CA2421319A1 - Novel polypeptides and nucleic acids encoding the same - Google Patents

Abstract

The present invention is directed to novel polypeptides and to nucleic acid molecules encoding those polypeptides. Also provided herein are vectors and host cells comprising those nucleic acid sequences, chimeric polypeptide molecules comprising the polypeptides of the present invention fused to heterologous polypeptide sequences, antibodies which bind to the polypeptides of the present invention and to methods for producing the polypeptides of the present invention.

Description

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NOVEL POLYPEPTIDES AND NUCLEIC ACIDS ENCODING THE SAME
F~E~.D OF THE INVENTION
_, The present invention relates generally to the identification and isolation of novel DNA and to the recombinant production of novel polypeptides encoded by that DNA.
BACKGROUND OF THF~,NV~jVTION
Extracellular proteins play an important role in the formation, differentiation and maintenance of multicelluiar organisms. The fate of many individual cells, e.g., proliferation, migration, differentiation, or interaction with other cells, is typically governed by information received from other cells andlor the immediate environment. This information is often transmitted by secreted polypeptides (for instance, mitogenic factors, survival factors, cytotoxic factors, differentiation factors, neuropeptides, and hormones) which are, in turn, received and interpreted by diverse cell receptors or membrane-bound proteins. These;
secreted polypeptides or signaling molecules normally pass through the cellular secretory pathway to reach their site of action in the exuacellular envirottment.
Secreted proteins have various industrial applications, including phatxttaceuticals, diagnostics, biosensors and bioreactors. Most protein drugs available at present, such as thromboiytic agents, interferons, interletikins, erythropoietins, colony stimulating factors, and various other cytokines; are secretory proteins. Their receptors, which are membrane proteins, also have potential as therapeutic or diagnostic agents. Efforts are being undertaken by both ittdvstry and academia to identify new, native secreted proteins. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel secreted proteins. Examples of screening methods and techniques are described in the literature jsee, for example, Klein et al., Proc. Natl. Acacj,, ~1., g~:?i08-7113 (1996); U.S. Patent No. 5,536,637)].
Membrane-bound proteins and receptors can play an important role in the formation, differentiation and maintenance of multicellttlar organisms. The fate of many individual cells, e.g., proliferation, migration, di0'ertumation, or interaction with other cells, is typically governed by information received from other cells andlor the immediate environment. This information is often transmitted by secreted polypeptides (for instance, mitogenic factors, survival factors, cytotoxic factors, differentiation factors, neuropeptides, and hormones) which are, in turn, received and imerpreted by diverse cell receptors or membrane-bound proteins.
Such membrane-bound proteins and ~ll receptors include, but are not limited to, cytokine receptors, receptor kinases, receptor phosphatases, receptors involved in cell-cell interactions, and cellular adhesin molecules like selectins and integrins. For instance, ttansduction of signals that regulate cell growth and differentiation is regulated in part by phosphorylation of various _ cellular proteins. Protein tyrosine kinases, enzymes that catalyze that process, can also act as growth factor receptors. Examples include fibroblast growth factor receptor and nerve growth factor receptor.
Membrane-bound proteins and receptor molecules have various industrial applications, including as pharmaceutical atxi diagnostic agents. Receptor immuttoadhesins, for instance, can be employed as therapeutic agents WO 99/x6281 PCT/US99105028 to block receptor-ligand interaction. The membrane-bound proteins can also be employed for screening of potential peptide or small molecule intu'bitors of the relevant receptorlligand interaction. Efforts are being undertaken by both industry and academia to identify new, native receptor proteins. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel receptor proteins.
We herein describe the identification and characterization of novel secreted and transmembrane polypeptides and novel nucleic acids encoding those polypeptides.
1. R 2 Human growth arrest-specific gene 6 (gash) encodes a protein that is expressed in a variety of different tissues and which has been reported to be highly expressed during periods of serum starvation and negatively regulated during growth induction. See Manfioletti et al., Mot. Celt. Biol.
13(8):4976-4985 (1993) and Stitt et al., Cell 80:661-670 (1995). ManfioIetti et al. (1993), supra, have suggested that the gash protein is member of the vitamin K-dependent family of proteins, wherein the members of the latter family of proteins (which include, for example, Protein S, Protein C and Factor X) all play regulatory roles in the blood coagulation pathway, Thus, it has been suggested that gash may play a role in the regulation of a protease cascade relevant in growth regulation or in the blood coagulation cascade.
Given the physiological importance of the gash protein, efforts are currently being undertaken by both industry and academia to identify new, native proteins which are homologous to gash. Many of these efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel secreted and membrane-bound receptor proteins, specifncally those having homology to gash. Examples of such screening methods and techniques are described in the literature [see, for example, Klein et al., roc. Nail. Acad.
~,,, Q3:7108 7113 (1996); U.S. Patern No. 5,536,637)]. We herein describe the identification of a novel polypeptide which has homology to the gash polypeptide.

2. PR0274 The 7-transmembrane ("7TM") proteins or receptors, also referred to in the literature as G-protein coupled receptors, are specialized proteins designed for recognition of ligands and the subsequent signal transduction of information contained within those ligands to the machinery of the cell. The primary purpose of cell surface receptors is to discriminate appropniate.ligands from the various extracellular stimuli which each cell encounters, then to activate an effector system that produces an intracellular signal, thereby controlling cellular processes. (Dohhnan, H.,Arnn. ev. Biochem., øt'1:653 (1991)]. The ability of 7TM receptors to bind ligand to a recognition domain and allostetically transmit the information to an intracellular domain is a specialized feature of 7TM proteins [Kenakin, T., Pharmacol. Rev., 4$:413 (1996)]. The gene family which encodes the 7TM
receptors or G-protein linked n~eceptors encode receptors which recognize a large number of ligands, including but rat limited to, CSa, interleukin 8 and related chemokines. Research in this area suggests that distinct signals at the cell surface feed into common pathways of cell activation. [Genard, C. and Gerard, N..CUTr. Op. Immunol., 6_:140 (1994), Gerard, C. and Gerard, N.,Atm. Rev. hnttrunol., x:775 (1994)]. The superfamily of 7TM or G-protein coupled receptors contains several hundred members able to recognize various messages such as photons, ions and amino acids among others [Schwartz, T.W., et al., H.,TrenrtC In Phar~col. Sci., 7~]:213 (1996)].
(DohhTtan; H."inn. Rev. B'E~qchem., x:653 (1991)]. (Schwartz. T.W., ei al"
H.,~ur J Pharm Sci , 2:85 (1994)].

WO 99146281 PCTlUS99105028 We describe herein the identification of a novel polypeptide (designated herein as PR0274) which has homology to the 7 uansmembrane segment receptor proteins and the Fn54 protein.

3. PR030_0 The Dill' 33 protein is over-expressed in mouse testicular tumors. At present its role is unclear, however;
it may play a role in cancer. Given the medical importance of understanding the physiology of cancer, efforts are currently being under fatten to identify new, native proteins which are involved in cancer. We describe herein the identification of a novel polypeptide which has homology to Diff 33, designated herein as PR0300.

4. PR0284 Efforts acre currently being undertaken to identify and characterize novel uartsmembrane proteins. We herein describe the identification and characterization of a novel transmembrane polypeptide, designated herein as PR0284.

5. PR0296 Cancerous cells often express numerous proteins that are not expressed in the corresponding normal cell type or are expressed at different levels than in the corresponding normal cell type. Many of these proteins are involved in inducing the transformation from a nam~al cell to a cancerous cell or in maintaining the cancer phenotype.
As such, there is significant interest in identifying and characterizing proteins that are expressed in cancerous cells.
We herein describe the identification and characterization of a novel polypeptide having homology to the sarcoma-amplified protein SAS, designated herein as PR0296.

6. PR0329 Irnmunoglobulin molecules play roles in many important matntnalian physiological processes. The structure of immunoglobulin molecules has been extensively studied and it has been well documented that intact immunoglobulins possess distinct domains, one of which is the constant domain or F~ region of the immunoglobulin molecule. The F~ domain of an immunoglobulin, while not being directly involved in antigen recognition and binding, does mediate the ability of the immunoglobulin molecule, either uncomplexed or complexed with its respective antigen, to bind to F~ receptors either circulating in the serum or on the surface of cells. The ability of an F~ domain of an immunoglobulin to bind to an F~ receptor molecule results in a variety of important activities, including for example, in maiu>ting an immune response against unwanted foreign particles.
As such, there is substantial interest in identifying novel F~ receptor proteins and subunits thereof. We herein describe the identification and characterization of a novel polypeptide having homology to a high affinity immunoglobulin F~ receptor protein, designated herein as PR0329.

7. PR036~
._ Colorectal carcinoma is a malignant neoplastic disease which has a high incidence in the Western world, particularly in the United States. Tumors of this type often metastasize through lymphatic and vascular channels and result in the death of some 62,000 persons in the Un9ted States annually.

wr Monoclonal antibody A33 (mAbA33) is a murine immunoglobulin that has undergone extensive preclinical analysis and localization studies in patients inflicted with colorectal carcinoma (Welt et al., J. Clin. Oncol. 8:1894-1906 (1990} and Welt et al., J. Clin. Oncol. 12:1561-1571 (1994)). mAbA33 has been shown to bind to an antigen found in and on the surface of normal colon cells and colon cancer cells. In carcinomas originating from the colonic tnucosa, the A33 antigen is expressed homogeneously in more than 95 % of the cases. The A33 antigen, however, S has not been detecting in a wide range of other nomtaI tissues, i.e., its expression appears to be rather organ specific Therefore, the A33 antigen appears to play an important role in the induction of colorectal cancer.
Given the obvious importance of the A33 antigen in tumor cell formation andlor proliferation, there is Substantial interest in identifying homologs of the A33 antigen, In this regard, we herein describe the identification and characterization of a novel polypeptide having homology to the A33 antigen protein, designated herein as PR0362.

8. 03 The cell surface protein HCAR is a membrane-bound protein that acts as a receptor for subgroup C of the adenoviruses and subgroup B of the coxsackieviruses. Thus, HCAR may provide a means for mediating viral infection of cells in that the presence of the HCAR receptor on the cellular surface provides a binding site for viral particles, thereby facilitating viral infection.
In light of the physiological importance of membrane-bound proteins and spcfcially those which serve a cell surface receptor for viruses, efforts are currently being undertaken by both industry and academia to identify new, native membrane-bound reeptor proteins. Many of these efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel receptor proteins. We herein describe a novel membrane-bound polypeptide having homology to the cell surface protein HCAR
and to various tumor antigens inchiding A33 and carcinoembryonic antigen, designated herein as PR0363, wherein this polypeptide may be a novel cell surface virus receptor or tumor antigen.

9. Rg 0868 Control of cell numbers in ma>rmoals is believed to be determined, in part, by a balance between cell proliferation and cell death. One form of cell death, sometimes referred to as necrotic cell death, is typically charaaerized as a pathologic form of cell death resulting from some uauma or cellular injury. 1n coturast, there is another, "physiologic" form of cell death which usually proceeds in an orderly or controlled manner. This orderly ~ comrolled form of cell death is often referred to as "apoptosis" [see, e.g., liarr et al., ~olTec~ology, 12:487-493 (1994); Steller et al., S l ce, x:1445-1449 (1995)]. Apoptotic cell death naturally occurs in many physiological ~, including embryonic development and clonal selection in the immune system [Itch et al., Cell, x:233 243 (1991)]. Decreased levels of apoptotic cell death have been associated with a variety of pathological conditions, including cancer, lupus, and herpes virus infection ['fhompson, ci e, x:1456-1462 (1995)]. Increased levels of apoptotic cell death may be associated with a variety of other pathological conditions, including AIDS, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, retinitis pigmentosa, cerebellar degeneration, aplastic anemia, myocardial infarction, stroke, reperfusion injury, and toxin-induced liver disease [see, Thompson, suvral.

Apoptotic cell death is typically accompanied by one or more characteristic morphological and biochemical changes in cells; such as condensation of cytoplasm, loss of plasma membrane microvilli, segmentation of the nucleus, degradation of chromosomal DNA or loss of mitochondria) function. A
varien~ of extrinsic and intrinsic signals are believed to trigger or induce such morphological and biochemical cellular changes [Raft, ature, 3,y56:397-400 (1992); Steller, ~unra; Sachs et al., B ood, 82:15 (1993}]. For instance, they can be triggered by hormonal stimuli, such as giucocorticoid hormones for immature thymocyCes, as well as withdrawal of certain growth factors (Watanabe-Fukunaga et al., Na r , ~5 :314-317 (1992)]. Also, some identified oncogenes such as myc, re), and EIA, and tumor suppressors, like p53, have been reported to have a role in inducing apoptosis. Certain chemotherapy. drugs and some forms of radiation have likewise been observed to have apoptosis-inducing activity [Thompson, su ra .
Various molecules, such as tumor necrosis factor-a ("TNF-a"), tumor necrosis factor-~i ("TNF-Vii" or "lymphotoxin-a"), lymphotoxin-p ("LT (3"), CD30 ligand, CD27 ligand, CD40 ligand, OX-40 ligand, 4-IBB ligand, Apo-l ligand (also referred to as Fas Iigand or CD95 ligand), and Apo-2 ligand (also referred to as TRAIL) have been identified as members of the tumor necrosis factor ("TNF") family of cytokines [See, e.g., Gruss and Dower, ood, $5:3378-3404 (199; Pith et al., J. Biol. Chem., 271:12687-12690 (1996); Wiley et al., Immunity, x:673-682 (1995);
Browning et al., Cue], x:847-856 (1993); Armitage et al. Nature, 3~7:80-82 (1992), WO 97101633 published January 16, 1997; WO 97)25428 published July 17, 1997]. Among these molecules, TNF-a, TNF-(3, CD30 ligand, 4-1BB
ligand, Apo-1 ligand, and Apo-2 ligand (TRAIL) have been reported to be involved in apoptotic cell death. Both TNF-a and TNF-(3 have been reported to induce apoptotic death in susceptible tumor cells [Schmid et al., Proc. Nat).
cad, c' , 83:1881 (1986); Dealtry et al., Eur. J. Immunol., X7:689 (1987)].
Zheng et al. have reported that TNF-a is involved in post stimulation apoptosis of CD8-positive T cells [Zheng et al., Na e, 377:348-351 (1995)]. Other investigators have reported that CD30 ligand may be involved in deletion of self reactive T cells in the thymus (Amahawa et al., Cold Spring Harbor Laboratory Symposium on Programmed Cell Death, Abstr. No. 10, (1995)].
Mutations in the mouse Fas/Apo-1 receptor or ligand genes (called ,)pr and gld, respectively) have been associated with some autoimmune disorders, indicating that Apo-1 ligand may play a role in regulating the clonal deletion of self reactive lymphocytes in the periphery jKratnmer et al., ~.
Op. hntr~unol., ø:279-289 (1994);
Nagata et al., Science, 07:1449-1456 (1995)). Apo-1 ligand is also reported to induce post-stimulation apoptosis in CD4-positive T lymphocytes and in B lymphocytes, and may be involved in the elimination of activated lymphocytes when their function is no longer needed [Krammer et al., supra;
Nagata et al., su . Agonist mouse monoclonal antibodies specifically binding to the Apo-1 receptor have been reported to exhibit cell killing activity that is comparable to or similar to that ofTNF-a [Yonehara et a).,1 Exp. Med., 169:1747-1756 (1989)]:
Induction of various cellular responses mediated by such TNF family cytokines is believed to be initiated by their binding to specific cell receptors. Two distinct TNF receptors of approximately 55-kDa (TNFRl) and 75-kDa (TNFR2) have been identified [Hohman et al:, j. Biol: Chem., x:14927-14934 (1989); Brockhaus et al., Proc.
Nat). Acad. Sci., $7:3127-3131 (/990); EP 417,563, published March 20, 1991]
and human and mouse cDNAs corresponding to both receptor types have been isolated and characterized [Loetscher et al., ~, ,øx:351 (1990);
Schall et al., ~I , ø1_:361 (1990); Smith et al., Science, ~$:1019-1023 (1990); Lewis et al., Proc. Natl. Acad. Sci., X8:2830-2834 (1991); Goodwin et al., Mol. Ce,[l. Biol., j;~:3020-3026 (1991)].
Extensive polymorphisms have been associated with both TNF receptor genes (see, e.g., Takao et at., ImmunoQenetics, X7:199-203 (1993)]. Both TNFRs share the typical strucwre of cell surface receptors including extracellular;
transmembrane and intracellular regions.
S

WO 99/46281 PCT/US99105028 .
The extracellular portions of both receptors are found naturally also as soluble TNF-binding proteins [Nophar, Y.
et ai., EM~ 80 J., _9:3269 (1990): and Kohno, T. et ai., Proc. Natl. Aca~l.
Sci. U.S.A., x'1:8331 (1990)]. More recently, the cloning of recombinant soluble TNF receptors was reported by Hale et al. LJ. Cell Biochem.
Suppjement 15F, 1991, p. 113 (P424)].
The extracellular portion of type 1 and type 2 TNFRs (TNFRI and TNFR2) contains a repetitive amino acid sequence pattern of four cysteine-rich domaizLS (CRDs) designated 1 through 4, starting from the NH,-terminus. Each CRD is about 40 amino acids Iong and contains 4 to 6 cysteine residues at positions which are well conserved [Schall et al., supra; L~oetscher et al., ~nra; Smith et al., suvra; Nophar et al., supra; Kohno et al., ~_upral. In TNFRl, the approximate boundaries of the four CRDs are as follows: CRD1- amino acids 14 to about 53; CRD2- amino acids from about 54 to about 97; CRD3- amino acids from about 98 to about 138; CRD4-amino acids from about 139 to about 167. In TNFR2, CRD1 includes amino acids 17 to about 54; CRD2- amino acids from about 55 to about 97;
CRD3- amino acids from about 98 to about 140; and CRD4- amino acids from about 141 to about 179 [Banner et al., .dell, x_3:431-435 (1993)]. The potential rose of the CRDs in ligand binding is also described by Banner et al., suvra.
A similar repetitive pattern of CRDs exists in several other cell-surface proteins, including the p75 nerve growth factor receptor (NGFR) (Johnson et al., Celj, 47:545 (1986); Radeke et al., N re, 325:593 (1987)], the B
cell antigen CD40 [Stamenkovic et al., ME BO J., _8:1403 (1989)), the T cell antigen OX40 [Mallet et al., EMBO J., Q:1063 (1990)] and the Fas antigen [Yonehara et ai., supra and Itoh et al., ell, 66:233-243 (1991)]. CRDs are also found in the soluble TNFR (sTNFR)-like T2 proteins of the Shope and myxoma poxviruses [LJpton et al., Virolossv, L~0-29 (1987); Smith et al., Biochem. Biophxs. Res. Commun., 176:335 (1991);
Upton et al., ViroloQV, 184:370 (1991)]. Optimal alignment of these sequences indicates that the positions of the cysteine residues are well conserved.
These receptors are sometirues collectively referred Lo as members of the TNFINGF receptor superfamily. Recent studies on p75NGFR showed that the deletion of CRDI (lVeicher, A.A. et aL, Proc. Natl. Acad. Sci. USA, $$:159-163 (1991)] pr a 5-amino acid insertion in this domain [Yap, H. and Chao, M.V., J. Biol. Chem., X66:12099-12104 (1991)] had little or no effect on NGF binding [Yap, H. and Chao, M.V., a ra , p75 NGFR contains a proiine-rich stretch of about 60 amino acids, between its CRD4 and transmembrane region, which is not involved in NGF binding [Peetre, C. et al., Eur. J. Het~a~ol., 4_x,:414-419 (1988); Seckinger, P. et al., J. Biol. Chem., x:11966-11973 (1989); Yan, H. and Chao, M.V., su . A similar proline-rich region is found in TNFR2 but not in TNFRl.
Tl~ TNF family ligands identified to date, with the exception of lymphotoxin-a, are type D transmembrane proteins, whose C-terminus is extracellular. In contrast, most receptors in the TNF receptor (TNFR) family identified to date are type I transmembrane proteins. In both the TNF ligand and receptor families, however, homology identified between family members has been found mainly in the extracellular domain ("F:CD"). Several of the TNF
family cytokirtes, including TNF-a, Apo-1 ligand and CD40 Iigand, are cieaved proteolytically at the cell surface;
the resorting protein in each case typically forms a homotrimeric molecule that functions as a soluble cytokine. TNF
receptor family proteins are also usually cleaved pmteolytically to reiease soiubie receptor ECDs that can function as inhibitors of the cognate cytokines.
Reoezuiy, other members of the TNFR family have been identified. Such newly identified members of the TNFR family include CARL, HVEM and osteoprotegerin (OPG) [Brojatsch et al., ~1, 82:845-855 (1996);
Montgomery et al., ~, x'1:427-436 (1996); Marsters et at., J. Biol. Chem., x_2:14029-14032 (1997); Simonet et al., ~1 , $Q:309-319 (1997)1. Unlike other kt~wn TNFR-like molecules. Simonet et al., , report that OPG
contains no hydrophobic transmembrane-spanning seduence.

WO 99!46281 PCT/US99/05028 Moreover, a new member of the TNFINGF receptor family has been identified in mouse, a receptor referred to as "GTI'R" for "glucocorticoid-induced tumor necrosis factor receptor family-related gene" [Nocentini et al., ]?roc.
,~latl. Acad. Sci. USA 94:6216-6221 (1997)]. The mouse GITR receptor is a 228 amino acid type I transmembrane protein that is expressed in normal mouse T lymphocytes from thymus, spleen and lymph nodes. Expression of the mouse GITR receptor was induced in T lymphocytes upon activation with anti-CD3 antibodies, Con A or phorbol 12-myristate 13-acetate. It was speculated by the authors that the mouse GITR
receptor was involved in the regulation of T cell receptor-mediated cell death.
In Marsters et al., Curr. Biol.; 6_:750 (1996), investigators describe a full length native sequence human polypeptide, called Apo-3, which exhibits similarity to the TNFR family in its extracellular cysteine-rich repeats and resembles TNFR1 and CD95 in that it contains a cytoplasmic death domain sequence [see also Marsters et al., rr.
lo!., ø:1669 (1996)]. Apo-3 has also been referred to by other investigators as DR3, wsl-1 and TRAMP
[Chinnaiyan et al., Sc' ce, 274:990 {1996); Kitson ec al., Nature, X4:372 (I996); Bodmer et al., Immunity, ø:79 (1997)] . ' Pan et al. have disclosed another TNF receptor family member referred to as "DR4" [Pan et al., Sci , x,7ø:111-1 I3 (1997)J. The DR4 was reported to contain a cytoplasmic death damain capable of engaging the cell suicide apparatus. Pan et al. disclose that DR4 is believed to ix a r~eptor for the ligand known as Apo-2 ligand or TRAIL.
In Sheridan et al., c'ence, 277:818-821 (1997) and Pan et al., S ' ce, ?7:815-818 (1997), another molecule believed to be a receptor for the Apo-2 ligand (TRAIL) is described.
That molecule is referred to as DR5 (it has also been alternatively referred to as Apo-2). Like DR4, DRS is reported to contain a cytoplasmic death domain and be capable of signaling apoptosis.
In Sheridan et al., ,s~Dra, a receptor called DcRI (or alternatively, Apo-2DcR) is disclosed as being a potential decoy receptor for Apo-2 Iigand (TRAIL). Sheridan et al, report that DcRl can inhibit Apo-2 ligand function in vitro. See also, Pan et al., ~,upra, for disclosure on the decoy receptor referred to as TRID.
For a review of the TNF family of cytokines and their receptors; see Gruss and Dower. SUDta.
As presently understood, the cell death program contains at least three important elements - activators, inhibitors, and effectors; in C, elegaru, these elements are encoded respectively by three genes, Ced-4, Ced 9 and Ced 3 [Steller, ie , x'7:1445 (1995); Chinnaiyan et al., ci , X5:1122-1126 (1997); Wang et a1, t~, QQ:I-20 (199'1)]. Two of the TNFR family members, TNFRI and FasIApol (CD95), can activate apoptotic cell death [Chinnaiyan and Dixit, Current Biology, ø:555-562 (1996); Fraser and Evan, Wit; X5;781-784 (1996)]. TNFRl is also known to mediate activation of the transcription factor, NF-xB (Tartaglia et al" ~, 74:845-853 (I993); Hsu et al., ~gj], $4:299-308 (1996)]. In addition to some ECD homology, these two receptors share homology in their intracellular domain øCD) in an oiigometization interface known as the death domain ['fartagIia et al., supra; Nagata, ~, $x:355 (I997)]. Death domains are also found in several metazoan proteins that regulate apoptosis, nar~ly, the Drosophila protein, Reaper, and the mammalian proteins referred to as FADDIMORTl , TRADD, and RIP
[Cleaveland and lttle, ~g[t, ,$],:479-482 (1995)].
Upon ligand binding and receptor clustering, TNFR1 and CD95 are believed to recruit FADD into a death-inducing signalling complex. CD95 purportedly binds FADD directly, while TNFRl binds FADD indirectly via TRADD (Chinnaiyan et al., t~, $[,:505-512 (1995); Boldin et al:, j~ol. Chem., 7~t :387-391 (1995); Hsu et al., supra; Chinnaiyan et al., J. Bip~. Chem., x:4961-4965 (1996)]. It has been reported that FADD serves as an adaptor protein which recruits the Ced-3-related protease, MACI~iaIFLICE
(caspase 8), into the death signalling complex [Boldin et al., Celi, 85:803-815 (1996); Muzio et al., Ce 1, 85:817-827 (1996)]. MACHa/FLICE appears to be the trigger that sets off a cascade of apoptotic proteases, including the interleukin-1 p converting enzyme (ICE) and CPP32IYatna, which may execute some critical aspects of the cell death programme [Eraser and Evan, a ra .
It was recently disclosed that programmed cel! death involves the activity of members of a family of cysteine pmteases related to the C. etegans cell death gene, ced-3, and to the mammalian IL-1-converting enzyme, ICE. The activity of the ICE and CPP32IYama proteases can be inhibited by the product of the cowpox virus gene, crmA [Ray et aL, C~,11, 69:597-604 (i992); Tewari et al., Cell, 8:801-809 (1995)].
Recent studies show that CrmA can inhibit TNFRl- and CD95-induced cell death [Enari et al., Na e, 37~. :?8-81 (1995);
Tewari et al., J. Biol. Chem., x:3255-3260 (1995)].
As reviewed recently by Tewari et al., TNFRl, TNFR2 and CD40 modulate the expression of proinflatnntatory and costimulatory cytoldnes, cytolcine receptors, and cell adhesion molecules through activation of the transcription factor, NF-xB (Tewari et al., burr. 0g. Genet. Develop., 6_:39-44 (1996)]. NF-xB is the prototype of a family of dimeric uanscription factors whose subunits contain conserved Rel regions [Verma et al., Genes Develop., x:2723-2735 (1996); Baldwin, Ann. Rev. Immunol., x_4:649-681 (1996)]. In its latent form, NF-tcB is complexed with members of the IxB inhibitor family; upon inactivation of the IxB in response to certain stimuli, released NF-xB translocates to the nucleus where it binds to specific DNA
sequences and activates gene transcription.

10. PR0382 Proteases are enzymatic proteins which are involved in a large number of very important biological processes in mammalian and non-mammalian organisms. Numerous different protease ertzyrnes from a variety of different mammalian and non-matrunalian organisms have been both identified and characterized, including the serine proteases which exhibit specific activity toward various serine-containing proteins. The mammalian protease enzymes play important roles in biological processes such as, for example, protein digestion, activation, inactivation, or modulation of peptide hormone activity, and alteration of the physical properties of proteins and enzymes.
In light of the important physiological roles played by protease enzymes, efforts are currently being undertaken by both industry and academia to identify new, native protease homologs. Many of these efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel membrane-bound receptor proteins. Examples of screertirtg methods and techniques are described in the literature [see, for example, Klein et al., Proc. Natl. Acad. Sci., 23:7108-7113 (1996);
U.S. Patent No. 5,536,637)]. We herein describe the identification of novel polypeptides having homology to serine protease enzymes, designated herein as PR0382 polypeptides.

11. pR0545 The ADAM (A Disintegrin And Metalloprotease) family of proteins of which meltrin is a member may have an important role in cell interactions and in modulating cellular responses.
[see, for example, Gilpin et al., . Biol Chem., 27311):157-166 {1998)]. The ADAM proteins have been implicated in carcinogenesis. Meltrin-a (ADAM 12) is a myoblast gene product reported to be required for cell fusion. [Harris et al., J. Cell. Biochem., ~70:136-142 (1997), Yagami-Hiromasa et al., Nature, .x:652-656 (1995)]. The meltrins contain disintegrin and metalloprotease donrairts and are implicated in cell adhesive events involved in development, through the integrin binding disintegrin domain, but also have an anti-adhesive function through a zinc-dependent metalloprotease domain. [Alfandari et al., Devel. Biol., l 2 2 :314-330 (1997)]. Given the medical importance of cell fusion and modulation of cellular responses in carcinogenesis and other disease mechanisms, efforts are currently being under taken to identify new, native proteins which are involved in cell fusion and modulation of cellular responses. We describe herein the identification of a novel polypeptide which has homology to meltrin, designated herein as PR0545.
I2. PR 7 CD24 is a protein that is associated with the cell surface of a variety of different cells of the mammalian immune system, including for example, neutrophils, monocytes and some lymphocytes, for example, B lymphocytes.
CD24 has been shown to be a ligand for the platelet-associated surface glycoprotein P-selectin (also known as granule membrane protein-140 or GMP-140), a glycoprotein that is constitutively synthesized in both platelets and endothelial cells and becomes exposed on the surface of platelets when those cells become activated. In this way, P-selectin mediates the calcium-dependent adhesion of activated platelets and endothelial cells to the various cells of the immune system that express one or more ligands for the P-selectin molecule, particularly CD24. This mechanism allows for recruitment of immune system cells to locations where they are most needed, for example, sites of injury. Thus, there is substantial interest in identifying novel polypeptides that exhibit homololry to the cell surface antigens of the immune system cells. We herein describe the identification and characterization of a novel polypeptide having homology to the CD24 protein, wherein that novel polypeptide is herein designated PR0617.
13. PR070a Protein-disulfide isomerase (PDn is a catalyst of disulfide formation and isomerization during protein folding. It has two catalytic sites housed in two domains homologous to thioredoxin, one near the N terminus and the other near the C terminus. [See for example, Gilbert HF, J.Biol.Chem., 47:29399-29402 (1997}, Mayfield KJ, Science, 278:1954-1957 (1997) and Puig et al., ~Biol.Chem., 52:32988-32994 (1997)]. PDl is useful for formation of natural type disulfide bonds in a protein which is produced in aprokaryotic cell. (See also, U.S. Patent Nos.
5,700,659 and 5,700,678).
Thus, PDI and molecules related thereto are of interest, particularly for ability to catalyze the fornnation of disulfide bonds. Moreover, these molecules are generally of interest in the study of redox reactions and related processes. PDI and related molecules are further described in Darby, et al., Biochemistry 34; 11725-11735 {1995).
We herein describe the identification and characterization of novel polypeptides having homology to protein disulfide isomerase, designated herein as PR0700 polypeptides.
14. PR0702 Conglutmin is a bovine serum protein that was originally described as a vertebrate lectin protein and which belongs to the family of C-type lectins that have four characteristic domains, (I) an N-terminal cysteine-rich domain, (2) a collagen-Like domain, (3) a neck domain and (4} a carbohydrate recognition domain (CRD). Recent reports have demonstrated that bovine conglutinin can inhibit hemagglutination by influenza A viruses as a result of their lectin properties (Eda et al., Biochem. J. 316:43-48 (1996)). It has also been suggested that Iectins such as conglutinin can function as immunoglobulin-independent defense molecules due to complement-mediated mechanisms. Thus, conglutinin has been shown to be useful for purifying immune complexes ire vitro and for removing circulating WO 99/46281 PCTlUS99/05028 immune complexes from patients plasma in vivo (Lim et al., Biochem. Biophys.
Res. Commun. 218:260-266 {1996)).
We herein describe the identification and characterization of a novel polypeptide having homology to the conglutinin protein, designated herein as PR0702.
15. PR0703 Very-long-chain acyl-CoA synthetase ("VLCAS") is a long-chain fatty acid transport protein which is active in the cellular transport of long and very long chain fatty acids. [see for example, Uchida et al., J iochem (Tokyo) 119(3):565-571 (1996) and Uchiyama et al., J Biol Chem 271(48):30360-30365 {/996). Given the biological importance of fatty acid u~anspor< mechanisms, efforts are currently being under taken to identify new, native proteins which are involved in fatty acid transport. We describe herein the identification of a novel polypeptide which has homology to VLCAS, designated herein as PRO703.
16. Rg 0705 The glypicans are a family of glycosylphosphatidylinositol {GPI)-anchored proteoglycans that, by virtue of their cell surface localization and possession of heparin sulfate chains, may regulate the responses of cells to numerous heparin binding growth factors, cell adhesion molecules and extracellular matrix components. Mutations in one glypican protein cause of syndrome of human birth defects, suggesting that the glypicans may play an important role in development (Litwack et al., Dev. 211:72-87 (1998)). Also, since the glypicans may interact with the various extracellular matrices, they may also play important roles in wound healing (McGrath et al., Pathol.
183:251-252 (1997)). Furthermore, since glypicans are expressed in neurons and glioma cells, they may also play an important role in the regulation of cell division and survival of cells of the nervous system (Liang et al., J. Cell.
Biol_ 139:851-864 (1997)). It is evident, therefore, that the glypicans are an extremely important family of groteoglycans. There is, therefore, substantial interest in identifying novel polypegtides having homology to members of the glypican family. We herein describe the identification and characterization of a novel polypeptide having homology to K-glypican, designated herein as PR0705.
17. R 8 Aryl sulfatases. ate enzymes that exist in a number of different isoforms, including aryl sulfatase A (ASA), aryl sulfatase B (ASB) and aryl sulfatase C (ASC), and that function to hydrolyze a variety of differem aromatic sulfates. Aryl sti)fatases have been isolated from a variety of different animal tissues and microbial sources and their structures and functions have been extensively studied (see, e.g., Nichol and Roy, J. Biochem. 55:643-651 (1964)).
ASA deficiency has been reported to be associated with metachromatic leukodystrophy (MLD) (tiles et al., Prenat.
is n. 7(4):245-252 (/987) and Herska et al" ,Ami J. Med. Genet. 26(3):629-635 (1987)). Additionally, other groups have reported that aryl sulfatases have been found in high levels in natural killer cells of the immune system and have hypothesized a possible role for these enzyrttes in NK cell-rt>ediated cellular lysis (see, e.g., Zucker-Franklin et al., Proc. ail. Acad. Sci. USA 80(22):6977-6981 (1983)). Given the obvious physiological importance of the aryl sulfatase enzymes, there is a substantial interest in identifying novel aryl sulfatase homolog polypeptides. We herein descn'be the identification and characterization of novel polypeptides having homology to the aryl sulfatases, wherein these novel polypeptides are herein designated PR0708 polypeptides.

18. P_ RO, 20 Fibulin-1 is a cysteine-rich, calcium-bituiing. extracellular matrix (ECM) component of basement membranes and connective tissue elastic fibers and plasma protein, which has four isoforms, A-D, derived from alternative splicing. Fibulin-I is a modular glycoprotein with amino-terminal anaphlatoxin-like modules followed by nine . epidermal growth factor (EGF)-like modules and, depending on alternative splicing, four possible carboxyl termini.
. 5 Fibulin 2 is a novel extracellular matrix protein frequently found in close association with microfibrils containing either fibronectin or fibrillin. There are multiple forms of fibulin-1 that differ in their C-terminal regions that are produced through the process of alternative splicing of their precursor RNA.
[see for example Tran et al., ati '~I 15(7):479-493 (1997).]
Northern and Western blotting analysis of 16 cell lines established from tumors formed in athymic mice and malignant cell lines derived from patients indicate that low expression of fibulin-1D plays a role in tumor formation and invasion. [Qing et al., Oncogene, 18:2159-2168 (1997)]. Ovarian-cancer cells are charactei'fzed by their ability to invade freely the peritoneal cavity: It has been demonstrated that estradiol stimulates the proliferation of estrogen-receptor (ER)-positive ovarian-cancer cells, as well as expression of fibulin-1. Studies on the effect of fibulin-i on motility of the MDA-MB231 breast-cancer cell line, indicated inhibition ofhaptotactic migration of MDA-MB231 cells, atxi the authors cotxluded that fibulin-1 can inhibit cancer cell motility inn vitro and therefore has the potential to inhibit tumor invasion. [Hayashido et al., lnt J Cancer , 75(4):654-658 (1998)]
Thus, fibulin, and molecules related thereto are of interest, particularly for the use of preventing cancer.
Moreover, these molecules are generally of interest in the study of connective tissue and attachmern molecules and related mechanisms. Fibulin and related molecules are further described in Adams, et al., J. Mgl. Biol., 272(2):226-36 (1997); Kielty and Shuttleworth, Microse. Res. Tech., 38(4):413-27 (1997); and Chil ..d 3CaL,. Surg,.

12(2Supp.):i31-5 (1997).
We herein describe the identification and characterization of novel polypeptides having homology to fibulin;
designated herein as PR0320 polypeptides.
19. PRO. ?~
Oxidoreductases are that catalyze a reaction in which two molecules of a compound interact so that one molecule is oxidized and the other is reduced, with a molecule of water entering the reaction. There are many different types of oxidoreductase enzy~s that play very important physiological roles in the mammalian organism.
Some of the most important oxidoreductases inchtde, for example, lyases, lactases, cholesterol oxidases, and the like.
These enzymes play roles in such essential processes as digestion, signal transduction, maintenance of ionic homeostasis, and the like. As such, given that oxidoreductase enzymes find various essential uses in the marturiafian organism, there is a substantial interest in identifying novel oxidoreductase enzyme homology. We herein describe the identification and characterization of a novel poiypepdde having homology to oxidoreductases, designated herein as PR0324.
20. PR03~
Prostasin is a novel human seritte proteinase purified from human seminal fluid. Imtrnmohistochemical localization reveals that prostasin is present in epithelial cells and ducts of the prostate gland. The cDNA for prostasin has been cloned and characterized. Southern blot analysis, following a reverse transcription polymerise WO 9914b281 PCTlUS99l05028 chain reaction, indicates that prostasin mRNA is expressed in prostate, liver, salivary gland, kidney, lung, pancreas, colon, bronchus, renal proximal tubular cells, and prostate carcinoma LNCaP
cells. Cellular localization of prostasin trtRNA was identified within epithelial cells of the human prostate gland by in situ hybridization histochemistry. [See for example, Yu et al., J Biol Chem. (1994) 269(29):18$43-18848, and Yu et a1.,1 Biol Chem. (1994) 270(22):13483-13489].
Thus, prostasin, and molecules related thereto are of interest, particularly for the study, diagnosis and treatment of medical conditions involving the prostate. Prostasin and related molecules are further described in Yu et al., Genomics (1996) 32(3):334-340. We herein describe the identification and characterization of novel polypeptides having homology to prostasin, designated herein as PR0351 polypeptides.
21. PR0352 Buryrophilin is a milk glycoprotein that constitutes more than 40% of the total protein associated with the fat globule tttembrane in marrunalian milk. Expression of butyrophilin mRNA
has been shown to correlate with the onset of milk fat production toward the end pregnancy and is maintained throughout lactation. Buryrophilin has been identified in bovine, murine and human (see Taylor et al., Bioci~ir~,, Biophys. Acta 1306:1-ll (1996), Ishii et al., Biochim. Biophys. Acts 1245:285-292 (1995), Mather et al., J.~ Sci. 76:3832-3850 (1993) and Banghart et al., ~. Biol. Chem. 2'13:4171-4179 (1998)) and is a type I transmembrane protein that is incorporated into the fat globulin membrane. It has been suggested that buryrophilin may play a role as the principle scaffold for the assembly of a complex with xanthine dehydrogenase/oxidase and other proteins that function in the budding and release of milk-fat globules from the apical surface during lactation (Banghart et al., supra).
Given that butyrophilin plays an obviously important role in mammalian milk production, there is substantial interest in identifying novel butyrophilin homologs. We herein describe the identification and characterization of a novel polypeptide having homology to buryrophilin, designated herein as PR0352.
22. P,~t0381 The imrnuttophilins are a family of proteins that function as receptors for immunosuppressant drugs, such as cyclosporin A, FK506, and rapamycin. The immunophilins occur in two separate classes, (1) the FK506-binding proteins (FKBPs), which bind to FIC506 and rapamycin, and (2) the cyclophiiins, which bind to cyclosporin A. With regard to the FKSt?6-binding proteins, it has been reported that the FK506lFKBP complex functions to inhibit the activity of the serinelthreonine protein phosphatase 2B (calcineurin), thereby providing immunosuppressant activity (Gold, Mol. Neu,~biol. 15:285-306 (1997)). It has also been reported that the FICBP immunophilins are found in the mammalian nervous system and may be involved in axonal regeneration in the cenual nervous system thr~gh a mechanism that is independent of the process by which immunosuppression is achieved (Gold, supra). Thus, there is substantial interest in identifying novel polypeptides having homology to the FKBP immunophilins. We herein describe the identification and characterization of a novel polypepiide having homology to an FKBP immunophiiin protein, designated herein as PR0381.
23. PR 8 Mammalian cell membranes perform very important functions relating to the structural integrity and activity of various cells and tissues. Of particular interest in membrane physiology is the study of transmembrane ion channels which act to directly control a variety of physiological, pharmacological and cellular processes. Numerous ion channels nave been identified including calcium (Ca), sodium (Na) and potassium (K) channels, each of which have been analyzed in detail to determine their roles in physiological processes in vertebrate and insect cells.
One type of cell membrane-associated ion channel, the sodium channel, plays an extremely important role in a cell's ability to maintain ionic homeostasis as well as transmit intraceilular~ and extracellular signals. Voltage-gated sodium channels in brain neurons have been shown to be complexes of a pore-forming alpha unit with smaller beta-1 and beta-2 sulntnits (Isom et al., CSI 83:433-442 (1995)). Given the obvious importance of sodium channels in cellular homeostasis and other important physiological functions, there is a significant interest in identifying novel polypeptides having homology to sodium channel subunits. We herein describe the identification and characterization of a novel polypeptide having homology to the beta-2 subunit of the rat sodium channel, designated herein as PR0386.
24. PR054l1 Lecithin-cholesterol acyltransferase {"LCAT"), also known as phosphatidylcholine-sterol acyltransferase is a key enzyrtre in the intravascular metabolism of high density lipoproteins, specifically in the process of cholesterol metabolism. (see, for example, Brousseau et a1.,1. Lipid Res., 38(12):2537-2547 (I997), Hill et aL, Biochem. J., 294:879-884 (1993), and Drayna et al., Na r 327 (6123):632-634 (1987)]. Given the medical importance of lipid metabolism, efforts are currently being tinder taken to identify new, native proteins which are involved in lipid transport. We describe herein the identification of a novel polypeptide which has homology to LCAT, designated herein as PR0540.
25. PR06I5 Synaptogyrin is a synaptic vesicle protein that is uniformly disuibuted in the nervous system. The cDNA
encoding synaptogyrin has been cloned and sequenced and the sequence predicts a protein with a molecular mass of 25,900 D with four membrane-spanning domains. Synaptogyrin has been implicated in membrar>e traffic to and from the plasma membrane. Stenius et al., J. Cell. Biol. 131{fi-2):18U1-1809 (1995). In addition, a novel isoform of synaptogyrin called cellugyrin exhibits sequence identity with synaptogyrin.
In rat tissues, cellugyrin and synaptogyrins are expressed in mirror image patterns. Cellugyrin is ubiquitously present in all tissues tested with the lowest levels in brain tissue, whereas synaptogyrin protein is only detectable in brain. In rat tissues, cellugyrin and synaptogyrins are expressed in mirror image patterns. The synaptic vesicle protein synaptogyrin may be a specialized version of a ubiquitous protein, cellugyrin, with the two proteins sharing structural similarity but differing in localization. 'This finding supports the emerging concept of synaptic vesicles as the simplified and specialized form of a generic uafficking organelle. [lanz et al., J. Biol. Chem. 273(5):2851-2857 {1998)] . The sequence for cellugyrin derived from the Norway rat, Ranus norvegicus has been deposited in the Genbank database on 23 December 1997, designated accession rntntber AF039085. See also, Janz et al., J. Biol. Chem. 273 (1998), in press.
Given the medical importance of synaptic transmission, efforts are currently being under taken to identify new, native proteins that may be pan of a simplified and specialized generic trafficking organelle in the form of synaptic vesicles. We describe herein the identification of a novel polypeptide which has homology to synaptogyrin, designated herein as PR0615.

26. PR0618 Enteropeptidase is a key enzyme in the intestinal digestion cascade specifically cleaves the acidic propeptide from trypsinogen to yield active trypsin. This cleavage initiates a cascade of proteolytic reactions leading to the activation of many pancreatic zymogens.
See, for example, Matsushima et al., J. 131o1. Chem. 269(31):19976-19982 (1994), Kitamoto et al., Proc: Nat. Acad.
~, 91(16):7588-7592 (1994). Enterokinase (enteropeptidase) is a related to mammalian serine proteases involved in digestion, coagulation, and fibrinolysis. LaVallie et al., J Biol Chem., 268(31):23311-23317 (1993).
Given the medical importance of digestive processes, efforts are currently being under taken to identify new, native proteins that may be involved in digestion, coagulation; and fibrinolysis. We describe herein the identification of a novel polypeptide which has homology to enteropeptidase, designated herein as PR0618.
27. RP 0719 Lipoprotein lipase is a key enzyme that mediates the hydrolysis of triglycerides and phospholipids present in circulating plasma lipoproteins (Dugi et al., J. Biol. Chem.. 270:25396-25401 (1995)). Moreover, lipoprotein lipase has been shown to mediate the uptake of lipoproteins into cells, wherein cellular uptake of lipoproteins is initiated by binding of lipoprotein lipase to cell surface proteoglycans and to the low density lipoprotein (LDL) receptor-related protein (Krapp et al., J. Lipid Res. 36:2362-2373 (1995)).
Thus, it is clear that lipoprotein lipase plays an extremely important role in lipoprotein and cholesterol metabolism.
There is, therefore, substantial interest in identifying novel polypeptides that share sequence homology and/or biological activity with lipoprotein lipase. We herein describe the idemificauon and characterization of a novel polypeptide having sequence homology to lipoprotein lipase H, designated heein as PR0719.
28. PR
The low density lipoprotein (LDL) receptor is a membrane-bound protein that plays a key role in cholesterol homeostasis, mediating cellular uptake of lipoprotein particles by high affinity binding to its ligands, apolipoprotein (apo) B-100 and apoE. The ligand-binding domain of the LDL receptor contains 7 cysteine-rich repeats of approximately 40 amino acids, wherein each repeat contains 6 cysteines, which form 3 intra-repeat disulfide bonds.
These unique structural features provide the LDL receptor with its ability to specifically interact with apo B-100 and apoE, thereby atlowing for transport of these lipoprotein particles across cellular membranes and metabolism of their components. Soluble fragments containing the extracetlular domain of the LDL
receptor have been shown to retain the ability to interact with its specific lipoprotein ligands (Simmons et al., jL~3iol. C ;em. 272:25531-25536 {1997)).
Thus, it is clear that the LDL t~ecxptor is intimately involved in importam physiological activities related to cholesterol tnetabolism. As such, there is substantial interest in identifying novel LDL
receptor homolog proteins. We herein describe the identification and characterization of a novel polygeptide having homology to the human LDL receptor protein, designated herein as PR0724..
29. ? 2 Expression of the human gene A4 is enriched in the colonic epithelium and is transcriptionally activated on differentiation of coIonic epithelial cells in vitro (OIiva et al. , arch.
Biochem. Bionhvs. 302:183-192 (1993) and Oliva tt al., Am. J. Physiol. 272:C957-0965 (1997)). A4 cDNA contains an open reading frame that predicts a polypeptide of approximately 17 kilodaltons in size. Hydropathy analysis of the A4 protein revealed four putative membrane-spanning alpha-helices. Immunocytochernical studies of cells expressiutg A4 protein indicated that expression is localized to the endoplasmic, reticulum. The four membrane-spanning domains and the biophysical characteristics of the A4 protein suggest that it belongs to a family of integral membrane proteins called proteoligids, some of which multimerize to form ion channels. In fact, preliminary evidence has suggested that A4 may itself multimerize and take on the properties of an ion channel (OIiva et al., Arr~ J. Phvsiol.
272:C957-C965 (1997)). Given the importance of ion channels in maintaining cellular homeostasis, there is a significant interest in identifying novel polypeptides having homology to lmown and putative ion channels. We herein describe the identification and characterization of a novel polypepdde having homology to the putative ion channel protein, A4, designated herein as PR0772.
I0 38. ~R0852 Proteases are enzymatic proteins which are involved in a large number of very important biological processes in mammalian and non-mammalian orgatusms. Numerous different protease enzymes from a variety of different mammalian and non-mammalian organisms have been both identified and characterized. The mammalian protease enzymes play important roles in many different biological processes including, for example, protein digestion, activation, inactivation, or modulation of peptide hormone activity, arid alteration of the physical properties of proteins and enzymes.
In light of the important physiological roles played by protease enzymes, efforts are currently being undertaken by both industry and academia to idenfify new, native protease homologs. Many of these efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel secreted and membrane-bound receptor proteins. Examples of screening methods and techniques are described in the literature [see, for example, Klein et aL, Proc. Natl. Acad. Set., x:7108-7113 (1996); U.S. Patent No.
5,536,637)]. We herein describe the identification of novel polypeptides having homology to various protease enzymes, designated herein as PR0852 polypeptides.
31. PR 853 Studies have reported that the redox state of the cell is an important determinant of the fate of the cell.
Furthermore, reactive oxygen species have been reported to be cytotoxic, causing inflammatory disease, including tissue necrosis, organ failure, atherosclerosis, infertility, birth defects, premature aging, mutations and malignancy.
Thus, the control of oxidation and reduction is important for a number of reasons, including the control and prevention of strokes, heart attacks, oxidative stress, hypertension and may be associated with the development of malignancies. The levels of antioxidant enzymes, such as reductases, which catalyze the conversion of reactive oxygen species to water have been simwn to be low in cancer cells. In particular, malignant prostate epithelium may have lowered expression of such antioxidant enzymes [Baker et ., s to 32(4):229-233 (I997)). In this regard, reductases, are of interest. In addition, the transcription factors, NF-kappa B and AP-1, are known to be regulated by redox state and to affect the expression of a large variety of genes thought to be involved in the pathogenesis of AIDS, cancer, atherosclerosis and diabetic complications. Publications further describing this subject matter include et aL, Anticancer Res. fGreecel, 17:4599-4605 (1997), Kelsey, et al., [3r. Ji Cancer, 76(7):852-4 (1997);
Friedrich acrd Weiss. 1. TheQr, 'o1., 187(4):529-00 (1997) and Pieulle, et al., J. Bacteriol., 179(18):5684-92 (1997).
Given the physiological importance of redox reactions in tdvo, efforts are currently being under talten to identify 'new, WO 99!46281 PCT/EJS99/05028 native proteins which are involved in redox reactions. We describe herein the identification of a novel prostate specific polypeptide which has sequence similarity to reductase, designated herein as PR0853.
32. PR 860 Neurofascin is a member of the Ll subgroup of the cellular adhesion molecule ("CAM") family of nervous system adhesion molecules and is involved in cellular aggregation. CeII-cell recognition and patterning of cell contacts have a critical role in mediating reversible assembly of a wide variety or transcellular complexes in the nervous system. Cell interactions may be regulated through modulation of anlryrin binding to neurofascin. See, for example, Tuvia et al., Proc. Nat Acad. Sci., 94(24) 12957-12962 (1997).
Neurofascin has been described as a member of the Ll subgroup of the immunoglobulin superfamily implicated in neurite extension during embryonic development for which numerous isoforms have been detected at various stages of development. See also Hassel et al., J. Biol. Chem., 272(45) 28742 28749 (1997), Grtlmet., Ce,~. Tissue Red 290(2) 423-428 (1997), Gatver et al., J. Cell. Biol., 137:703-7i4 (1997), and Lambent et al., J Neurosci., 17:7025-7-36 (1997),.
Given the physiological importance of cellular adhesion rnoiecules and development of the nervous system in vivo, efforts are currently being under taken to identify new, native proteins which are involved in regulation of cellular interactions in the nervous system. We describe herein the identification and characterization of a novel polypeptide which has sequence similarity to neurofascin, designated herein as PR0860.
33. ~,R_ 8046 The CMRF35 monoclonal antibody was used to identify a cell membrane antigen, designated CMRF35, which is present on the surf~e of moliochces; neutrophils, a proportion of peripheral blood T and B lymphocytes and lymphocytic cell lines. The CMRF35 cDNA encodes a novel integral membrane glycoprotein member of the immttnoglobulin (Ig) gene superfamily. The molecule comprises (a) a single extracelluiar Ig variable domain remarkably similar to the Fc receptor for polymeric IgA and IgM, (b) a membrane-proximal domain containing a high proportion of proIine, serine and threonine residues that was predicted to be heavily O-glycosylated, (c) an unusual transtnembrane anchor that contained a glutamic acid and a proline residue and (d) a short cytoplasmic tail.
Transcripts encoding the CMRF35 protein have been detected in early mortocyric cell lines, in peripheral blood T
cells and in some B Lymphoblastoid cell lines, confirming the results of immunocytological staining. Jackson et al., Eur. J~. Imnn>ttol. 22(5):1157-1163 (1992). CMRF-35 molecules are differentially expressed in hematopoietic cells, and the expression of the antigen was shown to be markedly influenced by stimulation with mitogens and cytokines.
See, for example, Clark et al:, Exp. Hematol. 25(8):759 (1997), Daish et al., ynol. 79(1):55-63 (1993), and Clark et al., Tjssue Antigens 48:461 (1996).
Given the physiological importance of the immune system and antigens associated with various immune system cells, efforts are currently being under taken to identify new, native proteins which are expressed on various cells of the immune system. We describe herein the identification of a novel polypeptide which has sequence similarity to CMRF35, designated herein as PR0846.
34. gR0862 Lysozyme is a protein which is widely distributed in several human tissues and secretions including milk, tears and saliva. It has been demonstrated to hydrolyze Linkages between N-aeetylglucosarnines. It has been !b demonstrated to be an inhibitor of chemotaxis and of the production of toxic oxygen free radicals and may also have some role in the calcification process. As such, there is substantial interest in identifying novel polypeptides having homology to lysozyme. We describe herein the identification of a novel polypeptide which has sequence similarity to lysozyme.
S 35. PR08b4 Wnt-4 is a secreted glycoprotein which correlates with, and is required for, kidney tubulogenesis. Mice _, lacking Wnt-4 activity fail to form precubular cell aggregates; however, other aspects of mesenchymal and ureterie development are unaffected. Thus, Wnt-4 appears to act as an aucoinducer of the mesenchyme to epithelial transition that underlies nephron development. Stark et al., a a ;372(6507):679-683 (1994). In addition, members of the Wnt gene family code for cysteine-rich, secreted proteins, which are differentially expressed in the developing brain and possibly act as intercellular signaling molecules. A Wnt gene, e.g., Wnt-1 is known to be essential for specification of the midbrain cell fate. Yoshioka et al., Bj;~Birap~vs. Rel.
Co~un. 203(3):1581-1588 (1994).
Several member of the Wnt family of secreted factors are suongly implicated as regulators of mammary cellular growth and differentiation. Shimizu et al., Cell Growth Differ. 8(12) 1349-1358. Wnt-4 is normally expressed in early pregnancy. Wnt-4 may therefore be a local signal driving epithelial branching in pregnancy. Edwards PA, Biochem Soc Symp.63:21-34 (19981. See also, Lipschutz JH, Am. J. ICidnev Dis.
31(3):383-397, (1998). We descxibe herein the identification and characterizaton of a novel polygeptide which has sequence similarity to Wnt-4, designated herein as PR0864.
36. PR0792 At least two cell-derived signals have been shown to be necessary for the induction of immunoglobulin isotype switching in B-cells. The first signal is given by either of the soluble lymphokines, interleukin (IL~4 or IL-13, which induce germline epsilon transcript expression, but this alone is insufficient to trigger secretion of immouttoglobulin E (IgE). The second signal is provided by a physical interaction between B-cells and activated T-cells, basophils and mast cells, and it has been shown that the CD40JCD40 ligand pairing is crucial for mediating IgE synthesis. Additionally, amongst the numerous pairs of surface adhesion molecules that are involved in IgE
synthesis, the CD231CD21 pair appears to play a key role in the generation of IgE. CD23 is a protein that is positively and negatively regulated by factors which increase or decrease IgE
production, respectively. Antibodies to CD23 have been shown to inhibit IL-4-induced human IgE production in vitro and to inhibit antigen-specific IgE
responses in a rat model, in an isotype selective manner (Bonnefoy et al., Eur. Respir. J. Suvnl. 22:63S-66S (1996)).
CD23 ittcetacu with CD21 on B-cells, preferentially driving IgE production.
Given that the CD23 protein plays an extremely important role in the induction of a mammalian IgE response, there is significant interest in identifying novel polypeptides having homology to CD23. We herein describe the identification and characterization of a novel polypeptide having homology to CD23, designated herein as PR0792.
37.
Mindin and spottdin proteir~ are sxreted proteins that are sttucturaily related to one another and which have been identified in a variety of organisms. For example, Higashijima et al:, Dev lo 192:211-227 (1997) have reported the identification of spondin and mmdin expression in floor plate cells in the 2ebrafish embryonic axis, WO 99/4628! PCT/US99/05028 thereby suggesting that mindin and spondin prtoteins play important roles in embryonic development. This same group has reported that mindin and spondin proteins function as extracellular matrix proteins that have a high affinity for the basal lamina. (Id.). It. has been reported that F-spondin is a secreted protein that promotes neural adhesion and neurite extension (Klar et al., Cell 69:95-110 (i992) and that M-spondin is an extracellular matrix protein that localizes to muscle attachment sites in Drosophila (IJmemiya et al., ev. Bi 1.
186:165-176 (1997)). 'Thus, there is significant inteest in identifying novel polypeptides having homology to the mindin and spondin proteins. We herein describe the identification and characterization of a novel polypeptide having homology to mindin2 and mindini, designated herein as PR0866_ 38. PR0871 Cyclophilins are a family of proteins that bind to cyclosporin A and possess peptidyl-prolyl cis-trans isomerase activity (Sherry et aL, Proc. Natl. Acad. Sci. USA 95:1758-1763 (1998)). In addition, cyclophilins are secreted by activated cells and act in a cytokine-like manner, presumably via signaling through a cell surface cyclophilin receptor. Host cell-derived cyclophilin A has been shown to be incorporated into HIV-1 virions and its incorporation has been shown to be essential for viral infectiviry. Thus, one or more the cyclophilins may be directly associated with HIV-1 infectivity. Given the obvious importance of the cyclophilin proteins, there is substantial interest in identifying novel polypeptides which have sequence homology to one or more of the cyclophilin proteins.
We herein describe the identification and characterization of a novel polypeptide having homology to cyclophilin-like protein CyP-60, designated herein as PR0871.
39. PRfJ873 Enzymatic proteins play important roles in the chemical reactions involved in the digestion of foods, the biosynthesis of macromolecules, the controlled release and utilization of chemical energy, and other processes necessary to sustain life. Enzymes have also been shown to play important roles in combating various diseases and disorders. For example, liver carboxylesterases have been reported to asslSt in sensitizing human tumor cells to the cancer prodrugs. Danks et al., report that stable expression of the cDNA
encoding a carboxylesterase in Rh30 human rhabdomyosarcoma cells increased the sensitivity of the cells to the CPT-1I
cancer prodrug 8.1-fold. Cancer Res.
(1998) 58(1):20-22. The authors propose that this prodruglenzyme combination could be exploited therapeutically in a manner analogous to approaches currently under investigation with the combinations of ganciclovirlherpes simplex virus thymidine kinase and 5-fluorocytosine/cytosine deaminase. van Pelt et al. demonsuated that a 55 kD
human liver carboxylesterase inhibits the invasion of Plasmodium falciparum malaria sporozoites imo primary human hepatocytes in culture. He t 1 (1997) 27(4):688-698.
Carboxylesterases have also been found to be of importance in the dewxification of drugs, pesticides and other xenobiotics. Purified htttnart liver carboxylesterases have been shown to be involved in the metabolism of various drugs including cocaine and heroin. Prindei et at. describe the purification anti cloning of a broad substrate specificity human liver carboxylesterase which catalyzes the hydrolysis of cocaine and heroin and which may play an important role in the degradation of these drugs in human tissues. J. 8iol.
Chem. (1997) 6:272(23):14769-14775.
Brienzinsld et al. describe a spectrophotometric competitive inhibition assay used to identify drug or environmental esters that are metabolized by carboxylesterases. jZrrn Iy~e b Dispos (1997) 25(9):1089-1096.

In light of the irriportant physiological roles played by carboxylesterases, efforts are being undertaken by both industry and academia to identify new, native carboxylesterase homologs.
We herein describe the identification and characterization of a novel polypeptide having homology to carboxylesterase, designated herein as PR0873.
40. ~R094_0 CD33 is a cell-surface protein that is a member of the sialoadhesin family of proteins that are capable of mediating sialic-acid dependent binding with distinct speciftcities for both the type of sialic acid and its linkage to subterminal sugars. CD33 is specifically expressed in early myeloid and some monocyte cell lineages and has been shown to be strongly associated with various myeloid tumors including, for example, acute non-lymphocytic leukemia {ANLL). As such, CD33 has been suggested as a potential target for the treatment of cancers associated with high level expression of the protein. There is, therefore, significant interest in the identification of novel polypeptides having homology to CD33. In fact, one CD33 homolog (designated CD33L) has already been identified and described (see Takei et al., C~rtogenet. Cell Genet. 78:295-300 (1997)). We herein describe the identification of another novel polypeptide having homology to CD33, designated herein as PR0940. The novel polypeptide described herein also exhibits significant homology to the human OB binding proteins designated HSU7I382'I and HSU7I383_1 in the Dayhoff database (version 35.45 SwissProt 35).
41. P l Cadherins are a large family of transmembrane proteins. Cadherins comprise a family of calcium-dependent glycoproteins that function in mediating cell-cell adhesion in virtually alt solid tissues of multicellular organisms.
At least cadherins 1-13 as well as types B, E, EP, M, N, P and R have been identified and characterized. Among the functions cadherins are known for, with some exceptions, are that cadherins participate in cell aggregation and are associated with cell-cell adhesion sites. Recently, it has been reported that while all cadherins share multiple repeats of a cadherin specific motif believed to correspond to folding of extracellular domains, members of the cadherin superfamily have divergent strictures and, possibly, functions. In particular it has been reported that members of the cadherin superfamiiy are involved in signal transduction. See;
Suzuki, J. Cell Biochem., b1(4):531-542 {1996). Cadtterins are further described in Tanihara et al., Dell Sci., 10?(6}:1697-1704 (1994), Aberle et al., J. Cell Biochem., 61(4}:514-523 (1996) and Tanihara et al., Cell Adhes, Commun., 2(I):15-26 (I994). We herein describe the identification and characterization of a novel polypeptide having homology to a cadherin protein, designated herein as PR0941.
42. PRn944 Clostridium perfringens entemtoxin (CPE) is considered to be the virulence factor responsible far causing the symptoms of C. perfringens type A food poisoning and may also be involved in other human and veterinary illnesses (McClane, Toadcon. 34:1335-1343 (1996)). CPE carries out its adverse cellular functions by binding to an approximately 50 kD celt surface r~eptor protein designated the Clostridium perfringens enterotoxin receptor (CPE-R) to form an approxin~ely 90,000 kD complex on the surface of the cell. cDNAs encoding the CPE-R protein have been identified characterized in both human and mouse (Katahira et aL, J. Cell Biol. 136:1239-1247 (1997) and Kata>ztra et al., J. Biol. Chem. 272:26652-26658 (1997)). Since the CPE toxin has been reported to cause a variety of iihtesses in mammalian hosts arid those illnesses are initiated by binding of the CPE toxin to the CPE-R, there is WO 99l46Z8I PCT/US99/05028 significant interest in identifying novel CPE-R homologs. We herein describe the identification and characterization of a novel polypeptide having homology to the CPE-R, designated herein as PR0944.
43. PR 83 Membrane-bound proteins include not only cell-surface membrane-bound proteins, but also proteins that are found on the surface of intracellular vesicles. These vesicles are involved in exocytosis, which is the fusion of _ secretory vesicles with the cellular plasma membrane, and have two main functions. One is the discharge of the vesicle contents into the extraceilular space, and the second is the incorporation of new proteins and lipids into the plasma membrane itself. Exocytosis can be either constitutive or regulated.
All eukaryotic cells exhibit constitutive exocytosis, which is marked by the immediate fusion of the secretory vesicle after formation. In contrast, regulated exocytosis results in the accumulation of the secretory vesicles that fuse with the plasma rrzembrane upon receipt of an appropriate signal by vesicle-associated membrane proteins. Usually, this signal is an increase in the cytosolic free Ca2'' concentration. However, regulated exocytosis that is independent of Cap' has been reported (see, e.g.
Fujita-Yoshigaki et al. J. Blot. Chem. (1996) 31:271(22):13130-13134).
Regulated exocytosis is crucial to many specialized cells, including neurons (neurotransmitter release from synaptic vesicles), adrenal chromaffm cells (adrenaline secretion); pancreatic acinar cells (digestive enzyme secretion), pancreatic ~i-cells (insulin secretion), mast cells (histamine secretion), mammary cells (milk protein secretion), sperm (enzyme secretion), egg cells (creation of fertilization envelope) and adipocyces (insertion of glucose transporters into the plasma membrane) Disorders involving exocytosis are known. For example, inflammatory mediator release from mast cells leads to a variety of disorders, including asthma. Similarly, Chediak-Higashi Syndrome (CHS) is a rare autosomal recessive disease in which neutrophils, monocytes and lymphocytes contain giant cytoplasmic granules. Accordingly, the proteins involved in exocytosis are of paramount interest and efforts are being undertaken by both industry and academia to identify new, vesicle-associated proteins. For example, Skehel et al, identified a 33-kilodalton membrane protein in Aplysia, termed VAP-33, which is required for the exocytosis of neurotransmitter. c'e ce (1995) 15:269(5230):1580-1583, and NeuronharmacoloQV (1995) 34(11}:1379-1385. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel vesicle- associated membrane proteins. It is an object of the invention to provide proteins having homology to the vesicle associated protein, VAP-33, designated herein as PR0983.
44. PROlU.~'7 Proteases are enzymatic proteins which are involved in a large number of very important biological processes in mammalian and non-mammalian organisms. Numerous different protease enzymes from a variety of different mammalian and non-marritnalian organisms have been both identified and characterized. The mammalian protease enzymes play important roles in many different biological processes including, for example, protein digestion, activation, inactivation, or modulation of peptide hormone activity, and alteration of the physical properties of proteins and enzymes.
In light of the important physiological roles played by protease enzymes, efforts are currently being undertaken by both industry and academia to identify new, native protease homologs. Many of these efforts are focused on the screening of mattttnalian recombinant DNA libraries to identify the coding sequences for novel secreted proteins. Examples of screening methods and techniques are described in the literature [see, for example, Klein et al., Proc. Natl. Acad" Sci., 9,x:7108-7113 (1996); U.S. Patent No.
5,536,637)]. We herein describe the identification of novel polypeptides having homology to various protease enzymes, designated herein as PR01057 polypeptides.
45. P 01 71 Thrombospondin-1 is a trimeric high molecular weight glycoprotein that is released from platelet alpha-granules in response to thrombin stimulation and that is also a transient component of the extracellular matrix in developing acid repairing tissues (Adams, Int. 1. B]o~hem. CeII Biol. 29:861-865 (1997) and Qian et al., ro .
E~cp. Biol. Mec~ 212:199 207 (1996)). A variety of factors regulate thrombospondin expression and the protein is degraded by both extracellular and intracellular routes. Thrombospondin-1 functions as a cell adhesion molecule and also modulates cell movement, cell proliferation, neurite outgrowth and angiogenesis. As such, there is substantial interest in identifying novel polypeptides having homology to thrombospondin.
We herein describe the identification and characterization of a novel polypeptide having homology to thrombospondin, designated herein as PR0107I.
46. R 072 Studies have reported that the redox state of the cell is an important determinant of the fate of the cell.
Furthermore, reactive oxygen species have been reported to be cytotoxic, causing inflammatory disease, including tissue necrosis, organ failure, atherosclerosis, infertility, birth defects, premature aging, mutations and malignancy.
Thus, the control of oxidation and reduction is important for a number of reasons, including the control and prevention of strokes, heart attacks, oxidative stress, hypertension and may be associated with the development of malignancies. The levels of antioxidant enzymes, such as reductases, which catalyze the conversion of reactive oxygen species to water have been shown to be low in cancer cells. In particular, malignant piostate epithelium may have lowered expression of such antioxidant enzymes [Baker et al., Prostate 32(4):229-233 (1997)]. In this regard, reductases, are of interest. In addition, the transcription factors, NF-kappa B and AP-1, are known to be regulated by redox state and to affect the expression of a large variety of genes thought to be involved in the pathogenesis of AIDS, cancer, atherosclerosis and diabetic complications. Publications further describing this subject matter include Engrnatt et al., ticancer Res. ~, 17:4599-4605 (1997), Kelsey, et al., Br, J.
Cancer, 76(7):852-854 (1997);
Friedrich and Weiss, J. Theor,,Biol., 1f7(4):529-40 (1997) and Pieulle, et al., ~, B~cteriol., 179(18):5684-92 (1997).
Given the physiological importance of redox~reactions in vivo, efforts are currently being under taken to identify new, native proteins which are involved in redox reactions. We describe herein the identification of a novel polypeptide which has sequence similarity to reductase enzymes, desiignated herein as .PR01072.
47. 2 ' Protein disulfide isomerase is an enzymatic protein which is involved in the promotion of correct refolding of proteins through the establishment of correct disulfide bond formation.
Protein disulfide isomerase was initially identified l~sed upon its ability to catalyze the renaturation of reduced denatured RNAse (Goldberger et al., J. Biol.
Chem. 239:1406-1410 (1964) and Epstein et al., Cold Sprring Harbor Symp.
Quart. Biol. 28:439-449 (1963)).
Protein disulfide isomerase has been shown to be a resident enzyme of the endoplasmic reticulum which is retained in the endoplasmic reticulutn via a -KDEL or -H1DEL amino acid sequence at its C-terminus.
Given the importance of disulfide bond-forming enzymes and their potential uses in a number of different WO 99!46281 PC'T/L1S99/05028 applications, for example in increasing the yield of correct refolding of recombinantly produced proteins, efforts are currently being undertaken by both industry and academia to identify new, native proteins having homology to protein disulfide isomerase. Many of these efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel protein disulfide isomerase homologs. Examples of screening methods and techniques are described in the literature [see, for example, Klein et al., Proc. Nat!. Acad. Sri., 93:7I08-71 I3 (1996);
U.S. Patent No. 5,536,637)]. We herein describe a novel polypeptide having homology to protein disulfide isomerase, designated herein as PR01075.
48. P 0181 In Drosophila, the dorsal-ventral polarity of the egg chamber depends on the localization of the oocyte nucleus and the gurken RNA to the dorsal-anterior corner of the oocyte. Gurken protein presumably acts as a Iigand for the drosophila EGF receptor (torpedo/DER) expressed in the somatic follicle cells surrounding the oocyte.
Cornichon is a gene required in the gertnline for dorsal-ventral signaling ~(Roth et al., CeI 81:967-978 (1995)).
Cornichon, gurken and torpedo also function in an earlier signaling event that establishes posterior follicle cell fates and specifies the anterior-posterior polarity of the egg chamber. Mutations in any or all of these genes prevent the i5 formation of a correctly polarized microtubule cytoskeleton required for proper localization of the anterior and posterior determinants bicoid and oskar and for the asymmetric positioning of the oocyte nucleus. Thus, it is clear that the cornichon gene product plays an important role in early development.
We herein describe the identification and characterization of a novel polypeptide having homology to the cornichon protein, designated herein as PR0181.
49. PR
Efforts acre currently being undertaken to identify and characterize novel uansmembrane proteins. We herein describe the identification and characterization of a novel transmembrane polypeptide, designated herein as PRO195.
50. PR 5 Efforts arre currently being undertaken to identify and characterize novel secreted proteins. We herein descn'he the identification and characterization of a novel secreted polypeptide, designated herein as PR0865.
51. ~R0827 VLA-2 is an cell-surface integrin protein that has been identified and characterized in a number of mammalian organisms, including both mouse and human. VLA-2 has been shown to be a receptor on the surface of cells for echovirus-1 (EV-1) which mediates infection of VLA-2-expressing cells by EV-1 (Zhang et al.; ViroloQv 235(2)293-301 (1997) and Bergelson et al., '~ 255:1718-1720 (I992)). VLA-2 has also been shown to mediate the interaction of collagen with endothelium during in vitro vascular tube formation (Jackson et al., ~el~,Biol.~int.
18(9):859-867 (1994)). Various other integrin proteins that share various degrees of amino acid sequence homology with VLA-2 have been identified and characterized in a variety of mammalian organism. These integrins have been reported to play important roles in a variety of differern physiological functions. Therefore, there is significant interest in identifying novel polypeptides having homology to o~ or more of the integrin proteins. We herein describe the identification and characterization of a novel polypeptide having homology to VLA-2 integrin protein, WO 9914b281 PCT/US99I05028 designated herein as PR0827.
52. P 114 Many important cytokine proteins have been identified and characterized and shown to signal through specific cell surface receptor complexes. For example, the class II cytokine receptor family (CRF2) includes the interferon receptors, the interleukin-ZO receptor and the tissue factor CRFB4 (Spencer et al., J. Exp. Med. 187:571-578 (1998) and Kotenko et al., ~MBO J. 16:5894-5903 (1997)). Thus, the multitude of biological activities exhibited by the various cytoldne proteins is absolutely dependent upon the presence of cytokine receptor proteins on the surface of target cells. There is, therefore, a significant interest in identifying and characterizing novel polypeptides having homology to one or more of the cytokine receptor family. We herein describe the identification and characterization of a novel polypeptide having homology to cytotcine receptor family-4 proteins; designated herein as PR01117.
Irtoerferons {IFNs) encompass a large family of secreted proteins occurring in vertebrates. Although they were originally named for their antivirai activity, growing evidence supports a critical role for IFNs in cell growth and differentiation (laramillo et al., ,Cancer IrJvPS~t'gation 13(3):327-338 (1995)). IFNs belong to a class of negative IS growth factors having the ability to inhibit the growth of a wide variety of cells with both normal and transformed phe~types. IFN therapy has been shown to be beneficial in the treatment of human malignancies such as Karposi's sarcoma, chronic myelogenous leukemia, non-Hodgkin's lymphoma, and hairy cell leukemia as well as in the treatment of infectious diseases such as hepatitis B (Gamliel et al., Scgnninp Microseoov 2(1):485-492 (1988), Einhorn et aL, MediOnco~,,, ~Tr ,P~rm~o.~r. 10:25 29 (1993), Ringenberg et al., isso~i Medicine 85(1):21-26 (1988), Saracco et al., Journal of Gasttoenterologlr~nd ~Ie-patoioev 10:668-673 (1995), Gonzalez-Mateos et al., Hepato-Gastroe~erologv 42:893-899 (1995) and Malaguamera et al:, Plgsr~n,~cotheranv 17(5):998-1005 (1997)).
Interferons can be classified into two major groups based upon their primary sequence. Type I interferons, IFN-a and 1FN-(3, are encoded by a superfamily of intronless genes consisting of the IFN-ac gene family and a single IFN-~ gene that are thought to have arisen from a common ancestral gene. Type I interferons tray be produced by most cell types. Type II IFN, or IFN-y, is restricted to lymphocytes (T cells and natural ldIler cells) and is stimulated by nonspecific T cell activators or specific antigens in vivo.
Although both type I and type ll IFNs produce similar antiviral and anuproliferative effects, they act on disti~t cell surface receptors, wherein the binding is get~rally species specific (l.anger et al., Immttttol. Todav 9:393-400 (1988}). Both IFN-ac and IFN-~i bind~competitively to the same high affinity type I receptor, whereas IFN-y binds to a distinct type ll receptor. The presence and number of IFN receptors on the surface of a cell does not ge~rally reflect the sensitivity of the cell to IFN, although it is clear that the effects of the IFN protein is mediated through binding to a cell surface interferon receptor. As such, the identification and characterization of novel interferon receptor proteins is of extreme interest.
We herein describe the identification anrl characterization of novel interferon receptor polypeptides, designated herein as "PR01114 interferon receptor" polypeptides. Thus, the PR01114 polypeptides of the present invention represents a novel cell surface interferon receptor WO 9914b281 PCT/US99/05028 53. 0237 Carbonic anhydrase is an enzymatic protein that which aids carbon dioxide transport and release in the mammalian blood system by catalyzing the synthesis (and the dehydration) of carbonic acid from (and to) carbon dioxide and water. Thus, the actions of carbonic anhydrase are essential for a variety of important physiological reactions in the mammal. As such, there is significant interest in the identification and characterization of novel polypeptides having homology to carbonic anhydrase. We herein describe the identification and characterization of a novel polypeptide having homology to carbonic anhydrase> designated herein as PR0237.
54. PR 1 Numerous trypsin inhibitory proteins have been identified and characterized (see, e.g., Yamakawa et al., l3iochim. Biophvs. Acta 1395:202-208 (1998) and Mizuki et al., Mammalian Genome 3:274-280 (1992)). Trypsin inhibitor proteins play important roles in a variety of different physiological and biological pathways and are specifically involved in such processes as the regulation of protein degradation, digestion, and the like. Given the important roles played by such enzymatic proteins, there is significant interest in identifying and characterizing novel polypeptides having homology to known trypsin inhibitor proteins. We herein describe the identification and characterisation of a novel poIygeptide having homology to a trypsin inhibitor protein, designated herein as PR0541.
55, PR 7 Ixukocytes include monocytes, macrophages, basophils, and eosinophils and play an important role in the immune response. These cells are important in the mechanisms initiated by T
and/or B lymphocytes and secrete a range of cytokines which recruit and activate other inflammatory ceps and contribute to tissue destruction.
Thus, investigation of the regulatory processes by which leukocytes move to their appropriate destination and interact with other cells is critical. Currently, leukocytes are thought to move from the blood to injured or inflamed tissues by rolling along the endothelial cells of the blood vessel wall. This movement is mediated by transient interactions between selectins and their ligands. Next, the leukocyte must move through the vessel wall and into the tissues. This diapedesis and extravasation step involves cell activation which promotes a more stable leukocyte-endothelial cell interaction, again mediated by integrins and their ligands.
Chemokines area large family of stntcturally related polypeptide cytokines.
These molecules stimulate leukocyte movement and may explain leukocyte uatftcinng in different inflammatory situations. Chemokines mediate the expression of particular adhesion molecules on endothelial cells, and they produce chemoattractants which activate specific cell types. In addition, the chemokines stimulate proliferation and regulate activation of specific cell types.
In both of these activities, chemokines demonstrate a high degree of target cell specificity.
The chemoldne family is divided into two subfamilies based on whether two amino terminal cysteine residues are immediately adjacent (C-C) or separated by one amino acid (C X-C):
Chemoldrtes of the C-X-C family generally activate neutrophils and fibroblasts while the C-C chemokines act on a more diverse group of target cells including monocytes/macrophages, basophils, eosinophils and T lymphocytes. The known chemokines of both subfamilies are synthesized by many diverse cell types as reviewed in Thomson A. (1994) The Cytokine Handbook, 2 d Ed.
Academic Press, N.Y. Chemokines are also reviewed in Schall TJ (1994) Chemotactic Cytokines: Targets for Therapeutic Development. International Business Communications, Southborough Mass: pp 180-270; and in Paul WE (1993) Fundamental Immunology, 3rd Ed. Raven Press, N.Y. pp 822-826.

WO 99146281 PCTlUS99/05028 Known chemokines of the C-X-C subfamily include macrophage inflammatory proteins alpha and beta (MIP-I and MIP-2 ), interleukin-8 (IL-8), and growth regulated protein (GRO-alpha and beta).
MIP-2 was first identified as a 6 kDa heparin binding protein secreted by the mouse macrophage cell line RAW 264.7 upon stimulation with lipopolysaccharide (LPS). MIP-2 is a member of the C-X-C (or CXC) subfamily of chemokines. Mouse MIP-2 is chemotactic for human ntutrophils and induces local neutrophil infiltration when injected into the foot pads of mice. Rat MIP-2 shows 86% amino acid homology to the mouse MIP-2 and is chemoractic for rat neutrophils but does not stimulate migration of rat alveolar macrophages or human peripheral blood eosinophils or lymphocytes. In addition, the rat MIP 2 has been shown to stimulate proliferation of rat alveolar epithelial cells but not fibrobtasts.
Current techniques for diagnosis of abnormalities in inflamed or diseased issues mainly rely on observation of clinical symptoms or serological analyses of body tissues or fluids for hormones, polypeptides or various metabolites. Problems exist with these diagnostic techniques. First, patients may not manifest clinical symptoms at early stages of disease. Second, serological tests do not always differentiate between invasive diseases and genetic syndromes. Thus, the identification of expressed chemokines is important to the development of new diagnostic techniques, effective therapies, and to aid in the understanding of molecular pathogenesis.
To date, chemokines have been implicated in at least the following conditions:
psoriasis, inflammatory bowel disease, renal disease, arthritis, immune-mediated aIopecia, stroke, encephalitis, MS, hepatitis, and others.
In ion, non-ELR-containing chemokines have been implicated in the inhibition of angiogenesis, thus indicating that these chemokines have a rule in tumor vascularization and tutnorigenesis.
Therefore it is the object of this invention to identify polypeptides and nucleic acids encoding the same which have sequence identity and similarity with cytokine-induced neutrophil chemaattractants, M1P-1, MIP-2, and other related proteins. The efforts of this object are provided herein.
56. ; 80701 Beta neurexins and neuroligins are plasma membrane proteins that are displayed on the neuronal cell surface.
Neuroligin 1 is ertric~d in synaptic plasma membranes and acts as a splice site-specific ligand for beta neurexins as descn'bed in Ichtchenko, et al., !'e , 81(3):435-443 (1995). The extracellular sequence of neuroligin 1 is composed of a catalytically inactive esterase domain homologous to acetylcholinesterase. NeuroIigin 2 and 3 are similar in structure and sequence to neuroligin 1. All neuroligins contain an N-terminal hydrophobic sequence with the cltatacteristics of a cleaved signal peptide followed by a large esterase homology domain, a highly conserved single traasmembrane region, and a short cytoplasmic domain. The three neuroligins are alternatively spliced at the same position and are expressed at high levels only in the brain. Tight binding of the three neuroligins to beta neurexins is observed oaly for beta neurexitts lacking an insert in splice site 4. Thus, neuroligins constitute a multigene family of brain-specific proteins with distinct isofotms that may have overlapping functions in tttediating recognition processes between neurons, see Ichtchenko, et al., J. Biol: Chem., 27I(5):2676-2682 (1996). Moreover, neurexins and neuroligins have been reported as functioning as adhesion molecules in a Ca" dependent reaction that is regulated by alternative splicing of beta neumacins, i.e., see Nguyen and Sudhof, J.
Bio~. Chem., 272(41):26032-26039 (1997).
Gives the foregoing, membrane bound proteins are of interest. More generally, membrane-bound proteins and receptors caa play an impoztaru role in the formation, differentiation and maintenance of multicelhtlar organisms.
The fate of many individual cells, e.g., proliferation, migration, differentiation, or interaction with other cells, is typically governed by information received from other cells andlor the immediate environment. This information is often transmitted by secreted polypepfides {for instance, mitogenic factors, survival factors, cytotoxic factors, differentiation factors, neuropeptides, and hormones) which are, in turn, received and interpreted by diverse cell receptors or membrane-bound proteins. Such membrane-bound proteins and cell receptors include, but are not limited to, cytokine receptors, receptor kinases, receptor phosphatases, receptors involved in cell-cell interactions, and cellular adhesin molecules like selectins and integrins. For instance, transduction of signals that regulate cell growth and differentiation is regulated in part by phosphorylation of various cellular proteins. Protein tyrosine kinases, enzymes that catalyze that process, can also act as growth factor receptors.
Examples include fibroblast growth factor receptor and nerve growth factor receptor.
Membrane-bound proteins and receptor molecules have various industrial applications, inchtding as pharmaceutical and diagnostic agents. Receptor immunoadhesins, for instance, can be employed as dterapeutic agents to block receptor-ligand interaction. The membrane-bound proteins can also be employed for screening of potential peptide or small molecule inhibitors of the relevant receptorlligand interaction.
Efforts are being undertaken by both industry and academia to identify new, native membrane-bound receptor proteins, particularly those having sequence identity and/or similarity with neuroligins 1, 2 and 3. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel secreted and membrane-bound receptor proteins. Examples of screening methods and techniques are described in the literature [see, for example, Klein et al., Proc. Nato, Acad. Sci., Q3_:7108-7113 (1996); U.S. Patent No.
5,536,037)]. The results of such efforts are provided herein.
57. PRO'704 VIP36 is localized to the Golgi apparatus and the cell surface, and belongs to a family of legume Iectin homologues in the animal secretory pathway that might be involved in the trafficking of glycopmteins, glycolipids, or both. It is fiu~ther believed that V1P36 binds to sugar residues of glycosphingolipids andlor gycosylphosphatidyl-inositol anchors and might provide a Link between the extracellularlluminal face of glycolipid rafts and the cytoplasmic protein segregation machinery. Further regarding VIP36, it is believed that there is a signal at its C-terminus that matches an internalization consensus sequence which confers its ability to cycle between the plasma membrane and Golgi. See, Fiedler, et al, EMBO J., 13(7):1729-1740 (1994); Fiedler and Simons, . ci., 109(1):2?1-27b (199; Itin, et al:, MB0 33., 14(10):2250-2256 (1995). ~ It is believed that VIP36 is either the same as or very closely related to the human GP36b protein. VIP36 andlor GP36b are of irnerest.
More generally, vesicular, cytoplasmic, extracellular and membrane-bound proteins play important roles in the formation, differentiation and maintenance of multicellular ozganisms.
The fate of many individual cells, e.g., proliferation, migration, differentiation, or interaction with other cells, is typically governed by information received from other cells andlor the immediate environment. This information is often transmitted by secreted poiypeptides (for instance, mitogenic factors, survival factors, cytatoxic factors, differentiation factors, neuropeptides, and hormones) which are, in rum, received and interpreted by diverse cell receptors or membrane-bound proteins. These secreted polypeptides or signaling molecules normally pass through the cellular secretory pathway to reach their site of action in the exuaceliular envirotttnent, usually at a membrane-bound receptor protein.
Secreted proteins have various industrial applications, including use as pharmaceuticals, diagnostics, biasensors and bioreactors. In fact, most protein drugs available at present, such as thrombolytic agents, interferons, interleukins, erythropoietins, colony stimulating factors, and various other cytokines. are secretory proteins. Their receptors, which are membrane-bound proteins, also have potential as therapeutic or diagnostic agents. Receptor immunoadhesins, for instance, can be employed as therapeutic agents to block receptor-Iigand interaction.
Membrane-bound proteins can also be employed for screening of potential peptide or small molecule inhibitors of the relevant receptor/ligand interaction. Such membrane bound proteins and cell receptors include, but are not limited to, cytokine receptors, receptor kinases, receptor phosphatases, receptors involved in cell-cell interactions, and cellular adhesin molecules like selectins and integrins. Transduction of signals that regulate cell growth and differentiation is regulated in part by phosphorylation of various cellular proteins. Protein tyrosine kinases, enzymes that catalyze that process, can also act as growth factor receptors. Examples include fibroblast growth factor receptor and nerve growth factor receptor.
Efforts are being undertaken by both industry and academia to identify new, native vesicular, cytoplasmic, secreted and membrane-bound receptor proteins, particularly those having sequence identity andlor similarity with V1P36. Many efforts ate focused on the screening of matnmaiian recombinant I~NA libraries to identify the coding sequences for novel secreoed and membrane-bound receptor proteins. Examples of screening methods and techniques are described in the literature [see, for example, Klein et at., Proc.,~T~:l.
Acad. Ski"" 9:7108-7113 (1996); U.S.
Patent No. 5,536,637)].
58. PR0706 Arid phophatase proteins are secreted proteins which dephophorylate terminal phosphate groups under acidic pIi conditions. Acid phophatases contain a RI-IGXRXP amino acid sequence, which is predicted to be mechanistically sigt>ificant. Acid phosphatases may have important functions in the diagnosis and treatment of human diseases. For example, prostatic acid phosphatase is a secreted protein uniquely expressed in prostatic tissue and prostate cancer.
The level of prostatic acid phosphatase is a potential prognostic factor for local and biochemical control in prostate cancer patients treated with radiotherapy, as described in LanlCford et al., int. J. Radiat. tZrtcol. Biol.~ P 3$
hJ'~. (2):
327-333 (1997). Research suggests that a cellular immune response to prostatic acid phosphatase may mediate destructive autoimmune prostatitis, and that xenogeneic forms of prostatic acid phosphatase may prove useful for im~notherapy of prostate cancer. See Fong et al.; J.J. Im unol. 169(7): 3113-3I I7 (1997). Seminal prostatic acid phospbatase levels correlate significantly with very low sperm levels (oligospernua) in individuals over 35, see Singh et aL, ,, ingapore Med. 1. 37(b): 598-599 (1996). Thus, prostatic acid phosphatase has been implicated in a variety of human diseases, and may have an important function in diagnosis and therapy of these diseases. A series of aminobenzylphosphatic acid compounds are highly potent inhibitors of prostatic acid phosphatase, as described in Beers et al., Bioorg_ Mcd. Ghern. 4(10): 1693-1701 (1996).
More generally, extracellnlar proteins play an important role in the formation, differentiation and maintenance of multicellular organisms. The fate of many individual cells, e.g., proliferation, migration, differentiation, or interaction with other cells, is typically governed by information received from other cells and/or the immediate environment. This information is often transmitted by secreted poiypeptides (for instance, mitogenic factors, survival factors, cywtoxic factors, differentiation factors, neuropeptides, and hormones) which are, in turn, received and interpreted by diverse cell receptors or membrane-bound proteins.
These secreted polypeptides or signaling molecules normally pass through the cellular secretory pathway to reach their site of action in the extracelhilar envirantnent.

Secreted proteins have various industrial applications, including pharmaceuticals, diagnostics, biosensors and bioreactors. Most protein drugs available at present, such as thrombolytic agents, interferons, interleulcins, erythropoietins, colony stimulating factors, and various other cytolcines, are secretory proteins. Their receptors, which are membrane proteins, also have potential as therapeutic or diagnostic agents. Efforts are being undertaken by both industry and academia to identify new, native secreted proteins, particularly those having sequence identity with prostate acid phosphatase precursor and lysosomaI acid phosphatase precursor and in some cases, those having identity with DNA found in fetal heart. Many efforts are focused on the screening of mammalian recombinant DNA
libraries to identify the coding sequences for novel secreted proteins, Examples of screening methods and techniques are described in the literature [see, for example, Klein et al., Proc. Natl.
Acad. Sci., 93:7108-71 I3 (1996); U.S.
Patent No. 5,536,637)].
59. PRa707 Cadherins are a large family of transmembrane proteins. At least cadherins 1-13 as well as types B, E, EP, M, N, P and R have been characterized. Among the functions cadherins are known for, with some exceptions, cadherins participate in cell aggregation and are associated with cell-cell adhesion sites. Cadherins are further described in Tanihara, et al., J. Cell Sci., 107(6):1697-I704 (1994) and Tanihara, et al., Cell Adhes. Cotnmun., 2{1):15-26 (1994). Moreover, it has been reported that some members of the cadherin superfamily are involved in general cell-cell interaction processes including transduction. See, Suz:uki,1. Cell Biochem., 61(4):531-542 (1996).
Therefore, novel members of the cadherin superfamily are of interest.
More generally, all novel proteins are of interest, including membrane-bound proteins. Membrane-bound pzoteins and receptors can play an important role in the formation, differentiation and maintenance of muhicellular organisms. The fate of many individual cells, e.g., proliferation, migration, differentiation, or interaction with other cells, is typically governed by information received from other cells and/or the immediate environment. This infonration is often transmitted by secreted polypeptides (for instance, mitogenic factors, survival factors, cytotoxic factors, differentiation factors, neuropeptides, and hormones) which are, in turn, received and interpreted by diverse cell receptors or membrane-bound proteins. Such membrane-bound proteins and cell receptors include, but are not limited to, cytokine receptors, receptor kinases, receptor phosphatases, receptors involved in cell-cell interactions, and cellular adhesin molecules like selectins and integrins. For instance, transduction of signals that regulate cell growth and differentiation is regulated in part by phosphorylation of various cellular proteins. Protein tyrosine kittases, enzymes that catalyze that process, can also act as growth factor receptors. Examples include fibroblast growth factor receptor and nerve growth factor receptor.
Membrane-bound proteins and receptor molecules have various industrial applications, including as pharmaceutical and diagnostic agents. Receptor immunoadhesins, for instance, can be employed as therapeutic agents to block receptor-ligand interaction. The membrane-bound proteins can also be employed for screening of potential peptide or small molecule inhibitors of the relevant receptorlligand interaction.
Efforts are being ut~ertaken by both itulustry and academia to identify new, native secreted and membrane-bound receptor proteins, particularly membrane bound proteins having identity with cadherins. The results of such efforts are provided herein.

