Methods of Using IL-1 Antagonists to Treat Autoinflammatory Disease

Abstract

Methods of treating, inhibiting, or ameliorating an autoinflammatory disorder, disease, or condition in a subject in need thereof, comprising administering to a subject in need a therapeutic amount of an interleukin 1 (IL-1) antagonist, wherein the autoinflammatory disorder, disease, or condition is treated, inhibited, or ameliorated. The IL-1 antagonist is an IL-1 trap, preferably comprising a sequence selected from the group consisting of SEQ ID NO: 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, or a substantially identical having at least 95% identity to the sequence shown in SEQ ID NO: 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26 and capable of binding and inhibiting IL-1. The therapeutic methods are useful for treating a human adult or child suffering from Neonatal Onset Multisystem Inflammatory Disorder (NOMID/CINCA), Muckle-Wells Syndrome (MWS), Familial Cold Autoinflammatory Syndrome (FCAS), familial mediterranean fever (FMF), or systemic onset juvenile rheumatoid arthritis (Still's Disease).

Description

RELATED APPLICATIONS

[0001] This application is a continuation of U.S. patent application Ser. No. 11/144,987, filed 3 Jun. 2005, now U.S. Pat. No. 0,000,000, which claims the benefit under 35 USC 119(e) of U.S. Ser. No. 60/577,023 filed 4 Jun. 2004, which applications are incorporated by reference in their entirety.

BACKGROUND

[0002] 1. Field of the Invention

[0003] The invention relates to methods of using interleukin-1 (IL-1) antagonists to treat autoinflammatory diseases, including familial mediterranean fever (FMF), cryopyrin mutation-associated disorders,

[0004] 2. Description of Related Art

[0005] One important group of autoinflammatory disorders encompasses autosomal dominant conditions associated with mutations in CIAS-1, a gene that encodes a pyrin-related protein called "cryopyrin" (Feldmann et al. (2002) Am. J. Hum. Genet. 71:198-203; Hoffman et al. (2001) Nat. Genet. 29:301-305). These disorders include Neonatal Onset Multisystem Inflammatory Disorder (NOMID/CINCA), Muckle-Wells Syndrome (MWS), and Familial Cold Autoinflammatory Syndrome (FCAS). These disorders present as a spectrum of clinical manifestations ranging from FCAS being the mildest to the seriously disabling disease of NOMID/CINCA. An urticaria like skin rash is common to the entire spectrum of CMSI associated diseases. In patients with FCAS, this rash is inducible by cold exposure while most patients with MWS or NOMID present with daily rashes that are consistently provoked by a number of different stimuli. Conjunctivitis is present in all forms of disease expression, however, hearing loss, aseptic meningitis and arthritis are mainly seen in patients with MWS and NOMID/CINCA. The disfiguring and disabling body overgrowth at the epiphyses and patellae is only seen in patients with NOMID/CINCA.

[0006] FMF is a recessively inherited condition characterized by episodes of fever and serositis or synovitis; some subjects also develop systemic amyloidosis (Balow et al. (1997) Genomics 44:280-291). The FMF gene encodes a novel protein called pyrin that is the prototype of a family of molecules involved in the regulation of apoptosis (cell-death) and inflammation. The precise biochemical mechanism by which these proteins function, and by which mutations cause disease, is still unknown.

[0007] Still's Disease (systemic onset juvenile rheumatoid arthritis), is manifest by spiking fevers, evanescent salmon color rash, arthritis, arthralgia, and hepatosplenomegaly (Masson et al. (1995) Rev. Rhum. Engl. Ed. 62:748-757; Spiegel et al. (2000) Arthritis Rheum. 43:2402-2409). There are as yet no definitive genetic associations with Still's Disease and the pathogenesis is poorly understood. Interestingly, many of the signs and symptoms of Still's disease are similar to those with autoinflammatory disease. Still's Disease typically first occurs during childhood, but can also have its onset in adulthood.

[0008] Similarly, Kawasaki disease is disease affecting children that is accompanied by fevers, swelling and arthritic joints, and rash, as well as vascular inflammation that can cause permanent coronary damage in approximately 15-25% of affected children. The etiology of this disease is very similar to autoinflammatory disease.

[0009] The pathogenesis of autoinflammatory disease is not completely understood. There is a growing body of evidence that interleukin-1 (IL-1) plays a role in a number of these conditions and that targeting of this cytokine can provide important benefits (Hoffman et al. (2004) Arthritis. Rheum. 50:345-349). There is clearly a need to develop improved therapeutic treatment of these autoinflammatory diseases

BRIEF SUMMARY OF THE INVENTION

[0010] In a first aspect, the invention features a method of treating, inhibiting, or ameliorating an autoinflammatory disorder, comprising administering to a subject in need an interleukin 1 (IL-1) antagonist. An IL-1 antagonist is a compound capable of blocking or inhibiting the biological action of IL-1, including fusion proteins capable of trapping IL-1, such as an IL-1 trap. In a preferred embodiment, the IL-1 trap is an IL-1-specific fusion protein comprising two IL-1 receptor components and a multimerizing component, for example, an IL-1 trap described in U.S. patent publication No. 2003/0143697, published 31 Jul. 2003, herein specifically incorporated by reference in its entirety. In a specific embodiment, the IL-1 trap is the fusion protein shown in SEQ ID NO: 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26. A preferred IL-1 trap is shown in SEQ ID NO:10. The invention encompasses the use of an IL-1 trap substantially identical to the protein of SEQ ID NO: 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, that is, a protein having at least 95% identity, at least 97% identity, at least 98% identity to the protein of SEQ ID NO: 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26 and capable of binding and inhibiting IL-1. Further, in specific embodiments, the IL-1 antagonist is a modified IL-1 trap comprising one or more receptor components and one or more immunoglobulin-derived components specific for IL-1 and/or an IL-1 receptor. In another embodiment, the IL-1 antagonist is a modified IL-1 trap comprising one or more immunoglobulin-derived components specific for IL-1 and/or an IL-1 receptor.

[0011] The subject being treated is most preferably a human diagnosed as suffering from an autoinflammatory disorder. More specifically, the subject is a human adult or child diagnosed with an autoinflammatory disorder associated with mutations in CIAS-1, such as Neonatal Onset Multisystem Inflammatory Disorder (NOMID/CINCA), Muckle-Wells Syndrome (MWS), and Familial Cold Autoinflammatory Syndrome (FCAS); familial mediterranean fever (FMF); or systemic onset juvenile rheumatoid arthritis (Still's Disease) or Kawasaki Disease.

[0012] The method of the invention includes administration of the IL-1 antagonist by any means known to the art, for example, subcutaneous, intramuscular, intranasal, intraarterial, intravenous, topical, transvaginal, transdermal, transanal administration or oral routes of administration.

[0013] In a second aspect, the invention features a method of treating, inhibiting, or ameliorating Neonatal Onset Multisystem Inflammatory Disorder (NOMID/CINCA), Muckle-Wells Syndrome (MWS), and Familial Cold Autoinflammatory Syndrome (FCAS); familial Mediterranean fever (FMF); or systemic onset juvenile rheumatoid arthritis (Still's Disease), the method comprising administering to a subject in need an interleukin 1 (IL-1) antagonist. In a preferred embodiment, the IL-1 antagonist is a fusion protein capable of trapping IL-1 (IL-1 trap). In a specific embodiment, the IL-1 trap is the fusion protein shown in SEQ ID NO: 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, or a substantially identical protein capable of binding and inhibiting IL-1. A preferred IL-1 trap is shown in SEQ ID NO:10. Preferably, the subject treated is a child or adult human diagnosed with a disease or condition selected from the group consisting of NOMID/CINCA, MWS, FCAS, FMF, Still's Disease and Kawasaki Disease.

[0014] In a third aspect, the invention features a method of treating, inhibiting, or ameliorating Neonatal Onset Multisystem Inflammatory Disorder (NOMID/CINCA), comprising administering to a subject in need an interleukin 1 (IL-1) antagonist. In a preferred embodiment, the IL-1 antagonist is a fusion protein capable of trapping IL-1 (IL-1 trap). In a specific embodiment, the IL-1 trap is the fusion protein shown in SEQ ID NO: 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, or a substantially identical protein capable of binding and inhibiting IL-1. A preferred IL-1 trap is shown in SEQ ID NO:10.

[0015] In a fourth aspect, the invention features a method of treating, inhibiting, or ameliorating Muckle-Wells Syndrome (MWS), the method comprising administering to a subject in need an interleukin 1 (IL-1) antagonist. In a preferred embodiment, the IL-1 antagonist is a fusion protein capable of trapping IL-1 (IL-1 trap). In a specific embodiment, the IL-1 trap is the fusion protein shown in SEQ ID NO: 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, or a substantially identical protein capable of binding and inhibiting IL-1. A preferred IL-1 trap is shown in SEQ ID NO:10.

[0016] In a fifth aspect, the invention features a method of treating, inhibiting, or ameliorating Familial Cold Autoinflammatory Syndrome (FCAS) the method comprising administering to a subject in need an interleukin 1 (IL-1) antagonist. In a preferred embodiment, the IL-1 antagonist is a fusion protein capable of trapping IL-1 (IL-1 trap). In a specific embodiment, the IL-1 trap is the fusion protein shown in SEQ ID NO: 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, or a substantially identical protein capable of binding and inhibiting IL-1. A preferred IL-1 trap is shown in SEQ ID NO:10.

[0017] In a sixth aspect, the invention features a method of treating, inhibiting, or ameliorating familial mediterranean fever (FMF), the method comprising administering to a subject in need an interleukin 1 (IL-1) antagonist. In a preferred embodiment, the IL-1 antagonist is a fusion protein capable of trapping IL-1 (IL-1 trap). In a specific embodiment, the IL-1 trap is the fusion protein shown in SEQ ID NO:4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, or a substantially identical protein capable of binding and inhibiting IL-1. A preferred IL-1 trap is shown in SEQ ID NO:10.

[0018] In a seventh aspect, the invention features a method of treating, inhibiting, or ameliorating systemic onset juvenile rheumatoid arthritis (Still's Disease), the method comprising administering to a subject in need an interleukin 1 (IL-1) antagonist. In a preferred embodiment, the IL-1 antagonist is a fusion protein capable of trapping IL-1 (IL-1 trap). In a specific embodiment, the IL-1 trap is the fusion protein shown in SEQ ID NO: 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, or a substantially identical protein capable of binding and inhibiting IL-1. A preferred IL-1 trap is shown in SEQ ID NO:10.

[0019] In specific embodiments of the therapeutic method of the invention, the subject is treated with a combination of an IL-1 trap and a second therapeutic agent. The second therapeutic agent may be a second IL-1 antagonist, such as, for example, anakinra (Kineret.RTM., Amgen), a recombinant, nonglycosylated form of the human IL-1 receptor antagonist (IL1Ra), or an anti-IL-18 drug such as IL-18BP or a derivative, an IL-18 Trap, anti-IL-18, anti-IL-18R1, or anti-IL-18Racp. Other co-therapies include low dose colchine for FMF, aspirin or other NSAIDs, steroids such as prednisolone, methotrexate, low dose cyclosporine A, TNF inhibitors such as Enbrel.RTM., or Humira.RTM., other inflammatory inhibitors such as inhibitors of caspase-1, p38, IKK1/2, CTLA-4Ig, anti-IL-6 or anti-IL6Ra, etc.

[0020] In an eighth aspect, the invention features a therapeutic method of treating an autoinflammatory disease or condition, comprising administering a pharmaceutical composition comprising an IL-1 trap and a pharmaceutically acceptable carrier, in a dose range of 50-100 mg/kg on a weekly basis for a treatment period of between 1 week to one year or more.

[0021] Other objects and advantages will become apparent from a review of the ensuing detailed description.

DETAILED DESCRIPTION

[0022] Before the present methods are described, it is to be understood that this invention is not limited to particular methods, and experimental conditions described, as such methods and conditions may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only the appended claims.

[0023] As used in this specification and the appended claims, the singular forms "a", "an", and "the" include plural references unless the context clearly dictates otherwise. Thus for example, a reference to "a method" includes one or more methods, and/or steps of the type described herein and/or which will become apparent to those persons skilled in the art upon reading this disclosure and so forth.

[0024] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference in their entirety.

General Description

[0025] In vitro experiments have demonstrated that cryopyrin can up-regulate IL-1 production through a pathway involving PYRIN domain interactions between cryopyrin and, ASC, and then homotypic caspase recruitment domain interactions between ASC and caspase-1 (interleukin 1 converting enzyme). IL-1 protein levels was found to be constitutively elevated on Western blot analysis from monocyte/macrophage lysates from two subjects with NOMID/CINCA (Aksentiejevich et al. (2002) Arthritis. Rheum. 46:3340-3348).

[0026] IL-1 is synthesized in pro-form and is activated via cleavage by the enzyme caspase-1. Caspase-1 can be activated by a protein called ASC, a protein usually under negative regulation by pyrin, the gene mutated in FMF. These mutations result in the inability of pyrin to inhibit ASC and thereby lead to the activation of caspase-1 and, secondarily, IL-1 (Srinivasula et al. (2002) J. Biol. Chem. 277:21119-21122). Studies of mice with targeted disruption of the pyrin gene show evidence of caspase 1 activation and increased IL-1 release. Studies of subjects with FMF have shown elevated levels of IL-1 gene expression. Colchicine has been found to often be effective in preventing FMF disease exacerbations (Dinarello et al. (1974) N. Engl. J. Med. 291:934-937); however, approximately 10% of subjects with FMF are refractory to treatment with this agent. Furthermore, persistent IL-1 over-expression and elevated levels of acute phase reactants have been observed in patients with FMF between flares, even when treated with colchicine (Notarnicola et. al. (2002) Genes Immun. 3:43-45).

[0027] IL-1 is generally recognized as an important regulator of inflammatory processes and yet there is currently only targeted therapy available that specifically works via inhibition of this cytokine, anakinra (Kineret.RTM., Amgen), a recombinant, nonglycosylated form of the human IL-1 receptor antagonist, IL-1Ra. This agent has a relatively short half-life and must be administered as a once-daily subcutaneous injection. While generally well tolerated, some subjects exhibit significant injection site reactions. The combination of once-daily administration and injection site reactions can be undesirable for many subjects. There is need for additional therapies with improved pharmacological characteristics that are targeted against IL-1.

DEFINITIONS

[0028] By the term "blocker", "inhibitor", or "antagonist" is meant a substance that retards or prevents a chemical or physiological reaction or response. Common blockers or inhibitors include but are not limited to antisense molecules, antibodies, antagonists and their derivatives. More specifically, an example of an IL-1 blocker or inhibitor is an IL-1 antagonist including, but not limited to, IL-1 trap, which binds and inhibits IL-1.

[0029] By the term "therapeutically effective dose" is meant a dose that produces the desired effect for which it is administered. The exact dose will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, for example, Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding).

[0030] By the term "substantially identical" is meant a protein sequence having at least 95% identity to an amino acid sequence selected from the group consisting of the amino acid sequences SEQ ID NOs: 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, and 26, and capable of binding IL-1 and inhibiting the biological activity of IL-1.

[0031] The term "identity" or "homology" is construed to mean the percentage of amino acid residues in the candidate sequence that are identical with the residue of a corresponding sequence to which it is compared, after aligning the sequences and introducing gaps, if necessary to achieve the maximum percent identity for the entire sequence, and not considering any conservative substitutions as part of the sequence identity. Neither N- or C-terminal extensions nor insertions will be construed as reducing identity or homology. Methods and computer programs for the alignment are well known in the art. Sequence identity may be measured using sequence analysis software (e.g., Sequence Analysis Software Package, Genetics Computer Group, University of Wisconsin Biotechnology Center, 1710 University Ave., Madison, Wis. 53705). This software matches similar sequences by assigning degrees of homology to various substitutions, deletions, and other modifications.

IL-1 Trap Antagonists

[0032] Interleukin-1 (IL-1) traps are multimers of fusion proteins containing IL-1 receptor components and a multimerizing component capable of interacting with the multimerizing component present in another fusion protein to form a higher order structure, such as a dimer. Cytokine traps are a novel extension of the receptor-Fc fusion concept in that they include two distinct receptor components that bind a single cytokine, resulting in the generation of antagonists with dramatically increased affinity over that offered by single component reagents. In fact, the cytokine traps that are described herein are among the most potent cytokine blockers ever described. Briefly, the cytokine traps called IL-1 traps are comprised of the extracellular domain of human IL-1R Type I (IL-1RI) or Type II (IL-1RII) followed by the extracellular domain of human IL-1 Accessory protein (IL-1AcP), followed by a multimerizing component. In a preferred embodiment, the multimerizing component is an immunoglobulin-derived domain, such as, for example, the Fc region of human IgG, including part of the hinge region, the CH2 and CH3 domains. An immunoglobulin-derived domain may be selected from any of the major classes of immunoglobulins, including IgA, IgD, IgE, IgG and IgM, and any subclass or isotype, e.g. IgG1, IgG2, IgG3 and IgG4; IgA-1 and IgA-2. Alternatively, the IL-1 traps are comprised of the extracellular domain of human IL-1AcP, followed by the extracellular domain of human IL-1RI or IL-1RII, followed by a multimerizing component. For a more detailed description of the IL-1 traps, see WO 00/18932, which publication is herein specifically incorporated by reference in its entirety. Preferred IL-1 traps have the amino acid sequence shown in SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, and 26, or a substantially identical protein at least 95% identity to a sequence of SEQ ID NO: 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, or 26, and capable of binding and inhibiting IL1.

[0033] In specific embodiments, the IL-1 antagonist comprises an antibody fragment capable of binding IL-1.alpha., IL-1.beta., IL-1R1 and/or IL-1 RAcp, or a fragment thereof. The preferred embodiment would an antagonist of IL-1.beta.. One embodiment of an IL-1 antagonist comprising one or more antibody fragments, for example, single chain Fv (scFv), is described in U.S. Pat. No. 6,472,179, which publication is herein specifically incorporated by reference in its entirety. In all of the IL-1 antagonist embodiments comprising one or more antibody-derived components specific for IL-1 or an IL-1 receptor, the components may be arranged in a variety of configurations, e.g., a IL-1 receptor component(s)-scFv(s)-multimerizing component; IL-1 receptor component(s)-multimerizing component-scFv(s); scFv(s)-IL-1 receptor component(s)-multimerizing component, ScFv-ScFv-Fc, etc., so long as the molecule or multimer is capable of inhibiting the biological activity of IL-1

Anti-IL-1 Human Antibodies and Antibody Fragments

[0034] In another embodiment of the IL-1 antagonist useful in the method of the invention, examples of anti-IL-1 antibodies are disclosed in U.S. Pat. No. 4,935,343; U.S. Pat. No. 5,681,933; WO 95/01997; EP 0267611, U.S. Pat. No. 6,419,944; WO 02/16436 and WO 01/53353. The IL-1 antagonist of the invention may include an antibody or antibody fragment specific for an IL-1 ligand (e.g., IL-1.alpha. or IL-1.beta.) and/or an IL-1 receptor (e.g., IL-1R1 and/or IL-1RAcp). Antibody fragments include any fragment having the required target specificity, e.g. antibody fragments either produced by the modification of whole antibodies (e.g. enzymatic digestion), or those synthesized de novo using recombinant DNA methodologies (scFv, single domain antibodies or dabs, single variable domain antibodies) or those identified using human phase display libraries (see, for example, McCafferty et al. (1990) Nature 348:552-554). Alternatively, antibodies can be isolated from mice producing human or human-mouse chimeric antibodies using standard immunization and antibody isolation methods, including but not limited to making hybridomas, or using B cell screening technologies, such as SLAM. Immunoglobulin binding domains also include, but are not limited to, the variable regions of the heavy (V.sub.H) or the light (V.sub.L) chains of immunoglobulins. Or by immunizing people and isolating antigen positive B cells and cloning the cDNAs encoding the heavy and light chain and coexpressing them in a cell, such as CHO.

[0035] The term "antibody" as used herein refers to a polypeptide comprising a framework region from an immunoglobulin gene or fragments thereof that specifically binds and recognizes an antigen. The recognized immunoglobulin genes include the kappa, lambda, alpha, gamma, delta, epsilon, and mu constant regions, as well as the myriad immunoglobulin variable region genes. Light chains are classified as either kappa or lambda. Heavy chains are classified as gamma, mu, alpha, delta, or epsilon, which in turn define the immunoglobulin classes, IgG, IgM, IgA, IgD, and IgE, respectively. Within each IgG class, there are different isotypes (eg. IgG.sub.1, IgG.sub.2, IgG.sub.3, IgG.sub.4). Typically, the antigen-binding region of an antibody will be the most critical in determining specificity and affinity of binding.

[0036] An exemplary immunoglobulin (antibody) structural unit comprises a tetramer. Each tetramer is composed of two identical pairs of polypeptide chains, each pair having one light chain (about 25 kD) and one heavy chain (about 50-70 kD). The N-terminus of each chain defines a variable region of about 100-110 or more amino acids primarily responsible for antigen recognition. The terms "variable light chain" (V.sub.L) and variable heavy chain (V.sub.H) refer to these light and heavy chains respectively.

[0037] Antibodies exist as intact immunoglobulins, or as a number of well-characterized fragments produced by digestion with various peptidases. For example, pepsin digests an antibody below the disulfide linkages in the hinge region to produce F(ab)'.sub.2, a dimer of Fab which itself is a light chain joined to V.sub.H-C.sub.H1 by a disulfide bond. The F(ab)'.sub.2 may be reduced under mild conditions to break the disulfide linkage in the hinge region, thereby converting the F(ab)'.sub.2 dimer into an Fab' monomer. The Fab' monomer is essentially Fab with part of the hinge region. While various antibody fragments are defined in terms of the digestion of an intact antibody, one of skill will appreciate that such fragments may be synthesized de novo either chemically or by using recombinant DNA methodology.

