DK2190469T3 - POLYPEPTIDES AND POLYNUCLEOTIDES AND USES THEREOF AS a drug FOR THE PRODUCTION OF PHARMACEUTICAL AND BIOTECHNOLOGY PRODUCTS - Google Patents

Description

DESCRIPTION

RELATED APPLICATIONS

[0001] This invention claims benefit of priority to and incorporates by reference in their entireties US provisional applications Serial No's: 60/969,865; 60/969,799; 60/969,780,60/969,806,60/969,769, and 60/969,788, all filed on September 4, 2007.

FIELD OF THE INVENTION

[0002] This invention relates to the discovery of certain proteins that are differentially expressed in specific tissues and their use as therapeutic and diagnostic targets. More specifically the invention relates to a protein C10RF32 and its variants, which are differentially expressed by some cancers, and therefore are suitable targets for immunotherapy, cancer therapy, and drug development. This invention further relates to the discovery of extracellular domains of C1ORF32 and its variants a which are suitable targets for immunotherapy, cancer therapy, and drug development [0003] Additionally, because the proteins of this invention, based on their B7-like structure, are believed to play a role in immune costimulation, the invention further relates to the use of these proteins, or drugs which modulate these proteins (agonistic and antagonistic), as immune modulators and for immune therapy, especially for treating cancer and immune related disorders such as cancers and autoimmune disorders. Also, the invention more specifically relates to therapeutic and diagnostic antibodies and therapies and diagnostic methods using same antibodies and antibody fragments that specifically bind to proteins of invention or a soluble or secreted portion thereof, especially the ectodomain.

BACKGROUND OF THE INVENTION

[0004] Tumor antigens are ideally positioned as biomarkers and drug targets, and they play a critical role in the development of novel strategies for active and passive immunotherapy agents, to be used as stand-alone therapies or in conjunction with conventional therapies for cancer. Tumor antigens can be classified as either tumor-specific antigens (TSAs) where the antigens are expressed only in tumor cells and not in normal tissues, or tumor-associated antigens (TAAs) where the antigens are overexpressed in tumor cells but nonetheless also present at low levels in normal tissues.

[0005] TAAs and TSAs are validated as targets for passive (antibody) therapy as well as active immunotherapy using strategies to break immune tolerance and stimulate the immune system. The antigenic epitopes that are targeted by these therapeutic approaches are present at the cell surface, overexpressed in tumor cells compared to non-tumor cells, and are targeted by antibodies that block functional activity, inhibit cell prohliferation, or induce cell death.

[0006] There are growing number of tumor-associated antigens against which monoclonal antibodies have been tested or are in use as treatment for cancer. The identification and molecular characterization of novel tumor antigens expressed by human malignancies is an active field in tumor immunology. Several approaches have been used to identify tumor-associated antigens as target candidates for immunotherapy, including high throughput bioinformatic approaches, based on genomics and proteomics. The identification of novel TAAs or TSAs expands the spectrum of tumor antigen targets available for immune recognition and provides new target molecules for the development of therapeutic agents for passive immunotherapy, including monoclonal antibodies, whether unmodified or armed. Such novel antigens may also point the way to more effective therapeutic vaccines for active or adoptive immunotherapy.

[0007] Cancer vaccination involves the administration of tumor antigens and is used to break immune tolerance and induce an active T-cell response to the tumor. Vaccine therapy includes the use of naked DNA, peptides, recombinant protein, and whole cell therapy, where the patient's own tumor cells are used as the source of the vaccine. With the identification of specific tumor antigens, vaccinations are more often carried out by dendritic cell therapy, whereby dendritic cells are loaded with the relevant protein or peptide, or transfected with vector DNA or RNA.

[0008] The major applications of anti-TAA antibodies for treatment of cancer are therapy with naked antibody, therapy with a drug-conjugated antibody, and fusion therapy with cellular immunity. Ever since their discovery, antibodies were envisioned as "magic bullets" that would deliver toxic agents, such as drugs, toxins, enzymes and radioisotopes, specifically to the diseased site 1 and leaving the non-target normal tissues unaffected. Indeed, antibodies, and in particular antibody fragments, can function as carriers of cytotoxic substances such as radioisotopes, drugs and toxins. Immunotherapy with such immunoconjugates is more effective than with the naked antibody.

[0009] In contrast to the overwhelming success of naked (such as Rituxan and Campath) and conjugated antibodies (such as Bexxar and Zevalin) in treating hematological malignancies, only modest success has been achieved in the immunotherapy of solid tumors. One of the major limitations in successful application of immunotherapy to solid tumors is the large molecular size of the intact immunoglobulin that results in prolonged serum half-life but in poor tumor penetration and uptake. Indeed, only a very small amount of administered antibody (as low as 0.01%) reaches the tumor. In addition to their size, antibodies encounter other impediments before reaching their target antigens expressed on the cell surface of solid tumors. Some of the barriers include poor blood flow in large tumors, permeability of vascular endothelium, elevated interstitial fluid pressure of tumor stroma, and heterogenous antigen expression.

[0010] With the advent of antibody engineering, small molecular weight antibody fragments exhibiting improved tumor penetration have been generated. Such antibody fragments are often conjugated to specific cytotoxic molecules and are designed to selectively deliver them to cancer cells. Still, solid tumors remain a formidable challenge for therapy, even with immunoconjugated antibody fragments.

[0011] The new wave of optimization strategies involves the use of biological modifiers to modulate the impediments posed by solid tumors. Thus, in combination to antibodies or their conjugated antibody fragments, various agents are being used to improve the tumor blood flow, enhance vascular permeability, lower tumor interstitial fluid pressure by modulating stromal cells and extracellular matrix components, upregulate expression of target antigens and improve penetration and retention of the therapeutic agent.

[0012] Immunotherapy with antibodies represents an exciting opportunity for combining with standard modalities, such as chemotherapy, as well as combinations with diverse biological agents to obtain a synergistic activity. Indeed, unconjugated mAbs are more effective when used in combination with other therapeutic agents, including other antibodies.

[0013] Another component of the immune system response to immunotherapy is the cellular response, specifically - the T cell response and activation of cytotoxic T cells (CTLs). The efficiency of the immune system in mediating tumor regression depends on the induction of antigen-specific T-cell responses through physiologic immune surveillance, priming by vaccination, or following adoptive transfer of T-cells. Although a variety of tumor-associated antigens have been identified and many immunotherapeutic strategies have been tested, objective clinical responses are rare. The reasons for this include the inability of current immunotherapy approaches to generate efficient T-cell responses, the presence of regulatory cells that inhibit T-cell responses, and other escape mechanisms that tumors develop, such as inactivation of cytolytic T-cells through expression of negative costimulatory molecules. Effective immunotherapy for cancer will require the use of appropriate tumor-specific antigens; the optimization of the interaction between the antigenic peptide, the APC and the T cell; and the simultaneous blockade of negative regulatory mechanisms that impede immunotherapeutic effects.

[0014] T -cell activation plays a central role in driving both protective and pathogenic immune responses, and it requires the completion of a carefully orchestrated series of specific steps that can be preempted or disrupted by any number of critical events. Naive T cells must receive two independent signals from antigen-presenting cells (APC) in order to become productively activated. The first, Signal 1, is antigen-specific and occurs when T cell antigen receptors encounter the appropriate antigen-MHC complex on the APC. A second, antigen-independent signal (Signal 2) is delivered through a T cell costimulatory molecule that engages its APC-expressed ligand. In the absence of a costimulatory signal, T-cell activation is impaired or aborted, which may lead to a state of antigen-specific unresponsiveness (known as T-cell anergy), or may result in T-cell apoptotic death.

[0015] Costimulatory signals can be either stimulatory (positive costimulation) or inhibitory (negative costimulation or coinhibition). Positive costimulation is required for optimal activation of naive T cells, while negative costimulation is required for the acquisition of immunologic tolerance to self, as well as the termination of effector T cell functions. Costimulatory signals, particularly positive costimulatory signals, also play a role in the modulation of B cell activity. For example, B cell activation and the survival of germinal center B cells require T cell-derived signals in addition to stimulation by antigen.

[0016] Both positive and negative costimulatory signals play critical roles in the regulation of cell-mediated immune responses, and molecules that mediate these signals have proven to be effective targets for immunomodulation. Based on this knowledge, several therapeutic approaches that involve targeting of costimulatory molecules have been developed, and were shown to be useful for prevention and treatment of cancer and autoimmune diseases, as well as rejection of allogenic transplantation, each by turning on, or preventing the turning off, of immune responses in subjects with these pathological conditions.

[0017] Costimulatory molecule pairs usually consist of ligands expressed on APCs and their cognate receptors expressed on T cells. The well characterized B7/CD28 and CD40/CD40L costimulatory molecules are critical in primary T-cell activation. In recent years, several additional costimulatory molecules have been identified, that belong to the B7/CD28 or the TNF/TNF-R gene families. The effects of costimulatory TNFR family members can often be functionally, temporally, or spatially segregated from those of CD28 family members and from each other. The sequential and transient regulation of T cell activation/survival signals by different costimulators may function to allow longevity of the response while maintaining tight control of T cell survival.

[0018] The B7 family consists of structurally related, cell-surface protein ligands, which bind to receptors on lymphocytes that regulate immune responses. Interaction of B7-family members with their respective costimulatory receptor, usually a member of the CD28-related family, augments immune responses, while interaction with coinhibitory receptors, such as CTLA4, attenuates immune responses. Members of the B7 family share 20-40% amino-acid identity and are structurally related, with the extracellular domain containing tandem domains related to variable and constant immunoglobulin domains.

[0019] There are currently seven known members of the family: B7.1 (CD80), B7.2 (CD86), B7-H1 (PD-L1), B7-H2 (ICOS-L), B7-DC (PD-L2), B7-H3, and B7-H4, each with unique, yet often overlapping functions. Clearly, each B7 molecule has developed its own indispensable niche in the immune system. As specific niches of B7 family members continue to be dissected, their diagnostic and therapeutic potential becomes ever more apparent. Many of the B7 superfamily members were initially characterized as T cell costimulatory molecules. However, more recently it has become clear they can also coinhibit T cell responses. Thus, B7 family members may have opposing effects on an immune response.

[0020] Central to the normal function of the immune system is its ability to distinguish between self and non-self, since failure to do so could provoke the onset of autoimmune disease. Most autoimmune disorders are known to involve autoreactive T cells and/or autoantibodies. Thus, agents that are capable of inhibiting or eliminating autoreactive lymphocytes have a promising therapeutic potential. Furthermore, the use of agents that exhibit such immunosuppressive activity should also be beneficial in order to inhibit normal immune responses to alloantigens in patients receiving a transplant. Thus, novel agents that are capable of modulating costimulatory signals, without compromising the immune system's ability to defend against pathogens, are highly advantageous for treatment and prevention of such pathological conditions.

[0021] The importance of the B7 family members in regulating immune responses to self and allo-antigens was demonstrated by the development of immunodeficiency and autoimmune diseases in mice with mutations in B7-family genes. Accordingly, manipulation of the signals delivered by B7 ligands has shown potential in the treatment of autoimmunity, inflammatory diseases, and transplant rejection. This approach relies, at least partially, on the eventual deletion of auto- or allo-reactive T cells, presumably because in the absence of costimulation (which induces cell survival genes) T cells become highly susceptible to induction of apoptosis.

[0022] Harnessing the immune system to treat chronic diseases is a major goal of immunotherapy. Active and passive immunotherapies are proving themselves as effective therapeutic strategies. Passive immunotherapy, using monoclonal antibodies or receptor Fc-fusion proteins, has come of age and has shown great clinical success. A growing number of such therapeutic agents have been approved or are in clinical trials to prevent allograft rejection or to treat autoimmune diseases and cancer. Active immunotherapy (i.e. vaccines) has been effective against agents that normally cause acute self-limiting infectious diseases followed by immunity and has been at the forefront of efforts to prevent the infectious diseases that plague humankind. However, active immunotherapy has been much less effective against cancer or chronic infectious diseases primarily because these have developed strategies to escape normal immune responses. Among these are negative costimulators of the B7 family, such as B7-H1 and B7-H4, which are highly expressed in certain tumors, and afford local protection from immune cells-mediated attack.

[0023] The efficiency of the immune system in mediating tumor regression depends on the induction of antigen-specific T-cell responses through physiologic immune surveillance, priming by vaccination, or following adoptive transfer of T-cells. Although a variety of tumor-associated antigens have been identified and many immunotherapeutic strategies have been tested, objective clinical responses are rare. The reasons for this include the inability of current immunotherapy approaches to generate efficient T-cell responses, the presence of regulatory cells that inhibit T-cell responses, and other escape mechanisms that tumors develop, such as inactivation of cytolytic T-cells through expression of negative costimulatory molecules. Effective immunotherapy for cancer will require the use of appropriate tumor-specific antigens; the optimization of the interaction between the antigenic peptide, the APC and the T cell; and the simultaneous blockade of negative regulatory mechanisms that impede immunotherapeutic effects.

[0024] Costimulators of the B7 family play a critical role in activation and inhibition of antitumor immune responses. Novel agents targeting these molecules could find significant use in the modulation of immune responses and the improvement of cancer immunotherapy. Such agents could be administered in conjunction with tumor-specific antigens, as an adjuvant that serves to enhance the immune response to the antigen in the patient. In addition, such agents could be of use in other types of cancer immunotherapy, such as adoptive immunotherapy, in which tumor-specific T cell populations are expanded and directed to attack and kill tumor cells. Agents capable of augmenting such anti-tumor response have great therapeutic potential and may be of value in the attempt to overcome the obstacles to tumor immunotherapy.

[0025] Passive tumor immunotherapy uses the exquisite specificity and lytic capability of the immune system to target tumor specific antigens and treat malignant disease with a minimum of damage to normal tissue. Several approaches have been used to identify tumor-associated antigens as target candidates for immunotherapy. The identification of novel tumor specific antigens expands the spectrum of tumor antigen targets available for immune recognition and provides new target molecules for the development of therapeutic agents for passive immunotherapy, including monoclonal antibodies, whether unmodified or armed. Such novel antigens may also point the way to more effective therapeutic vaccines for active or adoptive immunotherapy.

[0026] Clinical development of costimulation blockade came to fruition with the approval of CTI_A4lg (abatacept) for rheumatoid arthritis. This soluble fusion protein, which acts as competitive inhibitor of the B7/CD28 costimulatory pathway, is also in clinical trials for other immune diseases such as psoriasis and multiple sclerosis, and for transplant rejection. Promising results have also been obtained in a phase II clinical trial in kidney transplantation with belatacept, a re-engineered CTLA4lg with enhanced binding affinity to its ligands, B7.1 and B7.2 (CD80 and CD86, respectively). Two fully human anti-CTLA4 monoclonal antibodies, Ipilimumab and tremelimumab, abrogate the CTLA4/B7 inhibitory interaction, and are in clinical phase III for metastatic melanoma and other cancers, as well as HIV infection. Galiximab is a primatized monoclonal antibody targeting CD80, in Phase II for rheumatoid arthritis, psoriasis and Non-Hodgkin's lymphoma.

[0027] It is important to point out that strategies that use single agents to block costimulation have often proved to be insufficient. Given the diversity of the different costimulation molecules, future strategies may involve the simultaneous blockade of several selected pathways or combination therapy with conventional drugs, such as immunosuppressants for immune-related disorders or cytotoxic drugs for cancer.

[0028] Despite recent progress in the understanding of cancer biology and cancer treatment, as well as better understanding of the molecules involved in immune responses, the success rate for cancer therapy and for the treatment of autoimmune diseases remains low. Therefore, there is an unmet need for new therapies which can successfully treat both cancer and autoimmune disorders.

BRIEF SUMMARY OF THE INVENTION

[0029] It is an object of the invention to provide novel therapeutic and diagnostic compositions containing at least one of the C10RF32 proteins or one of the novel splice variants disclosed herein; specifically C10RF32 splice variants, and nucleic acid sequences encoding for same or fragments thereof especially the ectodomain or secreted forms of C10RF32 proteins and/or splice variants.

[0030] It is another object of the invention to use said proteins, splice variants and nucleic acid sequences as novel targets for development of drugs which specifically bind to the C10RF32 proteins and/or splice variants, and/or drugs which agonize or antagonize the binding of other moieties to the C10RF32 proteins and/or splice variants.

[0031] It is still another object of the invention to provide drugs which modulate (agonize or antagonize) at least one C10RF32 related biological activity. Such drugs include by way of example antibodies, small molecules, peptides, ribozymes, antisense molecules, siRNA's and the like. These molecules may directly bind or modulate an activity elicited by the C10RF32 proteins or C10RF32 DNAor portions or variants thereof or may indirectly modulate a C10RF32 associated activity or binding of molecules to C10RF32 and portions and variants thereof such as by modulating the binding of C10RF32 to its counterreceptor or endogenous ligand.

[0032] The novel LOC387597 splice variant is an isolated polynucleotide comprising a nucleic acid having a nucleic acid sequence as set forth in any one of H19011_1_T8 (SEQ ID NO:45), H19011_1_T9 (SEQ ID NO:46), or a sequence homologous thereto, the isolated polynucleotide is at least 95, 96, 97, 98 or 99% homologous to any one of H19911_11_T8 (SEQ ID NO:45), H19011_1_T9 (SEQ ID NO:46).

[0033] The novel splice LOC387597 variant is an isolated protein or polypeptide having an amino acid sequence as set forth in any one of H19011_1_P8 (SEQ ID NO:48), H19011_1_P9 (SEQ ID NO:50) or a sequence homologous thereto, the isolated

polypeptide is at least 95, 96, 97, 98 or 99% homologous to any one of H19011 1 P8 (SEQ ID NO:48), H19011 1 P9 (SEQ ID NO:50).

[0034] It is another object of the invention to provide molecules and isolated polypeptides comprising the soluble ectodomain (ECD) of the C10RF3 proteins and fragments thereof as well as nucleic acid sequences encoding said soluble ectodomain, as well as fragments thereof and conjugates and the use thereof as therapeutics including their use in immunotherapy (promoting or inhibiting immune costimulation).

[0035] According to yet further embodiments of the present invention there are discrete portions of the C10RF32 proteins

including different portions of the extracellular domain corresponding to residues 21-186 of the sequence H19011_1_P8 (SEQ ID NO:48), corresponding to amino acid sequence depicted in SEQ ID NO:147, or residues 21-169 of the sequence H19011_1_P9 (SEQ ID NO:50), corresponding to amino acid sequence depicted in SEQ ID NO:148, or residues 1-184 of the sequence H19011_1_P8 (SEQ ID NO:48), corresponding to amino acid sequence depicted in SEQ ID NO:299 or variants thereof possessing at least 95,96,97,98 or 99% sequence identity therewith.

[0036] It is another object of the invention to provide an isolated or purified soluble protein or nucleic acid sequence encoding having or encoding the extracellular domain of the C10RF3 protein which optionally may be directly or indirectly attached to a non-C1 ORF3 protein or nucleic acid sequence such as a soluble immunoglobulin domain or fragment.

[0037] It is another object of the invention to provide an isolated or purified soluble protein or nucleic acid sequence encoding having or encoding the extracellular domain of any one of the C10RF32 proteins which optionally may be directly or indirectly attached to a non-C10RF32 protein or nucleic acid sequence, respectively, such as a soluble immunoglobulin domain or fragment.

[0038] It is another object of the invention to provide molecules and isolated polypeptides comprising edge portion, tail or head portion, of any one of the C1ORF32 novel variants of the invention, or a homologue or a fragment thereof as well as nucleic acid sequences encoding said edge portion, tail or head portion, as well as fragments thereof and conjugates and the use thereof as therapeutics and/or for diagnostics.

[0039] It is further object of the invention to provide molecules and isolated polypeptides comprising a bridge, edge portion, tail or head portion or a homologue or a fragment thereof as well as nucleic acid sequences encoding said edge portion, tail or head portion, as well as fragments thereof and conjugates and the use thereof as therapeutics and/or for diagnostics.

[0040] It is another object of the invention to provide vectors such as plasmids and recombinant viral vectors and host cells containing the vectors that express any one of the ECD of the C10RF32 protein and variants thereof or polypeptide conjugates containing any of the foregoing.

[0041] It is another object of the invention to use these vectors such as plasmids and recombinant viral vectors and host cells containing that express any one of the ECD of the C10RF32, protein and variants thereof or polypeptide conjugates containing any of the foregoing to produce said C10RF32 protein, fragments or variants thereof and/or conjugates containing any one of the foregoing.

[0042] It is another object of the invention to provide pharmaceutical or diagnostic compositions containing any of the foregoing.

[0043] It is another object of the invention to provide and use compounds , which are suitable for treatment or prevention of cancer, autoimmune disorders, transplant rejection, graft versus host disease, and/or for blocking or promoting immune costimulation mediated by the C10RF32 polypeptide.

[0044] It is a specific object of the invention to develop novel monoclonal or polyclonal antibodies and antibody fragments and conjugates containing that specifically bind the C10RF32 ECD or conjugates or fragments thereof. These antibodies are potentially useful as therapeutics and/or diagnostic agents (both in vitro and in vivo diagnostic methods). Included in particular are antibodies and fragments that are immune activating or immune suppressing such as antibodies or fragments that target cells via ADCC (antibody dependent cellular cytotoxicity) or CDC (complement dependent cytotoxicity) activities.

[0045] It is another object of the invention to provide diagnostic methods that include the use of any of the foregoing including by way of example immunohistochemical assay, radioimaging assays, in-vivo imaging, radioimmunoassay (RIA), ELISA, slot blot, competitive binding assays, fluorimetric imaging assays, Western blot, FACS, and the like. In particular this includes assays which use chimeric or non-human antibodies or fragments that specifically bind the intact C10RF32 ECD, and or conjugates, fragments or variants thereof.

[0046] It is another object of the invention to use novel therapeutically effective polyclonal or monoclonal antibodies against anyone of the C10RF32 ECD and/or portions or variants thereof are differentially expressed including various cancers and malignancies including non-solid and solid tumors, sarcomas, hematological malignancies including but not limited to acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, multiple myeloma, Hodgkin's lymphoma, Non-Hodgkin's lymphoma, cancer of the breast, prostate, lung, ovary, colon, spleen, kidney, bladder, head and neck, uterus, testicles, stomach, cervix, liver, bone, skin, pancreas, brain and wherein the cancer is non-metastatic, invasive or metastatic.

[0047] It is another object of the invention to use novel therapeutically effective polyclonal or monoclonal antibodies against -C10RF32 fragments, conjugates and variants thereof for treating non-malignant disorders such as immune disorders including but not limited to autoimmune diseases, transplant rejection and graft versus host disease.

[0048] It is a specific object of the invention to use antibodies and antibody fragments against C10RF32 ECD and/or variants, conjugates, or fragments thereof and fragments and variants thereof for treating and diagnosing lung cancer, particularly small cell lung carcinoma, wherein this antigen is differentially expressed.

[0049] It is another object of the invention to use antibodies and antibody fragments, and conjugates containing, against C10RF32 in modulating (enhancing or inhibiting) immunity including antibodies that activate or suppress the immune costimulation in particular B7 related immune costimulation and are capable of treating related therapeutic applications, through positive stimulation of T cell activity against cancer cells, and negative stimulation of T cell activity for the treatment of autoimmunity and other immune disorders.

[0050] It is another specific object of the invention to produce antibodies and antibody fragments against discrete portions of the C10RF32 proteins including different portions of the extracellular domain corresponding to residues 21-186 of the C10RF32 protein sequence contained in the sequence of H190111P8 (SEQ ID NO:48), corresponding to amino acid sequence depicted in SEQ ID NO:147, or residues 21-169 of the C10RF32 protein sequence contained in the sequence of H19011_1_P9 (SEQ ID NO:50), corresponding to amino acid sequence depicted in SEQ ID NO:148, or residues 1-184 of the sequence H19011_1_P8 (SEQ ID NO:48), corresponding to amino acid sequence depicted in SEQ ID NO:299.

[0051] It is a specific object of the invention to provide polyclonal and monoclonal antibodies and fragments thereof or an antigen binding fragment thereof comprising an antigen bindings site that binds specifically to the C10RF32 ECD and/or variants and fragments thereof.

[0052] It is a specific object of the invention to use such antibodies and fragments thereof for treatment or prevention of cancer and/or for modulating (activating or blocking) the activity of the target in the immune co-stimulatory system.

[0053] It is a related object of the invention to select monoclonal and polyclonal antibodies and fragments thereof against C10RF32 which are suitable for treatment or prevention of autoimmune disorders, transplant rejection, GVHD, and/or for blocking or enhancing immune costimulation mediated by the C10RF32 polypeptide.

[0054] It is a specific object of the invention to use antibodies against anyone of the C1ORF32 ECD or fragment or variant thereof for the treatment and diagnosis of cancers including by way of example lung cancer, ovarian cancer, colon cancer, as well as other non-solid and solid tumors, sarcomas, hematological malignancies including but not limited to acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, multiple myeloma, Hodgkin's lymphoma, Non-Hodgkin's lymphoma, cancer of the breast, prostate, spleen, kidney, bladder, head and neck, uterus, testicles, stomach, cervix, liver, bone, skin, pancreas, brain and wherein the cancer is non-metastatic, invasive or metastatic.

[0055] With regard to lung cancer, the disease is selected from the group consisting of squamous cell lung carcinoma, lung adenocarcinoma, carcinoid, small cell lung cancer or non-small cell lung cancer.

[0056] It is another object of the invention to provide and use antibodies and antibody fragments against anyone of the C1QRF32 ECD and variants or fragments thereof as well as soluble polypeptides containing the ectodomain of the C1QRF32 antigen or a portion thereof vtfiich are useful for immune modulation, including treatment of autoimmunity and preferably for treating an autoimmune disease selected from autoimmune diseases: Multiple sclerosis; Psoriasis; Rheumatoid arthritis; Systemic lupus erythematosus; Ulcerative colitis; Crohn's disease; immune disorders associated with graft transplantation rejection, benign lymphocytic angiitis, lupus erythematosus, Hashimoto's thyroiditis, primary myxedema, Graves' disease, pernicious anemia, autoimmune atrophic gastritis, Addison's disease, insulin dependent diabetes mellitus, good pasture's syndrome, myasthenia gravis, pemphigus, sympathetic ophthalmia, autoimmune uveitis, autoimmune hemolytic anemia, idiopathic thrombocytopenia, primary biliary cirrhosis, chronic action hepatitis, ulceratis colitis, Sjogren's syndrome, rheumatic disease, polymyositis, scleroderma, mixed connective tissue disease, inflammatory rheumatism, degenerative rheumatism, extra- articular rheumatism, collagen diseases, chronic polyarthritis, psoriasis arthropathica, ankylosing spondylitis, juvenile rheumatoid arthritis, periarthritis humeroscapularis, panarteriitis nodosa, progressive systemic scleroderma, arthritis uratica, dermatomyositis, muscular rheumatism, myositis, myogelosis and chondrocalcinosis.

[0057] It is another object of the invention to provide and use compounds including drugs such as small molecules, peptides, antibodies and fragments that bind C10RF32 as well as ribozymes or antisense or siRNA's which target the C10RF32 nucleic acid sequence or fragments or variants thereof which are useful for treatment or prevention of cancer, autoimmune disorders, transplant rejection, GVHD, and/or for blocking or enhancing immune costimulation mediated by the C10RF32 polypeptide.

[0058] It is another object of the invention to provide and use compounds including drugs such as small molecules, peptides, antibodies and fragments that bind C10RF32.

[0059] It is a preferred object to provide therapeutic and diagnostic antibodies and fragments and conjugates containing useful in treating or diagnosing any of the foregoing that specifically bind to amino-acids residues 21-186 of the C10RF32 protein sequence contained in the sequence of H19011_1_P8 (SEQ ID NO:48), corresponding to amino acid sequence depicted in SEQ ID NO:147, or residues 21-169 of the sequence of the C10RF32 protein sequence contained in the sequence of H19011_1_P9 (SEQ ID NO:50), corresponding to amino acid sequence depicted in SEQ ID NO:149, or residues 1-184 of the sequence H19011_1_P8 (SEQ ID NO:48), corresponding to amino acid sequence depicted in SEQ ID NO:299.

[0060] It is also a preferred object to provide antibodies and fragments thereof that bind to C10RF32 and the specific residues above-identified and fragments thereof, wherein the antibody is a chimeric, humanized, fully human antibody and/or is an antibody or antibody fragment having CDC or ADCC activities on target cells.

[0061] It is also a preferred object to provide chimeric and human antibodies and fragments thereof and conjugates containing that bind to C10RF32 and the specific residues above-identified and fragments thereof.

[0062] It is another specific object of the invention to provide antibody fragments and conjugates containing useful in the foregoing therapies and related diagnostic methods including but not limited to Fab, F(ab')2, Fv or scFv fragment.

[0063] It is also an object of the invention to directly or indirectly attach the subject antibodies and fragments to markers and other effector moieties such as a detectable marker, or to an effector moiety such as an enzyme, a toxin, a therapeutic agent, or a chemotherapeutic agent.

[0064] In a preferred embodiment the inventive antibodies or fragments may be attached directly or indirectly to a radioisotope, a metal chelator, an enzyme, a fluorescent compound, a bioluminescent compound or a chemiluminescent compound.

[0065] It is also an object of the invention to provide pharmaceutical and diagnostic compositions that comprise a therapeutically or diagnostically effective form of an antibody or antibody fragment according to the invention.

[0066] It is another specific object of the invention to inhibit the growth of cells that express C10RF32 in a subject, comprising: administering to said subject an antibody that specifically binds to C10RF32.

[0067] It is another specific object of the invention to provide methods for treating or preventing cancer, comprising administering to a patient an effective amount of a monoclonal antibody that specifically binds to C1ORF32.

[0068] It is a more preferred object of the invention to use these antibodies for treating cancers selected from the group consisting of lung cancer, particularly lung small cell carcinoma, and wherein the lung cancer is non-metastatic, invasive or metastatic, wherein preferably the antibody has an antigen-binding region specific for the extracellular domain of H19011_1_P8 (SEQ ID NO:48), H19011_1_P9 (SEQ ID NQ:50).

[0069] It is another specific object of the invention to use part or all of the ectodomain of C1ORF32 or its variants and conjugates containing for administration as an anti-cancer vaccine, for immunotherapy of cancer, including but not limited to ovarian cancer.

[0070] In another embodiment of the invention the cancer is selected from the group consisting of non-solid and solid tumors, sarcoma, hematological malignancies including but not limited to acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, multiple myeloma, Hodgkin's lymphoma, Non-Hodgkin's lymphoma, cancer of the lung, ovary, breast, prostate, colon, spleen, kidney, bladder, head and neck, uterus, testicles, stomach, cervix, liver, bone, skin, pancreas, brain and wherein the cancer may be non-metastatic, invasive or metastatic.

[0071] In a preferred embodiment the autoimmune diseases include Multiple sclerosis; Psoriasis; Rheumatoid arthritis; Systemic lupus erythematosus; Ulcerative colitis; Crohn's disease; immune disorders associated with graft transplantation rejection, benign lymphocytic angiitis, lupus erythematosus, Hashimoto's thyroiditis, primary myxedema, Graves' disease, pernicious anemia, autoimmune atrophic gastritis, Addison's disease, insulin dependent diabetes mellitis, good pasture's syndrome, myasthenia gravis, pemphigus, sympathetic ophthalmia, autoimmune uveitis, autoimmune hemolytic anemia, idiopathic thrombocytopenia, primary biliary cirrhosis, chronic action hepatitis, ulceratis colitis, Sjogren's syndrome, rheumatic disease, polymyositis, scleroderma, mixed connective tissue disease, inflammatory rheumatism, degenerative rheumatism, extra- articular rheumatism, collagen diseases, chronic polyarthritis, psoriasis arthropathica, ankylosing spondylitis, juvenile rheumatoid arthritis, periarthritis humeroscapularis, panarteriitis nodosa, progressive systemic scleroderma, arthritis uratica, dermatomyositis, muscular rheumatism, myositis, myogelosis and chondrocalcinosis.

[0072] It is a specific object of the invention to provide methods for treating or preventing rejection of any organ transplant and/or graft versus host disease, comprising administering to a patient an effective amount of an antibody It is also preferred in the foregoing methods that the antibody possess an antigen-binding region specific for the extracellular domain of H19011_1_P8 (SEQ ID NO:48), H19011_1_P9 (SEQ ID NO:50).

[0073] According to the present invention, each one of the following: the C10RF32 ectodomain of the present invention, antibodies and fragments that bind C10RF32, the compounds including drugs such as small molecules, peptides, as well as ribozymes or antisense or siRNAs which target the C10RF32 nucleic acid sequence or fragments or variants thereof which are useful for treatment or prevention of cancer, autoimmune disorders, transplant rejection, GVHD, and/or for blocking or enhancing immune co-stimulation mediated by the C10RF32 polypeptide, can be used with simultaneous blockade of several co-stimulatory pathways or in combination therapy with conventional drugs, such as immunosuppressants or cytotoxic drugs for cancer.

[0074] It is another object of the invention to provide assays for detecting the presence of H190111P8 (SEQ ID NO:48) or H19011_1_P9 (SEQ ID NO:50) protein in vitro or in vivo in a biological sample or individual comprising contacting the sample with an antibody having specificity for H19011_1_P8 (SEQ ID NO:48) or H19011_1_P9 (SEQ ID NO:50) polypeptides, or a combination thereof, and detecting the binding of H19011_1_P8 (SEQ ID NO:48) or H19011_1_P9 (SEQ ID NO:50) protein in the sample.

[0075] It is another object of the invention to provide methods for detecting a disease, diagnosing a disease, monitoring disease progression or treatment efficacy or relapse of a disease, or selecting a therapy for a disease, comprising detecting expression of a H19011_1_P8 (SEQ ID NO:48) or H19011_1_P9 (SEQ ID NO:50).

[0076] In a related object the detected diseases will include cancers such as lung cancer, ovarian cancer, colon cancer, as well as other non-solid and solid tumors, sarcomas, hematological malignancies including but not limited to acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, multiple myeloma, Hodgkin's lymphoma, Non-Hodgkin's lymphoma, cancer of the breast, prostate, spleen, kidney, bladder, head and neck, uterus, testicles, stomach, cervix, liver, bone, skin, pancreas, brain and wherein the cancer is non-metastatic, invasive or metastatic.

[0077] With regard to lung cancer, the disease is selected from the group consisting of non-metastatic, invasive or metastatic lung cancer; squamous cell lung carcinoma, lung adenocarcinoma, carcinoid, small cell lung cancer or non-small cell lung cancer; detection of overexpression in lung metastasis (vs. primary tumor); detection of overexpression in lung cancer, for example non small cell lung cancer, for example adenocarcinoma, squamous cell cancer or carcinoid, or large cell carcinoma; identification of a metastasis of unknown origin which originated from a primary lung cancer; assessment of a malignant tissue residing in the lung that is from a non-lung origin, including but not limited to: osteogenic and soft tissue sarcomas; colorectal, uterine, cervix and corpus tumors; head and neck, breast, testis and salivary gland cancers; melanoma; and bladder and kidney tumors; distinguishing between different types of lung cancer, therefore potentially affecting treatment choice (e.g. small cell vs. non small cell tumors); analysis of unexplained dyspnea and/or chronic cough and/or hemoptysis; differential diagnosis of the origin of a pleural effusion; diagnosis of conditions which have similar symptoms, signs and complications as lung cancer and where the differential diagnosis between them and lung cancer is of clinical importance including but not limited to: non-malignant causes of lung symptoms and signs, including but not limited to: lung lesions and infiltrates, wheeze, stridor, tracheal obstruction, esophageal compression, dysphagia, recurrent laryngeal nerve paralysis, hoarseness, phrenic nerve paralysis with elevation of the hemidiaphragm and Horner syndrome; or detecting a cause of any condition suggestive of a malignant tumor including but not limited to anorexia, cachexia, weight loss, fever, hypercalcemia, hypophosphatemia, hyponatremia, syndrome of inappropriate secretion of antidiuretic hormone, elevated ANP, elevated ACTH, hypokalemia, clubbing, neurologic-myopathic syndromes and thrombophlebitis.

[0078] With regard to ovarian cancer, the compounds of the present invention can be used in the diagnosis, treatment or prognostic assessment of non-metastatic, invasive or metastatic ovarian cancer; correlating stage and malignant potential; identification of a metastasis of unknown origin which originated from a primary ovarian cancer; differential diagnosis between benign and malignant ovarian cysts; diagnosing a cause of infertility, for example differential diagnosis of various causes thereof; detecting of one or more non-ovarian cancer conditions that may elevate serum levels of ovary related markers, including but not limited to: cancers of the endometrium, cervix, fallopian tubes, pancreas, breast, lung and colon; nonmalignant conditions such as pregnancy, endometriosis, pelvic inflammatory disease and uterine fibroids; diagnosing conditions which have similar symptoms, signs and complications as ovarian cancer and where the differential diagnosis between them and ovarian cancer is of clinical importance including but not limited to: non-malignant causes of pelvic mass, including, but not limited to: benign (functional) ovarian cyst, uterine fibroids, endometriosis, benign ovarian neoplasms and inflammatory bowel lesions; determining a cause of any condition suggestive of a malignant tumor including but not limited to anorexia, cachexia, weight loss, fever, hypercalcemia, skeletal or abdominal pain, paraneoplastic syndrome, or ascites.

[0079] In another related object the detected diseases will include autoimmune and neoplastic disorders selected from the group consisting of Multiple sclerosis; Psoriasis; Rheumatoid arthritis; Systemic lupus erythematosus; Ulcerative colitis; Crohn's disease; immune disorders associated with graft transplantation rejection, benign lymphocytic angiitis, lupus erythematosus, Hashimoto's thyroiditis, primary myxedema, Graves' disease, pernicious anemia, autoimmune atrophic gastritis, Addison's disease, insulin dependent diabetes mellitis, good pasture's syndrome, myasthenia gravis, pemphigus, sympathetic ophthalmia, autoimmune uveitis, autoimmune hemolytic anemia, idiopathic thrombocytopenia, primary biliary cirrhosis, chronic action hepatitis, ulceratis colitis, Sjogren's syndrome, rheumatic disease, polymyositis, scleroderma, mixed connective tissue disease, inflammatory rheumatism, degenerative rheumatism, extra- articular rheumatism, collagen diseases, chronic polyarthritis, psoriasis arthropathica, ankylosing spondylitis, juvenile rheumatoid arthritis, periarthritis humeroscapularis, panarteriitis nodosa, progressive systemic scleroderma, arthritis uratica, dermatomyositis, muscular rheumatism, myositis, myogelosis and chondrocalcinosis.

[0080] In another related object the detected diseases wll include rejection of any organ transplant and/or Graft versus host disease.

[0081] In a related aspect the foregoing assays will detect cells affected by the disease using the antibody that binds specifically to the H19011_1_P8 (SEQ ID NO:48) or H19011_1_P9 (SEQ ID NO:50), protein wherein the assays may be effected in vitro or in vivo, and include RIA, ELISA, fluorimetric assays, FACS, slot blot, Western blot, immunohistochemical assays, radioimaging assays and the like. In some embodiments, this invention provides a method for diagnosing a disease in a subject, comprising detecting in the subject or in a sample obtained from said subject at least one polypeptide or polynucleotide selected from the group consisting of: [0082] a polypeptide comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 147,148 and 299; [0083] An oligonucleotide having a nucleic acid sequence as set forth in SEQ. ID NOs: 235, 238, 241,244.

[0084] According to one embodiment, detecting the presence of the polypeptide or polynucleotide is indicative of the presence of the disease and/or its severity and/or its progress. According to another embodiment, a change in the expression and/or the level of the polynucleotide or polypeptide compared to its expression and/or level in a healthy subject or a sample obtained therefrom is indicative of the presence of the disease and/or its severity and/or its progress. According to a further embodiment, a change in the expression and/or level of the polynucleotide or polypeptide compared to its level and/or expression in said subject or in a sample obtained therefrom at earlier stage is indicative of the progress of the disease. According to still further embodiment, detecting the presence and/or relative change in the expression and/or level of the polynucleotide or polypeptide is useful for selecting a treatment and/or monitoring a treatment of the disease.

[0085] According to one embodiment, detecting a polynucleotide of the invention comprises employing a primer pair, comprising a pair of isolated oligonucleotides capable of specifically hybridizing to at least a portion of a polynucleotide having a nucleic acid sequence as set forth in SEQ. ID NOs: 235, 238, 241, 244 or polynucleotides homologous thereto.

[0086] According to another embodiment, detecting a polynucleotide of the invention comprises employing a primer pair, comprising a pair of isolated oligonucleotides as set forth in SEQ. ID NOs: 233-234, 236-237,239-240,242-243.

[0087] In another embodiment the invention includes an isolated C10RF32 ectodomain polypeptide, or fragment or conjugate thereof.

[0088] In another embodiment the invention includes any of the foregoing polypeptides, comprising a sequence of amino acid

residues having at least 95, 96, 97, 98 or 99% sequence identity with amino acid residues 21-186 of H19011_1_P8 (SEQ ID NO:48), corresponding to amino acid sequence depicted in SEQ ID NO:147, or residues 21-169 of H19011_1_P9 (SEQ ID NO:50), corresponding to amino acid sequence depicted in SEQ ID NO:148, or residues 1-184 of the sequence H19011_1_P8 (SEQ ID NO:48), corresponding to amino acid sequence depicted in SEQ ID NO:299.

[0089] In another embodiment the invention includes any of the foregoing polypeptides, comprising the extracellular domain of H19011_1_P8 (SEQ ID NO:48) or H19011_1_P9 (SEQ ID NO:50).

[0090] In another embodiment the invention includes any of the foregoing polypeptides, attached to a detectable or therapeutic moiety.

[0091] In another embodiment the invention includes any of the foregoing nucleic acid sequences encoding any one of the C20RF32 ectodomain polypeptides and conjugates containing.

[0092] In another embodiment the invention includes an expression vector containing any of the foregoing nucleic acid sequences.

[0093] In another embodiment the invention includes a host cell comprising the foregoing expression vector or a virus containing a nucleic acid sequence encoding the CIORF32 ectodomain polypeptide, or fragment or conjugate thereof, wherein the cell expresses the polypeptide encoded by the DNA segment.

[0094] In another embodiment the invention includes a method of producing anyone of the CIORF32 ectodomain polypeptides, or fragment or conjugate thereof, comprising culturing the foregoing host cell, wherein the cell expresses the polypeptide encoded by the DNA segment or nucleic acid and recovering said polypeptide.

[0095] In another embodiment the invention includes any of the foregoing isolated soluble C10RF32 ectodomain wherein said polypeptide blocks or inhibits the interaction of H19011_1_P8 (SEQ ID NO:48), H19011_1_P9 (SEQ ID NO:50), or a fragment or variant thereof with a corresponding functional counterpart.

[0096] In another embodiment the invention includes the foregoing isolated soluble C10RF32 ectodomains, wherein said polypeptide replaces or augments the interaction of H19011_1_P8 (SEQ ID NO:48), H19011_1_P9 (SEQ ID NO:50), or a fragment or variant or conjugate thereof with a corresponding functional counterpart.

[0097] In another embodiment the invention includes a fusion protein comprising any of the foregoing isolated soluble C10RF32, ectodomain joined to a non-C10RF32 protein sequence, correspondingly.

[0098] In another embodiment the invention includes any of the foregoing fusion proteins, wherein the non-C10RF32 protein is at least a portion of an immunoglobulin molecule.

[0099] In another embodiment the invention includes any of the foregoing fusion proteins, wherein a polyalkyl oxide moiety such as polyethylene glycol is attached to the polypeptide.

[0100] In another embodiment the invention includes any of the foregoing fusion proteins, wherein the immunoglobulin heavy chain constant region is an Fc fragment.

[0101] In another embodiment the invention includes any one of the protein sequences of the C10RF32 ECDs fused to mouse Fc, as set forth in any one of amino acid sequences as depicted in SEQ ID NO: 105, or nucleic acid sequences encoding the C1QRF32 ECDs fused to mouse Fc. The invention further includes the nucleic acid sequences encoding the C10RF32 ECDs fused to mouse Fc, as set forth in any one of nucleic acid sequences depicted in SEQ ID NO:99.

[0102] In another embodiment the invention includes any of the foregoing fusion proteins wherein the immunoglobulin heavy chain constant region is an isotype selected from the group consisting of an lgG1, lgG2, lgG3, lgG4, IgM, IgE, IgA and IgD.

[0103] In another embodiment the invention includes any of the foregoing fusion proteins, wherein the polypeptide is fused to a VASP domain.

[0104] In another embodiment the invention includes any of the foregoing fusion proteins, wherein the fusion protein modulates lymphocyte activation.

[0105] In another embodiment the invention includes a pharmaceutical composition comprising any of the foregoing polynucleotide sequences and further comprising a pharmaceutically acceptable diluent or carrier.

[0106] In another embodiment the invention includes a pharmaceutical composition comprising the foregoing vector and further comprising a pharmaceutically acceptable diluent or carrier.

[0107] In another embodiment the invention includes a pharmaceutical composition comprising the foregoing host cell and further comprising a pharmaceutically acceptable diluent or carrier.

[0108] In another embodiment the invention includes a pharmaceutical composition comprising any of the foregoing C10RF32; ectodomains and further comprising a pharmaceutically acceptable diluent or carrier.

[0109] In another embodiment the invention includes a pharmaceutical composition comprising any of the foregoing polypeptides and further comprising a pharmaceutically acceptable diluent or carrier.

[0110] In another embodiment the invention includes a pharmaceutical composition comprising the foregoing fusion protein and further comprising a pharmaceutically acceptable diluent or carrier.

[0111] In another embodiment the invention includes a method for treating or preventing cancer, comprising administering to a subject in need thereof a pharmaceutical composition comprising: a soluble molecule having the extracellular domain of C10RF32 polypeptide, or fragment or conjugate thereof; or polypeptide, comprising a sequence of amino acid residues having at least 95, 96, 97, 98 or 99% sequence identity with amino acid residues 21-186 of H19011_1_P8 (SEQ ID NO:48), corresponding to amino acid sequence depicted in SEQ ID NO:147, or residues 21-169 of H19011_1_P9 (SEQ ID NO:50), corresponding to amino acid sequence depicted in SEQ ID NO:148, or residues 1-184 of the sequence H19011_1_P8 (SEQ ID NO:48), corresponding to amino acid sequence depicted in SEQ ID NO:299 or a nucleic acid sequence encoding the same.

[0112] In another embodiment the invention includes the foregoing method, wherein the cancer is selected from a group consisting of hematological malignancies such as acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, multiple myeloma, Hodgkin's lymphoma, Non-Hodgkin's lymphoma, and soft or solid tumors such as cancer of breast, prostate, lung, ovary, colon, spleen, kidney, bladder, head and neck, uterus, testicles, stomach, cervix, liver, bone, skin, pancreas, brain and wherein the cancer is non-metastatic, invasive or metastatic.

[0113] In another embodiment the invention includes the foregoing method wherein the cancer is selected from the group consisting of lung cancer, ovarian cancer or colon cancer, and wherein the lung cancer, the ovarian cancer or the colon cancer is non-metastatic, invasive or metastatic.

[0114] In another embodiment the invention includes a method for treating or preventing immune related conditions, such as autoimmune diseases or transplant rejection, comprising administering to a subject in need thereof a pharmaceutical composition comprising: a soluble molecule having the extracellular domain of C10RF32 polypeptide, or fragment or conjugate thereof; or polypeptide, comprising a sequence of amino acid residues having at least 95, 96, 97, 98 or 99% sequence identity with amino acid residues 21-186 of H19011_1_P8 (SEQ ID NO:48), corresponding to amino acid sequence depicted in SEQ ID NO:147, or residues 21-169 of H19011_1_P9 (SEQ ID NO:50), corresponding to amino acid sequence depicted in SEQ ID NO:148, residues 1-184 of the sequence H190111P8 (SEQ ID NO:48), corresponding to amino acid sequence depicted in SEQ ID NO:299, or a nucleic acid sequence encoding the same.

[0115] In another embodiment the invention includes the foregoing method, wherein the autoimmune diseases are selected from a group consisting of multiple sclerosis; psoriasis; rheumatoid arthritis; systemic lupus erythematosus; ulcerative colitis; Crohn's disease; immune disorders associated with graft transplantation rejection; benign lymphocytic angiitis, lupus erythematosus, Hashimoto's thyroiditis, primary myxedema, Graves' disease, pernicious anemia, autoimmune atrophic gastritis, Addison's disease, insulin dependent diabetes mellitis, Good pasture's syndrome, myasthenia gravis, pemphigus, sympathetic ophthalmia, autoimmune uveitis, autoimmune hemolytic anemia, idiopathic thrombocytopenia, primary biliary cirrhosis, chronic action hepatitis, ulceratis colitis, Sjogren's syndrome, rheumatic disease, polymyositis, scleroderma, mixed connective tissue disease, inflammatory rheumatism, degenerative rheumatism, extra- articular rheumatism, collagen diseases, chronic polyarthritis, psoriasis arthropathica, ankylosing spondylitis, juvenile rheumatoid arthritis, periarthritis humeroscapularis, panarteriitis nodosa, progressive systemic scleroderma, arthritis uratica, dermatomyositis, muscular rheumatism, myositis, myogelosis and chondrocalcinosis.

[0116] In another embodiment the invention includes the foregoing method, wherein the immune related disorders are selected from transplant rejection or graft versus host disease.

[0117] In another embodiment the invention includes a polyclonal or monoclonal antibody that specifically binds and/or modulates an activity elicited by any one of the C10RF32 polypeptides, selected from H19011_1_P8 (SEQ ID NO:48), H19011_1_P9 (SEQ ID NO:50), or a fragment or a variant thereof and conjugates containing.

[0118] In another embodiment the invention includes a monoclonal or polyclonal antibody or an antigen binding fragment thereof comprising an antigen binding site that binds specifically to any one of the C10RF32 polypeptides comprised in H19011_1_P8 (SEQ ID NO:48), H19011_1_P9 (SEQ ID NO:50), or fragment or variant thereof that is at least 80% identical thereto.

[0119] In another embodiment the invention includes any of the foregoing antibodies or fragments thereof, wherein said antibody blocks or inhibits the interaction of one of H19011_1_P8 (SEQ ID NO:48), H19011_1_P9 (SEQ ID NO:50), or a fragment or variant thereof with a counterpart activity or function.

[0120] In another embodiment the invention includes any of the foregoing antibodies or fragments wherein said antibody replaces or augments the interaction of H19011_1_P8 (SEQ ID NO:48), H19011_1_P9 (SEQ ID NO:50), or a fragment or variant thereof with a counterpart function or activity.

[0121] In another embodiment the invention includes a method for modulating lymphocyte activity, comprising contacting a H19011_1_P8 (SEQ ID NO:48), H19011_1_P9 (SEQ ID NO:50) positive lymphocyte with a bioactive agent capable of modulating C10RF32-mediated signaling in an amount effective to modulate at least one lymphocyte activity.

[0122] In another embodiment the invention includes the foregoing method, wherein said agent comprises an antagonist of C10RF32-mediated signaling and wherein said contacting inhibits the attenuation of lymphocyte activity mediated by such signaling.

[0123] In another embodiment the invention includes the foregoing method, wherein said contacting increases lymphocyte activity.

[0124] In another embodiment the invention includes the foregoing method wherein said antagonist comprises a blocking agent capable of interfering with the functional interaction of C1ORF32 antigen and its counterpart.

[0125] In another embodiment the invention includes the foregoing antibody or fragment which is suitable for treatment or prevention of cancer by modulating the activity of any one of the C1ORF32 proteins in a B7-like co-stimulatory system.

[0126] In another embodiment the invention includes the foregoing method wherein the administered antibody or fragment inhibits negative stimulation of T cell activity against cancer cells.

[0127] In another embodiment the invention includes any of the foregoing antibodies or fragments, wherein the cancer is selected from the group consisting of hematological malignancies such as acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, multiple myeloma, Hodgkin's lymphoma, Non-Hodgkin's lymphoma, and soft tissue or solid tumors such as cancer of breast, prostate, lung, ovary, colon, spleen, kidney, bladder, head and neck, uterus, testicles, stomach, cervix, liver, bone, skin, pancreas, brain and wherein the cancer is non-metastatic, invasive or metastatic.

[0128] In another embodiment the invention includes any of the foregoing antibodies or fragments, which are suitable for treatment or prevention of immune related disorders, such as autoimmune diseases or transplant rejection, by modulating the activity of anyone of the C1ORF32 proteins in a B7-like co-stimulatory system.

[0129] In another embodiment the invention includes any of the foregoing antibodies or fragments, which are suitable for treating an autoimmune disease selected from multiple sclerosis; psoriasis; rheumatoid arthritis; Systemic lupus erythematosus; ulcerative colitis; Crohn's disease, immune disorders associated with graft transplantation rejection, benign lymphocytic angiitis, lupus erythematosus, Hashimoto's thyroiditis, primary myxedema, Graves' disease, pernicious anemia, autoimmune atrophic gastritis, Addison's disease, insulin dependent diabetes mellitus, Good pasture's syndrome, myasthenia gravis, pemphigus, sympathetic ophthalmia, autoimmune uveitis, autoimmune hemolytic anemia, idiopathic thrombocytopenia, primary biliary cirrhosis, chronic action hepatitis, Sjogren's syndrome, rheumatic disease, polymyositis, scleroderma, mixed connective tissue disease, inflammatory rheumatism, degenerative rheumatism, extra- articular rheumatism, collagen diseases, chronic polyarthritis, psoriasis arthropathica, ankylosing spondylitis, juvenile rheumatoid arthritis, periarthritis humeroscapularis, panarteriitis nodosa, progressive systemic scleroderma, arthritis uratica, dermatomyositis, muscular rheumatism, myositis, myogelosis and chondrocalcinosis.

[0130] In another embodiment the invention includes any of the foregoing antibodies or fragments, suitable for treating transplant rejection or graft versus host disease.

[0131] In another embodiment the invention includes any of the foregoing antibodies or fragments, that specifically binds to amino-acids: amino acid residues 21-186 of H19011_1_P8 (SEQ ID NO:48), corresponding to amino acid sequence depicted in SEQ ID NO:147, or residues 21-169 of H19011_1_P9 (SEQ ID NO:50), corresponding to amino acid sequence depicted in SEQ ID NO:148, or residues 1-184 of the sequence H19011_1_P8 (SEQ ID NO:48), corresponding to amino acid sequence depicted in SEQ ID NO:299, or a variant or fragment or an epitope thereof.

[0132] In another embodiment the invention includes any of the foregoing antibodies or fragments, wherein the antigen binding site contains from about 3-7 contiguous or non-contiguous amino acids, more typically at least 5 contiguous or non-contiguous amino acids. These binding sites include conformational and non-conformational epitopes.

[0133] In another embodiment the invention includes any of the foregoing antibodies or fragments, wherein the antibody is a fully human antibody.

[0134] In another embodiment the invention includes any of the foregoing antibodies or fragments, wherein the antibody is a chimeric antibody.

[0135] In another embodiment the invention includes the foregoing antibodies or fragments wherein the antibody is a humanized or primatized antibody.

[0136] In another embodiment the invention includes any of the foregoing antibodies or fragments, wherein the fragment is selected from the group consisting of Fab, Fab', F(ab')2, F(ab'), F(ab), Fv or scFv fragment and minimal recognition unit.

[0137] In another embodiment the invention includes any of the foregoing antibodies or fragments, wherein the antibody or fragment is coupled to a detectable marker, or to an effector moiety.

[0138] In another embodiment the invention includes any of the foregoing antibodies or fragments, wherein the effector moiety is an enzyme, a toxin, a therapeutic agent, or a chemotherapeutic agent.

[0139] In another embodiment the invention includes any of the foregoing antibodies or fragments, wherein the detectable marker is a radioisotope, a metal chelator, an enzyme, a fluorescent compound, a bioluminescent compound or a chemiluminescent compound.

[0140] In another embodiment the invention includes a pharmaceutical composition that comprises any of the foregoing antibodies or a fragment thereof.

[0141] In another embodiment the invention includes a pharmaceutical composition that comprises the foregoing antibodies or a fragment thereof.

[0142] In another embodiment the invention includes a method of inducing or enhancing an immune response, comprising administering to a patient in need thereof any of the foregoing antibodies or fragments and detecting induction or enhancement of said immune response.

[0143] In another embodiment the invention includes a method for potentiating a secondary immune response to an antigen in a patient, which method comprises administering effective amounts any of the foregoing antibodies or fragments.

[0144] In another embodiment the invention includes the foregoing method, wherein the antigen is preferably a cancer antigen, a viral antigen or a bacterial antigen, and the patient has preferably received treatment with an anticancer vaccine or a viral vaccine.

[0145] In another embodiment the invention includes a method of treating a patient with a C1CRF32 positive malignancy, comprising administering to the patient an effective amount of any of the foregoing antibodies or fragments.

[0146] In another embodiment the invention includes the foregoing method further comprising co-administering a chemotherapeutic agent.

[0147] In another embodiment the invention includes the foregoing method, wherein said malignancy is selected from a group consisting of hematological malignancies such as acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, multiple myeloma, Hodgkin's lymphoma, Non-Hodgkin's lymphoma, and soft or solid tumors such as cancer of breast, prostate, lung, ovary, colon, spleen, kidney, bladder, head and neck, uterus, testicles, stomach, cervix, liver, bone, skin, pancreas, brain and wherein the cancer is non-metastatic, invasive or metastatic.

[0148] In another embodiment the invention includes the foregoing method, wherein said malignancy is selected from the group consisting of lung cancer, ovarian cancer, colon cancer, and wherein the lung cancer, the ovarian cancer or the colon cancer is non-metastatic, invasive or metastatic.

[0149] In another embodiment the invention includes an assay for detecting the presence of H19011_1_P8 (SEQ ID NO:48), H19011_1_P9 (SEQ ID NO:50), or a fragment or variant thereof in a biological sample comprising contacting the sample with an antibody of any one of the foregoing, and detecting the binding of H19011_1_P8 (SEQ ID NO:48), H19011_1_P9 (SEQ ID NO:50), or a fragment or variant thereof in the sample.

[0150] In another embodiment the invention includes a method for detecting a disease, diagnosing a disease, monitoring disease progression or treatment efficacy or relapse of a disease, or selecting a therapy for a disease, comprising detecting expression of a H19011_1_P8 (SEQ ID NO:48), H19011_1_P9 (SEQ ID NO:50), or a fragment or variant thereof.

[0151] In another embodiment the invention includes the forgoing method wherein detecting expression H19011_1_P8 (SEQ ID NO:48), H19011_1_P9 (SEQ ID NO:50), or a fragment or variant thereof is performed in vivo or in vitro.

[0152] In another embodiment the invention includes the foregoing method, wherein the disease is selected from lung cancer, ovarian cancer, or colon cancer, and wherein the lung cancer, the ovarian cancer or the colon cancer is non-metastatic, invasive or metastatic.

[0153] In another embodiment the invention includes the foregoing method, wherein the disease is multiple sclerosis; psoriasis; rheumatoid arthritis; Systemic lupus erythematosus; ulcerative colitis; Crohn's disease; immune disorders associated with graft transplantation rejection, benign lymphocytic angiitis, lupus erythematosus, Hashimoto's thyroiditis, primary myxedema, Graves' disease, pernicious anemia, autoimmune atrophic gastritis, Addison's disease, insulin dependent diabetes mellitis, good pasture's syndrome, myasthenia gravis, pemphigus, sympathetic ophthalmia, autoimmune uveitis, autoimmune hemolytic anemia, idiopathic thrombocytopenia, primary biliary cirrhosis, chronic action hepatitis, ulceratis colitis, Sjogren's syndrome, rheumatic disease, polymyositis, scleroderma, mixed connective tissue disease, inflammatory rheumatism, degenerative rheumatism, extra- articular rheumatism, collagen diseases, chronic polyarthritis, psoriasis arthropathica, ankylosing spondylitis, juvenile rheumatoid arthritis, periarthritis humeroscapularis, panarteriitis nodosa, progressive systemic scleroderma, arthritis uratica, dermatomyositis, muscular rheumatism, myositis, myogelosis or chondrocalcinosis.

[0154] In another embodiment the invention includes a method of inhibiting growth of cells that express a polypeptide selected from H19011_1_P8 (SEQ ID NO:48), H19011_1_P9 (SEQ ID NO:50), or a fragment or variant thereof in a subject, comprising: administering to said subject any of the foregoing antibodies or fragments.

[0155] In another embodiment the invention includes a method of treating or preventing cancer comprising the administration of a inerapeuncaiiy eneciive amount 01 an anuoouy or Dinaing tragmem inai specmcany Dinas ine i-i i yu 11_i_i-ό iu Nu:4aj, H19011_1_P9 (SEQ ID NO:50), or a fragment or variant thereof that possesses at least 80% sequence identity therewith.

[0156] In another embodiment the invention includes the foregoing method, wherein the cancer is selected from a group consisting of hematological malignancies such as acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, multiple myeloma, Hodgkin's lymphoma, Non-Hodgkin's lymphoma, and soft or solid tumors such as cancer of breast, prostate, lung, ovary, colon, spleen, kidney, bladder, head and neck, uterus, testicles, stomach, cervix, liver, bone, skin, pancreas, brain and wherein the cancer is non-metastatic, invasive or metastatic.

[0157] In another embodiment the invention includes the foregoing method, wherein the cancer is selected from the group consisting of lung cancer, ovarian cancer, or colon cancer, and wherein the lung cancer, the ovarian cancer or the colon cancer is non-metastatic, invasive or metastatic.

[0158] In another embodiment the invention includes the foregoing method wherein the antibody is a human, humanized or chimeric antibody or antigen binding fragment.

[0159] In another embodiment the invention includes the foregoing method wherein the antibody or fragment is attached directly or indirectly to an effector moiety.

[0160] In another embodiment the invention includes the foregoing method, wherein the effector is selected from a drug, toxin, radionuclide, fluorophore and an enzyme.

[0161] In another embodiment the invention includes a method for treating or preventing an immune disorder, such as autoimmune or transplant related disease, comprising administering to a patient a therapeutically effective amount of an antibody that specifically binds to H19011_1_P8 (SEQ ID NO:48), H19011_1_P9 (SEQ ID NO:50), [0162] or a fragment or variant thereof that possesses at least 80% sequence identity therewith.

[0163] In another embodiment the invention includes the foregoing method, wherein the antibody has an antigen-binding region specific for the extracellular domain of any one of said CTORF32, polypeptides.

[0164] In another embodiment the invention includes the foregoing method, wherein the antibody or fragment modulates the B7/co-stimulatory system in a manner that inhibits positive stimulation of T cell activity that created an autoimmune effect.

[0165] In another embodiment the invention includes the foregoing method, wherein the treatment is combined with a moiety useful for treating autoimmune or transplant rejection conditions.

[0166] In another embodiment the invention includes the foregoing method, wherein the moiety is a cytokine antibody, cytokine receptor antibody, drug, or another immunomodulatory agent.

[0167] In another embodiment the invention includes the foregoing method, wherein the autoimmune diseases are selected from a group consisting of multiple sclerosis; psoriasis; rheumatoid arthritis; systemic lupus erythematosus; ulcerative colitis; Crohn's disease; immune disorders associated with graft transplantation rejection, benign lymphocytic angiitis, lupus erythematosus, Hashimoto's thyroiditis, primary myxedema, Graves' disease, pernicious anemia, autoimmune atrophic gastritis, Addison's disease, insulin dependent diabetes mellitis, Good pasture's syndrome, myasthenia gravis, pemphigus, sympathetic ophthalmia, autoimmune uveitis, autoimmune hemolytic anemia, idiopathic thrombocytopenia, primary biliary cirrhosis, chronic action hepatitis, ulceratis colitis, Sjogren's syndrome, rheumatic disease, polymyositis, scleroderma, mixed connective tissue disease, inflammatory rheumatism, degenerative rheumatism, extra- articular rheumatism, collagen diseases, chronic polyarthritis, psoriasis arthropathica, ankylosing spondylitis, juvenile rheumatoid arthritis, periarthritis humeroscapularis, panarteriitis nodosa, progressive systemic scleroderma, arthritis uratica, dermatomyositis, muscular rheumatism, myositis, myogelosis and chondrocalcinosis.

[0168] In another embodiment the invention includes the foregoing method wherein the immune disorder is transplant rejection or graft versus host disease.

[0169] In another embodiment the invention includes a method of using an antibody or antigen binding fragment that specifically binds H19011_1_P8 (SEQ ID NO:48), H190111P9 (SEQ ID NO:50), or a fragment or variant thereof for in vivo imaging of tumors or inflammatory sites characterized by the differential expression of H190111P8 (SEQ ID NO:48), H190111P9 (SEQ ID NO:50), or a fragment or variant thereof.

[0170] In another embodiment the invention includes the foregoing method which is used in assessing cancer prognosis or a treatment protocol.

[0171] In another embodiment the invention includes a method for screening for a disease in a subject, comprising detecting in the subject or in a sample obtained from said subject a polypeptide having a sequence at least 85% homologous to the amino acid sequence as set forth in any one of H190111P8 (SEQ ID NO:48), H19011_1_P9 (SEQ ID NO:50), or with a polypeptide having a sequence comprising the extracellular domain of any one of H19011_1_P8 (SEQ ID NO:48), H190111P9 (SEQ. ID NO: 50) [0172] In another embodiment the invention includes the foregoing method wherein screening for a disease comprises detecting the presence or severity of the disease, disorder or condition, or prognosis of the subject, or treatment selection for said subject, or treatment monitoring of said subject.

[0173] In another embodiment the invention includes the foregoing method, wherein the disease is a cancer, selected from the group consisting of lung cancer, ovarian cancer, colon cancer, and wherein the lung cancer, the ovarian cancer and the colon cancer is non-metastatic, invasive or metastatic.

[0174] In another embodiment the invention includes the foregoing method wherein the disease is autoimmune disease and is selected from multiple sclerosis; psoriasis; rheumatoid arthritis; systemic lupus erythematosus; ulcerative colitis; Crohn's disease; immune disorders associated with graft transplantation rejection; benign lymphocytic angiitis, lupus erythematosus, Hashimoto's thyroiditis, primary myxedema, Graves' disease, pernicious anemia, autoimmune atrophic gastritis, Addison's disease, insulin dependent diabetes mellitis, Good pasture's syndrome, myasthenia gravis, pemphigus, sympathetic ophthalmia, autoimmune uveitis, autoimmune hemolytic anemia, idiopathic thrombocytopenia, primary biliary cirrhosis, chronic action hepatitis, ulceratis colitis, Sjogren's syndrome, rheumatic disease, polymyositis, scleroderma, mixed connective tissue disease, inflammatory rheumatism, degenerative rheumatism, extra- articular rheumatism, collagen diseases, chronic polyarthritis, psoriasis arthropathica, ankylosing spondylitis, juvenile rheumatoid arthritis, periarthritis humeroscapularis, panarteriitis nodosa, progressive systemic scleroderma, arthritis uratica, dermatomyositis, muscular rheumatism, myositis, myogelosis and chondrocalcinosis.

[0175] In another embodiment the invention includes the foregoing method, wherein the detection is conducted by immunoassay.

[0176] In another embodiment the invention includes the foregoing method, wherein the immunoassay utilizes an antibody which specifically interacts with the polypeptide having a sequence at least 85% homologous to the amino acid sequence as set forth in any one of H19011_1_P8 (SEQ ID NO:48), H19011_1_P9 (SEQ ID NO:50), or with a polypeptide having a sequence comprising the extracellular domain of any one of H19011_1_P8 (SEQ ID NO:48), H19011_1_P9 (SEQ ID NO:50), [0177] In another embodiment the invention includes an antibody specific to H19011_1_P8 (SEQ ID NO:48), H19011_1_P9 (SEQ ID NO:50), or a fragment or variant thereof that elicits apoptosis or lysis of cancer cells that express said protein.

[0178] In another embodiment the invention includes any of the foregoing antibodies or fragments, wherein said apoptosis or lysis activity involves CDC or ADCC activity of the antibody.

[0179] In another embodiment the invention includes any of the foregoing antibodies or fragments, wherein the cancer cells are selected from a group consisting of hematological malignancies such as acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, multiple myeloma, Hodgkin's lymphoma, Non-Hodgkin's lymphoma, and soft or solid tumors such as cancer of breast, prostate, lung, ovary, colon, spleen, kidney, bladder, head and neck, uterus, testicles, stomach, cervix, liver, bone, skin, pancreas, and brain.

[0180] In another embodiment the invention includes any of the foregoing antibodies or fragments, wherein the cancer cells are lung, ovarian or colon cancer cells.

[0181] In another embodiment the invention relates to any of the foregoing isolated soluble C10RF32 ectodomain polypeptides, wherein said polypeptide or a fragment or variant thereof is used as an anti-cancer vaccine for cancer immunotherapy.

[0182] In another embodiment the invention relates to any an isolated polynucleotide, comprising an amplicon having a nucleic acid sequence selected from the group consisting of 235, 238, 241,244, or polynucleotides homologous thereto.

[0183] In another embodiment the invention relates to any a primer pair, comprising a pair of isolated oligonucleotides capable of amplifying the above mentioned amplicon.

[0184] The primer pair, comprising a pair of isolated oligonucleotides having a sequence selected from the group consisting of SEQ. ID NOs: 233-234, 236-237, 239-240, 242-243 [0185] A method for screening for a disease, disorder or condition in a subject, comprising detecting in the subject or in a sample obtained from said subject a polynucleotide having a sequence at least 85% homologous to the nucleic acid sequence as set forth in any one of SEQ ID NOs: 235, 238, 241,244.

[0186] The method as above, wherein screening for a disease comprises detecting the presence or severity of the disease, disorder or condition, or prognosis of the subject, or treatment selection for said subject, or treatment monitoring.

[0187] The method as above, wherein the disease is a cancer, selected from the group consisting of lung cancer, colon cancer and ovarian cancer, and wherein the lung cancer, colon cancer and ovarian cancer is non-metastatic, invasive or metastatic.

[0188] The method as above, wherein the disease is autoimmune disease.

[0189] The method as above, wherein the detection is performed using an oligonucleotide pair capable of hybridizing to at least a portion of a nucleic acid sequence at least 85% homologous to the nucleic acid sequence set forth in SEQ. ID NO: 235, 238, 241,244.

[0190] The method as above wherein the detection is performed using an oligonucleotide pair as set forth in any one of SEQ. ID NOs: 233-234, 236-237, 239-240, 242-243.

BRIEF DESCRIPTION OF THE FIGURES

[0191]

Figure 1 shows a schematic summary of quantitative real-time PCR analysis.

Figures 38A-38B show alignment comparison of the H19011_1_P8 (Figure 38A) and H19011_1_P9 (Figure 38B) proteins to the known C10RF32 proteins Q71H61 _HUMAN and NP_955383 (SEQ ID NO: 47).

Figure 39 presents a histogram showing expression of C10RF32, chromosome 1 open reading frame 32, H19011 transcripts which are detectable by amplicon as depicted in sequence name H19011_seg13F2R2 (SEQ ID NO: 235) in normal and cancerous Colon tissues.

Figure 40 presents a histogram showing expression of C10RF32, chromosome 1 open reading frame 32, H19011 transcripts which are detectable by amplicon as depicted in sequence name H19011_seg13F2R2 (SEQ ID NO: 235) in normal and cancerous lung tissues.

Figures 41A-41B present a histogram showing expression of C10RF32, chromosome 1 open reading frame 32, H19011 transcripts which are detectable by amplicon as depicted in sequence name H19011_seg13F2R2 (SEQ ID NO: 235) in various normal tissues. Figure 41A shows expression of each sample relative to median of the colon samples; Figure 41B shows expression of each sample relative to median of the lung samples.

Figure 42 presents a histogram showing expression of C10RF32, chromosome 1 open reading frame 32, H19011 transcripts which are detectable by amplicon as depicted in sequence name H19011_seg8-13F1R1 (SEQ ID NO: 238) in normal and cancerous lung tissues.

Figure 43 presents a histogram showing expression of C10RF32, chromosome 1 open reading frame 32, H19011 transcripts which are detectable by amplicon as depicted in sequence name H19011-junc8-10seg13 (SEQ ID NO: 241) in normal and cancerous lung tissues.

Figure 44 presents a histogram showing expression of C10R2F32, chromosome 1 open reading frame 32, H19011 transcripts which are detectable by amplicon as depicted in sequence name H19011 Junc8-10seg13 (SEQ ID NO: 241) in normal and cancerous colon tissues.

Figures 45A-45B presents a histogram showing expression of C10RF32, chromosome 1 open reading frame 32, H19011 transcripts which are detectable by amplicon as depicted in sequence name H19011 Junc8-10seg13 (SEQ ID NO: 241) in various normal tissues. Figure 45A shows expression of each sample relative to median of the colon samples; Figure 45B shows expression of each sample relative to median of the lung samples.

Figure 46 presents a histogram showing expression of C10RF32, chromosome 1 open reading frame 32, H19011 transcripts which are detectable by amplicon as depicted in sequence name H19011Junc8-10seg13 (SEQ ID NO: 241) in blood-specific panel.

Figure 47 presents a histogram showing expression of 01ORF32, chromosome 1 open reading frame 32, H19011 transcripts which are detectable by amplicon as depicted in sequence name H19011Junc6-10F1R1 (SEQ ID NO: 244) in normal and cancerous lung tissues.

Figure 48 presents a histogram showing expression of C10RF32, chromosome 1 open reading frame 32, H19011 transcripts which are detectable by amplicon as depicted in sequence name H19011_junc6-10F1R1 (SEQ ID NO: 244) in normal and cancerous colon tissues.

Figure 56A-56J presents the nucleotide sequences of the recombinant full length_EGFP ORFs: gene specific sequence correspond to the candidate's full length sequence is marked in bold, EGFP sequence is unbold Italic and known SNPs/silence mutation are underlined. Figure 56A presents the full lengthEGFP ORF nucleic acid sequence of FXYD3T0P0EGFP DNA (996bp) (SEQ ID NO:77); Figure 56B presents the full length EGFP ORF nucleic acid sequence of FXYD3T25P14EGFP DNA (1083bp) (SEQ ID NO:78); Figure 56C presents the full length EGFP ORF nucleic acid sequence of AI216611_T0_P0_EGFP DNA (1371 bp) (SEQ ID NO:79); Figure 56D presents the full length_EGFP ORF nucleic acid sequence of AI21b611_T1_P1_EGFP DNA(1332bp) (SEQ ID NO:80); Figure 56E presents the full length_EGFP ORF nucleic acid sequence of C10RF32_T8_P8_EGFP DNA (1533bp) (SEQ ID NO:81); Figure 56F presents the full length_EGFP ORF nucleic acid sequence of LOC253012_T4_P5_EGFP DNA(2085bp) (SEQ ID NO:82); Figure 56G presents the full length_EGFP ORF nucleic acid sequence of ILDR1_T0_P3_EGFP DNA(2373bp) (SEQ ID NO:83); Figure 56H presents the full length EGFP ORF nucleic acid sequence of ILDR1_T2_P5_EGFP DNA(2241bp) (SEQ ID NO:84); Figure 56I presents the full length EGFP ORF nucleic acid sequence of VSIG1_T6_P5_EGFP DNA(2082bp) (SEQ ID NO:85); Figure 56J presents the full length EGFP ORF nucleic acid sequence of VSIG1_T5_P4_EGFP DNA (2004bp) (SEQ ID NO:86).

Figure 57A-57J presents the sequences of the full length EGFP fusion proteins. Candidate's specific sequence corresponding to the full length sequence of the protein is marked in bold, EGFP sequence is unbold Italic and amino acids modified due to known SNPs are underlined. Figure 57A presents the full length_EGFP ORF amino acid sequence of FXYD3 P0_EGFP protein (331aa) (SEQ ID NO:87); Figure 57B presents the full length_EGFP ORF amino acid sequence of FXYD3_P14_EGFP protein (360aa) (SEQ ID NO:88); Figure 57C presents the full length_EGFP ORF amino acid sequence of AI216611_P0_EGFP protein (456aa) (SEQ ID NO:89); Figure 57D presents the full length_EGFP ORF amino acid sequence of AI216611_P1_EGFP protein (443aa) (SEQ ID NO:90); Figure 57E presents the full length_EGFP ORF amino acid sequence of C10RF32_P8_EGFP protein (510aa) (SEQ ID NO:91); Figure 57F presents the full length_EGFP ORF amino acid sequence of LOC253012_P5_EGFP protein (694aa) (SEQ ID NO:92); Figure 57G presents the full length_EGFP ORF amino acid sequence of ILDR1_P3_EGFP protein (790aa) (SEQ ID NO:93); Figure 57H presents the full length_EGFP ORF amino acid sequence of ILDR1_P5_EGFP protein (746aa) (SEQ ID NO:94); Figure 57I presents the full length_EGFP ORF amino acid sequence of VSIG1_P5_EGFP protein (693aa) (SEQ ID NO:95); Figure 57J presents the full length_EGFP ORF amino acid sequence of VSIG1_P4_EGFP protein (667aa) (SEQ ID NO:96).

Figures 58A-58F demonstrate the localization of the proteins to cell membrane: Figure 58A shows cellular localization of AI216611-EG_FP_T0_P0 and AI216611-EGFP_T1_P1 proteins Figure 58B shows cellular localization of FXYD3-EGFP_T0_P0 and FXYD3-EGFP_T25_P14 proteins. Figure 58C shows cellular localization of C10RF32-EGFP_T8_P8 protein. Figure 58D shows cellular localization of LOC253012-EGFP_T4_P5 protein. Figure 58E shows cellular localization of VSIG1-EGFP_T6_P5 and VSIG1-EGFP_T5_P4 proteins. Figure 58F shows cellular localization of ILDR1-EGFP_T0_P3 and ILDR1-EGFP_T2_P5 proteins. All the images were obtained using the 40x objective of the confocal microscope.

Figures 59A-59F present the nucleotide sequences of the extracellular domains of the proteins, fused to mouse Fc: ECDjnFc ORFs. protein's specific sequence corresponding to the ECD sequence is marked in bold, TEV cleavage site sequence is underlined, mFc sequence is unbold Italic and IL6sp sequence is bold Italic. Figure 59A shows the FXYD3_T25_P14_ECD-_mFc DNA sequence (924bp) (SEQ ID NO:97); Figure 59B shows the AI216611_T0_P0_ECD_mFc DNA sequence (1170bp) (SEQ ID NO:98), Figure 59C shows the C10RF32_T8_P8_ECD_mFc DNA sequence (1287bp) (SEQ ID NO:99); Figure 59D shows the LOC253012_T4_P5_ECD_mFc DNA sequence (1740bp) (SEQ ID NO:100), Figure 59E shows the ILDR1_T0_P3_ECD_mFc DNA sequence (1167bp) (SEQ ID NO:101), and Figure 59F shows the VSIG1_T6_P5_ECD_mFc DNA sequence (1641 bp) (SEQ ID NO: 102).

Figures 60A- 60F present the amino acid sequence of the ECD_mFc fusion proteins, protein's specific sequence corresponding to the ECD sequence is marked in bold, TEV cleavage site sequence is underlined, mFc sequence is unbold Italic and IL6sp sequence is bold Italic. Figure 60A shows the FX7D3_T25_P14_ECD-_mFc amino acid sequence (307aa) (SEQ ID NO: 103); Figure 60B shows the AI216611_T0_P0_ECD_mFc amino acid sequence (389aa) (SEQ ID NO:104) Figure 60C shows the C10RF32_T8_P8_ECD_mFc amino acid sequence (428aa) (SEQ ID NO: 105); Figure 60D shows the LOC253012_T4_P5_ECD_mFc amino acid sequence (579aa) (SEQ ID NO:106), Figure 60E shows the ILDR1_T0_P3_ECD_mFc amino acid sequence (388aa) (SEQ ID NO: 107), and Figure 60F shows the VSIG1_T6_P5_ECD_mFc amino acid sequence (546aa) (SEQ ID NO: 108).

Figure 61 shows the results of a western blot analysis of the expressed FXYD3_ECD_mFc (SEQ ID NO: 103), AI216611 ECD_mFc (SEQ ID NO: 104), 01ORF32_ECD_mFc (SEQ ID NO:105), LOC253012_ECD_mFc (SEQ ID NO:106), ILDR1_ECD_mFc (SEQ ID NO:107), VSIG1_ECD_mFc (SEQ ID NO:108). The lanes are as follows: lane 1 Molecular weight markers (Amersham, full range ranbow,catalog number RPN800); lane 2- LOC253012_ECD_mFc; lane 3-FXYD3_ECD_mFc; lane 4-AI216611 ECDmFc; lane 5- C10RF32_ECD_mFc; lane 6-ILDR1_ECD_mFc; lane 7- VSIG1_ECD_mFc.

Figures 62A-62E present the binding of the Fc-fused B7-like proteins ECDs to resting T cells or T cells activated with Con A for different periods of time. Figure 62A shows the binding results for Fc-fused VSIG1 ECD; Figure 62B shows the binding results for Fc-fused LOC253012; Figure 62C shows the binding results for Fc-fused C10RF3 ECD; and Figure 62D shows the binding results for Fc-fused AI216611 ECD. Figure 62E shows the binding results for Fc-fused FXYD3 ECD.

Figure 63 presents the dose response of the binding of Fc-fused B7-like proteins ECDs to activated T cells. Purified T cells were cultured for 48 hours. Con A was added for the last 24 hours. Cells were then harvested and stained with increasing concentrations (3, 6, 12, 25 and 50 pg/ml) of Fc-fused VSIG1, LOC253012, C10RF32, AI216611, ILDR1 or FXYD3 ECDs. As negative controls, mouse lgG2a was used at the same concentrations.

Figures 64A-64B present the effect of the ECD-Fc fused proteins on T cells proliferation or IL-2 secretion, upon activation with anti-CD3 Ab. Figure 64A shows the levels of BrdU incorporation. Figure 64B shows the levels of IL-2 secretion.

Figure 65 illustrates the binding of the Fc-fused ECDs of the VSIG1, ILDR1, LOC253012, AI216611, FXYD3 or C10RF32 to lymphocytes.

Figure 66 illustrates the binding of the Fc-fused ECDs of the ILDR1, C10RF32 and AI216611 to CD4+ T cells.

Figure 67 shows the effect of B7-like proteins on T cell activation. “CD3" means CD3 only without the presence of a costimulatory molecule; "CDR3 + B7.2" means CD3 + a known B7 stimulatory control, B7.2; ''CD3+B7H4” means CD3 and B7H4 a known B7 inhibitory control; "CD3+B7H3" means CD3 and B7H3 a known B7 stimulatory protein; "CD3 + 702” means CD3 + LOC253012-ECD-Fc fused (SEQ ID NO:106); ”CD3 + 721” means CD3 + AI216611- ECD-Fc fused (SEQ ID NO:104); ”CD3 + 754" means CD3 + C10RF32-ECD-F fused (SEQ ID NO:105); ”CD3 + 768” means CD3 + VSIG1-ECD-Fc fused (SEQ ID NO:108) ”CD3 + 770” means CD3 + ILDIR1-ECD-Fc fused (SEQ ID NO:107); ,,CD3+789” means CD3 + FXYD3-ECD-Fc fused (SEQ ID NO:103). Figure 67A, B and C present 3 different experiments of 3 different donors

Figure 68A presents FACS results of binding of ILDR1-ECD-Fc (SEQ ID NO:107), C10RF32-ECD-F (SEQ ID NO:105), AI216611-ECD-Fc (SEQ ID NO:104), LOC253012-ECD-Fc (SEQ ID NO:106), FXYD3-ECD-Fc (SEQ ID NO:103), and VSIG1-ECD-Fc (SEQ ID NO: 108) to resting B cells

Figure 68B presents FACS results of binding of of binding of ILDR1-ECD-Fc (SEQ ID NO:107), C10RF32-ECD-F (SEQ ID NO: 105), AI216611-ECD-Fc (SEQ ID NO:104), LOC253012-ECD-Fc (SEQ ID NO:106), FXYD3-ECD-Fc (SEQ ID NO:103), and VSIGI-ECD-Fc (SEQ ID NO:108) to activated B cells.

Figure 68C presents FACS results of binding of IL DR1-ECD-Fc (SEQ ID NO: 107), C1 ORF32-ECD-Fc (SEQ ID NO: 105), AI216611-ECD-Fc (SEQ ID NO:104), LOC253012-ECD-Fc (SEQ ID NO:106), FXYD3-ECD-Fc (SEQ ID NO:103), and VSIGI-ECD-Fc (SEQ ID NO: 108) to B lymphoma cell lines.

DETAILED DESCRIPTION OF THE INVENTION 19 [0192] The present invention relates to C10RF32, and its corresponding nucleic acid sequence, and portions and variants thereof and conjugates containing and the use thereof as a therapeutic or diagnostic target. In particular the invention uses this antigen and discrete portions thereof as a drug target for therapeutic small molecules, peptides, antibodies, antisense RNAs, siRNAs, ribozymes, and the like. More particularly the invention relates to diagnostic and therapeutic polyclonal and monoclonal antibodies and fragments thereof that bind C10RF32 and portions and variants thereof, especially those that target the ectodomain or portions or variants thereof particularly human or chimeric monoclonal antibodies, that bind specifically to the antigen H19011_1_P8 (SEQ ID NO:48), H19011 1 P9 (SEQ ID NO:50), and variants thereof including those that promote or inhibit activities elicited by C10RF32, including those relating to modulation of immune costimulation, e.g. B7 related costimulation.

[0193] In certain embodiments, the antibodies of the invention are derived from particular heavy and light chain germline sequences and/or comprise particular structural features such as CDR regions comprising particular amino acid sequences. The invention provides isolated antibodies, methods of making such antibodies, immunoconjugates and bispecific molecules comprising such antibodies and pharmaceutical and diagnostic compositions containing the antibodies, immunoconjugates or bispecific molecules of the invention.

[0194] The invention also relates to in vitro and in vivo methods of using the antibodies and fragments, to detect C10RF32, as well as to treat diseases associated with expression of C10RF32. The invention further relates to methods of using the antibodies and fragments, specific for C10RF32 to treat autoimmune disorders and transplant and graft versus host disease. Accordingly, the invention also provides methods of using the anti-C10RF32 antibodies of the invention and other drugs that modulate C10RF32 to treat malignancies for example, in the treatment of lung cancer, ovarian cancer, colon cancer, non-solid and solid tumors, sarcomas, hematological malignancies including but not limited to acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, multiple myeloma, Fbdgkin's lymphoma, Non-Hodgkin's lymphoma, cancer of the breast, prostate, spleen, kidney, bladder, head and neck, uterus, testicles, stomach, cervix, liver, bone, skin, pancreas, brain and wherein the cancer may be non-metastatic, invasive or metastatic. The invention further provides methods of using the anti-C10RF32, antibodies of the invention and other drugs that modulate C10RF32 to treat non-malignant disorders such as immune disorders including but not limited to autoimmune diseases, transplant rejection and graft versus host disease. Preferably these antibodies will possess ADCC or CDC activity against target cells such as cancer cells.

[0195] Also, the invention relates to the C10RF32 antigen and portions thereof including soluble polypeptide conjugates containing the ectodomain of C10RF32 and/or the corresponding DNAs or vectors or cells expressing same for use in immunotherapy. Further the invention provides vectors, cells containing and use thereof for the expression of the C10RF32 antigen, as well as discrete portions and variants thereof Also, the invention provides non-antibody based C10RF32 modulatory agents such as peptides, antisense RNAs, siRNAs, carbohydrates, and other small molecules that specifically bind and/or modulate a C10RF32 related activity.

[0196] In order that the present invention may be more readily understood, certain terms are first defined. Additional definitions are set forth throughout the detailed description.

[0197] The terms C10RF32 refers to the protein encoded by any one of the H19011_1_T8 (SEQ ID NO:45), H19011_1_T9 (SEQ ID NO:46) transcripts reported herein, particularly to proteins as set forth in any one of H19011_1_P8 (SEQ ID NO:48), H19011_1_P9 (SEQ ID NO:50), and variants thereof that are differentially expressed e.g., in cancers such as lung cancer, particularly lung small cell carcinoma, wherein the cancer may be non-metastatic, invasive or metastatic as well as non-malignant disorders such as immune disorders including but not limited to autoimmune diseases, transplant rejection and graft versus host disease.

[0198] Preferably such C10RF32 variants will possess at least 80% sequence identity therewith, more preferably at least 90% sequence identity therewith and even more preferably at least 95% sequence identity therewith.

[0199] Any one of the C10RF32 proteins based on its domain structure is predicted to be an immune costimulatory protein, e.g., a B7 protein family member that is involved in B7 immune co-stimulation including for example T cell responses elicited against cancer cells and that elicit effects on immunity such as triggering of autoimmune effects.

[0200] The term the " soluble ectodomain (ECD)" or "ectodomain" of C10RF32 refers to the polypeptide sequences below or the corresponding nucleic acid sequences (which does not comprise the signal peptide and the TM of C10RF32 protein): [0201] >H19011 _1_P8 (SEQ ID NO:48) residues 21 to 186 (SEQ ID NO:147)

Lyv 1 V Γ LVINJNJX \ ,'Λ.ΥΙ I ΧΛ^Γ 1 V l !\^Γ1 ΓΓ> I DDi V V JXrjPO I V.V**IL/L\lVlVj

ESLGMSSTRAQSLSKRNLEWDPYLDCLDSRRTVRVVASKQGSTVTLGDFYRGREITI

VHDADLQIGKLMWGDSGLYYCIITTPDDLEGKNEGSLGLLVLGRTGLLADLLPSF

AVEIMPE

[0202] >H19011_1_P9 (SEQ ID NO:50) residues 21 to 169 (SEQ ID NO:148)

LQVTVPDKKKVAMLFQPTVLRCHFSISSHQPAWQWKFKSYCQDRMG

ESLGMSSTRAQSLSKRNLEWDPYLDCLDSRRTVRWASKQGSTVTLGDFYRGREITI VHDADLQIGKLMWGDSGLYYCinTPDDLEGKNEGSLGLLVLEWV, [0203] >H19011_1_P8 (SEQ ID NO:48) residues 1 to 184 (SEQ ID NO:299)

MDRVLLRWISLFWLTAMVEGLQVTVPDKKKVAMLFQPTVLRCHFSTSS HQPAVVQWKFKSYCQDRMGESLGMSSTRAQSLSKRNLEWDPYLDCLDSRRTVRV VASKQGSTVTLGDFYRGREmVHDADLQIGKLMWGDSGLYYCIITTPDDLEGKNE DS VELL VLGRT GLLADLLPSFAVEIM, [0204] and variants thereof possessing at least 95, 96, 97, 98 or 99% sequence identity therewith.

[0205] The term "immune response" refers to the action of, for example, lymphocytes, antigen presenting cells, phagocytic cells, granulocytes, and soluble macromolecules produced by the above cells or cells produced by the liver or spleen (including antibodies, cytokines, and complement) that results in selective damage to, destruction of, or elimination from the human body of invading pathogens, cells or tissues infected with pathogens, cancerous cells, or, in cases of autoimmunity or pathological inflammation, normal human cells or tissues.

[0206] A "signal, transduction pathway” refers to the biochemical relationship between a variety of signal transduction molecules that play a role in the transmission of a signal from one portion of a cell to another portion of a cell.

[0207] As used herein, the phrase "cell surface receptor" includes, for example, molecules and complexes of molecules capable of receiving a signal and the transmission of such a signal across the plasma membrane of a cell.

[0208] The term "antibody" as referred to herein includes whole polyclonal and monoclonal antibodies and any antigen binding fragment (i.e., "antigen-binding portion") or single chains thereof. An "antibody" refers to a glycoprotein comprising at least two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds, or an antigen binding portion thereof. Each heavy chain is comprised of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. The heavy chain constant region is comprised of three domains, CH1, CH2 and CH3. Each light chain is comprised of a light chain variable region (abbreviated herein as VL) and a light chain constant region. The light chain constant region is comprised of one domain, CL. The VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR). Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and light chains contain a binding domain that interacts with an antigen. The constant regions of the antibodies may mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (Clq) of the classical complement system.

[0209] The term "antigen-binding portion" of an antibody (or simply "antibody portion"), as used herein, refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen (e.g., C10RF32 proteins or C10RF32). It has been shown that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody. Examples of binding fragments encompassed within the term "antigen-binding portion" of an antibody include (i) a Fab fragment, a monovalent fragment consisting of the V Light, V Heavy, Constant light (CL) and CH1 domains; (ii) a F(ab').2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fd fragment consisting of the VH and CH1 domains; (iv) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody, (v) a dAb fragment (Ward et al., (1989) Nature 341:544-546), which consists of a VH domain; and (vi) an isolated complementarity determining region (CDR). Furthermore, although the two domains of the Fv fragment, VL and VH, are coded for by separate genes, they can be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules (known as single chain Fv (scFv); see e.g., Bird et al. (1988) Science 242:423-426; and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883). Such single chain antibodies are also intended to be encompassed within the term "antigen-binding portion" of an antibody. These antibody fragments are obtained using conventional techniques known to those with skill in the art, and the fragments are screened for utility in the same manner as are intact antibodies.

[0210] An "isolated antibody", as used herein, is intended to refer to an antibody that is substantially free of other antibodies having different antigenic specificities (e.g., an isolated antibody that specifically binds C10RF32 proteins or C10RF32 is substantially free of antibodies that specifically bind antigens other than C10RF32 proteins or C10RF32 respectively. An isolated antibody that specifically binds proteins or C10RF32 may, however, have cross-reactivity to other antigens, such as C10RF32 proteins or C10RF32 molecules from other species, respectively. Moreover, an isolated antibody may be substantially free of other cellular material and/or chemicals.

[0211] The terms "monoclonal antibody" or "monoclonal antibody composition" as used herein refer to a preparation of antibody molecules of single molecular composition. A monoclonal antibody composition displays a single binding specificity and affinity for a particular epitope.

[0212] The term "human antibody", as used herein, is intended to include antibodies having variable regions in which both the framework and CDR regions are derived from human germline immunoglobulin sequences. Furthermore, if the antibody contains a constant region, the constant region also is derived from human germline immunoglobulin sequences. The human antibodies of the invention may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo). However, the term "human antibody", as used herein, is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.

[0213] The term "human monoclonal antibody" refers to antibodies displaying a single binding specificity which have variable regions in which both the framework and CDR regions are derived from human germline immunoglobulin sequences. In one embodiment, the human monoclonal antibodies are produced by a hybridoma which includes a B cell obtained from a transgenic nonhuman animal, e.g., a transgenic mouse, having a genome comprising a human heavy chain transgene and a light chain transgene fused to an immortalized cell.

[0214] The term "recombinant human antibody", as used herein, includes all human antibodies that are prepared, expressed, created or isolated by recombinant means, such as (a) antibodies isolated from an animal (e.g., a mouse) that is transgenic or transchromosomal for human immunoglobulin genes or a hybridoma prepared therefrom (described further below), (b) antibodies isolated from a host cell transformed to express the human antibody, e.g., from a transfectoma, (c) antibodies isolated from a recombinant, combinatorial human antibody library, and (d) antibodies prepared, expressed, created or isolated by any other means that involve splicing of human immunoglobulin gene sequences to other DNA sequences. Such recombinant human antibodies have variable regions in which the framework and CDR regions are derived from human germline immunoglobulins sequences. In certain embodiments, however, such recombinant human antibodies can be subjected to in vitro mutagenesis (or, when an animal transgenic for human Ig sequences is used, in vivo somatic mutagenesis) and thus the amino acid sequences of the VH and VL regions of the recombinant antibodies are sequences that, while derived from and related to human germline VH and VL sequences, may not naturally exist within the human antibody germline repertoire in vivo.

[0215] As used herein, "isotype" refers to the antibody class (e.g., IgM or lgG1) that is encoded by the heavy chain constant region genes.

[0216] The phrases "an antibody recognizing an antigen" and "an antibody specific for an antigen" are used interchangeably herein with the term "an antibody which binds specifically to an antigen." [0217] As used herein, an antibody that "specifically binds to human C101FF32 proteins or C10RF32 is intended to refer to an antibody that binds to human C10RF32 proteins or C10RF32, respectively, preferably one with a KD of 5X10 -8 M or less, more preferably 3X10 -8 M or less, and even more preferably 1X10 -9 M or less.

[0218] The term "K-assoc" or "Ka", as used herein, is intended to refer to the association rate of a particular antibody-antigen interaction, whereas the term "Kdiss" or "Kd," as used herein, is intended to refer to the dissociation rate of a particular antibody-antigen interaction. The term "KD", as used herein, is intended to refer to the dissociation constant, which is obtained from the ratio of Kd to Ka (i.e., Kd/Ka) and is expressed as a molar concentration (M). KD values for antibodies can be determined using methods well established in the art. A preferred method for determining the KD of an antibody is by using surface Plasmon resonance, preferably using a biosensor system such as a BiacoreRTM. system.

[0219] As used herein, the term "high affinity" for an IgG antibody refers to an antibody having a KD of 10-8 M or less, more preferably 10 -9 M or less and even more preferably 10-10 M or less for a target antigen. However, "high affinity" binding can vary for other antibody isotypes. For example, "high affinity" binding for an IgM isotype refers to an antibody having a KD of 10 -7 M or less, more preferably 10 -8 M or less.

[0220] As used herein, the term "subject" includes any human or nonhuman animal. The term "nonhuman animal" includes all vertebrates, e.g., mammals and non-mammals, such as nonhuman primates, sheep, dogs, cats, horses, cows chickens, amphibians, reptiles, etc.

[0221] As used herein, the term "tail" refers to a peptide sequence at the end of an amino acid sequence that is unique to a splice variant according to the present invention. Therefore, a splice variant having such a tail may optionally be considered as a chimera, in that at least a first portion of the splice variant is typically highly homologous (often 100% identical) to a portion of the corresponding known protein, while at least a second portion of the variant comprises the tail.

[0222] As used herein, the term "head" refers to a peptide sequence at the beginning of an amino acid sequence that is unique to a splice variant according to the present invention. Therefore, a splice variant having such a head may optionally be considered as a chimera, in that at least a first portion of the splice variant comprises the head, while at least a second portion is typically highly homologous (often 100% identical) to a portion of the corresponding known protein.

[0223] As used herein, the term "an edge portion" refers to a connection between two portions of a splice variant according to the present invention that were not joined in the wild type or known protein. An edge may optionally arise due to a join between the above "known protein" portion of a variant and the tail, for example, and/or may occur if an internal portion of the wild type sequence is no longer present, such that two portions of the sequence are now contiguous in the splice variant that were not contiguous in the known protein. A "bridge" may optionally be an edge portion as described above, but may also include a join between a head and a "known protein" portion of a variant, or a join between a tail and a "known protein" portion of a variant, or a join between an insertion and a "known protein" portion of a variant.

[0224] In some embodiments, a bridge between a tail or a head or a unique insertion, and a "known protein" portion of a variant, comprises at least about 10 amino acids, or in some embodiments at least about 20 amino acids, or in some embodiments at least about 30 amino acids, or in some embodiments at least about 40 amino acids, in which at least one amino acid is from the tail/head/insertion and at least one amino acid is from the "known protein" portion of a variant. In some embodiments, the bridge may comprise any number of amino acids from about 10 to about 40 amino acids (for example,10, 11, 12,13...37, 38, 39, 40 amino acids in length, or any number in between).

[0225] It should be noted that a bridge cannot be extended beyond the length of the sequence in either direction, and it should be assumed that every bridge description is to be read in such manner that the bridge length does not extend beyond the sequence itself.

[0226] Furthermore, bridges are described with regard to a sliding window in certain contexts below. For example, certain descriptions of the bridges feature the following format: a bridge between two edges (in which a portion of the known protein is not present in the variant) may optionally be described as follows: a bridge portion of CONTIG-NAMEP1 (representing the name of the protein), comprising a polypeptide having a length "n", wherein n is at least about 10 amino acids in length, optionally at least about 20 amino acids in length, preferably at least about 30 amino acids in length, more preferably at least about 40 amino acids in length and most preferably at least about 50 amino acids in length, wherein at least two amino acids comprise XX (2 amino acids in the center of the bridge, one from each end of the edge), having a structure as follows (numbering according to the sequence of CONTIG-NAME_P1): a sequence starting from any of amino acid numbers 49-xto 49 (for example); and ending at any of amino acid numbers 50 + ((n-2) - x) (for example), in which x varies from 0 to n-2. In this example, it should also be read as including bridges in which n is any number of amino acids between 10-50 amino acids in length. Furthermore, the bridge polypeptide cannot extend beyond the sequence, so it should be read such that 49-x (for example) is not less than 1, nor 50 + ((n-2) - x) (for example) greater than the total sequence length.

[0227] Various aspects of the invention are described in further detail in the following subsections.

NUCLEIC ACIDS

[0228] A "nucleic acid fragment" or an "oligonucleotide" or a "polynucleotide" are used herein interchangeably to refer to a polymer of nucleic acid residues. A polynucleotide sequence of the present invention refers to a single or double stranded nucleic acid sequences which is isolated and provided in the form of an RNA sequence, a complementary polynucleotide sequence (cDNA), a genomic polynucleotide sequence and/or a composite polynucleotide sequences (e.g., a combination of the above).

[0229] Thus, the present invention encompasses nucleic acid sequences described hereinabove; fragments thereof, sequences hybridizable therewith, sequences homologous thereto [e.g., at least 90%, at least 95, 96, 97, 98 or 99 % or more identical to the nucleic acid sequences set forth herein], sequences encoding similar polypeptides with different codon usage, altered sequences characterized by mutations, such as deletion, insertion or substitution of one or more nucleotides, either naturally occurring or man induced, either randomly or in a targeted fashion. The present invention also encompasses homologous nucleic acid sequences (i.e., which form a part of a polynucleotide sequ.ence of the present invention), which include sequence regions unique to the polynucleotides of the present invention.

[0230] In cases where the polynucleotide sequences of the present invention encode previously unidentified polypeptides, the present invention also encompasses novel polypeptides or portions thereof, which are encoded by the isolated polynucleotide and respective nucleic acid fragments thereof described hereinabove.

[0231] Thus, the present invention also encompasses polypeptides encoded by the polynucleotide sequences of the present invention. The present invention also encompasses homologues of these polypeptides, such homologues can be at least 90 %, at least 95, 96, 97, 98 or 99 % or more homologous to the amino acid sequences set forth below, as can be determined using BlastP software of the National Center of Biotechnology Information (NCBI) using default parameters. Finally, the present invention also encompasses fragments of the above described polypeptides and polypeptides having mutations, such as deletions, insertions or substitutions of one or more amino acids, either naturally occurring or man induced, either randomly or in a targeted fashion.

[0232] As mentioned hereinabove, biomolecular sequences of the present invention can be efficiently utilized as tissue or pathological markers and as putative drugs or drug targets for treating or preventing a disease.

[0233] Oligonucleotides designed for carrying out the methods of the present invention for any of the sequences provided herein (designed as described above) can be generated according to any oligonucleotide synthesis method known in the art such as enzymatic synthesis or solid phase synthesis. Equipment and reagents for executing solid-phase synthesis are commercially available from, for example, Applied Biosystems. Any other means for such synthesis may also be employed; the actual synthesis of the oligonucleotides is well within the capabilities of one skilled in the art.

[0234] Oligonucleotides used according to this aspect of the present invention are those having a length selected from a range of about 10 to about 200 bases preferably about 15 to about 150 bases, more preferably about 20 to about 100 bases, most preferably about 20 to about 50 bases.

[0235] The oligonucleotides of the present invention may comprise heterocyclic nucleosides consisting of purines and the pyrimidines bases, bonded in a 3' to 5' phosphodiester linkage.

[0236] Preferable oligonucleotides are those modified in either backbone, internucleoside linkages or bases, as is broadly described hereinunder. Such modifications can oftentimes facilitate oligonucleotide uptake and resistivity to intracellular conditions.

[0237] Specific examples of preferred oligonucleotides useful according to this aspect of the present invention include oligonucleotides containing modified backbones or non-natural internucleoside linkages. Oligonucleotides having modified backbones include those that retain a phosphorus atom in the backbone, as disclosed in U.S. Patent Nos: 4,469,863; 4,476,301; 5,023,243; 5,177,196; 5,188,897; 5,264,423; 5,276,019; 5,278,302; 5,286,717; 5,321,131; 5,399,676; 5,405,939; 5,453,496; 5,455,233; 5,466, 677; 5,476,925; 5,519,126; 5,536,821; 5,541,306; 5,550,111; 5,563,253; 5,571,799; 5,587,361; and 5,625,050.

[0238] Preferred modified oligonucleotide backbones include, for example, phosphorothioates, chiral phosphorothioates, phosphorodithioates, phosphotriesters, aminoalkyl phosphotriesters, methyl and other alkyl phosphonates including 3'-alkylene phosphonates and chiral phosphonates, phosphinates, phosphoramidates including 3'-amino phosphoramidate and aminoalkylphosphoramidates, thionophosphoramidates, thionoalkylphosphonates, thionoalkylphosphotriesters, and boranophosphates having normal 3'-5' linkages, 2-5' linked analogs of these, and those having inverted polarity wherein the adjacent pairs of nucleoside units are linked 3-5' to 5'-3' or 2-5' to 5'-2'. Various salts, mixed salts and free acid forms can also be used.

[0239] Alternatively, modified oligonucleotide backbones that do not include a phosphorus atom therein have backbones that are formed by short chain alkyl or cycloalkyl internucleoside linkages, mixed heteroatom and alkyl or cycloalkyl internucleoside linkages, or one or more short chain heteroatomic or heterocyclic internucleoside linkages. These include those having morpholino linkages (formed in part from the sugar portion of a nucleoside); siloxane backbones; sulfide, sulfoxide and sulfone backbones; formacetyl and thioformacetyl backbones; methylene formacetyl and thioformacetyl backbones; alkene containing backbones; sulfamate backbones; methyleneimino and methylenehydrazino backbones; sulfonate and sulfonamide backbones; amide backbones; and others having mixed N, O, S and CH2 component parts, as disclosed in U.S. Pat. Nos. 5,034,506; 5,166,315; 5,185,444; 5,214,134; 5,216,141; 5,235,033; 5,264,562; 5,264,564; 5,405,938; 5,434,257; 5,466,677; 5,470,967; 5,489,677; 5,541,307; 5,561,225; 5,596,086; 5,602,240; 5,610,289; 5,602,240; 5,608,046; 5,610,289; 5,618,704; 5,623, 070; 5,663,312; 5,633,360; 5,677,437; and 5,677,439.

[0240] Other oligonucleotides which can be used according to the present invention, are those modified in both sugar and the internucleoside linkage, i.e., the backbone, of the nucleotide units are replaced with novel groups. The base units are maintained for complementation with the appropriate polynucleotide target. An example for such an oligonucleotide mimetic, includes peptide nucleic acid (PNA). A PNA oligonucleotide refers to an oligonucleotide where the sugar-backbone is replaced with an amide containing backbone, in particular an aminoethylglycine backbone. The bases are retained and are bound directly or indirectly to aza nitrogen atoms of the amide portion of the backbone. United States patents that teach the preparation of PNA compounds include, but are not limited to, U.S. Pat. Nos. 5,539,082; 5,714,331; and 5,719,262, each of which is herein incorporated by reference. Other backbone modifications, which can be used in the present invention are disclosed in U.S. Pat. No: 6,303,374.

[0241] Oligonucleotides of the present invention may also include base modifications or substitutions. As used herein, "unmodified" or "natural" bases include the purine bases adenine (A) and guanine (G), and the pyrimidine bases thymine (T), cytosine (C) and uracil (U). Modified bases include but are not limited to other synthetic and natural bases such as 5-methylcytosine (5-me-C), 5-hydroxymethyl cytosine, xanthine, hypoxanthine, 2-aminoadenine, 6-methyl and other alkyl derivatives of adenine and guanine, 2-propyl and other alkyl derivatives of adenine and guanine, 2-thiouracil, 2-thiothymine and 2-thiocytosine, 5-halouracil and cytosine, 5-propynyl uracil and cytosine, 6-azo uracil, cytosine and thymine, 5-uracil (pseudouracil), 4-thiouracil, 8-halo, 8-amino, 8-thiol, 8-thioalkyl, 8-hydroxyl and other 8-substituted adenines and guanines, 5-halo particularly 5-bromo, 5-trifluoromethyl and other 5-substituted uracils and cytosines, 7-methylguanine and 7-methyladenine, 8-azaguanine and 8-azaadenine, 7-deazaguanine and 7-deazaadenine and 3-deazaguanine and 3-deazaadenine. Further bases include those disclosed in U.S. Pat. No: 3,687,808, those disclosed in The Concise Encyclopedia Of Polymer Science and Engineering, pages 858-859, Kroschwitz, J. I., ed. John Wiley & Sons, 1990, those disclosed by Englisch et al., Angewandte Chemie, International Edition, 1991, 30, 613, and those disclosed by Sanghvi, Y S., Chapter 15, Antisense Research and Applications, pages 289-302, Crooke, S. T. and Lebleu, B., ed., CRC Press, 1993. Such bases are particularly useful for increasing the binding affinity of the oligomeric compounds of the invention. These include 5-substituted pyrimidines, 6-azapyrimidines and N-2, N-6 and 0-6 substituted purines, including 2-aminopropyladenine, 5-propynyluracil and 5-propynylcytosine. 5-methylcytosine substitutions have been shown to increase nucleic acid duplex stability by 0.6-1.2°C. [Sanghvi YS et al. (1993) Antisense Research and Applications, CRC Press, Boca Raton 276-278] and are presently preferred base substitutions, even more particularly when combined with 2'-0-methoxyethyl sugar modifications.

