WO2000015796A2 - Polypeptides secretes et transmembranaires et acides nucleiques codant pour ces polypeptides - Google Patents

Polypeptides secretes et transmembranaires et acides nucleiques codant pour ces polypeptides Download PDF

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Publication number
WO2000015796A2
WO2000015796A2 PCT/US1999/021090 US9921090W WO0015796A2 WO 2000015796 A2 WO2000015796 A2 WO 2000015796A2 US 9921090 W US9921090 W US 9921090W WO 0015796 A2 WO0015796 A2 WO 0015796A2
Authority
WO
WIPO (PCT)
Prior art keywords
seq
atcc
polypeptide
amino acid
sequence
Prior art date
Application number
PCT/US1999/021090
Other languages
English (en)
Other versions
WO2000015796A3 (fr
Inventor
Jian Chen
Audrey Goddard
Austin L. Gurney
Kenneth Hillan
Diane Pennica
William I. Wood
Jean Yuan
Original Assignee
Genentech, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from PCT/US1998/019330 external-priority patent/WO1999014328A2/fr
Application filed by Genentech, Inc. filed Critical Genentech, Inc.
Priority to JP2000570323A priority Critical patent/JP2004507201A/ja
Priority to MXPA01002592A priority patent/MXPA01002592A/es
Priority to KR1020017003385A priority patent/KR20010087359A/ko
Priority to AU59229/99A priority patent/AU5922999A/en
Priority to IL14153599A priority patent/IL141535A0/xx
Priority to EP99946924A priority patent/EP1114152A2/fr
Priority to CA002343577A priority patent/CA2343577A1/fr
Priority to AU17471/00A priority patent/AU1747100A/en
Priority to PCT/US1999/028214 priority patent/WO2001019987A1/fr
Priority to PCT/US1999/028313 priority patent/WO2000032221A2/fr
Priority to AU17482/00A priority patent/AU771751C/en
Priority to CA002347835A priority patent/CA2347835A1/fr
Priority to CA002503475A priority patent/CA2503475A1/fr
Priority to EP06014175A priority patent/EP1734051A3/fr
Priority to IL14274299A priority patent/IL142742A0/xx
Priority to NZ535590A priority patent/NZ535590A/en
Priority to EP99960624A priority patent/EP1135485B1/fr
Priority to KR10-2001-7006818A priority patent/KR100529270B1/ko
Priority to MXPA01005169A priority patent/MXPA01005169A/es
Priority to AT99960624T priority patent/ATE458050T1/de
Priority to JP2000584912A priority patent/JP3695642B2/ja
Priority to MXPA01006330A priority patent/MXPA01006330A/es
Priority to CA002353799A priority patent/CA2353799A1/fr
Priority to AU17498/00A priority patent/AU1749800A/en
Priority to ES04007617T priority patent/ES2281704T3/es
Priority to DK04007617T priority patent/DK1484338T3/da
Priority to DE69940964T priority patent/DE69940964D1/de
Priority to EP99960644A priority patent/EP1141284A2/fr
Priority to AT04007617T priority patent/ATE353339T1/de
Priority to KR10-2001-7007850A priority patent/KR100499600B1/ko
Priority to EP09004092A priority patent/EP2075335A3/fr
Priority to DE69935085T priority patent/DE69935085T2/de
Priority to EP07001711A priority patent/EP1820859B9/fr
Priority to IL14303199A priority patent/IL143031A0/xx
Priority to ES07001711T priority patent/ES2327785T3/es
Priority to PCT/US1999/028565 priority patent/WO2000037638A2/fr
Priority to PT04007617T priority patent/PT1484338E/pt
Priority to PCT/US1999/028564 priority patent/WO2000055319A1/fr
Priority to AT07001711T priority patent/ATE432987T1/de
Priority to AU17499/00A priority patent/AU768230B2/en
Priority to JP2000589692A priority patent/JP3993746B2/ja
Priority to CA002450402A priority patent/CA2450402A1/fr
Priority to EP04007617A priority patent/EP1484338B1/fr
Priority to EP99966374A priority patent/EP1141289A2/fr
Priority to KR1020017007877A priority patent/KR20010102960A/ko
Priority to CA002353775A priority patent/CA2353775A1/fr
Priority to IL14321299A priority patent/IL143212A0/xx
Priority to MXPA01006345A priority patent/MXPA01006345A/es
Priority to AU21928/00A priority patent/AU2192800A/en
Priority to JP2000589694A priority patent/JP2003524390A/ja
Priority to PCT/US1999/030095 priority patent/WO2000037640A2/fr
Priority to PCT/US1999/030911 priority patent/WO2000075316A1/fr
Priority to AU23907/00A priority patent/AU2390700A/en
Priority to AU22153/00A priority patent/AU2215300A/en
Priority to PCT/US1999/030999 priority patent/WO2001005836A1/fr
Priority to AU26008/00A priority patent/AU2600800A/en
Priority to PCT/US2000/000219 priority patent/WO2000053753A2/fr
Priority to AT05018353T priority patent/ATE422536T1/de
Priority to ES05018354T priority patent/ES2290834T3/es
Priority to PT05018355T priority patent/PT1623989E/pt
Priority to PT05018357T priority patent/PT1626058E/pt
Priority to EP05018358A priority patent/EP1623990B1/fr
Priority to EP00907270A priority patent/EP1173563A1/fr
Priority to DK05018358T priority patent/DK1623990T3/da
Priority to CA002365610A priority patent/CA2365610A1/fr
Priority to DK05018354T priority patent/DK1632499T3/da
Priority to EP05018354A priority patent/EP1632499B9/fr
Priority to DK05018356T priority patent/DK1607402T3/da
Priority to CA002479498A priority patent/CA2479498A1/fr
Priority to AT05018355T priority patent/ATE364628T1/de
Priority to EP05018355A priority patent/EP1623989B1/fr
Priority to ES05018356T priority patent/ES2279473T3/es
Priority to ES05018353T priority patent/ES2321954T3/es
Priority to AT05018354T priority patent/ATE363489T1/de
Priority to EP05018356A priority patent/EP1607402B1/fr
Priority to DK05018355T priority patent/DK1623989T3/da
Priority to PT05018356T priority patent/PT1607402E/pt
Priority to JP2001553947A priority patent/JP2004520003A/ja
Priority to AT05018357T priority patent/ATE377025T1/de
Priority to KR10-2001-7011391A priority patent/KR100512819B1/ko
Priority to CA002479511A priority patent/CA2479511A1/fr
Priority to ES05018358T priority patent/ES2298896T3/es
Priority to PT05018354T priority patent/PT1632499E/pt
Priority to DK05018357T priority patent/DK1626058T3/da
Priority to CA002479476A priority patent/CA2479476C/fr
Priority to ES05018355T priority patent/ES2289630T3/es
Priority to PT05018358T priority patent/PT1623990E/pt
Priority to EP05018357A priority patent/EP1626058B1/fr
Priority to EP05018353A priority patent/EP1626084B1/fr
Priority to AT05018356T priority patent/ATE348108T1/de
Priority to AU28794/00A priority patent/AU756400B2/en
Priority to AT05018358T priority patent/ATE380195T1/de
Priority to PCT/US2000/003565 priority patent/WO2001053486A1/fr
Priority to CA002479494A priority patent/CA2479494C/fr
Priority to ES05018357T priority patent/ES2296029T3/es
Priority to AU28839/00A priority patent/AU2883900A/en
Priority to PCT/US2000/004414 priority patent/WO2001004311A1/fr
Priority to EP00912015A priority patent/EP1159419A1/fr
Priority to KR1020017011378A priority patent/KR100553300B1/ko
Priority to PCT/US2000/005004 priority patent/WO2000053757A2/fr
Priority to AU33816/00A priority patent/AU768694B2/en
Priority to JP2000603378A priority patent/JP2003531811A/ja
Priority to KR1020017011378D priority patent/KR20010104373A/ko
Priority to CA002361849A priority patent/CA2361849A1/fr
Priority to CA002362427A priority patent/CA2362427A1/fr
Priority to JP2000603379A priority patent/JP2004516227A/ja
Priority to KR1020017011406A priority patent/KR20010103046A/ko
Priority to EP00913764A priority patent/EP1220905A2/fr
Priority to PCT/US2000/005841 priority patent/WO2000053758A2/fr
Priority to AU35144/00A priority patent/AU3514400A/en
Priority to PCT/US2000/006471 priority patent/WO2001018210A1/fr
Priority to SI200030879T priority patent/SI1214409T1/sl
Priority to MXPA02002491A priority patent/MXPA02002491A/es
Priority to KR1020027003131A priority patent/KR20020059591A/ko
Priority to ES00917878T priority patent/ES2264929T3/es
Priority to JP2001521746A priority patent/JP2004500037A/ja
Priority to DE60028054T priority patent/DE60028054T2/de
Priority to AU38784/00A priority patent/AU783117B2/en
Priority to PT00917878T priority patent/PT1214409E/pt
Priority to DK00917878T priority patent/DK1214409T3/da
Priority to AT00917878T priority patent/ATE326532T1/de
Priority to CA002384089A priority patent/CA2384089A1/fr
Priority to EP00917878A priority patent/EP1214409B1/fr
Priority to IL14818800A priority patent/IL148188A0/xx
Priority to CN00815274A priority patent/CN1387570A/zh
Priority to CNA2004100465359A priority patent/CN1560249A/zh
Publication of WO2000015796A2 publication Critical patent/WO2000015796A2/fr
Priority to EP00916675A priority patent/EP1210418B1/fr
Priority to JP2001500766A priority patent/JP2004522402A/ja
Priority to AT00916675T priority patent/ATE478145T1/de
Priority to PCT/US2000/008439 priority patent/WO2000073454A1/fr
Priority to CA002383254A priority patent/CA2383254A1/fr
Priority to AU37743/00A priority patent/AU3774300A/en
Priority to DE60044849T priority patent/DE60044849D1/de
Priority to EP07025116A priority patent/EP1953173B1/fr
Priority to EP00936172A priority patent/EP1208195A2/fr
Priority to AT07025116T priority patent/ATE449109T1/de
Priority to AU51527/00A priority patent/AU5152700A/en
Priority to DE60043367T priority patent/DE60043367D1/de
Priority to PCT/US2000/014042 priority patent/WO2000077037A2/fr
Priority to JP2001503894A priority patent/JP2003529324A/ja
Priority to EP07025118A priority patent/EP1956030B1/fr
Priority to CA2372511A priority patent/CA2372511C/fr
Priority to EP07025117A priority patent/EP1978029A3/fr
Priority to DE60043322T priority patent/DE60043322D1/de
Priority to AT07025118T priority patent/ATE448246T1/de
Priority to PCT/US2000/015264 priority patent/WO2000073452A2/fr
Priority to AU54601/00A priority patent/AU5460100A/en
Priority to PCT/US2000/020710 priority patent/WO2001009327A2/fr
Priority to AU63910/00A priority patent/AU6391000A/en
Priority to EP05019539A priority patent/EP1623993A3/fr
Priority to CA002645727A priority patent/CA2645727A1/fr
Priority to JP2001520864A priority patent/JP3951035B2/ja
Priority to ES05019537T priority patent/ES2341257T3/es
Priority to PCT/US2000/023328 priority patent/WO2001016318A2/fr
Priority to AU75730/00A priority patent/AU7573000A/en
Priority to EP07019808A priority patent/EP1892249A1/fr
Priority to EP00964919A priority patent/EP1208202A2/fr
Priority to AT05019537T priority patent/ATE459645T1/de
Priority to EP05019538A priority patent/EP1623992A3/fr
Priority to EP05019540A priority patent/EP1621620A3/fr
Priority to EP05019536A priority patent/EP1623991A3/fr
Priority to CA002380355A priority patent/CA2380355A1/fr
Priority to EP05019537A priority patent/EP1637541B1/fr
Priority to DE60043951T priority patent/DE60043951D1/de
Publication of WO2000015796A3 publication Critical patent/WO2000015796A3/fr
Priority to US09/767,609 priority patent/US20020042367A1/en
Priority to US09/828,366 priority patent/US20020010137A1/en
Priority to US09/866,028 priority patent/US6642360B2/en
Priority to US09/902,713 priority patent/US20030082541A1/en
Priority to US09/902,572 priority patent/US20030108983A1/en
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Priority to US09/902,759 priority patent/US20030077654A1/en
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Priority to US09/903,520 priority patent/US20030054401A1/en
Priority to US09/903,823 priority patent/US20030104381A1/en
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Priority to US09/903,925 priority patent/US20030096233A1/en
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Priority to US09/903,786 priority patent/US20030044793A1/en
Priority to US09/903,562 priority patent/US6965015B2/en
Priority to US09/904,011 priority patent/US20030003530A1/en
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Priority to US09/904,877 priority patent/US20030186358A1/en
Priority to US09/904,992 priority patent/US20030135025A1/en
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Priority to US09/904,786 priority patent/US7557192B2/en
Priority to US09/904,766 priority patent/US20030152999A1/en
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Priority to US09/905,056 priority patent/US20030054441A1/en
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Priority to US09/904,532 priority patent/US7151160B2/en
Priority to US09/904,820 priority patent/US20030036094A1/en
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Priority to US09/907,575 priority patent/US20030073079A1/en
Priority to US09/907,824 priority patent/US20020197671A1/en
Priority to US09/907,841 priority patent/US7033825B2/en
Priority to US09/907,979 priority patent/US20030082542A1/en
Priority to US09/907,652 priority patent/US20030104469A1/en
Priority to US09/908,093 priority patent/US20030017498A1/en
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Priority to US10/194,365 priority patent/US7381791B2/en
Priority to US10/194,423 priority patent/US7339025B2/en
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide

Definitions

  • the present invention relates generally to the identification and isolation of novel DNA and to the recombinant production of novel polypeptides.
  • Extracellular proteins play important roles in, among other things, the formation, differentiation and maintenance of multicellular organisms.
  • 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 as 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 proficient 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., Proc. Natl. Acad. Sci. 93:7108-7113 (1996); U.S. Patent No. 5,536,637)].
  • Membrane-bound proteins and receptors can play important roles in, among other things, the formation, differentiation and maintenance of multicellular organisms.
  • 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 interactions. The membrane-bound proteins can also be employed for screening of potential peptide or small molecule inhibitors of the relevant receptor/ligand interaction.
  • Epidermal growth factor is a conventional mitogenic factor that stimulates the proliferation of various types of cells including epithelial cells and fibroblasts. EGF binds to and activates the EGF receptor (EGFR), which initiates intracellular signaling and subsequent effects.
  • EGFR EGF receptor
  • the EGFR is expressed in neurons of the cerebral cortex, cerebellum, and hippocampus in addition to other regions of the central nervous system (CNS). In addition, EGF is also expressed in various regions of the CNS. Therefore, EGF acts not only on mitotic cells, but also on postmitotic neurons. In fact, many studies have indicated that EGF has neurotrophic or neuromodulatory effects on various types of neurons in the CNS.
  • EGF acts directly on cultured cerebral cortical and cerebellar neurons, enhancing neurite outgrowth and survival.
  • EGF also acts on other cell types, including septal cholinergic and mesencephalic dopaminergic neurons, indirectly through glial cells.
  • Evidence of the effects of EGF on neurons in the CNS is accumulating, but the mechanisms of action remain essentially unknown.
  • EGF-induced signaling in mitotic cells is better understood than in postmitotic neurons.
  • Studies of cloned pheochromocytoma PC 12 cells and cultured cerebral cortical neurons have suggested that the EGF-induced neurotrophic actions are mediated by sustained activation of the EGFR and mitogen-activated protein kinase (MAPK) in response to EGF.
  • MAPK mitogen-activated protein kinase
  • EGF is a multi-potent growth factor that acts upon various types of cells including mitotic cells and postmitotic neurons.
  • EGF is produced by the salivary and Brunner's glands of the gastrointestinal system, kidney, pancreas, thyroid gland, pituitary gland, and the nervous system, and is found in body fluids such as saliva, blood, cerebrospinal fluid (CSF), urine, amniotic fluid, prostatic fluid, pancreatic juice, and breast milk, Plata-Salaman, Peptides 12: 653-663 (1991).
  • EGF is mediated by its membrane specific receptor, which contains an intrinsic tyrosine kinase.
  • EGF is believed to function by binding to the extracellular portion of its receptor which induces a transmembrane signal that activates the intrinsic tyrosine kinase.
  • Non isolated peptides having this motif include TGF- ⁇ , amphiregulin, schwannoma-derived growth factor (SDGF), heparin-binding EGF-like growth factors and certain virally encoded peptides (e.g. , Vaccinia virus, Reisner, Nature 313: 801-803 (1985), Shope fibroma virus, Chang et al. , Mol Cell Biol. 7: 535-540 (1987), Molluscum contagiosum, Porter and Archard, /. Gen. Virol. 68: 673-682 (1987), and My xoma virus, Upton et al, J. Virol. 61_: 1271-1275 (1987), Prigent and Lemoine, Prog. Growth Factor Res. 4: 1-24 (1992).
  • EGF-like domains are not confined to growth factors but have been observed in a variety of cell -surface and extracellular proteins which have interesting properties in cell adhesion, protein-protein interaction and development, Laurence and Gusterson, Tumor Biol. JU : 229-261 (1990).
  • These proteins include blood coagulation factors (factors VI, IX, X, XII, protein C, protein S, protein Z, tissue plasminogen activator, urokinase), extracellular matrix components (laminin, cytotactin, entactin), cell surface receptors (LDL receptor, fhrombomodulin receptor) and immunity-related proteins (complement Clr, uromodulin).
  • EGF-like precursors are preserved through lower organisms as well as in mammalian cells.
  • a number of genes with developmental significance have been identified in invertebrates with EGF-like repeats.
  • the notch gene of Drosophila encodes 36 tandemly arranged 40 amino acid repeats which show homology to EGF, Wharton et al., Cell 43: 557-581 ( 1985) .
  • Hydropathy plots indicate a putative membrane spanning domain, with the EGF-related sequences being located on the extracellular side of the membrane.
  • EGF has been shown to have potential in the preservation and maintenance of gastrointestinal mucosa and the repair of acute and chronic mucosal lesions, Konturek et al., Eur. J. Gastroenterol Hepatol. 7 (10), 933-37 (1995), including the treatment of necrotizing enterocolitis, Zollinger- Ellison syndrome, gastrointestinal ulceration gastrointestinal ulcerations and congenital microvillus atrophy, Guglietta and Sullivan, Eur. J.
  • EGF is also implicated various skin disease characterized by abnormal keratinocyte differentiation, e.g., psoriasis, epithelial cancers such as squamous cell carcinomas of the lung, epidermoid carcinoma of the vulva and gliomas. King et al., Am. J. Med. Sci. 296: 154-158 (1988).
  • Nephritis is a condition characterized by inflammation of the kidney affecting the structure and normal function of the kidney. This condition can be chronic or acute and is generally caused by infection, degenerative process or vascular disease. In all cases, early detection is desirable so that the patient with nephritis can begin treatment of the condition.
  • TIN-ag tubulointerstitial nephritis antigen
  • the rabbit TIN-ag has a domain in the amino-terminal region containing an epidermal growth factor-like motif that shares homology with laminin A and S chains, alpha 1 chain of type I collagen, von Willebrand's factor and mucin, indicating structural and functional similarities. Studies have also been conducted in mice. However, it is desirable to identify tubulointerstitial nephritis antigens in humans to aid in the development of early detection methods and treatment of nephritis.
  • Proteins which have homology to tubulointerstitial nephritis antigens are of particular interest to the medical and industrial communities. Often, proteins having homology to each other have similar function. It is also of interest when proteins having homology do not have similar functions, indicating that certain structural motifs identify information other than function, such as locality of function.
  • hgerein a novel polypeptide, designated hgerein as PRO230, which has homology to tubulointerstitial nephritis antigens.
  • Stem cells are undifferentiated cells capable of (a) proliferation, (b) self maintenance, (c) the production of a large number of differentiated functional progeny, (d) regeneration of tissue after injury and/or (e) a flexibility in the use of these options .
  • Stem cells often express cell surface antigens which are capable of serving as cell specific markers that can be exploited to identify stem cells, thereby providing a means for identifying and isolating specific stem cell populations.
  • stem cell populations Having possession of different stem cell populations will allow for a number of important applications. For example, possessing a specific stem cell population will allow for the identification of growth factors and other proteins which are involved in their proliferation and differentiation. In addition, there may be as yet undiscovered proteins which are associated with (1) the early steps of dedication of the stem cell to a particular lineage, (2) prevention of such dedication, and (3) negative control of stem cell proliferation, all of which may be identified if one has possession of the stem cell population. Moreover, stem cells are important and ideal targets for gene therapy where the inserted genes promote the health of the individual into whom the stem cells are transplanted. Finally, stem cells may play important roles in transplantation of organs or tissues, for example liver regeneration and skin grafting.
  • PRQ187 Growth factors are molecular signals or mediators that enhance cell growth or proliferation, alone or in concert, by binding to specific cell surface receptors. However, there are other cellular reactions than only growth upon expression to growth factors. As a result, growth factors are better characterized as multifunctional and potent cellular regulators. Their biological effects include proliferation, chemotaxis and stimulation of extracellular matrix production. Growth factors can have both stimulatory and inhibitory effects. For example, transforming growth factor (TGF- ⁇ ) is highly pleiotropic and can stimulate proliferation in some cells, especially connective tissue, while being a potent inhibitor of proliferation in others, such as lymphocytes and epithelial cells.
  • TGF- ⁇ transforming growth factor
  • Peptide growth factors are elements of a complex biological language, providing the basis for intercellular communication. They permit cells to convey information between each other, mediate interaction between cells and change gene expression. The effect of these multifunctional and pluripotent factors is dependent on the presence or absence of other peptides.
  • FGF-8 is a member of the fibroblast growth factors (FGFs) which are a family of heparin-binding, potent mitogens for both normal diploid fibroblasts and established cell lines, Gospodarowicz et al. (1984), Proc. Natl. Acad. Sci. USA 81:6963.
  • the FGF family comprises acidic FGF (FGF-1), basic FGF (FGF-2), INT-2 (FGF-3), K-FGF/HST (FGF-4), FGF-5, FGF-6, KGF (FGF-7), AIGF (FGF-8) among others. All FGFs have two conserved cysteine residues and share 30-50% sequence homology at the amino acid level.
  • Fibroblast growth factors can also stimulate a large number of cell types in a non-mitogenic manner. These activities include promotion of cell migration into wound area (chemotaxis), initiation of new blood vessel formulation (angiogenesis), modulation of nerve regeneration and survival (neurotrophism), modulation of endocrine functions, and stimulation or suppression of specific cellular protein expression, extracellular matrix production and cell survival. Baird & Bohlen, Handbook of Exp. Pharmacol. 95(1): 369-418, Springer, (1990). These properties provide a basis for using fibroblast growth factors in therapeutic approaches to accelerate wound healing, nerve repair, collateral blood vessel formation, and the like. For example, fibroblast growth factors have been suggested to minimize myocardium damage in heart disease and surgery (U.S. P.
  • FGF-8 also known as androgen-induced growth factor (AIGF)
  • AIGF androgen-induced growth factor
  • FGF-8 has been proposed to be under androgenic regulation and induction in the mouse mammary carcinoma cell line SC3. Tanaka et al., Proc. Natl. Acad. Sci. USA 89: 8928-8932 (1992); Sato et al, J. Steroid Biochem. Molec. Biol. 47: 91-98 (1993).
  • FGF-8 may have a local role in the prostate, which is known to be an androgen-responsive organ.
  • FGF-8 can also be oncogenic, as it displays transforming activity when transfected into NIH-3T3 fibroblasts. Kouhara et al., Oncogene 9455-462 (1994). While FGF-8 has been detected in heart, brain, lung, kidney, testis, prostate and ovary, expression was also detected in the absence of exogenous androgens. Schmitt et al., J. Steroid Biochem. Mol. Biol. 57 (3-4): 173-78 (1996).
  • FGF-8 shares the property with several other FGFs of being expressed at a variety of stages of murine embryogenesis, which supports the theory that the various FGFs have multiple and perhaps coordinated roles in differentiation and embryogenesis. Moreover, FGF-8 has also been identified as a protooncogene that cooperates with Wnt-1 in the process of mammary tumorigenesis (Shackleford etal., Proc. Natl. Acad. Sci. USA 90, 740-744 (1993); Heikinheimo et al., Mech. Dev. 48: 129-138 (1994)).
  • FGF-8 exists as three protein isoforms, as a result of alternative splicing of the primary transcript. Tanaka et al., supra. Normal adult expression of FGF-8 is weak and confined to gonadal tissue, however northern blot analysis has indicated that FGF-8 mRNA is present from day 10 through day 12 or murine gestation, which suggests that FGF-8 is important to normal development. Heikinheimo et al., Mech Dev. 48(2): 129-38 (1994).
  • FGF-8 has a unique temporal and spatial pattern in embryogenesis and suggests a role for this growth factor in multiple regions of ectodermal differentiation in the post-gastrulation embryo.
  • novel poypeptides having homology to FGF-8 wherein those polypeptides are heein designated PRO 187 polypeptides.
  • Protein-protein interactions include 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.
  • Leucine-rich repeats are short sequence motifs present in a number 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, nonglubular shape.
  • von Willebrand factor is a protein which plays an important role in the maintenence of hemostasis. More specifically, von Willebrand factor is a protein which is known to participate in platelet-vessel wall interactions at the site of vascular injury via its ability to interact and form a complex with Factor VIII. The absence of von Willebrand factor in the blood causes an abnormality with the blood platelets that prevents platelet adhesion to the vascular wall at the site of the vascular injury. The result is the propensity for brusing, nose bleeds, intestinal bleeding, and the like comprising von Willebrand's disease.
  • 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 coxsackie viruses.
  • 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.
  • CD97 is a seven-span transmembrane receptor which has a cellular ligand, CD55, DAF. Hamann, et al., J. Exp. Med. (U.S.), 184(3): 1189 (1996). Additionally, CD97 has been reported as being a dedifferentiation marker in human thyroid carcinomas and as associated with inflammation. Aust, et al. , Cancer Res. (U.S.), 57(9): 1798 (1997); Gray, et al., J. Immunol. (U.S.), 157(12):5438 (1996).
  • CD97 has also been reported as being related to the secretin receptor superfamily, but unlike known members of that family, CD97 and EMR1 have extended extracellular regions that possess several EGF domains at the N-terminus.
  • EMR1 is further described in Lin, et al. , Genomics. 41(3):301 (1997) and Baud, et al. , Genomics, 26(2):334 (1995).
  • CD97 and EMR1 appear to be related to the secretin receptors
  • a known member of the secretin family of G protein-coupled receptors includes the alpha-latroxin receptor, latrophilin, which has been described as calcium independent and abundant among neuronal tissues.
  • latrophilin alpha-latroxin receptor
  • Both members of the secretin receptor superfamily and non-members which are related to the secretin receptor superfamily, or CRF and calcitonin receptors are of interest. In particular, new members of these families, identified by their homology to known proteins, are of interest.
  • Growth factors are molecular signals or mediators that enhance cell growth or proliferation, alone or in concert, by binding to specific cell surface receptors, however, there are other cellular reactions than only growth upon expression to growth factors. As a result, growth factors are better characterized as multifunctional and potent cellular regulators. Their biological effects include proliferation, chemotaxis and stimulation of extracellular matrix production. Growth factors can have both stimulatory and inhibitory effects.
  • TGF- ⁇ transforming growth factors
  • TGF- ⁇ is highly pleiotropic and can stimulate proliferation in some cells, especially connective tissues, while being a potent inhibitor of proliferation in others, such as lymphocytes and epithelial cells.
  • Peptide growth factors are elements of a complex biological language, providing the basis for intercellular communication. They permit cells to convey information between each other, mediate interaction between cells and change gene expression, the effect of these multifunctional and pluripotent factors is dependent on the presence or absence of other peptides.
  • Fibroblast growth factors are a family of heparin-binding, potent mitogens for both normal diploid fibroblasts and established cell lines, Godpodarowicz, D. et al. (1984), Proc. Natl. Acad. Sci. USA 81: 6983.
  • the FGF family comprises acidic FGF (FGF- 1 ) , basic FGF (FGF-2) , INT-2 (FGF-3) , K-FGF/HST (FGF- 4), FGF-5, FGF-6, KGF (FGF-7), AIGF (FGF-8) among others. All FGFs have two conserved cysteine residues and share 30-50% sequence homology at the amino acid level.
  • Fibroblast growth factors can also stimulate a large number of cell types in a non-mitogenic manner. These activities include promotion of cell migration into a wound area (chemotaxis), initiation of new blood vessel formulation (angiogenesis), modulation of nerve regeneration and survival (neurotrophism), modulation of endocrine functions, and stimulation or suppression of specific cellular protein expression, extracellular matrix production and cell survival. Baird, A. & Bohlen, P., Handbook of Exp. Phrmacol. 95(1): 369-418 (1990). These properties provide a basis for using fibroblast growth factors in therapeutic approaches to accelerate wound healing, nerve repair, collateral blood vessel formation, and the like.
  • fibroblast growth factors have been suggested to minimize myocardium damage in heart disease and surgery (U.S. P. 4,378,437).
  • PR0533 polypeptides have been suggested to minimize myocardium damage in heart disease and surgery.
  • Some of the most important proteins involved in the above described regulation and modulation of cellular processes are the enzymes which regulate levels of protein phosphorylation in the cell.