WO 99!46281 PC1'/US99105028 60. PR0322 Proteases are enzymatic proteins which are involved in a large number of very important biological processes in mamrnaIian and non-mammalian organisms. Numerous different protease enzymes from a variety of different marr>rnalian and non-marmnalian organisms have been both identified and characterized, including the serine proreases which exhibit specific activity toward various serine-containing proteins. The mammalian protease enzymes play important roles in biological processes such as, for example, protein digestion, activation, inactivation, or modulation of peptide hormone activity, and alteration of the physical properties of proteins and enzymes.
Neuropsin is a novel serine protease whose mRNA is expressed in the central nervous system. Mouse neuropsin has been cloned, and studies have shown that it is involved in the hippocampal plasticity. Neuropsin has also been indicated as associated with extracellular matrix modifications and cell migrations. See, generally, Chen, et al., a osci., 7(2):5088-5097 (1995) and Chen, et al., J. H,;'tstochem.
Cvtochem., 46:313-320 (1998).
Efforts are being undertaken by both industry and academia to identify new, native membrane-bound or secreted proteins, particularly those having homology to neuropsin, serine protease, neurosin and trypsinogen. Marry efforts are focused on the screening of marnr;>alian recombinant DNA libraries to identify the coding sequences for novel secreted and membra~-bound receptor proteins. Examples of screening methods and techniques are described IS in the literature [see, for example, Klein et al., Proc. Nat!. Acad. Sci., Q~:7108-7113 (1996); U.S. Patent No.
5,S36,637)).
61. PR0526 Protein protein interactions include those involved with receptor and antigen complexes and signaling mechanisms. As more is known about the structural and functional mechanisms underlying protein-protein interactions, protein-protein interactions can be more easily manipulated to regulate the particular result of the protein-protein interaction. Thus, the underlying mechanisms of protein-protein interactions are of interest to the scientific and medical community.
All proteins containing Ieucine-rich repeats are thought to be involved in protein-protein interactions.
heucine-rich repeats are short sequence motifs present in a ntunber of proteins with diverse functions and cellular locations. The crystal structure of ribonuclease inhibitor protein has revealed that leucine-rich repeats correspond to beta-alpha structural units. These units are arranged so that they form a parallel beta-sheet with one surface exposed to solvent, so that the protein acquires an unusual, nonglobuiar shape. These two features have been indicated as responsible for the protein-binding functions of proteins containing Ieucine-rich repeats. See, Kobe and Deisenhofer, TreO~ds Biochem. Sci., 19(1.0):415-421 (Oct. 1994).
A study has begirt reported on leucine-rich proteoglycans which serve as tissue organizers, orienting and ordering collagen fibrils during ontogeny and are involved in pathological processes such as.wound healing, tissue repair, and tumor stroma formation. Iozzo, R. V:, Crit. Rev: Bloc em.,~pj.
BioL, 32(2):141-174 (1997). Others studies implicating Ieucine rich proteins in wound healing and tissue repair are De La Salle, C., et al., Vouv. Rev:
Fr. Hematol: (), 37(4)215-222 (I995), reporting mutations in the leucine rich motif in a complex associated with the bleeding disorder Bernard-Sootier syndrome, Chlemetson, K. J., ~~ombiHaemost: (Germany), 74(1):111-i l6 (7uly 1995), reporting that platelets have Ieucine rich repeats and Ruosiahti, E. L, et al., W09110727-A by La Jo1)a Cancer Research Foutrdation reporting that decorin bimling to transforming gmwth factor~i has involvement in a treatment for cancer, wound healing and scarring. Related by function to this group of proteins is the insulin like WO 99/46281 PCT/US99l05028 growth factor (IGF), in that it is useful in wound-healing and associated therapies concerned with re-growth of tissue, such as connective tissue, skin and bone; in promoting body growth in humans and animals; and in stimulating other growth-related processes. The acid labile subunit (ALS) of IGF is also of interest in that it increases the half life of IGF and is pan of the IGF complex inin vivo. ALS is further described in Leong and Baxter, Mol. Endocrinol., 6(6):870-876 (1992); Baxter, J. Biol. Chem., 264(20}:11843-11848 (1989}: and Khosravi, et al., J. Ciin. Er~docrinol.
M~tab., 82(12):3944-3951 (I997).
Another protein which has been reported to have leucine-rich repeats is the SLIT protein which has been reported to be useful in treating neuro-degenerative diseases such as Alzheimer's disease, nerve damage such as in Parkinson's disease, and for diagnosis of cancer, see, Artavanistsakonas, S, and Rothberg, J. M., W09210518-A1 by Yale University. Also of interest is LIG-1, a membrane glycoprotein that is expressed specifically in glial cells in the mouse brain, and has Ieucine rich repeats and immunoglobulin-like domains. Suzuki, et al., I. Bioli Chem.
(U.S.), 271(37}:22522 (1996). Other studies reporting on the biological functions of proteins having ieucine rich repeats include: Tayar, N., et al., Mol. Cell EndocririoL; (Ireland), 125(1-2):65-70 (Dec. 1996) (gonadotropin receptor involvement); Miura, Y., et al., ~lippon Rinsho (Japan), 54(7):1784-1789 (July 1996) (apoptosis involvement); Harris, P. C., et al., J. Am. Soc.,~Tephrol., 6(4):1125-1133 (Oct. 1995) (kidney disease involvement).
I S Efforts are therefore being undertaken by both industry and academia to identify new proteins having Ieucine rich repeats to better understand protein-protein interactions. Of particular interest are those proteins having leucine rich repeats and identity or similarity to known proteins having leucine rich repeats such as ALS: Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel secreted and membrane bound proteins having leucine rich repeats. Examples of screening methods and techniques are described in the literature [see, for example, HIein et al., )'roc. Natl.
Acad. Sci., x:7108-7113 (I996); U.S.
Patent No. 5.536,637)].
62. P~531 Cadherins are a large family of ttansmembrane proteins. Cadherins comprise a family of calcium-dependent glycoproteins that function in mediating cell-cell adhesion in virtually ail solid tissues of multicellular organisms.
At least cadherins 1-13 as well as types B, E, EP, M, N, P and R have been characterized. Among the functions cadherins are known for, with some exceptions, cadherins participate in cell aggregation and are associated with cell-cell adhesion sites. Recently, it has been reported that while all cadherins share multiple repeats of a cadherin specific ~tif believed to correspond to folding of exuaceliular domains, members of the cadherin superfamily have divergent structures and, possibly, functions. In particular it has been reported that members of the cadherin superfatnily are involved in signal uansduction. See, Suzttla, ~. CeII
Biochem., 61(4):531-542 (1996). Cadherins are further described in Tanihara, et al., ~ Cgll Sci., 107(6):1697-1704 (1994), Aberle, et al., J. Cep ioche ., 61(4):514-523 (1996) and Tanihara, et al., Cell Adhes. Corrmtun., 2(1):15-26 {1994).
Protocadherins are members of the cadherin superfamily which are highly expressed in the brain. In some 3~ studies, protocadherins have shown cell adhesion activity. See, Sano, et al., EMBO J., 12(6):2249-2256 (1993).
However, studies have also shown that some protocadherins, such as protocadherin 3 (also referred to as Pcdb3 or pc3), .do not show strong calcium dependent cell aggregation activity. See, Sago, et al., Genomics, 29(3):631-640 (1995) for this study and further characteristics of Pcd63.

WO 99!46281 1'CTIUS99I05028 Therefore, novel members of the cadherin superfamily are of interest. More generally, all membrane-bound proteins and receptors are of interest: Such proteins can play an important role in the formation, differentiation and maintenance of multicellular organisms. The fate of many individual cells, e.g., proliferation, migration, differentiation, or interaction with other cells, is typically governed by information received from other cells andlor the immediate environment. This information is often transmitted by secreted polypeptides (for instance, mitogenic factors, survival factors, cytotoxic factors, differentiation factors, neuropeptides, and hormones) which are, in turn, ttceived and interpreted by diverse cell receptors or membrane-bound proteins.
Such membrane-bound proteins and cell receptors irxlude, but are not limited to, cytokine receptors, receptor kinases, receptor phosphatases, receptors involved in cell-cell interactions, and cellular adhesin molecules like selectins and integrins. For instance, transduction of signals that regulate cell growth and differentiation is regulated in part by phosphorylation of various cellular proteins. Protein tyrosine kinases, enzymes that catalyze that process, can also act as growth factoz receptors. Examples include fibroblast growth factor receptor and nerve growth factor receptor.
Membrane-bound proteins and receptor molecules have various industrial applications, inchtding as pharmaceutical and diagnostic agems. Receptor imttruttoadhesins, for instance, can be employed as therapeutic agents to block receptor-ligand interaction. The membrane-bound proteins can also be employed for screening of potential peptide or small molecule inhibitors of the relevant receptorlligand interaction.
Efforts are therefore being undertaken by both industry and academia to identify new, native membrane bound proteins, particular those having sequence identity with protocadherins, especially 3 and 4. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel membrane-bound proteins. Provided herein are the results of such efforts.
63. PR0534 Protein disulfide isomerase is an enzymatic protein which is involved in the promotion of correct refolding of proteins through the establishment of correct disulfide bond fot~tion.
Protein disulfide isomerase was initially fled based upon its ability to catalyze the renaturation of reduced denatured RNAse (Goldberger et al., J.J. Biol.
he . 239:1406-1410 (1964) and Epstein et al., Cold Siring arbor Syr~t p.
0~.~ant. Biol. 28:439-449 (1963)).
Protein disulfide isomerase has been shown to be a resident enzyme of the endoplasmic reticulum which is retained in the endoplasmic reticuhtm via a -ICDEL or -HDEL amino acid stquence at its C-termitnts. Protein disulfide isomerase and related proteins are further described in Laboissiere, tt al., J. Biol. Chem., 270(47:2800fi-28009 (1995); Jeettes, et al., ~, 193(2):151-156 (1997; Koivut~n, et al., en ' ~ , 42(3):397-404 (1997); and Desilva, et al., DNA CeI3'Biol,., 15(1):9-16 (1996). These studies indicate the importance of the identification of protein disulfide related proteins.
More generally, and also of interest are all novel membrane-bound proteins and receptors. Such proteins can play an important role in the formation, differentiation and maintenance of multicellular organisms. The fate of many individual cells, e.g., proliferation, migration, differentiation, or interaction with other cells, is typically governed by information received from other cells andlor the immediate environment. This information is often transmitted by secreted polypeptides (for instance, mitogenic factors, survival factors, cytotoxic factors, differentiation factors, neuropeptides, and hormones) which are, in turn, received and imerpreted by diverse cell receptors or rnembra~-bound proteins. Such membrane-boutxl proteins and .cell receptors include, but are not limited to, cytokine receptors, receptor kinases, receptor phosphatases, receptors involved in cell-cell interactions, and cellular adhesin WO 99146281 PCTlUS99l05028 molecules like selectins and integrins. For instance, transduction of signals that regulate cell growth and differentiation is regulated in pan by phosphorylation of various cellular proteins. Protein tyrosine kinases, enzymes that catalyze that process, can also act as growth factor receptors. Examples include fibroblast growth factor receptor and nerve growth factor receptor.
Membrane-bound proteins and receptor molecules have various industrial applications, including as pharmaceutical and diagnostic agents. Receptor itnmunoadhesins, for instance, can be employed as therapeutic agents to block receptor-ligand interaction. The membrane-bound proteins can also be employed for screening of potential peptide or small molecule inhibitors of the relevant receptorlligand interaction.
Given the importance of membrane bound proteins, efforts are under way to identity novel membrane bound proteins. Moreover, given the importance of disulfide bond-forming enzymes and their potential uses in a number of different applications, for example in increasing the yield of correct refolding of recombittantly produced proteins, efforts are currently being undertaken by both itiaus>ry and academia to identify new, native proteins having sequence identity with protein disulfide isomerase, Many of these efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel protein disulfide isomerase homologs. We herein describe a novel polypeptide having sequence identity with protein disulfide isomerase and the nucleic acids encoding the same.
64. PR0697 Secreted frizzled related proteins (sFRPs) are related to the frizzled family of transmembrane receptors.
The sFRPs are approximately 30 kDa in size, and each contains a putative signal sequence, a frizzled-Like cysteine-rich domain, and a conserved hydrophilic carboxy-terminal domain. It has been reported that sFRPs may function to modulate Wnt signaling, or function as ligands for certain receptors.
Ratmer, et al., PNAS USA, 94(7):2859-2863 (1997). Therefore, sFRPs and proteins having sequence identity andlar similarity to sFRPs are of interest.
Another secreted protein of interest is any member of the family of secreted apopwsis-related proteins (SARPs). Expression of SARPs modifies the intracellular levels of beta-catettin, suggesting that SARPs interfere with the Wnt-frizzled proteins signaling pathway. Melkonyan, et al., pNAS USA, 94(25):13636-13641 (1997).
Therefore, SARPs and proteins having sequence identity andlor similarity w SARPs are of interest.
In addition to sFRPs and SARPs, many extxacellular proteins are of interest.
Extracellular proteins play an important role in the formation, differentiation and maintenance of multicellular organisms. The fate of marry individual cells, e.g., proliferation, migration, differentiation, or interaction with other, cells, is typically governed by information received from other cells andlor the immediate environment.
This information is often transmitted by secreted polypegtides (for iactance, mitogenic factors, survival factors, cytotoxic factors, differentiation factors, neutopeptides, and hormones) which are, in txun, received and interpreted by diverse cell receptors or membrane-bound proteins. These secreted polypeptides or signaling molecules normally pass through the cellular secretory pathway to reach their site of action in the extracellular environment.
Secreted proteins have various industrial applications, including pharmaceuticals, diagnostics, biosensors land bioreactors. Most protein drugs available at present, such as thrombolytic agents, interferons, interleukins, erythropoietins, colotry stimulating factors, and various other cytokines, are secretory proteins. Their receptors, which are membrane proteins, also have potential as therapeutic or diagnostic agents.

Efforts are being undertaken by both industry and academia to identify new, native secreted proteins, particularly those having sequence identity or similarity with sFRP-2 and SARP-1. Many efforts are focused on the screening of mattltnalian recombinant DNA libraries to identify the coding sequences for novel secreted proteins.
Examples of screening methods and techniques are described in the literature [see, for example, Klein et al., Proc.
Natl. Acad. Sci., 93:7108-7113 (1996); U.S. Patent No. 5,536,637)).
65. PR0717 Efforts are being undertaken by both industry and academia to identify new, native transmembrane receptor proteins. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel receptor proteins. The results of such efforts are provided herein.
66. PR 731 Cadherins are a large family of transmembrane proteins. Cadlierins comprise a family of calcium-dependent glycoproteins that function in mediating cell-cell adhesion in virtually all solid tissues of multicellular organisms.
At least cadherins 1-13 as welt as types B, E, EP, M, N, P and R have been characterized. Among the ftmctions cadherins are known for, with some exceptions, cadherins participate in cell aggregation and are associated with cell-cell adhesion sites. Recently, it has been reported that while all cadherins share multiple repeats of a cadherin specific motif believed to correspond to folding of exuacellular domains, members of the cadherin superfamily have divergent structures and, possibly, functions, In particular it has been reported that members of the cadherin superfamily are involved in signal transduction. See, Suzuki,1. Cell Biochem., 61(4):531-542 (1996). Cadherins are further described in Tanihara, et al., J. Cell Sci., 107(6):1697-1704 (1994), Aberle, et al., J. Cell Biochem., 61(4):514-523 (1996) and Tanihara, et al., Cell Adhes: Commun., 2(1):15-26 (1994).
Protocadherins are members of the cadherin superfamily which are highly expressed in the brain. In some studies, protocadherins have shown cell adhesion activity, See, Sano; et al., Elv~B_O-J., 12(6):2249-2256 (1993).
However, studies have also shown that some protocadherins, such as protocadherin 3 (also referred to as Pcdh3 or pc3), do not show strong calcium dependent cell aggregationactiviry. See, Sago, et al., Genomics, 29(3):631-640 (1995) for this study and further characteristics of Pcdh3.
Therefore, novel members of the cadherin superfamily are of interest. More generally, all membrane-bound proteins and receptors are of interest: Such proteins can play an important role in the formation, differentiation and maintenance of multicellular organisms. The fate of many individual cells, e.g., proliferation, migration, differentiation, or interaction with other cells, is typically governed by information received from other cells andlor the immediate environment. This information is often transmitted by secreted polypeptides (for instance, mitogenic factors, survival factors, cytotoxic factors, differentiation factors, neuropeptides, and hormones) which are; in turn, received and interpreted by diverse cell receptors or membrane-bound proteins.
Such membrane-bound proteins and cell receptors include, but are not limited to, cytokine receptors; receptor kinases, receptor phosphatases, receptors involved in cell-cell interactions, and cellular adhesin molecules like selectins and integrins. For instance, transduction of signals that regulate cell growth and differentiation is regulated in part by phosphorylation of various cellular proteins. Protein tyrosine kinases, enzymes that catalyze that process, can also act as growth factor receptors. Examples include fibroblast growth factor receptor and nerve growth factor receptor.

Membrane-bound proteins and receptor molecules have various industrial applications, including as pharmaceutical and diagnostic agents. Receptor immunoadhesins, for instance, can be employed as therapeutic agents to block receptor-ligand interaction. The membrane-bound proteins can also be employed for screening of potential peptide or small molecule inhibitors of the relevant receptor/ligand interaction.
Efforts are therefore being undertaken by both industry and academia to identify new, native membrane botmd proteins, particular those having sequence identity with protocadherins, especially 4, 68, 43, 42, 3 and 5.
Many efforts are focused on the screening of manttt>itliatt recombinant DNA
libraries to identify the coding sequences for novel membrane-bound proteins. Provided herein are the results of such efforts.
67. ' PR0218 Efforts are being undertaken by both industry and academia to identify new, native membrane bound proteins, particularly those having sequence identity with membrane regulator proteins. Many efforts are focused on the screening of matnmaiian recombinant DNA libraries to identify the coding sequences for novel receptor proteins.
68. P 8 The integrins comprise a supergene family of cell-surface glycoprotein receptors that promote cellular adhesion. Each cell has numerous receptors that define its cell adhesive capabilities. Integrins are involved in a wide variety of interaction between cells and other cells or matrix components. The integrins are of particular importance in regulating movement and function of immune system cells. The platelet IIbIIIIA integrin complex is of particular importance in regulating platelet aggregation. A member of the integrin family, integrin ii-6, is expressed on epithelial cells and modulates epithelial inflammation. Another integrin, leucocyte-associated antigen-1 (LFA-1) is important in the adhesion of lymphocytes during an immune response.
Of particular interest is H36-alpha 7, an integrity alpha chain that is developmentally regulated during myogenesis as described in Song, et al., J. Cell Biol., 117(3):643-657 (1992).
The expression pattern of the laminin-binding alpha 7 beta 1 integrity is developmentally regulated in skeletal, cardiac, and smooth muscle. Ziober, et al., 1~V o1. Biol. yeil, 8(9):1723-1734 (1997). h has been reported that expression of the alpha 7-Xl/X2 integrity is a novel mechanism that regulates receptor affinity states in a cell-specific context and may modulate integrity dependent events during muscle development and repair. I_~. It has fiut?ter been reported that laminins promote the locomotion of skeletal myoblasts via the alpha 7 integrity receptor. In particular it was reported that alpha 7 beta 1 receptor can promote myoblast adhesion and motility on a resuicted number of laminin isofotms and may be important in myogenic precursor recruianent during regeneration and differentiation. Yao, et al., J a '., 109(/3):3139-3150 (1996). Spliced variants of integrity alpha 7 are also described in Ixtutg, et al., ,B'~oc~,em. Bio,~hys. Res. Cornmun., 243(/):317-325 (1998) and Fornaro and Languino, Matrix Biol,, 16(4):185-I93 (1997). Moreover, it has been reported that absence of integrity alpha 7 causes a form of muscular dystrophy. Thus integrins, particularly those related to integrity 7 and related molecules, are of interest.
In addition to the interest of integrins, more generally, all membrane-bound proteins and receptors are of interest since such proteins can play an important role in the formation, differentiation and maintenance of multicellular organisms. The fate of many individual cells, e.g., proliferation, migration, differentiation, or interaction with other cells, is typically governed by information received from other cells andlor the immediate environment. This information is often transmitted by secreted polypeptides (for instance, mitogenic factors, survival factors, cytotoxic factors, differentiation factors, tieuropeptides, and hormones) which are, in turn, received and interpreted by diverse cell receptors or membrane-bound proteins. Such membrane-bound proteins and cell receptors include, but are not limited to, cytoktne receptors, receptor kinases, receptor phosphatases, receptors involved in cell-cell interactions, and cellular adhesin molecules like selectins and integrins. For instance, transduction of signals that regulate cell growth and differentiation is regulated in pan by phosphorylation of various cellular proteins. Protein tyrosine kinases, enzymes that catalyze that process, can also act as growth factor receptors. Examples include fibroblast growth factor receptor and nerve growth factor receptor.
Membrane-bound proteins and receptor molecules have various industrial applications, including as pham~aceutical and diagnostic agents. Receptor imtnunoadhesins, for instance, can be employed as therapeutic agents to block receptor-ligand interaction. The membrane-bound proteins can also be employed for screening of potential peptide or small molecule inhibitors of the relevant receptor/ligand interaction.
Therefore, efforts are being undertaken by both industry and academia to identify new, native receptor proteins. Marry efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel receptor proteins. The results of such efforts, particularly those focused on identifying new IS polypeptides having sequence identity with integrins, are provided herein.
69. P~7 Testican is a multidomain testicular proteoglycan which is expressed in numerous tissue types including, but not limited to neuromuscular tissue, the brain and reproductive tissues.
Testican resembles modulators of cell social behavior such as the regulation of cell shape, adhesion, migration and proliferation. [Bonnet, F. et al., ~Biol.
Chem.; x(8):4373 {1996), Perin, J.P. et al., FAX (Switzerland); 70:191 (i994), Alliel, P.M., et al, Eur. J.J.
~iochem., x(1):346 (1993), Charbonnier, F., et al., C. R. Seances Soc: Biol.
Fil. (France), x(1):127 (1997)].
Among other reasons, since testicau has been implicated in neuronal processes and may be associated with the growth of connective tissue, testican and related molecules are of interest.
More generally, all excracellular proteins are of interest. Exuacellular proteins play an important role in the formation, differentiation and maintenance of multicellular organisms. The fate of many individual cells, e.g., proliferation, migration, differentiation, or interaction with other cells, is typically governed by information received from other cells and/or the immediate environment. This information is often transmitted by secreted polypeptides (for instance, mitogenic factors, survival factors; cytotoxic factors, differentiation factors, neuropeptides, and hormones) which are, in turn, received and ituetpreted by diverse cell receptors or membrane-bound proteins: These polypeptides or signaling molecules normally pass thmugh the celhtlar secretory pathway to reach their site of action in the extracellular enviromnent.
Secreted proteins have various industrial applications, including pharmaceuticals, diagnostics, biosensors and bioreactors. Most protein drugs available at present, such as thromboly6c agents, interferons, interltukins, erythropoietins, colony stimulating factors, and various other cytokines, are secretory proteins. Their receptors, which are membrane proteins, also have potential as therapeutic or diagnostic agents. Efforts are being undertaken by both industry and academia to identify new, native secreted proteins. Many efforts are focused on the screening of rttamtnaiian recombinant DNA libraries to identify the coding sequences for novel secreted proteins. Examples of screening methods and techniques are described in the literature [see, for example, Klein et al., Proc. Natl Acad ci., Q~:7108-7113 (1996); U.S. Patent No. 5,536,637)]. The results of such efforts, particularly those focused on identifying molecules having identity andlor similarity with testican are of interest.
70. PR0733 T1/ST2 is a receptor-like molecule homologous to the type I interleukin-1 receptor, believed to be involved in cell signaling. The Tl/ST2 receptor and/or putative ligands are further described in Gayle, et al., J. Biol. them,, 271(10):5784-5789 (1996), Ktunar, et al., J. Biol. Chem., 270(46):27905-27913 (1995), and Mitcham, et al., . Bi I.
Chem., 271(10):5777-5783 (1996). These proteins; and proteins related thereto are of interest.
More generally all membrane-bound proteins and receptors are of interest since they can play an important role in the formation, differentiation and maintenance of multicellular organisms. The fate of many individual cells, e.g., proliferation, migration, differentiation, or interaction with other cells, is typically governed by information received from other cells and/or the immediate environment. This information is often transmitted by secreted polypeptides (for instance, nvtogenic factors, survival factors, cytotoxic factors, differentiation factors, neuropeptides, and l~rmones) which are, in turn, received and interpreted by diverse cell receptors or membrane bound proteins.
Such membrane-bound proteins and cell receptors include, but are not limited to, cytokine receptors, receptor kinases, receptor phosphatases, receptors involved in cell-cell interactions, and cellular adhesin molecules like selectins and integrins. For instance, transduction of signals that regulate cell growth and differentiation is regulated in part by phosphorylation of various cellular proteins. Protein tyrosine kinases, enzymes that catalyze that process, can also act as growth factor receptors. Examples include fibroblast growth factor receptor and nerve growth factor receptor.
Membrane-bound proteins and receptor molecules have various industrial applications, including as pharmaceutical and diagnostic agents. Receptor immunoadhesins, for instance, can be employed as therapeutic agents to block receptor-ligand interaction. The membrane-bound proteins can also be employed for screening of potential peptide or small molecule inhibitors of the relevant receptor/ligand interaction.
Efforts are being undertaken by both industry and academia to identify new, native receptor proteins. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel receptor proteins. The results of such efforts ate provided herein.
71. PR0162 Pancreatitis-associated protein (PAP) is a secretory protein that is overexpressed by the pancreas during acute pancreatitis. Serum PAP concentrations have been shown to be abnormally high in patients with acute pancreatitis. Pezzilli et al., Am J Gastroenterol., 92(10):1887-1890 (1997).
PAP is syrnhesized by the pancreas due to pancreatic inflammation and has been shown to be a good serum marker for injury of the pancreas. In addition, sertun PAP levels appear to strongly correlate with creatittine clearance measurements. In patients with a pancreas-kidney transplantation, PAP may prove to be a useful biological and histologicai marker of pancreatic graft rejection. Van der Pij1 et al., ]f'r~nSplantation. 63(?):995-1003 (1997).
Further, PAP has been shown to be useful in screening neonates for cystic fibrosis. In fact, PAP may discriminate cystic fibrosis t~onates with better specificity than the current immunoreactive trypsis assay. Iovatuta et al., C-R.
tlcad. Aci. III, 317(6):561-564.
Secreted proteins such as PAP have various industrial applications, including pharmaceuticals, diagnostics, biosensors and bioreactors. Most protein drugs available at present, such as thrombolytic agents, interferons, interleulans, erythropoietins, colony stimulating factors, and various other cytokines, are secretory proteins. Their receptors, which are membrane proteins, also have potential as therapeutic or diagnostic agents.
Efforts are being undertaken by both industry and academia to identify new, native secreted proteins. Many efforts are focused an the screening of marntnalian recombinant DNA libraries to identify the coding sequences for novel secreted proteins. Examples of screening methods and techniques are described in the literature jsee, for S exatt~ple, Klein et al., Proc. Natl. Acad.Sci., Q~:7108-7113 (1996); U.S.
Patent No. 5,536,63'n]. The results of such efforts are presented herein.
7Z. P 7 Anti-neoplastic urinary protein (ANUP) was identified as the major protein present in a fraction of human urine which exhibits antiproliferative activity against human tumor cell lines without affecting the growth of several normal diploid cell lines or tumor cells of mouse or hamster origin. Sloane et al., Biochem. 1., 234(2):355-362 (1986).
ANUP is a unique cytokine that has beenfound in human granulocytes. The N-terminal amino acid sequence has been shown to be unique. A synthetic peptide corresponding to the first nine residues, with Cys at positions 4 and 7, was found to be an anti-tumor agent in vitro. Ridge and Sloane, Cvtolcine, 8(1):1-5 (1996).
Secreted proteins such as ANUP have various industrial applications, including pharmaceuticals, diagnostics, biosensors and bioreactors. Most protein drugs available at present, such as thrombolytic agents, interferons, interleukins, erythropoietins, colony stimulating factors, and various other cytokines, are secretory proteins. Their receptors, which are membrane proteins, also have potential as therapeutic or diagnostic agents. Efforts are being undertaken by both industry atxl academia to identify new, native secreted proteins. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel secreted proteins.
Examples of screening methods and techniques are described in the literature [see, for example, Klein et al., ro ~fatl. Aead. Sci., ,Q3:7108-7113 (1996); U.S. Patent No. 5,536,b37)].
73. PR01008 Diekkopf 1 (dkk-1) is a member of a family of secreted proteins and functions in head induction. Dkk 1 is an inducer of Spemarut organizer in amphibian embryos, Glinka, et al., Nature, 391 (6665):357-362 (1998). Dkk 1 is a potent arnagottist of Wnt signalling, suggesting that dkk genes encode a family of secreted Wnt inhibitors. Thus, dkk-1 family members and related molecules are of interest.
More generally, all .extracellular proteins are of interest since they can play an important role in the formation, differentiation and maintenance of mttlticellular organisms. The fate of many individual cells, e.g., proliferation, migration, differentiation, or irneraction with other cells, is typically governed by information received from other cells andlor the immediate environment. This information is often transmitted by secreted polypeptides (for instance, mitogenic factors, survival factors, cytotoxic factors, differentiation factors, neuropeptides, and horrn4nes) which are, in nun; received and inoe<preted by diverse cell receptors or membrane-bound proteins: These secreted polypeptides or signaling molecules normally pass through the cellular secretory pathway to reach their site of action in the extracellutar emrimmaent.
Secreted proteins have various industrial applications, including pharmaceuticals, diagnostics, biosensors and bioreactors. Most protein drugs available at present, such as thromboiytic agents, interferons, interleukins, erythropoietins, colony stimulating factors, and various other cytokines, are secretory proteins. Their receptors, which are membrane proteins, also have potential as therapeutic or diagnostic agents.
Efforts are being undertaken by both industry and academia to identify new, native secreted proteins, particularly those related to dkk-I. Many efforts are focused on the screening of mammalian recombinant DNA
Hbraries to identify the coding sequences for novel secreted proteins.
Examples of screening methods and techniques S are described in the literature (see, for example, Klein et al., Proc.~Vatl.
Acad. Sci., 93:7108-7113 (1996); U.S.
Patent No. 5,536,637)]. The results of such efforts to identify.molecules related to dkk-1 are provided herein.
74. PR01012 Protein disulfide isomerase is an enzymatic protein which is involved in the promotion of correct refolding of proteins through the establishment of correct disulfide bond formation.
Protein disulfide isomerase was initially identified based upon its ability to catalyze the renaturation of reduced denatured RNAse (Goldberger et al., J.J. Biol.
C_hem. 239:1406-1410 (1964) and Egstein et al., Cold Spring Harbor Symp.
Ouant. Biol. 28:439-449 (1963)).
Protein disulfic~ isomerase has been shown to be a resident enzyme of the endoplasmic reticulum which is retained in the endoplasmic reticulum via a -KDEL or -HDEL amino acid sequence at its C-terminus. Protein disulfide IS isomerase atui related proteins are further described in Laboissiere, et al., J. Biol. Chem., 270(4?:28006-28009 (1995); 3eenes, et al., a e, 193(2):151-156 (1997; Koivunen, et al., enomics, 42(3):397-404 (1997); and Desilva, et al., DNA Cel~~iol., 15(1):9-16 (1996). These studies indicate the importance of the identification of protein disulfide related proteins.
More generally, the identification of all extracellular and membrane-bound proteins is of interest since they play important roles in the formation, differentiation and maintenance of multicellular organisms. The fate of many individual cells, e.g., proliferation, migration, differentiation, or interaction with other cells, is typically governed by information received from other cells and/or the immediate environment.
This information is often iransmitted~
by secreted polypeptides (for instance, mitogenic factors, survival factors,, cytotoxic factors, differentiation factors, neuropeptides, and hormones) which are, in turn, received and interpreted by diverse cell receptors or membrane-bound proteins. These secreted polypeptides or signaling molecules normally pass through the cellular secretory pathway to reach their site of action in the extracellular environment, usually at a membrane-bound receptor protein.
Secreted proteins have various industrial applications, including use as pharmaceuticals, diagnostics, biosensors and bioreactors. In fact, most protein drugs available at present, such as thrombolytic agents; interferons, interleuktns, erythropoietins, colony stimulating factors, and various other cytokines, are secretory proteins. Their receptors, which are membrane-bound proteins, also have potential as therapeutic or diagnostic agents. Receptor immunoadhesins, for instance, can be employed as therapeutic agents to block receptor-ligand interaction.
Membrane-bound proteins can also be employed for screening of potential peptide or small molecule inhibitors of the relevam receptor/Iigand interaction. Such membrane-bound proteins and cell receptors include, but are not limited to, cytokine receptors, receptor kinases, receptor phosphatases, receptors involved in cell-cell interactions, and cellular adhesin molecules like selectins and integrins. Transduction of signals that regulate cell growth and differentiation is regulated in part by phc~phorylation of various cellular proteins. Protein tyrosine kinases, enzymes that catalyze that process, can also act as growth factor receptors. Examples include fibroblast growth factor receptor and nerve growth factoit receptor.

WO 99!4628! PCTIUS99105028 Of particular interest are cellular proteins having endoplasmic reticulum (ER) retention signals. These proteins are retained in the cell arid fut>ction closely with endoplasmic reticulum in protein production. Such proteins have been 'described previously, l.c., see Shorrosh and Dixon, Pl ., 2(1):51-58 (1992).
Efforts are being undertaken by both industry and academia to identify new, native secreted and membrane-bound receptor proteins, and in particular, cellular proteins having ER
retension signals. Many efforts' are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel secreted and membrane-bound receptor proteins. Examples of screening methods and techniques are described in the literature [see, for example, Klein et al., Proc. Nat!. Acad. Sci., X3_:7108-7113 (1996);
U.S. Patent No. 5,536,63']. The results of such efforts, particularly the identification of novel polypeptides and nucleic acids encoding the same, which have sequence identity and similarity to protein disulfide isomerase are presented herein.
75. PR01914 Oxygen free radicals and antioxidants appear to play an important role in the central nervous system after cerebral ischemia and reperfusion. Moreover, cardiac injury, related to ischaemia and reperfusion has been reported to be caused by the action of free radicals. Additionally, studies have reported that the redox state of the cell is a IS pivotal determinant of the face of the cells. Furthermore, reactive oxygen species have been reported to be eytotoxic, causing inflammatory disease, including tissue necrosis, organ failure, atheroselerosis, infertility, birth defects, ptetttature aging, mutations and malignancy. Thus, the control of oxidation and reduction is important for a number of reasons including for control and prevention of strokes, heart attacks, oxidative stress and hypertension. In this regard, reductases, and particularly, oxidoreductases, are of interest.
Publications further describing this subject matter include Kelsey, et al., Br. 1. Cancer, 76(7):852-4 (1997); Friedrich and Weiss, 1. Theor. Biol., 187(4):529-40 {199?) and Pieulle, et a!.,1. Bacceriol., 179(18):5684-92 (1997).
In addition to reductases in particular, novel polypeptides are generally of interest. Extracellutar proteins play an important role in the formation, differentiation and maintenance of multicellular organisms. The fate of many individual cells, e.g., proliferation, migration, differentiation, or interaction with other cells, is typically governed by information received from other cells audlor the immediate environment.
This information is often transmitted by secreted polypeptides (for instance, mitogenic factors, survival factors, cytotoxic factors, differentiation factors, neuropeptides, and hormones) which are, in turn,, received and interpreted by diverse cell receptors or membrane-bound proteins. These secreted polypeptides or signaling molecules normally pass through the cellular secretory pathway to reach their site of action in the extracellular environment.
Secreted groteins have various industrial applications; including pharmaceuticals, diagnostics, biosensors and bioreactors. Mast protein drugs available at present, such as thromboiytic agents, interferons, interleukins, erythropoietins, colony stimulating factors, and various other cytokines, are secretory proteins. Their receptors, which are membrane proteins, also have potential as therapeutic or diagnostic agents. Efforts are being undertaken by both industry and academia to identify new, native secreted proteins. Many efforts are focused on the screening of mamatalian recombinant DNA libraries to identify the coding sequences for novel secreted proteins. Examples of screening methods and techniques are described in the literature [see, for example, Klein et al., ~c. Nat!, g~~aa.
,iii, Q~:7108-7113 (1996); U.S. Patent No. 5,536,637)]. The results of such efforts, particularly those identifying polypeptides having sequet~e identity with redtxtases, and the nucleic acids encoding the same, are presented herein.

WO 99/46281 PCTlUS99I05028 76. PR01017 Enzymatic proteins play important roles in the chemical reactions involved in the digestion of foods, the biosynthesis of macromolecules, the controlled release and utilization of chemical energy. and other processes necessary to sustain life. Sulfouansferases are enzymes which transfer sulfate from a sulfate donor to acceptor substrates, particularly those containing terminal glucoronic acid. The HNK-1 carbohydrate epitope is expressed on several neural adhesion glycoproteins and a glycolipid, and is involved in cell interactions. The glucuronyltransferase and sulfotransferase are considered to be the key enzymes in the biosynthesis of this epitope because the rest of the structure occurs often in glycoconjugates. HNK-1 sulfouansfererase is further described in Bakker, H., et al., J. BioI. trhem., 272(47):29942-29946 (1997).
In addition to HNK-1 sulfouansfererase, and novel proteins related thereto, all novel proteins ate of IO interest. Extracellular and membrane-bound proteins play important roles in the formation, differentiation and maintenance of multicellular organisms. The fate of many individual cells, e.g., proliferation, migration, differentiation, or interaction with other cells, is typically governed by information received from other cells and/or the immediate environment. This information is often transmitted by secreted polypeptides (for instance, mitogenic factors, survival factors, cytotoxic factors, differentiation factors, neuropeptides, and hormones) which are, in turn, received and interpreted by diverse cell receptors or membrane-bound proteins.
These secreted polypeptides or signaling molecules normally pass through the cellular secretory pathway to reach their site of action in the extracellular environment, usually at a membrane-bound receptor protein.
Secreted proteins have various industrial applications, including use as pharmaceuticals, diagnostics, biosensors and bioreaetors. 1n fact, most protein drugs available at present, such as thrombolytic agents, interferons, interleukins, erythropoietins, colony stimulating factors, and various other cytakines, are secretory proteins. Their receptors, which are membrane-bound proteins, also have potential as therapeutic or diagnostic agents. Receptor immunoadliesins, for instance, can be employed as therapeutic agents to block receptor-ligand interaction.
Membrane-bound proteins can also be employed for screening of potential peptide or small molecule inhibitors of the relevant receptor/ligand interaction. Such membrane-bound proteins and cell receptors include, but are not limited to, cytokine receptors, receptor kinases, receptor phosphatases, receptors involved in cell-cell interactions, and cellular adhesin molecules like selectitts and integrins. Transduction of signals that regulate cell growth and differentiation is regulated in part by phosphorylation of various cellular proteins. Protein tyrosine kinases, enzymes that catalyze that process, can also act as growth factor receptors.
Exatriples include fibroblast growth factor receptor and nerve growth factor recepmr.
Efforts are being undertaken by both industry and academia to identify new, native secreted and membrane-bound receptor proteins, particularly those having sequence identity with HNK-1 sulfotransferase. Many efforts are focused on the screening of mammalian recombinant DNA libraries to idenrify the coding sequences for novel secreted and membrane-bound receptor proteins. Examples of screening rrtethods and techniques are described in the literature [see, for example, Klein et at., Proc. Nab. Acad. Sci., Q~:7108-7113 (1996); U.S. Patent No.
5,536,637)j. The results of such efforts are provided herein.
77. 74 Enzymatic proteins play important roles in the chemical reactions involved in the digestion of foods, the biosynthesis of macromolecules, the controlled release and utilization of chemical energy, and other processes necessary to sustain life. Glucose dehydrogettase functions in the oxidation of glucose to gluconate to generate metabolically useful energy. The regulation of the PQQ-linked glucose dehydrogenase in different organisms is reviewed in Neijssel, et al.,. ~ntonie Van Leeuwenhoek, 56{1):51-61 (1989).
Glucose dehydrogenase functions as an auxiliary energy generating mechanism, because it is maximally synthesized under conditions of energy stress.
In addition to molecules related to glucose dehydrogettase, all novel proteins are of interest. Extracellular and membrane-bound proteins play important roles in the formation, differentiation and maintenance of multicellular organisms. The fate of many individual cells, e.g., proliferation, migration, differentiation, or interaction with other cells, is typically governed by information received from other cells andlor the immediate environment. This information is often uansmitted by secreted polypeptides (for instance, mitogenic factors; survival factors, cytotoxic factors, differentiation factors, neuropeptides, and hormones) which are, in turn, received and interpreted by diverse cell receptors or membrane-bound proteins. These secreted polypeptides or signaling molecules normally pass through the cellular secretory pathway to reach their site of action in the extracellular environment, usually at a membrane-bound receptor protein.
Secreted proteins have various industrial applications, including use as pharmaceuticals, diagnostics, biosensors and bioreactors. In fact, most protein drugs available at present, such as thrombolytic agents, interferons, interleukuts, erythropoietins, colony stimulating factors, and various other cytokines, are secretory proteins. Their receptors, which are membrane-bound proteins, also have potential as therapeutic or diagnostic agents. Receptor immunoadhesins, for instance, can be empioyed as therapeutic agents to block receptor-ligand interaction.
Membrane-bound proteins can also be employed for screening of potential peptide or small molecule inhibitors of the relevant receptor/ligand interaction. Such membrane-bound proteit~ and cell receptors include, but are not limited to, cytokine receptors, receptor kinases, receptor phosphatases, receptors involved in cell-cell interactions, and -cellular adhesin molecules like selectins and integrins. Transduction of signals that regulate cell growth and differetroation is regulated in part by phosphorylation of various celiular proteins. Protein tyrosine kinases, enzymes that catalyze that process, can also act as growth factor receptors. Examples include fibroblast growth factor receptor and nerve growth factor receptor:
Efforts are being undertaken by both industry and academia to identify new, native secreted and membrane-bound receptor proteins, and particularly cellular proteins and those related to dehydrogenase or oxidoreductase.
Many efforts are focused on the screening of mammalian recombinant DNA
libraries to identify the coding sequences for novel secreted and membrane-bound receptor proteins. Examples of screening methods and techniques are described in the literature [see, for example; Klein et al., Proc.,_Natl.
Acad. Sci., Q~:7108-7113 (1996); U.S. Patent No. 5,536,637)]. The results of such efforts are presented herein.
?8. PR01031 It has been reported that the cytokine interletzlatt 17 (IL17) stimulates epithelial, endothelial, and fibroblastic cells to secrete cytokines such as IL-6, IL-8, and granulocyte-colony-stimulating factor, as well as prostaglandin E2.
Moreover, it has been shown that when cultured in the presence of IL-17, fibroblasts could sustain proliferation of CD34+ preferential maturation into neutrophils. Thus it has been suggested that IL-17 constitutes an early initiator of the T cell-dependent inflammatory reaction andlor an element of the cytokine network that bridges the immune system to hematopoiesis. See, Yao, et al., J.J. Im ni unol.; 155(12):5483-5486 (1995); Fossiez, et al., Ji];~~C .~ Med., 1830:2593-2603 (1996); Ket»dy, et ai., I. Inter~rr. on C'wtokine Res., 16(8):611-617 (1996). Thus, proteins related to IL-17 are of interest.
More generally, all novel proteins are of interest. Extracellular proteins play an important role in the formation, differentiation and maintenance of multicellular organisms. The fate of many individual cells, e.g., proIiferatian, migration, differentiation, ar interaction with other cells, is typically governed by information received from other cells andlor the immediate environment. This information is often transmitted by secreted polypeptides (for instance, mitogenic factors, survival factors, cytotoxic factors, differentiation factors, neuropeptides, and hormones) which are, in turn, received and interpreted by diverse cell receptors or membrane-bound proteins. These secreted polypeptides or signaling molecules normally pass through the cellular secretory pathway to reach their site of action in the extracellular environment.
Secreted proteins have various indusuial applications, including pharmaceuticals, diagnostics, biosensors and bioreactors. Most protein drugs available at present, such as thrombolytic agents; interferons, interleukins, erythropoietins, colony stimulating factors, and various other cytokines, are secretory proteins. Their receptors, which are membrane proteins, also have potential as therapeutic or diagnostic agents.
Efforts are being undertaken by both industry and academia to identify new, native secreted proteins, particularly those related to IL-17. Many efforts are focused on the screening of matntnalian recombinant DNA
libraries to identify the coding sequences for hovel secreted proteins.
Examples of screening methods and techniques ate described in the literature [see, for example, Klein et al., Proc. Natl.
Acad. Sci., x:7108-7113 (1996); U.S.
Patent No. 5,536,637)]. The results of such efforts are presented herein.
79. PR0938 Protein disulfide isomerase is an enzymatic protein which is involved in the promotion of correct refolding of proteins through the establishment of correct disulfide bond formation:
Protein disulfide isomerase was initially identified based upon its ability to catalyze the renaturation of reduced denatured RNAse (Goldberger et at., J t 1.
Chem. ~Q:1406-1410 (1964) and Epstein et al., ,old Spring Harbor Sym"p Ouant Bioi. .8,:439-449 (1963)).
Protein disulfide isomerase has been shown to be a resident enzyme of the endoplasmic reticulum which is retained 23 in the endoplasmic reticulum via a -KDEL or -HDEL amino acid sequence at its C-terminus. Protein disulfide isomerase and related proteins are further described in Laboissiere, et al., J-Bio . C,~em., 0 47 :28006-28009 (i995); Jeenes, et al., Ger e_, 193(21:151-156 (1997); Koivunen, et al., eno ' , x:397-404 (1997); Desilva, et at., DNA Cell Bio~., x:9-16 (1996); Freedman, et aI. T~e_xtds in B~chem. Sci.
,~,Q:331-336 (1994}; Bulleid, N.J.
Advances i~ Prot. Chem. 44:125-50 (1993); and Noiva, R., Prot. Exp. and Purification ~:1-13 (1994}. These studies indicate the importance of the identification of protein disulfide related proteins.
More generally; and also of interest are all novel membrane-bound proteins and receptors. Such proteins can play an implant role in the formation, differentiation and maintenance of multicellular organisms. The fate of many individual cells, e.g:, proliferation; migration, differentiation, or interaction with other cells, is typically governed by information received from other cells and/or the immediate environment. This information is often transmitted by secreted polypeptides (for ittstattce, rnitogettic factors, survival factors, cytotoxic factors, differentiation factors, neuropeptides, and hormones) which are, in mrn, received and interpreted by diverse cell receptors or r~nobrane-bound proteins. Such membrane-bound proteins and ceD receptors include, but are not limited to, cytokine receptors, receptor kinases, receptor phosphatases, recepwrs involved in cell-cell interactions, and cellular adhesin rnolecules like selectins and integrins. For instance, aansduction of signals that regulate cell growth and differentiation is regulated in part by phosphorylation of various cellular proteins. Protein tyrosine kinases, enrymes that catalyze that process, can also act as growth factor receptors. Examples include ftbroblast growth factor receptor and nerve growth factor receptor.
Membrane-bound proteins and receptor molecules have various industrial applications, including as pharmaceutical and diagnostic agents. Receptor intnnunoadhesins, far instance, can be employed as therapeutic agents to block receptor-ligand interaction. The membrane-bound proteins can also be employed for screening of potential peptide or small molecule inhibitors of the relevant receptor/ligand interaction.
Given the importance of membrane bound proteins, efforts are under way to identity novel membrane bound proteins. Moreover, given the importance of disulfide bond-forming enzymes and their potential uses in a number of different applications, for example in increasing the yield of correct refolding of recombinantly produced proteins, efforts are currently being undertaken by both industry and academia to identify new, native proteins having sequence identity with protein disulfide isomerase. Many of these efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel protein disulfide isomerase homologs.
We herein describe the identification and characterization of a novel polypeptide having homology to protein disulfide isomerase.
IS
80. PROIO,~
The low density lipoprotein (LDL) receptor is a membrane-bout protein that plays a key role in cholesterol ltorneostacis, mediating cellular uptake of lipoprotein particles by high affinity binding to its ligands, apolipoprotein (apo) B-100 and apoE. The ligand-bring domain of the LDL receptor contains 7 cysteine-rich repeats of approximately 40 amino acids, wherein each repeat contains 6 cys;eines, which form 3 infra-repeat disulfide bonds.
These unitNe s~cairal features provide the LDL receptor with its ability to specifically interact with apo B-100 and apoE, thereby allowing for transport of these lipoprotein particles across cellular membranes and metabolism of their componenic. Soluble fragments containing the extracellular domain of the LDL
receptor have been shown to retain the ability to interact with its specific lipoprotein ligands (Simmons et al., ,fi. Biol. Chem. 272:25531-25536 (1997)).
LDL receptors are further descn'bed in Javitt, ~5., 9(13):1378-1381 (1995) and Herz and Willnow, Acad. Sci., 737:14-19 (1994). Thus, proteins having sequence identity with LDL
receptors are of interest. .
More generally, ali membrane-bound proteins and receptors can play an important role in the formation, differentiation and maintenance of multicelhtlar organisms. The fate of many individual cells, e.g., proliferation, migration, differentiation, or interaction with other cells, is typically governed by information received from other cells atndlor the immediate environrr~rtt. This information is often uansmitted by secreted polypeptides (for instance, mitogeruc factors, survival factors, cytotoxic factors; differentiation factors; txuropeptides; and hormones) which are, in rum, received and interprtted by diverse cell receptors or membrane-bound proteins. Such membrane-bound proteitLS and cell receptors inchtde, but are not limited to; cytolatie receptors, receptor kinases, receptor phosphatases, trceptors imrolved in cell-cell interactions, and cellular adhesin molecules like selectins and integrins. For instance, transduction of that regulate cell growth and differentiation is regulated in part by phosphorylation of various cellular proteins. Protein tyrosine kinases, enzymes that catalyze that process, can also act as growth factor receptors. Examples include fibroblast growth factor receptor and nerve growth factor receptor. 'Of particular interest are membrane bound proteins that have type II transmembrane domains.

Membrane-bound proteins and receptor molecules have various indusuial applications, including as pharmaceutical and diagnostic agents. Receptor imrnunoadhesins, far instance, can be employed as therapeutic agents to block receptor-ligand interaction. The membrane-bound proteins can also be employed for screening of potential peptide or small molecule inhibitors of the relevant receptorlligand interaction.
Efforts are thus being undertaken by both industry and academia to identify new, native proteins, particularly membrane bound proteins including type II transmembrane bound proteins. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel receptor proteins.
The results of such efforts are provided herein.
81: P_-801083 Of particular interest are membrane bound proteins that belong to the seven uansmembrane (7TM) receptor superfamily. Hxamples of these receptors include G-protein coupled receptors such as ion receptors. Another example of a TTM receptor superfamily member is described in Osterhoff, et al., DNA CeIl,~iol., 16(4):3'79-389 (1997).
Membrane-bound proteins and receptor molecules have various industrial applications, including as pharmaceutical and diagnostic agents. Receptor immunoadhesins, for instance, can be employed as therapeutic agents to block receptor-ligand interaction. The membrane-bound proteins can also be employed for screening of potential peptide or small molecule inhibitors of the relevant receptorJligand interaction.
Efforts are being undertaken by both industry atxi academia to identify new, native receptor proteins. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences fox novel receptor proteins. The results of such efforts are presented herein.
82. PRO
Polypeptides involved in survival, proliferation and/or differentiation of cells are of interest. Polypeptides known to be involved in the survival, proliferation and/or differentiation of cells include VEGF and members of the bone morphogenetic protein family. Therefore, novel polypeptides which are related to either VEGF or the bone morphogenetic protein are of interest.
The heparin-binding endothelial cell-growth factor, VEGF, was identified and purified from media conditioned by bovine pituitary follicular or foliiculo-stellate cells over several years ago. See Ferrara et al., Biophys. Res. Comm. 161, 851 (1989). VEGF is a naturally occurring compound that is produced in follicular or folliculo-stellate cells (FC), a morphologically well characterized population of granular cells. The FC are stellate cells that send cytoplasmic processes between secretory cells. .
VEGF is expressed in a variety of tissues as multiple homodimeric forms (121, 165, 189 and 206 amino acids per monomer) resulting from alternative RNA splicing. VEGF,,1 is a soluble mitogen that does not bind heparin; the longer forms of VEGF bind heparin with progressively higher affinity. The heparin binding forms of VEGF can be cleaved in the carboxy terminus by plasmin to release (a) diffusible forms) of VEGF. Amino acid sequencing of the carboxy terrninal peptide identified after plasmin cleavage is Arg,~a Ala,l,. Amino terminal "core"
per, VEGF (1-110) isolated as a homoditner, binds neutralizing monoclonal antibodies (4.6.1 and 2E3) and soluble forms of FMS-like tyrosine kinase (FLT 1), kinase domain region (KDR) and fetal liver kinase (FLK) receptors with similar affinity compared to the intact VEGF,~ homodimer.

WO 99146281 ~ PCT/US99/05028 As noted, VEGF contains two domains that are responsible respectively for binding to the KDR and FLT-1 receptors. These receptors exist only on endothelial (vascular) cells. As cells become depleted in oxygen, because of trauma and the Like, VEGF production increases in such cells which then bind to the respective receptors in order to signal ultimate biological effect. The signal then increases vascular permeability and the cells divide and expand to form new vascular pathways - vasculogenesis and angiagenesis.
Thus, VEGF is useful for treating conditions in which a selected action on the vascular endothelial cells;
in the absence of excessive tissue growth, is important, for example, diabetic ulcers and vascular injuries resulting from trauma such as subcutaneous wounds. Being a vascular (artery and venus) endothelial cell growth factor, VEGF
restores cells that are damaged, a process referred to as vasculogenesis, and stimulates the formulation of new vessels, a process referred to as angiogenesis.
VEGF would also find use in the restoration of vasculature after a myocardial infarct, as well as other uses that can be deduced. In this regard, inhibitors of VEGF are sometimes desirable, particularly to mitigate processes such as angiogenesis and vasculogenesis in cancerous cells.
Regarding the bone morphogenetic protein family, members of this family have been reported as being involved in the differentiation of cartilage and the promotion of vascuiarization and osteoinduction in preformed hydroxyapatite. Zou, et al., Genes Dev. (U.S.), 11(i7):2191 (1997); L,evine, et al., Ann. last. Surø., 39(2):I58.
(1997). A number of related bane morphogenetic proteins have been identified, all members of the bone morphogenetic protein (BMP) family. Bone marphogenetic native and mutant proteins; nucleic acids encoding therefor, related compounds including receptors, host cells and uses are further described in at Least: U.S. Patent Nos.
5,670,33$; 5,454,419; 5,661,007; 5,637,480; 5,631,142; 5,166,058; 5,620,867;
5,543,394; 4,877,864; 5,013,649;
55,106,748; and 5,399,677. Of particular interest are proteins having hamology with bone morphogenetic protein I, a procollagen C-proteinase that plays key roles in regulating matrix deposition.
The present imrention is predicated upon research intended to identify novel polypeptides which are related to VEGF and the BMP family, and in particular, palypeptides which have a role in the survival, proliferation and/or differentiation of cells. While the novel polypeptides are not expected to have biological activity identical to the known polypeptides to which they have homology, the known polypeptide biological activities can be used to detern~ the relative biological activities of the novel polypeptides. In particular, the novel polypeptides described herein can be used in assays which are intended to determine the ability of a polypeptide to induce survival, proliferation or differentiation of cells. In turn, the results of these assays can be used accordingly, for diagnostic and therapeutic purposes. The results of such research is the subject of the present invention.
83. PR0285 and PR0286 The cloning of the Toll gene of Drosoptula, a maternal effect gene that plays a central role in ttte establishment of the embryonic dorsal-ventral pattern, has been reported by Hashimoto et at., ~e 5,~, 269-279 (1988). The Drosophila Toll gene encodes an integral membrane protein with an extracytoplasmic domain of 803 amino acids and a cytoplasrrric domain of 269 amino acids. The exaacytoplasmic domain has a potential membrane-spanning segment, and contains multiple copies of a leucine-rich segment, a structural motif found in many transmembrane proteins. The Toll protein controls dorsal-ventral patterning in Drosoptula embryos and activates the transcription factor Dorsal upon binding to its ligand Spatzle. (Morisato and Anderson, eI 76, 677-688 (1994).) In adult Drosopluta, the TollIDorsai signaling pathway participates in the anti-fungal imunme response. (ixnaitre et WO 99!46281 PCT/US99/05028 al., Ce~l_ $6, 973-983 (1996).) A human homologue of the Drosophila Toll protein has been described by Medzhitov et al., attire 388, 394-397 (1997). This human Toll, just as Drosophila Toll, is a type I
transmembrane protein, with an extracellular domain consisting of 21 tandemly repeated leucine-rich motifs (leucine-rich region - LRR), separated by a non-LRR
region, and a cytoplasmic domain homologous to the cytoplasmic domain of the human interleukin-1 (IL-1) receptor.
A constitutively active mutant of the human Toll uansfected into human cell lines was shown to be able to induce the activation of NF-xB and the ezpression of NF-tcB-controlled genes for the inflammatory cytokines IL-I, IL-6 and IL-8, as well as the expression of the constimulatory molecule B7.1; which is required for the activation of native T cells. It has been suggested that Toll functions in vertebrates as a non-clonal receptor of the immune system, which can induce signals for activating both an innate and an adaptive immune response in vertebrates. The human Toll gene reported by Medzhitov et al., supra was most strongly expressed in spleen and peripheral blood leukocytes (PBL), and the authors suggested that its expression in other tissues may be due to the presence of macrophages and dendritic cells, in which it could act as an early-warning system for infection. The public GenBank database contains the following Toll sequences: Toll! (DNAXII HSU88540-1, which is identical with the random sequenced full-length cDNA IfHUMRSC78b-1); TolI2 (DNAXIi HSU88878-1); To113 (DNAXII HSU88879-1); and To114 {DNAXII
HSU88880-1, which is identical with the DNA sequence reported by Medzhitov et al., supra}. A partial ToII
sequence (1'0115) is available from GenBank under DNAX~ HSU88881-1.
Further human homologues of the Drosophila Toll protein, designated as Toll-Like receptors (huTLRsl-5) were recently cloned and shown to mirror the topographic structure of the Drosophila counterpart (Rock et al., Proc.
Nal,[_,~cad. Sci. USA 95, 588-593 [1998]}. Overexpression of a constitutively active mutant of one human TLR
(Toll protein homologue - Medzhitov et al., supra; TLR4 - Rock et al., supra) leads to the activation of NF-x8 and induction of the inflammatory cytokines and constimulatory molecules.
Medzhitov et al., supra.
84. PR0213-1, PR01330 and PR014A9 Cancer is characterized by the increase in the number of abnormal, or neoplastic, cells derived from a normal tissue which proliferate to fotrn a tumor mass, the invasion of adjacent tissues by these neoplastic tumor cells, and the generation of malignant cells which eventually spread via the blood or lymphatic system to regional lymph nodes and to distant sites (metastasis). In a cancerous state a cell proliferates under conditions in which normal cells would not grow. Cancer manifests itself in a wide variety of forms, characterized by different degrees of invasiveness and aggressiveness.
Alteration of gene expression is. intimately related to the uncontrolled cell growth and de-differentiation which are a common feature of all cancers. The genomes of certain well studied tumors have been found to show decreased expression of recessive genes, usually referred to as tumor suppression genes, which would normally function to prevern malignant cell growth, and/or overexpression of certain dominant genes; such as oricogenes, that as to pror~ce malignant growth. Each of these genetic changes appears to be responsible for importing sotxzc of the traits that, in aggregate, represent the full neoplastic phenotype (Hunter, Cell CSI, l I29 [1991]; Bishop, Cell 64, 235-248 [1991]).
A well known trtiecchanism of gene (e.g. otxogene) overexpression in cancer cells is gene amplification. This is a process where in the chromosome of the ancestral cell multiple copies of a particular gene are produced. The process involves unscheduled replication of the region of chromosome comprising the gene, followed by WO 99146281 ~ PCT/US99105028 recombination of the replicated segments back into the chromosome (Alitalo et aL, Adv. Cancer Res. 47, 235-281 [I986]). It is believed that the overexpression of the gene parallels gene amplification, i.e. is proportionate to the number of copies made.
Proto-oncogenes that encode growth factors and growth factor receptors have been identified to play important roles in the pathogenesis of various human malignancies, including breast cancer. For example, it has been found that the human ErbB2 gene (erbB2, also known as her2, or c-erbB-2), which encodes a 185-kd transmembrane glycoprotein receptor (p185HER2; HER2) related to the epidermal. growth factor receptor (EGFR), is overexpressed in about ZS% to 30% of human breast cancer (Slamon et al., Science 235:177-I82 [i987J; Slamonet al., Science 244:707-712 [1989]).
It has been reported that gene amplification of a protooncogene is an event typically involved in the more malignant forms of cancer, and could act as a predictor of clinical outcome (Schwab et al., Genes Chromosomes Cancer l, 181-193 [1990]; Alitalo et al., supra). Thus, erbB2 overexpression is commonly regarded as a predictor of a poor prognosis, especially in patients with primary disease that involves axillary lymph nodes (Slamon et al., j1987] and [1989], supra; Ravdin and Chamness, Gene 159:19-27 [1995]; and Hynes and Stem, Biochem Biophys Acta 1198: 165-184 [1994]), and has been linked to sensitivity andlor resistance to hormone therapy and chemotherapeutic regimens, including CMF (cyclophosphatnide, methotrexate, and fluoruracil) and anthracyclines (Baselga et al., Oncology 1 I (3 Suppl 1): 43-48 [1997]). However, despite the association of erbB2 overexpression with poor prognosis, the odds of HER2-positive patients responding clinically to treatment with taxanes were greater than three times those of HER2-negative patients (Ibid). A recombinant humanized anti-ErbB2 (anti-HER2) raonoclonal antibody (a humanized version of the marine anti-ErbB2 antibody 4D5, referred to as rhuMAb HER2 ZO or Hereeptin 70) has been clinically active in patients'with ErbB2-overexpressing metastatic breast cancers that had received extensive prior anticancer therapy: ($aselga et al.; J. Clin. Oncol.

14;737-744 [1996]).
Tt~ protein Notch and its homologues are key regulatory receptors in determining the cell fate in various development processes. The protein Notch-4, also known as int-3 oncogene, was originally identified as a frequent uarget in mouse matnmary tumor virus (MMVS). Notch-4 is believed to be a transgene which affects the differentiation capacity of stem cells and Ieads to neoplastic proliferation in epithelial cells. Shirayoshi et al., Genes Cells Z(3): 2I3-224 (1997). During embryogenesis, the expression of Notch-4 was detected in endothelial cells of blood vessels forming tissues such as the dorsal aorta, intersegmental vessels, yolk sac vessels, cephalic vessels, heart, vessels in branchial arches, and capillary plexuses. Notch-4 expression in these tissues was also associated with flk 1, the major regulatory gene of vascttlogenesis and angiogenesis.
Notch-4 is also upreguiated in vitro during the dilfation of endothelial.stem cell. The endothelial cell specific expression pattern of Notch-4, as well as its s~cwray similarity to Notch suggest that Notch-4. is an endothelial cell specific homologue of Notch and that it may play a role in vaculogenesis and angiogenesis.
8~. PR029$
Efforts are being undertaken by both industry arid academia to identify new, native receptor proteins. Many efforts are focused an the screening of rmamma3ian recombinant DNA libraries to identify the coding sequences for novel receptor proteins. We herein describe the identification and characterization of novel transmembrane polypeptides, designated herein as PR0298 polypeptides.

WO 99/4b281 PCT/US99/05028 86. ~R0337 Neuronal development in higher vertebrates is characterized by processes that must successfully navigate distinct cellular environrnent.en route to their synaptic targets. The result is a functionally precise formation of neural circuits. The precision is believed to result form mechanisms that regulate growth cone pathfmding and target recognition, followed by latter refinement and remodeling of such projections by events that require neuronal activity, Goodman and Shatz, Cell/Neuron [Suppl.] 72(10): 77-98 (1993). It is further evident that different neurons extend nerve fibers that are biochemically distinct and rely on specific guidance cues provided by cell-cell, cell-matrix, and chemotrophic interactions to reach their appropriate synaptic targets, Goodman et al., supra.
One particular tz~ans by which diversity of the neuror>al cell surface may be generated is through differential expression of cell surface proteins referred to as cell adhesion molecules (CAMS). Neuronally expressed CAMS have been implicated in diverse developmental processes, including migration of neurons along radial glial cells, providing permissive or repulsive substrates for neurite extension, and in promoting the selective fasciculation of axons in projectional pathways. lessel, Neuron 1: 3-13 (1988); Edelinan and Crossin, Annu. Rev. Biochem. 60: 1S5-190 (1991). Interactions between CAMs present on the growth cone membrane and molecules on opposing cell membranes or in the extracellular matrix are thought to provide the specific guidance cues that direct nerve fiber outgrowth along appropriate projectional pathways. Such interactions are likely to result in the activation of various second messenger systems within the growth cone that regulate neurite outgrowth. Doherry and Walsh, Curr. Opin Neurobiol. 2: S95-601 (1992}.
In higher vertebrates, most neural CAMS have been found to be members of three major structural families of proteins: the irnegrins; the cadherins, and the immunoglobulin gene superfamily (igSF}. Jessel, supra.; Takeichi, Anrru. Rev. Biochem. 59: 237 2S2 (1990); Reichardt and Tomaselli, Annu. Rev.
Neurosci. 14: 531-S70 (1991). Cell adhesion molecules of the IgSF (or Ig-CAMs), in particular, constitute a large family of proteins frequently implicated in neural cell interactions and nerve fiber outgrowth during development, Salzer and Colman, Dev. Neurosci. 11:
37?-390 (1989); Briimmendorf and Rathjen, J. Neurochem. 6I: 1207-1219 (1993).
However, the majority of mammalian Ig-CAMs appear to be too widely expressed to specify navigational pathways or synaptic targets suggesting ihat other CAMS, yet to be identified, have role in these more selective interactions of neurons.
Many of the known neural Ig-CAMs have been found to be attached to the plasma membrane via a glycosylphosphatidylinositol (GPI) anchor. Additionally, many studies have implicated GPI-anchored proteins in providing specific guidance cues during the outgrowth on neurons in specific pathways. In studies of the grasshopper nervous system, treatment of embryos with phosphatidylinositol-specific phopholipase C tPIPLC), which selectively removes GPI-anchored proteins from the surfaces of cells, resulted in misdirection and faulty navigation among subsets of pioneering growth cones, as well as inhibited migratory patterns of a subset of early neurons, Chang et al., Devel. l I4: 507-519 (1992). The projection of retinal fibers w the optic rectum appears to depend, in part, on a 33 kDa GPI-anchored protein, however, the precise nature of this protein is unknown. Stahl et al., Neuron 5: 735-743 (1990).
3S The expression of various GPI-anchored proteins has been characterized amongst the different populations of primary rat neurons amongst dorsal root ganglion, sympathetic neurons of the cervical ganglion, sympathetic neurons of the superior cervical ganglion, and cerebellar granule neurons.
Rosen et al., J. Cell Biol. 117: 617-b27 (1992). In contrast to the similar pattern of total membrane protein expression by these different types of neurons, stribt~g differences were observed in the expression of GPI-anchored proteins between these neurons. Recently, a 65 kDa protein band known as neurotrimin was discovered and found to be differentially expressed by primary neurons (Rosen et al., supra), and restricted to the nervous system and found to be the most abundant and earliest expressed of the GPI-anchored species in the CNS. Struyk et aL, J.
Neuroscience IS(3): ZI41-2156 (1995). The discovery of neurotrimin has further lead to the identification of a family of IgSF members, each containing three Ig-Iike domains that share significant amino acididentity, rtow ternted IgLON.
Sttvyk et al., supra; Pimenta et al., Gene 170(2): 189-95 (1996).
Additional members of the IgLON subfamily include opiate binding cell adhesion molecule (OBCAM), Schofield et al" EMBO J. 8: 489-495 (1989); limbic associated membrane protein (LAMP), Pimenta et al:, supra;
CEPU-I; GPSS, Wilson et al., J. Cell Sci. 109: 3129-3138 (1996); Eur. J.
Neurosci. 9(2): 334-41 (1997); and AvGp50, Hancox et al., Brain Res. Mol. Brain Res. 44(2): 273-85 (1997).
While the expression of neurotrimin appears to be widespread, it does appear to correlated with the development of several neural circuits. For example, between E18 and P10, neurotimin mRNA expression within the forebrain is maintained at high levels in neurons of the developing thalamus, cortical subplate, and cortex, particularly laminae V and VI (with less intense expression in II, II, and IV;
and minimal expression in lamina I).
Cortical subplate neurons may provide an early; temporary scaffold for the ingrowing thalamic afferents en route to their final synaptic targets in the cortex. Atlendoerfer and Shatz, Anrnt.
Rev. Neurosci. 17: 185-218 (1994).
Conversely, subplate neurons have been suggested to be required for cortical neurons from layer V to select VI to grow into the thalamus, and neurons from layer V to select their targets in the colIiculus, pons, and spinal cord (McConnell et al., J. Neurosci. 14: 1892-1907 (1994). The high level expression of neurotrimin in many of these projections suggests that it could be involved in their development.
In the hindbrain, high levels of neurotrimin message expression were observed within the pontine nucleus and by the internal granule cells and Purkinje cells of the cerebellum. The pontine nucleus received afferent input from a variety of sources including corticopontirie fibers of layer V, and is a major source of afferent input, via mossy fibers, to the granule cells which, in turn, are a major source of afferent input via parallel fibers to Purkinje cells.
]Patsy and Chan-Palsy, The cerebellar cortex: cytology and organization. New York: Springer (1974]. High level expression of neurotrimin these neurons again suggests potential involvement in the establishment of these circuits.
Neurotrimin also exhibits a graded expression pattern in the early postnatal striatum. Increased neurotrimin expression is found overlying the dorsolateral striatum of the rat, while lesser hybridization intensity is seen overlying the ventromedial striatum. Struyk et aL, supra. This region of higher neurottimitt hybridization intensity does not cotrespo~i to a cytoarchitecturally differentiable region, rather it corresponds to the primary area of afferent input from layer VI of the contratateral sensorirnotor cortex (Gerfen, Nature 3I1:
461-464 (/984); Donoghue and Herkenham, Brain Res. 365: 397-403 (1986)). The venuomedial striatum, by contrast, receives the majority of its afferent input from the perirhinal and association: cortex. It is noteworthy that a complementary graded pattern of LAMP expression, has been observed within the striatium, with highest expression in venuomedial regions, and lowest expression dorsolaterally. Levitt, Science 223: 299-301 (1985);, Chesselet et al., Neuroscience 40: 725-733 (1991).
87. PR0403 Type II transmembrane proteins, also known as single pass ttansmembrane proteins have an N-terminal portion lodged in the cytoplasm while the C-terminal portion is exposed to the extracelhttar domain.

Endothelia is a family of vasoconstrictor peptides about which much activity has been focused to better understand its basic pharmacological, biochemical and molecular biological features, including the presence and structure of isopeptides and their genes (endothelia-I, -2 and u3), regulation of gene expression, intracellular processing, specific endothelia converting enzymes (ECE), receptor subtypes (ET-A and ET-B), intracellular signal transduction following receptor activation, etc.
The endothelia (ET) family of peptides have potent vascular, cardiac and renal actions which may be of pathophysiological importance in many human disease states. . ET-1 is expressed as an inactive 212 amino acid prepropeptide. The prepropeptide is first cleaved at Arg52-Cys53 and Arg92-AIa93 and then the carboxy terminal Lys91 and Arg92 are trimmed from the protein to generate the propeptide big ET-1.
Endothelia is generated from inactive intermediates, the big endothelins, by a unique processing event catalyzed by the zinc metalloprotease, endothelia converting enzyme (ECE). ECE
was recently cloned, and its structure was shown to be a single pass transmembrane protein with a short intracellular N-terminal and a long extracellular C-terminal that contains the catalytic domain and numerous N-glycosylation sites. ECEs cleave the endothelia propeptide betw~n Trp73 and Va174 producing the active peptide, ET, which appears to function as a Local xather than a circulating hormone (Rubanyi, G.M. & Polokoff, M.A., Pharmachological Reviews 46: 325-415 (1994): Thus ECE activity is a potential site of regulation of endothelia production and a possible target for therapeutic intervention in the endothelia system. By blocking ECE activity, it is possible stop the production of ET-I
by inhibiting the conversion of the relatively inactive precursor, big ET-1, to the physiologically active form.
Endothelins may play roles in the pathophysiology of a number of disease states including: 1) cardiovascular diseases (vasospasm, hypertension, myocardial ischemia; reperfusion injury and acute myochardial infarction, stroke (cerebral ischemia), congestive heart failure, shock, atherosclerosis, vascular chickening); 2) kidney disease (acute and chronic renal failure, glomeruionephritis, cirrhosis); 3) lung disease (bronchial asthma, pulmonary hypertension);
4) gastrointestinal disorders (gastric ulcer, inflammatory bowel diseases); 5) reproductive disorders (premature labor, dysmenorhea, preeclampsia) and 6) carcinogenesis. Rubanyi & Polokoff, supra.
SSIMMARY OF THE INVENTION
1. PRA
Applicants have identified a cDNA clone that encodes a novel polypeptide, wherein the polypeptide is designated in the present application as "PR0213".
In one embodimern, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0213 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0213 polypeptide having amino acid residues 1 to 293 of Figure 2 (SEQ ID N0:2), or is complementary to such encoding nucleic acid sequence, and remains siably bound to it under at least moderate, and optionally, under high stringency conditions.
In another embodiment, the invention provides isolated PR0213 polypeptide. In particular, the invention provides isolated native sequence PRO213 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 295 of Figure 2 (SEQ ID N0:2).

WO 99146281 ~ PCT/US99/05028 2. PR0274 Applicants have identified a cDNA clone that encodes a novel polypeptide, wherein the polypeptide is designated, in the present application as " PR0274".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0274 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0274 polypeptide having amino acid residues 1 to 492 of Figure 4 (SEQ ID N0:7), 'or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions.
The isolated nucleic acid sequence may comprise the cDNA insert of the DNA.39987-1184 vector deposited on April 21, 1998 as ATCC 209786 which includes the rntcleotide sequence encoding fRO274.
In another embodiment, the invention provides isolated PR0274 polypeptide. In particular, the invention provides isolated native sequence PR02?4 polypepude, which in one embodiment, includes an amino acid sequence comprising residues 1 to 492 of Figure 4 (SEQ ID N0:7). An additional embodiment of the present invention is directed to an isolated extracellular domain of a PR0274 polypeptide.
Optionally, the PRO274 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA
insert of the DNA39987-1184 vector deposited on April 21, 1998 as ATCC 209786.
IS In another embodiment, the invention provides three expressed sequence tags (EST) comprising the nucleotide sequences of SEQ ID N0:8 (herein designated as DNAI?873), SEQ ID
N0:9 (herein designated as DNA36I57) and SEQ ID NO:10 (herein designated as DNA28929) (see Figure S 7, respactively).
3. PR030Q
Applicants have identified a cDNA clone that encodes a novel polypeptide, wherein the polypeptide is designated in the present application as "PR0300"
In one embodiment; the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0300 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0300 polypeptide having amino acid residues I to 457 of Figure 9 (SEQ II) N0:19), or is complementary to such encoding nucleic acid ZS sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions.
Tlbe isolated nucleic acid sequence may comprise the cDNA insert of the DNA4062S-I 189 vector deposited on April 21; 1998 as ATCC 209788 which includes the nucleotide sequence encoding PR0300.
In another embodiment, the invention provides isolated PR0300 polypeptide. In particular, the invention provides isolated native sequence PR0300 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 4S7 of Figure 9 (SEQ ID N0:19). An additional embodiment of the present invention is directed to an isolated extracellular domain of a PR0300 polypeptide.
Optionally, the PR0300 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA
insert of the DNA4062S-I 189 vector deposited on April 21, 1998 as ATCC 20978$.
3S 4.
Applicants have identified a cDNA clone that encodes a novel transmembrane polypeptide, wherein the polypepiide is designated in the present application as °PR0284".
in one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0284 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0284 polypeptide WO 99/46281 ~ PCTIUS99l05028 having amino acid residues 1 to 285 of Figure 11 (SEQ ID N0:28), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. In other aspects, the isolated nucleic acid comprises DNA encoding the PR0284 polypeptide having amino acid residues about 25 to 285 of Figure 11 (SEQ ID N0:28) or I or about 25 to X of Figure 11 (SEQ ID
N0:28), where X is any amino acid from 71 to 80 of Figure 11 (SEQ 1D N0:28), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the DNA23318-1211 vector deposited on April 21, 1998 as ATCC 209787 which includes the nucleotide sequence encoding PR0284.
In another embodiment, the invention provides isolated PR0284 polypeptide. In particular, the invention provides isolated native sequence PR0284 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 285 of Figure I I {SEQ ID N0:28). Additional embodiments of the present invention are directed to isolated PR0284 polypeptides comprising amino acids about 25 to 285 of Figure 11 (SEQ ID N0:28) or 1 or about 25 to X of Figure 11 (SEQ ID N0:28), where X is any amino acid from 71 to 80 of Figure I 1 (SEQ 1D
N0:28}. Optionally, the PR0284 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA insert of the DNA23318-I21 I vector deposited on April 21, 1998 as ATCC 209787.
In another embodiment, the invention provides an expressed sequence tag (EST) designated herein as DNA12982 which comprises the nucleotide sequence of SEQ ID N0:29.
In another embodiment, the invention provides an expressed sequence tag (EST) designated herein as DNA15886 which comprises the nucleotide sequence of SEQ ID N0:30.
5. PR0296 Applicants have identified a cDNA clone that encodes a novel polypeptide having homology to the sarcoma-amplified protein SAS, wherein the polypeptide is designated in the present application as "PR0296".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0296 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0296 polypeptide having amino acid residues 1 to 204 of Figure 15 (SEQ ID N0:36}, or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. In other aspects, the isolated nucleic acid comprises DNA encoding the PR029b polypeptide having amino acid residues about 35 to 204 of Figure 15 (SEQ ID NO:36) or amino acid 1 or about 35 to X of Figure 15 (SEQ 1D N0:36), where X is any amino acid from 42 to 51 of Figure 15 (SEQ ID
N0:36), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the DNA39979-12I3 vector deposited on April 21, 1998 as ATCC 209789 which inchtdes the nucleotide sequence encoding PR0296.
In another embodi~nt, the invention provides isolated PR0296 polypeptide. In particular, the invention provides isolated native sequence PR0296 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 204 of Figure 15 (SEQ ID NO:36). Additional embodiments of the present invention are directed to PR0296 polypeptides comprising amino acids about 35 to 204 of Figure 15 (SEQ ID N0:36) or amino acid 1 or about 35 to X of Figure 15 (SEQ ID NO:36), where X is any amino acid from 42 to 51 of Figure 15 (SEQ
ID N0:36). Optionally, the PRO296 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA insert of the DNA39979-1213 vector deposited on April 21, 1998 as ATCC 209789.

In another embodiment, the invention provides an expressed sequence tag (EST) designated herein as DNA23020 comprising the rntcieotide sequence of SEQ ID N0:37.
In another embodiment, the invention provides an expressed sequence tag (EST) designated herein as DNA21971 comprising the nucleotide sequence of SEQ ID N0:38.
In another embodiment, the invention provides an expressed sequence tag (ES'17 designated herein as DNA29037 comprising the nucleotide sequence of SEQ ID N0:39.
6. P]It0329 Applicants have identified a cDNA clone that encodes a novel polypeptide having homology to a high affinity immunoglobulin F~ receptor, wherein the polypeptide is designated in the present application as "PR0329" .
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0329 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0329 polypeptide having amino acid residues 1 to 359 of Figure 20 (SEQ ID N0:45), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the DNA40594-1233 vector deposited on February 5, 1998 as ATCC 209617 which includes the nucleotide sequence encoding PR0329.
In another embodiment; the invention provides isolated PR0329 polypeptide. In particular, the invention provides isolated native sequence PR0329 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues I to 359 of Figure 20 (SEQ ID N0:45). Optionally, the PR0329 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA insert of the DNA40594-1233 vector deposited on February 5, 1998 as ATCC 209617.
7. PR0362 Applicants have identified a cDNA clone that encodes a novel polypeptide having hotrwlogy to A33 antigen and HCAR metnbrane~bo~.uid protein, wherein the polypeptide is designated in the present application as "PR0362".
1n one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0362 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0362 polypeptide having amino acid residues 1 to 321 of Figure 22 (SEQ ID N0:52), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. In another aspect, the isolated nucleic acid comprises DNA
encoding the PR0362 polypeptide having amino acid residues 1 to X of Figure 22 (SEQ ID N0:52) when X is any amino acid from amino acid 271 to 280, or is compn~ry to such encoding nt~leic acid sequence, and. remains stably bound to it under at least moderate, and o~ionally, utzder high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the DNA45416-1251 vector deposited on February 5 ~ 1998 as ATCC 209620 which includes: the nucleotide sequence encoding PR0362.
In another embodiment, the invention provides isolated PR0362 polypeptide. In particular, the invention provides isolated native sequence PR0362 polypeptide, which in one embodiment, includes an amino acid sequence comQrising residues 1 to 321 of Figure 22 (SEQ Ih N0:52). An additional embodiment of the present invention is directed to as isolated extracellular domain of a PR0362 poiypeptide comprising amino acids 1 to X of the amino acid sequence shown in Figure 23 (SEQ ID NO:52), wherein X is any amino acid from amino acid 271 to 280:

Optionally, the PR0362 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA
insert of the DNA45416-1251 vector deposited on February 5, 1998 as ATCC
209620:
8. PR0363 Applicants have identified a cDNA clone that encodes a novel polypeptide having homology to the cell surface receptor protein HCAR, wherein the polypeptide is designated in the present application as "PR0363".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0363 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0363 polypeptide having amino acid residues 1 to 373 of Figure 24 (SEQ ID NO:$9), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. In another aspect, the isolated nucleic acid comprises DNA
encoding a PR0363 extracellular domain poIypeptide having amino acid residues 1 to X of Figure 24 (SEQ ID N0:59) where X is any amino acid from amino acid 216 to amino acid 225, or is complementary to such encoding nucleic acid sequence, and remains stably bound to it tinder at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the DNA45419-1252 vector deposited on February 5, 1998 as ATCC 209616 which includes the nucleotide sequence encoding PR0363.
In another embodiment, the invention provides isolated PR0363 polypeptide. In particular, the invention provides isolated native sequence PRO363 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 373 of Figure 24 (SEQ ID N0:59). An additional embodiment of the present invention is directed to an isolated exuacellular domain of a PR0363 polypeptide, wherein that extracellular domain may comprise amino acids 1 to X of the sequence shown in Figure 24 (SEQ ID N0:59), where X is any amino acid from amino acid 216 to 225. Optionally, the PR0363 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA insert of the DNA45419-1252 vector deposited on February 5, 1998 as ATCC
209616.
9. PR
Applicants have identified a cDNA clone that encodes a novel poIypeptide having homology to tumor necrosis factor receptor, wherein the polypeptide is designated in the present application as "PR0868".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0868 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0868 polypeptide having amino acid residues l to 655 of Figure 26 (SEQ ID N0:64), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. In another aspect, the isolated nucleic acid comprises DNA
encoding the PR0868 polypeptide having amino acid residues 1 to X of Figure 26 (SEQ ID N0:64), where X is any amino acid from amino acid 343 to 352 of the sequence shown in Figure 26 (SEQ ID N0:64), oz is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high suiagency conditions. In yet another aspect, the isolated nucleic acid comprises DNA encoding the PR0868 polypeptide having amino acid residues X to 655 of Figure 26 (SEQ ID N0:64), where X is arty amino acid from amino acid 371 to 380 of the sequence shown in Figure 26 (SEQ ID N0:64), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated rntcleic acid sequence may comprise the cDNA insert of the DNAS2594-1270 vector deposited on March 17, 1998 as ATCC 209679 which includes the nucleotide sequence encoding PR0868.
In another embodiment, the invention provides isolated PR0868 potypeptide. In particular; the invention provides isolated native sequence PR0868 poiypeptide, which in one embodiment, includes an amino acid sequence compzising residues I to 655 of Figure 26 (SEQ ID N0:64). In another aspect, the isolated PR0868 polypeptide S comprises amino acid zesidues 1 to X of Figure 26 ($EQ ID N0:64), where X is any amino acid from amino acid 343 to 352 of the sequence shown in Figure 26 (SEQ ID NO:b4). In yet another aspect, the PR0868 poIypeptide comprises amino acid residues X to 6S5 of Figure 26 (SEQ ID N0:64), where X is any amino acid from amino acid 371 to 380 of the sequence shown in Figure 26 (SEQ ID N0:64). Optionally, the PR0868 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA insert of the DNA52594-1270 vector deposited on March 17, 1998 as ATCC 209679.
10. PR0382 Applicants have identified a cDNA clone that encodes a novel polypeptide having homology to serine proteases, wherein the polypeptide is designated in the present application as "PR0382".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0382 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PRO382 polypeptide having amino acid residues 1 to 453 of Figure 28 (SEQ ID N0:69), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the DNA45234-1277 vector deposited on March 5, 1998 as ATCC 209654 which includes the nucleotide sequence encoding PR0382.
In another embodiment, the invention provides isolated PR0382 poIypeptide. In particular, the invention provides isolated native sequence PR0382 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 453 of Figure 28 (SEQ ID N0:69). An additional embodimem of the present invention is directed to an isolated extracellular domain of a PR0382 polypeptide, with or without the signal peptide. Optionally, the PR0382 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA insert of the DNA45234-1277 vector deposited on March 5; 1998 as ATCC 209654.
11. PROS
Applicants have identified a cDNA clone that encodes a novel polypeptide having homology to meltrin, wherein the polypeptide is designated in the present application as "PR054S".
In one embodiment, the invention provides an isolated.nucleic acid molecule comprising DNA encoding a PR0545 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0545 polypeptide having amino acid residues 1 to 735 of Figure 30 (SEQ ID N0:74), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions, The isolated nucleic acid sequence may comprise the cDNA insert of the vector deposited on March 5, 1998 as ATCC 209655 which includes the nucleotide seguence encoding PR0545.
In another embodiment, the invention provides isolated PR0545 polypeptide. In particular, the invention pm'v~es isolated Native sequence PR0545 polypeptide, which in o~ embodiment, includes an amino acid sequence uprising residues 1 to 735 of Figure 30 (SEQ ID N0:74). An additional embodiment of the present invention is WO 99!46281 PCT/US99/05028 directed to an isolated extracellular domain of a PRO545 polypeptide.
Optionally, the PR0545 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA
insert of the vector deposited on March 5, 1998 as ATCC 209655.
In another embodiment, the invention provides an expressed sequence tag (EST) designated herein as DNA13217 comprising the nucleotide sequence of SEQ ID N0:75 (Figure 31).
I2. P~061?
Applicants have identified a cDNA clone that encodes a novel polypeptide having homology to CD24, wherein the polypeptide is designated in the present application as "PR06i7".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0617 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encodutg the PR0617 polypeptide having amino acid residues 1 to 67 of Figure 33 (SEQ ID N0:85), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions.
The isolated nucleic acid sequence may comprise the cDNA insert of the DNA48309-1280 vector deposited on March 5, 1998 as ATCC 209656 which includes the nucleotide sequence encoding PR0617.
In another embodiment, the invention provides isolated PR0617 polypeptide. In particular, the invention provides isolated native sequence PR06I7 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 67 of Figure 33 (SEQ ID N0:85). Optionally, the PR0617 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA insert of the DNA48309-1280 vector deposited on March 5, 1998 as ATCC 209656.
I3. PR070o Applicants have identified a cDNA clone that encodes a novel polypeptide having sequence similarity to protein disulfide isomerase, wherein the polypeptide is designated in the present application as "PR0700" .
In one embodiment, the invemion provides an isolated nucleic acid molecule comprising DNA encoding a PR0700 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0700 polypeptide having amino acid residues 1 to 432 of Figure 35 (SEQ ID N0:90), or is complementary to such encoding trucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. In another aspect, the isolated nucleic acid comprises DNA
encoding the PR0700 polypeptide having amino acid residues from about 34 to 432 of Figure 35 (SEQ ID NO:90), or is complementary to such encoding ntxleic acid sequerbce, and remains stably bound to it under at least moderate, and optionally, under high stringency conditiwns. The isolated tntcleic acid sequence may comprise the cDNA insert of the vector deposited on March 3I, 1998 as ATCC 209?21 which includes the nucleotide sequence etxoding PR0700.
In another embodiment, the invention provides isolated PR0700 polypeptide. In particular, the invention provides isolated native sequence PR0700 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 432 of Figure 35 (SEQ ID N0:90). In another embodiment, the invention provides an isolated PR0700 polypeptide absent the signal sequence, which includes an amino acid sequence comprising residues fra~at about 34 to 432 of Figure 35 (SEQ B? N0:90}. Optionally, the PR0700 polypeptide is obtained or is obtainable by expressing the poiypeptide encoded by the cDNA insert of the vector deposited on March 31, 1998 as ATCC
209721.

I4. R 0 Applicants have identified a cDNA clone that encodes a novel polypeptide having homology to conglutinin, wherein the polypeptide is designated in the present application-as "PR0702".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0702 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0702 polypeptide having amino acid residues I to 277 of Figure 37 (SEQ ID N0:97), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. In another aspect, the isolated nucleic acid comprises DNA
encoding the PR0702 polypeptide having amino acid residues 26 to 277 of Figure 37 (SEQ ID N0:97), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions.
The isolated nucleic acid sequence may comprise the cDNA insert of the DNA50980-1286 vector deposited on March 31, 1998 as ATCC 209717 which includes the nucleotide sequence encoding PR0702.
1n another embodiment, the invention provides isolated PR0702 polypeptide. In particular, the invention provides isolated native sequence PR0702 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 277 of Figure 37 (SEQ ID N0:97), An additional embodiment of the present invention is directed to an isolated PR0702 polypeptide comprising amino acid residues 26 to 277 of Figure 37 (SEQ ID N0:97).
Optionally, the PR0702 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA
insert of the DNA50980-1286 vector deposited on March 3i, 1998 as ATCC 209717.

15. PRO'103 Applicants have identified a cDNA clone that encodes a novel polypeptide having sequence similarity to VLCAS, wherein the polypeptide is designated in tire present application as "PR0703".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0703 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PRO?03 polypeptide having amino acid residues 1 to 730 of Figure 39 (SEQ ID N0:102), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. In another aspect, the isolates! nucleic acid comprises DNA
encoding the PR0703 polypeptide having amino acid residues from about 43 to 730 of Figure 39 (SEQ ID NO:102), or is complementary to such encoding nucleic acid sequence, and remains stably bound to ~it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the DNA50913-1287 vector deposited on March 31, 1998 as ATCC 209716 which includes the nucleotide sequence encoding PR0703.
In another embodiment, the invention provides isolated PRO703 polypeptide. In particular, the invention provides isolated native sequence PR0703 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues l to 730 of Figure 39 (SEQ ID NO:I02}. In another embodiment, the invention provides an isolated PR0703 polypeptide absent the signal sequence, which includes an amino acid sequence comprising residues from about 43 to 730 of Figure 30 (SEQ ID NO:I02). Optionally, the PR0730 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA insert of the DNA50913-1287 vector deposited on March 31, 1998 as ATCC 209716.

16. PR0705 Applicants have identified a cDNA clone that encodes a novel poiypeptide having homology to K-glypican, wherein the polypeptide is.designated in the present application as "PR0705".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0705 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0705 polypeptide S having amino acid residues 1 to 555 of Figure 41 (SEQ ID NO:109), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. In another aspect, the isolated nucleic acid comprises DNA
encoding the PR0705 polypeptide having amino acid residues about 24 to 555 of Figure 41 (SEQ ID N0:109), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the DNA50914-1289 vector deposited on March 31, 1998 as ATCC 209722 which includes the nucleotide sequence encoding PR0705.
In another embodiment, the invention provides isolated PR0705 polypeptide. In particular, the invention provides isolated native sequence PR0705 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 555 of Figure 41 {SEQ ID N0:109). An additional embodiment of the present invention is directed to an isolated PR0705 polypeptide comprising amino acid residues about 24 to 555 of Figure 41 (SEQ
ID N0:109). Optionally, the PR0705 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA insert of the DNA50914-1289 vector deposited on March 31, 1998 as ATCC 209722.

