Serine protease genes related to dppiv

Field of the Invention

The present invention relates to novel serine proteases related to dipeptidyl peptidase IV (DPPIV), and to isolated nucleic acids coding for these proteases, all of which are useful for the discovery of new therapeutic agents, for measuring protease 5 activity, and for determining the inhibitory activity of compounds against these proteases.

Background of the Invention

Proteases and peptidases are enzymes that catalyse the hydrolysis of peptidic amida bonds. Proteases play an important role in the regulation of biological processes 10 in almost every life-form from bacteria to virus to mammals. They perform critical functions in, for example, digestion, blood clotting, apoptosis, activation of immune responses, zymogen activation, viral maturation, protein secretion and protein trafficking. They can be classified according to a number of criteria, such as site of action, substrate preference, and mechanism. So, for example, aminopeptidases act 15 preferentially at the N-tenninal residues of a peptide, while carboxypeptidases act preferentially at the C-tenninus and endopeptidases act at sites removed from the two termini. Among the carboxy- and aminopeptidases, peptidyl peptidases cleave a single amino acid residue from the substrate, dipeptidyl peptidases cleave a dipeptide unit (two amino acids) from the substrate, and tripeptidases cleave three amino acids from the 20 substrate. Substrate preference is frequently expressed in terms of the amino acid residue immediately N-terminal to the cleavage site. For example, trypsin-like peptidases will preferentially cleave a peptide next to a basic amino acid (arginine or lysine), i.e. where the bond hydrolysed is the Arg/Lys-Xaa bond. As another example, the chymotrypsin-like family of peptidases preferentially hydrolyse peptides adjacent to 25 an aromatic residue. Mechanistically, peptidases are classified as being serinedependent, cysteine-dependent, aspartic acid-dependent or zinc-dependent.

Because peptidases and proteases are involved in the regulation of many physiological processes, they are attractive targets for the development of therapeutic agents. Protease and peptidase inhibitors are, for example, used in the treatment of 3 0 hypertension, coagulation disorders, and viral infection.

Proteolytic enzymes that exploit serine in their catalytic activity are ubiquitous, being found in viruses, bacteria and eukaryotes. Over 20 families (denoted SI - S27) of serine protease have been identified; these are grouped into 6 clans (SA, SB, SC, SE, SF

WO 02/31134 and SG) on the basis of structural similarity and other functional evidence. Structures are known for four of the clans (SA, SB, SC and SE); these appear to be totally unrelated, suggesting at least four evolutionary origins of serine peptidases and possibly many more, Rawlings and Barrett, Meth, Enzymol, 244:19-61 (1994).

The prolyl oligopeptidase family consists of a number of evolutionarily related peptidases whose catalytic activity seems to be provided by a charge relay system similar to that of the trypsin family of serine proteases, but which evolved by independent convergent evolution. A conserved serine residue has been shown experimentally (in E. coli protease H as well as in pig and bacterial PE) to be necessary for the catalytic mechanism. This serine, which is part of the catalytic triad (Ser, His, Asp), is generally located about 150 residues away from the C-terminal extremity of these enzymes (which are all proteins that contains about 700 to 800 amino acids).

One of the most intensively studied prolyl oligopeptidases is dipeptidyl peptidase IV (DPPIV, EC 3.414.5), a type II glycoprotein, which is the only well characterised dipeptidyl aminopeptidase known to be located on the outer side of plasma membranes. As indicated above, dipeptidyl aminopeptidases are characterised by their ability to cleave N-terminal dipeptides from a variety of small peptides. Dipeptidyl aminopeptidases show different substrate specificities and cellular localisation, suggesting different functions of each activity in peptide processing. DPPIV is characterised by its capacity to cleave Nterminal dipeptides containing proline or alanine as the penultimate residue. The DPPIV gene spans approximately 70 kb and contains 26 exons, ranging in size from 45 bp to 1.4 kb. The nucleotide sequence (3,465 bp) of the cDNA contains an open reading frame encoding a polypeptide comprising 766 amino acids. The nucleotides that encode the active site sequence (G-W-S-Y-G) are split between 2 exons. This clearly distinguishes the genomic organisation of the prolyl oligopeptidase family from that of the classic serine protease family.

DPPIV is widely distributed in mammalian tissues and is found in great abundance in the kidney, intestinal epithelium and placenta (Yaron, A. and Naider, F., Critical Reviews in Biochem, Mol, Biol, 1993 [1], 31). In the human immune system, the enzyme is expressed almost exclusively by activated T-lymphocytes of the CD4* type where the enzyme has been shown to be synonymous with the cell-surface antigen CD26. Although the exact role of DP-IV in human physiology is still not completely understood, recent research has shown that the enzyme clearly has a major role in human physiology and pathophysiology.

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On human T cells, DPPIV expression appears late in thymic differentiation and is preferentially restricted to the CD4⁺ helper/memory population, and CD26 can deliver a potent co-stimulatory T-cell activation signal. DPPIV, also known as T-cell activation antigen CD26, therefore plays an important role in the immune response via association 5 with CD45 tyrosine phosphatase and, through its ability to bind adenosine deaminase (ADA) to the T-cell surface, protects the T-cell from adenosine-mediated inhibition of proliferation. Furthermore, the regulation of the function of chemokines by CD26/DPPIV appears to be essential for lymphocyte trafficking and infectivity of HIV strains. DPPIV has been associated with numerous functions including involvement in 10 T-cell activation, cell adhesion, digestion of proline containing peptides in the kidney and intestines, HIV infection and apoptosis, and regulation of tumorigenicity in certain melanoma cells, Pethiyagoda et al., Clin, Exp, Metastasis 2000:18(5):391400. DPPIV is also implicated in the endocrine regulation and metabolic physiology. More particularly, DPPIV cleaves the amino-terminal His-Ala dipeptide of GLP-1, generating 15 a GLP-1 receptor antagonist, and thereby shortens the physiological response to GLP-1. Glucagon-like peptide-1 (GLP-1), an incretin that induces glucose-dependent insulin secretion, is rapidly degraded by DPPIV, and since the half-life for DPPIV cleavage is much shorter than the half-life for removal of GLP-1 from circulation, a significant increase inGLP-1 bioactivity (5־ to 10־ fold) is anticipated from DPP-IV inhibition.

Inhibitors of DPPIV are currently being studied in the clinic as potential therapeutic agents for type 2 diabetes and impaired glucose tolerance.

Various different inhibitors of DPPIV were known in 1993. One of these is a suicide inhibitor N-Ala-Pro-O־(nitrobenzoyl-) hydroxylamine. Another is a competitive inhibitor: e-(4־nitro) benzoxycarbonyl-Lys-Pro, and another is a polyclonal rabbit anti25 porcine kidney DPPIV immunoglobulin. Others have since been developed and are described in detail in U.S. Patents Nos. 5,939,560,6,110,949m 6,011,155 and 5,462,928.

In addition to, but independent of, its serine type catalytic activity, DPPIV binds closely to the soluble extracellular enzyme adenosine deaminase (ADA), acting as a receptor and is thought to mediate signal transduction. DPPIV structure is characterized 30 by two extracellular domains, an α/β fold hydrolase domain and a 7־blade beta-propeller domain consisting of repeated beta sheets of about 50 amino acids. Recently it has been shown that, besides selecting substrates by size, the beta-propeller domain, containihg 10 of the 12 highly conserved cysteine residues, contributes to catalysis of the peptidase domain. In addition, the cysteine-rich domain is responsible for DPPIV-binding to 35 collagen I and to extracellular ADA. DPPIV is also reported to play a role in fibronectin

WO 02/31134 mediated interactions of cells with extracellular matrix. Recent studies show that the protease activity of DPPIV is not required for its anti-invasive activity because mutants of DPPIV that lack the extracellular serine protease activity maintain such activity.

A number of proteins that share similarities with DPPIV have been reported in the literature. Several of these proteins have been cloned including DPP-I, DPP-II, DPP-ΠΙ, DPP-X and fibroblast activation protein (FAP). These have been identified and characterised either by molecular cloning and functional studies of expressed proteins or as biochemical activities in tissue extracts. DPPIV-beta and other novel peptidases with functional similarities to DPPIV are not yet cloned. The identification, characterization and/or appropriate classification of further members of the family of prolyl oligopeptidases, the elucidation of their physiological (and particularly pathophysiological) role, and the application of that knowledge to the development of new therapeutic agents are significant challenges.

Summary of the Invention

The present invention provides proteins with prolyloligopeptidase (post-proline cleaving) activities that constitute three novel members of a family of proteins related to DPPIV, including the full-length proteins, alternative splice forms, subunits, and mutants, as well as nucleotide sequences encoding the same. The present invention also provides methods of screening for substrates, interacting proteins, agonists, antagonists or inhibitors of the above proteins, and furthermore to pharmaceutical compositions comprising the proteins and/or mutants, derivatives and/or analogues thereof and/or ligands thereto.

These novel proteins having significant sequence homology to DPPIV are termed dipeptidyl peptidase IV־related protein-1,2 & 3 (DPRP-1, DPRP-2 and DPRP-3). The amino acid sequences of DPRP-1, DPRP-2 and DPRP-3 are given in SEQ. ID NOS:1,3 and 5 respectively. Further disclosed are nucleic acid sequences coding for these proteins (SEQ. ID NOS:2,4 and 6). Table 1 illustrates the homology (i.e. similarity) between the novel proteins DPRP-1, DPRP-2 and DPRP-3 and other known serine proteases.

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Table 1 - Comparison of the sequences of these three novel proteins with DPPIV and other Clan SC, Family S9 members and Subfamily B members

<td> Protease Family</td><td> Protease name</td><td> No. of a.a,</td><td> Homology with DPPIV</td><td> TM region</td><td> Ser-Asp-His Triad</td><td> Gene location</td><td> Optimal pH</td>

<td> Clan CA, Family Cl</td><td> DPPI</td><td> 463</td><td> N</td><td> N</td><td> N</td><td> . Ilql4.1-ql4.3</td><td> -</td>

<td rowspan="3"> Clan SC, Family S28</td><td> DPPII</td><td> 500</td><td> N</td><td> Y</td><td> N</td><td> -</td><td> 4.5-6.0_</td>

<td> QPP</td><td> 492</td><td> N</td><td> N</td><td> N</td><td> -</td><td> 4.5-7.5</td>

<td> PCP</td><td> 496</td><td> N</td><td> N</td><td> N</td><td> •</td><td> •</td>

<td> Unassigned</td><td> DPPIH</td><td> 737</td><td> N</td><td> N</td><td> N</td><td> -</td><td> -</td>

<td rowspan="6"> Clan SC, Family S9, Subfamily B</td><td> DPPIV</td><td> 766</td><td> 100</td><td> Y</td><td> Y</td><td> 2q24.3</td><td> 7.5-8.0</td>

<td> DPPV1</td><td> 865</td><td> 52</td><td> Y</td><td> Mutation</td><td> 7</td><td> -</td>

<td> FAP</td><td> 760</td><td> 70</td><td> Y</td><td> Y</td><td> 2q23</td><td> 7.5-8.0</td>

<td> DPRP-1</td><td> 882</td><td> 41</td><td> N</td><td> Y</td><td> 15q22.1-15q22.2</td><td> 7.5-8.0</td>

<td> DPRP-2</td><td> 864</td><td> 39</td><td> N</td><td> Y</td><td> 19pl3.3</td><td> 7.5-8.0</td>

<td> DPRP-3</td><td> 796</td><td> 54</td><td> Y</td><td> Mutation</td><td> 2q12.3-2q14.1</td><td> •</td>

The greatest homology between DPRP-1, DPRP-2 and DPPIV is seen in the Cterminal sequences. On the basis of sequence homology with DPPIV (see Figure 1), one 15 might predict that these DPRP proteins would have functions that include, but are not limited to, roles as enzymes. Cloning, expression, biochemical and molecular characterization have confirmed this hypothesis.

The expression pattern of DPRPs and the localization to specialized epithelial cells and plasma cells (Leydig cells, prostate epithelial cells, lymphocytes, B cells) is 20 consistent with a role in differentiation, proliferation and inflammation. The localization of the DPRP-1 gene in hormone sensitive cancers (breast, prostate, testicular), tissues regulated by testosterone and the abundant expression in poorly differentiated cancers, demonstrate that DPRP-activating or inhibiting molecules will have numerous therapeutic applications in the treatment of disorders characterized by disregulated 25 growth, differentiation and steroid or polypeptide hormone synthesis and degradation.

Data disclosed herein supports the hypothesis that DPRP-1 and DPRP-2 are involved in the regulation of proliferation of in vitro models of prostate and testis cancer well known to those skilled in the art.

DPRP-1 and DPRP-2 activities described herein and their expression patterns are 30 compatible with their having functional roles as physiological regulators of the immune and neuroendocrine systems through the enzymatic modification of biochemical mediators like peptides and chemokines. The numerous functions previously described

WO 02/31134 PCT/US01/31874 for DPPIV based upon the use of inhibitors may be due in part to its action and that of similar proteins, like the DPRPs. Therefore, the discovery of selective and potent inhibitors of DPPIV, of the DPRPs and of other related proteases like FAP is considered central to achieving effective and safe pharmaceutical use of these and any newly identified serine protease inhibitors, as well as other active compounds that modify the function(s) of such proteins.

The invention thus provides novel proteins or polypeptides, the nucleic acids coding therefor, cells which have been modified with the nucleic acid so as to express these proteins, antibodies to these proteins, a screening method for the discovery of new 10 therapeutic agents which are inhibitors of the activity of these proteins (or which are inhibitors of DPPIV and not of the proteins), and therapeutic agents discovered by such screening methods. Tlie novel proteins and the nucleic acids coding therefor can be used to discover new therapeutic agents for the treatment of certain diseases, such as for example, reproductive, inflammatory and metabolic disorders and also in the preparation 15 of antibodies with therapeutic or diagnostic value.

In accordance with one aspect of the present invention, there are provided novel, mature, biologically active proteins, principally of human origin. Such proteins may be isolated in small quantities from suitable animal (including human) tissue or biological fluids by standard techniques; however, larger quantities are more conveniently prepared 20 in cultures of cells genetically modified so as to express the protein.

In accordance with another aspect of the present invention, there are provided isolated nucleic acid molecules encoding polypeptides of the present invention including mRNAs, DNAs, cDNAs, genomic DNAs thereof.

In accordance with a further aspect of the present invention, nucleic acid probes 25 are also provided comprising nucleic acid molecules of sufficient length to specifically hybridize to a nucleic acid sequence of the present invention.

In accordance with a still further aspect of the present invention, processes utilizing recombinant techniques are provided for producing such polypeptides useful for in vitro scientific research, for example, synthesis of DNA and manufacture of DNA 30 vectors. Processes for producing such polypeptides include culturing recombinant prokaryotic and/or eukaryotic host cells that have been transfected with DNA vectors containing a nucleic acid sequence encoding such a polypeptide and/or the mature protein under conditions promoting expression of such protein and subsequent recovery of such protein or a fragment of the expressed product.

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In accordance with still another aspect, the invention provides methods for using DPRP polypeptides and polynucleotides, including the treatment of infections, such as bacterial, fungal, protozoan and viral infections, particularly infections caused by HIV-1 or HTV-2, pain, diabetes, precocious puberty, infertility, obesity, anorexia, bulimia, Parkinson's disease, acute heart failure, hypotension, hypertension, urinary retention, osteoporosis, angina pectoris, myocardial infarction, stroke, ulcers, asthma, allergies, benign prostatic hypertrophy, cancers including hormone-sensitive and androgenindependent cancers, migraines, vomiting, psychotic and neurological disorders, including anxiety, schizophrenia, manic depression, depression, dementia, and severe mental retardation, and dyskinesias, hereinafter collectively referred to as the Diseases.

In accordance with yet another aspect of the present invention, there is provided a process for utilizing such polypeptides, or polynucleotides encoding such polypeptides, for the discoveiy of compounds that inhibit the biological activity of the mature proteins thereof, e.g. by cleaving an N־terminal dipeptide, and such inhibitors are thus also provided.

In accordance with a more specific aspect, the invention provides iolated nucleic acid which encodes (a) a polypeptide which includes the amino acid sequence of one of SEQ ID NOS: 1,3 and 5, or (b) a polypeptide having an amino acid sequence that is at least about 70% similar thereto and exhibits the same biological function, or which is an alternative splice variant of one of SEQ ID NOS:2,4 and 6, or which is a probe comprising at least 14 contiguous nucleotides from said nucleic acid encoding (a) or (b), or which is complementary to any one of the foregoing.

In accordance with another specific aspect, the invention provides a polypeptide which may be optionally glycosylated, and which (a) has the amino acid sequence of a mature protein set forth in any one of SEQ ID NOS: 1,3 and 5; (b) has the amino acid sequence of a mature protein having at least about 70% similarity to one of the mature proteins of (a) and which exhibits the same biological function; (c) has the amino acid sequence of a mature protein having at least about 90% identity with a mature protein of any of SEQ ID NOS:1,3 and 5; or (d) is an immunologically reactive fragment of (a).

In accordance with still another specific aspect, the invention provides a method for the screening for a compound capable of inhibiting the enzymatic activity of at least one mature protein of the invention, which method comprises incubating said mature protein and a suitable substrate for said mature protein in the presence of one or more test compounds or salts thereof, measuring the enzymatic activity of said mature protein, comparing said activity with comparable activity determined in the absence of a test

WO 02/31134 compound, and selecting the test compound or compounds that reduce the enzymatic activity, and it also provides a method for screening for a compound capable of inhibiting the enzymatic activity of DPPIV that does not inhibit the enzymatic activity of at least one mature protein and a suitable substrate in the presence of one or more inhibitors of DPPIV or salts thereof, measuring the enzymatic activity of said mature protein, comparing said activity with comparable activity determined in the absence of the DPPIV inhibitor, and selecting a compound that does not reduce the enzymatic activity of said mature protein.

These and other aspects of the present invention should be apparent to those skilled in the art from the detailed description which follows.

Brief Description of the Drawings

FIGS. 1A and IB show the co-linear alignment of DPRP-1, DPRP-2, DPRP-3 and DPPIV, with shading being supplied to indicate the same (black) or similar (gray) amino acid residues at a particular location.

FIG. 2 is similar to FIG. 1 and shows co-linear alignment of human and mouse DPRP-2.

FIG. 3 is a graph which shows the effects of various tetrapeptide amide inhibitors on dipeptidyl peptidase enzyme activity.

FIGS. 4A-4C show the effects of three inhibitor compounds on the proliferation of PC3 prostate cancer cell lines at various doses.

Petalled Description of the Preferred Embodiments

In accordance with an aspect of the present invention, there are provided isolated nucleic acid sequences (polynucleotides), which encode the mature polypeptides having the deduced amino acid sequences of the three DPRP’s (SEQ ID NOS:1,3 and 5).

The polynucleotides of this invention were discovered using a human testis cDNA library (DPRP-1), a human colon library (DPRP-2) and a human hypothalamus cDNA library (DPRP-3). Isolated nucleic acid for DPRP-1 contains an open reading frame encoding a protein of approximately 882 amino acids in length which is structurally related to human DPPIV, showing 26% identity, and 41% similarity over the entire human DPPIV protein sequence. Isolated nucleic acid for DPRP-2 contains an open reading frame encoding for a protein of approximately 864 amino acids, which is 39% similar to the entire DPPIV amino acid sequence. Analysis of DPRP-1 and DPRP2 primary amino acid sequence using hydrophobicity plots predicts that these two proteins do not have a transmembrane domain. Despite this fact, it is possible that these intracellular serine proteases are secreted upon cellular activation. Quiescent cell proline

WO 02/31134 dipeptidase (QPP) is a serine protease that is targeted to intracellular vesicles that are distinct from lysosomes (Chiravuri M, et al., J. Immunol. 2000 Nov 15;165(10):5695702). This hypothesis expands the potential site(s) and scope of DPRP-1 and DPRP-2 involvement in mechanisms for post-translational regulation of chemokines, cytokines, peptides and polypeptides. The full length DPRP-3 sequence contains 796 amino acids, a signal peptide from 1 to 48, and a transmembrane domain between 34 and 56. The mature protein is predicted to be a type II membrane protein and may be cleaved to produce a soluble form. The amino acid sequence is set forth in SEQ ID NO:5 , which was deduced from SEQ ID NO:6 and has 54% similarity with DPPIV.

Amino acid sequence alignments of these polypeptides with members of the prolyloligopeptidase enzyme subfamily S9B show that all three DPRP proteins have overall sequence and structural homology to DPPIV and FAP. DPRPs are predicted to be a members of the enzyme Clan SC (Serine nucleophile) with catalytic residues in the order Ser, Asp, His and the active site sequence (G-W-S-Y-G).

Table 2, Homology (i.e. similarity) between DPRP-1, DPRP-2, DPRP-3 and members of the prolyl oligopeptidase family S9B enzymes.

DPPIV

<td> 41</td><td> DPRP-1</td><td rowspan="2"> DPRP-2</td><td colspan="2" rowspan="3"> DPRP-3</td>

<td> 39</td><td> 74</td>

<td> 54</td><td> 39</td><td> 40</td>

<td> 70</td><td> 41</td><td> 39</td><td> 52</td><td> FAP</td>

<td> . 52</td><td> 40</td><td> 42</td><td> 68</td><td> 54 DPPVI</td>

DPRP-1, DPRP-2 and DPRP-3 do not exhibit sequence similarity with any members of the classical serine protease families, chymotrypsin and subtilisin. The order of the catalytic triad residues is different in the three main related SC clan families: HisAsp-Ser in chymotrypsin, Asp-His-Ser in subtilisin and Ser-Asp-His in the prolyl oligopeptidases.

As shown in Table 2, DPRP-3 has the highest homology with DPPVI (68% homology and 51% identity). Wada et al isolated cDNA clones for DPPVI, a DPPIVrelated protein, from bovine, rat (Wada et al., Proc, Nat, Acad, Sci, 89:197-201. (1992)) and human (Yokotani et al., Hum, Molec. Genet, 2:1037-1039 (1993)) brain libraries. They demonstrated that, unlike DPPIV, the catalytic triad in DPPVI does not have the first serine residue. In DPRP-3 two of the amino acids in the catalytic triad

WO 02/31134 PCT/US01/31874 characteristic of the serine protease family are conserved. However, the serine residue itself is replaced by glycine. While the absence of the serine residue is likely to prevent protease activity at this site, it is possible that multiple other functions mediated by other functional domains of the protein remain intact.

As briefly described above, DPPJV is a multifunctional molecule that exerts important functions depending on the expressed cells and tissues, in addition to its catalytic activity as a peptidase. DPRP-3 and DPPVI are also likely to maintain multiple functions despite the absence of an intact catalytic triad. For example, DPPVI has been implicated in the regulation of neuronal plasticity. DPPVI is highly expressed in the hippocampus, thalamus, hypothalamus and stiatum. In addition, developmental arrest and embryonic lethality of rump white Rw/Rw embryos is thought to be due to disruption of the DPPIV gene. Rw mutation is associated with a chromosomal inversion spanning 30 cM of the proximal portion of mouse chromosome 5. Genomic analysis of the DPPVI gene on the Rw chromosome places the inversion breakpoint in the coding region resulting in loss of a significant fraction of the C-terminal region, Hough R.B. et al., Proc. Nat. Acad. Set., 95,13800-13805 (1998).

The human DPRP-1 gene, predicted to be 32668bp in length, has at least 22 exons and eight transcripts. It maps to chromosome 15 (NT_010265) at position 15q21.1 - 15q22.1. The lengths of predicted alternative splice variant transcripts vary 20 between 602bp and 4523bp (see SEQ ID NOS: 7-22). This is in agreement with the multiple transcripts observed by Northern blot analysis (See Example 2). ESTs representing the transcripts were found in numerous tissues including senescent fibroblasts, T-lymphocytes, germinal center B-cells, germ cell seminoma, testis, melanocytes, uterus, ovary breast, multiple sclerosis lesions, pancreas and placenta.

Human DPRP-2 belongs to a gene with at least 27 exons and nine splice variants (see SEQ ID NOS:23-40). One SNP was observed in the 3' UTR. (88% (37) C vs. 12% (5) T). The DPRP-2 gene maps to region 19pl3.3 of chromosome 19. This location is host to a number of disease markers and is associated with various disorders including hypocalciuric hypercalcemia, type II cerebellar ataxia, muscular dystrophy, convulsions, 30 susceptibility to atherosclerosis, psoriasis, ectodermal dysplasia, and acute myeloid leukemia. In agreement with the ubiquitous distribution of the mRNA observed by Northern blot analysis (see Example 2), DPRP-2 was expressed in a wide variety of. tissues upon examination of EST’s coverage (e.g. over 64 EST’s expressed in liver, spleen, muscle, melanocytes, heart, lung, placenta, skin, pancreas, stomach, brain parathyroid gland).

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Human DPRP-3 belongs to a gene with at least 23 exons and two splice variants (see SEQ ID NOS141-44). The gene maps to chromosome 2 (NT_005445) at position 2ql2.3-2ql4.1. Transcripts for DPRP-3 did not show as wide a distribution as DPRP-1 and DPRP-2. As shown by Northern blot in Example 2, DPRP-3 expression is restricted 5 to brain and pancreas. ESTs representing the DPRP-3 mRNA were abundant in tissue derived from multiple sclerosis lesions, hypothalamus, whole brain and nerves, with a few transcripts being found in uterus and colon.

The relationships among human and rodent proteases in clan SC, including DPRP-1 DPRP-2 and DPRP-3, were analyzed using Neighbor Joining method (NJ), see 10 Saitou and Nei, Mol, Biol, Evol., 4.406-525 (1987). Phylogenetic analysis shows that among the S9 proteases, DPRP-1 and DPRP-2, both lacking a transmembrane domain, are distinguished from DPPIV and its closely related proteins like FAP. Similarity is shown however between DPPIV and FAP and between DPRP-3 and DPPVI, which are all type II membrane proteins.

A datebase search for additional DPRP-related genes revealed the presence of a murine sequence related to DPRP-1. Alignment of this mouse sequence with the novel human proteases shows that the mDPRP-1 displays considerable homology with its human counterpart (FIG. 2). One skilled in the art will readily recognize that the novel mouse protease gene can be isolated using the sequence information disclosed herein and 20 can be readily incorporated into one of the routinely used expression constructs which are well known in the art. Use of this disclosed sequence by those skilled in the art to generate a transgenic mouse model will employ development of gene-targeting vectors, for example, that result in homologous recombination in mouse embryonic stem cells.

The use of knockout mice in further analysis of the function of DPRP genes is a valuable 25 tool.

The polynucleotides of the present invention may be in the form of RNA or in the form of DNA; DNA should be understood to include cDNA, genomic DNA, and synthetic DNA. The DNA may be double-stranded or single-stranded and, if singlestranded, may be the coding strand or non-coding (antisense) strand. The coding 30 sequence which encodes the mature polypeptide may be identical to the coding sequence shown in SEQ ID NOS:2,4 and 6 respectively, or it may be a different coding sequence encoding the same mature polypeptide, as a result of the redundancy or degeneracy of the genetic code or a single nucleotide polymorphism. For example, it may also be an RNA transcript which includes the entire length of any one of SEQ ID NOS:2,4 and 6.

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The polynucleotides which encode the mature proteins of SEQ ID NOS:1,3,5, respectively, may include but are not limited to the coding sequence for the mature protein alone; the coding sequence for the mature polypeptide plus additional coding sequence, such as a leader or secretory sequence or a proprotein sequence; and the coding sequence for the mature protein (and optionally additional coding sequence) plus non-coding sequence, such as introns or a non-coding sequence 5' and/or 3' of the coding sequence for the mature protein.

Thus, the term polynucleotide encoding a polypeptide or the term nucleic acid encoding a polypeptide should be understood to encompass a polynucleotide or nucleic acid which includes only coding sequence for the mature protein as well as one which includes additional coding and/or non-coding sequence. The terms polynucleotides and nucleic acid are used interchangeably.

The present invention also includes polynucleotides where the coding sequence for the mature protein may be fused in the same reading frame to a polynucleotide sequence which aids in expression and secretion of a polypeptide from a host cell; for example, a leader sequence which functions as a secretory sequence for controlling transport of a polypeptide from the cell may be so fused. The polypeptide having such a leader sequence is termed a preprotein or a preproprotein and may have the leader sequence cleaved, by the host cell to form the mature form of the protein. These polynucleotides may have a 5' extended region so that it encodes a proprotein, which is the mature protein plus additional amino acid residues at the N-terminus. The expression product having such a prosequence is termed a proprotein, which is an inactive form of the mature protein; however, once the prosequence is cleaved an active mature protein remains. Thus, for example, the polynucleotides of the present invention may encode mature proteins, or proteins having a prosequence, or proteins having both a prosequence and a presequence (leader sequence).

The polynucleotides of the present invention may also have the coding sequence fused in frame to a marker sequence which allows for purification of the polypeptides of the present invention. The marker sequence may be a polyhistidine tag, a hemagglutinin (HA) tag, a c־myc tag or a V5 tag when a mammalian host, e.g. COS-1 cells, is used. The HA tag would correspond to an epitope derived from the influenza hemagglutinin protein (Wilson, L, et al., Cell, 37:767 (1984)), and the c-myc tag may be an eptitope from h»man Myc protein (Evans, G.I. et al., Mol. Cell. Biol. 5:3610-3616 (1985)).

The term gene means the segment of DNA involved in producing a polypeptide chain; it includes regions preceding and following the coding region (leader and trailer)

WO 02/31134 as well as intervening sequences (introns) between individual coding segments (exons). The term “significant sequence homology” is intended to denote that at least 25%, preferably at least 40%, of the amino acid residues are conserved, and that, of the nonconserved residues, at least 40% are conservative substitutions.

Fragments of the full-length genes of the present invention may be used as a hybridization probe for a cDNA library to isolate full-length cDNA as well as to isolate other cDNAs which have significant sequence homology to the gene and will encode proteins or polypeptides having similar biological activity or function. By similar biological activity or function, for purposes of this application, is meant the ability to 10 cleave an N-terminal dipeptide having Ala or Pro as the penultimate residue or other amino acids. Such a probe of this type has at least 14 bases (at least 14 contiguous nucleotides from one of SEQ ID NOS:2,4 or 6), preferably at least 30 bases, and such may contain, for example, 50 or more bases. Such probe may also be used to identify a cDNA clone corresponding to a full-length transcript and/or a genomic clone or clones 15 that contains the complete gene, including regulatory and promoter regions, exons, and introns. Labelled oligonucleotides having a sequence complementary to that of the gene of the present invention are useful to screen a library of human cDNA, genomic DNA or mRNA to locate members of the library to which the probe hybridizes. As an example, a known DNA sequence may be used to synthesize an oligonucleotide probe which is then 20 used in screening a library to isolate the coding region of a gene of interest.

The present invention is considered to further provide polynucleotides which hybridize to the hereinabove-described sequences wherein there is at least 70%, preferably at least 90%, and more preferably at least 95% identity or similarity between the sequences, and thus encode proteins having similar biological activity. Moreover, as 25 known in the art, there is “similarity” between two polypeptides when the amino acid sequences contain the same or conserved amino acid substitutes for each individual residue in the sequence. Identity and similarity may be measured using sequence analysis software (e.g״ Sequence Analysis Software Package of the Genetics Computer Group, University of Wisconsin Biotechnology Center, 1710 University Avenue, 30 Madison, WI53705). The present invention particularly provides such polynucleotides which hybridize under stringent conditions to the hereinabove-described polynucleotides. As herein used, the term stringent conditions means conditions which permit hybridization between polynucleotides sequences and the polynucleotide sequences of SEQ ED NOS:2,4 and 6 where there is at least about 70% identity.

Suitably stringent conditions can be defined by, e.g., the concentrations of salt or

WO 02/31134 PCT/US01/31874 formamide in the prehybridization and hybridization solutions, or by the hybridization temperature, and are well known in the art. In particular, stringency can be increased by reducing the concentration of salt, by increasing the concentration of formamide, and/or by raising the hybridization temperature.

. For example, hybridization under high stringency conditions may employ about

50% formamide at about 37°C to 42°C, whereas hybridization under reduced stringency conditions might employ about 35% to 25% formamide at about 30°C to 35°C. One particular set of conditions for hybridization under high stringency conditions employs 42°C, 50% formamide, 5x. SSPE, 0.3% SDS, and 200 pg/ml sheared and denatured salmon sperm DNA. For hybridization under reduced stringency, similar conditions as described above may be used in 35% formamide at a reduced temperature of 35°C. The temperature range corresponding to a particular level of stringency can be further narrowed by calculating the purine to pyrimidine ratio of the nucleic acid of interest and adjusting the temperature accordingly. Variations on the above ranges and conditions are well known in the art. Preferably, hybridization should occur only if there is at least 95%, and more preferably at least 97%, identity between the sequences. The polynucleotides which hybridize to the hereinabove described polynucleotides in a preferred embodiment encode polypeptides which exhibit substantially the same biological function or activity as the mature protein encoded by one of the cDNAs of 20 SEQ ID NOS:2,4 and 6.

As mentioned, a suitable polynucleotide probe may have at least 14 bases, preferably 30 bases, and more preferably at least 50 bases, and will hybridize to a polynucleotide of the present invention which has an identity thereto, as hereinabove described, and which may or may not retain activity. For example, such polynucleotides 25 may be employed as a probe for hybridizing to the polynucleotides of SEQ ID NOS:2,4 and 6 respectively, for example, for recovery of such a polynucleotide, or as a diagnostic probe, or as a PCR primer. Thus, the present invention includes polynucleotides having at least a 70% identity, preferably at least a 90% identity, and more preferably at least a 95% identity to a polynucleotide which encodes the polypeptides of SEQ ID NOS: 1,3 30 and 5 respectively, as well as fragments thereof, which fragments preferably have at least 30 bases and more preferably at least 50 bases, and to polypeptides encoded by such-polynucleotides.

As is well known in the art, the genetic code is redundant in that certain amino acids are coded for by more than one nucleotide triplet (codon), and the invention 35 includes those polynucleotide sequences which encode the same amino acids using a

WO 02/31134 different codon from that specifically exemplified in the sequences herein. Such a polynucleotide sequence is referred to herein as an equivalent polynucleotide sequence. The present invention further includes variants of the hereinabove described polynucleotides which encode for fragments, such as part or all of the mature protein, analogs and derivatives of one of the polypeptides having the deduced amino acid sequence of SEQ ID NOS:1,3 and 5 respectively. The variant forms of the polynucleotides may be a naturally occurring allelic variant of the polynucleotides or a non-naturally occurring variant of the polynucleotides. For example, the variant in the nucleic acid may simply be a difference in codon sequence for the amino acid resulting from the degeneracy of .the genetic code, or there may be deletion variants, substitution variants and addition or insertion variants. As known in the art, an allelic variant is an alternative form of a polynucleotide sequence which may have a substitution, deletion or addition of one or more nucleotides that does not substantially alter the biological function of the encoded polypeptide.

The present invention further includes polypeptides which have the deduced amino acid sequence of SEQ ID NOS: 1,3 and 5, as well as fragments, analogs and derivatives of such polypeptides. The terms fragment, derivative and analog, when referring to the polypeptides of SEQ ID NOS: 1,3 and 5, means polypeptides that retain essentially the same biological function or activity as such polypeptides. An analog might, for example, include a proprotein which can be activated by cleavage of the proprotein portion to produce an active mature protein. The polypeptides of the present invention may be recombinant polypeptides, natural polypeptides or synthetic polypeptide; however, they are preferably recombinant polypeptides, glycosylated or unglycosylated.

The fragment, derivative or analog of a polypeptide of SEQ ID NOS: 1,3 and 5 respectively, may be (i) one in which one or more of the amino acid residues is substituted with a conserved or non-conserved amino acid residue (preferably a conserved amino acid residue) and such substituted amino acid residue may or may not be one encoded by the genetic code, or (ii) one in which one or more of the amino acid residues includes a substituent group, or (iii) one in which additional amino acids are fused to the mature protein, such as a leader or secretory sequence or a sequence which is employed for purification of the mature polypeptide or a proprotein sequence. Such fragments, derivatives and analogs are deemed to be within the scope of those skilled in the art to provide upon the basis of the teachings herein.

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The polypeptides and polynucleotides of the present invention should be in an . isolated form, and preferably they are purified to substantial homogeneity or purity. By substantial homogeneity is meant a purity of at least about 85%.

The term isolated is used to mean that the material has been removed from its original environment (e.g., the natural environment if it is naturally occurring). For example, a naturally occurring polynucleotide or polypeptide present in a living animal is not considered to be isolated, but the same polynucleotide or polypeptide, when separated from substantially all of the coexisting materials in the natural system, is considered isolated. For DNA, the term includes, for example, a recombinant DNA which is incorporated into a vector, into an autonomously replicating plasmid or virus, or into the genomic DNA of a prokaryote or eukaryote; or which exists as a separate molecule (e.g.־, a cDNA or a genomic or cDNA fragment produced by polymerase chain reaction (PCR) or restriction endonuclease digestion) independent of other sequences. It also includes a recombinant DNA which is part of a hybrid gene encoding additional polypeptide sequence, e.g., a fusion protein. Further included is recombinant DNA which includes a portion of the nucleotides shown in one of SEQ ID NO!2,4 or 6 which encodes an alternative splice variant of the DPRP. Various alternative splice variants are exemplified in SEQ ID NOS:8,10,12,14,16,18,20,22,24,26,28,30,32,34,36,38, 40,42,44 and 46.

The polypeptides of the present invention include any one of the polypeptide of SEQ ID NOS:1,3 and 5 (in particular the mature protein), as well as polypeptides which have at least 70% similarity (e.g. preferably at least 60% and more preferably at least 70% identity) to one of the polypeptides of SEQ ID NOS: 1,3 and 5, more preferably at least 90% similarity (e.g. preferably at least 90% identity) to one of the polypeptides of SEQ ID NOS:1,3 and 5, and most preferably at least 95% similarity (e.g. preferably at least 95% identity) to one of the polypeptides of SEQ ID NOS: 1,3 and 5. Moreover, they should preferably include exact portions of such polypeptides containing a sequence of at least 30 amino acids, and more preferably at least 50 amino acids.

Fragments or portions of the polypeptides of the present invention may be employed as intermediates for producing the corresponding full-length polypeptides by peptide synthesis. Fragments or portions of the polynucleotides of the present invention may also be used to synthesize full-length polynucleotides, of the present invention.

The present invention also includes vectors which include such polynucleotides, host cells which are genetically engineered with such vectors and the production of polypeptides by recombinant techniques using the foregoing. Host cells are genetically

WO 02/31134 engineered (transduced or transformed or transfected) with such vectors which may be, for example, a cloning vector or an expression vector. The vector may be, for example, in the form of a plasmid, a viral particle, a phage, etc. The engineered host cells can be cultured in conventional nutrient media modified as appropriate for activating promoters, selecting transformants or amplifying the genes of the present invention. The culture conditions, such as temperature, pH and the like, are those commonly used with the host cell selected for expression, as well known to the ordinarily skilled artisan.

The polynucleotides of the present invention may be employed for producing polypeptides by recombinant techniques. Thus, for example, the polynucleotides may be included in any one of a variety of expression vectors for expressing polypeptides. Such vectors include chromosomal, nonchromosomal and synthetic DNA sequences, e.g., derivatives of SV40; bacterial plasmids; phage DNA; baculovirus; yeast plasmids; vectors derived from combinations of plasmids and phage DNA, viral DNA such as vaccinia, adenovirus, fowl pox virus, and pseudorabies. However, any other vector may be used as long as it is replicable and viable in the host.

The appropriate DNA sequence may be inserted into the vector by any of a variety of procedures. In general, the DNA sequence is inserted into an appropriate restriction endonuclease site(s) by procedures well known in the art, which procedures are deemed, to be within the scope of those skilled in this art.

The DNA sequence in the expression vector is operatively linked to an appropriate expression control sequence(s) (promoter) to direct mRNA synthesis. As representative examples of such promoters, there may be mentioned: LTR or SV40 promoter, the E. coli. lac or tip, the phage lambda P.sub.L promoter and other promoters known to control expression of genes in prokaryotic or eukaryotic cells or their viruses. The expression vector should also contain a ribosome binding site for translation initiation and a transcription terminator. The vector may also include appropriate sequences for amplifying expression. In addition, the expression vectors preferably contain one or more selectable marker genes to provide a phenotypic trait for selection of transformed host cells, such as dihydrofolate reductase or neomycin-resistance for eukaryotic cell culture, or such as tetracycline or ampicillin-resistance in E. coli.

The vector containing the appropriate DNA sequence as hereinabove described, as well as an appropriate promoter or control sequence, may be employed to transform an appropriate host to permit the host to express the protein. As representative examples of appropriate hosts, there maybe mentioned: bacterial cells, such as E. coli, Streptomyces, Salmonella typhimurium; fungal cells, such as yeast; insect cells, such as

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Drosophila S2 and Spodoptera Sf9; animal cells, such as CHO, COS or Bowes melanoma; adenoviruses; plant cells, etc. The selection of an appropriate host is deemed to be within the scope of those skilled in the art from the teachings herein.

Synthetic production of nucleic acid sequences is well known in the art as is apparent from CLONTECH 95/96 Catalogue, pages 215-216, CLONTECH, 1020 East Meadow Circle, Palo Alto, Calif. 94303. Thus, the present invention also includes expression vectors useful for the production of the proteins of the present invention

The present invention further includes recombinant constructs comprising one or more ofthe sequences as broadly described above. The constructs may comprise a vector, such as a plasmid or viral vector, into which a sequence of the invention has been inserted, in a forward or reverse orientation. In a preferred aspect of this embodiment, the construct further comprises regulatory sequences, including, for example, a promoter, operably linked to the sequence. Large numbers of suitable vectors and promoters are known to those of skill in the art, and are commercially available. The following vectors are provided by way of example: Bacterial: pQE70, pQE60, pQE-9 (Qiagen), pBS, pDlO, phagescript, psiX174, pbluescript SK, pbsks, pNH8A, pNH16a, pNH18A, pNH46A (Stratagene), ptrc99a, pKK223-3, pKK233-3, pDR540 and pRIT5 (Pharmacia); and Eukaryotic: pWLNEO, pSV2CAT, pOG44, pXTl, pSG (Stratagene) pSVK3, pBPV, pMSG, and pSVL (Pharmacia). However, any other suitable plasmid or vector may be used as long as it is replicable and viable in the host

Promoter regions can be selected from any desired gene using CAT (chloramphenicol acetyl transferase) vectors or other vectors with selectable markers. Two appropriate vectors are pKK2328־ and pCM7. Particular named bacterial promoters include lad, lacZ, T3, T7, gpt, lambda P.sub.R, P.sub.L and trp. Eukaiyotic promoters include CMV immediate early, HSV thymidine kinase, early and late SV40, LTRs from retrovirus, and mouse metallothionein־I. Selection of the appropriate vector and promoter is well within the level of ordinary skill in the art.

Components of the expression vector may generally indude: 1) a neomycin phosphotransferase (G418), or hygromycin B phosphotransferase (hyg) gene as a selection marker, 2) an E. coli origin of replication, 3) a T7 and SP6 phage promoter sequence, 4) lac operator sequences, 5) the lactose operon repressor gene (laclq) and 6) a multiple cloning site linker region. Such an origin of replication (oriC) may be derived from pUCl 9 (LTI, Gaithersburg, Md.).

A nucleotide sequence encoding one of the polypeptides SEQ ID NOS:2,4 and 6 having the appropriate restriction sites is generated, for example, according to the PCR

18־

WO 02/31134 protocol described in Example 1 hereinafter, using PCR primers having restriction sites for Kpnl (as the 5' primer) and Notl or SacI (as the 3' primer) for DPRP-1, or sites for Hindm (as the 5’ primer) and Notl or BamHI (as the 3’ primer) for DPRP-2, The PCR inserts are gel-purified and digested with compatible restriction enzymes. The insert and 5 vector are ligated according to standard protocols.

In a further embodiment, the present invention provides host cells containing the • . above-described constructs. The host cell can be a higher eukaryotic cell, such as a mammalian cell, or a lower eukaryotic cell, such as a yeast cell, or the host cell can be a prokaryotic cell, such as a bacterial cell. Introduction of the construct into the host cell 10 can be effected by calcium phosphate transfection, DEAE-Dextran mediated transfection, lipofection or electroporation (Davis, L., Dibner, M., Battey, I, Basic Methods in Molecular Biology, (1986)).

Such constructs in host cells are preferably used in a conventional manner to produce the gene product encoded by the recombinant sequence. Alternatively, the 15 polypeptides of the invention can be synthetically produced by conventional peptide synthesizers or by chemical ligation of suitable fragments thus prepared.

Mature proteins can be expressed in mammalian cells, yeast, bacteria, or other cells under the control of appropriate promoters. Cell-free translation systems can also be employed to produce such proteins using RNAs derived from the DNA constructs of 20 the present invention. Appropriate cloning and expression vectors for use with prokaryotic and eukaryotic hosts are described by Sambrook, et al., Molecular Cloning: A Laboratoiy Manual, Second Edition, Cold Spring Harbor, N.Y., (1989).

Transcription of the DNA encoding the polypeptides of the present invention by higher eukaryotes is increased by inserting an enhancer sequence into the vector.

Enhancers include cis-acting elements of DNA, usually about from 10 to 300 bp, that act on a promoter to increase its transcription. Examples include the SV40 enhancer on the late side of the replication origin bp 100 to 270, a cytomegalovirus early promoter enhancer, the polyoma enhancer on the late side of the replication origin, and adenovirus enhancers.