  • the enzymes that catalyze these processes include the protein kinases, which function to phosphorylate various cellular proteins, and the protein phosphatases, which function to remove phosphate residues from various cellular proteins. The balance of the level of protein phosphorylation in the cell is thus mediated by the relative activities of these two types of enzymes.
  • Protein-protein interactions include 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.
  • Leucine-rich repeats are short sequence motifs present in a number 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, nonglubular shape.
  • Immunoglobulins are antibody molecules, the proteins that function both as receptors for antigen on the B-cell membrane and as the secreted products of the plasma cell. Like all antibody molecules, immunoglobulins perform two major functions: they bind specifically to an antigen and they participate in a limited number of biological effector functions. Therefore, new members of the Ig superfamily are always of interest. Molecules which act as receptors by various viruses and those which act to regulate immune function are of particular interest. Also of particular interest are those molecules which have homology to known Ig family members which act as virus receptors or regulate immune function. Thus, molecules having homology to poliovirus receptors, CRT AM and CD166 (a ligand for lymphocyte antigen CD6) are of particular interest.
  • Extracellular and membrane-bound proteins play important roles in the formation, differentiation and maintenance of multicellular organisms.
  • 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.
  • PR0258 polypeptides have homology to CRTAM, designated herein as PR0258 polypeptides.
  • Protein-protein interactions include receptorand 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.
  • Leucine-rich repeats are short sequence motifs present in a number 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, nonglobular shape.
  • Thrombomodulin binds to and regulates the activity of thrombin. It is important in the control of blood coagulation. Thrombomodulin functions as a natural anticoagulant by accelerating the activation of protein C by thrombin. Soluble thrombomodulin may have therapeutic use as an antithrombotic agent with reduced risk for hemorrhage as compared with heparin. Thrombomodulin is a cell surface trans-membrane glycoprotein, present on endothelial cells and platelets. A smaller, functionally active form of thrombomodulin circulates in the plasma and is also found in urine. (In Haeberli, A., Human Protein Data, VCH Oub., N.Y. , 1992). Peptides having homology to thrombomodulin are particularly desirable.
  • PR0269 polypeptides having homology to thrombomodulin, designated herein as PR0269 polypeptides.
  • PRQ287 Procollagen C-proteinase enhancer protein binds to and enhances the activity of bone morphogenic protein "BMP1 "/procollagen C-proteinase (PCP). It plays a role in extracellular matrix deposition. BMP1 proteins may be used to induce bone and/or cartilage formation and in wound healing and tissue repair. Therefore, procollagen C-proteinase enhancer protein, BMP1 and proteins having homology thereto, are of interest to the scientific and medical communities. We herein describe the identification and characterization of novel polypeptides having homology to procollagen C-proteinase enhancer protein precursor and procollagen C-proteinase enhancer protein, designated herein as PR0287 polypeptides.
  • PRQ214 Growth factors are molecular signals or mediators that enhances cell growth or proliferation, alone or in concert, by binding to specific cell surface receptors. However, there are other cellular reactions than only growth upon expression to growth factors. As a result, growth factors are better characterized as multifunctional and potent cellular regulators. Their biological effects include proliferation, chemotaxis and stimulation of extracellular matrix production. Growth factors can have both stimulatory and inhibitory effects. For example, transforming growth factor ⁇ (TGF- ⁇ ) is highly pleiotropic and can stimulate proliferation in some cells, especially connective tissue, while being a potent inhibitor of proliferation in others, such as lymphocytes and epithelial cells.
  • TGF- ⁇ transforming growth factor ⁇
  • Peptide growth factors are elements of a complex biological language, providing the basis for intercellular communication. They permit cells to convey information between each other, mediate interaction between cells and change gene expression. The effect of these multifunctional and pluripotent factors is dependent on the presence or absence of other peptides.
  • Epidermal growth factor is a conventional mitogenic factor that stimulates the proliferation of various types of cells including epithelial cells and fibroblasts. EGF binds to and activates the EGF receptor (EGFR), which initiates intracellular signaling and subsequent effects.
  • EGFR EGF receptor
  • the EGFR is expressed in neurons of the cerebral cortex, cerebellum, and hippocampus in addition to other regions of the central nervous system (CNS). In addition, EGF is also expressed in various regions of the CNS. Therefore, EGF acts not only on mitotic cells, but also on postmitotic neurons. In fact, many studies have indicated that EGF has neurotrophic or neuromodulatory effects on various types of neurons in the CNS.
  • EGF acts directly on cultured cerebral cortical and cerebellar neurons, enhancing neurite outgrowth and survival.
  • EGF also acts on other cell types, including septal cholinergic and mesencephalic dopaminergic neurons, indirectly through glial cells.
  • Evidence of the effects of EGF on neurons in the CNS is accumulating, but the mechanisms of action remain essentially unknown.
  • EGF-induced signaling in mitotic cells is better understood than in postmitotic neurons.
  • Studies of cloned pheochromocytoma PC 12 cells and cultured cerebral cortical neurons have suggested that the EGF-induced neurotrophic actions are mediated by sustained activation of the EGFR and mitogen-activated protein kinase (MAPK) in response to EGF.
  • MAPK mitogen-activated protein kinase
  • EGF is a multi-potent growth factor that acts upon various types of cells including mitotic cells and postmitotic neurons.
  • EGF is produced by the salivary and Brunner's glands of the gastrointestinal system, kidney, pancreas, thyroid gland, pituitary gland, and the nervous system, and is found in body fluids such as saliva, blood, cerebrospinal fluid (CSF), urine, amniotic fluid, prostatic fluid, pancreatic juice, and breast milk, Plata-Salaman, CR Peptides ⁇ V. 653-663 (1991).
  • EGF is mediated by its membrane specific receptor, which contains an intrinsic tyrosine kinase. Stoscheck CM et al, J. Cell Biochem. 3 .: 135-152 (1986). EGF is believed to function by binding to the extracellular portion of its receptor which induces a transmembrane signal that activates the intrinsic tyrosine kinase.
  • Non isolated peptides having this motif include TGF-a, amphiregulin, schwannoma-derived growth factor (SDGF), heparin-binding EGF-like growth factors and certain virally encoded peptides (e.g. , Vaccinia virus, Reisner AH, Nature 3_13: 801-803 (1985), Shope fibroma virus, Chang W., et al., Mol Cell Biol. 7: 535-540 (1987), Molluscum contagiosum, Porter CD & Archard LC, J. Gen. Virol. 68: 673-682 (1987), and Myxoma virus, Upton C et al, J. Virol. 61: 1271-1275 (1987).
  • EGF-like domains are not confined to growth factors but have been observed in a variety of cell-surface and extracellular proteins which have interesting properties in cell adhesion, protein-protein interaction and development, Laurence DJR & Gusterson BA, Tumor Biol. U : 229-261 (1990).
  • proteins include blood coagulation factors (factors VI, IX, X, XII, protein C, protein S, protein Z, tissue plasminogen activator, urokinase), extracellular matrix components (laminin, cytotactin, entactin), cell surface receptors (LDL receptor, thrombomodulin receptor) and immunity-related proteins (complement Clr, uromodulin).
  • EGF-like precursors are preserved through lower organisms as well as in mammalian cells.
  • a number of genes with developmental significance have been identified in invertebrates with EGF-like repeats.
  • the notch gene of Drosophila encodes 36 tandemly arranged 40 amino acid repeats which show homology to EGF, Wharton W et al, Cell 43: 557-581 (1985).
  • Hydropathy plots indicate a putative membrane spanning domain, with the EGF-related sequences being located on the extracellular side of the membrane.
  • Other homeotic genes with EGF-like repeats include Delta, 95F and 5ZD which were identified using probes based on Notch, and the nematode gene Lin-12 which encodes a putative receptor for a developmental signal transmitted between two specified cells.
  • EGF has been shown to have potential in the preservation and maintenance of gastrointestinal mucosa and the repair of acute and chronic mucosal lesions, Konturek, PC et al, Eur. J. Gastroenterol Hepatol. 7 (10), 933-37 (1995), including the treatment of necrotizing enterocolitis, Zollinger- Ellison syndrome, gastrointestinal ulceration gastrointestinal ulcerations and congenital microvillus atrophy, A. Guglietta & PB Sullivan, Eur. J. Gastroenterol Hepatol, 7(10), 945-50 (1995). Additionally, EGF has been implicated in hair follicle differentiation; CL. du Cros, J. Invest. Dermatol.
  • EGF is also implicated various skin disease characterized by abnormal keratinocyte differentiation, e.g.
  • psoriasis epithelial cancers such as squamous cell carcinomas of the lung, epidermoid carcinoma of the vulva and gliomas. King, LE et al, Am. J. Med. Sci. 296: 154-158 (1988).
  • TGF- ⁇ supergene family or simply TGF- ⁇ superfamily, a group of secreted proteins, includes a large number of related growth and differentiation factors expressed in virtually all phyla.
  • Superfamily members bind to specific cell surface receptors that activate signal transduction mechanisms to elicit their multifunctional cytokine effects. Kolodziejczyk and Hall, Biochem. Cell. Biol.. 74: 299-314 (1996); Attisano and Wrana, Cytokine Growth Factor Rev.. 7: 327-339 (1996); and Hill, Cellular Signaling. 8: 533-544 (1996).
  • Members of this family include five distinct forms of TGF- ⁇ (Sporn and Roberts, in Peptide Growth Factors and Their Receptors.
  • the proteins of the TGF- ⁇ superfamily are disulfide-linked homo- or heterodimers encoded by larger precursor polypeptide chains containing a hydrophobic signal sequence, a long and relatively poorly conserved N-terminal pro region of several hundred amino acids, a cleavage site (usually polybasic), and a shorter and more highly conserved C-terminal region.
  • This C-terminal region corresponds to the processed mature protein and contains approximately 100 amino acids with a characteristic cysteine motif, i.e. , the conservation of seven of the nine cysteine residues of TGF- ⁇ among all known family members.
  • TGF- ⁇ 1 TGF- ⁇ 2 , TGF- ⁇ 3, TGF- ⁇ 4, and
  • the activated form of TGF- ⁇ l is a homodimer formed by dimerization of the carboxy-terminal 112 amino acids of a 390 amino acid precursor.
  • Recombinant TGF- ⁇ l has been cloned (Derynck et al , Nature, 316:701-705 (1985)) and expressed in Chinese hamster ovary cells (Gentry et al. , Mol. Cell. Biol.. 7: 3418-3427 (1987)).
  • recombinant human TGF- ⁇ 2 deMartin et al. , EMBO J. , 6: 3673 (1987)
  • human and porcine TGF- ⁇ 3 Derynck et al.
  • TGF- ⁇ 2 has a precursor form of 414 amino acids and is also processed to a homodimer from the carboxy-terminal 112 amino acids that shares approximately 70% homology with the active form of TGF- ⁇ l (Marquardt et al. , J. Biol. Chem.. 262: 12127 (1987)). See also EP 200,341 ; 169,016; 268,561; and 267,463; U.S. Pat. No.
  • TGF- ⁇ 4 and TGF- ⁇ 5 were cloned from a chicken chondrocyte cDNA library (Jakowlew et al. , Molec. Endocrinol.. 2: 1186-1195 (1988)) and from a frog oocyte cDNA library, respectively.
  • the pro region of TGF- ⁇ associates non-covalently with the mature TGF- ⁇ dimer (Wakefield et al , J. Biol. Chem. , 263: 7646-7654 (1988); Wakefield et al , Growth Factors. 1: 203-218 (1989)), and the pro regions are found to be necessary for proper folding and secretion of the active mature dimers of both TGF- ⁇ and activin (Gray and Mason, Science. 247: 1328-1330 (1990)).
  • the association between the mature and pro regions of TGF- ⁇ masks the biological activity of the mature dimer, resulting in formation of an inactive latent form.
  • Latency is not a constant of the TGF- ⁇ superfamily, since the presence of the pro region has no effect on activin or inhibin biological activity.
  • a unifying feature of the biology of the proteins from the TGF- ⁇ superfamily is their ability to regulate developmental processes.
  • TGF- ⁇ has been shown to have numerous regulatory actions on a wide variety of both normal and neoplastic cells. TGF- ⁇ is multifunctional, as it can either stimulate or inhibit cell proliferation, differentiation, and other critical processes in cell function (Sporn and Roberts, supra).
  • EBAF TGF- ⁇ superfamily
  • the predicted protein sequence of EBAF showed a strong homology to the protein encoded by mouse lefty /stra3 of the TGF- ⁇ superfamily.
  • a motif search revealed that the predicted EBAF protein contains most of the cysteine residues which are conserved among the TGF- ⁇ -related proteins and which are necessary for the formation of the cysteine knot structure.
  • the EBAF sequence contains an additional cysteine residue, 12 amino acids upstream from the first conserved cysteine residue.
  • the only other family members known to contain an additional cysteine residue are TGF- ⁇ s, inhibins, and GDF-3.
  • EBAF similar to LEFTY, GDF-3/Vgr2, and GDF-9, lacks the cysteine residue that is known to form the intermolecular disulfide bond.
  • EBAF appears to be an additional member of the TGF- ⁇ superfamily with an unpaired cysteine residue that may not exist as a dimer.
  • hydrophobic contacts between the two monomer subunits may promote dimer formation.
  • Fluorescence in situ hybridization showed that the ebaf gene is located on human chromosome 1 at band q42.1.
  • TGF- ⁇ superfamily such as those related to EBAF
  • PR0317 polypeptides Additional members of the TGF- ⁇ superfamily, such as those related to EBAF, are being searched for by industry and academics.
  • PR0317 polypeptides novel polypeptides having homology to EBAF, designated herein as PR0317 polypeptides.
  • mAbs cancer specific monoclonal antibodies
  • Such mAbs which can distinguish between normal and cancerous cells are useful in the diagnosis, prognosis and treatment of the disease.
  • antigens are known to be associated with neoplastic diseases, such as colorectal cancer.
  • the A33 antigen is expressed in more than 90% of primary or metastatic colon cancers as well as normal colon epithelium. Since colon cancer is a widespread disease, early diagnosis and treatment is an important medical goal. Diagnosis and treatment of colon cancer can be implemented using monoclonal antibodies (mAbs) specific therefore having fluorescent, nuclear magnetic or radioactive tags. Radioactive gene, toxins and/or drug tagged mAbs can be used for treatment in situ with minimal patient description. mAbs can also be used to diagnose during the diagnosis and treatment of colon cancers. For example, when the serum levels of the A33 antigen are elevated in a patient, a drop of the levels after surgery would indicate the tumor resection was successful.
  • mAbs monoclonal antibodies
  • adenovirus-derived vectors have been proposed as a means of inserting antisense nucleic acids into tumors (U.S. P. 5,518,885).
  • antisense nucleic acids U.S. P. 5,518,885
  • PRO301 polypeptides having homology to certain cancer-associated antigens, designated herein as PRO301 polypeptides.
  • Cholesterol uptake can have serious implications on one ' s health . Cholesterol uptake provides cells with most of the cholesterol they require for membrane synthesis. If this uptake is blocked, cholesterol accumulates in the blood and can contribute to the formation of atherosclerotic plaques in blood vessel walls. Most cholesterol is transported in the blood bound to protein in the form of complexes known as low-density lipoproteins (LDLs). LDLs are endocytosed into cells via LDL receptor proteins. Therefore, LDL receptor proteins, and proteins having homology thereto, are of interest to the scientific and medical communities.
  • LDLs low-density lipoproteins
  • Membrane-bound proteins and receptors can play an important role in the formation, differentiation and maintenance of multicellular organisms.
  • the LDL receptors are an example of membrane-bound proteins which are involved in the synthesis and formation of cell membranes, wherein the health of an individual is affected directly and indirectly by its function.
  • Many membrane-bound proteins act as receptors such as the LDL receptor. These receptors can function to endocytose substrates or they can function as a receptor for a channel.
  • Other membrane-bound proteins function as signals or antigens.
  • Membrane-bound proteins and receptor molecules have various industrial applications, including as pharmaceutical and diagnostic agents.
  • the membrane-bound proteins can also be employed for screening of potential peptide or small molecule regulators of the relevant receptor/ligand interaction.
  • LDL receptor In the case of the LDL receptor, it is desirable to find molecules which enhance endocytosis so as to lower blood cholesterol levels and plaque formation. It is also desirable to identify molecules which inhibit endocytosis so that these molecules can be avoided or regulated by individuals having high blood cholesterol.
  • Polypeptides which are homologous to lipoprotein receptors but which do not function as lipoprotein receptors are also of interest in the determination of the function of the fragments which show homology.
  • Complement is a group of proteins found in the blood that are important in humoral immunity and inflammation. Complement proteins are sequentially activated by antigen-antibody complexes or by proteolytic enzymes. When activated, complement proteins kill bacteria and other microorganisms, affect vascular permeability, release histamine and attract white blood cells. Complement also enhances phagocytosis when bound to target cells. In order to prevent harm to autologous cells, the complement activation pathway is tightly regulated.
  • Deficiencies in the regulation of complement activation or in the complement proteins themselves may lead to immune-complex diseases, such as systemic lupus erythematosus, and may result in increased susceptibility to bacterial infection. In all cases, early detection of complement deficiency is desirable so that the patient can begin treatment. Thus, research efforts are currently directed toward identification of soluble and membrane proteins that regulate complement activation.
  • Factor H is a 150 kD soluble serum protein that interacts with complement protein C3b to accelerate the decay of C3 convertase and acts as a cofactor for Factor I-mediated cleavage of complement protein C4b.
  • Complement receptor type 1 is a 190-280 kD membrane bound protein found in mast cells and most blood cells.
  • CRl interacts with complement proteins C3b, C4b, and iC3b to accelerate dissociation of C3 convertases, acts as a cofactor for Factor I-mediated cleavage of C3b and C4b, and binds immune complexes and promotes their dissolution and phagocytosis.
  • Proteins which have homology to complement proteins are of particular interest to the medical and industrial communities. Often, proteins having homology to each other have similar function. It is also of interest when proteins having homology do not have similar functions, indicating that certain structural motifs identify information other than function, such as locality of function.
  • PR0222 polypeptides having homology to complement receptors, designated herein as PR0222 polypeptides.
  • oligosaccharide structures can be created through the differential activities of a smaller number of glycosyltransferases.
  • the diverse structures of oligosaccharides can be generated by transcription of relatively few gene products, which suggests that the oligosaccharides are a plausible mechanism by which is directed a wide range of cell-cell interactions. Examples of differential expression of cell surface carbohydrates and putative carbohydrate binding proteins (lectins) on interacting cells have been described (J. Dodd & T.M. Jessel, J. Neurosci. 5: 3278 (1985); L.J. Regan et al., Proc. Natl. Acad. Sci. USA 83: 2248 (1986); M.
  • cell adhesion molecules that are involved in the interaction between leukocytes and the endothelium during an inflammatory response currently stands at four: (1) selectins; (2) (carbohydrate and glycoprotein) ligands for selectins; (3) integrins; and (4) integrin ligands, which are members of the immunoglobulin gene superfamily.
  • selectins are cell adhesion molecules that are unified both structurally and functionally. Structurally, selectins are characterized by the inclusion of a domain with homology to a calcium-dependent lectin (C-lectins), an epidermal growth factor (egf)-like domain and several complement binding-like domains, Bevilacqua, M.P. et al, Science 243: 1160-1165 (1989); Johnston et al, Cell 56: 1033-1044 (1989); Lasky et al, Cell 56: 1045-1055 (1989); Siegalman, M. et al, Science 243: 1165-1172 (1989); Stoolman, L.M., Cell 56: 907-910 (1989).
  • C-lectins calcium-dependent lectin
  • egf epidermal growth factor
  • selectins share the common property of their ability to mediate cell binding through interactions between their lectin domains and cell surface carbohydrate ligands (Brandley, B, et al. , Cell 63, 861-863 (1990); Springer, T. and Lasky, L.A., Nature 349, 19-197 (1991); Bevilacqua, M.P. and Nelson, R.M. , J. Clin. Invest. 91379-387 (1993) and Tedder et al, J. Exp. Med. HO: 123-133 (1989).
  • L-selectin also called peripheral lymph node homing receptor (pnHR), LEC-CAM-1, LAM-1, gp90 ME , gpl00 MEL , gpl 10 MEL , MEL-14 antigen, Leu-8 antigen, TQ-1 antigen, DREG antigen
  • E-selectin LEC-CAM-2, LECAM-2, ELAM-1
  • P-selectin LEC-CAM-3, LECAM-3, GMP- 140, PADGEM
  • E-selectin is believed to recognize the carbohydrate sequence NeuNAc ⁇ 2-3Gal ⁇ l-4(Fuc ⁇ l-3)GlcNAc (sialyl-Lewis x, or sLe x ) and related oligosaccharides, Berg et al., J. Biol. Chem. 265: 14869-14872 (1991); Lowe et al, Cell 63: 475-484 (1990); Phillips et al, Science 250: 1130- 1132 (1990); Tiemeyer et al, Proc. Natl. Acad. Sci. USA 88: 1138-1142 (1991).
  • L-selectin which comprises a lectin domain, performs its adhesive function by recognizing carbohydrate-containing ligands on endothelial cells. L-selectin is expressed on the surface of leukocytes, such as lymphocytes, neutrophils, monocytes and eosinophils, and is involved with the trafficking of lymphocytes to peripheral lymphoid tissues ( Gallatin et al, Nature 303: 30-34 (1983)) and with acute neutrophil-medicated inflammatory responses (Watson, S.R., Nature 349: 164-167 (1991)).
  • leukocytes such as lymphocytes, neutrophils, monocytes and eosinophils
  • the amino acid sequence of L-selectin and the encoding nucleic acid sequence are, for example, disclosed in U.S. patent No. 5,098,833 issued 24 March 1992.
  • L-selectin (LECAM-1) is particularly interesting because of its ability to block neutrophil influx (Watson et al, Nature 349: 164-167 (1991). It is expressed in chronic lymphocytic leukemia cells which bind to HEV (Spertini et al, Nature 349: 691-694 (1991). It is also believed that HEV structures at sites of chronic inflammation are associated with the symptoms of diseases such as rheumatoid arthritis, psoriasis and multiple sclerosis.
  • E-selectin is particularly interesting because of its transient expression on endothelial cells in response to IL-1 or TNF. Bevilacqua et al. , Science 243: 1160 (1989). The time course of this induced expression (2-8 h) suggests a role for this receptor in initial neutrophil induced extravasation in response to infection and injury. It has further been reported that anti-ELAM-1 antibody blocks the influx of neutrophils in a primate asthma model and thus is beneficial for preventing airway obstruction resulting from the inflammatory response. Gundel et al, J. Clin. Invest. 88: 1407 (1991). The adhesion of circulating neutrophils to stimulated vascular endothelium is a primary event of the inflammatory response.
  • P-selectin has been reported to recognize the Lewis x structure (Gal ⁇ l-4(Fuc ⁇ l-3) GlcNAc), Larsen et al, Cell 63: 467-474(1990). Others report that an additional terminal linked sialic acid is required for high affinity binding, Moore et al, J. Cell. Biol. U2 . : 491-499 (1991). P-selectin has been shown to be significant in acute lung injury. Anti-P-selectin antibody has been shown to have strong protective effects in a rodent lung injury model. M.S. Mulligan et al, J. Clin. Invest. 90: 1600 (1991).
  • PR0234 polypeptides having homology to lectin proteins, herein designated as PR0234 polypeptides. 22. PRQ231
  • Some of the most important proteins involved in the above described regulation and modulation of cellular processes are the enzymes which regulate levels of protein phosphorylation in the cell.
  • the enzymes that catalyze these processes include the protein kinases, which function to phosphorylate various cellular proteins, and the protein phosphatases, which function to remove phosphate residues from various cellular proteins. The balance of the level of protein phosphorylation in the cell is thus mediated by the relative activities of these two types of enzymes.
  • Protein phosphatases represent a growing family of enzymes that are found in many diverse forms, including both membrane-bound and soluble forms. While many protein phosphatases have been described, the functions of only a very few are beginning to be understood (Tonks, Semin. Cell Biol. 4:373-453 (1993) and Dixon, Recent Prog. Horm. Res. 51 :405-414 (1996)). However, in general, it appears that many of the protein phosphatases function to modulate the positive or negative signals induced by various protein kinases. Therefore, it is likely that protein phosphatases play critical roles in numerous and diverse cellular processes. Given the physiological importance of the protein phosphatases, efforts are being undertaken by both industry and academia to identify new, native phosphatase proteins.
  • Scavenger receptors are known to protect IgG molecules from catabolic degradation. Riechmann and Hollinger, Nature Biotechnology. 15:617 (1997). In particular, studies of the CH2 and CH3 domains have shown that specific sequences of these domains are important in determining the half-lives of antibodies. Ellerson, et al., J. Immunol., 116: 510 (1976); Yasmeen, et al., J. Immunol. 116: 518 (1976; Pollock, et al., Eur. J. Immunol.. 20: 2021 (1990). Scavenger receptor proteins and antibodies thereto are further reported in U.S. Patent No. 5,510,466 to Krieger, et al. Due to the ability of scavenger receptors to increase the half-life of polypeptides and their involvement in immune function, molecules having homology to scavenger receptors are of importance to the scientific and medical community.
  • 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 pivotal determinant of the fate of the cells. 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 for control and prevention of strokes, heart attacks, oxidative stress and hypertension.
  • reductases and particularly, oxidoreductases, are of interest.
  • Publications further describing this subject matter include Kelsey, et al. , Br. J. Cancer. 76(7):852-4 (1997); Friedrich and Weiss, J. Theor. Biol., 187(4):529-40 (1997) and Pieulle, et al., J. Bacterio . 179(18):5684-92 (1997).
  • 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.
  • reductases and particularly, oxidoreductases
  • 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 Kelsey, et al., Br. J. Cancer. 76(7):852-4 (1997); Friedrich and Weiss, J. Theor. Biol.. 187(4):529-40 (1997) and Pieulle, et al., J. Bacteriol.. 179(18):5684-92 (1997).
  • PR0233 polypeptides which have homology to reductase
  • the carboxypeptidase family of exopeptidases constitutes a diverse group of enzymes that hydrolyze carboxyl-terminal amide bonds in polypeptides, wherein a large number of mammalian tissues produce these enzymes.
  • Many of the carboxypeptidase enzymes that have been identified to date exhibit rather strong cleavage specificities for certain amino acids in polypeptides.
  • carboxypeptidase enzymes have been identified which prefer lysine, arginine, serine or amino acids with either aromatic or branched aliphatic side chains as substrates at the carboxyl terminus of the polypeptide.
  • serine carboxypeptidases such amino acid specific enzymes have been identified from a variety of different mammalian and non-mammalian organisms.
  • the mammalian serine carboxypeptidase 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.
  • efforts are being undertaken by both industry and proficient to identify new, native secreted and membrane-bound receptor proteins and specifically novel carboxypeptidases. 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.
  • novel polypeptides having homology to one or more serine carboxypeptidase polypeptides, designated herein as PR0223 polypeptides.
  • Plexin was first identified in Xenopus tadpole nervous system as a membrane glycoprotein which was shown to mediate cell adhesion via a homophilic binding mechanism in the presence of calcium ions. Strong evolutionary conservation between Xenopus, mouse and human homologs of plexin has been observed. [Kaneyama et al., Biochem. And Biophys. Res. Comm. 226: 524-529 (1996)]. Given the physiological importance of cell adhesion mechanisms in vivo, efforts are currently being under taken to identify new, native proteins which are involved in cell adhesion. We describe herein the identification of a novel polypeptide which has homology to plexin, designated herein as PR0235.
  • PRQ236 and PRQ262 ⁇ -galactosidase is a well known enzymatic protein which functionsto hydrolyze ⁇ -galactoside molecules
  • ⁇ -galactosidase has been employed for a variety of different applications, both in vitro and in vivo and has proven to be an extremely useful research tool. As such, there is an interest in obtaining novel polypeptides which exhibit homology to the ⁇ -galactosidase polypeptide.
  • Densin is a glycoprotein which has been isolated from the brain which has all the hallmarks of an adhesion molecule. It is highly concentrated at synaptic sites in the brain and is expressed prominently in dendritic processes in developing neurons. Densin has been characterized as a member of the 0-linked sialoglycoproteins. Densin has relevance to medically important processes such as regeneration. Given the physiological importance of synaptic processes and cell adhesion mechanisms in vivo, efforts are currently being under taken to identify new, native proteins which are involved in synaptic machinery and cell adhesion. We describe herein the identification of novel polypeptides which have homology to densin, designated herein as PR0239 polypeptides.
  • Ebnerin is a cell surface protein associated with von Ebner glands in mammals. Efforts are being undertaken by both industry and proficient to identify new, native cell surface receptor proteins and specifically those which possess sequence homology to cell surface proteins such as ebnerin. 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 the identification of novel polypeptides having significant homology to the von Ebner's gland-associated protein ebnerin, designated herein as PR0257 polypeptides.
  • PRO260 Fucosidases are enzymes that remove fucose residues from fucose containing proteoglycans. In some pathological conditions, such as cancer, rheumatoid arthritis, and diabetes, there is an abnormal fucosylation of serum proteins. Therefore, fucosidases, and proteins having homology to fucosidase, are of importance to the study and abrogation of these conditions. In particular, proteins having homology to the alpha-1-fucosidase precursor are of interest. Fucosidases and fucosidase inhibitors are further described in U.S. Patent Nos.
  • PRO260 polypeptides having homology to fucosidases
  • PRQ263 CD44 is a cell surface adhesion molecule involved in cell-cell and cell-matrix interactions.
