1997).
Additional constructs would place the insulin cDNA at the 3′ end of the ELP for a C-terminal fusion, add linkers between the Insulin and ELP sequences, and/or use modified forms of insulin which have no C-peptide (single chain insulins as described) removing the need for additional processing.
Example 9
Synthesis of the ELP Gene for Conjugation
A gene encoding a 50 amino acid sequence was constructed from chemically-synthesized oligonucleotides using standard molecular biology protocols. The 50 amino acid sequence contained 10 repeats of the pentapeptide VPGXG (SEQ ID NO: 3), where the guest residues (V, G, and A in a 5:3:2 molar ratio) were selected to provide a Tt of 40° C. The gene was oligomerized end-to-end by standard molecular biology techniques, to produce an oligomeric ELP gene. Additionally a single 50 amino acid sequence was constructed containing the 10 repeat pentapeptide VPGXG (SEQ ID NO: 3) polypeptide where the guest residues were V, G, A and C in a 4:3:2:1 molar ratio. This sequence could be added at any cycle of the oligomerization process to introduce a single cysteine residue into the final construct at a chosen point along the length of the construct.
The example given here is with the ELP designated 1-90. This is based on the VPGXG (SEQ ID NO: 3) motif where X is a V, G or A in the ratio 5:3:2 in a 10-unit repeat, repeated 8× with a final (C-terminal) 10-unit repeat where X is a V, G, A and C in the ratio 4:3:2:1, i.e., [(VPGXG)10]9 (SEQ ID NO.: 3).
Alternatively, the residue could be one of either arginine, lysine, aspartic acid or glutamic acid. The purpose of these amino acids is to provide a reactive side chain for the chemical conjugation of, for example, insulin. In this particular case the use of an ELP would be to extend the circulating half-life of the therapeutic protein (e.g., insulin) to provide prolonged basal glucose control. Conjugated to an ELP that transitions at body temperature, the insulin would form a precipitated depot at the site of injection in a similar manner to Lantus® (Sanofi Aventis) but without the requirement for formulation in acidic (pH 4.0) conditions with m-cresol for a more tolerable injection.
Example 10
Potency and Half-Life of Factor VII-ELP
FIG. 11 shows the activation of Factor X by FactorVIIa-ELP1-90, and by Factor VIIa as a comparison. Factor VII-ELP was produced in HEK cells. Factor VIIa was derived from human plasma. As shown, FactorVIIa-ELP retains full activity.
When administered to rats by i.v., Factor VII-ELP demonstrated a half-life of about 690 minutes. In contrast, Factor VII demonstrated a half-life of 45-60 minutes. Half-life in this example was measured by sandwich ELISA for FactorVII. FIG. 12.
Also in contrast, the reported half-life for NovoSevenTM 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 EC50 of 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/di 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 T1/2 when administered by i.v. was about 12.9 hours. The T1/2 when 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 T1/2 when administered by i.v. was about 20 hours. The T1/2 when 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. A method of treating diabetes in a subject in need thereof, comprising administering an effective amount of a therapeutic agent comprising an insulin A chain and an insulin B chain,
wherein said insulin A chain is a recombinant fusion with an elastin-like peptide (ELP) comprising at least one repeating unit selected from SEQ ID NOs: 1-12.

2. The method of claim 1, wherein the insulin A chain amino acid sequence is positioned at the N-terminal side of the ELP.

3. The method of claim 1, wherein said repeating unit is VPGXG (SEQ ID NO: 3), and wherein X is any natural amino acid residue.

4. The method of claim 3, wherein each X is V, G, or A at a ratio of 5:3:2.

5. The method of claim 4, wherein the ELP comprises 60 repeats of VPGXG (SEQ ID NO: 3) wherein each X is V, G, or A at a ratio of 5:3:2.

6. The method of claim 4, wherein the ELP comprises 90 repeats of VPGXG (SEQ ID NO: 3) wherein each X is V, G, or A at a ratio of 5:3:2.

7. The method of claim 4, wherein the ELP comprises 120 repeats of VPGXG (SEQ ID NO: 3) wherein each X is V, G, or A at a ratio of 5:3:2.