Generally, recombinant expression vectors will include origins of replication and selectable markers permitting transformation of the host cell, e.g., the ampicillinresistance gene of E. coli and S. cerevisiae TRP1 gene, and a promoter derived from a highly expressed gene to direct transcription of a downstream structural sequence. Such promoters can be derived from operons encoding glycolytic enzymes, such as 3־ phosphoglycerate kinase (PGK), alpha-factor, acid phosphatase, or heat shock proteins,

I I I

WO 02/31134 among others. The heterologous structural sequence is assembled in appropriate phase with translation initiation and termination sequences, and preferably, a leader sequence capable of directing secretion of translated protein into the periplasmic space or extracellular medium. Optionally, the heterologous sequence can encode a fusion protein including an N-terminal identification peptide imparting desired characteristics, e.g., stabilization or simplified purification of expressed recombinant product.

Useful expression vectors for bacterial use are constructed by inserting a structural DNA sequence encoding a desired protein together with suitable translation initiation and termination signals in operable reading phase with a functional promoter. The vector will comprise one or more phenotypic selectable markers and an origin of replication to ensure maintenance of the vector and to, if desired, provide amplification within the host. Suitable prokaryotic hosts for transformation include E. coli, Bacillus subtilis, Salmonella typhimurium and various species within the genera Pseudomonas, Streptomyces, and Staphylococcus, although others may also be employed as a matter of choice.

As a representative but non-limiting example, useful expression vectors for bacterial use can comprise a selectable marker and bacterial origin of replication derived from commercially available plasmids comprising genetic elements of the well known cloning vector pBR322 (ATCC 37017). Such commercial vectors include, for example, pKK223-3 (Pharmacia Fine Chemicals, Uppsala, Sweden) and GEM1 (Promega Biotec, Madison, Wis., U.S.A.). These pBR322 backbone sections are combined with an appropriate promoter and the structural sequence to be expressed.

Following transformation of a suitable host strain and growth of the host strain to an appropriate cell density, the selected promoter is induced by appropriate means (e.g., temperature shift or chemical induction), and cells are cultured for an additional period. Cells are typically harvested by centrifugation and then disrupted by physical or chemical means, with the resulting crude extract being retained for further purification. Microbial cells employed in expression of proteins can be disrupted by any convenient method, including freeze-thaw cycling, sonication, mechanical disruption and use of cell-lysing agents; such methods are well known to those skilled in the art.

Various mammalian cell culture systems can also be employed to express a recombinant protein. Examples of mammalian expression systems include the COS-7 lines of monkey kidney fibroblasts, described by Gluzman, Cell, 23:175 (1981). Other cell lines capable of expressing a compatible vector include, for example, the C127,3T3, CHO, HeLa and BHK cell lines. Mammalian expression vectors will generally comprise .

WO 02/31134 an origin of replication, a suitable promoter and enhancer, and also any necessary ribosome binding sites, polyadenylation site, splice donor and acceptor sites, transcriptional termination sequences, and 5' flanking nontranscribed sequences. DNA sequences derived from the SV40 splice, and polyadenylation sites may be used to provide required nontranscribed genetic elements.

The polypeptides can be recovered and purified from recombinant cell cultures by methods including ammonium sulfate or ethanol precipitation, acid extraction, anion or cation exchange chromatography, phosphocellulose chromatography, hydrophobic interaction chromatography, affinity chromatography, hydroxylapatite chromatography and lectin chromatography. Recovery can be facilitated if the polypeptide is expressed at the surface of the cells, but such is not a prerequisite. Recovery may also be desirable of cleavage products that are cleaved following expression of a longer form of the polypeptide. Protein refolding steps as known in this art can be used, as necessary, to complete configuration of the mature protein. High performance liquid chromatography (HPLC) can be employed for final purification steps.

The polypeptides of the present invention may be purified natural products, or produced by recombinant techniques from a prokaryotic or eukaryotic host (for example, by bacterial, yeast, higher plant, insect or mammalian cells in culture). Depending upon the host employed in a recombinant production procedure, the polypeptides of the present invention may be glycosylated or may be non-glycosylated. Polypeptides of the invention may also include an initial methionine amino acid residue.

In a preferred embodiment, the proteins of the invention are isolated and purified so as to be substantially free of contamination from other proteins. For example, the proteins of the invention should constitute at least 80% by weight of the total protein present in a sample, more preferably at least 90%, even more preferably at least 95%, and most preferably at least 98% by weight of the total protein.

These proteins may be in the form of a solution in water, another suitable solvent, such as dimethyl sulphoxide (DMSO) or ethanol, or a mixture of suitable solvents. Examples of mixtures of solvents include 10% (by weight) ethanol in water and 2% (by weight) DMSO in water. A solution may further comprise salts, buffering agents, chaotropic agents, detergents, preservatives and the like. Alternatively, the proteins may be in the form of a solid, such as a lyophilised powder or a crystalline solid, which may also comprise a residual solvent, a salt of the like.

As used herein, the term ״antibodies includes polyclonal antibodies, affinity-purified polyclonal antibodies, monoclonal antibodies, and antigen-binding ־21WO 02/31134 PCT/US01/31874 fragments, such as F(ab')₂ and Fab' proteolytic fragments. Genetically engineered intact antibodies or fragments, such as chimeric antibodies, Fv fragments, single chain antibodies and the like, as well as synthetic antigen-binding peptides and polypeptides, are also included. Nou-human antibodies may be humanized by grafting non-human

CDRs onto human framework and constant regions, or by incorporating the entire non-human variable domains (optionally cloaking them with a human-like surface by replacement of exposed residues, wherein the result is a veneered antibody). In some instances, humanized antibodies may retain non-human residues within the human variable region framework domains to enhance proper binding characteristics. Through 10 humanizing antibodies, biological half-life may be increased, and the potential for adverse immune reactions upon administration to humans should be reduced.

Alternative techniques for generating or selecting antibodies useful herein include in vitro exposure of lymphocytes to human prohormone DPRP protein or a peptide therefrom, and selection of antibody display libraries in phage or similar vectors 15 (for instance, through use of immobilized or labeled human DPRP protein or peptide). Genes encoding polypeptides having potential human DPRP polypeptide binding domains can be obtained by screening random peptide libraries displayed on phage (phage display) or on bacteria, such as E. coli. Nucleotide sequences encoding such polypeptides can be obtained in a number of ways well known in this art.

As would be evident to one of ordinary skill in the art, polyclonal antibodies can be generated from inoculating a variety of warm-blooded animals, such as horses, cows, goats, sheep, dogs, chickens, rabbits, mice and rats, with a human DPRP polypeptide or a fragment thereof. The immunogenicity of a human prohonnone DPRP polypeptide may be increased through the use of an adjuvant, such as alum (aluminum hydroxide) or 25 Freund's complete or incomplete adjuvant, or surface active substances, such as lysolecithin, pluronic polyols, polyanions, peptides, oil emulsions, KLH or dinitrophenol. Among adjuvants used in humans, BCG (bacilli Calmette-Guerin) and Corynebacterium parvum are especially preferable. Polypeptides useful for immunization also include fusion polypeptides, such as fusions of DPRP or a portion 30 thereof with an immunoglobulin polypeptide or with maltose binding protein. The polypeptide immunogen may be a full-length molecule or a portion thereof. If the polypeptide portion is hapten-like, such portion may be advantageously joined or . linked to a macromolecular carrier, such as keyhole limpet hemocyanin (KLH), bovine serum albumin (BSA) or tetanus toxoid, for immunization. Antibodies to DPRP may 35 also be generated using methods that are well known in the art. Such antibodies may

WO 02/31134 include, but are not limited to, polyclonal, monoclonal, chimeric, and single chain antibodies, Fab fragments, and fragments produced by a Fab expression library. Neutralizing antibodies (i.e., those which block or modify interactions at the active sites) are especially preferred for therapeutic use.

For the production of antibodies, binding proteins, or peptides which bind specifically to DPRP, libraries of single chain antibodies, Fab fragments, other antibody fragments, non-antibody protein domains, or peptides may be screened. The libraries could be generated using phage display, other recombinant DNA methods, or peptide synthesis (Vaughan, T. J. et al. Nature Biotechnology 14:309-314 (1966)). Such libraries would commonly be screened using methods which are well known in the art to identify sequences which demonstrate specific binding to DPRP.

It is preferred that the oligopeptides, peptides, or fragments used to induce antibodies to DPRP have an amino acid sequence consisting of at least about 5 amino acids and, more preferably, of at least about 10 amino acids. It is also preferable that these oligopeptides, peptides, or fragments are identical to a portion of the amino acid sequence of the natural protein. Short stretches of DPRP amino acids may also be fused with those of another protein, such as KLH, and antibodies to the chimeric molecule may be produced.

Monoclonal antibodies to DPRP may be prepared using any well known technique which provides for the production of antibody molecules by continuous cell lines in culture. These include, but are not limited to, the hybridoma technique, the human B-cell hybridoma technique, and the EBV-hybridoma technique, although monoclonal antibodies produced by hybridoma cells may be preferred.

In addition, techniques developed for the production of chimeric antibodies, such as the splicing of mouse antibody genes to human antibody genes to obtain a molecule with appropriate antigen specificity and biological activity, can be used, see Neuberger, M.S. et al. Nature 312:604-608 (1984). Alternatively, techniques described for the production of single chain antibodies may be adapted, using methods known in the art, to produce DPRP-specific single chain antibodies. Antibodies with related specificity, but of distinct idiotypic composition, may be generated by chain shuffling from random combinatorial immunoglobulin libraries. (Burton D. R. Proc, Natl, Acad, ScjJ$: 11120-11123 (1991)).

Antibodies may also be produced by inducing in vivo production in the lymphocyte population or by screening immunoglobulin libraries or panels of highly

WO 02/31134 specific binding reagents as disclosed in the literature. (Orlandi, R. et al. Prpc^NatL Acad, Sci, 86: 3833-3837 (1989)).

Antibody fragments which contain specific binding sites for DPRP may also be generated. For example, such fragments include, but are not limited to, F(ab')₃ fragments produced by pepsin digestion of the antibody molecule and Fab fragments generated by reducing the disulfide bridges of the F(ab')j fragments. Alternatively, Fab expression libraries may be constructed to allow rapid and easy identification of monoclonal Fab fragments with the desired specificity. (Huse, W. D. et al. Science ¾54: 1275-1281 (1989)).

1Q Various immunoassays may be used to identify antibodies having the desired specificity. Numerous protocols for competitive binding or immunoradiometric assays using either polyclonal or monoclonal antibodies with established specificities are well known in the art. Such immunoassays typically involve the measurement of complex formation between DPRP and its specific antibody. A two-site, monoclonal-based immunoassay utilizing monoclonal antibodies reactive to two non-interfering DPRP epitopes is preferred, but a competitive binding assay may also be employed.

As earlier mentioned, the DPRPs can be used in treatment of the Diseases. Pharmaceutical compositions suitable for use in this aspect of the invention include compositions wherein the active ingredients are contained in an effective amount to 20 achieve the intended purpose relating to one of the Diseases. The determination of a therapeutically effective dose is well within the capability of those skilled in the art and can be estimated initially either in cell culture assays, e.g. of neoplastic cells, or in animal models, usually mice, rats, rabbits, dogs, or pigs. An animal model may also be used to determine the appropriate concentration range and route of administration, which 25 information is then commonly used to determine useful doses and routes for administration in humans.

A therapeutically effective dose refers to that amount of active ingredient, e.g. a DPRP or fragment thereof, antibodies of DPRP, or an agonist, antagonist or inhibitor of DPRP, which ameliorates particular symptoms or conditions of the Disease. For 30 example, the amount to be administered may be effective to cleave a desired target substrate upon contact therewith. Therapeutic efficacy and toxicity may likewise be determined by standard pharmaceutical procedures in cell cultures or with experimental animals, such as by calculating the ED50 (the dose therapeutically effective in 50% of the population) or LD50 (the dose lethal to 50% of the population) statistics. The dose 35 ratio of toxic to therapeutic effects is the therapeutic index, and it can be expressed as the

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LD50/ED50 ratio. Pharmaceutical compositions which exhibit large therapeutic indices are preferred. The data obtained from cell culture assays and animal studies is used in formulating a range of dosage for human use. The dosage contained in such compositions is preferably within a range of circulating concentrations that include the 5 ED50 with little or no toxicity. The dosage varies within this range depending upon the dosage form employed, the sensitivity of the patient, and the route of administration.

An exact dosage will normally be determined by the medical practitioner in light of factors related to the subject requiring treatment, with dosage and administration being adjusted to provide a sufficient level ofthe active moiety or to maintain a desired 10 effect. Factors to be taken into account include the severity of the disease state, the general health of the subject, the age, weight, and gender of the subject, diet, time and frequency of administration, drug combinations), reaction sensitivities, and tolerance/response to therapy. Long-acting pharmaceutical compositions may be administered every 3 to 4 days, every week, or even once every two weeks, depending 15 on the half-life and clearance rate of the particular formulation.

Yet another aspect of the invention provides polynucleotide molecules having sequences that are antisense to mRNA transcripts of DPRP1, DPRP2 and DPRP-3 polynucleotides. Administration of an antisense polynucleotide molecule can block the production of the protein encoded by DPRP-1, DPRP2 or DPRP-3. The techniques for 20 preparing antisense polynucleotide molecules and administering such molecules are known in the art. For example, antisense polynucleotide molecules can be encapsulated into liposomes for fusion with cells.

In particular, the expression of DPRP-1, DPRP-2 and DPRP-3 in specialized epithelial cells, immune cells (lymphocytes and B cells), astrocytic tumors, and in 25 various hormone sensitive cancers provides evidence of a potential role in the pathophysiology of cancer, metaplasia and metastasis. Therefore in a further aspect, the invention relates to diagnostic assays for detecting diseases associated with inappropriate DPRP activity or expression levels. Antibodies that specifically bind DPRP may be used for the diagnosis of disorders characterized by expression of DPRP, or in assays to 30 monitor patients being treated with DPRP or with agonists or antagonists (inhibitors) of DPRP. Antibodies useful for diagnostic purposes may be prepared in the same manner as those described above for therapeutics. Diagnostic assays for DPRP include methods that utilize the antibody and a label to detect DPRP in human body fluids or in extracts of cells or tissues. The antibodies may be used with or without modification, and they 35 may be labeled by covalent or non-covaleht joining with a reporter molecule. A wide

WO 02/31134 variety of reporter molecules are known in the art. Recombinant DPRP proteins that have been modified so as to be catalytically inactive can also be used as dominant negative inhibitors. Such modifications include, for example, mutation of the active site.

A variety of protocols for measuring DPRP, including ELISAs, RIAs and FACS, are known in the art and provide a basis for diagnosing altered or abnormal levels of DPRP expression. Normal or standard values for.DPRP expression are established by combining body fluids or cell extracts taken from normal mammalian subjects, preferably human, with antibody to DPRP under conditions suitable for complex formation. The method for detecting DPRP in a biological sample would comprise the steps of: a) providing a biological sample; b) combining the biological sample and an anti-DPRP antibody under conditions which are suitable for complex formation to occur between DPRP and the antibody; and c) detecting complex formation between DPRP and the antibody, thereby establishing the presence of DPRP in the biological sample. The amount of complex formation then may be quantified by various methods, preferably by photometric means. Quantities of DPRP expressed in subject, control, and disease samples from biopsied tissues are compared with the standard values. Deviation between standard and subject values establishes the parameters for diagnosing disease.

In another embodiment of the invention, the polynucleotides encoding DPRP are used for diagnostic purposes, which polynucleotides may include oligonucleotide sequences, complementary RNA and DNA molecules, and PNAs. These polynucleotides may be used to detect and quantitate gene expression in biopsied tissues in which expression of DPRP may be correlated with one of the Diseases. The diagnostic assay may be used to distinguish between absence, presence, and excess expression of DPRP and to monitor regulation of DPRP levels during therapeutic intervention. Moreover, phannacogenomic, single nucleotide polymorphisms (SNP) analysis of the DPRP genes can be used as a method to screen for mutations that indicate predisposition to disease or modified response to drugs.

DPRP polynucleotide and polypeptide sequences, fragments thereof, antibodies of DPRPs, and agonists, antagonists or inhibitors of DPRPs can be used to as discovery tools to identify molecular recognition events and therefore proteins, polypeptides and peptides that interact with DPRP proteins. A specific example is phage display peptide libraries where greater than 108 peptide sequences can be screened in a single round of panning. Such methods as well as others are known within the art and can be utilized to identify compounds that inhibit or enhance DPRP-1, DPRP-2 or DPRP-3 activity. Coupled links represent functional interactions such as complexes or pathways, and

WO 02/31134 PCT/US01/31874 proteins that interact with DPRPs can be identified by a yeast two-hybrid system, proteomics (differential 2D gel analysis and mass spectrometry) and genomics (differential gene expression by microarray or serial analysis of gene expression SAGE). Proteins identified as functionally linked to DPRPs and the process of interaction form 5 the basis of methods of screening for inhibitors, agonists and antagonists and modulators of these DPRP-protein interactions.

The term antagonist, as it is used herein, refers to an inhibitor molecule which, when bound to DPRP, decreases the amount or the duration of the effect of the biological or immunological activity of DPRP, e.g. decreasing the enzymatic activity of 10 the peptidase to cleave the N-terminal dipeptide. Antagonists may include proteins, nucleic acids, carbohydrates, antibodies, or any other molecules which decrease the effect of DPRP; for example, they may include small molecules and organic compounds that bind to and inactivate DPRPs by a competitive or non-competitive type mechanism. Specific examples of DPRP tetrapeptide peptidic enzyme activity inhibitors are described in Example 6 and 7. Inhibitors can be, for example, inhibitors of the DPRP protease activity, or alternatively inhibitors of the binding activity of the DPRP to . proteins with which they interact. Specific examples of such inhibitors can include, for example, anti-DPRP antibodies, peptides, protein fragments, or small peptidyl protease inhibitors, or small non-peptide, organic molecule inhibitors which are formulated in a 20 medium that allows introduction into the desired cell type. Alternatively, such inhibitors can be attached to targeting ligands for introduction by cell-mediated endocytosis and other receptor mediated events. Such methods are described further below and can be practiced by those skilled in the art given the DPRP nucleotide and amino acid sequences described herein.

A further use for DPRPs is for the screening of potential antagonists for use as therapeutic agents, for example, for inhibiting binding to DPRP, as well as for screening for agonists. DPRP, its immunogenic fragments, or oligopeptides thereof can be used for screening libraries of compounds which are prospective agonists or antagonists in any of a variety of drug screening techniques. The fragment employed in such screening 30 may be free in solution, affixed to a solid support, borne on a cell surface, or located intracellularly. The formation of binding complexes between DPRP and the agent being tested is then measured. Other assays to discover antagonists that will inhibit DPRP.are apparent from the disclosures ofU.S. Patents Nos. 6,011,155,6,107,317,6,110,949, 6,124,305 and 6,166,063, which describe inhibitors of DPPIV. Another worthwhile use

WO 02/31134 of these DPRPs is the screening of inhibitors of DPPIV to show that they will not have undesired side effects by also inhibiting one or more of the DPRPs.

A method provided for screening a library of small molecules to identify a molecule which binds DPRP generally comprises: a) providing a library of small molecules; b) combining the library of small molecules with the polypeptide of either SEQ ID NOS: 1,3 or 5, or with a fragment thereof, under conditions which are suitable for complex formation; and c) detecting complex formation, wherein the presence of such a complex identifies a.small molecule which binds DPRP.

One method for identifying an antagonist comprises delivering a small molecule which binds DPRP into extracts from cells transformed with a vector expressing DPRP along with a chromogenic substrate (e.g. Ala-Pro-AFC or Ala-Pro-AMC) under conditions where cleavage would normally occur, and then assaying for inhibition of cleavage by the enzyme by monitoring changes in fluorescence, or UV light absorption, by spectrophotometry to identify molecules that inhibit cleavage. A reduced rate of reaction or total amount of fluorescence or UV light absorption, in the presence of the molecule, establishes that the small molecule is an antagonist which reduces DPRP catalytic/enzymatic activity. Once such molecules are identified, they may be administered to reduce or inhibit cleaving by a DPRP.

The term agonist, as used herein, refers to a molecule which, when bound to DPRP, increases or prolongs the duration of the effect of DPRP. Agonists may include proteins, nucleic acids, carbohydrates, or any other molecules that bind to and modulate the effect of DPRP. Although it is less likely that small molecules will prove to be effective DPRP agonists, a method for identifying such a small molecule, which binds DPRP as an agonist, comprises delivering a chromogenic form of a small molecule that binds DPRP into cells transformed with a vector expressing DPRP and assaying for fluorescence or UV light absorption changes by spectrophotometry. An increased amount of UV absorption or fluorescence would establish that the small molecule is an agonist that increases DPRP activity.

Another technique for drug screening which may be used provides for high throughput screening of compounds having suitable binding affinity to the protein of interest as described in published PCT application WO84/03564. In this method, large numbers of different small test compounds are synthesized on a solid substrate, such as plastic pins or some other surface. The test compounds are reacted with DPRP, or with fragments thereof, and then washed. Bound DPRP is then detected by methods well known in the art. Purified DPRP can also be coated directly onto plates for use in the

WO 02/31134 aforementioned drug screening techniques. Alternatively, non-neutralizing antibodies can be used to capture the peptide and immobilize it on a solid support.

In another embodiment, one may use competitive drug screening assays in which neutralizing antibodies capable of binding DPRP specifically compete with a test ־ compound for binding DPRP. In this manner, antibodies can be used to detect the presence of any peptide that shares one or more antigenic determinants with DPRP.

As indicated above, by investigating the binding sites, ligands may be designed that, for example, have more interactions with DPRP than do its natural ligands. Such antagonist ligands will bind to DPRP with higher affinity and so function as competitive ligands. Alternatively, synthetic or recombinant proteins homologous or analogous to the ligand binding site of native DPRP may be designed, as may other molecules having high affinity for DPRP, Such molecules should also be capable of displacing DPRP and provide a protective effect.

As indicated above, the knowledge of the structures of DPRP enables synthetic binding site homologues and analogues to be designed, Such molecules will facilitate greatly the use of the binding properties to target potential therapeutic agents, and they may also be used to screen potential therapeutic agents. Furthermore, they may be used as immunogens in the production of monoclonal antibodies, which antibodies may themselves be used in diagnosis and/or therapy as described hereinbefore.

Given the ubiquitous expression of several members of the prolyl oligopeptidase S9B family, cell lines in which targeted gene disruption of DPPIV, DPRP-1, DPRP-2, DPRP-3, FAP and DPPVI to establish the null phenotype will be of great value to assist screening for selective and potent compounds. Accordingly, the invention provides such cell lines engineered with Lox-Neo IRES tk cassette and GFP-IRES-Neo Knock-in/out cassette DNA element for constructing somatic gene targeting vectors.

Example

Cloning and Expression of DPRP genes Using the Mammalian Expression System

DNA fragments encoding the full-length polypeptide DPRP-1 were amplified using PCR oligonucleotide primers corresponding to the 5' and 3' sequences of the gene, i.e, SEQ ID NO:45 and NO:46, In addition, DNA fragments encoding the full length polypeptide DPRP-2 were amplified using PCR oligonucleotide primers corresponding to the 5’ and 3' sequences of that gene, i.e. SEQ ID NO:50 and NO:51. Furthermore, DNA fragments encoding the full length polypeptide DPRP-3 were amplified using PCR oligonucleotide primers corresponding to the 5' and 3' sequences of that gene, i.e. SEQ IDNO155 andNO:56.

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The three amplified sequences were respectively isolated from a 0.7% agarose gel using commercially available kit (GFX PCR DNA and Gel Band Purification Kit, Amersham Pharmacia Biotech Inc., Piscataway NJ, USA). The fragments were then ligated into cloning vector, pGEM-7Zf(־) (Promega Corporation, Madison WI, USA) and sequenced. The corresponding cloning constructs were respectively designated pGEM7-DPRPl, pGEM7־DPRP2 and pGEM7-DPRP3. The DNA sequences encoding the truncated DPRP-1 or DPRP-2 or DPRP-3 were amplified using pGEM7-DPRPl or pGEM7-DPRP2 or pGEM7־DPRP3 as a template and BCR oligonucleotide primers. SEQ ID NO:45 and NO:47 were used for DPRP-1; SEQ ID NO:50 and NO:52 were used for DPRP-2; and SEQ ID NO:57 and NO:58 for DPRP-3. The amplified sequences were again isolated from a 0.7% agarose gel using the same purification kits and sub-cloned into pGEM-7Zf(-). The resulting constructs were designated pGEM7-DPRPlf, pGEM7DPRP2f and pGEM7־DPRP3f.

To make the DPRP-1 mammalian expression construct, pGEM7-DPRPl was digested with the restriction enzymes Kpnl and Notl to release the full length DPRP-1 gene. The DNA fragment carrying the DPRP-1 gene was gel band purified using the above kit and then inserted into expression vector pcDNA3 (Invitrogen, Carlsbad CA, USA) to make the native DPRP-1 expression construct, which was designated pcDNADPRP1. pGEM7-DPRP If was digested with the restriction enzymes Xbal and Hindlll to release the truncated DPRP-If gene. The DNA fragment carrying the DPRP-If gene was gel band purified using the above kit and then inserted into expression vector pcDNA3.1(-)/myc-His A (Invitrogen, Carlsbad CA, USA) to make the tagged DPRP-1 expression construct pcDNA-MycHis-DPRPl.

To make the DPRP-2 mammalian expression construct, pGEM7-DPRP2 was digested with the restriction enzymes Hindin and BamHI to release the full length DPRP-2 gene. The DNA fragment carrying the DPRP-2 gene was gel band purified using the above kit and then inserted into expression vector pcDNA3 (Invitrogen, Carlsbad CA, USA) to make the native DPRP-2 expression construct, which was designated pcDNA־DPRP2. pGEM7-DPRP2f was digested with the restriction enzymes EcoRI and BamHI to release the truncated DPRP-2f gene. The DNA fragment carrying the DPRP2־f gene was gel band purified using the above kit and then inserted into expression vector pcDNA3.1(-)/myc-His B (Invitrogen, Carlsbad CA, USA) to make the tagged DPRP-2 expression construct designated pcDNA-MycHis-DPRP2.

To make the DPRP-3 mammalian expression construct, pGEM7־DPRP3 was digested with the restriction enzymes EcoRI and Xhol to release the full length DPRP-3

WO 02/31134 PCT/US01/31874 gene. The DNA fragment carrying the DPRP-3 gene was gel band purified using the above kit and then inserted into expression vector pcDNA3 (Invitrogen, Carlsbad CA, USA) to make the native DPRP-3 expression construct designated pcDNA-DPRP3. pGEM7-DPRP3f was digested with the restriction enzymes Nhel and Apal to release the 5 truncated DPRP-3f gene. The DNA fragment carrying the DPRP-3f gene was gel band purified using the above kit and then inserted into expression vector pcDNA3.1(-)/mycHis B (Invitrogen, Carlsbad CA, USA) to make the tagged DPRP-3 expression construct pcDNA-MycHis-DPRP3.

Example

Expression Pattern of DPRP genes in human tissues

Quantitative PCR analysis was carried out to examine the levels of expression of the mRNAs for the polypeptides of the present invention in human tissues. RT PCR was also carried out on a number of human cell lines including but not limited to prostate cancer cells (LNCaP, PC3, DU145), the MLTC-1 line (mouse testis), and MDA-MB231 15 cells (breast cancer). Bands of the expected sizes for DPRP-1, DPRP-2 and DPPIV were all expressed in the various cancer cells lines, with FAP also being expressed at very low levels.

Northern Blot Analysis

Northern blot analysis was performed with 2gg poly(A)⁺ RNA isolated from 20 eight different tissues using DPRP probes. Specifically, a human Multiple Tissue Northern (MTN) blot (Clontech, Palo Alto, Calif.) was probed with a 1 kb N-tenninal fragment that had been radioactively labeled by randompriming in the presence of a ³²PdCTP (A. P. Feinberg et al״ Anal, Biochem., 132,6 (1983)). Hybridization was performed at 68°C overnight in ExpressHyb™ hybridization solution (Clontech, Palo 25 Alto, Calif.). The blots were first washed at room temperature in 2 times SSC and 0.05% SDS, and then washed at 60°C (DPRP-1 &amp; DPRP-2) and 50°C (DPRP-3) in 0.1 times SSC and 0.1% SDS.

Northern analysis showed expression of DPRP-1 in several tissues with the most abundant signal being in testis, prostate, muscle and brain. Testis showed 3 transcripts 30 approximately 7.5,4.5 and 2.5 kb in length. The shorter mRNA species was very abundant in testis but negligible in the other tissues tested. DPRP-2 was ubiquitously expressed in every tissue with highest levels in liver and muscle and a predominant transcript at 5kb. DPRP-3 expression was limited to brain and pancreas. Further analysis was conducted for the three proteases in specific brain regions (cerebellum, 35 cortex, medulla, spinal cord, occipital lobe, frontal lobe temporal lobe and putamen).

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DPRP-1 was expressed in all regions with low levels present in the spinal cord, while DPRP-2 was expressed in all brain regions tested.

Oligonucleotide primers SEQ ID NO:48 and NO:49 were used for DPRP-1 quantitative PCR, whereas oligonucleotide primers SEQ ID NO:53 and NO:54 were 5 used for DPRP-2 quantitative PCR. Human Multiple Tissue cDNA (MTC™) Panel I and Panel II (Clontech, Palo Alto CA, USA) were used as normalized cDNA templates. 0.5 ng of each cDNA were used in a-25 gl PCR reaction, with each primer at a final concentration of 300 nM. The PCR reaction was performed using a SYBR Green PCR Core Reagents Kit (Applied Biosystems, Foster City CA, USA) and detected with an 10 Applied Biosystems GeneAmp 5700 sequence detection system. Manufacturer's recommended thermal cycling parameter, e.g. 50°C for 2 min, 95°C for 10 min followed by 40 cycles of 95°C for 15 sec and 60°C for 1 min was used. Data obtained shows relatively high rates of expression for both DPRP-1 and DPRP-2 in the pancreas, ovary and testis, and a particularly high rate for DPRP-2 in the liver.

Example 3 - Production of DPRP Polyclonal Antibodies and Western Blotting

The amino acid sequence deduced from the cDNA encoding DPRP-1 was analyzed using DNASTAR software (DNASTAR, Inc.) to determine regions of high immunogenicity, and a corresponding oligopeptide was synthesized and used to raise anti-DPRP-1 antibodies. The procedure was repeated for DPRP-2 andDPRP-3. The 20 selection of appropriate peptide sequences and the techniques for antibody production are methods well known to those of skill in the art. Selection of appropriate epitopes, such as those near the C-terminus or in hydrophilic regions, is well known in this art.

Typically, oligopeptides that are about 15 to 20 residues in length, e.g. SEQ ID NO:59 for DPRP-1, SEQ ID NO:60 for DPRP-2 and SEQ ID NO:61 for DPRP-3, were 25 synthesized using an Applied Biosystems Peptide Synthesizer Model 431 A.

Fmoc-chemistry was used and the 19־ or 15-residue peptides were respectively coupled to keyhole limpet hemocyanin (KLH, Sigma, St Louis, Mo.) by reaction with N-maleimidobenzoyl־N-hydroxysuccinimide ester (MBS). Rabbits were immunized with the oligopeptide-KLH complex in complete Freund's adjuvant. The resulting 30 antisera were tested for antipeptide activity, e.g., by binding the peptide to plastic, blocking with 1% BSA, reacting with rabbit antisera, washing, and reacting with radioiodinated, goat anti-rabbit IgG.

Western blotting was performed using normal human protein samples (Protein Medley) obtained from Clontech (about 36 gg of total proteins). Proteins were 35 fractionated through 10% SDS-polyacrylamide gels, and transfened to 0.45 mm

־

WO 02/31134 nitrocellulose membranes. Membranes were blocked in Tris-buffered saline (TBS) with ' 0.05% Tween 20 and 1% BSA. Anti DPRP-1 or DPRP-2 specific antibodies were used as primary antibodies and were diluted 1:5,000 in Tris-buffered saline with 0.05% Tween 20 (TBST) and the Alkaline Phosphatase (AP) conjugated goat anti-Rabbit IgG (Promega) was diluted 1:5,000 in the same buffer before use. The positive reaction was visualized by incubating the membrane in Western Blue Stabilized Substrate (Promega) for AP until the bands of interest have reached the desired intensity. DPRP-1 and DPRP-2 proteins were detected in brain, muscles, kidney, prostate, testis and ovary tissues. DPRP-1 and DPRP-2 were synthesized as approximately lOlkDa and 100kDa forms, respectively, which are in good agreement with the molecular masses estimated ^Λ from their primary structure as shown in Table 3.

Table 3, Predicted Molecular Weight, Number of potential N-linked glycosylation sites (Asn residues) and predicted pl values of DPRP-1, DPRP-2 and DPRP-3, based on sequence analysis using the method developed by Hopp and Woods. Proc, Nat, Acad,

Sci, 78:3824-3828 (1981).

<td></td><td> M.W. (Da.)</td><td> No. of Asn</td><td> Pl</td>

<td> DPRP1</td><td> 101422</td><td> 26</td><td> 5.39</td>

<td> DPRP2</td><td> 98263</td><td> 27</td><td> 6.01</td>

<td> DPRP3</td><td> 90914</td><td> 33</td><td> 6.11</td>

Several additional bands of similar molecular weight were observed. These are 20 thought to be due to the presence of post-translational glycosylation of the proteins.

Table 3 also shows the number of potential N-glycosylation sites for the DPRP proteins.

The presence of glycosylated and unglcosylated forms of the proteins was evaluated using tunicamycin, an inhibitor of the oligosaccharide synthesis. It is evident that the smaller forms were unglycosylated forms. The correlation between mRNA (Northern analysis) and protein quantity (Western analysis) for DPRP-1 is shown in Table 4.

Table 4. Correlation of mRNA and protein expression of DPRP-1 in human tissues

<td></td><td> Heart</td><td> Brain</td><td> Placenta</td><td> Muscles</td><td> Kidney</td><td> Prostate</td><td> Testis</td><td> Ovary</td>

<td> Northern</td><td> ״H*</td><td> ' +++</td><td> +</td><td> +++</td><td> ++</td><td> +++</td><td> ++++</td><td> +׳</td>

<td> Western</td><td> -</td><td> ++++</td><td> -</td><td> +</td><td> ++</td><td> +</td><td> +++</td><td> j׳ I 1</td>

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Example

Immunohistochemical localization of DPRP proteins in human tissues Four-micron sections were prepared from a number of different formalin-fixed, paraffin-embedded human tissues. Tissue sections were deparaffined through 4 immersions in xylenes for 5 minutes, followed by a graded alcohol series to distilled water. Steam heat induced epitope recovery (SHIER) was used with several different SHIER solutions with and without enzyme digestion tissue in two different concentrations (Ladner et al, Cancer Res,: 60, p 34933503,2000־). The treatments and antibody dilutions employed are outlined below.

1. Blocking Reagent for 15 minutes (Normal Goat Serum)

2. Primary Antibody for 25,60 min or overnight incubation

3. Secondary Antibody for 25 minutes (Biotinylated Goat-anti-rabbit IgG)

4. Endogenous Peroxidase Blocking for 3 x 1.5 minutes

5. ABC (avidin-biotin complex) / Horse Radish Peroxidase for 25 minutes

6. DAB Chromogen for 3 x 5 minutes (Brown reaction product)

7. Light Hematoxylin Counter Stain 1 minute

Positive controls were run to assure the detection chemistries and antigen pretreatments were working appropriately. Rabbit IgG was run as a negative control. An avidin-biotin based tissue staining system was used for the detection of the DPRP-1 antibody. Horseradish peroxide was used as a reporter enzyme with DAB as chromogen. After staining, slides were dehydrated through an alcohol series to absolute ethanol followed by xylene rinses. Slides were permanently coverslipped with glass coverslips and permount. Digital images of representative staining, where positive staining was indicated by a dark brown chromogen (DAB-HRP reaction product), were captured using a video camera from Olympus. Hematoxylin counterstain provides a blue nuclear stain to assess cell and tissue morphology.

DPRP-1 rabbit polyclonal antibody labels formalin-fixed, paraffin-embedded human tissues, including normal testis, prostate glands, endometrial glands, tonsils and pancreas. It was also present in endothelial cells of normal ovary, bladder and kidney. Staining was localized in the cytoplasm in epithelial and some stromal cells such as fibroblasts, endothelial cells and lymphocytes. Interestingly in normal testis tested with DPRP-1 antibodies, there was distinctive expression in Leydig cells and multinucleated macrophages found in interstitial tissue, which is the space surrounding the seminiferous tubules. Tonsil B cells were stained with DPRP-1 antibody.

WO 02/31134

Example

Mammalian and Insect Cell Expression of DPRP Proteins and Purification Plasmid DNA of pcDNA-DPRP 1, pcDNA-MycHis-DPRP 1, pcDNA-DPRP-2 or pcDNA-MycHis-DPRP2 was transfected into PEAK (EdgeBioSystems, Gaithersburg 5 MD,USA) or COS-1 (ATCC CRL-1650) using LipofectAmine (Life Technologies, Gaithersburg MD, USA) method recommended by the manufacturer. Transfected cells were maintained in DMEM with 5% FBS at 37°C with 5% CO₂ for 48 hours. Cells were then collected and used for recombinant protein extraction. Cells were harvested 48 hours after transfection, homogenized and then spun at 18,000 x g for 40 min. The 10 supemata were collected as cytosolic fractions. This fraction was loaded on TALON spin column (Clontech), and His-tagged proteins were eluted with 50mM PBS, 150mM imidazole, pH 7. Recombinant proteins were then detected by western blotting with anti-myc antibody and visualized using a ProtoBlot IIAP system (Promega). Recombinant affinity purified fusions of the DPRP-1 and DPRP-2 were detected by 15 western blot, and DPRP-1 and DPRP-2 were synthesized as 112kDa and 109kDa forms as predicted.

Naturally occurring or recombinant DPRP proteins were substantially purified by immunoaffinity chromatography using antibodies specific for DPRP-1, DPRP-2 or DPRP-3. An immunoaffinity column was constructed by covalently coupling DPRP 20 antibodies to an activated chromatographic resin, such as CNBr-activated Sepharose (Pharmacia &amp; Upjohn). After the coupling, the resin was blocked and washed according to the manufacturer's instructions.

Media or cell extracts containing DPRP proteins were passed over the immunoaffinity column, and the column was washed under conditions that allow the 25 preferential absorbance of DPRPs (e.g., high ionic strength buffers in the presence of detergent). The column was eluted under conditions that disrupt antibody/DPRP binding (e.g., a buffer of pH 23־ or a high concentration of a chaotrope, such as urea or thiocyanate ion), and purified DPRP was collected.

Example

Enzymatic Activity of DPRP proteins and Methods of Screening for Inhibitors The kinetic properties of recombinant DPRP-1 and DPRP-2 were determined in a continuous fluorimetric assay. Buffer, pH and temperature dependence optimizationled to the following assay conditions: Enzyme assays were performed in 50mM PBS, pH7.4 50 pl (50 pg/ml) of purified enzymes were mixed with 1 pl of different concentration of 35 Ala-Pro-AMC (Enzyme Systems). Plates were then incubated at 37°C for 30 min, and

WO 02/31134 fluorescence was detected using a Wallac 1420 Fluorimeter with Xex40355 and Aem535. The K״, values of DPRP-1 and DPRP-2 were similar (208 and 161 μΜ respectively).

Further biochemical characterization reveals that DPRP-1 and DPRP-2 have similar profiles to DPPIV. The two purified proteases and DPPIV were preincubated with inhibitors at room temperature for 30 min. Substrate, Ala-Pro-AMC (100 μΜ), was then added, and the fluorescence intensity was recorded as 60 readings during a 60 min period. The irreversible serine protease inhibitor AEBSF was the only inhibitor tested that showed strong inhibition of all three enzymes (Table 5). This confirms the structural and domain analysis prediction that these proteins belong to the serine protease superfamily.

Table 5. Inhibition of DPRP-1 and DPRP-2 by Protease Inhibitors

<td rowspan="2"> Inhibitor</td><td rowspan="2"> Inhibitor Property</td><td rowspan="2"> Concentration</td><td colspan="3"> Residual activity (% of control)</td>

<td> DPRP-1</td><td> DPRP-2</td><td> DPPIV</td>

<td> AEBSF</td><td> serine, irreversible</td><td> 5mM</td><td> 29.6</td><td> 23.9</td><td> 21.1</td>

<td> Aprotinin</td><td> serine, reversible</td><td> 5pg/ml</td><td> 77.5</td><td> 63.2</td><td> 80.2</td>

<td> Pepstatin</td><td> aspartic, reversible</td><td> 2ug/ml</td><td> 97.3</td><td> 95.0</td><td> 93.5</td>

<td> DTT</td><td> cysteine</td><td> 2mM</td><td> 100.1</td><td> 94.8</td><td> 98.3</td>

<td> B-Mercaptoethonal</td><td> cysteine</td><td> lOOmM</td><td> 93.2</td><td> 84.0</td><td> 98.0</td>

<td> EDTA</td><td> metallo, reversible</td><td> 2mM</td><td> 91.5</td><td> 86.0</td><td> 93.5</td>

<td> Leupeptin</td><td> serine, reversible</td><td> 50pg/ml</td><td> 91.1</td><td> 90.4</td><td> 90.7</td>

In addition to Ala-Pro-AMC, additional substrates tested also confirmed that DPRP-1 and DPRP-2 are dipeptidyl peptidases. The data were derived by determining the fluorescence change following a 30-minute incubation of the substrates (125 μΜ) with enzymes as a percentage of the fluorescence measured at Ala-Pro-AMC and GlyPro-AMC were the only good substrates among those tested.

Table 6, DPRP-1 and DPRP-2 are dipeptidyl peptidases.

<td rowspan="2"> Substrate</td><td colspan="3"> % Change in Fluorescence at 30 minutes</td>

<td> DPRP-1</td><td> DPRP-2</td><td> DPPIV</td>

<td> Ala-Pro-AMC</td><td> 239.0</td><td> 127.5</td><td> 379.0</td>

<td> Gly-Pro-AMC</td><td> 341.5</td><td> 205.0</td><td> 444.0</td>

<td> Ala-Pro-pNA</td><td> 45.5</td><td> 44.0</td><td> 29.5</td>

<td> Pro-pNA</td><td></td><td>.5</td><td> 0.0</td>

<td> Gly-Arg-pNA</td><td>.5</td><td> 0.5־</td><td> 0.0</td>

<td> Lys-Ala-pNA</td><td> 2.5</td><td> 0.5</td><td> 0.5</td>

<td> Ala-Phe-Pro-pNA</td><td></td><td>.5</td><td> 2.0</td>

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Additional natural and non-natural amino acid di-, tri- and tetra-peptides were tested in order to find an optimal substrate for testing each of the DPRP proteins that will also show reduced activity when incubated DPPIV.

The enzyme assay method described here is one of a number of methods that can 5 be utilized to screen for peptide and non-peptide inhibitors of the DPRP enzymes.

Libraries of tetrapeptide inhibitors were tested to discover inhibitors of enzyme activity. Candidate inhibitors were prepared as 10-20 mM stock solutions in DMSO and stored at -20°C. Dilutions were made in assay buffer. Inhibition was determined by comparing the changes in fluorescence of the inhibited enzyme to the change in fluorescence of the 10 control (vehicle) enzyme. 100-(fl units of sample/fl units of control x 100) gives percent inhibition value. The percent inhibition and the inhibitor concentration at which the enzyme was 50% inhibited (IC₅₍₎) was ascertained by plotting percent inhibition vs. inhibitor concentration on the log scale. As shown in Figure 3, several tetrapeptides amides inhibited enzyme activity, wherein data are expressed as the % of activity in the presence of vehicle (0.02% DMSO) alone. Compounds were added at 1 mM. Most interesting was the apparent differential activity of some tetrapeptides for DPRP-1 and DPRP-2, compared to DPPIV. While all three enzymes were inhibited by Peptide-1, only DPRP-1 and DPRP-2 were significantly inhibited by Peptide-4 and Peptide-5. This demonstrates that selective inhibition of the purified enzymes is achievable.

The assay described in this example can also be used to screen additional synthetic or naturally occurring compound libraries, including macromolecules, for agents that either inhibit or enhance DPRP activity. The DPRP-1 and DPRP-2 polypeptides to be used in the assay can be obtained by, for example, in vitro translation, recombinant expression (see Example 5) or biochemical procedures. Methods other than those described here can also be used to screen and identify compounds that inhibit DPRP-1, DPRP-2 or DPRP-3, which methods can include, for example, binding assays such as ELISAs and RIAs.

Example

Effect of DPRP Inhibitors on the Proliferation of Human Cancer Cells In Vitro

In an attempt to assess the effect that several inhibitors of DPRP-1 and DPRP-2 activity may have on the proliferation of human cancer cells, LNCap, PC3 and Dul45, mouse testis line MLTC-1 and MDA-MB231 breast cancer cells were plated (10⁴ per well) in 96-well tissue culture plates and allowed to grow and attach for 24 hours at 37°C in a CO₂ incubator. Compounds at various dilutions (final dilutions: 0.1 nM -10 μΜ) were then added to the wells for various incubation periods from 24 hours to 96 hours,

WO 02/31134 with, fresh compound being replaced each day. Addition of the diluent DMSO alone served as the control. Following incubation with these compounds in triplicate, proliferation of the cells was determined using an XTT cell proliferation assay (Roche 1־ 465-015). The plates were read at 490 and 650nm 5 hours after the XTT mix was added.

An increase in cell proliferation was observed with three of the inhibitors at concentrations equal to 0.1,1,10 and 100 x IC_SO, and the results are shown in FIGS. 4A, 4B and .4C for PCS cells.

Overall, the DPRPs are expressed in a wide variety of tissues as has been demonstrated by mRNA amplification, western blotting and immunohistochemistry.