  • Hyaluronic acid a component of the extracellular matrix is a major ligand.
  • Other ligands include collagen, fibronectin, laminin, chrondroitin sulfate, mucosal addressin, serglycin and osteoponin.
  • CD44 is also important in regulating cell traffic, lymph node homing, transmission of growth signals, and presentation of chemokines and growth factors to traveling cells.
  • CD44 surface proteins are associated with metastatic tumors and CD44 has been used as a marker for HIV infection. Certain splice variants are associated with metastasis and poor prognosis of cancer patients.
  • CD44 molecules having homology with CD44 are of particular interest, as their homology indicates that they may have functions related to those functions of CD44.
  • CD44 is further described in U.S. Patent Nos. 5,506,119, 5,504, 194 and 5,108,904; Gerberick, et al. , Toxicol. Appl. Pharmacol. , 146(1): 1 (1997); Wittig, et al., Immunol. Letters (Netherlands), 57(1-3):217 (1997); and Oliveira and Odell, Oral Oncol. (England), 33(4):260 (1997).
  • PR0263 polypeptides having homology to CD44 antigen, designated herein as PR0263 polypeptides.
  • Thioredoxins effect reduction-oxidation (redox) state. Many diseases are potentially related to redox state and reactive oxygen species may play a role in many important biological processes.
  • the transcription factors, NF-kappa B and AP-1 are regulated by redox state and are known to affect the expression of a large variety of genes thought to be involved in the pathogenesis of AIDS, cancer, atherosclerosis and diabetic complications.
  • Such proteins may also play a role in cellular antioxidant defense, and in pathological conditions involving oxidative stress such as stroke and inflammation in addition to having a role in apoptosis. Therefore, thioredoxins, and proteins having homology thereto, are of interest to the scientific and medical communities.
  • PRO270 polypeptides having homology to thioredoxin, designated herein as PRO270 polypeptides.
  • the proteoglycan link protein is a protein which is intimately associated with various extracellular matrix proteins and more specifically with proteins such as collagen.
  • one primary component of collagen is a large proteoglycan called aggrecan. This molecule is retained by binding to the glycosaminoglycan hyaluronan through the amino terminal GI globular domain of the core protein. This binding is stabilized by the proteoglycan link protein which is a protein that is also associated with other tissues containing hyaluronan binding proteoglycans such as versican.
  • Link protein has been identified as a potential target for autoimmune antibodies in individuals who suffer from juvenile rheumatoid arthritis (see Guerassimov et al. , J. Rheumatology 24(5):959-964 (1997)). As such, there is strong interest in identifying novel proteins having homology to link protein. We herein describe the identification and characterization of novel polypeptides having such homology, designated herein as PR0271 polypeptides.
  • Reticulocalbin is an endoplasmic reticular protein which may be involved in protein transport and luminal protein processing. Reticulocalbin resides in the lumen of the endopladsmic rerticulum, is known to bind calcium, and may be involved in a luminal retention mechanism of the endoplasmic reticulum. It contains six domains of the EF-hand motif associated with high affinity calcium binding. We describe herein the identification and characterization of a novel polypeptide which has homology to the reticulocalbin protein, designated herein as PR0272.
  • PRQ294 Collagen, a naturally occurring protein, finds wide application in industry. Chemically hydrolyzed natural collagen can be denatured and renatured by heating and cooling to produce gelatin, which is used in photographic and medical, among other applications. Collagen has important properties such as the ability to form interchain aggregates having a conformation designated as a triple helix. We herein describe the identification and characterization of a novel polypeptide which has homology to portions of the collagen molecule, designated herein as PR0294.
  • 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 Ilb/IIIA integrin complex is of particular importance in regulating platelet aggregation. A member of the integrin family, integrin ⁇ -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.
  • LFA-1 leucocyte-associated antigen- 1
  • integrins are expressed as heterodimers of non-covalently associated alpha and beta subunits.
  • PR0295 The integrins are expressed as heterodimers of non-covalently associated alpha and beta subunits.
  • Protein-proteininteractions include 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.
  • Leucine-rich repeats are short sequence motifs present in a number 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, nonglubular shape.
  • PR0293 leucine rich repeat proteins
  • Protein-proteininteractions include 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 leucine-rich repeats are thought to be involved in protein-protein interactions.
  • Leucine-rich repeats are short sequence motifs present in a number 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, nonglubular shape.
  • Densin is a glycoprotein which has been isolated from the brain which has all the hallmarks of an adhesion molecule. It is highly concentrated at synaptic sites in the brain and is expressed prominently in dendritic processes in developing neurons. Densin has been characterized as a member of the O-linked sialoglycoproteins. Densin has relevance to medically important processes such as regeneration. Given the physiological importance of synaptic processes and cell adhesion mechanisms in vivo, efforts are currently being under taken to identify new, native proteins which are involved in synaptic machinery and cell adhesion. Pensin is further described in Kennedy, M.B, Trends Neurosci. (England), 20(6):264 (1997) and Apperson, et al., Neurosci.. 16(21):6839 (1996).
  • PR0247 leucine rich repeat proteins
  • PRO302. PRO303, PRO304. PRO307 and PRQ343 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-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, and alteration of the physical properties of proteins and enzymes.
  • the GLIP protein family has been characterized as comprising zinc-finger proteins which play important roles in embryogenesis. These proteins may function as transcriptional regulatory proteins and are known to be amplified in a subset of human tumors.
  • Glioma pathogenesis protein is structurally related to a group of plant pathogenesis-related proteins. It is highly expressed in glioblastoma. See US Pat. Nos. 5,582,981 (issued Dec. 10, 1996) and 5,322,801 (issued June 21, 1996), Ellington, A.D. et al. , Nature. 346:818 (1990), Grindley, J.C. et al. , Dev. Biol..
  • the CRISP or cysteine rich secretory protein family are a group of proteins which are also structurally related to a group of plant pathogenesis proteins. [Schwidetzky, U., Biochem. J., 321:325 (1997), Pfisterer, P., Mol. Cell Biol.. 16(111:6160 (1996), Kratzschmar, J., Eur. J. Biochem.. 236(3): 827 (1996)].
  • PR0328 polypeptides a novel polypeptide which has homology to GLIP and CRISP
  • Protein-protein interactions include 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 leucine-rich repeats are thought to be involved in protein-protein interactions.
  • Leucine-rich repeats are short sequence motifs present in a number 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, nonglubular shape.
  • IGF insulin like growth factor
  • the acid labile subunit of IGF is also of interest in that it increases the half-life of IGF and is part of the IGF complex in vivo.
  • 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., WO9210518-A1 by Yale University.
  • LIG-1 a membrane glycoprotein that is expressed specifically in glial cells in the mouse brain, and has leucine rich repeats and immunoglobulin-like domains. Suzuki, et al., J.
  • proteoglycans comprising a repeat characterized by an arrangement of conserved leucine residues (leucine-rich repeat motif) have diverse biological roles.
  • Certain proteoglycans such as biglycan, fibromodulin and decorin, are, for example, characterized by the presence of a leucine-rich repeat of about 24 amino acids [Ruoslahti, Ann. Rev. Cell. Biol. 4 229-255 (1988); Oldberg et al , EMBO J. 8, 2601-2604 (1989)].
  • proteoglycans are believed to play a role in regulating extracellular matrix, cartilage or bone function.
  • the proteoglycan decorin binds to collagen type I and II and affects the rate of fibril formation.
  • Fibromodulin also binds collagen and delays fibril formation. Both fibromodulin and decorin inhibit the activity of transforming growth factor beta (TGF- ⁇ ) (U.S. Patent No. 5,583, 103 issued Pecember 10, 1996). TGF- ⁇ is known to play a key role in the induction of extracellular matrix and has been implicated in the development of fibrotic diseases, such as cancer and glomerulonephritis. Accordingly, proteoglycans have been proposed for the treatment of fibrotic cancer, based upon their ability to inhibit TGF- ⁇ 's growth stimulating activity on the cancer cell.
  • TGF- ⁇ transforming growth factor beta
  • Proteoglycans have also been described as potentially useful in the treatment of other proliferative pathologies, including rheumatoid arthritis, arteriosclerosis, adult respiratory distress syndrome, cirrhosis of the liver, fibrosis of the lungs, post-myocardial infarction, cardiac fibrosis, post-angioplasty restenosis, renal interstitial fibrosis and certain dermal fibrotic conditions, such as keloids and scarring, which might result from burn injuries, other invasive skin injuries, or cosmetic or reconstructive surgery (U.S. Patent No. 5,654,270, issued August 5, 1997).
  • PR0332 polypeptides which have homology to proteins of the leucine rich repeat superfamily, designated herein as PR0332 polypeptides.
  • Fibrillin microfibrils define the continuous elastic network of skin, and are present in dermis as microfibril bundles devoid of measurable elastin extending from the dermal-epithelial junction and as components of the thick elastic fibres present in the deep reticular dermis.
  • Marfan syndrome has been linked to mutations which interfere with multimerization of fibrillin monomers or other connective tissue elements.
  • Fibulin- 1 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.
  • Fibulin-2 is a novel extracellular matrix protein frequently found in close association with microfibrils containing either fibronectin or fibrillin.
  • fibrillin, fibulin, and molecules related thereto are of interest, particularly for the use of preventing skin from being damaged from aging, injuries or the sun, or for restoring skin damaged from same.
  • these molecules are generally of interest in the study of connective tissue and attachment molecules and related mechanisms. Fibrillin, fibulin and related molecules are further described in Adams, et al., J.
  • PR0334 polypeptides having homology to fibulin and fibrillin, designated herein as PR0334 polypeptides.
  • mAbs tumor or cancer specific monoclonal antibodies
  • Such mAbs which can distinguish between normal and cancerous cells are useful in the diagnosis, prognosis and treatment of the disease.
  • Particular antigens are known to be associated with neoplastic diseases, such as colorectal and breast cancer. Since colon cancer is a widespread disease, early diagnosis and treatment is an important medical goal.
  • Piagnosis and treatment of cancer can be implemented using monoclonal antibodies (mAbs) specific therefore having fluorescent, nuclear magnetic or radioactive tags. Radioactive genes, toxins and/or drug tagged mAbs can be used for treatment in situ with minimal patient description.
  • CEA Carcinoembryonic antigen
  • CEA is a glycoprotein found in human colon cancer and the digestive organs of a 2-6 month human embryos.
  • CEA is a known human tumor marker and is widely used in the diagnosis of neoplastic diseases, such as colon cancer. For example, when the serum levels of CEA are elevated in a patient, a drop of CEA levels after surgery would indicate the tumor resection was successful. On the other hand, a subsequent rise in serum CEA levels after surgery would indicate that metastases of the original tumor may have formed or that new primary tumors may have appeared.
  • CEA may also be a target for mAb, antisense nucleotides
  • 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., /. Biol. Chem. 239: 1406-1410 (1964) and Epstein et al. , Cold Spring Harbor Symp. Quant. 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 reticulum via a -KPEL or -HPEL amino acid sequence at its C-terminus.
  • 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 proficient to identify new, native proteins having homology to protein disulfide isomerase. Many of these efforts are focused on the screening of mammalian recombinant PNA libraries to identify the coding sequences for novel protein disulfide isomerase homologs.
  • PR0268 a novel polypeptide having homology to protein disulfide isomerase
  • Prolyl 4-hydroxylase is an enzyme which functions to post-translationally hydroxylate proline residues at the Y position of the amino acid sequence Gly-X-Y, which is a repeating three amino acid sequence found in both collagen and procollagen. Hydroxylation of proline residues at the Y position of the Gly-X-Y amino acid triplet to form 4-hydroxyproline residues at those positions is required before newly synthesized collagen polypeptide chains may fold into their proper three-dimensional triple-helical conformation. If hydroxylation does not occur, synthesized collagen polypeptides remain non-helical, are poorly secreted by cells and cannot assemble into stable functional collagen fibrils. Vuorio et al. , Proc. Natl. Acad. Sci. USA 89:7467-7470 (1992). Prolyl 4-hydroxylase is comprised of at least two different polypeptide subunits, alpha and beta.
  • Fringe is a protein which specifically blocks serrate-mediated activation of notch in the dorsal compartment of the Prosophila wing imaginal disc.
  • novel polypeptides which may have a role in development and/or the regulation of serrate-like molecules.
  • novel polypeptides having homology to fringe as identified and described herein, designated herein as PR0339 and PRO310 polypeptides.
  • Lectins are a class of proteins comprising a region that binds carbohydrates specifically and non- covalently. Numerous lectins have been identified in higher animals, both membrane-bound and soluble, and have been implicated in a variety of cell-recognition phenomena and tumor metastasis.
  • lectins can be classified as either C-type (calcium-dependent) or S-type (thiol-dependent).
  • Lectins are thought to play a role in regulating cellular events that are initiated at the level of the plasma membrane.
  • plasma membrane associated molecules are involved in the activation of various subsets of lymphoid cells, e.g. T-lymphocytes, and it is known that cell surface molecules are responsible for activation of these cells and consequently their response during an immune reaction.
  • a particular group of cell adhesion molecules, selectins belong in the superfamily of C-type lectins.
  • This group includes L-selectin (peripheral lymph node homing receptor (pnHR), LEC-CAM-1, LAM-1, gp90 MEL , gpl00 MEL , gpl l0 MEL , MEL-14 antigen, Leu-8 antigen, TQ-1 antigen, PREG antigen), E-selectin (LEC-CAM-2, LECAM-2, ELAM-1), and P-selectin (LEC-CAM-3, LECAM-3, GMP-140, PAPGEM).
  • pnHR peripheral lymph node homing receptor
  • LEC-CAM-1 peripheral lymph node homing receptor (pnHR)
  • LAM-1 LAM-1
  • gp90 MEL gpl00 MEL
  • gpl l0 MEL MEL-14 antigen
  • Leu-8 antigen Leu-8 antigen
  • selectins consist of a C-type lectin (carbohydrate binding) domain, an epidermal growth factor-like (EGF-like) motif, and variable numbers of complement regulatory (CR) motifs.
  • Selectins are associated with leukocyte adhesion, e.g. the attachment of neutrophils to venular endothelial cells adjacent to inflammation (E- selectin), or with the trafficking of lymphocytes from blood to secondary lymphoid organs, e.g. lymph nodes and Peyer's patches (L-selectin).
  • Mac-2 Another exemplary lectin is the cell-associated macrophage antigen, Mac-2 that is believed to be involved in cell adhesion and immune responses. Macrophages also express a lectin that recognizes Tn Ag, a human carcinoma-associated epitope.
  • CP95 Fluorine-phosphate-phosphate-phosphate-semiconductor
  • Apoptosis is a non-necrotic cell death that takes place in metazoan animal cells following activation of an intrinsic cell suicide program.
  • the cloning of Fas antigen is described in PCT publication WO 91/10448, and European patent application EP510691.
  • the mature Fas molecule consists of 319 amino acids of which 157 are extracellular, 17 constitute the transmembrane domain, and 145 are intracellular. Increased levels of Fas expression at T cell surface have been associated with tumor cells and HI V-infected cells . Ligation of CP95 triggers apoptosis in the presence of interleukin- 1 (IL-2) .
  • IL-2 interleukin- 1
  • C-type lectins also include receptors for oxidized low-density lipoprotein (LPL). This suggests a possible role in the pathogenesis of atherosclerosis.
  • LPL oxidized low-density lipoprotein
  • Applicants have identified cPNA clones that encode novel polypeptides having homology to EGF, designated in the present application as "PR0211 " and "PR0217” polypeptides.
  • the invention provides an isolated nucleic acid molecule comprising PNA encoding a PR0211 or PR0217 polypeptide.
  • the isolated nucleic acid comprises PNA encoding EGF-like homologue PR0211 and PR0217 polypeptides of Fig. 2 (SEQ IP NO:2) and/or 4 (SEQ IP NO:4) indicated in Fig. 1 (SEQ IP NOl) and/or Fig. 3 (SEQ IP NO: 3), respectively, 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 invention provides isolated PR0211 and PR0217 EGF-like homologue
  • PR0211 and PR0217 polypeptides are isolated native sequence PR0211 and PR0217 EGF-like homologue polypeptides, which in one embodiment, includes an amino acid sequence comprising residues: 1 to 353 of Fig. 2 (SEQ IP NO:2) or (2) 1 to 379 of Fig. 4 (SEQ IP NO: 4).
  • PRO230 Applicants have identified a cDNA clone that encodes a novel polypeptide, wherein the polypeptide is designated in the present application as "PRO230".
  • the invention provides an isolated nucleic acid molecule comprising DNA encoding a PRO230 polypeptide.
  • the isolated nucleic acid comprises DNA encoding the PRO230 polypeptide having amino acid residues 1 through 467 of Figure 6 (SEQ ID NO: 12), 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 invention provides isolated PRO230 polypeptide.
  • the invention provides isolated native sequence PRO230 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 through 467 of Figure 6 (SEQ ID NO: 12).
  • the invention provides an expressed sequence tag (EST) comprising the nucleotide sequence of SEQ ID NO: 13 ( Figure 7) which is herein designated as DNA20088.
  • EST expressed sequence tag
  • PRQ232 Applicants have identified a cDNA clone that encodes a novel polypeptide, wherein the polypeptide is designated in the present application as "PR0232".
  • the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0232 polypeptide.
  • the isolated nucleic acid comprises DNA encoding the PR0232 polypeptide having amino acid residues 1 to 114 of Figure 9 (SEQ ID NO: 18), 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 invention provides isolated PR0232 polypeptide.
  • the invention provides isolated native sequence PR0232 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 114 of Figure 9 (SEQ ID NO: 18).
  • PRQ187 Applicants have identified a cDNA clone that encodes a novel polypeptide, designated in the present application as "PRO 187".
  • the invention provides an isolated nucleic acid molecule comprising DNA encoding a PRO 187 polypeptide.
  • the isolated nucleic acid comprises DNA encoding the PRO 187 polypeptide of Figure 11 (SEQ ID NO:23), 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 invention provides a nucleic acid comprising the coding sequence of Figure 10 (SEQ ID NO: 22) or its complement.
  • the invention provides a nucleic acid of the full length protein of clone DNA27864-1155, deposited with the ATCC under accession number ATCC 209375, alternatively the coding sequence of clone DNA27864-1155, deposited under accession number ATCC 209375.
  • the invention provides isolated PRO 187 polypeptide.
  • the invention provides isolated native sequence PR0187 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 205 of Figure 11 (SEQ ID NO:23).
  • the invention provides a polypeptide encoded by the nucleic acid deposited under accession number ATCC 209375.
  • the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0265 polypeptide.
  • the isolated nucleic acid comprises DNA encoding the PR0265 polypeptide having amino acid residues 1 to 660 of Figure 13 (SEQ ID NO: 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 invention provides isolated PR0265 polypeptide.
  • the invention provides isolated native sequence PR0265 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 660 of Figure 13 (SEQ ID NO:28).
  • An additional embodiment of the present invention is directed to an isolated extracellular domain of a PR0265 polypeptide.
  • the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0219 polypeptide.
  • the isolated nucleic acid comprises DNA encoding the PR0219 polypeptide having amino acid residues 1 to 915 of Figure 15 (SEQ ID NO:34), 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 invention provides isolated PR0219 polypeptide.
  • the invention provides isolated native sequence PR0219 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 915 of Figure 15 (SEQ ID NO:34).
  • the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0246 polypeptide.
  • the isolated nucleic acid comprises DNA encoding the PR0246 polypeptide having amino acid residues 1 to 390 of Figure 17 (SEQ IP N0:39), 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 invention provides isolated PR0246 polypeptide.
  • the invention provides isolated native sequence PR0246 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 390 of Figure 17 (SEQ IP NO:39).
  • An additional embodiment of the present invention is directed to an isolated extracellular domain of a PR0246 polypeptide.
  • Applicants have identified a cPNA clone that encodes a novel polypeptide having homology to CP97, EMR1 and latrophilin, wherein the polypeptide is designated in the present application as "PR0228".
  • the invention provides an isolated nucleic acid molecule comprising PNA encoding a PR0228 polypeptide.
  • the isolated nucleic acid comprises PNA encoding the PR0228 polypeptide having amino acid residues 1 to 690 of Figure 19 (SEQ ID NO:49), 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 invention provides isolated PR0228 polypeptide.
  • the invention provides isolated native sequence PR0228 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 690 of Figure 19 (SEQ ID NO:49).
  • An additional embodiment of the present invention is directed to an isolated extracellular domain of a PR0228 polypeptide.
  • the invention provides an expressed sequence tag (EST) comprising the nucleotide sequence of SEQ ID NO: 50, designated herein as DNA21951.
  • EST expressed sequence tag
  • the invention provides an isolated nucleic acid molecule having at least about 80% sequence identity to (a) a DNA molecule encoding a PR0533 polypeptide comprising the sequence of amino acids 23 to 216 of Figure 22 (SEQ ID NO:59), or (b) the complement of the DNA molecule of (a).
  • the sequence identity preferably is about 85%, more preferably about 90% , most preferably about 95% .
  • 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 polypeptide having amino acid residues 23 to 216 of Figure 22 (SEQ ID NO: 59).
  • the highest degree of sequence identity occurs within the secreted portion (amino acids 23 to 216 of Figure 22, SEQ ID NO:59).
  • the isolated nucleic acid molecule comprises DNA encoding a PR0533 polypeptide having amino acid residues 1 to 216 of Figure 22 (SEQ ID NO: 59), 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 invention provides a nucleic acid of the full length protein of clone DNA49435-1219, deposited with the ATCC under accession number ATCC 209480.
  • the invention provides isolated PR0533 polypeptide.
  • the invention provides isolated native sequence PR0533 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 23 to 216 of Figure 22 (SEQ ID NO:59).
  • Native PR0533 polypeptides with or without the native signal sequence (amino acids 1 to 22 in Figure 22 (SEQ ID NO:59)), and with or without the initiating methionine are specifically included.
  • the invention provides a PR0533 polypeptide encoded by the nucleic acid deposited under accession number ATCC 209480.
  • the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0245 polypeptide.
  • the isolated nucleic acid comprises DNA encoding the PR0245 polypeptide having amino acid residues 1 to 312 of Fig. 24 (SEQ ID NO: 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 invention provides isolated PR0245 polypeptide.
  • the invention provides isolated native sequence PR0245 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 312 of Figure 24 (SEQ ID NO:64).
  • an isolated nucleic acid comprises DNA encoding the PRO220 polypeptide having amino acid residues 1 through 708 of Figure 26 (SEQ ID NO: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.
  • an isolated nucleic acid comprises DNA encoding the PR0221 polypeptide having amino acid residues 1 through 259 of Figure 28 (SEQ ID NO:71), 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.
  • an isolated nucleic acid comprises DNA encoding the PR0227 polypeptide having amino acid residues 1 through 620 of Figure 30 (SEQ ID NO:73), 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 invention provides isolated PRO220, PR0221 and PR0227 polypeptides.
  • the isolated native sequence for the PRO220 polypeptide which in one embodiment, includes an amino acid sequence comprising residues 1 to 708 of Figure 26 (SEQ ID NO:69).
  • the isolated native sequence for the PR0221 polypeptide which in one embodiment, includes an amino acid sequence comprising residues 1 to 259 of Figure 28 (SEQ ID NO:71).
  • the isolated native sequence for the PR0227 polypeptide which in one embodiment, includes an amino acid sequence comprising residues 1 to 620 of Figure 30 (SEQ ID NO:73).
  • the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0258 polypeptide.
  • the isolated nucleic acid comprises DNA encoding the PR0258 polypeptide having amino acid residues 1 to 398 of Figure 32 (SEQ ID NO:84), 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 invention provides isolated PR0258 polypeptide.
  • the invention provides isolated native sequence PR0258 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 398 of Figure 32 (SEQ ID NO: 84).
  • An additional embodiment of the present invention is directed to an isolated extracellular domain of a PR0258 polypeptide.
  • the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0266 polypeptide.
  • the isolated nucleic acid comprises DNA encoding the PR0266 polypeptide having amino acid residues 1 to 696 of Figure 34 (SEQ ID NO:91), 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 invention provides isolated PR0266 polypeptide.
  • the invention provides isolated native sequence PR0266 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 696 of Figure 34 (SEQ ID NO:91).
  • PRQ269 Applicants have identified a cDNA clone that encodes a novel polypeptide, wherein the polypeptide is designated in the present application as PR0269.
  • the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0269 polypeptide.
  • the isolated nucleic acid comprises DNA encoding the PR0269 polypeptide having amino acid residues 1 to 490 of Fig. 36 (SEQ ID NO:96), 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 invention provides isolated PR0269 polypeptide.
  • the invention provides isolated native sequence PR0269 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 490 of Figure 36 (SEQ IP NO: 96).
  • An additional embodiment of the present invention is directed to an isolated extracellular domain of a PR0269 polypeptide.
  • the invention provides an isolated nucleic acid molecule comprising PNA encoding a PR0287 polypeptide.
  • the isolated nucleic acid comprises PNA encoding the PR0287 polypeptide having amino acid residues 1 to 415 of Fig. 38 (SEQ IP NO: 104), 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 invention provides isolated PR0287 polypeptide.
  • the invention provides isolated native sequence PR0287 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 415 of Figure 38 (SEQ IP NO: 104).
  • PRQ214 Applicants have identified a cDNA clone that encodes a novel polypeptide, designated in the present application as "PR0214" .
  • the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0214 polypeptide.
  • the isolated nucleic acid comprises DNA encoding the PR0214 polypeptide of Fig. 40 (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.
  • the invention provides a nucleic acid comprising the coding sequence of Fig. 39 (SEQ ID NO: 108) or its complement.
  • the invention provides a nucleic acid of the full length protein of clone DNA32286-1191, deposited with ATCC under accession number ATCC 209385.
  • the invention provides isolated PR0214 polypeptide.
  • the invention provides isolated native sequence PR0214 polypeptide, which in one embodiment, includes an amino acid sequence comprising the residues of Figure 40 (SEQ ID NO: 109).
  • the invention provides a polypeptide encoded by the nucleic acid deposited under accession number ATCC 209385.
  • the invention provides an isolated nucleic acid molecule comprising DNA encoding PR0317 polypeptide.
  • the isolated nucleic acid comprises DNA (SEQ ID NO: 113) encoding
  • the invention provides isolated PR0317 polypeptide.
  • the invention provides isolated native-sequence PR0317 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 366 of Figure 42 (SEQ ID NO: 114).
  • the invention supplies a method of detecting the presence of PR0317 in a sample, the method comprising: a) contacting a detectable anti-PR0317 antibody with a sample suspected of containing PR0317; and b) detecting binding of the antibody to the sample; wherein the sample is selected from the group consisting of a body fluid, a tissue sample, a cell extract, and a cell culture medium.
  • a method for determining the presence of PR0317 mRNA in a sample comprising: a) contacting a sample suspected of containing PR0317 mRNA with a detectable nucleic acid probe that hybridizes under moderate to stringent conditions to PR0317 mRNA; and b) detecting hybridization of the probe to the sample.
  • the sample is a tissue sample and the detecting step is by in situ hybridization, or the sample is a cell extract and detection is by Northern analysis.
  • the invention provides a method for treating a PR0317-associated disorder comprising administering to a mammal an effective amount of the PR0317 polypeptide or a composition thereof containing a carrier, or with an effective amount of a PR0317 agonist or PR0317 antagonist, such as an antibody which binds specifically to PR0317.
  • PRQ301 Applicants have identified a cDNA clone (DNA40628-1216) that encodes a novel polypeptide, designated in the present application as "PRO301 ".
  • the invention provides an isolated nucleic acid molecule having at least about 80% sequence identity to (a) a DNA molecule encoding a PRO301 polypeptide comprising the sequence of amino acids 28 to 258 of Fig. 44 (SEQ ID NO: 119), or (b) the complement of the DNA molecule of (a).
  • the sequence identity preferably is about 85 % , more preferably about 90 % , most preferably about 95 % .
  • 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 polypeptide having amino acid residues 28 to 258 of Fig. 44 (SEQ ID NO: 119).
  • the highest degree of sequence identity occurs within the extracellular domains (amino acids 28 to 258 of Fig. 44, SEQ ID NO: 119).
  • the isolated nucleic acid molecule comprises DNA encoding a PRO301 polypeptide having amino acid residues 28 to 299 of Fig.
  • the invention provides a nucleic acid of the full length protein of clone DNA40628-1216, deposited with the ATCC under accession number ATCC 209432, alternatively the coding sequence of clone DNA40628-1216, deposited under accession number ATCC 209432.
  • the invention provides isolated PRO301 polypeptide.
  • the invention provides isolated native sequence PRO301 polypeptide, which in one embodiment, includes an amino acid sequence comprising the extracellular domain residues 28 to 258 of Figure 44 (SEQ IP NO: 119).
  • Native PRO301 polypeptides with or without the native signal sequence amino acids 1 to 27 in Figure 44 (SEQ ID NO: 119), and with or without the initiating methionine are specifically included.
  • the sequences of the invention may also comprise the transmembrane domain (residues 236 to about 258 in Figure 44; SEQ ID NO: 119) and/or the intracellular domain (about residue 259 to 299 in Figure 44; SEQ ID NO: 119).
  • the invention provides a PRO301 polypeptide encoded by the nucleic acid deposited under accession number ATCC 209432.
  • PRQ224 Applicants have identified a cDNA clone that encodes a novel polypeptide, wherein the polypeptide is designated in the present application as "PR0224" .
  • the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0224 polypeptide.