17. PR0708 Applicants have identified a cDNA clone that encodes a novel polypeptide having homology to the aryl sulfatases, wherein the polypeptide is designated in the present application as "PRO708".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0708 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0708 polypeptide having amino acid residues 1 to 515 of Figure 43 (SEQ ID NO:I14), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the DNA48296-1292 vector deposited on March 11, 1998 as ATCC 209668 which includes the nucleotide sequence encoding PR0708.
In another embodiment, the invention provides isolated PRO?08 polypeptide. In particular, the invention provides isolated native sequence PR0708 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 5I5 of Figure 43 (SEQ ID N0:114). Another embodiment is directed to a PR0708 polypeptide comprising residues 38-515 of the amino acid .sequence shown in Figure 43 (SEQ ID N0:114).
Optionally, the PR0708 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA
insert of the DNA48296-1292 vector deposited on March 11, 1998 as ATCC 209668.
I8. ~R0320 Applicants have identified a cDNA clone that encodes a novel polypeptide having homology to fibulin, wherein the polypeptide is designated in the present application as "PR0320".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0320 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0320 polypeptide WO 99/46281 PCTlUS99/OS028 having amino acid t~esidues I to 338 of Figure 45 (SEQ ID N0:119), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence rnay comprise the cDNA insert of the vector deposited on March 1 I, 1998 as ATCC 209670 which includes the nucleotide sequence encoding PR0320.
In another embodiment, the invention provides isolated PR0320 polypeptide. In particular, the invention provides isolated native sequence PR0320 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues I to 338 of Figure 45 (SEQ ID N0:119). Optionally, the PR0320 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA insert of the vector deposited on March 11, 1998 as ATCC 209670.
19. PR 3 4 Applicants have identified a cDNA clone that encodes a novel polypeptide having homology to oxidoreductases, wherein the polypeptide is designated in the present application as "PR0324".
In one embodiment, the invention provides an isolated ztucleic acid molecule comprising DNA encoding a PR0324 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0324 polypeptide having amitw acid residues 1 to 289 of Figure 47 (SEQ ID N0:124), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. In other aspects, the isolated nucleic acid comprises DNA encoding the PR0324 polypeptide having amino acid residues 1 or about 32 to X of Figure 47 (SEQ ID N0:124), where X
is any amino acid from 131 to 140, or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the DNA36343-1310 vector deposited on March 30, 1998 as ATCC 209718 which includes the nucleotide sequence erncoding PR0324.
1n another embodiment, the invention provides isolated PR0324 polypeptide. In particular, the invention provides isolated native sequence PR0324 poiypeptide, which in one embodiment, inchtdes an amino acid sequence comprising residues 1 to 289 of Figure 47 (SEQ ID N0:124). The invention also provides isolated PR0324 polypeptide comprising residues I or about 32 to X of Figure 47 (SEQ ID
N0:124}, wherein X is any amino acid from about 131-140. Optionally, the PR0324 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA insert.of the DNA36343-1310 vector deposited on March 30, 1998 as ATCC 209718.
20. pR0351 Applicants have identified a cDNA clone that encodes a novel polypeptide having sequence similarity to prostasin, wherein the polypeptide is designated in the present application as "PR0351".
In one en>bodiment, the invention provides an isolated nucleic acid molecule comprising DNA et~oding a PR0351 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0351 polypeptide having amino acid residues 1 to 571 of Figure 49 (SEQ ID N0:132), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. In another aspect, the isolated nucleic acid comprises DNA
encoding the PRO351 polypeptide having amino acid residues about 16 to 571 of Figure 49 (SEQ ID N0:132), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the DNA40571-1315 vector deposited on April 21, 1998 as ATCC 209784 which includes the nucleotide sequence encoding PR0351.
In another embodiment, the invention provides isolated PR0351 polypeptide. In particular, the invention provides isolated native sequence PR0351 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 571 of Figure 49 (SEQ ID N0:132). In another embodiment, the invention provides an isolated PR0351 polypeptide absent the signal sequence, which includes an amino acid sequence comprising residues from about I6 to 5?I of Figure 49 (SEQ ID N0:132), Optionally, the PR0351 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA insert of the DNA40571-1315 vector deposited on April 21, 1998 as ATCC 209784.
21. PR0352 Applicants have identified a cDNA clone that encodes a novel polypeptide having homology to butyrophilin, wherein the polypeptide is designated in.the present application as "PR0352".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0352 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0352 polypeptide having atnitto acid residues 1 to 316 of Figure 51 (SEQ ID NO:137), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. in other aspects, the isolated nucleic acid comprises DNA encoding the PR0352 polypeptide having amino acid residues of about 29 to 316 of Figure 51 (SEQ ID N0:137), or 1 or about 29 to X of Figure 51, where X is any amino acid from 246 to 255, or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the DNA41386-1316 vector deposited on March 26, 1998 as ATCC
209703 which includes the nucleotide sequence encoding PR0352.
In another embodiment, the invention provides isolated PR0352 polypeptide. In particular, the invention provides isolated native sequence PR0352 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 316 of Figure 51 (SEQ ID N0:137). In other embodiments, the invention provides isolated PR0352 polypeptide comprising residues about 29 to 316 of Figure 51 (SEQ ID
NO:I37) and 1 or about 29 to X of Figure 51 (SEQ ID NO:I37), wherein X is any amino acid from 246 to 255.
Optionally, the PR0352 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA
insert of the DNA41386-1316 vector deposited on March 26, 1998 as ATCC 209703.
22. PR0381 Applies have identified a cDNA clone that encodes a novel poiypeptide having homology to immunophilin proteins, wherein the polypeptide is designated in the present application as "PR0381".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0381 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0381 polypeptide having amino acid residues 1 to 211 of Figure 53 (SEQ ID N0:145), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. In another aspect, the isolated nucleic acid comprises DNA
encoding the PR0381 polypeptide having amino acid residues about 21 to 211 of Figure 53 (SEQ ID N0:145), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at /east moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the DNA44194-1317 vector deposited on April 28, 1998 as ATCC 209808 which includes the nucleotide sequence encoding PR0381.
In another embodiment, the invention provides isolated PR0381 polypeptide. In particular; the invention provides isolated native sequence PRO381 poiypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 211 of Figure 53 (SEQ ID N0:145). Another embodiment is directed to a PR0381 plypeptide comprising amino acids about 21 to 211 of Figure 53 (SEQ ID
N0:145). Optionally; the PR0381 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA insert of the DNA44194-1317 vector deposited on April 28, 1998 as ATCC 209808.
23. P~0386 Applicants have identified a cDNA clone that encodes a novel polypeptide having homology to the beta-2 subunit of a soditun channel, wherein the polypeptide is designated in the present application as "PR0386".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0386 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0386 polypeptide having amino acid residues 1 to 215 of Figure 55 (SEQ ID NO:150), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. In another aspect, the isolated nucleic acid comprises DNA
encoding the PR0386 polypeptide having amino acid residues about 21 to 215 of Figure 55 (SEQ ID NO:150) or 1 or about 21 to X, where X is any amino acid from 156 to 165 of Figure 55 (SEQ ID N0:150), or is complementary to such encoding nucleic acid sequence, and remains stably bound to itunder at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the eDNA insert of the DNA45415-1318 vector deposited on April 28, 1998 as ATCC 209810 which includes the nucleotide sequence encoding PR0386.
In another embodiment, the invention provides isolated PR0386 polypeptide. In particular, the invention provides isolated native sequence PR0386 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 215 of Figure 55 (SEQ ID N0:150). Other embodiments of the present invention are directed to PR0386 polypeptides comprising amino acids about 21 to 215 of Figure 55 (SEQ ID NO:150) and 1 or about 21 to X of Figure 55 (SEQ ID N0:150), wherein X is airy amino acid from 156 to 165 of Figure 55 (SEQ ID
NO:150). Optionally, the PR0386 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA insert of the DNA45415-1318 vector deposited on April 28, 1998 as ATCC 209810.
In attori~r etttbodiment, the invention provides an expressed sequence tag (EST) comprising the nucleotide sequence of SEQ ID NO:151 which corrsponds to an EST designated herein as DNA23350.
In another embodiment, the invention provides an expressed sequence tag (EST) comprising the nucleotide sequence of SEQ ID NO: 352 which corrsgonds to an EST designated herein as DNA23S36.
24, pR05d~U_ Applicants have identified a cDNA clone that encodes a novel polypeptide having sequence similarity to LCAT, wherein the polypeptide is designated in the present application as °PR0540".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0540 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
eroding the PR054U polypeptide r having amino acid residues 1 to 412 of Figure 59 (SEQ ID N0:157), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. In another aspect, the isolated nucleic acid comprises DNA
encoding the PR0540 polypeptide having amino acid residues about 29 to 412 of Figure 59 (SEQ 1D N0:157), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the DNA44189-1322 vector deposited on March 26, 1998 as ATCC 209699 which includes the nucleotide sequence encoding PR0540.
In another embodiment, the invention provides isolated PR0540 polypeptide. In particular, the.invention provides isolated native sequence PR0540 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues I to 412 of Figure 59 (SEQ ID N0:157). The invention also provides isolated PR0540 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues about 29 to 412 of Figure 59 (S$Q ID N0:157}. Optionally, the PR0540 polypeptide is obtained or is obtainable by expressing the poiypeptide encoded by the cDNA insert of the DNA44i89-1322 vector deposited on March 26, 1998 as ATCC
209699.
25. PR0615 Applicants have identified a cDNA clone that encodes a novel polypepdde having sequence similarity to synaptogyrin, wherein the polypeptide is designated in the present application as "PR0615".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA et~oding a PR0615 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0615 polypeptide having amino acid residues 1 to 224 of Figure 61 (SEQ ID N0:162), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. In another aspect, the isolated nucleic acid comprises DNA
encoding the PR0615 poiypeptide having amino acid residues X to 224 of Figure 61 (SEQ ID N0:162), where X is any amino acid from 157 to 166, or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the DNA48304-1323 vector deposited on April 28, 1998 as ATCC 209811 which includes the nucleotide sequence encoding PR0615.
In another embodiment, the invention provides isolated PR0615 polypeptide. In particular, the invention provides isolated native sequence PR0615 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 224 of Figure 61 (SEQ ID N0:162). An additional embodiment of the present invention is directed to an isolated exuacellular domain of a PR0615 polypeptide which comprises amino acid residues X to 224 of Figure 61 (SfiQ ID N0:162), where X is any amino acid from 157 to 166 of Figure 61 (SEQ ID N0:162).
Optionally, the PROtilS polypeptide is obtained or is obtainable by ezpressing the polypeptide encoded by the cDNA
insert of the DNA48304-1323 vector deposited on April 28, 1998 as ATCC 209$11.
26. PR0618 Applicants have identified a cDNA clone that encodes a novel polypeptide having sequence similarity to enteropeptidase, wherein the poIypeptide is designated in the present application as "PR0618".
In one embodiment, the invention provides an isolated nucieic acid molecuie comprising DNA encoding a PR06I8 polypeptide. In one aspect, the isolated nucleic acid comprises D'NA
encoding the PRO618 polypeptide having amino acid residues 1 to 802 of Figure 63 (SEQ ID NO:169}, or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. In another aspect, the isolated nucleic acid comprises DNA
encoding an isolated extracellular domain of a PR0618 polypeptide having amino acid residues X to 802 of Figure 63 (SEQ
ID N0:169), where X is any amino acid from 63 to 72 of Figure 63 {SEQ ID N0:169), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence rnay comprise the cDNA insert: of the DNA49152-1324 vector deposited on April 28, 1998 as ATCC 209813 which includes the nucleotide sequence encoding PR0618.
In another embodiment, the invention provides isolated PR0618 poiypeptide. In particular, the invention provides isolated native sequence PR0618 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 802 of Figure 63 (SEQ ID N0:169). An additional embodiment of the present invention is directed to an isolated extracellular domain of a PR061~8 polypeptide comprising amino acid X to 802 where X
is any amino acid from 63 to 72 of Figure 63 (SEQ ID N0:169). Optionally, the PR0618 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA insert of the DNA49152-1324 vector deposited on April 28, 1998 as ATCC 209813.
In another emboditnetu, the invention provides an expressed sequence tag (EST) comprising the nucleotide sequence of SEQ ID N0:170, designated herein as DNA35597 (see Figure 64).
27. PR0719 Applicarns have identified a cDNA clone that encodes a novel palypeptide having homology to lipoprotein lipase H, wherein the polypeptide is designated in the present application as "PR0719".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0719 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0719 polypeptide having amino acid residues 1 to 354 of Figure 66 (SEQ ID N0:178), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. In another aspect, the isolated nucleic acid comprises DNA
encoding the PR0719 polypeptide having amino acid residues about 17 to 354 of Figure 66 (SEQ ID N0:178), or as complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cl:fNA insert of the DNA49646-I32? vector deposited on March 26, 1998 as ATCC 209705 which includes the nucleotide sequence encoding PR0719.
In another embodiment, the irrvention provides isolated PR0719 polypeptide. 1n particular, the invention provides isolated native sequence PR0719 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 354 of Figure 66 (SEQ ID N0:178). In another embodiment, the invention provides isolated PR0719 polypeptide which comprises residues about 17 to 354 of Figure 66 (SEQ
ID N0:178). Optionally, the 3S PR07i9 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the eDNA insert of the DNA49646-1327 vector deposited on March 26, 1998 as ATCC 209705.

i~VO 99/46281 PCT/US99/05028 28. RO!724 Applicants have identified a cDNA clone that encodes a novel polypeptide having homology to the LDL
receptor, wherein the polypeptide is designated in the present application as "PR0724".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0724 polypeptide, In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0724 polypeptide having amino acid residues 1 to 7I3 of Figure 68 (SEQ ID NO:I83), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. In another aspect, the isolated nucleic acid comprises DNA
encoding a soluble PR0724 polypeptide having amino acid residues 1 to X of Figure 68 (SEQ ID NO: I83) where X is any amino acid from amino acid' 437 to 446, or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least 10. moderate, and optionally, under high stringency conditions. The above two polypeptides may either possess or not possess the signal peptide. The isolated nucleic acid sequence may comprise the cDNA insert of the DNA49631-1328 vector deposited on April 28, 1998 as ATCC 209806 which includes the nucleotide sequence encoding PR0724.
In another embodiment, the invention provides isolated PR0724 polypeptide. In particular, the invention provides isolated native sequence PR0724 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 713 of Figure 68 (SEQ ID N0:183). In another embodiment, the invention provides isolated soluble PR0724 polypeptide. In particular, the invention provides isolated soluble PR0724 polypeptide, which in otte embodiment, inchides an amino acid sequence comprising residues 1 to X of Figure 68 (SEQ ID N0:183), where X is any amino acid from 437 to 446 of the sequence shown in Figure 68 (SEQ ID
NO:183). Optionally, the PR0724 polypeptide is obtaita:d or is obtainable by expressing the polypeptide encoded by the cDNA insert of the DNA49631 1328 vector deposited on April 28, 1998 as ATCC 209806:
29. PR0772 Applicants have identified a cDNA clone that encodes a novel polypeptide having homology to A4 protein, wherein the poiypeptide is designated in the present application as "PR0772" .
1n one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0772 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PRO772 polypeptide having amino acid residues 1 to 152 of Figure 70 (SEQ ID N0:190), or is complementary to such encoding nucleic acid sequence, and remains, stably bound to it under at least moderate, and optionally, under high stringency conditions. In other aspects, the isolated nucleic acid comprises DNA encoding the,PR0772 polypeptide having amino acid residues 1 to X of Figure 70 (SEQ ID N0:190), where X is any amino acid from 21 to 30 of Figure 70 (SEQ )D N0:190), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the DNA49645-1347 vector deposited on April 28, 1998 as ATCC 209809 which includes the nucleotide sequence etxoding PR0772.
In another embodiment, the invention provides isolated PR07?2 polypeptide. ht particular, the invention provides isolated native sequence PR0772 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 152 of Figure 70 (SEQ ID N0:190). Additional embodiments of the present invention are directed to PRO772 polypeptides comprising amino acids l to X of Figure 70 (SEQ 1D NO:I90), where X is any amino acid from 21 to 30 of Figure 70 (SEQ ID N0:190). Optionally, the PR0772 polypeptide is obtained or is s4 obtainable by expressing the polypeptide encoded by the cDNA insert of the DNA49645-1347 vector deposited on April 28, 1998 as ATCC 209809.
In another embodiment, the invention provides an expressed sequence tag (EST) designated herein as DNA43509 comprising the nucleotide sequence of SEQ ID N0:191 (Figure 71).
30. PR 8 Applicants have identified a cDNA clone that encodes a novel polypeptide having homology to various protease enzymes, wherein the polypeptide is designated in the present application as "PRO852".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0852 polypeptide. In one aspect, the isolated nucleic acid comprises DIVA
encoding the PR0852 polypeptide having amino acid residues 1 to 518 of Figure 73 (SEQ ID NO:I96), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. In other aspects, the isolated nucleic acid comprises DNA encoding the PR0852 polypeptide having amino acid residues about 21 to 518 of Figure 73 (SEQ 1D N0:196) or 1 or about 21 to X of Figure 73 (SEQ ID
N0:196) where X is any amino acid from amino acid 461 to amino acid 470 of Figure 73 (SEQ ID NO:196), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the DNA45493-1349 vector deposited on April 28, 1998 as ATCC 209805 which includes the nucleotide sequence encoding PR0852.
In another embodiment, the invention provides isolated PR0852 polypeptide. In particular; the invention provides isolated native sequence PR0852 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 518 of Figure 73 (SEQ ID N0:196). In other embodiments, the PR0852 comprises amino acids about 21 to amino acid 518 of Figure 73 (SEQ ID N0:196) or amino acids 1 or about 21 to X of Figure 73 (SEQ ID N0:196), where X is any amino acid from amino acid 461 to amino acid 470 of Figure 73 (SEQ ID
N0:196). Optionally, the PR0852 polypeptide is obtained or is obtainable by expressing the poIypeptide encoded by the cDNA insert of the DNA45493-1349 vectordeposited on April 28" 1998 as ATGC 209805.
31. PR0853 Applicants have identified a cDNA clone that encodes a novel polypeptide having sequence similarity to reductase, wherein the polypeptide is designated in the present application as "PRO$S3".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0853 polypeptide. In otne aspect, the isolated nucleic acid comprises DNA
encoding the PR0853 polypeptide having amino acid residues 1 to 377 of Figure 75 (SEQ ID N0:206), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and oprionally, under high stringency conditions. In another aspect, the isolated nucleic acid comprises DNA
encoding the PR0853 polypeptide having amino acid residues about 17 to 377 of Figure 75 (SEQ ID N0:206), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid seguence may comprise the cDNA insert of the DNA48227-1350 vector deposited on April 28, 1998 as ATGC 209812 which includes the nucleotide sequence encoding PR0853.
In another embodimern, the invention provides isolated PR0853 polypeptide. In particular, the invention provides isolated native sequence PR0853 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 377 of Figure 75 (SEQ ID N0:206). In another embodiment, the invention provides an isolated PR0853 golypeptide, absent the signal sequence, which includes an amino acid sequence comprising residues from about 17 to 377 of Figure 75 (SEQ ID N0:206). Optionally, the PR0853 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA insert of the DNA48227-1350 vector deposited on April 28, 1998 as ATCC 209812.
32. PR0860 Applicants have identified a cDNA clone that encodes a novel polypeptide having sequence similarity to neurofascin, wherein the polypeptide is designated in the present application as "PR0860".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0860 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0860 polypeptide having amino acid residues I to 985 of Figure 77 (SEQ ID NO:211), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. In another aspect, the isolated nucleic acid comprises DNA
encoding the PR0850 polypeptide having amino acid residues 1 to X of Figure 77 (SEQ ID N0:2I1), where X is any amino acid from 443-452 of Figure 77 (SEQ ID N0:211), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the DNA41404-1352 vector deposited on May 6, 1998 as ATCC
209844 which includes the rrucleotide sequence encoding PR0860.
In another embodiment, the invention provides isolated PR0860 polypeptide. In particular, the invention provides isolated native sequence PR0860 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 985 of Figure 77 (SEQ ID N0:211). In another embodiment, the invention provides an isolated PR0860 polypeptide which includes an amino acid sequence comprising residues 1 to X of Figure 77 (SEQ
ID N0:211), where X is any amino acid residue from 443 to 452 of Figure 77 (SEQ ID N0:211). Optionally, the PR0860 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA insert of the DNA41404-1352 vector deposited on May 6, 1998 as ATCC 209844.
33. ~R0846 Applicants have identified a cDNA clone that encodes a novel polypeptide having sequence similarity to CMRF35, wherein the polypeptide is designated in the present application as "PR0846".
1n one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0846 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0846 polypeptide having amino acid residues 1 to 332 of Figure 79 (SEQ ID N0:216), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. In other aspects, the isolated nucleic acid comprises DNA encoding the PR0846 polypeptide having amhto acid residues about 18 to 332 of I igute 79 (SEQ m N0:216) or 1 or about 18 to X of SEQ ID N0:216, where X is auy amino acid from 243 to 252 of Figure 79 (SEQ ID N0:216); or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the DNA44196-1353 vector deposited on May 6, 1998 as ATCC 209847 which includes the nucleotide sequence encoding PR0846.
in another embodiment, the invention provides isolated PR0846 polypeptide. In particular, the invention provides isolated native sequence PR0846 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 332 of Figure ?9 (SEQ ID N0:216). In ocher embodiments, the invention provides an isolated PR0846 polypeptide absem the signal sequence, which includes an amino acid sequence comprising residues from about 18 to 332 of Figure 79 (SEQ ID N0:216). ~rdditionaI embodiments of the present invention are directed to an isolated PR0846 polypeptide comprising amino acid 1 or about 18 to X of Figure 79 (SEQ ID N0:216), where X is any amino acid from 243 to 252 of Figure 79 (SEQ ID N0:216). <~tionally, the PR0846 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA
insert of the DNA44196-1353 vector deposited on May 6, 1998 as ATCC 209847.
34. _P_R0862 Applicants have identified a cDNA clone that encodes a novel polypeptide having sequence similarity to lysozyme, wherein the polypeptide is designated in the present application as "PR0862" .
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0862 poiypeptide. in one aspect, the isolated nucleic acid comprises DNA
encoding the PR0862 polypeptide having amino acid residues 1 to 146 of Figure 81 (SEQ ID N0:221), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate" and optionally, under high stringency conditions. in another aspect, the isolated nucleic acid comprises DNA
encoding the PR0862 polypeptide having amino acid residues about 19 to 146 of Figure 81 {SEQ ID N0:22i), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally; under high stringency conditions, The isolated nucleic acid sequence may comprise the eDNA insert of the DNA5218?-1354 vector deposited on May 6, 1998 as ATCC 209845 which includes the nucleotide sequence encoding PR0862.
In another embodiment, the invention provides isolated PR0862 polypeptide. In particular, the invention provides isolated native sequence PR0862 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 146 of Figure 81 (SEQ ID N0:22I). in another embodiment, the invention provides an isolated PR0862 polype~de absent the signal sequence, which includes an amino acid sequence comprising residues from about 19 to 146 of Figure 81 (SEQ ID N0:221 ). Optionally; the PR0862 polypeptide is obtained or is obtainable by expressing the,polypeptide encoded by the cDNA insert of the DNA52187-1354 vector deposited on May 6, 1998 as ATCC 209845.
35. P-R_0864 Applicants have identified a cDNA clone that encodes a novel polypeptide having sequence similarity to Wnt-4, wherein the polypeptide is designated in the present application as "PR0864".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0864 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0864 polypeptide having amino acid residues l to 351 of Figure 83 (SEQ ID N0:226), or is complementary to such encoding nucleic acid sequence, aril remains stabiy bound to it under at least moderate, and opaottatly, under high stringency conditions. In another aspect, the isolated nucleic acid comprises DN,A
encoding the PR0864 polypeptide having amid acid residues about 23 to 351 of Figure 83 (SEQ ID N0:226), or is complementary to such encoding nucleic WO 99/46281 PCTlUS99105028 acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the DNA48328-1355 vector deposited on May 6, 1998 as ATCC 209843 which includes the nucleotide sequence encoding PR0864.
In another embodiment, the invention provides isolated PR0864 polypeptide. In particular, the invention provides isolated native sequence PR0864 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 351 of Figure 83 (SEQ ID N0:226). In another embodiment, the invention provides an isolated PR0864 polygeptide absent the signal sequence, which includes an amino acid sequence comprising residues from about 23 to 351 of Figure 83 (SEQ ID N0:226). Optionally, the PR08b4 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA insert of the DNA48328-1355 vector deposited on May 6, 1998 as ATCC 209843 36. PR, 0792 Applicants have identified a cDNA clone that encodes a novel polypeptide having homology to CD23, wherein the golypeptide is designated in the present application as "PR0792".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PRO'792 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0792 polypeptide having amino acid residues 1 to 293 of Figure 85 (SEQ ID NO:231), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. In another aspect, the isolated nucleic acid comprises DNA
encoding the PR0792 polypeptide having amino acid residues X to 293 of Figure 85 (SEQ ID N0:231) where X is any amino acid from 50 to 59 of Figure 85 (SEQ ID N0:231), or is compiemen<ary to such encoding rnicleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the DNA56352-1358 vector deposited on May 6, 1998 as ATCC
209846 which includes the nucleotide sequence encoding PR0792.
1n another embodiment, the invention provides isolated PR0792 polypeptide. In particular, the invention provides isolated native sequence PR0792 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues i to 293 of Figure 85 (SEQ ID N0:231). An additional embodiment of the present invention is directed to PR0792 polygeptide comprising amino acids X to 293 of Figure 85 (SEQ ID N0:231), where X is any amino acid from 50 to 59 of. Figure 85 (SEQ ID N0:231). Optionally, the PR0792 poiypeptide is obtained or is obtainable by expressing the poIypeptide encoded by the cDNA insert of the DNA56352-1358 vector deposited on May 6, 1998 as ATCC 209846.
37. ~'R0866 Appii~s have identified a cDNA clone that encodes a novel polypeptide having homology to mindin and spondin proteins, wherein the polypeptide is designated in the present application as "PR0866".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0866 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0866 polypeptide having amitw acid residues 1 to 331 of Figure 87 (SEQ ID N0:236), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high suingency conditions. In another aspect, the isolated trucleic acid comprises DNA
encoding the PR0866 polypeptide having amino acid residues about 27 to 229 of Figure 87 (SEQ ID NO:236), or is complemezttary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the DNA53971-1359 vector deposited on April 7, 1998 as ATCC 209750 which includes the nucleotide sequence encoding PR0866.
In another embodiment, tire invention provides isolated PR0866 polypeptide. In particular, the invention provides isolated native sequence PR0866 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 331 of Figure 87 {SEQ ID NO:236). Another embodiment of the present invention is directed to PR0866 polypeptides comprising amino acids about 27 to 331 of Figure 87 (SEQ ID N0:236).
Optionally, the PR0866 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA
insert of the DNA53971-1359 vector deposited on April ?, 1998 as ATCC 209750.
38. PR087~
Applicants have identified a cDNA clone that encodes a novel palypeptide having homology to CyP-60, wherein the polypeptide is designated in the present application as "PR0871".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0871 polypeptide. In one aspect, the isolated nucleic acid comprises I)NA
encoding the PR0871 polypeptide having amino acid residues 1 to 472 of Figure 89 (SEQ ID N0:245), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. In other aspects, the isolated nucleic acid comprises DNA encoding the PR0871 polypeptide having amino acid residues about 22 to 472 of Figure 89 (SEQ ID N0:245), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the DNA50919-1361 vector deposited on May 6, 1998 as ATCC 209848 which includes the nucleotide sequence encoding PR0871.
In another embodiment, the invention provides isolated PR087I polypeptide. In particular, the invention provides isolated native sequence PR0871 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 472 of Figure 89 (SEQ i;D N0:245). An additional embodiment of the present invention is directed to PR0871 polypeptidea comprising amino acids about 22 to 472 of Figure 89 (SEQ ID N0:245).
Optionally, the PR0871 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA
insert of the DNA50919-1361 vector deposited on May 6, 1998 as ATCC 209848.
39. PR08~3 Applicants have identified a cDNA clone that encodes a novel polype~ptide having homology to carboxylesterase, wherein the polypeptide is designated in the present application as "PRO873".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PRO873 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0873 polypeptide having amino acid residues 1 to 545 of Figure 91 (SEQ ID N0:254), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high suingency conditions. In other aspects, the isolated nucleic acid comprises DNA.
encoding the PR0873 polypeptide haviag amino acid residues about 30 to about 545 of Figure 91 (SEQ ID N0:254), or is complementary to such encoding ra~cleic acid sequence, and remains stably bound to it under at least mode:race, and optionally, under high stringency WO 99/45281 PCTlUS99/05028 conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the DNA44179-1362 vector deposited on May 6, 1998 as ATCC 209851 which includes the nucleotide sequence encoding PR0873.
In another embodiment, the invention provides isolated PRO873 polypeptide. In particular, the invention provides isolated native sequence PR0873 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 545 of Figure 91 (SEQ ID N0:254). Additional embodiments of the present invention are directed to PR0873 polypeptides comprising amino acids about 30 to about 545 of Figure 91 (SEQ ID NO:254).
Optionally, the PR0873 polypeptide is obtained or is obtainable by expressing the poiypeptide encoded by the cDNA
insert of the DNA44179-1362 vector deposited on May 6, 1998 as ATCC 209851.
40. . PR
Applicants have identified a cDNA clone that encodes a novel polypeptide having homology to CD33 and OB binding protein-2, wherein the polypeptide is designated in the present application as "PR0940".
h~ one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0940 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0940 polypeptide having amino acid residues 1 to 544 of Figure 93 (SEQ ID N0:259), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. In other aspects, the isolated nucleic acid comprises DNA encoding the PR0940 polypeptide having amino acid residues about 16 to 544 of Figure 93 (SEQ ID N0:259) or 1 or about 16 to X of Figure 93 (SEQ ID
N0:259}, where X is any amino acid from 394 to 403 of Figure 93 (SEQ ID
N0:259), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the DNA54002-1367 vector deposited on April 7, 1998 as ATCC 209754 which includes the nucleotide sequence encoding PR0940.
In another embodiment, the invention provides isolated PR0940 polypeptide. In particular, the invention provides isolated native sequence PR0940 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 544 of Figure 93 (SEQ ID N0:259}. Other embodimerns of the present invention are directed to PR0940 polypeptides comprising amino acids about 16 to 544 of Figure 93 (SEQ 1D N0:259) or I or about 16 to X of Figure 93 (SEQ ID N0:259), where X is any amino acid from 394 to 403 of Figure 93 (SEQ ID
N0:259). Optionally, the PR0940 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA insert of the DNA54002-1367 vector deposited on April 7, 1998 as ATCC 209754.
41. PRO9$1 Applicants have identified a cDNA clone that encodes .a novel polypeptide having homology to a cadherin protein, wherein the polypeptide is designated in the present application as "PR0941".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0941 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR094i polypeptide having amino acid residues 1 to 772 of Figure 95 (SEQ ID N0:2b4), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. In other aspects, the isolated nucleic acid comprises DNA encoding the PR0941 polypeptide having amino acid residues about 22 to 772 of Figure 95 (SEQ ID N0:264) or l or about 22 to X of Figure 95 (SEQ ID
N0:264), where X is arty amino acid from 592 to 601 of Figure 95 (SEQ ID
N0:264), or is complementary to such _. i WO 99146281 PCTlUS99l05028 encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the DNA53906-1368 vector deposited on April 7, 1998 as ATCC 209747 which includes the nucleotide sequence encoding PR0941.
In another embodiment, the invention provides isolated PRO941 polypeptide. In particular, the invention provides isolated native sequence PR0941 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 772 of Figure 95 (SEQ ID N0:264). Additional embodiments of the present invention are directed to PR0941 polypeptides which comprise amino acid about 21 to 77:d of Figure 95 (SEQ ID N0:264) or 1 or about 22 to X of Figure 95 (SEQ ID N0:264), where X is any amino acid from 592 to 601 of Figure 95 (SEQ ID
N0264). Optionally, the PR0941 polypepdde is obtained or is obtainable by expressing the polypeptide encoded by the cDNA insert of the DNAS3906-1368 vector deposited on April 7, 1998 as In another embodiment, the invention provides an expressed sequence tag (EST) designated herein as DNA6415 comprising the nucleotide sequence of Figure 96 (SEQ ID N0:265).
42. PR0944 Applicants have identified a cDNA clone that encodes a novel polypeptide having homology to Clostridium IS perfringens enterotoxin receptor (CPE-R), wherein the polypegtide is designated in the present application as "PR0944" .
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0944 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0944 polypeptide having amino acid residues 1 to 211 of Figure 98 (SEQ ID N0:270), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. In other aspects, the isolated nucleic acid comprises DNA encoding the PR0944 polypeptide having amino acid residues about 22 to 229 of Figure 98 (SEQ ID N0:270) or amino acid I or about 22 to X of Figure 98 (SEQ ID N0:270) where X is any amino acid from 77 to 80 of Figure 98 (SEQ ID
N0:270), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the eDNA insert of the DNA52185 1370 vector deposited on May 14, 1998 as ATCC 209861 which includes the nucleotide sequence encoding PR0944.
In another embodiment; the invention provides isolated PR0944 polypeptide. In particular, the invention pzovides isolaoed native sequence PR0944 polypegtide, which in one embodiment, includes an amino acid sequence comprising residues I to 211 of Figure 98 (SEQ ID N0:270). Additional embodiments of the present invention are directed to PR0944 poiypepddes comprising amino acids about 22 to 2I 1 of Figure 98 (SEQ ID N0:270) or amino acid 1 or about 22 to X of Figure 98 (SEQ ID N0:270), where X is any amino acid from 77 to 86 of Figure 98 (SEQ
ID N0:270). Optionally, the PR0944 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the eDNA insert of the DNA52I85-1370 vector deposited on May 14,, 1998 as ATCC 209861.
In another embodiment, the invention provides an expressed sequence tag (EST) designated herein as DNA14007 comprising the nucleotide sequence of Figure 99 (SEQ ID NO:27I).
In another embodirc~nt, the invention provides an expressed sequence tag (FST) designated herein as DNA12733 comprising the nucleotide sequence of Figure 100 (SEQ ID N0:272).
In another embodiment, the invention provides an expressed sequence tag (EST) designated herein as DNA12746 comprising the nucleotide sequence of Figure 101 (SEQ ID N0:273).

WO 99!46281 PCT/US99/05028 In another embodiment, the invention provides an expressed sequence tag (EST) designated herein as DNA12834 comprising the nucleotide sequence of Figure 102 (SEQ ID N0:274).
In another embodiment, the invention provides an expressed sequence tag (EST) designated herein as DNA12846 comprising the nucleotide sequence of Fiugure 103 (SEQ ID N0:275).
In another embodiment, the invention provides an expressed sequence tag (EST) designated herein as DNA13104 comprising the nucleotide sequence of Figure 104 (SEQ ID N0:276).
In another embodiment, the invention provides an expressed sequence tag (ES'T) designated herein as DNA13259 comprising the nucleotide sequence of Figure 105 (SEQ ID N0:277).
In another embodiment, the invention provides an expressed sequence tag (EST) designated herein as DNAI3959 comprising the nucieotide sequence of Figure 106 (SEQ ID N0:278).
In another embodiment, the invention provides an expressed sequence tag {EST) designated herein as DNA13961 comprising the nucleotide sequence of Figure 107 {SEQ ID N0:279).
43. ~'R0983 Applicants have identified a cDNA clone that encodes a novel polypeptide having homology to a vesicle associated protein, VAP-33, wherein the polypeptide is designated in the present application as "PR0983".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0983 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0983 polypeptide having amino acid residues 1 to 243 of Figure 109 (SEQ ID N0:284), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. In other aspects, the isolated nucleic acid comprises DNA encoding the PR0983 polypeptide having amino acid residue 1 to X of Figure 109 (SEQ ID N0:284) where X is any amino acid from 219 to 228 of Figure 109 (SEQ ID N0:284), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions.
The isolated nucleic acid sequence may comprise the eDNA insert of the DNA53977-1371 vector deposited on May 14, 1998 as ATCC 209862 which includes the nucleotide sequence encoding PR0983.
In another embodiment, the invention provides isolated PR0983 polypeptide. In particular, the invention provides isolated native sequence PR0983 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 243 of Figure 109 (SEQ ID N0:284). Additional embodiments of the present invention are directed to PR0983 poiypeptides comprising amino acid 1 to X of Figure I09 (SEQ ID N0:284), where X is any amino acid from 219 to 228 of Figure 109 (SEQ ID N0:284). Optionally, the PR0983 poiypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA insert of the DNA53977-137I vector deposited on May 14, 1998 as ATCC 209862.
In another embodiment, the invention provides an expressed sequence tag (EST) designated herein as DNA17130 comprising the nucleotide sequence of Figure 110 (SEQ ID N0:285).
In another embodiment, the invention provides an expressed sequence tag (EST) designated herein as DNA23466 comprising the nucleotide sequence of Figure 111 (SEQ ID N0:286).
In another embodiment, the invention provides an expressed sequence tag (EST) designated herein as DNA26818 comprising the nucleotide sequence of Figure 112 (SEQ ID N0:287).
In another embodiment, the invention provides an expressed sequence tag (EST) designated herein as DNA37618 comprising the nucleotide sequence of Figure I13 (SEQ ID N0:288).
In another embodiment, the invention provides an expressed sequence tag (EST) designated herein as DNA41732 comprising the. nucleotide sequence of Figure 114 (SEQ ID N0:289).
In another embodiment, the invention provides an expressed sequence tag (EST) designated herein as DNA4S980 comprising the nucleotide sequence of Figure l IS (SEQ ID N0:290).
In another embodiment, the invention provides an expressed sequence tag {EST) designated herein as DNA46372 comprising the nucleotide sequence of Figure 116 (SEQ ID N0:291).
44. R007 Applicants have identified a cDNA clone that encodes a novel polypeptide having homology to proteases, wherein the polypeptide is designated in the present application as "PROIOS7".
In one embodiment, the invention provides an isolated nucleic acid. molecule comprising DNA encoding a PROlOS7 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR01057 polypeptide having amino acid residues I to 413 of Figure 118 (SEQ 1D N0:296), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency 1S conditions. in other aspects, the isolated nucleic acid comprises DNA
encoding the PROlOS7 poiypeptide having amino acid residues about 17 to 413 of Figure 1 I8 (SEQ ID N0:296), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the eDNA insert of the DNAS72S3-1382 vector deposited on May I4, 1998 as ATCC 209867 which includes the nucleotide sequence encoding PROlOS7.
In another embodiment, the invention provides isolated PROlOS7 polypeptide. In particular, the invention provides isolated native sequence PROlOS7 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues I to 413 of Figure 118 (SEQ ID NO:296). Additional embodiments of the present invention are directed to PROlOS7 polypeptides comprising amino acids about 17 to 413 of Figure 118 (SEQ iD N0:296).
Optionally, the PROIOS7 polypeptide is obtained or is obtainable by expressing the poiypeptide encoded by the cDNA
2S insert of the DNAS72S3-1382 vector deposited on May 14, 1998 as ATCC
209867.
45. PROI87I
Applicants have identified a cDNA clone that encodes a novel polypeptide having homology to thrombospondin, wherein the polypeptide is designated in the present application as "PROI071".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR01071 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR01071 polypeptide having amino acid residues 1 to S2S of Fgure I20 {SEQ ID N0:30i), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. In other aspects, the isolated tmcleic acid comprises DNA encoding the PR01071 polypeptide having amino acid residues about 26 to 525 of Figure 120 (SEQ ID N0:301), or is complementary to such encoding irueIeic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the eDNA insert of the DNAS8847-1383 vector deposited on May 20, 1998 as ATCC 209879 which includes the nucleotide sequence encoding PR01071.
In another embodiment: the invention provides isolated PROIO'71 polypeptide.
In particular, the invention provides isolated native sequence PR01071 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 525 of Figure 120 (SEQ ID N0:301). Additional embodiments of the present invention are directed to PR0107I polypeptides comprising amino acids about 26 to 525 of Figure 120 (SEQ ID N0:301).
Optionally, the PR01071 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA
insert of the DNA58847-1383 vector deposited on May 20, 1998 as ATCC 209879.
46. PR01072 Applicants have identified a cDNA clone that encodes a novel polypeptide having homology to reductase proteins, wherein the polypeptide is designated in the present application as "PR01072".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR01072 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR01072 polypeptide having amino acid residues 1 to 336 of Figure 122 (SEQ ID N0:303), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. In other aspects, the isolated nucleic acid comprises DNA encoding the PR01072 polypept:ide having amino acid residues about 22 to 336 of Figure 122 (SEQ ID N0:303), or is complementary to such encoding nucleic IS acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the DNA5874?-1384 vector deposited on May 14, 1998 as ATCC 209868 which includes the nucleotide sequence encoding PR01072.
In another embodiment, the invention provides isolated PR01072 polypeptide: In particular, the invention provides isolated native sequence PR01072 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 336 of Figure 122 (SEQ 1D N0:303). Additional embodiments of the present invention are directed to PR01072 polypeptides comprising amino acids about 22 to 336 of Figure 122 (SEQ ID N0:303).
Optionally, the PR01072 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA
insert of the DNA58747-1384 vector deposited on May 14, 1998 as ATCC 209868.
In another embodiment, the invention provides an expressed sequence tag (ES'I~
designated herein as DNA40210 comprising the nucleotide sequence of Figure 123 (SEQ ID N0:304).
47. PR01075 Applicants have identified a cDNA clone that encodes a novel polypeptide having homology to protein disulfide isomerase, wherein the polypeptide is designated in the present application as "PR01075".
In one embodiment, tl~ invention provides an isolated nucleic acid molecule comprising DNA encoding a PR01075 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PRO1075 polypeptide having amino acid residues 1 fo 406 of Figure 125 (SEQ ID N0:309), or is complementary to such encoding rrucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. In other aspects, the isolated nucleic acid comprises DNA encoding the PR01075 polypeptide having amino acrd residues about 30 to 406 of Figure 125 (SEQ ID N0:309), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the DNA57689-1385 vector deposited on May 14, 1998 as ATCC 209869 which includes the nucleotide sequence encoding PROI075 In anther embodiment, the invention provides isolated PR01075 polypeptide. In particular, the invention provides isolated native sequence PR01075 poiypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 406 of Figure 125 (SEQ ID N0:309). Additional embodiments of the present invention are directed to PR01075 polypeptides comprising amino acids about 30 to 406 of Figure 125 (SEQ ID N0:309).
Optionally, the PR01075 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA
insert of the DNA57689-1385 vector deposited on May i4, 1998 as ATCC 2 09869.
In another embodiment, the invention provides an expressed sequence tag (EST) designated herein as DNA13059 comprising the nucleotide sequence of Figure 126 (SEQ ID N0:310).
In another embodiment, the invention provides an expressed sequence tag (EST) designated herein as DNA19463 comprising the nucleotide sequence of Figure 127 (SEQ ID N0:311).
48. ~'ROl8I
Appli~rns have identified a cDNA cio~ that encodes a novel polypeptide having homology to the cornichon protein, wherein the polypeptide is designated in the present application as "PR0181".
In of embodittnt, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0181 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PROI81 polypeptide having amino acid residues 1 to 144 of Figure 129 (SEQ ID N0:322), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at Ieast moderate, and optionally, under high stringency conditions: In other aspects, the isolated nucleic acid comprises DNA encoding the PR0181 polypepdde having amino acid residues about 21 to 144 of Figure 129 (SEQ ID N0:322} or amino acid I or about 2I to X of Figure 129 {SEQ ID N0:322) where X is any amino acid from 52 to 61 of Figure 129 (SEQ ID
N0:322), or is complementary to such encoding rnxleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the DNA23330-1390 vector deposited on April 14, 1998 as ATCC 2U9775 which includes the nucleotide sequence encoding PR0181.
1n another embodiment, the invention pro~iides isolated PR018I polypeptide. In particular, the invention provides isolated native sequence PR0181 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 w 144 of Figure 129 (SEQ ID N0:322). Additional earlbodiments of the present invention are directed to PR018I polypepudes comprising amino acids about 2I to 144 of Figure 129 {SEQ ID N0:322) or amino acid 1 or about 2I to X of Figure 129 (SEQ ID N0:322}, where X is any amino acid from 52 to 61 of Figure 129 (SEQ m N0:322). Optionatlx, the PR0181 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA insert of the DNA23330-1390 vector deposited on April 14, 1998 as ATCC 209775.
In another embodiment, the invention provides an expressed sequence tag (EST) designated herein as DNA13242 comprising the mtcleotide sequence of Figure 130 (SEQ ID N0:323).
49. PR0195 Applicants have identified a cDNA clot that encodes a novel transmembrane polypeptide, wherein the polypeptide is designated in the 'present application as "PR0195".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PROI95 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0195 potypeptide having amino acid residues 1 to 323 of Figure 132 (SEQ ID N0:330), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency WO 99/46281 PCT/US99l05028 conditions. In other aspects, the isolated nucleic acid comprises DNA encoding the PR0195 polypepiide having amino acid residues about 32 no 323 of Figure 132 (SEQ ID N0:330) or amino acid 1 or about 32 to X of Figure 132 (SEQ B~ N0:330) where X is any amino acid from 236 to 245 of Figure 132 (SEQ
ID N0:330), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the DNA26847-1395 vector deposited on April 14, 1998 as ATCC 209772 which includes the nucleotide sequence encoding PR0195.
In another embodiment, the invention provides isolated PR0195 polypeptide. In particular, the invention provides isolated native sequence PR0195 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 323 of Figure 132 (SEQ 1D N0:330). Additional embodiments of the present invention are directed to PR0195 polypeptides comprising amino acids about 32 to 323 of Figure i32 (SEQ ID N0:330) or amino acid I or about 32 to X of Figure i32 (SEQ ID N0:330), where X is any amino acid from 236 to 245 of Figure 132 (SEQ ID N0:330). Optionally, the PR0195 polypeptide is obtained or is obtainable by expressing the palypeptide encoded by the cDNA insert of the DNA26847-1395 vector deposited on April 14, 1998 as ATCC 209772.
1n another embodiment, the invention provides an expressed sequence tag (EST) comprising the nucleotide sequence of Figure 133 (SEQ ID N0:331), herein designated DNA15062.
In another embodiment, the invention provides an expressed sequence tag (EST) comprising the nucleotide sequence of Figure I34 (SEQ TD N0:332), herein designated DNA13199.
50. PR0865 Applicants have identified a cDNA clone that encodes a novel secreted polypeptide, wherein the polypeptide is designated in the present application as "PR0865".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0865 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0865 polypepdde having amino acid residues 1 to 468 of Figure 136 (SEQ ID N0:337), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. In other aspects, the isolated nucleic acid comprises DNA encoding the PR0865 polypeptide having amino acid residues about 24 tn 229 of Figure 136 (SEQ ID N0:337), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the DNA539?4-1401 vector deposited on April 14, 1998 as ATCC 209774 which includes the nucleotide sequence encoding PR0865.
In another embodiment, the invention provides isolated PR0865 polypeptide. In particular, the invention provides isolated native sequence PR0865 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 468 of Figure 136 (SEQ ID N0:337). An additional embodiment of the present invention is directed to a PR0865 polypeptide comprising amino acids about 24 to 468 of Figure 136 (SEQ ID N0:337).
Optionally, the PR0865 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA
insert of the DNA53974-1401 vector deposited on April 14, 1998 as ATCC 209774.
In another embodiment, the invention provides an expressed sequence tag (EST) comprising the nucleotide sequence of Figure 137 (SEQ ID N0:338), herein designated as DNA37642.

51. PRQ827 Applicants have identified a cDNA clone that encodes a novel polypeptide having homology to integrin proteins, wherein the polypeptide is designated in the present application as "PRO827".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0827 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0827 polypeptide having amino acid residues 1 to 124 of Figure 139 (SEQ ID N0:346), or is complementary to such encoding nucleic acid sequence, and remains stabiy bound to it under at least moderate, and optionally, under high stringency conditions. In other aspects, the isolated nucleic acid comprises DNA encoding the PR0827 polypeptide having amino acid residues about 23 to 124 of Figure I39 (SEQ ID N0:346), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at Least moderate, and optionally, under high stringency IO conditions. The isolated nucleic acid sequence may comprise the eDNA insert of the DNA57039-1402 vector deposited on April 14, 1998 as ATCC 209777 which includes the nucleotide sequence encoding PR0827.
In another embodiment, the invention provides isolated PR0827 polypeptide. In particular, the invention provides isolated native sequence pR0827 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 124 of Figure 139 (SEQ ID N0:346). An additional embodiment of the present invention is directed to a PR0827 polypeptide comprising amino acids about 23 to 124 of Figure 139 (SEQ ID N0:346).
Optionally, the PR0827 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA
insert of the DNA57039-1402 vector deposited on April 14, 1998 as ATCC 2097?7.
SZ. PR01114 2d Applicants have identified a cDNA clone that encodes a novel polypeptide having homology to cytoltine receptor family! proteins, wherein the poiypeptide is designated in the present application as "PROI114".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR01114 poiypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR01114 polypeptide having amino acid trsidues 1 to 311 of Figure 142 (SEQ ID N0:352), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stt~ingency conditions. In other aspects, the isolated nucleic acid comprises DNA encoding the PR01114 polypeptide having amino acid residues about 30 to 311 of Figure i42 (SEQ ID N0:352} or amino acid 1 or about 30 to X of Figure 142 (SEQ ID N0:352), where, X is any amino acid from 225 to 234 of Figure 142 (SEQ
ID N0:35Z), or is completnentaty to stilt encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the DNA57033-1403 vector deposited on May 27, 1998 as ATCC 209905 which includes the nucleotide sequence encoding PR01114.
In another embodiment, the invention provides isolated PRO! 1:!4 polypeptide.
In particular, the invention Provides isolated native sequence PROs 114 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 311 of Figure 142 (SEQ ID N0:352). Additional embodiments of the present imrention are directed to PR01114 polypepttdes comprising amino acids about 30 to 311 of Figure 142 (SEQ ID N0:352) or amino acid 1 or about 30 to X of Figure 142 (SEQ ID N0:352), where X is any amino acid from 225 to 234 of Figure 142 (SEQ ID N0:352). Ogtsonally, the pR01114 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA insert of the DNA57033-1403 vector deposited on May 27, 1998 as ATCC 209905.

In another embodiment, the invention provides an expressed sequence tag (EST) designated herein as DNA48466 comprising the nucleotide sequence of Figure 143 (SEQ ID N0:353).
A cDNA clone (DNA57033-1403) has been identified that encodes a novel interferon receptor polypeptide, designated in the present application as "PROl I14 interferon receptor".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR01114 interferon receptor polypeptide.
In one aspect, the isolated nucleic acid comprises DNA having at least about 80% sequence identity, preferably at least about 85% sequence identity, more preferably at least about 90'~v sequence identity, most preferably at least about 95 k sequence identity to (a) a DNA molecule encoding a PR01114 interferon receptor polypeptide having the sequence of amino acid residues from about I or about 30 to about 311, inclusive of Figure 142 (SEQ ID N0:352), or (b) the complement of the DNA molecule of (a).
In another aspect, the invention concerns an isolated nucleic acid molecule encoding a PR01114 interferon receptor polypeptide comprising DNA hybridizing to the complement of the nucleic acid between about nucleotides 250 or about 337 and about 1182, inclusive, of Figure 141 (SEQ lD N0:351).
Preferably, hybridization occurs under stringent hybridization and wash conditions.
In a further aspect, the invention concerns an isolated nucleic acid molecule comprising DNA having at least about 80%n sequence identity, preferably at least about 85% sequence identity, mote preferably at least about 90%
sequence identity, most preferably at least about 95% sequence identity to (a) a DNA molecule encoding the same mature polypeptide encoded by the human protein cDNA in ATCC Deposit No.
209905 (DNA57033-1403) or (b) Lhe complement of the nucleic acid molecule of (a). In a preferred embodiment, the nucleic acid comprises a DNA
encoding the same mature polypeptide encoded by the human protein cDNA in ATCC
Deposit No. 209905 (DNAS?033-1403).
In still a further aspect, the invention concerns an isolated nucleic acid molecule comprising (a) DNA
a polypeptide having at least about 8096 sequence identity, preferably at least about 85% sequence identity, more preferably at Ieast about 90% sequeace identity, most preferably at least about 95% sequence identity to the sequence of amino acid residues 1 or about 30 to about 311, inclusive of Figure 142 (SEQ ID N0:352), or (b) the complement of the DNA of (a).
In a further aspect, the invention concerns an isolated nucleic acid molecule having at least 10 nucleotides and produced by hybridizing,a test DNA molecule under stringern conditions with (a) a DNA molecule encoding a PR01114 interferon receptor polypeptide having the sequence of amino acid residues from 1 or about 30 to about 311, iuch~sive of Figure 142 (SEQ 1D N0:352), or (b) the complement of the DNA
molecule of (a), and, if the DNA
molecule has at least about an 80 ~ sequence identity, prefereably at least about an 85 % sequence identity, more preferably at least about a 90 ~ sequence identity, most preferably at least about a 95 ~ sequence identity to (a) or (b), isolating the test DNA molecule.
by a specific aspect, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR01114 interferon receptor polypeptide, with or without the N-terminal signal sequence and/or the initiating metbionine, a3nd its soluble, i.e., transtnetnbrane domain deleted or inactivated variants, or is complementary to such encoding nucleic acid molecule. The signal peptide bas been tentatively identified as extending from about amino acid position 1 to about amino acid position 29 in the sequence of Figure 142 (SEQ ID N0:352). The transmembrane domain has been tentatively identified as extending from about amino acid position 230 to about amino acid position h WO 99/4628! PCT/US99/05028 255 in the PROs t 14 interferon receptor amino acid sequence (Figure 142, SEQ
ID N0:352).
In another aspect, the invention concerns an isolated nucleic acid molecule comprising (a) DNA encoding a polypeptide scoring at least about 80% positives, preferably at least about 85% positives, more preferably at least about 90~ positives, most preferably at least about 95% positives when compared with the amino acid sequence of residues 1 or about 30 to about 311, inclusive of Figure. I42 (SEQ ID N0:352), or (b) the complement of the DNA
S of (a).
Another embodiment is directed to fragments of a PR01114 interferon receptor polypeptide coding sequence that may find use as hybridization probes. Such nucleic acid fragments are fiom about 20 to about 80 nucleotides in length, preferably from about 20 to about 60 nucleotides in length, more preferably from about 20 to about 50 nucleotides in length and most preferably from about 20 to about 40 nucleotides in length and may be derived from the nucleotide sequence shown in Figure 141 ($EQ ID N0:351).
In another embodiment, the invention provides a vector comprising DNA encoding PR01114 interferon receptor or its variants. The vector may comprise any of the isolated nucleic acid molecules hereinabove identified.
A host ceU comprising such a vector is also provided. By way of example, the host cells may be CHO cells, E. colt, or yeast. A process for producing PROs 114 interferon receptor polypeptides is further provided and comprises culturing host cells under conditions suitable for expression of PR01114 interferon receptor and recovering PR01 I 14 interferon receptor from the cell culture.
In another embodiment, the invention provides isolated PRO/ ! I4 interferon receptor polypeptide encoded by any of the isolated nucleic acid sequences hereinabove identified.
In a specific aspect, the invention provides isolated native sequence PR01114 interferon receptor polypeptide, which in certain embodiments, includes an amino acid sequence comprising residues 1 or about 30 to about 31 ! of Figure 142 (SEQ ID N0:352).
In another aspect, the invention concerns an isolated PROI114 interferon receptor polypeptide, comprising an amino acid sequence /raving at least about 80 k sequence identity, preferably at least about 85 % sequence identity, more preferably at least about 909b sequence identity, most preferably at least about 95 % sequence identity to the sequence of amino acid residues 1 or about 30 to about 311, inclusive of Figure I42 (SEQ ID N0:352).
In a futtlrer aspect, the imerrtion concerns an isolated PR01114 interferon receptor polypepude, comprising an amino acid scquerrce scoring at least about 80% positives, preferably at least about 85 % positives, more preferably at least about 90% positives, most preferably at Least about 95% positives when compared with the amino acid sequence of residues 1 or about 30 to about 311, inclusive of Figure 142 (SEQ
ID N0:352).
In yet another aspect, the invention concerns an isolated PR01114 interferon receptor polypeptide, comprising the sequence of amir>o acid residues t or about 30 to about 311, inclusive of Figure 142 (SEQ ID
N0:352), or a fragrneru thereof sufficient to provide a binding site for an anti-PR01 I 14 interferon receptor antibody.
Preferably, the PR01114 interferon receptor fragment retains a qualitative biological activity of a motive PROl l l4 interferon receptor poIypeptide.
In a still further aspect, the invention provides a polypeptide produced by (t) hybridizing a test DNA
molecule under stringent conditions with {a) a DNA molecule encoding a PR01114 interferon receptor polypeptide having the seqrreace of amrim acid residues from about I or about 30 to about 31I, inclusive of Figure I42 (SEQ ID
N0:352), or (b) the complemeru of the DNA mrolecule of (a), and if the test DNA molecule has at least about an 80%
sequence identity, preferably at least above an 859b sequence identity, more preferably at least about a 90~ sequer~e WO 99/46281 PCT/US99l05028 identity, most preferably at least about a 95 'I6 sequence identity to (a) or (b), (ii) culturing a host cell comprising the test DNA molecule under conditions suitable for expression of the polypeptide, and {iii) recovering the polypeptide, from the cell culture.
In another embodiment, the invention provides chimeric molecules comprising a PRO1114 interferon receptor polypeptide fused to a heterologous polypeptide or amino acid sequence. An example of such a chimeric molecule comprises a PR01114 interferon receptor polypeptide fused to an epitope tag sequence or a Fc region of an iznmunoglobulin.
In another embodiment, the invention provides an antibody which specifically binds to a PROl 1 I4 interferon.
receptor poiypeptide. Optionally, the antibody is a monoclonal antibody.
In yet another ettlbodirttent, the invention concerns agonists and antagonists of a native PROl 114 interferon : receptor polypeptide. In a particular embodiment, the agonist or antagonist is an anti-PR01114 interferon receptor antibody.
In a further embodiment, the invention concerns a method of identifying agonists or antagonists of a native PR41114 interferon receptor polypeptide by contacting the native PR01114 interferon receptor polypeptide with a candidate molecule and monitoring a biological activity mediated by said polypeptide.
in a still further embodiment, the invention concerns a composition comprising a PRO11I4 interferon receptor polypeptide, or an agonist or antagonist as hereinabove defined, in combination with a phata~aceutically acceptable carrier.
53. PR0237 Applicants have identified a cDNA clone that encodes a novel polypeptide having homology to carbonic anhydrase, wherein the polypeptide is designated in the present application as "PR0237".
1n one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0237 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0237 polypeptide having amino acid residues 1 to 328 of Figure 145 {SEQ ID N0:358), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. In other aspects, the isolated nucleic acid comprises DNA encoding the PR0237 polypeptide having amino acid residues about 24 to 328 of Figure 145 (SEQ ID N0:358) or amino acid 1 or about 24 to X of Figure 145 {SEQ ID N0:358), where X is any amine acid from 172 to 181 of Figure 145 (SEQ
ID N0:358), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the DNA34353-1428 vector deposited on May 12, 1998 as ATCC 209855 which includes the nucleotide sequence encoding PR0237.
In another embodiment, the invention provides isolated PR0237 polypeptide. In particular, the invention provides isolated native sequence PR0237 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 328 of Figure 145 (SEQ 1D N0:358). Additional embodiments of the present invention are directed to PR0237 poiypeptides comprising amino acids about 24 to 328 of Figure 145 (SEQ ID N0:358) or amino acid 1 or about 24 to X of Figure 145 (SEQ ID N0:358), where X is arty amino acid from 172 to 181 of Figure 145 (SEQ ID N0:358). Optionally, the PR0237 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA insert of the DNA34353-1428 vector deposited on May 12, 1998 as ATCC 209855.

I

54. PR 5 1 Applicants have identified a cDNA clone that encodes a novel polypeptide having homology to a trypsin inhibitor protein, wherein the polypeptide is designated irt the present application as "PR0541 ".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0541 polypeptide. In one aspect; the isolated nucleic acid comprises DNA
encoding the PR0541 polypeptide having amino acid residues 1 to 500 of Figure 147 (SEQ ID N0:363), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least, moderate, and optionally, under high stringency conditions. In other aspects, the isolated nucleic acid comprises DNA encoding the PR054i polypeptide having amino acid residues about 21 to 500 of Figure 147 (SEQ 1D N0:363), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the DNA45417-1432 vector deposited on May 27, 1998 as ATCC 209910 which includes the nucleotide sequence encoding PR0541.
In another embodiment, the invention provides isolated PR0541 poiypeptide. In particular, the invention provides isolated native sequence PR0541 polypeptide, which in one embodiment;
includes an amino acid sequence corrtprising residues 1 to 500 of Figure 147 (SEQ 1D N0:363). Additional embodiments of the present invention are directed to PR054i polypeptides comprising amino acids about 21 to 500 of Figure 147 (SEQ ID N0:363).
Optionally, the PR0541 polypeptide is obtait~d or is obtainable by expressing the polypeptide encoded by the cDNA
insert of the DNA4541?-1432 vector deposited on May 27, 1998 as ATCC 209910.
55. ~R0273 Applicants have identified a cDNA clone that encodes a novel polypeptide, wherein the polypeptide is designated in the present application as "PR0273".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0273 poiypeptide. In one aspect, the isolated nucleic acid comprises 'DNA
encoding the PR0273 polypeptide having amino acid residues 1 through 111 of Figure 149 ($EQ ID N0:370), or is complementary to such encoding tnxxleic acid seq~ce, atui remains stably bound to it under at least moderate, and optionally, under high stringency conditions.
In another embodiment, the invention provides isolated PR0273 polypeptide. In particular, the invention provides isolated native sequence PR0273 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 through 111 of.Figure 149 (SEQ 1D N0:370).
56. PR0701 Applicants have identified a cDNA clone that encodes a novel golypeptide having homology to neuroligins I, 2, and 3, wherein the polypeptide is designated in the present application as "PR0701".
In one err~oditnent, the invention provides an isolated nucleic acid molecuie comprising DNA encoding a PR070I polypeptide. In orte aspect, the isolated nucleic acid comprises DNA
encoding the PR0701 polypeptide having amino acid residues 1 through 81b of Figure 1S1 (SEQ ID N0:375), or is complementary to such encoding tatcleic acid sequence, and remiains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated ttucleic acid sequence may comprise the cDNA insert of the vector deposited with the ATCC
on March 31, 1998 which includes the nucleotide sequence encoding PR0701.

In another embodiment, the invention provides isolated PR0701 polypeptide. In particular, the invention provides isolated native sequence PR070i polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 through 816 of Figure 151 (SEQ ID N0:375). An additional embodiment of the present invention is directed to an isolated extracellular domain of a PR0701 polypeptide. Optionally, the PR0701 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA insert of the vector S deposited with the ATCC on March 31, 1998.
57. PR0704 Applicants have identified a cDNA clone that encodes a novel polypeptide having sequence identity with VIP36, wherein the polypeptide is designated in the present application as "PR0704".
10: In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0704 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0704 polypeptide having amino acid residues 1 through 348 of Figure 153 (SEQ ID N0:380), or is complementary to such encoding nucleic acid sequence, and remains stabIy bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the vector deposited on March 31, 15 1998 with the ATCC as DNA509I I-1288, which includes the nucleotide sequence encoding PR0704.
In another embodiment, the invention provides isolated PR0704 polypeptide. In particular, the invention provides isolated native sequence PR0704 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 through 348 of Figure 153 (SEQ ID N0:380). An additional embodiment of the present invention is directed to an isolated extracellular domain of a PR0704 polypeptide. Optionally, the PR0704 20 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA insert of the vector deposited on March 31, 1998 with the ATCC as DNA50911-1288.
58. PRO?06 Applicants have identified a cDNA clone that encodes a novel polypeptide having homology to prostatic acid 25 phosphatase precursor and lysosomal acid phosphatase precursor, wherein the polypepdde is designated in the present application as "PR0706" .
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0706 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0706 polypeptide having amino acid residues 1 through 480 of Figure 155 (SEQ ID N0:385), or is complementary to such encoding 30 nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency editions. The isolated nucleic acid sequence may comprise the cDNA insert of the vector deposited on April 21, 1998 with the ATCC as DNA48329-1290 which includes the nucleotide sequence encoding PRO706.
In another embodiment, the invention provides isolated PR0706 polypeptide. In particular, the invention provides isolated native sequence PR0706 polypeptide, which in one embodiment, it~ludes an amino acid sequence 35 comprising residues 1 through 480 of Figure 155 (SEQ 1D N0:385), or comprising residues 19 through 480 of Figure 155 (SEQ ID N0:385). Optionally, the PR0706 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA insert of the vector deposited on April 21, 1998 with the ATCC as DNA48329-1290.

S9. R07 7 Applicants have identified a cDNA clone that encodes a novel polypeptide having homology to cadherins, particularly cadherin FIB3,_wherein the polypeptide is designated in the present application as "PR0707".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0707 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding.the PR0707 polypeptide having amino acid residues 1 to 916 of Figure 157 (SEQ ID N0:390), or is complementary to such encoding nucleic acid sequence, and remains stabIy bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the vector deposited on May 27, 1998 with the ATCC as DNA48306-1291 which includes the nucleotide sequence encoding PR0707.
In another embodiment, the invention provides isolated PR07U7 polypeptide. In particular, the invention provides isolated native sequence PR0707 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 916 of Figure 1S7 {SEQ ID N0:390). An additional embodiment of the present invention is directed to an isolated extracelIular domain of a PR0707 polypeptide:
Optionally, the PR0707 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA
insert of the vector deposited on May 27,.1998 with the ATCC as DNA48306-1291.
60. R( Applirams have identified a cDNA clone that encodes a novel polypeptide having homology to neuropsin, wherein the poIypeptide is designated in the present application as "PR0322".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0322 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PRO322 polypeptide having amino acid residues l or 24 through 260 of Figure 159 (SEQ ID N0:395), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the vector deposited on March I I, 1998 as ATCC no. 209669 which includes the nucleotide sequence encoding PR0322.
In another embodiment, the invention provides isolated PR0322 polypeptide. In particular, the invention provides isolated native sequence PR0322 polypeptide, which in one embodiment;
includes an amino acid sequence comprising residues l or 24 through 260 of Figure 159 {SEQ ID N0:395). An additional embodi~nt of the present invention is directed to an isolated extraceIlular domain of a PR0322 polypeptide. Optionally, the PR0322 po3ypeptide is obtai~d or is obtainable by expressing the polypeptide encoded by the cDNA insert of the vector deposited on March I1, 1998 as ATCC no. 209669.
61. P Z
Applicants have identified a cDNA ciotre that encodes a novel polypeptide having sequence identity with ALS, wherein the poiypeptide is designated in the present application as "PR0526".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0526 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0526 polypeptide having amino acid residues 1 to 473 of Figure 161 {SEQ ID N0:400), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the vector deposited on March 26, 1998 with the ATCC as DNA44184-1319 which includes the nucleotide sequence encoding PR0526.
In another embodiment, the invention provides isolated PR0526 polypeptide: In particular. the invention provides isolated native sequence PR0526 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 473 of Figure 161 (SEQ ID N0:400). Optionally, the PR0526 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA insert of the vector deposited on March 26, 1998 with the ATCC as DNA44184-1319 which includes the nucleotide sequence encoding PR0526.
62. PR 5 I
Applicants have identified a cDNA clone that encodes a novel poiypeptide having sequence identity with protocadherins, wherein the polypeptide is designated in the present application as "PR0531".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0531 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0531 polypeptide having amino acid residues 1 to 789 of Figure 163 (SEQ 1D N0:405), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the vector deposited on March 26, 1998 as DNA48314-1320 which includes the nucleotide sequence encoding PR0531.
In another embodiment, the invention provides isolated PR0531 polypeptide. In particular, the invention provides isolated native sequence PR053! polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 789 of Figure 163 (SEQ ID N0:405). An additional embodiment of the present invention is directed to an isolated extracellular domain of a PR0531 polypeptide.
Optionaliy, the PR0531 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA
insert of the vector deposited on March 26, 1998 as DNA48314-1320.
63. PR(~534 Applicams have identified a cDNA clone that encodes a novel polypeptide having sequence identity with disulfide isomerase (sometimes referred to herein as protein disulfide isomerase), wherein the polypeptide is designated in the present application as "PR0534".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0534 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0534 polypeptide having amino acid residues 1 to 360 of Figure 165 (SEQ ID N0:410), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the vector deposited on March 26, 1998 as DNA48333-1321 which includes the nucleotide sequence encoding PR0534.
In another embodiment, the invention provides isolated PR0534 polypeptide. In particular, the invention provides isolated native sequence PR0534 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 360 of Figure 165 (SEQ ID N0:410). An additional embodiment of the present invention is directed to an isolated exuacellular domain of a PR0534 polypeptide.
Optionally, the PR0534 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA
insert of the vector deposited on March 26, 1998 as DNA48333-1321.
$4 WO 99146281 PCTlUS99/05028 64. PROb97 Applicants have identified a cDNA clone that encodes a novel poIypeptide having sequence identity with shRPs, wherein the polypeptide is designated in the present application as "FR0697".
In one embodiment; the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0697 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0697 polypeptide having amino acid residues 1 through 295 of Figure 167 (SEQ 1D N0:415), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequetx;e may comprise the cDNA insert of the vector deposited with the ATCC
on March 26, 1998 as DNA50920-1325 which includes the nucleotide sequence encoding PR0697.
In another embodiment, the invention provides isolated PR0697 polypeptide. In particular, the invention provides isolated native sequence PR0697 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 through 295 of Figure 167 (SEQ ID N0:415). Optionally, the PR0697 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA insert of the vector deposited with the ATCC
on March 26, 1998 as DNA50920-1325.
65. . P 7 7 Applicants have identified a cDNA clone that encodes a novel 12 transmembrane polypeptide, wherein the polypeptide is designated is the present application as "PR0717".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0717 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0717 polypeptide having amino acid residues 1 through 560 of Figure 169 (SEQ ID N0:420), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the vector deposited on April 28', 1998 with the ATCC as DNA50988-1326 which includes the nucleotide sequence encoding PR0717.
In another embodiment, the invention provides isolated PR0717 polypeptide. In particular, the invention provides isolated native sequence PR0717 polypeptide, which in one embodiment, inchtdes an amino acid sequence comprising residues 1 through 560 of Figure 169 (SEQ ID N0:420). An additional embodiment of the present invention is directed to an isolated extracelIular domain of a FR0717 polypeptide. Optionally, the PR0717 polypeptide is obtained or is obtainable by expressing the polypepdde encoded by the cDNA insert of the vector deposited on April 28, 1998 with the ATCC as DNA50988-1326.
b6. PROZ31 Applicants have identified a cDNA clone that encodes a novel polypeptide having sequence identity with protocadherin 4, wherein the polypeptide is designated in the present application as "PR0731".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0731 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PRO731 polypeptide having at>utto acid residues 1 through 1 l84 of Figure 171 (SEQ ID N0:425), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency co~tians. The isolated nucleic acid sequence may comprise the cDNA insert of the vector deposited on March 31, 1998 with the ATCC as DNA48331-1329 which includes the nucleotide sequence encoding PR0731.

WO 99146281 y PCTIUS99/45028 In another embodiment, the invention provides isolated PR0731 polypeptide. In particular, the invention provides isolated native sequence PR0731 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 through 1184 of Figure 171 (SEQ ID N0:425). An additional embodiment of the present invention is directed to an isolated extracellular domain of a PR0731 poIypeptide. Optionally, the PR0731 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA insert of the vector deposited on March 31, 1998 with the ATCC as DNA48331-1329.
67. PR0218 Applicants have identified a cDNA clone that encodes a novel multi-transmembrane protein having sequence identity with membrane regulator proteins, wherein the polypeptide is designated in the present application as "PR0218" .
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0218 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0218 polypeptide having amino acid residues 1 through 455 of Figure 173 (SEQ ID N0:430), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the vector deposited on April 28, 1998 with the ATCC as DNA30867-1335 which includes the nucleotide sequence encoding PR0218.
In another embodiment, the invention provides isolated PR0218 polypeptide. In particular, the invention provides isolated native sequence PR0218 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 through 455 of Figure 173 (SEQ ID N0:430). Optionally, the PR0218 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA insert of the vector deposited on April 28, 1998 with the ATCC as DNA30867-1335.
1n another embodiment, the invention provides an expressed sequence tag (EST) sequence comprising the nucleotide sequence of Figure 174 (SEQ ID N0:431), designated herein as DNA14472.
In another embodiment, the invention provides an expressed sequence tag (EST) sequence comprising the nucleotide sequence of Figure 175 (SEQ ID N0:432), designated herein as DNA
15846.
68. PRO_'If_r8_ Applicants have identified a cDNA clone that encodes a novel polypeptide having stquence identity with integrins, wherein the polypegtide is designated in the present application as "PR0768" .
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0768 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PRO?68 polypeptide having amino acid residues 1 through 1141 of Figure 177 (SEQ ID N0:437), or is complementary to such encoding rn~cleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the vector deposited on April 6, 1998 as DNA55737-1345 which includes the nucleotide sequence encoding PR0768.
1n another embodiment, the invention provides isolated PR0768 polypeptide. In particular, the invention provides isolated native sequence PR0768 polypeptide, which in one emboditnent, includes an amino acid sequence comprising residues 1 through 1141 of Figure 177 (SEQ ID IV0:437). An additional embodiment of the present invention is directed to an isolated extracellular domain of a PR0768 polypeptide. Optionally, the PR0768 WO 99146281 PCTlUS99105038 potypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA insert of the vector deposited on April 6, 1998 as DNA55?37-1345.
69. PR0771 Applicants have identified a eDNA clone that encodes a novel polypeptide having sequence identity with testican, wherein the polypeptide is designated in the present application as "PR0771 ".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0771 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0771 polypeptide having atnino acid residues 1 through 436 of Figure 179 (SEQ ID N0:442), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the vector deposited on April 7, 1998 with the ATCC as DNA49829-1346 which includes the nucleotide sequence encoding PR0771.
In another embodiment, the invention provides isolated PR0771 polypeptide. In particular, the invention provides isolated native sequence PR0771 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 through 436 of Figure 179 (SEQ ID N0:442). Optionally, the PR0771 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA insert of the vector deposited on April 7, 1998 with the ATCC as DNA49829-1346.
?'0. PR0T33 Applicants have identified a cDNA clone that encodes a novel polypeptide having sequence identity with the TIlST2 receptor binding protein, wherein the polypeptide is designated in the present application as "PR0733".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0733 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0733 polypeptide having amino acid residues 1 through 229 of Figure 181 (SEQ ID N0:447), or is complementary to such encoding ta~leic mid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the vector deposited on April 7, 1998 with the ATCC as DNA52196-1348 which includes the nucleotide sequence encoding PR0733.
In another embodiment, the invention provides isolated PR0733 polypeptide. In particular, the invention provides isolated native sequence PR0733 polypeptide, which is one embodiment, includes an amino acid sequence . comprising residues 1 through 229 of Figure 181 (SEQ ID N0:447). An additional embodiment of the present invention is directed to an isolated extracellular domain of a PR0733 polypeptide. Optionally, the PR0733 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA insert of the vector deposited on April 7, 1998 as DNA52196-1348.
71. PR0162 Applicants have identified a cDNA clone that encodes a novel polypeptide having sequence identity with pattcreatitis-associated protein, wherein the polypeptide is designated in the present application as "PR0162".
In one embodiment, the invention provides an isolated nucleic acid rrx~lecuie comprising DNA encoding a PR0162 polypeptide. In one aspect,.the isolated nucleic acid comprises DNA
encoding the PR0162 polypeptide having amino acid residues 1 through 175 of Figure 183 (SEQ ID N0:452), or is complementary to such encoding WO 99/46281 PCT/US99f05028 nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the vector deposited on May 6, 1998 with the ATCC as DNA56965-1356 which includes the nucleotide sequence encoding PROi62.
In another embodiment, the invention provides isolated PR0162 polypeptide. In particular, the invention provides isolated native sequence PR0162 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues I through 175 of Figure 183 (SEQ ID N0:452). Optionally, the PR0162 polypeptide is obtained or is obtainable by expressing the poiypeptide encoded by the cDNA insert of the vector deposited on May 6, 1998 with the ATCC as DNA56965-1356.
72. PR0788 IO Applicants have identified a cDNA clone that encodes a novel polypeptide having sequence identity with anti-neoplastic urinary protein, wherein the polypeptide is designated in the present application as "PR0788".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PRO?88 poIypeptide. 1n one aspect, the isolated nucleic acid comprises DNA
encoding the PR0788 polypeptide having amino acid residues 1 through 125 of Figure 185 (SEQ ID NO:454), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the vector deposited on May 6, 1998 with the ATCC as DNA56405-1357 which includes the nucleotide sequence encoding PR0788.
in another embodiment, the invention provides isolated PR0788 polypeptide. In particular, the invention provides isolated native sequence PR0788 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 through 125 of Figure 185 (SEQ ID N0:454). An additional embodiment of the present invention is directed to an isolated extracellular domain of a PR0788 polypeptide. Optionally, the PR0788 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA insert of the vector deposited on May 6, 1998 with the ATCC as DNA56405-1357.
73. R0 8 Applicants have identified a cDNA clone that encodes a novel polypeptide having sequence identity with dickkopf 1 (dkk-1), wherein the polypeptide is designated in the present application as "PR41008".
In one embodiment,. the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR01008 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR01008 polypeptide having amino acid residues 1 through 266 of Figure 187 (SEQ ID N0:456), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the vector deposited on May 20, 1998 with the ATCC as DNA57530-1375 which includes the nucleotide sequence encoding PR01008.
In another embodiment, the invention provides isolated PR01008 polypeptide. In particular, the invention provides isolated native sequence PR01008 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 through 266 of Figure 187 (SEQ ID N0:456). Optionally, the PR01008 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA
insert of the vector deposited on May 20, 1998 with the ATCC as DNA57530-1375.

In another embodiment, the invention provides an expressed sequence tag (EST) designated herein as DNAI6508 comprising the nucleotide sequence of Figure I88 (SEQ ID N0:457).
~a. ~~Q39.1~
Applicants have identified a cDNA clone that encodes a novel polypeptide having sequence identity with disulfide isomerase and phospholipase C, wherein the poiypeptide is designated in the present application as "PR01012" .
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR01012 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR01012 polypeptide having amino acid residues 1 through 747 of Figure 190 (SEQ ID N0:459), or is complementary to such encoding nucleic acid sequence; and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the eDNA insert of the vector deposited on May 14, 1998 with the ATCC as DNA56439-1376, which includes the nucleotide sequence encoding PR01012.
In another embodiment, the invention provides isolated PR01012 polypeptide. In particular, the invention provides isolated native sequence PR01012 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 through 747 of Figure 190 (SEQ ID N0:459). Optionally, the PR01012 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA
insert of the vector deposited on May 14, 1998 with the ATCC as DNASb439-1376.
75. PR01014 Applicants have identified a cDNA clone that encodes a novel polypeptide having sequence identity with reductase, wherein the poIypeptide is designated in the present application as "PR01014" .
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR01014 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR01014 polypeptide having amino acid residues 1 through 300 of Figure l92 (SEQ ID N0:464), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, ark optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the vector deposited on May 20, 1998 as DNA564t19-1377 with the ATCC which includes the nucleotide sequence encoding PR01014.
In another embodiment, the invention provides isolated PR01014 polypeptide. In particular, the invention provides isolated native seque~e PR01014 polypeptide, which in one embodiment, includes an atznno acid sequence comprising residues 1 through 300 of Figure 192 (SEQ ID N0:464). Optionally, the PR01014 polypeptide is obtained or is obtainable by expressing the polypeptide encoded. by the cDNA
insert of the vector deposited on May 20, 1998 as DNA56409-1377 with the ATCC.
76. PROtOl~
Applicants have identified a cDNA clone that encodes a novel polypeptide having sequence irierniry with HNK-i sulfotransferase, wherein the polypeptide is designated in the present application as "PR01017" .
In one embodiment; the invention provides an isolated nucleic acid molecule comprising DNA et>coding a PRO101? polypeptide. in otie aspect, the isolated nucleic acid comprises DNA
encoding the PR01017 polypeptide having amino acid residues 1 through 414 of Figure 194 (SEQ ID N0:466), or is complementary to such encoding WO 99/46281 PCT/tJS99/05028 nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the vector deposited on May 20, 1998 with the ATCC as DNA56112-1379 which includes the nucleotide sequence encoding PR01017.
In another embodiment, the invention provides isolated PR01017 polypeptide. In particular, the invention provides isolated native sequence PR01017 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 through 414 of Figure 194 (SEQ ID N0:466). Optionally, the PR01017 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA
insert of the vector deposited on May 20, 1998 with the ATCC as DNA56112-1379.
77. PR0474 Applicants have identified a cDNA clone that encodes a novel polypeptide having sequence identity with dehydrogenase, wherein the polypeptide is designated in the present application as "PR0474".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0474 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0474 polypeptide having amino acid residues 1 through 270 of Figure 196 (SEQ iD N0:468), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency cot~itions. The isolated nucleic acid sequence may comprise the cDNA insert of the vector deposited on May I4, 1998 with the ATCC as DNA56045-1380 which includes the nucleotide sequence encoding PR0474.
In another embodiment, the invention provides isolated PR0474 polypeptide. In particular, the invention provides isolated native sequence PR0474 polypeptide, which in one embodiment, includes an amino acid sequence c~n~prising residues 1 through 270 of Figure 196 (SEQ ID N0:468). Optionally, the PR0474 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA insert of the vector deposited on May 14, 1998 with the ATCC as DNA56045-1380.
78. PR 1 1 Applicants have identified a cDNA clone that encodes a novel polypeptide having sequence identity with IL-17, wherein the polypeptide is designated in the present application as "PR01031".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR01031 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR01031 polypeptide having amino acid residues 1 through 180 of Figure 198 (SEQ ID N0:470), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the vector deposited on May 14, 1998 with the ATCC as DNA~9294-1381 which includes the nucleotide sequence encoding PR0103I.
In another emboditrtear, the invention provides isolated PROI031 polypeptide.
In particular, the invention provides isolated native sequence PR01031 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 through 180 of Figure 198 (SEQ ID N0:470). Optionally, the PROI031 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA
insert of the vector deposited on May 14, 1998 with the ATCC as DNA59294-1381.

79. P O 3 Applicants have identified a cDNA clone that encodes a navel polypeptide having sequence identity to protein disulfide isomerase,. wherein the polypeptide is designated in tine pre sent application as "PRO938".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0938 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0938 polypeptide having amino acid residues 1 to 349 of Figure 200 (SEQ ID N0:472), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. In other aspects, the isolated nucleic acid comprises DNA encoding the PR0938 polypeptide having amino acid residues about 23 to 349 of Figure 200 (SEQ ID N0:472) or amino acid 1 or about 23 to X of Figure 200 (SEQ ID N0:472), where X is any amino acid from 186 to 195 of Figure 200 (SEQ
ID N0:472), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequt:nce may comprise the cDNA insert of the DNA56433-1406 vector deposited on May 12, 1998, as ATCC Accession No.
209857 which includes the nucleotide sequence encoding PR0938:
In another embodiment, the invention provides isolated PR0938 polypeptide. In particular, the invention I5 provides isolated native sequence PR0938 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 349 of Figure 200 (SEQ ID N0:472). Additional embodiments of the present invention are directed to PR0938 polypeptides comprising amino acids about 23 to 349 of Figure 200 (SEQ ID N0:472) or amino acid 1 or about 23 to X of Figure 200 (SEQ ID N0:472), where X is any amino acid from 186 to 195 of Figure 200 (SEQ 1D N0:472). Optionally, the PR0938 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA inserrof the DNA56433-1406 vector deposited on May I2, 1998, as ATCC Accession No:
209857.
80. PR 1082 Applicants have identified a cDNA clone that encodes a novel polypeptide having sequence identity with a iectin-Like oxidized LDL receptor, wherein the polypeptide is designated irt the present application as °PR01082".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR01082 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR01082 poIypeptide having amino acid residues 1, through 201 of Figure 202 (SEQ ID N0:477), or is complementary to such encoding nucleic acid sequence, and remains stably bound to is under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the vector deposited on May 14, 1998 with the ATCC as DNA53912-1457 which includes the nucleotide sequence encoding PR01082.
In another embodiment, the invention provides isolated PR01082 polypeptide. In particular, the invention provides isolated native sequetxe PR01082 polypeptide, which in one embodiment, includes an amino acid sequet~e comprising residues 1 through 201 of Figure 202 (SEQ ID N0:477). An additional embodiment of the present invention is directed to an isolated domain of a PR01082 polypeptide, excluding the transtnembrane domain.
Optionally, the PR01082 polygeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA
insert of the vector deposited on May 14, 1998 with the ATCC as DNA53912-145?.

81. PR_ 01083 Applicants have identified a cDNA clone that encodes a novel polypeptide having sequence identity with a 7TM receptor, latrophilin-related protein 1, and a macrophage restricted cell surface glycoprotein, wherein the poiypeptide is designated in the present application as "PR01083".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR01083 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR01083 polypeptide having amino acid residues 1 through 693 of Figure 204 (SEQ ID N0:483), or is complementary to such encoding trucleic acid sequence, and remains stably bound to it under at ieasi moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the vector deposited on May 12, 1998 with the ATCC as DNA50921-1458 which includes the nucleotide sequence encoding PR01083.
In another embodiment, the invention provides isolated PR01083 polypeptide. In particular, the invention provides isolated native sequence PR01083 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 through 693 of Figure 204 (SEQ ID N0:483). An additional embodiment of the present invention is directed to an isolated exuacellular domain of a PR01083 polypeptide. Optionally, the PR01083 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA insert of the vector deposited on May 12, 1998 with the ATCC as DNA50921-1458.
In another embodiment, the invention provides an expressed sequence tag (EST) designated herein as DNA24256 which comprises the nucleotide sequence of Figure 205 (SEQ ID
N0:484).
82. PR020Q, The objects of this invention, as defined generally supra, are achieved at least in part by the provision of a novel polypeptide, VEGF-E also herein designated PR0200, (SEQ ID N0:488) and the nucleic acid encoding therefor, SEQ ID N0:487, residues 259 through 1293.
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a VEGF-E polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the VEGF-E polypeptide having amino acid residues 1 through 345 of Figure 207 (SEQ iD N0:488), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under low stringency conditions. In another embodiment, variants are provided wherein the VEGF-E nucleic acid has single or multiple deletions, substitutions, insertions, truncations or combinations.thereof.
In another embodiment, the invention provides isolated VEGF-E polypepiide. In particular, the invention provides an isolated native sequence VEGF-E polypeptide, which in one embodiment; includes an amino acid sequence comprising residues 1 through 345 of Figure 20? (SEQ ID N0:488). In another embodiment, variants are provided wherein the VEGF-E polypeptide has single or multiple deletions, substitutions, insertions, tnutcations or combinations thereof:
In yet further embodiments, the present invention is directed to compositions useful for treating indications where proliferation, survival and/or differentiation of cells is desired, comprising a therapeutically effective amount of a VEGF-E polypeptide hereof in admixture with a pharmaceutically acceptable carrier.
The invention fi>rlhes include<c associated embodiments of VEGF-E such as modified VEGF-E polypeptides and modified variants which have the same biological applications as VEGF-E, and pharmaceutical compositions incorporating same. Inhibitors of VEGF-E are also provided.

WO 99146281 ~ PCT/US99105028 83. 1aR0285 ar~c~,PR0286 Applicants have identified two novel cDNA clones that encode novel human Toll polypeptides, designated in the presem application as PR0285 (encoded by DNA4002I-1154) and PR0286 (encoded by DNA42663-1154).
In one embodiment, the invention provides an isolated nucleic acid molecule comprising a DNA encoding a polypeptide having at Ieast about 80% sequence identity, preferably at least about 85% sequence identity, more preferably at least about 90% sequence identity, most preferably at least about 95% sequence identity to (a) a DNA
molecule encoding a PR0285 polypeptide having amino acid residues 27 to 839 of Figure 209 (SEQ ID N0:496);
or (b) to a DNA tnolecuIe encoding a PR0286 polypeptide having amino acid residues 27 to 825 of Figure 211 (SEQ
ID N0:498) or (c) the complement of the DNA molecule of (a) or (b). The complementary DNA molecule preferably remains stably bound to such encoding nucleic acid sequence under at least moderate, and optionally, under high stringency conditions.
In a further embodiment, the isolated nucleic acid molecule comprises a polynucleotide that has at least about 90%, preferably at least about 95% sequence identity with a polynucleotide encoding a polypeptide comprising the sequence of amino acids 1 to 839 of Figure 209 (SEQ ID N0:496j; or at least about 90%, preferably at least about 95 % sequence identity with a polynucleotide encoding a polypeptide comprising the sequence of amino acids 1 to 1041 of Figure 211 (SEQ ID N0:498).
In a specific embodiment, the invention provides an isolated nucleic acid molecule comprising DNA
encoding native or variant PR0285 and PR0286 polypeptides, with or wifhout the N-teraur~al. signal sequence, and with or without the transmetrtbrane regions of the respective full-length sequences. In one aspect, the isolated nucleic acid comprises DNA encoding a mature, full-length native PR0285 or PR0286 polypeptide having amirw acid residues 1 to 1049 of Figure 209 (SEQ ID N0:496) and 1 to 1041 of Figure 211 (SEQ ID NO: 498), or is complementary to such encoding nucleic acid sequence, In another aspect, the invention concerns an isolated nucleic acid molecule that comprises DNA encoding a native PR0285 or PR028b polypeptide without an N-terminal signal sequence, or is complementary to such encoding nucleic acid sequence. In yet another embodiment, the invention concerns nucleic acid et~oding transmembrane-domain deleted or inactivated forms of the full-length native PR0285 ZS or PR0286 proteins.
In another embodiment, the invention the isolated nucleic acid molecule comprises the clone (DNA40021-1154) deposited on October 17, 1997, under ATCC number 209389; or the clone (DNA42663-1154) deposited on October 17, 1997, under ATCC number 209386.
In yet another embodiment, the invention provides a vector comprising DNA
encoding PR0285 and PR0286 polypeptides, or their variants. Thus, the vector may comprise any of the isolated nucleic acid molecules hereinabove defined.
In another embodi>nettt, the invention provides isolated PR0285 and PR0286 polypeptides. In particular, the invention provides isolated native sequetxe PR0285 and PR0286 polypeptides, which in one embodiment, include the amino acid sequences comprising residues 1 to 1049 and 1 to 1041 of Figures 209 and 21 I (SEQ ID NOS:496 and 498), respectively. The invention also provides for variants of the PR0285 and PR0286 polypeptides which are encoded by any of the isolated nucleic acid molecules hereinabove defined.
Specific variants include, but are not limited to, deletion (tnmcated) variants of the full-length native sequence PR0285 and PR0286 polypeptides which lack the respective N-terminal signal sequences andlor have their respective transmembrane and/or cytoplasmic domains .deleted or inactivated.

WO 99146281 PCTlUS99/05028 The invention also specifically includes antibodies with dual specificities, e.g., bispecifrc antibodies binding more than one Toll polypeptide.
In yet another embodiment, the invention concerns agonists and antagonists of the native PR0285 and PR0286 polypeptides. In a particular embodiment, the agonist or antagonist is an anti-PR028S or anti-PR0286 antibody. .
In a further embodiment, the invention concerns screening assays to identify agonists or antagonists of the native PR028S and PR0286 polypeptides.
In a still further embodiment, the invention concerns a composition comprising a PR0285 or PR0286 polypeptide, or an agonist or antagonist as hereinabove defined, in combination with a pharmaceutically acceptable carrier.
The invention further concerns a composition comprising an antibody specifically binding a PR0285 or PR0286 polypeptide, in combination with a pharmaceutically acceptable carrier.
The invention also concerns a method of treating septic shock comprising administering to a patient an effective amount of an antagonist of a PR028S or PR0286 polypeptide. In a specific embodiment, the antagonist is a blocking antibody specifically binding a native PR0285 or PR0286 polypeptide.
IS
84. PR0213-13,~R01330 and PR01449 The present invention concerns compositions and methods for the diagnosis and treatment of neoplastic cell growth and proliferation in mammals, including humans. The present invention is based on the identification of genes that are amplified in the genome of tumor cells. Such gene amplification is expected to be associated with the overexpression of the gene product and contribute to tumorigenesis.
Accordingly, the proteins encoded by the amplified genes are believed to be useful targets for the diagnosis andlor treatment (including prevention) of certain cancers, and may act as predictors of the prognosis of tumor treatment.
In one embodiment, the present invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0213-1, PR01330 and/or PR01449 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0213-1, PRO1330 andlor PR01449 polypeptide having amino acid residues 1-to 29S of Figure 213 (SEQ ID NO:S06), 20 to 2?3 of Figure 21S (SEQ ID NO:SOB) and 20 to 273 of Figure 217 (SEQ ID NO:S10), respectively, or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least rnaderate; and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the eDNA insert of the vector designated as DNA30943-1163 (ATCC 209791) deposited on April 21, 1998;
DNA64907-1163-1 (ATCC 203242) deposited on September 9, 1998 and/or DNA64908-1163-1 (ATCC 203243) deposited on September 9, 1998.
In another embodiment, the present invention comprises an isolated nucleic acid molecule having at least about 80% sequence identity, preferably at Ieast about 85% sequence identity, more preferably at least about 90~
sequence idemity, most preferably at least about 9S~ sequence identity to (a) a DNA molecule encoding a PR0213-1, PR01330 andlor FR01449 polypeptide having amino acid residues 1 to 295 of Figure 213 (SEQ ID NO:S06), 20 to 273 of Figure 215 (SEQ ID N0:508) and 20 to 273 of Figure 217 (SEQ ID
NO:S10), respectively; or (b) the complement of the DNA molecule of (a).
In another embodiment, the invention provides ~an isolated PR0213-1, PR01330 andlor PR01449 polypeptide. In.particular, the invention provides isolated native sequence PR0213-1, PR01330 and/or PR01449 polypepride, which in one embodirrtent, includes an amino acid sequence comprising residues 1 to 29S of Figure 213 {SEQ ID NO:S06), 20 to 273 of Figure 215 (SEQ ID N0:508) or 20 to 273 of Figure 217 (SEQ ID NO:S10), respectively. Optionally, the PR0213-1, PR01330.and/or PROI449 poiypeptide is obtained or obtainable by expressing the polypeptide encoded by the cDNA insert of the DNA30943-1 I63 (ATCC 209791), DNA64907-I 163-I
(ATCC 203242) or DNA64908-l I63-I {ATCC 203243).
In another aspect, the invention provides an isolated PR0213-I, PR01330, andlor PR01449 poly~peptide, comprising an amino acid sequence having at least about 80% sequence identity, preferably at least about 8596 seguence identity, more preferably at least about 95 % sequence identity to amino acid residues 1 to 29S of Figure 213 (SEQ ID NO:S06), 20 to 273 of Figure 21S (SEQ ID NO:S08) or 20 to 273 of Figure 2I7 (SEQ ID NO:S10), inclusive.
In yet another embodiment, the invention provides an isolated PR0213-1, PR01330, andlor PROI449 polypeptide, comprising the amino acid residues I to 29S of Figure 213 (SEQ ID
NO:S06), 20 to 273 of Figure 2IS
(SEQ ID N0:508) or 20 to 273 of Figure 217 (SEQ ID NO:S10), or a fragment thereof sufficient to provide a binding site for an anti-PR0213-1, anti-PROI330 andlor anti-PROI449 antibody.
Preferably, the PR0213-1, PR01330, and/or PR01449 fragment retains a qualitative biological activity of a native PR0213-1, PROi330, andlor PR01449 polypeptide.
1n a further aspect, tip invention concerns an isolated PR0213-1, PR01330, and/or PR01449 polypeptide, comprising an amino acid sequence scoring at least about 80% positives, preferably at least about 85 q6 positives, more preferably at least about 90~ positives, most preferably at least about 95 96 positives when compared with the amino acid sequence of residues 1 to 29S of Figure 213 (SEQ ID NO:SO~, 20 to 273 of Figure 215 (SEQ ID
NO:S08) and 20 to 273 of Figure 21? (SEQ ID NO:S10), respectively.
In still a further aspect, the invention provides a polypeptide produced by (l) hybridizing a test DNA
~lecule under stringent conditions with: (a) a DNA molecule encoding a PR0213-1, PR01330, andlor PR01449 polypeptide having the amino acid residues from 1 to 29S of Figure 213 (SEQ ID
NO:S06), 20 to 273 of Figure 21S
(SEQ ID NO:S08) and 20 to 273 of Figure 217 (SEQ ID NO:S10), respectively; or the complement of the DNA
2S molecule of (a), and if said test DNA molecule has at least about an 80 %
seguence identity to (a) or (b); (ii) culturing a host cell comprising said test DNA molecule under conditions suitable for the expression of said polypeptide, and (iii) recovering said polypeptide froth the cell culnue.
In one embodiment, the present invention concerns an isolated antibody which binds a PR0213-1, PROI330 andlor PR01449 polypeptide. In one aspect, the antibody induces death of a cell oyerexpressing a PR0213-1, PR01330 andlor PROI449 polypeptide. In another aspect, the antibody i,s a monoclonal antibody, which preferably has nonhuman complememarity determining region (CDR) residues and human framework region {,FR) residues, The antibody may be labeled ate may be immobilized on a solid support. In a further aspect, the antibody is an antibody fragment; a single-chain antibody, or an anti-idiotypic antibody.
In another embodiment, the invention concerns a composition comprising an antibody which binds a 3S PR0213-1, PR01330 atxllor PR01449 polypeptide in admixture with a phatynaceutically acceptable carrier. In one aspect, the composition comprises a therapeutically effective amount of the antibody. In another aspect, the composition comprises a further active ingredient; which may, for example, be a further antibody or a cytotoxic or clLemotherapeutic agent. Preferably, the composition is sterile.

In a further embodiment, the invention concerns nucleic acid encoding an anti-PR0213-1, anti-PR01330 and/or anti-PROla49 antibody, and vectors and recombinant host cells comprising such nucleic acid.
The invention further concerns antagonists and agonists of a PR0213-1, PR01330 and/or PR01449 polypeptide that inhibit one or more of the functions or activities of the PR0213-1, PR01330 andlor PR01449 polypeptide.
In a further embodiment, the invention concerns isolated nucleic acid molecules that hybridize to the complement of the nucleic acid molecules encoding the PR0213-1, PR01330 andlor PR01449 polypeptides. The nucleic acid preferably is DNA, and hybridization preferably occurs under stringent conditions. Such nucleic acid molecules can act as antisense molecules of the amplified genes identified herein, which, in turn, can find use in the modulation of the respective amplified genes, or as antisense primers in amplification reactions. Furthermore, such sequences can be used as part of ribozyme andlor triple helix sequence which, in turn, may be used in regulation of the amplified genes.
In another embodiment, the invention concerns a method for determining the presence of a PR02I3-1, PROI330 andlor PRO1449 polypeptide comprising exposing a cell suspected of containing the PR0213-1, PR01330 and/or PR01449 polypeptide to an anti-PR02I3-1, PR01330 andlor PROI449 antibody and determining binding of the antibody to the cell.
In yet another embodiment, the present invention concerns a method of diagnosing tumor in a matnrttal, comprising detecting the level of expression of a gene encoding a PR0213-I, PR01330 and/or PR01449 polypepdde (a) in a test sample of tissue cells obtained from the mammal, and (b) in a control sample of known normal tissue cells of the same cell type, wherein a higher expression level in the test sample indicates the presence of tumor iu the mammal from which the test tissue cells were obtained.
In another embodiment, the present invention concerns a method of diagnosing tu~r in a mammal, cantprising (a) contacting an anti-FR0213-1, anti-PR01330 andlor anti-PR01449 antibody with a test sample of tissue cells obtained from the mammal, and (b) detecting the formation of a complex between the anti PR0213-1, anti-PR01330 and/or anti-PR01449 antibody and the PR0213-1, PR01330 and/or PR01449 polypeptide in the test sample. The detection may be qualitative or quantitative, and may be performed in comparison with monitoring the complex formation in a control sample of known normal tissue cells of the same cell type. A larger quantity of complexes formed in the test sample indicates the presence of tumor in the mammal from which the test tissue cells were obtained. The antibody preferably carries .a detectable label. Complex formation can be monitored, for example, by light microscopy, flaw cytometry, fluorimetry, or other techniques known in the art. The test sample is usually obtained from an individual suspected to have neoplastic cell growth or proliferation (e.g. cancerous cells).
In another embodiment, the present invention rnncerns a cancer diagnostic kit, comprising an anti-PR0213-1, anti-PR01330 andlor anti-PR01449 atuibody and a carrier (e.g. a buffer) in suitable packaging. The kit preferably contains instructions for using the antibody to detect the PR0213-1, PR01330 andlor PR01449 polypeptide.
In yet another embodiment, the invention concerns a method for inhibiting the growth of tumor cells cotnptising exposing a cell which overexpresses a PR0213-1, PR01330 and/or PROI4419 polypeptide to an effective amount of an agent inhibiting the expression andlor activity of the PR0213-1;
PR01330 andlor PROlA49 polypeptide. The agent preferably is an anti-PR0213-1, anti-PR01330 and/or and-PR01449 anu'body, a small organic and inorganic molecule, peptide, phosphopeptide, antisense or ribozyme molecule, or a triple helix molecule.
In a specific aspect, the agent, e.g. anti-PR0213-1, anti-PR01330 and/or anti-PR01449 antibody induces cell death.

