WO2002014358A2 - Novel secreted proteins and their uses - Google Patents

Abstract

The present invention provides nucleic acid sequences encoding novel human proteins. These novel nucleic acids are useful for constructing the claimed DNA vectors and host cells of the invention and for preparing the claimed nucleic acids, recombinant proteins and antibodies that are useful in the claimed methods and medical uses.

Description

NOVEL SECRETED PROTEINS AND THEIR USES

FIELD OF THE INVENTION

This application claims priority of Provisional Applications Serial No. 60/224,642 filed August 11, 2000, and Serial No. 60/241,779 filed October 19, 2000.

The present invention relates to the identification and isolation of novel DNA, therapeutic and drug discovery uses, and the recombinant production of novel secreted polypeptides, designated herein as LP105, LP061, LP224, LP240, LP239(a), LP243 (a) , LP243 (b) , P253, LP218, LP251(a), LP252, LP239 (b) , LP223 (a) , LP255 (a) , LP244, LP186, LP251(b), LP255 (b) , and LP223 (b) . The present invention also relates to vectors, host cells, and antibodies directed to these polypeptides.

BACKGROUND OF THE INVENTION

Extracellular proteins play 'an important role in the formation, differentiation and maintenance of multi- cellular organisms. The fate of many individual cells, e.g., proliferation, migration, differentiation, or interaction with other cells, is typically governed by information received from other cells and/or the immediate environment. This information is often transmitted by secreted polypeptides (for instance, mitogenic factors, survival factors, cytotoxic factors, differentiation factors, neuropeptides, and hormones) which are, in turn, received and interpreted by diverse cell receptors or membrane-bound proteins . These secreted polypeptides or signaling molecules normally pass through the cellular secretory pathway to reach their site of action in the extracellular environment. Secreted proteins have various industrial applications, including pharmaceuticals, diagnostics, biosensors and bioreactors . Most protein drugs available at present such as thrombolytic agents, interferons, interleukins, erythropoietins, colony stimulating factors, and various other cytokines are secretory proteins . Their receptors, which are membrane proteins, also have potential as therapeutic or diagnostic agents.

The present invention describes the cloning and characterization of novel proteins, termed LP105, LP061, LP224, LP240, P239 (a) , LP243 (a) , LP243 (b) , LP253, LP218, LP251(a), LP252, LP239^'(b) , P223 (a) , LP255 (a) , LP244, LP186, LP251(b), P255 (b) , and P223 (b) , as well as active variants and/or fragments thereof .

SUMMARY OF THE INVENTION

The present invention provides isolated LP105, LP061, LP224, LP240, LP239 (a) , LP243 (a) , LP243 (b) , LP253, LP218, LP251(a), P252, LP239 (b) , P223 (a) , LP255 (a) , LP244, LP186, LP251(b), LP255(b), and P223 (b) polypeptide encoding nucleic acids and the polypeptides encoded thereby, including fragments and/or specified variants thereof. Contemplated by the present invention are LP probes, primers, recombinant vectors, host cells, transgenic animals, chimeric antibodies and constructs, LP polypeptide antibodies, as well as methods of making and using them diagnostically and therapeutically as described and enabled herein.

The present invention includes isolated nucleic acid molecules comprising polynucleotides that encode LP105,

LP061, LP224, LP240, LP239 (a) , LP243 (a) , LP243 (b) , LP253, LP218, LP251(a), LP252, LP239 (b) , LP223 (a) , LP255 (a) , LP244, LP186, LP251(b), LP255 (b) , and LP223 (b) polypeptides as defined herein, as well as fragments and/or specified variants thereof, or isolated nucleic acid molecules that are complementary to polynucleotides that encode such LP polypeptides, or fragments and/or specified variants thereof as defined herein.

A polypeptide of the present invention includes an isolated LP polypeptide comprising at least one fragment, domain, or specified variant of at least 90-100% of the contiguous amino acids of at least one portion of SEQ ID

NO:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, or 38.

The present invention also provides an isolated LP polypeptide as described herein, wherein the polypeptide further comprises at least one specified substitution, insertion, or deletion corresponding to portions or specific residues of SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, or 38.

The present invention also provides an isolated nucleic acid probe, primer, or fragment, as described herein, wherein the nucleic acid comprises a polynucleotide of at least 10 nucleotides, corresponding or complementary to at least 10 nucleotides of SEQ ID NO:l, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, or 37. The present invention also provides compositions, including pharmaceutical compositions, comprising an LP polypeptide, an LP polypeptide-encoding polynucleotide, an LP polynucleotide, and/or an LP polypeptide antibody, wherein the composition has a measurable effect on an activity associated with a particular LP polypeptide as disclosed herein. A method of treatment or prophylaxis based on an LP polypeptide associated activity as disclosed herein can be effected by administration of one or more of the polypeptides, nucleic acids, antibodies, vectors, host cells, transgenic cells, and/or compositions described herein to a mammal in need of such treatment or prophylactic. Accordingly, the present invention also includes methods for the prophylaxis or treatment of a patho-physiological condition in which at least one cell type involved in said condition is sensitive or responsive to an LP polypeptide, LP polypeptide-encoding polynucleotide, LP nucleic acid, LP polypeptide antibody, host cell, transgenic cell, and/or composition of the present invention.

The present invention also provides an article of manufacture comprising a container, holding a composition effective for treating a condition disclosed herein, and a label .

The present invention also provides a method for identifying compounds that bind an LP polypeptide, comprising: _. a) admixing at least one isolated LP polypeptide as described herein with a test compound or composition; and b) detecting at least one binding interaction between the polypeptide and the compound or composition, optionally further comprising detecting a change in biological activity, such as a reduction or increase.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Applicants have identified cDNA clones comprising polynucleotides that encode novel polypeptides or novel variants of known polypeptides: 1 ) LP105

LP105 polypeptides comprising the amino acid sequence of the open reading frame encoded by the polynucleotide sequence as shown in SEQ ID NO:l are contemplated as one embodiment of the present invention. Specifically, polypeptides of the present invention comprise the amino acid sequence as shown in SEQ ID NO: 2, as well as fragments, variants, and derivatives thereof. Accordingly, LP105 polynucleotides encoding the LP105 polypeptides of the present invention are also contemplated by the present invention. LP105 polynucleotides are predominantly expressed in prostate and kidney tissues.

The LP105 polypeptide as shown in SEQ ID NO: 2 shares sequence similarity with a recently reported human lefty protein (WO 99/09198) . Lefty proteins are members of the TGF-beta family and two LEFTY genes, LEFTY A and B, have been localized by FISH to lq42, a region syntenic to the location to which the mouse Lefty genes have been mapped at 1H5 [Kosaki, et al . , Am . J. Hum . Genet . 64(3):712-21 (1999); Meno, et al . , Genes Cells 2(8):513-24 (1997)]. LEFTY A is identical to EBAF [Kothapalli, efc al . , J. Clln . Invest . 99 (10) :2342-50 (1997)]. Analysis of 126 human cases of L-R axis malformation showed a single nonsense and a single missense mutation in the LEFTY A gene. Both mutations lay in the cysteine-knot region of the LEFTY A protein and the phenotype of affected individuals was very similar to that typically seen in Lefty-1 -/- mice with L-R axis malformations. Furthermore, the LP105 polypeptide as shown in SEQ ID NO: 2 shares sequence similarity with human bone morphogenic protein 18 (WO 99/29718) . Compositions comprising LP105 polypeptides, polynucleotides, and/or antibodies are useful for the treatment of defects in or wounds to tissues including, but not limited to, epidermis, nerve, muscle, cardiac muscle, and organs including, but not limited to liver, lung, epithelium, brain, spleen, cardiac, pancreas and kidney. Furthermore, compositions comprising LP105 polypeptides, polynucleotides, and/or antibodies can be useful for modulating sexual development, pituitary hormone production, hematopoiesis, wound healing, tissue repair, and the formation of bone and cartilage. Compositions comprising LP105 polypeptides, polynucleotides, and/or antibodies can also be used to treat such conditions as cancer including, but not limited to prostate and kidney cancer, interstitial lung disease, infectious diseases, autoimmune diseases, arthritis, leukemia, lymphomas, immunosuppression, immunity, humoral immunity, inflammatory bowel disease, myelosuppression, periodontal disease, osteoarthritis, osteoporosis, and other abnormalities of bone, cartilage, muscle, tendon, ligament, meniscus, and/or other connective tissues as well as dysfunctional growth and differentiation patterns of cells.

2) LP061

In another embodiment, polypeptides comprising the amino acid sequence of the open reading frame encoded by the polynucleotide sequence as shown in SEQ ID NO: 3 are contemplated by the present invention. Specifically, polypeptides of the present invention comprise the amino acid sequence as shown in SEQ ID NO: 4, as well as fragments, variants, and derivatives thereof. Accordingly, LP061 polynucleotides encoding LP061 polypeptides of the present invention are also contemplated by the present invention. LP061 polynucleotides are predominantly expressed in diseased thyroid. The present invention includes a human nucleotide sequence (Incyte clone 2719035H1) as shown in SEQ ID NO: 3 which appears to be a shortened splice-variant of the published human fukutin nucleotide sequence (GenBank AB008226) . Fukuyama-type congenital muscular dystrophy (FCMD) , one of the most common autosomal recessive disorders in Japan (incidence is 0.7 to 1.2 per 10,000 births), is characterized by congenital muscular dystrophy, in conjunction with brain malformation (micropolygria) . The FCMD gene was mapped to a region of less than 100 kilobases which included the marker locus D9S2107 on human chromosome 9q31. The mutation responsible for FCMD is a retrotransposal insertion of tandemly repeated sequences within this candidate-gene in all FCMD chromosomes carrying the founder haplotype (87%) . The inserted sequence is about 3 kilobases long and is located in the 3 ' untranslated region of a gene encoding a new 461 amino acid protein. This novel gene, termed fukutin, is expressed in heart, brain, skeletal muscle, pancreas and lymphoblasts in normal individuals, but not in FCMD patients who carry the insertion. Two independent point mutations confirm that mutation of this gene is responsible for FCMD. The predicted fukutin protein contains an amino-terminal signal sequence and one glycosylation site, which together with results from transfection experiments suggests that fukutin is a secreted protein. Abnormalities in basal lamina in FCMD muscle and brain have been seen by electron microscopy [Nakano, et al . , Acta Neuropathol . 91(3):313-21 (1996); Ishii, et al., Neuromuscul . Dlsord. 7(3):191-7 (1997)]. Therefore it has been suggested that secreted fukutin may be associated with the extracellular matrix surrounding expressing cells where it forms a complex with other extracellular components to stabilize a microenvironment supportive for normal cellular/tissue function. In muscle, fukutin complexes might stabilize the function of muscle fibers/sarcomeres; in brain, fukutin may assist the migration of neuronal precursors during cortical development [Fukuyama, et al . , Brain Dev. 3(l):l-29 (1981).

Accordingly, compositions comprising LP061 polypeptides, polynucleotides, and/or antibodies are useful for diagnosis, treatment and intervention of diseases, disorders, and/or conditions including, but not limited to, brain malformation (micropolygria) , Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, Tourette Syndrome, ALS, muscular pathologies including, but not limited to, muscular dystrophies including, but not limited to, congenital muscular dystrophies such as fukuyama-type congenital muscular dystrophy, meningitis, encephalitis, demyelinating diseases, peripheral neuropathies, neoplasia, trauma, spinal cord injuries, ischemia and infarction, aneurysms, hemorrhages, schizophrenia, mania, dementia, paranoia, obsessive compulsive disorder, panic disorder learning disabilities, psychoses, autism, and altered behaviors, including disorders in feeding, sleep patterns, balance, and perception.

3) LP224

In another embodiment, polypeptides comprising the amino acid sequence of the open reading frame encoded by the polynucleotide sequence as shown in SEQ ID NO: 5 are contemplated by the present invention. Specifically, polypeptides of the present invention comprise the amino acid sequence as shown in SEQ ID NO: 6, as well as fragments, variants, and derivatives thereof. Accordingly, LP224 polynucleotides encoding LP224 polypeptides of the present invention are also contemplated by the present invention.

The gene encoding the LP224 polypeptide has been localized to chromosome 4pl6 (GenBank hit g7022852) and the LP224 polypeptide as shown in SEQ ID NO: 6 shares sequence similarity with a protein encoded by the leucine-rich, glioma inactivated 1 tumor suppressor gene. LGIl has the highest ho ology with a number of transmembrane and extracellular proteins which function as receptors and adhesion proteins. LGIl is predominantly expressed in neural tissues, especially in brain; its expression is reduced in low grade brain tumors and it is significantly reduced or absent in malignant gliomas. Its localization to the 10q24 region, and rearrangements or inactivation in malignant brain tumors, suggest that LGIl is a candidate tumor suppressor gene involved in progression of glial tumors [Chernova, et al . , Oncogene 17 (22 ): 2873-81 (1998)]. Accordingly, compositions comprising LP224 polypeptides, polynucleotides, and/or antibodies are useful for diagnosis, treatment and intervention of bipolar affective disorder

[Ewald, et al . , Mol . Psychiatry 3 (5) : 442-8 (1998)], hearing defects [Van Camp, et al . , J. Med. Genet . 36(7):532-6, (1999)], cherubism [Mangion, et al . , Am. J. Hum. Genet . 65(l):151-7 (1999)], Wolf-Hirschhorn (WH) syndrome [Zollino, et al . , Am . J. Med. Genet . 82(5):371-5 (1999); Ann . Genet . 41(2):73-6 (1998)], Ellis-van Creveld syndrome [EVC; Polymeropoulos, et al . , Genomics 35(1) :l-5 (1996)], autosomal dominant postaxial polydactyly, nail dystrophy, and dental abnormalities [Howard, et al . , Am . J. Hum. Genet . 61(6) .1405-12 (1997)], Pitt-Rogers-Danks (PRD) syndrome and overgrowth syndrome [Partington, et al . , J. Med. Genet . 34(9):719-28 (1997)], bladder cancer and malignant brain tumors [Bell, et al . , Genes Chromosomes Cancer 17(2):108-17 (1996)] .

4) LP240 In another embodiment, polypeptides comprising the amino acid sequence of the open reading frame encoded by the polynucleotide sequence as shown in SEQ ID NO: 7 are contemplated by the present invention. Specifically, polypeptides of the present invention comprise the amino acid sequence as shown in SEQ ID NO: 8, as well as fragments, variants, and derivatives thereof. Accordingly, LP240 polynucleotides encoding LP240 polypeptides of the present invention are also contemplated by the present invention. The gene encoding the LP240 polypeptide as shown in SEQ ID NO: 8 has been localized to chromosome 19.

LP240 polynucleotides, polypeptides, and antibodies corresponding to LP240 are useful for diagnosis, treatment and intervention of diseases, disorders, and/or conditions including, but not limited to, stroke, Alzheimer's disease, Parkinson's disease, Huntington's disease, neurodegenerative disorders, brain cancer, cardiovascular disease, atherosclerosis, myocardial infarction, inflammation, and rheumatoid arthritis.

5) LP239(a) and LP239(b)

In another embodiment, polypeptides comprising the amino acid sequences of the open reading frames encoded by the polynucleotide sequences as shown in SEQ ID NO: 9 and SEQ ID NO: 23 are contemplated by the present invention. Specifically, LP239 (a) and LP239 (b) polypeptides of the present invention comprise the amino acid sequences as shown in SEQ ID NO: 10 and SEQ ID NO: 24, respectively, as well as fragments, variants, and derivatives thereof. Accordingly, LP239 (a) and LP239 (b) polynucleotides comprising polynucleotides as identified in SEQ ID NO: 9 and SEQ ID NO: 23, respectively, are also contemplated by the present invention.

LP239 polypeptide-encoding polynucleotide sequences are primarily expressed in digestive, hemic, immune, and nervous system tissues. The LP239 (a) and LP239 (b) polypeptides as shown in SEQ ID NO: 10 and SEQ ID NO: 24 share sequence similarity with a thyroxine-binding globulin [see AF204929; Mori, et al . , Endocr . J. 46(4): 613-9 (1999)]. LP239 polypeptides therefore may serve as hormone binding proteins in serum, protease inhibitors, or hormones when administered to patients suffering from a deficiency of endogenous LP239 polypeptides. LP239 polynucleotides, polypeptides, and antibodies corresponding to LP239 are useful for diagnosis, treatment and intervention of diseases, disorders, and/or conditions including, but not limited to, hypothyroidism, anemia, sepsis, gram negative bacteremia, allergic responses, allergic autoimmune diseases, type 1 diabetes, Thl-dependent insulitis, inflammation, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, liver failure, ARDS, cancers, leukemia, and immunodeficiency.

6) LP243(a) and LP243 (b)

In another embodiment, polypeptides comprising the amino acid sequences of the open reading frames encoded by the polynucleotide sequences as shown in SEQ ID NO: 11 and SEQ ID NO: 13 are contemplated by the present invention. Specifically, LP243 (a) and LP243 (b) polypeptides of the present invention comprise the amino acid sequences as shown in SEQ ID NO: 12 and SEQ ID NO: 14, respectively, as well as fragments, variants, and derivatives thereof. Accordingly, LP243 (a) and LP243 (b) polynucleotides comprising polynucleotides as identified in SEQ ID NO: 11 and SEQ ID NO: 13 are also contemplated by the present invention.

The gene encoding the disclosed LP243 polypeptides have been localized to chromosome 19pl3.3 (GenBank hit g2894631) and is mainly expressed in nervous system and digestive system. The LP243 polypeptides as shown in SEQ ID NO: 12 and SEQ ID NO: 14 share sequence similarity with the amino acid sequence of protein PR0227 disclosed in WO 99/14328, the amino acid sequence of the human Tango-79 protein disclosed in WO 99/06427, the glioma amplified on chromosome 1 (GAC1) protein (AF030435), and the Rattus norvegicus (AF133730) SLIT protein. GACl is a member of the leucine-rich repeat superfamily on chromosome band lq32.1. GACl is amplified and overexpressed in malignant gliomas [Almeida, et al . , Oncogene 16(23) :2997 (1998)]. In Drosophila, at least, SLIT proteins are believed to be involved in axon pathway development. The two predicted proteins LP243 (a) and

LP243 (b) as shown in SEQ ID NO:12 and 14, respectively, have different N-terminals but are identical starting from amino acid 27 through amino acid 557 as shown in SEQ ID NO: 12. The present invention provides isolated LP243 (a) and LP243 (b) polypeptides as described herein, wherein the polypeptide has at least one activity, such as, but not limited to, inducing cellular proliferation, tumorigenesis, synapse formation, neurotransmission, learning, cognition, homeostasis, neuronal outgrowth, differentiation or survival, or tissue regeneration including but not limited to neural tissue regeneration. An LP243 polynucleotide, polypeptide, and/or antibody can thus be screened for a corresponding activity according to known methods.

The present invention also provides a composition comprising an isolated LP243 nucleic acid, polypeptide, and/or antibody as described herein and a carrier or diluent. The carrier or diluent can optionally be pharmaceutically acceptable, according to known methods. LP243 polynucleotides are expressed in nervous tissues and the polypeptides encoded thereby appear to play a role in tumorigenesis, neurodegenerative diseases, behavioral disorders, and/or inflammatory conditions. Accordingly, compositions comprising LP243 polypeptides, polynucleotides, and/or antibodies are useful for diagnosis, treatment and intervention of diseases, disorders, and/or conditions including, but not limited to, cancer, including, but not limited to sporadic ovarian tumors [Wang, et al . , Br. J. Cancer 80(1-2) :70-2 (1999)], Peutz-Jeghers syndrome [Nakagawa, et al . , Hum . Genet . 102(2) :203-6 (1998); Olschwang, et al . , J. Med. Genet . 35(l):42-4 (1998)], adenoma malignum of the uterine cervix [Lee, et al . , Cancer Res . 15 ;58 (6) : 1140-3 (1998)], pancreatic carcinomas [Hoglund, et al . , Genes Chromosomes Cancer 21(1): 8-16 (1998)], multiple myeloma and plasma cell leukemia [Taniwaki, et al., Blood 84 (7) : 2283-90 (1994)], Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, Tourette Syndrome, meningitis, encephalitis, demyelinating diseases, peripheral neuropathies, neoplasia, trauma, congenital malformations, spinal cord injuries, ischemia and infarction, aneurysms, hemorrhages, schizophrenia, mania, dementia, paranoia, obsessive compulsive disorder, panic disorder, learning disabilities, ALS, psychoses, autism, and altered behaviors, including disorders in feeding, sleep patterns, balance, and perception.

7) LP253 Cytokines are secreted regulatory peptides that mediate a wide range of biological activities by binding to specific cell surface receptors on target cells. Cytokine actions include control of cell proliferation and differentiation, regulation of hematopoiesis, and immune inflammatory responses. Cytokines are also major orchestrators of host defense processes and, as such, are involved in responses to exogenous as well as endogenous insults and in repair or restoration of tissue integrity. In order for a cytokine to exert its effect on cells, it is now accepted by those skilled in the art that the molecule must interact with molecules, located on cell membranes, referred to as receptors. Patents which exemplify disclosures of interleukin receptors include Honjo, et al . , U.S. Patent 4,816,565; Urdal, et al . , U.S. Patent 4,578,335; Dower, et al . , U.S. Patent 5,180,812; and Taniguchi, et al . , U.S. Patent 5,198,359; and WO 2000/15759, the disclosures of which are incorporated by reference.

In another embodiment of the present invention, we provide polypeptides comprising the amino acid sequence of the open reading frame encoded by the polynucleotide sequence as shown in SEQ ID NO: 15. Specifically, LP253 polypeptides of the present invention comprise the amino acid^" sequence as shown in SEQ ID NO: 16, as well as fragments, variants, and derivatives thereof . Accordingly, LP253 polynucleotides comprising polynucleotides as identified in SEQ ID NO: 15 are also contemplated by the present invention. LP253 encoding polynucleotide sequences are primarily expressed in digestive, hemic, immune, and nervous system tissues. The LP253 polypeptide as shown in SEQ ID NO: 16 shares structural similarity with other interleukin receptors . The effects of IL-1 in vivo can be regulated via the administration of a soluble form of its receptor [Fanslow, et al . , Science 248:739-41 (1990)]. Systemic administration of a soluble, extracellular portion of the receptor for IL-1 (soluble IL-1R) had profound inhibitory effects on the development of in vivo alloreactivity . Survival of heterotopic heart allografts was prolonged from twelve days in controls to seventeen days in mice treated with soluble IL-1R. Lymph node hyperplasia in response to localized injection of allogeneic cells was completely blocked by soluble IL-1R treatment.

The availability of the purified LP253 polypeptide, in soluble form, presents therapeutic possibilities as well. The results that Fanslow report demonstrate the ability of a soluble cytokine receptor to modulate biological activity upon exogeneous administration in vivo, presumably by acting as a neutralizing agent for the endogeneously produced, corresponding ligand, and provides evidence of the therapeutic potential of soluble cytokine receptors in a variety of clinical disorders. Administration of a soluble form of LP253 would interfere with the effect of its endogenous ligand on the cells, since the ligand would not bind to the endogenous membrane bound LP253 as freely. Hence, an aspect of the present invention is the treatment of pathological conditions caused by excess expression and/or activity of LP253 polypeptides by adding an amount of soluble LP253 polypeptides sufficient to inhibit binding of a cytokine to the aforementioned cells. This methodology can also be modified, and the soluble receptor can also be used as a screening agent for pharmaceuticals. Briefly, a pharmaceutical which works as an LP253 antagonist can do so by blocking the binding of endogenous ligand to the LP253. Prior to determining whether a material would be effective in vivo, one may use the purified LP253 polypeptide in connection with a potential pharmaceutical to determine if there is binding. If there is in fact binding, further testing may be indicated.

Expression of recombinant polypeptides in high levels and its use as an antigen allows production of additional neutralizing monoclonal and polyclonal antibodies. Such neutralizing antibodies can be used in in vivo model settings to elucidate the role that LP253 and its ligand play in normal as well as pathologic immune responses (i.e., disease states that are aggravated by activated T- and NK- cells like auto-immune diseases, graft versus host disease and rheumatoid arthritis) . Thus, purified LP253 polypeptides, polynucleotides, and/or antibodies compositions will be useful in diagnostic assays for LP253 and its ligand, and also in raising antibodies to LP253 for use in diagnosis or therapy.

LP253 polypeptides, polynucleotides, and/or antibodies can be administered, for example, for the purpose of suppressing immune responses in a human. A variety of diseases or conditions are caused by an immune response to alloantigen, including allograft rejection and graft-versus- host reaction. In alloantigen-induced immune responses, soluble LP253 polypeptides may suppress lymphoproliferation and inflammation which result upon activation of T cells. Soluble LP253 polypeptides may therefore be used to effectively suppress alloantigen-induced immune responses in the clinical treatment of, for example, rejection of allografts (such as skin, kidney, and heart transplants) , and graft-versus-host reactions in patients who have received bone marrow transplants .

LP253 polypeptides, polynucleotides, and/or antibodies may also be used in clinical treatment of autoimmune dysfunctions, such a rheumatoid arthritis, diabetes and multiple sclerosis, which are dependent upon the activation of T cells against antigens not recognized as being indigenous to the host. LP253 polypeptides, polynucleotides, and/or antibodies may also be useful in treatment of septic shock in which interferon gamma produced in response to various interleukins plays a central role in causing morbidity, and mortality [Doherty, et al . , J. Immunol .

149:1666 (1992)]. In addition, compositions comprising soluble LP253 polypeptides may be used directly in therapy to bind or scavenge endogenous LP253 ligands, thereby providing a means for regulating the immune or inflammatory activities. In its use to prevent or reverse pathologic immune responses, soluble LP253 polypeptides can be combined with other cytokine antagonists such as antibodies to the other known interleukin receptors, soluble interleukin receptors, soluble TNF (tumor necrosis factor) receptors, and/or interleukin receptor antagonists, and the like.

The dose ranges for the administration of the LP253 polypeptides, polynucleotides, and/or antibodies and fragments thereof may be determined by those of ordinary skill in the art without undue experimentation. In general, appropriate dosages are those which are large enough to produce the desired effect, for example, blocking the binding of endogenous ligands of LP253 to endogenous LP253. 8 ) LP218

In another embodiment, polypeptides comprising the amino acid sequence of the open reading frame encoded by the polynucleotide sequence as shown in SEQ ID NO : 17 are contemplated by the present invention. Specifically, LP218 polypeptides of the present invention comprise the amino acid sequence as shown in SEQ ID NO: 18, as well as fragments, variants, and derivatives thereof. Accordingly, LP218 polynucleotides comprising polynucleotides as identified in SEQ ID NO: 17 are also contemplated by the present invention.

The gene encoding the LP218 polypeptide as shown in SEQ ID NO: 18 has been localized to chromosome 22qll and shares • sequence similarity with acetyl LDL receptor. LP218 polynucleotides are expressed in hemic, immune, reproductive, and urinary tract tissues. Accordingly, compositions comprising LP218 polypeptides, polynucleotides, and/or antibodies are useful for diagnosis, treatment and intervention of schizophrenia [Li, Mol . Psychiatry 5(1) :77- 84 (2000)], hypocalcemia [Garabedian, et al . , Genet Couns . 10(4):389-94 (1999)], rhabd id tumor [Zhou, et al . , Gene 241 (1) :133-41 (2000)], DiGeorge/velo-cardio-facial syndrome [Amati, et al . , Bur. J. ^' Hum. Genet . 7(8):903-9 (1999)], congenital heart disease [Borgmann, et al . , Eur. J. Pediatr. 158(12) :958-63 (1999)], and abdominal lymphatic dysplasia [Mansir, et al . , Genet . Couns . 10 (1) : 67-70 (1999)], oesophageal atresia [Digilio, et al . , J. Med. Genet . 36(2):137-9 (1999)].

9) LP251(a) and LP251(b) In another embodiment, polypeptides comprising the amino acid sequence of the open reading frames encoded by the polynucleotide sequences as shown in SEQ ID NO: 19 and SEQ ID NO: 33 are contemplated by the present invention. Specifically, LP251(a) and LP251(b) polypeptides of the present invention comprise the amino acid sequence as shown in SEQ ID NO: 20 and SEQ ID NO: 34, respectively, as well as fragments, variants, and derivatives thereof. Accordingly, LP251(a) and LP251(b) polynucleotides comprising polynucleotides as identified in SEQ ID NO: 19 or SEQ ID NO: 33 are also contemplated by the present invention.

The LP251 polypeptides as shown in SEQ ID NO: 20 and SEQ ID NO: 34 share sequence similarity with aqualysin I precursor, a subtilisin-type serine protease which is secreted into the culture medium by Thermus aquaticus YT-1, an extremely thermophilic gram-negative bacterium [Terada, et al . , J. Biol . Chem. 265 (12 ): 6576-81 (1990)].

The gene encoding the disclosed polypeptides has been localized to chromosome Ip33-p34.3. Accordingly, compositions comprising LP251 polypeptides, polynucleotides, and/or antibodies are useful for diagnosis, treatment and intervention of breast cancer [Emi, et al . , Genes Chromosomes Cancer 26(2):134-41 (1999)], myelodysplastic syndromes including but not limited to thrombocytemia and abnormal megakaryopoiesis [Jondeau, et al . , Leukemia 10(11) :1692-5 (1996)], Schnyder's crystalline corneal dystrophy [Shearman, et al . , Hum. Mol . Genet . 5 (10) : 1667-72 1996) , tumorigenesis including, but not limited to, colorectal cancer [Praml, et al . , Oncogene 11 (7) : 1357-62 (1995)], Schwartz-Jampel syndrome [Nicole, Hum . Mol . Genet . 4(9):1633-6 (1995), and autosomal dominant hypercholesterol- emia [Varret, et al . , Am . J. Hum. Genet . 64 (5) : 1378-87 (1999) ] .

Furthermore, LP251 polynucleotides are mainly expressed in skin and liver. Accordingly, compositions comprising LP251 polypeptides, polynucleotides, and/or antibodies are generally useful for the treatment of defects in or wounds to tissues including, but not limited to skin and liver.

10) LP252 In another embodiment, polypeptides comprising the amino acid sequence of the open reading frame encoded by the polynucleotide sequence as shown in SEQ ID NO: 21 are contemplated by the present invention. Specifically, LP252 polypeptides of the present invention comprise the amino acid sequence as shown in SEQ ID NO: 22, as well as fragments, variants, and derivatives thereof. Accordingly, LP252 polynucleotides comprising polynucleotides as identified in SEQ ID NO: 21 are also contemplated by the present invention. The LP252 polypeptide as shown in SEQ ID NO: 22 shares sequence similarity with thyroid hormone-induced protein B precursor. Furthermore, the gene encoding the disclosed polypeptide has been localized to chromosome 9pl2-13. Accordingly, compositions comprising LP252 polypeptides, polynucleotides, and/or antibodies are useful for diagnosis, treatment and intervention of ectrodactyly, ectodermal dysplasia and cleft lip/palate syndrome [Fukushima, et al . , Clin . Genet . 44(1) :50 (1993); Hasegawa, et al . , Clin . Genet . 40(3):202-6 (1991)]; and cancer, including, but not limited to, kidney cancer and carcinoma of the respiratory tract

[Schraml, et al . , J. Pathol . 190 (4) : 457-61 (2000); Higashi, et al . , Genes Chromosomes Cancer 3(l):21-3 (1991)]. 11 ) LP223 (a) and (b)

In another embodiment, polypeptides comprising the amino acid sequences of the open reading frames encoded by the polynucleotide sequences as shown in SEQ ID NO: 25 and SEQ ID NO: 37 are contemplated by the present invention. Specifically, LP223 (a) and LP223 (b) polypeptides of the present invention comprise the amino acid sequences as shown in SEQ ID NO: 26 and SEQ ID NO: 38, respectively, as well as fragments, variants, and derivatives thereof. Accordingly, LP223 (a) and LP223 (b) polynucleotides comprising polynucleotides as identified in SEQ ID NO: 25 and SEQ ID NO: 37 are also contemplated by the present invention. The LP223(a) and LP223 (b) polypeptides as shown in SEQ ID NO:26 and SEQ ID NO: 38 share sequence similarity with a human secreted protein sequence disclosed in WO 2000/04140.

The present invention also provides isolated LP223 polypeptides as described herein, wherein the polypeptides have at least one activity, such as, but not limited to, inducing cellular proliferation, synapse formation, neurotransmission, learning, cognition, homeostasis, neuronal outgrowth, differentiation or survival, or tissue regeneration including but not limited to neural tissue regeneration. An LP223 polynucleotide, polypeptide, and/or antibody can thus be screened for a corresponding activity according to known methods .

The present invention also provides a composition comprising an isolated LP223 nucleic acid, polypeptide, and/or antibody as described herein and a carrier or diluent. The carrier or diluent can optionally be pharmaceutically acceptable, according to known methods. LP223 polynucleotides and polypeptides are expressed in nervous tissues and appear to play a role in neurodegenerative diseases, behavioral disorders, and/or inflammatory conditions. Accordingly, compositions comprising LP223 polypeptides, polynucleotides, and/or antibodies are useful for diagnosis, treatment and intervention of diseases, disorders, and/or conditions including, but not limited to, Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, Tourette Syndrome, meningitis, encephalitis, demyelinating diseases, peripheral neuropathies, neoplasia, trauma, congenital malformations, spinal cord injuries, ischemia and infarction, aneurysms, hemorrhages, schizophrenia, mania, dementia, paranoia, obsessive compulsive disorder, panic disorder learning disabilities, ALS, psychoses, autism, and altered behaviors, including disorders in feeding, sleep patterns, balance, and perception. In addition, the gene or gene product may also play a role in the treatment and/or detection of developmental disorders associated with the developing embryo, sexually-linked disorders, or disorders of the cardiovascular system.

12) LP255(a) and LP255(b)

In another embodiment, polypeptides comprising the amino acid sequences of the open reading frames encoded by the polynucleotide sequences as shown in SEQ ID NO: 27 and SEQ ID NO: 35 are contemplated by the present invention. Specifically, LP255(a) and LP255(b) polypeptides of the present invention comprise the amino acid sequences as shown in SEQ ID NO: 28 and SEQ ID NO: 36, respectively, as well as fragments, variants, and derivatives thereof. Accordingly, LP255(a) and LP255 (b) polynucleotides comprising polynucleotides as identified in SEQ ID NO: 27 and SEQ ID NO:35 are also contemplated by the present invention. The LP255(a) and LP255 (b) polypeptides as shown in SEQ ID NO-.28 and SEQ ID NO: 36 share sequence similarity with a human secreted protein sequence disclosed in WO 99/14328 as PR0332.

The present invention also provides isolated LP255 polypeptides as described herein, wherein the polypeptides have at least one activity, such as, but not limited to, promoting cell growth. An LP255 polynucleotide, polypeptide, and/or antibody can thus be screened for a corresponding activity according to known methods.

The present invention also provides a composition comprising an isolated LP255 nucleic acid, polypeptide, and/or antibody as described herein and a carrier or diluent. The carrier or diluent can optionally be pharmaceutically acceptable, according to known methods. LP255 polynucleotides and polypeptides are expressed in nervous tissues and appear to play a role in neurological disorders. Accordingly, compositions comprising LP255 polypeptides, .polynucleotides, and/or antibodies are useful for diagnosis, treatment and intervention of diseases, disorders, and/or conditions arising from Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, Tourette Syndrome, meningitis, encephalitis, demyelinating diseases, peripheral neuropathies, neoplasia, trauma, congenital malformations, spinal cord injuries, ischemia and infarction, aneurysms, hemorrhages, schizophrenia, mania, dementia, paranoia, obsessive compulsive disorder, panic disorder learning disabilities, ALS, psychoses, autism, and altered behaviors, including disorders in feeding, sleep patterns, balance, and perception. 13 ) LP244

In another embodiment, polypeptides comprising the amino acid sequence of the open reading frame encoded by the polynucleotide sequence as shown in SEQ ID NO: 29 are contemplated by the present invention. Specifically, LP244 polypeptides of the present invention comprise the amino acid sequence as shown in SEQ ID NO: 30, as well as fragments, variants, and derivatives thereof. Accordingly, LP244 polynucleotides comprising polynucleotides as identified in SEQ ID NO: 29 are also contemplated by the present invention.

The gene encoding the LP244 polypeptide has been localized to chromosome 19 and is predominantly expressed in embryonic structures. The LP244 polypeptide as shown in SEQ ID NO: 30 appears to be a novel shortened splice-variant of the human Epstein-Barr virus induced gene 3 (EBI3; GenBank accession no. NP_005746 ) wherein the first 67 amino acids of the LP244 polypeptide are identical to those of EBI3. EBI3 is reported to be a hematopoietin receptor family member related to the p40 subunit of interleukin-12 and to the ciliary neurotrophic factor receptor, whose expression is induced in B lymphocytes by Epstein-Barr virus (EBV) infection [Devergne, et al . , J. Virology 70 (2) : 1143-53 (1996)]. The gene encodes a 34-kDa glycoprotein which lacks a membrane-anchoring motif and is secreted. Despite the absence of a membrane-anchoring motif and of cysteines likely to mediate covalent linkage to an integral membrane protein, EBI3 is also present on the plasma membrane of EBV- transformed B lymphocytes and of transfected cells. Most newly synthesized EBI3 is retained in the endoplasmic reticulu in an endoglycosidase H-sensitive form associated with the molecular chaperone calnexin and with a novel 60- kDa protein. EBI3 is expressed in vivo by scattered cells in interfollicular zones of tonsil tissue, by cells associated with sinusoids in perifollicular areas of spleen tissue, and at very high levels by placental syncytio- trophoblasts . EBI3 expression in vi tro is induced in EBV- negative cell lines by expression of the EBV latent infection membrane protein-1 and in peripheral blood mononuclear cells by pokeweed mitogen stimulation. EBI3 maps to chromosome 19pl3.2/3, near genes encoding the erythropoietin receptor and the cytokine receptor-associated kinase, Tyk2. EBI3 synthesis by trophoblasts and by EBV- transformed cells and similarities to interleukin-12 p40 are compatible with a role for EBI3 in regulating cell-mediated immune responses. LP244 therefore may function as a modulator of EBI3 activity. Administration of a soluble form of LP244 would interfere with the effect of its endogenous ligand on the cells, since the ligand would not bind to the endogenous membrane bound LP244 as freely. Hence, an aspect of the present invention is the treatment of pathological conditions caused by excessive expression of LP244 polypeptides by adding an amount of soluble LP244 polypeptides sufficient to inhibit binding of a cytokine to the aforementioned cells. This methodology can also be modified, and the soluble receptor can also be used as a screening agent for pharmaceuticals. Briefly, a pharmaceutical which works as an LP244 antagonist can do so by blocking the binding of endogenous ligand to the LP244. Prior to determining whether a material would be effective in vivo, one may use the purified LP244 polypeptide in connection with a potential pharmaceutical to determine if there is binding. if there is in fact binding, further testing may be indicated. Expression of recombinant polypeptides in high levels and its use as an antigen allows production of additional neutralizing monoclonal and polyclonal antibodies. Such neutralizing antibodies can be used in in vivo model settings to elucidate the role that LP244 and its ligand play in normal as well as pathologic immune responses (i.e., disease states that are aggravated by activated T- and NK- cells like autoimmune diseases, graft versus host disease, and rheumatoid arthritis) . Thus, purified LP244 polypep- tides, polynucleotides, and/or antibodies compositions will be useful in diagnostic assays for LP244 and its ligand, and also in raising antibodies to LP244 for use in diagnosis or therapy. More specifically, compositions comprising LP244 polypeptides, polynucleotides, and/or antibodies are useful for diagnosis, treatment and intervention of diseases, disorders, and/or conditions including, but not limited to, infectious diseases, hypothyroidism, anemia, sepsis, gram negative bacteremia, allergic responses, allergic autoimmune diseases, type 1 diabetes, Thl-dependent insulitis, inflammation, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, liver failure, ARDS, cancers, leukemia, and immuno-deficiency, arthritis, leukemia, lymphomas, immuno-suppression, immunity, humoral immunity, myelosuppression, periodontal disease, and osteoarthritis . LP244 polypeptides, polynucleotides, and/or antibodies can be administered, for example, for the purpose of suppressing immune responses in a human. A variety of diseases or conditions are caused by an immune response to alloantigen, including allograft rejection and graft-versus- host reaction. In alloantigen-induced immune responses, soluble LP244 polypeptides may suppress lymphoproliferation and inflammation which result upon activation of T cells. Soluble LP244 polypeptides may therefore be used to effectively suppress alloantigen-induced immune responses in the clinical treatment of, for example, rejection of allografts (such as skin, kidney, and heart transplants) , and graft-versus-host reactions in patients who have received bone marrow transplants .

LP244 polypeptides, polynucleotides, and/or antibodies may also be used in clinical treatment of autoimmune dysfunctions, such a rheumatoid arthritis, diabetes and multiple sclerosis, which are dependent upon the activation i of T cells against antigens not recognized as being indigenous to the host. LP244 polypeptides, polynucleotides, and/or antibodies may also be useful in treatment of septic shock in which interferon gamma produced in response to various interleukins plays a central role in causing morbidity and mortality [Doherty, et al . , J. Immunol . 149:1666 (1992)]. In addition, compositions comprising soluble LP244 compositions may be used directly in therapy to bind or scavenge endogenous LP244 ligands, thereby providing a means for regulating the immune or inflammatory activities. In its use to prevent or reverse pathologic immune responses, soluble LP244 polypeptides can be combined with other cytokine antagonists such as antibodies to the other known interleukin receptors, soluble interleukin receptors, soluble TNF (tumor necrosis factor) receptors, and/or interleukin receptor antagonists, and the like.

14) LP186

In another embodiment, polypeptides comprising the amino acid sequence of the open reading frame encoded by the polynucleotide sequence as shown in SEQ ID NO: 31 are contemplated by the present invention. Specifically, LP186 polypeptides of the present invention comprise the amino acid sequence as shown in SEQ ID NO: 32, as well as fragments, variants, and derivatives thereof. Accordingly, LP186 polynucleotides comprising polynucleotides as identified in SEQ ID NO: 31 are also contemplated by the present invention.

The LP186 polypeptide as shown in SEQ ID NO: 32 shares sequence similarity with the human delta homologue, DLL3 [Bul an, et al . , Nature Genetics 24(4):438-41 (2000)]. Mutations in the human delta homologue, DLL3 , cause axial skeletal defects in spondylocostal dysostosis. Two of the mutations predict truncations within conserved extracellular domains . The third is a missense mutation in a highly conserved glycine residue of the fifth epidermal growth factor (EGF) repeat, which has revealed an important functional role for this domain. Spondylocostal dysostosis (SD) is a group of vertebral malsegmentation syndromes with reduced stature resulting from axial skeletal defects. SD is characterized by multiple hemivertebrae, rib fusions and deletions with a non-progressive kyphoscoliosis . D113 is mutated in the X-ray-induced mouse mutant pudgy (pu) , causing a variety of vertebrocostal defects similar to SD phenotypes [Kusumi, et al . , Nature Genetics 19(3):274-8 (1998)]. These mutations highlight the critical role of the Notch signalling pathway and its components in patterning the mammalian axial .

LP186 polypeptide-encoding polynucleotide sequences are primarily expressed in the nervous system. Thus, polynucleotides, polypeptides, and antibodies corresponding to this gene are useful for diagnosis, treatment and intervention of diseases, disorders, and conditions of the nervous system. Thus, the present sequence represents a polypeptide which suppresses proliferation and differentiation of undifferentiated cells such as neurons and blood cells. The polypeptide may be used for the prevention and control of disorders involving undifferentiated cells, such as leukaemia and malignant tumours, and improvement of blood formation, e.g., after immunosuppression.

The polynucleotides and polypeptides of the present invention are designated herein as "LP polynucleotides" or "LP polypeptide-encoding polynucleotides" and "LP polypeptides." When immediately followed by a numerical designation (i.e., LP105), the term "LP" refers to a specific group of molecules as defined herein. A complete designation wherein the term "LP" is immediately followed by a numerical designation and a molecule type (i.e., LP105 polypeptide) refers to a specific type of molecule within the designated group of molecules as designated herein.

The terms "LP polypeptide-encoding polynucleotides" or "LP polynucleotides" and "LP polypeptides" wherein the term "LP" is followed by an actual numerical designation as used herein encompass novel polynucleotides and polypeptides, respectively, which are further defined herein. The LP molecules described herein may be isolated from a variety of sources including, but not limited to human tissue types, or prepared by recombinant or synthetic methods. One aspect of the present invention provides an isolated nucleic acid molecule comprising a polynucleotide which encodes an LP105, LP061, LP224, LP240, LP239(a), LP243(a), LP243 (b) , LP253, LP218, LP251 (a) , LP252, LP239(b), LP223 (a) , LP255 (a) , LP244, LP186, LP251(b),

LP255(b), or LP223 (b) polypeptide as defined herein. In a preferred embodiment of the present invention, the isolated nucleic acid comprises 1) a polynucleotide encoding an LP105, LP061, LP224, LP240, LP239 (a) , LP243 (a) , LP243 (b) , LP253, LP218, LP251(a), LP252, LP239 (b) , LP223 (a) , LP255(a), LP244, LP186, LP251(b), LP255 (b) , or LP223 (b) polypeptide having an amino acid sequence as shown in SEQ ID NO:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, or 38, respectively; 2) a polynucleotide complementary to such encoding nucleic acid sequences, and which remain stably bound to them under at least moderate, and optionally, high stringency conditions; or 3) any fragment and/or variant of 1) or 2 ) .

The term "LP polypeptide" specifically encompasses truncated or secreted forms of an LP polypeptide, (e.g., soluble forms containing, for instance, an extracellular domain sequence), variant forms (e.g., alternatively spliced forms) and allelic variants of an LP polypeptide.

In one embodiment of the invention, the native sequence LP polypeptide is a full-length or mature LP polypeptide comprising amino acids as shown in SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32,

34, 36, or 38. The predicted signal peptides are indicated in the sequence listing of the present application by negative integers below the amino acids disclosed for a particular polypeptide. Also, while the LP polypeptides disclosed herein are shown to begin with a methionine residue designated as amino acid position 1, it is conceivable and possible that another methionine residue located either upstream or downstream from amino acid position 1 may be employed as the starting amino acid residue.

A "portion" of an LP polypeptide sequence is at least about 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 contiguous amino acid residues in length.

"LP polypeptide variant" is intended to refer to an "active" LP polypeptide, wherein activity is as defined herein, having at least about 90% amino acid sequence identity with an LP polypeptide having a deduced amino acid sequences as shown above. Such LP polypeptide variants include, for instance, LP polypeptides, wherein one or more amino acid residues are added, substituted or deleted, at the N- or C-terminus or within the sequences shown.

Ordinarily, an LP polypeptide variant will have at least about 90% amino acid sequence identity, preferably at least about 91% sequence identity, yet more preferably at least about 92% sequence identity, yet more preferably at least about 93% sequence identity, yet more preferably at least about 94% sequence identity, yet more preferably at least about 95% sequence identity, yet more preferably at least about 96% sequence identity, yet more preferably at least about 97% sequence identity, yet more preferably at least about 98% sequence identity, yet more preferably at least about 99% amino acid sequence identity with the amino acid sequence described, with or without the signal peptide.

"Percent (%) amino acid sequence identity" with respect to the LP amino acid sequences identified herein is defined as the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in an LP polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as ALIGN, ALIGN-2, Megalign (DNASTAR) or BLAST (e.g., Blast, Blast-2, WU-Blast-2) software. Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared. For example, the percent identity values used herein are generated using WU-BLAST-2 [Altschul, et al . , Methods in Enzymology 266 : 460-80 (1996)]. Most of the WU- BLAST-2 search parameters are set to the default values. Those not set to default values, i.e., the adjustable parameters, are set with the following values: overlap span = 1; overlap fraction = 0.125; word threshold (T) = 11; and scoring matrix = BLOSUM 62. For purposes herein, a percent amino acid sequence identity value is determined by dividing (a) the number of matching identical amino acid residues between the amino acid sequence of the LP polypeptide of interest and the comparison amino acid sequence of interest (i.e., the sequence against which the LP polypeptide of interest is being compared) as determined by WU-BLAST-2, by (b) the total number of amino acid residues of the LP polypeptide of interest, respectively. An "LP variant polynucleotide, " "LP polynucleotide variant," or "LP variant nucleic acid sequence" are intended to refer to an nucleic acid molecule as defined below having at least about 75% nucleic acid sequence identity with the polynucleotide sequence as shown in SEQ ID NO: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, or 37. Ordinarily, an LP polynucleotide variant will have at least about 75% nucleic acid sequence identity, more preferably at least about 80% nucleic acid sequence identity, yet more preferably at least about 81% nucleic acid sequence identity, yet more preferably at least about 82% nucleic acid sequence identity, yet more preferably at least about 83% nucleic acid sequence identity, yet more preferably at least about 84% nucleic acid sequence identity, yet more preferably at least about 85% nucleic acid sequence identity, yet more preferably at least about 86% nucleic acid sequence identity, yet more preferably at least about 87% nucleic acid sequence identity, yet more preferably at least about 88% nucleic acid sequence identity, yet more preferably at least about 89% nucleic acid sequence identity, yet more preferably at least about 90% nucleic acid sequence identity, yet more preferably at least about 91% nucleic acid sequence identity, yet more preferably at least about 92% nucleic acid sequence identity, yet more preferably at least about 93% nucleic acid sequence identity, yet more preferably at least about 94% nucleic acid sequence identity, yet more preferably at least about 95% nucleic acid sequence identity, yet more preferably at least about 96% nucleic acid sequence identity, yet more preferably at least about 97% nucleic acid sequence identity, yet more preferably at least about 98% nucleic acid sequence identity, yet more preferably at least about 99% nucleic acid sequence identity with the nucleic acid sequences shown above. Variants specifically exclude or do not encompass the native nucleotide sequence, as well as those prior art sequences that share 100% identity with the nucleotide sequences of the invention. "Percent (%) nucleic acid sequence identity" with respect to the LP polynucleotide sequences identified herein is defined as the percentage of nucleotides in a candidate sequence that are identical with the nucleotides in the LP polynucleotide sequence after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity. Alignment for purposes of determining percent nucleic acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as ALIGN, Align-2, Megalign (DNASTAR) , or BLAST (e.g., Blast, Blast-2) software. Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared. For purposes herein, however, % nucleic acid identity values are generated using the WU-BLAST-2 (BlastN module) program [Altschul, et al . , Methods in Enzymology 266:460-80 (1996)]. Most of the WU-BLAST-2 search parameters are set to the default values. Those not set default values, i.e., the adjustable parameters, are set with the following values: overlap span = 1; overlap fraction = 0.125; word threshold (T) = 11; and scoring matrix = BLOSUM62. For purposes herein, a percent nucleic acid sequence identity value is determined by dividing (a) the number of matching identical nucleotides between the nucleic acid sequence of the LP polypeptide-encoding nucleic acid molecule of interest and the comparison nucleic acid molecule of interest (i.e., the sequence against which the LP polypeptide-encoding nucleic acid molecule of interest is being compared) as determined by WU-BLAST-2, by (b) the total number of nucleotides of the LP polypeptide-encoding nucleic acid molecule of interest. In other embodiments, the LP variant polypeptides are encoded by nucleic acid molecules which are capable of hybridizing, preferably under stringent hybridization and wash conditions, to nucleotide sequences encoding the full- length LP polypeptide as shown in SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, or 38. This scope of variant polynucleotides specifically excludes those sequences that are known as of the filing and/or priority dates of the present application. The term "mature protein" or "mature polypeptide" as used herein refers to the form(s) of the protein produced by expression in a mammalian cell. It is generally hypothesized that once export of a growing protein chain across the rough endoplasmic reticulum has been initiated, proteins secreted by mammalian cells have a signal peptide (SP) sequence which is cleaved from the complete polypeptide to produce a "mature" form of the protein. Oftentimes, cleavage of a secreted protein is not uniform and may result in more than one species of mature protein. The cleavage site of a secreted protein is determined by the primary amino acid sequence of the complete protein and generally cannot be predicted with complete accuracy. Methods for predicting whether a protein has an SP sequence, as well as the cleavage point for that sequence, are available. A cleavage point may exist within the N- terminal domain between amino acid 10 and amino acid 35. More specifically the cleavage point is likely to exist after amino acid 15 but before amino acid 30, more likely after amino acid 27. As one of ordinary skill would appreciate, however, cleavage sites sometimes vary from organism to organism and cannot be predicted with absolute certainty. Optimally, cleavage sites for a secreted protein are determined experimentally by amino-terminal sequencing of the one or more species of mature proteins found within a purified preparation of the protein.