[0242] Another modification of the oligonucleotides of the invention involves chemically linking to the oligonucleotide one or more moieties or conjugates, which enhance the activity, cellular distribution or cellular uptake of the oligonucleotide. Such moieties include but are not limited to lipid moieties such as a cholesterol moiety, cholic acid, a thioether, e.g., hexyl-S-tritylthiol, a thiocholesterol, an aliphatic chain, e.g., dodecandiol or undecyl residues, a phospholipid, e.g., di-hexadecyl-rac-glycerol or triethylammonium 1,2-di-0-hexadecyl-rac-glycero-3-H-phosphonate, a polyamine or a polyethylene glycol chain, or adamantane acetic acid, a palmityl moiety, or an octadecylamine or hexylamino-carbonyl-oxycholesterol moiety, as disclosed in U.S. Pat. No: 6,303,374.

[0243] It is not necessary for all positions in a given oligonucleotide molecule to be uniformly modified, and in fact more than one of the aforementioned modifications may be incorporated in a single compound or even at a single nucleoside within an oligonucleotide.

PEPTIDES

[0244] The terms "polypeptide," "peptide" and "protein" are used interchangeably herein to refer to a polymer of amino acid residues. The terms apply to amino acid polymers in which one or more amino acid residue is an analog or mimetic of a corresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers. Polypeptides can be modified, e.g., by the addition of carbohydrate residues to form glycoproteins. The terms "polypeptide," "peptide" and "protein" include glycoproteins, as well as non-glycoproteins.

[0245] Polypeptide products can be biochemically synthesized such as by employing standard solid phase techniques. Such methods include exclusive solid phase synthesis, partial solid phase synthesis methods, fragment condensation, classical solution synthesis. These methods are preferably used when the peptide is relatively short (i.e., 10 kDa) and/or when it cannot be produced by recombinant techniques (i.e., not encoded by a nucleic acid sequence) and therefore involves different chemistry.

[0246] Solid phase polypeptide synthesis procedures are well known in the art and further described by John Morrow Stewart and Janis Dillaha Young, Solid Phase Peptide Syntheses (2nd Ed., Pierce Chemical Company, 1984).

[0247] Synthetic polypeptides can be purified by preparative high performance liquid chromatography [Creighton T. (1983) Proteins, structures and molecular principles. WH Freeman and Co. N.Y.] and the composition of which can be confirmed via amino acid sequencing.

[0248] In cases where large amounts of a polypeptide are desired, it can be generated using recombinant techniques such as described by Bitter et al., (1987) Methods in Enzymol. 153:516-544, Studier et al. (1990) Methods in Enzymol. 185:60-89, Brisson et al. (1984) Nature 310:511-514, Takamatsu et al. (1987) EMBO J. 6:307-311 , Coruzzi et al. (1984) EMBO J. 3:1671-1680 and Brogli et al., (1984) Science 224:838-843, Gurley et al. (1986) Mol. Cell. Biol. 6:559-565 and Weissbach & Weissbach, 1988, Methods for Plant Molecular Biology, Academic Press, NY, Section VIII, pp 421-463.

[0249] It will be appreciated that peptides identified according to the teachings of the present invention may be degradation products, synthetic peptides or recombinant peptides as well as peptidomimetics, typically, synthetic peptides and peptoids and semipeptoids which are peptide analogs, which may have, for example, modifications rendering the peptides more stable while in a body or more capable of penetrating into cells. Such modifications include, but are not limited to N terminus modification, C terminus modification, peptide bond modification, including, but not limited to, CH2-NH, CH2-S, CH2-S=0, 0=C-NH, CH2-0, CH2-CH2, S=C-NH, CH=CH or CF=CH, backbone modifications, and residue modification. Methods for preparing peptidomimetic compounds are well known in the art and are specified, for example, in Quantitative Drug Design, C.A. Ramsden Gd., Chapter 17.2, F. Choplin Pergamon Press (1992), which is incorporated by reference as if fully set forth herein. Further details in this respect are provided hereinunder.

[0250] Peptide bonds (-CO-NH-) within the peptide may be substituted, for example, by N-methylated bonds (-N(CH3)-CO-), ester bonds (-C(R)H-C-0-0-C(R)-N-), ketomethylen bonds (-CO-CH2-), α-aza bonds (-NH-N(R)-CO-), wherein R is any alkyl, e.g., methyl, carba bonds (-CH2-NH-), hydroxyethylene bonds (-CH(OH)-CH2-), thioamide bonds (-CS-NH-), olefinic double bonds (-CH=CH-), retro amide bonds (-NH-CO-), peptide derivatives (-N(R)-CH2-CO-), wherein R is the "normal" side chain, naturally presented on the carbon atom.

[0251] These modifications can occur at any of the bonds along the peptide chain and even at several (2-3) at the same time.

[0252] Natural aromatic amino acids, Trp, Tyr and Phe, may be substituted by synthetic non-natural acid such as Phenylglycine, TIC, naphthylelartine (Nol), ring-methylated derivatives of Phe, halogenated derivatives of Phe or o-methyl-Tyr.

[0253] In addition to the above, the peptides of the present invention may also include one or more modified amino acids or one or more non-amino acid monomers (e.g. fatty acids, complex carbohydrates etc).

[0254] As used herein in the specification and in the claims section below the term “amino acid” or "amino acids" is understood to include the 20 naturally occurring amino acids; those amino acids often modified post-translationally in vivo, including, for example, hydroxyproline, phosphoserine and phosphothreonine; and other unusual amino acids including, but not limited to, 2-aminoadipic acid, hydroxylysine, isodesmosine, nor-valine, nor-leucine and ornithine. Furthermore, the term "amino acid" includes both D- and L-amino acids.

[0255] Since the peptides of the present invention are preferably utilized in therapeutics which require the peptides to be in soluble form, the peptides of the present invention preferably include one or more non-natural or natural polar amino acids, including but not limited to serine and threonine which are capable of increasing peptide solubility due to their hydroxyl-containing side chain.

[0256] The peptides of the present invention are preferably utilized in a linear form, although it will be appreciated that in cases where cyclization does not severely interfere with peptide characteristics, cyclic forms of the peptide can also be utilized.

[0257] The peptides of the present invention can be biochemically synthesized such as by using standard solid phase techniques. These methods include exclusive solid phase synthesis, partial solid phase synthesis methods, fragment condensation, classical solution synthesis. These methods are preferably used when the peptide is relatively short (i.e., 10 kDa) and/or when it cannot be produced by recombinant techniques (i.e., not encoded by a nucleic acid sequence) and therefore involves different chemistry.

[0258] Solid phase peptide synthesis procedures are well known in the art and further described by John Morrow Stewart and Janis Dillaha Young, Solid Phase Peptide Syntheses (2nd Ed., Pierce Chemical Company, 1984).

[0259] Synthetic peptides can be purified by preparative high performance liquid chromatography [Creighton T. (1983) Proteins, structures and molecular principles. WH Freeman and Co. N.Y.] and the composition of which can be confirmed via amino acid sequencing.

[0260] In cases where large amounts of the peptides of the present invention are desired, the peptides of the present invention can be generated using recombinant techniques such as described by Bitter et al., (1987) Methods in Enzymol. 153:516-544, Studier et al. (1990) Methods in Enzymol. 185:60-89, Brisson et al. (1984) Nature 310:511-514, Takamatsu et al. (1987) EMBO J. 6:307-311, Coruzzi et al. (1984) EMBO J. 3:1671-1680 and Brogli et al., (1984) Science 224:838-843, Gurley et al. (1986) Mol. Cell. Biol. 6:559-565 and Weissbach & Weissbach, 1988, Methods for Plant Molecular Biology, Academic Press, NY, Section VIII, pp 421-463.

EXPRESSION SYSTEMS

[0261] To enable cellular expression of the polynucleotides of the present invention, a nucleic acid construct according to the present invention may be used, which includes at least a coding region of one of the above nucleic acid sequences, and further includes at least one cis acting regulatory element. As used herein, the phrase "cis acting regulatory element" refers to a polynucleotide sequence, preferably a promoter, which binds a trans acting regulator and regulates the transcription of a coding sequence located downstream thereto.

[0262] Any suitable promoter sequence can be used by the nucleic acid construct of the present invention.

[0263] Preferably, the promoter utilized by the nucleic acid construct of the present invention is active in the specific cell population transformed. Examples of cell type-specific and/or tissue-specific promoters include promoters such as albumin that is liver specific [Pinkert et al., (1987) Genes Dev. 1:268-277], lymphoid specific promoters [Calame et al., (1988) Adv. Immunol. 43:235-275]; in particular promoters of T-cell receptors [Winoto et al., (1989) EMBO J. 8:729-733] and immunoglobulins; [Banerji et al. (1983) Cell 33729-740], neuron-specific promoters such as the neurofilament promoter [Byrne et al. (1989) Proc. Natl. Acad. Sci. USA 86:5473-5477], pancreas-specific promoters [Edlunch et al. (1985) Science 230:912-916] or mammary gland-specific promoters such as the milk whey promoter (U.S. Pat. No. 4,873,316 and European Application Publication No. 264,166). The nucleic acid construct of the present invention can further include an enhancer, which can be adjacent or distant to the promoter sequence and can function in up regulating the transcription therefrom.

[0264] The nucleic acid construct of the present invention preferably further includes an appropriate selectable marker and/or an origin of replication. Preferably, the nucleic acid construct utilized is a shuttle vector, which can propagate both in E. coli (wherein the construct comprises an appropriate selectable marker and origin of replication) and be compatible for propagation in cells, or integration in a gene and a tissue of choice. The construct according to the present invention can be, for example, a plasmid, a bacmid, a phagemid, a cosmid, a phage, a virus or an artificial chromosome.

[0265] Examples of suitable constructs include, but are not limited to, pcDNA3, pcDNA3.1 (+/-), pGL3, PzeoSV2 (+/-), pDisplay, pEF/myc/cyto, pCMV/myc/cyto each of which is commercially available from Invitrogen Co. (www.invitrogen.com). Examples of retroviral vector and packaging systems are those sold by Clontech, San Diego, Calif., including Retro-X vectors pLNCX and pLXSN, which permit cloning into multiple cloning sites and the transgene is transcribed from CMV promoter. Vectors derived from Mo-MuLV are also included such as pBabe, where the transgene will be transcribed from the 5'LTR promoter.

[0266] Currently preferred in vivo nucleic acid transfer techniques include transfection with viral or non-viral constructs, such as adenovirus, lentivirus, Herpes simplex I virus, or adeno-associated virus (AAV) and lipid-based systems. Useful lipids for lipid-mediated transfer of the gene are, for example, DOTMA, DOPE, and DC-Chol [Tonkinson et al., Cancer Investigation, 14(1): 54-65 (1996)]. The most preferred constructs for use in gene therapy are viruses, most preferably adenoviruses, AAV, lentiviruses, or retroviruses. A viral construct such as a retroviral construct includes at least one transcriptional promoter/enhancer or locusdefining elements, or other elements that control gene expression by other means such as alternate splicing, nuclear RNAexport, or post-translational modification of messenger. Such vector constructs also include a packaging signal, long terminal repeats (LTRs) or portions thereof, and positive and negative strand primer binding sites appropriate to the virus used, unless it is already present in the viral construct. In addition, such a construct typically includes a signal sequence for secretion of the peptide from a host cell in which it is placed. Preferably the signal sequence for this purpose is a mammalian signal sequence or the signal sequence of the polypeptides of the present invention. Optionally, the construct may also include a signal that directs polyadenylation, as well as one or more restriction sites and a translation termination sequence. By way of example, such constructs will typically include a 5' LTR, a tRNA binding site, a packaging signal, an origin of second-strand DNA synthesis, and a 3' LTR or a portion thereof. Other vectors can be used that are non-viral, such as cationic lipids, polylysine, and dendrimers.

RECOMBINANT EXPRESSION VECTORS AND HOST CELLS

[0267] Another aspect of the invention pertains to vectors, preferably expression vectors, containing a nucleic acid encoding a protein of the invention, or derivatives, fragments, analogs or homologs thereof. As used herein, the term "vector" refers to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked. One type of vector is a "plasmid", which refers to a circular double stranded DNA loop into which additional DNA segments can be ligated. Another type of vector is a viral vector, wherein additional DNA segments can be ligated into the viral genome. Certain vectors are capable of autonomous replication in a host cell into which they are introduced (e.g., bacterial vectors having a bacterial origin of replication and episomal mammalian vectors). Other vectors (e.g., non-episomal mammalian vectors) are integrated into the genome of a host cell upon introduction into the host cell, and thereby are replicated along with the host genome. Moreover, certain vectors are capable of directing the expression of genes to which they are operatively-linked. Such vectors are referred to herein as "expression vectors". In general, expression vectors of utility in recombinant DNA techniques are often in the form of plasmids. In the present specification, "plasmid" and "vector" can be used interchangeably as the plasmid is the most commonly used form of vector. However, the invention is intended to include such other forms of expression vectors, such as viral vectors (e.g., replication defective retroviruses, adenoviruses and adeno-associated viruses), which serve equivalent functions.

[0268] The recombinant expression vectors of the invention comprise a nucleic acid of the invention in a form suitable for expression of the nucleic acid in a host cell, which means that the recombinant expression vectors include one or more regulatory sequences, selected on the basis of the host cells to be used for expression, that is operatively-linked to the nucleic acid sequence to be expressed. Within a recombinant expression vector, "operably-linked" is intended to mean that the nucleotide sequence of interest is linked to the regulatory sequences in a manner that allows for expression of the nucleotide sequence (e.g., in an in vitro transcription/translation system or in a host cell when the vector is introduced into the host cell).

[0269] The term "regulatory sequence" is intended to includes promoters, enhancers and other expression control elements (e.g., polyadenylation signals). Such regulatory sequences are described, for example, in Goeddel, Gene Expression Technology: Methods in Enzymology 185, Academic Press, San Diego, Calif. (1990). Regulatory sequences include those that direct constitutive expression of a nucleotide sequence in many types of host cell and those that direct expression of the nucleotide sequence only in certain host cells (e.g., tissue-specific regulatory sequences). It will be appreciated by those skilled in the art that the design of the expression vector can depend on such factors as the choice of the host cell to be transformed, the level of expression of protein desired, etc. The expression vectors of the invention can be introduced into host cells to thereby produce proteins or peptides, including fusion proteins or peptides, encoded by nucleic acids as described herein.

[0270] The recombinant expression vectors of the invention can be designed for production of variant proteins in prokaryotic or eukaryotic cells. For example, proteins of the invention can be expressed in bacterial cells such as Escherichia coli, insect cells (using baculovirus expression vectors) yeast cells or mamunalian cells. Suitable host cells are discussed further in Goeddel, Gene Expression Technology: Methods in Enzymology 185, Academic Press, San Diego, Calif. (1990). Alternatively, the recombinant expression vector can be transcribed and translated in vitro, for example using T7 promoter regulatory sequences and T7 polymerase.

[0271] Expression of proteins in prokaryotes is most often carried out in Escherichia coli with vectors containing constitutive or inducible promoters directing the expression of either fusion or non-fusion proteins. Fusion vectors add a number of amino acids to a protein encoded therein, to the amino or C terminus of the recombinant protein. Such fusion vectors typically serve three purposes: (i) to increase expression of recombinant protein; (ii) to increase the solubility of the recombinant protein; and (iii) to aid in the purification of the recombinant protein by acting as a ligand in affinity purification. Often, in fusion expression vectors, a proteolytic cleavage site is introduced at the junction of the fusion moiety and the recombinant protein to enable separation of the recombinant protein from the fusion moiety subsequent to purification of the fusion protein. Such enzymes, and their cognate recognition sequences, include Factor Xa, thrombin, PreScission, TEV and enterokinase. Typical fusion expression vectors include pGEX (Pharmacia Biotech Inc; Smith and Johnson, 1988. Gene 67: 31-40), pMAL (New England Biolabs, Beverly, Mass.) and pRIT5 (Pharmacia, Piscataway, N.J.) that fuse glutathione S-transferase (GST), maltose E binding protein, or protein A, respectively, to the target recombinant protein.

[0272] Examples of suitable inducible non-fusion E. coli expression vectors include pTrc (Amrann et aL, (1988) Gene 69:301-315) and pET 11d (Studier et al., Gene Expression Technology: Methods in Enzymology 185, Academic Press, San Diego, Calif. (1990) 60-89)- not accurate, pET11a-d have N terminal T7 tag.

[0273] One strategy to maximize recombinant protein expression in E. coli is to express the protein in a host bacterium with an impaired capacity to proteolytically cleave the recombinant protein. See, e.g., Gottesman, Gene Expression Technology: Methods in Enzymology 185, Academic Press, San Diego, Calif. (1990) 119-128. Another strategy is to alter the nucleic acid sequence of the nucleic acid to be inserted into an expression vector so that the individual codons for each amino acid are those preferentially utilized in E. coli (see, e.g., Wada, et al., 1992. Nucl. Acids Res. 20: 2111-2118 ). Such alteration of nucleic acid sequences of the invention can be carried out by standard DNA synthesis techniques. Another strategy to solve codon bias is by using BL21-codon plus bacterial strains (Invitrogen) or Rosetta bacterial strain (Novagen), these strains contain extra copies of rare E.coli tRNA genes.

[0274] In another embodiment, the expression vector encoding for the protein of the invention is a yeast expression vector. Examples of vectors for expression in yeast Saccharomyces cerevisiae include pYepSed (Baldari, et al., 1987. EMBO J. 6: 229-234), pMFa (Kurjan and Flerskowitz, 1982. Cell 30: 933-943), pJRY88 (Schultzet al., 1987. Gene 54: 113-123), pYES2 (Invitrogen Corporation, San Diego, Calif.), and picZ (InVitrogen Corp, San Diego, Calif.).

[0275] Alternatively, polypeptides of the present invention can be produced in insect cells using baculovirus expression vectors. Baculovirus vectors available for expression of proteins in cultured insect cells (e.g., SF9 cells) include the pAc series (Smith, et al., 1983. Mol. Cell. Biol. 3: 2156-2165) and the pVL series (Lucklowand Summers, 1989. Virology 170: 31-39).

[0276] In yet another embodiment, a nucleic acid of the invention is expressed in mammalian cells using a mammalian expression vector. Examples of mammalian expression vectors include pCDM8 (Seed, 1987. Nature 329: 840) and pMT2PC (Kaufman, et al., 1987. EMBO J. 6: 187-195), pIRESpuro (Clontech), pUB6 (Invitrogen), pCEP4 (Invitrogen) pREP4 (Invitrogen), pcDNA3 (Invitrogen). When used in mammalian cells, the expression vector's control functions are often provided by viral regulator elements. For example, commonly used promoters are derived from polyama, adenovirus 2, cytomegalovirus, Rous Sarcoma Virus, and simian virus 40. For other suitable expression systems for both prokaryotic and eukaryotic cells see, e.g., Chapters 16 and 17 of Sambrook, et al., Molecular Cloning: A Laboratory Manual. 2nd ed., Cold Spring Flarbor Laboratory, Cold Spring Flarbor Laboratory Press, Cold Spring Harbor, N.Y.,1989.

[0277] In another embodiment, the recombinant mammalian expression vector is capable of directing expression of the nucleic acid preferentially in a particular cell type (e.g., tissue-specific regulatory elements are used to express the nucleic acid). Tissue-specific regulatory elements are known in the art. Non-limiting examples of suitable tissue-specific promoters include the albumin promoter (liver-specific; Pinkert, et al., 1987. Genes Dev. 1: 268-277), lymphoid-specific promoters (Calame and Eaton, 1988. Adv. Immunol. 43: 235-275), in particular promoters of T cell receptors (Winoto and Baltimore, 1989. EMBO J. 8: 729-733) and immunoglobulins (Banerji, et al., 1983. Cell 33: 729-740; Queen and Baltimore, 1983. Cell 33: 741-748), neuron-specific promoters (e.g., the neurofilament promoter; Byrne and Ruddle, 1989. Proc. Natl. Acad. Sci. USA 86: 5473-5477), pancreas-specific promoters (Edlund, et al., 1985. Science 230: 912-916), and mammary gland-specific promoters (e.g., milk whey promoter; U.S. Pat. No. 4,873,316 and European Application Publication No. 264,166). Developmentally-regulated promoters are also encompassed, e.g., the murine hox promoters (Kessel and Gruss, 1990. Science 249: 374-379) and the alpha-fetoprotein promoter (Campes and Tilghman, 1989. Genes Dev. 3: 537-546).

[0278] The invention further provides a recombinant expression vector comprising a DNA molecule of the invention cloned into the expression vector in an antisense orientation. That is, the DNA molecule is operatively-linked to a regulatory sequence in a manner that allows for expression (by transcription of the DNA molecule) of an RNA molecule that is antisense to mRNA encoding for protein of the invention. Regulatory sequences operatively linked to a nucleic acid cloned in the antisense orientation can be chosen that direct the continuous expression of the antisense RNA molecule in a variety of cell types, for instance viral promoters and/or enhancers, or regulatory sequences can be chosen that direct constitutive, tissue specific or cell type specific expression of antisense RNA The antisense expression vector can be in the form of a recombinant plasmid, phagemid or attenuated virus in which antisense nucleic acids are produced under the control of a high efficiency regulatory region, the activity of which can be determined by the cell type into which the vector is introduced. For a discussion of the regulation of gene expression using antisense genes see, e.g., Weintraub, et al., "Antisense RNA as a molecular tool for genetic analysis," Reviews-Trends in Genetics, Vol. 1(1) 1986.

[0279] Another aspect of the invention pertains to host cells into which a recombinant expression vector of the invention has been introduced. The terms "host cell” and "recombinant host cell" are used interchangeably herein. It is understood that such terms refer not only to the particular subject cell but also to the progeny or potential progeny of such a cell. Because certain modifications may occur in succeeding generations due to either mutation or environmental influences, such progeny may not, in fact, be identical to the parent cell, but are still included within the scope of the term as used herein.

[0280] A host cell can be any prokaryotic or eukaryotic cell. For example, protein of the invention can be produced in bacterial cells such as E. coli, insect cells, yeast, plant or mammalian cells (such as Chinese hamster ovary cells (CHO) or COS or 293 cells). Other suitable host cells are known to those skilled in the art.

[0281] Vector DNA can be introduced into prokaryotic or eukaryotic cells via conventional transformation or transfection techniques. As used herein, the terms "transformation" and "transfection" are intended to refer to a variety of art-recognized techniques for introducing foreign nucleic acid (e.g., DNA) into a host cell, including calcium phosphate or calcium chloride coprecipitation, DEAE-dextran-mediated transfection, lipofection, or electroporation. Suitable methods for transforming or transfecting host cells can be found in Sambrook, et al. (Molecular Cloning: A Laboratory Manual. 2nd ed., Cold Spring Harbor Laboratory, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1989), and other laboratory manuals.

[0282] For stable transfection of mammalian cells, it is known that, depending upon the expression vector and transfection technique used, only a small fraction of cells may integrate the foreign DNA into their genome. In order to identify and select these integrants, a gene that encodes a selectable marker (e.g., resistance to antibiotics) is generally introduced into the host cells along with the gene of interest. Various selectable markers include those that confer resistance to drugs, such as G418, hygromycin, puromycin, blasticidin and methotrexate. Nucleic acids encoding a selectable marker can be introduced into a host cell on the same vector as that encoding protein of the invention or can be introduced on a separate vector. Cells stably transfected with the introduced nucleic acid can be identified by drug selection (e.g., cells that have incorporated the selectable marker gene will survive, while the other cells die).

[0283] A host cell of the invention, such as a prokaryotic or eukaryotic host cell in culture, can be used to produce (i.e., express) protein of the invention. Accordingly, the invention further provides methods for producing proteins of the invention using the host cells of the invention. In one embodiment, the method comprises culturing the host cell of the present invention (into which a recombinant expression vector encoding protein of the invention has been introduced) in a suitable medium such that the protein of the invention is produced. In another embodiment, the method further comprises isolating protein of the invention from the medium or the host cell.

[0284] For efficient production of the protein, it is preferable to place the nucleotide sequences encoding the protein of the invention under the control of expression control sequences optimized for expression in a desired host. For example, the sequences may include optimized transcriptional and/or translational regulatory sequences (such as altered Kozak sequences).

PROTEIN MODIFICATIONS FUSION PROTEINS

[0285] According to the present invention, a fusion protein may be prepared from a protein of the invention by fusion with a portion of an immunoglobulin comprising a constant region of an immunoglobulin. More preferably, the portion of the immunoglobulin comprises a heavy chain constant region which is optionally and more preferably a human heavy chain constant region. The heavy chain constant region is most preferably an IgG heavy chain constant region, and optionally and most preferably is an Fc chain, most preferably an IgG Fc fragment that comprises CH2 and CH3 domains. Although any IgG subtype may optionally be used, the IgG 1 subtype is preferred. The Fc chain may optionally be a known or "wild type" Fc chain, or alternatively may be mutated. Non-limiting, illustrative, exemplary types of mutations are described in US Patent Application No. 20060034852, published on February 16, 2006, hereby incorporated by reference as if fully set forth herein. The term "Fc chain" also optionally comprises any type of Fc fragment.

[0286] Several of the specific amino acid residues that are important for antibody constant region-mediated activity in the IgG subclass have been identified. Inclusion, substitution or exclusion of these specific amino acids therefore allows for inclusion or exclusion of specific immunoglobulin constant region-mediated activity. Furthermore, specific changes may result in aglycosylation for example and/or other desired changes to the Fc chain. At least some changes may optionally be made to block a function of Fc which is considered to be undesirable, such as an undesirable immune system effect, as described in greater detail below.

[0287] Non-limiting, illustrative examples of mutations to Fc which may be made to modulate the activity of the fusion protein include the following changes (given with regard to the Fc sequence nomenclature as given by Kabat, from Kabat EA et al: Sequences of Proteins of Immunological Interest. US Department of Health and Human Services, NIH, 1991): 220C - > S; 233-238 ELLGGP - > EAEGAP; 265D - > A, preferably in combination with 434N -> A; 297N - > A (for example to block N-glycosylation); 318-322 EYKCK - > AYACA; 330-331AP - > SS; or a combination thereof (see for example M. Clark, "Chemical Immunol and Antibody Engineering", pp 1-31 for a description of these mutations and their effect). The construct for the Fc chain which features the above changes optionally and preferably comprises a combination of the hinge region with the CH2 and CH3 domains.

[0288] The above mutations may optionally be implemented to enhance desired properties or alternatively to block non-desired properties. For example, aglycosylation of antibodies was shown to maintain the desired binding functionality while blocking depletion of T-cells or triggering cytokine release, which may optionally be undesired functions (see M. Clark, "Chemical Immunol and Antibody Engineering", pp 1-31). Substitution of 331 proline for serine may block the ability to activate complement, which may optionally be considered an undesired function (see M. Clark, "Chemical Immunol and Antibody Engineering", pp 1-31). Changing 330alanine to serine in combination with this change may also enhance the desired effect of blocking the ability to activate complement.

[0289] Residues 235 and 237 were shown to be involved in antibody-dependent cell-mediated cytotoxicity (ADCC), such that changing the block of residues from 233-238 as described may also block such activity if ADCC is considered to be an undesirable function.

[0290] Residue 220 is normally a cysteine for Fc from lgG1, which is the site at which the heavy chain forms a covalent linkage with the light chain. Optionally, this residue may be changed to a serine, to avoid any type of covalent linkage (see M. Clark, "Chemical Immunol and Antibody Engineering", pp 1-31).

[0291] The above changes to residues 265 and 434 may optionally be implemented to reduce or block binding to the Fc receptor, which may optionally block undesired functionality of Fc related to its immune system functions (see "Binding site on Human lgG1 for Fc Receptors", Shields et al, Vol 276, pp 6591-6604, 2001).

[0292] The above changes are intended as illustrations only of optional changes and are not meant to be limiting in any way. Furthermore, the above explanation is provided for descriptive purposes only, without wishing to be bound by a single hypothesis.

ADDITION OF GROUPS

[0293] If a protein according to the present invention is a linear molecule, it is possible to place various functional groups at various points on the linear molecule which are susceptible to or suitable for chemical modification. Functional groups can be added to the termini of linear forms of the protein of the invention. In some embodiments, the functional groups improve the activity of the protein with regard to one or more characteristics, including but not limited to, improvement in stability, penetration (through cellular membranes and/or tissue barriers), tissue localization, efficacy, decreased clearance, decreased toxicity, improved selectivity, improved resistance to expulsion by cellular pumps, and the like. For convenience sake and without wishing to be limiting, the free N-terminus of one of the sequences contained in the compositions of the invention will be termed as the N-terminus of the composition, and the free C-terminal of the sequence will be considered as the C-terminus of the composition. Either the C-terminus or the N-terminus of the sequences, or both, can be linked to a carboxylic acid functional groups or an amine functional group, respectively.

[0294] Non-limiting examples of suitable functional groups are described in Green and Wuts, "Protecting Groups in Organic Synthesis", John Wiley and Sons, Chapters 5 and 7, 1991, the teachings of which are incorporated herein by reference. Preferred protecting groups are those that facilitate transport of the active ingredient attached thereto into a cell, for example, by reducing the hydrophilicity and increasing the lipophilicity of the active ingredient, these being an example for "a moiety for transport across cellular membranes".

[0295] These moieties can optionally and preferably be cleaved in vivo, either by hydrolysis or enzymatically, inside the cell. (Ditter et al., J. Pharm. Sci. 57:783 (1968); Ditter et al., J. Pharm. Sci. 57:828 (1968); Ditter et al., J. Pharm. Sci. 58:557 (1969); King et al., Biochemistry 26:2294 (1987); Lindberg et al., Drug Metabolism and Disposition 17:311 (1989); and Tunek et al., Biochem. Pharm. 37:3867 (1988), Anderson et al., Arch. Biochem. Biophys. 239:538 (1985) and Singhal et al., FASEB J. 1:220 (1987)). Hydroxyl protecting groups include esters, carbonates and carbamate protecting groups. Amine protecting groups include alkoxy and aryloxy carbonyl groups, as described above for N-terminal protecting groups. Carboxylic acid protecting groups include aliphatic, benzylic and aryl esters, as described above for C-terminal protecting groups. In one embodiment, the carboxylic acid group in the side chain of one or more glutamic acid or aspartic acid residue in a composition of the present invention is protected, preferably with a methyl, ethyl, benzyl or substituted benzyl ester, more preferably as a benzyl ester.

[0296] Non-limiting, illustrative examples of N-terminal protecting groups include acyl groups (-CO-R1) and alkoxy carbonyl or aryloxy carbonyl groups (-C0-0-R1), wherein R1 is an aliphatic, substituted aliphatic, benzyl, substituted benzyl, aromatic or a substituted aromatic group. Specific examples of acyl groups include but are not limited to acetyl, (ethyl)-CO-, n-propyl-CO-, iso-propyl-CO-, n-butyl-CO-, sec-butyl-CO-, t-butyl-CO-, hexyl, lauroyl, palmitoyl, myristoyl, stearyl, oleoyl phenyl-CO-, substituted phenyl-CO-, benzyl-CO- and (substituted benzyl)-CO-. Examples of alkoxy carbonyl and aryloxy carbonyl groups include CH3-0-CO-, (ethyl)-O-CO-, n-propyl-O-CO-, iso-propyl-O-CO-, n-butyl-O-CO-, sec-butyl-O-CO-, t-butyl-O-CO-, phenyl-O- CO-, substituted phenyl-O-CO- and benzyl-O-CO-, (substituted benzyl)- Ο-CO-, Adamantan, naphtalen, myristoleyl, toluen, biphenyl, cinnamoyl, nitrobenzoy, toluoyl, furoyl, benzoyl, cyclohexane, norbornane, or Z-caproic. In order to facilitate the N-acylation, one to four glycine residues can be present in the N-terminus of the molecule.

[0297] The carboxyl group at the C-terminus of the compound can be protected, for example, by a group including but not limited to an amide (i.e., the hydroxyl group at the C-terminus is replaced with -NH 2, -NHR2 and -NR2R3) or ester (i.e. the hydroxyl group at the C-terminus is replaced with -OR2). R2 and R3 are optionally independently an aliphatic, substituted aliphatic, benzyl, substituted benzyl, aryl or a substituted aryl group. In addition, taken together with the nitrogen atom, R2 and R3 can optionally form a C4 to C8 heterocyclic ring with from about 0-2 additional heteroatoms such as nitrogen, oxygen or sulfur. Non-limiting suitable examples of suitable heterocyclic rings include piperidinyl, pyrrolidinyl, morpholino, thiomorpholino or piperazinyl. Examples of C-terminal protecting groups include but are not limited to -NH2, -NHCH3, -N(CH3)2, -NH(ethyl), -N(ethyl)2, -N(methyl) (ethyl), -NH(benzyl), -N(C1-C4 alkyl)(benzyl), -NH(phenyl), -N(C1-C4 alkyl) (phenyl), -OCH3, -O-(ethyl), -O-(n-propyl), -O-(n-butyl), -O-(iso-propyl), -O-(sec-butyl), -O-(t-butyl), -O-benzyl and -O-phenyl.

SUBSTITUTION BY PEPTIDOMIMETIC MOIETIES

[0298] A ".peptidomimetic organic moiety" can optionally be substituted for amino acid residues in the composition of this invention both as conservative and as non-conservative substitutions. These moieties are also termed "non-natural amino acids" and may optionally replace amino acid residues, amino acids or act as spacer groups within the peptides in lieu of deleted amino acids. The peptidomimetic organic moieties optionally and preferably have steric, electronic or configurational properties similar to the replaced amino acid and such peptidomimetics are used to replace amino acids in the essential positions, and are considered conservative substitutions. However such similarities are not necessarily required. According to preferred embodiments of the present invention, one or more peptidomimetics are selected such that the composition at least substantially retains its physiological activity as compared to the native protein according to the present invention.

[0299] Peptidomimetics may optionally be used to inhibit degradation of the peptides by enzymatic or other degradative processes. The peptidomimetics can optionally and preferably be produced by organic synthetic techniques. Non-limiting examples of suitable peptidomimetics include D amino acids of the corresponding L amino acids, tetrazol (Zabrocki et al., J. Am. Chem. Soc. 110:5875-5880 (1988)); isosteres of amide bonds (Jones et al., Tetrahedron Lett. 29: 3853-3856 (1988)); LL-3-amino-2-propenidone-6-carboxylic acid (LL-Acp) (Kemp et al., J. Org. Chem. 50:5834-5838 (1985)). Similar analogs are shown in Kemp et al., Tetrahedron Lett. 29:5081-5082 (1988) as well as Kemp et al., Tetrahedron Lett. 29:5057-5060 (1988), Kemp et al., Tetrahedron Lett. 29:4935-4938 (1988) and Kemp et al., J. Org. Chem. 54:109-115 (1987). Other suitable but exemplary peptidomimetics are shown in Nagai and Sato, Tetrahedron Lett. 26:647-650 (1985); Di Maio et al., J. Chem. Soc. Perkin Trans., 1687 (1985); Kahn et al., Tetrahedron Lett. 30:2317 (1989); Olson et al., J. Am. Chem. Soc. 112:323-333 (1990); Garvey et al., J. Org. Chem. 56:436 (1990). Further suitable exemplary peptidomimetics include hydroxy-1,2,3,4-tetrahydroisoquinoline- 3-carboxylate (Miyake et al., J. Takeda Res. Labs 43:53-76 (1989)); 1,2,3,4-tetrahydro- isoquinoline-3-carboxylate (Kazmierski et urver z 1u al., J. Am. Chem. Soc. 133:2275-2283 (1991)); histidine isoquinolone carboxylic acid (HIC) (Zechel et al., Int. J. Pep. Protein Res. 43 (1991)); (2S, 3S)-methyl-phenylalanine, (2S, 3R)-methyl-phenylalanine, (2R, 3S)-methyl- phenylalanine and (2R, 3R)-methyl-phenylalanine (Kazmierski and Hruby, Tetrahedron Lett. (1991)).

[0300] Exemplary, illustrative but non-limiting non-natural amino acids include beta-amino acids (beta3 and beta2), homo-amino acids, cyclic amino acids, aromatic amino acids, Pro and Pyr derivatives, 3-substituted Alanine derivatives, Glycine derivatives, ring-substituted Phe and Tyr Derivatives, linear core amino acids or diamino acids. They are available from a variety of suppliers, such as Sigma-Aldrich (USA) for example.

CHEMICAL MODIFICATIONS

[0301] In the present invention any part of a protein of the invention may optionally be chemically modified, i.e. changed by addition of functional groups. For example the side amino acid residues appearing in the native sequence may optionally be modified, although as described below alternatively other parts of the protein may optionally be modified, in addition to or in place of the side amino acid residues. The modification may optionally be performed during synthesis of the molecule if a chemical synthetic process is followed, for example by adding a chemically modified amino acid. However, chemical modification of an amino acid when it is already present in the molecule ("in situ" modification) is also possible.

[0302] The amino acid of any of the sequence regions of the molecule can optionally be modified according to any one of the following exemplary types of modification (in the peptide conceptually viewed as "chemically modified"). Non-limiting exemplary types of modification include carboxymethylation, acylation, phosphorylation, glycosylation or fatty acylation. Ether bonds can optionally be used to join the serine or threonine hydroxyl to the hydroxyl of a sugar. Amide bonds can optionally be used to join the glutamate or aspartate carboxyl groups to an amino group on a sugar (Garg and Jeanloz, Advances in Carbohydrate Chemistry and Biochemistry, Vol. 43, Academic Press (1985); Kunz, Ang. Chem. Int. Ed. English 26:294-308 (1987)). Acetal and ketal bonds can also optionally be formed between amino acids and carbohydrates. Fatty acid acyl derivatives can optionally be made, for example, by acylation of a free amino group (e.g., lysine) (Toth et al., Peptides: Chemistry, Structure and Biology, Rivier and Marshal, eds., ESCOM Publ., Leiden, 1078-1079 (1990)).

[0303] As used herein the term "chemical modification", when referring to a protein or peptide according to the present invention, refers to a protein or peptide where at least one of its amino acid residues is modified either by natural processes, such as processing or other post-translational modifications, or by chemical modification techniques which are well known in the art. Examples of the numerous known modifications typically include, but are not limited to: acetylation, acylation, amidation, ADP-ribosylation, glycosylation, GPI anchor formation, covalent attachment of a lipid or lipid derivative, methylation, myristylation, pegylation, prenylation, phosphorylation, ubiquitination, or any similar process.

[0304] Other types of modifications optionally include the addition of a cycloalkane moiety to a biological molecule, such as a protein, as described in PCT Application No. WO 2006/050262, hereby incorporated by reference as if fully set forth herein.

These moieties are designed for use with biomolecules and may optionally be used to impart various properties to proteins.

[0305] Furthermore, optionally any point on a protein may be modified. For example, pegylation of a glycosylation moiety on a protein may optionally be performed, as described in PCT Application No. WO 2006/050247, hereby incorporated by reference as if fully set forth herein. One or more polyethylene glycol (PEG) groups may optionally be added to O-linked and/or N-linked glycosylation. The PEG group may optionally be branched or linear. Optionally any type of water-soluble polymer may be attached to a glycosylation site on a protein through a glycosyl linker.

ALTERED GLYCOSYLATION

[0306] Proteins of the invention may be modified to have an altered glycosylation pattern (i.e., altered from the original or native glycosylation pattern). As used herein, "altered" means having one or more carbohydrate moieties deleted, and/or having at least one glycosylation site added to the original protein.

[0307] Glycosylation of proteins is typically either N-linked or O-linked. N-linked refers to the attachment of the carbohydrate moiety to the side chain of an asparagine residue. The tripeptide sequences, asparagine-X-serine and asparagine-X-threonine, where X is any amino acid except proline, are the recognition sequences for enzymatic attachment of the carbohydrate moiety to the asparagine side chain. Thus, the presence of either of these tripeptide sequences in a polypeptide creates a potential glycosylation site. O-linked glycosylation refers to the attachment of one of the sugars N-acetylgalactosamine, galactose, or xylose to a hydroxyamino acid, most commonly serine or threonine, although 5-hydroxyproline or 5-hydroxylysine may also be used.

[0308] Addition of glycosylation sites to proteins of the invention is conveniently accomplished by altering the amino acid sequence of the protein such that it contains one or more of the above-described tripeptide sequences (for N-linked glycosylation sites). The alteration may also be made by the addition of, or substitution by, one or more serine or threonine residues in the sequence of the original protein (for O-linked glycosylation sites). The protein's amino acid sequence may also be altered by introducing changes at the DNA level.

[0309] Another means of increasing the number of carbohydrate moieties on proteins is by chemical or enzymatic coupling of glycosides to the amino acid residues of the protein. Depending on the coupling mode used, the sugars may be attached to (a) arginine and histidine, (b) free carboxyl groups, (c) free sulfhydryl groups such as those of cysteine, (d) free hydroxyl groups such as those of serine, threonine, or hydroxyproline, (e) aromatic residues such as those of phenylalanine, tyrosine, or tryptophan, or (f) the amide group of glutamine. These methods are described in WO 87/05330, and in Aplin and Wriston, CRC Crit. Rev. Biochem., 22: 259-306 (1981).

[0310] Removal of any carbohydrate moieties present on proteins of the invention may be accomplished chemically or enzymatically. Chemical deglycosylation requires exposure of the protein to trifluoromethanesulfonic acid, or an equivalent compound. This treatment results in the cleavage of most or all sugars except the linking sugar (N-acetylglucosamine or N-acetylgalactosamine), leaving the amino acid sequence intact.

[0311] Chemical deglycosylation is described by Hakimuddin et al., Arch. Biochem. Biophys., 259: 52 (1987); and Edge et al., Anal. Biochem., 118: 131 (1981). Enzymatic cleavage of carbohydrate moieties on proteins can be achieved by the use of a variety of endo- and exo-glycosidases as described by Thotakura et al., Meth. Enzymol.,138: 350 (1987).

METHODS OF TREATMENT

[0312] As mentioned hereinabove the C10RF32 proteins or C10RF32 proteins and polypeptides of the present invention or nucleic acid sequence or fragments thereof especially the ectodomain or secreted forms of C10RF32 proteins, as well as drugs which specifically bind to the C10RF32 proteins and/or splice variants, and/or drugs which agonize or antagonize the binding of other moieties to the C10RF32 proteins and/or splice variants, and/or drugs which modulate (agonize or antagonize) at least one C10RF2 related biological activity (such drugs include by way of example antibodies, small molecules, peptides, ribozymes, antisense molecules, siRNA's and the like), can be used to treat cancer, including but not limited to non-solid and solid tumors, sarcomas, hematological malignancies including but not limited to acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, multiple myeloma, Hodgkin's lymphoma, Non-Hodgkin's lymphoma, cancer of the breast, prostate, lung, ovary, colon, spleen, kidney, bladder, head and neck, uterus, testicles, stomach, cervix, liver, bone, skin, pancreas, brain and wherein the cancer may be non-metastatic, invasive or metastatic.

[0313] The C10RF32 proteins or C10RF32 proteins and polypeptides of the present invention or nucleic acid sequence or fragments thereof especially the ectodomain or secreted forms of C10RF32, proteins, as well as drugs which specifically bind to the C10RP32 proteins and/or splice variants, and/or drugs which agonize or antagonize the binding of other moieties to the C10RF32 proteins and/or splice variants, and/or drugs which modulate (agonize or antagonize) at least one C10RF32 related biological activity (such drugs include by way of example antibodies, small molecules, peptides, ribozymes, antisense molecules, siRNA's and the like), can be further used to treat non-malignant disorders such as immune disorders including but not limited to autoimmune diseases, transplant rejection and graft versus host disease, and/or for blocking or promoting immune costimulation mediated by the C10RF32, polypeptide.

[0314] Thus, according to an additional aspect of the present invention there is provided a method of treating cancer, including but not limited to non-solid and solid tumors, sarcomas, hematological malignancies including but not limited to acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, multiple myeloma, Hodgkin's lymphoma, Non-Hodgkin's lymphoma, cancer of the breast, prostate, lung, ovary, colon, spleen, kidney, bladder, head and neck, uterus, testicles, stomach, cervix, liver, bone, skin, pancreas, brain and wherein the cancer may be non-metastatic, invasive or metastatic as well as non-malignant disorders such as immune disorders including but not limited to autoimmune diseases, transplant rejection and graft versus host disease, and/or for blocking or promoting immune costimulation mediated by the C10FR32 polypeptide in a subject.

[0315] The subject according to the present invention is a mammal, preferably a human which is diagnosed with one of the disease, disorder or conditions described hereinabove, or alternatively is predisposed to at least one type of cancer, including but not limited to non-solid and solid tumors, sarcomas, hematological malignancies including but not limited to acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, multiple myeloma, Hodgkin's lymphoma, Non-Hodgkin's lymphoma, cancer of the breast, prostate, lung, ovary, colon, spleen, kidney, bladder, head and neck, uterus, testicles, stomach, cervix, liver, bone, skin, pancreas, brain, as well as non-malignant disorders such as immune disorders including but not limited to autoimmune diseases, transplant rejection and graft versus host disease.

[0316] As used herein the term "treating" refers to preventing, curing, reversing, attenuating, alleviating, minimizing, suppressing or halting the deleterious effects of the above-described diseases, disorders or conditions.

[0317] Treating, according to the present invention, can be effected by specifically upregulating the expression of at least one of the polypeptides of the present invention in the subject.

[0318] Optionally, upregulation may be effected by administering to the subject at least one of the polypeptides of the present invention (e.g., recombinant or synthetic) or an active portion thereof, as described herein. However, since the bioavailability of large polypeptides may potentially be relatively small due to high degradation rate and low penetration rate, administration of polypeptides is preferably confined to small peptide fragments (e.g., about 100 amino acids). The polypeptide or peptide may optionally be administered in as part of a pharmaceutical composition, described in more detail below.

[0319] It will be appreciated that treatment of the above-described diseases according to the present invention may be combined with other treatment methods known in the art (i.e., combination therapy). Thus, treatment of malignancies using the agents of the present invention may be combined with, for example, radiation therapy, antibody therapy and/or chemotherapy.

[0320] Alternatively or additionally, an upregulating method may optionally be effected by specifically upregulating the amount (optionally expression) in the subject of at least one of the polypeptides of the present invention or active portions thereof.

[0321] As is mentioned hereinabove and in the Examples section which follows, the biomolecular sequences of this aspect of the present invention may be used as valuable therapeutic tools in the treatment of diseases, disorders or conditions in which altered activity or expression of the wild-type gene product (known protein) is known to contribute to disease, disorder or condition onset or progression. For example, in case a disease is caused by overexpression of a membrane bound-receptor, a soluble variant thereof may be used as an antagonist which competes with the receptor for binding the ligand, to thereby terminate signaling from the receptor.

[0322] Anti-C10RF32 Antibodies [0323] The antibodies of the invention including those having the particular germline sequences, homologous antibodies, antibodies with conservative modifications, engineered and modified antibodies are characterized by particular functional features or properties of the antibodies. For example, the antibodies bind specifically to human C10RF32 Preferably, an antibody of the invention binds to corresponding C10RF32 with high affinity, for example with a KD of 10 -8 M or less or 10 -9 M or less or even 10 -10 M or less. The anti-C1 ORF32 antibodies of the invention preferably exhibit one or more of the following characteristics: 1. (i) binds to corresponding human C10RF32 with a KD of 5.X10 -8 M or less; 2. (ii) modulates (enhances or inhibits) B7 immune costimulation and related activities and functions such a T cell responses involved in antitumor immunity and autoimmunity, and / or 3. (iii) binds to C10RF32 antigen expressed by cancer cells including for example lung cancer, ovarian cancer, colon cancer, but does not substantially bind to normal cells In addition, preferably these antibodies and conjugates thereof will be effective in eliciting selective killing of such cancer cells and for modulating immune responses involved in autoimmunity and cancer.

[0324] More preferably, the antibody binds to corresponding human C10RF32 antigen with a KD of 3X10 -8 M or less, or with a KD of 1X10 -9 M or less, or with a KD of 0.1.X10 -9 M or less, or with a KD Of 0.05.X10 -9 M or less or with a KD of between 1X10 -9 and 1X10-11 M.

[0325] Standard assays to evaluate the binding ability of the antibodies toward C10RF32 are known in the art, including for example, ELISAs, Western blots and RIAs. Suitable assays are described in detail in the Examples. The binding kinetics (e.g., binding affinity) of the antibodies also can be assessed by standard assays known in the art, such as by Biacore analysis.

[0326] Upon production of anti-C10RF32 antibody sequences from antibodies can bind to C10RF32 the VH and VL sequences can be "mixed and matched" to create other C10RF32 binding molecules of the invention. C10RF32 binding of such "mixed and matched" antibodies can be tested using the binding assays described above, e.g., ELISAs). Preferably, when VH and VL chains are mixed and matched, a VH sequence from a particular VH/VL pairing is replaced with a structurally similar VH sequence. Likewise, preferably a VL sequence from a particular VH/VL pairing is replaced with a structurally similar VL sequence. For example, the VH and VL sequences of homologous antibodies are particularly amenable for mixing and matching.

ANTIBODIES HAVING PARTICULAR GERMUNE SEQUENCES

[0327] In certain embodiments, an antibody of the invention comprises a heavy chain variable region from a particular germline heavy chain immunoglobulin gene and/or a light chain variable region from a particular germline light chain immunoglobulin gene.

[0328] As used herein, a human antibody comprises heavy or light chain variable regions that is "the product of or "derived from" a particular germline sequence if the variable regions of the antibody are obtained from a system that uses human germline immunoglobulin genes. Such systems include immunizing a transgenic mouse carrying human immunoglobulin genes with the antigen of interest or screening a human immunoglobulin gene library displayed on phage with the antigen of interest. A human antibody that is "the product of or "derived from" a human germline immunoglobulin sequence can be identified as such by comparing the amino acid sequence of the human antibody to the amino acid sequences of human germline immunoglobulins and selecting the human germline immunoglobulin sequence that is closest in sequence (i.e., greatest % identity) to the sequence of the human antibody.

[0329] A human antibody that is "the product of or "derived from" a particular human germline immunoglobulin sequence may contain amino acid differences as compared to the germline sequence, due to, for example, naturally-occurring somatic mutations or intentional introduction of site-directed mutation. However, a selected human antibody typically is at least 90% identical in amino acids sequence to an amino acid sequence encoded by a human germline immunoglobulin gene and contains amino acid residues that identify the human antibody as being human when compared to the germline immunoglobulin amino acid sequences of other species (e.g., murine germline sequences). In certain cases, a human antibody may be at least 95, 96, 97, 98 or 99%, or even at least 96%, 97%, 98%, or 99% identical in amino acid sequence to the amino acid sequence encoded by the germline immunoglobulin gene. Typically, a human antibody derived from a particular human germline sequence waII display no more than 10 amino acid differences from the amino acid sequence encoded by the human germline immunoglobulin gene. In certain cases, the human antibody may display no more than 5, or even no more than 4, 3, 2, or 1 amino acid difference from the amino acid sequence encoded by the germline immunoglobulin gene.

HOMOLOGOUS ANTIBODIES

[0330] In yet another embodiment, an antibody of the invention comprises heavy and light chain variable regions comprising amino acid sequences that are homologous to isolated antiC10RF32 amino acid sequences of preferred anti-C10RF32 antibodies, respectively, wherein the antibodies retain the desired functional properties of the parent anti-C10RF32 antibodies.

[0331] As used herein, the percent homology between two amino acid sequences is equivalent to the percent identity between the two sequences. The percent identity between the two sequences is a function of the number of identical positions shared by the sequences (i.e., % homology=# of identical positions/total # of positions X 100), taking into account the number of gaps, and the length of each gap, which need to be introduced for optimal alignment of the two sequences. The comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm, as described in the non-limiting examples below.

[0332] The percent identity between two amino acid sequences can be determined using the algorithm of E. Meyers and W. Miller (Comput. Appl. Biosci., 4:11-17 (1988)) which has been incorporated into the ALIGN program (version 2.0), using a PAM120 weight residue table, a gap length penalty of 12 and a gap penalty of 4. In addition, the percent identity between two amino acid sequences can be determined using the Needleman and Wunsch (J. Mol. Biol. 48:444-453 (1970)) algorithm which has been incorporated into the GAP program in the GCG software package (available commercially), using either a Blossum 62 matrix or a PAM250 matrix, and a gap weight of 16,14, 12,10, 8, 6, or 4 and a length weight of 1,2, 3, 4, 5, or 6.

[0333] Additionally or alternatively, the protein sequences of the present invention can further be used as a "query sequence" to perform a search against public databases to, for example, identify related sequences. Such searches can be performed using the XBLAST program (version 2.0) of Altschul, et al. (1990) J Mol. Biol. 215:403-10. BLAST protein searches can be performed with the XBLAST program, score=50, wordlength=3 to obtain amino acid sequences homologous to the antibody molecules of the invention. To obtain gapped alignments for comparison purposes, Gapped BLAST can be utilized as described in Altschul et al., (1997) Nucleic Acids Res. 25(17):3389-3402. When utilizing BLAST and Gapped BLAST programs, the default parameters of the respective programs (e.g., XBLAST and NBLAST) can be used.

Antibodies with Conservative Modifications [0334] In certain embodiments, an antibody of the invention comprises a heavy chain variable region comprising CDR1, CDR2 and CDR3 sequences and a light chain variable region comprising CDR1, CDR2 and CDR3 sequences, wherein one or more of these CDR sequences comprise specified amino acid sequences based on preferred anti-C10RF32 antibodies isolated and produced using methods herein, or conservative modifications thereof, and wherein the antibodies retain the desired functional properties of the antiC10RF32 antibodies of the invention, respectively.

[0335] In various embodiments, the anti-C10RF32 antibody can be, for example, human antibodies, humanized antibodies or chimeric antibodies.

[0336] As used herein, the term "conservative sequence modifications" is intended to refer to amino acid modifications that do not significantly affect or alter the binding characteristics of the antibody containing the amino acid sequence. Such conservative modifications include amino acid substitutions, additions and deletions. Modifications can be introduced into an antibody of the invention by standard techniques known in the art, such as site-directed mutagenesis and PCR-mediated mutagenesis. Conservative amino acid substitutions are ones in which the amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been defined in the art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, seine, threonine, tyrosine, cysteine, tryptophan), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). Thus, one or more amino acid residues within the CDR regions of an antibody of the invention can be replaced with other amino acid residues from the same side chain family and the altered antibody can be tested for retained function (i.e., the functions set forth in (c) through (j) above) using the functional assays described herein.

[0337] Antibodies that Bind to the Same Epitope as Anti-C1 ORF32 Antibodies of the Invention [0338] In another embodiment, the invention provides antibodies that bind to preferred epitopes on human C10RF32 which possess desired functional properties such as modulation of B7 costimulation and related functions. Other antibodies with desired epitope specificity may be selected and will have the ability to cross-compete for binding to C10RF32 antigen with the desired antibodies.

ENGINEERED AND M ODIFIED ANTIBODIES

[0339] An antibody of the invention further can be prepared using an antibody having one or more of the VH and/or VL sequences derived from an anti-C10RF32 antibody starting material to engineer a modified antibody, which modified antibody may have altered properties from the starting antibody. An antibody can be engineered by modifying one or more residues within one or both variable regions (i.e., VH and/or VL), for example within one or more CDR regions and/or within one or more framework regions. Additionally or alternatively, an antibody can be engineered by modifying residues within the constant regions, for example to alter the effector functions of the antibody.

[0340] One type of variable region engineering that can be performed is CDR grafting. Antibodies interact with target antigens predominantly through amino acid residues that are located in the six heavy and light chain complementarity determining regions (CDRs). For this reason, the amino acid sequences within CDRs are more diverse between individual antibodies than sequences outside of CDRs. Because CDR sequences are responsible for most antibody-antigen interactions, it is possible to express recombinant antibodies that mimic the properties of specific naturally occurring antibodies by constructing expression vectors that include CDR sequences from the specific naturally occurring antibody grafted onto framework sequences from a different antibody with different properties (see, e.g., Riechmann, L. et al. (1998) Nature 332:323-327; Jones, R et al. (1986) Nature 321:522-525; Queen, C. et al. (1989) Proc. Natl. Acad. See. U.S.A. 86:10029-10033; U.S. Pat. No. 5,225,539 to Winter, and U.S. Pat. Nos. 5,530,101; 5,585,089; 5,693,762 and 6,180,370 to Queen et al.) [0341] Suitable framework sequences can be obtained from public DNA databases or published references that include germline antibody gene sequences. For example, germline DNA sequences for human heavy and light chain variable region genes can be found in the "VBase" human germline sequence database (available on the Internet), as well as in Kabat, E. A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242; Tomlinson, I. M., et al. (1992) "The Repertoire of Human Germline VH Sequences Reveals about Fifty Groups of VH Segments with Different Hypervariable Loops" J. Mol. Biol. 227:776-798; and Cox, J. P. L. et al. (1994) "A Directory of Human Germ-line VH Segments Reveals a Strong Bias in their Usage" Eur. J Immunol. 24:827-836; the contents of each of which are expressly incorporated herein by reference.

[0342] Another type of variable region modification is to mutate amino acid residues within the VH and/or VL CDR 1, CDR2 and/or CDR3 regions to thereby improve one or more binding properties (e.g., affinity) of the antibody of interest. Site-directed mutagenesis or PCR-mediated mutagenesis can be performed to introduce the mutations and the effect on antibody binding, or other functional property of interest, can be evaluated in appropriate in vitro or in vivo assays. Preferably conservative modifications (as discussed above) are introduced. The mutations may be amino acid substitutions, additions or deletions, but are preferably substitutions. Moreover, typically no more than one, two, three, four or five residues within a CDR region are altered.

[0343] Engineered antibodies of the invention include those in vtfiich modifications have been made to framework residues within VH and/or VL, e.g. to improve the properties of the antibody. Typically such framework modifications are made to decrease the immunogenicity of the antibody. For example, one approach is to 'backmutate" one or more framework residues to the corresponding germline sequence. More specifically, an antibody that has undergone somatic mutation may contain framework residues that differ from the germline sequence from which the antibody is derived. Such residues can be identified by comparing the antibody framework sequences to the germline sequences from which the antibody is derived.

[0344] In addition or alternative to modifications made within the framework or CDR regions, antibodies of the invention may be engineered to include modifications within the Fc region, typically to alter one or more functional properties of the antibody, such as serum half-life, complement fixation, Fc receptor binding, and/or antigen-dependent cellular cytotoxicity. Furthermore, an antibody of the invention may be chemically modified (e.g., one or more chemical moieties can be attached to the antibody) or be modified to alter its glycosylation, again to alter one or more functional properties of the antibody. Such embodiments are described further below. The numbering of residues in the Fc region is that of the EU index of Kabat.

[0345] In one embodiment, the hinge region of CH1 is modified such that the number of cysteine residues in the hinge region is altered, e.g., increased or decreased. This approach is described further in U.S. Pat. No. 5,677,425 by Bodmer et al. The number of cysteine residues in the hinge region of CH1 is altered to, for example, facilitate assembly of the light and heavy chains or to increase or decrease the stability of the antibody.

[0346] In another embodiment, the Fc hinge region of an antibody is mutated to decrease the biological half life of the antibody. More specifically, one or more amino acid mutations are introduced into the CH2-CH3 domain interface region of the Fc-hinge fragment such that the antibody has impaired Staphylococcyl protein A (SpA) binding relative to native Fc-hinge domain SpA binding. This approach is described in further detail in U.S. Pat. No. 6,165,745 by Ward et al.

[0347] In another embodiment, the antibody is modified to increase its biological half life. Various approaches are possible. For example, one or more of the following mutations can be introduced: T252L, T254S, T256F, as described in U.S. Pat. No. 6,277,375 to \Nard. Alternatively, to increase the biological half life, the antibody can be altered within the CH1 or CL region to contain a salvage receptor binding epitope taken from two loops of a CH2 domain of an Fc region of an IgG, as described in U.S. Pat. Nos. 5,869,046 and 6,121,022 by Presta et al.

[0348] In yet other embodiments, the Fc region is altered by replacing at least one amino acid residue with a different amino acid residue to alter the effector functions of the antibody. For example, one or more amino acids selected from amino acid residues 234, 235, 236, 237, 297, 318, 320 and 322 can be replaced with a different amino acid residue such that the antibody has an altered affinity for an effector ligand but retains the antigen-binding ability of the parent antibody. The effector ligand to which affinity is altered can be, for example, an Fc receptor or the C1 component of complement. This approach is described in further detail in U.S. Pat. Nos. 5,624,821 and 5,648,260, both by Winter et al.

[0349] In another example, one or more amino acids selected from amino acid residues 329, 331 and 322 can be replaced with a different amino acid residue such that the antibody has altered C1q binding and/or reduced or abolished complement dependent cytotoxicity (CDC). This approach is described in further detail in U.S. Pat. Nos. 6,194,551 by Idusogie et al.

[0350] In another example, one or more amino acid residues within amino acid positions 231 and 239 are altered to thereby alter the ability of the antibody to fix complement. This approach is described further in PCT Publication WO 94/29351 by Bodmer et al.

[0351] In yet another example, the Fc region is modified to increase the ability of the antibody to mediate antibody dependent cellular cytotoxicity (ADCC) and/or to increase the affinity of the antibody for an Fey receptor by modifying one or more amino acids at the following positions: 238, 239, 248, 249, 252, 254, 255, 256, 258, 265, 267, 268, 269, 270, 272, 276, 278, 280, 283, 285, 286, 289, 290, 292, 293, 294, 295, 296, 298, 301, 303, 305, 307, 309, 312, 315, 320, 322, 324, 326, 327, 329, 330, 331, 333, 334, 335, 337, 338, 340, 360, 373, 376, 378, 382, 388, 389, 398, 414, 416, 419, 430, 434, 435, 437, 438 or 439. This approach is described further in PCT Publication WO 00/42072 by Presta. Moreover, the binding sites on human IgG 1 for Fc grammar, Fc gamma Rll, Fc gammaRIII and FcRn have been mapped and variants with improved binding have been described (see Shields, R. L. et al. (2001) J. Biol. Chem. 276:6591-6604). Specific mutations at positions 256, 290, 298, 333, 334 and 339 are shown to improve binding to FcyRIII. Additionally, the following combination mutants are shown to improve Fcgamma.RIII binding: T256A/S298A, S298A/E333A, S298A/K224Aand S298A/E333A/K334A.

[0352] In still another embodiment, the glycosylation of an antibody is modified. For example, an aglycoslated antibody can be made (i.e., the antibody lacks glycosylation). Glycosylation can be altered to, for example, increase the affinity of the antibody for antigen. Such carbohydrate modifications can be accomplished by, for example, altering one or more sites of glycosylation within the antibody sequence. For example, one or more amino acid substitutions can be made that result in elimination of one or more variable region framework glycosylation sites to thereby eliminate glycosylation at that site. Such aglycosylation may increase the affinity of the antibody for antigen. Such an approach is described in further detail in U.S. Pat. Nos. 5,714,350 and 6,350,861 by Co et al.

[0353] Additionally or alternatively, an antibody can be made that has an altered type of glycosylation, such as a hypofucosylated antibody having reduced amounts of fucosyl residues or an antibody having increased bisecting GIcNac structures. Such altered glycosylation patterns have been demonstrated to increase the ADCC ability of antibodies. Such carbohydrate modifications can be accomplished by, for example, expressing the antibody in a host cell with altered glycosylation machinery. Cells with altered glycosylation machinery have been described in the art and can be used as host cells in which to express recombinant antibodies of the invention to thereby produce an antibody with altered glycosylation. For example, the cell lines Ms704, Ms705, and Ms709 lack the fucosyltransferase gene, FUT8 (alpha (1,6) fucosyltransferase), such that antibodies expressed in the Ms704, Ms705, and Ms709 cell lines lack fucose on their carbohydrates. The Ms704, Ms705, and Ms709 FUT8.-/- cell lines are created by the targeted disruption of the FLTT8 gene in CHO/DG44 cells using two replacement vectors (see U.S. Patent Publication No. 20040110704 by Yamane et al. andYamane-Ohnuki et al. (2004) Biotechnol Bioeng 87:614-22). As another example, EP 1,176,195 by Hanai et al. describes a cell line with a functionally disrupted FUT8 gene, which encodes a fucosyl transferase, such that antibodies expressed in such a cell line exhibit hypofucosylation by reducing or eliminating the alpha 1,6 bond-related enzyme. Hanai et al. also describe cell lines which have a low enzyme activity for adding fucose to the N-acetylglucosamine that binds to the Fc region of the antibody or does not have the enzyme activity, for example the rat myeloma cell line YB2/0 (ATCC CRL 1662). PCT Publication WO 03/035835 by Presta describes a variant CHO cell line, Led 3 cells, with reduced ability to attach fucose to Asn(297)-linked carbohydrates, also resulting in hypofucosylation of antibodies expressed in that host cell (see also Shields, R. L. et al. (2002) J. Biol. Chem. 277:26733-26740). PCT Publication WO 99/54342 by Umana et al. describes cell lines engineered to express glycoprotein-modifying glycosyl transferases (e.g., beta(1,4)-N- acetylglucosaminyltransferase III (GnTIII)) such that antibodies expressed in the engineered cell lines exhibit increased bisecting GIcNac structures which results in increased ADCC activity of the antibodies (see also Umana et al. (1999) Nat. Biotech. 17:176-180). Alternatively, the fucose residues of the antibody may be cleaved off using a fucosidase enzyme. For example, the fucosidase alpha-L-fucosidase removes fucosyl residues from antibodies (Tarentino, A. L. et al. (1975) Biochem. 14:5516-23).

[0354] Another modification of the antibodies herein that is contemplated by the invention is pegylation. An antibody can be pegylated to, for example, increase the biological (e.g., serum) half life of the antibody. To pegylate an antibody, the antibody, or fragment thereof, typically is reacted with polyethylene glycol (PEG), such as a reactive ester or aldehyde derivative of PEG, under conditions in wlnich one or more PEG groups become attached to the antibody or antibody fragment. Preferably, the pegylation is carried out via an acylation reaction or an alkylation reaction with a reactive PEG molecule (or an analogous reactive water-soluble polymer). As used herein, the term "polyethylene glycol" is intended to encompass any of the forms of PEG that have been used to derivatize other proteins, such as mono (C1-C10) alkoxy- or aryloxy-polyethylene glycol or polyethylene glycol-maleimide. In certain embodiments, the antibody to be pegylated is an aglycosylated antibody. Methods for pegylating proteins are known in the art and can be applied to the antibodies of the invention. See for example, EP 0 154 316 by Nishimura et al. and EP 0 401 384 by Ishikawa et al.

METHODS OF ENGINEERING ANTIBODIES

[0355] As discussed above, the anti-C10RF32 antibodies having VH and VK sequences disclosed herein can be used to create newanti-C10RF32 antibodies, respectively, by modifying the VH and/or VL sequences, or the constant regions attached thereto. Thus, in another aspect of the invention, the structural features of an anti-C10RF32, antibody of the invention, are used to create structurally related anti-C10RF32; antibodies that retain at least one functional property of the antibodies of the invention, such as binding to human C10RF32 . For example, one or more CDR regions of one C10RF32 antibody or mutations thereof, can be combined recombinantly with known framework regions and/or other CDRs to create additional, recombinantly-engineered, anti-C10RF32 antibodies of the invention, as discussed above. Other types of modifications include those described in the previous section. The starting material for the engineering method is one or more of the VH and/or VK sequences provided herein, or one or more CDR regions thereof. To create the engineered antibody, it is not necessary to actually prepare (i.e., express as a protein) an antibody having one or more of the VH and/or VK sequences provided herein, or one or more CDR regions thereof. Rather, the information contained in the sequences is used as the starting material to create a "second generation" sequences derived from the original sequences and then the "second generation" sequences is prepared and expressed as a protein.

[0356] Standard molecular biology techniques can be used to prepare and express altered antibody sequence.

[0357] Preferably, the antibody encoded by the altered antibody sequences is one that retains one, some or all of the functional properties of the anti-C10F32 antibodies; produced by methods and with sequences provided herein, which functional properties include binding to C10RF32 antigen with a specific KD level or less and/or modulating B7 costimulation and/or selectively binding to desired target cells such as lung cancer, ovarian cancer, colon cancer, that express C10RF32 antigen.

[0358] The functional properties of the altered antibodies can be assessed using standard assays available in the art and/or described herein.

[0359] In certain embodiments of the methods of engineering antibodies of the invention, mutations can be introduced randomly or selectively along all or part of an ani-C10RF32 antibody coding sequence and the resulting modified ani-C10RF32 antibodies can be screened for binding activity and/or other desired functional properties.

[0360] Mutational methods have been described in the art. For example, PCT Publication WO 02/092780 by Short describes methods for creating and screening antibody mutations using saturation mutagenesis, synthetic ligation assembly, or a combination thereof. Alternatively, PCT Publication WO 03/074679 by Lazar et al. describes methods of using computational screening methods to optimize physiochemical properties of antibodies.

NUCLEIC ACID MOLECULES ENCODING ANTIBODIES OF THE INVENTION

[0361] Another aspect of the invention pertains to nucleic acid molecules that encode the antibodies of the invention. The nucleic acids may be present in whole cells, in a cell lysate, or in a partially purified or substantially pure form. A nucleic acid is "isolated" or "rendered substantially pure" when purified away from other cellular components or other contaminants, e.g., other cellular nucleic acids or proteins, by standard techniques, including alkaline/SDS treatment, CsCI banding, column chromatography, agarose gel electrophoresis and others well known in the art. See, F. Ausubel, et al., ed. (1987) Current Protocols in Molecular Biology, Greene Publishing and Wiley Interscience, New York. A nucleic acid of the invention can be, for example, DNA or RNA and may or may not contain intronic sequences. In a preferred embodiment, the nucleic acid is a cDNA molecule.

[0362] Nucleic acids of the invention can be obtained using standard molecular biology techniques. For antibodies expressed by hybridomas (e.g., hybridomas prepared from transgenic mice carrying human immunoglobulin genes as described further below), cDNAs encoding the light and heavy chains of the antibody made by the hybridoma can be obtained by standard PCR amplification or cDNA cloning techniques. For antibodies obtained from an immunoglobulin gene library (e.g., using phage display techniques), nucleic acid encoding the antibody can be recovered from the library.

[0363] Once DNA fragments encoding VH and VL segments are obtained, these DNA fragments can be further manipulated by standard recombinant DNA techniques, for example to convert the variable region genes to full-length antibody chain genes, to Fab fragment genes or to a scFv gene. In these manipulations, a VL-or VH-encoding DNA fragment is operatively linked to another DNA fragment encoding another protein, such as an antibody constant region or a flexible linker.

[0364] The term "operatively linked", as used in this context, is intended to mean that the two DNA fragments are joined such that the amino acid sequences encoded by the two DNA fragments remain in-frame.

[0365] The isolated DNA encoding the VH region can be converted to a full-length heavy chain gene by operatively linking the VH-encoding DNA to another DNA molecule encoding heavy chain constant regions (CH1, CH2 and CH3). The sequences of human heavy chain constant region genes are known in the art (see e.g., Kabat, E. A., el al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242) and DNA fragments encompassing these regions can be obtained by standard PCR amplification. The heavy chain constant region can be an lgG1, lgG2, lgG3, lgG4, IgA, IgE, IgM or IgD constant region, but most preferably is an lgG1 or lgG4 constant region. For a Fab fragment heavy chain gene, the VH-encoding DNA can be operatively linked to another DNA molecule encoding only the heavy chain CH1 constant region.

[0366] The isolated DNA encoding the VL region can be converted to a full-length light chain gene (as well as a Fab light chain gene) by operatively linking the VL-encoding DNA to another DNA molecule encoding the light chain constant region, CL. The sequences of human light chain constant region genes are known in the art (see e.g., Kabat, E. A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242) and DNA fragments encompassing these regions can be obtained by standard PCR amplification. The light chain constant region can be a kappa or lambda constant region, but most preferably is a kappa constant region.

[0367] To create a scFv gene, the VH- and VL-encoding DNA fragments are operatively linked to another fragment encoding a flexible linker, e.g., encoding the amino acid sequence (Gly4-Ser)3, such that the VH and VL sequences can be expressed as a contiguous single-chain protein, with the VL and VH regions joined by the flexible linker (see e.g., Bird et al. (1988) Science 242:423-426; Huston et al. (1988) Proc. Natl. Acad. Sri. USA85:5879-5883; McCafferty et al., (1990) Nature 348:552-554).

[0368] Production Of Anti-VSIG1, Anti-ILDR1, Anti-LOC253012, Anti-AI216611, Ani-C10RF32, or Anti-FXYD3 Monoclonal

Antibodies Of The Invention [0369] Monoclonal antibodies (mAbs) of the present invention can be produced by a variety of techniques, including conventional monoclonal antibody methodology e.g., the standard somatic cell hybridization technique of Kohler and Milstein (1975) Nature 256:495. Although somatic cell hybridization procedures are preferred, in principle, other techniques for producing monoclonal antibody can be employed e.g., viral or oncogenic transformation of B lymphocytes.

[0370] A preferred animal system for preparing hybridomas is the murine system. Hybridoma production in the mouse is a very well-established procedure. Immunization protocols and techniques for isolation of immunized splenocytes for fusion are known in the art. Fusion partners (e.g., murine myeloma cells) and fusion procedures are also known.

[0371] Chimeric or humanized antibodies of the present invention can be prepared based on the sequence of a murine monoclonal antibody prepared as described above. DNA encoding the heavy and light chain immunoglobulins can be obtained from the murine hybridoma of interest and engineered to contain non-murine (e.g.,. human) immunoglobulin sequences using standard molecular biology techniques. For example, to create a chimeric antibody, the murine variable regions can be linked to human constant regions using methods known in the art (see e.g., U.S. Pat. No. 4,816,567 to Cabilly et al.). To create a humanized antibody, the murine CDR regions can be inserted into a human framework using methods known in the art (see e.g., U.S. Pat. No. 5,225,539 to Winter, and U.S. Pat. Nos. 5,530,101; 5,585,089; 5,693,762 and 6,180,370 to Queen et al.).

[0372] In a preferred embodiment, the antibodies of the invention are human monoclonal antibodies. Such human monoclonal antibodies directed against VSIG1 can be generated using transgenic or transchromosomic mice carrying parts of the human immune system rather than the mouse system. These transgenic and transchromosomic mice include mice referred to herein as the HuMAb Mouse RTM and KM Mouse. RTM. respectively, and are collectively referred to herein as "human Ig mice." The HuMAb Mouse TM. (Medarex. Inc.) contains human immunoglobulin gene miniloci that encode unrearranged human heavy (.mu. and.gamma.) and.kappa, light chain immunoglobulin sequences, together with targeted mutations that inactivate the endogenous.mu. and.kappa, chain loci (see e.g., Lonberg, et al. (1994) Nature 368(6474): 856-859). Accordingly, the mice exhibit reduced expression of mouse IgM or.kappa., and in response to immunization, the introduced human heavy and light chain transgenes undergo class switching and somatic mutation to generate high affinity human IgGkappa. monoclonal (Lonberg, N. et al. (1994), supra; reviewed in Lonberg, N. (1994) Handbook of Experimental Pharmacology 113:49-101; Lonberg, N. and Huszar, et al. (1993) Proc. Natl. Acad. Sci. USA 90:3720-3724; Choi et al. (1993) Nature Genetics 4:117-123; Chen, J. et al. (1993) EMBO J. 12: 821-830; Tuaillon et al. (1994) J. Immunol. 152:2912-2920; Taylor, L. et al. (1994) International Immunology 6:579-591; and Fishwild, D. et al. (1996) Nature Biotechnology 14: 845-851, the contents of all of which are hereby specifically incorporated by reference in their entirety. See further, U.S. Pat. Nos. 5,545,806; 5,569,825; 5,625,126; 5,633,425; 5,789,650; 5,877,397; 5,661,016; 5,814,318; 5,874,299; and 5,770,429; all to Lonberg and Kay; U.S. Pat. No. 5,545,807 to Surani et al.; PCT Publication Nos. WO 92/03918, WO 93/12227, WO 94/25585, WO 97/13852, WO 98/24884 and WO 99/45962, all to Lonberg and Kay; and PCT Publication No. WO 01/14424 to Korman et al.

[0373] In another embodiment, human antibodies of the invention can be raised using a mouse that carries human immunoglobulin sequences on transgenes and transchomosomes, such as a mouse that carries a human heavy chain transgene and a human light chain transchromosome. Such mice, referred to herein as "KM mice TM.", are described in detail in PCT Publication WO 02/43478 to Ishida et al.

[0374] Still further, alternative transgenic animal systems expressing human immunoglobulin genes are available in the art and can be used to raise anti-VSIG1 antibodies of the invention. For example, an alternative transgenic system referred to as the Xenomouse (Abgenix, Inc.) can be used; such mice are described in, for example, U.S. Pat. Nos. 5,939,598; 6,075,181; 6,114,598; 6, 150,584 and 6,162,963 to Kucherlapati et al.

[0375] Moreover, alternative transchromosomic animal systems expressing human immunoglobulin genes are available in the art and can be used to raise ani-C10RF32 antibodies of the invention. For example, mice carrying both a human heavy chain transchromosome and a human light chain transchromosome, referred to as "TC mice" can be used; such mice are described in Tomizuka et al. (2000) Proc. Natl. Acad Sci. USA 97:722-727 . Furthermore, cows carrying human heavy and light chain transchrornosomes have been described in the art (Kuroiwa et al. (2002) Nature Biotechnology 20:889-894) and can be used to raise anti-VSIG1 antibodies.

[0376] Human monoclonal antibodies of the invention can also be prepared using phage display methods for screening libraries of human immunoglobulin genes. Such phage display methods for isolating human antibodies are established in the art. See for example: U.S. Pat. Nos. 5,223,409; 5,403,484; and 5,571,698 to Ladner et al.; U.S. Pat. Nos. 5,427,908 and 5,580,717 to Dower et al.; U.S. Pat. Nos. 5,969,108 and 6,172,197 to McCafferty et al.; and U.S. Pat. Nos. 5,885,793; 6,521,404; 6,544,73 1; 6,555,313; 6,582,915 and 6,593,081 to Griffiths et al.

[0377] Human monoclonal antibodies of the invention can also be prepared using SCID mice into which human immune cells have been reconstituted such that a human antibody response can be generated upon immunization. Such mice are described in, for example, U.S. Pat. Nos. 5,476,996 and 5,698,767 to Wilson et al.

IMMUNIZATION OF HUMAN IG MICE

[0378] When human Ig mice are used to raise human antibodies of the invention, such mice can be immunized with a purified or enriched preparation of C10RF32 antigen and/or recombinant C10RF32, or C10RF32 fusion protein, as described by Lonberg, N. et al. (1994) Nature 368(6474): 856-859; Fishwild, D. et al. (1996) Nature Biotechnology 14: 845-851; and PCT Publication WO 98/24884 and WO 01/14424. Preferably, the mice will be 6-16 weeks of age upon the first infusion. For example, a purified or recombinant preparation (5-50.mu.g) of C10RF32 antigen can be used to immunize the human Ig mice intraperitoneally.

[0379] Prior experience with various antigens by others has shown that the transgenic mice respond when initially immunized intraperitoneally (IP) with antigen in complete Freund's adjuvant, followed by every other week IP immunizations (up to a total of 6) with antigen in incomplete Freund's adjuvant. However, adjuvants other than Freund's are also found to be effective. In addition, whole cells in the absence of adjuvant are found to be highly immunogenic. The immune response can be monitored over the course of the immunization protocol with plasma samples being obtained by retroorbital bleeds. The plasma can be screened by ELISA (as described below), and mice with sufficient titers of anti-C10RF32 human immunoglobulin can be used for fusions. Mice can be boosted intravenously with antigen 3 days before sacrifice and removal of the spleen. It is expected that 2-3 fusions for each immunization may need to be performed. Between 6 and 24 mice are typically immunized for each antigen. Usually both HCo7 and HCo12 strains are used. In addition, both HCo7 and HCo12 transgene can be bred together into a single mouse having two different human heavy chain transgenes (HCo7/HCo 12). Alternatively or additionally, the KM Mouse. RTM. strain can be 42 used.

GENERATION OF HYBRIDOMAS PRODUCING HUMAN MONOCLONAL ANTIBODIES OF THE INVENTION

[0380] To generate hybridomas producing human monoclonal antibodies of the invention, splenocytes and/or lymph node cells from immunized mice can be isolated and fused to an appropriate immortalized cell line, such as a mouse myeloma cell line. The resulting hybridomas can be screened for the production of antigen-specific antibodies. For example, single cell suspensions of splenic lymphocytes from immunized mice can be fused to one-sixth the number of P3X63-Ag8.653 nonsecreting mouse myeloma cells (ATCC, CRL 1580) with 50% PEG. Cells are plated at approximately 2X10-5 in flat bottom microtiter plate, followed by a two week incubation in selective medium containing 20% fetal Clone Serum, 18% "653” conditioned media, 5% origen (IGEN), 4 mM L-glutamine, 1 mM sodium pyruvate, 5 mM HEPES, 0.055 mM 2-mercaptoethanol, 50 units/ml penicillin, 50 mg/ml streptomycin, 50 mg/ml gentamycin and 1X HAT (Sigma; the HAT is added 24 hours after the fusion). After approximately two weeks, cells can be cultured in medium in which the HAT is replaced with ΗΓ. Individual wells can then be screened by ELISA for human monoclonal IgM and IgG antibodies. Once extensive hybridoma growth occurs, medium can be observed usually after 10-14 days. The antibody secreting hybridomas can be replated, screened again, and if still positive for human IgG, the monoclonal antibodies can be subcloned at least twice by limiting dilution. The stable subclones can then be cultured in vitro to generate small amounts of antibody in tissue culture medium for characterization.

[0381] To purify human monoclonal antibodies, selected hybridomas can be grown in two-liter spinner-flasks for monoclonal antibody purification. Supernatants can be filtered and concentrated before affinity chromatography with protein A-Sepharose (Pharmacia, Piscataway, N.J.). Eluted IgG can be checked by gel electrophoresis and high performance liquid chromatography to ensure purity. The buffer solution can be exchanged into PBS, and the concentration can be determined by OD280 using 1.43 extinction coefficient. The monoclonal antibodies can be aliquoted and stored at -80 degrees C.

GENERATION OF TRANSFECTOMAS PRODUCING MONOCLONAL ANTIBODIES OF THE INVENTION

[0382] Antibodies of the invention also can be produced in a host cell transfectoma using, for example, a combination of recombinant DNA techniques and gene transfection methods as is well known in the art (e.g., Morrison, S. (1985) Science 229:1202).

[0383] For example, to express the antibodies, or antibody fragments thereof, DNAs encoding partial or full-length light and heavy chains, can be obtained by standard molecular biology techniques (e.g., PCR amplification or cDNA cloning using a hybridoma that expresses the antibody of interest) and the DNAs can be inserted into expression vectors such that the genes are operatively linked to transcriptional and translational control sequences. In this context, the term "operatively linked" is intended to mean that an antibody gene is ligated into a vector such that transcriptional and translational control sequences within the vector serve their intended function of regulating the transcription and translation of the antibody gene. The expression vector and expression control sequences are chosen to be compatible with the expression host cell used. The antibody light chain gene and the antibody heavy chain gene can be inserted into separate vector or, more typically, both genes are inserted into the same expression vector. The antibody genes are inserted into the expression vector by standard methods (e.g., ligation of complementary restriction sites on the antibody gene fragment and vector, or blunt end ligation if no restriction sites are present). The light and heavy chain variable regions of the antibodies described herein can be used to create full-length antibody genes of any antibody isotype by inserting them into expression vectors already encoding heavy chain constant and light chain constant regions of the desired isotype such that the VH segment is operatively linked to the CH segments within the vector and the VK segment is operatively linked to the CL segment within the vector. Additionally or alternatively, the recombinant expression vector can encode a signal peptide that facilitates secretion of the antibody chain from a host cell. The antibody chain gene can be cloned into the vector such that the signal peptide is linked in-frame to the amino terminus of the antibody chain gene. The signal peptide can be an immunoglobulin signal peptide or a heterologous signal peptide (i.e., a signal peptide from a nonimmunoglobulin protein).

[0384] In addition to the antibody chain genes, the recombinant expression vectors of the invention carry regulatory sequences that control the expression of the antibody chain genes in a host cell. The term "regulatory sequence" is intended to include promoters, enhancers and other expression control elements (e.g., polyadenylation signals) that control the transcription or translation of the antibody chain genes. Such regulatory sequences are described, for example, in Goeddel (Gene Expression Technology. Methods in Enzymology 185, Academic Press, San Diego, Calif. (1990 )). It will be appreciated by those skilled in the art that the design of the expression vector, including the selection of regulatory sequences, may depend on such factors as the choice of the host cell to be transformed, the level of expression of protein desired, etc. Preferred regulatory sequences for mammalian host cell expression include viral elements that direct high levels of protein expression in mammalian cells, such as promoters and/or enhancers derived from cytomegalovirus (CMV), Simian Virus 40 (SV40), adenovirus, (e.g., the adenovirus major late promoter (AdMLP) and polyoma. Alternatively, nonviral regulatory sequences may be used, such as the ubiquitin promoter or.beta.-globin promoter. Still further, regulatory elements composed of sequences from different sources, such as the SR alpha, promoter system, which contains sequences from the SV40 early promoter and the long terminal repeat of human T cell leukemia virus type 1 (Takebe, Y. et al. (1988) Mol. Cell. Biol. 8:466-472).

[0385] In addition to the antibody chain genes and regulatory sequences, the recombinant expression vectors of the invention may carry additional sequences, such as sequences that regulate replication of the vector in host cells (e.g., origins of replication) and selectable marker genes. The selectable marker gene facilitates selection of host cells into which the vector has been introduced (see, e.g., U.S. Pat. Nos. 4,399,216, 4,634,665 and 5,179,017, all by Axel et al.). For example, typically the selectable marker gene confers resistance to drugs, such as G418, hygromycin or methotrexate, on a host cell into which the vector has been introduced. Preferred selectable marker genes include the dihydrofolate reductase (DHFR) gene (for use in dhfr-host cells with methotrexate selection/amplification) and the neo gene (for G418 selection).

[0386] For expression of the light and heavy chains, the expression vectors encoding the heavy and light chains is transfected into a host cell by standard techniques. The various forms of the term "transfection" are intended to encompass a wide variety of techniques commonly used for the introduction of exogenous DNAinto a prokaryotic or eukaryotic host cell, e.g., electroporation, calcium-phosphate precipitation, DEAE-dextran transfection and the like. Although it is theoretically possible to express the antibodies of the invention in either prokaryotic or eukaryotic host cells, expression of antibodies in eukaryotic cells, and most preferably mammalian host cells, is the most preferred because such eukaryotic cells, and in particular mammalian cells, are more likely than prokaryotic cells to assemble and secrete a properly folded and immunologically active antibody. Prokaryotic expression of antibody genes has been reported to be ineffective for production of high yields of active antibody (Boss, M. A and Wood, C. R. (1985) Immunology Today 6:12-13).

[0387] Preferred mammalian host cells for expressing the recombinant antibodies of the invention include Chinese Hamster Ovary (CHO cells) (including dhfr- CHO cells, described in Urlaub and Chasin, (1980) Proc. Natl. Acad. Sci. USA 77:4216-4220 , used with a DHFR selectable marker, e.g, as described in R. J. Kaufman and P. A. Sharp (1982) Mol. Biol. 159:601-621 ), NSO myeloma cells, COS cells and SP2 cells. In particular, for use with NSO myeloma cells, another preferred expression system is the GS gene expression system disclosed in WO 87/04462, WO 89/01036 and EP 338,841. When recombinant expression vectors encoding antibody genes are introduced into mammalian host cells, the antibodies are produced by culturing the host cells for a period of time sufficient to allow for expression of the antibody in the host cells or, more preferably, secretion of the antibody into the culture medium in which the host cells are grown. Antibodies can be recovered from the culture medium using standard protein purification methods.

CHARACTERIZATION OF ANTIBODY BINDING TO ANTIGEN

[0388] Antibodies can be tested for binding to VSIG1, ILDR1, LOC253012, AI216611, C10RF32, or FXYD3 by, for example, standard ELISA. Briefly, microtiter plates are coated with purified VSIG1 at 0.25.mu.g/ml in PBS, and then blocked with 5% bovine serum albumin in PBS. Dilutions of antibody (e.g., dilutions of plasma from VSIG1, ILDR1, LOC253012, AI216611, C10RF32, or FXYD3-immunized mice) are added to each well and incubated for 1-2 hours at 37 degrees C. The plates are washed with PBS/Tween and then incubated with secondary reagent (e.g, for human antibodies, a goat-anti-human IgG Fc-specific polyclonal reagent) conjugated to alkaline phosphatase for 1 hour at 37 degrees C. After washing, the plates are developed with pNPP substrate (1 mg/ml), and analyzed at OD of 405-650. Preferably, mice which develop the highest titers will be used for fusions.

[0389] An ELISA assay as described above can also be used to screen for hybridomas that show positive reactivity with C1ORF32 immunogen. One clone from each hybridoma, which retains the reactivity of the parent cells (by ELISA), can be chosen for making a 5-10 vial cell bank stored at -140 degrees C, and for antibody purification.

[0390] To purify antiC10RF32 antibodies, selected hybridomas can be grown in two-liter spinner-flasks for monoclonal antibody purification. Supernatants can be filtered and concentrated before affinity chromatography with protein A-sepharose (Pharmacia, Piscatavway, N.J.). Eluted IgG can be checked by gel electrophoresis and high performance liquid chromatography to ensure purity. The buffer solution can be exchanged into PBS, and the concentration can be determined by OD280 using 1.43 extinction coefficient. The monoclonal antibodies can be aliquoted and stored at -80 degrees C.

[0391] To determine if the selected anti-C10RF32 monoclonal antibodies bind to unique epitopes, each antibody can be biotinylated using commercially available reagents (Pierce, Rockford, III.). Competition studies using unlabeled monoclonal antibodies and biotinylated monoclonal antibodies can be performed using C1ORF32 coated-ELISA plates as described above. Biotinylated mAb binding can be detected with a strep-avidin-alkaline phosphatase probe.

[0392] To determine the isotype of purified antibodies, isotype ELISAs can be performed using reagents specific for antibodies of a particular isotype. For example, to determine the isotype of a human monoclonal antibody, wells of microtiter plates can be coated with 1 mu.g/ml of anti-human immunoglobulin overnight at 4 degrees C. After blocking with 1% BSA, the plates are reacted with 1 mug /ml or less of test monoclonal antibodies or purified isotype controls, at ambient temperature for one to two hours. The wells can then be reacted with either human lgG1 or human IgM-specific alkaline phosphatase-conjugated probes. Plates are developed and analyzed as described above.

[0393] Anti-C10RF32 human IgGs can be further tested for reactivity with C10RF32 antigen by Western blotting. Briefly, C10RF32 antigen can be prepared and subjected to sodium dodecyl sulfate polyacrylamide gel electrophoresis. After electrophoresis, the separated antigens are transferred to nitrocellulose membranes, blocked with 10% fetal calf serum, and probed with the monoclonal antibodies to be tested. Human IgG binding can be detected using anti-human IgG alkaline phosphatase and developed with BCIP/NBT substrate tablets (Sigma Chem. Co., St. Louis, Mo.).

CONJUGATES OR IMMUNOCONJUGATES

[0394] The present invention encompasses conjugates for use in immune therapy comprising the C10RF32 antigen and soluble portions thereof including the ectodomain or portions or variants thereof. For example the invention encompasses conjugates wherein the ECD of the C10RF32 antigen is attached to an immunoglobulin or fragment thereof. The invention contemplates the use thereof for promoting or inhibiting C10RF32 antigen activities such as immune costimulation and the use thereof in treating transplant, autoimmune, and cancer indications described herein.

[0395] In another aspect, the present invention features immunoconjugates comprising an antiC10RF32 antibody, or a fragment thereof, conjugated to a therapeutic moiety, such as a cytotoxin, a drug (e.g., an immunosuppressant) or a radiotoxin. Such conjugates are referred to herein as "immunoconjugates”. Immunoconjugates that include one or more cytotoxins are referred to as "immunotoxins." A cytotoxin or cytotoxic agent includes any agent that is detrimental to (e.g., kills) cells. Examples include taxol, cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicin, doxorubicin, daunorubicin, dihydroxy anthracin dione, mitoxantrone, mithramycin, actinomycin D, 1-dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, propranolol, and puromycin and analogs or homologs thereof. Therapeutic agents also include, for example, antimetabolites (e.g., methotrexate, 6-mercaptopurine, 6-thioguanine, cytarabine, 5-fluorouracil decarbazine), alkylating agents (e.g., mechlorethamine, thioepa chlorambucil, melphalan, carmustine (BSNU) and lomustine (CCNU), cyclothosphamide, busulfan, dibromomannitol, streptozotocin, mitomycin C, and cis-dichlorodiamine platinum (II) (DDP) cisplatin), anthracyclines (e.g., daunorubicin (formerly daunomycin) and doxorubicin), antibiotics (e.g., dactinomycin (formerly actinomycin), bleomycin, mithramycin, and anthramycin (AMC)), and anti-mitotic agents (e.g., vincristine and vinblastine).

[0396] Other preferred examples of therapeutic cytotoxins that can be conjugated to an antibody of the invention include duocarmycins, calichearnicins, maytansines and auristatins, and derivatives thereof. An example of a calicheamicin antibody conjugate is commercially available (Mylotarg.TM.; Wyeth).

[0397] Cytotoxins can be conjugated to antibodies of the invention using linker technology available in the art. Examples of linker types that have been used to conjugate a cytotoxin to an antibody include, but are not limited to, hydrazones, thioethers, esters, disulfides and peptide-containing linkers. A linker can be chosen that is, for example, susceptible to cleavage by low pH within the lysosomal compartment or susceptible to cleavage by proteases, such as proteases preferentially expressed in tumor tissue such as cathepsins (e.g., cathepsins B, C, D).

[0398] For further discussion of types of cytotoxins, linkers and methods for conjugating therapeutic agents to antibodies, see also Saito, G. et al. (2003) Adv. Drug Deliv. Rev. 55:199-215 ; Trail, R A. et al. (2003) Cancer Immunol. Immunother. 52:328-337 ; Payne, G. (2003) Cancer Cell 3:207-212; Allen, T. M. (2002) Nat. Rev. Cancer 2:750-763 ; Pastan, I. and Kreitman, R. J. (2002) Curr. Opin. Investig. Drugs 3:1089-1091; Senter, P. D. and Springer, C. J. (2001) Adv. Drug Deliv. Rev. 53:247-264.

[0399] Antibodies of the present invention also can be conjugated to a radioactive isotope to generate cytotoxic radiopharmaceuticals, also referred to as radioimmunoconjugates. Examples of radioactive isotopes that can be conjugated to antibodies for use diagnostically or therapeutically include, but are not limited to, iodine 131, indium 111, yttrium 90 and lutetium 177. Method for preparing radioimmunconjugates are established in the art. Examples of radioimmunoconjugates are commercially available, including Zevalin.TM. (IDEC Pharmaceuticals) and Bexxar.TM. (Corixa Pharmaceuticals), and similar methods can be used to prepare radioimmunoconjugates using the antibodies of the invention.

[0400] The antibody conjugates of the invention can be used to modify a given biological response, and the drug moiety is not to be construed as limited to classical chemical therapeutic agents. For example, the drug moiety may be a protein or polypeptide possessing a desired biological activity. Such proteins may include, for example, an enzymatically active toxin, or active fragment thereof, such as abrin, ricin A, pseudomonas exotoxin, or diphtheria toxin; a protein such as tumor necrosis factor or interferon-.gamma.; or, biological response modifiers such as, for example, lymphokines, interleukin-1 ("IL-1"), interleukin-2 ("IL-2”), interleukin-6 ("IL-6"), granulocyte macrophage colony stimulating factor ("GM-CSF"), granulocyte colony stimulating factor ("G-CSF"), or other growth factors.

[0401] Techniques for conjugating such therapeutic moiety to antibodies are well known, see, e.g., Arnon et al., "Monoclonal Antibodies For Immunotargeting Of Drugs In Cancer Therapy", in Monoclonal Antibodies And Cancer Therapy, Reisfeld et al. (eds.), pp. 243-56 (Alan R. Liss, Inc. 1985); Hellstrom et al., "Antibodies For Drug Delivery", in Controlled Drug Delivery (2nd Ed.), Robinson et al. (eds.), pp. 623-53 (Marcel Dekker, Inc. 1987); Thorpe, "Antibody Carriers Of Cytotoxic Agents In Cancer Therapy: A Review", in Monoclonal Antibodies '84: Biological And Clinical Applications, Pinchera et al. (eds.), pp. 475-506 (1985 ); "Analysis, Results, And Future Prospective Of The Therapeutic Use Of Radiolabeled Antibody In Cancer Therapy", in Monoclonal Antibodies For Cancer Detection And Therapy, Baldwin et al. (eds.), pp. 303-16 (Academic Press 1985), and Thorpe et al., "The Preparation And Cytotoxic Properties Of Antibody-Toxin Conjugates", Immunol. Rev., 62:119-58 (1982).

BISPECIFIC MOLECULES

[0402] In another aspect, the present invention features bispecific molecules comprising an antiC10RF32 antibody, or a fragment thereof, of the invention. An antibody of the invention, or antigen-binding portions thereof, can be derivatized or linked to another functional molecule, e g., another peptide or protein (e.g., another antibody or ligand for a receptor) to generate a bispecific molecule that binds to at least two different binding sites or target molecules. The antibody of the invention may in fact be derivatized or linked to more than one other functional molecule to generate multispecific molecules that bind to more than two different binding sites and/or target molecules; such multispecific molecules are also intended to be encompassed by the term "bispecific molecule" as used herein. To create a bispecific molecule of the invention, an antibody of the invention can be functionally linked (e.g., by chemical coupling, genetic fusion, noncovalent association or otherwise) to one or more other binding molecules, such as another antibody, antibody fragment, peptide or binding mimetic, such that a bispecific molecule results.

[0403] Accordingly, the present invention includes bispecific molecules comprising at least one first binding specificity for C10RF32 and a second binding specificity for a second target epitope. In a particular embodiment of the invention, the second target epitope is an Fc receptor, e.g., human Fc gamma RI (CD64) or a human Fc alpha receptor (CD89). Therefore, the invention includes bispecific molecules capable of binding both to Fc gamma. R, Fc alpha R or Fc epsilon R expressing effector cells (e.g., monocytes, macrophages or polymorphonuclear cells (PMNs)), and to target cells expressing C10RF32 These bispecific molecules target C10RF32 expressing cells to effector cell and trigger Fc receptor-mediated effector cell activities, such as phagocytosis of an C10RF32 expressing cells, antibody dependent cell-mediated cytotoxicity (ADCC), cytokine release, or generation of superoxide anion.

[0404] In an embodiment of the invention in which the bispecific molecule is multispecific, the molecule can further include a third binding specificity, in addition to an anti-Fc binding specificity and an anti-6f binding specificity. In one embodiment, the third binding specificity is an anti-enhancement factor (EF) portion, e.g., a molecule which binds to a surface protein involved in cytotoxic activity and thereby increases the immune response against the target cell.

[0405] The "anti-enhancement factor portion" can be an antibody, functional antibody fragment or a ligand that binds to a given molecule, e.g., an antigen or a receptor, and thereby results in an enhancement of the effect of the binding determinants for the Fc receptor or target cell antigen. The "anti-enhancement factor portion" can bind an Fc receptor or a target cell antigen. Alternatively, the anti-enhancement factor portion can bind to an entity that is different from the entity to which the first and second binding specificities bind. For example, the anti-enhancement factor portion can bind a cytotoxic T-cell (e.g., via CD2, CD3, CD8, CD28, CD4, CD40, ICAM-1 or other immune cell that results in an increased immune response against the target cell).

[0406] In one embodiment, the bispecific molecules of the invention comprise as a binding specificity at least one antibody, or an antibody fragment thereof, including, e.g., an Fab, Fab', F(ab').sub.2, Fv, or a single chain Fv. The antibody may also be a light chain or heavy chain dimer, or any minimal fragment thereof such as a Fv or a single chain construct as described in Ladner et al. U.S. Pat. No. 4,946,778, the contents of which is expressly incorporated by reference.

[0407] In one embodiment, the binding specificity for an Fey receptor is provided by a monoclonal antibody, the binding of which is not blocked by human immunoglobulin G (IgG). As used herein, the term "IgG receptor" refers to any of the eight.gamma.-chain genes located on chromosome 1. These genes encode a total of twelve transmembrane or soluble receptor isoforms which are grouped into three Fc.gamma. receptor classes: Fc gamma R1 (CD64), Fc gamma RII(CD32), and Fc gamma.Rill (CD 16). In one preferred embodiment, the Fc gamma, receptor a human high affinity Fc.gamma Rl. The human Fc gammaRI is a 72 kDa molecule, which shows high affinity for monomeric IgG (10 8-10 -9 M. -1).

[0408] The production and characterization of certain preferred anti-Fc gamma, monoclonal antibodies are described by Fanger et al. in PCT Publication WO 88/00052 and in U.S. Pat. No. 4,954,617, the teachings of which are fully incorporated by reference herein. These antibodies bind to an epitope of Fc.gamma.R1, FcyRII or FcyRIII at a site which is distinct from the Fc.gamma. binding site of the receptor and, thus, their binding is not blocked substantially by physiological levels of IgG. Specific anti-Fc.gamma.RI antibodies useful in this invention are mAb 22, mAb 32, mAb 44, mAb 62 and mAb 197. The hybridoma producing mAb 32 is available from the American Type Culture Collection, ATCC Accession No. FIB9469. In other embodiments, the anti-Fcy receptor antibody is a humanized form of monoclonal antibody 22 (H22). The production and characterization of the H22 antibody is described in Graziano, R.F. et al. (1995) J. Immunol. 155 (10): 4996-5002 and PCT Publication WO 94/10332. The H22 antibody producing cell line is deposited at the American Type Culture Collection under the designation HA022CLI and has the accession no. CRL 11177.

[0409] In still other preferred embodiments, the binding specificity for an Fc receptor is provided by an antibody that binds to a human IgA receptor, e g., an Fc-alpha receptor (Fc alpha.RI(CD89)), the binding of which is preferably not blocked by human immunoglobulin A (IgA). The term "IgA receptor" is intended to include the gene product of one alpha.-gene (Fc alpha.Rl) located on chromosome 19. This gene is known to encode several alternatively spliced transmembrane isoforms of 55 to 10 kDa [0410] Fc.alpha.RI (CD89) is constitutively expressed on monocytes/macrophages, eosinophilic and neutrophilic granulocytes, but not on non-effector cell populations. Fc alpha Rl has medium affinity (Approximately 5X10-7 M-1) for both lgA1 and lgA2, which is increased upon exposure to cytokines such as G-CSF or GM-CSF (Morton, H. C. et al. (1996) Critical Reviews in Immunology 16:423-440). Four FcaRI-specific monoclonal antibodies, identified as A3, A59, A62 and A77, which bind Fc.alpha.RI outside the IgA ligand binding domain, have been described (Monteiro, R. C. etal. (1992) J. Immunol. 148:1764).

[0411] Fc. alpha. Rl and Fc gamma. Rl are preferred trigger receptors for use in the bispecific molecules of the invention because they are (1) expressed primarily on immune effector cells, e.g., monocytes, PMNs, macrophages and dendritic cells; (2) expressed at high levels (e.g., 5,000-100,000 per cell); (3) mediators of cytotoxic activities (e.g., ADCC, phagocytosis); (4) mediate enhanced antigen presentation of antigens, including self-antigens, targeted to them.

[0412] While human monoclonal antibodies are preferred, other antibodies which can be employed in the bispecific molecules of the invention are murine, chimeric and humanized monoclonal antibodies.

[0413] The bispecific molecules of the present invention can be prepared by conjugating the constituent binding specificities, e.g., the anti-FcR and anti-C10RF32 binding specificities, using methods known in the art. For example, each binding specificity of the bispecific molecule can be generated separately and then conjugated to one another. When the binding specificities are proteins or peptides, a variety of coupling or cross-linking agents can be used for covalent conjugation. Examples of cross-linking agents include protein A, carbodiimide, N-succinimidyl-S-acetyl-thioacetate (SATA), 5,5'-dithiobis(2-nitrobenzoic acid) (DTNB), o-phenylenedimaleimide (oPDM), N-succinimidyl-3-(2-pyridyld- ithio)propionate (SPDP), and sulfosuccinimidyl 4-(N-maleimidomethyl) cyclohaxane-1-carboxylate (sulfo-SMCC) (see e.g., Karpovsky et al. (1984) J. Exp. Med. 160:1686; Liu, M Aet al. (1985) Proc. Natl. Acad. Sci. USA82:8648). Other methods include those described in Paulus (1985) bering Ins. Mitt. No. 78, 118-132; Brennan et al. (1985) Science 229:81-83), and Glennie et al. (1987) J. Immunol. 139: 2367-2375). Preferred conjugating agents are SATA and sulfo-SMCC, both available from Pierce Chemical Co. (Rockford, III.).

[0414] When the binding specificities are antibodies, they can be conjugated via sulfhydryl bonding of the C-terminus hinge regions of the two heavy chains. In a particularly preferred embodiment, the hinge region is modified to contain an odd number of sulfhydryl residues, preferably one, prior to conjugation.

[0415] Alternatively, both binding specificities can be encoded in the same vector and expressed and assembled in the same host cell. This method is particularly useful where the bispecific molecule is a mAbXmAb, mAbXFab, FabXF(ab')2 or ligandXFab fusion protein. A bispecific molecule of the invention can be a single chain molecule comprising one single chain antibody and a binding determinant, or a single chain bispecific molecule comprising two binding determinants. Bispecific molecules may comprise at least two single chain molecules. Methods for preparing bispecific molecules are described for example in U.S. Pat. No. 5,260,203; U.S. Pat. No. 5,455,030; U.S. Pat. No. 4,881,175; U.S. Pat. No. 5,132,405; U.S. Pat. No. 5,091,513; U.S. Pat. No. 5,476,786; U.S. Pat. No. 5,013,653; U.S. Pat. No. 5,258,498; and U.S. Pat. No. 5,482,858.

[0416] Binding of the bispecific molecules to their specific targets can be confirmed by, for example, enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), FACS analysis, bioassay (e.g., growth inhibition), or Western Blot assay. Each of these assays generally detects the presence of protein-antibody complexes of particular interest by employing a labeled reagent (e.g., an antibody) specific for the complex of interest. For example, the FcR-antibody complexes can be detected using e.g., an enzyme-linked antibody or antibody fragment which recognizes and specifically binds to the antibody FcR complexes. Alternatively, the complexes can be detected using any of a variety of other immunoassays. For example, the antibody can be radioactively labeled and used in a radioimmunoassay (RIA) (see, for example, Weintraub, B., Principles of Radioimmunoassays, Seventh Training Course on Radioligand Assay Techniques, The Endocrine Society, March, 1986 , which is incorporated by reference herein). The radioactive isotope can be detected by such means as the use of a gamma, counter or a scintillation counter or by autoradiography.

PHARMACEUTICAL COMPOSITIONS

[0417] In another aspect, the present invention provides a composition, e.g., a pharmaceutical composition, containing one or a combination of monoclonal antibodies, or antigen-binding portions thereof, of the present invention, formulated together with a pharmaceutically acceptable carrier. Such compositions may include one or a combination of (e.g., two or more different) antibodies, or immunoconjugates or bispecific molecules of the invention. For example, a pharmaceutical composition of the invention can comprise a combination of antibodies (or immunoconjugates or bispecifics) that bind to different epitopes on the target antigen or that have complementary activities.

[0418] As discussed supra, C10RF32 the invention further embraces identifying other molecules such as small organic molecules, peptides, ribozymes, carbohydrates, glycoprotein, siRNAs, antisense RNAs and the like which specifically bind and/or modulate (enhance or inhibit) an activity elicited by the C10RF32 antigen. These molecules may be identified by known screening methods such as binding assays. Typically these assays will be high throughput and will screen a large library of synthesized or native compounds in order to identify putative drug candidates that bind and/or modulate C10RF32 related activities.

[0419] Specifically, the invention embraces the development of drugs containing the ectodomain of the C10RF32 antigen or a fragment or variant thereof or a corresponding nucleic acid sequence encoding. These conjugates may contain a targeting or other moiety such as an immunoglobulin domain. These conjugates may be expressed in known vector systems or cells or vectors containing the corresponding nucleic acid sequences may be used for cancer treatment and in immune therapy such as in the treatment of autoimmunity, transplant, GVHD, cancer, and other immune disorders or conditions.

[0420] Thus, the present invention features a pharmaceutical composition comprising a therapeutically effective amount of a therapeutic agent according to the present invention. According to the present invention the therapeutic agent could be any one of C10RF32 ectodomain, or a fragment or variant thereof, or a corresponding nucleic acid sequence encoding.

[0421] The pharmaceutical composition according to the present invention is further preferably used for the treatment of cancers including by way of example non-solid and solid tumors, sarcomas, hematological malignancies including but not limited to acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, multiple myeloma, Hodgkin's lymphoma, Non-Hodgkin's lymphoma, cancer of the breast, prostate, lung, ovary, colon, spleen, kidney, bladder, head and neck, uterus, testicles, stomach, cervix, liver, bone, skin, pancreas, brain and wherein the cancer may be non-metastatic, invasive or metastatic.