  • the isolated nucleic acid comprises DNA encoding the PR0224 polypeptide having amino acid residues 1 to 282 of Figure 46 (SEQ ID NO: 127), 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 invention provides isolated PR0224 polypeptide.
  • the invention provides isolated native sequence PR0224 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 282 of Figure 46 (SEQ ID NO: 127).
  • Applicants have identified a cDNA clone that encodes a novel polypeptide, wherein the polypeptide is designated in the present application as "PR0222" .
  • the invention provides an isolated nucleic acid molecule comprising PNA encoding a PR0222 polypeptide.
  • he isolated nucleic acid comprises PNA encoding the PR0222 polypeptide having amino acid residues 1 to 490 of Fig. 48 (SEQ IP NO: 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 invention provides isolated PR0222 polypeptide.
  • the invention provides isolated native sequence PR0222 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 490 of Figure 48 (SEQ IP NO: 132).
  • Applicants have identified a cPNA clone that encodes a novel lectin polypeptide molecule, designated in the present application as "PR0234".
  • the invention provides an isolated nucleic acid encoding a novel lectin comprising PNA encoding a PR0234 polypeptide.
  • the isolated nucleic acid comprises the PNA encoding PR0234 polypeptides having amino acid residues 1 to 382 of Fig. 50 (SEQ IP 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.
  • the invention provides an isolated nucleic acid molecule comprising the nucleotide sequence of Fig. 49 (SEQ ID NO: 136).
  • the invention provides isolated novel PR0234 polypeptides.
  • the invention provides isolated native sequence PR0234 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 382 of Figure 50 (SEQ ID NO: 137).
  • the invention provides oligonucleotide probes useful for isolating genomic and cDNA nucleotide sequences.
  • Applicants have identified a cDNA clone that encodes a novel polypeptide having homology to a putative acid phosphatase, wherein the polypeptide is designated in the present application as "PR0231 " .
  • the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0231 polypeptide.
  • the isolated nucleic acid comprises DNA encoding the PR0231 polypeptide having amino acid residues 1 to 428 of Fig. 52 (SEQ ID NO: 142), 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 invention provides isolated PR0231 polypeptide.
  • the invention provides isolated native sequence PR0231 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 428 of Figure 52 (SEQ IP NO: 142). 23. PRQ229
  • Applicants have identified a cDNA clone that encodes a novel polypeptide having homology to scavenger receptors wherein the polypeptide is designated in the present application as "PR0229" .
  • the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0229 polypeptide.
  • the isolated nucleic acid comprises DNA encoding the PR0229 polypeptide having amino acid residues 1 to 347 of Figure 54 (SEQ ID NO: 148), 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 invention provides isolated PR0229 polypeptide.
  • the invention provides isolated native sequence PR0229 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 347 of Figure 54 (SEQ ID NO: 148).
  • the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0238 polypeptide.
  • the isolated nucleic acid comprises DNA encoding the PR0238 polypeptide having amino acid residues 1 to 310 of Figure 56 (SEQ ID NO: 153), 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 invention provides isolated PR0238 polypeptide.
  • the invention provides isolated native sequence PR0238 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 310 of Figure 56 (SEQ ID NO: 153).
  • PRQ233 Applicants have identified a cDNA clone that encodes a novel polypeptide, wherein the polypeptide is designated in the present application as "PR0233".
  • the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0233 polypeptide.
  • the isolated nucleic acid comprises DNA encoding the PR0233 polypeptide having amino acid residues 1 to 300 of Figure 58 (SEQ ID NO: 159), 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 invention provides isolated PR0233 polypeptide.
  • the invention provides isolated native sequence PR0233 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 300 of Figure 58 (SEQ ID NO: 159).
  • Applicants have identified a cDNA clone that encodes a novel polypeptide having homology to serine carboxypeptidase polypeptides, wherein the polypeptide is designated in the present application as "PR0223" .
  • the invention provides an isolated nucleic acid molecule comprising PNA encoding a PR0223 polypeptide.
  • the isolated nucleic acid comprises PNA encoding the PR0223 polypeptide having amino acid residues 1 to 476 of Figure 60 (SEQ IP NO: 164), 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 invention provides isolated PR0223 polypeptide.
  • the invention provides isolated native sequence PR0223 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 476 of Figure 60 (SEQ IP NO: 164).
  • Applicants have identified a cPNA clone that encodes a novel polypeptide, wherein the polypeptide is designated in the present application as "PR0235" .
  • the invention provides an isolated nucleic acid molecule comprising PNA encoding a PR0235 polypeptide.
  • the isolated nucleic acid comprises PNA encoding the PR0235 polypeptide having amino acid residues 1 to 552 of Figure 62 (SEQ IP NO: 170), 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 invention provides isolated PR0235 polypeptide.
  • the invention provides isolated native sequence PR0235 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 552 of Figure 62 (SEQ IP NO: 170).
  • the invention provides an isolated nucleic acid molecule comprising PNA encoding a PR0236 polypeptide.
  • the isolated nucleic acid comprises PNA encoding the PR0236 polypeptide having amino acid residues 1 to 636 of Figure 64 (SEQ IP NO: 175), 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 invention provides an isolated nucleic acid molecule comprising PNA encoding a PR0262 polypeptide.
  • the isolated nucleic acid comprises PNA encoding the PR0262 polypeptide having amino acid residues 1 to 654 of Figure 66 (SEQ IP NO: 177), 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 invention provides isolated PR0236 polypeptide.
  • the invention provides isolated native sequence PR0236 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 636 of Figure 64 (SEQ ID NO: 175).
  • the invention provides isolated PR0262 polypeptide.
  • the invention provides isolated native sequence PR0262 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 654 of Figure 66 (SEQ ID NO: 177).
  • PRQ239 Applicants have identified a cPNA clone that encodes a novel polypeptide, wherein the polypeptide is designated in the present application as "PR0239" .
  • the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0239 polypeptide.
  • the isolated nucleic acid comprises DNA encoding the PR0239 polypeptide having amino acid residues 1 to 501 of Figure 68 (SEQ ID NO: 185), 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 invention provides isolated PR0239 polypeptide.
  • the invention provides isolated native sequence PR0239 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 501 of Figure 68 (SEQ ID NO: 185).
  • Applicants have identified a cDNA clone that encodes a novel polypeptide, wherein the polypeptide is designated in the present application as "PR0257” .
  • the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0257 polypeptide.
  • the isolated nucleic acid comprises DNA encoding the PR0257 polypeptide having amino acid residues 1 to 607 of Figure 70 (SEQ ID NO: 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 invention provides isolated PR0257 polypeptide.
  • the invention provides isolated native sequence PR0257 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 607 of Figure 70 (SEQ ID NO : 190) .
  • An additional embodiment of the present invention is directed to an isolated extracellular domain of a PR0257 polypeptide.
  • PRO260 Applicants have identified a cDNA clone that encodes a novel polypeptide, wherein the polypeptide is designated in the present application as "PRO260" .
  • the invention provides an isolated nucleic acid molecule comprising DNA encoding a PRO260 polypeptide.
  • the isolated nucleic acid comprises DNA encoding the PRO260 polypeptide having amino acid residues 1 to 467 of Figure 72 (SEQ ID NO: 195), 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 invention provides isolated PRO260 polypeptide.
  • the invention provides isolated native sequence PRO260 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 467 of Figure 72 (SEQ ID NO: 195).
  • PRQ263 Applicants have identified a cDNA clone that encodes a novel polypeptide having homology to CD44 antigen, wherein the polypeptide is designated in the present application as "PR0263" .
  • the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0263 polypeptide.
  • the isolated nucleic acid comprises DNA encoding the PR0263 polypeptide having amino acid residues 1 to 322 of Figure 74 (SEQ ID NO:201), 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 invention provides isolated PR0263 polypeptide.
  • the invention provides isolated native sequence PR0263 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 322 of Figure 74 (SEQ IP NO:201).
  • An additional embodiment of the present invention is directed to an isolated extracellular domain of a PR0263 polypeptide.
  • the invention provides an isolated nucleic acid molecule comprising DNA encoding a PRO270 polypeptide.
  • the isolated nucleic acid comprises DNA whivch includes the sequence encoding the PRO270 polypeptide having amino acid residues 1 to 296 of Fig. 76 (SEQ ID NO:207), 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 invention provides isolated PRO270 polypeptide.
  • the invention provides isolated native sequence PRO270 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 296 of Figure 76 (SEQ ID NO:207).
  • PRQ271 Applicants have identified a cDNA clone that encodes a novel polypeptide having homology to the proteoglycan link protein, wherein the polypeptide is designated in the present application as "PR0271 " .
  • the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0271 polypeptide.
  • the isolated nucleic acid comprises PNA encoding the PR0271 polypeptide having amino acid residues 1 to 360 of Figure 78 (SEQ IP NO:213), 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 invention provides isolated PR0271 polypeptide.
  • the invention provides isolated native sequence PR0271 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 360 of Figure 78 (SEQ IP N0:213).
  • PRQ272 Applicants have identified a cPNA clone that encodes a novel polypeptide, wherein the polypeptide is designated in the present application as "PR0272" .
  • the invention provides an isolated nucleic acid molecule comprising PNA encoding a PR0272 polypeptide.
  • the isolated nucleic acid comprises PNA encoding the PR0272 polypeptide having amino acid residues 1 to 328 of Figure 80 (SEQ ID NO: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.
  • the invention provides isolated PR0272 polypeptide.
  • the invention provides isolated native sequence PR0272 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 328 of Figure 80 (SEQ ID NO:211).
  • Applicants have identified a cDNA clone that encodes a novel polypeptide, wherein the polypeptide is designated in the present application as "PR0294" .
  • the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0294 polypeptide.
  • the isolated nucleic acid comprises DNA encoding the PR0294 polypeptide having amino acid residues 1 to 550 of Figure 82 (SEQ ID NO:227), 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 invention provides isolated PR0294 polypeptide.
  • the invention provides isolated native sequence PR0294 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 550 of Figure 82 (SEQ ID NO: 227).
  • the invention provides an isolated nucleic acid molecule comprising PNA encoding a PR0295 polypeptide.
  • the isolated nucleic acid comprises PNA encoding the PR0295 polypeptide having amino acid residues 1 to 350 of Figure 84 (SEQ IP NO: 236), 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 invention provides isolated PR0295 polypeptide.
  • the invention provides isolated native sequence PR0295 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 350 of Figure 84 (SEQ IP NO: 236).
  • the invention provides an isolated nucleic acid molecule comprising PNA encoding a PR0293 polypeptide.
  • the isolated nucleic acid comprises DNA encoding the PR0293 polypeptide having amino acid residues 1 to 713 of Figure 86 (SEQ ID NO: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 invention provides isolated PR0293 polypeptide.
  • the invention provides isolated native sequence PR0293 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 713 of Figure 86 (SEQ ID NO:245).
  • An additional embodiment of the present invention is directed to an isolated extracellular domain of a PR0293 polypeptide.
  • the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0247 polypeptide.
  • the isolated nucleic acid comprises DNA encoding the PR0247 polypeptide having amino acid residues 1 to 546 of Figure 88 (SEQ ID NO:250), 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 invention provides isolated PR0247 polypeptide.
  • the invention provides isolated native sequence PR0247 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 546 of Figure 88 (SEQ ID NO:250).
  • An additional embodiment of the present invention is directed to an isolated extracellular domain of a PR0247 polypeptide.
  • the invention provides an isolated nucleic acid molecule comprising DNA encoding a PRO302 polypeptide.
  • the isolated nucleic acid comprises DNA encoding the PRO302 polypeptide having amino acid residues 1 to 452 of Figure 90 (SEQ ID NO: 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 invention provides an isolated nucleic acid molecule comprising PNA encoding a PRO303 polypeptide.
  • the isolated nucleic acid comprises DNA encoding the PRO303 polypeptide having amino acid residues 1 to 314 of Figure 92 (SEQ ID NO:257), 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 invention provides an isolated nucleic acid molecule comprising DNA encoding a PRO304 polypeptide.
  • the isolated nucleic acid comprises DNA encoding the PRO304 polypeptide having amino acid residues 1 to 556 of Figure 94 (SEQ ID NO: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 invention provides an isolated nucleic acid molecule comprising DNA encoding a PRO307 polypeptide.
  • the isolated nucleic acid comprises DNA encoding the PRO307 polypeptide having amino acid residues 1 to 383 of Figure 96 (SEQ ID NO:261), 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 invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0343 polypeptide.
  • the isolated nucleic acid comprises DNA encoding the PR0343 polypeptide having amino acid residues 1 to 317 of Figure 98 (SEQ ID NO:263), 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 invention provides isolated PRO302 polypeptide.
  • the invention provides isolated native sequence PRO302 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 452 of Figure 90 (SEQ ID NO:255).
  • the invention provides isolated PRO303 polypeptide.
  • the invention provides isolated native sequence PRO303 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 314 of Figure 92 (SEQ ID NO:257).
  • the invention provides isolated PRO304 polypeptide.
  • the invention provides isolated native sequence PRO304 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 556 of Figure 94 (SEQ ID NO:259).
  • the invention provides isolated PRO307 polypeptide.
  • the invention provides isolated native sequence PRO307 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 383 of Figure 96 (SEQ ID NO:261).
  • the invention provides isolated PR0343 polypeptide.
  • the invention provides isolated native sequence PR0343 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 317 of Figure 98 (SEQ ID NO:263). 41. PRQ328
  • the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0328 polypeptide.
  • the isolated nucleic acid comprises DNA encoding the PR0328 polypeptide having amino acid residues 1 to 463 of Figure 100 (SEQ ID NO:285), 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 invention provides isolated PR0328 polypeptide.
  • the invention provides isolated native sequence PR0328 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 463 of Figure 100 (SEQ ID NO:285).
  • An additional embodiment of the present invention is directed to an isolated extracellular domain of a PRO306 polypeptide.
  • Applicants have identified three cDNA clones that respectively encode three novel polypeptides, each having leucine rich repeats and homology to LIG-1 and ALS. These polypeptides are designated in the present application as PR0335, PR0331 and PR0326, respectively.
  • the invention provides three isolated nucleic acid molecules comprising DNA respectively encoding PR0335, PR0331 and PR0326, respectively.
  • an isolated nucleic acid comprising DNA encoding the PR0335 polypeptide having amino acid residues 1 through 1059 of Figure 102 (SEQ ID NO:290), 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.
  • an isolated nucleic acid comprises DNA encoding the PR0331 polypeptide having amino acid residues 1 through 640 of Figure 104 (SEQ ID NO:292), 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. Additionally provided herein is an isolated nucleic acid comprises DNA encoding the PR0326 polypeptide having amino acid residues 1 through 1119 of Figure 106 (SEQ ID NO:294), 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 invention provides isolated PR0335, PR0331 and PR0326 polypeptides or extracellular domains thereof.
  • the invention provides isolated native sequence for the PR0335 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 through 1059 of Figure 102 (SEQ ID NO:290).
  • the isolated native sequence for the PR0331 polypeptide which in one embodiment, includes an amino acid sequence comprising residues 1 through 640 of Figure 104 (SEQ ID NO:292).
  • the isolated native sequence for the PR0326 polypeptide which in one embodiment, includes an amino acid sequence comprising residues 1 through 1119 of Figure 106 (SEQ ID NO:294).
  • the invention provides an isolated nucleic acid molecule comprising PNA having at least about 80% sequence identity to (a) a PNA molecule encoding a PR0358 polypeptide comprising the sequence of amino acids 49 to 642 of Fig. 108 (SEQ IP NO: 310), or (b) the complement of the PNA molecule of (a) .
  • the sequence identity preferably is about 85 % , more preferably about 90 % , most preferably about 95 % .
  • 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 polypeptide having amino acid residues 1 to 642 of Fig.
  • the isolated nucleic acid molecule comprises PNA encoding a PR0332 polypeptide having amino acid residues 49 to 642 of Fig. 108 (SEQ IP NO: 310), 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 invention provides isolated PR0332 polypeptides.
  • the invention provides isolated native sequence PR0332 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 49 to 624 of Figure 108 (SEQ IP NO:310).
  • Native PR0332 polypeptides with or without the native signal sequence amino acids 1 to 48 in Figure 108, SEQ ID NO:310, and with or without the initiating methionine are specifically included.
  • Applicants have identified a cDNA clone that encodes a novel polypeptide having homology to fibulin and fibrillin, wherein the polypeptide is designated in the present application as "PR0334".
  • the invention provides an isolated nucleic acid molecule comprising PNA encoding a PR0334 polypeptide.
  • the isolated nucleic acid comprises PNA encoding the PR0334 polypeptide having amino acid residues 1 to 509 of Figure 110 (SEQ IP NO:315), 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 invention provides isolated PR0334 polypeptide.
  • the invention provides isolated native sequence PR0334 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 509 of Figure 110 (SEQ ID NO:315).
  • the invention provides an isolated nucleic acid molecule having at least about 80% sequence identity to (a) a PNA molecule encoding a PR0346 polypeptide comprising the sequence of amino acids 19 to 339 of Fig. 112 (SEQ ID NO: 320), or (b) the complement of the DNA molecule of (a).
  • the sequence identity preferably is about 85 % , more preferably about 90 % , most preferably about 95 % .
  • 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 polypeptide having amino acid residues 19 to 339 of Fig. 112 (SEQ IP NO:320).
  • the highest degree of sequence identity occurs within the extracellular domains (amino acids 19 to 339 of Fig. 112, SEQ ID NO:320).
  • the polypeptide by which the homology is measured comprises the residues 1-339, 19-360 or 19- 450 of Fig. 112, SEQ ID NO:320).
  • the isolated nucleic acid molecule comprises DNA encoding a PR0346 polypeptide having amino acid residues 19 to 339 of Fig. 112 (SEQ ID NO:320), alternatively residues 1-339, 19-360 or 19-450 of Fig.
  • the invention provides a nucleic acid of the full length protein of clone DNA44167- 1243, deposited with the ATCC under accession number ATCC 209434, alternatively the coding sequence of clone DNA44167- 1243, deposited under accession number ATCC 209434.
  • the invention provides isolated PR0346 polypeptide.
  • the invention provides isolated native sequence PR0346 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 19 to 339 of Figure 112 (SEQ ID NO: 320).
  • Native PR0346 polypeptides with or without the native signal sequence (residues 1 to 18 in Figure 112 (SEQ ID NO:320), with or without the initiating methionine, with or without the transmembrane domain (residues 340 to 360) and with or without the intracellular domain (residues 361 to 450) are specifically included.
  • the invention provides a PR0346 polypeptide encoded by the nucleic acid deposited under accession number ATCC 209434.
  • the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0268 polypeptide.
  • the isolated nucleic acid comprises DNA encoding the PR0268 polypeptide having amino acid residues 1 to 280 of Figure 114 (SEQ ID NO:325), 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 invention provides isolated PR0268 polypeptide.
  • the invention provides isolated native sequence PR0268 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 280 of Figure 114 (SEQ ID NO:325).
  • An additional embodiment of the present invention is directed to an isolated extracellular domain of a PR0268 polypeptide.
  • the invention provides an isolated nucleic acid molecule comprising PNA encoding a PRO330 polypeptide.
  • the isolated nucleic acid comprises PNA encoding the PRO330 polypeptide having amino acid residues 1 to 533 of Figure 116 (SEQ ID NO: 332), 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 invention provides isolated PRO330 polypeptide.
  • the invention provides isolated native sequence PRO330 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 533 of Figure 116 (SEQ ID NO: 332).
  • PRQ339 and PRO310 Applicants have identified two cDNA clones wherein each clone encodes a novel polypeptide having homology to fringe, wherein the polypeptides are designated in the present application as "PR0339” and "PRO310".
  • the invention provides isolated nucleic acid molecules comprising DNA encoding a PR0339 and/or a PRO310 polypeptide.
  • the isolated nucleic acid comprises PNA encoding the PR0339 polypeptide having amino acid residues 1 to 772 of Figure 118 (SEQ IP NO: 339), 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 comprises PNA encoding the PRO310 polypeptide having amino acid residues 1 to 318 of Figure 120 (SEQ IP NO:341), 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 invention provides isolated PR0339 as well as isolated PRO310 polypeptides.
  • the invention provides isolated native sequence PR0339 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 772 of Figure 118 (SEQ IP NO: 339).
  • the invention further provides isolated native sequence PRO310 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 318 of Figure 120 (SEQ IP NO:341).
  • the invention provides an isolated nucleic acid molecule comprising DNA encoding
  • the isolated nucleic acid comprises DNA encoding PR0244 polypeptide having amino acid residues 1 to 219 of Fig. 122 (SEQ ID NO:377), 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 invention provides isolated PR0244 polypeptide.
  • the invention provides isolated native sequence PR0244 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 219 of Figure 122 (SEQ ID NO:377). 50. Additional Embodiments
  • the invention provides vectors comprising DNA encoding any of the herein described polypeptides.
  • Host cell comprising any such vector are also provided.
  • the host cells may be CHO cells, E. coli, or yeast.
  • a process for producing any of the herein described polypeptides is further provided and comprises culturing host cells under conditions suitable for expression of the desired polypeptide and recovering the desired polypeptide from the cell culture.
  • the invention provides chimeric molecules comprising any of the herein described polypeptides fused to a heterologous polypeptide or amino acid sequence.
  • Example of such chimeric molecules comprise any of the herein described polypeptides fused to an epitope tag sequence or a Fc region of an immunoglobulin.
  • the invention provides an antibody which specifically binds to any of the above or below described polypeptides.
  • the antibody is a monoclonal antibody, humanized antibody, antibody fragment or single-chain antibody.
  • 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.
  • the invention provides an isolated nucleic acid molecule comprising a nucleotide sequence that encodes a PRO polypeptide.
  • the isolated nucleic acid molecule comprises a nucleotide sequence having at least about 80% sequence identity, preferably at least about 81 % sequence identity, more preferably at least about 82% sequence identity, yet more preferably at least about 83% sequence identity, yet more preferably at least about 84% sequence identity, yet more preferably at least about 85% sequence identity, yet more preferably at least about 86% sequence identity, yet more preferably at least about 87% sequence identity, yet more preferably at least about 88% sequence identity, yet more preferably at least about 89% sequence identity, yet more preferably at least about 90% sequence identity, yet more preferably at least about 91 % sequence identity, yet more preferably at least about 92% sequence identity, yet more preferably at least about 93 % sequence identity, yet more preferably at least about 94% sequence identity, yet more preferably at least about 95% sequence identity, yet more preferably at least about 96% sequence identity, yet more preferably at least about 97% sequence identity, yet more preferably at least about 98% sequence identity and yet more preferably at least about
  • the isolated nucleic acid molecule comprises a nucleotide sequence having at least about 80% sequence identity, preferably at least about 81 % sequence identity, more preferably at least about 82% sequence identity, yet more preferably at least about 83% sequence identity, yet more preferably at least about 84% sequence identity, yet more preferably at least about 85% sequence identity, yet more preferably at least about 86% sequence identity, yet more preferably at least about 87% sequence identity, yet more preferably at least about 88% sequence identity, yet more preferably at least about 89% sequence identity, yet more preferably at least about 90% sequence identity, yet more preferably at least about 91 % sequence identity, yet more preferably at least about 92% sequence identity, yet more preferably at least about 93% sequence identity, yet more preferably at least about 94% sequence identity, yet more preferably at least about 95% sequence identity, yet more preferably at least about 96% sequence identity, yet more preferably at least about 97% sequence identity, yet more preferably at least about 98% sequence identity and yet more preferably at least about 99%
  • the invention concerns an isolated nucleic acid molecule comprising a nucleotide sequence having at least about 80% sequence identity, preferably at least about 81 % sequence identity, more preferably at least about 82% sequence identity, yet more preferably at least about 83% sequence identity, yet more preferably at least about 84% sequence identity, yet more preferably at least about 85% sequence identity, yet more preferably at least about 86% sequence identity, yet more preferably at least about 87% sequence identity, yet more preferably at least about 88% sequence identity, yet more preferably at least about 89% sequence identity, yet more preferably at least about 90% sequence identity, yet more preferably at least about 91 % sequence identity, yet more preferably at least about 92% sequence identity, yet more preferably at least about 93% sequence identity, yet more preferably at least about 94% sequence identity, yet more preferably at least about 95 % sequence identity, yet more preferably at least about 96% sequence identity, yet more preferably at least about 97% sequence identity, yet more preferably at least about 98% sequence identity and yet more
  • Another aspect the invention provides an isolated nucleic acid molecule comprising a nucleotide sequence encoding a PRO polypeptide which is either transmembrane domain-deleted or transmembrane domain- inactivated, or is complementary to such encoding nucleotide sequence, wherein the transmembrane domain(s) of such polypeptide are disclosed herein. Therefore, soluble extracellular domains of the herein described PRO polypeptides are contemplated.
  • Another embodiment is directed to fragments of a PRO polypeptide coding sequence, or the complement thereof, that may find use as, for example, hybridization probes or for encoding fragments of a PRO polypeptide that may optionally encode a polypeptide comprising a binding site for an anti-PRO antibody.
  • nucleic acid fragments are usually at least about 20 nucleotides in length, preferably at least about 30 nucleotides in length, more preferably at least about 40 nucleotides in length, yet more preferably at least about 50 nucleotides in length, yet more preferably at least about 60 nucleotides in length, yet more preferably at least about 70 nucleotides in length, yet more preferably at least about 80 nucleotides in length, yet more preferably at least about 90 nucleotides in length, yet more preferably at least about 100 nucleotides in length, yet more preferably at least about 110 nucleotides in length, yet more preferably at least about 120 nucleotides in length, yet more preferably at least about 130 nucleotides in length, yet more preferably at least about 140 nucleotides in length, yet more preferably at least about 150 nucleotides in length, yet more preferably at least about 160 nucleotides in length, yet more preferably at least about 170 nucleot
  • novel fragments of a PRO polypeptide-encoding nucleotide sequence may be determined in a routine manner by aligning the PRO polypeptide-encoding nucleotide sequence with other known nucleotide sequences using any of a number of well known sequence alignment programs and determining which PRO polypeptide-encoding nucleotide sequence fragment(s) are novel. All of such PRO polypeptide-encoding nucleotide sequences are contemplated herein. Also contemplated are the PRO polypeptide fragments encoded by these nucleotide molecule fragments, preferably those PRO polypeptide fragments that comprise a binding site for an anti-PRO antibody.
  • the invention provides isolated PRO polypeptide encoded by any of the isolated nucleic acid sequences hereinabove identified.
  • the invention concerns an isolated PRO polypeptide, comprising an amino acid sequence having at least about 80% sequence identity, preferably at least about 81 % sequence identity, more preferably at least about 82% sequence identity, yet more preferably at least about 83% sequence identity, yet more preferably at least about 84% sequence identity, yet more preferably at least about 85% sequence identity, yet more preferably at least about 86% sequence identity, yet more preferably at least about 87% sequence identity, yet more preferably at least about 88% sequence identity, yet more preferably at least about 89% sequence identity, yet more preferably at least about 90% sequence identity, yet more preferably at least about 91 % sequence identity, yet more preferably at least about 92% sequence identity, yet more preferably at least about 93% sequence identity, yet more preferably at least about 94% sequence identity, yet more preferably at least about 95% sequence identity, yet more preferably at least about 96% sequence identity, yet
  • the invention concerns an isolated PRO polypeptide comprising an amino acid sequence having at least about 80% sequence identity, preferably at least about 81 % sequence identity, more preferably at least about 82% sequence identity, yet more preferably at least about 83% sequence identity, yet more preferably at least about 84% sequence identity, yet more preferably at least about 85% sequence identity, yet more preferably at least about 86% sequence identity, yet more preferably at least about 87% sequence identity, yet more preferably at least about 88% sequence identity, yet more preferably at least about 89% sequence identity, yet more preferably at least about 90% sequence identity, yet more preferably at least about 91 % sequence identity, yet more preferably at least about 92% sequence identity, yet more preferably at least about 93 % sequence identity, yet more preferably at least about 94% sequence identity, yet more preferably at least about 95 % sequence identity, yet more preferably at least about 96 % sequence identity, yet more preferably at least about 97% sequence identity, yet more preferably at least about 98% sequence identity and yet more preferably
  • the invention concerns an isolated PRO polypeptide comprising an amino acid sequence scoring at least about 80% positives, preferably at least about 81 % positives, more preferably at least about 82% positives, yet more preferably at least about 83% positives, yet more preferably at least about 84% positives, yet more preferably at least about 85% positives, yet more preferably at least about 86% positives, yet more preferably at least about 87% positives, yet more preferably at least about 88% positives, yet more preferably at least about 89% positives, yet more preferably at least about 90% positives, yet more preferably at least about 91 % positives, yet more preferably at least about 92% positives, yet more preferably at least about 93% positives, yet more preferably at least about 94% positives, yet more preferably at least about 95% positives, yet more preferably at least about 96% positives, yet more preferably at least about 97% positives, yet more preferably at least about 98% positives and yet more preferably at least about 99%
  • the invention provides an isolated PRO polypeptide without the N-terminal signal sequence and/or the initiating methionine and is encoded by a nucleotide sequence that encodes such an amino acid sequence as hereinbefore described.
  • Processes for producing the same are also herein described, wherein those processes comprise culmring a host cell comprising a vector which comprises the appropriate encoding nucleic acid molecule under conditions suitable for expression of the PRO polypeptide and recovering the PRO polypeptide from the cell culture.
  • Another aspect the invention provides an isolated PRO polypeptide which is either transmembrane domain-deleted or transmembrane domain-inactivated.