The term "positives," in the context of sequence comparison performed as described above, includes residues in the sequences compared that are not identical but have similar properties (e.g., as a result of conservative substitutions) . The percent identity value of positives is determined by the fraction of residues scoring a positive value in the BLOSUM 62 matrix. This value is determined by dividing (a) the number of amino acid residues scoring a positive value in the BLOSUM62 matrix of WU-BLAST-2 between the LP polypeptide amino acid sequence of interest and the comparison amino acid sequence (i.e., the amino acid sequence against which the LP polypeptide sequence is being compared) as determined by WU-BLAST-2, by (b) the total number of amino acid residues of the LP polypeptide of interest .

"Isolated, " when used to describe the various polypeptides disclosed herein, means a polypeptide that has been identified and separated and/or recovered from a component of its natural environment. Preferably, the isolated polypeptide is free of association with all components with which it is naturally associated. Contaminant components of its natural environment are materials that would typically interfere with diagnostic or therapeutic uses for the polypeptide, and may include enzymes, hormones, and other proteinaceous or non- proteinaceous solutes. In preferred embodiments, the polypeptide will be purified (1) to a degree sufficient to obtain at least 15 residues of N-terminal or internal amino acid sequence by use of a spinning cup sequenator, or (2) to homogeneity by SDS-PAGE under non-reducing or reducing conditions using Coomassie blue or, preferably, silver stain. Isolated polypeptide includes polypeptide in si tu within recombinant cells, since at least one component of the LP polypeptide natural environment will not be present. Ordinarily, however, isolated polypeptide will be prepared by at least one purification step.

An "isolated LP polypeptide-encoding nucleic acid" or "isolated LP nucleic acid" is a nucleic acid molecule that is identified and separated from at least one contaminant nucleic acid molecule with which it is ordinarily associated in the natural source of the nucleic acid. Such an isolated nucleic acid molecule is other than in the form or setting in which it is found in nature. Isolated nucleic acid molecules therefore are distinguished from the nucleic acid molecule as it exists in natural cells. However, an isolated LP polypeptide-encoding nucleic acid molecule includes LP polypeptide-encoding nucleic acid molecules contained in cells that ordinarily express LP polypeptide where, for example, the nucleic acid molecule is in a chromosomal location different from that of natural cells .

Nucleic acid is "operably linked" when it is placed into a functional relationship with another nucleic acid sequence. For example, DNA for a presequence or secretory leader is operably linked to DNA for a polypeptide if it is expressed as a preprotein that participates in the secretion of the polypeptide; a promoter or enhancer is operably linked to a coding sequence if it affects the transcription of the sequence; or a ribosome binding site is operably linked to a coding sequence if it is positioned so as to facilitate translation. Generally, "operably linked" means that the DNA sequences being linked are contiguous, and, in the case of a secretory leader, contiguous and in reading phase. However, enhancers do not have to be contiguous. Linking is accomplished by ligation at convenient restriction sites. If such sites do not exist, the. synthetic oligonucleotide adapters or linkers are used in accordance with conventional practice.

The term "amino acid" is used herein in its broadest sense, and includes naturally occurring amino acids as well as non-naturally occurring amino acids, including amino acid analogs and derivatives . The latter includes molecules containing an amino acid moiety. One skilled in the art will recognize, in view of this broad definition, that reference herein to an amino acid includes, for example, naturally occurring proteogenic L-amino acids; D- amino acids; chemically modified amino acids such as amino acid analogs and derivatives; naturally-occurring non- proteogenic amino acids such as norleucine, beta-alanine, ornithine, etc.; and chemically synthesized compounds having properties known in the art to be characteristic of ^■ amino acids. As used herein, the term "proteogenic" indicates that the amino acid can be incorporated into a peptide, polypeptide, or protein in a cell through a metabolic pathway. The incorporation of non-natural amino acids, including synthetic non-native amino acids, substituted amino acids, or one or more D-amino acids into the LP peptides, polypeptides, or proteins of the present invention ("D-LP polypeptides") is advantageous in a number of different ways. D-amino acid-containing peptides, polypeptides, or proteins exhibit increased stability in vi tro or in vivo compared to L-amino acid-containing counterparts . Thus, the construction of peptides, polypeptides, or proteins incorporating D-amino acids can be particularly useful when greater intracellular stability is desired or required. More specifically, D-peptides, polypeptides, or proteins are resistant to endogenous peptidases and proteases, thereby providing improved bioavailability of the molecule and prolonged lifetimes in vivo when such properties are desirable. When it is desirable to allow the peptide, polypeptide, or protein to remain active for only a short period of time, the use of L-amino acids therein will permit endogenous peptidases, proteases, etc., in a cell to digest the molecule in vivo, thereby limiting the cell's exposure to the molecule. Additionally, D-peptides, polypeptides, or proteins cannot be processed efficiently for major histocompatibility complex class II-restricted presentation to T helper cells, and are therefore less likely to induce humoral immune responses in the whole organism.

In addition to -using D-amino acids, those of ordinary skill in the art are aware that modifications in the amino acid sequence of a peptide, polypeptide, or protein can result in equivalent, or possibly improved, second generation peptides, polypeptides, or proteins, that display equivalent or superior functional characteristics when compared to the original amino acid sequences.

Alterations in the LP peptides, polypeptides, or proteins of the present, invention can include one or more amino acid insertions, deletions, substitutions, truncations, fusions, shuffling of subunit sequences, and the like, either from natural mutations or human manipulation, provided that the sequences produced by such modifications have substantially the same (or improved or reduced, as may be desirable) activity (ies) as the naturally-occurring counterpart sequences disclosed herein.

One factor that can be considered in making such changes is the hydropathic index of amino acids. The importance of the hydropathic amino acid index in conferring interactive biological function on a protein has been discussed by Kyte and Doolittle [J^". Mol . Biol . 157:105-32 (1982)]. It is accepted that the relative hydropathic character of amino acids contributes to the secondary structure of the resultant protein. This, in turn, affects the interaction of the protein with molecules such as enzymes, substrates, receptors, ligands, DNA, antibodies, antigens, etc. Based on its hydrophobicity and charge characteristics, each amino acid has been assigned a hydropathic index as follows: isoleucine (+4.5); valine (+4.2); leucine (+3.8); phenylalanine (+2.8); cysteine/cystine (+2.5); methionine (+1.9); alanine (+1.8); glycine (-0.4); threonine (-0.7); serine (-0.8); tryptophan (-0.9); tyrosine (-1.3); proline (-1.6); histidine (-3.2); glutamate/glutamine/aspartate/asparagine (-3.5); lysine (-3.9); and arginine (-4.5).

As is known in the art, certain amino acids in a peptide, polypeptide, or protein can be substituted for other amino acids having a similar hydropathic index or score and produce a resultant peptide, polypeptide, or protein having similar biological activity, i.e., which still retains biological functionality. In making such changes, it is preferable that amino acids having hydropathic indices within ±2 are substituted for one another. More preferred substitutions are those wherein the amino acids have hydropathic indices within ±1. Most preferred substitutions are those wherein the amino acids have hydropathic indices within ±0.5.

Like amino acids can also be substituted on the basis of hydrophilicity. U.S. Patent 4,554,101 discloses that the greatest local average hydrophilicity of a protein, as governed by the hydrophilicity of its adjacent amino acids, correlates with a biological property of the protein. The following hydrophilicity values have been assigned to amino acids: arginine/lysine (+3.0); aspartate/glutamate (+3.0±1); serine (+0.3); asparagine/glutamine (+0.2); glycine (0) ; threonine (-0.4); proline (-0.5±1); alanine/histidine (-0.5); cysteine (-1.0); methionine (-1.3); valine (-1.5); leucine/isoleucine (-1.8); tyrosine (-2.3); phenylalanine (-2.5); and tryptophan (-3.4). Thus, one amino acid in a peptide, polypeptide, or protein can be substituted by another amino acid having a similar hydrophilicity score and still produce a resultant peptide, polypeptide, or protein having similar biological activity, i.e., still retaining correct biological function. In making such changes, amino acids having hydropathic indices within ± 2 are preferably substituted for one another, those within ± 1 are more preferred, and those within ± 0.5 are most preferred.

As outlined above, amino acid substitutions in the LP polypeptides of the present invention can be based on the relative similarity of the amino acid side-chain substituents, for example, their hydrophobicity, hydrophilicity, charge, size, etc. Exemplary substitutions that take various of the foregoing characteristics into consideration in order to produce conservative amino acid changes resulting in silent changes within the present peptides, polypeptides, or proteins can be selected from other members of the class to which the naturally occurring amino acid belongs . Amino acids can be divided into the following four groups: (1) acidic amino acids; (2) basic amino acids; (3) neutral polar amino acids; and (4) neutral non-polar amino acids. Representative amino acids within these various groups include, but are not limited to: (1) acidic (negatively charged) amino acids such as aspartic acid and glutamic acid; (2) basic (positively charged) amino acids such as arginine, histidine, and lysine; (3) neutral polar amino acids such as glycine, serine, threonine, cysteine, cystine, tyrosine, asparagine, and glutamine; and (4) neutral non-polar amino acids such as alanine, leucine, isoleucine, valine, proline, phenyl- alanine, tryptophan, and methionine.

It should be noted that changes which are not expected to be advantageous can also be useful if these result in the production of functional sequences. Since small peptides polypeptides, and some proteins can be easily produced by conventional solid phase synthetic techniques, the present invention includes peptides, polypeptides, or proteins such as those discussed herein, containing the amino acid modifications discussed above, alone or in various combinations. To the extent that such modifications can be made while substantially retaining the activity of the peptide, polypeptide, or protein, they are included within the scope of the present invention. The utility of such modified peptides, polypeptides, or proteins can be determined without undue experimentation by, for example, the methods described herein.

While biologically functional equivalents of the present LP polypeptides can have any number of conservative or non-conservative amino acid changes that do not significantly affect their activity (ies) , or that increase or decrease activity as desired, 40, 30, 20, 10, 5, or 3 changes, such as 1 to 30 changes or any range or value therein, may be preferred. In particular, ten or fewer amino acid changes may be preferred. More preferably, seven or fewer amino acid changes may be preferred; most preferably, five or fewer amino acid changes may be preferred. The encoding nucleotide sequences (gene, plasmid DNA, cDNA, synthetic DNA, or mRNA, for example) will thus have corresponding base substitutions, permitting them to code on expression for the biologically functional equivalent forms of the LP polypeptides. In any case, the LP peptides, polypeptides, or proteins exhibit the same or similar biological or immunological activity (ies) as that (those) of the LP polypeptides specifically disclosed herein, or increased or reduced activity, if desired. The activity (ies) of the variant LP polypeptides can be determined by the methods described herein. Variant LP polypeptides biologically functionally equivalent to those specifically disclosed herein have activity (ies) differing from those of the presently disclosed molecules by about ±50% or less, preferably by about ±40% or less, more preferably by about ±30% or less, more preferably by about ±20% or less, and even more preferably by about ±10% or less, when assayed by the methods disclosed herein.

Amino acids in an LP polypeptide of the present invention that are essential for activity can be identified by methods known in the art, such as site-directed mutagenesis or alanine-scanning mutagenesis [Cunningham and Wells, Science 244:1081-5 (1989)]. The latter procedure introduces single alanine mutations at every residue in the molecule. The resulting mutant molecules are then tested for biological activity. Sites that are critical for ligand-protein binding can also be identified by structural analysis such as crystallization, nuclear magnetic resonance, or photoaffinity labeling [Smith, et al . , J. Mol . Biol . 224:899-904 (1992); de Vos, et al . , Science 255:306-12 (1992)] .

"Stringency" of hybridization reactions is readily determinable by one of ordinary skill in the art, and generally is an empirical calculation dependent upon probe length, washing temperature, and salt concentration. In general, longer nucleic acid probes required higher temperatures for proper annealing, while shorter nucleic acid probes need lower temperatures. Hybridization generally depends on the ability of denatured DNA to reanneal when complementary strands are present in an environment below their melting temperature . The higher the degree of desired homology between the probe and hybridizable sequence, the higher the relative temperature that can be used. As a result, it follows that higher relative temperatures would tend to make the reactions more stringent, while lower temperatures less so. For additional details and explanation of stringency of hybridization reactions, see Ausubel, et al . , Current Protocols in Molecular Biology, Wiley Interscience Publishers (1995) . "Stringent conditions" or "high stringency conditions, " as defined herein, may be identified by those that (1) employ low ionic strength and high temperature for washing, for example, 15 mM sodium chloride/1.5 mM sodium citrate/0.1% sodium dodecyl sulfate at 50 degrees C;

(2) employ during hybridization a denaturing agent, such as formamide, for example, 50% (v/v) formamide with 0.1% bovine serum albumin/0.1% ficoll/0.1% polyvinylpyrrol- idone/50 mM sodium phosphate buffer at pH 6.5 with 750 mM sodium chloride/75 mM sodium citrate at 42 degrees C; or (3) employ 50% formamide, 5X SSC (750 mM sodium chloride, 75 mM sodium citrate), 50 mM sodium phosphate (pH 6.8), 0.1% sodium pyrophosphate, 5X Denhardt's solution, sonicated salmon sperm DNA (50 μg/mL) , 0.1% SDS, and 10% dextran sulfate at 42 degrees C with washes at 42 degrees C in 0.2X SSC (30 mM sodium chloride/3 mM sodium citrate) and 50% formamide at 55 degrees C, followed by a high- stringency wash consisting of 0. IX SSC containing EDTA at 55 degrees C.

"Moderately stringent conditions" may be identified as described by Sambrook, et al . [Molecular Cloning: A Laboratory Manual , New York: Cold Spring Harbor Press, (1989)], and include the use of washing solution and hybridization conditions (e.g., temperature, ionic strength and %SDS) less stringent than those described above. An example of moderately stringent conditions is overnight incubation at 37 degrees C in a solution comprising: 20% formamide, 5X SSC (750 mM sodium chloride, 75 mM sodium citrate), 50 mM sodium phosphate at pH 7.6, 5X Denhardt's solution, 10% dextran sulfate, and 20 mg/mL denatured sheared salmon sperm DNA, followed by washing the filters in IX SSC at about 37 to 50 degrees C. The skilled artisan will recognize how to adjust the temperature, ionic strength, etc., as necessary to accommodate factors such as probe length and the like .

The term "epitope tagged" where used herein refers to a chimeric polypeptide comprising an LP polypeptide, or domain sequence thereof, fused to a "tag polypeptide." The tag polypeptide has enough residues to provide an epitope against which an antibody may be made, or which can be identified by some other agent, yet is short enough such that it does not interfere with the activity of the LP polypeptide. The tag polypeptide preferably is also fairly unique so that the antibody does not substantially cross- react with other epitopes. Suitable tag polypeptides generally have at least six amino acid residues and usually between about eight to about fifty amino acid residues (preferably, between about ten to about twenty residues) . As used herein, the term "immunoadhesin, " sometimes referred to as an Fc fusion, designates antibody-like molecules that combine the binding specificity of a heterologous protein (an "adhesin") with the effector functions of immunoglobulin constant domains. Structurally, the immunoadhesins comprise a fusion of an amino acid sequence with the desired binding specificity which is other than the antigen recognition and binding site of an antibody (i.e., is "heterologous"), and an immunoglobulin constant domain sequence. The adhesin part of an immunoadhesin molecule typically is a contiguous amino acid sequence comprising at least the binding site of a receptor or a ligand. The immunoglobulin constant domain sequence in the immunoadhesin may be obtained from any immunoglobulin, such as IgG-1, IgG-2, IgG-3 or IgG-4 subtypes, IgA (including IgA-1 and IgA-2), IgE, IgD or IgM. "Active" or "activity" for the purposes herein refers to form(s) of LP polypeptide which retain all or a portion of the biologic and/or immunologic activities of native or naturally-occurring LP polypeptide. Elaborating further, "biological" activity refers to a biological function

(either inhibitory or stimulatory) caused by a native or naturally-occurring LP polypeptide other than the ability to induce the production of an antibody against an antigenic epitope possessed by a native or naturally- occurring LP polypeptide. An "immunological" activity refers only to the ability to induce the production of an antibody against an antigenic epitope possessed by a native or naturally-occurring LP polypeptide.

The term "antagonist" is used in the broadest sense and includes any molecule that partially or fully blocks, inhibits, or neutralizes a biological activity of a native LP polypeptide disclosed herein. In a similar manner, the term "agonist" is used in the broadest sense and includes any molecule that mimics a biological activity of a native LP polypeptide disclosed herein. Suitable agonist or antagonist molecules specifically include agonist or antagonist antibodies or antibody fragments, fragments or amino acid sequence variants of native LP polypeptides, peptides, ribozymes, anti-sense nucleic acids, small organic molecules, etc. Methods for identifying agonists or antagonists of an LP polypeptide may comprise contacting an LP polypeptide with a candidate agonist or antagonist molecule and measuring a detectable change in one or more biological activities normally associated with the LP polypeptide .

"Antibodies" (Abs) and "immunoglobulins" (Igs) are glycoproteins having the same structural characteristics. While antibodies exhibit binding specificity to a specific antigen, immunoglobulins include both antibodies and other antibody-like molecules that lack antigen specificity. Polypeptides of the latter kind are, for example, produced at low levels by the lymph system and at increased levels by myelomas. The term "antibody" is used in the broadest sense and specifically covers, without limitation, intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies) formed from at least two intact antibodies, and antibody fragments so long as they exhibit the desired biological activity. The terms "treating, " "treatment, " and "therapy" as used herein refer to curative therapy, prophylactic therapy, and preventive therapy. An example of "preventive therapy" is the prevention or lessened targeted pathological condition or disorder. Those in need of treatment include those already with the disorder as well as those prone to have the disorder or those in whom the disorder is to be prevented.

"Chronic" administration refers to administration of the agent (s) in a continuous mode as opposed to an acute mode, so as to maintain the initial therapeutic effect

(activity) for an extended period of time. "Intermittent" administration is treatment that is not consecutively done without interruption but, rather, is cyclic in nature. Administration "in combination with" one or more further therapeutic agents includes simultaneous

(concurrent) and consecutive administration in any order. A "therapeutically-effective amount" is the minimal amount of active agent (e.g., an LP polypeptide, antagonist or agonist thereof) which is necessary to impart therapeu- tic benefit to a mammal. For example, a "therapeutically- effective amount" to a mammal suffering or prone to suffering or to prevent it from suffering is such an amount which induces, ameliorates, or otherwise causes an improvement in the pathological symptoms, disease progression, physiological conditions associated with or resistance to succumbing to the aforedescribed disorder. "Carriers" as used herein include pharmaceutically- acceptable carriers, excipients, or stabilizers which are nontoxic to the cell or mammal being exposed thereto at the dosages and concentrations employed. Often the physiologically-acceptable carrier is an aqueous pH buffered solution. Examples of physiologically acceptable carriers include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid; low molecule weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinyl- pyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine or lysine; monosaccharides, disac- charides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; and/or nonionic surfactants such as TWEEN^®, polyethylene glycol (PEG), and PLURONIC^®. "Antibody fragments" comprise a portion of an intact antibody, preferably the antigen binding or variable region of the intact antibody. Examples of antibody fragments include Fab, Fab', F(ab')₂ and Fv fragments; diabodies; linear antibodies [Zapata, et al . , Protein Engin . 8 (10):1057-62 (1995)]; single-chain antibody molecules; and multispecific antibodies formed from antibody fragments.

"Fv" is the minimum antibody fragment which contains a complete antigen-recognition and binding site. This region consists of a di er of one heavy- and one light-chain variable domain in tight, non-covalent association. It is in this configuration that the three CDRs of each variable domain interact to define an antigen-binding site on the surface of the V_HV_L dimer. Collectively, the six CDRs confer antigen-binding specificity to the antibody. However, even a single variable domain (or half of an Fv comprising only three CDR specific for an antigen) has the ability to recognize and bind antigen, although at a lower affinity than the entire binding site.

"Single-chain Fv" or "sFv" antibody fragments comprise the V_H and V domains of antibody, wherein these domains are present in a single polypeptide chain. Preferably, the Fv polypeptide further comprises a polypeptide linker between the V_H and V_L domain, which enables the sFv to form the desired structure for antigen binding. For a review of sFv, see Pluckthun, The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore, eds . , Springer- Verlag, New York, pp. 269-315 (1994) . The term "diabodies" refers to small antibody fragments with two antigen-binding sites, which fragments comprise a heavy-chain variable domain (V_H) connected to a light-chain variable domain (V_L) in the same polypeptide chain (V_H-V_L) . By using a linker that is too short to allow pairing between the two domains on the same chain, the domains are forced to pair with the complementary domains of another chain and create two antigen-binding sites. Diabodies are described more fully in, for example, EP 404 097; WO 93/11161; and Hollinger, et al . , Proc . Natl . Acad. Sci . USA 90:6444-8 (1993).

An "isolated" antibody is one which has been identified and separated and/or recovered from a component of its natural environment. Contaminant components of its natural environment are materials which would interfere with diagnostic or therapeutic uses for the antibody, and may include enzymes, hormones, and other proteinaceous or non-proteinaceous solutes. In preferred embodiments, the antibody will be purified (1) to greater than 95% by weight of antibody as determined by the Lowry method, and most preferably more than 99% by weight, (2) to a degree sufficient to obtain at least 15 residues of N-terminal or internal amino acid sequence by use of a spinning cup sequenator, or (3) to homogeneity by SDS-PAGE under reducing or nonreducing conditions using Coomassie blue, or preferably, silver stain. Isolated antibody includes the antibody in si tu within recombinant cells since at least one component of the antibody's natural environment will not be present. Ordinarily, however, isolated antibody will be prepared by at least one purification step.

An "LP polypeptide antibody" or "LP antibody" refers to an antibody as defined herein that recognizes and binds at least one epitope of an LP polypeptide of the present invention. The term "LP polypeptide antibody" or "LP antibody" wherein the term "LP" is followed by a numerical designation refers to an antibody that recognizes and binds to at least one epitope of that particular LP polypeptide as disclosed herein.

A "liposome" is a small vesicle composed of various types of lipids, phospholipids and/or surfactant which is useful for delivery of a drug (such as an LP polypeptide or antibody thereto) to a mammal. The components of the liposome are commonly arranged in a bilayer formation, similar to the lipid arrangement of biological membranes.

A "small molecule" is defined herein to have a molecular weight below about 500 daltons .

The term "modulate" means to affect (e.g., either upregulate, downregulate or otherwise control) the level of a signaling pathway. Cellular processes under the control of signal transduction include, but are not limited to, transcription of specific genes, normal cellular functions, such as metabolism, proliferation, differentiation, adhesion, apoptosis and survival, as well as abnormal processes, such as transformation, blocking of differentiation and metastasis.

An LP polynucleotide can be composed of any polyribo- nucleotide or polydeoxyribonucleotide, which may be unmodified RNA or DNA or modified RNA or DNA. For example, the LP polynucleotides can be composed of single- and double-stranded DNA, DNA that is a mixture of single- and double-stranded regions, single- and double-stranded RNA, and RNA that is mixture of single- and double-stranded regions, hybrid molecules comprising DNA and RNA that may be single-stranded or, more typically, double-stranded or a mixture of single- and double-stranded regions . In addition, LP polynucleotides can be composed of triple- stranded regions comprising RNA or DNA or both RNA and DNA. LP polynucleotides may also contain one or more modified bases or DNA or RNA backbones modified for stability or for other reasons. "Modified" bases include, for example, tritylated bases and unusual bases such as inosine. A variety of modifications can be made to DNA and RNA; thus, "polynucleotide" embraces chemically, enzymatically, or metabolically modified forms. LP polypeptides can be composed of amino acids joined to each other by peptide bonds or modified peptide bonds, i.e., peptide isosteres, and may contain amino 'acids other than the gene-encoded amino acids . The LP polypeptides may be modified by either natural processes, such as post- translational processing, or by chemical modification techniques which are well known in the art. Such modifications are well described in basic texts and in more detailed monographs, as well as in a voluminous research literature. Modifications can occur anywhere in the LP polypeptides, including the peptide backbone, the amino acid side-chains and the amino or carboxyl termini . It will be appreciated that the same type of modification may be present in the same or varying degrees at several sites in a given LP polypeptide. Also, a given LP polypeptide may contain many types of modifications. LP polypeptides may be branched, for example, as a result of ubiquitination, and they may be cyclic, with or without branching. Cyclic, branched, and branched cyclic LP polypeptides may result from post-translation natural processes or may be made by synthetic methods. Modifications include acetylation, acylation, ADP-ribosylation, amidation, covalent attachment of flavin, covalent attachment of a heme moiety, covalent attachment of a nucleotide or nucleotide derivative, covalent attachment of a lipid or lipid derivative, covalent attachment of phosphotidylinositol, cross-linking, cyclization, disulfide bond formation, demethylation, formation of covalent cross-links, formation of cysteine, formation of pyroglutamate, formylation, gamma- carboxylation, glycosylation, GPI anchor formation, hydroxylation, iodination, methylation, myristoylation, oxidation, pegylation, proteolytic processing, phosphorylation, prenylation, racemization, selenoylation, sulfation, transfer-RNA mediated addition of amino acids to proteins such as arginylation, and ubiquitination. See, for instance, Creighton, Proteins - Structure and Molecular Properties, 2nd Ed. , W. H. Freeman and Company, New York (1993); Johnson, Post-translational Covalent Modification of Proteins, Academic Press, New York, pp. 1-12 (1983); Seifter, et al . , Meth . Enzymol . 182:626-46 (1990); Rattan, et al . , Ann . NY Ac ad. Sci . 663:48-62 (1992).

Variations in the full-length sequence LP polypeptide or in various domains of the LP polypeptide described herein can be made, for example, using any of the techniques and guidelines for conservative and non- conservative mutations set forth, for instance, in U.S. Patent 5,364,934. Variations may be a substitution, deletion or insertion of one or more codons encoding LP polypeptide that results in a change in the amino acid sequence of the LP polypeptide as compared with the native sequence LP polypeptide or an LP polypeptide as disclosed herein. Optionally the variation is by substitution of at least one amino acid with any other amino acid in one or more of the domains of the LP polypeptide. Guidance in determining which amino acid residue may be inserted, substituted or deleted without adversely affecting the desired activity may be found by comparing the sequence of the LP polypeptide with that of homologous known protein molecules and minimizing the number of amino acid sequence changes made in regions of high homology. Amino acid substitutions can be the result of replacing one amino acid with another amino acid having similar structural and/or chemical properties, such as the replacement of a leucine with a serine, i.e., conservative amino acid replacements. Insertions or deletions may optionally be in the range of one to five amino acids . The variation allowed may be determined by systematically making insertions, deletions or substitutions of amino acids in the sequence and testing the resulting variants for activity (such as in any of the in vi tro assays described herein) for activity exhibited by the full-length or mature polypeptide sequence. LP polypeptide fragments are also provided herein. Such fragments may be truncated at the N-terminus or C-terminus, or may lack internal residues, for example, when compared with a full length or native protein. Certain fragments contemplated by the present invention may lack amino acid residues that are not essential for a desired biological activity of the LP polypeptide.

LP polypeptide fragments may be prepared by any of a number of conventional techniques. Desired peptide fragments may be chemically synthesized. An alternative approach involves generating LP fragments by enzymatic digestion, e.g., by treating the protein with an enzyme known to cleave proteins at sites defined by particular amino acid residues, or by digesting the DNA with suitable restriction enzymes and isolating the desired fragment. Yet another suitable technique involves isolating and amplifying a DNA fragment encoding a desired polypeptide fragment by polymerase chain reaction (PCR) . Oligonucleo- tides that define the desired termini of the DNA fragment are employed at the 5' and 3' primers in the PCR.

Preferably, LP polypeptide fragments share at least one biological and/or immunological activity with at least one of the LP polypeptides as shown in SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, or 38.

Covalent modifications of LP polypeptides are included within the scope of this invention. One type of covalent modification includes reacting targeted amino acid residues of an LP polypeptide with an organic derivatizing agent that is capable of reacting with selected side chains or the N- or C-terminal residues of an LP polypeptide. Derivatization with bifunctional agents is useful, for instance, for crosslinking LP polypeptide to a water- insoluble support matrix or surface for use in the method for purifying anti-LP polypeptide antibodies, and vice- versa. Commonly used crosslinking agents include, e.g., 1, 1-bis (diazoacetyl) -2-phenylethane, glutaraldehyde, N-hydroxysuccinimide esters, for example, esters with 4-azidosalicylic acid, homobifunctional imidoesters, including disuccinimidyl esters such as 3 , 3'-dithiobis- (succinimidylproprionate) , bifunctional maleimides such as bis-N-maleimido-1, 8-octane and agents such as methyl-3- [ (p- azidophenyl ) dithiolproprioimidate .

Other modifications include deamidation of glutaminyl and asparaginyl residues to the corresponding glutamyl and aspartyl residues, respectively, hydroxylation of proline and lysine, phosphorylation of hydroxyl groups of seryl or threonyl residues, methylation of the alpha-amino groups of lysine, arginine, and histidine side chains [Creighton, Proteins : Structure and Molecular Properties, W.H. Freeman & Co., San Francisco, pp. 79-86 (1983)], acetylation of the N-terminal amine, and amidation of any C-terminal carboxyl group .

Another type of covalent modification of the LP polypeptides included within the scope of this invention comprises altering the native glycosylation pattern of the polypeptide. "Altering the native glycosylation pattern" is intended for purposes herein to mean deleting one or more carbohydrate moieties found in native sequence LP polypeptide and/or adding one or more glycosylation sites that are not present in the native sequences of LP polypeptides. Additionally, the phrase includes qualitative changes in the glycosylation of the native proteins, involving a change in the nature and proportions of the various carbohydrate moieties present.

Addition of glycosylation sites to LP polypeptides may be accomplished by altering the amino acid sequence thereof. The alteration may be made, for example, by the addition of, or substitution by, one or more serine or threonine residues to the native sequences of LP polypeptides (for O-linked glycosylation sites) . The LP amino acid sequences may optionally be altered through changes at the DNA level, particularly by mutating the DNA encoding the LP polypeptides at preselected bases such that codons are generated that will translate into the desired amino acids .

Another means of increasing the number of carbohydrate moieties on the LP polypeptides is by chemical or enzymatic coupling of glycosides to the polypeptide. Such methods are described in the art, e.g., in WO 87/05330, and in Aplin and Wriston, CRC Cri t . Rev. Biochem. , pp. 259-306 (1981) . Removal of carbohydrate moieties present on the LP polypeptide may be accomplished chemically or enzymatically or by mutational substitution of codons encoding for amino acid residues that serve as targets for glycosylation. Chemical deglycosylation techniques are known in the art and described, for instance, by Sojar, et al . , Arch .

Biochem . Biophys . 259:52-7 (1987), and by Edge, et al . , Anal . Biochem. 118:131-7 (1981). Enzymatic cleavage of carbohydrate moieties on polypeptides can be achieved by the use of a variety of endo- and exo-glycosidases as described by Thotakura, et al . , Meth . Enzymol . 138:350-9 (1987) . Another type of covalent modification of LP comprises linking any one of the LP polypeptides to one of a variety of non-proteinaceous polymers (e.g., polyethylene glycol, polypropylene glycol, or polyoxyalkylenes) in the manner set forth in U.S. Patent Nos . 4,640,835; 4,496,689; 4,301,144; 4,670,417; 4,791,192, or 4,179,337.

LP polypeptides of the present invention may also be modified in a way to form chimeric molecules comprising an LP polypeptide fused to another heterologous polypeptide or amino acid sequence. In one embodiment, such a chimeric molecule comprises a fusion of an LP polypeptide with a tag polypeptide which provides an epitope to which an anti-tag antibody can selectively bind. The epitope tag is generally placed at the amino- or carboxyl- terminus of LP105, LP061, LP224, LP240, LP239 (a) , LP243 (a) , LP243 (b) , LP253, LP218, LP251(a), LP252, LP239 (b) , LP223 (a) , LP255(a), LP244, LP186, LP251(b), LP255 (b) , or LP223 (b) polypeptide. The presence of such epitope-tagged forms of an LP polypeptide can be detected using an antibody against the tag polypeptide. Also, provision of the epitope tag enables an LP polypeptide to be readily purified by affinity purification using an anti-tag antibody or another type of affinity matrix that binds to the epitope tag.

In an alternative embodiment, the chimeric molecule may comprise a fusion of an LP polypeptide with an immunoglobulin or a particular region of an immunoglobulin. For a bivalent form of the chimeric molecule, such a fusion could be to the Fc region of an IgG molecule. The Ig fusions preferably include the substitution of a soluble transmembrane domain deleted or inactivated form of an LP polypeptide in place of at least one variable region within an Ig molecule. In a particularly preferred embodiment, the immunoglobulin fusion includes the hinge, CH2 and CH3 or the hinge, CHI, CH2 and CH3 regions of an IgGl molecule. For the production of immunoglobulin fusions, see also U.S. Patent 5,428,130. In yet a further embodiment, the LP polypeptides of the present invention may also be modified in a way to form a chimeric molecule comprising an LP polypeptide fused to a leucine zipper. Various leucine zipper polypeptides have been described in the art. See, e.g., Landschulz, et al . , Science 240 (4860) : 1759-64 (1988); WO 94/10308; Hoppe, et al . , FEBS Letters 344 (2-3) : 191-5 (1994); Abel, et al . , Nature 341 (6237) : 24-5 (1989). It is believed that use of a leucine zipper fused to an LP polypeptide may be desirable to assist in dimerizing or trimerizing soluble LP polypeptide in solution. Those skilled in the art will appreciate that the zipper may be fused at either the N- or C-terminal end of an LP polypeptide.

The description below relates primarily to production of LP polypeptides by culturing cells transformed or transfected with a vector containing an LP polypeptide- encoding nucleic acid. It is, of course, contemplated that alternative methods, which are well known in the art, may be employed to prepare LP polypeptides. For instance, the LP polypeptide sequence, or portions thereof, may be produced by direct peptide synthesis using solid-phase techniques [see, e.g., Stewart, et al . , Solid-Phase Peptide Synthesis, W.H. Freeman & Co., San Francisco, CA (1969); Merrifield, J. Am . Chem. Soc . 85:2149-2154 (1963)]. In vi tro protein synthesis may be performed using manual techniques or by automation. Automated synthesis may be accomplished, for instance, using an Applied Biosystems Peptide Synthesizer (Foster City, CA) using manufacturer's instructions . Various portions of an LP polypeptide may be chemically synthesized separately and combined using chemical or enzymatic methods to produce a full-length LP polypeptide . DNA encoding an LP polypeptide may be obtained from a cDNA library prepared from tissue believed to possess the LP polypeptide-encoding mRNA and to express it at a detectable level. Libraries can be screened with probes (such as antibodies to an LP polypeptide or oligonucleotides of at least about 20 to 80 bases) designed to identify the gene of interest or the protein encoded by it. Screening the cDNA or genomic library with the selected probe may be conducted using standard procedures, such as described in Sambrook, et al . , Molecular Cloning: A Laboratory Manual , Cold Spring Harbor Laboratory Press, NY (1989). An alternative means to isolate the gene encoding an LP polypeptide is to use PCR methodology [Sambrook, et al . , supra; Dieffenbach, et al . , PCR Primer: A Laboratory Manual , Cold Spring Harbor Laboratory Press, NY (1995)]. Nucleic aci-d.s having protein coding sequence may be obtained by screening selected cDNA or genomic libraries using the deduced amino acid sequence disclosed herein for the first time and, if necessary, using conventional primer extension procedures as described in Sambrook, et al . , supra, to detect precursors and processing intermediates of mRNA that may not have been reverse-transcribed into cDNA.

Host cells are transfected or transformed with expression or cloning vectors described herein for LP polypeptide production and cultured in conventional nutrient media modified as appropriate for inducing promoters, selecting transformants, or amplifying the genes encoding the desired sequences. The culture conditions, such as media, temperature, pH and the like, can be selected by the skilled artisan without undue experimentation. In general, principles, protocols, and practical techniques for maximizing the productivity of cell cultures can be found in Mammalian Cell Biotechnology: A Practical Approach, Butler, ed. (IRL Press, 1991) and Sambrook, et al . , supra. Methods of transfection are known to the ordinarily skilled artisan, for example, calcium phosphate and electroporation. General aspects of mammalian cell host system transformations have been described in U.S. Patent 4,399,216. Transformations into yeast are typically carried out according to the method of van Solingen, et al . , J Bact . 130(2):946-7 (1977) and Hsiao, et al . , Proc . Natl . Acad. Sci . USA 76 (8) : 3829-33 (1979) . However, other methods for introducing DNA into cells, such as by nuclear microinjection, electroporation, bacterial protoplast fusion with intact cells, or polycations, e.g., polybrene or polyornithine, may also be used. For various techniques for transforming mammalian cells, see Keown, et al . , Methods in Enzymology 185:527-37 (1990) and Mansour, et al . , Nature 336 (6197 ): 348-52 (1988).

Suitable host cells for cloning or expressing the nucleic acid (e.g., DNA) in the vectors herein include prokaryote, yeast, or higher eukaryote cells. Suitable prokaryotes include but are not limited to eubacteria, such as Gram-negative or Gram-positive organisms, for example, Enterobacteriacea such as E. coli . Various E. coli strains are publicly available, such as E. coli K12 strain MM294 (ATCC 31,446); E. coli strain X1776 (ATCC 31,537); E. coli strain W3110 (ATCC 27,325) and K5 772 (ATCC 53,635). Other suitable prokaryotic host cells include Enterobacteriaceae such as Escherichia, e.g., E. coli , Enterobacter, Erwinia, Klebsiella, Proteus, Salmonella, e.g., Salmonella typhimurium, Serratia, e.g., Serratia marcescans, and Shigella, as well as Bacilli such as B. subtilis and B. licheniformis (e.g., B. licheniformis 41P disclosed in DD 266,710, published 12 April 1989),

Pseudomonas such as P. aeruginosa, and Streptomyces . These examples are illustrative rather than limiting. Strain W3110 is one particularly preferred host or parent host because it is a common host strain for recombinant DNA product fermentations. Preferably, the host cell secretes minimal amounts of proteolytic enzymes. For example, strain W3 110 may be modified to effect a genetic mutation in a gene encoding proteins endogenous to the host, with examples of such hosts including E. coli W3110 strain 1A2 , which has the complete genotype tonAD; E. coli W3110 strain 9E4, which has the complete genotype tonAD ptr3 ; E. coli W3110 strain 27C7 (ATCC 55,244), which has the complete genotype tonAD ptr3 phoADEl5 D (argF-lac) 169 ompTD

R' degP41kan ; E. coli W3110 strain 37D6, which has the complete genotype tonAD ptr3 phoADEl5 D (argF-lac) 169 ompTD degP41kan^R rbs7D ilvG; E. coli W3110 strain 40B4, which is strain 37D6 with a non-kanamycin resistant degP deletion mutation; and an E. coli strain having mutant periplasmic protease as disclosed in U.S. Patent 4,946,783 issued 7 August 1990. Alternatively, in vivo methods of cloning, e.g., PCR or other nucleic acid polymerase reactions, are suitable .

In addition to prokaryotes, eukaryotic microbes such as filamentous fungi or yeast are suitable cloning or expression hosts for LP vectors. Saccharomyces cerevisiae is a commonly used lower eukaryotic host microorganism.

Others include Schizosaccharomyces pombe [Beach and Nurse, Nature 290:140-3 (1981); EP 139,383 published 2 May 1995]; Muyveromyces hosts [U.S. Patent 4,943,529 Fleer, et al . , Bio/Technology 9 (10) : 968-75 (1991)] such as, e.g., K lactis (MW98-8C, CBS683, CBS4574) [de Louvencourt, et al . , J. Bacteriol . 154 (2 ): 737-42 (1983)]; K. fiagilis (ATCC

12,424), K. bulgaricus (ATCC 16,045), K wickeramii (ATCC 24,178), K waltii (ATCC 56,500), K. drosophilarum (ATCC 36.906) [Van den Berg, et al . , Bio/Technology 8(2):135-9 (1990)]; K. thermotolerans, and K. marxianus; yarrowia (EP 402,226); Pichia pastoris (EP 183,070) [Sreekrishna, et al . , J. Basic Microbiol . 28(4):265-78 (1988)]; Candida; Trichoderma reesia (EP 244,234); Neurospora crassa [Case, et al . , Proc . Natl . Acad Sci . USA 76 (10) : 5259-63 (1979)]; Schwanniomyces such as Schwanniomyces occidentulis (EP 394,538 published 31 October 1990); and filamentous fungi such as, e.g., Neurospora, Penicillium, Tolypocladium (WO 91/00357 published 10 January 1991) , and Aspergillus hosts such as A. nidulans [Ballance, et al . , Biochem . Biophys . Res . Comm. 112(1) :284-9 (1983); Tilburn, et al . , Gene 26 (2-3) : 205-21 ..(1983); Yelton, et al . , Proc . Natl .

Acad. Sci . USA 81(5):1470-4 (1984)] and A. niger [Kelly and Hynes, EMBO J . 4(2):475-9 (1985)]. Methylotropic yeasts are selected from the genera consisting of Hansenula, Candida, Kloeckera, Pichia, Saccharomyces, Torulopsis, and Rhodotoruia. A list of specific species that are exemplary of this class of yeast may be found in Antony, The Biochemistry of Methylotrophs 269 (1982) .

Suitable host cells for the expression of glycosylated LP polypeptides are derived from multicellular organisms. Examples of invertebrate cells include insect cells such as Drosophila S2 and Spodoptera Sp, Spodoptera high.5 as well as plant cells. Examples of useful mammalian host cell lines include Chinese hamster ovary (CHO) and COS cells. More specific examples include monkey kidney CVl line transformed by SV40 (COS-7, ATCC CRL 1651); human embryonic kidney line [293 or 293 cells subcloned for growth in suspension culture, Graham, et al . , J. Gen Virol . ,

36(l):59-74 (1977)]; Chinese hamster ovary cells/-DHFR [CHO, Urlaub and Chasin, Proc. Natl . Acad. Sci . USA, 77 (7) :4216-20 (1980)]; mouse sertoli cells [TM4, Mather, Biol . Reprod. 23(l):243-52 (1980)]; human lung cells (W138, ATCC CCL 75); human liver cells (Hep G2 , HB 8065); and mouse mammary tumor (MMT 060562, ATCC CCL51) . The selection of the appropriate host cell is deemed to be within the skill in the art.

LP polypeptides may be produced recombinantly not only directly, but also as a fusion polypeptide with a heterologous polypeptide, which may be a signal sequence or other polypeptide having a specific cleavage site at the N-terminus of the mature protein or polypeptide. In general, the signal sequence may be a component of the vector, or it may be a part of the LP polypeptide-encoding DNA that is inserted into the vector. The signal sequence may be a prokaryotic signal sequence selected, for example, from the group of the alkaline phosphatase, penicillinase, lpp, or heat-stable enterotoxin II leaders. For yeast secretion the signal sequence may be, e.g., the yeast invertase leader, alpha factor leader (including Saccharomyces and Kluyveromyces cc-factor leaders, the latter described in U.S. Patent 5,010,182), or acid phosphatase leader, the C. albicans glucoamylase leader (EP 362,179), or the signal described in WO 90/13646. In mammalian cell expression, mammalian signal sequences may be used to direct secretion of the protein, such as signal sequences from secreted polypeptides of the same or related species as well as viral secretory leaders.

Both expression and cloning vectors contain a nucleic acid sequence that enables the vector to replicate in one or more selected host cells. Such sequences are well known for a variety of bacteria, yeast, and viruses. The origin of replication from the plasmid pBR322 is suitable for most Gram-negative bacteria, the 2μ plasmid origin is suitable for yeast, and various viral origins (SV40, polyoma, adenovirus, VSV or BPV) are useful for cloning vectors in mammalian cells.

Expression and cloning vectors will typically contain a selection gene, also termed a selectable marker. Typical selection genes encode proteins that (a) confer resistance to antibiotics or other toxins, e.g., ampicillin, neomycin, methotrexate , or tetracycline, (b) complement auxotrophic deficiencies, or (c) supply critical nutrients not available from complex media, e.g., the gene encoding D- alanine racemase for Bacilli. An example of suitable selectable markers for mammalian cells are those that enable the identification of cells competent to take up the LP polypeptide-encoding nucleic acid, such as DHFR or thymidine kinase. An appropriate host cell when wild-type DHFR is employed is the CHO cell line deficient in DHFR activity, prepared and propagated as described Urlaub and Chasin, Proc. Natl . Acad. Sci . USA, 77 (7) : 4216-20 (1980). A suitable selection gene for use in yeast is the trpl gene present in the yeast plasmid YRp7 [Stinchcomb, et al . , Nature 282 (5734) : 39-43 (1979); Kingsman, et al . , Gene 7(2): 141-52 (1979);

Tschumper, et al . , Gene 10(2):157-66 (1980)]. The trpl gene provides a selection marker for a mutant strain of yeast lacking the ability to grow in tryptophan, for example, ATCC No. 44076 or PEPC1 [Jones, Genetics 85:23-33 (1977) ] .

Expression and cloning vectors usually contain a promoter operably linked to the LP polypeptide-encoding nucleic acid sequence to direct mRNA synthesis. Promoters recognized by a variety of potential host cells are well known. Promoters suitable for use with prokaryotic hosts include the P-lactamase and lactose promoter systems [Chang, et al . , Nature 275 (5681) : 617-24 (1978); Goeddel, et al . , Nature 281(5732) :544-8 (1979)], alkaline phosphatase, a tryptophan (up) promoter system [Goeddel, Nucleic Acids Res . 8(18) :4057-74 (1980); EP 36,776 published 30 September 1981] , and hybrid promoters such as the tat promoter [deBoer, et al . , Proc . Natl . Acad. Sci . USA 80(l):21-5

(1983)]. Promoters for use in bacterial systems also will contain a Shine-Dalgarno (S.D.) sequence operably linked to the DNA encoding LP polypeptide .

Examples of suitable promoting sequences for use with yeast hosts include the promoters for 3-phosphoglycerate kinase [Hitzeman, et al . , J. Biol . Chem. 255 (24) : 12073-80 (1980)] or other glycolytic enzymes [Hess, et al . , J. Adv. Enzyme Reg. 7:149 (1968); Holland, Biochemistry 17 (23) :4900-7 (1978)], such as enolase, glyceraldehyde-3- phosphate dehydrogenase, hexokinase, pyruvate decarboxylase, phosphofructokinase, glucose-6-phosphate isomerase, 3-phosphoglycerate mutase, pyruvate kinase, triosephosphate isomerase, phosphoglucose isomerase, and glucokinase. Other yeast promoters, which are inducible promoters having the additional advantage of transcription controlled by growth conditions, are the promoter regions for alcohol dehydrogenase 2, isocytochro e C, acid phosphatase, degradative enzymes associated with nitrogen metabolism, metallothionein, glyceraldehyde-3-phosphate dehydrogenase, and enzymes responsible for maltose and galactose utilization. Suitable vectors and promoters for use in yeast expression are further described in EP 73,657. LP transcription from vectors in mammalian host cells is controlled, for example, by promoters obtained from the genomes of viruses such as polyoma virus, fowlpox virus, adenovirus (such as Adenovirus 2), bovine papilloma virus, avian sarcoma virus, cytomegalovirus, a retrovirus, hepatitis-B virus and Simian Virus 40 (SV40) , from heterologous mammalian promoters, e.g., the actin promoter or an immunoglobulin promoter, and from heat-shock promoters, provided such promoters are compatible with the host cell systems.

Transcription of a polynucleotide encoding an LP polypeptide by higher eukaryotes may be increased by inserting an enhancer sequence into the vector. Enhancers are cis-acting elements of DNA, usually about from 10 to 300 bp, that act on a promoter to increase its transcription. Many enhancer sequences are now known from mammalian genes (globin, elastase, albumin, alpha- ketoprotein, and insulin) . Typically, however, one will use an enhancer from a eukaryotic cell virus. Examples include the SV40 enhancer on the late side of the replication origin (bp 100-270) , the cytomegalovirus early promoter enhancer, the polyoma enhancer on the late side of the replication origin, and adenovirus enhancers. The enhancer may be spliced into the vector at a position 5' or 3' to the LP polypeptide coding sequence but is preferably located at a site 5' from the promoter. Expression vectors used in eukaryotic host cells (yeast, fungi, insect, plant, animal, human, or nucleated cells from other multicellular organisms) will also contain sequences necessary for the termination of transcription and for stabilizing the mRNA. Such sequences are commonly available from the 5' and occasionally 3' untranslated regions of eukaryotic or viral DNAs or cDNAs . These regions contain nucleotide segments transcribed as polyadenylated fragments in the untranslated portion of the mRNA encoding LP.

Gene amplification and/or expression may be measured in a sample directly, for example, by conventional Southern blotting, Northern blotting to quantitate the transcription of mRNA [Thomas, Proc. Natl . Acad. Sci . USA 77(9):5201-5 (1980)], dot blotting (DNA analysis), or in si tu hybridization, using an appropriately labeled probe, based on the sequences provided herein. Alternatively, antibodies may be employed that can recognize specific duplexes, including DNA duplexes, RNA duplexes, and DNA-RNA hybrid duplexes or DNA-protein duplexes. The antibodies in turn may be labeled and the assay may be carried out where the duplex is bound to a surface, so that upon the formation of duplex on the surface, the presence of antibody bound to the duplex can be detected. Gene expression, alternatively, may be measured by immunological methods, such as immunohistochemical staining of cells or tissue sections and assay of cell culture or body fluids, to quantitate directly the expression of gene product. Antibodies useful for immunohistochemical staining and/or assay of sample fluids may be either monoclonal or polyclonal and may be prepared in any mammal. Conveniently, the antibodies may be prepared against a native sequence provided herein or against exogenous sequence fused to an LP polypeptide-encoding DNA and encoding a specific antibody epitope.

Various forms of an LP polypeptide may be recovered from culture medium or from host cell lysates . If membrane-bound, it can be released from the membrane using a suitable detergent solution (e.g., Triton X-100™) or by enzymatic cleavage. Cells employed in expression of an LP polypeptide can be disrupted by various physical or chemical means, such as freeze-thaw cycling, sonication, mechanical disruption, or cell lysing agents .

It may be desireable to purify LP polypeptides from recombinant cell proteins or polypeptides. The following procedures are exemplary of suitable purification procedures: by fractionation on an ion-exchange column; ethanol precipitation; reversed-phase HPLC.; chromatography on silica or on a cation-exchange resin such as DEAE; chromatofocusing; SDS-PAGE; ammonium sulfate precipitation; gel filtration using, for example, Sephadex G-75; protein A Sepharose columns to remove contaminants such as IgG; and metal chelating columns to bind epitope-tagged forms of an LP polypeptide. Various methods of protein purification may be employed and such methods are known in the art and described, for example, in Deutscher, Methods in Enzymology 182:83-9 (1990) and Scopes, Protein Purification :

Principles and Practice, Springer-Verlag, NY (1982) . The purification step(s) selected will depend, for example, on the nature of the production process used and the particular LP polypeptide produced. Nucleotide sequences (or their complement) encoding LP polypeptides have various applications in the art of molecular biology, including uses as hybridization probes, in chromosome and gene mapping and in the generation of anti-sense RNA and DNA. LP polypeptide-encoding nucleic acids will also be useful for the preparation of LP polypeptides by the recombinant techniques described herein.

The full-length LP polypeptide-encoding nucleotide sequence (e.g., SEQ ID NO:l, 3, 5, 7, 9, 11, 13, ^'15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, or 37), or portions thereof, may be useful as hybridization probes for probing a cDNA or genomic library to isolate the full-length LP polypeptide-encoding cDNA or genomic sequences including promoters, enhancer elements and introns of native sequence LP polypeptide-encoding DNA or to isolate still other genes (for instance, those encoding naturally-occurring variants of LP polypeptides or the same from other species) which have a desired sequence identity to the LP polypeptide- encoding nucleotide sequence disclosed in SEQ ID N0:1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, or 37. Hybridization techniques are well known in the art and some of which are described in further detail in the Examples below.