[0422] The pharmaceutical composition according to the present invention is further used for the treatment of autoimmunity and preferably for treating an autoimmune disease selected from: Multiple sclerosis; Psoriasis; Rheumatoid arthritis; Systemic lupus erythematosus; Ulcerative colitis; Crohn's disease; immune disorders associated with graft transplantation rejection, benign lymphocytic angiitis, lupus erythematosus, Hashimoto's thyroiditis, primary myxedema, Graves' disease, pernicious anemia, autoimmune atrophic gastritis, Addison's disease, insulin dependent diabetes mellitis, good pasture's syndrome, myasthenia gravis, pemphigus, sympathetic ophthalmia, autoimmune uveitis, autoimmune hemolytic anemia, idiopathic thrombocytopenia, primary biliary cirrhosis, chronic action hepatitis, ulceratis colitis, Sjogren's syndrome, rheumatic disease, polymyositis, scleroderma, mixed connective tissue disease, inflammatory rheumatism, degenerative rheumatism, extra- articular rheumatism, collagen diseases, chronic polyarthritis, psoriasis arthropathica, ankylosing spondylitis, juvenile rheumatoid arthritis, periarthritis humeroscapularis, panarteriitis nodosa, progressive systemic scleroderma, arthritis uratica, dermatomyositis, muscular rheumatism, myositis, myogelosis and chondrocalcinosis.

[0423] The pharmaceutical composition according to the present invention is preferably used for the treatment of for rejection of any organ transplant and/or Graft versus host disease which might develop after bone marrow transplantation.

[0424] "Treatment" refers to both therapeutic treatment and prophylactic or preventative measures. Those in need of treatment include those already with the disorder as well as those in which the disorder is to be prevented. Hence, the mammal to be treated herein may have been diagnosed as having the disorder or may be predisposed or susceptible to the disorder. "Mammal" for purposes of treatment refers to any animal classified as a mammal, including humans, domestic and farm animals, and zoo, sports, or pet animals, such as dogs, horses, cats, cows, etc. Preferably, the mammal is human.

[0425] The term "therapeutically effective amount" refers to an amount of agent according to the present invention that is effective to treat a disease or disorder in a mammal.

[0426] The therapeutic agents of the present invention can be provided to the subject alone, or as part of a pharmaceutical composition where they are mixed with a pharmaceutically acceptable carrier.

[0427] Pharmaceutical compositions of the invention also can be administered in combination therapy, i.e., combined with other agents. For example, the combination therapy can include an antiC10RF32 antibody or C10RF32 modulating agent according to the present invention such as a soluble polypeptide conjugate containing the ectodomain of the CLORF32 antigen or a small molecule such as a peptide, ribozyme, siRNA, or other drug that binds C10RF32 combined with at least one other therapeutic or immune modulatory agent. Examples of therapeutic agents that can be used in combination therapy are described in greater detail below in the section on uses of the antibodies of the invention.

[0428] As used herein, "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible. Preferably, the carrier is suitable for intravenous, intramuscular, subcutaneous, parenteral, spinal or epidermal administration (e.g., by injection or infusion). Depending on the route of administration, the active compound, i.e., antibody, immunoconjugate, or bispecific molecule, may be coated in a material to protect the compound from the action of acids and other natural conditions that may inactivate the compound. The pharmaceutical compounds of the invention may include one or more pharmaceutically acceptable salts. A "pharmaceutically acceptable salt" refers to a salt that retains the desired biological activity of the parent compound and does not impart any undesired toxicological effects (see e.g., Berge, S. M., et al. (1977) J. Pharm. Sri. 66: 1-19). Examples of such salts include acid addition salts and base addition salts. Acid addition salts include those derived from nontoxic inorganic acids, such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, phosphorous and the like, as well as from nontoxic organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, aromatic acids, aliphatic and aromatic sulfonic acids and the like. Base addition salts include those derived from alkaline earth metals, such as sodium, potassium, magnesium, calcium and the like, as well as from nontoxic organic amines, such as N,N'-dibenzylethylenediamine, N-methylglucamine, chloroprocaine, choline, diethanolamine, ethylenediamine, procaine and the like.

[0429] A pharmaceutical composition of the invention also may include a pharmaceutically acceptable anti-oxidant. Examples of pharmaceutically acceptable antioxidants include: (1) water soluble antioxidants, such as ascorbic arid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palpitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

[0430] A pharmaceutical composition of the invention also may include a pharmaceutically acceptable anti-oxidant. Examples of pharmaceutically acceptable antioxidants include: (1) water soluble antioxidants, such as ascorbic arid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like. Examples of suitable aqueous and nonaqueous carriers that may be employed in the pharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0431] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of presence of microorganisms may be ensured both by sterilization procedures, supra, and by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.

[0432] Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. The use of such media and agents for pharmaceutically active substances is known in the art. Except insofar as any conventional media or agent is incompatible wth the active compound, use thereof in the pharmaceutical compositions of the invention is contemplated. Supplementary active compounds can also be incorporated into the compositions.

[0433] Therapeutic compositions typically must be sterile and stable under the conditions of manufacture and storage. The composition can be formulated as a solution, microemulsion, liposome, or other ordered structure suitable to high drug concentration. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, monostearate salts and gelatin. Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by sterilization microfiltration. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying (lyophilization) that yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

[0434] Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by sterilization microfiltration. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying (lyophilization) that yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

[0435] The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the subject being treated, and the particular mode of administration. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the composition which produces a therapeutic effect. Generally, out of one hundred per cent, this amount will range from about 0.01 per cent to about ninety-nine percent of active ingredient, preferably from about 0.1 per cent to about 70 per cent, most preferably from about I per cent to about 30 per cent of active ingredient in combination with a pharmaceutically acceptable carrier.

[0436] Dosage regimens are adjusted to provide the optimum desired response (e.g., a therapeutic response). For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subjects to be treated; each unit contains a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active compound for the treatment of sensitivity in individuals.

[0437] For administration of the antibody, the dosage ranges from about 0.0001 to 100 mg/kg, and more usually 0.01 to 5 mg/kg, of the host body weight. For example dosages can be 0.3 mg/kg body weight, 1 mg/kg body weight, 3 mg/kg body weight, 5 mg/kg body weight or 10 mg/kg body weight or within the range of 1-10 mg/kg. An exemplary treatment regime entails administration once per week, once every two weeks, once every three weeks, once every four weeks, once a month, once every 3 months or once every three to 6 months. Preferred dosage regimens for an anti-VSIG1 antibody of the invention include 1 mg/kg body weight or 3 mg/kg body weight via intravenous administration, with the antibody being given using one of the following dosing schedules: (i) every four weeks for six dosages, then every three months; (ii) every three weeks; (iii) 3 mg/kg body weight once followed by 1 mg/kg body weight every three weeks.

[0438] In some methods, two or more monoclonal antibodies with different binding specificities are administered simultaneously, in which case the dosage of each antibody administered falls within the ranges indicated. Antibody is usually administered on multiple occasions. Intervals between single dosages can be, for example, weekly, monthly, every three months or yearly. Intervals can also be irregular as indicated by measuring blood levels of antibody to the target antigen in the patient. In some methods, dosage is adjusted to achieve a plasma antibody concentration of about 1-1000 mug/ml and in some methods about 25-300.mu.g /ml.

[0439] Alternatively, antibody can be administered as a sustained release formulation, in which case less frequent administration is required. Dosage and frequency vary depending on the half-life of the antibody in the patient. In general, human antibodies show the longest half life, followed by humanized antibodies, chimeric antibodies, and nonhuman antibodies. The dosage and frequency of administration can vary depending on whether the treatment is prophylactic or therapeutic. In prophylactic applications, a relatively low dosage is administered at relatively infrequent intervals over a long period of time. Some patients continue to receive treatment for the rest of their lives. In therapeutic applications, a relatively high dosage at relatively short intervals is sometimes required until progression of the disease is reduced or terminated, and preferably until the patient shows partial or complete amelioration of symptoms of disease. Thereafter, the patient can be administered a prophylactic regime.

[0440] Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present invention may be varied so as to obtain an amount of the active ingredient winich is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient. The selected dosage level vull depend upon a variety of pharmacokinetic factors including the activity of the particular compositions of the present invention employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compositions employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.

[0441] A "therapeutically effective dosage" of an anti-C10RF32 antibody of the invention preferably results in a decrease in severity of disease symptoms, an increase in frequency and duration of disease symptom-free periods, an increase in lifepan, disease remission, or a prevention of impairment or disability due to the disease affliction. For example, for the treatment of C10RF32 positive tumors, e g., lung tumors, ovarian tumors, and colon tumors, a "therapeutically effective dosage" preferably inhibits cell growth or tumor growth by at least about 20%, more preferably by at least about 40%, even more preferably by at least about 60%, and still more preferably by at least about 80% relative to untreated subjects. The ability of a compound to inhibit tumor growth can be evaluated in an animal model system predictive of efficacy in human tumors. Alternatively, this property of a composition can be evaluated by examining the ability of the compound to inhibit, such inhibition in vitro by assays known to the skilled practitioner. A therapeutically effective amount of a therapeutic compound can decrease tumor size, or otherwise ameliorate symptoms in a subject. One of ordinary skill in the art would be able to determine such amounts based on such factors as the subject's size, the severity of the subject's symptoms, and the particular composition or route of administration selected.

[0442] A composition of the present invention can be administered via one or more routes of administration using one or more of a variety of methods known in the art. As will be appreciated by the skilled artisan, the route and/or mode of administration will vary depending upon the desired results. Preferred routes of administration for antibodies of the invention include intravenous, intramuscular, intradermal, intraperitoneal, subcutaneous, spinal or other parenteral routes of administration, for example by injection or infusion. The phrase "parenteral administration" as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion.

[0443] Alternatively, an antibody or other C10RF32 drug or molecule and their conjugates and combinations thereof that modulates a C10RF32 antigen activity according to the invention can be administered via a non-parenteral route, such as a topical, epidermal or mucosal route of administration, for example, intranasally, orally, vaginally, rectally, sublingually or topically.

[0444] The active compounds can be prepared with carriers that will protect the compound against rapid release, such as a controlled release formulation, including implants, transdermal patches, and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Many methods for the preparation of such formulations are patented or generally known to those skilled in the art. See, e.g., Sustained and Controlled Release Drug Delivery Systems, J. R. Robinson, ed., Marcel Dekker, Inc., New York, 1978.

[0445] Therapeutic compositions can be administered with medical devices known in the art. For example, in a preferred embodiment, a therapeutic composition of the invention can be administered with a needles hypodermic injection device, such as the devices disclosed in U.S. Pat. Nos. 5,399,163; 5,383,851; 5,312,335; 5,064,413; 4,941,880; 4,790,824; or 4,596,556. Examples of well-known implants and modules useful in the present invention include: U.S. Pat. No. 4,487,603, which discloses an implantable micro-infusion pump for dispensing medication at a controlled rate; U.S. Pat. No. 4,486,194, winich discloses a therapeutic device for administering medicaments through the skin; U.S. Pat. No. 4,447,233, which discloses a medication infusion pump for delivering medication at a precise infusion rate; U.S. Pat. No. 4,447,224, which discloses a variable flow implantable infusion apparatus for continuous drug delivery; U.S. Pat. No. 4,439,196, which discloses an osmotic drug delivery system having multi-chamber compartments; and U.S. Pat. No. 4,475,196, which discloses an osmotic drug delivery system. These patents are incorporated herein by reference. Many other such implants, delivery systems, and modules are known to those skilled in the art.

[0446] The antibodies or other VSIG1 related drugs can be formulated to ensure proper distribution in vivo. For example, the blood-brain barrier (BBB) excludes many highly hydrophilic compounds. To ensure that the therapeutic compounds cross the BBB (if desired), they can be formulated, for example, in liposomes. For methods of manufacturing liposomes, see, e.g., U.S. Pat. Nos. 4,522,811; 5,374,548; and 5,399,331. The liposomes may comprise one or more moieties which are selectively transported into specific cells or organs, thus enhance targeted drug delivery (see, e.g., V. V. Ranade (1989) J. Clin. Pharmacol. 29:685). Exemplary targeting moieties include folate or biotin (see, e.g., U.S. Pat. No. 5,416,016 to Lowet al.); mannosides (Umezawa et al., (1988) Biochem. Biophys. Res. Commun. 153:1038); antibodies (P. G. Bloeman et al. (1995) FEBS Lett. 357:140; M. Owais et al. (1995) Antimicrob. Agents Chemother. 39:180); surfactant protein A receptor (Briscoe et al. (1995) Am. J Physiol. 1233:134); p120 (Schreier et al. (1994) J. Biol. Chem. 269:9090); see also K. Keinanen; M. L. Laukkanen (1994) FEBS Lett. 346:123; J. J. Killion; I. J. Fidler (1994) Immunomethods 4:273.

DIAGNOSTIC USES OF C10RF32 ANTIGEN AND CORRESPONDING POLYNUCLEOTIDES

[0447] According to some embodiments, the sample taken from a subject (patient) to perform the diagnostic assay according to the present invention is selected from the group consisting of a body fluid or secretion including but not limited to blood, serum, urine, plasma, prostatic fluid, seminal fluid, semen, the external secretions of the skin, respiratory, intestinal, and genitourinary tracts, tears, cerebrospinal fluid, sputum, saliva, milk, peritoneal fluid, pleural fluid, cyst fluid, secretions of the breast ductal system (and/or lavage thereof), broncho alveolar lavage, lavage of the reproductive system and lavage of any other part of the body or system in the body; samples of any organ including isolated cells or tissues, wherein the cell or tissue can be obtained from an organ selected from, but not limited to lung, colon, ovarian and/or breast tissue; stool or a tissue sample, or any combination thereof. In some embodiments, the term encompasses samples of in vivo cell culture constituents. Prior to be subjected to the diagnostic assay, the sample can optionally be diluted with a suitable eluant.

[0448] In some embodiments, the phrase "marker" in the context of the present invention refers to a nucleic acid fragment, a peptide, or a polypeptide, which is differentially present in a sample taken from patients (subjects) having one of the herein-described diseases or conditions, as compared to a comparable sample taken from subjects who do not have one the above-described diseases or conditions.

[0449] In some embodiments, the term "polypeptide" is to be understood to refer to a molecule comprising from at least 2 to several thousand or more amino acids. The term "polypeptide" is to be understood to include, inter alia, native peptides (either degradation products, synthetically synthesized peptides or recombinant peptides), peptidomimetics, such as peptoids and semipeptoids or peptide analogs, which may comprise, for example, any desirable modification, including, inter alia, modifications rendering the peptides more stable while in a body or more capable of penetrating into cells, or others as will be appreciated by one skilled in the art. Such modifications include, but are not limited to N terminus modification, C terminus modification, peptide bond modification, backbone modifications, residue modification, or others. Inclusion of such peptides within the polypeptides of this invention may produce a polypeptide sharing identity with the polypeptides described herein, for example, those provided in the sequence listing.

[0450] In some embodiments, the phrase "differentially present" refers to differences in the quantity or quality of a marker present in a sample taken from patients having one of the herein-described diseases or conditions as compared to a comparable sample taken from patients who do not have one of the herein-described diseases or conditions. For example, a nucleic acid fragment may optionally be differentially present between the two samples if the amount of the nucleic acid fragment in one sample is significantly different from the amount of the nucleic acid fragment in the other sample, for example as measured by hybridization and/or NAT-based assays. A polypeptide is differentially present between the two samples if the amount of the polypeptide in one sample is significantly different from the amount of the polypeptide in the other sample. It should be noted that if the marker is detectable in one sample and not detectable in the other, then such a marker can be considered to be differentially present. Optionally, a relatively low amount of up-regulation may serve as the marker, as described herein. One of ordinary skill in the art could easily determine such relative levels of the markers; further guidance is provided in the description of each individual marker below.

[0451] In some embodiments, the phrase "diagnostic" means identifying the presence or nature of a pathologic condition. Diagnostic methods differ in their sensitivity and specificity. The "sensitivity" of a diagnostic assay is the percentage of diseased individuals who test positive (percent of "true positives"). Diseased individuals not detected by the assay are "false negatives." Subjects who are not diseased and who test negative in the assay are termed "true negatives." The "specificity" of a diagnostic assay is 1 minus the false positive rate, where the "false positive" rate is defined as the proportion of those without the disease who test positive. While a particular diagnostic method may not provide a definitive diagnosis of a condition, it suffices if the method provides a positive indication that aids in diagnosis.

[0452] In some embodiments, the phrase "qualitative" when in reference to differences in expression levels of a polynucleotide or polypeptide as described herein, refers to the presence versus absence of expression, or in some embodiments, the temporal regulation of expression, or in some embodiments, the timing of expression, or in some embodiments, any post-translational modifications to the expressed molecule, and others, as will be appreciated by one skilled in the art. In some embodiments, the phrase "quantitative" when in reference to differences in expression levels of a polynucleotide or polypeptide as described herein, refers to absolute differences in quantity of expression, as determined by any means, known in the art, or in other embodiments, relative differences, which may be statistically significant, or in some embodiments, when viewed as a whole or over a prolonged period of time, etc., indicate a trend in terms of differences in expression.

[0453] In some embodiments, the term "diagnosing" refers to classifying a disease or a symptom, determining a severity of the disease, monitoring disease progression, forecasting an outcome of a disease and/or prospects of recovery. The term "detecting" may also optionally encompass any of the above.

[0454] Diagnosis of a disease according to the present invention can, in some embodiments, be affected by determining a level of a polynucleotide or a polypeptide of the present invention in a biological sample obtained from the subject, wherein the level determined can be correlated with predisposition to, or presence or absence of the disease. It should be noted that a "biological sample obtained from the subject" may also optionally comprise a sample that has not been physically removed from the subject, as described in greater detail below.

[0455] In some embodiments, the term "level" refers to expression levels of RNA and/or protein or to DNA copy number of a marker of the present invention.

[0456] Typically the level of the marker in a biological sample obtained from the subject is different (i.e., increased or decreased) from the level of the same marker in a similar sample obtained from a healthy individual (examples of biological samples are described herein).

[0457] Numerous well known tissue or fluid collection methods can be utilized to collect the biological sample from the subject in order to determine the level of DNA, RNA and/or polypeptide of the marker of interest in the subject.

[0458] Examples include, but are not limited to, fine needle biopsy, needle biopsy, core needle biopsy and surgical biopsy (e.g., brain biopsy), and lavage. Regardless of the procedure employed, once a biopsy/sample is obtained the level of the marker can be determined and a diagnosis can thus be made.

[0459] Determining the level of the same marker in normal tissues of the same origin is preferably effected along-side to detect an elevated expression and/or amplification and/or a decreased expression, of the marker as opposed to the normal tissues.

[0460] In some embodiments, the term "test amount" of a marker refers to an amount of a marker in a subject's sample that is consistent with a diagnosis of a particular disease or condition. A test amount can be either in absolute amount (e.g., microgram/ml) or a relative amount (e.g., relative intensity of signals).

[0461] In some embodiments, the term "control amount" of a marker can be any amount or a range of amounts to be compared against a test amount of a marker. For example, a control amount of a marker can be the amount of a marker in a patient with a particular disease or condition or a person without such a disease or condition. A control amount can be either in absolute amount (e.g., microgram/ml) or a relative amount (e.g., relative intensity of signals).

[0462] In some embodiments, the term "detect" refers to identifying the presence, absence or amount of the object to be detected.

[0463] In some embodiments, the term "label" includes any moiety or item detectable by spectroscopic, photo chemical, biochemical, immunochemical, or chemical means. For example, useful labels include 32P, 35S, fluorescent dyes, electron-dense reagents, enzymes (e.g., as commonly used in an ELISA), biotin-streptavadin, dioxigenin, haptens and proteinsforw^ich antisera or monoclonal antibodies are available, or nucleic acid molecules with a sequence complementary to a target. The label often generates a measurable signal, such as a radioactive, chromogenic, or fluorescent signal, that can be used to quantify the amount of bound label in a sample. The label can be incorporated in or attached to a primer or probe either covalently, or through ionic, van der Waals or hydrogen bonds, e.g., incorporation of radioactive nucleotides, or biotinylated nucleotides that are recognized by streptavadin. The label may be directly or indirectly detectable. Indirect detection can involve the binding of a second label to the first label, directly or indirectly. For example, the label can be the ligand of a binding partner, such as biotin, which is a binding partner for streptavadin, or a nucleotide sequence, which is the binding partner for a complementary sequence, to which it can specifically hybridize. The binding partner may itself be directly detectable, for example, an antibody may be itself labeled with a fluorescent molecule. The binding partner also may be indirectly detectable, for example, a nucleic acid having a complementary nucleotide sequence can be a part of a branched DNA molecule that is in turn detectable through hybridization with other labeled nucleic acid molecules (see, e.g., P. D. Fahrlander and A. Klausner, Bio/Technology 6:1165 (1988 )). Quantitation of the signal is achieved by, e.g., scintillation counting, densitometry, or flow cytometry.

[0464] Exemplary detectable labels, optionally and preferably for use with immunoassays, include but are not limited to magnetic beads, fluorescent dyes, radiolabels, enzymes (e.g., horse radish peroxide, alkaline phosphatase and others commonly used in an ELISA), and calorimetric labels such as colloidal gold or colored glass or plastic beads. Alternatively, the marker in the sample can be detected using an indirect assay, wherein, for example, a second, labeled antibody is used to detect bound marker-specific antibody, and/or in a competition or inhibition assay wherein, for example, a monoclonal antibody which binds to a distinct epitope of the marker are incubated simultaneously with the mixture.

[0465] "Immunoassay" is an assay that uses an antibody to specifically bind an antigen. The immunoassay is characterized by the use of specific binding properties of a particular antibody to isolate, target, and/or quantify the antigen.

[0466] The phrase "specifically (or selectively) binds" to an antibody or "specifically (or selectively) immunoreactive with," or "specifically interacts or binds" when referring to a protein or peptide (or other epitope), refers, in some embodiments, to a binding reaction that is determinative of the presence of the protein in a heterogeneous population of proteins and other biologies. Thus, under designated immunoassay conditions, the specified antibodies bind to a particular protein at least two times greater than the background (non-specific signal) and do not substantially bind in a significant amount to other proteins present in the sample. Specific binding to an antibody under such conditions may require an antibody that is selected for its specificity for a particular protein. For example, polyclonal antibodies raised to seminal basic protein from specific species such as rat, mouse, or human can be selected to obtain only those polyclonal antibodies that are specifically immunoreactive with seminal basic protein and not with other proteins, except for polymorphic variants and alleles of seminal basic protein. This selection may be achieved by subtracting out antibodies that cross-react with seminal basic protein molecules from other species. A variety of immunoassay formats may be used to select antibodies specifically immunoreactive with a particular protein. For example, solid-phase ELISA immunoassays are routinely used to select antibodies specifically immunoreactive with a protein (see, e.g., Harlow & Lane, Antibodies, A Laboratory Manual (1988), for a description of immunoassay formats and conditions that can be used to determine specific immunoreactivity). Typically a specific or selective reaction will be at least twice background signal or noise and more typically more than 10 to 100 times background.

[0467] In another embodiment, this invention provides a method for detecting the polypeptides of this invention in a biological sample, comprising: contacting a biological sample with an antibody specifically recognizing a polypeptide according to the present invention and detecting said interaction; wherein the presence of an interaction correlates with the presence of a polypeptide in the biological sample.

[0468] In some embodiments of the present invention, the polypeptides described herein are non-limiting examples of markers for diagnosing a disease and/or an indicative condition. Each marker of the present invention can be used alone or in combination, for various uses, including but not limited to, prognosis, prediction, screening, early diagnosis, determination of progression, therapy selection and treatment monitoring of a disease and/or an indicative condition.

[0469] In a related object the detected diseases will include cancers such as non-solid and solid tumors, sarcomas, hematological malignancies including but not limited to acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, multiple myeloma, Hodgkin's lymphoma, Non-Hodgkin's lymphoma, cancer of the breast, prostate, lung, ovary, colon, spleen, kidney, bladder, head and neck, uterus, testicles, stomach, cervix, liver, bone, skin, pancreas, brain and wherein the cancer may be non-metastatic, invasive or metastatic.

[0470] In another related object the detected diseases will include autoimmune and neoplastic disorders selected from the group consisting of Multiple sclerosis; Psoriasis; Rheumatoid arthritis; Systemic lupus erythematosus; Ulcerative colitis; Crohn's disease; immune disorders associated with graft transplantation rejection, benign lymphocytic angiitis, lupus erythematosus, Hashimoto's thyroiditis, primary myxedema, Graves' disease, pernicious anemia, autoimmune atrophic gastritis, Addison's disease, insulin dependent diabetes mellitis, good pasture's syndrome, myasthenia gravis, pemphigus, sympathetic ophthalmia, autoimmune uveitis, autoimmune hemolytic anemia, idiopathic thrombocytopenia, primary biliary cirrhosis, chronic action hepatitis, ulceratis colitis, Sjogren's syndrome, rheumatic disease, polymyositis, scleroderma, mixed connective tissue disease, inflammatory rheumatism, degenerative rheumatism, extra- articular rheumatism, collagen diseases, chronic polyarthritis, psoriasis arthropathica, ankylosing spondylitis, juvenile rheumatoid arthritis, periarthritis humeroscapularis, panarteriitis nodosa, progressive systemic scleroderma, arthritis uratica, dermatomyositis, muscular rheumatism, myositis, myogelosis and chondrocalcinosis.

[0471] In another related object the detected diseases will include rejection of any organ transplant and/or Graft versus host disease.

[0472] Each polypeptide/polynucleotide of the present invention can be used alone or in combination, for various uses, including but not limited to, prognosis, prediction, screening, early diagnosis, determination of progression, therapy selection and treatment monitoring of disease and/or an indicative condition, as detailed above.

[0473] Such a combination may optionally comprise any subcombination of markers, and/or a combination featuring at least one other marker, for example a known marker. Furthermore, such a combination may optionally and preferably be used as described above with regard to determining a ratio between a quantitative or semi-quantitative measurement of any marker described herein to any other marker described herein, and/or any other known marker, and/or any other marker.

[0474] According to further embodiments of the present invention markers of the present invention might optionally be used alone or in combination with known markers for lung cancer, including but not limited to CEA, CA15-3, Beta-2-microglobulin, CA19-9, TPA, and/or in combination with the known proteins for the variant marker as described herein.

[0475] According to further embodiments of the present invention markers of the present invention might optionally be used alone or in combination with known markers for ovarian cancer, including but not limited to CEA, CA125 (Mucin 16), CA72-4TAG, CA-50, CA 54-61, CA-195 and CA19-9 in combination with CA-125, and/or in combination with the known proteins for the variant marker as described herein.

[0476] According to further embodiments of the present invention markers of the present invention might optionally be used alone or in combination with known markers for colon cancer, including but not limited to CEA, CA19-9, CA50, and/or in combination with the known proteins for the variant marker as described herein.

[0477] In some embodiments of the present invention, there are provided of methods, uses, devices and assays for the diagnosis of a disease or condition. Optionally a plurality of markers may be used with the present invention. The plurality of markers may optionally include a markers described herein, and/or one or more known markers. The plurality of markers is preferably then correlated with the disease or condition. For example, such correlating may optionally comprise determining the concentration of each of the plurality of markers, and individually comparing each marker concentration to a threshold level. Optionally, if the marker concentration is above or below the threshold level (depending upon the marker and/or the diagnostic test being performed), the marker concentration correlates with the disease or condition. Optionally and preferably, a plurality of marker concentrations correlates with the disease or condition.

[0478] Alternatively, such correlating may optionally comprise determining the concentration of each of the plurality of markers, calculating a single index value based on the concentration of each of the plurality of markers, and comparing the index value to a threshold level.

[0479] Also alternatively, such correlating may optionally comprise determining a temporal change in at least one of the markers, and wherein the temporal change is used in the correlating step.

[0480] Also alternatively, such correlating may optionally comprise determining whether at least "X' number of the plurality of markers has a concentration outside of a predetermined range and/or above or below a threshold (as described above). The value of "X' may optionally be one marker, a plurality of markers or all of the markers; alternatively or additionally, rather than including any marker in the count for "X', one or more specific markers of the plurality of markers may optionally be required to correlate with the disease or condition (according to a range and/or threshold).

[0481] Also alternatively, such correlating may optionally comprise determining whether a ratio of marker concentrations for two markers is outside a range and/or above or below a threshold. Optionally, if the ratio is above or below the threshold level and/or outside a range, the ratio correlates with the disease or condition.

[0482] Optionally, a combination of two or more these correlations may be used with a single panel and/or for correlating between a plurality of panels.

[0483] Optionally, the method distinguishes a disease or condition with a sensitivity of at least 70% at a specificity of at least 85% when compared to normal subjects. As used herein, sensitivity relates to the number of positive (diseased) samples detected out of the total number of positive samples present; specificity relates to the number of true negative (non-diseased) samples detected out of the total number of negative samples present. Preferably, the method distinguishes a disease or condition with a sensitivity of at least 80% at a specificity of at least 90% when compared to normal subjects. More preferably, the method distinguishes a disease or condition with a sensitivity of at least 90% at a specificity of at least 90% when compared to normal subjects. Also more preferably, the method distinguishes a disease or condition with a sensitivity of at least 70% at a specificity of at least 85% when compared to subjects exhibiting symptoms that mimic disease or condition symptoms.

[0484] A marker panel may be analyzed in a number of fashions well known to those of skill in the art. For example, each member of a panel may be compared to a "normal" value, or a value indicating a particular outcome. A particular diagnosis/prognosis may depend upon the comparison of each marker to this value; alternatively, if only a subset of markers is outside of a normal range, this subset may be indicative of a particular diagnosis/prognosis. The skilled artisan will also understand that diagnostic markers, differential diagnostic markers, prognostic markers, time of onset markers, disease or condition differentiating markers, etc., may be combined in a single assay or device. Markers may also be commonly used for multiple purposes by, for example, applying a different threshold or a different weighting factor to the marker for the different purposes.

[0485] In one embodiment, the panels comprise markers for the following purposes: diagnosis of a disease; diagnosis of disease and indication if the disease is in an acute phase and/or if an acute attack of the disease has occurred; diagnosis of disease and indication if the disease is in a non-acute phase and/or if a non-acute attack of the disease has occurred; indication whether a combination of acute and non-acute phases or attacks has occurred; diagnosis of a disease and prognosis of a subsequent adverse outcome; diagnosis of a disease and prognosis of a subsequent acute or non-acute phase or attack; disease progression (for example for cancer, such progression may include for example occurrence or recurrence of metastasis).

[0486] The above diagnoses may also optionally include differential diagnosis of the disease to distinguish it from other diseases, including those diseases that may feature one or more similar or identical symptoms.

[0487] In certain embodiments, one or more diagnostic or prognostic indicators are correlated to a condition or disease by merely the presence or absence of the indicators. In other embodiments, threshold levels of a diagnostic or prognostic indicators can be established, and the level of the indicators in a patient sample can simply be compared to the threshold levels. The sensitivity and specificity of a diagnostic and/or prognostic test depends on more than just the analytical "quality" of the test—they also depend on the definition of what constitutes an abnormal result. In practice, Receiver Operating Characteristic curves, or "ROC" curves, are typically calculated by plotting the value of a variable versus its relative frequency in "normal" and "disease" populations, and/or by comparison of results from a subject before, during and/or after treatment.

[0488] According to embodiments of the present invention C10RF32 protein, polynucleotide or a fragment thereof, may be featured as a biomarker for detecting disease and/or an indicative condition, as detailed above.

[0489] According to still other embodiments, the present invention optionally and preferably encompasses any amino acid sequence or fragment thereof encoded by a nucleic acid sequence corresponding to C10RF32 as described herein. Any oligopeptide or peptide relating to such an amino acid sequence or fragment thereof may optionally also (additionally or alternatively) be used as a biomarker.

[0490] In still other embodiments, the present invention provides a method for detecting a polynucleotide of this invention in a biological sample, using NAT based assays, comprising: hybridizing the isolated nucleic acid molecules or oligonucleotide fragments of at least about a minimum length to a nucleic acid material of a biological sample and detecting a hybridization complex; wherein the presence of a hybridization complex correlates with the presence of the polynucleotide in the biological sample. Non-limiting examples of methods or assays are described below.

[0491] The present invention also relates to kits based upon such diagnostic methods or assays. NUCLEIC ACID TECHNOLOGY (NAT) BASED ASSAYS: [0492] Detection of a nucleic acid of interest in a biological sample may also optionally be effected by NAT-based assays, which involve nucleic acid amplification technology, such as PCR for example (or variations thereof such as real-time PCR for example). As used herein, a “primer" defines an oligonucleotide which is capable of annealing to (hybridizing with) a target sequence, thereby creating a double stranded region which can serve as an initiation point for DNA synthesis under suitable conditions. Amplification of a selected, or target, nucleic acid sequence may be carried out by a number of suitable methods known in the art. Non-limiting examples of amplification techniques include polymerase chain reaction (PCR), ligase chain reaction (LCR), strand displacement amplification (SDA), transcription-based amplification, the q3 replicase system and NASBA(Kwoh et al., 1989, Proc. Natl. Acad. Sci. USA 86, 1173-1177 ; Lizardi et al., 1988, BioTechnology 6:1197-1202 ; Malek et al., 1994, Methods Mol. Biol., 28:253-260; and Sambrook et al., 1989, supra). Non-limiting examples of Nucleic Acid Technology-based assay is selected from the group consisting of a PCR, Real-Time PCR, LCR, Self-Sustained Synthetic Reaction, Q-Beta Replicase, Cycling probe reaction, Branched DNA, RFLP analysis, DGGE/TGGE, Single-Strand Conformation Polymorphism, Dideoxy fingerprinting, microarrays, Fluorescense In Situ Hybridization and Comparative Genomic Hybridization. The terminology "amplification pair" (or "primer pair") refers herein to a pair of oligonucleotides (oligos) of the present invention, which are selected to be used together in amplifying a selected nucleic acid sequence by one of a number of types of amplification processes, preferably a polymerase chain reaction. As commonly known in the art, the oligos are designed to bind to a complementary sequence under selected conditions. In one particular embodiment, amplification of a nucleic acid sample from a patient is amplified under conditions which favor the amplification of the most abundant differentially expressed nucleic acid. In one preferred embodiment, RT-PCR is carried out on an mRNA sample from a patient under conditions which favor the amplification of the most abundant mRNA. In another preferred embodiment, the amplification of the differentially expressed nucleic acids is carried out simultaneously. It will be realized by a person skilled in the art that such methods could be adapted for the detection of differentially expressed proteins instead of differentially expressed nucleic acid sequences. The nucleic acid (i.e. DNA or RNA) for practicing the present invention may be obtained according to well known methods.

[0493] Oligonucleotide primers of the present invention may be of any suitable length, depending on the particular assay format and the particular needs and targeted genomes employed. Optionally, the oligonucleotide primers are at least 12 nucleotides in length, preferably between 15 and 24 molecules, and they may be adapted to be especially suited to a chosen nucleic acid amplification system. As commonly known in the art, the oligonucleotide primers can be designed by taking into consideration the melting point of hybridization thereof with its targeted sequence (Sambrook et al., 1989, Molecular Cloning -A Laboratory Manual, 2nd Edition, CSH Laboratories; Ausubel et al., 1989, in Current Protocols in Molecular Biology, John Wiley & Sons Inc., N.Y.).

IMMUNOASSAYS

[0494] In another embodiment of the present invention, an immunoassay can be used to qualitatively or quantitatively detect and analyze markers in a sample. This method comprises: providing an antibody that specifically binds to a marker; contacting a sample with the antibody; and detecting the presence of a complex of the antibody bound to the marker in the sample.

[0495] To prepare an antibody that specifically binds to a marker, purified protein markers can be used. Antibodies that specifically bind to a protein marker can be prepared using any suitable methods known in the art.

[0496] After the antibody is provided, a marker can be detected and/or quantified using any of a number of well recognized immunological binding assays. Useful assays include, for example, an enzyme immune assay (EIA) such as enzyme-linked immunosorbent assay (ELISA), a radioimmune assay (RIA), a Western blot assay, or a slot blot assay see, e.g., U.S. Pat. Nos. 4,366,241; 4,376,110; 4,517,288; and 4,837,168). Generally, a sample obtained from a subject can be contacted with the antibody that specifically binds the marker.

[0497] Optionally, the antibody can be fixed to a solid support to facilitate washing and subsequent isolation of the complex, prior to contacting the antibody with a sample. Examples of solid supports include but are not limited to glass or plastic in the form of, e.g., a microtiter plate, a stick, a bead, or a microbead. Antibodies can also be attached to a solid support.

[0498] After incubating the sample with antibodies, the mixture is washed and the antibody-marker complex formed can be detected. This can be accomplished by incubating the washed mixture with a detection reagent. Alternatively, the marker in the sample can be detected using an indirect assay, wherein, for example, a second, labeled antibody is used to detect bound marker-specific antibody, and/or in a competition or inhibition assay wherein, for example, a monoclonal antibody which binds to a distinct epitope of the marker are incubated simultaneously with the mixture.

[0499] Throughout the assays, incubation and/or washing steps may be required after each combination of reagents. Incubation steps can vary from about 5 seconds to several hours, preferably from about 5 minutes to about 24 hours. However, the incubation time will depend upon the assay format, marker, volume of solution, concentrations and the like. Usually the assays will be carried out at ambient temperature, although they can be conducted over a range of temperatures, such as 10 °C to 40 °C.

[0500] The immunoassay can be used to determine a test amount of a marker in a sample from a subject. First, a test amount of a marker in a sample can be detected using the immunoassay methods described above. If a marker is present in the sample, it will form an antibody-marker complex with an antibody that specifically binds the marker under suitable incubation conditions described above. The amount of an antibody-marker complex can optionally be determined by comparing to a standard. As noted above, the test amount of marker need not be measured in absolute units, as long as the unit of measurement can be compared to a control amount and/or signal.

[0501] Radio-immunoassay (RIA): In one version, this method involves precipitation of the desired substrate and in the methods detailed herein below, with a specific antibody and radiolabeled antibody binding protein (e.g., protein A labeled with 1125) immobilized on a precipitable carrier such as agarose beads. The number of counts in the precipitated pellet is proportional to the amount of substrate.

[0502] In an alternate version of the RIA, a labeled substrate and an unlabelled antibody binding protein are employed. Asample containing an unknown amount of substrate is added in varying amounts. The decrease in precipitated counts from the labeled substrate is proportional to the amount of substrate in the added sample.

[0503] Enzyme linked immunosorbent assay (ELISA): This method involves fixation of a sample (e.g., fixed cells or a proteinaceous solution) containing a protein substrate to a surface such as a well of a microtiter plate. A substrate specific antibody coupled to an enzyme is applied and allowed to bind to the substrate. Presence of the antibody is then detected and quantitated by a colorimetric reaction employing the enzyme coupled to the antibody. Enzymes commonly employed in this method include horseradish peroxidase and alkaline phosphatase. If well calibrated and within the linear range of response, the amount of substrate present in the sample is proportional to the amount of color produced. A substrate standard is generally employed to improve quantitative accuracy.

[0504] Western blot: This method involves separation of a substrate from other protein by means of an acrylamide gel followed by transfer of the substrate to a membrane (e.g., nylon or PVDF). Presence of the substrate is then detected by antibodies specific to the substrate, which are in turn detected by antibody binding reagents. Antibody binding reagents may be, for example, protein A, or other antibodies. Antibody binding reagents may be radiolabeled or enzyme linked as described hereinabove. Detection may be by autoradiography, colorimetric reaction or chemiluminescence. This method allows both quantitation of an amount of substrate and determination of its identity by a relative position on the membrane which is indicative of a migration distance in the acrylamide gel during electrophoresis.

[0505] Immunohistochemical analysis: This method involves detection of a substrate in situ in fixed cells by substrate specific antibodies. The substrate specific antibodies may be enzyme linked or linked to fluorophores. Detection is by microscopy and subjective evaluation. If enzyme linked antibodies are employed, a colorimetric reaction may be required.

[0506] Fluorescence activated cell sorting (FACS): This method involves detection of a substrate in situ in cells by substrate specific antibodies. The substrate specific antibodies are linked to fluorophores. Detection is by means of a cell sorting machine which reads the wavelength of light emitted from each cell as it passes through a light beam. This method may employ two or more antibodies simultaneously.

RADIO-IMAGING METHODS

[0507] These methods include but are not limited to, positron emission tomography (PET) single photon emission computed tomography (SPECT). Both of these techniques are non-invasive, and can be used to detect and/or measure a wide variety of tissue events and/or functions, such as detecting cancerous cells for example. Unlike PET, SPECT can optionally be used with two labels simultaneously. SPECT has some other advantages as well, for example with regard to cost and the types of labels that can be used. For example, US Patent No. 6,696,686 describes the use of SPECT for detection of breast cancer, and is hereby incorporated by reference as if fully set forth herein. THERANOSTICS: [0508] The term theranostics describes the use of diagnostic testing to diagnose the disease, choose the correct treatment regime according to the results of diagnostic testing and/or monitor the patient response to therapy according to the results of diagnostic testing. Theranostic tests can be used to select patients for treatments that are particularly likely to benefit them and unlikely to produce side-effects. They can also provide an early and objective indication of treatment efficacy in individual patients, so that (if necessary) the treatment can be altered with a minimum of delay. For example: DAKO and Genentech together created FlercepTest and Flerceptin (trastuzumab) for the treatment of breast cancer, the first theranostic test approved simultaneously with a new therapeutic drug. In addition to HercepTest (which is an immunohistochemical test), other theranostic tests are in development which use traditional clinical chemistry, immunoassay, cell-based technologies and nucleic acid tests. PPGx's recently launched TPMT (thiopurine S-methyltransferase) test, which is enabling doctors to identify patients at risk for potentially fatal adverse reactions to 6-mercaptopurine, an agent used in the treatment of leukemia. Also, Nova Molecular pioneered SNP genotyping of the apolipoprotein E gene to predict Alzheimer's disease patients' responses to cholinomimetic therapies and it is now widely used in clinical trials of new drugs for this indication. Thus, the field of theranostics represents the intersection of diagnostic testing information that predicts the response of a patient to a treatment with the selection of the appropriate treatment for that particular patient. SURROGATE MARKERS: [0509] A surrogate marker is a marker, that is detectable in a laboratory and/or according to a physical sign or symptom on the patient, and that is used in therapeutic trials as a substitute for a clinically meaningful endpoint. The surrogate marker is a direct measure of how a patient feels, functions, or survives which is expected to predict the effect of the therapy. The need for surrogate markers mainly arises when such markers can be measured earlier, more conveniently, or more frequently than the endpoints of interest in terms of the effect of a treatment on a patient, wfiich are referred to as the clinical endpoints. Ideally, a surrogate marker should be biologically plausible, predictive of disease progression and measurable by standardized assays (including but not limited to traditional clinical chemistry, immunoassay, cell-based technologies, nucleic acid tests and imaging modalities).

[0510] Surrogate endpoints were used first mainly in the cardiovascular area. For example, antihypertensive drugs have been approved based on their effectiveness in lowering blood pressure. Similarly, in the past, cholesterol-lowering agents have been approved based on their ability to decrease serum cholesterol, not on the direct evidence that they decrease mortality from atherosclerotic heart disease. The measurement of cholesterol levels is now an accepted surrogate marker of atherosclerosis. In addition, currently two commonly used surrogate markers in HIV studies are CD4+ T cell counts and quantitative plasma HIV RNA (viral load). In some embodiments of this invention, the polypeptide/polynucleotide expression pattern may serve as a surrogate marker for a particular disease, as will be appreciated by one skilled in the art.

USES AND METHODS OF THE INVENTION

[0511] The C10RF32 drugs according to the invention, especially antibodies, particularly the human antibodies, antibody compositions, and soluble conjugates containing the ectodomain of the C10RF32 antigen or a fragment or variant thereof, or a corresponding nucleic acid sequence or vector or cell expressing same and methods of the present invention have numerous in vitro and in vivo diagnostic and therapeutic utilities involving the diagnosis and treatment of C10RF32 antigen related disorders and/or disorders wherein modulation of immune co-stimulation e.g., involving B7 -related immune costimulation involving C10RF32 antigen is therapeutically desirable. As noted these conditions include in particular cancers that differentially express the C10RF32 antigen such as lung cancer, ovarian cancer, colon cancer, including invasive and metastatic forms thereof, and/or autoimmune conditions wherein modulation of costimulation such as involving B7 is therapeutically desirable. The subject anti-C10RF32 antibodies may prevent B7 mediated negative stimulation of T cell activity against cancer cells and/or prevent positive stimulation of T cell activity. Such antibodies may be used in the treatment of conditions including cancers such non-solid and solid tumors, sarcomas, hematological malignancies including but not limited to acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, multiple myeloma, Hodgkin's lymphoma, Non-Hodgkin's lymphoma, cancer of the breast, prostate, lung, ovary, colon, spleen, kidney, bladder, head and neck, uterus, testicles, stomach, cervix, liver, bone, skin, pancreas, brain and wherein the cancer may be non-metastatic, invasive or metastatic as well as non-malignant disorders such as immune disorders including but not limited to transplant rejection and graft versus host disease, and autoimmune disorders such as afore-mentioned.

[0512] For example, these molecules can be administered to cells in culture, in vitro or ex vivo, or to human subjects, e.g., in vivo, to treat, prevent and to diagnose a variety of disorders. Preferred subjects include human patients having disorders mediated by cells expressing the C10RF32 antigen and cells that posses C10RF32 activity. The methods are particularly suitable for treating human patients having a disorder associated with aberrant C10RF32 antigen expression using antibodies that specifically bind H19011_1_P8 (SEQ ID NO:48), H19011_1_P9 (SEQ ID NO:50) [0513] C1ORF32 drugs according to the invention, are administered together with another agent, the two can be administered in either order or simultaneously.

[0514] Given the specific binding of the antibodies of the invention for C10RF32 the antibodies of the invention can be used to specifically detect C10RF32 expression on the surface of cells and, moreover, can be used to purify C10RF32 antigen via immunoaffinity purification.

[0515] Furthermore, given the expression of C10RF32 on various tumor cells, the human antibodies, antibody compositions and methods of the present invention can be used to treat a subject with a tumorigenic disorder, e.g., a disorder characterized by the presence of tumor cells expressing C1ORF32 antigen such as lung cancer and ovarian cancer, as mentioned.

[0516] In one embodiment, the antibodies (e.g., human monoclonal antibodies, multispecific and bispecific molecules and compositions) of the invention can be used to detect levels of C10RF32 or levels of cells wfnich contain C10RP32 on their membrane surface, which levels can then be linked to certain disease symptoms. Alternatively, the antibodies can be used to inhibit or block C10RF32 function which, in turn, can be linked to the prevention or amelioration of certain disease symptoms, thereby implicating C10RF32 as a mediator of the disease. This can be achieved by contacting a sample and a control sample with the anti-C10RF32 antibody under conditions that allow for the formation of a complex between the corresponding antibody and C10RF32. Any complexes formed between the antibody and C10RF32 are detected and compared in the sample and the control.

[0517] In another embodiment, the antibodies (e.g., human antibodies, multispecific and bispecific molecules and compositions) of the invention can be initially tested for binding activity associated with therapeutic or diagnostic use in vitro. For example, compositions of the invention can be tested using low cytometric assays.

[0518] The antibodies (e.g., human antibodies, multispecific and bispecific molecules, immunoconjugates and compositions) of the invention have additional utility in therapy and diagnosis of C10RF32 -related diseases. For example, the human monoclonal antibodies, the multispecific or bispecific molecules and the immunoconjugates can be used to elicit in vivo or in vitro one or more of the following biological activities: to inhibit the growth of and/or kill a cell expressing C10RF32; to mediate phagocytosis or ADCC of a cell expressing C10RF32 in the presence of human effector cells, or to block C10RF32 ligand binding to C10RF32 [0519] In a particular embodiment, the antibodies (e.g., human antibodies, multispecific and bispecific molecules and compositions) are used in vivo to treat, prevent or diagnose a variety of related diseases. Examples of C10RF32 related diseases include, among others, cancer, such as lung cancer, ovarian cancer, colon cancer, other non-solid and solid tumors, sarcomas, hematological malignancies including but not limited to acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, multiple myeloma, Hodgkin's lymphoma, Non-Hodgkin's lymphoma, cancer of the breast, prostate, spleen, kidney, bladder, head and neck, uterus, testicles, stomach, cervix, liver, bone, skin, pancreas, brain and wherein the cancer may be non-metastatic, invasive or metastatic. Additional examples of C10RF32 related diseases include, among others, non-malignant disorders such as immune disorders including but not limited to autoimmune diseases, transplant rejection and graft versus host disease. Such disorders include by way of example autoimmune diseases selected from multiple sclerosis; psoriasis; rheumatoid arthritis; Systemic lupus erythematosus; Ucerative colitis; Crohn's' disease, immune disorders associated with graft transplantation rejection, benign lymphocytic angiitis, lupus erythematosus, Hashimoto's thyroiditis, primary myxedema, Graves' disease, pernicious anemia, autoimmune atrophic gastritis, Addison's disease, insulin dependent diabetes mellitis, Good pasture's syndrome, myasthenia gravis, pemphigus, sympathetic ophthalmia, autoimmune uveitis, autoimmune hemolytic anemia, idiopathic thrombocytopenia, primary biliary cirrhosis, chronic action hepatitis, ulceratis colitis, Sjogren's syndrome, rheumatic disease, polymyositis, scleroderma, mixed connective tissue disease, inflammatory rheumatism, degenerative rheumatism, extra- articular rheumatism, collagen diseases, chronic polyarthritis, psoriasis arthropathica, ankylosing spondylitis, juvenile rheumatoid arthritis, periarthritis humeroscapularis, panarteriitis nodosa, progressive systemic scleroderma, arthritis uratica, dermatomyositis, muscular rheumatism, myositis, myogelosis and chondrocalcinosis.

[0520] Suitable routes of administering the antibody compositions (e.g., human monoclonal antibodies, multispecific and bispecific molecules and immunoconjugates) of the invention in vivo and in vitro are well known in the art and can be selected by those of ordinary skill. For example, the antibody compositions can be administered by injection (e.g., intravenous or subcutaneous). Suitable dosages of the molecules used will depend on the age and weight of the subject and the concentration and/or formulation of the antibody composition.

[0521] As previously described, human anti-C10RF32 antibodies of the invention can be co-administered with one or other more therapeutic agents, e.g., an cytotoxic agent, a radiotoxic agent or an immunosuppressive agent. The antibody can be linked to the agent (as an immunocomplex) or can be administered separate from the agent. In the latter case (separate administration), the antibody can be administered before, after or concurrently with the agent or can be co-administered with other known therapies, e.g., an anti-cancer therapy, e.g., radiation. Such therapeutic agents include, among others, anti-neoplastic agents such as doxorubicin (adriamycin), cisplatin bleomycin sulfate, carmustine, chlorambucil, and cyclophosphamide hydroxyurea which, by themselves, are only effective at levels which are toxic or subtoxic to a patient. Cisplatin is intravenously administered as a 100 mg/dose once every four weeks and adriamycin is intravenously administered as a 60-75 mg/ml dose once every 21 days. Co-administration of the human anti-C10RF32 antibodies, or antigen binding fragments thereof, of the present invention with chemotherapeutic agents provides two anti-cancer agents wfnich operate via different mechanisms which yield a cytotoxic effect to human tumor cells. Such co-administration can solve problems due to development of resistance to drugs or a change in the antigenicity of the tumor cells which would render them unreactive with the antibody.

[0522] Target-specific effector cells, e.g., effector cells linked to compositions (e.g., human antibodies, multispecific and bispecific molecules) of the invention can also be used as therapeutic agents. Effector cells for targeting can be human leukocytes such as macrophages, neutrophils or monocytes. Other cells include eosinophils, natural killer cells and other IgG- or IgA-receptor bearing cells. If desired, effector cells can be obtained from the subject to be treated. The target-specific effector cells can be administered as a suspension of cells in a physiologically acceptable solution. The number of cells administered can be in the order of 10 -8 to 10-9 but will vary depending on the therapeutic purpose. In general, the amount will be sufficient to obtain localization at the target cell, e.g., a tumor cell expressing C10RF32 and to effect cell killing by, e.g., phagocytosis. Routes of administration can also vary.

[0523] Therapy with target-specific effector cells can be performed in conjunction with other techniques for removal of targeted cells. For example, anti-tumor therapy using the compositions (e.g., human antibodies, multispecific and bispecific molecules) of the invention and/or effector cells armed with these compositions can be used in conjunction with chemotherapy. Additionally, combination immunotherapy may be used to direct two distinct cytotoxic effector populations toward tumor cell rejection. For example, anti-C10RF32 antibodies linked to anti-Fc-gamma Rl or anti-CD3 may be used in conjunction with IgG- or IgA-receptor specific binding agents.

[0524] Bispecific and multispecific molecules of the invention can also be used to modulate FcgammaR or FcgammaR levels on effector cells, such as by capping and elimination of receptors on the cell surface. Mixtures of anti-Fc receptors can also be used for this purpose.

[0525] The compositions (e.g., human antibodies, multispecific and bispecific molecules and immunoconjugates) of the invention which have complement binding sites, such as portions from IgG 1, -2, or -3 or IgM which bind complement, can also be used in the presence of complement. In one embodiment, ex vivo treatment of a population of cells comprising target cells vuth a binding agent of the invention and appropriate effector cells can be supplemented by the addition of complement or serum containing complement. Phagocytosis of target cells coated with a binding agent of the invention can be improved by binding of complement proteins. In another embodiment target cells coated with the compositions (e.g., human antibodies, multispecific and bispecific molecules) of the invention can also be lysed by complement. In yet another embodiment, the compositions of the invention do not activate complement.

[0526] The compositions (e.g., human antibodies, multispecific and bispecific molecules and immunoconjugates) of the invention can also be administered together with complement. Accordingly, within the scope of the invention are compositions comprising human antibodies, multispecific or bispecific molecules and serum or complement. These compositions are advantageous in that the complement is located in close proximity to the human antibodies, multispecific or bispecific molecules. Alternatively, the human antibodies, multispecific or bispecific molecules of the invention and the complement or serum can be administered separately.

[0527] Also within the scope of the present invention are kits comprising the C10RF32 antigen or C10RF32 conjugates or antibody compositions of the invention (e.g., human antibodies, bispecific or multispecific molecules, or immunoconjugates) and instructions for use. The kit can further contain one ore more additional reagents, such as an immunosuppressive reagent, a cytotoxic agent or a radiotoxic agent, or one or more additional human antibodies of the invention (e.g., a human antibody having a complementary activity which binds to an epitope in the C10RF32 antigen distinct from the first human antibody).

[0528] Accordingly, patients treated with antibody compositions of the invention can be additionally administered (prior to, simultaneously with, or following administration of a human antibody of the invention) vuth another therapeutic agent, such as a cytotoxic or radiotoxic agent, which enhances or augments the therapeutic effect of the human antibodies.

[0529] In other embodiments, the subject can be additionally treated with an agent that modulates, e.g., enhances or inhibits, the expression or activity of Fey or Fey receptors by, for example, treating the subject with a cytokine. Preferred cytokines for administration during treatment with the multispecific molecule include of granulocyte colony-stimulating factor (G-CSF), granulocyte- macrophage colony-stimulating factor (GM-CSF), interferon-.gamma. (IFN-.gamma.), and tumor necrosis factor (TNF).

[0530] The compositions (e.g., human antibodies, multispecific and bispecific molecules) of the invention can also be used to target cells expressing Fc gamma R or C10RF32 for example for labeling such cells. For such use, the binding agent can be linked to a molecule that can be detected. Thus, the invention provides methods for localizing ex vivo or in vitro cells expressing Fc receptors, such as FcgammaR, or C10RF32 antigen. The detectable label can be, e.g., a radioisotope, a fluorescent compound, an enzyme, or an enzyme co-factor.

[0531] In a particular embodiment, the invention provides methods for detecting the presence of C10RF32 antigen in a sample, or measuring the amount of C10RF32 antigen, respectively, comprising contacting the sample, and a control sample, with a human monoclonal antibody, or an antigen binding portion thereof, which specifically binds to C10RF32 under conditions that allow for formation of a complex between the antibody or portion thereof and C10RF32. The formation of a complex is then detected, wherein a difference complex formation between the sample compared to the control sample is indicative the presence of C10RF32 antigen in the sample. As noted the invention in particular embraces assays for detecting C10RF32 antigen in vitro and in vivo such as immunoassays, radioimmunassays, radioassays, radioimaging assays, ELISAs, Western blot, FACS, slot blot, immunohistochemical assays, and other assays well known to those skilled in the art.

[0532] In other embodiments, the invention provides methods for treating an C10RF32 mediated disorder in a subject, e.g., cancer, such as non-solid and solid tumors, sarcomas, hematological malignancies including but not limited to acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, multiple myeloma, Flodgkin's lymphoma, Non-Flodgkin's lymphoma, cancer of the breast, prostate, lung, ovary, colon, spleen, kidney, bladder, head and neck, uterus, testicles, stomach, cervix, liver, bone, skin, pancreas, brain and wherein the cancer may be non-metastatic, invasive or metastatic, as well as non-malignant disorders such as immune disorders including but not limited to transplant rejection and graft versus host disease, or an autoimmune disease selected from those aforementioned and methods of treating any condition wherein modulation of immune costimulation that involves C10RF32 is therapeutically desirable using anti-C10RF32 antibodies or soluble C10RF32 antigen conjugates or other drugs that target and modulate (promote or inhibit) one or more C10RF32 biological activities.

[0533] By administering the anti-C10RF2 antibody, soluble C10RF32 antigen conjugate or other drug that targets the C10RF32 antigen or a portion thereof to a subject, the ability of C1QRF32 antigen to induce such activities is inhibited or promoted and, thus, the associated disorder is treated. The soluble C10RF32 antigen or antigen conjugate or anti-C10RF32 antibody or fragment containing composition or other drug that targets and modulates C10RF32 can be administered alone or along with another therapeutic agent, such as a cytotoxic or a radiotoxic agent which acts in conjunction with or synergistically with the antibody composition to treat or prevent the C1ORF32 antigen mediated disease.

[0534] In yet another embodiment, immunoconjugates of the invention can be used to target compounds (e.g., therapeutic agents, labels, cytotoxins, radiotoxins immunosuppressants, etc.) to cells which have C10RF32 cell surface receptors by linking such compounds to the antibody. Thus, the invention also provides methods for localizing ex vivo or in vivo cells expressing C10RF32 (e.g., with a detectable label, such as a radioisotope, a fluorescent compound, an enzyme, or an enzyme co-factor). Alternatively, the immunoconjugates can be used to kill cells which have C10RF32 cell surface receptors by targeting cytotoxins or radiotoxins to C10RF32 antigen.

[0535] The present invention is further illustrated by the following sequence characterization of a DNA transcript encoding the C10RF32 antigen, its domains and expression data in normal and cancerous tissues as well as prophetic examples describing the manufacture of fully human antibodies thereto. This information and examples is illustrative and should not be construed as further limiting. The contents of all figures and all references, patents and published patent applications cited throughout this application are expressly incorporated herein by reference. EXAMPLES EXAMPLE 1:

METHODS USED TO ANALYZE THE EXPRESSION OF THE RNA ENCODING THE PROTEINS OF THE INVENTION

[0536] The targets of the present invention were tested with regard to their expression in various cancerous and non-cancerous tissue samples and/or with regard to its expression in a wide panel of human samples which contains various types of immune cells, and hematological malignancies samples and cell lines, as well as several samples of normal tissues. The list of the blood specific RNA samples used for the qRT-PCR analysis is provided in Table 1 below. A description of the samples used in the normal tissue panel is provided in Table 2. A description of the samples used in the lung cancer testing panel is provided in Table 3 below. A description of the samples used in the ovary cancer testing panel is provided in Table 4 below. A description of the samples used in the colon cancer testing panel is provided in Table 5 below. The keys for the table 3, 4 and 5 are given in tables 31,41, and 5_1, respectively. Tests were then performed as described in the "Materials and Experimental Procedures" section below.

Table 1 Samples in blood specific panel

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Materials and Experimental Procedures Used to Obtain Expression Data RNA preparation - 148 [0537] RNA was obtained fromABS (Wilmington, DE 19801, USA, http://vwvw.absbioreagents.com), BioChain Inst. Inc. (Hayward, CA 94545 USAvvww.biochain.com), GOG for ovary samples- Pediatic Cooperative Human Tissue Network, Gynecologic Oncology Group Tissue Bank, Children Hospital of Columbus (Columbus OH 43205 USA), Clontech (Franklin Lakes, NJ USA 07417, www.clontech.com), Ambion (Austin, TX 78744 USA, http://www.ambion.com), Asternad (Detroit, Ml 48202-3420, USA, www.asterand.com), and from Genomics Collaborative Inc.a Division of Seracare (Cambridge, MA 02139, USA, www.genomicsinc.com). Alternatively, RNA was generated from blood cells, cell lines or tissue samples using TRI-Reagent (Molecular Research Center), according to Manufacturer's instructions. Tissue and RNA samples were obtained from patients or from postmortem. Most total RNA samples were treated with DNasel (Ambion).

[0538] RT PCR - Purified RNA(2-10 pg) was mixed with 300-1500 ng Random Hexamer primers (Invitrogen) and 500 μΜ dNTP in a total volume of 31.2 to 156 pi. The mixture was incubated for 5 min at 65 °C and then quickly chilled on ice. Thereafter, 10-50 pi of 5X Superscript!! first strand buffer (Invitrogen), 4.8 to 24 pi 0.1 M DTT and 80-400 units RNasin (Promega) were added, and the mixture was incubated for 10 min at 25 °C, followed by further incubation at 42 °C for 2 min. Then, 2-10 pi (400-2000 units) of Superscript!! (Invitrogen) was added and the reaction (final volume of 50-250pl) was incubated for 50 min at 42 °C and then inactivated at 70 °Cfor 15min. The resulting cDNAwas diluted 1:20 in TE buffer (10 mM Tris pH=8,1 mM EDTA pH=8).

[0539] Real-Time RT-PCR analysis carried out as described below- cDNA (5pl), prepared as described above, was used as a template in Real-Time PCR reactions (final volume of 20 pi) using the SYBR Green I assay (PE Applied Biosystem) with specific primers and UNG Enzyme (Eurogentech or ABI or Roche). The amplification was effected as follows: 50 °C for 2 min, 95 °C for 10 min, and then 40 cycles of 95 °C for 15 sec, followed by 60 °C for 1 min, following by dissociation step. Detection was performed by using the PE Applied Biosystem SDS 7000. The cycle in which the reactions achieved a threshold level of fluorescence (Ct= Threshold Cycle, described in detail below) was registered and was used to calculate the relative transcript quantity in the RT reactions. The relative quantity was calculated using the equation Q=efficiencyA-Ct. The efficiency of the PCR reaction was calculated from a standard curve, created by using different dilutions of several reverse transcription (RT) reactions. To minimize inherent differences in the RT reaction, the resulting relative quantities were normalized using a normalization factor calculated in the following way: [0540] The expression of several housekeeping (HSKP) genes was checked on every panel. The relative quantity (Q) of each housekeeping gene in each sample, calculated as described above, was divided by the median quantity of this gene in all panel samples to obtain the "relative Q rel to MED". Then, for each sample the median of the "relative Q rel to MED" of the selected housekeeping genes was calculated and served as normalization factor of this sample for further calculations. Schematic summary of quantitative real-time PCR analysis is presented in Figure 1. As shown, the x-axis shows the cycle number. The CT = Threshold Cycle point, which is the cycle that the amplification curve crosses the fluorescence threshold that was set in the experiment. This point is a calculated cycle number in which PCR products signal is above the background level (passive dye ROX) and still in the Geometric/Exponential phase (as shown, once the level of fluorescence crosses the measurement threshold, it has a geometrically increasing phase, during which measurements are most accurate, followed by a linear phase and a plateau phase; for quantitative measurements, the latter two phases do not provide accurate measurements). The y-axis shows the normalized reporter fluorescence. It should be noted that this type of analysis provides relative quantification.

[0541] For each RT sample, the expression of the specific amplicon was normalized to the normalization factor calculated from the expression of different house keeping genes as described in section above.

[0542] These house keeping genes are different for each panel. For colon panel - HPRT1 (GenBank Accession No. NM_000194 (SEQ ID NO: 118); amplicon - HPRT 1-amplicon (SEQ ID NO:181)), PBGD (GenBank Accession No. BC019323 (SEQ ID NO: 117); amplicon - PBGD-amplicon (SEQ ID NO: 178)), and G6PD (GenBank Accession No. NM_000402 (SEQ ID NO: 119); G6PD amplicon (SEQ ID NO: 184)). For lung panel - HPRT1 (GenBank Accession No. NM_000194 (SEQ ID NO: 118); amplicon -HPRT 1-amplicon (SEQ ID NO:181)), PBGD (GenBank Accession No. BC019323 (SEQ ID NO: 117); amplicon - PBGD-amplicon (SEQ ID NO:178)), SDHA (GenBank Accession No. NM_004168 (SEQ ID NO: 116); amplicon - SDHA-amplicon (SEQ ID NO:175)) and Ubiquitin (GenBank Accession No. BC000449 (SEQ ID NO: 115); amplicon - Ubiquitin-amplicon (SEQ ID NO: 172)). For ovary panel - SDHA (GenBank Accession No. NM_004168 (SEQ ID NO: 116); amplicon - SDHA-amplicon (SEQ ID NO: 175)), HPRT1 (GenBank Accession No. NM_000194 (SEQ ID NO: 118); amplicon - HPRT1-amplicon (SEQ ID NO:181)) and G6PD (GenBank Accession No. NM_000402 (SEQ ID NO: 119); G6PD amplicon (SEQ ID NO: 184)). For normal panel - SDHA (GenBank Accession No. NM_004168 (SEQ ID NO: 116); amplicon - SDHA-amplicon (SEQ ID NO:175)), Ubiquitin (GenBank Accession No. BC000449 (SEQ ID NO: 115); amplicon - Ubiquitin-amplicon (SEQ ID NO: 172)), and TATA box (GenBank Accession No. NM_003194 (SEQ ID NO: 114); TATA amplicon (SEQ ID NO: 169)). For blood panel - HSB1 L_HUMAN (Accession No. Q9Y450)(SEQ ID NO: 109), DHSAJHUMAN (SEQ ID NO: 110) (Accession No P31040), SFRS4JHUMAN (SEQ ID NO: 111) (Accession No Q08170) and SLC25A3 (Accession No Q7Z7N7) (SEQ ID NO: 112). 149 [0543] The sequences of the housekeeping genes measured in all the examples of blood panel were as follows: [0544] HSB1 L_HUMAN (SEQ ID NO: 109) (Accession No. Q9Y450)

[0545] T05337_seg30-34F1-Forward primer (SEQ ID NO: 152): GOTCCAGGCCATAAGGACTTC

[0546] T05337_seg30-34R1 (SEQ ID NO: 153)-Reverse primer: CAGCTTCAAACTCTCCCCTGC

[0547] Amplicon (SEQ ID NO: 154):

GCTCCAGGCCATAAGGACTTCATTCCAAATATGATTACAGGAGCAGCCCAG

GCGGATGTAGCTGTnTAGTTGTAGATGCCAGCAGGGGAGAGTTrGAAGCT

G

[0548] DHSA_HUMAN (SEQ ID NO: 110) (Accession No P31040)

[0549] M78124_seg45-48F 1 (SEQ ID NO: 155)-Forward primer: TTCCTTGCCAGGACCTAGAG

[0550] M78124-seg45-48R1-Reverse primer (SEQ ID NO: 156): CATAAACCTTTCGCCTTGAC

[0551] Amplicon (SEQ ID NO: 157):

TTCCTTGCCAGGACCTAGAGTTTGTTCAGTTCCACCCCACAGGCATATATGG

TGCTGGTTGTCTCATTACGGAAGGATGTCGTGGAGAGGGAGGCATTCTCATT

AACAGTCAAGGCGAAAGGTTTATG

[0552] SFRS4_HUMAN (SEQ ID NO: 111) (Accession No Q08170)

[0553] HUMSRP75Aseg30-33F 1 (SEQ ID NO: 158)- Forward primer: AATTTGTCAAGTCGGTGCAGC

[0554] HUMSRP75Aseg30-33R1 (SEQ ID NO: 159)- Reverse primer: TCACCCCTTCATTTTTGCGT

[0555] Amplicon (SEQ ID NO: 160):

AATTTGTCAAGTCGGTGCAGCTGGC AAGACCTAAAGGATTATATGCGTCAG GCAGGAGAAGTGACTTATGCAGATGCTCACAAGGGACGCAAAAATGAAGG GGTGA

[0556] SLC25A3 (Accession No Q7Z7N7) (SEQ ID NO: 112)

[0557] SSMPCPseg24-25-29F 1 - Forward primer (SEQ ID NO:161): CCCAAAATGTATAAGGAAGAAGGC

[0558] SSMPCPseg24-25-29R1 - Reverse primer (SEQ ID NO: 162): TTCAAAGCAGGCGAACTTCA

[0559] Amplicon (SEQ ID NO: 163):

CAGCCAGGTTATGCCAACACTTTGAGGGATGCAGCTCCCAAAATGTATAAG

GAAGAAGGCCTAAAAGCATTCTACAAGGGGGTTGCTCCTCTCTGGATGAGA

CAGATACCATACACCATGATGAAGTTCGCCTGCTTTGA

[0560] The sequences of the housekeeping genes measured in all the examples on normal tissue samples panel were as follows: [0561] TATA box (GenBank Accession No. NM_003194 (SEQ ID NO: 114)),

[0562] TATA box Forward primer (SEQ ID NO: 167): CGGTTTGCTGCGGTAATCAT

[0563] TATA box Reverse primer (SEQ ID NO: 168): TTTCTTGCTGCCAGTCTGGAC

[0564] TATA box -amplicon (SEQ ID NO: 169): cggtttgctgcggtaatcatgaggataagagagccacgaaccacggcact

GATTTTCAGTTCTGGGAAAATGGTGTGCACAGGAGCCAAGAGTGAAGAAC

AGTCCAGACTGGCAGCAAGAAA

[0565] Ubiquitin (GenBank Accession No. BC000449 (SEQ ID NO: 115))

[0566] Ubiquitn Forward primer (SEQ ID NO: 170): ATTTGGGTCGCGGTTCTTG

[0567] Ubiquitin Reverse primer (SEQ ID NO:171): TGCCTTGACATTCTCGATGGT

[0568] Ubiquitin-amplicon (SEQ ID NO: 172)

ATTTGGGTCGCGGTTCTTGTTTGTGGATCGCTGTGATCGTCACTTG

ACAATGCAGATCTTCGTGAAGACTCTGACTGGTAAGACCATCACCCTCGAG G TTGAGCCCAGTGACACCATCGAGAATGTCAAGGCA

[0569] SDHA (GenBank Accession No. NM_004168 (SEQ ID NO: 116))

[0570] SDHA Forward primer (SEQ ID NO: 173): T G G G AACAAG AG G G CAT CT G

[0571] SDHA Reverse primer (SEQ ID NO:174): CCACCACTGCATCAAATTCATG

[0572] SDHA-amplicon (SEQ ID NO: 175):

TGGGAACAAGAGGGCATCTGCTAAAGTTTCAGATTCCATTTCTGCTCAGTAT

CCAGTAGTGGATCATGAATTTGATGCAGTGGTGG

[0573] The sequences for primers and amplicons of the housekeeping genes measured in all the cancer examples are listed below. For colon panel - HPRT1, PBGD and G6PD were used. For lung panel - PBGD, HPRT1, Ubiquitin and SDHA were used. For ovary panel - HPRT1, SDHA and G6PD were used.

[0574] SDHA (GenBank Accession No. NM 004168 (SEQ ID NO: 116):

[0575] SDHA Forward primer (SEQ ID NO: 173): TGGGAACAAGAGGGCATCTG

[0576] SDHA Reverse primer (SEQ ID NO: 174): CCACCACT GOAT CAAATT CAT G

[0577] SDHA-amplicon (SEQ ID NO: 175):

TGGGAACAAGAGGGCATCTGCTAAAGTrTCAGATTCCATTTCrGCTCAGTAT

CCAGTAGTGGATCATGAATTTGATGCAGTGGTGG

[0578] PBGD (GenBank Accession No. BC019323 (SEQ ID NO: 117)),

[0579] PBGD Forward primer (SEQ ID NO: 176): TG AG AGT GATT CGCGT GGG

[0580] PBGD Reverse primer (SEQ ID NO:177): CCAGGGTACGAGGCTTTCAAT

[0581] PBGD-amplicon (SEQ ID NO:178):

TGAGAGTGATTCGCGTGGGTACCCGCAAGAGCCAGCTTGCTCGCATACAGA

CGGACAGTGTGGTGGCAACATTGAAAGCCTCGTACCCTGG 151 [0582] HPRT1 (GenBank Accession No. NM_000194 (SEQ ID NO:118)),

[0583] HPRT1 Forward primer (SEQ ID NO:179): TGACACTGGCAAAACAATGCA

[0584] HPRT1 Reverse primer (SEQ ID NO: 180): GGTCCTTTTCACCAGCAAGCT

[0585] HPRT1-amplicon (SEQ ID NO:181):

TGACACTGGCAAAACAATGCAGACTTTGCTTTCCrTGGTCAGGCAGTATAA TCC A AAG AT GGTCA AGGTCGCAAGCTTGCTGGTG AA AAGGACC

[0586] G6PD (GenBank Accession No. NM_000402 (SEQ ID NO: 119)) [0587] G6PD Forward primer (SEQ ID NO: 182): gaggccgtcaccaagaacat [0588] G6PD Reverse primer (SEQ ID NO: 183): ggacagccggtcagagctc [0589] G6PD-amplicon (SEQ ID NO: 184): gaggccgtcaccaagaacattcacgagtcctgcatgagccagataggctggaaccgcatcatcgtggagaagcccttc gggagggacctgcagagctetgaccggctgtcc [0590] Ubiquitin (GenBank Accession No. BC000449 (SEQ ID NO: 115))

[0591] Ubiquitin Forward primer (SEQ ID NO: 170): ATTTGGGTCGCGGTTCTTG

[0592] Ubiquitin Reverse primer (SEQ ID NO:171): TGCCTTGACATTCTCGATGGT

[0593] Ubiquitin Amplicon (SEQ ID NO: 172):

ATTTGGGTCGCGGTTCTTGnTGTGGATCGCTGTGATCGTCACTTGACAATGC

AGATCTTCGTGAAGACTCTGACTGGTAAGACCATCACCCTCGAGG

TrGAGCCCAGTGACACCATCGAGAATGTCAAGGCA

[0594] Another methodology used to predict the expression pattern of the proteins of the invention was MED discovery engine: [0595] MED is a platform for collection of public gene-expression data, normalization, annotation and performance of various queries. Expression data from the most widely used Affymetrix microarrays is downloaded from the Gene Expression Omnibus (GEO - www.ncbi.nlm.nih.gov/GEO). Data is multiplicatively normalized by setting the 95 percentile to a constant value (normalized expression=1200), and noise is filtered by setting the lower 30% to 0. Experiments are annotated, first automatically, and then manually, to identify tissue and condition, and chips are grouped according to this annotation, and cross verification of this grouping by comparing the overall expression pattern of the genes of each chip to the overall average expression pattern of the genes in this group. Each probeset in each group is assigned an expression value which is the median of the expressions of that probeset in all chips included in the group. The vector of expression of all probesets within a certain group is the virtual chip of that group, and the collection of all such virtual chips is a virtual panel. The panel (or sub-panels) can be queried to identify probesets with a required behavior (e.g. specific expression in a sub-set of tissues, or differential expression between disease and healthy tissues). These probesets are linked to LEADS contigs and to RefSeqs (http://www.ncbi.nlm.nih.gov/RefSeq/) by probe-level mapping, for further analysis.

[0596] The Affymetrix platforms that are downloaded are HG-U95Aand the HG-U133 family (Α,Β, A2.0 and PLUS 2.0). Than three virtual panels were created: U95 and U133 Plus 2.0, based on the corresponding platforms, and U133 which uses the set of common probesets for HG-U133A, HG-U133A2.0 and HG-U133 PLUS 2.0+.

[0597] The results of the MED discovery engine are presented in scatter plots. The scatter plot is a compact representation of a given panel (collection of groups). The y-axis is the (normalized) expression and the x-axis describes the groups in the panel. For each group, the median expression is represented by a solid marker., and the expression values of the different chips in the group are represented by small dashes ("-"). The groups are ordered and marked as follow® - "Other" groups (e.g. benign, noncancer diseases, etc.) with a triangle, Treated cells with a square, Normal with a circle, Matched with a cross, and Cancer with a 152 diamond. The number of chips in each group is also written adjacent to it's name. EXAMPLE 6 DESCRIPTION FOR CLUSTER H19011_1 [0598] The present invention relates to C10RF32 polypeptides, novel splice variants and diagnostics and therapeutics based thereon.

[0599] Cluster H19011_1 (internal ID 76432827) features 2 transcripts and 5 segments of interest, the names for which are given in Tables 91 and 92, respectively. The selected protein variants are given in table 93.

Table 91 - TranscriDts of interest

[0600] These sequences are variants of the known protein hypothetical protein LOC387597 (RefSeq accession identifier NP_955383 (SEQ ID NO: 47), synonims: C10RF32, NP_955383; LISCH-like;RP4-782G3.2; dJ782G3.1), referred to herein as the previously known protein.

[0601] C1ORF32 is a hypothetical protein that was computationally discovered during the annotation of chromosome 1 (Gregory SG et al. 2006, Nature 441 (7091) 315-321). Its closest annotated homolog belongs to the LISCH7 family, a subfamily of the immunoglobulin super family. One of the annotated members of this family is the lipolysis-stimulated lipoprotein receptor which has a probable role in the clearance of triglyceride-rich lipoprotein from blood (Swissprot annotation of accession Q86X29).

[0602] According to the present invention, C10RF32 was predicted to be a novel B7/CD28 member based on the presence of an IgV domain, in addition of its being a type I membrane protein, like other known B7 members. Also, two alternatively spliced variants (H190111P8 (SEQ ID NO:48) and H190111P9 (SEQ ID NO:50)), which share only the first 5 exons with the wild type C10RF32, are similar to the known B7 family members in their exons' sizes and the position of the IgV and transmembrane domains within these exons. In addition, C10RF32 was shown in the present invention to be overexpressed in small cell lung cancer.

[0603] As noted above, cluster H19011 features 2 transcripts, which were listed in Table 91 above. These transcripts encode for proteins which are variants of protein hypothetical protein LOC387597 (SEQ ID NO:47). A description of each variant protein is now provided.

[0604] Variant protein FU90111P8 (SEQ ID NO:48) has an amino acid sequence as encoded by transcript H19011_1_T8 (SEQ ID NO:45). Alignments to one or more previously published protein sequences are shown in Figure 38A. A brief description of the relationship of the variant protein to each such aligned protein is as follows: [0605] Comparison report between H190111P8 (SEQ ID NO:48) and known proteins Q71H61HUMAN and NP 955383 (SEQ ID NO: 47) (Figure 38A):

[0606] A. An isolated chimeric polypeptide encoding for H19011_1_P8 (SEQ ID NO:48), comprising a first amino acid sequence being at least 90% homologous to MDRVLLRWISLFWLTAMVEG LQVTVPDKKKVAMLF QPTVLRCHF ST SSHQPAV VQWKFKSYCQDRMGESLGMSSTRAQSLSKRNLEWDPYLDCLDSRRTVRWASK QGSTVTLGDFYRGREITIVHDADLQIGKLMWGDSGLYYCIITTPDDLEGKNE corresponding to amino acids 1 - 158 of known proteins Q71H61-HUMAN and NP 955383 (SEQ ID NO: 47), which also corresponds to amino acids 1 - 158 of H19011_1_P8 (SEQ ID NO:48), a bridging amino acid G corresponding to amino acid 159 of H190111P8 (SEQ ID NO:48), a second amino acid sequence being at least 90% homologous to S corresponding to amino acids 160 - 160 of known proteins Q71H61_HUMAN and NP_955383 (SEQ ID NO: 47), which also corresponds to amino acids 160 - 160 of H190111P8 (SEQ ID NO:48), bridging amino acids LG corresponding to amino acid 161 - 162 of H19011_1_P8 (SEQ ID NO:48), a third amino acid sequence being at least 90% homologous to LLVLGRTGLLADLLPSFAVEIMPEWVFVGLVLLGVFLFFVLVGICWCQCCPHSCC CYVRCPCCPDSC corresponding to amino acids 163 - 229 of known proteins Q71H61_HUMAN and NP_955383 (SEQ ID NO: 47), which also corresponds to amino acids 163 - 229 of H190111P8 (SEQ ID NO:48), a bridging amino acid W corresponding to amino acid 230 of H19011_1_P8 (SEQ ID NO:48), a fourth amino acid sequence being at least 90% homologous to CPQA corresponding to amino acids 231 - 234 of known proteins Q71H61HUMAN and NP_955383 (SEQ ID NO: 47), which also corresponds to amino acids 231 - 234 of H19011_1_P8 (SEQ ID NO:48), and a fifth amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95, 96, 97, 98 or 99% homologous to a polypeptide having the sequence CEYSDRWGDRAIERNVYLST (SEQ ID NO: 293) corresponding to amino acids 235 - 254 of H19011_1_P8 (SEQ ID NO:48), wherein said first amino acid sequence, bridging amino acid, second amino acid sequence, bridging amino acid, third amino acid sequence, bridging amino acid, fourth amino acid sequence and fifth amino acid sequence are contiguous and in a sequential order.

[0607] B. An isolated polypeptide encoding for an edge portion of H19011_1_P8 (SEQ ID NO:48), comprising an amino acid sequence being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95, 96, 97, 98 or 99% homologous to the sequence CEYSDRWGDRAIERNVYLST (SEQ ID NO: 293) of H19011_1_P8 (SEQ ID NO:48).

[0608] The localization of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: membrane.

[0609] Variant protein H190111P8 (SEQ ID NO:48) also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 94, (given according to their positions on the amino acid sequence, with the alternative amino acids listed (SEQ ID NO:48)). An example of such a deduced sequence, with alternative amino-acids, that was produced (using part of the SNPs below), is given under the name H19011_1_P8_V1 (SEQ ID NO:49).

Table 94 - Amino acid mutations CMD ΜΑοίίιΛηο am omin/N <m!#l ΡΛ^ΜΛηΛΛ

a AltAm<alSifA ααιλΙα j 154 [0611] Variant protein H19Q111P8 (SEQ ID NO:48) is encoded by the transcript H19011_1_T8 (SEQ ID NO:45), for which the coding portion starts at position 181 and ends at position 942. The transcript also has the following SNPs as listed in Table 96 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed).

Table 96 - Nucleic acid SNPs

[0612] The genomic structure of protein H19011_1_P8 (SEQ ID NO:48) (number of exons relevant to the extra-cellular region of the protein, the length of these exons, the frame of the codon in which the intrans are inserted and the location of the protein features and domains in the gene structure) is characteristic to the ligands of the B7 /co-stimulatory protein family, as given in table 97

[0613] Variant protein H19011_1_P9 (SEQ ID NO:50) has an amino acid sequence as encoded by transcript H190111T9 (SEQ ID NO:46). Alignments to one or more previously published protein sequences are shown in Figure 38B. A brief description of the relationship of the variant protein according to the present invention to each such aligned protein is as follows: [0614] Comparison report between H190111P9 (SEQ ID NO:50) and known proteins Q71H61_HUMAN and NP955383 (SEQ ID NO: 47) (Figure 38B):

[0615] A. An isolated chimeric polypeptide encoding for H19011_1_P9 (SEQ ID NO:50), comprising a first amino acid sequence being at least 90% homologous to MDRVLLRWISLFWLTAMVEGLQVTVPDKKKVAMLFQPTVLRCHFSTSSHQPAV VQWKFKSYCQDRMGESLGMSSTRAQSLSKRNLEWDPYLDCLDSRRTVRWASK QGSTVTLGDFYRGREITIVHDADLQIGKLMWGDSGLYYCIITTPDDLEGKNE corresponding to amino acids 1 - 158 of known proteins Q71H61HUMAN and NP 955383 (SEQ ID NO: 47), which also corresponds to amino acids 1 - 158 of H19011_1_P9 (SEQ ID NO:50), a bridging amino acid G corresponding to amino acid 159 of H19011_1_P9 (SEQ ID NO:50), a second amino acid sequence being at least 90% homologous to S corresponding to amino acids 160 - 160 of known proteins Q71H61_HUMAN and NP 955383 (SEQ ID NO: 47), which also corresponds to amino acids 160 - 160 of H19011_1_P9 (SEQ ID NO:50), bridging amino acids LG corresponding to amino acid 161 - 162 of H190111P9 (SEQ ID NO:50), a third amino acid sequence being at least 90% homologous to LLVL corresponding to amino acids 163 - 166 of known proteins Q71H61_HUMAN and NP_955383 (SEQ ID NO: 47), which also corresponds to amino acids 163 - 166 of H19011_1_P9 (SEQ ID NO:50), a fourth amino acid sequence being at least 90% homologous to EWVFVGLVLLGVFLFFVLVGICWCQCCPHSCCCYVRCPCCPDSC corresponding to amino acids 186 - 229 of known proteins Q71H61HUMAN and NP 955383 (SEQ ID NO: 47), which also corresponds to amino acids 167 - 210 of H19011_1_P9 (SEQ ID NO:50), a bridging amino acid W corresponding to amino acid 211 of H19011_1_P9 (SEQ ID NO:50), a fifth amino acid sequence being at least 90% homologous to CPQA corresponding to amino acids 231 - 234 of known proteins Q71H61HUMAN and NP 955383 (SEQ ID NO: 47), which also corresponds to amino acids 212 - 215 of H190111P9 (SEQ ID NO:50), and a sixth amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95, 96, 97, 98 or 99% homologous to a polypeptide having the sequence CEYSDRWGDRAIERNVYLST (SEQ ID NO: 293) corresponding to amino acids 216 - 235 of H19011_1_P9 (SEQ ID NO:50), wherein said first amino acid sequence, bridging amino acid, second amino acid sequence, bridging amino acid, third 155 amino acid sequence, fourth amino acid sequence, bridging amino acid, fifth amino acid sequence and sixth amino acid sequence are contiguous and in a sequential order.

[0616] B. An isolated chimeric polypeptide encoding for an edge portion of H19011_1_P9 (SEQ ID NO:50), comprising a polypeptide having a length "n", wherein n is at least about 10 amino acids in length, optionally at least about 20 amino acids in length, preferably at least about 30 amino acids in length, more preferably at least about 40 amino acids in length and most preferably at least about 50 amino acids in length, wherein at least two amino acids comprise LE, having a structure as follows: a sequence starting from any of amino acid numbers 166-x to 166; and ending at any of amino acid numbers 167 + ((n-2) - x), in which x varies from 0 to n-2.

[0617] C. An isolated polypeptide encoding for an edge portion of H19011_1_P9 (SEQ ID NO:50), comprising an amino acid sequence being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95, 96, 97, 98 or 99% homologous to the sequence CEYSDRWGDRAIERNVYLST (SEQ ID NO: 293) of H19011_1_P9 (SEQ ID NO:50).

[0618] The localization of the variant protein was determined according to results from a number of different software programs and analyses, including analyses from SignalP and other specialized programs. The variant protein is believed to be located as follows with regard to the cell: membrane.

[0619] Variant protein H19011_1_P9 (SEQ ID NO:50) also has the following non-silent SNPs (Single Nucleotide Polymorphisms) as listed in Table 98, (given according to their positions on the amino acid sequence, with the alternative amino acids listed (SEQ ID NO:50)).

Table 98 - Amino acid mutations

[0620] Variant protein H190111P9 (SEQ ID NO:50) is encoded by the transcript H190111T9 (SEQ ID NO:46), for which the coding portion starts at position 181 and ends at position 885. The transcript also has the following SNPs as listed in Table 99 (given according to their position on the nucleotide sequence, with the alternative nucleic acid listed).

Table 99 - Nucleic acid SNPs

[0621] As noted above, cluster H19011 features 5 segments, which were listed in Table 92 above. These segments are portions of nucleic acid sequences wfnich are described herein separately because they are of particular interest. A description of each segment is now provided.

[0622] Segment cluster H190111N13 (SEQ ID NO:129) is supported by 3 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcripts: H190111T8 (SEQ ID NO:45) and H190111T9 (SEQ ID NO:46). Table 100 below describes the starting and ending position of this segment on each transcript.

Table 100 - Segment location on transcripts 156

[0623] short segments related to the above cluster are also provided. These segments are up to about 120 bp in length, and so are included in a separate description.

[0624] Segment cluster H19011_1_N8 (SEQ ID NO:130) is supported by 4 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcripts: H19011_1_T8 (SEQ ID NO:45). Table 101 below describes the starting and ending position of this segment on each transcript.

Table 101 - Segment location on transcripts

[0625] Segment cluster H19011_1_N10 (SEQ ID NO: 131) is supported by 5 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcripts: H19011_1_T8 (SEQ ID NO:45) and H19011_1_T9 (SEQ ID NO:46). Table 102 below describes the starting and ending position of this segment on each transcript.

Table 102 - Segment location on transcripts

[0626] Segment cluster H19011_1_N11 (SEQ ID NO:132) is supported by 3 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcripts: H19011_1_T8 (SEQ ID NO:45) and H19011_1_T9 (SEQ ID NO:46). Table 103 below describes the starting and ending position of this segment on each transcript.

Table 103 - Segment location on transcripts

[0627] Segment cluster H19011_1_N12 (SEQ ID NO:133) is supported by 5 libraries. The number of libraries was determined as previously described. This segment can be found in the following transcripts: H19011_1_T8 (SEQ ID NO:45) and H19011_1_T9 (SEQ ID NO:46). Table 104 below describes the starting and ending position of this segment on each transcript.

Table 104 - Segment location on transcripts

TransnriDt name i Sea ment startina Dosition ISenment enrlinn nosition

[0628] Expression of C10RF32, chromosome 1 open reading frame 32, H19011 transcripts which are detectable by amplicon as depicted in sequence name H19011_seg13F2R2 (SEQ ID NO: 235) in normal and cancerous Colon tissues, in normal and cancerous Lung tissues and in different normal tissues [0629] Expression of C10RF32, chromosome 1 open reading frame 32, transcripts detectable by or according to seg13 -H19011_seg13F2R2 (SEQ ID NO: 235) amplicon and primers H19011_seg13F2 (SEQ ID NO: 233) and H19011_seg13R2 (SEQ ID NO: 234) was measured by real time PCR on colon panel, lung panel and normal panel. The samples used are detailed in Table 5, Table 3 and Table 2 above, respectively. For each RT sample, the expression of the above amplicon was normalized to the normalization factor calculated from the expression of several house keeping genes as described in Example 1. 157 [0630] Colon panel - The normalized quantity of each RT sample was then divided by the median of the quantities of the normal samples (sample numbers 42-70, Table 5 above). Then the reciprocal of this ratio was calculated, to obtain a value of fold down-regulation for each sample relative to median of the normal samples.

[0631] Figure 39 is a histogram showing down regulation of the above-indicated C10RF32 transcripts in cancerous Colon samples relative to the normal samples.

[0632] As is evident from Figure 39, the expression of C10RF32 transcripts detectable by the above amplicon in cancer samples was significantly lower than in the non-cancerous samples (sample numbers 42-70, Table 5 above). Notably down regulation of at least 6 fold was found in 17 out of 55 adenocarcinoma samples.

[0633] Statistical analysis was applied to verify the significance of these results, as described below. The P value for the difference in the expression levels of C10RF32 transcripts detectable by the above amplicon in Colon cancer samples versus the normal tissue samples was determined by T test as 9.36e-004.

[0634] Threshold of 6 fold down regulation was found to differentiate between cancer and normal samples with P value of 2.67e-004 as checked by exact Fisher test.

[0635] The above values demonstrate statistical significance of the results.

[0636] Lung panel - The normalized quantity of each RT sample was then divided by the median of the quantities of the normal samples (sample numbers 51-64 and 69-70, Table 3 above), to obtain a value of fold up-regulation for each sample relative to median of the normal samples.

[0637] Figure 40 is a histogram showing over expression of the above-indicated C10RF32 transcripts in cancerous Lung samples relative to the normal samples.

[0638] As is evident from Figure 40, the expression of C10RF32 transcripts detectable by the above amplicon in small cell carcinoma samples was significantly higher than in the non-cancerous samples (sample numbers 51-64 and 69-70, Table 3 above). Notably an over-expression of at least 6 fold was found in 9 out of 9 small cell carcinoma samples.

[0639] Statistical analysis was applied to verify the significance of these results, as described below.

[0640] The P value for the difference in the expression levels of C10RF32 transcripts detectable by the above amplicon in Lung small cell carcinoma samples versus the normal tissue samples was determined by T test as 3.43e-003.

[0641] Threshold of 6 fold over expression was found to differentiate between small cell carcinoma and normal samples wth P value of 4.89e-007 as checked by exact Fisher test.

[0642] The above values demonstrate statistical significance of the results.

[0643] Normal panel -The normalized quantity of each RT sample was then divided by the median of the quantities of the colon samples (sample numbers 3, 4 and 5, Table 2 above), to obtain a value of relative expression of each sample relative to median of the colon samples, as shown in Figure 41 A. The normalized quantity of each RT sample was then divided by the median of the quantities of the lung samples (sample numbers 26, 28, 29 and 30, Table 2 above), to obtain a value of relative expression of each sample relative to median of the lung samples, as shown in figure 41B.

[0644] for the above experiment, the following primer pair was used as a non-limiting illustrative example only of a suitable primer pair: H19011_seg13F2 (SEQ ID NO: 233) forward primer; and H19011_seg13R2 (SEQ ID NO: 234) reverse primer.

[0645] For the above experiment, the following amplicon was obtained as a non-limiting illustrative example only of a suitable amplicon: H19011_seg13F2R2 (SEQ ID NO: 235).

[0646] Forward Primer >H19011_seg13F2 (SEQ ID NO: 233): GTGAGTACAGTGACCGCTGGG

[0647] Reverse Primer >1-119011_seg13R2 (SEQ ID NO: 234):GGAGAAGAGTCTGGAATGACCAA

[0648] Amplicon >H19011_seg13F2R2 (SEQ ID NO: 235)

GTGAGTACAGTGACCGCTGGGGAGACAGAGCGATCGAGAGAAAT

GTCTACCTCTCTACCTGACAGCTGTGTGCGCTGGGTTCCTCCTCCACCTCCTG

TCCTGCCACCCCCAAGATTGGTCATTCCAGACTCrrCTCC

[0649] Expression of C1ORF32, chromosome 1 open reading frame 32, H19011 transcripts which are detectable by amplicon as depicted in sequence name H19011_seg8-13F1R1 (SEQ ID NO: 238) in normal and cancerous Lung tissues [0650] Expression of C10RF32, chromosome 1 open reading frame 32, transcripts detectable by or according to seg8-13F1R1 - H19011_seg8-13F1R1 (SEQ ID NO: 238) amplicon and primers H19011_seg8-13F1 (SEQ ID NO: 236) and H19011_seg8-13R1 (SEQ ID NO: 237) was measured by real time PCR on lung panel. The samples used are detailed in Table 3 above. Samples that showed no detection of the amplicon (samples no. 1,2, 4-10, 12-27, 29-35, 37-41, 51-64 and 69-70, Table 3) were assigned Ct value of 41 and were calculated accordingly. These samples showed a primer-dimer product with a characteristic dissociation curve and a significantly lower TM (this artefactual product was identified by its appearance in the negative control without RT sample). For each RT sample, the expression of the above amplicon was normalized to the normalization factor calculated from the expression of several house keeping genes as described in Example 1. The normalized quantity of each RT sample was then divided by the median of the quantities of the normal samples (sample numbers 51-64 and 69-70, Table 3 above), to obtain a value of fold up-regulation for each sample relative to median of the normal samples.

[0651] Figure 42 is a histogram showing over expression of the above-indicated C10RF32 transcripts in cancerous Lung samples relative to the normal samples.

[0652] As is evident from Figure 42, the expression of C10RF32 transcripts detectable by the above amplicon in small cell carcinoma samples was significantly higher than in the non-cancerous samples (sample numbers 51-64 and 69-70, Table 3 above). Notably an over-expression of at least 500 fold was found in 9 out of 9 small cell carcinoma samples.

[0653] Statistical analysis was applied to verify the significance of these results, as described below. The P value for the difference in the expression levels of C10RF32 transcripts detectable by the above amplicon in Lung small cell carcinoma samples versus the normal tissue samples was determined by T test as 6.70e-003.

[0654] Threshold of 500 fold over expression was found to differentiate between small cell carcinoma and normal samples with P value of 4.89e-007 as checked by exact Fisher test.

[0655] The above values demonstrate statistical significance of the results.

[0656] For the above experiment, the following primer pair was used as a non-limiting illustrative example only of a suitable primer pair: H19011_seg8-13F1 (SEQ ID NO: 236) forward primer; and H19011_seg8-13R1 (SEQ ID NO: 237) reverse primer.

[0657] For the above experiment, the following amplicon was obtained as a non-limiting illustrative example only of a suitable amplicon: H19011_seg8-13F1R1 (SEQ ID NO: 238).

[0658] Forward Primer >H19011_seg8-13F1 (SEQ ID NO: 236):GCCCAGTTTTGCTGTGGAGA

[0659] Reverse Primer >H19011_seg8-13R1 (SEQ ID NO: 237):GGTAGACATTTCTCTCGATCGCTC

[0660] Amplicon >H19011_seg8-13F1R1 (SEQ ID NO: 238)

GCCCAGTTTTGCTGTGGAGATTATGCCAGAGTGGGTGTTTGTTGGC

CTGGTGCTCCTGGGCGTCTTCCTCTTCTTCGTCCTGGTGGGGATCTGCTGGTG

CCAGTGCTGCCCTCACAGCTGCTGCTGCTATGTCCGCTGCCCATGCTGCCCA

GATTCCTGCTGGTGCCCTCAAGCCTGTGAGTACAGTGACCGCTGGGGAGAC

AGAGCGATCGAGAGAAATGTCTACC

[0661] Expression of C1ORF32, chromosome 1 open reading frame 32, H19011 transcripts which are detectable by amplicon as depicted in sequence name FI19011-junc8-10seg13 (SEQ ID NO: 241) in normal and cancerous lung tissues, in normal and cancerous colon tissues, in different normal tissues and in the blood-specific panel.

[0662] Expression of C10RF32 transcripts detectable by or according to junc8-10seg13 - H19011Junc8-10seg13 (SEQ ID NO: 241) amplicon and primers H19011 Junc8-10seg13F1 (SEQ ID NO: 239) and H19011_junc8-10seg13R1 (SEQ ID NO: 240) was measured by real time PCR lung panel, colon panel, normal panel and blood panel. The samples used are detailed in Table 3, Table 5, Table 2 and Table 1 above, respectively. For each RT sample, the expression of the above amplicon was normalized to the normalization factor calculated from the expression of several house keeping genes as described in Example 1.

[0663] For lung panel- Non-detected sample (sample no. 69, Table 3) was assigned Ct value of 41 and was calculated accordingly. The normalized quantity of each RT sample was then divided by the median of the quantities of the normal samples (sample numbers 51, 53, 54, 56, 57, 59, 61, 62, 64 and 70, Table 3 above), to obtain a value of fold up-regulation for each sample relative to median of the normal samples.

[0664] Figure 43 is a histogram showing over expression of the above-indicated C10RF3 transcripts in cancerous Lung samples relative to the normal samples.

[0665] As is evident from Figure 43, the expression of C10RF32 transcripts detectable by the above amplicon in small cell carcinoma samples was significantly higher than in the non-cancerous samples (sample numbers 51, 53, 54, 56, 57, 59, 61, 62, 64 and 70, Table 3 above). Notably an over-expression of at least 7 fold was found in 9 out of 9 small cell carcinoma samples.

[0666] Statistical analysis was applied to verify the significance of these results, as described below.

[0667] The P value for the difference in the expression levels of C10RF32 transcripts detectable by the above amplicon in Lung small cell carcinoma samples versus the normal tissue samples was determined by T test as 2.34e-003.

[0668] Threshold of 7 fold over expression was found to differentiate between small cell carcinoma and normal samples with P value of 1,08e-005 as checked by exact Fisher test.

[0669] The above values demonstrate statistical significance of the results.

[0670] For colon panel- Non-detected sample (sample no. 79, Table 5) was assigned Ct value of 41 and was calculated accordingly. The normalized quantity of each RT sample was then divided by the median of the quantities of the normal samples (sample numbers 42-62 and 65-70, Table 5 above). Then the reciprocal of this ratio was calculated, to obtain a value of fold down-regulation for each sample relative to median of the normal samples.

[0671] Figure 44 is a histogram showing down regulation of the above-indicated C10RF32 transcripts in cancerous colon samples relative to the normal samples.

[0672] As is evident from Figure 44, the expression of C10RF32 transcripts detectable by the above amplicon in cancer samples was significantly lower than in the non-cancerous samples (sample numbers 42-62 and 65-70, Table 5 above). Notably down regulation of at least 5 fold was found in 15 out of 36 adenocarcinoma samples.

[0673] Statistical analysis was applied to verify the significance of these results, as described below. Threshold of 5 fold down regulation was found to differentiate between cancer and normal samples with P value of 4.29e-004 as checked by exact Fisher test.

[0674] The above values demonstrate statistical significance of the results.

[0675] For normal panel- Non-detected samples (samples no. 42 and 49, Table 2) were assigned Ct value of 41 and were calculated accordingly. The normalized quantity of each RT sample was then divided by the median of the quantities of the colon samples (sample numbers 4 and 5, Table 2 above), to obtain a value of relative expression of each sample relative to median of the colon samples, as shown in Figure 45A. The normalized quantity of each RT sample was then divided by the median of the quantities of the lung samples (sample numbers 26, 29 and 30, Table 2 above), to obtain a value of relative expression of each sample relative to median of the lung samples, as shown in Figure 45B.

[0676] For blood panel- The normalized quantity of each RT sample was then divided by the median of the quantities of the kidney normal samples (sample numbers 65-67, Table 1 above), to obtain a value of relative expression of each sample relative to median of the kidney normal samples.

[0677] The results of this analysis are depicted in the histogram in Figure 46. Expression of the above-indicated C10RF32 transcript is high in one lymphoma sammple (sample no. 33, Table 1) but in normal brain sample too.

[0678] For the above experiment, the following primer pair was used as a non-limiting illustrative example only of a suitable primer pair: H19011_junc8-10seg13F1 (SEQ ID NO: 239) forward primer; and H19011 Junc8-10seg13R1 (SEQ ID NO: 240) reverse primer.

[0679] For the above experiment, the following amplicon was obtained as a non-limiting illustrative example only of a suitable amplicon: H19011Junc8-10seg13F1R1 (SEQ ID NO: 241).

[0680] Forward Primer >H19011Junc8-10seg13F1 (SEQ ID NO: 239)

[0681] TGTGGAGATTATGCCAGAGTGG

[0682] Reverse Primer >1-119011 Junc8-10seg13R1 (SEQ ID NO: 240)

[0683] GACATTT CTCTCGATCG CTCTGT

[0684] Amplicon >H19011Junc8-10seg13F1R1 (SEQ ID NO: 241)

TGTGGAGATTATGCCAGAGTGGGTGTTTGTTGGCCTGGTGCTCCTG

GGCGTCTTCCTCTTCTTCGTCCTGGTGGGGATCTGCTGGTGCCAGTGCTGCCC

TCACAGCTGCTGCTGCTATGTCCGCTGCCCATGCTGCCCAGATTCCTGCTGG

TGCCCTCAAGCCTGTGAGTACAGTGACCGCTGGGGAGACAGAGCGATCGA

GAGAAATGTC

[0685] Expression of C10RF32, chromosome 1 open reading frame 32, H19011 transcripts which are detectable by amplicon as depicted in sequence name H19011Junc6-10 (SEQ ID NO: 244) in normal and cancerous lung tissues and in normal and cancerous Colon tissues [0686] Expression of C10RF32 transcripts detectable by or according to junc6-10 - H19011_junc6-10F1R1 (SEQ ID NO: 244) amplicon and primers H19011Junc6-10F1 (SEQ ID NO: 242) and H19011 Junc6-10R1 (SEQ ID NO: 243) was measured by real time PCR on lung panel and colon panel. The samples used are detailed in Table 3 and Table 5 above, respectively. For each RT sample, the expression of the above amplicon was normalized to the normalization factor calculated from the expression of several house keeping genes as described in Example 1.

[0687] Lung panel- The normalized quantity of each RT sample was then divided by the median of the quantities of the normal samples (sample numbers 51-64, 69 and 70, Table 3 above). Then the reciprocal of this ratio was calculated, to obtain a value of fold down-regulation for each sample relative to median of the normal samples.

[0688] Figure 47 is a histogram showing down regulation of the above-indicated C10RF32 transcripts in cancerous Lung samples relative to the normal samples.

[0689] As is evident from Figure 47, the expression of C10RF32 transcripts detectable by the above amplicon in non-small cell carcinoma samples, adenocarcinoma and squamous cell carcinoma was significantly lower than in the non-cancerous samples (sample numbers 51-64, 69 and 70, Table 3 above). Notably down regulation of at least 5 fold was found in 23 out of 39 nonsmall cell carcinoma samples especially in 8 out of 17 adenocarcinoma samples and in 12 out of 16 squamous cell carcinoma samples.

[0690] Statistical analysis was applied to verify the significance of these results, as described below. The P value for the difference in the expression levels of C10RF32 transcripts detectable by the above amplicon lung non-small cell carcinoma, lung adenocarcinoma and lung squamous cell carcinoma samples, versus the normal tissue samples was determined by T test as 1.18e-003, 2.87e-002 and 3.55e-004, respectively.

[0691] Threshold of 5 fold down regulation was found to differentiate between lung non-small cell carcinoma, lung adenocarcinoma and lung squamous cell carcinoma samples and normal samples with P value of 1.59e-003, 3.54e-002 and 4.78e-004, respectively, as checked by exact Fisher test.

[0692] The above values demonstrate statistical significance of the results.

[0693] Colon panel- The normalized quantity of each RT sample was then divided by the median of the quantities of the normal samples (sample numbers 42-70, Table 5 above). Then the reciprocal of this ratio was calculated, to obtain a value of fold down-regulation for each sample relative to median of the normal samples.

[0694] Figure 48 is a histogram showing down regulation of the above-indicated C10RF32 transcripts in cancerous Colon samples relative to the normal samples.

[0695] As is evident from Figure 48, the expression of C10RF32 transcripts detectable by the above amplicon in cancer samples was significantly lower than in the non-cancerous samples (sample numbers 42-70, Table 5 above). Notably down regulation of at least 9 fold was found in 23 out of 55 adenocarcinoma samples.

[0696] Statistical analysis was applied to verify the significance of these results, as described below.

[0697] Threshold of 9 fold down regulation was found to differentiate between cancer and normal samples with P value of 7.39e-006 as checked by exact Fisher test.

[0698] The above values demonstrate statistical significance of the results.

[0699] For the above experiment, the following primer pair was used as a non-limiting illustrative example only of a suitable primer pair: H19011Junc6-10F1 (SEQ ID NO: 242) forward primer; and H19011Junc6-10R1 (SEQ ID NO: 243) reverse primer.

[0700] For the above experiment, the following amplicon was obtained as a non-limiting illustrative example only of a suitable amplicon: H19011Junc6-10F1R1 (SEQ ID NO: 244).

[0701] Forward Primer >H19011Junc6-10F1 (SEQ ID NO: 242)

[0702] ACT CT ATT ACT GT ATT AT CACCACCCCAG

[0703] Reverse Primer >1-119011Junc6-10R1 (SEQ ID NO: 243)

[0704] CCCAACAAACACCCACTCCAAC

[0705] Amplicon >H19011Junc6-10F1R1 (SEQ ID NO: 244)

ACTCTATTACTGTATTATCACCACCCCAGATGACCTGGAGGGGAA AAATGAGGGCTCACTGGGACTGCTGGTGTTGGAGTGGGTGTTTGTTGG EXAMPLE 8

CLONING OF FULL LENGTH TRANSCRIPTS ENCODING VSIG1, ILDR1, LOC253012, AI216611, C10RF32, FXYD3 FUSED TO EGFP

[0706] Cloning of Full Length transcripts encoding VSIG1, ILDR1, LOC253012, AI216611, C10RF32, FXYD3 fused to EGFP was done as described below.

[0707] First, EGFP expression vector was constructed and then the VSIG1, ILDR1, LOC253012, AI216611, C10RF32 or FXYD3 open reading frames (ORFs) were cloned. EGFP was subcloned into plRESpuro3 (Clontech catalog number: 631619) as follows: EGFP-N1 vector (Clontech cataloge number: 6085-1) was digested with Nhel and Notl to excise the EGFP gene. The EGFP insert was then ligated into plRESpuro3 (Clontech cataloge number: 631619), which was previously digested with the same enzymes, in order to obtain the EGFP-plRESpuro3 vector.

[0708] Cloning of the VSIG1, ILDR1, LOC253012, AI216611, C10RF32, FXYD3 open reading frames (ORFs) was done using the following steps: [0709] 1. A reverse transcription reaction was carried out as follows: 10pg of purified RNA was mixed with 150ng Random Hexamer primers (Invitrogen, Carlsbad, CA, USA, catalog number: 48190-011) and 500μΜ dNTPs in a total volume of 156μΙ. The mixture was incubated for 5 min at 65dC and then quickly chilled on ice. Thereafter, 50d of 5X Superscriptll first strand buffer (Invitrogen, catalog number: 18064-014, part number: Y00146), 24μΙ 0.1 M DTT and 400 units RNasin (Promega, Milwaukee, WS, U.S.A., catalog number: N2511) were added, and the mixture was incubated for 10 min at 25dC, followed by further incubation at 42dC for 2 min. Then, 10μΙ (2000 units) of Superscriptll (Invitrogen, catalog number: 18064-014) was added and the reaction (final volume of 250μΙ) was incubated for 50 min at 42dC and then inactivated at 70pC for 15min. The resulting cDNAwas diluted 1:20 in TE buffer (10mM Tris, 1 mM EDTA pH 8).