8. The method of claim 4, wherein the ELP comprises 180 repeats of VPGXG (SEQ ID NO: 3) wherein each X is V, G, or A at a ratio of 5:3:2.

9. The method of claim 3, wherein each Xis K, V, or F at a ratio of 1:2:1.

10. The method of claim 9, wherein the ELP comprises 32 repeats of VPGXG (SEQ ID NO: 3) wherein each X is K, V, or F at a ratio of 1:2:1.

11. The method of claim 9, wherein the ELP comprises 64 repeats of VPGXG (SEQ ID NO: 3) wherein each X is K, V, or F at a ratio of 1:2:1.

12. The method of claim 3, wherein each Xis K, V, or F at a ratio of 1:7:1.

13. The method of claim 12, wherein the ELP comprises 36 repeats of VPGXG (SEQ ID NO: 3) wherein each X is K, V, or F at a ratio of 1:7:1.

14. The method of claim 12, wherein the ELP comprises 72 repeats of VPGXG (SEQ ID NO: 3) wherein each X is K, V, or F at a ratio of 1:7:1.

15. The method of claim 12, wherein the ELP comprises 144 repeats of VPGXG (SEQ ID NO: 3) wherein each X is K, V, or F at a ratio of 1:7:1.

16. The method of claim 3, wherein each X is V.

17. The method of claim 16, wherein the ELP comprises 60 repeats of VPGXG (SEQ ID NO: 3) wherein each X is V.

18. The method of claim 16, wherein the ELP comprises 120 repeats of VPGXG (SEQ ID NO: 3) wherein each X is V.

19. The method of claim 1, wherein said repeating unit is AVGVP (SEQ ID NO: 4).

20. The method of claim 19, wherein the ELP comprises 30 repeats of AVGVP (SEQ ID NO: 4).

21. The method of claim 19, wherein the ELP comprises 60 repeats of AVGVP (SEQ ID NO: 4).

22. The method of claim 1, wherein said repeating unit is IPGXG (SEQ ID NO: 5), wherein X is V.

23. The method of claim 22, wherein the ELP comprises 15 repeats of IPGXG (SEQ ID NO: 5), wherein X is V.

24. The method of claim 1, wherein said repeating unit is LPGXG (SEQ ID NO: 7), wherein X is V.

25. The method of claim 24, wherein the ELP comprises 30 repeats of LPGXG (SEQ ID NO: 5), wherein X is V.

26. The method of claim 24, wherein the ELP comprises 60 repeats of LPGXG (SEQ ID NO: 5), wherein X is V.

27. The method of claim 1, wherein the ELP has a Tt of from about 35° C. to about 60° C.

28. The method of claim 1, wherein the ELP has a Tt of about 35° C.

29. The method of claim 1, wherein the therapeutic agent is administered with a pharmaceutically acceptable carrier and/or excipient.

30. A method of treating diabetes in a subject in need thereof, comprising administering an effective amount of a therapeutic agent comprising an insulin A chain and an insulin B chain united 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 each X is V, G, or A at a ratio of 5:3:2.

31. The method of claim 1, wherein the insulin A chain 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: 15 and amino acid sequence having 1 to 10 amino acid insertions, deletions, and/or substitutions relative to SEQ ID NO: 16.

32. The method of claim 30 wherein the peptidase processing comprises trypsin processing and carboxypeptidase B processing.

33. The method of claim 1, wherein the insulin A chain sequence comprises an amino acid sequence having 1 to 10 amino acid insertions, deletions, and/or substitutions relative to SEQ ID NO: 15.

34. The method of claim 1, wherein the insulin B chain sequence comprises an amino acid sequence having 1 to 10 amino acid insertions, deletions, and/or substitutions relative to SEQ ID NO: 16.

35. The method of claim 1 wherein the insulin A chain sequence is SEQ ID NO: 15.

36. The method of claim 1 wherein the insulin B chain sequence is SEQ ID NO: 16.

37. The method of claim 1 wherein the insulin A chain sequence is SEQ ID NO: 15 and the insulin B chain sequence is SEQ ID NO: 16.