Other useful fragments of the LP polypeptide-encoding nucleic acids include anti-sense or sense oligonucleotides comprising a single-stranded nucleic acid sequence (either RNA or DNA) capable of binding to target LP polypeptide- encoding mRNA (sense) of LP polypeptide-encoding DNA (anti- sense) sequences. Anti-sense or sense oligonucleotides, according to the present invention, comprise a fragment of the coding region of LP polypeptide-encoding DNA. Such a fragment generally comprises at least about 14 nucleotides, preferably from about 14 to 30 nucleotides. The ability to derive an anti-sense or a sense oligonucleotide, based upon a cDNA sequence encoding a given protein is described in, for example, Stein and Cohen, Cancer Res . 48 (10) : 2659-68 (1988) and van der Krol, et al . , Bio /Techniques 6(10):958-76 (1988) . Binding of anti-sense or sense oligonucleotides to target nucleic acid sequences results in the formation of duplexes that block transcription or translation of the target sequence by one of several means, including enhanced degradation of the duplexes, premature termination of transcription or translation, or by other means. The anti- sense oligonucleotides thus may be used to block expression of LP mRNA and therefore any LP polypeptide encoded thereby. Anti-sense or sense oligonucleotides further comprise oligonucleotides having modified sugar- phosphodiester backbones (or other sugar linkages, such as those described in WO 91/06629) and wherein such sugar linkages are resistant to endogenous nucleases . Such oligonucleotides with resistant sugar linkages are stable in vivo (i.e., capable of resisting enzymatic degradation) but retain sequence specificity to be able to bind to target nucleotide sequences.

Other examples of sense or anti-sense oligonucleotides include those oligonucleotides which are covalently linked to organic moieties, such as those described in WO 90/10448, and other moieties that increase affinity of the oligonucleotide for a target nucleic acid sequence, such poly-L-lysine. Further still, intercalating agents, such as ellipticine, and alkylating agents or metal complexes may be attached to sense or anti-sense oligonucleotides to modify binding specificities of the anti-sense or sense oligonucleotide for the target nucleotide sequence. Anti-sense or sense oligonucleotides may be introduced into a cell containing the target nucleic acid sequence by any gene transfer method, including, for example, calcium phosphate-mediated DNA transfection, electroporation, or by using gene transfer vectors such as Epstein-Barr virus. In a preferred procedure, an anti-sense or sense oligonucleotide is inserted into a suitable retroviral vector. A cell containing the target nucleic acid sequence is contacted with the recombinant retroviral vector, either in vivo or ex vivo . Suitable retroviral vectors include, but are not limited to, those derived from the murine retrovirus M-MSV, N2 (a retrovirus derived from M-MuLV) , or the double copy vectors designated CDTSA, CTSB and DCTSC (see WO 90/13641) . Alternatively, a sense or an anti-sense oligonucleo- tide may be introduced into a cell containing the target nucleic acid sequence by formation of an oligonucleotide- lipid complex, as described in WO 90/10448. The sense or anti-sense oligonucleotide-lipid complex is preferably dissociated within the cell by an endogenous lipase. When the amino acid sequence for an LP polypeptide encodes a protein which binds to another protein (for example, where the LP polypeptide functions as a receptor) , the LP polypeptide can be used in assays to identify the other proteins or molecules involved in the binding interaction. By such methods, inhibitors of the . receptor/ligand binding interaction can be identified. Proteins involved in such binding interactions can also be used^" to screen for peptide or small molecule inhibitors or agonists of the binding interaction. Also, the receptor LP polypeptide can be used to isolate correlative ligand (s) . Screening assays can be designed to find lead compounds that mimic the biological activity of the LP polypeptides disclosed herein or a receptor for such LP polypeptides. Typical screening assays will include assays amenable to high-throughput screening of chemical libraries, making them particularly suitable for identifying small molecule drug candidates . Small molecules contemplated include synthetic organic or inorganic compounds. The assays can be performed in a variety of formats, including protein- protein binding assays, biochemical screening assays, immunoassays and cell based assays, which are well characterized in the art.

Nucleic acids which encode an LP polypeptide of the present invention or any of its modified forms can also be used to generate either transgenic animals or "knockout" animals which, in turn, are useful in the development and screening of therapeutically useful reagents^'. Methods for generating transgenic animals, particularly animals such as mice or rats, have become conventional in the art and are described, for example, in U.S. Patents 4,736,866 and 4,870,009. Typically, particular cells would be targeted for an LP transgene incorporation with tissue-specific enhancers. Transgenic animals that include a copy of a transgene introduced into the germ line of the animal at an embryonic stage can be used to examine the effect of increased expression of DNA encoding an LP polypeptide. Such animals can be used as tester animals for reagents thought to confer protection from, for example, pathological conditions associated with its overexpression. In accordance with this facet of the invention, an animal is treated with the reagent and a reduced incidence of the pathological condition, compared to untreated animals bearing the transgene, would indicate a potential therapeutic intervention for the pathological condition. Alternatively, non-human homologs of LP polynucleotides can be used to construct a "knockout" animal which has a defective or altered gene encoding a particular LP polypeptide as a result of homologous recombination between the endogenous gene encoding the LP polypeptide and the altered genomic DNA introduced into an embryonic cell of the animal. For example, cDNA encoding an LP polypeptide can be used to clone genomic DNA encoding that LP polypeptide in accordance with established techniques. A portion of the genomic DNA encoding an LP polypeptide can be deleted or replaced with another gene, such as a gene encoding a selectable marker which can be used to monitor integration. Typically, several kilobases of unaltered flanking DNA (both at the 5' and 3' ends) are included in the vector [see, e.g., Thomas and Capecchi, Cell 51(3):503-12 (1987) for a description of homologous recombination vectors] . The vector is introduced into an embryonic stem cell line (e.g., by electroporation), and cells in which the introduced DNA has homologously recombined with the endogenous DNA are selected [see, e.g., Li, et al . , Cell 69(6):915-26 (1992)]. The selected cells are then injected into a blastocyst of an animal ('e.g., a mouse or rat) to form aggregation chimeras [see, e.g., Bradley, Teratocarcinomas and Embryonic Stem Cells : A Practical Approach, E. J. Robertson, ed. , pp. 113-152 (IRL, Oxford, 1987)]. A chimeric embryo can then be implanted into a suitable pseudopregnant female foster animal and the embryo brought to term to create a "knockout" animal. Progeny harboring the homologously recombined DNA in their germ cells can be identified by standard techniques and used to breed animals in which all cells of the animal contain the homologously recombined DNA. Knockout animals can be characterized, for instance, for their ability to defend against certain pathological conditions and for their development of pathological conditions due to absence of the native LP polypeptide . Transgenic non-human mammals are useful as an animal models in both basic research and drug development endeavors . Transgenic animals expressing at least one LP polypeptide or nucleic acid can be used to test compounds or other treatment modalities which may prevent, suppress, or cure a pathology or disease associated with at least one of the above mentioned activities . Such transgenic animals can also serve as a model for the testing of diagnostic methods for those same diseases. Furthermore, tissues derived from such transgenic non-human mammals are useful as a source of cells for cell culture in efforts to develop in vi tro bioassays to identify compounds that modulate LP polypeptide activity or LP polypeptide dependent signaling. Accordingly, another aspect of the present invention contemplates a method of identifying compounds efficacious in the treatment of at least one previously described disease or pathology associated with an LP polypeptide associated activity. A non-limiting example of such a method comprises: a) generating a transgenic non-human animal which expresses an LP polypeptide of the present invention and which is, as compared to a wild-type animal, pathologically distinct in some detectable or measurable manner from wild- type version of said non-human mammal; b) exposing said transgenic animal to a compound, and; c) determining the progression of the pathology in the treated transgenic animal, wherein an arrest, delay, or reversal in disease progression in transgenic animal treated with said compound as compared to the progression of the pathology in an untreated control animals is indicative that the compound is useful for the treatment of said pathology. Another embodiment of the present invention provides a method of identifying compounds capable of inhibiting LP polypeptide activity in vivo and/or in vi tro wherein said method comprises: a) administering an experimental compound to an LP polypeptide expressing transgenic non-human animal, or tissues derived therefrom, exhibiting one or more physiological or pathological conditions attributable to the expression of an LP transgene; and b) observing or assaying said animal and/or animal tissues to detect changes in said physiological or pathological condition or conditions.

Another embodiment of the invention provides a method for identifying compounds capable of overcoming deficiencies in LP polypeptide activity in vivo or in vi tro wherein said method comprises: a) administering an experimental compound to an LP polypeptide expressing transgenic non-human animal, or tissues derived therefrom, exhibiting one or more physiological or pathological conditions attributable to the disruption of the endogenous LP polypeptide-encoding gene; and b) observing or assaying said animal and/or animal tissues to detect changes in said physiological or pathological condition or conditions.

Various means for determining a compound's ability to modulate the activity of an LP polypeptide in the body of the transgenic animal are consistent with the invention. Observing the reversal of a pathological condition in the LP polypeptide expressing transgenic animal- fter administering a compound is one such means. Another more preferred means is to assay for markers of LP activity in the blood of a transgenic animal before and after administering an experimental compound to the animal. The level of skill of an artisan in the relevant arts readily provides the practitioner with numerous methods for assaying physiological changes related to therapeutic modulation of LP activity. "Gene therapy" includes both conventional gene therapy, where a lasting effect is achieved by a single treatment, and the administration of gene therapeutic agents, which involves the one time or repeated administration of a therapeutically effective DNA or mRNA. Anti-sense RNAs and DNAs can be used as therapeutic agents for blocking the expression of certain genes in vivo . It has already been shown that short anti-sense oligonucleotides can be imported into cells where they act as inhibitors, despite their low intracellular concentrations caused by their restricted uptake by the cell membrane

[Zamecnik, et al . , Proc . Natl . Acad Sci . USA 83 (12) : 4143-6 (1986)]. The oligonucleotides can be modified to enhance their uptake, e.g., by substituting their negatively charged phosphodiester groups with uncharged groups. There: are a variety of techniques available for introducing nucleic acids into viable cells. The techniques vary depending upon whether the nucleic acid is transferred into cultured cell in vi tro or in vivo in the cells of the intended host. Techniques suitable for the transfer of nucleic acid into mammalian cells in vi tro include the use of liposomes, electroporation, micro- injection, cell fusion, DEAE-dextran, the calcium phosphate precipitation method, etc. The currently preferred in vivo gene transfer techniques include transfection with viral (typically, retroviral) vectors and viral coat protein- liposome mediated transfection [Dzau, et al . , Trends in Biotechnology 11(5):205-10 (1993)]. In some situations it is desirable to provide the nucleic acid source with an agent that targets the target cells, such as an antibody specific for a cell surface membrane protein or the target cell, a ligand for a receptor on the target cells, etc. Where liposomes are employed, proteins which bind to a cell surface membrane protein associated with endocytosis may by used for targeting and/or to facilitate uptake, e.g., capsid proteins or fragments thereof trophic for a particular cell type, antibodies for proteins which undergo internalization in cycling, proteins that target intracellular localization and enhance intracellular half- life. The technique of receptor-mediated endocytosis is described, for example, by Wu, et al . , J. Biol . Chem. 262 (10) :4429-32 (1987); and Wagner, et al . , Proc . Natl . Acad. Sci . USA 87(9):3410-4 (1990). For a review of gene marking and gene therapy protocols, see Anderson, Science 256(5058) :808-13 (1992) .

The nucleic acid molecules encoding LP polypeptides or fragments thereof described herein are useful for chromosome identification. In this regard, there exists an ongoing need to idenfity new chromosome markers, since relatively few chromosome marking reagents, based upon actual sequence data, are presently available. Each LP polypeptide-encoding nucleic acid molecule of the present invention can be used as a chromosome marker. An LP polypeptide-encoding nucleic acid or fragments thereof can also be used for chromosomal localization of the gene encoding that LP polypeptide.

The present invention further provides anti-LP polypeptide antibodies . Exemplary antibodies include polyclonal, monoclonal, humanized, bispecific, and heteroconjugate antibodies.

The anti-LP polypeptide antibodies of the present invention may comprise polyclonal antibodies. Methods of preparing polyclonal antibodies are known to the skilled artisan. Polyclonal antibodies can be raised in a mammal, for example, by one or more injections of an immunizing agent and, if desired, an adjuvant. Typically, the immunizing agent and/or adjuvant will be injected in the mammal by multiple subcutaneous or intraperitoneal injections. The immunizing agent may include the LP polypeptide or a fusion protein thereof. It may be useful to conjugate the immunizing agent to a protein known to be immunogenic in the mammal being immunized. Examples of such immunogenic proteins include, but are not limited to, keyhole limpet hemocyanin, serum albumin, bovine thyroglobulin, and soybean trypsin inhibitor. Examples of adjuvants which may be employed include Freund's complete adjuvant and MPL-TDM adjuvant (monophosphoryl Lipid A, synthetic trehalose dicorynomycolate) . The immunization protocol may be selected by one skilled in the art without undue experimentation.

The anti-LP polypeptide antibodies may, alternatively, be monoclonal antibodies. Monoclonal antibodies may be prepared using hybridoma methods, such as those described by Kohler and Milstein, Nature 256 (5517 ): 495-7 (1975). In a hybridoma method, a mouse, hamster, or other appropriate host animal is typically immunized with an immunizing agent to elicit lymphocytes that produce or are capable of producing antibodies that will specifically bind to the immunizing agent. Alternatively, the lymphocytes may be immunized in vi tro . The immunizing agent will typically include an LP polypeptide or a fusion protein thereof. Generally, either peripheral blood lymphocytes ("PBLs") are used, if cells of human origin are desired, or spleen cells or lymph node cells are used, if non-human mammalian sources are desired. The lymphocytes are then fused with an immortalized cell line using a suitable fusing agent, such as polyethylene glycol, to form a hybridoma cell [Goding, Monoclonal Antibodies : Principles and Practice, Academic Press, pp. 59-103 (1986)] . Immortalized cell lines are usually transformed mammalian cells, particularly myeloma cells of rodent, bovine and human origin. Usually, rat or mouse •myeloma cell lines are employed. The hybridoma cells may be cultured in a suitable culture medium that preferably contains one or more substances that inhibit the growth or survival of the unfused, immortalized cells. For example, if the parental cells lack the enzyme hypoxanthine guanine phosphoribosyl transferase (HGPRT or HPRT) , the culture medium for the hybridomas typically will include hypoxanthine, aminopterin, and thymidine ("HAT medium"), which prevents the growth of HGPRT-deficient cells.

Preferred immortalized cell lines are those that fuse efficiently, support stable high level expression of antibody by the selected antibody-producing cells, and are sensitive to a medium such as HAT medium. More preferred immortalized cell lines are murine myeloma lines, which can be obtained, for instance, from the Salk Institute Cell Distribution Center, San Diego, CA, and the American Type Culture Collection (ATCC), Rockville, MD. Human myeloma and mouse-human heteromyeloma cell lines also have been described for the production of human monoclonal antibodies [Kozbor, J. Immunol . 133 (6) : 3001-5 (1984); Brodeur, et al . , Monoclonal Antibody Production Techniques and Applications , Marcel Dekker, Inc., NY, pp. 51-63 (1987)].

The culture medium in which the hybridoma cells are cultured can then be assayed for the presence of monoclonal antibodies directed against an LP polypeptide. Preferably, the binding specificity of monoclonal antibodies produced by the hybridoma cells is determined by immunoprecipitation or by an in vi tro binding assay, such as radioimmunoassay (RIA) or enzyme-linked immunoabsorbent assay (ELISA) . Such techniques and assays are known in the art . The binding affinity of the monoclonal antibody can, for example, be determined by the Scatchard analysis of Munson and Rodbard, Anal . Biochem. 107 (1) : 220-39 ( 1980).

After the desired hybridoma cells are identified, the clones may be subcloned by limiting dilution procedures and grown by standard methods [Goding, Monoclonal Antibodies : Principles and Practice, Academic Press, pp. 59-103 (1986) ] . Suitable culture media for this purpose include, for example, Dulbecco's Modified Eagle's Medium and RPMI- 1640 medium. Alternatively, the hybridoma cells may be grown in vivo as ascites in a mammal.

The monoclonal antibodies may also be made by recombinant DNA methods, such as those described in U.S. Patent 4,816,567. DNA encoding the monoclonal antibodies of the invention can be readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that are capable of binding specifically to genes encoding the heavy and light chains of murine antibodies) . The hybridoma cells of the invention serve as a preferred source of such DNA. Once isolated, the DNA may be placed into expression vectors, which are then transfected into host cells such as simian COS cells, Chinese hamster ovary (CHO) cells, or myeloma cells that do not otherwise produce immunoglobulin protein, to obtain the synthesis of monoclonal antibodies in the recombinant host cells. The DNA also may be modified, for example, by substituting the coding sequence for human heavy and light chain constant domains in place of the homologous murine sequences [U.S. Patent 4,816,567; Morrison, et al . , Proc . Natl . Acad . Sci . USA 81 (21) : 6851-5 (1984) ] or by covalently joining to the immunoglobulin coding sequence all or part of the coding sequence for a non-immunoglobulin polypeptide. Such a non-immunoglobulin polypeptide can be substituted for the constant domains of an antibody of the invention or can be substituted for the variable domains of one antigen-combining site of an antibody of the invention to create a chimeric bivalent antibody.

The antibodies may be monovalent antibodies . Methods for preparing monovalent antibodies are well known in the art. For example, one method involves recombinant expression of immunoglobulin light chain and modified heavy chain. The heavy chain is truncated generally at any point in the Fc region so as to prevent heavy chain crosslinking. Alternatively, the relevant cysteine residues are substituted with another amino acid residue or are deleted so as to prevent crosslinking. In vi tro methods are also suitable for preparing monovalent antibodies . Digestion of antibodies to produce fragments thereof, particularly Fab fragments, can be accomplished using routine techniques known in the art.

The anti-LP polypeptide antibodies of the invention may further comprise humanized antibodies or human antibodies. Humanized forms of non-human (e.g., murine) antibodies are chimeric immunoglobulins, immunoglobulin chains or fragments thereof (such as Fv, Fab, Fab', F(ab')₂ or other antigen-binding subsequences of antibodies) which contain minimal sequence derived from non-human immunoglobulin. Humanized antibodies include human immunoglobulins (recipient antibody) in which residues from a complementary-determining region (CDR) of the recipient are replaced by residues from a CDR of a non-human species (donor antibody) such as mouse, rat or rabbit having the desired specificity, affinity and capacity. In some instances, Fv framework residues of the human immunoglobulin are replaced by corresponding non-human residues . Humanized antibodies may also comprise residues which are found neither in the recipient antibody nor in the imported CDR or framework sequences. In general, the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin, and all or substantially all of the FR regions are those of a human immunoglobulin consensus sequence. The humanized antibody optimally also will comprise at least a portion of an immunoglobulin constant region (Fc) , typically that of a human immunoglobulin [Jones, et al . , Nature 321 (6069) : 522-5 (1986); Riechmann, et al . , Nature 332 (6162) :323-7 (1988); and Presta, Curr. Op . Struct . Biol . 2:593-6 (1992)]. Methods for humanizing non-human antibodies are well known in the art. Generally, a humanized antibody has one or more amino acid residues introduced into it from a source which is non-human. These non-human amino acid residues are often referred to as "import" residues, which are typically taken from an "import" variable domain. Humanization can be essentially performed following the method of Winter and co-workers [Jones, et al . , Nature 321(6069) : 522-5 (1986); Riechmann, et al . , Nature 332 (6162) :323-7 (1988); Verhoeyen, et al . , Science

239(4847) :1534-6 (1988)], by substituting rodent CDRs or CDR sequences for the corresponding sequences of a human antibody. Accordingly, such "humanized" antibodies are chimeric antibodies (U.S. Patent 4,816,567) wherein substantially less than an intact human variable domain has been substituted by the corresponding sequence from a non- human species. In practice, humanized antibodies are typically human antibodies in which some CDR residues and possibly some FR residues are substituted by residues from analogous sites in rodent antibodies.

Human antibodies can also be produced using various techniques known in the art, including phage display libraries [Hoogenboom and Winter, J. Mol . Biol . 227(2) :381- 8 (1992); Marks, et al . , J. Mol . Biol . 222 (3 ): 581-97 (1991)]. The techniques of Cole, et al . , and Boerner, et al . , are also available for the preparation of human monoclonal antibodies (Cole, et al . , Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77 (1985), and Boerner, et al . , J. Immunol . 147(1): 86-95 (1991)]. Similarly, human antibodies can be made by introducing human immunoglobulin loci into transgenic animals, e.g., mice in which the endogenous immunoglobulin genes have been partially or complete inactivated. Upon challenge, human antibody production is observed, which closely resembles that seen in humans in all respects, including gene rearrangement, assembly and antibody repertoire. This approach is described, for example, in U.S. Patents

5,545,807; 5,545,806; 5,569,825; 5,625,126; 5,633,425; 5,661,016, and in the following scientific publications: Marks, et al . , Biotechnology 10 (7 ): 779-83 (1992); Lonberg, et al . , Nature 368 (6474) : 856-9 (1994); Morrison, Nature 368(6474) : 812-3 (1994); Fishwild, et al . , Nature

Biotechnology 14 (7) : 845-51 (1996); Neuberger, Nature Biotechnology 14(7) :826 (1996); Lonberg and Huszar, Jut. Rev. Immunol . 13(l):65-93 (1995).

Bispecific antibodies are monoclonal, preferably human or humanized, antibodies that have binding specificities for at least two different antigens. In the present case, one of the binding specificities is for an LP polypeptide, the other one is for any other antigen, and preferably for a cell-surface protein or receptor or receptor subunit. Methods for making bispecific antibodies are known in the art. Antibodies with more than two valencies are contemplated. For example, trispecific antibodies can be prepared [Tutt, et al . , J Immunol . 147(1) :60-9 (1991)].

Heteroconjugate antibodies are also within the scope of the present invention. Heteroconjugate antibodies are composed of two covalently joined antibodies. Such antibodies have, for example, been proposed to target immune system cells to unwanted cells [U.S. Patent 4,676,980], and for treatment of HIV infection [WO 91/00360; WO 92/20373]. It is contemplated that the antibodies may be prepared in vi tro using known methods in synthetic protein chemistry, including those involving crosslinking agents. For example, immunotoxins may be constructed using a disulfide exchange reaction or by forming a thioether bond. Examples of suitable reagents for this purpose include iminothiolate and methyl-4- mercaptobutyrimidate and those disclosed, for example, in U.S. Patent 4,676,980.

The invention also pertains to immunoconjugates comprising an antibody conjugated to a cytotoxic agent such as a chemotherapeutic agent, toxin (e.g., an enzymatically active toxin of bacterial, fungal, plant or animal origin, or fragments thereof, or a small molecule toxin) , or a radioactive isotope (i.e., a radioconjugate) .

Conjugates of the antibody and cytotoxic agent are made using a variety of bifunctional protein coupling agents such as N-succinimidyl-3- (2-pyridyldithiol) propionate (SPDP) , iminothiolane (IT) , bifunctional derivatives of imidoesters (such as dimethyl adipimidate HCL) , active esters (such as disuccinimidyl suberate) , aldehydes (such as glutaraldehyde) , bis-azido compounds, bis-diazonium derivatives (such as bis-2-diazoniumbenzoyl) - ethylenediamine) diisocyanates (such as tolylene-2 , 6- diisocyanate) , and bioactive fluorine compounds. For example, a ricin immunotoxin can be prepared as described in Vitetta, et al . , Science 238 (4830) : 1098-104 (1987). Carbon-14-labeled l-isothiocyanatobenzyl-3-methyldiethylene triaminepentaacetic acid (MX-DTPA) is an exemplary chelating agent for conjugation of radionucleotide to the antibody.

In another embodiment, the antibody may be conjugated to a "receptor" (such as streptavidin) for utilization in tumor pretargeting wherein the antibody-receptor conjugate is administered to the patient, followed by removal of unbound conjugate from the circulation using a clearing agent, and then administration of a "ligand" (e.g., avidin) which is conjugated to a cytotoxic agent (e.g., a radionucleotide) . The antibodies disclosed herein may also be formulated as immunoliposo es . Liposomes containing the antibody are prepared by methods known in the art, such as described in Eppstein, et al . , Proc . Natl . Acad. Sci . USA 82:3688-92 (1985); Hwang, _ι et al . , Proc . Natl . Acad. Sci . USA 77(7):4030-4 (1980); and U.S. Patents 4,485,045 and ,

4,544,545. Liposomes with enhanced circulation time are disclosed in U.S. Patent 5,013,556.

Particularly useful liposomes can be generated by the reverse phase evaporation method with a lipid composition comprising phosphatidylcholine, cholesterol and PEG- derivatized phosphatidylethanolamine (PΞG-PE) . Liposomes are extruded through filters of defined pore size to yield liposomes with the desired diameter. Fab' fragments of the antibody of the present invention can be conjugated to the liposomes as described in Martin, et al . , J. Biol . Chem. 257(1) -.286-8 (1982) via a disulfide interchange reaction. A cheirtotherapeutic agent (such as Doxorubicin) is optionally contained within the liposome. See Gabizon, et al . , J. National Cancer Inst . 81(19) :484-8 ( 1989). Antibodies specifically binding an LP polypeptide identified herein, as well as other molecules identified by the screening assays disclosed hereinbefore, can be administered for the treatment of various disorders in the form of pharmaceutical compositions . If an LP polypeptide is intracellular and whole antibodies are used as inhibitors, internalizing antibodies are preferred. However, lipofections or liposomes can also be used to deliver the antibody or an antibody fragment into cells. Where antibody fragments are used, the smallest inhibitory fragment that specifically binds to the binding domain of the target protein is preferred. For example, based upon the variable-region sequences of an antibody, peptide molecules can be designed that retain the ability to bind the target protein sequence. Such peptides can be synthesized chemically and/or produced by recombinant DNA technology. See, e.g., Marasco, et al . , Proc. Natl. Acad . Sci . USA 90 (16) -.7889-93 (1993).

The formulation herein may also contain more than one active compound as necessary for the particular indication being treated, preferably those with complementary ^' activities that do not adversely affect each other. Alternatively, or in addition, the composition may comprise an agent that enhances its function, such as, for example, a cytotoxic agent, cytokines, chemotherapeutic agent, or growth-inhibitory agent. Such molecules are suitable present in combination in amounts that are effective for the purpose intended. The active ingredients may also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethy1cellulose or gelatin- microcapsules and poly- (methylmethacrylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles, and nanocapsules) or in macroemulsions . Such techniques are disclosed in Remington ' s Pharmaceutical Sciences 16th edition (1980) . The formulations to be used for in vivo administration must be sterile. This is readily accomplished by filtration through sterile filtration membranes. Sustained-release preparations may be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the antibody, which matrices are in the form of shaped articles, e.g., films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (for example, poly (2-hydroxyethyl-methacrylate) , or poly(vinylalcohol) , polylactides (U.S. Patent 3,773,919), copolymers of L-glutamic acid gamma-ethyl-L-glutamate, non- degradable ethylene-vinylacetate, degradable lactic acid- glycolic acid copolymers such as the LUPRON DEPOT™ (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(-)3- hydroxylbutyric acid. While polymers such as ethylene- vinyl acetate and lactic acid-glycolic acid enable release of molecules for over 100 days, certain hydrogels release proteins for shorter time periods . When encapsulated antibodies remain in the body for a long time, they may denature or aggregate as a result of exposure to moisture at 37 degrees C, resulting in a loss of biological activity and possible changes in immunogenicity . Rational strategies can be devised for stabilization depending on the mechanisms involved. For example, if the aggregation mechanism is discovered to be intermolecular S-S bond formation through thiosulfide interchange, stabilization may be achieved by modifying sulfhydryl residues, lyophilizing from acidic solutions, controlling moisture content, using appropriate additives, and developing specific polymer matrix compositions. The anti-LP polypeptide antibodies of the present invention have various utilities. For example, such antibodies may be used in diagnostic assays for LP polypeptide expression, e.g., detecting expression in specific cells, tissues, or serum. Various diagnostic assay techniques known in the art may be used, such as competitive binding assays, direct or indirect sandwich assays and immunoprecipitation assays conducted in either heterogeneous or homogeneous phases [Zola, Monoclonal Antibodies :A Manual of Techniques, CRC Press, Inc., pp. 147-158 (1987)] . The antibodies used in the assays can be labeled with a detectable moiety. The detectable moiety should be capable of producing, either directly or indirectly, a detectable signal. For example, the detectable moiety may be a radioisotope, such as ³H, ¹⁴C, ³²P, ³⁵S, or ¹²⁵I, a fluorescent or chemiluminescent compound, such as fluorescein isothiocyanate, rhodamine, or luciferin, or an enzyme, such as alkaline phosphatase, beta-galactosidase or horseradish peroxidase. Any method known in the art for conjugating the antibody to the detectable moiety may be employed, including those methods described by Hunter, et al . , Nature 144:945 (1962); David, et al . , Biochemistry 13 (5) .-1014-21 ( 1974); Pain, et al . , J Immunol . Meth . , 40(2):219-30 (1981); and Nygren, J^". Histochem . Cytochem. 30(5):407-12 (1982).

Anti-LP polypeptide antibodies also are useful for affinity purification from recombinant cell culture or natural sources. In this process, the antibodies are immobilized on a suitable support, such a Sephadex" resin or filter paper, using methods well known in the art. The immobilized antibody is then contacted with a sample containing the LP polypeptide to be purified, and thereafter the support is washed with a suitable solvent that will remove substantially all the material in the sample except the LP polypeptide, which is bound to the immobilized antibody. Finally, the support is washed with another suitable solvent that will release the desired polypeptide from the antibody.

This invention encompasses methods of screening compounds to identify those that mimic the activity of the LP polypeptide (agonists) disclosed herein or prevent the effects of the LP polypeptide (antagonists) . Screening assays for antagonist drug candidates are designed to identity compounds that bind or complex with an LP polypeptide encoded by the genes identified herein or otherwise interfere with the interaction of LP polypeptides with other cellular proteins. Such screening assays will include assays amenable to high-throughput screening of chemical libraries, making them particularly suitable for identifying small molecule drug candidates.

The assays can be performed in a variety of formats. In binding assays, the interaction is binding, and the complex formed can be isolated or detected in the reaction mixture. In a particular embodiment, an LP polypeptide encoded by a gene identified herein or the drug candidate is immobilized on a solid phase, e.g., on a microtiter plate, by covalent or non-covalent attachments. Non- covalent attachment generally is accomplished by coating the solid surface with a solution comprising LP polypeptide and drying. Alternatively, an immobilized antibody, e.g., a monoclonal antibody, specific for the polypeptide to be immobilized can be used to anchor it to a solid surface. The assay is performed by adding the non-immobilized component, which may be labeled by a detectable label, to the immobilized component, e.g., the coated surface containing the anchored component. When the reaction is complete, the non-reacted components are removed, e.g., by washing, and complexes anchored on the solid surface are detected. When the originally non-immobilized component carries a detectable label, the detection of label immobilized on the surface indicates that complexing occurred. Where the originally non-immobilized component does not carry a label, complexing can be detected, for example, by using a labeled antibody specifically binding the immobilized complex.

If the candidate compound interacts with but does not bind to an LP polypeptide, its interaction with that polypeptide can be assayed by methods well known for detecting protein-protein interactions. Such assays include traditional approaches, such as, e.g., cross- linking, co-immunoprecipitation, and co-purification through gradients or chromatographic columns. In addition, protein-protein interactions can be monitored through gradients or chromatographic columns. In addition, protein-protein interactions can be monitored by using a yeast-based genetic system described by Fields and co- workers [Fields and Song, Nature 340 (6230) :245-6 (1989); Chien, et al . , Proc . Natl . Acad. Sci . USA 88 (21) : 9578-82 (1991); Chevray and Nathans, Proc . Natl . Acad. Sci . USA 89 (13) : 5789-93 (1992)]. Many transcriptional activators, such as yeast GAL4 , consist of two physically discrete modular domains, one acting as the DNA-binding domain, while the other functions as the transcription-activation domain. The yeast expression system described in the foregoing publications (generally referred to as the "two- hybrid system") takes advantage of this property, and employs two hybrid proteins, one in which the target protein is fused to the DNA-binding domain of GAL4, and another in which candidate activating proteins are fused to the activation domain. The expression of GALl-lacZ reporter gene under control of a GAL4-activated promoter depends on reconstitution of GAL4 activity via protein- protein interaction. Colonies containing interacting polypeptides are detected with chromogenic substrate for beta-galactosidase. A complete kit (MATCHMAKER™) for identifying protein-protein interactions between two specific proteins using the two-hybrid technique is commercially available from Clontech. This system can also be extended to map protein domains involved in specific protein interactions as well as to pinpoint amino acid residues that are crucial for these interactions .

Compounds that interfere with the interaction of an LP polypeptide identified herein and other intra- or extracellular components can be tested as follows: usually a reaction mixture is prepared containing the product of the gene and the intra- or extracellular component under conditions and for a time allowing for the interaction and binding of the two products. To test the ability of a candidate compound to inhibit binding, the reaction is run in the absence and in the presence of the test compound. In addition, a placebo may be added to a third reaction mixture to serve as a positive control. The binding (complex formation) between the test compound and the intra- or extracellular component present in the mixture is monitored as described hereinabove. The formation of a complex in the control reaction (s) but not in the reaction mixture containing the test compound indicates that the test compound interferes with the interaction of the test compound and its reaction partner.

Antagonists may be detected by combining at least one LP polypeptide and a potential antagonist with a membrane- bound or recombinant receptor for that LP polypeptide under appropriate conditions for a competitive inhibition assay. The LP polypeptide can be labeled, such as by radioactivity, such that the number of LP polypeptide molecules bound to the receptor can be used to determine the effectiveness of the potential antagonist. The gene encoding the receptor for an LP polypeptide can be identified by numerous methods known to those of skill in the art, for example, ligand panning and FACS sorting. See Coligan, et al . , Current Protocols in Immunology 1(2) :Ch. 5 (1991) . Preferably, expression cloning is employed such that polyadenylated mRNA is prepared from a cell responsive to the secreted form of a particular LP polypeptide, and a cDNA library created from this mRNA is divided into pools and used to transfect COS cells or other cells that are not responsive to the secreted LP polypeptide. Transfected cells that are grown on glass slides are exposed to the labeled LP polypeptide. The LP polypeptide can be labeled by a variety of means including iodination or inclusion of a recognition site for a site-specific protein kinase.

Following fixation and incubation, the slides are subjected to autoradiographic analysis. Positive pools are identified and sub-pools are prepared and re-transfected using an interactive sub-pooling and re-screening process, eventually yielding a single clone that encodes the putative receptor.

As an alternative approach for receptor identification, a labeled LP polypeptide can be photoaffinity-linked with cell membrane or extract preparations that express the receptor molecule. Cross-linked material is resolved by PAGE and exposed to X-ray film. The labeled complex containing the receptor can be excised, resolved into peptide fragments, and subjected to protein micro- sequencing. The amino acid sequence obtained from micro- sequencing would be used to design a set of degenerate oligonucleotide probes to screen a cDNA library to identify the gene encoding the putative receptor.

In another assay for antagonists, mammalian cells or a membrane preparation expressing the receptor would be incubated with a labeled LP polypeptide in the presence of the candidate compound. The ability of the compound to enhance or block this interaction could then be removed.

Alternatively, a potential antagonist may be a closely related protein, for example, a mutated form of the LP polypeptide that recognizes the receptor but imparts no effect, thereby competitively inhibiting the action of the polypeptide.

Another potential LP antagonist is an anti-sense RNA or DNA construct prepared using anti-sense technology, where, e.g., an anti-sense RNA or DNA molecule acts to block directly the translation of mRNA by hybridizing to targeted mRNA and prevent its translation into protein. Anti-sense technology can be used to control gene expression through triple-helix formation or anti-sense DNA or RNA, both of which methods are based on binding of a polynucleotide to DNA or RNA. For example, the 5' coding portion of the polynucleotide sequence, which encodes the mature form of an LP polypeptide can be used to design an anti-sense RNA oligonucleotide sequence of about 10 to 40 base pairs in length. A DNA oligonucleotide is designed to be complementary to a region of the gene involved in transcription [triple helix; see Lee, et al . , Nucl . Acids Res 6(9):3073-91 (1979); Cooney, et al . , Science 241(4864) :456-9 (1988); Beal and Dervan, Science 251 (4999) : 1360-3 (1991)], thereby preventing transcription and production of the LP polypeptide. The anti-sense RNA oligonucleotide hybridizes to the mRNA in vivo and blocks translation of the mRNA molecules [anti-sense; see Okano, J^". Neurochem . 56(2):560-7 (1991); Oligodeoxynucleotides as Anti-sense Inhibi tors of Gene Expression (CRC Press: Boca Raton, FL 1988) ] . The oligonucleotides described above can also be delivered to cells such that the anti-sense RNA or DNA may be expressed in vivo to inhibit production of the LP polypeptide. When anti-sense DNA is used, oligodeoxy- ribonucleotides derived from the translation-initiation site, e.g., between about -10 and +10 positions of the target gene nucleotide sequence, are preferred.

Potential antagonists include small molecules that bind to the active site, the receptor binding site, or growth factor or other relevant binding site of the LP polypeptide, thereby blocking the normal biological activity of the LP polypeptide. Examples of small molecules include, but are not limited to, small peptides or peptide-like molecules, preferably soluble peptides, and synthetic non-peptidyl organic or inorganic compounds . Ribozymes are enzymatic RNA molecules capable of catalyzing the specific cleavage of RNA. Ribozymes act by sequence-specific hybridization to the complementary target RNA, followed by endonucleolytic cleavage. Specific ribozyme cleavage sites within a potential RNA target can be identified by known techniques. For further details, see, e.g., Rossi, Current Biology 4 (5) : 469-71 (1994) and PCT publication No. WO 97/33551 (published September 18, 1997).

Nucleic acid molecules in triple-helix formation used to inhibit transcription should be single-stranded and composed of deoxynucleotides . The base composition of these oligonucleotides is designed such that it promotes triple-helix formation via Hoogsteen base-pairing rules, which generally require sizeable stretches of purines or pyrimidines on one strand of a duplex. For further details see, e.g., PCT publication No. WO 97/33551, supra.

Another use of the compounds of the invention (e.g., LP polypeptides, fragments and variants thereof and LP antibodies directed thereto) described herein is to help diagnose whether a disorder is driven to some extent by the modulation of signaling by an LP polypeptide

A diagnostic assay to determine whether a particular disorder is driven by LP polypeptide dependent signaling can be carried out using the following steps: a) culturing test cells or tissues expressing an LP polypeptide ; b) administering a compound which can inhibit LP polypeptide dependent signaling; and c) measuring LP polypeptide mediated phenotypic effects in the test cells.

The steps can be carried out using standard techniques in light of the present disclosure. Appropriate controls take into account the possible cytotoxic effect of a compound, such as treating cells not associated with a cell proliferative disorder (e.g., control cells) with a test compound and can also be used as part of the diagnostic assay. The diagnostic methods of the invention involve the screening for agents that modulate the effects of LP polypeptide-associated disorders. The LP polypeptides or antibodies thereto as well as LP polypeptide antagonists or agonists can be employed as therapeutic agents . Such therapeutic agents are formulated according to known methods to prepare pharmaceutically useful compositions, whereby the LP polypeptide or antagonist or agonist thereof is combined in a mixture with a pharmaceutically acceptable carrier. In the case of LP polypeptide antagonistic or agonistic antibodies, if the LP polypeptide is intracellular and whole antibodies are used as inhibitors, internalizing antibodies are preferred. However, lipofections or liposomes can also be used to deliver the antibody, or an antibody fragment, into cells. Where antibody fragments are used, the smallest inhibitory fragment which specifically binds to the binding domain of the target protein is preferred. For example, based upon the variable region sequences of an antibody, peptide molecules can be designed which retain the ability to bind the target protein sequence . Such peptides can be synthesized chemically and/or produced by recombinant DNA technology [see, e.g., Marasco, et al . , Proc . Natl . Acad. Sci . USA 90(16) :7889-93 (1993)]. Therapeutic formulations are prepared for storage by mixing the active ingredient having the desired degree of purity with optional pharmaceutically acceptable carriers, excipients or stabilizers [.Remington's Pharmaceutical Sciences 16th edition (1980)], in the form of lyophilized formulations or aqueous solutions.

The formulation herein may also contain more than one active compound as necessary for the particular indication being treated, preferably those with complementary activities that do not adversely affect each other. Such molecules are suitably present in combination in amounts that are effective for the purpose intended. The active ingredients may also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly- (methylmethacrylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions . Such techniques are disclosed in Remington ' s Pharmaceutical Sciences, supra . The formulations to be used for in vivo administration must be sterile. This is readily accomplished by filtration through sterile filtration membranes.

Therapeutic compositions herein generally are placed into a container having a sterile access port, for example, and intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle.

Sustained-release preparations may be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent (s), which matrices are in the form of shaped articles, e.g., films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels [for example, poly (2-hydroxyethyl-methacrylate) , or poly (vinylalcohol) ] , polylactides, copolymers of L- glutamic acid and gamma-ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOT™ (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D- (-) -3- hydroxybutyric acid. Microencapsulation of recombinant proteins for sustained release has been successfully performed with human growth hormone (rhGH) , interferon, and interleukin-2. Johnson, et al . , Nat . Med. 2(7):795-9 (1996); Yasuda, et al . , Biomed. Ther . 27:1221-3 (1993); Hora, et al . , Bio /Technology 8 (8) :755-8 (1990); Cleland, "Design and Production of Single Immunization Vaccines Using Polylactide Polyglycolide Microsphere Systems" in Vaccine Design : The Subuni t and Adjuvant Approach, Powell and Newman, Eds., Plenum Press, NY, 1995, pp. 439-462 WO 97/03692; WO 96/40072; WO 96/07399; and U.S. Patent 5,654,010. The sustained-release formulations of these proteins may be developed using polylactic-coglycolic acid (PLGA) polymer due to its biocompatibility and wide range of biodegradable properties. The degradation products of PLGA, lactic and glycolic acids, can be cleared quickly within the human body. Moreover, the degradability of this polymer can be adjusted from months to years depending on its molecular weight and composition. See Lewis, "Controlled release of bioactive agents from lactide/glycolide polymer" in Biodegradable Polymers as Drug Delivery Systems (Marcel Dekker; New York, 1990) , M. Chasin and R. Langer (Eds.) pp. 1-41.

While polymers such as ethylene-vinyl acetate and lactic acid-glycolic acid enable release of molecules for over 100 days, certain hydrogels release proteins for shorter time periods. When encapsulated antibodies remain in the body for a long time, they may denature or aggregate as a result of exposure to moisture at 37 degrees C, resulting in a loss of biological activity and possible changes in immunogenicity. It is contemplated that the compounds, including, but not limited to, antibodies, small organic and inorganic molecules, peptides, anti-sense molecules, ribozymes, etc., of the present invention may be used to treat various conditions including those characterized by overexpression and/or activation of the disease-associated genes identified herein. The active agents of the present invention (e.g., antibodies, polypeptides, nucleic acids, ribozymes, small organic or inorganic molecules) are administered to a mammal, preferably a human, in accord with known methods, such as intravenous administration as a bolus or by continuous infusion over a period of time, by intramuscular, intraperitoneal, intracerebral, intracerobrospinal, subcutaneous, intra-articular, intrasynovial, intrathecal, intraoccular, intralesional, oral, topical, inhalation, pulmonary, and/or through sustained release. Other therapeutic regimens may be combined with the administration of LP polypeptide antagonists or antagonists, anti-cancer agents, e.g., antibodies of the instant invention.

For the prevention or treatment of disease, the appropriate dosage of an active agent, (e.g., an antibody, polypeptide, nucleic acid, ribozyme, or small organic or inorganic molecule) will depend on the type of disease to be treated, as defined above, the severity and course of the disease, whether the agent is administered for preventive or therapeutic purposes, previous therapy, the patient's clinical history and response to the agent, and the discretion of the attending physician. The agent is suitably administered to the patient at one time or over a series of treatments. Dosages and desired drug concentration of pharmaceutical compositions of the present invention may vary depending on the particular use envisioned. The determination of the appropriate dosage or route of administration is well within the skill of an ordinary artisan. Animal experiments provide reliable guidance for the determination of effective does for human therapy. Interspecies scaling of effective doses can be performed following the principles laid down by Mordenti and Chappell, "The Use of Interspecies Scaling in Toxicokinetics, " in Toxicokinetics and New Drug Development, Yacobi, et al . , Eds., Pergamon Press, NY, p.4246 (1989) .

When in vivo administration of a composition comprising an LP polypeptide, an LP polypeptide antibody, an LP polypeptide-encoding nucleic acid, ribozyme, or small organic or inorganic molecule is employed, normal dosage amounts may vary from about 1 ng/kg up to 100 mg/kg of mammal body weight or more per day, preferably about 1 pg/kg/day up to 100 mg/kg of mammal body weight or more per day, depending upon the route of administration. Guidance as to particular dosages and methods of delivery is provided in the literature; see, for example, U.S.

Patents 4,657,760, 5,206,344 or 5,225,212. It is within the scope of the invention that different formulations will be effective for different treatment compounds and different disorders, that administration targeting one organ or tissue, for example, may necessitate delivery in a manner different from that to another organ or tissue. Moreover, dosages may be administered by one or more separate administrations or by continuous infusion. For repeated administrations over several days or longer, depending on the condition, the treatment is sustained until a desired suppression of disease symptoms occurs. However, other dosage regimens may be useful. The progress of this therapy is easily monitored by conventional techniques and assays .

In another embodiment of the invention, an article of manufacture containing materials useful for the diagnosis or treatment of the disorders described above is provided. The article of manufacture comprises a container and a label. Suitable containers include, for example, bottles, vials, syringes, and test tubes. The containers may be formed from a variety of materials such as glass or plastic. The container holds a composition which is effective for diagnosing or treating the condition and may have a sterile access port (for example, the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle) . The active agent in the composition is typically an LP polypeptide, antagonist or agonist thereof. The label on, or associated with, the container indicates that the composition is used for diagnosing or treating the condition of choice. The article of manufacture may further comprise a second container comprising a pharmaceutically-acceptable buffer, such as phosphate-buffered saline, Ringer's solution and dextrose solution. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, syringes, and package inserts with instructions for use.

In another embodiment of the invention, therapeutic utility of the LP polypeptide is determined by measuring phosphorylation of tyrosine residues on specific cell lines. The early cellular response of cells stimulated with the majority of proteins is protein phosphorylation of the tyrosine residues. This response includes autophos- phorylation of corresponding receptors, which thereby leads to the activation of catalytic properties and the initiation of intracellular pathways specific to the cell type. Moreover, signaling downstream of receptors requires phosphorylation of specific kinases inside the cell and other intracellular enzymes of different origin as well as the phosphorylation of multiple adapter/scaffold, structural proteins and transcriptional f ctors . Therefore, diverse protein-induced cell responses can be visualized by monitoring the state of protein phosphorylation after cell stimulation.

Immunodetection is used to detect the protein phosphorylation of the stimulated cell. Several antibodies that are directed against specific phosphorylated epitopes in signaling molecules are readily available. Two specific antibodies are used: phosphospecific anti-MAPK and anti-AKT antibodies. Additionally, non-specific anti-phosphotyro- sine antibodies, which recognize tyrosine-phosphorylated proteins, are used. While anti-phosphotyrosine antibodies allow detection of diverse tyrosine phosphorylated proteins without directly addressing the nature of their identity, the phosphospecific anti-MAPK and anti-AKT antibodies recognize only the corresponding proteins in their phosphorylated form.

Another assay to determine utility of LP polypeptides involves transfection of cell lines with reporter plasmids followed by cell stimulation with an LP polypeptide. Each reporter consists of a defined element, responsive to specific intracellular signaling pathways, upstream of a sequence involving a reporter protein such as luciferase. Upon stimulation of the element, reporter transcription and translation ensues, and the resulting protein levels can be detected using an assay such as a luminescence assay. The cell stimulation period depends on the reporter plasmid used.

For each reporter used, positive controls are designed in the form of agonist cocktails which include approximately maximal stimulatory doses of several ligands known to stimulate the represented signaling pathway. Using this design, the chances of finding a positive stimulus for each cell line is maximized. The caveat, however, is that some cell line / reporter combinations will not be stimulated by the specific agonist cocktail, due to lack of an appropriate ligand in the cocktail. Alternately, the lack of signal induction by an agonist cocktail may be the lack of all signaling components within a particular cell line to activate the transcriptional element. Cell line / reporter combinations with no exogenous stimulus added make up the negative controls.

Another assay to determine utility of LP polypeptides involves transfection of cell lines with reporter plasmids followed by cell stimulation with an LP polypeptide. Each reporter consists of a defined element, responsive to specific intracellular signaling pathways, upstream of a sequence involving a reporter protein such as luciferase. Upon stimulation of the element, reporter transcription and translation ensues, and the resulting protein levels can be detected using an assay such as a luminescence assay. The cell stimulation period depends on the reporter plasmid used.

For each reporter used, positive controls are designed in the form of agonist cocktails which include approximately maximal stimulatory doses of several ligands known to stimulate the represented signaling pathway. Using this design, the chances of finding a positive stimulus for each cell line is maximized. The caveat, however, is that some cell line/reporter combinations will not be stimulated by the specific agonist cocktail, due to lack of an appropriate ligand in the cocktail. Alternately, the lack of signal induction by an agonist cocktail may be the lack of all signaling components within a particular cell line to activate the transcriptional element. Cell line / reporter combinations with no exogenous stimulus added make up the negative controls. In another assay, utility of LP polypeptide is determined by proliferation of cells. In this assay, gross changes in the number of cells remaining in a culture are monitored after exposure to an LP polypeptide for three days. The cells are incubated in an appropriate assay medium to produce a sub-optimal growth rate. For example, usually a 1:10 or 1:20 dilution of normal culture medium results in a 40 to 60% reduction in cell number compared to the undiluted culture medium. This broad growth zone is chosen so that if an LP polypeptide is a stimulator of growth, the cells have room to expand, and conversely, if the LP polypeptide is deleterious, a reduction in cell density can be detected. After a period of exposure, the assay media is replaced with media containing a detection agent such as Calcein AM, a membrane-permeant fluorescent dye, allowing quantification of the cell number.

For use in another assay, a FLAG-HIS (FLIS) -tagged version of the LP polypeptide is expressed using mammalian cells such as HEK-293EBNA, COS-7, or HEK293T. The coding region of the cDNA is amplified by PCR of a vector containing a fragment encoding the LP polypeptide. The

PCR-generated fragment is cleaved with restriction enzymes and gel-purified. The fragment is then ligated into a mammalian expression vector containing the FLIS epitope tag fused to the C-terminus. Protein expressed by this plasmid construct includes both the FLAG tag (Asp-Tyr-Lys-Asp-Asp- Asp-Asp-Lys) and the 6X His tag at the COOH -terminus of the protein. This tag provides epitopes for commercially available tag-specific antibodies, enabling detection of the protein.

To determine expression of the LP polypeptide in tissues, a protein-binding assay is performed. The fixed tissue sample is exposed to the FLIS-tagged LP polypeptide, followed by exposure to a primary antibody and a secondary antibody containing a fluorescent dye . Tagged LP polypeptide that binds to the antigens in the tissue will fluoresce. Binding of the protein to an antigen in the tissue suggests that the protein is expressed in that tissue. Thus, protein expression can be determined by measuring which tissues fluoresce.

Having generally described the invention, the same will be more readily understood by reference to the following examples, which are provided by way of illustration and are not intended as limiting.