[0710] 2. PCR was done using Platinum PFX™ (Invitrogen., Carlsbad, CA, USA, catalog number: 1178-021) under the following conditions: 5μΙ Platinum PFX 10x buffer; 5 μΙ - cDNAfrom the above; 2μΙ - 10 mM dNTPs (2.5mM of each nucleotide); 0.5μΙ -Platinum PFX enzyme; 37 μΙ - H20; and 1.5μΙ - of each primer (15μΜ) in a total reaction volume of 50μΙ; with a reaction program of 5 minutes in 95°C; 35 cycles of: 30 seconds at 94°C, 30 seconds at 55°C, 50 seconds at 68°C; then 10 minutes at 68°C. Primers which were used include gene specific sequences corresponding to the desired coordinates of the protein and restriction enzyme sites and Kozak sequence, as listed in table 136, below. Bold letters in Table 136 represent the specific gene sequence while the restriction site extensions utilized for cloning purposes are in Italic and kozak sequences are underlined.

[0711] Table 136 demonstartes the cloning steps of ORF targets. For example, FXYD3_T25_P14 and VSIG1_T6_P5 were cloned by PCR amplification of two overlapping fragments of the full length at step 1, followed by additional PCR at step 2 using both PCR fragments from step 1 as a template for generating the full length. VSIG1_T5_P4 was cloned using both PCR fragments generated at step 1 for digestion and direct ligation, AI216611 _T 1 _P1 was cloned by performing nested PCR on the PCR product generated from step 1. 5μΙ of products No.1,4,5,8,9,10,11,12,15,16 and 17 (Table 136), were loaded onto a 1 % agarose gel stained with ethidium bromide, electrophoresed in 1xTBE solution at 100V, and visualized with UV light. After verification of expected size band, remaining PCR product was processed for DNA purification using Qiaquick PCR purification kit (Qiagen™, Valencia, CA, U.S.A., catalog number 28106). The extracted PCR products were digested with the appropriate restriction enzymes (New England Biolabs, Beverly, MA, U.S.A.), as listed in table 136. After digestion, DNAs were loaded onto a 1 % agarose gel as described above. The expected band size was excised and extracted from the gel using QiaQuick™ Gel Extraction kit (Qiagen, catalog number: 28707).

[0712] The digested targets' ORF DNAs were ligated to EGFP_plRESpuro3 vector using the LigaFastTM Rapid DNA Ligation System (Promega, catalog number: M8221 ). The resulting DNAs were transformed into competent E.Coli bacteria DH5a (RBC Bioscience, Taipei, Taiwan, catalog number: RPI816) according to manufacturer's instructions, then plated on LB-ampicillin agar plates for selection of recombinant plasmids, and incubated overnight at 37°C.

[0713] The following day, a number of colonies from each transformation that grew on the selective plates were taken for further analysis by streak-plating on another selective plate and by PCR using GoTaq ReadyMix (Promega, catalog number: M7122.). Screening positive clones was performed by PCR using plRESpuro3 vector specific primer and gene specific primer (data not shown). After completion of all PCR cycles, half of the reaction was analyzed using 1 % agarose gel as described above. After verification of expected size band, 2 positive colonies from each ligation reactions were grown in 5 ml Terrific Broth supplemented with 100pg/ml ampicillin, with shaking overnight at 37°C. Plasmid DNA was isolated from bacterial cultures using Qiaprep™ Spin Miniprep Kit (Qiagen, catalog number: 27106). Accurate cloning was verified by sequencing the inserts (Weizmann Institute, Rehovot, Israel). Upon verification of an error-free colony (i.e. no mutations within the ORF), recombinant plasmids were processed for further analysises.

[0714] The DNA sequences of the resulting VSIG1, ILDR1, LOC253012, AI216611, C10RF32 or FXYD3 full length fused to EGFP are shown in Figures 56A-J. In Figures 56A-J gene specific sequence correspond to the target's full length sequence is marked in bold faced, EGFP sequence is unbold Italic and known SNPs/silence mutations are underlined. Figure 56A presents the DNA sequence of FXYD3_T0_P0_EGFP (996bp)(SEQ ID NO:77); Figure 56B presents the DNA sequence of FXYD3_T25_P 14_EGFP (1083bp) (SEQ ID NO:78); Figure 56C presents the DNA sequence of AI216611_T0_P0_EGFP (1371 bp) (SEQ ID NO:79); Figure 56D presents the DNA sequence of AI216611_T1_P1_EGFP (1332bp) (SEQ ID NO:80); Figure 56E presents the DNA sequence of C10RF32_T8_P8_EGFP (1533bp) (SEQ ID NO:81); Figure 56F presents the DNA sequence of LOC253012_T4 P5 EGFP (2085bp) (SEQ ID NO:82); Figure 56G presents the DNA sequence of ILDR1_T0_P3_EGFP DNA sequence (2373bp) (SEQ ID NO:83); Figure 56H presents the DNA sequence of ILDR1_T2_P5_EGFP (2241bp) (SEQ ID NO:84); Figure 56I presents the DNA sequence of VSIG1T6P5EGFP (2082bp) (SEQ ID NO:85); Figure 56J presents the DNA sequence of VSIG1_T5_P4_EGFP DNA (2004bp) (SEQ ID NO:86).

[0715] The amino acid sequences of the resulting VSIG1, ILDR1, LOC253012, AI216611, C1QRF32 or FXYD3 full length fused to EGFP are show) in Figure 57A-J; gene specific sequence correspond to the full length sequence of the protein is marked in bold faced, EGFP sequence is unbold Italic and amino acids modified due to known SNPs are underlined. Figure 57A presents the amino acid sequence of FXYD3 PO EGFP protein (331aa) (SEQ ID NO:87); Figure 57B presents the amino acid sequence of FXYD3_P14_EGFP protein (360aa) (SEQ ID NO:88); Figure 57C presents the amino acid sequence of AI216611P0 EGFP protein (456aa) (SEQ ID NO:89); Figure 57D presents the amino acid sequence of AI216611_P1_EGFP protein (443aa) (SEQ ID NO:90); Figure 57E presents the amino acid sequence of C10RF32 P8 EGFP protein (510aa) (SEQ ID NO:91); Figure 57F presents the amino acid sequence of LOC253012 P5 EGFP protein (694aa) (SEQ ID NO:92); Figure 57G presents the amino acid sequence of ILDR1_P3_EGFP protein (790aa) (SEQ ID NO:93); Figure 57H presents the amino acid sequence of ILDR1_ P5_EGFP protein (746aa) (SEQ ID NO:94); Figure 57I presents the amino acid sequence of VSIG1_ P5_EGFP protein (693aa) (SEQ ID NO:95); Figure 57J presents the amino acid sequence of VSIG1_ P4 EGFP protein (667aa) (SEQ ID NO:96).

Table 136: full length cloning details__

166

167 : Γ'Γ'Πκι 1 τ«^«Λι. ΙΤ..Μ mr*D πκιλ

ιγ\ EXAMPLE 9 DETERMINING CELL LOCALIZATION OF VSIG1, ILDR1, LOC253012, AI216611, C10RF32 AND FXYD3 [0716] In order to determine the cellular localization of the protein targets, they were cloned as EGFP (Enhanced Green Fluorescent Protein) fusion proteins. Proteins localization was observed upon transient transfection (Chen et al., Molecular vision 2002; 8; 372-388) using the confocal microscope. The cells were observed for the presence of fluorescent products 48 hours following transfection.

[0717] Determining cell localization of VSIG1, ILDR1, LOC253012, AI216611, C10RF32 and FXYD3 was done by transient transfection of the recombinant ORF-EGFP constructs which were described above.

[0718] The VSIC1, ILDR1, LOC253012, AI216611, C10RF32 and FXYD3-EGFP plRESpuro3 constructs were subsequently transiently transfected into HEK-293T cells as follows: [0719] HEK-293T (ATCC, CRL-11268) cells were plated on sterile glass coverslips, 13mm diameter (Marienfeld, catalog number: 01 115 30), which were placed in a 6 well plate, using 2ml pre-warmed DMEM [Dulbecco's modified Eagle's Media, Biological Industries (Beit Ha'Emek, Israel), cataloge number: 01-055-1A] + 10% FBS (Fetal Bovin Serum) + 4mM L-Glutamine. 500,000 cells per well were transfected with 2pg of the DNA construct using 6μΙ FuGENE 6 reagent (Roche, catalog number: 11-814-443- 001) diluted into 94ul DMEM. The mixture was incubated at room temperature for 15 minutes. The complex mixture was added dropwise to the cells and swirled. Cells were placed in incubator maintained at 37°C with 5% C02 content.

[0720] 48 hours post transient transfection the cells were further processed for analysis in confocal microscopy. The cover slips were washed 3 times in phosphate buffered saline (PBS) and fixed for 15 minutes with 3.7% or 1% paraformaldehyde (PFA) (Sigma, catalog number: P-6148). After 2 washes in PBS, the fixed coverslips were glued to a slide using mounting solution (Sigma, catalog number: G0918) and cells were observed for the presence of fluorescent product using confocal microscope. The results are presented in Figure 58A-F.

[0721] Figure 58A demonstrates that the AI216611_P0_EGFP (SEQ ID NO:89) and AI216611_P1_EGFP (SEQ ID NO:90) fused proteins localizes to cell membrane upon expression in HEK 293T cells. The image was obtained using the 40x objective of the confocal microscope.

[0722] Figure 58B demonstrates that the FXYD3P0EGFP (SEQ ID NO:87) and FXYD3_P14_EGFP (SEQ ID NO:88) fused proteins localizes to cell membrane upon expression in HEK 293T cells. The image was obtained using the 40x objective of the confocal microscope.

[0723] Figure 58C demonstrates that the C10RF32 P8 EGFP (SEQ ID NO:91) fused protein localizes to cell membrane; endoplasmatic reticulum (ER) membrane and to cell junctions upon expression in HEK 293T cells. The image was obtained using the 40x objective of the confocal microscope.

[0724] Figure 58D demonstrates that the LOC253012_P5_EGFP(SEQ ID NO:92) fused protein localizes to cell membrane and 168 endoplasmatic reticulum (ER) membrane upon expression in HEK 293T cells. The image was obtained using the 40x objective of the confocal microscope.

[0725] Figure 58E demonstrates that the VSIG1 _P5_EGFP (SEQ ID NO:95) and VSIG1- _P4 EGFP (SEQ ID NO:96) fused proteins localizes to nuclear cell membrane and endoplasmatic reticulum membrane upon expression in HEK 293T cells. The image was obtained using the 40x objective of the confocal microscope.

[0726] Figure 58F demonstrates that the ILDR1 _P3_EGFP (SEQ ID NO:93) and ILDR1_P5_EGFP (SEQ ID NO:94) fused proteins localizes to cell membrane and endoplasmatic reticulum membrane upon expression in HEK 293T cells. The image was obtained using the 40x objective of the confocal microscope. EXAMPLE 10

CLONING AND EXPRESSION OF VSIG1, ILDR1, LOC253012, AI216611, C10RF32 AND FXYD3 EXTRACELLULAR DOMAIN (ECD) FUSED TO MOUSE FC

[0727] The purpose of this analysis was to clone the VSIG1, ILDR1, LOC253012, AI216611, C10RF32 and FXYD3 ECDs fused via its corresponding C terminus to mouse Fc (mFc), and to express the fused ECDs in HEK293T cells (ATCC- CRL-11268), in order to be further used for antibody production as well as for functional assessment of VSIG1, ILDR1, LOC253012, AI216611, C10RF32 and FXYD3 ECDs.

[0728] The coordinates of the cloned ECD are described in table 137:

Table 137:

[0729] The cloning of the fusion proteins (ECDjmFc) was done in two steps: 1. 1. Cloning of ECD to plRESpuro3. 2. 2. Subcloning of the mouse Fc lgG2a in frame to the C terminus of the ECD previously cloned into plRESpuro3, from stepl [0730] The cloning of ECD to plRESpuro3 was carried out as follows: [0731] Cloning of the ECD for each one of the VSIG1, ILDR1, LOC253012, AI216611, C10RF32 and FXYD3 was done by PCR delimit partial amino acids sequence of its ECD as described in table 137, using its full length sequence as a template, and primers as listed in table 138.

Table 138: ECD cloning details

I

I

[0732] In Table 138, above the bold letters represent the gene specific sequence while the restriction site extensions utilized for cloning purposes are Italic and Kozak sequence is underlined.

[0733] The PCR products were purified and digested with the appropriate restriction enzymes as describe in table 138. PCR products for FXYD3, AI216611, C10RF32 and LOC253012 were ligated into plRESpuro3, while PCR products for VSIG1 and ILDR1 were ligated into IL6sp_plRESpuro3 in order to increase their secretion. The ligation mixture was transformed into DH5a competent cells. Positive transformants were screened and verified by DNA sequencing.

Cloning of ECD-mFc plRESpuro3 [0734] Mouse Fc (lgG2a) (Accession- CAA49868 aa 237-469) protein sequence followed by TEV cleavage site sequence was codon optimized to boost protein expression in mammalian system. The optimized sequence was synthesized by GeneArt (Germany) with flanking BamHI restriction site at the Ν' terminus and Notl restriction site at the C terminus. The DNA fragment was digested with BamHI/Notl and ligated in frame into ECD_plRESpuro3 constructs previously digested with the same enzymes to give ECD_mFc_plRESpuro3. The ligation mixture was transformed into DH5a competent cells. Positive transformants were screened and verified by DNA sequencing.

[0735] The nucleotide sequences of the resulting ECDjnFc ORFs are shown in Figure 59A-F: gene specific sequence correspond to the ECD sequence is marked in bold faced, TEV cleavage site sequence is underlined, mFc sequence is unbold Italic and IL6sp sequence is bold Italic. Figure 59A shows the FXYD3_T25_P14_ECD-_mFc DNA sequence (924bp) (SEQ ID NO:97); Figure 59B shows the AI216611_T0_P0_ECDjnFc DNA sequence (1170bp) (SEQ ID NO:98), Figure 59C shows the C10RF32_T8_P8_ECD_mFc DNA sequence (1287bp) (SEQ ID NO:99); Figure 59D shows the LOC253012_T4_P5_ECD_mFc DNA sequence (1740bp) (SEQ ID NO:100), Figure 59E shows the ILDR1_T0_P3_ECD_mFc DNA sequence (1167bp) (SEQ ID NO:101), and Figure 59F shows the VSIG1_T6_P5_ECD_mFc DNA sequence (1641bp) (SEQ ID NO:102).

[0736] The sequence of the resulting ECDjmFc fusion proteins are shown in Figure 60A - 60F; gene specific sequence correspond to the ECD sequence is marked in bold faced, TEV cleavage site sequence is underlined, mFc sequence is unbold Italic and IL6sp sequence is bold Italic. Figure 60Ashows the FXYD3_T25_P14_ECD_mFc amino acid sequence (307aa) (SEQ ID NO: 103); Figure 60B shows the AI216611_T0_P0_ECD_mFc amino acid sequence (389aa) (SEQ ID NO:104), Figure 60C shows the C10RF32_T8_P8_ECD_mFc amino acid sequence (428aa) (SEQ ID NO: 105); Figure 60D shows the LOC253012_T4_P5_ECD_mFc amino acid sequence (579aa) (SEQ ID NO:106), Figure 60E shows the ILDR1_T0_P3_ECD_mFc amino acid sequence (388aa) (SEQ ID NO: 107), and Figure 60F shows the VSIG1_T6_P5_ECD_mFc amino acid sequence (546aa) (SEQ ID NO: 108).

[0737] To generate ECD-mFc expressing cells, HEK-293T cells were transfected with the above described constructs corresponding to VSIG1, ILDR1, LQC253012, AI216611, C1QRF32 and FXYO3 extra cellular domain fused to mouse Fc. Stable pools wore generated as follows 48 hrs post transfection, the cells were trypsinized and transferred to T75 flask containing selection medium (DMEM 10% FCS and 5 pg/ml puromycin) for obtaining stable pool. Media was changed every 3 to 4 days until colonies formation.

[0738] To verify the identity of cells, genomic PCR was performed, indicating the correct sequences integrated into the cell genome (data not shown).

[0739] Cell-deprived medium was collected and purified by Protein A-Sepharose beads (Amersham catalog number 17-5280-04) as follows: 1ml of cell-deprived medium was incubated with 50μΙ Protein A sepharose beads for 45 minutes at room temperature. At the end of incubation time proteins were eluted from the beads pellet with 50μΙ sample buffer containing 100mM Citrate Phosphate pH 3.5 and 10mM DTT. The samples were boiled for 3 minutes and 25μΙ were loaded on 12% NuPAGE Bis Tris gel (Invitrogen,catalog number NP0342). The proteins were transferred to a nitrocellulose membrane and blocked with 10% low fat milk in PBST (PBS supplemented with 0.05% tween-20). The membrane was then blotted for 1 hour with Goat anti mouse IgG Fc fragment HRP (Jackson, catalog number 115-035-206.) (1:40,000 in blocking solution) at room temperature. Following incubation with ECL solution (Amersham Biosciences, Catalog No. RPN2209), the membrane was exposed to film.

[0740] Figure 61 shows the results of a western blot on expressed FXYD3_ECD_mFc (SEQ ID NO:103), AI216611 ECD_mFc (SEQ ID NO: 104), C10RF32_ECD_mFc(SEQ ID NO:105), LOC253012_ECD_mFc (SEQ ID NO:106), ILDR1_ECD_mFc (SEQ ID NO: 107), VSIG1_ECD_mFc (SEQ ID NO:108).

[0741] The lanes are as follows: lane 1 Molecular weight markers (Amersham, full range ranbow, catalog number RPN800); lane 2- LOC253012_ECD_mFc(SEQ ID NO:106); lane 3- FXYD3_ECD_mFc (SEQ ID NO:103); lane 4-AI216611 ECD_mFc(SEQ ID NO: 104); lane 5- C10RF32_ECD_mFc (SEQ ID NO:105); lane 6-ILDR1_ECD_mFc(SEQ ID NO:107); lane 7- VSIG1_ECD_mFc (SEQ ID NO: 108). EXAMPLE 11

PROTEIN PRODUCTION OF VSIG1, ILDR1, LOC253012, AI216611, C10RF32 AND FXYD3 EXTRACELLULAR DOMAIN (ECD) FUSED TO MOUSE FC

[0742] To produce VSIG1, ILDR1, LOC253012, AI216611, C10RF32 and FXYD3 ECD fused to mouse Fc, pool of transfected HEK293T cells stably transfected with the corresponding constructs described herein above, were used. The transfected cells, usually maintained in 10% serum supplemented medium, were transferred into serum free medium (EX-CELL293, SAFC) supplemented with 4 mM glutamine and selection antibiotics (5 ug/ml puromycin), and grown in suspension in shake flasks at 37°C, with agitation. The culture volume was increased by sequential dilutions until a production phase of 3-4 days carried out in 2L spinners flasks. Medium from the spinners was harvested, cleared from cells by centrifugation, filtered through a 0.22 pm filter and kept at -20°C.

[0743] The VSIG1, ILDR1, LOC253012, AI216611, C10RF32 and FXYD3 ECD fused to mouse Fcwere purified using nProteinA -affinity chromatography as described below.

[0744] Harvests were concentrated approximately 10 fold using PALL ultrafiltration system on two 10 kD cassettes. The concentrate was then adjusted to pH 7.5, by the addition of 5M NaOH and filtrated through 0.2pm Stericup filter.

[0745] Purification process was carried out using AKTA Explorer (GE Healthcare). 2 ml of nProtein A Sepharose TM, Fast Flow resin (cat# 17-5280-02) were washed on Poly-prep chromatograohy column under vacumn with 10 column volumes (CV) of 70% ethanol, 10 CV WFI (Sterile \Nater for Irrigation (TEVA)) followed by 10CV buffer A. 2 ml resin were transffered into two 500 ml tubes (1 ml each) and the concentrated harvest was added. The tube was icubated overnight at 4°C on a roller to allow binding of the protein. Bound resin was then transffered and packed under constant flow into XK16 coulmn (GE Healthcare, cat#18-8773-01). The column was washed with 20CV buffer A (100 Mm Tris pH 7.4) and elution was carried out in one step using 100% buffer B (Citrate/Phosphate pH 3.0). The fractions were titrated with 12.5% (v/v) buffer C (2M Tris pH 8.5) to adjust the pH to -7.5 and pooled.

[0746] The final buffer was exchanged to DPBS (Dulbecco's Phosphate bufferes saline pH 7.4, /o Ca, w/o Mg) pH 7.4 w/o Ca, w/o Mg using a 53 ml HiPrep TM (GE Healthcare, cat# 17-5087-01) desalting column. The protein was filtered through 0.22pm filter, aliqouted under sterile conditions, and stored at -800C.

[0747] The final protein concentration was determined by BCA total protein assay and protein was analyzed by coomassie stained reducing SDS/PAGE (data not shown). Endotoxin level was determined by colorimetric LAL assay (Limulus Amebocyte Lysate, QCL-1000, Cambrex). The identities of the specific proteins were verified by MS (at the Smoler Proteomics Center, Technion, Haifa, data not shown).

[0748] The resulted protein analyses are summerized in table 139.

Table 139

EXAMPLE 12

BINDING OF THE ECDs Fc-FUSED PROTEINS TO ACTIVATED T CELLS

[0749] In order to examine of the ability of the VSIG1, ILDR1, LOC253012, AI216611, C10RF32 and FXYD3 Fc-fused ECDs described above to bind a putative counter-receptor on T cells, these Fc-fused ECDs were tested on resting or activated T cells. Purified T cells were activated with ConA (Sigma Aldrich, Cat # C5275), followed by incubation with the VSIG1, ILDR1, LOC253012, AI216611, C10RF32 or FXYD3 Fc-fused ECDs and analyzed by flow cytometry.

[0750] T cells were purified from whole blood by negative selection using RosetteSep™ Human T Cell Enrichment Cocktail (StemCell Technologies, CAT # 15061). This resulted in a population of T (CD3+) cells with a purity of-90 %. Purified T cells (1X 105) were cultured for 48 hours in 10Oul of complete RPMI 1640 medium containing 10% FBS, either without any activation or activated with ConA (Concovalin A, 10ug/ml, Sigma Aldrich, Cat # C5275). Cultures were harvested and stained with the ECDs Fc-fused proteins for 1 hour at 4°C (VSIG1, ILDR1, LOC253012, AI216611, FXYD3 or C10RF32 ECDs fused to mouse lgG2 Fc). The bound proteins were detected with FITC-conjugated F(ab)2 goat anti-mouse Fc for half an hour at 4°C (Jackson ImmunoResearch Laboratories. CAT #115-096-071). Samples were analyzed using a FACSCalibur (BD Immunocytometry Systems) and CellQuest software.

[0751] Figures 62A-D present the binding of the ECDs Fc-fused proteins (VSIG1 (SEQ ID NO:108), LOC253012 (SEQ ID NO:106), AI216611 (SEQ ID NO:104) or C10RF32 (SEQ ID NO:105)) to resting T cells or T cells activated with Con Afor different periods of time. Primary human T cells from three different donors were cultured for a total of 48 hours in the absence of stimulus (0 hrs) or in the presence of Con A, which was added to a final concentration of 10pg/ml for the last 6, 18, 24 or 48 hours of culture (T cells from donor 5 were cultured with Con Afor 0,6, 18 and 24 hrs, while donors 6 &amp; 7 were cultured for 0, 6, 24 and 48 hrs). Cells were then harvested and incubated with 10pg/ml of the indicated ECDs Fc-fused proteins. Figure 62A shows the binding results for Fc-fused VSIG1 ECD; Figure 62B shows the binding results for Fc-fused LOC253012; Figure 62C shows the binding results for Fc-fused C10RF32 ECD; Figure 62D shows the binding results for Fc-fused AI216611 ECD and Figure 62E shows the binding results for Fc-fused FXYD3 ECD. The percentage of positive cells was determined as the difference between the positive cells with the indicated protein and the positive cells obtained with FITC-conjugated F(ab)2 goat anti-mouse Fc. Figure 63 presents the dose response of the binding of B7 -like proteins to activated T cells. Purified T cells were cultured for 48 hours. Con A was added for the last 24 hours. Cells were then harvested and stained with increasing concentrations (3, 6,12, 25 and 50 pg/ml) of Fc-fused VSIG1, LOC253012, C10RF32, AI216611 or ILDR1 ECDs. As a negative controls, mouse lgG2a was used at the same concentrations.

[0752] The results presented in Figures 62A-D and 63 demonstrate binding of all the ECDs Fc-fused proteins tested (VSIG1, ILDR1, LQC253012, AI216611 or C1QRF32 ECDs fused to mouse lgG2 Fc, SEQ ID NQ:108, 107, 106, 104, or 105, respectively), at binding levels above those of the negative controls: mouse lgG2a (R&amp;D Systems, CAT # MAB003) as isotype control. A substantial binding was detected for Fc-fused VSIG1 ECD and for LOC253012 ECD-Fc to T cells stimulated with ConA. Fc-fused ECDs of C10RF32 and AI216611 showed a weaker binding to these cells, as can be seen from Figures 62A-D and 63. Each protein was found to bind a certain percentage of activated T cells. The rating of binding levels was as follows VSIG1>LOC253012>ILDR1=AI216611>C1ORF32. None of the proteins bound resting T cells (i.e O hrs of ConA in Figures 62A-D).

[0753] Effect of the ECDs Fc-fused proteins of the invention on T cells activation.

[0754] In order to test potential costimulatory or/and coinhibitory activity of the soluble proteins, VSIG1, ILDR1, LOC253012, AI216611, FXYD3 or C10RF32 ECDs fused to mouse lgG2 Fc, SEQ ID NO:108, 107, 106, 104, or 105, respectively, on T cells proliferation and IL-2 secretion, human T cells were cultured in the presence of anti-CD3 ((clone OKT3, eBioscience, CAT #16-0037-85) and the B7-like proteins of the invention, described above. Recombinant human B7-1 protein (R&amp;D Systems, CAT # 140-B1) was used as a positive control for costimulatory activity. Recombinant mouse B7-FI4 protein (R&amp;D Systems, CAT # 4206-B7) was used as positive control for coinhibitory activity.

[0755] Flat-bottom 96-well plates were first coated at 4°C overnight with 3pg/ml of anti-CD3 mAb (clone OKT3) and subsequently coated with the indicated concentrations of human B7-1 (R&amp;D, 3pg/ml), mouse B7-H4 (R&amp;D, 10pg/ml) or the ECDs Fc-fused proteins, VSIG1, ILDR1, LOC253012, AI216611, FXYD3 or C10RF32 ECDs fused to mouse lgG2 Fc, for 4 h at 37°C. Human T cells were purified from whole blood as described above, and were cultured in the precoated 96-well plates (1x105cells/well) in 250 μΙ of complete RPMI 1640 medium containing 10% FBS for 48 hrs. Coated plates were washed with PBS three times before seeding of the cells. T cell proliferation was determined by BrdU incorporation by Cell proliferation ELISA, BrdU (colorimetric) (Roche). Cells were labeled with BrdU labeling reagent at a final concentration of 100μΜ for the last 18 hours. The plates were then centrifuged (at 300g, for 10 min,), and supernatants were aspirated and stored at -20°C for subsequent IL-2 determination using a Human IL-2 ELISA (Diaclone, CAT #850.010 096). BrdU incorporation was measured according to instructions of the manufacturer of the Cell proliferation ELISA, BrdU (colorimetric) (Roche, CAT # 11-647-229).

[0756] Figures 64A-B presents the effect of the ECDs Fc-fused proteins on T cell proliferation or IL-2 secretion, upon activation with anti-CD3 Ab. Figure 64A shows the levels of BrdU incorporation. Figure 64B shows the levels of IL-2 secretion.

[0757] The results, presented in Figure 64A-B, indicate that none of the ECD-Fc fused proteins VSIG1, ILDR1, LOC253012, AI216611, FXYD3 or C10RF32 ECDs fused to mouse lgG2 Fc, showed costimulatory activity. The positive control, B7-1, showed a strong costimulatory activity, as expected. Fc-fused ILDR1 ECD and Fc-fused AI216611 ECD appear to have coinhibitory activity, since they inhibited cell proliferation similarly to B7-H4, in comparison to that obtained in the presence of the negative control: mouse lgG2a (Figure 64A). However, no significant effect was observed on IL-2 secretion of any of the ECD-Fc fused proteins, VSIG1, ILDR1, LOC253012, AI216611, FX7D3 orC10RF32 Fc-fused ECDs (Figure 64B). EXAMPLE 13

BINDING OF THE ECDs Fc-FUSED PROTEINS TO LYMPHOCYTES AND TO AND TO CD4 POSITIVE CELLS

[0758] In order to further examine of the ability of the VSIG1, ILDR1, LOC253012, AI216611, FXYD3 and C10RF32 Fc-fused ECDs to bind a putative counter-receptor on T cells, these Fc-fused ECDs were tested first on lymphocyes. PBMCs were prepared from human peripheral blood, in FACS buffer at 1x10e7/ml. Fc blocker (hlgG (16D10), lot#080706, 1.3mg/ml) at 30ug/ml was added and cells were incubated with the blocker on ice for 30 min. Fusion proteins were added at 1ug/10e6 per stain on ice for 30 min. 2nd Ab was added at 1 ug/100ul/stain for 25-30min (G@mlgG-Fc-FITC: Jackson Immunol Lab, 1mg/ml, code#115-096-071, lot# 71453, 1.0mg/ml, used at 1ug/stain). Cells were washed with the buffer at each step outlined above. The binding was analyzed by flow cytometry.

[0759] Figure 65 illustrates the binding of the ECDs Fc-fused of the VSIG1, ILDR1, LOC253012, AI216611, FXYD3 or C10RF32 to lymphocytes. As can be seen from Figure 65, C10RF32, AI216611 and ILDR1 bind to a counterpart expressed on lymphocytes.

[0760] Next, binding of the VSIG1, ILDR1, LOC253012, AI216611, FXYD3 and C10RF32 Fc-fused ECDs to CD4+ cells. Fc blocker (hlgG (16D10), lot# 080706, 1.3mg/ml) at 30ug/ml was added and cells were incubated with the blocker on ice for 30 min. 174

Fusion proteins were added at 1ug/10e6 per stain on ice for 30 min. Add 2nd Ab at 1ug/100ul/stain for 25-30min (G@mlgG-Fc-FITC: Jackson Immunol Lab, 1mg/ml, code#115-096-071, lot# 71453, 1.0mg/ml, used at 1ug/stain). @CD4 (m@hCD4-APC: BD, cat3555349, lot#44331) was added 20ul of each per stain, on ice for 30min.

[0761] Cells were washed with the buffer at each step outlined above. The binding was analyzed by flow cytometry.

[0762] Figure 66 illustrates the binding of the ECDs Fc-fused of ILDR1, C1ORF32 and AI216611 to CD4+ cells. EXAMPLE 14 EFFECT OF THE ECDs Fc-FUSED PROTEINS ON T CELL ACTIVATION.

[0763] In order to test potential costimulatory or/and (»inhibitory activity of the B7-like proteins, the affect of the VSIG1, ILDR1, LOC253012, AI216611 or C10RF32 ECDs fused to mouse lgG2 Fc on T cells proliferation was tested. T cells were purified from whole blood by positive selection using CD3 microbeads (microbeads conjugated to monoclonal anti-human CD3 antibodies (isotype: mouse lgG2a) (MACS Whole Blood CD3 Microbeads # 130-090-874). Dynabeads are coated with CD3 +/- B7 with M-450 Epoxy Dynabeads (Invitrogen cat. No. 140.11). For activation of CD3 T cells, purified CD3 T cells are stimulated with the CD3+CD28coated beads at 1:1 or 1:05 ratio for various time points as needed. The cells were seeded at 2x10e5 per well in presence or absence of CD3+CD28 (2ug/ml each)-coated beads and the cell proliferation was measured after 72 hours by tritium -thymidine incorporation. The results are shown in Figure 67. "CD3" in Figure 67 mean CD3 only without the presence of a costimulatory or coinhibitory molecule; "CD3 + B7.2" means CD3 + a known B7 stimulatory control, B7.2; "CD3+B7H4" means CD3 and B7H4 a known B7 inhibitory control; "CD3+B7H3" means CD3 and B7H3 a known B7 stimulatory protein; "CD3 + 702" means CD3 + LOC253012-ECD-Fc fused (SEQ ID NO:106); "CD3 + 721" means CD3 + AI216611- ECD-Fc fused (SEQ ID NO:104); "CD3 + 754" means CD3 + C10RF32-ECD-Fc fused (SEQ ID NO:105); ”CD3 + 768” means CD3 + VSIG1-ECD-Fc fused (SEQ ID NO: 108) "CD3 + 770" means CD3 + ILDR1-ECD-Fc fused (SEQ ID NO: 107); "CD3+789" means CD3 + FXYD3-ECD-Fc fused (SEQ ID NO: 103). EXAMPLE 15

INTERACTION OF THE ECDs-Fc FUSED PROTEINS WITH RESTING B CELLS, ACTIVATED B CELLS, AND B CELL DERIVED LYMPHOMA CELL LINES

[0764] Following demonstration of binding of the proteins to lymphocytes (Example 12 and 13, herein), the ability of the soluble proteins to bind to B cells was examined.

[0765] PBMCs were prepared from human peripheral blood, in FACS buffer at 1x10e7/ml. Fc blocker (hlgG (16D10), lot#080706, 1.3mg/ml) at 30pg/ml was added and cells were incubated with the blocker on ice for 30 min. Fusion proteins ILDR1-ECD-Fc (SEQ ID NO:107), C10RF32-ECD-Fc (SEQ ID NO:105), AI216611-ECD-Fc (SEQ ID NO:104), LOC253012-ECD-Fc (SEQ ID NO:106), FXYD3-ECD-Fc (SEQ ID NO:103), and VSIG1-ECD-Fc (SEQ ID NO:108) were added at 1pg/10e6 per stain on ice for 30 minutes. 2nd Ab was added at 1pg/100pl/stain for 25-30min (G@mlgG-Fc-FITC: Jackson Immunol Lab, 1mg/ml, code#115-096-071, lot# 71453, 1.0mg/ml, used at 1ug/stain). Cells were washed with the buffer at each step outlined above. The binding was analyzed by flow cytometry. After that cells were stained with mouse @human IgM-PE (BD Bioscience, CA, USA, cat#555783) which is specific for B cells. The stained cells analyzed by flow cytometry. The @human IgM positive cells were gated to analyze the binding of the fusion proteins of invention to the B cells.

[0766] As shown in Figure 68A, ILDR1-ECD-Fc and C10RF32-ECD-Fc bound to B cells of all 3 donors tested. AI216611-ECD-Fc exhibited binding to B cells in 1 donor only.

[0767] In order to determine the existence of the counterpart on activated B cells, PBMCs were activated with LPS for 72 hours with LPS. Thereafter, binding with the ECDs Fc-fused proteins ILDR1-ECD-Fc (SEQ ID NO: 107), C10RF32-ECD-Fc (SEQ ID NO: 105), AI216611-ECD-Fc (SEQ ID NO:104), LOC253012-ECD-Fc (SEQ ID NO:106), FXYD3-ECD-Fc (SEQ ID NO:103), and VSIG1-ECD-Fc (SEQ ID NO:108) was done as described above, and cells were stained with mouse @human CD86-Cy5PE (BD 175

Bioscience, CA, USA, S, cat#555659) and mouse @human CD19-PE(BD Bioscience, CA, USA)antibodies. The activated B cells were defined as double positive CD19+/CD86+ population of cells.

[0768] As demonstrated in Figure 68B, ILDR1-ECD-Fc (SEQ ID NO: 107), C10RF32-ECD-Fc (SEQ ID NO:105) and AI216611-ECD-Fc (SEQ ID NO: 104) showed binding to activated B cells.

[0769] In order to determine the existence of the counterpart in B cell malignancies, the binding of the ECDs Fc-fused proteins ILDRI-ECD-Fc (SEQ ID NO:107), C10RF32-ECD-Fc (SEQ ID NO:105), AI216611-ECD-Fc (SEQ ID NO: 104), LOC253012-ECD-Fc (SEQ ID NO: 106), FXYD3-ECD-Fc (SEQ ID NO:103), and VSIG1-ECD-Fc (SEQ ID NO:108) were analysed in B cell lymphoma cell lines. Raji (ATCC# CCL-86) and Daudi (ATCC# CCL-213) cells were purchased from ATCC and maintained in RPMI+10% FBS. The cells were stained with B7s protein or controls at 10pg/ml and thereafter with FITC-conjugated goat anti-mouse IgG Fc (Jackson Immunol Lab, NJ, USA, cat#115-096-071, lot# 71453).

[0770] Figure 68C illustrates the binding of the Fc-fused ECDs of the B7-like proteins (ILDR1-ECD-Fc (SEQ ID NO:107), C10RF32-ECD-Fc (SEQ ID NO:105), AI216611-ECD-Fc (SEQ ID NO:104), LOC253012-ECD-Fc (SEQ ID NO: 106), FXYD3-ECD-Fc (SEQ ID NO: 103), and VSIG1-ECD-Fc (SEQ ID NO:108)) to the B cell lymphoma cell lines. ILDR1-ECD-Fc (SEQ ID NO:107) showed a clear binding the both B cell lymphoma cell lines. EXAMPLE 17

DEVELOPMENT OF MOUSE MONOCLONAL ANTI-VSIG1, ANTI-ILDR1, ANTI-LOC253012, ANTI-AI216611, ANTI-C10RF32 AND ANTI-FXYD3 ANTIBODIES

[0771] In order to test the expression of B7-Like proteins in different cancer tissues by immunohistochemistry, monoclonal mouse antibodies specific for Fc-fused ECDs of the proteins were developed.

Development of Mouse monoclonal antibodies: [0772] Four groups of the Balb/c mice (3 mice per group) were immunized with 4 Fc-fused ECDs proteins: VSIG1 (SEQ ID NO: 108), LOC253012 (SEQ ID NO:106), C10RF32 (SEQ ID NO:105) and FXYD3(SEQ ID NO:103). The immunizations were performed 8 times at one week intervals in multiple sites, subcutaneous and intraperitoneal. Mice were bled ten days following the 4th and 8th immunizations. Serum was screened for antibody titer using a Direct ELISA protocol described below.

[0773] ELISA plates were coated with 50 μΙ/well of 2.5 pg/mL Fc-fused proteins (VSIG1, LOC253012, C10RF32, FXYD3 ECDs fused to mouse lgG2 Fc, SEQ ID NOs: 108, 106, 105, 103, respectively) diluted in DPBS for 1 hour at room temperature (RT). Fluman IgG fused to mouse Fc region was used as a negative control. After that, plates were blocked with 300μΙ/well of 1% BSA/DPBS for 15 min at RT. Following the blocking step, serially diluted sera from immunized mice and irrelevant mouse IgG were transferred to the blocked ELISA plates and incubated for 1 hour at RT. Afterwards, plates were washed 3 times with 300 pl/well washing buffer (DPBS with 0.05% Tween 20, pH 7.2 - 7.4). For detection, plates were incubated for 1 hour at RT with 50 μΙ/well of Goat anti-Mouse Kappa Light Chain Antibody at 1:1000 dilution followed by an extensive wash (6 times with 300 μΙ/well of washing buffer) and incubation with the substrate. The substrate, 2,2'-Azino-bis-(3-ethylbenzthiazDline-6-sulfonic acid (ABTS), at 100 pL/well was added and incubated for about 5 min at RT before plates were read at 414nm using a Molecular Devices SPECTRAmax340 PC plate reader and SOFTmax PRO software.

[0774] Serum antibody titer was defined as the dilution of serum that produces a signal that was twice that of the background.

[0775] Results of the ELISA test of the immunized sera after 4 immunizations are summarized in the Table 140. Data show that after 4 immunizations, 2 mice groups (immunized with LOC253012 and VSIG1 Fc fused proteins ECDs) developed antibody titers sufficient for hybridoma production.

[0776] The mice that showed highest antibody serum titers, were selected for hybridoma production. The splenocytes were fused with mouse myeloma cell line Ag8.653. The supernatant of the hybridoma clones were tested by direct ELISA(as described above) using plates coated with relevant and irrelevant coatings. The results are summzarised in Table 141Aand Table 141B. 176 [0777] The results demonstrate that production of hybridoma cell lines resulted in 14 clones specifically recognizing LOC253012 (Table 141 A, bold) and 14 clones specifically recognizing VSIG1 (Table 141B, bold).

[0778] For the rest of the proteins, four additional immunizations were performed in order to facilitate the serum antibody titers development for the rest of the proteins. The sera titers after the 8th immunization were tested by direct ELISA. Results are summarized in Table 142. The results demonstrate that after 8 immunizations the mice immunized with FXYD-Fc fused ECD (SEQ ID NO: 103) and C10RF32-Fc fused ECD (SEQ ID NO: 103) developed sufficient antibody titers for hybridoma production. In the next step, the best responders will be selected for hybridoma production and monoclonal antibody manufacturing.

[0779] The Monoclonal Antibodies for each of the antigens (VSIG1, LOC253012, C10RF32, FXYD3, AI216611 and ILDR1, SEQ ID NOs: 108, 106, 105, 103, 104 and 107, respectively) are used for Immunohistochemistry analysis in order to verify the expression profile of each of these putative proteins in cancer and healthy tissues.

Table 140. Antibody sera titers of the immunized mice after 4 immunizations.

177

178

Immunohistochemical analysis [0780] Immunohistochemistry enables the visualization (using light or confocal microscopy) of the tissue distribution of specific antigens (or epitopes). The process localizes protein targets of interest by applying specific monoclonal or polyclonal antibodies to tissue surfaces in a process called antibody incubation.

[0781] This method involves detection of a substrate in situ in fixed cells by substrate specific antibodies. The substrate specific antibodies may be enzyme linked or linked to fluorophores. Detection is carried out by microscopy and subjective evaluation. If enzyme linked antibodies are employed, a colorimetric reaction may be required.

[0782] The immunohistochemical analysis performed for the antigens (VSIG1, LOC253012, C10RF32, FXYD3, AI216611 and ILDR1, SEQ ID NOs: 108, 106, 105, 103, 104 and 107, respectively) consist of two phases: [0783] Phase I: Antibody calibration: A dilution series of each of the antibodies developed against the specific protein antigens is run using selected formalin-fixed paraffin-embedded (FFPE) control tissues and cell lines. The best performing antibody is selected for Phase II.

[0784] Phase II: Protein distribution and localization analysis: Using the optimal antibody concentration selected in Phase I, the distribution and localization of VSIG1, LOC253012, C10RF32, FXYD3, AI216611 and ILDR1 proteins is analyzed in Tissue Arrays consisting of cancer and healthy tissues, looking for differential expression of the in some of the cancer samples, as compared with healthy samples. EXAMPLE 17

DEVELOPMENT OF FULLY HUMAN ANTI-VSIG1, ANTI-ILDR1, ANTI-LOC253012, ANTI-AI216611, ANTI-C10RF32 AND ΑΝΠ-FXYD3 ANTIBODIES

Generation Of Human Monoclonal Antibodies Against VSIG1, ILDR1, LOC253012, AI216611, C10RF32 and FXYD3 Antigen [0785] Fusion proteins composed of the extracellular domain of the VSIG1, ILDR1, LOC253012, AI216611, C10RF32 and FXYD3 linked to a mouse lgG2 Fc polypeptide are generated by standard recombinant methods and used as antigen for immunization.

Transgenic HuMab Mouse.

[0786] Fully human monoclonal antibodies to VSIG1, ILDR1, LOC253012, AI216611, C10RF32 and FXYD3 are prepared using mice from the HCo7 strain of the transgenic HuMab Mouse. RTM., which expresses human antibody genes. In this mouse strain, the endogenous mouse kappa light chain gene has been homozygously disrupted as described in Chen et al. (1993) EMBO J. 12:811-820 and the endogenous mouse heavy chain gene has been homozygously disrupted as described in Example 1 of PCT Publication WO 01/09187. Furthermore, this mouse strain carries a human kappa light chain transgene, KCo5, as described in Fishwild et al. (1996) Nature Biotechnology 14:845-851, and a human heavy chain transgene, HCo7, as described in U.S. Pat. Nos. 5,545,806; 5,625,825; and 5,545,807.

Human Immunizations: [0787] To generate fully human monoclonal antibodies to VSIG1, ILDR1, LOC253012, AI216611, C10RF32 and FXYD3, mice of the HCo7 HuMab Mouse. RTM. (strain can be immunized with purified recombinant VSIG1 fusion protein derived from mammalian cells that are transfected with an expression vector containing the gene encoding the fusion protein. General immunization schemes for the HuMab Mouse. RTM. are described in Lonberg, N. et al (1994) Nature 368(6474): 856-859; Fishwild, D. et al. (1996) Nature Biotechnology 14: 845-851 and PCT Publication WO 98/24884. The mice are 6-16 weeks of age upon the first infusion of antigen. A purified recombinant VSIG1 antigen preparation (5-50.mu.g, purified from transfected mammalian cells expressing VSIG1 fusion protein) is used to immunize the HuMab mice intraperitoneally.

[0788] Transgenic mice are immunized twice with antigen in complete Freund's adjuvant or Ribi adjuvant IP, followed by 3-21 days IP (up to a total of 11 immunizations) with the antigen in incomplete Freund's or Ribi adjuvant. The immune response is monitored by retroorbital bleeds. The plasma is screened by ELISA (as described below), and mice with sufficient titers of anti-VSIG1 human immunoglobulin are used for fusions. Mice are boosted intravenously with antigen 3 days before sacrifice and removal of the spleen.

Selection of HuMab mice.TM. Producing Anti- VSIG1, ILDR1, LOC253012, AI216611, C10RF32 and FXYD3 Antibodies: [0789] To select HuMab mice.TM. producing antibodies that bind VSIG1, ILDR1, LOC253012, AI216611, C10RF32 or FXYD3 sera from immunized mice is tested by a modified ELISA as originally described by Fishwild, D. et al. (1996). Briefly, microtiter plates are coated with purified recombinant VSIG1 fusion protein at 1-2.mu.g/ml in PBS, 50.mu.l/wells incubated 4 degrees C. overnight then blocked with 200.mu.l/well of 5% BSA in PBS. Dilutions of plasma from VSIG1, ILDR1, LOC253012, AI216611, C10RF32 or FXYD3 -immunized mice are added to each well and incubated for 1-2 hours at ambient temperature. The plates are washed with PBS/Tween and then incubated with a goat-anti-human kappa light chain polyclonal antibody conjugated with alkaline phosphatase for 1 hour at room temperature. After washing, the plates are developed with pNPP substrate and analyzed by spectrophotometer at OD 415-650. Mice that developed the highest titers of anti- VSIG1, anti-ILDR1, anti-LOC253012, anti-AI216611, antiC10RF32 or anti-FXYD3 antibodies are used for fusions. Fusions are performed as described below and hybridoma supernatants are tested for anti- VSIG1, anti-ILDR1, anti-LOC253012, anti-AI216611, anti-C10RF32 or anti-FXYD3 activity by ELISA.

Generation Of Hybridomas Producing Human Monoclonal Antibodies To VSIG1, ILDR1, LOC253012, AI216611, C10RF32 orFXYD3 [0790] The mouse splenocytes, isolated from the HuMab mice, are fused with PEG to a mouse myeloma cell line based upon standard protocols. The resulting hybridomas are then screened for the production of antigen-specific antibodies. Single cell suspensions of splenic lymphocytes from immunized mice are fused to one-fourth the number of P3X63 Ag8.6.53 (ATCC CRL 1580) nonsecreting mouse myeloma cells with 50% PEG (Sigma). Cells are plated at approximately 1X10 -5 /well in flat bottom microtiter plate, followed by about two week incubation in selective medium containing 10% fetal calf serum, supplemented with origen (IGEN) in RPMI, L-glutamine, sodium pyruvate, HEPES, penicillin, streptamycin, gentamycin, 1x HAT, and beta-mercaptoethanol. After 1-2 weeks, cells are cultured in medium in which the HAT is replaced with HT. Individual wells are then screened by ELISA (described above) for human anti- VSIG1, anti-ILDR1, anti-LOC253012, anti-AI216611, anti-C10RF32 or anti-FXYD3 monoclonal IgG antibodies. Once extensive hybridoma growth occurred, medium is monitored usually after 10-14 days. The antibody secreting hybridomas are replated, screened again and, if still positive for human IgG, anti- VSIG1, anti-ILDR1, anti-LOC253012, anti-AI216611, anti-C10RF32 or anti-FXYD3 monoclonal antibodies are subcloned at least twice by limiting dilution. The stable subclones are then cultured in vitro to generate small amounts of antibody in tissue culture medium for further characterization.

Hybridoma clones are selected for further analysis.

Structural Characterization Of Desired Anti- VSIG1, anti-ILDR1, anti-LOC253012, anti-AI216611, anti-C10RF32 or anti-FXYD3 Human Monoclonal Antibodies [0791] The cDNA sequences encoding the heavy and light chain variable regions of the obtained anti- VSIG1, anti-ILDR1, anti-LOC253012, anti-AI216611, anti-C10RF32 or anti-FXYD3 monoclonal antibodies are obtained from the resultant hybridomas, respectively, using standard PCR techniques and are sequenced using standard DNA sequencing techniques.

[0792] The nucleotide and amino acid sequences of the heavy chain variable region and of the light chain variable region are identified. These sequences may be compared to known human germline immunoglobulin light and heavy chain sequences and the CDRs of each heavy and light of the obtained anti- VSIG1, anti-ILDR1, anti-LOC253012, anti-AI216611, anti-C10RF32 or anti-FXYD3 sequences identified.

Characterization Of Binding Specificity And Binding Kinetics Of Anti-VSIG1, anti-ILDR1, anti-LOC253012, anti-AI216611, anti-C10RF32 or anti-FXYD3 Human Monoclonal Antibodies [0793] The binding affinity, binding kinetics, binding specificity, and cross-competition of anti- VSIG1, anti-ILDR1 anti-LOC253012, anti-AI216611, antiCI ORF32 or anti-FXYD3 antibodies are examined by Biacore analysis. Also, binding specificity is examined by flow cytometry.

Binding affinity and kinetics [0794] Anti-C10RF32 antibodies produced according to the invention are characterized for affinities and binding kinetics by Biacore analysis (Biacore AB, Uppsala, Sweden). Purified recombinant human C10RF32 fusion protein is covalently linked to a CM5 chip (carboxy methyl dextran coated chip) via primary amines, using standard amine coupling chemistry and kit provided by Biacore. Binding is measured by flowing the antibodies in HBS EP buffer (provided by BIAcore AB) at a concentration of 267 nM at a flow rate of 50.mu.l/min. The antigen-association antibodies association kinetics is followed for 3 minutes and the dissociation kinetics is followed for 7 minutes. The association and dissociation curves are fit to a 1:1 Langmuir binding model using BIAevaluation software (Biacore AB). To minimize the effects of avidity in the estimation of the binding constants, only the initial segment of data corresponding to association and dissociation phases are used for fitting.

Epitope Mapping of Obtained anti-C10RF32 Antibodies [0795] Biacore is used to determine epitope grouping of anti-C10RF32 HuMAbs. Obtained anti-C10RF32 antibodies are used to map their epitopes on the C10RF32 antigen antibodies are coated on three different surfaces of the same chip to 8000 RUs each. Dilutions of the mAbs are made, starting at 10 mu.g/mL and is incubated with Fc fused C10RF32 (50 nM) for one hour. The incubated complex is injected over all the three surfaces (and a blank surface) at the same time for 1.5 minutes at a flow rate of 20.mu.L/min. Signal from each surface at end of 1.5 minutes, after subtraction of appropriate blanks, has been plotted against concentration of mAb in the complex Upon analysis of the data, the anti-C10RF32 antibodies are categorized into different epitope groups depending on the epitope mapping results. The functional properties thereof are also compared.

[0796] Chinese hamster ovary (CHO) cell lines that express C10RF32 protein at the cell surface are developed and used to determine the specificity of the C10RF32 HuMAbs by flow cytometry. CHO cells are transfected with expression plasmids containing full length cDNA encoding a transmembrane forms of C10RF32 antigen or a variant thereof. The transfected proteins contained an epitope tag at the N-terminus are used for detection by an antibody specific for the epitope. Binding of a antiCI ORF32 MAb is assessed by incubating the transfected cells with the C1ORF32 Abs at a concentration of 10 mu.g/ml. The cells are washed and binding is detected with a FITC-labeled anti-human IgG Ab. A murine anti-epitope tag Ab, followed by labeled anti-murine IgG, is used as the positive control. Non-specific human and murine Abs are used as negative controls. The obtained data is used to assess the specificity of the HuMAbs for the C1ORF32 antigen target.

[0797] These antibodies and other antibodies specific to C10RF32 may be used in the afore-described anti- C10RF32 related therapies such as treatment of cancers wherein C10RF32 antigen is differentially expressed such as lung cancer, colon cancer and ovarian cancer and/or for modulating (enhancing or inhibiting) B7 immune co-stimulation involving the C10RF32 antigen such as in the treatment of cancers and autoimmune diseases wherein such antibodies will e.g., prevent negative stimulation of T cell activity against desired target cancer cells or prevent the positive stimulation of T cell activity thereby eliciting a desired anti-autoimmune effect.

[0798] The invention has been described and prophetic embodiments provided relating to manufacture and selection of desired anti- C10RF32 antibodies for use as therapeutics and diagnostic methods wherein the disease or condition is associated with C10RF32 antigen. The invention is now further described by the claims which follow.

SEQUENCE LISTING

[0799] <110> Compugen Ltd

<120> POLYPEPTIDES AND POLYNUCLEOTIDES, AND USES THEREOF AS A DRUG TARGET FOR PRODUCING DRUGSAND BIOLOGICS <130> <160> 302 <210> 1 <211> 3137

<212> DNA <213> Homo Sapiens <400> 1 gtactgaaaa aagtctatac gcaataagta agcccaaaga ggcatgtttg cttggcgatg 60 cccagcagat aagccaggca aacctcggtg tgatcgaaga agccaatttg agactcagcc 120 tagtccaggc aagctactgg cacctgctgc tctcaactaa cctccacaca atggtgttcg 180 cattttggaa ggtctttctg atcctaagct gccttgcagg tcaggttagt gtggtgcaag 240 tgaccatccc agacggtttc gtgaacgtga ctgttggatc taatgtcact ctcatctgca 300 tctacaccac cactgtggcc tcccgagaac agctttccat ccagtggtct ttcttccata 360 agaaggagat ggagccaatt tctatttact tttctcaagg tggacaagct gtagccatcg 420 ggcaatttaa agatcgaatt acagggtcca acgatccagg taatgcatct atcactatct 480 cgcatatgca gccagcagac agtggaattt acatctgcga tgttaacaac cccccagact 540 ttctcggcca aaaccaaggc atcctcaacg tcagtgtgtt agtgaaacct tctaagcccc 600 tttgtagcgt tcaaggaaga ccagaaactg gccacactat ttccctttcc tgtctctctg 660 cgcttggaac accttcccct gtgtaatact ggcataaact tgagggaaga gacatcgtgc 720 cagtgaaaga aaacttcaac ccaaccaccg ggattttggt cattggaaat ctgacaaatt 780 ttgaacaagg ttattaccag tgtactgcca tcaacagact tggcaatagt tcctgcgaaa 840 tcgatctcac ttcttcacat ccagaagttg gaatcattgt tggggccttg attggtagcc 900 tggtaggtgc cgccatcatc atctctgttg tgtgcttcgc aaggaataag gcaaaagcaa 960 aggcaaaaga aagaaattct aagaccatcg cggaacttga gccaatgaca aagataaacc 1020 caaggggaga aagcgaagca atgccaagag aagacgctac ccaactagaa gtaactctac 1080 catcttccat tcatgagact ggccctgata ccatccaaga accagactat gagccaaagc 1140 ctactcagga gcctgcccca gagcctgccc caggatcaga gcctatggca gtgcctgacc 1200 ttgacatcga gctggagctg gagccagaaa cgcagtcgga attggagcca gagccagagc 1260 cagagccaga gtcagagcct ggggttgtag ttgagccctt aagtgaagat gaaaagggag 1320 tggttaaggc ataggctggt ggcctaagta cagcattaat cattaaggaa cccattactg 1380 ccatttggaa ttcaaataac ctaaccaacc tccacctcct ccttccattt tgaccaacct 1440 tcttctaaca aggtgctcat tcctactatg aatccagaat aaacacgcca agataacagc 1500 taaatcagca agggttcctg tattaccaat atagaatact aacaatttta ctaacacgta 1560 agcataacaa atgacagggc aagtgatttc taacttagtt gagttttgca acagtacctg 1620 tgttgttatt tcagaaaata ttatttctct ctttttaact actctttttt tttattttgg 1680 acagagtctt gctccgtcgc gcaggctgtg atcgtagtgg tgcgatctcg gctcactgca 1740 gcctccgctc cctgggttca agcgattctc ctgcctgagc ctcctgagta gctgggactg 1800 caggcacgtg ccaccacgcc cggctaattt tttgtatttt tagtagagat ggggtttcac 1860 gttgttggcc aggatggtct ccstctcctg acctcatgat ccgcccacct tggcctccca 1920 aaatgctggg attacaggca tgagccactg cgcccggcct ctttttagct actcttatgt 1980 tccacatgca catatgacaa ggtggcatta attagattca atattatttc taggaatagt 2040 tcctcattca tttttatatt gaccactaag aaaataattc atcagcatta tctcatagat 2100 tggaaaattt tctccaaata caatagagga gaatatgtaa agggtataca ttaattggta 2160 cgtagcattt aaaatcaggt cttataatta atgcttcatt cctcatatta gatttcccaa 2220 gaaatcaccc tggtatccaa tatctgagca tggcaaattt aaaaaataac acaatttctt 2280 gcctgtaacc ctagcacttt gggaggccga ggcaggtgga tcacctgagg tcaggagttc 2340 gagaccagcc tggccggcat ggcgaaaccc cttctctgct gaaaatacag aaattagctg 2400 ggcgtggtgg tgcatgcctg tagtcccagc tacttgggag gctgaggcag gagaatcgct 2460 tgaacccagg aggtggaggt tgcagtgagc cgagattgtg ccactgcact ccaacctggg 2520 tgacagagtg agattccatc tgaaaaacaa aaacaaaaac agaaaacaaa caaacaaaaa 2580 acaaaaaatc cccacaactt tgtcaaataa tgtacaggca aacactttca aatataattt 2640 ccttcagtga atacaaaatg ttgatatcat aggtgatgta caatttagtt ttgaatgagt 2700 tattatgtta tcactgtgtc tgatgttatc tactttgaaa ggcagtccag aaaagtgttc 2760 taagtgaact cttaagatct attttagata atttcaacta attaaataac ctgttttact 2820 gcctgtacat tccacattaa taaagcgata ccaatcttat atgaatgcta atattactaa 2880 aatgcactga tatcacttct tcttcccctg ttgaaaagct ttctcatgat catatttcac 2940 ccacatctca ccttgaagaa acttacaggt agacttacct tttcacttgt ggaattaatc 3000 atatttaaat cttactttaa ggctcaataa ataatactca taatgtctca ttttagtgac 3060 tcctaaggct agtcctttta taaacaactt tttctgacat agcatttatg tataataaac 3120 cagacattta aagtgta 3137 <210> 2 <211 >3049

<212> DNA <213> Homo Sapiens <400>2 gtactgaaaa aagtctatac gcaataagta agcccaaaga ggcatgtttg cttggcgatg 60 cccagcagat aagccaggca aacctcggtg tgatcgaaga agccaatttg agactcagcc 120 tagtccaggc aagctactgg cacctgctgc tctcaactaa cctccacaca atggtgttcg 180 cattttggaa ggtctttctg atcctaagct gccttgcagg tcaggttagt gtggtgcaag 240 tgaccatccc agacggtttc gtgaacgtga ctgttggatc taatgtcact ctcatctgca 300 tctacaccac cactgtggcc tcccgagaac agctttccat ccagtggtct ttcttccata 360 agaaggagat ggagccaatt tctatttact tttctcaagg tggacaagct gtagccatcg 420 ggcaatttaa agatcgaatt acagggtcca acgatccagg taatgcatct atcactatct 480 cgcatatgca gccagcagac agtggaattt acatctgcga tgttaacaac cccccagact 540 ttctcggcca aaaccaaggc atcctcaacg tcagtgtgtt agtgaaacct tctaagcccc 600 tttgtagcgt tcaaggaaga ccagaaactg gccacactat ttccctttcc tgtctctctg 660 cgcttggaac accttcccct gtgtactact ggcataaact tgagggaaga gacatcgtgc 720 cagtgaaaga aaacttcaac ccaaccaccg ggattttggt cattggaaat ctgacaaatt 780 ttgaacaagg ttattaccag tgtactgcca tcaacagact tggcaatagt tcctgcgaaa 840 tcgatctcac ttcttcacat ccagaagttg gaatcattgt tggggccttg attggtagcc 900 tggtaggtgc cgccatcatc atctctgttg tgtgcttcgc aaggaataag gcaaaagcaa 960 aggcaaaaga aagaaattct aagaccatcg cggaacttga gccaatgaca aagataaacc 1020 caaggggaga aagcgaagca atgccaagag aagacgctac ccaactagaa gtaactctac 1080 catcttccat tcatgagact ggccctgata ccatccaaga accagactat gagccaaagc 1140 ctactcagga gcctgcccca gagcctgccc caggatcaga gcctatggca gtgcctgacc 1200 ttgacatcga gctggagctg gagccagaaa cgcagtcgga attggagcca gagccagagc 1260 cagagccaga gtcagagcct ggggttgtag ttgagccctt aagtgaagat gaaaagggag 1320 tggttaaggc ataggctggt ggcctaagta cagcattaat cattaaggaa cccattactg 1380 ccatttggaa ttcaaataac ctaaccaacc tccacctcct ccttccattt tgaccaacct 1440 tcttctaaca aggtgctcat tcctactatg aatccagaat aaacacgcca agataacagc 1500 taaatcagca agggttcctg tattaccaat atagaatact aacaatttta ctaacacgta 1560 agcataacaa atgacagggc aagtgatttc taacttagtt gagttttgca acagtacctg 1620 tgttgttatt tcagaaaata ttatttctct ctttttaact actctttttt tttattttgg 1680 acagagtctt gctccgtcgc gcaggctgtg atcgtagtgg tgcgatctcg gctcactgca 1740 gcctccgctc cctgggttca agcgattctc ctgcctgagc ctcctgagta gctgggactg 1800 caggcacgtg ccaccacgcc cggctaattt tttgtatttt tagtagagat ggggtttcac 1860 gttgttggcc aggatggtct ccatctcctg acctcatgat ccgcccacct tggcctccca 1920 aaatgctggg attacaggca tgagccactg cgcccggcct ctttttagct actcttatgt 1980 tccacatgca catatgacaa ggtggcatta attagattca atattatttc taggaatagt 2040 tcctcattca tttttatatt gaccactaag aaaataattc atcagcatta tctcatagat 2100 tggaaaattt tctccaaata caatagagga gaatatgtaa agggtataca ttaattggta 2160 cgtagcattt aaaatcaggt cttataatta atgcttcatt cctcatatta gatttcccaa 2220 gaaatcaccc tggtatccaa tatctgagca tggcaaattt aaaaaataac acaatttctt 2280 gcctgtaacc ctagcacttt gggaggccga ggcaggtgga tcacctgagg tcaggagttc 2340 gagaccagcc tggccggcat ggcgaaaccc cttctctgct gaaaatacag aaattagctg 2400 ggcgtggtgg tgcatgcctg tagtcccagc tacttgggag gctgaggcag gagaatcgct 2460 tgaacccagg aggtggaggt tgcagtgagc cgagattgtg ccactgcact ccaacctggg 2520 tgacagagtg agattccatc tgaaaaacaa aaacaaaaac agaaaacaaa caaacaaaaa 2580 acaaaaaatc cccacaactt tgtcaaataa tgtacaggca aacactttca aatataattt 2640 ccttcagtga atacaaaatg ttgatatcat aggtgatgta caatttagtt ttgaatgagt 2700 tattatgtta tcactgtgtc tgatgttatc tactttgaaa ggcagtccag aaaagtgttc 2760 taagtgaact cttaagatct attttagata atttcaacta attaaataac ctgttttact 2820 gcctgtacat tccacattaa taaagcgata ccaatcttat atgaatgcta atattactaa 2880 aatgcactga tatcacttct tcttcccctg ttgaaaagct ttctcatgat catatttcac 2940 ccacatctca ccttgaagaa acttacaggt agacttacct tttcacttgt ggaattaatc 3000 atatttaaat cttactttaa ggctcaataa ataatactca taatgtctc 3049 <210> 3 <211 >2448

<212> DNA <213> Homo Sapiens <400>3 gtactgaaaa aagtctatac gcaataagta agcccaaaga ggcatgtttg cttggcgatg 60 cccagcagat aagccaggca aacctcggtg tgatcgaaga agccaatttg agactcagcc 120 tagtccaggc aagctactgg cacctgctgc tctcaactaa cctccacaca atggtgttcg 180 cattttggaa ggtctttctg atcctaagct gccttgcagg tcaggttagt gtggtgcaag 240 tgaccatccc agacggtttc gtgaacgtga ctgttggatc taatgtcact ctcatctgca 300 tctacaccac cactgtggcc tcccgagaac agctttccat ccagtggtct ttcttccata 360 agaaggagat ggagccaatt tctatttact tttctcaagg tggacaagct gtagccatcg 420 ggcaatttaa agatcgaatt acagggtcca acgatccagg taatgcatct atcactatct 480 cgcatatgca gccagcagac agtggaattt acatctgcga tgttaacaac cccccagact 540 ttctcggcca aaaccaaggc atcctcaacg tcagtgtgtt agtgaaacct tctaagcccc 600 tttgtagcgt tcaaggaaga ccagaaactg gccacactat ttccctttcc tgtctctctg 660 cgcttggaac accttcccct gtgtactact ggcataaact tgagggaaga gacatcgtgc 720 cagtgaaaga aaacttcaac ccaaccaccg ggattttggt cattggaaat ctgacaaatt 780 ttgaacaagg ttattaccag tgtactgcca tcaacagact tggcaatagt tcctgcgaaa 840 tcgatctcac ttcttcacat ccagaagttg gaatcattgt tggggccttg attggtagcc 900 tggtaggtgc cgccatcatc atctctgttg tgtgcttcgc aaggaataag gcaaaagcaa 960 aggcaaaaga aagaaattct aagaccatcg cggaacttga gccaatgaca aagataaacc 1020 caaggggaga aagcgaagca atgccaagag aagacgctac ccaactagaa gtaactctac 1080 catcttccat tcatgagact ggccctgata ccatccaaga accagactat gagccaaagc 1140 ctactcagga gcctgcccca gagcctgccc caggatcaga gcctatggca gtgcctgacc 1200 ttgacatcga gctggagctg gagccagaaa cgcagtcgga attggagcca gagccagagc 1260 cagagccaga gtcagagcct ggggttgtag ttgagccctt aagtgaagat gaaaagggag 1320 tggttaaggc ataggctggt ggcctaagta cagcattaat cattaaggaa cccattactg 1380 ccatttggaa ttcaaataac ctaaccaacc tccacctcct ccttccattt tgaccaacct 1440 tcttctaaca aggtgctcat tcctactatg aatccagaat aaacacgcca agataacagc 1500 taaatcagca agggttcctg tattaccaat atagaatact aacaatttta ctaacacgta 1560 agcataacaa atgacagggc aagtgatttc taacttagtt gagttttgca acagtacctg 1620 tgttgttatt tcagaaaata ttatttctct ctttttaact actctttttt tttattttgg 1680 acagagtctt gctccgtcgc gcaggctgtg atcgtagtgg tgcgatctcg gctcactgca 1740 gcctccgctc cctgggttca agagaatcgc ttgaacccag gaggtggagg ttgcagtgag 1800 ccgagattgt gccactgcac tccaacctgg gtgacagagt gagattccat ctgaaaaaca 1860 aaaacaaaaa cagaaaacaa acaaacaaaa aacaaaaaat ccccacaact ttgtcaaata 1920 atgtacaggc aaacactttc aaatataatt tccttcagtg aatacaaaat gttgatatca 1980 taggtgatgt acaatttagt tttgaatgag ttattatgtt atcactgtgt ctgatgttat 2040 ctactttgaa aggcagtcca gaaaagtgtt ctaagtgaac tcttaagatc tattttagat 2100 aatttcaact aattaaataa cctgttttac tgcctgtaca ttccacatta ataaagcgat 2160 accaatctta tatgaatgct aatattacta aaatgcactg atatcacttc ttcttcccct 2220 gttgaaaagc tttctcatga tcatatttca cccacatctc accttgaaga aacttacagg 2280 tagacttacc ttttcacttg tggaattaat catatttaaa tcttacttta aggctcaata 2340 aataatactc ataatgtctc attttagtga ctcctaaggc tagtcctttt ataaacaact 2400 ttttctgaca tagcatttat gtataataaa ccagacattt aaagtgta 2448 <210> 4 <211 >2368

<212> DNA <213> Homo Sapiens <400>4 gtactgaaaa aagtctatac gcaataagta agcccaaaga ggcatgtttg cttggcgatg 60 cccagcagat aagccaggca aacctcggtg tgatcgaaga agccaatttg agactcagcc 120 tagtccaggc aagctactgg cacctgctgc tctcaactaa cctccacaca atggtgttcg 180 cattttggaa ggtctttctg atcctaagct gccttgcagg tcaggttagt gtggtgcaag 240 tgaccatccc agacggtttc gtgaacgtga ctgttggatc taatgtcact ctcatctgca 300 tctacaccac cactgtggcc tcccgagaac agctttccat ccagtggtct ttcttccata 360 agaaggagat ggagccaatt tctatttact tttctcaagg tggacaagct gtagccatcg 420 ggcaatttaa agatcgaatt acagggtcca acgatccagg taatgcatct atcactatct 480 cgcatatgca gccagcagac agtggaattt acatctgcga tgttaacaac cccccagact 540 ttctcggcca aaaccaaggc atcctcaacg tcagtgtgtt agtgaaacct tctaagcccc 600 tttgtagcgt tcaaggaaga ccagaaactg gccacactat ttccctttcc tgtctctctg 660 cgcttggaac accttcccct gtgtactact ggcataaact tgagggaaga gacatcgtgc 720 cagtgaaaga aaacttcaac ccaaccaccg ggattttggt cattggaaat ctgacaaatt 780 ttgaacaagg ttattaccag tgtactgcca tcaacagact tggcaatagt tcctgcgaaa 840 tcgatctcac ttcttcacat ccagaagttg gaatcattgt tggggccttg attggtagcc 900 tggtaggtgc cgccatcatc atctctgttg tgtgcttcgc aaggaataag gcaaaagcaa 960 aggcaaaaga aagaaattct aagaccatcg cggaacttga gccaatgaca aagataaacc 1020 caaggggaga aagcgaagca atgccaagag aagacgctac ccaactagaa gtaactctac 1080 catcttccat tcatgagact ggccctgata ccatccaaga accagactat gagccaaagc 1140 ctactcagga gcctgcccca gagcctgccc caggatcaga gcctatggca gtgcctgacc 1200 ttgacatcga gctggagctg gagccagaaa cgcagtcgga attggagcca gagccagagc 1260 cagagccaga gtcagagcct ggggttgtag ttgagccctt aagtgaagat gaaaagggag 1320 tggttaaggc ataggctggt ggcctaagta cagcattaat cattaaggaa cccattactg 1380 ccatttggaa ttcaaataac ctaaccaacc tccacctcct ccttccattt tgaccaacct 1440 tcttctaaca aggtgctcat tcctactatg aatccagaat aaacacgcca agataacagc 1500 taaatcagca agggttcctg tattaccaat atagaatact aacaatttta ctaacacgta 1560 agcataacaa atgacagggc aagtgatttc taacttagtt gagttttgca acagtacctg 1620 tgttgttatt tcagaaaata ttatttctct ctttttaact actctttttt tttattttgg 1680 acagagtcgc ttgaacccag gaggtggagg ttgcagtgag ccgagattgt gccactgcac 1740 tccaacctgg gtgacagagt gagattccat ctgaaaaaca aaaacaaaaa cagaaaacaa 1800 acaaacaaaa aacaaaaaat ccccacaact ttgtcaaata atgtacaggc aaacactttc 1860 aaatataatt tccttcagtg aatacaaaat gttgatatca taggtgatgt acaatttagt 1920 tttgaatgag ttattatgtt atcactgtgt ctgatgttat ctactttgaa aggcagtcca 1980 gaaaagtgtt ctaagtgaac tcttaagatc tattttagat aatttcaact aattaaataa 2040 cctgttttac tgcctgtaca ttccacatta ataaagcgat accaatctta tatgaatgct 2100 aatattacta aaatgcactg atatcacttc ttcttcccct gttgaaaagc tttctcatga 2160 tcatatttca cccacatctc accttgaaga aacttacagg tagacttacc ttttcacttg 2220 tggaattaat catatttaaa tcttacttta aggctcaata aataatactc ataatgtctc 2280 attttagtga ctcctaaggc tagtcctttt ataaacaact ttttctgaca tagcatttat 2340 gtataataaa ccagacattt aaagtgta 2368 <210>5 <211 > 1501

<212> DNA <213> Homo Sapiens <400>5 c aagctactgg cacctgctgc tctcaactaa cctccacaca atggtgttcg 180 ia ggtctttctg atcctaagct gccttgcagg tcaggttagt gtggtgcaag 240 ic agacggtttc gtgaacgtga ctgttggatc taatgtcact ctcatctgca 300 ic cactgtggcc tcccgagaac agctttccat ccagtggtct ttcttccata 360 it ggagccaatt tctatttact tttctcaagg tggacaagct gtagccatcg 420 ia agatcgaatt acagggtcca acgatccagg taatgcatct atcactatct 480 :a gccagcagac agtggaattt acatctgcga tgttaacaac cccccagact 540 ia aaaccaaggc atcctcaacg tcagtgtgtt agtgaaacct tctaagcccc 600 ft tcaaggaaga ccagaaactg gccacactat ttccctttcc tgtctctctg 660 .c accttcccct gtgtactact ggcataaact tgagggaaga gacatcgtgc 720 ra aaacttcaac ccaaccaccg ggattttggt cattggaaat ctgacaaatt 780 rg ttattaccag tgtactgcca tcaacagact tggcaatagt tcctgcgaaa 840 .c ttcttcacat ccagaagttg gaatcattgt tggggccttg attggtagcc 900 rc cgccatcatc atctctgttg tgtgcttcgc aaggaataag gcaaaagcaa 960 ra aagaaattct aagaccatcg cggaacttga gccaatgaca aagataaacc 1020 ra aagcgaagca atgccaagag aagacgctac ccaactagaa gtaactctac 1080 t tcatgagact ggccctgata ccatccaaga accagactat gagccaaagc 1140 ia gcctgcccca gagcctgccc caggatcaga gcctatggca gtgcctgacc 1200 ia gctggagctg gagccagaaa cgcagtcgga attggagcca gagccagagc 1260 ia gtcagagcct ggggttgtag ttgagccctt aagtgaagat gaaaagggag 1320 rc ataggctggt ggcctaagta cagcattaat cattaaggaa cccattactg 1380 a ttcaaataac ctaaccaacc tccacctcct ccttccattt tgaccaacct 1440 •a aggtgctcat tcctactatg aatccagaat aaacacgcca agataacagc 1500 1501 15 no Sapiens a aagtctatac gcaataagta agcccaaaga ggcatgtttg cttggcgatg 60 ,t aagccaggca aacctcggtg tgatcgaaga agccaatttg agactcagcc 120 c aagctactgg cacctgctgc tctcaactaa cctccacaca atggtgttcg 180 a ggtctttctg atcctaagct gccttgcagg tcaggttagt gtggtgcaag 240 188 tgaccatccc agacggtttc gtgaacgtga ctgttggatc taatgtcact ctcatctgca 300 tctacaccac cactgtggcc tcccgagaac agctttccat ccagtggtct ttcttccata 360 agaaggagat ggagccaatt tctcacagct cgtgcctcag tactgagggt atggaggaaa 420 aggcagtcgg tcagtgtcta aaaatgacgc acgtaagaga cgctcgggga agatgtagct 480 ggacctctga gatttacttt tctcaaggtg gacaagctgt agccatcggg caatttaaag 540 atcgaattac agggtccaac gatccaggta atgcatctat cactatctcg catatgcagc 600 cagcagacag tggaatttac atctgcgatg ttaacaaccc cccagacttt ctcggccaaa 660 accaaggcat cctcaacgtc agtgtgttag tgaaaccttc taagcccctt tgtagcgttc 720 aaggaagacc agaaactggc cacactattt ccctttcctg tctctctgcg cttggaacac 780 cttcccctgt gtactactgg cataaacttg agggaagaga catcgtgcca gtgaaagaaa 840 aottcaaccc aaccaccggg attttggtca ttggaaatct gacaaatttt gaacaaggtt 900 attaccagtg tactgccatc aacagacttg gcaatagttc ctgcgaaatc gatctcactt 960 cttcacatcc agaagttgga atcattgttg gggccttgat tggtagcctg gtaggtgccg 1020 ccatcatcat ctctgttgtg tgcttcgcaa ggaataaggc aaaagcaaag gcaaaagaaa 1080 gaaattctaa gaccatcgcg gaacttgagc caatgacaaa gataaaccca aggggagaaa 1140 gcgaagcaat gccaagagaa gacgctaccc aactagaagt aactctacca tcttccattc 1200 atgagactgg ccctgatacc atccaagaac cagactatga gccaaagcct actcaggagc 1260 ctgccccaga gcctgcccca ggatcagagc ctatggcagt gcctgacctt gacatcgagc 1320 tggagctgga gccagaaacg cagtcggaat tggagccaga gccagagcca gagccagagt 1380 cagagcctgg ggttgtagtt gagcccttaa gtgaagatga aaagggagtg gttaaggcat 1440 aggctggtgg cctaagtaca gcattaatca ttaaggaacc cattactgcc atttggaatt 1500 caaataacct aaccaacctc cacctcctcc ttccattttg accaaccttc ttctaacaag 1560 gtgctcattc ctactatgaa tccagaataa acacgccaag ataacagcta aatcagcaag 1620 ggttcctgta ttaccaatat agaatactaa caattttact aacacgtaag cataacaaat 1680 gacagggcaa gtgatttcta acttagttga gttttgcaac agtacctgtg ttgttatttc 1740 agaaaatatt atttctctct ttttaactac tctttttttt tattttggac agagtcttgc 1800 tccgtcgcgc aggctgtgat cgtagtggtg cgatctcggc tcactgcagc ctccgctccc 1860 tgggttcaag cgattctcct gcctgagcct cctgagtagc tgggactgca ggcacgtgcc 1920 accacgcccg gctaattttt tgtattttta gtagagatgg ggtttcacgt tgttggccag 1980 gatggtctcc atctcctgac ctcatgatcc gcccaccttg gcctcccaaa atgctgggat 2040 tacaggcatg agccactgcg cccggcctct ttttagctac tcttatgttc cacatgcaca 2100 tatgacaagg tggcattaat tagattcaat attatttcta ggaatagttc ctcattcatt 2160 tttatattga ccactaagaa aataattcat cagcattatc tcatagattg gaaaattttc 2220 tccaaataca atagaggaga atatgtaaag ggtatacatt aattggtacg tagcatttaa 2280 aatcaggtct tataattaat gcttcattcc tcatattaga tttcccaaga aatcaccctg 2340 gtatccaata tctgagcatg gcaaatttaa aaaataacac aatttcttgc ctgtaaccct 2400 agcactttgg gaggccgagg caggtggatc acctgaggtc aggagttcga gaccagcctg 2460 gccggcatgg cgaaacccct tctctgctga aaatacagaa attagctggg cgtggtggtg 2520 catgcctgta gtcccagcta cttgggaggc tgaggcagga gaatcgcttg aacccaggag 2580 gtggaggttg cagtgagccg agattgtgcc actgcactcc aacctgggtg acagagtgag 2640 attccatctg aaaaacaaaa acaaaaacag aaaacaaaca aacaaaaaac aaaaaatccc 2700 cacaactttg tcaaataatg tacaggcaaa cactttcaaa tataatttcc ttcagtgaat 2760 acaaaatgtt gatatcatag gtgatgtaca atttagtttt gaatgagtta ttatgttatc 2820 actgtgtctg atgttatcta ctttgaaagg cagtccagaa aagtgttcta agtgaactct 2880 taagatctat tttagataat ttcaactaat taaataacct gttttactgc ctgtacattc 2940 cacattaata aagcgatacc aatcttatat gaatgctaat attactaaaa tgcactgata 3000 tcacttcttc ttcccctgtt gaaaagcttt ctcatgatca tatttcaccc acatctcacc 3060 ttgaagaaac ttacaggtag acttaccttt tcacttgtgg aattaatcat atttaaatct 3120 tactttaagg ctcaataaat aatactcata atgtctcatt ttagtgactc ctaaggctag 3180 tccttttata aacaactttt tctgacatag catttatgta taataaacca gacatttaaa 3240 gtgta 3245 <210>7 <211 >3323

<212> DNA <213> Homo Sapiens <400>7 gtactgaaaa aagtctatac gcaataagta agcccaaaga ggcatgtttg cttggcgatg 60 cccagcagat aagccaggca aacctcggtg tgatcgaaga agccaatttg agactcagcc 120 tagtccaggc aagctactgg cacctgctgc tctcaactaa cctccacaca atggtgttcg 180 cattttggaa ggtctttctg atcctaagct gccttgcagg tcaggttagt gtggtgcaag 240 tgaccatccc agacggtttc gtgaacgtga ctgttggatc taatgtcact ctcatctgca 300 tctacaccac cactgtggcc tcccgagaac agctttccat ccagtggtct ttcttccata 360 agaaggagat ggagccaatt tctcacagct cgtgcctcag tactgagggt atggaggaaa 420 aggcagtcgg tcagtgtcta aaaatgacgc acgtaagaga cgctcgggga agatgtagct 480 ggacctctga gtctccttgg gaggagggga agtggccaga tgttgaggct gtgaagggca 540 ctcttgatgg acagcaggct gaactccaga tttacttttc tcaaggtgga caagctgtag 600 ccatcgggca atttaaagat cgaattacag ggtccaacga tccaggtaat gcatctatca 660 ctatctcgca tatgcagcca gcagacagtg gaatttacat ctgcgatgtt aacaaccccc 720 cagactttct cggccaaaac caaggcatcc tcaacgtcag tgtgttagtg aaaccttcta 780 agcccctttg tagcgttcaa ggaagaccag aaactggcca cactatttcc ctttcctgtc 840 tctctgcgct tggaacacct tcccctgtgt actactggca taaacttgag ggaagagaca 900 tcgtgccagt gaaagaaaac ttcaacccaa ccaccgggat tttggtcatt ggaaatctga 960 caaattttga acaaggttat taccagtgta ctgccatcaa cagacttggc aatagttcct 1020 gcgaaatcga tctcacttct tcacatccag aagttggaat cattgttggg gccttgattg 1080 gtagcctggt aggtgccgcc atcatcatct ctgttgtgtg cttcgcaagg aataaggcaa 1140 aagcaaaggc aaaagaaaga aattctaaga ccatcgcgga acttgagcca atgacaaaga 1200 taaacccaag gggagaaagc gaagcaatgc caagagaaga cgctacccaa ctagaagtaa 1260 ctctaccatc ttccattcat gagactggcc ctgataccat ccaagaacca gactatgagc 1320 caaagcctac tcaggagcct gccccagagc ctgccccagg atcagagcct atggcagtgc 1380 ctgaccttga catcgagctg gagctggagc cagaaacgca gtcggaattg gagccagagc 1440 cagagccaga gccagagtca gagcctgggg ttgtagttga gcccttaagt gaagatgaaa 1500 agggagtggt taaggcatag gctggtggcc taagtacagc attaatcatt aaggaaccca 1560 ttactgccat ttggaattca aataacctaa ccaacctcca cctcctcctt ccattttgac 1620 caaccttctt ctaacaaggt gctcattcct actatgaatc cagaataaac acgccaagat 1680 aacagctaaa tcagcaaggg ttcctgtatt accaatatag aatactaaca attttactaa 1740 cacgtaagca taacaaatga cagggcaagt gatttctaac ttagttgagt tttgcaacag 1800 tacctgtgtt gttatttcag aaaatattat ttctctcttt ttaactactc ttttttttta 1860 ttttggacag agtcttgctc cgtcgcgcag gctgtgatcg tagtggtgcg atctcggctc 1920 actgcagcct ccgctccctg ggttcaagcg attctcctgc ctgagcctcc tgagtagctg 1980 ggactgcagg cacgtgccac cacgcccggc taattttttg tatttttagt agagatgggg 2040 tttcacgttg ttggccagga tggtctccat ctcctgacct catgatccgc ccaccttggc 2100 ctcccaaaat gctgggatta caggcatgag ccactgcgcc cggcctcttt ttagctactc 2160 ttatgttcca catgcacata tgacaaggtg gcattaatta gattcaatat tatttctagg 2220 aatagttcct cattcatttt tatattgacc actaagaaaa taattcatca gcattatctc 2280 atagattgga aaattttctc caaatacaat agaggagaat atgtaaaggg tatacattaa 2340 ttggtacgta gcatttaaaa tcaggtctta taattaatgc ttcattcctc atattagatt 2400 tcccaagaaa tcaccctggt atccaatatc tgagcatggc aaatttaaaa aataacacaa 2460 tttcttgcct gtaaccctag cactttggga ggccgaggca ggtggatcac ctgaggtcag 2520 gagttcgaga ccagcctggc cggcatggcg aaaccccttc tctgctgaaa atacagaaat 2580 tagctgggcg tggtggtgca tgcctgtagt cccagctact tgggaggctg aggcaggaga 2640 atcgcttgaa cccaggaggt ggaggttgca gtgagccgag attgtgccac tgcactccaa 2700 cctgggtgac agagtgagat tccatctgaa aaacaaaaac aaaaacagaa aacaaacaaa 2760 caaaaaacaa aaaatcccca caactttgtc aaataatgta caggcaaaca ctttcaaata 2820 taatttcctt cagtgaatac aaaatgttga tatcataggt gatgtacaat ttagttttga 2880 atgagttatt atgttatcac tgtgtctgat gttatctact ttgaaaggca gtccagaaaa 2940 gtgttctaag tgaactctta agatctattt tagataattt caactaatta aataacctgt 3000 tttactgcct gtacattcca cattaataaa gcgataccaa tcttatatga atgctaatat 3060 tactaaaatg cactgatatc acttcttctt cccctgttga aaagctttct catgatcata 3120 tttcacccac atctcacctt gaagaaactt acaggtagac ttaccttttc acttgtggaa 3180 ttaatcatat ttaaatctta ctttaaggct caataaataa tactcataat gtctcatttt 3240 agtgactcct aaggctagtc cttttataaa caactttttc tgacatagca tttatgtata 3300 ataaaccaga catttaaagt gta 3323 <210> 8 <211 > 3014

<212> DNA <213> Homo Sapiens <400>8 gtactgaaaa aagtctatac gcaataagta agcccaaaga ggcatgtttg cttggcgatg 60 cccagcagat aagccaggca aacctcggtg tgatcgaaga agccaatttg agactcagcc 120 tagtccaggc aagctactgg cacctgctgc tctcaactaa cctccacaca atggtgttcg 180 cattttggaa ggtctttctg atcctaagct gccttgcagg tcaggttagt gtggtgcaag 240 tgaccatccc agacggtttc gtgaacgtga ctgttggatc taatgtcact ctcatctgca 300 tctacaccac cactgtggcc tcccgagaac agctttccat ccagtggtct ttcttccata 360 agaaggagat ggagccaatt tctatttact tttctcaagg tggacaagct gtagccatcg 420 ggcaatttaa agatcgaatt acagggtcca acgatccagt gaaaccttct aagccccttt 480 gtagcgttca aggaagacca gaaactggcc acactatttc cctttcctgt ctctctgcgc 540 ttggaacacc ttcccctgtg tactactggc ataaacttga gggaagagac atcgtgccag 600 tgaaagaaaa cttcaaccca accaccggga ttttggtcat tggaaatctg acaaattttg 660 aacaaggtta ttaccagtgt actgccatca acagacttgg caatagttcc tgcgaaatcg 720 atctcacttc ttcacatcca gaagttggaa tcattgttgg ggccttgatt ggtagcctgg 780 taggtgccgc catcatcatc tctgttgtgt gcttcgcaag gaataaggca aaagcaaagg 840 caaaagaaag aaattctaag accatcgcgg aacttgagcc aatgacaaag ataaacccaa 900 ggggagaaag cgaagcaatg ccaagagaag acgctaccca actagaagta actctaccat 960 cttccattca tgagactggc cctgatacca tccaagaacc agactatgag ccaaagccta 1020 ctcaggagcc tgccccagag cctgccccag gatcagagcc tatggcagtg cctgaccttg 1080 acatcgagct ggagctggag ccagaaacgc agtcggaatt ggagccagag ccagagccag 1140 agccagagtc agagcctggg gttgtagttg agcccttaag tgaagatgaa aagggagtgg 1200 ttaaggcata ggctggtggc ctaagtacag cattaatcat taaggaaccc attactgcca 1260 tttggaattc aaataaccta accaacctcc acctcctcct tccattttga ccaaccttct 1320 tctaacaagg tgctcattcc tactatgaat ccagaataaa cacgccaaga taacagctaa 1380 atcagcaagg gttcctgtat taccaatata gaatactaac aattttacta acacgtaagc 1440 ataacaaatg acagggcaag tgatttctaa cttagttgag ttttgcaaca gtacctgtgt 1500 tgttatttca gaaaatatta tttctctctt tttaactact cttttttttt attttggaca 1560 gagtcttgct ccgtcgcgca ggctgtgatc gtagtggtgc gatctcggct cactgcagcc 1620 tccgc'tccct gggttcaagc gattctcctg cctgagcctc ctgagtagct gggactgcag 1680 gcacgtgcca ccacgcccgg ctaatttttt gtatttttag tagagatggg gtttcacgtt 1740 gttggccagg atggtctcca tctcctgacc tcatgatccg cccaccttgg cctcccaaaa 1800 tgctgggatt acaggcatga gccactgcgc ccggcctctt tttagctact cttatgttcc 1860 acatgcacat atgacaaggt ggcattaatt agattcaata ttatttctag gaatagttcc 1920 tcattcattt ttatattgac cactaagaaa ataattcatc agcattatct catagattgg 1980 aaaattttct ccaaatacaa tagaggagaa tatgtaaagg gtatacatta attggtacgt 2040 agcatttaaa atcaggtctt ataattaatg cttcattcct catattagat ttcccaagaa 2100 atcaccctgg tatccaatat ctgagcatgg caaatttaaa aaataacaca atttcttgcc 2160 tgtaacccta gcactttggg aggccgaggc aggtggatca cctgaggtca ggagttcgag 2220 accagcctgg ccggcatggc gaaacccctt ctctgctgaa aatacagaaa ttagctgggc 2280 gtggtggtgc atgcctgtag tcccagctac ttgggaggct gaggcaggag aatcgcttga 2340 acccaggagg tggaggttgc agtgagccga gattgtgcca ctgcactcca acctgggtga 2400 cagagtgaga ttccatctga aaaacaaaaa caaaaacaga aaacaaacaa acaaaaaaca 2460 aaaaatcccc acaactttgt caaataatgt acaggcaaac actttcaaat ataatttcct 2520 tcagtgaata caaaatgttg atatcatagg tgatgtacaa tttagttttg aatgagttat 2580 tatgttatca ctgtgtctga tgttatctac tttgaaaggc agtccagaaa agtgttctaa 2640 gtgaactctt aagatctatt ttagataatt tcaactaatt aaataacctg ttttactgcc 2700 tgtacattcc acattaataa agcgatacca atcttatatg aatgctaata ttactaaaat 2760 gcactgatat cacttcttct tcccctgttg aaaagctttc tcatgatcat atttcaccca 2820 catctcacct tgaagaaact tacaggtaga cttacctttt cacttgtgga attaatcata 2880 tttaaatctt actttaaggc tcaataaata atactcataa tgtctcattt tagtgactcc 2940 taaggctagt ccttttataa acaacttttt ctgacatagc atttatgtat aataaaccag 3000 acatttaaag tgta 3014

<210>9 <211> 3135 <212> DNA <213> Homo Sapiens <400>9 gtactgaaaa aagtctatac gcaataagta agcccaaaga ggcatgtttg cttggcgatg 60 cccagcagat aagccaggca aacctcggtg tgatcgaaga agccaatttg agactcagcc 120 tagtccaggc aagctactgg cacctgctgc tctcaactaa cctccacaca atggtgttcg 180 cattttggaa ggtctttctg atcctaagct gccttgcagg tcaggttagt gtggtgcaag 240 tgaccatccc agacggtttc gtgaacgtga ctgttggatc taatgtcact ctcatctgca 300 tctacaccac cactgtggcc tcccgagaac agctttccat ccagtggtct ttcttccata 360 agaaggagat ggagccaatt tctatttact tttctcaagg tggacaagct gtagccatcg 420 ggcaatttaa agatcgaatt acagggtcca acgatccagg taatgcatct atcactatct 480 cgcatatgca gccagcagac agtggaattt acatctgcga tgttaacaac cccccagact 540 ttctcggcca aaaccaaggc atcctcaacg tcagtgtgtt agtgaaacct tctaagcccc 600 tttgtagcgt tcaaggaaga ccagaaactg gccacactat ttccctttcc tgtctctctg 660 cgcttggaac accttcccct gtgtactact ggcataaact tgagggaaga gacatcgtgc 720 cagtgaaaga aaacttcacc aaccaccggg attttggtca ttggaaatct gacaaatttt 780 gaacaaggtt attaccagtg tactgccatc aacagacttg gcaatagttc ctgcgaaatc 840 gatctcactt cttcacatcc agaagttgga atcattgttg gggccttgat tggtagcctg 900 gtaggtgccg ccatcatcat ctctgttgtg tgcttcgcaa ggaataaggc aaaagcaaag 960 gcaaaagaaa gaaattctaa gaccatcgcg gaacttgagc caatgacaaa gataaaccca 1020 aggggagaaa gcgaagcaat gccaagagaa gacgctaccc aactagaagt aactctacca 1080 tcttccattc atgagactgg ccctgatacc atccaagaac cagactatga gccaaagcct 1140 actcaggagc ctgccccaga gcctgcccca ggatcagagc ctatggcagt gcctgacctt 1200 gacatcgagc tggagctgga gccagaaacg cagtcggaat tggagccaga gccagagcca 1260 gagccagagt cagagcctgg ggttgtagtt gagcccttaa gtgaagatga aaagggagtg 1320 gttaaggcat aggctggtgg cctaagtaca gcattaatca ttaaggaacc cattactgcc 1380 atttggaatt caaataacct aaccaacctc cacctcctcc ttccattttg accaaccttc 1440 ttctaacaag gtgctcattc ctactatgaa tccagaataa acacgccaag ataacagcta 1500 aatcagcaag ggttcctgta ttaccaatat agaatactaa caattttact aacacgtaag 1560 cataacaaat gacagggcaa gtgatttcta acttagttga gttttgcaac agtacctgtg 1620 ttgttatttc agaaaatatt atttctctct ttttaactac tctttttttt tattttggac 1680 agagtcttgc tccgtcgcgc aggctgtgat cgtagtggtg cgatctcggc tcactgcagc 1740 ctccgctccc tgggttcaag cgattctcct gcctgagcct cctgagtagc tgggactgca 1800 ggcacgtgcc accacgcccg gctaattttt tgtattttta gtagagatgg ggtttcacgt 1860 tgttggccag gatggtctcc atctcctgac ctcatgatcc gcccaccttg gcctcccaaa 1920 atgctgggat tacaggcatg agccactgcg cccggcctct ttttagctac tcttatgttc 1980 cacatgcaca tatgacaagg tggcattaat tagattcaat attatttcta ggaatagttc 2040 ctcattcatt tttatattga ccactaagaa aataattcat cagcattatc tcatagattg 2100 gaaaattttc tccaaataca atagaggaga atatgtaaag ggtatacatt aattggtacg 2160 tagcatttaa aatcaggtct tataattaat gcttcattcc tcatattaga tttcccaaga 2220 aatcaccctg gtatccaata tctgagcatg gcaaatttaa aaaataacac aatttcttgc 2280 ctgtaaccct agcactttgg gaggccgagg caggtggatc acctgaggtc aggagttcga 2340 gaccagcctg gccggcatgg cgaaacccct tctctgctga aaatacagaa attagctggg 2400 cgtggtggtg catgcctgca gtcccagcta cttgggaggc tgaggcagga gaatcgcttg 2460 aacccaggag gtggaggttg cagtgagccg agattgtgcc actgcactcc aacctgggtg 2520 acagagtgag attccatctg aaaaacaaaa acaaaaacag aaaacaaaca aacaaaaaac 2580 aaaaaatccc cacaactttg tcaaataatg tacaggcaaa cactttcaaa tataatttcc 2640 ttcagtgaat acaaaatgtt gatatcatag gtgatgtaca atttagtttt gaatgagtta 2700 ttatgttatc actgtgtctg atgttatcta ctttgaaagg cagtccagaa aagtgttcta 2760 agtgaactct taagatctat tttagataat ttcaactaat taaataacct gttttactgc 2820 ctgtacattc cacattaata aagcgatacc aatcttatat gaatgctaat attactaaaa 2880 tgcactgata tcacttcttc ttcccctgtt gaaaagcttt ctcatgatca tatttcaccc 2940 acatctcacc ttgaagaaac ttacaggtag acttaccttt tcacttgtgg aattaatcat 3000 atttaaatct tactttaagg ctcaataaat aatactcata atgtctcatt ttagtgactc 3060 ctaaggctag tccttttata aacaactttt tctgacatag catttatgta taataaacca 3120 gacatttaaa gtgta 3135 <210> 10 <211 >2995

<212> DNA <213> Homo Sapiens <400> 10 gtactgaaaa aagtctatac gcaataagta agcccaaaga ggcatgtttg cttggcgatg 60 cccagcagat aagccaggca aacctcggtg tgatcgaaga agccaatttg agactcagcc 120 tagtccaggc aagctactgg cacctgctgc tctcaactaa cctccacaca atggtgttcg 180 cattttggaa ggtctttctg atcctaagct gccttgcagg tcaggttagt gtggtgcaag 240 tgaccatccc agacggtttc gtgaacgtga ctgttggatc taatgtcact ctcatctgca 300 tctacaccac cactgtggcc tcccgagaac agctttccat ccagtggtct ttcttccata 360 agaaggagat ggagccaatt tctatttact tttctcaagg tggacaagct gtagccatcg 420 ggcaatttaa agatcgaatt acagggtcca acgatccagg taatgcatct atcactatct 480 cgcatatgca gccagcagac agtggaattt acatctgcga tgttaacaac cccccagact 540 ttctcggcca aaaccaaggc atcctcaacg tcagtgtgtt agtgaaacct tctaagcccc 600 tttgtagcgt tcaaggaaga ccagaaactg gccacactat ttccctttcc tgtctctctg 660 cgcttggaac accttcccct gtgtactact ggcataaact tgagggaaga gacatcgtgc 720 cagtgaaaga aaacttcaac ccaaccaccg ggattttggt cattggaaat ctgacaaatt 780 ttgaacaagg ttattaccag tgtactgcca tcaacagact tggcaatagt tcctgcgaaa 840 tcgatctcac ttcttcacgc caatgacaaa gataaaccca aggggagaaa gcgaagcaat 900 gccaagagaa gacgctaccc aactagaagt aactctacca tcttccattc atgagactgg 960 ccctgatacc atccaagaac cagactatga gccaaagcct actcaggagc ctgccccaga 1020 gcctgcccca ggatcagagc ctatggcagt gcctgacctt gacatcgagc tggagctgga 1080 gccagaaacg cagtcggaat tggagccaga gccagagcca gagccagagt cagagcctgg 1140 ggttgtagtt gagcccttaa gtgaagatga aaagggagtg gttaaggcat aggctggtgg 1200 cctaagtaca gcattaatca ttaaggaacc cattactgcc atttggaatt caaataacct 1260 aaccaacctc cacctcctcc ttccattttg accaaccttc ttctaacaag gtgctcattc 1320 ctactatgaa tccagaataa acacgccaag ataacagcta aatcagcaag ggttcctgta 1380 ttaccaatat agaatactaa caattttact aacacgtaag cataacaaat gacagggcaa 1440 gtgatttcta acttagttga gttttgcaac agtacctgtg ttgttatttc agaaaatatt 1500 atttctctct ttttaactac tctttttttt tattttggac agagtcttgc tccgtcgcgc 1560 aggctgtgat cgtagtggtg cgatctcggc tcactgcagc ctccgctccc tgggttcaag 1620 cgattctcct gcctgagcct cctgagtagc tgggactgca ggcacgtgcc accacgcccg 1680 gctaattttt tgtattttta gtagagatgg ggtttcacgt tgttggccag gatggtctcc 1740 atctcctgac ctcatgatcc gcccaccttg gcctcccaaa atgctgggat tacaggcatg 1800 agccactgcg cccggcctct ttttagctac tcttatgttc cacatgcaca tatgacaagg 1860 tggcattaat tagattcaat attatttcta ggaatagttc ctcattcatt tttatattga 1920 ccactaagaa aataattcat cagcattatc tcatagattg gaaaattttc tccaaataca 1980 atagaggaga atatgtaaag ggtatacatt aattggtacg tagcatttaa aatcaggtct 2040 tataattaat gcttcattcc tcatattaga tttcccaaga aatcaccctg gtatccaata 2100 tctgagcatg gcaaatttaa aaaataacac aatttcttgc ctgtaaccct agcactttgg 2160 gaggccgagg caggtggatc acctgaggtc aggagttcga gaccagcctg gccggcatgg 2220 cgaaacccct tctctgctga aaatacagaa attagctggg cgtggtggtg catgcctgta 2280 gtcccagcta cttgggaggc tgaggcagga gaatcgcttg aacccaggag gtggaggttg 2340 cagtgagccg agattgtgcc actgcactcc aacctgggtg acagagtgag attccatctg 2400 aaaaacaaaa acaaaaacag aaaacaaaca aacaaaaaac aaaaaatccc cacaactttg 2460 tcaaataatg tacaggcaaa cactttcaaa tataatttcc ttcagtgaat acaaaatgtt 2520 gatatcatag gtgatgtaca atttagtttt gaatgagtta ttatgttatc actgtgtctg 2580 atgttatcta ctttgaaagg cagtccagaa aagtgttcta agtgaactct taagatctat 2640 tttagataat ttcaactaat taaataacct gttttactgc ctgtacattc cacattaata 2700 aagcgatacc aatcttatat gaatgctaat attactaaaa tgcactgata tcacttcttc 2760 ttcccctgtt gaaaagcttt ctcatgatca tatttcaccc acatctcacc ttgaagaaac 2820 ttacaggtag acttaccttt tcacttgtgg aattaatcat atttaaatct tactttaagg 2880 ctcaataaat aatactcata atgtctcatt ttagtgactc ctaaggctag tccttttata 2940 aacaactttt tctgacatag catttatgta taataaacca gacatttaaa gtgta 2995 <210 11 <211 > 387

<212> PRT <213> Homo Sapiens <400 11

Met Val Phe Ala Phe Trp Lys Val Phe Leu lie Leu Ser Cys Leu Ala 1 5 10 15

Gly Gin Val Ser Val Val Gin Val Thr lie Pro Asp Gly Phe Val Asn 20 25 30

Val Thr Val Gly Ser Asn Val Thr Leu Ile Cys Ile Tyr Thr Thr Thr 35 40 45

Val Ala Ser Arg Glu Gin Leu Ser He Gin Trp Ser Phe Phe His Lys 50 55 60

Lys Glu Met Glu Pro He Ser He Tyr Phe Ser Gin Gly Gly Gin Ala 65 70 75 80

Val Ala He Gly Gin Phe Lys Asp Arg He Thr Gly Ser Asn Asp Pro 85 90 95

Gly Asn Ala Ser He Thr He Ser His Met Gin Pro Ala Asp Ser Gly 100 105 110

He Tyr He Cys Asp Val Asn Asn Pro Pro Asp Phe Leu Gly Gin Asn 115 120 125

Gin Gly lie Leu Asn Val Ser Val Leu Val Lys Pro Ser Lys Pro Leu 130 135 140

Cys Ser Val Gin Gly Arg Pro Glu Thr Gly His Thr He Ser Leu Ser 145 150 155 160

Cys Leu Ser Ala Leu Gly Thr Pro Ser Pro Val Tyr Tyr Trp His Lys 165 170 175

Leu Glu Gly Arg Asp He Val Pro Val Lys Glu Asn Phe Asn Pro Thr 180 185 190

Thr Gly Ile Leu Val Ile Gly Asn Leu Thr Asn Phe Glu Gin Gly Tyr 195 200 205

Tyr Gin Cys Thr Ala Ile Asn Arg Leu Gly Asn Ser Ser Cys Glu Ile 210 215 220

Asp Leu Thr Ser Ser His Pro Glu Val Gly Ile Ile Val Gly Ala Leu 225 230 235 240

Ile Gly Ser Leu Val Gly Ala Ala Ile Ile Ile Ser Val Val Cys Phe 245 250 255

Ala Arg Asn Lys Ala Lys Ala Lys Ala Lys Glu Arg Asn Ser Lys Thr 260 265 270

Ile Ala Glu Leu Glu Pro Met Thr Lys Ile Asn Pro Arg Gly Glu Ser 275 280 285

Glu Ala Met Pro Arg Glu Asp Ala Thr Gin Leu Glu Val Thr Leu Pro 290 295 300

Ser Ser Ile His Glu Thr Gly Pro Asp Thr Ile Gin Glu Pro Asp Tyr 305 310 315 320

Glu Pro Lys Pro Thr Gin Glu Pro Ala Pro Glu Pro Ala Pro Gly Ser 325 330 335

Glu Pro Met Ala Val Pro Asp Leu Asp Ile Glu Leu Glu Leu Glu Pro 340 345 350

Glu Thr Gin Ser Glu Leu Glu Pro Glu Pro Glu Pro Glu Pro Glu Ser 355 360 365

Glu Pro Gly Val Val Val Glu Pro Leu Ser Glu Asp Glu Lys Gly Val 370 375 380

Val Lys Ala 385 <210> 12 <211 > 423

<212> PRT <213> Homo Sapiens <400> 12

Met Val Phe Ala Phe Trp Lys Val Phe Leu lie Leu Ser Cys Leu Ala 15 10 15

Gly Gin Val Ser Val Val Gin Val Thr lie Pro Asp Gly Phe Val Asn 20 25 30

Val Thr Val Gly Ser Asn Val Thr Leu Ile Cys Ile Tyr Thr Thr Thr 35 40 45 val Ala Ser Arg Glu Gin Leu Ser Ile Gin Trp Ser Phe Phe His Lys 50 55 60