WO 99/4628] PCTIUS99105028 In a further aspect, the tumor cells are further exposed to radiation treatment and/or a cytotoxic or chemotherapeutic agent.
In a further embodiment, the invention concerns an article of manufacture, comprising:
a) a container;
b) a label on the container; and c) a composition comprising an active agent contained within the container;
wherein the composition is effective for inhibiting the growth of tumor cells, the label on the container indicates that the composition can be used for treating conditions characterized by overexpression of a PR0213-1, PR01330 and/or PR01449 polypeptide, and the active agent in the composition is an agent inhibiting the expression andlor activity of the PR0213-1, PR01330 andlor PR01449 polypeptide. In a preferred aspect, the active agent is an anti-PR0213-1, anti-PR01330 andlor anti PR01449 antibody.
In yet a further embodiment, the invention provides a method for identifying a compound capable of inhibiting the expression andlor activity of a PR0213-1, PR01330 and/or PR01449 polypeptide, comprising contacting a candidate compound with a PR0213-1, PR01330 andlor PR01449 polypeptide under conditions and for a tire sufficient to allow these two components to interact. . In a specific aspect, either the candidate compound or the PR0213-1, PR01330 andlor PR01449 polypeptide is immobilized on a solid support. In another aspect, the non immobilized component carries a detectable label.
85. PR0298 Applicants have identified a cDNA clone that encodes a novel polypeptide. The DNA is designated in the present application as "DNA39975-1210", encoding a novel mufti-transmembxane protein, referred to as "PR0298".
1n one embodiment, the invention pnwides an isolated nucleic acid molecule comprising DNA having at least about 809& , preferably at least about 85 ~, more preferably at least about 90 %, most preferably at least about 95 %
sequence identity to (a) a DNA molecule encoding PR0298, comprising the sequence of amino acids 1 to 364 of Figure 219 (SEQ ID NO:515), or (b) the complett~nt of the DNA molecule of (a).
1n one aspect, the isolated nucleic acid comprises DNA encoding a PR0298 polypeptide having amino acid residues 1 to 364 of Figure 219 (SEQ ID
NO:515}, or is complerrterimry to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions.
In a further embodiment, the invention concerns an isolated nucleic acid molecule comprising DNA having at least as 809b sequence identity to (a) a DNA molecule encoding the same tnataue polypeptide encoded by the human prosein cDNA in ATCC Deposit No. 209783 (DNA39975-12I0); or (b) the complement of the DNA molecule of (a).
In a still further embodiment, the invention concerns mtcieic acid which comprises a DNA molecule encoding the same mature polypeptide encoded by the human protein cDNA in ATCC
Deposit No. 209783 (DNA39975-1210).
In another embodiment, the invention provides isolated PR029?3 polypeptide. In particular, the invention provides isolated native sequence PR0298 polypeptide, which in one embodiment, includes as amino acid sequence comprising residues 1 to 364 of Figure 219 (SEQ ID NO:515).
in another embodiment, the invention provides an expressed sequence tag (EST) designated DNA26832 comprising the nucleotide sequence of Figure 220 (SEQ ID N0:516).

86. PR 337 Applicants have identified a cDNA clone (DNA43316-1237) that encodes a novel polypeptide, designated in the present application as- "PR0337".
In one embodiment, the invention provides an isolated nucleic acid molecule having at least about 80%
sequence identity to (a) a DNA molecule encoding a PR0337 polypeptide comprising the sequence of amino acids 1 to 344 of Figure 222 (SEQ ID N0:523), or (b) the cotrtplement of the DNA
molecule of (a). The sequence Identity preferably is about 85%, more preferably about 90%, most preferably about 95'0. In one aspect, the isolated nucleic acid has at least about 803'0, preferably at least about 85 %, more preferably at least about 90%, and most preferably at least about 95 (including 96, 97> 98 and 99%) sequence identity with a polypeptide having amino acid residues 1 to 344 of Figure 222 (SEQ ID N0:523). Preferably, the highest degree of sequence identity occurs within the itnmunoglobulin and major histocompatibility domains (amino acids 113 to 130 of Figure 222, SEQ ID N0:523).
In a further embodiment, the isolated nucleic acid molecule comprises DNA
encoding a neurouimin polypeptide haying amino acid residues 1 to 344 of Figure 222 (SEQ ID N0:523), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. In another aspect, the invention provides a nucleic acid of the full length protein of clone DNA43316-1237, deposited with the ATCC under accession number ATCC 209487, alternatively the coding sequence of clone DNA43316-1237, deposited under accession number ATCC 209487.
In yet another embodiment, the invention provides isolated PR0337 polypeptide.
In particular, the invention provides isolated native sequence PR0337 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 344 of Figure 222 (SEQ ID N0:523). Native PR0337 polypeptides with or without the native signal sequence (amino acids 1 to about 28 in Figure 222 (SEQ ID
N0:523), and with or without the initiating methionine are specifically included. Alternatively, the invention provides a PR0337 poIypeptide encoded by the nucleic acid deposited under accession number ATCC 20948?.
In yet another embodiment, the invention provides an expressed sequence tag (EST) comprising the nucleotide sequences identified in Figure 223 as DNA42301 (SEQ ID N0:524).
87. PR0403 Applicants have identified a cDNA clone (DNA55800-1263) that encodes a novel polypeptide, designated in the present application as "PR0443".
In one embodiment, the invention provides an isolated nucleic acid molecule having at least about 809'0 sequence identity to (a) a DNA molecule encoding a PR0403 palypeptide comprising the sequence of amino acids 1 to ?36 of Figure 225 (SEQ ID N0:526), or (b) the complement of the DNA
molecule of (a). The sequence identity preferably is about 8S%, more preferably about 90%, most preferably about 95 %. In one aspect, the isolated nucleic acid has at least about 80%, preferably at least about 85 % , more preferably at least about 90% , and most preferably at least about 95 % sequence identity with a poiypeptide having amino acid residues 1 to 736 of Figure 225 (SEQ ID
NO:526). Preferably, the highest degree of sequence identity occurs within:
(1) the putative N-glycosylatation sites {amino acid residues I32, 136,177, 237, 282, 349, 505, 598 and 606; {2) Cys residues conserved with the Kell blood group protein family (amino acid residues 65, 70, 88 and 96) and the putative zinc binding motif (amino acid residues 570 579).

In a further embodiment, the isolated nucleic acid molecule comprises 1f?NA
encoding a PR04a3 polypeptide having amino acid residues 1 to 736 of Figure 225 {SEQ ID N0:526), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally; under high stringency conditions. In another aspect, the invention provides a nucleic acid of the full length protein of clone DNA55800-1263, deposited with the ATCC under accession number ATCC 209680, alternatively the coding sequence of clone DNA55800-1263, deposited under accession number ATCC 209680.
In yet another embodiment, the invention provides isolated PR0403 polypeptide.
In particular, the invention provides isolated native sequence PR0403 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 736 of Figure 225 (SEQ ID N0:526). Native PRO403 polypeptides with or the initiating methionine are specifically included. Alternatively, the invention provides a PR0403 polypeptide encoded by the nucleic acid deposited under accession number ATCC 209680.
In yet another embodiment, the invention provides an expressed sequence tag (EST)~and other sequence fragtnentc comprising the nucleotide sequences identified herein as DNA344I5 (Figures 226A-B; SEQ ID N0:527);
DNA49830 (Figure 227 ; SEQ ID N0:528) and DNA49831 (Figure 228; ~EQ ID
N0:529).
88. Additional Embodimen In other embodiments of the present invention, the invention provides vectors comprising DNA encoding any of the above or below described polygeptides. A host cell comprising any such vector is also provided. By way of example, the hit cells may be CHO cells, E. coli, or yeast. A process for producing any of the above or below described polypeptides is further provide and comprises culturing host cells under conditions suitable for expression of the desired polypeptide and recovering the desired polypeptide from the cell culture.
In other embodiments, the invention provides chimeric molecules comprising any of the above or below descn'bed polypepttdes fused to a heterologous polypeptide or amino acid sequence. An example of such a chimeric molecule comprises arty of the above or below described palypeptides fused to an epitope tag sequence or a Fc region of an immunoglobulin.
In artottrer embodiment, the invention provides an antibody which specifically binds to arty of the above or below described polypeptides. Optionally, the antibody is a monoclonal antibody.
In yet other embodiments, the invention provides oligonucleotide probes useful for isolating genomic and cDNA nucleotide sequences, wherein those probes may be derived from any of the above or below described nucleotide sequences.
$RIEF DFSs:.~~Q~~,~>V~~
Figure 1 shows a nucleotide sequence (SEQ ID NO:I) of a native sequence PRO2I3 cDNA, wherein SEQ
ID NO:1 is a clone designated herein as "UNQ187" andlor "DNA30943-1163".
Figtue 2 shows the amino acid sequence (SEQ 1D N0:2) derived from the coding sequence of SEQ ID NO;1 shown in Figure I .
Figure 3 shows a nucleotide sequence (SEQ ID N0:6) of a native sequence PRO274 cDNA, wherein SEQ
ID N0:6 is a clone designated herein as "UNQ241" and/or "DNA39987-1184".
Figure 4 shows the amino acid sequence (SEQ >D N0:7) derived from the coding sequence of SEQ ID N0:6 shown in Figure 3.

Figure S shows an EST nucleotide sequence designated herein as DNA17873 (SEQ
ID N0:8).
Figure 6 shows an EST nucleotide sequence designated herein as DNA36157 (SEQ
ID N0:9).
Figure ? shows an EST nucleotide sequence designated herein as DNA28929 (SEQ
ID NO:10}.
Figure 8 shows a nt~clwtide sequence (SEQ ID N0:18) of a native sequence PR0300 cDNA, wherein SEQ
ID N0:18 is a clone designated herein as "UNQ263" andlor "DNA40625-1189".
Figure 9 shows the amino acid sequence (SEQ ID N0.19) derived from the coding sequence of SEQ ID
N0:18 shown in Figure 8.
Figure 10 shows a nucleotide sequence (SEQ ID N0:27) of a native sequence PR0284 cDNA, wherein SEQ
ID N0:27 is a clone designated herein as "UNQ247" and/or "DNA23318-1211".
Figure 11 shows the amino acid sequence (SEQ ID N0:28) derived from the coding sequence of SEQ ID
N0:27 shown in Figure 10.
Figure 12 shows an EST nucleotide sequence designated herein as DNAI2982 (SEQ
1D N0:29).
Figure 13 shows an EST nucleotide sequence designated herein as DNAI5886 (SEQ
ID N0:30).
Figtzne 14 shows a nucleotide sequence ($EQ ID N0:35) of a native sequence PR0296 cDNA, wherein SEQ
ID N0:35 is a clone designated herein as "UNQ260" andlor "DNA39979-1213".
Figure 15 shows the amino acid sequence (SEQ ID N0:36) derived from the coding sequence of SEQ ID
N0:35 shown in Figure 14.
Figure 16 shows an EST nucleotide sequence designated herein as DNA23020 (SEQ
ID N0:3?).
Figure 17 shows an EST nucleotide sequence designated herein as DNA2197I (SEQ
ID N0:38).
Figure 18 shows an EST nucleotide sequence designated herein as DNA29037 {SEQ
ID N0:39).
Figure 19 shows a nucleotide sequence (SEQ ID N0:44) of a native sequence PR0329 cDNA, wherein SEQ
ID N0:44 is a clone designated herein as "UNQ291 " and/or "DNA40594-1233".
Figure 20 shows the amino acid sequence (SEQ ID N0:45) derived from the coding sequence of SEQ ID
N0:44 shown in Figure 19.
Figure 21 shows a nucleotide sequence (SEQ ID NO:51) of a native sequence PR0362 cDNA, wherein SEQ
1D NO:51 is a clone designated herein as "UNQ317" and/or "DNA454I6-125I"
Figure 22 shows the amino acid sequence (SEQ ID N0:52} derived from the coding sequence of SEQ ID
NO:51 shown in Figure 21.
Figure 23 shows a nuchtide sequence (SEQ ID N0:58) of a native sequence PR0363 cDNA, wherein SEQ
ID N0:58 is a clone designated herein as "UNQ318" and/or "DNA45419-1252" .
Figure 24 shows the amino acid.sequence (SEQ ID N0:59) derived from the coding sequence of SEQ ID
NO:58 shown in Figure 23.
Figure 25 shows a nucleotide sequence (SEQ U7 NO:b3) of a native sequence PR0868 cDNA, wherein SEQ
ID N0:63 is a clone designated herein as "UNQ437" and/or "DNA52594-1270".
Figure 26 shows the amino acid sequence (SEQ iD N0:64) derived from the coding sequence of SEQ ID
N0:63 shown in Figure 25.
Figure 27 shows a nucleotide sequence (SEQ ID N0:68) of a native sequence PR0382 cDNA, wherein SEQ
ID N0:68 is a clone designated herein as "UNQ323" andlor "DNA45234-1277".
Figure 28 shows the amino acid sequence (SEQ ID N0:69) derived from the coding sequence of SEQ ID
N0;68 shown in Figure 27.

WO 99146281 PCTlUS99105028 Figure 29 shows a nucleotide sequence (SEQ ID N0:73) of a native sequence PR054S cDNA, wherein SEQ
ID NO:?3 is a clone designated herein as "UNQ346" and/or "DNA49624-I279".
Figure 30 shows the, amino acid sequence {SEQ ID N0:74) derived :from the coding sequence of SEQ ID
NO:73 shown in Figure 29.
Figure 31 shows an EST rntcleotide sequence designated herein as DNA13217 (SEQ
ID N0:75).
Figure 32 shows a nucleotide sequence (SEQ ID N0:84) of a native sequence PR06I7 cDNA, wherein SEQ
ID N0:84 is a clone designated herein as "UNQ353" and/or "DNA48309-1280".
Figure 33 shows the amino acid sequence (SEQ ID N0:85) derived from the coding sequence of SEQ ID
N0:84 shown in Figure 32.
Figure 34 shows a nucleotide sequence (SEQ ID N0:89) of a native sequence PR0700 cDNA, wherein SEQ
ID N0:89 is a clone designated herein as "UNQ364" and/or "DNA46776-1284".
Figure 35 shows the amino acid sequence (SEQ ID N0:90) derived from the coding sequence of SEQ ID
N0:89 shown in Figure 34.
Figure 36 shows a nucleotide sequence (SEQ 1D N0:96) of a native sequence PR0702 cDNA, wherein SEQ
ID N0:96 is a clone designated herein as "UNQ366" and/or "DNA50980-1286".
Figure 37 shows the amino acid sequence (SEQ ID N0:97) derived from the coding sequence of SEQ ID
N0:96 shown in Figure 36.
Figure 38 shows a nucleotide sequence (SEQ ID N0:101) of a nauive sequence PR0703 cDNA, wherein SEQ ID NO:IOI is a clone designated herein as "UNQ367" and/or "DNA50913-1287".
Figure 39 shows the amino acid sequence {SEQ ID N0:102) dezived from the coding sequence of SEQ ID
N0:10I shown in Figure 38.
Figure 40 shows a nucleotide sequence (SEQ ID NO:108) of a native sequence PR0705 cDNA, wherein SEQ ID N0:108 is a clone designated herein as "UNQ369" and/or "DNA5U914-1289".
Figure 41 stews the amino acid sequence (SF.Q ID N0:109) derived from the coding sequence of SEQ ID
NO:108 shown in Figure 40.
Figures 42A-B show a nucleotide sequence (SEQ ID N0:113) of a native sequence PR0708 cDNA, wherein SEQ ID N0:113 is a clone designated herein as "UNQ372" and/or "DNA48296-1292".
Figure 43 straws the amino acid sequence (SEQ ID N0:114) derived from the coding sequence of SEQ ID
N0:113 shown in Figures 42A-B.
Figure 44 shows a nucleotide sequence (SEQ ID NO:118) of a native sequence PR0320 cDNA, wherein SEQ ID N0:118 is a clone designated herein as "UNQ281" and/or "DNA32284-1307".
Figure 45 shows the amino acid sequence (SEQ ID N0:119) derived from the coding sequence of SEQ ID
N0:118 shown in Figure 44.
Figure 46 shows a nucleotide sequence (SEQ ID N0:123) of a native sequence PR0324 cDNA, wherein SEQ ID NO:123 is a clone designated herein as "UNQ285" and/or "DN,A36343-1310".
Figure 47 shows the amino acid sequence (SF.Q ID NO:I24) derived from the coding sequence of SEQ ID
N0:123 shown in Figure 46.
Figure 48 shows a nucleotide sequence (SEQ ID N0:131) of a native sequence PR035I cDNA, wherein SEQ ID N0:131 is a clone designated herein as "UNQ308" and/or "DNA40571-1315".

WO 99/x6281 PCT/US99/05028 Figure 49 shows the amino acid sequence (SEQ ID N0:132) derived from the coding sequence of SEQ ID
N0:131 shown in Figure 48.
Figure 50 shows a nucleotide sequence (SEQ ID N0:136) of a native sequence PR0352 cDNA, wherein SEQ ID N0:136 is a clone designated herein as "UNQ309" and/or "DNA41386-1316"
Figure 51 shows the amino acid sequence (SEQ 1D NO:137) derived from the coding sequence of SEQ ID
NO:I36 shown in Figure 50.
Figure 52 shows a nucleotide sequence (SEQ ID N0:144) of a native sequence PR0381 cDNA, wherein SEQ ID N0:144 is a clone designated herein as "UNQ322" andlor "DNA44194-1317".
Figure 53 shows the amino acid sequence (SEQ 1D N0:145) derived from the coding sequence of SEQ ID
NO:I44 shown in Figure 52.
Figure 54 shows a nucleotide sequence {SEQ ID N0:149) of a native sequence PR0386 cDNA, wherein SEQ ID N0:149 is a clone designated herein as "UNQ326" andlor "DNA45415-1318".
Figure 55 shows the amino acid sequence (SEQ ID N0:150) derived from the coding sequence of SEQ ID
N0:149 shown in Figure 54.
Figure 56 shows an EST nucleotide sequence designated herein as DNA23350 (SEQ
ID N0:151).
Figure 57 shows an EST nucleotide sequence designated herein as DNA23536 (SEQ
ID N0:152).
Figure 58 shows a nucleotide sequence (SEQ ID N0:156) of a native sequence PR0540 cDNA, wherein SEQ ID N0:156 is a clone designated herein as "UNQ341" andlor "DNA44189-1322".
Figure 59 shows the amino acid sequence (SEQ ID N0:157) derived from the coding sequence of SEQ ID
N0:156 shown in Figure 58.
Figure 60 shows a nucleotide sequence {SEQ ID N0:161) of a native sequence PR0615 cDNA, wherein SEQ ID N0:16I is a clone designated herein as "UNQ352" and/or "DNA48304-1323".
Figure 61 shows the amino acid sequence (SEQ ID N0:162) derived from the coding sequence of SEQ ID
NO:161 shown in Figure 60.
Figure 62 shows a nucleotide sequence {SEQ ID N0:168) of a native sequence PR0618 cDNA, wherein SEQ ID N0:168 is a clone designated herein as "UNQ354" andlor "DNA49152-1324".
Figure 63 shows the amino acid sequence (SEQ ID N0:169) dexived from the coding sequence of SEQ ID
N0:168 shown in Figure 62.
Figure 64 shows an EST nucleotide sequence designated herein as DNA35597 (SEQ
ID NO:I70).
Figure 65 shows a nucleotide sequence (SEQ ID N0:17?) of a native sequence PR0719 cDNA, wherein SEQ ID N0:17? is a clone designated heiein as "UNQ387" and/or "DNA49646-1327".
Figure 66 shows the amino acid sequence (SEQ ID N0:178) derived from the coding sequence of SEQ ID
N0:177 shown in Figure 65.
Figure 67 shows a nucleotide sequence (SEQ ID N0:182) of a native sequence PR0724 cDNA, wherein SEQ ID NO:182 is a clone designated herein as "UNQ389" and/or "DNA49631-1328".
Figure 58 shows the amino acid sequence (SEQ ID N0:183) derived from the coding sequence of SEQ ID
N0:182 shown in Figure 67.
Figure 69 shows a nucleotide sequence (SEQ ID N0:189) of a native sequence PR0772 cDNA, wherein SEQ ID N0:189 is a clone designated herein as "UNQ410" and/or "DNA4964S-1347".

Figure 70 shows the amino acid sequence (SEQ ID N0:190) derived from the coding sequence of SEQ ID
N0:189 shown in Figure 69.
Figure ?1 shows an EST nucleotide sequence designated herein as DNA43509 (SEQ
ID N0:191).
Figure 72 shows a nucleotide sequence (SEQ ID N0:195) of a native sequence PR0852 cDNA, wherein SEQ ID N0:195 is a clone designated herein as "UNQ418" andlor "DNA45493-1349".
Figure 73 shows the amino acid sequence (SEQ ID N0:196) derived from the coding sequence of SEQ ID
N0:195 shown in Figure 72:
Figure 74 shows a nucleotide sequence (SEQ ID N0:205) of a native sequence PR0853 cDNA, wherein SEQ ID N0:205 is a clone designated herein as "UNQ419" andlor "DNA48227-1350".
Figure 75 shows the amino acid sequence (SEQ ID N0:206) derived from the coding sequence of SEQ ID
N0:245 shown in Figure ?4.
Figures 76A-B show a nucleotide sequence (SEQ ID N0:210) of a native sequence PR0860 cDNA, wherein SEQ ID N0:210 is a clone designated herein as "UNQ42I" andlor "DNA41404-1352".
Figure 77 shows the amino acid sequence (SEQ ID N0:211) derived from the coding sequence of SEQ ID
N0:210 shown in Figures 76A-B.
Figure 78 shows a nucleotide sequence (SEQ ID N0:215) of a native sequence PR0846 cDNA, wherein SEQ ID N0:215 is a clone designated herein as "UNQ422" andlor "DNA44196-1353".
Figure 79 shows the amino acid sequence (SEQ ID N0:216) derived from the coding sequence of SEQ ID
N0:215 shown in Figure 78.
Figure 80 shows a nucleotide sequence (SEQ ID N0:220) of a native sequence PR0862 cDNA, wherein SEQ ID N0:220 is a clone designated herein as "UNQ424" andlor "DNA52187-1354".
Figure 81 shows the amino acid sequence (SEQ ID N0:221) derived from the coding sequence of SEQ ID
N0:220 shown in Figure 80.
Figure 82 shows a nucleotide sequence (SEQ ID N0:225) of a native sequence PR0864 cDNA, wherein SEQ ID N0:225 is a clone designated herein as "UNQ426" andlor "DNA48328-1355".
Figure 83 shows the amino acid sequence (SEQ ID N0:22b) derived from the coding sequence of SEQ ID
N0:225 shown in Figure ~,.
Figure 84 shows a nucleotide sequence (SEQ 1D N0:230) of a native sequence PR0792 cDNA, wherein SEQ ID N0:230 is a clone designated herein as "UNQ431" andlor °DNA56352-1358".
Figure 85 shows the amino acid sequence (SEQ ID N0:231) derived from the coding sequence of SEQ ID
N0:230 shown in Figure 84.
Figure 86 shows a nucleotide sequence (SEQ ID N0:235) of a native sequence PR0866 cDNA, wherein SEQ ID N0:235 is a clone designated herein as "UNQ435" andlor "DNA53971-1359".
Figure 87 shows the amino acid sequence (SEQ ID N0:236) derived from the coding sequence of SEQ ID
N0:235 shown in Figure 86.
Figure 88 shows a nucleotide sequence (SEQ ID N0:244) of a native sequence PR0871 cDNA, wherein SEQ ID N0:244 is a clone designated herein as "UNQ438" andlor "DT1A50919-1361 ".
Figure 89 shows the amino acid sequence (SEQ ID N0:245) derived from the coding sequence of SEQ ID
N0:244 shown in Figure 88.

WO 99!46Z81 PCTIUS99/05028 Figure 90 shows a nucleotide sequence (SEQ ID N0:253) of a native sequence PR0873 cDNA, wherein SEQ ID N0:253 is a clone designated herein as "UNQ440" andlor "DNA44179-1362".
Figure 91 shows the. amino acid sequence (SEQ ID N0:254} derived from the coding sequence of SEQ ID
N0:253 shown in Figure 90.
Figure 92 shows a nucleotide sequence (SEQ ID N0:258} of a native sequence PR0940 cDNA, wherein SEQ ID N0:258 is a done designated herein as °UNQ477" and/or "DNA54002-1367".
Figure 93 shows the amino acid sequence (SEQ ID N0:259) derived from the coding sequence of SEQ ID
N0:258 shown in Figure 92.
Figure 94 shows a nucleotide sequence (SEQ ID N0:263) of a native sequence PR0941 cDNA, wherein SEQ ID N0:263 is a clone designated herein as "UNQ478" and/or "DNA53906-1368".
Figure 95 shows the amino acid sequence (SEQ ID N0:264) derived from the coding sequence of SEQ ID
NO:263 shown in Figure 94.
Figure 96 shows an EST nucleotide sequence designated herein as DNA6415 (SEQ
ID N0:265).
Figure 97 shows a nucleotide sequence (SEQ ID N0:269) of a native sequence FR0944 cDNA, wherein SEQ ID N0:269 is a clone designated herein as "UNQ481" andlor "DNA52185-1370".
Figure 98 shows the amino acid sequence (SEQ ID N0:270} derived from the coding sequence of SEQ ID
N0:269 shown in Figure 97.
Figure 99 shows an EST nucleotide sequence designated herein as DNA140t17 (SEQ
ID N0:271).
Figure 100 shows an EST nucleotide sequence designated herein as DNA12773 (SEQ
ID N0:272).
Figure 101 shows an EST nucleotide sequence designated herein as DNAi2746 (SEQ
ID N0:273).
Figure 102 shows an EST nucleotide sequence designated herein as DNA12834 (SEQ
ID N0:274).
Figure 103 shows an EST nucleotide sequence designated herein as DNA12846 (SEQ
ID N0:275).
Figure 104 shows an EST nucleotide sequence designated herein as DNA13104 {SEQ
ID N0:276).
Figure 105 shows an EST nucleotide sequence designated herein as DNA13259 (SEQ
ID N0:277).
Figure 106 shows an EST nucleotide sequence designated herein as DNA13959 {SEQ
ID N0:278).
Figure 107 shows an EST nucleotide sequence designated herein as DNA23961 (SEQ
ID N0:279).
Figure 108 shows a nucleotide sequence (SEQ ID N0:283) of a native sequence PR0983 cDNA, wherein SEQ ID N0:283 is a clone designated herein as pUNQ484" andlor "DNA5397?-1371".
Figure I09 shows the amino acid sequetxe (SEQ 1D N0:284) derived from the coding sequence of SEQ ID
N0:283 shown in Figure 108.
Figure I IO shows an EST nucleotide sequence designated herein as DNA17130 (SEQ ID N0:285}.
Figure 11 i shows an EST nucleotide sequence designated herein as DNA23466 (SEQ ID N0:286).
Figure 1 i2 shows an EST nucleotide sequence designated herein as DNA26818 (SEQ 1D N0:287).
Figure 113 shows an EST nucleotide sequence designated herein as DNA37618 (SEQ
ID N0:288).
Figure 114 shows an EST nucleotide sequence designated herein as DNA41732 (SEQ
ID N0:289).
Figure 115 shows an EST nucleotide sequence designated herein as DNA45980 (SEQ
ID N0:290).
Figure 116 shows an EST nucleotide sequence designated herein as DNA463?2 (SEQ
ID N0:291).
Figure 117 shows a nucleotide sequence (SEQ ID N0:295) of a native sequence PR01057 cDNA, wherein SEQ ID N0:295 is a clone designated herein as "UNQ522" andlor "DNA57253-1382".

Figure 118 shows the amino acid sequence (SEQ ID N0:296) derived from the coding sequence of SEQ ID
N0:295.shown in Figure 117.
Figure l l9 shows a nucleotide sequence {SEQ ID N0:300) of a native sequence PR01071 cDNA, wherein SEQ ID N0:300 is a clone designated herein as "UNQ528" andlor "DNA58847-1383".
Figure 120 shows the amino acid sequence (SEQ ID N0:301) derived from the coding sequence of SEQ ID
N0:300 shown in Figure 119.
Figure 121 shows a nucleotide sequence {SEQ ID N0:302) of a native sequence PR01072 cDNA, wherein SEQ ID N0:302 is a clone designated herein as "UNQ529" and/or "DNA58747-1384".
Figure 122 shows the amino acid sequence (SEQ ID N0:303) derived from the coding sequence of SEQ ID
N0:302 shown in Figure 121.
Figure 123 shows an EST nucleotide sequence designated herein as DNA40210 (SEQ
ID N0:304).
Figure 124 shows a nucleotide sequence (SEQ ID N0:308) of a native sequence PR01075 cDNA, wherein SEQ ID N0:308 is a clone designated herein as "UNQ532" andlor "DNA57b89-1385".
Figure 125 shows the amino acid sequence (SEQ ID N0:309) derived from the coding sequence of SEQ ID
N0:308 shown in Figure I24.
Figure 126 shows an EST nucleotide sequence designated herein as DNAI3059 (SEQ
ID N0:3I0).
Figure 127 shows an EST nucleotide sequence designated herein as DNA194b3 (SEQ
ID N0:311).
Figure I28 shows a nucleotide sequence (SEQ ID N0:321) of a native sequence PR0181 cDNA, wherein SEQ iD N0:321 is a clone designated herein as "UNQ155" andlor "DNA23330-1390".
Figure I29 shows the amino acid sequence (SEQ ID N0:322) derived from the coding sequence of SEQ ID
N0:321 shown in Figure 128.
Figure 130 shows an EST nucleotide sequence designated herein as DNA13242 (SEQ
ID N0:323).
Figure 131 shows a nucleotide sequence (SEQ ID N0:329) of a native sequence PR0195 cDNA, wherein SEQ ID N0:329 is a clone designated herein as "UNQ169" and/or "DNA'26847-I395".
Figure 132 shows the amino acid sequence (SEQ ID N0:330) derived from the coding sequence of SEQ ID
N0:329 shown in Figure 131.
Figure I33 shows an EST nucleotide sequence designated herein as DNA15062 (SEQ
ID N0:331).
Figure 134 shows an EST nucleotide sequence designated herein as DNA13199 {SEQ
ID N0:332).
Figu~te 135 shows a nucleotide sequence (SEQ ID N0:336) of a native sequence PR0865 cDNA, wherein SEQ ID N0:336 is a clone designated herein as "UNQ434" andlor "DNA53974-1401".
Figure 136 shows the amino acid sequence (SEQ ID N0:33?) derived from the coding sequence of SEQ ID
N0:336 shown in Figure 135.
Figure 137 shows an EST nucleotide sequence designated herein as DNA37642 (SEQ
ID N0:338).
Figure 138 shows a nucleotide sequence (SEQ 1D N0:345) of a native sequence PR0827 cDNA, wherein SEQ ID N0:345 is a clone designated herein as "UNQ468" andlor "DNA57039-1402".
Figure I39 shows the amitm acid sequence (SEQ 1D N0:346) derived from the coding sequence of SEQ ID
N0:345 shown in Figure 138. .
Figure 140 shows an EST nucleotide sequence designated herein as DNA47751 (SEQ
ID N0:347).
Figure I41 shows a nucleotide sequence (SEQ ID N0:351) of a native sequence PR01114 cDNA, wherein SEQ ID N0:351 is a clone designated herein as "UNQ557" andlor "DNA57033-1403".

WO 99!46281 PCT/US99/05028 Figure 142 shows the amino acid sequence (SEQ ID N0:352) derived from the coding sequence of SEQ ID
N0:351 shown in Figure 141.
Figure 143 shows an EST nucleotide sequence designated herein as DNA48466 (SEQ
1D N0:353).
Figure 144 shows a nucleotide sequence {SEQ ID N0:357) of a native sequence PR0237 cDNA, wherein SEQ ID N0:357 is a clone designated herein as "UNt2211" and/or "DNA34353-1428".
Figure 145 shows the amino acid sequence {SEQ 1D N0:358) derived from the coding sequence of SEQ ID
N0:357 shown in Figure 144.
Figure 146 shows a nucleotide sequence (SEQ ID N0:362) of a native sequence PR0541 cDNA, wherein SEQ ID N0:362 is a clone designated herein as "UNQ342" and/or "DNA45417-1432".
Figure 147 shows the amino acid sequence (SEQ ID N0:363) derived from the coding sequence of SEQ ID
N0:362 shown in Figure 146.
Figure 148 shows a nucleotide sequence (SEQ ID N0:369) of a native sequence PR0273 cDNA> wherein SEQ ID N0:369 is a clone designated herein as "UNQ240" andlor "DNA39523-1192".
Figure 149 shows the amino acid sequence (SEQ ID N0:370) derived from the coding sequence of SEQ ID
N0:369 shown in Figure 148.
Figure 150 shows a nucleotide sequence (SEQ ID N0:374) of a native sequence PR0701 cDNA, wherein SEQ ID N0:374 is a clone designated herein as "UNQ365" andlor "DNA44205-1285", Figure 151 shows the amino acid sequence (SEQ ID N0:375) derived from the coding sequence of SEQ ID
N0:374 shown in Figure 150.
Figure 152 shows a nucleotide sequence (SEQ.ID N0:379) of a native sequence PR0704 cDNA, wherein SEQ ID N0:379 is a clone designated herein as "UNQ368" atxl/or "DNA50911-1288".
Figure 153 shows the amino acid sequence (SEQ ID N0:380) derived from the coding sequence of SEQ ID
N0:379 shown in Figure 152.
Figure 154 shows a nucleotide sequence (SEQ ID N0:384) of a native sequence PRO706 cDNA, wherein SEQ ID N0:384 is a clone designated herein as "UNQ370" andlor "DNA48329-1290".
Figure 155 shows the amino acid sequence (SEQ ID N0:385) derived from the coding sequence of SEQ ID
N0:384 shown in Figure 154.
Figure 156 shows a nucleotide sequence (SEQ ID N0:389) of a native sequence PR0707 cDNA, wherein SEQ ID N0:389 is a clone designated herein as "UNQ371" and/or "DNA48306-1291".' Figure 157 shows the atnino acid sequence (SEQ ID N0:390) derived from the coding sequence of SEQ ID
N0:389 shown in Figure 156.
Figure 158 shows a nucleotide seduence (SEQ ID N0:394) of a native sequence PR0322 cDNA, wherein SEQ ID N0:394 is a clone designated herein as "UNQ283" and/or °DNA48336-1309" .
Figure 159 shows the amino acid sequence (5EQ ID N0:395) derived from the coding sequence of SEQ ID
N0:394 shown in Figure 158.
Figure 160 shows a nucleotide sequence (SEQ ID N0:399) of a native sequence PR0526 cDNA, wherein SEQ ID N0:399 is a clone designated herein as "UNQ330" and/or "DNA44184-1319".
Figure 161 shows dte amino acid sequence (SEQ ID N0:4p0) derived from the coding sequence of SEQ ID
N0:399 shown in Figure 160.

r' . .

Figure 162 shows a nucleotide sequence (SEQ ID N0:404) of a nati~oe sequence PR0531 cDNA, wherein SEQ ID N0:404 is a clone designated herein as "UNQ332" and/or "DNA48314-1320"_ Figure i63 shows the amino acid sequence (SEQ ID N0:405) derived from the coding sequence of SEQ ID
N0:404 shown in Figure 162.
Figure 164 shows a nucleotide sequence (SEQ ID N0:409) of a native sequence PR0534 cDNA, wherein S SEQ ID N0:409 is a clone designated herein as "UNQ33S" andlor "DNA48333-1321".
Figure i65 shows the amino acid sequence (SEQ 1D N0:410) derived from the coding sequence of SEQ ID
N0:409 shown in Figure 164.
Figure 166 shows a nucleotide sequence (SEQ ID N0:4I4) of a native sequence PR0697 cDNA, wherein SEQ 1D N0:414 is a clone designated herein as "UNQ36i" and/or "DNA50920-1325".
Figure 167 shows the amino acid sequence (SEQ ID N0:415) derived from the coding sequence of SEQ ID
N0:414 shown in Figure 166: ,, Figure I68 shows a nucleotide sequence (SEQ ID N0:419) of a native sequence PR07I7 cDNA, wherein SEQ ID N0:419 is a clone designated herein as "UNQ385" andJor "DNA50988-1326".
Figure i69 shows the amino acid sequence (SEQ ID N0:420) derived from the coding sequence of SEQ iD
i5 N0:419 shown in Figure 168:
Figures 170A-B show a nucleotide sequence (SEQ ID N0:424) of a native sequence PR0731 cDNA, wherein SEQ ID N0:424 is a cio~ designated herein as "UNQ39S" and/or "DNA48331-1329".
Figure 171 shows the amino acid sequence (SEQ ID N0:425) derived from the coding sequence of SEQ ID
N0:424 shown in Figures I70A-B.
Figure 172 shows a nucleotide sequence (SEQ ID N0:429} of a naive sequence PR0218 cDNA, wherein SEQ ID N0:429 is a clone designated herein as "UNQ192" andlor 'DNA30867-1335".
Figure i73 shows the amino acid sequence (SEQ ID N0:430) derived from the coding sequence of SEQ ID
N0:429 shown in Figure 172.
Figure 174 shows an EST nucleotide sequence designated herein as DNA14472 (SEQ
ID N0:431).
Figure 175 shows an EST nucleotide sequence designated herein as DNA15846 (SEQ
iD N0:432).
Figures 176A-B show a nucleotide sequence (SEQ ID N0:436) of a native sequence PR0768 cDNA, wherein SEQ ID NQ:436 is a clone designated herein as "UNQ446" and/or 'DNA55737-1345".
Figure i77 shows the amino acid sequence (SEQ iD'N0:437) derived from the coding sequence of SEQ ID
N0:436 shown in Figures 176A-B.
Figure 178 shows a nucleotide, sequence (SEQ ID N0:441) of a native sequence PR0771 cDNA, wherein SEQ ID N0:441 is a clone designated herein as "UNQ409" andlor "DNA49829-1346".
Figure 179 shows the amino acid sequence (SEQ ID N0:442) derived froth the coding sequence of SEQ ID
N0:441 shown in Figure 178.
Figures 180A-B show a nucleotide sequence (SEQ ID N0:446) of a native sequence PR0733 cDNA, wherein SEQ ID N0:446 is a clone designated herein as 'UNQ42I" andlor "DNA52196-1348".
Figure 181 shows the amino acid sequetxe (SEQ ID N0:447) derived from the coding sequence of SEQ ID
N0:446 shown in Figures I80A-B.
Figure 182 shows a nucleotide sequence (SEQ ID N0:451) of a native seauetice PR0162 eDNA, wherein SEQ iD N0:451 is a clone designated herein as "UNQ429" and/or "DNA56965-1356".

Figure 183 shows the amino acid sequence (SEQ ID N0:452) derived from the coding sequence of SEQ 1D
N0:451 shown in Figure 182.
Figure 184 shows a.nucleotide sequence (SEQ ID N0:453) of a native sequence PR0788 cDNA, wherein SEQ ID N0:453 is a clone designated herein as "UNQ430" andlor "DNA56405-1357".
Figure 185 shows the amino acid sequence (SEQ ID N0:454) derived from the coding sequence of SEQ ID
N0:453 shown in Figure 184.
Figure 186 shows a nucleotide sequence (SEQ ID N0:455) of a native sequence PR01008 cDNA, wherein SEQ ID N0:455 is a clone designated herein as "UNQ492" andlor "DNA57530-1375".
Figure 187 shows the amino acid sequence (SEQ ID N0:456) derived from the coding sequence of SEQ ID
N0:455 shown in Figure 186.
Figure 188 shows an EST nucleotide sequence designated herein as DNA16508 (SEQ
ID N0:457).
Figures 189A-B show a nucleotide sequence (SEQ ID NO:458) of a native sequence PR01012 cDNA, wherein SEQ ID NO:458 is a clone designated herein as "UNQ495" andlor "DNA56439-137b".
Figure 190 shows the amino acid sequencx (SEQ ID N0:459) derived from the coding sequence of SEQ ID
N0:458 shown in Figures 189A-B.
Figure 191 shows a nucleotide sequence {SEQ ID N0:463) of a native sequence PR01014 cDNA, wherein SEQ ID N0:463 is a clone designated herein as "UNQ497" andlor "DNA56409-1377".
Figure 192 shows the amino acid sequence (SEQ ID N0:464) derived from the coding sequence of SEQ ID
N0:4b3 shown in Figure 191.
Figure 193 shows a nucleotide sequence {SEQ ID N0:465) of a native sequence PRO101? cDNA, wherein SEQ ID N0:465 is a clone designated herein as "UNQ500" andlor "DNA56112-1379"
.
Figure 194 shows the amino acid sequence (SEQ ID N0:466) derived from the coding sequence of SEQ 113 N0:465 shown in Figure 193.
Figure 195 shows a nucleotide sequence (SEQ ID N0:467) of a native sequence PR0474 cDNA, wherein SEQ ID NO:467 is a clone designated herein as "UNQ502" andlor "DNA56045-1380".
Ftgure 196 shows the amino acid sequence (SEQ ID N0:4b8) derived from the coding sequence of SEQ ID
N0:467 shown in Figure 195.
Figure 197 shows a nucleotide sequence (SEQ ID N0:469) of a native sequence PRO1031 cDNA, wherein SEQ ID N0:469 is a clone designated herein as "UNQ516" and/or "DNA59294-1381".
Figure 198 shows the amino acid sequence (SEQ ID N0:4?0) derived from the coding sequence of SEQ ID
N0:469 shown in Figure 197.
Figure 199 shows a nucleotide sequence (SEQ ID N0:471) of a native sequence PR0938 cDNA, wherein SEQ ID N0:471 is a clone designated herein as "UNQ475" and/or "DNA56433-1406".
Figure 200 shows the amino acid sequence (SEQ ID N0:472) derived from the coding sequence of SEQ ID
N0:471 shown in Figure 199.
Figure 201 shows a nucleotide sequence (SEQ ID N0:476) of a native sequence PR01082 cDNA, wherein SEQ ID N0:476 is a clone designated herein as "UNQ539" andlor "DNA53912-1457".
Figure 202 shows the amino acid sequence (SEQ ID N0:477) derived from the coding sequence of SEQ ID
N0:476 shown in Figure 201.

Figure 203 shows a nucleotide sequence (SEQ ID N0:482) of a native: sequence PR01083 cDNA, wherein SEQ ID N0:482 is a clone designated herein as "UNQ540" andlor "DNA50921-1458".
Figure 204 shows the amino acid sequence (SEQ ID N0:483) derived from the coding sequence of SEQ ID
N0:482 shown in Figure 203.
Figure 205 shows an EST nucleotide sequence designated herein as DNA24256 (SEQ
ID N0:484).
Figure 206 shows a nucleotide sequence (SEQ ID N0:487} of a native sequence PR0200 cDNA, wherein SEQ ID N0:487 is a clone designated herein as "UNQ1?4" and/or "DNA29101-1122".
Figure 207 shows the amino acid sequence (SEQ ID N0:488) derived from the coding sequence of SEQ ID
N0487 shown in Figure 206.
Figure 208 shows a nucleotide sequence {SEQ 1D N0:495) of a native sequence PR0285 cDNA, wherein SEQ ID N0:495 is a clone designated herein as "DNA44021-1154".
Figure 209 shows the amino acid sequence (SEQ ID N0:496) derived from the coding sequence of SEQ ID
NO:495 shown in Figure 208.
Figures 210A-B show a nucleotide sequence (SEQ ID N0:497) of a native sequence PR0286 cDNA;
wherein SEQ ID N0:49? is a clone designated herein as "DNA42663-1154".
Figure 211 shows the amitw acid sequence (SEQ ID N0:498) derived from the coding, sequence of SEQ ID
N0:497 shown in Figures 210A-8.
Figure 212 shows a nucleotide sequence {SEQ ID N0:505) of a native sequence PR0213-1 cDNA, wherein SEQ ID N0:505 is a clone: designated herein as °DNA30943-I-l I63-1".
Figure 213 shows tire amino acid sequence (SEQ ID N0:506} derived from the coding sequence of SEQ ID
NO:505 shown in Figure 212.
Figure 2I4 shows a nucleotide sequence (SEQ ID N0:507) of a native sequence PR01330 cDNA, wherein SEQ ID N0:507 is a clone designated herein as "DNA64907-I I63-1".
Figure 215 shows the amine acid sequence (SEQ ID N0:508) derived from the coding sequence of SEQ ID
N0:507 shown in Figure 214.
Figure 216 shows a rexleotide sequence (SEQ ID N0:509) of a native sequence PROI449 cDNA, wherein SEQ ID N0:509 is a clone designated herein as "DNA64908-1163-1".
Figure 217 shows the amino acid sequence (SEQ ID N0:510) derived from the coding sequence of SEQ ID
N0:509 shown in Figure 216.
Figure 218 shows a nucleotide sequence (SEQ ID N0:514) of a native sequence PR0298 cDNA, wherein SEQ ID N0:514 is a clone designated herein as "UNQ261" and/or "DNA39975-1210".
Figure 219 shows the amino acid sequence (SEQ ID N0:515) derived from the coding sequence of SEQ ID
N0:5I4 shown in Figure 218.
Figure 220 shows an EST nucleotide sequence designated herein as DNA26832 (SEQ
ID N0:516).
Figure 221 shows a nucleotide sequence (SEQ ID N0:522) of a native sequence PR0337 cDNA, wherein SEQ ID N0:522 is a clone designated herein as "DNA43316-1237".
Figure 222 shows the amino acid sequence (SEQ ID N0:523) derived from the coding sequence of SEQ ID
N0:522 shown in Figure 221.
Figure 223 shows an EST nucleotide sequence designated hereon as DNA42301 (SEQ
ID N0:524).

.J

Figure 224 shows a nucleotide sequence (SEQ ID N0:525) of a native sequence PR0403 cDNA, wherein SEQ ID N0:525 is a clone designated herein as "DNA55800-1263".
Figure 225 shows the amino acid sequence (SEQ iD N0:526) derived from the coding sequence of SEQ ID
N0:525 shown in Figure 224.
Figures 226A-B show an EST nucleotide sequence designated herein as DNA344I5 (SEQ ID N0:527).
Figure 22? shows an EST nucleotide sequence designated herein as DNA49830 (SEQ
ID N0:528).
Figure 228 shows an EST nucleotide sequence designated herein as DNA49831 (SEQ
iD N0:529).
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
I. Deflnitiotts The terms "PRO polypeptide" and "PRO" as used herein and when immediately followed by a numerical designation refer to various polypeptides, wherein the complete designation (i.e., PRO/number) refers to specific polypeptide sequences as described herein. The terms "PROlnumber polypeptide"
and "PROlnumber" as used herein encompass native sequence poiypeptides and polypeptide variants (which are further defined herein). The PRO
poIypeptides described herein may be isolated from a variety of sources, such as from human tissue types or from another source, or prepared by recombinant or synthetic methods.
A "native sequence PRO polypeptide" comprises a polypeptide having the same amino acid sequence as the corresponding PRO polypeptide derived from nature. Such native sequence PRO
polypeptides can be isolated from nature or can be produced by recombinant or synthetic means. The term "native sequence PRO polypeptide"
specifically encompasses naturally-occurring truncated or secreted forms of the specific PRO polypeptide (e.g., an extracellular domain sequence), naturally-occurring variant forms (e.g., alternatively spliced forms) and naturally-occurring allelic variants of the polypeptide. In various embodiments of the invention, the native sequence PR0213 poiypeptide is a mature or full length native sequence PR0213 polypeptide comprising amino acids 1 to 295 of Figure 2 (SEQ ID N0:2), the native sequence PR0274 polypeptide is a mature or full-length native sequence PR0274 polypeptide comprising amino acids 1 to 492 of Figure 4 (SEQ 1D N0:7), the native sequence PR0300 polypeptide is a mature or full-length native sequence PR0300 polypeptide comprising amino acids 1 to 457 of Figure 9 (SEQ
ID N0:19), the native sequence PR0284 polypeptide is a mature or full-length native sequence PR0284 polypeptide comprising amino acids 1 to 285 of Figure 11 (SEQ 1D N0:28}, the native sequence PR0296 polypeptide is a mature or full-length native sequence PR0296 polypeptide comprising amino acids 1 to 204 of Figure IS (SEQ ID N0:36), the native sequence PR0329 polypeptide is a mature or full-length native sequence PR0329 polypeptide comprising amino acids 1 to 359 of Figure 2D (SEQ ID N0:45), the native sequence PR0362 polypeptide is a mature or full-length native sequence PR0362 polypeptide comprising amino acids 1 to 321 of Figure 22 (SEQ ID N0:52), the native sequence PR0363 polypeptide is a mature or full-length native sequence PR0363 polypeptide comprising amino acids 1 to 373 of Figure 24 (SEQ ID N0:59), the native sequence PR0868 polypeptide is a mature or full-length native sequence PR0868 polypeptide comprising amino acids 1 to 655 of Figure 26 (SEQ ID N0:64), the native sequence PR0382 polypeptide is a mature or full-length native sequence PR0382 polypeptide comprising amino acids 1 to 453 of Figure 28 (SEQ ID N0:69), the native sequence PR0545 polypeptide is a mature or full-iength native sequence PR0545 polypeptide comprising amino acids 1 to 735 of Figure 30 (SEQ ID N0:74), the native sequence PR0617 polypeptide is a mature or foil-length native sequence PR0617 polypeptide comprising amino acids 1 to 6? of Figure 33 (SEQ ID NO:85), the native sequence PR0700 polypeptide is a mature or full-length native sequence PR0700 polypeptide comprising amino acids I to 432 of Figure 35 (SEQ ID N0:90), the native sequence PR0702 polypeptide is a mature or full-length native sequence PR0702 polypeptide comprising amino acids 1 to 277 of Figure 37 (SEQ ID N0:97), the native sequence PR0703 polypeptide is a mature or full-length native sequence PR0703 poiypeptide comprising amino acids I to 730 of Figure 39 (SEQ
ID N0:102), the native sequence PR0705 polypeptide is a mature or full-length native sequence PR0705 polypeptide comprising amino acids 1 to 555 of Figure 41 (SEQ ID NO:i09), the native sequence PR0708 polypeptide is a mature or full-length native sequence PR07U8 polypeptide comprising amino acids 1 to 515 of Figure 43 (SEQ ID
N0:114), the native sequence PR0320 polypeptide is a mature or full-lengdt native sequence PR0320 polypeptide comprising amino acids 1 to 338 of Figure 45 (SEQ ID N0:119), the native sequence PRU324 polypeptide is a mature or full-length native sequence PR0324 polypeptide comprising amino acids 1 to 289 of Figure 47 (SEQ 1D N0:124), the native sequence PR0351 polypeptide is a mature or full-length native sequence PR0351 polypeptide comprising amino acids I to 571 of Figure 49 (SEQ m N0:132), the native sequence PR0352 polypeptide is a mature or full-length native sequence PR0352 polypeptide comprising amino acids l to 316 of Figure 51 (SEQ ID N0:137), the native sequence PR0381 polypeptide is a mature or full-length native sequet~e PR0381 polypeptide comprising amino acids l to 21 I of Figure S3 (SEQ ?3) N0:145), the native sequence PR0386 polypeptide is a mature or full-length native sequence PR0386 1S polypeptide comprising amino acids 1 to 215 of Figure 55 (SEQ ID NO:150), the native sequence PR0540 polypeptide is a mature or full-length native sequence PR0540 polypeptide comprising amino acids 1 to 412 of Figure 59 (SEQ ID N0:157), the native sequence PR0615 polypeptide is a mature or full-length native sequence PR06i5 polypeptide comprising amino acids l to 224 of Figure 61 (SEQ ID N0:162), the native sequence PR0618 polypeptide is a mature or full-length native sequence PR06I8 polypeptide comprising amino acids I to 802 of Figure 63 (SEQ ID N0:169), the native sequence PR0719 polypeptide is a mature or full-length native sequence PR0719 polypeptide comprising atnnno acids 1 to 354 of Figure 66 (SEQ ID NOa78), the native sequence PR0724 polypeptide is a mature or full-length native sequence PR0724 polypeptide comprising amino acids 1 to 713 of Figure 68 (5EQ ID NO:I83), the native sequence PR0772 poiypeptide is a mature or full-length native sequence PR0772 polypeptide comprising amino acids 1 to 152 of Figure 70 (SEQ ID N0:190), the native sequence PR0852 polypeptide is a mature or foil-length native sequence PR0852 polypeptide comprising amino acids 1 to 518 of Figure 73 (SEQ ID N0:196), the native sequence PR0853 polypeptide is a mature or full-length native sequence PR0853 polypeptide comprising amino acids 1 to 3?7 of Figure 75 (SEQ Il) N0:206), the native sequence PR0860 polypeptide is a mature or full-length native sequence PR0860 polypeptide comprising amino acids 1 to 985 of Figure 77 (SEQ ID N0:211), the native sequence PR0846 polypeptide is a mature or full-length native sequence PR0846 polypeptide comprising amino acids l ~ to 332 of Figure 79 (SEQ ID N0:216), the native sequence PR0862 polypepude is a mature or full-length native sequet~ PR0862 polypeptide comprising amino acids 1 to 146 of Figure 81 (SEQ ID N0:221), the native sequence PR0864 polypeptide is a mature or full-length native sequence PR0864 polypeptide comprising amino acids 1 to 331 of Figure 83 (SEQ ID N0:226), the native sequence PR0792 polypeptide is a mature or full-length native sequence PR0792 polypeptide comprising amino acids 1 to 293 of Figure 85 (SEQ 1D N0:231), the native sequence PRO866 polypeptide is a mature or full-length native sequence PR0866 polypepude comprising amino acids 1 to 331 of Figure 87 (SEQ ID N0:236), the native sequence PR0871 polypeptide is a mature or full-length native sequence PR087I polypeptide comprising amino acids 1 to 472 of Figure 89 (SEQ ID N0:245), the native sequence PR0873 polypeptide is a mature or full-length native sequence PR0873 polypeptide comprising amino acids l to 545 of Figure 91 (SEQ ID N0:254), the native sequence PR0940 r WO 9914b281 PCTlUS99/05028 polypeptide is a mature or full-length native sequence PR0940 polypeptide comprising amino acids 1 to 544 of Figure 93 (SEQ ID N0:259), the native sequence PR0941 polypeptide is a mature or full-length native sequence PR0941 polypeptide comprising amino acids 1 to 772 of Figure 95 (SEQ ID N0:264), the native sequence PR0944 polypeptide is a mature or full-length native sequence PR0944 polypeptide comprising amino acids 1 to 211of Figure 98 (SEQ ID N0:270), the native sequence PR0983 polypeptide is a mature or full-length native sequence PR0983 polypeptide comprising amino acids 1 to 243 of Figure 109 (SEQ ID N0:284), the native sequence PROI057 polypeptide is a mature or full-length native sequence PR01057 polypeptide comprising amino acids 1 to 413 of Figure 118 (SEQ ID N0:296), the native sequence PROI071 polypeptide is a mature or full-length native sequence PR01071 polypeptide comprising amino acids 1 to 525 of Figure 120 (SEQ ID
NO:301), the native sequence PR01072 polypeptide is a mature or full-length native sequence PR01072 polypeptide comprising amino acids 1 to 336 of Figure 122 (SEQ ID N0:303), the native sequence PR01075 polypeptide is a mature or full-length native sequence PR01075 polypeptide comprising amino acids 1 to 406 of Figure 125 (SEQ ID N0:309), the native sequence PRO181 polypeptide is a mature or full-length native sequence PR0181 polypeptide comprising amino acids 1 to 144 of Figure 129 (SEQ ID N0:322), the native sequence PR0195 polypeptide is a mature or full-length native sequence PR0195 polypeptide comprising amino acids 1 to 323 of Figure I32 (SEQ
ID N0:330), the native sequence PR08b5 polypeptide is a mature or full-length native sequence PR0865 polypeptide comprising amino acids 1 to 468 of Figure 136 (SEQ 1D N0:337), the native sequence PR082? poIypeptide is a mature or full-length native sequence PR0827 polypeptide comprising amino acids 1 to 124 of Figure 39 (SEQ ID
N0:34b), the native sequence PR01114 polypeptide is a mature or full-length native sequence FRO1114 polypeptide comprising amino acids l to 311 of Figure 142 (SEQ ID N0:352), the native sequence PR0237 polypeptide is a matuze or full-length native sequence PR0237 polypeptide comprising amino acids 1 to 328 of Figure 145 (SEQ ID
N0:358).> the native sequence PR0541 polypeptide is a mature or full-length native sequence PR0541 polypepride' comprising amino acids 1 to 500 of Figure 14? (SEQ ID N0:363), the native sequence PR0273 polypeptide is a mature oz full-length native sequence PR0273 polypeptide comprising amino acids 1 through l 11 of Figure 149 (SEQ ID
NO:370), the native sequence PRO?01 polypeptide is a mature or full-length native sequence PR0701 polypeptide comprising amino acids 1 to 816 of Figure 151 (SEQ 1D N0:375), the native sequence PRO704 polypeptide is a full-length or mature native sequence PRO704 polypeptide comprising amino acids 1 or 40 through 348 of Figure 153 (SEQ ID
N0:380), the native sequence PR0706 polypeptide is a mature or full-length native sequence PR0706 polypeptide comprising amino acids 1 to 480 of Figure 155 (SEQ ID N0385), the native sequence PR0707 polypeptide is a full-length or mature native sequence PR0707 polypeptide comprising amino acids 1 or 31 through 916 of Figure 157 (SEQ ID N0:390), the native sequence PR0322 polypeptide is a mature or full-Length native sequence PR0322 polypeptide comprising amino acids 24 or 1 to 260 of Figure 159 (SEQ ID N0:395), the native sequence PR0526 polypeptide is a full-length or mature native sequence PR052b polypeptide comprising amino acids 1 or 27 through 4'73 of Figure 161 (SEQ ID N0:400), the native sequence PR0531 polypeptide is a mature PR0531 polypeptide comprising amino acids l to 789 of Figure 1b3 (SEQ ID N0:405), the native sequence PR0534 polypeptide is a mature or full-length native sequence PR0534 polypeptide comprising amino acids 1 to 360 of Figure i65 (SEQ ID N0:410), the native sequence PROb97 polypeptide is a full-length or mature native sequence PR0697 polypeptide comprising amino acids 1 or 21 through 295 of Figure 1b? (SEQ ID N0:415), the native sequence FR0717 polypeptide is a mature or full-length native sequence PR07I7 polypeptide comprising amino acids l through 560 of Figure 169 (SEQ ID N0:420), the native sequence PRO731 polypeptide is a full-length or mature native sequence PR0731 polypeptide comprising amino acids WO 99146281 PCTIUS99l05028 1 or I4 through 1184 of Figure 171 (SEQ ID N0:425), the native sequence PR0218 polypeptide is a full-length or mature native sequence PR0218 polypeptide comprising amino acids 1 or 24 through 455 of Figure 173 (SEQ ID
N0:430), the native sequence PR0768 polypeptide is a full-length or mature native sequence PR0768 polypeptide comprising amino acids 1 or 34 through 1141 of Figure 177 (SEQ ID N0:437), the native sequence PR0771 polypeptide is a full-length or mature native sequence PRO?7i polypeptide comprising amino acids 1 or 17 through 436 of Figure 179 (SEQ iD N0:442), the native sequence PR0733 polypeptide is a mature or full-length native seguence PRO733 polypeptide comprising amino acids 24 or 1 through 229 of Figure 181 (SEQ ID N0:447), the native sequence PR0162 polypeptide is a full-length or mature native sequence PR0162 polypeptide comprising amino acids 1 or 27 through 175 of Figure 183 (SEQ ID N0:452), the native sequence PR0788 polypeptide is a full-length or mature native sequence PR0788 polypeptide comprising amino acids 1 or 18 through I25 of Figure I85 (SEQ ID N0:454), the native sequence PR01008 polypegtide is a full-length or mature native sequence PR01008 polypeptide comprising amino acids 1 or 24 through 266 of Figure 187 (SEQ ID
N0:456), the native sequence PR01012 polypeptide is a mature or full-length native sequence PR01012 polypeptide comprising amino acids I
through 747 of Figure 190 (SEQ ID N0:459), the native sequence PR01014 polypeptide is a full-length or mature native sequence PR01014 polypeptide rn~nprising amino acids 1 or 20 through 300 of Figure 192 (SEQ ID N0:464), the native sequence PR01017 polypeptide is a full-length or mature native sequence PR01017 polypeptide comprising amino acids 1 or 32 through 414 of Figure 194 (SEQ ID N0:466), the native sequence PR0474 poiypeptide is a mature or full-length native sequence PRQ474 polypeptide c:otr>prising amino acids 1 through 270 of Figure 196 (SEQ
ID N0:468), the native sequence PR01031 polypeptide is a full-length or mature native sequence PR01031 polypeptide comprising amino acids 1 or 21 through 180 of Figure 198 (SEQ ID
N0:470), the native sequence PRO938 poIypeptide is a mature or full-length native sequence PR0938 polypeptide comprising amino acids 1 to 349 of Figure 200 (SEQ ID N0:472); the native sequence PR01082 polypeptide is a full-length or mature native sequence PR01082 poIypeptide comprising amino acids 1 through 201 of Figure 202 (SEQ ID
N0:47?), the native sequence PR01083 polypeptide is a full-length or mature native sequence PR01083 polypeptide comprising amino acids 1 or 26 through 693 of Figure 204 (SEQ ID N0:483), the native sequence VEGF-E
poIypeptide is a mature or full-length native sequence VEGF-E polypeptide comprising amino acids 1 through 345 as depicted in Figure 207 (SEQ ID
N0:488), the native sequence PR0285 is a mature or full-length native sequence PR0285 polypeptide comprising amino acids 1 to 1049 of Figure 209 (SEQ m N0:496), the native sequence PR0286 is a mature or full-length native sequence PR0286 polypeptide comprising amino acids I to 1041 of 1 figure 211 (SEQ ID N0:298), the native se,quen~ PR0298 is a mature or full length native sequence PR0298 comprising amino acids 1 to 364 of Figure 219 (SEQ ID N0:515), the native sequeixe PR0337 is a mature or full-length native sequence human neurotrimin comprising amino acids 1 to 344 of Figure 222 (SEQ ID N0:523), with or without the N-terminal signal sequence (residues 1 to about 28), and with or without the initiating methionine at position 1 and the native sequence PR0403 is a mature or full-length native sequence comprising amino acids 1 to 'l36 of Figure 225 (SEQ ID NO:S26), with or without the initiating methionine at position 1.
The PRO polypeptide "extracellular domain" or "ECD" refers to a form of the PRO polypeptide which is essentially free of the transmembrane and cytoplasmic domains. Ordinarily, a PRO polypeptids ECD will have less than 1 % of such transmembrane andlor cytoplasmic domains and preferably; will have less than 0.596 of such domains. 1t will be tmderstood that any transmembrane domains identified for the PRO polypeptides of the present invention are identified pursuant to criteria routinely employed in the art for identifying that type of hydrophobic WO 99146281 PCTlUS99105028 domain. The exact boundaries of a transnaembrane domain may vary but most likely by no more than about 5 amino acids at either end of the domain as initially identified. Optionally, therefore, an extracellular domain of a PRO
polypeptide may contain from about 5 or fewer amino acids on either or the transmembrane domain as initially identified.
"PRO polypeptide variant" means an active PRO polypeptide as defined above or below having at least about 80% amino acid sequence identity with the full-length native sequence PRO
polypegtide sequence as disclosed herein.
Such PRO polypeptide variants include, for instance, PRO polypeptides wherein one or more amino acid residues are added, or deleted, at the N- or C-terminus of the full-length native amino acid sequence. Ordinarily, a PRO
polypeptide variant will have at least about 80% amino acid sequence identity, more preferably at least about 85%
amino acid sequence identity, and even more preferably at least about 90%
amino acid sequence identity, even more preferably at least about 91 % amino acid sequence identity, even more preferably at least about 92 % amino acid sequence identity, even more preferably at least about 93 % amino acid sequence identity, even more preferably at least about 94% amino acid sequence identity, even more preferably at least about 95 % amino acid sequence identity;
yet more preferably at least about 96 % amino acid sequence identity, yet more preferably at least about 97 % amino acid sequence identity, yet more preferably at least about 98% amino acid sequence identity and most preferably at least about 99% amino acid sequence identity with rite amino acid sequence of the full-length native amino acid sequence as disclosed herein.
"Percent (%) amino acid sequence identity" with respect to the PRO polypeptide sequences identified herein is defined as the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the specifrc PRO polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. The preferred software alignment program is BLAST. Those skilled in the art can determine: appropriate parameters for measuring alignment, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared. The %
identity values used herein have been generated using the WU-BL.AST 2 computer program (Altschul et al., Methods jsb .~nz5mnolo~ ~:4b0-480 (1996); http:f/blast.wustl/edult>last/README.htm1).
Most of the WU-BLAST-2 search parameters were set to the default values. The adjustable parameters were set with the following values: overlap span = 1, overlap fraction = 0.125, word threshold (T~ = 11, and scoring matrix =
BLOSUM62. The HSP S and HSP
S2 parameters, which are dynamic values used by BLAST-2, are established by the program itself depending upon the composition of the sequence of interest and composition of the database against which the sequence is being searched. However, the values may be adjusted to increase sensitivity. A %
sequence identity value is determined by the fraction of matching identical residues divided by the total number of residues in the aligned region.
"Percent (%) rntcleic acid sequence identity" with respect to PRO-encoding nucleic acid sequences identified herein is defined as the percentage of nucleotides in a candidate sequence that are identical with the nucleotides in the PRO nucleic acid sequence of interest, after aligning the sequences and introducing gags, if necessary, to achieve the maximum percent sequence identity. Alignment for purposes of determining percent nucleic acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available caa>puter software such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms needed to achieve maximal aiigttment over the foil length of the sequences being compared. The identity values used herein were generated by the BLASTN module of WU-BLAST-2 set to the default parameters, with overlap span and overlap fraction set to 1 and 0.125, respectively.
The term "positives", in the context of sequence comparison performed as described above, includes residues in the sequences compared that are nat identical but have similar properties (e.g. as a result of conservative substitutions). The °6 value of positives is determined by the fraction of residues scoring a positive value in the BLOSUM 62 matrix divided by the total number of residues in the aligned region, as defined above.
The term "epitope tagged" where used herein refers to a chimeric polypeptide comprising a PRO
polypeptide, or domain sequence thereof, fused to a "tag polypeptide". The tag polypeptitie has enough residues to provide an epitope against which an antibody may be made, or which can be identified by some other agent, yet is short enough such that it does ~t interfere with the activity of the PRO
pol;ypeptide of interest. The tag polypeptide preferably is also fairly unique so that the antibody does not substantially cross-react with other epitopes. Suitable tag polypeptides generally have at least six amino acid residues and usually between about 8 to about 50 amino acid residues (preferably, between about 10 to about 20 residues).
"Isolated," when used to describe the various polypeptides disclosed herein, means poIypeptide that has been identified and separated andlor recovered from a component of its natural environment. Contaminant components of its natural environment are materials that would typically interfere with diagnostic or therapeutic uses for the polypc~de, and may include enzymes, hormones; and other proteinaceous or non-proteinaceous solutes. In preferred embodiments, the polypeptide will be purified (1) to a degree sufficient to obtain at least 15 residues of N-terminal oar internal amino acid sequence by use of a spinning cup sequenator, or (2) to homogeneity by SDS-PAGE under non-reducing or reducing conditions using Coomassie blue or, preferably, silver stain. Isolated polypeptide includes polypegtide in situ within recombinant cells, since at least one component of the PRO polypeptide natural environment will not be present. Ordinarily, however, isolated polypeptide will be prepared by at least one purification step.
An "isolated" PRO poiypeptide-encoding nucleic acid is a nucleic acid molecule that is identified and separated from at least one contaminant nucleic acid .molecule with which it is ordinarily associated in the natural source of the PRO polypeptide nucleic acid. An isolated PRO polypeptide nucleic acid molecule is other than in the form or setting in which it is found in nature. Isolated PRO polypeptide nucleic acid molecules therefore are distinguished from the specific PRO polypeptide nucleic acid molecule as it exists in natural cells. However, an isolated PRO polypeptide nucleic acid molecule includes PRO polypeptide rnicleic acid molecules contained in cells , that ordinarily express the PRO golypegtide where, for example, the nucleic acid molecule is in a chromosomal location different from that of natural cells.
The term "control sequences" refers to DNA sequences necessary for the expression of an operably linked coding sequence in a particular host organism. The cornrol sequences that are suitable for prokaryotes, for example, include a promoter, optionally an operator sequence, and a ribosome binding site. Eukaryotic cells are known to utilize promoters, poiyademrlation signals, and enhancers.
Nucleic acid is "operably linked" when it is placed into a fitnetional relationship with another nucleic acid sequence. For example, DNA for a presequence or secretory leader is operahly linked to DNA for a polypeptide if it is expressed as a preprotein that participates in the secretion of the polypeptide; a promoter or enhancer is operabiy linked to a coding sequence if it affects the transcription of the sequet~e; or a ribosome binding site is WO 99!46281 PCT/US99/05028 operably linked to a coding sequence if it is positioned so as to facilitate translation. Generally, "operabiy linked"
means that the DNA sequences being linked are contiguous, and, in the case of a secretory leader, contiguous and in reading phase. However, enhancers do not have to be contiguous. Linking is accomplished by Iigation at convenient restriction sites. If such sites do not exist, the synthetic oligonucleotide adaptors or Linkers are used in accordance with conventional practice.
The term "antibody~ is used in the broadest sense and specifically covers single anti-PRO polypeptide monoclonal antibodies (including agonist, antagonist, and neutralizing antibodies) and anti-PRO polypeptide antibody compositions with polyepitopic specificity. The term "monoclonal antibody" as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally-occurring mutations that may be present in minor amounts.
"Active" or "activity" for the purposes herein refers to fotm(s) of PRO
polypeptide which retain the biologic andlor immunologic activities of the specific native or naturally-occurring PRO polypeptide.
"Treatment" or "txeating" refers to both therapeutic treatment and prophylactic or preventative measures.
Those in need of treatment include those already with the disorder as well as those prone to have the disorder of those in which the disorder is to be prevented.
"Mammal~ for purposes of treaunent refers to any animal classified as a mammal, including humans, domestic and farm animals, and zoo, sports, or pet animals, such as sheep, dogs, horses, cats, cows, and the like.
Preferably, the mammal herein is a human.
"Carriers" as used herein include pharmaceutically acceptable carriers, excipients, or stabilizers which are nontoxic to the cell or mammal being exposed thereto at the dosages and concentrations employed. Often the physiologically acceptable carrier is an aqueous pH buffered solution.
Examples of physiologically acceptable carriers include buffers such as phosphate, citrate, and other organic acids;
antioxidants including ascorbic acid; low molecular weight (less than about 10 residues) polypeptide; proteins, such as serum albumin, gelatin, or ittamunoglobulins; hydrophilic polymers such as poLyvinyIpyrrolidone; amino acids such as glycine, glutatnine, asparagine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose. mannose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming eounterions such as sodium; and/or nonionic surfactants such as TWEENT"", polyethyle~
glycol (PEG), and PLURONICSt"".
The term "agonist" is used to refer to peptide and non-peptide analogs of the native PRO polypeptides (where native PRO polypeptide refers to pro-PRO polypeptide, pre-PRO
polypeptide, prepro-PRO polypeptide, or mature PRO polypeptide) of the present invention and to antibodies specifically binding such native PRO
polypeptides, provided that they retain at least one biological activity of a native PRO polypeptide. Preferably, the agonists of the present invention retain the qualitative binding recognition properties and receptor activation properties of the native PRO poiypeptide.
The term "antagonist" is used to refer to a molecule inhibiting a biological activity of a native PRO
polypeptide of the present invention wherein native PRO polypeptide refers to pro-PRO polypeptide, pre-PRO
polypeptide, prepro-PRO polypeptide, or mature PRO polypeptide. Preferably, the antagonises herein inhibit the binding of a native PRO polypeptide of the present im~ention to a binding partner. A PRO polypeptide "antagonist"
is a ztmlecule which prevents, or interferes with, a PRO antagonist effector function (e.g. a molecule which prevents or interferes with binding and/or activation of a PRO poLypeptide receptor by PRO polypeptide). Such molecules can be screened for their ability to competitively inhibit PRO polypeptide receptor activation by monitoring binding of native PRO polypeptide in the presence and absence of the test antagonist molecule, for example. An antagonist of the invention also encompasses an antisense polynucleotide against the PRO
polypeptide gene, which antisense polynucleotide blocks transcription or uanslation of the PRO polypeptide gene, thereby inhibiting its expression and biological activity.
"Stringency" of hybridization reactions is readily determinable by one of ordinary skill in the art, and generally is an empirical calculation dependent upon probe length, washing tc;mperature, and salt concentration. In general, longer probes require higher temperatures far proper annealing, while shorter probes need lower temperatures. Hybridization generally depends on the ability of denatured I)NA
to reanneal when complementary strands are present in an environment below their melting temperature. The higher the degree of desired homology between the probe and hybridizabie sequence, the higher the relative temperature which can be used. As a result, it follows that higher relative temperatures would tend to make the reaction conditions more stringent, while lower temperatures less so. For additional details and explanation of stringency of hybridization reactions, see Ausubel et al., Current Protocols in Molecular Bioloev; Wiley Interscience Publishers, (1995).
"Stringent conditions" means (1) employing tow ionic strength and high temperature for washing, for example, 0.015 sodium chlorideJ0.0015 M sodium citrateJO.l % sodium dodecyl sulfate at 50°C, or (2) employing during hybridization a denaturing agent, such as formamide, for example, 5096 (vollvol) formamide with 0.1 % bovine serum aIburttin/0.l % Ficoll/0.1 % polyvinylpyrrolidane/50 nIVi sodium phosphate buffer at pH 6.5 with 750 mM
sodium chloride, ?5 mM sodium citrate at 42°C. .Another example is use of 50% formamide; 5 x SSC (0.75 M
NaCI, 0.075 M sodium citrate), 50 mM sodium phosphate (pH 618), 0.1 % sodium pyrophosphate, 5 x Denhardt's solution, sonicated salmon sperm DNA (50 ~cglml), 4.1 % SDS, and 10%a dextran sulfate at 42°C, with washes at 42°C in 0.2 x SSC and 0.1 % SDS. Yet another example is hybridization using a buffer of 10% dextran sulfate, 2 x SSC (sodium chloridelsodium citrate) and SO% formamide at 55°C, followed by a high-stringency wash consisting of 0.1 x SSC containing F.DTA at 55°C.
"Moderately srtingent cotx3itions" are described in Sambrook et al., supra, and include the use of a washing solution and hybridization conditions (e.g., temperature, ionic strength, and %SDS) less stringent than described above. An example of moderately saingent conditions is a condition such as overnight incubation at 37°C in a sohttion co~rising: 2096 formarnick, S x SSC (150 mM NaCI, 15 mM trisodium citrate), 50 mM sodium phosphate (pH 7.6), 5 x Denhardt's solution, 10% dextran sulfate, and 20 mglmL denatured sheared salmon sperm DNA, followed by washing the filters in 1 x SSC at about 37-50°C. The skilled artisan will recognize how to adjust the temperature, ionic strength, etc., as necessary to accommodate factors such as probe length and the Like.
"Southern analysis" or "Southern blotting" is a method by which the presence of DNA sequences in a restriction endotntclease digest of DNA or a DNA-containing composition is confirmed by hybridization to a known, labeled oligonucleodde or DNA fragment. Southern analysis typically involves electrophoretic separation of DNA
digests on agarose gels, denaturation of the DNA after electrophoretic separation, and tramfer of the DNA to nitr~ca xllulose, nyktrt, or another suitable membrane support for analysis with a radiolabeled, biotinylated, or enzyme-labeled probe as described in sections 9.37-9.52 of Sambrook et al. , M~1 color Cloning ~ A Labora~ ~nual (New York: Cold Spring Harbor Laboratory Press, 1989).
"Northern analysis" or "Northern blotting" is a method used to identify RNA
sequences that hybridize to a known probe such as an oliganucl~dde, DNA fragttettt, cDNA or fragment thereof, or RNA fragment. The probe is labeled with a radioisotope such as'~P, or by biotinylation, or with an enzyme. The RNA to be analyzed is usually WO 99/46281 PCTlUS99105028 electrophoretically separated on an agarose or polyacrylamide gel, transferred to nitrocellulose, nylon, or other suitable membrane, and hybridized with the probe, using standard techniques well known in the art such as those described in sections ?.39-?.52 of Sambrook et al., supra.
As used herein, the term "immunoadhesin" designates antibody-like molecules which combine the binding specificity of a heterologous protein (an "adhesin") with the effector functions of immunoglobulin constant domains.
Structurally, the itnmunoadhesins comprise a fusion of an amino acid sequence with the desired binding speciftciry which is other than the antigen recognition and binding site of an antibody (i.e., is "heterologous"), and an irnrrntnoglobuIin constant domain sequence. The adhesin part of an immunoadhesin molecule typically is a contiguous amino acid sequence comprising at least the binding site of a receptor or a ligand. The immunoglobulin constant domain sequence in the immunoadhesin tray be obtained from am immunoglobulin, such as IgG-1, IgG-2, IgG-3, or IgG-4 subtypes, IgA (including IgA-1 and IgA-2), IgE, IgD or IgM.
"Chronic" administration refers to administration of the agents) in a continuous mode as opposed to an acute mode, so as to maintain the initial therapeutic effect (activity) for an extended period of time. "Intermittent"
administration is treatment that is not consecutively done without interruption, but rather is cyclic in nature.
Administration "in combination with" one or more further therapeutic agents includes simultaneous (concurrent) and consecutive administration in any order.
As used herein, "vascular endothelial cell growth factor-E," or "VEGF-E,"
refers to a marntnalian growth factor as ascribed herein, including the human amino acid sequence of Figure 207, a sequence which has homology to VEGF and bone morphogenetic protein 1 and which includes complete conservation of all VEGF cysteine residues, which have been shown to be required for biological activity of VEGF. VEGF-E
expression includes expression in human fetal bone, thymus, and the gastrointestinal tract. The biological activity of native VEGF-E is shared by any analogue or variant thereof that is capable of promoting selective growth and/or survival of umbilical vein endothelial cells, induces proliferation of pluripotent fibroblast cells, induces immediate early gene c-fos in human endothelial cell lines and causes myocyte hypertrophy in cardiac cells, or which possesses an immune epitope that is immunologically cross-reactive with an antibody raised against at least one epitope of the corresponding native VEGF-E. The human VEGF-E herein is active on rat and mouse cells indicating conservation across species. Moreover, the VEGF-E herein is expressed at the growth plate region and has been shown to embrace fetal myocytes.
As used herein, "vascular endothelial cell growth factor;" or "VEGF," refears to a mammalian growth factor as defined in U.S. Patent 5,332,671. The biological activity of native VEGF is shared by any analogue or variant thereof that is capable of promoting selective growth of vascular endothelial cells but not of bovine corneal endothelial cells, lens epithelial cells, adrenal cortex cells, BHiK-21 fibroblasts, or keratinocytes, or that possesses an immune epitope that is immunologically cross-reactive with an antibody raised against at least one epitope of the corresponding native VEGF.
The terms "VEGF-E poiypeptide" and "VEGF-E" when used herein encompass native sequence VEGF-E
poiypeptide and VEGF-E palypeptide variants (which are further defined herein). The VEGF-E polypeptides may be isolated from a variety of sources, such as from human tissue types or from another source, or prepared by recombinant or synthetic methods.
Inhibitors of VEGF-E include those which reduce or inhibit the activity or expression of VEGF-E and includes antisense molecules.

The abbreviation "ICDR" refers to the kinase domain region of the VEGF
molecule. VEGF-E has no homology with VEGF in this domain.
The abbreviation _"FLT-1 " refers to the FMS-like tyrosine kinase binding domain which is known to bind to the corresponding FLT-I receptor. VEGF-E has no homology with VEGF in this domain.
"Toll receptor2", "TLRZ" and "huTLR2" are used interchangeably, and refer to a human Toll receptor designated as "HuT'LRZ" by Rack et al:, Proc. htatl. Acad. Sci. USA ~5, 588-593 (1998).
The term "expression vector" is used to define a vector, in which a raucleic acid encoding a PRO polypeptide herein is operably linked to control sequences capable of affecting its expression is a suitable host cells. Vectors ordinarily carry a replication site (although this is not necessary where chromosomal integration will occur).
Expression vectors also include marker sequences which are capable of providing phenotypic selection in transformed cells. For example, E. colt is typically transformed using pBR322, a plasmid derived from an E. colt species (BoIivar, et al., Gene ~: 95 (I977]). pBR322 contains genes for ampicillin and tetracycline resistance and thus provides easy means for identifying transformed cells, whether for purposes of cloning or expression. Expression vectors also optimally will contain sequences which are useful for the control of transcription and translation; e.g., promoters and Shine-Dalgatno sequences (for prokaryotes) or promoters and enhancers (for mamnwlian cells). The prottwters may be, but need not be, inducible; even powerful constitutive promoters such as the CMV promoter for mammalian hosts have been found to produce the LHR without host cell toxicity.
While it is conceivable that expression vectors need not contain any expression control, replicative sequences or selection genes, their absence may hamper the identification of hybrid transformants and the achievement of high level hybrid immunoglobulin expression.
The term "tipopolysaccharide" or "LPS" is used herein as a synonym of "endotoxin." Lipopolysaccharides (LPS) are characteristic cornpor~nts of the outer membrane of Grate-negative bacteria, e.g., Escherichia colt. They consist of a polysaccharide part and a fat called Lipid A. The polysaccharide, which varies from one bacterial species to another, is made up of the O-specific chain (built from repeating units of three to eight sugars) and the two-part core. Lipid A virtually always includes two glucosamine sugars modified by phosphate and a variable number of fatty acids. For further information see, for example, ltietschel and Brade, Scientific merican August 1992, 54-6I.
The term "septic slmek" is used herein in the broadest sense, including all defunftions disclosed in Bone, ~t Intern Med. l~,g, 332-333 (1991). Specifically, septic shock starts with a systemic response to infection, a syndrome called sepsis. When this syndrome results inhypotension and organ dysfunction, it is called septic shock. Septic shock may be initiated by gram-positive organisms and fungi, as welt as endotoxin-containing Grate-negative organisms. Accordingly, the present definition is not limited to "endotoxin shock."
The phrases "gene amplification" and "gene duplication" are used interchangeably and refer to a process by which multiple copies of a gene or gene fragment arc formed in a particular cell or cell line. The duplicated region (a stretch of amplified DNA) is often referred to as "amplicon". Usually, the amount of the messenger RNA
(mRNA) produced, i.e., the level of gene expression, also increases in the proportion of the number of copies made of the particular gene expressed.
"'I~mor", as used herein, refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all pre-cancerous and cancerous cells and tissues: The terms "cancer" and "cancerous" refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth. Examples of cancer include but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia. More particular examples WO 99146281 , PCT/US99/05028 of such cancers include breast cancer, prostate cancer, colon cancer, squamous cell cancer, small-cell Lung cancer, non small cell lung cancer, gastrointestinal cancer, pancreatic cancer, gliobIastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, colorectal cancer, endometrial carcinoma, salivary gland carcinoma, kidney cancer, vulval cancer, thyroid cancer, hepatic carcinoma and various types of head and neck cancer.
The term "cytotoxic agent" as used herein refers to a substance that inhibits or prevents the function of cells andlor causes destruction of cells. The term is intended to include radioactive isotopes (e.g. I131, I125, Y90 and Re186), chemotherapeutic agents, and toxins such as enzymatically active toxins of bacterial, fungal, plant or animal origin, or fragments thereof.
A "chemotherapeutic agent" is a chemical compound useful in the treatment of cancer. Examples of chemotherapeutic agents include adriamycin, doxorubicin, epirubicin, 5-fiuorouracil, cytosine arabinoside ("Ara-C "), cyclophosphamide, thiotepa, busulfan, cytoxin, taxoids, e.g. paclitaxel (Taxol; Bristol-Myers Squibb Oncology, Princeton, NJ), and doxetaxei (Taxotere~~, Rhone-Pouienc Rorer, Antony, France), toxotere, methotrexate, cisplatin, melphalan, vinblastine, bleomycin, etoposide, ifosfamide, mitomycin C, mitoxantrone, vincristine, vinorelbine, carboplatin, teniposide, daunomycin, carminomycin, aminopterin, dactinomycin, mitomycins, esperannicins (see U.S.
Pat. No. 4,675,187), melphalan and other related nitrogen mustards. Also included in this defueition are hormonal IS agents that act to regulate or inhibit hormone action on rumors such as tamoxifen and onapristone.
A "growth inhibitory agent" when used herein refers to a compound or composition which inhibits growth of a cell, especially cancer cell overexpressing any of the genes identified herein, either in viuo or in vivo. Thus, the growth inhibitory agent is one which significantly reduces the percentage of cells overexpressing such genes in S please. Examples of growth inhibitory agents include agents that block cell cycle progression (at a place other than S phase), such as agents that induce G1 arrest and M-phase arrest. Classical M-phase blockers include the vincas (vincristine and vinbiastine), taxol, and topo II inhibitors such as doxorubicin, epirubicin, daunorubicin, etoposide, and bleomycin. Those agents that arrest Gl also spill over into S-phase arrest, for example, DNA aikylating agents such as tamoxifen, prednisone, dacarbazine, mechlorethamine, cisplatin, methotrexate, S-fluorouracil, and ara-C.
Further information can be found in The Molecular Basis of Cancer, Mendeisohn and Israel, eds., Chapter 1, entitled "Cell cycle regulation, oncogens, and antineoplastic drugs "by Murakami et al.
(WB Saunders: Philadelphia, 1995), especially p.13.
"Doxorubicin" is an athracycline antibiotic.
The term "cytakine" is a generic term for proteins released by one cell population which act on another cell as intercellular mediators. Examples of such cytokines are iymphokines, monokines, and traditional polypeptide hormones. Ixicluded among the cytokines are growth hormone such as human growth hormone, N-methionyl human growth hormone, and bovine growth hormone; parathyroid hormone; thyroxine;
insulin; proinsuliii; relaxin;
prorelaxin; and the like. As used herein, the term cytokine includes proteins from natural sources or from recombinant cell culture and biologically active equivalents of the native sequence cytokines.
"Immunological cross-reactivity" as used herein means that the candidate polypeptide is capable of 3S competitively inhibiting the qualitative biological activity of a PR0213-1, PR01330, or PR01449 polypeptide having this activity with polyclonal antisera raised against the known active PR0213-1, PR01330, or PR01449 polypeptide.
Such antisera may be prepared in conventional fashion by injecting goats or rabbits, for example, subcutaneousiy with the known active analogue in complete Freund's adjuvant, followed by booster intraperitoneal or. subcutaneous injection in incomplete Freunds. The immunological cross-reactivity preferably is "specific", which means that the w binding affinity of the immunological cross-reactive molecule (e.g., antibody) identified, to the corresponding PR0213-1, PR01330, or FROla49 polypegtide is significantly higher (preferably at least about 2-times, more preferably at least about 4-tithes, even more preferably at least about 6-times, most preferably at least about 8-times higher) than the binding afftniry of that molecule to any other known native polypeptide.
"Native antibodies" and "native immunoglobulins" are usually heterotetrameric glycoproteins of about 150,000 daltons, composed of two identical light (L) chains and two identical heavy (H) chains. Each light chain is linked to a heavy chain by one covalent disulfide bond, while the number of disulfide linkages varies among the heavy chains of differern itnmunoglobulin isotypes. Each heavy and light chain also has regularly spaced intrachain disulfide bridges. Each heavy chain has at one end a variable domain (VH) followed by a number of constant domains. Each Sight chain has a variable domain at one end (VL) and a constant domain at its other end; the constant IO domain of the light chain is aligned with the first constant domain of the heavy chain, and the light chain variable don~airris aligned with the variable domain of the heavy chain. Pat2icular amino acid residues are believed to form an interface between the light- and heavy-chain variable domains.
The term "variable" refers to the fact that certain portions of the variable domains differ extensively in sequence among antibodies and are used in the binding and specificity of .each particular antibody for its particular antigen. However, the variability is not evenly distributed throughout the variable domains of antibodies. It is concentrated in three segments called complementarily-determining regions (CDRs) or hypervariable regions both in the light-chain and the heavy-chain variable domains. The more highly conserved portions of variable domains are called the framework (FR). The variable domains of native heavy and light chains each comprise four FR
regions, largely adopting a ~i-sheet configuration, connected by three CI)Rs, which form loops connecting, and in some cases forming part of, the (i-sheet structure. The CDRs in each chain are held together in close proximity by the FR regions and, with the CDRs from the other chain, cornribute to the formation of the antigen-binding site of ana'bodies (see Kabat et al., NIH Publ. No.91-3242, Vol. l, pages G47-(i69 (1991)). The constant domains are not involved directly in binding an antibody to an antigen, but exhibit various effector functions, such as participation of the antibody in antibody-dependent celhzlar toxicity.
"Antibody fragments" comprise a portion of an intact antibody, preferably the antigen binding or variable region of the intact antibody. Examples of antibody fragments include Fab, Fab', F(ab')2, and Fv fragments;
diabodies; linear antibodies (Zapata et al. , Protein Eng. 8(10): 105'7-1062 [1995J); single-chain antibody molecules;
and multispecifrc antibodies formed from antibody fragments.
Papain digestion of antibodies produces two identical antigen-binding fragments, called "Fab" fragments, each with a single antigen binding site, and a residual "Fc" fragment, a designation reflecting the ability to crystallize readily. Pepsin treatment yields an F(ab'~ fragttiettt that has two.antigen combining sites and is still capable of cross-linking antigen.
"Fv" is the minimum antibody fragment which contains a complete antigen-recognition and -binding site.
This region consists of a dirtier of one heavy- and one light-chain variable domain in tight, non-covalent association.
It is in this configuration that the three CDRs of each variable domain interact to define an antigen-binding site on the surface of the VH-VL dimer. Collectively, the six CDRs confer antigen-binding specificity to the antibody.
However, even a single variable domain (or half of an Fv comprising only three CDRs specific for an antigen) has the ability to recognize and bind antigen; although at a lower affinity than the entire binding site:

r WO 99!46281 ~ PCT/US99/OSU28 The Fab fragment also contains the constant domain of the light chain and the first constant domain (CH l ) of the heavy chain. Fab fragments differ from Fab fragments by the addition of a few residues at the carboxy terminus of the heavy chain CHl domain including one or more cysteines from the antibody hinge region. Fab'-SH
is the designation herein for Fab' in which the cysteine residues) of the constant domains bear a free thiol group.
F(ab')2 antibody fragments originally were produced as pairs of Fab' fragments which have hinge cysteines between them. Other chemical couplings of antibody fragments are also known.
The "light chains" of antibodies (immunoglobulins) from any vertebrate species can be assigned to one of two clearly distinct types, called kappa and lambda, based on the amino acid sequences of their constant domains.
Depending on the amino acid sequence of the constant domain of their heavy chains, itnmunoglobulins can be assigned to different classes. There are five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, and several of these may be farther divided into subclasses (isotypes), e.g., IgGl, IgG2, lgG3, IgG4, IgA, and IgA2.
"Single-chain Fv" or "sFv" antibody fragments comprise the VH and VL domains of antibody, wherein these domains are present in a single polypeptide chain. Preferably, the Fv polypeptide further comprises a polypeptide linker between the VH and VL domains which enables the sFv to form the desired structure for antigen binding. For a review of sFv see Pluckthun in The Pharmacology of Monoclonal, Antibodies, vol. 113, Rosenburg and Moore eds., Springer-Verlag, New York, pp. 269-315 (1994).
The term "diabodies" refers to small antibody fragments with two antigen-binding sites, which fragments comprise a heavy-chain variable domain (VH) connected to a light-chain variable domain (VL) in the same poiypeptide chain (VH - VL). By using a linker that is too short to allow pairing between the two domains on the same chain, the domains are forced to pair with the complementary domains of another chain and create two antigen-binding sites. Diabodies are described more fully in, for example, EP 404,097;
WO 93II1161; and Hollinger et al., Proc. Nat!. Acad. Sci. USA, 90:b444-6448 (1993).
An "isolated" antibody is one which has been identified and separated and/or recovered from a component of its natwal environment. Contaminate components of its natural environment are materials which would interfere with diagnostic or therapeutic uses for the antibody, and may include enzymes, hormones, and other proteinaceous or nonproteinaceous solutes. In preferred embodiments, the anubody will be purified (1) to greater than 95% by weight of antibody as determined by the Lowry method, and most preferably more than 99~ by weight, (2) to a degree sufficient to obtain at Least 15 residues of N-terminal or internal amino acid sequence by use of a spinning cup sequenator, or (3) to homogeneity by SDS-PAGE under reducing or noraeducing conditions using Coomassie blue or, preferably, silver stain. Isolated antibody includes the antibody in situ within recombinant veils since at least one component of the antibody's natural environment will not be present.
Ordinarily, however, isolated antibody will be prepared by at least one purification step.
The word "label" when used herein refers to a detectable compound or composition which is conjugated directly or indirectly to the antibody so as to generate a "labelled"
antibody. The label tnay be detectable by itself (e.g. radioisotope labels or fluorescem Labels) or, in the case of an enzymatic label, may catalyze chemical alteration of a substrate compound or cottiposition which is detestable.
By "solid phase" is meant a non-aqueous matrix to which the antibody of the present invention can adhere.
Exattiples of solid phases encompassed herein include those formed partially or entirely of glass (e.g., controlled pore glass), polysaccharides (e.g., agarose), polyacrylamides, polystyrene, polyvinyl alcohol and silicones. In cetYairi embodiments, depending on the context, the solid phase can comprise the well of an assay plate; in others it is a purification cohlmn (e.g., an affinity chromatography column). This term also includes a discontinuous solid phase of discrete particles, such as those described in U.S. Patent No. 4,275,149.
A "liposome" is a small vesicle composed of various types of lipids, phospholipids and/or surfactant which is useful for delivery of a drug (such as the anti-ErbB2 ann'bodies disclosed herein and, optionally, a chemotherapeutic agent) to a mattunal. The components of the liposome are commonly arranged in a bilayer formation, similar to the lipid arrangement of biological membranes.
II. Com~sitions and Methods Q,f the Invention 1. Fill!-~e~gth PR0213 Polypept~~
The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0213. In particular, Applicants have identified and isolated cDNA
encoding a PR0213 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicants found that a portion of the PRO213 polypeptide has sigrtificant homology with the human growth arrest-specific 6 {gash) protein. Accordingly, it is presently believed thai PR0213 polypeptide disclosed in the present application may have the same or simtilar activity as does the gash protein.
2. . Furl-length PR0274 Pwnentides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0274. In particular, Applicants have identified and isolated cDNA
encoding a PR0274 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicants found that various portions of the PR0274 polypeptide have significant homology with the ? transmembrane segment receptor proteins and FnS4 protein. Accordingly, it is presently believed that PR0274 polypeptide disclosed in the present application is a newly identified member of the ? transmembrane segment receptor protein andlor Fn54 protein family.
3. Full-length PR0300 Polvoep~ide The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0300. Ln particular, Applicants have identified and isolated cDNA
encoding a PR0300 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicants found that various poxtions of the PR0300 polypeptide have significant homology with the human Difl;' 33 protein. Accordingly, it is presently believed that PR0300 polypeptide disclosed in the present application is a newly identified mem>~r of the Diff 33 family.
4. Full-to h PR0284 Poly~e ti'~de~c The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0284. In particular, Applicants have identified and isolated cDNA
encoding a PR0284 polypeptide, as disclosed in further detail in the Examples below, To Applicants present Imowledge, the UNQ247 (DNA23318-1211) nucleotide sequence encodes a novel factor; using BLAST and FastA
sequence alignment computer programs, no sequence identities to arty lmown proteins were revealed.