EXAMPLES

Example 1 Expression and Purification of LP polypeptides in E. coli

The bacterial expression vector pQE60 is used for bacterial expression in this example. (QIAGEN, Inc.,

Chatsworth, CA) . pQE60 encodes ampicillin antibiotic resistance ("Apr") and contains a bacterial origin of replication ("ori"), an IPTG inducible promoter, a ribosome binding site ("RBS"), six codons encoding histidine residues that allow affinity purification using nickel-nitrilo- triacetic acid ("Ni-NTA") affinity resin sold by QIAGEN, Inc., and suitable single restriction enzyme cleavage sites. These elements are arranged such that a DNA fragment encoding a polypeptide can be inserted in such a way as to produce that polypeptide with the six His residues (i.e., a "6 X His tag") covalently linked to the carboxyl terminus of that polypeptide. However, a polypeptide coding sequence can optionally be inserted such that translation of the six His codons is prevented and, therefore, a polypeptide is produced with no 6 X His tag.

The nucleic acid sequence encoding the desired portion of an LP polypeptide lacking the hydrophobic leader sequence is amplified from a cDNA clone using PCR oligonucleotide primers (based on the sequences presented, e.g., in SEQ ID NO:l, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, or 37) which anneal to the amino terminal encoding DNA sequences of the desired portion of the LP polypeptide-encoding nucleic acid and to sequences in the construct 3' to the cDNA coding sequence. Additional nucleotides containing restriction sites to facilitate cloning in the pQE60 vector are added to the 5' and 3' sequences, respectively.

For cloning, the 5' and 3' primers have nucleotides corresponding or complementary to a portion of the coding sequence of the LP polypeptide-encoding nucleic acid, e.g., as presented in SEQ ID N0:1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, or 37, according to known method steps. One of ordinary skill in the art would appreciate, of course, that the point in a polynucleotide sequence where the 5' primer begins can be varied to amplify a desired portion of the complete polypeptide-encoding polynucleotide shorter or longer than the polynucleotide which encodes the mature form of the polypeptide.

The amplified nucleic acid fragments and the vector pQE60 are digested with appropriate restriction enzymes, and the digested DNAs are then ligated together. Insertion of the LP polypeptide-encoding DNA into the restricted pQE60 vector places the LP105, LP061, LP224, LP240, LP239 (a) , LP243(a), LP243(b), LP253, LP218, LP251 (a) , LP252, LP239 (b) , LP223(a), LP255 (a) , LP244, LP186, LP251(b), LP255 (b) , or LP223 (b) polypeptide coding region including its associated stop codon downstream from the IPTG-inducible promoter and in-frame with an initiating AUG codon. The associated stop codon prevents translation of the six histidine codons downstream of the insertion point . The ligation mixture is transformed into competent E. coli cells using standard procedures such as those described in Sambrook, et al . , 1989; Ausubel, 1987-1998. E. coli strain M15/rep4, containing multiple copies of the plasmid pREP4, which expresses the lac repressor and confers kanamycin resistance ("Kanr"), is used in carrying out the illustrative example described herein. This strain, which is only one of many that are suitable for expressing LP polypeptides, is available commercially from QIAGEN, Inc. Transformants are identified by their ability to grow on LB plates in the presence of ampicillin and kanamycin. Plasmid DNA is isolated from resistant colonies and the identity of the cloned DNA confirmed by restriction analysis, PCR and DNA sequencing.

Clones containing the desired constructs are grown overnight ("0/N") in liquid culture in LB media supplemented with both ampicillin (100 μg/mL) and kanamycin (25 μg/mL) . The O/N culture is used to inoculate a large culture, at a dilution of approximately 1:25 to 1:250. The cells are grown to an optical density at 600 nm ("OD600") of between 0.4 and 0.6. Isopropyl-beta-D-thiogalacto- pyranoside ("IPTG") is then added to a final concentration of 1 mM to induce transcription from the lac repressor sensitive promoter, by inactivating the lacl repressor. Cells subsequently are incubated further for three to four hours. Cells then are harvested by centrifugation.

The cells are then stirred for three to four hours at 4 degree^'s C in 6 M guanidine hydrochloride, pH 8. The cell debris is removed by centrifugation, and the supernatant containing the LP polypeptide is dialyzed against 50 mM sodium acetate buffer, pH 6, supplemented with 200 mM sodium chloride. Alternatively, a polypeptide can be successfully refolded by dialyzing it against 500 mM sodium chloride, 20% glycerol, 25 mM Tris hydrochloride, pH 7.4, containing protease inhibitors .

If insoluble protein is generated, the protein is made soluble according to known method steps . After renaturation, the polypeptide is purified by ion exchange, hydrophobic interaction, and size exclusion chromatography. Alternatively, an affinity chromatography step such as an antibody column is used to obtain pure LP polypeptide. The purified polypeptide is stored at 4 degrees C or frozen at negative 40 degrees C to negative 120 degrees C.

Example 2 Cloning and Expression of LP polypeptidesin a Baculovirus

Expression System In this example, the plasmid shuttle vector pA2 GP is used to insert the cloned DNA encoding the mature LP polypeptide into a baculovirus, using a baculovirus leader and standard methods as described in Summers, et al . , A Manual of Methods for Baculovirus Vectors and Insect Cell Cul ture Procedures, Texas Agricultural Experimental Station Bulletin No. 1555 (1987) . This expression vector contains the strong polyhedrin promoter of the Autographa californica nuclear polyhedrosis virus (AcMNPV) followed by the secretory signal peptide (leader) of the baculovirus gp67 polypeptide and convenient restriction sites such as BamHI, Xba I, and Asp718. The polyadenylation site of the simian virus 40 ("SV40") is used for efficient polyadenylation. For easy selection of recombinant virus, the plasmid contains the beta-galactosidase gene from E. coli under control of a weak Drosophila promoter in the same orientation, followed by the polyadenylation signal of the polyhedrin gene. The inserted genes are flanked on both sides by viral sequences for cell-mediated homologous recombination with wild-type viral DNA to generate viable virus that expresses the cloned polynucleotide.

Other baculovirus vectors are used in place of the vector above, such as pAc373, pVL941 and pAcIMl, as one skilled in the art would readily appreciate, as long as the construct provides appropriately located signals for transcription, translation, secretion and the like, including a signal peptide and an in-frame AUG as required. Such vectors are described, for instance, in Luckow, et al . , Virology 170:31-39.

The cDNA sequence encoding the mature LP polypeptide in a clone, lacking the AUG initiation codon and the naturally associated nucleotide binding site, is amplified using PCR oligonucleotide primers corresponding to the 5' and 3' sequences of the gene. Non-limiting examples include 5' and 3 ' primers having nucleotides corresponding or complementary to a portion of the coding sequence of an LP polypeptide- encoding polynucleotide, e.g., as presented in SEQ ID NO:l, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, or 37 according to known method steps. The amplified fragment is isolated from a 1% agarose gel using a commercially available kit (e.g., "Geneclean," BIO 101 Inc., La Jolla, CA) . The fragment is then digested with the appropriate restriction enzyme and again is purified on a 1% agarose gel. This fragment is designated herein "FI."

The plasmid is digested with the corresponding restriction enzymes and optionally, can be dephosphorylated using calf intestinal phosphatase, using routine procedures known in the art. The DNA is then isolated from a 1% agarose gel using a commercially available kit ("Geneclean" BIO 101 Inc., La Jolla, CA) . This vector DNA is designated herein "VI . "

Fragment Fl and the dephosphorylated plasmid VI are ligated together with T4 DNA ligase. E. coli HB101 or other suitable E. coli hosts such as XL-1 Blue (Stratagene Cloning Systems, La Jolla, CA) cells are transformed with the ligation mixture and spread on culture plates. Bacteria are identified that contain the plasmid bearing a human LP polypeptide-encoding polynucleotide using the PCR method, in which one of the primers that is used to amplify the gene and the second primer is from well within the vector so that only those bacterial colonies containing an LP polypeptide- encoding polynucleotide will show amplification of the DNA. The sequence of the cloned fragment is confirmed by DNA sequencing. The resulting plasmid is designated herein as pBacLP . Five μg of the plasmid pBacLP plasmid construct is co- transfected with 1.0 μg of a commercially available linearized baculovirus DNA ( "BaculoGold" baculovirus DNA", PharMingen, San Diego, CA) , using the lipofection method described by Feigner, et al . , Proc . Natl . Acad. Sci . USA 84: 7413-7 (1987) . 1 μg of BaculoGold^® virus DNA and 5 μg of the plasmid pBacLP are mixed in a sterile well of a microtiter plate containing 50 μL of serum-free Grace's medium (Life Technologies, Inc., Rockville, MD) . Afterwards, 10 μL Lipofectin plus 90 μL Grace's medium are added, mixed and incubated for fifteen minutes at room temperature. Then, the transfection mixture is added drop- wise to Sf9 insect cells (ATCC CRL 1711) seeded in a 35 mm tissue culture plate with 1 mL Grace's medium without serum. The plate is rocked back and forth to mix the newly added solution. The plate is then incubated for five hours at 27 degrees C. After five hours, the transfection solution is removed from the plate and 1 mL of Grace's insect medium supplemented with 10% fetal calf serum is added. The plate is put back into an incubator and cultivation is continued at 27 degrees C for four days.

After four days, the supernatant is collected, and a plaque assay is performed. An agarose gel with "Blue Gal" (Life Technologies, Inc., Rockville, MD) is used to allow easy identification and isolation of gal-expressing clones, which produce blue-stained plaques. (A detailed description of a "plaque assay" of this type can also be found in the user's guide for insect cell culture and baculovirology distributed by Life Technologies, Inc., Rockville, MD, pp. 9-10) . After appropriate incubation, blue stained plaques are picked with a micropipettor tip (e.g., Eppendorf) . The agar containing the recombinant viruses is then resuspended in a microcentrifuge tube containing 200 μL of Grace's medium and the suspension containing the recombinant baculovirus is used to infect Sf9 cells seeded in 35 mm dishes. Four days later, the supernatants of these culture dishes are harvested and then stored at 4 degrees C.

To verify the expression of the LP polypeptide, Sf9 cells are grown in Grace's medium supplemented with 10% heat-inactivated FB . The cells are infected with the recombinant baculovirus at a multiplicity of infection ("MOI") of about two. Six hours later, the medium is removed and replaced with SF900 II medium minus methionine and cysteine (available, e.g., from Life Technologies, Inc., Rockville, MD) . If radiolabeled polypeptides are desired, 42 hours later, 5 Ci of ³⁵S-methionine and 5 mCi

³⁵S-cysteine (available from Amersham, Piscataway, NJ) are added. The cells are further incubated for sixteen hours and then harvested by centrifugation. The polypeptides in the supernatant as well as the intracellular polypeptides are analyzed by SDS-PAGE, followed by autoradiography (if radiolabeled) . Microsequencing of the amino acid sequence of the amino terminus of purified polypeptide can be used to determine the amino terminal sequence of the mature polypeptide and, thus, the cleavage point and length of the secretory signal peptide.

Example 3

Cloning and Expression of an LP Polypeptide in Mammalian Cells A typical mammalian expression vector contains at least one promoter element, which mediates the initiation of transcription of mRNA, the polypeptide coding sequence, and signals required for the termination of transcription and polyadenylation of the transcript. Additional elements include enhancers, Kozak sequences and intervening sequences flanked by donor and acceptor sites for RNA splicing. Highly efficient transcription can be achieved with the early and late promoters from SV40, the long terminal repeats (LTRS) from Retroviruses, e.g., RSV, HTLVI, HIVI and the early promoter of the cytomegalovirus (CMV) . However, cellular elements can also be used (e.g., the human actin promoter) . Suitable expression vectors for use in practicing the present invention include, for example, vectors such as pIRESlneo, pRetro-Off, pRetro-On, PLXSN, or pLNCX (Clontech Labs, Palo Alto, CA) , pcDNA3.1 (+/-), pcDNA/Zeo (+/-) or pcDNA3.1/Hygro (+/-)

(Invitrogen) , PSVL and PMSG (Pharmacia, Uppsala, Sweden), pRSVcat (ATCC 37152), pSV2dhfr (ATCC 37146) and pBC12MI (ATCC 67109) . Other suitable mammalian host cells include human Hela 293, H9 , Jurkat cells, mouse NIH3T3, C127 cells, Cos 1, Cos 7 and CV 1, quail QCl-3 cells, mouse L cells, and Chinese hamster ovary (CHO) cells.

Alternatively, the gene is expressed in stable cell lines that contain the gene integrated into a chromosome. The co-transfection with a selectable marker such as DHRF (dihydrofolate reductase) , GPT neomycin, or hygromycin allows the identification and isolation of the transfected cells .

The transfected gene can also be amplified to express large amounts of the encoded polypeptide. The DHFR marker is useful to develop cell lines that carry several hundred or even several thousand copies of the gene of interest. Another useful selection marker is the enzyme glutamine synthase (GS) [Murphy, et al . , Biochem. J. 227:277-9 (1991); Bebbington, et al . , Bio /Technology 10:169-75 (1992)]. Using these markers, the mammalian cells are grown in selective medium and the cells with the highest resistance are selected. These cell lines contain the amplified gene(s) integrated into a chromosome. Chinese hamster ovary (CHO) and NSO cells are often used for the production of polypeptides .

The expression vectors pCl and pC4 contain the strong promoter (LTR) of the Rous Sarcoma Virus [Cullen, et al . , Mol . Cell . Biol . 5:438-47 (1985)] plus a fragment of the CMV-enhancer [Boshart, et al . , Cell 41:521-30 (1985)]. Multiple cloning sites, e.g., with the restriction enzyme cleavage sites BamHI, Xbal, and Asp718, facilitate the cloning of the gene of interest. The vectors contain in addition the 3' intron, the polyadenylation and termination signal of the rat preproinsulin gene .

Example 3 (a) Cloning and Expression in COS Cells

The expression plasmid, pLP HA, is made by cloning a cDNA encoding LP polypeptide into the expression vector pcDNAI/Amp or pcDNAIII (which can be obtained from Invitrogen, Inc.) . The expression vector pcDNAI/amp contains: (1) an E. coli origin of replication effective for propagation in E. coli and other prokaryotic cells; (2) an ampicillin resistance gene for selection of plasmid-containing prokaryotic cells; (3) an SV40 origin of replication for propagation in eukaryotic cells; (4) a CMV promoter, a polylinker, an SV40 intron; (5) several codons encoding a hemagglutinin fragment (i.e., an "HA" tag to facilitate purification) or HIS tag (see, e.g., Ausubel, supra) followed by a termination codon and polyadenylation signal arranged so that a cDNA can be conveniently placed under expression control of the CMV promoter and operably linked to the SV40 intron and the polyadenylation signal by means of restriction sites in the polylinker. The HA tag corresponds . to an epitope derived from the influenza hemagglutinin polypeptide described by Wilson, et al . , Cell 37:767-8 (1984). The fusion of the HA tag to the target polypeptide allows easy detection and recovery of the recombinant polypeptide with an antibody that recognizes the HA epitope. pcDNAIII contains, in addition, the selectable neomycin marker.

A DNA fragment encoding the LP polypeptide is cloned into the polylinker region of the vector so that recombinant polypeptide expression is directed by the CMV promoter. The plasmid construction strategy is as follows. The LP polypeptide-encoding cDNA of a clone is amplified using primers that contain convenient restriction sites, much as described above for construction of vectors for expression of LP polypeptides in E. coli . Non-limiting examples of suitable primers include those based on the coding sequences presented in SEQ ID NO:l, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, and 37. The PCR amplified DNA fragment and the vector, pcDNAI/Amp, are digested with suitable restriction enzyme (s) and then ligated. The ligation mixture is transformed into E. coli strain SURE (available from Stratagene Cloning Systems, La Jolla, CA) , and the transformed culture is plated on ampicillin media plates which then are incubated to allow growth of ampicillin resistant colonies. Plasmid DNA is isolated from resistant colonies and examined by restriction analysis or other means for the presence of the LP polypeptide-encoding fragment .

For expression of recombinant LP polypeptide, COS cells are transfected with an expression vector, as described above, using DEAE-DEXTRAN, as described, for instance, in Sambrook, et al . , Molecular Cloning: a Laboratory Manual , Cold Spring Laboratory Press, Cold Spring Harbor, New York (1989) . Cells are incubated under conditions for expression of the LP polypeptide-encoding polynucleotide by the vector.

Expression of the LP polypeptide-HA fusion is detected by radiolabeling and immunoprecipitation, using methods described in, for example Harlow, et al . , Antibodies : A Laboratory Manual, 2nd Ed. , Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York (1988) . To this end, two days after transfection, the cells are labeled by incubation in media containing ³⁵S-cysteine for eight hours. The cells and the media are collected, and the cells are washed and lysed with detergent-containing RIPA buffer:

150 mM sodium chloride, 1% NP-40, 0.1% SDS, 0.5% DOC, 50 mM TRIS, pH 7.5, as described by Wilson, et al . , cited above. Proteins are precipitated from the cell lysate and from the culture media using an HA-specific monoclonal antibody. The precipitated polypeptides then are analyzed by SDS-PAGE and autoradiography. An expression product of the expected size is seen in the cell- lysate, which is not seen in ^"negative controls. Example 3 (b) Cloning and Expression in CHO Cells The vector pC4 is used for the expression of the LP polypeptide. Plasmid pC4 is a derivative of the plasmid pSV2-dhfr (ATCC Accession No. 37146) . The plasmid contains the mouse DHFR gene under control of the SV40 early promoter. Chinese hamster ovary cells or other cells lacking dihydrofolate activity that are transfected with these plasmids can be selected by growing the cells in a selective medium (alpha minus MEM, Life Technologies) supplemented with methotrexate. The amplification of the DHFR genes in cells resistant to methotrexate (MTX) has been well documented [see, e.g., Alt, et al . , J. Biol . Chem. 253:1357-70 (1978); Hamlin and Ma, Biochem . et Biophys . Acta 1097:107-43 (1990); and Page and Sydenham, Biotechnology 9:64-8 (1991)]. Cells grown in increasing concentrations of MTX develop resistance to the drug by overproducing the target enzyme, DHFR, as a result of amplification of the DHFR gene. If a second gene is linked to the DHFR gene, it is usually co-amplified and over- expressed. It is known in the art that this approach can be used to develop cell lines carrying more than 1,000 copies of the amplified gene(s). Subsequently, when the methotrexate is withdrawn, cell lines are obtained which contain the amplified gene integrated into one or more chromosome (s) of the host cell.

Plasmid pC4 contains for expressing the gene of interest the strong promoter of the long terminal repeat (LTR) of the Rous Sarcoma Virus [Cullen, et al . , Mol . Cell . Biol . 5: 438-47 (1985)] plus a fragment isolated from the enhancer of the immediate early gene of human cytomegalovirus (CMV) [Boshart, et al . , Cell 41: 521-30 (1985)]. Downstream of the promoter are BamHI, Xbal, and Asp718 restriction enzyme cleavage sites that allow integration of the genes. Behind these cloning sites, the plasmid contains the 3 ' intron and polyadenylation site of the rat preproinsulin gene. Other high efficiency promoters can also be used for the expression, e.g., the human beta-actin promoter, the SV40 early or late promoters or the long terminal repeats from other retroviruses, e.g., HIV and HTLVI . Clontech's Tet-Off and Tet-On gene expression systems and similar systems can be used to express the LP polypeptide in a regulated way in mammalian cells [Gossen, and Bujard, Proc . Natl . Acad. Sci . USA 89:5547-51 (1992)]. For the polyadenylation of the mRNA other signals, e.g., from the human growth hormone or globin genes can be used as well. Stable cell lines carrying a gene of interest integrated into the chromosomes can also be selected upon co-transfection with a selectable marker such as gpt, G418 or hygromycin. It is advantageous to use more than one selectable marker in the beginning, e.g., G418 plus methotrexate.

The plasmid pC4 is digested with restriction enzymes and then dephosphorylated using calf intestinal phosphatase by procedures known in the art. The vector is then isolated from a 1% agarose gel. The DNA sequence encoding the complete the LP polypeptide is amplified using PCR oligonucleotide primers corresponding to the 5' and 3' sequences of the gene. Non- limiting examples include 5' and 3' primers having nucleotides corresponding or complementary to a portion of the coding sequences of an LP polypeptide-encoding polynucleotide, e.g., as presented in SEQ ID NO:l, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, or 37, according to known method steps.

The amplified fragment is digested with suitable endonucleases and then purified again on a 1% agarose gel. The isolated fragment and the dephosphorylated vector are then ligated with T4 DNA ligase. E. coli HB101 or XL-1 Blue cells are then transformed and bacteria are identified that contain the fragment inserted into plasmid pC4 using, for instance, restriction enzyme analysis. Chinese hamster ovary (CHO) cells lacking an active DHFR gene are used for transfection. Five μg of the expression plasmid pC4 is cotransfected with 0.5 μg of the plasmid pSV2-neo using lipofectin. The plasmid pSV2-neo contains a dominant selectable marker, the neo gene from Tn5 encoding an enzyme that confers resistance to a group of antibiotics including G418. The cells are seeded in alpha minus MEM supplemented with 1 μg/mL G418. After two days, the cells are trypsinized and seeded in hybridoma cloning plates (Greiner, Germany) in alpha minus MEM supplemented with 10, 25, or 50 ng/mL of methotrexate plus 1 μg/mL G418. After about ten to fourteen days, single clones are trypsinized and then seeded in six-well petri dishes or 10 mL flasks using different concentrations of methotrexate (50 nM, 100 nM, 200 nM, 400 nM, 800 nM) . Clones growing at the highest concentrations of methotrexate are then transferred to new six-well plates containing even higher concentrations of methotrexate (1 mM, 2 mM, 5 mM, 10 mM, 20 mM) . The same procedure is repeated until clones are obtained which grow at a concentration of 100 to 200 mM. Expression of the desired gene product is analyzed, for instance, by SDS-PAGE and Western blot or by reversed phase HPLC analysis. Example 4 Tissue Distribution of LP polypeptide-encoding mRNA Northern blot analysis is carried out to examine expression of LP-polypeptide mRNA in human tissues, using methods described by, among others, Sambrook, et al . , cited above. A cDNA preferably probe encoding the entire LP polypeptide is labeled with ³²P using the Rediprime™ DNA labeling system (Amersham Life Science) , according to the manufacturer's instructions. After labeling, the probe is purified using a CHROMA SPIN-100™ column (Clontech Laboratories, Inc.) according to the manufacturer's protocol number PT1200-1. The purified and labeled probe is used to examine various human tissues for LP polypeptide mRNA. Multiple Tissue Northern (MTN) blots containing various human tissues (H) or human immune system tissues (IM) are obtained from Clontech and are examined with the labeled probe using ExpressHyb™ hybridization solution (Clontech) according to manufacturer's protocol number PT1190-1. Following hybridization and washing, the blots are mounted, exposed to film at negative 70 degrees C overnight, and developed according to standard procedures .

Example 5 Protein Phosphorylation on Tyrosine Residues

Protein-induced cell responses are determined by monitoring tyrosine phosphorylation upon stimulation of cells by addition of LP polypeptides. This is accomplished in two steps: cell manipulation and immunodetection. Protein phosphorylation is measured using the SK-N-MC neuroblastoma cell line (ATCC HTB-10) . On day one, the cells are plated into poly-D-lysine-coated, 96 well plates containing cell propagation medium [DMEM.-F12 (3:1), 20 mM HEPES at pH 7.5, 5% FBS, and 50 μg/mL Gentamicin] . The cells are seeded at a concentration of 20,000 cells per well in 100 μL medium. On day two, the propagation medium in each well is replaced with 100 μL starvation medium containing DMEM:F12 (3:1), 20 mM HEPES at pH 7.5, 0.5% FBS, and 50 μg/mL Gentamicin. The cells are incubated overnight. On day three, pervanadate solution is made ten minutes before cell lysis; pervanadate is prepared by mixing 100 μL of sodium orthovanadate (100 mM) and 3.4 μL of hydrogen peroxide (producing 100X stock pervanadate solution) . The lysis buffer is then prepared: 50 mM HEPES at pH 7.5, 150 mM sodium chloride, 10% glycerol, 1% TRITON-X100™, 1 mM EDTA, 1 mM pervanadate, and BM protease inhibitors. The cells are stimulated by adding 10 μL of the LP polypeptide solution to the cells, and incubating for ten minutes. Next, the medium is aspirated, and 75 μL lysis buffer are added to each well . The cells are lysed at 4 degrees C for fifteen minutes, then 25 μL of 4X loading buffer are added to the cell lysates. The resultant solution is mixed then heated to 95 degrees C.

Detection of tyrosine phosphorylation is accomplished by Western immunoblotting. Twenty microliters of each cell sample are loaded onto SDS-PAGE eight to sixteen percent amino acid-ready gels from Bio-Rad, and the gels are run. The proteins are electrotransferred in transfer buffer (25 mM Tris base at pH 8.3 , 0.2 M glycine, 20% methanol) from the gel to a nitrocellulose membrane using 250 mA per gel over a one hour period. The membrane is incubated for one hour at ambient conditions in blocking buffer consisting of TBST (20 mM Tris hydrochloride at pH 7.5, 150 mM sodium chloride, 0.1% TWEEN^®-20) with 1% BSA. Next, the antibodies are added to the membrane. The membrane is incubated overnight at 4 degrees C with gentle rocking in primary antibody solution consisting of the antibody, TBST, and 1% BSA. The next day, the membrane is washed three times, five minutes per wash, with TBST. The membrane is then incubated in the secondary antibody solution consisting of the antibody, TBST, and 1% BSA for one hour at ambient conditions with gentle rocking. After the incubation, the membrane is washed four times with TBST, ten minutes per wash.

Detection is accomplished by incubating the membrane with 10 to 30 mL of SuperSignal Solution for one minute at ambient conditions. After one minute, excess developing solution is removed, and the membrane is wrapped in plastic wrap. The membrane is exposed to X-ray film for twenty second, one minute, and two minute exposures (or longer if needed) . The number and intensity of immunostained protein bands are compared to bands for the negative control- stimulated cells (basal level of phosphorylation) by visual comparison.

LP251(a) stimulates phosphorylation in the SK-N-MC cell line and activates the AKT pathway.

Example 6 Cell Stimulation with Detection Utilizing Reporters Protein-induced cell responses are measured using reporters. The SK-N-MC cell line (neuroblastoma; ATCC HTB- 10) / NFKB reporter combination is used.

For the reporter used, positive controls are designed in the form of agonist cocktails. These cocktails include approximate maximal stimulatory doses of several ligands known to stimulate the regulated signal pathway. For the NFKB reporter, the NFKB / PkC pathway is stimulated by an agonist cocktail containing LPS and TNF-alpha as positive controls . Cell lines and reporters with no exogenous stimulus added are used as negative controls. At time zero, the cells are transiently transfected with the reporter plasmids in tissue culture flasks using a standard optimized protocol for all cell lines (see Example 1) . After 24 hours, the cells are trypsinized and seeded into 96-well poly-D-lysine coated assay plates at a rate of 20,000 cells per well in growth medium. After four to five hours, the medium is replaced with serum-free growth medium. At that time, stimulants for those reporters which required a 24-hour stimulation period are added. After 48 hours, stimulants for the reporters which required a five-hour stimulation period are added. Five hours later, all conditions are lysed using a lysis/luciferin cocktail, and the fluorescence of the samples is determined using a Micro Beta reader.

Each assay plate is plated to contain four positive control wells, sixteen negative control wells, and sixty- four test sample wells (two replicates of thirty-two test samples) . The threshold value for a positive "hit" is a fluorescence signal equal to the mean plus two standard deviations of the negative control wells. Any test sample that, in both replicates, generates a signal above that threshold is defined as a "hit."

LP240 stimulates the NFKB pathway of the neuroblastoma cell line SK-N-MC. Example 7 Cell Proliferation and Cytotoxicity Determination Utilizing

Fluorescence Detection This assay is designed to monitor gross changes in the number of cells remaining in culture after exposure to LP polypeptides for a period of three days. The following cells are used in this assay:

U373MG (astrocytoma cell line, ATCC HTB-22) T1165 (plastocyto a cell line) ECV304 endothelial cell line)

Prior to assay, cells are incubated in an appropriate assay medium to produce a sub-optimal growth rate, e.g., a 1:10 or 1:20 dilution of normal culture medium. Cells are grown in T-150 flasks, then harvested by trypsin digestion and replated at 40 to 50% confluence into poly-D-lysine- treated 96-well plates. Cells are only plated into the inner thirty-two wells to prevent edge artifacts due to medium evaporation; the outer wells are filled with buffer alone. Following incubation overnight to stabilize cell recovery, LP polypeptides are added to the appropriate wells. Each polypeptide is assayed in triplicate at two different concentrations, IX and 0. IX dilution in assay medium. Two controls are also included on each assay plate: assay medium and normal growth medium.

After approximately 72 hours of exposure, the plates are processed to determine the number of viable cells. Plates are spun to increase the attachment of cells to the plate. The medium is then discarded, and 50 μL of detection buffer is added to each well. The detection buffer consisted on MEM medium containing no phenol red (Gibco) with calcein AM (Molecular Probes) and PLURONIC^® F-127 (Molecular Probes), each at a 1:2000 dilution. After incubating the plates in the dark at room temperature for thirty minutes, the fluorescence intensity of each well is measured using a Cytofluor 4000-plate reader (PerSeptive Biosystems) . For a given cell type, the larger the fluorescence intensity, the greater the number of cells in the well. To determine the effects on cell growth from each plate, the intensity of each well containing cells stimulated with an LP polypeptide is subtracted from the intensity of the wells containing assay medium only

(controls) . Thus, a positive number indicated stimulation of cell growth; a negative number indicated a reduction in growth. Additionally, confidence limits at 95 and 90% are calculated from the mean results. Results lying outside the 95% confidence limit are scored as "definite hits." Results lying between the 95 and 90% confidence limits are scored as "maybes . " The distinction between definite hits and maybes varied due to intraplate variability; thus, subjective scoring is used as a final determination for "hits." LP251(a) stimulates the growth of T1165 cells and suppresses the growth of U373MG cells. LP240 stimulates the proliferation of the ECV304 endothelial cell line.

Claims

WE CLAIM :

1. Isolated nucleic acid comprising DNA having at least 90% sequence identity to a polynucleotide selected from the group consisting of:

(a) a polynucleotide having a nucleotide sequence as shown in SEQ ID NO:l, 3, 5, 7, 9, 11, 13, 15,

17, 19, 21, 23, 25, 27, 29, 31, 33, 35, or 37;

(b) a polynucleotide encoding a polypeptide having the amino acid sequence as shown in SEQ ID NO: 2,

4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, or 38;

(c) a polynucleotide encoding the mature form of a polypeptide having the amino acid sequence as shown in SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 16,

18, 20, 22, 24, 26, 28, 30, 32, 34, 36, or 38;

(d) a polynucleotide fragment of a polynucleotide as in (a) , (b) , or (c) ; and

(e) a polynucleotide having a nucleotide sequence which is complementary to the nucleotide sequence of a polynucleotide as in (a) , (b) , (c) , or (d) .

2. An isolated nucleic acid molecule encoding an polypeptide comprising DNA that hybridizes to the complement of the nucleic acid sequence that encodes LP105, LP061, LP224, LP240, LP239(a), LP243 (a) , LP243 (b) , LP253, LP218, LP251(a), LP252, LP239(b), LP223 (a) , LP255(a), LP244, LP186, LP251(b), LP255 (b) , LP223 (b) , or any fragment or variant thereof.

3. The isolated nucleic acid molecule of claim 2, wherein hybridization occurs under stringent hybridization and wash conditions.

4. A vector comprising the nucleic acid molecule of any of Claims 1 to 3.

5. The vector of Claim 4, wherein said nucleic acid molecule is operably linked to control sequences recognized by a host cell transformed with the vector.

6. A host cell comprising the vector of Claim 5.

7. A process for producing an LP polypeptide comprising culturing the host cell of Claim 6 under conditions suitable for expression of said LP polypeptide and recovering said LP polypeptide from the cell culture .

8. An isolated polypeptide comprising an amino acid sequence comprising about 90% sequence identity to a sequence of amino acid residues comprising LP105, LP061, LP224, LP240, LP239(a), LP243 (a) , LP243 (b) , LP253, LP218, LP251(a), LP252, LP239(b), LP223(a), LP255 (a) , LP244, LP186, LP251(b), LP255(b), or LP223 (b) as shown in SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, or 38, respectively.

9. An isolated polypeptide comprising a sequence of amino acid residues selected from the group consisting of: (a) SEQ ID NO : 2 , 4, 6, 8, 10, 12, 14, 16, 18, 20,

22, 24, 26, 28, 30, 32, 34, 36, or 38; (b) fragments of (a) sufficient to provide a binding site for an LP polypeptide antibody; and

(c) variants of (a) or (b) .

10. An isolated polypeptide produced by the method of Claim 7.

11. A chimeric molecule comprising an LP polypeptide fused to a heterologous amino acid sequence.

12. The chimeric molecule of Claim 11, wherein said heterologous amino acid sequence is an epitope tag sequence.

13. The chimeric molecule of Claim 12, wherein said heterologous amino acid sequence is an Fc region of an immunoglobulin .

14. An antibody which specifically binds to an LP polypeptide.

15. The antibody of Claim 14, where said antibody is a monoclonal antibody .

16. The antibody of Claim 15, wherein said antibody is selected from the group consisting of a humanized antibody and a human antibody.

17. A composition comprising a therapeutically effective amount of an active agent selected from the group consisting of:

(a) an LP polypeptide;

(b) an agonist to an LP polypeptide; (c) an antagonist to an LP polypeptide;

(d) an LP polypeptide antibody;

(e) an anti-LP polypeptide-encoding mRNA specific ribozyme; and (f) a polynucleotide as in Claim 1, in combination with a pharmaceutically acceptable carrier.

18. A method of treating a mammal suffering from a disease, condition, or disorder associated with aberrant levels of an LP-polypeptide comprising administering a therapeutically effective amount of an LP polypeptide or LP polypeptide agonist.

19. A method of diagnosing a disease, condition, or disorder associated with aberrant levels of an LP polypeptide by: (1) culturing test cells or tissues expressing LP polypeptide; (2) administering a compound which can inhibit LP polypeptide modulated signaling; and (3) measuring the LP polypeptide-mediated phenotypic effects in the test cells or tissues.

20. An article of manufacture comprising a container, label and therapeutically effective amount of the composition of Claim 17.

21. Use of an LP polypeptide in the manufacture of a medicament for the treatment of a disease, condition, or disorder associated with aberrant levels of an LP polypeptide. SEQUENCE LISTING

<110> Eli Lilly & Company

<120> Novel secreted proteins and their uses

<130> X-14001

<160> 38

<170> Patentln version 3.0

<210> 1

<211> 1438

<212> DNA

<213> Homo sapiens

<220>

<221> CDS

<222> (69).. (1196)

<220>

<221> mat_peptide

<222> (132) .. ()

<400> 1 ctgagaccct ccttcaacct ccctagagga cagccccact ctgcctcctg ctcccccagg 60 gcagcacc atg tgg ccc ccg tgg etc tgc tgg gca etc tgg gtg ctg ccc 110 Met Trp Pro Pro Trp Leu Cys Trp Ala Leu Trp Val Leu Pro -20 -15 -10 ctg get ggc ccc ggg gcg gcc ctg ace gag gag cag etc ctg ggc age 158 Leu Ala Gly Pro Gly Ala Ala Leu Thr Glu Glu Gin Leu Leu Gly Ser -5 -1 1 5 ctg ctg egg cag ctg cag etc age gag gtg ccc gta ctg gac agg gcc 206 Leu Leu Arg Gin Leu Gin Leu Ser Glu Val Pro Val Leu Asp Arg Ala 10 15 20 25 gac atg gag aag ctg gtc ate ccc gcc cac gtg agg gcc cag tat gta 254 Asp Met Glu Lys Leu Val lie Pro Ala His Val Arg Ala Gin Tyr Val 30 35 40 gtc ctg ctg egg cgc age cac ggg gac cgc tec cgc gga aag agg ttc 302 Val Leu Leu Arg Arg Ser His Gly Asp Arg Ser Arg Gly Lys Arg Phe 45 50 55 age cag age ttc cga gag gtg gcc ggc agg ttc ctg gcg teg gag gcc 350 Ser Gin Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala 60 65 70 age aca cac ctg ctg gtg ttc ggc atg gag cag egg ctg ccg ccc aac 398 Ser Thr His Leu Leu Val Phe Gly Met Glu Gin Arg Leu Pro Pro Asn 75 80 85 age gag ctg gtg cag gcc gtg ctg egg etc ttc cag gag ccg gtc ccc 446 Ser ^' Glu Leu Val Gin Ala Val Leu Arg Leu Phe Gin Glu Pro Val Pro 90 95 100 105 aag gcc gcg ctg cac agg cac ggg egg ctg tec ccg cgc age gcc cag 494 Lys Ala Ala Leu His Arg His Gly Arg Leu Ser Pro Arg Ser Ala Gin 110 115 120 gcc egg gtg get gtc gag tgg ctg cgc gtc cgc gac gac ggc tec aac 542 Ala Arg Val Ala Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn 125 130 135 cgc ace tec etc ate gac tec agg ctg gtg tec gtc cac gag age ggc 590 Arg Thr Ser Leu lie Asp Ser Arg Leu Val Ser Val His Glu Ser Gly 140 ,145 150 tgg aag gcc ttc gac gtg ace gag gcc gtg aac ttc tgg cag cag ctg 638 Trp Lys Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gin Gin Leu 155 160 165 age egg ccc egg cag ccg ctg ctg eta cag gtg teg gtg cag agg gag 686 Ser Arg Pro Arg Gin Pro Leu Leu Leu Gin Val Ser Val Gin Arg Glu 170 175 180 185 cat ctg ggc ccg ctg gcg tec ggc gcc cac aag ctg gtc cgc ttt gcc 734 His Leu Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala 190 195 200 teg cag ggg gcg cca gcc ggg ctt ggg gag ccc cag ctg gag ctg cac 782 Ser Gin Gly Ala Pro Ala Gly Leu Gly Glu Pro Gin Leu Glu Leu His 205 210 215 ace ctg gac etc agg gac tat gga get cag ggc gac tgt gac cct gaa 830 Thr Leu Asp Leu Arg Asp Tyr Gly Ala Gin Gly Asp Cys Asp Pro Glu 220 225 230 gca cca gtg ace gag ggc ace tgc tgc tgc cac cag gag atg tac act 878 Ala Pro Val Thr Glu Gly Thr Cys Cys Cys His Gin Glu Met Tyr Thr 235 240 245 gac ctg cag ggg atg aag tgg gcc aag aac tgg atg ccg gag ccc ctg 926 Asp Leu Gin Gly Met Lys Trp Ala Lys Asn Trp Met Pro Glu Pro Leu 250 255 260 265 ggc ttc ctg get tac aag tgt gtg ggc ace tgc cag cag ccc ctg gag 974 Gly Phe Leu Ala Tyr Lys Cys Val Gly Thr Cys Gin Gin Pro Leu Glu 270 275 280 gcc ctg gcc ttc aat tgg cca ttt ctg ggg ccg cga cac tgc ate gcc 1022 Ala Leu Ala Phe Asn Trp Pro Phe Leu Gly Pro Arg His Cys lie Ala 285 290 295 tea gag act gcc teg ctg ccc atg ate gtc age ate aag gag gga ggc 1070 Ser Glu Thr Ala Ser Leu Pro Met lie Val Ser lie Lys Glu Gly Gly 300 305 310 agg ace agg ccc cag gtg gtc age ctg cct aac atg agg gtc cac cac 1118 Arg Thr Arg Pro Gin Val Val Ser Leu Pro Asn Met Arg Val His His 315 320 325 tac gcc ccg eta atg ttt gtg att tta gta gag atg agg ttt cac cat 1166 Tyr Ala Pro Leu Met Phe Val lie Leu Val Glu Met Arg Phe His His 330 335 340 345 gtt ggc cag get ggt etc aaa etc ctg ace tgaggtgggc ggatcacaag 1216 Val Gly Gin Ala Gly Leu Lys Leu Leu Thr 350 355 gteaggagat cgagaccate ctggctaaca aggtgaaaec ccgtctctac taaaaataca 1276 aaaaattagc tgggtgtegt ggcgggtgcc tgtagtetca ggtactcggg aggctgaggc 1336 aggagaatgg catgaacccg ggaggcggag gttgeagcga gccaagatea cgecaetgca 1396 cttcagcctg ggcaacagag caagactcca tctcaaaaaa aa 1438

<210> 2

<211> 376

<212> PRT

<213> Homo sapiens

<400> 2

Met Trp Pro Pro Trp Leu Cys Trp Ala Leu Trp Val Leu Pro Leu Ala -20 -15 -10

Gly Pro Gly Ala Ala Leu Thr Glu Glu Gin Leu Leu Gly Ser Leu Leu -5 -1 1 5 10

Arg Gin Leu Gin Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met 15 20 25

Glu Lys Leu Val lie Pro Ala His Val Arg Ala Gin Tyr Val Val Leu 30 35 40

Leu Arg Arg Ser His Gly Asp Arg Ser Arg Gly Lys Arg Phe Ser Gin 45 50 55 Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr 60 65 70 75

His Leu Leu Val Phe Gly Met Glu Gin Arg Leu Pro Pro Asn Ser Glu 80 85 90

Leu Val Gin Ala Val Leu Arg Leu Phe Gin Glu Pro Val Pro Lys Ala 95 100 105

Ala Leu His Arg His Gly Arg Leu Ser Pro Arg Ser Ala Gin Ala Arg 110 115 120

Val Ala Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr 125 130 135

Ser Leu lie Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp Lys 140 145 150 155

Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gin Gin Leu Ser Arg 160 165 170

Pro Arg Gin Pro Leu Leu Leu Gin Val Ser Val Gin Arg Glu His Leu 175 180 185

Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser Gin 190 195 200

Gly Ala Pro Ala Gly Leu Gly Glu Pro Gin Leu Glu Leu His Thr Leu 205 210 215

Asp Leu Arg Asp Tyr Gly Ala Gin Gly Asp Cys Asp Pro Glu Ala Pro 220 225 230 235

Val Thr Glu Gly Thr Cys Cys Cys His Gin Glu Met Tyr Thr Asp Leu 240 245 250

Gin Gly Met Lys Trp Ala Lys Asn Trp Met Pro Glu Pro Leu Gly Phe 255 260 265 Leu Ala Tyr Lys Cys Val Gly Thr Cys Gin Gin Pro Leu Glu Ala Leu 270 275 280

Ala Phe Asn Trp Pro Phe Leu Gly Pro Arg His Cys lie Ala Ser Glu 285 290 295

Thr Ala Ser Leu Pro Met lie Val Ser lie Lys Glu Gly Gly Arg Thr 300 305 310 315

Arg Pro Gin Val Val Ser Leu Pro Asn Met Arg Val His His Tyr Ala 320 325 330

Pro Leu Met Phe Val lie Leu Val Glu Met Arg Phe His His Val Gly 335 340 345

Gin Ala Gly Leu Lys Leu Leu Thr 350 355

<210> 3

<211> 1041

<212> DNA

<213> Homo sapiens

<220>

<221> CDS

<222> (66) .. (878)

<220>

<221> mat_peptide

<222> (129).. ()

<400> 3 geggccgcca gtgtgatgga tatetgeaga attegccett aeaaceaagt gageageaea 60 gacta atg agt aga ate aat aag aac gtg gtt ttg gcc ctt tta acg ctg 110 Met Ser Arg lie Asn Lys Asn Val Val Leu Ala Leu Leu Thr Leu -20 -15 -10 aca agt tct gca ttt ctg ctg ttt cag ttg tac tac tac aag cac tat 158 Thr Ser Ser Ala Phe Leu Leu Phe Gin Leu Tyr Tyr Tyr Lys His Tyr -5 -1 1 5 10 tta tea aca aag aat gga get ggt ttg tea aaa tec aaa gga age cga 206 Leu Ser Thr Lys Asn Gly Ala Gly Leu Ser Lys Ser Lys Gly Ser Arg 15 20 25 att gga ttt gat age aca cag tgg cgt gca gtt aaa aaa ttt att atg 254 lie Gly Phe Asp Ser Thr Gin Trp Arg Ala Val Lys Lys Phe lie Met 30 35 40 tta aca tec aac caa aat gta cca gtg ttt ctt att gat cct ttg ata 302 Leu Thr Ser Asn Gin Asn Val Pro Val Phe Leu lie Asp Pro Leu lie 45 50 55 ctg gaa ttg att aat aag aac ttt gaa caa gtc aaa aat act tct cat 350 Leu Glu Leu lie Asn Lys Asn Phe Glu Gin Val Lys Asn Thr Ser His 60 65 70 ggc tct act tea caa tgc aag ttt ttc tgt gtt cca aga gac ttt act 398 Gly Ser Thr Ser Gin- Cys Lys Phe Phe Cys Val Pro Arg Asp Phe Thr 75 80 85 90 gca ttt gca ctg cag tat cac eta tgg aag aat gag gaa ggc tgg ttt 446 Ala Phe Ala Leu Gin Tyr His Leu Trp Lys Asn Glu Glu Gly Trp Phe 95 100 105 egg ata get gag aat atg gga ttt cag tgc eta aag att gag agt aaa 494 Arg lie Ala Glu Asn Met Gly Phe Gin Cys Leu Lys lie Glu Ser Lys 110 115 120 gat ccc egg eta gac ggg ata gac tea etc tct gga act gaa ate ccc 542 Asp Pro Arg Leu Asp Gly lie Asp Ser Leu Ser Gly Thr Glu lie Pro 125 130 135 ctg cac tat ate tgc aaa ctg gcc act cat gcg ate cac ttg gta gtc 590 Leu His Tyr lie Cys Lys Leu Ala Thr His Ala lie His Leu Val Val 140 145 150 ttt cat gag agg agt ggc aac tac etc tgg cac ggc cac ttg aga ctt 638 Phe His Glu Arg Ser Gly Asn Tyr Leu Trp His Gly His Leu Arg Leu 155 160 165 170 aaa gaa cac att gac agg aaa ttt gtt ccc ttc caa aag tta cag ttt 686 Lys Glu His lie Asp Arg Lys Phe Val Pro Phe Gin Lys Leu Gin Phe 175 180 185 ggt cgt tat cca gga get ttt gac agg cca gag tta cag caa gtt act 734 Gly Arg Tyr Pro Gly Ala Phe Asp Arg Pro Glu Leu Gin Gin Val Thr 190 195 200 gtt gat gga ctg gaa gtt etc att cca aag gat cca atg cac ttt gta 782 Val Asp Gly Leu Glu Val Leu lie Pro Lys Asp Pro Met His Phe Val 205 210 215 gaa gaa gta cca cac tct agg ttt att gag tgt agg tat aaa gaa get 830 Glu Glu Val Pro His Ser Arg Phe lie Glu Cys Arg Tyr Lys Glu Ala 220 225 230 cga gca ttc ttt cag ata cct gtt tec gaa gtt tac act gtg ctg gac 878 Arg Ala Phe Phe Gin lie Pro Val Ser Glu Val Tyr Thr Val Leu Asp 235 240 245 250 tgagtttgta gacatgaagg teeatgtaee ctgtgaaacc ctegaataca ttgaagceaa 938 etatggtaag aectggaaga ttcctgtaaa gaegtgggac tggaagcget ctccteeeaa 998 tgtgcaaccc aatggaatct ggcctatttc tgagtgggat gag 1041

<210> 4

<211> 271

<212> PRT

<213> Homo sapiens

<400> 4

Met Ser Arg lie Asn Lys Asn Val Val Leu Ala Leu Leu Thr Leu Thr -20 -15 -10

Ser Ser Ala Phe Leu Leu Phe Gin Leu Tyr Tyr Tyr Lys His Tyr Leu -5 -1 1 5 10

Ser Thr Lys Asn Gly Ala Gly Leu Ser Lys Ser Lys Gly Ser Arg lie 15 20 25

Gly Phe Asp Ser Thr Gin Trp Arg Ala Val Lys Lys Phe lie Met Leu 30 35 40

Thr Ser Asn Gin Asn Val Pro Val Phe Leu lie Asp Pro Leu lie Leu 45 50 55

Glu Leu lie Asn Lys Asn Phe Glu Gin Val Lys Asn Thr Ser His Gly 60 65 70 75

Ser Thr Ser Gin Cys Lys Phe Phe Cys Val Pro Arg Asp Phe Thr Ala 80 85 90

Phe Ala Leu Gin Tyr His Leu Trp Lys Asn Glu Glu Gly Trp Phe Arg 95 100 105

lie Ala Glu Asn Met Gly Phe Gin Cys Leu Lys lie Glu Ser Lys Asp 110 115 120 Pro Arg Leu Asp Gly lie Asp Ser Leu Ser Gly Thr Glu lie Pro Leu 125 130 135

His Tyr lie Cys Lys Leu Ala Thr His Ala lie His Leu Val Val Phe 140 145 150 155

His Glu Arg Ser Gly Asn Tyr Leu Trp His Gly His Leu Arg Leu Lys 160 165 170

Glu His lie Asp Arg Lys Phe Val Pro Phe Gin Lys Leu Gin Phe Gly 175 180 185

Arg Tyr Pro Gly Ala Phe Asp Arg Pro Glu Leu Gin Gin Val Thr Val 190 195 200

Asp Gly Leu Glu Val Leu lie Pro Lys Asp Pro Met His Phe Val Glu 205 210 215

Glu Val Pro His Ser Arg Phe lie Glu Cys Arg Tyr Lys Glu Ala Arg 220 225 230 235

Ala Phe Phe Gin lie Pro Val Ser Glu Val Tyr Thr Val Leu Asp 240 245 250

<210> 5

<211> 3664

<212> DNA

<213> Homo sapiens

<220>

<221> CDS

<222> (347) .. (1981)

<220>

<221> mutation

<222> (383).. (385)

<223> variant wherein nucleotides 383-385 are deleted

<220>

<221> mat_peptide

<222> (416).. () <220>

<221> sig_peptide

<222> (1) .. (23)

<223> wherein Leu at position -11 may be deleted

<400> 5 gccggcgctg gccccctccc ccgcggggeg ggceccgcca tgeattattc attggeeaga 60 geegggetgc gggcgcgagt getgatgtca ggeaggcgcg agtgcggegg gcgcagcgge 120 ggcggccgcc cagcagcccg ggctcgggtg ggggggcgcc gagtgggggt ggcggccagc 180 atgctgctcg gctgcggctc ggcctcccac acccgcggct ccctagtcct cgccagcagc 240 ggcggeggea gagcagcgag cggcgeeegc gtctgcageg gegccgggte egagcgcgcg 300 gcgcggcggt gggggtcggg gcccgggcgg ggagcgggga ccgggc atg gcg ctg 355