Lys Glu Met Glu Pro lie Ser His Ser Ser Cys Leu Ser Thr Glu Gly 65 70 75 80

Met Glu Glu Lys Ala Val Gly Gin Cys Leu Lys Met Thr His Val Arg 85 90 95

Asp Ala Arg Gly Arg Cys Ser Trp Thr Ser Glu lie Tyr Phe Ser Gin 100 105 110

Gly Gly Gin Ala Val Ala lie Gly Gin Phe Lys Asp Arg lie Thr Gly 115 120 · 125

Ser Asn Asp Pro Gly Asn Ala Ser lie Thr lie Ser His Met Gin Pro 130 135 140

Ala Asp Ser Gly lie Tyr lie Cys Asp Val Asn Asn Pro Pro Asp Phe 145 150 155 160

Leu Gly Gin Asn Gin Gly lie Leu Asn Val Ser Val Leu Val Lys Pro 165 170 175

Ser Lys Pro Leu Cys Ser Val Gin Gly Arg Pro Glu Thr Gly His Thr 180 185 190

He Ser Leu Ser Cys Leu Ser Ala Leu Gly Thr Pro Ser Pro Val Tyr 195 200 205

Tyr Trp His Lys Leu Glu Gly Arg Asp lie Val Pro Val Lys Glu Asn. 210 215 220

Phe Asn Pro Thr Thr Gly lie Leu Val He Gly Asn Leu Thr Asn Phe 225 230 235 240

Glu Gin Gly Tyr Tyr Gin Cys Thr Ala He Asn Arg Leu Gly Asn Ser 260 265 270

Val Gly Ala Leu Ile Gly Ser Leu Val Gly Ala Ala Ile Ile Ile Ser 275 280 285

Val Val Cys Phe Ala Arg Asn Lys Ala Lys Ala Lys Ala Lys Glu Arg 290 295 300

Asn Ser Lys Thr ile Ala Glu Leu Glu Pro Met Thr Lys Ile Asn Pro 305 310 315 320

Arg Gly Glu Ser Glu Ala Met Pro Arg Glu Asp Ala Thr Gin Leu Glu 325 330 335

Val Thr Leu Pro Ser Ser ile His Glu Thr Gly Pro Asp Thr Ile Gin 340 345 350

Glu Pro Asp Tyr Glu Pro Lys Pro Thr Gin Glu Pro Ala Pro Glu Pro 355 360 365

Ala Pro Gly Ser Glu Pro Met Ala Val Pro Asp Leu Asp Ile Glu Leu 370 375 380

Glu Leu Glu Pro Glu Thr Gin Ser Glu Leu Glu Pro Glu Pro Glu Pro 385 390 395 400

Glu Pro Glu Ser Glu Pro Gly Val Val Val Glu Pro Leu Ser Glu Asp 405 410 415

Glu Lys Gly Val Val Lys Ala 420 <210> 13 <211 >449

<212> PRT <213> Homo Sapiens <400> 13

Met Val Phe Ala Phe Trp Lys Val Phe Leu Ile Leu Ser Cys Leu Ala 15 10 15

Gly Gin Val Ser Val Val Gin Val Thr Ile Pro Asp Gly Phe Val Asn 20 25 30

Val Thr Val Gly Ser Asn Val Thr Leu Ile Cys Ile Tyr Thr Thr TUr 35 40 45

Val Ala Ser Arg Glu Gin Leu Ser Ile Gin Trp Ser Phe Phe His Lys 50 55 60

Lys Glu Met Glu Pro Ile Ser His Ser Ser Cys Leu Ser Thr Glu Gly 65 70 75 80

Met Glu Glu Lys Ala Val Gly Gin Cys Leu Lys Met Thr His Val Arg 85 90 95

Asp Ala Arg Gly Arg Cys Ser Trp Thr Ser Glu Ser Pro Trp Glu Glu 100 105 110

Gly Lys Trp Pro Asp Val Glu Ala Val Lys Gly Thr Leu Asp Gly Gin 115 120 125

Gin Ala Glu Leu Gin Ile Tyr Phe Ser Gin Gly Gly Gin Ala Val Ala 130 135 140

Ile Gly Gin Phe Lys Asp Arg Ile Thr Gly Ser Asn Asp Pro Gly Asn 145 150 155 160

Ala Ser Ile Thr Ile Ser His Met Gin Pro Ala Asp Ser Gly Ile Tyr 165 170 175

Ile Cys Asp Val Asn Asn Pro Pro Asp Phe Leu Gly Gin Asn Gin Gly 180 185 190

Ile Leu Asn Val Ser Val Leu Val Lys Pro Ser Lys Pro Leu Cys Ser 195 200 205

Val Gin Gly Arg Pro Glu Thr Gly His Thr Ile Ser Leu Ser Cys Leu 210 215 220

Ser Ala Leu Gly Thr Pro Ser Pro Val Tyr Tyr Trp His Lys Leu Glu 225 230 235 240

Gly Arg Asp Ile Val Pro Val Lys Glu Asn Phe Asn Pro Thr Thr Gly 245 250 255

Ile Leu Val Ile Gly Asn Leu Thr Asn Phe Glu Gin Gly Tyr Tyr Gin 260 265 270 275 280 285

Thr Ser Ser His Pro Glu Val Gly Ile Ile Val Gly Ala Leu Ile Gly 290 295 300

Ser Leu Val Gly Ala Ala Ile Ile Ile Ser Val Val Cys Phe Ala Arg 305 310 315 320

Asn Lys Ala Lys Ala Lys Ala Lys Glu Arg Asn Ser Lys Thr Ile Ala 325 330 335

Glu Leu Glu Pro Met Thr Lys Ile Asn Pro Arg Gly Glu Ser Glu Ala 340 345 350

Met Pro Arg Glu Asp Ala Thr Gin Leu Glu Val Thr Leu Pro Ser Ser 355 360 365

Ile His Glu Thr Gly Pro Asp Thr Ile Gin Glu Pro Asp Tyr Glu Pro 370 375 380

Lys Pro Thr Gin Glu Pro Ala Pro Glu Pro Ala Pro Gly Ser Glu Pro 385 390 395 400

Met Ala Val Pro Asp Leu Asp Ile Glu Leu Glu Leu Glu Pro Glu Thr 405 410 415

Gin Ser Glu Leu Glu Pro Glu Pro Glu Pro Glu Pro Glu Ser Glu Pro 420 425 430

Gly Val Val Val Glu Pro Leu Ser Glu Asp Glu Lys Gly Val Val Lys 435 440 445

Ala <210> 14 <211 > 346

<212> PRT <213> Homo Sapiens <400> 14

Met Val Phe Ala Phe Trp Lys Val Phe Leu Ile Leu Ser Cys Leu Ala 15 10 15

Gly Gin Val Ser Val Val Gin Val Thr Ile Pro Asp Gly Phe Val Asn 20 25 30

Val Thr Val Gly Ser Asn Val Thr Leu Ile Cys Ile Tyr Thr Thr Thr 35 40 45

Val Ala Ser Arg Glu Gin Leu Ser Ile Gin Trp Ser Phe Phe His Lys 50 55 60

Lys Glu Met Glu Pro Ile Ser Ile Tyr Phe Ser Gin Gly Gly Gin Ala 65 70 75 80

Val Ala Ile Gly Gin Phe Lys Asp Arg Ile Thr Gly Ser Asn Asp Pro 85 90 95

Val Lys Pro Ser Lys Pro Leu Cys Ser Val Gin Gly Arg Pro Glu Thr 100 105 110

Gly His Thr Ile Ser Leu Ser Cys Leu Ser Ala Leu Gly Thr Pro Ser 115 120 125

Pro Val Tyr Tyr Trp His Lys Leu Glu Gly Arg Asp Ile Val Pro Val 130 135 140

Lys Glu Asn Phe Asn Pro Thr Thr Gly Ile Leu Val Ile Gly Asn Leu 145 150 155 160

Thr Asn Phe Glu Gin Gly Tyr Tyr Gin Cys Thr Ala Ile Asn Arg Leu 165 170 175

Gly Asn Ser Ser Cys Glu Ile Asp Leu Thr Ser Ser His Pro Glu Val 180 185 190

Gly Ile Ile Val Gly Ala Leu Ile Gly Ser Leu Val Gly Ala Ala Ile 195 200 205

Ile Ile Ser Val Val Cys Phe Ala Arg Asn Lys Ala Lys Ala Lys Ala 210 215 220

Lys Glu Arg Asn Ser Lys Thr Ile Ala Glu Leu Glu Pro Met Thr Lys 225 230 235 240

Ile Asn Pro Arg Gly Glu Ser Glu Ala Met Pro Arg Glu Asp Ala Thr 245 250 255

Gin Leu Glu Val Thr Leu Pro Ser Ser Ile His Glu Thr Gly Pro Asp 260 265 270

Thr Ile Gin Glu Pro Asp Tyr Glu Pro Lys Pro Thr Gin Glu Pro Ala 275 280 285

Pro Glu Pro Ala Pro Gly Ser Glu Pro Met Ala Val Pro Asp Leu Asp 290 295 300

Ile Glu Leu Glu Leu Glu Pro Glu Thr Gin Ser Glu Leu Glu Pro Glu 305 310 315 320

Pro Glu Pro Glu Pro Glu Ser Glu Pro Gly Val Val Val Glu Pro Leu 325 330 335

Ser Glu Asp Glu Lys Gly Val Val Lys Ala 340 345 <210> 15 <211 > 203

<212> PRT <213> Homo Sapiens <400> 15

Met Val Phe Ala Phe Trp Lys Val Phe Leu lie Leu Ser Cys Leu Ala 15 10 15

Gly Gin Val Ser Val Val Gin Val Thr lie Pro Asp Gly Phe Val Asn 20 25 30

Val Thr Val Gly Ser Asn Val Thr Leu Ile Cys Ile Tyr Thr Thr Thr 35 40 45

Val Ala Ser Arg Glu Gin Leu Ser Ile Gin Trp Ser Phe Phe His Lys 50 55 60

Lys Glu Met Glu Pro lie Ser lie Tyr Phe Ser Gin Gly Gly Gin Ala 65 70 75 80

Val Ala lie Gly Gin Phe Lys Asp Arg lie Thr Gly Ser Asn Asp Pro 85 90 95

Gly Asn Ala Ser lie Thr lie Ser His Met Gin Pro Ala Asp Ser Gly 100 105 110 lie Tyr lie Cys Asp Val Asn Asn Pro Pro Asp Phe Leu Gly Gin Asn 115 120 125

Gin Gly lie Leu Asn Val Ser Val Leu Val Lys Pro Ser Lys Pro Leu 130 135 140

Cys Ser Val Gin Gly Arg Pro Glu Thr Gly His Thr He Ser Leu Ser 145 150 155 160

Cys Leu Ser Ala Leu Gly Thr Pro Ser Pro Val Tyr Tyr Trp His Lys 165 170 175

Leu Glu Gly Arg Asp lie Val Pro Val Lys Glu Asn Phe Thr Asn His 180 185 190

Arg Asp Phe Gly His Trp Lys Ser Asp Lys Phe 195 200 <210> 16 <211> 231

<212> PRT <213> Homo Sapiens <400> 16

Met Val Phe Ala Phe Trp Lys Val Phe Leu lie Leu Ser Cys Leu Ala 15 10 15

Gly Gin Val Ser Val Val Gin Val Thr He Pro Asp Gly Phe Val Asn 20 25 30

Val Thr Val Gly Ser Asn Val Thr Leu He Cys He Tyr Thr Thr Thr 35 40 45

Val Ala Ser Arg Glu Gin Leu Ser He Gin Trp Ser Phe Phe His Lys 50 55 60

Lys Glu Met Glu Pro He Ser He Tyr Phe Ser Gin Gly Gly Gin Ala 65 70 75 80

Val Ala lie Gly Gin Phe Lys Asp Arg He Thr Gly Ser Asn Asp Pro 85 90 95

Gly Asn Ala Ser lie Thr He Ser His Met Gin Pro Ala Asp Ser Gly 100 105 110 lie Tyr lie Cys Asp Val Asn Asn Pro Pro Asp Phe Leu Gly Gin Asn 115 120 125

Gin Gly Ile Leu Asn Val Ser Val Leu Val Lys Pro Ser Lys Pro Leu 130 135 140

Cys Ser Val Gin Gly Arg Pro Glu Thr Gly His Thr Ile Ser Leu Ser 145 150 155 160

Cys Leu Ser Ala Leu Gly Thr Pro Ser Pro Val Tyr Tyr Trp His Lys 165 170 175

Leu Glu Gly Arg Asp lie Val Pro Val Lys Glu Asn Phe Asn Pro Thr 180 185 190

Thr Gly lie Leu Val lie Gly Asn Leu Thr Asn Phe Glu Gin Gly Tyr 195 200 205

Tyr Gin Cys Thr Ala lie Asn Arg Leu Gly Asn Ser Ser Cys Glu lie 210 215 220

Asp Leu Thr Ser Ser Arg Gin 225 230 <210> 17 <211 >2888

<212> DNA <213> Homo Sapiens <400> 17 . agccgtgggg agcgccgcag gtggggacga gccgggcggc acctgccccg ggaccagagc 60 ggacgctccc tccccgctgc gccgagggag gggaaacccg aggggttcct tggagaaggt 120 ggtgcgtcct ggggcggcag ctgaggaaga aagacgcagt gccccgaagc ccctgagctg 180 aaaagggcca gaaagggggc ggcatggcat ggcccaaact gcccgcacct tggctgctgc 240 tctgcacctg gctcccagca gggtgcctgt ccttgcttgt gacggtccag cacacagaac 300 gctatgtcac cctgtttgcc tctatcatcc tcaaatgtga ctacaccacc tctgcccagc 360 tccaggacgt ggtggtgaca tggcgcttca agtccttctg caaggaccct atctttgact 420 actactcagc gtcataccag gcagctttat ccctgggcca ggacccatcc aatgactgca 480 acgacaacca gcgggaagtt cgcatagtgg cccagcggcg ggggcagaat gagcccgtgc 540 tgggggtaga ttaccggcag cgcaagatca ccatccagaa ccgagcagat ctcgtgataa 600 atgaagtgat gtggtgggac catggagtgt attactgcac cattgaggct ccaggggaca 660 catcaggaga ccccgataag gaagtaaagc tcatcgtcct acactggctg acagtgatct 720 tcatcatcct gggagccctc ctcctcctgc tgctgattgg agtgtgctgg tgccagtgct 780 gtcctcagta ttgctgctgc tatatccgct gtccctgctg tcctgcccac tgctgctgtc B40 ctgaggaagc cctggcccgc caccgctaca tgaagcaggc ccaggcccta ggtcctcaga 900 tgatgggaaa acccctgtac tggggggcgg acaggagctc ccaggtttca tcttatccaa 960 tgcacccgct gctgcagcga gatttgtccc tgccgtccag cctcccgcag atgccaatga 1020 cccagaccac caatcagcct cccatcgcca atggtgtcct ggagtatttg gagaaagaac 1080 tgcggaacct caacctggcc cagcctctgc cccctgacct caaaggcaga tttggccatc 1140 cctgcagcat gctgtcctcc ctgggctctg aggtcgtgga acgcagaatc atccacctgc 1200 ccccactgat cagagacctg tcatcctcaa ggaggaccag tgactccctg caccagcagt 1260 ggctcacccc aattccctcc aggccctggg atctgaggga ggggagaagc caccaccatt 1320 accctgattt ccaccaggag ctecaggace gggggccaaa gtcttgggca ttggaaagaa 1380 gggagttgga cccatcgtgg agtggaaggc accgtagctc taggctgaat gggtcaccca 1440 tacactggtc agacagggac agcctaagcg atgtcccctc atccagtgag gcacgctggc 1500 ggccgagcca ccctcctttc aggagccgct gtcaggagag gccccgcagg cccagccccc 1560 gggagagcac tcagaggcac gggagacgac gcaggcaccg cagctactct cctcccttgc 1620 cctccggcct cagttcctgg agctctgaag aggacaagga gaggcagccc cagagctggc 1680 gggcccaccg ccgcggctcg cactccccac actggcccga ggagaagccg cctagctacc 1740 gctcactgga tatcactcca ggcaagaata gcaggaaaaa agggagtgtg gagaggcgct 1800 cggagaaaga cagctctcat agtggaagga gtgtggtcat ttagtcacca agcacagcac 1860 aacttctgtg gctacttctc ggctcctgtg tgtcatcagc atcacctagg tttccagctg 1920 acttgggaac tgcaagtctg agtctaacag tttttggctt agattctgag aatcaaatag 1980 aagaatttta aatacaagag tttgagattg ggtatagtgg ctcacacctg taatcacagc 2040 actttgggag gctaagaatc acttgagact aggagttcaa gatcagcctg ggaaacatag 2100 tgagaccccg tctctacaaa aaatataaaa attagttagg tgtggtggca tgcacttgta 2160 gtcccagcta ctcaagaggc tgaggcagaa ggatcccttg agcccaggag tgcaaggctg 2220 caatgagcca ggatcccatg atcacacatc tgtattccag cctgggcaat agagcaagtc 2280 cccattacta aaaaacccaa aaggccaaaa aacaaaaaag ttagagttcg aggaattacc 2340 aactgtagtt ttagccttgg ttcatgctct cttgcatatt tatataatct ctgacttgta 2400 atggaccctg actggaatgt gatccctcag gaacttagta gcctgagtct ttcagtagac 2460 tacactgccc agaaccctgg ccattctcaa aatgagaact tgggaatgtt taagaagaaa 2520 tcaaacatgt ttcaggaaaa ggaaatctat ggagtattat agggacattc ccatgggaat 2580 gtatcttcct ccatggcatg tcttgagggt cctttcttgt taggagttta tcctgccagc 2640 ccataaatgg actatttatt gtaagtgtag aaaatcacag agaagcagtt ttgcaccagc 2700 cttattcctg tgccttgttt tcctcttgct ctttttttac ctgtatatct aatttatatt 2760 ttcatatata ttgtgtattg attgaagtca ctttaaatcc ttcttgggaa tgacacagta 2820 tataaataag gaagaaagaa aacatgccaa gctgagcatg ctgctccaaa taaatatctg 2880 ctttccta 2888 <210> 18 <211 >2756

<212> DNA <213> Homo Sapiens <400> 18 agccgtgggg agcgccgcag gtggggacga gccgggcggc acctgccccg ggaccagagc 60 ggacgctccc tccccgctgc gccgagggag gggaaacccg aggggttcct tggagaaggt 120 ggtgcgtcct ggggcggcag ctgaggaaga aagacgcagt gccccgaagc ccctgagctg 180 aaaagggcca gaaagggggc ggcatggcat ggcccaaact gcccgcacct tggctgctgc 240 tctgcacctg gctcccagca gggtgcctgt ccttgcttgt gacggtccag cacacagaac 300 gctatgtcac cctgtttgcc tctatcatcc tcaaatgtga ctacaccacc tctgcccagc 360 tccaggacgt ggtggtgaca tggcgcttca agtccttctg caaggaccct atctttgact 420 actactcagc gtcataccag gcagctttat ccctgggcca ggacccatcc aatgactgca 480 acgacaacca gcgggaagtt cgcatagtgg cccagcggcg ggggcagaat gagcccgtgc 540 tgggggtaga ttaccggcag cgcaagatca ccatccagaa ccgagcagat ctcgtgataa 600 atgaagtgat gtggtgggac catggagtgt attactgcac cattgaggct ccaggggaca 660 catcaggaga ccccgataag gaagtaaagc tcatcgtect acactggctg acagtgatct 720 tcatcatcct gggagccctc ctcctcctgc tgctgattgg agtgtgctgg tgccagtgct 780 gtcctcagta ttgctgctgc tatatccgct gtccctgctg tcctgcccac tgctgctgtc 840 ctgaggaaga tttgtccctg ccgtccagcc tcccgcagat gccaatgacc cagaccacca 900 atcagcctcc catcgccaat ggtgtcctgg agtatttgga gaaagaactg cggaacctca 960 acctggccca gcctctgccc cctgacctca aaggcagatt tggccatccc tgcagcatgc 1020 tgtcctccct gggctctgag gtcgtggaac gcagaatcat ccacctgccc ccactgatca 1080 gagacctgtc atcctcaagg aggaccagtg actccctgca ccagcagtgg ctcaccccaa 1140 ttccctccag gccctgggat ctgagggagg ggagaagcca ccaccattac cctgatttcc 1200 accaggagct ccaggaccgg gggccaaagt cttgggcatt ggaaagaagg gagttggacc 1260 catcgtggag tggaaggcac cgtagctcta ggctgaatgg gtcacccata cactggtcag 1320 acagggacag cctaagcgat gtcccctcat ccagtgaggc acgctggcgg ccgagccacc 1380 ctcctttcag gagccgctgt caggagaggc cccgcaggcc cagcccccgg gagagcactc 1440 agaggcacgg gagacgacgc aggcaccgca gctactctcc tcccttgccc tccggcctca 1500 gttcctggag ctctgaagag gacaaggaga ggcagcccca gagctggcgg gcccaccgcc 1560 gcggctcgca ctccccacac tggcccgagg agaagccgcc tagctaccgc tcactggata 1620 tcactccagg caagaatagc aggaaaaaag ggagtgtgga gaggcgctcg gagaaagaca 1680 gctctcatag tggaaggagt gtggtcattt agtcaccaag cacagcacaa cttctgtggc 1740 tacttctcgg ctcctgtgtg tcatcagcat cacctaggtt tccagctgac ttgggaactg 1800 caagtctgag tctaacagtt tttggcttag attctgagaa tcaaatagaa gaattttaaa 1860 tacaagagtt tgagattggg tatagtggct cacacctgta atcacagcac tttgggaggc 1920 taagaatcac ttgagactag gagttcaaga tcagcctggg aaacatagtg agaccccgtc 1980 tctacaaaaa atataaaaat tagttaggtg tggtggcatg cacttgtagt cccagctact 2040 caagaggctg aggcagaagg atcccttgag cccaggagtg caaggctgca atgagccagg 2100 atcccatgat cacacatctg tattccagcc tgggcaatag agcaagtccc cattactaaa 2160 aaacccaaaa ggccaaaaaa caaaaaagtt agagttcgag gaattaccaa ctgtagtttt 2220 agccttggtt catgctctct tgcatattta tataatctct gacttgtaat ggaccctgac 2280 tggaatgtga tccctcagga acttagtagc ctgagtcttt cagtagacta cactgcccag 2340 aaccctggcc attctcaaaa tgagaacttg ggaatgttta agaagaaatc aaacatgttt 2400 caggaaaagg aaatctatgg agtattatag ggacattccc atgggaatgt atcttcctcc 2460 atggcatgtc ttgagggtcc tttcttgtta ggagtttatc ctgccagccc ataaatggac 2520 tatttattgt aagtgtagaa aatcacagag aagcagtttt gcaccagcct tattcctgtg 2580 ccttgttttc ctcttgctct ttttttacct gtatatctaa tttatatttt catatatatt 2640 gtgtattgat tgaagtcact ttaaatcctt cttgggaatg acacagtata taaataagga 2700 agaaagaaaa catgccaagc tgagcatgct gctccaaata aatatctgct ttccta 2756 <210> 19 <211> 2621

<212> DNA <213> Homo Sapiens <400> 19 agccgtgggg agcgccgcag gtggggacga gccgggcggc acctgccccg ggaccagagc 60 ggacgctccc tccccgctgc gccgagggag gggaaacccg aggggttcct tggagaaggt 120 ggtgcgtcct ggggcggcag ctgaggaaga aagacgcagt gccccgaagc ccctgagctg 180 aaaagggcca gaaagggggc ggcatggcat ggcccaaact gcccgcacct tggctgctgc 240 tctgcacctg gctcccagca gggtgcctgt ccttgcttgt gacggtccag cacacagaac 300 gctatgtcac cctgtttgcc tctatcatcc tcaaatgtga ctacaccacc tctgcccagc 360 tccaggacgt ggtggtgaca tggcgcttca agtccttctg caaggaccct atctttgact 420 actactcagc gtcataccag gcagctttat ccctgggcca ggacccatcc aatgactgca 480 acgacaacca gcgggaagtt cgcatagtgg cccagcggcg ggggcagaat gagcccgtgc 540 tgggggtaga ttaccggcag cgcaagatca ccatccagaa ccccctggcc cgccaccgct 600 acatgaagca ggcccaggcc ctaggtcctc agatgatggg aaaacccctg tactgggggg 660 cggacaggag ctcccaggtt tcatcttatc caatgcaccc gctgctgcag cgagatttgt 720 ccctgccgtc cagcctcccg cagatgccaa tgacccagac caccaatcag cctcccatcg 780 ccaatggtgt cctggagtat ttggagaaag aactgcggaa cctcaacctg gcccagcctc 840 tgccccctga cctcaaaggc agatttggcc atccctgcag catgctgtcc tccctgggct 900 ctgaggtcgt ggaacgcaga atcatccacc tgcccccact gatcagagac ctgtcatcct 960 caaggaggac cagtgactcc ctgcaccagc agtggctcac cccaattccc tccaggccct 1020 gggatctgag ggaggggaga agccaccacc attaccctga tttccaccag gagctccagg 1080 accgggggcc aaagtcttgg gcattggaaa gaagggagtt ggacccatcg tggagtggaa 1140 ggcaccgtag ctctaggctg aatgggtcac ccatacactg gtcagacagg gacagcctaa 1200 gcgatgtccc ctcatccagt gaggcacgct ggcggccgag ccaccctcct ttcaggagcc 1260 gctgtcagga gaggccccgc aggcccagcc cccgggagag cactcagagg cacgggagac 1320 gacgcaggca ccgcagctac tctcctccct tgccctccgg cctcagttcc tggagctctg 1380 aagaggacaa ggagaggcag ccccagagct ggcgggccca ccgccgcggc tcgcactccc 1440 cacactggcc cgaggagaag ccgcctagct accgctcact ggatatcact ccaggcaaga 1500 atagcaggaa aaaagggagt gtggagaggc gctcggagaa agacagctct catagtggaa 1560 ggagtgtggt catttagtca ccaagcacag cacaacttct gtggctactt ctcggctcct 1620 gtgtgtcatc agcatcacct aggtttccag ctgacttggg aactgcaagt ctgagtctaa 1680 cagtttttgg cttagattct gagaatcaaa tagaagaatt ttaaatacaa gagtttgaga 1740 ttgggtatag tggctcacac ctgtaatcac agcactttgg gaggctaaga atcacttgag 1800 actaggagtt caagatcagc ctgggaaaca tagtgagacc ccgtctctac aaaaaatata 1860 aaaattagtt aggtgtggtg gcatgcactt gtagtcccag ctactcaaga ggctgaggca 1920 gaaggatccc ttgagcccag gagtgcaagg ctgcaatgag ccaggatccc atgatcacac 1980 atctgtattc cagcctgggc aatagagcaa gtccccatta ctaaaaaacc caaaaggcca 2040 aaaaacaaaa aagttagagt tcgaggaatt accaactgta gttttagcct tggttcatgc 2100 tctcttgcat atttatataa tctctgactt gtaatggacc ctgactggaa tgtgatccct 2160 caggaactta gtagcctgag tctttcagta gactacactg cccagaaccc tggccattct 2220 caaaatgaga acttgggaat gtttaagaag aaatcaaaca tgtttcagga aaaggaaatc 2280 tatggagtat tatagggaca ttcccatggg aatgtatctt cctccatggc atgtcttgag 2340 ggtcctttct tgttaggagt ttatcctgcc agcccataaa tggactattt attgtaagtg 2400 tagaaaatca cagagaagca gttttgcacc agccttattc ctgtgccttg ttttcctctt 2460 gctctttttt tacctgtata tctaatttat attttcatat atattgtgta ttgattgaag 2520 tcactttaaa tccttcttgg gaatgacaca gtatataaat aaggaagaaa gaaaacatgc 2580 caagctgagc atgctgctcc aaataaatat ctgctttcct a 2621 <210> 20 <211> 2717

<212> DNA <213> Homo Sapiens <400> 20 agccgtgggg agcgccgcag gtggggacga gccgggcggc acctgccccg ggaccagagc 60 ggacgctccc tccccgctgc gccgagggag gggaaacccg aggggttcct tggagaaggt 120 ggtgcgtcct ggggcggcag ctgaggaaga aagacgcagt gccccgaagc ccctgagctg 180 aaaagggcca gaaagggggc ggcatggcat ggcccaaact gcccgcacct tggctgctgc 240 tctgcacctg gctcccagca gcataccagg cagctttatc cctgggccag gacccatcca 300 atgactgcaa cgacaaccag cgggaagttc gcatagtggc ccagcggcgg gggcagaatg 360 agcccgtgct gggggtagat taccggcagc gcaagatcac catccagaac cgagcagatc 420 tcgtgataaa tgaagtgatg tggtgggacc atggagtgta ttactgcacc attgaggctc 480 caggggacac atcaggagac cccgataagg aagtaaagct catcgtccta cactggctga 540 cagtgatctt catcatcctg ggagccctcc tcctcctgct gctgattgga gtgtgctggt 600 gccagtgctg tcctcagtat tgctgctgct atatccgctg tccctgctgt cctgcccact 660 gctgctgtcc tgaggaagcc ctggcccgcc accgctacat gaagcaggcc caggccctag 720 gtcctcagat gatgggaaaa cccctgtact ggggggcgga caggagctcc caggtttcat 780 cttatccaat gcacccgctg ctgcagcgag atttgtccct gccgtccagc ctcccgcaga 840 tgccaatgac ccagaccacc aatcagcctc ccatcgccaa tggtgtcctg gagtatttgg 900 agaaagaact gcggaacctc aacctggccc agcctctgcc ccctgacctc aaaggcagat 960 ttggccatcc ctgcagcatg ctgtcctccc tgggctctga ggtcgtggaa cgcagaatca 1020 tccacctgcc cccactgatc agagacctgt catcctcaag gaggaccagt gactccctgc 1080 accagcagtg gctcacccca attccctcca ggccctggga tctgagggag gggagaagcc 1140 accaccatta ccctgatttc caccaggagc tccaggaccg ggggccaaag tcttgggcat 1200 tggaaagaag ggagttggac ccatcgtgga gtggaaggca ccgtagctct aggctgaatg 1260 ggtcacccat acactggtca gacagggaca gcctaagcga tgtcccctca tccagtgagg 1320 cacgctggcg gccgagccac cctcctttca ggagccgctg tcaggagagg ccccgcaggc 1380 ccagcccccg ggagagcact cagaggcacg ggagacgacg caggcaccgc agctactctc 1440 ctcccttgcc ctccggcctc agttcctgga gctctgaaga ggacaaggag aggcagcccc 1500 agagctggcg ggcccaccgc cgcggctcgc actccccaca ctggcccgag gagaagccgc 1560 ctagctaccg ctcactggat atcactccag gcaagaatag caggaaaaaa gggagtgtgg 1620 agaggcgctc ggagaaagac agctctcata gtggaaggag tgtggtcatt tagtcaccaa 1680 gcacagcaca acttctgtgg ctacttctcg gctcctgtgt gtcatcagca tcacctaggt 1740 ttccagctga cttgggaact gcaagtctga gtctaacagt ttttggctta gattctgaga 1800 atcaaataga agaattttaa atacaagagt ttgagattgg gtatagtggc tcacacctgt 1860 aatcacagca ctttgggagg ctaagaatca cttgagacta ggagttcaag atcagcctgg 1920 gaaacatagt gagaccccgt ctctacaaaa aatataaaaa ttagttaggt gtggtggcat 1980 gcacttgtag tcccagctac tcaagaggct gaggcagaag gatcccttga gcccaggagt 2040 gcaaggctgc aatgagccag gatcccatga tcacacatct gtattccagc ctgggcaata 2100 gagcaagtcc ccattactaa aaaacccaaa aggccaaaaa acaaaaaagt tagagttcga 2160 ggaattacca actgtagttt tagccttggt tcatgctctc ttgcatattt atataatctc 2220 tgacttgtaa tggaccctga ctggaatgtg atccctcagg aacttagtag cctgagtctt 2280 tcagtagact acactgccca gaaccctggc cattctcaaa atgagaactt gggaatgttt 2340 aagaagaaat caaacatgtt tcaggaaaag gaaatctatg gagtattata gggacattcc 2400 catgggaatg tatcttcctc catggcatgt cttgagggtc ctttcttgtt aggagtttat 2460 cctgccagcc cataaatgga ctatttattg taagtgtaga aaatcacaga gaagcagttt 2520 tgcaccagcc ttattcctgt gccttgtttt cctcttgctc tttttttacc tgtatatcta 2580 atttatattt tcatatatat tgtgtattga ttgaagtcac tttaaatcct tcttgggaat 2640 gacacagtat ataaataagg aagaaagaaa acatgccaag ctgagcatgc tgctccaaat 2700 aaatatctgc tttccta 2717 <210>21 <211> 502

<212> PRT <213> Homo Sapiens <400> 21

Met Ala Trp Pro Lys Leu Pro Ala Pro Trp Leu Leu Leu Cys Thr Trp 15 10 15

Leu Pro Ala Gly Cys Leu Ser Leu Leu Val Thr Val Gin His Thr Glu 20 25 30

Arg Tyr Val Thr Leu Phe Ala Ser lie lie Leu Lys Cys Asp Tyr Thr 35 40 45

Thr Ser Ala Gin Leu Gin Asp Val Val Val Thr Trp Arg Phe Lys Ser 50 55 60

Phe Cys Lys Asp Pro lie Phe Asp Tyr Tyr Ser Ala Ser Tyr Gin Ala 65 70 75 80

Ala Leu Ser Leu Gly Gin Asp Pro Ser Asn Asp Cys Asn Asp Asn Gin 85 90 95

Arg Glu Val Arg lie Val Ala Gin Arg Arg Gly Gin Asn Glu Pro Val 100 105 110

Leu Gly Val Asp Tyr Arg Gin Arg Lys lie Thr lie Gin Asn Arg Ala 115 120 125

Asp Leu Val lie Asn Glu Val Met Trp Trp Asp His Gly Val Tyr Tyr 130 135 140

Cys Thr lie Glu Ala Pro Gly Asp Thr Ser Gly Asp Pro Asp Lys Glu 145 150 155 160

Val Lys Leu lie Val Leu His Trp Leu Thr Val lie Phe lie lie Leu 165 170 175

Gly Ala Leu Leu Leu Leu Leu Leu lie Gly Val Cys Trp Cys Gin Cys 180 185 190

Cys Pro Gin Tyr Cys Cys Cys Tyr lie Arg Cys Pro Cys Cys Pro Ala 195 200 205

His Cys Cys Cys Pro Glu Glu Asp Leu Ser Leu Pro Ser Ser Leu Pro 210 215 220

Gin Met Pro Met Thr Gin Thr Thr Asn Gin Pro Pro Ile Ala Asn Gly 225 230 235 240

Val Leu Glu Tyr Leu Glu Lys Glu Leu Arg Asn Leu Asn Leu Ala Gin 245 250 255

Pro Leu Pro Pro Asp Leu Lys Gly Arg Phe Gly His Pro Cys Ser Met 260 265 270

Leu Ser Ser Leu Gly Ser Glu Val Val Glu Arg Arg Ile Ile His Leu 275 280 285

Pro Pro Leu Ile Arg Asp Leu Ser Ser Ser Arg Arg Thr Ser Asp Ser 290 295 300

Leu His Gin Gin Trp Leu Thr Pro Ile Pro Ser Arg Pro Trp Asp Leu 305 310 315 320

Arg Glu Gly Arg Ser His His His Tyr Pro Asp Phe His Gin Glu Leu 325 330 335

Gin Asp Arg Gly Pro Lys Ser Trp Ala Leu Glu Arg Arg Glu Leu Asp 340 345 350

Pro Ser Trp Ser Gly Arg His Arg Ser Ser Arg Leu Asn Gly Ser Pro 355 360 365

Ile His Trp Ser Asp Arg Asp Ser Leu Ser Asp Val Pro Ser Ser Ser 370 375 380

Glu Ala Arg Trp Arg Pro Ser His Pro Pro Phe Arg Ser Arg Cys Gin 385 390 395 400

Glu Arg Pro Arg Arg Pro Ser Pro Arg Glu Ser Thr Gin Arg His Gly 405 410 415

Arg Arg Arg Arg His Arg Ser Tyr Ser Pro Pro Leu Pro Ser Gly Leu 420 425 430

Ser Ser Trp Ser Ser Glu Glu Asp Lys Glu Arg Gin Pro Gin Ser Trp 435 440 445

Arg Ala His Arg Arg Gly Ser His Sér Pro His Trp Pro Glu Glu Lys 450 455 460

Pro Pro Ser Tyr Arg Ser Leu Asp Ile Thr Pro Gly Lys Asn Ser Arg 465 470 475 480

Lys Lys Gly Ser Val Glu Arg Arg Ser Glu Lys Asp Ser Ser His Ser 485 490 495

Gly Arg Ser Val Val Ile 500 <210> 22 <211> 546

<212> PRT <213> Homo Sapiens <400> 22

Met Ala Trp Pro Lys Leu Pro Ala Pro Trp Leu Leu Leu Cys Thr Trp 15 10 15

Leu Pro Ala Gly Cys Leu Ser Leu Leu Val Thr Val Gin His Thr Glu 20 25 30

Arg Tyr Val Thr Leu Phe Ala Ser lie lie Leu Lys Cys Asp Tyr Thr 35 40 45

Thr Ser Ala Gin Leu Gin Asp Val Val Val Thr Trp Arg Phe Lys Ser 50 55 60

Phe Cys Lys Asp Pro lie Phe Asp Tyr Tyr Ser Ala Ser Tyr Gin Ala 65 70 75 80

Ala Leu Ser Leu Gly Gin Asp Pro Ser Asn Asp Cys Asn Asp Asn Gin 85 90 95

Arg Glu Val Arg lie Val Ala Gin Arg Arg Gly Gin Asn Glu Pro Val 100 105 110

Leu Gly Val Asp Tyr Arg Gin Arg Lys lie Thr lie Gin Asn Arg Ala 115 120 125

Asp Leu Val lie Asn Glu Val Met Trp Trp Asp His Gly Val Tyr Tyr 130 135 140 213

Cys Thr ile Glu Ala Pro Gly Asp Thr Ser Gly Asp Pro Asp Lys Glu 145 150 155 160

Val Lys Leu Ile Val Leu His Trp Leu Thr Val Ile Phe Ile Ile Leu 165 170 175

Gly Ala Leu Leu Leu Leu Leu Leu Ile Gly Val Cys Trp Cys Gin Cys 180 185 190

Cys Pro Gin Tyr Cys Cys Cys Tyr Ile Arg Cys Pro Cys Cys Pro Ala 195 200 205

His Cys Cys Cys Pro Glu Glu Ala Leu Ala Arg His Arg Tyr Met Lys 210 215 220

Gin Ala Gin Ala Leu Gly Pro Gin Met Met Gly Lys Pro Leu Tyr Trp 225 230 235 240

Gly Ala Asp Arg Ser Ser Gin Val Ser Ser Tyr Pro Met His Pro Leu 245 '250 255

Leu Gin Arg Asp Leu Ser Leu Pro Ser Ser Leu Pro Gin Met Pro Met 260 265 270

Thr Gin Thr Thr Asn Gin Pro Pro Ile Ala Asn Gly Val Leu Glu Tyr 275 280 285

Leu Glu Lys Glu Leu Arg Asn Leu Asn Leu Ala Gin Pro Leu Pro Pro 290 295 300

Asp Leu Lys Gly Arg Phe Gly His Pro Cys Ser Met Leu Ser Ser Leu 305 310 315 320

Gly Ser Glu Val Val Glu Arg Arg Ile Ile His Leu Pro Pro Leu Ile 325 330 335

Arg Asp Leu Ser Ser Ser Arg Arg Thr Ser Asp Ser Leu His Gin Gin 340 345 350

Trp Leu Thr Pro Ile Pro Ser Arg Pro Trp Asp Leu Arg Glu Gly Arg 355 360 365

Ser His His His Tyr Pro Asp Phe His Gin Glu Leu Gin Asp Arg Gly 370 375 380

Pro Lys Ser Trp Ala Leu Glu Arg Arg Glu Leu Asp Pro Ser Trp Ser 385 390 395 400

Gly Arg His Arg Ser Ser Arg Leu Asn Gly Ser Pro Ile His Trp Ser 405 410 415

Asp Arg Asp Ser Leu Ser Asp Val Pro Ser Ser Ser Glu Ala Arg Trp 420 425 430

Arg Pro Ser His Pro Pro Phe Arg Ser Arg Cys Gin Glu Arg Pro Arg 435 440 445

Arg Pro Ser Pro Arg Glu Ser Thr Gin Arg His Gly Arg Arg Arg Arg 450 455 460

His Arg Ser Tyr Ser Pro Pro Leu Pro Ser Gly Leu Ser Ser Trp Ser 465 470 475 480

Ser Glu Glu Asp Lys Glu Arg Gin Pro Gin Ser Trp Arg Ala His Arg 485 490 495

Arg Gly Ser His Ser Pro His Trp Pro Glu Glu Lys Pro Pro Ser Tyr 500 505 510

Arg Ser Leu Asp Ile Thr Pro Gly Lys Asn Ser Arg Lys Lys Gly Ser 515 520 525

Val Glu Arg Arg Ser Glu Lys Asp Ser Ser His Ser Gly Arg Ser Val 530 535 540

Val Ile 545 <210> 23 <211 >457

<212> PRT <213> Homo Sapiens <400> 23

Met Ala Trp Pro Lys Leu Pro Ala Pro Trp Leu Leu Leu Cys Thr Trp 15 10 15

Leu Pro Ala Gly Cys Leu Ser Leu Leu Val Thr Val Gin His Thr Glu 20 25 30

Arg Tyr Val Thr Leu Phe Ala Ser Ile Ile Leu Lys Cys Asp Tyr Thr

Thr Ser Ala Gin Leu Gin Asp Val Val Val Thr Trp Arg Phe Lys Ser 50 55 60

Phe Cys Lys Asp Pro Ile Phe Asp Tyr Tyr Ser Ala Ser Tyr Gin Ala 65 70 75 80

Ala Leu Ser Leu Gly Gin Asp Pro Ser Asn Asp Cys Asn Asp Asn Gin 85 90 95

Arg Glu Val Arg Ile Val Ala Gin Arg Arg Gly Gin Asn Glu Pro Val 100 105 110

Leu Gly Val Asp Tyr Arg Gin Arg Lys Ile Thr Ile Gin Asn Pro Leu 115 120 125

Ala Arg Kis Arg Tyr Met Lys Gin Ala Gin Ala Leu Gly Pro Gin Met 130 135 140

Met Gly Lys Pro Leu Tyr Trp Gly Ala Asp Arg Ser Ser Gin Val Ser 145 150 155 160

Ser Tyr Pro Met His Pro Leu Leu Gin Arg Asp Leu Ser Leu Pro Ser 165 170 175

Ser Leu Pro Gin Met Pro Met Thr Gin Thr Thr Asn Gin Pro Pro Ile 180 185 190

Ala Asn Gly Val Leu Glu Tyr Leu Glu Lys Glu Leu Arg Asn Leu Asn 195 200 205

Leu Ala Gin Pro Leu Pro Pro Asp Leu Lys Gly Arg Phe Gly His Pro 210 215 220

Cys Ser Met Leu Ser Ser Leu Gly Ser Glu Val Val Glu Arg Arg Ile 225 230 235 240

Ile His Leu Pro Pro Leu Ile Arg Asp Leu Ser Ser Ser Arg Arg Thr 245 250 255

Ser Asp Ser Leu His Gin Gin Trp Leu Thr Pro Ile Pro Ser Arg Pro 260 265 270

Trp Asp Leu Arg Glu Gly Arg Ser His His His Tyr Pro Asp Phe His 275 280 285

Gin Glu Leu Gin Asp Arg Gly Pro Lys Ser Trp Ala Leu Glu Arg Arg 290 295 300

Glu Leu Asp Pro Ser Trp Ser Gly Arg His Arg Ser Ser Arg Leu Asn 305 310 315 320

Gly Ser Pro lie His Trp Ser Asp Arg Asp Ser Leu Ser Asp Val Pro 325 330 335

Ser Ser Ser Glu Ala Arg Trp Arg Pro Ser His Pro Pro Phe Arg Ser 340 345 350

Arg Cys Gin Glu Arg Pro Arg Arg Pro Ser Pro Arg Glu Ser Thr Gin 355 360 365

Arg His Gly Arg Arg Arg Arg His Arg Ser Tyr Ser Pro Pro Leu Pro 370 375 380

Ser Gly Leu Ser Ser Trp Ser Ser Glu Glu Asp Lys Glu Arg Gin Pro 385 390 395 400

Gin Ser Trp Arg Ala His Arg Arg Gly Ser His Ser Pro His Trp Pro 405 410 415

Glu Glu Lys Pro Pro Ser Tyr Arg Ser Leu Asp lie Thr Pro Gly Lys 420 425 430

Asn Ser Arg Lys Lys Gly Ser Val Glu Arg Arg Ser Glu Lys Asp Ser 435 440 445

Ser His Ser Gly Arg Ser Val val lie 450 455 <210> 24 <211 > 489

<212> PRT <213> Homo Sapiens <400> 24

Met Ala Trp Pro Lys Leu Pro Ala Pro Trp Leu Leu Leu Cys Thr Trp 1 5 10 15

Leu Pro Ala Ala Tyr Gin Ala Ala Leu Ser Leu Gly Gin Asp Pro Ser 20 25 30

Asn Asp Cys Asn Asp Asn Gin Arg Glu Val Arg Ile Val Ala Gin Arg 35 40 45

Arg Gly Gin Asn Glu Pro Val Leu Gly Val Asp Tyr Arg Gin Arg Lys 50 55 60

Ile Thr Ile Gin Asn Arg Ala Asp Leu Val Ile Asn Glu Val Met Trp 65 70 75 80

Trp Asp His Gly Val Tyr Tyr Cys Thr Ile Glu Ala Pro Gly Asp Thr 85 90 95

Ser Gly Asp Pro Asp Lys Glu Val Lys Leu Ile Val Leu His Trp Leu 100 105 110

Thr Val Ile Phe Ile Ile Leu Gly Ala Leu Leu Leu Leu Leu Leu Ile 115 120 125

Gly Val Cys Trp Cys Gin Cys Cys Pro Gin Tyr Cys Cys Cys Tyr Ile 130 135 140

Arg Cys Pro Cys Cys Pro Ala His Cys Cys Cys Pro Glu Glu Ala Leu 145 150 155 160

Ala Arg His Arg Tyr Met Lys Gin Ala Gin Ala Leu Gly Pro Gin Met 165 170 175

Met Gly Lys Pro Leu Tyr Trp Gly Ala Asp Arg Ser Ser Gin Val Ser 180 185 190

Ser Tyr Pro Met His Pro Leu Leu Gin Arg Asp Leu Ser Leu Pro Ser 195 200 205

Ser Leu Pro Gin Met Pro Met Thr Gin Thr Thr Asn Gin Pro Pro Ile 210 215 220

Ala Asn Gly Val Leu Glu Tyr Leu Glu Lys Glu Leu Arg Asn Leu Asn 225 230 235 240

Leu Ala Gin Pro Leu Pro Pro Asp Leu Lys Gly Arg Phe Gly His Pro 245 250 255

Cys Ser Met Leu Ser Ser Leu Gly Ser Glu Val Val Glu Arg Arg Ile 260 265 270

Ile His Leu Pro Pro Leu Ile Arg Asp Leu Ser Ser Ser Arg Arg Thr 275 280 285

Ser Asp Ser Leu His Gin Gin Trp Leu Thr Pro Ile Pro Ser Arg Pro 290 295 300

Trp Asp Leu Arg Glu Gly Arg Ser His His His Tyr Pro Asp Phe His 305 310 315 320

Gin Glu Leu Gin Asp Arg Gly Pro Lys Ser Trp Ala Leu Glu Arg Arg 325 330 335

Glu Leu Asp Pro Ser Trp Ser Gly Arg His Arg Ser Ser Arg Leu Asn 340 345 350

Gly Ser Pro Ile His Trp Ser Asp Arg Asp Ser Leu Ser Asp Val Pro 355 360 365

Ser Ser Ser Glu Ala Arg Trp Arg Pro Ser His Pro Pro Phe Arg Ser 370 375 380

Arg Cys Gin Glu Arg Pro Arg Arg Pro Ser Pro Arg Glu Ser Thr Gin 385 390 395 400

Arg His Gly Arg Arg Arg Arg His Arg Ser Tyr Ser Pro Pro Leu Pro 405 410 415

Ser Gly Leu Ser Ser Trp Ser Ser Glu Glu Asp Lys Glu Arg Gin Pro 420 425 430

Gin Ser Trp Arg Ala His Arg Arg Gly Ser His Ser Pro His Trp Pro 435 440 445

Glu Glu Lys Pro Pro Ser Tyr Arg Ser Leu Asp Ile Thr Pro Gly Lys 450 455 460

Asn Ser Arg Lys Lys Gly Ser Val Glu Arg Arg Ser Glu Lys Asp Ser 465 470 475 480

Ser His Ser Gly Arg Ser Val Val Ile 485 <210> 25 <211 > 2148

<212> DNA <213> Homo Sapiens <400> 25 acctcactgc taatttccct agcaaataaa ccagcagctg ctggtccaag ttaccactga 60 gaacagggca ctgcatgcat gggacaggat gctttcatgg agcccttcgg tgacacactt 120 ggggtctttc agtgcaaaat atacctcctt ctcttcggtg cttgctcggg gctgaaggtg 180 acagtgccat cacacactgt ccatggcgtc agaggtcagg ccctctacct acccgtccac 240 tatggcttcc acactccagc atcagacatc cagatcatat ggctatttga gagaccccac 300 acaatgccca aatacttact gggctctgtg aataagtctg tggttcctga cttggaatac 360 caacacaagt tcaccatgat gccacccaat gcatctctgc ttatcaaccc actgcagttc 420 cctgatgaag gcaattacat cgtgaaggtc aacattcagg gaaatggaac tctatctgcc 480 agtcagaaga tacaagtcac ggttgatgat cctgtcacaa agccagtggt gcagattcat 540 cctccctctg gggctgtgga gtatgtgggg aacatgaccc tgacatgcca tgtggaaggg 600 ggcactcggc tagcttacca atggctaaaa aatgggagac ctgtccacac cagctccacc 660 tactcctttt ctccccaaaa caataccctt catattgctc cagtaaccaa ggaagacatt 720 gggaattaca gctgcctggt gaggaaccct gtcagtgaaa tggaaagtga tatcattatg 780 cccatcatat attatggacc ttatggactt caagtgaatt ctgataaagg gctaaaagta 840 ggggaagtgt ttactgttga ccttggagag gccatcctat ttgattgttc tgctgattct 900 catcccccca acacctactc ctggattagg aggactgaca atactacata tatcattaag 960 catgggcctc gcttagaagt tgcatctgag aaagtagccc agaagacaat ggactatgtg 1020 tgctgtgctt acaacaacat aaccggcagg caagatgaaa ctcatttcac agttatcatc 1080 acttccgtag gactggagaa gcttgcacag aaaggaaaat cattgtcacc tttagcaagt 1140 ataactggaa tatcactatt tttgattata tccatgtgtc ttctcttcct atggaaaaaa 1200 tatcaaccct acaaagttat aaaacagaaa ctagaaggca ggccagaaac agaatacagg 1260 aaagctcaaa cattttcagg ccatgaagat gctctggatg acttcggaat atatgaattt 1320 gttgcttttc cagatgtttc tggtgtttcc aggatcccaa gcaggtctgt tccagcctct 1380 gattgtgtat cggggcaaga tttgcacagt acagtgtatg aagttattca gcacatccct 1440 gcccagcagc aagaccatcc agagtgaact ttcatgggct aaacagtaca ttcgagtgaa 1500 attctgaaga aacattttaa ggaaaaacag tggaaaagta tattaatctg gaatcagtga 1560 agaaaccaag accaacacct cttactcatt attcctttac atgcagaata gaggcattta 1620 tgcaaattga actgcaggtt tttcagcata tacacaatgt cttgtgcaac agaaaaacat 1680 gttggggaaa tattcctcag tggagagtcg ttctcatgct gacggggaga acgaaagtga 1740 caggggtttc ctcgtaagtt ttgtatgaaa tatctctaca aacctcaatt agttctactc 1800 tacactttca ctatcatcaa cactgagact atcctgtctc acctacaaat gtggaaactt I860 tacattgttc gatttttcag cagactttgt tttattaaat ttttattagt gttaagaatg 1920 ctaaatttat gtttcaattt tatttccaaa tttctatctt gttatttgta caacaaagta 1980 ataaggatgg ttgtcacaaa aacaaaacta tgccttctct tttttttcaa tcaccagtag 2040 tatttttgag aagacttgtg aacacttaag gaaatgacta ttaaagtctt atttttattt 2100 ttttcaagga aagatggatt caaataaatt attctgtttt tgctttta 2148 <210> 26 <211> 2135

<212> DNA <213> Homo Sapiens <400> 26 gtaaccagta ctagaatagt cagtacctag aagccactct tctttgaaaa ggattatcac 60 ctgatcaggt tctctctgca tttgcccctt tagattgtga aatgtggctc aaggtcttca 120 caactttcct ttcctttgca acaggtgctt gctcggggct gaaggtgaca gtgccatcac 180 acactgtcca tggcgtcaga ggtcaggccc tctacctacc cgtccactat ggcttccaca 240 ctccagcatc agacatccag atcatatggc tatttgagag accccacaca atgcccaaat 300 acttactggg ctctgtgaat aagtctgtgg ttcctgactt ggaataccaa cacaagttca 360 ccatgatgcc acccaatgca tctctgctta tcaacccact gcagttccct gatgaaggca 420 attacatcgt gaaggtcaac attcagggaa atggaactct atctgccagt. cagaagatac 480 aagtcacggt tgatgatcct gtcacaaagc cagtggtgca gattcatcct ccctctgggg 540 ctgtggagta tgtggggaac atgaccctga catgccatgt ggaagggggc actcggctag 600 cttaccaatg gctaaaaaat gggagacctg tccacaccag ctccacctac tccttttctc 660 cccaaaacaa tacccttcat attgctccag taaccaagga agacattggg aattacagct 720 gcctggtgag gaaccctgtc agtgaaatgg aaagtgatat cattatgccc atcatatatt 780 atggacctta tggacttcaa gtgaattctg ataaagggct aaaagtaggg gaagtgttta 840 ctgttgacct tggagaggcc atcctatttg attgttctgc tgattctcat ccccccaaca 900 cctactcctg gattaggagg actgacaata ctacatatat cattaagcat gggcctcgct 960 tagaagttgc atctgagaaa gtagcccaga agacaatgga ctatgtgtgc tgtgcttaca 1020 acaacataac cggcaggcaa gatgaaactc atttcacagt tatcatcact tccgtaggac 1080 tggagaagct tgcacagaaa ggaaaatcat tgtcaccttt agcaagtata actggaatat 1140 cactattt.tt gattatatcc atgtgtcttc tcttcctatg gaaaaaatat caaccctaca 1200 aagttataaa acagaaacta gaaggcaggc cagaaacaga atacaggaaa gctcaaacat 1260 tttcaggcca tgaagatgct ctggatgact tcggaatata tgaatttgtt gcttttccag 1320 atgtttctgg tgtttccagg atcccaagca ggtctgttcc agcctctgat tgtgtatcgg 1380 ggcaagattt gcacagtaca gtgtatgaag ttattcagca catccctgcc cagcagcaag 1440 accatccaga gtgaactttc atgggctaaa cagtacattc gagtgaaatt ctgaagaaac 1500 attttaagga aaaacagtgg aaaagtatat taatctggaa tcagtgaaga aaccaagacc 1560 aacacctctt actcattatt cctttacatg cagaatagag gcatttatgc aaattgaact 1620 gcaggttttt cagcatatac acaatgtctt gtgcaacaga aaaacatgtt ggggaaatat 1680 tcctcagtgg agagtcgttc tcatgctgac ggggagaacg aaagtgacag gggtttcctc 1740 gtaagttttg tatgaaatat ctctacaaac ctcaattagt tctactctac actttcacta 1800 tcatcaacac tgagactatc ctgtctcacc tacaaatgtg gaaactttac attgttcgat 1860 ttttcagcag actttgtttt attaaatttt tattagtgtt aagaatgcta aatttatgtt 1920 tcaattttat ttccaaattt ctatcttgtt atttgtacaa caaagtaata aggatggttg 1980 tcacaaaaac aaaactatgc cttctctttt ttttcaatca ccagtagtat ttttgagaag 2040 acttgtgaac acttaaggaa atgactatta aagtcttatt tttatttttt tcaaggaaag 2100 atggattcaa ataaattatt ctgtttttgc tttta 2135 <210> 27 <211> 2109

<212> DNA <213> Homo Sapiens <400> 27 acctcactgc taatttccct agcaaataaa ccagcagctg ctggtccaag ttaccactga 60 gaacagggca ctgcatgcat gggacaggat gctttcatgg agcccttcgg tgacacactt 120 ggggtctttc agtgcaaaat atacctcctt ctcttcggtg cttgctcggg gctgaaggtg 180 acagtgccat cacacactgt ccatggcgtc agaggtcagg ccctctacct acccgtccac 240 tatggcttcc acactccagc atcagacatC cagatcatat ggctatttga gagaccccac 300 acaatgccca aatacttact gggctctgtg aataagtctg tggttcctga cttggaatac 360 caacacaagt tcaccatgat gccacccaat gcatctctgc ttatcaaccc actgcagttc 420 cctgatgaag gcaattacat cgtgaaggtc aacattcagg gaaatggaac tctatctgcc 480 agtcagaaga tacaagtcac ggttgatgat cctgtcacaa agccagtggt gcagattcat 540 cctccctctg gggctgtgga gtatgtgggg aacatgaccc tgacatgcca tgtggaaggg 600 ggcactcggc tagcttacca atggctaaaa aatgggagac ctgtccacac cagctccacc 660 tactcctttt ctccccaaaa caataccctt catattgctc cagtaaccaa ggaagacatt 720 gggaattaca gctgcctggt gaggaaccct gtcagtgaaa tggaaagtga tatcattatg 780 cccatcatat attatggacc ttatggaott caagtgaatt ctgataaagg gctaaaagta 840 ggggaagtgt ttactgttga ccttggagag gccatcctat ttgattgttc tgctgattct 900 catcccccca acacctactc ctggattagg aggactgaca atactacata tatcattaag 960 catgggcctc gcttagaagt tgcatctgag aaagtagccc agaagacaat ggactatgtg 1020 tgctgtgctt acaacaacat aaccggcagg caagatgaaa ctcatttcac agttatcatc 1080 acttccgtag gactggagaa gcttgcacag aaaggaaaat cattgtcacc tttagcaagt 1140 ataactggaa tatcactatt tttgattata tccatgtgtc ttctcttcct atggaaaaaa 1200 tatcaaccct acaaagttat aaaacagaaa ctagaaggca ggccagaaac agaatacagg 1260 aaagctcaaa cattttcagg ccatgaagat gctctggatg acttcggaat atatgaattt 1320 gttgcttttc cagatgtttc tggtgtttcc aggatcccaa gcaggtctgt tccagcctct 1380 gattgtgtat cggggcaaga tttgcacagt acagtgtatg aagttattca gcacatccct 1440 gcccagcagc aagaccatcc agagtgaact ttcatgggct aaacagtaca ttcgagtgaa 1500 attctgaaga aacattttaa ggaaaaacag tggaaaagta tattaatctg gaatcagtga 1560 agaaaccaag accaacacct cttactcatt attcctttac atgcagaata gaggcattta 1620 tgcaaattga actgcaggtt tttcagcata tacacaatgt cttgtgcaac agaaaaacat 1680 gttggggaaa tattcctcag tggagagtcg ttctcatgct gacggggaga acgaaagtga 1740 caggggtttc ctcgtaagtt ttgtatgaaa tatctctaca aacctcaatt agttctactc 1800 tacactttca ctatcatcaa cactgagact atcctgtctc acctacaaat gtggaaactt 1860 tacattgttc gatttttcag cagactttgt tttattaaat ttttattagt gttaagaatg 1920 ctaaatttat gtttcaattt tatttccaaa tttctatctt gttatttgta caacaaagta 1980 ataaggatgg ttgtcacaaa aacaaaacta tgccttctct tttttttcaa tcaccagtag 2040 tatttttgag aagacttgtg aacacttaag gaaatgacta ttaaagtctt atttttattt 2100 ttttcaagg 2109 <210> 28 <211 > 2110

<212> DNA <213> Homo Sapiens <400> 28 gtaaccagta ctagaatagt cagtacctag aagccactct tctttgaaaa ggattatcac 60 ctgatcaggt tctctctgca tttgcccctt tagattgtga aatgtggctc aaggtcttca 120 caactttcct ttcctttgca acaggtgctt gctcggggct gaaggtgaca gtgccatcac 180 acactgtcca tggcgtcaga ggtcaggccc tctacctacc cgtccactat ggcttccaca 240 ctccagcatc agacatccag atcatatggc tatttgagag accccacaca atgcccaaat 300 acttactggg ctctgtgaat aagtctgtgg ttcctgactt ggaataccaa cacaagttca 360 ccatgatgcc acccaatgca tctctgctta tcaacccact gcagttccct gatgaaggca 420 attacatcgt gaaggtcaac attcagggaa atggaactct atctgccagt cagaagatac 480 aagtcacggt tgatgatcct gtcacaaagc cagtggtgca gattcatcct ccctctgggg 540 ctgtggagta tgtggggaac atgaccctga catgccatgt ggaagggggc actcggctag 600 cttaccaatg gctaaaaaat gggagacctg tccacaccag ctccacctac tccttttctc 660 cccaaaacaa tacccttcat attgctccag taaccaagga agacattggg aattacagct 720 gcctggtgag gaaccctgtc agtgaaatgg aaagtgatat cattatgccc atcatatatt 780 atggacctta tggacttcaa gtgaattctg ataaagggct aaaagtaggg gaagtgttta 840 ctgttgacct tggagaggcc atcctatttg attgttctgc tgattctcat ccccccaaca 900 cctactcctg gattaggagg actgacaata ctacatatat cattaagcat gggcctcgct 960 tagaagttgc atctgagaaa gtagcccaga agacaatgga ctatgtgtgc tgtgcttaca 1020 acaacataac cggcaggcaa gatgaaactc atttcacagt tatcatcact tccgtaggac 1080 tggagaagct tgcacagaaa ggaaaatcat tgtcaccttt agcaagtata actggaatat 1140 cactattttt gattatatcc atgtgtcttc tcttcctatg gaaaaaatat caaccctaca 1200 aaggccagaa acagaataca ggaaagctca aacattttca ggccatgaag atgctctgga 1260 tgacttcgga atatatgaat ttgttgcttt tccagatgtt tctggtgttt ccaggatccc 1320 aagcaggtct gttccagcct ctgattgtgt atcggggcaa gatttgcaca gtacagtgta 1380 tgaagttatt cagcacatcc ctgcccagca gcaagaccat ccagagtgaa ctttcatggg 1440 ctaaacagta cattcgagtg aaattctgaa gaaacatttt aaggaaaaac agtggaaaag 1500 tatattaatc tggaatcagt gaagaaacca agaccaacac ctcttactca ttattccttt 1560 acatgcagaa tagaggcatt tatgcaaatt gaactgcagg tttttcagca tatacacaat 1620 gtcttgtgca acagaaaaac atgttgggga aatattcctc agtggagagt cgttctcatg 1680 ctgacgggga gaacgaaagt gacaggggtt tcctcgtaag ttttgtatga aatatctcta 1740 caaacctcaa ttagttctac tctacacttt cactatcatc aacactgaga ctatcctgtc 1800 tcacctacaa atgtggaaac tttacattgt tcgatttttc agcagacttt gttttattaa 1860 atttttatta gtgttaagaa tgctaaattt atgtttcaat tttatttcca aatttctatc 1920 ttgttatttg tacaacaaag taataaggat ggttgtcaca aaaacaaaac tatgccttct 1980 cttttttttc aatcaccagt agtatttttg agaagacttg tgaacactta aggaaatgac 2040 tattaaagtc ttatttttat ttttttcaag gaaagatgga ttcaaataaa ttattctgtt 2100 tttgctttta 2110 <210> 29 <211 > 2189

<212> DNA <213> Homo Sapiens <400> 29 gtaaccagta ctagaatagt cagtacctag aagccactct tctttgaaaa ggattatcac 60 ctgatcaggt tctctctgca tttgcccctt tagattgtga aatgtggctc aaggtcttca 120 caactttcct ttcctttgca acaggtgctt gctcggggct gaaggtgaca gtgccatcac 180 acactgtcca tggcgtcaga ggtcaggccc tctacctacc cgtccactat ggcttccaca 240 ctccagcatc agacatccag atcatatggc tatttgagag accccacaca atgcccaaat 300 acttactggg ctctgtgaat aagtctgtgg ttcctgactt ggaataccaa cacaagttca 360 ccatgatgcc acccaatgca tctctgctta tcaacccact gcagttccct gatgaaggca 420 attacatcgt gaaggtcaac attcagggaa atggaactct atctgccagt cagaagatac 480 aagtcacggt tgatgatcct gtcacaaagc cagtggtgca gattcatcct ccctctgggg 540 ctgtggagta tgtggggaac atgaccctga catgccatgt ggaagggggc actcggctag 600 cttaccaatg gctaaaaaat gggagacctg tccacaccag ctccacctac tccttttctc 660 cccaaaacaa tacccttcat attgctccag taaccaagga agacattggg aattacagct 720 gcctggtgag gaaccctgtc agtgaaatgg aaagtgatat cattatgccc atcatatatt 780 atggacctta tggacttcaa gtgaattctg ataaagggct aaaagtaggg gaagtgttta 840 ctgttgacct tggagaggcc atcctatttg attgttctgc tgattctcat ccccccaaca 900 cctactcctg gattaggagg actgacaata ctacatatat cattaagcat gggcctcgct 960 tagaagttgc atctgagaaa gtagcccaga agacaatgga ctatgtgtgc tgtgcttaca 1020 acaacataac cggcaggcaa gatgaaactc atttcacagt tatcatcact tccgtaggac 1080 tggagaagct tgcacagaaa ggaaaatcat tgtcaccttt agcaagtata actggaatat 1140 cactattttt gattatatcc atgtgtcttc tcttcctatg gaaaaaatat caaccctaca 1200 aagttataaa acagaaacta gaaggcaggc cagaaacaga atacaggaaa gctcaaacat 1260 tttcaggcca tgaagatgct ctggatgact tcggaatata tgaatttgtt gcttttccag 1320 atgtttctgg tgtttccagg gttggttttc ctagtggctg attaaccgag aagtagaatt 1380 ctgcttcacc agagatccca agcaggtctg ttccagcctc tgattgtgta tcggggcaag 1440 atttgcacag tacagtgtat gaagttattc agcacatccc tgcccagcag caagaccatc 1500 cagagtgaac tttcatgggc taaacagtac attcgagtga aattctgaag aaacatttta 1560 aggaaaaaca gtggaaaagt atattaatct ggaatcagtg aagaaaccaa gaccaacacc 1620 tcttactcat tattccttta catgcagaat agaggcattt atgcaaattg aactgcaggt 1680 ttttcagcat atacacaatg tcttgtgcaa cagaaaaaca tgttggggaa atattcctca 1740 gtggagagtc gttctcatgc tgacggggag aacgaaagtg acaggggttt cctcgtaagt 1800 tttgtatgaa atatctctac aaacctcaat tagttctact ctacactttc actatcatca 1860 acactgagac tatcctgtct cacctacaaa tgtggaaact ttacattgtt cgatttttca 1920 gcagactttg ttttattaaa tttttattag tgttaagaat gctaaattta tgtttcaatt 1980 ttatttccaa atttctatct tgttatttgt acaacaaagt aataaggatg gttgtcacaa 2040 aaacaaaact atgccttctc ttttttttca atcaccagta gtatttttga gaagacttgt 2100 gaacacttaa ggaaatgact attaaagtct tatttttatt tttttcaagg aaagatggat 2160 tcaaataaat tattctgttt ttgctttta 2189 <210> 30 <211 > 2191

<212> DNA <213> Homo Sapiens <400> 30 gtaaccagta ctagaatagt cagtacctag aagccactct tctttgaaaa ggattatcac 60 ctgatcaggt tctctctgca tttgcccctt tagattgtga aatgtggctc aaggtcttca 120 caactttcct ttcctttgca acaggtgctt gctcggggct gaaggtgaca gtgccatcac 180 acactgtcca tggcgtcaga ggtcaggccc tctacctacc cgtccactat ggcttccaca 240 ctccagcatc agacatccag atcatatggc tatttgagag accccacaca atgcccaaat 300 acttactggg ctctgtgaat aagtctgtgg ttcctgactt ggaataccaa cacaagttca 360 ccatgatgcc acccaatgca tctctgctta tcaacccact gcagttccct gatgaaggca 420 attacatcgt gaaggtcaac attcagggaa atggaactct atctgccagt cagaagatac 480 aagtcacggt tgatgatcct gtcacaaagc cagtggtgca gattcatcct ccctctgggg 540 ctgtggagta tgtggggaac atgaccctga catgccatgt ggaagggggc actcggctag 600 cttaccaatg gctaaaaaat gggagacctg tccacaccag ctccacctac tccttttctc 660 cccaaaacaa tacccttcat attgctccag taaccaagga agacattggg aattacagct 720 gcctggtgag gaaccctgtc agtgaaatgg aaagtgatat cattatgccc atcatatatt 780 atggacctta tggacttcaa gtgaattctg ataaagggct aaaagtaggg gaagtgttta 840 ctgttgacct tggagaggcc atcctatttg attgttctgc tgattctcat ccccccaaca 900 cctactcctg gattaggagg actgacaata ctacatatat cattaagcat gggcctcgct 960 tagaagttgc atctgagaaa gtagcccaga agacaatgga ctatgtgtgc tgtgcttaca 1020 acaacataac cggcaggcaa gatgaaactc atttcacagt tatcatcact tccgtaggac 1080 tggagaagct tgcacagaaa ggaaaatcat tgtcaccttt agcaagtata actggaatat 1140 cactattttt gattatatcc atgtgtcttc tcttcctatg gaaaaaatat caaccctaca 1200 aagttataaa acagaaacta gaaggcaggc cagaaacaga atacaggaaa gctcaaacat 1260 tttcaggcca tgaagatgct ctggatgact tcggaatata tgaatttgtt gcttttccag 1320 atgtttctgg tgtttccagg gttggttttc ctagtggctg attaaccgag aagtagaatt 1380 ctgcttcacc agaggtatcc caagcaggtc tgttccagcc tctgattgtg tatcggggca 1440 agatttgcac agtacagtgt atgaagttat tcagcacatc cctgcccagc agcaagacca 1500 tccagagtga actttcatgg gctaaacagt acattcgagt gaaattctga agaaacattt 1560 taaggaaaaa cagtggaaaa gtatattaat ctggaatcag tgaagaaacc aagaccaaca 1620 cctcttactc attattcctt tacatgcaga atagaggcat ttatgcaaat tgaactgcag 1680 gtttttcagc atatacacaa tgtcttgtgc aacagaaaaa catgttgggg aaatattcct 1740 cagtggagag tcgttctcat gctgacgggg agaacgaaag tgacaggggt ttcctcgtaa 1800 gttttgtatg aaatatctct acaaacctca attagttcta ctctacactt tcactatcat I860 caacactgag actatcctgt ctcacctaca aatgtggaaa ctttacattg ttcgattttt 1920' cagcagactt tgttttatta aatttttatt agtgttaaga atgctaaatt tatgtttcaa 1980 ttttatttcc aaatttctat cttgttattt gtacaacaaa gtaataagga tggttgtcac 2040 aaaaacaaaa ctatgccttc tctttttttt caatcaccag tagtattttt gagaagactt 2100 gtgaacactt aaggaaatga ctattaaagt cttattttta tttttttcaa ggaaagatgg 2160 attcaaataa attattctgt ttttgctttt a 2191 <210>31 <211 >2229

<212> DNA <213> Homo Sapiens <400 31 gtaaccagta ctagaatagt cagtacctag aagccactct tctttgaaaa ggattatcac 60 ctgatcaggt tctctctgca tttgcccctt tagattgtga aatgtggcto aaggtcttca 120 caactttcct ttcctttgca acaggtgctt gctcggggct gaaggtgaca gtgccatcac 180 acactgtcca tggcgtcaga ggtcaggccc tctacctacc cgtccactat ggcttccaca 240 ctccagcatc agacatccag atcatatggc tatttgagag accccacaca atgcccaaat 300 acttactggg ctctgtgaat aagtctgtgg ttcctgactt ggaataccaa cacaagttca 360 ccatgatgcc acccaatgca tctctgctta tcaacccact gcagttccct gatgaaggca 420 attacatcgt gaaggtcaac attcagggaa atggaactct atctgccagt cagaagatac 480 aagtcacggt tgatgatcct gtcacaaagc cagtggtgca gattcatcct ccctctgggg 540 ctgtggagta tgtggggaac atgaccctga catgccatgt ggaagggggc actcggctag 600 cttaccaatg gctaaaaaat gggagacctg tccacaccag ctccacctac tccttttctc 660 cccaaaacaa tacccttcat attgctccag taaccaagga agacattggg aattacagct 720 gcctggtgag gaaccctgtc agtgaaatgg aaagtgatat cattatgccc atcatatatt 780 atggacctta tggacttcaa gtgaattctg ataaagggct aaaagtaggg gaagtgttta 840 ctgttgacct tggagaggcc atcctatttg attgttctgc tgattctcat ccccccaaca 900 cctactcctg gattaggagg actgacaata ctacatatat cattaagcat gggcctcgct 960 tagaagttgc atctgagaaa gtagcccaga agacaatgga ctatgtgtgc tgtgcttaca 1020 acaacataac cggcaggcaa gatgaaactc atttcacagt tatcatcact tccgtaggac 1080 tggagaagct tgcacagaaa ggaaaatcat tgtcaccttt agcaagtata actggaatat 1140 cactattttt gattatatcc atgtgtcttc tcttcctatg gaaaaaatat caaccctaca 1200 aagttataaa acagaaacta gaaggcaggt aatgcatctg tttctatgaa aatagttgtt 1260 ttccttagat gcttattcct caattattat ccctgacaaa aatacctatt ttgtcttttc 1320 aggccagaaa cagaatacag gaaagctcaa acattttcag gccatgaaga tgctctggat 1380 gacttcggaa tatatgaatt tgttgctttt ccagatgttt ctggtgtttc caggatccca 1440 agcaggtctg ttccagcctc tgattgtgta tcggggcaag atttgcacag tacagtgtat 1500 gaagttattc agcacatccc tgcccagcag caagaccatc cagagtgaac tttcatgggc 1560 taaacagtac attcgagtga aattctgaag aaacatttta aggaaaaaca gtggaaaagt 1620 atattaatct ggaatcagtg aagaaaccaa gaccaacacc tcttactcat tattccttta 1680 catgcagaat agaggcattt atgcaaattg aactgcaggt ttttcagcat atacacaatg 1740 tcttgtgcaa cagaaaaaca tgttggggaa atattcctca gtggagagtc gttctcatgc 1800 tgacggggag aacgaaagtg acaggggttt cctcgtaagt tttgtatgaa atatctctac 1860 aaacctcaat tagttctact ctacactttc actatcatca acactgagac tatcctgtct 1920 cacctacaaa tgtggaaact ttacattgtt cgatttttca gcagactttg ttttattaaa 1980 tttttattag tgttaagaat gctaaattta tgtttcaatt ttatttccaa atttctatct 2040 tgttatttgt acaacaaagt aataaggatg gttgtcacaa aaacaaaact atgccttctc 2100 ttttttttca atcaccagta gtatttttga gaagacttgt gaacacttaa ggaaatgact 2160 attaaagtct tatttttatt tttttcaagg aaagatggat tcaaataaat tattctgttt 2220 ttgctttta 2229 <210> 32 <211 >2229

<212> DNA <213> Homo Sapiens <400> 32 gtaaccagta ctagaatagt cagtacctag aagccactct tctttgaaaa ggattatcac 60 ctgatcaggt tctctctgca tttgcccctt tagattgtga aatgtggctc aaggtcttca 120 caactttcct ttcctttgca acaggtgctt gctcggggct gaaggtgaca gtgccatcac 180 acactgtcca tggcgtcaga ggtcaggccc tctacctacc cgtccactat ggcttccaca 240 ctccagcatc agacatccag atcatatggc tatttgagag accccacaca atgcccaaat 300 acttactggg ctctgtgaat aagtctgtgg ttcctgactt ggaataccaa cacaagttca 360 ccatgatgcc acccaatgca tctctgctta tcaacccact gcagttccct gatgaaggca 420 attacatcgt gaaggtcaac attcagggaa atggaactct atctgccagt cagaagatac 480 aagtcacggt tgatgatcct gtcacaaagc cagtggtgca gattcatcct ccctctgggg 540 ctgtggagta tgtggggaac atgaccctga catgccatgt ggaagggggc actcggctag 600 cttaccaatg gctaaaaaat gggagacctg tccacaccag ctccacctac tccttttctc 660 cccaaaacaa tacccttcat attgctccag taaccaagga agacattggg aattacagct 720 gcctggtgag gaaccctgtc agtgaaatgg aaagtgatat cattatgccc atcatatatt 780 atggacctta tggacttcaa gtgaattctg ataaagggct aaaagtaggg gaagtgttta 840 ctgttgacct tggagaggcc atcctatttg attgttctgc tgattctcat ccccccaaca 900 cctactcctg gattaggagg actgacaata ctacatatat cattaagcat gggcctcgct 960 tagaagttgc atctgagaaa gtagcccaga agacaatgga ctatgtgtgc tgtgcttaca 1020 acaacataac cggcaggcaa gatgaaactc atttcacagt tatcatcact tccgtaggac 1080 tggagaagct tgcacagaaa ggaaaatcat tgtcaccttt agcaagtata actggaatat 1140 cactattttt gattatatcc atgtgtcttc tcttcctatg gaaaaaatat caaccctaca 1200 aagttataaa acagaaacta gaaggcaggc cagaaacaga atacaggaaa gctcaaacat 1260 tttcaggcca tgaagatgct ctggatgact tcggaatata tgaatttgtt gcttttccag 1320 atgtttctgg tgtttccagg gttggttttc ctagtggctg attaaccgag aagtagaatt 1380 ctgcttcacc agaggtgtaa aaagcatttg tttaagcact gggcagtgtg gtcaaatggc 1440 tgcattaccc attactgcat taagcagtgt tgacttactc cgtaatgaat ggcattgcca 1500 gatttgggaa gctaaagcat cttacttcgc ctttataagt aaagctaaca caaataagga 1560 agttatgcta attcataaat agtctttacc tggtaatctc agtgaagaga gaactaacta 1620 ggttgaaagt caagagaact gaataaacaa gctgggcgtg gtggctcaca tctgtattcc 1680 tagggctttg ggaggctgag atggaaagat cacttgagcc caggagtttg agatcagcct 1740 gggcaaagac cccatcccaa caaatattta aaaattagcc aagcatggtt atgcatgcct 1800 ctggtcccag cttcttggga gaccgaggca ggaggatcat tgagcccagg agttcaaggc I860 tacagtgagc cgtgatcaca ctaccgcact ccagcctggg cagcagagta agaccctgtc 1920 tcaaataaat aaatactgaa taaacagcgg atcaggagac cctaatttaa gtcattctgc 1980 atcacttggg tgactgcaac ccatcacttt actaaactct ctctgttcct cagttttccc 2040 tttattgccc cctcatatct tttgacaaca ttgcaaagac aattgatcac acccttgaag 2100 atacctcatg cttcaggagg aagttaccat ataggcccaa agtatgcaag tatacatctt 2160 tattattgcc ctaaaggtgc atgagatggc aaaggagctt tcatatagtt gaagtcattt 2220 cagtccgga 2229 <210> 33 <211 >2323

<212> DNA <213> Homo Sapiens <400> 33 gtaaccagta ctagaatagt cagtacctag aagccactct tctttgaaaa ggattatcac 60 ctgatcaggt tctctctgca tttgcccctt tagattgtga aatgtggctc aaggtcttca 120 caactttcct ttcctttgca acaggtgctt gctcggggct gaaggtgaca gtgccatcac 180 acactgtcca tggcgtcaga ggtcaggccc tctacctacc cgtccactat ggcttccaca 240 ctccagcatc agacatccag atcatatggc tatttgagag accccacaca atgcccaaat 300 acttactggg ctctgtgaat aagtctgtgg ttcctgactt ggaataccaa cacaagttca 360 ccatgatgcc acccaatgca tctctgctta tcaacccact gcagttccct gatgaaggca 420 attacatcgt gaaggtcaac attcagggaa atggaactct atctgccagt cagaagatac 480 aagtcacggt tgatgatcct gtcacaaagc cagtggtgca gattcatcct ccctctgggg 540 ctgtggagta tgtggggaac atgaccctga catgccatgt ggaagggggc actcggctag 600 cttaccaatg gctaaaaaat gggagacctg tccacaccag ctccacctac tccttttctc 660 cccaaaacaa tacccttcat attgctccag taaccaagga agacattggg aattacagct 720 gcctggtgag gaaccctgtc agtgaaatgg aaagtgatat cattatgccc atcatatatt 780 atggacctta tggacttcaa gtgaattctg ataaagggct aaaagtaggg gaagtgttta 840 ctgttgacct tggagaggcc atcctatttg attgttctgc tgattctcat ccccccaaca 900 cctactcctg gattaggagg actgacaata ctacatatat cattaagcat gggcctcgct 960 tagaagttgc atctgagaaa gtagcccaga agacaatgga ctatgtgtgc tgtgcttaca 1020 acaacataac cggcaggcaa gatgaaactc atttcacagt tatcatcact tccgtaggac 1080 tggagaagct tgcacagaaa ggaaaatcat tgtcaccttt agcaagtata actggaatat 1140 cactattttt gattatatcc atgtgtcttc tcttcctatg gaaaaaatat caaccctaca 1200 aagttataaa acagaaacta gaaggcaggt aatgcatctg tttctatgaa aatagttgtt 1260 ttccttagat gcttattcct caattattat ccctgacaaa aatacctatt ttgtcttttc 1320 aggccagaaa cagaatacag gaaagctcaa acattttcag gccatgaaga tgctctggat 1380 gacttcggaa tatatgaatt tgttgctttt ccagatgttt ctggtgtttc cagggttggt 1440 tttcctagtg gctgattaac cgagaagtag aattctgctt caccagaggt gtaaaaagca 1500 tttgtttaag cactgggcag tgtggtcaaa tggctgcatt acccattact gcattaagca 1560 gtgttgactt actccgtaat gaatggcatt gccagatttg ggaagctaaa gcatcttact 1620 tcgcctttat aagtaaagct aacacaaata aggaagttat gctaattcat aaatagtctt 1680 tacctggtaa tctcagtgaa gagagaacta actaggttga aagtcaagag aactgaataa 1740 acaagctggg cgtggtggct cacatctgta ttcctagggc tttgggaggc tgagatggaa 1800 agatcacttg agcccaggag tttgagatca gcctgggcaa agaccccatc ccaacaaata 1860 tttaaaaatt agccaagcat ggttatgcat gcctctggtc ccagcttctt gggagaccga 1920 ggcaggagga tcattgagcc caggagttca aggctacagt gagccgtgat cacactaccg 1980 cactccagcc tgggcagcag agtaagaccc tgtctcaaat aaataaatac tgaataaaca 2040 gcggatcagg agaccctaat ttaagtcatt ctgcatcact tgggtgactg caacccatca 2100 ctttactaaa ctctctctgt tcctcagttt tccctttatt gccccctcat atcttttgac 2160 aacattgcaa agacaattga tcacaccctt gaagatacct catgcttcag gaggaagtta 2220 ccatataggc ccaaagtatg caagtataca tctttattat tgccctaaag gtgcatgaga 22B0 tggcaaagga gctttcatat agttgaagtc atttcagtcc gga 2323 <210> 34 <211> 1578

<212> DNA <213> Homo Sapiens <400> 34 gtaaccagta ctagaatagt cagtacctag aagccactct tctttgaaaa ggattatcac 60 ctgatcaggt tctctctgca tttgcccctt tagattgtga aatgtggctc aaggtcttca 120 caactttcct ttcctttgca aeaggtgctt gctcggggct gaaggtgaca gtgccatcac 180 acactgtcca tggcgtcaga ggtcaggccc tctacctacc cgtccactat ggcttccaca 240 ctccagcatc agacatccag atcatatggc tatttgagag accccacaca atgcccaaat 300 acttactggg ctctgtgaat aagtctgtgg ttcctgactt ggaataccaa cacaagttca 360 ccatgatgcc acccaatgca tctctgctta tcaacccact gcagttccct gatgaaggca 420 attacatcgt gaaggtcaac attcagggaa atggaactct atctgccagt cagaagatac 480 aagtcacggt tgatgatcct gtcacaaagc cagtggtgca gattcatcct ccctctgggg 540 ctgtggagta tgtggggaac atgaccctga catgccatgt ggaagggggc actcggctag 600 cttaccaatg gctaaaaaat gggagacctg tccacaccag ctccacctac tccttttctc 660 cccaaaacaa tacccttcat attgctccag taaccaagga agacattggg aattacagct 720 gcctggtgag gaaccctgtc agtgaaatgg aaagtgatat cattatgccc atcatatatt 780 atggacctta tggacttcaa gtgaattctg ataaagggct aaaagtaggg gaagtgttta 840 ctgttgacct tggagaggcc atcctatttg attgttctgc tgattctcat ccccccaaca 900 cctactcctg gattaggagg actgacaata ctacatatat cattaagcat gggcctcgct 960 tagaagttgc atctgagaaa gtagcccaga agacaatgga ctatgtgtgc tgtgcttaca 1020 acaacataac cggcaggcaa gatgaaactc atttcacagt tatcatcact tccgtaggac 1080 tggagaagct tgcacagaaa ggaaaatcat tgtcaccttt agcaagtata actggaatat 1140 cactattttt gattatatcc atgtgtcttc tcttcctatg gaaaaaatat caaccctaca 1200 aagttataaa acagaaacta gaaggcaggc cagaaacaga atacaggaaa gctcaaacat 1260 tttcaggttt catgctggca gctccatccc aaagagaaga ggaaaagaag atttggcagg 1320 ggccaggatt gcttctttgt ccccactgta accctcatta tcatcaatat tgactgtact 1380 gacttattat aagttaacaa agttttggct caggccacaa aatcacaggg agccaagttt 1440 cagttttatt tcccctcatg tcaccttagg aaaattattt ttcttaaccg caacttcctc 1500 ttctatataa tagggataaa aacttccccc ttaaggttgc tatgagaatt aaataaaatg 1560 atataggtgg agtgcctg 1578 <210> 35 <211 > 462

<212> PRT <213> Homo Sapiens <400> 35

Met Gly Gin Asp Ala Phe Met Glu Pro Phe Gly Asp Thr Leu Gly Val 15 10 15

Phe Gin. Cys Lys Ile Tyr Leu Leu Leu Phe Gly Ala CyS Ser Gly Leu 20 25 30

Lys Val Thr Val Pro Ser His Thr Val His Gly Val Arg Gly Gin Ala 35 40 45

Leu Tyr Leu Pro Val His Tyr Gly Phe His Thr Pro Ala Ser Asp He 50 55 60

Gin lie lie Trp Leu Phe Glu Arg Pro His Thr Met Pro Lys Tyr Leu 65 70 75 80

Leu Gly Ser Val Asn Lys Ser Val Val Pro Asp Leu Glu Tyr Gin His 85 90 95

Lys Phe Thr Met Met Pro Pro Asn Ala Ser Leu Leu lie Asn Pro Leu 100 105 110

Gin Phe Pro Asp Glu Gly Asn Tyr lie Val Lys Val Asn lie Gin Gly 115 120 125

Asn Gly Thr Leu Ser Ala Ser Gin Lys lie Gin Val Thr Val Asp Asp 130 135 140

Pro Val Thr Lys Pro Val Val Gin lie His Pro Pro Ser Gly Ala Val 145 150 155 160

Glu Tyr Val Gly Asn Met Thr Leu Thr Cys His Val Glu Gly Gly Thr 165 170 175

Arg Leu Ala Tyr Gin Trp Leu Lys Asn Gly Arg Pro Val His Thr Ser 180 185 190

Ser Thr Tyr Ser Phe Ser Pro Gin Asn Asn Thr Leu His He Ala Pro 195 200 205

Val Thr Lys Glu Asp Ile Gly Asn Tyr Ser Cys Leu Val Arg Asn Pro 210 215 220

Val Ser Glu Met Glu Ser Asp Ile Ile Met Pro Ile Ile Tyr Tyr Gly 225 230 235 240

Pro Tyr Gly Leu Gin Val Asn Ser Asp Lys Gly Leu Lys Val Gly Glu 245 250 255

Val Phe Thr Val Asp Leu Gly Glu Ala Ile Leu Phe Asp Cys Ser Ala 260 265 270

Asp Ser His Pro Pro Asn Thr Tyr Ser Trp Ile Arg Arg Thr Asp Asn 275 280 285

Thr Thr Tyr Ile Ile Lys His Gly Pro Arg Leu Glu Val Ala Ser Glu 290 295 300

Lys Val Ala Gin Lys Thr Met Asp Tyr Val Cys Cys Ala Tyr Asn Asn 305 310 315 320

Ile Thr Gly Arg Gin Asp Glu Thr His Phe Thr Val Ile Ile Thr Ser 325 330 335

Val Gly Leu Glu Lys Leu Ala Gin Lys Gly Lys Ser Leu Ser Pro Leu 340 345 350

Ala Ser Ile Thr Gly Ile Ser Leu Phe Leu Ile Ile Ser Met Cys Leu 355 360 365

Leu Phe Leu Trp Lys Lys Tyr Gin Pro Tyr Lys Val Ile Lys Gin Lys 370 375 380

Leu Glu Gly Arg Pro Glu Thr Glu Tyr Arg Lys Ala Gin Thr Phe Ser 385 390 395 400

Gly His Glu Asp Ala Leu Asp Asp Phe Gly Ile Tyr Glu Phe Val Ala 405 410 415

Phe Pro Asp Val Ser Gly Val Ser Arg Ile Pro Ser Arg Ser Val Pro 420 425 430

Ala Ser Asp Cys Val Ser Gly Gin Asp Leu His Ser Thr Val Tyr Glu 435 440 445

Val Ile Gin His Ile Pro Ala Gin Gin Gin Asp His Pro Glu 450 455 460 <210> 36 <211 >450

<212> PRT <213> Homo Sapiens <400> 36

Met Trp Leu Lys Val Phe Thr Thr Phe Leu Ser Phe Ala Thr Gly Ala 15 10 15'

Cys Ser Gly Leu Lys Val Thr Val Pro Ser His Thr Val His Gly Val 20 25 30

Arg Gly Gin Ala Leu Tyr Leu Pro Val His Tyr Gly Phe His Thr Pro 35 40 45

Ala Ser Asp lie Gin lie lie Trp Leu Phe Glu Arg Pro His Thr Met 50 55 60

Pro Lys Tyr Leu Leu Gly Ser Val Asn Lys Ser Val Val Pro Asp Leu 65 70 75 80

Glu Tyr Gin His Lys Phe Thr Met Met Pro Pro Asn Ala Ser Leu Leu 85 90 95 lie Asn Pro Leu Gin Phe Pro Asp Glu Gly Asn Tyr lie Val Lys Val 100 105 110

Asn lie Gin Gly Asn Gly Thr Leu Ser Ala Ser Gin Lys lie Gin Val 115 120 125

Thr Val Asp Asp Pro Val Thr Lys Pro Val Val Gin lie His Pro Pro 130 135 140

Ser Gly Ala Val Glu Tyr Val Gly Asn Met Thr Leu Thr Cys His Val 145 150 155 160

Glu Gly Gly Thr Arg Leu Ala Tyr Gin Trp Leu Lys Asn Gly Arg Pro 165 170 175

Val His Thr Ser Ser Thr Tyr Ser Phe Ser Pro Gin Asn Asn Thr Leu 180 185 190

His lie Ala Pro Val Thr Lys Glu Asp lie Gly Asn Tyr Ser Cys Leu 195 200 205

Val Arg Asn Pro Val Ser Glu Met Glu Ser Asp Ile Ile Met Pro Ile 210 215 220

Ile Tyr Tyr Gly Pro Tyr Gly Leu Gin Val Asn Ser Asp Lys Gly Leu 225 230 235 240

Lys Val Gly Glu Val Phe Thr Val Asp Leu Gly Glu Ala Ile Leu Phe 245 250 255

Asp Cys Ser Ala Asp Ser His Pro Pro Asn Thr Tyr Ser Trp Ile Arg 260 265 270

Arg Thr Asp Asn Thr Thr Tyr Ile Ile Lys His Gly Pro Arg Leu Glu 275 280 285

Val Ala Ser Glu Lys Val Ala Gin Lys Thr Met Asp Tyr Val Cys Cys 290 295 300

Ala Tyr Asn Asn Ile Thr Gly Arg Gin Asp Glu Thr His Phe Thr Val 305 310 315 320

Ile Ile Thr Ser Val Gly Leu Glu Lys Leu Ala Gin Lys Gly Lys Ser 325 330 335

Leu Ser Pro Leu Ala Ser Ile Thr Gly Ile Ser Leu Phe Leu Ile Ile 340 345 350

Ser Met Cys Leu Leu Phe Leu Trp Lys Lys Tyr Gin Pro Tyr Lys Val 355 360 365

Ile Lys Gin Lys Leu Glu Gly Arg Pro Glu Thr Glu Tyr Arg Lys Ala 370 375 380

Gin Thr Phe Ser Gly His Glu Asp Ala Leu Asp Asp Phe Gly Ile Tyr 385 390 395 400

Glu Phe Val Ala Phe Pro Asp Val Ser Gly Val Ser Arg Ile Pro Ser 405 410 415

Arg Ser Val Pro Ala Ser Asp Cys Val Ser Gly Gin Asp Leu His Ser 420 425 430

Thr Val Tyr Glu Val Ile Gin His Ile Pro Ala Gin Gin Gin Asp His 435 440 445

Pro Glu 450 <210> 37 <211 >455

<212> PRT <213> Homo Sapiens <400> 37

Met Trp Leu Lys Val Phe Thr Thr Phe Leu Ser Phe Ala Thr Gly Ala 15 10 15

Cys Ser Gly Leu Lys Val Thr Val Pro Ser His Thr Val His Gly Val 20 25 30

Arg Gly Gin Ala Leu Tyr Leu Pro Val His Tyr Gly Phe His Thr Pro 35 40 45

Ala Ser Asp lie Gin lie lie Trp Leu Phe Glu Arg Pro His Thr Met 50 55 60

Pro Lys Tyr Leu Leu Gly Ser Val Asn Lys Ser Val Val Pro Asp Leu 65 70 75 80

Glu Tyr Gin His Lys Phe Thr Met Met Pro Pro Asn Ala Ser Leu Leu 85 90 95 lie Asn Pro Leu Gin Phe Pro Asp Glu Gly Asn Tyr lie Val Lys Val 100 105 110

Asn lie Gin Gly Asn Gly Thr Leu Ser Ala Ser Gin Lys lie Gin Val 115 120 125

Thr Val Asp Asp Pro Val Thr Lys Pro Val Val Gin lie His Pro Pro 130 135 140

Ser Gly Ala Val Glu Tyr Val Gly Asn Met Thr Leu Thr Cys His Val 145 150 155 160

Glu Gly Gly Thr Arg Leu Ala Tyr Gin Trp Leu Lys Asn Gly Arg Pro 165 170 175

Val His Thr Ser Ser Thr Tyr Ser Phe Ser Pro Gin Asn Asn Thr Leu 180 185 190

His Ile Ala Pro Val Thr Lys Glu Asp Ile Gly Asn Tyr Ser Cys Leu 195 200 205

Val Arg Asn Pro Val Ser Glu Met Glu Ser Asp Ile Ile Met Pro Ile 210 215 220

Ile Tyr Tyr Gly Pro Tyr Gly Leu Gin Val Asn Ser Asp Lys Gly Leu 225 230 235 240

Lys Val Gly Glu Val Phe Thr Val Asp Leu Gly Glu Ala Ile Leu Phe 245 250 255

Asp Cys Ser Ala Asp Ser His Pro Pro Asn Thr Tyr Ser Trp Ile Arg 260 265 270

Arg Thr Asp Asn Thr Thr Tyr Ile Ile Lys His Gly Pro Arg Leu Glu 275 280 285

Val Ala Ser Glu Lys Val Ala Gin Lys Thr Met Asp Tyr Val Cys Cys . 290 295 300

Ala Tyr Asn Asn Ile Thr Gly Arg Gin Asp Glu Thr His Phe Thr Val 305 310 315 320

Ile Ile Thr Ser Val Gly Leu Glu Lys Leu Ala Gin Lys Gly Lys Ser 325 330 335

Leu Ser Pro Leu Ala Ser Ile Thr Gly Ile Ser Leu Phe Leu Ile Ile 340 345 350

Ser Met Cys Leu Leu Phe Leu Trp Lys Lys Tyr Gin Pro Tyr Lys Gly 355 360 365

Gin Lys Gin Asn Thr Gly Lys Leu Lys His Phe Gin Ala Met Lys Met 370 375 380

Leu Trp Met Thr Ser Glu Tyr Met Asn Leu Leu Leu Phe Gin Met Phe 385 390 395 400

Leu Val Phe Pro Gly Ser Gin Ala Gly Leu Phe Gin Pro Leu Ile Val 405 410 415

Tyr Arg Gly Lys Ile Cys Thr Val Gin Cys Met Lys Leu Phe Ser Thr 420 425 430

Ser Leu Pro Ser Ser Lys Thr Ile Gin Ser Glu Leu Ser Trp Ala Lys 435 440 445

Gin Tyr Ile Arg Val Lys Phe 450 455 <210> 38 <211 > 419

<212> PRT <213> Homo Sapiens <400> 38

Met Trp Leu Lys Val Phe Thr Thr Phe Leu Ser Phe Ala Thr Gly Ala 15 10 15

Cys Ser Gly Leu Lys Val Thr Val Pro Ser His Thr Val His Gly Val 20 25 30

Arg Gly Gin Ala Leu Tyr Leu Pro Val His Tyr Gly Phe His Thr Pro 35 40 45

Ala Ser Asp lie Gin lie lie Trp Leu Phe Glu Arg Pro His Thr Met 50 55 60

Pro Lys Tyr Leu Leu Gly Ser Val Asn Lys Ser Val Val Pro Asp Leu 65 70 75 80

Glu Tyr Gin His Lys Phe Thr Met Met Pro Pro Asn Ala Ser Leu Leu 85 90 95 lie Asn Pro Leu Gin Phe Pro Asp Glu Gly Asn Tyr lie Val Lys Val 100 105 110

Asn He Gin Gly Asn Gly Thr Leu Ser Ala Ser Gin Lys lie Gin Val 115 120 125

Thr Val Asp Asp Pro Val Thr Lys Pro Val Val Gin' lie His Pro Pro 130 135 140

Ser Gly Ala Val Glu Tyr Val Gly Asn Met Thr Leu Thr Cys His Val 145 150 155 160

Glu Gly Gly Thr Arg Leu Ala Tyr Gin Trp Leu Lys Asn Gly Arg Pro 165 170 175

Val His Thr Ser Ser Thr Tyr Ser Phe Ser Pro Gin Asn Asn Thr Leu

His Ile Ala Pro Val Thr Lys Glu Asp Ile Gly Asn Tyr Ser Cys Leu 195 200 205

Val Arg Asn Pro Val Ser Glu Met Glu Ser Asp Ile Ile Met Pro Ile 210 215 220

Ile Tyr Tyr Gly Pro Tyr Gly Leu Gin Val Asn Ser Asp Lys Gly Leu 225 230 235 240

Lys. Val Gly Glu Val Phe Thr Val Asp Leu Gly Glu Ala Ile Leu Phe 245 250 , 255

Asp Cys Ser Ala Asp Ser His Pro Pro Asn Thr Tyr Ser Trp Ile Arg 260 ‘ 265 270

Arg Thr Asp Asn Thr Thr Tyr Ile Ile Lys His Gly Pro Arg Leu Glu 275 280 285 val Ala Ser Glu Lys Val Ala Gin Lys Thr Met Asp Tyr Val Cys Cys 290 295 300

Ala Tyr Asn Asn ile Thr Gly Arg Gin Asp Glu Thr His Phe Thr Val 305 310 315 320

Ile Ile Thr Ser Val Gly Leu Glu Lys Leu Ala Gin Lys Gly Lys Ser 325 330 335

Leu Ser Pro Leu Ala Ser Ile Thr Gly Ile Ser Leu Phe Leu Ile Ile 340 345 350

Ser Met Cys Leu Leu Phe Leu Trp Lys Lys Tyr Gin Pro Tyr Lys Val 355 360 365

Ile Lys Gin Lys Leu Glu Gly Arg Pro Glu Thr Glu Tyr Arg Lys Ala 370 375 380

Gin Thr Phe Ser Gly His Glu Asp Ala Leu Asp Asp Phe Gly Ile Tyr 385 390 395 400

Glu Phe Val Ala Phe Pro Asp Val Ser Gly Val Ser Arg Val Gly Phe 405 410 415

Pro Ser Gly <210> 39 <211 > 376

<212> PRT <213> Homo Sapiens <400> 39

Met Trp Leu Lys Val Phe Thr Thr Pile Leu Ser Phe Ala Thr Gly Ala 15 10 15

Cys Ser Gly Leu Lys Val Thr Val Pro Ser His Thr Val His Gly Val 20 25 30

Arg Gly Gin Ala Leu Tyr Leu Pro Val His Tyr Gly Phe His Thr Pro 35 40 45

Ala Ser Asp lie Gin lie lie Trp Leu Phe Glu Arg Pro His Thr Met 50 55 60

Pro Lys Tyr Leu Leu Gly Ser Val Asn Lys Ser Val Val Pro Asp Leu 65 70 75 80

Glu Tyr Gin His Lys Phe Thr Met Met Pro Pro Asn Ala Ser Leu Leu 85 90 95 lie Asn Pro Leu Gin Phe Pro Asp Glu Gly Asn Tyr lie Val Lys Val 100 105 110

Asn lie Gin Gly Asn Gly Thr Leu Ser Ala Ser Gin Lys lie Gin Val 115 120 125

Thr Val Asp Asp Pro Val Thr Lys Pro Val Val Gin lie His Pro Pro 130 135 140

Ser Gly Ala Val Glu Tyr Val Gly Asn Met Thr Leu Thr Cys His Val 145 150 155 160

Glu Gly Gly Thr Arg Leu Ala Tyr Gin Trp Leu Lys Asn Gly Arg Pro 165 170 175

Val His Thr Ser Ser Thr Tyr Ser Phe Ser Pro Gin Asn Asn Thr Leu 180 185 190

His lie Ala Pro Val Thr Lys Glu Asp lie Gly Asn Tyr Ser Cys Leu 195 200 205

Val Arg Asn Pro Val Ser Glu Met Glu Ser Asp lie lie Met Pro lie 210 215 220 lie Tyr Tyr Gly Pro Tyr Gly Leu Gin Val Asn Ser Asp Lys Gly Leu 225 230 235 240

Lys Val Gly Glu Val Phe Thr Val Asp Leu Gly Glu Ala lie Leu Phe 245 250 255

Asp Cys Ser Ala Asp Ser His Pro Pro Asn Thr Tyr Ser Trp lie Arg 260 265 ’ 270

Arg Thr Asp Asn Thr Thr Tyr lie lie Lys His Gly Pro Arg Leu Glu 275 280 285

Val Ala Ser Glu Lys Val Ala Gin Lys Thr Met Asp Tyr Val Cys Cys 29Q 295 300

Ala Tyr Asn Asn He Thr Gly Arg Gin Asp Glu Thr His Phe Thr Val 305 310 315 320

He lie Thr Ser Val Gly Leu Glu Lys Leu Ala Gin Lys Gly Lys Ser 325 330 335

Leu Ser Pro Leu Ala Ser lie Thr Gly lie Ser Leu Phe Leu Ile He 340 345 350

Ser Met Cys Leu Leu Phe Leu Trp Lys Lys Tyr Gin Pro Tyr Lys Val 355 360 365

He Lys Gin Lys Leu Glu Gly Arg 370 375 <210> 40 <211 > 423

<212> PRT <213> Homo Sapiens <400> 40

Met Trp Leu Lys Val Phe Thr Thr Phe Leu Ser Phe Ala Thr Gly Ala 15 10 15

Cys Ser Gly Leu Lys Val Ihr Val Pro Ser His Ihr Val His Gly Val 20 25 30

Arg Gly Gin Ala Leu Tyr Leu Pro Val His Tyr Gly Phe His Thr Pro 35 40 45

Ala Ser Asp Ile Gin Ile Ile Trp Leu Phe Glu Arg Pro His Thr Met 50 55 60

Pro Lys Tyr Leu Leu Gly Ser Val Asn Lys Ser Val Val Pro Asp Leu 65 70 75 80

Glu Tyr Gin His Lys Phe Thr Met Met Pro Pro Asn Ala Ser Leu Leu 85 90 95

Ile Asn Pro Leu Gin Phe Ero Asp Glu Gly Asn Tyr Ile Val Lys Val 100 - 105 110

Asn Ile Gin Gly Asn‘ Gly Thr Leu Ser Ala Ser Gin Lys lie Gin Val 115 120 125

Thr Val Asp Asp Pro Val Thr Lys Pro Val Val Gin lie His Pro Pro 130 135 140

Ser Gly Ala Val Glu Tyr Val Gly Asn Met Thr Leu Thr Cys His Val 145 150 155 160

Glu Gly Gly Thr Arg Leu Ala Tyr Gin Trp Leu Lys Asn Gly Arg Pro 165 170 175

Val His Thr Ser Ser Thr Tyr Ser Phe Ser Pro Gin Asn Asn Thr Leu 180 185 190

His lie Ala Pro Val Thr Lys Glu Asp lie Gly Asn Tyr Ser Cys Leu 195 200 205

Val Arg Asn Pro Val Ser Glu Met Glu Ser Asp lie lie Met Pro lie 210 215 220 lie Tyr Tyr Gly Pro Tyr Gly Leu Gin Val Asn Ser Asp Lys Gly Leu 225 230 235 240

Lys Val Gly Glu Val Phe Thr Val Asp Leu Gly Glu Ala lie Leu Phe 245 250 255

Asp Cys Ser Ala Asp Ser His Pro Pro Asn Thr Tyr Ser Trp lie Arg 260 265 270

Arg Thr Asp Asn Thr Thr Tyr lie lie Lys His Gly Pro Arg Leu Glu 275 280 285

Val Ala Ser Glu Lys Val Ala Gin Lys Thr Met Asp Tyr Val Cys Cys 290 295 300

Ala Tyr Asn Asn Ile Thr Gly Arg Gin Asp Glu Thr His Phe Thr Val 305 310 315 320 ile Ile Thr Ser Val Gly Leu Glu Lys Leu Ala Gin Lys Gly Lys Ser 325 330 335

Leu Ser Pro Leu Ala Ser Ile Thr Gly Ile Ser Leu Phe Leu Ile Ile 340 345 350

Ser Met Cys Leu Leu Phe Leu Trp Lys Lys Tyr Gin Pro Tyr Lys Val 355 360 365

Ile Lys Gin Lys Leu Glu Gly Arg Pro Glu Thr Glu Tyr Arg Lys Ala 370 375 380

Gin Thr Phe Ser Gly Phe Met Leu Ala Ala Pro Ser Gin Arg Glu Glu 385 390 395 400

Glu Lys Lys Ile Trp Gin Gly Pro Gly Leu Leu Leu Cys Pro His Cys 405 410 415

Asn Pro His Tyr His Gin Tyr 420 <210>41 <211> 1520

<212> DNA <213> Homo Sapiens <400> 41 atgaggcctc tgcccagcgg gaggaggaag acccgaggca tctccctagg actcttcgcc 60 ctctgcctgg ccgcagcccg ctgtctgcag agtcagggtg tgtccctata cattcctcag 120 gccaccatca atgccactgt caaagaagac atcctgctct cagttgagta ctcctgtcat 180 ggagtgccca ccatcgaatg gacatattca tccaattggg gaacgcagaa gatcgtggag 240 tggaaaccag ggactcaggc caacatctct caaagccaca aggacagagt ctgcaccttt 300 gacaacggct ccatccagct cttcagcgtg ggagtgaggg attccggcta ctatgtcatc 360 accgtgacgg agcgcctggg gagcagccag tttggcacca tcgtgctgca cgtctctgag 420 atcctctatg aagacctgca ctttgtcgct gtcatccttg cttttctcgc tgctgtggcc 480 gcagtattaa tcagcctcat gtgggtttgt aataagtgtg catataaatt tcagaggaag 540 agaagacaca aactcaaaga aagcacaact gaggagattg agctggaaga tgttgagtgt 600 tagccaaggc tgggcctgac tgcattccta cctcaagagg aaaccattct ccaacaaaaa 660 gagcaagcac agctattata cccattgtgt gtggtcctgt tgcagcccgc tcctaacagg 720 acagtgggag attaacaaca ttgactgcat ggagttgagg actgtggatg ggacaaagct 780 agtattagga ctcgcgctaa gttcaaggag aagagtgatt gaggctttga accaggagct 840 tcgcttggct gcagcatcag ggccgtgctg acacataacc aatggdagtc ggaggaacca 900 ggctctgggc caggacagtt tccagtgctg tgaagaaacg aggtgagcag tatccaaggg 960 gctcaaggat aatctgctga tttctttctc gtctttcaca cagagaggcc accagcagga 1020 aagcagtggg agttgggtag ctgctggggc cagcatgtcc tcttccacac tacctgcctt 1080 tcagaactct gctcttccgc ttgtcccgaa gtcagggctg gcaatcttca taatcaaagg 1140 ggagttggaa aagaacaccc actaagaggc ctccatggca gatgtcaatt aaattgcccc 1200 cccccccaaa tctcatgaca gtttattcac atcagtagtg tgggaagtta caatgttttt 1260 tttaaaaaaa gcttctttcc ttggctttcc atttctttga aaaaagggtt tcttttgaat 1320 ttttaaagct ctgccatact gaacattcct gtggaaaggt ttaaaatgca gagcctgagg 1380 tttttgcttt tcagaaaaat aaaaatcata gagattaget agtgtaaatg ttaagetata 1440 aattatgttt caaactgtga aaaaaaaaag ttttaaagaa tgaatgaaat aaaacctgaa 1500 aataaagccc tggtcctttg 1520 <210 42 <211 > 1650