[0038] Methods for preparing antibodies are known to the art. See, for example, Kohler & Milstein (1975) Nature 256:495-497; Harlow & Lane (1988) Antibodies: a Laboratory Manual, Cold Spring Harbor Lab., Cold Spring Harbor, N.Y.). The genes encoding the heavy and light chains of an antibody of interest can be cloned from a cell, e.g., the genes encoding a monoclonal antibody can be cloned from a hybridoma and used to produce a recombinant monoclonal antibody. Monoclonal antibodies can be humanized using standard cloning of the CDR regions into a human scaffold. Gene libraries encoding human heavy and light chains of monoclonal antibodies can also be made from hybridoma or plasma cells. Random combinations of the heavy and light chain gene products generate a large pool of antibodies with different antigenic specificity. Techniques for the production of single chain antibodies or recombinant antibodies (U.S. Pat. No. 4,946,778; U.S. Pat. No. 4,816,567) can be adapted to produce antibodies used in the fusion proteins and methods of the instant invention. Also, transgenic mice, or other organisms such as other mammals, may be used to express human, human-mouse chimeric, or humanized antibodies. Alternatively, phage display technology can be used to identify human antibodies and heteromeric Fab fragments that specifically bind to selected antigens.

Antibody Screening and Selection

[0039] Screening and selection of preferred antibodies can be conducted by a variety of methods known to the art. Initial screening for the presence of monoclonal antibodies specific to a target antigen may be conducted through the use of ELISA-based methods, for example. A secondary screen is preferably conducted to identify and select a desired monoclonal antibody for use in construction of the multi-specific fusion proteins of the invention. Secondary screening may be conducted with any suitable method known to the art. One preferred method, termed "Biosensor Modification-Assisted Profiling" ("BiaMAP") is described in co-pending U.S. Ser. No. 60/423,017 filed 1 Nov. 2002, herein specifically incorporated by reference in its entirety. BiaMAP allows rapid identification of hybridoma clones producing monoclonal antibodies with desired characteristics. More specifically, monoclonal antibodies are sorted into distinct epitope-related groups based on evaluation of antibody:antigen interactions. Antibodies capable of blocking either a ligand or a receptor may be identified by a cell based assay, such as a luciferase assay utilizing a luciferase gene under the control of an NFKB driven promoter. Stimulation of the IL-1 receptors by IL-1 ligands leads to a signal through NFKB thus increasing luciferase levels in the cell. Blocking antibodies are identified as those antibodies that blocked IL-1 induction of luciferase activity.

Treatment Population

[0040] The therapeutic methods of the invention are useful for treating individuals affected with CIAS-1 mutation disorders (NOMID, MWS, FCAS), FMF, or Still's Disease. Commonly accepted diagnostic criteria for CIAS-1 mutation associated disease (NOMID, MWS, FCAS), Familial Mediterranean Fever, or Still's Disease (adult- or juvenile-onset) are know to those skilled in the art. In the case of patients diagnosed with FMF, the therapeutic method of the invention may be particularly useful for those with disease refractory to therapy with colchicine.

Methods of Administration

[0041] The invention provides methods of treatment comprising administering to a subject an effective amount of an agent of the invention. In a preferred aspect, the agent is substantially purified (e.g., substantially free from substances that limit its effect or produce undesired side-effects).

[0042] Various delivery systems are known and can be used to administer an agent of the invention, e.g., encapsulation in liposomes, microparticles, microcapsules, recombinant cells capable of expressing the compound, receptor-mediated endocytosis (see, e.g., Wu and Wu, 1987, J. Biol. Chem. 262:4429-4432), construction of a nucleic acid as part of a retroviral or other vector, etc. Methods of introduction can be enteral or parenteral and include but are not limited to intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. The compounds may be administered by any convenient route, for example by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.) and may be administered together with other biologically active agents. Administration can be systemic or local. In addition, it may be desirable to introduce the pharmaceutical compositions of the invention into the central nervous system by any suitable route, including intraventricular and intrathecal injection; intraventricular injection may be facilitated by an intraventricular catheter, for example, attached to a reservoir, such as an Ommaya reservoir. Pulmonary administration can also be employed, e.g., by use of an inhaler or nebulizer, and formulation with an aerosolizing agent.

[0043] In a specific embodiment, it may be desirable to administer the pharmaceutical compositions of the invention locally to the area in need of treatment; this may be achieved, for example, and not by way of limitation, by local infusion during surgery, topical application, e.g., by injection, by means of a catheter, or by means of an implant, said implant being of a porous, non-porous, or gelatinous material, including membranes, such as sialastic membranes, fibers, commercial skin substitutes or angioplasty balloons or stents.

[0044] In another embodiment, the active agent can be delivered in a vesicle, in particular a liposome (see Langer (1990) Science 249:1527-1533). In yet another embodiment, the active agent can be delivered in a controlled release system. In one embodiment, a pump may be used (see Langer (1990) supra). In another embodiment, polymeric materials can be used (see Howard et al. (1989) J. Neurosurg. 71:105). In another embodiment where the active agent of the invention is a nucleic acid encoding a protein, the nucleic acid can be administered in vivo to promote expression of its encoded protein, by constructing it as part of an appropriate nucleic acid expression vector and administering it so that it becomes intracellular, e.g., by use of a retroviral vector (see, for example, U.S. Pat. No. 4,980,286), or by direct injection, or by use of microparticle bombardment (e.g., a gene gun; Biolistic, Dupont), or coating with lipids or cell-surface receptors or transfecting agents, or by administering it in linkage to a homeobox-like peptide which is known to enter the nucleus (see e.g., Joliot et al., 1991, Proc. Natl. Acad. Sci. USA 88:1864-1868), etc. Alternatively, a nucleic acid can be introduced intracellularly and incorporated within host cell DNA for expression, by homologous recombination.

Combination Therapies

[0045] In numerous embodiments, the IL-1 antagonists of the present invention may be administered in combination with one or more additional compounds or therapies. Combination therapy may be simultaneous or sequential. The IL-1 traps of the invention may be combined with, for example, TNF-inhibiting agents such as etanercept (Enbrel.RTM., Amgen), infliximab (Remicade.RTM., Centocor), Humira.RTM. (Abbott), thalidomide, steroids, anakinra (Kinaret.RTM., Amgen), or colchicine. Colchicine is a mainstay of therapy for subjects with FMF; in this study, subjects will not be removed from treatment with this medication. For Still's Disease (and classical autoinflammatory diseases), compounds such as methotrexate, cyclosporine, chlorambucil, cyclophosphamide (DMARDs) have been used as monotherapy or in combination with no consistent response. Some subjects respond to high doses of steroids. DMARDs, and more recently anti-TNF agents have been used with variable success. The IL-1 traps of the invention may also be combined with anti-IL-18 drugs, such as for example, IL-18BP or a derivative, an IL-18 Trap, anti-IL-18, anti-IL-18R1, or anti-IL-18Racp. Other co-therapies include low dose colchine for FMF, aspirin or other NSAIDs, steroids such as prednisolone, methotrexate, low dose cyclosporine A, TNF inhibitors such as Enbrel.RTM., or Humira.RTM., other inflammatory inhibitors such as inhibitors of caspase-1, p38, IKK1/2, CTLA-4Ig, anti-IL-6 or anti-IL6Ra, etc.

Pharmaceutical Compositions

[0046] The present invention also provides pharmaceutical compositions. Such compositions comprise a therapeutically effective amount of an active agent, and a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable" means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly, in humans. The term "carrier" refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. The composition, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. These compositions can take the form of solutions, suspensions, emulsion, tablets, pills, capsules, powders, sustained-release formulations and the like. The composition can be formulated as a suppository, with traditional binders and carriers such as triglycerides. Oral formulation can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. Examples of suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by E. W. Martin.

[0047] In a preferred embodiment, the composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous administration to human beings. Where necessary, the composition may also include a solubilizing agent and a local anesthetic such as lidocaine to ease pain at the site of the injection. Where the composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline. Where the composition is administered by injection, an ampoule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to administration.

[0048] The active agents of the invention can be formulated as neutral or salt forms. Pharmaceutically acceptable salts include those formed with free amino groups such as those derived from hydrochloric, phosphoric, acetic, oxalic, tartaric acids, etc., and those formed with free carboxyl groups such as those derived from sodium, potassium, ammonium, calcium, ferric hydroxides, isopropylamine, triethylamine, 2-ethylamino ethanol, histidine, procaine, etc.

[0049] The amount of the active agent of the invention which will be effective in the treatment of delayed-type hypersensitivity can be determined by standard clinical techniques based on the present description. In addition, in vitro assays may optionally be employed to help identify optimal dosage ranges. The precise dose to be employed in the formulation will also depend on the route of administration, and the seriousness of the condition, and should be decided according to the judgment of the practitioner and each subject's circumstances. However, suitable dosage ranges for intravenous administration are generally about 20 micrograms to 2 grams of active compound per kilogram body weight. Suitable dosage ranges for intra-nasal administration are generally about 0.01 pg/kg body weight to 1 mg/kg body weight. Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0050] For systemic administration, a therapeutically effective dose can be estimated initially from in vitro assays. For example, a dose can be formulated in animal models to achieve a circulating concentration range that includes the IC.sub.50 as determined in cell culture. Such information can be used to more accurately determine useful doses in humans. Initial dosages can also be estimated from in vivo data, e.g., animal models, using techniques that are well known in the art. One having ordinary skill in the art could readily optimize administration to humans based on animal data.

[0051] Dosage amount and interval may be adjusted individually to provide plasma levels of the compounds that are sufficient to maintain therapeutic effect. In cases of local administration or selective uptake, the effective local concentration of the compounds may not be related to plasma concentration. One having skill in the art will be able to optimize therapeutically effective local dosages without undue experimentation.

[0052] The amount of compound administered will, of course, be dependent on the subject being treated, on the subject's weight, the severity of the affliction, the manner of administration, and the judgment of the prescribing physician. The therapy may be repeated intermittently while symptoms are detectable or even when they are not detectable. The therapy may be provided alone or in combination with other drugs.

Kits

[0053] The invention also provides an article of manufacturing comprising packaging material and a pharmaceutical agent contained within the packaging material, wherein the pharmaceutical agent comprises at least one IL-1-specific fusion protein of the invention and wherein the packaging material comprises a label or package insert which indicates that the IL-1-specific fusion protein can be used for treating an autoinflammatory disease or condition.

[0054] Other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments which are given for illustration of the invention and are not intended to be limiting thereof.

EXAMPLES

[0055] The following example is put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the methods and compositions of the invention, and are not intended to limit the scope of what the inventors regard as their invention. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperature, etc.) but some experimental errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, molecular weight is average molecular weight, temperature is in degrees Centigrade, and pressure is at or near atmospheric.

Example 1

Effect of IL-1 Trap on Human Autoinflammatory Disease

[0056] An initial study is conducted with 10 adult subjects suffering from autoinflammatory disease or Still's Disease. Subjects are screened for eligibility, clinical symptoms determined, and baseline blood is drawn on 3 occasions one week apart to determine baseline levels of inflammation.

[0057] All subjects receive IL-1 trap with a dosing regimen of 100 mg once a day for 3 consecutive days, a regimen expected to provide 2-4 weeks of significant IL-1 inhibitory activity. The primary outcomes are measured during this period and include drug safety, clinical efficacy analysis, and the change in biomarkers of inflammation (e.g., acute phase reactants such as CRP, serum amyloid A, and ESR) at Day 10 following initiation of treatment with IL-1 trap. Patients receive IL-1 trap for 3 days, and are observed for up to 8 weeks (with no additional treatment) following their first dose of IL-1 trap with weekly assessment of acute phase reactants, cytokine levels, and safety lab measurements

[0058] History and Physical Exam. A careful, complete standardized history and physical exam is performed, appropriate for the disease under study to assure uniform data collection on every patient. Vital signs and weight is obtained at each visit. The clinical data is based on a detailed questionnaire including all the reported clinical manifestations. The following evaluation procedures pertain specifically to CIAS-1 mutation associated disorders and are performed as clinically indicated: dermatological evaluation; opthalmologic evaluation; ear/nose/throat evaluation; neurology evaluation; lumbar puncture; head MRI; radiographs, joint MRI; and pharmacokinetic profiling.

Example 2

Treatment of CAPS with an IL-1 Antagonist

[0059] An open label pilot study of IL-1 trap (SEQ ID NO:10) for the treatment of three autoinflammatory diseases was conducted. Diseases under study include CAPS, familial Mediterranean fever (FMF), and adult Still's disease.

[0060] CAPS Study. Four subjects with CAPS were initially enrolled. The dosing strategy includes an initial "loading regimen" of 300 mg administered subcutaneously (administered as 100 mg once daily on three consecutive days). The rationale for this regimen was to enable rapid attainment of drug levels compatible with steady state dosing of 100 mg IL-1 trap protein per week, a regimen previously shown to offer promise for the treatment of rheumatoid arthritis. After initial dosing, subjects were observed to ascertain response of signs and symptoms of autoinflammatory disease. If a favorable response was observed, subjects are observed (with no further treatment) until return of signs and symptoms (flare). Upon flare, subjects are eligible for entry into an extension phase that entails re-treatment with the loading regimen and then once-weekly dosing with 100 mg.

[0061] Preliminary Results. Results indicated that all subjects experienced rapid and extensive improvement in inflammatory signs and symptoms upon treatment with IL-1 trap, including improvement in both patient- and physician-reported disease manifestation. Major declines in inflammatory biomarkers, such as CRP and SAA were also observed. Signs and symptoms returned within a median of 21 days (range 9-26) of initial dosing and then responded promptly to re-treatment. Table 1 provides a summary of the daily diary scores, acute phase reactants and clinical assessments (.dagger-dbl. Performed on 3 patients; * statistically significant difference from previous timepoint at p<0.1 level; ** statistically significant difference from previous timepoint at p<0.05 level).

TABLE-US-00001 TABLE 1 Baseline Maximal Efficacy Flare median (range) median (range) median (range) Daily Diary Score 6.06 (2.2-7.56) 1.67 (0-3.3)* 4.5 (2-7.33) Acute phase reactants SAA (mg/L) 96 (16.1-468) 8.25 (2-19) 84 (50-236).dagger-dbl. CRP (mg/dL) 7.28 (2.32-8.65) 0.72 (0.07-1.15)** 2.93 (0.076-6.21) ESR (mm/hr) 56.67 (22-92) 24 (7-45)** 34 (11-70)* Blood Count WBC 15.28 (9.33-19.4) 7.58 (7.21-9.9)** 8.48 (6.34-11.47) Hgb 12.95 (8.1-14.7) 13.3 (8.2-15.6)* 13.1 (7.9-14.57) Plt 356.5 (291-445.5) 303.25 (240-377)** 291 (257-359.3) Questionnaires.dagger-dbl. Physician global VAS (cm) 6.85 (4.1-6.95) 0.2 (0.2-2.6) 3.3 (3.1-3.5) Patient global VAS (cm) 5.2 (3.95-6.9) 1.1 (0.95-3.05)** 3.6 (3.1-6.45)** Fatigue VAS (cm) 5.55 (3.25-8) 1.15 (0.5-3.9) 6.6 (3.15-6.9) Pain VAS (cm) 7.55 (3.6-7.7) 0.95 (0.2-1.05)* 4.1 (0.5-6.55) SF-36 Physical Health 44.38 (42.5-47.5) 50.63 (33.75-92.5) 41.56 (35-69.4) SF-36 Mental Health 41.625 (28.5-57.8) 75.88 (55-96) 39.6 (37-57)