  • Processes for producing the same are also herein described, wherein those processes comprise culturing a host cell comprising a vector which comprises the appropriate encoding nucleic acid molecule under conditions suitable for expression of the PRO polypeptide and recovering the PRO polypeptide from the cell culture.
  • the invention concerns agonists and antagonists of a native PRO polypeptide as defined herein.
  • the agonist or antagonist is an anti-PRO antibody or a small molecule.
  • the invention concerns a method of identifying agonists or antagonists to a PRO polypeptide which comprise contacting the PRO polypeptide with a candidate molecule and monitoring a biological activity mediated by said PRO polypeptide.
  • the PRO polypeptide is a native PRO polypeptide.
  • the invention concerns a composition of matter comprising a PRO polypeptide, or an agonist or antagonist of a PRO polypeptide as herein described, or an anti-PRO antibody, in combination with a carrier.
  • the carrier is a pharmaceutically acceptable carrier.
  • Another embodiment of the present invention is directed to the use of a PRO polypeptide, or an agonist or antagonist thereof as hereinbefore described, or an anti-PRO antibody, for the preparation of a medicament useful in the treatment of a condition which is responsive to the PRO polypeptide, an agonist or antagonist thereof or an anti-PRO antibody.
  • Figure 1 shows a nucleotide sequence (SEQ ID NO:l) of a native sequence PR0211 cDNA, wherein SEQ ID NO: l is a clone designated herein as "DNA32292-1131 ".
  • Figure 2 shows the amino acid sequence (SEQ ID NO:2) derived from the coding sequence of SEQ ID NO: l shown in Figure 1.
  • Figure 3 shows a nucleotide sequence (SEQ ID NO: 3) of a native sequence PR0217 cDNA, wherein
  • SEQ ID NO:3 is a clone designated herein as "DNA33094-1131 " .
  • Figure 4 shows the amino acid sequence (SEQ ID NO:4) derived from the coding sequence of SEQ ID NO: 3 shown in Figure 3.
  • Figure 5 shows a nucleotide sequence (SEQ ID NO: 11) of a native sequence PRO230 cDNA, wherein SEQ ID NO: 11 is a clone designated herein as "DNA33223-1136" .
  • Figure 6 shows the amino acid sequence (SEQ ID NO: 12) derived from the coding sequence of SEQ ID NO: 11 shown in Figure 5.
  • Figure 7 shows a nucleotide sequence designated herein as DNA20088 (SEQ ID NO: 13).
  • Figure 8 shows a nucleotide sequence (SEQ ID NO: 17) of a native sequence PR0232 cDNA, wherein SEQ ID NO: 17 is a clone designated herein as "DNA34435-1140" .
  • Figure 9 shows the amino acid sequence (SEQ ID NO: 18) derived from the coding sequence of SEQ ID NO: 17 shown in Figure 8.
  • Figure 10 shows a nucleotide sequence (SEQ ID NO:22) of a native sequence PR0187 cDNA, wherein SEQ ID NO:22 is a clone designated herein as "DNA27864-1155".
  • Figure 11 shows the amino acid sequence (SEQ ID NO: 23) derived from the coding sequence of SEQ
  • Figure 12 shows a nucleotide sequence (SEQ IP NO: 27) of a native sequence PR0265 cPNA, wherein SEQ IP NO:27 is a clone designated herein as "PNA36350-1158".
  • Figure 13 shows the amino acid sequence (SEQ IP NO:28) derived from the coding sequence of SEQ ID NO:27 shown in Figure 12.
  • Figure 14 shows a nucleotide sequence (SEQ ID NO:33) of a native sequence PR0219 cDNA, wherein SEQ ID NO: 33 is a clone designated herein as "DNA32290-1164".
  • Figure 15 shows the amino acid sequence (SEQ IP NO: 34) derived from the coding sequence of SEQ ID NO:33 shown in Figure 14.
  • Figure 16 shows a nucleotide sequence (SEQ ID NO:38) of a native sequence PR0246 cDNA, wherein SEQ ID NO:38 is a clone designated herein as "DNA35639-1172".
  • Figure 17 shows the amino acid sequence (SEQ ID NO:39) derived from the coding sequence of SEQ ID NO:38 shown in Figure 16.
  • Figure 18 shows a nucleotide sequence (SEQ ID NO:48) of a native sequence PR0228 cDNA, wherein SEQ ID NO:48 is a clone designated herein as "DNA33092-1202" .
  • Figure 19 shows the amino acid sequence (SEQ ID NO:49) derived from the coding sequence of SEQ ID NO:48 shown in Figure 18.
  • Figure 20 shows a nucleotide sequence designated herein as PNA21951 (SEQ IP NO: 50).
  • Figure 21 shows a nucleotide sequence (SEQ IP NO:58) of a native sequence PR0533 cPNA, wherein SEQ IP NO:58 is a clone designated herein as "PNA49435-1219" .
  • Figure 22 shows the amino acid sequence (SEQ IP NO: 59) derived from the coding sequence of SEQ ID NO:58 shown in Figure 21.
  • Figure 23 shows a nucleotide sequence (SEQ ID NO:63) of a native sequence PR0245 cDNA, wherein
  • SEQ ID NO:63 is a clone designated herein as "DNA35638-1141 ".
  • Figure 24 shows the amino acid sequence (SEQ ID NO: 64) derived from the coding sequence of SEQ ID NO: 63 shown in Figure 23.
  • Figure 25 shows a nucleotide sequence (SEQ ID NO: 68) of a native sequence PRO220 cDNA, wherein SEQ ID NO:68 is a clone designated herein as "DNA32298-1132".
  • Figure 26 shows the amino acid sequence (SEQ ID NO: 69) derived from the coding sequence of SEQ ID NO: 68 shown in Figure 25.
  • Figure 27 shows a nucleotide sequence (SEQ ID NO: 70) of a native sequence PR0221 cDNA, wherein SEQ ID NO:70 is a clone designated herein as "DNA33089-1132".
  • Figure 28 shows the amino acid sequence (SEQ ID NO:71) derived from the coding sequence of SEQ
  • Figure 29 shows a nucleotide sequence (SEQ ID NO: 72) of a native sequence PR0227 cDNA, wherein SEQ ID NO:72 is a clone designated herein as "DNA33786-1132".
  • Figure 30 shows the amino acid sequence (SEQ ID NO: 73) derived from the coding sequence of SEQ ID NO:72 shown in Figure 29.
  • Figure 31 shows a nucleotide sequence (SEQ ID NO:83) of a native sequence PR0258 cDNA, wherein SEQ ID NO:83 is a clone designated herein as "DNA35918-1174".
  • Figure 32 shows the amino acid sequence (SEQ ID NO: 84) derived from the coding sequence of SEQ ID NO: 83 shown in Figure 31.
  • Figure 33 shows a nucleotide sequence (SEQ ID NO:90) of a native sequence PR0266 cDNA, wherein
  • SEQ ID NO:90 is a clone designated herein as "DNA37150-1178".
  • Figure 34 shows the amino acid sequence (SEQ ID NO:91) derived from the coding sequence of SEQ ID NO: 90 shown in Figure 33.
  • Figure 35 shows a nucleotide sequence (SEQ ID NO: 95) of a native sequence PR0269 cDNA, wherein SEQ IP NO:95 is a clone designated herein as "PN A38260- 1180".
  • Figure 36 shows the amino acid sequence (SEQ ID NO: 96) derived from the coding sequence of SEQ ID NO: 95 shown in Figure 35.
  • Figure 37 shows a nucleotide sequence (SEQ ID NO: 103) of a native sequence PR0287 cDNA, wherein SEQ ID NO: 103 is a clone designated herein as "DNA39969-1185" .
  • Figure 38 shows the amino acid sequence (SEQ ID NO: 104) derived from the coding sequence of SEQ ID NO: 103 shown in Figure 37.
  • Figure 39 shows a nucleotide sequence (SEQ ID NO: 108) of a native sequence PR0214 cDNA, wherein
  • SEQ ID NO: 108 is a clone designated herein as "DNA32286-1191 " .
  • Figure 40 shows the amino acid sequence (SEQ ID NO: 109) derived from the coding sequence of SEQ ID NO: 108 shown in Figure 39.
  • Figure 41 shows a nucleotide sequence (SEQ ID NO: 113) of a native sequence PR0317 cPNA, wherein SEQ ID NO: 113 is a clone designated herein as "DNA33461-1199".
  • Figure 42 shows the amino acid sequence (SEQ ID NO: 114) derived from the coding sequence of SEQ ID NO: 113 shown in Figure 41.
  • Figure 43 shows a nucleotide sequence (SEQ ID NO: 118) of a native sequence PRO301 cDNA, wherein SEQ ID NO: 118 is a clone designated herein as "DNA40628-1216".
  • Figure 44 shows the amino acid sequence (SEQ ID NO: 119) derived from the coding sequence of SEQ ID NO: 118
  • Figure 45 shows a nucleotide sequence (SEQ ID NO: 126) of a native sequence PR0224 cDN A , wherein SEQ ID NO: 126 is a clone designated herein as "DNA33221-1133".
  • Figure 46 shows the amino acid sequence (SEQ ID NO: 127) derived from the coding sequence of SEQ ID NO: 126 shown in Figure 45.
  • Figure 47 shows a nucleotide sequence (SEQ ID NO: 131) of a native sequence PR0222 cDNA, wherein SEQ ID NO: 131 is a clone designated herein as "DNA33107-1135".
  • Figure 48 shows the amino acid sequence (SEQ ID NO: 132) derived from the coding sequence of SEQ ID NO: 131 shown in Figure 47.
  • Figure 49 shows a nucleotide sequence (SEQ ID NO: 136) of a native sequence PR0234 cDNA, wherein
  • SEQ ID NO: 136 is a clone designated herein as "DNA35557-1137".
  • Figure 50 shows the amino acid sequence (SEQ ID NO: 137) derived from the coding sequence of SEQ ID NO: 136 shown in Figure 49.
  • Figure 51 shows a nucleotide sequence (SEQ ID NO: 141) of a native sequence PR0231 cDNA, wherein SEQ ID NO: 141 is a clone designated herein as "DNA34434-1139".
  • Figure 52 shows the amino acid sequence (SEQ ID NO: 142) derived from the coding sequence of SEQ ID NO: 141 shown in Figure 51.
  • Figure 53 shows a nucleotide sequence (SEQ ID NO: 147) of a native sequence PR0229 cDNA, wherein SEQ ID NO: 147 is a clone designated herein as "DNA33100-1159".
  • Figure 54 shows the amino acid sequence (SEQ IP NO: 148) derived from the coding sequence of SEQ IP NO: 147 shown in Figure 53.
  • Figure 55 shows a nucleotide sequence (SEQ ID NO: 152) of a native sequence PR0238 cDNA, wherein SEQ ID NO: 152 is a clone designated herein as "DNA35600-1162" .
  • Figure 56 shows the amino acid sequence (SEQ ID NO: 153) derived from the coding sequence of SEQ ID NO: 152 shown in Figure 55.
  • Figure 57 shows a nucleotide sequence (SEQ ID NO: 158) of a native sequence PR0233 cDNA, wherein SEQ ID NO: 158 is a clone designated herein as "DNA34436-1238".
  • Figure 58 shows the amino acid sequence (SEQ ID NO: 159) derived from the coding sequence of SEQ
  • Figure 59 shows a nucleotide sequence (SEQ ID NO: 163) of a native sequence PR0223 cDNA, wherein SEQ ID NO: 163 is a clone designated herein as "PNA33206-1165” .
  • Figure 60 shows the amino acid sequence (SEQ ID NO: 164) derived from the coding sequence of SEQ ID NO : 163 shown in Figure 59.
  • Figure 61 shows a nucleotide sequence (SEQ ID NO : 169) of a native sequence PR0235 cDN A , wherein SEQ ID NO: 169 is a clone designated herein as "PNA35558-1167".
  • Figure 62 shows the amino acid sequence (SEQ ID NO: 170) derived from the coding sequence of SEQ ID NO: 169 shown in Figure 61.
  • Figure 63 shows a nucleotide sequence (SEQ ID NO: 174) of a native sequence PR0236 cDNA, wherein
  • SEQ ID NO: 174 is a clone designated herein as "DNA35599-1168" .
  • Figure 64 shows the amino acid sequence (SEQ ID NO: 175) derived from the coding sequence of SEQ IP NO: 174 shown in Figure 63.
  • Figure 65 shows a nucleotide sequence (SEQ IP NO: 176) of a native sequence PR0262 cPNA, wherein SEQ IP NO : 176 is a clone designated herein as " PN A36992- 1168" .
  • Figure 66 shows the amino acid sequence (SEQ IP NO: 177) derived from the coding sequence of SEQ IP NO: 176 shown in Figure 65.
  • Figure 67 shows a nucleotide sequence (SEQ IP NO: 184) of a native sequence PR0239 cPNA, wherein SEQ IP NO: 184 is a clone designated herein as "PNA34407-1169".
  • Figure 68 shows the amino acid sequence (SEQ IP NO: 185) derived from the coding sequence of SEQ
  • IP NO: 184 shown in Figure 67.
  • Figure 69 shows a nucleotide sequence (SEQ ID NO: 189) of a native sequence PR0257 cDNA, wherein SEQ ID NO: 189 is a clone designated herein as "PNA35841-1173".
  • Figure 70 shows the amino acid sequence (SEQ ID NO: 190) derived from the coding sequence of SEQ IP NO: 189 shown in Figure 69.
  • Figure 71 shows a nucleotide sequence (SEQ IP NO: 194) of a native sequence PRO260 cPNA, wherein SEQ ID NO: 194 is a clone designated herein as "DNA33470-1175" .
  • Figure 72 shows the amino acid sequence (SEQ ID NO: 195) derived from the coding sequence of SEQ ID NO: 194 shown in Figure 71.
  • Figure 73 shows a nucleotide sequence (SEQ ID NO:200) of a native sequence PR0263 cDNA, wherein SEQ ID NO:200 is a clone designated herein as "DNA34431-1177".
  • Figure 74 shows the amino acid sequence (SEQ ID NO:201) derived from the coding sequence of SEQ ID NO: 200 shown in Figure 73.
  • Figure 75 shows a nucleotide sequence (SEQ ID NO:206) of a native sequence PRO270 cDNA, wherein SEQ ID NO:206 is a clone designated herein as "DNA39510-1181 ".
  • Figure 76 shows the amino acid sequence (SEQ ID NO: 207) derived from the coding sequence of SEQ ID NO:206 shown in Figure 75.
  • Figure 77 shows a nucleotide sequence (SEQ ID NO : 212) of a native sequence PR0271 cDN A , wherein
  • SEQ ID NO:212 is a clone designated herein as "DNA39423-1182".
  • Figure 78 shows the amino acid sequence (SEQ ID NO:213) derived from the coding sequence of SEQ ID NO:212 shown in Figure 77.
  • Figure 79 shows a nucleotide sequence (SEQ IP NO:220) of a native sequence PR0272 cPNA, wherein SEQ IP NO:220 is a clone designated herein as "ONA40620-1183".
  • Figure 80 shows the amino acid sequence (SEQ IP NO: 221) derived from the coding sequence of SEQ IP NO:220 shown in Figure 79.
  • Figure 81 shows a nucleotide sequence (SEQ IP NO:226) of a native sequence PR0294 cPNA, wherein SEQ IP NO:226 is a clone designated herein as "ONA40604-1187" .
  • Figure 82 shows the amino acid sequence (SEQ IP NO:227) derived from the coding sequence of SEQ
  • IP NO: 226 shown in Figure 81.
  • Figure 83 shows a nucleotide sequence (SEQ IP NO:235) of a native sequence PR0295 cDNA, wherein SEQ ID NO:235 is a clone designated herein as "DNA38268-1188" .
  • Figure 84 shows the amino acid sequence (SEQ ID NO:236) derived from the coding sequence of SEQ ID NO:235 shown in Figure 83.
  • Figure 85 shows a nucleotide sequence (SEQ ID NO:244) of a native sequence PR0293 cDNA, wherein SEQ ID NO:244 is a clone designated herein as "DNA37151-1193".
  • Figure 86 shows the amino acid sequence (SEQ ID NO: 245) derived from the coding sequence of SEQ ID NO: 244 shown in Figure 85.
  • Figure 87 shows a nucleotide sequence (SEQ ID NO: 249) of a native sequence PR0247 cDNA, wherein
  • SEQ ID NO:249 is a clone designated herein as "DNA35673-1201 " .
  • Figure 88 shows the amino acid sequence (SEQ ID NO:250) derived from the coding sequence of SEQ ID NO:249 shown in Figure 87.
  • Figure 89 shows a nucleotide sequence (SEQ ID NO:254) of a native sequence PRO302 cDNA, wherein SEQ ID NO:254 is a clone designated herein as "DNA40370-1217".
  • Figure 90 shows the amino acid sequence (SEQ ID NO:255) derived from the coding sequence of SEQ ID NO:254 shown in Figure 89.
  • Figure 91 shows a nucleotide sequence (SEQ ID NO:256) of a native sequence PRO303 cDNA, wherein SEQ ID NO:256 is a clone designated herein as "DNA42551-1217" .
  • Figure 92 shows the amino acid sequence (SEQ ID NO: 257) derived from the coding sequence of SEQ ID NO: 256 shown in Figure 91.
  • Figure 93 shows a nucleotide sequence (SEQ ID NO:258) of a native sequence PRO304 cDNA, wherein SEQ ID NO:258 is a clone designated herein as "DNA39520-1217" .
  • Figure 94 shows the amino acid sequence (SEQ ID NO:259) derived from the coding sequence of SEQ ID NO:258 shown in Figure 93.
  • Figure 95 shows a nucleotide sequence (SEQ ID NO:260) of a native sequence PRO307 cDNA, wherein SEQ ID NO:260 is a clone designated herein as "DNA41225-1217" .
  • Figure 96 shows the amino acid sequence (SEQ ID NO:261) derived from the coding sequence of SEQ
  • Figure 97 shows a nucleotide sequence (SEQ ID NO: 262) of a native sequence PR0343 cDNA, wherein SEQ ID NO:262 is a clone designated herein as "DNA43318-1217".
  • Figure 98 shows the amino acid sequence (SEQ ID NO:263) derived from the coding sequence of SEQ ID NO: 262 shown in Figure 97.
  • Figure 99 shows a nucleotide sequence (SEQ ID NO :284) of a native sequence PR0328 cDNA, wherein SEQ ID NO:284 is a clone designated herein as "DNA40587-1231 ".
  • Figure 100 shows the amino acid sequence (SEQ ID NO:285) derived from the coding sequence of SEQ ID NO:284 shown in Figure 99.
  • Figure 101 shows a nucleotide sequence (SEQ ID NO: 289) of a native sequence PR0335 cDNA, wherein SEQ ID NO:289 is a clone designated herein as "DNA41388-1234".
  • Figure 102 shows the amino acid sequence (SEQ ID NO:290) derived from the coding sequence of SEQ ID NO:289 shown in Figure 101.
  • Figure 103 shows a nucleotide sequence (SEQ ID NO:291) of a native sequence PR0331 cDNA, wherein SEQ ID NO:291 is a clone designated herein as "PNA40981-1234" .
  • Figure 104 shows the amino acid sequence (SEQ ID NO:292) derived from the coding sequence of SEQ ID NO:291 shown in Figure 103.
  • Figure 105 shows a nucleotide sequence (SEQ ID NO:293) of a native sequence PR0326 cDNA, wherein SEQ ID NO:293 is a clone designated herein as "DNA37140-1234" .
  • Figure 106 shows the amino acid sequence (SEQ ID NO:294) derived from the coding sequence of SEQ
  • Figure 107 shows a nucleotide sequence (SEQ ID NO:309) of a native sequence PR0332 cDNA, wherein SEQ ID NO:309 is a clone designated herein as "DNA40982-1235".
  • Figure 108 shows the amino acid sequence (SEQ ID NO:310) derived from the coding sequence of SEQ ID NO:309 shown in Figure 107.
  • Figure 109 shows a nucleotide sequence (SEQ ID NO:314) of a native sequence PR0334 cDNA, wherein SEQ ID NO:314 is a clone designated herein as "DNA41379-1236" .
  • Figure 110 shows the amino acid sequence (SEQ ID NO:315) derived from the coding sequence of SEQ ID NO:314 shown in Figure 109.
  • Figure 111 shows a nucleotide sequence (SEQ ID NO:319) of a native sequence PR0346 cPNA, wherein SEQ IP NO:319 is a clone designated herein as "PNA44167- 1243".
  • Figure 112 shows the amino acid sequence (SEQ IP NO:320) derived from the coding sequence of SEQ IP NO:319 shown in Figure 111.
  • Figure 113 shows a nucleotide sequence (SEQ IP NO: 324) of a native sequence PR0268 cPNA, wherein SEQ IP NO: 324 is a clone designated herein as "PNA39427-1179".
  • Figure 114 shows the amino acid sequence (SEQ IP NO: 325) derived from the coding sequence of SEQ IP NO: 324 shown in Figure 113.
  • Figure 115 shows a nucleotide sequence (SEQ ID NO:331) of a native sequence PRO330 cDNA, wherein SEQ ID NO:331 is a clone designated herein as "DNA40603-1232".
  • Figure 116 shows the amino acid sequence (SEQ ID NO: 332) derived from the coding sequence of SEQ ID NO:331 shown in Figure 115.
  • Figure 117 shows a nucleotide sequence (SEQ ID NO:338) of a native sequence PR0339 cDNA, wherein SEQ ID NO:338 is a clone designated herein as "DNA43466-1225".
  • Figure 118 shows the amino acid sequence (SEQ ID NO : 339) derived from the coding sequence of SEQ ID NO:338 shown in Figure 117.
  • Figure 119 shows a nucleotide sequence (SEQ ID NO: 340) of a native sequence PRO310 cDNA, wherein SEQ ID NO: 340 is a clone designated herein as "DNA43046-1225".
  • Figure 120 shows the amino acid sequence (SEQ ID NO : 341 ) derived from the coding sequence of SEQ
  • Figure 121 shows a nucleotide sequence (SEQ ID NO:376) of a native sequence PR0244 cDNA, wherein SEQ ID N0:376 is a clone designated herein as "DNA35668-1171 " .
  • Figure 122 shows the amino acid sequence (SEQ ID NO:377) derived from the coding sequence of SEQ ID NO:376 shown in Figure 121.
  • 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.
  • PRO/number polypeptide and “PRO/number” wherein the term “number” is provided as an actual numerical designation as used herein encompass native sequence polypeptides and polypeptide variants (which are further defined herein).
  • the PRO polypeptides 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.
  • the native sequence PRO polypeptides disclosed herein are mature or full-length native sequence polypeptides comprising the full-length amino acids sequences shown in the accompanying figures. Start and stop codons are shown in bold font and underlined in the figures. However, while the PRO polypeptide disclosed in the accompanying figures are shown to begin with methionine residues designated herein as amino acid position 1 in the figures, it is conceivable and possible that other methionine residues located either upstream or downstream from the amino acid position 1 in the figures may be employed as the starting amino acid residue for the PRO polypeptides.
  • 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 polypeptide ECD will have less than 1 % of such transmembrane and/or cytoplasmic domains and preferably, will have less than 0.5% of such domains. It will be understood 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 domain. The exact boundaries of a transmembrane domain may vary but most likely by no more than about 5 amino acids at either end of the domain as initially identified herein.
  • an extracellular domain of a PRO polypeptide may contain from about 5 or fewer amino acids on either side of the transmembrane domain/extracellular domain boundary as identified in the Examples or specification and such polypeptides, with or without the associated signal peptide, and nucleic acid encoding them, are comtemplated by the present invention.
  • cleavage of a signal sequence from a secreted polypeptide is not entirely uniform, resulting in more than one secreted species.
  • These mature polypeptides, where the signal peptide is cleaved within no more than about 5 amino acids on either side of the C-terminal boundary of the signal peptide as identified herein, and the polynucleotides encoding them, are contemplated by the present invention.
  • PRO polypeptide variant means an active PRO polypeptide as defined above or below having at least about 80% amino acid sequence identity with a full-length native sequence PRO polypeptide sequence as disclosed herein, a PRO polypeptide sequence lacking the signal peptide as disclosed herein, an extracellular domain of a PRO polypeptide, with or without the signal peptide, as disclosed herein or any other fragment of a full-length PRO polypeptide 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.
  • a PRO polypeptide variant will have at least about 80% amino acid sequence identity, preferably at least about 81 % amino acid sequence identity, more preferably at least about 82% amino acid sequence identity, more preferably at least about 83% amino acid sequence identity, more preferably at least about 84% amino acid sequence identity, more preferably at least about 85% amino acid sequence identity, more preferably at least about 86% amino acid sequence identity, more preferably at least about 87% amino acid sequence identity, more preferably at least about 88% amino acid sequence identity, more preferably at least about 89% amino acid sequence identity, more preferably at least about 90% amino acid sequence identity, more preferably at least about 91 % amino acid sequence identity, more preferably at least about 92% amino acid sequence identity, more preferably at least about 93% amino acid sequence identity, more preferably at least about 94% amino acid sequence identity, more preferably at least about 95 % amino acid sequence identity, more preferably at least about 96% amino acid sequence identity, more preferably at least about 97% amino acid sequence identity, more preferably at least about 98%
  • PRO variant polypeptides are at least about 10 amino acids in length, often at least about 20 amino acids in length, more often at least about 30 amino acids in length, more often at least about 40 amino acids in length, more often at least about 50 amino acids in length, more often at least about 60 amino acids in length, more often at least about 70 amino acids in length, more often at least about 80 amino acids in length, more often at least about 90 amino acids in length, more often at least about 100 amino acids in length, more often at least about 150 amino acids in length, more often at least about 200 amino acids in length, more often at least about 300 amino acids in length, or more.
  • 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 specific 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. 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.
  • % amino acid sequence identity values are generated using the sequence comparison computer program ALIGN-2, wherein the complete source code for the ALIGN-2 program is provided in Table 10 below.
  • the ALIGN-2 sequence comparison computer program was authored by Genentech, Inc. and the source code shown in Table 10 below has been filed with user documentation in the U.S. Copyright Office, Washington D.C., 20559, where it is registered under U.S. Copyright Registration No. TXU510087.
  • the ALIGN-2 program is publicly available through Genentech, Inc. , South San Francisco, California or may be compiled from the source code provided in Table 10 below.
  • the ALIGN-2 program should be compiled for use on a UNIX operating system, preferably digital UNIX V4.0D .
  • % amino acid sequence identity of a given amino acid sequence A to, with, or against a given amino acid sequence B is calculated as follows:
  • a % amino acid sequence identity value is determined by dividing (a) the number of matching identical amino acid residues between the amino acid sequence of the PRO polypeptide of interest having a sequence derived from the native PRO polypeptide and the comparison amino acid sequence of interest (i.e. , the sequence against which the PRO polypeptide of interest is being compared which may be a PRO variant polypeptide) as determined by WU-BLAST-2 by (b) the total number of amino acid residues of the PRO polypeptide of interest.
  • amino acid sequence A is the comparison amino acid sequence of interest and the amino acid sequence B is the amino acid sequence of the PRO polypeptide of interest.
  • Percent amino acid sequence identity may also be determined using the sequence comparison program NCBI-BLAST2 (Altschul et al., Nucleic Acids Res. 25:3389-3402 (1997)).
  • NCBI-BLAST2 sequence comparison program may be downloaded from http://www.ncbi.nlm.nih.gov.
  • % amino acid sequence identity of a given amino acid sequence A to, with, or against a given amino acid sequence B is calculated as follows:
  • PRO variant polynucleotide or "PRO variant nucleic acid sequence” means a nucleic acid molecule which encodes an active PRO polypeptide as defined below and which has at least about 80% nucleic acid sequence identity with a nucleotide acid sequence encoding a full-length native sequence PRO polypeptide sequence as disclosed herein, a full-length native sequence PRO polypeptide sequence lacking the signal peptide as disclosed herein, an extracellular domain of a PRO polypeptide, with or without the signal peptide, as disclosed herein or any other fragment of a full-length PRO polypeptide sequence as disclosed herein.
  • a PRO variant polynucleotide will have at least about 80% nucleic acid sequence identity, more preferably at least about 81 % nucleic acid sequence identity, more preferably at least about 82% nucleic acid sequence identity, more preferably at least about 83 % nucleic acid sequence identity, more preferably at least about 84% nucleic acid sequence identity, more preferably at least about 85 % nucleic acid sequence identity, more preferably at least about 86% nucleic acid sequence identity, more preferably at least about 87% nucleic acid sequence identity, more preferably at least about 88% nucleic acid sequence identity, more preferably at least about 89% nucleic acid sequence identity, more preferably at least about 90% nucleic acid sequence identity, more preferably at least about 91 % nucleic acid sequence identity, more preferably at least about 92% nucleic acid sequence identity, more preferably at least about 93% nucleic acid sequence identity, more preferably at least about 94% nucleic acid sequence identity, more preferably at least about 95% nucle
  • 60 nucleotides in length more often at least about 90 nucleotides in length, more often at least about 120 nucleotides in length, more often at least about 150 nucleotides in length, more often at least about 180 nucleotides in length, more often at least about 210 nucleotides in length, more often at least about 240 nucleotides in length, more often at least about 270 nucleotides in length, more often at least about 300 nucleotides in length, more often at least about 450 nucleotides in length, more often at least about 600 nucleotides in length, more often at least about 900 nucleotides in length, or more.