DPRP-1 was most abundant in the testis by Northern blot and western blot. The large number of expressed sequence tags (ESTs) from testis cDNA sources that are homologous to DPRP-1 also confirms abundant expression of DPRP-1 in testis. Example 4 describes the immunohistochemical localization of DPRP-1 protein in human testis using a specific DPRP-1 antibody. DPRP-1 is strongly expressed in epitheloid

Leydig cells, and Leydig cells are the primary source of testicular androgens (male steroid hormones) in the mammalian male. In the interstitium of the testis, Leydig cells and macrophages are in close association with “digitation” of Leydig cell process extending onto macrophage surface. Multinucleated cells in close proximity to the Leydig cells were also stained with DPRP-1 antibody suggesting that the protease was also expressed in macrophages, and macrophages in the testis play an important role in the paracrine regulation of Leydig cells. Cytokines secreted by the testicular macrophages are mitogenic to Leydig cells and play an important role in the differentiation of mesenchymal progenitor cell into mature Leydig cells. A clearer understanding of the proteins and pathways involved in the maturation of the testis is important for the discovery of new treatments for precocious puberty. In addition, Leydig cells cause tumors such as sex cord-stromal tumors via sexual steroid production (predominantly testosterone). Testosterone is associated with several neoplasia and diseases such as breast carcinoma and uterine cancers, ovarian carcinoma and androgenic alopecia (hair loss). Further examination of the localization of DPRP proteins in other glands in the body (e.g. adrenal glands) that produce testosterone and other androgenic hormones arc currently under investigation. The possible association of DPRP-1 with steroid and polypeptide hormone biosynthetic pathways functions is being investigated, and Example 7 is relevant to understanding the role of DPRP proteins in prostate, testis and breast in vitro cell models.

/2

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Immunohistochemical analysis also localized DPRP-1 to endometrial glands in the uterus (see Example 4), pancreatic acini, glomeruli of the kidney, plasma cells in the bladder, a subset of B־cells in the tonsils, columnar epithelial cells of the prostate and poorly differentiated prostate squamous metaplasia, Gleason grade 4 prostatic carcinoma, and hyperplastic glands in benign prostatic hyperplasia. Positive staining in breast carcinoma, as well as in seminoma and prostate squamous metaplasia, suggests a general association of DPRP-1 with hormone-sensitive tissues, particularly in cells that become poorly differentiated. The presence of the DPRP-1 in specialized epithelial cells and in inflammatory plasma cells (lymphocytes) is also of interest. Inflammatory breast carcinoma has an abundance of infiltrating lymphocytes and an overall bad prognosis. DPRP-1 and other DPRP proteins appear in medullary carcinomas that typically have a constant infiltrating lymphoplasmacytic component at the periphery of the tumor, which is thought to represent a reaction of the host tissues to the neoplasm. Most of the lymphocytes are T Cells, and most of the plasma cells are of the IgG-producing type. Several antigens are abundant on B cells, a subgroup of breast-cancer cells, and other epithelial cancer cells, and these antigens are targets for a new class of therapeutic monoclonal antibodies with some notable success having been achieved with a humanized monoclonal antibody against the B-cell—specific antigen CD20. Accordingly, monoclonal antibodies to DPRP proteins are felt to be useful to diagnose and treat diseases in which they are involved, including cancer.

The expression of DPRP-1 in specialized epithelial cells of a number of tissues suggests that DPRP-1 and other DPRP proteins may be involved in growth and differentiation thereof. Testing using inhibitors described in Example 6 in in vitro models of prostate and testis cancer (Example 7) showed that DPRP-l/DPRP-2 inhibitors caused a 50-60% increase in proliferation of PC3 cells at nM concentrations as shown in FIGS. 4A-4C.

Although the invention has been described in accordance with its preferred embodiments, which constitute the best mode presently known to the inventors, it should be understood that changes and modifications as would be obvious to those skilled in this art may be made without departing from its scope which is set forth in the claims appended hereto. For example, although the disclosure focuses on DPRP-1 and DPRP-2 in certain instances, DPRP-3 and its fragments are considered to be similarly useful, as are nucleic acids encoding same. Particular features of the invention are emphasized in the claims that follow.

***

Passages of the description, which are not within the scope of the claims, do not consist part of the claimed invention.

WO 02/31134 PCT/US01/31874

Sequence Listing Summary

SEQID.

1. DPRP1 a.a. sequence

2. DPRP1 DNA sequence

3. DPRP2 a.a. sequence

4. DPRP2 DNA sequence

5. DPRP-3 a.a. sequence

6. DPRP-3 DNA sequence

7. DPRP-1 transcript 0 a.a. sequence

8. DPRP-1 transcript 0 DNA sequence

9. DPRP-1 transcript 1 a.a. sequence

10. DPRP-1 transcript 1 DNA sequence

11. DPRP-1 transcript 2 a.a. sequence

12. DPRP-1 transcript 2 DNA sequence

13. DPRP-1 transcript 3 a.a. sequence

14. DPRP-1 transcript 3 DNA sequence

15. DPRP-1 transcript 4 a.a. sequence

16. DPRP-1 transcript 4 DNA sequence

17. DPRP-1 transcript 5 a.a. sequence

18. DPRP-1 transcript 5 DNA sequence

19. DPRP-1 transcript 6 a.a. sequence

20. DPRP-1 transcript 6 DNA sequence

21. DPRP-1 transcript 7 a.a. sequence

22. DPRP-1 transcript 7 DNA sequence

23. DPRP-2 transcript 0 a.a. sequence

24. DPRP-2 transcript 0 DNA sequence

25. DPRP-2 transcript 1 a.a. sequence

26. DPRP-2 transcript 1 DNA sequence

27. DPRP-2 transcript 2 a.a. sequence

28. DPRP-2 transcript 2 DNA sequence

29. DPRP-2 transcript 3 a.a. sequence

30. DPRP-2 transcript 3 DNA sequence

31. DPRP-2 transcript 4 a.a. sequence

32. DPRP-2 transcript 4 DNA sequence

33. DPRP-2 transcript 5 a.a. sequence

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34. DPRP-2 transcript 5 DNA sequence

35. DPRP-2 transcript 6 a.a. sequence

36. DPRP-2 transcript 6 DNA sequence

37. DPRP-2 transcript 7 a.a. sequence

38. DPRP-2 transcript 7 DNA sequence

39. DPRP-2 transcript 8 a.a. sequence

40. DPRP-2 transcript 8 DNA sequence

41. DPRP-3 transcript 0 a.a. sequence

42. DPRP-3 transcript 0 DNA. Sequence

43. DPRP-3 transcript 1 a. a. sequence

44. DPRP-3 transcript 1 DNA sequence

45. DPRP1 forward primer used for cloning

46. DPRP1 reverse primer used for cloning full length gene

47. DPRP1 reverse primer used for cloning fusion gene

48. DPRP1 forward primer used for expression profiling

49. DPRP1 reverse primer used for expression profiling

50. DPRP2 forward primer used for cloning

51. DPRP2 reverse primer used for cloning full length gene

52. DPRP2 reverse primer used for cloning fusion gene

53. DPRP2 forward primer used for expression profiling

54. DPRP2 reverse primer used for expression profiling

55. DPRP3 forward primer used for cloning

56. DPRP3 reverse primer used for cloning full length gene

57. DPRP3 forward primer used for cloning fusion gene

58. DPRP3 reverse primer used for cloning fusion gene

59. DPRP1 peptide antigen sequences

60. DPRP2 peptide antigen sequences

61. DPRP3 peptide antigen sequences

WO 02/31134

SEQUENCE LISTING <11O> Qi, Steve Akinsanya, Karen Riviere, Pierre Junien, Jean-Louis <120> NOVEL SERINE PROTEASE GENES RELATED TO DPPIV

<td> &lt;130&gt;</td><td> 70669</td>

<td> &lt;150&gt;</td><td> US 60/240,117</td>

<td> &lt;151&gt;</td><td> 2000-10-12</td>

<td> &lt;160&gt;</td><td> 61</td>

<td> &lt;170&gt;</td><td> Patent In version 3.1</td>

־210>

<211> 882 <212> PRT <213> Homo sapiens <400> 1

<td> Met Ala Ala Ala Met</td><td> Glu Thr Glu Gin</td><td> Leu</td><td> Gly Vai Glu lie Phe</td><td> Glu</td>

<td> 1 5</td><td></td><td> 10</td><td> 15</td><td></td>

<td> Thr Ala Asp Cys Glu 20</td><td> Glu Asn He Glu 25</td><td> Ser</td><td> Gin Asp Arg Pro Lys 30</td><td> Leu</td>

<td> Glu Pro Phe Tyr Vai 35</td><td> Glu Arg Tyr Ser 40</td><td> Trp</td><td> Ser Gin Leu Lys Lys 45</td><td> Leu</td>

<td> Leu Ala Asp Thr Arg ⁵⁰</td><td colspan="2"> Lys Tyr His Gly Tyr 55</td><td> Met Met Ala Lys Ala 60</td><td> Pro</td>

<td> His Asp Phe Met Phe 65</td><td> Vai Lys Arg Asn 70</td><td> Asp</td><td> Pro Asp Gly Pro His 75</td><td> Ser 80</td>

<td> Asp Arg He Tyr Tyr 85</td><td> Leu Ala Met Ser</td><td> Gly 90</td><td> Glu Asn Arg Glu Asn 95</td><td> Thr</td>

<td> Leu Phe Tyr Ser Glu 100</td><td> lie Pro Lys Thr 105</td><td> He</td><td> Asn Arg Ala Ala Vai 110</td><td> Leu</td>

<td> Met Leu Ser Trp Lys 115</td><td> Pro Leu Leu Asp 120</td><td> Leu</td><td> Phe Gin Ala Thr Leu 125</td><td> Asp</td>

<td> Tyr Gly Met Tyr Ser 130</td><td> Arg Glu Glu Glu 135</td><td> Leu</td><td> Leu Arg Glu Arg Lys 140</td><td> Arg</td>

<td> He Gly Thr Vai Gly 145</td><td colspan="3"> lie Ala Ser Tyr Asp Tyr His Gin Gly Ser 150 155</td><td> Gly 160</td>

<td> Thr Phe Leu Phe Gin 165</td><td> Ala Gly Ser Gly</td><td> lie 170</td><td> Tyr His Vai Lys Asp 175</td><td> Gly</td>

<td> Gly Pro Gin Gly Phe 180</td><td> Thr Gin Gin Pro 185</td><td> Leu</td><td> Arg Pro Asn Leu Vai 190</td><td> Glu</td>

<td> Thr Ser Cys Pro Asn 195</td><td> lie Arg Met Asp 200</td><td> Pro</td><td> Lys Leu Cys Pro Ala 205</td><td> Asp</td>

<td> Pro Asp Trp He Ala 210</td><td> Phe lie His Ser 215</td><td> Asn</td><td> Asp lie Trp lie Ser 220</td><td> Asn</td>

<td> He Vai Thr Arg Glu 225</td><td> Glu Arg Arg Leu 230</td><td> Thr</td><td> Tyr Vai His Asn Glu 235</td><td> Leu 240</td>

<td> Ala Asn Met Glu Glu 245</td><td> Asp Ala Arg Ser</td><td> Ala 250</td><td> Gly Vai Ala Thr Phe 255</td><td> Vai</td>

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Leu Gin Glu Glu Phe Asp Arg Tyr 260

Ala Glu Thr Thr Pro Ser Gly Gly 275280

Glu Asn Asp Glu Ser Glu Vai Glu 290295

Leu Glu Thr Arg Arg Ala Asp Ser 305310

Ala Asn Pro Lys Vai Thr Phe Lys 325

Glu Gly Arg lie lie Asp Vai lie 340

Glu lie Leu Phe Glu Gly Vai Glu 355360

Pro Glu Gly Lys Tyr Ala Trp Ser 370375

Arg Leu Gin He Vai Leu He Ser 385390

Asp Asp Vai Met Glu Arg Gin Arg 405 val Thr Pro Leu He He Tyr Glu 420

He His Asp lie Phe His Val Phe 435440

Glu Phe He Phe Ala Ser Glu Cys 450455

Lys He Thr Ser He Leu Lys Glu 465470

Gly Leu Pro Ala Pro Ser Asp Phe 485

Ala He Thr Ser Gly Glu Trp Glu 500 lie Gin Val Asp Glu Val Arg Arg 515520

Asp Ser Pro Leu Glu His His Leu 530535

Gly Glu Val Thr Arg Leu Thr Asp 545550 lie Ser Gin His Cys Asp Phe Phe 565

Asn Pro His Cys Val Ser Leu Tyr 580

Pro Thr Cys Lys Thr Lys Glu Phe 595600

Gly Pro Leu Pro Asp Tyr Thr Pro 610615

Thr Thr Gly Phe Thr Leu Tyr Gly 625630

Gin Pro Gly Lys Lys Tyr Pro Thr 645

Gin Val Gin Leu Val Asn Asn Arg 660

Leu Asn Thr Leu Ala Ser Leu Gly 675680

Arg Gly Ser Cys His Arg Gly Leu 690695

Lys Met Gly Gin He Glu He Asp 705710

Ser Gly Tyr Trp Trp Cys Pro Lys 265270

Lys He Leu Arg He Leu Tyr Glu 285

He He His Val Thr Ser Pro Met 300

Phe Arg Tyr Pro Lys Thr Gly Thr 315320

Met Ser Glii He Met He Asp Ala 330335

Asp Lys Glu Leu He Gin Pro Phe 345350

Tyr He Ala Arg Ala Gly Trp Thr 365 lie Leu Leu Asp Arg Ser Gin Thr 380

Pro Glu Leu Phe He Pro Val Glu 395400

Leu lie Glu Ser Val Pro Asp Ser 410415

Glu Thr Thr Asp He Trp lie Asn 425430

Pro Gin Ser His Glu Glu Glu lie 445

Lys Thr Gly Phe Arg His Leu Tyr 460

Ser Lys Tyr Lys Arg Ser Ser Gly 475480

Lys Cys Pro He Lys Glu Glu lie 490495

Val Leu Gly Arg His Gly Ser Asn 505510

Leu Val Tyr Phe Glu Gly Thr Lys 525

Tyr Val Val Ser Tyr Val Asn Pro 540

Arg Gly Tyr Ser His Ser Cys cys 555560 lie Ser Lys Tyr Ser Asn Gin Lys 570575

Lys Leu Ser Ser Pro Glu Asp Asp 585590

Trp Ala Thr lie Leu Asp ser Ala 605

Pro Glu He Phe Ser Phe Glu Ser 620

Met Leu Tyr Lys Pro His Asp Leu 635640

Val Leu Phe He Tyr Gly Gly Pro 650655

Phe Lys Gly Val Lys Tyr Phe Arg 665670

Tyr Val Val Val Val He Asp Asn 685

Lys Phe Glu Gly Ala Phe Lys Tyr 700

Asp Gin Val Glu Gly Leu Gin Tyr 715 720

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Leu Ala Ser Arg Tyr Asp Phe lie Asp Leu Asp Arg Vai Gly He His 725 730735

Gly Trp Ser Tyr Gly Gly Tyr Leu Ser Leu Met Ala Leu Met Gin Arg 740 745750

Ser Asp He Phe Arg Vai Ala He Ala Gly Ala Pro Vai Thr Leu Trp 755 760765

He Phe Tyr Asp Thr Gly Tyr Thr Glu Arg Tyr Met Gly His Pro Asp 770 775780

Gin Asn Glu Gin Gly Tyr Tyr Leu Gly Ser Vai Ala Met Gin AlaGlu .

785 790 795800

Lys Phe Pro Ser Glu Pro Asn Arg Leu Leu Leu Leu His Gly PheLeu

805 810815

Asp Glu Asn Vai His Phe Ala His Thr Ser He Leu Leu Ser Phe Leu 820 825830

Vai Arg Ala Gly Lys Pro Tyr Asp Leu Gin lie Tyr Pro Gin Glu Arg 835 840845

His Ser lie Arg Vai Pro Glu Ser Gly Glu His Tyr Glu Leu His Leu 850 855 ^;860

Leu His Tyr Leu Gin Glu Asn Leu Gly Ser Arg lie Ala Ala Leu Lys 865 870 875880

Vai lie <210? 2 <211> 2671 <212? DNA <213? Homo sapiens <400? 2 cggtaccatg gcagcagcaa tggaaacaga acagctgggt gttgagatat ttgaaactgc60 ggactgtgag gagaatattg aatcacagga tcggcctaaa ttggagcctt tttatgttga120 gcggtattcc tggagtcagc ttaaaaagct gcttgccgat accagaaaat atcatggcta180 catgatggct aaggcaccac atgatttcat gtttgtgaag aggaatgatc cagatggacc240 tcattcagac agaatctatt accttgccat gtctggtgag aacagagaaa atacactgtt300 ttattctgaa attcccaaaa ctatcaatag agcagcagtc ttaatgctct cttggaagcc360 tcttttggat ctttttcagg caacactgga ctatggaatg tattctcgag aagaagaact420 attaagagaa agaaaacgca ttggaacagt cggaattgct tcttacgatt atcaccaagg480 aagtggaaca tttctgtttc aagccggtag tggaatttat cacgtaaaag atggagggcc540 acaaggattt acgcaacaac ctttaaggcc caatctagtg gaaactagtt gtcccaacat600 acggatggat ccaaaattat gccctgctga tccagactgg attgctttta tacatagcaa660 cgatatttgg atatctaaca tcgtaaccag agaagaaagg agactcactt atgtgcaoaa720 tgagctagcc aacatggaag aagatgccag atcagctgga gtcgctacct ttgttctcca780 agaagaattt gatagatatt ctggctattg gtggtgtcca aaagctgaaa caactcccag840 tggtggtaaa attcttagaa ttctatatga agaaaatgat gaatctgagg tggaaattat900 tcatgttaca tcccctatgt tggaaacaag gagggcagat tcattccgtt atcctaaaac960 aggtacagca aatcctaaag tcacttttaa gatgtcagaa ataatgattg atgctgaagg1020 aaggatcata gatgtcatag ataaggaact aattcaacct tttgagattc tatttgaagg1080 agttgaatat attgccagag ctggatggac tcctgaggga aaatatgctt ggtccatcct1140 actagatcgc tcccagactc gcctgcagat agtgttgatc tcacctgaat tatttatocc1200 agtagaagat gatgttatgg aaaggcagag actcattgag tcagtgcctg attctgtgac1260 gccactaatt atctatgaag aaacaacaga catctggata aatatccatg acatctttca1320 tgtttttccc caaagtcacg aagaggaaat tgagtttatt tttgcctctg aatgcaaaac1380 aggtttccgt catttataca aaattacatc tattttaaag gaaagcaaat ataaacgatc1440 cagtggtggg ctgcctgctc caagtgattt caagtgtcct atcaaagagg agatagcaat1500 taccagtggt gaatgggaag ttcttggccg gcatggatct aatatccaag ttgatgaagt1560 cagaaggctg gtatattttg aaggcaccaa agactcccct ttagagcatc acctgtacgt1620 agtcagttac gtaaatcctg gagaggtgac aaggctgact gaccgtggct actcacattc16B0 ttgctgcatc agtcagcact gtgacttctt tataagtaag tatagtaacc agaagaatcc1740 acactgtgtg tccctttaca agctatcaag tcctgaagat gacccaactt gcaaaacaaa1800 ggaattttgg gccaccattt tggattcagc aggtcctctt cctgactata ctcctccaga1860 aattttctct tttgaaagta ctactggatt tacattgtat gggatgctct acaagcctca1920

WO 02/31134 PCT/US01/31874 tgatctacag cctggaaaga aatatcctac tgtgctgttc atatatggtg gtcctcaggt1980 gcagttggtg aataatcgat ttaaaggagt caagtatttc cgcttgaata ccctagcctc2040 tctaggttat gtggttgtag tgatagacaa caggggatcc tgtcaccgag ggcttaaatt210.0 tgaaggcgcc tttaaatata aaatgggtca aatagaaatt gacgatcagg tggaaggact2160 ccaatatcta gcttctcgat atgatttcat tgacttagat cgtgtgggca tccacggctg2220 gtcctatgga ggatacctct ccctgatggc attaatgcag aggtcagata tcttcagggt2280 tgctattgct ggggccccag tcactctgtg gatcttctat gatacaggat acacggaacg2340 ttatatgggt caccctgacc agaatgaaca gggctattac ttaggatctg tggccatgca2400 agcagaaaag ttcccctctg aaccaaatcg tttactgctc ttacatggtt tcctggatga2460 gaatgtccat tttgcacata ccagtatatt actgagtttt ttagtgaggg ctggaaagcc2520 atatgattta cagatctatc ctcaggagag acacagcata agagttcctg aatcgggaga2580 acattatgaa ctgcatcttt tgcactacct tcaagaaaac cttggatcac gtattgctgc2640 tctaaaagtg atatgagcgg ccgcgagctc c2671 <210> 3 <211> 863.

<212> PRT <213> Homo sapiens <400> 3

Met Ala Thr Thr Gly Thr Pro Thr Ala Asp Arg Gly Asp Ala Ala Ala

5 1015

Thr Asp Asp Pro Ala Ala Arg Phe Gin Vai Gin Lys His Ser TrpAsp

2530

Gly Leu Arg Ser He He His Gly Ser Arg Lys Tyr Ser Gly Leu He 35 4045

Vai Asn Lys Ala Pro His Asp Phe Gin Phe Vai Gin Lys Thr Asp Glu 50 5560

Ser Gly Pro His Ser His Arg Leu Tyr Tyr Leu Gly Met Pro TyrGly

70 7580

Ser Arg Glu Asn Ser Leu Leu Tyr Ser Glu He Pro Lys Lys VaiArg

9095

Lys Glu Ala Leu Leu Leu Leu Ser Trp Lys Gin Met Leu Asp His Phe 100 105no

G1D Ala Thr pro His His Gly Vai Tyr Ser Arg Glu Glu Glu Leu Leu 115 120125

Arg Glu Arg Lys Arg Leu Gly Vai Phe Gly He Thr Ser Tyr Asp Phe 130 135140

His Ser Glu Ser Gly Leu Phe Leu Phe Gin Ala Ser Asn Ser LeuPhe

145 150 155160

His Cys Arg Asp Gly Gly Lys Asn Gly Phe Met val Ser Pro MetLys

165 170175 pro Leu Glu He Lys Thr Gin Cys Ser Gly Pro Arg Met Asp Pro Lys 180 185190 lie cys Pro Ala Asp Pro Ala Phe Phe Ser Phe lie Asn Asn ser Asp 195 200205

Leu Trp Val Ala Asn He Glu Thr Gly Glu Glu Arg Arg Leu Thr Phe 210 215220

Cys His Gin Gly Leu Ser Asa Val Leu Asp Asp Pro Lys Ser Ala Gly

225 230 235240

Val Ala Thr Phe Val He Gin Glu Glu Phe Asp Arg Phe Thr Gly Tyr

245 250255

Trp Trp cys Pro Thr Ala Ser Trp Glu Gly Ser Glu Gly Leu Lys Thr 260 265270

Leu Arg He Leu Tyr Glu Glu Val Asp Glu Ser Glu Val Glu Val He 275 280285

His Val Pro Ser Pro Ala Leu Glu Glu Arg Lys Thr Asp Ser Tyr Arg 290 295300

Tyr Pro Arg Thr Gly Ser Lys Asa Pro Lys He Ala Leu Lys Leu Ala 305 310 315320

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Lys He Vai Ser Thr Gin Glu Lys 330 335

Leu Phe Pro Lys Vai Glu Tyr He 345 350

Gly Lys Tyr Ala Trp Ala Met Phe

׳ 365

Gin Leu Vai Leu Leu Pro Pro Ala 380

Glu Glu Gin Arg Leu Ala Ser Ala 395400 pro Tyr val Vai Tyr Glu Glu Vai 410415

Asp He Phe Tyr pro Phe Pro Gin 425430

Phe Leu Arg Ala Asn Glu Cys Lys 445

Val Thr Ala Val Leu Lys Ser Gin 460

Ser Pro Gly Glu Asp Glu Phe Lys 475480

Leu Thr Ser Gly Glu Trp Glu Val 490495

Trp Val Asn Glu Glu Thr Lys Leu 505510

Thr Pro Leu Glu His His Leu Tyr 525

Glu lie Val Arg Leu Thr Thr Pro 540

Ser Gin Asn Phe Asp Met Phe Val 555560 pro Pro cys Val His val Tyr Lys 570.575

Leu His Lys Gin Pro Arg Phe Trp 585590

Cys Pro Pro Asp Tyr Val Pro Pro 605

Ser Asp Val Arg Leu Tyr Gly Met 620

Pro Gly Lys Lys His Pro Thr val 635640

Val Gin Leu Val Asn Asn Ser Phe 650655

Asn Thr Leu Ala Ser Leu Gly Tyr 665670

Gly Ser Cys Gin Arg Gly Leu Arg 685

Met Gly Gin Val Glu He Glu Asp 700

Ala Glu Lys Tyr Gly Phe He Asp 715720

Trp Ser Tyr Gly Gly Phe Leu Ser 730735

Gin Val Phe Lys Val Ala He Ala 745750

Ala Tyr Asp Thr Gly Tyr Thr Glu 765

Glu Phe Gin Thr Asp Ser Gin Gly 325

Glu Leu Vai Gin Pro Phe Ser Ser 340

Ala Arg Ala Gly Trp Thr Arg Asp 355360

Leu Asp Arg Pro Gin Gin Trp Leu 370375

Leu Phe He Pro Ser Thr Glu Asn 385390

Arg Ala Vai Pro Arg Asn Vai Gin 405

Thr Asn Vai Trp He Asn Vai His 420

Ser Glu Gly Glu Asp Glu Leu Cys

435440

Thr Gly Phe Cys His Leu Tyr Lys 450455

Gly Tyr Asp Trp Ser Glu Pro Phe 465470

Cys Pro lie Lys Glu Glu lie Ala 485

Leu Ala Arg His Gly Ser Lys He 500

Vai Tyr Phe Gin Gly Thr Lys Asp 515520

Vai Vai Ser Tyr Glu Ala Ala Gly 530535

Gly Phe Ser His Ser Cys Ser Met 545550

Ser His Tyr Ser Ser Vai Ser Thr 565

Leu Ser Gly Pro Asp Asp Asp Pro 580

Ala Ser Met Met Glu Ala Ala Ser 595600

Glu He Phe His Phe His Thr Arg 610615 lie Tyr Lys Pro His Ala Leu Gin 625630

Leu Phe Vai Tyr Gly Gly Pro Gin 645

Lys Gly lie Lys Tyr Leu Arg Leu 660

Ala Vai Vai Vai He Asp Gly Arg 675680

Phe Glu Gly Ala Leu Lys Asn Gin 690695

Gin Vai Glu Gly Leu Gin Phe Vai 705 ⁷¹⁰

Leu Ser Arg Vai Ala lie His Gly 725

Leu Met Gly Leu lie His Lys Pro 740

Gly Ala Pro Vai Thr Vai Trp Met 755 760

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Arg Tyr Met Asp Vai Pro Glu Asn Asn Gin His Gly Tyr Glu Ala Gly 770 775780

Ser Vai Ala Leu His Vai Glu Lys Leu Pro Asn Glu Pro Asn ArgLeu

785 790 795800

Leu lie Leu His Gly Phe Leu Asp Glu Asn Vai His Phe Phe HisThr

805 810815

Asn Phe Leu Vai Ser Gin Leu He Arg Ala Gly Lys Pro Tyr Gin Leu 820 525830

Gin He Tyr Pro Asn Glu Arg His Ser He Arg Cys Pro Glu Ser Gly 835 840845

Glu His Tyr Glu Vai Thr Leu Leu His Phe Leu Gin Glu Tyr Leu 850 855860 <210> 4 <211> 2617 <212> DNA <213> Homo sapiens <400> 4 caagcttacc atggccacca ccgggacccc aacggccgac cgaggcgacg cagccgccac agatgacccg gccgcccgct tccaggtgca gaagcactcg tgggacgggc tccggagcat catccacggc agccgcaagt actcgggcct cattgtcaac aaggcgcccc acgacttcca gtttgtgcag aagacggatg agtctgggcc ccactcccac cgcctctact acctgggaat gccatatggc agccgagaga actccctcct ctactctgag attcccaaga aggtccggaa agaggctctg ctgctcctgt cctggaagca gatgctggat catttccagg ccacgcccca ccatggggtc tactctcggg aggaggagct gctgagggag cggaaacgcc tgggggtctt cggcatcacc tcctacgaot tccacagcga gagtggcctc ttcctcttcc aggccagcaa cagcctcttc cactgtcgcg acggcggcaa gaacggcttc atggtgtccc ctatgaaacc gctggaaatc aagacccagt gotcagggcc ccggatggac occaaaatct gccctgccga ccctgccttc ttctccttca tcaataacag cgacctgtgg gtggccaaca tcgagaoagg cgaggagcgg cggctgacct tctgccacca aggtttatco aatgtcctgg atgaccccaa gtctgcgggt gtggcoacct tcgtcataca ggaagagttc gaccgcttca ctgggtactg gtggtgcccc acagcctcct gggaaggttc agagggcctc aagacgctgc gaatcctgta tgaggaagtc gatgagtccg aggtggaggt cattcacgtc ccctctcctg cgctagaaga aaggaagacg gactcgtatc ggtaccccag gacaggcagc aagaatccca agattgcctt gaaactggct gagttccaga ctgacagcca gggcaagatc gtctcgaccc aggagaagga gctggtgcag cccttcagct cgctgttccc gaaggtggag tacatcgcca gggccgggtg gacccgggat ggcaaatacg cctgggccat gttcctggac cggccccagc agtggctcca gctcgtcctc ctccccccgg ccctgttcat cccgagcaca gagaatgagg agcagcggct agcctctgcc agagctgtcc ccaggaatgt ccagccgtat gtggtgtacg aggaggtcac caacgtctgg atcaatgttc atgacatctt otatocottc ccccaatcag agggagagga cgagctctgc tttctccgcg ccaatgaatg caagaccggc ttctgccatt tgtacaaagt caccgccgtt ttaaaatccc agggctacga ttggagtgag cccttcagco ccggggaaga tgaatttaag tgccccatta aggaagagat tgctctgacc agcggtgaat gggaggtttt ggegaggcao ggctccaaga tctgggtcaa tgaggagacc aagctggtgt acttcoaggg caccaaggac acgccgctgg agcaccacct ctacgtggtc agctatgagg cggccggcga gatcgtacgc ctcaccacgc ccggcttctc ccatagctgc tccatgagcc agaacttcga catgttcgtc agccactaca gcagcgtgag cacgccgocc tgcgtgcacg tctacaagct gagcggcccc gacgacgacc ccctgcacaa gcagccccgc ttctgggcta gcatgatgga ggcagccagc tgccccccgg attatgttcc tccagagatc ttccatttcc acacgcgctc ggatgtgcgg ctctacggca tgatctacaa gccccacgcc ttgcagccag ggaagaagca ccccaccgtc ctctttgtat atggaggccc ccaggtgcag ctggtgaata actccttcaa aggcatcaag tacttgcggc tcaacacact ggcctccctg ggctacgccg tggttgtgat tgacggcagg ggctcctgtc agcgagggct tcggttcgaa ggggccctga aaaaccaaat gggccaggtg gagatcgagg accaggtgga gggcctgcag ttcgtggccg agaagtatgg cttcatcgac ctgagccgag ttgccatcca tggctggtcc tacgggggct tcctctcgct catggggcta atccacaagc cccaggtgtt caaggtggcc atcgcgggtg ccccggtcac cgtctggatg gcctacgaca cagggtacac tgagcgatac atggacgtcc ctgagaacaa ccagcacggc tatgaggcgg gttccgtggc cctgcacgtg gagaagctgc ccaatgagcc caaccgcttg cttatcctcc acggcttcot ggacgaaaac gtgcactttt tccacacaaa

120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 13B0 1440 1500 1560 1620 1680 1740 1800 1860 1920 1980 2040 •2100 2160 2220 2280 2340 2400 2460

WO 02/31134 cttcctcgtc tcccaactga cgagagacac agtattcgct ctttctacag gaatacctct tccgagcagg gaaaccttac gccccgagtc gggcgagcac gagcggccgc ggatccg cagctccaga tctaccccaa tatgaagtca cgttgctgca

2520

2580

2617 <210> 5 <211> 796 <212> PRT <213 > Homo sapiens <400:. 5

His His lie Lys Cys Gin Pro Ser

15

Asn Ser Pro Pro Gin Arg Asn Trp 25 ³O

Val He Leu val Val Cys Ser Leu

Ser Pro Asp Glu Leu Thr Asn Ser 60

Asp Leu Phe Arg Lys Asp Phe Val 758° lie Asn Asp Thr Asp Val Val Tyr 90

Lys Leu Asn lie Glu Thr Asn Ala 105Η®

Thr Phe Val Thr Phe Lys Ala Ser 125

Lys Tyr Val Leu Leu Ala Tyr Asp 140

Tyr Thr Ala Ser Tyr Val He Tyr 155ISO

Glu Leu Asn Pro Pro Glu Val Glu 170175

Trp Gly Val Gin Gly Gin Gin Leu 185

Tyr Tyr Gin Pro Asp Xie Lys Ser 205

Gly Lys Glu Glu He He Phe Asn 220

Glu Glu Leu Leu His Ser His lie

235240

Glu Arg Leu Ala Phe Leu Met He 250

Val He Pro Arg Phe Thr Gly Ala 265270

Pro Tyr Pro Lys Ala Gly Gin Val

Val Asn Leu Tyr Gly Pro Thr His 300

Ser Phe Lys Ser Arg Glu Tyr Tyr 315

Asn Thr Lys Thr val val Arg Trp 330

He Leu Thr val Cys Glu Thr Thr 345

Glu Met Thr Ser Asp Thr Trp Leu 365

Phe Ser Arg Asp Gly Ser Lys Phe 380

Gly Gly Arg Gly Glu Phe His His 395 400

Met Aan Gin Thr Ala Ser Vai Ser 1 ⁵

Lys Thr lie Lys Glu Leu Gly Ser 20

Lys Gly He Ala He Ala Leu Leu 3540

He Thr Met Ser Vai lie Leu Leu 50 ⁵⁵

Ser Glu Thr Arg Leu Ser Leu Glu 6570

Leu His Asp Pro Glu Ala Arg Trp 85

Lys Ser Glu Asn Gly His Vai He 100

Thr Thr Leu Leu Leu Glu Asn Thr

115120

Arg His Ser Vai Ser Pro Asp Leu 130

Vai Lys Gin He Phe His Tyr Ser 14515®

Asn lie His Thr Arg Glu Vai Trp 165

Asp Ser Val Leu Gin Tyr Ala Ala 180

He Tyr lie Phe Glu Asn Asn He

Ser Ser Leu Arg Leu Thr Ser Ser 210215

Gly lie Ala Asp Trp Leu Tyr Glu 225230

Ala His Trp Trp Ser Pro Asp Gly 245

Asn Asp ser Leu val Pro Thr Met 260

Leu Tyr Pro Lys Gly Lys Gin Tyr

275280

Asn Pro Thr He Lys Leu Tyr Val

290295

Thr Leu Glu Leu Met Pro Pro Asp 305 lie Thr Met val Lys Trp Val Ser 325

Leu Asn Arg Pro Gin Asn lie Ser 340

Thr Gly Ala Cys Ser Lys Lys Tyr 355 ³⁶⁰

Ser Gin Gin Asn Glu Glu Pro val 370

Phe Met Thr Val Pro Val Lys Gin 385

WO 02/31134

He

Ala

Met

Phe

His

Leu

Thr

Glu

Thr

Gly Arg 450 He

Thr 435 Gin

Ser 420 Gin

Leu

Cys 465 Ser

Ser

Cys

Phe

Ser

Arg

Vai

Phe

He

Lys

Leu 545 Tyr

Thr

Asn

Leu

Leu 405 Gly

Pro lie

Asn

Gin

Trp

Ser Lys

Glu

Lys

He

Tyr

Tyr

Asn

Ser val 500 Leu Glu 515 Gly Lys

Pro

Met 485 Val

Phe 470 Asn

Ala 455 Met

Gin

Ser

Ser Asn

He 530 Pro Leu Gin

Ala Leu

Asp Lys

Leu pro Glu

Leu

Lys 625 Asp

Val He 595 Lys He 610 Asp Gin

Phe 580 Val

Leu 565 His

Ala

Leu Gin

He Thr

Ala

Vai

Glu

Ala 705 He

Ser 550 lie

Phe 440 Ser

Lys

His

Vai 425 Leu

Thr

Glu

Leu His

He

Arg Leu 645 Ser Met lie Leu 660

Val Ala Pro lie 675

Arg Tyr Leu Gly 690

Ser Val Leu His

Ser Lys

He His Gly

Glu

Vai

Leu

He 785

Leu He Lys 740 Tyr pro Asp 755

Tyr Ser Thr 770

Ser Val Leu <210> <211> <212> <213> <400>

Ser 410 He

Ser

Glu

Gin

Glu

Lys

Leu 490 Ser Thr 505 Leu Lys

Phe

Thr

Gly

Gin

Cys 475 Leu

Asp

He

Thr

Vai 415

Arg lie

Leu

Glu

Leu 460 Thr

Ser 445 Leu

Ala 430 Ser

Asn

Tyr Phe

Pro

Glu

Asp

Arg

Arg Gin

Phe

Cys Glu

Asp Ala 480 Pro

Gly 495 Lys

Asn Pro Ala

Ala He Leu Lys

He Asp Asp Tyr

Tyr

Ser Met 520 lie Lys He Leu His 535 Leu Pro Lys Asp Phe Met Asp Arg Asn 555 Met Asp Glu Glu Pro Gly Gly 570

Asp Trp Asp Ser Val Leu 585

Arg Phe Asp Gly Arg Gly Ser 600

Glu lie His Arg 615

Ala Val Lys 630 Ser He

Lys Ser

Thr Asp

Met

He

Lys

Glu

Gin 560 Val

Phe

Asp

Thr 725 His

Glu lie

Asn 710 Ala

Pro 695 Val

Leu 680 Ser

His

Pro

Asp

Gin Leu

Asp Met Asp

Phe Gin Gly

Gly 605 Ser

Vai Glu Val

Arg Leu Gly 620 Lys

Leu Leu 635 Gly Lys Gly 650 Lys Leu

Phe

Glu 665 Lys

Lys

Gly

Thr Lys

Leu

Leu Tyr

Glu Glu

Leu

Lys Ala 745 Gly His Asn Val 760

Leu Lys Phe Phe 775

Gin Glu Pro Glu 790

Leu lie val 730 Gly

Lys 715 His

Ser

Ser

Glu

Tyr

Gly

Phe

Lys

Pro Tyr He 640 Gly Tyr He 655 Gly Ser

Vai

Ala

Glu

Asp

Ser 700 Glu

Asp 795

Phe

Asn

Lys

Ser 685 Thr

Cys 670 Ala

Tyr

Phe Ser

Gin Ala

Glu

Cys 780 Glu

Asn

Gin His

Tyr Thr

Ser Lys 765 Leu Lys lie Leu 720 Ser Ala 735 Met Gin

Tyr His

Glu Glu

2583 DNA Homo sapiens 6 gcctgggatt tcacatcaag gagaaactgg gtgcactgtc tgtcaaccct aagggaattg cagggtcctg caaaaaoaat ctattgctct aaacatgaac caaggaactg gctggtgatt caaactgcca ggaagtaaca ttagttgtat gcgtgtccca gccctccaca gctcactcat

PCT7US01/31874

WO 02/31134 tgaactcaca aattcgtcag aaaccagatt tgtgcttcac gatccagagg ctcggtggat gaatggacat gtcattaaac tgaatataga cacaactttt gtaaccttca aagcatcaag ccttctggca tatgatgtca aacagatttt ttacaacata cacactaggg aagtttggga cttgcagtac gcggcotggg gtgtccaagg tatctactat caacctgata taaagagcag agaaataatt tttaatggga ttgctgactg catcgcccac tggtggtcac cagatggaga tttggtaccc accatggtta tccctcggtt gtatccgtat cctaaggcag gtcaagtgaa gtatggacca actcacactt tggagctcat ctatatcact atggttaaat gggtaagcaa acctcagaac atctccatcc tcacagtctg atatgagatg acatcagata cgtggctctc agacggcagc aaattcttta tgacagtgcc ccacatagct atgttcctca tccagagtaa atcaggaaac tgggaagtga taaagatctt ctttctgagc actgaatctt ctcccagagg attattgaat cgccaatgca tttcatgtaa tgccagtttt agtcccatga atcaacattt agtggtcagc ctacatagta cggacaaccc tatgctgaag gaagctatcc tgaagaagaa tattgacgac tatgaacttc ctttacagtt ccagtatgct cttctgttaa taatggatga gttccatatt gactgggatt ccgtactcat tgatggcaga ggaagtggat tccagggtct aggttcagta gaagtaaagg accaaataac cattgactcc aaaagattaa gcatttttgg gatcttaaaa tcagatgaaa agctttttaa cttgaaattg tatgcctcag ctttctctga aagcacttac caggcagcca gtgtgctaca attaataatt catggaaotg ctgacacaaa caagcaccta ataaaagctg gagtgaatta taacgtatct gagaagagca agtatcatct ttgtttgaag gaagaaatat ctgtgctacc cgtatttata cagaactgaa gggaatattg aatattgtag ttgctccaga atgtcaaggg gctcagagac agtgaactag catttgaata cactatgtca gtcatcctct taagcccaga gtctttggaa gacctcttta ggaaagactt caatgataca gatgtggtgt ataaaagcga aacaaatgct accacattat tattggaaaa acattcagtt tcaccagatt taaaatatgt tcattattcg tatactgctt catatgtgat gttaaatcct ccagaagtag aggactccgt gcagcagctg atttatattt ttgaaaataa ttcattgcga ctgacatctt ctggaaaaga gttatatgaa gaggaactcc tgcattctca aagacttgoc ttcctgatga taaatgactc tactggagcg ttgtatccca aaggaaagca cccaacaata aaattatatg ttgtaaacct gccacctgac agctttaaat caagagaata taccaagact gtggtaagat ggttaaaccg tgagaccact acaggtgctt gtagtaaaaa tcagcagaat gaggagcccg tgttttctag tgttaagcaa gggggacgtg gagaatttca aagtgagcaa attaccgtgc ggcatctgac ggcatacgat gaaactactc aaaaaattta aaggcagctg tacagtgctt ctactgaagg tttcatgaaa gaacaatgta catattttga cttattattc tgtgaaggtc caagggtccc agoaaaatat tttatattgg aaagcaattc gataggaaag ccagaaatta aaatccttca gtcccttccc aaagatttta tggaccgaaa agaaccagga ggccagctgg ttacagataa tgacatggat aatgtcattg tagcaagatt gaaaattttg caggagattc atcgaagatt agctgtgaaa tttttgctga aactgcctta aaagggttat ggtggctata ttgcatcaat atgtggatcc gtggttgcac ctatcacaga aagatacctt gggatgccat ctaaggaaga taatgttcat ggcttgaaag aagaaaatat agttcatttc caacactcag cagaattaat tactatgcag gtctacocag atgaaggtca ctacagcaca atcctcaaat tcttcagtga acaggaacca gaagaagatg aataatggac aggctcaatg aaacctgaca aagagactgt cagcttacgg agatgtcact ggagcagcac cac

240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 1620 1680 1740 1800 1860 1920 1980 2040 2100 2160 2220 2280 2340 2400 2460 2520 2580 2583 <210> 7 <211> 690 <212> PRT <213> Homo sapiens <400> 7

Met Ala Ala Ala Met Glu Thr Glu Gin Leu Gly Vai Glu lie Phe Glu

Thr Ala Asp Cys Glu Glu Asn Xie Glu Ser Gin Asp Arg Pro Lys, Leu 20 ^{25 30}

Glu pro Phe Tyr Vai Glu Arg Tyr ser Trp Ser Gin Leu Lys Lys Leu 35 4045

Leu Ala Asp Thr Arg Lys Tyr His Gly Tyr Met Met Ala Lys Ala Pro 50 ⁵⁵⁶⁰

His Asp Phe Met Phe val Lys Arg Asn Asp Pro Asp Gly Pro His Ser

70 ⁷⁵⁸⁰

Asp Arg lie Tyr Tyr Leu Ala Met Ser Gly Glu Asn Arg Glu Asn Thr

Thr lie Asn Arg Ala Ala Val Leu 105 HO

Asp Leu Phe Gin Ala Thr Leu Asp 125

Glu Leu Leu Arg Glu Arg Lys Arg 140

Tyr Asp Tyr His Gin Gly Ser Gly 155160

Gly lie Tyr His Val Lys Asp Gly 170175

Pro Leu Arg Pro Asn Leu Val Glu 185190

Asp Pro Lys Leu Cys Pro Ala Asp 205

Ser Asn Asp He Trp lie Ser Asn 220

Leu Thr Tyr Val His Asn Glu Leu 235240

Ser Ala Gly Val Ala Thr Phe Val 250255

Ser Gly Tyr Trp Trp Cys Pro Lys 265270

Lys lie Leu Arg He Leu Tyr Glu 285

He He His Val Thr Ser Pro Met 300

Phe Arg Tyr Pro Lys Thr Gly Thr 315 ³²

Met Ser Glu lie Met lie Asp Ala 330335

Asp Lys Glu Leu lie Gin Pro Phe 345350

Tyr lie Ala Arg Ala Gly Trp Thr 365

He Leu Leu Asp Arg Ser Gin Thr 380

Pro Glu Leu Phe lie Pro Val Glu 395

Leu He Glu Ser Val Pro Asp Ser 410

Glu Thr Thr Asp lie Trp lie Asn 425430

Pro Gin Ser His Glu Glu Glu He

Lys Thr Gly Phe Arg His Leu Tyr 460

Ser Lys Tyr Lys Arg Ser Ser Gly 475480

Lys Cys Pro lie Lys Glu Glu He 4904S5

Val Leu Gly Arg His Gly Ser Asn 505510

Leu Val Tyr Phe Glu Gly Thr Lys 525

Tyr val Val Ser Tyr Val Asn Pro 540

Arg Gly Tyr Ser His Ser cys Cys 555 560 lie Ser Lys Tyr Ser Asn Gin Lys 570 575

WO 02/31134

Leu Phe Tyr Ser Glu He Pro Lys 100

Met Leu Ser Trp Lys Pro Leu Leu

115120

Tyr Gly Met Tyr Ser Arg Glu Glu

130I³⁵

He Gly Thr Vai Gly He Ala Ser

145150

Thr Phe Leu Phe Gin Ala Gly Ser

Gly Pro Gin Gly Phe Thr Gin Gin 180

Thr Ser Cys Pro Asn He Arg Met

195200

Pro Asp Trp He Ala Phe He His

210215

He Vai Thr Arg Glu Glu Arg Arg

225230

Ala Asn Met Glu Glu Asp Ala Arg

Leu Gin Glu Glu Phe Asp Arg Tyr 260

Ala Glu Thr Thr Pro Ser Gly Gly

275280

Glu Asn Asp Glu Ser Glu Vai Glu 290295

Leu Glu Thr Arg Arg Ala Asp Ser 305 ³¹⁰

Ala Asn Pro Lys Vai Thr Phe Lys

Glu Gly Arg He He Asp Vai He 340

Glu lie Leu Phe Glu Gly val Glu

355360

Pro Glu Gly Lys Tyr Ala Trp Ser 370

Arg Leu Gin Xie Val Leu lie Ser 385

Asp Asp Val Met Glu Arg Gin Arg

Val Thr Pro Leu lie lie Tyr Glu 420 lie His Asp lie Phe His Val Phe

Glu Phe lie Phe Ala Ser Glu Cys 450

Lys lie Thr Ser Xie Leu Lys Glu

Gly Leu Pro Ala Pro Ser Asp Phe 485

Ala lie Thr Ser Gly Glu Trp Glu 500

He Gin Val Asp Glu Val Arg Arg

Asp Ser Pro Leu Glu His His Leu 530535

Gly Glu Val Thr Arg Leu Thr Asp 545550 lie Ser Gin His Cys Asp Phe Phe

WO 02/31134

Asn Pro His Cya Vai Ser Leu Tyr Lya Leu Ser Ser Pro Glu Asp Aap ^{580 585 590} ״T.1