Sequence CWU 1

1

2612733DNAHomo sapiens 1atg gtg ctt ctg tgg tgt gta gtg agt ctc tac ttt tat gga atc ctg 48caa agt gat gcc tca gaa cgc tgc gat gac tgg gga cta gac acc atg 96agg caa atc caa gtg ttt gaa gat gag cca gct cgc atc aag tgc cca 144ctc ttt gaa cac ttc ttg aaa ttc aac tac agc aca gcc cat tca gct 192ggc ctt act ctg atc tgg tat tgg act agg cag gac cgg gac ctt gag 240gag cca att aac ttc cgc ctc ccc gag aac cgc att agt aag gag aaa 288gat gtg ctg tgg ttc cgg ccc act ctc ctc aat gac act ggc aac tat 336acc tgc atg tta agg aac act aca tat tgc agc aaa gtt gca ttt ccc 384ttg gaa gtt gtt caa aaa gac agc tgt ttc aat tcc ccc atg aaa ctc 432cca gtg cat aaa ctg tat ata gaa tat ggc att cag agg atc act tgt 480cca aat gta gat gga tat ttt cct tcc agt gtc aaa ccg act atc act 528tgg tat atg ggc tgt tat aaa ata cag aat ttt aat aat gta ata ccc 576gaa ggt atg aac ttg agt ttc ctc att gcc tta att tca aat aat gga 624aat tac aca tgt gtt gtt aca tat cca gaa aat gga cgt acg ttt cat 672ctc acc agg act ctg act gta aag gta gta ggc tct cca aaa aat gca 720gtg ccc cct gtg atc cat tca cct aat gat cat gtg gtc tat gag aaa 768gaa cca gga gag gag cta ctc att ccc tgt acg gtc tat ttt agt ttt 816ctg atg gat tct cgc aat gag gtt tgg tgg acc att gat gga aaa aaa 864cct gat gac atc act att gat gtc acc att aac gaa agt ata agt cat 912agt aga aca gaa gat gaa aca aga act cag att ttg agc atc aag aaa 960gtt acc tct gag gat ctc aag cgc agc tat gtc tgt cat gct aga agt 1008gcc aaa ggc gaa gtt gcc aaa gca gcc aag gtg aag cag aaa gtg cca 1056gct cca aga tac aca gtg tcc ggt ggc gcg cct atg ctg agc gag gct 1104gat aaa tgc aag gaa cgt gaa gaa aaa ata att tta gtg tca tct gca 1152aat gaa att gat gtt cgt ccc tgt cct ctt aac cca aat gaa cac aaa 1200ggc act ata act tgg tat aag gat gac agc aag aca cct gta tct aca 1248gaa caa gcc tcc agg att cat caa cac aaa gag aaa ctt tgg ttt gtt 1296cct gct aag gtg gag gat tca gga cat tac tat tgc gtg gta aga aat 1344tca tct tac tgc ctc aga att aaa ata agt gca aaa ttt gtg gag aat 1392gag cct aac tta tgt tat aat gca caa gcc ata ttt aag cag aaa cta 1440ccc gtt gca gga gac gga gga ctt gtg tgc cct tat atg gag ttt ttt 1488aaa aat gaa aat aat gag tta cct aaa tta cag tgg tat aag gat tgc 1536aaa cct cta ctt ctt gac aat ata cac ttt agt gga gtc aaa gat agg 1584ctc atc gtg atg aat gtg gct gaa aag cat aga ggg aac tat act tgt 1632cat gca tcc tac aca tac ttg ggc aag caa tat cct att acc cgg gta 1680ata gaa ttt att act cta gag gaa aac aaa ccc aca agg cct gtg att 1728gtg agc cca gct aat gag aca atg gaa gta gac ttg gga tcc cag ata 1776caa ttg atc tgt aat gtc acc ggc cag ttg agt gac att gct tac tgg 1824aag tgg aat ggg tca gta att gat gaa gat gac cca gtg cta ggg gaa 1872gac tat tac agt gtg gaa aat cct gca aac aaa aga agg agt acc ctc 1920atc aca gtg ctt aat ata tcg gaa att gag agt aga ttt tat aaa cat 1968cca ttt acc tgt ttt gcc aag aat aca cat ggt ata gat gca gca tat 2016atc cag tta ata tat cca gtc act aat tcc gga gac aaa act cac aca 2064tgc cca ccg tgc cca gca cct gaa ctc ctg ggg gga ccg tca gtc ttc 2112ctc ttc ccc cca aaa ccc aag gac acc ctc atg atc tcc cgg acc cct 2160gag gtc aca tgc gtg gtg gtg gac gtg agc cac gaa gac cct gag gtc 2208aag ttc aac tgg tac gtg gac ggc gtg gag gtg cat aat gcc aag aca 2256aag ccg cgg gag gag cag tac aac agc acg tac cgt gtg gtc agc gtc 2304ctc acc gtc ctg cac cag gac tgg ctg aat ggc aag gag tac aag tgc 2352aag gtc tcc aac aaa gcc ctc cca gcc ccc atc gag aaa acc atc tcc 2400aaa gcc aaa ggg cag ccc cga gaa cca cag gtg tac acc ctg ccc cca 2448tcc cgg gag gag atg acc aag aac cag gtc agc ctg acc tgc ctg gtc 2496aaa ggc ttc tat ccc agc gac atc gcc gtg gag tgg gag agc aat ggg 2544cag ccg gag aac aac tac aag acc acg cct ccc gtg ctg gac tcc gac 2592ggc tcc ttc ttc ctc tat agc aag ctc acc gtg gac aag agc agg tgg 2640cag cag ggg aac gtc ttc tca tgc tcc gtg atg cat gag gct ctg cac 2688aac cac tac acg cag aag agc ctc tcc ctg tct ccg ggt aaa 2730tga 27332910PRTHomo sapiens 2Met Val Leu Leu Trp Cys Val Val Ser Leu Tyr Phe Tyr Gly Ile Leu 1 5 10 15Gln Ser Asp Ala Ser Glu Arg Cys Asp Asp Trp Gly Leu Asp Thr Met 20 25 30Arg Gln Ile Gln Val Phe Glu Asp Glu Pro Ala Arg Ile Lys Cys Pro 35 40 45Leu Phe Glu His Phe Leu Lys Phe Asn Tyr Ser Thr Ala His Ser Ala 50 55 60Gly Leu Thr Leu Ile Trp Tyr Trp Thr Arg Gln Asp Arg Asp Leu Glu65 70 75 80Glu Pro Ile Asn Phe Arg Leu Pro Glu Asn Arg Ile Ser Lys Glu Lys 85 90 95Asp Val Leu Trp Phe Arg Pro Thr Leu Leu Asn Asp Thr Gly Asn Tyr 100 105 110Thr Cys Met Leu Arg Asn Thr Thr Tyr Cys Ser Lys Val Ala Phe Pro 115 120 125Leu Glu Val Val Gln Lys Asp Ser Cys Phe Asn Ser Pro Met Lys Leu 130 135 140Pro Val His Lys Leu Tyr Ile Glu Tyr Gly Ile Gln Arg Ile Thr Cys145 150 155 160Pro Asn Val Asp Gly Tyr Phe Pro Ser Ser Val Lys Pro Thr Ile Thr 165 170 175Trp Tyr Met Gly Cys Tyr Lys Ile Gln Asn Phe Asn Asn Val Ile Pro 180 185 190Glu Gly Met Asn Leu Ser Phe Leu Ile Ala Leu Ile Ser Asn Asn Gly 195 200 205Asn Tyr Thr Cys Val Val Thr Tyr Pro Glu Asn Gly Arg Thr Phe His 210 215 220Leu Thr Arg Thr Leu Thr Val Lys Val Val Gly Ser Pro Lys Asn Ala225 230 235 240Val Pro Pro Val Ile His Ser Pro Asn Asp His Val Val Tyr Glu Lys 245 250 255Glu Pro Gly Glu Glu Leu Leu Ile Pro Cys Thr Val Tyr Phe Ser Phe 260 265 270Leu Met Asp Ser Arg Asn Glu Val Trp Trp Thr Ile Asp Gly Lys Lys 275 280 285Pro Asp Asp Ile Thr Ile Asp Val Thr Ile Asn Glu Ser Ile Ser His 290 295 300Ser Arg Thr Glu Asp Glu Thr Arg Thr Gln Ile Leu Ser Ile Lys Lys305 310 315 320Val Thr Ser Glu Asp Leu Lys Arg Ser Tyr Val Cys His Ala Arg Ser 325 330 335Ala Lys Gly Glu Val Ala Lys Ala Ala Lys Val Lys Gln Lys Val Pro 340 345 350Ala Pro Arg Tyr Thr Val Ser Gly Gly Ala Pro Met Leu Ser Glu Ala 355 360 365Asp Lys Cys Lys Glu Arg Glu Glu Lys Ile Ile Leu Val Ser Ser Ala 370 375 380Asn Glu Ile Asp Val Arg Pro Cys Pro Leu Asn Pro Asn Glu His Lys385 390 395 400Gly Thr Ile Thr Trp Tyr Lys Asp Asp Ser Lys Thr Pro Val Ser Thr 405 410 415Glu Gln Ala Ser Arg Ile His Gln His Lys Glu Lys Leu Trp Phe Val 420 425 430Pro Ala Lys Val Glu Asp Ser Gly His Tyr Tyr Cys Val Val Arg Asn 435 440 445Ser Ser Tyr Cys Leu Arg Ile Lys Ile Ser Ala Lys Phe Val Glu Asn 450 455 460Glu Pro Asn Leu Cys Tyr Asn Ala Gln Ala Ile Phe Lys Gln Lys Leu465 470 475 480Pro Val Ala Gly Asp Gly Gly Leu Val Cys Pro Tyr Met Glu Phe Phe 485 490 495Lys Asn Glu Asn Asn Glu Leu Pro Lys Leu Gln Trp Tyr Lys Asp Cys 500 505 510Lys Pro Leu Leu Leu Asp Asn Ile His Phe Ser Gly Val Lys Asp Arg 515 520 525Leu Ile Val Met Asn Val Ala Glu Lys His Arg Gly Asn Tyr Thr Cys 530 535 540His Ala Ser Tyr Thr Tyr Leu Gly Lys Gln Tyr Pro Ile Thr Arg Val545 550 555 560Ile Glu Phe Ile Thr Leu Glu Glu Asn Lys Pro Thr Arg Pro Val Ile 565 570 575Val Ser Pro Ala Asn Glu Thr Met Glu Val Asp Leu Gly Ser Gln Ile 580 585 590Gln Leu Ile Cys Asn Val Thr Gly Gln Leu Ser Asp Ile Ala Tyr Trp 595 600 605Lys Trp Asn Gly Ser Val Ile Asp Glu Asp Asp Pro Val Leu Gly Glu 610 615 620Asp Tyr Tyr Ser Val Glu Asn Pro Ala Asn Lys Arg Arg Ser Thr Leu625 630 635 640Ile Thr Val Leu Asn Ile Ser Glu Ile Glu Ser Arg Phe Tyr Lys His 645 650 655Pro Phe Thr Cys Phe Ala Lys Asn Thr His Gly Ile Asp Ala Ala Tyr 660 665 670Ile Gln Leu Ile Tyr Pro Val Thr Asn Ser Gly Asp Lys Thr His Thr 675 680 685Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe 690 695 700Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro705 710 715 720Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val 725 730 735Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 740 745 750Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val 755 760 765Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys 770 775 780Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser785 790 795 800Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro 805 810 815Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val 820 825 830Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly 835 840 845Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp 850 855 860Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp865 870 875 880Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His 885 890 895Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 900 905 91032703DNAHomo sapiens 3atggtgttac tcagacttat ttgtttcata gctctactga tttcttctct ggaggctgat 60aaatgcaagg aacgtgaaga aaaaataatt ttagtgtcat ctgcaaatga aattgatgtt 120cgtccctgtc ctcttaaccc aaatgaacac aaaggcacta taacttggta taaggatgac 180agcaagacac ctgtatctac agaacaagcc tccaggattc atcaacacaa agagaaactt 240tggtttgttc ctgctaaggt ggaggattca ggacattact attgcgtggt aagaaattca 300tcttactgcc tcagaattaa aataagtgca aaatttgtgg agaatgagcc taacttatgt 360tataatgcac aagccatatt taagcagaaa ctacccgttg caggagacgg aggacttgtg 420tgcccttata tggagttttt taaaaatgaa aataatgagt tacctaaatt acagtggtat 480aaggattgca aacctctact tcttgacaat atacacttta gtggagtcaa agataggctc 540atcgtgatga atgtggctga aaagcataga gggaactata cttgtcatgc atcctacaca 600tacttgggca agcaatatcc tattacccgg gtaatagaat ttattactct agaggaaaac 660aaacccacaa ggcctgtgat tgtgagccca gctaatgaga caatggaagt agacttggga 720tcccagatac aattgatctg taatgtcacc ggccagttga gtgacattgc ttactggaag 780tggaatgggt cagtaattga tgaagatgac ccagtgctag gggaagacta ttacagtgtg 840gaaaatcctg caaacaaaag aaggagtacc ctcatcacag tgcttaatat atcggaaatt 900gagagtagat tttataaaca tccatttacc tgttttgcca agaatacaca tggtatagat 960gcagcatata tccagttaat atatccagtc actaattcag aacgctgcga tgactgggga 1020ctagacacca tgaggcaaat ccaagtgttt gaagatgagc cagctcgcat caagtgccca 1080ctctttgaac acttcttgaa attcaactac agcacagccc attcagctgg ccttactctg 1140atctggtatt ggactaggca ggaccgggac cttgaggagc caattaactt ccgcctcccc 1200gagaaccgca ttagtaagga gaaagatgtg ctgtggttcc ggcccactct cctcaatgac 1260actggcaact atacctgcat gttaaggaac actacatatt gcagcaaagt tgcatttccc 1320ttggaagttg ttcaaaaaga cagctgtttc aattccccca tgaaactccc agtgcataaa 1380ctgtatatag aatatggcat tcagaggatc acttgtccaa atgtagatgg atattttcct 1440tccagtgtca aaccgactat cacttggtat atgggctgtt ataaaataca gaattttaat 1500aatgtaatac ccgaaggtat gaacttgagt ttcctcattg ccttaatttc aaataatgga 1560aattacacat gtgttgttac atatccagaa aatggacgta cgtttcatct caccaggact 1620ctgactgtaa aggtagtagg ctctccaaaa aatgcagtgc cccctgtgat ccattcacct 1680aatgatcatg tggtctatga gaaagaacca ggagaggagc tactcattcc ctgtacggtc 1740tattttagtt ttctgatgga ttctcgcaat gaggtttggt ggaccattga tggaaaaaaa 1800cctgatgaca tcactattga tgtcaccatt aacgaaagta taagtcatag tagaacagaa 1860gatgaaacaa gaactcagat tttgagcatc aagaaagtta cctctgagga tctcaagcgc 1920agctatgtct gtcatgctag aagtgccaaa ggcgaagttg ccaaagcagc caaggtgaag 1980cagaaagtgc cagctccaag atacacagtg gaatccggag acaaaactca cacatgccca 2040ccgtgcccag cacctgaact cctgggggga ccgtcagtct tcctcttccc cccaaaaccc 2100aaggacaccc tcatgatctc ccggacccct gaggtcacat gcgtggtggt ggacgtgagc 2160cacgaagacc ctgaggtcaa gttcaactgg tacgtggacg gcgtggaggt gcataatgcc 2220aagacaaagc cgcgggagga gcagtacaac agcacgtacc gtgtggtcag cgtcctcacc 2280gtcctgcacc aggactggct gaatggcaag gagtacaagt gcaaggtctc caacaaagcc 2340ctcccagccc ccatcgagaa aaccatctcc aaagccaaag ggcagccccg agaaccacag 2400gtgtacaccc tgcccccatc ccgggaggag atgaccaaga accaggtcag cctgacctgc 2460ctggtcaaag gcttctatcc cagcgacatc gccgtggagt gggagagcaa tgggcagccg 2520gagaacaact acaagaccac gcctcccgtg ctggactccg acggctcctt cttcctctat 2580agcaagctca ccgtggacaa gagcaggtgg cagcagggga acgtcttctc atgctccgtg 2640atgcatgagg ctctgcacaa ccactacacg cagaagagcc tctccctgtc tccgggtaaa 2700tga 27034900PRTHomo sapiens 4Met Val Leu Leu Arg Leu Ile Cys Phe Ile Ala Leu Leu Ile Ser Ser 1 5 10 15Leu Glu Ala Asp Lys Cys Lys Glu Arg Glu Glu Lys Ile Ile Leu Val 20 25 30Ser Ser Ala Asn Glu Ile Asp Val Arg Pro Cys Pro Leu Asn Pro Asn 35 40 45Glu His Lys Gly Thr Ile Thr Trp Tyr Lys Asp Asp Ser Lys Thr Pro 50 55 60Val Ser Thr Glu Gln Ala Ser Arg Ile His Gln His Lys Glu Lys Leu65 70 75 80Trp Phe Val Pro Ala Lys Val Glu Asp Ser Gly His Tyr Tyr Cys Val 85 90 95Val Arg Asn Ser Ser Tyr Cys Leu Arg Ile Lys Ile Ser Ala Lys Phe 100 105 110Val Glu Asn Glu Pro Asn Leu Cys Tyr Asn Ala Gln Ala Ile Phe Lys 115 120 125Gln Lys Leu Pro Val Ala Gly Asp Gly Gly Leu Val Cys Pro Tyr Met 130 135 140Glu Phe Phe Lys Asn Glu Asn Asn Glu Leu Pro Lys Leu Gln Trp Tyr145 150 155 160Lys Asp Cys Lys Pro Leu Leu Leu Asp Asn Ile His Phe Ser Gly Val 165 170 175Lys Asp Arg Leu Ile Val Met Asn Val Ala Glu Lys His Arg Gly Asn 180 185 190Tyr Thr Cys His Ala Ser Tyr Thr Tyr Leu Gly Lys Gln Tyr Pro Ile 195 200 205Thr Arg Val Ile Glu Phe Ile Thr Leu Glu Glu Asn Lys Pro Thr Arg 210 215 220Pro Val Ile Val Ser Pro Ala Asn Glu Thr Met Glu Val Asp Leu Gly225 230 235 240Ser Gln Ile Gln Leu Ile Cys Asn Val Thr Gly Gln Leu Ser Asp Ile 245 250 255Ala Tyr Trp Lys Trp Asn Gly Ser Val Ile Asp Glu Asp Asp Pro Val 260 265 270Leu Gly Glu Asp Tyr Tyr Ser Val Glu Asn Pro Ala Asn Lys Arg Arg 275 280 285Ser Thr Leu Ile Thr Val Leu Asn Ile Ser Glu Ile Glu Ser Arg Phe 290 295 300Tyr Lys His Pro Phe Thr Cys Phe Ala Lys Asn Thr His Gly Ile Asp305 310 315 320Ala Ala Tyr Ile Gln Leu Ile Tyr Pro Val Thr Asn Ser Glu Arg Cys 325 330 335Asp Asp Trp Gly Leu Asp Thr Met Arg Gln Ile Gln Val Phe Glu Asp 340 345 350Glu Pro Ala Arg Ile Lys Cys Pro Leu Phe Glu His Phe Leu Lys Phe 355 360 365Asn Tyr Ser Thr Ala His Ser Ala Gly Leu Thr Leu Ile Trp Tyr Trp 370 375 380Thr Arg Gln Asp Arg Asp Leu Glu Glu Pro Ile Asn Phe Arg Leu Pro385 390 395 400Glu Asn Arg Ile Ser Lys Glu Lys Asp Val Leu Trp Phe Arg Pro Thr 405 410 415Leu Leu Asn Asp Thr Gly Asn Tyr Thr Cys Met Leu Arg Asn Thr Thr 420 425 430Tyr Cys Ser Lys Val Ala Phe Pro Leu Glu Val Val Gln Lys Asp Ser 435 440 445Cys Phe Asn Ser Pro Met Lys Leu Pro Val His Lys Leu Tyr Ile Glu 450 455 460Tyr Gly Ile Gln Arg Ile Thr Cys Pro Asn Val Asp Gly Tyr Phe Pro465 470 475 480Ser Ser Val Lys Pro Thr Ile Thr Trp Tyr Met Gly Cys Tyr Lys Ile 485 490 495Gln Asn Phe Asn Asn Val Ile Pro Glu Gly Met Asn Leu Ser Phe Leu 500 505 510Ile Ala Leu Ile Ser Asn Asn Gly Asn Tyr Thr Cys Val Val Thr Tyr 515 520