  • Percent (%) nucleic 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 gaps, if necessary, to achieve the maximum percent sequence identity. Alignment for purposes of determining percent nucleic acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software.
  • % nucleic acid sequence identity values are generated using the sequence comparison computer program ALIGN-2, wherein the complete source code for the ALIGN-2 program is provided in Table 10 below.
  • the ALIGN-2 sequence comparison computer program was authored by Genentech, Inc. and the source code shown in Table 10 below has been filed with user documentation in the U.S. Copyright Office, Washington D.C., 20559, where it is registered under U.S. Copyright Registration No. TXU510087.
  • the ALIGN-2 program is publicly available through Genentech, Inc. , South San Francisco, California or may be compiled from the source code provided in Table 10 below.
  • the ALIGN-2 program should be compiled for use on a UNIX operating system, preferably digital UNIX V4.0D. All sequence comparison parameters are set by the ALIGN-2 program and do not vary.
  • sequence identity of a given nucleic acid sequence C to, with, or against a given nucleic acid sequence D is calculated as follows:
  • a % nucleic acid sequence identity value is determined by dividing (a) the number of matching identical nucleotides between the nucleic acid sequence of the PRO polypeptide-encoding nucleic acid molecule of interest having a sequence derived from the native sequence PRO polypeptide-encoding nucleic acid and the comparison nucleic acid molecule of interest (i.e., the sequence against which the PRO polypeptide-encoding nucleic acid molecule of interest is being compared which may be a variant PRO polynucleotide) as determined by WU-BLAST-2 by (b) the total number of nucleotides of the PRO polypeptide-encoding nucleic acid molecule of interest.
  • nucleic acid sequence A is the comparison nucleic acid molecule of interest and the nucleic acid sequence B is the nucleic acid sequence of the PRO polypeptide- encoding nucleic acid molecule of interest.
  • Percent nucleic acid sequence identity may also be determined using the sequence comparison program NCBI-BLAST2 (Altschul et al. , Nucleic Acids Res. 25:3389-3402 (1997)).
  • NCBI-BLAST2 sequence comparison program may be downloaded from http://www.ncbi.nlm.nih.gov.
  • % nucleic acid sequence identity of a given nucleic acid sequence C to, with, or against a given nucleic acid sequence P is calculated as follows:
  • PRO variant polynucleotides are nucleic acid molecules that encode an active
  • PRO polypeptide and which are capable of hybridizing, preferably under stringent hybridization and wash conditions, to nucleotide sequences encoding a full-length PRO polypeptide as disclosed herein.
  • PRO variant polypeptides may be those that are encoded by a PRO variant polynucleotide.
  • the term "positives”, in the context of sequence comparison performed as described above, includes residues in the sequences compared that are not identical but have similar properties (e.g. as a result of conservative substitutions, see Table 1 below).
  • the % value of positives is determined by dividing (a) the number of amino acid residues scoring a positive value between the PRO polypeptide amino acid sequence of interest having a sequence derived from the native PRO polypeptide sequence and the comparison amino acid sequence of interest (i.e., the amino acid sequence against which the PRO polypeptide sequence is being compared) as determined in the BLOSUM62 matrix of WU-BLAST-2 by (b) the total number of amino acid residues of the PRO polypeptide of interest.
  • % value of positives is calculated as described in the immediately preceding paragraph.
  • amino acid sequence identity comparisons performed as described for ALIGN-2 and NCBI-BLAST2 above includes amino acid residues in the sequences compared that are not only identical, but also those that have similar properties.
  • Amino acid residues that score a positive value to an amino acid residue of interest are those that are either identical to the amino acid residue of interest or are a preferred substitution (as defined in Table 1 below) of the amino acid residue of interest.
  • % value of positives of a given amino acid sequence A to, with, or against a given amino acid sequence B is calculated as follows:
  • Contaminant components of its natural environment are materials that would typically interfere with diagnostic or therapeutic uses for the polypeptide, and may include enzymes, hormones, and other proteinaceous or non-proteinaceous solutes.
  • the polypeptide will be purified (1) to a degree sufficient to obtain at least 15 residues of N-terminal or internal amino acid sequence by use of a spinning cup sequenator, or (2) to homogeneity by SPS-PAGE under non-reducing or reducing conditions using Coomassie blue or, preferably, silver stain.
  • Isolated polypeptide includes polypeptide 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 polypeptide-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.
  • an isolated PRO polypeptide nucleic acid molecule includes PRO polypeptide nucleic acid molecules contained in cells that ordinarily express the PRO polypeptide where, for example, the nucleic acid molecule is in a chromosomal location different from that of natural cells.
  • control sequences refers to DNA sequences necessary for the expression of an operably linked coding sequence in a particular host organism.
  • the control sequences that are suitable for prokaryotes include a promoter, optionally an operator sequence, and a ribosome binding site.
  • Eukaryotic cells are known to utilize promoters, polyadenylation signals, and enhancers.
  • Nucleic acid is "operably linked" when it is placed into a functional relationship with another nucleic acid sequence.
  • DNA for a presequence or secretory leader is operably linked to DNA for a polypeptide if it is expressed as a preprotein that participates in the secretion of the polypeptide;
  • a promoter or enhancer is operably linked to a coding sequence if it affects the transcription of the sequence; or
  • a ribosome binding site is operably linked to a coding sequence if it is positioned so as to facilitate translation.
  • "operably linked” means that the DNA sequences being linked are contiguous, and, in the case of a secretory leader, contiguous and in reading phase. However, enhancers do not have to be contiguous. Linking is accomplished by ligation at convenient restriction sites. If such sites do not exist, the synthetic oligonucleotide adaptors or linkers are used in accordance with conventional practice.
  • antibody is used in the broadest sense and specifically covers, for example, single anti-PRO monoclonal antibodies (including agonist, antagonist, and neutralizing antibodies), anti-PRO antibody compositions with polyepitopic specificity, single chain anti-PRO antibodies, and fragments of anti-PRO antibodies (see below).
  • monoclonal antibody 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.
  • “Stringency” of hybridization reactions is readily determinable by one of ordinary skill in the art, and generally is an empirical calculation dependent upon probe length, washing temperature, and salt concentration. In general, longer probes require higher temperatures for proper annealing, while shorter probes need lower temperatures. Hybridization generally depends on the ability of denatured DNA to reanneal when complementary strands are present in an environment below their melting temperature. The higher the degree of desired homology between the probe and hybridizable sequence, the higher the relative temperature 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 Biology. Wiley Interscience Publishers, (1995).
  • “Stringent conditions” or “high stringency conditions”, as defined herein, may be identified by those that: (1) employ low ionic strength and high temperature for washing, for example 0.015 M sodium chloride/0.0015 M sodium citrate/0.1 % sodium dodecyl sulfate at 50°C; (2) employ during hybridization a denaturing agent, such as formamide, for example, 50% (v/v) formamide with 0.1 % bovine serum albumin/0.1 % Ficoll/0.1 % poly vinylpyrrolidone/50mM sodium phosphate buffer at pH 6.5 with 750 mM sodium chloride, 75 mM sodium citrate at 42°C; or (3) employ 50% formamide, 5 x SSC (0.75 M NaCl, 0.075 M sodium citrate), 50 mM sodium phosphate (pH 6.8), 0.1 % sodium pyrophosphate, 5 x Denhardt's solution, sonicated salmon sperm DNA (50 ⁇ g/ml), 0.1 % SDS, and
  • Modely stringent conditions may be identified as described by Sambrook et al. , Molecular Cloning: A Laboratory Manual, New York: Cold Spring Harbor Press, 1989, and include the use of washing solution and hybridization conditions (e.g., temperature, ionic strength and %SDS) less stringent that those described above.
  • washing solution and hybridization conditions e.g., temperature, ionic strength and %SDS
  • An example of moderately stringent conditions is overnight incubation at 37° C in a solution comprising: 20% formamide, 5 x SSC (150 mM NaCl, 15 mM trisodium citrate), 50 mM sodium phosphate (pH
  • epitope tagged when used herein refers to a chimeric polypeptide comprising a PRO polypeptide fused to a "tag polypeptide" .
  • the tag polypeptide has enough residues to provide an epitope against which an antibody can be made, yet is short enough such that it does not interfere with activity of the polypeptide to which it is fused.
  • the tag polypeptide preferably also is 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 and 50 amino acid residues (preferably, between about 10 and 20 amino acid residues).
  • immunoadhesin designates antibody-like molecules which combine the binding specificity of a heterologous protein (an “adhesin”) with the effector functions of immunoglobulin constant domains.
  • the immunoadhesins comprise a fusion of an amino acid sequence with the desired binding specificity which is other than the antigen recognition and binding site of an antibody (i.e. , is “heterologous”), and an immunoglobulin constant domain sequence.
  • the adhesin part of an immunoadhesin molecule typically is a contiguous amino acid sequence comprising at least the binding site of a receptor or a ligand.
  • the immunoglobulin constant domain sequence in the immunoadhesin may be obtained from any immunoglobulin, such as IgG-1, IgG-2, IgG-3, or IgG-4 subtypes, IgA (including IgA-1 and IgA-2), IgE, IgD or IgM.
  • immunoglobulin such as IgG-1, IgG-2, IgG-3, or IgG-4 subtypes, IgA (including IgA-1 and IgA-2), IgE, IgD or IgM.
  • Active or “activity” for the purposes herein refers to form(s) of a PRO polypeptide which retain a biological and/or an immunological activity of native or naturally-occurring PRO, wherein "biological” activity refers to a biological function (either inhibitory or stimulatory) caused by a native or naturally-occurring PRO other than the ability to induce the production of an antibody against an antigenic epitope possessed by a native or naturally-occurring PRO and an "immunological” activity refers to the ability to induce the production of an antibody against an antigenic epitope possessed by a native or naturally-occurring PRO.
  • antagonist is used in the broadest sense, and includes any molecule that partially or fully blocks, inhibits, or neutralizes a biological activity of a native PRO polypeptide disclosed herein.
  • agonist is used in the broadest sense and includes any molecule that mimics a biological activity of a native PRO polypeptide disclosed herein.
  • Suitable agonist or antagonist molecules specifically include agonist or antagonist antibodies or antibody fragments, fragments or amino acid sequence variants of native PRO polypeptides, peptides, antisense oligonucleotides, small organic molecules, etc.
  • Methods for identifying agonists or antagonists of a PRO polypeptide may comprise contacting a PRO polypeptide with a candidate agonist or antagonist molecule and measuring a detectable change in one or more biological activities normally associated with the PRO polypeptide.
  • Treatment refers to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) the targeted pathologic condition or disorder.
  • Those in need of treatment include those already with the disorder as well as those prone to have the disorder or those in whom the disorder is to be prevented.
  • “Chronic” administration refers to administration of the agent(s) in a continuous mode as opposed to an acute mode, so as to maintain the initial therapeutic effect (activity) for an extended period of time.
  • “Intermittent” administration is treatment that is not consecutively done without interruption, but rather is cyclic in nature.
  • “Mammal” for purposes of treatment refers to any animal classified as a mammal, including humans, domestic and farm animals, and zoo, sports, or pet animals, such as dogs, cats, cattle, horses, sheep, pigs, goats, rabbits, etc. Preferably, the mammal is 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.
  • 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 immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, 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 counterions such as sodium; and/or nonionic surfactants such as TWEENTM, polyethylene glycol (PEG), and PLURONICSTM.
  • buffers such as phosphate, citrate, and other organic acids
  • antioxidants including ascorbic acid
  • proteins such as serum albumin
  • Antibody fragments comprise a portion of an intact antibody, preferably the antigen binding or variable region of the intact antibody.
  • antibody fragments include Fab, Fab' , F(ab') 2 , and Fv fragments; diabodies; linear antibodies (Zapata et al. , Protein Eng. 8(10): 1057-1062 [1995]); single-chain antibody molecules; and multispecific 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') 2 fragment 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 dimer 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.
  • the six CDRs confer antigen-binding specificity to the antibody.
  • a single variable domain or half of an Fv comprising only three CDRs specific for an antigen
  • the Fab fragment also contains the constant domain of the light chain and the first constant domain (CHI) 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 CHI domain including one or more cysteines from the antibody hinge region.
  • Fab'-SH is the designation herein for Fab' in which the cysteine residue(s) 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.
  • immunoglobulins 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 further divided into subclasses (isotypes), e.g. , IgGl , IgG2, IgG3, IgG4, IgA, and IgA2.
  • immunoglobulins There are five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g. , IgGl , IgG2, IgG3, 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.
  • 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.
  • a polypeptide linker between the VH and VL domains which enables the sFv to form the desired structure for antigen binding.
  • Diabodies are described more fully in, for example, EP 404,097; WO 93/11161; and Hollinger et al. , Proc. Natl. Acad. Sci. USA. 90:6444-6448 (1993).
  • an “isolated” antibody is one which has been identified and separated and/or recovered from a component of its natural environment. Contaminant components of its natural environment are materials which would interfere with diagnostic or therapeutic uses for the antibody, and may include enzymes, hormones, and other proteinaceous or nonproteinaceous solutes.
  • the antibody will be purified (1) to greater than 95% by weight of antibody as determined by the Lowry method, and most preferably more than 99% by weight, (2) to a degree sufficient to obtain at least 15 residues of N-terminal or internal amino acid sequence by use of a spinning cup sequenator, or (3) to homogeneity by SDS-PAGE under reducing or nonreducing conditions using Coomassie blue or, preferably, silver stain.
  • Isolated antibody includes the antibody in situ within recombinant cells since at least one component of the antibody's natural environment will not be present. Ordinarily, however, isolated antibody will be prepared by at least one purification step.
  • 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 "labeled" antibody.
  • the label may be detectable by itself (e.g. radioisotope labels or fluorescent labels) or, in the case of an enzymatic label, may catalyze chemical alteration of a substrate compound or composition which is detectable.
  • solid phase is meant a non-aqueous matrix to which the antibody of the present invention can adhere.
  • 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.
  • the solid phase can comprise the well of an assay plate; in others it is a purification column (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 a PRO polypeptide or antibody thereto) to a mammal.
  • a drug such as a PRO polypeptide or antibody thereto
  • the components of the liposome are commonly arranged in a bilayer formation, similar to the lipid arrangement of biological membranes.
  • PR0317-associated disorder refers to a pathological condition or disease wherein PR0317 is over- or underexpressed.
  • disorders include diseases of the female genital tract or of the endometrium of a mammal, including hyperplasia, endometritis, endometriosis, wherein the patient is at risk for infertility due to endometrialfactor, endometrioma, and endometrial cancer, especially those diseases involving abnormal bleeding such as a gynecological disease.
  • diseases involving angiogenesis include diseases involving angiogenesis, wherein the angiogenesis results in a pathological condition, such as cancer involving solid tumors (the therapy for the disorder would result in decreased vascularization and a decline in growth and metastasis of a variety of tumors).
  • the angiogenesis may be beneficial, such as for ischemia, especially coronary ischemia.
  • these disorders include those found in patients whose hearts are functioning but who have a blocked blood supply due to atherosclerotic coronary artery disease, and those with a functioning but underperfused heart, including patients with coronary arterial disease who are not optimal candidates for angioplasty and coronary artery by-pass surgery.
  • the disorders also include diseases involving the kidney or originating from the kidney tissue, such as poly cystic kidney disease and chronic and acute renal failure.
  • the present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PRO polypeptides.
  • cDNAs encoding various PRO polypeptides have 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.
  • PRO/number the protein encoded by the full length native nucleic acid molecules disclosed herein as well as all further native homologues and variants included in the foregoing definition of PRO, will be referred to as "PRO/number", regardless of their origin or mode of preparation.
  • the present invention provides newly identified and isolated nucleotide sequences encodingpolypeptides referred to in the present application as PR0211 and PR0217.
  • Applicants have identified and isolated cDN A encoding PR0211 and PR0217 polypeptides, as disclosed in further detail in the Examples below.
  • BLAST Fast A format sequence alignment computer programs, Applicants found that cDNA sequences encoding full-length native sequence PR0211 and PR0217 have homologies to known proteins having EGF-like domains.
  • the cDNA sequence DNA32292-1131 ( Figure 1, SEQ ID NO: l) has certain identify and a Blast score of 209 with PAC6 RAT and certain identify and a Blast score of 206 with Fibulin- 1 , isoform c precursor.
  • the cDNA sequence DNA33094-1131 ( Figure 3, SEQ ID NO:3) has 36% identity and a Blast score of 336 with eastern newt tenascin, and 37 % identity and a Blast score of 331 with human tenascin- X precursor. Accordingly, it is presently believed that PR0211 and PR0217 polypeptides disclosed in the present application are newly identified members of the EGF-like family and possesses properties typical of the EGF-like protein family.
  • the present invention provides newly identifiedand isolated nucleotide sequences encoding polypeptides referred to in the present application as PRO230.
  • Applicants have identified and isolated cDNA encoding a PRO230 polypeptide, as disclosed in further detail in the Examples below.
  • BLAST and FastA sequence alignment computer programs Applicants found that a cDNA sequence encoding full-length native sequence PRO230 has 48% amino acid identity with the rabbit tubulointerstitial nephritis antigen precursor.
  • PRO230 polypeptide disclosed in the present application is a newly identified member of the tubulointerstitial nephritis antigen family and possesses the ability to be recognized by human autoantibodies in certain forms of tubulointerstitial nephritis.
  • the present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0232.
  • Applicants have identified and isolated cDNA encoding a PR0232 polypeptide, as disclosed in further detail in the Examples below.
  • BLAST and FastA sequence alignment computer programs Applicants found that a portion of the full-length native sequence PR0232 (shown in Figure 9 and SEQ ID NO: 18) has 35% sequence identity with a stem cell surface antigen from Gallus gallus. Accordingly, it is presently believed that the PR0232 polypeptide disclosed in the present application may be a newly identified stem cell antigen.
  • the present invention provides newly identifiedand isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0187.
  • Applicants have identified and isolated cDNA encoding a PRO 187 polypeptide, as disclosed in further detail in the Examples below.
  • BLAST and FastA sequence alignment computer programs Applicants found that a full-length native sequence PRO 187 (shown in Figure 15) has 74% amino acid sequence identity and BLAST score of 310 with various androgen-induced growth factors and FGF-8. Accordingly, it is presently believed that PRO 187 polypeptide disclosed in the present application is a newly identified member of the FGF-8 protein family and may possess identify activity or property typical of the FGF-8-like protein family.
  • the present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0265.
  • Applicants have identified and isolated cDNA encoding a PR0265 polypeptide, as disclosed in further detail in the Examples below.
  • programs such as BLAST and FastA sequence alignment computer programs, Applicants found that various portions of the PR0265 polypeptide have significant homology with the fibromodulin protein and fibromodulin precursor protein.
  • Applicants have also found that the DNA encoding the PR0265 polypeptide has significant homology with platelet glycoprotein V, a member of the leucine rich related protein family involved in skin and wound repair.
  • PR0265 polypeptide disclosed in the present application is a newly identified member of the leucine rich repeat family and possesses protein protein binding capabilities, as well as be involved in skin and wound repair as typical of this family. 6. Full-length PRQ219 Polypeptides
  • the present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0219.
  • PR0219 polypeptides referred to in the present application as PR0219.
  • Applicants have identified and isolated cDNA encoding a PR0219 polypeptide, as disclosed in further detail in the Examples below.
  • BLAST and FastA sequence alignment computer programs Applicants found that various portions of the PR0219 polypeptide have significant homology with the mouse and human matrilin-2 precursor polypeptides. Accordingly, it is presently believed that PR0219 polypeptide disclosed in the present application is related to the matrilin-2 precursor polypeptide.
  • PR0246 nucleotide sequences encoding polypeptides referred to in the present application as PR0246.
  • Applicants have identified and isolated cDNA encoding a PR0246 polypeptide, as disclosed in further detail in the Examples below.
  • BLAST and FastA sequence alignment computer programs Applicants found that a portion of the PR0246 polypeptide has significant homology with the human cell surface protein HCAR. Accordingly, it is presently believed that PR0246 polypeptide disclosed in the present application may be a newly identified membrane-bound virus receptor or tumor cell-specific antigen.
  • the present invention provides newly identifiedand isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0228.
  • PR0228 polypeptides referred to in the present application as PR0228.
  • Applicants have identified and isolated cDNA encoding a PR0228 polypeptide, as disclosed in further detail in the Examples below.
  • BLAST and FastA sequence alignment computer programs Applicants found that various portions of the PR0228 polypeptide have significant homology with the EMR1 protein.
  • Applicants have also found that the DNA encoding the PR0228 polypeptide has significant homology with latrophilin, macrophage-restricted cell surface glycoprotein, B0457.1 and leucocyte antigen CD97 precursor.
  • PR0228 polypeptide disclosed in the present application is a newly identified member of the seven transmembrane superfamily and possesses characteristics and functional properties typical of this family.
  • PR0228 is a new member of the subgroup within this family to which CD97 and EMR1 belong.
  • the present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0533.
  • Applicants have identified and isolated cDNA encoding a PR0533 polypeptide, as disclosed in further detail in the Examples below.
  • BLAST-2 and FastA sequence alignment computer programs Applicants found that a full-length native sequence PR0533 (shown in Figure 22 and SEQ ID NO:59) has a Blast score of 509 and 53 % amino acid sequence identity with fibroblast growth factor (FGF). Accordingly, it is presently believed that PR0533 disclosed in the present application is a newly identified member of the fibroblast growth factor family and may possess activity typical of such polypeptides.
  • FGF fibroblast growth factor
  • the present invention provides newly identified and isolated nucleotide sequences encodingpolypeptides referred to in the present application as PR0245.
  • PR0245 nucleotide sequences encodingpolypeptides referred to in the present application as PR0245.
  • Applicants have identified and isolated cDNA encoding a PR0245 polypeptide, as disclosed in further detail in the Examples below.
  • BLAST and FastA sequence alignment computer programs Applicants found that a portion of the amino acid sequence of the PR0245 polypeptide has 60% amino acid identity with the human c-myb protein. Accordingly, it is presently believed that the PR0245 polypeptide disclosed in the present application may be a newly identified member of the transmembrane protein tyrosine kinase family.
  • the present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PRO220, PR0221 and PR0227.
  • PRO220 has identified and isolated cDNAs encoding a PRO220, PR0221 and PR0227 polypeptide, respectively, as disclosed in further detail in the Examples below.
  • PRO220 has amino acid identity with the amino acid sequence of a leucine rich protein wherein the identity is 87% .
  • PRO220 additionally has amino acid identity with the neuronal leucine rich protein wherein the identity is 55 % .
  • the neuronal leucine rich protein is further described in Taguchi, et al, Mol. Brain Res.. 35:31-40 (1996).
  • PR0221 has amino acid identity with the SLIT protein precursor, wherein different portions of these two proteins have the respective percent identities of 39% , 38% , 34%, 31 % , and 30% .
  • PR0227 has amino acid identity with the amino acid sequence of platelet glycoprotein V precursor. The same results were obtained for human glycoprotein V. Different portions of these two proteins show the following percent identities of 30%, 28% , 28% , 31 % , 35%, 39% and 27% .
  • PRO220, PR0221 and PR0227 polypeptides disclosed in the present application are newly identified members of the leucine rich repeat protein superfamily and that each possesses protein-protein binding capabilities typical of the leucine rich repeat protein superfamily. It is also believed that they have capabilities similar to those of SLIT, the leucine rich repeat protein and human glycoprotein V.
  • the present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0258.
  • PR0258 polypeptides referred to in the present application as PR0258.
  • Applicants have identified and isolated cDNA encoding a PR0258 polypeptide, as disclosed in further detail in the Examples below.
  • BLAST and FastA sequence alignment computer programs Applicants found that various portions of the PR0258 polypeptide have significant homology with the CRTAM and poliovirus receptors. Accordingly, it is presently believed that PR0258 polypeptide disclosed in the present application is a newly identified member of the Ig superfamily and possesses virus receptor capabilities or regulates immune function as typical of this family. 13.
  • PRQ266 Polypeptides are newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0258.
  • the present invention provides newly identified and isolated nucleotide sequences encodingpolypeptides referred to in the present application as PR0266.
  • PR0266 nucleotide sequences encodingpolypeptides referred to in the present application as PR0266.
  • Applicants have identified and isolated cDNA encoding a PR0266 polypeptide, as disclosed in further detail in the Examples below.
  • BLAST and FastA sequence alignment computer programs Applicants found that various portions of the PR0266 polypeptide have significant homology with the SLIT protein from Drosophilia. Accordingly, it is presently believed that PR0266 polypeptide disclosed in the present application is a newly identified member of the leucine rich repeat family and possesses ligand-ligand binding activity and neuronal development typical of this family.
  • SLIT has been shown to be useful in the study and treatment of Alzheimer's disease, supra, and thus, PR0266 may have involvement in the study and cure of this disease.
  • the present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0269.
  • PR0269 polypeptides referred to in the present application as PR0269.
  • Applicants have identified and isolated cDNA encoding a PR0269 polypeptide, as disclosed in further detail in the Examples below.
  • BLAST Altschul et al.
  • FAST Altschul et al.
  • sequence alignment computer programs Applicants found that the amino acid sequence encoded by nucleotides 314 to 1783 of the full-length native sequence PR0269 (shown in Figure 35 and SEQ ID NO:95) has significanthomology to human urinary thrombomodulin and various thrombomodulin analogues respectively, to which it was aligned. Accordingly, it is presently believed that PR0269 polypeptide disclosed in the present application is a newly identified member of the thrombomodulin family.
  • the present invention provides newly identified and isolated nucleotide sequences encodingpolypeptides referred to in the present application as PR0287.
  • PR0287 has identified and isolated cDNA encoding a PR0287 polypeptide, as disclosed in further detail in the Examples below.
  • BLAST and FastA sequence alignment computer programs Applicants found that various portions of the PR0287 polypeptide have significant homology with the type 1 procollagen C-proteinase enhancer protein precursor and type 1 procollagen C-proteinase enhancer protein. Accordingly, it is presently believed that PR0287 polypeptide disclosed in the present application is a newly identified member of the C-proteinase enhancer protein family.
  • the present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0214.
  • Applicants have identified and isolated cDNA encoding a PR0214 polypeptide, as disclosed in further detail in the Examples below.
  • BLAST and FastA sequence alignment computer programs Applicants found that a full-length native sequence PR0214 polypeptide (shown in Figure 40 and SEQ ID NO: 109) has 49% amino acid sequence identity with HT protein, a known member of the EGF-family.
  • the comparison resulted in a BLAST score of 920, with 150 matching nucleotides.
  • the PR0214 polypeptide disclosed in the present application is a newly identified member of the family comprising EGF domains and may possess activities or properties typical of the EGF-domain containing family.
  • the present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0317.
  • cDNA encoding a PR0317 polypeptide has been identified and isolated, as disclosed in further detail in the Examples below.
  • BLAST TM and FastATM sequence alignment computer programs it was found that a full-length native-sequence PR0317 (shown in Figure 42 and SEQ ID NO: 114) has 92% amino acid sequence identity with EBAF-1. Further, it is closely aligned with many other members of the TGF- superfamily.
  • PR0317 disclosed in the present application is a newly identified member of the TGF- superfamily and may possess properties that are therapeutically useful in conditions of uterine bleeding, etc.
  • PR0317 may be useful in diagnosing or treating abnormal bleeding involved in gynecological diseases, for example, to avoid or lessen the need for a hysterectomy.
  • PR0317 may also be useful as an agent that affects angiogenesis in general, so PR0317 may be useful in anti-tumor indications, or conversely, in treating coronary ischemic conditions.
  • PR0317 has shown up in several tissues as well, but it does look to have a greater concentration in uterus. Hence, PR0317 may have a broader use by the body than EBAF-1. It is contemplated that, at least for some indications, PR0317 may have opposite effects from EBAF-1.
  • the present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PRO301.
  • Applicants have identified and isolated cDNA encoding a PRO301 polypeptide, as disclosed in further detail in the Examples below.
  • BLAST and FastA sequence alignment computer programs Applicants found that a full-length native sequence PRO301 (shown in Figure 44 and SEQ ID NO: 119) has a Blast score of 246 corresponding to 30% amino acid sequence identity with human A33 antigen precursor.
  • PRO301 disclosed in the present application is a newly identified member of the A33 antigen protein family and may be expressed in human neoplastic diseases such as colorectal cancer.
  • the present invention provides newly identifiedand isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0224.
  • Applicants have identified and isolated cDNA encoding a PR0224 polypeptide, as disclosed in further detail in the Examples below.
  • BLAST and FastA sequence alignment computer programs Applicants found that full-length native PR0224 ( Figure 46, SEQ ID NO: 127) has amino acid identity with apolipoprotein E receptor 2906 from homo sapiens .
  • the alignments of different portions of these two polypeptides show amino acid identities of 37 % , 36 % , 30% , 44% , 44% and 28% respectively.
  • Full-length native PR0224 (Figure 46, SEQ ID NO: 127) also has amino acid identity with very low-density lipoprotein receptor precursor from gall. The alignments of different portions of these two polypeptides show amino acid identities of 38%, 37%, 42%, 33%, and 37% respectively. Additionally, full-length native PR0224 ( Figure 46, SEQ ID NO: 127) has amino acid identity with the chicken oocyte receptor P95 from Gallus gallus. The alignments of different portions of these two polypeptides show amino acid identities of 38% , 37%, 42%, 33% , and 37% respectively. Moreover, full-length native PR0224 (Figure 46, SEQ ID NO: 127) has amino acid identity with very low density lipoprotein receptor short form precursor from humans.