<212> DNA <213> Homo Sapiens <400> 42 atgaggcctc tgcccagcgg gaggaggaag acccgaggca tctccctagg actcttcgcc 60 ctctgcctgg ccgcagcccg ctgtctgcag agtcagggtg tgtccctata cattcctcag 120 gccaccatca atgccactgt caaagaagac atcctgctct cagttgagta ctcctgtcat 180 ggagtgccca ccatcgaatg gaeatattea tccaattggg gaacgcagaa gategtggag 240 tggaaaccag ggactcaggc caacatctct caaagccaca aggaeagagt ctgcaccttt 300 gaeaaegget ccatccagct etteagegtg ggagtgaggg atteeggeta ctatgtcatc 360 accgtgacgg agcgcctggg gagcagccag tttggcacca tegtgetgea egtetetgag 420 atcctctatg aagacctgca ctttgtcgct gtcatccttg cttttctcgc tgctgtggcc 480 gcagtattaa tcagcctcat gtgggtttgt aataagtgtg catataaatt tcagaggaag 540 agaagacaca aactcaaagg taaccccctg ggccttgtga taatccatga gtggttttga 600 ggccagaggt ggcatgtgtt atcttgttct cacgaagaaa gcactatgtg gcttgatttc 660 caactcattg acttgtcttt gctttacaga aagcacaact gaggagattg agctggaaga 720 tgttgagtgt tagccaaggc tgggcctgac tgcattccta cctcaagagg aaaccattct 780 ccaacaaaaa gagcaagcac agctattata cccattgtgt gtggtcctgt tgcagcccgc 840 tcctaacagg acagtgggag attaacaaca ttgactgcat ggagttgagg actgtggatg 900 ggacaaagct agtattagga ctcgcgctaa gttcaaggag aagagtgatt gaggctttga 960 accaggagct tcgcttggct gcagcatcag ggccgtgctg acacataacc aatggcagtc 1020 ggaggaacca ggctctgggc caggacagtt tccagtgctg tgaagaaacg aggtgagcag 1080 tatccaaggg gctcaaggat aatctgctga tttctttctc gtctttcaca cagagaggcc 1140 accagcagga aagcagtggg agttgggtag ctgctggggc cagcatgtcc tcttccacac 1200 tacctgcctt tcagaactct gctcttccgc ttgtcccgaa gtcagggctg gcaatcttca 1260 taatcaaagg ggagttggaa aagaacaccc actaagaggc ctccatggca gatgtcaatt 1320 aaattgcccc cccccccaaa tctcatgaca gtttattcac atcagtagtg tgggaagtta 1380 caatgttttt tttaaaaaaa gcttctttcc ttggctttcc atttctttga aaaaagggtt 1440 tcttttgaat ttttaaagct ctgccatact gaacattcct gtggaaaggt ttaaaatgca 1500 gagcctgagg tttttgcttt tcagaaaaat aaaaatcata gagattagct agtgtaaatg 1560 ttaagctata aattatgttt caaactgtga aaaaaaaaag ttttaaagaa tgaatgaaat 1620 aaaacctgaa aataaagccc tggtcctttg 1650 <210> 43 <211 > 200

<212> PRT <213> Homo Sapiens <400> 43

Met Arg Pro Leu Pro Ser Gly Arg Arg Lys Thr Arg Gly Ile Ser Leu 15 10 15

Gly Leu Phe Ala Leu Cys Leu Ala Ala Ala Arg Cys Leu Gin Ser Gin 20 25 30

Gly Val Ser Leu Tyr lie Pro Gin Ala Thr Ile Asn Ala Thr Val Lys 35 40 45

Glu Asp Ile Leu Leu Ser Val Glu Tyr Ser Cys His Gly Val Pro Thr 50 55 60

Ile Glu Trp Thr Tyr Ser Ser Asn Trp Gly Thr Gin Lys Ile Val Glu 65 70 75 80

Trp Lys Pro Gly Thr Gin Ala Asn Ile Ser Gin Ser His Lys Asp Arg 85 90 95

Val Cys Thr Phe Asp Asn Gly Ser Ile Gin Leu Phe Ser Val Gly Val 100 105 110

Arg Asp Ser Gly Tyr Tyr Val Ile Thr Val Thr Glu Arg Leu Gly Ser 115 120 125

Ser Gin Phe Gly Thr Ile Val Leu His Val Ser Glu Ile Leu Tyr Glu 130 135 140

Asp Leu His Phe Val Ala Val Ile Leu Ala Phe Leu Ala Ala Val Ala 145 150 155 160

Ala Val Leu Ile Ser Leu Met Trp Val Cys Asn Lys Cys Ala Tyr Lys 165 170 175

Phe Gin Arg Lys Arg Arg His Lys Leu Lys Glu Ser Thr Thr Glu Glu 180 185 190

Ile Glu Leu Glu Asp Val Glu Cys 195 200 <210> 44 <211 > 199

<212> PRT <213> Homo Sapiens <400> 44

Met Arg Pro Leu Pro Ser Gly Arg Arg Lys Thr Arg Gly Ile Ser Leu 15 10 15

Gly Leu Phe Ala Leu Cys Leu Ala Ala Ala Arg Cys Leu Gin Ser Gin 20 25 30

Gly Val Ser Leu Tyr Ile Pro Gin Ala Thr Ile Asn Ala Thr Val Lys 35 40 45

Glu Asp Ile Leu Leu Ser Val Glu Tyr Ser Cys His Gly Val Pro Thr

Ile Glu Trp Thr Tyr Ser Ser Asn Trp Gly Thr Gin Lys Ile Val Glu

65 70 75 SO

Trp Lys Pro Gly Thr Gin Ala Asn Ile Ser Gin Ser His Lys Asp Arg 85 90 95

Val Cys Thr Phe Asp Asn Gly Ser ile Gin Lev Phe Ser Val Gly Val 100 105 110

Arg Asp Ser Gly Tyr Tyr Val Ile Thr Val Thr Glu Arg Leu Gly Ser 115 120 125

Ser Gin Phe Gly Thr Ile Val Leu His Val Ser Glu Ile Leu Tyr Glu 130 135 140

Asp Leu His Phe Val Ala Val Ile Leu Ala Phe Leu Ala Ala Val Ala 145 150 155 160

Ala Val Leu Ile Ser Leu Met Trp Val Cys Asn Lys Cys Ala Tyr Lys 165 170 175

Phe Gin Arg Lys Arg Arg His Lys Leu Lys Gly Asn Pro Leu Gly Leu 180 185 190

Val Ile Ile His Glu Trp Phe 195 <210> 45 <211 > 1407

<212> DNA <213> Homo Sapiens <400> 45 ccggcggcgc gatccagccc ccggccccgc ctgcgcggcc ggcccggcgg gcgctgcgcc 60 cagggacgcc cggtgcccgc cgctccgccg ccgcccgctg ccgcggggtg acagcgatcc 120 ttctgttcca gccatttccc actttcctca ctccgtaatt cggctgggaa gttggggaag 180 atggataggg tcttgctgag gtggatttct ctcttctggc taacagccat ggtcgaaggc 240 cttcaggtca cagtgcccga caagaagaag gtggccatgc tcttccagcc cactgtgctt 300 cgctgccact tctcaacatc ctcccatcag cctgcagttg tgcagtggaa gttcaagtcc 360 tactgccagg atcgcatggg agaatccttg ggcatgtcct ctacccgggc ccaatctctc 420 agcaagagaa acctggaatg ggacccctac ttggattgtt tggacagcag gaggactgtt 480 cgagtagtag cttcaaaaca gggctcgact gtcaccctgg gagatttcta caggggcaga 540 gagatcacga ttgttcatga tgcagatctt caaattggaa agcttatgtg gggagacagc 600 ggactctatt actgtattat caccacccca gatgacctgg aggggaaaaa tgagggctca 660 ctgggactgc tggtgttggg caggacaggg ctgcttgctg atctcttgcc cagttttgct 720 gtggagatta tgccagagtg ggtgtttgtt ggcctggtgc tcctgggcgt cttcctcttc 780 ttcgtcctgg tggggatctg ctggtgccag tgctgccctc acagctgctg ctgctatgtc 840 cgctgcccat gctgcccaga ttcctgctgg tgccctcaag cctgtgagta cagtgaccgc 900 tggggagaca gagcgatcga gagaaatgtc tacctctcta cctgacagct gtgtgcgctg 960 ggttcctcct ccacctcctg tcctgccacc cccaagattg gtcattccag actcttctcc 1020 gctgggtgcc cctggcctca gggatgacca ttctcatttg ccttttcacc tacatacacc 1080 tctccacact tcttatccat atctatcact ccatgcattt ggaattctca tggacactat 1140 tgataaaatg gaagggcagg tttggcgtgg tgaggttgtg gtgtaagact gttccctctc 1200 cctggggcat tcaaactaga ggaaaccttc tctggtcgtt cccttcccat gcagagaagt 1260 tcctttttat atgagaagag tgtgcaaact gtggcctttg ggcacccacc cagccacaga 1320 tttgttttat ttactcccat gatgacatgg gccacaatag ggcctagttc ttatttgagg 1380 attcacaatt tttaccttac tggccaa 1407 <210> 46 <211 > 1350

<212> DNA <213> Homo Sapiens <400> 46 ccggcggcgc gatccagccc ccggccccgc ctgcgcggcc ggcccggcgg gcgctgcgcc 60 cagggacgcc cggtgcccgc cgctccgccg ccgcccgctg' ccgcggggtg acagcgatcc 120 ttctgttcca gccatttccc actttcctca ctccgtaatt cggctgggaa gttggggaag 180 atggataggg tcttgctgag gtggatttct ctcttctggc taacagccat ggtcgaaggc 240 cttcaggtca cagtgcccga caagaagaag gtggccatgc tcttccagcc cactgtgctt 300 cgctgccact tctcaacatc ctcccatcag cctgcagttg tgcagtggaa gttcaagtcc 360 tactgccagg atcgcatggg agaatccttg ggcatgtcct ctacccgggc ccaatctctc 420 agcaagagaa acctggaatg ggacccctac ttggattgtt tggacagcag gaggactgtt 480 cgagtagtag cttcaaaaca gggctcgact gtcaccctgg gagatttcta caggggcaga 540 gagatcacga ttgttcatga tgcagatctt caaattggaa agcttatgtg gggagacagc 600 ggactctatt actgtattat caccacccca gatgacctgg aggggaaaaa tgagggctca 660 ctgggactgc tggtgttgga gtgggtgttt gttggcctgg tgctcctggg cgtcttcctc 720 ttcttcgtcc tggtggggat ctgctggtgc cagtgctgcc ctcacagctg ctgctgctat 780 gtccgctgcc catgctgccc agattcctgc tggtgccctc aagcctgtga gtacagtgac 840 cgctggggag acagagcgat cgagagaaat gtctacctct ctacctgaca gctgtgtgcg 900 ctgggttcct cctccacctc ctgtcctgcc acccccaaga ttggtcattc cagactcttc 960 tccgctgggt gcccctggcc tcagggatga ccattctcat ttgccttttc acctacatac 1020 acctctccac acttcttatc catatctatc actccatgca tttggaattc tcatggacac 1080 tattgataaa atggaagggc aggtttggcg tggtgaggtt gtggtgtaag actgttccct 1140 ctccctgggg cattcaaact agaggaaacc ttctctggtc gttcccttcc catgcagaga 1200 agttcctttt tatatgagaa gagtgtgcaa actgtggcct ttgggcaccc acccagccac 1260 agatttgttt tatttactcc catgatgaca tgggccacaa tagggcctag ttcttatttg 1320 aggattcaca atttttacct tactggccaa 1350 <210> 47 <211 > 639

<212> PRT <213> Homo Sapiens <400> 47

Met Asp Arg Val Leu Leu Arg Trp Ile Ser Leu Phe Trp Leu Thr Ala 15 10 15

Met Val Glu Gly Leu Gin Val Thr Val Pro Asp Lys Lys Lys Val Ala 20 25 30

Met Leu Phe Gin Pro Thr Val Leu Arg Cys His Phe Ser Thr Ser Ser 35 40 45

His Gin Pro Ala Val Val Gin Trp Lys Phe Lys Ser Tyr Cys Gin Asp 50 55 60

Arg Met Gly Glu Ser Leu Gly Met Ser Ser Thr Arg Ala Gin Ser Leu 65 70 75 80

Ser Lys Arg Asn Leu Glu Trp Asp Pro Tyr Leu Asp Cys Leu Asp Ser 85 90 95

Arg Arg Thr Val Arg Val Val Ala Ser Lys Gin Gly Ser Thr Val Thr 100 105 110

Leu Gly Asp Phe Tyr Arg Gly Arg Glu Ile Thr Ile Val His Asp Ala 115 120 125

Asp Leu Gin Ile Gly Lys Leu Met Trp Gly Asp Ser Gly Leu Tyr Tyr 130 135 140

Cys Ile Ile Thr Thr Pro Asp Asp Leu Glu Gly Lys Asn Glu Asp Ser 145 150 155 160

Val Glu Leu Leu Val Leu Gly Arg Thr Gly Leu Leu Ala Asp Leu Leu 165 170 175

Pro Ser Phe Ala Val Glu Ile Met Pro Glu Trp Val Phe Val Gly Leu 180 185 190

Val Leu Leu Gly Val Phe Leu Phe Phe Val Leu Val Gly Ile Cys Trp 195 200 205

Cys Gin Cys Cys Pro His Ser Cys Cys Cys Tyr Val Arg Cys Pro Cys 210 215 220

Cys Pro Asp Ser Cys Cys Cys Pro Gin Ala Leu Tyr Glu Ala Gly Lys 225 230 235 240

Ala Ala Lys Ala Gly Tyr Pro Pro Ser Val Ser Gly Val Pro Gly Pro 245 250 255

Tyr Ser Ile Pro Ser Val Pro Leu Gly Gly Ala Pro Ser Ser Gly Met 260 265 270

Leu Met Asp Lys Pro His Pro Pro Pro Leu Ala Pro Ser Asp Ser Thr 275 280 285

Gly Gly Ser His Ser Val Arg Lys Gly Tyr Arg Ile Gin Ala Asp Lys 290 295 300

Glu Arg Asp Ser Met Lys Val Leu Tyr Tyr Val Glu Lys Glu Leu Ala 305 310 315 320

Gin Phe Asp Pro Ala Arg Arg Met Arg Gly Arg Tyr Asn Asn Thr Ile 325 330 335

Ser Glu Leu Ser Ser Leu His Glu Glu Asp Ser Asn Phe Arg Gin Ser 340 345 350

Phe His Gin Met Arg Ser .Lys Gin Phe Pro Val Ser Gly· Asp Leu Glu 355 360 365

Ser Asn Pro Asp Tyr Trp Ser Gly Val Met Gly Gly Ser Ser Gly Ala 370 375 380

Ser Arg Gly Pro Ser Ala Met Glu Tyr Asn Lys Glu Asp Arg Glu Ser 385 390 395 400

Phe Arg His Ser Gin Pro Arg Ser Lys Ser Glu Met Leu Ser Arg Lys 405 410 415

Asn Phe Ala Thr Gly Val Pro Ala Val Ser Met Asp Glu Leu Ala Ala 420 425 430

Phe Ala Asp Ser Tyr Gly Gin Arg Pro Arg Arg Ala Asp Gly Asn Ser 435 440 445

His Glu Ala Arg Gly Gly Ser Arg Phe Glu Arg Ser Glu Ser Arg Ala 450 455 460

His Ser Gly Phe Tyr Gin Asp Asp Ser Leu Glu Glu Tyr Tyr Gly Gin 465 470 475 480

Arg Ser Arg Ser Arg Glu Pro Leu Thr Asp Ala Asp Arg Gly Trp Ala 485 490 495

Phe Ser Pro Ala Arg Arg Arg Pro Ala Glu Asp Ala His Leu Pro Arg 500 505 510

Leu Val Ser Arg Thr Pro Gly Thr Ala Pro Lys Tyr Asp His Ser Tyr 515 520 525

Leu Gly Ser Ala Arg Glu Arg Gin Ala Arg Pro Glu Gly Ala Ser Arg 530 535 540

Gly Gly Ser Leu Glu Thr Pro Ser Lys Arg Ser Ala Gin Leu Gly Pro 545 550 555 560

Arg Ser Ala Ser Tyr Tyr Ala Trp Ser Pro Pro Gly Thr Tyr Lys Ala 565 570 575

Gly Ser Ser Gin Asp Asp Gin Glu Asp Ala Ser Asp Asp Ala Leu Pro 580 585 590

Pro Tyr Ser Glu Leu Glu Leu Thr Arg Gly Pro Ser Tyr Arg Gly Arg 595 600 605

Asp Leu Pro Tyr His Ser Asn Ser Glu Lys Lys Arg Lys Lys Glu Pro 610 615 620

Ala Lys Lys Thr Asn Asp Phe Pro Thr Arg Met Ser Leu Val Val 625 630 635 <210> 48 <211 > 254

<212> PRT <213> Homo Sapiens <400> 48

Met Asp Arg Val Leu Leu Arg Trp Ile Ser Leu Phe Trp Leu Thr Ala 15 10 15

Met Val Glu Gly Leu Gin Val Thr Val Pro Asp Lys Lys Lys Val Ala 20 25 30

Met Leu Phe Gin Pro Thr Val Leu Arg Cys His Phe Ser Thr Ser Ser 35 40 45

His Gin Pro Ala Val Val Gin Trp Lys Phe Lys Ser Tyr Cys Gin Asp 50 55 60

Arg Met Gly Glu Ser Leu Gly Met Ser Ser Thr Arg Ala Gin Ser Leu 65 70 75 80

Ser Lys Arg Asn Leu Glu Trp Asp Pro Tyr Leu Asp Cys Leu Asp Ser 85 90 95

Arg Arg Thr Val Arg Val Val Ala Ser Lys Gin Gly Ser Thr Val Thr 100 105 110

Leu Gly Asp Phe Tyr Arg Gly Arg Glu lie Thr lie Val His Asp Ala 115 120 125

Asp Leu Gin lie Gly Lys Leu Met Trp Gly Asp Ser Gly Leu Tyr Tyr 130 135 140

Cys lie lie Thr Thr Pro Asp Asp Leu Glu Gly Lys Asn Glu Gly Ser 145 150 155 160

Leu Gly Leu Leu Val Leu Gly Arg Thr Gly Leu Leu Ala Asp Leu Leu 165 170 175

Pro Ser Phe Ala Val Glu lie Met Pro Glu Trp Val Phe Val Gly Leu 180 185 190

Val Leu Leu Gly Val Phe Leu Phe Phe Val Leu Val Gly lie Cys Trp 195 200 205

Cys Gin Cys Cys Pro His Ser Cys Cys Cys Tyr Val Arg Cys Pro Cys 210 215 220

Cys Pro Asp Ser Cys Trp Cys Pro Gin Ala Cys Glu Tyr Ser Asp Arg 225 230 235 240

Trp Gly Asp Arg Ala lie Glu Arg Asn Val Tyr Leu Ser Thr 245 250 <210> 49 <211 > 254

<212> PRT <213> Homo Sapiens <400> 49

Met Asp Arg Val Leu Leu Arg Trp Ile Ser Leu Phe Trp Leu Thr Ala 15 10 15

Met Val Glu Gly Leu Gin Val Thr Val Pro Asp Lys Lys Lys Val Ala 20 25 30

Met Leu Phe Gin Pro Thr Val Leu Arg Cys His Phe Ser Thr Ser Ser 35 40 45

His Gin Pro Ala Val Val Gin Trp Lys Phe Lys Ser Tyr Cys Gin Asp 50 55 60

Arg Met Gly Glu Ser Leu Gly Met Ser Ser Thr Arg Ala Gin Ser Leu 65 70 75 80

Ser Lys Arg Asn Leu Glu Trp Asp Pro Tyr Leu Asp Cys Leu Asp Ser 85 90 95

Arg Arg Thr Val Arg Val Val Ala Ser Lys Gin Gly Ser Thr Val Thr 100 105 · 110

Leu Gly Asp Phe Tyr Arg Gly Arg Glu lie Thr lie Val His Asp Ala 115 120 125

Asp Leu Gin lie Gly Lys Leu Met Trp Gly Asp Ser Gly Leu Tyr Tyr 130 135 140

Cys lie lie Thr Thr Pro Asp Asp Leu Glu Gly Lys Asn Glu Asp Ser 145 150 155 160

Val Glu Leu Leu Val Leu Gly Arg Thr Gly Leu Leu Ala Asp Leu Leu 165 170 175

Pro Ser Phe Ala Val Glu lie Met Pro Glu Trp Val Phe Val Gly Leu 180 185 190

Val Leu Leu Gly Val Phe Leu Phe Phe Val Leu Val Gly lie Cys Trp 195 200 205

Cys Gin Cys Cys Pro His Ser Cys Cys Cys Tyr Val Arg Cys Pro Cys 210 215 220

Cys Pro Asp Ser Cys Cys Cys Pro Gin Ala Cys Glu Tyr Ser Asp Arg 225 230 235 240

Trp Gly Asp Arg Ala lie Glu Arg Asn Val Tyr Leu Ser Thr 245 250 <210> 50 <211 > 235

<212> PRT <213> Homo Sapiens <400> 50

Met Asp Arg Val Leu Leu Arg Trp lie Ser Leu Phe Trp Leu Thr Ala 15 10 15

Met Val Glu Gly Leu Gin Val Thr Val Pro Asp Lys Lys Lys Val Ala 20 25 30

Met Leu Phe Gin Pro Thr Val Leu Arg Cys His Phe Ser Thr Ser Ser 35 40 45

His Gin Pro Ala Val Val Gin Trp Lys Phe Lys Ser Tyr Cys Gin Asp 50 55 60

Arg Met Gly Glu Ser Leu Gly Met Ser Ser Thr Arg Ala Gin Ser Leu 65 70 75 80

Ser Lys Arg Asn Leu Glu Trp Asp Pro Tyr Leu Asp Cys Leu Asp Ser 85 90 95

Arg Arg Thr Val Arg Val Val Ala Ser Lys Gin Gly Ser Thr Val Thr 100 105 110

Leu Gly Asp Phe Tyr Arg Gly Arg Glu Ile Thr Ile Val His Asp Ala 115 120 125

Asp Leu Gin Ile Gly Lys Leu Met Trp Gly Asp Ser Gly Leu Tyr Tyr 130 135 140

Cys Ile Ile Thr Thr Pro Asp Asp Leu Glu Gly Lys Asn Glu Gly Ser 145 150 155 160

Leu Gly Leu Leu Val Leu Glu Trp val Phe Val Gly Leu Val Leu Leu 165 170 175

Gly Val Phe Leu Phe Phe Val Leu Val Gly Ile Cys Trp Cys Gin Cys 180 185 190

Cys Pro His Ser Cys Cys Cys Tyr Val Arg Cys Pro Cys Cys Pro Asp 195 200 205

Ser Cys Trp Cys Pro Gin Ala Cys Glu Tyr Ser Asp Arg Trp Gly Asp 210 215 220

Arg Ala Ile Glu Arg Asn Val Tyr Leu Ser Thr 225 230 235 <210>51 <211 > 1621

<212> DNA <213> Homo Sapiens <400> 51 gtggactagg aggcagccgc ccccaccagc acccactctg tagacccagg cgtctggctc 60 ccagcaccca cggaaagagc ctggctagga aactgcagcc tggtgcctgg cagacagttc 120 tcattctccc cagggcaggg agcaggttat gaccaggact aaggtcccag agtccccacc 180 ctgacccctc cctgctgttc cagccgctcc ctcatatcca cccctgcccc atctcctgac 240 tttggtcacg ctagcatctt ctgctgatcc tgaaattgta ccagcggcaa gatgtggcct 300 ggaaggggac tttaagttct ccacaactgc cagcaatcct tccaccaggc aaaacacatc 360 atctaaggaa aagaagtgag gtttgcttag ggcgtggcag cttcggataa acgcaggact 420 ccgcctggca gcccgatttc tcccggaacc tctgctcagc ctggtgaacc acacaggcca 480 gcgctctgac atgcagaagg tgaccctggg cctgcttgtg ttcctggcag gctttcctgt 540 cctggacgcc aatgacctag aagataaaaa cagtcctttc tactatgact ggcacagcct 600 ccaggttggc gggctcatct gcgctggggt tctgtgcgcc atgggcatca tcatcgtcat 660 gagtgcaaaa tgcaaatgca agtttggcca gaagtccggt caccatccag gggagactcc 720 acctctcatc accccaggct cagcccaaag ctgatgagga cagaccagct gaaattgggt 780 ggaggaccgt tctctgtccc caggtcctgt ctctgcacag aaacttgaac tccaggatgg 840 aattcttcct cctctgctgg gactcctttg catggcaggg cctcatctca cctctcgcaa 900 gagggtctct ttgttcaatt ttttttaatc taaaatgatt gtgcctctgc ccaagcagcc 960 tggagacttc ctatgtgtgc attggggtgg ggcttggggc accatgagaa ggttggcgtg 1020 ccctggaggc tgacacagag gctggcactg agcctgcttg ttgggaaaag cccacaggcc 1080 tgttcccttg tggcttggga catggcacag gcccgccctc tgcctcctca gccatgggaa 1140 cctcatatgc aatttgggat ttactagtag ccaaaaggaa tgaaagagag ctctaaccag 1200 atggaacact ggaacattcc agtggaccct ggaccattcc aggaaaactg ggacatagga 1260 tcgtcccgct atgatggaag tgttcagaca gtttataata gtaagcccct gtgaccctct 1320 cacttacccc gagacctcac tttattacaa gatctttcca aatacccaaa tgtccctgca 1380 agcccgttaa ataattccct atgctaccct taataacata caatgaccac atagtgtgag 1440 aacttccaac aagcctcaaa gtcccttgag actccccaat acctaataag gcatgcgaaa 1500 tgttctcatg aactacccca caacacgcct aaaactcaaa acacccaaaa atatctcctc 1560 caatgtcctg agacatgaac ccaaaaagag acccacaata aactcgtgac ttgtcccctc 1620 a 1621 <210> 52 <211> 1925

<212> DNA <213> Homo Sapiens <400> 52 gtggactagg aggcagccgc ccccaccagc acccactctg tagacccagg cgtctggctc 60 ccagcaccca cggaaagagc ctggctagga aactgcagcc tggtgcctgg cagacagttc 120 tcattctccc cagggcaggg agcaggttat gaccaggact aaggtcccag agtccccacc 180 ctgacccctc cctgctgttc cagccgctcc ctcatatcca cccctgcccc atctcctgac 240 tttggtcacg ctagcatctt ctgctgatcc tgaaattgta ccagcggcaa gatgtggcct 300 ggaaggggac tttaagttct ccacaactgc cagcaatcct tccaccaggc aaaacacatc 360 atctaaggaa aagaagtgag gtcggaacac caacgcatca tctcactgca tggccctgga 420 ggctctgccg tttaaagacc ccagaacctt ccccattcaa ggtcctctcc tgggcacagg 480 agattggaga aagctcctcc cttaattcca gggaccgagt tccagcccat ccaattctcc 540 gtctcacctg aggctgctgt ggtcctggtg accccaggga gcaacctgcc gcccatggct 600 ggggaggggg tgaagctgtc tctttaagag caggaatgga gcccctgggc ctcagggcat 660 ctgacttgtt ttctacctgc ccaggtttgc ttagggcgtg gcagcttcgg ataaacgcag 720 gactccgcct ggcagcccga tttctcccgg aacctctgct cagcctggtg aaccacacag 780 gccagcgctc tgacatgcag aaggtgaccc tgggcctgct tgtgttcctg gcaggctttc 840 ctgtcctgga cgccaatgac ctagaagata aaaacagtcc tttctactat gactggcaca 900 gcctccaggt tggcgggctc atctgcgctg gggttctgtg cgccatgggc atcatcatcg 960 tcatgagtgc aaaatgcaaa tgcaagtttg gccagaagtc cggtcaccat ccaggggaga 1020 ctccacctct catcacccca ggctcagccc aaagctgatg aggacagacc agctgaaatt 1080 gggtggagga ccgttctctg tccccaggtc ctgtctctgc acagaaactt gaactccagg 1140 atggaattct tcctcctctg ctgggactcc tttgcatggc agggcctcat ctcacctctc 1200 gcaagagggt ctctttgttc aatttttttt aatctaaaat gattgtgcct ctgcccaagc 1260 agcctggaga cttcctatgt gtgcattggg gtggggcttg gggcaccatg agaaggttgg 1320 cgtgccctgg aggctgacac agaggctggc actgagcctg cttgttggga aaagcccaca 1380 ggcctgttcc cttgtggctt gggacatggc acaggcccgc cctctgcctc ctcagccatg 1440 ggaacctcat atgcaatttg ggatttacta gtagccaaaa ggaatgaaag agagctctaa 1500 ccagatggaa cactggaaca ttccagtgga ccctggacca ttccaggaaa actgggacat 1560 aggatcgtcc cgctatgatg gaagtgttca gacagtttat aatagtaagc ccctgtgacc 1620 ctctcactta ccccgagacc tcactttatt acaagatctt tccaaatacc caaatgtccc 1680 tgcaagcccg ttaaataatt ccctatgcta cccttaataa catacaatga ccacatagtg 1740 tgagaacttc caacaagcct caaagtccct tgagactccc caatacctaa taaggcatgc 1800 gaaatgttct catgaactac cccacaacac gcctaaaact caaaacaccc aaaaatatct 1860' cctccaatgt cctgagacat gaacccaaaa agagacccac aataaactcg tgacttgtcc 1920 cctca 1925 <210> 53 <211> 1808

<212> DNA <213> Homo Sapiens <400> 53 gtggactagg aggcagccgc ccccaccagc acccactctg tagacccagg cgtctggctc 60 ccagcaccca cggaaagagc ctggctagga aactgcagcc tggtgcctgg cagacagttc 120 tcattctccc cagggcaggg agcaggttat gaccaggact aaggtcccag agtccccacc 180 ctgacccctc cctgctgttc cagccgctcc ctcatatcca cccctgcccc atctcctgac 240 tttggtcacg ctagcatctt ctgctgatcc tgaaattgta ccagcggcaa gatgtggcct 300 ggaaggggac tttaagttct ccacaactgc cagcaatcct tccaccaggc aaaacacatc 360 atctaaggaa aagaagtgag gtcggaacac caacgcatca tctcactgca tggccctgga 420 ggctctgccg tttaaagacc ccagaacctt ccccattcaa ggtcctctcc tgggcacagg 480 agattggaga aagctcctcc cttaattcca gggaccgagt tccagcccat ccaattctcc 540 gtctcacctg aggctgctgt ggtcctggtt tgcttagggc gtggcagctt cggataaacg 600 caggactccg cctggcagcc cgatttctcc cggaacctct gctcagcctg gtgaaccaca 660 caggccagcg ctctgacatg cagaaggtga ccctgggcct gcttgtgttc ctggcaggct 720 ttcctgtcct ggacgccaat gacctagaag ataaaaacag tcctttctac tatgactggc 780 acagcctcca ggttggcggg ctcatctgcg ctggggttct gtgcgccatg ggcatcatca 840 tcgtcatgag tgcaaaatgc aaatgcaagt ttggccagaa gtccggtcac catccagggg 900 agactccacc tctcatcacc ccaggctcag cccaaagctg atgaggacag accagctgaa 960 attgggtgga ggaccgttct ctgtccccag gtcctgtctc tgcacagaaa cttgaactcc 1020 aggatggaat tcttcctcct ctgctgggac tcctttgcat ggcagggcct catctcacct 1080 ctcgcaagag ggtctctttg ttcaattttt tttaatctaa aatgattgtg cctctgccca .1140 agcagcctgg agacttccta tgtgtgcatt ggggtggggc ttggggcacc atgagaaggt 1200 tggcgtgccc tggaggctga cacagaggct ggcactgagc ctgcttgttg ggaaaagccc 1260 acaggcctgt tcccttgtgg cttgggacat ggcacaggcc cgccctctgc ctcctcagcc 1320 atgggaacct catatgcaat ttgggattta ctagtagcca aaaggaatga aagagagctc 1380 taaccagatg gaacactgga acattccagt ggaccctgga ccattccagg aaaactggga 1440 cataggatcg tcccgctatg atggaagtgt tcagacagtt tataatagta agcccctgtg 1500 accctctcac ttaccccgag acctcacttt attacaagat ctttccaaat acccaaatgt 1560 ccctgcaagc ccgttaaata attccctatg ctacccttaa taacatacaa tgaccacata 1620 gtgtgagaac ttccaacaag cctcaaagtc ccttgagact ccccaatacc taataaggca 1680 tgcgaaatgt tctcatgaac taccccacaa cacgcctaaa actcaaaaca cccaaaaata 1740 tctcctccaa tgtcctgaga catgaaccca aaaagagacc cacaataaac tcgtgacttg 1800 tcccctca 1808 <210> 54 <211> 1702

<212> DNA <213> Homo Sapiens <400> 54 gtggactagg aggcagccgc ccccaccagc acccactctg tagacccagg cgtctggctc 60 ccagcaccca cggaaagagc ctggctagga aactgcagcc tggtgcctgg cagacagttc 120 tcattetccc cagg$caggg agcaggttat gaccaggact aaggtcccag agtccccacc 180 ctgacccctc cctgctgttc cagccgctcc ctcatatcca cccctgcccc atctcctgac 240 tttggtcacg ctagcatctt ctgctgatcc tgaaattgta ccagcggcaa gatgtggcct 300 ggaaggggac tttaagttct ccacaactgc cagcaatcct tccaccaggc aaaacacatc 360 atctaaggaa aagaagtgag gtcggaacac caacgcatca tctcactgca tggccctgga 420 ggctctgccg tttaaagacc ccagaacctt ccccattcaa ggtttgctta gggcgtggca 480 gcttcggata aacgcaggac tccgcctggc agcccgattt ctcccggaac ctctgctcag 540 cctggtgaac cacacaggcc agcgctctgå catgcagaag gtgaccctgg gcctgcttgt 600 gttcctggca ggctttcctg tcctggacgc caatgaccta gaagataaaa acagtccttt 660 ctactatgac tggcacagcc tccaggttgg cgggctcatc tgcgctgggg ttctgtgcgc 720 catgggcatc atcatcgtca tgagtgcaaa atgcaaatgc aagtttggcc agaagtccgg 780 tcaccatcca ggggagactc cacctctcat caccccaggc tcagcccaaa gctgatgagg 840 acagaccagc tgaaattggg tggaggaccg ttctctgtcc ccaggtcctg tctctgcaca 900 gaaacttgaa ctccaggatg gaattcttcc tcctctgctg ggactccttt gcatggcagg 960 gcctcatctc scctctcgca agagggtctc tttgttcaat tttttttaat ctaaaatgat 1020 tgtgcctctg cccaagcagc ctggagactt cctatgtgtg cattggggtg gggcttgggg 1080 caccatgaga aggttggcgt gccctggagg ctgacacaga ggctggcact gagcctgctt 1140 gttgggaaaa gcccacaggc ctgttccctt gtggcttggg acatggcaca ggcccgccct 1200 ctgcctcctc agccatggga acctcatatg caatttggga tttactagta gccaaaagga 1260 atgaaagaga gctctaacca gatggaacac tggaacattc cagtggaccc tggaccattc 1320 caggaaaact gggacatagg atcgtcccgc tatgatggaa gtgttcagac agtttataat 1380 agtaagcccc tgtgaccctc tcacttaccc cgagacctca ctttattaca agatctttcc 1440 aaatacccaa atgtccctgc aagcccgtta aataattccc tatgctaccc ttaataacat 1500 acaatgacca catagtgtga gaacttccaa caagcctcaa agtcccttga gactccccaa 1560 tacctaataa ggcatgcgaa atgttctcat gaactacccc acaacacgcc taaaactcaa 1620 aacacccaaa aatatctcct ccaatgtcct gagacatgaa cccaaaaaga gacccacaat 1680 aaactcgtga cttgtcccct ca 1702 <210> 55 <211 > 1705

<212> DNA <213> Homo Sapiens <400> 55 gtggactagg aggcagccgc ccccaccagc acccactctg tagacccagg cgtctggctc 60 ccagcaccca cggaaagagc ctggctagga aactgcagcc tggtgcctgg cagacagttc 120 tcattctccc cagggcaggg agcaggttat gaccaggact aaggtcccag agtccccacc 180 ctgacccctc cctgctgttc cagccgctcc ctcatatcca cccctgcccc atctcctgac 240 tttggtcacg ctagcatctt ctgctgatcc tgaaattgta ccagcggcaa gatgtggcct 300 ggaaggggac tttaagttct ccacaactgc cagcaatcct tccaccaggc aaaacacatc 360 atctaaggaa aagaagtgag gtttgcttag ggcgtggcag cttcggataa acgcaggact 420 ccgcctggca gcccgatttc tcccggaacc tctgctcagc ctggtgaacc acacaggccc 480 gagtttcacc cagtccccac tccacggtgc agctgcggct tatctctcag cccagcgaga 540 tgccagcctt cctgtcccgg gccagcgctc tgacatgcag aaggtgaccc tgggcctgct 600 tgtgttcctg gcaggctttc ctgtcctgga cgccaatgac ctagaagata aaaacagtcc 660 tttctactat gactggcaca gcctccaggt tggcgggctc atctgcgctg gggttctgtg 720 cgccatgggc atcatcatcg tcatgagtgc aaaatgcaaa tgcaagtttg gccagaagtc 780 cggtcaccat ccaggggaga ctccacctct catcacccca ggctcagccc aaagctgatg 840 aggacagacc agctgaaatt gggtggagga ccgttctctg tccccaggtc ctgtctctgc 900 acagaaactt gaactccagg atggaattct tcctcctctg ctgggactcc tttgcatggc 960 agggcctcat ctcacctctc gcaagagggt ctctttgttc aatttttttt aatctaaaat 1020 gattgtgcct ctgcccaagc agcctggaga cttcctatgt gtgcattggg gtggggcttg 1080 gggcaccatg agaaggttgg cgtgccctgg aggctgacac agaggctggc actgagcctg 1140 cttgttggga aaagcccaca ggcctgttcc cttgtggctt gggacatggc acaggcccgc 1200 cctctgcctc ctcagccatg ggaacctcat atgcaatttg ggatttacta gtagccaaaa 1260 ggaatgaaag agagctctaa ccagatggaa cactggaaca ttccagtgga ccctggacca 1320 ttccaggaaa actgggacat aggatcgtcc cgctatgatg gaagtgttca gacagtttat 1380 aatagtaagc ccctgtgacc ctctcactta ccccgagacc tcactttatt acaagatctt 1440 tccaaatacc caaatgtccc tgcaagcccg ttaaataatt ccctatgcta cccttaataa 1500 catacaatga ccacatagtg tgagaacttc caacaagcct caaagtccct tgagactccc 1560 caatacctaa taaggcatgc gaaatgttct catgaactac cccacaacac gcctaaaact 1620 caaaacaccc aaaaatatct cctccaatgt cctgagacat gaacccaaaa agagacccac 1680 aataaactcg tgacttgtcc cctca 1705 <210> 56 <211> 1786

<212> DNA <213> Homo Sapiens <400> 56 gtggactagg aggcagccgc ccccaccagc acccactctg tagacccagg cgtctggctc 60 ccagcaccca cggaaagagc ctggctagga aactgcagcc tggtgcctgg cagacagttc 120 tcattctccc cagggcaggg agcaggttat gaccaggact aaggtcccag agtccccacc 180 ctgacccctc cctgctgttc cagccgctcc ctcatatcca cccctgcccc atctcctgac 240 tttggtcacg ctagcatctt ctgctgatcc tgaaattgta ccagcggcaa gatgtggcct 300 ggaaggggac tttaagttct ccacaactgc cagcaatcct tccaccaggc aaaacacatc 360 atctaaggaa aagaagtgag gtcggaacac caacgcatca tctcactgca tggccctgga 420 ggctctgccg tttaaagacc ccagaacctt ccccattcaa ggtttgctta gggcgtggca 480 gcttcggata aacgcaggac tccgcctggc agcccgattt ctcccggaac ctctgctcag 540 cctggtgaac cacacaggcc cgagtttcac ccagtcccca ctccacggtg cagctgcggc 600 ttatctctca gcccagcgag atgccagcct tcctgtcccg ggccagcgct ctgacatgca 660 gaaggtgacc ctgggcctgc ttgtgttcct ggcaggcttt cctgtcctgg acgccaatga 720 cctagaagat aaaaacagtc ctttctacta tgactggcac agcctccagg ttggcgggct 780 catctgcgct ggggttctgt gcgccatggg catcatcatc gtcatgagtg caaaatgcaa 840 atgcaagttt ggccagaagt ccggtcacca tccaggggag actccacctc tcatcacccc 900 aggctcagcc caaagctgat gaggacagac cagctgaaat tgggtggagg accgttctct 960 gtccccaggt cctgtctctg cacagaaact tgaactccag gatggaattc ttcctcctct 1020 gctgggactc ctttgcatgg cagggcctca tctcacctct cgcaagaggg tctctttgtt 1080 caattttttt taatctaaaa tgattgtgcc tctgcccaag cagcctggåg acttcctatg 1140 tgtgcattgg ggtggggctt ggggcaccat gagaaggttg gcgtgccctg gaggctgaca 1200 cagaggctgg cactgagcct gcttgttggg aaaagcccac aggcctgttc ccttgtggct 1260 tgggacatgg cacaggcccg ccctctgcct cctcagccat gggaacctca tatgcaattt 1320 gggatttact agtagccaaa aggaatgaaa gagagctcta accagatgga acactggaac 1380 attccagtgg accctggacc attccaggaa aactgggaca taggatcgtc ccgctatgat 1440 ggaagtgttc agacagttta taatagtaag cccctgtgac cctctcactt accccgagac 1500 ctcactttat tacaagatct ttccaaatac ccaaatgtcc ctgcaagccc gttaaataat 1560 tccctatgct acccttaata acatacaatg accacatagt gtgagaactt ccaacaagcc 1620 tcaaagtccc ttgagactcc ccaataccta ataaggcatg cgaaatgttc tcatgaacta 1680 ccccacaaca cgcctaaaac tcaaaacacc caaaaatatc tcctccaatg tcctgagaca 1740 tgaacccaaa aagagaccca caataaactc gtgacttgtc ccctca 1786 <210> 57 <211> 1827

<212> DNA <213> Homo Sapiens <400> 57 gtggactagg aggcagccgc ccccaccagc acccactctg tagacccagg cgtctggctc 60 ccagcaccca cggaaagagc ctggctagga aactgcagcc tggtgcctgg cagacagttc 120 tcattctccc cagggcaggg agcaggttat gaccaggact aaggtcccag agtccccacc 180 ctgacccctc cctgctgttc cagccgctcc ctcatatcca cccctgcccc atctcctgac 240 tttggtcacg ctagcatctt ctgctgatcc tgaaattgta ccagcggcaa gatgtggcct 300 ggaaggggac tttaagttct ccacaactgc cagcaatcct tccaccaggc aaaacacatc 360 atctaaggaa aagaagtgag gtttgcttag ggcgtggcag cttcggataa acgcaggact 420 ccgcctggca gcccgatttc tcccggaacc tctgctcagc ctggtgaacc acacagaggc 480 tggggcgagg aggataccat ctgtcagtct tggctggatg acatcatggg aagggggtat 540 agtggggcct tgcaggccag aggtggcttg gaggagcccc tggaaagagg cttaagaggc 600 ccgagtttca cccagtcccc actccacggt gcagctgcgg cttatctctc agcccagcga 660 gatgccagcc ttcctgtccc gggccagcgc tctgacatgc agaaggtgac cctgggcctg 720 cttgtgttcc tggcaggctt tcctgtcctg gacgccaatg acctagaaga taaaaacagt 780 cctttctact atgactggca cagcctccag gttggcgggc tcatctgcgc tggggttctg 840 tgcgccatgg gcatcatcat cgtcatgagt gcaaaatgca aatgcaagtt tggccagaag 900 tccggtcacc atccagggga gactccacct ctcatcaccc caggctcagc ccaaagctga 960 tgaggacaga ccagctgaaa ttgggtggag gaccgttctc tgtccccagg tcctgtctct 1020 gcacagaaac ttgaactcca ggatggaatt cttcctcctc tgctgggact cctttgcatg 1080 gcagggcctc atctcacctc tcgcaagagg gtctctttgt tcaatttttt ttaatctaaa 1140 atgattgtgc ctctgcccaa gcagcctgga gacttcctat gtgtgcattg gggtggggct 1200 tggggcacca tgagaaggtt ggcgtgccct ggaggctgac acagaggctg gcactgagcc 1260 tgcttgttgg gaaaagccca caggcctgtt cccttgtggc ttgggacatg gcacaggccc 1320 gccctctgcc tcctcagcca tgggaacctc atatgcaatt tgggatttac tagtagccaa 1380 aaggaatgaa agagagctct aaccagatgg aacactggaa cattccagtg gaccctggac 1440 cattccagga aaactgggac ataggatcgt cccgctatga tggaagtgtt cagacagttt 1500 ataatagtaa gcccctgtga ccctctcact taccccgaga cctcacttta ttacaagatc 1560 tttccaaata cccaaatgtc cctgcaagcc cgttaaataa ttccctatgc tacccttaat 1620 aacatacaat gaccacatag tgtgagaact tccaacaagc ctcaaagtcc cttgagactc 1680 cccaatacct aataaggcat gcgaaatgtt ctcatgaact accccacaac acgcctaaaa 1740 ctcaaaacac ccaaaaatat ctcctccaat gtcctgagac atgaacccaa aaagagaccc 1800 acaataaact cgtgacttgt cccctca 1827 <210> 58 <211 >3605

<212> DNA <213> Homo Sapiens <400> 58 gtggactagg aggcagccgc ccccaccagc acccactctg tagacccagg cgtctggctc 60 ccagcaccca cggaaagagc ctggctagga aactgcagcc tggtgcctgg cagacagttc 120 tcattctccc cagggcaggg agcaggttat gaccaggact aaggtcccag agtccccacc 180 ctgacccctc cctgctgttc cagccgctcc ctcatatcca cccctgcccc atctcctgac 240 tttggtcacg ctagcatctt ctgctgatcc tgaaattgta ccagcggcaa gatgtggcct 300 ggaaggggac tttaagttct ccacaactgc cagcaatcct tccaccaggc aaaacacatc 360 atctaaggaa aagaagtgag gtttgcttag ggcgtggcag cttcggataa acgcaggact 420 ccgcctggca gcccgatttc tcccggaacc tctgctcagc ctggtgaacc acacagaggc 480 tggggcgagg aggataccat ctgtcagtct tggctggatg acatcatggg aagggggtat 540 agtggggcct tgcaggccag aggtggcttg gaggagcccc tggaaagagg cttaagaggt 600 gagactcaac agccatggcg acagagcata gggctttaag atgaatttgc aggggttaca 660 ggattacaac tgcaatgtgg gctaataata gtgccccctg cattaagctg cagagattga 720 gcgagtaagt gggaagctga gaaaatgccc ccatggggta gacactcaat aagcatctgc 780 tgttattacc aggactcgta tggtcatggg tgacagottc agaccacagg cagtccacct 840 acaacctgtg cccctatcca ccatgccatc ctgcccaccc acccacgcca gctcccccaa 900 cccccaacac ttttggggat cctaaacact tcctgggcct cagtaatgct ccccaaagcc 960 tcaggctttc ttcccgcaaa aaaaggaaaa gaaatggatg ctccaactaa aattgtgagt 1020 tcagcatgtg gaattaactg ggaagctgag aggattccca ggcctggggt gcgcaggcag 1080 agggaggagt ctgtgccaac ctgcaaggac cacccgcacc gttggttgcg ggcaccaccc 1140 tctctcagca tttttgctgt tcgtgaaatg aggacatagt ggacgacgtc ggggattgct 1200 ggggggttaa gtgagtgaga acacggcaag gtcagtgtgc actccagggc aaggtggagg 1260 aagtgccagc tctcgctatc aaaattataa ctaggccagg cgtggtggct cacacctgta 1320 atcccagcac tgagggaggc cggggtgggt ggatcacctg aggtcaggag ttggagacca 1380 gcctggccaa cacagtgaaa ccctggctct accaaaaatg caaaaattag ccgagactgg 1440 tggcacacgc ctgtagtctc agctactcag gaggctgagg caggagaatc acttgaaccc 1500 aggaggcaga ggttgcagtg agctgagatt atgccattgc actccagcct gggtgacaga 1560 gtgaaactcc gcctcaaaaa aaaaaaacaa ttatgataac tatgcactca gcatttgggc 1620 agggacaggg cagggacagg gcaggggagg gcatgctcgg aggccagggc ttggtgcagc 1680 cttgcaggct ggtgagaggg caggactgat gccaggtcag gaaggagaga gaaacgagtt 1740 ccttatgctg agcaggtcta cctgggaaag agaaagtgtt tgctgtcacc aggaactctg 1800 ctgggcctag ggtagggtca ggggctgggc tggggacccc ggctaggcag agccagggct 1860 gggaccggga agggcatggg tgtgggatga ggggcaggag gttcggggga acagagatgg 1920 agctagggct gcagccagga ggtagagtcc ccctctaccc ccagtcccag cctcacgtca 1980 attcctccac acaccacccc acccccaagc agcttgaaga acctgctcag tcctcagcct 2040 gaagtctgca atgtcctggc agggccgggc aggctctgag cggtctacgg agacactcct 2100 gggaagcggg cctcctgccg cctggctccc aatgccccgc ttccccaaac accccaaggc 2160 cctgacagtc cctagttagg agcagctgct ggggagccag gcctggctta aatcctactt 2220 cctggctaga gcacctagtt tcacctctca gagcctcagt ctccccatct gtccagtgag 2280 aacagtgggc agtggcgccc ttgtttggtt gcggggcgat tcccagaaag cctgaagtcc 2340 atgtccagtg agttattatg gctcctcccg cctcaggccc gagtttcacc cagtccccac 2400 tccacggtgc agctgcggct tatctctcag cccagcgaga tgccagcctt cctgtcccgg 2460 gccagcgctc tgacatgcag aaggtgaccc tgggcctgct tgtgttcctg gcaggctttc 2520 ctgtcctgga cgccaatgac ctagaagata aaaacagtcc tttctactat gactggcaca 2580 gcctccaggt tggcgggctc atctgcgctg gggttctgtg cgccatgggc atcatcatcg 2640 tcatgagtgc aaaatgcaaa tgcaagtttg gccagaagtc cggtcaccat ccaggggaga 2700 ctccacctct catcacccca ggctcagccc aaagctgatg aggacagacc agctgaaatt 2760 gggtggagga ccgttctctg tccccaggtc ctgtctctgc acagaaactt gaactccagg 2820 atggaattct tcctcctctg ctgggactcc tttgcatggc agggcctcat ctcacctctc 2880 gcaagagggt ctctttgttc aatttttttt aatctaaaat gattgtgcct ctgcccaagc 2940 agcctggaga cttcctatgt gtgcattggg gtggggcttg gggcaccatg agaaggttgg 3000 cgtgccctgg aggctgacac agaggctggc actgagcctg cttgttggga aaagcccaca 3060 ggcctgttcc cttgtggct't gggacatggc acaggcccgc cctctgcctc ctcagccatg 3120 ggaacctcat atgcaatttg ggatttacta gtagccaaaa ggaatgaaag agagctctaa 3180 ccagatggaa cactggaaca ttccagtgga ccctggacca ttccaggaaa actgggacat 3240 aggatcgtcc cgctatgatg gaagtgttca gacagtttat aatagtaagc ccctgtgacc 3300 ctctcactta ccccgagacc tcactttatt acaagatctt tccaaatacc caaatgtccc 3360 tgcaagcccg ttaaataatt ccctatgcta cccttaataa catacaatga ccacatagtg 3420 tgagaacttc caacaagcct caaagtccct tgagactccc caatacctaa taaggcatgc 3480 gaaatgttct catgaactac cccacaacac gcctaaaact caaaacaccc aaaaatatct 3540 cctccaatgt cctgagacat gaacccaaaa agagacccac aataaactcg tgacttgtcc 3600 cctca 3605 <210> 59 <211 >2459

<212> DNA <213> Homo Sapiens <400> 59 gtggactagg aggcagccgc ccccaccagc acccactctg tagacccagg cgtctggctc 60 ccagcaccca cggaaagagc ctggctagga aactgcagcc tggtgcctgg cagacagttc 120 tcattctccc cagggcaggg agcaggttat gaccaggact aaggtcccag agtccccacc 180 ctgacccctc cctgctgttc cagccgctcc ctcatatcca cccctgcccc atctcctgac 240 tttggtcacg ctagcatctt ctgctgatcc tgaaattgta ccagcggcaa gatgtggcct 300 ggaaggggac tttaagttct ccacaactgc cagcaatcct tccaccaggc aaaacacatc 360 atctaaggaa aagaagtgag gtttgcttag ggcgtggcag cttcggataa acgcaggact 420 ccgcctggca gcccgatttc tcccggaacc tctgctcagc ctggtgaacc acacagaggc 480 tqqqqcqa.gg aggataccat ctgtcagtct tggctggatg acatcatggg aagggggtat 540 agtggggcct tgcaggccag aggtggcttg gaggagcccc tggaaagagg cttaagaggt 600 gagactcaac agccatggcg acagagcata gggctttaag atgaatttgc aggggttaca 660 ggattacaac tgcaatgtgg gctaataata gtgccccctg cattaagctg cagagattga 720 gcgagtaagt gggaagctga gaaaatgccc ccatggggta gacactcaat aagcatctgc 780 tgttattacc aggactcgta tggtcatggg tgacagcttc agaccacagg cagtccacct 840 acaacctgtg cccctatcca ccatgccatc ctgcccaccc acccacgcca gctcccccaa 900 cccccaacac ttttggggat cctaaacact tcctgggcct cagtaatgct ccccaaagcc 960 tcaggctttc ttcccgcaaa aaaaggaaaa gaaatggatg ctccaactaa aattgtgagt 1020 tcagcatgtg gaattaactg ggaagctgag aggattccca ggcctggggt gcgcaggcag 1080 agggaggagt ctgtgccaac ctgcaaggac cacccgcacc gttggttgcg ggcaccaccc 1140 tctctcagca tttttgctgt tcgtgaaatg aggacatagt ggacgacgtc ggggattgct 1200 ggggggttaa gtgagtgaga acacggcaag gcccgagttt cacccagtcc ccactccacg 1260 gtgcagctgc ggcttatctc tcagcccagc gagatgccag ccttcctgtc ccgggccagc 1320 gctctgacat gcagaaggtg accctgggcc tgcttgtgtt cctggcaggc tttcctgtcc 1380 tggacgccaa tgacctagaa gataaaaaca gtcctttcta ctatgactgg cacagcctcc 1440 aggttggcgg gctcatctgc gctggggttc tgtgcgccat gggcatcatc atcgtcatga 1500 gtgcaaaatg caaatgcaag tttggccaga agtccggtca ccatccaggg gagactccac 1560 ctctcatcac cccaggctca gcccaaagct gatgaggaca gaccagctga aattgggtgg 1620 aggaccgttc tctgtcccca ggtcctgtct ctgcacagaa acttgaactc caggatggaa 1680 ttcttcctcc tctgctggga ctcctttgca tggcagggcc tcatctcacc tctcgcaaga 1740 gggtctcttt gttcaatttt ttttaatcta aaatgattgt gcctctgccc aagcagcctg 1800 gagacttcct atgtgtgcat tggggtgggg cttggggcac catgagaagg ttggcgtgcc 1860 ctggaggctg acacagaggc tggcactgag cctgcttgtt gggaaaagcc cacaggcctg 1920 ttcccttgtg gcttgggaca tggcacaggc ccgccctctg cctcctcagc catgggaacc 1980 tcatatgcaa tttgggattt actagtagcc aaaaggaatg aaagagagct ctaaccagat 2040 ggaacactgg aacattccag tggaccctgg accattccag gaaaactggg acataggatc 2100 gtcccgctat gatggaagtg ttcagacagt ttataatagt aagcccctgt gaccctctca 2160 cttaccccga gacctcactt tattacaaga tctttccaaa tacccaaatg tccctgcaag 2220 cccgttaaat aattccctat gctaccctta ataacataca atgaccacat agtgtgagaa 2280 cttccaacaa gcctcaaagt cccttgagac tccccaatac ctaataaggc atgcgaaatg 2340 ttctcatgaa ctaccccaca acacgcctaa aactcaaaac acccaaaaat atctcctcca 2400 atgtcctgag acatgaaccc aaaaagagac ccacaataaa ctcgtgactt gtcccctca 2459 <210> 60 <211> 3716

<212> DNA <213> Homo Sapiens <400> 60 gtggactagg aggcagccgc ccccaccagc acccactctg tagacccagg cgtctggctc 60 ccagcaccca cggaaagagc ctggctagga aactgcagcc tggtgcctgg cagacagttc 120 tcattctccc cagggcaggg agcaggttat gaccaggact aaggtcccag agtccccacc 180 ctgacccctc cctgctgttc cagccgctcc ctcatatcca cccctgcccc atctcctgac 240 tttggtcacg ctagcatctt ctgctgatcc tgaaattgta ccagcggcaa gatgtggcct 300 ggaaggggac tttaagttct ccacaactgc cagcaatcct tccaccaggc aaaacacatc 360 atctaaggaa aagaagtgag gtttgcttag ggcgtggcag cttcggataa acgcaggact 420 ccgcctggca gcccgatttc tcccggaacc tctgctcagc ctggtgaacc acacagaggc 480 tggggcgagg aggataccat ctgtcagtct tggctggatg acatcatggg aagggggtat 540 agtggggcct tgcaggccag aggtggcttg gaggagcccc tggaaagagg cttaagaggt 600 gagactcaac agccatggcg acagagcata gggctttaag atgaatttgc aggggttaca 660 ggattacaac tgcaatgtgg gctaataata gtgccccctg cattaagctg cagagattga 720 gcgagtaagt gggaagctga gaaaatgccc ccatggggta gacactcaat aagcatctgc 780 tgttattacc aggactcgta tggtcatggg tgacagcttc agaccacagg cagtccacct 840 acaacctgtg cccctatcca ccatgccatc ctgcccaccc acccacgcca gctcccccaa 900 cccccaacac ttttggggat cctaaacact tcctgggcct cagtaatgct ccccaaagcc 960 tcaggctttc ttcccgcaaa aaaaggaaaa gaaatggatg ctccaactaa aattgtgagt 1020 tcagcatgtg gaattaactg ggaagctgag aggattccca ggcctggggt gcgcaggcag 1080 agggaggagt ctgtgccaac ctgcaaggac cacccgcacc gttggttgcg ggcaccaccc 1140 tctctcagca tttttgctgt tcgtgaaatg aggacatagt ggacgacgtc ggggattgct 1200 gtgagtgaga acacggcaag gtcagtgtgc actccagggc aaggtggagg 1260 aagtgccagc tctcgctatc aaaattataa ctaggccagg cgtggtggct cacacctgta 1320 atcccagcac tgagggaggc cggggtgggt ggatcacctg aggtcaggag ttggagacca 1380 gcctggccaa cacagtgaaa ccctggctct accaaaaatg caaaaattag ccgagactgg 1440 tggcacacgc ctgtagtctc agctactcag gaggctgagg caggagaatc acttgaaccc 1500 aggaggcaga ggttgcagtg agctgagatt atgccattgc actccagcct gggtgacaga 1560 gtgaaactcc gcctcaaaaa aaaaaaacaa ttatgataac tatgcactca gcatttgggc 1620 agggacaggg cagggacagg gcaggggagg gcatgctcgg aggccagggc ttggtgcagc 1680 cttgcaggct ggtgagaggg caggactgat gccaggtcag gaaggagaga gaaacgagtt 1740 ccttatgctg agcaggtcta cctgggaaag agaaagtgtt tgctgtcacc aggaactctg 1800 ctgggcctag ggtagggtca ggggctgggc tggggacccc ggctaggcag agccagggct 1860 gggaccggga agggcatggg tgtgggatga ggggcaggag gttcggggga acagagatgg 1920 agctagggct gcagccagga ggtagagtcc ccctctaccc ccagtcccag cctcacgtca 1980 attcctccac acaccacccc acccccaagc agcttgaaga acctgctcag tcctcagcct 2040 gaagtctgca atgtcctggc agggccgggc aggctctgag cggtctacgg agacactcct 2100 gggaagcggg cctcctgccg cctggctccc aatgccccgc ttccccaaac accccaaggc 2160 cctgacagtc cctagttagg agcagctgct ggggagccag gcctggctta aatcctactt 2220 cctggctaga gcacctagtt tcacctctca gagcctcagt ctccccatct gtccagtgag 2280 aacagtgggc agtggcgccc ttgtttggtt gcggggcgat tcccagaaag cctgaagtcc 2340 atgtccagtg agttattatg gctcctcccg cctcaggccc gagtttcacc cagtccccac 2400 tccacggtgc agctgcggct tatctctcag cccagcgaga tgccagcctt cctgtcccgg 2460 gtgagctgcg caccctgcct ggggagcagg ggaggagggt tggggagcca caggcacagg 2520 gccagcctcc cggtggctct gctaaggccg gacctcccgc cacccctcta ggccagcgct 25B0 ctgacatgca gaaggtgacc ctgggcctgc ttgtgttcct ggcaggcttt cctgtcctgg 2640 acgccaatga cctagaagat aaaaacagtc ctttctacta tgactggcac agcctccagg 2700 ttggcgggct catctgcgct ggggttctgt gcgccatggg catcatcatc gtcatgagtg 2760 caaaatgcaa atgcaagttt ggccagaagt ccggtcacca tccaggggag actccacctc 2B20 tcatcacccc aggctcagcc caaagctgat gaggacagac cagctgaaat tgggtggagg 2B80 accgttctct gtccccaggt cctgtctctg cacagaaact tgaactccag gatggaattc 2940 ttcctcctct gctgggactc ctttgcatgg cagggcctca tctcacctct cgcaagaggg 3000 tctctttgtt caattttttt taatctaaaa tgattgtgcc tctgcccaag cagcctggag 3060 acttcctatg tgtgcattgg ggtggggctt ggggcaccat gagaaggttg gcgtgccctg 3120 gaggctgaca cagaggctgg cactgagcct gcttgttggg aaaagcccac aggcctgttc 3180 ccttgtggct tgggacatgg cacaggcccg ccctctgcct cctcagccat gggaacctca 3240 tatgcaattt gggatttact agtagccaaa aggaatgaaa gagagctcta accagatgga 3300 acactggaac attccagtgg accctggacc attccaggaa aactgggaca taggatcgtc 3360 ccgctatgat ggaagtgttc agacagttta taatagtaag cccctgtgac cctctcactt 3420 accccgagac ctcactttat tacaagatct ttccaaatac ccaaatgtcc ctgcaagccc 3480 gttaaataat tccctatgct acccttaata acatacaatg accacatagt gtgagaactt 3540 ccaacaagcc tcaaagtccc ttgagactcc ccaataccta ataaggcatg cgaaatgttc 3600 tcatgaacta ccccacaaca cgcctaaaac tcaaaacacc caaaaatatc tcctccaatg 3660 tcctgagaca tgaacccaaa aagagaccca caataaactc gtgacttgtc ccctca 3716 <210>61 <211 >2956

<212> DNA <213> Homo Sapiens <400 61 gtggactagg aggcagccgc ccccaccagc acccactctg tagacccagg cgtctggctc 60 ccagcaccca cggaaagagc ctggctagga aactgcagcc tggtgcctgg cagacagttc 120 tcattctccc cagggcaggg agcaggttat gaccaggact aaggtcccag agtccccacc 180 ctgacccctc cctgctgttc cagccgctcc ctcatatcca cccctgcccc atctcctgac 240 tttggtcacg ctagcatctt ctgctgatcc tgaaattgta ccagcggcaa gatgtggcct 300 ggaaggggac tttaagttct ccacaactgc cagcaatcct tccaccaggc aaaacacatc 360 atctaaggaa aagaagtgag gtttgcttag ggcgtggcag cttcggataa acgcaggact 420 ccgcctggca gcccgatttc tcccggaacc tctgctcagc ctggtgaacc acacagaggc 480 tggggcgagg aggataccat ctgtcagtct tggctggatg acatcatggg aagggggtat 540 agtggggcct tgcaggccag aggtggcttg gaggagcccc tggaaagagg cttaagaggt 600 gagactcaac agccatggcg acagagcata gggctttaag atgaatttgc aggggttaca 660 ggattacaac tgcaatgtgg gctaataata gtgccccctg cattaagctg cagagattga 720 gcgagtaagt gggaagctga gaaaatgccc ccatggggta gacactcaat aagcatctgc 780 tgttattacc aggactcgta tggtcatggg tgacagcttc agaccacagg cagtccacct 840 acaacctgtg cccctatcca ccatgccatc ctgcccaccc acccacgcca gctcccccaa 900 cccccaacac ttttggggat cctaaacact tcctgggcct cagtaatgct ccccaaagcc 960 tcaggctttc ttcccgcaaa aaaaggaaaa gaaatggatg ctccaactaa aattgtgagt 1020 tcagcatgtg gaattaactg ggaagctgag aggattccca ggcctggggt gcgcaggcag 1080 agggaggagt ctgtgccaac ctgcaaggac cacccgcacc gttggttgcg ggcaccaccc 1140 tctctcagca tttttgctgt tcgtgaaatg aggacatagt ggacgacgtc ggggattgct 1200 ggggggttaa gtgagtgaga acacggcaag gtcagtgtgc actccagggc aaggtggagg 1260 aagtgccagc tctcgctatc aaaattataa ctaggccagg cgtggtggct cacacctgta 1320 atcccagcac tgagggaggc cggggtgggt ggatcacctg aggtcaggag ttggagacca 1380 gcctggccaa cacagtgaaa ccctggctct accaaaaatg caaaaattag ccgagactgg 1440 tggcacacgc ctgtagtctc agctactcag gaggctgagg caggagaatc acttgaaccc 1500 aggaggcaga ggttgcagtg agctgagatt atgccattgc actccagcct gggtgacaga 1560 gtgaaactcc gccteaaaaa aaaaaaacaa ttatgataac tatgcactca gcatttgggc 1620 agggacaggg cagggacagg gcaggggagg gcatgctcgg aggccagggc ttggtgcagc 1680 cttgcaggct ggtgagaggg caggactgat gccaggtcag gaaggagaga gaaacgagtt 1740 ccttatgctg agcaggtcta cctgggaaag agaaagtgtt tgctgtcacc aggaactctg 1800 ctgggcctag ggccagcgct ctgacatgca gaaggtgacc ctgggcctgc ttgtgttcct 1860 ggcaggcttt cctgtcctgg acgccaatga cctagaagat aaaaacagtc ctttctacta 1920 tgactggcac agcctccagg ttggcgggct catctgcgct ggggttctgt gcgccatggg 1980 catcatcatc gtcatgagtg caaaatgcaa atgcaagttt ggccagaagt ccggtcacca 2040 tccaggggag actccacctc tcatcacccc aggctcagcc caaagctgat gaggacagac 2100 cagctgaaat tgggtggagg accgttctct gtccccaggt cctgtctctg cacagaaact 2160 tgaactccag gatggaattc ttcctcctct gctgggactc ctttgcatgg cagggcctca 2220 tctcacctct cgcaagaggg tctctttgtt caattttttt taatctaaaa tgattgtgcc 2280 tctgcccaag cagcctggag acttcctatg tgtgcattgg ggtggggctt ggggcaccat 2340 gagaaggttg gcgtgccctg gaggctgaca cagaggctgg cactgagcct gcttgttggg 2400 aaaagcccac aggcctgttc ccttgtggct tgggacatgg cacaggcccg ccctctgcct 2460 cctcagccat gggaacctca tatgcaattt gggatttact agtagccaaa aggaatgaaa 2520 gagagctcta accagatgga acactggaac attccagtgg accctggacc attccaggaa 2580 aactgggaca taggatcgtc ccgctatgat ggaagtgttc agacagttta taatagtaag 2640 cccctgtgac cctctcactt accccgagac ctcactttat tacaagatct ttccaaatac 2700 ccaaatgtcc ctgcaagccc gttaaataat tccctatgct acccttaata acatacaatg 2760 accacatagt gtgagaactt ccaacaagcc tcaaagtccc ttgagactcc ccaataccta 2820 ataaggcatg cgaaatgttc tcatgaacta ccccacaaca cgcctaaaac tcaaaacacc 2880 caaaaatatc tcctccaatg tcctgagaca tgaacccaaa aagagaccca caataaactc 2940 gtgacttgtc ccctca 2956 <210> 62 <211> 1743

<212> DNA <213> Homo Sapiens <400> 62 gtggactagg aggcagccgc ccccaccagc acccactctg tagacccagg cgtctggctc 60 ccagcaccca cggaaagagc ctggctagga aactgcagcc tggtgcctgg cagacagttc 120 tcattctccc cagggcaggg agcaggttat gaccaggact aaggtcccag agtccccacc 180 ctgacccctc cctgctgttc cagccgctcc ctcatatcca cccctgcccc atctcctgac 240 tttggtcacg ctagcatctt ctgctgatcc tgaaattgta ccagcggcaa gatgtggcct 300 ggaaggggac tttaagttct ccacaactgc cagcaatcct tccaccaggc aaaacacatc 360 atctaaggaa aagaagtgag gtttgcttag ggcgtggcag cttcggataa acgcaggact 420 ccgcctggca gcccgatttc tcccggaacc tctgctcagc ctggtgaacc acacagaggc 480 tggggcgagg aggataccat ctgtcagtct tggctggatg acatcatggg aagggggtat 540 agtggggcct tgcaggccag aggtggcttg gaggagcccc tggaaagagg cttaagaggc 600 cagcgctctg acatgcagaa ggtgaccctg ggcctgcttg tgttcctggc aggctttcct 660 gtcctggacg ccaatgacct agaagataaa aacagtcctt tctactatga ctggcacagc 720 ctccaggttg gcgggctcat ctgcgctggg gttctgtgcg ccatgggcat catcatcgtc 780 atgagtgcaa aatgcaaatg caagtttggc cagaagtccg gtcaccatcc aggggagact 840 ccacctctca tcaccccagg ctcagcccaa agctgatgag gacagaccag ctgaaattgg 900 gtggaggacc gttctctgtc cccaggtcct gtctctgcac agaaacttga actccaggat 960 ggaattcttc ctcctctgct gggactcctt tgcatggcag ggcctcatct cacctctcgc 1020 aagagggtct ctttgttcaa ttttttttaa tctaaaatga ttgtgcctct gcccaagcag 1080 cctggagact tcctatgtgt gcattggggt ggggcttggg gcaccatgag aaggttggcg 1140 tgccctggag gctgacacag aggctggcac tgagcctgct tgttgggaaa agcccacagg 1200 cctgttccct tgtggcttgg gacatggcac aggcccgccc tctgcctcct cagccatggg 1260 aacctcatat gcaatttggg atttactagt agccaaaagg aatgaaagag agctctaacc 1320 agatggaaca ctggaacatt ccagtggacc ctggaccatt ccaggaaaac tgggacatag 1380 gatcgtcccg ctatgatgga agtgttcaga cagtttataa tagtaagccc ctgtgaccct 1440 ctcacttacc ccgagacctc actttattac aagatctttc caaataccca aatgtccctg 1500 caagcccgtt aaataattcc ctatgctacc cttaataaca tacaatgacc acatagtgtg 1560 agaacttcca acaagcctca aagtcccttg agactcccca atacctaata aggcatgcga 1620 aatgttctca tgaactaccc cacaacacgc ctaaaactca aaacacccaa aaatatctcc 1680 tccaatgtcc tgagacatga acccaaaaag agacccacaa taaactcgtg acttgtcccc 1740 tea 1743 <210> 63 <211> 1841

<212> DNA <213> Homo Sapiens <400> 63 gtggactagg aggcagccgc ccccaccagc acccactctg tagacccagg cgtctggctc 60 ccagcaccca cggaaagagc ctggctagga aactgcagcc tggtgcctgg cagacagttc 120 tcattctccc cagggcaggg agcaggttat gaccaggact aaggtcccag agtccccacc 180 ctgacccctc cctgctgttc cagccgctcc ctcatatcca cccctgcccc atctcctgac 240 tttggtcacg ctagcatctt ctgctgatcc tgaaattgta ccagcggcaa gatgtggcct 300 ggaaggggac tttaagttct ccacaactgc cagcaatcct tccaccaggc aaaacacatc 360 atctaaggaa aagaagtgag gtttgcttag ggcgtggcag cttcggataa acgcaggact 420 ccgcctggca gcccgatttc tcccggaacc tctgctcagc ctggtgaacc acacaggtga 480 gcagctgggg ccccttcctc caagccctcc ttgtctctgc ccctaaatta ggaagtatct 540 acctgccccc tgaccctgcc ccatagaagc ttttatgtta aagcgcctaa aatcttgtga 600 aatgcttttc tggagccagg agataaacgg aagtcccttc ccctaatgtc cctttcccca 660 ccattctcct ctcagggact tgttgaacca gctgaggcca gcgctctgac atgcagaagg 720 tgaccctggg cctgcttgtg ttcctggcag gctttcctgt cctggacgcc aatgacctag 780 aagataaaaa cagtcctttc tactatgact ggcacagcct ccaggttggc gggctcatct 840 gcgctggggt tctgtgcgcc atgggcatca tcatcgtcat gagtgcaaaa tgcaaatgca 900 agtttggcca gaagtccggt caccatccag gggagactcc acctctcatc accccaggct 960 cagcccaaag ctgatgagga cagaccagct gaaattgggt ggaggaccgt tctctgtccc 1020 caggtcctgt ctctgcacag aaacttgaac tccaggatgg aattcttcct cctctgctgg 1080 gactcctttg catggcaggg cctcatctca cctctcgcaa gagggtctct ttgttcaatt 1140 ttttttaatc taaaatgatt gtgcctctgc ccaagcagcc tggagacttc ctatgtgtgc 1200 attggggtgg ggcttggggc accatgagaa ggttggcgtg ccctggaggc tgacacagag 1260 gctggcactg agcctgcttg ttgggaaaag cccacaggcc tgttcccttg tggcttggga 1320 catggcacag gcccgccctc tgcctcctca gccatgggaa cctcatatgc aatttgggat 1380 ttactagtag ccaaaaggaa tgaaagagag ctctaaccag atggaacact ggaacattcc 1440 agtggaccct ggaccattcc aggaaaactg ggacatagga tcgtcccgct atgatggaag 1500 tgttcagaca gtttataata gtaagcccct gtgaccctct cacttacccc gagacctcac 1560 tttattacaa gatctttcca aatacccaaa tgtccctgca agcccgttaa ataattccct 1620 atgctaccct taataacata caatgaccac atagtgtgag aacttccaac aagcctcaaa 1680 gtcccttgag actccccaat acctaataag gcatgcgaaa tgttctcatg aactacccca 1740 caacacgcct aaaactcaaa acacccaaaa atatctcctc caatgtcctg agacatgaac 1800 ccaaaaagag acccacaata aactcgtgac ttgtcccctc a 1841 <210> 64 <211> 2145

<212> DNA <213> Homo Sapiens <400> 64 gtggactagg aggcagccgc ccccaccagc acccactctg tagacccagg cgtctggctc 60 ccagcaccca cggaaagagc ctggctagga aactgcagcc tggtgcctgg cagacagttc 120 tcattctccc cagggcaggg agcaggttat gaccaggact aaggtcccag agtccccacc 180 ctgacccctc cctgctgttc cagccgctcc ctcatatcca cccctgcccc atctcctgac 240 tttggtcacg ctagcatctt ctgctgatcc tgaaattgta ccagcggcaa gatgtggcct 300 ggaaggggac tttaagttct ccacaactgc cagcaatcct tccaccaggc aaaacacatc 360 atctaaggaa aagaagtgag gtcggaacac caacgcatca tctcactgca tggccctgga 420 ggctctgccg tttaaagacc ccagaacctt ccccattcaa ggtcctctcc tgggcacagg 480 agattggaga aagctcctcc cttaattcca gggaccgagt tccagcccat ccaattctcc 540 gtctcacctg aggctgctgt ggtcctggtg accccaggga gcaacctgcc gcccatggct 600 ggggaggggg tgaagctgtc tctttaagag caggaatgga gcccctgggc ctcagggcat 660 ctgacttgtt ttctacctgc ccaggtttgc ttagggcgtg gcagcttcgg ataaacgcag 720 gactccgcct ggcagcccga tttctcccgg aacctctgct cagcctggtg aaccacacag 780 gtgagcagct ggggcccctt cctccaagcc ctccttgtct ctgcccctaa attaggaagt 840 atctacctgc cccctgaccc tgccccatag aagcttttat gttaaagcgc ctaaaatctt 900 gtgaaatgct tttctggagc caggagataa acggaagtcc cttcccctaa tgtccctttc 960 cccaccattc tcctctcagg gacttgttga accagctgag gccagcgctc tgacatgcag 1020 aaggtgaccc tgggcctgct tgtgttcctg gcaggctttc ctgtcctgga cgccaatgac 1080 ctagaagata aaaacagtcc tttctactat gactggcaca gcctccaggt tggcgggctc 1140 atctgcgctg gggttctgtg cgccatgggc atcatcatcg tcatgagtgc aaaatgcaaa 1200 tgcaagtttg gccagaagtc cggtcaccat ccaggggaga ctccacctct catcacccca 1260 ggctcagccc aaagctgatg aggacagacc agctgaaatt gggtggagga ccgttctctg 1320 tccccaggtc ctgtctctgc acagaaactt gaactccagg atggaattct tcctcctctg 1380 ctgggactcc tttgcatggc agggcctcat ctcacctctc gcaagagggt ctctttgttc 1440 aatttttttt aatctaaaat gattgtgcct ctgcccaagc agcctggaga cttcctatgt 1500 gtgcattggg gtggggcttg gggcaccatg agaaggttgg cgtgccctgg aggctgacac 1560 agaggctggc actgagcctg cttgttggga aaagcccaca ggcctgttcc cttgtggctt 1620 gggacatggc acaggcccgc cctctgcctc ctcagccatg ggaacctcat atgcaatttg 1680 ggatttacta gtagccaaaa ggaatgaaag agagctctaa ccagatggaa cactggaaca 1740 ttccagtgga ccctggacca ttccaggaaa actgggacat aggatcgtcc cgctatgatg 1800 gaagtgttca gacagtttat aatagtaagc ccctgtgacc ctctcactta ccccgagacc 1860 tcactttatt acaagatctt tccaaatacc caaatgtccc tgcaagcccg ttaaataatt 1920 ccctatgcta cccttaataa catacaatga ccacatagtg tgagaacttc caacaagcct 1980 caaagtccct tgagactccc caatacctaa taaggcatgc gaaatgttct catgaactac 2040 cccacaacac gcctaaaact caaaacaccc aaaaatatct cctccaatgt cctgagacat 2100 gaacccaaaa agagacccac aataaactcg tgacttgtcc cctca 2145 <210> 65 <211 > 1708

<212> DNA <213> Homo Sapiens <400> 65 gtggactagg aggcagccgc ccccaccagc acccactctg tagacccagg cgtctggctc 60 ccagcaccca cggaaagagc ctggctagga aactgcagcc tggtgcctgg cagacagttc 120 tcattctccc cagggcaggg agcaggttat gaccaggact aaggtcccag agtccccace 180 ctgacccctc cctgctgttc cagccgctcc ctcatatcca cccctgcccc atctcctgac 240 tttggtcacg ctagcatctt ctgctgatcc tgaaattgta ccagcggcaa gatgtggcct 300 ggaaggggac tttaagttct ccacaactgc cagcaatcct tccaccaggc aaaacacatc 360 atctaaggaa aagaagtgag gtttgcttag ggcgtggcag cttcggataa acgcaggact 420 ccgcctggca gcccgatttc tcccggaacc tctgctcagc ctggtgaacc acacaggcca 480 gcgctctgac atgcagaagg tgaccctggg cctgcttgtg ttcctggcag gctttcctgt 540 cctggacgcc aåtgacctag aagataaaaa cagtcctttc tactatggtg ctccatatat 600 atttgtcaag agaatggggg gacagatgaa gaggacacag gctggcactg aggtcccctc 660 cactttcctc ctagactggc acagcctcca ggttggcggg ctcatctgcg ctggggttct 720 gtgcgccatg ggcatcatca tcgtcatgag tgcaaaatgc aaatgcaagt ttggccagaa 780 gtccggtcac catccagggg agactccacc tctcatcacc ccaggctcag cccaaagctg 840 atgaggacag accagctgaa attgggtgga ggaccgttct ctgtccccag gtcctgtctc 900 tgcacagaaa cttgaactcc aggatggaat tcttcctcct ctgctgggac tcctttgcat 960 ggcagggcct catctcacct ctcgcaagag ggtctctttg ttcaattttt tttaatctaa 1020 aatgattgtg cctctgccca agcagcctgg agacttccta tgtgtgcatt ggggtggggc 1080 ttggggcacc atgagaaggt tggcgtgccc tggaggctga cacagaggct ggcactgagc 1140 ctgcttgttg ggaaaagccc acaggcctgt tcccttgtgg cttgggacat ggcacaggcc 1200 cgccctctgc ctcctcagcc atgggaacct catatgcaat ttgggattta ctagtagcca 1260 aaaggaatga aagagagctc taaccagatg gaacactgga acattccagt ggaccctgga 1320 ccattccagg aaaactggga cataggatcg tcccgctatg atggaagtgt tcagacagtt 1380 tataatagta agcccctgtg accctctcac ttaccccgag acctcacttt attacaagat 1440 ctttccaaat acccaaatgt ccctgcaagc ccgttaaata attccctatg ctacccttaa 1500 taacatacaa tgaccacata gtgtgagaac ttccaacaag cctcaaagtc ccttgagact 1560 ccccaatacc taataaggca tgcgaaatgt tctcatgaac taccccacaa cacgcctaaa 1620 actcaaaaca cccaaaaata tctcctccaa tgtcctgaga catgaaccca aaaagagacc 1680 cacaataaac tcgtgacttg tcccctca 1708 <210> 66 <211 > 1792

<212> DNA <213> Homo Sapiens <400> 66 gtggactagg aggcagccgc ccccaccagc acccactctg tagacccagg cgtctggctc 60 ccagcaccca cggaaagagc ctggctagga aactgcagcc tggtgcctgg cagacagttc 120 tcattctccc cagggcaggg agcaggttat gaccaggact aaggtcccag agtccccacc 180 ctgacccctc cctgctgttc cagccgctcc ctcatatcca cccctgcccc atctcctgac 240 tttggtcacg ctagcatctt ctgctgatcc tgaaattgta ccagcggcaa gatgtggcct 300 ggaaggggac tttaagttct ccacaactgc cagcaatcct tccaccaggc aaaacacatc 360 atctaaggaa aagaagtgag gtttgcttag ggcgtggcag cttcggataa acgcaggact 420 ccgcctggca gcccgatttc tcccggaacc tctgctcagc ctggtgaacc acacaggccc 480 gagtttcacc cagtccccac tccacggtgc agctgcggct tatctctcag cccagcgaga 540 tgccagcctt cctgtcccgg gccagcgctc tgacatgcag aaggtgaccc tgggcctgct 600 tgtgttcctg gcaggctttc ctgtcctgga cgccaatgac ctagaagata aaaacagtcc 660 tttctactat ggtgctccat atatatttgt caagagaatg gggggacaga tgaagaggac 720 acaggctggc actgaggtcc cctccacttt cctcctagac tggcacagcc tccaggttgg 780 cgggctcatc tgcgctgggg ttctgtgcgc catgggcatc atcatcgtca tgagtgcaaa 840 atgcaaatgc aagtttggcc agaagtccgg tcaccatcca ggggagactc cacctctcat 900 caccccaggc tcagcccaaa gctgatgagg acagaccagc tgaaattggg tggaggaccg 960 ttctctgtcc ccaggtcctg tctctgcaca gaaacttgaa ctccaggatg gaattcttcc 1020 tcctctgctg ggactccttt gcatggcagg gcctcatctc acctctcgca agagggtctc 1080 tttgttcaat tttttttaat ctaaaatgat tgtgcctctg cccaagcagc ctggagactt 1140 cctatgtgtg cattggggtg gggcttgggg caccatgaga aggttggcgt gccctggagg 1200 ctgacacaga ggctggcact gagcctgctt gttgggaaaa gcccacaggc ctgttccctt 1260 gtggcttggg acatggcaca ggcccgccct ctgcctcctc agccatggga acctcatatg 1320 caatttggga tttactagta gccaaaagga atgaaagaga gctctaacca gatggaacac 1380 tggaacattc cagtggaccc tggaccattc caggaaaact gggacatagg atcgtcccgc 1440 tatgatggaa gtgttcagac agtttataat agtaagcccc tgtgaccctc tcacttaccc 1500 cgagacctca ctttattaca agatctttcc aaatacccaa atgtccctgc aagcccgtta 1560 aataattccc tatgctaccc ttaataacat acaatgacca catagtgtga gaacttccaa 1620 caagcctcaa agtcccttga gactccccaa tacctaataa ggcatgcgaa atgttctcat 1680 gaactacccc acaacacgcc taaaactcaa aacacccaaa aatatctcct ccaatgtcct 1740 gagacatgaa cccaaaaaga gacccacaat aaactcgtga cttgtcccct ca 1792 <210> 67 <211 >2660

<212> DNA <213> Homo Sapiens <400> 67 gtggactagg aggcagccgc ccccaccagc acccactctg tagacccagg cgtctggctc 60 ccagcaccca cggaaagagc ctggctagga aactgcagcc tggtgcctgg cagacagttc 120 tcattctccc cagggcaggg agcaggttat gaccaggact aaggtcccag agtccccacc 180 ctgacccctc cctgctgttc cagccgctcc ctcatatcca cccctgcccc atctcctgac 240 tttggtcacg ctagcatctt ctgctgatcc tgaaattgta ccagcggcaa gatgtggcct 300 ggaaggggac tttaagttct ccacaactgc cagcaatcct tccaccaggc aaaacacatc 360 atctaaggaa aagaagtgag gtttgcttag ggcgtggcag cttcggataa acgcaggact 420 ccgcctggca gcccgatttc tcccggaacc tctgctcagc ctggtgaacc acacagaggc 480 tggggcgagg aggataccat ctgtcagtct tggctggatg acatcatggg aagggggtat 540 agtggggcct tgcaggccag aggtggcttg gaggagcccc tggaaagagg cttaagaggt 600 gagactcaac agccatggcg acagagcata gggctttaag atgaatttgc aggggttaca 660 ggattacaac tgcaatgtgg gctaataata gtgccccctg cattaagctg cagagattga 720 gcgagtaagt gggaagctga gaaaatgccc ccatggggta gacactcaat aagcatctgc 780 tgttattacc aggactcgta tggtcatggg tgacagcttc agaccacagg cagtccacct 840 acaacctgtg cccctatcca ccatgccatc ctgcccaccc acccacgcca gctcccccaa 900 cccccaacac ttttggggat cctaaacact tcctgggcct cagtaatgct ccccaaagcc 960 tcaggctttc ttcccgcaaa aaaaggaaaa gaaatggatg ctccaactaa aattgtgagt 1020 tcagcatgtg gaattaactg ggaagctgag aggattccca ggcctggggt gcgcaggcag 1080 agggaggagt ctgtgccaac ctgcaaggac cacccgcacc gttggttgcg ggcaccaccc 1140 tctctcagca tttttgctgt tcgtgaaatg aggacatagt ggacgacgtc ggggattgct 1200 ggggggttaa gtgagtgaga acacggcaag gtcagtgtgc actccagggc aaggtggagg 1260 aagtgccagc tctcgctatc aaaattataa ctaggccagg cgtggtggct cacacctgta 1320 atcccagcac tgagggaggc cggggcccga gtttcaccca gtccccactc cacggtgcag 1380 ctgcggctta tctctcagcc cagcgagatg ccagccttcc tgtcccgggc cagcgctctg 1440 acatgcagaa ggtgaccctg ggcctgcttg tgttcctggc aggctttcct gtcctggacg 1500 ccaatgacct agaagataaa aacagtcctt tctactatgg tgctccatat atatttgtca 1560 agagaatggg gggacagatg aagaggacac aggctggcac tgaggtcccc tccactttcc 1620 tcctagactg gcacagcctc caggttggcg ggctcatctg cgctggggtt ctgtgcgcca 1680 tgggcatcat catcgtcatg agtgcaaaat gcaaatgcaa gtttggccag aagtccggtc 1740 accatccagg ggagactcca cctctcatca ccccaggctc agcccaaagc tgatgaggac 1800 agaccagctg aaattgggtg gaggaccgtt ctctgtcccc aggtcctgtc tctgcacaga 1860 aacttgaact ccaggatgga attcttcctc ctctgctggg actcctttgc atggcagggc 1920 ctcatctcac ctctcgcaag agggtctctt tgttcaattt tttttaatct aaaatgattg 1980 tgcctctgcc caagcagcct ggagacttcc tatgtgtgca ttggggtggg gcttggggca 2040 ccatgagaag gttggcgtgc cctggaggct gacacagagg ctggcactga gcctgcttgt 2100 tgggaaaagc ccacaggcct gttcccttgt ggcttgggac atggcacagg cccgccctct 2160 gcctcctcag ccatgggaac ctcatatgca atttgggatt tactagtagc caaaaggaat 2220 gaaagagagc tctaaccaga tggaacactg gaacattcca gtggaccctg gaccattcca 2280 ggaaaactgg gacataggat cgtcccgcta tgatggaagt gttcagacag tttataatag 2340 taagcccctg tgaccctctc acttaccccg agacctcact ttattacaag atctttccaa 2400 atacccaaat gtccctgcaa gcccgttaaa taattcccta tgctaccctt aataacatac 2460 aatgaccaca tagtgtgaga acttccaaca agcctcaaag tcccttgaga ctccccaata 2520 cctaataagg catgcgaaat gttctcatga actaccccac aacacgccta aaactcaaaa 2580 cacccaaaaa tatctcctcc aatgtcctga gacatgaacc caaaaagaga cccacaataa 2640 actcgtgact tgtcccctca 2660 <210> 68 <211> 2015

<212> DNA <213> Homo Sapiens <400> 68 gtggactagg aggcagccgc ccccaccagc acccactctg tagacccagg cgtctggctc 60 ccagcaccca cggaaagagc ctggctagga aactgcagcc tggtgcctgg cagacagttc 120 tcattctccc cagggcaggg agcaggttat gaccaggact aaggtcccag agtccccacc 180 ctgacccctc cctgctgttc cagccgctcc ctcatatcca cccctgcccc atctcctgac 240 tttggtcacg ctagcatctt ctgctgatcc tgaaattgta ccagcggcaa gatgtggcct 300 ggaaggggac tttaagttct ccacaactgc cagcaatcct tccaccaggc aaaacacatc 360 atctaaggaa aagaagtgag gtttgcttag ggcgtggcag cttcggataa acgcaggact 420 ccgcctggca gcccgatttc tcccggaacc tctgctcagc ctggtgaacc acacaggcca 480 gcgctctgac atgcagaagg tgaccctggg cctgcttgtg ttcctggcag gctttcctgt 540 cctggacgcc aatgacctag aagataaaaa cagtcctttc tactatgact ggcacagcct 600 ccaggttggc gggctcatct gcgctggggt tctgtgcgcc atgggcatca tcatcgtcat 660 gagtgagtgg aggagctcgg gggagcaggc gggccggggc tggggctccc ctcccctgac 720 cactcagctc tccccaacag gtgcaaaatg caaatgcaag tttggccaga agtccgggta 780 agatactgtt ccggcatgcc cgcctcaggc tgactggacg cttttcaggg tgaaagggct 840 aactctccca gcaggagagg cctcggggct ctgcccttta gagttcctgc cgctaagatt 900 tccaggttta ttgtttctag ctggtaatcc ccagggggcc ccaaatcctg aaatgctttg 960 gcccctggga ttgcacaacc ccccaaatgg aaaggcagcc aggaagacat gtctgggcag 1020 gctaagaacc ctctatccgg agggagaggg caaatggggg cggacaccaa tctcaccact 1080 tttgtctcct tagtcaccat ccaggggaga ctccacctct catcacccca ggctcagccc 1140 aaagctgatg aggacagacc agctgaaatt gggtggagga ccgttctctg tccccaggtc 1200 ctgtctctgc acagaaactt gaactccagg atggaattct tcctcctctg ctgggactcc 1260 tttgcatggc agggcctcat ctcacctctc gcaagagggt ctctttgttc aatttttttt 1320 aatctaaaat gattgtgcct ctgcccaagc agcctggaga cttcctatgt gtgcattggg 1380 QFtggggcttg gggcaccatg agaaggttgg cgtgccctgg aggctgacac agaggctggc 1440 actgagcctg cttgttggga aaagcccaca ggcctgttcc cttgtggctt gggacatggc 1500 acaggcccgc cctctgcctc ctcagccatg ggaacctcat atgcaatttg ggatttacta 1560 gtagccaaaa ggaatgaaag agagctctaa ccagatggaa cactggaaca ttccagtgga 1620 ccctggacca ttccaggaaa actgggacat aggatcgtcc cgctatgatg gaagtgttca 1680 gacagtttat aatagtaagc ccctgtgacc ctctcactta ccccgagacc tcactttatt 1740 acaagatctt tccaaatacc caaatgtccc tgcaagcccg ttaaataatt ccctatgcta 1800 cccttaataa catacaatga ccacatagtg tgagaacttc caacaagcct caaagtccct 1860 tgagactccc caatacctaa taaggcatgc gaaatgttct catgaactac cccacaacac 1920 gcctaaaact caaaacaccc aaaaatatct cctccaatgt cctgagacat gaacccaaaa 1980 agagacccac aataaactcg tgacttgtcc cctca 2015 <210> 69 <211> 1991

<212> DNA <213> Homo Sapiens <400> 69 gtggactagg aggcagccgc ccccaccagc acccactctg tagacccagg cgtctggctc 60 ccagcaccca cggaaagagc ctggctagga aactgcagcc tggtgcctgg cagacagttc 120 tcattctccc cagggcaggg agcaggttat gaccaggact aaggtcccag agtccccacc 180 ctgacccctc cctgctgttc cagccgctcc ctcatatcca cccctgcccc atctcctgac 240 tttggtcacg ctagcatctt ctgctgatcc tgaaattgta ccagcggcaa gatgtggcct 300 ggaaggggac tttaagttct ccacaactgc cagcaatcct tccaccaggc aaaacacatc 360 atctaaggaa aagaagtgag gtttgcttag ggcgtggcag cttcggataa acgcaggact 420 ccgcctggca gcccgatttc tcccggaacc tctgctcagc ctggtgaacc acacaggcca 480 gcgctctgac atgcagaagg tgaccctggg cctgcttgtg ttcctggcag gctttcctgt 540 cctggacgcc aatgacctag aagactggca cagcctccag gttggcgggc tcatctgcgc 600 tggggttctg tgcgccatgg gcatcatcat cgtcatgagt gagtggagga gctcggggga 660 gcaggcgggc cggggctggg gctcccctcc cctgaccact cagctctccc caacaggtgc 720 aaaatgcaaa tgcaagtttg gccagaagtc cgggtaagat actgttccgg catgcccgcc 780 tcaggctgac tggacgcttt tcagggtgaa agggctaact ctcccagcag gagaggcctc 840 ggggctctgc cctttagagt tcctgccgct aagatttcca ggtttattgt ttctagctgg 900 taatccccag ggggccccaa atcctgaaat gctttggccc ctgggattgc acaacccccc 960 aaatggaaag gcagccagga agacatgtct gggcaggcta agaaccctct atccggaggg 1020 agagggcaaa tgggggcgga caccaatctc accacttttg tctccttagt caccatccag 1080 gggagactcc acctctcatc accccaggct cagcccaaag ctgatgagga cagaccagct 1140 gaaattgggt ggaggaccgt tctctgtccc caggtcctgt ctctgcacag aaacttgaac 1200 tccaggatgg aattcttcct cctctgctgg gactcctttg catggcaggg cctcatctca 1260 cctctcgcaa gagggtctct ttgttcaatt ttttttaatc taaaatgatt gtgcctctgc 1320 ccaagcagcc tggagacttc ctatgtgtgc attggggtgg ggcttggggc accatgagaa 1380 ggttggcgtg ccctggaggc tgacacagag gctggcactg agcctgcttg ttgggaaaag 1440 cccacaggcc tgttcccttg tggcttggga catggcacag gcccgccctc tgcctcctca 1500 gccatgggaa cctcatatgc aatttgggat ttactagtag ccaaaaggaa tgaaagagag 1560 ctctaaccag atggaacact ggaacattcc agtggaccct ggaccattcc aggaaaactg 1620 ggacatagga tcgtcccgct atgatggaag tgttcagaca gtttataata gtaagcccct 1680 gtgaccctct cacttacccc gagacctcac tttattacaa gatctttcca aatacccaaa 1740 tgtccctgca agcccgttaa ataattccct atgctaccct taataacata caatgaccac 1800 atagtgtgag aacttccaac aagcctcaaa gtcccttgag actccccaat acctaataag 1860 gcatgcgaaa tgttctcatg aactacccca caacacgcct aaaactcaaa acacccaaaa 1920 atatctcctc caatgtcctg agacatgaac ccaaaaagag acccacaata aactcgtgac 1980 ttgtcccctc a 1991 <210> 70 <211> 87

<212> PRT <213> Homo Sapiens <400> 70

Met Gin Lys val Thr Leu Gly Leu Leu Val Phe Leu Ala Gly Phe Pro 15 10 15

Val Leu Asp Ala Asn Asp Leu Glu Asp Lys Asn Ser Pro Phe Tyr Tyr 20 25 30

Asp Trp His Ser Leu Gin Val Gly Gly Leu Ile Cys Ala Gly Val Leu 35 40 45

Cys Ala Met Gly ile ile Ile val Met Ser Ala Lys Cys Lys Cys Lys 50 55 60

Phe Gly Gin Lys Ser Gly His His Pro Gly Glu Thr Pro Pro Leu Ile 65 70 75 80

Thr Pro Gly Ser Ala Gin Ser 85

<210>71 <211 > 113 <212> PRT <213> Homo Sapiens <400> 71

Met Gin Lys Val Thr Leu Gly Leu Leu Val Phe Leu Ala Gly Phe Pro 15 10 15 val Leu Asp Ala Asn Asp Leu Glu Asp Lys Asn Ser Pro Phe Tyr Tyr 20 25 30

Asp Trp His Ser Leu Gin Val Gly Gly Leu Ile Cys Ala Gly Val Leu 35 40 45

Cys Ala Met Gly Ile Ile Ile Val Met Ser Glu Trp Arg Ser Ser Gly 50 55 60

Glu Gin Ala Gly Arg Gly Trp Gly Ser Pro Pro Leu Thr Thr Gin Leu 65 70 75 80

Ser Pro Thr Gly Ala Lys Cys Lys Cys Lys Phe Gly Gin Lys Ser Gly 85 90 95

His His Pro Gly Glu Thr Pro Pro Leu Ile Thr Pro Gly Ser Ala Gin 100 105 110

Ser <210> 72 <211> 116

<212> PRT <213> Homo Sapiens <400> 72

Met Gin Lys Val Thr Leu Gly Leu Leu Val Phe Leu Ala Gly Phe Pro 15 10 15

Val Leu Asp Ala Asn Asp Leu Glu Asp Lys Asn Ser Pro Phe Tyr Tyr 20 25 30

Gly Ala Pro Tyr Ile Phe Val Lys Arg Met Gly Gly Gin Met Lys Arg 35 40 45

Thr Gin Ala Gly Thr Glu Val Pro Ser Thr Phe Leu Leu Asp Trp His 50 55 60

Ser Leu Gin Val Gly Gly Leu ile Cys Ala Gly val Leu Cys Ala Met 65 70 75 80

Gly Ile Ile Ile Val Met Ser Ala Lys Cys Lys Cys Lys Phe Gly Gin 85 90 95

Lys Ser Gly His His Pro Gly Glu Thr Pro Pro Leu Ile Thr Pro Gly 100 105 110

Ser Ala Gin Ser 115 <210> 73 <211 > 96

<212> PRT <213> Homo Sapiens <400> 73

Met Gin Lys Val Thr Leu Gly Leu Leu Val Phe Leu Ala Gly Phe Pro 15 10 15

Val Leu Asp Ala Asn Asp Leu Glu Asp Lys Asn Ser Pro Phe Tyr Tyr 20 25 30

Asp Trp His Ser Leu Gin Val Gly Gly Leu Ile Cys Ala Gly Val Leu 35 40 45

Cys Ala Met Gly lie lie He Val Met Ser Glu Trp Arg Ser Ser Gly 50 55 60

Glu Gin Ala Gly Arg Gly Trp Gly Ser Pro Pro Leu Thr Thr Gin Leu 65 70 75 80

Ser Pro Thr Gly Ala Lys Cys Lys Cys Lys Phe Gly Gin Lys Ser Gly 85 90 95 <210> 74 <211> 88

<212> PRT <213> Homo Sapiens <400> 74

Met Gin Lys Val Thr Leu Gly Leu Leu Val Phe Leu Ala Gly Phe Pro 15 10 15

Val Leu Asp Ala Asn Asp Leu Glu Asp Trp His Ser Leu Gin Val Gly 20 25 30

Gly Leu lie Cys Ala Gly Val Leu Cys Ala Met Gly lie lie lie Val 35 40 45

Met Ser Glu Trp Arg Ser Ser Gly Glu Gin Ala Gly Arg Gly Trp Gly 50 55 60

Ser Pro Pro Leu Thr Thr Gin Leu Ser Pro Thr Gly Ala Lys Cys Lys 65 70 75 80

Cys Lys Phe Gly Gin Lys Ser Gly 85 <210> 75 <211 > 139

<212> PRT <213> Homo Sapiens <400> 75

Leu Leu Val Thr Val Gin His Thr Glu Arg Tyr Val Thr Leu Phe Ala 15 10 15

Ser lie lie Leu Lys Cys Asp Tyr Thr Thr Ser Ala Gin Leu Gin Asp 20 25 30

Val Val Val Thr Trp Arg Phe Lys Ser Phe Cys Lys Asp Pro lie Phe 35 40 45

Asp Tyr Tyr Ser Ala Ser Tyr Gin Ala Ala Leu Ser Leu Gly Gin Asp 50 55 60

Pro Ser Asn Asp Cys Asn Asp Asn Gin Arg Glu Val Arg lie Val Ala 65 70 75 80

Gin Arg Arg Gly Gin Asn Glu Pro Val Leu Gly Val Asp Tyr Arg Gin 85 90 95

Arg Lys lie Thr lie Gin Asn Arg Ala Asp Leu Val lie Asn Glu Val 100 105 110

Met Trp Trp Asp His Gly Val Tyr Tyr Cys Thr lie Glu Ala Pro Gly 115 120 125

Asp Thr Ser Gly Asp Pro Asp Lys Glu Val Lys 130 135 <210> 76 <211 > 434 <212> PRT <213> Homo Sapiens <400> 76

Leu Leu Val Thr Val Gin Hia Thr Glu Arg lyr Val Ihr Leu Phe Ala 15 10 15

Ser Ile Ile Leu Lys Cys Asp Tyr Thr Thr Ser Ala Gin Leu Gin Asp 20 25 30

Val Val Val Thr Trp Arg Phe Lys Ser Phe Cys Lys Asp Pro Ile Phe 35 40 45

Asp Tyr Tyr Ser Ala Ser Tyr Gin Ala Ala Leu Ser Leu Gly Gin Asp 50 55 60

Pro Ser Asn Asp Cys Asn Asp Asn Gin Arg Glu Val Arg Ile Val Ala 65 70 75 80

Gin Arg Arg Gly Gin Asn Glu Pro Val Leu Gly Val Asp Tyr Arg Gin 85 90 95

Arg Lys Ile Thr Ile Gin Asn Pro Leu Ala Arg His Arg Tyr Met Lys 100 105 110

Gin Ala Gin Ala Leu Gly Pro Gin Met Met Gly Lys Pro Leu Tyr Trp 115 120 125

Gly Ala Asp Arg Ser Ser Gin Val Ser Ser Tyr Pro Met His Pro Leu 130 135 140

Leu Gin Arg Asp Leu Ser Leu Pro Ser Ser Leu Pro Gin Met Pro Met 145 150 155 160

Thr Gin Thr Thr Asn Gin Pro Pro Ile Ala Asn Gly Val Leu Glu Tyr 165 170 175

Leu Glu Lys Glu Leu Arg Asn Leu Asn Leu Ala Gin Pro Leu Pro Pro 180 185 190

Asp Leu Lys Gly Arg Phe Gly His Pro Cys Ser Met Leu Ser Ser Leu 195 200 205

Gly Ser Glu Val Val Glu Arg Arg Ile Ile His Leu Pro Pro Leu Ile 210 215 220

Arg Asp Leu Ser Ser Ser Arg Arg Thr Ser Asp Ser Leu His Gin Gin 225 230 235 240

Trp Leu Thr Pro Ile Pro Ser Arg Pro Trp Asp Leu Arg Glu Gly Arg 245 250 255

Ser His His His Tyr Pro Asp Phe His Gin Glu Leu Gin Asp Arg Gly 260 265 270

Pro Lys Ser Trp Ala Leu Glu Arg Arg Glu Leu Asp Pro Ser Trp Ser 275 280 285

Gly Arg His Arg Ser Ser Arg Leu Asn Gly Ser Pro Ile His Trp Ser 290 295 300

Asp Arg Asp Ser Leu Ser Asp Val Pro Ser Ser Ser Glu Ala Arg Trp 305 310 315 320

Arg Pro Ser His Pro Pro Phe Arg Ser Arg Cys Gin Glu Arg Pro Arg 325 330 335

Arg Pro Ser Pro Arg Glu Ser Thr Gin Arg His Gly Arg Arg Arg Arg 340 345 350

His Arg Ser Tyr Ser Pro Pro Leu Pro Ser Gly Leu Ser Ser Trp Ser 355 360 365

Ser Glu Glu Asp Lys Glu Arg Gin Pro Gin Ser Trp Arg Ala His Arg 370 375 380

Arg Gly Ser His Ser Pro His Trp Pro Glu Glu Lys Pro Pro Ser Tyr 385 390 395 400

Arg Ser Leu Asp Ile Thr Pro Gly Lys Asn Ser Arg Lys Lys Gly Ser 405 410 415

Val Glu Arg Arg Ser Glu Lys Asp Ser Ser His Ser Gly Arg Ser Val 420 425 430

Val Ile <210> 77 <211> 996

<212> DNA <213> Homo Sapiens <400> 77 atgcagaagg tgaccctggg cctgcttgtg ttcctggcag gctttcctgt cctggacgcc 60 aatgacctag aagataaaaa cagtcctttc tactatgact ggcacagcct ccaggttggc 120 gggctcatct gcgctggggt tctgtgcgcc atgggcatca tcatcgtcat gagtgcaaaa 180 tgcaaatgca agtttggcca gaagtccggt caccatccag gggagactcc acctctcatc 240 accccaggct cagcccaaag cggaccggtc gccaccatgg tgagcaaggg cgaggagctg 300 ttcaccgggg tggtgcccat cctggtcgag ctggacggcg acgtaaacgg ccacaagttc 360 agcgtgtccg gcgagggcga gggcgatgcc acctacggca agctgaccct gaagttcatc 420 tgcaccaccg gcaagctgcc cgtgccctgg cccaccctcg tgaccaccct gacctacggc 480 gtgcagtgct tcagccgcta ccccgaccac atgaagcagc acgacttctt caagtccgcc 540 atgcccgaag gctacgtcca ggagcgcacc atcttcttca aggacgacgg caactacaag 600 acccgcgccg aggtgaagtt cgagggcgac accctggtga accgcatcga gctgaagggc 660 atcgacttca aggaggacgg caacatcctg gggcacaagc tggagtacaa ctacaacagc 720 cacaacgtct atatcatggc cgacaagcag aagaacggca tcaaggtgaa cttcaagatc 780 cgccacaaca tcgaggacgg cagcgtgcag ctcgccgacc actaccagca gaacaccccc 840 atcggcgacg gccccgtgct gctgcccgac aaccactacc tgagcaccca gtccgccctg 900 agcaaagacc ccaacgagaa gcgcgatcac atggtcctgc tggagttcgt gaccgccgcc 960 gggatcactc tcggcatgga cgagctgtac aagtaa 996 <210> 78 <211> 1083

<212> DNA <213> Homo Sapiens <400> 78 atgcagaagg tgaccctggg cctgcttgtg ttcctggcag gctttcctgt cctggacgcc 60 aatgacctag aagataaaaa cagtcctttc tactatggtg ctccatatat atttgtcaag 120 agaatggggg gacagatgaa gaggacacag gctggcactg aggtcccctc cactttcctc 180 ctagactggc acagcctcca ggttggcggg ctcatctgcg ctggggttct gtgcgccatg 240 ggcatcatca tcgtcatgag tgcaaaatgc aaatgcaagt ttggccagaa gtccggtcac 300 catccagggg agactccacc tctcatcacc ccaggctcag cccaaagcgg accggtcgcc 360 accatggtga gcaagggcga ggagctgttc accggggtgg tgcccatcct ggtcgagctg 420 gacggcgacg taaacggcca caagttcagc gtgtccggcg agggcgaggg cgatgccacc 480 tacggcaagc tgaccctgaa gttcatctgc accaccggca agctgcccgt gccctggccc 540 accctcgtga ccaccctgac ctacggcgtg cagtgcttca gccgctaccc cgaccacatg 600 aagcagcacg acttcttcaa gtccgccatg cccgaaggct acgtccagga gcgcaccatc 660 ttcttcaagg acgacggcaa ctacaagacc cgcgccgagg tgaagttcga gggcgacacc 720 ctggtgaacc gcatcgagct gaagggcatc gacttcaagg aggacggcaa catcctgggg 780 cacaagctgg agtacaacta caacagccac aacgtctata tcatggccga caagcagaag 840 aacggcatca aggtgaactt caagatccgc cacaacatcg aggacggcag cgtgcagctc 900 gccgaccact accagcagaa cacccccatc ggcgacggcc ccgtgctgct gcccgacaac 960 cactacctga gcacccagtc cgccctgagc aaagacccca acgagaagcg cgatcacatg 1020 gtcctgctgg agttcgtgac cgccgccggg atcactctcg gcatggacga gctgtacaag 1080 taa 1083 <210> 79 <211 > 1371