525Pro Glu Asn Gly Arg Thr Phe His Leu Thr Arg Thr Leu Thr Val Lys 530 535 540Val Val Gly Ser Pro Lys Asn Ala Val Pro Pro Val Ile His Ser Pro545 550 555 560Asn Asp His Val Val Tyr Glu Lys Glu Pro Gly Glu Glu Leu Leu Ile 565 570 575Pro Cys Thr Val Tyr Phe Ser Phe Leu Met Asp Ser Arg Asn Glu Val 580 585 590Trp Trp Thr Ile Asp Gly Lys Lys Pro Asp Asp Ile Thr Ile Asp Val 595 600 605Thr Ile Asn Glu Ser Ile Ser His Ser Arg Thr Glu Asp Glu Thr Arg 610 615 620Thr Gln Ile Leu Ser Ile Lys Lys Val Thr Ser Glu Asp Leu Lys Arg625 630 635 640Ser Tyr Val Cys His Ala Arg Ser Ala Lys Gly Glu Val Ala Lys Ala 645 650 655Ala Lys Val Lys Gln Lys Val Pro Ala Pro Arg Tyr Thr Val Glu Ser 660 665 670Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 675 680 685Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 690 695 700Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser705 710 715 720His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 725 730 735Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 740 745 750Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 755 760 765Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro 770 775 780Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln785 790 795 800Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val 805 810 815Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 820 825 830Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 835 840 845Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr 850 855 860Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val865 870 875 880Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 885 890 895Ser Pro Gly Lys 90052709DNAHomo sapiens 5atggtgttac tcagacttat ttgtttcata gctctactga tttcttctct ggaggctgat 60aaatgcaagg aacgtgaaga aaaaataatt ttagtgtcat ctgcaaatga aattgatgtt 120cgtccctgtc ctcttaaccc aaatgaacac aaaggcacta taacttggta taaggatgac 180agcaagacac ctgtatctac agaacaagcc tccaggattc atcaacacaa agagaaactt 240tggtttgttc ctgctaaggt ggaggattca ggacattact attgcgtggt aagaaattca 300tcttactgcc tcagaattaa aataagtgca aaatttgtgg agaatgagcc taacttatgt 360tataatgcac aagccatatt taagcagaaa ctacccgttg caggagacgg aggacttgtg 420tgcccttata tggagttttt taaaaatgaa aataatgagt tacctaaatt acagtggtat 480aaggattgca aacctctact tcttgacaat atacacttta gtggagtcaa agataggctc 540atcgtgatga atgtggctga aaagcataga gggaactata cttgtcatgc atcctacaca 600tacttgggca agcaatatcc tattacccgg gtaatagaat ttattactct agaggaaaac 660aaacccacaa ggcctgtgat tgtgagccca gctaatgaga caatggaagt agacttggga 720tcccagatac aattgatctg taatgtcacc ggccagttga gtgacattgc ttactggaag 780tggaatgggt cagtaattga tgaagatgac ccagtgctag gggaagacta ttacagtgtg 840gaaaatcctg caaacaaaag aaggagtacc ctcatcacag tgcttaatat atcggaaatt 900gagagtagat tttataaaca tccatttacc tgttttgcca agaatacaca tggtatagat 960gcagcatata tccagttaat atatccagtc actaattcag aacgctgcga tgactgggga 1020ctagacacca tgaggcaaat ccaagtgttt gaagatgagc cagctcgcat caagtgccca 1080ctctttgaac acttcttgaa attcaactac agcacagccc attcagctgg ccttactctg 1140atctggtatt ggactaggca ggaccgggac cttgaggagc caattaactt ccgcctcccc 1200gagaaccgca ttagtaagga gaaagatgtg ctgtggttcc ggcccactct cctcaatgac 1260actggcaact atacctgcat gttaaggaac actacatatt gcagcaaagt tgcatttccc 1320ttggaagttg ttcaaaaaga cagctgtttc aattccccca tgaaactccc agtgcataaa 1380ctgtatatag aatatggcat tcagaggatc acttgtccaa atgtagatgg atattttcct 1440tccagtgtca aaccgactat cacttggtat atgggctgtt ataaaataca gaattttaat 1500aatgtaatac ccgaaggtat gaacttgagt ttcctcattg ccttaatttc aaataatgga 1560aattacacat gtgttgttac atatccagaa aatggacgta cgtttcatct caccaggact 1620ctgactgtaa aggtagtagg ctctccaaaa aatgcagtgc cccctgtgat ccattcacct 1680aatgatcatg tggtctatga gaaagaacca ggagaggagc tactcattcc ctgtacggtc 1740tattttagtt ttctgatgga ttctcgcaat gaggtttggt ggaccattga tggaaaaaaa 1800cctgatgaca tcactattga tgtcaccatt aacgaaagta taagtcatag tagaacagaa 1860gatgaaacaa gaactcagat tttgagcatc aagaaagtta cctctgagga tctcaagcgc 1920agctatgtct gtcatgctag aagtgccaaa ggcgaagttg ccaaagcagc caaggtgaag 1980cagaaagtgc cagctccaag atacacagtg gaatccggag agtccaaata cggtccgcca 2040tgcccatcat gcccagcacc tgagttcctg gggggaccat cagtcttcct gttcccccca 2100aaacccaagg acactctcat gatctcccgg acccctgagg tcacgtgcgt ggtggtggac 2160gtgagccagg aagaccccga ggtccagttc aactggtacg tggatggcgt ggaggtgcat 2220aatgccaaga caaagccgcg ggaggagcag ttcaacagca cgtaccgtgt ggtcagcgtc 2280ctcaccgtcc tgcaccagga ctggctgaac ggcaaggagt acaagtgcaa ggtctccaac 2340aaaggcctcc cgtcctccat cgagaaaacc atctccaaag ccaaagggca gccccgagag 2400ccacaggtgt acaccctgcc cccatcccag gaggagatga ccaagaacca ggtcagcctg 2460acctgcctgg tcaaaggctt ctaccccagc gacatcgccg tggagtggga gagcaatggg 2520cagccggaga acaactacaa gaccacgcct cccgtgctgg actccgacgg ctccttcttc 2580ctctacagca ggctaaccgt ggacaagagc aggtggcagg aggggaatgt cttctcatgc 2640tccgtgatgc atgaggctct gcacaaccac tacacacaga agagcctctc cctgtctctg 2700ggtaaatga 27096902PRTHomo sapiens 6Met Val Leu Leu Arg Leu Ile Cys Phe Ile Ala Leu Leu Ile Ser Ser 1 5 10 15Leu Glu Ala Asp Lys Cys Lys Glu Arg Glu Glu Lys Ile Ile Leu Val 20 25 30Ser Ser Ala Asn Glu Ile Asp Val Arg Pro Cys Pro Leu Asn Pro Asn 35 40 45Glu His Lys Gly Thr Ile Thr Trp Tyr Lys Asp Asp Ser Lys Thr Pro 50 55 60Val Ser Thr Glu Gln Ala Ser Arg Ile His Gln His Lys Glu Lys Leu65 70 75 80Trp Phe Val Pro Ala Lys Val Glu Asp Ser Gly His Tyr Tyr Cys Val 85 90 95Val Arg Asn Ser Ser Tyr Cys Leu Arg Ile Lys Ile Ser Ala Lys Phe 100 105 110Val Glu Asn Glu Pro Asn Leu Cys Tyr Asn Ala Gln Ala Ile Phe Lys 115 120 125Gln Lys Leu Pro Val Ala Gly Asp Gly Gly Leu Val Cys Pro Tyr Met 130 135 140Glu Phe Phe Lys Asn Glu Asn Asn Glu Leu Pro Lys Leu Gln Trp Tyr145 150 155 160Lys Asp Cys Lys Pro Leu Leu Leu Asp Asn Ile His Phe Ser Gly Val 165 170 175Lys Asp Arg Leu Ile Val Met Asn Val Ala Glu Lys His Arg Gly Asn 180 185 190Tyr Thr Cys His Ala Ser Tyr Thr Tyr Leu Gly Lys Gln Tyr Pro Ile 195 200 205Thr Arg Val Ile Glu Phe Ile Thr Leu Glu Glu Asn Lys Pro Thr Arg 210 215 220Pro Val Ile Val Ser Pro Ala Asn Glu Thr Met Glu Val Asp Leu Gly225 230 235 240Ser Gln Ile Gln Leu Ile Cys Asn Val Thr Gly Gln Leu Ser Asp Ile 245 250 255Ala Tyr Trp Lys Trp Asn Gly Ser Val Ile Asp Glu Asp Asp Pro Val 260 265 270Leu Gly Glu Asp Tyr Tyr Ser Val Glu Asn Pro Ala Asn Lys Arg Arg 275 280 285Ser Thr Leu Ile Thr Val Leu Asn Ile Ser Glu Ile Glu Ser Arg Phe 290 295 300Tyr Lys His Pro Phe Thr Cys Phe Ala Lys Asn Thr His Gly Ile Asp305 310 315 320Ala Ala Tyr Ile Gln Leu Ile Tyr Pro Val Thr Asn Ser Glu Arg Cys 325 330 335Asp Asp Trp Gly Leu Asp Thr Met Arg Gln Ile Gln Val Phe Glu Asp 340 345 350Glu Pro Ala Arg Ile Lys Cys Pro Leu Phe Glu His Phe Leu Lys Phe 355 360 365Asn Tyr Ser Thr Ala His Ser Ala Gly Leu Thr Leu Ile Trp Tyr Trp 370 375 380Thr Arg Gln Asp Arg Asp Leu Glu Glu Pro Ile Asn Phe Arg Leu Pro385 390 395 400Glu Asn Arg Ile Ser Lys Glu Lys Asp Val Leu Trp Phe Arg Pro Thr 405 410 415Leu Leu Asn Asp Thr Gly Asn Tyr Thr Cys Met Leu Arg Asn Thr Thr 420 425 430Tyr Cys Ser Lys Val Ala Phe Pro Leu Glu Val Val Gln Lys Asp Ser 435 440 445Cys Phe Asn Ser Pro Met Lys Leu Pro Val His Lys Leu Tyr Ile Glu 450 455 460Tyr Gly Ile Gln Arg Ile Thr Cys Pro Asn Val Asp Gly Tyr Phe Pro465 470 475 480Ser Ser Val Lys Pro Thr Ile Thr Trp Tyr Met Gly Cys Tyr Lys Ile 485 490 495Gln Asn Phe Asn Asn Val Ile Pro Glu Gly Met Asn Leu Ser Phe Leu 500 505 510Ile Ala Leu Ile Ser Asn Asn Gly Asn Tyr Thr Cys Val Val Thr Tyr 515 520 525Pro Glu Asn Gly Arg Thr Phe His Leu Thr Arg Thr Leu Thr Val Lys 530 535 540Val Val Gly Ser Pro Lys Asn Ala Val Pro Pro Val Ile His Ser Pro545 550 555 560Asn Asp His Val Val Tyr Glu Lys Glu Pro Gly Glu Glu Leu Leu Ile 565 570 575Pro Cys Thr Val Tyr Phe Ser Phe Leu Met Asp Ser Arg Asn Glu Val 580 585 590Trp Trp Thr Ile Asp Gly Lys Lys Pro Asp Asp Ile Thr Ile Asp Val 595 600 605Thr Ile Asn Glu Ser Ile Ser His Ser Arg Thr Glu Asp Glu Thr Arg 610 615 620Thr Gln Ile Leu Ser Ile Lys Lys Val Thr Ser Glu Asp Leu Lys Arg625 630 635 640Ser Tyr Val Cys His Ala Arg Ser Ala Lys Gly Glu Val Ala Lys Ala 645 650 655Ala Lys Val Lys Gln Lys Val Pro Ala Pro Arg Tyr Thr Val Glu Ser 660 665 670Gly Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro Ala Pro Glu 675 680 685Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 690 695 700Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp705 710 715 720Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly 725 730 735Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn 740 745 750Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 755 760 765Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro 770 775 780Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu785 790 795 800Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn 805 810 815Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 820 825 830Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 835 840 845Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg 850 855 860Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys865 870 875 880Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 885 890 895Ser Leu Ser Leu Gly Lys 90072709DNAHomo sapiens 7atggtgttac tcagacttat ttgtttcata gctctactga tttcttctct ggaggctgat 60aaatgcaagg aacgtgaaga aaaaataatt ttagtgtcat ctgcaaatga aattgatgtt 120cgtccctgtc ctcttaaccc aaatgaacac aaaggcacta taacttggta taaggatgac 180agcaagacac ctgtatctac agaacaagcc tccaggattc atcaacacaa agagaaactt 240tggtttgttc ctgctaaggt ggaggattca ggacattact attgcgtggt aagaaattca 300tcttactgcc tcagaattaa aataagtgca aaatttgtgg agaatgagcc taacttatgt 360tataatgcac aagccatatt taagcagaaa ctacccgttg caggagacgg aggacttgtg 420tgcccttata tggagttttt taaaaatgaa aataatgagt tacctaaatt acagtggtat 480aaggattgca aacctctact tcttgacaat atacacttta gtggagtcaa agataggctc 540atcgtgatga atgtggctga aaagcataga gggaactata cttgtcatgc atcctacaca 600tacttgggca agcaatatcc tattacccgg gtaatagaat ttattactct agaggaaaac 660aaacccacaa ggcctgtgat tgtgagccca gctaatgaga caatggaagt agacttggga 720tcccagatac aattgatctg taatgtcacc ggccagttga gtgacattgc ttactggaag 780tggaatgggt cagtaattga tgaagatgac ccagtgctag gggaagacta ttacagtgtg 840gaaaatcctg caaacaaaag aaggagtacc ctcatcacag tgcttaatat atcggaaatt 900gagagtagat tttataaaca tccatttacc tgttttgcca agaatacaca tggtatagat 960gcagcatata tccagttaat atatccagtc actaattcag aacgctgcga tgactgggga 1020ctagacacca tgaggcaaat ccaagtgttt gaagatgagc cagctcgcat caagtgccca 1080ctctttgaac acttcttgaa attcaactac agcacagccc attcagctgg ccttactctg 1140atctggtatt ggactaggca ggaccgggac cttgaggagc caattaactt ccgcctcccc 1200gagaaccgca ttagtaagga gaaagatgtg ctgtggttcc ggcccactct cctcaatgac 1260actggcaact atacctgcat gttaaggaac actacatatt gcagcaaagt tgcatttccc 1320ttggaagttg ttcaaaaaga cagctgtttc aattccccca tgaaactccc agtgcataaa 1380ctgtatatag aatatggcat tcagaggatc acttgtccaa atgtagatgg atattttcct 1440tccagtgtca aaccgactat cacttggtat atgggctgtt ataaaataca gaattttaat 1500aatgtaatac ccgaaggtat gaacttgagt ttcctcattg ccttaatttc aaataatgga 1560aattacacat gtgttgttac atatccagaa aatggacgta cgtttcatct caccaggact 1620ctgactgtaa aggtagtagg ctctccaaaa aatgcagtgc cccctgtgat ccattcacct 1680aatgatcatg tggtctatga gaaagaacca ggagaggagc tactcattcc ctgtacggtc 1740tattttagtt ttctgatgga ttctcgcaat gaggtttggt ggaccattga tggaaaaaaa 1800cctgatgaca tcactattga tgtcaccatt aacgaaagta taagtcatag tagaacagaa 1860gatgaaacaa gaactcagat tttgagcatc aagaaagtta cctctgagga tctcaagcgc 1920agctatgtct gtcatgctag aagtgccaaa ggcgaagttg ccaaagcagc caaggtgaag 1980cagaaagtgc cagctccaag atacacagtg gaatccggag agtccaaata cggtccgcca 2040tgcccaccat gcccagcacc tgagttcctg gggggaccat cagtcttcct gttcccccca 2100aaacccaagg acactctcat gatctcccgg acccctgagg tcacgtgcgt ggtggtggac 2160gtgagccagg aagaccccga ggtccagttc aactggtacg tggatggcgt ggaggtgcat 2220aatgccaaga caaagccgcg ggaggagcag ttcaacagca cgtaccgtgt ggtcagcgtc 2280ctcaccgtcc tgcaccagga ctggctgaac ggcaaggagt acaagtgcaa ggtctccaac 2340aaaggcctcc cgtcctccat cgagaaaacc atctccaaag ccaaagggca gccccgagag 2400ccacaggtgt acaccctgcc cccatcccag gaggagatga ccaagaacca ggtcagcctg 2460acctgcctgg tcaaaggctt ctaccccagc gacatcgccg tggagtggga gagcaatggg 2520cagccggaga acaactacaa gaccacgcct cccgtgctgg actccgacgg ctccttcttc 2580ctctacagca ggctaaccgt ggacaagagc aggtggcagg aggggaatgt cttctcatgc 2640tccgtgatgc atgaggctct gcacaaccac tacacacaga agagcctctc cctgtctctg 2700ggtaaatga 27098902PRTHomo sapiens 8Met Val Leu Leu Arg Leu Ile Cys Phe Ile Ala Leu Leu Ile Ser Ser 1 5 10 15Leu Glu Ala Asp Lys Cys Lys Glu Arg Glu Glu Lys Ile Ile Leu Val 20 25 30Ser Ser Ala Asn Glu Ile Asp Val Arg Pro Cys Pro Leu Asn Pro Asn 35 40 45Glu His Lys Gly Thr Ile Thr Trp Tyr Lys Asp Asp Ser Lys Thr Pro 50 55 60Val Ser Thr Glu Gln Ala Ser Arg Ile His Gln His Lys Glu Lys Leu65 70 75 80Trp Phe Val Pro Ala Lys Val Glu Asp Ser Gly His Tyr Tyr Cys Val 85 90 95Val Arg Asn Ser Ser Tyr Cys Leu Arg Ile Lys Ile Ser Ala Lys Phe 100 105 110Val Glu Asn Glu Pro Asn Leu Cys Tyr Asn Ala Gln Ala Ile Phe Lys 115 120 125Gln Lys Leu Pro Val Ala Gly Asp Gly Gly Leu Val Cys Pro Tyr Met 130 135 140Glu Phe Phe Lys Asn Glu Asn Asn Glu Leu Pro Lys Leu Gln Trp Tyr145 150 155 160Lys Asp Cys Lys Pro Leu Leu Leu Asp Asn Ile His Phe Ser Gly Val 165 170 175Lys Asp Arg Leu Ile Val Met Asn Val Ala Glu Lys His Arg Gly Asn 180 185 190Tyr Thr Cys His Ala Ser Tyr Thr Tyr Leu Gly Lys Gln Tyr Pro Ile 195 200 205Thr Arg Val Ile Glu Phe Ile Thr Leu Glu Glu Asn Lys Pro Thr Arg 210 215 220Pro Val Ile Val Ser Pro Ala Asn Glu Thr Met Glu Val Asp Leu Gly225 230 235 240Ser Gln Ile Gln Leu Ile Cys Asn Val Thr Gly Gln Leu Ser Asp Ile 245 250 255Ala Tyr Trp Lys Trp Asn Gly Ser Val Ile Asp Glu Asp Asp Pro Val 260 265 270Leu Gly Glu Asp Tyr Tyr Ser Val Glu Asn Pro Ala

Asn Lys Arg Arg 275 280 285Ser Thr Leu Ile Thr Val Leu Asn Ile Ser Glu Ile Glu Ser Arg Phe 290 295 300Tyr Lys His Pro Phe Thr Cys Phe Ala Lys Asn Thr His Gly Ile Asp305 310 315 320Ala Ala Tyr Ile Gln Leu Ile Tyr Pro Val Thr Asn Ser Glu Arg Cys 325 330 335Asp Asp Trp Gly Leu Asp Thr Met Arg Gln Ile Gln Val Phe Glu Asp 340 345 350Glu Pro Ala Arg Ile Lys Cys Pro Leu Phe Glu His Phe Leu Lys Phe 355 360 365Asn Tyr Ser Thr Ala His Ser Ala Gly Leu Thr Leu Ile Trp Tyr Trp 370 375 380Thr Arg Gln Asp Arg Asp Leu Glu Glu Pro Ile Asn Phe Arg Leu Pro385 390 395 400Glu Asn Arg Ile Ser Lys Glu Lys Asp Val Leu Trp Phe Arg Pro Thr 405 410 415Leu Leu Asn Asp Thr Gly Asn Tyr Thr Cys Met Leu Arg Asn Thr Thr 420 425 430Tyr Cys Ser Lys Val Ala Phe Pro Leu Glu Val Val Gln Lys Asp Ser 435 440 445Cys Phe Asn Ser Pro Met Lys Leu Pro Val His Lys Leu Tyr Ile Glu 450 455 460Tyr Gly Ile Gln Arg Ile Thr Cys Pro Asn Val Asp Gly Tyr Phe Pro465 470 475 480Ser Ser Val Lys Pro Thr Ile Thr Trp Tyr Met Gly Cys Tyr Lys Ile 485 490 495Gln Asn Phe Asn Asn Val Ile Pro Glu Gly Met Asn Leu Ser Phe Leu 500 505 510Ile Ala Leu Ile Ser Asn Asn Gly Asn Tyr Thr Cys Val Val Thr Tyr 515 520 525Pro Glu Asn Gly Arg Thr Phe His Leu Thr Arg Thr Leu Thr Val Lys 530 535 540Val Val Gly Ser Pro Lys Asn Ala Val Pro Pro Val Ile His Ser Pro545 550 555 560Asn Asp His Val Val Tyr Glu Lys Glu Pro Gly Glu Glu Leu Leu Ile 565 570 575Pro Cys Thr Val Tyr Phe Ser Phe Leu Met Asp Ser Arg Asn Glu Val 580 585 590Trp Trp Thr Ile Asp Gly Lys Lys Pro Asp Asp Ile Thr Ile Asp Val 595 600 605Thr Ile Asn Glu Ser Ile Ser His Ser Arg Thr Glu Asp Glu Thr Arg 610 615 620Thr Gln Ile Leu Ser Ile Lys Lys Val Thr Ser Glu Asp Leu Lys Arg625 630 635 640Ser Tyr Val Cys His Ala Arg Ser Ala Lys Gly Glu Val Ala Lys Ala 645 650 655Ala Lys Val Lys Gln Lys Val Pro Ala Pro Arg Tyr Thr Val Glu Ser 660 665 670Gly Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu 675 680 685Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 690 695 700Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp705 710 715 720Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly 725 730 735Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn 740 745 750Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 755 760 765Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro 770 775 780Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu785 790 795 800Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn 805 810 815Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 820 825 830Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 835 840 845Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg 850 855 860Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys865 870 875 880Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 885 890 895Ser Leu Ser Leu Gly Lys 90092703DNAHomo sapiens 9atggtgcttc tgtggtgtgt agtgagtctc tacttttatg gaatcctgca aagtgatgcc 60tcagaacgct gcgatgactg gggactagac accatgaggc aaatccaagt gtttgaagat 120gagccagctc gcatcaagtg cccactcttt gaacacttct tgaaattcaa ctacagcaca 180gcccattcag ctggccttac tctgatctgg tattggacta ggcaggaccg ggaccttgag 240gagccaatta acttccgcct ccccgagaac cgcattagta aggagaaaga tgtgctgtgg 300ttccggccca ctctcctcaa tgacactggc aactatacct gcatgttaag gaacactaca 360tattgcagca aagttgcatt tcccttggaa gttgttcaaa aagacagctg tttcaattcc 420cccatgaaac tcccagtgca taaactgtat atagaatatg gcattcagag gatcacttgt 480ccaaatgtag atggatattt tccttccagt gtcaaaccga ctatcacttg gtatatgggc 540tgttataaaa tacagaattt taataatgta atacccgaag gtatgaactt gagtttcctc 600attgccttaa tttcaaataa tggaaattac acatgtgttg ttacatatcc agaaaatgga 660cgtacgtttc atctcaccag gactctgact gtaaaggtag taggctctcc aaaaaatgca 720gtgccccctg tgatccattc acctaatgat catgtggtct atgagaaaga accaggagag 780gagctactca ttccctgtac ggtctatttt agttttctga tggattctcg caatgaggtt 840tggtggacca ttgatggaaa aaaacctgat gacatcacta ttgatgtcac cattaacgaa 900agtataagtc atagtagaac agaagatgaa acaagaactc agattttgag catcaagaaa 960gttacctctg aggatctcaa gcgcagctat gtctgtcatg ctagaagtgc caaaggcgaa 1020gttgccaaag cagccaaggt gaagcagaaa gtgccagctc caagatacac agtggaaaaa 1080tgcaaggaac gtgaagaaaa aataatttta gtgagctcag caaatgaaat cgatgttcgt 1140ccctgtcctc ttaacccaaa tgaacacaaa ggcactataa cttggtataa ggatgacagc 1200aagacacctg tatctacaga acaagcctcc aggattcatc aacacaaaga gaaactttgg 1260tttgttcctg ctaaggtgga ggattcagga cattactatt gcgtggtaag aaattcatct 1320tactgcctca gaattaaaat aagtgcaaaa tttgtggaga atgagcctaa cttatgttat 1380aatgcacaag ccatatttaa gcagaaacta cccgttgcag gagacggagg acttgtgtgc 1440ccttatatgg agttttttaa aaatgaaaat aatgagttac ctaaattaca gtggtataag 1500gattgcaaac ctctacttct tgacaatata cactttagtg gagtcaaaga taggctcatc 1560gtgatgaatg tggctgaaaa gcatagaggg aactatactt gtcatgcatc ctacacatac 1620ttgggcaagc aatatcctat tacccgggta atagaattta ttactctaga ggaaaacaaa 1680cccacaaggc ctgtgattgt gagcccagct aatgagacaa tggaagtaga cttgggatcc 1740cagatacaat tgatctgtaa tgtcaccggc cagttgagtg acattgctta ctggaagtgg 1800aatgggtcag taattgatga agatgaccca gtgctagggg aagactatta cagtgtggaa 1860aatcctgcaa acaaaagaag gagtaccctc atcacagtgc ttaatatatc ggaaattgag 1920agtagatttt ataaacatcc atttacctgt tttgccaaga atacacatgg tatagatgca 1980gcatatatcc agttaatata tccagtcact aattccggag acaaaactca cacatgccca 2040ccgtgcccag cacctgaact cctgggggga ccgtcagtct tcctcttccc cccaaaaccc 2100aaggacaccc tcatgatctc ccggacccct gaggtcacat gcgtggtggt ggacgtgagc 2160cacgaagacc ctgaggtcaa gttcaactgg tacgtggacg gcgtggaggt gcataatgcc 2220aagacaaagc cgcgggagga gcagtacaac agcacgtacc gtgtggtcag cgtcctcacc 2280gtcctgcacc aggactggct gaatggcaag gagtacaagt gcaaggtctc caacaaagcc 2340ctcccagccc ccatcgagaa aaccatctcc aaagccaaag ggcagccccg agaaccacag 2400gtgtacaccc tgcccccatc ccgggatgag ctgaccaaga accaggtcag cctgacctgc 2460ctggtcaaag gcttctatcc cagcgacatc gccgtggagt gggagagcaa tgggcagccg 2520gagaacaact acaagaccac gcctcccgtg ctggactccg acggctcctt cttcctctac 2580agcaagctca ccgtggacaa gagcaggtgg cagcagggga acgtcttctc atgctccgtg 2640atgcatgagg ctctgcacaa ccactacacg cagaagagcc tctccctgtc tccgggtaaa 2700tga 270310900PRTHomo sapiens 10Met Val Leu Leu Trp Cys Val Val Ser Leu Tyr Phe Tyr Gly Ile Leu 1 5 10 15Gln Ser Asp Ala Ser Glu Arg Cys Asp Asp Trp Gly Leu Asp Thr Met 20 25 30Arg Gln Ile Gln Val Phe Glu Asp Glu Pro Ala Arg Ile Lys Cys Pro 35 40 45Leu Phe Glu His Phe Leu Lys Phe Asn Tyr Ser Thr Ala His Ser Ala 50 55 60Gly Leu Thr Leu Ile Trp Tyr Trp Thr Arg Gln Asp Arg Asp Leu Glu65 70 75 80Glu Pro Ile Asn Phe Arg Leu Pro Glu Asn Arg Ile Ser Lys Glu Lys 85 90 95Asp Val Leu Trp Phe Arg Pro Thr Leu Leu Asn Asp Thr Gly Asn Tyr 100 105 110Thr Cys Met Leu Arg Asn Thr Thr Tyr Cys Ser Lys Val Ala Phe Pro 115 120 125Leu Glu Val Val Gln Lys Asp Ser Cys Phe Asn Ser Pro Met Lys Leu 130 135 140Pro Val His Lys Leu Tyr Ile Glu Tyr Gly Ile Gln Arg Ile Thr Cys145 150 155 160Pro Asn Val Asp Gly Tyr Phe Pro Ser Ser Val Lys Pro Thr Ile Thr 165 170 175Trp Tyr Met Gly Cys Tyr Lys Ile Gln Asn Phe Asn Asn Val Ile Pro 180 185 190Glu Gly Met Asn Leu Ser Phe Leu Ile Ala Leu Ile Ser Asn Asn Gly 195 200 205Asn Tyr Thr Cys Val Val Thr Tyr Pro Glu Asn Gly Arg Thr Phe His 210 215 220Leu Thr Arg Thr Leu Thr Val Lys Val Val Gly Ser Pro Lys Asn Ala225 230 235 240Val Pro Pro Val Ile His Ser Pro Asn Asp His Val Val Tyr Glu Lys 245 250 255Glu Pro Gly Glu Glu Leu Leu Ile Pro Cys Thr Val Tyr Phe Ser Phe 260 265 270Leu Met Asp Ser Arg Asn Glu Val Trp Trp Thr Ile Asp Gly Lys Lys 275 280 285Pro Asp Asp Ile Thr Ile Asp Val Thr Ile Asn Glu Ser Ile Ser His 290 295 300Ser Arg Thr Glu Asp Glu Thr Arg Thr Gln Ile Leu Ser Ile Lys Lys305 310 315 320Val Thr Ser Glu Asp Leu Lys Arg Ser Tyr Val Cys His Ala Arg Ser 325 330 335Ala Lys Gly Glu Val Ala Lys Ala Ala Lys Val Lys Gln Lys Val Pro 340 345 350Ala Pro Arg Tyr Thr Val Glu Lys Cys Lys Glu Arg Glu Glu Lys Ile 355 360 365Ile Leu Val Ser Ser Ala Asn Glu Ile Asp Val Arg Pro Cys Pro Leu 370 375 380Asn Pro Asn Glu His Lys Gly Thr Ile Thr Trp Tyr Lys Asp Asp Ser385 390 395 400Lys Thr Pro Val Ser Thr Glu Gln Ala Ser Arg Ile His Gln His Lys 405 410 415Glu Lys Leu Trp Phe Val Pro Ala Lys Val Glu Asp Ser Gly His Tyr 420 425 430Tyr Cys Val Val Arg Asn Ser Ser Tyr Cys Leu Arg Ile Lys Ile Ser 435 440 445Ala Lys Phe Val Glu Asn Glu Pro Asn Leu Cys Tyr Asn Ala Gln Ala 450 455 460Ile Phe Lys Gln Lys Leu Pro Val Ala Gly Asp Gly Gly Leu Val Cys465 470 475 480Pro Tyr Met Glu Phe Phe Lys Asn Glu Asn Asn Glu Leu Pro Lys Leu 485 490 495Gln Trp Tyr Lys Asp Cys Lys Pro Leu Leu Leu Asp Asn Ile His Phe 500 505 510Ser Gly Val Lys Asp Arg Leu Ile Val Met Asn Val Ala Glu Lys His 515 520 525Arg Gly Asn Tyr Thr Cys His Ala Ser Tyr Thr Tyr Leu Gly Lys Gln 530 535 540Tyr Pro Ile Thr Arg Val Ile Glu Phe Ile Thr Leu Glu Glu Asn Lys545 550 555 560Pro Thr Arg Pro Val Ile Val Ser Pro Ala Asn Glu Thr Met Glu Val 565 570 575Asp Leu Gly Ser Gln Ile Gln Leu Ile Cys Asn Val Thr Gly Gln Leu 580 585 590Ser Asp Ile Ala Tyr Trp Lys Trp Asn Gly Ser Val Ile Asp Glu Asp 595 600 605Asp Pro Val Leu Gly Glu Asp Tyr Tyr Ser Val Glu Asn Pro Ala Asn 610 615 620Lys Arg Arg Ser Thr Leu Ile Thr Val Leu Asn Ile Ser Glu Ile Glu625 630 635 640Ser Arg Phe Tyr Lys His Pro Phe Thr Cys Phe Ala Lys Asn Thr His 645 650 655Gly Ile Asp Ala Ala Tyr Ile Gln Leu Ile Tyr Pro Val Thr Asn Ser 660 665 670Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 675 680 685Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 690 695 700Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser705 710 715 720His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 725 730 735Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 740 745 750Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 755 760 765Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro 770 775 780Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln785 790 795 800Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val 805 810 815Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 820 825 830Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 835 840 845Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr 850 855 860Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val865 870 875 880Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 885 890 895Ser Pro Gly Lys 900112709DNAHomo sapiens 11atggtgcttc tgtggtgtgt agtgagtctc tacttttatg gaatcctgca aagtgatgcc 60tcagaacgct gcgatgactg gggactagac accatgaggc aaatccaagt gtttgaagat 120gagccagctc gcatcaagtg cccactcttt gaacacttct tgaaattcaa ctacagcaca 180gcccattcag ctggccttac tctgatctgg tattggacta ggcaggaccg ggaccttgag 240gagccaatta acttccgcct ccccgagaac cgcattagta aggagaaaga tgtgctgtgg 300ttccggccca ctctcctcaa tgacactggc aactatacct gcatgttaag gaacactaca 360tattgcagca aagttgcatt tcccttggaa gttgttcaaa aagacagctg tttcaattcc 420cccatgaaac tcccagtgca taaactgtat atagaatatg gcattcagag gatcacttgt 480ccaaatgtag atggatattt tccttccagt gtcaaaccga ctatcacttg gtatatgggc 540tgttataaaa tacagaattt taataatgta atacccgaag gtatgaactt gagtttcctc 600attgccttaa tttcaaataa tggaaattac acatgtgttg ttacatatcc agaaaatgga 660cgtacgtttc atctcaccag gactctgact gtaaaggtag taggctctcc aaaaaatgca 720gtgccccctg tgatccattc acctaatgat catgtggtct atgagaaaga accaggagag 780gagctactca ttccctgtac ggtctatttt agttttctga tggattctcg caatgaggtt 840tggtggacca ttgatggaaa aaaacctgat gacatcacta ttgatgtcac cattaacgaa 900agtataagtc atagtagaac agaagatgaa acaagaactc agattttgag catcaagaaa 960gttacctctg aggatctcaa gcgcagctat gtctgtcatg ctagaagtgc caaaggcgaa 1020gttgccaaag cagccaaggt gaagcagaaa gtgccagctc caagatacac agtggaaaaa 1080tgcaaggaac gtgaagaaaa aataatttta gtgagctcag caaatgaaat cgatgttcgt 1140ccctgtcctc ttaacccaaa tgaacacaaa ggcactataa cttggtataa ggatgacagc 1200aagacacctg tatctacaga acaagcctcc aggattcatc aacacaaaga gaaactttgg 1260tttgttcctg ctaaggtgga ggattcagga cattactatt gcgtggtaag aaattcatct 1320tactgcctca gaattaaaat aagtgcaaaa tttgtggaga atgagcctaa cttatgttat 1380aatgcacaag ccatatttaa gcagaaacta cccgttgcag gagacggagg acttgtgtgc 1440ccttatatgg agttttttaa aaatgaaaat aatgagttac ctaaattaca gtggtataag 1500gattgcaaac ctctacttct tgacaatata cactttagtg gagtcaaaga taggctcatc 1560gtgatgaatg tggctgaaaa gcatagaggg aactatactt gtcatgcatc ctacacatac 1620ttgggcaagc aatatcctat tacccgggta atagaattta ttactctaga ggaaaacaaa 1680cccacaaggc ctgtgattgt gagcccagct aatgagacaa tggaagtaga cttgggatcc 1740cagatacaat tgatctgtaa tgtcaccggc cagttgagtg acattgctta ctggaagtgg 1800aatgggtcag taattgatga agatgaccca gtgctagggg aagactatta cagtgtggaa 1860aatcctgcaa acaaaagaag gagtaccctc atcacagtgc ttaatatatc ggaaattgag 1920agtagatttt ataaacatcc atttacctgt tttgccaaga atacacatgg tatagatgca 1980gcatatatcc agttaatata tccagtcact aattccggag agtccaaata cggtccgcca 2040tgcccatcat gcccagcacc tgagttcctg gggggaccat cagtcttcct gttcccccca 2100aaacccaagg acactctcat gatctcccgg acccctgagg tcacgtgcgt ggtggtggac 2160gtgagccagg aagaccccga ggtccagttc aactggtacg tggatggcgt ggaggtgcat 2220aatgccaaga caaagccgcg ggaggagcag ttcaacagca cgtaccgtgt ggtcagcgtc 2280ctcaccgtcc tgcaccagga ctggctgaac ggcaaggagt acaagtgcaa ggtctccaac 2340aaaggcctcc cgtcctccat cgagaaaacc atctccaaag ccaaagggca gccccgagag 2400ccacaggtgt acaccctgcc cccatcccag gaggagatga ccaagaacca ggtcagcctg 2460acctgcctgg tcaaaggctt ctaccccagc gacatcgccg tggagtggga gagcaatggg 2520cagccggaga acaactacaa gaccacgcct cccgtgctgg actccgacgg ctccttcttc 2580ctctacagca ggctaaccgt ggacaagagc aggtggcagg aggggaatgt cttctcatgc 2640tccgtgatgc atgaggctct gcacaaccac tacacacaga agagcctctc cctgtctctg 2700ggtaaatga 270912902PRTHomo sapiens 12Met Val Leu Leu Trp Cys Val Val Ser Leu Tyr Phe Tyr Gly Ile Leu 1 5 10 15Gln Ser Asp Ala Ser Glu Arg Cys Asp Asp Trp Gly Leu Asp Thr Met 20 25