Met Ala Leu

egg aga ggc ggc tgc gga gcg etc ggg ctg ctg ctg ctg ctg ctg ggc 403 Arg Arg Gly Gly Cys Gly Ala Leu Gly Leu Leu Leu Leu Leu Leu Gly -20 -15 -10 -5 gcc gcg tgc ctg ata ccg egg age gcg cag gtg agg egg ctg gcg cgc 451 Ala Ala Cys Leu lie Pro Arg Ser Ala Gin Val Arg Arg Leu Ala Arg -1 1 5 10 tgc ccc gcc act tgc age tgt ace aag gag tct ate ate tgc gtg ggc 499 Cys Pro Ala Thr Cys Ser Cys Thr Lys Glu Ser lie lie Cys Val Gly 15 20 25 tct tec tgg gtg ccc agg ate gtg ccg ggc gac ate age tec ctg age 547 Ser Ser Trp Val Pro Arg lie Val Pro Gly Asp lie Ser Ser Leu Ser 30 35 40 ctg gta aat ggg acg ttt tea gaa ate aag gac cga atg ttt tec cat 595 Leu Val Asn Gly Thr Phe Ser Glu lie Lys Asp Arg Met Phe Ser His 45 50 55 60 ctg cct tct ctg cag ctg eta ttg ctg aat tct aac tea ttc acg ate 643 Leu Pro Ser Leu Gin Leu Leu Leu Leu Asn Ser Asn Ser Phe Thr lie 65 70 75 ate egg gat gat get ttt get gga ctt ttt cat ctt gaa tac ctg ttc 691 lie Arg Asp Asp Ala Phe Ala Gly Leu Phe His Leu Glu Tyr Leu Phe 80 85 90 att gaa ggg aac aaa ata gaa ace att tea aga aat gcc ttt cgt ggc 739 lie Glu Gly Asn Lys lie Glu Thr lie Ser Arg Asn Ala Phe Arg Gly 95 100 105 etc cgt gac ctg act cac ctt tct ttg gcc aat aac cac ata aaa gca 787 Leu Arg Asp Leu Thr His Leu Ser Leu Ala Asn Asn His lie Lys Ala 110 115 120 eta cca agg gat gtc ttc agt gat tta gac tct ctg att gaa eta gat 835 Leu Pro Arg Asp Val Phe Ser Asp Leu Asp Ser Leu lie Glu Leu Asp 125 130 135 140 ttg agg ggt aat aaa ttt gaa tgt gac tgc aaa gcc aag tgg eta tac 883 Leu Arg Gly Asn Lys Phe Glu Cys Asp Cys Lys Ala Lys Trp Leu Tyr 145 150 155 ctg tgg ttg aag atg aca aat tec ace gtt tct gat gtg ctg tgt att 931 Leu Trp Leu Lys Met Thr Asn Ser Thr Val Ser Asp Val Leu Cys lie 160 165 170 ggt cca cca gag tat cag gaa aag aag eta aat gac gtg ace age ttt 979 Gly Pro Pro Glu Tyr Gin Glu Lys Lys Leu Asn Asp Val Thr Ser Phe 175 180 185 gac tat gaa tgc aca act aca gat ttt gtt gtt cat cag act tta ccc 1027 Asp Tyr Glu Cys Thr Thr Thr Asp Phe Val Val His Gin Thr Leu Pro 190 195 200 tac cag teg gtt tea gtg gat acg ttc aac tec aag aac gat gtg tac 1075 Tyr Gin Ser Val Ser Val Asp Thr Phe Asn Ser Lys Asn Asp Val Tyr 205 210 215 220 gtg gcc ate gcg cag ccc age atg gag aac tgc atg gtg ctg gag tgg 1123 Val Ala lie Ala Gin Pro Ser Met Glu Asn Cys Met Val Leu Glu Trp 225 230 235 gac cac att gaa atg aat ttc egg age tat gac aac att aca ggt cag 1171 Asp His lie Glu Met Asn Phe Arg Ser Tyr Asp Asn lie Thr Gly Gin 240 245 250 tec ate gtg ggc tgt aag gcc att etc ate gat gat cag gtc ttt gtg 1219 Ser lie Val Gly Cys Lys Ala lie Leu lie Asp Asp Gin Val Phe Val 255 260 265 gtg gta gcc cag etc ttc ggt ggc tct cac att tac aaa tac gac gag 1267 Val Val Ala Gin Leu Phe Gly Gly Ser His lie Tyr Lys Tyr Asp Glu 270 275 280 agt tgg ace aaa ttt gtc aaa ttc caa gac ata gag gtc tct cgc att 1315 Ser Trp Thr Lys Phe Val Lys Phe Gin Asp lie Glu Val Ser Arg lie 285 290 295 300 tec aag ccc aat gac ate gag ctg ttt cag ate gac gac gag acg ttc 1363 Ser Lys Pro Asn Asp lie Glu Leu Phe Gin lie Asp Asp Glu Thr Phe 305 310 315 ttt gtc ate gca gac age tea aag get ggt ctg tec aca gtt tat aaa 1411 Phe Val lie Ala Asp Ser Ser Lys Ala Gly Leu Ser Thr Val Tyr Lys 320 325 330 tgg aac age aaa gga ttc tat tct tac cag tea ctg cac gag tgg ttc 1459 Trp Asn Ser Lys Gly Phe Tyr Ser Tyr Gin Ser Leu His Glu Trp Phe 335 340 345 a g gac acg gat gcg gag ttt gtt gat ate gat gga aaa teg cat etc 1507 Arg Asp Thr Asp Ala Glu Phe Val Asp lie Asp Gly Lys Ser His Leu 350 355 360 ate ctg tec age cgc tec cag gtc ccc ate ate etc cag tgg aat aaa 1555 lie Leu Ser Ser Arg Ser Gin Val Pro lie lie Leu Gin Trp Asn Lys 365 370 375 380 age tct aag aag ttt gtc ccc cat ggt gac ate ccc aac atg gag gac 1603 Ser Ser Lys Lys Phe Val Pro His Gly Asp lie Pro Asn Met Glu Asp 385 390 395 gta ctg get gtg aag age ttc cga atg caa aat ace etc tac ctt tec 1651 Val Leu Ala Val Lys Ser Phe Arg Met Gin Asn Thr Leu Tyr Leu Ser 400 405 410 ctt ace cgc ttc ate ggg gac tec egg gtc atg agg tgg aac agt aag 1699 Leu Thr Arg Phe lie Gly Asp Ser Arg Val Met Arg Trp Asn Ser Lys 415 420 425 cag ttt gtg gag ate caa get ctt cca tec egg ggg gcc atg ace ctg 1747 Gin Phe Val Glu lie Gin Ala Leu Pro Ser Arg Gly Ala Met Thr Leu 430 435 440 cag ccc ttt tct ttt aaa gat aat cac tac ctg gcc ctg ggg agt gac 1795 Gin Pro Phe Ser Phe Lys Asp Asn His Tyr Leu Ala Leu Gly Ser Asp 445 450 455 460 tat aca ttc tct cag ata tac cag tgg gat aaa gag aag cag eta ttc 1843 Tyr Thr Phe Ser Gin lie Tyr Gin Trp Asp Lys Glu Lys Gin Leu Phe 465 470 475 aaa aag ttt aag gag att tac gtg cag gcg cct cgt tea ttc aca get 1891 Lys Lys Phe Lys Glu lie Tyr Val Gin Ala Pro Arg Ser Phe Thr Ala 480 485 490 gtc tec ace gac agg aga gat ttc ttt ttt gca tec agt ttc aaa ggg 1939 Val Ser Thr Asp Arg Arg Asp Phe Phe Phe Ala Ser Ser Phe Lys Gly 495 500 505 aaa aca aag att ttt gaa cat ata att gtt gac tta agt ttg 1981

Lys Thr Lys lie Phe Glu His lie lie Val Asp Leu Ser Leu 510 515 520 tgaaggtgtg gtgggtgaaa ctaagagaaa tgtagcatta getctcaeaa aagaggacca 2041 agaaaaatca acaaacaaat caaagccagg ctcagagctc tgaaattaaa aagcactgaa 2101 atagttagat gtttteaaac ttttagaact eaeattttaa tcagggattg eatttattgg 2161 ctaactgcat gacatgccca ttctaccatt ttaaaaaaaa tcttaaagcc tgtaatttct 2221 gagaaaagag tacagcattt actcttatca tctagaaatg taatatgctt cccccccgct 2281 ttttgatgag gaagaagaca attggataag atgggacagc acttataatg aaataaaaaa 2341 aaactttgag cccctctcat tccactttag caatcttttt ggtaagaact cttaaagcca 2401 aaagtctgct gaaaagattt gctgattatt agtttaaaaa tettgtaaca ctcagcagtg 2461 ctattttgag tcatcccagt ttcctgaaag taatgcccag tcttcctgaa tcctccttaa 2521 tagcagaacc ttggtgattt tgttggctca tatgaatgct tgtcatggat atgttaacaa 2581 tttagtgttt gacattgctt cctctgccac aaagacaata ctctggtgac acatgtctag 2641 acccagcaca ggctgtaggc ccaggagtga ctcaaaggag tttttccctc tttcttacgg 2701 ttcaaaggtg accctggtgg tggccagagc agtaatgctt gtttgatgct cttcatggct 2761 catctgcttc tcagaaccca cccgttgagt ttgtgggtaa ccagcaggca ggccaaagac 2821 tggtgctttt catttcatcc tttagaggga tgaaacagtt atttccgtct gatgagcatt 2881 cggtagaatt tttgaagtga gattttatga agtcaaaggg gactttacac agatctcgac 2941 ctgctttgaa acctagaggt ggccctttga tttgtgcgtg tccttgccct ctggacaact 3001 taatatttca agtaatcgaa taccaacttc cctgccagcc cacctgcctt ccgccccgct 3061 tgtgtaacag tcctgttttg ttgagttgct gctattgcac tgccagtgca gcccacacca 3121 aatcaeaaec caagataetc agataggaag actcctteet etceeagtac tttaccaaag 3181 gaacccccgc caggacccac atggggccac gtgttggcag tggaatcagc ctgtgcaggc 3241 tggggatctc aggctgatca gtaggggcca gctttggagc cagccaagct gaatcccaca 3301 ctccaggtct gtgctcaaga gaccagatgg tgtatttcca aatgggcctc tctggtatgg 3361 gcaataggca agctcctggg gtctggttat gtggaagatt cttagtggat gttccgcctg 3421 gttagctggt tctcttcaga gaatataaag tgaatgcctt taggggtagc tctgaaagag 3481 aaacccaaca acttcattcc tagccatgaa agtagcacga tcatattgta ctgtattgtt 3541 attgtaaaat gactatttgc catgtcatga gtaggtagat gttttgccac aaatatgaat 3601 gtgtttgttg tttcetgact ttaagcaatg aagattgaga caataaatag cactcagaga 3661 atg 3664

<210> 6

<211> 545

<212> PRT

<213> Homo sapiens

<400> 6

Met Ala Leu Arg Arg Gly Gly Cys Gly Ala Leu Gly Leu Leu Leu Leu -20 -15 -10

Leu Leu Gly Ala Ala Cys Leu lie Pro Arg Ser Ala Gin Val Arg Arg -5 -1 1 5

Leu Ala Arg Cys Pro Ala Thr Cys Ser Cys Thr Lys Glu Ser lie lie 10 15 20 25

Cys Val Gly Ser Ser Trp Val Pro Arg lie Val Pro Gly Asp lie Ser 30 35 40

Ser Leu Ser Leu Val Asn Gly Thr Phe Ser Glu lie Lys Asp Arg Met 45 50 55

Phe Ser His Leu Pro Ser Leu Gin Leu Leu Leu Leu Asn Ser Asn Ser 60 65 70

Phe Thr lie lie Arg Asp Asp Ala Phe Ala Gly Leu Phe His Leu Glu 75 80 85

Tyr Leu Phe lie Glu Gly Asn Lys lie Glu Thr lie Ser Arg Asn Ala 90 95 100 105

Phe Arg Gly Leu Arg Asp Leu Thr His Leu Ser Leu Ala Asn Asn His 110 115 120

lie Lys Ala Leu Pro Arg Asp Val Phe Ser Asp Leu Asp Ser Leu lie 125 130 135

Glu Leu Asp Leu Arg Gly Asn Lys Phe Glu Cys Asp Cys Lys Ala Lys 140 145 150 Trp Leu Tyr Leu Trp Leu Lys Met Thr Asn Ser Thr Val Ser Asp Val 155 160 165

Leu Cys lie Gly Pro Pro Glu Tyr Gin Glu Lys Lys Leu Asn Asp Val 170 175 180 185

Thr Ser Phe Asp Tyr Glu Cys Thr Thr Thr Asp Phe Val Val His Gin 190 195 200

Thr Leu Pro Tyr Gin Ser Val Ser Val Asp Thr Phe Asn Ser Lys Asn 205 210 215

Asp Val Tyr Val Ala lie Ala Gin Pro Ser Met Glu Asn Cys Met Val 220 225 230

Leu Glu Trp Asp His lie Glu Met Asn Phe Arg Ser Tyr Asp Asn lie 235 240 245

Thr Gly Gin Ser lie Val Gly Cys Lys Ala lie Leu lie Asp Asp Gin 250 255 260 265

Val Phe Val Val Val Ala Gin Leu Phe Gly Gly Ser His lie Tyr Lys 270 275 280

Tyr Asp Glu Ser Trp Thr Lys Phe Val Lys Phe Gin Asp lie Glu Val 285 290 295

Ser Arg lie Ser Lys Pro Asn Asp lie Glu Leu Phe Gin lie Asp Asp 300 305 310

Glu Thr Phe Phe Val lie Ala Asp Ser Ser Lys Ala Gly Leu Ser Thr 315 320 325

Val Tyr Lys Trp Asn Ser Lys Gly Phe Tyr Ser Tyr Gin Ser Leu His 330 335 340 345

Glu Trp Phe Arg Asp Thr Asp Ala Glu Phe Val Asp lie Asp Gly Lys 350 355 360 Ser His Leu lie Leu Ser Ser Arg Ser Gin Val Pro lie lie Leu Gin 365 370 375

Trp Asn Lys Ser Ser Lys Lys Phe Val Pro His Gly Asp lie Pro Asn 380 385 390

Met Glu Asp Val Leu Ala Val Lys Ser Phe Arg Met Gin Asn Thr Leu 395 400 405

Tyr Leu Ser Leu Thr Arg Phe lie Gly Asp Ser Arg Val Met Arg Trp 410 415 420 425

Asn Ser Lys Gin Phe Val Glu lie Gin Ala Leu Pro Ser Arg Gly Ala 430 435 440

Met Thr Leu Gin Pro Phe Ser Phe Lys Asp Asn His Tyr Leu Ala Leu 445 450 455

Gly Ser Asp Tyr Thr Phe Ser Gin lie Tyr Gin Trp Asp Lys Glu Lys 460 465 470

Gin Leu Phe Lys Lys Phe Lys Glu lie Tyr Val Gin Ala Pro Arg Ser 475 480 485

Phe Thr Ala Val Ser Thr Asp Arg Arg Asp Phe Phe Phe Ala Ser Ser 490 495 500 505

Phe Lys Gly Lys Thr Lys lie Phe Glu His lie lie Val Asp Leu Ser 510 515 520

Leu

<210> 7

<211> 898

<212> DNA

<213> Homo sapiens

<220>

<221> CDS

<222> (19) .. (642) <220>

<221> mat_peptide

<222> (64) .. ()

<400> 7 cggcgggccg ggacgggc atg gcc ctg ctg ctg tgc ctg gtg tgc ctg acg 51

Met Ala Leu Leu Leu Cys Leu Val Cys Leu Thr -15 -10 -5 gcg gcg ctg gcc cac ggc tgt ctg cac tgc cac age aac ttc tec aag 99 Ala Ala Leu Ala His Gly Cys Leu His Cys His Ser Asn Phe Ser Lys -1 1 5 10 aag ttc tec ttc tac cgc cac cat gtg aac ttc aag tec tgg tgg gtg 147 Lys Phe Ser Phe Tyr Arg His His Val Asn Phe Lys Ser Trp Trp Val 15 20 25 ggc gac ate ccc gtg tea ggg gcg ctg etc ace gac tgg age gac gac 195 Gly Asp lie Pro Val Ser Gly Ala Leu Leu Thr Asp Trp Ser Asp Asp 30 35 40 acg atg aag gag ctg cac ctg gcc ate ccc gcc aag ate ace egg gag 243 Thr Met Lys Glu Leu His Leu Ala lie Pro Ala Lys lie Thr Arg Glu 45 50 55 60 aag ctg gac caa gtg gcg aca gca gtg tac cag atg atg gat cag ctg 291 Lys Leu Asp Gin Val Ala Thr Ala Val Tyr Gin Met Met Asp Gin Leu 65 70 75 tac cag ggg aag atg tac ttc ccc ggg tat ttc ccc aac gag ctg cga 339 Tyr Gin Gly Lys Met Tyr Phe Pro Gly Tyr Phe Pro Asn Glu Leu Arg 80 85 90 aac ate ttc egg gag cag gtg cac etc ate cag aac gcc ate ate gaa 387 Asn lie Phe Arg Glu Gin Val His Leu lie Gin Asn Ala lie lie Glu 95 100 105 age cgc ate gac tgt cag cac cgc tgt ggc ate ttc cag tac gag ace 435 Ser Arg lie Asp Cys Gin His Arg Cys Gly lie Phe Gin Tyr Glu Thr 110 115 120 ate tec tgc aac aac tgc aca gac teg cac gtc gcc tgc ttt ggc tat 483 lie Ser Cys Asn Asn Cys Thr Asp Ser His Val Ala Cys Phe Gly Tyr 125 130 135 140 aac tgc gag tec teg gcg cag tgg aag tea get gtc cag ggc etc ctg 531 Asn Cys Glu Ser Ser Ala Gin Trp Lys Ser Ala Val Gin Gly Leu Leu 145 150 155 aac tac ata aat aac tgg cac aac ctg gta teg cca gcc tta agg tgt 579 Asn Tyr lie Asn Asn Trp His Asn Leu Val Ser Pro Ala Leu Arg Cys 160 165 170 ctg gag ccc cca cac ttg gcc aac ctg ace ttg gaa aat get get gag 627 Leu Glu Pro Pro His Leu Ala Asn Leu Thr Leu Glu Asn Ala Ala Glu 175 180 185 tgt etc aag cag cac tgacagcagc tgggcctgcc ccagggcaac gtgggggcgg 682 Cys Leu Lys Gin His 190 agaeteaget ggacagcccc tgeetgtcac tctggagetg ggctgctgct geetcaggac 742 cccctctccg aeeeeggaca gagctgaget ggccagggcc aggagggcgg gagggaggga 802 atgggggtgg gctgtgcgea gcatcagcge ctgggcaggt eegeagagct gcgggatgtg 862 attaaagtcc ctgatgtttc tcaaaaaaaa aaaaaa 898

<210> 8

<211> 208

<212> PRT

<213> Homo sapiens

<400> 8

Met Ala Leu Leu Leu Cys Leu Val Cys Leu Thr Ala Ala Leu Ala His -15 -10 -5 -1 1

Gly Cys Leu His Cys His Ser Asn Phe Ser Lys Lys Phe Ser Phe Tyr 5 10 15

Arg His His Val Asn Phe Lys Ser Trp Trp Val Gly Asp lie Pro Val 20 25 30

Ser Gly Ala Leu Leu Thr Asp Trp Ser Asp Asp Thr Met Lys Glu Leu 35 40 45

His Leu Ala lie Pro Ala Lys lie Thr Arg Glu Lys Leu Asp Gin Val 50 55 60 65

Ala Thr Ala Val Tyr Gin Met Met Asp Gin Leu Tyr Gin Gly Lys Met 70 75 80

Tyr Phe Pro Gly Tyr Phe Pro Asn Glu Leu Arg Asn lie Phe Arg Glu 85 90 95

Gin Val His Leu lie Gin Asn Ala lie lie Glu Ser Arg He Asp Cys 100 105 110 Gin His Arg Cys Gly He Phe Gin Tyr Glu Thr He Ser Cys Asn Asn 115 120 125

Cys Thr Asp Ser His Val Ala Cys Phe Gly Tyr Asn Cys Glu Ser Ser 130 135 140 145

Ala Gin Trp Lys Ser Ala Val Gin Gly Leu Leu Asn Tyr He Asn Asn 150 155 160

Trp His Asn Leu Val Ser Pro Ala Leu Arg Cys Leu Glu Pro Pro His 165 170 175

Leu Ala Asn Leu Thr Leu Glu Asn Ala Ala Glu Cys Leu Lys Gin His 180 185 190

<210> 9

<211> 1580

<212> DNA

<213> Homo sapiens

<220>

<221> CDS

<222> (136) .. (1386)

<220>

<221> mat_peptide

<222> (196) .. ()

<400> 9 ctcaattett aaaaaataag tecatgaage agaaacatea aaaageatgg gatttggaat 60 ttgagaeetg actttgaage ccacacagaa caeagaeaag teaaccatgc tatttgggac 120 atattttgtt ccaaa atg gca tct tac ctt tat gga gta etc ttt get gtt 171 Met Ala Ser Tyr Leu Tyr Gly Val Leu Phe Ala Val -20 -15 -10 ggc etc tgt get cca ate tac tgt gtg tec ccg gcc aat gcc ccc agt 219 Gly Leu Cys Ala Pro He Tyr Cys Val Ser Pro Ala Asn Ala Pro Ser -5 -1 1 5 gca tac ccc cgc cct tec tec aca aag age ace cct gcc tea cag gtg 267 Ala Tyr Pro Arg Pro Ser Ser Thr Lys Ser Thr Pro Ala Ser Gin Val 10 15 20 tat tec etc aac ace gac ttt gcc ttc cgc eta tac cgc agg ctg gtt 315 Tyr Ser Leu Asn Thr Asp Phe Ala Phe Arg Leu Tyr Arg Arg Leu Val 25 30 35 40 ttg gag ace ccg agt cag aac ate ttc ttc tec cct gtg agt gtc tec 363 Leu Glu Thr Pro Ser Gin Asn He Phe Phe Ser Pro Val Ser Val Ser 45 50 55 act tec ctg gcc atg etc tec ctt ggg gcc cac tea gtc ace aag ace 411 Thr Ser Leu Ala Met Leu Ser Leu Gly Ala His Ser Val Thr Lys Thr 60 65 70 cag att etc cag ggc ctg ggc ttc aac etc aca cac aca cca gag tct 459 Gin He Leu Gin Gly Leu Gly Phe Asn Leu Thr His Thr Pro Glu Ser 75 80 85 gcc ate cac cag ggc ttc cag cac ctg gtt cac tea ctg act gtt ccc 507 Ala He His Gin Gly Phe Gin His Leu Val His -Ser Leu Thr Val Pro 90 95 100 age aaa gac ctg ace ttg aag atg gga agt gcc etc ttc gtc aag aag 555 Ser Lys Asp Leu Thr Leu Lys Met Gly Ser Ala Leu Phe Val Lys Lys 105 110 115 120 gag ctg cag ctg cag gca aat ttc ttg ggc aat gtc aag agg ctg tat 603 Glu Leu Gin Leu Gin Ala Asn Phe Leu Gly Asn Val Lys Arg Leu Tyr 125 130 135 gaa gca gaa gtc ttt tct aca gat ttc tec aac ccc tec att gcc cag 651 Glu Ala Glu Val Phe Ser Thr Asp Phe Ser Asn Pro Ser He Ala Gin 140 145 150 gcg agg ate aac age cat gtg aaa aag aag ace caa ggg aag gtt gta 699 Ala Arg He Asn Ser His Val Lys Lys Lys Thr Gin Gly Lys Val Val 155 160 165 gac ata ate caa ggc ctt gac ctt ctg acg gcc atg gtt ctg gtg aac 747 Asp He He Gin Gly Leu Asp Leu Leu Thr Ala Met Val Leu Val Asn 170 175 180 cac att ttc ttt aaa gcc aag tgg gag aag ccc ttt cac cct gaa tat 795 His He Phe Phe Lys Ala Lys Trp Glu Lys Pro Phe His Pro Glu Tyr 185 190 195 200 aca aga aag aac ttc cca ttc ctg gtg ggc gag cag gtc act gtg cat 843 Thr Arg Lys Asn Phe Pro Phe Leu Val Gly Glu Gin Val Thr Val His 205 210 215 gtc ccc atg atg cac cag aaa gag cag ttc get ttt ggg gtg gat aca 891 Val Pro Met Met His Gin Lys Glu Gin Phe Ala Phe Gly Val Asp Thr 220 225 230 gag ctg aac tgc ttt gtg ctg cag atg gat tac aag gga gat gcc gtg 939 Glu Leu Asn Cys Phe Val Leu Gin Met Asp Tyr Lys Gly Asp Ala Val 235 240 245 gcc ttc ttt gtc etc cct age aag ggc aag atg agg caa ctg gaa cag 987 Ala Phe Phe Val Leu Pro Ser Lys Gly Lys Met Arg Gin Leu Glu Gin 250 255 260 gcc ttg tea gcc aga aca ctg aga aag tgg age cac tea etc cag aaa 1035 Ala Leu Ser Ala Arg Thr Leu Arg Lys Trp Ser His Ser Leu Gin Lys 265 270 275 280 agg tgg ata gag gtg ttc ate ccc aga ttt tec att tct gcc tec tac 1083 Arg Trp He Glu Val Phe He Pro Arg Phe Ser He Ser Ala Ser Tyr 285 290 295 aat ctg gaa ace ate etc ccg aag atg ggc ate caa aat gtc ttt gac 1131 Asn Leu Glu Thr He Leu Pro Lys Met Gly He Gin Asn Val Phe Asp 300 305 310 aaa aat get gat ttt tct gga att gca aag aga gac tec ctg cag gtt 1179 Lys Asn Ala Asp Phe Ser Gly He Ala Lys Arg Asp Ser Leu Gin Val 315 320 325 tct aaa gca ace cac aag get gtg ctg gat gtc agt gaa gag ggc act 1227 Ser Lys Ala Thr His Lys Ala Val Leu Asp Val Ser Glu Glu Gly Thr 330 335 340 gag gcc aca gca get ace ace ace aag ttc ata gtc cga teg aag gat 1275 Glu Ala Thr Ala Ala Thr Thr Thr Lys Phe He Val Arg Ser Lys Asp 345 350 355 360 ggc ccc tct tac ttc act gtc tec ttc aat agg ace ttc ctg atg atg 1323 Gly Pro Ser Tyr Phe Thr Val Ser Phe Asn Arg Thr Phe Leu Met Met 365 370 375 att aca aat aaa gcc aca gac ggt att etc ttt eta ggg aaa gtg gaa 1371 He Thr Asn Lys Ala Thr Asp Gly He Leu Phe Leu Gly Lys Val Glu 380 385 390 aat ccc act aaa tec taggtgggaa atggcctgtt aactgatggc acattgctaa 1426 Asn Pro Thr Lys Ser 395 tgcaeaagaa ataacaaaee aeatcectct ttctgttctg agggtgeatt tgaeeceagt 1486 ggagctggat tcgctggeag ggatgccaet teeaaggcte aatcaccaaa ecatcaaeag 1546 ggaccccagt cacaagccaa cacccattaa cccc 1580 <210> 10

<211> 417

<212> PRT

<213> Homo sapiens

<400> 10

Met Ala Ser Tyr Leu Tyr Gly Val Leu Phe Ala Val Gly Leu Cys Ala -20 -15 -10 -5

Pro He Tyr Cys Val Ser Pro Ala Asn Ala Pro Ser Ala Tyr Pro Arg -1 1 5 10

Pro Ser Ser Thr Lys Ser Thr Pro Ala Ser Gin Val Tyr Ser Leu Asn 15 20 25

Thr Asp Phe Ala Phe Arg Leu Tyr Arg Arg Leu Val Leu Glu Thr Pro 30 35 40

Ser Gin Asn He Phe Phe Ser Pro Val Ser Val Ser Thr Ser Leu Ala 45 50 55 60

Met Leu Ser Leu Gly Ala His Ser Val Thr Lys Thr Gin He Leu Gin 65 70 75

Gly Leu Gly Phe Asn Leu Thr His Thr Pro Glu Ser Ala He His Gin 80 85 90

Gly Phe Gin His Leu Val His Ser Leu Thr Val Pro Ser Lys Asp Leu 95 100 105

Thr Leu Lys Met Gly Ser Ala Leu Phe Val Lys Lys Glu Leu Gin Leu 110 115 120

Gin Ala Asn Phe Leu Gly Asn Val Lys Arg Leu Tyr Glu Ala Glu Val 125 130 135 140

Phe Ser Thr Asp Phe Ser Asn Pro Ser He Ala Gin Ala Arg He Asn 145 150 155

Ser His Val Lys Lys Lys Thr Gin Gly Lys Val Val Asp He He Gin 160 165 170 Gly Leu Asp Leu Leu Thr Ala Met Val Leu Val Asn His He Phe Phe 175 180 185

Lys Ala Lys Trp Glu Lys Pro Phe His Pro Glu Tyr Thr Arg Lys Asn 190 195 200

Phe Pro Phe Leu Val Gly Glu Gin Val Thr Val His Val Pro Met Met 205 210 215 220

His Gin Lys Glu Gin Phe Ala Phe Gly Val Asp Thr Glu Leu Asn Cys 225 230 235

Phe Val Leu Gin Met Asp Tyr Lys Gly Asp Ala Val Ala Phe Phe Val 240 245 250

Leu Pro Ser Lys Gly Lys Met Arg Gin Leu Glu Gin Ala Leu Ser Ala 255 260 265

Arg Thr Leu Arg Lys Trp Ser His Ser Leu Gin Lys Arg Trp He Glu 270 275 280

Val Phe He Pro Arg Phe Ser He Ser Ala Ser Tyr Asn Leu Glu Thr 285 290 295 300

He Leu Pro Lys Met Gly He Gin Asn Val Phe Asp Lys Asn Ala Asp 305 310 315

Phe Ser Gly He Ala Lys Arg Asp Ser Leu Gin Val Ser Lys Ala Thr 320 325 330

His Lys Ala Val Leu Asp Val Ser Glu Glu Gly Thr Glu Ala Thr Ala 335 340 345

Ala Thr Thr Thr Lys Phe He Val Arg Ser Lys Asp Gly Pro Ser Tyr 350 355 360

Phe Thr Val Ser Phe Asn Arg Thr Phe Leu Met Met He Thr Asn Lys 365 370 375 380 Ala Thr Asp Gly He Leu Phe Leu Gly Lys Val Glu Asn Pro Thr Lys 385 390 395

Ser

<210> 11

<211> 2080

<212> DNA

<213> Homo sapiens

<220>

<221> CDS

<222> (12) . .. (1682)

<220>

<221> mat_peptide

<222> (96).. ()

<220>

<221> variation

<222> (82).. (82)

<223> wherein n is A, G, C, or T

<400> 11 tcaceaeeat c atg gtg tec ace gcc atg ggc tgc ate ace ttc ctg ggc 50 Met Val Ser Thr Ala Met Gly Cys He Thr Phe Leu Gly -25 -20 gtg gtc etc ttg ctg ctt teg tgc tgc tgt tnc gtg tgg age cgc aac 98 Val Val Leu Leu Leu Leu Ser Cys Cys Cys Xaa Val Trp Ser Arg Asn -15 -10 -5 -1 1 cgc ate cgc tgc ctg aac ccg ggc gac ctg gcc gcg ctg ccc gcg ctg 146 Arg He Arg Cys Leu Asn Pro Gly Asp Leu Ala Ala Leu Pro Ala Leu 5 10 15 gag gag ctg gac ctg age gag aac gcc ate gcg cac gtg gag ccc ggc 194 Glu Glu Leu Asp Leu Ser Glu Asn Ala He Ala His Val Glu Pro Gly 20 25 30 gcc ttc gcc aac ctg ccg cgc ctg cgc gtc ctg cgt etc cgt ggc aac 242 Ala Phe Ala Asn Leu Pro Arg Leu Arg Val Leu Arg Leu Arg Gly Asn 35 40 45 cag ctg aag etc ate ccg ccc ggg gtc ttc acg cgc ctg gac aac etc 290 Gin Leu Lys Leu He Pro Pro Gly Val Phe Thr Arg Leu Asp Asn Leu 50 55 60 65 acg ctg ctg gac ctg age gag aac aag ctg gta ate ctg ctg gac tac 338 Thr Leu Leu Asp Leu Ser Glu Asn Lys Leu Val He Leu Leu Asp Tyr 70 75 80 act ttc cag gac ctg cac age ctg cgc egg ctg gaa gtg ggc gac aac 386 Thr Phe Gin Asp Leu His Ser Leu Arg Arg Leu Glu Val Gly Asp Asn 85 90 95 gac ctg gta ttc gtc teg cgc cgc gcc ttc gcg ggg ctg ctg gcc ctg 434 Asp Leu Val Phe Val Ser Arg Arg Ala Phe Ala Gly Leu Leu Ala Leu 100 105 110 gag gag ctg ace ctg gag cgc tgc aac etc acg get ctg tec ggg gag 482 Glu Glu Leu Thr Leu Glu Arg Cys Asn Leu Thr Ala Leu Ser Gly Glu 115 120 125 teg ctg ggc cat ctg cgc age ctg ggc gcc ctg egg ctg cgc cac ctg 530 Ser Leu Gly His Leu Arg Ser Leu Gly Ala Leu Arg Leu Arg His Leu 130 135 140 145 gcc ate gcc tec ctg gag gac cag aac ttc cgc agg ctg ccc ggg ctg 578 Ala He Ala Ser Leu Glu Asp Gin Asn Phe Arg Arg Leu Pro Gly Leu 150 155 160 ctg cac ctg gag att gac aac tgg ccg ctg ctg gag gag gtg gcg gcg 626 Leu His Leu Glu He Asp Asn Trp Pro Leu Leu Glu Glu Val Ala Ala 165 170 175 ggc age ctg egg ggc ctg aac ctg ace teg ctg teg gtc ace cac ace 674 Gly Ser Leu Arg Gly Leu Asn Leu Thr Ser Leu Ser Val Thr His Thr 180 185 190 aac ate ace gcc gtg ccg gcc gcc gcg ctg egg cac cag gcg cac etc 722 Asn He Thr Ala Val Pro Ala Ala Ala Leu Arg His Gin Ala His Leu 195 200 205 ace tgc etc aat ctg teg cac aac ccc ate age acg gtg ccg egg ggg 770 Thr Cys Leu Asn Leu Ser His Asn Pro He Ser Thr Val Pro Arg Gly 210 215 220 225 teg ttc egg gac ctg gtc cgc ctg cgc gag ctg cac ctg gcc ggg gcc 818 Ser Phe Arg Asp Leu Val Arg Leu Arg Glu Leu His Leu Ala Gly Ala 230 235 240 ctg ctg get gtg gtg gag ccg cag gcc ttc ctg ggc ctg cgc cag ate 866 Leu Leu Ala Val Val Glu Pro Gin Ala Phe Leu Gly Leu Arg Gin He 245 250 255 cgc ctg etc aac etc tec aac aac ctg etc tec acg ttg gag gag age 914 Arg Leu Leu Asn Leu Ser Asn Asn Leu Leu Ser Thr Leu Glu Glu Ser 260 265 270 ace ttc cac teg gtg aac acg eta gag acg ctg cgc gtg gac ggg aac 962 Thr Phe His Ser Val Asn Thr Leu Glu Thr Leu Arg Val Asp Gly Asn 275 280 285 ccg ctg gcc tgc gac tgt cgc ctg ctg tgg ate gtg cag cgt cgc aag 1010 Pro Leu Ala Cys Asp Cys Arg Leu Leu Trp He Val Gin Arg Arg Lys 290 295 300 305 ace etc aac ttc gac ggg egg ctg ccg gcc tgc gcc ace ccg gcc gag 1058 Thr Leu Asn Phe Asp Gly Arg Leu Pro Ala Cys Ala Thr Pro Ala Glu 310 315 320 gtg cgc ggc gac gcg ctg cga aac ctg ccg gac tec gtg ctg ttc gag 1106 Val Arg Gly Asp Ala Leu Arg Asn Leu Pro Asp Ser Val Leu Phe Glu 325 330 335 tac ttc gtg tgc cgc aaa ccc aag ate egg gag egg egg ctg cag cgc 1154 Tyr Phe Val Cys Arg Lys Pro Lys He Arg Glu Arg Arg Leu Gin Arg 340 345 350 gtc acg gcc ace gcg ggc gaa gac gtc cgc ttc etc tgc cgc gcc gag 1202 Val Thr Ala Thr Ala Gly Glu Asp Val Arg Phe Leu Cys Arg Ala Glu 355 360 365 ggc gag ccg gcg ccc ace gtg gcc tgg gtg ace ccc cag cac egg ccg 1250 Gly Glu Pro Ala Pro Thr Val Ala Trp Val Thr Pro Gin His Arg Pro 370 375 380 385 gtg acg gcc ace age gcg ggc egg gcg cgc gtg etc ccc ggg ggg acg 1298 Val Thr Ala Thr Ser Ala Gly Arg Ala Arg Val Leu Pro Gly Gly Thr 390 395 400 ctg gag ate cag gac gcg egg ccg cag gac age ggc ace tac acg tgc 1346 Leu Glu He Gin Asp Ala Arg Pro Gin Asp Ser Gly Thr Tyr Thr Cys 405 410 415 gtg gcc age aac gcg ggc ggc aac gac ace tac ttc gcc acg ctg ace 1394 Val Ala Ser Asn Ala Gly Gly Asn Asp Thr Tyr Phe Ala Thr Leu Thr 420 425 430 gtg cgc ccc gag ccg gcc gcc aac egg ace ccg ggc gag gcc cac aac 1442 Val Arg Pro Glu Pro Ala Ala Asn Arg Thr Pro Gly Glu Ala His Asn 435 440 445 gag acg ctg gcg gcc ctg cgc gcg ccg etc gac etc ace ace ate ctg 1490 Glu Thr Leu Ala Ala Leu Arg Ala Pro Leu Asp Leu Thr Thr He Leu 450 455 460 465 gtg tec ace gcc atg ggc tgc ate ace ttc ctg ggc gtg gtc etc ttc 1538 Val Ser Thr Ala Met Gly Cys He Thr Phe Leu Gly Val Val Leu Phe 470 475 480 tgc ttc gtg ctg ctg ttc gtg tgg age cgc ggc cgc ggg cag cac aaa 1586

Cys Phe Val Leu Leu Phe Val Trp Ser Arg Gly Arg Gly Gin His Lys

485 490 495 aac aac ttc teg gtg gag tac tec ttc cgc aag gtg gat ggg ccg gcc 1634

Asn Asn Phe Ser Val Glu Tyr Ser Phe Arg Lys Val Asp Gly Pro Ala

500 505 510 gcc gcg gcg ggc cag gga ggc gcg cgc aag ttc aac atg aag atg ate 1682

Ala Ala Ala Gly Gin Gly Gly Ala Arg Lys Phe Asn Met Lys Met He

515 520 525 tgaggggtcc ccagggcgga ccctcccctc ccctcccccg cgggccggcc gctcgcgtgt 1742 eeacctatgc atttcccgga ggggaagggg aeggetgeac ggcgetccee aggeagaact 1802 tccccttttt ttgtagacgc ccaaccgcag gactgttttt catcagcatg cgtctttttt 1862 gcagtttete aagegtttte taaagattte aaeecgtett cetgtceetg etatggtggc 1922 tgagctgggg ggtgggggtg cgggctgcaa ggatgggggg atgggctccc gtctaccaac 1982 eeggggtggc tgggggegct eagagaeecc aggateetca gggceegcaa tteaeaccea 2042 ggaggcacaa gactgctgcc cccaagccct gggcttcc 2080

<210> 12

<211> 557

<212> PRT

<213> Homo sapiens

<400> 12

Met Val Ser Thr Ala Met Gly Cys He Thr Phe Leu Gly Val Val Leu -25 -20 -15

Leu Leu Leu Ser Cys Cys Cys Xaa Val Trp Ser Arg Asn Arg He Arg -10 -5 -1 1

Cys Leu Asn Pro Gly Asp Leu Ala Ala Leu Pro Ala Leu Glu Glu Leu 5 10 15 20

Asp Leu Ser Glu Asn Ala He Ala His Val Glu Pro Gly Ala Phe Ala 25 30 35

Asn Leu Pro Arg Leu Arg Val Leu Arg Leu Arg Gly Asn Gin Leu Lys 40 45 50 Leu He Pro Pro Gly Val Phe Thr Arg Leu Asp Asn Leu Thr Leu Leu 55 60 65

Asp Leu Ser Glu Asn Lys Leu Val He Leu Leu Asp Tyr Thr Phe Gin 70 75 80

Asp Leu His Ser Leu Arg Arg Leu Glu Val Gly Asp Asn Asp Leu Val 85 90 95 100

Phe Val Ser Arg Arg Ala Phe Ala Gly Leu Leu Ala Leu Glu Glu Leu 105 110 115

Thr Leu Glu Arg Cys Asn Leu Thr Ala Leu Ser Gly Glu Ser Leu Gly 120 125 130

His Leu Arg Ser Leu Gly Ala Leu Arg Leu Arg His Leu Ala He Ala 135 140 145

Ser Leu Glu Asp Gin Asn Phe Arg Arg Leu Pro Gly Leu Leu His Leu 150 155 160

Glu He Asp Asn Trp Pro Leu Leu Glu Glu Val Ala Ala Gly Ser Leu 165 170 175 180

Arg Gly Leu Asn Leu Thr Ser Leu Ser Val Thr His Thr Asn He Thr 185 190 195

Ala Val Pro Ala Ala Ala Leu Arg His Gin Ala His Leu Thr Cys Leu 200 205 210

Asn Leu Ser His Asn Pro He Ser Thr Val Pro Arg Gly Ser Phe Arg 215 220 225

Asp Leu Val Arg Leu Arg Glu Leu His Leu Ala Gly Ala Leu Leu Ala 230 235 240

Val Val Glu Pro Gin Ala Phe Leu Gly Leu Arg Gin He Arg Leu Leu 245 250 ^' 255 260

Asn Leu Ser Asn Asn Leu Leu Ser Thr Leu Glu Glu Ser Thr Phe His 265 270 275 Ser Val Asn Thr Leu Glu Thr Leu Arg Val Asp Gly Asn Pro Leu Ala 280 285 290

Cys Asp Cys Arg Leu Leu Trp He Val Gin Arg Arg Lys Thr Leu Asn 295 300 305

Phe Asp Gly Arg Leu Pro Ala Cys Ala Thr Pro Ala Glu Val Arg Gly 310 315 320

Asp Ala Leu Arg Asn Leu Pro Asp Ser Val Leu Phe Glu Tyr Phe Val 325 330 335 340

Cys Arg Lys Pro Lys He Arg Glu Arg Arg Leu Gin Arg Val Thr Ala 345 350 355

Thr Ala Gly Glu Asp Val Arg Phe Leu Cys Arg Ala Glu Gly Glu Pro 360 365 370

Ala Pro Thr Val Ala Trp Val Thr Pro Gin His Arg Pro Val Thr Ala 375 380 385

Thr Ser Ala Gly Arg Ala Arg Val Leu Pro Gly Gly Thr Leu Glu He 390 395 400

Gin Asp Ala Arg Pro Gin Asp Ser Gly Thr Tyr Thr Cys Val Al Ser 405 410 415 420

Asn Ala Gly Gly Asn Asp Thr Tyr Phe Ala Thr Leu Thr Val Arg Pro 425 430 435

Glu Pro Ala Ala Asn Arg Thr Pro Gly Glu Ala His Asn Glu Thr Leu 440 445 450

Ala Ala Leu Arg Ala Pro Leu Asp Leu Thr Thr He Leu Val Ser Thr 455 460 465

Ala Met Gly Cys He Thr Phe Leu Gly Val Val Leu Phe Cys Phe Val 470 475 480 Leu Leu Phe Val Trp Ser Arg Gly Arg Gly Gin His Lys Asn Asn Phe 485 490 495 500

Ser Val Glu Tyr Ser Phe Arg Lys Val Asp Gly Pro Ala Ala Ala Ala 505 510 515

Gly Gin Gly Gly Ala Arg Lys Phe Asn Met Lys Met He 520 525

<210> 13

<211> 2222

<212> DNA

<213> Homo sapiens

<220>

<221> CDS

<222> (49) . .. (1824)

<220>

<221> mat_peptide

<222> (121).. ()

<400> 13 aggtgcgcag gaggatggtg gcgcggeeet aggeeeaegc tccgcaee atg ace tgc 57

Met Thr Cys

tgg ctg tgc gtc ctg age ctg ccc ctg etc ctg ctg ccc gcg gcg ccg 105 Trp Leu Cys Val Leu Ser Leu Pro Leu Leu Leu Leu Pro Ala Ala Pro -20 -15 -10 ccc ccg get gga ggc tgc ccg gcc cgc tgc gag tgc ace gtg cag ace 153 Pro Pro Ala Gly Gly Cys Pro Ala Arg Cys Glu Cys Thr Val Gin Thr -5 -1 1 5 10 cgc gcg gtg gcc tgc acg cgc cgc cgc ctg ace gcc gtg ccc gac ggc 201 Arg Ala Val Ala Cys Thr Arg Arg Arg Leu Thr Ala Val Pro Asp Gly 15 20 25 ate ccg gcc gag ace cgc ctg ctg gag etc age cgc aac cgc ate cgc 249 He Pro Ala Glu Thr Arg Leu Leu Glu Leu Ser Arg Asn Arg He Arg 30 35 40 tgc ctg aac ccg ggc gac ctg gcc gcg ctg ccc gcg ctg gag gag ctg 297 Cys Leu Asn Pro Gly Asp Leu Ala Ala Leu Pro Ala Leu Glu Glu Leu 45 50 55 gac ctg age gag aac gcc ate gcg cac gtg gag ccc ggc gcc ttc gcc 345 Asp Leu Ser Glu Asn Ala He Ala His Val Glu Pro Gly Ala Phe Ala 60 65 70 75 aac ctg ccg cgc ctg cgc gtc ctg cgt etc cgt ggc aac cag ctg aag 393 Asn Leu Pro Arg Leu Arg Val Leu Arg Leu Arg Gly Asn Gin Leu Lys 80 85 90 etc ate ccg ccc ggg gtc ttc acg cgc ctg gac aac etc acg ctg ctg 441 Leu He Pro Pro Gly Val Phe Thr Arg Leu Asp Asn Leu Thr Leu Leu 95 100 105 gac ctg age gag aac aag ctg gta ate ctg ctg gac tac act ttc cag 489 Asp Leu Ser Glu Asn Lys Leu Val He Leu Leu Asp Tyr Thr Phe Gin 110 115 120 gac ctg cac age ctg cgc egg ctg gaa gtg ggc gac aac gac ctg gta 537 Asp Leu His Ser Leu Arg Arg Leu Glu Val Gly Asp Asn Asp Leu Val 125 130 135 ttc gtc teg cgc cgc gcc ttc gcg ggg ctg ctg gcc ctg gag gag ctg 585 Phe Val Ser Arg Arg Ala Phe Ala Gly Leu Leu Ala Leu Glu Glu Leu 140 145 150 155 ace ctg gag cgc tgc aac etc acg get ctg tec ggg gag teg ctg ggc 633 Thr Leu Glu Arg Cys Asn Leu Thr Ala Leu Ser Gly Glu Ser Leu Gly 160 ^' 165 170 cat ctg cgc age ctg ggc gcc ctg egg ctg cgc cac ctg gcc ate gcc 681 His Leu Arg Ser Leu Gly Ala Leu Arg Leu Arg His Leu Ala He Ala 175 180 185 tec ctg gag gac cag aac ttc cgc agg ctg ccc ggg ctg ctg cac ctg 729 Ser Leu Glu Asp Gin Asn Phe Arg Arg Leu Pro Gly Leu Leu His Leu 190 195 200 gag att gac aac tgg ccg ctg ctg gag gag gtg gcg gcg ggc age ctg 777 Glu He Asp Asn Trp Pro Leu Leu Glu Glu Val Ala Ala Gly Ser Leu 205 210 215 egg ggc ctg aac ctg ace teg ctg teg gtc ace cac ace aac ate ace 825 Arg Gly Leu Asn Leu Thr Ser Leu Ser Val Thr His Thr Asn He Thr 220 225 230 235 gcc gtg ccg gcc gcc gcg ctg egg cac cag gcg cac etc ace tgc etc 873 Ala Val Pro Ala Ala Ala Leu Arg His Gin Ala His Leu Thr Cys Leu 240 245 250 aat ctg teg cac aac ccc ate age acg gtg ccg egg ggg teg ttc egg 921 Asn Leu Ser His Asn Pro He Ser Thr Val Pro Arg Gly Ser Phe Arg 255 260 265 gac ctg gtc cgc ctg cgc gag ctg cac ctg gcc ggg gcc ctg ctg get 969 Asp Leu Val Arg Leu Arg Glu Leu His Leu Ala Gly Ala Leu Leu Ala 270 275 280 gtg gtg gag ccg cag gcc ttc ctg ggc ctg cgc cag ate cgc ctg etc 1017 Val Val Glu Pro Gin Ala Phe Leu Gly Leu Arg Gin He Arg Leu Leu 285 290 295 aac etc tec aac aac ctg etc tec acg ttg gag gag age ace ttc cac 1065 Asn Leu Ser Asn Asn Leu Leu Ser Thr Leu Glu Glu Ser Thr Phe His 300 305 310 315 teg gtg aac acg eta gag acg ctg cgc gtg gac ggg aac ccg ctg gcc 1113 Ser Val Asn Thr Leu Glu Thr Leu Arg Val Asp Gly Asn Pro Leu Ala 320 325 330 tgc gac tgt cgc ctg ctg tgg ate gtg cag cgt cgc aag ace etc aac 1161 Cys Asp Cys Arg Leu Leu Trp He Val Gin Arg Arg Lys Thr Leu Asn 335 340 345 ttc gac ggg egg ctg ccg gcc tgc gcc ace ccg gcc gag gtg cgc ggc 1209 Phe Asp Gly Arg Leu Pro Ala Cys Ala Thr Pro Ala Glu Val Arg Gly 350 355 360 gac gcg ctg cga aac ctg ccg gac tec gtg ctg ttc gag tac ttc gtg 1257 Asp Ala Leu Arg Asn Leu Pro Asp Ser Val Leu Phe Glu Tyr Phe Val 365 370 375 tgc cgc aaa ccc aag ate egg gag egg egg ctg cag cgc gtc acg gcc 1305 Cys Arg Lys Pro Lys He Arg Glu Arg Arg Leu Gin Arg Val Thr Ala 380 385 390 395 ace gcg ggc gaa gac gtc cgc ttc etc tgc cgc gcc gag ggc gag ccg 1353 Thr Ala Gly Glu Asp Val Arg Phe Leu Cys Arg Ala Glu Gly Glu Pro 400 405 410 gcg ccc ace gtg gcc tgg gtg ace ccc cag cac egg ccg gtg acg gcc 1401 Ala Pro Thr Val Ala Trp Val Thr Pro Gin His Arg Pro Val Thr Ala 415 420 425 ace age gcg ggc egg gcg cgc gtg etc ccc ggg ggg acg ctg gag ate 1449 Thr Ser Ala Gly Arg Ala Arg Val Leu Pro Gly Gly Thr Leu Glu He 430 435 440 cag gac gcg egg ccg cag gac age ggc ace tac acg tgc gtg gcc age 1497 Gin Asp Ala Arg Pro Gin Asp Ser Gly Thr Tyr Thr Cys Val Ala Ser ■ 445 450 455 aac gcg ggc ggc aac gac ace tac ttc gcc acg ctg ace gtg cgc ccc 1545 Asn Ala Gly Gly Asn Asp Thr Tyr Phe Ala Thr Leu Thr Val Arg Pro 460 465 470 475 gag ccg gcc gcc aac egg ace ccg ggc gag gcc cac aac gag acg ctg 1593 Glu Pro Ala Ala Asn Arg Thr Pro Gly Glu Ala His Asn Glu Thr Leu 480 485 490 gcg gcc ctg cgc gcg ccg etc gac etc ace ace ate ctg gtg tec ace 1641 Ala Ala Leu Arg Ala Pro Leu Asp Leu Thr Thr He Leu Val Ser Thr 495 500 505 gcc atg ggc tgc ate ace ttc ctg ggc gtg gtc etc ttc tgc ttc gtg 1689 Ala Met Gly Cys He Thr Phe Leu Gly Val Val Leu Phe Cys Phe Val 510 515 520 ctg ctg ttc gtg tgg age cgc ggc cgc ggg cag cac aaa aac aac ttc 1737 Leu Leu Phe Val Trp Ser Arg Gly Arg Gly Gin His Lys Asn Asn Phe 525 530 535 teg gtg gag tac tec ttc cgc aag gtg gat ggg ccg gcc gcc gcg gcg 1785 Ser Val Glu Tyr Ser Phe Arg Lys Val Asp Gly Pro Ala Ala Ala Ala 540 545 550 555 ggc cag gga ggc gcg cgc aag ttc aac atg aag atg ate tgaggggtcc 1834 Gly Gin Gly Gly Ala Arg Lys Phe Asn Met Lys Met He 560 565 ccagggcgga ccctcccctc ccctcccccg cgggccggcc gctcgcgtgt eeacctatgc 1894 atttcccgga ggggaagggg aeggetgeac ggcgetccee aggeagaact tccccttttt 1954 ttgtagacgc ccaaccgcag gactgttttt catcagcatg cgtctttttt gcagtttete 2014 aagegtttte taaagattte aaeecgtett cetgtceetg etatggtggc tgagctgggg 2074 ggtgggggtg cgggctgcaa ggatgggggg atgggctccc gtctaccaac eeggggtggc 2134 tgggggegct eagagaeecc aggateetca gggceegcaa tteaeaccea ggaggcacaa 2194 gactgctgcc cccaagccct gggcttcc 2222