Pro Thr Cys Lya Thr Lya Glu Phe Trp Ala Thr lie Leu Asp SerAla

595 600605

Glv Pro Leu Pro Asp Tyr Thr Pro Pro Glu He Phe Ser Phe Glu Ser 610 615620

Thr Thr Gly Phe Thr Leu Tyr Gly Met Leu Tyr Lya Pro His Asp Leu 625 ^{630 635}י f

Gin Pro Gly Lys Lya Tyr Pro Thr Vai Leu Phe He Tyr Gly Gly Arg 645 650

Leu Leu Leu Leu Gly Pro Gin Ser Leu Cya Gly Ser Ser Met lie Gin 660 ^665δ&lt;

Asn Thr Arg Asn Vai He Trp Vai Thr Leu Thr Arg Met Asn Arg Ala g75 680685 lie Thr 690 <210> <211> <212 > <213> <400>

4523 DNA Homo 8 sapiens aagtgctaaa ן cgttcgccgc ! gagtggaggc ׳ tccgggcggg ׳ ctgggtgttg cctaaattgg gccgatacca gtgaagagga ggtgagaaca gcagtcttaa ggaatgtatt attgcttctt atttatcacg ctagtggaaa gactggattg gaaaggagac gctggagtcg tgtccaaaag aatgatgaat gcagattcat tcagaaataa caaccttttg gagggaaaat ttgatctcac attgagtcag tggataaata tttatttttg ttaaaggaaa tgtcctatca ggatctaata tcccctttag ctgactgacc agtaagtata gaagatgacc cctcttcctg ttgtatggga coaaggccgc ( accggcgccg &lt; gaagcggcgc &lt; aggaaaatgc &lt; aactgcggac tgttgagcgg tggctacatg tggacctcat actgttttat gaagcctctt agaactatta ccaaggaagt agggccacaa caacatacgg tagcaacgat gcacaatgag tctccaagaa tcccagtggt aattattcat taaaacaggt tgaaggaagg tgaaggagtt catcctacta tatcccagta tgtgacgcca ctttcatgtt caaaacaggt . acgatccagt , agcaattacc i tgaagtcaga gcctccgagg &lt; ctgggttgtc 1 ggcgcagcat ! gccgggggga ; agatatttga agccttttta gaaaatatca atgatccaga gagaaaatac tgctctcttg ctcgagaaga acgattatca taaaagatgg ctagttgtcc cttttataca tcacttatgt ctacctttgt ctgaaacaac ctgaggtgga tccgttatcc tgattgatgc agattctatt atgcttggtc ctgaattatt tgoctgattc . tccatgacat 1 cctctgaatg , gcaaatataa . aagaggagat tccaagttga agcatcacct gtacgtagtc gtggctactc gtaaccagaa caacttgcaa actatactcc tgctctacaa acattcttgc gaatccacac aacaaaggaa tccagaaatt gcctcatgat tgctactgcc &lt; ccgccgagga 1 aggcccgctc ! aacatggcag &lt; tgtgaggaga tattcctgga atggctaagg tcagacagaa totgaaattc ttggatcttt agagaaagaa ggaacatttc ggatttacgc atggatccaa atttggatat ctagccaaca gaatttgata ggtaaaattc gttacatccc acagcaaatc atcatagatg gaatatattg gatcgctccc gaagatgatg ctaattatct tttccccaaa ttccgtcatt ggtgggctgc 1 agtggtgaat . aggctggtat ! agttacgtaa tgcatcagtc tgtgtgtcco ttttgggcca ttctcttttg ctacagcctg gccgctgctt &lt; agccactgca &lt; catagcgcac &lt; cagcaatgga 1 atattgaatc gtcagcttaa caccacatga tctattacct ccaaaactat ttcaggcaac aacgcattgg tgtttcaagc aacaaccttt aattatgccc ctaacatcgt tggaagaaga gatattctgg ttagaattct ctatgttgga ctaaagtcac tcatagataa ccagagctgg agactcgcct ttatggaaag atgaagaaac . gtcacgaaga , tatacaaaat : ctgctccaag : gggaagttct . attttgaagg i atcctggaga ; agcactgtga tttacaagct ccattttgga aaagtactac gaaagaaata cttagtgccg accaggaccg gtcgggacgg aacagaacag acaggatcgg aaagctgctt tttcatgttt tgccatgtct caatagagca actggactat aacagtcgga cggtagtgga aaggcccaat tgctgatcca aaccagagaa tgccagatca ctattggtgg atatgaagaa aacaaggagg ttttaagatg ggaactaatt atggactcct acagatagtg gcagagactc aacagacatc ggaaattgag tacatctatt : tgatttcaag tggccggcat ׳ caccaaagac . ggtgacaagg i cttctttata atcaagtcct ttcagcaggt tggatttaca tcctactgtg

120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 1620 1680 1740 1800 I860 1920 1980 2040 2100 2160

WO 02/31134 ctggggcccc agtcactctg tggatcttct gtcaccctga ccagaatgaa cagggctatt agttcccctc tgaaccaaat cgtttactgc attttgcaca taccagtata ttactgagtt tacagatcta tcctcaggag agacacagca aactgcatct tttgcactac cttcaagaaa tgatataatt ttgacctgtg tagaactctc gaggtttaat caacagaaaa cacagaattg atctactcct gaaaataaat gtggtgccat aataccttaa ccccacatgc tcaaaatcaa accataagaa ttactaaaaa aaaaaaaaaa accctatttt cacttttaat agtattataa agtatacttt tgagtttgtt aaaatatgat gaatctttga ctagttacag atttgatagc attgcttggg catatccagc atgttatgaa cattcattaa taatttttca aggataactt ctgaccagtt tttagccaat ttaatctgta atgatattaa cagagtgggc ttttcctttt tggatttaat tagtcatgat attgataatt gagcttaaat atttgcaggo aagttttttt ttcactagaa ttcttcagaa aatttagtgg aaatattcta gaattttaag gagattgaag ttggggaatg acagagagaa gaggtggtga tttaacaaaa atactcatga aaatgtttgg ggaaaccaga atcaataaat cactgtcttg gggaggaaaa gttccttaga gttactttta gaaatcttac aaatttaaac tttatccttt taagcttaaa atacaaatgt ttatagataa ccatggctct cttttttttt ttggtgttta tgaacttttc ttggtttagc actaggattt tgctaattga gatctgccct gttagagtct gtggcaggga aggcatctat gagtttgatg gttattacca atacttttaa acaacactcc ctacagagag agtagatttc cccatagaga attggtaaga ggtggacttc attgacacca aggatgatat ggtggttctg tcgttgggaa ctgtataata gataccacgc tttttcttat atattttccc atgccaagat ttgtttatat ggtaactttc ttccccaaga aagtattttc ctgttcatat atggtggtcg gttgctattg atgatacagg atacacggaa cgttatatgg acttaggatc tgtggccatg caagcagaaa tcttacatgg tttcctggat gagaatgtcc ttttagtgag ggctggaaag ccatatgatt taagagttcc tgaatcggga gaacattatg accttggatc acgtattgct gctctaaaag tggtatacac tggctattta acoaaatgag atcatcacat tttgatacct gccatgtaac gcaggggtct acggtttgtg gtagtaatct atgatacata ttcctgagag acccagcaat aaaaagacat tagcaccatg tattcatact acttcatgaa cttaattagt gtatttttac gatattagtg attggtttgg ttcagttcca acttaaatgt aattgaatag cttatgcttc ctaataacta ttaaacttga cttaaccagt agtggcctcc taaagacact tgttttggca tctagtataa ataattctca tttttctttg gcataaaggc tagtaactgt atatgtagca acaggcagaa aatttttaat caaatgatta ttttccttta agaaaaggaa aaagtacaca tgccagtttc catttggtat ttccttatta ggaatcacag tggggtgggg agacctgggt gggcctgatt aaaaactaag cagaagtagt aaactgaaat ttaaacaact gtaatattaa ccagcacagc tacagagtaa catgattcag taattctttt tttttttcct cttaggttta taaaattatt tgaacataat ttagatattg cctctttacc ataaactaat ccctggcaag aagcctgtaa acagtttttc tgaatgatca agctatgaag agagctcata ggctttcagg tggggtgcta gattggtcac attgacacca ctttttatca cacacttcag tgtttagaaa aagaaaattt gctatatttc tttctcatca gcacagcctc cattagtaag gttggtgact agtgggaggt agggaaagcc cagaaatggc aggtattggg ttttgctgtt tgtatttata tatctgtata tgtattgctt ttcatgtttg atattttcaa tgttaaatta aattgatttg ccccttaagt ataaatctga ctg

2220 2280 2340 2400 2460 2520 2580 2640 2700 2760 2820 2880 2940 3000 3060 3120 3180 3240 3300 3360 3420 3480 3540 3600 3660 3720 3780 3840 3900 3960 4020 4080 4140 4200 4260 4320 4380 4440 4500 4523 <210> 9 <211> 241 <212> PRT <213> Homo sapiens <400> 9

Met Ala Ala Ala Met Glu Thr Glu

Thr Ala Asp Cys Glu Glu Asn lie

Glu Pro Phe Tyr Vai Glu Arg Tyr נ>⁴35

Leu Ala Asp Thr Arg Lys Tyr His

5055

His Asp Phe Met Phe val Lys Arg

6570

Asp Arg lie Tyr Tyr Leu Ala Met

Leu Phe Tyr Ser Glu He Pro Lys

Gin Leu Gly Val Glu He Phe Glu 1015

Glu Ser Gin Asp Arg Pro Lys Leu 253° ser Trp Ser Gin Leu Lys Lys Leu 45

Gly Tyr Met Met Ala Lys Ala Pro 60

Asn Asp Pro Asp Gly Pro His Ser 75 θ°

Ser Gly Glu Asn Arg Glu Asn Thr 90 ⁹⁵

Thr He Asn Arg Ala Ala Val Leu

WO 02/31134

105 11°

Asp Leu Phe Gin Ala Thr Leu Asp 125

Glu Leu Leu Arg Glu Arg Lys Arg 140

Tyr Asp Tyr His Gin Gly Ser Gly 155160

Gly He Tyr His Vai Lys Asp Gly

5י1170

Pro Leu Arg Pro Asn Leu val Glu 18519°

Asp Pro Lys Leu Cys Pro Ala Asp 205

Ser Asn Asp He Trp He Ser Asn 220

Thr Tyr val His Asn Gly Lys 235 240

Met Leu Ser Trp Lys Pro Leu Leu 115 ¹²⁰

Tyr Gly Met Tyr Ser Arg Glu Glu 130

He Gly Thr Vai Gly He Ala Ser 145

Thr Phe Leu Phe Gin Ala Gly Ser 165

Gly Pro Gin Gly Phe Thr Gin Gin 180

Thr Ser Cys Pro Asn lie Arg Met !95200

Pro Asp Trp He Ala Phe He His 210 ²¹⁵ lie Vai Thr Arg Glu Glu Arg Arg 225

Ala <210> 10 <211> 1356 <212> DNA <213> Homo sapiens <400> 10 aagtgctaaa gcctccgagg ccaaggccgc cgttcgccgc ctgggttgtc accggogccg gagtggaggc ggcgcagcat gaagcggcgc tccgggoggg gccgggggga aggaaaatgc ctgggtgttg agatatttga aactgcggac cctaaattgg agccttttta tgttgagcgg gccgatacca gaaaatatca tggctacatg gtgaagagga atgatccaga tggacctcat ggtgagaaca gagaaaatac actgttttat gcagtcttaa tgctctcttg gaagcctctt ggaatgtatt ctcgagaaga agaactatta attgcttctt acgattatca ccaaggaagt atttatcacg taaaagatgg agggccacaa ctagtggaaa ctagttgtcc caacatacgg gactggattg cttttataca tagcaaogat gaaaggagac tcacttatgt gcacaatggt aacagtattt tttgaagtat aatttgctgc gtgatcttta tatttgaaat tcaagtcttt aggataactt gtatgtacca catgtataat aaacagtgaa acaaaagaac otctgacatg aattttccca aaactgttct tattaaaata ctgtaatcct agcactctgg gaggctgagg gatcaggatg ggcaacatgg tgacacctcg <210> 11 <211> 661 <212> PRT <213> Homo sapiens <400> H

Met Ala Ala Ala Met Glu Thr Glu Gin 1 5

Thr Ala Asp Cys Glu Glu Asn lie Glu 20 25

Glu Pro Phe Tyr Vai Glu Arg Tyr Ser tgctactgcc gccgctgctt cttagtgccg ccgccgagga agccactgca accaggaccg aggcccgctc catagcgcac gtcgggacgg aacatggcag cagcaatgga aacagaacag tgtgaggaga atattgaatc acaggatcgg tattcctgga gtcagcttaa aaagctgctt atggctaagg caccacatga tttcatgttt tcagacagaa tctattacct tgccatgtct tctgaaattc ccaaaactat caatagagca ttggatcttt ttcaggcaac actggactat agagaaagaa aacgcattgg aacagtcgga ggaacatttc tgtttcaagc cggtagtgga ggatttacgc aacaaccttt aaggcccaat atggatccaa aattatgccc tgctgatcca atttggatat ctaacatcgt aaccagagaa aaggcgtagt tcttcagatt tacttttctg ttgcattttg aaattagatt accacgttgg aaaattttta aaaaatggag aaaagtacag attcatttta atgttttaat gttcattttc attgttcttt tagcttgcta agactgccag aaattttagg ctaggcatgg tggctcatgc caggcagatt gtttgagccc agaagttoaa tttgac

120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1356

Leu Gly Val Glu He Phe Glu 10 ¹⁵

Ser Gin Asp Arg Pro Lys Leu

Trp Ser Gin Leu Lys Lys Leu

WO 02/31134

Gly Tyr Met Met Ala Lys Ala Pro 60

Asn Asp Pro Asp Gly Pro His Ser

7580

Ser Gly Glu Asn Arg Glu Asn Thr

Thr He Asn Arg Ala Ala Val Leu

105Π0

Asp Leu Phe Gin Ala Thr Leu Asp

Glu Leu Leu Arg Glu Arg Lys Arg 140

Tyr Asp Tyr His Gin Gly Ser Gly

155160

Gly lie Tyr His Val Lys Asp Gly

170175

Pro Leu Arg Pro Asn Leu Val Glu

185190

Asp Pro Lys Leu Cys Pro Ala Asp

Ser Asn Asp He Trp He Ser Aan

Leu Thr Tyr Val His Asn Glu Leu

235240

Ser Ala Gly Val Ala Thr Phe Val

250255

Ser Gly Tyr Trp Trp Cys Pro Lys

265270

Lys He Leu Arg He Leu Tyr Glu

He lie His Val Thr Ser Pro Met 300

Phe Arg Tyr Pro Lys Thr Gly Thr

315320

Met Ser Glu lie Met He Asp Ala

330335

Asp Lys Glu Leu lie Gin Pro Phe

345350

Tyr He Ala Arg Ala Gly Trp Thr lie Leu Leu Asp Arg Ser Glh Thr

Pro Glu Leu Phe He Pro Val Glu

395 ⁴⁰

Leu He Glu Ser Val Pro Asp Ser

Glu Thr Thr Asp He Trp He Asn

425 ⁴³ pro Gin Ser His Glu Glu Glu He

Lys Thr Gly Phe Arg His Leu Tyr 460

Ser Lys Tyr Lys Arg Ser Ser Gly

475480

Lys Cys Pro He Lys Glu Glu He

Val Leu Gly Arg His Gly Ser Asn

505510

Leu Val Tyr Phe Glu Gly Thr Lys ⁴⁰

Leu Ala Asp Thr Arg Lys Tyr His

His Asp Pile Met Phe Vai Lys Arg 6570

Asp Arg He Tyr Tyr Leu Ala Met 85

Leu Phe Tyr Ser Glu He Pro Lys 100

Met Leu Ser Trp Lys Pro Leu Leu

Tyr Gly Met Tyr Ser Arg Glu Glu

130135 lie Gly Thr Vai Gly lie Ala Ser 14515°

Thr Phe Leu Phe Gin Ala Gly Ser 165

Gly Pro Gin Gly Phe Thr Gin Gin 180

Thr Ser Cys Pro Asn lie Arg Met

Pro Asp Trp He Ala Phe He His 210 215 lie Vai Thr Arg Glu Glu Arg Arg 225 230

Ala Asn Met Glu Glu Asp Ala Arg

Leu Gin Glu Glu Phe Asp Arg Tyr 260

Ala Glu Thr Thr Pro Ser Gly Gly

275280

Glu Asn Asp Glu Ser Glu Vai Glu 290295

Leu Glu Thr Arg Arg Ala Asp Ser 305310

Ala Asn Pro Lys Vai Thr Phe Lys

Glu Gly Arg lie lie Asp Vai He 340

Glu lie Leu Phe Glu Gly Vai Glu

355360

Pro Glu Gly Lys Tyr Ala Trp Ser 370375

Arg Leu Gin lie Vai Leu He Ser 385

Asp Asp Vai Met Glu Arg Gin Arg

Val Thr Pro Leu He He Tyr Glu 420 lie His Asp He Phe His Val Phe

435 ⁴⁴

Glu Phe He Phe Ala Ser Glu Cys 450455

Lys He Thr Ser He Leu Lys Glu 465*70

Gly Leu Pro Ala Pro Ser Asp Phe

Ala He Thr Ser Gly Glu Trp Glu 500 lie Gin Val Asp Glu Val Arg Arg

WO 02/31134

Asp Ser Pro Leu Glu His His Leu Tyr Vai Vai Ser Tyr Vai Asn Pro 530 535540

Gly Glu val Thr Arg Leu Thr Asp Arg Gly Tyr Ser His Ser CysCys

545 550 555560 lie Ser Gin His Cys Asp Phe Phe He Ser Lys Tyr Ser Asn GinLys

565 570575

Asn Pro His Cys Val Ser Leu Tyr Lys Leu ser Ser Pro Glu Asp Asp 580 585590

Pro Thr Cys Lys Thr Lys Glu Phe Trp Ala Thr lie Leu Asp Ser Ala 595 600605

Gly Pro Leu Pro Asp Tyr Thr Pro Pro Glu He Phe Ser Phe Glu Ser 610 615620

Thr Thr Gly Phe Thr Leu Tyr Gly Met Leu Tyr Lys Pro His AspLeu

625 630 635640

Gin Pro Gly Lys Lys Tyr Pro Thr Val Leu Phe lie Tyr Gly GlyLeu

645 650655

Leu Arg Cys Ser Trp 660 <210> 12 <211> 4B29 <212> DNA <213> Homo sapiens <400> 12 aagtgctaaa gcctccgagg ccaaggccgc tgctactgcc gccgctgctt cttagtgccg60 cgttcgccgc ctgggttgtc accggcgccg ccgccgagga agccactgca accaggaccg120 gagtggaggc ggcgcagcat gaagcggcgc aggcccgctc catagcgcac gtcgggacgg180 tccgggcggg gccgggggga aggaaaatgc aacatggcag cagcaatgga aacagaacag240 ctgggtgttg agatatttga aactgcggac tgtgaggaga atattgaatc acaggatcgg300 cctaaattgg agccttttta tgttgagcgg tattcctgga gtcagcttaa aaagctgctt360 gccgatacca gaaaatatca tggctacatg atggctaagg caccacatga tttcatgttt420 gtgaagagga atgatccaga tggacctcat tcagacagaa tctattacct tgccatgtct480 ggtgagaaca gagaaaatac actgttttat tctgaaattc ccaaaactat caatagagca540 gcagtcttaa tgctctcttg gaagcctctt ttggatcttt ttcaggcaac actggactat600 ggaatgtatt ctcgagaaga agaactatta agagaaagaa aacgcattgg aacagtcgga660 attgcttctt acgattatca ccaaggaagt ggaacatttc tgtttcaagc cggtagtgga720 atttatcacg taaaagatgg agggccacaa ggatttacgc aacaaccttt aaggcccaat780 ctagtggaaa ctagttgtcc caacatacgg atggatccaa aattatgccc tgctgatcca840 gactggattg cttttataca tagcaacgat atttggatat ctaacatcgt aaccagagaa900 gaaaggagac tcacttatgt gcacaatgag ctagccaaca tggaagaaga tgccagatca960 gctggagtcg ctacctttgt tctccaagaa gaatttgata gatattctgg ctattggtgg1020 tgtccaaaag ctgaaacaac tcccagtggt ggtaaaattc ttagaattct atatgaagaa1080 aatgatgaat ctgaggtgga aattattcat gttacatccc ctatgttgga aacaaggagg1140 gcagattcat tccgttatcc taaaacaggt acagcaaatc ctaaagtcac ttttaagatg1200 tcagaaataa tgattgatgc tgaaggaagg atcatagatg tcatagataa ggaactaatt1260 caaccttttg agattctatt tgaaggagtt gaatatattg ccagagctgg atggactcct1320 gagggaaaat atgcttggtc catcotacta gatcgctccc agactcgcct acagatagtg1380 ttgatctcao ctgaattatt tatcccagta gaagatgatg ttatggaaag gcagagactc1440 attgagtcag tgcctgattc tgtgacgcca ctaattatct atgaagaaao aacagacatc1500 tggataaata tccatgacat ctttcatgtt tttccccaaa gtcacgaaga ggaaattgag1560 tttatttttg cctctgaatg caaaacaggt ttccgtcatt tatacaaaat tacatctatt1620 ttaaaggaaa gcaaatataa acgatccagt ggtgggctgc ctgctecaag tgatttcaag1680 tgtcctatca aagaggagat agcaattacc agtggtgaat gggaagttct tggccggcat1740 ggatctaata tccaagttga tgaagtcaga aggctggtat attttgaagg caccaaagac1800 tcccctttag agcatcacct gtacgtagtc agttacgtaa atcctggaga ggtgacaagg1860 ctgactgacc gtggctactc acattcttgc tgcatcagtc agcactgtga cttctttata1920 agtaagtata gtaaccagaa gaatccacac tgtgtgtccc tttacaagct atcaagtcct1980 gaagatgacc caacttgcaa aaoaaaggaa ttttgggcca ccattttgga ttcagcaggt2040

WO 02/31134 ttctcttttg aaagtactac tggatttaca ctacagcctg gaaagaaata tcctactgtg agttggtgaa taatcggttt aaaggagtca taggttatgt ggttgtagtg atagacaaca aaggcgcctt taaatataaa atgggtcaaa aatatctagc ttctcgatat gatttcattg cctatggagg atacctctcc ctgatggcat ctattgctgg ggccccagtc actctgtgga atatgggtca ccctgaccag aatgaacagg cagaaaagtt cccctctgaa ccaaatcgtt atgtccattt tgcacatacc agtatattac atgatttaca gatctatcct caggagagac attatgaact gcatcttttg cactaccttc taaaagtgat ataattttga cctgtgtaga aatgaggagg tttaatcaac agaaaacaca tgtaacatct actcctgaaa ataaatgtgg taatctaata ccttaacccc acatgctcaa agcaatacca taagaattac taaaaaaaaa catactaccc tattttcact tttaatagta ttttacagta tacttttgag tttgttaaaa gttccagaat ctttgactag ttacagattt tgcttcattg cttgggcata tccagcatgt accagtcatt cattaataat ttttcaagga ttggcactga ccagttttta gccaatttaa tctttgatga tattaacaga gtgggctttt gtagcatgga tttaattagt catgatattg tgattagagc ttaaatattt gcaggcaagt tacacattca ctagaattct tcagaaaatt ttattaaaat attctagaat tttaaggaga ctgggtttgg ggaatgacag agagaagagg agtagtttta acaaaaatac tcatgaaaat tattaaggaa accagaatca ataaatcact attcagggga ggaaaagttc cttagagtta ggtttagaaa tcttacaaat ttaaacttta atattgtaag cttaaaatac aaatgtttat ggcaagccat ggctctcttt ttttttttgg tgatcatgaa cttttcttgg tttagcacta ttcaggtgct aattgagatc tgccctgtta acaccagtgg cagggaaggc atctatgagt tagaaagtta ttaccaatao ttttaaacaa tcatcactac agagagagta gatttcccca gtgactattg gtaagaggtg gacttoattg aatggcagga tgatatggtg gttctgtcgt tttatactgt ataatagata ccacgctttt tgtttgatat tttcccatgc caagatttgt gatttgggta actttcttcc ccaagaaagt cctcttcctg actatactcc tccagaaatt ttgtatggga tgctctacaa gcctcatgat ctgttcatat atggtggtct cctcaggtgc agtatttccg cttgaatacc ctagcctctc ggggatcctg toaccgaggg cttaaatttg tagaaattga cgatcaggtg gaaggactcc acttagatcg tgtgggcatc cacggctggt taatgcagag gtcagatatc ttcagggttg tcttctatga tacaggatac acggaacgtt gctattactt aggatctgtg gccatgcaag tactgctctt acatggtttc ctggatgaga tgagtttttt agtgagggct ggaaagccat acagcataag agttcctgaa tcgggagaac aagaaaacct tggatcacgt attgctgctc actctctggt atacactggc tatttaacca gaattgatca tcacattttg atacctgcca tgccatgcag gggtctacgg tttgtggtag aatcaaatga tacatattcc tgagagaccc aaaaaaaaaa agacattago accatgtatt ttataaactt catgaactta attagtgtat tatgatgata ttagtgattg gtttggttca gatagcactt aaatgtaatt gaatagctta tatgaactaa taactattaa acttgactta taacttagtg gcctcctaaa gacacttgtt tctgtatcta gtataaataa ttctcatttt ccttttgcat aaaggctagt aactgtatat ataattacag gcagaaaatt tttaatcaaa tttttttttt cctttaagaa aaggaaaaag tagtggtgcc agtttccatt tggtatttcc ttgaagggaa tcacagtggg gtggggagac tggtgagggc ctgattaaaa actaagcaga gtttggaaac tgaaatttaa acaactgtaa gtcttgccag cacagctaca gagtaacatg cttttataat tctttttttt tttcctctta tccttttaaa attatttgaa cataatttag agataacctc tttaccataa actaatccct tgtttaaagc ctgtaaacag tttttctgaa ggatttagct atgaagagag ctcataggct gagtcttggg gtgctagatt ggtcacattg ttgatgcttt ttatcacaca cttoagtgtt cactccaaga aaatttgcta tatttctttc tagagagcac agcctccatt agtaaggttg acaccaagtg ggaggtaggg aaagcccaga tgggaaaggt attgggtttt gctgtttgta tcttattatc tgtatatgta ttgcttttca ttatatatat tttcaatgtt aaattaaatt attttccccc ttaagtataa atctgactg <210> 13 <211> 358 <212> PRT <213> Homo sapiens <400> 13

Met Ala Ala Ala Met Glu Thr Glu Gin 1 ⁵

Thr Ala Asp Cys Glu Glu Asn He Glu ²⁵

Glu Pro Phe Tyr Vai Glu Arg Tyr Ser ⁴⁰

Leu Gly Vai Glu He 10

Ser Gin Asp Arg Pro

Trp Ser Gin Leu Lys 45

Phe Glu 15 Lys Leu

Lys Leu

2100 2160 2220 2280 2340 2400 2460 2520 2580 2640 2700 2760 2820 2880 2940 3000 3060 3120 3180 3240 3300 3360 3420 3480 3540 3600 3660 3720 3780 3840 3900 3960 4020 4080 4140 4200 4260 4320 4380 4440 4500 4560 4620 4680 4740 4800 4829

Gly Tyr Met Met Ala Lys Ala Pro 60

Asn Asp Pro Asp Gly Pro His Ser

Ser Gly Glu Asn Arg Glu Asn Thr

Thr lie Asn Arg Ala Ala Val Leu

Asp Leu Phe Gin Ala Thr Leu Asp

Glu Leu Leu Arg Glu Arg Lys Arg 140

Tyr Asp Tyr His Gin Gly Ser Gly

155ISO

Gly He Tyr His Val Lys Asp Gly

170175

Pro Leu Arg Pro Asn Leu Val Glu

Asp Pro Lys Leu Cys Pro Ala Asp

Ser Asn Asp He Trp He Ser Asn 220

Leu Thr Tyr Val His Asn Glu Leu

Ser Ala Gly val Ala Thr Phe Val

Ser Gly Tyr Trp Trp Cys Pro Lys

Lys lie . Leu Arg He Leu Tyr Glu lie He His Val Thr Ser Pro Met

Phe Arg Tyr Pro Lys Thr Gly Thr

Met Ser Glu He Met lie Asp Ala

Ser Glu Gly Trp Tyr He Leu Lys

WO 02/31134

Leu Ala Asp Thr׳ Arg Lys Tyr His 50 ⁵⁵

His Asp phe Met Phe Vai Lys Arg 65 ^{* * * * * * * * * * 70}

Asp Arg lie Tyr Tyr Leu Ala Met 85

Leu Phe Tyr Ser Glu lie Pro Lys 100

Met Leu Ser Trp Lys Pro Leu Leu

Tyr Gly Met Tyr Ser Arg Glu Glu

130I

He Gly Thr val Gly He Ala Ser 145

Thr Phe Leu Phe Gio Ala Gly Ser 165

Gly Pro Gin Gly Phe Thr Gin Gin 180

Thr Ser Cys Pro Asn He Arg Met

195 ²⁰⁰

Pro Asp Trp He Ala Phe He His lie val Thr Arg Glu Glu Arg Arg 225230

Ala Asn Met Glu Glu Asp Ala Arg 245

Leu Gin Glu Glu Phe Asp Arg Tyr 260

Ala Glu Thr Thr Pro Ser Gly Gly 275280

Glu Asn Asp Glu Ser Glu Val Glu 290

Leu Glu Thr Arg Arg Ala Asp Ser 305

Ala Asn Pro Lys Val Thr Phe Lys 325

Glu Gly Arg Ser Lys Leu Met Lys 340

Ala Pro Lys Thr Pro Leu 355 <210> 14 <211> 4309 <212> DMA <213 > Homo sapiens <400> 14 aagtgctaaa gcctccgagg ccaaggocgc cgttcgccgc ctgggttgtc accggcgccg gagtggaggo ggcgcagcat gaagcggcgc tccgggcggg gccgggggga aggaaaatgc ctgggtgttg agatatttga aactgcggac cctaaattgg agccttttta tgttgagcgg gccgatacca gaaaatatca tggctacatg gtgaagagga atgatccaga tggacctcat ggtgagaaca gagaaaatac actgttttat gcagtcttaa tgctctcttg gaagcctctt ggaatgtatt ctcgagaaga agaactatta attgcttctt acgattatca ccaaggaagt atttatcacg taaaagatgg agggccacaa tgctactgco gocgctgctt cttagtgccg ccgccgagga agccactgoa accaggaccg aggcccgctc catagcgcac gtcgggacgg aacatggcag oagcaatgga aacagaacag tgtgaggaga atattgaatc acaggatcgg tattcctgga gtcagottaa aaagotgctt atggctaagg caccacatga tttcatgttt tcagacagaa tctattacct tgccatgtct tctgaaattc ccaaaactat caatagagca ttggatcttt ttcaggoaac actggactat agagaaagaa aacgcattgg aacagtcgga ggaacatttc tgtttcaagc cggtagtgga ggatttaogc aacaaccttt aaggcccaat

120 180 240 300 360 420 480 540 600 660 720 780

WO 02/31134 ctagtggaaa ctagttgtcc gactggattg cttttataca gaaaggagac tcacttatgt gctggagtcg ctacctttgt tgtccaaaag ctgaaacaac aatgatgaat ctgaggtgga gcagattcat tccgttatcc tcagaaataa tgattgatgc attttgaagg caccaaagac atcctggaga ggtgacaagg agcactgtga cttctttata tttacaagot atcaagtcct ccattttgga ttcagcaggt aaagtactac tggatttaca gaaagaaata tcctactgtg taatcggttt aaaggagtca ggttgtagtg atagacaaoa taaatataaa atgggtcaaa ttctcgatat gatttcattg atacctctcc ctgatggcat ggccccagtc actctgtgga ccctgaccag aatgaacagg cccctctgaa ccaaatcgtt tgcacatacc agtatattac gatctatcct caggagagac gcatcttttg cactaccttc ataattttga cctgtgtaga tttaatcaac agaaaacaca actcctgaaa ataaatgtgg ccttaacccc acatgctcaa taagaattac taaaaaaaaa tattttcact tttaatagta tacttttgag tttgttaaaa ctttgactag ttaeagattt cttgggcata tccagcatgt cattaataat ttttcaagga ccagttttta gccaatttaa tattaacaga gtgggctttt tttaattagt catgatattg ttaaatattt gcaggcaagt ctagaattct tcagaaaatt attctagaat tttaaggaga ggaatgacag agagaagagg acaaaaatac tcatgaaaat accagaatca ataaatcact ggaaaagttc cttagagtta tcttacaaat ttaaacttta cttaaaatac aaatgtttat ggctctcttt ttttttttgg cttttcttgg tttagcacta aattgagatc tgccctgtta cagggaaggc atctatgagt ttaccaatac ttttaaacaa agagagagta gatttcccca gtaagaggtg gacttcattg tgatatggtg gttctgtcgt ataatagata ccacgctttt tttcccatgc caagatttgt actttcttcc ccaagaaagt caacatacgg atggatccaa tagcaacgat atttggatat gcacaatgag ctagccaaca tctccaagaa gaatttgata tcccagtggt ggtaaaattc aattattcat gttacatccc taaaacaggt acagcaaatc tgaaggaaga tccaagttga tcccctttag agcatcacct ctgactgacc gtggctactc agtaagtata gtaaccagaa gaagatgacc caacttgcaa cctcttcctg actatactcc ttgtatggga tgctctacaa ctgttcatat atggtggtct agtatttccg cttgaatacc ggggatcctg tcaccgaggg tagaaattga cgatcaggtg acttagatcg.tgtgggcatc taatgcagag gtcagatatc tcttctatga tacaggatac gctattactt aggatctgtg tactgctctt acatggtttc tgagtttttt agtgagggct acagcataag agttcctgaa aagaaaacct tggatcacgt actctctggt atacactggc gaattgatca tcacattttg tgccatgcag gggtctacgg aatcaaatga tacatattcc aaaaaaaaaa agacattagc ttataaactt catgaactta tatgatgata ttagtgattg gatagcactt aaatgtaatt tatgaactaa taactattaa taacttagtg gcctcctaaa tctgtatcta gtataaataa ccttttgcat aaaggctagt ataattacag gcagaaaatt tttttttttt cctttaagaa tagtggtgcc agtttccatt ttgaagggaa tcacagtggg tggtgagggo ctgattaaaa gtttggaaac tgaaatttaa gtcttgccag cacagctaca cttttataat tctttttttt tccttttaaa attatttgaa agataacctc tttaccataa tgtttaaagc ctgtaaacag ggatttagot atgaagagag gagtcttggg gtgctagatt ttgatgcttt ttatcacaca cactccaaga aaatttgcta tagagagcac agcctccatt acaccaagtg ggaggtaggg tgggaaaggt attgggtttt tcttattatc tgtatatgta ttatatatat tttcaatgtt attttccccc ttaagtataa aattatgccc tgctgatcca ctaacatcgt aaccagagaa tggaagaaga tgccagatca gatattctgg ctattggtgg ttagaattct atatgaagaa ctatgttgga aacaaggagg ctaaagtcac ttttaagatg tgaagtcaga aggctggtat gtacgtagtc agttacgtaa acattcttgc tgcatcagtc gaatccacac tgtgtgtccc aacaaaggaa ttttgggcca tccagaaatt ttctcttttg gcctcatgat ctacagcctg cctcaggtgc agttggtgaa ctagcctctc taggttatgt cttaaatttg aaggcgcctt gaaggactcc aatatctagc cacggctggt cctatggagg ttcagggttg ctattgctgg acggaacgtt atatgggtca gccatgcaag cagaaaagtt ctggatgaga atgtccattt ggaaagccat atgatttaca tcgggagaac attatgaact attgctgctc taaaagtgat tatttaacca aatgaggagg atacctgcca tgtaacatct tttgtggtag taatctaata tgagagaccc agcaatacca accatgtatt catactaccc attagtgtat ttttacagta gtttggttca gttccagaat gaatagctta tgcttcattg acttgactta accagtcatt gacacttgtt ttggcactga ttctcatttt tctttgatga aactgtatat gtagcatgga tttaatcaaa tgattagagc aaggaaaaag tacacattca tggtatttcc ttattaaaat gtggggagac ctgggtttgg actaagcaga agtagtttta acaactgtaa tattaaggaa gagtaacatg attcagggga tttcctctta ggtttagaaa cataatttag atattgtaag actaatccct ggcaagccat tttttotgaa tgatcatgaa ctcataggct ttcaggtgct ggtcacattg acaccagtgg cttcagtgtt tagaaagtta tatttctttc tcatcactac agtaaggttg gtgactattg aaagcccaga aatggcagga gctgtttgta tttatactgt ttgcttttca tgtttgatat aaattaaatt gatttgggta atctgactg

840 900 960

1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 1620 1680 1740 1800 1860 1920 1980 2040 2100 2160 2220 2280 2340 2400 2460 2520 2580 2640 2700 2760 2820 2880 2940 3000 3060 3120 3180 3240 3300 3360 3420 3480 3540 3600 3660 3720 3780 3840 3900 3960 4020 4080 4140 4200 4260 4309

WO 02/31134 <210> 15 <211> 108 <212 > PRT <213> Homo sapiens <נ400>

Met Ala Ala Ala Met Glu Thr Glu Gin Leu Gly Vai Glu lie Phe Glu

5 ^{10 15}

Thr Ala Asp Cys Glu Glu Asn He Glu Ser Gin Asp Arg Pro LysLeu ^{25 30} ,Glu Pro Phe Tyr Vai Glu Arg Tyr Ser Trp Ser Gin Leu Lys LysLeu

4045

Leu Ala Asp Thr Arg Lys Tyr His Gly Tyr Met Met Ala Lys Ala Pro

. ׳ ^{60 55}50

His Asp Phe Met Phe Vai Lys Arg Asn Asp Pro Asp Gly Pro His Ser

^{80 75} סל65

Asn Arg He Tyr Tyr Leu Gly Asn Lys Ser Leu He Asp His Asp Arg * 85 5095

Phe Ser Lys Ser Lys Met Pro Glu lie Ala Ser Ser

100105 <210> 16 <211> 620 <212> DMA <213> Homo sapiens <400> 16 aagtgctaaa cgttcgccgc gagtggaggo tccgggcggg ctgggtgttg cctaaattgg gccgatacca gtgaagagga tcattaattg agctagcttg tagtttgttc <210> 17 <211> 194 <212> PRT <213 > Homo sapiens <400> 17 gcotccgagg ccaaggacgc tgctactgcc gccgctgctt cttagtgccg60 ctgggttgtc accggcgccg ccgccgagga agccactgca accaggaccg2 ggcgcagcat gaagcggcgc aggcccgctc catagcgcac gtcgggacgg1B0 gccgggggga aggaaaatgc aacatggcag cagcaatgga aacagaacag240 agatatttga aactgcggac tgtgaggaga atattgaatc acaggatcgg300 agccttttta tgttgagcgg tattcctgga gtcagcttaa aaagctgctt360 gaaaatatca tggctacatg atggctaagg caccacatga tttcatgttt420 atgatccaga tggacctcat tcagacagaa tctattacct tggtaacaag480 atcatgatcg tttttcaaaa tcgaagatgo cagaaattgc ttcttcctaa540 aaatgccttt otttagatgg tctgattagg aaaacaaaoa ataaaaccat600 coactcaaca

WO 02/31134

Met Ala Ala Ala Met Glu Thr Glu Gin Leu Gly Val Glu He Phe Glu _χ 5 1015

Thr Ala Asp Cys Glu Glu Asn He Glu Ser Gin Asp Arg Pro LysLeu

2530

Glu Pro Phe Tyr Val Glu Arg Tyr Ser Trp Ser Gin Leu Lys Lys Leu 35 4045

Leu Ala Asp Thr Arg Lys Tyr His Gly Tyr Met Met Ala Lys Ala Pro 50 5560

His Asp Phe Met Phe Val Lys Arg Asn Asp Pro Asp Gly Pro HisSer ₆₅ 70 7500

Asp Arg He Tyr Tyr Leu Ala Met Ser Gly Glu Asn Arg Glu AsnThr

9095

Leu Phe Tyr Ser Glu He Pro Lys Thr lie Asn Arg Ala Ala val Leu 100 10511°

Met Leu Ser Trp Lys Pro Leu Leu Asp Leu Phe Gin Ala Thr Leu Asp 115 120125

Tyr Gly Met Tyr Ser Arg Glu Glu Glu Leu Leu Arg Glu Arg Lys Arg 130 1353-40

He Gly Thr Val Gly He Ala Ser Tyr Asp Tyr His Gin Gly SerGly

145 I^{50 1551}

Thr Phe Leu Phe Gin Ala Gly Ser Gly He Tyr His Val Lys AspGly

165 170175

Glv pro Gin Gly Phe Thr Gin Pro Leu Arg Pro Asn Leu val Glu Thr 180 185190

Cys Ala <210> 18 <211> 832 <212> DMA <213> Homo sapiens <400> 13 aagtgctaaa gcctccgagg ccaaggccgc cgttcgccgc ctgggttgtc accggcgccg gagtggaggc ggcgcagcat gaagcggcgc tccgggcggg gccgggggga aggaaaatgc ctgggtgttg agatatttga aactgcggac cctaaattgg agccttttta tgttgagcgg gccgatacca gaaaatatca tggctacatg gtgaagagga atgatccaga tggacctcat ggtgagaaca gagaaaatac actgttttat gcagtcttaa tgctctcttg gaagcctctt ggaatgtatt ctegagaaga agaactatta attgcttctt acgattatca ccaaggaagt atttatcacg taaaagatgg agggccacaa ctagtggaaa ctasttgtsc caracytgca tgctactgcc gccgctgctt cttagtgccg 60 ccgccgagga agccactgca accaggaccg 120 aggcccgctc catagcgcac gtcgggacgg 180 aacatggcag cagcaatgga aacagaacag 240 tgtgaggaga atattgaatc acaggatcgg 300 tattcctgga gtcagcttaa aaagctgctt 360 atggctaagg caocacatga tttcatgttt 420 tcagacagaa tctattacct tgccatgtct 480 tctgaaattc ccaaaactat caatagagca 540 ttggatcttt ttcaggcaac actggactat 600 agagaaagaa aacgcattgg aacagtcgga 660 ggaacatttc tgtttcaagc cggtagtgga 720 ggatttacgc wacaaccttt aaggcccaat 780 tgacccaatc agatcctgta ga 832 <210> 19 <211> 658 <212> PRT <213 > Homo sapiens <400> 19