WO 99/46281 PCTtUS99/05028 5. Full-leneth PR0296 Polypeptides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0296. In particular, Applicants have identified and isolated cDNA
encoding a PR0296 polypeptide, as disclosed in further detail in the Examples below. Using. BLAST and FastA
sequence aligntr~ent computer programs, Applicants found that the PR0296 polypeptide has significant similarity to the sarcoma-amplified SAS protein. Accordingly, it is presently believed that PR0296 polypeptide disclosed in the present application is a newly identified SAS protein homolog.
6. Full-length PR0329 Polvpeptides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0329. in particular, Applicants have identified and isolated cDNA
encoding a PR0329 poiypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicants found that the PR0329 polypeptide has significant similarity to a high affuiity immunoglobulin F~ receptor. Accordingly, it is presently believed that PR0329 polypeptide disclosed in the present application is a newly identified F~ receptor homolog.
?. Full-length PR0362 Poiy~eptides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR03b2. In particular, Applicants have identified and isolated cDNA
encoding a PR0362 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicants found that the PR0362 polypeptide has significant similarity to the A33 antigen protein as well as the HCAR protein and the NrCAM related cell adhesion molecule. Accordingly, it is presently believed that PR0362 polypeptide disclosed in the present application is a newly A33 antigen and HCAR protein homolog.
8. Full-length PR0363 Polypeptides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0363. In particular, Applicants have identified and isolated cDNA
encoding a PR0363 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA.
sequence alignment computer programs, Applicants found that the PR0363 polypeptide has significant similarity to tl~ cell surface protein HCAR. Accordingly, it is presently believed that PRO363 polypeptide disclosed in the present application is a newly HCAR hotnolog.
9. dull-leneth PR0868 Polvoeotides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0868. In particular, Applicants have identified and isolated cDNA
encoding a PR08b8 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence aiigttinettt computer programs, Applicants found that the PR0868 polypeptide has significant similarity to the tumor necrosis factor receptor. Accordingly, it is presently believed that PR0868 golypeptide disclosed in the present application is a newly identified member of the tumor necrosis factor receptor family of proteins.

WO 99146281 PCT/US99l05028 I0. Full-le~gtjh PR0382 Poivoeotides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present.application as PR0382. In particular, App3icants have identified and isolated cDNA
encoding a PR0382 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicants found that the native PR0382 polypeptide shares significant S homology with various serine protease proteins. Applicants have also found that the DNA encoding the PR0382 polypeptide shares significant homology with nucleic acid encoding various setvte protease proteins. Accordingly, it is presently believed that PR0382 polypeptide disclosed in the present application is a newly identified serine protease homolog.
11. Full-ie~gth PR0545 Polvneotides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PROS4S. In particular, Applicants have identified and isolated cDNA
encoding a PR0545 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignnnent computer programs, Applicants found that various portions of the PROS4S polypeptide have significant homology with the sequences identified designated as; human metalloproteinase ("P W01825 "), mouse meltrin alpha ("S602S7"), mctalloprotease-disintegrin meltrin-alpha ("GENI3G9S"), ADAM 13 - Xenopeis laevis ("XLUb6003_I "), mouse meluin beta ("S60258"), rabbit metalloprotease-disintegrin meltrin-beta, ("GEN13696"), human meltrin S ("AF023477_1 "), human meltrin precursor ("AF023475 1 "), human ADAM 21 ("AF029900 1 "), and human ADAM 20 ("AF029899 1 "), thereby indicating that PROS4S may be a novel mcltrin protein.
Accordingly, it is presently believed that the PROS4S polypeptide disclosed in the present application is a newly identified member of the meltrin family and possesses the cellular adhesiveness typical of the rneltrin proteins which comprise both metalloprotease and disintegrin domains.
12: Full-lenEth PR0617 Pojv~ptldes The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0617. In particular, Applicants have identified and isolated cDNA
encoding a PR0617 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer-programs, Applicants found that the PR0617 polypeptide shares significant homology with the CD24 protein. Applicants have also found that the DNA encoding the PR06I7 polypeptide has significant homology with DNA encoding the CD24 protein. Accordingly, it is presently believed that PR0617 polypeptide disclosed in the present application is a newly identified CD2.4 homolog.
13. ly'ull-length laRQ700 Pol3y to ides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides 3S referred to in the present application as PRO700. In particular, Applicants have identified and isolated cDNA
encoding a PR0700 polypeptide, as disclosed in further detail in the: Examples below. Analysis of the amino acid sequence of the fall-length PR0700 polypeptide using BLAST and FastA sequence alignment computer programs, suggests that various portions of the PR0700 polypeptide possess significant sequence similarity to various protein disulfide isomerases. More specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 3S) evidenced significant sequence similarity between the PR0700 amino acid sequence and the following Dayhoff sequences;
polypeptide with protein disulfide isomerase activity, designated as ("P
P80664"), human FDI, designated as ("P~R51696"), human PDI, designated as (P 825297"), probable protein disulfide isomerase er-60 precursor, designated as ("ER60 SCHMA"), protein disulfide isomerase precursor -Drosophila n:elanogaster, designated as ("PDI DROME"), protein disulfide-isomerase precursor - Nicotiana tabaccum, designated as ("NTPDIGENE 1 "), protein disulfide isomerase - Onchocerca volvulus, designated as ("OW 22440 I
"), human probable protein disulfide isomerase p5 precursor , designated as ("ERPS HUMAN"), human protein disulfide isomerase-related protein 5, ("HSU79278_l "), and protein disulfide isomerase precursor J prolyl 4-hydroxy, ("PDI HUMAN"), thereby indicating that PR0700 may be a novel protein disulfide isomerase.
Accordingly, it is presently believed that PR0700 polypeptide disclosed in the present application is a newly identified member of the protein disulfide isomerase family and possesses the ability to catalyze the formation of disulfide bonds typical of the protein disulfide isomerase family.
14. ~u11-length PR0702 Poiypeptides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0702. In particular, Applicants have identified and isolated cDNA
encoding a PR0702 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FaSIA
sequence alignment computer programs, Applicants found that the PR0702 polypeptide has significant similarity to the conglutinin protein. Accordingly, it is presently believed that PR0702 polypeptide disclosed in the present application is a newly identified conglutinin homolog.
15. Full length PR0703 Polypeotides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides~
referred to in the present application as PRO?03. In particular, Applicants have identified and isolated cDNA
encoding a PR0703 polypeptide, as disclosed in further detail in the Examp2es below. Analysis of the amino acid sequence of the full-length PR0703 polypeptide using BLAST and FastA sequence alignment computer programs, suggests that various portions of the PR0703 polypeptide possess significant sequence similarity to the VLCAS
protein, thereby indicating that PR0703 may be a novel VLCAS protein. More specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced significam sequence similarity between the PR0703 amino acid sequence and the following Dayhoff sequences, human m'RNA for very-long-chain acyl-CoA, ("D88308"), rat mRNA for very-long-chain aryl-CoA synthetase, ("D85100"), Mus musculus fatty acid uansport protein, ("MMU15976"), human very-long-chain aryl-CoA synthetase, ("D88308~1 "), Mus musculus very-long-chain aryl-CoA synthetase, ~'AI~033031 1 "), very-long-chain acyl-CoA synthetase -Ramcs, ("D85100~1 "), rat long-chain fatty acid transport protein, ("FATP,-RAT"), mouse long-chain fatty acid transport protein, ("FATP~MOUSE"), probable long-chain fatty acid transport protein, ("FATi YEAST"), and fatty acid transporter protein, ("CHY15839 2") , thereby indicating that PR0703 may be a novel VLCAS.
Accordingly, it is presently believed that PR0703 polypeptide disclosed in the present application is a newly identified member of the VLCAS family and possesses the ability to facilitate the cellular transport of long and very long chain fatty acids typical of the VLCAS
family.

WO 99!46281 PCTIUS99/05028 16. Full-IenQt~ PR0705 Polvnentides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides, referred to in the present application as PRO705. In particular, Applicants nave identified and isolated cDNA
encoding a PRO705 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence atignt~nt computer programs, Applicants found that the PR0705 polypeptide has significant similarity to the K-gIypican protein. Accordingly, it is presently believed that PR0705 polypeptide disclosed in the present application is a newly identified member of the glypican family of proteoglycan proteins.
l?. Full-lgngth P~Q708 Polvoeutides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PRO?08. In particular, Applicants have identified and isolated cDNA
encoding a PR0708 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicants found that the PR070$
polypeptide has significant homology with the aryl suifatase proteins. Applicants have also found that the DNA encoding the PR0708 polypeptide has significant homology with DNA encoding the aryl sulfatase proteins.
Accordingly, it is presently believed that PR0708 polypeptide disclosed in the present application is a newly identified aryl sulfatase homolog.
18. Full-le h P_R_-O~'~0 Palvaeotides The present invention provides newly identified and isolated nucievtide sequences encoding polypepiides referred to in the present application as PR0320. In particular, Applicants have identified and isolated cDNA
encoding a PR0320 polypeptide, as disclosed in further detail in the Examples below. Analysis of the amino acid sequence of the full-length PR0320 polypeptide using BLAST and FastA sequence alignment computer programs, suggests that various portions of the PR0320 polypeptide have significant homology to the fibulin protein. More specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced significant homology between the PR0320 amino acid sequence and the following Dayhoff sequences, human fibulin-2 precursor, designated "FBL2,HUMAN", hutt~an fibulin-1 isofotm a precursor, designated "FBLA HUMAN", ZK783.1 Caenorhabditis elegans, designated "CELZK783_l ", human-notch2, designated "HSU77493 I", Nel protein psectusor - rattus norvegicus, designated "NEL RAT", Mus musculus cefl surface protein, designated "D32210 1 ", mouse (fragment) Notch B protein, designated '"A49175", C50H2.3a -Caenorhabditis elegans, designated "CECSOH2~3", MEC-9L - Caenorhabditis elegans, designated "CEt)33933_1 ", and Mus musculus notch 4, designated "10 MMMHC29N7l2", thereby indicating that PRO320 may be a novel fitiulin or fibulin-like protein.
Accordingly, it is preseniiy believed that PR0320 poIypeptide disclosed in the present application is a newly identified member of the fibuIin family and possesses biological activity typical of the fibulin family.

19. Full-len~h, P]It032a Polvnentides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0324. In particular, Applicants have identified and isolated eDNA
encoding a PR0324 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
seqt~ce align computer programs, Applicants found that the PR0324 polypeptide has significant similarity to oxidorecbuctases. Acmrdiiigly, it is presently believed that PRO324 polypeptide disclosed in the present application is a newly identified oxidoreductase homolog.

20. Full-length PR0351 Polypeptides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0351. In particular, Applicants have identified and isolated cDNA
encoding a PRO35I polypeptide, as disclosed in further detail in the Examples below. Analysis of the amino acid sequence of the full-length PR0351 polypeptide using BLAST and FastA sequence alignment computer programs, suggests that various portions of the PR0351 polypeptide possess significant sequence similarity to the prostasin protein, thereby indicating that PR0351 may be a novel prostasin protein. More specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced significant sequence similarity between the PR0351 amino acid sequence and the following Dayhoff sequences, "AC003965_1", "CELLO?Gi ?", "GEN1291?", °HEPS HUMAN», "GF.N14584", "MCT6~MOUSE", "HSU7532911", "PLMN ERIEU", "TRYB HUMAN", and "P W2298?". Accordingly, it is presently believed that FR0351 polypeptide disclosed in the present application is a newly identified member of the prostasin family and possesses properties and activities typical of the prostasin family.

21. Full-length PR0352 Polypeptides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0352. In particular, Applicants have identified and isolated cDNA
encoding a PR0352 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicants found that the PR0352 polypeptide has significant similarity to the buryrophilin protein. Accordingly, it is presently believed that PR0352 polypeptide disclosed in the present application is a newly identified butyrophilin homolog.

22. dull-length PR0381 Polypeptides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0381. In particular, Applicants have identified and isolated eDNA
encoding a PR0381 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicants found that the PR0381 polypeptide has significant similarity to immunoghilin groteins. Accordtngiy, it is presently believed that PR0381 polypeptide disclosed in the present application is a newly identified FKBP immunophilin homolog.

23. FuliaenQth PRO386 Polvpeptides The present invention provides newly identified and isolated nucleotide sequences encoding golypeptides referred to in the present application as PR0386. In particular, Applicants have identified and isolated cDNA
encoding a PR0386 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
seqt>etice alignment computer programs, Applicants found that the PR0386 polypeptide has significant similarity to the beta-2 subunit of a sodium channel protein. Accordingly, it is presently believed that PR0386 polypeptide disclosed in the present application is homolog of a beta-2 subunit of a sodium channel expressed in mammalian cells.

24. Full-length PR054t1 Polvneotides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PROS40. In particular, Applicants have identified and isolated cDNA
encoding a PR0540 polypeptide, as disclosed in further detail in the Examples below. Analysis of the amino acid sequence of the full-length PR0540 polypeptide using BLAST and FastA sequence alignment computer programs, suggests that various portions of the PR0540 polypeptide possess significant sequence similarity to the LCAT protein, thereby indicating that PR0540 may be a novel LCAT protein. More specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced significant sequence similarity between the PR0540 amino acid sequence and the following Dayhoff sequences, phosphatidylcholine-sterol acyltransferase, designated "LCAT HUMAN", hypothetical 75.4 kd protein, designated "YN84 YEAST", Bacillus licheniformis esterase, designated "BLU35855_1 ", macrotetrolide resistance protein - Streptomyces, designated "JH0555", T-cell receptor delta chain precursor, designated "C3U583", Rhesus kringle 2, designated "P_W07551", RAGE-1 ORFS, designated "HSU46191 3", human Ig kappa chain VKIIi-JK3, designated "HSU0746fi_I", and Alstroemeria inodora reverse transcriptase, designated "AL1223606_1": Accordingly, it is presently believed that PR0540 polypeptide disclosed in the present application is a newly identified member of the LCAT protein family and possesses lipid transport capability typical of the LCAT family.

25. Full-ien$t~ PR0615 Poly eD tn ides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0615. In particular, Applicants have identified and isolated cDNA
encoding a PR0615 polypeptide, as disclosed in further detail in the Examples below. Analysis of the amino acid sequence of the foil-length PR0615 polypeptide using BLAST and FastA sequence alignment computer programs, suggests that various portions of the PR0615 polypeptide possess significant sequence similarity to the human synaptogyrin protein, thereby indicating that PR061S tray be a novel synaptogyrin protein. More specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced significant sequence similarity between the PR0615 amino acid sequence and the following Dayhoff sequences, "AF039085,1", "RNU39549 1", "CELTO8A9_8", "FSU62028_l", "S73645", "Y348 MYCPN", "AC000103_S", "", "RT12 LE1TA", and "EBVLMP218 1". Accordingly, it is presently believed that PR0615 polypeptide disclosed in the present application is a newly identified member of the synaptogyrin family and possesses activity and properties typical of the synaptogyrin family.

26. Full-length PR0618 PolyRg tn ides .
The present invention provides newly identified and isolated rnucleotide sequences encoding polypeptides referred to in the present application as PR0618. In particular, AppTiicauts have identified and isolated eDNA
encoding a PR0618 polypeptide, as disclosed in further detail in the Examples below. Analysis of the amino acid sequence of the full-length PR0618 polypeptide using BLAST and FastA sequence alignment computer programs, suggests that various portions of the PR0618 polypeptide possess significant sequence similarity to the enteropeptidase protein, thereby indicating that PR0618 may be a novel enteropeptidase. More specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced significant sequence similarity between the PR0618 amino acid sequence and the following Dayhoff sequences, "P W22987", "KAL HUMAN", WO 9914b281 PCTIUS99/05028 "AC003965_I", "GEN12917", "EN'TK_HUMAN", "FA11 HUMAN", "HSU75329 1", "P
W22986", and "PLMN HORSE". Accordingly, it is presently believed that PR0618 polypeptide disclosed in the present application is a newly identified member of the enteropeptidase family and possesses catalytic activity typical of the enteropeptidase family.
6 27. 1~ ull-len~"th ~R0719 Polvnentides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PRO?19. In particular, Applicants have identified and isolated cDNA.
encoding a PR0719 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence a3igtunent computer programs, Applicants found that the PR0719 polypeptide has significant similarity to 10' the lipoprotein lipase H protein. Accordingly, it is presently believed that PR0719 polypeptide disclosed in the present application is a newly identified lipoprotein lipase H homolog.
28. Full-len_eth PR0724 Polypeptides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides 15 referred to in the present application as PR0724. In particular, Applicants have identified and isolated cDNA
encoding a PR0724 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence aligtmnent computer programs, Applicants found that the PR0724 polypeptide has significant similarity to the hutnatt low density lipoprotein (LDL) receptor protein. Accordingly, it is presently believed that PR0724 polypeptide disclosed in the present application is a newly identified LDL
receptor homoiog.
29. dull IenQth PR0772 Polynentides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0772. In particular, Applicants have identified and isolated cDNA
encoding a PR0772 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicants found that the PR0772 polypeptide has significant similarity to the human A4 protein. Accordingly, it is presently believed that PR0772 poiypeptide disclosed in the present application is a newly identified A4 protein homolog.
30. ~.tll lgn~th PR0852 PolvneDtides The presept invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0852. In particular, Applicants have identified and isolated cDNA
encoding a PR0852 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicants found that the PR0852 polypeptide has significant similarity to various protease proteins. Accordingly, it is presently believed that PR0852 polypeptide disclosed in the present application is a newly identified protease enzyme homolog.
31. Full-fenath PR0853 Po~,ypg t» ides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the 'present application as PR0853. In particular, Applicants have identified and isolated cDNA

encoding a PR0853 poIypeptide, as disclosed in further detail in the Examples below. Analysis of the amino acid sequence of the full-length PR0853 polypeptide using BLAST and FastA sequence alignment computer programs, suggests that various portions of the PR0853 polypeptide possess significant sequence similarity to the reductase protein, thereby indicating that PR0853 may be a novel reductase. More specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced significant sequence similarity between the PR0853 amino acid sequence and the following Dayhoff sequences, "P W03I98", "CEC15H11 6", "MTV030 12", "P WI5759", "542651", "ATAC00234314", "MTV022 13", "SCU43704 I", "CELE04F6 7", and "ALFA
1". Accordingly, iL
is presently believed that PR0853 polypeptide disclosed in the present application is a newly identified member of the reductase family and possesses the antioxidant enzymatic activity typical of the reductase family.
32. Full-length PR0860 Polyp~ptic~e.~
The present invention provides newly identified and isolated nucleotide sequences encoding poiypeptides referred to in the present application as PR0860. In particular, Applicants have identified and isolated cDNA
encoding a PR0860 poiypeptide, as disclosed in further detail in the Examples below. Analysis of the amino acid sequence of the full-length PR0860 polypeptide using BLAST and FastA sequence alignment computer programs, suggests that various portions of the PR0860 polypeptide possess significant sequence similarity to the neurofascin protein, thereby indicating that PR0860 may be a novel neurofascin. More specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced significant sequence sinviarity between the PR0860 amino acid seqtier>ce and tb:e following Dayhoff sequences, "AF040990 1 ", "AF041053_I", "CELZK377 2", "RNU8I035 1", "D86983_I", "S2b180", "MMBIG2A 1", "546216", and "RNU68726 1". Accordingly, it is presently believed that PR0860 polypeptide disclosed in the present application is a newly identified member of the neurofascin family and possesses the cellular adhesion properties typical of the neurofascin family.
33. Full-leng~, PR~6 Poly~e, tides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0846. In particular, Applicants have identified and isolated cDNA
encoding a PR0846 polypeptide, as disclosed in further detail in the Examples below, Analysis of the amino acid sequence of the full-length PR0846 polypeptide using BLAST and FastA sequence aiignrnent computer programs;
suggests that various portions of the PR0846 polypeptide possess significant sequence similarity to the CMRF35 protein, thereby indicating that 1'R0846 may be a novel CMRF35 protein. More specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced significant sequence similarity between the PR0846 amino acid sequence and the following Dayhoff sequences,"CM35~HUIVtAN", "AF035963_1", "PIGR~RABTT", "AF043724;1 ", "RNU89744 1", "A52091'1 ", "S48841", "ELK06A9 3", and "AF049588 1 ". Accordingly, it is presently believed that PR0846 polypeptide disclosed in the present application is a newly identified member of the CMRF35 protein family and possesses properties typical of the CMRF35 protein family.
34. Full-lengtl~PR0862 Polvoentldes The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0862. In particular, Applicants have identified and isolated cDNA
encoding a PR0862 polypepdde, as disclosed in further detail in the Examples below. Analysis of the amino acid WO 99!46281 PCT/US99/OS028 sequence of the full-length PR08b2 polypeptide using BLAST and FastA sequence alignment computer programs, suggests that various portions of the PR0862 polypeptide possess significant sequence similarity to the lysoryme protein, thereby indicating .that PR0862 may be a novel Iysoryme protein. More specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced significant sequence similarity between the PR0862 amino acid sequence and the following Dayhoff sequences, "P P90343", and "LYC HUMAN.
Accordingly, it is presently believed that PR0862 polypeptide disclosed in the present application is a newly identified member of the lysozyme family and possesses catalytic activity typical of the lysazyme family.
35. Full-length PR0~64 Polvne~tides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0864. In particular, Applicants have identified and isolated cDNA
encoding a PR0864 polypeptide, as disclosed in further detail in the Examples below. Analysis of the amino acid sequence of the full-length PR0864 polypeptide using BLAST and FastA sequence alignmem computer programs, suggests that various portions of the PR0864 polypeptide possess significant sequence similarity to the Wnt-4 protein, thereby indicating that PR0864 may be a novel Wnt-4 protein. More specifically, an analysis of the Dayhoff database (version 35.45 SwissPrat 35) evidenced significant sequence similarity between the PR0864 amino acid sequence and the following Dayhoff sequences, "WNT4 MOUSE", "WNT3 MOUSE", "WNSA HUMAN", "~VN7B MOUSE", "WN3A MOUSE", "XLU66288 1", "WN13_IiUMAN", "WNSB ORYLA", "WNT2 MOUSE", and "WN7A MOUSE". Accordingly, it is presently believed that PR0864 polypeptide disclosed in the present a~lication is a newly identified member of the Wnt-4 protein family and possesses properties typical of the Wnt-4 protein family.
36. Full-length PR0792 Polvge ides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0792. In particular, Applicants have identified and isolated cDNA
encoding a PRO792 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicants found that the PR0792 polypeptide has significant similarity to the CD23 protein. Accordingly, it is presently believed that PR0792 polypeptide disclosed in the present application is a newly identified CD23 homolog.
37. Fu! ten t~h ,Pjt0866 Poivne t~ ides The present invention provides newly ideruified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0866. In particular, Applicant's have identified and isolated cDNA
encoding a PR0866 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicants found that the PR0866 golypeptide has significant similarity to various mindin and spondin proteins. Accordingly, it is presently believed that PR0866 polypeptide disclosed in the present application is a newly identified mindin/spondin homolog.
i32 38. Full-Iengt~R0873 Poly~ptides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0871. In particular, Applicants have identified and isolated cDNA
encoding a PR0871 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicants found that the PR0871 polypeptide has significant similarity to the CyP-60 protein. Accordingly, it is presently believed that PRO871 polypeptide disclosed in the presem application is a newly identified member of the cycloghilin protein family and possesses activity typical of the cyclophilin protein family.
39. Full-length PR0873 Poiypeptides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0873. In particular; Applicants have identified and isolated cDNA
encoding a PR0873 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignmern computer programs, Applicants found that the PR0873 polypeptide has significant similarity to a human liver carboxylesterase. Accordingly, it is presently believed that PR0873 polypeptide disclosed in the present application is a newly identified tnember of the carboxylesterase family and possesses enzymatic activity typical of ttte carboxylesterase family.
40. FuTI-length PR09a0 Polyp~p '~c, The present invention provides newly identified anc3 isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0940. In particular, Applicants have identified and isolated cDNA
encoding a PR0940 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence aligntnetu computer programs, Applicants found that the PR094G
polypeptide has significant similarity to CD33 and the OB binding protein-2. Accordingly, it is presently believed that PR0940 polypeptide disclosed in the present application is a newly CD33 and/or OB binding protein-2 homolog.
41. Full-length PR0941 Polvnentides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR094I. In particular, Applicants have identified and isolated cDNA
encoding a PR0941 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence ~ computer programs, Applicants found that the PR0941 polypeptide has significant similarity to o~ or more cadherin proteins. Accordingly, it is presently believed that PRO941 polypeptide disclosed in the present application is a newly identified cadherin homolog.
42. Pttli-leng~gR0~44 Poly~gp i~
The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0944. In particular, Applicants have identified and isolated cDNA
encoding a PR0944 polypeptide, as disclosed in further detail in the Faramples below. Using BLAST and FastA
sequence alignment computer programs; App3icants found that the PR0944 polypepdde has significant similarity to the CPE-R cell surface protein. Accordingly, it is presently believed that PR0944 polypeptide disclosed in the present application is a newly identified CPE-R homolog.
43. Full-length PR0983 Polypeptides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0983. In particular, Applicants have identified and isolated cDNA
encoding a PR0983 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicants found that the PR0983 polypeptide has significant similarity to the vesicle-associated protein, VAP-33. Accordingly, it is presently believed that PR0983 polypeptide disclosed in the present application is a newly identified member of the vesicle-associated membrane protein family and possesses activity typical of vesicle-associated membrane proteins.
44. Fall-ietlgth PR01057 Polypeptides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR01057. In particular, Applicants have identified and isolated cDNA
encoding a PRO105? polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicants found that the PR01057 polypeptide has significant similarity to various protease proteins. Accordingly, it is presently believed that PR01057 polypeptide disclosed in the present application is a newly identified protease homolog:
45. Full-length PROltI71 Polypeptides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR01071. In particular, Applicants have identified and isolated cDNA
encoding a PR01071 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicants found that the PR01071 polypeptide has significant similarity to the thrombospondin protein. Accordingly, it is presently believed that PR01071 polypeptide disclosed in the present application is a newly identified thrombospondin homolog.
46. Full-length PRO't072 Polvneotides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR01072. In particular, Applicants have identified and isolated cDNA
encoding a PR01072 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicants found that the PR01072 polypeptide has significant similarity to various reductase proteins. Accordingly, it is presently believed that PR01072 polypeptide disclosed in the present application is a newly identified member of the reductase protein family.
47. Full length PR01075 Po~yoeotides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR01075. In particular, Applicants have identified and isolated cDNA
encoding a PR01075 polypeptide, as disclosed in futtkter detail in the Examples below. Using BLAST and FastA
sequence aligtunent computer programs, Applicants found that the PR01075 poiypeptide has significant similarity to protein disulfide isomerase. Accordingly, it is presently believed that PR01075 polypeptide disclosed in the present application is a newly identified member of the protein disulfide isomerase family and possesses activity typical of that family.
48. Full- enEth PRO18I PolyQeptides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PRO/81: In particular, Applicants have identified and isolated cDNA
encoding a PRO181 polypeptide, as disclosed in further detail in the Ex<lmples below. Using BLAST and FastA
sequence align~nt computer programs, Applicants found that the PR018I
polypeptide has significant similarity to the cornichon protein. Accordingly, it is presently believed that PR0181 polypeptide disclosed in the present application is a newly identified cornichon homolog.
49. Full-left hgt PR0195 Polypgptides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0195. In particular, Applicants have identified and isolated cDNA
IS et~oding a PR0195 polypeptide, as disclosed in further detail in the Examples below. The PR0195-encoding clone was isolated from a human fetal placenta library using a capping technique which selects for nucleotide sequences encoding secreted proteins. To Applicants present knowledge, the UNQl69 (DNA26847-1395) nucleotide sequence encodes a novel factor; using BLAST and FastA sequence alignment computer programs, no sequence identities to any known proteins were revealed.
50. ull-teng~,t PR0865 ~ brides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0865. In particular, Applicants have identified and isolated cDNA
encodipg a PR086r5 polypeptide, as disclosed in further detail in the Examples below. The PRO865-encoding clone was isolated from a human fetal kidney library using a trapping technique which selects for nucleotide sequences encoding secreted proteins. Thus, the PR0865-encoding clone may encode a secreted factor. To Applicants present knowledge; the UNQ434 (DNA53974-1401) nucleotide sequence encodes a novel factor; using BLAST and FastA
sequence alignment computer programs, no sequence identities to any known proteins were revealed.
51. Full-le0;gth PR0827 Polvuentides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0827. In particular, Applicants have identified and isoiaud cDNA
encoding a PR0827 polypeptide, as disclosed in fisrttter detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicants found that the PR0827 polypeptide has significant similarity to VIA-2 and various other itvegrin proteins. Accordingly, it is presently believed that PR0827 polypeptide disclosed in the present application is a novel integrin protein or splice variant thereof.

52. Full-len~h PR01114 Po~peptides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PRO/l I4. In particular, Applicants have identified and isolated cDNA
encoding a PR01114 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FasiA.
sequence alignment computer programs, Applicants found that the PRO/ I I4 polypeptide has significant similarity to the cytokine receptor family of proteins. Accordingly, it is presently believed that PROl 114 polypeptide disclosed in the present application is a newly identified member of the cytoldne receptor family of proteins and possesses activity typical of that family.
The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR01114 interferon receptor (UNQ557). In particular, cDNA encoding a PRO1I14 interferon receptor poiypeptide has been identified and isolated, as disclosed in further detail in the Examples below. It is noted that proteins produced in separate expression rounds may be given different PRO
numbers but the UNQ number is unique for any given DNA and the encoded protein, and will not be changed.
However, for sake of simplicity, in the present specification the protein encoded by DNA57033-1403 as well as all fimtter native homologues and variants included in the foregoing definition of PRO1114 interferon receptor, will be referred to as "PR01114 interferon receptor", regardless of their origin or mode of preparation.
Using the WLJ-BLAST2 sequence alignment computer program, it has been found that a full-length native sequence PR01114 interferon receptor poIypeptide (shown in Figure 142 and SEQ
ID N0:352) has sequence identity with the other known interferon receptors. Accordingly, it is presently believed that PR01114 interferon receptor possesses activity typical of other interferon receptors.
53. Full-length PR0237 Polype tn ides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR023?. In particular, Applicants have identified and isolated cDNA
encoding a PR023? polypeptide, as disclosed in filrther detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicants found that the PR0237 polypeptide has significant similarity to carbonic anhydrase. Accordingly, it is presently believed that PR0237 polypeptide disclosed in the present application is a newly identified carbonic anhydrase homolog.
5q, mil ien~rth PR0541 Poivoentides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0541. In particular, Applicants have identified and isolated cDNA
encoding a PR0541 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicants found that the PR0541 poiypeptide has significant similarity to a zrypsin inhibitor protein. Accordingly, it is presently believed that PR0541 polypeptide disclosed in the present application is a newly identified member of the trypsin inhibitor protein family.
55. fit-lenvth PRO273 Polvnentidea The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0273. In particular, Applicants have identified and isolated cDNA

encoding a PR0273 poIypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicants found that various portions of the PR02?3 polypeptide have significant sequence identity with various chemoldnes. Accordingly; it is presently believed that PR0273 polypepdde disclosed in the present application is a newly identified member of the chemokine family and possesses activity typical of the ehemolcine family.
56. Full-lenEt~R070I Polyp_eptic~es The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PRO?Ol. In particular, Applicants have identified and isolated cDNA
encoding a PR0701 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
IO sequence alignment computer programs; Applicants found that various pardons of the PR0701 polypeptide have significant homology with the neuroligins 1, 2 and 3 and esterases including carboxyesterases and acytlcholinesterases. Accordingly, it is presently believed that PR0701 polypeptide disclosed in the present app3ication is a newly identified member of the neuroligin family and is involved in mediating recognution processes between neurons andlor functions as a cell adhesin molecule as is typical of neuroligins.
IS
5?. Full-Hen~h PR0704 PolYpe The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0704. In particular, Applicants have identified and isolated cDNA
encoding a PR0704 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
20 sequence alignment computer programs, Applicants found that various portions of the PR0704 polypeptide have . significant homology with the VIP36 and GP36b. Accordingly, it is presently believed that PR0704 polypeptide disclosed in the present application is a newly identified member of the vesicular integral membrane protein family and possesses the ability to bind to sugars and cycle between the plasma membrane and the Golgi typical of this family.
58. Full length PR0706 Polvneotides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0706. In particular, Applicants have identified and isolated cDNA
encoding a PR0706 poIypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs; Applicants found that various portions of the PR0706 polypepdde have sequence identity with the human prostatic acid phosphatase precursor and the human lysosornal acid phosphatase precursor. Accordingly, ii is presently believed that PR0706 polypeptide disclosed in the present application is a newly identified member of the human prostatic acid phosphatase precursor family and possesses phosphatase typical of the acid phosphatase fatuity.
59. Full-ieng~h PR0707 PolvpgRt~des The present invention provides newly identified and isolated nucleotide sequences encoding poiypeptides referred to in the present application as PR0707. In particular, Applicants have identified and isolated cDNA
encoding a PR0707 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA

sequence alignment computer programs, Applicants found that various portions of the PR0707 polypeptide have significant homology with cadherins, particularly cadherin FIB3 found in fibroblasts. Accordingly, it is presently believed that PR0707 poiypeptide disclosed in the present application is a newly identified member of the cadherin family and possesses cell imeraction signaling typical of the cadherin family.
60. Full-length PR0322 Pojvpe~tides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0322. In particular, Applicants have identified and isolated cDNA
encoding a PR0322 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicants found that various portions of the PR0322 polypeptide have significant homology with human neuropsin, serine protease, neurosin and trypsinogen. Accordingly, it is presently believed that PR0322 polypeptide disclosed in the present application is a newly identified member of the serine protease family and possesses protease activity typical of this family. It is also believed that PRO322 is izrvoIved in hippocampal plasticity and is associated with extracellular matrix modifications and cell migrations.
61. Full-length PR0526 Pol~peptides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0526. In particular, Applicants have identified and isolated cDNA
encoding a PR0526 polypeptide, as disclosed in further detail in the Examples below: Using BLAST and FastA
sequence alignment computer programs, Applicants found that various portions of the PR0526 polypeptide have significant homology with the acid labile subunit of the insulin-like growth factor complex (ALS), as well carboxypeptidase, SLiT, and platelet glycoprotein V. Accordingly, it is presently believed that PR0526 polypeptide disclosed in the present application is a newly identified member of the leucine-repeat rich superfamily, and possesses protein-protein interaction capabilities typical of this family.
62. Full-le PR053I Polygeptides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0531. In particular, Applicants have identified and isolated cDNA
encoding a PR0531 poIypeptide, as disclosed in fiuther detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicants found that various portions of the PR0531 polypeptide have significant sequence identity and similarity with members of the cadherin superfamily, particularly, protocadherin 3. Accordingly, it is presently believed that PROS3i polypeptide disclosed in the present application is a newly imemiber of the cadherin superfamily, and is a protocadherin. PR0531 is a transmembrane protein which has extracelhtlar cadherin motifs. PRO531 is believed to be involved in cell-cell activity, in particular, cell signaling.
63. ~utl length PRO534 Polvnentides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0534. In particular, Applicants have identified and isolated cDNA
encoding a PR0534 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicants found that various portions of the PR0534 polypeptide have significant identity or similarity with the putative disulfide isomerase erp38 precursor and thioredoxin c-3.
Accordingly, it is presently believed that PR0534 polypeptide disclosed in the present application is a newly identified member of the disulfide isomerase family and possesses the ability to recognize and unscramble either intermediate or incorrect folding patterns typical of this family.
64. F~l-IenQth PR0697 lPo~ypeptides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0697. In particular, Applicants have identified and isolated cDNA
encoding a PR0697 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicants found that various portions of the PR0697 polypeptide have significant identity or similarity with sFRP-2, sFRP-1 and SARP-1, -2 and -3.
Accordingly, it is presently believed that PR0697 palypeptide disclosed in the present application is a newly identified member of the sFRP family and possesses activity related to the Wnt signal pathway.
65. Full-length PRO?I7 Pol3rpe tides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0717. In particular, Applicants have identified and isolated cDNA
encoding a PRO?I7 polypeptide, as disclosed in further detail in the Examples below. To Applicants present knowledge, the UNQ385 (DNA50988-1326} nucleotide sequence encodes a novel factor; using BLAST and FastA
sequence alignment computer programs, no significant sequence identities to airy known human proteins were revealed.
66. Full-le~,glh ~PR0731 Poly~~Qtides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0731.. 1n particular, Applicants have identified and isolated cDNA
encoding a PR073I polypeptide, as disclosed in further detail in the Examples below: Using BLAST and FastA
sequence alignment computer programs, Applicants found that various portions of the PR073I polypeptide have significant homology with the protocadherins 4, 68, 43, 42, 3, and 5.
Accordingly, it is presently believed that PR0731 polypeptide disclosed in the present application is a newly identi$ed member of the protocadherin family and possesses cell-cell aggregation or signaling activity or signal trar>sduction involvement typical of this family.
67. Full-length PR02I8 Pnlvo~ntir~~
The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0218. In particular, Applicants have identified and isolated cDNA
encoding a PR02I8 polypeptide, as disclosed in further detail in the Examples below. The PR02I8-encoding clone was isolated from a human fetal kidney library. To Applicants present knowledge, the UNQ192 (DNA30867-1335) nucleotide sequence encodes a novel factor; using BLAST and FastA sequence alignment computer programs, no significant sequence identities to any known proteins were revealed. Some sequence identity was found with ~mbrane regulator proteins, indicating that PR0218 may function as a membrane regulator.

WO 99!46281 PCTJUS99/05028 68. Full-lei3gth PR0768 Polypeptides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0768. In particular, Applicants have identified and isolated cDNA
encoding a PR0768 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
seguence alignment computer programs, Applicants found that various portions of the PR0768 polypeptide have S significant homology with integrins, including integrin 7 and 6.
Accordingly, it is presently believed that PR0768 polypeptide disclosed in the present application is a newly identified member of the integrin family, either a homologue or a splice variant of integrin 7, and is involved with cell adhesion and communication between muscle cells and the extraceIlular matrix.
69. Full-leneth PR077I PolYpeptides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR077I. In particular, Applicants have identified and isolated cDNA
encoding a PR0771 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicants found that various portions of the PR0771 polypeptide have significant sequence identity and similarity with testican. Accordingly, it is pxesently believed that PR0771 polypeptide disclosed in the present application is a newly identified member of the testican family and possesses cell signaling, binding, or adhesion properties, typical of this family.
70. Full-length PR0733 Polvoentides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0733. In particular, Applicants have identified and isolated cDNA
encoding a PR0733 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicants found that various portions of the PRO733 polypeptide have significant sequence identity with the Tl/ST receptor binding protein.
Accordingly, it is presently believed that PR0733 poIypeptide disclosed in the present application is a newly identified member of the interleukin-like family binding proteins which may be a cytokine and which may be involved in cell signaling. It is believed that PRO733 is an ApoAIV homologue.
71. ~ 1_i lllenE"th,~'R0162 Polppeptides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0162. In particular., Applicants have identified and isolated cDNA
encoding a PR0162 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicants found that various portions of the PR0162 polypeptide have sigoi$cant homology with human pancreatitis-associated protein (PAP).
Applicants have also found that the DNA
encoding the PR0162 polypeptide has significant homology with bovine lithosiathine precursor and bovine pancreatic thread protein (PTP). Accordingly, it is presently believed that PR0162 polypeptide disclosed in the present application is a newly identified member of the pancreatitis-associated protein family and possesses activity typical of the paricreatitis-associated protein family.
i40 WO 99/46281 PCTlUS99/05028 72. dull-lgnpth PR0788 Polypeptides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0788. In particular; Applicants have identified and isolated cDNA
encoding a PRO788 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicatus found that various portions of the PR0788 polypeptide have significant homology with the anti-neoplastic urinary protein. Applicants have also found that the DNA encoding the PR0788 polypeptide has significant homology with human E48 antigen, human component B protein, and human prostate stem cell antigen. Accordingly, it is presently believed that PR0788 polypeptide disclosed in the present application is a newly identified member of the anti-neoplastic urinary protein family and possesses anti-neoplastic activity typical of the anti-neoplastic urinary protein family.
73. Full-length PR01008 Polype ides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR01008. In particular, Applic,~nts have identified and isolated cDNA
encoding a PR01008 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicants found that various portions of the PR01008 polypeptide have significant sequence identity and similarity with mouse dkk-1 (mdkk-i).
Accordingly, it is presently believed that PROI008 polypeptide disclosed in the present application is a newly identified member of the dlck-1 family and possesses head inducing activity typical of this family.
74. Full-length PROl0I2 Poiypeptic~es The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR01012. In particular, Applicants have identified and isolated cDNA
encoding a PR01012 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicants found that various portions of the PROl0i2 polypeptide have sequence identity with disulfide isomerase. Accordingly, it is presently believed that PR01012 polypeptide disclosed in the present application is a newly identified member of the ER retained protein family and possesses activity related to the processing, production andior folding of polypeptides typical of the disulfide isotr~erase family.
75. Full-lepgth P1It01014 Polype,Rti~s The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR01014. In particular, Applicants have identified and isolated cDNA
encoding a PR01014 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicants found that various portions of the PROi0i4 polypeptide have sequence identity with reductase and dehydrogenase. Accordingly, it is presently believed that PR01014 polypeptide disclosed in the present application is a newly identified member of the reductase super family and possesses reduction capabilities typical of this family.

76. Full-Ienglh PR01017 PoiyPeptides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR01017. In particular, Applicants have identified and isolated cDNA
encoding a PR01017 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicants found that various portions of the PR01017 polypeptide have sequence identity with HNK-I sulfotransferase. Accordingly, it is presently believed that PR01017 polypeptide disclosed in the present application is a newly identified ember of the HNK-I
sulfotransferase family and is involved with the synthesis of HNK-1 carbohydrate epitopes typical of this family.
77. Full-length PR0474 Polypeptides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0474. In particular, Applicants have identified and isolated cDNA
encoding a PR0474 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence aligtunent computer programs, Applicants found that various portions of the PR0474 polypeptide have sequence identity with dehydrogenase, glucose dehydrogenase and oxidoreductase. Accordingly, it is presently believed that PRO474 polypeptide disclosed in the present application is a newly identified member of the dehydrogenase family and is involved in the oxidation of glucose.
78. Full-length PR01031 Polvp~ptides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PRO1031. In particular, Applicants have identified and isolated cDNA
encoding a PR01031 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicants found that various portions of the PRO1031 polypeptide have ~quenoe identity with IL 17 and CTLA-8. Accordingly, it is presently believed that PR01031 polypeptide disclosed in the present application is a newly identified member of the cytoldne family and thus may be involved in inflammation and/or the immune system.
79. ~uil-leneth PRO938 Polv~,eotides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0938. In particular; Applicants have identified and isolated cDNA
encoding a PR0938 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence aligz>rnent computer programs, Applicants found that the PR0938 polypeptide has significant similarity to protein disulfide isomerase. Accordingly, it is presently believed that PR0938 polypeptide disclosed in the present application is a newly identified member of the thioredoxin family proteins and possesses activity typical of protein disulfide isomerase.
gp_ ~ ~11_ip IZ,)iR 10 X82 P_oivneotides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR01082. In particular, Applicants have identified and isolated cDNA
encoding a PR01082 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA

WO 99/46281 PCTlU599/0502$
sequence alignment computer programs, Applicants found that various portions of the PR01082 polypeptide have sequence identity with a lectin-like oxidized LDL receptor appearing in the database as "AB010710~1 ". Accordingly, it is presently believed shat PR01082 poiypeptide disclosed in the present application is a newly identified member of the LDL receptor family.
81. Full-length PR01083 PoiyRe_ptides The present invention provides newsy identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR01083. In particular, Applicants have identified and isolated cDNA
encoding a PR01083 polypeptide, as disclosed in further detail in the Examples below. The PROI083-encoding clone was isolated from a human fetal kidney library using a trapping technique which selects for nucleotide sequences encoding secreted proteins. To Applicants present knowledge, the UNQ540 (DNA50921-1458) nucleotide sequence encodes a novel factor; using BLAST and FastA sequence alignment computer programs, some sequence identity with a 7TM receptor; latrophilin related protein l and a macrophage restricted cell surface glycoprotein was shown. The kinase phosphorylation site and G-coupled receptor domain shown in Figure 204 indicate that PR01083 is a novel member of the 7TM receptor superfamily.
82. Full-leng~,h PR0200 Pq,~yoentides The present invention provides newly identified and isolated nucleotide sequences encoding polypepiides referred to in the present application as VEGF-E: In particular; Applicants have identified and isolated cDNA
encoding a VEGF-E palypepGde, as disclosed in further detail in the Examples below. Using BLAST sequence alignment computer programs, Applicants found that the VEGF-E polypeptide has significant homology with VEGF
arnl bone morghogenetic protein 1. In particular, the cDNA sequence of VEGF-E
exhibits 24~ amino acid similarity with VEGF and has structural conservation. In addition, VEGF-E contains a N-terminal half which is not present in VEGF and that has 28~ homology to bone morphogenetic protein 1.
83. Full-iength~,~0~85 and ~~~,poJ nodes The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0285 and PR0286 In particular, Applicants have identified and isolated cDNAs encoding PR0285 and. PRO286 poiypeptides, as disclosed in further detail in the Examples below. Using BLAST and FastA sequence alignment computer programs, Applicants found that the coding sequences of PR0285 and PR0286 are highly homologous to DNA sequences HSU88540 I, HSU88878_l, HSU88879 1, HSU88880 1, and HSU88881 1 in the GenBank database.
Accordingly, it is presently believed that the PR0285 and PR0286 proteins disclosed in the present application are newly identified human homologues of the Drosophila protein Toll, and are likely to play an important role in adaptive immunity. More specifically, PR0285 and PR0286 may be involved in inflammation, septic shock, and response to pathogens, and play possible roles in diverse medical conditions that are aggravated by immune response, such as, for example, diabetes, ALS, cancer, rheumatoid arthritis, and ulcers. The role of PR0285 and PR0286 as pathogen pattern recognition receptors, sensing the presence of conserved molecular structures present on microbes, is further supported by the data disclosed in the present application, showing that a known human Toll-like receptor, TLR2 is a direct mediator of LPS signaling.

84. Full-length PR0213-1. PR013 0 and PR01449 Polypeptides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0213-I, PR01330 and/or PR01449. In particular, cDNA encoding a PR0213-I, PROi330 and/or PR01449 polypeptide has been identified and isolated, as disclosed in further detail in the Examples below. It is noted that proteins produced in separate expression rounds may be given different PRO
numbers but the UNQ number is unique for any given DNA and the encoded protein, and will not be changed.
However, for sake of simplicity, in the present specification the protein encoded by DNA30943-1 I63-1, DNA64907-1163-1 and DNA64908-1163-1 as well as all further native homologues and variants included in the foregoing definition of PR0213-1, PR01330 and/or PR01449, will be referred to as "PR0213-1, PR01330 andlor PR01449", regardless of their origin or mode of preparation.
85. Full-length PR0298 Poivventides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as FR0298. (It is noted chat PR0298 is an arbitrary designation of a protein encoded by the nucleic acid shown in Figure 218, SEQ ID NO: 514, and having the amino acid sequence shown in Figure 219, SEQ ID NO:515. Further proteins having the same amino acid sequence but expressed in different rounds of expression, may be given different "PRO" numbers.) In particular, Applicants have identified and isolated cDNA encoding a PRQ298 polypeptide, as disclosed in further detail in the Examples below. Using BLASTX 2.Oa8MP-WashU computer program, socring parameters:
T=12, S=68, S2=36, Matrix: BLOSUM62, Applicants found that the PR0298 protein specifically disclosed herein shows a limited {27-38%) sequence identity with the following sequences found in the GenBank database: S59392 (probable membrane protein YLR246w - yeast); 558154 (hypothetical protein SPAC2F7.10 - yeast); CELF33D11 9 (F33D11.9b _- Caenorhabditis elegans); Y041 CAEEL (hypothetical 68.7 kd protein zk75?.1); CEAC3 5 (AC3.4 Caenorhabditis elegans); 552691 (probable transmembrane protein YDR126w -yeast); ATT12H17_14 (protein Arabidopsis _thaliana); S55963 (probable membrane protein YNL326c - yeast);
CELC43H6 2 (C43H6.7 Caenorhabditis elegans); TM018A10 14 (A TM018A10.8 - Arabinosa thaliana).
86. Full leneth PR0337 Polvneotides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR033?. In particular, Applicants have identified and isolated cDNA
encoding a PR0337 polypeptide, as disclosed in further detail in the Examples below. Using BLAST, BLAST-2 and FastA sequence alignment computer programs, Applicants found that a full-length native sequence PR0337 has 97 %
amino acid sequerxe identity with rat neurotrimin, 85% sequence identity with chicken CEPU, 7386 sequence identity with chicken G55, 59°k homology with human LAMP and 84% homology with human OPCAM. Accordingly, it is presently believed that PR0337 disclosed in the present application is a newly identified member of the IgLON
sub family of the immunoglobulin superfamily and may possess neurite growth and differentiation potentiating properties.

87. Full-IenEth P1,~0403 Polvoeotldes The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0403. In particular, Applicants have identified and isolated cDNA
encoding a PR0403 polypeptide, as disclosed in further detail in the Examples below. Using a BLAST, BLAST-2 and FastA sequence alignment computer programs, Applicants found that a full-length native sequence PR0403 has 94% identity to bovine ECE-2 and 64% identity to human ECE-1. Accordingly is presently believed that PR0403 is a new member of the ECE protein family and may posses ability to catalyze the production of active endothelin.
88. PRO Poiypgptide Variants In addition to the full-length native sequence PRO polypep;ides described herein, it is contemplated that PRO
polypeptide variants can be prepared. PRO polypeptide variants can be prepared by introducing appropriate nucleotide changes into the PRO polypeptide DNA, or by synthesis of the desired PRO polypeptide. Those skilled in the art will appreciate that amino acid changes may alter post translational processes of the PRO polypeptides, such as changing the number or position of glycosylation sites or altering the membrane anchoring characteristics.
Variations in the native full-length sequence PRO polypeptides or in various domains of the PRO
polypeptides described herein; can be made, for example, using any of the techniques and guidelines for conservative and non-conservative mutations set forth, for instance, in U,S. Patent No.
5,364,934. Variations may be a substitution, deletion or insertion of one or more codons encoding the PltO
polypeptide that results in a change in the amino acid sequence of the PRO polypeptide as compared with the native sequence PRO polypeptide. Optionally the variation is by substitution of at least one amino acid with arty other amino acid in one or more of the domains of the PRO polypeptide. Guidance in determining which amino acid residue may be inserted, substituted or deleted without adversely aff~ting the desired activity may be found by comparing 'the sequence of the PRO poIypeptide with that of homologous known protein molecules and minimizing the number of amino acid sequence changes made in regions of high homology. Amina acid substitutions can be the result of replacing one amino acid with another amino acid having similar sttnctural andlor chemical properties; such as the replacement of a leucine with a serine, i.e., conservative amino acid replacements. Insertions or deletions may optionally be in the range of 1 to 5 amino acids.
The variation allowed may be determined by systematically making insertions, deletions or substitutions of amino acids in the sequence and testing the resulting variants for activity in the in vitro assay described in the Examples below.
In particular embodiments, conservative substitutions of interest are shown in Table I under the heading of preferred substitutions. If such substitutions result in a change in biological activity, then more substantial changes, denominated exemplary substitutions in Table I , or as further described below in reference to amino acid classes, are introduced and the products screed.

Tab a 1 Original Exemplary Preferred Res' a Substitutions substitutions S Ala (A) vai; leu; ile val Arg (R) lys; gln; asn lys Asn (N) gln; his; lys; arg gln Asp (D) glu gIu Cys (C) ser ser 10Gln (Q) asn asn Glu {E) asp asp Gly (G) pro; ala ala His (H) asn; gln; lys; arg arg De (1] leu; val; met; ala; phe;

15 norleucine leu Leu (L) norleucine; ile; val;

met; ala; phe ile Lys (K) arg; gln; asn arg l~let (M) leu; phe; ile leu 20Phe (F) leu; val; ile; ala; tyr leu Pro (P) ala ala Ser (S) thr thr Thr (T) ser ser Trp t;W) tyr; phe tyr 25Tyr (1~ trp; phe; thr; ser phe Va1 (V) ile; leu; met; phe;

aIa; norleucine leu Substantial modifications in function or immunoIogical identity of the PRO
polypeptide are accomplished 30 by selecting substitutions that differ significantly in their effect on maintaining (a) the structure of the polypeptide backbone in the area of the substitution, for example, as a sheet or helical conformation, (b) the charge or hydrophobicity of the molecule at the target site, or (c) the bulk of the side chain. Naturally occurring residues are divided into groups based on common side-chain properties:
(1) hydrophobic: norleucine, met, ala, vai, leu, ile;
35 (2) neutral hydrophilic: cys, ser, thr;
(3) acidic: asp, glu;
(4) basic: asn, gin, his, lys, arg;
(5) residues that influence chain orientation: gly, pro; and (6) aromatic: trp, tyr, phe.
40 Non-conservative substitutions will entail exchanging a member of one of these classes for another class.
Such substituted residues also tray be introduced into the conservative substitution sites or, more preferably, into the remaining (non-conserved) sites.
The variations can be made using methods known in the an such as oligonucleotide-mediated (site-directed) mutagenesis, alanine scanning, and PCR mutagenesis. Site-directed mutagenesis [Carter et al., Nucl. Acids Res.;
45 x:4331 (i98~; Zoller et al., Nucl. Acids Res., ~Q:6487 (1987)], cassette mutagenesis [Wells et al., Gene, x:315 (1985)], restriction selection mutagenesis [Wells et al., Plilos. Trans. R.
Soc. London SerA, x:415 (1986)) or other known techniques can be performed on the cloned DNA to produce the desired PRO
polypeptide variant DNA.

Scanning amino acid analysis can also be employed to identify one or more amino acids along a contiguous sequence. Among the preferred scanning amino acids are relatively small, neuual amino acids. Such amino acids include alanine, glycine, serine, and cysteine. Alanine is typically a preferred scanning amino acid among this group because it eliminates the side-chain beyond the beta-carbon and is less likely to alter the main-chain conformation of the variant. Alanitte is also typically preferred because it is the most common amino acid. Further, it is frequently found in both buried and exposed positions [Creighton, 'the Protgins, (W.H.
Freeman & Co., N.Y.); Chothia, J.
of B'o , 250:1 (1976)]. If alanine substitution does not yield adequate amounts of variant, an isoteric amino acid can be used.
89. Modif~,ations of ]:'RO~o"~y~e tn id_es_ Covalent modifications of PRO polypeptides are included within the scope of this invention. One type of covalent modification includes reacting targeted amino acid residues of the PRO polypeptide with an organic derivatiz5ng agent that is capable of reacting with selected side chains or the N- or C- terminal residues of the PRO
polypeptide. Derivatization with bifunctional agents is useful, for instance, for crosslinlting a PRO polypeptide to a vrater-insoluble support matrix or surface for use in the method for purifying anti-PRO polypeptide antibodies, and vice versa. Commonly used crosslinking agents include, e.g. , 1,1-bis(diaroaceryl)-2-phenylechane, glutaraldehyde, N-hydroxysuccinurude esters, far example, esters with 4-azidosalicylic acid, homobifunctional imidoesters, including disuccinimidyl esters such as 3,3'-dithiobis(succinimidylpropionate), bifunctional maleimides such as bis-N-maleimido-1,8-octane and agents such as methyl-3-[(p-azidophenyl)dithio]propioimidate.
Other modifications include deamidation of glutaminyI and asparaginyl residues to the corresponding glutamyl and aspartyl residues, respectively, hydroxylation of proline and lysine, phosphorylation of hydroxyl gmups of seryl or threonyl residues, methylation of the a-amino groups of lysine, arginine, and histidine side chains j3'.E.
Creightoa, Proteins' Strucnire and Molecular Propertiet, W.H. Freeman & Co., San Francisco, pp. 79-86 (1983)], acetylation of the N-terminal amine, and amidation of any C-terminal carboxyl group.
Another type of covalent modification of the PRO polypeptides included within the scope of this invention comprises altering the native gIycosyIation pattern of the polypeptide.
"A,ltering the native glycosylation pattern" is intended for purposes herein to mean deleting one or more carbohydrate moieties found in a native sequence PRO
polypeptide, and/or adding one or more glycosylation sites that are not present in the native sequence PRO
polypeptide, and/or alteration of the ratio andlor composition of the sugar residues attached to the glycosylation site(s).
Addition of glycosylation sites to the PRO polypeptide may be accomplished by altering the amino acid sequence. The alteration may be made, for example, by the addition of; or substitution by; one or more serine or threottine residues to the r~dve sequence PRO polypeptide (for O-linked glycosylation sites). The PRO polypeptide amino acid sequence may optionally be altered through changes at the DNA
level, particularly by mutating the DNA
eroding the PRO polypeptide at preselected bases such that codons are generated that will translate into the desired amino acids.
Another means of increasing the number of carbohydrate moieties on the PRO
polypeptide polypeptide is by chemical or enzymatic coupling of glycosides to the polypeptide. Such methods are described in the art, e.g., in WO 87/45330 published 11 September 1987, and in Aplin and Wriston, CRC Crit.
Rev. Biochem., pp. 259-306 (1981).

WO 99146281 PCT/US99l05028 Removal of carbohydrate moieties present on the PRO polypeptide may be accomplished chemically or enzymatically or by mutational substitution of codons encoding for amino acid residues that serve as targets for glycosylation. Chemical deglycosylation techniques are known in the art and described, for instance, by Hakimuddin, et al., Arch. Biochem. Bionhvs., 25:52 (1987) and by Edge et al., Anal.
Biochem., ,[ 18:131 (198I). Enzymatic cleavage of carbohydrate moieties on poiypeptides can be achieved by the use of a variety of endo- and exo-glycosidases as described by Thotakura et al., Meth. Enz~ol., L8_:350 (1987).
Another type of covalent modification of PRO polypeptides of the invention comprises linking the PRO
polypeptide to one of a variety of nonproteinaceous polymers, e.g., polyethylene glycol, polypropylene glycol, or polyoxyalkylenes, in the manner set forth in U.S. Patent Nos. 4,640,835;
4,496,689; 4,301,144; 4,670,417;
4,791,192 or 4,179,337.
The PRO polypeptides of the present invention may also be modified in a way to form a chitneric molecule comprising a PRO polypeptide fused to another, heterologous polypeptide or amino acid sequence. In one embodiment, such a chimeric molecule comprises a fusion of the PRO poiypeptide with a tag polypeptide which provides an epitope to which an anti-tag antibody can selectively bind. The epitope tag is generally placed at the amino- or carboxyl- terminus of the PRO polypeptide. The presence of such.
epitope-tagged forms of the PRO
polypegtide can be detected using an antibody against the tag polypeptide:
Also, provision of the epitope tag enables the PRO polypeptide to be readily purified by affinity purification using an anti-tag antibody or another type of affinity matrix that binds to the epitope tag. In an alternative embodiment, the chimeric molecule may comprise a fusion of the PRO polypeptide with an immunoglobulin or a particular region of an immunoglobulin. For a bivalent form of the chitneric molecule, such a fusion could be to the Fc region of an IgG
molecule.
Various tag polypeptides and their respective antibodies are well iatown in the art. Examples include poly-histidine (poly-his) or poly-histidine-glycine (poly-his-gly) tags; the flu HA
tag polypeptide and its antibody 12CA5 [Field et al., Mol. Cell. Biol., $:2159-2165 (1988)]; the c-myc tag and the 8F9, 3C7, 6E10, G4, B7 and 9E10 antibodies thereto [Evan et al., Iy olecula~ and Cellular Biology, x:3610-3b16 (1985)]; and the Herpes Simplex virus glycoprotein D (gD) tag and its antibody [Paborsky et al., Protein Engineering, 3_(6):547-553 (1990)]. Other tag polypeptides include the Flag-peptide [Hopp et al., BioTechnoloQV, _6:1204-1210 (1988)]; the KT3 epitope peptide [Martin et al" Science, X55:192-194 (1992)]: an a tubulin epitope peptide [Skinner et al., J. Biol. Chem., 2~6:15163-15166 (1991)]; and the T7 gene 10 protein peptide tag [Iutz-Freyermuth et al., Proc. Natl Acad.Sci.USA, 87:6393-6397 (1990)].
90. P~paration of PRO Polypentides The description below relates primarily to production of PRO polypeptides by culturing cells transformed or transfected with a vector containing the desired PRO polypeptide nucleic acid. It is, of course, contemplated that alternative methods, which are well known in the art, may be employed to prepare the PRO polypeptide. For instance, the PRO poIypeptide sequence, or portions thereof, may be produced by direct peptide synthesis using solid-phase techniques [see, e.g., Stewart et aL, Solid-Phase Peptide Synthesis, W.H. Fzeeman Co., San Francisco, CA
(1969); Merrifield, ~ Am. Chem. Soc., $5_:2149-2134 (1963)]. In vitro protein synthesis may be performed using manual techniques or by automation. Automated synthesis may be accomplished, for instance, using an Applied Biosystems Peptide Synthesizer (Foster City, CA) using manufacturer's instructions. Various portions of the desired PRO polypeptide may be chemically synthesized separately and combined using chemical or enzymatic methods to produce the full-length PRO polypeptide.
A. Isolation of DATA, Encoding_PRO Poly~e~ides DNA encoding PRO polypeptides may be obtained from a cDNA library prepared from tissue believed to possess the desired PRO polypeptide mRNA and to express it at a detectable level. Accordingly, human PRO
polypeptide DNA can be conveniently obtained from a cDNA library prepared from human tissue, such as described in the Examples. The PRO poiypeptide-encoding gene may also be obtained from a genotnic library or by oligonucleotide synthesis.
Libraries can be screened with probes (such as antibodies to the desired PRO
polypeptide or oligonucleotides of at least about 20-80 bases) designed to identify the gene of interest or the protein encoded by it. Screening the cDNA or genomic library with the selected probe may be conducted using standard procedures, such as described in Sambrook et al., Mole~ul3r ~,loning.: A I,aborator~Njgnual (New York: Cold Spring Harbor Laboratory Press, 1989). An alternative means to isolate the gene encoding the desired PRO
polypeptide is to use PCR methodology [Sambrook et al., supra; Dieffenbach et al., PGR Primer:A I,a~oratorv Manual (Cold Spring Harbor Laboratory Press, 1995)).
The Examples below describe techniques for screening a cDN.A library. The oligonucleotide sequences selected as probes should be of sufficient length and suiBciently unambiguous that false positives are minimized. The oligonucleotide is preferably labeled such that it can be detected upon hybridization to DNA in the library being screened. Methods of labeling are well known in the art, and include the use of radiolabels like ~P-labeled ATP, biotitrylation or enzyme labeling. Hybridization conditions, including moderate stringency and high stringe~y, are provided in Sambrook et al., supra.
Sequences identified in such library screening methods can be compared and aligned to other known sequences deposited and available in public databases such as GenBank or other private sequence databases.
Sequence identity (at either the amino acid or nucleotide level) within defined regions of the molecule or across the full-length sequence can be determined through sequence alignment using computer software programs such as BLAST, ALIGN; DNAstar, and INHERIT which employ various algorithms to measure homology.
Nucleic acid having protein coding sequence may be obtained by screening selected cDNA or genomic libraries using the deduced amino acid sequence disclosed herein for the first time, and, if necessary; using conventional primer extension procedures as descn'bed in Sambrook et al., a r , to detect precursors and processing intermediates of mRNA that may not have been reverse-transcribed into cDNA.
B. Sglg~ion and nsfor~~tion of Host Cells Host cells are transfected or transformed with expression or cloning vectors descn'bed herein for PRO
polypeptide production and cultured in conventional nutrient media modified as appropriate for inducing promoters, selecting uansformatus, or amplifying the genes encoding the desired sequences. The culture conditions, such as media, temperature, pH and the like, can be selected by the skilled artisan without endue experimentation. In general, principles, protocols, and practical techniques for maximizing the productivity of cell cultures can be found in Mammali~gCel~Biotechnology a Practical Ap rp oach, M. Butler, ed. (/R1, Press, 1991) and Satnbrook et al:, WO 99!46281 PCTlUS99l05028 Methods of transfection are known to the ordinarily sidlled artisan, for example, CaPO, and electroporation.
Depending on the host cell used, transforntation is performed using standard techniques appropriate to such cells.
The calcium treatment employing calcium chloride, as described in Sambrook et al., suvra, or electroparation is generally used for prokaryotes or other cells that contain substantial cell-waft barriers. Infection with Agrobacterium tumefaciens is used for transformation of certain plant cells, as described by Shaw et al., Gene, 2_x:315 (I983) and WO 89105859 published 29 June 1989. For martunalian cells without such cell walls, the calcium phosphate precipitation method of Graham and van der Eb, ViroloQV, X2_:456-457 (1978) can be employed. General aspects of mammalian cell host system transformations have been described in U.S.
Patent No. 4,399,216. Transformations into yeast are typically carried out according to the method of Van Solingen et al., 3.- Bact., 130:946 (1977) and Hsiao et al:, Proc. Nat!. Acad. Sci. (USA), 76:3829 (1979). However, other methods for introducing DNA into cells, such as by nuclear microinjection, electroporation, bacterial protoplast fusion with intact cells, or polycations, e.g. , polybrene, polyornithine, may also be used. For various techniques for transfonttirtg mammalian cells, see Keown et al., Methods,~n Enzy~ology, 185:527-537 (1990) and Mansour et al., Nature, 336:348-352 (1988).
Suitable host cells for cloning or expressing the DNA in the vectors herein include prokaryote, yeast, or higher eukaryote cells. Suitable prokaryotes include but are not limited to eubacteria, such as Gram-negative or Gram-positive organisms, for example, Enterobacteriaceae such as E. coti.
Various E. coli strains are publicly available, such as E. coli,Kl2 swain MM294 (ATCC 31,446); E. coti X1776 (ATCC
31,537); E. toll strain W31I0 (ATCC 27,325) and KS 772 (ATCC 53,635): Other suitable prokaryotic host cells include Enterobacteriaceae such as Escherichia, e.g., E. toll, Enterobaaer, Erwinia, Klebsietla, Proteus, Salmonella, e.g., Salmonella typhimurium, Serraria, e.g., Serratia marcescans, and Shigetia, as well as Bacilli such as B. subtilis and B. licheniformis (e.g., B.
licheniformis 41P disclosed in DD 266,710 published I2 April 1989), Pseudomonas such as P. aeruginasa, and Streptomyces. Various E. toll strains are publicly available, such as E. toll KI2 strain MM294 (ATCC 31,446); E.
toll XI776 (ATCC 31,537); E. toll strain W3110 (ATCC 27,325); and KS ?72 (ATCC
53,635). These examples are illustrative rather than limiting. Strain W3110 is one particularly preferred host or parent host because it is a common host strain for recombinant DNA product fermentations. Preferably, the host cell secretes minimal amounts of proteolytic enzymes. For example, strain W3110 may be modified to effect a genetic mutation in the genes ettcoditlg proteins endogenous to the host, with examples of such hosts including E. toll W3110 strain 1A2, which has the complete genotype tonA ; E. toll W3110 swain 9E4, which has the complete genotype tonA ptr3; E. toll W3110 strain 27C7 (ATCC 55,244), which has the complete genotype tonA ptr3 phoA E15 (argF tac)169 degP
ompT kan ; E. toll W3110 strain 37D6, which has the complete genotype tonA
ptr3 phoA EIS (argF tac)169 degP
ompT rbs7 itvG kan'; E. toll W3110 sttaiw40B4, which is strain 37D6 with a non-kattamycin resistant degP deletion mutation; and an E. toll strain having mutant periplasmic protease disclosed in U.S. Patent No. 4,946,783 issued 7 August 1990. Alternatively, in vitro methods of cloning, e.g., PCR or other nucleic acid polymerase reactions, are suitable.
In addition to prokaryotes, eukaryotic nvcrobes such as filamemous fungi or yeast are suitable cloning or expression hosts for PRO polypeptide-encoding vectors: Saccharomyces cerevisiae is a commonly used lower eukaryotic host microorganism. Others include Schizosaccharomyces pombe (Beach and Nurse, Nature-, ~: 140 [1981); EP 139,383 published 2 May 1985); Kluyveromyces bolts (U.S. Patent No.
4,943,529; Fleer et at., BiofTechnology, Q: 968-975 (1991)) such as, e.g., K. tacos (MW98-8C, CBS683;
CBS45?4; Louvencourt et at., J
B~teriol., 737 [1983]), K.,fragitis (ATCC 12,424), K, bulgaricus (ATCC
16,045), K. wickeramii (ATCC 24,178), K waltii (ATCC 56,500); K. drosophilarum (ATCC 36,906; Van den Berg et u1., BioITechnoioev, $: 135 (1990)), K. thennotolerans, and K. marxianus; ynrrowia (FP 402,226); Piehia paswris (EP
183,070; Sreekrishna et al., ~.
Basic 1 icrobiol., ~: 26S-278 [1988)); Candida; Trichoderma reesia (EP
244,234); Neurospora crassa (Case et al., Proc. Natl. Acad. Sci. USA, ?6: 5259-5263 [1979]); Schwanniomyces such as Schwanniomyces occidentalis (EP
394,538 published 31 October 1990); and filamentous fungi such as, e.g., Neurospora, Penicillium, Tolypocladium (WO 91100357 published i0 January 1991), and Aspergillus hosts such as A.
nidulans fBallance et al., Bioc a Biophys. Res. Colruxn~~, 112: 284-289 [1983]; Tiiburn et al., a e, 26: 205-221 [1983]; Yelton et al., Prod Natl.
Aca~, Sei. USA, 81: 1470-1474 [1984]) and A. niger (Kelly and Hynes, EIvJ$O
J., 4_: 475-479 [1985]).
Methylotropic yeasts are suitable herein and include, but are not limited to, yeast capable of growth on methanol selected from the genera consisting of Hansenula, Candida, Kloeckera, Pichia, Saccharomyces, Torulopsis, and Rhodotorula. A list of specific species that are exemplary of this class of yeasts may be found in C. Anthony, ie Biochemistry of Mgt3ly otronhs, 269 (I982).
Suitable host cells for the expression of glycosylated PRO polypeptides are derived from tnulticelluiar organisms. Examples of invertebrate cells include insect cells such as Drosophila S2 and Spodoptera Sf9, as well.
as plant cells. Exazrtples of useful mammalian host cell lines include Chinese hamster ovary (CHO) and COS cells.
More specific examples itxlude monkey kidney CV1 line transformed by SV40 (COS-7, ATCC CRL 1651); human embryonic kidney line (293 or 293 cells subcloned for growth in suspension culture, Graham et al., J. Gen Virol., $6_:59 (19'17)); Chinese hamster ovary cells!-DHFR (CHO, Urlaub and Chasin, Proc. Natl. Acad. Sci. USA, ?7:4216 (1980)); fuse sertoli cells fTM4, Mather, Bioj~R, X3_:243 251 (1980)); human lung cells (W138, ATCC CCL
75); human liver cells (Hep G2, HB 8065); and mouse mammary tumor (MMT 060562, ATCC CCL51). The selection of the appropriate host cell is deemed to be within the skill in the art.
C. Selection and Use of a Realicab a Vector The nucleic acid (e.g., cDNA or genomic DNA) encoding a desired PRO
polypeptide may be inserted into a repHcable vector for cloning (amplification of the DNA) or for expression.
Various vectors are publicly available.
The vector may, for example, be in the form of a plasmid, cosmid, viral particle, or phage. The appropriate nucleic acid sequence may be izLCerted into the vector by a variety of procedures. In general, DNA is inserted into an appropriate restriction endonuclease sice(s) using techniques known in the art. Vector components generally include, but are not limited to, one or more of a signal sequence, an origin of replication, one or more marker genes, an enharxrer element, a promoter, and a transcription termination sequence.
Construction of suitable vectors containing one or more of these components employs standard ligation techniques which are latown to the skilled artisan.
The PRO polypeptide of interest may be produced recombinantly not only~directly, but also as a fusion polypeptide with a heterologous polypeptide, which may be a signal sequence or other polypegtide having a specific cleavage site at the N-terminus of the mature protein or polypeptide. In general, the signal sequence may be a carnponettt of the vector, or it may be a part of the PRO polypeptide DNA chat is inserted into the vector. The signal sequence may be a prokaryotic signal sequence selected, for example, fi om the group of the alkaline phosphatase, penicillittase, ipp, or heat-stable enterotoxin Il leaders. For yeast secretian the signal sequence may be, e.g., the yeast invenase leader, aipha factor leader (including Saccharomyces and Kluyveromyces a-factor leaders, the latter described in U.S. Patent No. 5,010,182), or acid phosphatase leader, the C.
albicans glucoamylase leader (EP
362,179 published 4 April 1990), or the signal described in WO 901'13646 published 15 November 1990. In WO 99!46281 PCT/US99105028 ntarttrttaIian cell expression, mammalian signal sequences may be used to direct secretion of the protein, such as signal sequences from secreted polypeptides of the same or related species, as well as viral secretory leaders.
Both expression and cloning vectors contain a nucleic acid sequence that enables the vector to replicate in one or more selected host cells. Such sequences are well known for a variety of bacteria, yeast, and viruses. The origin of replication from the plasmid pBR322 is suitable for most Gram-negative bacteria, the 2~c plasmid origin is suitable for yeast, and various viral origins (SV40, poIyoma, adenovirus, VSV
or BPV) are useful for cloning vectors in matttrrtalian cells.
Expression and cloning vectors will typically contain a selection gene, also termed a selectable marker.
Typical selection genes encode proteins that (a) confer resistance to antibiotics or other toxins, e.g" ampicillin, neomycin, methotrexate, or tetracycline> (b) complement auxotrophic deficiencies, or (c) supply critical nutrients not available from complex media, e.g., the gene encoding D-alutine racemase for Bacilli.
An example of suitable selectable markers for mammalian cells are those that enable the identification of cells competent to take up the PRO polypeptide nucleic acid, such as DHFR or thymidine kinase. An appropriate host cell when wild-type DHFR is employed is the CHO cell line deficient in DHFR activity, prepared and propagated as described by Urlaub et al., Proc. Nat!. Acid. Sci. USA, 77:4216 .(1980). A suitable selection gene for use in yeast is the trill gene present in the yeast plasmid YRp7 [Stinchcomb et al., attire, 282:39 (1979);
Kingsman et al., C~eng, 7:141 (1979); Tschemper et al., Gene, 10:157 (1980)].
The trill gene provides a selection marker for a mutant strain of yeast lacking the ability to grow in tryptophan, for example, ATCC No. 44076 or PEP4-1 [Jones, Genetics, $5:12 (1977)].
Expression and cloning vectors usually contain a promoter operably linked to the PRO polypeptide nucleic acid sequence to direct mRNA synthesis. Promoters recognized by a variety of potential host cells are well known.
Promoters suitable for use with prokaryotic hosts include the (3-lactamase and lactose promoter systems [Chang et al., atur , 275:615 (1978}; Goeddel et ii., N- attire, 281:544 (1979)], alkaline phosphatase, a tryptophan (trp) promoter system [Goeddel, ,~l.~cke'c Acids Res., 8_:4057 (1980); EP 36,776], and hybrid promoters such as the tic promoter [deBoer et al., ~~ Nart. Acid. Sci. USA, 8Q:21-25 (1983)]. Promoters for use in bacterial systems also will contain a Shine-Dalgatno (S.D.) sequence operably linked to the DNA
encoding the desired PRO polypeptide.
Examples of suitable promoting sequences for use with yeast hosts include the promoters for 3-phosphoglycerate lactase [Hitzeman et al., J. Biol. Chem., X5.5:2073 (I980)]
or other gkycolytic enzymes [Hess et al., y, Advj~e Reg., x:149. (1968); Holland, Biochemistry, 17:4900 (1978)], such as enolase, glyceraldehyde-3-phosphate dehydrogenase, hexokinase, pyruvate decarboxylase, phosphofructokinase, glucose-6-phosphate isomerase, 3-phosphoglycerate mutase, pyruvate kinase, trioseghosphate isomerase, phosphoglucose isomerase, and glucokinase.
Other yeast promoters, which are inducible promoters having the additional advantage of transcription controlled by growth conditions, are the promoter regions for alcohol dehydrogenase 2, isocytochrome C, acid phosphatase, degradative enzymes associated with nitrogen metabolism, metallothionein, glyceraldehyde-3-phosphate dehydrogenase, and enzymes responsible for maltose and galactose utilization.
Suitable vectors and promoters for use in yeast expression are further described in EP 73,657.
PRO polypeptide transcription from vectors in mammalian host cells is controkked, for example, by promoters obtained from the genomes of viruses such as polyoma virus, fowlpox virus (UK 2,211,504 published 5 July 1989), adenovizus (such as Adenovirus 2), bovine papilloma virus, avian sarcoma virus, cytomegalovirus, a retrovirus, hepatitis-B virus and Simian Virus 40 (SV40), from heterologous mammalian promoters, e.g., the actin promoter or an immunoglobulirt promoter, and from heat-shock promoters, provided such promoters are compatible with the host cell systems.
Transcription of a DNA encoding the desired PRO polypeptide by higher eukaryotes may be increased by inserting an enhancer sequence into the vector. $nhancers are cis-acting elements of DNA, usually about from 10 to 300 bp, that act on a promoter to increase its transcription. Many enhaneer sequences are now known from mammalian genes (globin, elastase, albumin, a-fetoprotein, and insulin).
Typically, however, one will use an enhancer from a eukaryotic cell virus. Examples include the SV40 enhancer on the late side of the replication origin (bp 100-270), the cytomegalovirus early promoter enhancer, the polyoma enhancer on the late side of the replication origin, and adenovirus enhancers. The enhancer may be spliced into the vector at a position S' or 3' to the PRO
polypeptide coding sequence, but is preferably located at a site 5' from the promoter.
Expression vectors used in eukaryotic host cells (yeast, fungi, insect, plant, animal, human, or nucleated cells from other multiceliular organisms) will also contain sequences necessary for the termination of transcription and for stabilizing the mRNA. Such sequences are commonly available from the 5' and, occasionally 3', untranslated regions of eukaryotic or viral DNAs or cDNAs. These regions contain nucleotide segments transcribed as polyadenylated fragments in the tutuanslated portion of the mRNA encoding PRO
polypeptides.
Still other methods, vectors, and host cells suitable for adaptation to the synthesis of PRO polypeptides in recombinant vertebrate cell culture are described in Gething et al., stance, 23_:620-625 (1981); Mantel et al., .Nab er , ~$~,:40-46 (1979); EP 117;060; and EP 117,U58.
D, Detecting Gene Am~liflcafionlhxnressior~
Gene amplification and/or expression may be measured in a sample directly, for example, by conventional Southern blotting, Northern blotting to quantitate the transcription of mRNA
[Thomas, Psoc Nat1 Acad Sue, USA, 77:5201-5205 (1980)), dot blotting (DNA analysis), or in situ hybridization, using an appropriately labeled pmbe, based on the sequetxes provided herein. Alternatively, antibodies may be employed that can recognize specific duplexes, including DNA duplexes, RNA duplexes, and DNA-RNA hybrid duplexes or DNA-protein duplexes. The antibodies in turn may be labeled and the assay may be carried out where the duplex is bound to a surface, so that upon the formation of duplex on the surface; the presence of antibody bound to the duplex can be detected.
Gene expression, alternatively, may be measured by immunologit:al methods, such as imtnunohistochemica!
staining of cells or tissue sections and assay of cetL culture or body fluids, to quantitate directly the expression of gene Product. Antibodies useful for inmtunohistocheznical staining andlor assay of sample fluids may .be either monoclonal or polyclonal, and may be prepared in any mammal: Conveniently, the antibodies may be prepared against a native sequence PRO potypeptide or against a syrnhetie peptide based on the DNA
sequences provided herein or against exogenous sequence fused to a PRO poiypeptide DNA and encoding a specific antibody epitope.
E. ~~a~f(_catioe g~,Polyp~ tide Fomts of PRO polypeptides mayy be recovered from culture trtedium or from host cell lysates. If membrane-bound, it can be released from the membrane using a suitable detergent solution (e.g. Triton-X 100) or by enzymatic cleavage. Cells employed in expression of PRO polypeptides can be disrupted by various physical or chemical means, such as freeze-thaw cycling, sonication, mechanical disruption, or cell lysing agents, It may be desired to purify PRO polypeptides from recombinant cell proteins or polypeptides. The following procedures are exemplary of suitable purification procedures: by fractionation on an ion-exchange column; ethanol precipitation; reverse phase HPLC; chromatography on silica or on a ration-exchange resin such as DEAF; .
chromatofocusing; SDS-PAGE; ammonium sulfate precipitation; gel filtration using, for example, Sephadex G-75;
protein A Sepharose columns to remove contaminants such as IgG; and metal chelating columns to bind epitope-tagged forms of the PRO polypeptide. Various methods of protein purification may be employed and such methods are known in the art and described for example in Deutscher, Methods in Enzvmologx, 1 2 (1990); Scopes, Protein Purification: Princitxles and Practice, Springer-Verlag, New York (1982). The purification steps) selected will depend, for example, on the nature of the production process used and the particular PRO polypeptide produced.
91. Uses for PRO Polypeptides Nucleotide sequences (or their complement) encoding the PRO polypeptides of the present invention have various applications in the art of molecular biology, including uses as hybridization probes, in chromosome and gene mapping and in the generation of anti-sense RNA and DNA. PRO polypeptide-encoding nucleic acid will also be useful for the preparation of PRO polypeptides by the recombinant techniques described herein.
The full-length native sequence PRO polypeptide-encoding nucleic acid or portions thereof, may be used as hybridization probes for a cDNA library to isolate the full-length PRO
polypeptide gene or to isolate still other genes (for instance, those encoding naturally-occurring variants of the PRO
polypeptide or PRO polypeptides from other species) which have a desired sequence identity to the PRO polypeptide nucleic acid sequences. Optionally, the length of the probes will be about 20 to about 50 bases. The hybridization probes may be derived from the naicleotide sequence of any of the DNA molecules disclosed herein or from genomic sequences including promoters, erthancer elements and introns of native sequence PRO polypeptide encoding DNA. By way of example, a screening method will comprise isolating the coding region of the PRO polypeptide gene using the known DNA sequence to synthesize a selected probe of about 40 bases. Hybridization probes may be labeled by a variety of labels. including radionucleotides such as ~ZP orss S, or enzymatic labels such as alkaline phosphatase coupled to the probe via avidinlbiotin coupling systems. Labeled probes having a sequence complementary to thaf of the specific PRO
polypeptide gene of the present invention can be used to screen libraries of human cDNA, genomic DNA or mRNA
to determine which members of such libraries the probe hybridizes to.
Hybridization techniques are described in further detail in the Examples below.
The ESTs disclosed in the present application may similarly be employed as probes, using the methods disclosed herein.
The probes may also be employed in PCR techniques to generate a pool of sequences for identification of closely related PRO polypeptide sequences.
Nucleotide sequences encoding a PRO polypeptide can also be used to construct hybridization probes for mapping the gene which encodes that PRO polypeptide and for the genetic analysis of individuals with genetic disorders. The nucleotide sequences provided herein may be mapped to a chromosome and specific regions of a chromosome using known techniques, such as in situ hybridization, linkage analysis against known chromosomal markers, and hybridization screening with libraries.
When the coding sequence for the PRO polypeptide encodes a protein which binds to another protein, the PRO polypeptide can be used in assays to identify its ligands. Similarly, inhibitors of the receptor/ligand binding interaction can be identified. Proteins involved in such binding interactions can.also be used to screen for peptide WO 99/46281 PCTlUS99/05028 or small molecule inhibitors or agonists of the binding interaction. Screening assays can be designed to find lead compounds that mimic the biological activity of a native PRO polypeptide or a ligand for the PRO polypeptide. Such screening assays will include assays amenable to high-throughput screening of chemical libraries, making them particularly suitable for identifying small molecule drug candidates. Small molecules contemplated include synthetic organic or inorganic compounds. The assays can be performed in a variety of formats, including protein-protein binding assays, biochemical screening assays, immunoassays and cell based assays, which are well characterized in the art.
Nucleic acids which encode a PRO polypeptide or its modified forms can also be used to generate either uansgenic animals or "knock out" animals which, in turn, are useful in the development and screening of therapeutically useful reagents. A transgenic animal (e.g., a mouse or rat) is an animal having cells that contain a transgene, which transgene was introduced into the animal or an ancestor of the animal at a prenatal, e.g., an embryonic stage. A tran~gene is a DNA which is integrated into the genome of a cell from which a uansgenic animal develops. 1n one embodiment, cDNA encoding a PRO polypeptide of interest can be used to clone genomic DNA
encoding the PRO polypeptide in accordance with established techniques and the genomic sequences used to generate uansgenic animals that contain cells which express DNA encoding the PR.O
polypeptide: Methods for generating tz~ansgenic animals, particularly animals such as mice or rats, have become conventional in the art and are described, for example, in U,&. Patent Nos. 4,736,866 arid 4,870,009. Typically, particular cells would be targeted for PRO
polypeptide uansgene incorporation with tissue-specific etthancers. Transgenic animals that intbide a copy of a transgene encoding a PRO polypeptide introduced into the germ line of the animal at an embryonic stage can be used to examine the effect of increased expression of DNA encoding the PRO
palypeptide. Such animals can be used as tester animals for reagents thought to confer protection from, for example, pathological conditions associated with its overexpression. In accordance with this facet of the invention, an animal is ueated with the reagent and a reduced incidence of the pathological condition, compared to unueated animals bearing the transgene, would indicate a potential therapeutic intervention for the pathological condition.
Alternatively, non-human homologues of PRO polypeptides can be used to construct a PRO polypeptide "knock out" animal which has a defective or altered gene encoding the PRO
polypeptide of interest as a result of homologous recombination between the endogenous gene etxoding the PRO
polypeptide a~ alters genomic DNA
encoding the PRO polypeptide introduced into an embryonic cell of the animal.
For example, cDNA encoding a PRO
polypeptide can be used to clone genomic DNA encoding the PRO polypeptide in accordance with established techniques. A portion of the genomic DNA encoding a PRO polypeptide can be deleted or replaced with another gene, such as a gene encoding a selectable marker which can be used to monitor integration. Typically, several kilobases of unaltered flanidng DNA (both at the 5' and 3' ends) are i>tcluded in the vector (see e.g., Thomas and Capecchi, ~e , _5:503 {1987) for a description of homologous recombination vectors]. The vector is introduced into an embryonic stem cell line (e.g., by electropora6on) and cells in which the inuoduced DNA has homologously recombined with the endogenous DNA are selected (see e.g., Li et al., ( ej(, ~,x:915 (1992)). The selected cells are then injected into a blastocyst of an animal (e.g., a mouse or rat) to forma aggregation chimeras (see e.g.. Bradley, in Teratocarcinomas a»d Embryonic Stem Cells: A Practical Appr~clt, lc. J.
Robertson, ed. (IRL, Oxford, 1987), pp. 113-152]. A ehimeric embryo can then be implanted into a su'ttable pseudopregnant female foster animal and the embryo brought to term to create a "knock out" animal. Progeny harboring the homologously recombined DNA in their germ cells can be identified by standard techniques and used to breed animals in which all cells of the anima!

WO 99!46281 PCT/US99/05028 contain the homologously recombined DNA. Knockout animals can be characterized for instance, for their ability to defend against certain pathological conditions and for their development of pathological conditions due to absence of the PRO poiypeptide.
When in vivo administration of a PRO polypeptide is employed, normal dosage amounts may vary from about 10 nglkg to up to I00 mg/kg of mammal body weight or more per day, preferably about 1 kglkglday to 10 S mg/kglday, depending upon the route of adminisuation. Guidance as to particular dosages and methods of delivery is provided in the literature; see, for example, U.S. Pat. Nos. 4,657,760;
5,206,344; or 5,225,212. It is anticipated that different formulations will be effective for different treatment compounds and different disorders, that administration targeting one organ or tissue, for example, may necessitate delivery in a manner different from that to another organ or tissue.
Where sustained-release administration of a PRO poiypeptide is desired in a formulation with release characteristics suitable for the ueatment of any disease or disorder requiring administration of the PRO polypeptide, microencapsulation of the PRO polypeptide is contemplated. Microencapsulation of recombinant proteins for sustained release has been successfully performed with human growth hormone (rhGH), interferon- (rhlFN- ), interleukin-2, and MN rgp120. Johnson et al., Nat. Med,, _2: 795-799 (1996);
Yasuda. Biomed. Ther., 27: 1221-1223 (1993); Hora et al., Bio/Techrtologv. _8: 7SS-7S8 (1990); Cleland, "Design and Production of Single Immunization Vaccines Using Polylactide Polyglycolide Microsphere Systems," in Vaccine Designi The Subunit and Adjuvant Approach, Powell and Newman, eds, (Plenum Press: New York, 1995), pp.
439462; WO 97/03692, WO
96/40072, WO 96107399; and U.5 Pat. No. 5,654,010.
The sustained-release formulations of these proteins were developed using poly-lactic-coglycolic acid (PLGA) polymer due to its biocompaubiliry and wide range of biodegradable properties. The degradation products of PLGA, lactic and glycolic acids, can be cleared quickly within the human body. Moreover, the degradability of this polymer can be adjusted from months to years depending on its molecular weight and composition. Lewis, "Conuolled release of bioactive agents from lactidelglycolide polymer," in: M.
Chasin and R. Lattger (Eds.), B',~egradable Polymers as Drug Delivetv Systems (Marcel Dekker: New York, 1990), pp. 1-41.
For example, for a formulation that can provide a dosing of approximately 80 g/kg/day in mammals with a m~utimum body weight of 8S kg, the largest dosing would be approximately 6.8 mg of the PRO polypeptide per day.
In order to achieve this dosing level, a sustained- release formulation which contains a maximum possible protein krading (1S-20°~c w/w PRO polypeptide) with the lowest possible initial burst (<20~) is necessary. A continuous (zero-order) release of the PRO polypeptide from microparticles for 1-2 weeks is also desirable. In addition, the encapsulated protein to be released should maintain its integrity and stability over the desired release period.
PR0213 polypeptides and portions thereof which possess .the ability to regulate the growth induction cascade and/or the blood coagulation cascade may also be employed for such purposes both in vivo therapy and in vitro.
Those of ordinary skill in the art will well know how to employ PR0213 polypeptides for such uses.
PR0274 polypeptides and portions thereof which have homology to 7TM protein and Ftt54 may also be 33 useful for in vivo therapeutic purposes, as well as for various other applications. The identification of novel 7TM
protein and FnS4-like molecules may have relevance to a number of human disorders which involve recognition of ligands and the subsequent signal transduction of information contained within those ligands in order to control cellular processes. Thus, the identification of new 7TM protein and Fn54-like molecules is of special importance in that such proteins may serve as potential therapeutics for a variety of different human disorders. Such polypeptides may also play important roles in biotechnological and medical research as well as in various industrial applications.
As a result, there is particular scientific and medical interest in new molecules, such as PR0274.
PR0300 polypeptides and portions thereof which have homology to Diff 33 may also be useful for in vivo therapeutic purposes, as well as for various other applications. The identification of novel Diff 33-like molecules may have relevance to a number of human disorders such as the physiology of cancer. Thus, the identification of new Diff 33-like molecules is of special importance in that such proteins may seine as potential therapeutics for a variety of different human disorders. Such po3ypeptides may also play important roles in biotechnological and medical research as well as various industrial applications. As a result, there is particular scientific and medical interest in new molecules, such as PR0300.
PR0296 poIypeptides of the present invention which possess biological activity related to that of the sarcoma-amplified SAS protein may be employed both in vivo for therapeutic purposes and in vitro. Those of ordinary skill in the art will well know how to employ the PR0296 polypeptides of the present invention for such purposes.
PR0329 polypeptides of the present invention which possess biological activity related to that of immunoglobulin F~ receptor protein or suburut thereof may be employed both in vivo for therapeutic purposes and in vitro. Those of ordinary skill in the an will well know how to employ the PR0329 polypeptides of the present invention for such purposes.
PR0362 polypeptides of the present invention which possess biological activity related to that of the A33 antigen protein, HCAR protein or the NrCAM related cell adhesion molecule may be employed both in vivo for therapeutic purposes and in vitro.
PR03b3 polypeptides of the present invention which possess biological activity related to that of the cell surface HCAR prooein may be employed both in vivo for therapeutic purposes and in vitro. Those of ordinary skill in the art wilt well know how to employ the PR0363 polypeptides of the present invention for such purposes.
Specifically, exuacellular domains derived from the PR0363 polypeptides may be employed therapeutically in vivo for lessening the effects of viral infection.
PR0868 polypeptides of the present invention which possess biological activity related to that of the tumor necrosis factor protein may be employed both in vivo for therapeutic purposes and in vitro. Those of ordinary skill in the art will well know how to employ the PR0868 poiypeptides of the present invention for such purposes.
PR0382 polypeptides of the present invention which possess biological activity related to that of the serine protease proteins may be employed both in vivo for therapeutic purposes and in vitro. Those of ordinary skill in the art will well know how to employ the PR0382 polypeptides of the present invention for such purposes.
PROS45 polypeptides and portions thereof which have, homology to meltrin may also be useful for in vivo ~c purposes, as well as for various other applications. The identification of novel molecules associated with cellular adhesion may be relevant to a number of human disorders. Given that the meltrin proteins may play an important role in a number of disease processes, the identification of new meltrin proteins and meluin-like molecules is of special importance in that such proteins may serve as potential thera~utics for a variety of different human disorders. Such polypeptides may also play important roles in biotechnological and medical research, as well as various industrial applications. As a result, there is particular scientific and medical interest in new molecules, such as PR0545.
15?