30Arg Gln Ile Gln Val Phe Glu Asp Glu Pro Ala Arg Ile Lys Cys Pro 35 40 45Leu Phe Glu His Phe Leu Lys Phe Asn Tyr Ser Thr Ala His Ser Ala 50 55 60Gly Leu Thr Leu Ile Trp Tyr Trp Thr Arg Gln Asp Arg Asp Leu Glu65 70 75 80Glu Pro Ile Asn Phe Arg Leu Pro Glu Asn Arg Ile Ser Lys Glu Lys 85 90 95Asp Val Leu Trp Phe Arg Pro Thr Leu Leu Asn Asp Thr Gly Asn Tyr 100 105 110Thr Cys Met Leu Arg Asn Thr Thr Tyr Cys Ser Lys Val Ala Phe Pro 115 120 125Leu Glu Val Val Gln Lys Asp Ser Cys Phe Asn Ser Pro Met Lys Leu 130 135 140Pro Val His Lys Leu Tyr Ile Glu Tyr Gly Ile Gln Arg Ile Thr Cys145 150 155 160Pro Asn Val Asp Gly Tyr Phe Pro Ser Ser Val Lys Pro Thr Ile Thr 165 170 175Trp Tyr Met Gly Cys Tyr Lys Ile Gln Asn Phe Asn Asn Val Ile Pro 180 185 190Glu Gly Met Asn Leu Ser Phe Leu Ile Ala Leu Ile Ser Asn Asn Gly 195 200 205Asn Tyr Thr Cys Val Val Thr Tyr Pro Glu Asn Gly Arg Thr Phe His 210 215 220Leu Thr Arg Thr Leu Thr Val Lys Val Val Gly Ser Pro Lys Asn Ala225 230 235 240Val Pro Pro Val Ile His Ser Pro Asn Asp His Val Val Tyr Glu Lys 245 250 255Glu Pro Gly Glu Glu Leu Leu Ile Pro Cys Thr Val Tyr Phe Ser Phe 260 265 270Leu Met Asp Ser Arg Asn Glu Val Trp Trp Thr Ile Asp Gly Lys Lys 275 280 285Pro Asp Asp Ile Thr Ile Asp Val Thr Ile Asn Glu Ser Ile Ser His 290 295 300Ser Arg Thr Glu Asp Glu Thr Arg Thr Gln Ile Leu Ser Ile Lys Lys305 310 315 320Val Thr Ser Glu Asp Leu Lys Arg Ser Tyr Val Cys His Ala Arg Ser 325 330 335Ala Lys Gly Glu Val Ala Lys Ala Ala Lys Val Lys Gln Lys Val Pro 340 345 350Ala Pro Arg Tyr Thr Val Glu Lys Cys Lys Glu Arg Glu Glu Lys Ile 355 360 365Ile Leu Val Ser Ser Ala Asn Glu Ile Asp Val Arg Pro Cys Pro Leu 370 375 380Asn Pro Asn Glu His Lys Gly Thr Ile Thr Trp Tyr Lys Asp Asp Ser385 390 395 400Lys Thr Pro Val Ser Thr Glu Gln Ala Ser Arg Ile His Gln His Lys 405 410 415Glu Lys Leu Trp Phe Val Pro Ala Lys Val Glu Asp Ser Gly His Tyr 420 425 430Tyr Cys Val Val Arg Asn Ser Ser Tyr Cys Leu Arg Ile Lys Ile Ser 435 440 445Ala Lys Phe Val Glu Asn Glu Pro Asn Leu Cys Tyr Asn Ala Gln Ala 450 455 460Ile Phe Lys Gln Lys Leu Pro Val Ala Gly Asp Gly Gly Leu Val Cys465 470 475 480Pro Tyr Met Glu Phe Phe Lys Asn Glu Asn Asn Glu Leu Pro Lys Leu 485 490 495Gln Trp Tyr Lys Asp Cys Lys Pro Leu Leu Leu Asp Asn Ile His Phe 500 505 510Ser Gly Val Lys Asp Arg Leu Ile Val Met Asn Val Ala Glu Lys His 515 520 525Arg Gly Asn Tyr Thr Cys His Ala Ser Tyr Thr Tyr Leu Gly Lys Gln 530 535 540Tyr Pro Ile Thr Arg Val Ile Glu Phe Ile Thr Leu Glu Glu Asn Lys545 550 555 560Pro Thr Arg Pro Val Ile Val Ser Pro Ala Asn Glu Thr Met Glu Val 565 570 575Asp Leu Gly Ser Gln Ile Gln Leu Ile Cys Asn Val Thr Gly Gln Leu 580 585 590Ser Asp Ile Ala Tyr Trp Lys Trp Asn Gly Ser Val Ile Asp Glu Asp 595 600 605Asp Pro Val Leu Gly Glu Asp Tyr Tyr Ser Val Glu Asn Pro Ala Asn 610 615 620Lys Arg Arg Ser Thr Leu Ile Thr Val Leu Asn Ile Ser Glu Ile Glu625 630 635 640Ser Arg Phe Tyr Lys His Pro Phe Thr Cys Phe Ala Lys Asn Thr His 645 650 655Gly Ile Asp Ala Ala Tyr Ile Gln Leu Ile Tyr Pro Val Thr Asn Ser 660 665 670Gly Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro Ala Pro Glu 675 680 685Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 690 695 700Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp705 710 715 720Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly 725 730 735Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn 740 745 750Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 755 760 765Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro 770 775 780Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu785 790 795 800Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn 805 810 815Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 820 825 830Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 835 840 845Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg 850 855 860Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys865 870 875 880Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 885 890 895Ser Leu Ser Leu Gly Lys 900132709DNAHomo sapiens 13atggtgcttc tgtggtgtgt agtgagtctc tacttttatg gaatcctgca aagtgatgcc 60tcagaacgct gcgatgactg gggactagac accatgaggc aaatccaagt gtttgaagat 120gagccagctc gcatcaagtg cccactcttt gaacacttct tgaaattcaa ctacagcaca 180gcccattcag ctggccttac tctgatctgg tattggacta ggcaggaccg ggaccttgag 240gagccaatta acttccgcct ccccgagaac cgcattagta aggagaaaga tgtgctgtgg 300ttccggccca ctctcctcaa tgacactggc aactatacct gcatgttaag gaacactaca 360tattgcagca aagttgcatt tcccttggaa gttgttcaaa aagacagctg tttcaattcc 420cccatgaaac tcccagtgca taaactgtat atagaatatg gcattcagag gatcacttgt 480ccaaatgtag atggatattt tccttccagt gtcaaaccga ctatcacttg gtatatgggc 540tgttataaaa tacagaattt taataatgta atacccgaag gtatgaactt gagtttcctc 600attgccttaa tttcaaataa tggaaattac acatgtgttg ttacatatcc agaaaatgga 660cgtacgtttc atctcaccag gactctgact gtaaaggtag taggctctcc aaaaaatgca 720gtgccccctg tgatccattc acctaatgat catgtggtct atgagaaaga accaggagag 780gagctactca ttccctgtac ggtctatttt agttttctga tggattctcg caatgaggtt 840tggtggacca ttgatggaaa aaaacctgat gacatcacta ttgatgtcac cattaacgaa 900agtataagtc atagtagaac agaagatgaa acaagaactc agattttgag catcaagaaa 960gttacctctg aggatctcaa gcgcagctat gtctgtcatg ctagaagtgc caaaggcgaa 1020gttgccaaag cagccaaggt gaagcagaaa gtgccagctc caagatacac agtggaaaaa 1080tgcaaggaac gtgaagaaaa aataatttta gtgagctcag caaatgaaat cgatgttcgt 1140ccctgtcctc ttaacccaaa tgaacacaaa ggcactataa cttggtataa ggatgacagc 1200aagacacctg tatctacaga acaagcctcc aggattcatc aacacaaaga gaaactttgg 1260tttgttcctg ctaaggtgga ggattcagga cattactatt gcgtggtaag aaattcatct 1320tactgcctca gaattaaaat aagtgcaaaa tttgtggaga atgagcctaa cttatgttat 1380aatgcacaag ccatatttaa gcagaaacta cccgttgcag gagacggagg acttgtgtgc 1440ccttatatgg agttttttaa aaatgaaaat aatgagttac ctaaattaca gtggtataag 1500gattgcaaac ctctacttct tgacaatata cactttagtg gagtcaaaga taggctcatc 1560gtgatgaatg tggctgaaaa gcatagaggg aactatactt gtcatgcatc ctacacatac 1620ttgggcaagc aatatcctat tacccgggta atagaattta ttactctaga ggaaaacaaa 1680cccacaaggc ctgtgattgt gagcccagct aatgagacaa tggaagtaga cttgggatcc 1740cagatacaat tgatctgtaa tgtcaccggc cagttgagtg acattgctta ctggaagtgg 1800aatgggtcag taattgatga agatgaccca gtgctagggg aagactatta cagtgtggaa 1860aatcctgcaa acaaaagaag gagtaccctc atcacagtgc ttaatatatc ggaaattgag 1920agtagatttt ataaacatcc atttacctgt tttgccaaga atacacatgg tatagatgca 1980gcatatatcc agttaatata tccagtcact aattccggag agtccaaata cggtccgcca 2040tgcccaccat gcccagcacc tgagttcctg gggggaccat cagtcttcct gttcccccca 2100aaacccaagg acactctcat gatctcccgg acccctgagg tcacgtgcgt ggtggtggac 2160gtgagccagg aagaccccga ggtccagttc aactggtacg tggatggcgt ggaggtgcat 2220aatgccaaga caaagccgcg ggaggagcag ttcaacagca cgtaccgtgt ggtcagcgtc 2280ctcaccgtcc tgcaccagga ctggctgaac ggcaaggagt acaagtgcaa ggtctccaac 2340aaaggcctcc cgtcctccat cgagaaaacc atctccaaag ccaaagggca gccccgagag 2400ccacaggtgt acaccctgcc cccatcccag gaggagatga ccaagaacca ggtcagcctg 2460acctgcctgg tcaaaggctt ctaccccagc gacatcgccg tggagtggga gagcaatggg 2520cagccggaga acaactacaa gaccacgcct cccgtgctgg actccgacgg ctccttcttc 2580ctctacagca ggctaaccgt ggacaagagc aggtggcagg aggggaatgt cttctcatgc 2640tccgtgatgc atgaggctct gcacaaccac tacacacaga agagcctctc cctgtctctg 2700ggtaaatga 270914902PRTHomo sapiens 14Met Val Leu Leu Trp Cys Val Val Ser Leu Tyr Phe Tyr Gly Ile Leu 1 5 10 15Gln Ser Asp Ala Ser Glu Arg Cys Asp Asp Trp Gly Leu Asp Thr Met 20 25 30Arg Gln Ile Gln Val Phe Glu Asp Glu Pro Ala Arg Ile Lys Cys Pro 35 40 45Leu Phe Glu His Phe Leu Lys Phe Asn Tyr Ser Thr Ala His Ser Ala 50 55 60Gly Leu Thr Leu Ile Trp Tyr Trp Thr Arg Gln Asp Arg Asp Leu Glu65 70 75 80Glu Pro Ile Asn Phe Arg Leu Pro Glu Asn Arg Ile Ser Lys Glu Lys 85 90 95Asp Val Leu Trp Phe Arg Pro Thr Leu Leu Asn Asp Thr Gly Asn Tyr 100 105 110Thr Cys Met Leu Arg Asn Thr Thr Tyr Cys Ser Lys Val Ala Phe Pro 115 120 125Leu Glu Val Val Gln Lys Asp Ser Cys Phe Asn Ser Pro Met Lys Leu 130 135 140Pro Val His Lys Leu Tyr Ile Glu Tyr Gly Ile Gln Arg Ile Thr Cys145 150 155 160Pro Asn Val Asp Gly Tyr Phe Pro Ser Ser Val Lys Pro Thr Ile Thr 165 170 175Trp Tyr Met Gly Cys Tyr Lys Ile Gln Asn Phe Asn Asn Val Ile Pro 180 185 190Glu Gly Met Asn Leu Ser Phe Leu Ile Ala Leu Ile Ser Asn Asn Gly 195 200 205Asn Tyr Thr Cys Val Val Thr Tyr Pro Glu Asn Gly Arg Thr Phe His 210 215 220Leu Thr Arg Thr Leu Thr Val Lys Val Val Gly Ser Pro Lys Asn Ala225 230 235 240Val Pro Pro Val Ile His Ser Pro Asn Asp His Val Val Tyr Glu Lys 245 250 255Glu Pro Gly Glu Glu Leu Leu Ile Pro Cys Thr Val Tyr Phe Ser Phe 260 265 270Leu Met Asp Ser Arg Asn Glu Val Trp Trp Thr Ile Asp Gly Lys Lys 275 280 285Pro Asp Asp Ile Thr Ile Asp Val Thr Ile Asn Glu Ser Ile Ser His 290 295 300Ser Arg Thr Glu Asp Glu Thr Arg Thr Gln Ile Leu Ser Ile Lys Lys305 310 315 320Val Thr Ser Glu Asp Leu Lys Arg Ser Tyr Val Cys His Ala Arg Ser 325 330 335Ala Lys Gly Glu Val Ala Lys Ala Ala Lys Val Lys Gln Lys Val Pro 340 345 350Ala Pro Arg Tyr Thr Val Glu Lys Cys Lys Glu Arg Glu Glu Lys Ile 355 360 365Ile Leu Val Ser Ser Ala Asn Glu Ile Asp Val Arg Pro Cys Pro Leu 370 375 380Asn Pro Asn Glu His Lys Gly Thr Ile Thr Trp Tyr Lys Asp Asp Ser385 390 395 400Lys Thr Pro Val Ser Thr Glu Gln Ala Ser Arg Ile His Gln His Lys 405 410 415Glu Lys Leu Trp Phe Val Pro Ala Lys Val Glu Asp Ser Gly His Tyr 420 425 430Tyr Cys Val Val Arg Asn Ser Ser Tyr Cys Leu Arg Ile Lys Ile Ser 435 440 445Ala Lys Phe Val Glu Asn Glu Pro Asn Leu Cys Tyr Asn Ala Gln Ala 450 455 460Ile Phe Lys Gln Lys Leu Pro Val Ala Gly Asp Gly Gly Leu Val Cys465 470 475 480Pro Tyr Met Glu Phe Phe Lys Asn Glu Asn Asn Glu Leu Pro Lys Leu 485 490 495Gln Trp Tyr Lys Asp Cys Lys Pro Leu Leu Leu Asp Asn Ile His Phe 500 505 510Ser Gly Val Lys Asp Arg Leu Ile Val Met Asn Val Ala Glu Lys His 515 520 525Arg Gly Asn Tyr Thr Cys His Ala Ser Tyr Thr Tyr Leu Gly Lys Gln 530 535 540Tyr Pro Ile Thr Arg Val Ile Glu Phe Ile Thr Leu Glu Glu Asn Lys545 550 555 560Pro Thr Arg Pro Val Ile Val Ser Pro Ala Asn Glu Thr Met Glu Val 565 570 575Asp Leu Gly Ser Gln Ile Gln Leu Ile Cys Asn Val Thr Gly Gln Leu 580 585 590Ser Asp Ile Ala Tyr Trp Lys Trp Asn Gly Ser Val Ile Asp Glu Asp 595 600 605Asp Pro Val Leu Gly Glu Asp Tyr Tyr Ser Val Glu Asn Pro Ala Asn 610 615 620Lys Arg Arg Ser Thr Leu Ile Thr Val Leu Asn Ile Ser Glu Ile Glu625 630 635 640Ser Arg Phe Tyr Lys His Pro Phe Thr Cys Phe Ala Lys Asn Thr His 645 650 655Gly Ile Asp Ala Ala Tyr Ile Gln Leu Ile Tyr Pro Val Thr Asn Ser 660 665 670Gly Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu 675 680 685Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 690 695 700Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp705 710 715 720Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly 725 730 735Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn 740 745 750Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 755 760 765Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro 770 775 780Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu785 790 795 800Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn 805 810 815Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 820 825 830Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 835 840 845Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg 850 855 860Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys865 870 875 880Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 885 890 895Ser Leu Ser Leu Gly Lys 900152748DNAHomo sapiens 15atggtgcgct tgtacgtgtt ggtaatggga gtttctgcct tcacccttca gcctgcggca 60cacacagggg ctgccagaag ctgccggttt cgtgggaggc attacaagcg ggagttcagg 120ctggaagggg agcctgtagc cctgaggtgc ccccaggtgc cctactggtt gtgggcctct 180gtcagccccc gcatcaacct gacatggcat aaaaatgact ctgctaggac ggtcccagga 240gaagaagaga cacggatgtg ggcccaggac ggtgctctgt ggcttctgcc agccttgcag 300gaggactctg gcacctacgt ctgcactact agaaatgctt cttactgtga caaaatgtcc 360attgagctca gagtttttga gaatacagat gctttcctgc cgttcatctc atacccgcaa 420attttaacct tgtcaacctc tggggtatta gtatgccctg acctgagtga attcacccgt 480gacaaaactg acgtgaagat tcaatggtac aaggattctc ttcttttgga taaagacaat 540gagaaatttc taagtgtgag ggggaccact cacttactcg tacacgatgt ggccctggaa 600gatgctggct attaccgctg tgtcctgaca tttgcccatg aaggccagca atacaacatc 660actaggagta ttgagctacg catcaagaaa aaaaaagaag agaccattcc tgtgatcatt 720tcccccctca agaccatatc agcttctctg gggtcaagac tgacaatccc atgtaaggtg 780tttctgggaa ccggcacacc cttaaccacc atgctgtggt ggacggccaa tgacacccac 840atagagagcg cctacccggg aggccgcgtg accgaggggc cacgccagga atattcagaa 900aataatgaga actacattga agtgccattg atttttgatc ctgtcacaag agaggatttg 960cacatggatt ttaaatgtgt tgtccataat accctgagtt ttcagacact acgcaccaca 1020gtcaaggaag cctcctccac gttctcagaa cgctgcgatg actggggact agacaccatg 1080aggcaaatcc aagtgtttga agatgagcca gctcgcatca agtgcccact ctttgaacac 1140ttcttgaaat tcaactacag cacagcccat tcagctggcc ttactctgat ctggtattgg 1200actaggcagg accgggacct tgaggagcca attaacttcc gcctccccga gaaccgcatt 1260agtaaggaga aagatgtgct gtggttccgg cccactctcc tcaatgacac tggcaactat 1320acctgcatgt taaggaacac tacatattgc agcaaagttg catttccctt ggaagttgtt 1380caaaaagaca gctgtttcaa ttcccccatg aaactcccag tgcataaact gtatatagaa 1440tatggcattc agaggatcac