Met Ala Ala Ala Met Glu Thr Glu Gin Leu Gly Val Glu He Phe Glu , 5 10 .15

Thr Ala Asp Cys Glu Glu Asn He Glu Ser Gin Asp Arg Pro LysLeu

25

Glu Pro Phe Tyr val Glu Arg Tyr Ser Trp Ser Gin Leu Lys Lys Leu 35 4045

Leu Ala Asp Thr Arg Lys Tyr His Gly Tyr Mat Met Ala Lys Ala Pro

WO 02/31134

Asn Asp Pro Asp Gly Pro His Ser 7580

Ser Gly Glu Asn Arg Glu Asn Thr 9095

Thr He Asn Arg Ala Ala Val Leu 105HO

Asp Leu Phe Gin Ala Thr Leu Asp 125

Glu Leu Leu Arg Glu Arg Lys Arg 140

Tyr Asp Tyr His Gin Gly Ser Gly 155160

Gly He Tyr His Val Lys Asp Gly 170175

Pro Leu Arg Pro Asn Leu Val Glu 185190

Asp Pro Lys Leu Cys Pro Ala Asp 205

Ser Asn Asp He Trp He Ser Asn 220

Leu Thr Tyr Val His Asn Glu Leu 235240

Ser Ala Gly Val Ala Thr Phe val 250255

Ser Gly Tyr Trp Trp Cys Pro Lys 265270

Lys He Leu Arg He Leu Tyr Glu 285

He He His Val Thr Ser Pro Met 300

Phe Arg Tyr Pro Lys Thr Gly Thr 315320

Met Ser Glu He Met He Asp Ala 330335

Asp Lys Glu Leu He Gin Pro Phe 345350

Tyr He Ala Arg Ala Gly Trp Thr 365 lie Leu Leu Asp Arg Ser Gin Thr 380

Pro Glu Leu Phe He Pro Val Glu 395400

Leu He Glu Ser Val Pro Asp Ser 410415

Glu Thr Thr Asp lie Trp He Asn 425430

Pro Gin Ser His Glu Glu Glu lie 445

Lys Thr Gly Phe Arg His Leu Tyr 460

Ser Lys Tyr Lys Arg Ser Ser Gly 475480

Lys Cys Pro He Lys Glu Glu He 490495

Val Leu Gly Arg His Gly Ser Asn 505510

Leu Val Tyr Phe Glu Gly Thr Lys 525

Tyr Val Val Ser Tyr Val Asn Pro ⁵⁵

His Asp Phe Met Phe val Lys Arg 65 70

Asp Arg He Tyr Tyr Leu Ala Met

Leu Phe Tyr Ser Glu He Pro Lys 100

Met Leu Ser Trp Lys Pro Leu Leu

115120

Tyr Gly Met Tyr Ser Arg Glu Glu

130 ¹³⁵ lie Gly Thr Val Gly He Ala Ser 145150

Thr Phe Leu Phe Gin Ala Gly Ser

Gly Pro Gin Gly Phe Thr Gin Gin 180

Thr Ser Cys Pro Asn lie Arg Met

195200

Pro Asp Trp lie Ala Phe He His 210215 lie val Thr Arg Glu Glu Arg Arg 225230

Ala Asn Met Glu Glu Asp Ala Arg

245 Leu Gin Glu Glu Phe Asp Arg Tyr

260 Ala Glu Thr Thr Pro Ser Gly Gly 275280

Glu Aen Asp Glu Ser Glu Val Glu

290295

Leu Glu Thr Arg Arg Ala Asp Ser 305

Ala Asn Pro Lys Val Thr Phe Lys

Glu Gly Arg He He Asp Val He 340

Glu lie Leu Phe Glu Gly Val Glu

355360

Pro Glu Gly Lys Tyr Ala Trp Ser 370375

Arg Leu Gin He Val Leu lie Ser 385390

Asp Asp Val Met Glu Arg Gin Arg

Val Thr Pro Leu He He Tyr Glu 420 lie His Asp lie Phe His Val Phe

435440

Glu Phe lie Phe Ala Ser Glu Cys 450455

Lys He Thr Ser lie Leu Lys Glu 465470

Gly Leu Pro Ala Pro Ser Asp Phe

Ala He Thr Ser Gly Glu Trp Glu 500 lie Gin Val Asp Glu Val Arg Arg 515 520

Asp Ser Pro Leu Glu His His Leu

WO 02/31134

530 ⁵³⁵

Gly Glu Vai Thr Arg Leu Thr 545 550

He Ser Gin His Cys Asp Phe

Asn Pro His Cys Vai ser Leu 500 pro Thr Cys Lys Thr Lys Glu

Gly Pro Leu Pro Asp Tyr Thr

610 615

Thr Thr Gly Phe Thr Leu Tyr

625 630

Gin Pro Gly Lys Lys Tyr Pro 645

Vai Lys

Asp Arg Gly Tyr Ser His Ser Cys Cys 555560

Phe He Ser Lys Tyr Ser Asn Gin Lys 570575

Tyr Lys Leu Ser Ser Pro Glu Asp Asp 585 590,

Phe Trp Ala Thr lie Leu Asp Ser Ala

60060S pro Pro Glu He Phe Ser Phe Glu Ser

Gly Met Leu Tyr Lys Pro His Asp Leu

635640

Thr val Leu Phe He Tyr Gly Gly Arg 650655 c210> 20 <211> 4676 <212> DNA <213> Homo sapiens <400> 20 aagtgctaaa cgttcgccgc gagtggaggc tccgggcggg ctgggtgttg cctaaattgg gccgatacca gtgaagagga ggtgagaaca gcagtcttaa ggaatgtatt attgcttctt atttatcacg ctagtggaaa gactggattg gaaaggagac gctggagtcg tgtccaaaag aatgatgaat gcagattcat tcagaaataa caaccttttg gagggaaaat ttgatctcac attgagtcag tggataaata tttatttttg ttaaaggaaa tgtcctatca ggatctaata tcccctttag ctgactgacc agtaagtata gaagatgacc cctcttcctg ttgtatggga ctgttcatat gcctccgagg ctgggttgto ggcgcagcat gccgggggga agatatttga agccttttta gaaaatatca atgatccaga gagaaaatac tgctctcttg ctcgagaaga acgattatca taaaagatgg ctagttgtcc cttttataca tcacttatgt ctacctttgt ctgaaacaac ctgaggtgga tccgttatcc tgattgatgc agattctatt atgcttggtc ctgaattatt tgcctgattc tccatgacat cctctgaatg gcaaatataa aagaggagat tccaagttga agcatcacct gtggctactc gtaaccagaa caacttgcaa actatactcc tgctctacaa atggtggtcg ccaaggccge accggcgccg gaagcggcgc aggaaaatgc aactgcggac tgttgagcgg tggctacatg tggacctcat actgttttat gaagcctctt agaactatta ccaaggaagt agggccacaa caacatacgg tagcaacgat gcacaatgag tctccaagaa toccagtggt aattattcat taaaacaggt tgaaggaagg tgaaggagtt catcctacta tatcccagta tgtgacgcca ctttcatgtt caaaacaggt acgatccagt agcaattacc tgaagtcaga gtaogtagtc acattcttgc gaatccacac aacaaaggaa tccagaaatt gcctcatgat ggtcaaatag tgctactgcc ccgccgagga aggcccgctc aacatggcag tgtgaggaga tattcctgga atggctaagg tcagacagaa tctgaaattc ttggatcttt agagaaagaa ggaacatttc ggatttacgc atggatccaa atttggatat ctagccaaca gaatttgata ggtaaaattc gttacatccc acagcaaatc atcatagatg gaatatattg gatcgctccc gaagatgatg ctaattatct tttccccaaa ttccgtcatt ggtgggctgc agtggtgaat aggctggtat agttacgtaa tgcatcagtc tgtgtgtccc ttttgggcca ttctcttttg ctacagcctg aaattgacga gccgctgctt agccactgca catagcgcac cagcaatgga atattgaatc gtcagcttaa caccacatga tctattacct ccaaaactat ttcaggcaac aacgcattgg tgtttcaagc aacaaccttt aattatgccc ctaacatcgt tggaagaaga gatattctgg ttagaattct ctatgttgga ctaaagtcac tcatagataa ccagagctgg agactcgcct ttatggaaag atgaagaaac gtcacgaaga tatacaaaat ctgctccaag gggaagttct attttgaagg atcctggaga agcactgtga tttacaagct ccattttgga aaagtactac gaaagaaata tcaggtggaa cttagtgccg accaggaccg gtcgggacgg aacagaacag aoaggatcgg aaagctgctt tttcatgttt tgccatgtct caatagagca actggactat aacagtcgga cggtagtgga aaggcccaat tgctgatcca aaccagagaa tgccagatca ctattggtgg atatgaagaa aacaaggagg ttttaagatg ggaactaatt atggactcct acagatagtg gcagagactc aacagacatc ggaaattgag tacatctatt tgatttcaag tggccggcat caccaaagac ggtgacaagg cttctttata atcaagtcct ttcagcaggt tggatttaca tcctactgtg ggactccaat

120 1B0 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 1620 16B0 1740 1800 1860 1920 1980 2040 2100 2160 2220

WO 02/31134 tagatcgtgt gggcatccac ggctggtcct tgcagaggtc agatatcttc agggttgcta tctatgatac aggatacacg gaacgttata attacttagg atctgtggcc atgcaagcag tgctcttaca tggtttcctg gatgagaatg gttttttagt gagggctgga aagccatatg gcataagagt tcctgaatcg ggagaacatt aaaaccttgg atcacgtatt gctgctctaa ctctggtata cactggctat ttaaccaaat ttgatcatca cattttgata cctgccatgt catgcagggg tctacggttt gtggtagtaa caaatgatac atattoctga gagacccagc aaaaaaaaga cattagcacc atgtattcat taaacttcat gaacttaatt agtgtatttt gatgatatta gtgattggtt tggttcagtt agcacttaaa tgtaattgaa tagcttatgc gaactaataa ctattaaact tgacttaacc cttagtggcc tcctaaagac acttgttttg gtatctagta taaataattc tcatttttct tttgcataaa ggctagtaac tgtatatgta attacaggca gaaaattttt aatcaaatga tttttttcct ttaagaaaag gaaaaagtac tggtgccagt ttccatttgg tatttcctta aagggaatca cagtggggtg gggagacctg tgagggcctg attaaaaact aagcagaagt tggaaactga aatttaaaca actgtaatat ttgccagcac agctacagag taacatgatt ttataattct tttttttttt cctcttaggt ttttaaaatt atttgaaoat aatttagata taacotcttt accataaact aatccctggc ttaaagcctg taaacagttt ttctgaatga tttagctatg aagagagotc ataggctttc tottggggtg ctagattggt cacattgaca atgcttttta tcacacactt cagtgtttag tccaagaaaa tttgctatat ttctttctca agagcacagc ctccattagt aaggttggtg ccaagtggga ggtagggaaa gcccagaaat gaaaggtatt gggttttgct gtttgtattt tattatctgt atatgtattg cttttcatgt tatatatttt caatgttaaa ttaaattgat ttccccctta agtataaatc tgactg atctagcttc tcgatatgat ttcattgact atggaggata cctctccctg atggcattaa ttgctggggc cccagtcact ctgtggatct tgggtcaccc tgaccagaat gaacagggct aaaagttccc ctctgaacca aatcgtttao tccattttgc acataccagt atattactga atttaoagat ctatcctcag gagagacaca atgaactgca tcttttgcac tiaccttcaag aagtgatata attttgacct gtgtagaact gaggaggttt aatcaacaga aaacacagaa aacatctact cctgaaaata aatgtggtgc tctaatacct taaocccaca tgctcaaaat aataccataa gaattactaa aaaaaaaaaa actaccctat tttcactttt aatagtatta tacagtatac ttttgagttt gttaaaatat ccagaatctt tgactagtta cagatttgat ttcattgctt gggcatatcc agcatgttat agtcattcat taataatttt tcaaggataa gcactgacca gtttttagcc aatttaatct ttgatgatat taacagagtg ggcttttcct gcatggattt aattagtcat gatattgata ttagagctta aatatttgca ggcaagtttt acattcacta gaattcttca gaaaatttag ttaaaatatt ctagaatttt aaggagattg ggtttgggga atgacagaga gaagaggtgg agttttaaca aaaatactca tgaaaatgtt taaggaaacc agaatcaata aatcactgtc caggggagga aaagttcctt agagttactt ttagaaatct tacaaattta aactttatcc ttgtaagctt aaaatacaaa tgtttataga aagccatggc tctctttttt tttttggtgt tcatgaactt ttcttggttt agcactagga aggtgctaat tgagatctgc cctgttagag ccagtggcag ggaaggcatc tatgagtttg aaagttatta ccaatacttt taaacaacac tcactacaga gagagtagat ttccccatag actattggta agaggtggac ttcattgaca ggcaggatga tatggtggtt ctgtcgttgg atactgtata atagatacca cgctttttct ttgatatttt cccatgccaa gatttgttta ttgggtaact ttcttcccca agaaagtatt

2280 2340 2400 2460 2520 2580 2640 2700 2760 2820 2880 2940 3000 3060 3120 3180 3240 3300 3360 3420 3480 3540 3600 3660 3720 3780 3840 3900 3960 4020 4080 4140 4200 4260 4320 4380 4440 4500 4560 4620 4676 <210? 21 <211> 613 <212> PRT <213? Homo sapiens <400? 21

Met Ala Ala Ala Met Glu Thr Glu ⁵

Thr Ala Asp Cys Glu Glu Asn He

Glu Pro Phe Tyr Vai Glu Arg Tyr 35

Leu Ala Asp Thr Arg Lys Tyr His 50

His Asp Phe Met Phe Vai Lys Arg

6570

Asp Arg He Tyr Tyr Leu Ala Met

Gin Leu Gly Vai Glu lie Phe Glu 10

Glu Ser Gin Asp Arg Pro Lys Leu 25

Ser Trp Ser Gin Leu Lys Lys Leu 45

Gly Tyr Met Met Ala Lys Ala Pro 60

Asn Asp Pro Asp Gly Pro His Ser 75 ⁸⁰ ser Gly Glu Asn Arg Glu Asn Thr 90 ⁹⁵

Xie Pro Lys Thr He Asn 105

Pro Leu Leu Asp Leu Phe 120

Arg Glu Glu Glu Leu Leu 135

He Ala Ser Tyr Asp Tyr 150 155

Ala Gly Ser Gly lie Tyr 170

Thr Gin Gin Pro Leu Arg 185 lie Arg Met Asp Pro Lys 200

Phe He His Ser Asn Asp 215

Glu Arg Arg Leu Thr Tyr 230 235

Asp Ala Arg Ser Ala Gly 250

Asp Arg Tyr Ser Gly Tyr 265

Ser Gly Gly Lys He Leu 280

Glu Val Glu lie lie His 295

Ala Asp Ser Phe Arg Tyr 310 315

Thr Phe Lys Met Ser Glu 330

Asp Val He Asp Lys Glu 345

Gly Val Glu Tyr lie Ala 360

Ala Trp Ser He Leu Leu 375

Leu He Ser Pro Glu Leu 390 395

Arg Gin Arg Leu He Glu 410 lie Tyr Glu Glu Thr Thr 425

His Val Phe Pro Gin Ser 440

Ser Glu Cys Lys Thr Gly 455

Leu Lys Glu Ser Lys Tyr 470 475

Ser Asp Phe Lys Cys Pro 490

Glu Trp Glu Val Leu Gly 505

Val Arg Arg Leu Val Tyr 520

His His Leu Tyr val val 535

Leu Thr Asp Arg Gly Tyr 550 555

Asp Phe Phe He Ser Lys 570

WO 02/31134

Leu Phe Tyr Ser Glu 100

Met Leu Ser Trp Lys 115

Tyr Gly Met Tyr Ser 130 lie Gly Thr Val Gly 145

Thr Phe Leu Phe Gin 165

Gly Pro Gin Gly Phe 180

Thr Ser Cys Pro Asn 195

Pro Asp Trp He Ala 210 lie Val Thr Arg Glu 225

Ala Asn Met Glu Glu 245

Leu Gin Glu Glu Phe 260

Ala Glu Thr Thr Pro 275

Glu Asn Asp Glu Ser 290

Leu Glu Thr Arg Arg 305

Ala Asn Pro Lys Val 325

Glu Gly Arg He He 340

Glu lie Leu Phe Glu 355

Pro Glu Gly Lys Tyr 370

Arg Leu Gin lie Val 385

Asp Asp Val Met Glu 405

Val Thr Pro Leu He 420 lie His Asp lie Phe 435

Glu Phe lie Phe Ala 450

Lys lie Thr Ser lie 465

Gly Leu Pro Ala Pro 485

Ala lie Thr Ser Gly 500

He Gin Val Asp Glu 515

Asp Ser Pro Leu Glu 530

Gly Glu Val Thr Arg 545

He Ser Gin His Cys 565

Arg Ala Ala Val Leu 110

Gin Ala Thr Leu Asp 125

Arg Glu Arg Lys Arg 140

His Gin Gly Ser Gly 160

His val Lys Asp Gly 175

Pro Asn Leu Val Glu 190

Leu Cys Pro Ala Asp 205

He Trp lie Ser Asn 220

Val His Asn Glu Leu 240

Val Ala Thr Phe Val 255

Trp Trp Cys Pro Lys 270

Arg He Leu Tyr Glu 285

Val Thr Ser Pro Met 300

Pro Lys Thr Gly Thr 320 lie Met lie Asp Ala 335

Leu lie Gin Pro Phe 350

Arg Ala Gly Trp Thr 365

Asp Arg Ser Gin Thr 380

Phe lie Pro Val Glu 400

Ser Val Pro Asp Ser 415

Asp lie Trp He Asn 430

His Glu Glu Glu He 445

Phe Arg His Leu Tyr 460

Lys Arg Ser Ser Gly 480

He Lys Glu Glu He 495

Arg His Gly Ser Asn 510

Phe Glu Gly Thr Lys 525

Ser Tyr Val Asn Pro 540

Ser His Ser Cys Cys 560

Tyr Ser Asn Gin Lys 575

WO 02/31134

Aan Pro His Cys Val Ser Leu Tyr 580

Pro Thr Cys Lys Thr Lys Glu Phe

Leu Arg Cys Ser Trp

Lys Leu Ser Ser Pro Glu Asp Asp 585 590

Trp Ala Thr He Leu Asp Ser Val <210> 22 <211>. 4605 <212 > DNA <213> Homo sapiens <400> 22 aagtgctaaa gcctccgagg ccaaggccgc cgttcgccgc ctgggttgtc accggcgccg gagtggaggc ggcgcagcat gaagcggcgc tccgggcggg gccgggggga aggaaaatgc ctgggtgttg agatatttga aactgcggac cctaaattgg agccttttta tgttgagcgg gccgatacca gaaaatatca tggctacatg gtgaagagga atgatccaga tggacctcat ggtgagaaca gagaaaatac actgttttat gcagtcttaa tgctctcttg gaagcctctt ggaatgtatt ctcgagaaga agaactatta attgcttctt aogattatca ccaaggaagt atttatcacg taaaagatgg agggccacaa ctagtggaaa ctagttgtcc caacatacgg gactggattg cttttataca tagcaacgat gaaaggagac tcacttatgt gcacaatgag gctggagtog ctacctttgt tctccaagaa tgtccaaaag ctgaaacaac tcccagtggt aatgatgaat otgaggtgga aattattcat gcagattcat tccgttatcc taaaacaggt tcagaaataa tgattgatgc tgaaggaagg caaccttttg agattctatt tgaaggagtt gagggaaaat atgcttggtc catcctacta ttgatctcac ctgaattatt tatcccagta attgagtcag tgcctgattc tgtgacgcca tggataaata tccatgacat ctttcatgtt tttatttttg cctctgaatg caaaacaggt ttaaaggaaa gcaaatataa acgatccagt tgtcctatca aagaggagat agcaattacc ggatctaata tccaagttga tgaagtcaga tcccctttag agcatcacct gtacgtagtc ctgactgacc gtggctactc acattottgc agtaagtata gtaaccagaa gaatccacac gaagatgacc caacttgcaa aacaaaggaa aggtgcagtt ggtgaataat cggtttaaag cctctctagg ttatgtggtt gtagtgatag aatttgaagg cgcctttaaa tataaaatgg gactccaata tctagcttct cgatatgatt gctggtccta tggaggatac ctctccctga gggttgctat tgctggggcc ccagtcactc aacgttatat gggtcaccct gaceagaatg tgcaagcaga aaagttcccc tctgaaccaa atgagaatgt ccattttgca cataccagta agccatatga tttacagatc tatcctcagg gagaacatta tgaactgcat cttttgcact ctgctctaaa agtgatataa ttttgacctg taaccaaatg aggaggttta atcaacagaa tgctactgcc gccgatgctt cttagtgccg ccgccgagga agccactgca accaggaccg aggcccgctc catagcgcac gtcgggacgg aacatggcag oagcaatgga aacagaacag tgtgaggaga atattgaatc acaggatcgg tattcctgga gtcagcttaa aaagctgctt atggctaagg caccacatga tttcatgttt tcagacagaa tctattacct tgocatgtct tctgaaattc ccaaaactat caatagagca ttggatcttt ttcaggcaac actggactat agagaaagaa aacgcattgg aacagtcgga ggaaoatttc tgtttcaagc cggtagtgga ggatttacgc aacaaccttt aaggcccaat atggatccaa aattatgccc tgctgatcca atttggatat ctaacatcgt aaccagagaa ctagccaaca tggaagaaga tgccagatca gaatttgata gatattctgg ctattggtgg ggtaaaattc ttagaattct atatgaagaa gttacatccc ctatgttgga aacaaggagg acagcaaatc ctaaagtcac ttttaagatg atcatagatg tcatagataa ggaaotaatt gaatatattg ccagagctgg atggactcct gatcgctccc agactcgcct acagatagtg gaagatgatg ttatggaaag gcagagactc ctaattatct atgaagaaac aacagacatc tttccccaaa gtcacgaaga ggaaattgag ttccgtcatt tatacaaaat tacatctatt ggtgggctgc ctgctccaag tgatttcaag agtggtgaat gggaagttct tggccggcat aggctggtat attttgaagg caccaaagac agttacgtaa atcctggaga ggtgacaagg tgcatcagtc agcactgtga cttctttata tgtgtgtccG tttacaagct atcaagtcct ttttgggcca ccattttgga ttcagtcctc gagtcaagta tttccgcttg aataacctag acaacagggg atcctgtcac cgagggctta gtcaaataga aattgacgat caggtggaag tcattgactt agatcgtgtg ggcatccacg tggcattaat gcagaggtca gatatcttca tgtggatctt ctatgataca ggatacacgg aacagggcta ttacttagga tctgtggcca atcgtttact gctcttacat ggtttcctgg tattactgag ttttttagtg agggctggaa agagacacag cataagagtt cctgaatcgg accttcaaga aaaccttgga tcacgtattg tgtagaactc tctggtatac actggctatt aacacagaat tgatcatcac attttgatac

120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 1620 1680 1740 1800 1860 1920 1980 2040 2100 2160 2220 2280 2340 2400 2460 '2520 2580 2640 2700 2760 2820

WO 02/31134 ctgccatgta acatctactc ctgaaaataa atgtggtgcc atgcaggggt ctacggtttg tggtagtaat ctaatacctt aaccccacat gctcaaaatc aaatgataca tattcctgag agacccagca ataccataag aattactaaa aaaaaaaaaa aaaaaaagac attagcacca tgtattcata ctaccctatt ttcactttta atagtattat aaacttcatg aacttaatta gtgtattttt acagtatact tttgagtttg ttaaaatatg atgatattag tgattggttt ggttcagttc cagaatcttt gactagttac agatttgata gcacttaaat gtaattgaat agcttatgct tcattgcttg ggcatatcca gcatgttatg aactaataac tattaaactt gacttaacca gtcattcatt aataattttt caaggataac ttagtggcct cctaaagaca cttgttttgg cactgaccag tttttagcca atttaatctg tatctagtat aaataattct catttttctt tgatgatatt aacagagtgg gcttttcctt ttgcataaag gctagtaact gtatatgtag catggattta attagtcatg atattgataa ttacaggcag aaaattttta atcaaatgat tagagcttaa atatttgcag gcaagttttt ttttttcctt taagaaaagg aaaaagtaca Cattcactag aattcttcag aaaatttagt ggtgccagtt tccatttggt atttccttat taaaatatto tagaatttta aggagattga agggaatcac agtggggtgg ggagacctgg gtttggggaa tgacagagag aagaggtggt gagggcctga ttaaaaacta agcagaagta gttttaacaa aaatactcat gaaaatgttt ggaaactgaa atttaaacaa ctgtaatatt aaggaaacca gaatcaataa atcactgtct tgccagcaca gctacagagt aacatgattc aggggaggaa aagttcctta gagttacttt tataattctt tttttttttc ctcttaggtt tagaaatctt acaaatttaa actttatcct tttaaaatta tttgaacata atttagatat tgtaagctta aaatacaaat gtttatagat aacctcttta ccataaacta atccctggca agccatggct ctcttttttt ttttggtgtt taaagcctgt aaacagtttt tctgaatgat catgaacttt tcttggttta gcactaggat ttagctatga agagagctca taggctttca ggtgctaatt gagatctgcc ctgttagagt cttggggtgc tagattggtc acattgacac cagtggcagg gaaggcatct atgagtttga tgctttttat cacacacttc agtgtttaga aagttattac caatactttt aaacaacact ccaagaaaat ttgctatatt tctttctcat cactacagag agagtagatt tccccataga gagcacagcc tccattagta aggttggtga ctattggtaa gaggtggact tcattgacac caagtgggag gtagggaaag cccagaaatg gcaggatgat atggtggttc tgtcgttggg aaaggtattg ggttttgctg tttgtattta tactgtataa tagataccac gctttttctt attatctgta tatgtattgc ttttcatgtt tgatattttc ccatgccaag atttgtttat atatattttc aatgttaaat taaattgatt tgggtaactt tcttccccaa gaaagtattt tcccccttaa gtataaatct gactg <210> 23 <211> 892 <212> PRT, <213> Homo sapiens <400> 23

Met Arg Lys Val Lys Lys Leu Arg Leu Asp Lys Glu Asn Thr GlySer

5 1015

Trp Arg Ser Phe Ser Leu Asn Ser Glu Gly Ala Glu Arg Met AlaThr

253°

Thr Gly Thr Pro Thr Ala Asp Arg Gly Asp Ala Ala Ala Thr Asp Asp 35 4045

Pro Ala Ala Arg Phe Gin val Gin Lys His Sar Trp Asp Gly Leu Arg 50 5560

Ser He He His Gly Ser Arg Lys Tyr Ser Gly Leu He Val AsnLys

70 7580

Ala Pro His Asp Phe Gin Phe val Gin Lys Thr Asp Glu Ser GlyPro

BS 9095

His Ser His Arg Leu Tyr Tyr Leu Gly Met Pro Tyr Gly Ser Arg Glu 100 105HO

Asn Ser Leu Leu Tyr Ser Glu He Pro Lys Lys Val Arg Lys Glu Ala 115 120125

Leu Leu Leu Leu Ser Trp Lys Gin Met Leu Asp His Phe Gin Ala Thr 130 135140

Pro His His Gly Val Tyr Ser Arg Glu Glu Glu Leu Leu Arg GluArg

145 150 155160

Lys Arg Leu Gly Val Phe Gly He Thr Ser Tyr Asp Phe His Ser Glu

28B0 2940 3000 3060 3120 3180 3240 3300 3360 3420 3480 3540 3600 3660 3720 3780 3840 3900 3960 4020 4080 4140 4200 4260 4320 4380 4440 4500 4560 4620 4680 4685

WO 02/31134

170 ' . 175

Ser Asn Ser Leu Phe His Cys Arg 185 150

Val Ser Pro Met Lys Pro Leu Glu 205

Arg Met Asp Pro Lys He Cys Pro 220 lie Asn Asn Ser Asp Leu Trp Val 235240

Arg Arg Leu Thr Phe Cys His Gin 250255

Pro Lys Ser Ala Gly Val Ala Thr 265270

Arg Phe Thr Gly Tyr Trp Trp Cys 285

Glu Gly Leu Lys Thr Leu Arg He 300

Glu Val Glu Val He His Val Pro 31S320

Thr Asp Ser Tyr Arg Tyr Pro Arg 330335

Ala Leu Lys Leu Ala Glu Phe Gin 345350

Ser Thr Gin Glu Lys Glu Leu Val 365

Lys Val Glu Tyr He Ala Arg Ala 380

Ala Trp Ala Met Phe Leu Asp Arg 395400

Leu Leu Pro Pro Ala Leu Phe lie 410415

Arg Leu Ala Ser Ala Arg Ala Val 425430

Val Tyr Glu Glu val Thr Asn Val 445

Tyr Pro Phe Pro Gin Ser Glu Gly 460

Ala Asn Glu Cys Lys Thr Gly Phe 475480 val Leu Lys Ser Gin Gly Tyr Asp 490455

Glu Asp Glu Phe Lys Cys Pro He 505510

Gly Glu Trp Glu Val Leu Ala Arg 525

Glu Glu Thr Lys Leu Val Tyr Phe 540

Glu His His Leu Tyr Val Val Ser 555560

Arg Leu Thr Thr Pro Gly Phe Ser 570575

Phe Asp Met Phe Val ser His Tyr 585590

Val His Val Tyr Lys Leu Ser Gly 605

Gin Pro Arg Phe Trp Ala Ser Met 620

Asp Tyr Val Pro Pro Glu He Phe 635 640

Arg Leu Tyr Gly Met lie Tyr Lys

Ser Gly Leu Phe Leu Phe Gin Ala 180

Asp Gly Gly Lys Asn Gly Phe Met 19s200

He Lys Thr Gin Cys Ser Gly Pro 210

Ala Asp Pro Ala Phe Phe Ser Phe

225230

Ala Asn He Glu Thr Gly Glu Glu 245

Gly Leu Ser Asn Val Leu Asp Asp 260

Phe Val He Gin Glu Glu Phe Asp

275280

Pro Thr Ala Ser Trp Glu Gly Ser 290295

Leu Tyr Glu Glu Val Asp Glu Ser

Ser Pro Ala Leu Glu Glu Arg Lys 325

Thr Gly Ser Lys Asn Pro Lys He 340

Thr Asp Ser Gin Gly Lys He Val

Gin Pro Phe Ser Ser Leu Phe Pro 370375

Gly Trp Thr ^AsP ^1,Y^{8 1}Υ*

385390

Pro Gin Gin Trp Leu Gin Leu Val 405

Pro Ser Thr Glu Asn Glu Glu Gin 420

Pro Arg Asn Val Gin Pro Tyr Val

Trp He Asn Val His Asp He Phe 450453

Glu Asp Glu Leu Cys Phe Leu Arg

Cys His Leu Tyr Lys Val Thr Ala 485

Trp Ser Glu Pro Phe Ser Pro Gly 500

Lys Glu Glu He Ala Leu Thr Ser

515520

His Gly Ser Lys lie Trp Val Asn 530535

Gin Gly Thr Lys Asp Thr Pro Leu

545550

Tyr Glu Ala Ala Gly Glu He Val 565

His Ser Cys ser Met Ser Gin Asn 580

Ser Ser Val Ser Thr Pro Pro Cys

595600

Pro Asp Asp Asp Pro Leu His Lys 610

Met Glu Ala Ala Ser Cys Pro Pro

625530

His Phe His Thr Arg Ser Asp Val

WO 02/31134

Thr Val Leu Phe Val ... 670

Ser Phe Lys Gly lie

6Θ5

Gly Tyr Ala Val Val 700

Leu Arg Phe Glu Gly

Glu Asp Gin Val Glu 735

645550

Pro His Ala Leu Gin Pro Gly Lys Lys His Pro 6606

Tyr Gly Gly Pro Gin Val Gin Leu Val Asn Asn 675680

Lys Tyr Leu Arg Leu Asn Thr Leu Ala Ser Leu 690

Val He Asp Gly Arg Gly Ser Cys Gin Arg Gly

^{715 10}י705

Ala Leu Lys Asn Gin Met Gly Gin Val Glu lie

ט3ל725

Gly Leu Gin Phe val Ala Glu Lys Tyr Gly Phe 740 ⁷⁴⁵

Val Ala lie His Gly Trp Ser Tyr Gly Gly Phe 755

Leu lie His Lys Pro Gin val Phe Lys Val Ala 770

Val Thr val Trp Met Ala Tyr Asp Thr Gly Tyr

⁷⁹⁵ 790־705

Asp Val Pro Glu Asn Asn Gin His Gly Tyr Glu 805

Leu His Val Glu Lys Leu Pro Asn Glu Pro Asn 820

His Gly Phe Leu Asp Glu Asn Val His Phe Phe B35

Val Ser Gin Leu He Arg Ala Gly Lys Pro Tyr 850

Pro Asn Glu Arg His Ser He Arg Cys Pro Glu 865 ⁸⁷⁰⁸⁷⁵

Glu Val Thr Leu Leu His Phe Leu Gin Glu Tyr 885 <210> 24 <211> 4302 <212> DNA <213> Homo sapiens <400> 24 caggccgccg cctgggtcgc tcaaottccg tgtgtccgcc gcggctgtcg tcccccgctc tggagccgcg accgtgaggc gccgctggac cccacgtccc ggtctgtgtc ccacgcctgc gaaggcaccc ctgccctcct gaggtcagct cgcotggaca aggagaacac cggaagttgg gagaggatgg ccaccaccgg gaccccaacg gacccggccg cccgcttcca ggtgcagaag cacggcagcc gcaagtactc gggcctcatt gtgcagaaga cggatgagtc tgggccccac tatggoagcc gagagaactc cctoctctao gctctgctgc tcctgtcctg gaagcagatg ggggtctact ctcgggagga ggagctgctg atcacctcct acgacttcca cagcgagagt ctcttccact gccgcgacgg cggcaagaac gaaatcaaga cccagtgctc agggccccgg gccttcttct cottcatcaa taacagcgac gagcggcggc tgaacttctg ccaccaaggt gcgggtgtgg ccaccttcgt catacaggaa tgccccacag cctcctggga aggttcagag gaagtcgatg agtccgaggt ggaggtcatt aagacggact cgtatcggta ccccaggaca

He Asp Leu Ser Arg 750

Leu Ser Leu Met Gly 765

He Ala Gly Ala Pro

Thr Glu Arg Tyr Met

Ala Gly Ser Val Ala 815

Arg Leu Leu He Leu

His Thr Asn Phe Leu 845

Gin Leu Gin He Tyr

Ser Gly Glu His Tyr

8B0

X^eu

120 1Θ0 240 300 360 420 480 540 600 660 720 780 840 ' 900 960 1020 1080 1140 1200 1260 1320 ggtcaaaggt gcctgagccg gcgggtcccc ccgccacttc cggggtcgca gtcccgggca ccgggacgac ctgcccagtc cggccgccgc agctggaatg gaggctctat ggacccttta gagcggttaa tgcggaaggt taagaaactg agaagcttct cgctgaattc cgagggggct gccgaccgag gcgacgcagc cgccacagat cactcgtggg acgggctccg gagcatcatc gtcaacaagg cgccccacga cttccagttt tcccaccgcc totactacct gggaatgcca tctgagattc ccaagaaggt ccggaaagag ctggatcatt tccaggccac gccccaccat agggagogga aacgcctggg ggtcttcggc ggcctcttcc tcttccaggc cagcaacagc ggcttcatgg tgtcccctat gaaaccgctg atggacccca aaatctgccc tgccgaccct ctgtgggtgg ccaacatcga gacaggegag ttatccaatg tcctggatga ccccaagtct gagttcgaoc gcttcactgg gtactggtgg ggcctcaaga cgctgcgaat cctgtatgag cacgtcccct ctcctgcgct agaagaaagg ggcagcaaga atcccaagat tgcottgaaa

WO 02/31134

PCT7US01/31874 ctggctgagt gtgcagccct cgggatggca gtcctcctcc tctgccagag gtctggatca ctctgctttc gccgttttaa tttaagtgcc aggcacggct aaggacacgc gtacgcctca ttcgtcagcc ggccccgacg gccagctgcc gtgcggctct accgtcctct atcaagtact ggcaggggct caggtggaga atcgacctga gggctaatcc tggatggcct cacggctatg cgcttgctta ctcgtctccc agacacagta ctacaggaat cagcctccgc tttgtcccgc tttatccttt agagatggtg cgctgatggg ggctccctgt tgcaattgcc ggatattttt cagcactttg ggccaacatg cgcgtgccta aggtggaggt gaaactctgt agacttgggg ttcccaagcc ggggcaccac ccgaacttcc ccacatgtgt cccacctcag cgggcaaaaa atattatgga agtagacaca tccagactga tcagctcgct aatacgcctg ccccggccct ctgtccccag atgttcatga tccgcgccaa aatcccaggg ccattaagga ccaagatctg cgctggagca ccacgcccgg actacagcag acgaccccct ccccggatta acggcatgat ttgtatatgg tgcggctcaa cctgtcagcg tcgaggacca gccgagttgc acaagcccca acgacacagg aggcgggttc tcctccacgg aactgatccg ttcgctgccc acctctgagc ggggaaccag ccagcgctgg tttaaacgct gtctcgggcc cactggagag gacctctcag tgtccccccc cataattatt ggaggctgag gggaaacccc taatcccagc tgcggtgagc ctcaaaataa tccacaccgg cgagcagagg ctgtggacag acgctctgct ctgcctgacc ggttatattt aaaaagtaaa aagaaaatat ttaaacgatt cagccagggc gttcccgaag ggccatgttc gttcatcccg gaatgtccag catcttctat tgaatgcaag ctacgattgg agagattgct ggtcaatgag ccacctctac cttctcccat cgtgagcacg gcacaagcag tgttcctcca ctacaagccc aggcccccag cacactggcc agggcttcgg ggtggagggc catccatggc ggtgttcaag gtacactgag cgtggccctg cttcctggac agcagggaaa cgagtcgggc ctgcccaccg gcgggaggga ccagccccga cttgggtttt agcccctcct gccagaagag tcccctggcc ggccagcctc taaaagacag gcgggcggat gtctctacta tactcgggag caagatcgca ataaaaaata gcagcggggt gtcatgcggg ccctcctgtc ggtcagtggc cgtacacacc ccctctcccc aagaaaagaa ttttgtcgat ccagttggaa aagatcgtct gtggagtaca ctggaccggc agcacagaga ccgtatgtgg cccttccccc accggcttct agtgagccct ctgaccagcg gagaccaagc gtggtcagct agctgctcca ccgccctgcg ccccgcttct gagatcttcc cacgccttgc gtgcagctgg tccctgggct ttcgaagggg ctgcagttcg tggtcctacg gtggccatcg cgctacatgg cacgtggaga gaaaacgtgc ccttaccagc gagcactatg ggagccgcca ctgagtggcc ggagccgctg atgtccgctg ctccccgcct actcagagga cggcaagcca cccaacttga gccgggcgcg cacctgaggt aaaatacaaa gctgaggcag ccattgcact aaagacagaa tgcaacccag ccccacagga cccaagcttt ggctgtcccc aggggttccg ttccctcccc aaaaaaaaaa tcttattctt acatgtcacc cgacccagga tcgccagggc cccagcagtg atgaggagca tgtacgagga aatcagaggg gccatttgta tcagccccgg gtgaatggga tggtgtactt atgaggcggc tgagccagaa tgcacgtcta gggctagcat atttccacac agccagggaa tgaataactc acgccgtggt ccctgaaaaa tggccgagaa ggggcttcct cgggtgcccc acgtccctga agctgcccaa actttttcca tccagatcta aagtcacgtt catcacagca cgcgggcccc ccttcaccgc cttcttggtt tctgggagga gcgggctgcc ccgtccccag tgtttgtgtt gtggctcacg tgggagttca aaattagccg gagaatcgct ccagcctggg agcaaggggt cacctggtag gaagcggcca caggcaggca tccccagccc gggttgggag gccaagagct aagaaacaaa ttataattat tg gaaggagctg cgggtggacc gctccagctc gcggctagcc ggtcaccaac agaggacgag caaagtcacc ggaagatgaa ggttttggcg ccagggcacc cggcgagatc cttcgacatg caagctgagc gatggaggca gcgctcggat gaagcacccc cttcaaaggc tgtgattgac ccaaatgggc gtatggcttc ctcgctcatg ggtcaccgtc gaacaaccag tgagcccaac cacaaacttc ccccaacgag gctgcacttt caagtggctg agtgaggcac cccgacgcct gccgagacag ggaggtcaca ttccgcctgg cacccaagca ttgtttgggg tctgtaatcc agaccagcct ggtgtggtgg tgaacccggg caacaagagc gcctaaatct gctccatttc gggcccgcgg ctgaaacgca agccgcccag ctgaaccatc ctgccagggg ccacctctac gcgtggaaga

1380 ' 1440 1500 1560 1620 1680 1740 1800 1860 1920 1980 2040 2100 2160 2220 2280 2340 2400 2460 2520 2580 2640 2700 2760 2820 2880 2940 3000 3060 3120 3180 3240 3300 3360 3420 3480 3540 3600 3660 3720 3780 3840 3900 3960 4020 4080 4140 4200 4260 4302 <210>

<211>

<212>

<213>

<400>

518 PRT Komo 25 sapiens

Met Arg Lys Vai Lys Lys Leu Arg Leu Asp Lys Glu Asn Thr Gly Ser 5 10 15

Trp Arg Ser Phe Ser Leu Asn Ser Glu Gly Ala Glu Arg Met Ala Thr

WO 02/31134

Thr

Gly

Pro

Ser 65 Ala

Ala 50 lie

Pro

His

Ser

Asn

Leu

Pro 145 Lys

Ser

Asp

He

Thr 35 Ala

He

His

His

Pro

Arg

His

Asp

Thr

Phe

Gly

Ala Asp Arg 40 Gin

Gin Val 55 Arg

<td> 25</td><td></td>

<td> Gly</td><td> Asp</td>

<td> Lys</td><td> His</td>

<td> Tyr</td><td> Ser</td>

<td> Gin</td><td> Lys</td>

<td></td><td> 90</td>

<td> Gly</td><td> Met</td>

<td> 105</td><td></td>

<td> Pro</td><td> Lys</td>

<td> Met</td><td> Leu</td>

Glu

<td colspan="2"> Ala Ala Ala Thr Asp Asp</td>

<td></td><td> 45</td>

<td> ser</td><td> Trp Asp Gly Leu Arg 60</td>

<td> Gly 75</td><td> Leu He Val Asn Lys 80</td>

<td> Thr</td><td> Asp Glu Ser Gly Pro 95</td>

<td> Pro</td><td> Tyr Gly Ser Arg Glu 110</td>

<td> Lys</td><td> Val Arg Lys Glu Ala 125</td>

<td> Asp</td><td> His Phe Gin Ala Thr 140</td>

<td> Glu 155</td><td> Leu Leu Arg Glu Arg 160</td>

<td> Tyr</td><td> Asp Phe His Ser Glu 175</td>

<td> Ser</td><td> Leu Phe His Cys Arg 190</td>

<td> Pro</td><td> Met Lys Pro Leu Glu 205</td>

<td> Asp</td><td> Pro Lys He Cys Pro 220</td>

<td> . Asn 235</td><td> Ser Asp Leu Trp Val 240</td>

<td> I Leu 1</td><td> Thr Phe Cys His Gin 255</td>

<td> 1 Ser</td><td> Ala Gly Val Ala Thr</td>

Cys

Trp

Thr

Trp

Lys

Ser 70 Gin

Vai

Phe

Phe 85 Leu

Tyr Leu

Tyr

Arg 100 Leu

Ser

Glu lie 120

Lys Gin 135

Ser Arg Glu

Tyr

Leu 115 Leu Leu Leu Ser 130 His His

Ser

Trp

Arg Leu

Gly Leu

Tyr 150 Gly Val Phe 165

Phe Leu Phe 180

Gly Gly Lys 195 Lys Thr 210

Ala Asp Pro 225

Ala Asn He

Gly val

Gly Leu Ser

Gin

Ala

Glu

Asn Gly

Cys Ser

Gly He Thr Ser 170

Gin Ala Ser Asn 185

Phe Met Val Ser 200

Gly Pro Arg Met 215

Ser Phe He Asn phe Val He pro Thr Ala

Leu Tyr Glu

Ser Pro Ala

Asn 260 Gin ser

Glu

Thr Gly

Ser

Thr Asp

Gin

Gly 385 Pro

Pro 370 Trp

Gin

Pro

Ser

Pro

Arg

Trp

Glu 465 Cys lie 450 Asp

His

Trp

Ser 355 Phe

Thr

Gin

Thr

Asn 435 Asn

Ser

Phe Phe

Thr Gly Glu Glu Arg Arg 245 Val Leu Asp Asp

Glu Glu Phe Asp 280 Trp Glu Gly Ser 295

Val Asp Glu Ser 310

Leu Glu Glu Arg Lys 325

Lys Asn Pro Lys He 340

Gin Gly Lys lie Val 360 Pro

Ser Ser Leu Phe 375 Arg Asp Gly Lys 390 Gin

Trp Leu 405 Glu Asn 420 Val Gin val His

Leu

Glu

Leu

Glu

Leu Cys

Tyr Lys

485 pro Phe

Glu

Glu

Pro

Asp phe 470 Val

Ser

Tyr

He 455 Leu

Thr

Pro 265 Arg

Glu

Glu

Thr

Ala 345 Ser

Lys

Tyr

Val

Gin

Val 440 Phe

Arg

Ala

Pro

Lys

Ala

Leu

Phe

Gly

Val

Arg 425 Val

Leu

Glu 315 Ser

Asp 330

Leu Lys

Thr Gin

Val Glu

Trp

Leu 410 Leu

Tyr

Tyr

Ala

Val

Pro

Asn

Gly

Glu

Gly Tyr 285 Thr

Lys 300 Val lie

Tyr Arg

Leu

Glu

Leu Arg

His Val

Tyr

He

Ala

Ala 395 Pro

Leu 490 Gly

Tyr 380 Met

Lys 365 lie

Glu 350 Glu

Ala

Pro

Ala Ser

Glu Glu

Phe

Ala

Leu

Leu

Pro 335 Phe

Leu

Arg

Asp

Phe 415 Ala

Pro 320 Arg

Gin

Val

Ala

Arg 400 lie

Val

Asn Val

Glu Gly

Gly Phe 480

Ala Arg

Val Thr

Phe Pro Gin Ser

Glu Cys Lys Thr

Lys ser Gin Gly Tyr Asp

Glu Gin Ser Leu Thr Asn

WO 02/31134

Ala val Asp Ser Ser Arg 515 <210> 26 <211> 2411 <212> DNA <213> Homa sapiens <400;» 26