<210> 14

<211> 592

<212> PRT

<213> Homo sapiens

<400> 14

Met Thr Cys Trp Leu Cys Val Leu Ser Leu Pro Leu Leu Leu Leu Pro -20 -15 -10

Ala Ala Pro Pro Pro Ala Gly Gly Cys Pro Ala Arg Cys Glu Cys Thr -5 -1 1 5

Val Gin Thr Arg Ala Val Ala Cys Thr Arg Arg Arg Leu Thr Ala Val 10 15 20 Pro Asp Gly He Pro Ala Glu Thr Arg Leu Leu Glu Leu Ser Arg Asn 25 30 35 40

Arg He Arg Cys Leu Asn Pro Gly Asp Leu Ala Ala Leu Pro Ala Leu 45 50 55

Glu Glu Leu Asp Leu Ser Glu Asn Ala He Ala His Val Glu Pro Gly 60 65 70

Ala Phe Ala Asn Leu Pro Arg Leu Arg Val Leu Arg Leu Arg Gly Asn 75 80 85

Gin Leu Lys Leu He Pro Pro Gly Val Phe Thr Arg Leu Asp Asn Leu 90 95 100

Thr Leu Leu Asp Leu Ser Glu Asn Lys Leu Val He Leu Leu Asp Tyr 105 110 115 120

Thr Phe Gin Asp Leu His Ser Leu Arg Arg Leu Glu Val Gly Asp Asn 125 130 135

Asp Leu Val Phe Val Ser Arg Arg Ala Phe Ala Gly Leu Leu Ala Leu 140 145 150

Glu Glu Leu Thr Leu Glu Arg 'Cys Asn Leu Thr Ala Leu Ser Gly Glu 155 160 165

Ser Leu Gly His Leu Arg Ser Leu Gly Ala Leu Arg Leu Arg His Leu 170 175 180

Ala He Ala Ser Leu Glu Asp Gin Asn Phe Arg Arg Leu Pro Gly Leu 185 190 195 200

Leu His Leu Glu He Asp Asn Trp Pro Leu Leu Glu Glu Val Ala Ala 205 210 215

Gly Ser Leu Arg Gly Leu Asn Leu Thr Ser Leu Ser Val Thr His Thr 220 225 230

Asn He Thr Ala Val Pro Ala Ala Ala Leu Arg His Gin Ala His Leu 235 240 245 Thr Cys Leu Asn Leu Ser His Asn Pro He Ser Thr Val Pro Arg Gly 250 255 260

Ser Phe Arg Asp Leu Val Arg Leu Arg Glu Leu His Leu Ala Gly Ala 265 270 275 280

Leu Leu Ala Val Val Glu Pro Gin Ala Phe Leu Gly Leu Arg Gin He 285 290 295

Arg Leu Leu Asn Leu Ser Asn Asn Leu Leu Ser Thr Leu Glu Glu Ser 300 305 310

Thr Phe His Ser Val Asn Thr Leu Glu Thr Leu Arg Val Asp Gly Asn 315 320 325

Pro Leu Ala Cys Asp Cys Arg Leu Leu Trp He Val Gin Arg Arg Lys 330 335 340

Thr Leu Asn Phe Asp Gly Arg Leu Pro Ala Cys Ala Thr Pro Ala Glu 345 350 355 360

Val Arg Gly Asp Ala Leu Arg Asn Leu Pro Asp Ser Val Leu Phe Glu 365 370 375

Tyr Phe Val Cys Arg Lys Pro Lys He Arg Glu Arg Arg Leu Gin Arg 380 385 390

Val Thr Ala Thr Ala Gly Glu Asp Val Arg Phe Leu Cys Arg Ala Glu 395 400 405

Gly Glu Pro Ala Pro Thr Val Ala Trp Val Thr Pro Gin His Arg Pro 410 415 420

Val Thr Ala Thr Ser Ala Gly Arg Ala Arg Val Leu Pro Gly Gly Thr 425 430 435 440

Leu Glu He Gin Asp Ala Arg Pro Gin Asp Ser Gly Thr Tyr Thr Cys 445 450 455 Val Ala Ser Asn Ala Gly Gly Asn Asp Thr Tyr Phe Ala Thr Leu Thr 460 465 470

Val Arg Pro Glu Pro Ala Ala Asn Arg Thr Pro Gly Glu Ala His Asn 475 480 485

Glu Thr Leu Ala Ala Leu Arg Ala Pro Leu Asp Leu Thr Thr He Leu 490 495 500

Val Ser Thr Ala Met Gly Cys He Thr Phe Leu Gly Val Val Leu Phe 505 510 515 520

Cys Phe Val Leu Leu Phe Val Trp Ser Arg Gly Arg Gly Gin His Lys 525 530 535

Asn Asn Phe Ser Val Glu Tyr Ser Phe Arg Lys Val Asp Gly Pro Ala 540 545 550

Ala Ala Ala Gly Gin Gly Gly Ala Arg Lys Phe Asn Met Lys Met He 555 560 565

<210> 15

<211> 4392

<212> DNA

<213> Homo sapiens

<220>

<221> CDS

<222> (1)..(1662)

<220>

<221> mat_peptide

<222> (82).. ()

<400> 15 atg gcc ccg tgg ctg cag etc tgc tec gtc ttc ttt acg gtc aac gcc 48 Met Ala Pro Trp Leu Gin Leu Cys Ser Val Phe Phe Thr Val Asn Ala -25 -20 -15 tgc etc aac ggc teg cag ctg get gtg gcc get ggc ggg tec ggc cgc 96 Cys Leu Asn Gly Ser Gin Leu Ala Val Ala Ala Gly Gly Ser Gly Arg -10 -5 -1 1 5 gcg egg ggc gcc gac ace tgt ggc tgg agg gga gtg ggg cca gcc age 144 Ala Arg Gly Ala Asp Thr Cys Gly Trp Arg Gly Val Gly Pro Ala Ser 10 15 20 aga aac agt ggg ctg tac aac ate ace ttc aaa tat gac aat tgt ace 192 Arg Asn Ser Gly Leu Tyr Asn He Thr Phe Lys Tyr Asp Asn Cys Thr 25 30 35 ace tac ttg aat cca gtg ggg aag cat gtg att get gac gcc cag aat 240 Thr Tyr Leu Asn Pro Val Gly Lys His Val He Ala Asp Ala Gin Asn 40 45 50 ate ace ate age cag tat get tgc cat gac caa gtg gca gtc ace att 288 He Thr He Ser Gin Tyr Ala Cys His Asp Gin Val Ala Val Thr He 55 60 65 ctt tgg tec cca ggg gcc etc ggc ate gaa ttc ctg aaa gga ttt egg 336 Leu Trp Ser Pro Gly Ala Leu Gly He Glu Phe Leu Lys Gly Phe Arg 70 75 80 85 gta ata ctg gag gag ctg aag teg gag gga aga cag tgc caa caa ctg 384 Val He Leu Glu Glu Leu Lys Ser Glu Gly Arg Gin Cys Gin Gin Leu 90 95 100 att eta aag gat ccg aag cag etc aac agt age ttc aaa aga act gga 432 He Leu Lys Asp Pro Lys Gin Leu Asn Ser Ser Phe Lys Arg Thr Gly 105 110 115 atg gaa tct caa cct ttc ctg aat atg aaa ttt gaa acg gat tat ttc 480 Met Glu Ser Gin Pro Phe Leu Asn Met Lys Phe Glu Thr Asp Tyr Phe 120 125 130 gta aag gtt gtc cct ttt cct tec att aaa aac gaa age aat tac cac 528 Val Lys Val Val Pro Phe Pro Ser He Lys Asn Glu Ser Asn Tyr His 135 140 145 cct ttc ttc ttt aga ace cga gcc tgt gac ctg ttg tta cag ccg gac 576 Pro Phe Phe Phe Arg Thr Arg Ala Cys Asp Leu Leu Leu Gin Pro Asp 150 155 160 165 aat eta get tgt aaa ccc ttc tgg aag cct egg aac ctg aac ate age 624 Asn Leu Ala Cys Lys Pro Phe Trp Lys Pro Arg Asn Leu Asn He Ser 170 175 180 cag cat ggc teg gac atg cag gtg tec ttc gac cat gca ccg cac aac 672 Gin His Gly Ser Asp Met Gin Val Ser Phe Asp His Ala Pro His Asn 185 190 195 ttc ggc ttc cgt ttc ttc tat ctt cac tac aag etc aag cac gaa gga 720 Phe Gly Phe Arg Phe Phe Tyr Leu His Tyr Lys Leu Lys His Glu Gly 200 205 210 cct ttc aag cga aag ace tgt aag cag gag caa act aca gag acg ace 768 Pro Phe Lys Arg Lys Thr Cys Lys Gin Glu Gin Thr Thr Glu Thr Thr 215 220 225 age tgc etc ctt caa aat gtt tct cca ggg gat tat ata att gag ctg 816 Ser Cys Leu Leu Gin Asn Val Ser Pro Gly Asp Tyr He He Glu Leu 230 235 240 245 gtg gat gac act aac aca aca aga aaa gtg atg cat tat gcc tta aag 864 Val Asp Asp Thr Asn Thr Thr Arg Lys Val Met His Tyr Ala Leu Lys 250 255 260 cca gtg cac tec ccg tgg gcc ggg ccc ate aga gcc gtg gcc ate aca 912 Pro Val His Ser Pro Trp Ala Gly Pro He Arg Ala Val Ala He Thr 265 270 275 gtg cca ctg gta gtc ata teg gca ttc gcg acg etc ttc act gtg atg 960 Val Pro Leu Val Val He Ser Ala Phe Ala Thr Leu Phe Thr Val Met 280 285 290 tgc cgc aag aag caa caa gaa aat ata tat tea cat tta gat gaa gag 1008 Cys Arg Lys Lys Gin Gin Glu Asn He Tyr Ser His Leu Asp Glu Glu 295 300 305 age tct gag tct tec aca tac act gca gca etc cca aga gag agg etc 1056 Ser Ser Glu Ser Ser Thr Tyr Thr Ala Ala Leu Pro Arg Glu Arg Leu 310 315 320 325 egg ccg egg ccg aag gtc ttt etc tgc tat tec agt aaa gat ggc cag 1104 Arg Pro Arg Pro Lys Val Phe Leu Cys Tyr Ser Ser Lys Asp Gly Gin 330 335 340 aat cac atg aat gtc gtc cag tgt ttc gcc tac ttc etc cag gac ttc 1152 Asn His Met Asn Val Val Gin Cys Phe Ala Tyr Phe Leu Gin Asp Phe 345 350 355 tgt ggc tgt gag gtg get ctg gac ctg tgg gaa gac ttc age etc tgt 1200 Cys Gly Cys Glu Val Ala Leu Asp Leu Trp Glu Asp Phe Ser Leu Cys 360 365 370 aga gaa ggg cag aga gaa tgg gtc ate cag aag ate cac gag tec cag 1248 Arg Glu Gly Gin Arg Glu Trp Val He Gin Lys He His Glu Ser Gin 375 380 385 ttc ate att gtg gtt tgt tec aaa ggt atg aag tac ttt gtg gac aag 1296 Phe He He Val Val Cys Ser Lys Gly Met Lys Tyr Phe Val Asp Lys 390 395 400 405 aag aac tac aaa cac aaa gga ggt ggc cga ggc teg ggg aaa gga gag 1344 Lys Asn Tyr Lys His Lys Gly Gly Gly Arg Gly Ser Gly Lys Gly Glu 410 415 420 etc ttc ctg gtg gcg gtg tea gcc att gcc gaa aag etc cgc cag gcc 1392 Leu Phe Leu Val Ala Val Ser Ala He Ala Glu Lys Leu Arg Gin Ala 425 430 435 aag cag agt teg tec gcg gcg etc age aag ttt ate gcc gtc tac ttt 1440 Lys Gin Ser Ser Ser Ala Ala Leu Ser Lys Phe He Ala Val Tyr Phe 440 445 450 gat tat tec tgc gag gga gac gtc ccc ggt ate eta gac ctg agt ace 1488 Asp Tyr Ser Cys Glu Gly Asp Val Pro Gly He Leu Asp Leu Ser Thr 455 460 465 aag tac aga etc atg gac aat ctt tec tea get ctg ttc cca etc tgc 1536 Lys Tyr Arg Leu Met Asp Asn Leu Ser Ser Ala Leu Phe Pro Leu Cys 470 475 480 485 act ccc gag ace acg gcc tec agg age egg ggc atg cac acg cga cag 1584 Thr Pro Glu Thr Thr Ala Ser Arg Ser Arg Gly Met His Thr Arg Gin 490 495 500 ggc agg gag aag gaa eta ctt ccg gag caa gtc agg ccg gtc cct ata 1632 Gly Arg Glu Lys Glu Leu Leu Pro Glu Gin Val Arg Pro Val Pro He 505 510 515 cgt cgc cat ttg caa cat gca cca gtt tat tgacgaggag cccgactggt 1682 Arg Arg His Leu Gin His Ala Pro Val Tyr 520 525 tcgaaaagca gttcgttccc ttccatcctc ctccactgcg ctaccgggag ccagtcttgg 1742 agaaatttga ttegggettg gttttaaatg atgtcatgtg caaaccaggg eetgagagtg 1802 acttctgcct aaaggtagag gcggctgttc ttggggcaac cggaccagcc gactcccagc 1862 acgagagtca gcatgggggc ctggaccaag acggggaggc ccggcctgcc cttgacggta 1922 gcgccgccct gcaacccctg ctgcacacgg tgaaagccgg cagcccctcg gacatgccgc 1982 gggaetcagg catetatgac tcgtctgtgc cctcatcega gctgtctetg eeactgatgg 2042 aaggactctc gacggaccag acagaaacgt cttccctgac ggagagcgtg tcctcctctt 2102 caggcctggg tgaggaggaa cctcctgccc ttccttccaa gctcctctct tctgggtcat 2162 gcaaagcaga tcttggttgc cgcagctaca ctgatgaact ccacgcggtc gcccctttgt 2222 aaeaaaaega aagagtetaa gcattgceae tttagctgct geetecctet gattccccag 2282 ctcatctccc tggttgcatg gcccacttgg agctgaggtc tcatacaagg atatttggag 2342 tgaaatgctg gccagtactt gttctccctt gccccaaccc tttaccggat atcttgacaa 2402 actctccaat tttctaaaat gatatggagc tctgaaaggc atgtccataa ggtctgacaa 2462 cagcttgcca aatttggtta gtccttggat cagagcctgt tgtgggaggt agggaggaaa 2522 tatgtaaaga aaaacaggaa gatacctgca ctaatcattc agacttcatt gagctctgca 2582 aactttgcct gtttgctatt ggctaccttg atttgaaatg ctttgtgaaa aaaggcactt 2642 ttaacatcat agccacagaa atcaagtgcc agtctatctg gaatccatgt tgtattgcag 2702 ataatgttct catttatttt tgatgtagaa tttacattgc catgggtgtt aaataagctt 2762 tgagtcaaaa gteaagaaag tgaetgaata taeagteaee ttttatgaaa tgagtctctg 2822 tgttactggg tggcatgact gattgaggtg aagctcacgg ggccaggctg accgtcttga 2882 ccgttccact tgagataggt tggtcatcgt gcagaaggcc ccaggacctc agcacacaca 2942 gcctcctctt ggtctgagta ggcatcatgt gggggccaga tctgcctgct gtttccatgg 3002 gttacattta ctgtgctgta tctcagatgt tggtgtctgg aagtttattc ttaagagact 3062 gctacccagc tggtctgtat tattggaagt tgcagttcgt gctttggttg gccttctggt 3122 ctaaagctgt gtcctgaata ttagggatca caattcactg aaatacagca gtgtgtggag 3182 gtgatggcca gttaatctgc tgaactggtt ttgaetaatg aeaaacetet ttttaagatg 3242 gtagaatgga ggtgatagtc acaaaagtaa atgttccatt tttatgaatg actttctaca 3302 gagtttctat ttctaaagaa aaaacaattg ttcacatccc atctgatgat tagcatgtgt 3362 gtaatgaatg ctgtcttggt ctcccctgtg gaaacccttc tccctgtgcc ttagagcagg 3422 tgtgtacatc tctcactacc tttctcatgg gtgctgttag attttggcac ccgttttctc 3482 agcattcage eeagggaatg tggttttcae ttettegtea gataagaeea acatgaaggg 3542 gtatgttgag aaacatcctg aggcaaggtg ggaggtggga tggggcagga ctttcccttc 3602 caagcacatg catggcaggt ggggaaaggg gggcttgcac ccctgctgga aagaaaaggt 3662 ttgtgtatat ttctgatgca aatgtcatac tcactgctct gtaaaggcag ctggcagctt 3722 tttgggaaaa gaacgtgctc gtctgttctc tggcatcaag tttcttgcag ctgctctgag 3782 ggagagacag tgagctgcaa gactgcctcc ccataacaac aggcaactca gagaagagtc 3842 attttatgtt gttcctatgg aatctggaat gagtgcagag ctcctaccca cacatgactg 3902 ccccgccatt tcatcctagg cattctgtga aggagattgg ttagtccaaa cttgctaaca 3962 tacgaaaatt cacttggaac atgatgagag atttcttatt gaggccaaga gatgtttcct 4022 gtcccagagg aaccattagg agtcgctttt agggtattca gctttgttca tgaaataagg 4082 catctctgag aaagtggccc cagggagaga atggaggact gggaggagaa gcattaactg 4142 agctccaagg gtgtgtgggc agagagcttg ctatgtgaac tcactcctta agaaaatgga 4202 agagaaaaag agagtgctag ttaaaaaatc gggatgtttt agtttggatt tagggttttg 4262 ataettatgt tgaaatacta atgtttetga tcaataaaat eaaaetetta atataccgag 4322 taatgaaaec atagtgtgat tgcctcagaa taaattgaga agtccaaaaa aaaaaaaaaa 4382 aaaaaaaaaa 4392

<210> 16

<211> 554

<212> PRT

<213> Homo sapiens

<400> 16

Met Ala Pro Trp Leu Gin Leu Cys Ser Val Phe Phe Thr Val Asn Ala -25 -20 -15

Cys Leu Asn Gly Ser Gin Leu Ala Val Ala Ala Gly Gly Ser Gly Arg -10 -5 -1 1 5

Ala Arg Gly Ala Asp Thr Cys Gly Trp Arg Gly Val Gly Pro Ala Ser 10 15 20

Arg Asn Ser Gly Leu Tyr Asn He Thr Phe Lys Tyr Asp Asn Cys Thr 25 30 35

Thr Tyr Leu Asn Pro Val Gly Lys His Val He Ala Asp Ala Gin Asn 40 45 50

He Thr He Ser Gin Tyr Ala Cys His Asp Gin Val Ala Val Thr He 55 60 65

Leu Trp Ser Pro Gly Ala Leu Gly He Glu Phe Leu Lys Gly Phe Arg 70 75 80 85

Val He Leu Glu Glu Leu Lys Ser Glu Gly Arg Gin Cys Gin Gin Leu 90 95 100

He Leu Lys Asp Pro Lys Gin Leu Asn Ser Ser Phe Lys Arg Thr Gly 105 110 115

Met Glu Ser Gin Pro Phe Leu Asn Met Lys Phe Glu Thr Asp Tyr Phe 120 125 130 Val Lys Val Val Pro Phe Pro Ser He Lys Asn Glu Ser Asn Tyr His 135 140 145

Pro Phe Phe Phe Arg Thr Arg Ala Cys Asp Leu Leu Leu Gin Pro Asp 150 155 160 165

Asn Leu Ala Cys Lys Pro Phe Trp Lys Pro Arg Asn Leu Asn He Ser 170 175 180

Gin His Gly Ser Asp Met Gin Val Ser Phe Asp His Ala Pro His Asn 185 . 190 195

Phe Gly Phe Arg Phe Phe Tyr Leu His Tyr Lys Leu Lys His Glu Gly 200 205 210

Pro Phe Lys Arg Lys Thr Cys Lys Gin Glu Gin Thr Thr Glu Thr Thr 215 220 225

Ser Cys Leu Leu Gin Asn Val Ser Pro Gly Asp Tyr He He Glu Leu 230 235 240 245

Val Asp Asp Thr Asn Thr Thr Arg Lys Val Met His Tyr Ala Leu Lys 250 255 260

Pro Val His Ser Pro Trp Ala Gly Pro He Arg Ala Val Ala He Thr 265 270 275

Val Pro Leu Val Val He Ser Ala Phe Ala Thr Leu Phe Thr Val Met 280 285 290

Cys Arg Lys Lys Gin Gin Glu Asn He Tyr Ser His Leu Asp Glu Glu 295 300 305

Ser Ser Glu Ser Ser Thr Tyr Thr Ala Ala Leu Pro Arg Glu Arg Leu 310 315 320 325

Arg Pro Arg Pro Lys Val Phe Leu Cys Tyr Ser Ser Lys Asp Gly Gin 330 335 340 Asn His Met Asn Val Val Gin Cys Phe Ala Tyr Phe Leu Gin Asp Phe 345 350 355

Cys Gly Cys Glu Val Ala Leu Asp Leu Trp Glu Asp Phe Ser Leu Cys 360 365 370

Arg Glu Gly Gin Arg Glu Trp Val He Gin Lys He His Glu Ser Gin 375 380 385

Phe He He Val Val Cys Ser Lys Gly Met Lys Tyr Phe Val Asp Lys 390 395 400 405

Lys Asn Tyr Lys His Lys Gly Gly Gly Arg Gly Ser Gly Lys Gly Glu 410 415 420

Leu Phe Leu Val Ala Val Ser Ala He Ala Glu Lys Leu Arg Gin Ala 425 430 435

Lys Gin Ser Ser Ser Ala Ala Leu Ser Lys Phe He Ala Val Tyr Phe 440 445 450

Asp Tyr Ser Cys Glu Gly Asp Val Pro Gly He Leu Asp Leu Ser Thr 455 460 ^' 465

Lys Tyr Arg Leu Met Asp Asn Leu Ser Ser Ala Leu Phe Pro Leu Cys 470 475 480 485

Thr Pro Glu Thr Thr Ala Ser Arg Ser Arg Gly Met His Thr Arg Gin 490 495 500

Gly Arg Glu Lys Glu Leu Leu Pro Glu Gin Val Arg Pro Val Pro He 505 510 515

Arg Arg His Leu Gin His Ala Pro Val Tyr 520 525

<210> 17

<211> 1010

<212> DNA

<213> Homo sapiens <220>

<221> CDS

<222> (162) .. (923)

<220>

<221> mat_peptide

<222> (279) .. ()

<400> 17 gccggccgcg gctggcccgg gatcagggag ccgatgtgga atttcctgcc cggctcggcg 60 ceeetectgc cgcccccegc ccggcctcgc aetccgcttc cggccgctct cgctgcggcc 120 gcacccgcgc ccgtgcccgc cccgcgcctg ccccgcgcct c atg gag ggc gca ggg 176

Met Glu Gly Ala Gly -35 ccc egg ggg gcc ggg ccg gcg egg cgc egg gga gcc ggg ggg ccg ccg 224 Pro Arg Gly Ala Gly Pro Ala Arg Arg Arg Gly Ala Gly Gly Pro Pro -30 -25 -20 tea ccg ctg ctg ccg teg ctg ctg ctg ctg ctg ctg etc tgg atg ctg 272 Ser Pro Leu Leu Pro Ser Leu Leu Leu Leu Leu Leu Leu Trp Met Leu -15 -10 -5 ccg gac ace gtg gcg cct cag gaa ctg aac cct cgc ggc cgc aac gtg 320 Pro Asp Thr Val Ala Pro Gin Glu Leu Asn Pro Arg Gly Arg Asn Val -1 1 5 10 tgc cgt get ccc ggc tec cag gtg ccc acg tgc tgc get ggc tgg agg 368 Cys Arg Ala Pro Gly Ser Gin Val Pro Thr Cys Cys Ala Gly Trp Arg 15 20 25 30 cag caa ggg gac gag tgt ggg att gcg gtg tgc gaa ggc aac tec acg 416 Gin Gin Gly Asp Glu Cys Gly He Ala Val Cys Glu Gly Asn Ser Thr 35 40 45 tgc tea gag aac gag gtg tgc gtg agg cct ggc gag tgc cgc tgc cgc 464 Cys Ser Glu Asn Glu Val Cys Val Arg Pro Gly Glu Cys Arg Cys Arg 50 55 60 cac ggc tac ttc ggt gcc aac tgc gac ace aag tgc ccg cgc cag ttc 512 His Gly Tyr Phe Gly Ala Asn Cys Asp Thr Lys Cys Pro Arg Gin Phe 65 70 75 tgg ggc ccc gac tgc aag gag ctg tgt age tgc cac cca cac ggg cag 560 Trp Gly Pro Asp Cys Lys Glu Leu Cys Ser Cys His Pro His Gly Gin 80 85 90 tgc gag gac gtg aca ggc cag tgt act tgt cac gcg egg cgc tgg ggc 608 Cys Glu Asp Val Thr Gly Gin Cys Thr Cys His Ala Arg Arg Trp Gly 95 100 105 110 gcg cgc tgc gag cat gcg tgc cag tgc cag cac ggc acg tgc cac ccg 656 Ala Arg Cys Glu His Ala Cys Gin Cys Gin His Gly Thr Cys His Pro 115 120 125 egg age ggc gcg tgc cgc tgt gag ccc ggc ccc gcc cct ccg etc aga 704 Arg Ser Gly Ala Cys Arg Cys Glu Pro Gly Pro Ala Pro Pro Leu Arg 130 135 140 ccc cgc ccc cgc agg gag ctt teg ctt ggg agg aag aag gcg ccg cac 752 Pro Arg Pro Arg Arg Glu Leu Ser Leu Gly Arg Lys Lys Ala Pro His 145 150 155 cga eta tgc ggg cgc ttc agt cgc ate age atg aag ctg ccc egg ate 800 Arg Leu Cys Gly Arg Phe Ser Arg He Ser Met Lys Leu Pro Arg He 160 165 170 ccg etc egg agg cag aaa eta ccc aaa gtc gta ggt aag gat gac age 848 Pro Leu Arg Arg Gin Lys Leu Pro Lys Val Val Gly Lys Asp Asp Ser 175 180 185 190 gcg ggg gat ctg gga gaa aca cct etc gac gca gga age tgc tgg gaa 896 Ala Gly Asp Leu Gly Glu Thr Pro Leu Asp Ala Gly Ser Cys Trp Glu 195 200 205 atg ggt gtg agg ggg tec aga tct cag tgaggaaatg ggggaccttg 943

Met Gly Val Arg Gly Ser Arg Ser Gin 210 215 agtgttgatg tgcgtgggcc eeaggaggtg egaeeagagg gaaggtaaga ggtgtggeag 1003 ctgctga 1010

<210> 18

<211> 254

<212> PRT

<213> Homo sapiens

<400>

Met Glu Gly Ala Gly Pro Arg Gly Ala Gly Pro Ala Arg Arg Arg Gly -35 -30 -25

Ala Gly Gly Pro Pro Ser Pro Leu Leu Pro Ser Leu Leu Leu Leu Leu -20 -15 -10

Leu Leu Trp Met Leu Pro Asp Thr Val Ala Pro Gin Glu Leu Asn Pro -5 -1 1 5

Arg Gly Arg Asn Val Cys Arg Ala Pro Gly Ser Gin Val Pro Thr Cys 10 15 20 25 Cys Ala Gly Trp Arg Gin Gin Gly Asp Glu Cys Gly He Ala Val Cys 30 35 40

Glu Gly Asn Ser Thr Cys Ser Glu Asn Glu Val Cys Val Arg Pro Gly 45 50 55

Glu Cys Arg Cys Arg His Gly Tyr Phe Gly Ala Asn Cys Asp Thr Lys 60 65 70

Cys Pro Arg Gin Phe Trp Gly Pro Asp Cys Lys Glu Leu Cys Ser Cys 75 80 85

His Pro His Gly Gin Cys Glu Asp Val Thr Gly Gin Cys Thr Cys His 90 95 100 105

Ala Arg Arg Trp Gly Ala Arg Cys Glu His Ala Cys Gin Cys Gin His 110 115 120

Gly Thr Cys His Pro Arg Ser Gly Ala Cys Arg Cys Glu Pro Gly Pro 125 130 135

Ala Pro Pro Leu Arg Pro Arg Pro Arg Arg Glu Leu Ser Leu Gly Arg 140 145 150

Lys Lys Ala Pro His Arg Leu Cys Gly Arg Phe Ser Arg He Ser Met 155 160 165

Lys Leu Pro Arg He Pro Leu Arg Arg Gin Lys Leu Pro Lys Val Val 170 175 180 185

Gly Lys Asp Asp Ser Ala Gly Asp Leu Gly Glu Thr Pro Leu Asp Ala 190 195 200

Gly Ser Cys Trp Glu Met Gly Val Arg Gly Ser Arg Ser Gin 205 210 215

<210> 19

<211> 2210

<212> DNA

<213> Homo sapiens <220>

<221> CDS

<222> (39) .. (2114)

<220>

<221> mat_peptide

<222> (93).. ()

<400> 19 gtctcetege eaggacagca accteteeec tggccete atg ggc ace gtc age tec 56

Met Gly Thr Val Ser Ser -15 agg egg tec tgg tgg ccg ctg cca ctg ctg ctg ctg ctg ctg ctg etc 104 Arg Arg Ser Trp Trp Pro Leu Pro Leu Leu Leu Leu Leu Leu Leu Leu -10 ^• -5 . -1 1 ctg ggt ccc gcg ggc gcc cgt gcg cag gag gac gag gac ggc gac tac 152 Leu Gly Pro Ala Gly Ala Arg Ala Gin Glu Asp Glu Asp Gly Asp Tyr 5 10 15 20 gag gag ctg gtg eta gcc ttg cgt tec gag gag gac ggc ctg gcc gaa 200 Glu Glu Leu Val Leu Ala Leu Arg Ser Glu Glu Asp Gly Leu Ala Glu 25 30 35 gca ccc gag cac gga ace aca gcc ace ttc cac cgc tgc gcc aag gat 248 Ala Pro Glu His Gly Thr Thr Ala Thr Phe His Arg Cys Ala Lys Asp 40 45 50 ccg tgg agg ttg cct ggc ace tac gtg gtg gtg ctg aag gag gag ace 296 Pro Trp Arg Leu Pro Gly Thr Tyr Val Val Val Leu Lys Glu Glu Thr 55 60 65 cac etc teg cag tea gag cgc act gcc cgc cgc ctg cag gcc cag get 344 His Leu Ser Gin Ser Glu Arg Thr Ala Arg Arg Leu Gin Ala Gin Ala 70 75 80 gcc cgc egg gga tac etc ace aag ate ctg cat gtc ttc cat ggc ctt 392 Ala Arg Arg Gly Tyr Leu Thr Lys He Leu His Val Phe His Gly Leu 85 90 95 100 ctt cct ggc ttc ctg gtg aag atg agt ggc gac ctg ctg gag ctg gcc 440 Leu Pro Gly Phe Leu Val Lys Met Ser Gly Asp Leu Leu Glu Leu Ala 105 110 115 ttg aag ttg ccc cat gtc gac tac ate gag gag gac tec tct gtc ttt 488 Leu Lys Leu Pro His Val Asp Tyr He Glu Glu Asp Ser Ser Val Phe 120 125 130 gcc cag age ate ccg tgg aac ctg gag egg att ace cct cca egg tac 536 Ala Gin Ser He Pro Trp Asn Leu Glu Arg He Thr Pro Pro Arg Tyr 135 140 145 e g gcg gat gaa tac cag ccc ccc gac gga ggc age ctg gtg gag gtg 584 Arg Ala Asp Glu Tyr Gin Pro Pro Asp Gly Gly Ser Leu Val Glu Val 150 155 160 tat etc eta gac ace age ata cag agt gac cac egg gaa ate gag ggc 632 Tyr Leu Leu Asp Thr Ser He Gin Ser Asp His Arg Glu He Glu Gly 165 170 175 180 agg gtc atg gtc ace gac ttc gag aat gtg ccc gag gag gac ggg ace 680 Arg Val Met Val Thr Asp Phe Glu Asn Val Pro Glu Glu Asp Gly Thr 185 190 195 cgc ttc cac aga cag gcc age aag tgt gac agt cat ggc ace cac ctg 728 Arg Phe His Arg Gin Ala Ser Lys Cys Asp Ser His Gly Thr His Leu 200 205 210 gca ggg gtg gtc age ggc egg gat gcc ggc gtg gcc aag ggt gcc age 776 Ala Gly Val Val Ser Gly Arg Asp Ala Gly Val Ala Lys Gly Ala Ser 215 220 225 atg cgc age ctg cgc gtg etc aac tgc caa ggg aag ggc acg gtt age 824 Met Arg Ser Leu Arg Val Leu Asn Cys Gin Gly Lys Gly Thr Val Ser 230 235 240 ggc ace etc ata ggc ctg gag ttt att egg aaa age cag ctg gtc cag 872 Gly Thr Leu He Gly Leu Glu Phe He Arg Lys Ser Gin Leu Val Gin 245 250 255 260 cct gtg ggg cca ctg gtg gtg ctg ctg ccc ctg gcg ggt ggg tac age 920 Pro Val Gly Pro Leu Val Val Leu Leu Pro Leu Ala Gly Gly Tyr Ser 265 270 275 cgc gtc etc aac gcc gcc tgc cag cgc ctg gcg agg get ggg gtc gtg 968 Arg Val Leu Asn Ala Ala Cys Gin Arg Leu Ala Arg Ala Gly Val Val 280 285 290 ctg gtc ace get gcc ggc aac ttc egg gac gat gcc tgc etc tac tec 1016 Leu Val Thr Ala Ala Gly Asn Phe Arg Asp Asp Ala Cys Leu Tyr Ser 295 300 305 cca gcc tea get ccc gag gtc ate aca gtt ggg gcc ace aat gcc cag 1064 Pro Ala Ser Ala Pro Glu Val He Thr Val Gly Ala Thr Asn Ala Gin 310 315 320 gac cag ccg gtg ace ctg ggg act ttg ggg ace aac ttt ggc cgc tgt 1112 Asp Gin Pro Val Thr Leu Gly Thr Leu Gly Thr Asn Phe Gly Arg Cys 325 330 335 340 gtg gac etc ttt gcc cca ggg gag gac ate att ggt gcc tec age gac 1160 Val Asp Leu Phe Ala Pro Gly Glu Asp He He Gly Ala Ser Ser Asp 345 350 355 tgc age ace tgc ttt gtg tea cag agt ggg aca tea cag get get gcc 1208 Cys Ser Thr Cys Phe Val Ser Gin Ser Gly Thr Ser Gin Ala Ala Ala 360 365 370 cac gtg get ggc att gca gcc atg atg ctg tct gcc gag ccg gag etc 1256 His Val Ala Gly He Ala Ala Met Met Leu Ser Ala Glu Pro Glu Leu 375 380 385 ace ctg gcc gag ttg agg cag aga ctg ate cac ttc tct gcc aaa gat 1304 Thr Leu Ala Glu Leu Arg Gin Arg Leu He His Phe Ser Ala Lys Asp 390 395 400 gtc ate aat gag gcc tgg ttc cct gag gac cag egg gta ctg ace ccc 1352 Val He Asn Glu Ala Trp Phe Pro Glu Asp Gin Arg Val Leu Thr Pro 405 410 415 420 aac ctg gtg gcc gcc ctg ccc ccc age ace cat ggg gca ggt tgg cag 1400 Asn Leu Val Ala Ala Leu Pro Pro Ser Thr His Gly Ala Gly Trp Gin 425 430 435 ctg ttt tgc agg act gtg tgg tea gca cac teg ggg cct aca egg atg 1448 Leu Phe Cys Arg Thr Val Trp Ser Ala His Ser Gly Pro Thr Arg Met 440 445 450 gcc aca gcc ate gcc cgc tgc gcc cca gat gag gag ctg ctg age tgc 1496 Ala Thr Ala He Ala Arg Cys Ala Pro Asp Glu Glu Leu Leu Ser Cys 455 460 465 tec agt ttc tec agg agt ggg aag egg egg ggc gag cgc atg gag gcc 1544 Ser Ser Phe Ser Arg Ser Gly Lys Arg Arg Gly Glu Arg Met Glu Ala 470 475 480 caa ggg ggc aag ctg gtc tgc egg gcc cac aac get ttt ggg ggt gag 1592 Gin Gly Gly Lys Leu Val Cys Arg Ala His Asn Ala Phe Gly Gly Glu 485 490 495 500 ggt gtc tac gcc att gcc agg tgc tgc ctg eta ccc cag gcc aac tgc 1640 Gly Val Tyr Ala He Ala Arg Cys Cys Leu Leu Pro Gin Ala Asn Cys 505 510 515 age gtc cac aca get cca cca get gag gcc age atg ggg ace cgt gtc 1688 Ser Val His Thr Ala Pro Pro Ala Glu Ala Ser Met Gly Thr Arg Val 520 525 530 cac tgc cac caa cag ggc cac gtc etc aca ggc tgc age tec cac tgg 1736 His Cys His Gin Gin Gly His Val Leu Thr Gly Cys Ser Ser His Trp 535 540 545 gag gtg gag gac ctt ggc ace cac aag ccg cct gtg ctg agg cca cga 1784 Glu Val Glu Asp Leu Gly Thr His Lys Pro Pro Val Leu Arg Pro Arg 550 555 560 ggt cag ccc aac cag tgc gtg ggc cac agg gag gcc age ate cac get 1832 Gly Gin Pro Asn Gin Cys Val Gly His Arg Glu Ala Ser He His Ala 565 570 575 580 tec tgc tgc cat gcc cca ggt ctg gaa tgc aaa gtc aag gag cat gga 1880 Ser Cys Cys His Ala Pro Gly Leu Glu Cys Lys Val Lys Glu His Gly 585 590 595 ate ccg gcc cct cag gag cag gtg ace gtg gcc tgc gag gag ggc tgg 1928 He Pro Ala Pro Gin Glu Gin Val Thr Val Ala Cys Glu Glu Gly Trp 600 605 610 ace ctg act ggc tgc agt gcc etc cct ggg ace tec cac gtc ctg ggg 1976 Thr Leu Thr Gly Cys Ser Ala Leu Pro Gly Thr Ser His Val Leu Gly 615 620 625 gcc tac gcc gta gac aac acg tgt gta gtc agg age egg gac gtc age 2024 Ala Tyr Ala Val Asp Asn Thr Cys Val Val Arg Ser Arg Asp Val Ser 630 635 640 act aca -ggc age ace age gaa gag gcc gtg aca gcc gtt gcc ate tgc 2072 Thr Thr Gly Ser Thr Ser Glu Glu Ala Val Thr Ala Val Ala He Cys 645 650 655 660 tgc egg age egg cac ctg gcg cag gcc ttc cag gag etc cag 2114

Cys Arg Ser Arg His Leu Ala Gin Ala Phe Gin Glu Leu Gin 665 670 tgacageeee ateeeaggat gggtgtctgg ggagggtcaa gggetgggge tgagetttaa 2174 aatggttccg acttgtccct ctctcagccc ttcatg 2210

<210> 20

<211> 692

<212> PRT

<213> Homo sapiens

<400> 20

Met Gly Thr Val Ser Ser Arg Arg Ser Trp Trp Pro Leu Pro Leu Leu -15 -10 -5

Leu Leu Leu Leu Leu Leu Leu Gly Pro Ala Gly Ala Arg Ala Gin Glu -1 1 5 10

Asp Glu Asp Gly Asp Tyr Glu Glu Leu Val Leu Ala Leu Arg Ser Glu 15 20 25 30

Glu Asp Gly Leu Ala Glu Ala Pro Glu His Gly Thr Thr Ala Thr Phe 35 40 45

His Arg Cys Ala Lys Asp Pro Trp Arg Leu Pro Gly Thr Tyr Val Val 50 55 60 Val Leu Lys Glu Glu Thr His Leu Ser Gin Ser Glu Arg Thr Ala Arg 65 70 75

Arg Leu Gin Ala Gin Ala Ala Arg Arg Gly Tyr Leu Thr Lys He Leu 80 85 90

His Val Phe His Gly Leu Leu Pro Gly Phe Leu Val Lys Met Ser Gly 95 100 105 110

Asp Leu Leu Glu Leu Ala Leu Lys Leu Pro His Val Asp Tyr He Glu 115 120 125

Glu Asp Ser Ser Val Phe Ala Gin Ser He Pro Trp Asn Leu Glu Arg 130 135 140

He Thr Pro Pro Arg Tyr Arg Ala Asp Glu Tyr Gin Pro Pro Asp Gly 145 150 155

Gly Ser Leu Val Glu Val Tyr Leu Leu Asp Thr Ser He Gin Ser Asp 160 165 170

His Arg Glu He Glu Gly Arg Val Met Val Thr Asp Phe Glu Asn Val 175 180 185 190

Pro Glu Glu Asp Gly Thr Arg Phe His Arg Gin Ala Ser Lys Cys Asp 195 200 205

Ser His Gly Thr His Leu Ala Gly Val Val Ser Gly Arg Asp Ala Gly 210 215 220

Val Ala Lys Gly Ala Ser Met Arg Ser Leu Arg Val Leu Asn Cys Gin 225 230 235

Gly Lys Gly Thr Val Ser Gly Thr Leu He Gly Leu Glu Phe He Arg 240 245 250

Lys Ser Gin Leu Val Gin Pro Val Gly Pro Leu Val Val Leu Leu Pro 255 260 265 270 Leu Ala Gly Gly Tyr Ser Arg Val Leu Asn Ala Ala Cys Gin Arg Leu 275 280 285

Ala Arg Ala Gly Val Val Leu Val Thr Ala Ala Gly Asn Phe Arg Asp 290 295 300

Asp Ala Cys Leu Tyr Ser Pro Ala Ser Ala Pro Glu Val He Thr Val 305 310 315

Gly Ala Thr Asn Ala Gin Asp Gin Pro Val Thr Leu Gly Thr Leu Gly 320 325 330

Thr Asn Phe Gly Arg Cys Val Asp Leu Phe Ala Pro Gly Glu Asp He 335 340 345 350

He Gly Ala Ser Ser Asp Cys Ser Thr Cys Phe Val Ser Gin Ser Gly 355 360 365

Thr Ser Gin Ala Ala Ala His Val Ala Gly He Ala Ala Met Met Leu 370 375 380

Ser Ala Glu Pro Glu Leu Thr Leu Ala Glu Leu Arg Gin Arg Leu He 385 390 395

His Phe Ser Ala Lys Asp Val He Asn Glu Ala Trp Phe Pro Glu Asp 400 405 410

Gin Arg Val Leu Thr Pro Asn Leu Val Ala Ala Leu Pro Pro Ser Thr 415 420 425 430

His Gly Ala Gly Trp Gin Leu Phe Cys Arg Thr Val Trp Ser Ala His 435 440 445

Ser Gly Pro Thr Arg Met Ala Thr Ala He Ala Arg Cys Ala Pro Asp 450 455 460

Glu Glu Leu Leu Ser Cys Ser Ser Phe Ser Arg Ser Gly Lys Arg Arg 465 470 475

Gly Glu Arg Met Glu Ala Gin Gly Gly Lys Leu Val Cys Arg Ala His 480 485 490 Asn Ala Phe Gly Gly Glu Gly Val Tyr Ala He Ala Arg Cys Cys Leu 495 500 505 510

Leu Pro Gin Ala Asn Cys Ser Val His Thr Ala Pro Pro Ala Glu Ala 515 520 525

Ser Met Gly Thr Arg Val His Cys His Gin Gin Gly His Val Leu Thr 530 535 540

Gly Cys Ser Ser His Trp Glu Val Glu Asp Leu Gly Thr His Lys Pro 545 550 555

Pro Val Leu Arg Pro Arg Gly Gin Pro Asn Gin Cys Val Gly His Arg 560 565 570

Glu Ala Ser He His Ala Ser Cys Cys His Ala Pro Gly Leu Glu Cys 575 580 585 590

Lys Val Lys Glu His Gly He Pro Ala Pro Gin Glu Gin Val Thr Val 595 600 605

Ala Cys Glu Glu Gly Trp Thr Leu Thr Gly Cys Ser Ala Leu Pro Gly 610 615 620

Thr Ser His Val Leu Gly Ala Tyr Ala Val Asp Asn Thr Cys Val Val 625 630 635

Arg Ser Arg Asp Val Ser Thr Thr Gly Ser Thr Ser Glu Glu Ala Val 640 645 650

Thr Ala Val Ala He Cys Cys Arg Ser Arg His Leu Ala Gin Ala Phe 655 660 665 670

Gin Glu Leu Gin <210> 21

<211> 2492

<212> DNA

<213> Homo sapiens

<220>

<221> CDS

<222> (322) .. (2379)

<220>

<221> mat_peptide

<222> (376) .. ()

<220>

<221> variation

<222> (2484) .. (2484)

<223> wherein n is A, G, C, or T

<400> 21 ggccttteaa agtgtgcagt tgteteetcc ctgtccagec ccatcgtcgc eeaggaeeag 60 ctgggccgcg gtctgacctg aggctgctgc tcagcgccgg ggcgctggcg ctctccattc 120 gageaccttc cagcataccg ctcggctccg ggageegetc tgcaaagttg ggcagctcag 180 agegeaaget ttgecteteg acttctccct cettgggtcc ccggcgccce cgcctcccac 240 gatccctttc actaggagca gccagtccca gcgggctggc aacttgcacc ccttcctagt 300 catcctccct gaaacgcgac c atg ctg tta agg ggc gtc etc ctg gcg ttg 351

Met Leu Leu Arg Gly Val Leu Leu Ala Leu -15 -10 caa gcc ctg cag etc gcc ggt gcc etc gac ctg ccc get ggg tec tgt 399 Gin Ala Leu Gin Leu Ala Gly Ala Leu Asp Leu Pro Ala Gly Ser Cys -5 -1 1 5 gcc ttt gaa gag age act tgc ggc ttt gac tec gtg ttg gcc tct ctg 447 Ala Phe Glu Glu Ser Thr Cys Gly Phe Asp Ser Val Leu Ala Ser Leu 10 15 20 ccg tgg att tta aat gag gaa ggc cat tac att tat gtg gat ace tec 495 Pro Trp He Leu Asn Glu Glu Gly His Tyr He Tyr Val Asp Thr Ser 25 30 35 40 ttt ggc aag cag ggg gag aaa get gtg ctg eta agt cct gac tta cag 543 Phe Gly Lys Gin Gly Glu Lys Ala Val Leu Leu Ser Pro Asp Leu Gin 45 50 55 get gag gaa tgg age tgc etc cgt ttg gtc tac cag ata ace aca tct 591 Ala Glu Glu Trp Ser Cys Leu Arg Leu Val Tyr Gin He Thr Thr Ser 60 65 70 teg gag tct ctg tea gat ccc age cag ctg aac etc tac atg aga ttt 639 Ser Glu Ser Leu Ser Asp Pro Ser Gin Leu Asn Leu Tyr Met Arg Phe 75 80 85 gaa gat gaa age ttt gat cgc ttg ctt tgg tea get aag gaa cct tea 687 Glu Asp Glu Ser Phe Asp Arg Leu Leu Trp Ser Ala Lys Glu Pro Ser 90 95 100 gac age tgg etc ata gcc age ttg gat ttg caa aac agt tec aag aaa 735 Asp Ser Trp Leu He Ala Ser Leu Asp Leu Gin Asn Ser Ser Lys Lys 105 110 115 120 ttc aag att tta ata gaa ggt gta eta gga cag gga aac aca gcc age 783 Phe Lys He Leu He Glu Gly Val Leu Gly Gin Gly Asn Thr Ala Ser 125 130 135 ate gca eta ttt gaa ate aag atg aca ace ggc tac tgt att gaa tgt 831 He Ala Leu Phe Glu He Lys Met Thr Thr Gly Tyr Cys He Glu Cys 140 145 150 gac ttt gaa gaa aat cat etc tgt ggc ttt gtg aac cgc tgg aat ccc 879 Asp Phe Glu Glu Asn His Leu Cys Gly Phe Val Asn Arg Trp Asn Pro 155 160 165 aat gtg aac tgg ttt gtt gga gga gga agt att egg aat gtc cac tec 927 Asn Val Asn Trp Phe Val Gly Gly Gly Ser He Arg Asn Val His Ser 170 175 180 att etc cca cag gat cac ace ttc aag agt gaa ctg ggc cac tac atg 975 He Leu Pro Gin Asp His Thr Phe Lys Ser Glu Leu Gly His Tyr Met 185 190 195 200 tac gtg gac tea gtt tat gtg aag cac ttc cag gag gtg gca cag etc 1023 Tyr Val Asp Ser Val Tyr Val Lys His Phe Gin Glu Val Ala Gin Leu 205 210 215 ate tec ccg ttg ace acg gcc ccc atg get ggc tgc ctg tea ttt tat 1071 He Ser Pro Leu Thr Thr Ala Pro Met Ala Gly Cys Leu Ser Phe Tyr 220 225 230 tac cag ate cag cag ggg aat gac aat gtc ttt tec ctt tac act egg 1119 Tyr Gin He Gin Gin Gly Asn Asp Asn Val Phe Ser Leu Tyr Thr Arg 235 240 245 gat gtg get ggc ctt tac gag gaa ate tgg aaa gca gac agg cca ggg 1167 Asp Val Ala Gly Leu Tyr Glu Glu He Trp Lys Ala Asp Arg Pro Gly 250 255 260 aat get gcc tgg aac ctt gcg gag gtc gag ttc aat get cct tac ccc 1215 Asn Ala Ala Trp Asn Leu Ala Glu Val Glu Phe Asn Ala Pro Tyr Pro 265 270 275 280 atg gag gtt att ttt gaa gtt get ttc aat ggt ccc aag gga ggt tat 1263 Met Glu Val He Phe Glu Val Ala Phe Asn Gly Pro Lys Gly Gly Tyr 285 290 295 gtt gcc ctg gat gat att tea ttc tct cct gtt cac tgc cag aat cag 1311 Val Ala Leu Asp Asp He Ser Phe Ser Pro Val His Cys Gin Asn Gin 300 305 310 aca gaa ctt ctg ttc agt gcc gtg gaa gcc age tgc aat ttt gag caa 1359 Thr Glu Leu Leu Phe Ser Ala Val Glu Ala Ser Cys Asn Phe Glu Gin 315 320 325 gat etc tgc aac ttt tac caa gat aaa gaa ggt cca ggt tgg ace cga 1407 Asp Leu Cys Asn Phe Tyr Gin Asp Lys Glu Gly Pro Gly Trp Thr Arg 330 335 340 gtg aaa gta aaa cca aac atg tat egg get gga gac cac act aca ggc 1455 Val Lys Val Lys Pro Asn Met Tyr Arg Ala Gly Asp His Thr Thr Gly 345 350 355 360 tta ggg tat tac ctg eta gcc aac aca aag ttc aca tct cag cct ggc 1503 Leu Gly Tyr Tyr Leu Leu Ala Asn Thr Lys Phe Thr Ser Gin Pro Gly 365 370 375 tac att gga agg etc tat ggg ccc tec eta cca gga aac ttg cag tat 1551 Tyr He Gly Arg Leu Tyr Gly Pro Ser Leu Pro Gly Asn Leu Gin Tyr 380 385 390 tgt ctg cgt ttt cat tat gcc ate tat gga ttt tta aaa atg agt gac 1599 Cys Leu Arg Phe His Tyr Ala He Tyr Gly Phe Leu Lys Met Ser Asp 395 400 405 ace eta gca gtt tac ate ttt gaa gag aac cat gtg gtt caa gag aag 1647 Thr Leu Ala Val Tyr He Phe Glu Glu Asn His Val Val Gin Glu Lys 410 415 420 ate tgg tct gtg ttg gag tec cca agg ggt gtt tgg atg caa get gaa 1695 He Trp Ser Val Leu Glu Ser Pro Arg Gly Val Trp Met Gin Ala Glu 425 430 435 440 ate ace ttt aag aag ccc atg cct ace aag gtg gtt ttc atg age eta 1743 He Thr Phe Lys Lys Pro Met Pro Thr Lys Val Val Phe Met Ser Leu 445 450 455 tgc aaa agt ttc tgg gac tgt ggg ctt gta gcc ctg gat gac att aca 1791 Cys Lys Ser Phe Trp Asp Cys Gly Leu Val Ala Leu Asp Asp He Thr 460 465 470 ata caa ttg gga age tgc tea tct tea gag aaa ctt cca cct cca cct 1839 He Gin Leu Gly Ser Cys Ser Ser Ser Glu Lys Leu Pro Pro Pro Pro 475 480 485 gga gag tgt act ttc gag caa gat gaa tgt aca ttt act cag gag aaa 1887 Gly Glu Cys Thr Phe Glu Gin Asp Glu Cys Thr Phe Thr Gin Glu Lys 490 495 500 aga aac egg age age tgg cac agg agg agg gga gaa act ccc act tec 1935 Arg Asn Arg Ser Ser Trp His Arg Arg Arg Gly Glu Thr Pro Thr Ser 505 510 515 520 tac aca gga cca aag gga gat cac act act ggg gta ggc tac tac atg 1983 Tyr Thr Gly Pro Lys Gly Asp His Thr Thr Gly Val Gly Tyr Tyr Met 525 530 535 tac att gag gcc tec cat atg gtg tat gga caa aaa gca cgc etc ttg 2031 Tyr He Glu Ala Ser His Met Val Tyr Gly Gin Lys Ala Arg Leu Leu 540 545 550 tec agg cct ctg cga gga gtc tct gga aaa cac tgc ttg ace ttt ttc 2079 Ser Arg Pro Leu Arg Gly Val Ser Gly Lys His Cys Leu Thr Phe Phe 555 560 565 tac cac atg tat gga ggg ggc act ggc ctg ctg agt gtt tat ctg aaa 2127 Tyr His Met Tyr Gly Gly Gly Thr Gly Leu Leu Ser Val Tyr Leu Lys 570 575 580 aag gaa gaa gac agt gaa gag tec etc tta tgg agg aga aga ggt gaa 2175 Lys Glu Glu Asp Ser Glu Glu Ser Leu Leu Trp Arg Arg Arg Gly Glu 585 590 595 600 cag age att tec tgg eta cga gca ctg att gaa tac age tgt gag agg 2223 Gin Ser He Ser Trp Leu Arg Ala Leu He Glu Tyr Ser Cys Glu Arg 605 610 615 caa cac cag ata att ttt gaa gcc att cga gga gta tea ata aga agt 2271 Gin His Gin He He Phe Glu Ala He Arg Gly Val Ser He Arg Ser 620 625 630 gat att gcc att gat gat gtt aaa ttt cag gca gga ccc tgt gga gaa 2319 Asp He Ala He Asp Asp Val Lys Phe Gin Ala Gly Pro Cys Gly Glu 635 640 645 atg gaa gat aca act caa caa tea tea gga tat tct gag gac tta aat 2367 Met Glu Asp Thr Thr Gin Gin Ser Ser Gly Tyr Ser Glu Asp Leu Asn 650 655 660 gaa att gag tat taagaaatga tctgcattgg atttactaga cgaaaaccat 2419