  • the present invention provides newly identifiedand isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0222.
  • PR0222 has identified and isolated cDNA encoding a PR0222 polypeptide, as disclosed in further detail in the Examples below.
  • BLAST and FastA sequence alignment computer programs Applicants found that a sequence encoding full-length native sequence PR0222 (shown in Figure 48 and SEQ ID NO: 132) has 25-26% amino acid identity with mouse complement factor h precursor, has 27-29% amino acid identity with complement receptor, has 25-47% amino acid identity with mouse complement C3b receptor type 2 long form precursor, has 40% amino acid identity with human hypothetical protein kiaa0247.
  • PR0222 polypeptide disclosed in the present application is a newly identified member of the complement receptor family and possesses activity typical of the complement receptor family.
  • the present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0234.
  • Applicants have identified and isolated cDNA encoding a PR0234 polypeptide, as disclosed in further detail in the Examples below.
  • BLAST FastA- format sequence alignment computer programs
  • Applicants found that a cDNA sequence encoding full-length native sequence PR0234 has 31 % identity and Blast score of 134 with E-selectin precursor. Accordingly, it is presently believed that the PR0234 polypeptides disclosed in the present application are newly identified members of the lectin/selectin family and possess activity typical of the lectin/selectin family. 22. Full-length PRQ231 Polypeptides
  • the present invention provides newly identified and isolated nucleotide sequences encodingpolypeptides referred to in the present application as PR0231.
  • Applicants have identified and isolated cDNA encoding a PR0231 polypeptide, as disclosed in further detail in the Examples below.
  • BLAST and FastA sequence alignment computer programs Applicants found that the full-length native sequence PR0231 polypeptide (shown in Figure 52 and SEQ ID NO: 142) has 30 % and 31 % amino acid identity with human and rat prostatic acid phosphatase precursor proteins, respectively. Accordingly, it is presently believed that the PR0231 polypeptide disclosed in the present application may be a newly identified member of the acid phosphatase protein family.
  • the present invention provides newly identified and isolatednucleotidesequences encoding polypeptides referred to in the present application as PR0229.
  • PR0229 polypeptides referred to in the present application as PR0229.
  • Applicants have identified and isolated cDNA encoding a PR0229 polypeptide, as disclosed in further detail in the Examples below.
  • BLAST and FastA sequence alignment computer programs Applicants found that various portions of the PR0229 polypeptide have significant homology with antigen wcl . l, M130 antigen, T cell surface glycoprotein CD6 and CD6. It also is related to Sp-alpha.
  • PR0229 polypeptide disclosed in the present application is a newly identified member of the family containing scavenger receptor homology, a sequence motif found in a number of proteins involved in immune function and thus possesses immune function and /or segments which resist degradation, typical of this family.
  • the present invention provides newly identified and isolated nucleotide sequences encodingpolypeptides referred to in the present application as PR0238.
  • PR0238 has identified and isolated cDNA encoding a PR0238 polypeptide, as disclosed in further detail in the Examples below.
  • BLAST and FastA sequence alignment computer programs Applicants found that various portions of the PR0238 polypeptide have significant homology with reductases, including oxidoreductase and fatty acyl-CoA reductase. Accordingly, it is presently believed that PR0238 polypeptide disclosed in the present application is a newly identified member of the reductase family and possesses reducing activity typical of the reductase family.
  • the present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0233.
  • PR0233 polypeptides referred to in the present application as PR0233.
  • Applicants have identified and isolated cDNA encoding a PR0233 polypeptide, as disclosed in further detail in the Examples below.
  • BLAST and FastA sequence alignment computer programs Applicants found that various portions of the PR0233 polypeptide have significant homology with the reductase protein.
  • the DNA encoding the PR0233 polypeptide has significant homology with proteins from Caenorhabditis elegans. Accordingly, it is presently believed that PR0233 polypeptide disclosed in the present application is a newly identified member of the reductase family and possesses the ability to effect the redox state of the cell typical of the reductase family.
  • the present invention provides newly identified and isolated nucleotide sequences encodingpolypeptides referred to in the present application as PR0223.
  • PR0223 has identified and isolated cDNA encoding a PR0223 polypeptide, as disclosed in further detail in the Examples below.
  • BLAST and FastA sequence alignment computer programs Applicants found that the PR0223 polypeptide has significant homology with various serine carboxypeptidase polypeptides. Accordingly, it is presently believed that PR0223 polypeptide disclosed in the present application is a newly identified serine carboxypeptidase.
  • the present invention provides newly identified and isolatednucleotidesequences encoding polypeptides referred to in the present application as PR0235.
  • PR0235 polypeptides referred to in the present application as PR0235.
  • Applicants have identified and isolated cDNA encoding a PR0235 polypeptide, as disclosed in further detail in the Examples below.
  • BLAST and FastA sequence alignment computer programs Applicants found that various portions of the PR0235 polypeptide have significant homology with the various plexin proteins. Accordingly, it is presently believed that PR0235 polypeptide disclosed in the present application is a newly identified member of the plexin family and possesses cell adhesion properties typical of the plexin family.
  • PR0236 and PR0262 Full-length PRQ236 and PRQ262 Polypeptides
  • the present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0236 and PR0262.
  • Applicants have identified and isolated cDNA encoding PR0236 and PR0262 polypeptides, as disclosed in further detail in the Examples below.
  • BLAST and FastA sequence alignment computer programs Applicants found that various portions of the PR0236 and PR0262 polypeptides have significant homology with various ⁇ -galactosidase and ⁇ - galactosidase precursor polypeptides. Accordingly, it is presently believed that the PR0236 and PR0262 polypeptides disclosed in the present application are newly identified ⁇ -galactosidase homologs.
  • the present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0239.
  • Applicants have identified and isolated cDNA encoding a PR0239 polypeptide, as disclosed in further detail in the Examples below.
  • BLAST and FastA sequence alignment computer programs Applicants found that various portions of the PR0239 polypeptide have significant homology with densin proteins. Accordingly, it is presently believed that PR0239 polypeptide disclosed in the present application is a newly identified member of the densin family and possesses cell adhesion and the ability to effect synaptic processes as is typical of the densin family. 30. Full-length PRQ257 Polypeptides
  • the present invention provides newly identified and isolated nucleotide sequences encodingpolypeptides referred to in the present application as PR0257.
  • PR0257 has identified and isolated cDNA encoding a PR0257 polypeptide, as disclosed in further detail in the Examples below.
  • BLAST and FastA sequence alignment computer programs Applicants found that various portions of the PR0257 polypeptide have significant homology with the ebnerin precursor and ebnerin protein. Accordingly, it is presently believed that PR0257 polypeptide disclosed in the present application is a newly identified protein member which is related to the ebnerin protein.
  • PRO260 Polypeptides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PRO260.
  • Applicants have identified and isolated cDNA encoding a PRO260 polypeptide, as disclosed in further detail in the Examples below.
  • programs such as BLAST and FastA sequence alignment computer programs Applicants found that various portions of the PRO260 polypeptide have significant homology with the alpha-1-fucosidase precursor. Accordingly, it is presently believed that PRO260 polypeptide disclosed in the present application is a newly identified member of the fucosidase family and possesses enzymatic activity related to fucose residues typical of the fucosidase family.
  • PR0263 Full-length PRQ263 Polypeptides
  • the present invention provides newly identified and isolated nucleotide sequences encodingpolypeptides referred to in the present application as PR0263.
  • Applicants have identified and isolated cDNA encoding a PR0263 polypeptide, as disclosed in further detail in the Examples below.
  • BLAST and FastA sequence alignment computer programs Applicants found that various portions of the PR0263 polypeptide have significant homology with the CD44 antigen and related proteins.
  • PR0263 polypeptide disclosed in the present application is a newly identified member of the CD44 antigen family and possesses at least one of the properties associated with these antigens, i.e., cancer and HIV marker, cell-cell or cell-matrix interactions, regulating cell traffic, lymph node homing, transmission of growth signals, and presentation of chemokines and growth facors to traveling cells.
  • the present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PRO270.
  • Applicants have identified and isolated cDNA encoding a PRO270 polypeptide, as disclosed in further detail in the Examples below.
  • BLAST BLAST, FastA and sequence alignment computer programs
  • Applicants found that that various portions of the PRO270 polypeptide have significant homology with various thioredoxin proteins. Accordingly, it is presently believed that PRO270 polypeptide disclosed in the present application is a newly identified member of the thioredoxin family and possesses the ability to effect reduction-oxidation (redox) state typical of the thioredoxin family.
  • redox reduction-oxidation
  • the present invention provides newly identified and isolated nucleotide sequences encodingpolypeptides referred to in the present application as PR0271.
  • PR0271 nucleotide sequences encodingpolypeptides referred to in the present application as PR0271.
  • Applicants have identified and isolated cDNA encoding a PR0271 polypeptide, as disclosed in further detail in the Examples below.
  • BLAST and FastA sequence alignment computer programs Applicants found that the PR0271 polypeptide has significant homology with various link proteins and precursors thereof. Accordingly, it is presently believed that PR0271 polypeptide disclosed in the present application is a newly identified link protein homolog.
  • the present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0272.
  • PR0272 polypeptides referred to in the present application as PR0272.
  • Applicants have identified and isolated cDNA encoding a PR0272 polypeptide, as disclosed in further detail in the Examples below.
  • BLAST and FastA sequence alignment computer programs Applicants found that various portions of the PR0272 polypeptide have significant homology with the human reticulocalbin protein and its precursors.
  • the DNA encoding the PR0272 polypeptide has significant homology with the mouse reticulocalbin precursor protein. Accordingly, it is presently believed that PR0272 polypeptide disclosed in the present application is a newly identified member of the reticulocalbin family and possesses the ability to bind calcium typical of the reticulocalbin family.
  • PR0294 Full-length PRQ294 Polypeptides
  • the present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0294.
  • Applicants have identified and isolated cDNA encoding a PR0294 polypeptide, as disclosed in further detail in the Examples below.
  • BLAST and FastA sequence alignment computer programs Applicants found that various portions of the PR0294 polypeptide have significant homology with the various portions of a number of collagen proteins. Accordingly, it is presently believed that PR0294 polypeptide disclosed in the present application is a newly identified member of the collagen family.
  • the present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0295.
  • Applicants have identified and isolated cDNA encoding a PR0295 polypeptide, as disclosed in further detail in the Examples below.
  • BLAST and FastA sequence alignment computer programs Applicants found that various portions of the PR0295 polypeptide have significant homology with integrin proteins. Accordingly, it is presently believed that PR0295 polypeptide disclosed in the present application is a newly identified member of the integrin family and possesses cell adhesion typical of the integrin family. 38. Full-length PRQ293 Polypeptides
  • the present invention provides newly identified and isolated nucleotide sequences encodingpolypeptides referred to in the present application as PR0293.
  • PR0293 nucleotide sequences encodingpolypeptides referred to in the present application as PR0293.
  • Applicants have identified and isolated cDNA encoding a PR0293 polypeptide, as disclosed in further detail in the Examples below.
  • BLAST and FastA sequence alignment computer programs Applicants found that portions of the PR0293 polypeptide have significant homology with the neuronal leucine rich repeat proteins 1 and 2, (NLRR-1 and NLRR-2), particularly NLRR-2.
  • PR0293 polypeptide disclosed in the present application is a newly identified member of the neuronal leucine rich repeat protein family and possesses ligand-ligand binding activity typical of the NRLL protein family.
  • the present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0247.
  • PR0247 polypeptides referred to in the present application as PR0247.
  • Applicants have identified and isolated cDNA encoding a PR0247 polypeptide, as disclosed in further detail in the Examples below.
  • BLAST and FastA sequence alignment computer programs Applicants found that various portions of the PR0247 polypeptide have significant homology with densin.
  • the DNA encoding the PR0247 polypeptide has significant homology with a number of other proteins, including KIAA0231. Accordingly, it is presently believed that PR0247 polypeptide disclosed in the present application is a newly identified member of the leucine rich repeat family and possesses ligand binding abilities typical of this family.
  • the present invention provides newly identifiedand isolated nucleotide sequences encoding polypeptides referred to in the present application as PRO302, PRO303, PRO304, PRO307 and PR0343.
  • PRO302, PRO303, PRO304, PRO307 and PR0343 polypeptides referred to in the present application as PRO302, PRO303, PRO304, PRO307 and PR0343.
  • Applicants have identified and isolated cDNA encoding PRO302, PRO303, PRO304, PRO307 and PR0343 polypeptides, as disclosed in further detail in the Examples below.
  • BLAST and FastA sequence alignment computer programs Applicants found that various portions of the PRO302, PRO303, PRO304, PRO307 and PR0343 polypeptides have significant homology with various protease proteins. Accordingly, it is presently believed that the PRO302, PRO303, PRO304, PRO307 and PR0343 polypeptides disclosed in the present application are newly identified protease proteins.
  • the present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0328.
  • PR0328 polypeptides referred to in the present application as PR0328.
  • Applicants have identified and isolated cDNA encoding a PR0328 polypeptide, as disclosed in further detail in the Examples below.
  • GLIP human glioblastoma protein
  • CRISP cysteine rich secretory protein
  • PR0328 polypeptide disclosed in the present application is a newly identified member of the GLIP or CRISP families and possesses transcriptional regulatory activity typical of the GLIP or CRISP families.
  • PRQ331 and PRQ326 Polypeptides The present invention provides newly identified and isolated nucleotide sequences encodingpolypeptides referred to in the present application as PR0335, PR0331 or PR0326.
  • PR0335, PR0331 or PR0326 Applicants have identified and isolated cDNA encoding a PR0335, PR0331 or PR0326 polypeptide, as disclosed in further detail in the Examples below.
  • BLAST and FastA sequence alignment computer programs Applicants found that various portions of the PR0335, PR0331 or PR0326 polypeptide have significant homology with LIG-1, ALS and in the case of PR0331, additionally, decorin.
  • PR0335, PR0331 and PR0326 polypeptides disclosed in the present application are newly identified members of the leucine rich repeat superfamily, and particularly, are related to LIG-1 and possess the biological functions of this family as discussed and referenced herein.
  • the present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0332.
  • Applicants have identified and isolated cDNA encoding PR0332 polypeptides, as disclosed in further detail in the Examples below.
  • a full-length native sequence PR0332 (shown in Figure 108 and SEQ ID NO:310) has about 30-40% amino acid sequence identity with a series of known proteoglycan sequences, including, for example, fibromodulin and fibromodulin precursor sequences of various species (FMOD_BOVIN, FMOD_CHICK, FMOD_RAT, FMOD_MOUSE, FMOD_HUMAN, P_R36773), osteomodulin sequences (AB000114 _1 , AB007848 ), decorin sequences (CFU83141 , OCU03394 , P R42266, P.R42267, P R42260, P R89439), keratan sulfate proteoglycans (BTU48360 .
  • fibromodulin and fibromodulin precursor sequences of various species FMOD_BOVIN, FMOD_CHICK, FMOD_RAT, FMOD_MOUSE, FMOD_HUMAN, P_R36773
  • osteomodulin sequences AB000114
  • PR0332 disclosed in the present application is a new proteoglycan-type molecule, and may play a role in regulating extracellular matrix, cartilage, and/or bone function.
  • the present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0334.
  • PR0334 polypeptides referred to in the present application as PR0334.
  • Applicants have identified and isolated cDNA encoding a PR0334 polypeptide, as disclosed in further detail in the Examples below.
  • BLAST and FastA sequence alignment computer programs Applicants found that various portions of the PR0334 polypeptide have significant homology with fibulin and fibrillin. Accordingly, it is presently believed that PR0334 polypeptide disclosed in the present application is a newly identified member of the epidermal growth factor family and possesses properties and activities typical of this family. 45. Full-length PRQ346 Polypeptides
  • the present invention provides newly identified and isolated nucleotide sequences encodingpolypeptides referred to in the present application as PR0346.
  • PR0346 has identified and isolated cDNA encoding a PR0346 polypeptide, as disclosed in further detail in the Examples below.
  • BLAST and FastA sequence alignment computer programs Applicants found that a full-length native sequence PR0346 (shown in Figure 112 and SEQ ID NO: 320) has 28 % amino acid sequence identity with carcinoembryonic antigen. Accordingly, it is presently believed that PR0346 disclosed in the present application is a newly identified member of the carcinoembryonic protein family and may be expressed in association with neoplastic tissue disorders.
  • the present invention provides newly identified and isolatednucleotidesequences encoding polypeptides referred to in the present application as PR0268.
  • PR0268 polypeptides referred to in the present application as PR0268.
  • Applicants have identified and isolated cDNA encoding a PR0268 polypeptide, as disclosed in further detail in the Examples below.
  • BLAST and FastA sequence alignment computer programs Applicants found that portions of the PR0268 polypeptide have significant homology with the various protein disulfide isomerase proteins . Accordingly , it is presently believed that PR0268 polypeptide disclosed in the present application is a homolog of the protein disulfide isomerase p5 protein.
  • PRO330 Polypeptides The present invention provides newly identified and isolated nucleotide sequences encodingpolypeptides referred to in the present application as PRO330.
  • Applicants have identified and isolated cDNA encoding a PRO330 polypeptide, as disclosed in further detail in the Examples below.
  • BLAST and FastA sequence alignment computer programs Applicants found that various portions of the PRO330 polypeptide have significant homology with the murine prolyl 4-hydroxylase alpha-II subunit protein. Accordingly, it is presently believed that PRO330 polypeptide disclosed in the present application is a novel prolyl 4-hydroxylase subunit polypeptide.
  • the present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0339 and PRO310.
  • PR0339 and PRO310 have identified and isolated cDNA encoding a PR0339 polypeptide, as disclosed in further detail in the Examples below.
  • Applicants have also identified and isolated cDNA encoding a PRO310 polypeptide, as disclosed in further detail in the Examples below.
  • BLAST and FastA sequence alignment computer programs Applicants found that various portions of the PR0339 and PRO310 polypeptides have significant homology with small secreted proteins from C. elegans and are distantly related to fringe.
  • PR0339 also shows homology to collagen-like polymers.
  • PR0244 Full Length PRQ244 Polypeptides
  • the present invention provides newly identified and isolated nucleotide sequences encoding C-type lectins referred to in the present application as PR0244.
  • applicants have identified and isolated cDNA encoding PR0244 polypeptides, as disclosed in further detail in the Examples below.
  • BLAST and FastA sequence alignment computer programs Applicants found that a full-length native sequence PR0244 (shown in Figure 122 and SEQ ID NO: 377) has 43 % amino acid sequence identity with the hepatic lectin gallus gallus (LECH-CHICK), and 42% amino acid sequence identity with an HIV gpl20 binding C-type lectin (A46274).
  • PR0244 disclosed in the present application is a newly identified member of the C-lectin superfamily and may play a role in immune function, apoptosis, or in the pathogenesis of atherosclerosis.
  • PR0244 may be useful in identifying tumor-associated epitopes.
  • PRO variants can be prepared.
  • PRO variants can be prepared by introducing appropriate nucleotide changes into the PRO DNA, and/or by synthesis of the desired PRO polypeptide.
  • amino acid changes may alter post-translational processes of the PRO, such as changing the number or position of glycosylation sites or altering the membrane anchoring characteristics.
  • Variations in the native full-length sequence PRO or in various domains of the PRO 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 PRO that results in a change in the amino acid sequence of the PRO as compared with the native sequence PRO.
  • the variation is by substitution of at least one amino acid with any other amino acid in one or more of the domains of the PRO.
  • Guidance in determining which amino acid residue may be inserted, substituted or deleted without adversely affecting the desired activity may be found by comparing the sequence of the PRO with that of homologous known protein molecules and minimizing the number of amino acid sequence changes made in regions of high homology.
  • Amino acid substitutions can be the result of replacing one amino acid with another amino acid having similar structural and/or chemical properties, such as the replacement of a leucine with a serine, i.e. , conservative amino acid replacements.
  • Insertions or deletions may optionally be in the range of about 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 exhibited by the full-length or mature native sequence.
  • PRO polypeptide fragments are provided herein. Such fragments may be truncated at the N-terminus or C-terminus, or may lack internal residues, for example, when compared with a full length native protein. Certain fragments lack amino acid residues that are not essential for a desired biological activity of the PRO polypeptide.
  • PRO fragments may be prepared by any of a number of conventional techniques. Desired peptide fragments may be chemically synthesized.
  • An alternative approach involves generating PRO fragments by enzymatic digestion, e.g. , by treating the protein with an enzyme known to cleave proteins at sites defined by particular amino acid residues, or by digesting the DNA with suitable restriction enzymes and isolating the desired fragment.
  • Yet another suitable technique involves isolating and amplifying a DNA fragment encoding a desired polypeptide fragment, by polymerase chain reaction (PCR). Oligonucleotides that define the desired termini of the DNA fragment are employed at the 5' and 3' primers in the PCR.
  • PRO polypeptide fragments share at least one biological and/or immunological activity with the native PRO polypeptide disclosed herein.
  • conservative substitutions of interest are shown in Table 1 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 1 , or as further described below in reference to amino acid classes, are introduced and the products screened.
  • Substantial modifications in functionor immunologicalidentity of the PRO polypeptide are accomplished 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:
  • hydrophobic norleucine, met, ala, val, leu, ile
  • neutral hydrophilic cys, ser, thr
  • Such substituted residues also may 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 art such as oligonucleotide-mediated (site- directed) mutagenesis, alanine scanning, and PCR mutagenesis.
  • Site -directed mutagenesis [Carter et al. , Nucl. Acids Res., 13:4331 (1986); Zoller et al., Nucl. Acids Res., 10:6487 (1987)]
  • cassette mutagenesis [Wells et al., Gene, 34:315 (1985)]
  • restriction selection mutagenesis [Wells et al. , Philos. Trans. R. Soc. London Ser A. 317:415 (1986)] or other known techniques can be performed on the cloned DNA to produce the PRO variant DNA.
  • Scanning amino acid analysis can also be employed to identify one or more amino acids along a contiguous sequence.
  • preferred scanning amino acids are relatively small, neutral 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 [Cunningham and Wells, Science. 244: 1081-1085 (1989)].
  • Alanine 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 Proteins. (W.H. Freeman & Co. , N.Y.); Chothia, J. Mol. Biol.. 150: 1 (1976)] . If alanine substitution does not yield adequate amounts of variant, an isoteric amino acid can be used.
  • Covalent modifications of PRO are included within the scope of this invention.
  • One type of covalent modification includes reacting targeted amino acid residues of a PRO polypeptide with an organic derivatizing agent that is capable of reacting with selected side chains or the N- or C- terminal residues of the PRO.
  • Derivatization with bifunctional agents is useful, for instance, for crosslinking PRO to a water-insoluble support matrix or surface for use in the method for purifying anti-PRO antibodies, and vice-versa.
  • crosslinking agents include, e.g., l , l-bis(diazoacetyl)-2-phenylefhane, glutaraldehyde, N-hydroxysuccinimide esters, for 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.
  • Another type of covalent modification of the PRO polypeptide included within the scope of this invention comprises altering the native glycosylation pattern of the polypeptide.
  • "Altering the native glycosylation pattern” is intended for purposes herein to mean deleting one or more carbohydrate moieties found in native sequence PRO (either by removing the underlying glycosylation site or by deleting the glycosylation by chemical and/or enzymatic means), and/or adding one or more glycosylation sites that are not present in the native sequence PRO.
  • the phrase includes qualitative changes in the glycosylation of the native proteins, involving a change in the nature and proportions of the various carbohydrate moieties present.
  • Addition of glycosylation sites to 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 threonine residues to the native sequence PRO (for O-linked glycosylation sites).
  • the PRO amino acid sequence may optionally be altered through changes at the DNA level, particularly by mutating the DNA encoding 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 is by chemical or enzymatic coupling of glycosides to the polypeptide. Such methods are described in the art, e.g. , in WO 87/05330 published 11 September 1987, and in Aplin and Wriston, CRC Crit. Rev. Biochem.. pp. 259- 306 (1981).
  • 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. Biophys.. 259:52 (1987) and by Edge et al. , Anal. Biochem.. 118:131 (1981).
  • Enzymatic cleavage of carbohydrate moieties on polypeptides can be achieved by the use of a variety of endo- and exo-glycosidases as described by Thotakura et al. , Meth.
  • PRO polypeptide comprises linking the PRO polypeptide to one of a variety of nonproteinaceous polymers, e.g., polyethylene glycol (PEG), polypropylene glycol, or poly oxy alky lenes, 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 or4,179,337.
  • the PRO of the present invention may also be modified in a way to form a chimeric molecule comprising PRO fused to another, heterologous polypeptide or amino acid sequence.
  • such a chimeric molecule comprises a fusion of the PRO 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. The presence of such epitope-tagged forms of the PRO can be detected using an antibody against the tag polypeptide. Also, provision of the epitope tag enables the PRO to be readily purified by affinity purification using an anti-tag antibody or another type of affinity matrix that binds to the epitope tag.
  • tag polypeptides and their respective antibodies are well known in the art.
  • poly-histidine poly-his
  • poly-histidine-glycine poly-his-glycine tags
  • flu HA tag polypeptide and its antibody 12CA5 [Field et al., Mol. Cell. Biol., 8:2159-2165 (1988)]
  • c-myc tag and the 8F9, 3C7, 6E10, G4, B7 and 9E10 antibodies thereto [Evan et al. , Molecular and Cellular Biology. 5:3610-3616 (1985)]
  • Herpes Simplex virus glycoprotein D (gD) tag and its antibody [Paborsky et al. , Protein Engineering. 3(6):547- 553 (1990)].
  • tag polypeptides include the Flag-peptide [Hopp et al. , BioTechnology. 6: 1204-1210 (1988)]; the KT3 epitope peptide [Martin et al., Science, 255: 192-194 (1992)]; an ⁇ -tubulin epitope peptide [Skinner et al. , J. Biol. Chem. , 266: 15163-15166 (1991)]; and the T7 gene 10 protein peptide tag [Lutz- Freyermuth et al., Proc. Natl. Acad. Sci. USA, 87:6393-6397 (1990)].
  • the chimeric molecule may comprise a fusion of the PRO with an immunoglobulin or a particular region of an immunoglobulin.
  • an immunoglobulin also referred to as an "immunoadhesin”
  • a fusion could be to the Fc region of an IgG molecule.
  • the Ig fusions preferably include the substitution of a soluble (transmembrane domain deleted or inactivated) form of a PRO polypeptide in place of at least one variable region within an Ig molecule.
  • the immunoglobulin fusion includes the hinge, CH2 and CH3, or the hinge, CHI , CH2 and CH3 regions of an IgGl molecule.
  • PRO sequence may be produced by direct peptide synthesis using solid-phase techniques [see, e.g. , Stewart et al.. Solid-Phase Peptide Synthesis, W.H. Freeman Co.. San Francisco. CA (1969): Merrifield. J. Am. Chem. Soc , 85:2149-2154 (1963)] .
  • In 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 PRO may be chemically synthesized separately and combined using chemical or enzymatic methods to produce the full-length PRO.
  • DNA encoding PRO may be obtained from a cDNA library prepared from tissue believed to possess the PRO mRNA and to express it at a detectable level. Accordingly, human PRO DNA can be conveniently obtained from a cDNA library prepared from human tissue, such as described in the Examples.
  • the PRO- encoding gene may also be obtained from a genomic library or by known synthetic procedures (e.g., automated nucleic acid synthesis).
  • Probes such as antibodies to the PRO or oligonucleotides of at least about 20-80 bases
  • Screening the cDNA or genomic library with the selected probe may be conducted using standard procedures, such as described in
  • the oligonucleotide sequences selected as probes should be of sufficient length and sufficiently 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 32 P-labeled ATP, biotinylation or enzyme labeling. Hybridization conditions, including moderate stringency and high stringency, 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 using methods known in the art and as described herein.
  • 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 described in Sambrook et al., supra, to detect precursors and processing intermediates of mRNA that may not have been reverse-transcribed into cDNA. 2. Selection and Transformation of Host Cells
  • Host cells are transfected or transformed with expression or cloning vectors described herein for PRO production and cultured in conventional nutrient media modified as appropriate for inducing promoters, selecting transformants, or amplifying the genes encoding the desired sequences.
  • the culture conditions such as media, temperature, pH and the like, can be selected by the skilled artisan without undue experimentation. In general, principles, protocols, and practical techniques for maximizing the productivity of cell cultures can be found in Mammalian Cell Biotechnology: a Practical Approach, M. Butler, ed. (IRL Press, 1991) and Sambrook et al. , supra.
  • Methods of eukaryotic cell transfection and prokaryotic cell transformation are known to the ordinarily skilled artisan, for example, CaCl 2 , CaP0 4 , liposome-mediated and electroporation.
  • transformation is performed using standard techniques appropriate to such cells.
  • the calcium treatment employing calcium chloride, as described in Sambrook et al., supra, or electroporation is generally used for prokaryotes.
  • Infection with Agrobacterium tumefaciens is used for transformation of certain plant cells, as described by Shaw et al. , Gene, 23:315 (1983) and WO 89/05859 published 29 June 1989.
  • 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.
  • polycations e.g., polybrene, polyornithine.
  • 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. coli.
  • Various E. coli strains are publicly available, such as E. coli K12 strain MM294 (ATCC 31,446); E. coli X1776 (ATCC 31 ,537); E. coli strain W3110 (ATCC 27,325) and K5 772 (ATCC 53,635).