505 510 ggtcaaaggt gcctgagccg gcgggtcccc ccgccacttc cggggtcgca gtcccgggca ccgggacgao ctgcccagtc cggccgccgc agctggaatg gaggctctct ggacccttta gagcggttaa tgcggaaggt taagaaactg agaagcttct cgctgaattc cgagggggct gccgaccgag gcgacgcagc cgccacagat cactcgtggg acgggctccg gagcatcatc gtcaacaagg cgccccacga cttccagttt tcccaccgcc tctactacct gggaatgcca tctgagattc ccaagaaggt ccggaaagag ctggatcatt tccaggccac gccccaccat agggagcgga aacgcctggg ggtcttcggo ggcctottcc tcttcoaggc cagcaacagc ggcttcatgg tgtcccctat gaaaccgctg atggacccca aaatctgccc tgccgaccct ctgtgggtgg ccaacatcga gacaggcgag ttatccaatg tcctggatga ccccaagtct gagttcgacc gcttcactgg gtactggtgg ggcatcaaga cgctgcgaat cctgtatgag cacgtcccct ctcctgcgct agaagaaagg ggcagcaaga atcccaagat tgccttgaaa aagatcgtct cgacccagga gaaggagctg gtggagtaca tcgccagggc cgggtggacc ctggaccggc cccagcagtg gctccagctc agcacagaga atgaggagca gcggctagcc ccgtatgtgg tgtacgagga ggtcaccaac cccttccccc aatcagaggg agaggacgag accggcttct gccatttgta caaagtcacc agtgagccct tcagccocgg ggaaggtgag cgttagtcac gtgtggttca atatgctgtt gcacaccctg cgggagaagg aacagggatc atgatctggc agggcttaga gcacccaact gcacctcccc tgtgccaggc ccttagcaca tcaaatccgg cccaccacct gtgttcataa acttgtttac agagactgtc tgtggtcgct ccagcagaaa ctgttgtgca aggccaagat ccagctcctg ctgtaggtag ctgtgatgga atccctgctc ttgggacctt ctagtggagg tgcctctggt gtgctgtggg tggcagatgc caggccgccg cctgggtcgc tcaacttccg tgtgtccgcc gcggctgtcg tcccccgctc tggagccgcg accgtgaggc gccgctggac cccacgtccc ggtctgtgtc ccacgcctgc gaaggcaccc ctgccctcct gaggtcagct cgcctggaca aggagaacac cggaagttgg gagaggatgg ccaccaacgg gaccccaacg gacccggccg cccgcttcca ggtgcagaag cacggcagcc gcaagtactc gggcctcatt gtgcagaaga cggatgagtc tgggccccac tatggoagcc gagagaactc cctcctctac gctctgctgc tcctgtcctg gaagcagatg ggggtctact ctcgggagga ggagctgctg atcacctcct acgacttcca cagcgagagt ctcttccact gccgcgacgg cggcaagaac gaaatcaaga cccagtgctc agggccccgg gcottcttct ccttcatcaa taacagcgac gagcggcggc tgaccttctg ccaccaaggt gcgggtgtgg ccaccttcgt catacaggaa tgccccacag cctcctggga aggttcagag gaagtcgatg agtccgaggt ggaggtcatt aagacggact cgtatcggta ccccaggaca ctggctgagt tccagactga cagccagggc gtgcagccct tcagctcgct gttcccgaag cgggatggca aatacgcotg ggccatgttc gtcctcctcc ccccggccct gttcatcccg tctgccagag ctgtccccag gaatgtccag gtctggatca atgttcatga catcttctat ctctgctttc tccgcgccaa tgaatgcaag gccgttttaa aatcccaggg ctacgattgg cagagcctga cgaatgctgt cgactcatcg tgttcattgg tcggcccccc cactcagcca ggcaggaagc cagccttccc cagtgactgc gttggcttat tcaggcagca gatttactga accaggggtt ggccacctac ggcccacagg ataaagtttt attggcactg agccacagcc tttgtgctgc agcagcagaa ctgggtagtc ttactgtcta gccctttgta gaaacatttg attgttcact gtaaataaag aaaaaggaaa aggcagtatt ccagaaacag ttagaggtgc agatcctagt c

120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 1620 1680 1740 1800 I860 1920 1980 2040 2100 2160 2220 2280 2340 2400 2411 <210> <211> <212> <213> <400>

892 PRT Homo 27 sapiens

Met Arg Lys val Lys Lys Leu Arg Leu Asp Lys Glu Asn Thr Gly Ser 15 10 15

WO 02/31134

Glu Gly Ala Glu Arg Met Ala Thr 25 30

Gly Asp Ala Ala Ala Thr Asp Asp 45

Lys His Ser Trp Asp Gly Leu Arg 60

Tyr Ser Gly Leu lie Val Asn Lys 75SO

Gin Lys Thr Asp Glu Ser Gly Pro 90

Gly Met Pro Tyr Gly Ser Arg Glu 105110

Pro Lys Lys Val Arg Lys Glu Ala 125

Met Leu Asp His Phe Gin Ala Thr 140

Glu Glu Glu Leu Leu Arg Glu Arg 155160

Thr Ser Tyr Asp Phe His Ser Glu 170175

Ser Asn Ser Leu Phe His Cys Arg 185190

Val Ser Pro Met Lys Pro Leu Glu 205

Arg Met Asp Pro Lys lie Cys Pro 220 lie Asn Asn Ser Asp Leu Trp Val 235

Arg Arg Leu Thr Phe Cys His Gin 250255

Pro Lys Ser Ala Gly Val Ala Thr 265270

Arg Phe Thr Gly Tyr Trp Trp Cys 285

Glu Gly Leu Lys Thr Leu Arg lie 300

Glu Val Glu Val He His Val Pro 315

Thr Asp Ser Tyr Arg Tyr Pro Arg 330

Ala Leu Lys Leu Ala Glu Phe Gin 345350

Ser Thr Gin Glu Lys Glu Leu Val 365

Lys Val Glu Tyr He Ala Arg Ala 380

Ala Trp Ala Met Phe Leu Asp Arg 395

Leu Leu Pro Pro Ala Leu Phe lie 410

Arg Leu Ala Ser Ala Arg Ala Val 425

Val Tyr Glu Glu Val Thr Asn Val 445

Tyr Pro Phe Pro Gin Ser Glu Gly 460

Ala Asn Glu cys Lys Thr Gly Phe 475 ⁴⁸⁰

Val Leu Lys Ser Gin Gly Tyr Asp 490 ⁴⁹⁵

Trp Arg Ser Phe Ser Leu Asn Ser 20

Thr Gly Thr Pro Thr Ala Asp Arg 35

Pro Ala Ala Arg Phe Gin Val Gin 5055

Ser He He His Gly Ser Arg Lys

Ala Pro His Asp Phe Gin Phe Val 85

His Ser His Arg Leu Tyr Tyr Leu 100

Asn Ser Leu Leu Tyr Ser Glu lie

115120

Leu Leu Leu Leu Ser Trp Lys Gin

Pro His His Gly Val Tyr Ser Arg

145 ¹⁵⁰

Lys Arg Leu Gly Val Phe Gly He 165

Ser Gly Leu Phe Leu Phe Gin Ala 180

Asp Gly Gly Lys Asn Gly Phe Met

195200

He Lys Thr Gin Cys Ser Gly Pro

Ala Asp Pro Ala Phe Phe Ser Phe

Ala Asn He Glu Thr Gly Glu Glu 245

Gly Leu Ser Asn val Leu Asp Asp 260

Phe Val He Gin Glu Glu Phe Asp

275280

Pro Thr Ala Ser Trp Glu Gly Ser

Leu Tyr Glu Glu Val Asp Glu Ser

Ser Pro Ala Leu Glu Glu Arg Lys 325

Thr Gly Ser Lys Asn Pro Lys lie 340

Thr Asp Ser Gin Gly Lys He Val 355

Gin Pro Phe Ser Ser Leu Phe Pro 370 ³⁷⁵

Gly Trp Thr Arg Asp Gly Lys Tyr 385

Pro Gin Gin Trp Leu Gin Leu Val 405 . Pro Ser Thr Glu Asn Glu Glu Gin 420

Pro Arg Asn Val Gin Pro Tyr val 435

Trp He Asn Val His Asp lie Phe 450«5

Glu Asp Glu Leu Cys Phe Leu Arg 465

Cys His Leu Tyr Lys val Thr Ala 485

WO 02/31134

Pro Gly Glu Asp Glu 505

Thr Ser Gly Glu Trp 520

Val Asn Glu Glu Thr 535

Pro Leu Glu His His 555 lie Val Arg Leu Thr 570

Gin Asn Phe Asp Met 585

Pro Cys Val His val 600

His Lys Gin Pro Arg 615

Pro Pro Asp Tyr Val 635

Asp Val Arg Leu Tyr 650

Gly Lys Lys His Pro 665

Gin Leu Val Asn Asn 680

Thr Leu Ala Ser Leu 695

Ser Cys Gin Arg Gly 715

Gly Gin val Glu He 730

Glu Lys Tyr Gly Phe 745

Ser Tyr Gly Gly Phe 760

Val Phe Lys Val Ala 775

Tyr Asp Thr Gly Tyr 795

Gin His Gly Tyr Glu 810

Pro Asn Glu Pro Asn 825

Asn Val His Phe Phe 840

Ala Gly Lys Pro Tyr 855

Trp

Lys

His

Gin 545 Tyr

His

Ser

Pro

Met 625 His

Pro

Tyr

Lys

Val 705 Ala

Gly val

Leu

Val 785 Asp

Leu

His

Val

Ser Glu Pro Phe Ser 500

Glu Glu He Ala Leu 515

Gly Ser Lys He Trp

Gly Thr Lys Asp Thr

Glu Ala Ala Gly Glu 565

Ser Cys Ser Met Ser 580

Ser val Ser Thr Pro 595

Asp Asp Asp Pro Leu

Glu Ala Ala Ser Cys

Phe His Thr Arg Ser

His Ala Leu Gin Pro 660

Gly Gly Pro Gin Val 675

Tyr Leu Arg Leu Asn

He Asp Gly Arg Gly

Leu Lys Asn Gin Met 725

Leu Gin Phe Val Ala 740

Ala lie His Gly Trp 755 lie His Lys Pro Gin

Thr Val Trp Met Ala

Val Pro Glu Asn Asn

His Val Glu Lys Leu 820

Gly Phe Leu Asp Glii 835

Ser Gin Leu lie Arg

Phe Lys Cys Pro He 510

Glu Val Leu Ala Arg

Lys Leu Val Tyr Phe

Leu Tyr Val Val Ser

Thr Pro Gly Phe Ser

Phe Val Ser His Tyr

Tyr Lys Leu Ser Gly 605

Phe Trp Ala Ser Met

Pro Pro Glu He Phe

Gly Met He Tyr Lys 655

Thr Val Leu Phe Val 670

Ser Phe Lys Gly He 685

Gly Tyr Ala Val Val

Leu Arg Phe Glu Gly

Glu Asp Gin Val Glu 735

He Asp Leu Ser Arg

Leu Ser Leu Met Gly 765

He Ala Gly Ala pro

Thr Glu Arg Tyr Met

Ala Gly Ser Val Ala 815

Arg Leu Leu He Leu 830

His Thr Asn Phe Leu 845

Gin Leu Gin He Tyr 860

WO 02/31134

Pro Asn Glu Arg His Ser He Arg Cys Pro Glu Ser Gly Glu His Tyr ₈₆₅ 870 875 880

Glu Val Thr Leu Leu His Phe Leu Gin Glu Tyr Leu

885 890 <210> 28 <211> 4219 <212 > DNA <213> Homo sapiens <400> 28 caggccgccg cctgggtcgc tcaacttccg ggtcaaaggt gcctgagccg gcgggtcccc tgtgtccgcc gcggctgtcg tcccccgctc ccgccacttc cggggtcgca gtcccgggca tggagccgcg aacgtgaggc gccgctggac ccgggacgac ctgcccagtc cggccgccgc cccacgtccc ggtctgtgtc ccacgcctgc agctggaatg gaggctctot ggacccttta gaaggcaccc ctgccctcot gaggtcagct gagcggttaa tgcggaaggt taagaaactg cgcctggaca aggagaacac cggaagttgg agaagcttct cgctgaattc cgagggggct aagaggatgg ccaccaccgg gaccccaacg gccgaccgag gcgacgcagc cgccacagat gacccggccg cccgcttcca ggtgcagaag cactcgtggg acgggctccg gagcatcatc cacggcagco gcaagtactc gggcctcatt gtcaacaagg cgccccacga cttccagttt gtgcagaaga cggatgagtc tgggocccac tcccaccgcc tctactacct gggaatgcca f._atg_gcag_C0 gagagaactc cctcctctac tctgagattc ccaagaaggt ccggaaagag gctctgctgc tcctgtcctg gaagcagatg ctggatoatt tccaggccac gccccaccat ggggtctact ctcgggagga ggagctgctg agggagcgga aacgcctggg ggtcttcggc atcacotcct acgacttcca cagcgagagt ggcctcttcc tcttccaggo cagcaacagc ctcttccact gccgcgacgg cggcaagaac ggcttcatgg tgtcccctat gaaaccgctg gaaatcaaga cccagtgctc agggccccgg atggacccca aaatctgccc tgccgaccct gocttcttct ccttcataaa taacagcgac ctgtgggtgg ccaacatcga gacaggcgag gagcggcggc tgaccttctg ccaccaaggt ttatccaatg toctggatga ccccaagtct gcgggtgtgg ccaccttcgt catacaggaa gagttcgacc gottcactgg gtactggtgg tgccccacag cctcotggga aggttcagag ggcctcaaga cgctgcgaat cctgtatgag gaagtcgatg agtccgaggt ggaggtcatt cacgtcccct ctcctgcgct agaagaaagg aagacggact cgtatcggta ccccaggaca ggcagcaaga atcccaagat tgccttgaaa ctggctgagt tccagactga cagccagggc aagatcgtct cgacccagga gaaggagctg gtgcagccct tcagctcgct gttcccgaag gtggagtaca tcgccagggc cgggtggacc cgggatggca aatacgcctg ggccatgttc ctggaccggc cccagcagtg gotccagctc gtcctcctcc ccccggocct gttcatcccg agcacagaga atgaggagca gcggotagcc tctgccagag ctgtccccag gaatgtccag ccgtatgtgg tgtacgagga ggtcaccaac gtctggatca atgttcatga catcttctat cccttccccc aatcagaggg agaggacgag ctctgctttc tccgogccaa tgaatgcaag accggcttct gccatttgta caaagtcacc gccgttttaa aatcccaggg ctacgattgg agtgagccct tcagccccgg ggaagatgaa tttaagtgcc ccattaagga agagattgct ctgaccagcg gtgaatggga ggttttggcg aggcacggct ccaagatctg ggtcaatgag gagaccaagc tggtgtactt ccagggcacc aaggacacgc cgctggagca ccacctctac gtggtcagct atgaggcggc cggcgagatc gtacgcctca ccacgcccgg cttctcccat agctgctcca tgagccagaa cttcgacatg ttcgtcagcc actacagcag cgtgagcacg ccgccctgcg tgcacgtcta caagctgagc ggccccgacg acgaccccct gcacaagcag ccccgcttct gggctagcat gatggaggca gccagctgoc ccccggatta tgttcctcca gagatcttcc atttccaoac gcgctcggat gtgcggctct acggcatgat ctacaagcco oacgccttgc agccagggaa gaagcacccc accgtcctct ttgtatatgg aggcccccag gtgcagctgg tgaataactc cttcaaaggc atcaagtact tgcggctcaa cacactggcc tccctgggct acgccgtggt tgtgattgac ggcaggggct cctgtcagcg agggcttcgg ttcgaagggg ccctgaaaaa ccaaatgggc caggtggaga tcgaggaoca ggtggagggc ctgcagttcg tggcegagaa gtatggcttc atcgacctga gccgagttgc catccatggc tggtoctacg ggggcttoct ctcgctcatg gggctaatcc acaagcccca ggtgttcaag gtggccatcg cgggtgcccc ggtcaccgtc tggatggcct acgacacagg gtacactgag cgctacatgg acgtccctga gaacaaccag cacggctatg aggcgggttc cgtggccctg cacgtggaga agctgcccaa tgagcccaac cgcttgctta taotccacgg cttcctggac gaaaacgtgc actttttcca cacaaacttc ctcgtctccc aftSflgatccg agcagggaaa ccttaccagc tccagatcta ccccaacgag agacacagta ttcgctgcco cgagtcgggc gagcactatg aagtcacgtt gctgcacttt

120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 1620 1680 1740 1800 1860 1920 1980 2040 2100 2160 2220 2280 2340 2400 2460 2520 2580 2640 2700 2760 2820 28.80 2940

PCT7US01/31874

WO 02/31134 ggagccgcca catcacagca caagtggctg ctgagtggcc cgcgggcccc agtgaggcac ggagccgctg ccttcaccgc cccgacgcct atgtccgctg cttcttggtt gccgagacag ctccccgcct tctgggagga ggaggtcaca actcagagga gcgggctgcc ttccgcctgg cggccagcca ccgtccccag cacccaagca cccaacttga tgtttgtgtt ttgtttgggg gccgggcgcg gtggctcacg tctgtaatcc cacctgaggt tgggagttca agaccagcct aaaatacaaa aaattagccg ggtgtggtgg gctgaggcag gagaatcgct tgaacccggg ccattgcact ccagcctggg caacaagagc aaagacagaa agcaaggggt gcctaaatct tgcaacccag cacctggtag gctccatttc aaacgcaccg aacttccacg ctctgctggt cgcccagcca catgtgtctg cctgacccgt aaccatcccc acctcagggt tatatttccc ccaggggcgg gcaaaaaaaa aagtaaaaag cctctacata ttatggaaag aaaatatttt tggaagaagt agacacatta aacgattcca ctacaggaat acctctgagc ctgcccaccg cagcctccgc ggggaaccag gcgggaggga tttgtcccgc ccagcgctgg ccagccccga tttatccttt tttaaacgct cttgggtttt agagatggtg gtctcgggcc agcccctcct cgctgatggg cactggagag gccagaagag ggctccctgt gacctctcag tcccctggcc tgcaattgcc tgtccccccc ggccagcctc ggatattttt cataattatt taaaagacag cagcactttg ggaggctgag gcgggcggat ggccaacatg gggaaacccc gtctctaota cgcgtgccta taatcccagc tactcgggag aggtggaggt tgcggtgagc caagatcgca gaaactctgt ctcaaaataa ataaaaaata agacttgggg tccacaccgg gcagcggggt ttcccaagcc cgactttcag gcaggcactg cagtggcggc tgtcccctcc ccagcccagc acacaccagg ggttccgggg ttgggagctg tctccccttc cctccccgcc aagagctctg aaaagaaaaa aaaaaaaaag aaacaaacca tgtcgattct tattctttta taattatgcg gttggaaaca tgtcacctg

3000 3060 3120 31B0 3240 3300 3360 3420 3480 3540

3600 3660 3720 3780 3840 3900 3960 4020 4080 4140 4200 4219 <210> 29 <211> 832 <212> PRT <213> Homo sapiens <400> 29

Met Arg Lys Val Lys Lys Leu Arg Leu Asp Lys Glu Asn Thr Gly Ser , 5 1015

Trp Arg Ser Phe Ser Leu Asn Ser Glu Gly Ala Glu Arg Met AlaThr ²⁵30

Thr Gly Thr Pro Thr Ala Asp Arg Gly Asp Ala Ala Ala Thr Asp Asp 35

Pro-Ala Ala Arg Phe Gin Val Gin Lys His Ser Trp Asp Gly Leu Arg 50 ⁵⁵⁶⁰

Ser He lie His Gly Ser Arg Lys Tyr Ser Gly Leu lie Val Asn Lys 65

Ala Pro His Asp Phe Gin Phe Val Gin Lys Thr Asp Glu Ser Gly Pro 85 ⁹⁰⁹⁵

His Ser His Arg Leu Tyr Tyr Leu Gly Met Pro Tyr Gly Ser Arg Glu 100 105110

Asn Ser Leu Leu Tyr Ser Glu He Pro Lys Lys Val Arg Lys Glu Ala !15 120125

Leu Leu Leu Leu Ser Trp Lys Gin Met Leu Asp His Phe Gin Ala Thr 130 I^{35 140}

Pro His His Gly Val Tyr Ser Arg Glu Glu Glu Leu Leu Arg GluArg

145 150 II’O

Lys Arg Leu Gly Val Phe Gly He Thr Sar Tyr Asp Phe His SerGlu

16s !¹⁷⁵סד

Ser Gly Leu Phe Leu Phe Gin Ala Ser Asn Ser Leu Phe His Cya Arg !80 1853-90

Asp Gly Gly Lys Asn Gly Phe Met Val Ser Pro Met Lys Pro Leu Glu 195 200205

He Lys Thr Gin Cys Ser Gly Pro Arg Met Asp Pro Lys He Cys Pro 210 215220

Ala Asp Pro Ala Phe Phe Ser Phe He Asn Asn Ser Asp Leu Trp Val

Ala Asn lie Glu Thr Gly Glu Glu Arg Arg Leu Thr Phe Cys His Gin

WO 02/31134

250 255

Pro Lys Ser Ala Gly Val Ala Thr 265 270

Arg Phe Thr Gly Tyr Trp Trp Cys 285

Glu Gly Leu Lys Thr Leu Arg He 300

Glu Val Glu Val He His Val Pro 315320

Thr Asp Ser Tyr Arg Tyr Pro Arg 330335

Ala Leu Lys Leu Ala Glu Phe Gin 345350

Ser Thr Gin Glu Lys Glu Leu Val 365

Lys val Glu Tyr lie Ala Arg Ala 380

Ala Trp Ala Met Phe Leu Asp Arg 395400

Leu Leu Pro Pro Ala Leu Phe lie 410415

Arg Leu Ala Ser Ala Arg Ala Val 425430

Val Tyr Glu Glu Val Thr Asn Val 445

Tyr Pro Phe Pro Gin Ser Glu Gly 460

Ala Asn Glu Cys Lys Thr Gly Phe 475480

Val Leu Lys Ser Gin Gly Tyr Asp 490495

Glu Asp Glu Phe Lys Cys Pro lie 505510

Gly Glu Trp Glu val Leu Ala Arg 525

Glu Glu Thr Lys Leu Val Tyr Phe 540

Glu His His Leu Tyr Val Val Ser 555560

Arg Leu Thr Thr Pro Gly Phe Ser 570575

Phe Asp Met Phe Val Ser His Tyr 585590

Val His Val Tyr Lys Leu Ser Gly 605

Gin Pro Arg Phe Trp Ala Ser Met 620

Asp Tyr Val Pro Pro Glu He Phe 635640

Arg Leu Tyr Gly Met He Tyr Lys 650655

Lys His Pro Thr Val Leu Phe Val 665670

Val Asn Asn Ser Phe Lys Gly He 685

Ala Ser Leu Gly Tyr Ala val val 700

Gin Arg Gly Leu Arg Phe Glu Gly 715 ⁷²°

Val Glu lie Glu Asp Gin Val Glu

Gly Leu Ser Asn Vai Leu Asp Asp 260

Phe Vai He Gin Glu Glu Phe Asp

275280 pro Thr Ala Ser Trp Glu Gly Ser 290 ²⁹⁵

Leu Tyr Glu Glu Vai Asp Glu Ser

305310

Ser Pro Ala Leu Glu Glu Arg Lys

Thr Gly Ser Lys Asn Pro Lys He 340

Thr Asp Ser Gin Gly Lys lie Vai

355360

Gin Pro Phe Ser Ser Leu Phe Pro

Gly Trp Thr Arg Asp Gly Lys Tyr 3B5390 pro Gin Gin Trp Leu Gin Leu Vai 405

Pro Ser Thr Glu Asn Glu Glu Gin 420 pro Arg Asn Vai Gin Pro Tyr Vai

43s440

Trp He Asn Vai His Asp He Phe 450455

Glu Asp Glu Leu Cys Phe Leu Arg 465470

Cys His Leu Tyr Lys Vai Thr Ala 485

Trp Ser Glu Pro Phe Ser Pro Gly 500

Lys Glu Glu lie Ala Leu Thr Ser

515520

His Gly Ser Lys lie Trp Vai Asn 530535

Gin Gly Thr Lys Asp Thr Pro Leu 545550

Tyr Glu Ala Ala Gly Glu He Vai

His Ser Cys Ser Met Ser Gin Asn 580

Ser Ser Vai Ser Thr Pro Pro Cys

595600

Pro Asp Asp Asp Pro Leu His Lys 610615

Met Glu Ala Ala Ser Cys Pro Pro 625630

His Phe His Thr Arg Ser Asp Vai

645 pro His Ala Leu Gin Pro Gly Lys

Tyr Gly Gly Pro Gin Vai Gin Leu

675680

Lys Tyr Leu Arg Leu Asn Thr Leu

690695 val He Asp Gly Arg Gly Ser Cys 70571°

Ala Leu Lys Asn Gin Met Gly Gin

WO 02/31134

Gly Leu Gin Phe Val Ala 740

Val Ala He His Gly Trp 755

Leu lie His Lys Pro Gin 770

Pro Arg Leu Pro Gly Arg 705 790

Arg Leu Pro Thr Asp Pro Θ05

Pro Gin Arg Glu Thr Gin 820

Glu Lys Tyr Gly Phe lie 745

Ser Tyr Gly Gly Phe Leu

Val Phe Lys Ala Gin Pro

775 780

Lys Arg Ala Leu Phe Pro

Ser Arg Glu Thr Leu Pro

Tyr Ser Leu Pro Arg val

Asp Leu Ser Arg 750

Ser Leu Met Gly

Leu Ala Tyr Pro

His Lys Leu Pro

Ala Pro Asp I!eu

Gly Arg Ala Leu <210> 30 <211> 4159 <212> DNA <213> Homo sapiens <400> 30 caggccgccg cctgggtcgc tcaacttccg ggtcaaaggt gcctgagccg gcgggtcccc tgtgtccgcc gcggctgtcg tcccccgctc ccgccacttc cggggtcgca gtcccgggca tggagccgcg accgtgaggo gccgctggac ccgggacgac ctgcccagtc cggccgocgc cccacgtccc ggtctgtgtc ccacgcctgc agctggaatg gaggctctct ggacccttta gaaggcaccc ctgccctcct gaggtaagct gagcggttaa tgcggaaggt taagaaactg cgcctggaca aggagaacac cggaagttgg agaagcttct cgctgaattc cgagggggct gagaggatgg ccaccaccgg gaccccaacg gccgaccgag gcgacgcagc cgccacagat gacccggccg cccgcttcca ggtgcagaag cactcgtggg acgggctccg gagcatcatc cacggcagco gcaagtactc gggcctcatt gtcaacaagg cgccccacga cttccagttt gtgcagaaga cggatgagtc tgggccccac tcccaccgcc tctactacct gggaatgcca tatggcagcc gagagaactc cctcctctac tctgagattc ccaagaaggt ccggaaagag gctctgotgc tcctgtcctg gaagcagatg ctggatcatt tccaggccac gccccaccat ggggtctact ctcgggagga ggagctgotg agggagcgga aacgcctggg ggtcttcggc atcacctcot acgacttcca cagcgagagt ggcctcttcc tcttccaggc cagcaacagc ctcttccact gccgcgacgg cggcaagaac ggcttcatgg tgtcccctat gaaaccgctg gaaatcaaga cccagtgcto agggccocgg atggacccca aaatctgccc tgccgaooct gccttcttct ccttcatcaa taacagcgac ctgtgggtgg coaacatcga gacaggcgag gagcggcggc tgaccttctg ccaccaaggt ttatccaatg tcctggatga ccccaagtct gcgggtgtgg ccacottcgt catacaggaa gagttcgacc gcttcaotgg gtaatggtgg tgccccacag cctcctggga aggttcagag ggcctoaaga cgctgcgaat cctgtatgag gaagtcgatg agtccgaggt ggaggtcatt cacgtcccct ctcctgcgct agaagaaagg aagacggact cgtatcggta ccccaggaca ggcagcaaga atcccaagat tgccttgaaa ctggctgagt tccagactga cagooagggc aagatcgtct cgacccagga gaaggagctg gtgcagccct tcagctcgct gttcccgaag gtggagtaca tcgccagggc cgggtggacc cgggatggca aatacgcctg ggccatgttc ctggaccggc cccagcagtg gctccagctc gtcctcctcc ccccggccct gttcatcccg agcacagaga atgaggagca gcggctagco tctgccagag ctgtccccag gaatgtccag ccgtatgtgg tgtacgagga ggtcaccaac gtctggatca atgttcatga catcttctat cccttccccc aatcagaggg agaggacgag ctctgctttc tccgcgccaa tgaatgcaag accggcttct gccatttgta caaagtcacc gccgttttaa aatcccaggg ctacgattgg agtgagccct tcagooccgg ggaagatgaa tttaagtgcc ccattaagga agagattgct ctgaccagcg gtgaatggga ggttttggcg aggcacggct ccaagatctg ggtcaatgag gagaccaagc tggtgtactt ccagggoacc aaggacacgc cgctggagca ccacctctac gtggtcagct atgaggcggc cggcgagatc gtacgcctca ccacgcocgg ottctcccat agctgctcca tgagccagaa cttcgacatg ttcgtcagcc actacagcag cgtgagcacg ccgccctgcg tgcacgtcta caagctgagc ggccccgacg acgaccccct gcacaagcag ccocgcttct gggctagcat gatggaggca gccagctgcc ccccggatta tgttcctcca gagatcttcc atttccacac gcgctcggat gtgcggctct acggcatgat ctacaagccc cacgccttgc agccagggaa gaagcacccc accgtcctct ttgtatatgg aggcocccag gtgcagctgg tgaataacto cttcaaaggc atcaagtact tgcggctcaa cacactggcc tccctgggct acgccgtggt tgtgattgac

120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 1620 1680 1740 1800 1860 1920 1980 2040 2100 2160 2220 2280 2340 2400

WO 02/31134 ttcgaagggg ccctgaaaaa ccaaatgggc ctgcagttcg tggccgagaa gtatggcttc tggtcctacg ggggcttcct ctcgctcatg gcccaaccgc ttgcttatcc tccacggctt aaacttcctc gtctcccaac tgatccgagc caacgagaga cacagtattc gctgccccga gcactttcta caggaatacc tctgagcctg gtggotgcag cctccgcggg gaaccaggcg gaggcacttt gtcccgccca gcgctggcca gacgcctttt atcctttttt aaacgctctt gagacagaga gatggtggtc tcgggocagc ggtcacacgc tgatgggcac tggagaggcc cgcctggggc tccctgtgac ctctcagtcc ccaagcatgc aattgcctgt cccccccggc tttgggggga tatttttcat aattatttaa gtaatcccag cactttggga ggctgaggcg ccagcctggc caacatgggg aaaocccgtc gtggtggcgc gtgcctataa tcccagctac acccgggagg tggaggttgc ggtgagccaa caagagcgaa actctgtctc aaaataaata taaatctaga cttggggtcc acaccgggca ccatttcttc ccaagcccga gcagagggtc cccgcggggg gcaccacctg tggacagccc aaacgcaccg aacttccacg ctctgctggt cgcccagcca catgtgtctg cctgacocgt aaccatcccc acctcagggt tatatttccc ocaggggcgg gcaaaaaaaa aagtaaaaag cctctacata ttatggaaag aaaatatttt tggaagaagt agacaoatta aacgattcca ggcaggggct cctgtcagcg agggcttcgg caggtggaga tcgaggacca ggtggagggc atogacctga gccgagttgc catccatggc gggctaatcc acaagoccca ggtgttcaag cctggacgaa aacgtgcact ttttccacac agggaaacct taccagctcc agatctaccc gtcgggcgag cactatgaag tcacgttgct cccaccggga gccgccacat cacagcacaa ggagggactg agtggccogc gggccccagt gccccgagga gccgctgcct tcaccgcccc gggttttatg tccgctgctt cttggttgcc ccctcctctc cccgccttct gggaggagga agaagagact cagaggagcg ggctgccttc cctggcccgg ccagccaccg tccocagcac cagcctcccc aacttgatgt ttgtgttttg aagacaggcc gggcgcggtg gctcacgtct ggcggatcac ctgaggttgg gagttcaaga tctactaaaa atacaaaaaa ttagccgggt tcgggaggct gaggcaggag aatcgcttga gatcgcacca ttgcactcca gcctgggcaa aaaaataaaa gacagaaagc aaggggtgcc gcggggttgc aacccagcac ctggtaggct atgcgggccc cacaggagaa gcggccaggg tcctgtcccc aagctttcag gcaggcactg cagtggcggc tgtcccctcc ccagoccagc acacaccagg ggttccgggg ttgggagctg tctccccttc cctccccgcc aagagctctg aaaagaaaaa aaaaaaaaag aaacaaacca tgtcgattct tattctttta taattatgcg gttggaaaca tgtcacctg

2460 2520 2580 2640 2700 2760 2820 2880 2940 3000 3060 3120 3180 3240 3300 3360 3420 3480 3540 3600 3660 3720 3780 3840 3900 3960 4020 4080 4140 4159 <210> 31 <211> 832 <212> PRT <213> Homo sapiens <400> 31

Leu Asp Lys Glu Asn Thr Gly Ser 10 ¹⁵

Glu Gly Ala Glu Arg Met Ala Thr 25 ³⁰

Gly Asp Ala Ala Ala Thr Asp Asp 45

Lys His Ser Trp Asp Gly Leu Arg 60

Tyr Ser Gly Leu lie Val Asn Lys

80 ₇₅׳

Gin Lys Thr Asp Glu Ser Gly Pro 9055

Gly Met Pro Tyr Gly Ser Arg Glu 1052.10

Pro Lys Lys Val Arg Lys Glu Ala 125

Met Leu Asp His Phe Gin Ala Thr 140

Glu Glu Glu Leu Leu Arg Glu Arg 155 ¹⁶⁰

Thr Ser Tyr Asp Phe His Ser Glu

⁵י1 170

Ser Asn Ser Leu Phe His Cys Arg

Met Arg Lys Val Lys Lys Leu Arg 1 ⁵

Trp Arg Ser Phe Ser Leu Asn Ser 20

Thr Gly Thr Pro Thr Ala Asp Arg 3540

Pro Ala Ala Arg Phe Gin val Gin 50 ser He He His Gly Ser Arg Lys 65

Ala Pro His Asp Phe Gin Phe Val 85

His Ser His Arg Leu Tyr Tyr Leu 100

Asn Ser Leu Leu Tyr Ser Glu He 115120

Leu Leu Leu Leu Ser Trp Lys Gin 130115 pro His His Gly val Tyr Ser Arg 14515°

Lys Arg Leu Gly Val Phe Gly lie 165

Ser Gly Leu Phe Leu Phe Gin Ala

WO 02/31134

185 150

Vai Ser Pro Met Lys Pro Leu Glu 205

Arg Met Asp Pro Lys lie Cys Pro 220

He Asn Asn Ser Asp Leu Trp Vai 235240

Arg Arg Leu Thr Phe Cys His Gin 250255

Pro Lys Ser Ala Gly Vai Ala Thr 26527o

Arg Phe Thr Gly Tyr Trp Trp Cys 285

Glu Gly Leu Lys Thr Leu Arg lie 300

Glu Vai Glu Vai He His Vai Pro 315320

Thr Asp Ser Tyr Arg Tyr Pro Arg 330 ³³³

Ala Leu Lys Leu Ala Glu Phe Gin 345350

Ser Thr Gin Glu Lys Glu Leu Vai 365

Lys val Glu Tyr He Ala Arg Ala 380

Ala Trp Ala Met Phe Leu Asp Arg 395400

Leu Leu Pro Pro Ala Leu Phe lie 410

Arg Leu Ala Ser Ala Arg Ala Val 425430

Val Tyr Glu Glu Val Thr Asn Val 445

Tyr Pro Phe Pro Gin Ser Glu Gly 460

Ala Asn Glu Cys Lya Thr Gly Phe 475

Val Leu Lya Ser Gin Gly Tyr Asp 490

Glu Asp Glu Phe Lys Cys Pro He 505510

Gly Glu Trp Glu Val Leu Ala Arg 525

Glu Glu Thr Lya Leu Val Tyr Phe 540

Glu His His Leu Tyr Val Val Ser 555

Arg Leu Thr Thr Pro Gly Phe Ser 570 .575

Phe Asp Met Phe Val Ser His Tyr 585590

Val His Val Tyr Lys Leu Ser Gly 605

Gin Pro Arg Phe Trp Ala Ser Met 620

Asp Tyr Val Pro Pro Glu He Phe 635 ³⁴⁸

Arg Leu Tyr Gly Met lie Tyr Lys 650 ³55

Lys His Pro Thr Val Leu Phe Val

Asp Gly Gly Lys Aan Gly Phe Met 195200

He Lys Thr Gin Cys Ser Gly Pro 210

Ala Asp Pro Ala Phe Phe Ser Phe 225230

Ala Asn He Glu Thr Gly Glu Glu 245

Gly Leu Ser Asn Vai Leu Asp Asp 260

Phe Vai He Gin Glu Glu Phe Asp 275

Pro Thr Ala Ser Trp Glu Gly Ser 290

Leu Tyr Glu Glu Vai Asp Glu Ser 305

Ser Pro Ala Leu Glu Glu Arg Lys 325

Thr Gly Ser Lys Asn Pro Lys He 340

Thr Asp Ser Gin Gly Lys He Vai

Gin Pro Phe Ser Ser Leu Phe Pro 370

Gly Trp Thr Arg Asp Gly Lys Tyr 385 pro Gin Gin Trp Leu Gin Leu Vai 405

Pro Ser Thr Glu Asn Glu Glu Gin 420

Pro Arg Asn Vai Gin Pro Tyr Vai 435

Trp He Asn Vai His Asp lie Phe 450

Glu Asp Glu Leu Cys Phe Leu Arg

Cys His Leu Tyr Lys Vai Thr Ala 485

Trp Ser Glu Pro Phe Ser Pro Gly 500

Lys Glu Glu lie Ala Leu Thr Ser 515

His Gly Ser Lys He Trp Vai Asn 530

Gin Gly Thr Lys Asp Thr Pro Leu

Tyr Glu Ala Ala Gly Glu lie Vai 565

His Ser Cys Ser Met Ser Gin Asn 580

Ser Ser Vai Ser Thr Pro Pro Cys 595600 pro Asp Asp Asp Pro Leu Hie Lya 610«15

Met Glu Ala Ala Ser Cys Pro Pro

Hia Phe His Thr Arg Ser Asp Vai 645

Pro His Ala Leu Gin Pro Gly Lys

WO 02/31134

Tyr Gly Gly Pro Gin Val Gin Leu 675680

Lys Tyr Leu Arg Leu Asn Thr Leu 690695

Val He Asp Gly Arg Gly Ser Cys 705710

Ala Leu Lys Asn Gin Met Gly Gin 725

Gly Leu Gin Phe Val Ala Glu Lys 740

Val Ala lie His Gly Trp Ser Tyr 755760

Leu He His Lys Pro Gin Val Phe 770775

Pro Arg Leu Pro Gly Arg Lys Arg 785790

Arg Leu Pro Thr Asp Pro Ser Arg 805

Pro Gin Arg Glu Thr Gin Tyr Ser 820

665 670 val Asn Asn Ser Phe Lys Gly lie 685

Ala Ser Leu Gly Tyr Ala Val Val 700

Gin Arg Gly Leu Arg Phe Glu Gly 715720

Val Glu He Glu Asp Gin Val Glu 730735

Tyr Gly Phe He Asp Leu Ser Arg 745750

Gly Gly Phe Leu Ser Leu Met Gly 765

Lys Ala Gin Pro Leu Ala Tyr Pro 780

Ala Leu Phe Pro His Lys Leu Pro 795800

Glu Thr Leu Pro Ala Pro Asp Leu 810815

Leu Pro Arg Val Gly Arg Ala Leu 825830 <210> 32 <211> 4076 <212> DNA <213> Homo sapiens <400> 32 caggccgccg cctgggtcgc tcaacttccg ggtcaaaggt gcctgagccg gcgggtcccc tgtgtccgcc gcggctgtcg tcccccgctc ccgccacttc cggggtcgca gtcccgggca tggagccgcg accgtgaggc gccgctggac ccgggacgac ctgcccagtc cggccgccgc cccacgtccc ggtctgtgtc ccacgcctgc agctggaatg gaggctctct ggacccttta gaaggcaccc ctgccctcct gaggtcagct gagcggttaa tgcggaaggt taagaaactg cgcctggaoa aggagaacac cggaagttgg agaagcttct cgctgaattc cgagggggct gagaggatgg ccaccaccgg gaccccaacg gccgaccgag gcgacgcagc cgccacagat gacccggccg cccgcttcca ggtgoagaag cactcgtggg acgggctccg gagcatcatc cacggcagco gcaagtactc gggcctcatt gtcaacaagg cgccccacga cttccagttt gtgcagaaga cggatgagtc tgggccccac tcccaccgcc tctactaoct gggaatgcca tatggcagcc gagagaactc cctcatctac tctgagattc ccaagaaggt ccggaaagag gctctgctgc tcctgtcctg gaagcagatg ctggatcatt tccaggccac gccccaccat ggggtctact ctcgggagga ggagctgctg agggagcgga aacgcctggg ggtcttcggc atcacctcct acgacttcca cagcgagagt ggcctcttcc tcttccaggc cagcaacagc ctcttccact gccgcgacgg cggcaagaac ggcttcatgg tgtcccctat gaaaccgctg gaaatcaaga cccagtgotc agggccccgg atggacccca aaatctgccc tgccgaccct gccttcttct ccttcatcaa taacagcgac ctgtgggtgg ccaacatcga gacaggcgag gagcggcggc tgaccttctg ccaccaaggt ttatccaatg tcctggatga ccccaagtct gcgggtgtgg ccaccttcgt catacaggaa gagttcgacc gcttcactgg gtactggtgg tgccccacag cctcctggga aggttcagag ggcctcaaga cgctgcgaat cctgtatgag gaagtcgatg agtccgaggt ggaggtcatt cacgtcccot ctcctgcgct agaagaaagg aagacggact cgtatcggta ccccaggaca ggcagcaaga atcccaagat tgccttgaaa ctggctgagt tccagactga cagccagggc aagatcgtct cgacccagga gaaggagctg gtgcagccot tcagctcgct gttcccgaag gtggagtaca tcgccaggge cgggtggacc cgggatggca aatacgcctg ggccatgttc ctggaccggc cccagcagtg gctccagctc gtcctcctcc ccccggccct gttcatcccg agcacagaga atgaggagca gcggctagcc tctgccagag ctgtccccag gaatgtccag ccgtatgtgg tgtacgagga ggtcaccaac gtctggatca atgttcatga catcttctat cccttccccc aatcagaggg agaggacgag ctctgctttc tccgcgccaa tgaatgcaag accggcttct gccatttgta caaagtcacc gccgttttaa aatcccaggg ctacgattgg agtgagccct tcagccccgg ggaagatgaa tttaagtgcc ccattaagga agagattgct ctgaccagcg gtgaatggga ggttttggog aggcacggct ccaagatctg ggtcaatgag gagaccaagc tggtgtactt ceagggcacc

120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 1620 1680 1740 1800 1860 1920

WO 02/31134 gtggtcagct atgaggcggc cggcgagatc agctgctcca tgagccagaa cttcgacatg ccgcoctgcg tgcacgtcta caagctgagc ccccgcttct gggctagcat gatggaggca gagatcttcc atttccacac gcgctcggat cacgccttgc agccagggaa gaagcacccc gtgcagctgg tgaataactc cttcaaaggc tccctgggct acgccgtggt tgtgattgac ttcgaagggg ccotgaaaaa ccaaatgggc ctgcagttcg tggccgagaa gtatggcttc tggtcctacg ggggcttcct ctcgctoatg gcccaaacgc ttgcttatcc tccacggctt aaacttcctc gtctoccaac tgatccgagc caacgagaga cacagtatto gctgcoocga gcactttcta caggaatacc tctgagcctg gtggctgcag cctccgcggg gaaccaggcg gaggcacttt gtcccgccca gcgctggcca gacgcctttt atcctttttt aaacgctctt gagacagaga gatggtggtc tcgggccagc ggtcacacgc tgatgggcac tggagaggcc cgcctggggc tccctgtgac ctctcagtcc ccaagcatgo aattgcctgt cccccccggc tttgggggga tatttttcat aattatttaa gtaatcccag cactttggga ggctgaggcg ccagcctggc caacatgggg aaaccccgtc gtggtggcgc gtgcctataa tcccagctac acccgggagg tggaggttgc ggtgagccaa caagagcgaa actctgtctc aaaataaata taaatctaga cttggggtcc acaccgggca ccatttcttc ccaagcccga ctttcaggca tgctggtcag tggcggctgt cccctcccca gacccgtaca caccaggggt tccggggttg atttccctct ccccttccct ccccgccaag taaaaagaaa agaaaaaaaa aaaaaagaaa atatttttgt cgattcttat tcttttataa gattccagtt ggaaacatgt cacctg aaggacacgc cgctggagca ccacctctac gtacgcctca ccacgcccgg cttctcccat ttcgtcagcc actacagcag cgtgagcacg ggccccgacg acgaccccct gcacaagcag gccagctgcc ccccggatta tgttcctcca gtgcggctct acggcatgat ctacaagccc accgtcctct ttgtatatgg aggcccccag atcaagtact tgcggctoaa cacactggcc ggcaggggct cctgtcagcg agggcttcgg caggtggaga tcgaggacca ggtggagggc atcgacctga gccgagttgc catccatggc gggctaatcc acaagcccca ggtgttcaag cctggacgaa aacgtgcact ttttccacac agggaaacct taccagctcc agatctaccc gtcgggcgag cactatgaag tcacgttgct cccaccggga gccgccacat cacagcacaa ggagggactg agtggcccgc gggccccagt gccccgagga gccgctgcct tcaccgcccc gggttttatg tccgctgctt cttggttgcc ccctcctctc cccgccttct gggaggagga agaagagact cagaggagcg ggctgccttc cctggcccgg ccagccaccg tccccagcac cagcctcccc aacttgatgt ttgtgttttg aagacaggcc gggcgcggtg gctcacgtct ggcggatcac ctgaggttgg gagttcaaga tctactaaaa atacaaaaaa ttagccgggt tcgggaggct gaggcaggag aatcgcttga gatcgcacca ttgcactcca gcctgggcaa aaaaataaaa gacagaaagc aaggggtgcc gcggggttgc aacccagcac ctggtaggct ggcactgaaa cgcaocgaac ttccacgctc gcccagccgc ccagccacat gtgtctgcct ggagctgaao catccccacc tcagggttat agctctgcca ggggcgggca aaaaaaaaag caaaccacct ctacatatta tggaaagaaa ttatgcgtgg aagaagtaga cacattaaac <210> 33 <211> 879 <212> PRT <213> Homo sapiens <400> 33