<212> DNA <213> Homo Sapiens <400> 79 atgaggcctc tgcccagcgg gaggaggaag acccgaggca tctccctagg actcttcgcc 60 ctctgcctgg ccgcagcccg ctgtctgcag agtcagggtg tgtccctata cattcctcag 120 gccaccatca atgccactgt caaagaagac atcctgctct cagttgagta ctcctgtcat 180 ggagtgccca ccatcgaatg gacatattca tccaattggg gaacgcagaa gatcgtggag 240 tggaaaccag ggactcaggc caacatctct caaagccaca aggacagagt ctgcaccttt 300 gacaacggct ccatccagct cttcagcgtg ggagtgaggg attccggcta ctatgtcatc 360 accgtgacgg agcgcctggg gagcagccag tttggcacca tcgtgctgca cgtctctgag 420 atcctctatg aagacctgca ctttgtcgct gtcatccttg cttttctcgc tgctgtggcc 480 gcagtattaa tcagcctcat gtgggtttgt aataagtgtg catataaatt tcagaggaag 540 agaagacaca aactcaaaga aagcacaact gaggagattg agctggaaga tgttgagtgt 600 cgaattctgc agtcgacggt accgcgggcc cgggatccac cggtcgccac catggtgagc 660 aagggcgagg agctgttcac cggggtggtg cccatcctgg tcgagctgga cggcgacgta 720 aacggccaca agttcagcgt gtccggcgag ggcgagggcg atgccaccta cggcaagctg 780 accctgaagt tcatctgcac caccggcaag ctgcccgtgc cctggcccac cctcgtgacc 840 accctgacct acggcgtgca gtgcttcagc cgctaccccg accacatgaa gcagcacgac 900 ttcttcaagt ccgccatgcc cgaaggctac gtccaggagc gcaccatctt cttcaaggac 960 gacggcaact acaagacccg cgccgaggtg aagttcgagg gcgacaccct ggtgaaccgc 1020 atcgagctga agggcatcga cttcaaggag gacggcaaca tcctggggca caagctggag 1080 tacaactaca acagccacaa cgtctatatc atggccgaca agcagaagaa cggcatcaag 1140 gtgaacttca agatccgcca caacatcgag gacggcagcg tgcagctcgc cgaccactac 1200 cagcagaaca cccccatcgg cgacggcccc gtgctgctgc ccgacaacca ctacctgagc 1260 acccagtccg ccctgagcaa agaccccaac gagaagcgcg atcacatggt cctgctggag 1320 ttcgtgaccg ccgccgggat cactctcggc atggacgagc tgtacaagta a 1371 <210> 80 <211 > 1332

<212> DNA <213> Homo Sapiens <400> 80 atgaggcctc tgcccagcgg gaggaggaag acccgaggca tctccctagg actcttcgcc 60 ctctgcctgg ccgcagcccg ctgtctacag agtcagggtg tgtccctata cattcctcag 120 gccaccatca atgccactgt caaagaagac atcctgctct cagttgagta ctcctgtcat 180 ggagtgccca ccatcgaatg gacatattca tccaattggg gaacgcagaa gatcgtggag 240 tggaaaccag ggactcaggc caacatctct caaagccaca aggacagagt ctgcaccttt 300 gacaacggct ccatccagct cttcagcgtg ggagtgaggg attccggcta ctatgtcatc 360 accgtgacgg agcgcctggg gagcagccag tttggcacca tcgtgctgca cgtctctgag 420 atcctctatg aagacctgca ctttgtcgct gtcatccttg cttttctcgc tgctgtggcc 480 gcagtattaa tcagcctcat gtgggtttgt aataagtgtg catataaatt tcagaggaag 540 agaagacaca aactcaaagg taaccccctg ggccttgtga taatccatga gtggtttgga 600 ccggtcgcca ccatggtgag caagggcgag gagctgttca ccggggtggt gcccatcctg 660 gtcgagctgg acggcgacgt aaacggccac aagttcagcg tgtccggcga gggcgagggc 720 gatgccacct acggcaagct gaccctgaag ttcatctgca ccaccggcaa gctgcccgtg 780 ccctggccca ccctcgtgac caccctgacc tacggcgtgc agtgcttcag ccgctacccc 840 gaccacatga agcagcacga cttcttcaag tccgccatgc ccgaaggcta cgtccaggag 900 cgcaccatct tcttcaagga cgacggcaac tacaagaccc gcgccgaggt gaagttcgag 960 ggcgacaccc tggtgaaccg catcgagctg aagggcatcg acttcaagga ggacggcaac 1020 atcctggggc acaagctgga gtacaactac aacagccaca acgtctatat catggccgac 1080 aagcagaaga acggcatcaa ggtgaacttc aagatccgcc acaacatcga ggacggcagc 1140 gtgcagctcg ccgaccacta ccagcagaac acccccatcg gcgacggccc cgtgctgctg 1200 cccgacaacc actacctgag cacccagtcc gccctgagca aagaccccaa cgagaagcgc 1260 gatcacatgg tcctgctgga gttcgtgacc gccgccggga tcactctcgg catggacgag 1320 ctgtacaagt aa 1332 <210>81 <211> 1533

<212> DNA <213> Homo Sapiens <400 81 atggataggg tcttgctgag gtggatttct ctcttctggc taacagccat ggtcgaaggc 60 cttcaggtca cagtgcccga caagaagaag gtggccatgc tcttccagcc cactgtgctt 120 cgctgccact tctcaacatc ctcccatcag cctgcagttg tgcagtggaa gttcaagtcc 180 tactgccagg atcgcatggg agaatccttg ggcatgtcct ctacccgggc ccaatctctc 240 agcaagagaa acctggaatg ggacccctac ttggattgtt tggacagcag gaggactgtt 300 cgagtagtag cttcaaaaca gggctcgact gtcaccctgg gagatttcta caggggcaga 360 gagatcacga ttgttcatga tgcagatctt caaattggaa agcttatgtg gggagacagc 420 ggactctatt actgtattat caccacccca gatgacctgg aggggaaaaa tgaggactca 480 gtggaactgc tggtgttggg caggacaggg ctgcttgctg atctcttgcc cagttttgct 540 gtggagatta tgccagagtg ggtgtttgtt ggcctggtgc tcctgggcgt cttcctcttc 600 ttcgtcctgg tggggatctg ctggtgccag tgctgccctc acagctgctg ctgctatgtc 660 cgctgcccat gctgcccaga ttcctgctgc tgccctcaag cctgtgagta cagtgaccgc 720 tggggagaca gagcgatcga gagaaatgtc tacctctcta cccgaattct gcagtcgacg 780 gtaccgcggg cccgggatcc accggtcgcc accatggtga gcaagggcga ggagctgttc 840 accggggtgg tgcccatcct ggtcgagctg gacggcgacg taaacggcca caagttcagc 900 gtgtccggcg agggcgaggg cgatgccacc tacggcaagc tgaccctgaa gttcatctgc 960 accaccggca agctgcccgt gccctggccc accctcgtga ccaccctgac ctacggcgtg 1020 cagtgcttca gccgctaccc cgaccacatg aagcagcacg acttcttcaa gtccgccatg 1080 cccgaaggct acgtccagga gcgcaccatc ttcttcaagg acgacggcaa ctacaagacc 1140 cgcgccgagg tgaagttcga gggcgacacc ctggtgaacc gcatcgagct gaagggcatc 1200 gacttcaagg aggacggcaa catcctgggg cacaagctgg agtacaacta caacagccac 1260 aacgtctata tcatggccga caagcagaag aacggcatca aggtgaactt caagatccgc 1320 cacaacatcg aggacggcag cgtgcagctc gccgaccact accagcagaa cacccccatc 1380 ggcgacggcc ccgtgctgct gcccgacaac cactacctga gcacccagtc cgccctgagc 1440 aaagacccca acgagaagcg cgatcacatg gtcctgctgg agttcgtgac cgccgccggg 1500 atcactctcg gcatggacga gctgtacaag taa 1533 <210> 82 <211 >2085

<212> DNA <213> Homo Sapiens <400> 82 atgtggctca aggtcttcac aactttcctt tcctttgcaa caggtgcttg ctcggggctg 60 aaggtgacag tgccatcaca cactgtccat ggcgtcagag gtcaggccct ctacctaccc 120 gtccactatg gcttccacac tccagcatca gacatccaga tcatatggct atttgagaga 180 ccccacacaa tgcccaaata cttactgggc tctgtgaata agtctgtggt tcctgacttg 240 gaataccaac acaagttcac catgatgcca cccaatgcat ctctgcttat caacccactg 300 cagttccctg atgaaggcaa ttacatcgtg aaggtcaaca ttcagggaaa tggaactcta 360 tctgccagtc agaagataca agtcacggtt gatgatcctg tcacaaagcc agtggtgcag 420 attcatcctc cctctggggc tgtggagtat gtggggaaca tgaccctgac atgccatgtg 480 gaagggggca ctcggctagc ttaccaatgg ctaaaaaatg ggagacctgt ccacaccagc 540 tccacctact ccttttctcc ccaaaacaat acccttcata ttgctccagt aaccaaggaa 600 gacattggga attacagctg cctggtgagg aaccctgtca gtgaaatgga aagtgatatc 660 attatgccca tcatatatta tggaccttat ggacttcaag tgaattctga taaagggcta 720 aaagtagggg aagtgtttac tgttgacctt ggagaggcca tcctatttga ttgttctgct 780 gattctcatc cccccaacac ctactcctgg attaggagga ctgacaatac tacatatatc 840 attaagcatg ggcctcgctt agaagttgca tctgagaaag tagcccagaa gacaatggac 900 tatgtgtgct gtgcttacaa caacataacc ggcaggcaag atgaaactca tttcacagtt 960 atcatcactt ccgtaggact ggagaagctt gcacagaaag gaaaatcatt gtcaccttta 1020 gcaagtataa ctggaatatc actatttttg attatatcca tgtgtcttct cttcctatgg 1080 aaaaaatatc aaccctacaa agttataaaa cagaaactag aaggcaggcc agaaacagaa 1140 tacaggaaag ctcaaacatt ttcaggccat gaagatgctc tggatgactt cggaatatat ' 1200 gaatttgttg cttttccaga tgtttctggt gtttccagga tcccaagcag gtctgttcca 1260 gcctctgatt gtgtatcggg gcaagatttg cacagtacag tgtatgaagt tattcagcac 1320 atccctgccc agcagcaaga ccatccagag ggaccggtcg ccaccatggt gagcaagggc 1380 gaggagctgt tcaccggggt ggtgcccatc ctggtcgagc tggacggcga cgtaaacggc 1440 cacaagttca gcgtgtccgg cgagggcgag ggcgatgcca cctacggcaa gctgaccctg 1500 aagttcatct gcaccaccgg caagctgccc gtgccctggc ccaccctcgt gaccaccctg 1560 acctacggcg tgcagtgctt cagccgctac cccgaccaca tgaagcagca cgacttcttc 1620 aagtccgcca tgcccgaagg ctacgtccag gagcgcacca tcttcttcaa ggacgacggc 1680 aactacaaga cccgcgccga ggtgaagttc gagggcgaca ccctggtgaa ccgcatcgag 1740 ctgaagggca tcgacttcaa ggaggacggc aacatcctgg ggcacaagct ggagtacaac 1800 tacaacagcc acaacgtcta tatcatggcc gacaagcaga agaacggcat caaggtgaac 1860 ttcaagatcc gccacaacat cgaggacggc agcgtgcagc tcgccgacca ctaccagcag 1920 aacaccccca tcggcgacgg ccccgtgctg ctgcccgaca accactacct gagcacccag 1980 tccgccctga gcaaagaccc caacgagaag cgcgatcaca tggtcctgct ggagttcgtg 2040 accgccgccg ggatcactct cggcatggac gagctgtaca agtaa 2085 <210> 83 <211 >2373

<212> DNA <213> Homo Sapiens <400> 83 atggcatggc ccaaactgcc cgcaccttgg ctgctgctct gcacctggct cccagcaggg 60 tgcctgtcct tgcttgtgac ggtccagcac acagaacgct atgtcaccct gtttgcctct 120 atcatcctca aatgtgacta caccacctct gcccagctcc aggacgtggt ggtgacatgg 180 cgcttcaagt ccttctgcaa ggaccctatc tttgactact actcagcgtc ataccaggca 240 gctttatccc tgggccagga cccatccaat gactgcaacg acaaccagcg ggaagttcgc 300 atagtggccc agcggcgggg gcagaatgag cccgtgctgg gggtagatta ccggcagcgc 360 aagatcacca tccagaaccg agcagatctc gtgataaatg aagtgatgtg gtgggaccat 420 ggagtgtatt actgcaccat tgaggctcca ggggacacat caggagaccc cgataaggaa 480 gtaaagctca tcgtcctaca ctggctgaca gtgatcttca tcatcctggg agccctcctc 540 ctcctgctgc tgattggagt gtgctggtgc cagtgctgtc ctcagtattg ctgctgctat 600 atccgctgtc cctgctgtcc tgcccactgc tgctgtcctg aggaagccct ggcccgccac 660 cgctacatga agcaggccca ggccctaggt cctcagatga tgggaaaacc cctgtactgg 720 ggggcggaca ggagctccca ggtttcatct tatccaatgc acccgctgct gcagcgagat 780 ttgtccctgc ggtccagcct cccgcagatg ccaatgsccc agaccaccaa tcagcctccc 840 atcgccaatg gtgtcctgga gtatttggag aaagaactgc ggaacctcaa cctggcccag 900 cctctgcccc ctgacctcaa aggcagattt ggccatccct gcagcatgct gtcctccctg 960 ggctctgagg tcgtggaacg cagaatcatc cacctgcccc cactgatcag agacctgtca 1020 tcctcaagga ggaccagtga ctccctgcac cagcagtggc tcaccccaat tccctccagg 1080 ccctgggatc tgagggaggg gagaagccac caccattacc ctgatttcca ccaggagctc 1140 caggaccggg ggccaaagtc ttgggcattg gaaagaaggg agttggaccc atcgtggagt 1200 ggaaggcacc gtagctctag gctgaatggg tcacccatac actggtcaga cagggacagc 1260 ctaagcgatg tcccctcatc cagtgaggca cgctggcggc cgagccaccc tcctttcagg 1320 agccgctgtc aggagaggcc ccgcaggccc agcccccggg agagcactca gaggcacggg 1380 agacgacgca ggcaccgcag ctactctcct cccttgccct ccggcctcag ttcctggagc 1440 tctgaagagg acaaggagag gcagccccag agctggcggg cccaccgccg cggctcgcac 1500 tccccacact ggcccgagga gaagccgcct agctaccgct cactggatat cactccaggc 1560 aagaatagca ggaaaaaagg gagtgtggag aggcgctcgg agaaagacag ctctcatagt 1620 ggaaggagtg tggtcattgg accggtcgcc accatggtga gcaagggcga ggagctgttc 1680 accggggtgg tgcccatcct ggtcgagctg gacggcgacg taaacggcca caagttcagc 1740 gtgtccggcg agggcgaggg cgatgccacc tacggcaagc tgaccctgaa gttcatctgc 1800 accaccggca agctgcccgt gccctggccc accctcgtga ccaccctgac ctacggcgtg 1860 cagtgcttca gccgctaccc cgaccacatg aagcagcacg acttcttcaa gtccgccatg 1920 cccgaaggct acgtccagga gcgcaccatc ttcttcaagg acgacggcaa ctacaagacc 1980 cgcgccgagg tgaagttcga gggcgacacc ctggtgaacc gcatcgagct gaagggcatc 2040 gacttcaagg aggacggcaa catcctgggg cacaagctgg agtacaacta caacagccac 2100 aacgtctata tcatggccga caagcagaag aacggcatca aggtgaactt caagatccgc 2160 cacaacatcg aggacggcag cgtgcagctc gccgaccact accagcagaa cacccccatc 2220 ggcgacggcc ccgtgctgct gcccgacaac cactacctga gcacccagtc cgccctgagc 2280 aaagacccca acgagaagcg cgatcacatg gtcctgctgg agttcgtgac cgccgccggg 2340 atcactctcg gcatggacga gctgtacaag taa 2373 <210> 84 <211> 2241

<212> DNA <213> Homo Sapiens <400> 84 atggcatggc ccaaactgcc cgcaccttgg ctgctgctct gcacctggct cccagcaggg 60 tgcctgtcct tgcttgtgac ggtccagcac acagaacgct atgtcaccct gtttgcctct 120 atcatcctca aatgtgacta caccacctct gcccagctco aggacgtggt ggtgacatgg 180 cgcttcaagt ccttctgcaa ggaccctatc tttgactact actcagcgtc ataccaggca 240 gctttatccc tgggccagga cccatccaat gactgcaacg acaaccagcg ggaagttcgc 300 atagtggccc agcggcgggg gcagaatgag cccgtgctgg gggtagatta ccggcagcgc 360 aagatcacca tccagaaccg agcagatctc gtgataaatg aagtgatgtg gtgggaccat 420 ggagtgtatt actgcaccat tgaggctcca ggggacacat caggagaccc cgataaggaa 480 gtaaagctca tcgtcctaca ctggctgaca gtgatcttca tcatcctggg agccctcctc 540 ctcctgctgc tgattggagt gtgctggtgc cagtgctgtc ctcagtattg ctgctgctat 600 atccgctgtc cctgctgtcc tgcccactgc tgctgtcctg aggaagattt gtccctgccg 660 tccagcctcc cgcagatgcc aatgacccag accaccaatc agcctcccat cgccaatggt 720 gtcctggagt atttggagaa agaactgcgg aacctcaacc tggcccagcc tctgccccct 780 gacctcaaag gcagatttgg ccatccctgc agcatgctgt cctccctggg ctctgaggtc 840 gtggaacgca gaatcatcca cctgccccca ctgatcagag acctgtcatc ctcaaggagg 900 accagtgact ccctgcacca gcagtggctc accccaattc cctccaggcc ctgggatctg 960 agggagggga gaagccacca ccattaccct gatttccacc aggagctcca ggaccggggg 1020 ccaaagtctt gggcattgga aagaagggag ttggacccat cgtggagtgg aaggcaccgt 1080 agctctaggc tgaatgggtc acccatacac tggtcagaca gggacagcct aagcgatgtc 1140 ccctcatcca gtgaggcacg ctggcggccg agccaccctc ctttcaggag ccgctgtcag 1200 gagaggcccc gcaggcccag cccccgggag agcactcaga ggcacgggag acgacgcagg 1260 caccgcagct actctcctcc cttgccctcc ggcctcagtt cctggagctc tgaagaggac 1320 aaggagaggc agccccagag ctggcgggcc caccgccgcg gctcgcactc cccacactgg 1380 cccgaggaga agccgcctag ctaccgctca ctggatatca ctccaggcaa gaatagcagg 1440 aaaaaaggga gtgtggagag gcgctcggag aaagacagct ctcatagtgg aaggagtgtg 1500 gtcattggac cggtcgccac catggtgagc aagggcgagg agctgttcac cggggtggtg 1560 cccatcctgg tcgagctgga cggcgacgta aacggccaca agttcagcgt gtccggcgag 1620 ggcgagggcg atgccaccta cggcaagctg accctgaagt tcatctgcac caccggcaag 1680 ctgcccgtgc cctggcccac cctcgtgacc accctgacct acggcgtgca gtgcttcagc 1740 cgctaccccg accacatgaa gcagcacgac ttcttcaagt ccgccatgcc cgaaggctac 1800 gtccaggagc gcaccatctt cttcaaggac gacggcaact acaagacccg cgccgaggtg 1860 aagttcgagg gcgacaccct ggtgaaccgc atcgagctga agggcatcga cttcaaggag 1920 gacggcaaca tcctggggca caagctggag tacaactaca acagccacaa cgtctatatc 1980 atggccgaca agcagaagaa cggcatcaag gtgaacttca agatccgcca caacatcgag 2040 gacggcagcg tgcagctcgc cgaccactac cagcagaaca cccccatcgg cgacggcccc 2100 gtgctgctgc ccgacaacca ctacctgagc acccagtccg ccctgagcaa agaccccaac 2160 gagaagcgcg atcacatggt cctgctggag ttcgtgaccg ccgccgggat cactctcggc 2220 atggacgagc tgtacaagta a 2241 <210> 85 <211 >2082

<212> DNA <213> Homo Sapiens <400> 85 atggtgttcg cattttggaa ggtctttctg atcctaagct gccttgcagg tcaggttagt 60 gtggtgcaag tgaccatccc agacggtttc gtgaacgtga ctgttggatc taatgtcact 120 ctcatctgca tctacaccac cactgtggcc tcccgagaac agctttccat ccagtggtct 180 ttcttccata agaaggagat ggagccaatt tctcacagct cgtgcctcag tactgagggt 240 atggaggaaa aggcagtcag tcagtgtcta aaaatgacgc acgcaagaga cgctcgggga 300 agatgtagct ggacctctga gtctccttgg gaggagggga agtggccaga tgttgaggct 360 gtgaagggca ctcttgatgg acagcaggct gaactccaga tttacttttc tcaaggtgga 420 caagctgtag ccatcgggca atttasagat cgaattacag ggtccaacga tccaggtaat 480 gcatctatca ctatctcgca tatgcagcca gcagacagtg gaatttacat ctgcgatgtt 540 aacaaccccc cagactttct cggccaaaac caaggcatcc tcaacgtcag tgtgttagtg 600 aaaccttcta agcccctttg tagcgttcaa ggaagaccag aaactggcca cactatttcc 660 ctttcctgtc tctctgcgct tggaacacct tcccctgtgt actactggca taaacttgag 720 ggaagagaca tcgtgccagt gaaagaaaac ttcaacccaa ccaccgggat tttggtcatt 780 ggaaatctga caaattttga acaaggttat taccagtgta ctgccatcaa cagacttggc 840 aatagttcct gcgaaatcga tctcacttct tcacatccag aagttggaat cattgttggg 900 gccttgattg gtagcctggt aggtgccgcc atcatcatct ctgttgtgtg cttcgcaagg 960 aataaggcaa aagcaaaggc aaaagaaaga aattctaaga ccatcgcgga acttgagcca 1020 atgacaaaga taaacccaag gggagaaagc gaagcaatgc caagagaaga cgctacccaa 1080 ctagaagtaa ctctaccatc ttccattcat gagactggcc ctgataccat ccaagaacca 1140 gactatgagc caaagcctac tcaggagcct gccccagagc ctgccccagg atcagagcct 1200 atggcagtgc ctgaccttga catcgagctg gagctggagc cagaaacgca gtcggaattg 1260 gagccagagc cagagccaga gccagagtca gagcctgggg ttgtagttga gcccttaagt 1320 gaagatgaaa agggagtggt taaggcagga ccggtcgcca ccatggtgag caagggcgag 1380 gagctgttca ccggggtggt gcccatcctg gtcgagctgg acggcgacgt aaacggccac 1440 aagttcagcg tgtccggcga gggcgagggc gatgccacct acggcaagct gaccctgaag 1500 ttcatctgca ccaccggcaa gctgcccgtg ccctggccca ccctcgtgac caccctgacc 1560 tacggcgtgc agtgcttcag ccgctacccc gaccacatga agcagcacga cttcttcaag 1620 tccgccatgc ccgaaggcta cgtccaggag cgcaccatct tcttcaagga cgacggcaac 1680 tacaagaccc gcgccgaggt gaagttcgag ggcgacaccc tggtgaaccg catcgagctg 1740 aagggcatcg acttcaagga ggacggcaac atcctggggc acaagctgga gtacaactac 1800 aacagccaca acgtctatat catggccgac aagcagaaga acggcatcaa ggtgaacttc I860 aagatccgcc acaacatcga ggacggcagc gtgcagctcg ccgaccacta ccagcagaac 1920 acccccatcg gcgacggccc cgtgctgctg cccgacaacc actacctgag cacccagtcc 1980 gccctgagca aagaccccaa cgagaa'gcgc gatcacatgg tcctgctgga gttcgtgacc 2040 gccgccggga tcactctcgg catggacgag ctgtacaagt aa 2082 <210> 86 <211 >2004

<212> DNA <213> Homo Sapiens <400> 86 cccaccrgca rccacaccac cactgtggcc ccccgagaac agcr.cr.ccar. ccagrggrcc lau ttcttccata agaaggagat ggagccaatt tctcacagct cgtgcctcag tactgagggt 240 atggaggaaa aggcagtcag tcagtgtcta aaaatgacgc acgcaagaga cgctcgggga 300 agatgtagct ggacctctga gatttacttt tctcaaggtg gacaagctgt agccatcggg 360 caatttaaag atcgaattac agggtccaac gatccaggta atgcatctat cactatctcg 420 catatgcagc cagcagacag tggaatttac atctgcgatg ttaacaaccc cccagacttt 480 ctcggccaaa accaaggcat cctcaacgtc agtgtgttag tgaaaccttc taagcccctt 540 tgtagcgttc aaggaagacc agaaactggc cacactattt ccctttcctg tctctctgcg 600 cttggaacac cttcccctgt gtactactgg cataaacttg agggaagaga catcgtgcca 660 gtgaaagaaa acttcaaccc aaccaccggg attttggtca ttggaaatct gacaaatttt 720 gaacaaggtt attaccagtg tactgccatc aacagacttg gcaatagttc ctgcgaaatc 780 gatctcactt cttcacatcc agaagttgga atcattgttg gggccttgat tggtagcctg 840 gtaggtgccg ccatcatcat· ctctgttgtg tgcttcgcaa ggaataaggc aaaagcaaag 900 gcaaaagaaa gaaattctaa gaccatcgcg gaacttgagc caatgacaaa gataaaccca 960 aggggagaaa gcgaagcaat gccaagagaa gacgctaccc aactagaagt aactctacca 1020 tcttccattc atgagactgg ccctgatacc atccaagaac cagactatga gccaaagcct 1080 actcaggagc ctgccccaga gcctgcccca ggatcagagc ctatggcagt gcctgacctt 1140 gacatcgagc tggagctgga gccagaaacg cagtcggaat tggagccaga gccagagcca 1200 gagccagagt cagagcctgg ggttgtagtt gagcccttaa gtgaagatga aaagggagtg 1260 gttaaggcag gaccggtcgc caccatggtg agcaagggcg aggagctgtt caccggggtg 1320 gtgcccatcc tggtcgagct ggacggcgac gtaaacggcc acaagttcag cgtgtccggc 1380 gagggcgagg gcgatgccac ctacggcaag ctgaccctga agttcatctg caccaccggc 1440 aagctgcccg tgccctggcc caccctcgtg accaccctga cctacggcgt gcagtgcttc 1500 agccgctacc ccgaccacat gaagcagcac gacttcttca agtccgccat gcccgaaggc 1560 tacgtccagg agcgcaccat cttcttcaag gacgacggca actacaagac ccgcgccgag 1620 gtgaagttcg agggcgacac cctggtgaac cgcatcgagc tgaagggcat cgacttcaag 1680 gaggacggca acatcctggg gcacaagctg gagtacaact acaacagcca caacgtctat 1740 atcatggccg acaagcagaa gaacggcatc aaggtgaact tcaagatccg ccacaacatc 1800 gaggacggca gcgtgcagct cgccgaccac taccagcaga acacccccat cggcgacggc 1860 cccgtgctgc tgcccgacaa ccactacctg agcacccagt ccgccctgag caaagacccc 1920 aacgagaagc gcgatcacat ggtcctgctg gagttcgtga ccgccgccgg gatcactctc 1980 ggcatggacg agctgtacaa gtaa 2004 <210> 87 <211> 331

<212> PRT <213> Homo Sapiens <400> 87

Met Gin Lys Val Thr Leu Gly Leu Leu Val Pile Leu Ala Gly Phe Pro 15 10 15

Val Leu Asp Ala Asn Asp Leu Glu Asp Lys Asn Ser Pro Phe Tyr Tyr 20 25 30

Asp Trp His Ser Leu Gin Val Gly Gly Leu lie Cys Ala Gly Val Leu 35 40 45

Cys Ala Met Gly Ile Ile He Val Met Ser Ala Lys Cys Lys Cys Lys 50 55 60

Phe Gly Gin Lys Ser Gly His His Pro Gly Glu Thr Pro Pro Leu lie 65 70 75 80

Thr Pro Gly Ser Ala Gin Ser Gly Pro Val Ala Thr Met Val Ser Lys 85 90 95

Gly Glu Glu Leu Phe Thr Gly Val Val Pro lie Leu Val Glu Leu Asp 100 105 110

Gly Asp Val Asn Gly His Lys Phe Ser Val Ser Gly Glu Gly Glu Gly 115 120 125

Asp Ala Thr Tyr Gly Lys Leu Thr Leu Lys Phe lie Cys Thr Thr Gly 130 135 140

Lys Leu Pro Val Pro Trp Pro Thr Leu Val Thr Thr Leu Thr Tyr Gly 145 150 155 160

Val Gin Cys Phe Ser Arg Tyr Pro Asp His Met Lys Gin His Asp Phe 165 170 175

Phe Lys Ser Ala Met Pro Glu Gly Tyr Val Gin Glu Arg Thr lie Phe 180 185 190

Phe Lys Asp Asp Gly Asn Tyr Lys Thr Arg Ala Glu Val Lys Phe Glu 195 200 205

Gly Asp Thr Leu Val Asn Arg lie Glu Leu Lys Gly lie Asp Phe Lys 210 215 220

Glu Asp Gly Asn lie Leu Gly His Lys Leu Glu Tyr Asn Tyr Asn Ser 225 230 235 240

His Asn Val Tyr lie Met Ala Asp Lys Gin Lys Asn Gly lie Lys Val 245 250 255

Asn Phe Lys lie Arg His Asn lie Glu Asp Gly Ser val Gin Leu Ala 260 265 270

Asp His Tyr Gin Gin Asn Thr Pro lie Gly Asp Gly Pro Val Leu Leu 275 280 285

Pro Asp Asn His Tyr Leu Ser Thr Gin Ser Ala Leu Ser Lys Asp Pro 290 · 295 300

Asn Glu Lys Arg Asp His Met Val Leu Leu Glu Phe Val Thr Ala Ala 305 310 315 320

Gly lie Thr Leu Gly Met Asp Glu Leu Tyr Lys 325 330 <210> 88 <211 > 360

<212> PRT <213> Homo Sapiens <400> 88

Met Gin Lys Val Thr Leu Gly Leu Leu Val Pile Leu Ala Gly Phe Pro 15 10 15

Val Leu Asp Ala Asn. Asp Leu Glu Asp Lys Asn Ser Pro Phe Tyr Xyr 20 25 30

Gly Ala Pro Tyr Ile Phe Val Lys Arg Met Gly Gly Gin Met Lys Arg 35 40 45

Thr Gin Ala Gly Thr Glu Val Pro Ser Thr Phe Leu Leu Asp Trp His 50 55 60

Ser Leu Gin Val Gly Gly Leu lie Cys Ala Gly Val Leu Cys Ala Met 65 70 75 80

Gly lie lie lie Val Met Ser Ala Lys Cys Lys Cys Lys Phe Gly Gin 85 90 95

Lys Ser Gly His His Pro Gly Glu Thr Pro Pro Leu lie Thr Pro Gly 100 105 110

Ser Ala Gin Ser Gly Pro Val Ala Thr Met Val Ser Lys Gly Glu Glu 115 120 125

Leu Phe Thr Gly val Val Pro lie Leu Val Glu Leu Asp Gly Asp Val 130 135 140

Asn Gly His Lys Phe Ser Val Ser Gly Glu Gly Glu Gly Asp Ala Thr 145 150 155 160

Tyr Gly Lys Leu Thr Leu Lys Phe lie Cys Thr Thr Gly Lys Leu Pro 165 170 175

Val Pro Trp Pro Thr Leu Val Thr Thr Leu Thr Tyr Gly Val Gin Cys 180 . 185 190

Phe Ser Arg Tyr Pro Asp His Met Lys Gin His Asp Phe Phe Lys Ser 195 200 205

Ala Met Pro Glu Gly Tyr Val Gin Glu Arg Thr lie Phe Phe Lys Asp 210 215 220

Asp Gly Asn Tyr Lys Thr Arg Ala Glu Val Lys Phe Glu Gly Asp Thr 225 230 235 240

Leu Val Asn Arg lie Glu Leu Lys Gly lie Asp Phe Lys Glu Asp Gly 245 250 255

Asn He Leu Gly His Lys Leu Glu Tyr Asn Tyr Asn Ser His Asn Val 260 265 270

Tyr lie Met Ala Asp Lys Gin Lys Asn Gly lie Lys Val Asn Phe Lys 275 280 285

He Arg His Asn lie Glu Asp Gly Ser Val Gin Leu Ala Asp His Tyr 290 295 300

Gin Gin Asn Thr Pro He Gly Asp Gly Pro Val Leu Leu Pro Asp Asn 305 310 315 320

His Tyr Leu Ser Thr Gin Ser Ala Leu Ser Lys Asp Pro Asn Glu Lys 325 330 335

Arg Asp His Met Val Leu Leu Glu Phe Val Thr Ala Ala Gly lie Thr 340 345 350

Leu Gly Met Asp Glu Leu Tyr Lys 355 360 <210> 89 <211 >456

<212> PRT <213> Homo Sapiens <400> 89

Met Arg Pro Leu Pro Ser Gly Arg Arg Lys Thr Arg Gly Ile Ser Leu 15 10 15

Gly Leu Phe Ala Leu Cys Leu Ala Ala Ala Arg Cys Leu Gin Ser Gin 20 25 30

Gly Val Ser Leu Tyr Ile Pro Gin Ala Thr Ile Asn Ala Thr Val Lys 35 40 45

Glu Asp Ile Leu Leu Ser Val Glu Tyr Ser Cys His Gly Val Pro Thr 50 55 60

Ile Glu Trp Thr Tyr Ser Ser Asn Trp Gly Thr Gin Lys Ile Val Glu 65 7 0 75 80

Trp Lys Pro Gly Thr Gin Ala Asn ile Ser Gin Ser His Lys Asp Arg 85 90 95

Val Cys Thr Phe Asp Asn Gly Ser Ile Gin Leu Phe Ser Val Gly Val 100 105 110

Arg Asp Ser Gly Tyr Tyr Val Ile Thr Val Thr Glu Arg Leu Gly Ser 115 120 125

Ser Gin Phe Gly Thr Ile Val Leu His Val Ser Glu Ile Leu Tyr Glu 130 135 140

Asp Leu His Phe Val Ala Val Ile Leu Ala Phe Leu Ala Ala Val Ala 145 150 155 160

Ala Val Leu Ile Ser Leu Met Trp Val Cys Asn Lys Cys Ala Tyr Lys 165 170 175

Phe Gin Arg Lys Arg Arg His Lys Leu Lys Glu Ser Thr Thr Glu Glu 180 185 190

Ile Glu Leu Glu Asp Val Glu Cys Arg Ile Leu Gin Ser Thr Val Pro 195 200 205

Arg Ala Arg Asp Pro Pro Val Ala Thr Met Val Ser Lys Gly Glu Glu 210 215 220

Leu Phe Thr Gly Val Val Pro Ile Leu Val Glu Leu Asp Gly Asp Val 225 230 235 240

Asn Gly His Lys Phe Ser Val Ser Gly Glu Gly Glu Gly Asp Ala Thr 245 250 255

Tyr Gly Lys Leu Thr Leu Lys Phe Ile Cys Thr Thr Gly Lys Leu Pro 260 265 270

Val Pro Trp Pro Thr Leu Val Thr Thr Leu Thr Tyr Gly Val Gin Cys 275 280 285

Phe Ser Arg Tyr Pro Asp His Met Lys Gin His Asp Phe Phe Lys Ser 290 295 300

Ala Met Pro Glu Gly Tyr Val Gin Glu Arg Thr Ile Phe Phe Lys Asp 305 310 315 320

Asp Gly Asn Tyr Lys Thr Arg Ala Glu Val Lys Phe Glu Gly Asp Thr 325 330 335

Leu Val Asn Arg Ile Glu Leu Lys Gly Ile Asp Phe Lys Glu Asp Gly 340 345 350

Asn Ile Leu Gly His Lys Leu Glu Tyr Asn Tyr Asn Ser His Asn Val 355 360 365

Tyr Ile Met Ala Asp Lys Gin Lys Asn Gly Ile Lys Val Asn Phe Lys 370 375 3S0 ile Arg His Asn ile Glu Asp Gly Ser Val Gin Leu Ala Asp His Tyr 385 390 395 400

Gin Gin Asn Thr Pro Ile Gly Asp Gly Pro Val Leu Leu Pro Asp Asn 405 410 415

His Tyr Leu Ser Thr Gin Ser Ala Leu Ser Lys Asp Pro Asn Glu Lys 420 425 430

Arg Asp His Met Val Leu Leu Glu Phe Val Thr Ala Ala Gly Ile Thr 435 440 445

Leu Gly Met Asp Glu Leu Tyr Lys 450 455 <210> 90 <211 > 443

<212> PRT <213> Homo Sapiens <400> 90

Met Arg Pro Leu Pro Ser Gly Arg Arg Lys Thr Arg Gly Ile Ser Leu 15 10 15

Gly Leu Phe Ala Leu Cys Leu Ala Ala Ala Arg Cys Leu Gin Ser Gin 20 25 30

Gly Val Ser Leu Tyr Ile Pro Gin Ala Thr Ile Asn Ala Thr Val Lys 35 40 45

Glu Asp Ile Leu Leu Ser Val Glu Tyr Ser Cys His Gly Val Pro Thr 50 55 60

Ile Glu Trp Thr Tyr Ser Ser Asn Trp Gly Thr Gin Lys Ile Val Glu 65 70 75 80

Trp Lys Pro Gly Thr Gin Ala Asn Ile Ser Gin Ser His Lys Asp Arg 85 90 95

Val Cys Thr Phe Asp Asn Gly Ser Ile Gin Leu Phe Ser Val Gly Val 100 105 110

Arg Asp Ser Gly Tyr Tyr Val Ile Thr Val Thr Glu Arg Leu Gly Ser 115 120 125

Ser Gin Phe Gly Thr Ile Val Leu His Val Ser Glu Ile Leu Tyr Glu 130 135 140

Asp Leu His Phe Val Ala Val Ile Leu Ala Phe Leu Ala Ala Val Ala 145 150 155 160

Ala Val Leu Ile Ser Leu Met Trp Val Cys Asn Lys Cys Ala Tyr Lys 165 170 175

Phe Gin Arg Lys Arg Arg His Lys Leu Lys Gly Asn Pro Leu Gly Leu 180 185 190

Val Ile Ile His Glu Trp Phe Gly Pro Val Ala Thr Met Val Ser Lys 195 200 205

Gly Glu Glu Leu Phe Thr Gly Val Val Pro Ile Leu Val Glu Leu Asp 210 215 220

Gly Asp Val Asn Gly His Lys Phe Ser Val Ser Gly Glu Gly Glu Gly 225 230 235 240

Asp Ala Thr Tyr Gly Lys Leu Thr Leu Lys Phe Ile Cys Thr Thr Gly 245 250 255

Lys Leu Pro Val Pro Trp Pro Thr Leu Val Thr Thr Leu Thr Tyr Gly 260 265 270

Val Gin Cys Phe Ser Arg Tyr Pro Asp His Met Lys Gin His Asp Phe 275 280 285

Phe Lys Ser Ala Met Pro Glu Gly Tyr Val Gin Glu Arg Thr Ile Phe 290 295 300

Phe Lys Asp Asp Gly Asn Tyr Lys Thr Arg Ala Glu Val Lys Phe Glu 305 310 315 320

Gly Asp Thr Leu Val Asn Arg Ile Glu Leu Lys Gly Ile Asp Phe Lys 325 330 335

Glu Asp Gly Asn Ile Leu Gly His Lys Leu Glu Tyr Asn Tyr Asn Ser 340 345 350

His Asn Val Tyr Ile Met Ala Asp Lys Gin Lys Asn Gly Ile Lys Val 355 360 365

Asn Phe Lys ile Arg His Asn Ile Glu Asp Gly Ser Val Gin Leu Ala 370 375 380

Asp His Tyr Gin Gin Asn Thr Pro Ile Gly Asp Gly Pro Val Leu Leu 385 390 395 400

Pro Asp Asn His Tyr Leu Ser Thr Gin Ser Ala Leu Ser Lys Asp Pro 405 410 415

Asn Glu Lys Arg Asp His Met Val Leu Leu Glu Phe Val Thr Ala Ala 420 425 430

Gly Ile Thr Leu Gly Met Asp Glu Leu Tyr Lys 435 440 <210>91 <211> 510

<212> PRT <213> Homo Sapiens <400> 91

Met Asp Arg Val Leu Leu Arg Trp Ile Ser Leu Phe Trp Leu Thr Ala 15 10 15

Met Val Glu Gly Leu Gin Val Thr Val Pro Asp Lys Lys Lys Val Ala 20 25 30

Met Leu Phe Gin Pro Thr Val Leu Arg Cys His Phe Ser Thr Ser Ser 35 40 45

His Gin Pro Ala Val Val Gin Trp Lys Phe Lys Ser Tyr Cys Gin Asp 50 55 60

Arg Met Gly Glu Ser Leu Gly Met Ser Ser Thr Arg Ala Gin Ser Leu 65 70 75 80

Ser Lys Arg Asn Leu Glu Trp Asp Pro Tyr Leu Asp Cys Leu Asp Ser 85 90 95

Arg Arg Thr Val Arg Val Val Ala Ser Lys Gin Gly Ser Thr Val Thr 100 105 110

Leu Gly Asp Phe Tyr Arg Gly Arg Glu Ile Thr Ile Val His Asp Ala 115 120 125

Asp Leu Gin Ile Gly Lys Leu Met Trp Gly Asp Ser Gly Leu Tyr Tyr 130 135 140

Cys Ile Ile Thr Thr Pro Asp Asp Leu Glu Gly Lys Asn Glu Asp Ser 145 150 155 160

Val Glu Leu Leu Val Leu Gly Arg Thr Gly Leu Leu Ala Asp Leu Leu „ 165 170 175

Pro Ser Phe Ala Val Glu Ile Met Pro Glu Trp Val Phe Val Gly Leu 180 185 190

Val Leu Leu Gly Val Phe Leu Phe Phe Val Leu Val Gly Ile Cys Trp 195 200 205

Cys Gin Cys Cys Pro His Ser Cys Cys Cys Tyr Val Arg Cys Pro Cys 210 215 220

Cys Pro Asp Ser Cys Cys Cys Pro Gin Ala Cys Glu Tyr Ser Asp Arg 225 230 235 240

Trp Gly Asp Arg Ala Ile Glu Arg Asn Val Tyr Leu Ser Thr Arg Ile 245 250 255

Leu Gin Ser Thr Val Pro Arg Ala Arg Asp Pro Pro Val Ala Thr Met 260 265 270

Val Ser Lys Gly Glu Glu Leu Phe Thr Gly Val Val Pro Ile Leu Val 275 280 285

Glu Leu Asp Gly Asp Val Asn Gly His Lys Phe Ser Val Ser Gly Glu 290 295 300

Gly Glu Gly Asp Ala Thr Tyr Gly Lys Leu Thr Leu Lys Phe Ile Cys 305 310 315 320

Thr Thr Gly Lys Leu Pro Val Pro Trp Pro Thr Leu Val Thr Thr Leu 325 330 335

Thr Tyr Gly Val Gin Cys Phe Ser Arg Tyr Pro Asp His Met Lys Gin 340 345 350

His Asp Phe Phe Lys Ser Ala Met Pro Glu Gly Tyr Val Gin Glu Arg 355 360 365

Thr Ile Phe Phe Lys Asp Asp Gly Asn Tyr Lys Thr Arg Ala Glu Val 370 375 380

Lys Phe Glu Gly Asp Thr Leu Val Asn Arg Ile Glu Leu Lys Gly Ile 385 390 395 400

Asp Phe Lys Glu Asp Gly Asn Ile Leu Gly His Lys Leu Glu Tyr Asn 405 410 415

Tyr Asn Ser His Asn Val Tyr Ile Met Ala Asp Lys Gin Lys Asn Gly 420 425 430

Ile Lys Val Asn Phe Lys Ile Arg His Asn Ile Glu Asp Gly Ser Val 435 440 445

Gin Leu Ala Asp His Tyr Gin Gin Asn Thr Pro Ile Gly Asp Gly Pro 450 455 460

Val Leu Leu Pro Asp Asn His Tyr Leu Ser Thr Gin Ser Ala Leu Ser 465 470 475 480

Lys Asp Pro Asn Glu Lys Arg Asp His Met Val Leu Leu Glu Phe Val 485 490 495

Thr Ala Ala Gly Ile Thr Leu Gly Met Asp Glu Leu Tyr Lys 500 505 510 <210> 92 <211 > 694

<212> PRT <213> Homo Sapiens <400> 92

Met Trp Leu Lys Val Phe Thr Thr Phe Leu Ser Phe Ala Thr Gly Ala 15 10 15

Cys Ser Gly Leu Lys Val Thr Val Pro Ser His Thr Val His Gly Val 20 25 30

Arg Gly Gin Ala Leu Tyr Leu Pro Val His Tyr Gly Phe His Thr Pro 35 40 45

Ala Ser Asp Ile Gin Ile Ile Trp Leu Phe Glu Arg Pro His Thr Met 50 55 60

Pro Lys Tyr Leu Leu Gly Ser Val Asn Lys Ser Val Val Pro Asp Leu 65 70 75 80

Glu Tyr Gin His Lys Phe Thr Met Met Pro Pro Asn Ala Ser Leu Leu 85 90 95

Ile Asn Pro Leu Gin Phe Pro Asp Glu Gly Asn Tyr Ile Val Lys Val 100 105 110

Asn Ile Gin Gly Asn Gly Thr Leu Ser Ala Ser Gin Lys lie Gin Val 115 120 125

Thr Val Asp Asp Pro Val Thr Lys Pro Val Val Gin lie His Pro Pro 130 135 140

Ser Gly Ala Val Glu Tyr Val Gly Asn Met Thr Leu Thr Cys His Val 145 150 155 160

Glu Gly Gly Thr Arg Leu Ala Tyr Gin Trp Leu Lys Asn Gly Arg Pro 165 170 175

Val His Thr Ser Ser Thr Tyr Ser Phe Ser Pro Gin Asn Asn Thr Leu 180 185 190

His lie Ala Pro Val Thr Lys Glu Asp lie Gly Asn Tyr Ser Cys Leu 195 200 205

Val Arg Asn Pro Val Ser Glu Met Glu Ser Asp lie lie Met Pro lie 210 215 220 lie Tyr Tyr Gly Pro Tyr Gly Leu Gin Val Asn Ser Asp Lys Gly, Leu 225 230 235 240

Lys Val Gly Glu Val Phe Thr Val Asp Leu Gly Glu Ala lie Leu Phe 245 250 255

Asp Cys Ser Ala Asp Ser His Pro Pro Asn Thr Tyr Ser Trp lie Arg 260 265 270

Arg Thr Asp Asn Thr Thr Tyr lie lie Lys His Gly Pro Arg Leu Glu 275 280 285

Val Ala Ser Glu Lys Val Ala Gin Lys Thr Met Asp Tyr Val Cys Cys 290 295 300

Ala Tyr Asn Asn Ile Thr Gly Arg Gin Asp Glu Thr His Phe Thr Val 305 310 315 320

Ile Ile Thr Ser val Gly Leu Glu Lys Leu Ala Gin Lys Gly Lys Ser 325 330 335

Leu Ser Pro Leu Ala Ser Ile Thr Gly Ile Ser Leu Phe Leu Ile Ile 340 345 350

Ser Met Cys Leu Leu Phe Leu Trp Lys Lys Tyr Gin Pro Tyr Lys Val 355 360 365

Ile Lys Gin Lys Leu Glu Gly Arg Pro Glu Thr Glu Tyr Arg Lys Ala 370 375 380

Gin Thr Phe Ser Gly His Glu Asp Ala Leu Asp Asp Phe Gly Ile Tyr 385 390 395 400

Glu Phe Val Ala Phe Pro Asp Val Ser Gly Val Ser Arg Ile Pro Ser 405 410 415

Arg Ser Val Prc Ala Ser Asp Cys Val Ser Gly Gin Asp Leu His Ser 420 425 430

Thr Val Tyr Glu Val Ile Gin His Ile Pro Ala Gin Gin Gin Asp His 435 440 445

Pro Glu Gly Pro Val Ala Thr Met Val Ser Lys Gly Glu Glu Leu Phe 450 455 460

Thr Gly Val Val Pro Ile Leu Val Glu Leu Asp Gly Asp Val Asn Gly 465 470 475 480

His Lys Phe Ser Val Ser Gly Glu Gly Glu Gly Asp Ala Thr Tyr Gly 485 490 495

Lys Leu Thr Leu Lys Phe Ile Cys Thr Thr Gly Lys Leu Pro Val Pro 500 505 510

Trp Pro Thr Leu Val Thr Thr Leu Thr Tyr Gly Val Gin Cys Phe Ser 515 520 525

Arg Tyr Pro Asp His Met Lys Gin His Asp Phe Phe Lys Ser Ala Met

Pro Glu Gly Tyr Val Gin Glu Arg Thr Ile Phe Phe Lys Asp Asp Gly 545 550 555 560

Asn Tyr Lys Thr Arg Ala Glu Val Lys Phe Glu Gly Asp Thr Leu Val 565 570 575

Asn Arg Ile Glu Leu Lys Gly Ile Asp Phe Lys Glu Asp Gly Asn Ile 580 585 590

Leu Gly His Lys Leu Glu Tyr Asn Tyr Asn Ser His Asn Val Tyr Ile 595 600 605

Met Ala Asp Lys Gin Lys Asn Gly Ile Lys Val Asn Phe Lys Ile Arg 610 615 620

His Asn Ile Glu Asp Gly Ser Val Gin Leu Ala Asp His Tyr Gin Gin 625 630 635 640

Asn Thr Pro Ile Gly Asp Gly Pro Val Leu Leu Pro Asp Asn His Tyr 645 650 655

Leu Ser Thr Gin Ser Ala Leu Ser Lys Asp Pro Asn Glu Lys Arg Asp 660 665 670

His Met Val Leu Leu Glu Phe Val Thr Ala Ala Gly Ile Thr Leu Gly 675 680 685

Met Asp Glu Leu Tyr Lys 690 <210> 93 <211> 790

<212> PRT <213> Homo Sapiens <400> 93

Met Ala Trp Pro Lys Leu Pro Ala Pro Trp Leu Leu Leu Cys Thr Trp 15 10 15

Leu Pro Ala Gly Cys Leu Ser Leu Leu Val Thr Val Gin His Thr Glu 20 25 30

Arg Tyr Val Thr Leu Phe Ala Ser Ile Ile Leu Lys Cys Asp Tyr Thr 35 40 45

Ttir Ser Ala Gin Leu Gin Asp Val Val Val Thr Trp Arg Phe Lys Ser 50 55 60

Phe Cys Lys Asp Pro Ile Phe Asp Tyr Tyr Ser Ala Ser Tyr Gin Ala 65 70 75 80

Ala Leu Ser Leu Gly Gin Asp Pro Ser Asn Asp Cys Asn Asp Asn Gin 85 90 95

Arg Glu Val Arg Ile Val Ala Gin Arg Arg Gly Gin Asn Glu Pro Val 100 105 110

Leu Gly Val Asp Tyr Arg Gin Arg Lys Ile Thr Ile Gin Asn Arg Ala 115 120 125

Asp Leu Val ile Asn Glu Val Met Trp Trp Asp His Gly Val Tyr Tyr 130 135 140

Cys Thr Ile Glu Ala Pro Gly Asp Thr Ser Gly Asp Pro Asp Lys Glu 145 150 155 160

Val Lys Leu Ile Val Leu His Trp Leu Thr Val Ile Phe ile ile Leu 165 170 175

Gly Ala Leu Leu Leu Leu Leu Leu Ile Gly Val Cys Trp Cys Gin Cys 180 185 190

Cys Pro Gin Tyr Cys Cys Cys Tyr Ile Arg Cys Pro Cys Cys Pro Ala 195 200 205

His Cys Cys Cys Pro Glu Glu Ala Leu Ala Arg His Arg Tyr Met Lys 210 215 220

Gin Ala Gin Ala Leu Gly Pro Gin Met Met Gly Lys Pro Leu Tyr Trp 225 230 235 240

Gly Ala Asp Arg Ser Ser Gin Val Ser Ser Tyr Pro Met His Pro Leu 245 250 255

Leu Gin Arg Asp Leu Ser Leu Arg Ser Ser Leu Pro Gin Met Pro Met 260 265 270

Thr Gin Thr Thr Asn Gin Pro Pro Ile Ala Asn Gly Val Leu Glu Tyr 275 280 285

Leu Glu Lys Glu Leu Arg Asn Leu Asn Leu Ala Gin Pro Leu Pro Pro 290 295 300

Asp Leu Lys Gly Arg Phe Gly His Pro Cys Ser Met Leu Ser Ser Leu 305 310 315 320

Gly Ser Glu Val Val Glu Arg Arg Ile Ile His Leu Pro Pro Leu Ile 325 330 335

Arg Asp Leu Ser Ser Ser Arg Arg Thr Ser Asp Ser Leu His Gin Gin 340 345 350

Trp Leu Thr Pro Ile Pro Ser Arg Pro Trp Asp Leu Arg Glu Gly Arg 355 360 365

Ser His His His Tyr Pro Asp Phe His Gin Glu Leu Gin Asp Arg Gly 370 375 380

Pro Lys Ser Trp Ala Leu Glu Arg Arg Glu Leu Asp Pro Ser Trp Ser 385 390 395 400

Gly Arg His Arg Ser Ser Arg Leu Asn Gly Ser Pro Ile His Trp Ser 405 410 415

Asp Arg Asp Ser Leu Ser Asp Val Pro Ser Ser Ser Giu Ala Arg Trp 420 425 430

Arg Pro Ser His Pro Pro Phe Arg Ser Arg Cys Gin Glu Arg Pro Arg 435 440 445

Arg Pro Ser Pro Arg Glu Ser Thr Gin Arg His Gly Arg Arg Arg Arg 450 455 460

His Arg Ser Tyr Ser Pro Pro Leu Pro Ser Gly Leu Ser Ser Trp Ser 465 470 475 480

Ser Glu Glu Asp Lys Glu Arg Gin Pro Gin Ser Trp Arg Ala His Arg 485 490 495

Arg Gly Ser His Ser Pro His Trp Pro Glu Glu Lys Pro Pro Ser Tyr 500 505 510

Arg Ser Leu Asp Ile Thr Pro Gly Lys Asn Ser Arg Lys Lys Gly Ser 515 520 525

Val Glu Arg Arg Ser Glu Lys Asp Ser Ser His Ser Gly Arg Ser Val 530 535 540

Val Ile Gly Pro Val Ala Thr Met Val Ser Lys Gly Glu Glu Leu Phe 545 550 555 560

Thr Gly Val val Pro ile Leu Val Glu Leu Asp Gly Asp Val Asn Gly 565 570 575

His Lys Phe Ser Val Ser Gly Glu Gly Glu Gly Asp Ala Thr Tyr Gly 580 585 590

Lys Leu Thr Leu Lys Phe Ile Cys Thr Thr Gly Lys Leu Pro Val Pro 595 . 600 605

Trp Pro Thr Leu Val Thr Thr Leu Thr Tyr Gly Val Gin Cys Phe Ser 610 615 620

Arg Tyr Pro Asp His Met Lys Gin His Asp Phe Phe Lys Ser Ala Met 625 630 635 640

Pro Glu Gly Tyr Val Gin Glu Arg Thr Ile Phe Phe Lys Asp Asp Gly 645 650 655

Asn Tyr Lys Thr Arg Ala Glu Val Lys Phe Glu Gly Asp Thr Leu Val 660 665 670

Asn Arg Ile Glu Leu Lys Gly Ile Asp Phe Lys Glu Asp Gly Asn Ile 675 680 685

Leu Gly His Lys Leu Glu Tyr Asn Tyr Asn Ser His Asn Val Tyr Ile 690 695 700

Met Ala Asp Lys Gin Lys Asn Gly Ile Lys Val Asn Phe Lys Ile Arg 705 710 715 720

His Asn Ile Glu Asp Gly Ser Val Gin Leu Ala Asp His Tyr Gin Gin 725 730 735

Asn Thr Pro Ile Gly Asp Gly Pro Val Leu Leu Pro Asp Asn His Tyr 740 745 750

Leu Ser Thr Gin Ser Ala Leu Ser Lys Asp Pro Asn Glu Lys Arg Asp 755 760 765

His Met Val Leu Leu Glu Phe Val Thr Ala Ala Gly Ile Thr Leu Gly 770 775 780

Met Asp Glu Leu Tyr Lys 785 790 <210> 94 <211 > 746

<212> PRT <213> Homo Sapiens <400> 94

Met Ala Trp Pro Lys Leu Pro Ala Pro Trp Leu Leu Leu Cys Thr Trp 15 10 15

Leu Pro Ala Gly Cys Leu Ser Leu Leu Val Thr Val Gin His Thr Glu 20 25 30

Arg Tyr Val Thr Leu Phe Ala Ser lie lie Leu Lys Cys Asp Tyr Thr 35 40 45

Thr Ser Ala Gin Leu Gin Asp Val Val Val Thr Trp Arg Phe Lys Ser 50 55 60

Phe Cys Lys Asp Pro lie Phe Asp Tyr Tyr Ser Ala Ser Tyr Gin Ala 65 70 75 80

Ala Leu Ser Leu Gly Gin Asp Pro Ser Asn Asp Cys Asn Asp Asn Gin 85 90 95

Arg Glu Val Arg lie Val Ala Gin Arg Arg Gly Gin Asn Glu Pro Val 100 105 110

Leu Gly Val Asp Tyr Arg Gin Arg Lys lie Thr lie Gin Asn Arg Ala 115 120 125

Asp Leu Val lie Asn Glu Val Met Trp Trp Asp His Gly Val Tyr Tyr 130 135 140

Cys Thr lie Glu Ala Pro Gly Asp Thr Ser Gly Asp Pro Asp Lys Glu 145 150 155 160

Val Lys Leu lie Val Leu His Trp Leu Thr Val lie Phe lie lie Leu 165 170 175

Gly Ala Leu Leu Leu Leu Leu Leu lie Gly Val Cys Trp Cys Gin Cys 180 185 190

Cys Pro Gin Tyr Cys Cys Cys Tyr Ile Arg Cys Pro Cys Cys Pro Ala 195 200 205

His Cys Cys Cys Pro Glu Glu Asp Leu Ser Leu Pro Ser Ser Leu Pro 210 215 220

Gin Met Pro Met Thr Gin Thr Thr Asn Gin Pro Pro Ile Ala Asn Gly 225 230 235 240

Val Leu Glu Tyr Leu Glu Lys Glu Leu Arg Asn Leu Asn Leu Ala Gin 245 250 255

Pro Leu Pro Pro Asp Leu Lys Gly Arg Phe Gly His Pro Cys Ser Met 260 265 270

Leu Ser Ser Leu Gly Ser Glu val val Glu Arg Arg Ile Ile His Leu 275 280 285

Pro Pro Leu Ile Arg Asp Leu Ser Ser Ser Arg Arg Thr Ser Asp Ser 290 295 300

Leu His Gin Gin Trp Leu Thr Pro Ile Pro Ser Arg Pro Trp Asp Leu 305 310 315 320

Arg Glu Gly Arg Ser His His His Tyr Pro Asp Phe His Gin Glu Leu 325 330 335

Gin Asp Arg Gly Pro Lys Ser Trp Ala Leu Glu Arg Arg Glu Leu Asp 340 345 350

Pro Ser Trp Ser Gly Arg His Arg Ser Ser Arg Leu Asn Gly Ser Pro 355 360 365

Ile His Trp Ser Asp Arg Asp Ser Leu Ser Asp Val Pro Ser Ser Ser 370 375 380

Glu Ala Arg Trp Arg Pro Ser His Pro Pro Phe Arg Ser Arg Cys Gin 385 390 395 400

Glu Arg Pro Arg Arg Pro Ser Pro Arg Glu Ser Thr Gin Arg His Gly 405 410 415

Arg Arg Arg Arg His Arg Ser Tyr Ser Pro Pro Leu Pro Ser Gly Leu 420 425 430 .is Arg Arg bly Ser His Ser Fro his irp Fro blu blu Lys 455 450 ler Tyr Arg Ser Leu Asp Ile Thr Pro Gly Lys Asn Ser Arg 470 475 480 rly Ser Val Glu Arg Arg Ser Glu Lys Asp Ser Ser His Ser 485 490 495 ;er Val Val Ile Gly Pro Val Ala Thr Met Val Ser Lys Gly 500 505 510 .eu Phe Thr Gly Val Val Pro ile Leu Val Glu Leu Asp Gly 15 520 525 .sn Gly His Lys Phe Ser Val Ser Gly Glu Gly Glu Gly Asp 535 540 yr Gly Lys Leu Thr Leu Lys Phe Ile Cys Thr Thr Gly Lys 550 555 560 'al Pro Trp Pro Thr Leu Val Thr Thr Leu Thr Tyr Gly Val 565 570 575 he Ser Arg Tyr Pro Asp His Met Lys Gin His Asp Phe Phe 580 585 590 „la Met Pro Glu Gly Tyr Val Gin Glu Arg Thr Ile Phe Phe .95 600 605

Lsp Gly Asn Tyr Lys Thr Arg Ala Glu Val Lys Phe Glu Gly 615 620 ,eu Val Asn Arg Ile Glu Leu Lys Gly Ile Asp Phe Lys Glu 630 635 640 .sn Ile Leu Gly His Lys Leu Glu Tyr Asn Tyr Asn Ser His 645 650 655 ’yr Ile Met Ala Asp Lys Gin Lys Asn Gly Ile Lys Val Asn 660 665 670 le Arg His Asn Ile Glu Asp Gly Ser Val Gin Leu Ala Asp 175 680 685 iln Gin Asn Thr Pro Ile Gly Asp Gly Pro Val Leu Leu Pro 695 700 iis Tyr Leu Ser Thr Gin Ser Ala Leu Ser Lys Asp Pro Asn 710 715 720 .rg Asp His Met Val Leu Leu Glu Phe Val Thr Ala Ala Gly 725 730 735 .eu Gly Met Asp Glu Leu Tyr Lys 740 745 i r no Sapiens 300

Met Val Phe Ala Phe Trp Lys Val Phe Leu lie Leu Ser Cys Leu Ala 15 10 15

Gly Gin Val Ser Val Val Gin Val Thr He Pro Asp Gly Phe Val Asn 20 25 30

Val Thr Val Gly Ser Asn Val Thr Leu Ile Cys Ile Tyr Thr Thr Thr 35 40 45

Val Ala Ser Arg Glu Gin Leu Ser Ile Gin Trp Ser Phe Phe His Lys 50 55 60

Lys Glu Met Glu Pro lie Ser His Ser Ser Cys Leu Ser Thr Glu Gly 65 70 75 80

Met Glu Glu Lys Ala Val Ser Gin Cys Leu Lys Met Thr His Ala Arg 85 90 95

Asp Ala Arg Gly Arg Cys Ser Trp Thr Ser Glu Ser Pro Trp Glu Glu 100 105 110

Gly Lys Trp Pro Asp Val Glu Ala Val Lys Gly Thr Leu Asp Gly Gin 115 120 125

Gin Ala Glu Leu Gin He Tyr Phe Ser Gin Gly Gly Gin Ala Val Ala 130 135 140 lie Gly Gin Phe Lys Asp Arg He Thr Gly Ser Asn Asp Pro Gly Asn 145 150 155 160

Ala Ser lie Thr He Ser His Met Gin Pro Ala Asp Ser Gly He Tyr 165 170 175

He Cys Asp Val Asn Asn Pro Pro Asp Phe Leu Gly Gin Asn Gin Gly 180 185 190

He Leu Asn Val Ser Val Leu Val Lys Ero Ser Lys Pro Leu Cys Ser 195 200 205

Val Gin Gly Arg Pro Glu Thr Gly His Thr lie Ser Leu Ser Cys Leu 210 215 220

Ser Ala Leu Gly Thr Pro Ser Pro Val Tyr Tyr Trp His Lys Leu Glu 225 230 235 240

Gly Arg Asp He Val Pro Val Lys Glu Asn Phe Asn Pro Thr Thr Gly 245 250 255 lie Leu Val He Gly Asn Leu Thr Asn Phe Glu Gin Gly Tyr Tyr Gin 260 265 270

Cys Thr Ala lie Asn Arg Leu Gly Asn Ser Ser Cys Glu He Asp Leu 275 280 285

Thr Ser Ser His Pro Glu Val Gly He He Val Gly Ala Leu He Gly 290 295 300

Ser Leu Val Gly Ala Ala He lie He Ser Val .Val Cys Phe Ala Arg 305 310 315 320

Asn Lys Ala Lys Ala Lys Ala Lys Glu Arg Asn Ser Lys Thr He Ala 325 330 335

Glu Leu Glu Pro Met Thr Lys He Asn Pro Arg Gly Glu Ser Glu Ala 340 345 350

Met Pro Arg Glu Asp Ala Thr Gin Leu Glu Val Thr Leu Pro Ser Ser 355 360 365

He His Glu Thr Gly Pro Asp Thr He Gin Glu Pro Asp Tyr Glu Pro 370 375 380

Lys Pro Thr Gin Glu Pro Ala Pro Glu Pro Ala Pro Gly Ser Glu Pro 385 390 395 400

Met Ala Val Pro Asp Leu Asp Ile Glu Leu Glu Leu Glu Pro Glu Thr 405 410 415

Gin Ser Glu Leu Glu Pro Glu Pro Glu Pro Glu Pro Glu Ser Glu Pro 420 425 430

Gly Val Val Val Glu Pro Leu Ser Glu Asp Glu Lys Gly Val Val Lys 435 440 445

Ala Gly Pro Val Ala Thr Met Val Ser Lys Gly Glu Glu Leu Phe Thr 450 455 460

Gly Val Val Pro Ile Leu Val Glu Leu Asp Gly Asp Val Asn Gly His 465 470 475 480

Lys Phe Ser Val Ser Gly Glu Gly Glu Gly Asp Ala Thr Tyr Gly Lys 485 490 495

Leu Thr Leu Lys Phe Ile Cys Thr Thr Gly Lys Leu Pro Val Pro Trp 500 505 510

Pro Thr Leu Val Thr Thr Leu Thr Tyr Gly Val Gin Cys Phe Ser Arg 515 520 525

Tyr Pro Asp His Met Lys Gin His Asp Phe Phe Lys Ser Ala Met Pro 530 535 540

Glu Gly Tyr Val Gin Glu Arg Thr Ile Phe Phe Lys Asp Asp Gly Asn 545 550 555 560

Tyr Lys Thr Arg Ala Glu Val Lys Phe Glu Gly Asp Thr Leu Val Asn 565 570 575

Arg Ile Glu Leu Lys Gly ile Asp Phe Lys Glu Asp Gly Asn Ile Leu 580 585 590

Gly His Lys Leu Glu Tyr Asn Tyr Asn Ser His Asn Val Tyr Ile Met 595 600 605

Ala Asp Lys Gin Lys Asn Gly Ile Lys Val Asn Phe Lys Ile Arg His 610 615 620

Asn Ile Glu Asp Gly Ser Val Gin Leu Ala Asp His Tyr Gin Gin Asn 625 630 635 640

Thr Pro Ile Gly Asp Gly Pro Val Leu Leu Pro Asp Asn His Tyr Leu 645 650 655

Ser Thr Gin Ser Ala Leu Ser Lys Asp Pro Asn Glu Lys Arg Asp His 660 665 670

Met Val Leu Leu Glu Phe Val Thr Ala Ala Gly Ile Thr Leu Gly Met 675 680 685

Asp Glu Leu Tyr Lys 690 <210> 96 <211 > 667

<212> PRT <213> Homo Sapiens <400> 96

Met Val Phe Ala Phe Trp Lys Val Phe Leu lie Leu Ser Cys Leu Ala 1 5 10 15

Gly Gin Val Ser Val Val Gin Val Thr He Pro Asp Gly Phe Val Asn 20 25 30

Val Thr Val Gly Ser Asn Val Thr Leu Ile Cys Ile Tyr Thr Thr Thr 35 40 45

Val Ala Ser Arg Glu Gin Leu Ser Ile Gin Trp Ser Phe Phe His Lys 50 55 60

Lys Glu Met Glu Pro He Ser His Ser Ser Cys Leu Ser Thr Glu Gly 65 70 75 80

Met Glu Glu Lys Ala Val Ser Gin Cys Leu Lys Met Thr His Ala Arg 85 90 95

Asp Ala Arg Gly Arg Cys Ser Trp Thr Ser Glu He Tyr Phe Ser Gin 100 105 110

Gly Gly Gin Ala Val Ala He Gly Gin Phe Lys Asp Arg He Thr Gly 115 120 125

Ser Asn Asp Pro Gly Asn Ala Ser He Thr He Ser His Met Gin Pro 130 135 140

Ala Asp Ser Gly lie Tyr lie Cys Asp Val Asn Asn Pro Pro Asp Phe 145 150 155 160

Leu Gly Gin Asn Gin Gly He Leu Asn Val Ser Val Leu Val Lys Pro 165 170 175

Ser Lys Pro Leu Cys Ser Val Gin Gly Arg Pro Glu Thr Gly His Thr 180 185 190 lie Ser Leu Ser Cys Leu Ser Ala Leu Gly Thr Pro Ser Pro Val Tyr 195 200 205

Tyr Trp His Lys Leu Glu Gly Arg Asp He Val Pro Val Lys Glu Asn . 210 215 220

Phe Asn Pro Thr Thr Gly lie Leu Val lie Gly Asn Leu Thr Asn Phe 225 230 235 240

Glu Gin Gly Tyr Tyr Gin Cys Thr Ala He Asn Arg Leu Gly Asn Ser 245 250 255

Ser Cys Glu lie Asp Leu Thr Ser Ser His Pro Glu Val Gly lie lie 260 265 270

Val Gly Ala Leu lie Gly Ser Leu Val Gly Ala Ala He He He Ser 275 280 285

Val Val Cys Phe Ala Arg Asn Lys Ala Lys Ala Lys Ala Lys Glu Arg 290 295 300

Asn Ser Lys Thr He Ala Glu Leu Glu Pro Met Thr Lys lie Asn Pro 305 310 315 320

Arg Gly Glu Ser Glu Ala Met Pro Arg Glu Asp Ala Thr Gin Leu Glu 325 330 335

Val Thr Leu Pro Ser Ser He His Glu Thr Gly Pro Asp Thr He Gin 340 345 350

Glu Pro Asp Tyr Glu Pro Lys Pro Thr Gin Glu Pro Ala Pro Glu Pro 355 360 365

Ala Pro Gly Ser Glu Pro Met Ala Val Pro Asp Leu Asp He Glu Leu 370 375 380

Glu Leu Glu Pro Glu Thr Gin Ser Glu Leu Glu Pro Glu Pro Glu Pro 385 390 395 400

Glu Pro Glu Ser Glu Pro Gly Val Val Val Glu Pro Leu Ser Glu Asp 405 410 415

Glu Lys Gly Val Val Lys Ala Gly Pro Val Ala Thr Met Val Ser Lys 420 425 430

Gly Glu Glu Leu Phe Thr Gly val val Pro ile Leu val Glu Leu Asp 435 440 445

Gly Asp Val Asn Gly His Lys Phe Ser Val Ser Gly Glu Gly Glu Gly 450 455 460

Asp Ala Thr Tyr Gly Lys Leu Thr Leu Lys Phe Ile Cys Thr Thr Gly 465 470 475 4&amp;0

Lys Leu Pro Val Pro Trp Pro Thr Leu Val Thr Thr Leu Thr Tyr Gly 485 490 495

Val Gin Cys Phe Ser Arg Tyr Pro Asp His Met Lys Gin His Asp Phe 500 505 510

Phe Lys Ser Ala Met Pro Glu Gly Tyr Val Gin Glu Arg Thr ile Phe 515 520 525

Phe Lys Asp Asp Gly Asn Tyr Lys Thr Arg Ala Glu Val Lys Phe Glu 530 535 540

Gly Asp Thr Leu Val Asn Arg Ile Glu Leu Lys Gly Ile Asp Phe Lys 545 550 555 560

Glu Asp Gly Asn Ile Leu Gly His Lys Leu Glu Tyr Asn Tyr Asn Ser 565 570 575

His Asn Val Tyr Ile Met Ala Asp Lys Gin Lys Asn Gly Ile Lys Val 580 585 590

Asn Phe Lys Ile Arg His Asn Ile Glu Asp Gly Ser Val Gin Leu Ala 595 600 605

Asp His Tyr Gin Gin Asn Thr Pro Ile Gly Asp Gly Pro Val Leu Leu 610 615 620

Pro Asp Asn His Tyr Leu Ser Thr Gin Ser Ala Leu Ser Lys Asp Pro 625 630 635 640 A9n Glu Lys Arg Asp His Met Val Leu Leu Glu Phe Val Thr Ala Ala 645 650 655

Gly Ile Thr Leu Gly Met Asp Glu Leu Tyr Lys 660 665 <210> 97 <211> 924

<212> DNA <213> Homo Sapiens <400> 97 rg gacagatgaa gaggacacag gctggcactg aggtcccctc cacttxcctc i»u rg gatccgagaa cctgtacttt cagggcagcg gcgagcccag aggccccacc 240 :t gccccccctg caagtgccca gcccctaacc tgctgggcgg acccagcgtg 300 :c cccccaagat caaggacgtg ctgatgatca gcctgagccc catcgtgacc 360 rg tggacgtgag cgaggacgac cccgacgtgc agatcagctg gttcgtgaac 420 rg tgcacaccgc ccagacccag acccaccggg aggactacaa cagcaccctg 480 rt ccgccctgcc catccagcac caggactgga tgagcggcaa agaattcaag 540 ra acaacaagga cctgcctgcc cccatcgagc ggaccatcag caagcccaag 600 ra gagcccccca ggtgtacgtg ctgccccctc ccgaggaaga gatgaccaag 660 a ccctgacctg catggtgacc gacttcatgc ccgaggacat ctacgtggag 720 a acggcaagac cgagctgaac tacaagaaca ccgagcccgt gctggacagc 780 t acttcatgta tagcaagctg agagtcgaga agaaaaactg ggtggagcgg 840 a gctgcagcgt ggtgcacgag ggcctgcaca accaccacac caccaagagc 900 a cccccggcaa gtga 924 '0 no Sapiens c tgcccagcgg gaggaggaag acccgaggca tctccctagg actcttcgcc 60 rg ccgcagcccg ctgtctgcag agtcagggtg tgtccctata cattcctcag 120 :a atgccactgt caaagaagac atcctgctct cagttgagta ctcctgtcat 180 :a ccatcgaatg gacatattca tccaattggg gaacgcagaa gatcgtggag 240 g ggactcaggc caacatctct caaagccaca aggacagagt ctgcaccttt 300 :t ccatccagct cttcagcgtg ggagtgaggg attccggcta ctatgtcatc 360 rg agcgcctggg gagcagccag tttggcacca tcgtgctgca cgtctctgag 420 g aagacggatc cgagaacctg tactttcagg gcagcggcga gcccagaggc 480 a agccctgccc cccctgcaag tgcccagccc ctaacctgct gggcggaccc 540 a tcttcccccc caagatcaag gacgtgctga tgatcagcct gagccccatc .600 g tggtggtgga cgtgagcgag gacgaccccg acgtgcagat cagctggttc 660 g tggaggtgca caccgcccag acccagaccc accgggagga ctacaacagc 720 g tggtgtccgc cctgcccatc cagcaccagg actggatgag cggcaaagaa 780 a aggtgaacaa caaggacctg cctgccccca tcgagcggac catcagcaag 840 a gcgtgagagc cccccaggtg tacgtgctgc cccctcccga ggaagagatg 900 c aggtgaccct gacctgcatg gtgaccgact tcatgcccga ggacatctac 960 a ccaacaacgg caagaccgag ctgaactaca agaacaccga gcccgtgctg 1020 g gcagctactt catgtatagc aagctgagag tcgagaagaa aaactgggtg 1080 a gctacagctg cagcgtggtg cacgagggcc tgcacaacca ccacaccacc 1140 a gccggacccc cggcaagtga 1170 57 no Sapiens 305 atggataggg tcttgctgag gtggatttct ctcttctggc taacagccat ggtcgaaggc 60 cttcaggtca cagtgcccga caagaagaag gtggccatgc tcttccagcc cactgtgctt 120 cgctgccact tctcaacatc ctcccatcag cctgcagttg tgcagtggaa gttcaagtcc 180 tactgccagg atcgcatggg agaatccttg ggcatgtcct ctacccgggc ccaatctctc 240 agcaagagaa acctggaatg ggacccctac ttggattgtt tggacagcag gaggactgtt 300 cgagtagtag cttcaaaaca gggctcgact gtcaccctgg gagatttcta caggggcaga 360 gagatcacga ttgttcatga tgcagatctt caaattggaa agcttatgtg gggagacagc 420 ggactctatt actgtattat caccacccca gatgacctgg aggggaaaaa tgaggactca 480 gtggaactgc tggtgttggg caggacaggg ctgcttgctg atctcttgcc cagttttgct 540 gtggagatta tgggatccga gaacctgtac tttcagggca gcggcgagcc cagaggcccc 600 accatcaagc cctgcccccc ctgcaagtgc ccagccccta acctgctggg cggacccagc 660 gtgttcatct tcccccccaa gatcaaggac gtgctgatga tcagcctgag ccccatcgtg 720 acctgcgtgg tggtggacgt gagcgaggac gaccccgacg tgcagatcag ctggttcgtg 780 aacaacgtgg aggtgcacac cgcccagacc cagacccacc gggaggacta caacagcacc 840 ctgcgggtgg tgtccgccct gcccatccag caccaggact ggatgagcgg caaagaattc 900 aagtgcaagg tgaacaacaa ggacctgcct gcccccatcg agcggaccat cagcaagccc 960 aagggcagcg tgagagcccc ccaggtgtac gtgctgcccc ctcccgagga agagatgacc 1020 aagaaacagg tgaccctgac ctgcatggtg accgacttca tgcccgagga catctacgtg 1080 gagtggacca acaacggcaa gaccgagctg aactacaaga acaccgagcc cgtgctggac 1140 agcgacggca gctacttcat gtatagcaag ctgagagtcg agaagaaaaa ctgggtggag 1200 cggaacagct acagctgcag cgtggtgcac gagggcctgc acaaccacca caccaccaag 1260 agcttcagcc ggacccccgg caagtga 1287 <210> 100 <211> 1740

<212> DNA <213> Homo Sapiens <400>100 atgtggctca aggtcttcac aactttcctt tcctttgcaa caggtgcttg ctcggggctg 60 aaggtgacag tgccatcaca cactgtccat ggcgtcagag gtcaggccct ctacctaccc 120 gtccactatg gcttccacac tccagcatca gacatccaga tcatatggct atttgagaga 180 ccccacacaa tgcccaaata cttactgggc tctgtgaata agtctgtggt tcctgacttg 240 gaataccaac acaagttcac catgatgcca cccaatgcat ctctgcttat caacccactg 300 cagttccctg atgaaggcaa ttacatcgtg aaggtcaaca ttcagggaaa tggaactcta 360 tctgccagtc agaagataca agtcacggtt gatgatcctg tcacaaagcc agtggtgcag 420 attcatcctc cctctggggc tgtggagtat gtggggaaca tgaccctgac atgccatgtg 480 gaagggggca ctcggctagc ttaccaatgg ctaaaaaatg ggagacctgt ccacaccagc 540 tccacctact ccttttctcc ccaaaacaat acccttcata ttgctccagt aaccaaggaa 600 gacattggga attacagctg cctggtgagg aaccctgtca gtgaaatgga aagtgatatc 660 attatgccca tcatatatta tggaccttat ggacttcaag tgaattctga taaagggcta 720 aaagtagggg aagtgtttac tgttgacctt ggagaggcca tcctatttga ttgttctgct 780 gattctcatc cccccaacac ctactcctgg attaggagga ctgacaatac tacatatatc 840 attaagcatg ggcctcgctt agaagttgca tctgagaaag tagcccagaa gacaatggac 900 tatgtgtgct gtgcttacaa caacataacc ggcaggcaag atgaaactca tttcacagtt 960 atcatcactt ccgtaggact ggagaagctt gcacagaaag gaaaaggatc cgagaacctg 1020 tactttcagg gcagcggcga gcccagaggc cccaccatca agccctgccc cccctgcaag 1080 tgcccagccc ctaacctgct gggcggaccc agcgtgttca tcttcccccc caagatcaag 1140 gacgtgctga tgatcagcct gagccccatc gtgacctgcg tggtggtgga cgtgagcgag 1200 gacgaccccg acgtgcagat cagctggttc gtgaacaacg tggaggtgca caccgcccag 1260 acccagaccc accgggagga ctacaacagc accctgcggg tggtgtccgc cctgcccatc 1320 cagcaccagg actggatgag cggcaaagaa ttcaagtgca aggtgaacaa caaggacctg 1380 cctgccccca tcgagcggac catcagcaag cccaagggca gcgtgagagc cccccaggtg 1440 tacgtgctgc cccctcccga ggaagagatg accaagaaac aggtgaccct gacctgcatg 1500 gtgaccgact tcatgcccga ggacatctac gtggagtgga ccaacaacgg caagaccgag 1560 ctgaactaca agaacaccga gcccgtgctg gacagcgacg gcagctactt catgtatagc 1620 aagctgagag tcgagaagaa aaactgggtg gagcggaaca gctacagctg cagcgtggtg 1680 cacgagggcc tgcacaacca ccacaccacc aagagcttca gccggacccc cggcaagtga 1740 <210> 101 <211> 1167

<212> DNA <213> Homo Sapiens <400> 101 atgaacagct tcagcaccag cgccttcggc cccgtggcct tcagcctggg cctgctgctg 60 gtgctgcctg ccgccttccc tgcccccgtg ccccccttcg aagcccagct ccaggacgtg 120 gtggtgacat ggcgcttcaa gtccttctgc aaggacccta tctttgacta ctactcagcg 180 tcataccagg cagctttatc cctgggccag gacccatcca atgactgcaa cgacaaccag 240 cgggaagttc gcatagtggc ccagcggcgg gggcagaatg agcccgtgct gggggtagat 300 taccggcagc gcaagatcac catccagaac cgagcagatc tcgtgataaa tgaagtgatg 360 tggtgggacc atggagtgta ttactgcacc attgaggctc caggggacac atcaggagac 420 cccgataagg aaggatccga gaacctgtac tttcagggca gcggcgagcc cagaggcccc 480 accatcaagc cctgcccccc ctgcaagtgc ccagccccta acctgctggg cggacccagc 540 gtgttcatct tcccccccaa gatcaaggac gtgctgatga tcagcctgag ccccatcgtg 600 acctgcgtgg tggtggacgt gagcgaggac gaccccgacg tgcagatcag ctggttcgtg 660 aacaacgtgg aggtgcacac cgcccagacc cagacccacc gggaggacta caacagcacc 720 ctgcgggtgg tgtccgccct gcccatccag caccaggact ggatgagcgg caaagaattc 780 aagtgcaagg tgaacaacaa ggacctgcct gcccccatcg agcggaccat cagcaagccc 840 aagggcagcg tgagagcccc ccaggtgtac gtgctgcccc ctcccgagga agagatgacc 900 aagaaacagg tgaccctgac ctgcatggtg accgacttca tgcccgagga catctacgtg 960 gagtggacca acaacggcaa gaccgagctg aactacaaga acaccgagcc cgtgctggac 1020 agcgacggca gctacttcat gtatagcaag ctgagagtcg agaagaaaaa ctgggtggag 1080 cggaacagct acagctgcag cgtggtgcac gagggcctgc acaaccacca caccaccaag 1140 agcttcagcc ggacccccgg caagtga 1167 <210> 102 <211 > 1641

<212> DNA <213> Homo Sapiens <400> 102 atgaacagct tcagcaccag cgccttcggc cccgtggcct tcagcctggg cctgctgctg 60 gtgctgcctg ccgccttccc tgcccccgtg ccccccttcg aaatcccaga cggtttcgtg 120 aacgtgactg ttggatctaa tgtcactctc atctgcatct acaccaccac tgtggcctcc 180 cgagaacagc tttccatcca gtggtctttc ttccataaga aggagatgga gccaatttct 240 cacagctcgt gcctcagtac tgagggtatg gaggaaaagg cagtcagtca gtgtctaaaa 300 atgacgcacg caagagacgc tcggggaaga tgtagctgga cctctgagtc tccttgggag 360 gaggggaagt ggccagatgt tgaggctgtg aagggcactc ttgatggaca gcaggctgaa 420 ctccagattt acttttctca aggtggacaa gctgtagcca tcgggcaatt taaagatcga 480 attacagggt ccaacgatcc aggtaatgca tctatcacta tctcgcatat gcagccagca 540 gacagtggaa tttacatctg cgatgttaac aaccccccag actttctcgg ccaaaaccaa 600 ggcatcctca acgtcagtgt gttagtgaaa ccttctaagc ccctttgtag cgttcaagga 660 agaccagaaa ctggccacac tatttccctt tcctgtctct ctgcgcttgg aacaccttcc 720 cctgtgtact actggcataa acttgaggga agagacatcg tgccagtgaa agaaaacttc 780 aacccaacca ccgggatttt ggtcattgga aatctgacaa attttgaaca aggttattac 840 cagtgtactg ccatcaacag acttggcaat agttcctgcg aaatcgatct cacttcttca 900 catccaggat ccgagaacct gtactttcag ggcagcggcg agcccagagg ccccaccatc 960 aagccctgcc ccccctgcaa gtgcccagcc cctaacctgc tgggcggacc cagcgtgttc 1020 atcttccccc ccaagatcaa ggacgtgctg atgatcagcc tgagccccat cgtgacctgc 1080 gtggtggtgg acgtgagcga ggacgacccc gacgtgcaga tcagctggtt cgtgaacaac 1140 gtggaggtgc acaccgccca gacccagacc caccgggagg actacaacag caccctgcgg 1200 gtggtgtccg ccctgcccat ccagcaccag gactggatga gcggcaaaga attcaagtgc 1260 aaggtgaaca acaaggacct gcctgccccc atcgagcgga ccatcagcaa gcccaagggc 1320 agcgtgagag ccccccaggt gtacgtgctg ccccctcccg aggaagagat gaccaagaaa 1380 caggtgaccc tgacctgcat ggtgaccgac ttcatgcccg aggacatcta cgtggagtgg 1440 accaacaacg gcaagaccga gctgaactac aagaacaccg agcccgtgct ggacagcgac 1500 ggcagctact tcatgtatag caagctgaga gtcgagaaga aaaactgggt ggagcggaac 1560 agctacagct gcagcgtggt gcacgagggc ctgcacaacc accacaccac caagagcttc 1620 agccggaccc ccggcaagtg a 1641 <210> 103 <211 > 307 <212> PRT <213> Homo Sapiens <400> 103

Met Gin Lys Val Thr Leu Gly Leu Leu Val Phe Leu Ala Gly Phe Pro 15 10 15

Val Leu Asp Ala Asn Asp Leu Glu Asp Lys Asn Ser Pro Phe Tyr Tyr 20 25 30

Gly Ala Pro Tyr Ile Phe Val Lys Arg Met Gly Gly Gin Met Lys Arg 35 40 45

Thr Gin Ala Gly Thr Glu Val Pro Ser Thr Phe Leu Leu Asp Trp Gly 50 55 60

Ser Glu Asn Leu Tyr Phe Gin Gly Ser Gly Glu Pro Arg Gly Pro Thr 65 70 75 80

Ile Lys Pro Cys Pro Pro Cys Lys Cys Pro Ala Pro Asn Leu Leu Gly 85 90 95

Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu Met 100 105 110

Ile Ser Leu Ser Pro Ile Val Thr Cys Val Val Val Asp Val Ser Glu 115 120 125

Asp Asp Pro Asp Val Gin Ile Ser Trp Phe Val Asn Asn Val Glu Val 130 135 140

His Thr Ala Gin Thr Gin Thr His Arg Glu Asp Tyr Asn Ser Thr Leu 145 150 155 160

Arg Val Val Ser Ala Leu Pro Ile Gin His Gin Asp Trp Met Ser Gly 165 170 175

Lys Glu Phe Lys Cys Lys Val Asn Asn Lys Asp Leu Pro Ala Pro Ile 180 185 190

Glu Arg Thr Ile Ser Lys Pro Lys Gly Ser Val Arg Ala Pro Gin Val 195 200 205

Tyr Val Leu Pro Pro Pro Glu Glu Glu Met Thr Lys Lys Gin Val Thr 210 215 220

Leu Thr Cys Met Val Thr Asp Phe Met Pro Glu Asp Ile Tyr Val Glu 225 230 235 240

Trp Thr Asn Asn Gly Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu Pro 245 250 255

Val Leu Asp Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg Val 260 265 270

Glu Lys Lys Asn Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser Val Val 275 280 285

His Glu Gly Leu His Asn His His Thr Thr Lys Ser Phe Ser Arg Thr 290 295 300

Pro Gly Lys 305 <210> 104 <211 > 389 <212> PRT <213> Homo Sapiens <400> 104

Met Arg Pro Leu Pro Ser Gly Arg Arg Lys Thr Arg Gly Ile Ser Leu 15 10 15

Gly Leu Phe Ala Leu Cys Leu Ala Ala Ala Arg Cys Leu Gin Ser Gin 20 25 30

Gly Val Ser Leu Tyr lie Pro Gin Ala Thr Ile Asn Ala Thr Val Lys 35 40 45

Glu Asp lie Leu Leu Ser Val Glu Tyr Ser Cys His Gly Val Pro Thr 50 55 60 lie Glu Trp Thr Tyr Ser Ser Asn Trp Gly Thr Gin Lys lie Val Glu 65 70 75 80

Trp Lys Pro Gly Thr Gin Ala Asn lie Ser Gin Ser His· Lys Asp Arg 85 90 95

Val Cys Thr Phe Asp Asn Gly Ser lie Gin Leu Phe Ser Val Gly Val 100 105 110

Arg Asp Ser Gly Tyr Tyr Val He Thr Val Thr Glu Arg Leu Gly Ser 115 120 125

Ser Gin Phe Gly Thr lie Val Leu His Val Ser Glu He Leu Tyr Glu 130 135 140

Asp Gly Ser Glu Asn Leu Tyr Phe Gin Gly Ser Gly Glu Pro Arg Gly 145 150 155 160

Pro Thr He Lys Pro Cys Pro Pro Cys Lys Cys Pro Ala Pro Asn Leu 165 170 175

Leu Gly Gly Pro Ser Val Phe He Phe Pro Pro Lys He Lys Asp Val 180 185 190

Leu Met lie Ser Leu Ser Pro He Val Thr Cys Val Val Val Asp Val 195 200 205

Ser Glu Asp Asp Pro Asp Val Gin lie Ser Trp Phe Val Asn Asn Val 210 215 220

Glu Val His Thr Ala Gin Thr Gin Thr His Arg Glu Asp Tyr Asn Ser 225 230 235 240

Thr Leu Arg Val Val Ser Ala Leu Pro Ile Gin His Gin Asp Trp Met 245 250 255

Ser Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Lys Asp Leu Pro Ala 260 265 270

Pro Ile Glu Arg Thr Ile Ser Lys Pro Lys Gly Ser Val Arg Ala Pro 275 280 285

Gin Val Tyr Val Leu Pro Pro Pro Glu Glu Glu Met Thr Lys Lys Gin 290 295 300

Val Thr Leu Thr Cys Met Val Thr Asp Phe Met Pro Glu Asp Ile Tyr 305 310 315 320

Val Glu Trp Thr Asn Asn Gly Lys Thr Glu Leu Asn Tyr Lys Asn Thr 325 330 335

Glu Pro Val Leu Asp Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu 340 345 350

Arg Val Glu Lys Lys Asn Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser 355 360 365

Val Val His Glu Gly Leu His Asn His His Thr Thr Lys Ser Phe Ser 370 375 380

Arg Thr Pro Gly Lys 385 <210> 105 <211 > 428 <212> PRT <213> Homo Sapiens <400> 105

Met Asp Arg Val Leu Leu Arg Trp Ile Ser Leu Phe Trp Leu Thr Ala 15 10 15

Met Val Glu Gly Leu Gin Val Thr Val Pro Asp Lys Lys Lys Val Ala 20 25 30

Met Leu Phe Gin Pro Thr Val Leu Arg Cys His Phe Ser Thr Ser Ser 35 40 45

His Gin Pro Ala Val Val Gin Trp Lys Phe Lys Ser Tyr Cys Gin Asp

Arg Met Gly Glu Ser Leu Gly Met Ser Ser Thr Arg Ala Gin Ser Leu 65 70 75 80

Ser Lys Arg Asn Leu Glu Trp Asp Pro Tyr Leu Asp Cys Leu Asp Ser 85 90 95

Arg Arg Thr Val Arg Val Val Ala Ser Lys Gin Gly Ser Thr Val Thr 100 105 110

Leu Gly Asp Phe Tyr Arg Gly Arg Glu ile Thr ile val His Asp Ala 115 120 125

Asp Leu Gin Ile Gly Lys Leu Met Trp Gly Asp Ser Gly Leu Tyr Tyr 130 135 140

Cys Ile Ile Thr Thr Pro Asp Asp Leu Glu Gly Lys Asn Glu Asp Ser 145 150 155 160

Val Glu Leu Leu Val Leu Gly Arg Thr Gly Leu Leu Ala Asp Leu Leu 165 170 175

Pro Ser Phe Ala Val Glu Ile Met Gly Ser Glu Asn Leu Tyr Phe Gin 180 185 190

Gly Ser Gly Glu Pro Arg Gly Pro Thr ile Lys Pro Cys Pro Pro Cys 195 200 205

Lys Cys Pro Ala Pro Asn Leu Leu Gly Gly Pro Ser Val Phe Ile Phe 210 215 220

Pro Pro Lys Ile Lys Asp Val Leu Met Ile Ser Leu Ser Pro Ile Val 225 230 235 240

Thr Cys Val Val Val Asp Val Ser Glu Asp Asp Pro Asp Val Gin Ile 245 250 255

Ser Trp Phe Val Asn Asn Val Glu Val His Thr Ala Gin Thr Gin Thr 260 265 270

His Arg Glu Asp Tyr Asn Ser Thr Leu Arg Val Val Ser Ala Leu Pro 275 280 285

Ile Gin His Gin Asp Trp Met Ser Gly Lys Glu Phe Lys Cys Lys Val 290 295 300

Asn Asn Lys Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile Ser Lys Pro 305 310 315 320

Lys Gly Ser Val Arg Ala Pro Gin Val Tyr Val Leu Pro Pro Pro Glu 325 330 335

Glu Glu Met' Thr Lys Lys Gin Val Thr Leu Thr Cys Met Val Thr Asp 340 345 350

Phe Met Pro Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn Gly Lys Thr 355 360 365

Glu Leu Asn Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser Asp Gly Ser 370 375 380

Tyr Phe Met Tyr Ser Lys Leu Arg Val Glu Lys Lys Asn Trp Val Glu 385 390 395 400

Arg Asn Ser Tyr Ser Cys Ser Val Val His Glu Gly Leu His Asn His 405 410 415

His Thr Thr Lys Ser Phe Ser Arg Thr Pro Gly Lys 420 425 <210> 106 <211>579 <212> PRT <213> Homo Sapiens <400> 106

Met Trp Leu Lys Val Phe Thr Thr Phe Leu Ser Phe Ala Thr Gly Ala 15 10 15

Cys Ser Gly Leu Lys Val Thr Val Pro Ser His Thr Val His Gly Val 20 25 30

Arg Gly Gin Ala Leu Tyr Leu Pro Val His Tyr Gly Phe His Thr Pro 35 40 45

Ala Ser Asp Ile Gin Ile Ile Trp Leu Phe Glu Arg Pro His Thr Met 50 55 60

Pro Lys Tyr Leu Leu Gly Ser Val Asn Lys Ser Val Val Pro Asp Leu 65 70 75 80

Glu Tyr Gin His Lys Phe Thr Met Met Pro Pro Asn Ala Ser Leu Leu 85 90 95

Ile Asn Pro Leu Gin Phe Pro Asp Glu Gly Asn Tyr Ile Val Lys Val 100 105 110

Asn Ile Gin Gly Asn Gly Thr Leu Ser Ala Ser Gin Lys lie Gin Val 115 120 125

Thr Val Asp Asp Pro Val Thr Lys Pro Val Val Gin lie His Pro Pro 130 135 140

Ser Gly Ala Val Glu Tyr Val Gly Asn Met Thr Leu Thr Cys His Val 145 150 155 160

Glu Gly Gly Thr Arg Leu Ala Tyr Gin Trp Leu Lys Asn Gly Arg Pro 165 170 175

Val His Thr Ser Ser Thr Tyr Ser Phe Ser Pro Gin Asn Asn Thr Leu 180 185 190

His lie Ala Pro Val Thr Lys Glu Asp lie Gly Asn Tyr Ser Cys Leu 195 200 205

Val Arg Asn Pro Val Ser Glu Met Glu Ser Asp lie lie Met Pro lie 210 215 220 lie Tyr Tyr Gly Pro Tyr Gly Leu Gin Val Asn Ser Asp Lys Gly Leu 225 230 235 240

Lys Val Gly Glu Val Phe Thr Val Asp Leu Gly Glu Ala He Leu Phe 245 250 255

Asp Cys Ser Ala Asp Ser His Pro Pro Asn Thr Tyr Ser Trp lie Arg 260 265 270

Arg Thr Asp Asn Thr Thr Tyr lie lie Lys His Gly Pro Arg Leu Glu 275 280 285

Val Ala Ser Glu Lys Val Ala Gin Lys Thr Met Asp Tyr Val Cys Cys 290 295 300

Ala Tyr Asn Asn lie Thr Gly Arg Gin Asp Glu Thr His Phe Thr Val 305 310 315 320

Ile Ile Thr Ser Val Gly Leu Glu Lys Leu Ala Gin Lys Gly Lys Gly 325 330 335

Ser Glu Asn Leu Tyr Fhe Gin Gly Ser Gly Glu Pro Arg Gly Pro Thr 340 345 350

Ile Lys Pro Cys Pro Pro Cys Lys Cys Pro Ala Pro Asn Leu Leu Gly 355 360 365

Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu Met 370 375 380

Ile Ser Leu Ser Pro Ile Val Thr Cys val val Val Asp Val Ser Glu 385 390 395 400

Asp Asp Pro Asp Val Gin Ile Ser Trp Phe Val Asn Asn Val Glu Val 405 410 415

His Thr Ala Gin Thr Gin Thr His Arg Glu Asp Tyr Asn Ser Thr Leu 420 425 430

Arg Val Val Ser Ala Leu Pro Ile Gin His Gin Asp Trp Met Ser Gly 435 440 445

Lys Glu Phe Lys Cys Lys Val Asn Asn Lys Asp Leu Pro Ala Pro Ile 450 455 460

Glu Arg Thr Ile Ser Lys Pro Lys Gly Ser Val Arg Ala Pro Gin Val 465 470 475 480

Tyr Val Leu Pro Pro Pro Glu Glu Glu Met Thr Lys Lys Gin Val Thr 485 490 495

Leu Thr Cys Met Val Thr Asp Phe Met Pro Glu Asp Ile Tyr Val Glu 500 505 510

Trp Thr Asn Asn Gly Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu Pro 515 520 525

Val Leu Asp Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg Val 530 535 540

Glu Lys Lys Asn Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser Val Val 545 550 555 560

His Glu Gly Leu His Asn His His Thr Thr Lys Ser Phe Ser Arg Thr 565 570 575

Pro Gly Lys <210> 107 <211 > 388 <212> PRT <213> Homo Sapiens <400> 107

Met Asn Ser Phe Ser Thr Ser Ala Phe Gly Pro Val Ala Phe Ser Leu 15 10 15

Gly Leu Leu Leu Val Leu Pro Ala Ala Phe Pro Ala Pro Val Pro Pro 20 25 30

Phe Glu Ala Gin Leu Gin Asp Val Val Val Thr Trp Arg Phe Lys Ser 35 40 45

Phe Cys Lys Asp Pro Ile Phe Asp Tyr Tyr Ser Ala Ser Tyr Gin Ala 50 55 60

Ala Leu Ser Leu Gly Gin Asp Pro Ser Asn Asp Cys Asn Asp Asn Gin 65 70 75 80

Arg Glu Val Arg Ile Val Ala Gin Arg Arg Gly Gin Asn Glu Pro Val 85 90 95

Leu Gly Val Asp Tyr Arg Gin Arg Lys Ile Thr rie Gin Asn Arg Ala 100 105 110

Asp Leu Val Ile Asn Glu Val Met Trp Trp Asp His Gly Val Tyr Tyr 115 120 125

Cys Thr Ile Glu Ala Pro Gly Asp Thr Ser Gly Asp Pro Asp Lys Glu 130 135 140

Gly Ser Glu Asn Leu Tyr Phe Gin Gly Ser Gly Glu Pro Arg Gly Pro 145 150 155 160

Thr Ile Lys Pro Cys Pro Pro Cys Lys Cys Pro Ala Pro Asn Leu Leu 165 170 175

Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu 180 185 190

Met Ile Ser Leu Ser Pro Ile Val Thr Cys Val Val Val Asp Val Ser 195 200 205

Glu Asp Asp Pro Asp Val Gin Ile Ser Trp Phe val Asn Asn Val Glu 210 215 220

Val His Thr Ala Gin Thr Gin Thr His Arg Glu Asp Tyr Asn Ser Thr 225 230 235 240

Leu Arg Val Val Ser Ala Leu Pro Ile Gin His Gin Asp Trp Met Ser 245 250 255

Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Lys Asp Leu Pro Ala Pro 260 265 270

Ile Glu Arg Thr Ile Ser Lys Pro Lys Gly Ser Val Arg Ala Pro Gin 275 280 285

Val Tyr Val Leu Pro Pro Pro Glu Glu Glu Met Thr Lys Lys Gin Val 290 295 300

Thr Leu Thr Cys Met Val Thr Asp Phe Met Pro Glu Asp Ile Tyr Val 305 310 315 320

Glu Trp Thr Asn Asn Gly Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu 325 330 335

Pro Val Leu Asp Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg 340 345 350

Val Glu Lys Lys Asn Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser Val 355 360 365

Val His Glu Gly Leu His Asn His His Thr Thr Lys Ser Phe Ser Arg 370 375 380

Thr Pro Gly Lys 385 <210> 108 <211 > 546 <212> PRT <213> Homo Sapiens <400> 108

Met Asn Ser Phe Ser Thr Ser Ala Phe Gly Pro Val Ala Phe Ser Leu 15 10 15

Gly Leu Leu Leu Val Leu Pro Ala Ala Phe Pro Ala Pro Val Pro Pro 20 25 30

Phe Glu Ile Pro Asp Gly Phe Val Asn Val Thr Val Gly Ser Asn Val 35 40 45

Thr Leu Ile Cys Ile Tyr Thr Thr Thr Val Ala Ser Arg Glu Gin Leu 50 55 60

Ser Ile Gin Trp Ser Phe Phe His Lys Lys Glu Met Glu Pro ile Ser 65 70 75 80

His Ser Ser Cys Leu Ser Thr Glu Gly Met Glu Glu Lys Ala Val Ser 85 90 95

Gin Cys Leu Lys Met Thr His Ala Arg Asp Ala Arg Gly Arg Cys Ser 100 105 110

Trp Thr Ser Glu Ser Pro Trp Glu Glu Gly Lys Trp Pro Asp Val Glu 115 120 125

Ala Val Lys Gly Thr Leu Asp Gly Gin Gin Ala Glu Leu Gin Ile Tyr 130 135 140

Phe Ser Gin Gly Gly Gin Ala Val Ala Ile Gly Gin Phe Lys Asp Arg 145 150 155 160

Ile Thr Gly Ser Asn Asp Pro Gly Asn Ala Ser Ile Thr Ile Ser His 165 170 175

Met Gin Pro Ala Asp Ser Gly Ile Tyr Ile Cys Asp Val Asn Asn Pro 180 185 190

Pro Asp Phe Leu Gly Gin Asn Gin Gly ile Leu Asn Val Ser Val Leu 195 200 205

Val Lys Pro Ser Lys Pro Leu Cys Ser Val Gin Gly Arg Pro Glu Thr 210 215 220

Gly His Thr Ile Ser Leu Ser Cys Leu Ser Ala Leu Gly Thr Pro Ser 225 230 235 240

Pro Val Tyr Tyr Trp His Lys Leu Glu Gly Arg Asp Ile Val Pro Val 245 250 255

Lys Glu Asn Phe Asn Pro Thr Thr Gly Ile Leu Val Ile Gly Asn Leu 260 265 270

Thr Asn Phe Glu Gin Gly Tyr Tyr Gin Cys Thr Ala Ile Asn Arg Leu 275 280 285

Gly Asn Ser Ser Cys Glu Ile Asp Leu Thr Ser Ser His Pro Gly Ser 290 295 300

Glu Asn Leu Tyr Phe Gin Gly Ser Gly Glu Pro Arg Gly Pro Thr Ile 305 310 315 320

Lys Pro Cys Pro Pro Cys Lys Cys Pro Ala Pro Asn Leu Leu Gly Gly 325 330 335

Pro Ser Val Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu Met Ile 340 345 350

Ser Leu Ser Pro Ile Val Thr Cys Val Val Val Asp Val Ser Glu Asp 355 360 365

Asp Pro Asp Val Gin Ile Ser Trp Phe Val Asn Asn Val Glu Val His 370 375 380

Thr Ala Gin Thr Gin Thr His Arg Glu Asp Tyr Asn Ser Thr Leu Arg 385 390 395 400

Val Val Ser Ala Leu Pro Ile Gin His Gin Asp Trp Met Ser Gly Lys 405 410 415

Glu Phe Lys Cys Lys Val Asn Asn Lys Asp Leu Pro Ala Pro Ile Glu 420 425 430

Arg Thr Ile Ser Lys Pro Lys Gly Ser Val Arg Ala Pro Gin Val Tyr 435 440 445

Val Leu Pro Pro Pro Glu Glu Glu Met Thr Lys Lys Gin Val Thr Leu 450 455 460

Thr Cys Met Val Thr Asp Phe Met Pro Glu Asp Ile Tyr Val Glu Trp 465 470 475 480

Thr Asn Asn Gly Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu Pro Val 485 490 495

Leu Asp Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg Val Glu 500 505 510

Lys Lys Asn Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser Val Val His 515 520 525

Glu Gly Leu His Asn His His Thr Thr Lys Ser Phe Ser Arg Thr Pro 530 535 540

Gly Lys 545 <210> 109 <211 > 684 <212> PRT <213> Homo Sapiens <400> 109

Met Ala Arg His Arg Asn Val Arg Gly Tyr Asn Tyr Asp Glu Asp Phe 15 10 15

Glu Asp Asp Asp Leu Tyr Gly Gin Ser Val Glu Asp Asp Tyr Cys Ile 20 25 30

Ser Pro Ser Thr Ala Ala Gin Phe Ile Tyr Ser Arg Arg Asp Lys Pro 35 40 45

Ser Val Glu Pro Val Glu Glu Tyr Asp Tyr Glu Asp Leu Lys Glu Ser 50 55 60

Ser Asn Ser Val Ser Asn His Gin Leu Ser Gly Phe Asp Gin Ala Arg 65 70 75 80

Leu Tyr Ser Cys Leu Asp His Met Arg Glu Val Leu Gly Asp Ala Val 85 90 95

Pro Asp Glu Ile Leu Ile Glu Ala Val Leu Lys Asn Lys Phe Asp Val 100 105 110

Gin Lys Ala Leu Ser Gly Val Leu Glu Gin Asp Arg Val Gin Ser Leu 115 120 125

Lys Asp Lys Asn Glu Ala Thr Val Ser Thr Gly Lys Ile Ala Lys Gly 130 135 140

Lys Pro Val Asp Ser Gin Thr Ser Arg Ser Glu Ser Glu Ile Val Pro 145 150 155 160

Lys Val Ala Lys Met Thr Val Ser Gly Lys Lys Gin Thr Met Gly Phe 165 170 175

Glu Val Pro Gly Val Ser Ser Glu Glu Asn Gly His Ser Phe His Thr 180 185 190

Pro Gin Lys Gly Pro Pro Ile Glu Asp Ala Ile Ala Ser Ser Asp Val 195 200 205

Leu Glu Thr Ala Ser Lys Ser Ala Asn Pro Pro His Thr Ile Gin Ala 210 215 220

Ser Glu Glu Gin Ser Ser Thr Pro Ala Pro Val Lys Lys Ser Gly Lys 225 230 235 240

Leu Arg Gin Gin Ile Asp Val. Lys Ala Glu Leu Glu Lys Arg Gin Gly 245 250 255

Gly Lys Gin Leu Leu Asn Leu val val ile Gly His Val Asp Ala Gly 260 265 270

Lys Ser Thr Leu Met Gly His Met Leu Tyr Leu Leu Gly Asn Ile Asn 275 280 285

Lys Arg Thr Met His Lys Tyr Glu Gin Glu Ser Lys Lys Ala Gly Lys 290 295 300

Ala Ser Phe Ala Tyr Ala Trp Val Leu Asp Glu Thr Gly Glu Glu Arg 305 310 315 320

Glu Arg Gly Val Thr Met Asp Val Gly Met Thr Lys Phe Glu Thr Thr 325 330 335

Thr Lys Val Ile Thr Leu Met Asp Ala Pro Gly His Lys Asp Phe Ile 340 345 350

Pro Asn Met Ile Thr Gly Ala Ala Gin Ala Asp Val Ala Val Leu Val 355 360 365

Val Asp Ala Ser Arg Gly Glu Phe Glu Ala Gly Phe Glu Thr Gly Gly 370 375 380

Gin Thr Arg Glu His Gly Leu Leu Val Arg Ser Leu Gly Val Thr Gin 385 390 395 400

Leu Ala Val Ala Val Asn Lys Met Asp Gin Val Asn Trp Gin Gin Glu 405 410 415

Arg Phe Gin Glu Ile Thr Gly Lys Leu Gly His Phe Leu Lys Gin Ala 420 425 430

Gly Phe Lys Glu Ser Asp Val Gly Phe Ile Pro Thr Ser Gly Leu Ser 435 440 445

Gly Glu Asn Leu Ile Thr Arg Ser Gin Ser Ser Glu Leu Thr Lys Trp 450 455 460

Tyr Lys Gly Leu Cys Leu Leu Glu Gin Ile Asp Ser Phe Lys Pro Pro 465 470 475 480

Gin Arg Ser Ile Asp Lys Pro Phe Arg Leu Cys Val Ser Asp Val Phe 485 490 495

Lys Asp Gin Gly Ser Gly Phe Cys Ile Thr Gly Lys Ile Glu Ala Gly 500 505 510

Tyr ile Gin Thr Gly Asp Arg Leu Leu Ala Met Pro Pro Asn Glu Thr 515 520 525

Cys Thr Val Lys Gly ile Thr Leu His Asp Glu Pro Val Asp Trp Ala 530 535 540

Ala Ala Gly Asp His Val Ser Leu Thr Leu Val Gly Met Asp Ile Ile 545 550 555 560

Lys Ile Asn Val Gly Cys Ile Phe Cys Gly Pro Lys Val Pro Ile Lys 565 570 575

Ala Cys Thr Arg Phe Arg Ala Arg Ile Leu Ile Phe Asn Ile Glu Ile 580 585 590

Pro Ile Thr Lys Gly Phe Pro Val Leu Leu His Tyr Gin Thr Val Ser 595 600 605

Glu Pro Ala Val ile Lys Arg Leu ile Ser Val Leu Asn Lys Ser Thr 610 615 620

Gly Glu Val Thr Lys Lys Lys Pro Lys Phe Leu Thr Lys Gly Gin Asn 625 630 635 640

Ala Leu Val Glu Leu Gin Thr Gin Arg Pro Ile Ala Leu Glu Leu Tyr 645 650 655

Lys Asp Phe Lys Glu Leu Gly Arg Phe Met Leu Arg Tyr Gly Gly Ser 660 665 670

Thr Ile Ala Ala Gly Val Val Thr Glu Ile Lys Glu 675 680 <210> 110 <211 > 664 <212> PRT <213> Homo Sapiens <400> 110