PR0617 polypeptides of the present invention which possess biological activity related to that of the CD24 protein may be employed both in vivo for therapeutic purposes and in vitro.
Those of ordinary skill in the art will well know how to employ the PR0617 polypeptides of the present invention for such purposes.
PR0700 polypeptides and portions thereof which have homology to protein disulfide isomerase may also be useful for in vivo therapeutic purposes, as well as for various other applications. The identification of novel protein disulfide isomerases and related molecules may be relevant to a number of human disorders. Given that formation of disulfide bonds and protein folding play important roles in a number of biological processes, the identification of new protein disulfide isomerases and protein disulfide isomerase-like molecules is of special importance in that such proteins may serve as potential therapeutics for a variety of different human disorders. Such polypeptides may also play important roles in biotechnological and medical research, as well as various industrial applications. As a result, there is particular scientific and medical interest in new molecules, such as PR0700.
PRO702 polypeptides of the present invention which possess biological activity related to that of the conglutinin protein may be employed both in vivo for therapeutic purposes and in vitro. Those of ordinary skill in the art will well know now to employ the PR0702 polypeptides of the present invention for such purposes. PR0702 polypeptides having conglutinin activity would be expected to be capable of inhibiting haemagglutinin activity by i5 influenza viruses andlor function as immunoglobulin-independent defense molecules as a result of a complement-mediated rtiechat>ism.
PR0703 polypeptides of the present invention which possess biological activity related to that of the VLCAS
protein may be employed both in vivo for therapeutic purposes and in vitro.
Those of ordinary skill in the art will well know how to employ the PR0703 polypeptides of the present invention for such purposes.
PR0703 polypeptides and portions thereof which have homology to VLCAS may also be useful for in vivo therapeutic purposes, as well as for various ocher applications. The identification of novel VLCAS proteins and related molecules may be relevant to a number of human disorders. Thus, the identification of new VLCAS proteins and VLCAS protein-like molecules is of special importance in that such proteins may serve as potential therapeutics for a variety of different human disorders. Such polypeptides may also play important roles in biotechnological and medical research as well as various industrial applications. As a result, there is particular scientific and medical interest in new molecules, such as PR0703.
PR0705 poiypeptides of the present invention which possess biological activity related to that of the K-glypicatt protein may be employed both in vivo for therapeutic purposes and in vitro. Those of ordinary skill in the art will well know how to employ the PR0705 polypeptides of the present invention for such purposes.
PR0708 polypeptides of the present invention which possess biological activity related to that of the aryl sulfatase proteins may be employed both in vivo for therapeutic purposes and in vitro. Those of ordinary skill in the art will well know how to employ the PR0708 polypeptides of the present invention for such purposes.
PR0320 polypeptides of the present invention which possess biological activity related to that of the fibulin protein may be employed both in vivo for therapeutic purposes and in vitro.
Those of ordinary skill in the art will well know how to employ the PRO320 polypeptides of the present invention for such purposes.
PR0320 polypeptides and portions thereof which have homology to fibulin may also be useful for in vivo therapeutic purposes, as well as for various other applications. The identification of novel fibulin proteins and related molecules may be relevant to a number of human disorders such as cancer or those involving connective tissue, attachment molecules and related mechanisms. Thus, the identification of new fibulin proteins and fibulin WO 99/x6281 PCTNS99/05028 protein-like molecules is of special importance in that such proteins may serve as potential therapeutics for a variety of different human disorders. Such polypeptides may also play important roles in biotechnological and medical research as well as various industrial applications. As a result, there is particular scientific and medical interest in new molecules, such as PR0320.
PRO324 polypeptides of the present invention which possess biological activity related to that of oxidoreductases may be employed both in vivo for therapeutic purposes and in vitro. Those of ordinary skill in the art will well know how to employ the PR0324 polypeptides of the present invention for such purposes.
PR0351 poiypeptides of the present invention which possess 1>iological activity related to that of the prostasin protein may be employed both in vivo for therapeutic purposes and in vitro. Those of ordinary skill in the art will well know how to employ the PR0351 polypeptides of the present invention for such puiposes.
PR0351 polypeptides and portions thereof which have homology to proscasin may also be useful for in vivo therapeutic purposes, as well as for various other applications. The identification of novelprostasin proteins and related molecules may be relevant to a number of human disorders. Thus; the identification of new prostasin proteins and prostasin -like molecules is of special importance in that such proteins may serve as potential therapeutics for a variety of different human disorders. Such poiypeptides may also play important roles in biotechnological and medical research as well as various industrial applications. As a result, there is particular scientific and medical interest in new molecules, such as PR0351.
PR0352 polypeptides of the present invention which possess biological activity related to that of the ~tyrophilinprotein may be employed both in vivo for therapeutic purposes and in vitro. Those of ordinary skill in the an will well know how to employ the PR0352 polypeptides of the present invention for such purposes.
PR038I polypeptides of the present invention which possess biological activity related to that of one or more of the FKPB immunophilin proteins may be employed both in vivo for therapeutic purposes and in vitro, for example for enhancing immunosuppressant activity and/or for axonal regeneration. Those of ordinary skill in the art will well know how to employ the PR0381 polypeptides of the present invention for such purposes.
PR0386 polypeptides of the present invention which possess biological activity related to that of the beta-2 subunit of a sodium channel expressed in mammalian cells may be emplayed both in vivo for therapeutic purposes and in vitro. Those of ordinary skill in tine art will well know how to employ the PR038b polypeptides of the present invention for such purposes.
PR0540 polypeptides of tire present invention which possess biological activity related to that of the LCAT
protein may be employed both in vivo for therapeutic purposes and in vitro.
Those of ordinary skill in the art will well know how to employ the PR0540 polypeptides of the present invention for such purposes.
PR0615 polypeptides of the present invention which possess. biological activity related to that of the synaptogyrin protein may be employed both in viva for therapeutic purposes and in vitro. Those of ordinary skill in the art will well know how to employ the PR0615 polypeptides of the present invention for such purposes.
PR0615 polypeptides and portions thereof which have homology to synaptogyrin may also be useful for in vivo therapeutic purposes, as well as for various other applications. The identification of novel synaptogyrin proteins and related molecules may be relevant to a cumber of human disorders. Thus, the identification of new synaptogyrin proteins and synaptogyrin-like molecules is of special importance in that such. proteins may serve as potential therapeutics 'for a variety of different human disorders. Such polypeptides may also play important roles in biotechnological and medical research as well as various industrial applications. As a result, there is particular scientific and medical interest in new molecules, such as PR0615.
PR0618 polypeptides of the present invention which possess biological activity related to that of an ' enteropeptidase may be employed both in vivo for therapeutic purposes and in vitro. Those of ordinary skill in the art will well know how to employ the PR0618 polypeptides of the present invention for such purposes.
PR0618 polypeptides and portions thereof which have homology to enteropeptidase may also be useful for in vivo therapeutic purposes, as well as for various other applications. The identification of novel enteropeptidase proteins and related molecules may be relevant to a number of human disorders.
Thus, the identification of new ettteropeptidase proteins and enteropeptidase-like molecules is of special importance in that such proteins may serve as potential therapeutics for a variety of different human disorders. Such polypeptides may also play important roles in biotechnological and medical research as well as various industrial applications. As a result, there is particular scientific and medical interest in new molecules, such as PR0618.
PR0719 polypeptides of the present invention which possess biological activity related to that of the lipoprotein lipase H protein may be employed both in vivo for therapeutic purposes and in vitro. Those of ordinary skill in the art will well know how to employ the PR0~19 polypeptides of the present invention for such purposes.
PR0724 polypeptides of the present invention which possess biological activity related to that of the human LDL receptor protein tray be employed both in vivo for therapeutic purposes and in vitro. Those of ordinary skill in the art will well know how to employ the PR0724 polypeptides of the present invention for such purposes.
PR0772 polypeptides of the present invention which possess biological activity related to that of the human A4 protein tray be employed both in vivo for therapeutic purposes and in vitro. Those of ordinary skill in the art will well know how to employ the PR0772 polypeptides of the present invention for such purposes.
PR0852 polypeptides of the present invention which possess biological activity related to that of cet~tain protease protein tray be employed both in vivo for therapeutic purposes and in vitro. Those of ordinary skill in the art will well know how to employ the PR0852 polypeptides of the present invention for such purposes.
PR0853 polypeptides of the present invention which possess biological activity related to that of the reductase protein may be employed both in vivo for therapeutic purposes and in vitro. Those of ordinary skill in the art will well know how to employ the PR0853 polypeptides of the present invention for such purposes.
PR0853 polypeptides and portions thereof which have homology to reductase proteins tray also be useful for in vivo therapeutic purposes, as well as for various other applications.
Given that oxygen free radicals and antioxidants appear to play important roles in a number of disease processes, the identification of new reductase proteins and reductase-like molecules is of special importance in that such proteins may serve as potential therapeutics for a variety of differern human disorders. Such polypeptides may also play important roles in biotechnological and medical research as well as various industrial applications. As a result, there is particular scietuific and medical interest in new molecules, such as PR0853.
PR0860 polypeptides of the present invention which possess biological activity related to that of the neurofasein protein may be employed both in vivo far therapeutic purposes and in vitro. Those of ordinary skill in the art will well know how to employ the PR0860 polypeptides of the present invention for such purposes.
PR0860 polypeptides and portions thereof which have homology to neurofascin may also be useful for in vive therapeutic proposes, as well as for various other applications. The identification of novel neurofascin proteins arid related molecules may be relevant to a number of human disorders which involve cellular adhesion. Thus, the idetuification of new rteurofascin proteins and neurofascin protein-like molecules is of special importance in that such WO 99/46281 PCTNS99l05028 proteins may serve as potential therapeutics for a variety of different human disorders. Such polypeptides may also play importarn roles in biotechnological and medical research as well as various industrial applications. As a result, there is particular scientific and medical interest in new molecules, such as PR0860.
PR084b polypeptides of the present invention which possess biological activity related to that of the CMRF35 protein may be employed both in vi o for therapeutic purposes and in vitro. Those of ordinary skill in the art will well know how to employ the PR0846 polypeptides of the present invention for such purposes.
PR0846 polypeptides and portions thereof which have homology to the CMRF35 protein may also be useful for in vivo therapeutic purposes, as well as for various other applications.
The identification of novel CMRF35 protein and related molecules may be relevant to a number of human disorders.
Thus; the identification of new CMRF35 protein and CMRF35 protein-like molecules is of special importance in that such proteins may serve as potential therapeutics for a variety of different human disorders. Such polypeptides may also play important roles in biotechnological and medical research as well as various industrial applications. As a result, there is particular scientific and medical interest in new molecules, such as PR0846.
PR0862 polypeptides of the present invention which possess biological activity related to that of the lysozyme protein may be employed both in vivo for therapeutic purposes and in vitro. Those of ordinary skill in the art will well know how to employ the PR0862 polypeptides of the present invention for such purposes.
PR0862 polypeptides and portions thereof which have homology to the lysozyme protein may also be useful for in vivo therapeutic purposes, as well as for various other applications.
The identification of novel lysozyme proteins and related molecules may be relevant to a number of human disorders.
Thus, the identification of new lysozymes and lysozyme-like molecules is of special importance in that such proteins may serve as potential therapeutics for a variety of different human disorders. Such polypeptides may also play important roles in biotechnological and medical research as well as various industrial applications. As a result, there is particular scientific and medical interest in new molecules, such as PRO8b2.
PR0864 poiypeptides of tl~ present invention which possess biological activity related to that of the Wnt-4 protein may be employed both in vivo for therapeutic purposes and in vitro.
Those of ordinary skill in the art will well know how to employ the PR0864 polypeptides of the present invention for such purposes.
PR0864 polypeptides and portions thereof which have homology to the Wnt-4 protein may also be useful for in vivo therapeutic purposes, as well as for various other applications.
The identification of novel Wnt-4 proteins attd related molecules may be rekvatz to a rnmnber of human disorders. Thus, the identification of new Wnt-4 protein and Wnt-4 protein-like molecules is of special importance in that such proteins may serve as potential therapeutics for a variety of different human disorders. Such polypeptides may also play important roles in biotechnological and medical research as well as various industrial applications. As a result, there is particular scientific and medical interest in new molecules, such as PR0864.
PR0792 polypeptides of the present invention which possess biological activity related to that of the CD23 protein may be employed both in vivo for therapeutic purposes and in vitro.
Those of ordinary skill in the art will well know how to employ the PR0792 polypeptides of the present invention for such purposes.
PR0866 polypeptides of the present invention which possess biological activity related to that of mindin amllor spondin protein may be employed both in vivo for therapeutic purposes and in vitro. Those of ordinary skill in the art will well latow how to employ the PR0866 polypeptides of the present invention for such purposes.

WO 99/46281 PCT/US99l05028 PR0871 polypeptides of the present invention which possess biological activity related to that of the cyclophiiin protein family may be employed both in vivo for therapeutic purposes and in vitro. Those of ordinary skill in the art will well lrnow how io employ the PR0871 polypeptides of the .present invention for such purposes.
PR0873 polypegtides of the present invention which possess biological activity related to that of carboxylesterases may be employed both in viva for therapeutic purposes and in vitro. For example, they be used in conjunction with prodrugs to convert the prodrug to its active form (see Danks et al.,sttpra). They may be used to inhibit parasite infection (see van Pelt et al., supra). Methods for employ the PR0873 polypeptides of the present invention for these, and other purposes will be readily apparent to those of ordinary skill in the art.
PR0940 polypeptides of the present invention which possess biological activity related to that of the CD33 protein andlor OB binding protein-2 tray be employed both in vivo for therapeutic purposes and in vitro. Those of ordinary skill in the art will well know how to employ the PR0940 polypeptides of the present invention for such purposes.
PR0941 polypeptides of the present invention which possess biological activity related to that of a cadherin protein may be employed both in vivo for therapeutic purposes and in vitro.
Those of ordinary skill in the art will well know how to employ the PR0941 polypeptides of the present invention for such purposes.
PR0944 polypeptides of the present invention which possess biologicai activity related to that of the CPE-R
protein may be employed both in vivo for therapeutic purposes and in vitro.
Those of ordinary skill in the art will well know how to employ the PR0944 polypeptides of the present invention for such purposes. PR0944 polypeptides of the present invention that function to bind to Clostridium perfringens enterotoxin (CPE) may find use for effectively treating infection by the CPE endotoxia.
PR0983 polypeptides of the present invention which possess biological activity related to that of the vesicle-associated r~mbra~ protein, VAP-33, tray be employed both in vivo for therapeutic purposes and in vitro. Those of ordinary skill in the art will well know how to employ the PR0983 polypeptides of the present invention for such purposes.
PR01057 polypeptides of the present invention which possess biological activity related to that of protease proteins may be employed both in vivo for therapeutic purposes and in vitro.
Those of ordinary skill in the art will well know how to employ the PR01057 polypeptides of the present invention for such purposes.
PR01071 polypeptides of tlae present invention which possess biological activity related to that of the thrombospondin protein may be employed both in vivo for therapeutic purposes and in vitro. Those of ordinary skill in the an will well know how to employ the PR01071 poIypeptides of the present invention for such purposes.
PR01072 polypeptides of the presetu invention which possess biological activity related to that of reductase proteins may be employed both in vivo for therapeutic purposes.and in vitro.
Those of ordinary skill in the art will well know how to employ the PR01072 polypeptides of the present invention for such purposes.
PR01075 polypeptides of the present invention which possess biological activity related to that of protein disulfide isomerase may be employed both in vivo for therapeutic purposes and in vitro. Those of ozdittary skill in the art will well know how to employ the PR01075 polypeptides of the present invention for such purposes.
PR0181 polypeptides of the present invention which possess biological activity related to that of the cotnichon protein may be employed both in vivo for therapeutic purposes and in vitro. Those of ordinary skill in the art will well know how to employ the PROl8i polypeptides of the present invention for such purposes.

PR0827 polypeptides of the present invention which possess biological activity related to that of various integrity proteins may be employed both in vivo for therapeutic purposes and in vitro. Those of ordinary skill in the art will well know how to employ the PR0827 polypeptides of the present invention for such purposes.
PRO1114 polypeptides of the present invention which possess biological activity related to that of the cytokine receptor family of proteins may be employed both in vivo for therapeutic purposes and in vitro. Those of ordinary skill in the art will well know how to employ the PROl l 14 polypeptides of the present invention for such purposes.
1n addition to the above, the PR01114 interferon receptor polypeptides may be employed in applications, both in vivo and in vitro, where the ability to bind to an interferon ligand is desired. Such applications will be well within the skill level in the an.
PR023? polypeptides of the present invention which possess biological activity related to that of the carbonic anhydrase protein may be employed both in vivo for therapeutic purposes and in vitro. Those of ordinary skill in the art will well know how to employ the PR0237 polypeptides of the present invention for such purposes.
PR0541 polypeptides of the present invention which possess biological activity related to that of a trypsin iniu'bitor protein may be employed both in vivo for therapeutic purposes and in vitro. Those of ordinary skill in the art will well know how to employ the PR0541 polypeptides of the present invention for such purposes.
PR0273 polypeptides can be used in assays that other chemokines would be used in to perform comparative assays. The results can be used accordingly.
PR0701 polypeptides of the present invention which possess biological activity related to that of the r~urofigin fatnt~y may be employed both in vivo for therapeutic purposes and in vitro. Those of ordinary skill in the art will well know how to employ the PR0701 polypeptides of the present invention for such purposes.
PR0701 can be used in assays with neurons and its activity thereon c;an be compared with that of neuroligins 1, 2 and 3. The results can be applied accordingly.
PR0704 polypeptides of the present invemion which possess biological activity related to that of vesicular integral membrane proteins may be employed both in vivo for therapeutic purposes and in vitro. Those of ordinary skill in tt~ art will well know how to employ the PR0704 polypeptides of the present invention for such purposes.
PR0704 can be used in assays with the polypeptides to which they have identity with to detertnine the relative activities. The resuks can be applied accordingly. PR0704 can be tagged or measured for activity to measure endocytosis activity and thereby used to screen for agents which effect endocytosis.
PR0706 polypeptides of the present invention which possess biological activity related to that of the erogenous prostatic acid phosphatase precursor may be employed both in vivo for therapeutic purposes and. in vitro.
Those of ordinary skill in the art will well know how to employ the PRO'706 poiypeptides of the present invention for such purposes.
PR0706 can be used in assays with human prostatic acid phosphat~ise or human IysosomaI acid phosphatase and its activity thereon can be compared with that of human prostatic acid phosphatase or human lysosomal acid phosphatase. The results can be applied at;cordiagly.
PR0707 polypeptides of the present invention which possess biological activity related to that of cadherins may be employed both in vivo for therapeutic purposes and in vitro. Those of ordinary skill in the art will well know how to employ the PR0707 polypeptides of the present invention for such purposes.

PR0707 can be used in assays to determine its activity in relation to other cadherins, particularly cadherin FIB3. The results can be applied accordingly.
PR0322 polypeptides of the present invention which possess biological activity related to that of neuropsin may be employed both in vivo for therapeutic purposes and in vitro. Those of ordinary skill in the art will well know how to employ the PR0322 polypeptides of the present invention for such purposes.
PR0322 can be used in assays to determine its activity relative to neuropsin, trypsinogen, serine protease and neurosin, and the results applied accordingly.
PR0526 polypeptides of the present invention which possess biological activity related to that of protein-protein binding proteins may be employed both in vivo for therapeutic purposes and in vitro. Those of ordinary skill in the art will well know how to employ the PR0526 polypeptides of the present invention for such purposes.
Assays can be performed with growth factors and other proteins which are known to form complexes to determine whether PR0526 binds thereto and whether there is increased half life due to such binding. The results can be used accordingly.
PR0531 polypeptides of the present invention which possess biological activity related to that of the protocadherins tnay be employed both in vivo for therapeutic purposes and in vitro. Those of ordinary skill in the an will well know how to employ the PR0531 polypeptides of the present invention for such purposes.
PR0531 can be used in assays against protocadherin 3 and other protocadherins, to determine their relative activities. The results can be applied accordingly.
PR0534 polypeptides of the present invention which possess biological activity related to that of the protein disulfide isomerase may be employed both in vivo for therapeutic purposes and in vitro. Those of ordinary skill in the art will well know how to employ the PR0534 polypeptides of the present invention for such purposes.
PR0534 can be used in assays with protein disulfide isomerase to determine the relative activities. The results can be applied accordingly.
PR0697 polypeptides of the present invention which possess biological activity related to that of the sFRP
family may be employed both in vivo for therapeutic purposes and in vitro.
Those of ordinary skill in the art will well know how to employ the PR0697 polypeptides of the present invention for such purposes.
PR0697 can be used in assays with sFRPs and SARPs to determine the relative activities. The results can be applied accordingly.
PR0731 polypeptides of the present invention which possess biological activity related to that of any protocadtterin may be employed both in vivo for therapeutic purposes and in vitro. Those of ordinary skill in the art will well know how to employ the PR0731 polypeptides of the present invention for such purposes.
PR0731 can be used in assays with the polypeptides to which they have identity with to determine the relative activities. The results can be applied accordingly.
PR0768 polypeptides of the present invention which possess biological activity related to that of integrins tray be employed both in vivo for therapeutic purposes and in vitro. Those of ordinary skill in the art will well know how to employ the PR0768 polypeptides of the present invention for such purposes.
PR0768 can be used in assays with the polypeptides to which they have identity with to determine the relative activities. The results can be applied accordingly.
PR0771 polypeptides of the present invention which possess biological activity related to that of the testican protein may be employed both in vivo for therapeutic purposes and in vitro.
Those of ordinary skill in the art will 1b4 well know how to employ the PR0771 palypeptides of the present invention for such purposes.
PR0771 can be used in assays with the polypeptides to which they have identity with to determine the relative activities. The results can be applied accordingly.
PR0733 polypepddes of the present invention which possess biological activity related to that of the proteins which bind the T1/ST2 receptor may be employed both in vivo for therapeutic purposes and in vitro. Those of ordinary skill in the art will well know how to employ the PR0733 polypeptides of the present invention for such purposes.
PR0733 can be used in assays with the polypeptides to which they have identity with to determine the relative activities. The results can be applied accordingly.
PR0162 polypeptides of the present invention which possess biological activity related to that of the patios-associated protein may be employed both in vivo for therapeutic purposes and in vitro. Those of ordinary skill in the art will well know how to employ the PROl62 polypeptides of the present invention for such purposes.
PR0162 can be used in assays with the polypeptides to which they have identity with to determine the relative activities. The results can be applied accordingly.
PR0788 polypeptides of the present invention which possess biological activity related to that of the anti-neoplastic urinary protein may be employed both in vivo for therapeutic purposes and in vitro. Those of ordinary skill in the art will well know how to employ the PR0788 polypeptides of the present invention for such purposes.
PR0788 can be used in assays with the polypeptides to which they have identity with to determine the relative activities. The results can be applied accordingly.
PR01008 polypeptides of the presetu im~ention which possess biological activity related to that of dkk 1 may be empioyed both in vivo for therapeutic purposes and in vitro. Those of ordinary skill in the art will well know how to employ the PR01008 polypeptides of the present invention for such purposes.
PR01008 can be used in assays with the polypeptides to which they have identity with to determine the relative activities. The results can be applied accordingly.
PROl0I2 polypeptides of the present invention which possess biological activity related to that of the protein disulfide isomerase may be employed both in vivo and in vitro purposes. Those of ordinary skill in the art will well know how to employ the PR01012 polypeptides of the present invention for such purposes.
PROI0I2 can be used in assays with the polypepticles to which they have identity with to determine the relative activities. The results. can be applied accordingly.
PROlUI4 polypeptides of the present invention which possess biological activity related to that of reductase may be employed both in vivo for therapeutic purposes and in vitro. Those of ordinary skill in the art will well know how to employ the PR01014 polypeptides of the present invention for such purposes.
PR01014 can be used in assays with the polypeptides to which they have identity with to determine the relative activities. Inhibitors of PROI014 are particularly preferred. The results can be applied accordingly.
PR01017 polypeptides of the present invention which possess biological activity related to that of sulfotransferase tray be employed both in vivo for therapeutic purposes and!
in vitro. Those of ordinary skill is the art will well know how to employ the PR01017 polypeptides of the present invention for such purses.
PR01017 can be used in assays with the polypeptides to which they have identity wide to determine the relative activities. The results can be applied accordingly.

..,.

PR0474 polypeptides of the present invention which possess biological activity related to that of dehydrogenase may be employed both in vivo for therapeutic purposes and in vitro. Those of ordinary skill in the art will well know how to employ the PR0474 polypeptides of the present invention for such purposes.
PR0474 can be used in assays with the polypeptides to which they have identity with to determine the relative activities. The results can be applied accordingly.
PR01031 polypeptides of the present invention which possess biological activity related to that of IL-17 may be employed both in vivo for therapeutic purposes and in vitro. Those of ordinary skill in the art will well know how to employ the PR01031 polypeptides of the present invention for such purposes.
PR01031 can be used in assays with the polypeptides to which they have identity with to determine the relative activities. The results can be applied accordingly.
PR0938 polypeptides of the present invention which possess biological activity related to that of protein disulfide isomerase may be employed both in vivo for therapeutic purposes and in vitro. Those of ordinary skill in the art will well know how to employ the PR0938 polypeptides of the present invention for such purposes.
PR01082 polypeptides of the present invention which possess biological activity related to that of the LDL
receptor may be employed both in vivo for therapeutic purposes and in vitro.
Those of ordinary skill in the art will well know how to employ the PR01082 polypeptides of the present invention for such purposes.
PR01082 can be used in assays with the polypeptides to which they have identity with to determine the relative activities. The results can be applied accordingly. PR01082 can also be used in assays to identify candidate agents which modulate the receptors.
PR01083 polypeptides of the present invention which possess biological activity related to that of 7TM
receptors may be employed both in vivo for therapeutic purposes and in vitro.
Those of ordinary stall in the art will well know how to employ the PR01083 polypeptides of the present invention for such purposes.
In particular PR01083 can be used in assays to determine candidate agents which control or modulate PR01083, i.e., have an effect on the receptor.
The VEGF-E molecules herein have a number of therapeutic uses associated with survival, proliferation and/or differention of cells. Such uses include the treatment of umbilical vein endothelial cells, in view of the trated ability of VEGF-E to increase survival of human umbilical vein endothelial cells. Treatment may be needed if the vein were subjected to traumata, or situations wherein artificial means are employed to enhance the survival of the umbilical vein, for example, where it is weak, diseased, based on an artificial matrix, or in an artificial environment. Other physiological conditions that could be improved based on the selective mitogenic character of VEGF-E are also included herein. Uses also include the ueatment of fibroblasts and myocytes, in view of the demonstrated ability of VEGF-E to induce proliferation of fibroblasts and hypertrophy in myocytes. In particular, VEGF-E can be used in wound healing, tissue growth and musclc generation and regeneration.
For the indications referred to above, the VEGF-E molecule will.be formulated and dosed in a fashion consistent with good medical practice taking into account the specific disorder to be ueated, the condition of the individual patient, the site of delivery of the VEGF-E, the method of administration, and other factors known to practitioners. Thus, for purposes herein, the "therapeutically effective amount" of the VEGF-E is an amount that is effective either to prevent, lessen the worsetW g of, alleviate, or cure the ueated condition, in particular that amount which is sufficient to enhance the survival, proliferation and/or differentiation of the treated cells in vivo.

a _ VEGF-E amino acid variant sequences and derivatives that are itnmunologically crossreactive with antibodies raised against native VEGF are useful in immunoassays for VEGF-E as standards, or, when labeled, as competitive reagents.
The VEGF-E is prepared for storage or administration by mixing VEGF-E having the desired degree of purity with physiologically acceptable carriers, excipients, or stabilizers.
Such materials are non-toxic to recipients at the dosages and concentrations employed. If the VEGF-E is water soluble, it may be formulated in a buffer such as phosphate or other organic acid salt preferably at a pH of about 7 to 8. if the VEGF-E is only partially soluble in water, it may be prepared as a microemuIsion by formulating it with a nonionic surfactant such as Tween, Pluronics, or PEG, e.g., Tween 80, in an amount of 0.04-0.05 % (wlv), to increase its solubility.
Optionally other ingredients may be added such as antioxidants, e.g., ascorbic acid; low molecular weight (less than about ten residues) polypeptides, e.g., polyarginine or tripeptides; proteins, such as serum albumin, gelatin, or inununoglobulins; hydrophilic polymers such as polyvirryipyrrolidone; amino acids, such as glycine, glutamic acid, aspartic acid, or arginine; monosaccharides, disaccharides, and other carbohydrates including cellulose or its derivatives, glucose, mannose, or dexuins; chelating agents such as EDTA; and sugar alcohols such as mannitol or sorbitol.
The VEGF-E to be used for therapeutic administration must be sterile.
Sterility is readily accomplished by filtration through sterile filtration membranes (e.g., 0.2 micron membranes).
The VEGF-E ordinarily will be stored in lyophilized form or as an aqueous solution if it is highly stable to thermal and oxidative denaturation. The pH of the VEGF-E preparations typically will be about from 6 to 8, although 1>igher or lower pH values may also be appropriate in certain instances. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of salts of the VEGF-E.
if the VEGF-E is to be used parenterally, therapeutic compositions containing the VEGF-E generally are placed into a container having a sterile access port, for example, an inuavenous solution bag or vial having a stopper pierceable by a hypodermic injection needle.
Generally, where the disorder permits, one should formulate and dose the VEGF-E for site-specific delivery.
This is convenient in the case of wounds and ulcers.
Sustained release formulations may also be prepared, and include the formation of microcapsular particles and implantable articles. For preparing sustained-release VEGF-E compositions, the VEGF-E is preferably incorporated into a biodegradable matrix or microcapsule. A suitable rnateriai for this purpose is a polylactide, although, other polymers of poly-(a-hydroxycarboxylic acids), such as poly-D-{-)-3-hydroxybutyric acid (EP 133,988A), can be used.
Other biodegradable polymers include poly{lactones), poly(acetals), poly(orthoesters), or poly(orthocarbonates). The initial consideration here must be that the carrier itself, or its degradation products, is nontoxic in the target tissue and will not further aggravate the condition. This can be determined by rbutine screening in animal models of the target disorder or, if such models are unavailable, in normal animals:
Numerous scientific publications document such animal models.
For examples of sustained release compositions, see U.S. Patent No. 3,773,919, EP 58,481A; U.S. Patent No. 3,887,699, EP 158;277A, Canadian Patent No. 1176565, U. Sidman et al., Biopolymers 22, 547 [1983]; and R. Larger et al., Chem. Tech. 12, 98 [1982).
When applied topically, the VEGF-E is suitably combined with other ingredients, such as carriers andlor adjuvants. There are no limitations on the nature of such other ingredients, except that they must be pharmaceutically ..

acceptable and efficacious for their intended administration, and catmot degrade the activity of the active ingredients of the composition. Examples of suitable vehicles include ointments, creams, gels, or suspensions, with or without purified collagen. The compositions also may be impregnated into transdermal patches, plasters, and bandages, preferably in liquid or semi-liquid form.
For obtaining a gel formulation, the VEGF-E formulated in a liquid composition may be mixed with an effective amount of a water-soluble polysaccharide or synthetic polymer such as polyethylene glycol to form a gel of the proper viscosity to be applied topically. The polysaccharide that may be used includes, for example, cellulose derivatives such as etherified cellulose derivatives, including alkyl celluloses, hydroxyalkyl ceiluloses, and alkylhydroxyalkyl celluloses, for example, methyiceIlulose, hydroxyethyl cellulose, carboxymethyl ceihtIose, hydroxypropyl methylcellulose, and hydroxypropyl cellulose; starch and fractionated starch; agar; alginic acid and alginates; gum arabic; pullulian; agarose; carrageenan; dextrans; dexuins;
ftuctans; inulin; mannans; xylans;
arabinans; chitosans; glycogens; glucans; and synthetic biopolymers; as well as gums such as xanthan gum; guar gum; locust bean gum; gum arabic; tragacanth gum; and karaya gum; and derivatives and mixtures thereof. The preferred gelling agent herein is one that is inert to biological systems;
nontoxic, simple to prepare, and not too runny or viscous, and will not destabilize the VEGF-E held within it.
Preferably the polysaccharide is an etherified cellulose derivative, more preferably one that is well defined, purified, aid listed in USP, e.g., methylcellulose and the hydroxyalkyl cellulose derivatives, such as hydroxypropyl cellulose; hydroxyethyl cellulose, and hydroxypropyl methylcelhtlose. Most preferred herein is tnethylcellulose.
The polyethylene glycol useful for gelling is typically a mixture of low and high molecular weight polyethylene glycols to obtain the proper viscosity. For example, a mixture of a polyethylene glycol of molecular weight 400-600 with one of molecular weight 1500 would be effective for this purpose when mixed in the proper ratio to obtain a paste.
The term "water soluble" as applied to the polysaccharides and polyethylene giycols is meant to include colloidal solutions and dispersions. In general, the solubility of the cellulose derivatives is determined by the degree of substitution of ether groups, and the stabilizing derivatives useful herein should have a sufficient quantity of such ether groin per anhydroglucose unit in the cellulose chant to render the derivatives water soluble. A degree of ether substitution of at least 0.35 ether groups per anhydroglucose unit is generally sufficient. Additionally, the cellulose derivatives may be in. the form of alkali metal salts, for example, the Li, Na, K, or Cs salts.
If methylcellulose is employed in the gel, preferably it comprises about 2-5 %
, more preferably about 3 ~, of the gel and the VEGF is present in an amount of about 300-1000 mg per ml of gel.
The dosage to be employed is dependent upon the factors described above. As a general proposition, the VEGF-E is formulated and delivered to the target site or tissue at a dosage capable of establishing in the tissue a VEGF-E level greater than about 0.1 ng/cc up to a maximum dose that is efficacious but not unduly toxic. This infra-tissue concentration should be maintained if possible by continuous infusion, sustained release, topical application, or injection at empirically determined freque~ies.
It is within the scope hereof to combine the VEGF-E therapy with other novel or conventional therapies (e.g., growth factors such as VEGF, aFGF, bFGF, PDGF, IGF, NGF, anabolic steroids, EGF or TGF-a) for enhancing the activity of any of the growth factors, including VEGF-E, in promoting cell proliferation, survival, differentiation and repair. It is not necessary that such cocreatment drugs be included per se in the compositions of this invention, although this will be convenient where such drugs are proteinaceous. Such admixtures are suitably administered in the same manner and for the same purposes as the VEGF-E used alone. The useful molar ratio of VEGF-E to such secondary growth factors is typically 1:0.1-10, with about equimolar amounts being preferred.
The compounds of the present invention can be formulated according to known methods to prepare pharmaceutically useful compositions, whereby the PRO polypeptide hereof is combined in admixture with a pharmaceutically acceptable carrier vehicle. Suitable carrier vehicles and their formulation, inclusive of other human proteins, e.g., human serum albumin, are described, for example, in Remington's Pjtaarmaceutical Sciences, 16th ed.;
1980, Mack Publishing Co., edited by Oslo et al. the disclosure of which is hereby incorporated by reference. The VEGF-E herein may be administered parenterally to subjects suffering from cardiovascular diseases or conditions, or by other methods that ensure its delivery to the bloodstream in an effective form.
Compositions particularly well suited for the clinical administration of VEGF-E hereof employed in the practice of the present invention include, for example, sterile aqueous solutions, or sterile hydratable powders such as lyophilized protein. It is generally desirable to include further in the formulation an appropriate amount of a pharmaceutically acceptable salt, generally in an amount sufficient to render the formulation isotonic. A pH regulator such as arginine base, and phosphoric acid, are also typically included in sufficient quantities to maintain an appropriate pH, generally from 5.5 to 7.5. Moreover, for improvement of shelf life or stability of aqueous formulations, it may also be desirable to include furthez agents such as glycerol. In this manner, variant t-PA
formulations are rendered appropriate for parenteral administration, and, in particular, intravenous administration.
Dosages and desired drug concentrations of pharmaceutical compositions of the present invention may vary depending on the particular use envisioned: For example, in the treatment of deep vein thrombosis or peripheral vascular disease, "bolus" doses, will typically be preferred with subsequent administrations being given to maintain an approximately constant blood level, preferably on the order of about 3 pg;/ml.
However, for use in connection with emergency medical care facilities where infusion capability is generally not available and due to the generally critical nature of the underlying disease (e.g., embolism, infarct), it will generally be desirable to provide somewhat larger initial doses, such as an intravenous bolus.
For the various therapeutic indications referred to for the compoumis hereof, Lhe VEGF-E molecules will be formulated and dosed in a fashion consistent with good medical practice taking into account the specific disorder to be treated, the condition of the individual patient; the site of delivery, the method of administration and other factors known to practitioners in the respective art. Thus, for purposes herein, the "therapeutically effective amount"
of the VEGF-E molecules hereof is an amount that is effective either to prevent, lessen the worsening of, alleviate, or cure the treated condition, in particular that amount which is sufficient to enhance the survival, proliferation or differentiation of targeted cells in vivo. In general a dosage is employed capable of establishing in the tissue that is the target for the therapeutic indication being ueated a level of a VEGF-E
hereof greater than about 0.1 nglcm' up to a maximum dose that is efficacious but not unduly toxic. It is contemplated that infra-tissue administration may be the choice for certain of the therapeutic indications for the compounds hereof.
The human Toll proteins of the present invention can also be used in assays to identify other proteins or molecules involved in Toll-mediated signal transduaion. For example, PR0285 and PR0286 are useful in identifying the as of yet unknown natural ligands of human Tolls, or other factors that participate (directly or indirectly) in the activation of and/or signaling through a human Toll receptor, such as potential Toll receptor associated kinases. In addition, inhibitors of the receptorlligand binding interaction can be identified. Proteins involved in such binding itueractions can also be used to screen for peptide or small molecule inhibitors or agonists of the binding interaction.

Screening assays can be designed to find lead compounds that mimic the biological activity of a native Toll polypeptide or a ligand for a native Toll polypeptide. Such screening assays will include assays amenable to high-throughput screening of chemical libraries, making them particularly suitable for identifying small molecule drug candidates. Small molecules contemplated include synthetic organic or inorganic compounds. The assays can be performed in a variety of formats, including protein-protein binding assays, biochemical screening assays, immunoassays and cell based assays, which are well characterized in the art.
In vitro assays employ a mixture of components including a Toll receptor polypeptide, which may be part of fusion product with another peptide or polypeptide, e.g., a tag for detecting or anchoring, etc. The assay mixtures may further comprise (for binding assays) a natural infra- or extracellular ToII binding target (i.e. a Toll Iigand, or another molecule known to activate andlor signal through the Toll receptor).
While native binding targets may be used, it is frequently preferred to use portion of such native binding targets (e.g. peptides), so long as the portion.
provides binding affinity and avidity to the subject Toll protein conveniently measurable in the assay. The assay mixture also contains a candidate pharmacological agent. Candidate agents encompass numerous chemical classes, through typically they are organic compounds, preferably small organic compounds, ate are obtained from a wide variety of sources, including libraries of synthetic or natural compounds. A
variety of other reagents may also be IS included in the mixture, such as, salts, buffers, neutral proteins, e.g.
albumin, detergents, protease inhibitors, nuclease inhibitors, antimicrobial agents, etc In in vitro birxiirtg assays, the resultant mixture is incubated under conditions whereby, but for the presence of the candidate molecule, the Toll protein specifically binds the cellular binding target, portion or analog, with a reference binding affinity. The mixture cornponetus can be added in any order that provides for the requisite bindings and incubations may be performed at any temperature which facilitates optimal binding. Incubation periods are likewise selected for optimal binding but also minimized to facilitate rapid high-throughput screening.
After incubation, the agent-biased binding between the Toll protein and one or more binding targets is detecoed by any convenient technique. For cell-free binding type assays, a separation step is often used to separate bound from unbound compo~nts. Separation may be effected by precipitation (e.g. TCA precipitation, immunoprecipitation, etc.), immobilization (e.g on a solid substrate), etc., followed by washing by, for example, membrane filtration (e.g. Whattnan's P-18 ion exchange paper, Polyfiltronic's hydrophobic GFC membrane, etc.), gel chromatography (e.g. gel filtration, affinity, etc.), For Toll-dependent transcription assays, binding is detected by a change in the expression of a Toll-dependent reporter.
Detection may be effected in any convenient way. For cell-free binding assays, one of the components usually comprises or is coupled to a label. The label may provide for direct detection as radioactivity, luminescence, optical or elecuort density, etc., or indirect detection, such as, an epitope tag, an enzyme, etc. A variety of methods may be used to detect the label depending on the nature of the label and other assay components, e.g. through optical or electron density, radiative emissions, nonradiative energy transfers, etc.
or indirectly detected with antibody conjugates, etc.
Nucleic acid encoding the Toll polypeptides disclosed herein may also be used in gene therapy. In gene therapy applications, genes are introduced inw cells in order to achieve in vivo synthesis of a therapeutically effective genetic product, for example for replacement of a defective gene. "Gene therapy" includes both conventional gene therapy where a lasting effect is achieved by a single treatment, and the administration of gene therapeutic agents, which involves the one time or repeated administration of a therapeutically effective DNA or mRNA. Antisense WO 99146281 PCT/US991t)5018 RNAs and DNAs can be used as therapeutic agents for blocking the expression of certain genes in vivo. It has already been shown that short antisense oligonucleotides can be imported into cells where they act as inhibitors, despite their low intracellular concentrations caused by their restricted uptake by the cell membrane. (Zamecnik er al., Proc. Natl: Acad. Sci. USA 83, 4143-4146 [1986]). The oligonucleotides can be modified to enhance their uptake, e.g. by substituting their negatively charged phosphodiester groups by uncharged groups.
There ate a variety of techniques available for introducing nucleic acids into viable cells. The techniques vary depending upon whether the nucleic acid is transferred into cultured cells in vitro, or in vivo in the cells of the intended host. Techniques suitable for the transfer of nucleic acid into mammalian cells in vitro include the use of liposomes, electroporation, microinjection, cell fusion, DEAF-dexuan, the calcium phosphate precipitation method, etc. The currently preferred in vivo gene transfer techniques include transfection with viral (typically retrovirai) vectors and viral coat protein-liposome mediated transfection (Dzau et al. , Trends in Biotechnologx ~, 205-210 [1993n. In some situations it is desirable to provide the nucleic acid source with an agent that targets the target cells, such as an antibody specific for a cell surface membrane protein or the target cell, a ligand for a receptor on the target cell, etc. Where liposomes are employed, proteins which bind to a cell surface membrane protein associated with endocytosis may be used for targeting andlor to facilitate uptake, e.g. capsid proteins or fragments thereof tropic for a particular cell type, antibodies for proteins which undergo internalization in cycling, proteins that target intracellular localization and enhance intracellular half life. The technique of receptor-mediated endocytosis is described, for example, by Wu et al., ~ Biol. Chem. ~, 4429-4432 (1987); and Wagner et al., Proc. Natl. Acad. Sci. USA $;Z, 3410-3414 (1990). For review of the currently lrnown gene marking and gene therapy protocols see Anderson et al., 'Science ~, 8U8-813 (1992).
The various uses listed in connection with the Toll proteins herein, are also available for agonists of the native Toll receptors, which mimic at least one biological function of a native Toll receptor.
Neurotrimin as well as other members of the IgL.ON subfamily of the immttnoglobulin superfamily have been identified to have effect upon neural patterning, differentiation, maturation and growth. As a result, PR0337 the human neurotrimin homolog polypeptides would be expected to have utility in diseases which are characterized by neural disfunction. For example, motoneuron disorders such as amyotrophic lateral sclerosis (Lou Gehrig's disease), Bell's palsy, and various condition involving spinal muscular atrophy, or paralysis. NGF variant formulations of the invention can be used to neat human neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis; Huntington's chorea, Down's Syndrome, t~rve deafr~ss; and Meniere's disease. Moreover PR0337 polypeptide may also be used as a cognitive enhartcer, to enhance learning particularly in dementia or trauma, such as those associated with the above diseases.
Further, PR0337 may be employed to treat neuropathy; and especially peripheral neuropathy. "Peripheral neuropathy" refers to a disorder affecting the peripheral nervous system, most often ~tifested as one or a combination of motor, sensory, sensorimotor, or autonomic neural dysfunction.
The wide variety of morphologies exhibited by peripheral tieuropathies can each be attributed uniquely to an equally wide number of causes. For example, peripheral neuropathies can be genetically acquired, can result from a systemic disease, or can be induced by a toxic agent. Examples include but are not limited to diabetic peripheral neuropathy, distal sensorimotor neuropathy, or autonomic neuropathies such as reduced motility of the gastrointestinal uact or stony of the urinary bladder. Examples of nev>~athies associated with systemic disease include post-polio syndrome or AIDS-associated neuropathy; examples of hereditary neuropathies include Charcot-Marie-Tooth disease, Refsum's disease, WO 99!46281 PCT/US99/05028 Abetalipoproteinemia, Tangier disease, Krabbe's disease, Metachromatic leukodysuophy, Fabry's disease, and Dejerine-Soaas syndrome; and examples of neuropathies caused by a toxic agent include those caused by ueatment with a chemotherapeutic agent such as vincristine, cisplatin, methouexace, or 3'-azido-3'-deoxythymidine.
Correspondingly, neurotrimin antagonists would be expected to have utility in diseases characterized by excessive neuronal activity.
Endothelia is generated from inactive intermediates, the big endothelins, by a unique processing event catalyzed by the zinc metalloprotease, endothelia convening enzyme (ECE). ECE
was recently cloned, and its structure was shown to be a single pass transmembrane protein with a short inuacellular N-tetrninal and a long extracellular C-terminal that contains the catalytic domain and numerous N-glycosylation sites. ECEs cleave the endothelia propeptide between Trp73 and Va174 producing the active peptide, ET, which appears to function as a ZO local rather than a circulating hormone (Rubanyi, G.M. & Polokoff, M.A., Pharmachological Reviews 46: 325-4I5 (1994). Thus ECE activity is a potential site of regulation of endothelia production and a possible target for therapeutic intervention in the endothelia system. By blocking ECE activity, it is possible stop the production of ET-I
by inhibiting the conversion of the relatively inactive precursor, big ET-1, to the physiologically active form.
ECE 2 is 64% identical to bovine ECE-2 at the amino acid level. ECE-2 is closely related to ECE-1 (63%
identical, 80 % conserved), neutral endopeptidase 24.11 and the Kell blood group protein. Bovine ECE-2 is a type II membrane-bound metalIoproteinase localized in the traps-Golgi network where it acts as an intracellular enzyme converting endogenous big endothelia-1 imo active endothelia (Einoto, N. and Yanangisawa, M., J: Biol. Chem. 270:
15262-15268 (1995). The bovine ECE-2 mRNA expression is highest in parts of the brain, cerebral cortex, cerebellum and adrenal medulla. It is expressed at lower levels in mymetrium, testes, ovary, and endothelial cells.
Bovine ECE-2 and ECE-1 both are more active on ET 1 as a substrate compared to ET-2 or ET-3, Emoto and Yanangisawa, supra.
Human ECE-2 is 736 amino acids in length with a 31 residue amino-terminal tail, a 23 residue transmembrane helix and a 682 carboxy-terminal domain. It is 94% identical to bovine ECE-2 and 643b identical to human ECE-1. The predicted transmembrane domain is highly conserved between the human and bovine ECE-2 proteins and between human ECE-1 and human ECE 2, as are the putative N-linked glycosylation sites, Cys residues conserved in the neutral endopeptidase 24.11 and the Kell blood group protein family and the putative zinc binding motif. The sequence suggests, that like other members of the NEP-ECE-Kell family, human ECE-2 encodes a type II
transmembrane zinc-binding metalloproteinase, which, by exuapolation from what is known about bovine ECE-2, is an intracellular enzyme located within the secretory pathway which processes endogenously produced big ET-1 while it is still in the secretory vesicles. Emoto and Yanangisawa, supra.
The expression pattern of ECE-2 differs from that observed for EC&1. Northern blot analysis of mRNA
levels indicated low levels of expression of a 3.3 kb transcript in adult brain (highest in the cerebellum, putamen, rrtedulla and temporal lobe, and lower in the cerebral cortex, occipital lobe and frontal lobe), spinal cord, lung and pancreas and higher levels of a 4.5 kb uanscript in fetal brain and kidney.
The two transcript sizes probably represent the use of alternative polyadenylation sites as has been observed for bovine ECE 2 (Emoto and Yaaangisawa, supra) and ECE-I (Xu et al., Cell 78: 473-485 (1994). PCR on cDNA
libraries indicated low levels of expression in fetal brain, fetal kidney, fetal small intestine and adult testis. Fetal liver, fetal lung and adult pancreas were all negative.

The endotheiin (ET) family of peptides have potent vascular, cardiac and renal actions which may be of pathophysiological importance in many human disease states. ET 1 is expressed as an inactive 212 amino acid prepmpeptide. The prepropeptide is first cleaved at Arg52-Cys53 and Arg92-A1a93 and then the carboxy terminal I:ys91 and Arg92 are trimmed from the protein to generate the propeptide big ET-1. ECEs then cleave the propeptide between Trp73 and Va174, producing the active peptide, ET, which appears to function as a local rather than a circulating hormone (Rubanyi and Polokoff, Pharma. R. 46: 325-415 (1994).
Endothelins may play roles in the path~ysiology of a number of disease states including: 1) cardiovascular diseases (vasospasm, hypertension, myocardial ischemia; reperfusion injury and acute myochardial infarction, stroke (cerebral ischemia), congestive heart failure, shock, atherosclerosis, vascular thickening); 2) kidney disease (acute and chronic renal faihire, glometulonephritis, cirrhosis); 3) lung disease (bronc:hial asthma, pulmonary hypertension);
4) gastrointestinal disorders (gastric ulcer, inflammatory bowel diseases); 5) reproductive disorders (premature labor, dysmertorhea, preeclampsia) and 6) carcinogenesis. Rubanyi & Polokoff, supra.
' Diseases can be evaluated for the impact of ET upon them by exanuning: I) increased production of ETs;
2) increased reactivity to ETs; andlor 3) efficacy of an ET receptor antagonist, antibody or ECE inhibitor. Response to the previous criteria suggest that ETs likely play roles in cerebral vasospasm following subarachnoid hemorrhage, hypertension (fulminant/complications), acute renal failure and congestive heart failure. While inhibitors of ET
production or activity have not been used in models of coronary vasospasm, acute myocardial infarction, and attarrosclerosis, they do have elevated ET levels and increase reactivity to ETs. Shock and pulmonary hypertension also exhibit elevated ET levels (Rubanyi and Polokoff, supra). Inhibition .of ECEs in these conditions may be of therapeutic value.
The expression pattern of ECE-2 differs from that observed for ECE-1. ECE-2 was observed at low levels in the adult brain, lung and pancreas and higher levels in feral brain and kidney by Northern blot analysis (Fig. 8). PCR
revealed low levels of expression in additional tissues: fetal lung, fetal small intestine and adult testis. Fetal liver was ' negative. A similar pattern was reported for bovine ECE 2 (Emoto and Yanangisawa, supra): It is expressed in brain tissues (cerebral cortex, cerebellum and adrenal medulla), myotnetriutn and testis, and in low levels in ovary and very low levels in many other tissues. Bovine ECE-1 (Xu et al, supra) is more widely and more abundantly expressed.
It is observed in vascular endothelial cells of most organs and in sorry parenchymal cells. With the exception for brain, bovine ECE 2 mRNA was present at lower levels than ECE-1. Applicants believe ECE-2 to be a particularly good target for the therapeutic intervention for diseases such as cerebral vasospasm following subarachnoid hemorrhage and stroke.
92. Anti-PRO Polv~eptide Antibodies The present invention further provides and-PRO polygeptide antibodies.
Exemplary antibodies include polyclonal, mo~clonal, humanized, bispecific, and heteroconjugate antibodies.
A. Polyclonai Antibodies The anti~"RO polypeptide antibodies may comprise polyclonal antibodies.
Methods of preparing polyclonal antibodies are known to the skilled artisan. Polyclonai antibodies can be raised in a mammal, for example, by one or more injections of an irrnttunizing agent and, if desired, an adjuvant.
Typically, the immunizing agent andlor adjuvant will be in~cted in the rnarmrtal by multiple subcutaneous or intraperitoneal injections. The ~ agent tray include the PRO poiypeptide or a fusion protein thereof. It may be useful to conjugate the immunizing agent to a protein known to be immunogenic in the mammal being immunized. Examples of such itnmunogettic proteins include but are not limited to keyhole limpet hemocyanin, serum albumin, bovine thyroglobulin, and soybean trypsin inhibitor. Examples of adjuvants which may be employed include Freund's complete adjuvant and MPL-TDM
adjuvant (monophosphoryl Lipid A, synthetic trehalose dicorynomycolate). The immunization protocol may be selected by one skilled in the art without undue experimentation.
B. Monoclonal Antibodies The anti-PRO polypeptide antibodies may, alternatively, be monoclonal antibodies. Monoclonal antibodies tray be prepared using hybridoma methods, such as those described by Kohler and Milstein, Nature, 256:495 (1975).
i0 In a hybridoma method, a mouse, hamster, or other appropriate host animal, is typically immunized with an immunizing agent to elicit lymphocytes that produce or are capable of producing antibodies that will specifically bind to the immunizing agent. Alternatively, the lymphocytes may be immunized in vitro.
The immunizing agent will typically include the PRO polypeptide of interest or a fusion protein thereof.
Generally, either peripheral blood lymphocytes ("PBIs") are used if cells of human origin are desired, or spleen cells or lymph node cells are used if non-human mammalian sources are desired. The lymphocytes are then fused with an immortalized cell line using a suitable fusing agent, such as polyethylene glycol, to form a hybridoma cell (coding, Monoclonal Antibodies: Princ't~les and Practice, Academic Press, (1986) pp. 59-103j. Immortalized cell lines are usually transformed mammalian cells, particularly myeloma cells of rodent, bovine and human origin. Usually, rat or mouse myeloma cell lines are employed. The hybridoma cells may be cultured in a suitable culture medium that preferably contains one or more substances that inhibit the growth or survival of the unfused, immortalized cells.
For example, if the parental cells lack the enzyme hypoxanthine guanine phosphoribosyl uansferase (HGPRT or HPRT), the culture medium for the hybridomas typically will include hypoxanthine, aminopterin, and tltymidine ("HAT medium"), which substances prevent the growth of HGPRT-deficient cells.
Preferred immortalized cell lines are those that fuse efficiently, support stable high level expression of antibody by the selected antibody-producing cells, and are sensitive to a medium such as HAT medium. More preferred immortalized cell lines are marine myeloma lines, which can be obtained, for instance, from the Salk Institute Cell Distribution Center, San Diego, California and the American Type Culture Collection, Rockville, Maryland. Human myeloma and mouse-human heteromyelotna cell lines also have been described for the production of human monoclonal antibodies [Kozbor, J. Immunol., 133:3001 (1984); Brodeur et al., Monoclonal Antibody Production Techniques and Applications, Marcel Dekker, Inc., New York, (1987) pp. 51-63].
The culture medium in which the hybridoma cells are cultured can then be assayed for the presence of monoclonal antibodies directed against the PRO polypeptide of interest.
Preferably, the binding specificity of monoclonal antibodies produced by the hybridoma cells is determined by immunoprecipitation or by an in vitro binding assay, such as radioirntnunoassay (RIA) or enzyme-linked immunoabsorbent assay (ELISA). Such techniques and assays are known in the art. The binding affinity of the monoclonal antibody can, for example, be determined by the Scatchard analysis of Munson and Pollard, Anal. Biocltern., 107:220 (1980).
After the desired hybridoma cells are identified, the clones may be subcloned by limiting dilution procedures and grown by standard methods [coding, surral. Suitable culture media for this purpose .include, for example, Dulbecco's Modified Eagle's Medium and RPMI-1640 medium. Alternatively, the hybtidotna cells tray be grown in vivo as ascites in a mammal.
The monoclonal antibodies secreted by the subclones may be isolated or purified from the culture medium or ascites fluid by conventional immunoglobulin purification procedures such as, for example, protein A-Sepharose, hydroxylapatite chromatography, gel electrophoresis, dialysis, or affinity chromatography.
T'he monoclonal antibodies may also be made by recombinant DNA methods, such as those described in U.S. Patent No. 4,816,567. DNA encoding the monoclonal antibodies of the invention can be readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that are capable of binding specifically to genes encoding the heavy and light chains of marine antibodies). The hybridoma cells of the invention serve as a preferred source of such DNA. Once isolated, the DNA may be placed into expression vectors, which are then transfected into host cells such as simian COS cells, Chinese hamster ovary (CHO) cells, or myeloma cells that do not otherwise produce immunoglobulin protein, to obtain the synthesis of monoclonal antibodies in the recombinant host cells. The DNA also may be modified, for example, by substituting the coding sequence for human heavy and light chain constant domains in place of the homologous marine sequences [U.S. Patent No. 4,816,567;
Morrison et al:, su r or by covalently joining to the immunoglobulin coding sequence all or part of the coding sequence for a non-immunogiobulin polypeptide. Such a non-immunoglobulin polypeptide can be substituted for the constant domains of an antibody of the invention, or can be substituted for the variable domains of one antigen-combining site of an antibody of the invention to create a chimeric bivalent antibody.
The antibodies may be monovalent antibodies. Methods for preparing manovalent antibodies are well known in the art. For example, one method involves recombinant expression of immunoglobulin light chain and modified heavy chain. The heavy chain is truncated generally at any point in the Fc region so as to prevent heavy chain crosslinking. Alternatively, the relevant cysteine residues are substituted with another amino acid residue or are deleted so as to prevent crosslinldng.
In vitro methods are also suitable for preparing monovalent antibodies.
Digestion of antibodies to produce fragments thereof, particularly, Fab fragments, can be accomplished using routine techniques known in the art.
C. Humanized Antibodies The anti-PRO polypeptide ann'bodies of the invention may further comprise humanized antibodies or human antibodies. Humanized forms of non-human (e.g., marine) antibodies are chimeric immunoglobulins, immunoglobutin chains or fragments thereof (such as Fv, Fab, Fab', F{ab')z or other antigen-binding subsequences of antibodies) which contain minimal sequence derived from non-human immunoglobulin. Humanized antibodies include human immunoglobulins (recipient antibody) in which residues from a complementary determining region (CDR) of the recipient are replaced by residues from a CDR of a non-human species (donor antibody) such as mouse, rat or rabbit having the desired specificity, affinity and capacity. In some instances, Fv framework residues of the human immunoglobulin are replaced by corresponding non human residues.
Humanized antibodies may also comprise residues which are found neither in the recipient antibody nor in the imported CDR or framework sequences. In general, the humanized antibody will comprise substantially alll of at least one; and typically two, variable domains, in which all or substantially all of the CDR regions correspond to those of a non-human itnmunoglobulin and all or substantially all of the FR regions are those of a human immunogiobulin consensus sequence. The humanized antibody optimally also will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human imtnttnoglobulin [Jones et al., Nature, ,~: 522-525 (1986); Riechmann et al., Nature, X32:323-329 (i988): and Presta, Curr. Op. Struct. Biol., x:593-596 (1992)].
Methods for humanizing non-human antibodies are well known in the art.
Generally, a humanized antibody has otre or more amino acid residues introduced into it from a source which is non-human. These non-human amino acid residues are often referred to as "import" residues, which are typically taken from an "import" variable domain.
Humanization can be essentially performed following the method of Winter and co-workers [3ones et al., Nature, 21:
522-525 (1986); Riechrnann et al., Nature, X32:323-327 (1988); Verhoeyen et al., Science, x:1534-1536 (1988)], by substituting rodent CDRs or CDR sequences for the corresponding sequences of a human antibody. Accordingly, such "humanized" antibodies are chimeric antibodies (U.S. Patent No.
4,816,567), wherein substantially less than an intact human variable domain has been substituted by.the corresponding sequence from a non-human species. In practice, humanized antibodies are typically human antibodies in which some CDR residues and possibly some FR
residues are substituted by residues from analogous sites in rodent antibodies.
Human antibodies can also be produced using various techniques known in the art, including phage display libraries [Hoogenboom and Winter, J. Mol. Biol., 2:381 (1991); Marks et al.;
J. Mol. Biol., 222:581 (1991)]. The techniques of Cole et al. and Boerner et al. are also available for the preparation of human monoclonal antibodies (Cole et al., Monoclonal Aruibodies and Cancer Therapy, Alan R. Liss, p. 77 (1985) and Boerner et al., J. Immunol., 14111:86-95 (1991)].
D. Bis~ecific Antibodies Bispecific antibodies are monoclonal, preferably human or humanized, antibodies that have binding specificities for at least two different antigens. 1n the present case, one of the binding specificities is for the PRO
polypeptide, the other one is for any other antigen, and preferably for a cell-surface protein or receptor or receptor subutvt.
Methods for making bis~cific antibodies are known in the art. Traditionally, the recombinant production of bispecific antibodies is based on the co-expression of two immunoglobulin heavy-chainllight-chain pairs, where the two heavy chains have different specificities [Miistein and Cuello, Nature, 30:537-539 (1983)]. Because of the random assortment of immunoglobulin heavy and light chains, these hybridomas (quadromas) produce a potential mixture of ten different antibody molecules, of which only one has the correct bispecific structure. The purification of the correct molecule is usually accomplished by affinity chromatography steps. Similar procedures are disclosed in WO 93108829, published 13 May 1993, and in Traunecker et al., EMBD J., 10:3655-3659 (1991).
Antibody variable domains with the desired binding specificities (antibody-antigen combining sites) can be fused to immunoglobutin constant domain sequences. The fusion preferably is with an imtrnmoglobutin heavy-chain constant domain, comprising at least part of the hinge, CH2, and CH3 regions.
It is preferred to have the first heavy chain constant region (CH1) containing the site necessary for light-chain binding present in at least one of the fusions.
DNAs encoding the immunoglobulin heavy-chain fusions and, if desired, the immunoglobulin light chain, are inserted into separate expression vectors, and are co-transfected into a suitable host organism. For fiu~ther details of generating bispecific antibodies see, for example, Suresh et al., Methods in Enrymology, ,x..,21:210 (1986).
E. HeteroconiuQate Antibodies Heteroconjugate antibodies are also within the scope of the present invention.
Heteroconjugate antibodies are composed of two covalently joined antibodies. Such antibodies have, for example, been proposed to target immune system cells to unwanted cells (U.S. Patent No. 4;676;980), and for treatment of HIV infection (WO
91/00360; WO 921200373; EP 03089]. it is contemplated that the antibodies may be prepared in vitro using known .
methods in synthetic protein chemistry, including those involving crosslinking agents. For example, immunotoxins may be constructed using a disulfide exchange reaction or by fornvng a thioether bond. Examples of suitable reagents for this purpose include iminothiolate and methyl-4-mercaptoburyrimidate and those disclosed, for example, in U.S.
Patent No. 4,676;980.
93. Uses for Anti-PRO Polypeptide Antibodies The anti-PRO polypeptide antibodies of the invention have various utilities.
For example, anti-PRO
polypeptide antibodies may be used in diagnostic assays for a PRO polypeptide, e.g., detecting its expression in specific cells, tissues, or serum. Various diagnostic assay techniques known in the art may be used, such as competitive binding assays, direct or indirect sandwich assays and immunoprecipitation assays conducted in either heterogeneous or homogeneous phases [Zola, Monoclonal Antibodies: A Manual of Techniques, CRC Press, lnc.
(1987) pp. 147-158). The antibodies used in the diagnostic assays can be labeled with a detectable moiety. The detectable moiety should be capable of producing, either directly or indirectly, a detectable signal. For example, the detectable moiety may be a radioisotope, such as 'H, '° C,'2 P,'S S, ot"~ I, a fluorescent or chemilumineseent compound, such as fluorescein isothiocyanate, rhodamine, or luciferin, or an enzyme, such as alkaline phosphatase, beta-galactosidase or horseradish peroxidase. Any method known in the a.rt for conjugating the antibody to the detectable moiety may be employed, including those methods described by Hunter et al., Nature, 144:945 (1962);
David et al., Biochemistry, 13:1014 (1974); Pain et al., J. Immunol. Meth., gQ:219 (1981); and Nygren, J.
Histochem. and Cytochem., X0_:407 (1982).
Anti-PRO polypeptide antibodies also are useful for the affinity purification of PRO polypeptide from recombinant cell culture or natural sources. In this process, the antibodies against the PRO polypeptide are immobilized on a suitable support, such a Sephadex resin or filter paper, using methods well known in the art. The immobilized antibody then is contacted with a sample containing the PRO
polypeptide to be purified, and thereafter the support is washed with a suitable solvent that will remove substantially all the material in the sample except the PRO polypeptide, which is bound to the immobilized antibody. Finally, the support is washed with another suitable solvent that will release the PRO polypeptide from the antibody.
Anti-Toll receptor (i.e., anti-PR0285 and anti-PR0286 antibodies) may also be useful in blocking the biological activities of the respective Toll receptors. The primary function of the family of Toll receptors is believed to be to act as pathogen pattern recognition receptors sensing the presence of conserved molecular pattern present on microbes. Lipopolysaccharides (LPS, also known as endotoxins), potentially lethal molecules produced by various bacteria, bind to the lipopolysaccharide binding protein (LBP) in P.he blood. The complex formed then activates a receptor latown as CD14. There is no consensus in the art about what happens next. According to a hypothesis, CD14 does not directly instruct macrophages to produce cytokines, cell adhesion proteins and enrymes involved in the production of lower molecular weight proinflammatory mediators, rather enables LPS to activate a second receptor. Alternatively, it has been suggested that LPS may activate certain receptors directly, without heap from LBP or CD14. The data disclosed in the present application indicate that the human toll-like receptors are signaling receptors that are activated by LPS in an LBP and CD14 responsive manner. As this mechanism, under pathophysiologic conditions can lead to an often fatal syndrome called septic shack, anti-Toll receptor antibodies (just as other Toll receptor antagonists) might be useful in the treatment of septic shock. It is foreseen that the different Toll receptors might recognize different pathogens, e.g., various strains of Gram-negative or Gram-positive bacteria.
Accordingly, in certain situations, combination therapy with a mixture of antibodies specifically binding different Toll receptors, or the use of bispecific anti-Toll antibodies may be desirable.
It is specifically demonstrated that anti-huTLlt2 antibodies are believed to be specifically useful in blocking the induction of this receptor by LPS. As it has been shown that LPS exposure can lead to septic shock (Parrillo, N. Erg!. J. Med. 328, 1471-1477 (1993]), anti-huTLR2 antibodies are potentially useful in the ueatment of septic shock.
The foregoing therapeutic and diagnostic uses listed in connection with the anti-Toll receptor antibodies are also applicable to.other Toll antagonists, i.e., other molecules (proteins, peptides, small organic molecules, etc.) that ' block Toll receptor activation and/or signal transduction mediated by Toll receptors.
In view of their therapeutic potentials, the Toll proteins (including variants of the native Toll homologues), and their agonists and antagonists (including but not limited to anti-Toll antibodies) are incorporated in compositions suitable for therapeutic use. Therapeutic compositions are prepared for storage by mixing the active ingredient having the desired degree of purity with optional physiologically acceptable carriers, excipients or stabilizers (Remington's Pharmaceutical Sciences 16th Edition, Osol, A. Ed. 1980) in the form of lyophilized formulations or aqueous solutions. Acceptable carriers, excipients or stabilizers are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate and other organic acids; antioxidants including ascorbic acid; low molecular weight {less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone, amino acids such as glycir~, glutamitte, as~ragine, argini~ or lysine; monosaccharides, disaccharides and other carbohydrates including glucose, mannose, or dextrins; cheiating agents such as EDTA; sugar alcohols such as manttitol or sorbitol; salt-forming counterions such as sodium; and/or nonionic surfactants such as Tween, Pluronics or PEG.
The active ingredients may also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(rnethylmethacylate) microcapsules, respectively), in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions. Such techniques are disclosed in Reming~n's Pharmaceutical Sciences, supra.
The formulations to be used for in vivo administration must be sterile. This is readily accomplished by filtration through sterile filtration membranes, prior to or following lyophilization and reconstitution.
Therapeutic compositions herein generally are placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle.
The route of administration is in accord with known methods, e.g. injection or infusion by intravenous, intraperitoneal, intracerebral, intramuscular, intraocular, intraarterial or intralesional routes, topical administration, or by sustai~d release systems.
Suitable examples of sustained release preparations include semipenneable polymer matrices in the form of shaped articles, e.g. films, or microcapsules. Sustained. release matrices include polyesters, hydrogels, polylactides t',U.S. Patent 3,773,919, EP 58,481), copolymers of L-glutamic acid and gamma ethyl-L-glutamate (L1.
Sidman gt al., ~iopolvmers 2,,~ (1): 547-556 [1983]), poly (2-hydroxyethyl-methacrylate) (R. Larger, e,~ ~., J.
Biomed. Mates. Res. ~: 167-277 [1981] and R. Larger, Cbem. Tech. 12: 98-105 [1982]), ethylene vinyl acetate (R. Larger e_t g11., Id.) or poly-D-(-)-3-hydroxybutyric acid (EP 133,988).
Sustained release compositions also include liposomes. Liposomes containing a molecule within the scope of the present invention are prepared by methods known per se: DE 3,218,121; Epstein e1 al., ProcNatl. Acad. Sci. tJSA, $2_:
3688-3692 (1985); Hwang ~ g~., groc. Nat,. Acad. Sci. USA 77: 4030-4034 (1980); EP 523?2; EP 36676A; EP
88046; EP 143949; EP 142641;
Japanese patent application 83-118008; U.S. patents 4,485,045 and 4,544,545;
and EP 102,324. Ordinarily the liposomes are of the small (about 200-800 Angstroms) unilamelar eype in which the lipid content is greater than about 30 mot. % cholesterol, the selected proportion being adjusted for the optimal NT-4 therapy.
An effective amount of the active ingredient will depend, for example, upon the therapeutic objectives, the route of administration, and the condition of the patient. Accordingly, it will be necessary for the therapist to titer the dosage and modify the route of administration as required to obtain the optimal therapeutic effect. A typical daily dosage might range from about 1 ~tglkg to up to 100 mglkg or more, depending on the factors mentioned above.
Typically, the clinician will administer a molecule of the present invention until a dosage is reached that provides the required biological effect. The progress of this therapy is easily monitored by conventional assays.
The following examples are offered for illustrative purposes only, and are not intended to limit the scope of the present invention in any way.
All patent and literature references cited in the present specification are hereby incorporated by reference in their entirety.
EXAMPLES
Commercially available reagents referred to in the examples were used according to manufacturer's instructions tuiless otherwise indicated. The source of those cells identified iii the following examples, and throughout the specification, by ATCC accession numbers is the American Type Culture Collection, Rockville, Maryland.
EXAMPLE 1: xt ell I o in H mol creenin to Ide-ti V ve Pol a 'd c A n o ' Therefor The exu~acelltilar domain (ECD) sequences (including the secretion signal sequence, if any) from about 950 known secreted proteins from the Swiss-Prot public database were used to search EST databases. The EST databases included public databases (e.g., Dayhoff, GenBank), and proprietary databases (e.g. LIFESEQT"'', Ineyte Pharmaceuticals, Palo Alto, CA). The search was performed using the computer program BLAST or BLAST2 (Altschul and Gish, Methods j_n EmJrmolo>rv ~6ø: 460-480 (1996)) as a comparison of the ECD protein sequences to a 6 frame translation of the EST sequences. Those comparisons with a Blast score of 70 (or in some cases 90) or greater that did not encode known proteins were clustered and assembled into consensus DNA sequences with the program "phrap" (Phil Green; University of Washington, Seattle, WA;
(http:l/bowman.mbt.washington.edulphrap.docslphrap.html).
Using this exuacellular domain homology screen, consensus DNA sequences were assembled relative to the other identified EST sequences using phrap: in addition, the consensus DNA
sequences obtained were often (but not always) extended using repeated cycles of BLAST and phrap to extend the consensus sequence as far as possible using the sources of EST sequences discussed above.
Based upon the consensus sequences obtained as described above, oligonucleotides were then synthesized and used to identify by PCR a cDNA library that contained the sequence of interest and for use as probes to isolate WO 99146281 PCTlUS99/05028 a clone of the full-length coding sequence for a PRO polypeptide. Forward (.f) and reverse (.r) PCR primers generally range from 20 to 30 nucleotides and are often designed to give a PCR
product of about 100-1000 by in length. The probe (.p) sequences are typically 40-55 by in length. In some cases, additional oligonucleotides are synthesized when the consensus sequence is greater than about 1-1.Skbp. In order to screen several libraries for a full-length clone, DNA from the libraries was screened by PCR amplification, as per Ausubel et al., Current Protocols in Molecular BioloQV, with the PCR primer pair. A positive library was then used to isolate clones encoding the gene of interest using the probe oligonucleotide and one of the primer pairs.
The cDNA libraries used to isolate the cDNA clones were constructed by standard methods using commercially available reagents such as those from lnvitrogen, San Diego, CA.
The cDNA was primed with oligo dT containing aNod site, linked with blunt to SaII hemikinased adaptozs, cleaved with Notl, sized appropriately by : gel electrophoresis, and cloned in a defined orientation into a suitable cloning vector (such as pRKB or pRKD;
pRKSB is a precursor of pRKSD that does not contain the SftI site; see, Holmes et al., Science, 25:1278-1280 (1991)) in the unique Xhol and Notl sites.
EXAMPLE 2: Isolation of cDNA clones by Amylase Screening 1. )'reparation of oligo dT primed cDNA library mRNA was isolated from a human tissue of interest using reagents and protocols from Invitrogen, San Diego, CA (Fast Track 2). This RNA was used to generate an oligo dT primed cDNA library in the vector pRKSD
using reagents and protocols from Life Technologies, Gaithersburg, MD (Super Script Plasmid System). In this procedure, the double stranded cDNA was sized to greater than 1000 by and the SalI/Nod Tinkered cDNA was cloned into XhoIINotI cleaved vector. pRKSD is a cloning vector that has an spb transcription initiation site followed by an SfiI restriction enzyme site preceding the XhoIINotI cDNA cloning sites.
2. preparation of random primed cDNA library A secondary cDNA library was generated in order to preferentially represent the 5' ends of the primary cDNA clones. Sp6 RNA was generated from the primary library {described above), and this RNA was used to generate a random primed cDNA library in the vector pSST-AMY.O using reagents and protocols from Life Technologies (Super Script Plasmid System, referenced above). In this procedure the double stranded cDNA was sized to 500-1000 bp, Tinkered with blunt to NotI adaptors, cleaved with SfiI, and cloned into SfiIINotl cleaved vector. pSST-AMY.O is a cloning vector that has a yeast alcohol dehydrogenase promoter pseceding the cDNA
cloning sites and the mouse amylase sequence (the mature sequence without the secretion signal) followed by the yeast alcohol dehydrogenase terminator, after the cloning sites. Thus, cDNAs cloned into this vector that are fused in frame with amylase sequence will lead to the secretion of amylase from appropriately transfected yeast colonies.
3, Trancfnrmation and Detection DNA from the library described in paragraph 2 above was chilled on ice to which was added electrocompetent DNIOB bacteria (Life Technologies, 20 ml). The bacteria and vector mixture was then electroporated as recommended by the manufacturer. Subsequently, SOC media (Life Technologies, 1 ml) was added and the mixture was incubated at 37°C for 30 minutes. The transformants were then plated onto 20 standard 150 mm LB plates containing ampicillin and incubated for 16 hours {37°C).
Positive colonies were scraped off the plates and the DNA was isolated from the bacterial pellet using standard protocols, e.g. CsCI-gradient. The purified DNA
was then carried on to the yeast protocols below.
The yeast methods were divided into three categories: (1) Transformation of yeast with the plasmidlcDNA
combined vector; (2} Detection and isolation of yeast clones secreting amylase; and (3) PCR amplification of the insert directly from the yeast colony and purification of the DNA for sequencing and further analysis.
The yeast swain used was HD56-SA (ATCC-90785). This strain has the following genotype: MAT alpha, ura3-52, leu2-3, leu2-112, his3-11, his3-15, MAL+, SUC+, GAL''. Preferably, yeast mutants can be employed that have deficient post-translational pathways. Such mutants may have uanslocation deficient alleles in sec7l, sec72, sec62, with truncated sec71 being most preferred. Ahernatively, antagonists (including antisense nucleotides andlor Iigands) which interfere with the normal operation of these genes, other proteins implicated in this pcast translation pathway (e.g., SEC6lp, SEC72p, SEC62p, SEC63p, TDl 1p or SSAlp~lp) or the complex formation of these proteins may also be preferably employed in combination with the amylase-expressing yeast.
Transformation was performed based on the protocol outlined by Gietz et al., Nucl. Acid. Rtes., ~l;1425 (1992). Transformed cells were tlten inoculated from agar into YEPD complex media broth (100 ml) and grown overnight at 30°C. The YEPD broth was prepared as described in Kaiser et al., Methods in Yeast Genetics, Cold Spring Harbor Press, Cold Spring Harbor, NY, p. 207 (1994). The overnight culture was then diluted to about 2 x 106 cellslml (approx. ODD=0.1) into fresh YEPD broth (500 mt) and regrown to 1 x' IO cellslml (approx.
ODD=0.4-0.S).
The cells were then harvested and prepared for transformation by transfer into GS3 rotor bottles in a Sorval GS3 rotor at 5,000 rpm for 5 minutes, ~ supernatant discarded, and then resuspended into sterile water, and centrifuged again in 50 ml falcon tubes at 3,500 rpm in a Beckman GS-6KR
centrifuge. The supernatant was discarded and the cells were subsequently washed with LiAclT'E (10 ml, 10 mM
Tris-HCI, 1 mM EDTA pH 7.5, 100 mM LiZOOCCH~), and resuspended into iaAclTE (2.5 ml).
Transformation took place by mixing the prepared cells (100 ~c1) with freshly denatured single stranded salmon testes DNA (Lofstrand Labs, Gaithersburg, MD) and transforming DNA {I
fig, vol. < IO ~l) in microfuge tubes. The mixture was mixed briefly by vortexing, then 40% PEGITE (600 1l, 40% polyethylene glycol-4000, 10 mM Tris-HCI, 1 mM EDTA, 100 nnM LizOOCCH3, pH 7.5) was added. This mixture was gently mixed and incubated at 30°C while agitating for 30 minutes. The cells were then heat shocked at 42°C for 15 minutes, and the reaction vessel centrifuged in a microfuge at 12,000 rpm for 5-10 seconds, decanted and resuspended into TE (500 1c1, 10 mM Tris ICI, 1 mM EDTA pH 7.5) followed by recentrifugation. The cells were then diluted into TE (I ml) and aliquots (200 u1) were spread onto the selective media previously prepared in 150 mm growth plates (VWR).
Alternatively, instead of multiple small reactions, the transformation was performed using a single, large scale reaction, wherein reagent amounts were scaled up accordingly.
The selective media used was a synthetic complete dextrose agar lacking uracil (SCD-Ura) prepared as descn'bed in Kaiser et aL,1_ylethcxis in~east Genetic, Cold Spring Harbor Press, Cold Spring Harbor, NY, p. 208-2i0 (1994). Transformants were grown at 30°C for 2-3 days.
The detection of colonies secreting amylase was performed by including red starch is the selective growth media. Starch was coupled to the red dye (Reactive Red-120, Sigma) as per the procedure described by Biely et al. , A~l- Biochem , 1~:i76-179 (1988). The coupled starch was incorporated into the SCD-Ura agar plates at a final concentration of 0.15 i6 (w/v), and was buffered with potassium phosphate to a pH of 7.0 (50-100 mM final WO 9914d281 PCT/US99/05028 concentration).
The positive colonies were picked and streaked across fresh selective media (onto 150 tnm plates) in order to obtain well isolated and identifiable single colonies. WeII isolated single colonies positive for amylase secretion were detected by direct incorporation of red starch into buffered SCD-Ura agar. Positive colonies were determined by their ability to break down starch resulting in a clear halo around the positive colony visualized directly.
4. Isolation of DNA by PCR Amplification When a positive colony was isolated, a portion of it was picked by a toothpick and diluted into sterile water (30 p1) in a 96 well plate. At this time, the positive colonies were either frozen and stored for subsequent analysis or immediately amplified. An aliquot of cells (5 ~.I) was used as a template for the PCR reaction in a 25 gel volume i0 containing: 0.5 p.1 Klentaq (Clontech, Palo Alto, CA); 4.0 ~d 10 mM dNTP's (Perkin Elmer-Cecus); 2.5 uI Kentaq buffet (Clontech); 0.25 ~1 forward oligo 1; 0.25 u1 reverse oligo 2; 12.5 u1 distilled water. The sequence of the forward oligonucleotide 1 was:
5'-TGTAAAACGACGGCCAGTTAAATAGACCTGCAATTATTAATCT-3' {SEQ ID N0:324) The sequence of reverse oligonucleotide 2 was:
5'-CAGGAAACAGCTATGACCACCTGCACACCTGCAAATCCATT-3' (SEQ ID N0:325) PCR was then performed as follows:
a. Denature 92°C, 5 minutes b. 3 cycles of: Denature 92°C, 30 seconds Anneal 59°C, 30 seconds Extend 72°C, 50 seconds c. 3 cycles of: Denature 92°C, 30 seconds Anneal 57°C, 30 seconds Extend 72°C, 60 seconds d. 25 cycles of: Denature 92°C, 30 seconds Anneal S5°C, 30 seconds Extend 72°C, b0 seconds e. Hold 4°C
The underlined regions of the oligonucleotides annealed to the ADH promoter region and the amylase region, respectively, and amplified a 307 by region from vector pSST-AMY.O
when no insert was present. Typically, the first 18 nucleotides of the 5' end of these oligonucleotides contained annealing sites for the sequencing primers.
Thus, the total product of the PCR reaction from an empty vector was 343 bp.
However, signal sequence-fused cDNA resulted in considerably longer nucleotide sequences.
Following the PCR, an aliquot of the reaction (5 u1) was examined by agarose gel electrophoresis in a 1 ~
agarose gel using a Tris-Borate-EDTA (TBE) buffering system as described by Sambrook et al., supra. Clones resulting in a single strong PCR product larger than 400 by were further analyzed by DNA sequencing after purification with a 96 Qiaquick PCR clean-up column (Qiagen Inc., Chatsworrh, CA).

WO 99146281 PCTIUS99l05028 FxAMPLE 3: Isolation of cDNA Clones Encodi~g,~uman 1'Rf,~213 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA2873S. Based on the DNA28735 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA
library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR02I3.
A pair of PCR primers (forward and reverse) were synthesized:
forward PCR Erimer 5'-TGGAGCAGCAATATGCCAGCC-3' (SHQ ID N0:3) reverse PCR primer 5'-TTTTCCACTCCTGTCGGGTTGG-3' (SEQ ID N0:4) Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA28735 sequence which had the following nucleotide sequence hy~ri~dization probe 5'-GGTGACACTTGCCAGTCAGATGTGGATGAATGCAGTGCTAGG.AGGG-3' (SEQ ID NO:S) In order to screen several libraries for a source of a full-length clone. DNA
from the libraries was screened by PCR amplification with the PCR primer pair idemified above. A positive library was then used to isolate clones encoding the PR0213 gene using the probe oligonucleotide and one of the PCR
primers. RNA for construction of the cDNA libraries was isolated from human fetal lung tissue.
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0213 jherein designated as UNQ187 (DNA30943-1163)] (SEQ ID NO:1) and the derived protein sequence for PR0213.
The entire nucleotide sequence of UNQ187 (DNA30943-1163) is shown in Figure 1 (SEQ ID NO:1). Clone UNQ187 (DNA30943-1163) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 336-338 and ending at the stop codon at nucleotide positions 1221-1223 (Figure 1). The predicted polypeptide precursor is 295 antino acids long (Figure 2). Clone UNQ187 (DNA30943-1163) has been deposited with ATCC.
Analysis of the amino acid sequence of the full-length PR0213 polypeptide suggests that a portion of it possesses significant homology to the human growth arrest-specific gene 6 protein. More specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced significant homology between the PR0213 amino acid sequence and the following Dayhoff sequences, HSMHC3WSA 6 and B48089.
]AMPLE 4: Isolation~f~,DNA Clones Encoding~t PR0274 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA36469. Based on the DNA36469 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA
library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0274. ESTs proprietary to Genentech were employed in the consensus assembly. The ESTs are shown in Figures 5-7 and are herein designated DNA17873, DNA36157 and DNA28929, respectively.
Pairs of PCR primers (forward and reverse) were synthesized:
forward PCR~primer ,~6469_fl,~ 5'-CTGATCCGGTTCTTGGTGCCCCTG-3' (SEQ ID NO:11) forward PCR pr.~'meT ~ t~~469 fZ) 5'-GCTCTGTCACTCACGCTC-3' (SEQ ID N0:12) f~ arw td PCR prim r (3=5469 f3) 5'-TCATCTCTTCCCTCTCCC-3' (SEQ ID N0:13) forward PCR primer 4 (~ 69 f415'-CCTTCCGCCACGGAGTTC-3' (SEQ ID N0:14) WO 99/46281 PCTlUS99/05028 reverse PCR primer I 36469.r1) S'-GGCAAAGTCCACTCCGATGATGTC-3' (SEQ ID NO:15) reverse PC~2 primer 2 136469.f~ 5'-GCCTGCTGTGGTCACAGGTCTCCG-3' (SEQ ID N0:16) Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA36469 sequence which had the following nucleotide sequence hybridization vrobe t36469.n1) 5'-TCGGGGAGCAGGCCTTGAACCGGGGCATTGCTGCTGTCAAGGAGG-3' (SEQ ID N0:17) In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PR0274 gene using the probe oligonucleotide and one of the PCR
primers. RNA for construction of the cDNA libraries was isolated from human fetal liver tissue (LIB229).
. DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0274 [herein designated as UNQ241 (DNA39987-1184)j (SEQ ID NO:1) and the derived protein sequence for PR0274.
The entire nucleotide sequence of UNQ241 (DNA39987-1184) is shown in Figure 3 (SEQ ID N0:6). Clone UNQ241 (DNA39987-1184) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 83-85 and ending at the stop codon at nucleotide positions 1559-1561 (Figure 3). The predicted polypeptide precursor is 492 amino acids long (Figure 4), has an estimated molecular weight of about 54,241 daltons and an estimated pI of about 8.21. Clone UNQ241 (DNA39987-1184) has been deposited with ATCC and is assigned ATCC deposit no. 209786.
Analysis of the amino acid sequence of the full-length PR0274 polypeptide suggests that it possesses significant homology to the Fn54 protein. More specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced significant homology between the PR0274 amino acid sequence and the following Dayhoff sequences, MMFN54S2 1, MMFN54S1l1, CELF48C1'8, CEF38B7 6, PRP3 RAT, INL3 PIG, MTCY07A?_13, YNAX_KLEAE, A47234 and HME2_MOUSE.
EXAMPLE 5: lsol tion of cDNA Clones Encoding Human PRO300 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA35930. Based on the DNA35930 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA
library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0300.
Forward and reverse PCR primers were synthesized:
forward PCR primer 1 (35930.f1) 5'-GCCGCCTCATCTTCACGTTCTTCC-3' (SEQ ID N0:20) forwgrd PCR primer 2 (35930,,~2~ 5'-TCATCCAGCTGGTGCTGCTC-3' (SEQ ID N0:21) forward PCR vrimer 3 (35930.f3) 5'-CTTCTTCCACTTCTGCCTGG-3' (SEQ ID N0:22) forward PCR grimer 4 f35930.f4) 5'-CCTGGGCAAAAATGCAAC-3' (SEQ ID N0:23) reverse PCR primer 1 (35930.r1) 5'-CAGGAATGTAGAAGGCACCCACGG-3' (SEQ ID N0:24) reverse PCR primer 2~35930,;~~ S'-TGGCACAGATCTTCACCCACACGG-3' (SEQ ID N0:25) Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA35930 sequence which had the following nucleotide sequence hybridization probe 135930.n11 5'-TGTCCATCATTATGCTGAGCCCGGGCGTGGAGAGTCAGCTCTACAAGCTG-3' (SEQ ID N0:26) In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PR0300 gene using the probe oligonucieotide and one of the PCR
primers. RNA for construction of the cDNA libraries was isolated from human fetal kidney tissue.
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0300 (herein designated as UNQ263 (DNA40625-1189)] (SEQ ID NO:18) and the derived protein sequence for PR0300.
The entire, nucleotide sequence of UNQ263 (DNA40625-1189) is shown in Figure 8 (SEQ ID N0:18).
Clone UNQ263 (DNA40b25-1189) contains a single open reading frame with an apparent translationaI initiation site at nucleotide positions 457 and ending at the stop colon at nucleotide positions 1416-1418 (Figure 8). The predicted polypeptide precursor is 457 amino acids long (Figure 9). Clone UNQ263 (DNA40625-I 189} has been deposited with ATCC and is assigned ATCC deposit no. 209788.
Analysis of the amino acid sequence of the full-length PR0300 polypeptide suggests 'that portions of it possess significant homology to the Diff 33 protein. More specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced significant homology between the PR0300 ;amino acid sequence and the following Dayhoff sequence, HSU49188 1.
EXAMPLE 6: Isolation of cDNA Clones E,~coding Human PR0~84 Two cDNA sequences were isolated in the amylase screen described in Example 2 and those cDNA
sequences are,herein designated DNA12982 (see Figure 12; human placenta-derived) and DNA15886 (see Figure 13; human salivary gland-derived). The DNA12982 and DNA15886 sequences were then clustered and aligned, giving rise to a consensus nucleotide sequence herein designated DNA18832.
Based on the DNA18832 consensus sequence, oligonucleotide probes were generated and used to screen a human placenta library (LI$89) prepared as described in paragraph I of Example 2 above. The cloning vector was -pRKSB (pRKSB is a precursor of pRKSD that does not contain the SfiI site; see, Holmes et al., Sc_ fence, ~53:1278-1280 (1991)), and the cDNA size cut was less than 2800 bp.
PCR primers (forward and reverse) were synthesized:
~rward PCR p~ em r 1 (~$l~~t",f~ 5'-TCGTACAGTTACGCTCTCCC-3' (SEQ ID N0:31) forward PCR vrimer 2 (18832 t~ 5'-CTTGAGGAGCGTCAGAAGCG-3' (SEQ ID N0:32) reverse PCR prZmer ~8832.rt 5'-ATAACGAATGAAGCCTCGTG-3' (SEQ ID N0:33) Additionally, a synthetic oIigonucieotide hybridization probe was constructed from the DNAI8$32 sequence which had the following nucleotide sequence hvbridizatio0 probg (18832 b1 S'-GCTAATATCTGTAAGACGGCAGCTACAGCAGGCATCATTG-3' (SEQ ID N0:34) In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with the PCR primer pairs identified above: A positive library was then used to isolate clones encoding the PR0284 gene using the probe oligonucleotide and one of the PCR
primers.
A full length clone was identified that contained a single open reading frame with an apparent transiational initiation site at nucleotide positions 167-169 and ending at the stop colon found at nucleotide positions 1022-1024 (Figure Z0; SEQ ID NO:Z?). The predicted poiypeptide precursor is 285 amino acids long, has a calculated molecular weight of approximately 32,190 daltons and an estimated pI of approximately 9.03. Analysis of the full-WO 9914b281 PCT/US99/05028 length PR0284 sequence shown in Figure l I (SEQ ID N0:28) evidences the presence of the following: a signal peptide from about amino acid 1 to about amino acid 24, transmembrane domains from about amino acid 76 to about amino acid 96 and from about amino acid I71 to about amino acid 195 and a potential N-glycosylation site from about amino acid 153 to about amino acid 156. Clone UNQ247 (DNA23318-1211) has been deposited with ATCC on April 21, 1998 and is assigned ATCC deposit no. 209787.
Analysis of the amino acid sequence of the full-length PR0284 polypeptide suggests that it possesses no significant sequence similarity to any known protein. However, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced some degree of homology between the PR0284 amino acid sequence and the following Dayhoff sequences, JQ0124, CELE04A4 5, AB006451~1, AF030162_l, IM23 YEAST, 571194, NIA_CUCMA, IM17 YEAST, I50479 and HUMZFIiP'1.
EXAMPLE 7: Isolation of cDNA Clones Encoding HurJnan PR0296 A cDNA sequence isolated in the amylase screen as described in Example 2 above was found, by BLAST
and FastA sequence alignment, to have sequence homology to a nucleotide sequence encoding sarcoma-associated protein SAS. This cDNA sequence is herein designated DNA23020 (see Figure 16).
The DNA23020 sequence was IS then compared to a variety of expressed sequence tag (EST) databases which included public EST databases (e.g., GenBank) and a proprietary EST DNA database (LIFESEQT"', Incyte Pharmaceuticals, Palo Alto, CA) to identify existing homologies. The homology search was performed using the computer program BLAST or BLAST2 (Altshul et al., Methods in Enz~tmoiogy 2~"ø6 :460-480 (1996)). Those comparisons resulting in a BLAST score of 70 (or in some cases 90) or greater that did not encode known proteins were clustered and assembled into a consensus DNA
sequence with the program "phrap" (Phil Green, University of Washington, Seattle, Washington;
http:llbozeman.mbt.Washington.edulphrap.docslphrap.html). The consensus sequence obtained therefrom is herein designated DNA35858. Two proprietary Genentech ESTs were employed in the assembly wherein those EST
sequences are herein identified as DNA2I97I (Figure 17; SEQ ID N0:38) and DNA29037 (Figure 18; SEQ ID
N0:39).
Based on the DNA35858 consensus sequence, oligonucleotide probes were generated and used to screen a human kidney library (LIB228) library prepared as described in paragraph 1 of Example 2 above. The cloning vector was pRKSB (pRKSB is a precursor of pRKSD that does not contain the SfiI
site; see, Holines et al., Sci" epee, 25:1278-1280 (1991)), and the cDNA size cut was less than 2800 bp.
PCR primers (forward and reverse) were synthesized:
~rward PCR primer 1 135858.f115'-ACCCACGTCTGCGTTGCTGCC-3' (SEQ ID N0:40) forward PCR primer 2 t35858.f1) 5'-GAGAATATGCTGGAGAGG-3' (SEQ ID N0:41) reverse PCR~rimerS33858.r115'-AGGAATGCACTAGGATTCGCGCGG-3' (SEQ ID N0:42) Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA35858 sequence which had the following nucleotide sequence hybridization probe f35858.v~1 5'-GGCCCCAAAGGCAAGGACAAAGCAGCTGTCAGGGAACCTCCGCCG-3' (SEQ ID N0:43) In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PR0296 gene using the probe -oligonucleotide and one of the PCR
primers.