Glu He Glu Tyr

665 acctetette aatcaaaatg aaaacaaage aaatgaatac tggaeagtet taacaattta 2479 taagntataa aat 2492 <210> 22

<211> 686

<212> PRT

<213> Homo sapiens

<400> 22

Met Leu Leu Arg Gly Val Leu Leu Ala Leu Gin Ala Leu Gin Leu Ala -15 -10 -5

Gly Ala Leu Asp Leu Pro Ala Gly Ser Cys Ala Phe Glu Glu Ser Thr -1 1 5 10

Cys Gly Phe Asp Ser Val Leu Ala Ser Leu Pro Trp He Leu Asn Glu 15 20 25 30

Glu Gly His Tyr He Tyr Val Asp Thr Ser Phe Gly Lys Gin Gly Glu 35 40 45

Lys Ala Val Leu Leu Ser Pro Asp Leu Gin Ala Glu Glu Trp Ser Cys 50 55 60

Leu Arg Leu Val Tyr Gin He Thr Thr Ser Ser Glu Ser Leu Ser Asp 65 70 75

Pro Ser Gin Leu Asn Leu Tyr Met Arg Phe Glu Asp Glu Ser Phe Asp 80 85 90

Arg Leu Leu Trp Ser Ala Lys Glu Pro Ser Asp Ser Trp Leu He Ala 95 ^' 100 105 110

Ser Leu Asp Leu Gin Asn Ser Ser Lys Lys Phe Lys He Leu He Glu 115 120 125

Gly Val Leu Gly Gin Gly Asn Thr Ala Ser He Ala Leu Phe Glu He 130 135 140

Lys Met Thr Thr Gly Tyr Cys He Glu Cys Asp Phe Glu Glu Asn His 145 150 155

Leu Cys Gly Phe Val Asn Arg Trp Asn Pro Asn Val Asn Trp Phe Val 160 165 170 Gly Gly Gly Ser He Arg Asn Val His Ser He Leu Pro Gin Asp His 175 180 185 190

Thr Phe Lys Ser Glu Leu Gly His Tyr Met Tyr Val Asp Ser Val Tyr 195 200 205

Val Lys His Phe Gin Glu Val Ala Gin Leu He Ser Pro Leu Thr Thr 210 215 220

Ala Pro Met Ala Gly Cys Leu Ser Phe Tyr Tyr Gin He Gin Gin Gly 225 230 235

Asn Asp Asn Val Phe Ser Leu Tyr Thr Arg Asp Val Ala Gly Leu Tyr 240 245 250

Glu Glu He Trp Lys Ala Asp Arg Pro Gly Asn Ala Ala Trp Asn Leu 255 260 265 270

Ala Glu Val Glu Phe Asn Ala Pro Tyr Pro Met Glu Val He Phe Glu 275 280 285

Val Ala Phe Asn Gly Pro Lys Gly Gly Tyr Val Ala Leu Asp Asp He 290 295 300

Ser Phe Ser Pro Val His Cys Gin Asn Gin Thr Glu Leu Leu Phe Ser 305 310 315

Ala Val Glu Ala Ser Cys Asn Phe Glu Gin Asp Leu Cys Asn Phe Tyr 320 325 330

Gin Asp Lys Glu Gly Pro Gly Trp Thr Arg Val Lys Val Lys Pro Asn 335 340 345 350

Met Tyr Arg Ala Gly Asp His Thr Thr Gly Leu Gly Tyr Tyr Leu Leu 355 360 365

Ala Asn Thr Lys Phe Thr Ser Gin Pro Gly Tyr He Gly Arg Leu Tyr 370 375 380 Gly Pro Ser Leu Pro Gly Asn Leu Gin Tyr Cys Leu Arg Phe His Tyr 385 390 395

Ala He Tyr Gly Phe Leu Lys Met Ser Asp Thr Leu Ala Val Tyr He 400 405 410

Phe Glu Glu Asn His Val Val Gin Glu Lys He Trp Ser Val Leu Glu 415 420 425 430

Ser Pro Arg Gly Val Trp Met Gin Ala Glu He Thr Phe Lys Lys Pro 435 440 ^' 445

Met Pro Thr Lys Val Val Phe Met Ser Leu Cys Lys Ser Phe Trp Asp 450 455 460

Cys Gly Leu Val Ala Leu Asp Asp He Thr He Gin Leu Gly Ser Cys 465 470 475

Ser Ser Ser Glu Lys Leu Pro Pro Pro Pro Gly Glu Cys Thr Phe Glu 480 485 490

Gin Asp Glu Cys Thr Phe Thr Gin Glu Lys Arg Asn Arg Ser Ser Trp 495 500 505 510

His Arg Arg Arg Gly Glu Thr Pro Thr Ser Tyr Thr Gly Pro Lys Gly 515 520 525

Asp His Thr Thr Gly Val Gly Tyr Tyr Met Tyr He Glu Ala Ser His 530 535 540

Met Val Tyr Gly Gin Lys Ala Arg Leu Leu Ser Arg Pro Leu Arg Gly 545 550 555

Val Ser Gly Lys His Cys Leu Thr Phe Phe Tyr His Met Tyr Gly Gly 560 565 570

Gly Thr Gly Leu Leu Ser Val Tyr Leu Lys Lys Glu Glu Asp Ser Glu 575 580 585 590

Glu Ser Leu Leu Trp Arg Arg Arg Gly Glu Gin Ser He Ser Trp Leu 595 600 605 Arg Ala Leu He Glu Tyr Ser Cys Glu Arg Gin His Gin He He Phe 610 615 620

Glu Ala He Arg Gly Val Ser He Arg Ser Asp He Ala He Asp Asp 625 630 635

Val Lys Phe Gin Ala Gly Pro Cys Gly Glu Met Glu Asp Thr Thr Gin 640 645 650

Gin Ser Ser Gly Tyr Ser Glu Asp Leu Asn Glu He Glu Tyr 655 660 665

<210> 23

<211> 1581

<212> DNA

<213> Homo sapiens

<220>

<221> CDS

<222> (136) .. (1386)

<220>

<221> mat_peptide

<222> (196).. ()

<400> 23 ctcaattett aaaaaataag tecatgaage agaaacatea aaaageatgg gatttggaat 60 ttgagaeetg actttgaage ccacacagaa caeagaeaag teaaccatgc tatttgggac 120 atattttgtt ccaaa atg gca tct tac ctt tat gga gta etc ttt get gtt 171 Met Ala Ser Tyr Leu Tyr Gly Val Leu Phe Ala Val -20 -15 -10 ggc etc tgt get cca ate tac tgt gtg tec ccg gtc aat gcc ccc agt 219 Gly Leu Cys Ala Pro He Tyr Cys Val Ser Pro Val Asn Ala Pro Ser -5 -1 1 5 gca tac ccc cgc cct tec tec aca aag age ace cct gcc tea cag gtg 267 Ala Tyr Pro Arg Pro Ser Ser Thr Lys Ser Thr Pro Ala Ser Gin Val 10 15 20 tat tec etc aac ace gac ttt gcc ttc cgc eta tac cgc agg ctg gtt 315 Tyr Ser Leu Asn Thr Asp Phe Ala Phe Arg Leu Tyr Arg Arg Leu Val 25 30 35 40 ttg gag ace ccg agt cag aac ate ttc ttc tec cct gtg agt gtc tec 363 Leu Glu Thr Pro Ser Gin Asn He Phe Phe Ser Pro Val Ser Val Ser 45 50 55 act tec ctg gcc atg etc tec ctt ggg gcc cac tea gtc ace aag ace 411 Thr Ser Leu Ala Met Leu Ser Leu Gly Ala His Ser Val Thr Lys Thr 60 65 70 cag att etc cag ggc ctg ggc ttc aac etc aca cac aca cca gag tct 459 Gin He Leu Gin Gly Leu Gly Phe Asn Leu Thr His Thr Pro Glu Ser 75 80 85 gcc ate cac cag ggc ttc cag cac ctg gtt cac tea ctg act gtt ccc 507 Ala He His Gin Gly Phe Gin His Leu Val His Ser Leu Thr Val Pro 90 95 100 age aaa gac ctg ace ttg aag atg gga agt gcc etc ttc gtc aag aag 555 Ser Lys Asp Leu Thr Leu Lys Met Gly Ser Ala Leu Phe Val Lys Lys 105 110 115 120 gag ctg cag ctg cag gca aat ttc ttg ggc aat gtc aag agg ctg tat 603 Glu Leu Gin Leu Gin Ala Asn Phe Leu Gly Asn Val Lys Arg Leu Tyr 125 130 135 gaa gca gaa gtc ttt tct aca gat ttc tec aac ccc tec att gcc cag 651 Glu Ala Glu Val Phe Ser Thr Asp Phe Ser Asn Pro Ser He Ala Gin 140 145 150 gcg agg ate aac age cat gtg aaa aag aag ace caa ggg aag gtt gta 699 Ala Arg He Asn Ser His Val Lys Lys Lys Thr Gin Gly Lys Val Val 155 160 165 gac ata ate caa ggc ctt gac ctt ctg acg gcc atg gtt ctg gtg aat 747 Asp He He Gin Gly Leu Asp Leu Leu Thr Ala Met Val Leu Val Asn 170 175 180 cac att ttc ttt aaa gcc aag tgg gag aag ccc ttt cac ctt gaa tat 795 His He Phe Phe Lys Ala Lys Trp Glu Lys Pro Phe His Leu Glu Tyr 185 190 195 200 aca aga aag aac ttc cca ttc ctg gtg ggc gag cag gtc act gtg caa 843 Thr Arg Lys Asn Phe Pro Phe Leu Val Gly Glu Gin Val Thr Val Gin 205 210 215 gtc ccc atg atg cac cag aaa gag cag ttc get ttt ggg gtg gat aca 891 Val Pro Met Met His Gin Lys Glu Gin Phe Ala Phe Gly Val Asp Thr 220 225 230 gag ctg aac tgc ttt gtg ctg cag atg gat tac aag gga gat gcc gtg 939 Glu Leu Asn Cys Phe Val Leu Gin Met Asp Tyr Lys Gly Asp Ala Val 235 240 245 gcc ttc ttt gtc etc cct age aag ggc aag atg agg caa ctg gaa cag 987 Ala Phe Phe Val Leu Pro Ser Lys Gly Lys Met Arg Gin Leu Glu Gin 250 255 260 gcc ttg tea gcc aga aca ctg ata aag tgg age cac tea etc cag aaa 1035 Ala Leu Ser Ala Arg Thr Leu He Lys Trp Ser His Ser Leu Gin Lys 265 270 275 280 agg tgg ata gag gtg ttc ate ccc aga ttt tec att tct gcc tec tac 1083 Arg Trp He Glu Val Phe He Pro Arg Phe Ser He Ser Ala Ser Tyr 285 290 295 aat ctg gaa ace ate etc ccg aag atg ggc ate caa aat gcc ttt gac 1131 Asn Leu Glu Thr He Leu Pro Lys Met Gly He Gin Asn Ala Phe Asp 300 305 310 aaa aat get gat ttt tct gga att gca aag aga gac tec ctg cag gtt 1179 Lys Asn Ala Asp Phe Ser Gly He Ala Lys Arg Asp Ser Leu Gin Val 315 320 325 tct aaa gca ace cac aag get gtg ctg gat gtc agt gaa gag ggc act 1227 Ser Lys Ala Thr His Lys Ala Val Leu Asp Val Ser Glu Glu Gly Thr 330 335 340 gag gcc aca gca get ace ace ace aag ttc ata gtc cga teg aag gat 1275 Glu Ala Thr Ala Ala Thr Thr Thr Lys Phe He Val Arg Ser Lys Asp 345 350 355 360 ggt ccc tct tac ttc act gtc tec ttc aat agg ace ttc ctg atg atg 1323 Gly Pro Ser Tyr Phe Thr Val Ser Phe Asn Arg Thr Phe Leu Met Met 365 370 375 att aca aat aaa gcc aca gac ggt att etc ttt eta ggg aaa gtg gaa 1371 He Thr Asn Lys Ala Thr Asp Gly He Leu Phe Leu Gly Lys Val Glu 380 385 390 aat ccc act aaa tec taggtgggaa atggcctgtt aactgatggc acattgctaa 1426 Asn Pro Thr Lys Ser 395 tgcaeaagaa ataacaaaee aeatcetctt tctgttctga gggtgeattt gaccccagtg 1486 ggagctggat tcgctggeag ggatgeeaee ttccaagget eaatcaccaa aecatcaaea 1546 gggaccccag tcacaagcca acacccatta acccc 1581

<210> 24

<211> 417

<212> PRT

<213> Homo sapiens <400> 24

Met Ala Ser Tyr Leu Tyr Gly Val Leu Phe Ala Val Gly Leu Cys Ala -20 -15 -10 -5

Pro He Tyr Cys Val Ser Pro Val Asn Ala Pro Ser Ala Tyr Pro Arg -1 1 5 10

Pro Ser Ser Thr Lys Ser Thr Pro Ala Ser Gin Val Tyr Ser Leu Asn 15 20 25

Thr Asp Phe Ala Phe Arg Leu Tyr Arg Arg Leu Val Leu Glu Thr Pro 30 35 40

Ser Gin Asn He Phe Phe Ser Pro Val Ser Val Ser Thr Ser Leu Ala 45 50 55 60

Met Leu Ser Leu Gly Ala His Ser Val Thr Lys Thr Gin He Leu Gin 65 70 75

Gly Leu Gly Phe Asn Leu Thr His Thr Pro Glu Ser Ala He His Gin 80 85 90

Gly Phe Gin His Leu Val His Ser Leu Thr Val Pro Ser Lys Asp Leu 95 100 105

Thr Leu Lys Met Gly Ser Ala Leu Phe Val Lys Lys Glu Leu Gin Leu 110 115 - 120

Gin Ala Asn Phe Leu Gly Asn Val Lys Arg Leu Tyr Glu Ala ^' Glu Val 125 130 135 140

Phe Ser Thr Asp Phe Ser Asn Pro Ser He Ala Gin Ala Arg He Asn 145 150 155

Ser His Val Lys Lys Lys Thr Gin Gly Lys Val Val Asp He He Gin 160 165 170

Gly Leu Asp Leu Leu Thr Ala Met Val Leu Val Asn His He Phe Phe 175 180 185 Lys Ala Lys Trp Glu Lys Pro Phe His Leu Glu Tyr Thr Arg Lys Asn 190 195 200

Phe Pro Phe Leu Val Gly Glu Gin Val Thr Val Gin Val Pro Met Met 205 210 215 220

His Gin Lys Glu Gin Phe Ala Phe Gly Val Asp Thr Glu Leu Asn Cys 225 230 235

Phe Val Leu Gin Met Asp Tyr Lys Gly Asp Ala Val Ala Phe Phe Val 240 245 250

Leu Pro Ser Lys Gly Lys Met Arg Gin Leu Glu Gin Ala Leu Ser Ala 255 260 265

Arg Thr Leu He Lys Trp Ser His Ser Leu Gin Lys Arg Trp He Glu 270 275 280

Val Phe He Pro Arg Phe Ser He Ser Ala Ser Tyr Asn Leu Glu Thr 285 290 295 300

He Leu Pro Lys Met Gly He Gin Asn Ala Phe Asp Lys Asn Ala Asp 305 310 315

Phe Ser Gly He Ala Lys Arg Asp Ser Leu Gin Val Ser Lys Ala Thr 320 325 330

His Lys Ala Val Leu Asp Val Ser Glu Glu Gly Thr Glu Ala Thr Ala 335 340 345

Ala Thr Thr Thr Lys Phe He Val Arg Ser Lys Asp Gly Pro Ser Tyr 350 355 360

Phe Thr Val Ser Phe Asn Arg Thr Phe Leu Met Met He Thr Asn Lys 365 370 375 380

Ala Thr Asp Gly He Leu Phe Leu Gly Lys Val Glu Asn Pro Thr Lys 385 390 395

Ser <210> 25

<211> 3027

<212> DNA

<213> Homo sapiens

<220>

<221> CDS

<222> (133) .. (2271)

<220>

<221> mat_peptide

<222> (241) .. ()

<400> 25 tggagaactg gggaggcaga gaccecgget ggeeggaggc atgtggaggg gggggcctgg 60 gcgcagggag aggcccagcg gaagecaage eaeeaggccc cccagegtee aegeggagca 120 tgaacattga gg atg gcg cgt gcc cgc ggc tec ccg tgc ccc ccg ctg ccg 171 Met Ala Arg Ala Arg Gly Ser Pro Cys Pro Pro Leu Pro -35 -30 -25 ccc ggt agg atg tec tgg ccc cac ggg gca ttg etc ttc etc tgg etc 219 Pro Gly Arg Met Ser Trp Pro His Gly Ala Leu Leu Phe Leu Trp Leu -20 -15 -10 ttc tec cca ccc ctg ggg gcc ggt gga ggt gga gtg gcc gtg acg tct 267 Phe Ser Pro Pro Leu Gly Ala Gly Gly Gly Gly Val Ala Val Thr Ser -5 -1 1 5 gcc gcc gga ggg ggc tec ccg ccg gcc ace tec tgc ccc gtg gcc tgc 315 Ala Ala Gly Gly Gly Ser Pro Pro Ala Thr Ser Cys Pro Val Ala Cys 10 15 20 25 tec tgc age aac cag gcc age egg gtg ate tgc aca egg aga gac ctg 363 Ser Cys Ser Asn Gin Ala Ser Arg Val He Cys Thr Arg Arg Asp Leu 30 35 40 gcc gag gtc cca gcc age ate ccg gtc aac acg egg tac ctg aac ctg 411 Ala Glu Val Pro Ala Ser He Pro Val Asn Thr Arg Tyr Leu Asn Leu 45 50 55 caa gag aac ggc ate cag gtg ate egg acg gac acg ttc aag cac ctg 459 Gin Glu Asn Gly He Gin Val He Arg Thr Asp Thr Phe Lys His Leu 60 65 70 egg cac ctg gag att ctg cag ctg age aag aac ctg gtg cgc aag ate 507 Arg His Leu Glu He Leu Gin Leu Ser Lys Asn Leu Val Arg Lys He 75 80 85 gag gtg ggc gcc ttc aac ggg ctg ccc age etc aac acg ctg gag ctt 555 Glu Val Gly Ala Phe Asn Gly Leu Pro Ser Leu Asn Thr Leu Glu Leu 90 95 100 105 ttt gac aac egg ctg ace acg gtg ccc acg cag gcc ttc gag tac ctg 603 Phe Asp Asn Arg Leu Thr Thr Val Pro Thr Gin Ala Phe Glu Tyr Leu 110 115 120 tec aag ctg egg gag etc tgg ctg egg aac aac ccc ate gag age ate 651 Ser Lys Leu Arg Glu Leu Trp Leu Arg Asn Asn Pro He Glu Ser He 125 130 135 ccc tec tac gcc ttc aac cgc gtg ccc teg ctg egg cgc ctg gac ctg 699 Pro Ser Tyr Ala Phe Asn Arg Val Pro Ser Leu Arg Arg Leu Asp Leu 140 145 150 ggc gag etc aag egg ctg gaa tac ate teg gag gcg gcc ttc gag ggg 747 Gly Glu Leu Lys Arg Leu Glu Tyr He Ser Glu Ala Ala Phe Glu Gly 155 160 165 ctg gtc aac ctg cgc tac etc aac ctg ggc atg tgc aac etc aag gac 795 Leu Val Asn Leu Arg Tyr Leu Asn Leu Gly Met Cys Asn Leu Lys Asp 170 175 180 185 ate ccc aac ctg acg gcc ctg gtg cgc ctg gag gag ctg gag ctg teg 843 He Pro Asn Leu Thr Ala Leu Val Arg Leu Glu Glu Leu Glu Leu Ser 190 195 200 ggc aac egg ctg gac ctg ate cgc ccg ggc tec ttc cag ggt etc ace 891 Gly Asn Arg Leu Asp Leu He Arg Pro Gly Ser Phe Gin Gly Leu Thr 205 210 215 age ctg cgc aag ctg tgg etc atg cac gcc cag gta gcc ace ate gag 939 Ser Leu Arg Lys Leu Trp Leu Met His Ala Gin Val Ala Thr He Glu 220 225 230 cgc aac gcc ttc gac gac etc aag teg ctg gag gag etc aac ctg tec 987 Arg Asn Ala Phe Asp Asp Leu Lys Ser Leu Glu Glu Leu Asn Leu Ser 235 240 245 cac aac aac ctg atg teg ctg ccc cac gac etc ttc acg ccc ctg cac 1035 His Asn Asn Leu Met Ser Leu Pro His Asp Leu Phe Thr Pro Leu His 250 255 260 265 cgc etc gag cgc gtg cac etc aac cac aac ccc tgg cat tgc aac tgc 1083 Arg Leu Glu Arg Val His Leu Asn His Asn Pro Trp His Cys Asn Cys 270 275 280 gac gtg etc tgg ctg age tgg tgg etc aag gag acg gtg ccc age aac 1131 Asp Val Leu Trp Leu Ser Trp Trp Leu Lys Glu Thr Val Pro Ser Asn 285 290 295 acg acg tgc tgc gcc cgc tgt cat gcg ccc gcc ggc etc aag ggg cgc 1179 Thr Thr Cys Cys Ala Arg Cys His Ala Pro Ala Gly Leu Lys Gly Arg 300 305 310 tac att ggg gag ctg gac cag teg cat ttc ace tgc tat gcg ccc gtc 1227 Tyr He Gly Glu Leu Asp Gin Ser His Phe Thr Cys Tyr Ala Pro Val 315 320 325 ate gtg gag ccg ccc acg gac etc aac gtc ace gag ggc atg get gcc 1275 He Val Glu Pro Pro Thr Asp Leu Asn Val Thr Glu Gly Met Ala Ala 330 335 340 345 gag etc aaa tgc cgc acg ggc ace tec atg ace tec gtc aac tgg ctg • 1323 Glu Leu Lys Cys Arg Thr Gly Thr Ser Met Thr Ser Val Asn Trp Leu 350 355 360 acg ccc aac ggc ace etc atg ace cac ggc tec tac cgc gtg cgc ate 1371 Thr Pro Asn Gly Thr Leu Met Thr His Gly Ser Tyr Arg Val Arg He 365 370 375 tec gtc ctg cat gac ggc acg ctt aac ttc ace aac gtc ace gtg cag 1419 Ser Val Leu His Asp Gly Thr Leu Asn Phe Thr Asn Val Thr Val Gin 380 385 390 gac acg ggc cag tac acg tgc atg gtg acg aac tea gcc ggc aac ace 1467 Asp Thr Gly Gin Tyr Thr Cys Met Val Thr Asn Ser Ala Gly Asn Thr 395 400 405 ace gcc teg gcc acg etc aac gtc teg gcc gtg gac ccc gtg gcg gcc 1515 Thr Ala Ser Ala Thr Leu Asn Val Ser Ala Val Asp Pro Val Ala Ala 410 415 420 425 ggg ggc ace ggc age ggc ggg ggc ggc cct ggg ggc agt ggt ggt gtt 1563 Gly Gly Thr Gly Ser Gly Gly Gly Gly Pro Gly Gly Ser Gly Gly Val 430 435 440 gga ggg ggc agt ggc ggc tac ace tac ttc ace acg gtg ace gtg gag 1611 Gly Gly Gly Ser Gly Gly Tyr Thr Tyr Phe Thr Thr Val Thr Val Glu 445 450 455 ace ctg gag acg cag ccc gga gag gag gcc ctg cag ccg egg ggg acg 1659 Thr Leu Glu Thr Gin Pro Gly Glu Glu Ala Leu Gin Pro Arg Gly Thr 460 465 470 gag aag gaa ccg cca ggg ccc acg aca gac ggt gtc tgg ggt ggg ggc 1707 Glu Lys Glu Pro Pro Gly Pro Thr Thr Asp Gly Val Trp Gly Gly Gly 475 480 485 egg cct ggg gac gcg gcc ggc cct gcc teg tct tct ace acg gca ccc 1755 Arg Pro Gly Asp Ala Ala Gly Pro Ala Ser Ser Ser Thr Thr Ala Pro 490 495 500 505 gcc ccg cgc tec teg egg ccc acg gag aag gcg ttc acg gtg ccc ate 1803 Ala Pro Arg Ser Ser Arg Pro Thr Glu Lys Ala Phe Thr Val Pro He 510 515 520 acg gat gtg acg gag aac gcc etc aag gac ctg gac gac gtc atg aag 1851 Thr Asp Val Thr Glu Asn Ala Leu Lys Asp Leu Asp Asp Val Met Lys 525 530 535 ace ace aaa ate ate ate ggc tgc ttc gtg gcc ate acg ttc atg gcc 1899 Thr Thr Lys He He He Gly Cys Phe Val Ala He Thr Phe Met Ala 540 545 550 gcg gtg atg etc gtg gcc ttc tac aag ctg cgc aag cag cac cag etc 1947 Ala Val Met Leu Val Ala Phe Tyr Lys Leu Arg Lys Gin His Gin Leu 555 560 565 cac aag cac cac ggg ccc acg cgc ace gtg gag ate ate aac gtg gag 1995 His Lys His His Gly Pro Thr Arg Thr Val Glu He He Asn Val Glu 570 575 580 585 gac gag ctg ccc gcc gcc teg gcc gtg tec gtg gcc gcc gcg gcc gcc 2043 Asp Glu Leu Pro Ala Ala Ser Ala Val Ser Val Ala Ala Ala Ala Ala 590 595 600 gtg gcc agt ggg ggt ggt gtg ggc ggg gac age cac ctg gcc ctg ccc 2091 Val Ala Ser Gly Gly Gly Val Gly Gly Asp Ser His Leu Ala Leu Pro 605 610 615 gcc ctg gag cga gac cac etc aac cac cac cac tac gtg get gcc gcc 2139 Ala Leu Glu Arg Asp His Leu Asn His His His Tyr Val Ala Ala Ala 620 625 630 ttc aag gcg cac tac age age aac ccc age ggc ggg ggc tgc ggg ggc 2187 Phe Lys Ala His Tyr Ser Ser Asn Pro Ser Gly Gly Gly Cys Gly Gly 635 640 645 aaa ggc ccg cct ggc etc aac tec ate cac gaa cct ctg etc ttc aag 2235 Lys Gly Pro Pro Gly Leu Asn Ser He His Glu Pro Leu Leu Phe Lys 650 655 660 665 age ggc tec aag gag aac gtg caa gag acg cag ate tgaggcggcg 2281

Ser Gly Ser Lys Glu Asn Val Gin Glu Thr Gin He 670 675 gggeegggcg ggegaggggc gtggagcccc ceacccaggt cceageecgg gegeagectg 2341 accgggaccc ctccctccca cagcccagcc caccttctgg gaccacgcag ggaattgggg 2401 agaggtggct tccagcccca tctggggctc ggacccccag taaggacagg gtggggctcc 2461 aggagcggag tctctgggat eetcgectca cccccgccaa tcceeggtga egggagggga 2521 egtgggacee aggagaagtg gcetgagttc teegegtttc ctcctcgctc tcceaeeaag 2581 egtteeggge cegccgcctt ecaggggaga gaggagcttt ctccaggggt gteettteec 2641 ctcggcccca aacaccttcc ttttacggtt cagtttttgc agtttgacgc ccgtccctcc 2701 ctcccactcc tecgeeetca aaactgaaga gatggaeaeg tegecagagc tccegteeea 2761 gcgcccggct ctgctcccgg ccggcggtcc ctgtcgtcgg cgcggggggg agcctccacc 2821 cgccccagcc eeaeetgccc cacagacact tttgatactg aagggaggtt tgegtcaacg 2881 actacctgct ctgtaattac tttaaaaaaa aaacatggaa aaagtaaaaa aatatttttt 2941 ttggtcatga aagcacggag gagagaaaac aaagtgaatg tgggtggggg cggaaggaga 3001 ggctggagag ccagcctcgc agctcc 3027

<210> 26

<211> 713

<212> PRT

<213> Homo sapiens

<400> 26

Met Ala Arg Ala Arg Gly Ser Pro Cys Pro Pro Leu Pro Pro Gly Arg -35 -30 -25

Met Ser Trp Pro His Gly Ala Leu Leu Phe Leu Trp Leu Phe Ser Pro -20 -15 -10 -5

Pro Leu Gly Ala Gly Gly Gly Gly Val Ala Val Thr Ser Ala Ala Gly -1 1 5 10

Gly Gly Ser Pro Pro Ala Thr Ser Cys Pro Val Ala Cys Ser Cys Ser 15 20 25

Asn Gin Ala Ser Arg Val He Cys Thr Arg Arg Asp Leu Ala Glu Val 30 35 40

Pro Ala Ser He Pro Val Asn Thr Arg Tyr Leu Asn Leu Gin Glu Asn 45 50 55 60

Gly He Gin Val He Arg Thr Asp Thr Phe Lys His Leu Arg His Leu 65 70 75

Glu He Leu Gin Leu Ser Lys Asn Leu Val Arg Lys He Glu Val Gly 80 85 90 Ala Phe Asn Gly Leu Pro Ser Leu Asn Thr Leu Glu Leu Phe Asp Asn 95 100 105

Arg Leu Thr Thr Val Pro Thr Gin Ala Phe Glu Tyr Leu Ser Lys Leu 110 115 120

Arg Glu Leu Trp Leu Arg Asn Asn Pro He Glu Ser He Pro Ser Tyr 125 130 135 140

Ala Phe Asn Arg Val Pro Ser Leu Arg Arg Leu Asp Leu Gly Glu Leu 145 150 155

Lys Arg Leu Glu Tyr He Ser Glu Ala Ala Phe Glu Gly Leu Val Asn 160 165 170

Leu Arg Tyr Leu Asn Leu Gly Met Cys Asn Leu Lys Asp He Pro Asn 175 180 185

Leu Thr Ala Leu Val Arg Leu Glu Glu Leu Glu Leu Ser Gly Asn Arg 190 195 200

Leu Asp Leu He Arg Pro Gly Ser Phe Gin Gly Leu Thr Ser Leu Arg 205 210 215 220

Lys Leu Trp Leu Met His Ala Gin Val Ala Thr He Glu Arg Asn Ala 225 230 235

Phe Asp Asp Leu Lys Ser Leu Glu Glu Leu Asn Leu Ser His Asn Asn 240 245 250

Leu Met Ser Leu Pro His Asp Leu Phe Thr Pro Leu His Arg Leu Glu 255 260 265

Arg Val His Leu Asn His Asn Pro Trp His Cys Asn Cys Asp Val Leu 270 275 280

Trp Leu Ser Trp Trp Leu Lys Glu Thr Val Pro Ser Asn Thr Thr Cys 285 290 295 300 Cys Ala Arg Cys His Ala Pro Ala Gly Leu Lys Gly Arg Tyr He Gly 305 310 315

Glu Leu Asp Gin Ser His Phe Thr Cys Tyr Ala Pro Val He Val Glu 320 325 330

Pro Pro Thr Asp Leu Asn Val Thr Glu Gly Met Ala Ala Glu Leu Lys 335 340 345

Cys Arg Thr Gly Thr Ser Met Thr Ser Val Asn Trp Leu Thr Pro Asn 350 355 360

Gly Thr Leu Met Thr His Gly Ser Tyr Arg Val Arg He Ser Val Leu 365 370 375 380

His Asp Gly Thr Leu Asn Phe Thr Asn Val Thr Val Gin Asp Thr Gly 385 390 395

Gin Tyr Thr Cys Met Val Thr Asn Ser Ala Gly Asn Thr Thr Ala Ser 400 405 410

Ala Thr Leu Asn Val Ser Ala Val Asp Pro Val Ala Ala Gly Gly Thr 415 420 425

Gly Ser Gly Gly Gly Gly Pro Gly Gly Ser Gly Gly Val Gly Gly Gly 430 435 440

Ser Gly Gly Tyr Thr Tyr Phe Thr Thr Val Thr Val Glu Thr Leu Glu 445 450 455 460

Thr Gin Pro Gly Glu Glu Ala Leu Gin Pro Arg Gly Thr Glu Lys Glu 465 470 475

Pro Pro Gly Pro Thr Thr Asp Gly Val Trp Gly Gly Gly Arg Pro Gly 480 485 490

Asp Ala Ala Gly Pro Ala Ser Ser Ser Thr Thr Ala Pro Ala Pro Arg 495 500 505

Ser Ser Arg Pro Thr Glu Lys Ala Phe Thr Val Pro He Thr Asp Val 510 515 520 Thr Glu Asn Ala Leu Lys Asp Leu Asp Asp Val Met Lys Thr Thr Lys 525 530 535 540

He He He Gly Cys Phe Val Ala He Thr Phe Met Ala Ala Val Met 545 550 555

Leu Val Ala Phe Tyr Lys Leu Arg Lys Gin His Gin Leu His Lys His 560 565 570

His Gly Pro Thr Arg Thr Val Glu He He Asn Val Glu Asp Glu Leu 575 580 585

Pro Ala Ala Ser Ala Val Ser Val Ala Ala Ala Ala Ala Val Ala Ser 590 595 600

Gly Gly Gly Val Gly Gly Asp Ser His Leu Ala Leu Pro Ala Leu Glu 605 610 615 620

Arg Asp His Leu Asn His His His Tyr Val Ala Ala Ala Phe Lys Ala 625 630 635

His Tyr Ser Ser Asn Pro Ser Gly Gly Gly Cys Gly Gly Lys Gly Pro 640 645 650

Pro Gly Leu Asn Ser He His Glu Pro Leu Leu Phe Lys Ser Gly Ser 655 660 665

Lys Glu Asn Val Gin Glu Thr Gin He 670 675

<210> 27

<211> 1416

<212> DNA

<213> Homo sapiens

<220>

<221> CDS

<222> (96) .. (1364)

<220>

<221> mat_peptide

<222> (171).. () <400> 27 gtetggagat ggggggeggt ggtggccaca gcagaggctc caggaggtga eegeetggtt 60 tccattagga agtcctggtc agcagcttgg gcgag atg gca gag tea ggg ctg 113

Met Ala Glu Ser Gly Leu -25 -20 gcc atg tgg ccg age ctg ctg ctg etc ctg ctg ttg ccg ggg ccc ccg 161 Ala Met Trp Pro Ser Leu Leu Leu Leu Leu Leu Leu Pro Gly Pro Pro -15 -10 -5 ccc gtc gcc ggc ttg gaa gac get gcc ttc ccc cac ctg ggg gag age 209 Pro Val Ala Gly Leu Glu Asp Ala Ala Phe Pro His Leu Gly Glu Ser -1 1 5 10 ttg cag ccc ctg ccc egg gcc tgt ccc ctg cgc tgc tec tgc ccc cga 257 Leu Gin Pro Leu Pro Arg Ala Cys Pro Leu Arg Cys Ser Cys Pro Arg 15 20 25 gtc gac act gtg gac tgt gat ggc ttg gac ctt cga gtg ttc ccg gac 305 Val Asp Thr Val Asp Cys Asp Gly Leu Asp Leu Arg Val Phe Pro Asp 30 35 40 45 aac ate ace aga gcc get cag cac etc tec ctg cag aac aac cag etc 353 Asn He Thr Arg Ala Ala Gin His Leu Ser Leu Gin Asn Asn Gin Leu 50 55 60 cag gaa etc ccc tac aat gag ctg tec cgc etc agt ggc ctg cga ace 401 Gin Glu Leu Pro Tyr Asn Glu Leu Ser Arg Leu Ser Gly Leu Arg Thr 65 70 75 etc aac etc cac aac aac etc ate tec tec gaa ggc ctg cct gac gag 449 Leu Asn Leu His Asn Asn Leu He Ser Ser Glu Gly Leu Pro Asp Glu 80 85 90 gcc ttc gag tec etc ace cag ctg cag cac etc tgc gtg get cac aac 497 Ala Phe Glu Ser Leu Thr Gin Leu Gin His Leu Cys Val Ala His Asn 95 100 105 aag aac aat etc ate tec aag gtg ccc cga gga gcc ctg age cgc cag 545 Lys Asn Asn Leu He Ser Lys Val Pro Arg Gly Ala Leu Ser Arg Gin 110 115 120 125 act caa etc cgt gag etc tac etc cag cac aac cag ctg aca gac agt 593 Thr Gin Leu Arg Glu Leu Tyr Leu Gin His Asn Gin Leu Thr Asp Ser 130 135 140 ggc ctg gat gcc ace ace ttc age aag ctg cat age ctt gaa tac ctg 641 Gly Leu Asp Ala Thr Thr Phe Ser Lys Leu His Ser Leu Glu Tyr Leu 145 150 155 gat etc tec cac aac cag ctg ace aca gtg ccc gcc ggc ctg ccc egg 689 Asp Leu Ser His Asn Gin Leu Thr Thr Val Pro Ala Gly Leu Pro Arg 160 165 170 ace ctg get ate ctg cac ctg ggc cgc aac cgc ate egg cag gtg gag 737 Thr Leu Ala He Leu His Leu Gly Arg Asn Arg He Arg Gin Val Glu 175 180 185 gcg get egg ctg cac ggg gcg cgt ggt ctg cgc tat ttg ttg ctg cag 785 Ala Ala Arg Leu His Gly Ala Arg Gly Leu Arg Tyr Leu Leu Leu Gin 190 195 200 205 cac aac cag ctg ggg age tea ggg ctg ccc gcc ggg get ctg egg ccg 833 His Asn Gin Leu Gly Ser Ser Gly Leu Pro Ala Gly Ala Leu Arg Pro 210 215 220 ctg egg ggc ctg cac acg ctg cac etc tat ggc aat ggg ctg gac cgc 881 Leu Arg Gly Leu His Thr Leu His Leu Tyr Gly Asn Gly Leu Asp Arg 225 230 235 gtg cct cca gcc ctg ccc cgc cgc ctg cgt gcc ctg gtg ctg ccc cac 929 Val Pro Pro Ala Leu Pro Arg Arg Leu Arg Ala Leu Val Leu Pro His 240 245 250 aac cac gtg gcc gcg ctg ggt gcc cgt gac ctg gtc gcc aca ccg ggc 977 Asn His Val Ala Ala Leu Gly Ala Arg Asp Leu Val Ala Thr Pro Gly 255 260 265 ctg acg gag ctt aac ctg gcc tat aac cgc ctg gcc age gcc cgt gtg 1025 Leu Thr Glu Leu Asn Leu Ala Tyr Asn Arg Leu Ala Ser Ala Arg Val 270 275 280 285 cac cac egg gcc ttc cgc egg ttg cgt gcc ctg cgc age etc gac ctg 1073 His His Arg Ala Phe Arg Arg Leu Arg Ala Leu Arg Ser Leu Asp Leu 290 295 300 gca ggg aat cag eta ace egg ctg ccc atg ggc ctg ccc act ggc ctg 1121 Ala Gly Asn Gin Leu Thr Arg Leu Pro Met Gly Leu Pro Thr Gly Leu 305 310 315 cgc ace ctg cag ctg caa cgc aac cag ctg egg atg etc gag ccc gag 1169 Arg Thr Leu Gin Leu Gin Arg Asn Gin Leu Arg Met Leu Glu Pro Glu 320 325 330 cct ctg gcc ggc ctg gac caa ctg egg gag etc age ctg gcg cac aac 1217 Pro Leu Ala Gly Leu Asp Gin Leu Arg Glu Leu Ser Leu Ala His Asn 335 340 345 egg etc egg gtc ggc gac ate ggg cca ggc ace tgg cat gag etc caa 1265 Arg Leu Arg Val Gly Asp He Gly Pro Gly Thr Trp His Glu Leu Gin 350 355 360 365 gcc etc cag gtc agg cac agg ctg gtt age cac act gtc ccc agg gcc 1313 Ala Leu Gin Val Arg His Arg Leu Val Ser His Thr Val Pro Arg Ala 370 375 380 cct cca tec ccc tgc ctg ccc tgc cac gtc cca aac att eta gtt age 1361 Pro Pro Ser Pro Cys Leu Pro Cys His Val Pro Asn He Leu Val Ser 385 390 395 tgg taaagcaatc agaacaagaa aatgataaga gtgggttaga aggtgatgag ga 1416 Trp

<210> 28

<211> 423

<212> PRT

<213> Homo sapiens

<400> 28

Met Ala Glu Ser Gly Leu Ala Met Trp Pro Ser Leu Leu Leu Leu Leu -25 -20 -15 -10

Leu Leu Pro Gly Pro Pro Pro Val Ala Gly Leu Glu Asp Ala Ala Phe -5 -1 1 5

Pro His Leu Gly Glu Ser Leu Gin Pro Leu Pro Arg Ala Cys Pro Leu 10 15 20

Arg Cys Ser Cys Pro Arg Val Asp Thr Val Asp Cys Asp Gly Leu Asp 25 30 35

Leu Arg Val Phe Pro Asp Asn He Thr Arg Ala Ala Gin His Leu Ser 40 45 50 55

Leu Gin Asn Asn Gin Leu Gin Glu Leu Pro Tyr Asn Glu Leu Ser Arg 60 65 70

Leu Ser Gly Leu Arg Thr Leu Asn Leu His Asn Asn Leu He Ser Ser 75 80 85

Glu Gly Leu Pro Asp Glu Ala Phe Glu Ser Leu Thr Gin Leu Gin His 90 95 100

Leu Cys Val Ala His Asn Lys Asn Asn Leu He Ser Lys Val Pro Arg 105 110 115 Gly Ala Leu Ser Arg Gin Thr Gin Leu Arg Glu Leu Tyr Leu Gin His 120 125 130 135

Asn Gin Leu Thr Asp Ser Gly Leu Asp Ala Thr Thr Phe Ser Lys Leu 140 145 150

His Ser Leu Glu Tyr Leu Asp Leu Ser His Asn Gin Leu Thr Thr Val 155 160 165

Pro Ala Gly Leu Pro Arg Thr Leu Ala He Leu His Leu Gly Arg Asn 170 175 180

Arg He Arg Gin Val Glu Ala Ala Arg Leu His Gly Ala Arg Gly Leu 185 190 195

Arg Tyr Leu Leu Leu Gin His Asn Gin Leu Gly Ser Ser Gly Leu Pro 200 205 210 215

Ala Gly Ala Leu Arg Pro Leu Arg Gly Leu His Thr Leu His Leu Tyr 220 225 230

Gly Asn Gly Leu Asp Arg Val Pro Pro Ala Leu Pro Arg Arg Leu Arg 235 240 245

Ala Leu Val Leu Pro His Asn His Val Ala Ala Leu Gly Ala Arg Asp 250 ^' 255 260

Leu Val Ala Thr Pro Gly Leu Thr Glu Leu Asn Leu Ala Tyr Asn Arg 265 270 275

Leu Ala Ser Ala Arg Val His His Arg Ala Phe Arg Arg Leu Arg Ala 280 285 290 295

Leu Arg Ser Leu Asp Leu Ala Gly Asn Gin Leu Thr Arg Leu Pro Met 300 305 310

Gly Leu Pro Thr Gly Leu Arg Thr Leu Gin Leu Gin Arg Asn Gin Leu 315 320 325 Arg Met Leu Glu Pro Glu Pro Leu Ala Gly Leu Asp Gin Leu Arg Glu 330 335 340

Leu Ser Leu Ala His Asn Arg Leu Arg Val Gly Asp He Gly Pro Gly 345 350 355

Thr Trp His Glu Leu Gin Ala Leu Gin Val Arg His Arg Leu Val Ser 360 365 370 375

His Thr Val Pro Arg Ala Pro Pro Ser Pro Cys Leu Pro Cys His Val 380 385 390

Pro Asn He Leu Val Ser Trp 395

<210> 29

<211> 445

<212> DNA

<213> Homo sapiens

<220>

<221> CDS

<222> (25) .. (330)

<220>

<221> mat_peptide

<222> (76) .. ()

<400> 29 ctgagagcag agctggccgc agcc atg ace ccg cag ctt etc ctg gcc ctt 51

Met Thr Pro Gin Leu Leu Leu Ala Leu -15 -10 gtc etc tgg gcc age tgc ccg ccc tgc agt gga agg aaa ggg ccc cca 99 Val Leu Trp Ala Ser Cys Pro Pro Cys Ser Gly Arg Lys Gly Pro Pro -5 -1 1 5 gca get ctg aca ctg ccc egg gtg caa tgc cga gcc tct egg tac ccg 147 Ala Ala Leu Thr Leu Pro Arg Val Gin Cys Arg Ala Ser Arg Tyr Pro 10 15 20 ate gcc gtg gat tgc tec tgg ace ctg ccg cct get cca aac tec ace 195 He Ala Val Asp Cys Ser Trp Thr Leu Pro Pro Ala Pro Asn Ser Thr 25 30 35 40 age ccc gtg tec ttc att gcc acg tac agg teg gag age ctg gaa ggg 243 Ser Pro Val Ser Phe He Ala Thr Tyr Arg Ser Glu Ser Leu Glu Gly 45 50 55 ggc etc agg gac act gga ctt cct gga gag ccc aga act ctg gcc ctg 291 Gly Leu Arg Asp Thr Gly Leu Pro Gly Glu Pro Arg Thr Leu Ala Leu 60 65 70 aga gcc ctg ggg tea gga aaa ctg gag ace ccg aca tec tgaaccccag 340 Arg Ala Leu Gly Ser Gly Lys Leu Glu Thr Pro Th Ser 75 80 85 gcctatggaa ttctagggeg gceccgtcea atagaaatat actttctggg ccaggaaaaa 400 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa gaaaaaaaaa aaaaa 445

<210> 30

<211> 102

<212> PRT

<213> Homo sapiens

<400> 30

Met Thr Pro Gin Leu Leu Leu Ala Leu Val Leu Trp Ala Ser Cys Pro -15 -10 -5

Pro Cys Ser Gly Arg Lys Gly Pro Pro Ala Ala Leu Thr Leu Pro Arg -1 1 5 10 15

Val Gin Cys Arg Ala Ser Arg Tyr Pro He Ala Val Asp Cys Ser Trp 20 25 30

Thr Leu Pro Pro Ala Pro Asn Ser Thr Ser Pro Val Ser Phe He Ala 35 40 45

Thr Tyr Arg Ser Glu Ser Leu Glu Gly Gly Leu Arg Asp Thr Gly Leu 50 55 60

Pro Gly Glu Pro Arg Thr Leu Ala Leu Arg Ala Leu Gly Ser Gly Lys 65 70 75

Leu Glu Thr Pro Thr Ser 80 85

<210> 31

<211> 1858

<212> DNA

<213> Homo sapiens <220>

<221> CDS

<222> (1)..(1761)

<220>

<221> mat_peptide

<222> (79) .. ()

<400> 31 atg gtc tec cca egg atg tec ggg etc etc tec cag act gtg ate eta 48 Met Val Ser Pro Arg Met Ser Gly Leu Leu Ser Gin Thr Val He Leu -25 -20 -15 gcg etc att ttc etc ccc cag aca egg ccc get ggc gtc ttc gag ctg 96 Ala Leu He Phe Leu Pro Gin Thr Arg Pro Ala Gly Val Phe Glu Leu -10 -5 -1 1 5 cag ate cac tct ttc ggg ccg ggt cca ggc cct ggg gcc ccg egg tec 144 Gin He His Ser Phe Gly Pro Gly Pro Gly Pro Gly Ala Pro Arg Ser 10 15 20 ccc tgc age gcc egg etc ccc tgc cgc etc ttc ttc aga gtc tgc ctg 192 Pro Cys Ser Ala Arg Leu Pro Cys Arg Leu Phe Phe Arg Val Cys Leu 25 30 35 aag cct ggg etc tea gag gag gcc gcc gag tec ccg tgc gcc ctg ggc 240 Lys Pro Gly Leu Ser Glu Glu Ala Ala Glu Ser Pro Cys Ala Leu Gly 40 45 50 gcg gcg ctg agt gcg cgc gga ccg gtc tac ace gag cag ccc gga gcg 288