Met Arg Lys Val Lys Lys Leu Arg 15

Trp Arg Ser Phe Ser Leu Asn Ser 20

Thr Gly Thr Pro Thr Ala Asp Arg 35&lt;0 pro Ala Ala Arg Phe Gin Val Gin 50

Ser He He His Gly Ser Arg Lys 6570

Ala Pro His Asp Phe Gin Phe Val 85

His Ser His Arg Leu Tyr Tyr Leu 100

Asn Ser Leu Leu Tyr Ser Glu He 115 120

Leu Leu Leu Leu Ser Trp Lys Gin

Leu Asp Lys Glu Asn Thr Gly Ser

15

Glu Gly Ala Glu Arg Met Ala Thr

30

Gly Asp Ala Ala Ala Thr Asp Asp 45

Lys His Ser Trp Asp Gly Leu Arg 60

Tyr ser Gly Leu lie Val Asn Lys

750°

Gin Lys Thr Asp Glu Ser Gly Pro 9095

Gly Met Pro Tyr Gly Ser Arg Glu

10511°

Pro Lys Lys Val Arg Lys Glu Ala

Met Leu Asp His Phe Gin Ala Thr

1980 2040 2100 2160 2220 2280 2340

2400 2460 2520 2580 2640 2700 2760

2820 2880 2940 3000 3060 3120 3180

3240 3300 3360

3420 3480 3540 3600 3660 3720 3780

3840 3900 3960

4020 ׳ 4076

WO 02/31134

Glu Glu Glu Leu Leu Arg Glu Arg

155160

Thr Ser Tyr Asp Phe His Ser Glu

170175

Ser Asn Ser Leu Phe His Cys Arg 185190

Val Ser Pro Met Lys Pro Leu Glu 205

Arg Met Asp Pro Lys lie Cys Pro 220

He Asn Asn Ser Asp Leu Trp Val

235240

Arg Arg Leu Thr Phe Cys His Gin

250255

Pro Lys Ser Ala Gly Val Ala Thr

265270

Arg Phe Thr Gly Tyr Trp Trp Cys 285

Glu Gly Leu Lys Thr Leu Arg He 300

Glu Val Glu Val He His Val Pro

315320

Thr Asp Ser Tyr Arg Tyr Pro Arg

330335

Ala Leu Lys Leu Ala Glu Phe Gin

345350

Ser Thr Gin Glu Lys Glu Leu Val

Lys Val Glu Tyr He Ala Arg Ala 380

Ala Trp Ala Met Phe Leu Asp Arg

395400

Leu Leu Pro Pro Ala Leu Phe He 410415

Arg Leu Ala Ser Ala Arg Ala Val

425430

Val Tyr Glu Glu val Thr Asn Val

Tyr Pro Phe Pro Gin Ser Glu Gly 460

Ala Asn Glu Cys Lys Thr Gly Phe

475480

Val Leu Lys Ser Gin Gly Tyr Asp

490495

Glu Asp Glu Phe Lys Cys Pro lie

505510

Gly Glu Trp Glu Val Leu Ala Arg 525

Thr Pro Leu Glu His His Leu Tyr 540

Glu lie Val Arg Leu Thr Thr Pro

555 560

130 ¹³⁵ pro His His Gly Val Tyr Ser Arg 145 ¹⁵⁰

Lys Arg Leu Gly Val Phe Gly He 165

Ser Gly Leu Phe Leu Phe Gin Ala 180

Asp Gly Gly Lys Asn Gly Phe Met 195200 lie Lys Thr Gin cys Ser Gly Pro 210215

Ala Asp Pro Ala Phe Phe Ser Phe 225230

Ala Asn He Glu Thr Gly Glu Glu 245

Gly Leu Ser Asn Val Leu Asp Asp 260

Phe Val He Gin Glu Glu Phe Asp 275280

Pro Thr Ala Ser Trp Glu Gly Ser 290295

Leu Tyr Glu Glu Val Asp Glu Ser 305 ³¹⁰

Ser Pro Ala Leu Glu Glu Arg Lys 325

Thr Gly Ser Lys Asn Pro Lys He 340

Thr Asp Ser Gin Gly Lys He Val 355360

Gin Pro Phe Ser Ser Leu Phe Pro 370375

Gly Trp Thr Arg Asp Gly Lys Tyr 385390

Pro Gin Gin Trp Leu Gin Leu Val 405

Pro Ser Thr Glu Asn Glu Glu Gin 420

Pro Arg Asn val Gin Pro Tyr Val 435

Trp lie Asn Val His Asp He Phe 450455

Glu Asp Glu Leu Cys Phe Leu Arg 465

Cys His Leu Tyr Lys Val Thr Ala 485

Trp Ser Glu Pro Phe Ser Pro Gly 500

Lys Glu Glu lie Ala Leu Thr Ser 515520

His Gly Ser Lys Gly Thr Lys Asp 530535

Val Val Ser Tyr Glu Ala Ala Gly 545550

WO 02/31134

Ser Gin Asn Phe Asp Met Phe Val 570 575

Pro Pro Cys Val His Val Tyr Lys 585 590

Leu His Lys Gin Pro Arg Phe Trp 605

Cys Pro Pro Asp Tyr Val Pro Pro 620

Ser Asp Val Arg Leu Tyr Gly Met 635640

Pro Gly Lys Lys His Pro Thr Val 650655

Val Gin Leu Val Asn Asn Ser Phe 665670

Asn Thr Leu Ala Ser Leu Gly Tyr 685

Gly Ser Cys Gin Arg Gly Leu Arg 700

Met Gly Gin Val Glu lie Glu Asp 715720

Ala Glu Lys Tyr Gly Phe He Asp 730735

Trp Ser Tyr Gly Gly Phe Leu Ser 745750

Gin Val Phe Lys val Ala lie Ala 765

Ala Tyr Asp Thr Gly Tyr Thr Glu 780

Asn Gin His Gly Tyr Glu Ala Gly . 795800

Leu Pro Asn Glu Pro Asn Arg Leu 810815

Glu Asn Val His Phe Phe His Thr 825830

Arg Ala Gly Lys Pro Tyr Gin Leu 845

Ser He Arg Cys Pro Glu Ser Gly 860

His Phe Leu Gin Glu Tyr Leu 875

Gly Phe Ser Hie Ser Cys Ser Met 565

Ser His Tyr Ser Ser val ser Thr 580

Leu Ser Gly Pro Asp Asp Asp Pro 595600

Ala Ser Met Met Glu Ala Ala Ser 610615

Glu He Phe His Phe His Thr Arg 625630 lie Tyr Lys Pro His Ala Leu Gin 645

Leu Phe Val Tyr Gly Gly Pro Gin 660

Lys Gly He Lys Tyr Leu Arg Leu 675680

Ala Val Val Val He Asp Gly Arg 690695

Phe Glu Gly Ala Leu Lys Asn Gin 705710

Gin Val Glu Gly Leu Gin Phe Val 725

Leu Ser Arg Val Ala He His Gly 740

Leu Met Gly Leu lie Hia Lys Pro 755760

Gly Ala Pro Val Thr Val Trp Met 770775

Arg Tyr Met Asp Val Pro Glu Asn 785790

Ser Val Ala Leu His Val Glu Lys 805

Leu He Leu His Gly Phe Leu Asp 820

Asn Phe Leu Val Ser Gin Leu He 835840

Gin lie Tyr Pro Asn Glu Arg His B50855

Glu His Tyr Glu Val Thr Leu Leu 865870

<td> &lt;210&gt;</td><td> 34</td>

<td> &lt;211&gt;</td><td> 4263</td>

<td> &lt;212&gt;</td><td> DNA</td>

<td> &lt;213&gt;</td><td> Homo sapiens</td>

<td> &lt;400&gt;</td><td> 34</td>

caggccgccg cctgggtcgc tcaacttccg tgtgtccgcc gcggctgtcg tcccccgctc tggagccgcg accgtgaggc gccgctggac cccacgtccc ggtctgtgtc ccacgcctgc gaaggcaccc ctgccctcct gaggtcagot cgcctggaca aggagaacac cggaagttgg gagaggatgg ccacoaccgg gaccccaacg gacccggccg cccgcttcca ggtgcagaag cacggcagcc gcaagtactc gggcctcatt gtgcagaaga cggatgagtc tgggccccac tatggcagcc gagagaactc cctcctctac gctctgctgc tcctgtcctg gaagcagatg ggggtctact ctcgggagga ggagctgctg ggtcaaaggt gcctgagccg gcgggtcccc ccgccacttc cggggtcgca gtcccgggca ccgggacgac ctgcccagtc cggccgccgc agctggaatg gaggctctct ggacccttta gagcggttaa tgcggaaggt taagaaactg agaagcttct cgctgaattc cgagggggct gccgaocgag gcgacgcagc cgccacagat cactcgtggg acgggctccg gagcatcatc gtcaacaagg cgccccacga cttccagttt tcccaccgcc tctactacct gggaatgcca tctgagattc ccaagaaggt ccggaaagag ctggatcatt tccaggccac gccccaccat agggagcgga aacgcctggg ggtcttcggc

120 180 240 300 360 420

480 540 600 660 720 780

WO 02/31134 ggcctcttcc tcttccaggc cagcaacagc ggcttcatgg tgtcccctat gaaaccgctg atggacccca aaatctgccc tgccgaccct ctgtgggtgg ccaacatcga gacaggcgag ttatccaatg tcctggatga ccccaagtct gagttcgacc gcttcactgg gtactggtgg ggcctcaaga cgctgcgaat cctgtatgag cacgtcccct ctcctgcgct agaagaaagg ggcagcaaga atcccaagat tgccttgaaa aagatcgtct cgacccagga gaaggagctg gtggagtaca tcgccagggc cgggtggacc ctggaccggc cccagcagtg gctccagctc agcacagaga atgaggagca gcggctagcc ccgtatgtgg tgtacgagga ggtcaccaac cccttccccc aatcagaggg agaggacgag accggcttct gccatttgta caaagtcacc agtgagccct tcagccccgg ggaagatgaa ctgaccagcg gtgaatggga ggttttggcg ccgatggagc accacctcta cgtggtcagc accacgcccg gcttctccca tagctgctcc cactacagca gcgtgagcac gccgccctgc gacgaccccc tgcacaagca gccccgcttc cccccggatt atgttcctcc agagatcttc tacggcatga tctacaagcc ccacgccttg tttgtatatg gaggccccca ggtgcagctg ttgcggctca acacactggc ctccctgggc tcctgtcagc gagggcttcg gttcgaaggg atcgaggacc aggtggaggg cctgcagttc agccgagttg ccatccatgg ctggtcctac cacaagcccc aggtgttcaa ggtggccatc tacgacacag ggtacactga gcgctacatg gaggcgggtt ccgtggccct gcacgtggag atcctccacg gcttcctgga cgaaaacgtg caactgatcc gagcagggaa accttaccag attcgctgcc ccgagtcggg cgagcactat tacctctgag cctgcccacc gggagccgcc cggggaacca ggcgggaggg actgagtggc cccagcgctg gccagccccg aggagccgct ttttaaacgc tcttgggttt tatgtccgct ggtctcgggc cagcccctcc tctccccgcc gcactggaga ggccagaaga gactcagagg tgacctctca gtcccctggc ccggccagcc ctgtcccccc cggccagcct ccccaacttg tcataattat ttaaaagaca ggccgggcgc gggaggctga ggcgggcgga tcacctgagg ggggaaaccc cgtctctact aaaaatacaa ataatcccag ctactcggga ggctgaggca ttgcggtgag ccaagatcgc accattgcac tctcaaaata aataaaaaat aaaagacaga gtccacaccg ggcagcgggg ttgcaaccca ccgagcagag ggtcatgcgg gccccacagg cctgtggaca gccctcctgt ccccaagott cacgctctgc tggtcagtgg cggctgtccc tctgcctgac ccgtacacac caggggttcc gggttatatt tccctctccc cttccctccc aaaaaagtaa aaagaaaaga aaaaaaaaaa aaagaaaata tttttgtcga ttcttattct attaaacgat tccagttgga aacatgtcac atcacctcct acgacttcca cagcgagagt ctcttccact gccgcgacgg cggcaagaac gaaatcaaga cccagtgctc agggccccgg gccttcttct ccttcatcaa taacagcgac gagcggcggc tgaccttctg ccaccaaggt gcgggtgtgg ccaccttcgt catacaggaa tgccccacag cctcctggga aggttcagag gaagtcgatg agtccgaggt ggaggtcatt aagacggact cgtatcggta ccccaggaca ctggctgagt tccagactga cagccagggc gtgcagccct tcagctcgct gttcccgaag cgggatggca aatacgcctg ggccatgttc gtcctcctcc ccccggccct gttcatcccg tctgccagag ctgtccccag gaatgtccag gtctggatca atgttcatga catcttctat ctctgctttc tccgcgccaa tgaatgcaag gccgttttaa aatcccaggg ctacgattgg tttaagtgcc ccattaagga agagattgct aggcacggct ccaagggcac caaggacacg tatgaggcgg ccggcgagat cgtacgcctc atgagccaga acttcgacat gttcgtcagc gtgcacgtct acaagctgag cggccccgac tgggctagca tgatggaggc agccagctgc catttccaca cgcgctcgga tgtgcggctc cagccaggga agaagcaccc caccgtcctc gtgaataact ccttcaaagg catcaagtac tacgccgtgg ttgtgattga cggcaggggc gccctgaaaa accaaatggg ccaggtggag gtggccgaga agtatggctt catcgacctg gggggcttcc tctcgctcat ggggctaatc gcgggtgccc cggtcaccgt ctggatggcc gacgtccctg agaacaacca gcacggctat aagctgccca atgagcccaa ccgcttgctt cactttttcc acacaaactt cctcgtctcc ctccagatct accccaacga gagacacagt gaagtcacgt tgctgcactt tctacaggaa acatcacagc acaagtggct gcagcctccg ccgcgggccc cagtgaggca ctttgtcccg gccttcaccg ccccgacgcc ttttatcctt gcttcttggt tgccgagaca gagagatggt ttctgggagg aggaggtcac acgctgatgg agcgggctgc cttccgcctg gggctccctg accgtcccca gcacccaagc atgcaattgc atgtttgtgt tttgtttggg gggatatttt ggtggctcac gtctgtaatc ccagcacttt ttgggagttc aagaccagcc tggccaacat aaaattagcc gggtgtggtg gcgcgtgcct ggagaatcgc ttgaacccgg gaggtggagg tccagcctgg gcaacaagag cgaaactctg aagcaagggg tgcctaaatc tagacttggg gcacctggta ggctccattt cttcccaagc agaagcggcc agggcccgcg gggggcacca tcaggcaggc actgaaacgc accgaacttc ctccccagcc cagccgccca gccacatgtg ggggttggga gctgaaccat ccccacctca cgccaagagc tctgccaggg gcgggcaaaa aaagaaacaa accacctcta catattatgg tttataatta tgcgtggaag aagtagacac ctg

840 ’

900 960

1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 1620 1680 1740 1800 1860 1920 1980 2040 2100 2160 2220 2280 2340 2400 2460 2520 2580 2640 2700 2760 2820 2880 2940 3000 3060 3120 3180 3240 3300 3360 3420 3480 3540 3600 3660 3720 3780 3840 3900 3960 4020 4080 4140 4200 4260 4263

WO 02/31134 <210> 35 <211> 879 <212 > PRT <213 > Homo sapiens <400i 35

Leu Asp Lys Glu Asn Thr Gly Ser 10 15

Glu Gly Ala Glu Arg Met Ala Thr 25 30

Gly Asp Ala Ala Ala Thr Asp Asp

Lys His Ser Trp Asp Gly Leu Arg 60

Tyr Ser Gly Leu He Val Asn Lys 7580

Gin Lys Thr Asp Glu Ser Gly Pro 9095

Gly Met Pro Tyr Gly Ser Arg Glu 105no pro Lys Lys Val Arg Lys Glu Ala

Met Leu Asp His Phe Gin Ala Thr 140

Glu Glu Glu Leu Leu Arg Glu Arg . 155160

Thr Ser Tyr Asp Phe His Ser Glu 170175 ser Asn ser Leu Phe His Cys Arg 185190

Val Ser Pro Met Lys Pro Leu Glu

Arg Met Asp Pro Lys lie Cys Pro 220

He Asn Asn Ser Asp Leu Trp Val

Arg Arg Leu Thr Phe Cys His Gin

250255

Pro Lys Ser Ala Gly Val Ala Thr 265270

Arg Phe Thr Gly Tyr Trp Trp Cys

Glu Gly Leu Lys Thr Leu Arg He 300

Glu Val Glu Val He His Val Pro

Thr Asp ser Tyr Arg Tyr Pro Arg 330335

Ala Leu Lys Leu Ala Glu Phe Gin 345350

Ser Thr Gin Glu Lys Glu Leu Val

Lys Val Glu Tyr lie Ala Arg Ala 380

Ala Trp Ala Met Phe Leu Asp Arg

395 400

Leu Leu Pro Pro Ala Leu Phe He 410 415

Met Arg Lys val Lys Lys Leu Arg 15

Trp Arg Ser Phe Ser Leu Asn Ser 20

Thr Gly Thr Pro Thr Ala Asp Arg 35

Pro Ala Ala Arg Phe Gin Val Gin 50

Ser He lie His Gly Ser Arg Lys 6570

Ala Pro His Asp Phe Gin Phe Val 85

His Ser His Arg Leu Tyr Tyr Leu 100

Asn Ser Leu Leu Tyr Ser Glu He 115120

Leu Leu Leu Leu Ser Trp Lys Gin 130I

Pro His His Gly Val Tyr Ser Arg 145I⁵⁰

Lys Arg Leu Gly Val Phe Gly He 165

Ser Gly Leu Phe Leu Phe Gin Ala 1B0

Asp Gly Gly Lys Asn Gly Phe Met 195 lie Lys Thr Gin Cys Ser Gly Pro 210215

Ala Asp Pro Ala Phe Phe Ser Phe 225230

Ala Asn He Glu Thr Gly Glu Glu 245

Gly Leu Ser ash Val Leu Asp Asp 260

Phe Val lie Gin Glu Glu Phe Asp 275280

Pro Thr Ala Ser Trp Glu Gly Ser 290295

Leu Tyr Glu Glu Val Asp Glu ser 305

Ser Pro Ala Leu Glu Glu Arg Lys 325

Thr Gly Ser Lys Asn Pro Lys He 340

Thr Asp Ser Gin Gly Lys He Val 355360

Gin Pro Phe Ser Ser Leu Phe Pro 370375

Gly Trp Thr Arg Asp Gly Lys Tyr 38539°

Pro Gin Gin Trp Leu Gin Leu Val 405

WO 02/31134

Arg Leu Ala Ser Ala Arg Ala Val 425 430 val Tyr Glu Glu Val Thr Asn Val 445

Tyr Pro Phe Pro Gin ser Glu Gly 460

Ala Asn Glu Cys Lys Thr Gly Phe 475480

Val Leu Lys Ser Gin Gly Tyr Asp 490495

Glu Asp Glu Phe Lys Cys Pro He 505510

Gly Glu Trp Glu Val Leu Ala Arg 525

Thr Pro Leu Glu His His Leu Tyr 540

Glu He Val Arg Leu Thr Thr Pro 555560

Ser Gin Asn Phe Asp Met Phe Val 570575

Pro Pro Cys Val His Val Tyr Lys 585590

Leu His Lys Gin Pro Arg Phe Trp 605

Cys Pro Pro Asp Tyr Val Pro.Pro 620

Ser Asp Val Arg Leu Tyr Gly Met 635640

Pro Gly Lys Lys His Pro Thr Val 650655

Val Gin Leu Val Asn Asn Ser Phe 665670

Asn Thr Leu Ala Ser Leu Gly Tyr 685

Gly Ser Cys Gin Arg Gly Leu Arg 700

Met Gly Gin Val Glu He Glu Asp 715720

Ala Glu Lys Tyr Gly Phe He Asp 730735

Trp Ser Tyr Gly Gly Phe Leu Ser 745750

Gin Val Phe Lys Val Ala He Ala 765

Ala Tyr Asp Thr Gly Tyr Thr Glu 780

Asn Gin His Gly Tyr Glu Ala Gly 795800

Leu Pro Asn Glu Pro Asn Arg Leu 810815

Glu Asn Val His Phe Phe His Thr 825830

Arg Ala Gly Lys Pro Tyr Gin Leu 845

Ser He Arg Cys Pro Glu Ser Gly 860

His Phe Leu Gin Glu Tyr Leu 875

Pro Ser Thr Glu Asn Glu Glu Gin 420 pro Arg Asn Vai Gin Pro Tyr Vai

ג»⁴435

Trp lie Asn val His Asp He Phe

450455

Glu Asp Glu Leu Cys Phe Leu Arg 465470

Cys His Leu Tyr Lys val Thr Ala 485

Trp Ser Glu Pro Phe Ser Pro Gly 500

Lys Glu Glu He Ala Leu Thr Ser 515520

His Gly Ser Lys Gly Thr Lys Asp 530535 val Val Ser Tyr Glu Ala Ala Gly 545550

Gly Phe Ser His Ser Cys Ser Met 565

Ser His Tyr Ser Ser Val Ser Thr 500

Leu Ser Gly Pro Asp Asp Asp Pro 595500

Ala Ser Met Met Glu Ala Ala Ser 510615

Glu lie Phe His Phe His Thr Arg 625630 lie Tyr Lys Pro His Ala Leu Gin 645

Leu Phe Val Tyr Gly Gly Pro Gin 660

Lys Gly He Lys Tyr Leu Arg Leu 675680

Ala Val Val Val He Asp Gly Arg 690695

Phe Glu Gly Ala Leu Lys Asn Gin 705710

Gin Val Glu Gly Leu Gin Phe Val 725

Leu Ser Arg val Ala lie His Gly 740

Leu Met Gly Leu He His Lys Pro 755760

Gly Ala Pro Val Thr Val Trp Met 770775

Arg Tyr Met Asp Val Pro Glu Asn 705790

Ser Val Ala Leu His val Glu Lys 805

Leu He Leu His Gly Phe Leu Asp 820

Asn Phe Leu Val Ser Gin Leu lie 835840

Gin lie Tyr Pro Asn Glu Arg His 850855

Glu His Tyr Glu Val Thr Leu Leu 865870

WO 02/31134 &lt;2107 36 &lt;2117 4180 &lt;2127 DNA &lt;2137 Homo sapiens &lt;4007 36 caggccgccg cctgggtcgc tcaacttccg ggtcaaaggt gcctgagacg gcgggtcccc tgtgtccgcc gcggctgtcg tcocccgctc ccgccacttc cggggtcgca gtcccgggca tggagoogcg accgtgaggc gccgctggac ccgggacgac ctgcocagtc cggccgccgc cccacgtccc ggtctgtgtc ccacgcctgc agctggaatg gaggctctct ggaoccttta gaaggcaccc ctgccctcot gaggtcagct gagcggttaa tgcggaaggt taagaaactg cgcctggaca aggagaacac cggaagttgg agaagcttct cgctgaattc cgagggggct gagaggatgg ccaccaccgg gaccccaacg gccgaccgag gcgacgcagc cgccacagat gacccggccg cccgcttcca ggtgcagaag cactcgtggg acgggctccg gagcatcatc cacggcagcc gcaagtactc gggcctcatt gtcaacaagg cgccccacga cttccagttt gtgcagaaga cggatgagtc tgggccccac tcccaccgcc tctactacct gggaatgcca tatggcagcc gagagaactc cctcctctac tctgagattc ccaagaaggt ccggaaagag gctctgctgc tcctgtcctg gaagcagatg ctggatcatt tccaggccac gccccaccat ggggtctact ctcgggagga ggagctgctg agggagcgga aacgcctggg ggtcttcggc atcacctcct acgacttcca cagcgagagt ggcctcttcc tcttccaggc cagcaacagc ctcttccact gccgcgacgg cggcaagaao ggcttcatgg tgtcccctat gaaacogctg gaaatcaaga cccagtgctc agggccccgg atggacccca aaatctgccc tgccgaccct gcottcttct ccttcatcaa taacagcgac ctgtgggtgg ccaacatcga gacaggcgag gagcggcggc tgaccttctg ccaccaaggt ttatccaatg tcctggatga ococaagtct gcgggtgtgg ccaocttcgt catacaggaa gagttcgacc gcttcactgg gtactggtgg tgccccacag cctcctggga aggttcagag ggcctcaaga cgctgcgaat cctgtatgag gaagtcgatg agtccgaggt ggaggtcatt cacgtcccct ctcctgcgct agaagaaagg aagacggact cgtatcggta ccccaggaca ggcagcaaga atcccaagat tgccttgaaa ctggctgagt tccagactga cagccagggc aagatcgtct cgacccagga gaaggagctg gtgcagccct tcagctcgct gttcccgaag gtggagtaca tcgccagggc cgggtggacc cgggatggca aatacgcctg ggccatgttc ctggaccggc cccagcagtg gctccagcto gtcctcctcc ccccggccct gttcatcccg agcacagaga atgaggagca gcggctagcc tctgccagag ctgtccccag gaatgtccag ccgtatgtgg tgtacgagga ggtcaccaac gtctggatca atgttcatga catcttctat cccttccccc aatcagaggg agaggacgag ctctgctttc tccgcgccaa tgaatgcaag accggcttct gccatttgta caaagtcacc gccgttttaa aatcccaggg ctacgattgg agtgagccct tcagcccogg ggaagatgaa tttaagtgcc ccattaagga agagattgct ctgaccagcg gtgaatggga ggttttggcg aggcacggct ccaagggcac caaggacacg ccgotggagc accacctcta cgtggtcagc tatgaggcgg ccggcgagat cgtacgcctc accacgcccg gcttctccca tagctgctcc atgagccaga acttcgacat gttcgtcagc caotacagca gcgtgagcac gocgccctgc gtgcacgtct acaagctgag cggccccgac gacgaccccc tgcacaagca gccccgcttc tgggctagca tgatggaggc agccagctgc cccooggatt atgttcctco agagatcttc catttccaca cgcgctogga tgtgcggctc tacggcatga tctacaagcc ccacgccttg cagccaggga agaagcaccc caccgtcctc tttgtatatg gaggccccca ggtgoagctg gtgaataact ccttcaaagg catcaagtac ttgcggctca acacactggc ctccctgggc tacgccgtgg ttgtgattga cggcaggggc tcctgtcagc gagggcttcg gttcgaaggg gccctgaaaa accaaatggg ccaggtggag atcgaggacc aggtggaggg cctgcagttc gtggccgaga agtatggctt catcgacctg agocgagttg ccatccatgg ctggtcctac gggggcttcc tctcgctcat.ggggctaatc cacaagcccc aggtgttcaa ggtggccatc gcgggtgccc cggtcaccgt ctggatggcc taogacacag ggtacactga gcgctacatg gacgtccctg agaacaacca gcacggctat gaggcgggtt ccgtggccct gcacgtggag aagctgccca atgagcccaa ccgcttgctt atcctccacg gcttcctgga cgaaaacgtg cactttttcc acacaaactt cctcgtctcc caactgatcc gagcagggaa accttaccag ctccagatct accocaacga gagacacagt attcgctgca ccgagtcggg cgagoaetat gaagtcacgt tgctgcactt tctacaggaa tacctctgag cctgcccacc gggagccgcc acatoacagc acaagtggct gcagcctccg cggggaacca ggcgggaggg aotgagtggc ccgcgggccc cagtgaggca ctttgtcccg cccagcgctg gccagccccg aggagccgct gccttcaccg ccccgacgcc ttttatcctt ttttaaacgc tcttgggttt tatgtccgct gcttcttggt tgccgagaca gagagatggt ggtctcgggc cagcccctcc tctccccgcc

120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 . 1200 1260 1320 1380 1440 1500 1560 1620 1680 1740 1800 1860 1920 1980 2040 2100 2160 2220 2280 2340 2400 2460 2520 2580 2640 2700 2760 2820 2880 2940 3000 3060 3120 3180

WO 02/31134 ttctgggagg aggaggtcac agcgggctgc cttccgcctg accgtcccca gcacccaagc atgtttgtgt tttgtttggg ggtggctcac gtctgtaatc ttgggagttc aagaccagcc aaaattagcc gggtgtggtg ggagaatcgc ttgaacccgg tccagcotgg gcaacaagag aagcaagggg tgcctaaatc gcacctggta ggctccattt gaacttccac gctctgctgg acatgtgtct gcctgacccg cacctcaggg ttatatttcc ggcaaaaaaa aaagtaaaaa attatggaaa gaaaatattt tagacacatt aaacgattcc acgctgatgg gcactggaga gggctccctg tgacctctca atgcaattgc ctgtcccccc gggatatttt tcataattat ccagcacttt gggaggctga tggccaacat ggggaaaccc gcgcgtgcct ataatcccag gaggtggagg ttgcggtgag cgaaactctg tctcaaaata tagacttggg gtccacaccg cttcccaagc ccgactttca tcagtggcgg ctgtcccctc tacacaccag gggttccggg ctctcccctt ccctccccgc gaaaagaaaa aaaaaaaaaa ttgtcgattc ttattctttt agttggaaac atgtcacctg ggccagaaga gactcagagg gtcccctggc ccggccagcc cggccagcct ccccaacttg ttaaaagaca ggccgggcgo ggcgggcgga tcacctgagg cgtctctact aaaaatacaa ctactcggga ggctgaggca ccaagatcgc accattgcac aataaaaaat aaaagacaga ggcagcgggg ttgcaaccca ggcaggcact gaaacgcacc ccoagcccag ccgcccagcc gttgggagct gaaccatccc caagagctct gccaggggcg gaaacaaacc acctctacat ataattatgc gtggaagaag

3240 3300 3360 3420 3480 3540 3600 3660 3720 3780 3840 3900 3960 4020 4080 4140 4180 <210> 37 <211> 819 <212 > PRT <213 > Homo sapiens <400> 37

Gly Ser 15 Ala Thr

Asp Asp

Leu Arg

Asn Lys 80

Gly Pro 95 Arg Glu

Glu Ala

Ala Thr

Glu Arg

Ser Glu 175 Cys Arg

Leu Glu

Cys Pro

Trp Val

His Gin 255 Ala Thr

Met Arg Lys Val Lys Lys Leu Arg Leu Asp Lys Glu Asn Thr 1510

Tro Arg ser Phe Ser Leu Asn Ser Glu Gly Ala Glu Arg Met 20 ²⁵³⁰

Thr Gly Thr Pro Thr Ala Asp Arg Gly Asp Ala Ala Ala Thr 35 4045

Pro Ala Ala Arg Phe Gin val Gin Lys His Ser Trp Asp Gly 50 55 ⁶⁰

Ser He He His Gly Ser Arg Lys Tyr Ser Gly Leu He Val 65 ⁷⁰⁷⁵

Ala Pro His Asp Phe Gin Phe Val Gin Lys Thr Asp Glu Ser 8590

His Ser His Arg Leu Tyr Tyr Leu Gly Met Pro Tyr Gly Ser 100 i°5HO

Asn Ser Leu Leu Tyr Ser Glu He Pro Lys Lys Val Arg Lys 115 120

Leu Leu Leu Leu Ser Trp Lys Gin Met Leu Asp His Phe Gin 130 135140 pro His His Gly Val Tyr Ser Arg Glu Glu Glu Leu Leu Arg 145 15° ^x55.

Lys Arg Leu Gly Val Phe Gly lie Thr Ser Tyr Asp Phe His 165170

Sex Glv Leu phe Leu Phe Gin Ala Ser Asn Ser Leu Phe.His 180 185190

Asp Gly Gly Lys Asn Gly Phe Met Val Ser Pro Met Lys Pro 395 200205 lie Lys Thr Gin Cys Ser Gly Pro Arg Met Asp Pro LysHe

210 215 ²²⁰ __

Ala Asp Pro Ala Phe Phe Ser Phe lie Asn Asn Ser Asp Leu ²²⁵

225 ^{230 233}

Ala Asn He Glu Thr Gly Glu Glu Arg Arg Leu Thr Phe Cys 245 250

Gly Leu Ser Asn Val Leu Asp Asp Pro Lys Ser Ala Gly val ¹ 260 265 ²⁷Ο

WO 02/31134

Arg Phe Thr Gly Tyr Trp Trp Cys 285

Glu Gly Leu Lys Thr Leu Arg lie 300

Glu Val Glu Val He His Val Pro 315320

Thr Asp Ser Tyr Arg Tyr Pro Arg 330335

Ala Leu Lys Leu Ala Glu Phe Gin 345350

Ser Thr Gin Glu Lys Glu Leu val 365

Lys Val Glu Tyr lie Ala Arg Ala 380

Ala Trp Ala Met Phe Leu Asp Arg 395400

Leu Leu Pro Pro Ala Leu Phe lie 410415

Arg Leu Ala Ser Ala Arg Ala Val 425430

Val Tyr Glu Glu Val Thr Asn Val 445

Tyr Pro Phe Pro Gin Ser Glu Gly 460

Ala Asn Glu Cys Lys Thr Gly Phe 475

Val Leu Lys Ser Gin Gly Tyr Asp 490495

Glu Asp Glu Phe Lys Cys pro He 505510

Gly Glu Trp Glu Val Leu Ala Arg 525

Thr Pro Leu Glu His His Leu Tyr 540

Glu He Val Arg Leu Thr Thr Pro 555560

Ser Gin Asn Phe Asp Met Phe Val 570575

Pro Pro Cys Val His val Tyr Lys 585590

Leu His Lys Gin Pro Arg Phe Trp 605

Cys Pro Pro Asp Tyr Val Pro Pro 620

Ser Asp Val Arg Leu Tyr Gly Met 635640

Pro Gly Lys Lys His Pro Thr Val 650655

Val Gin Leu Val Asn Asn ser Phe 665670

Asn Thr Leu Ala Ser Leu Gly Tyr 685

Gly Ser Cys Gin Arg Gly Leu Arg 700

Met Gly Gin Val Glu He Glu Asp 715 720

Ala Glu Lys Tyr Gly Phe lie Asp 730 735

Phe Vai lie Gin Glu Glu Phe Asp 275 ²⁸⁰

Pro Thr Ala ser Trp Glu Gly Ser 290255

Leu Tyr Glu Glu Vai Asp Glu Ser 305310

Ser Pro Ala Leu Glu Glu Arg Lys 325

Thr Gly Ser Lya Asn Pro Lys lie 340

Thr Asp Ser Gin Gly Lys He Vai 355360

Gin Pro Phe Ser Ser Leu Phe Pro 370375

Gly Trp Thr Arg Asp Gly Lys Tyr 385390

Pro Gin Gin Trp Leu Gin Leu Vai 405

Pro Ser Thr Glu Asn Glu Glu Gin 420 pro Arg Asn Vai Gin Pro Tyr Vai 435440

Trp He Asn Vai His Asp He Phe 450455

Glu Asp Glu Leu Cys Phe Leu Arg 465

Cys His Leu Tyr Lys Vai Thr Ala 485

Trp Ser Glu Pro Phe Ser Pro Gly 500

Lys Glu Glu lie Ala Leu Thr Ser 515520

His Gly Ser Lys Gly Thr Lys Asp 530535

Vai Vai Ser Tyr Glu Ala Ala Gly 545

Gly Phe Ser His Ser Cys Ser Met 565

Ser His Tyr Ser Ser Vai Ser Thr 580

Leu Ser Gly Pro Asp Asp Asp Pro 595500

Ala Ser Met Met Glu Ala Ala Ser 610615

Glu He Phe His Phe His Thr Arg 625630

He Tyr Lys Pro His Ala Leu Gin 645

Leu Phe val Tyr Gly Gly Pro Gin 660

Lys Gly He Lys Tyr Leu Arg Leu 675680

Ala Val Val Val lie Asp Gly Arg 690695

Phe Glu Gly Ala Leu Lys Asn Gin 705710

Gin Val Glu Gly Leu Gin Phe Val 725

WO 02/31134

Leu Ser Arg Val Ala He His Gly Trp Ser Tyr Gly Gly Phe Leu Ser 740 745750

Leu Met Gly Leu He Hia Lys Pro Gin Val Phe Lys Ala Gin Pro Leu 755 760765

Ala Tyr Pro Pro Arg Leu Pro Gly Arg Lys Arg Ala Leu Phe Pro His 770 775780

Lys Leu Pro Arg Leu Pro Thr Asp Pro Ser Arg Glu Thr Leu ProAla

785 790 795800

Pro Asp Leu Pro Gin Arg Glu Thr Gin Tyr Ser Leu Pro Arg ValGly

805 810815

Arg Ala Leu <210> 38 <211> 4120 <212 > DNA <213 > Homo sapiens <400> 38 caggccgccg cctgggtcgc tcaaottccg ggtcaaaggt gcctgagccg gcgggtcccc tgtgtccgcc gcggctgtcg tcccccgctc ccgccacttc cggggtcgca gtcccgggca tggagccgcg accgtgaggc gccgctggac ccgggacgac ctgcccagtc cggccgccgc cccacgtccc ggtctgtgtc ccacgcctgc agctggaatg gaggctctct ggacccttta qaaggcaccc ctgccctcct gaggtcagct gagcggttaa tgcggaaggt taagaaactg cgcctggaca aggagaacac cggaagttgg agaagcttct cgctgaattc cgagggggct gagaggatgg ccaccaccgg gaccccaacg gccgaccgag gcgacgcagc cgccacagat gacccggcog cccgcttcca ggtgcagaag cactcgtggg acgggctccg gagcatcatc cacggcagcc gcaagtactc gggcctcatt gtcaacaagg cgccccacga cttccagttt qtgcagaaga cggatgagtc tgggccccac tcccaccgcc tctactacct gggaatgcca tatggcagcc gagagaactc cctcctctac tctgagattc ccaagaaggt ccggaaagag gctctgctgc tcctgtcctg gaagcagatg ctggatcatt tccaggccac gccccaccat qqqgtctact ctcgggagga ggagctgctg agggagogga aacgoctggg ggtcttcggc atcacctcct acgacttcca cagcgagagt ggactcttcc tcttccaggc cagcaacagc ctcttccact gccgcgacgg cggcaagaac ggcttcatgg tgtcccctat gaaaccgctg gaaatcaaga cccagtgctc agggccccgg atggaccoca aaatctgccc tgccgaccct gccttcttct ccttcatcaa taacagcgac ctgtgggtgg ccaacatcga gacaggcgag gagcggcggc tgaccttctg ccaccaaggt ttatccaatg tcctggatga ccccaagtct gcgggtgtgg ccaccttcgt catacaggaa gagttcgacc gcttcactgg gtactggtgg tgccccacag cctcctggga aggttcagag ggcctcaaga cgctgcgaat octgtatgag gaagtcgatg agtccgaggt ggaggtcatt cacgtcccct ctcctgcgot agaagaaagg aagacggact cgtatcggta ccccaggaca ggcagcaaga atcccaagat tgccttgaaa ctggctgagt tccagactga cagccagggc aagatcgtct cgacccagga gaaggagctg gtgcagccct tcagctcgct gttcccgaag gtggagtaca tcgccagggc cgggtggacc cgggatggca aatacgcctg ggccatgttc ctggaccggc cccagcagtg gctccagctc gtoctcctcc ccccggccct gttcatcccg agcacagaga atgaggagca gcggctagcc tctgccagag ctgtccccag gaatgtccag ccgtatgtgg tgtacgagga ggtcaccaac gtctggatca atgttcatga catcttctat cccttccccc aatcagaggg agaggacgag ctctgctttc tccgcgccaa tgaatgcaag accggcttct gccatttgta caaagtcacc gccgttttaa aatcccaggg ctacgattgg agtgagccct tcagccccgg ggaagatgaa tttaagtgcc ccattaagga agagattgct ctgaccagcg gtgaatggga ggttttggcg aggcacggct ccaagggcao caaggacacg ccgctggagc accacctcta cgtggtcagc tatgaggcgg ccggcgagat cgtacgcctc accacgcccg gcttctccca tagctgctcc atgagccaga acttcgacat gttcgtcagc cactacagca gcgtgagcac gccgccctgc gtgcacgtct acaagctgag cggocccgac gacgaccccc tgcacaagca gccccgcttc tgggctagca tgatggaggc agccagotgc cccccggatt atgttcctcc agagatcttc catttccaca cgcgctcgga tgtgcggctc tacggcatga tctacaagcc ccacgccttg cagccaggga agaagcaccc caccgtcctc tttgtatatg gaggccccca ggtgcagctg gtgaataaet ccttcaaagg oatcaagtac ttgcggctca acacaetggc ctccctgggc tacgccgtgg ttgtgattga cggcaggggc tcctgtcagc gagggcttcg gttcgaaggg gccctgaaaa accaaatggg ccaggtggag atcgaggacc aggtggaggg cctgcagttc

120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 1620 1680 1740 1800 1860 1920 1980 2040 2100 2160 2220 2280 2340 2400 2460

WO 02/31134 gtggccgaga agtatggctt catcgacctg agccgagttg ccatccatgg ctggtcctac2520 gggggcttcc tctcgctcat ggggctaatc cacaagcccc aggtgttcaa ggcccaaccg2580 cttgcttatc ctccacggct tcctggacga aaacgtgcac tttttccaca caaacttc.ct2640 cgtctcccaa ctgatccgag cagggaaacc ttaccagctc cagatctacc ccaacgagag2700 acacagtatt cgctgccccg agtcgggcga gcactatgaa gtcacgttgc tgcactttct2760 acaggaatac ctctgagcct gcccaccggg agccgccaca tcacagcaca agtggctgca2820 gcctccgcgg ggaaccaggc gggagggact gagtggcccg cgggccccag tgaggcactt2880 tgtcccgccc agcgctggcc agccccgagg agccgctgcc ttcaccgccc cgacgccttt2940 tatccttttt taaacgctct tgggttttat gtccgctgct tcttggttgc cgagacagag3000 agatggtggt ctcgggccag cccctcctct ccccgcottc tgggaggagg aggtcacacg3060 ctgatgggca ctggagaggc cagaagagac tcagaggagc gggctgcctt ccgcctgggg3120 ctccctgtga cctctcagtc ccctggcccg gccagccacc gtcccoagca cccaagcatg3180 caattgcctg tcccccccgg ccagcctccc caacttgatg tttgtgtttt gtttgggggg3240 atatttttca taattattta aaagacaggc cgggcgcggt ggctcacgtc tgtaatccca3300 gcactttggg aggctgaggc gggcggatca cctgaggttg ggagttcaag accagcctgg3360 ccaacatggg gaaaccccgt ctctactaaa aatacaaaaa attagccggg tgtggtggcg3420 cgtgcctata atcccagcta ctcgggaggc tgaggcagga gaatcgcttg aacccgggag3480 gtggaggttg cggtgagcca agatcgcacc attgcactcc agcctgggca acaagagcga3540 aactctgtct caaaataaat aaaaaataaa agacagaaag caaggggtgc ctaaatctag3600 acttggggtc cacaccgggc agcggggttg caacccagca cctggtaggc tccatttctt3660 cccaagcccg agcagagggt catgcgggcc ccacaggaga agcggccagg gcccgcgggg3720 ggcaccacct gtggacagcc ctcctgtccc caagctttca ggcaggcact gaaacgcacc3780 gaacttccac gctctgctgg tcagtggcgg ctgtcccctc cccagcccag ocgcccagcc3840 acatgtgtct gcctgacccg tacacaccag gggttccggg gttgggagct gaaccatccc3900 oacctcaggg ttatatttcc ctctcccctt ccctccccgc caagagctct gccaggggcg3960 ggcaaaaaaa aaagtaaaaa gaaaagaaaa aaaaaaaaaa gaaacaaacc acctctacat4020 attatggaaa gaaaatattt ttgtcgattc ttattctttt ataattatgc gtggaagaag4080 tagacacatt aaacgattcc agttggaaac atgtcacctg4120 <210> 39 <211> 819 <212> PRT <213> Homo sapiens <400> 39

Met Arg Lys Val Lys Lys Leu Arg Leu Asp Lys Glu Asn Thr Gly Ser

5 1015

Trp Arg Ser Phe Ser Leu Asn Ser Glu Gly Ala Glu Arg Met AlaThr

2530

Thr Gly Thr Pro Thr Ala Asp Arg Gly Asp Ala Ala Ala Thr Asp Asp 35 4045

Pro Ala Ala Arg Phe Gin Val Gin Lys Hia Ser Trp Asp Gly Leu Arg 50 5560

Ser He He His Gly Ser Arg Lys Tyr Ser Gly Leu He Val AsnLys

70 7580

Ala Pro His Asp Phe Gin Phe Val Gin Lys Thr Asp Glu Ser GlyPro

9095

His Ser His Arg Leu Tyr Tyr Leu Gly Met Pro Tyr Gly Ser Arg Glu 100 105110

Asn Ser Leu Leu Tyr Ser Glu He Pro Lys Lys Val Arg Lys Glu Ala 115 120125

Leu Leu Leu Leu Ser Trp Lys Gin Met Leu Asp His Phe Gin Ala Thr 130 135140

Pro His His Gly Val Tyr Ser Arg Glu Glu Glu Leu Leu Arg Glu Arg

145 150 155ISO

Lys Arg Leu Gly val Phe Gly He Thr Ser Tyr Asp Phe His Ser Glu

165 170175

Ser Gly Leu Phe Leu Phe Gin Ala Ser Asn Ser Leu Phe His Cys Arg !80 185190

WO 02/31134

<td colspan="4"> Asp Gly Gly Lys Asn Gly Phe Met Val Ser Pro Met Lys Pro</td><td rowspan="2"> Leu Glu</td>