WO 99/46281 PCTlUS99105028 A full length clone was identified that contained a single open reading frame with an apparent translational initiation site at nucleotide positions 174-176 and ending at the stop colon found at nucleotide positions 786-788 (Figure 14; SEQ ID N0:35). The predicted polypeptide precursor is 204 amino acids Long, has a calculated molecular weight of approximately 22,147 daltons and an estimated pI of approximately 8.37. Analysis of the full-length PR0296 sequence shown in Figure 15 (SEQ ID N0:36) evidences the presence of the following: a signal peptide from about amino acid I to about amino acid 34 and transmembrathe domains from about amino acid 47 to about amino acid 63, from about amino acid ?2 to about amino acid 95 and from about amino acid 162 to about amino acid 182. Clone UNQ260 (DNA39979-1213) has been deposited with A'TCC on April 21, 1998 and is assigned ATCC deposit no. 209789.
Analysis of the amino acid sequence of the full-length PR0296 polypeptide suggests that it possesses significant sequence similarity to the sarcoma-amplifed SAS protein, thereby indicating that PR0296 may be a novel SAS homolog. More specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 3S) evidenced significant homology between the PR0296 amino acid sequence and the following Dayhoff sequences, I5839i, GEN11,061, SSC2B04 1, HSU81031 2, CD63 RAT, CD63 MOUSE, CD63 HUMAN, AF022813_I, CD63 RABIT and C002 HUMAN.
IS
EXAMPLE 8: Isolation of cDN,A Clqnes Encoding Human PR0329 A consensus sequence was obtai~d relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA3S612. Based on the DNA3S6I2 consensus sequence, oligonucIeotides were synthesized: 1) to identify by PCR a cDNA
library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0329.
PCR primers (forward and reverse) were synthesized:
forward PCR rp ime~l (35612 f1) 5'-TGGGCTGTGTCCTCATGG-3' (SEQ ID N0:46) forward PCR primer 2 135612 f215'-TTTCCAGCGCCAATTCTC-3' (SEQ ID N0:47) reverse PCR vrimer I 13,6,12 r() 5'-AGTTCTTGGACTGTGATAGCCAC-3' (SEQ ID N0:48) reverse PCR primed 21356I2 r2) 5'-AAACTTGGTTGTCCTCAGTGGCTG-3' (SEQ ID N0:49) Additionally, a synthetic oligoaucleotide hybridization probe was constructed from the.consensus DNA3S612 sequence which had the following nucleotide sequence hvbridi~ation_probe (3S6I2 nIl S'-GTGAGGGACCTGTCTGCACTGAGGAGAGCAGCTGCCACACGGAGG-3' (SEQ ID NO:50) In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with the PCR primer pairs identified above: A positive library was then used to isolate clones etxoding the PR0329 gene using the probe oIigonucleotide and one of the PCR
primers. RNA for constntction of the cDNA libraries was isolated from (roman fetal liver tissue (LIB6).
DNA sof the clones isolated as described above gave the full-length DNA
sequence for PR0329 [herein designated as UNQ29I (DNA40594-1233)) (SEQ ID N0:44) and the derived protein sequence for PR0329.
The entire nucleotide sequence of UNQ291 (DNA40594-1233) is shown in Figure 19 (SEQ ID N0:44).
Clone UNQ291 t'DNA40594-1233) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 9-11 and ending at the stop colon at nucleotide positions 1086-10$8 (Figure 19). The predicted polypeptide precursor is 359 amino acids song (Figure 20). The full-length PR0329 protein shown in WO 99/d6281 PCT/US99/05028 Figure 20 has an estimated molecular weight of about 38,899 daltons and a pI
of about 5.21. Clone UNQ291 (DNA40594-1233) has been deposited with ATCC on February S, 1998 and is assigned ATCC deposit no. 209617.
Analysis of the amino acid sequence of the full-length PR0329 polypeptide suggests that it possesses significant sequence similarity to a high affinity immunoglobulin F~ receptor protein. More specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced significant homology between the PR0329 amino acid sequence and the following Dayhoff sequences, FCG1 HUMAN, FCGO HUMAN, P
891439, P 822549, P R9I438, P W00859, P~R20811, P 822550, HUMCD6406 1 and FCG1 MOUSE.
EXAMPLE 9: Isolation of cDNA Clones Encoding Human PR0362 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA42257. Based on the DNA42257 consensus .
sequence, oIigonucleotides were synthesized: 1 ) to identify by PCR a cDNA
library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0362.
PCR primers (forward and reverse) were synthesized:
forward primerf42257.f1)5'-TATCCCTCCAATTGAGCACCCTGG-3' (SEQ
PCR 1 ID N0:53}

~rward primer142~57.t215'-GTCGGAAGACATCCCAACAAG-3' (SEQ ID
PCR 2 N0:54) reverse timer 142257.r1)5'-CTTCACAATGTCGCTGTGCTGCTC-3' (SEQ
PCR 1 ID N0:55) reverse primer(42257.r2)5'-AGCCAAATCCAGCAGCTGGCTTAC-3' (SEQ
PC~t_ 2 1D N0:56) Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA42257 sequence which had the following nucleotide sequence hybridization probe 142257.n1) 5'-TGGATGACCGGAGCCACTACACGTGTGAAGTCACCTGGCAGACTCCTGAT-3' (SEQ ID N0:57) In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened' by PCR amplification with the PCR primer pairs identified above. A positive library was then used to isolate clones encoding the PR0362 gene using the probe oligonucleotide and one of the PCR
primers. RNA for construction of the cDNA libraries was isolated from human fetal brain tissue (LIB153).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0362 [herein designated as UNQ317 (DNA45416-1251)] (SEQ ID N0:51) and the derived protein sequence for. P80362.
The entire nucleotide sequence of UNQ317 (DNA45416-1251} is shown in Figure 21 (SEQ ID N0:51).
Clone UNQ317 (DNA45416-1251) contains a single open reading frame with an apparent uanslational initiation site at nucleotide positions 119-121 and ending at the stop codon at nucleotide positions 1082-1084 (Figure 21}. The predicted polypeptide precursor is 321 amino acids long (Figure 22). The full-length PR0362 protein shown in Figure 2 has an estimated molecular weight of about 35,544 dahons and a p1 of about 8.51. Analysis of the full-length PR0362 polypeptide as shown in Figure 22 evidences the presence of a glycosaminoglycan attachment site at about amino acid 149 to about amino acid 152 and a transmembratte domain from about amino acid 276 to about amino acid 306. Clone UNQ317 (DNA45416-1251) has been deposited with ATCC on February 5, 1998 and is assigned ATCC
deposit no. 209620.
Analysis of the amino acid sequence of the full-length PR0362 polypeptide suggests that it possesses significant sequence similarity to the A33 antigen protein and the HCAR
protein. More specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced significant homology between the PRO362 amino acid 1$$

WO 99!46281 PCTIUS99105028 sequence and the following I?ayhoff seguences, AB00234I_l, HSU55258.-1, HSC?NRCAM~1, RNU81037~1, A33 HUMAN, P WI4158, NMNCAMRI_l, HST1TINN2_t, S71824_1 and HSU63041_l.
)jXAMPLE 14: Isolation of cDNA Clones Encoding Human PR03b3 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is hereindesignated DNA42828. Based on the DNA42828 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA
library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0363.
A pair of PCR primers (forward and reverse) were synthesized:
forward PCR,pi'imer ~42828.f_l~ 5'-CCAGTGCACAGCAGGCAACGAAGC-3' (SEQ ID N0:60) reverse PCR primer (428~8.r1) 5'-ACTAGGCTGTATGCCTGGGTGGGC-3' (SEQ ID N0:61) Additionally, a synthetic oligonucieotide hybridization probe was constructed from the consensus DNA42828 sequence which had the following nucleotide sequence hybridization probe (42828 n!) 5'-GTATGTACAAAGCATCGGCATGGTTGCAGGAGCAGTGACAGGC-3' (SEQ ID N0:62) In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with the FCR primer pair identified above. A positive library was then used to isolate clones encoding the PR03b3 gene using the probe oligonucleotide and one of the PCR
primers. RNA for construction of the cDNA libraries was isolated from human fetal kidney tissue (LiB227).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0363 [herein designated as UNQ318 (DNA45419-1252)] (SEQ ID N0:58) and tire derived protein sequence for PR03b3.
The entire nucleotide sequence of UNQ318 (DNA45419-1252) us shown in Figure 23 (SEQ ID N0:58).
Clone UNQ318 (DNA45419-1252) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 190-192 and ending at the stop codon at nucleotide positions 1309-131 I (Figure 23). The predicted polypeptide precursor is 373 amino acids long (Figure 24). The futi-length PR0363 protein shown in Figure 24 has an estimated molecular weight of about 41,281 daItons and a p1 of about 8.33. A transmernbrane domain exists at amino acids 221 to 254 of the amino acid sequence shown in Figure 24 (SEQ ID N0:59). The PR0363 polypeptide also possesses at least two myelin PO protein domains from about amino acids 15 to 56 and from about amino acids 87 to l I6. . Clone UNQ318 (DNA45419-1252) has been deposited with ATCC on February 5, 1998 and is assigned ATCC deposit no. 209616.
Analysis of the amino acid sequence of the full-length PR0353 polypeptide suggests that it possesses significant sequence similarity to the cell surface protein HCAR, thereby indicating that PR0363 may be a novel HCAR homolog. More specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced significant homology between the PR0363 atnino acid sequence and the following Dayhoff sequences, HS46KDA_1, HSU90716 1, MMCARH_l, MMCARHOM_l, MMU90715_l, A33 HUMAN, P_W14146, P_W14158, and B42632.
FXA~1 ,: Isolation of cDNg,~Clonec Enco~l'~t Human PR"~868 A consensus sequence was obtaica~d relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA38133. Based on the DNA38133 consensus sequence, oligonucleotides were synthesized: 1 ) to identify by PCR a cDNA
library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0868.
A pair of PCR primers (forward and reverse) were synthesized:
forward PCR~rimer (38133.f115'-GTAGCAGTGCACATGGGGTGTTGG-3' (SEQ 1D N0:65) reverse PCR primer (38133.r1) 5'-ACCGCACATCCTCAGTCTCTGTCC-3' (SEQ ID NO:b6) Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA38I33 sequence which had the following nucleotide sequence hybridization probe 138133.x11 5'-ACGATGATCGCGGGCTCCCTTCTCCTGCTTGGATTCCTTAGCACCACCAC-3' (SEQ ID N0:67) In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PR0868 gene using the probe oligonucleotide and one of the PCR
primers. RNA for construction of the cDNA libraries was isolated from human fetal kidney tissue (LIB227).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PRO868 (herein designated as UNQ437 (DNA52594-1270)) (SEQ ID N0:63) and the derived protein sequence for PR0868.
The entire nucleotide sequence of UNQ437 (DNA52594-1270) is shown in Figure 25 (SEQ ID N0:63).
Clone UNQ437 (DNA52594-1270) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 325-327 and ending at the stop codon at nucleotide positions 2290-2292 (Figure 25). The predicted polypeptide precursor is 655 amino acids long (Figure 26). The full-length PR0868 protein shown in Figure 26 has an estimated molecular weight of about 71,845 daltons and a pI
of about 8.22. Analysis of the full-length PR0868 polypeptide sequence demonstrates the presence of conserved cysteine-containing domains from about amino acid 66 to about amino acid 78 and from about amino acid 123 to about amino acid 134 of the sequence shown in Figure 26 (SEQ ID N0:3), a TNFR death domain from about amino acid 85 to about amino acid 110, a FASA mouse death domain block from about amino acid 159 to about amino acid 175 and a transmembrane domain from about amino acid 347 to about amino acid 375. Clone UNQ437 (DNA52594-1270) has been deposited with ATCC on March 17, 1998 and is assigned ATCC deposit no. 209679 Analysis of the amino acid sequence of the full-length PR0868 polypeptide suggests that it possesses significant sequence similarity to the tumor necrosis factor receptor protein, thereby indicating that PR0868 may be a novel meraber of the tutnor necr~is factor receptor family. More specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced significant homology between the PR0868 amino acid sequence and the following Dayhoff sequences, RNU94330_l, P 899933, P 899945, P 899950, HSU94332 1, CD40 HUMAN, S63368_l, T'NRZ HUMAN, MVU87844 1 AND CVU87837_l.
EX~iPLE 12: Isolation of cDNA Clones Encoding Human PR0382 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA30892. Based on the DNA30892 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA
library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0382.
A pair of PCR primers (forward and reverse) were synthesized:
forward PCR primer 5'-TGACATCGCCCTTATGAAGCTGGC-3' (SEQ ID N0:70) reverse PCR primer 5'-TACACGTCCCTGTGGTTGCAGATC-3' (SEQ ID N0:71) Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA30892 sequence which had the following nucleotide sequence bKt~idization probe 5'-CGTTCAATGCAGAAATGATCCAGCCTGTGTGCCTGCCCAACTCTGAAGAG-3' (SEQ ID N0:72) In order to screen several libraries for a source of a foil-length clone; DNA
from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PR03$2 gene using the probe oligonucleotide and one of the PCR
primers. RNA for construction of the cDNA libraries was isolated from human fetal kidney tissue (LIB227).
DNA sequencing of the clones isolated as described above gave the ifull-length DNA sequence for PR0382 jherein designated as UNQ323 (DNA45234-1277)] (SEQ ID N0:68) and the derived protein sequence for PR0382.
The entire nucleotide sequence of UNQ323 (DNA45234-I277) is .shown in Figure 27 (SEQ ID N0:68).
Clone UNQ323 (DNA45234-1277) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 126-128 and ending at the stop codon at nucleotide positions 1485-1487 (Figure 27). The predicted polypeptide precursor is 453 amino acids long {Figure 28). The full-length PR0382 protein shown in Figure 28 has an estimated molecular weight of about 49,334 daltons and a pI
of about 6.32. Analysis of the native PR0382 amino acid sequence shown in Figure 28 (SEQ ID N0:69) indicates the presence of a putative transmembrane domain from about amino acid 240 to about amino acid 284, a putative signal peptide at about amino acid 1 to about amino acid 20, a putative apple domain at about amino acid 386 to about amino acid 4I9, a putative Kringle domain at about amino acid 394 to about amino acid 406 and a histidine-containing protease active site at about amino acid 253 to about amino acid 258. Clone UNQ323 (DNA45234-1277) has been deposited with ATCC
on March 5, 1998 and is assigned ATCC deposit no. 209654.
Analysis of the amino acid sequence of the full-length PR0382 polypeptide suggests that it possess significant homology to serine protease proteins, thereby indicating that PR0382 may be a novel serine protease.
Specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced significant homology ZS between the PR0382 amino acid sequence and the following Dayhoff sequences, HSU75329 I, ENTK_MOUSE, HEPS HUMAN, AF030065_l, HEPS RAT, PLMN PIG, P 889430, P 889935, PLMN HORSE;
PLMN BOVIN
and P 883959.
EXAMPLE i3: Isolation of cDNA Tones Encoding Human PR0545 A consensus sequence was obtained relative to a variety of EST seqltences as described in Example I above, wherein the consensus sequence obtained is herein designated DNA44706. An EST
proprietary to Genentech was employed in the consensus assembly and is herein designated DNA13217 (Figure 31; SEQ ID N0:75). Based on the DNA44706 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0545.
Forward and reverse PCR primers were synthesized:
forward PCR primers 5'-GTCTCAGCACGTGTTCTGGTCTCAGGG-3' (SEQ ID N0:7fi) f~vyrard pCR primer 2 5'-CATGAGCATGTGCACGGC-3' (SEQ ID NO:77) forward PCR primer 3 5'-TACCTGCACGATGGGCAC-3' (SEQ ID NO:78) forward PCR primer 4 5'-CACTGGGCACCTCCCTTC-3' (SEQ ID N0:79) reverse PCR~rirr~,er I 5'-CTCCAGGCTGGTCTCCAAGTCCTTCC-3' (SEQ ID N0:80) reverse PCR primer 2 5'-TCCCTGTTGGACTCTGCAGCTTCC-3' (SEQ ID N0:8I) reverse PCR,primer 3 5'-CTTCGCTGGGAAGAGTTTG-3' (SEQ ID N0:82) Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA44706 sequence which had the following nucleotide sequence hybridization pro,~e S'-GTGCAACCAACAGATACAAACTCTTCCCAGCGAAGAAGCTGAAAAGCGTC-3' (SEQ ID N0:83) In order to screen several libraries, for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with one of the PCR primer pairs identified above. A
positive library was then used to isolate clones encoding the PR0545 gene using the probe oligonucleotide and one of the PCR primers. RNA for construction of the cDNA libxaries was isolated from human placenta tissue (L1B90).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0545 [herein designated as UNQ346 (DNA49624-1279)] (SEQ ID NO:?3) and the derived protein sequence for PR0545.
The entire nucleotide sequence of UNQ346 (DNA49624-1279) is shown in Figure 29 (SEQ 1D N0:73).
Clone UNQ346 (DNA49624-1279) contains a single open reading frame with an apparent uanslational initiation site at nucleotide positions 3I1-313 and ending at the stop codon at nucleotide positions 2516 2518 (Figure 29). The predicted polypeptide precursor is 735 amino acids long (Figure 30): The full-length PR0545 protein shown in Figure 30 has an estimated molecular weight of about 80,177 daltons and a pI
of about 7.08. Important regions of the PR0545 amino acid sequence include the signal peptide, corresponding to amino acids 1-28, five potential N-glycosylation sites, from about amino acid 111-114, amino acids 146-149, amino acids 348-351, amino acids 449-452, and amino acids 648-651, and a neutral zinc metallopeptidase, zinc-binding region signature sequence, from about amino acids 344-353. Clone UNQ346 (DNA49624-1279) has been deposited with ATCC and is assigned ATCC deposit no. 209655.
EXAMPLE 14: Isolation o~cD~C~ne~Encoding Human PR0617 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA42798. Based on the DNA42798 sequence, oligorntcleotides were synthesized: 1) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0617.
A pair of PCR primers (forward and reverse) were synthesized:
forward PCR prim,.gr 5'-ACGGGCACACTGGATCCCAAATG-3' (SEQ ID N0:86) Feverse PCR primer 5'-GGTAGAGATGTAGAAGGGCAAGCAAGACC-3' (SEQ ID NO:8?) Additionally, a synthetic oligoztucleotide hybridization probe was constructed from the consensus DNA42798 sequence which had the following nucleotide sequence hybridization ro ~
5'-GCTCCCTACCCGTGCAGGTTTCTTCATTTGTTCCTTTAACCAGTATGCCG-3' (SEQ ID NO:88) In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PR0617 gene using the probe oligonucleotide and one of the PCR
primers. RNA for construction of the cDNA libraries was isolated from human fetal kidney tissue (LIB227).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0617 (herein designated as UNQ353 (DNA48309-1280)} (SEQ ID NO:1) and the derived protein sequence for PR0617.
The entire nucleotide sequence of UNQ353 (DNA48309-1280) is shown in Figure 32 (SEQ ID N0:84).
Clone UNQ353 (DNA48309-1280) contains a single open reading frame wiith an apparent uanslational initiation site at nucleotide positions ?23-725 and ending at the stop codon at nucleotide positions 924-926 (Figure 32). The predicted polypeptide precursor is 67 amino acids long (Figure 33). The ful>I-length PR0617 protein shown in Figure 33 has an estimated molecular weight of about 6,981 daltons and a pI of about 7.47. Analy~js of the PR0617 amino acid sequence also evidences the existence of a putative signal peptide from about amino acid 15 to about amino acid 27 and a putative protein kinase C phosphorylation site from about amino acid 41 to about amino acid 43. Clone UNQ353 t',DNA48309-1280) has been deposited on March 5, 1998 with .ATCC and is assigned ATCC deposit no.
209656.
Analysis of the amino acid sequence of the full-length PR0617 polypeptide suggests that it possesses significant homology to the CD24 protein, thereby indicating that PR0617 may be a novel CD24 homolog. More specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced significant homology between the PR0617 amino acid sequence and the following Dayhoff sequences, CD24 HUMAN, CD24 MOUSE, S15785, CD24 RAT, VGE BPG4, MSES HUMAN, HSMHC3W36A 2, MLUI51$4 8, P 885075, SEPL HUMAN
and MTCY63 13.
EXAMPLE 15: Isolation of cDNA Clones EneodingHuman PR0700 A consensus sequence was obtained relative tn a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA30837. Based on the DNA30837 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA
library that contained the sequence of interest, and 2) for use as prolxs to isolate a clone of the full-length coding sequence for PR0700.
Fotvvard and reverse PCR primers were synthesized:
forwa PCR nFimer 1 5'-ATGTTCTTCGCGCCCTGGTG-3' (SEQ ID N0:91) forward PCR pn'me_r 2? 5'-CCAAGCCAACACACTCTACAG-3' (SEQ ID N0:92) averse PCR"p~mer 1 5 -AAGTGGTCGCCTTGTGCAACGTGC-3 ' (SEQ ID N0:93) averse PC rimer 5'-GGTCAAAGGGGATATATCGCCAC-3' (SEQ ID NO~.94) Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA30837 sequence which had the following mtcleotide sequence hybridiz tion probe 5'-GCATGGAAGATGCCAAAGTCTATGTGGCTAAAGTGGACTGCACGGCCCA-3' (SEQ ID N0:95) In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with one of the PCR primer pairs identified above. A
positive library was then used to isolate clones encoding the PR07D0 gene using the probe oligonucleotide and one of the PCR primers. RNA for constrnction of the cDNA libraries was isolated from human fetal kidney tissue (L,IB227).

WO 99!46281 PCTlUS99/05828 DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0700 [herein designated as UNQ364 (DNA46776-1284)] (SEQ ID N0:89) and the derived protein sequence for PR0700.
The entire nucleotide sequence of UNQ364 (DNA46776-1284) is shown in Figure 34 (SEQ ID N0:89).
Clone UNQ3b4 (DNA46776-1284) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 33-35 and ending at the stop codon at nucleotide positions 1329-1331 (Figure 34). The predicted polypeptide precursor is 432 amino acids long (Figure 35). The full-length PR0700 protein shown in Figure 35 has an estimated molecular weight of about 47,629 daltons and a pI
of about 5.90. Important regions of the amino acid sequence of PR0700 include the signal peptide, corresponding to amino acids from about 1 to 33, regions homologous to disulfide isomerase, corresponding to amino acids from about 82-99, 210-255, and 345-360, a tyrosine kinase phosphorylation site, corresponding to amino acids from about 143-151, and an endoplasmic reticulum targeting sequence, corresponding to amino acids from about 429-432.
Clone UNQ364 (DNA46776-1284) has been deposited with ATCC and is assigned ATCC Deposit No. 209721.
EXAMP~.E 16: T~nlaric,n of cDNA Clones Encoding Human PR0702 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA36623. Based on the DNA36623 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA
library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PRO?02.
A pair of PCR primers (forward and reverse) were synthesized:
forward PCR~rimer (36623.f1) 5'-CGCTGACTATGTTGCCAAGAGTGG-3' (SEQ ID N0:98) reverse PCR printer 136623.r1) 5'-GATGATGGAGGCTCCATACCTCAG-3' (SEQ ID N0:99) Additionally, a synthetic oligorntcleotide hybridization probe was constructed from the consensus DNA36623 sequence which had the following nucleotide sequence ~,tvbridization probe 136623.n1) 5'-GTGTTCATTGGCGTGAATGACCTTGAAAGGGAGGGACAGTACATGTTCAC-3' (SEQ ID N0:100) 1n order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PR0702 gene using the probe oligonucleotide and one of the PCR
primers. RNA for construction of the cDNA libraries was isolated from human fetal liver tissue (L.IB229).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0702 [herein designated as UNQ366 tDNA50980-1286)] (SEQ ID N0:96) and the derived protein sequence for PR0702.
The entire nucleotide sequence of UNQ366 (DNA50980-1286) is shown in Figure 36 (SEQ ID N0:96).
C1one UNQ366 (DNA50980-1286) contains a single open reading frame with an apparent uanslational initiation site at nucleotide positions 22-24 and ending at the stop codon at nucleotide positions 853-855 (Figure 36). The predicted polypeptide precursor is 277 amino acids long (Figure 37). The full-length PR0702 protein shown in Figure 3? has an estimated molecular weight of about 30,645 daltons and a pI of about 7.47.
Analysis of the full-length native PR0702 amino acid sequence evidences the presence of a putative signal peptide from about amino acid 1 to about amino acid 25, potential N-glycosylation sites from about amino acid 230 to about amino acid 233 and from about amino acid 258 to about amino acid 261 and a C-type lectin domain signature sequence from about amino acid 248 to about amino acid 270. Glove UNQ366 (DNA50980-1286) has been deposited with ATCC on March 31, 1998 and is assigned ATCC deposit no. 209717.
Analysis of the amino acid sequence of the full-length PR0702 polypeptide suggests that it possesses significant sequence similarity to the conglutinin protein, thereby indicating that PR0702 may be a novel conglutinin homolog. More specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced significant homology between the PR0702 amino acid sequence and the following Dayhoff sequences, S32436, P 875642, P
WI8780, P W18781, A53330, AC002528 1, HSPPA2IC0 1; CA21 HUMAN, CA14 HUMAN and A61262.
EXAMPLE I7: Isolation of cDNA Clones Fncodin~l-I,t~trna~ PRQZ,O~
A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA43047. Based on the DNA43047 consensus sequence, oIigonucleotides were synthesized: 1) to identify by PCR a cDNA
library that contained the sequence of interest, and 2) far use as probes to isolate a clone of the full-length coding sequence for PR0703.
Forward and reverse PCR primers were synthesized:
forward PCR ,primer 5'-GAGAGCCATGGGGCTCCACCTG-3' (SEQ fD N0:103) reve se CR pritrter 1 5'-GGAGAATGTGGCCACAAC-3' (SEQ ID N0:104) reverse PCR primer 2 5'-GCCCTGGCACAGTGACTCCATAGACG-3' ($EQ ID NO:105) reverse PCR rimer 3 5'-ATCCACTTCAGCGGACAC-3' (SEQ ID N0:106) Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA40654 sequence which had the following nucleotide sequence hybridi~,alion probe 5'-CCAGTGCCAGGATACCTCTCTTCCCCCCAGAGCATAACAGACACG-3' (SEQ ID N0:107) 1n order to screen several libraries far a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with one of the PCR primer pairs identified above. A
positive library was then used to isolate clones encoding the PR0703 gene using the probe oligonucieotide and one of the PCR primers. RNA for construction of the cDNA libraries was isolated from human fetal kidney tissue (LIB227).
DNA sequencing of tla; clones isolated as described above gave the fitIl-length DNA sequence for PR0703 [herein designated as UNQ367 (DNA50913-1287)] (SEQ ID NO:I01 ) and the derived protein sequence for PR0703.
The entire nucleotide sequence of UNQ357 (DNA50913-1287) is shown in Figure 38 (SEQ ID NO:101).
Clone UNQ367 (DNA50913-1287) contains a single open reading frame with an apparent translational initiation site at nucleotide positions I IS-I17 and ending at the stop codon at nucleotide positions 2305-2307 (Figure 38). The predicted polypeptide precursor is 730 amino acids long (Figure 39). The full-length PR0703 protein shown in Figure 39 has an estimated molecular weight of about 78,644 daltons, and a p1 of about: 7.b5. Impor~taant regions of the PR0703 amino acid sequence include the signal peptide, a CAMP- and cGMP-dependent protein kinase phosphorylation site, a CUB domain protein motif, N-glycosyIation sites and a putative AMP-binding domain signature. Clone UNQ367 (DNAS0913-1287) has been deposited with ATCC and is assigned ATCC deposit no.
20971b.

EXAMPLE I8: Isolation of cDNA Clones Encoding Human FR0745 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA43437. Based on the DNA43437 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA
library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0705.
A pair of PCR primers (forward and reverse) were synthesized:
forward PCR~rimer 5'-AAGCGTGACAGCGGGCACGTC-3' (SEQ ID NO:110) reverse PCR primer 5'-TGCACAGTCTCTGCAGTGCCCAGG-3' (SEQ ID NO:111) Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA43437 sequence which had the following nucleotide sequence . h~rbridization probe 143437.n11 5'-GAATGCTGGAACGGGCACAGCAAAGCCAGATACTTGCCTG-3' (SEQ ID N0:112) In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PRO705 gene using the probe oligonucleotide and one of the PCR
primers. RNA for construction of the cDNA libraries was isolated from human fetal kidney tissue (LIB22?).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PRO?05 [herein designated as UNQ369 (DNA50914-1289)] (SEQ ID N0:108) and the derived protein sequence for PR0705.
The entire nucleotide sequence of UNQ369 (DNA50914-1289) is shown in Figure 40 (SEQ ID N0:108).
Clone UNQ369 fDNA50914-1289) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 566-568 and ending at the stop codon at nucleotide positions 2231-2233 (Figure 40). The predicted polypeptide precursor is 555 amino acids long (Figure 41). The full-length PR0705 protein shown in Figure 41 has an estimated molecular weight of about 62,736 daltons and a pI
of about 5.36. Analysis of the full-length PR0705 sequence as shown in Figure 41 evidences the presence of the following: a signal peptide from about amino acid 1 to about amino acid 23, a eukaryotic DNA topoisomerase I active site from about amino acid 418 to about amino acid 436, and various regions that show homology to various glypican proteins from about amino acid 237 to about amino acid 279, about amino acid 421 to about amino acid 458, about amino acid 53 to about amino acid 74, about amino acid 466 to about amino acid 504, about amino acid 308 to about amino acid 355, about amino acid 104 to about amino acid 156 and about amino acid 379 to about amino acid 410.
Clone UNQ369 (DNA50914-1289) has been deposited with ATCC on March 31, 1998 and is assigned ATCC deposit no.209722.
Analysis of the amino acid sequence of the full-length PR0705 poIypeptide suggests that it possesses significant sequence similarity to the K-glypican protein, thereby indicating that PR0705 may be a novel glypican protein family member. More specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced significant homology between the PR0705 amino acid sequence and the following Dayhoff sequences, GFCK _ - -MOUSE, GLYP CHICK, GLYP RA?, GLYP HUMAN, GPC2 RAT, GPCS HUMAN, GPC3 HUMAN, GPC3 RAT, P 830168 and CEC03H12 2.
E~MPLE 19: Zs_olation of cDNA Clones Encoding, Human PR0708 A consensus sequence was obtained relative to a variety of EST sequences as described in bxample 1 above, wherein the consensus sequence obtained is herein designated DNA34024. Based on the DNA34024 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA
library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0708.
A'pair of PCR primers (forward and reverse) were synthesized:
forward PCR primer 5'-CCCAACCCAACTGTTTACCTCTGG-3' (SEQ ID NO:115) reverse PAR primer S '-CTCTCTGAGTGTACATCTGTGTGG-3' (SEQ ID NO:I I6) Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA34024 sequence which had the following nucleotide sequence hybridization pro>2e 5'-GCCACCCTACCTCAGAAACTGAAGGAGGTTGGNTATTCAACGCATATGGTCGG-3' (SEQ ID NO:137) In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PR0708 gene using the probe oligonucleotide and one of the PCR
primers. RNA for construction of the cDNA libraries was isolated from human bone marrow tissue (LIB255).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PRO?08 [herein designated as UNQ372 (DNA48296-1292)] (SEQ ID NO: l I3) and the derived protein sequence for PR0708.
The entire nucleotide sequence of UNQ372 (DNA48296-1292) is shown in Figures 42A-B (SEQ ID
NO:I 13). Clone UNQ372 (DNA48296-1292) contains a single open reading frame with an apparent. translational initiation site at nucleotide positions 891-893 and ending at the stop codon at nucleotide positions 2436-2438 (Figures 42A-B). The predicted polypeptide precursor is 515 amino acids long (Figure 43). The full-length PR0708 protein shown in Figure 43 has an estimated molecular weight of about 56,885 daltons and a pI of about 6.49. Analysis of ZO the PR0708 amino acid sequence shown in Figure 43 (SEQ ID N0:114) evidences the existence of a putative signal peptide at about amine acid 1 to about amino acid 37, putative sulfatase signature sequences at about amino acid 120 to about amino acid 332 and about amino acid 168 to about amino acid I77, a putative tyrosine ldnase phosphorylation site from about amino acid 163 to about amino acid 169 and potential N-glycosylation sites from about amino acid 357 to about amino acid 160, about amino acid 306 to about amino acid 309 and about amino acid 318 to about amino acid 321. Clone UNQ372 (DNA48296-1292) has been deposited with ATCC on March i i , 1998 and is assigned ATCC deposit no. 209668.
Analysis of the amino acid sequence of the full-length PR0708 polypeptide suggests that it possesses significant homology to the aryl sulfatase proteins, thereby indicating that PR0708 may be a novel aryl sulfatase homolog. More specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced significant homology between the PR0708 amino acid sequence and the following Dayhoff sequences, ARSB_HUMAN, CELC54D2 2, 602857, STS HUMAN, I37186, I37187, GEN12648, CELD1014 ?, GAGS
HUMAN and SPHM HUMAN.
EXAMPLE 20: Isolation of cDNA Clones Enco_~Og HLma~PRCt~~
A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA2f739. Based on the DNA28739 consensus sequence, oligonucleotides were synthesized: i) to identify by PCR a cDNA
library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding equence for PR0320.

A pair of PCR primers (forward and reverse) were synthesized:
forward PCR~r~mer 5'-CCTCAGTGGCCACATGCTCATG-3' (SEQ ID N0:120) :reverse PCR primer 5'-GGCTGCACGTATGGCTATCCATAG-3' (SEQ ID N0:121) Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA28739 sequence which had the following nucleotide sequence S hvbridization probe 5'-GATAAACTGTCAGTACAGCTGTGAAGACACAGAAGAAGGGCCACAGTGCC-3' (SEQ ID N0:122) In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PR0320 gene using the probe oligonucleotide and one of the PCR
primers. RNA for construction of the cDNA libraries was isolated from human fetal lung tissue (LIB25).
DNA sequencing of the clones isolated as described above gave the fall-length DNA sequence for PR0320 [herein designated as UNQ281 (DNA32284-1307)] (SEQ ID N0:118) and the derived protein sequence for PR0320.
The entire nucleotide sequence of UNQ281 {DNA32284-1307) is shown in Figure 44 (SEQ ID N0:118).
Clone UNQ281 (DNA32284-1307) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 135-137 and ending at the stop codon at nucleotide positions 1149-i 151 (Figure 44). The predicted polypeptide precursor is 338 amino acids long (Figure 45). The full-length PR0320 protein shown in Figure 45 has an estimated molecular weight of about 37,143 daltons and a p1 of about 8.92. Important regions of the PR0320 amirm acid sequence include the signal peptide, corresponding to amino acids 1-21, an EGF-like domain cysteine pattern signature, corresponding to amino acids 80-91, and three calcium-binding EGF-like domains, corresponding to amino acids 103-124. 230-151 and 185-206, respectively. Clone UNQ281 (DNA32284-I307) has been deposited with ATCC and is assigned ATCC deposit no. 209670.
EXAMPLE 21: Isolation of cDN ~ Clones Encoding Human PR0324 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA34347. Based on the DNA34347 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA
library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0324.
PCR primers (forward and reverse) were synthesized:
forward~CR Qrimer 1 5'-GCAATGAACTGGGAGCTGC-3' (SEQ ID N0:125) fear PAR primer 2 5'-CTGTGAATAGCATCCTGGG-3' (SEQ ID N0:126) fo arv~R primer 3 5'-C1T1~TCAAGCCACTGGAGGG-3' . (SEQ ID N0:127) rgyerse PCR primer 1 5'-CTGTAGACATCCAAGCTGGTATCC-3' (SEQ ID N0:128) reverse PCR primer 2 S'-AAGAGTCTGCATCCACACCACTC-3' (SEQ ID N0:129) Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA34347 sequence which had the following nucleotide sequence I?yrridizati~n ,probe 5'-ACCTGACGCTACTATGGGCCGAGTGGCAGGGACGACGCCCAGAATG-3' (SEQ ID N0:130) In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with one of the PCR primer pairs identified above. A
positive library was then used to isolate clones encoding the PR0324 gene using the probe oligonucleotide and one of the PCR primers. RNA for construction of the cDNA libraries was isolated from human fetal liver tissue (LIB6).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PRO324 (herein designated as UNQ285 (DNA36343-1310)] (SI:Q ID N0:123) and the derived protein sequence for PR0324.
The entire nucleotide sequence of UNQ285 (DNA36343-1310) is shown in Figure 46 (SEQ ID NO:123).
Clone UNQ285 (DNA36343-I3I0) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 144-14b and ending at the stop colon at nucleotide positions 1011-1013 (Figure 46). The predicted poIypeptide precursor is 289 amino acids long (Figure 47). The full-length PR0324 protein shown in Figure 47 has an estimated molecular weight of about 32,268 dahons and a pI of about 9.21. Analysis of the PR0324 polypeptide sequence shown in Figure 47 (SEQ ID N0:124) evidence the presence of the following: a signal peptide IO from about amino acid I to about amino acid 31, a transmembrane domain from about amino acid 136 to about amino acid 157, tyrosine Iattase phosphorylation sites from about amino acid 106 or about amino acid 107 to about amino acid 113 and regions that are homologous to short-chain alcohol dehydrogenase regions from about amino acid 80 to about amino acid 90, from about amino acid I3l to about amino acid 168, from about amino acid 1 to about amino acid 13 and from about amino acid 176 to about amino acid I85. Clone UNQ285 (DNA36343-1310) has been deposited with ATCC on March 30, 1998 and is assigned ATCC deposit no. 209718.
Analysis of the amino acid sequence of the full-length PR0324 polypeptide suggests that it possesses significant sequence similarity to oxidoreductases; thereby indicating that PR0324 may be a novel oxidoreduetase homolog. More specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced significant homology between the PR0324 amino acid sequence and the following Dayhoff sequences, 861209, A69965, YQJQ BACSU, D69930, 576124, FABG ECOLI, C70023, 577280, FABG VIBHA and MTV013 6.
EXAMPLE 22: Isolation of ~DN~Clortes Er~coding",~Iuman PRO351 A consensus sequence was obtained relative to a variety of EST sequences as described in Example I above, wherein the consensus sequence obtained is herein designated DNA35950. Based on the DNA3S950 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA
library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0351.
Forward and reverse PCR primers were synthesized:
forward PCR primer 5'-CCTGTGCTGTGCCTCGAGCCTGAC-3' (SEI~ ID N0:133) reverse PCR primer 5'-GTGGGCAGCAGTTAGCACCGCCTC-3' (SEQ ID N0:134) Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA35950 sequence which had the following nucleotide sequence ~,tybridi2ation 5'-GGCTGGCATCATCAGCTTTGCATCAAGCTGTGCCCAGGAGGACGC-3' (SEQ ID N0:135) In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with one of the PCR primer pairs identified above. A
positive library was then used to isolate clones encoding the PR0351 gene using the probe oligonucleotide and one of the PCR primers. RNA for construction of the cDNA libraries was isolated from human fetal liver tissue (Li8230).

WO 99/46281 PCTlUS99/05028 DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0351 [herein designated as UNQ308 (DNA40571-1315)) (SEQ ID NO: I31 ) and the derived protein sequence for PR0351.
The entire nucleotide sequence of UNQ308 (DNA40571-1315) is shown in Figure 48 (SEQ ID N0:131}.
Clone UNQ308 tDNA4057I-1315) contains two open reading frames with an apparent translational initiation site at nucleotide positions 189-191 and a second open reading frame beginning at nucleotide 4?0, with the two open reading frames ending at the stop codons at nucleotide positions 363-365 and 2009-2011, respectively (Figure 48). The predicted polypeptide precursor is 571 amino acids long (Figure 49). Important regions of the amino acid sequence of PR0351 include the signal peptide, regions having sequence similarity to serine proteases of the trypsin family, two N-glycosylation sites, and three Kringle domains. Clone UNQ308 (DNA40571-1315) has been deposited with ATCC and is assigned ATCC deposit no. 209784.
EX,QMPLE 23: Isolation of cDNA Clones Encoding~Human PR0352 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA36950. Based on the DNA36950 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA
library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0352.
PCR primers (forward and reverse) were synthesized:
forward primer I 5'-CTGGCACAGCTCAACCTCATCTGG-3' PCR (SEQ ID . :I38) forward primer 2 5'-GCTGTCTGTCTGTCTCATTG-3' (SEQ
PCR ID N0:139) forward rimer 3 5'-GGACACAGTATACTGACCAC-3' (SEQ
PCR~ ID N0:140) reverse rimer 1 5'-TGCGAACCAGGCAGCTGTAAGTGC-3' (SEQ
PCRp ID N0:141) reverse rimer 2 5'-TGGAAGAAGAGGGTGGTGATGTGG-3' (SEQ
PQR~ ID N0:142) Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA36950 sequence which had the following nucleotide sequence ~,rbridization probe 5'-CAGCTGACAGACACCAAACAGCTGGTGCACAGTTTCACCGAAGGC-3' (SEQ ID NO:143) In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones erioodi<tg the PR0352 gene using the probe oligonucleotide and one of the PCR
primers. RNA for construction of the cDNA libraries was isolated from human fetal kidneytissue (LIB227).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0352 (herein designated as UNQ309 (DNA41386-1316)] (SEQ ID N0:136) and the derived protein sequence for PR0352.
The entire nucleotide sequence of UNQ309 (DNA41386-1316) is shown in Figure 50 (SEQ ID N0:136).
Clone UNQ309 (DNA41386-1316) contains a single open reading frame with an apparern translational initiation site at nucleotide positions 152-154 and ending at the stop codon at nucleotide positions 1100-1102 (Figure 50). The predicted polypeptide precursor is 316 amino acids long (Figure 51). The full-length PR0352 protein shown in Figure 2 has an estimated pI of about 4.62. Analysis of the full-length PR0352 sequence evidences the presence of a signal peptide from about amino acid 1 to about amino acid 28, a transmembrane domain from about amino acid 251 to about amino acid 270, potential N-glycosylation sites from about amino acid 91 to about amino acid 94, about amino acid 104 to about amino acid 107, about amino acid 189 to about amino acid 192 and about amino acid 215 WO 99J4b281 PCT/US99105028 to about amino acid 218 and a region having homology to immunoglobulins and MHC from about amine acid 217 to about amino acid 234. Clone UNQ309 (DNA41386-1316) has been deposited with ATCC on March 26, 1998 and is assigned ATCC deposit tio. 209703.
Analysis of the amino acid sequence of the full-length PR0352 polypeptide suggests that it possesses significant sequence similarity to the buryrophilin protein, thereby indicating that PR0352 is a novel buryrophilin homolog. More specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced significant homology between the PR0352 amino acid sequence and the following Dayhoff sequences, BUTY HUMAN, HSB73~1, GGCD80_l, 146690, A33 HUMAN, P 867988, CD86 MOUSE, P R713b0, B39371 and D50558~1.
EXAMPLE 24: Isolation of cDNA CZ~s Encoding Humarl ~R0381 A consensus sequence was obtained relative'to a variety of EST sequences as described in Example I above, wherein the consensus sequence obtained is herein designated DNA396S1. Based on the DNA39651 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA
library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0381.
A pair of PCR primers (forward and reverse) were synthesized:
IS forward PC~,~rimer 5'-CTTTCCTTGCTTCAGCAACATGAGGC-3' (SEQ ID N0:146) reverse SCR primer 5'-GCCCAGAGCAGGAGGAATGATGAGC-3' (SEQ ID NO:I47) Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA39651 sequence which had the following nucleotide sequence hybridization probe 5'-GTGGAACGCGGTCTTGACTCTGTTCGTCACTTCTTTGATTGGGGCTTTG-3' (SEQ ID N0:148) 1n order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PR038I gene using the probe oligonucleatide and one of flue PCR
primers. RNA for construction of the cDNA libraries was isolated from human fetal kidney tissue (L1B22'7).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0381 ll~rein designated as UNQ322 (DNA44194-1317) (SEQ ID NO: I44) and the derived protein sequence for PR0381.
The entire nucleotide sequence of UNQ3z2 (DNA44194-1317) is shown in Figure 52 (SEQ ID N0:144).
Clone UNQ322 (DNA44194-I3I7) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 174-176 and ending at the stop codon at nucleotide positions 807-809 (Figure 52). The predicted polypeptide precursor is ZI1 amino acids long (Figure 53). The foil-length PR0381 protein shown in Figure 53 has an estimated molecular weight of about 24,I72 daltons arid a p1 of about 5.99. Analysis of the full-length PR0381 polypeptide shown in Figure 53 (SEQ ID N0:145) evidences the presence of the following; a signal peptide from about amino acid 1 to about amino acid 20, a potential N-glycosylation site from about amino acid 1?6 to about amino acid 179, potential casein kinase II phosphoryladon sites from about amino acid 143 to about amino acid 146, from about amino acid 156 to about amino acid I59, from about amino acid I78 to about amino acid 181, and from about amino acid 200 to about amino acid 203, an endoplasmic reticulum targeting sequence from about amino aad 208 to about amino acid 211, FKBP-type pegtidyl-prolyl cis~trans isomerase sites from about amino acid ~8 to about amino acid 114 and from about amino acid 118 to about amino acid 131, EF-hand calcium binding 'vies from about amino acid 191 to about amino acid 203, from about amino acid 184 to about amino acid 203 and from about amino acid 140 to about anvno acid 159> and an S-100/ICaBP type calcium binding domain from about amino acid 183 to about amino acid 203. Clone UNQ322 (DNA44194-1317) has been deposited with ATCC
on April 28, 1998 and is assigned ATCC deposit no. 209808.
Analysis of the amino acid sequence of the full-length PR0381 polypeptide suggests that it possesses significant sequence similarity to FKBP immunophilin proteins, thereby indicating that PR0381 may be a novel FKBP
itnnaunophilin homolog. More specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced significant homology between the PR0381 amino acid sequence and the following Dayhoff sequences, AF040252_l, 149669, P 893551, S71238, CELCOSC8_l, CEU27353_l, MIP TRYCR, CEZC455 3, FKB4 HUMAN and 140718.
EXAMPLE 25: Isolation of cDNA Clones Encoding Human PR0386 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA406?4. Two proprietary Genentech EST
sequences were employed in the consensus sequence assembly, wherein those EST
sequences are herein designated DNA23350 (Figure 56; SEQ ID NO:151) and DNA23536 (Figure 5?; SEQ ID N0:152).
Based on the DNA40674 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0386.
A pair of PCR primers (forward and reverse) were synthesized:
forward PCR.primer 5'-ACGGAGCATGGAGGTCCACAGTAC-3' (SEQ ID N0:153) revere PC n~mer 5'-GCACGTTTCTCAGCATCACCGAC-3' (SEQ ID N0:154) Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA40674 sequence which had the following nucleotide sequence h~r~ridization probe 5'-CGCCTGCCCTGCACCTTCAACTCCTGCTACACAGTGAACCACAAACAGTT-3' (SEQ ID N0:155) In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PR0386 gene using the probe oligonucleotide and one of the PCR
primers. RNA for construction of the cDNA libraries was isolated from human fetal brain tissue (LIBI53).
DNA sequencing of the.clones isolated as described above gave the full-length DNA sequence for PR0386 [herein designated as UNQ326 (DNA45415-1318)] (SEQ ID N0:149) and the derived protein sequence for PR0386.
The entire nucleotide sequence of UNQ326 (DNA45415-1318) is shown in Figure 54 (SEQ ID N0:149).
Clone UNQ326 (DNA45415-1318) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 146-148 and ending at the stop codon at nucleotide positions 791-793 (Figure 54). The predicted polypeptide precursor is 215 amino acids long (Figure 55). The full-length PR038ti protein shown in Figure 55 has an estimated molecular weight of about 24,326 daltons and a p1 of about 6.32. Analysis of the full-length PR0386 sequence shown in Figure 55 (SEQ ID NO:150) evidences the presence of the following: a signal peptide from about amino acid 1 to about amino acid 20, a transmembrane domain from about amino acid 161 to about amino acid 179, an itnmunoglobulin-like fold from about amino acid 83 to about amino acid 127 and potential N-glycosylation sites from about amino acid 42 to about amino acid 45, from about amino acid 66 to about amino acid 69 and from about amino acid 74 to about amino acid 77. Clone UNQ326 (DNA45415-1318) bas been deposited .J

with ATCC on April 28, 1998 and is assigned ATCC deposit no. 209810.
Analysis of the amino acid sequence of the full-length PR0386 polypeptide suggests that it possesses significant sequence similarity to the sodium channel beta-2 subunit, thereiby indicating that PR0386 is a novel homolog thereof. More specifically, an analysis of the Dayhoff database (version 35.45 Swissfrot 35) evidenced significant homology between the PR0386 amitw acid sequence and the following Dayhoff sequences; A57843, MYPO HUMAN, GEN14531, X4024, I-iS46ICDA 1, HSU90716 t, D86996 2, MUSIGLVD I, and S19247.
EXAMPLE ,~6_: Isolation of cDNA Clones Encoding Human PR0540 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA39631. Based on the DNA39631 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA;
library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0540.
Forward and reverse PCR primers were synthesized:
forward PCR primer 5'-CTGGGGCTACACACGGGGTGAGG-3' (SEQ ID NO:158) IS reverse PCR Drimer 5'-GGTGCCGCTGCAGAAAGTAGAGCG-3' (SEQ ID N0:159) Additionally, a synthetic oligonucleoiide hybridization probe was constructed from the consensus DNA40b54 sequence which had the following nucleotide sequence l~,vbridization probe 5'-GCCCCAAATGAAAACGGGCCCTACTTCCTGGCCCTCCGCGAGATG-3' 2l? (SEQ ID N0:160) In order to screen several libraries for a source of a fesll-length clone, DNA
from the libraries was screened by PCR amplification with one of the PCR primer pairs identified above. A
positive library was then used to isolate clones encoding the PR0540 gene using the probe oligonucleotide and one of the PCR primers. RNA for construction of the cDNA libraries was isolated from human fetal kidney tissue (LIB227).
25 DNA sequencing of the clotres isolated as described above gave the full-length DNA sequence for PR0540 [herein designated as UNQ341 (DNA44189-1322)] {SEQ ID N0:156) and the derived protein sequence for PR0540.
The entire nucleotide sequence of UNQ341 (DNA44189-1322) is shown in Figure 58 (SEQ ID N0:156).
Clone UNQ341 (DNA44189-1322) contains a single open reading frame with an apparent uanslational initiation site at nucleotide positions 21-23 and ending at the stop codon at nucleotide positions 1257-1259 (Figure 58). The 30 predicted polypeptide precursor is 412 amino acids long {Figure 59). Tike full-length PR0540 protein shown in Figure 59 has an estimated molecular weight of about 46,658 daltons and a pi of about 6.65. Important regions of the amino acid sequence of PR0540 include the signal peptide, potential N-glycosylation sites, a potential lipid substrate binding site, a sequence typical of lipases and serine proteins, and a beta-uansducin family Trp-Asp repeat.
Clone UNQ341 (DNA44189-1322) has been deposited with ATCC and is assigned ATCC
deposit no. 209699.
FXAMPhE 27: Isolation of cDN~,Clonr"s En_coy~g~uma_n PRCW15 A consensus sequence was obtained relative to a variety of ES1' sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA42240. Based on the DNA42240 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA
library that contained the sequence of J

interest, and 2} for use as probes to isolate a clone of the full-length coding sequence for PR0615.
Forward and reverse PCR primers were synthesized:
forward PCR primer 5'-TGGTCTTCGCCTTGATCGTGTTCT-3' (SEQ ID N0;163) forward PCR primer 5'-GTGTACTGAGCGGCGGTTAG-3' (SEQ ID N0:154) reverse PCR primer 5'-CTGAAGGTGATGGCTGCCCTCAC-3' (SEQ ID N0:165) reverse PCR primer 5'-CCAGGAGGCTCATGGGAAAGTCC-3' (SEQ ID NO:I66) Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA42240 sequence which had the following nucleotide sequence:
hybridization vrobe 5'-CCACGAGTCTAAGCAGATGTACTGCGTGTTCAACCGCAACGAGGATGCCT-3' (SEQ ID NO:lb7) In order to screen several Fibraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with one of the PCR primer pairs identified above. A
positive library was then used to isolate clones encoding the PR0615 gene using the probe oligonucleotide~ and one of the PCR primers. RNA for construction of the cDNA libraries was isolated from human bone marrow tissue (LIB255).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0615 [herein designated as UNQ352 (DNA48304-1323)) (SEQ ID N0:161) and the derived protein sequence for PR0615.
The entire nucleotide sequence of UNQ352 (DNA48304-1323) is shown in Figure 60 (SEQ ID NO:161).
Clone UNQ352 (DNA48304-1323) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 51-53 and ending at the stop codon at nucleotide positions ?23-725 (Figure 60). The predicted polypeptide precursor 'ss 224 amino acids long (Figure 61). The full-length PR0615 protein shown in Figure 6I has an estimated molecular weight of about 24,810 daltons and a p1 of about 4.75.
Important regions of the amino acid sequence of PR0615 include a type II transmembrane domain, corresponding to about amino acids 24-43, other transmembrane domains, corresponding to about amino acids 74-90, 108-126, and 145-161, respectively, and a potential N-glycosylation site, corresponding to about amino acids 97-100.
Clone UNQ352 (DNA48304-1323) has been deposited with ATCC and is assigned ATCC deposit no. 209811.
EXAMPLE 28: Isolation of cDNA Clones Encoding Human PR0618 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA30900. Based on the DNA30900 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA
library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0618.
Forward and reverse PCR primers were synthesized:
~rward PCR yritner 5'-TAACAGCTGCCCACTGCTTCCAGG-3' (SEQ ID N0:171) reverse PCR primer 5'-TAATCCAGCAGTGCAGGCCGGG-3' (SEQ ID N0:172) Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA30900 sequence which had the following nucleotide sequence hybridization probe 5'-ATGGCCTCCACGGTGCTGTGGACCGTGTTCCTGGGCAAGGTGTGGCAGAA-3' (SEQ ID N0:173) WO 99!46281 PCT/US99105028 Screening of the above described library gave rise to the partial cDNA clone designated herein DNA35597 (SEQ )D N0:170). Extension of this sequence using repeated cycles of BLAST and phrap gave rise to a nucleotide sequence designated herein as DNA43335. Primers based upon the DNA43335 consensus sequence were then prepared as follows.
forward PQ,R ,primer 5'-TGCCTATGCACTGAGGAGGCAGAAG-3' (SEQ ID N0:174) reverge PCR primer 5'-AGGCAGGGACACAGAGTCCATTCAC-3' (SEQ ID N0:175) Additionally; a synthetic oligorntcleotide hybridization probe was constructed from the consensus DNA43335 sequence which had the following nucleotide sequence ~bridization ,probe 5'-AGTATGATTTGCCGTGCACCCAGGGCCAGTGGACGATCCAGAACAGGAGG-3' (SEQ ID N0:176) In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with one of the PCR primer pairs identified above. A
positive Library was then used to isolate foil length clones encoding the PR0618 gene using the second probe oligonucleotide and one of the second set of PCR
primers. RNA for construction of the cDNA libraries was isolated from human fetal liver tissue (LIB229).
DNA sequetxittg of the clones isolated as described above gave the tall-length DNA sequence for PR0618 [herein designated as UNQ354 (DNA49152-1324)] (SEQ ID NO:I68) and the derived protein sequence for PR0618.
The entire nucleotide sequence of UNQ354 (DNA49152-1324) is shown in Figure 62 (SEQ ID N0:168).
Clone UNQ354 (DNA49152-I324) contains a single open reading frame with an apparent transIational initiation site at nucleotide positions 73-75 and ending at the stop codon at nucleotide positions 2479-2481 (Figure fi2). The predicted polypeptide precursor is 802 amino acids long (Figure 63). The full-length PR0618 protein shown in Figure 63 has an estimated molecular weight of about 88,846 daltons and a pI
of about 6.41. Important regions of the amino acid sequence of PR0618 include type II uansmembrane domain, a sequence typical of a protease, trypsin family, histidine active site, multiple N-glycosylation sites, two sequences typical of a Kringle domain, two regions having sequence similarity to Kallilaein light chain, and a region having sequence similarity to low-density lipoprotein receptor. Clone UNQ354 (DNA49152-1324) has been deposited with ATCC and is assigned ATCC deposit no.
209813.
F~MPLE 29: Is9lation of cDNA Cloneq Encodinsr Huna~R0719 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA44851. Based on the DNA448S1 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA
library that captained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0719.
A pair of PCR primers (forward and reverse) vrere synthesized:
5'-GTGAGCATGAGCGAGCCGTCCAC-3' (SEQ ID N0:179) reverse P,~~,pri_~rter 5'-GCTATTACAACGGTTC'iTGCGGCAGC-3' (SEQ ID NO:I80) Additionally, a synthetic oligonucleotide hybridization probe was constructed from the cotuensus DNA448S 1 sequence which had the following nucleotide sequence h~:>~~~~
5 =TTGACTCTCTGGTGAATCAGGACAAGCCGAGTTTTGCCTTCCAG-3' (SEQ ID N0:181) In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PR0719 gene using the probe oligonucleotide and one of the PCR
primers. RNA for construction of the cDNA libraries was isolated from human placenta tissue (LIB90).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0719 therein designated as UNQ387 (DNA49646-1327)] (SEQ 1D N0:177) and the derived protein sequence for PR0719.
The entire nucleotide sequence of UNQ387 (DNA49646-1327) is shown in Figure 65 (SEQ ID N0:177).
Clone UNQ387 (DNA49646-1327) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 223-225 and ending at the stop codon at nucleotide positions 1285-1287 (Figure 65). The predicted polypeptide precursor is 354 amino acids long (Figure 66). The full-length PR0719 protein shown in Figure 66 has an estimated molecular weight of about 39,362 daltons and a pI
of about 8.35. Analysis of the full length PR0719 sequence evidences the presence of a signal peptide from about amino acid 1 to about amino acid 16 as shown in Figure 66 (SEQ ID N0:178), a lipase-associated serine-containing active site at about amino acid 163 to about amino acid 172, and two potential N-glycosylation sites from about amino acid 80 to about amino acid 83 and about amino acid 136 to about amino acid 139. Clone UNQ387 (DNA49646-1327) has been deposited with ATCC on March 26, 1998 and is assigned ATCC deposit no. 209705.
Analysis of the amino acid sequence of the full-length PR0719 polypeptide suggests that it possesses significant sequence similarity to the lipoprotein lipase H protein, thereby indicating that PR0719 may be a navel lipoprotein lipase homolog. More specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced significant homology between the PR0719 amino acid sequence and the following Dayhoff sequences, LIPL HUMAN, LIPH HUMAN, D83548_l, A24059l1, P 830740, D88666_l, A43357, A46696, B43357 and A49488.
EXAMPLE 30: Violation of cDNA Clones Encoding Human PR0724 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA35603. Based on the DNA35603 consensus sequence, oligonueleotides were synthesized: 1) to identify by PCR a cDNA
library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0724.
Pairs of PCR primers (forward and reverse) were synthesized:
forward PCR~rimer 1 5'-GGCTGTGACTGTGGAGACAC-3' (SEQ ID N0:184) forward PCRp itir mer 2 5'-GCAAGGTCATTACAGCTG-3' (SEQ ID N0:185) reverse PCR orimer1 5'-AGAACATAGGAGCAGTCCCACTC-3' (SEQ ID NO:186) reverse PCR Timer 2 5'-TGCCTGCTGCTGCACAATCTCAG-3' (SEQ ID NO:I87) Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA35603 sequence which had the following nucleotide sequence hybridization r8 obe 5'-GGCTATTGCTTGCCTTGGGACAGACCCTGTGGCTTAGGCTCTGGC-3' (SEQ ID NO:I88) In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with the PCR primer pairs identified above. A positive library was then used to isolate clones erxoding the PR0724 gene using the probe oligonucleotide and one of the PCR
primers. RNA for construction of the eDNA libraries was isolated from human fetal lung tissue (LIB26).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PRO?24 [herein designated as UNQ389 (DNA49631-1328)] (SEQ ID N0:182) and the derived protein sequence for PRO724.
The entire nucleotide sequence of UNQ389 (DNA49631-1328) is shown in Figure 67 (SEQ iD N0:182).
Clone UNQ389 (DNA49631-1328) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 546-S48 and ending at the stop codon at nucleotide positions 2685-2687 (Figure 67). The predicted polypeptide precursor is 713 amino acids long (Figure 68): The full-length PR0724 protein shown in Figure 68 has an estimated molecular weight of about 76;193 daltons and a pI
of about 5.42. Analysis of the full-length PR0724 amino acid sequence shown in Figure b8 (SEQ ID N0:183) evidences the presence of the following:
a signal peptide from about amino acid 1 to about amino acid 16, a uansme:mbrane domain from about amino acid IO 442 to about amino acid 462 and LDL receptor class A domain regions from about amino acid 1S2 to about amino acid 171, about amino acid 331 to about amino acid 350, about amino acid 3?4 to about amino acid 393 and about amino acid 411 to about amino acid 430: Clone UNQ389 (DNA49631-1328) has been deposited with ATCC on April 28, 1998 and is assigned ATCC deposit no. 209806 Analysis of the amino acid sequence of the fall-length PR0724 polypeptide suggests that it possesses 1S significant sequence similarity to the human LDL receptor protein, thereby indicating that PR0724 may be a novel LDL receptor homolog. More specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced significant homology between the PR0724 amino acid sequence and the following Dayhoff sequences, P R48S47, MMAM2R 1, LRP2 RAT, P RbOSl7, P 847861, P R05S33, A44513~1, A30363, P 874692 and LMLIPOPHO l.
E~,AMPLE 3I: Isolation of cDNA Clones Encoding Human PR0772 One cDNA sequence was isolated in the amylase screen described in Example 2, wherein that cDNA
sequence is herein designated DNA43S09 (see Figure 71). Based on the DNA43S09 sequence, oligonucleotide probes were generated and used to screen a human fetal lung library (LI825) prepared as described in paragraph 1 of Example 2 above. The cloning vector was pRKSB (pRKSB is a precursor of pRKSD
that does not contain the Sfil site; see, Hohnes et al., 'e ce, 25:1278-1280 (1991)), and the cDNA size cut was less than 2800 bp.
A pair of PCR primers (forward and reverse) were synthesized based on the DNA43S09 sequence:
forward PCR arimer S'-CGTTTTGCAGAACCTACTCAGGCAG-3' (SEQ ID N0:192) reverse PCR~rimer S'-CCTCCACCAACTGTCAATGTTGTGG-3' (S1EQ ID N0:193) Additionally, a synthetic oligotutcleotide hybridization probe was constructed from the consensus DNA43S09 sequence which had the following nucleotide sequence hybridization rp obe S'-AAAGTGCTGCTGCTGGGTCTGCAGACGCGATGGATAACGT-3' (SEQ ID N0:194) Using the above described primers and library, a full length clone was identified that contained a single open 3S reading frame with an apparent translational initiation site at nucleotide positions 131-133 and ending at the stop colon found at nucleotide positions 587-S89 (Figure 69; SEQ ID N0:189). The predicted polypeptide precursor is 152 amino acids long, has a calculated molecular weight of approximately 17,170 daltons and an estimated pI of approximately 9.62. Analysis of the full-length PR0772 sequence shown in Figure 70 (SEQ iD N0:19U) evidences the presence of the following: a potential type II aansmembrane domain from about amino acid 26 to about amino WO 99/46281 PCT/US99I~5028 acid 42, other potential transmembrane domains from about amino acid 44 to about amino acid 65, from about amino acid 81 to about amino acid 101 and from about amino acid 109 to about amino acid 129, leucine zipper pattern sequences from about amino. acid 78 to about amino acid 99 and from about amino acid 85 to about amino acid 106.
Clone UNQ410 (DNA49645-1347) has been deposited with ATCC on April 28, 1998 and is assigned ATCC deposit no. 209809.
Analysis of the amino acid sequence of the full-length PR0772 polypeptide suggests that it possesses significant sequence similarity to the human A4 protein, thereby indicating that PR0772 tray be a novel A4 protein homolog. More specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced significant homology between the PR0772 amino acid sequence and the following Dayhoff sequences, HSU9330S_l, A4P HUMAN, CELB0454 2, VPU 1SRV, CELC12D12 2, OCCM AGRTl, LBPHIG1E 50, YIGK
ECOLI, S76245 and P 850807.
EXAMPLE 32: Isolation of cDNA Clones Encoding Human PR0852 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA34364. Based on the DNA34364 consensus sequence; oligonucleotides were synthesized: 1) to identify by PCR a cDNA
library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0852.
PCR primers (forward and reverse) were synthesized:
forward PCR nrit~,er 1 5'-CGCAGAAGCTACAGATTCTCG-3' (SEQ ID N0:197) forward PCI~primer 2 5'-GGAAATTGGAGGCCAAAGC-3' (SEQ ID N0:198) forward primer 3 5'-GGATGTAGCCAGCAACTGTG-3' (SEQ ID N0:199) PCR

fotwvard primer 4 5'-GCCTTGGCTCGTTCTCTTC-3' (SEQ ID N0:200) PCR

forward PCR primer 5 5'-GGTCCTGTGCCTGGATGG-3' (SEQ ID N0:201) reverse PCR,primer 1 5'-GACAAGACTACCTCCGTTGGTC-3' (SEQ ID N0:202) reverse PCR rimer 2 5'-TGATGCACAGTTCAGCACCTGTTG-3' (SEQ ID N0:203) p Additionally,a synthetic oligonucleodde hybridization probe was constructed from the consensus DNA34364 sequence which had the following rntcleotide sequence hvbridization~robe 5'-CGCTCCAAGGGCTTTGACGTCACAGTGAAGTACACACAAGGAAGCTG-3' (SEQ ID N0:204) In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PR0852 gene using the probe oligonucleotide and one of the PCR
primers. RNA for construction of the cDNA libraries was isolated from human fetal kidney tissue (LIB228).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0852 [herein designated as UNQ418 {DNA45493-I349)) (SEQ ID N0:195) and the derived protein sequence for PR0852.
The entire nucleotide sequence of UNQ418 (DNA45493-1349) is shown in Figure 72 (SEQ ID N0:195).
Clone UNQ418 (DNA45493-1349) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 94-96 and ending at the stop codon at nucleotide positions 16748-1650 (Figure 72). The predicted polypeptide precursor is 518 amino acids long (Figure ?3). The full-length PRO852 protein shown in Figure 73 has an estimated molecular weight of about 56.180 daltons and a pI
of about 5.08. Analysis of the full-length PRO852 sequence shown in Figure 73 (SEQ ID N0:196) evidences the presence of the following: a signal peptide from about amino acid I to about amino acid 20, a transmembrane domain from about amino acid 466 to about amino acid 494, potential N-glycosylation sites from about amino acid 170 to about amino acid 173 and about amino acid 366 to about amino acid 369, leucine zipper sequence pattern blocks from about amino acid 10 to about amino acid 3I and from about amino acid 197 to about amino acid 2I8 and blocks of amino acids having sequence homology to eukaryotic and viral aspartyl proteases from about amino acid 109 to about amino acid 1 I8; from about amino acid 252 to about amino acid 26I and from about amino acid 298 to about amino acid 310: Clone UNQ418 (DNA45493-1349) has been deposited with ATCC on April 28, 1998 and is assigned ATCC deposit no: 209805.
Analysis of the amino acid sequence of the full-length PR0852 polypeptide suggests that it possesses significant sequence similarity to various protease proteins, thereby indicating that PR0852 may be a novel protease protein or homolog thereof. More specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced signifecant homology between the PRO852 amino acid sequence and the following Dayhoff sequences, PEPC HUMAN> S66516, S66517, PEPS CHICK, CATD HUMAN, P 874207, CARP YEAST, PEP2_RABIT, CATS HUMAN and RENI MOUSE.
IS EXAMPLE 33: Isolation of cpNA Clones Encoding Hqman PR0853 A consensus sequetxe was obtained relative to a variety of EST sequences as described in Example l above, wherein the consensus sequence obtained is herein designated DNA43050: Based on the DNA43050 consensus sequence, oligonucieotides were synthesized: 1) to identify by PCR a cDNA
library that contained the sequence of irnerest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0853.
Forward and reverse PCR primers were synthesized:
forward PCR Diner 5'-CTTCATGGCCTTGGACTTGGCCAG-3' (SEQ ID N0:207) reverse PCR primer 5'-ACGCCAGTGGCCTCAAGCTGGTTG-3' (SEQ ID N0:208) Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA43050 sequence which had the following nucleotide sequence hv,~~ridization probe 5'-CTTTCTGAGCTCTGAGCCACGGTTGGACATCCTCATCCACAATGC-3' (SEQ ID N0209) In order to screen several Hbraties for a source of a full-length clone; DNA
from the libraries was screened by PCR atnplificarion with otte of the PCR primer pairs identified above. A
positive library was then used to isolate clones encoding the PR0853 gene using the probe oiigonucleotide and one of the PCR primers. RNA for construction of the cDNA libraries was isolated from human fetal Iddney tissue (LIB228).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0853 (herein desigmted as UNQ419 (DNA48227-1350)] (SEQ ID N0:205) and ttie derived protein sequence for PR0853.
The entire nucleotide sequence of UNQ419 (DNA48227-1350) is shown in Figure 74 (SEQ ID N0:205).
Clone UNQ419 (DNA48227-1350) oorttaains a single open reading frame with an apparent translational initiation site at nucleotide positions I28-130 and ending at the stop codon at nucleotide positions 1259-1261 (Figure 74). The predicted polypeptide precursor is 377 amino acids long (Figure 75). 'Ihe full-length PR0853 protein shown in Figure 75 has an estimated molecular weight of about 40,849 daltons and a pI
of about 7.98. Important regions of the amino acid sof PR0853 include tht signal peptide, corresponding to amino acids from about 1 to about I6 of SEQ >D N0:206, the glycosaminoglycan attachment site, corresponding to amino acids from about 46 to about J

49 of SEQ ID N0;206, and two sequences typical of the short-chain alcohol dehydrogenase family, corresponding to amino acids from about 37 to about 49 and about 114 to about 124 of SEQ ID
N0:206, respectively. Clone UNQ419 (DNA48227-1350) has been deposited with ATCC and is assigned ATCC
deposit no. 209812.
EJ,~AMPLE 34: Isolation of cDNA Clones Encoding Human PR0860 S A consensus sequence was obtained relative to a variety of EST sequences as described in Example I above, wherein the consensus sequence obtained is herein designated DNA38137. Based on the DNA38137 consensu sequence, oligonucleotides were synthesized: I) to identify by PCR a cDNA
library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0860.
Forward and reverse PCR primers were synthesized:
. forward~CR primer 5'-GAAGGGACCTACATGTGTGTGGCC-3' (SEQ ID N0:212) reverse PCR gt~imer S'-ACTGACCTTCCAGCTGAGCCACAC-3' (SEQ ID N0:213) Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA406S4 sequence which had the following nucleotide sequence hybridization rya obe S'-AGGACTACACGGAGCCTGTGGAGCTTCTGGCTGTGCGAATTCAGCTGGAA-3' (SEQ ID N0:214) In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with one of the PCR primer pairs identified above. A
positive library was then used to isolate clones encoding the PR0860 gene using the probe oligonucleotide and one of the PCR primers. RNA for construction of the cDNA libraries was isolated from human fetal lung tissue (LIB26).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0860 [herein designated as UNQ421 (DNA41404-1352)J (SEQ ID N0:210) and the derived protein sequence for PR0860.
The entire nucleotide sequence of UNQ421 (DNA47404-1352) is shown in Figures 76A-B (SEQ ID
N0:210). Clone UNQ421 (DNA4I404-1352) contains a single open reading frame with an apparent translatianal 2S initiation site at nucleotide positions S8-60 and ending at the stop codon at nucleotide positions 3013-30iS (Figures 76A-8). The predicted polypeptide precursor is 985 amino acids tong (Figure 77). The full-length PR0860 protein shown in Figure 77 has an estimated molecular weight of about 10S,336 daltons and a p1 of about 6.5S. Important regions of the amino acid sequence. of PR0860 include the transmembrane region corresponding to about amino acids 448-467, the extracellular domain, corresponding to amino acids about 1-447, several N-glycosylation sites, numerous N-myristoylation sites and a sequence typical of phosphotyrosine interaction domain proteins.. Clone UNQ421 (DNA41404-1352) has been deposited with ATCC and is assigned ATCC deposit no.
209844.
SAMPLE 35: Isolation of cDNA Clones ncoding Human PR0846 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA39949. Based on the DNA39949 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA
library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0846.
Forward and reverse PCR primers were synthesized:
forward PCR timer S'-CCCTGCAGTGCACCTACAGGGAAG-3' (SEQ ID NO:2I7) averse P ~t primer 5'-CTGTCTTCCCCTGCTTGGCTGTGG-3' (SEQ 1D N0:218) Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA39949 sequence which had the following nucleotide sequence hybridization probe S '-GGTGCAGGAAGGGTGGGATCCTCTTCTCTCGCTGCTCTGGCCACATC-3' S (SEQ ID N0:219) In order to streets several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with one of the PCR~ primer pairs identified above. A
positive library was then used to isolate clones encoding the PR0846 gene using the probe oligonucleotide and one of the PCR primers. RNA for construction of the cDNA libraries was isolated from human fetal kidney itissue (LIB227).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0846 (herein designated as UNQ422 {DNA44196-1353)] (SEQ 1D N0:215) and the derived protein scqtience for PR0846.
The entire nucleotide sequence of UNQ422 (DNA44196-1353) is shown in Figure 78 (SEQm N0:2I5).
Clone UNQ422 (DNA4419tr1353) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 25-27 and ending at the stop codon at nucleotide positions 1021-1023 (Figure 78). The predicted poiypeptide precursor is 332 amino acids long (Figure 79). The full-length PR0846 protein shown in Figure 79 has an estimated molecular weight of about 36,143 daltons and a pI
of about 5.89. Important regions of the amino acid sequence of PR0846 include the signal peptide, the transmetnbrane domain, an N-glycosylation site, a atypical of fibrinogen beta and gamma chains C-terminal domain, and a sequence typical of Ig like V-type dwmain as shown in Fgure 79. Clone UNQ422 t'DNA44196-1353) rtes been deposited with ATCC and is assigned ATCC deposit no.-209847_ EXAMPLE 36. Lsolation of cDNA Clones Encoding Human PR0862 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA47370. Based on the DNA47370 consensus sequence, oligonucleotides were synthesized: I) to identify by PCR a cDNA
library that contained the sequence of intcrcst, and 2) for use as probe to isolate a clone of the full-length codittl; sequence for PR0862.
Forward and teversc pCR primers were synthesized:
forward PCR~,rriLn~r 5'GGGATCATG'TTGT'I'GGCCCTGGTC-3' (SEQ ID N0:222) reverse PCR primer 5'-GCAAGGCAGACCCAGTCAGCCAG-3' (SEQ ID N0:223) Additionally, a synthcac oligonucleotide~ hybridization probe was constructed from the consensus DNA47370 sequetxc which had the following nucleotide sequence ltyt~n~dization nrobc 5'-CTGCCTGCTACCCTCCAAGTGAGGCCAAGCTCTACGGTCGTTGTG-3' (SEQ ID N0:22~
in order to screen severer h'braries for a soutrx of a full-length clone, DNA
from the libraries was screened by PCR ampIifi~rion with one of dbe PCR primer parts identified above. A
positive library was then used to isolate clones encoding the PR08b2 gene using site probe oligonuclcotidc and orre of the PCR primers. RNA for cotzsuuaroa of the cDNA Libraries was isolated from human pa~reas tissue (I
IB55).

WO 99!46281 PCTIUS99105028 DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0862 (herein designated as UNQ424 (DNA52187-1354)] (SEQ ID N0:220) and the derived protein sequence for PRO862.
The entire nucleotide sequence of UNQ424 (DNA52187-1354) is shown in Figure 80 (SEQ 1D N0:220}, Clone UNQ424 (DNA52I87-1354) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 41012 and ending at the stop codon at nucleotide positions 848-850 (Figure 80). The predicted polypeptide precursor is 146 amino acids long (Figure 81). The full-length PR0862 protein shown in Figure 81 has an estimated molecular weight of about 15,430 daltons and a pI
of about 5.05. Important regions of the amino acid sequence of PR0862 include the signal peptide, an N-myristoylation site, and sequences having similarity to region to Alpha-lactalbuminllysozyme C proteins as shown in Figure 81. Clone UNQ424 (DNA52I87-1354) has been deposited with the ATCC and is assigned ATCC deposit no.
209845.
10:
EXAMPLE 37: Isolation of cDNA Clones Encodi~ Human PR0864 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA40666. Based on the DNA40666 consensus sequence, oligonucleotides were synthesized: l) to identify by PCR a cDNA
library that contained the sequence of IS interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR08b4.
Forward and reverse PCR-primers were synthesized:
Forward PCR primer 5'-GCTGCAGCTGCAAATTCCACTGG-3' (SEQ ID N0:22?) zgverse PCR_primer 5'-TGGTGGGAGACTGTTTAAATTATCGGCC-3' (SEQ ID N0:228) Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA40666 20 sequence which had the following nucleotide sequence hybridization pmbe 5'-TGCTTCGTCAAGTGCCGGCAGTGCCAGCGGCTCGTGGAGTT-3' (SEQ ID N0:229) 1n order to screen several libraries for a source of a full-length clone, DNA
from the Libraries was screened 25 by PCR amplification with orte of the PCR primer pairs identified above. A
positive library was then used to isolate clones encoding the PR0864 gene using the probe oligonucleotide and one of the PCR primers. RNA for construction of the cDNA libraries was isolated from human fetal brain tissue (L1B153).
DNA sequencing of ttte clones isolated as described above gave the full-length DNA sequence for PR0864 [herein designated as UNQ426 (DNA48328-1355)] (SEQ ID N0:225) and the derived protein sequence for PR0864.
30 The entire nucleotide sequence of UNQ426 (DNA48328-1355) is shown in Figure 82 (SEQ ID N0:225).
Clone UNQ426 (DNA48328-1355) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 37-39 and ending at the stop codon at nucleotide positions 1090-1092 (Figure 82). The predicted poLypeptide precursor is 351 amino acids long (Figure 83). The full-length PR0864 protein shown in Figure 83 has an estimated molecular weight of about 39,052 and a p1 of about 8.97. Important regions of the amino 35 acid sequence of PR0864 include the signal peptide, two N-glycosylation sites, a Wnt-1 family signature sequence, and sequence regions homologous to Wnt-1 family proteins as shown in Figure 83. Clone UNQ426 (DNA48328-1355) has been deposited with ATCC and is assigned ATCC deposit no. 209843.

EXAMPLE 38: Isolation of cDNA Clones Eneod~pg Human PR0792 A conserzsus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA3810ti. Based on the DNA38106 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a eDNA
library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0792.
A pair of PCR primers (forward and reverse) were synthesized:
forward PCR rp imer 5'-GCGAGAACTGTGTCATGATGCTGC-3' (SEQ ID N0:232) reverse PCR primer 5'-GTTTCTGAGACTCAGCAGCGGTGG-3' (SEQ ID N0:233) Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA38106 sequence which had the following nucleotide sequence Itybri~,iza~,gn probe 5'-CACCGTGTGACAGCGAGAAGGACGGCTGGATCTGTGAGAAAAGGCACAAC-3' (SEQ ID N0:234) In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PR0792 gene using the probe oligonucleotide and one of the PCR
primers. RNA for construction of the cDNA libraries was isolated from human bone marrow tissue (LIB255).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0792 (herein designated as UNQ431 (DNA56352-1358)] (SEQ ID N0:230) and the derived protein sequence for PR0792.
The entire nucleotide sequence of UNQ431 (DNA56352-1358) is shown in Figure 84 (SEQ ID N0:230).
Clone UNQ431 (DNA56352-1358) contains a single open reading frame with an apparent uanslational initiation site at nucleotide positions 67-69 and ending at the stop codon at nucleotide positions 946-948 (Figure 84). The predicted polypeptide precursor is 293 amino acids long (Figure 8S). The full-length PR0792 protein shown in Figure 85 has an estimated molecular weight of about 32,562 daltons and a pI of about G.53.
Analysis of the full-length PR0792 sequence shown in Figure 85 (SEQ ID N0:231) evidences the presence of the following: a type I1 transmembrane domain from about amino acid 31 to about amino acid 54; potential N-glycosylation sites from about amino acid 73 to about amino acid 76 ar>d from about amino acid 159 to about amino acid 162, a leueine zipper amino acid sequence pattern from about amino acid 102 to about amino acid 123, potential N-myristolation sites from about amino acid 18 to about amino acid 23, from about amino acid 133 to about amino acid 138 and from about amino acid 242 to about amino acid 247 and a C-type lectin domain signature block from about amino acid 2b4 to about amino acid 287.
Clone UNQ431 (DNA56352-1358) has been deposited with ATCC on May 6, 1998 and is assigned ATCC deposit no. 209846.
Analysis of the amino acid sequence of the full-length PR0792 polypeptide suggests that it possesses significant sequence similarity to the CD23 protein, thereby indicating that PR0792 may be a novel CD23 homolog.
More specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced significant homology between the PR0792 amino acid sequence and the following Dayhoff sequences, S34198, A07100 1, A05303_l, P 841689, P P82839, A10871_l, P Ri2796, P 847199, A46274 and P 832188.
EXAMP1_.F_ 39: Isolation of cDNA Clones Encoding Human PR08G6 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA44708. Based on the DNA44708 consensus sequence, oligonucleotides were synthesized: 1).to idemify by PCR a cDNA
library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0866.
PCR primers (forward and reverse) were synthesized:
forward PCR Rrimgr 1 5'-CAGCACTGCCAGGGGAAGAGGG-3' (SEQ ID N0:237) forward PCR primer 2 5'-CAGGACTCGCTACGTCCG-3' (SEQ ID N0:238) forward PCR primer 3 5'-CAGCCCCTTCTCCTCCTTTCTCCC-3' (SEQ ID N0:239) reverse PCR primer 1 5'-GCAGTTATCAGGGACGCACTCAGCC-3' (SEQ ID N0:240) reverse PCR primer 2 5'-CCAGCGAGAGGCAGATAG-3' (SEQ ID N0:241) reverse PCR primer 3 5'-CGGTCACCGTGTCCTGCGGGATG-3' (SEQ ID N0:242}
Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA44708 sequence which had the following nucleotide sequence hybridization probe 5'-CAGCCCCTTCTCCTCCTTTCTCCCACGTCCTATCTGCCTCTC-3' (SEQ ID NO:243) In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with one of the PCR primer pairs identified above. A
positive library was then used to isolate clones encoding the PR0866 gene using the probe oligonucleotide and one of the PCR primers. RNA for construction of the cDNA libraries was isolated from human fetal kidney tissue {LIB228).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0866 [herein designated as UNQ435 (DNA53971-1359)) (SEQ ID N0:235} and the derived protein sequence for PR0866.
The entire nucleotide sequence of UNQ435 (DNA53971-1359) is shown in Figure 86 (SEQ ID NO:235).
Clone UNQ435 {DNA53971-1359) contains a single open reading frame with an apparent translationa3 initiation site at nucleotide positions 275-277 and ending at the stop codon at nucleotide positions 1268-1270 (Figure 86). The predicted polypeptide precursor is 331 amino acids long (Figure 87). The full-length PR0866 protein shown in Figure 8? has an estimated molecular weight of about 35,844 daltons and a pI
of about 5.45. Analysis of the full-length PR0866 sequence shown in Figure 87 (SEQ ID NO:236) evidences the presence of the following: a signal peptide from about amino acid 1 to about amino acid 26. Clone UNQ435 (DNA5397I-1359) has been deposited with ATCC on April 7, 1998 and is assigned ATCC deposit no. 209750.
Analysis of the amino acid sequence of the full-length PR0866 polypeptide suggests that it possesses significant sequence similarity to the mindinlspondin family of proteins, thereby indicating that PR0866 may be a novel mindin homolog. More specifically, an analysis of the. Dayhoff database (version 35.45 SwissProt 35) evidenced significant homology between the PR0866 amino acid sequence and the following Dayhoff sequences,AB006085_l, AB006084_l, AB006086 I, AF017267~1, CWU422I3~1, AC004160_l, CPM1CRP_l, S49108, A48569 and 146687.
EXAM,~'LE 40: j~~~~n of cDNA Clones Encoding Human PR0871 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA40324. Based on the DNA40324 consensus sequence, oligonucleotides were synthesized: I) to identify by PCR a cDNA
library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0871.
PCR primers (forward and reverse) were synthesized:
forward PCR grimed S'-TGCGGAGATCCTACTGGCACAGGG-3' (SEQ ID N0:246) forward FCR p~im~ 2 S'-CGAGTTAGTCAGAGCATG-3' (SEQ ID N0:247) forward PCR primer 3 S'-CAGATGGTGCTGTTGCCG-3' (SEQ ID N0:248) S reverse PCR urimer i S'-CAACTGGAACAGGAACTGAGATGTGGATC-3' (SEQ ID N0:249) reverse PAR primer 2 S'-CTGGTTCAGCAGTGCAAGGGTCTG-3' (SEQ ID N0:2S0) reverse PCR primer 3 S'-CCTCTCCGATTAAAACGC-3' (SEQ ID N0:2S1) Additionally, a synthetic oligonucleotide 'hybridization probe was constmcted from the consensus DNA40324 sequence which had the following nucleotide sequence hybridization g~robe 5'-GAGAGGACTGGTTGCCATGGCAAATGCTGGTTCTCATGATAATGG-3' (SEQ ID N0:2S2) In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screed by PCR amplification with one of the PCR primer pairs idernified above. A
positive library was then used to isolate clones encoding the PR0871 gene using the probe oligonucleotide and one of the PCR primers. RNA .for construction of the cDNA libraries was isolated from human fetal kidney tissue {LIB227).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0871 [herein designated as UNQ438 (DNA50919-136I)] {SEQ ID N0:244) and the derived protein sequence for PR0871.
The entire nucleotide sequence of UNQ438 {DNA50919-1361) is shown in Figure 88 (SEQ ID N0:244).
Clone UNQ438 {DNA50919-1361) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 191-193 and ending at the stop codon at nucleotide positions 1607-1609 (Figure 88). The predicted polypeptide precursor is 472 amino acids long (Figure 89). The full-length PR0871 protein shown in Figure 89 has an estimated molecular weight of about 53,847 daltons and a pI
of about 5.75. Analysis of the full length PR0871 sequence shown in Figure 89 {SEQ ID N0:245) evidences the presence of the following: a signal peptide from about amino acid 1 to about amino acid 2l, potential N-glycosylation sites from about amino acid 109 to about amino acid 112 and from about amino acid 201 to about amino acid 204, a cyclophilin-type peptidy-prolyl cis-cans isomerase signature sequence from about amino acid 49 to about amino acid 66 and regions that are homologous to cyclophilin-type peptidy prolyl cis-traps isomerases from about amino acid 96 to about amino acid 140, from about amino acid 49 to about amino acid 89 and from about amino acid 22 to about amino acid 51. Clone UNQ438 (DNA50919-1361) has been deposited with ATCC on May 6, 1998 and is assigned ATCC deposit no.
209848.
Analysis of the amino acid sequence of the full-length PR0871 polypeptide suggests that it possesses significant sequence similarity to the cyclophilin family of proteins, thereby indicating that PR0871 may be a novel cyclophiiin protein family member. More specifically; an analysis of the Da;yhoff database (version 3S.4S SwissProt 35) evidenced significant homology between the PR0871 amino acid sequence and the following Dayhoff sequences, SPBC16H5 S, S64705, YALS_SCHPO, CYP4 CAEEL, CELC34D4- 7, CYPA CAEEL, HUMORF006_1, CYPI MYCTU, AF043642 1 and HSSRCYP 1.
IXAMP1 E 41: Isolat~n of cDNA (',ones Encoding I~uman PR0873 A consensus sequence was obtained relative to a variety of EST sequences as described in Example I above.
wherein the consensus sequence obtained is herein designated DNA39621. Based on the DNA3962I consensus .
sequence, oligonucleotides were synthesized: I ) to identify by PCR a cDNA
library ti~at contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0873.
A pair of PCR primers (forward and reverse) were synthesized:
]'orward PCR primeF 5'-AGGTGCCTGCAGGAGTCCTGGGG-3' (SEQ ID N0:255) reverse PCR primer 5'- CCACCTCAGGAAGCCGAAGATGCC-3' (SEQ ID N0:256) Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA39621 sequence which had the following nucleotide sequence:
hybridization probe .. 5'-GA.ACGGTACAAGTGGCTGCGCTTCAGCGAGGACTGTCTGTACCTG-3' (SEQ ID N0:257) 1n order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PR0873 gene using the probe oligonucleotide and one of the PCR
primers. RNA for construction of the cDNA libraries was isolated from human fetal liver tissue (LIB229).
IS DNA sequencing of the clones isolated as described above gave the foil-length DNA sequence for PR0873 [herein designated as UNQ440 (DNA44179-1362)] (SEQ ID N0:253) and the derived protein sequence for PR0873.
The entire nucleotide sequence of UNQ440 (DNA44179-1362) is shown in Figure 90 (SEQ ID N0:253).
Clone UNQ440 (DNA44179-1362) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 139-141 and ending at the stop codon at nucleotide positions 1774-1776 (Figure 90). The predicted polypeptide precursor is 545 amino acids long (Figure 91). The full-length PR0873 protein shown in Figure 91 has an estimated molecular weight of about 58,934 daltons and a pI
of about 9.45. Analysis of the full-length PR0873 sequence shown in Figure 9I (SEQ ID N0:254) evidences the presence of the following features:
a signal peptide from about amino acid 1 to about amino acid 29; a carboxylesterase type-B serine active site at about amino acid 312 to about amino acid 327; a carboxylesterase type-B signature 2 motif at about amino acid 218 to about amino acid 228; and three potential N-glycosylation sites at about amino acid 318 to about amino acid 321, about amino acid 380 to about amino acid 383, and about amino acid 465 to about amino acid 468. Clone UNQ440 (DNA44I79-1362) has been deposited with ATCC on May 6, 1998 and is assigned ATCC deposit no. 209851.
Analysis of the amino acid sequence of the full-length PR0873 polypeptide suggests that it possesses significant sequence similarity to a human liver carboxylesterase, thereby indicating that PR0873 may be a novel carboxylesterase. More specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced significant homology between the PR0873 _amino acid sequence and the following Dayhoff sequences: ES 10 RAT, GEN12405, ABOlOb33_l, EST4 RAT, A48809, SASB ANAPL, RNU41662_l, RNU22952 1, BAL RAT, GEN13522.
EXAMPLE 42: Isolation of cDNA Clones Encodint=_ Human PRO940 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA47442. Based on the DNA47442 consensus sequence, oligonucleotides were synthesized: 1 ) to identify by PCR a cDNA
library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0940.