ttgtccaaat gtagatggat attttccttc cagtgtcaaa 1500ccgactatca cttggtatat gggctgttat aaaatacaga attttaataa tgtaataccc 1560gaaggtatga acttgagttt cctcattgcc ttaatttcaa ataatggaaa ttacacatgt 1620gttgttacat atccagaaaa tggacgtacg tttcatctca ccaggactct gactgtaaag 1680gtagtaggct ctccaaaaaa tgcagtgccc cctgtgatcc attcacctaa tgatcatgtg 1740gtctatgaga aagaaccagg agaggagcta ctcattccct gtacggtcta ttttagtttt 1800ctgatggatt ctcgcaatga ggtttggtgg accattgatg gaaaaaaacc tgatgacatc 1860actattgatg tcaccattaa cgaaagtata agtcatagta gaacagaaga tgaaacaaga 1920actcagattt tgagcatcaa gaaagttacc tctgaggatc tcaagcgcag ctatgtctgt 1980catgctagaa gtgccaaagg cgaagttgcc aaagcagcca aggtgaagca gaaagtgcca 2040gctccaagat acacagtgtc cggagacaaa actcacacat gcccaccgtg cccagcacct 2100gaactcctgg ggggaccgtc agtcttcctc ttccccccaa aacccaagga caccctcatg 2160atctcccgga cccctgaggt cacatgcgtg gtggtggacg tgagccacga agaccctgag 2220gtcaagttca actggtacgt ggacggcgtg gaggtgcata atgccaagac aaagccgcgg 2280gaggagcagt acaacagcac gtaccgtgtg gtcagcgtcc tcaccgtcct gcaccaggac 2340tggctgaatg gcaaggagta caagtgcaag gtctccaaca aagccctccc agcccccatc 2400gagaaaacca tctccaaagc caaagggcag ccccgagaac cacaggtgta caccctgccc 2460ccatcccggg atgagctgac caagaaccag gtcagcctga cctgcctggt caaaggcttc 2520tatcccagcg acatcgccgt ggagtgggag agcaatgggc agccggagaa caactacaag 2580accacgcctc ccgtgctgga ctccgacggc tccttcttcc tctatagcaa gctcaccgtg 2640gacaagagca ggtggcagca ggggaacgtc ttctcatgct ccgtgatgca tgaggctctg 2700cacaaccact acacgcagaa gagcctctcc ctgtctccgg gtaaatga 274816915PRTHomo sapiens 16Met Val Arg Leu Tyr Val Leu Val Met Gly Val Ser Ala Phe Thr Leu 1 5 10 15Gln Pro Ala Ala His Thr Gly Ala Ala Arg Ser Cys Arg Phe Arg Gly 20 25 30Arg His Tyr Lys Arg Glu Phe Arg Leu Glu Gly Glu Pro Val Ala Leu 35 40 45Arg Cys Pro Gln Val Pro Tyr Trp Leu Trp Ala Ser Val Ser Pro Arg 50 55 60Ile Asn Leu Thr Trp His Lys Asn Asp Ser Ala Arg Thr Val Pro Gly65 70 75 80Glu Glu Glu Thr Arg Met Trp Ala Gln Asp Gly Ala Leu Trp Leu Leu 85 90 95Pro Ala Leu Gln Glu Asp Ser Gly Thr Tyr Val Cys Thr Thr Arg Asn 100 105 110Ala Ser Tyr Cys Asp Lys Met Ser Ile Glu Leu Arg Val Phe Glu Asn 115 120 125Thr Asp Ala Phe Leu Pro Phe Ile Ser Tyr Pro Gln Ile Leu Thr Leu 130 135 140Ser Thr Ser Gly Val Leu Val Cys Pro Asp Leu Ser Glu Phe Thr Arg145 150 155 160Asp Lys Thr Asp Val Lys Ile Gln Trp Tyr Lys Asp Ser Leu Leu Leu 165 170 175Asp Lys Asp Asn Glu Lys Phe Leu Ser Val Arg Gly Thr Thr His Leu 180 185 190Leu Val His Asp Val Ala Leu Glu Asp Ala Gly Tyr Tyr Arg Cys Val 195 200 205Leu Thr Phe Ala His Glu Gly Gln Gln Tyr Asn Ile Thr Arg Ser Ile 210 215 220Glu Leu Arg Ile Lys Lys Lys Lys Glu Glu Thr Ile Pro Val Ile Ile225 230 235 240Ser Pro Leu Lys Thr Ile Ser Ala Ser Leu Gly Ser Arg Leu Thr Ile 245 250 255Pro Cys Lys Val Phe Leu Gly Thr Gly Thr Pro Leu Thr Thr Met Leu 260 265 270Trp Trp Thr Ala Asn Asp Thr His Ile Glu Ser Ala Tyr Pro Gly Gly 275 280 285Arg Val Thr Glu Gly Pro Arg Gln Glu Tyr Ser Glu Asn Asn Glu Asn 290 295 300Tyr Ile Glu Val Pro Leu Ile Phe Asp Pro Val Thr Arg Glu Asp Leu305 310 315 320His Met Asp Phe Lys Cys Val Val His Asn Thr Leu Ser Phe Gln Thr 325 330 335Leu Arg Thr Thr Val Lys Glu Ala Ser Ser Thr Phe Ser Glu Arg Cys 340 345 350Asp Asp Trp Gly Leu Asp Thr Met Arg Gln Ile Gln Val Phe Glu Asp 355 360 365Glu Pro Ala Arg Ile Lys Cys Pro Leu Phe Glu His Phe Leu Lys Phe 370 375 380Asn Tyr Ser Thr Ala His Ser Ala Gly Leu Thr Leu Ile Trp Tyr Trp385 390 395 400Thr Arg Gln Asp Arg Asp Leu Glu Glu Pro Ile Asn Phe Arg Leu Pro 405 410 415Glu Asn Arg Ile Ser Lys Glu Lys Asp Val Leu Trp Phe Arg Pro Thr 420 425 430Leu Leu Asn Asp Thr Gly Asn Tyr Thr Cys Met Leu Arg Asn Thr Thr 435 440 445Tyr Cys Ser Lys Val Ala Phe Pro Leu Glu Val Val Gln Lys Asp Ser 450 455 460Cys Phe Asn Ser Pro Met Lys Leu Pro Val His Lys Leu Tyr Ile Glu465 470 475 480Tyr Gly Ile Gln Arg Ile Thr Cys Pro Asn Val Asp Gly Tyr Phe Pro 485 490 495Ser Ser Val Lys Pro Thr Ile Thr Trp Tyr Met Gly Cys Tyr Lys Ile 500 505 510Gln Asn Phe Asn Asn Val Ile Pro Glu Gly Met Asn Leu Ser Phe Leu 515 520 525Ile Ala Leu Ile Ser Asn Asn Gly Asn Tyr Thr Cys Val Val Thr Tyr 530 535 540Pro Glu Asn Gly Arg Thr Phe His Leu Thr Arg Thr Leu Thr Val Lys545 550 555 560Val Val Gly Ser Pro Lys Asn Ala Val Pro Pro Val Ile His Ser Pro 565 570 575Asn Asp His Val Val Tyr Glu Lys Glu Pro Gly Glu Glu Leu Leu Ile 580 585 590Pro Cys Thr Val Tyr Phe Ser Phe Leu Met Asp Ser Arg Asn Glu Val 595 600 605Trp Trp Thr Ile Asp Gly Lys Lys Pro Asp Asp Ile Thr Ile Asp Val 610 615 620Thr Ile Asn Glu Ser Ile Ser His Ser Arg Thr Glu Asp Glu Thr Arg625 630 635 640Thr Gln Ile Leu Ser Ile Lys Lys Val Thr Ser Glu Asp Leu Lys Arg 645 650 655Ser Tyr Val Cys His Ala Arg Ser Ala Lys Gly Glu Val Ala Lys Ala 660 665 670Ala Lys Val Lys Gln Lys Val Pro Ala Pro Arg Tyr Thr Val Ser Gly 675 680 685Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 690 695 700Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met705 710 715 720Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 725 730 735Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 740 745 750His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 755 760 765Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 770 775 780Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile785 790 795 800Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 805 810 815Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 820 825 830Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 835 840 845Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 850 855 860Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val865 870 875 880Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 885 890 895His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 900 905 910Pro Gly Lys 915172754DNAHomo sapiens 17atggtgcgct tgtacgtgtt ggtaatggga gtttctgcct tcacccttca gcctgcggca 60cacacagggg ctgccagaag ctgccggttt cgtgggaggc attacaagcg ggagttcagg 120ctggaagggg agcctgtagc cctgaggtgc ccccaggtgc cctactggtt gtgggcctct 180gtcagccccc gcatcaacct gacatggcat aaaaatgact ctgctaggac ggtcccagga 240gaagaagaga cacggatgtg ggcccaggac ggtgctctgt ggcttctgcc agccttgcag 300gaggactctg gcacctacgt ctgcactact agaaatgctt cttactgtga caaaatgtcc 360attgagctca gagtttttga gaatacagat gctttcctgc cgttcatctc atacccgcaa 420attttaacct tgtcaacctc tggggtatta gtatgccctg acctgagtga attcacccgt 480gacaaaactg acgtgaagat tcaatggtac aaggattctc ttcttttgga taaagacaat 540gagaaatttc taagtgtgag ggggaccact cacttactcg tacacgatgt ggccctggaa 600gatgctggct attaccgctg tgtcctgaca tttgcccatg aaggccagca atacaacatc 660actaggagta ttgagctacg catcaagaaa aaaaaagaag agaccattcc tgtgatcatt 720tcccccctca agaccatatc agcttctctg gggtcaagac tgacaatccc atgtaaggtg 780tttctgggaa ccggcacacc cttaaccacc atgctgtggt ggacggccaa tgacacccac 840atagagagcg cctacccggg aggccgcgtg accgaggggc cacgccagga atattcagaa 900aataatgaga actacattga agtgccattg atttttgatc ctgtcacaag agaggatttg 960cacatggatt ttaaatgtgt tgtccataat accctgagtt ttcagacact acgcaccaca 1020gtcaaggaag cctcctccac gttctcagaa cgctgcgatg actggggact agacaccatg 1080aggcaaatcc aagtgtttga agatgagcca gctcgcatca agtgcccact ctttgaacac 1140ttcttgaaat tcaactacag cacagcccat tcagctggcc ttactctgat ctggtattgg 1200actaggcagg accgggacct tgaggagcca attaacttcc gcctccccga gaaccgcatt 1260agtaaggaga aagatgtgct gtggttccgg cccactctcc tcaatgacac tggcaactat 1320acctgcatgt taaggaacac tacatattgc agcaaagttg catttccctt ggaagttgtt 1380caaaaagaca gctgtttcaa ttcccccatg aaactcccag tgcataaact gtatatagaa 1440tatggcattc agaggatcac ttgtccaaat gtagatggat attttccttc cagtgtcaaa 1500ccgactatca cttggtatat gggctgttat aaaatacaga attttaataa tgtaataccc 1560gaaggtatga acttgagttt cctcattgcc ttaatttcaa ataatggaaa ttacacatgt 1620gttgttacat atccagaaaa tggacgtacg tttcatctca ccaggactct gactgtaaag 1680gtagtaggct ctccaaaaaa tgcagtgccc cctgtgatcc attcacctaa tgatcatgtg 1740gtctatgaga aagaaccagg agaggagcta ctcattccct gtacggtcta ttttagtttt 1800ctgatggatt ctcgcaatga ggtttggtgg accattgatg gaaaaaaacc tgatgacatc 1860actattgatg tcaccattaa cgaaagtata agtcatagta gaacagaaga tgaaacaaga 1920actcagattt tgagcatcaa gaaagttacc tctgaggatc tcaagcgcag ctatgtctgt 1980catgctagaa gtgccaaagg cgaagttgcc aaagcagcca aggtgaagca gaaagtgcca 2040gctccaagat acacagtgtc cggagagtcc aaatacggtc cgccatgccc atcatgccca 2100gcacctgagt tcctgggggg accatcagtc ttcctgttcc ccccaaaacc caaggacact 2160ctcatgatct cccggacccc tgaggtcacg tgcgtggtgg tggacgtgag ccaggaagac 2220cccgaggtcc agttcaactg gtacgtggat ggcgtggagg tgcataatgc caagacaaag 2280ccgcgggagg agcagttcaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 2340caggactggc tgaacggcaa ggagtacaag tgcaaggtct ccaacaaagg cctcccgtcc 2400tccatcgaga aaaccatctc caaagccaaa gggcagcccc gagagccaca ggtgtacacc 2460ctgcccccat cccaggagga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 2520ggcttctacc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 2580tacaagacca cgcctcccgt gctggactcc gacggctcct tcttcctcta cagcaggcta 2640accgtggaca agagcaggtg gcaggagggg aatgtcttct catgctccgt gatgcatgag 2700gctctgcaca accactacac acagaagagc ctctccctgt ctctgggtaa atga 275418917PRTHomo sapiens 18Met Val Arg Leu Tyr Val Leu Val Met Gly Val Ser Ala Phe Thr Leu 1 5 10 15Gln Pro Ala Ala His Thr Gly Ala Ala Arg Ser Cys Arg Phe Arg Gly 20 25 30Arg His Tyr Lys Arg Glu Phe Arg Leu Glu Gly Glu Pro Val Ala Leu 35 40 45Arg Cys Pro Gln Val Pro Tyr Trp Leu Trp Ala Ser Val Ser Pro Arg 50 55 60Ile Asn Leu Thr Trp His Lys Asn Asp Ser Ala Arg Thr Val Pro Gly65 70 75 80Glu Glu Glu Thr Arg Met Trp Ala Gln Asp Gly Ala Leu Trp Leu Leu 85 90 95Pro Ala Leu Gln Glu Asp Ser Gly Thr Tyr Val Cys Thr Thr Arg Asn 100 105 110Ala Ser Tyr Cys Asp Lys Met Ser Ile Glu Leu Arg Val Phe Glu Asn 115 120 125Thr Asp Ala Phe Leu Pro Phe Ile Ser Tyr Pro Gln Ile Leu Thr Leu 130 135 140Ser Thr Ser Gly Val Leu Val Cys Pro Asp Leu Ser Glu Phe Thr Arg145 150 155 160Asp Lys Thr Asp Val Lys Ile Gln Trp Tyr Lys Asp Ser Leu Leu Leu 165 170 175Asp Lys Asp Asn Glu Lys Phe Leu Ser Val Arg Gly Thr Thr His Leu 180 185 190Leu Val His Asp Val Ala Leu Glu Asp Ala Gly Tyr Tyr Arg Cys Val 195 200 205Leu Thr Phe Ala His Glu Gly Gln Gln Tyr Asn Ile Thr Arg Ser Ile 210 215 220Glu Leu Arg Ile Lys Lys Lys Lys Glu Glu Thr Ile Pro Val Ile Ile225 230 235 240Ser Pro Leu Lys Thr Ile Ser Ala Ser Leu Gly Ser Arg Leu Thr Ile 245 250 255Pro Cys Lys Val Phe Leu Gly Thr Gly Thr Pro Leu Thr Thr Met Leu 260 265 270Trp Trp Thr Ala Asn Asp Thr His Ile Glu Ser Ala Tyr Pro Gly Gly 275 280 285Arg Val Thr Glu Gly Pro Arg Gln Glu Tyr Ser Glu Asn Asn Glu Asn 290 295 300Tyr Ile Glu Val Pro Leu Ile Phe Asp Pro Val Thr Arg Glu Asp Leu305 310 315 320His Met Asp Phe Lys Cys Val Val His Asn Thr Leu Ser Phe Gln Thr 325 330 335Leu Arg Thr Thr Val Lys Glu Ala Ser Ser Thr Phe Ser Glu Arg Cys 340 345 350Asp Asp Trp Gly Leu Asp Thr Met Arg Gln Ile Gln Val Phe Glu Asp 355 360 365Glu Pro Ala Arg Ile Lys Cys Pro Leu Phe Glu His Phe Leu Lys Phe 370 375 380Asn Tyr Ser Thr Ala His Ser Ala Gly Leu Thr Leu Ile Trp Tyr Trp385 390 395 400Thr Arg Gln Asp Arg Asp Leu Glu Glu Pro Ile Asn Phe Arg Leu Pro 405 410 415Glu Asn Arg Ile Ser Lys Glu Lys Asp Val Leu Trp Phe Arg Pro Thr 420 425 430Leu Leu Asn Asp Thr Gly Asn Tyr Thr Cys Met Leu Arg Asn Thr Thr 435 440 445Tyr Cys Ser Lys Val Ala Phe Pro Leu Glu Val Val Gln Lys Asp Ser 450 455 460Cys Phe Asn Ser Pro Met Lys Leu Pro Val His Lys Leu Tyr Ile Glu465 470 475 480Tyr Gly Ile Gln Arg Ile Thr Cys Pro Asn Val Asp Gly Tyr Phe Pro 485 490 495Ser Ser Val Lys Pro Thr Ile Thr Trp Tyr Met Gly Cys Tyr Lys Ile 500 505 510Gln Asn Phe Asn Asn Val Ile Pro Glu Gly Met Asn Leu Ser Phe Leu 515 520 525Ile Ala Leu Ile Ser Asn Asn Gly Asn Tyr Thr Cys Val Val Thr Tyr 530 535 540Pro Glu Asn Gly Arg Thr Phe His Leu Thr Arg Thr Leu Thr Val Lys545 550 555 560Val Val Gly Ser Pro Lys Asn Ala Val Pro Pro Val Ile His Ser Pro 565 570 575Asn Asp His Val Val Tyr Glu Lys Glu Pro Gly Glu Glu Leu Leu Ile 580 585 590Pro Cys Thr Val Tyr Phe Ser Phe Leu Met Asp Ser Arg Asn Glu Val 595 600 605Trp Trp Thr Ile Asp Gly Lys Lys Pro Asp Asp Ile Thr Ile Asp Val 610 615 620Thr Ile Asn Glu Ser Ile Ser His Ser Arg Thr Glu Asp Glu Thr Arg625 630 635 640Thr Gln Ile Leu Ser Ile Lys Lys Val Thr Ser Glu Asp Leu Lys Arg 645 650 655Ser Tyr Val Cys His Ala Arg Ser Ala Lys Gly Glu Val Ala Lys Ala 660 665 670Ala Lys Val Lys Gln Lys Val Pro Ala Pro Arg Tyr Thr Val Ser Gly 675 680 685Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro Ala Pro Glu Phe 690 695 700Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr705 710 715 720Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 725 730 735Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val 740 745 750Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser 755 760 765Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 770 775 780Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser785 790 795 800Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 805 810 815Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln 820 825 830Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 835 840 845Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 850 855 860Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu865 870 875 880Thr Val Asp Lys

Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser 885 890 895Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 900 905 910Leu Ser Leu Gly Lys 915192754DNAHomo sapiens 19atggtgcgct tgtacgtgtt ggtaatggga gtttctgcct tcacccttca gcctgcggca 60cacacagggg ctgccagaag ctgccggttt cgtgggaggc attacaagcg ggagttcagg 120ctggaagggg agcctgtagc cctgaggtgc ccccaggtgc cctactggtt gtgggcctct 180gtcagccccc gcatcaacct gacatggcat aaaaatgact ctgctaggac ggtcccagga 240gaagaagaga cacggatgtg ggcccaggac ggtgctctgt ggcttctgcc agccttgcag 300gaggactctg gcacctacgt ctgcactact agaaatgctt cttactgtga caaaatgtcc 360attgagctca gagtttttga gaatacagat gctttcctgc cgttcatctc atacccgcaa 420attttaacct tgtcaacctc tggggtatta gtatgccctg acctgagtga attcacccgt 480gacaaaactg acgtgaagat tcaatggtac aaggattctc ttcttttgga taaagacaat 540gagaaatttc taagtgtgag ggggaccact cacttactcg tacacgatgt ggccctggaa 600gatgctggct attaccgctg tgtcctgaca tttgcccatg aaggccagca atacaacatc 660actaggagta ttgagctacg catcaagaaa aaaaaagaag agaccattcc tgtgatcatt 720tcccccctca agaccatatc agcttctctg gggtcaagac tgacaatccc atgtaaggtg 780tttctgggaa ccggcacacc cttaaccacc atgctgtggt ggacggccaa tgacacccac 840atagagagcg cctacccggg aggccgcgtg accgaggggc cacgccagga atattcagaa 900aataatgaga actacattga agtgccattg atttttgatc ctgtcacaag agaggatttg 960cacatggatt ttaaatgtgt tgtccataat accctgagtt ttcagacact acgcaccaca 1020gtcaaggaag cctcctccac gttctcagaa cgctgcgatg actggggact agacaccatg 1080aggcaaatcc aagtgtttga agatgagcca gctcgcatca agtgcccact ctttgaacac 1140ttcttgaaat tcaactacag cacagcccat tcagctggcc ttactctgat ctggtattgg 1200actaggcagg accgggacct tgaggagcca attaacttcc gcctccccga gaaccgcatt 1260agtaaggaga aagatgtgct gtggttccgg cccactctcc tcaatgacac tggcaactat 1320acctgcatgt taaggaacac tacatattgc agcaaagttg catttccctt ggaagttgtt 1380caaaaagaca gctgtttcaa ttcccccatg aaactcccag tgcataaact gtatatagaa 1440tatggcattc agaggatcac ttgtccaaat gtagatggat attttccttc cagtgtcaaa 1500ccgactatca cttggtatat gggctgttat aaaatacaga attttaataa tgtaataccc 1560gaaggtatga acttgagttt cctcattgcc ttaatttcaa ataatggaaa ttacacatgt 1620gttgttacat atccagaaaa tggacgtacg tttcatctca ccaggactct gactgtaaag 1680gtagtaggct ctccaaaaaa tgcagtgccc cctgtgatcc attcacctaa tgatcatgtg 1740gtctatgaga aagaaccagg agaggagcta ctcattccct gtacggtcta ttttagtttt 1800ctgatggatt ctcgcaatga ggtttggtgg accattgatg gaaaaaaacc tgatgacatc 1860actattgatg tcaccattaa cgaaagtata agtcatagta gaacagaaga tgaaacaaga 1920actcagattt tgagcatcaa gaaagttacc tctgaggatc tcaagcgcag ctatgtctgt 1980catgctagaa gtgccaaagg cgaagttgcc aaagcagcca aggtgaagca gaaagtgcca 2040gctccaagat acacagtgtc cggagagtcc aaatacggtc cgccatgccc accatgccca 2100gcacctgagt tcctgggggg accatcagtc ttcctgttcc ccccaaaacc caaggacact 2160ctcatgatct cccggacccc tgaggtcacg tgcgtggtgg tggacgtgag ccaggaagac 2220cccgaggtcc agttcaactg gtacgtggat ggcgtggagg tgcataatgc caagacaaag 2280ccgcgggagg agcagttcaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 2340caggactggc tgaacggcaa ggagtacaag tgcaaggtct ccaacaaagg cctcccgtcc 2400tccatcgaga aaaccatctc caaagccaaa gggcagcccc gagagccaca ggtgtacacc 2460ctgcccccat cccaggagga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 2520ggcttctacc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 2580tacaagacca cgcctcccgt gctggactcc gacggctcct tcttcctcta cagcaggcta 2640accgtggaca agagcaggtg gcaggagggg aatgtcttct catgctccgt gatgcatgag 2700gctctgcaca accactacac acagaagagc ctctccctgt ctctgggtaa atga 275420917PRTHomo sapiens 20Met Val Arg Leu Tyr Val Leu Val Met Gly Val Ser Ala Phe Thr Leu 1 5 10 15Gln Pro Ala Ala His Thr Gly Ala Ala Arg Ser Cys Arg Phe Arg Gly 20 25 30Arg His Tyr Lys Arg Glu Phe Arg Leu Glu Gly Glu Pro Val Ala Leu 35 40 45Arg Cys Pro Gln Val Pro Tyr Trp Leu Trp Ala Ser Val Ser Pro Arg 50 55 60Ile Asn Leu Thr Trp His Lys Asn Asp Ser Ala Arg Thr Val Pro Gly65 70 75 80Glu Glu Glu Thr Arg Met Trp Ala Gln Asp Gly Ala Leu Trp Leu Leu 85 90 95Pro Ala Leu Gln Glu Asp Ser Gly Thr Tyr Val Cys Thr Thr Arg Asn 100 105 110Ala Ser Tyr Cys Asp Lys Met Ser Ile Glu Leu Arg Val Phe Glu Asn 115 120 125Thr Asp Ala Phe Leu Pro Phe Ile Ser Tyr Pro Gln Ile Leu Thr Leu 130 135 140Ser Thr Ser Gly Val Leu Val Cys Pro Asp Leu Ser Glu Phe Thr Arg145 150 155 160Asp Lys Thr Asp Val Lys Ile Gln Trp Tyr Lys Asp Ser Leu Leu Leu 165 170 175Asp Lys Asp Asn Glu Lys Phe Leu Ser Val Arg Gly Thr Thr His Leu 180 185 190Leu Val His Asp Val Ala Leu Glu Asp Ala Gly Tyr Tyr Arg Cys Val 195 200 205Leu Thr Phe Ala His Glu Gly Gln Gln Tyr Asn Ile Thr Arg Ser Ile 210 215 220Glu Leu Arg Ile Lys Lys Lys Lys Glu Glu Thr Ile Pro Val Ile Ile225 230 235 240Ser Pro Leu Lys Thr Ile Ser Ala Ser Leu Gly Ser Arg Leu Thr Ile 245 250 255Pro Cys Lys Val Phe Leu Gly Thr Gly Thr Pro Leu Thr Thr Met Leu 260 265 270Trp Trp Thr Ala Asn Asp Thr His Ile Glu Ser Ala Tyr Pro Gly Gly 275 280 285Arg Val Thr Glu Gly Pro Arg Gln Glu Tyr Ser Glu Asn Asn Glu Asn 290 295 300Tyr Ile Glu Val Pro Leu Ile Phe Asp Pro Val Thr Arg Glu Asp Leu305 310 315 320His Met Asp Phe Lys Cys Val Val His Asn Thr Leu Ser Phe Gln Thr 325 330 335Leu Arg Thr Thr Val Lys Glu Ala Ser Ser Thr Phe Ser Glu Arg Cys 340 345 350Asp Asp Trp Gly Leu Asp Thr Met Arg Gln Ile Gln Val Phe Glu Asp 355 360 365Glu Pro Ala Arg Ile Lys Cys Pro Leu Phe Glu His Phe Leu Lys Phe 370 375 380Asn Tyr Ser Thr Ala His Ser Ala Gly Leu Thr Leu Ile Trp Tyr Trp385 390 395 400Thr Arg Gln Asp Arg Asp Leu Glu Glu Pro Ile Asn Phe Arg Leu Pro 405 410 415Glu Asn Arg Ile Ser Lys Glu Lys Asp Val Leu Trp Phe Arg Pro Thr 420 425 430Leu Leu Asn Asp Thr Gly Asn Tyr Thr Cys Met Leu Arg Asn Thr Thr 435 440 445Tyr Cys Ser Lys Val Ala Phe Pro Leu Glu Val Val Gln Lys Asp Ser 450 455 460Cys Phe Asn Ser Pro Met Lys Leu Pro Val His Lys Leu Tyr Ile Glu465 470 475 480Tyr Gly Ile Gln Arg Ile Thr Cys Pro Asn Val Asp Gly Tyr Phe Pro 485 490 495Ser Ser Val Lys Pro Thr Ile Thr Trp Tyr Met Gly Cys Tyr Lys Ile 500 505 510Gln Asn Phe Asn Asn Val Ile Pro Glu Gly Met Asn Leu Ser Phe Leu 515 520 525Ile Ala Leu Ile Ser Asn Asn Gly Asn Tyr Thr Cys Val Val Thr Tyr 530 535 540Pro Glu Asn Gly Arg Thr Phe His Leu Thr Arg Thr Leu Thr Val Lys545 550 555 560Val Val Gly Ser Pro Lys Asn Ala Val Pro Pro Val Ile His Ser Pro 565 570 575Asn Asp His Val Val Tyr Glu Lys Glu Pro Gly Glu Glu Leu Leu Ile 580 585 590Pro Cys Thr Val Tyr Phe Ser Phe Leu Met Asp Ser Arg Asn Glu Val 595 600 605Trp Trp Thr Ile Asp Gly Lys Lys Pro Asp Asp Ile Thr Ile Asp Val 610 615 620Thr Ile Asn Glu Ser Ile Ser His Ser Arg Thr Glu Asp Glu Thr Arg625 630 635 640Thr Gln Ile Leu Ser Ile Lys Lys Val Thr Ser Glu Asp Leu Lys Arg 645 650 655Ser Tyr Val Cys His Ala Arg Ser Ala Lys Gly Glu Val Ala Lys Ala 660 665 670Ala Lys Val Lys Gln Lys Val Pro Ala Pro Arg Tyr Thr Val Ser Gly 675 680 685Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe 690 695 700Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr705 710 715 720Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 725 730 735Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val 740 745 750Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser 755 760 765Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 770 775 780Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser785 790 795 800Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 805 810 815Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln 820 825 830Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 835 840 845Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 850 855 860Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu865 870 875 880Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser 885 890 895Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 900 905 910Leu Ser Leu Gly Lys 915212748DNAHomo sapiens 21atggtgcttc tgtggtgtgt agtgagtctc tacttttatg gaatcctgca aagtgatgcc 60tcagaacgct gcgatgactg gggactagac accatgaggc aaatccaagt gtttgaagat 120gagccagctc gcatcaagtg cccactcttt gaacacttct tgaaattcaa ctacagcaca 180gcccattcag ctggccttac tctgatctgg tattggacta ggcaggaccg ggaccttgag 240gagccaatta acttccgcct ccccgagaac cgcattagta aggagaaaga tgtgctgtgg 300ttccggccca ctctcctcaa tgacactggc aactatacct gcatgttaag gaacactaca 360tattgcagca aagttgcatt tcccttggaa gttgttcaaa aagacagctg tttcaattcc 420cccatgaaac tcccagtgca taaactgtat atagaatatg gcattcagag gatcacttgt 480ccaaatgtag atggatattt tccttccagt gtcaaaccga ctatcacttg gtatatgggc 540tgttataaaa tacagaattt taataatgta atacccgaag gtatgaactt gagtttcctc 600attgccttaa tttcaaataa tggaaattac acatgtgttg ttacatatcc agaaaatgga 660cgtacgtttc atctcaccag gactctgact gtaaaggtag taggctctcc aaaaaatgca 720gtgccccctg tgatccattc acctaatgat catgtggtct atgagaaaga accaggagag 780gagctactca ttccctgtac ggtctatttt agttttctga tggattctcg caatgaggtt 840tggtggacca ttgatggaaa aaaacctgat gacatcacta ttgatgtcac cattaacgaa 900agtataagtc atagtagaac agaagatgaa acaagaactc agattttgag catcaagaaa 960gttacctctg aggatctcaa gcgcagctat gtctgtcatg ctagaagtgc caaaggcgaa 1020gttgccaaag cagccaaggt gaagcagaaa gtgccagctc caagatacac agtgcacaca 1080ggggctgcca gaagctgccg gtttcgtggg aggcattaca agcgggagtt caggctggaa 1140ggggagcctg tagccctgag gtgcccccag gtgccctact ggttgtgggc ctctgtcagc 1200ccccgcatca acctgacatg gcataaaaat gactctgcta ggacggtccc aggagaagaa 1260gagacacgga tgtgggccca ggacggtgct ctgtggcttc tgccagcctt gcaggaggac 1320tctggcacct acgtctgcac tactagaaat gcttcttact gtgacaaaat gtccattgag 1380ctcagagttt ttgagaatac agatgctttc ctgccgttca tctcataccc gcaaatttta 1440accttgtcaa cctctggggt attagtatgc cctgacctga gtgaattcac ccgtgacaaa 1500actgacgtga agattcaatg gtacaaggat tctcttcttt tggataaaga caatgagaaa 1560tttctaagtg tgagggggac cactcactta ctcgtacacg atgtggccct ggaagatgct 1620ggctattacc gctgtgtcct gacatttgcc catgaaggcc agcaatacaa catcactagg 1680agtattgagc tacgcatcaa gaaaaaaaaa gaagagacca ttcctgtgat catttccccc 1740ctcaagacca tatcagcttc tctggggtca agactgacaa tcccatgtaa ggtgtttctg 1800ggaaccggca cacccttaac caccatgctg tggtggacgg ccaatgacac ccacatagag 1860agcgcctacc cgggaggccg cgtgaccgag gggccacgcc aggaatattc agaaaataat 1920gagaactaca ttgaagtgcc attgattttt gatcctgtca caagagagga tttgcacatg 1980gattttaaat gtgttgtcca taataccctg agttttcaga cactacgcac cacagtcaag 2040gaagcctcct ccacgttctc cggagacaaa actcacacat gcccaccgtg cccagcacct 2100gaactcctgg ggggaccgtc agtcttcctc ttccccccaa aacccaagga caccctcatg 2160atctcccgga cccctgaggt cacatgcgtg gtggtggacg tgagccacga agaccctgag 2220gtcaagttca actggtacgt ggacggcgtg gaggtgcata atgccaagac aaagccgcgg 2280gaggagcagt acaacagcac gtaccgtgtg gtcagcgtcc tcaccgtcct gcaccaggac 2340tggctgaatg gcaaggagta caagtgcaag gtctccaaca aagccctccc agcccccatc 2400gagaaaacca tctccaaagc caaagggcag ccccgagaac cacaggtgta caccctgccc 2460ccatcccggg atgagctgac caagaaccag gtcagcctga cctgcctggt caaaggcttc 2520tatcccagcg acatcgccgt ggagtgggag agcaatgggc agccggagaa caactacaag 2580accacgcctc ccgtgctgga ctccgacggc tccttcttcc tctatagcaa gctcaccgtg 2640gacaagagca ggtggcagca ggggaacgtc ttctcatgct ccgtgatgca tgaggctctg 2700cacaaccact acacgcagaa gagcctctcc ctgtctccgg gtaaatga 274822915PRTHomo sapiens 22Met Val Leu Leu Trp Cys Val Val Ser Leu Tyr Phe Tyr Gly Ile Leu 1 5 10 15Gln Ser Asp Ala Ser Glu Arg Cys Asp Asp Trp Gly Leu Asp Thr Met 20 25 30Arg Gln Ile Gln Val Phe Glu Asp Glu Pro Ala Arg Ile Lys Cys Pro 35 40 45Leu Phe Glu His Phe Leu Lys Phe Asn Tyr Ser Thr Ala His Ser Ala 50 55 60Gly Leu Thr Leu Ile Trp Tyr Trp Thr Arg Gln Asp Arg Asp Leu Glu65 70 75 80Glu Pro Ile Asn Phe Arg Leu Pro Glu Asn Arg Ile Ser Lys Glu Lys 85 90 95Asp Val Leu Trp Phe Arg Pro Thr Leu Leu Asn Asp Thr Gly Asn Tyr 100 105 110Thr Cys Met Leu Arg Asn Thr Thr Tyr Cys Ser Lys Val Ala Phe Pro 115 120 125Leu Glu Val Val Gln Lys Asp Ser Cys Phe Asn Ser Pro Met Lys Leu 130 135 140Pro Val His Lys Leu Tyr Ile Glu Tyr Gly Ile Gln Arg Ile Thr Cys145 150 155 160Pro Asn Val Asp Gly Tyr Phe Pro Ser Ser Val Lys Pro Thr Ile Thr 165 170 175Trp Tyr Met Gly Cys Tyr Lys Ile Gln Asn Phe Asn Asn Val Ile Pro 180 185 190Glu Gly Met Asn Leu Ser Phe Leu Ile Ala Leu Ile Ser Asn Asn Gly 195 200 205Asn Tyr Thr Cys Val Val Thr Tyr Pro Glu Asn Gly Arg Thr Phe His 210 215 220Leu Thr Arg Thr Leu Thr Val Lys Val Val Gly Ser Pro Lys Asn Ala225 230 235 240Val Pro Pro Val Ile His Ser Pro Asn Asp His Val Val Tyr Glu Lys 245 250 255Glu Pro Gly Glu Glu Leu Leu Ile Pro Cys Thr Val Tyr Phe Ser Phe 260 265 270Leu Met Asp Ser Arg Asn Glu Val Trp Trp Thr Ile Asp Gly Lys Lys 275 280 285Pro Asp Asp Ile Thr Ile Asp Val Thr Ile Asn Glu Ser Ile Ser His 290 295 300Ser Arg Thr Glu Asp Glu Thr Arg Thr Gln Ile Leu Ser Ile Lys Lys305 310 315 320Val Thr Ser Glu Asp Leu Lys Arg Ser Tyr Val Cys His Ala Arg Ser 325 330 335Ala Lys Gly Glu Val Ala Lys Ala Ala Lys Val Lys Gln Lys Val Pro 340 345 350Ala Pro Arg Tyr Thr Val His Thr Gly Ala Ala Arg Ser Cys Arg Phe 355 360 365Arg Gly Arg His Tyr Lys Arg Glu Phe Arg Leu Glu Gly Glu Pro Val 370 375 380Ala Leu Arg Cys Pro Gln Val Pro Tyr Trp Leu Trp Ala Ser Val Ser385 390 395 400Pro Arg Ile Asn Leu Thr Trp His Lys Asn Asp Ser Ala Arg Thr Val 405 410 415Pro Gly Glu Glu Glu Thr Arg Met Trp Ala Gln Asp Gly Ala Leu Trp 420 425 430Leu Leu Pro Ala Leu Gln Glu Asp Ser Gly Thr Tyr Val Cys Thr Thr 435 440 445Arg Asn Ala Ser Tyr Cys Asp Lys Met Ser Ile Glu Leu Arg Val Phe 450 455 460Glu Asn Thr Asp Ala Phe Leu Pro Phe Ile Ser Tyr Pro Gln Ile Leu465 470 475 480Thr Leu Ser Thr Ser Gly Val Leu Val Cys Pro Asp Leu Ser Glu Phe 485 490 495Thr Arg Asp Lys Thr Asp Val Lys Ile Gln Trp Tyr Lys Asp Ser Leu 500 505 510Leu Leu Asp Lys Asp Asn Glu Lys Phe Leu Ser Val Arg Gly Thr Thr 515 520 525His Leu Leu Val His Asp Val Ala Leu Glu Asp Ala Gly Tyr Tyr Arg 530 535 540Cys Val Leu Thr Phe Ala His Glu Gly Gln Gln Tyr Asn Ile Thr Arg545 550 555 560Ser Ile Glu Leu Arg Ile Lys Lys Lys Lys Glu Glu Thr Ile Pro Val 565 570 575Ile Ile Ser Pro Leu Lys Thr Ile Ser Ala Ser Leu Gly Ser Arg Leu 580 585 590Thr Ile Pro Cys Lys Val Phe Leu Gly Thr Gly Thr Pro Leu Thr Thr 595