<td></td><td> 195</td><td> 200</td><td> 205</td>

<td> He Lys</td><td> Thr Gin</td><td> Cys Ser Gly Pro</td><td> Arg Met Asp Pro Lys He</td><td> Cys Pro</td>

<td> 210</td><td></td><td> 215</td><td> 220</td><td></td>

<td> Ala Asp</td><td> Pro Ala</td><td> Phe Phe Ser Phe</td><td> He Asn Asn ser Asp Leu</td><td> Trp Val</td>

<td> 225</td><td></td><td> 230</td><td> 235</td><td> 240</td>

<td> Ala Asn</td><td> He Glu</td><td> Thr Gly Glu Glu</td><td> Arg Arg Leu Thr Phe Cys</td><td> His Gin</td>

<td></td><td></td><td> 245</td><td> 250</td><td> 255</td>

<td> Gly Leu</td><td> Ser Asn</td><td> Val Leu Asp Asp</td><td> Pro Lys Ser Ala Gly Val</td><td> Ala Thr</td>

<td></td><td> 260</td><td></td><td> 265 270</td><td></td>

<td> Phe Val</td><td> He Gin</td><td> Glu Glu Phe Asp</td><td> Arg Phe Thr Gly Tyr Trp</td><td> Trp cys</td>

<td></td><td> 275</td><td> 280</td><td> 285</td><td></td>

<td> Pro Thr</td><td> Ala Ser</td><td> Trp Glu Gly Ser</td><td> Glu Gly Leu Lys Thr Leu</td><td> Arg Xie</td>

<td> 290</td><td></td><td> 295</td><td> 300</td><td></td>

<td> Leu Tyr</td><td> Glu Glu</td><td> Val Asp Glu Ser</td><td> Glu Val Glu Val He His</td><td> Val Pro</td>

<td> 305</td><td></td><td> 310</td><td> 315</td><td> 320</td>

<td> Ser Pro</td><td> Ala Leu</td><td> Glu Glu Arg Lys</td><td> Thr Asp Ser Tyr Arg Tyr</td><td> Pro Arg</td>

<td></td><td></td><td> 325</td><td> 330</td><td> 335</td>

<td> Thr Gly</td><td> Ser Lys</td><td> Asn Pro Lys He</td><td> Ala Leu Lys Leu Ala.Glu</td><td> Phe Gin</td>

<td></td><td> 340</td><td></td><td> 345 350</td><td></td>

<td> Thr Asp</td><td> Ser Gin</td><td> Gly Lys lie Val</td><td> Ser Thr Gin Glu Lys Glu</td><td> Leu Val</td>

<td></td><td> 355</td><td> 360</td><td> 365</td><td></td>

<td> Gin Pro</td><td> Phe Ser</td><td> Ser Leu Phe Pro</td><td> Lys Val Glu Tyr lie Ala</td><td> Arg Ala</td>

<td> 370</td><td></td><td> 375</td><td> 380</td><td></td>

<td> Gly Trp</td><td> Thr Arg</td><td> Asp Gly Lys Tyr</td><td> Ala Trp Ala Met Phe Leu</td><td> Asp Arg</td>

<td> 385</td><td></td><td> 390</td><td> 395</td><td> 400</td>

<td> Pro Gin</td><td> Gin Trp</td><td> Leu Gin Leu Val</td><td> Leu Leu Pro Pro Ala Leu</td><td> Phe He</td>

<td></td><td></td><td> 405</td><td> 410</td><td> 415</td>

<td> Pro Ser</td><td> Thr Glu</td><td> Asn Glu Glu Gin</td><td> Arg Leu Ala Ser Ala Arg</td><td> Ala val</td>

<td></td><td> 420</td><td></td><td> 425 430</td><td></td>

<td> Pro Arg</td><td> Asn Val</td><td> Gin Pro Tyr Val</td><td> Val Tyr Glu Glu val Thr</td><td> Asn Val</td>

<td></td><td> 435</td><td> 440</td><td> 445</td><td></td>

<td> Trp lie</td><td> Asn Val</td><td> His Asp lie Phe</td><td> Tyr Pro Phe Pro Gin Ser</td><td> Glu Gly</td>

<td> 450</td><td></td><td> 455</td><td> 460</td><td></td>

<td> Glu Asp</td><td> Glu Leu</td><td> Cys Phe Leu Arg</td><td> Ala Asn Glu Cys Lys Thr</td><td> Gly Phe</td>

<td> 465</td><td></td><td> 470</td><td> 475</td><td> 480</td>

<td> Cys His</td><td> Leu Tyr</td><td> Lys val Thr Ala</td><td colspan="2"> Val Leu Lys Ser Gin Gly Tyr Asp</td>

<td></td><td></td><td> 485</td><td> 490</td><td> 495</td>

<td> Trp Ser</td><td> Glu Pro</td><td> Phe Ser Pro Gly</td><td> Glu Asp Glu Phe Lys Cys</td><td> Pro He</td>

<td></td><td> 500</td><td></td><td> 505 510</td><td></td>

<td> Lys Glu</td><td> Glu lie</td><td> Ala Leu Thr Ser</td><td> Gly Glu Trp Glu Val Leu</td><td> Ala Arg</td>

<td></td><td> 515</td><td> 520</td><td> 525</td><td></td>

<td> His Gly</td><td> Ser Lys</td><td> Gly Thr Lys Asp</td><td> Thr Pro Leu Glu His His</td><td> Leu Tyr</td>

<td> 530</td><td></td><td> 535</td><td> 540</td><td></td>

<td> Val Val</td><td> Ser Tyr</td><td> Glu Ala Ala Gly</td><td> Glu lie Val Arg Leu Thr</td><td> Thr Pro</td>

<td> 545</td><td></td><td> 550</td><td> 555</td><td> 560</td>

<td> Gly Phe</td><td> Ser His</td><td> Ser Cys Ser Met</td><td> Ser Gin Asn Phe Asp Met</td><td> Phe val</td>

<td></td><td></td><td> 565</td><td> 570</td><td> 575</td>

<td> Ser His</td><td> Tyr Ser</td><td> Ser Val Ser Thr</td><td colspan="2"> Pro Pro Cys Val His Val Tyr Lys</td>

<td></td><td> 580</td><td></td><td> 585 590</td><td></td>

<td> Leu Ser</td><td> Gly Pro</td><td> Asp Asp Asp Pro</td><td> Leu His Lys Gin Pro Arg</td><td> Phe Trp</td>

<td></td><td> 595</td><td> 600</td><td> 605</td><td></td>

<td> Ala Ser</td><td> Met Met</td><td> Glu Ala Ala Ser</td><td> Cys Pro Pro Asp Tyr Val</td><td> pro Pro</td>

<td> 610</td><td></td><td> 615</td><td> 620</td><td></td>

<td> Glu lie</td><td> Phe His</td><td> Phe His Thr Arg</td><td> Ser Asp Val Arg Leu Tyr</td><td> Gly Met</td>

<td> 625</td><td></td><td> 630</td><td> 635</td><td> 640</td>

<td> lie Tyr</td><td> Lys Pro</td><td> His Ala Leu Gin</td><td> Pro Gly Lys Lys His Pro</td><td> Thr Val</td>

<td></td><td></td><td> 645</td><td> 650</td><td> 655</td>

WO 02/31134

Leu Phe Val Tyr Gly Gly Pro Gin Val Gin Leu Val Asn Asn Ser Phe 660 665670

Lys Gly He Lys Tyr Leu Arg Leu Asn Thr Leu Ala Ser Leu Gly Tyr 675 680685

Ala val val Val lie Asp Gly Arg Gly Ser Cys Gin Arg Gly Leu Arg 690 695700

Phe Glu Gly Ala Leu Lys Asn Gin Met Gly Gin Val Glu He GluAsp

705 710 715720

Gin Val Glu Gly Leu Gin Phe Val Ala Glu Lys Tyr Gly Phe HeAsp

725 730735

Leu Ser Arg Val Ala He His Gly Trp Ser Tyr Gly Gly Phe Leu Ser 740 745750

Leu Met Gly Leu lie His Lys Pro Gin Val Phe Lys Ala Gin Pro Leu 755 760765

Ala Tyr Pro Pro Arg Leu Pro Gly Arg Lys Arg Ala Leu Phe Pro His 770 775780

Lvs Leu Pro Arg Leu pro Thr Asp Pro Ser Arg Glu Thr Leu ProAla

785 790 795800

Pro Asp Leu Pro Gin Arg Glu Thr Gin Tyr Ser Leu Pro Arg ValGly

805 810815

Arg Ala Leu <210> 40 <211> 4037 <212 > DNA <213ג> Homo sapiens <400> 40 caggccgccg cctgggtcgc tcaacttccg ggtcaaaggt gcctgagccg gcgggtcccc tgtgtccgcc gcggctgtcg tcccccgctc ccgccacttc cggggtcgca gtcccgggca tggagccgcg accgtgaggc gccgctggac ccgggacgac ctgcccagtc cggccgccgc cccacgtccc ggtctgtgt.c ccacgcctgc agctggaatg gaggctctct ggacccttta gaaggcaccc ctgccctcct gaggtcagct gagcggttaa tgcggaaggt taagaaactg cgcctggaca aggagaacao cggaagttgg agaagettct cgctgaattc cgagggggct gagaggatgg ccaccaccgg gaccccaacg gccgaccgag gcgacgcagc cgccaoagat gacocggccg cccgcttcca ggtgcagaag cactcgtggg acgggctccg gagcatcatc cacggcagcc gcaagtactc gggcctcatt gtcaacaagg cgccccacga cttccagttt gtgcagaaga cggatgagtc tgggccccac tcccaccgcc tctactacot gggaatgcca tatggcagcc gagagaactc cctcctctac tctgagattc ccaagaaggt ccggaaagag gctctgctgc tcctgtoctg gaagcagatg ctggatcatt tccaggccac gccccaccat gqggtctact ctcgggagga ggagctgctg agggagcgga aacgcctggg ggtcttcggc atcacctcct acgacttcca cagcgagagt ggcctcttcc tcttccaggc cagcaacago ctcttccact gccgcgacgg cggcaagaac ggcttcatgg tgtcccctat gaaaccgctg gaaatcaaga cccagtgctc agggccccgg atggacocca aaatctgccc tgccgaccct gccttcttct ccttcatcaa taacagcgac ctgtgggtgg ccaacatcga gacaggcgag gagcggcgga tgaccttctg ccaccaaggt ttatccaatg tcctggatga ccccaagtct gcgggtgtgg ccaccttcgt catacaggaa gagttcgacc gcttcactgg gtactggtgg tgccocacag cctcctggga aggttcagag ggcctcaaga cgctgcgaat cctgtatgag gaagtcgatg agtccgaggt ggaggtcatt cacgtcccot ctcctgcgct agaagaaagg aagacggact cgtatcggta ccccaggaca ggcagcaaga atcccaagat tgccttgaaa ctggctgagt tccagactga cagccagggc aagatcgtct cgacccagga gaaggagctg gtgcagccct tcagctcgct gttcccgaag gtggagtaca tcgccagggc cgggtggacc cgggatggca aatacgcctg ggccatgttc ctggaccggc cccagcagtg gctccagctc gtcctcctcc ccccggccct gttcatcccg agcacagaga atgaggagca gcggctagcc tctgccagag ctgtccccag gaatgtccag acgtatgtgg tgtacgagga ggtoaccaac gtctggatca atgttcatga catcttctat cccttccccc aatcagaggg agaggacgag ctctgctttc tccgcgccaa tgaatgcaag accggcttct gccatttgta caaagtcacc gccgttttaa aatcccaggg ctacgattgg agtgagccct tcagccccgg ggaagatgaa tttaagtgcc ccattaagga agagattgct ctgaccagcg gtgaatggga ggttttggcg

120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 1620 1680 1740 1800 1860

WO 02/31134 aggcacggct ccaagggcac caaggacacg ccgctggagc accacctcta cgtggtcagc1920 tatgaggcgg ccggcgagat cgtacgcctc accacgcccg gcttctccca tagctgctcc1980 atgagccaga acttcgacat gttcgtcagc cactacagca gcgtgagcac gccgccctgc 2040 gtgcacgtct acaagctgag cggccccgac gacgaccccc tgcacaagca gccccgcttc2100 tgggctagca tgatggaggc agccagctgc cccccggatt atgttcotcc agagatcttc2160 catttccaca cgcgctcgga tgtgcggcto tacggcatga tctacaagcc ccacgccttg2220 cagccaggga agaagcaccc caccgtcctc tttgtatatg gaggccocca ggtgcagctg2280 gtgaataact ccttcaaagg catcaagtac ttgcggctoa acacactggc ctccctgggc2340 tacgccgtgg ttgtgattga cggcaggggc tcctgtcagc gagggcttcg gttcgaaggg2400 gccctgaaaa accaaatggg ccaggtggag atcgaggacc aggtggaggg cctgcagttc2460 gtggccgaga agtatggctt catcgacctg agccgagttg ccatccatgg ctggtcctac2520 gggggcttcc tctcgctcat ggggctaatc cacaagcccc aggtgttcaa ggcccaaccg25BO cttgcttatc ctccacggct tcctggacga aaacgtgcac tttttccaca caaacttcct2640 cgtctcccaa ctgatccgag cagggaaacc ttacoagcto cagatctacc ccaacgagag2700 acacagtatt cgctgcoccg agtcgggcga gcactatgaa gtcacgttgc tgcactttct2760 acaggaatac ctctgagcct gcccaccggg agccgccaca tcacagcaca agtggctgca2820 gcctccgcgg ggaaccaggc gggagggact gagtggcccg cgggccccag tgaggcactt2800 tgtcocgcoc agcgctggcc agccccgagg agccgctgcc ttcaccgccc cgacgccttt2940 tatccttttt taaacgctct tgggttttat gtccgctgct tcttggttgc cgagaoagag3000 agatggtggt ctcgggocag cccotcctct ccccgccttc tgggaggagg aggtcacacg3060 ctgatgggca ctggagaggc cagaagagac tcagaggagc gggctgcctt ccgcctgggg3120 ctccctgtga cctctcagtc ccctggcccg gccagccaoo gtccccagca cccaagcatg3180 caattgcctg tococcocgg ccagcctccc caacttgatg tttgtgtttt gtttgggggg3240 atatttttca taattattta aaagacaggc cgggcgcggt ggctcacgtc tgtaatccca3300 gcactttggg aggctgaggc gggcggatca octgaggttg ggagttcaag accagcctgg3360 ccaacatggg gaaaccccgt ctctactaaa aatacaaaaa attagccggg tgtggtggcg3420 cgtgcctata atcccagcta ctcgggaggc tgaggcagga gaatogottg aacccgggag3400 gtggaggttg cggtgagcca agatcgcacc attgcactcc agcctgggca acaagagoga3540 aactctgtct caaaataaat aaaaaataaa agacagaaag caaggggtgc ctaaatctag3600 acttggggtc cacaccgggc agcggggttg caacccagca cctggtaggc tccatttctt3660 cccaagoccg actttcaggc aggcactgaa acgcaccgaa cttccacgct ctgctggtca3720 gtggcggctg tcccctcccc agcccagccg cccagccaca tgtgtctgcc tgacccgtac3780 acaccagggg ttccggggtt gggagctgaa ccatccocac ctcagggtta tatttccctc3640 tccccttccc tccccgccaa gagctctgcc aggggcgggc aaaaaaaaaa gtaaaaagaa3900 aagaaaaaaa aaaaaaagaa acaaaccacc tctacatatt atggaaagaa aatatttttg3960 tcgattctta ttcttttata attatgcgtg gaagaagtag acacattaaa cgattccagt 4020 tggaaacatg tcacctg <210> 41 <211> 706 <212> PRT <213> Homo sapiens <400> 41

Asp Thr Asp Val Val Tyr Lys Ser Glu Asn Gly His Val He Lys Leu

5 1015

Asn lie Glu Thr Asn Ala Thr Thr Leu Leu Leu Glu Asn Thr Thr Phe

2530

Val Thr Phe Lys Ala Ser Arg His Ser Val Ser Pro Asp Leu Lys Tyr 35 4045 val Leu Leu Ala Tyr Asp Val Lys Gin He Phe His Tyr Ser Tyr Thr 50 5560

Ala Ser Tyr Val He Tyr Asn He His Thr Arg Glu Val Trp GluLeu

70 7580

Asn Pro Pro Glu Val Glu Asp Ser Val Leu Gin Tyr Ala Ala TrpGly

9095

Val Gin Gly Gin Gin Leu He Tyr He Phe Glu Asn Asn He Tyr Tyr 100 105110

WO 02/31134

Leu Arg Leu Thr Ser Ser Gly Lys 125

Ala Asp Trp Leu Tyr Glu Glu Glu 140

Trp Trp Ser Pro Asp Gly Glu Arg 155160

Ser Leu Val Pro Thr Met Val He 170175

Pro Lys Gly Lys Gin Tyr Pro Tyr 185190

Thr He Lys Leu Tyr Val Val Asn 205

Glu Leu Met Pro Pro Asp Ser Phe 220

Met Val Lys Trp Val Ser Asn Thr 235240

Arg Pro Gin Asn He Ser He Leu 250255

Ala Cys Ser Lys Lys Tyr Glu Met 265270

Gin Asn Glu Glu Pro Val Phe Ser 285

Thr Val Pro Val Lys Gin Gly Gly 300

Met Phe Leu lie Gin Ser Lys Ser 315320

Thr Ser Gly Asn Trp Glu Val He 330335

Thr Gin Lys He Tyr Phe Leu Ser 345350

Gin Leu Tyr Ser Ala Ser Thr Glu 365

Ser Cys Asn Phe Met Lys Glu Gin 380

Ser Pro Net Asn Gin His Phe Leu 395400

Pro Val Val Ser Leu His Ser Thr 410415

Leu Glu Ser ash Ser Met Leu Lys 42S430

Gly Lys Pro Glu lie Lys lie Leu 445

Leu Gin Leu Ser Leu Pro Lys Asp 460

Leu Leu Leu He Met Asp Glu Glu 475480

Lys Phe His He Asp Trp Asp Ser 490495

He Val Ala Arg Phe Asp Gly Arg 505510

He Leu Gin Glu He His Arg Arg 525

Gin lie Thr Ala Val Lys Phe Leu 540

Lys Arg Leu Ser lie Phe Gly Lys 555 560

Met lie Leu Lys Ser Asp Glu Lys 570 575

Gin Pro Asp He Lys Ser Ser Ser 115120

Glu Glu lie He Phe Asn Gly He 130135

Leu Leu His Ser His lie Ala His 145150

Leu Ala Phe Leu Met He Asn Asp 165

Pro Arg Phe Thr Gly Ala Leu Tyr 160 pro Lys Ala Gly Gin val Asn Pro 195200

Leu Tyr Gly Pro Thr His Thr Leu 210215

Lys Ser Arg Glu Tyr Tyr lie Thr 225230

Lys Thr Val Val Arg Trp Leu Asn 245

Thr val Cys Glu Thr Thr Thr Gly 260

Thr Ser Asp Thr Trp Leu Ser Gin 275280

Arg Asp Gly Ser Lys Phe Phe Met 290295

Arg Gly Glu Phe His His lie Ala 305310

Glu Gin lie Thr Val Arg His Leu 325

Lys lie Leu Ala Tyr Asp Glu Thr 340

Thr Glu Ser Ser Pro Arg Gly Arg 355360

Gly Leu Leu Asn Arg Gin Cys He 370375

Cys Thr Tyr Phe Asp Ala Ser Phe 385390

Leu Phe Cys Glu Gly Pro Arg val 405

Asp Asn Pro Ala Lys Tyr Phe lie 420

Glu Ala He Leu Lys Lys Lys He 435440

His lie Asp Asp Tyr Glu Leu Pro 450455

Phe Met Asp Arg Asn Gin Tyr Ala 455470

Pro Gly Gly Gin Leu Val Thr Asp 485

Val Leu He Asp Met Asp Asn Val 500

Gly Ser Gly Phe Gin Gly Leu Lys 515520

Leu Gly Ser Val Glu Val Lys Asp 530535

Leu Lys Leu Pro Tyr He Asp Ser 545550

Gly Tyr Gly Gly Tyr He Ala Ser 565

WO 02/31134

Leu Phe Lys Cys Gly Ser Val Val Ala Pro He Thr Asp Leu Lys Leu 580 585590

Tyr Ala Ser Ala Phe Ser Glu Arg Tyr Leu Gly Met Pro Ser Lys Glu 595 600605

Glu Ser Thr Tyr Gin Ala Ala Ser val Leu His Asn Val His Gly Leu₍610 615620

Lys Glu Glu Asn He Leu He He His Gly Thr Ala Asp Thr LysVal

625 630 635640

His Phe Gin His Ser Ala Glu Leu He Lys His Leu He Lys AlaGly

645 650655

Val Asn Tyr Thr Met Gin Val Tyr Pro Asp Glu Gly His Asn Val Ser 660 665670

Glu Lys Ser Lys Tyr His Leu Tyr ser Thr lie Leu Lys Phe Phe Ser 675 680685

Asp Cys Leu Lys Glu Glu He Ser Val Leu Pro Gin Glu Pro Glu Glu 690 695700

Asp Glu 705 <210> 42 <211> 4541 <212> DNA <213> Homo sapiens <400> 42 gkctykgtkg wtsmagatac agatgtggtg tataaaagcg agaatggaca tgtcattaaa60 ctgaatatag aaacaaatgc taccacatta ttattggaaa acacaacttt tgtaaccttc120 aaagcatcaa gacattcagt ttcaccagat ttaaaatatg tccttctggc atatgatgtc180 aaacagattt ttcattattc gtatactgct tcatatgtga tttacaacat acacactagg240 gaagtttggg agttaaatcc tccagaagta gaggactccg tcttgcagta cgcggcctgg300 ggtgtccaag ggcagcagct gatttatatt tttgaaaata atatctacta tcaacctgat360 ataaagagca gttcattgcg actgacatct tctggaaaag aagaaataat ttttaatggg420 attgctgact ggttatatga agaggaactc ctgcattctc acatcgccca ctggtggtca480 ccagatggag aaagacttgc cttcctgatg ataaatgact ctttggtacc caccatggtt540 atccctcggt ttactggagc gttgtatccc aaaggaaagc agtatccgta tcctaaggca600 ggtcaagtga acccaacaat aaaattatat gttgtaaacc tgtatggaca aactcacact660 ttggagctca tgccacctga cagctttaaa tcaagagaat actatatcac tatggttaaa720 tgggtaagca ataccaagac tgtggtaaga tggttaaacc gacctcagaa catctccatc780 ctcacagtct gtgagaccac tacaggtgct tgtagtaaaa aatatgagat gacatcagat840 acgtggctct ctcagcagaa tgaggagccc gtgttttcta gagacggcag caaattcttt900 atgacagtgc ctgttaagca agggggacgt ggagaatttc accacatagc tatgttcctc960 atccagagta aaagtgagca aattaccgtg cggcatctga catcaggaaa otgggaagtg1020 ataaagatct tggcatacga tgaaaetact oaaaaaattt actttctgag cactgaatct1080 tctcccagag gaaggcagct gtacagtgct tctactgaag gattattgaa tcgccaatgc1140 atttcatgta atttcatgaa agaacaatgt acatattttg atgccagttt tagtcccatg1200 aatcaacatt tcttattatt ctgtgaaggt ccaagggtcc cagtggtcag cctacatagt1260 acggacaacc cagcaaaata ttttatattg gaaagcaatt ctatgctgaa ggaagctatc1320 ctgaagaaga agataggaaa gccagaaatt aaaatccttc atattgacga ctatgaactt1380 cctttacagt tgtcccttcc caaagatttt atggaccgaa accagtatgc tcttctgtta1440 ataatggatg aagaaccagg aggccagctg gttacagata agttccatat tgactgggat1500 tccgtactca ttgacatgga taatgtcatt gtagcaagat ttgatggcag aggaagtgga1560 ttccagggtc tgaaaatttt gcaggagatt catcgaagat taggttcagt agaagtaaag1620 gaccaaataa cagctgtgaa atttttgctg aaactgcctt aoattgactc caaaagatta1680 agcatttttg gaaagggtta tggtggctat attgcatcaa tgatcttaaa atcagatgaa1740 aagcttttta aatgtggatc cgtggttgca cctatcacag acttgaaatt gtatgcctca1800 gctttctctg aaagatacct tgggatgcca tctaaggaag aaagcactta ccaggcagcc1860 agtgtgctac ataatgttca tggcttgaaa gaagaaaata tattaataat tcatggaact1920 gctgacacaa aagttcattt ccaacactca gcagaattaa tcaagcacct aataaaagct1980 ggagtgaatt atactatgca ggtctaccca gatgaaggtc ataacgtatc tgagaagagc2040

WO 02/31134 aagtatcatc tctacagcac aatcctcaaa ttcttcagtg attgtttgaa ggaagaaata tctgtgctac cacaggaaco agaagaagat gaataatgga ccgtatttat acagaactga agggaatatt gaggctcaat gaaacctgac aaagagactg taatattgta gttgctccag aatgtcaagg gcagcttacg gagatgtcao tggagcagca cgctcagaga cagtgaacta gcatttgaat acacaagtcc aagtctactg tgttgctagg ggtgcagaac ccgtttcttt gtatgagaga ggtcaaaggg ttggtttcct gggagaaatt agttttgcat taaagtagga gtagtgcatg ttttcttctg ttatccccct gtttgttctg taactagttg ctctcatttt aatttcaotg gccaccatca tctttgcata taatgcacaa tctatcatct gtcctacagt ccctgatctt tcatggctga gctgcaatct aacactttac tgtaccttta taataagtgc aattctttca ttgtctatta ttatgcttaa gaaaatattc agttaataaa aaacagagta ttttatgtaa tttctgtttt taaaaagaca ttattaaatg ggtcaaagga catatagaaa tgtggatttc agcaccttcc aaagttcagc cagttatcag tagatacaat atctttaaat gaacacacga gtgtatgtct cacaatatat atacacaagt gtgcatatac agttaatgaa actatcttta aatgttattc atgctataaa gagtaaacgt ttgatgaatt agaagagatg ctcttttcca agctataatg gatgctttgt ttaatgagcc aaatatgatg aaacattttt tccaattcaa attctagcta ttgctttcct ataaatgttt gggttgtgtt tggtattgtt tttagtggtt aatagttttc cagttgcatt taattttttg aatatgatac cttgtcacat gtaaattaga tacttaaata ttaaattata gtttctgata aagaaatttt gttaacaatg caatgccact gagtgctatt ttgctctttt ggtggagaag gcttttttca aaactcttgg tccttttact tctttctctc agtgcagaat caattctcat tttcatcgta aaagcaaata gctggattat ttcatttgcc agtttctatt tagtattcca tgcctgccca attcatctgt tactgtttaa tttcaattct tctggtgaga attagaaatg aaatattttt tattcattgg ccaaaaagtt cacagacagc agtgtttgct atttactttg aattgaaggc acaaaatgca tcaattcctg tgctgtgttg acttgcagta gtaagtaact gagagcataa aataaacctg actgtatgaa gtcaatttaa gtgatgagaa catttaactt tggtgactaa agtcagaata tcttctcact tcacttaagg gatcttccag aagatatcta aaagtctgta ataagcttag aagttcagat aaatctaggc aggatactgc atttttgtgg ttttaaaaaa gtccttagga cagactgaat tatcataact tatggcatca ggaggaaact ttaaaatatc aaggaatcac tcagtcaccc tcctgttttg ttgaaggatc aaccccaaat tctgggtatt tgagtacatg tgaatcatgg atttggtatt caactttttc cctggatgct ttggaatcgt gtcttccatg ctccactggg ttcaatttaa aataggagag gctttctctt ctgaaagatc cattttaggt ctttttcaag aatagtgaac acatttttta acaaaataag ttgtaatttt aaaaggaaag ttttgcctat tttattaaga tggaaatttc tttttaggct aatttgaaat ccaactgaag ctttttaacc aatattttaa atttgaacca ctagagtttt ttatgatgca aatgattatg ttgtctgaaa ggtgtggttt tattgaatgt ctatttgagt atcatttaaa aagtatttgc cttttactgt catcatttct cttgttttat tattattatc aatgtttatc tatttttcaa ttaatttaat acagtttcta atgtgaaaga catttttctg gaacccgttt tccocttaaa cactaaagag acctcaagtg aaagcatatt gcttagtagg aaggtagaaa atgttaatcc ctgcgattct ttgagtttta atgacagggt cattttcagt aaaggaaatg ctcaccaaca catagtcacc aactattaaa ggaatcatgt gattggattt tcccctgtat acatgtaccc ttggtcataa tcccactatt tcatacatat ttatgcattg ctagattttc ctaggactcc aatagcatgc tttccaagtg ttattattcc cttaatgtta a <210> 43 <211> 691 <212> PRT <213> Homo sapiens <400> 43

Asp Thr Asp Val Val Tyr Lys Ser Glu Asn Gly His Val He Lys Leu

5 10 ¹⁵

Asn He Glu Thr Asn Ala Thr Thr Leu Leu Leu Glu Asn Thr ThrPhe

2530

Val Thr Phe Lys Ala Ser Arg His Ser Val Ser Pro Asp Leu Lys Tyr 35 4045

Val Leu Leu Ala Tyr Asp Val Lys Gin He Phe His Tyr Ser Tyr Thr 50 5560

Ala Ser Tyr Val He Tyr Asn He His Thr Arg Glu val Trp Glu Leu 65 70 7580

2100 2160 2220 2280 2340 2400 2460 2520 2580 2640 2700 2760 2820 2880 2940 3000 3060 3120 3180 3240 3300 3360 3420 3480 3540 3600 3660 3720 3780 3840 3900 3960 4020 4080 4140 4200 4260 4320 4380 4440 4500 4541

WO 02/31134

PCT7US01/31874

Val Leu Gin Tyr Ala Ala Trp Gly 90 95

He Phe Glu Asn Asn He Tyr Tyr 105 110

Leu Arg Leu Thr Ser Ser Gly Lys 125

Ala Asp Trp Leu Tyr Glu Glu Glu 140

Trp Trp Ser Pro Asp Gly Glu Arg 155160

Ser Leu Val Pro Thr Met Val He 170175

Pro Lys Gly Lys Gin Tyr Pro Tyr 185190

Thr lie Lys Leu Tyr Val Val Asn 205

Glu Leu Met Pro Pro Asp Ser Phe 220

Met val Lys Trp val Ser Asn Thr 235240

Arg Pro Gin Asn lie Ser He Leu 250255

Ala Cys Ser Lys Lys Tyr Glu Met 265270

Gin Asn Glu Glu Pro Val Phe Ser 285

Thr Val Pro Val Lys Gin Gly Gly 300

Met Phe Leu He Gin Ser Lys Ser 315320

Thr Ser Gly Asn Trp Glu Val He 330335

Thr Gin Lys He Ser Ala Ser Thr 345350 lie Ser Cys Asn Phe Met Lys Glu 365

Phe Ser Pro Met Asn Gin His Phe 380

Val Pro Val Val Ser Leu His Ser 395400

He Leu Glu Ser Asn Ser Met Leu 410415 lie Gly Lys Pro Glu He Lys He .425430

Pro Leu Gin Leu Ser Leu Pro Lys 445

Ala Leu Leu Leu lie Met Asp Glu 460

Asp Lys Phe His He Asp Trp Asp 475480

Val He Val Ala Arg Phe Asp Gly 490495

Lys He Leu Gin Glu He His Arg 505510

Asp Gin He Thr Ala Val Lys Phe 525'

Ser Lys Arg Leu Ser lie Phe Gly 540

Asn Pro Pro Glu Val Glu Asp Ser 85

Val Gin Gly Gin Gin Leu He Tyr 100

Gin Pro Asp He Lys Ser Ser Ser 115120

Glu Glu lie lie Phe Asn Gly He 130135

Leu Leu His Ser His He Ala His 145150

Leu Ala Phe Leu Met lie Asn Asp 165

Pro Arg Phe Thr Gly Ala Leu Tyr 180

Pro Lys Ala Gly Gin Val Asn Pro 195200

Leu Tyr Gly Pro Thr His Thr Leu 210215

Lys Ser Arg Glu Tyr Tyr lie Thr 225230

Lys Thr Val Val Arg Trp Leu Asn 245

Thr Val Cys Glu Thr Thr Thr Gly 260

Thr Ser Asp Thr Trp Leu Ser Gin 275280

Arg Asp Gly Ser Lys Phe Phe Met 290295

Arg Gly Glu Phe His His He Ala 305310

Glu Gin lie Thr Val Arg His Leu 325

Lys He Leu Ala Tyr Asp Glu Thr 340

Glu Gly Leu Leu Asn Arg Gin cys 355360

Gin Cys Thr Tyr Phe Asp Ala Ser 370375

Leu Leu Phe Cys Glu Gly Pro Arg 385390

Thr Asp Asn Pro Ala Lys Tyr Phe 405

Lys Glu Ala He Leu Lys Lys Lys 420

Leu His He Asp Asp Tyr Glu Leu 435440

Asp Phe Met Asp Arg Asn Gin Tyr 450455

Glu Pro Gly Gly Gin Leu Val Thr 465470

Ser Val Leu lie Asp Met Asp Asn 485

Arg Gly Ser Gly Phe Gin Gly Leu 500

Arg Leu Gly Ser Val Glu Val Lys 515 520

Leu Leu Lys Leu Pro Tyr He Asp 530 535

WO 02/31134 PCT/US01/31874

Lys Gly Tyr Gly Gly Tyr He Ala Ser Met He Leu Lys Ser Asp Glu

545 550 555560

Lys Leu Phe Lys Cys Gly Ser Val Val Ala Pro He Thr Asp LeuLys

565 570575

Leu Tyr Ala Ser Ala Phe Ser Glu Arg Tyr Leu Gly Met Pro Ser Lys 580 565590

Glu Glu Ser Thr Tyr Gin Ala Ala Ser Val Leu His Asn Val His Gly 595 600605

Leu Lys Glu Glu Asn He Leu He lie His Gly Thr Ala Asp Thr Lys 610 615620 val His Phe Gin His Ser Ala Glu Leu He Lys His Leu He LysAla

625 630 635640

Gly Val Asn Tyr Thr Met Gin Val Tyr Pro Asp Glu Gly His AsnVal

645 650655

Ser Glu Lys Ser Lys Tyr His Leu Tyr Ser Thr lie Leu Lys Phe Phe 660 665670

Ser Asp Cys Leu Lys Glu Glu lie Ser Val Leu Pro Gin Glu Pro Glu 675 680685

Glu Asp Glu 690 <210? 44 <211> 4496 <212? DNA <213? Homo sapiens <400? 44 gkctykgtkg wtsmagatac agatgtggtg tataaaagcg agaatggaca tgtcattaaa60 ctgaatatag aaacaaatgc taccacatta ttattggaaa acacaacttt tgtaaccttc120 aaagcatcaa gacattcagt ttcaccagat ttaaaatatg tccttctggc atatgatgtc180 aaacagattt ttcattatto gtatactgct tcatatgtga tttacaacat acacactagg240 gaagtttggg agttaaatcc tccagaagta gaggactccg tcttgcagta cgcggcctgg300 ggtgtccaag ggcagcagct gatttatatt tttgaaaata atatctacta tcaacctgat360 ataaagagca gttcattgcg actgacatct tctggaaaag aagaaataat ttttaatggg420 attgctgact ggttatatga agaggaactc ctgcattotc acatcgccca ctggtggtca480 ccagatggag aaagacttgc cttcctgatg ataaatgact ctttggtacc caccatggtt540 atccctcggt ttactggagc gttgtatccc aaaggaaagc agtatccgta tcctaaggca600 ggtcaagtga acccaacaat aaaattatat gttgtaaacc tgtatggacc aactcacact660 ttggagctca tgccacctga cagctttaaa tcaagagaat actatatcac tatggttaaa720 tgggtaagca ataccaagac tgtggtaaga tggttaaacc gacotcagaa catctccatc780 ctcacagtct gtgagaccac tacaggtgct tgtagtaaaa aatatgagat gacatcagat840 acgtggctct ctcagcagaa tgaggagccc gtgttttcta gagacggcag caaattcttt900 atgacagtgc ctgttaagca agggggacgt ggagaatttc accacatagc tatgttcctc960 atccagagta aaagtgagca aattaccgtg cggcatctga catcaggaaa ctgggaagtg1020 ataaagatct tggcatacga tgaaactact caaaaaatca gtgcttctac tgaaggatta1080 ttgaatcgcc aatgcatttc atgtaatttc atgaaagaac aatgtacata ttttgatgcc1140 agttttagtc ccatgaatca acatttctta ttattctgtg aaggtccaag ggtcccagtg1200 gtcagcctac atagtacgga caacccagca aaatatttta tattggaaag caattctatg1260 ctgaaggaag ctatcctgaa gaagaagata ggaaagecag aaattaaaat ccttcatatt1320 gacgactatg aacttccttt acagttgtcc cttcccaaag attttatgga ccgaaaccag1380 tatgctcttc tgttaataat ggatgaagaa ccaggaggcc agctggttac agataagttc1440 catattgact gggattccgt acteattgac atggataatg tcattgtagc aagatttgat1500 ggcagaggaa gtggattcoa gggtctgaaa attttgcagg agattcatcg aagattaggt1560 tcagtagaag taaaggacca aataacagct gtgaaatttt tgctgaaact gccttacatt1620 gactccaaaa gattaagcat ttttggaaag ggttatggtg gctatattgc atcaatgatc1680 ttaaaatcag atgaaaagct ttttaaatgt ggatccgtgg ttgcacctat cacagacttg1740 aaattgtatg ectcagcttt ctotgaaaga taccttggga tgccatctaa ggaagaaagc1800 acttaccagg cagccagtgt gctacataat gttcatggct tgaaagaaga aaatatatta1860 ataattcatg gaactgctga cacaaaagtt catttccaac actcagcaga attaatcaag1920

WO 02/31134 cacctaataa aagctggagt gaattatact atgcaggtct acccagatga aggtcataac1980 gtatctgaga agagcaagta tcatctctac agcacaatcc'tcaaattctt cagtgattgt2040 ttgaaggaag aaatatctgt gctaccacag gaaccagaag aagatgaata atggaccgta2100 tttatacaga actgaaggga atattgaggc tcaatgaaac ctgacaaaga gactgtaata2160 ttgtagttgc tccagaatgt caagggcagc ttacggagat gtcactggag cagcacgctc2220 agagacagtg aactagcatt tgaatacaca agtccaagtc tactgtgttg ctaggggtgc2280 agaacccgtt tctttgtatg agagaggtca aagggttggt ttcctgggag aaattagttt2340 tgcattaaag taggagtagt gcatgttttc ttctgttatc cccctgtttg ttctgtaact2400 agttgctctc attttaattt cactggccac catcatcttt gcatataatg cacaatctat2460 catctgtcct acagtccctg atctttcatg gctgagctgc aatctaacac tttactgtac2520 ctttataata agtgcaattc tttcattgtc tattattatg cttaagaaaa tattcagtta2580 ataaaaaaca gagtatttta tgtaatttct gtttttaaaa agacattatt aaatgggtca2640 aaggacatat agaaatgtgg atttcagcac cttccaaagt tcagccagtt atcagtagat2700 acaatatctt taaatgaaoa cacgagtgta tgtctcacaa tatatataca caagtgtgca2760 tatacagtta atgaaactat ctttaaatgt tattcatgct ataaagagta aacgtttgat2820 gaattagaag agatgctctt ttccaagcta taatggatgc tttgtttaat gagccaaata2880 tgatgaaaca ttttttccaa ttcaaattct agctattgct ttcctataaa tgtttgggtt2940 gtgtttggta ttgtttttag tggttaatag ttttccagtt gcatttaatt ttttgaatat3000 gataccttgt cacatgtaaa ttagatactt aaatattaaa ttatagtttc tgataaagaa3060 attttgttaa caatgcaatg ccactgagtg ctattttgct cttttggtgg agaaggcttt3120 tttcaaaact cttggtcctt ttacttcttt ctctcagtgc agaatcaatt ctcattttca3180 tcgtaaaagc aaatagctgg attatttcat ttgccagttt ctatttagta ttccatgoct3240 gcccaattca tctgttactg tttaatttca attcttctgg tgagaattag aaatgaaata3300 ttttttattc attggccaaa aagttcacag acagcagtgt ttgctattta ctttgaattg3360 aaggcacaaa atgcatcaat tcctgtgctg tgttgacttg cagtagtaag taactgagag3420 cataaaataa acctgactgt atgaagtcaa tttaagtgat gagaacattt aactttggtg3480 actaaagtca gaatatcttc tcacttcact taagggatct tccagaagat atctaaaagt3540 ctgtaataag cttagaagtt cagataaatc taggcaggat actgcatttt tgtggtttta3600 aaaaagtcct taggacagac tgaattatca taacttatgg catcaggagg aaactttaaa3660 atatcaagga atcactcagt caccctcctg ttttgttgaa ggatcaaccc caaattctgg3720 gtatttgagt acatgtgaat catggatttg gtattcaact ttttccctgg atgctttgga3780 atcgtgtctt ccatgctcca ctgggttcaa tttaaaatag gagaggcttt ctcttctgaa3840 agatccattt taggtctttt tcaagaatag tgaacaoatt ttttaacaaa ataagttgta3900 attttaaaag gaaagttttg cctattttat taagatggaa atttcttttt aggctaattt3960 gaaatccaac tgaagctttt taaccaatat tttaaatttg aaccactaga gttttttatg4020 atgcaaatga ttatgttgtc tgaaaggtgt ggttttattg aatgtctatt tgagtatcat4080 ttaaaaagta tttgcctttt actgtcatca tttctcttgt tttattatta ttatcaatgt4140 ttatctattt ttcaattaat ttaatacagt ttctaatgtg aaagacattt ttctggaacc4200 cgttttcccc ttaaacacta aagagacctc aagtgaaagc atattgctta gtaggaaggt4260 agaaaatgtt aatccctgcg attctttgag ttttaatgac agggtcattt tcagtaaagg4320 aaatgctcac caacacatag tcaccaacta ttaaaggaat catgtgattg gattttcccc4380 tgtatacatg tacccttggt cataatccca ctatttcata catatttatg cattgctaga4440 ttttcctagg actccaatag catgctttcc aagtgttatt attcccttaa tgttaa4496 <210> 45 <211> 29 <2125 DNA <2135 Homo sapiens <400> 45 cggtaccatg gcagcagcaa tggaaacag 29 <210> 46 <211> 39 <212> DMA <213> Hom□ sapiens <400> 46 ggagctcgcg gccgctcata tcacttttag agcagcaat ³⁹ f,

WO 02/31134 כ210>

<2U> 27 <212> DNA <213> Homo sapiens <400> 47 caagctttat cacttttaga gcagcaa <210> 48 <211> 22 <212> DNA <213 > Homo sapiens <400> 48 cacattcttg ctgcatcagt ca <210> 49 <211> 22 <212> DNA <213> Homo sapiens <400> 49 ttgggtcatc ttcaggactt ga <210> 50 <211> 27 <212> DNA <213> Homo sapiens <400> 50 caagcttacc atggccacca ccgggac <210> 51 <211> 37 <212> DNA <213> Homo sapiens <400> 51 cggatccgcg gccgctcaga ggtattcctg tagaaag

<td> &lt;210&gt;</td><td> 52</td>

<td> &lt;211&gt;</td><td> 27</td>

<td> &lt;212&gt;</td><td> DNA</td>

<td> &lt;213&gt;</td><td> Homo sapiens</td>

<td> &lt;400&gt;</td><td> 52</td>

cggatccagg tattcctgta gaaagtg <210> 53 <211> 20 <212> DNA <213> Homo sapiens <400> 53 tacgccgtgg ttgtgattga <210>

<211>

<212>

DNA

WO 02/31134

<td colspan="2"> &lt;213&gt; Homo sapiens &lt;400&gt; 54 ccatacttct cggccacgaa ²⁰</td>

<td> &lt;210&gt; 55 &lt;211&gt; 19 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;400&gt; 55 gcctgggatt gtgcactgt &lt;210&gt; 56 &lt;211&gt; 29 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;400&gt; 56</td><td> 19</td>

<td> gtgtattcaa atgctagttc actgtctct &lt;210&gt; 57 &lt;211&gt; 22 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;400&gt; 57</td><td> 29</td>

<td> agctagcact gtccagggtc ct &lt;210&gt; 58 &lt;211&gt; 25 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;400&gt; 58</td><td> 22</td>

<td> agggcccttc atcttcttct ggttc &lt;210&gt; 59 &lt;211&gt; 19 &lt;212&gt; PRT &lt;213&gt; Homo sapiens &lt;400&gt; 59</td><td> 25</td>

Val Glu Asp Asp Val Met Glu Arg Gin Arg Leu He Glu Ser Val Pro

<td> 1 Asp Ser Val</td><td> 5</td><td> 10</td><td> 15</td>

<td> &lt;210&gt; 60 &lt;211&gt; 19 &lt;212&gt; PRT &lt;213&gt; Homo &lt;400&gt; 60 Ser Thr Glu</td><td> sapiens Asn Glu Glu Gin Arg</td><td> Leu Ala</td><td> Ser Ala Arg Ala Val Pro</td>

<td> 1</td><td> 5</td><td> 10</td><td> 15</td>

Arg Asn Val <210> 61 <211> 15

WO 02/31134

<td> &lt;212 &gt; &lt;213&gt; &lt;400&gt;</td><td> PRT Homo sapiens 61</td>

Lys Glu Ala He Leu Lys Lys Lys He Gly Lys Pro Glu lie Lys 1 5 10 15