Met Ser Gly Val Arg Gly Leu Ser Arg Leu Leu Ser Ala Arg Arg Leu 15 10 15

Ala Leu Ala Lys Ala Trp Pro Thr.Val Leu Gin Thr Gly Thr Arg Gly 20 25 30

Phe His Phe Thr Val Asp Gly Asn Lys Arg Ala Ser Ala Lys Val Ser 35 40 45

Asp Ser Ile Ser Ala Gin Tyr Pro Val Val Asp His Glu Phe Asp Ala 50 55 60

Val Val Val Gly Ala Gly Gly Ala Gly Leu Arg Ala Ala Phe Gly Leu 65 70 75 80

Ser Glu Ala Gly Phe Asn Thr Ala Cys Val Thr Lys Leu Phe Pro Thr' 85 90 95

Arg Ser His Thr Val Ala Ala Gin Gly Gly Ile Asn Ala Ala Leu Gly 100 105 110

Asn Met Glu Glu Asp Asn Trp Arg Trp His Phe Tyr Asp Thr Val Lys 115 120 125

Gly Ser Asp Trp Leu Gly Asp Gin Asp Ala Ile His Tyr Met Thr Glu 130 135 140

Gin Ala Pro Ala Ala Val Val Glu Leu Glu Asn Tyr Gly Met Pro Phe

Ser Arg Thr Glu Aap Gly Lys Ile Tyr Gin Arg Ala Phe Gly Gly Gin 165 170 175

Ser Leu Lys Phe Gly Lys Gly Gly Gin Ala His Arg Cys Cys Cys Val 180 185 190

Ala Asp Arg Thr Gly His Ser Leu Leu His Thr Leu Tyr Gly Arg Ser 195 200 205

Leu Arg Tyr Asp Thr Ser Tyr Phe Val Glu Tyr Phe Ala Leu Asp Leu 210 215 220

Leu Met Glu Asn Gly Glu Cys Arg Gly Val Ile Ala Leu Cys Ile Glu 225 230 235 240

Asp Gly Ser ile His Arg ile Arg Ala Lys Asn Thr val val Ala Thr 245 250 255

Gly Gly Tyr Gly Arg Thr Tyr Phe Ser Cys Thr Ser Ala His Thr Ser 260 265 270

Thr Gly Asp Gly Thr Ala Met Ile Thr Arg Ala Gly Leu Pro Cys Gin 275 280 285

Asp Leu Glu Phe Val Gin Phe His Pro Thr Gly Ile Tyr Gly Ala Gly 290 295 300

Cys Leu Ile Thr Glu Gly Cys Arg Gly Glu Gly Gly Ile Leu Ile Asn 305 310 315 320

Ser Gin Gly Glu Arg Phe Met Glu Arg Tyr Ala Pro Val Ala Lys Asp 325 330 335

Leu Ala Ser Arg Asp Val Val Ser Arg Ser Met Thr Leu Glu Ile Arg 340 345 350

Glu Gly Arg Gly Cys Gly Pro Glu Lys Asp His Val Tyr Leu Gin Leu 355 360 365

His His Leu Pro Pro Glu Gin Leu Ala Thr Arg Leu Pro Gly Ile Ser 370 375 380

Glu Thr Ala Met Ile Phe Ala Gly Val Asp Val Thr Lys Glu Pro Ile 385 390 395 400

Pro Val Leu Pro Thr Val His Tyr Asn Met Gly Gly lie Pro Thr Asn 405 410 415

Tyr Lys Gly Gin Val Leu Arg His Val Asn Gly Gin Asp Gin Ile Val 420 425 430

Pro Gly Leu Tyr Ala Cys Gly Glu Ala Ala Cys Ala Ser Val His Gly 435 440 445

Ala Asn Arg Leu Gly Ala Asn Ser Leu Leu Asp Leu Val Val Phe Gly 450 455 460

Arg Ala Cys Ala Leu Ser lie Glu Glu Ser Cys Arg Pro Gly Asp Lys 465 470 475 480

Val Pro Pro lie Lys Pro Asn Ala Gly Glu Glu Ser Val Met Asn Leu 485 490 495

Asp Lys Leu Arg Phe Ala Asp Gly Ser lie Arg Thr Ser Glu Leu Arg 500 505 510

Leu Ser Met Gin Lys Ser Met Gin Asn His Ala Ala Val Phe Arg Val 515 520 525

Gly Ser Val Leu Gin Glu Gly Cys Gly Lys lie Ser Lys Leu Tyr Gly 530 535 540

Asp Leu Lys His Leu Lys Thr Phe Asp Arg Gly Met Val Trp Asn Thr 545 550 555 560

Asp Leu Val Glu Thr Leu Glu Leu Gin Asn Leu Met Leu Cys Ala Leu 565 570 575

Gin Thr lie Tyr Gly Ala Glu Ala Arg Lys Glu Ser Arg Gly Ala His 580 585 590

Ala Arg Glu Asp Tyr Lys Val Arg lie Asp Glu Tyr Asp Tyr Ser Lys 595 600 605

Pro lie Gin Gly Gin Gin Lys Lys Pro Phe Glu Glu His Trp Arg Lys 610 615 620

His Thr Leu Ser Tyr Val Asp Val Gly Thr Gly Lys Val Thr Leu Glu 625 630 635 640

Tyr Arg Pro Val lie Asp Lys Thr Leu'Asn Glu Ala Asp Cys Ala Thr 645 650 655

Val Pro Pro Ala lie Arg Ser Tyr 660 <210 111 <211 >494

<212> PRT <213> Homo Sapiens <400 111

Met Pro Arg Val Tyr Ile Gly Arg Leu Ser Tyr Gin Ala Arg Glu Arg 15 10 15

Asp Val Glu Arg Phe Phe Lys Gly Tyr Gly Lys Ile Leu Glu Val Asp 20 25 30

Leu Lys Asn Gly Tyr Gly Phe Val Glu Phe Asp Asp Leu Arg Asp Ala 35 40 45

Asp Asp Ala Val Tyr Glu Leu Asn Gly Lys Asp Leu Cys Gly Glu Arg 50 55 60

Val Ile Val. Glu His Ala Arg Gly Pro Arg Arg Asp Gly Ser Tyr Gly 65 7 0 75 80

Ser Gly Arg Ser Gly Tyr Gly Tyr Arg Arg Ser Gly Arg Asp Lys Tyr 85 90 95

Gly Pro Pro Thr Arg Thr Glu Tyr Arg Leu Ile Val Glu Asn Leu Ser 100 105 110

Ser Arg Cys Ser Trp Gin Asp Leu Lys Asp Tyr Met Arg Gin Ala Gly 115 120 125

Glu Val Thr Tyr Ala Asp Ala His Lys Gly Arg Lys Asn Glu Gly Val 130 135 140

Ile Glu Phe Val Ser Tyr Ser Asp Met Lys Arg Ala Leu Glu Lys Leu 145 150 155 160

Asp Gly Thr Glu Val Asn Gly Arg Lys Ile Arg Leu Val Glu Asp Lys 165 170 175

Pro Gly Ser Arg Arg Arg Arg Ser Tyr Ser Arg Ser Arg Ser His Ser 180 185 190

Arg Ser Arg Ser Arg Ser Arg His Ser Arg Lys Ser Arg Ser Arg Ser 195 200 205

Gly Ser Ser Lys Ser Ser His Ser Lys Ser Arg Ser Arg Ser Arg Ser 210 215 220

Gly Ser Arg Ser Arg Ser Lys Ser Arg Ser Arg Ser Gin Ser Arg Ser 225 230 235 240

Arg Ser Lys Lys Glu Lys Ser Arg Ser Pro Ser Lys Glu Lys Ser Arg 245 250 255

Ser Arg Ser His Ser Ala Gly Lys Ser Arg Ser Lys Ser Lys Asp Gin 260 265 270

Ala Glu Glu Lys Ile Gin Asn Asn Asp Asn Val Gly Lys Pro Lys Ser 275 280 285

Arg Ser Pro Ser Arg His Lys Ser Lys Ser Lys Ser Arg Ser Arg Ser 290 295 300

Gin Glu Arg Arg Val Glu Glu Glu Lys Arg Gly Ser Val Ser Arg Gly 305 310 315 320

Arg Ser Gin Glu Lys Ser Leu Arg Gin Ser Arg Ser Arg Ser Arg Sør 325 330 335

Lys Gly Gly Ser Arg Ser Arg Ser Arg Ser Arg Ser Lys Ser Lys Asp 340 345 350

Lys Arg Lys Gly Arg Lys Arg Ser Arg Glu Glu Ser Arg Ser Arg Ser 355 360 365

Arg Ser Arg Ser Lys Ser Glu Arg Ser Arg Lys Arg Gly Ser Lys Arg 370 375 380

Asp Ser Lys Ala Gly Ser Ser Lys Lys Lys Lys Lys Glu Asp Thr Asp 385 390 395 400

Arg Ser Gin Ser Arg Ser Pro Ser Arg Ser Val Ser Lys Glu Arg Glu 405 410 415

His Ala Lys Ser Glu Ser Ser Gin Arg Glu Gly Arg Gly Glu Ser Glu 420 425 430

Asn Ala Gly Thr Asn Gin Glu Thr Arg Ser Arg Ser Arg Ser Asn Ser 435 440 445

Lys Ser Lys Pro Asn Leu Pro Ser Glu Ser Arg Ser Arg Ser Lys Ser 450 455 460

Ala Ser Lys Thr Arg Ser Arg Ser Lys Ser Arg Ser Arg Ser Ala Ser 465 470 475 480

Arg Ser Pro Ser Arg Ser Arg Ser Arg Ser His Ser Arg Ser 485 490 <210> 112 <211> 376 <212> PRT <213> Homo Sapiens <400> 112

Thr Phe Pro Arg Glu Trp Leu Cys Asp Arg His Leu Arg Glu Lys Met 15 10 15

Phe Ser Ser Val Ala His Leu Ala Arg Ala Asn Pro Phe Asn Thr Pro 20 25 30

His Leu Gin Leu Val His Asp Gly Leu Gly Asp Leu Arg Ser Ser Ser 35 40 45

Pro Gly Pro Thr Gly Gin Pro Arg Arg Pro Arg Asn Leu Ala Ala Ala 50 55 60

Ala Val Glu Glu Tyr Ser Cys Glu Phe Gly Ser Ala Lys Tyr Tyr Ala 65 70 75 80

Leu Cys Gly Phe Gly Gly Val Leu Ser Cys Gly Leu Thr His Thr Ala 85 90 95

Val Val Pro Leu Asp Leu Val Lys Cys Arg Met Gin Val Asp Pro Gin 100 105 110

Lys Tyr Lys Gly Ile Phe Asn Gly Phe Ser Val Thr Leu Lys Glu Asp 115 120 125

Gly Val Arg Gly Leu Ala Lys Gly Trp Ala Pro Thr Phe Leu Gly Tyr 130 135 140

Ser Met Gin Gly Leu Cys Lys Phe Gly Phe Tyr Glu Val Phe Lys Val 145 150 155 160

Leu Tyr Ser Asn Met Leu Gly Glu Glu Asn Thr Tyr Leu Trp Arg Thr 165 170 175

Ser Leu Tyr Leu Ala Ala Ser Ala Ser Ala Glu Phe Phe Ala Asp Ile 180 185 190

Ala Leu Ala Pro Met Glu Ala Ala Lys Val Arg ile Gin Thr Gin Pro 195 200 205

Gly Tyr Ala Asn Thr Leu Arg Asp Ala Ala Pro Lys Met Tyr Lys Glu 210 215 220

Glu Gly Leu Lys Ala Phe Tyr Lys Gly Val Ala Pro Leu Trp Met Arg 225 230 235 240

Gin Ile Pro Tyr Thr Met Met Lys Phe Ala Cys Phe Glu Arg Thr Val 245 250 255

Glu Ala Leu Tyr Lys Phe Val Val Pro Lys Pro Arg Ser Glu Cys Ser 260 265 270

Lys Pro Glu Gin Leu Val Val Thr Phe Val Ala Gly Tyr Ile Ala Gly 275 280 285

Val Phe Cys Ala Ile Val Ser His Pro Ala Asp Ser Val Val Sér Val 290 295 300

Leu Asn Lys Glu Lys Gly Ser Ser Ala Ser Leu Val Leu Lys Arg Leu 305 310 315 320

Gly Phe Lys Gly Val Trp Lys Gly Leu Phe Ala Arg Ile Ile Met Ile 325 330 335

Gly Thr Leu Thr Ala Leu Gin Trp Phe Ile Tyr Asp Ser Val Lys Val 340 345 350

Tyr Phe Arg Leu Pro Arg Pro Pro Pro Pro Glu Met Pro Glu Ser Leu 355 360 365

Lys Lys Lys Leu Gly Leu Thr Gin 370 375 <210> 113 <211> 748

<212> DNA <213> Homo Sapiens <400> 113 gcagataatg ggaggagccg ggcccgagcg agctctttcc tttcgctgct gcggccgcag 60 ccatgagtat gctcaggctt cagaagaggc tcgcctctag tgtcctccgc tgtggcaaga 120 agaaggtctg gttagacccc aatgagacca atgaaatcgc caatgccaac tcccgtcagc 180 agatccggaa gctcatcaaa gatgggctga tcatccgcaa gcctgtgacg gtccattccc 240 gggctcgatg ccggaaaaac accttggccc gccggaaggg caggcacatg ggcataggta 300 agcggaaggg tacagccaat gcccgaatgc cagagaaggt cacatggatg aggagaatga 360 ggattttgcg ccggctgctc agaagatacc gtgaatctaa gaagatcgat cgccacatgt 420 atcacagcct gtacctgaag gtgaagggga atgtgttcaa aaacaagcgg attctcatgg 480 aacacatcca caagctgaag gcagacaagg cccgcaagaa gctcctggct gaccaggctg 540 aggcccgcag gtctaagacc aaggaagcac gcaagcgccg tgaagagcgc ctccaggcca 600 agaaggagga gatcatcaag actttatcca aggaggaaga gaccaagaaa taaaacctcc 660 cactttgtct gtacatactg gcctctgtga ttacatagat cagccattaa aataaaacaa 720 gccttaatct gcaaaaaaaa aaaaaaaa 748 <210> 114 <211 > 1867

<212> DNA <213> Homo Sapiens <400> 114 ggttcgctgt ggcgggcgcc tgggccgccg gctgtttaac ttcgcttccg ctggcccata 60 gtgatctttg cagtgaccca gcagcatcac tgtttcttgg cgtgtgaaga taacccaagg 120 aattgaggaa gttgctgaga agagtgtgct ggagatgctc taggaaaaaa ttgaatagtg 180 agacgagttc cagcgcaagg gtttctggtt tgccaagaag aaagtgaaca tcatggatca 240 gaacaacagc ctgccacctt acgctcaggg cttggcctcc cctcagggtg ccatgactcc 300 cggaatccct atctttagtc caatgatgcc ttatggcact ggactgaccc cacagcctat 360 tcagaacacc aatagtctgt ctattttgga agagcaacaa aggcagcagc agcaacaaca 420 acagcagcag cagcagcagc agcagcaaca gcaacagcag cagcagcagc agcagcagca 480 gcagcagcag cagcagcagc agcagcagca gcaacaggca gtggcagctg cagccgttca 540 gcagtcaacg tcccagcagg caacacaggg aacctcaggc caggcaccac agctcttcca 600 ctcacagact ctcacaactg cacccttgcc gggcaccact ccactgtatc cctcccccat 660 gactcccatg acccccatca ctcctgccac gccagcttcg gagagttctg ggattgtacc 720 gcagctgcaa aatattgtat ccacagtgaa tcttggttgt aaacttgacc taaagaccat 780 tgcacttcgt gcccgaaacg ccgaatataa tcccaagcgg tttgctgcgg taatcatgag 840 gataagagag ccacgaacca cggcactgat tttcagttct gggaaaatgg tgtgcacagg 900 agccaagagt gaagaacagt ccagactggc agcaagaaaa tatgctagag ttgtacagaa 960 gttgggtttt ccagctaagt tcttggactt caagattcag aatatggtgg ggagctgtga 1020 tgtgaagttt cctataaggt tagaaggcct tgtgctcacc caccaacaat ttagtagtta 1080 tgagccagag ttatttcctg gtttaatcta cagaatgatc aaacccagaa ttgttctcct 1140 tatttttgtt tctggaaaag ttgtattaac aggtgctaaa gtcagagcag aaatttatga 1200 agcatttgaa aacatctacc ctattctaaa gggattcagg aagacgacgt aatggctctc 1260 atgtaccctt gcctccccca cccccttctt tttttttttt taaacaaatc agtttgtttt 1320 ggtaccttta aatggtggtg ttgtgagaag atggatgttg agttgcaggg tgtggcacca 1380 ggtgatgccc ttctgtaagt gcccaccgcg ggatgccggg aaggggcatt atttgtgcac 1440 tgagaacacc gcgcagcgtg actgtgagtt gctcataccg tgctgctatc tgggcagcgc 1500 tgcccattta tttatatgta gattttaaac actgctgttg acaagttggt ttgagggaga 1560 aaactttaag tgttaaagcc acctctataa ttgattggac tttttaattt taatgttttt 1620 ccccatgaac cacagttttt atatttctac cagaaaagta aaaatctttt ttaaaagtgt 1680 tgtttttcta atttataact cctaggggtt atttctgtgc cagacacatt ccacctctcc 1740 agtattgcag gacagaatat atgtgttaat gaaaatgaat ggctgtacat atttttttct 1800 ttcttcagag tactctgtac aataaatgca gtttataaaa gtgttaaaaa aaaaaaaaaa 1860 aaaaaaa 1867 <210> 115 <211> 2201

<212> DNA <213> Homo Sapiens <400> 115 cgggatttgg gtcgcggttc ttgtttgtgg atcgctgtga tcgtcacttg acaatgcaga 60 tcttogtgaa gactctgact ggtaagacca tcaccctcga ggttgagocc agtgacacca 120 tcgagaatgt caaggcaaag atccaagata aggaaggcat ccctcctgac cagcagaggc 180 tgatctttgc tggaaaacag ctggaagatg ggcgcaccct gtctgactac aacatccaga 240 aagagtccac cctgcacctg gtgctccgtc tcagaggtgg gatgcaaatc ttcgtgaaga 300 cactcactgg caagaccatc acccttgagg tggagcccag tgacaccatc gagaacgtca 360 aagcaaagat ccaggacaag gaaggcattc ctcctgacca gcagaggttg atctttgccg 420 gaaagcagct ggaagatggg cgcaccctgt ctgactacaa catccagaaa gagtctaccc 480 tgcacctggt gctccgtctc agaggtggga tgcagatctt cgtgaagacc ctgactggta 540 agaccatcac cctcgaggtg gagcccagtg acaccatcga gaatgtcaag gcaaagatcc 600 aagataagga aggcattcct cctgatcagc agaggttgat ctttgccgga aaacagctgg 660 aagatggtcg taccctgtct gactacaaca tccagaaaga gtccaccttg cacctggtac 720 tccgtctcag aggtgggatg caaatcttcg tgaagacact cactggcaag accatcaccc 780 ttgaggtcga gcccagtgac actatcgaga acgtcaaagc aaagatccaa gacaaggaag 840 gcattcctcc tgaccagcag aggttgatct ttgccggaaa gcagctggaa gatgggcgca 900 ccctgtctga ctacaacatc cagaaagagt ctaccctgca cctggtgctc cgtctcagag 960 gtgggatgca gatcttcgtg aagaccctga ctggtaagac catcaccctc gaagtggagc 1020 cgagtgacac cattgagaat gtcaaggcaa agatccaaga caaggaaggc atccctcctg 1080 accagcagag gttgatcttt gccggaaaac agctggaaga tggtcgtacc ctgtctgact 1140 acaacatcca gaaagagtcc accttgcacc tggtgctccg tctcagaggt gggatgcaga 1200 tcttcgtgaa gaccctgact ggtaagacca tcactctcga ggtggagccg agtgacacca 1260 ttgagaatgt caaggcaaag atccaagaca aggaaggcat ccctcctgat cagcagaggt 1320 tgatctttgc tgggaaacag ctggaagatg gacgcaccct gtctgactac aacatccaga 1380 aagagtccac cctgcacctg gtgctccgtc ttagaggtgg gatgcagatc ttcgtgaaga 1440 ccctgactgg taagaccatc actctcgaag tggagccgag tgacaccatt gagaatgtca 1500 aggcaaagat ccaagacaag gaaggcatcc ctcctgacca gcagaggttg atctttgctg 1560 ggaaacagct ggaagatgga cgcaccctgt ctgactacaa catccagaaa gagtccaccc 1620 tgcacctggt gctccgtctt agaggtggga tgcagatctt cgtgaagacc ctgactggta 1680 agaccatcac tctcgaagtg gagccgagtg acaccattga gaatgtcaag gcaaagatcc 1740 aagacaagga aggcatccct cctgaccagc agaggttgat ctttgctggg aaacagctgg 1800 aagatggacg caccctgtct gactacaaca tccagaaaga gtccaccctg cacctggtgc 1860 tccgtctcag aggtgggatg cagatcttcg tgaagaccct gactggtaag accatcaccc 1920 tcgaggtgga gcccagtgac accatcgaga atgtcaaggc aaagatccaa gataaggaag 1980 gcatccctcc tgatcagcag aggttgatct ttgctgggaa acagctggaa gatggacgca 2040 ccctgtctga ctacaacatc cagaaagagt ccactctgca cttggtcctg cgcttgaggg 2100 ggggtgtcta agtttcccct tttaaggttt caacaaattt cattgcactt tcctttcaat 2160 aaagttgttg cattcccaaa aaaaaaaaaa aaaaaaaaaa a 2201 <210> 116 <211 >2405

<212> DNA <213> Homo Sapiens <400> 116 tccggcgtgg tgcgcaggcg cggtatcccc cctcccccgc cagctcgacc ccggtgtggt 60 gcgcaggcgc agtctgcgca gggactggcg ggactgcgcg gcggcaacag cagacatgtc 120 gggggtccgg ggcctgtcgc ggctgctgag cgctcggcgc ctggcgctgg ccaaggcgtg 180 gccaacagtg ttgcaaacag gaacccgagg ttttcacttc actgttgatg ggaacaagag 240 ggcatctgct aaagtttcag attccatttc tgctcagtat ccagtagtgg atcatgaatt 300 tgatgcagtg gtggtaggcg ctggaggggc aggcttgcga gctgcatttg gcctttctga 360 ggcagggttt aatacagcat gtgttaccaa gctgtttcct accaggtcac acactgttgc 420 agcacaggga ggaatcaatg ctgctctggg gaacatggag gaggacaact ggaggtggca 480 tttctacgac accgtgaagg gctccgactg gctgggggac caggatgcca tccactacat 540 gacggagcag gcccccgccg ccgtggtcga gctagaaaat tatggcatgc cgtttagcag 600 aactgaagat gggaagattt atcagcgtgc atttggtgga cagagcctca agtttggaaa 660 gggcgggcag gcccatcggt gctgctgtgt ggctgatcgg actggccact cgctattgca 720 caccttatat ggaaggtctc tgcgatatga taccagctat tttgtggagt attttgcctt 780 ggatctcctg atggagaatg gggagtgccg tggtgtcatc gcactgtgca tagaggacgg 840 gtccatccat cgcataagag caaagaacac tgttgttgcc acaggaggct acgggcgcac 900 ctacttcagc tgcacgtctg cccacaccag cactggcgac ggcacggcca tgatcaccag 960 ggcaggcctt ccttgccagg acctagagtt tgttcagttc caccctacag gcatatatgg 1020 tgctggttgt ctcattacgg aaggatgtcg tggagaggga ggcattctca ttaacagtca 1080 aggcgaaagg tttatggagc gatacgcccc tgtcgcgaag gacctggcgt ctagagatgt 1140 ggtgtctcgg tccatgactc tggagatccg agaaggaaga ggctgtggcc ctgagaaaga 1200 tcacgtctac ctgcagctgc accacctacc tccagagcag ctggccacgc gcctgcctgg 1260 catttcagag acagccatga tcttcgctgg cgtggacgtc acgaaggagc cgatccctgt 1320 cctccccacc gtgcattata acatgggcgg cattcccacc aactacaagg ggcaggtcct 1380 gaggcacgtg aatggccagg atcagattgt gcccggcctg tacgcctgtg gggaggccgc 1440 ctgtgcctcg gtacatggtg ccaaccgcct cggggcaaac tcgctcttgg acctggttgt 1500 ctttggtcgg gcatgtgccc tgagcatcga agagtcatgc aggcctggag ataaagtccc 1560 tccaattaaa ccaaacgctg gggaagaatc tgtcatgaat cttgacaaat tgagatttgc 1620 tgatggaagc ataagaacat cggaactgcg actcagcatg cagaagtcaa tgcaaaatca 1680 tgctgccgtg ttccgtgtgg gaagcgtgtt gcaagaaggt tgtgggaaaa tcagcaagct 1740 ctatggagac ctaaagcacc tgaagacgtt cgaccgggga atggtctgga acacggacct 1800 ggtggagacc ctggagctgc agaacctgat gctgtgtgcg ctgcagacca tctacggagc I860 agaggcacgg aaggagtcac ggggcgcgca tgccagggaa gactacaagg tgcggattga 1920 tgagtacgat tactccaagc ccatccaggg gcaacagaag aagccctttg aggagcactg 1980 gaggaagcac accctgtcct atgtggacgt tggcactggg aaggtcactc tggaatatag 2040 acccgtgatc gacaaaactt tgaacgaggc tgactgtgcc accgtcccgc cagccattcg 2100 ctcctactga tgagacaaga tgtggtgatg acagaatcag cttttgtaat tatgtataat 2160 agctcatgca tgtgtccatg tcataactgt cttcatacgc ttctgcactc tggggaagaa 2220 ggagtacatt gaagggagat tggcacctag tggctgggag cttgccagga acccagtggc 2280 cagggagcgt ggcacttacc tttgtccctt gcttcattct tgtgagatga taaaactggg 2340 cacagctctt aaataaaata taaatgaaca aactttcttt tatttccaaa aaaaaaaaaa 2400 aaaaa 2405 <210> 117 <211> 1536

<212> DNA <213> Homo Sapiens <400> 117 gtgacgcgag gctctgcgga gaccaggagt cagactgtag gacgacctcg ggtcccacgt 60 gtccccggta ctcgccggcc ggagcccccg gcttcccggg gccgggggac cttagcggca 120 cccacacaca gcctactttc caagcggagc catgtctggt aacggcaatg cggctgcaac 180 ggcggaagaa aacagcccaa agatgagagt gattcgcgtg ggtacccgca agagccagct 240 tgctcgcata cagacggaca gtgtggtggc aacattgaaa gcctcgtacc ctggcctgca 300 gtttgaaatc attgctatgt ccaccacagg ggacaagatt cttgatactg cactctctaa 360 gattggagag aaaagcctgt ttaccaagga gcttgaacat gccctggaga agaatgaagt 420 ggacctggtt gttcactcct tgaaggacct gcccactgtg cttcctcctg gcttcaccat 480 cggagccatc tgcaagcggg aaaaccctca tgatgctgtt gtctttcacc caaaatttgt 540 tgggaagacc ctagaaaccc tgccagagaa gagtgtggtg ggaaccagct ccctgcgaag 600 agcagcccag ctgcagagaa agttcccgca tctggagttc aggagtattc ggggaaacct 660 caacacccgg cttcggaagc tggacgagca gcaggagttc agtgccatca tcctggcaac 720 agctggcctg cagcgcatgg gctggcacaa ccgggtgggg cagatcctgc accctgagga 780 atgcatgtat gctgtgggcc agggggcctt gggcgtggaa gtgcgagcca aggaccagga 840 catcttggat ctggtgggtg tgctgcacga tcccgagact ctgcttcgct gcatcgctga 900 aagggccttc ctgaggcacc tggaaggagg ctgcagtgtg ccagtagccg tgcatacagc 960 tatgaaggat gggcaactgt acctgactgg aggagtctgg agtctagacg gctcagatag 1020 catacaagag accatgcagg ctaccatcca tgtccctgcc cagcatgaag atggccctga 1080 ggatgaccca cagttggtag gcatcactgc tcgtaacatt ccacgagggc cccagttggc 1140 tgcccagaac ttgggcatca gcctggccaa cttgttgctg agcaaaggag ccaaaaacat 1200 cctggatgtt gcacggcagc ttaacgatgc ccattaactg gtttgtgggg cacagatgcc 1260 tgggttgctg ctgtccagtg cctacatccc gggcctcagt gccccattct cactgctatc 1320 tggggagtga ttaccccggg agactgaact gcagggttca agccttccag ggatttgcct 1380 caccttgggg ccttgatgac tgccttgcct cctcagtatg tgggggcttc atctctttag 1440 agaagtccaa gcaacagcct ttgaatgtaa ccaatcctac taataaacca gttctgaagg 1500 taaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaa 1536 <210> 118 <211> 1435

<212> DNA <213> Homo Sapiens <400> 118 ggcggggcct gcttctcctc agcttcaggc ggctgcgacg agccctcagg cgaacctctc 60 ggctttcccg cgcggcgccg cctcttgctg cgcctccgcc tcctcctctg ctccgccacc 120 ggcttcctcc tcctgagcag tcagcccgcg cgccggccgg ctccgttatg gcgacccgca 180 gccctggcgt cgtgattagt gatgatgaac caggttatga ccttgattta ttttgcatac 240 ctaatcatta tgctgaggat ttggaaaggg tgtttattcc tcatggacta attatggaca 300 ggactgaacg tcttgctcga gatgtgatga aggagatggg aggccatcac attgtagccc 360 tctgtgtgct caaggggggc tataaattct ttgctgacct gctggattac atcaaagcac 420 tgaatagaaa tagtgataga tccattccta tgactgtaga ttttatcaga ctgaagagct 480 attgtaatga ccagtcaaca ggggacataa aagtaattgg tggagatgat ctctcaactt 540 taactggaaa gaatgtcttg attgtggaag atataattga cactggcaaa acaatgcaga 600 ctttgctttc cttggtcagg cagtataatc caaagatggt caaggtcgca agcttgctgg 660 tgaaaaggac cccacgaagt gttggatata agccagactt tgttggattt gaaattccag 720 acaagtttgt tgtaggatat gcccttgact ataatgaata cttcagggat ttgaatcatg 780 tttgtgtcat tagtgaaact ggaaaagcaa aatacaaagc ctaagatgag agttcaagtt 840 gagtttggaa acatctggag tcctattgac atcgccagta aaattatcaa tgttctagtt 900 ctgtggccat ctgcttagta gagctttttg catgtatctt ctaagaattt tatctgtttt 960 gtactttaga aatgtcagtt gctgcattcc taaactgttt atttgcacta tgagcctata 1020 gactatcagt tccctttggg cggattgttg tttaacttgt aaatgaaaaa attctcttaa 1080 accacagcac tattgagtga aacattgaac tcatatctgt aagaaataaa gagaagatat 1140 attagttttt taattggtat tttaattttt atatatgcag gaaagaatag aagtgattga 1200 atattgttaa ttataccacc gtgtgttaga aaagtaagaa gcagtcaatt ttcacatcaa 1260 agacagcatc taagaagttt tgttctgtcc tggaattatt ttagtagtgt ttcagtaatg 1320 ttgactgtat tttccaactt gttcaaatta ttaccagtga atctttgtca gcagttccct 1380 tttaaatgca aatcaataaa ttcccaaaaa tttaaaaaaa aaaaaaaaaa aaaaa 1435 <210> 119 <211 >2395

<212> DNA <213> Homo Sapiens <400> 119 agaggcaggg gctggcctgg gatgcgcgcg cacctgccct cgccccgccc cgcccgcacg 60 aggggtggtg gccgaggccc cgccccgcac gcctcgcctg aggcgggtcc gctcagccca 120 ggcgcccgcc cccgcccccg ccgattaaat gggccggcgg ggctcagccc ccggaaacgg 180 tcgtacactt cggggctgcg agcgcggagg gcgacgacga cgaagcgcag acagcgtcat 240 ggcagagcag gtggccctga gccggaccca ggtgtgcggg atcctgcggg aagagctttt 300 ccagggcgat gccttccatc agtcggatac acacatattc atcatcatgg gtgcatcggg 360 tgacctggcc aagaagaaga tctaccccac catctggtgg ctgttccggg atggccttct 420 gcccgaaaac accttcatcg tgggctatgc ccgttcccgc ctcacagtgg ctgacatccg 480 caaacagagt gagcccttct tcaaggccac cccagaggag aagctcaagc tggaggactt 540 ctttgcccgc aactcctatg tggctggcca gtacgatgat gcagcctcct accagcgcct 600 caacagccac atgaatgccc tccacctggg gtcacaggcc aaccgcctct tctacctggc 660 cttgcccccg accgtctacg aggccgtcac caagaacatt cacgagtcct gcatgagcca 720 gataggctgg aaccgcatca tcgtggagaa gcccttcggg agggacctgc agagctctga 780 ccggctgtcc aaccacatct cctccctgtt ccgtgaggac cagatctacc gcatcgacca 840 ctacctgggc aaggagatgg tgcagaacct catggtgctg agatttgcca acaggatctt 900 cggccccatc tggaaccggg acaacatcgc ctgcgttatc ctcaccttca aggagccctt ‘ 960 tggcactgag ggtcgcgggg gctatttcga tgaatttggg atcatccggg acgtgatgca 1020 gaaccaccta ctgcagatgc tgtgtctggt ggccatggag aagcccgcct ccaccaactc 1080 agatgacgtc cgtgatgaga aggtcaaggt gttgaaatgc atctcagagg tgcaggccaa 1140 caatgtggtc ctgggccagt acgtggggaa ccccgatgga gagggcgagg ccaccaaagg 1200 gtacctggac gaccccacgg tgccccgcgg gtccaccacc gccacttttg cagccgtcgt 1260 cctctatgtg gagaatgaga ggtgggatgg ggtgcccttc atcctgcgct gcggcaaggc 1320 cctgaacgag cgcaaggccg aggtgaggct gcagttccat gatgtggccg gcgacatctt 1380 ccaccagcag tgcaagcgca acgagctggt gatccgcgtg cagcccaacg aggccgtgta 1440 caccaagatg atgaccaaga agccgggcat gttcttcaac cccgaggagt cggagctgga 1500 cctgacctac ggcaacagat acaagaacgt gaagctccct gacgcctacg agcgcctcat 1560 cctggacgtc ttctgcggga gccagatgca cttcgtgcgc agcgacgagc tccgtgaggc 1620 ctggcgtatt ttcaccccac tgctgcacca gattgagctg gagaagccca agcccatccc 1680 ctatatttat ggcagccgag gccccacgga ggcagacgag ctgatgaaga gagtgggttt 1740 ccagtatgag ggcacctacs agtgggtgaa cccccacaag ctctgagccc tgggcaccca 1800 cctccacccc cgccacggcc accctccttc ccgccgcccg accccgagtc gggaggactc 1860 cgggaccatt gacctcagct gcacattcct ggccccgggc tctggccacc ctggcccgcc 1920 cctcgctgct gctactaccc gagcccagct acattcctca gctgccaagc actcgagacc 1980 atcctggccc ctccagaccc tgcctgagcc caggagctga gtcacctcct ccactcactc 2040 cagcccaaca gaaggaagga ggagggcgcc cattcgtctg tcccagagct tattggccac 2100 tgggtctcac tcctgagtgg ggccagggtg ggagggaggg acaaggggga ggaaaggggc 2160 gagcacccac gtgagagaat ctgcctgtgg ccttgcccgc cagcctcagt gccacttgac 2220 attccttgtc accagcaaca tctcgagccc cctggatgtc ccctgtccca ccaactctgc 2280 actccatggc caccccgtgc cacccgtagg cagcctctct gctataagaa aagcagacgc 2340 agcagctggg acccctccca acctcaatgc cctgccatta aatccgcaaa cagcc 2395 <210> 120 <211 > 108 <212> DNA <213> Artificial <400> 120 cacagctcgt gcctcagtac tgagggtatg gaggaaaagg cagtcggtca gtgtctaaaa 60 atgacgcacg taagagacgc tcggggaaga tgtagctgga cctctgag 108 <210> 121 <211> 78 <212> DNA <213> Artificial <400> 121 tctccttggg aggaggggaa gtggccagat gttgaggctg tgaagggcac tcttgatgga 60 cagcaggctg aactccag 78 <210> 122 <211 > 630 <212> DNA <213> Artificial <400> 122 gtcgtggaac gcagaatcat ccacctgccc ccactgatca gagacctgtc atcctcaagg 60 aggaccagtg actccctgca ccagcagt^g ctcaccccaa ttccctccag gccctgggat 120 ctgagggagg ggagaagcca ccaccattac cctgatttcc accaggagct crcaggaccgg 180 gggccaaagt cttgggcatt ggaaagaagg gagttggacc catcgtggag tggaaggcac 240 cgtagctcta ggctgaatgg gtcacccata cactggtcag acagggacag cctaagcgat 300 gtcccctcat ccagtgaggc acgctggcgg ccgagccacc ctcctttcag gagccgctgt 360 caggagaggc cccgcaggcc cagcccccgg gagagcactc agaggcacgg gagacgacgc 420 aggcaccgca gctactctcc tcccttgccc tccggcctca gttcctggag ctctgaagag 480 gacaaggaga ggcagcccca gagctggcgg gcccaccgcc gcggctcgca ctccccacac 540 tggcccgagg agaagccgcc tagctaccgc tcactggata tcactccagg caagaatagc 600 aggaaaaaag ggagtgtgga gaggcgctcg 630 <210> 123 <211 > 351 <212> DNA <213> Artificial <400> 123 gtgcttgctc ggggctgaag gtgacagtgc catcacacac tgtccatggc gtcagaggtc 60 aggccctcta cctacccgtc cactatggct tccacactcc agcatcagac atccagatca 120 tatggctatt tgagagaccc cacacaatgc ccaaatactt actgggctct gtgaataagt 180 ctgtggttcc tgacttggaa taccaacaca agttcaccat gatgccaccc aatgcatctc 240 tgcttatcaa cccactgcag ttccctgatg aaggcaatta catcgtgaag gtcaacattc 300 agggaaatgg aactctatct gccagtcaga agatacaagt cacggttgat g 351 <210> 124 <211 > 297 <212> DNA <213> Artificial <400> 124 atggacctta tggacttcaa gtgaattctg ataaagggct aaaagtaggg gaagtgttta 60 ctgttgacct tggagaggcc atcctatttg attgttctgc tgattctcat ccccccaaca 120 cctactcctg gattaggagg actgacaata ctacatatat cattaagcat gggcctcgct 180 tagaagttgc atctgagaaa gtagcccaga agacaatgga ctatgtgtgc tgtgcttaca 240 acaacataac cggcaggcaa gatgaaactc atttcacagt tatcatcact tccgtag 297 <210> 125 <211 > 126 <212> DNA <213> Artificial <400> 125 gactggagaa gcttgcacag aaaggaaaat cattgtcacc tttagcaagt ataactggaa 60 tatcactatt tttgattata tccatgtgtc ttctcttcct atggaaaaaa tatcaaccct 120 acaaag 126 <210> 126 <211 > 327 <212> DNA <213> Artificial <400> 126 gtcagggtgt gtccctatac attcctcagg ccaccatcaa tgccactgtc aaagaagaca 60 tcctgctctc agttgagtac tcctgtcatg gagtgcccac catcgaatgg acatattcat 120 ccaattgggg aacgcagaag atcgtggagt ggaaacoagg gactcaggcc aacatctctc 180 aaagccacaa ggacagagtc tgcacctttg acaacggctc catccagctc ttcagcgtgg 240 gagtgaggga ttccggctac tatgtcatca ccgtgacgga gcgcctgggg agcagccagt 300 ttggcaccat cgtgctgcac gtctctg 327 <210> 127 <211 > 141 <212> DNA <213> Artificial <400> 127 agatcctcta tgaagacctg cactttgtcg ctgtcatcct tgcttttctc gctgctgtgg 60 ccgcagtatt aatcagcctc atgtgggttt gtaataagtg tgcatataaa tttcagagga 120 agagaagaca caaactcaaa g 141 <210> 128 <211 > 326 <212> DNA <213> Artificial <400> 128 aaagcacaac tgaggagatt gagctggaag atgttgagtg ttagccaagg ctgggcctga 60 ctgcattcct acctcaagag gaaaccattc tccaacaaaa agagcaagca cagctattat 120 acccattgtg tgtggtcctg ttgcagcccg ctcctaacag gacagtggga gattaacaac 180 attgactgca tggagttgag gactgtggat gggacaaagc tagtattagg actcgcgcta 240 agttcaagga gaagagtgat tgaggctttg aaccaggagc ttcgcttggc tgcagcatca 300 gggccgtgct gacacataac caatgg 326 <210> 129 <211>524 <212> DNA <213> Artificial <400> 129 gtgagtacag tgaccgctgg ggagacagag cgatcgagag aaatgtctac ctctctacct 60 gacagctgtg tgcgctgggt tcctcctcca cctcctgtcc tgccaccccc aagattggtc 120 attccagact cttctccgct gggtgcccct ggcctcaggg atgaccattc tcatttgcct 180 tttcacctac atacacctct ccacacttct tatccatatc tatcactcca tgcatttgga 240 attctcatgg acactattga taaaatggaa gggcaggttt ggcgtggtga ggttgtggtg 300 taagactgtt ccctctccct ggggcattca aactagagga aaccttctct ggtcgttccc 360 ttcccatgca gagaagttcc tttttatatg agaagagtgt gcaaactgtg gcctttgggc 420 acccacccag ccacagattt gttttattta ctcccatgat gacatgggcc acaatagggc 480 ctagttctta tttgaggatt cacaattttt accttactgg ccaa 524 <210> 130 <211> 57 <212> DNA <213> Artificial <400> 130 gcaggacagg gctgcttgct gatctcttgc ccagttttgc tgtggagatt atgccag 57

<210> 131 <211 > 61 <212> DNA <213> Artificial <400> 131 agtgggtgtt tgttggcctg gtgctcctgg gcgtcttcct cttcttcgtc ctggtgggga 60 t 61 <210> 132 <211> 66 <212> DNA <213> Artificial <400> 132 ctgctggtgc cagtgctgcc ctcacagctg ctgctgctat gtccgctgcc catgctgccc 60 agattc 66 <210> 133 <211> 20 <212> DNA <213> Artificial <400> 133 ctgctggtgc cctcaagcct 20 <210> 134 <211> 87 <212> DNA <213> Artificial <400> 134 gtgctccata tatatttgtc aagagaatgg ggggacagat gaagaggaca caggctggca 60 ctgaggtccc ctccactttc ctcctag 87 <210> 135 <211> 44 <212> DNA <213> Artificial <400> 135 actggcacag cctccaggtt ggcgggctca tctgcgctgg ggtt 44 <210> 136 <211 > 31 <212> DNA <213> Artificial <400> 136 ctgtgcgcca tgggcatcat catcgtcatg a 31 <210> 137 <211> 37 <212> DNA <213> Artificial <400> 137 gtgcaaaatg caaatgcaag tttggccaga agtccgg 37 <210> 138 <211 > 212 <212> PRT <213> Artificial <400> 138

Gin Val Thr Ile Pro Asp Gly Phe Val Asn Val Thr Val Gly Ser Asn 15 10 15

Val Thr Leu Ile Cys Ile Tyr Thr Thr Thr Val Ala Ser Arg Glu Gin 20 25 30

Leu Ser Ile Gin Trp Ser Phe Phe His Lys Lys Glu Met Glu Pro lie 35 40 45

Ser Ile Tyr Phe Ser Gin Gly Gly Gin Ala Val Ala lie Gly Gin Phe 50 55 60

Lys Asp Arg lie Thr Gly Ser Asn Asp Pro Gly Asn Ala Ser lie Thr 65 70 75 80 lie Ser His Met Gin Pro Ala Asp Ser Gly He Tyr lie Cys Asp Val 85 90 95

Asn Asn Pro Pro Asp Phe Leu Gly Gin Asn Gin Gly He Leu Asn Val 100 105 110

Ser Val Leu Val Lys Pro Ser Lys Pro Leu Cys Ser Val Gin Gly Arg 115 120 125

Pro Glu Thr Gly His Thr He Ser Leu Ser Cys Leu Ser Ala Leu Gly 130 135 140

Thr Pro Ser Pro Val Tyr Tyr Trp His Lys Leu Glu Gly Arg Asp lie 145 150 155 160

Val Pro Val Lys Glu Asn Phe Asn Pro Thr Thr Gly lie Leu Val lie 165 170 175

Gly Asn Leu Thr Asn Phe Glu Gin Gly Tyr Tyr Gin Cys Thr Ala lie 180 185 190

Asn Arg Leu Gly Asn Ser Ser Cys Glu lie Asp Leu Thr Ser Ser His 195 200 205

Pro Glu Val Gly 210 <210> 139 <211> 248 <212> PRT <213> Artificial <400> 139

Gin Val Thr lie Pro Asp Gly Phe Val Asn Val Thr Val Gly Ser Asn 15 10 15

Val Thr leu lie Cys lie Tyr Thr Thr Thr Val Ala Ser Arg Glu Gin 20 25 30

Leu Ser lie Gin Trp Ser Phe Phe His Lys Lys Glu Met Glu Pro lie 35 40 45

Ser His Ser Ser Cys Leu Ser Thr Glu Gly Met Glu Glu Lys Ala Val 50 55 60

Gly Gin Cys Leu Lys Met Thr His Val Arg Asp Ala Arg Gly Arg Cys 65 70 75 80

Ser Trp Thr Ser Glu He Tyr Phe Ser Gin Gly Gly Gin Ala Val Ala 85 90 95 lie Gly Gin Phe Lys Asp Arg lie Thr Gly Ser Asn Asp Pro Gly Asn 100 105 110

Ala Ser Ile Thr Ile Ser His Met Gin Pro Ala Asp Ser Gly Ile Tyr 115 120 125

Ile Cys Asp Val Asn Asn Pro Pro Asp Phe Leu Gly Gin Asn Gin Gly 130 135 140

Ile Leu Asn Val Ser Val Leu Val Lys Pro Ser Lys Pro Leu Cys Ser 145 150 155 160

Val Gin Gly Arg Pro Glu Thr Gly His Thr Ile Ser Leu Ser Cys Leu 165 170 175

Ser Ala Leu Gly Thr Pro Ser Pro Val Tyr Tyr Trp His Lys Leu Glu 180 185 190

Gly Arg Asp Ile Val Pro Val Lys Glu Asn Phe Asn Pro Thr Thr Gly 195 200 205

Ile Leu Val Ile Gly Asn Leu Thr Asn Phe Glu Gin Gly Tyr Tyr Gin 210 215 220

Cys Thr Ala Ile Asn Arg Leu Gly Asn Ser Ser Cys Glu Ile Asp Leu 225 230 235 240

Thr Ser Ser His Pro Glu Val Gly 245 <210> 140 <211 > 274 <212> PRT <213> Artificial <400> 140

Gin Val Thr Ile Pro Asp Gly Phe Val Asn val Thr Val Gly Ser Asn 15 10 15

Val Thr Leu ile Cys ile Tyr Thr Thr Thr Val Ala Ser Arg Glu Gin 20 25 30

Leu Ser Ile Gin Trp Ser Phe Phe His Lys Lys Glu Met Glu Pro Ile 35 40 45

Ser His Ser Ser Cys Leu Ser Thr Glu Gly Met Glu Glu Lys Ala Val 50 55 60

Gly Gin Cys Leu Lys Met Thr His Val Arg Asp Ala Arg Gly Arg Cys 65 70 75 80

Ser Trp Thr Ser Glu Ser Pro Trp Glu Glu Gly Lys Trp Pro Asp Val 85 90 95

Glu Ala Val Lys Gly Thr Leu Asp Gly Gin Gin Ala Glu Leu Gin Ile 100 105 110

Tyr Phe Ser Gin Gly Gly Gin Ala Val Ala Ile Gly Gin Phe Lys Asp 115 120 125

Arg Ile Thr Gly Ser Asn Asp Pro Gly Asn Ala Ser Ile Thr Ile Ser 130 135 140

His Met Gin Pro Ala Asp Ser Gly Ile Tyr Ile Cys Asp Val Asn Asn 145 150 155 160

Pro Pro Asp Phe Leu Gly Gin Asn Gin Gly Ile Leu Asn Val Ser Val 165 170 175 '

Leu Val Lys Pro Ser Lys Pro Leu Cys Ser Val Gin Gly Arg Pro Glu 180 185 190

Thr Gly His Thr Ile Ser Leu Ser Cys Leu Ser Ala Leu Gly Thr Pro 195 200 205

Ser Pro Val Tyr Tyr Trp His Lys Leu Glu Gly Arg Asp Ile Val Pro 210 215 220

Val Lys Glu Asn Phe Asn Pro Thr Thr Gly Ile Leu Val Ile Gly Asn 225 230 235 240

Leu Thr Asn Phe Glu Gin Gly Tyr Tyr Gin Cys Thr Ala Ile Asn Arg 245 250 255

Leu Gly Asn Ser Ser Cys Glu Ile Asp Leu Thr Ser Ser His Pro Glu 260 265 270

Val Gly <210> 141 <211 > 171 <212> PRT <213> Artificial <400> 141

Gin Val Thr Ile Pro Asp Gly Phe Val Asn Val Thr Val Gly Ser Asn 15 10 15

Val Thr Leu Ile Cys Ile Tyr Thr Thr Thr Val Ala Ser Arg Glu Gin 20 25 30

Leu Ser Ile Gin Trp Ser Phe Phe His Lys Lys Glu Met Glu Pro lie 35 40 45

Ser Ile Tyr Phe Ser Gin Gly Gly Gin Ala Val Ala lie Gly Gin Phe 50 55 60

Lys Asp Arg lie Thr Gly Ser Asn Asp Pro Val Lys Pro Ser Lys Pro 65 70 75 80

Leu Cys Ser Val Gin Gly Arg Pro Glu Thr Gly His Thr He Ser Leu 85 90 95

Ser Cys Leu Ser Ala Leu Gly Thr Pro Ser Pro Val Tyr Tyr Trp His 100 105 110

Lys Leu Glu Gly Arg Asp He Val Pro Val Lys Glu Asn Phe Asn Pro 115 120 125

Thr Thr Gly He Leu Val He Gly Asn Leu Thr Asn Phe Glu Gin Gly 130 135 140

Tyr Tyr Gin Cys Thr Ala He Asn Arg Leu Gly Asn Ser Ser Cys Glu 145 150 155 160

He Asp Leu Thr Ser Ser His Pro Glu Val Gly 165 170 <210> 142 <211 > 181 <212> PRT <213> Artificial <400> 142

Gin Val Thr lie Pro Asp Gly Phe Val Asn Val Thr Val Gly Ser Asn 15 10 15

Val Thr Leu lie Cys He Tyr Thr Thr Thr Val Ala Ser Arg Glu Gin 20 25 30

Leu Ser Ile Gin Trp Ser Phe Phe His Lys Lys Glu Met Glu Pro Ile 35 40 45

Ser Ile Tyr Phe Ser Gin Gly Gly Gin Ala Val Ala Ile Gly Gin Phe 50 55 60

Lys Asp Arg Ile Thr Gly Ser Asn Asp Pro Gly Asn Ala Ser Ile Thr 65 70 75 80

Ile Ser His Met Gin Pro Ala Asp Ser Gly Ile Tyr Ile Cys Asp Val 85 90 95

Asn Asn Pro Pro Asp Phe Leu Gly Gin Asn Gin Gly ile Leu Asn Val 100 105 110

Ser Val Leu Val Lys Pro Ser Lys Pro Leu Cys Ser Val Gin Gly Arg 115 120 125

Pro Glu Thr Gly His Thr Ile Ser Leu Ser Cys Leu Ser Ala Leu Gly 130 135 140

Thr Pro Ser Pro Val Tyr Tyr Trp His Lys Leu Glu Gly Arg Asp Ile 145 150 155 160

Val Pro Val Lys Glu Asn Phe Thr Asn His Arg Asp Phe Gly His Trp 165 170 175

Lys Ser Asp Lys Phe 180 <210> 143 <211 > 209 <212> PRT <213> Artificial <400> 143

Gin Val Thr Ile Pro Asp Gly Phe Val Asn Val Thr Val Gly Ser Asn 15 10 15

Val Thr Leu Ile Cys Ile Tyr Thr Thr Thr Val Ala Ser Arg Glu Gin 20 25 30

Leu Ser Ile Gin Trp Ser Phe Phe His Lys Lys Glu Met Glu Pro Ile 35 40 45

Ser Ile Tyr Phe Ser Gin Gly Gly Gin Ala Val Ala Ile Gly Gin Phe 50 55 60

Lys Asp Arg Ile Thr Gly Ser Asn Asp Pro Gly Asn Ala Ser Ile Thr 65 70 75 80

Ile Ser His Met Gin Pro Ala Asp Ser Gly Ile Tyr Ile Cys Asp Val 85 90 95

Asn Asn Pro Pro Asp Phe Leu Gly Gin Asn Gin Gly Ile Leu Asn Val 100 105 110

Ser Val Leu Val Lys Pro Ser Lys Pro Leu Cys Ser Val Gin Gly Arg 115 120 125

Pro Glu Thr Gly His Thr Ile Ser Leu Ser Cys Leu Ser Ala Leu Gly 130 135 140

Thr Pro Ser Pro Val Tyr Tyr Trp His Lys Leu Glu Gly Arg Asp Ile 145 150 155 160

Val Pro Val Lys Glu Asn Phe Asn Pro Thr Thr Gly Ile Leu Val Ile 165 170 175

Gly Asn Leu Thr Asn Phe Glu Gin Gly Tyr Tyr Gin Cys Thr Ala Ile 180 185 190

Asn Arg Leu Gly Asn Ser Ser Cys Glu Ile Asp Leu Thr Ser Ser Arg 195 200 205

Gin <210> 144 <211 > 312 <212> PRT <213> Artificial <400> 144

Ser His Thr Val His Gly Val Arg Gly Gin Ala Leu Tyr Leu Pro Val 1.5 10 15

His Tyr Gly Phe His Thr Pro Ala Ser Asp Ile Gin ile Ile Trp Leu 20 25 30

Phe Glu Arg Pro His Thr Met Pro Lys Tyr Leu Leu Gly Ser Val Asn 35 40 45

Lys Ser Val Val Pro Asp Leu Glu Tyr Gin His Lys Phe Thr Met Met 50 55 60

Pro Pro Asn Ala Ser Leu Leu Ile Asn Pro Leu Gin Ehe Pro Asp Glu 65 70 75 80

Gly Asn Tyr Ile Val Lys Val Asn Ile Gin Gly Asn Gly Thr Leu Ser 85 90 95

Ala Ser Gin Lys Ile Gin Val Thr Val Asp Asp Pro Val Thr Lys Pro 100 105 110

Val Val Gin lie His Pro Pro Ser Gly Ala Val Glu Tyr Val Gly Asn 115 120 125

Met Thr Leu Thr Cys His Val Glu Gly Gly Thr Arg Leu Ala Tyr Gin 130 135 140

Trp Leu Lys Asn Gly Arg Pro Val His Thr Ser Ser Thr Tyr Ser Phe 145 150 155 160

Ser Pro Gin Asn Asn Thr Leu His He Ala Pro Val Thr Lys Glu Asp 165 170 175 lie Gly Asn Tyr Ser Cys Leu Val Arg Asn Pro Val Ser Glu Met Glu 180 185 190

Ser Asp lie He Met Pro lie lie Tyr Tyr Gly Pro Tyr Gly Leu Gin 195 200 205

Val Asn Ser Asp Lys Gly Leu Lys Val Gly Glu Val Phe Thr Val Asp 210 215 220

Leu Gly Glu Ala lie Leu Phe Asp Cys Ser Ala Asp Ser His Pro Pro 225 230 235 240

Asn Thr Tyr Ser Trp He Arg Arg Thr Asp Asn Thr Thr Tyr He He 245 250 255

Lys His Gly Pro Arg Leu Glu Val Ala Ser Glu Lys Val Ala Gin Lys 260 265 270

Thr Met Asp. Tyr Val Cys Cys Ala Tyr Asn Asn He Thr Gly Arg Gin 275 280 285

Asp Glu Thr His Phe Thr Val lie lie Thr Ser Val Gly Leu Glu Lys 290 295 300

Leu Ala Gin Lys Gly Lys Ser Leu 305 310 <210> 145 <211 > 320 <212> PRT <213> Artificial <400> 145

Gly Leu Lys Val Thr Val Pro Ser His Thr Val His Gly Val Arg Gly 15 10 15

Gin Ala Leu Tyr Leu Pro Val His Tyr Gly Phe His Thr Pro Ala Ser 20 25 30

Asp Ile Gin Ile Ile Trp Leu Phe Glu Arg Pro His Thr Met Pro Lys 35 40 45

Tyr Leu Leu Gly Ser Val Asn Lys Ser Val Val Pro Asp Leu Glu Tyr 50 55 60

Gin His Lys Phe Thr Met Met Pro Pro Asn Ala Ser Leu Leu Ile Asn 65 70 75 80

Pro Leu Gin Phe Pro Asp Glu Gly Asn Tyr Ile Val Lys Val Asn lie 85 90 95

Gin Gly Asn Gly Thr Leu Ser Ala Ser Gin Lys lie Gin Val Thr Val 100 105 110

Asp Asp Pro Val Thr Lys Pro Val Val Gin lie His Pro Pro Ser Gly 115 120 125

Ala Val Glu Tyr Val Gly Asn Met Thr Leu Thr Cys His Val Glu Gly 130 135 140

Gly Thr Arg Leu Ala Tyr Gin Trp Leu Lys Asn Gly Arg Pro Val His 145 150 155 160

Thr Ser Ser Thr Tyr Ser Phe Ser Pro Gin Asn Asn Thr Leu His lie 165 170 175

Ala Pro Val Thr Lys Glu Asp He Gly Asn Tyr Ser Cys Leu Val Arg 180 185 190

Asn Pro Val Ser Glu Met Glu Ser Asp lie lie Met Pro lie He Tyr 195 200 205

Tyr Gly Pro Tyr Gly Leu Gin Val Asn Ser Asp Lys Gly Leu Lys Val 210 215 220

Gly Glu Val Phe Thr Val Asp Leu Gly Glu Ala lie Leu Phe Asp Cys 225 230 235 240

Ser Ala Asp Ser His Pro Pro Asn Thr Tyr Ser Trp He Arg Arg Thr 245 250 255

Asp Asn Thr Thr Tyr He He Lys His Gly Pro Arg Leu Glu Val Ala 260 265 270

Ser Glu Lys Val Ala Gin Lys Thr Met Asp Tyr Val Cys Cys Ala Tyr 275 280 285

Asn Asn He Thr Gly Arg Gin Asp Glu Thr His Phe Thr Val He He 290 295 300

Thr Ser Val Gly Leu Glu Lys Leu Ala Gin Lys Gly Lys Ser Leu 305 310 315 <210> 146 <211 > 119 <212> PRT <213> Artificial <400> 146

Leu Gin Ser Gin Gly Val Ser Leu Tyr lie Pro Gin Ala Thr lie Asn 15 10 15

Ala Thr Val Lys Glu Asp lie Leu Leu Ser Val Glu Tyr Ser Cys His 20 25 30

Gly Val Pro Thr lie Glu Trp Thr Tyr Ser Ser Asn Trp Gly Thr Gin 35 40 45

Lys lie Val Glu Trp Lys Pro Gly Thr Gin Ala Asn lie Ser Gin Ser 50 55 60

His Lys Asp Arg Val Cys Thr Phe Asp Asn Gly Ser lie Gin Leu Phe 65 70 75 80

Ser Val Gly Val Arg Asp Ser Gly Tyr Tyr Val lie Thr Val Thr Glu 85 90 95

Arg Leu Gly Ser Ser Gin Phe Gly Thr lie Val Leu His Val Ser Glu 100 105 110 lie Leu Tyr Glu Asp Leu His 115 <210> 147 <211 > 166 <212> PRT <213> Artificial <400> 147

Leu Gin Val Thr Val Pro Asp Lys Lys Lys Val Ala Met Leu Phe Gin 15 10 15

Pro Thr Val Leu Arg Cys His Phe Ser Thr Ser Ser His Gin Pro Ala 20 25 30

Val Val Gin Trp Lys Phe Lys Ser Tyr Cys Gin Asp Arg Met Gly Glu 35 40 45

Ser Leu Gly Met Ser Ser Thr Arg Ala Gin Ser Leu Ser Lys Arg Asn 50 55 60

Leu Glu Trp Asp Pro Tyr Leu Asp Cys Leu Asp Ser Arg Arg Thr Val 65 70 75 80

Arg Val Val Ala Ser Lys Gin Gly Ser Thr Val Thr Leu Gly Asp Phe 85 90 95

Tyr Arg Gly Arg Glu lie Thr lie Val His Asp Ala Asp Leu Gin lie 100 105 110

Gly Lys Leu Met Trp Gly Asp Ser Gly Leu Tyr Tyr Cys lie lie Thr 115 120 125

Thr Pro Asp Asp Leu Glu Gly Lys Asn Glu Gly Ser Leu Gly Leu Leu 130 135 140

Val Leu Gly Arg Thr Gly Leu Leu Ala Asp Leu Leu Pro Ser Phe Ala 145 150 155 160

Val Glu lie Met Pro Glu 165 <210> 148 <211 > 149 <212> PRT <213> Artificial <400> 148

Leu Gin Val Thr Val Pro Asp Lys Lys Lys Val Ala Met Leu Phe Gin 15 10 15

Pro Thr Val Leu Arg Cys His Phe Ser Thr Ser Ser His Gin Pro Ala 20 25 30

Val Val Gin Trp Lys Phe Lys Ser Tyr Cys Gin Asp Arg Met Gly Glu 35 40 45

Ser Leu Gly Met Ser Ser Thr Arg Ala Gin Ser Leu Ser Lys Arg Asn 50 55 60

Leu Glu Trp Asp Pro Tyr Leu Asp Cys Leu Asp Ser Arg Arg Thr Val 65 70 75 80

Arg Val Val Ala Ser Lys Gin Gly Ser Thr Val Thr Leu Gly Asp Phe 85 90 95

Tyr Arg Gly Arg Glu He Thr lie Val His Asp Ala Asp Leu Gin lie 100 105 110 '

Gly Lys Leu Met Trp Gly Asp Ser Gly Leu Tyr Tyr Cys He He Thr 115 120 125

Thr Pro Asp Asp Leu Glu Gly Lys Asn Glu Gly Ser Leu Gly Leu Leu 130 135 140

Val Leu Glu Trp Val 145 <210> 149 <211 > 16 <212> PRT <213> Artificial <400> 149

Asn Asp Leu Glu Asp Lys Asn Ser Pro Phe Tyr Tyr Asp Trp His Ser 15 10 15 <210> 150 <211> 45 <212> PRT <213> Artificial <400> 150

Asn Asp Leu Glu Asp Lys Asn Ser Pro Phe Tyr Tyr Gly Ala Pro Tyr 15 10 15 lie Phe Val Lys Arg Met Gly Gly Gin Met Lys Arg Thr Gin Ala Gly 20 25 30

Thr Glu Val Pro Ser Thr Phe Leu Leu Asp Trp His Ser 35 40 45 <210> 151 <211 > 5 <212> PRT <213> Artificial <400> 151

Asn Asp Leu Glu Asp 1 5

<210> 152 <211 > 21 <212> DNA <213> Artificial Organism <220> <223> Synthetic oligonucleotide <400> 152 gctccaggcc ataaggactt c 21

<210> 153 <211 > 21 <212> DNA <213> Artificial Organism <220> <223> Synthetic oligonucleotide <400> 153 cagcttcaaa ctctcccctg c 21

<210> 154 <211 > 103 <212> DNA <213> Artificial Organism <220> <223> Synthetic oligonucleotide <400> 154 gctccaggcc ataaggactt cattccaaat atgattacag gagcagccca ggcggatgta 60 gctgttttag ttgtagatgc cagcagggga gagtttgaag ctg 103

<210> 155 <211> 20 <212> DNA <213> Artificial Organism <220> <223> Synthetic oligonucleotide <400> 155 ttccttgcca ggacctagag 20

<210> 156 <211> 20 <212> DNA <213> Artificial Organism <220> <223> Synthetic oligonucleotide <400> 156 cataaacctt tcgccttgac 20

<210> 157 <211 > 128 <212> DNA <213> Artificial Organism <220> <223> Synthetic oligonucleotide <400> 157 ttccttgcca ggacctagag tttgttcagt tccaccccac aggcatatat ggtgctggtt 60 gtctcattac ggaaggatgt cgtggagagg gaggcattct cattaacagt caaggcgaaa 120 ggtttatg 128

<210> 158 <211 > 21 <212> DNA <213> Artificial Organism <220> <223> Synthetic oligonucleotide <400> 158 aatttgtcaa gtcggtgcag c 21

<210> 159 <211> 20 <212> DNA <213> Artificial Organism <220> <223> Synthetic oligonucleotide <400> 159 tcaccccttc atttttgcgt 20

<210> 160 <211 > 106 <212> DNA <213> Artificial Organism <220> <223> Synthetic oligonucleotide <400> 160 aatttgtcaa gtcggtgcag ctggcaagac ctaaaggatt atatgcgtca ggcaggagaa 60 gtgacttatg cagatgctca caagggacgc aaaaatgaag gggtga 106

<210> 161 <211> 24 <212> DNA <213> Artificial Organism <220> <223> Synthetic oligonucleotide <400> 161 cccaaaatgt ataaggaaga aggc 24

<210> 162 <211> 20 <212> DNA <213> Artificial Organism <220> <223> Synthetic oligonucleotide <400> 162 ttcaaagcag gcgaacttca 20

<210> 163 <211 > 140 <212> DNA <213> Artificial Organism <220> <223> Synthetic oligonucleotide <400> 163 cagccaggtt atgccaacac tttgagggat gcagctccca aaatgtataa ggaagaaggc 60 ctaaaagcat tctacaaggg ggttgctcct ctctggatga gacagatacc atacaccatg 120 atgaagttcg cctgctttga 140

<210> 164 <211> 23 <212> DNA <213> Artificial Organism <220> <223> Synthetic oligonucleotide <400> 164 tggcaagaag aaggtctggt tag 23

<210> 165 <211> 22 <212> DNA <213> Artificial Organism <220> <223> Synthetic oligonucleotide <400> 165 tgatcagccc atctttgatg ag 22

<210> 166 <211 > 101 <212> DNA <213> Artificial Organism <220> <223> Synthetic oligonucleotide <400> 166 tggcaagaag aaggtctggt tagaccccaa tgagaccaat gaaatcgcca atgccaactc 60 ccgtcagcag atccggaagc tcatcaaaga tgggctgatc a 101

<210> 167 <211> 20 <212> DNA <213> Artificial Organism <220> <223> Synthetic oligonucleotide <400> 167 cggtttgctg cggtaatcat 20

<210> 168 <211 > 21 <212> DNA <213> Artificial Organism <220> <223> Synthetic oligonucleotide <400> 168 tttcttgctg ccagtctgga c 21 <210> 169 <211 > 122

<212> DNA <213> Artificial Organism <220> <223> Synthetic oligonucleotide <400> 169 cggtttgctg cggtaatcat gaggataaga gagccacgaa ccacggcact gattttcagt 60 tctgggaaaa tggtgtgcac aggagccaag agtgaagaac agtccagact ggoagcaaga 120 aa 122

<210> 170 <211 > 19 <212> DNA <213> Artificial Organism <220> <223> Synthetic oligonucleotide <400> 170 atttgggtcg cggttcttg 19

<210> 171 <211 > 21 <212> DNA <213> Artificial Organism <220> <223> Synthetic oligonucleotide <400> 171 tgccttgaca ttctcgatgg t 21

<210> 172 <211 > 133 <212> DNA <213> Artificial Organism <220> <223> Synthetic oligonucleotide <400> 172 atttgggtcg cggttcttgt ttgtggatcg ctgtgatcgt cacttgacaa tgcagatctt 60 cgtgaagact ctgactggta agaccatcac cctcgaggtt gagcccagtg acaccatcga 120 gaatgtcaag gca 133

<210> 173 <211> 20 <212> DNA <213> Artificial Organism <220> <223> Synthetic oligonucleotide <400> 173 tgggaacaag agggcatctg 20

<210> 174 <211> 22 <212> DNA <213> Artificial Organism <220> <223> Synthetic oligonucleotide <400> 174 ccaccactgc atcaaattca tg 22

<210> 175 <211> 86 <212> DNA <213> Artificial Organism <220> <223> Synthetic oligonucleotide <400> 175 tgggaacaag agggcatctg ctaaagtttc agattccatt tctgctcagt atccagtagt 60 ggatcatgaa tttgatgcag tggtgg 86

<210> 176 <211 > 19 <212> DNA <213> Artificial Organism <220> <223> Synthetic oligonucleotide <400> 176 tgagagtgat tcgcgtggg 19

<210> 177 <211 > 21 <212> DNA <213> Artificial Organism <220> <223> Synthetic oligonucleotide <400> 177 ccagggtacg aggctttcaa t 21

<210> 178 <211 > 91 <212> DNA <213> Artificial Organism <220> <223> Synthetic oligonucleotide <400> 178 tgagagtgat tcgcgtgggt acccgcaaga gccagcttgc tcgcatacag acggacagtg 60 tggtggcaac attgaaagcc tcgtaccctg g 91

<210> 179 <211 > 21 <212> DNA <213> Artificial Organism <220> <223> Synthetic oligonucleotide <400> 179 tgacactggc aaaacaatgc a 21 <210> 180

<211 > 21 <212> DNA <213> Artificial Organism <220> <223> Synthetic oligonucleotide <400> 180 ggtccttttc accagcaagc t 21

<210> 181 <211> 94 <212> DNA <213> Artificial Organism <220> <223> Synthetic oligonucleotide <400> 181 tgacactggc aaaacaatgc agactttgct ttccttggtc aggcagtata atccaaagat 60 ggtcaaggtc gcaagcttgc tggtgaaaag gacc 94

<210> 182 <211> 20 <212> DNA <213> Artificial Organism <220> <223> Synthetic oligonucleotide <400> 182 gaggccgtca ccaagaacat 20

<210> 183 <211 > 19 <212> DNA <213> Artificial Organism <220> <223> Synthetic oligonucleotide <400> 183 ggacagccgg tcagagctc 19

<210> 184 <211> 111 <212> DNA <213> Artificial Organism <220> <223> Synthetic oligonucleotide <400> 184 gaggccgtca ccaagaacat tcacgagtcc tgcatgagcc agataggctg gaaccgcatc 60 atcgtggaga agcccttcgg gagggacctg cagagctctg accggctgtc c 111 <210> 185 <211 > 21 <212> DNA <213> Artificial <400> 185 aatgacgcac gtaagagacg c 21 <210> 186 <211> 20 <212> DNA <213> Artificial <400> 186 gagtgccctt cacagcctca 20 <210> 187 <211 > 101 <212> DNA <213> Artificial <400> 187 aatgacgcac gtaagagacg ctcggggaag atgtagctgg acctctgagt ctccttggga 60 ggaggggaag tggccagatg ttgaggctgt gaagggcact c 101 <210> 188 <211> 22 <212> DNA <213> Artificial <400> 188 cacagctcgt gcctcagtac tg 22 <210> 189 <211> 20 <212> DNA <213> Artificial <400> 189 agctacatct tccccgagcg 20 <210> 190 <211> 97 <212> DNA <213> Artificial <400>190 cacagctcgt gcctcagtac tgagggtatg gaggaaaagg cagtcggtca gtgtctaaaa 60 atgacgcacg taagagacgc tcggggaaga tgtagct 97 <210> 191 <211> 28 <212> DNA <213> Artificial <400> 191 gaagatgtag ctggacctct gagattta 28 <210> 192 <211 > 24 <212> DNA <213> Artificial <400> 192 gttggaccct gtaattcgat cttt 24 <210> 193 <211> 92 <212> DNA <213> Artificial <400> 193 gaagatgtag ctggacctct gagatttact tttctcaagg tggacaagct gtagccatcg 60 ggcaatttaa agatcgaatt acagggtcca ac 92 <210> 194 <211> 23 <212> DNA <213> Artificial <400> 194 atgacgcacg taagagacgc tcg 23 <210> 195 <211> 25 <212> DNA <213> Artificial <400> 195 ggagttcagc ctgctgtcca tcaag 25 <210> 196 <211 > 124 <212> DNA <213> Artificial <400> 196 atgacgcacg taagagacgc tcggggaaga tgtagctgga cctctgagtc tccttgggag 60 gaggggaagt ggccagatgt tgaggctgtg aagggcactc ttgatggaca gcaggctgaa 120 ctcc 124 <210> 197 <211> 20 <212> DNA <213> Artificial <400> 197 agccaccacc attaccctga 20 <210> 198 <211 > 19 <212> DNA <213> Artificial <400>198 tgccttccac tccacgatg 19 <210> 199 <211 > 104 <212> DNA <213> Artificial <400> 199 agccaccacc attaccctga tttccaccag gagctccagg accgggggcc aaagtcttgg 60 gcattggaaa gaagggagtt ggacccatcg tggagtggaa ggca 104 <210> 200 <211> 19 <212> DNA <213> Artificial <400> 200 gccaccgcta catgaagca 19 <210> 201 <211> 19 <212> DNA <213> Artificial <400> 201 ctggacggca gggacaaat 19 <210> 202 <211 > 142 <212> DNA <213> Artificial <400> 202 gccaccgcta catgaagcag gcccaggccc taggtcctca gatgatggga aaacccctgt 60 actggggggc ggacaggagc tcccaggttt catcttatcc aatgcacccg ctgctgcagc 120 gagatttgtc cctgccgtcc ag 142 <210> 203 <211 > 21 <212> DNA <213> Artificial <400> 203 tcctcctcct gctgctgatt g 21 <210> 204 <211> 20 <212> DNA <213> Artificial <400> 204 tgggcctgct tcatgtagcg 20 <210> 205 <211 > 145 <212> DNA <213> Artificial <400> 205 tcctcctcct gctgctgatt ggagtgtgct ggtgccagtg ctgtcctcag tattgctgct 60 gctatatccg ctgtccctgc tgtcctgccc actgctgctg tcctgaggaa gccctggccc 120 gccaccgcta catgaagcag gccca 145

<210> 206 <211> 23 <212> DNA <213> Artificial Organism <220> <223> Synthetic oligonucleotide <400> 206 ccgcagtatt aatcagcctc atg 23

<210> 207 <211> 25 <212> DNA <213> Artificial Organism <220> <223> Synthetic oligonucleotide <400> 207 aatctcctca gttgtgcttt ctttg 25

<210> 208 <211 > 101 <212> DNA <213> Artificial Organism <220> <223> Synthetic oligonucleotide <400> 208 ccgcagtatt aatcagcctc atgtgggttt gtaataagtg tgcatataaa tttcagagga 60 agagaagaca caaactcaaa gaaagcacaa ctgaggagat t 101

<210> 209 <211 > 21 <212> DNA <213> Artificial Organism <220> <223> Synthetic oligonucleotide <400> 209 gaacgcagaa gatcgtggag t 21

<210>210 <211> 20 <212> DNA <213> Artificial Organism <220> <223> Synthetic oligonucleotide <400 210 ctgaagagct ggatggagcc 20

<210211 <211 > 106 <212> DNA <213> Artificial Organism <220 <223> Synthetic oligonucleotide <400 211 gaacgcagaa gatcgtggag tggaaaccag ggactcaggc caacatctct caaagccaca 60 aggacagagt ctgcaccttt gacaacggct ccatccagct cttcag 106

<210> 212 <211 > 21 <212> DNA <213> Artificial Organism <220> <223> Synthetic oligonucleotide <400 212 ctgcactttg tcgctgtcat c 21

<210 213 <211> 26 <212> DNA <213> Artificial Organism <220> <223> Synthetic oligonucleotide <400> 213 caatctcctc agttgtgctt tctttg 26

<210> 214 <211> 145 <212> DNA <213> Artificial Organism <220> <223> Synthetic oligonucleotide <400 214 ctgcactttg tcgctgtcat ccttgctttt ctcgctgctg tggccgcagt attaatcagc 60 ctcatgtggg tttgtaataa gtgtgcatat aaatttcaga ggaagagaag acacaaactc 120 aaagaaagca caactgagga gattg 145

<210 215 <211 > 21 <212> DNA <213> Artificial Organism <220> <223> Synthetic oligonucleotide <400> 215 tgctgcacgt ctctgagatc c 21

<210> 216 <211> 23 <212> DNA <213> Artificial Organism <220> <223> Synthetic oligonucleotide <400> 216 cacctctggc ctcaaaacca ctc 23

<210> 217 <211 > 208 <212> DNA <213> Artificial Organism <220 <223> Synthetic oligonucleotide <400> 217 tgctgcacgt ctctgagatc ctctatgaag acctgcactt tgtcgctgtc atccttgctt 60 ttctcgctgc tgtggccgca gtattaatca gcctcatgtg ggtttgtaat aagtgtgcat 120 ataaatttca gaggaagaga agacacaaac tcaaaggtaa ccccctgggc cttgtgataa 180 tccatgagtg gttttgaggc cagaggtg 208

<210 218 <211 > 21 <212> DNA <213> Artificial Organism <220> <223> Synthetic oligonucleotide <400> 218 gctgcacgtc tctgagatcc t 21

<210 219 <211> 20 <212> DNA <213> Artificial Organism <220 <223> Synthetic oligonucleotide <400 219 cacctctggc ctcaaaacca 20

<210 220 <211 > 207 <212> DNA <213> Artificial Organism <220 <223> Synthetic oligonucleotide <400 220 gctgcacgtc tctgagatcc tctatgaaga cctgcacttt gtcgctgtca tccttgcttt 60 tctcgctgct gtggccgcag tattaatcag cctcatgtgg gtttgtaata agtgtgcata 120 taaatttcag aggaagagaa gacacaaact caaaggtaac cccctgggcc ttgtgataat 180 ccatgagtgg ttttgaggcc agaggtg 207

<210 221 <211 > 21 <212> DNA <213> Artificial Organism <220 <223> Synthetic oligonucleotide <400 221 atgggcctcg cttagaagtt g 21

<210 222 <211> 22 <212> DNA <213> Artificial Organism <220 <223> Synthetic oligonucleotide <400 222 ttctgtgcaa gcttctccag tc 22

<210> 223 <211> 151 <212> DNA <213> Artificial Organism <220 <223> Synthetic oligonucleotide <400> 223 atgggcctcg cttagaagtt gcatctgaga aagtagccca gaagacaatg gactatgtgt 60 gctgtgctta caacaacata accggcaggc aagatgaaac tcatttcaca gttatcatca 120 cttccgtagg actggagaag cttgcacaga a 151

<210> 224 <211 > 21 <212> DNA <213> Artificial Organism <220> <223> Synthetic oligonucleotide <400> 224 atcacacact gtccatggcg t 21

<210> 225 <211> 26 <212> DNA <213> Artificial Organism <220> <223> Synthetic oligonucleotide <400> 225 gtctctcaaa tagccatatg atctgg 26

<210> 226 <211 > 107 <212> DNA <213> Artificial Organism <220> <223> Synthetic oligonucleotide <400> 226 atcacacact gtccatggcg tcagaggtca ggccctctac ctacccgtcc actatggctt 60 ccacactcca gcatcagaca tccagatcat atggctattt gagagac 107

<210> 227 <211> 19 <212> DNA <213> Artificial Organism <220> <223> Synthetic oligonucleotide <400> 227 gctttcatgg agcccttcg 19

<210> 228 <211> 18 <212> DNA <213> Artificial Organism <220> <223> Synthetic oligonucleotide <400> 228 gcctgacctc tgacgcca 18

<210> 229 <211 > 131 <212> DNA <213> Artificial Organism <220> <223> Synthetic oligonucleotide <400> 229 gctttcatgg agcccttcgg tgacacactt ggggtctttc agtgcaaaat atacctcctt 60 ctcttcggtg cttgctcggg gctgaaggtg acagtgccat cacacactgt ccatggcgtc 120 agaggtcagg c 131

<210> 230 <211 > 21 <212> DNA <213> Artificial Organism <220> <223> Synthetic oligonucleotide <400> 230 ctctgcattt gcccctttag a 21

<210> 231 <211 > 21 <212> DNA <213> Artificial Organism <220> <223> Synthetic oligonucleotide <400> 231 gatggcactg tcaccttcag c 21

<210> 232 <211 > 105 <212> DNA <213> Artificial Organism <220> <223> Synthetic oligonucleotide <400> 232 ctctgcattt gcccctttag attgtgaaat gtggctcaag gtcttcacaa ctttcctttc 60 ctttgcaaca ggtgcttgct cggggctgaa ggtgacagtg ccatc 105

<210> 233 <211 > 21 <212> DNA <213> Artificial Organism <220> <223> Synthetic oligonucleotide <400> 233 gtgagtacag tgaccgctgg g 21

<210> 234 <211> 23 <212> DNA <213> Artificial Organism <220> <223> Synthetic oligonucleotide <400> 234 ggagaagagt ctggaatgac caa 23

<210> 235 <211 > 137 <212> DNA <213> Artificial Organism <220> <223> Synthetic oligonucleotide <400> 235 gtgagtacag tgaccgctgg ggagacagag cgatcgagag aaatgtctac ctctctacct 60 gacagctgtg tgcgctgggt tcctcctcca cctcctgtcc tgccaccccc aagattggtc 120 attccagact cttctcc 137

<210> 236 <211> 20 <212> DNA <213> Artificial Organism <220> <223> Synthetic oligonucleotide <400> 236 gcccagtttt gctgtggaga 20

<210> 237 <211 > 24 <212> DNA <213> Artificial Organism <220> <223> Synthetic oligonucleotide <400> 237 ggtagacatt tctctcgatc gctc 24

<210> 238 <211 > 227 <212> DNA <213> Artificial Organism <220> <223> Synthetic oligonucleotide <400> 238 gcccagtttt gctgtggaga ttatgccaga gtgggtgttt gttggcctgg tgctcctggg 60 cgtcttcctc ttcttcgtcc tggtggggat ctgctggtgc cagtgctgcc ctcacagctg 120 ctgctgctat gtccgctgcc catgctgccc agattcctgc tggtgccctc aagcctgtga 180 gtacagtgac cgctggggag acagagcgat cgagagaaat gtctacc 227

<210> 239 <211> 22 <212> DNA <213> Artificial Organism <220> <223> Synthetic oligonucleotide <400> 239 tgtggagatt atgccagagt gg 22

<210> 240 <211> 23 <212> DNA <213> Artificial Organism <220> <223> Synthetic oligonucleotide <400> 240 gacatttctc tcgatcgctc tgt 23

<210> 241 <211 > 211 <212> DNA <213> Artificial Organism <220> <223> Synthetic oligonucleotide <400> 241 tgtggagatt atgccagagt gggtgtttgt tggcctggtg ctcctgggcg tcttcctctt 60 cttcgtcctg gtggggatct gctggtgcca gtgctgccct cacagctgct gctgotatgt 120 ccgctgccca tgctgcccag attcctgctg gtgccctcaa gcctgtgagt acagtgaccg 180 ctggggagac agagcgatcg agagaaatgt c 211

<210> 242 <211> 29 <212> DNA <213> Artificial Organism <220> <223> Synthetic oligonucleotide <400> 242 actctattac tgtattatca ccaccccag 29

<210> 243 <211 > 21 <212> DNA <213> Artificial Organism <220> <223> Synthetic oligonucleotide <400> 243 ccaacaaaca cccactccaa c 21

<210> 244 <211 > 93 <212> DNA <213> Artificial Organism <220> <223> Synthetic oligonucleotide <400> 244 actctattac tgtattatca ccaccccaga tgacctggag gggaaaaatg agggctcact 60 gggactgctg gtgttggagt gggtgtttgt tgg 93

<210> 245 <211> 29 <212> DNA <213> Artificial Organism <220> <223> Synthetic oligonucleotide <400> 245 gtgctccata tatatttgtc aagagaatg 29

<210> 246 <211> 20 <212> DNA <213> Artificial Organism <220> <223> Synthetic oligonucleotide <400> 246 ggaggctgtg ccagtctagg 20

<210> 247 <211 > 102 <212> DNA <213> Artificial Organism <220> <223> Synthetic oligonucleotide <400> 247 gtgctccata tatatttgtc aagagaatgg ggggacagat gaagaggaca caggctggca 60 ctgaggtccc ctccactttc ctcctagact ggcacagcct cc 102

<210> 248 <211> 18 <212> DNA <213> Artificial Organism <220> <223> Synthetic oligonucleotide <400> 248 actggcacag cctccagg 18

<210> 249 <211 > 21 <212> DNA <213> Artificial Organism <220> <223> Synthetic oligonucleotide <400> 249 catttgcatt ttgcactcat g 21

<210> 250 <211 > 91 <212> DNA <213> Artificial Organism <220> <223> Synthetic oligonucleotide <400> 250 actggcacag cctccaggtt ggcgggctca tctgcgctgg ggttctgtgc gccatgggca 60 tcatcatcgt catgagtgca aaatgcaaat g 91

<210> 251 <211> 20 <212> DNA <213> Artificial Organism <220> <223> Synthetic oligonucleotide <400> 251 ttgtgttcct ggcaggcttt 20

<210> 252 <211> 20 <212> DNA <213> Artificial Organism <220> <223> Synthetic oligonucleotide <400> 252 tcatctgtcc ccccattctc 20

<210> 253 <211 > 114 <212> DNA <213> Artificial Organism <220> <223> Synthetic oligonucleotide <400> 253 ttgtgttcct ggcaggcttt cctgtcctgg acgccaatga cctagaagat aaaaacagtc 60 ctttctacta tggtgctcca tatatatttg tcaagagaat ggggggacag atga 114 <210> 254 <211 > 31 <212> DNA <213> Artificial <400> 254 ctagctagcc accatgcaga aggtgaccct g 31 <210> 255 <211> 30 <212> DNA <213> Artificial <400> 255 cgcgaccggt ccgctttggg ctgagcctgg 30 <210> 256 <211 > 21 <212> DNA <213> Artificial <400> 256 cctgtgtcct cttcatctgt c 21 <210> 257 <211 > 21 <212> DNA <213> Artificial <400> 257 gacagatgaa gaggacacag g 21 <210> 258 <211> 32 <212> DNA <213> Artificial <400> 258 ctagctagcc accatgaggc ctctgcccag cg 32 <210> 259 <211 > 31 <212> DNA <213> Artificial <400> 259 cgcgaattcg acactcaaca tcttccagct c 31 <210> 260 <211> 18 <212> DNA <213> Artificial <400> 260 aaggctgcat aggagctg 18 <210> 261 <211> 23 <212> DNA <213> Artificial <400> 261 caatgagttg gaaatcaagc cac 23 <210> 262 <211> 70 <212> DNA <213> Artificial <400> 262 cgcgaccggt ccaaaccact catggattat oacaaggccc agggggttac ctttgagttt 60 gtgtcttctc 70 <210> 263 <211> 33 <212> DNA <213> Artificial <400> 263 ctagctagcc accatggata gggtcttgct gag 33 <210> 264 <211> 30 <212> DNA <213> Artificial <400> 264 cgcgaattcg ggtagagagg tagacatttc 30 <210> 265 <211> 36 <212> DNA <213> Artificial <400> 265 gcgcttcgaa gccaccatgt ggctcaaggt cttcac 36 <210> 266 <211> 33 <212> DNA <213> Artificial <400> 266 cgcgaccggt ccctctggat ggtcttgctg ctg 33 <210> 267 <211> 33 <212> DNA <213> Artificial <400> 267 ctagctagcc accatggcat ggcccaaact gcc 33 <210> 268 <211 > 34 <212> DNA <213> Artificial <400> 268 cgcgaccggt ccaatgacca cactccttcc acta 34 <210> 269 <211 > 34 <212> DNA <213> Artificial <400> 269 ctagctagcc accatggtgt tcgcattttg gaag 34 <210> 270 <211> 29 <212> DNA <213> Artificial <400> 270 ctggagttca gcctgctgtc catcaagag 29 <210> 271 <211> 29 <212> DNA <213> Artificial <400> 271 ctcttgatgg acagcaggct gaactccag 29 <210> 272 <211> 33 <212> DNA <213> Artificial <400> 272 cgcgaccggt cctgccttaa ccactccctt ttc 33 <210> 273 <211> 25 <212> DNA <213> Artificial <400> 273 cctcagtact gaggcacgag ctgtg 25 <210> 274 <211> 20 <212> DNA <213> Artificial <400> 274 cctcagtact gagggtatgg 20 <210> 275 <211> 29 <212> DNA <213> Artificial <400> 275 cgcggatccc cagtctagga ggaaagtgg 29 <210> 276 <211> 29 <212> DNA <213> Artificial <400> 276 cgcggatccg tcttcataga ggatctcag 29 <210> 277 <211> 29 <212> DNA <213> Artificial <400> 277 cgcggatccc ataatctcca cagcaaaac 29 <210> 278 <211> 33 <212> DNA <213> Artificial <400> 278 aaccggtgcc accatgtggc tcaaggtctt cac 33 <210> 279 <211> 29 <212> DNA <213> Artificial <400> 279 cgcggatcct tttcctttct gtgcaagct 29 <210> 280 <211> 30 <212> DNA <213> Artificial <400> 280 gcgttcgaag cccagctcca ggacgtggtg 30 <210> 281 <211> 29 <212> DNA <213> Artificial <400> 281 cgcggatcct tccttatcgg ggtctcctg 29 <210> 282 <211> 28 <212> DNA <213> Artificial <400> 282 gcgcttcgaa atcccagacg gtttcgtg 28 <210> 283 <211> 29 <212> DNA <213> Artificial <400> 283 cgcggatcct ggatgtgaag aagtgagat 29

<210> 284 <211> 36 <212> PRT <213> Artificial Organism <220> <223> Synthetic peptide <400> 284

His Ser Ser Cys Leu Ser Thr Glu Gly Met Glu Glu Lys Ala Val Gly 15 10 15

Gin Cys Leu Lys Met Thr His Val Arg Asp Ala Arg Gly Arg Cys Ser 20 25 30

Trp Thr Ser Glu 35

<210> 285 <211 > 62 <212> PRT <213> Artificial Organism <220> <223> Synthetic peptide <400> 285

His Ser Ser Cys Leu Ser Thr Glu Gly Met Glu Glu Lys Ala Val Gly 15 10 15

Gin Cys Leu Lys Met Thr His Val Arg Asp Ala Arg Gly Arg Cys Ser 20 25 30

Trp Thr Ser Glu Ser Pro Trp Glu Glu Gly Lys Trp Pro Asp Val Glu 35 40 45

Ala Val Lys Gly Thr Leu Asp Gly Gin Gin Ala Glu Leu Gin 50 55 60 <210> 286

<211 > 14 <212> PRT <213> Artificial Organism <220> <223> Synthetic peptide <400> 286

Thr Asn His Arg Asp Phe Gly His Trp Lys Ser Asp Lys Phe 15 10

<210> 287 <211 > 2 <212> PRT <213> Artificial Organism <220> <223> Synthetic peptide <400> 287

Arg Gin 1

<210> 288 <211> 44 <212> PRT <213> Artificial Organism <220> <223> Synthetic peptide <400> 288

Ala Leu Ala Arg His Arg Tyr Met Lys Gin Ala Gin Ala Leu Gly Pro 15 10 15

Gin Met Met Gly Lys Pro Leu Tyr Trp Gly Ala Asp Arg Ser Ser Gin 20 25 30

Val Ser Ser Tyr Pro Met His Pro Leu Leu Gin Arg 35 40

<210> 289 <211 > 14 <212> PRT <213> Artificial Organism <220> <223> Synthetic peptide <400> 289

Met Trp Leu Lys Val Phe Thr Thr Phe Leu Ser Phe Ala Thr 1 5 10

<210> 290 <211> 88 <212> PRT <213> Artificial Organism <220> <223> Synthetic peptide <400> 290

Gly Gin Lys Gin Asn Thr Gly Lys Leu Lys His Phe Gin Ala Met Lys 15 10 15

Met Leu Trp Met Thr Ser Glu Tyr Met Asn Leu Leu Leu Phe Gin Met 20 25 30

Phe Leu Val Phe Pro Gly Ser Gin Ala Gly Leu Phe Gin Pro Leu Ile 35 40 45

Val Tyr Arg Gly Lys Ile Cys Thr Val Gin Cys Met Lys Leu Phe Ser 50 55 60

Thr Ser Leu Pro Ser Ser Lys Thr Ile Gin Ser Glu Leu Ser Trp Ala 65 70 75 80

Lys Gin Tyr Ile Arg Val Lys Phe 85

<210> 291 <211 > 6 <212> PRT <213> Artificial Organism <220> <223> Synthetic peptide <400> 291

Val Gly Phe Pro Ser Gly 1 5

<210> 292 <211 > 34 <212> PRT <213> Artificial Organism <220> <223> Synthetic peptide <400> 292

Phe Met Leu Ala Ala Pro Ser Gin Arg Glu Glu Glu Lys Lys Ile Trp 15 10 15

Gin Gly Pro Gly Leu Leu Leu Cys Pro His Cys Asn Pro His Tyr His 20 25 30

Gin Tyr

<210> 293 <211> 20 <212> PRT <213> Artificial Organism <220> <223> Synthetic peptide <400> 293

Cys Glu Tyr Ser Asp Arg Trp Gly Asp Arg Ala Ile Glu Arg Asn Val 1 5 10 15

Tyr Leu Ser Thr 20

<210> 294 <211> 29 <212> PRT <213> Artificial Organism <220> <223> Synthetic peptide <400> 294

Gly Ala Pro Tyr Ile Phe Val Lys Arg Met Gly Gly Gin Met Lys Arg 15 10 15

Thr Gin Ala Gly Thr Glu Val Pro Ser Ihr Phe Leu Leu 20 25

<210> 295 <211> 26 <212> PRT <213> Artificial Organism <220> <223> Synthetic peptide <400> 295

Glu Trp Arg Ser Ser Gly Glu Gin Ala Gly Arg Gly Trp Gly Ser Pro 15 10 15

Pro Leu Thr Thr Gin Leu Ser Pro Thr Gly 20 25 <210> 296 <211 > 82

<212> PRT <213> Homo sapiens <400> 296

Ala Leu Ser Leu Gly Gin Asp Pro Ser Asn Asp Cys Asn Asp Asn Gin 15 10 15

Arg Glu Val Arg lie Val Ala Gin Arg Arg Gly Gin Asn Glu Pro Val 20 25 30

Leu Gly Val Asp Tyr Arg Gin Arg Lys lie Thr lie Gin Asn Arg Ala 35 40 45

Asp Leu Val lie Asn Glu Val Met Trp Trp Asp His Gly Val Tyr Tyr 50 55 60

Cys Thr lie Glu Ala Pro Gly Asp Thr Ser Gly Asp Pro Asp Lys Glu 65 70 75 80

Val Lys <210> 297 <211 > 63

<212> PRT <213> Homo sapiens <400> 297

Met Gin Lys Val Thr Leu Gly Leu Leu Val Phe Leu Ala Gly Phe Pro 15 10 15

Val Leu Asp Ala Asn Asp Leu Glu Asp Lys Asn Ser Pro Phe Tyr Tyr 20 25 30

Gly Ala Pro Tyr lie Phe Val Lys Arg Met Gly Gly Gin Met Lys Arg 35 40 45

Thr Gin Ala Gly Thr Glu Val Pro Ser Thr Phe Leu Leu Asp Trp 50 55 60 <210> 298 <211 > 145 <212> PRT <213> Homo sapiens <400> 298

Met Arg Pro Leu Pro Ser Gly Arg Arg Lys Thr Arg Gly Ile Ser Leu 15 10 15

Gly Leu Phe Ala Leu Cys Leu Ala Ala Ala Arg Cys Leu Gin Ser Gin 20 25 30

Gly Val Ser Leu Tyr ile Pro Gl.n Ala Thr Ile Asn Ala Thr Val Lys 35 40 45

Glu Asp ile Leu Leu Ser val Glu Tyr Ser Cys His Gly Val Pro Thr 50 55 60 ile Glu Trp Thr Tyr Ser Ser Asn Trp Gly Thr Gin Lys Ile Val Glu 55 70 75 80

Trp Lys Pro Gly Thr Gin Ala Asn Ile Ser Gin Ser His Lys Asp Arg 85 90 95

Val Cys Thr Phe Asp Asn Gly Ser Ile Gin Leu Phe Ser Val Gly Val 100 105 110

Arg Asp Ser Gly Tyr Tyr Val Ile Thr Val Thr Glu Arg Leu Gly Ser 115 120 125

Ser Gin Phe Gly Thr Ile Val Leu His Val Ser Glu Ile Leu Tyr Glu 130 135 140

Asp 145 <210> 299 <211> 184 <212> PRT <213> Homo sapiens <400> 299

Met Asp Arg Val Leu Leu Arg Irp Ile Ser Leu Phe Trp Leu Thr Ala 15 10 15

Met Val Glu Gly Leu Gin Val Thr Val Pro Asp Lys Lys Lys Val Ala 20 25 30

Met Leu Phe Gin Pro Thr Val Leu Arg Cys His Phe Ser Thr Ser Ser 35 40 45

His Gin Pro Ala Val Val Gin Trp Lys Phe Lys Ser Tyr Cys Gin Asp 50 55 60

Arg Met Gly Glu Ser Leu Gly Met Ser Ser Thr Arg Ala Gin Ser Leu 65 70 75 80

Ser Lys Arg Asn Leu Glu Trp Asp Pro Tyr Leu Asp Cys Leu Asp Ser 85 90 95

Arg Arg Thr Val Arg Val Val Ala Ser Lys Gin Gly Ser Thr Val Thr 100 105 110

Leu Gly Asp Phe Tyr Arg Gly Arg Glu lie Thr lie Val His Asp Ala 115 120 125

Asp Leu Gin lie Gly Lys Leu Met Trp Gly Asp Ser Gly Leu Tyr Tyr 130 135 14.0

Cys He lie Thr Thr Pro Asp Asp Leu Glu Gly Lys Asn Glu Asp Ser 145 150 155 160

Val Glu Leu Leu Val Leu Gly Arg Thr Gly Leu Leu Ala Asp Leu Leu 165 170 175

Pro Ser Phe Ala Val Glu lie Met 180 <210> 300 <211 > 335 <212> PRT <213> Homo sapiens <400> 300

Met Trp Leu Lys Val Phe Thr Thr Phe Leu Ser Phe Ala Thr Gly Ala 15 10 15

Cys Ser Gly Leu Lys Val Thr Val Pro Ser His Thr Val His Gly Val 20 25 30

Arg Gly Gin Ala Leu Tyr Leu Pro Val His Tyr Gly Phe His Thr Pro 35 40 45

Ala Ser Asp Ile Gin Ile Ile Trp Leu Phe Glu Arg Pro His Thr Met 50 55 60

Pro Lys Tyr Leu Leu Gly Ser Val Asn Lys Ser Val Val Pro Asp Leu 65 70 75 80

Glu Tyr Gin His Lys Phe Thr Met Met Pro Pro Asn Ala Ser Leu Leu 85 90 95

Ile Asn Pro Leu Gin Phe Pro Asp Glu Gly Asn Tyr Ile Val Lys Val 100 105 110

Asn Ile Gin Gly Asn Gly Thr Leu Ser Ala Ser Gin Lys lie Gin Val 115 120 125

Thr Val Asp Asp Pro Val Thr Lys Pro Val Val Gin lie His Pro Pro 130 135 140

Ser Gly Ala Val Glu Tyr Val Gly Asn Met Thr Leu Thr Cys His Val 145 150 155 160

Glu Gly Gly Thr Arg Leu Ala Tyr Gin Trp Leu Lys Asn Gly Arg Pro 165 170 175

Val His Thr Ser Ser Thr Tyr Ser Phe Ser Pro Gin Asn Asn Thr Leu 180 185 190

His lie Ala Pro Val Thr Lys Glu Asp lie Gly Asn Tyr Ser Cys Leu 195 200 205

Val Arg Asn Pro Val Ser Glu Met Glu Ser Asp lie lie Met Pro lie 210 215 220 lie Tyr Tyr Gly Pro Tyr Gly Leu Gin Val Asn Ser Asp Lys Gly Leu 225 230 235 240

Lys Val Gly Glu val Phe Thr val Asp Leu Gly Glu Ala lie Leu Phe 245 250 255

Asp Cys Ser Ala Asp Ser His Pro Pro Asn Thr Tyr Ser Trp lie Arg 260 265 270

Arg Thr Asp Asn Thr Thr Tyr lie lie Lys His Gly Pro Arg Leu Glu 275 280 285

Val Ala Ser Glu Lys Val Ala Gin Lys Thr Met Asp Tyr Val Cys Cys 290 295 300

Ala Tyr Asn Asn lie Thr Gly Arg Gin Asp Glu Thr His Phe Thr Val 305 310 315 320

Ile He Thr Ser Val Gly Leu Glu Lys Leu Ala Gin Lys Gly Lys 325 330 335 <210> 301 <211> 110

<212> PRT <213> Homo sapiens <400> 301

Ala Gin Leu Gin Asp Val Val Val Thr Trp Arg Phe Lys Ser Phe Cys 15 10 15

Lys Asp Pro Ile Phe Asp Tyr Tyr Ser Ala Ser Tyr Gin Ala Ala Leu 20 25 30

Ser Leu Gly Gin Asp Pro Ser Asn Asp Cys Asn Asp Asn Gin Arg Glu 35 40 45

Val Arg Ile Val Ala Gin Arg Arg Gly Gin Asn Glu Pro Val Leu Gly 50 55 60

Val Asp Tyr Arg Gin Arg Lys lie Thr lie Gin Asn Arg Ala Asp Leu 65 70 75 80

Val lie Asn Glu Val Met Trp Trp Asp His Gly Val Tyr Tyr Cys Thr 85 90 95 lie Glu Ala Pro Gly Asp Thr Ser Gly Asp Pro Asp Lys Glu 100 105 110 <210> 302 <211 > 268 <212> PRT <213> Homo sapiens <400> 302 lie Pro Asp Gly Phe Val Asn Val Thr Val Gly Ser Asn Val Thr Leu 15 10 15 lie Cys lie Tyr Thr Thr Thr Val Ala Ser Arg Glu Gin Leu Ser He

Gin Trp Ser Phe Phe His Lys Lys Glu Met Glu Pro Ile Ser His Ser 35 40 45

Ser Cys Leu Ser Thr Glu Gly Met Glu Glu Lys Ala Val Ser Gin Cys 50 55 60

Leu Lys Met Thr His Ala Arg Asp Ala Arg Gly Arg Cys Ser Trp Thr 65 70 75 80

Ser Glu Ser Pro Trp Glu Glu Gly Lys Trp Pro Asp Val Glu Ala Val 85 90 95

Lys Gly Thr Leu Asp Gly Gin Gin Ala Glu Leu Gin Ile Tyr Phe Ser 100 105 110

Gin Gly Gly Gin Ala Val Ala He Gly Gin Phe Lys Asp Arg lie Thr 115 120 125

Gly Ser Asn Asp Pro Gly Asn Ala Ser lie Thr He Ser His Met Gin 130 135 140

Pro Ala Asp Ser Gly Tie Tyr lie Cys Asp Val Asn Asn Pro Pro Asp 145 150 155 160

Phe Leu Gly Gin Asn Gin Gly lie Leu Asn Val Ser Val Leu Val Lys 165 170 175

Pro Ser Lys Pro Leu Cys Ser Val Gin Gly Arg Pro Glu Thr Gly His 180 185 190

Thr lie Ser Leu Ser Cys Leu Ser Ala Leu Gly Thr Pro Ser Pro Val 195 200 205

Tyr Tyr Trp His Lys Leu Glu Gly Arg Asp lie Val Pro Val Lys Glu 210 215 220

Asn Phe Asn Pro Thr Thr Gly lie Leu Val lie Gly Asn Leu Thr Asn 225 230 235 240

Phe Glu Gin Gly Tyr Tyr Gin Cys Thr Ala lie Asn Arg Leu Gly Asn 245 250 255

Ser Ser Cys Glu He Asp Leu Thr Ser Ser His Pro 260 265

REFERENCES CITED IN THE DESCRIPTION

This list of references cited by the applicant is for the reader's convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.

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Claims (16)

A pharmaceutical composition comprising at least one C10RF32 ectodomain polypeptide selected from the group consisting of: 1. a C10RF32 ectodomain polypeptide consisting of the amino acid sequence of SEQ ID NO: 299; ii. a ClORF32 ectodomain polypeptide consisting of the amino acid sequence of SEQ ID NO: 147; iii. a C10RF32 ectodomain polypeptide consisting of the amino acid sequence of SEQ ID NO: 148; iv. a ClORF32 ectodomain variant polypeptide having at least 95% sequence identity to the amino acid sequences of SEQ ID NO: 299, SEQ ID NO: 147 or SEQ ID NO: 148; and a pharmaceutically acceptable diluent or carrier. The composition of claim 1, wherein the polypeptide consists of the amino acid sequence of SEQ ID NO: 147, SEQ ID NO: 148, or SEQ ID NO: 299. An isolated polynucleotide encoding the polypeptide of claim 1 or 2. An expression vector containing at least one nucleic acid sequence according to claim 3. The recombinant cell comprising an expression vector or virus containing a nucleic acid sequence according to claim 3, wherein the cell expresses the polypeptide encoded by the DNA segment constitutively or inducibly. A method of producing a C10RF32 ectodomain polypeptide or fragment or conjugate thereof comprising culturing the recombinant cell of claim 5 under conditions wherein the cell expresses the polypeptide encoded by the DNA segment or nucleic acid and recovery of the polypeptide. An antibody or antibody fragment comprising an antigen binding site that specifically binds to a polypeptide selected from the group consisting of: i) a C10RF32 ectodomain polypeptide consisting of the amino acid sequence of SEQ ID NO: 299; ii) a C10RF32 ectodomain polypeptide consisting of the amino acid sequence of SEQ ID NO: 147; iii) a C10RF32 ectodomain polypeptide consisting of the amino acid sequence of SEQ ID NO: 148. The antibody or fragment of claim 7, wherein the antibody is a fully human antibody, a chimeric antibody, a humanized or primated antibody; a Fab, Fab', F (ab ') 2-, F (ab'), F (ab), Fv or scFv fragment and smallest recognition unit. The antibody or fragment of claim 7 or 8, wherein the antibody is coupled to a moiety selected from: an enzyme, a toxin, a therapeutic agent, a chemotherapeutic agent or a detectable marker; and wherein the detectable marker is a radioisotope, a metal chelator, an enzyme, a fluorescent compound, a bioluminescent compound or a chemiluminescent compound. A pharmaceutical composition comprising the antibody of any one of claims 7-9. A fusion protein comprising isolated, soluble C10RF32 ectodomain polypeptide coupled to a non-C10RF32 protein sequence. The fusion protein of claim 11, wherein the non-C10RF32 protein sequence is at least part of an immunoglobulin molecule. The fusion protein of claim 11 or 12, wherein the C10RF32 ectodomain polypeptide is selected from a polypeptide consisting of the amino acid sequence of SEQ ID NO: 147, SEQ ID NO: 148, or SEQ ID NO: 299. The fusion protein of at least one of claims 11 to 13, wherein the fusion protein comprises an Fc fragment. A fusion protein according to at least one of claims 11 to 14 having the sequence of SEQ ID NO: 105.