600 605Met Leu Trp Trp Thr Ala Asn Asp Thr His Ile Glu Ser Ala Tyr Pro 610 615 620Gly Gly Arg Val Thr Glu Gly Pro Arg Gln Glu Tyr Ser Glu Asn Asn625 630 635 640Glu Asn Tyr Ile Glu Val Pro Leu Ile Phe Asp Pro Val Thr Arg Glu 645 650 655Asp Leu His Met Asp Phe Lys Cys Val Val His Asn Thr Leu Ser Phe 660 665 670Gln Thr Leu Arg Thr Thr Val Lys Glu Ala Ser Ser Thr Phe Ser Gly 675 680 685Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 690 695 700Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met705 710 715 720Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 725 730 735Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 740 745 750His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 755 760 765Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 770 775 780Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile785 790 795 800Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 805 810 815Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 820 825 830Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 835 840 845Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 850 855 860Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val865 870 875 880Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 885 890 895His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 900 905 910Pro Gly Lys 915232754DNAHomo sapiens 23atggtgcttc tgtggtgtgt agtgagtctc tacttttatg gaatcctgca aagtgatgcc 60tcagaacgct gcgatgactg gggactagac accatgaggc aaatccaagt gtttgaagat 120gagccagctc gcatcaagtg cccactcttt gaacacttct tgaaattcaa ctacagcaca 180gcccattcag ctggccttac tctgatctgg tattggacta ggcaggaccg ggaccttgag 240gagccaatta acttccgcct ccccgagaac cgcattagta aggagaaaga tgtgctgtgg 300ttccggccca ctctcctcaa tgacactggc aactatacct gcatgttaag gaacactaca 360tattgcagca aagttgcatt tcccttggaa gttgttcaaa aagacagctg tttcaattcc 420cccatgaaac tcccagtgca taaactgtat atagaatatg gcattcagag gatcacttgt 480ccaaatgtag atggatattt tccttccagt gtcaaaccga ctatcacttg gtatatgggc 540tgttataaaa tacagaattt taataatgta atacccgaag gtatgaactt gagtttcctc 600attgccttaa tttcaaataa tggaaattac acatgtgttg ttacatatcc agaaaatgga 660cgtacgtttc atctcaccag gactctgact gtaaaggtag taggctctcc aaaaaatgca 720gtgccccctg tgatccattc acctaatgat catgtggtct atgagaaaga accaggagag 780gagctactca ttccctgtac ggtctatttt agttttctga tggattctcg caatgaggtt 840tggtggacca ttgatggaaa aaaacctgat gacatcacta ttgatgtcac cattaacgaa 900agtataagtc atagtagaac agaagatgaa acaagaactc agattttgag catcaagaaa 960gttacctctg aggatctcaa gcgcagctat gtctgtcatg ctagaagtgc caaaggcgaa 1020gttgccaaag cagccaaggt gaagcagaaa gtgccagctc caagatacac agtgcacaca 1080ggggctgcca gaagctgccg gtttcgtggg aggcattaca agcgggagtt caggctggaa 1140ggggagcctg tagccctgag gtgcccccag gtgccctact ggttgtgggc ctctgtcagc 1200ccccgcatca acctgacatg gcataaaaat gactctgcta ggacggtccc aggagaagaa 1260gagacacgga tgtgggccca ggacggtgct ctgtggcttc tgccagcctt gcaggaggac 1320tctggcacct acgtctgcac tactagaaat gcttcttact gtgacaaaat gtccattgag 1380ctcagagttt ttgagaatac agatgctttc ctgccgttca tctcataccc gcaaatttta 1440accttgtcaa cctctggggt attagtatgc cctgacctga gtgaattcac ccgtgacaaa 1500actgacgtga agattcaatg gtacaaggat tctcttcttt tggataaaga caatgagaaa 1560tttctaagtg tgagggggac cactcactta ctcgtacacg atgtggccct ggaagatgct 1620ggctattacc gctgtgtcct gacatttgcc catgaaggcc agcaatacaa catcactagg 1680agtattgagc tacgcatcaa gaaaaaaaaa gaagagacca ttcctgtgat catttccccc 1740ctcaagacca tatcagcttc tctggggtca agactgacaa tcccatgtaa ggtgtttctg 1800ggaaccggca cacccttaac caccatgctg tggtggacgg ccaatgacac ccacatagag 1860agcgcctacc cgggaggccg cgtgaccgag gggccacgcc aggaatattc agaaaataat 1920gagaactaca ttgaagtgcc attgattttt gatcctgtca caagagagga tttgcacatg 1980gattttaaat gtgttgtcca taataccctg agttttcaga cactacgcac cacagtcaag 2040gaagcctcct ccacgttctc cggagagtcc aaatacggtc cgccatgccc atcatgccca 2100gcacctgagt tcctgggggg accatcagtc ttcctgttcc ccccaaaacc caaggacact 2160ctcatgatct cccggacccc tgaggtcacg tgcgtggtgg tggacgtgag ccaggaagac 2220cccgaggtcc agttcaactg gtacgtggat ggcgtggagg tgcataatgc caagacaaag 2280ccgcgggagg agcagttcaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 2340caggactggc tgaacggcaa ggagtacaag tgcaaggtct ccaacaaagg cctcccgtcc 2400tccatcgaga aaaccatctc caaagccaaa gggcagcccc gagagccaca ggtgtacacc 2460ctgcccccat cccaggagga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 2520ggcttctacc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 2580tacaagacca cgcctcccgt gctggactcc gacggctcct tcttcctcta cagcaggcta 2640accgtggaca agagcaggtg gcaggagggg aatgtcttct catgctccgt gatgcatgag 2700gctctgcaca accactacac acagaagagc ctctccctgt ctctgggtaa atga 275424917PRTHomo sapiens 24Met Val Leu Leu Trp Cys Val Val Ser Leu Tyr Phe Tyr Gly Ile Leu 1 5 10 15Gln Ser Asp Ala Ser Glu Arg Cys Asp Asp Trp Gly Leu Asp Thr Met 20 25 30Arg Gln Ile Gln Val Phe Glu Asp Glu Pro Ala Arg Ile Lys Cys Pro 35 40 45Leu Phe Glu His Phe Leu Lys Phe Asn Tyr Ser Thr Ala His Ser Ala 50 55 60Gly Leu Thr Leu Ile Trp Tyr Trp Thr Arg Gln Asp Arg Asp Leu Glu65 70 75 80Glu Pro Ile Asn Phe Arg Leu Pro Glu Asn Arg Ile Ser Lys Glu Lys 85 90 95Asp Val Leu Trp Phe Arg Pro Thr Leu Leu Asn Asp Thr Gly Asn Tyr 100 105 110Thr Cys Met Leu Arg Asn Thr Thr Tyr Cys Ser Lys Val Ala Phe Pro 115 120 125Leu Glu Val Val Gln Lys Asp Ser Cys Phe Asn Ser Pro Met Lys Leu 130 135 140Pro Val His Lys Leu Tyr Ile Glu Tyr Gly Ile Gln Arg Ile Thr Cys145 150 155 160Pro Asn Val Asp Gly Tyr Phe Pro Ser Ser Val Lys Pro Thr Ile Thr 165 170 175Trp Tyr Met Gly Cys Tyr Lys Ile Gln Asn Phe Asn Asn Val Ile Pro 180 185 190Glu Gly Met Asn Leu Ser Phe Leu Ile Ala Leu Ile Ser Asn Asn Gly 195 200 205Asn Tyr Thr Cys Val Val Thr Tyr Pro Glu Asn Gly Arg Thr Phe His 210 215 220Leu Thr Arg Thr Leu Thr Val Lys Val Val Gly Ser Pro Lys Asn Ala225 230 235 240Val Pro Pro Val Ile His Ser Pro Asn Asp His Val Val Tyr Glu Lys 245 250 255Glu Pro Gly Glu Glu Leu Leu Ile Pro Cys Thr Val Tyr Phe Ser Phe 260 265 270Leu Met Asp Ser Arg Asn Glu Val Trp Trp Thr Ile Asp Gly Lys Lys 275 280 285Pro Asp Asp Ile Thr Ile Asp Val Thr Ile Asn Glu Ser Ile Ser His 290 295 300Ser Arg Thr Glu Asp Glu Thr Arg Thr Gln Ile Leu Ser Ile Lys Lys305 310 315 320Val Thr Ser Glu Asp Leu Lys Arg Ser Tyr Val Cys His Ala Arg Ser 325 330 335Ala Lys Gly Glu Val Ala Lys Ala Ala Lys Val Lys Gln Lys Val Pro 340 345 350Ala Pro Arg Tyr Thr Val His Thr Gly Ala Ala Arg Ser Cys Arg Phe 355 360 365Arg Gly Arg His Tyr Lys Arg Glu Phe Arg Leu Glu Gly Glu Pro Val 370 375 380Ala Leu Arg Cys Pro Gln Val Pro Tyr Trp Leu Trp Ala Ser Val Ser385 390 395 400Pro Arg Ile Asn Leu Thr Trp His Lys Asn Asp Ser Ala Arg Thr Val 405 410 415Pro Gly Glu Glu Glu Thr Arg Met Trp Ala Gln Asp Gly Ala Leu Trp 420 425 430Leu Leu Pro Ala Leu Gln Glu Asp Ser Gly Thr Tyr Val Cys Thr Thr 435 440 445Arg Asn Ala Ser Tyr Cys Asp Lys Met Ser Ile Glu Leu Arg Val Phe 450 455 460Glu Asn Thr Asp Ala Phe Leu Pro Phe Ile Ser Tyr Pro Gln Ile Leu465 470 475 480Thr Leu Ser Thr Ser Gly Val Leu Val Cys Pro Asp Leu Ser Glu Phe 485 490 495Thr Arg Asp Lys Thr Asp Val Lys Ile Gln Trp Tyr Lys Asp Ser Leu 500 505 510Leu Leu Asp Lys Asp Asn Glu Lys Phe Leu Ser Val Arg Gly Thr Thr 515 520 525His Leu Leu Val His Asp Val Ala Leu Glu Asp Ala Gly Tyr Tyr Arg 530 535 540Cys Val Leu Thr Phe Ala His Glu Gly Gln Gln Tyr Asn Ile Thr Arg545 550 555 560Ser Ile Glu Leu Arg Ile Lys Lys Lys Lys Glu Glu Thr Ile Pro Val 565 570 575Ile Ile Ser Pro Leu Lys Thr Ile Ser Ala Ser Leu Gly Ser Arg Leu 580 585 590Thr Ile Pro Cys Lys Val Phe Leu Gly Thr Gly Thr Pro Leu Thr Thr 595 600 605Met Leu Trp Trp Thr Ala Asn Asp Thr His Ile Glu Ser Ala Tyr Pro 610 615 620Gly Gly Arg Val Thr Glu Gly Pro Arg Gln Glu Tyr Ser Glu Asn Asn625 630 635 640Glu Asn Tyr Ile Glu Val Pro Leu Ile Phe Asp Pro Val Thr Arg Glu 645 650 655Asp Leu His Met Asp Phe Lys Cys Val Val His Asn Thr Leu Ser Phe 660 665 670Gln Thr Leu Arg Thr Thr Val Lys Glu Ala Ser Ser Thr Phe Ser Gly 675 680 685Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro Ala Pro Glu Phe 690 695 700Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr705 710 715 720Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 725 730 735Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val 740 745 750Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser 755 760 765Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 770 775 780Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser785 790 795 800Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 805 810 815Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln 820 825 830Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 835 840 845Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 850 855 860Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu865 870 875 880Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser 885 890 895Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 900 905 910Leu Ser Leu Gly Lys 915252754DNAHomo sapiens 25atggtgcttc tgtggtgtgt agtgagtctc tacttttatg gaatcctgca aagtgatgcc 60tcagaacgct gcgatgactg gggactagac accatgaggc aaatccaagt gtttgaagat 120gagccagctc gcatcaagtg cccactcttt gaacacttct tgaaattcaa ctacagcaca 180gcccattcag ctggccttac tctgatctgg tattggacta ggcaggaccg ggaccttgag 240gagccaatta acttccgcct ccccgagaac cgcattagta aggagaaaga tgtgctgtgg 300ttccggccca ctctcctcaa tgacactggc aactatacct gcatgttaag gaacactaca 360tattgcagca aagttgcatt tcccttggaa gttgttcaaa aagacagctg tttcaattcc 420cccatgaaac tcccagtgca taaactgtat atagaatatg gcattcagag gatcacttgt 480ccaaatgtag atggatattt tccttccagt gtcaaaccga ctatcacttg gtatatgggc 540tgttataaaa tacagaattt taataatgta atacccgaag gtatgaactt gagtttcctc 600attgccttaa tttcaaataa tggaaattac acatgtgttg ttacatatcc agaaaatgga 660cgtacgtttc atctcaccag gactctgact gtaaaggtag taggctctcc aaaaaatgca 720gtgccccctg tgatccattc acctaatgat catgtggtct atgagaaaga accaggagag 780gagctactca ttccctgtac ggtctatttt agttttctga tggattctcg caatgaggtt 840tggtggacca ttgatggaaa aaaacctgat gacatcacta ttgatgtcac cattaacgaa 900agtataagtc atagtagaac agaagatgaa acaagaactc agattttgag catcaagaaa 960gttacctctg aggatctcaa gcgcagctat gtctgtcatg ctagaagtgc caaaggcgaa 1020gttgccaaag cagccaaggt gaagcagaaa gtgccagctc caagatacac agtgcacaca 1080ggggctgcca gaagctgccg gtttcgtggg aggcattaca agcgggagtt caggctggaa 1140ggggagcctg tagccctgag gtgcccccag gtgccctact ggttgtgggc ctctgtcagc 1200ccccgcatca acctgacatg gcataaaaat gactctgcta ggacggtccc aggagaagaa 1260gagacacgga tgtgggccca ggacggtgct ctgtggcttc tgccagcctt gcaggaggac 1320tctggcacct acgtctgcac tactagaaat gcttcttact gtgacaaaat gtccattgag 1380ctcagagttt ttgagaatac agatgctttc ctgccgttca tctcataccc gcaaatttta 1440accttgtcaa cctctggggt attagtatgc cctgacctga gtgaattcac ccgtgacaaa 1500actgacgtga agattcaatg gtacaaggat tctcttcttt tggataaaga caatgagaaa 1560tttctaagtg tgagggggac cactcactta ctcgtacacg atgtggccct ggaagatgct 1620ggctattacc gctgtgtcct gacatttgcc catgaaggcc agcaatacaa catcactagg 1680agtattgagc tacgcatcaa gaaaaaaaaa gaagagacca ttcctgtgat catttccccc 1740ctcaagacca tatcagcttc tctggggtca agactgacaa tcccatgtaa ggtgtttctg 1800ggaaccggca cacccttaac caccatgctg tggtggacgg ccaatgacac ccacatagag 1860agcgcctacc cgggaggccg cgtgaccgag gggccacgcc aggaatattc agaaaataat 1920gagaactaca ttgaagtgcc attgattttt gatcctgtca caagagagga tttgcacatg 1980gattttaaat gtgttgtcca taataccctg agttttcaga cactacgcac cacagtcaag 2040gaagcctcct ccacgttctc cggagagtcc aaatacggtc cgccatgccc accatgccca 2100gcacctgagt tcctgggggg accatcagtc ttcctgttcc ccccaaaacc caaggacact 2160ctcatgatct cccggacccc tgaggtcacg tgcgtggtgg tggacgtgag ccaggaagac 2220cccgaggtcc agttcaactg gtacgtggat ggcgtggagg tgcataatgc caagacaaag 2280ccgcgggagg agcagttcaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 2340caggactggc tgaacggcaa ggagtacaag tgcaaggtct ccaacaaagg cctcccgtcc 2400tccatcgaga aaaccatctc caaagccaaa gggcagcccc gagagccaca ggtgtacacc 2460ctgcccccat cccaggagga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 2520ggcttctacc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 2580tacaagacca cgcctcccgt gctggactcc gacggctcct tcttcctcta cagcaggcta 2640accgtggaca agagcaggtg gcaggagggg aatgtcttct catgctccgt gatgcatgag 2700gctctgcaca accactacac acagaagagc ctctccctgt ctctgggtaa atga 275426917PRTHomo sapiens 26Met Val Leu Leu Trp Cys Val Val Ser Leu Tyr Phe Tyr Gly Ile Leu 1 5 10 15Gln Ser Asp Ala Ser Glu Arg Cys Asp Asp Trp Gly Leu Asp Thr Met 20 25 30Arg Gln Ile Gln Val Phe Glu Asp Glu Pro Ala Arg Ile Lys Cys Pro 35 40 45Leu Phe Glu His Phe Leu Lys Phe Asn Tyr Ser Thr Ala His Ser Ala 50 55 60Gly Leu Thr Leu Ile Trp Tyr Trp Thr Arg Gln Asp Arg Asp Leu Glu65 70 75 80Glu Pro Ile Asn Phe Arg Leu Pro Glu Asn Arg Ile Ser Lys Glu Lys 85 90 95Asp Val Leu Trp Phe Arg Pro Thr Leu Leu Asn Asp Thr Gly Asn Tyr 100 105 110Thr Cys Met Leu Arg Asn Thr Thr Tyr Cys Ser Lys Val Ala Phe Pro 115 120 125Leu Glu Val Val Gln Lys Asp Ser Cys Phe Asn Ser Pro Met Lys Leu 130 135 140Pro Val His Lys Leu Tyr Ile Glu Tyr Gly Ile Gln Arg Ile Thr Cys145 150 155 160Pro Asn Val Asp Gly Tyr Phe Pro Ser Ser Val Lys Pro Thr Ile Thr 165 170 175Trp Tyr Met Gly Cys Tyr Lys Ile Gln Asn Phe Asn Asn Val Ile Pro 180 185 190Glu Gly Met Asn Leu Ser Phe Leu Ile Ala Leu Ile Ser Asn Asn Gly 195 200 205Asn Tyr Thr Cys Val Val Thr Tyr Pro Glu Asn Gly Arg Thr Phe His 210 215 220Leu Thr Arg Thr Leu Thr Val Lys Val Val Gly Ser Pro Lys Asn Ala225 230 235 240Val Pro Pro Val Ile His Ser Pro Asn Asp His Val Val Tyr Glu Lys 245 250 255Glu Pro Gly Glu Glu Leu Leu Ile Pro Cys Thr Val Tyr Phe Ser Phe 260 265 270Leu Met Asp Ser Arg Asn Glu Val Trp Trp Thr Ile Asp Gly Lys Lys 275 280 285Pro Asp Asp Ile Thr Ile Asp Val Thr Ile Asn Glu Ser Ile Ser His 290 295 300Ser Arg Thr Glu Asp Glu Thr Arg Thr Gln Ile Leu Ser Ile Lys Lys305 310 315 320Val Thr Ser Glu Asp Leu Lys Arg Ser Tyr Val Cys

His Ala Arg Ser 325 330 335Ala Lys Gly Glu Val Ala Lys Ala Ala Lys Val Lys Gln Lys Val Pro 340 345 350Ala Pro Arg Tyr Thr Val His Thr Gly Ala Ala Arg Ser Cys Arg Phe 355 360 365Arg Gly Arg His Tyr Lys Arg Glu Phe Arg Leu Glu Gly Glu Pro Val 370 375 380Ala Leu Arg Cys Pro Gln Val Pro Tyr Trp Leu Trp Ala Ser Val Ser385 390 395 400Pro Arg Ile Asn Leu Thr Trp His Lys Asn Asp Ser Ala Arg Thr Val 405 410 415Pro Gly Glu Glu Glu Thr Arg Met Trp Ala Gln Asp Gly Ala Leu Trp 420 425 430Leu Leu Pro Ala Leu Gln Glu Asp Ser Gly Thr Tyr Val Cys Thr Thr 435 440 445Arg Asn Ala Ser Tyr Cys Asp Lys Met Ser Ile Glu Leu Arg Val Phe 450 455 460Glu Asn Thr Asp Ala Phe Leu Pro Phe Ile Ser Tyr Pro Gln Ile Leu465 470 475 480Thr Leu Ser Thr Ser Gly Val Leu Val Cys Pro Asp Leu Ser Glu Phe 485 490 495Thr Arg Asp Lys Thr Asp Val Lys Ile Gln Trp Tyr Lys Asp Ser Leu 500 505 510Leu Leu Asp Lys Asp Asn Glu Lys Phe Leu Ser Val Arg Gly Thr Thr 515 520 525His Leu Leu Val His Asp Val Ala Leu Glu Asp Ala Gly Tyr Tyr Arg 530 535 540Cys Val Leu Thr Phe Ala His Glu Gly Gln Gln Tyr Asn Ile Thr Arg545 550 555 560Ser Ile Glu Leu Arg Ile Lys Lys Lys Lys Glu Glu Thr Ile Pro Val 565 570 575Ile Ile Ser Pro Leu Lys Thr Ile Ser Ala Ser Leu Gly Ser Arg Leu 580 585 590Thr Ile Pro Cys Lys Val Phe Leu Gly Thr Gly Thr Pro Leu Thr Thr 595 600 605Met Leu Trp Trp Thr Ala Asn Asp Thr His Ile Glu Ser Ala Tyr Pro 610 615 620Gly Gly Arg Val Thr Glu Gly Pro Arg Gln Glu Tyr Ser Glu Asn Asn625 630 635 640Glu Asn Tyr Ile Glu Val Pro Leu Ile Phe Asp Pro Val Thr Arg Glu 645 650 655Asp Leu His Met Asp Phe Lys Cys Val Val His Asn Thr Leu Ser Phe 660 665 670Gln Thr Leu Arg Thr Thr Val Lys Glu Ala Ser Ser Thr Phe Ser Gly 675 680 685Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe 690 695 700Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr705 710 715 720Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 725 730 735Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val 740 745 750Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser 755 760 765Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 770 775 780Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser785 790 795 800Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 805 810 815Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln 820 825 830Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 835 840 845Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 850 855 860Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu865 870 875 880Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser 885 890 895Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 900 905 910Leu Ser Leu Gly Lys 915

Claims

1. A method of treating, inhibiting, or ameliorating an autoinflammatory disorder, disease, or condition in a subject in need thereof, comprising administering to the subject a therapeutic amount of an interleukin 1 (IL-1) fusion protein antagonist once a week, wherein the autoinflammatory disorder, disease, or condition is treated, inhibited, or ameliorated, wherein the IL-1 fusion protein antagonist comprises two IL-1 receptor components and a multimerizing component, wherein the fusion protein comprises an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:10, wherein the subject is a human adult or child diagnosed with Neonatal Onset Multisystem Inflammatory Disorder (NOMID/CINCA), Muckle-Wells Syndrome (MWS), Familial Cold Autoinflammatory Syndrome (FCAS), familial Mediterranean fever (FMF), tumor necrosis factor receptor-associated periodic fever syndrome (TRAPS), or systemic onset juvenile idiopathic arthritis (Still's Disease).

2. The method of claim 1, wherein the fusion protein comprises a sequence that is at least 97% identical to the amino acid sequence of SEQ ID NO:10.

3. The method of claim 1, wherein administration is subcutaneous, intramuscular, or intravenous.

4. The method of claim 1, wherein the therapeutically effective amount is between 1-20 mg/kg.

5. A method of treating, inhibiting, or ameliorating an autoinflammatory disorder associated with mutations in CIAS-1 in a subject in need thereof, comprising administering once a week to the subject a therapeutic amount of an interleukin 1 (IL-1) antagonist, wherein the IL-1 antagonist comprises an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:10, wherein the autoinflammatory disorder is treated, inhibited, or ameliorated, and wherein the autoinflammatory disorder associated with mutations in CIAS-1 is one of Neonatal Onset Multisystem Inflammatory Disorder (NOMID/CINCA), Muckle-Wells Syndrome (MWS), and Familial Cold Autoinflammatory Syndrome (FCAS).

6. The method according to claim 5, wherein the IL-1 antagonist comprises an amino acid sequence that is at least 97% identical to the amino acid sequence of SEQ ID NO:10.

7. The method of claim 5, wherein administration is subcutaneous, intramuscular, or intravenous.

8. The method of claim 5, wherein the therapeutically effective amount is between 1-20 mg/kg.