A pair of PCR primers (forward and reverse) were syntltcsizred:
forward PCR primer 5'-CAAAGCCTGCGCCTGGTCTGTG-3' (SEQ 1D N0:260) , reverse PCR primer S' TTCTGGAGCCCAGAGGGTGCTGAG-3' (SEQ ID N0:261) Additionally, a synthuic oligonucleotide hybridization probe was constructed from the consensus DNA47442 sequence which had the following nucleotide sequence hybridization p~obe 5'-GGAGCTGCCACCCATTCAAATGGAGCACGAAGGAGAGTTCACCTG-3' (SEQ ID N0:262) in order to screen several Lbraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PR0940 gene using the probe oligonucJeotide and one of the PCR
primers. RNA for construction of IO the cDNA libraries was isolated from human fetal liver tissue (LIB229).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0940 [liereim designated as UNQ477 (DNA54002-1367)j (SEQ ID N0:258) and the derived protein sequence=for PRO940.
The entire nucleotide sequence of UNQ477 (DNA54002-1367) is shown in Figure 92 (SEQ ID N0:258)_ Clone UNQ477 (DNA54002136'~ contains a single open reading frame with an apparent translational initiation site IS at nucleotide positions 46-08 and ending at the stop codon at nucleotide positions 1678-I680 (Figure 92). The predicted polypeptide preausor is 544 amino acids long (Figure 93). The full-length PR0940 protein shown in Figure 93 has an estimated molecxtlar weight of about 60,268 daltons and a pI
of about 9.53. Analysis of the full-length PR0940 sequence shown in Figure 93 (SEQ ID N0:259) cvidetxa the presence of the following: a signal peptide fc~om about amino acid 1 to about amino acid 15, potential N~lyeosylation sites from about amino acid 100 20 to about amino acid 103, fra~t about amino acid 297 to about aW i~ acid 300 and from about amino acid 306 to about amino acid 309 and an immunoglobulin and major histocompatibiliry complez signature sequence block from about amino acid 365 to about amino acid 37I . Clone UNQ477 (DNA54002-1367) has been deposited with ATCC on April 7, 1998 and is assigned ATCC deposit no. 209754.
Analysis of the amino acid sequence of the full-length PR0940 polypeptide suggtsu that it possesses 2S significaru seqt~C similarity w CD33 and the OB binding protein-2. More specifically, an analysis of the Dayhoff dataltase (version 35.45 SwissProt 35) evidenced significant homology between the PR0940 amino acid sequence and the following Dayhoff sequences, CD33 HUMAN, HSU71382_l, HSU71383_l, D86359 1, PGBM HUMAN, MAGS MOUSE, D86983 I, C22B HUMAN, P W01002 and HW2411G 1.
30 SAMPLE 43: Isolation of eDNA Clones ,j_ttcodin>i Human PRO941 A consensus scqtiettoc was oMai>ted relative to a variety of EST sequences as described in Exarttple I above, wherein the conscruus seqti~ee obtained is heroin designated DNA359~4I. An EST
sequence proprietary to Genentectt was employed in the assembly and is herein designated DNA641S
(Figure 96; SEQ ID N0:265). Based on the DNA35941 conscrrcus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA library 35 that contained the sequence of interest, and 2). for use as probes to isolate a clone of the full-length coding sequence for PR0941.
A pair of PCR primers (forward and reverse) were synthesized:
forward P('.R R~ 5'-C71'GAG'TGTCT'CTGAATCTGCACCC-3' (SEQ iD N0:266) reverse E~primsr 5'-AAG1'GGTGGAAGCCTCCAGTGTGG-3' (SEQ ID N0:267) WO 99146281 PCTlUS99l05028 Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA35941 sequence which had the following nucleotide sequence hybridization probe 5'-CCACTACGGTATTAGAGCAAAAGTTAAAAACCATCATGGTTCCTGGAGCAGC-3' (SEQ ID N0:268) In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PR094I gene using the probe oligonucleotide and one of the PCR
primers. RNA for construction of the cDNA libraries was isolated from human fetal kidney tissue (LIB227).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0941 [herein designated as UNQ478 (DNA53906-1368)] (SEQ ID N0:263) and the derived protein sequence for PR0941.
The entire nucleotide sequence of UNQ478 {DNA53906-1368) is shown in Figure 94 (SEQ ID N0:263).
Clone UNQ478 (DNA53906-1368) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 37-39 and ending at the stop codon of nucleotide positions 2353-2355 (Figure 94). The predicted polypepiide precursor is 772 amino acids long (Figure 95). The full-length PR0941 protein shown in Figure 95 has an estimated molecular weight of about 87,002 daltons and a pI
of about 4.64. Analysis of the full-length PR0941 sequence shown in Figure 95 (SEQ ID N0:264) evidences the presence of the following: a signal peptide from about amino acid 1 to about amino acid 21, potential N-glycosylation sites from about amino acid 57 to about amino acid 60, from about amino acid 74 to about amino add 77, from about amino acid 419 to about amino acid 422, from about amino acid 437 to about amino acid 440, from about amino acid 508 to about amino acid 511, from about amino acid 515 to about amino acid 518, from about amino acid 516 to about amino acid 519 and from about amino aad 534 to about amino acid 537, and cadherin extracellular repeated domain signature sequences from about amino acid 136 to about amino acid 146 and from about amino acid 244 to about amino acid 254. Clone UNQ478 (DNA53906-1368) has been deposited with ATCC on April 7, 1998 and is assigned ATCC deposit no.
209747.
Analysis of the amino acid sequence of the full-length PR0941 polypeptide suggests that it possesses significant sequence similarity to a cadhetin protein, thereby indicating that PR0941 may be a novel cadberin protein family member. More specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced significant homology between the PR0941 amino acid sequence and the following Dayhoff sequences, I50180, CADA CHICK, I50178, GEN12782, CADC HUMAN, P W25637, A38992, P 849731, D38992 and 602678.
~,XAMPLE 44: Isolation of cDNA Clones Encoding Human PR0944 A consensus sequence was obtained relative to a variety of FST sequences as described in Example 1 above, wherein the cot>sensus seque»ce obtained is herein designated DNA47374. A
variety of proprietary Genentech EST
sequences were employed in the assembly and are shown in Figures 99-107. Based on the DNA47374 consensus sequence, oligonucleotictes were synthesized: I) to identify by PCR a cDNA
library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0944.
A pair of PCR pritners (forward and reverse) were synthesized:
~gtward PCR~rimer 5'-CGAGCGAGTCATGGCCAACGC-3' (SEQ ID N0:280) reverse PCR ~m_er_ 5'-GTGTCACACGTAGTCTTTCGCGCTGG-3' (SEQ ID N0:281) WO 99146281 PCTlUS99/05028 Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA47374 sequence which had the following nucleotide sequence hybridig_ation probe 5'-CTGCAGCTGTTGGGCTTCATTCTCGCCTTCCTGGGATGGATCG-?~' (SEQ ID N0:282) In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PR0944 gene using the probe oligonucleotide and one of the PCR
primers. RNA for construction of the cDNA libraries was isolated from human fetal kidney tissue (LIB22?).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0944 [herein designated as UNQ481 (DNA52I85-1370)] (SEQ ID N0:269) and the derived protein sequence for PR0944.
The entire nucleotide sequence of UNQ481 (DNA52185-1370) is shown in Figure 9?
(SEQ ID N0:269).
Clone UNQ481 (DNA52185-1370) contains a single open reading frame with an apparent translatioital initiation site at nucleotide positions 2I9-221 and ending at the stop codon at nucleotide positions 852-854 (Figure 97). The predicted polypeptide precursor is 211 amino acids long (Figure 98). The full-length PR0944 protein shown in Figure 98 has an estimated moiecuiar weight of about 22,744 dalfons and a pI
of about 8.51. Analysis of the full-length PR0944 sequence shown in Figure 98 (SEQ ID N0:270) evidences the presence of the following: a signal peptide from about amino acid I to about amino acid 21, transmembrane domains from about amino acid 82 to about amino acid 102, from about amino acid 1 i 8 to about amino acid I42 and from about amino acid 161 to about amino acid 187, a potential N-glycosylation site from about amino acid 72 to about amino acid 75, a sequence block having homology to PMP-22IEMP/MP20 family of proteins from about amino acid 70 to about amino acid 1 l l and a sequence block having homology to ABC-2 type transport system integral membrane protein from about amino acid 119 to about amino acid 133. Clone UNQ481 (DNA52185-1370) has been deposited with ATCC on May 14, 1998 and is assigned ATCC deposit no. 209861.
Analysis of the amino acid sequence of the full-length PR0944 polypeptide suggests that it possesses significant sequence similarity to the CPE-R protein, thereby indicating that PR0944 may be a novel CPE-R
hotnolog. More specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced significant homology between the PR0944 amino acid sequence and the following Dayhoff sequences, AB000713_I, AB000714~l, AF035814'l, AF000959 1, HSU89916 1, EMP2_HUMAN, JC5732, CELF53B3 6, PM22 MOUSE
and CGU49797 1.
EXAMPLE 45: Isolation of cDNA Clones Encoding Hummn PRO983 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA47473. Various proprietary Genentech EST
sequences were employed in the assembly, wherein those EST sequences are shown in Figures 110-116. Based on the DNA4?473 consensus sequence, oligonucieotides were synthesized: 1) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0983.
A pair of PCR primers (forward and reverse) were synthesized:
forward PCR primer 5'-GCACCACCGTAGGTACTTGTGTGAGGC-3' (SEQ ID N0:292) reverse 5'-AACCACCAGAGCCAAGAGCCGGG -3' (SEQ ID N0:293) WO 99!46281 PCTlUS99105028 Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA47473 sequence which had the following nucleotide sequence hybridization probe 5'-CAGCGGAATCATCGATGCAGGGGCCTCAATTAATGTATCTGTGATGTTAC-3' (SEQ 1D N0:294) In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PR0983 gene using the probe oligonucleotide and one of the PCR
primers. RNA for construction of the cDNA libraries was isolated from human bone marrow (LIB256).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0983 [herein designated as UNQ484 (DNA53977-1371)] (SEQ ID N0:283) and the derived protein sequence for PR0983.
The entire nucleotide sequence of UNQ484 (DNA53977-1371) is shown in Figure 108 (SEQ ID N0:283).
Clone UNQ484 (DNA53977-1371) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 234-236 and ending at the stop codon at nucleotide positions 963-965 (Figure 108). The predicted polypeptide precursor is 243 amino acids long (Figure 109). The full-length PR0983 protein shown in Figure 109 has an estimated molecular weight of about 27,228 daltons and a p1 of about 7.43. Analysis of the full-length PR0983 sequence shown in Figure 109 (SEQ ID N0:284) evidences the presence of the following features:
a putative transmembrane domain from about amino acid 224 to about amino acid 239; a potential N-glycosylation site from about amino acid 68 to about amino acid 71; and three potential N-myristoylation sites from about amino acid 59 to about amino acid 64, from about amino acid 64 to about amino acid 69, and froth about amino acid 235 to about amino acid 240. Clog UNQ484 (DNA53977-1371) has been deposited with ATCC on May 14, 1998 and is assigned ATCC deposit no. 209862.
Analysis of the amino acid sequence of the foil-length PR0983 polypeptide suggests that it possesses significant sequence similarity to the vesicle-associated protein, VAP-33, thereby indicating that PR0983 may be a novel vesicle associated membrane protein. More specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced significant homology between the PR0983 amino acid sequence and the following Dayhoff sequences: VP33 APLCA, CELF33D11 12, CELF42G2 2, S50623, YDFC SCHPO, CELF54H5 2, CELZC196 8, CEF57A10 3, MSP3~GLORO, CEC15H11_l.
EXAMPLE 46: Isolation of eDNA Clones Enco~ng Human PR01057 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA49808. Based on the DNA49808 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA
library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR01057.
PCR primers (forward and reverse) were synthesized:
forward PCR primer 5'-GCATCTGCAGGAGAGAGCGAAGGG-3' (SEQ ID N0:297) ~e_vetse PCR primer 5'-CATCGTTCCCGTGAATCCAGAGGC-3' (SEQ ID N0:298) Additionally, a synthetic oligonucleotide hybridization probe was constructed from the comcensus DNA49808 sequence which had the following nucleotide sequence hybridization vrobe 5'-GAAGGGAGGCCTTCCTTTCAGTGGACCCGGGTCAAGAATACCCAC-3' (SEQ ID N0:299) In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PR01057 gene using the probe oligonucleotide and one of the PCR
primers. RNA for construction of the cDNA libraries was isolated from human fetal kidney tissue (LIB227).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PROlOS7 (t>erein designated as UNQS22 (DNAS?2S3-1382)) (SEQ ID N0:29S) and the derived protein sequence for PR010S7.
The entire nucleotide sequence of UNQS22 (DNAS7253-1382) is shown in Figure 117 (SEQ ID N0:29S).
Clone UNQS22 (DNAS7253-1382) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 275-27? and ending at the stop codon at nucleotide positions 1514-1516 (Figure 117). The predicted polypeptide precursor is 413 amino acids long (Figure 118). The full-length PR01057 protein shown in Figure 118 has an estimated molecular weight of about 47,070 daltons and a p1 of about 9.92. Analysis of the full-length PROlOS7 sequence shown in Figure 118 (SEQ ID N0:296) evidences the presence of the following: a signal peptide from about amino acid 1 to about amino acid 16, potential N-glycosylation sites from about amino acid 90 to about amino acid 93, from about amino acid 110 to about amino acid 113 and from about amino acid 193 to about amino acid 196, a glycosaminoglycan attachment site from about amino acid 236 to about amino acid 239 and a serine protease histidine-containing active site from about amino acid 165 to about amino acid 170. Clone UNQ522 (DNA57253-1382) has been deposited with ATCG on May 14, 1998 and is assigned ATCC deposit no. 209867.
Analysis of the amino acid sequence of the full-length PROIOS7 polypeptide suggests that it possesses significant sequence similarity to various protease proteins, thereby indicating that PROlOS7 may be a novel protease.
More specifically, an analysis of the Dayhoff database (version 3S.4S
SwissProt 3S) evidenced significant homology between the PROlOS7 amino acid sequence and the following Dayhoff sequences,TRYE DROER, P 814159, A69660, EBN1 EBV, S65494, GEN12688, A51084 1, P R99S71, AS7S14 and AF003200 1.
EXI~VIPLE 47: Isolation o~ cDNA Cones Encodi~; Human PR01071 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, 2S wherein the consensus sequence obtained is herein designated DNA5303S.
Based on the DNA5303S consensus sequence, it was determined that that consensus sequence shared significant sequence identity with Incyte EST clone no. 2872569, a clone that upon review appeared to encode a full Iengtlt protein. As such, Incyte EST clone no.
28?2569 was purchased and its insert was obtained and sequenced so as to confirm the proper sequence. This sequence is herein designated UNQS28 or DNAS8847-1383.
DNA sequencing of the clone isolated as described above gave the foil-length DNA sequence for PR01071 [herein designated as UNQS28 (DNA58847-1383)] (SEQ m N0:300) and the derived protein sequence for PR01071.
The entire rtucieotide sequence of UNQ528 (DNA58847-1383) is shown in Figure 119 (SEQ ID N0:300).
Clone UNQS28 (DNAS8848-1383) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 133-13S and ending at the stop codon at nucleotide positions 1708-1710 (Figure 119). The 3S predicted polypeptide precursor is 525 amino acids long (Figure 120). The foil-length PR01071 protein shown in Figure 120 has an estimated molecular weight of about 58,416 daltons and a pI
of about 6.62. Analysis of the fuil-length PR01071 sequence shown in Figure 120 (SEQ ID N0:301) evidences the presence of the following: a signal peptide from about amino acid 1 to about amino acid 2S, a potential N-glycnsylation site from about amino acid 2S1 to about amino acid 254, a thrombospondin-I homology block from about amino acid 385 to about amino acid 399 WO 99!46281 PCTlUS99/05028 and von Willibtands factor type C homology blocks from about amino acid 385 to about amino acid 399, from about amino acid 445 to about amino acid 459 and from about amino acid 42 to about amino acid 56. Clone UNQ528 (DNA58847-1383) has been deposited with ATCC on May 20, 1998 and is assigned ATCC deposit no. 2098?9.
Analysis of the amino acid sequence of the full-length PR01071 polypeptide suggests that it possesses significant sequence similarity to the thrombospondin protein, thereby indicating that PR01071 may be a novel thrombospondin homolog. More specifically, an analysis of the Dayhoff database (version 3.45 SwissProt 35) evidenced significant homology between the PR01071 amino acid sequence and the following Dayhoff sequences, AB002364 1, D67076 I, BTPC1NPGN_1, CET13H10 1, CEF25H8,5, CEF53B6 2, CEC26C6 6, HSSEMG_l;
CET21B6 4 and BTY08561 1.
EXAMPLE 48: Isolation of cDNA Clones Encodine Human PR01072 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA53125. Based on the DNA53125 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA
library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR01072.
PCR primers (forward and reverse) were synthesized:
forward PCR primer 5'-CCAGGAAATGCTCCAGGAAGAGCC-3' (SEQ ID N0:305) reverse PCR primer 5'-GCCCATGACACCAAATTGAAGAGTGG-3' (SEQ ID N0:306) Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA53125 sequence which had the following nucleotide sequence hX ridization_probe 5'-AACGCAGGGATCTTCCAGTGCCCTTACATGAAGACTGAAGATGGG-3' (SEQ ID NO:307) In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PR01072 gene using the probe oligonucleotide and one of the PCR
primers. RNA for construction of the cDNA libraries was isolated from human fetal lung tissue (LIB26}.
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR01072 [herein designated as UNQ529 (DNA58747-1384)) (SEQ ID N0:302) and the derived protein sequence for PR01072.
The entire nucleotide sequence of UNQ529 (DNA58747-1384) is shown in Figure 121 (SEQ ID N0:302).
Clone UNQ529 (DNA58747-1384) contains a single open reading frame with an apparent translational.initiation site at nucleotide positions 65-67 and ending. at the stop codon at nucleotide positions 1073-1075 (Figure I21). The predicted polypeptide precursor is 336 amino acids long (Figure 122). The full-length PR01072 protein shown in Figure 122 has an estimated molecular weight of about 36,865 daltons and a pI
of about 9.15. Analysis of the full-length PR01072 sequence shown in Figure 122 (SEQ ID N0:303) evidences the presence of the following: a signal peptide from about amino acid 1 to about amino acid 21, short-chain alcohol dehydrogenase protein homology blocks from about amino acid 134 to about amino acid 144, from about amino acid 44 to about amino acid 56 and from about amino acid 239 to about atnitio acid 248 and potential N-glycosylation sites from about amino acid 212 to about amino acid 215 and from about amino acid 239 to about amino acid 242. Clone UNQ529 (DNA58747-1384) has been deposited with ATCC on May 14, 1998 and is assigned ATCC deposit no. 209868.

WO 99!46281 PCT/US99/05028 Analysis of the amino acid sequence of the full-length PR01072 polypeptide suggests that it possesses significant sequence sinlilariry to the reductase family of proteins, thereby indicating that PROI072 tray be a novel reductase. More specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced significant homology between the PR01072 amino acid sequence and the following Dayhoff sequences, P W03198, P W15759>
P_R60800, MTV037'3, CEC15H11 6, ATAC00234314, MTV022~13, SCU43704_1, OXIR
STRAT AND
CELCOI G8 3.
EXAMPLE 49: Isolation of cDNA Clones Encoding Human PR01075 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA34363. Based on the DNA34363 sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA library that contained the sequence of interest, and 2} for use as probes to isolate a clone of the full-length coding sequence for PRO10'75.
PCR primers (forward and reverse) were synthesized:
forward,~CR ~rimel 5'-TGAGAGGCCTCTCTGGAAGTTG-3' (SEQ ID N0:312) forward PCR primer_ 5'-GTCAGCGATCAGTGAAAGC-3' (SEQ ID N0:3I3) forward PCR ,primer 5'-CCAGAATGAAGTAGCTCGGC-3' (SEQ ID N0:314) forward PCR timer 5'-CCGACTCAAAATGCATTGTC-3' (SEQ ID N0:315) forward PCR rn imer 5'-CATTTGGCAGGAATTGTCC-3' (SEQ ID N0:31b}
forward PCR Timer 5'-GGTGCTATAGGCCAAGGG-3' (SEQ ID N0:317) reverse PCR grimer 5'-CTGTATCTCTGGGCTATGTCAGAG-3' (SEQ ID N0:318) reverse PCR primer 5'-CTACATATAATGGCACATGTCAGCC-3' (SEQ ID N0:319) Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA34363 sequence which had the following nucleotide sequence ridi~ation probe 5'-CGTCTTCCTATCCTTACCCGACCTCAGATGCTCCCTTCTGCTC:CTG-3' (SEQ ID N0:320}
In order to screezt several libraries for a source of a full-length clone; DNA
from the libraries was screened by PCR atnpii5cation with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PRO1075 gene using the probe oligonucieotide and one of the PCR
primers. RNA for construction of the cDNA libraries was isolated from human skin tumor tissue (LIB324).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR01075 (herein designated as UNQ532 (DNA57689-I385)] (SEQ ID N0:308) and the derived protein sequence for PROI075:
TI~ entire rntcleotide sequence of UNQ532 (DNA57689-1385) is shown in Figure 124 (SEQ ID N0:308).
Clone UNQ532 (DNA57689-1385) contains a single open reading frame with an apparent uanslational initiation site at nucleotide positions 137-139 and ending at the stop codon at nucleotide positions 1355-1357 (Figure 124). The predicted polypeptide precursor is 406 amino acids long (Figure 125). The full-length PR01075 protein shown in Figure 125 has an estimated molecular weight of about 46,927 daltons and a p1 of about 5.21. Analysis of the full-length PR01075 sequence shown in Figure 125 (SEQ ID N0:309) evidences the presence of the following: a signal peptide from about amino acid 1 to about amino acid 29, an endoplasraic reticulum targeting sequence from about amino acid 403 to about amino acid 406, a tyrosine kinase phosphorylation site from about amino acid 203 to about amino acid 211 and a sequence block having homology to the thioredoxin family of proteins from about amino acid WO 99/46281 PCT/US99l05028 50 to about amino acid 66. Clone UNQ532 (DNA57689-1385) has been deposited with ATCC on May 14, 1998 and is assigned ATCC deposit no. 209869.
Analysis of the amino acid sequence of the full-length PR01075 polypeptide suggests that it possesses significant sequence similarity to protein disulfide isomerase, thereby indicating that PR01075 may be a novel protein disulfide isotnerase. More specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced significant homology between the PR01075 amino acid sequence and the following Dayhoff sequences, CELC30H7 2, CELC06A6 3, CELF42G8 3, S57942, ER72 CAEEL, CELC07A12 3, CEH06001 4 and P 851696.
EXAMPLE 50: lsolatio~t of cDNA Cion~ Encoding Human PR0181 A cDNA sequence isolated in the amylase screen described in Example 2 above was found; by BLAST and FastA sequence alignment, to have sequence homology to a nucleotide sequence encoding the cornichon protein. This cDNA sequence is herein designated DNA13242 (Figure 130; SEQ ID N0:323). Based on the sequence homology, oligonucleotide probes were generated from the sequence of the DNA13242 molecule and used to screen a human placenta (LIB89) library prepared as described in paragraph 1 of Example 2 above. The cloning vector was pRKSB
(pRKSB is a precursor of pRKSD that does not contain the SfiI site; see, Holmes et al., Science, 253:1278-1280 (1991)), and the cDNA size cut was less than 2800 bp.
The oligonucleotide probes employed included:
forward PCR primer 5'-GTGCAGCAGAGTGGCTTACA-3' (SEQ ID N0:326) reverse PCR primer 5'-ACTGGACCAATTCTTCTGTG-3' (SEQ ID N0:32?) lybridization~robe S'-GATATTCTAGCATATTGTCAGAAGGAAGGATGGTGCAAATTAGCT-3' (SEQ ID N0:328) A fitll length clone was identified that contained a single open reading frame with an apparent translational initiation site at nucleotide positions 14-16 and ending at the stop codon found at nucleotide positions 446-448 (Figure 128; SEQ 1D N0:321). The predicted polypeptide precursor is 144 amino acids long, has a calculated molecular weight of approximately 16,699 dahons and an estimated pI of approximately 5.6. Analysis of the full-length PR0181 sequence shown in Figure 129 (SEQ 1D N0:322) evidences the presence of the following: a signal peptide from about amino acid 1 to about amino acid 20, a putative type II transmembrane domain from about amino acid 11 to about amino acid 31 and other transmembrane domains from about amino acid 57 to about amino acid 77 and from about amino acid 123 to about amino acid 143. Clone UNQ155 (DNA23330-1390) has been deposited with ATCC on April 14, 1998 and is assigned ATCC deposit no: 209775.
Analysis of the amino acid sequence of the full-length PR0181 polypeptide suggests that it possesses significant sequence similarity to the corttichon protein, thereby indicating that PR0181 may be a novel cornichon homolog. More specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced significant homology between the PR0181 amino acid sequence and the following Dayhoff sequences, AF022811,1, CET09E8,3, S64058, YGF4~YEAST, YB60_YEAST, EBU89455_1, SIU36383~3 and PH1371.
EXAN1~LE 51: js~~ion of cDNA Clones EncodinE Human PR0195 A cDNA sequence was isolated in the amylase screen described in Example 2 above and is herein designated DNA13199 (Figure 134; SEQ ID N0:332). The DNA13199 sequence was then compared to a variety of expressed sequence tag (EST) databases which included public EST databases (e.g., GenBank) to identify existing homologies. The homology search was performed using the computer program BLAST
or BLAST2 (Altshul et al., l~ethc,~ds jp~mologyr 2t~6:4b0-080 (1996)). Those comparisons resulting in a BLAST score of 70 (or in some cases 90) or greater that did not encode knOWn proteins were clustered and assembled into consensus DNA sequences with the program "phrap" (Phil Green, University of 'Washington, Seattle, Washington;
hap:l/bozeman.mbt.washington.edulphrap.docs/phrap.html). The consensus sequence obtained therefrom is herein designated as DNA22778.
Based on the DNA22778 sequence; oligonucleotide probes were generated and used to screen a human placenta library (i.IB89) prepared as described in paragraph I of Example 2 above. The cloning vector was pRRSB
(pRKSB is a precursor of pRI~SD that does not contain the SfiI site; see, Holmes et al., 'enc , 2_x:1278-1280 IO (1991)), and the cDNA size cut was less than 2800 bp.
PCR primers (forward and reverse) were synthesized:
forward PCR Timer 5'-ACAAGCTGAGCTGCTGTGACAG-3' (SEQ ID NO:333) reverse PCR primer 5'-TGATTCTGGCAACCAAGATGGC-3' (SEQ ID N0:334) Additionally, a synthetic oligonucleatide hybridization probe was constructed from the DNA22778 sequence which had the following nucleotide sequence hybridization robe 5'-ATGGCCTTGGCCGGAGGTTCGGGGACCGCTTCGGCTGAAG-3' (SEQ ID N0:335) 1n order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PR0195 gertc using the probe oligonucleotide and one of the PCR
primers.
A full length clone was identified that contained a single open reading frame with an apparent translational initiation site at nucleotide positions 70-72 and ending at the stop codon found at nucleotide positions 1039-1041 (Figure 132; SEQ 1D N0:330). The predicted polypeptide precursor is 323 amino acids long, has a calculated molecular weight of approximately 36,223 daltons and an estimated pI of approximately 5.06. Analysis of the full-length PROI95 sequence shown in Figure 132 (SEQ ID N0:330) evidences the presence of the following: a signal peptide from about amino acid I to about amino acid 3I, a transmembrane domain from about amino acid 241 to about amino acid 260 and a potential N-glycosylation site from about amino acid 90 to about amino acid 93. Clone UNQ169 (DNA26847-1395) has been deposited with ATCC on April 14, 1998 and is assigned ATCC deposit no.
209772.
Analysis of the amino acid sequence of the full-length PR0195 polypeptide suggests that it possesses no significant sequence similarity to any known protein. However, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced some degree of homology between the PR019~5 amino acid sequence and the following Dayhoff sequences, P P91380, AF035118_l, HUMTROPCS 1, NUOD_SALTY and E70002.
EXAMPLE 52: Isolation of cDN~A Clones Encoding Human PR0865 A cDNA sequence isolated in the amylase screen described in Example 2 above was herein designated DNA37642 (Figure 137, SEQ I?? N0:338). The DNA37642 sequence was then compared to a variety of expressed sequence tag (EST) databases which included public EST databases (e.g.;
GenBank) and a proprietary EST DNA
database (LIFESEQ"', htcyte Pharmaceuticals, Palo Alto, CA) to identify homologies therebetween. The homology WO 99!46281 PCT/US99105028 search was performed using the computer program BLAST or BLAST2 (Altshul et al., Methods~n Enzymology 266:46080 (I996)). Those comparisons resulting in a BLAST score of 70 (or in some cases 90) or greater that did not encode Irnown proteins were clustered and assembled into consensus DNA
sequences with the program "phrap"
( P h t 1 Green, University of Washington, Seattle, Washington;
http:/Ibozeman.mbt.Washington.edulphrap.docslphrap.html). The consensus sequence obtained is herein designated DNA48615.
Based on the DNA486I5 consensus sequence, probes were generated and used to screen a human fetal kidney {LIB227) library prepared as described in paragraph 1 of Example 2 above. The cloning vector was pRKSB
(pRKSB is a precursor of pRKSD that does not contain the SfiI site; see, Holmes et al., S fence, 53:1278-1280 (199i)), and the cDNA size cut was less than 2800 bp.
10. PCR primers (forward and reverse) were synthesized:
forward PCR primer 1 5'-AAGCTGCCGGAGCTGCAATG-3' (SEQ ID N0:339) ' forward PCR primer 2 5'-TTGCTTCTTAATCCTGAGCGC-3' (SEQ ID N0:340) forward PCR primer 3 5'-AAAGGAGGACTTTCGACTGC-3' (SEQ ID N0:341) rgverse PCR primer 1 5'-AGAGATTCATCCACTGCTCCAAGTCG-3' (SEQ ID N0:342) reverse PCR primer 2 5'-TGTCCAGAAACAGGCACATATCAGC-3' (SEQ ID N0:343) Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA48615 sequence which had the following nucleotide sequence hybridization~robe 5'-AGACAGCGGCACAGAGGTGCTTCTGCCAGGTTAGTGGTTACTTGGATGAT-3' (SEQ ID N0:344) In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with the PCR primer pairs identified above. A positive library was then used to isolate clones encoding the PR0865 gene using the probe oligonucleotide and one of the PCR
primers.
A full length clone was identified that contained a single open reading frame with an apparent translational initiation site at nucleotide positions 173-175 and ending at the stop colon found at nucleotide positions 1577-1579 (Figure 135; SEQ ID N0:336). The predicted polypeptide precursor is 468 amino acids long, has a calculated molecular weight of approximately 54,393 daltons and an estimated pI of approximately 5.63. Analysis of the full-Iength PR0865 sequence shown in Figure 136 (SEQ ID N0:337) evidences the presence of the following: a signal peptide from about amino acid 1 to about amino acid 23, potential N-glycosylation sites from about amino acid 280 to about amir~ acid 283 and from about amino acid 384 to about amino acid 387, a potential amidation site from about amino acid 94 to about amino acid 97, glycosaminoglycan attachment sites from about amino acid 20 to about amino acid 23 and from about amino acid 223 to about amino acid 226, an aminotransferase class-V pyridoxyl-phosphate amino acid sequence block from about amino acid 216 to about amino acid 222 and an amino acid sequence block similar to that found in the interleukin-7 protein from about amino acid 338 to about amino acid 343. Clone UNQ434 (DNA539?4-1401) has been deposited with ATCC on April 14, 1998 and is assigned ATCC deposit no.
209774.
Analysis of the amino acid sequence of the full-length PR0865 polypeptide suggests that it possesses no significant sequence similarity to any known protein. However, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced some degree of homology between the PR0865 amino acid sequence and the following Dayhoff sequences, YMNO YEAST, ATFCA4 43, S44168, P W14549 and RABTCRG4 1.

WO 99146281 PCT/US99f05028 EXAMPLI~ 53: Isolation o~cDNA Clones Encodin~Human PR0827 A cDNA sequence isolated in the amylase screen described in Example 2 above was found, by BLAST and.
FastA sequence alignment, to have sequence homology to nucleotide sequences encoding various integrin proteins.
This cDNA sequence is herein designated DNA47751 (see Figure 140; SEQ ID
N0:347). Based on the sequence homology, probes were generated from the sequence of the DNA47751 molecule and used to screen a human fetal pigment epithelium library (LIB113) prepared as described in paragraph 1 of Example 2 above. The cloning vector was pRKSB (pRKSB is a precursor of pRKSD that does not contain the Sfil site;
see, Holmes et al., Science, 25:1278-1280 {I991)), and the cDNA size cut was less than 2800 bp.
PCR primers (forward and reverse) were synthesized:
forward PCR rimer 5'-AGGGACAGAGGCCAGAGGACTTC-3' (SEQ ID N0:348) reyerse PCR primp 5'-CAGGTGCATATTCACAGCAGGATG-3' {SEQ ID N0:349) Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA47751 sequence which had the following nucleotide sequence hvbrid_~zation probe 5'-GGAACTCCCCTTCGTCACTCACCTGTTCTTGCCCCTGGTGTTCI:T-3' (SEQ ID
N0:350) In order to screen several libraries for a source of a full-length clone, DNA
from the Iibraties was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PR0827 gene using the probe oligonucleotide and one of the PCR
primers.
A full length clone was identified that contained a single open reading frame with an apparent translational initiation site at nucleotide positions 134-136 and ending at the stop codon found at nucleotide positions 506-508 (Figure 138; SEQ ID N0:345). The predicted polypeptide precursor is 124 amino acids long, has a calculated molecular weight of approximately 13,352 daltons and an estimated pI of approximately 5.99. Analysis of the full-length PR0827 sequence shown in Figure 139 (SEQ ID N0:346) evidences the presence of the following: a signal peptide from about amino acid 1 to about amino acid 22, a cell attachment sequence from about amino acid 70 to about amino acid 72, a potential N-glycosylation site 'from about amino acid 98 to about amino acid 101 and an integrin alpha chain protein homology sequence from about amino acid 67 to about amino acid 81. Clone UNQ468 (DNA57039-1402) has been deposited with ATCC on April 14, 1998 and is assigned ATCC deposit no. 209777.
Analysis of the amino acid sequence of the full-length PR0827 polypeptide suggests that it possesses significant sequence similarity to the VLA-2 integrin protein and various other integrin proteins, thereby indicating that PR0827 may be a novel integrin or splice variant thereof. More specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced significant homology between the PR0240 amino acid sequence and the following Dayhoff sequences, S44142, ITA2 HUMAN, ITAl RAT, ITAl HUMAN, ITA4 HUMAN, fTA9 HUMAN, AF032108 l, iTAM MOUSE, ITA8 CRICK and ITA6 CHICK.
EXAMPLE 54: Isolation of cDNt~ Cjones Encoding_Human P,~tOI I 14 A cDNA sequence isolated in the amylase screen described in Example 2 was found, by the WU-BLAST2 sequence alignment computer program, to have certain sequence identity to other lo~own interferon receptors. This cDNA sequence is herein designated DNA48466 (Figure 143; SEQ ID N'0:352).
Based on the sequence identity, probes were generated from the sequence of the DNA48466 molecule anti used to screen a human breast carconoma WO 99146281 PCTlUS99/05028 library (LIBI35) prepared as described in paragraph 1 of Example 2 above. The cloning vector was pRKSB (pRKSB
is a precursor of pRKSD that does not contain the Sfil site; see, Holmes et al., Science, 253:1278-1280 (1991)), and the cDNA size cut was less than 2800 bp.
The oligonucleotide probes employed were as follows:
forward PCR primer S'-AGGCTTCGCTGCGACTAGACCTC-3' (SEQ ID N0:354) reverse PCR primer S'-CCAGGTCGGGTAAGGATGGTTGAG-3' (SEQ ID N0:355) )~bridization probe S'-TTTCTACGCATTGATTCCATGTTTGCTCACAGATGAAGTGGCCATTCTGC-3' (SEQ ID N0:356) A full length clone was identified that contained a single open reading frame with an apparent translational initiation site at nucleotide positions 250-252, and a stop signal at nucleotide positions 1183-1185 (Figure 141, SEQ
ID N0:351). The predicted polypeptide precursor is 311 amino acids long, has a calculated molecular weight of approximately 35,076 daltons and an estimated p1 of approximately 5.04.
Analysis of the full-length PR01114 interferon receptor sequence shown in Figure 142 (SEQ 1D N0:352) evidences the presence of the following: a signal peptide from about amino acid 1 to about amino acid 29, a transmembrane domain from about amino acid 230 to about amino acid 255, potential N-glycosylation sites from about amino acid 40 to about amino acid 43 and from about amino acid 134 to about amino acid 137, an amino acid sequence block having homology to tissue factor proteins from about amino acid 92 to about amino acid 119 and an amino acid sequence block having homology to integrin alpha chain proteins from about amino acid 232 to about amino acid 262. Clone UNQ557 (DNA57033-1403) has been deposited 'with ATCC on May 27, 1998 and is assigned ATCC deposit no.
209905.
An analysis of the Dayhoff database (version 35.45 SwissProt 35), using a WU-BLAST2 sequence alignment analysis of the full-length sequence shown in Figure 142 (SEQ ID N0:352), evidenced significant homology between the PR01114 interferon receptor amino acid sequence and the following Dayhoff sequences: 601418, INRl MOUSE, P 871035, INGS HUMAN, A26595_i, A26593_l, I56215 and TF HUMAN.
EXAMPLE 55: TsolatiQn of cDNA Clones Encoding Human PR0237 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA30905. Based on the DNA30905 consensus sequence, oligonucieotides were synthesized: I) to identify by PCR a cDNA
library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0237.
PCR primers (forward and reverse) were synthesized:
forward PCR primer 5'-TCTGCTGAGGTGCAGCTCATTCAC-3' (SEQ ID N0:359) reverse PCR vrimer 5'-GAGGCTCTGGAAGATCTGAGATGG-3' (SEQ ID N0:360) Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA30905 sequence which had the following rrucleotide sequence hybridization Bxobe 5'-GCCTCTTTGTCAACGTTGCCAGTACCTCTAACCCATTCCTCAGTCGCCTC-3' (SEQ ID N0:361) In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PR0237 gene using the probe oligonucleotide and one of the PCR
primers. RNA for construction of the cDNA libraries was isolated from human fetal brain tissue {LIB153).

DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0237 [herein designated as UNQ211 (DNA34353-1428)] (SEQ ID N0:357) and the derived protein sequence for PR0237.
The entire nucleotide sequence of UNQ211 (DNA34353-1428) is shown in Figure 144 (SEQ ID N0:357).
Clone UNQ211 (DNA34353-1428) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 586-588 and ending at the stop codon at nucleotide positions 1570-1572 (Figure 144). The predicted polypeptide precursor is 328 amino acids long (Figure 145): The full-length PR0237 protein shown in Figure 145 has an estimated molecular weight of about 36,238 daltons and a pI
of about 9.90. Analysis of the full-length PR0237 sequence shown in Figure 145 (SEQ ID N0:358) evidences the presence of the following: a signal peptide from about amino acid 1 to about amino acid 23, a transmembrane domain from about amino acid 177 to about amino acid 199, potential N-glycosylation sites from about amino acid 118 to about amino acid i21, from about amino acid 170 to about amino acid 173 and from about amino acid 26(1 to about amino acid 263 and eukaryotic-type carbonic anhydrase sequence homology blocks from about amino acid 222 to about amino acid 270, from about amino acid 128 to about amino acid 164 and from about amino acid 45 to about amino acid 92. Clone UNQZ11 (DNA34353-1428) has been deposited with ATCC on May 12, 1998 and is assigned ATCC deposit no. 209855.
Analysis of the amino acid sequence of the full-length PR0237 polypeptide suggests that it possesses significant sequence similarity to the carbonic anhydrase protein. More specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced significant homology between the PR0237 amino acid sequence and the following Dayhoff sequences, AF050106_l, OACALP_1, CELD1022 8, CAH2~HUMAN, 1CAC, CAHS~HUMAN, CARP HUMAN, CAH3 HUMAN, CAH1 HUMAN and 2CAB.
~XA~~uIPLE 56: ~solatiort of cDNA Clones Encoding Human PR0541 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA42259. Based on the DNA42259 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA
library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0541.
PCR primers (forward and reverse) were synthesized:
forward PCR primer 5'-GGACAGAATTTGGGAGCACACTGG-3' (SEQ ID N0:364) forward PAR primer 5'-CCAAGAGTATACTGTCCTCG-3' (SEQ ID N0:365) reverse PCR primer 5'-AGCACAGATTTTCTCTACAGCCCCC-3' (SEQ ID NO:366) reverse PCR primer 5'-AACCACTCCAGCATGTACTGCTGC-3' (SEQ ID N0:367) Additionally, a synthetic oligonucieotide hybridization probe was constructed from the consensus DNA42259 sequence which had the following nucleotide sequence hvbridizattq~n probe 5'-CCATTCAGGTGTTCTGGCCCTGTATGTACACATTATACACAGGTCGTGTG-3' (SEQ ID N0:368) In order to screen several libraries for a sowce of a full-length clone, DNA
from the libraries was screened by PCR amplification with one of the PCR primer pairs identified above. A
positive library was then used to isolate clones encoding the PR0541 gene using the probe oIigonucleotide and one of the PCR primers. RNA for construction of the cDNA libraries was isolated from human fetal kidney ~ussue (LIB227).
DNA sequencing of the clones isolated as described about gave the full-length DNA sequence for PR0541 (herein designated as UNQ342 (DNA45417-1432)] (SEQ ID N0:362) and the derived protein sequence for PR0541.

The entire nucleotide sequence of UNQ342 (DNA45417-1432) is shown in Figure 146 (SEQ ID N0:362).
Clone UNQ342 (DNA45417-1432) contains a single open reading frame with an apparent translationaI initiation site at nucleotide positions 469-47I and ending at the stop codon at nucleotide positions 1969-1971 (Figure 146). The predicted polypeptide precursor is 500 amino acids long (Figure 147), The full-length PR0541 protein shown in Figure 147 has an estimated molecular weight of about 56,888 daltons and a p1 of about 8.53. Analysis of the full-length PR0541 sequence shown in Figure 147 (SEQ ID N0:363) evidences the presence of the following: a signal peptide from about amino acid 1 to about amino acid 20, amino acid sequence blocks having homology to extracelIular proteins SCPlTpx-1/AgSIPR-l/Sc7 from about amino acid 165 to about amino acid I86, from about amino acid 196 to about amino acid 218, from about amino acid 134 to about amino acid 146, from about amino acid 96 to about amitw acid 108 and from about amino acid 58 to about amino acid 77 and a potential N-glycosylation site from about amino acid 28 to about amino acid 31. Clone UNQ342 (DNA45417-1432) has been deposited with ATCC
on May 27, 1998 and is assigned ATCC deposit no. 209910.
Analysis of the amino acid sequence of the full-length PR0541 polypeptide suggests that it possesses significant sequence similarity to a trypsin inhibitor protein, thereby indicating that PR054i may be a novel irypsin inhibitor. More specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced significant homology between the PR0541 amino acid sequence and the following Dayhoff sequences, D45027-1, AB009609 1, JC5308, CRS3 HORSE, TPXl HUMAN, HELD HELHO, GEN14351, A28112_1, CETOSA10 4 and P W11485.
EXAMPLE 57: IsolatiQn~f cDNA Clones Encoding Human~R0273 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA36465. Based on the DNA36465 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA
library that contained the sequence of interest, and 2) for use as probes to isolate a cione of the full-length coding sequence for PR0273.
A pair of PCR primers (forward and reverse) were synthesized:
forward PCR~ritr~e_r 5'-CAGCGCCCTCCCCATGTCCCTG-3' (SEQ ID N0:371) reverse PCR primer 5'-TCCCAACTGGTTTGGAGTTTTCCC-3' (SEQ ID N0:372) Additionally, a synthetic oligotntcleotide hybridization probe was constructed from the consensus DNA36465 sequence which had the following nucleotide sequence hvbridiz~t,, ion.prob~
5'-CTCCGGTCAGCATGAGGCTCCTGGCGGCCGCTGCTCCTGCTGCTG-3' (SEQ ID NO:373) In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was than used to isolate clones encoding the PR0273 gene using the probe oligonucleotide and one of the PCR
primers. RNA for construction of the cDNA libraries was isolated from human fetal kidney tissue.
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0273 jherein designated as UNQ240 (DNA39523-1192)] (SEQ ID N0:369) and the derived protein sequence for PR0273.
The entire nucleotide sequence of UNQ240 {DNA39523-1192) is shown in Figure 148 (SEQ ID N0:369).
Clone UNQ240 (DNA39523-1192) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 167-169 and ending at the stop codon at nucleotide positions 500-502 {Figure 148). The predicted polypeptide precursor is 111 amino acids long {Figure 149). Clone UNQ240 (DNA39523-1192) has been WO 99146281 PCTIUS99I0~028 deposited with the ATCC. It is understood that the deposited clone contains the actual sequence and that the sequences provided herein are merely representative based on current sequencing techniques. Moreover, given the sequences provided herein and knowledge of the universal genetic code, the corresponding nucleotides for any given amino acid can be routinely identified and vice versa.
Analysis of the amino acid sequence of the full-length PR0273 polypeptide suggests that portions of it possess sequence identity with human macrophage inflammatory protein-2, cytokine-induced neutrophil chemoamactant 2, and neutrophiI chemotactic factor 2-beta, thereby indicating that PR0273 is a novel chemokine.
As discussed further below, the cDNA was subcloned into a baculovirus vector and expressed in insect cells as a C-terminally tagged IgG fusion protein. N-terminal sequencing of the resultant protein identified the signal sequence cleavage site, yielding a mature poIypeptide of 77 amino acids. The mature sequence, showing 3I-40%
identity to other human CXC chemokines, includes the four canonical cysteine residues but lacks the ELR motif.
Northern analysis demonstrates expression at least in the small intestine, colon, spleen, lymph node and kidney. By in situ hybridization, also described in detail below, mRNA is localized to the lamina propria of intestinal villi and to renal tubules.
EXAMPLE 58: Isolation of cDNA Clones Encoding Human PR070I
A consensus sequence was obtairred relative to a variety of EST sequences as described in Example l above, wherein the consensus sequence obtained is herein designated DNA39848. Based on the DNA39848 consensus sequence, oligonucleotides were synthesized: I) to identify by PCR a cDNA
library that contained the sequence of interest; and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0701.
A pair of PCR primers (forward and reverse) were synthesized:
forward PCR rimer 5'-GGCAAGCTACGGAAACGTCATCGTG-3' (SEQ ID N0:376) reverse PCR rimer 5'-AACCCCCGAGCCAAAAGATGGTCAC-3' (SEQ ID N0:377) Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA39848 sequence which had the following nucleotide sequence:
hybridization probe 5'-GTACCGGTGACCAGGCAGCAAAAGGCAACTATGGGCTCCTGGATCAG-3' (SEQ ID N0:378).
In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PR0701 gene using the probe oligonucleotide and one of the PCR
primers. RNA for construction of the cDNA libraries was isolated from human fetal kidney tissue (LIB227).
DNA sequencing of the cioties isolated as described above gave the full-length DNA sequence for PR0701 [herein designated as UNQ365 (DNA44205-1285)j (SEQ ID N0:374) and the derived protein sequence for PR0701.
The entire nucleotide sequence of UNQ365 (DNA44205-1285) is shown in Figure 150 (SEQ ID N0:374).
Clog UNQ365 (DNA44205-1285) contains a single open reading frame with an apparent transiational initiation site at nucleotide positions 50-52 and ending at the stop codon at nucleotide positions 2498-3000 (Figure 150). The predicted polypeptide precursor is 816 amino acids long (Figure 151). The full-length PR0701 protein shown in Figure 151 has an estimated molecular weight of almut 91,794 daltons, a p1 of about 5.88 and NX(S!T) being 4.
Clone UNQ365 (DNA44205-1285) has been deposited with the ATCC on March 31, 1998. It is understood that the clone was the correct and actual sequence, wherein the sequences provided herein are representative based on sequencing techniques.
Still regarding the amino acid sequence shown in Figure 151, there is a potential signal peptide cleavage site at about amino acid 25. There are potential N-glycosylation sites at about amino acid positions 83, 511, 716 and 803.
The carboxyIesterases type-B signature 2 sequence is at about residues 125 to 135. Regions homologous with carboxylesterase type-B are also at about residues 54-74, 197-212 and 221-261.
A potential transmembrane region corresponds approximately to amino acids 671 through about 700. The corresponding nucleic acids can be routinely determined from the sequences provided herein.
Analysis of the amino acid sequence of the full-Length PR0701 polypeptide suggests that it possess significant homology to the neuroligins from rattus norvegicus indicating that PR0701 may be a novel human neuioligin.
EXAMPLE 59: Isolation of cDNA Clones Encoding Human PR0704 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA43033. Based on the DNA43033 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA
library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0704.
A pair of PCR primers (forward and reverse) were synthesized:
forward PCR Q_rimer 5'-CCTTGGGTCGTGGCAGCAGTGG-3' (SEQ ID N0:381);
reverse PCR primer 5'-CACTCTCCAGGCTGCATGCTCAGG-3' (SEQ ID N0:382).
Additionally, a synthetic oligonucleotide hybridization probe was constructed from the DNA43033 consensus sequence which had the following nucleotide sequence:
hybridization lobe 5'-GTCAAACGTTCGAGTACTTGAAACGGGAGCACTCGCTGTCGAAGC-3' (SEQ ID N0:383).
In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR art>plification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PR0704 gene using the probe oligonucleotide and one of the PCR
primers. RNA for construction of the cDNA libraries was isolated from human fetal kidney tissue (LIB227).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0704 [herein designated as UNQ368 (DNA50911-1288)] (SEQ ID N0:3?9) and the derived protein sequence for PR0704.
The entire ttttcleotide sequence of UNQ368 (DNA50911-1288) is shown in Figure 152 (SEQ ID N0:379).
Clone UNQ368 (DNA50911-1288) contains a single open reading frame with an apparent translatianal initiation site at nucleotide positions 8-10 and ending at the stop codon at nucleotide positions 1052-1054 (Figure 152). The predicted polypeptide precursor is 348 amino acids long (Figure 153). The full-length PR0704 protein shown in Figure 153 has an estimated molecular weight of about 39,711 and a pI of about 8.7. Clone UNQ368 (DNA50911-1288) has been deposited with the ATCC on March 31, 1998. Regarding the sequence, it is understood that the deposited clone contains the correct sequence, and the sequences provided herein are based on known sequencing techniques.
Analysis of the amino acid sequence of the full-length PR0704 polypeptide suggests that portions of it possess significant homology to the vesicular integral membrane protein 36, thereby indicating that PR0704 tttay be a novel vesicular integral membrane protein.

, Still analyzing the amino acid sequence of SEQ ID N0:380, the putative signal peptide is at about amino acids 1-39 of SEQ ID N0:380. The transmembrane domain is at amino acids 310-335 of SEQ ID N0:380. A
potential N-glycosylation site is at about amino acids 180-183 of SEQ ID
N0:380. The corresponding nucleotides can be routinely determined given the sequences provided herein.
EXAMPLE 60: Iso-,lalion o~eDNA Clones Encgding Human PR07Q6 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA40669. Based on the DNA40669 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA
library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0706.
A pair of PCR primers (forward and reverse) were synthesized:
forward PCR 'met 5'-CCAAGCAGCTTAGAGCTCCAGACC-3' (SEQ ID N0:386) reverse PCR primer 5'-TTCCCTATGCTCTGTATTGGCATGG-3' (SEQ ID N0:387) Additionally, a synthetic oligotntcleotide hybridization probe was constructed from the consensus DNA40669 sequence which had the following nucleotide sequence h bridi anon probe 5'-GCCACTTCTGCCACAATGTCAGCTTTCCCTGTACCAGAAATGGCTGTGTT-3' (SEQ ID N0:388) In order to screen several libraries for a source of a full-length clone, DNA
from the -libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PR0706 gene using the probe oligonucleotide and one of the PCR
primers. RNA for construction of the cDNA libraries was isolated from human fetal brain tissue (LIB153).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0706 [herein designated as UNQ370 (DNA48329-1290)] (SEQ ID N0:384) and the derived protein sequence for PR0706.
It is understood that the deposited clone contains the actual sequence, and that the sequences provided herein are representative based on current sequencing techniques.
The entire nucleotide sequence of UNQ370 (DNA48329-1290) is shown in Figure 154 (SEQ ID N0:384).
Clone UNQ370 (DNA48329-1290) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 279-281 and ending at the stop codon at nucleotide positions 1719-1721 (Figure 154). The predicted polypeptide precursor is 480 amino acids long (Figure 155). Tlte full-length PR0706 protein shown in Figure 155 has an estimated molecular weight of about 55,239 daltons and a pI
of about 9.30. Clotic UNQ370 (DNA48329-1290) has been deposited with the ATCC on April 21, 1998.
Still regarding the amino acid sequence shown in Figure 155, there is a potential signal peptide cleavage site at about amino acid 19. There are potential N-glycosylation sites at about amino acid positions 305 and 354. There is a potential tyrosine ldnase phosphorylation site at about amino acid position 333. A region homologous with histidine acid phosphatase is at about residues 87-102. The corresponding nucleic acid regions can be routinely determined given the provided sequences, i.e., the eadons can be determined from the specifically named amino acids given.
Analysis of the amino acid sequence of the full-length PR0706 polypeptide suggests that portions of it possess significam homology to the human prostatic acid phosphatase precursor thereby indicating that PR0706 may T
WO 99!46281 PCTJUS99105028 be a novel human prostatic acid phosphatase.
EXAMPLE 6i: Isolation of cDNrA Clones )incoding Human PR0707 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA42775. Based on DNA42775, olieonucleotides were synthesized: l) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0707.
A pair of PCR primers (forward and reverse) were synthesized:
forward PCR p~ir~er 5'-TCCGTCTCTGTGAACCGCCCCAC-3' (SEQ ID N0:391);
reverse PCR primer 5'-CTCGGGCGCATTGTCGTTCTGGTC-3' (SEQ ID N0:392}.
Additionally, a synthetic oligonucleotide hybridization probe was constructed from the DNA42775 sequence which had the following nucleotide sequence:
hybridization probe 5'-CCGACTGTGAAAGAGAACGCCCCAGATCCACTTATTCCCC-3' (SEQ ID N0:393).
In order to screen several libraries for a source of a foil-length clone, DNA
from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PR0707 gene using the probe oligonucleotide and one of the PCR
primers. RNA for construction of the cDNA libraries was isolated from human fetal kidney tissue {LIB22?).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0707 [herein designated as UNQ371 (DNA4830tr1291)] (SEQ ID N0:389) and the derived protein sequence for PR0707.
The entire nucleotide sequence of UNQ371 (DNA48306-1291) is shown in Figure 156 (SEQ ID N0:389).
Clone UNQ371 (DNA48306-I291) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 371-373 and ending at the stop codon at nucleotide positions 3119-3121 of SEQ ID N0:389.
The predicted polypeptide precursor is 91b amino acids long (Figure 157). The full-length PR0707 protein shown in Figure 157 has an estimated molecular weight of about 100,204 daltons and a pI of about 4.92. Clone UNQ371 (DNA48306-1291) has been deposited with ATCC on May 27, 1998. It is understood that the clone UNQ371 which is deposited is that which encodes PR0707, and that the sequences herein are merely representations based on known sequencing techniques which may be subject to minor errors.
Regarding analysis of the amino acid sequence, the signal sequence appears to be at about 1 through 30 of SEQ )D N0:390. Cadhetins extracellular repeated domain signature sequence is at about amino acids 121-131, 230-240, 333-345, 4401150, and 550-X60 of SEQ ID N0:390. Tyrosine kinase phosphorylation sites are at about amino acids 124-132 and 580-5$6 of SEQ ID NO:390. A potential transmembrane domain is at about amino acids 682-715 t 5. The nucleic acid positions can be derived by referring to the corresponding codon for the named amino acid.
Analysis of the amino acid sequence of the full-length PR0707 polypeptide suggests that portions of it possess significant homology to the cadherin FIBS protein, expressed in human fibroblasts, thereby indicating that PR0707 may be a novel cadherin.

EXAMPLE 62: Isolation of eDNA Clones Encoding Human PR0322 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA48336. Based on the DNA48336 consensus sequence, oligonucleotides were synthesized: I) to identify by PCR a cDNA
library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0322.
A pair of PCR primers (forward and reverse) were synthesized:
forward PCR primer 5'-CAGCCTACAGAATAAAGATGGCCC-3' (SEQ ID N0:396) reverse PCR primer 5'-GGTGCAATGATCTGCCAGGCTGAT-3' (SEQ. ID N0:397) Additionally, a synthetic oligonucleotide hybridization probe was constructed from the DNA48336 consensus sequence which had the following nucleotide sequence:
~bridization probe 5'-AGAAATACCTGTGGTTCAGTCCATCCCAAACCCCTGCTACAACAGCAG-3' (SEQ ?D N0:398).
In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PR0322 gene using the probe oligonucleotide and one of the PCR
primers. RNA for construction of the cDNA libraries was isolated from human fetal kidney tissue (LIB227).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0322 [herein designated as UNQ283 {DNA48336-1309)) (SEQ ID N0:394) and the derived protein sequence for PR0322.
It is understood that UNQ283 (DNA48336-1309) in fact encodes PRO322, and that SEQ ID N0:394 is a representation of the sequence based on sequencing techniques known in the art.
The entire nucleotide sequence of UNQ283 (DNA48336-1309) is shown in Figure 158 (SEQ ID N0:394).
Clone UNQ283 (DNA48336-1309) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 166-168 and ending at the stop codon at nucleotide positions 946-948 (Figure 158). The predicted polypeptide precursor is 260 amino acids long (Figure 159). The full-length PR0322 protein shown in Figure 159 has an estimated molecular weight of about 28,028 daltons and a p1 of about 7.87. Clone UNQ283 (DNA48336-1309) has been deposited with ATCC and is assigned ATCC deposit no.
209669.
Regarding the amino acid sequence of Figure 159, a potential N-glycosylation site is at amino acid 110 of SEQ ID N0:395. The serine proteases, trypsin family and histidine active site is identified at amino acids 69 through 74 of SEQ ID N0:395 and the consensus sequence is identified at amino acids 207 through 217 of SEQ ID N0:395.
The kringle domain proteins motif is identified at amino acids 205 tluoug;h 217 of SEQ ID N0:395. The putative signal peptide is encoded at about amino acids 1-23.
Analysis of the amino acid sequence of the full-length PR0322 polypeptide suggests that portions of it possess significant homology to neuropsin and other serine proteases, thereby indicating that PR0322 is a novel serine protease related to'neuropsin.
EXAMPLE 63: Isolation of cDNA Clones Encoding Numan_PR0526 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA39626. Based on the DNA39626 consensus sequence, oligonucleotides were synthesized: I) to identify by PCR a cDNA
library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0526.

A pair of PCR primers (forward and reverse) were synthesized:
forward PCR ri~mer 5'-TGGCTGCCCTGCAGTACCTCTACC-3' (SEQ ID N0:401);
_rgverse,~~R rimer 5'-CCCTGCAGGTCATTGGCAGCTAGG-3' (SEQ 1D N0:402).
Additionally, a synthetic oligonucleotide hybridization probe was constructed from the DNA39626 consensus sequence which had the following nucleotide sequence:
~bridization probe 5'-AGGCACTGCCTGATGACACCTTCCGCGACCTGGGCAACCTCACAC-3' {SEQ ID N0:403).
In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PR0526 gene using the probe oligonucleotide and one of the PCR
primers. RNA for construction of the cDNA libraries was isolated from human fetal liver tissue (LIB228).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0526 [herein designated as UNQ330 (DNA44184-1319)] (SEQ ID N0:399) and the derived protein sequence for PR0526.
The entire nucleotide sequence of UNQ330 (DNA44184-1319) is shown in Figure 160 (SEQ ID N0:399).
Clone UNQ330 (DNA44184-1319) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 514-516 and ending at the stop codon at nucleotide positions 1933-1935 (Figure 160). The predicted polypeptide precursor is 473 amino acids long (Figure 161). The full-length PR0526 protein shown in Figure 161 has an estimated molecular weight of about 50,708 daltons and a p1 of about 9.28. Clone UNQ330 (DNA44184-1319) has been deposited with the ATCC on March 26, 1998. It is understood that the clone contains the actual sequence, whereas the sequences presented herein are representative based on current sequencing techniques.
Analysis of the amino acid sequence of the full-length PR0526 polypeptide suggests that portions of it possess significant homology to the ieucine repeat rich proteins including ALS, SLIT, carboxypeptidase and platelet glycoprotein V thereby indicating that PR0526 is a novel protein which is involved in protein-protein interactions.
Still analyzing SEQ 1D N0:400, the signal peptide sequence is at about amino acids 1-26. A leucine zipper pattern is at about amino acids 135-156. A glycosaminoglycan attachment is at about amino acids 436139. N-glycosylation sites are at about amino acids 82-85, 179-182, 237-240 and 423-426. A von Willebrand factor (VWF) type C domains) is found at about amino acids 411-42$. The skilled artisan can understand which nucleotides correspond to these amino acids based on the sequences provided herein.
EXAMPLE 64: Isolation _o~' cDNA Clones EncodZng Human PR0531 An ECD database was searched and an expressed sequence tag (EST) from LIFESEQT"', Incyte Pharmaceuticals; Palo Alto, CA was identified which showed homology to protocadherin 3. Based on this sequence, a search was performed using the computer program BLAST or BLAST2 (Altshul et al., Methods in E_n~ymology xø:460-480 (1996)) as a comparison of the ECD protein sequences to a 6 frame translation of the EST sequence.
Those comparisons resulting in a BLAST score of 70 (or in sori~e cases 90) or greater that did not encode known proteins were clustered and assembled into consensus DNA sequences with the program "phrap" (Phil Green, University of Washington, Seattle, Washington;
http:l/bozeman.mbt.washington.edulphrap.docslphrap.html).
A consensus DNA sequence was assembled relative to other EST sequences using phrap. Based on the consensus sequence obtained, oligonucleotides were synthesized: 1) to identify by PCR a cDNA library that contained A
WO 99!46281 PCT/US99/05028 the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0531.
A pair of PCR primers (forward and reverse) were synthesized:
forward PCR prim~e_r 5'-CTGAGAACGCGCCTGAAACTGTG-3' (SEQ 1D N0:406);
reverse PCR primer 5'-AGCGTTGTCATTGACATCGGCG-3' (SEQ ID N0:407).
Additionally, a synthetic oiigonucleotide hybridization probe was constructed from the consensus DNA sequence which had the following nucleotide sequence:
hybridisation probe 5'-TTAGTTGCTCCATTCAGGAGGATCTACCCTTCCTCCTGAAATCCGCGGAA-3' (SEQ 1D N0:408).
In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PR0531 gene using the probe oligonucleotide and one of the PCR
primers. RNA for construction of the cDNA libraries was isolated from human fetal brain tissue (LIB153). The cDNA libraries used to isolate the eDNA clones were constructed by standard methods using commercially available reagents such as those from Invitrogen, San Diego, CA. The cDNA was primed with oligo dT containing a NotI
site, linked with blunt to SaII
hemikinased adaptors, cleaved with Notl, sized appropriately by gel electrophoresis, and cloned in a defined orientation into a suitable cloning vector (such as pRKB or pRICD; pRKSB is a precursor of pRKSD that does not contain the SfI site; see, Holmes et al., c' nee, X53:1278-1280 (1991)) in the unique XhoI and NotI sites.
DNA sequencing of the clones isolated as described above gave thE: full-length DNA sequence for PR0531 (herein designated as UNQ332 (DNA48314-1320)] (SEQ ID N0:404) and the derived protein sequence for PR0531:
The entire represenmtive nucleotide sequence of UNQ332 (DNA48314-1320) is shown in Figure 162 (SEQ
ID N0:404}. 1t is understood that the actual sequence is that within the clone deposited with the ATCC as DNA48314-1320. Clone UNQ332 tDNA48314-1320) contains a single open reading frame with an apparent translational initiation site at nucleotide positions I71-173 and ending at the stop colon at nucleotide positions 2565 2567 (Figure 162). The predicted polypeptide precursor is 789 amino acids long (Figure 163). The full-length PR0531 protein shown in Figure 163 has an estimated molecular weight of about 87,552 daltons ate a p! of about 4.84. Clone UNQ332 (DNA48314-1320) has been deposited with the ATCC on March 26, 1998:
Analysis of the amino acid sequence of the full-length PR0531 polypeptide suggests that portions of it possess significant homology to protocadherin 3. Moreover, PR0531 is found in the brain, Like other protocadherins, thereby indicating that PR0531 is a novel member of the cadherin superfamily.
Still analyzing the amino acid sequence of SEQ ID N0:405, the cadherin exaacellular repeated domain signature is found at about amino acids 122-132, 231-241, 336-34b, 439-449 and 549-559 of SEQ ID N0:405. An ATP/GTP-binding site motif A (P-loop) is found at about amino acids 285-292 of SEQ 1D N0:405. N-glycosyladon sites are found at least at about amino acids 56?-570, 786-790, 418-421 and 336-339 of SEQ ID NO:405. The signal peptide is at about amino acids 1-26, and the transmembrane domain is at about amino acids 685-712 of SEQ ID
N0:405.
EXAMPLE 65: Isolation of~~j~A Clones En~od~g Human PRO 34 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the cons sequence obtained is herein designated DNA43038. Based on the 43048 consensus sequence, oiigonucleotides were synthesized; 1} to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0534.
A pair of PCR primers (forward and reverse) were synthesized:
f~,rward PCR primer S'-CACAGAGCCAGAAGTGGCGGAATC-3' (SEQ ID N0:411);
reverse PCR primer S'-CCACATGTTCCTGCTCTTGTCCTGG-3' (SEQ ID N0:412).
Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA43038 sequence which had the following nucleotide sequence:
hybridization probe S'-CGGTAGTGACTGTACTCTAGTCCTGTTTTACACCCCGTGGTGCCG-3' {SEQ ID NO:413).
In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones ~ encoding the PR0534 gene using the probe oligonucleotide and one of the PCR
primers. RNA for conswction of the cDNA libraries was isolated from human fetal lung tissue (LIB26).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence far PR0534 [herein designated as UNQ335 (DNA48333-1321)) (SEQ ID N0:409) and the derived protein sequence for PR0534.
The entire nucleotide sequence of UNQ33S (DNA48333-1321) is shown in Figure 164 (SEQ ID N0:409).
Clone UNQ335 (DNA48333-1321) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 87-89 and ending at the stop codon at nucleotide positions 1167-1169 {Figure 164). The predicted polypeptide precursor is 360 amino acids long (Figure 165). The full-length PR0534 protein shown in Figure 165 has an estimated molecular weight of about 39,885 daltons and a pI
of about 4.?9. Clone UNQ33S
(DNA48333-1321) has been deposited with ATCC on March 26, 1998. It is understood that the deposited clone contains the actual sequence, and that the sequences provided herein are representative based on current sequencing techniques.
Analysis of the amino acid sequence of the full-length PR0534 polypeptide suggests that portions of it possess significant sequence identity with the protein disulfide isomerase, thereby indicating that PR0534 may be a novel disulfide isomerase.
Still analyzing the amino acid sequence of PR0534, the signal peptides is at about amino acids 1-25 of SEQ
ID N0:410. The transmembrane domain is at about amino acids 321-340 of SEQ ID
N0:410. The disulfide isomerase corresponding region is at amino acids 212-302 of SEQ ID N0:410. The thioredoxin domain is at amino acids 211-227 of SEQ ID N0:410. N-glycosylation sites are at: 165-168, 18I-184, 187-190, 194-197, 206-209, 278-281, and 293-296 of SEQ ID N0:410. The corresponding nucleotides can routinely be determined from the sequences provided herein. PR0534 has'a transmembrane domain rather than an ER
retention peptide like other protein disulfide isomerases. Additionally, PR0534 may have an intron at the 5 prime end.
EXAMPLE 66: lcntation of cDNA Clones Enco~tQ r~uman PR0697 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is here'sn designated DNA43052. Based on this consensus sequence, oligorntcleotides were synthesized: 1) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0697.
A pair of PCR primers (forward and reverse) were synthesized:
forward PCR Timer S'-CCTGGCTCGCTGCTGCTGCTC-3' (SEQ ID N0:416);

~everse PCR primer 5'-CCTCACAGGTGCACTGCAAGCTGTC-3' (SEQ ID N0:4I7).
Additionally, a synthetic oligonucleotide hybridization probe was constn~cted from the DNA43052 consensus sequence which had the following nucleotide sequence:
3lybriøization Brobe 5'-CTCTTCCTCTTTGGCCAGCCCGACTTCTCCTACAAGCGCAGAATTGC-3' {SEQ ID N0:418).
In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with the PCR primer pair identifted above. A positive library was then used to isolate clones encoding the PR0697 gene using the probe oligonueleotide and one of the PCR
primers. RNA for construction of the cDNA libraries was isolated from human fetal kidney tissue (LIB227).
DNA sequencing of the clotres isolated as described above gave the fall-length DNA sequence for PR0697 [herein designated as UNQ361 (DNA50920-1325)) (SEQ 1D N0:414) and the derived protein sequence for PR0697.
The entire nucleotide sequence of UNQ361 (DNA50920-1325) is shown in Figure 166 {SEQ ID N0:414).
Clone UNQ361 (DNA50920-1325) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 446 and ending at the stop codon at nucleotide positions 929-931 (Figure 166). The predicted polypeptide precursor is 295 amino acids long (Figure 167). The full-length PR0697 protein shown in Figure 167 has an estimated molecular weight of about 33,518 daltons and a pi of about 7.74. Clone UNQ361 (DNA50920-1325) was deposited with the ATCC on March 26, 1998. It is understood that the deposited clone contains the actual sequence, and that the sequences provided herein are representative based on current sequencing techniques.
Analysis of the amino acid sequence of the full-length PR0697 polypeptide suggests that portions of it possess significant sequence identity with sl;RPs, thereby indicating that PR0697 may be a novel sFRP family member.
Still analyzing tta: amino acid sequence of PR0697, the signal peptides is at about amino acids 1-20 of SEQ
ID N0:415. The cystein rich domain, having identity with the frizzled N-terminus, is at about amino acids 6-153 of SEQ ID N0:415. The corresponding nucleotides can routinely be determined from the sequences provided herein.
EXAMPLE 67: Isolation of cDNA Clones Encoding Human PR0717 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA42829. Based on the DNA42829 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA
library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0717.
A pair of PCR primers (forward and reverse) were synthesized:
forward PCR~rimer 5'-AGCTTCTCAGCCCTCCTGGAGCAG-3' (SEQ ID NO:421);
reverse PCR primer 5'-CGGGTCAATAAACCTGGACGCTTGG-3' (SEQ ID N0:422).
Additionally, a synthetic oligonucleotide hybridization probe was constructed from the DNA42829 consensus sequence which had the following nucleotide sequence:
$ybridization probe 5'-TATGTGGACCGGACCAAGCACTTCACTGAGGCCACCAAGATTG-3' (SEQ ID N0:423).
In order to screen several libraries for a source of a full-length clone; DNA
from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PR0737 gene using the probe oligonucleotide and one of the PCR
primers. RNA far construction of the cDNA libraries was isolated from human fetal liver tissue (LIB229).
DNA sequencing of.the clones isolated as described above gave the full-length DNA sequence for PR0717 (herein designated as UNQ385 (DNA50988-1326)] (SEQ ID N0:419) and the derived protein sequence for PR0717.
The entire nucleotide sequence of UNQ385 (DNA50988-1326) is shown in Figure 168 (SEQ iD N0:419).
Clone UNQ385 (DNA50988-1326) contains a single open reading frame with an apparent uanslational initiation site at nucleotide positions 17-19 and ending at the stop codon at nucleotide positions 1697-1699 (Figure 168). The predicted polypeptide precursor is 560 amino acids long (Figure 169). The full-length PR0717 protein shown in Figure 169 has an estimated molecular weight of about 58,427 daltons and a pI
of about 6.86. Clone UNQ385 (DNA50988-1326) has been deposited with the ATCC on April 28, 1998. Regarding the sequence, it is understood that the deposited clone contains the correct sequence, and the sequences provided herein are based on known sequencing techniques.
Analysis of the amino acid sequence of the full-length PR0717 polypeptide suggests that PR0717 may be a novel 12 transmembrane receptor. The reverse complement strand of DNA50988 has a stretch that matches identically with human regulatory myosin light strand.
Still analyzing the amino acid sequence of SEQ ID N0:420, transmembrane domains are at about amino acids 30-50, 61-79, 98-112, 126-146, 169-182, 201-215, 248-268, 280-300, 318-337, 341-357, 375-387, and 420-441 of SEQ ID N0:420. N-glycosylation sites are at about amino acids 40-43 and 43-46 of SEQ ID N0:420. A
glycosaminoglycan attachment site is at about amino acids 468-471 of SEQ ID
N0:420. The corresponding nucleotides can be routinely determined given the sequences provided herein.
EXAMPLE 68: Isolati n of cDNA Clones Encoding~Human PR0731 A database was used to search expressed sequence tag (EST) databases. The EST
database used herein was the proprietary EST DNA database LIFESEQTM, of Incyte Pharmaceuticals, Palo Alto, CA. Incyte clone 2581326 was herein identified and termed DNA42801. Based on the DNA42801 sequence, oligonucleotides were synthesized:
1 ) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0731.
A pair of PCR primers (forward and reverse) were synthesized:
forward ~('~R~rimer 5'-GTAAGCACATGCCTCCAGAGGTGC-3' (SEQ ID N0:426);
rever_~e PClt~rimer 5'-GTGACGTGGATGCTTGGGATGTTG-3' (SEQ ID N0:427).
Additionally, a synthetic oligonucleotide hybridization probe was constructed from the DNA42801 sequence which had the following nucleotide sequence:
hybridization r 5'-TGGACACCTTCAGTATTGATGCCAAGACAGGCCAGGTCATTCTGCGTCGA-3' (SEQ ID N0:428).
In order to screen several libraries for a source of a full-length clone, DNA
from the Libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PR0731 gene using the probe oligonucleotide and one of the PCR
primers. RNA for construction of the cDNA libraries was isolated from human bone marrow tissue (LIB255). The cDNA libraries used to isolate the cDNA clones were constructed by standard methods using commercially available reagents such as those from Invitrogen, San Diego, CA. The cDNA was primed with oligo dT containing a NotI
site, linked with blunt to SaII
a4a WO 99!46281 PCT/US99/05028 hemikinased adaptors, cleaved with NotI, sized appropriately by gel electrophoresis, and cloned in a defined orientation into a suitable cloning vector (such as pRKB or pRK.D; pRKSB is a precursor of pRKSD that does not contain the SfiI site; see, Hohnes et al., Science, x_3:1278-1280 (1991)) in the unique XhoI and Notl sites.
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0731 [herein designated as UNQ395 (DNA48331-1329)] (SEQ ID N0:424) and the derived protein sequence for PR0731.
The entire nucleotide sequence of UNQ395 (DNA48331-1329) is shown in Figures 170A-B (SEQ ID
N0:424). Clone UNQ395 (DNA48331-1329) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 329-331 and ending at the stop codon at nucleotide positions 3881-3883 (Figures 170A-B). The predicted polypeptide precursor is 1184 amino acids long (Figure 17l ). The full=length PR0731 protein shown in Figure I71 has an estimated molecular weight of about 129,022 daltons and a p! of about 5.2. Clone IO UNQ395 (DNA48331-1329) was deposited with the ATCC on March 31, 1998.
Regarding the sequence, it is tmderstood that the deposited clone contains the correct sequence, and the sequences provided herein are based on lrnown sequencing techniques.
Analysis of the amino acid sequence of the full-length PR0731 polypeptide suggests that portions of it possess significant identity and similarity to members of the protocadherin family, thereby indicating that PR0731 may be a novel protocadherin.
Still analyzing the amino acid sequence of SEQ ID N0:425, the putative signal peptide is at about amino acids 1-13 of SEQ ID N0:425. The transmembrane domain is at amino acids 719-739 of SEQ ID N0:425. The N-glycosylation of SEQ ID N0:425 are as follows: 415-418, 582-586, 659-662, 662-665, and 857-860. The cadherin extracellular repeated domain signatures are at about amino acids (of SEQ ID
N0:425): I23-133, 232-242, 340-350, 448-458, and 553-563. The corresponding nucleotides can be routinely determined given the sequences provided herein.
EXAMPLE 69: Isolation of cDNA Clones Encoding Human PRO218 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA174I1. Two proprietary Genentech EST
sequences were employed in the consensus assembly and are shown in Figure I74 and 175. Based on the DNA17411 consensus sequence, oligonucleotides were synthesized: I) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0218.
A pair of PCR primers (forward.and reverse) were synthesized:
forwar~PCR primer 5'-AAGTGGAGCCGGAGCCTTCC-3' (SEQ ID I'd0:433);
reverse PCR primer 5'-TCGTTGTTTATGCAGTAGTCGG-3' (SEQ ID N0:434).
Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA17411 sequence which had the following nucleotide sequence:
hvbridization robe 5'-ATTGTTTAAAGACTATGAGATACGTCAGTATGTTGTACAGG-3' (SEQ ID N0:435).
In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PR0218 gene using the probe oligonucleotide and one of the PCR
primers. RNA for construction of the cDNA libraries was isolated from human fetal kidney tissue (i.IB28).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0218 [herein designated as UNQ192 (DNA30867-1335)] (SEQ ID N0:429) and the derived protein sequence for PR0218.
The entire nucleotide sequence of UNQ192 (DNA30867-1335) is shown in Figure 172 (SEQ ID N0:429).
Clone UNQ192 (DNA30867-1335) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 150-152 and ending at the stop colon at nucleotide positions 1515-151? (Figure 172). The predicted polypeptide precursor is 455 amino acids long (Figure 173). The full-length PR0218 protein shown in Figure 173 has an estimated molecular weight of about 52,917 daltons and a pI
of about 9.5. Clone UNQ192 (DNA30867-1335) has been deposited with the ATCC on April 28, 1998. Regarding the sequence, it is understood that the deposited clone contains the correct sequence, and the sequences provided herein are based on known sequencing techniques.
Analysis of the amino acid sequence of the full-length PR0218 polypeptide suggests that PR0218 may be a novel transmembrane protein.
Still analyzing the amino acid sequence of SEQ ID N0:430, the putative signal peptide is at about amino acids 1 through 23 of SEQ ID N0:430. Transmembrane domains are potentially at about amino acids 37-55, 81-102, 150-168, 288-311, 338-356, 375-398, and 425-444 of SEQ ID N0:430. N-glycosylation sites are at about amino acids 67, 180, and 243 of SEQ ID N0:430. Eukaryotic cobalamin-binding protein is at about amino acids 151-160 of SEQ ID N0:430. Tl~ cotiesponding nucleotides can be routinely determined given the sequences provided herein.
EJ~AMPLE 70: ~Z~~n of cDNA Clones Encoding Human PR0768 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA43448. Based on the DNA43448 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA
library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0768.
A pair of PCR primers (forward and reverse) were synthesized:
forward PCR primer 5'-GGCTGACACCGCAGTGCTCTTCAG-3' (SEQ ID N0:438);
reverse PCR primer 5'-GCTGCTGGGGACTGCAATGTAGCTG-3' (SEQ 1D N0:439).
Additionally, a synthetic oligonucleotide hybridization probe was constructed from the DNA43448 consensus sequence which had the following nucleotide sequence:
h_Ybridization probe 5'-CATCCTCCATGTCTCCCATGAGGTCTCTATTGCTCCACGAAGCATC-3' (SEQ ID N0:440).
In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PR0768 gene using the probe oligonucleotide and one of the PCR
primers. RNA for construction of the cDNA libraries was isolated from human bone marrow tissue tl,IB255).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0768 [herein designated as UNQ4U6 {DNAS573?-1345)] (SEQ ID N0:436) and the derived protein sequence for PRO768.
The entire nucleotide sequence of UNQ406 (DNA55737-1345) is shown in Figures 176A-B (SEQ ID
N0:436). Clone UNQ406 (DNA55737-1345) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 20-22 and ending at the stop colon at nucleotide positions 3443-3445 (Figures WO 99/46281 ' PCT/US99/05028 176A-B). The predicted polypeptide precursor is 1141 amino acids long (Figure 177). The full-length PR0768 protein shown in Figure 177 has an estimated molecular weight of about 124;671 daltons and a pLof about 5.82.
Clone UNQ406 (DNA55737-1345) has been deposited with the ATCC on Apri16, 1998.
Regarding the sequence, it is urxlerstood that the deposited clone contains the correct sequence, and the sequences provided herein are based on Irnown sequencing techniques.
Analysis of the amino acid sequence of the ful3-length PR0768 polypeptide suggests that portions of it possess significant sequence identity and similarity with integrin 7.
Still analyzing the amino acid sequence of SEQ ID N0:437, the putative signal peptide is at about amino acids 1-33 of SEQ ID N0:437. The transmembrane domain is at amino acids 1039-1064 of SEQ ID N0:437. N-glycosylation sites are at amino acids: 86-89, 746-749, 949-952, 985-988 and 1005-1008 of SEQ ID N0:437.
Integrin alpha chain protein domains are identified at about amino acids: 1064-1071, 3841109, 1041-.1071, 3I7-346, 443-465, 385-407, 2I5-224, 634-647, 85-99, 322-346, 470-479, 442-46fi, 379-408 and I03I-1047 of SEQ ID
N0:437. The corresponding nucleotides can be routinely determined given the sequences provided herein.
EXAI~IPLE 71: Isolation of cDNA ~on~s Encod~i g Human PR0773 A cor>sensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, whereia the consensus sequence obtained is herein designated DNA43330. Based on the DNA43330 sequence, oligorn»cleotides were synthesized: 1) w identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0771.
A pair of PCR primers (forward and reverse) were synthesized:
fo~vard PC Timer 5'-CAGCAATATTCAGAAGCGGCAAGGG-3' (SEQ ID N0:443);
reverse PCR primer 5'-CATCATGGTCATCACCACCATCATCATC-3' (SEQ ID N0:444).
Additionally, a synthetic oligonucleotide hybridization probe was constructed from the DNA43330 consensus sequence which had the following nucleotide sequence:
hybridization probe 5'-GGTTACTACAAGCCAACACAATGTCATGGCAGTGTTGGACAGTGCTGG-3' (SEQ ID N0:445).
In order to screen several libraries for a source of a full-length clone; DNA
from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones eroding the PR0771 gene using the probe oligotrucleotide and one of the PCR
primers. RNA for construction of the cDNA libraries was isolated from human fetal kidney tissue (LIB28).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0771 [herein designated as UNQ409 (DNA49829-1346)) (SEQ ID N0:441) and the derived protein sequence for PR0771.
The entire ~tcleotide sequere of UNQ409 (DNA49829-1346) is shown in Figure 178 (SEQ ID N0:441).
Clotre UNQ409 (DNA49829-1346) contains a single open reading frame with an apparent translationai initiation site at nucleotide positions 134-136 and ending at the stop codon at nucleotide positions 1442-1444 (Figure 178). The predicted polypeptide precursor is 436 amino acids long (Figure 179). 7"he full-length PR0771 protein shown in Figure 179 has an estimated molecular weight of about 49,429 daltons and a p1 of about 4.8. Clone UNQ409 (DNA49829-1346) has been deposited with the ATCC on April 7, 1998. Regarding the sequence, it is understood that the deposited clone contains the correct sequence, and the sequences provided herein are based on lrnown sequencing techniques.

yr WO 99!46281 PCT/IJS99lOS028 Analysis of the amino acid sequence of the full-length PR0771 polypeptide suggests that portions of ii possess significant homology to the testican protein, thereby indicating that PR0771 may be a novel testican homologue.
Still analyzing the amino acid sequence of SEQ ID N0:442, the putative signal peptide, leucine zipper pattern, N-myristoylation sites, and thyroglobulin type-1 repeats are also shown in Figure 179. The corresponding nucleotides can be routinely determined given the sequences provided herein.
EXAMPLE 72: Isolation of cDNA~lones Encoding Numan PR0733 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA45600. Based on the DNA45600 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA
library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0733.
A pair of PCR primers (forward and reverse) were synthesized:
forward PCR primer 5'-CCCAGCAGGGATGGGCGACAAGA-3' (SEQ ID N0:448);
reverse PCR primer 5'-GTCTTCCAGTTTCATATCCAATA-3' (SEQ ID N0:449).
Additionally, a synthetic oligonucleotide hybridization probe was constructed from the DNA45600 consensus sequence which had the following nucleotide sequence:
~ybridization_p~obe 5'-CCAGAAGGAGCACGGGGAAGGGCAGCCAGATCTTGTCGCCCAT-3' (SEQ ID N0:450).
In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PR0733 gene using the probe oligonucleotide and one of the PCR
primers. RNA for construction of the cDNA libraries was isolated from human bone marrow tissue {LIB255).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0733 [herein designated as UNQ411 f,DNA5219b-1348)] (SEQ ID N0:446) and the derived protein sequence for PR0733.
The entire nucleotide sequence of UNQ411 (DNA52196-1348) is shown in Figures 180A-B (SEQ ID
N0:446). Clone UNQ411 (DNA52196-1348) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 106-108 and ending at the stop codon at nucleotide positions 793-795 (Figures 180A-B). The predicted polypeptide precursor is 229 amino acids long (Figure 181). The full-length PR0733 protein shown in Figure 181 has an estimated molecular weight of about 26,017 daltons and a pI of about 4.73. Clone UNQ411 (DNA52196-1348) has been deposited with the ATCC on April 7, 1998.
Regarding the sequence, it is understood that the deposited clone contains the correct sequence, and the sequences provided herein are based on lawwn sequencing techniques.
Analysis of the amino acid sequence of the full-length PR0733 polypeptide suggests that portions of it possess significant sequence identity and similarity to the TllST2 receptor binding protein precursor and therefore may have a similar function in cell signaling. If it is a cytoltine, it may be useful in the treatment of inflammation and cancer.
Still analyzing the amino acid sequence of SEQ ID N0:447, the putative signal peptide, transmembratx domain, N-myristoylation site, and tyrosine !anise site are also shown in Figure 181. The corresponding nucleotides can be routinely determined given the sequences provided herein.

WO 99146281 PCTlUS99105028 EXAMPLE 73: I~ol tion of eDNA Clones Encoding Human PR016~
An expressed sequence tag (EST) DNA database (Merck/Washington University) was searched and an EST
AA397543 was identified which showed homology to human pancreatitis-associated protein. The EST AA397543 .
Cole was purchased anrl its insert obtained and sequenced and the sequence obtained is shown in Figuze 182 (SEQ
ID N0:451).
The entire nucleotide sequence of PR0162 is shown in Figure 182 (SEQ ID
N0:451). DNA sequencing of the clone gave the full-length DNA sequence for FR0162 [herein designated as UNQ429 (DNA56965-1356)) (SEQ
ID N0:451) and the derived protein sequence for PR0162. Clone UNQ429 (DNA56965-1356) contains a single open reading frame with an apparent translational inntiation site at nucleotide positions 86-88 and ending at the stop colon at nucleotide positions 611-613 (Figure 182). The predicted polypeptide precursor is 175 amino acids long (Figure 183). The full-length PROI62 protein shown in Figure 183 has an estimated molecular weight of about 19,330 daltons and a pI of about 7.25. Clone UNQ429 (DNA56965-1356) has been deposited with the ATCC. Regarding the sequence, it is understood that the deposited clone contains the correct sequence, and the sequences provided herein are based an lrnown sequencing techniques.
Analysis of the amino acid sequence of the full-length PR0162 polypeptide suggests that portions of it possess significant homology to the human pancreatitis-associated protein, thereby indicating that PR0162. may be a novel pancreatitis-associated protein.
Still analyzing the amino acid sequence of SEQ ID N0:452, the putative signal peptide is at about amino acids 1-26 of SEQ ID N0:452. A C-type leetin domain signature is at about amino acids 146-171 of SEQ ID
N0:452. The corresponding nucleotides can be routinely determined given the sequences provided herein.
EXALVIPL]~74: Isolation of cDNA Clones Encoding Human O?88 A consensus DNA sequence (designated herein as DNA49308) was assembled relative to other EST
sequer~es using phrap as described in Example 1 above. Based upon an observed homology between the DNA49308 consensus sequence and the Incyte EST clo0ne no. 2777282, the Incyte EST clone no. 2777282 was purchased and its insert obtained and sequenced, which gave the full-length DNA sequence for PR0788 [herein designated as UNQ430 (DNA56405-1357)] (SEQ ID N0:453) and the derived protein sequence for PR0788.
Clone UNQ430 (DNA56405-I357) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 84-86 and ending at the stop colon at nucleotide positions 459-461 (Figure 184).
The predicted poiypeptide precursor is 125 amino acids long (Figure 185): The full-length PR0788 protein shown in Figure 185 has an estimated molecular weight of about 13,115 daltons and a p1 of about 5.90, CIone UNQ430 (DNA56405-1357) has been deposited with the ATCC. Regarding the sequence, it is understood that the deposited clone contains the correct sequence, and the sequences provided herein are based on latown sequencing techniques.
Still analyzing Figure 185, a signal peptide is shown at about amino acids 1-17 of SEQ ID N0:454. An N-glycosylation site is at about amino acids 46-49 of SEQ ID N0:454.
EXAMPLE 75: Isolation of cDNA Clones EncodingJHurr~n PR01008_ A consensus DNA sequence was assembled relative to other EST sequences using phrap as described in Example 1 above. This consensus sequence is herein desig aced as DNA49804. An EST proprietary to Genentcch was employed in the consensus assembly and is herein designated as DNA16508 (Figure 188; SEQ ID N0:457).

T

Based upon an observed homology between the DNA49804 sequence and Merck EST
clone no. AA143670, the Merck EST clone no. AA143670 was purchased and its insert obtained and sequenced. That sequence is shown herein in Figure 186 (SEQ ID N0:455).
Sequencing gave the foil length sequence for PR01008 [herein designated as UNQ492 (DNA57530-1375)) (SEQ ID N0:455) and the detyved protein sequence for PR01408 were identified.
The entire nucleotide sequence of UNQ492 (DNA57530-1375) is shown in Figure 186 (SEQ ID N0:455).
Clone UNQ492 (DNA57530-I375) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 138-140 and ending at the stop colon at nucleotide positions 936-938 (Figure 186). The predicted polypeptide precursor is 266 amino acids long (Figure 187). The full-length PR01008 protein shown in Figure 187 has an estimated molecular weight of about 28,672 daltons and a pI
of about 8.85. Clone UNQ492 (DNA57530-1375) has been deposited with the ATCC on May 20, 1998. Regarding the sequence, it is understood that the deposited clone contains the correct sequence, and the sequences provided herein are based on known sequencing techniques.
Analysis of the amino acid sequence of the full-length PR01008 polypeptide suggests that portions of it possess significant sequence identity andlor similarity with mdkk-l, thereby indicating, that PR01008 may be a novel IS member of this family and have head inducing activity.
Still analyzing the amino acid sequence of SEQ ID N0;456, the putative signal peptide is at about amino acids. l-23 of SEQ ID N0:456. The N-glycosylation site is at about amino acids 256-259 of SEQ ID N0:456, and the fungal zn-(2)-cys(6) binuclear cluster domain is at about amino acids 110-126 of SEQ ID N0:456. The corresponding nucleotides can of all the amino acids can be routinely determined given the sequences provided herein.
EXAMPLE 76: Isolation of cDNA Clues Encoding Human PR01012 A consensus DNA sequence was assembled relative to other EST sequences using phrap as described in Example 1 above, wherein the consensus seguence is herein designated DNA49313.
Based on the DNA49313 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA library that contained the sequence of interest, and 2} for use as probes to isolate a clone of the full-length coding sequence for PR01012.
A pair of PCR primers (forward and reverse) were synthesized:
~~rd PCR primer 5'-ACTCCCCAGGCTGTTCACACTGCC-3' (SEQ ID N0:460);
rever;zg PC$ rg imer 5'-GATCAGCCAGCCAATACCAGCAGC-3' {SEQ ID N0:461}.
Additionally, a synthetic oligonucleotide hybridization probe was constructed from the DNA49313 consensus sequence which had the following nucleotide sequence:
~,Y~jdization globe 5'-GTGGTGATGATAGAATGCTTTGCCGAATGAAAGGAGTCAACAGCTATCCC-3' (SEQ ID N0:462).
In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PR01012 gene using the probe oligonucleotide and one of the PCR
primers. RNA for construction of the cDNA libraries was isolated from human fetal kidney tissue (LIB227).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR01012 [herein designated as UNQ495 (DNA5b439-1376)] (SEQ ID N0:458) and the derived protein sequence for PR01012.

The entire nucleotide sequence of UNQ495 (DNA56439-1376) is shown in Figures 189A-B (SEQ ID
N0:458). Clone UNQ495 (DNA56439-1376) contains a single open reading frame with an apparent translational initiarion site at tntcleotide positions 4U4-406 and ending at the stop colon at nucleotide positions 2645-2647 (Figures 189A-B). The predicted polypeptide precursor is 747 amino acids long (Figure 190). The full-length PR01012 protein shown in Figure 190 has an estimated molecular weight of about 86,127 daltons and a pI of about 7.46. Clone UNQ495 (DNA56439-1376) has been deposited with ATCC. on May 14, 1998, Regarding the sequence, it is understood that the deposited clone contains the correct sequence, and the sequences provided herein are based on known sequencing techniques.
Analysis of the amino acid sequence of the full-length PR01012 poiypeptide suggests that portions of it possess sequence identity with disulfide isomerase thereby indicating that PRO1012 may be a novel disulfide IO isomerase related protein.
Still analyzing the amino acid sequence of SEQ ID N0:459, the cytochrome C
family heme-binding site signature is at about amino acids 158-163 of SEQ 1D N0:459. The Nt-DNAJ domain signature is at about amino acids 77-96 of SEQ 1D N0:459. An N-glycosylation site is at about amino acids 484-487 of SEQ ID N0:459. The ER targeting sequence is at about amino acids ?44-747 of SEQ ID N0:459. 1t is understood that the polypeptide and nucleic acids disclosed can be routinely fortrted with or without, these portions as desired, in alternative embodiments.
For example, it may be desirable to produce PROlUi2 without the ER targeting sequence.. Ttte corresponding nucleotides can be routinely determined given the sequences provided herein.
E7~AMPLE 77: Isolation of cDNA Clones ~ncodiltg. Human PROi014 A consensus DNA sequence was assembled relative to other EST sequences using phrap as described in Example 1 abobe, wherein the consensus sequence obtained is herein designated DNA49811. Based upon an observed homology between the DNA49811 sequence and Incyte EST clone no.
2612207, Incyte EST clone no:
2612207 was purchased aril its insert was obtained and sequenced, wherein the sequence obtained is shown in Figure 191 (SEQ OD N0:463).
DNA sequencing gave the full-length DNA sequence for PR01014 [herein designated as UNQ497 (DNA56409-1377)] (SEQ ID N0:463) and the derived protein sequence for PR01014.
The entire rtueleotide sequence of UNQ497 (DNA56409-1377) is shown in Figure 191 (SEQ ID N0:463).
Clone UNQ497 (DNA56409-1377) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 66-68 and ending at the stop colon at nucleotide positions 966-968 (Figure 191), The predicted polypepade precursor is 300 amino acids long (Figure 192). the full-length PR01014 protein shown in Figure 192 has an estimated molecular weight of about 33,655 daltons and a pI
of about 9.31. Clone UNQ497 (DNASb409-1377) has been deposited with the ATCC on May 20, 1998. Regarding the sequence, it is understood that the deposited clone contains the correct sequence, and the sequences provided herein aye based on known sequencing techniques.
Analysis of the amino acid sequence of the full-length PR01014 polypeptide suggests that portions of it possess sequence idenriry with reductase, thereby indicating that PR01014 may be a novel member of the reductase family.
Still analyzing the amino acid sequence of SEQ ID N0:464, the putative signal peptide is at about amino acids 1-19 of SEQ ID N0:464, The cAMP and cGMP dependent protein kinase phosphorylation sites are at about amino acids 30-33 and 58-dl of SEQ ID N0:464. Short chain alcohol dehydrogenase family proteins are at about amino acids 165-202, 37-49, 112-122 and 210-219 of SEQ ID N0:464. The corresponding nucleotides of these domains and any other amino acids provided herein can be routinely determined given the sequences provided herein.
EXAMPLE 78: Isolation of cDNA Clones EncodingHurt~an PR0~017 A consensus DNA sequence was assembled relative to other EST sequences using phrap as described in Example 1 above, wherein that consensus DNA sequence is herein designated DNA53235. Based upon an observed homology between the DNA53235 consensus sequence and the Merck EST clone no.
AA243086, the Merck EST
clone no. AA243086 was purchased and its insert obtained and sequenced, wherein the sequence obtained is shown in Figure 193 (SEQ ID N0:465). DNA sequencing gave the full-length DNA
sequence for PR01017 [herein designated as UNQ500 (DNA56112-1379)) (SEQ ID N0:465) and the derived protein sequence for PR01017.
The entire nucleotide sequence of UNQ500 (DNA56112-1379) is shown in Figure 193 (SEQ ID N0:465).
Clone UNQ500 (DNA56112-1379) contains a single open reading frame with an apparent aanslational initiation site at nucleotide positions 128-130 and ending at the stop codon at nucleotide positions 1370-1372 (Figure 193). The predicted polypeptide precursor is 414 amino acids long (Figure 194). The full-length PR01017 protein shown in Figure 194 has an estimated molecular weight of about 48,414 daltons and a p1 of about 9.54. Clone UNQ500 {DNA56112-1379) has been deposited with the ATCC. Regarding the sequence, it is understood that the deposited clone contains the correct sequence, and the sequences provided herein are based an known sequencing techniques.
Analysis of the amino acid sequence of the full-length PR01017 polypeptide suggests that portions of it possess sequence identity with HNK-1 sulfotransferase, thereby indicating that PR01017 may be a novel sulfotransferase.
Still analyzing the amino acid sequence of SEQ ID N0:466, the putative signal peptide is at about amino acids 131 of SEQ ID N0:466. N-glycosylation sites are at about amino acids 134-137, 209-212, 280-283 and 370-273 of SEQ ID N0:466. The TNFRINGFR family cystein-rich region protein is at about amino acids 329-332 of SEQ m NO:466. The corresponding nucleotides can be routinely determined given the sequences provided herein.
The protein can be secreted.
~, M~ PLE 79: Isolation of cDNA Clones EncodinE Human PR0474 A consensus DNA sequence was assembled relative to other EST sequences using phrap as desctibed in Example 1 above, wherein the consensus sequence obtained is herein designated DNA49818. Based upon an observed homology between the DNA49818 consensus sequence and the Merck EST
clone no. H77889, the Merck EST clone no.1377889 was purchased and its insert obtained and sequenced, wherein the sequence obtained is herein shown in Figure 195 (SEQ ID N0:467). DNA sequencing gave the full-length DNA
sequence for PR0474 [herein designated as UNQ502 (DNA56045-1380)] (SEQ ID N0:467) and the derived protein sequence for PR0474.
Ttie entire nucleotide sequence of UNQ502 (DNA56045-1380) is shown in Figure 193 (SEQ ID N0:467).
Clone UNQ502 (DNA56045-1380) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 106-108 and ending at the stop codon at nucleotide positions 916-918 (Figure 195). The predicted polypeptide precursor is 270 amino acids long (Figure 196). The full-length PR0474 protein shown in Figure 196 has an estimated molecular weight of about 28,317 daltons and a p1 of about 6Ø Clone UNQ502 DEMANDES OU BREVETS VOLUMINEUX
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Claims (25)

1. Isolated nucleic acid having at least 80% sequence identity to a nucleotide sequence that encodes a polypeptide comprising the amino acid sequence shown in Figure 61 (SEQ ID NO:162).

2. The nucleic acid of Claim 1, wherein said nucleotide sequence comprises the nucleotide sequence shown in Figure 60 (SEQ ID NO:161).

3. The nucleic acid of Claim 1 or Claim 2, wherein said nucleotide sequence comprises the full-length coding sequence from within the sequence shown in Figure 60 (SEQ ID
NO:161).

4. The nucleic acid of Claim 1 which comprises the full-length coding sequence of the DNA deposited under accession number ATCC 209811.

5. Isolated nucleic acid having a nucleotide sequence that encodes a polypeptide comprising the amino acid sequence shown in Figure 61 (SEQ ID NO:162).

6. The nucleic acid of Claim 5, wherein said nucleotide sequence comprises the nucleotide sequence shown in Figure 60 (SEQ ID NO:161).

7. The nucleic acid of Claim 5 or Claim 6, wherein said nucleotide sequence comprises the full-length coding sequence from within the sequence shown in Figure 60 (SEQ ID
NO:161).

8. The nucleic acid of Claim 5 which comprises the full-length coding sequence of the DNA deposited under accession number ATCC 209811.

9. A vector comprising the nucleic acid of any one of claims Claim 1 to 8.

10. The vector of Claim 9 wherein said nucleic acid is operably linked to control sequences recognized by a host cell transformed with the vector.

11. A host cell comprising the vector of Claim 9 or Claim 10.

12 The host cell of Claim 11 wherein said cell is a CHO cell, an E. coli or a yeast cell.

13. A process for producing a polypeptide comprising culturing the host cell of Claim 11 or Claim 12 under conditions suitable for expression of said polypeptide and recovering said polypeptide from the cell culture.

14. Isolated polypeptide comprising a sequence having at least 80% sequence identity to the amino acid sequence shown in Figure 61 (SEQ ID NO:162).

15. Isolated polypeptide comprising a sequence having at least 80% sequence identity to the amino acid sequence encoded by the nucleotide deposited under accession number ATCC
209811.

16. Isolated polypeptide comprising a sequence having the amino acid sequence shown in Figure 61 (SEQ ID NO:162).

17. Isolated polypeptide comprising a sequence having the amino acid sequence encoded by the nucleotide deposited under accession number ATCC 209811.

18. A chimeric molecule comprising a polypeptide according to any one of Claims 14 to 17, fused to a heterologous amino acid sequence.

19. The chimeric molecule of Claim 18 wherein said heterologous amino acid sequence is an epitope tag sequence.

20. The chimeric molecule of Claim 18 wherein said heterologous amino acid sequence is a Fc region of an immunoglobulin.

21. An antibody which specifically binds to a polypeptide according to any one of Claims 14 to 17.

22. The antibody of Claim 21 wherein said antibody is a humanised antibody.

23. The antibody of Claim 21 wherein said antibody is a monoclonal antibody.

24. The antibody of Claim 23 wherein said antibody is a chimeric antibody.

25 A composition comprising an antibody according to any one of Claims 21 to inadmixture with a pharmaceutically acceptable carrier.