Ala Ala Leu Ser Ala Arg Gly Pro Val Tyr Thr Glu Gin Pro Gly Ala 55 60 65 70 ccc gcg cct gat etc cca ctg ccc gac ggc etc ttg cag gtg ccc ttc 336 Pro Ala Pro Asp Leu Pro Leu Pro Asp Gly Leu Leu Gin Val Pro Phe 75 80 85 egg gac gcc tgg cct ggc ace ttc tct ttc ate ate gaa ace tgg aga 384 Arg Asp Ala Trp Pro Gly Thr Phe Ser Phe He He Glu Thr Trp Arg 90 95 100 gag gag tta gga gac cag att gga ggg ccc gcc tgg age ctg ctg gcg 432 Glu Glu Leu Gly Asp Gin He Gly Gly Pro Ala Trp Ser Leu Leu Ala 105 110 115 cgc gtg get ggc agg egg cgc ttg gca gcc gga ggc ccg tgg gcc egg 480 Arg Val Ala Gly Arg Arg Arg Leu Ala Ala Gly Gly Pro Trp Ala Arg 120 125 130 gac att cag cgc gca ggc gcc tgg gag ctg cgc tgc teg tac cgc gcg 528 Asp He Gin Arg Ala Gly Ala Trp Glu Leu Arg Cys Ser Tyr Arg Ala 135 140 145 150 cgc tgc gag ccg cct gcg gtc ggg ace gcg tgc acg cgc etc tgc cgt 576 Arg Cys Glu Pro Pro Ala Val Gly Thr Ala Cys Thr Arg Leu Cys Arg 155 160 165 ccg cgc age gcc ccc teg egg tgc ggt ccg gga ctg cgc ccc tgc gca 624 Pro Arg Ser Ala Pro Ser Arg Cys Gly Pro Gly Leu Arg Pro Cys Ala 170 175 180 ccg etc gag gac gaa tgt gag gcg ccg ccg gtg tgc cga gca ggc tgc 672 Pro Leu Glu Asp Glu Cys Glu Ala Pro Pro Val Cys Arg Ala Gly Cys 185 190 195 age cct gag cat ggc ttc tgt gaa cag ccc ggt gaa tgc cga tgc eta 720 Ser Pro Glu His Gly Phe Cys. Glu Gin Pro Gly Glu Cys Arg Cys Leu 200 205 210 gag ggc tgg act gga ccc etc tgc acg gtc cct gtc tec ace age age 768 Glu Gly Trp Thr Gly Pro Leu Cys Thr Val Pro Val Ser Thr Ser Ser 215 220 225 230 tgc etc age ccc agg ggc ccg tec tct get ace ace gga tgc ctt gtc 816 Cys Leu Ser Pro Arg Gly Pro Ser Ser Ala Thr Thr Gly Cys Leu Val 235 240 245 cct ggg cct ggg ccc tgt gac ggg aac ccg tgt gcc aat gga ggc age 864 Pro Gly Pro Gly Pro Cys Asp Gly Asn Pro Cys Ala Asn Gly Gly Ser 250 255 260 tgt agt gag aca ccc agg tec ttt gaa tgc ace tgc ccg cgt ggg ttc 912 Cys Ser Glu Thr Pro Arg Ser Phe Glu Cys Thr Cys Pro Arg Gly Phe 265 270 275 tac ggg ctg egg tgt gag gtg age ggg gtg aca tgt gca gat gga ccc 960 Tyr Gly Leu Arg Cys Glu Val Ser Gly Val Thr Cys Ala Asp Gly Pro 280 285 290 tgc ttc aac ggc ggc ttg tgt gtc ggg ggt gca gac cct gac tct gcc 1008 Cys Phe Asn Gly Gly Leu Cys Val Gly Gly Ala Asp Pro Asp Ser Ala 295 300 305 310 tac ate tgc cac tgc cca cct ggt ttc caa ggc tec aac tgt gag aag 1056 Tyr He Cys His Cys Pro Pro Gly Phe Gin Gly Ser Asn Cys Glu Lys 315 320 325 agg gtg gac egg tgc age ctg cag cca tgc cgc aat ggc gga etc tgc 1104 Arg Val Asp Arg Cys Ser Leu Gin Pro Cys Arg Asn Gly Gly Leu Cys 330 335 340 ctg gac ctg ggc cac gcc ctg cgc tgc cgc tgc cgc gcc ggc ttc gcg 1152 Leu Asp Leu Gly His Ala Leu Arg Cys Arg Cys Arg Ala Gly Phe Ala 345 350 355 ggt cct cgc tgc gag cac gac ctg gac gac tgc gcg ggc cgc gcc tgc 1200 Gly Pro Arg Cys Glu His Asp Leu Asp Asp Cys Ala Gly Arg Ala Cys 360 365 370 get aac ggc ggc acg tgt gtg gag ggc ggc ggc gcg cac cgc tgc tec 1248 Ala Asn Gly Gly Thr Cys Val Glu Gly Gly Gly Ala His Arg Cys Ser 375 380 385 390 tgc gcg ctg ggc ttc ggc ggc cgc gac tgc cgc gag cgc gcg gac ccg 1296 Cys Ala Leu Gly Phe Gly Gly Arg Asp Cys Arg Glu Arg Ala Asp Pro 395 400 405 tgc gcc gcg cgc ccc tgt get cac ggc ggc cgc tgc tac gcc cac ttc 1344 Cys Ala Ala Arg Pro Cys Ala His Gly Gly Arg Cys Tyr Ala His Phe 410 415 420 tec ggc etc gtc tgc get tgc get ccc ggc tac atg gga gcg egg tgt 1392 Ser Gly Leu Val Cys Ala Cys Ala Pro Gly Tyr Met Gly Ala Arg Cys 425 430 435 gag ttc cca gtg cac ccc gac ggc gca age gcc ttg ccc gcg gcc ccg 1440 Glu Phe Pro Val His Pro Asp Gly Ala Ser Ala Leu Pro Ala Ala Pro 440 445 450 ccg ggc etc agg ccc ggg gac cct cag cgc tac ctt ttg cct ccg get 1488 Pro Gly Leu Arg Pro Gly Asp Pro Gin Arg Tyr Leu Leu Pro Pro Ala 455 460 465 470 ctg gga ctg etc gtg gcc gcg ggc gtg gcc ggc get gcg etc ttg ctg 1536 Leu Gly Leu Leu Val Ala Ala Gly Val Ala Gly Ala Ala Leu Leu Leu 475 480 485 gtc cac gtg cgc cgc cgt ggc cac tec cag gat get ggg tct cgc ttg 1584 Val His Val Arg Arg Arg Gly His Ser Gin Asp Ala Gly Ser Arg Leu 490 495 500 ctg get ggg ace ccg gag ccg tea gtc cac gca etc ccg gat gca etc 1632 Leu Ala Gly Thr Pro Glu Pro Ser Val His Ala Leu Pro Asp Ala Leu 505 510 515 aac aac eta agg acg cag gag ggt tec ggg gat ggt ccg age teg tec 1680 Asn Asn Leu Arg Thr Gin Glu Gly Ser Gly Asp Gly Pro Ser Ser Ser 520 525 530 gta gat tgg aat cgc cct gaa gat gta gac cct caa ggg att tat gtc 1728 Val Asp Trp Asn Arg Pro Glu Asp Val Asp Pro Gin Gly He Tyr Val 535 540 545 550 ata tct get cct tec ate tac get egg gag gcc tgacgcgtct cctccateeg 1781 He Ser Ala Pro Ser He Tyr Ala Arg Glu Ala 555 560 eacctggagt cagagcgtgg atttttgtat ttgetcggtg gtgeeeagtc tctgccecag 1841 aggctttgga gttcaat 1858

<210> 32

<211> 587

<212> PRT

<213> Homo sapiens

<400> 32

Met Val Ser Pro Arg Met Ser Gly Leu Leu Ser Gin Thr Val He Leu -25 -20 -15

Ala Leu He Phe Leu Pro Gin Thr Arg Pro Ala Gly Val Phe Glu Leu -10 -5 -1 1 5

Gin He His Ser Phe Gly Pro Gly Pro Gly Pro Gly Ala Pro Arg Ser 10 15 20

Pro Cys Ser Ala Arg Leu Pro Cys Arg Leu Phe Phe Arg Val Cys Leu 25 30 35

Lys Pro Gly Leu Ser Glu Glu Ala Ala Glu Ser Pro Cys Ala Leu Gly 40 45 50

Ala Ala Leu Ser Ala Arg Gly Pro Val Tyr Thr Glu Gin Pro Gly Ala 55 60 65 70

Pro Ala Pro Asp Leu Pro Leu Pro Asp Gly Leu Leu Gin Val Pro Phe 75 80 85

Arg Asp Ala Trp Pro Gly Thr Phe Ser Phe He He Glu Thr Trp Arg 90 95 100

Glu Glu Leu Gly Asp Gin He Gly Gly Pro Ala Trp Ser Leu Leu Ala 105 110 115

Arg Val Ala Gly Arg Arg Arg Leu Ala Ala Gly Gly Pro Trp Ala Arg 120 125 130

Asp He Gin Arg Ala Gly Ala Trp Glu Leu Arg Cys Ser Tyr Arg Ala 135 140 145 150 Arg Cys Glu Pro Pro Ala Val Gly Thr Ala Cys Thr Arg Leu Cys Arg 155 160 165

Pro Arg Ser Ala Pro Ser Arg Cys Gly Pro Gly Leu Arg Pro Cys Ala 170 175 180

Pro Leu Glu Asp Glu Cys Glu Ala Pro Pro Val Cys Arg Ala Gly Cys 185 190 195

Ser Pro Glu His Gly Phe Cys Glu Gin Pro Gly Glu Cys Arg Cys Leu 200 205 210

Glu Gly Trp Thr Gly Pro Leu Cys Thr Val Pro Val Ser Thr Ser Ser 215 220 225 230

Cys Leu Ser Pro Arg Gly Pro Ser Ser Ala Thr Thr Gly Cys Leu Val 235 240 245

Pro Gly Pro Gly Pro Cys Asp Gly Asn Pro Cys Ala Asn Gly Gly Ser 250 255 260

Cys Ser Glu Thr Pro Arg Ser Phe Glu Cys Thr Cys Pro Arg Gly Phe 265 270 275

Tyr Gly Leu Arg Cys Glu Val Ser Gly Val Thr Cys Ala Asp Gly Pro 280 285 290

Cys Phe Asn Gly Gly Leu Cys Val Gly Gly Ala Asp Pro Asp Ser Ala 295 300 305 310

Tyr He Cys His Cys Pro Pro Gly Phe Gin Gly Ser Asn Cys Glu Lys 315 320 325

Arg Val Asp Arg Cys Ser Leu Gin Pro Cys Arg Asn Gly Gly Leu Cys 330 335 340

Leu Asp Leu Gly His Ala Leu Arg Cys Arg Cys Arg Ala Gly Phe Ala 345 350 355

Gly Pro Arg Cys Glu His Asp Leu Asp Asp Cys Ala Gly Arg Ala Cys 360 365 370 Ala Asn Gly Gly Thr Cys Val Glu Gly Gly Gly Ala His Arg Cys Ser 375 380 385 390

Cys Ala Leu Gly Phe Gly Gly Arg Asp Cys Arg Glu Arg Ala Asp Pro 395 400 405

Cys Ala Ala Arg Pro Cys Ala His Gly Gly Arg Cys Tyr Ala His Phe 410 415 420

Ser Gly Leu Val Cys Ala Cys Ala Pro Gly Tyr Met Gly Ala Arg Cys 425 430 435

Glu Phe Pro Val His Pro Asp Gly Ala Ser Ala Leu Pro Ala Ala Pro 440 445 450

Pro Gly Leu Arg Pro Gly Asp Pro Gin Arg Tyr Leu Leu Pro Pro Ala 455 460 465 470

Leu Gly Leu Leu Val Ala Ala Gly Val Ala Gly Ala Ala Leu Leu Leu 475 480 485

Val His Val Arg Arg Arg Gly His Ser Gin Asp Ala Gly Ser Arg Leu 490 495 500

Leu Ala Gly Thr Pro Glu Pro Ser Val His Ala Leu Pro Asp Ala Leu 505 510 515

Asn Asn Leu Arg Thr Gin Glu Gly Ser Gly Asp Gly Pro Ser Ser Ser 520 525 530

Val Asp Trp Asn Arg Pro Glu Asp Val Asp Pro Gin Gly He Tyr Val 535 540 545 550

He Ser Ala Pro Ser He Tyr Ala Arg Glu Ala 555 560 <210> 33

<211> 1968

<212> DNA

<213> Homo sapiens

<220>

<221> CDS

<222> (25) .. (1926)

<220>

<221> mat_peptide

<222> (79).. ()

<400> 33 acagcaacct ctcccctggc cctc atg ggc ace gtc age tec agg egg tec 51

Met Gly Thr Val Ser Ser Arg Arg Ser -15 -10 tgg tgg ccg ctg cca ctg ctg ctg ctg ctg ctg ctg etc ctg ggt ccc 99 Trp Trp Pro Leu Pro Leu Leu Leu Leu Leu Leu Leu Leu Leu Gly Pro -5 -1 1 5 gcg ggc gcc cgt gcg cag gag gac gag gac ggc gac tac gag gag ctg 147 Ala Gly Ala Arg Ala Gin Glu Asp Glu Asp Gly Asp Tyr Glu Glu Leu 10 15 20 gtg eta gcc ttg cgt tec gag gag gac ggc ctg gcc gaa gca ccc gag 195 Val Leu Ala Leu Arg Ser Glu Glu Asp Gly Leu Ala Glu Ala Pro Glu 25 30 35 cac gga ace aca gcc ace ttc cac cgc tgc gcc aag gat ccg tgg agg 243 His Gly Thr Thr Ala Thr Phe His Arg Cys Ala Lys Asp Pro Trp Arg 40 45 50 55 ttg cct ggc ace tac gtg gtg gtg ctg aag gag gag ace cac etc teg 291 Leu Pro Gly Thr Tyr Val Val Val Leu Lys Glu Glu Thr His Leu Ser 60 65 70 cag tea gag cgc act gcc cgc cgc ctg cag gcc cag get gcc cgc egg 339 Gin Ser Glu Arg Thr Ala Arg Arg Leu Gin Ala Gin Ala Ala Arg Arg 75 80 85 gga tac etc ace aag ate ctg cat gtc ttc cat ggc ctt ctt cct ggc 387 Gly Tyr Leu Thr Lys He Leu His Val Phe His Gly Leu Leu Pro Gly 90 95 100 ttc ctg gtg aag atg agt ggc gac ctg ctg gag ctg gcc ttg aag ttg 435 Phe Leu Val Lys Met Ser Gly Asp Leu Leu Glu Leu Ala Leu Lys Leu 105 110 115 ccc cat gtc gac tac ate gag gag gac tec tct gtc ttt gcc cag age 483 Pro His Val Asp Tyr He Glu Glu Asp Ser Ser Val Phe Ala Gin Ser 120 125 130 135 ate ccg tgg aac ctg gag egg att ace cct cca egg tac egg gcg gat 531 He Pro Trp Asn Leu Glu Arg He Thr Pro Pro Arg Tyr Arg Ala Asp 140 145 150 gaa tac cag ccc ccc gac gga ggc age ctg gtg gag gtg tat etc eta 579 Glu Tyr Gin Pro Pro Asp Gly Gly Ser Leu Val Glu Val Tyr Leu Leu 155 160 165 gac ace age ata cag agt gac cac egg gaa ate gag ggc agg gtc atg 627 Asp Thr Ser He Gin Ser Asp His Arg Glu He Glu Gly Arg Val Met 170 175 180 gtc ace gac ttc gag aat gtg ccc gag gag gac ggg ace cgc ttc cac 675 Val Thr Asp 'Phe Glu Asn Val Pro Glu Glu Asp Gly Thr Arg Phe His 185 190 195 aga cag gcc age aag tgt gac agt cat ggc ace cac ctg gca ggg gtg 723 Arg Gin Ala Ser Lys Cys Asp Ser His Gly Thr His Leu Ala Gly Val 200 205 210 215 gtc age ggc egg gat gcc ggc gtg gcc aag ggt gcc age atg cgc age 771 Val Ser Gly Arg Asp Ala Gly Val Ala Lys Gly Ala Ser Met Arg Ser 220 225 230 ctg cgc gtg etc aac tgc caa ggg aag ggc acg gtt age ggc ace etc 819 Leu Arg Val Leu Asn Cys Gin Gly Lys Gly Thr Val Ser Gly Thr Leu 235 240 245 ata ggc ctg gag ttt att egg aaa age cag ctg gtc cag cct gtg ggg 867 He Gly Leu ,Glu Phe He Arg Lys Ser Gin Leu Val Gin Pro Val Gly 250 255 260 cca ctg gtg gtg ctg ctg ccc ctg gcg ggt ggg tac age cgc gtc etc 915 Pro Leu Val Val Leu Leu Pro Leu Ala Gly Gly Tyr Ser Arg Val Leu 265 270 275 aac gcc gcc tgc cag cgc ctg gcg agg get ggg gtc gtg ctg gtc ace 963 Asn Ala Ala Cys Gin Arg Leu Ala Arg Ala Gly Val Val Leu Val Thr 280 285 290 295 get gcc ggc aac ttc egg gac gat gcc tgc etc tac tec cca gcc tea 1011 Ala Ala Gly Asn Phe Arg Asp Asp Ala Cys Leu Tyr Ser Pro Ala Ser 300 305 310 get ccc gag gtc ate aca gtt ggg gcc ace aat gcc cag gac cag ccg 1059 Ala Pro Glu Val He Thr Val Gly Ala Thr Asn Ala Gin Asp Gin Pro 315 320 325 gtg ace ctg ggg act ttg ggg ace aac ttt ggc cgc tgt gtg gac etc 1107 Val Thr Leu Gly Thr Leu Gly Thr Asn Phe Gly Arg Cys Val Asp Leu 330 335 340 ttt gcc cca ggg gag gac ate att ggt gcc tec age gac tgc age ace 1155 Phe Ala Pro Gly Glu Asp He He Gly Ala Ser Ser Asp Cys Ser Thr 345 350 355 tgc ttt gtg tea cag agt ggg aca tea cag get get gcc cac gtg get 1203 Cys Phe Val Ser Gin Ser Gly Thr Ser Gin Ala Ala Ala His Val Ala 360 365 370 375 ggt tgg cag ctg ttt tgc agg act gtg tgg tea gca cac teg ggg cct 1251 Gly Trp Gin Leu Phe Cys Arg Thr Val Trp Ser Ala His Ser Gly Pro 380 385 390 aca egg atg gcc aca gcc ate gcc cgc tgc gcc cca gat gag gag ctg 1299 Thr Arg Met Ala Thr Ala He Ala Arg Cys Ala Pro Asp Glu Glu Leu 395 400 405 ctg age tgc tec agt ttc tec agg agt ggg aag egg egg ggc gag cgc 1347 Leu Ser Cys Ser Ser Phe Ser Arg Ser Gly Lys Arg Arg Gly Glu Arg 410 415 420 atg gag gcc caa ggg ggc aag ctg gtc tgc egg gcc cac aac get ttt 1395 Met Glu Ala Gin Gly Gly Lys Leu Val Cys Arg Ala His Asn Ala Phe 425 430 435 g gt gag ggt gtc tac gcc att gcc agg tgc tgc ctg eta ccc cag 1443 Gly Gly Glu Gly Val Tyr Ala He Ala Arg Cys Cys Leu Leu Pro Gin 440 445 450 455 gcc aac tgc age gtc cac aca get cca cca get gag gcc age atg ggg 1491 Ala Asn Cys Ser Val His Thr Ala Pro Pro Ala Glu Ala Ser Met Gly 460 465 470 ace cgt gtc cac tgc cac caa cag ggc cac gtc etc aca ggc tgc age 1539 Thr Arg Val His Cys His Gin Gin Gly His Val Leu Thr Gly Cys Ser 475 480 485 tec cac tgg gag gtg gag gac ctt ggc ace cac aag ccg cct gtg ctg 1587 Ser His Trp Glu Val Glu Asp Leu Gly Thr His Lys Pro Pro Val Leu 490 495 500 agg cca cga ggt cag ccc aac cag tgc gtg ggc cac agg gag gcc age 1635

Arg Pro Arg Gly Gin Pro Asn Gin Cys Val Gly His Arg Glu Ala Ser 505 510 515 ate cac get tec tgc tgc cat gcc cca ggt ctg gaa tgc aaa gtc aag 1683 He His Ala Ser Cys Cys His Ala Pro Gly Leu Glu Cys Lys Val Lys 520 525 530 535 gag cat gga ate ccg gcc cct cag gag cag gtg ace gtg gcc tgc gag 1731 Glu His Gly He Pro Ala Pro Gin Glu Gin Val Thr Val Ala Cys Glu 540 545 550 gag ggc tgg ace ctg act ggc tgc agt gcc etc cct ggg ace tec cac 1779 Glu Gly Trp Thr Leu Thr Gly Cys Ser Ala Leu Pro Gly Thr Ser His 555 560 565 gtc ctg ggg gcc tac gcc gta gac aac acg tgt gta gtc agg age egg 1827 Val Leu Gly Ala Tyr Ala Val Asp Asn Thr Cys Val Val Arg Ser Arg 570 575 580 gac gtc age act aca ggc age ace age gaa ggg gcc gtg aca gcc gtt 1875 Asp Val Ser Thr Thr Gly Ser Thr Ser Glu Gly Ala Val Thr Ala Val 585 590 595 gcc ate tgc tgc egg age egg cac ctg gcg cag gcc tec cag gag etc 1923 Ala He Cys Cys Arg Ser Arg His Leu Ala Gin Ala Ser Gin Glu Leu 600 605 610 615 cag tgacageeee ateeeaggat gggtgtctgg ggagggtcaa gg 1968

Gin

<210> 34

<211> 634

<212> PRT

<213> Homo sapiens

<400> 34

Met Gly Thr Val Ser Ser Arg Arg Ser Trp Trp Pro Leu Pro Leu Leu -15 -10 -5

Leu Leu Leu Leu Leu Leu Leu Gly Pro Ala Gly Ala Arg Ala Gin Glu -1 1 5 10

Asp Glu Asp Gly Asp Tyr Glu Glu Leu Val Leu Ala Leu Arg Ser Glu 15 20 25 30

Glu Asp Gly Leu Ala Glu Ala Pro Glu His Gly Thr Thr Ala Thr Phe 35 40 45

His Arg Cys Ala Lys Asp Pro Trp Arg Leu Pro Gly Thr Tyr Val Val 50 55 ^• 60

Val Leu Lys Glu Glu Thr His Leu Ser Gin Ser Glu Arg Thr Ala Arg 65 70 75

Arg Leu Gin Ala Gin Ala Ala Arg Arg Gly Tyr Leu Thr Lys He Leu 80 85 90 His Val Phe His Gly Leu Leu Pro Gly Phe Leu Val Lys Met Ser Gly 95 100 105 110

Asp Leu Leu Glu Leu Ala Leu Lys Leu Pro His Val Asp Tyr He Glu 115 120 125

Glu Asp^' Ser Ser Val Phe Ala Gin Ser He Pro Trp Asn Leu Glu Arg 130 135 . 140

He Thr Pro Pro Arg Tyr Arg Ala Asp Glu Tyr Gin Pro Pro Asp Gly 145 - 150 155

Gly Ser Leu Val Glu Val Tyr Leu Leu Asp Thr Ser He Gin Ser Asp 160 165 170

His Arg Glu He Glu Gly Arg Val Met Val Thr Asp Phe Glu Asn Val 175 180 185 190

Pro Glu Glu Asp Gly Thr Arg Phe His Arg Gin Ala Ser Lys Cys Asp 195 200 205

Ser His Gly Thr His Leu Ala Gly Val Val Ser Gly Arg Asp Ala Gly 210 215 220

Val Ala Lys Gly Ala Ser Met Arg Ser Leu Arg Val Leu Asn Cys Gin 225 230 235

Gly Lys Gly Thr Val Ser Gly Thr Leu He Gly Leu Glu Phe He Arg 240 245 250

Lys Ser Gin Leu Val Gin Pro Val Gly Pro Leu Val Val Leu Leu Pro 255 260 265 270

Leu Ala Gly Gly Tyr Ser Arg Val Leu Asn Ala Ala Cys Gin Arg Leu 275 280 285

Ala Arg Ala Gly Val Val Leu Val Thr Ala Ala Gly Asn Phe Arg Asp 290 295 300 Asp Ala Cys Leu Tyr Ser Pro Ala Ser Ala Pro Glu Val He Thr Val 305 310 315

Gly Ala Thr Asn Ala Gin Asp Gin Pro Val Thr Leu Gly Thr Leu Gly 320 325 330

Thr Asn Phe Gly Arg Cys Val Asp Leu Phe Ala Pro Gly Glu Asp He 335 340 345 350

He Gly Ala Ser Ser Asp Cys Ser Thr Cys Phe Val Ser Gin Ser Gly 355 360 365

Thr Ser Gin Ala Ala Ala His Val Ala Gly Trp Gin Leu Phe Cys Arg 370 375 380

Thr Val Trp Ser Ala His Ser Gly Pro Thr Arg Met Ala Thr Ala He 385 390 395

Ala Arg Cys Ala Pro Asp Glu Glu Leu Leu Ser Cys Ser Ser Phe Ser 400 405 410

Arg Ser Gly Lys Arg Arg Gly Glu Arg Met Glu Ala Gin Gly Gly Lys 415 420 425 430

Leu Val Cys Arg Ala _His Asn Ala Phe Gly Gly Glu Gly Val Tyr Ala 435^* 440 445

He Ala Arg Cys Cys Leu Leu Pro Gin Ala Asn Cys Ser Val His Thr 450 455 460

Ala Pro Pro Ala Glu Ala Ser Met Gly Thr Arg Val His Cys His Gin 465 470 475

Gin Gly His Val Leu Thr Gly Cys Ser Ser His Trp Glu Val Glu Asp 480 485 490

Leu Gly Thr His Lys Pro Pro Val Leu Arg Pro Arg Gly Gin Pro Asn 495 500 505 510

Gin Cys Val Gly His Arg Glu Ala Ser He His Ala Ser Cys Cys His 515 520 525 Ala Pro Gly Leu Glu Cys Lys Val Lys Glu His Gly He Pro Ala Pro 530 535 540

Gin Glu Gin Val Thr Val Ala Cys Glu Glu Gly Trp Thr Leu Thr Gly 545 550 555

Cys Ser Ala Leu Pro Gly Thr Ser His Val Leu Gly Ala Tyr Ala Val 560 565 570

Asp Asn Thr Cys Val Val Arg Ser Arg Asp Val Ser Thr Thr Gly Ser 575 580 585 590

Thr Ser Glu Gly Ala Val Thr Ala Val Ala He Cys Cys Arg Ser Arg 595 600 605

His Leu Ala Gin Ala Ser Gin Glu Leu Gin 610 615

<210> 35

<211> 1507

<212> DNA

<213> Homo sapiens

<220>

<221> CDS

<222> (54).. (1454)

<220>

<221> matjpeptide

<222> (129).. ()

<400> 35 ggaggtgacc gcctggtttc cattaggaag tcctggtcag cagcttgggc gag atg 56

Met -25 gca gag tea ggg ctg gcc atg tgg ccg age ctg ctg ctg etc ctg ctg 104 Ala Glu Ser Gly Leu Ala Met Trp Pro Ser Leu Leu Leu Leu Leu Leu -20 -15 -10 ttg ccg ggg ccc ccg ccc gtc gcc ggc ttg gaa gac get gcc ttc ccc 152 Leu Pro Gly Pro Pro Pro Val Ala Gly Leu Glu Asp Ala Ala Phe Pro -5 -1 1 5 cac ctg ggg gag age ttg cag ccc ctg ccc egg gcc tgt ccc ctg cgc 200 His Leu Gly Glu Ser Leu Gin Pro Leu Pro Arg Ala Cys Pro Leu Arg 10 15 • 20 tgc tec tgc ccc cga gtc gac act gtg gac tgt gat ggc ttg gac ctt 248 Cys Ser Cys Pro Arg Val Asp Thr Val Asp Cys Asp Gly Leu Asp Leu 25 30 35 40 cga gtg ttc ccg gac aac ate ace aga gcc get cag cac etc tec ctg 296 Arg Val Phe Pro Asp Asn He Thr Arg Ala Ala Gin His Leu Ser Leu 45 50 55 cag aac aac cag etc cag gaa etc ccc tac aat gag ctg tec cgc etc 344 Gin Asn Asn Gin Leu Gin Glu Leu Pro Tyr Asn Glu Leu Ser Arg Leu 60 65 70 agt ggc ctg cga ace etc aac etc cac aac aac etc ate ttc tec gaa 392 Ser Gly Leu Arg Thr Leu Asn Leu His Asn Asn Leu He Phe Ser Glu 75 80 85 ggc ctg cct gac gag gcc ttc gag tec etc ace cag ctg cag cac etc 440 Gly Leu Pro Asp Glu Ala Phe Glu Ser Leu Thr Gin Leu Gin His Leu 90 95 100 tgc gtg get cac aac aag ctg age aac get ggc ctg ccc ccc gac gcc 488 Cys Val Ala His Asn Lys Leu Ser Asn Ala Gly Leu Pro Pro Asp Ala 105 110 115 120 ttc cgc ggc tec gag gcc ate gcc ace etc age etc tec aac aac cag 536 Phe Arg Gly Ser Glu Ala He Ala Thr Leu Ser Leu Ser Asn Asn Gin 125 130 135 etc age tac ctg ccg ccc age ctg ccg ccc tea etc gag egg etc cac 584 Leu Ser Tyr Leu Pro Pro Ser Leu Pro Pro Ser Leu Glu Arg Leu His 140 145 150 ctg cag aac aat etc ate tec aag gtg ccc cga gga gcc ctg age cgc 632 Leu Gin Asn Asn Leu He Ser Lys Val Pro Arg Gly Ala Leu Ser Arg 155 160 165 cag act caa etc cgt gag etc tac etc cag cac aac cag ctg aca gac 680 Gin Thr Gin Leu Arg Glu Leu Tyr Leu Gin His Asn Gin Leu Thr Asp 170 175 180 agt ggc ctg gat gcc ace ace ttc age aag ctg cat age ctt gaa tac 728 Ser Gly Leu Asp Ala Thr Thr Phe Ser Lys Leu His Ser Leu Glu Tyr 185 190 195 200 ctg gat etc tec cac aac cag ctg ace aca gtg ccc gcc ggc ctg ccc 776 Leu Asp Leu Ser His Asn Gin Leu Thr Thr Val Pro Ala Gly Leu Pro 205 210 215 egg ace ctg get ate ctg cac ctg ggc cgc aac cgc ate egg cag gtg 824 Arg Thr Leu Ala He Leu His Leu Gly Arg Asn Arg He Arg Gin Val 220 225 230 gag gcg get egg ctg cac ggg gcg cgt ggt ctg cgc tat ttg ttg ctg 872 Glu Ala Ala Arg Leu His Gly Ala Arg Gly Leu Arg Tyr Leu Leu Leu 235 240 245 cag cac aac cag ctg ggg age tea ggg ctg ccc gcc ggg get ctg egg 920

Gin His Asn Gin Leu Gly Ser Ser Gly Leu Pro Ala Gly Ala Leu Arg 250 255 260 ccg ctg egg ggc ctg cac acg ctg cac etc tat ggc aat ggg ctg gac 968 Pro Leu Arg Gly Leu His Thr Leu His Leu Tyr Gly Asn Gly Leu Asp 265 270 275 280 cgc gtg cct cca gcc ctg ccc cgc cgc ctg cgt gcc ctg gtg ctg ccc 1016 Arg Val Pro Pro Ala Leu Pro Arg Arg Leu Arg Ala Leu Val Leu Pro 285 290 295 cac aac cac gtg gcc gcg ctg ggt gcc cgt gac ctg gtc gcc aca ccg 1064

His Asn His Val Ala Ala Leu Gly Ala Arg Asp Leu Val Ala Thr Pro 300 305 310 ggc ctg acg gag ctt aac ctg gcc tat aac cgc ctg gcc age gcc cgt 1112 Gly Leu Thr Glu Leu Asn Leu Ala Tyr Asn Arg Leu Ala Ser Ala Arg 315 320 325 gtg cac cac egg gcc ttc cgc egg ttg cgt gcc ctg cgc age etc gac 1160 Val His His Arg Ala Phe Arg Arg Leu Arg Ala Leu Arg Ser Leu Asp 330 335 340 ctg gca ggg aat cag eta ace egg ctg ccc atg ggc ctg ccc act ggc 1208 Leu Ala Gly Asn Gin Leu Thr Arg Leu Pro Met Gly Leu Pro Thr Gly 345 350 355 360 ctg cgc ace ctg cag ctg caa cgc aac cag ctg egg atg etc gag ccc 1256 Leu Arg Thr Leu Gin Leu Gin Arg Asn Gin Leu Arg Met Leu Glu Pro 365 370 375 gag cct ctg gcc ggc ctg gac caa ctg egg gag etc age ctg gcg cac 1304 Glu Pro Leu Ala Gly Leu Asp Gin Leu Arg Glu Leu Ser Leu Ala His 380 385 390 aac egg etc egg gtc ggc gac ate ggg cca ggc ace tgg cat gag etc 1352 Asn Arg Leu Arg Val Gly Asp He Gly Pro Gly Thr Trp His Glu Leu 395 400 405 caa gcc etc cag gtc agg cac agg ctg gtt age cac act gtc ccc agg 1400 Gin Ala Leu Gin Val Arg His Arg Leu Val Ser His Thr Val Pro Arg 410 415 420 gcc cct cca tec ccc tgc ctg ccc tgc cac gtc cca aac att eta gtt 1448 Ala Pro Pro Ser Pro Cys Leu Pro Cys His Val Pro Asn He Leu Val 425 430 435 440 age tgg taaagcaatc agaacaagaa aatgataaga gtgggttaga aggtgataag 1504 Ser Trp

ggc 1507

<210> 36

<211> 467

<212> PRT

<213> Homo sapiens

<400> 36

Met Ala Glu Ser Gly Leu Ala Met Trp Pro Ser Leu Leu Leu Leu Leu -25 -20 -15 -10

Leu Leu Pro Gly Pro Pro Pro Val Ala Gly Leu Glu Asp Ala Ala Phe -5 -1 1 5

Pro His Leu Gly Glu Ser Leu Gin Pro Leu Pro Arg Ala Cys Pro Leu 10 15 20

Arg Cys Ser Cys Pro Arg Val Asp Thr Val Asp Cys Asp Gly Leu Asp 25 30 35

Leu Arg Val Phe Pro Asp Asn He Thr Arg Ala Ala Gin His Leu Ser 40 45 50 55

Leu Gin Asn Asn Gin Leu Gin Glu Leu Pro Tyr Asn Glu Leu Ser Arg 60 65 70

Leu Ser Gly Leu Arg Thr Leu Asn Leu His Asn Asn Leu He Phe Ser 75 80 85

Glu Gly Leu Pro Asp Glu Ala Phe Glu Ser Leu Thr Gin Leu Gin His 90 95 100

Leu Cys Val Ala His Asn Lys Leu Ser Asn Ala Gly Leu Pro Pro Asp 105 110 115 Ala Phe Arg Gly Ser Glu Ala He Ala Thr Leu Ser Leu Ser Asn Asn 120 125 130 135

Gin Leu Ser Tyr Leu Pro Pro Ser Leu Pro Pro Ser Leu Glu Arg Leu 140 145 150

His Leu Gin Asn Asn Leu He Ser Lys Val Pro Arg Gly Ala Leu Ser 155 160 165

Arg Gin Thr Gin Leu Arg Glu Leu Tyr Leu Gin His Asn Gin Leu Thr 170 175 180

Asp Ser Gly Leu Asp Ala Thr Thr Phe Ser Lys Leu His Ser Leu Glu 185 190 195

Tyr Leu Asp Leu Ser His Asn Gin Leu Thr Thr Val Pro Ala Gly Leu 200 205 210 215

Pro Arg Thr Leu Ala He Leu His Leu Gly Arg Asn Arg He Arg Gin 220 225 230

Val Glu Ala Ala Arg Leu His Gly Ala Arg Gly Leu Arg Tyr Leu Leu 235 240 245

Leu Gin His Asn Gin Leu Gly Ser Ser Gly Leu Pro Ala Gly Ala Leu 250 255 260

Arg Pro Leu Arg Gly Leu His Thr Leu His Leu Tyr Gly Asn Gly Leu 265 270 275

Asp Arg Val Pro Pro Ala Leu Pro Arg Arg Leu Arg Ala Leu Val Leu 280 285 290 295

Pro His Asn His Val Ala Ala Leu Gly Ala Arg Asp Leu Val Ala Thr 300 305 310

Pro Gly Leu Thr Glu Leu Asn Leu Ala Tyr Asn Arg Leu Ala Ser Ala 315 320 325

Arg Val His His Arg Ala Phe Arg Arg Leu Arg Ala Leu Arg Ser Leu 330 335 340 Asp Leu Ala Gly Asn Gin Leu Thr Arg Leu Pro Met Gly Leu Pro Thr 345 350 355

Gly Leu Arg Thr Leu Gin Leu Gin Arg Asn Gin Leu Arg Met Leu Glu 360 365 370 375

Pro Glu Pro Leu Ala Gly Leu Asp Gin Leu Arg Glu Leu Ser Leu Ala 380 385 390

His Asn Arg Leu Arg Val Gly Asp He Gly Pro Gly Thr Trp His Glu 395 400 405

Leu Gin Ala Leu Gin Val Arg His Arg Leu Val Ser His Thr Val Pro 410 415 420

Arg Ala Pro Pro Ser Pro Cys Leu Pro Cys His Val Pro Asn He Leu 425 430 435

Val Ser Trp 440

<210> 37

<211> 2397

<212> DNA

<213> Homo sapiens

<220>

<221> CDS

<222> (133) .. (2100)

<220>

<221> mat_peptide

<222> (244).. ()

<400> 37 tggagaactg gggaggcaga gaccecgget ggeeggaggc atgtggaggg gggggcctgg 60 gcgcaaggag aggcccagcg gaagecaage eaeeaggccc cccagegtee aegeggagca 120 tgaacattga gg atg gcg cgt gcc cgc ggc tec ccg tgc ccc ccg ctg ccg 111

Met Ala Arg Ala Arg Gly Ser Pro Cys Pro Pro Leu Pro -35 -30 -25 ccc ggt agg atg tec tgg ccc cac ggg gca ttg etc ttc etc tgg etc 219 Pro Gly Arg Met Ser Trp Pro His Gly Ala Leu Leu Phe Leu Trp Leu -20 -15 -10 ttc tec cca ccc ctg ggg gcc ggt gga ggt gga gtg gcc gtg acg tct 267 Phe Ser Pro Pro Leu Gly Ala Gly Gly Gly Gly Val Ala Val Thr Ser -5 -1 1 5 gcc gcc gga ggg ggc tec ccg ccg gcc ace tec tgc ccc gtg gcc tgc 315 Ala Ala Gly Gly Gly Ser Pro Pro Ala Thr Ser Cys Pro Val Ala Cys 10 15 20 tec tgc age aac cag gcc age egg gtg ate tgc aca egg aga gac ctg 363 Ser Cys Ser Asn Gin Ala Ser Arg Val He Cys Thr Arg Arg Asp Leu 25 30 35 40 gcc gag gtc cca gcc age ate ccg gtc aac acg egg tac ctg aac ctg 411 Ala Glu Val Pro Ala Ser He Pro Val Asn Thr Arg Tyr Leu Asn Leu 45 50 55 caa gag aac ggc ate cag gtg ate egg acg gac acg ttc aag cac ctg 459 Gin Glu Asn Gly He Gin Val He Arg Thr Asp Thr Phe Lys His Leu 60 65 70 egg cac ctg gag att ctg cag ctg age aag aac ctg gtg cgc aag ate 507 Arg His Leu Glu He Leu Gin Leu Ser Lys Asn Leu Val Arg Lys He 75 80 85 gag gtg ggc gcc ttc aac ggg ctg ccc age etc aac acg ctg gag ctt 555 Glu Val Gly Ala Phe Asn Gly Leu Pro Ser Leu Asn Thr Leu Glu Leu 90 95 100 ttt gac aac egg ctg ace acg gtg ccc acg cag gcc ttc gag tac ctg 603 Phe Asp Asn Arg Leu Thr Thr Val Pro Thr Gin Ala Phe Glu Tyr Leu 105 110 115 120 tec aag ctg egg gag etc tgg ctg egg aac aac ccc ate gag age ate 651 Ser Lys Leu Arg Glu Leu Trp Leu Arg Asn Asn Pro He Glu Ser He 125 130 135 ccc tec tac gcc ttc aac cgc gtg ccc teg ctg egg cgc ctg gac ctg 699 Pro Ser Tyr Ala Phe Asn Arg Val Pro Ser Leu Arg Arg Leu Asp Leu 140 145 150 ggc gag etc aag egg ctg gaa tac ate teg gag gcg gcc ttc gag ggg 747 Gly Glu Leu Lys Arg Leu Glu Tyr He Ser Glu Ala Ala Phe Glu Gly 155 160 165 ctg gtc aac ctg cgc tac etc aac ctg ggc atg tgc aac etc aag gac 795 Leu Val Asn Leu Arg Tyr Leu Asn Leu Gly Met Cys Asn Leu Lys Asp 170 175 180 ate ccc aac ctg acg gcc ctg gtg cgc ctg gag gag ctg gag ctg teg 843 He Pro Asn Leu Thr Ala Leu Val Arg Leu Glu Glu Leu Glu Leu Ser 185 190 195 200 ggc aac egg ctg gac ctg ate cgc ccg ggc tec ttc cag ggt etc ace 891 Gly Asn Arg Leu Asp Leu He Arg Pro Gly Ser Phe Gin Gly Leu Thr 205 210 215 age ctg cgc aag ctg tgg etc atg cac gcc cag gta gcc ace ate gag 939 Ser Leu Arg Lys Leu Trp Leu Met His Ala Gin Val Ala Thr He Glu 220 225 230 cgc aac gcc ttc gac gac etc aag teg ctg gag gag etc aac ctg tec 987 Arg Asn Ala Phe Asp Asp Leu Lys Ser Leu Glu Glu Leu Asn Leu Ser 235 240 245 cac aac aac ctg atg teg ctg ccc cac gac etc ttc acg ccc ctg cac 1035 His Asn Asn Leu Met Ser Leu Pro His Asp Leu Phe Thr Pro Leu His 250 255 260 cgc etc gag cgc gtg cac etc aac cac aac ccc tgg cat tgc aac tgc 1083 Arg Leu Glu Arg Val His Leu Asn His Asn Pro Trp His Cys Asn Cys 265 270 275 280 gac gtg etc tgg ctg age tgg tgg etc aag gag acg gtg ccc age aac 1131 Asp Val Leu Trp Leu Ser Trp Trp Leu Lys Glu Thr Val Pro Ser Asn 285 290 295 acg acg tgc tgc gcc cgc tgt cat gcg ccc gcc ggc etc aag ggg cgc 1179 Thr Thr Cys Cys Ala Arg Cys His Ala Pro Ala Gly Leu Lys Gly Arg 300 305 310 tac att ggg gag ctg gac cag teg cat ttc ace tgc tat gcg ccc gtc 1227 Tyr He Gly Glu Leu Asp Gin Ser His Phe Thr Cys Tyr Ala Pro Val 315 320 325 ate gtg gag ccg ccc acg gac etc aac gtc ace gag ggc atg get gcc 1275 He Val Glu Pro Pro Thr Asp Leu Asn Val Thr Glu Gly Met Ala Ala 330 335 340 gag etc aaa tgc cgc acg ggc ace tec atg ace tec gtc aac tgg ctg 1323 Glu Leu Lys Cys Arg Thr Gly Thr Ser Met Thr Ser Val Asn Trp Leu 345 350 355 360 acg ccc aac ggc ace etc atg ace cac ggc tec tac cgc gtg cgc ate 1371 Thr Pro Asn Gly Thr Leu Met Thr His Gly Ser Tyr Arg Val Arg He 365 370 375 tec gtc ctg cat gac ggc acg ctt aac ttc ace aac gtc ace gtg cag 1419 Ser Val Leu His Asp Gly Thr Leu Asn Phe Thr Asn Val Thr Val Gin 380 385 390 gac acg ggc cag tac acg tgc atg gtg acg aac tea gcc ggc aac ace 1467 Asp Thr Gly Gin Tyr Thr Cys Met Val Thr Asn Ser Ala Gly Asn Thr 395 400 405 ace gcc teg gcc acg etc aac gtc teg gcc gtg gac ccc gtg gcg gcc 1515 Thr Ala Ser Ala Thr Leu Asn Val Ser Ala Val Asp Pro Val Ala Ala 410 415 420 ggg ggc ace ggc age ggc ggg ggc ggc cct ggg ggc agt ggt ggt gtt 1563 Gly Gly Thr Gly Ser Gly Gly Gly Gly Pro Gly Gly Ser Gly Gly Val 425 430 435 440 gga ggg ggc agt ggc ggc tac ace tac ttc ace acg gtg ace gtg gag 1611 Gly Gly Gly Ser Gly Gly Tyr Thr Tyr Phe Thr Thr Val Thr Val Glu 445 450 455 ace ctg gag acg cag ccc gga gag gag gcc ctg cag ccg egg ggg acg 1659 Thr Leu Glu Thr Gin Pro Gly Glu Glu Ala Leu Gin Pro Arg Gly Thr 460 ^' 465 470 gag aag gaa ccg cca ggg ccc acg aca gac ggt gtc tgg ggt ggg ggc 1707 Glu Lys Glu Pro Pro Gly Pro Thr Thr Asp Gly Val Trp Gly Gly Gly 475 480 485 egg cct ggg gac gcg gcc ggc cct gcc teg tct tct ace acg gca ccc 1755 Arg Pro Gly Asp Ala Ala Gly Pro Ala Ser Ser Ser Thr Thr Ala Pro 490 495 500 gcc ccg cgc tec teg egg ccc acg gag aag gcg ttc acg gtg ccc ate 1803 Ala Pro Arg Ser Ser Arg Pro Thr Glu Lys Ala Phe Thr Val Pro He 505 510 515 520 acg gat gtg acg gag aac gcc etc aag gac ctg gac gac gtc atg aag 1851 Thr Asp Val Thr Glu Asn Ala Leu Lys Asp Leu Asp Asp Val Met Lys 525 530 535 ace ace aaa ate ate ate ggc tgc ttc gtg gcc ate acg ttc atg gcc 1899 Thr Thr Lys He He He Gly Cys Phe Val Ala He Thr Phe Met Ala 540 545 550 gcg gtg atg etc gtg gcc ttc tac aag ctg cgc aag cag cac cag etc 1947 Ala Val Met Leu Val Ala Phe Tyr Lys Leu Arg Lys Gin His Gin Leu 555 560 565 cac aag cac cac ggg ccc acg cgc ace gtg gag ate ate aac gtg gag 1995 His Lys His His Gly Pro Thr Arg Thr Val Glu He He Asn Val Glu 570 575 580 gac gag ctg ccc gcc gcc teg gcc gtg tec gtg gcc gcc gcg gcc gcc 2043 Asp Glu Leu Pro Ala Ala Ser Ala Val Ser Val Ala Ala Ala Ala Ala 585 590 595 600 gtg gcc agt ggg ggt ggt gtg ggc ggg gac age cac ctg gcc ctg ccc 2091 Val Ala Ser Gly Gly Gly Val Gly Gly Asp Ser His Leu Ala Leu Pro 605 610 615 gcc ctg gag tgagaccacc tcaaccacca ccactacgtg gctgccgcct 2140

Ala Leu Glu

tcaaggegea ctacageagc aaeeecagcg gcgggggctg cgggggeaaa ggeecgcctg 2200 geeteaactc eatceacgaa ectctgetet tcaagagcgg etecaaggag aacgtgcaag 2260 agacgcagat etgaggcgge ggggeegggc gggcgagggg egtggageee cccaceeagg 2320 tcccagcccg ggcgcagcct gaccgggacc cctccctccc acagcccagc ccaccttctg 2380 ggaccacgca gggaatt 2397

<210> 38

<211> 656

<212> PRT

<213> Homo sapiens

<400> 38

Met Ala Arg Ala Arg Gly Ser Pro Cys Pro Pro Leu Pro Pro Gly Arg -35 -30 -25

Met Ser Trp Pro His Gly Ala Leu Leu Phe Leu Trp Leu Phe Ser Pro -20 -15 -10

Pro Leu Gly Ala Gly Gly Gly Gly Val Ala Val Thr Ser Ala Ala Gly -5 -1 1 5 10

Gly Gly Ser Pro Pro Ala Thr Ser Cys Pro Val Ala Cys Ser Cys Ser 15 20 25

Asn Gin Ala Ser Arg Val He Cys Thr Arg Arg Asp Leu Ala Glu Val 30 35 40

Pro Ala Ser He Pro Val Asn Thr Arg Tyr Leu Asn Leu Gin Glu Asn 45 50 55

Gly He Gin Val He Arg Thr Asp Thr Phe Lys His Leu Arg His Leu 60 65 70 75 Glu He Leu Gin Leu Ser Lys Asn Leu Val Arg Lys He Glu Val Gly 80 85 90

Ala Phe Asn Gly Leu Pro Ser Leu Asn Thr Leu Glu Leu Phe Asp Asn 95 100 105

Arg Leu Thr Thr Val Pro Thr Gin Ala Phe Glu Tyr Leu Ser Lys Leu 110 115 120

Arg Glu Leu Trp Leu Arg Asn Asn Pro He Glu Ser He Pro Ser Tyr 125 130 135

Ala Phe Asn Arg Val Pro Ser Leu Arg Arg Leu Asp Leu Gly Glu Leu 140 145 150 155

Lys Arg Leu Glu Tyr He Ser Glu Ala Ala Phe Glu Gly Leu Val Asn 160 165 170

Leu Arg Tyr Leu Asn Leu Gly Met Cys Asn Leu Lys Asp He Pro Asn 175 180 185

Leu Thr Ala Leu Val Arg Leu Glu Glu Leu Glu Leu Ser Gly Asn Arg 190 195 200

Leu Asp Leu He Arg Pro Gly Ser Phe Gin Gly Leu Thr Ser Leu Arg 205 210 215

Lys Leu Trp Leu Met His Ala Gin Val Ala Thr He Glu Arg Asn Ala 220 225 230 235

Phe Asp Asp Leu Lys Ser Leu Glu Glu Leu Asn Leu Ser His Asn Asn 240 245 250

Leu Met Ser Leu Pro His Asp Leu Phe Thr Pro Leu His Arg Leu Glu 255 260 265

Arg Val His Leu Asn His Asn Pro Trp His Cys Asn Cys Asp Val Leu 270 275 280

Trp Leu Ser Trp Trp Leu Lys Glu Thr Val Pro Ser Asn Thr Thr Cys 285 290 295 Cys Ala Arg Cys His Ala Pro Ala Gly Leu Lys Gly Arg Tyr He Gly 300 305 310 315

Glu Leu Asp Gin Ser His Phe Thr Cys Tyr Ala Pro Val He Val Glu 320 325 330

Pro Pro Thr Asp Leu Asn Val Thr Glu Gly Met Ala Ala Glu Leu Lys 335 340 345

Cys Arg Thr Gly Thr Ser Met Thr Ser Val Asn Trp Leu Thr Pro Asn 350 355 360

Gly Thr Leu Met Thr His Gly Ser Tyr Arg Val Arg He Ser Val Leu 365 370 375

His Asp Gly Thr Leu Asn Phe Thr Asn Val Thr Val Gin Asp Thr Gly 380 . 385 390 395

Gin Tyr Thr Cys Met Val Thr Asn Ser Ala Gly Asn Thr Thr Ala Ser 400 405 410

Ala Thr Leu Asn Val Ser Ala Val Asp Pro Val Ala Ala Gly Gly Thr 415 420 425

Gly Ser Gly Gly Gly Gly Pro Gly Gly Ser Gly Gly Val Gly Gly Gly 430 435 440

Ser Gly Gly Tyr Thr Tyr Phe Thr Thr Val Thr Val Glu Thr Leu Glu 445 450 455

Thr Gin Pro Gly Glu Glu Ala Leu Gin Pro Arg Gly Thr Glu Lys Glu 460 465 470 475

Pro Pro Gly Pro Thr Thr Asp Gly Val Trp Gly Gly Gly Arg Pro Gly 480 485 490

Asp Ala Ala Gly Pro Ala Ser Ser Ser Thr Thr Ala Pro Ala Pro Arg 495 500 505 Ser Ser Arg Pro Thr Glu Lys Ala Phe Thr Val Pro He Thr Asp Val 510 515 520

Thr Glu Asn Ala Leu Lys Asp Leu Asp Asp Val Met Lys Thr Thr Lys 525 530 535

He He He Gly Cys Phe Val Ala He Thr Phe Met Ala Ala Val Met 540 545 550 555

Leu Val Ala Phe Tyr Lys Leu Arg Lys Gin His Gin Leu His Lys His 560 565 570

His Gly Pro Thr Arg Thr Val Glu He He Asn Val Glu Asp Glu Leu 575 580 585

Pro Ala Ala Ser Ala Val Ser Val Ala Ala Ala Ala Ala Val Ala Ser 590 595 600

Gly Gly Gly Val Gly Gly Asp Ser His Leu Ala Leu Pro Ala Leu Glu 605 610 615