  • suitable prokaryotic host cells include Enterobacteriaceae such as Escherichia, e.g., E. coli, Enterobacter , Erwinia, Klebsiella, Proteus, Salmonella, e.g., Salmonella typhimurium, Serratia, e.g., Serratia marcescans, and Shigella, as well as Bacilli such as B. subtilis and B. licheniformis (e.g. , B. licheniformis 41P disclosed in DD 266,710 published 12 April 1989), Pseudomonas such as P. aeruginosa, and Streptomyces . These examples are illustrative rather than limiting.
  • Strain W3110 is one particularly preferred host or parent host because it is a common host strain for recombinant DNA product fermentations. Preferably, the host cell secretes minimal amounts of proteolytic enzymes.
  • strain W3110 may be modified to effect a genetic mutation in the genes encoding proteins endogenous to the host, with examples of such hosts including E. coli W3110 strain 1A2, which has the complete genotype tonA ; E. coli W3110 strain 9E4, which has the complete genotype tonA ptr3; E.
  • coli W3110 strain 27C7 (ATCC 55,244), which has the complete genotype tonA ptr3 phoA E15 (argF-lac)169 degP ompTkan r ;
  • E. coli W3110 strain 37D6 which has the complete genotype tonA ptr3 phoA E15 (argF-lac)169 degP ompT rbs7 ilvG kan r ;
  • E. coli W3110 strain 40B4 which is strain 37D6 with a non-kanamycin resistant degP deletion mutation; and an E. coli strain having mutant periplasmic protease disclosed in U.S. Patent No. 4,946,783 issued 7 August 1990.
  • in vitro methods of cloning e.g. , PCR or other nucleic acid polymerase reactions, are suitable.
  • eukaryotic microbes such as filamentous fungi or yeast are suitable cloning or expression hosts for PRO-encoding vectors.
  • Saccharomyces cerevisiae is a commonly used lower eukaryotic host microorganism.
  • Others include Schizosaccharomycespom.be (Beach and Nurse, Nature. 290: 140 [1981]; EP 139,383 published 2 May 1985); Kluyveromyces hosts (U.S. Patent No. 4,943,529; Fleer et al. , Bio/Technology.
  • Schwanniomyces such as Schwanniomyces occidentalis (EP 394,538 published 31 October 1990); and filamentous fungi such as, e.g., Neurospora, Penicillium, Tolypocladium (WO 91/00357 published 10 January 1991), and Aspergillus hosts such as A. nidulans (Ballance et al. , Biochem. Biophys. Res. Commun.. 112:284-289 [1983]; Tilburn et al. , Gene. 26:205-221 [1983]; Yelton et al., Proc. Natl. Acad. Sci.
  • 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, The Biochemistry of Methylotrophs. 269 (1982).
  • Suitable host cells for the expression of glycosylated PRO are derived from multicellular organisms.
  • invertebrate cells include insect cells such as Drosophila S2 and Spodoptera Sf9, as well as plant cells.
  • useful mammalian host cell lines include Chinese hamster ovary (CHO) and COS cells. More specific examples include 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., 36:59 (1977)); Chinese hamster ovary cells/-DHFR (CHO, Urlaub and Chasin, Proc. Natl. Acad. Sci.
  • mice sertoli cells TM4, Mather, Biol. Reprod.. 23:243-251 (1980)
  • human lung cells W138, ATCC CCL 75
  • human liver cells Hep G2, HB 8065
  • mouse mammary tumor MMT 060562, ATCC CCL51. The selection of the appropriate host cell is deemed to be within the skill in the art.
  • the nucleic acid (e.g., cDNA or genomic DNA) encoding PRO may be inserted into a replicable vector for cloning (amplification of the DNA) or for expression.
  • a replicable vector for cloning (amplification of the DNA) or for expression.
  • the vector may, for example, be in the form of a plasmid, cosmid, viral particle, or phage.
  • the appropriate nucleic acid sequence may be inserted into the vector by a variety of procedures. In general, DNA is inserted into an appropriate restriction endonuclease site(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 enhancer 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 known to the skilled artisan.
  • the PRO may be produced recombinantly not only directly, but also as a fusion polypeptide with a heterologous polypeptide, which may be a signal sequence or other polypeptide having a specific cleavage site at the N-terminus of the mature protein or polypeptide.
  • a heterologous polypeptide which may be a signal sequence or other polypeptide having a specific cleavage site at the N-terminus of the mature protein or polypeptide.
  • the signal sequence may be a component of the vector, or it may be a part of the PRO-encoding DNA that is inserted into the vector.
  • the signal sequence may be a prokaryotic signal sequence selected, for example, from the group of the alkaline phosphatase, penicillinase, lpp, or heat-stable enterotoxin II leaders.
  • the signal sequence may be, e.g., the yeast invertase leader, alpha factor leader (including Saccharomyces and Kluyveromyces -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 90/13646 published 15 November 1990.
  • 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 ⁇ BR322 is suitable for most Gram-negative bacteria, the 2 ⁇ plasmid origin is suitable for yeast, and various viral origins (SV40, polyoma, adenovirus, VSV or BPV) are useful for cloning vectors in mammalian cells.
  • Selection genes will typically contain a selection gene, also termed a selectable marker.
  • Typical selection genes encode proteins that (a) confer resistance to antibiotics or other toxins, e.g. , ampicillin, neomycin, methotrexate, or tetracycline, (b) complement auxotrophic deficiencies, or (c) supply critical nutrients not available from complex media, e.g. , the gene encoding D-alanine racemase for Bacilli.
  • suitable selectable markers for mammalian cells are those that enable the identification of cells competent to take up the PRO-encoding nucleic acid, such as DHFR or thymidine kinase.
  • DHFR DHFR activity
  • yeast plasmid YRp7 yeast plasmid YRp7
  • the trpl gene provides a selection marker for a mutant strain of yeast lacking the ability to grow in tryptophan, for example, ATCC No. 44076 or PEP4-1 [Jones, Genetics. 85: 12 (1977)].
  • Expression and cloning vectors usually contain a promoter operably linked to the PRO-encoding nucleic acid sequence to direct mRNA synthesis. Promoters recognized by a variety of potential host cells are well known. Promoters suitable for use with prokaryotic hosts include the ⁇ -lactamase and lactose promoter systems [Chang et al., Nature, 275:615 (1978); Goeddel et al., Nature, 281:544 (1979)], alkaline phosphatase, a tryptophan (trp) promoter system [Goeddel, Nucleic Acids Res., 8:4057 (1980); EP 36,776], and hybrid promoters such as the tac promoter [deBoer et al. , Proc. Natl. Acad. Sci. USA. 80:21-25 (1983)]. Promoters for use in bacterial systems also will contain a Shine-Dalgarno (S.D.) sequence operably linked to the DNA encoding PRO
  • Suitable promoting sequences for use with yeast hosts include the promoters for 3- phosphoglycerate kinase [Hitzeman et al., J. Biol. Chem.. 255:2073 (1980)] or other glycolytic enzymes [Hess et al., J. Adv. Enzyme Reg.
  • enolase such as enolase, glyceraldehyde-3-phosphate dehydrogenase , hexokinase , py ruvate decarboxy lase , phosphofructokinase , glucose- 6-phosphate isomerase, 3-phosphoglycerate mutase, pyruvate kinase, triosephosphateisomerase,phosphoglucose isomerase, and glucokinase.
  • 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 transcription from vectors in mammalian host cells is controlled, for example, by promoters obtained from the genomes of viruses such as polyoma virus, fowlpox virus (UK 2,211,504 published 5 July 1989), adenovirus (such as Adenovirus 2), bovine papilloma virus, avian sarcoma virus, cytomegalovirus, a retrovirus, hepatitis-B virus and Simian Virus 40 (SV40), from heterologous mammalian promoters, e.g., the actin promoter or an immunoglobulin promoter, and from heat-shock promoters, provided such promoters are compatible with the host cell systems.
  • viruses such as polyoma virus, fowlpox virus (UK 2,211,504 published 5 July 1989), adenovirus (such as Adenovirus 2), bovine papilloma virus, avian sarcoma virus, cytomegalovirus, a retrovirus, he
  • Enhancers are cis-acting elements of DNA, usually about from 10 to 300 bp, that act on a promoter to increase its transcription.
  • Many enhancer sequences are now known from mammalian genes (globin, elastase, albumin, ⁇ -fetoprotein, and insulin).
  • an enhancer from a eukaryotic cell virus. Examples include the SV40 enhancer on the late side of the replication origin (bp 100-270), the cytomegalovirus early promoter enhancer, the polyoma enhancer on the late side of the replication origin, and adenovirus enhancers.
  • the enhancer may be spliced into the vector at a position 5' or 3' to the PRO coding sequence, but is preferably located at a site 5' from the promoter.
  • Expression vectors used in eukaryotic host cells will alsc contain sequences necessary for the termination of transcription and for stabilizing the mRNA. Such sequences are commonly available from the 5' and, occasionally 3' , untranslated regions of eukaryotic or viral DNAs or cDNAs. These regions contain nucleotide segments transcribed as polyadenylated fragments in the untranslated portion of the mRNA encoding PRO.
  • Gene amplification and/or expression may be measured in a sample directly, for example, by conventional Southern blotting, Northern blotting to quantitate the transcription of mRNA [Thomas, Proc. Natl. Acad. Sci. USA, 77:5201-5205 (1980)], dot blotting (DNA analysis), or in situ hybridization, using an appropriately labeled probe, based on the sequences provided herein.
  • 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 may be measured by immunological methods, such as immunohistochemical staining of cells or tissue sections and assay of cell culture or body fluids, to quantitate directly the expression of gene product.
  • Antibodies useful for immunohistochemical staining and/or assay of sample fluids may be either monoclonal or polyclonal, and may be prepared in any mammal. Conveniently, the antibodies may be prepared against a native sequence PRO polypeptide or against a synthetic peptide based on the DNA sequences provided herein or against exogenous sequence fused to PRO DNA and encoding a specific antibody epitope.
  • PRO may be recovered from culture medium or from host cell lysates. If membrane-bound, it can be released from the membrane using a suitable detergent solution (e.g. Triton-X 100) or by enzymatic cleavage. Cells employed in expression of PRO can be disrupted by various physical or chemical means, such as freeze-thaw cycling, sonication, mechanical disruption, or cell lysing agents.
  • a suitable detergent solution e.g. Triton-X 100
  • Cells employed in expression of PRO can be disrupted by various physical or chemical means, such as freeze-thaw cycling, sonication, mechanical disruption, or cell lysing agents.
  • 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 cation-exchange resin such as DEAE; chromatofocusing; SDS-PAGE; ammonium sulfate precipitation; gel filtration using, for example, Sephadex G-75; protein A Sepharose columns to remove contaminants such as IgG; and metal chelating columns to bind epitope-tagged forms of the PRO.
  • Various methods of protein purification may be employed and such methods are known in the art and described for example in Deutscher, Methods in Enzymology. 182 (1990); Scopes, Protein Purification: Principles and Practice. Springer- Verlag, New York (1982).
  • the purification step(s) selected will depend, for example, on the nature of the production process used and the particular PRO produced.
  • PRO Nucleotide sequences (or their complement) encoding PRO 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 nucleic acid will also be useful for the preparation of PRO polypeptides by the recombinant techniques described herein.
  • the full-length native sequence PRO gene, or portions thereof, may be used as hybridization probes for a cDNA library to isolate the full-length PRO cDNA or to isolate still other cDNAs (for instance, those encoding naturally-occurring variants of PRO or PRO from other species) which have a desired sequence identity to the native PRO sequence disclosed herein.
  • the length of the probes will be about 20 to about 50 bases.
  • the hybridization probes may be derived from at least partially novel regions of the full length native nucleotide sequence wherein those regions may be determined without undue experimentation or from genomic sequences including promoters, enhancer elements and introns of native sequence PRO.
  • a screening method will comprise isolating the coding region of the PRO 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 32 P or 35 S, or enzymatic labels such as alkaline phosphatase coupled to the probe via avidin/biotin coupling systems.
  • Labeled probes having a sequence complementary to that of the PRO 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.
  • antisense or sense oligonucleotides comprising a singe-stranded nucleic acid sequence (either RNA or DNA) capable of binding to target PRO mRNA (sense) or PRO DNA (antisense) sequences.
  • Antisense or sense oligonucleotides comprise a fragment of the coding region of PRO DNA. Such a fragment generally comprises at least about 14 nucleotides, preferably from about 14 to 30 nucleotides.
  • Stein and Cohen Cancer Res. 48:2659. 1988
  • van der Krol et al. BioTechniques 6:958. 1988.
  • binding of antisense or sense oligonucleotides to target nucleic acid sequences results in the formation of duplexes that block transcription or translation of the target sequence by one of several means, including enhanced degradation of the duplexes, premature termination of transcription or translation, or by other means.
  • the antisense oligonucleotides thus may be used to block expression of PRO proteins.
  • Antisense or sense oligonucleotides further comprise oligonucleotides having modified sugar-phosphodiester backbones (or other sugar linkages, such as those described in WO 91/06629) and wherein such sugar linkages are resistant to endogenous nucleases.
  • Such oligonucleotides with resistant sugar linkages are stable in vivo (i.e., capable of resisting enzymatic degradation) but retain sequence specificity to be able to bind to target nucleotide sequences.
  • sense or antisense oligonucleotides include those oligonucleotides which are covalently linked to organic moieties, such as those described in WO 90/10048, and other moieties that increases affinity of the oligonucleotide for a target nucleic acid sequence, such as poly-(L-lysine).
  • intercalating agents such as ellipticine, and alkylating agents or metal complexes may be attached to sense or antisense oligonucleotides to modify binding specificities of the antisense or sense oligonucleotide for the target nucleotide sequence.
  • Antisense or sense oligonucleotides may be introduced into a cell containing the target nucleic acid sequence by any gene transfer method, including, for example, CaP0 4 -mediated DNA transfection, electroporation, or by using gene transfer vectors such as Epstein-Barr virus.
  • an antisense or sense oligonucleotide is inserted into a suitable retroviral vector.
  • a cell containing the target nucleic acid sequence is contacted with the recombinant retroviral vector, either in vivo or ex vivo.
  • Suitable retroviral vectors include, but are not limited to, those derived from the murine retrovirus M-MuLV, N2 (a retrovirus derived from M-MuLV), or the double copy vectors designated DCT5A, DCT5B and DCT5C (see WO 90/13641).
  • Sense or antisense oligonucleotides also may be introduced into a cell containing the target nucleotide sequence by formation of a conjugate with a ligand binding molecule, as described in WO 91/04753.
  • Suitable ligand binding molecules include, but are not limited to, cell surface receptors, growth factors, other cytokines, or other ligands that bind to cell surface receptors.
  • conjugation of the ligand binding molecule does not substantially interfere with the ability of the ligand binding molecule to bind to its corresponding molecule or receptor, or block entry of the sense or antisense oligonucleotide or its conjugated version into the cell.
  • a sense or an antisense oligonucleotide may be introduced into a cell containing the target nucleic acid sequence by formation of an oligonucleotide-lipid complex, as described in WO 90/10448.
  • the sense or antisense oligonucleotide-lipid complex is preferably dissociated within the cell by an endogenous lipase .
  • Antisense RNA or DNA molecules are generally at least about 5 bases in length, about 10 bases in length, about 15 bases in length, about 20 bases in length, about 25 bases in length, about 30 bases in length, about 35 bases in length, about 40 bases in length, about 45 bases in length, about 50 bases in length, about 55 bases in length, about 60 bases in length, about 65 bases in length, about 70 bases in length, about 75 bases in length, about 80 bases in length, about 85 bases in length, about 90 bases in length, about 95 bases in length, about 100 bases in length, or more.
  • the probes may also be employed in PCR techniques to generate a pool of sequences for identification of closely related PRO coding sequences.
  • Nucleotide sequences encoding a PRO can also be used to construct hybridization probes for mapping the gene which encodes that PRO 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.
  • the PRO can be used in assays to identify the other proteins or molecules involved in the binding interaction. By such methods, inhibitors of the receptor/ligand binding interaction can be identified. Proteins involved in such binding interactions can also be used to screen for peptide or small molecule inhibitors or agonists of the binding interaction. Also, the receptor PRO can be used to isolate correlative ligand(s). Screening assays can be designed to find lead compounds that mimic the biological activity of a native PRO or a receptor for PRO. 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 PRO or its modified forms can also be used to generate either transgenic 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
  • a transgenic animal 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 transgene is a DNA which is integrated into the genome of a cell from which a transgenic animal develops.
  • cDNA encoding PRO can be used to clone genomic DNA encoding PRO in accordance with established techniques and the genomic sequences used to generate transgenic animals that contain cells which express DNA encoding PRO.
  • Methods for generating transgenic animals, particularly animals such as mice or rats, have become conventional in the art and are described, for example, in U.S. Patent Nos. 4,736,866 and 4,870,009.
  • particular cells would be targeted for PRO transgene incorporation with tissue-specific enhancers.
  • Transgenic animals that include a copy of a transgene encoding PRO 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 PRO.
  • Such animals can be used as tester animals for reagents thought to confer protection from, for example, pathological conditions associated with its overexpression.
  • an animal is treated with the reagent and a reduced incidence of the pathological condition, compared to untreated animals bearing the transgene, would indicate a potential therapeutic intervention for the pathological condition.
  • non-human homologues of PRO can be used to construct a PRO "knock out" animal which has a defective or altered gene encoding PRO as a result of homologous recombination between the endogenous gene encoding PRO and altered genomic DNA encoding PRO introduced into an embryonic stem cell of the animal.
  • cDNA encoding PRO can be used to clone genomic DNA encoding PRO in accordance with established techniques. A portion of the genomic DNA encoding PRO can be deleted or replaced with another gene, such as a gene encoding a selectable marker which can be used to monitor integration.
  • flanking DNA typically, several kilobases of unaltered flanking DNA (both at the 5' and 3' ends) are included in the vector [see e.g., Thomas and Capecchi, Cell. 51:503 (1987) for a description of homologous recombination vectors] .
  • the vector is introduced into an embryonic stem cell line (e.g. , by electroporation) and cells in which the introduced DNA has homologously recombined with the endogenous DNA are selected [see e.g., Li et al., Cell, 69:915 (1992)].
  • the selected cells are then injected into a blastocyst of an animal (e.g., a mouse or rat) to form aggregation chimeras [see e.g., Bradley, in Teratocarcinomas and Embryonic Stem Cells: A Practical Approach, E. J. Robertson, ed. (IRL, Oxford, 1987), pp. 113-152].
  • a chimeric embryo can then be implanted into a suitable 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 animal contain the homologously recombined DNA.
  • Knockout animals can be characterized for instance, for their ability to defend against certain pathological conditions and for their development of pathological conditions due to absence of the PRO polypeptide.
  • Nucleic acid encoding the PRO polypeptides may also be used in gene therapy.
  • genes are introduced into 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 RNAs and DNAs can be used as therapeutic agents for blocking the expression of certain genes in vivo.
  • oligonucleotides can be imported into cells where they act as inhibitors, despite their low intracellular concentrations caused by their restricted uptake by the cell membrane. (Zamecnik et al , Proc. Natl. Acad. Sci. USA 83:4143-4146 [1986]).
  • the oligonucleotides can be modified to enhance their uptake, e.g. by substituting their negatively charged phosphodiester groups by uncharged groups.
  • nucleic acids there are a variety of techniques available for introducing nucleic acids into viable cells.
  • the techniques vary depending upon whether the nucleic acid is transferred into cultured 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, DEAE-dextran, the calcium phosphate precipitation method, etc .
  • the currently preferred in vivo gene transfer techniques include transfection with viral (typically retroviral) vectors and viral coat protein-liposome mediated transfection (Dzau et al., Trends in Biotechnology 11, 205-210 [1993]).
  • 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.
  • 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.
  • proteins which bind to a cell surface membrane protein associated with endocytosis may be used for targeting and/or 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 intracellularlocalization and enhance intracellular half-life.
  • the technique of receptor-mediated endocytosis is described, for example, by Wu et al., J. Biol. Chem.
  • PRO polypeptides described herein may also be employed as molecular weight markers for protein electrophoresis purposes and the isolated nucleic acid sequences may be used for recombinantly expressing those markers.
  • nucleic acid molecules encoding the PRO polypeptides or fragments thereof described herein are useful for chromosome identification.
  • there exists an ongoing need to identify new chromosome markers since relatively few chromosome marking reagents, based upon actual sequence data are presently available.
  • Each PRO nucleic acid molecule of the present invention can be used as a chromosome marker.
  • PRO polypeptides and nucleic acid molecules of the present invention may also be used for tissue typing, wherein the PRO polypeptides of the present invention may be differentially expressed in one tissue as compared to another.
  • PRO nucleic acid molecules will find use for generating probes for PCR, Northern analysis, Southern analysis and Western analysis.
  • the PRO polypeptides described herein may also be employed as therapeutic agents.
  • the PRO polypeptides of the present invention can be formulated according to known methods to prepare pharmaceutically useful compositions, whereby the PRO product hereof is combined in admixture with a pharmaceutically acceptable carrier vehicle.
  • Therapeutic formulations 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 glycine, glutamine, 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 counterions such as sodium; and/or nonionic surfactants such as TWEENTM, PLURONICSTM or PEG.
  • buffers such as phosphate, citrate and other organic acids
  • antioxidants including ascorbic acid
  • 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.
  • 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 sustained release systems.
  • Dosages and desired drug concentrations of pharmaceutical compositions of the present invention may vary depending on the particular use envisioned. The determination of the appropriate dosage or route of administration is well within the skill of an ordinary physician. Animal experiments provide reliable guidance for the determination of effective doses for human therapy. Interspecies scaling of effective doses can be performed following the principles laid down by Mordenti, J. and Chappell, W. "The use of interspecies scaling in toxicokinetics" In Toxicokinetics and New Drug Development, Yacobi et al., Eds., Pergamon Press, New York 1989, pp. 42-96.
  • normal dosage amounts may vary from about 10 ng/kg to up to 100 mg/kg of mammal body weight or more per day, preferably about 1 jug/kg/day to 10 mg/kg/day, depending upon the route of administration.
  • Guidance as to particular dosages and methods of delivery is provided in the literature; see, for example, U.S. 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.
  • 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 rgpl20. Johnson et al. , Nat. Med., 2:795-799 (1996); Yasuda, Biomed. Ther., 27: 1221-1223 (1993); Hora et al.
  • the sustained-release formulations of these proteins were developed using poly-lactic-coglycolic acid (PLGA) polymer due to its biocompatibility and wide range of biodegradable properties.
  • PLGA poly-lactic-coglycolic acid
  • the degradation products of PLGA, lactic and glycolic acids, can be cleared quickly within the human body.
  • the degradability of this polymer can be adjusted from months to years depending on its molecular weight and composition. Lewis, "Controlled release of bioactive agents from lactide/glycolide polymer, " in: M. Chasin and R. Langer (Eds.), Biodegradable Polymers as Drug Delivery Systems (Marcel Dekker: New York, 1990), pp. 1-41.
  • This invention encompasses methods of screening compounds to identify those that mimic the PRO polypeptide (agonists) or prevent the effect of the PRO polypeptide (antagonists).
  • Screening assays for antagonist drug candidates are designed to identify compounds that bind or complex with the PRO polypeptides encoded by the genes identified herein, or otherwise interfere with the interaction of the encoded polypeptides with other cellular proteins.
  • Such screening assays will include assays amenable to high-throughput screening of chemical libraries, making them particularly suitable for identifying small molecule drug candidates.
  • the assays can be performed in a variety of formats, including protein-protein binding assays, biochemical screening assays, immunoassays, and cell-based assays, which are well characterized in the art. All assays for antagonists are common in that they call for contacting the drug candidate with a PRO polypeptide encoded by a nucleic acid identified herein under conditions and for a time sufficient to allow these two components to interact.
  • the interaction is binding and the complex formed can be isolated or detected in the reaction mixture.
  • the PRO polypeptide encoded by the gene identified herein or the drug candidate is immobilized on a solid phase, e.g., on a microtiter plate, by covalent or non-covalent attachments.
  • Non-covalent attachment generally is accomplished by coating the solid surface with a solution of the PRO polypeptide and drying.
  • an immobilized antibody e.g. , a monoclonal antibody, specific for the PRO polypeptide to be immobilized can be used to anchor it to a solid surface.
  • the assay is performed by adding the non-immobilized component, which may be labeled by a detectable label, to the immobilized component, e.g., the coated surface containing the anchored component.
  • the non-reacted components are removed, e.g., by washing, and complexes anchored on the solid surface are detected.
  • the detection of label immobilized on the surface indicates that complexing occurred.
  • complexing can be detected, for example, by using a labeled antibody specifically binding the immobilized complex.
  • the candidate compound interacts with but does not bind to a particular PRO polypeptide encoded by a gene identified herein, its interaction with that polypeptide can be assayed by methods well known for detecting protein-protein interactions.
  • assays include traditional approaches, such as, e.g., cross-linking, co- immunoprecipitation, and co-purification through gradients or chromatographic columns.
  • protein- protein interactions can be monitored by using a yeast-based genetic system described by Fields and co-workers (Fields and Song. Nature (London). 340:245-246 (19891: Chien et al.. Proc. Natl. Acad. Sci. USA.
  • yeast GAL4 consist of two physically discrete modular domains, one acting as the DNA-binding domain, the other one functioning as the transcription-activation domain.
  • the yeast expression system described in the foregoing publications (generally referred to as the "two-hybrid system") takes advantage of this property, and employs two hybrid proteins, one in which the target protein is fused to the DNA-binding domain of GAL4, and another, in which candidate activating proteins are fused to the activation domain.
  • GALl-/ ⁇ cZ reporter gene under control of a GAL4-activated promoter depends on reconstitution of GAL4 activity via protein-protein interaction. Colonies containing interacting polypeptides are detected with a chromogenic substrate for ⁇ -galactosidase.
  • a complete kit (MATCHMAKERTM) for identifying protein-protein interactions between two specific proteins using the two- hybrid technique is commercially available from Clontech. This system can also be extended to map protein domains involved in specific protein interactions as well as to pinpoint amino acid residues that are crucial for these interactions.
  • a reaction mixture is prepared containing the product of the gene and the intra- or extracellular component under conditions and for a time allowing for the interaction and binding of the two products.
  • a candidate compound to inhibit binding, the reaction is run in the absence and in the presence of the test compound.
  • a placebo may be added to a third reaction mixmre, to serve as positive control.
  • the binding (complex formation) between the test compound and the intra- or extracellular component present in the mixture is monitored as described hereinabove. The formation of a complex in the control reaction(s) but not in the reaction mixture containing the test compound indicates that the test compound interferes with the interaction of the test compound and its reaction partner.
  • the PRO polypeptide may be added to a cell along with the compound to be screened for a particular activity and the ability of the compound to inhibit the activity of interest in the presence of the PRO polypeptide indicates that the compound is an antagonist to the PRO polypeptide.
  • antagonists may be detected by combining the PRO polypeptide and a potential antagonist with membrane-bound PRO polypeptide receptors or recombinant receptors under appropriate conditions for a competitive inhibition assay.
  • the PRO polypeptide can be labeled, such as by radioactivity, such that the number of PRO polypeptide molecules bound to the receptor can be used to determine the effectiveness of the potential antagonist.
  • the gene encoding the receptor can be identified by numerous methods known to those of skill in the art, for example, ligand panning and FACS sorting. Coligan et al., Current Protocols in Immun., 1(2): Chapter 5 (1991).
  • expression cloning is employed wherein polyadenylated RNA is prepared from a cell responsive to the PRO polypeptide and a cDNA library created from this RNA is divided into pools and used to transfect COS cells or other cells that are not responsive to the PRO polypeptide. Transfected cells that are grown on glass slides are exposed to labeled PRO polypeptide.
  • the PRO polypeptide can be labeled by a variety of means including iodination or inclusion of a recognition site for a site-specific protein kinase. Following fixation and incubation, the slides are subjected to autoradiographic analysis. Positive pools are identified and sub-pools are prepared and re-transfected using an interactive sub-pooling and re-screening process, eventually yielding a single clone that encodes the putative receptor.
  • labeled PRO polypeptide can be photoaffinity- linked with cell membrane or extract preparations that express the receptor molecule. Cross-linked material is resolved by PAGE and exposed to X-ray film. The labeled complex containing the receptor can be excised, resolved into peptide fragments, and subjected to protein micro-sequencing. The amino acid sequence obtained from micro- sequencing would be used to design a set of degenerate oligonucleotide probes to screen a cDNA library to identify the gene encoding the putative receptor.
  • mammalian cells or a membrane preparation expressing the receptor would be incubated with labeled PRO polypeptide in the presence of the candidate compound. The ability of the compound to enhance or block this interaction could then be measured.
  • potential antagonists include an oligonucleotide that binds to the fusions of immunoglobulin with PRO polypeptide, and, in particular, antibodies including, without limitation, poly- and monoclonal antibodies and antibody fragments, single-chain antibodies, anti-idiotypic antibodies, and chimeric or humanized versions of such antibodies or fragments, as well as human antibodies and antibody fragments.
  • a potential antagonist may be a closely related protein, for example, a mutated form of the PRO polypeptide that recognizes the receptor but imparts no effect, thereby competitively inhibiting the action of the PRO polypeptide.
  • Another potential PRO polypeptide antagonist is an antisense RNA or DNA construct prepared using antisense technology, where, e.g. , an antisense RNA or DNA molecule acts to block directly the translation of mRNA by hybridizing to targeted mRNA and preventing protein translation.
  • Antisense technology can be used to control gene expression through triple-helix formation or antisense DNA or RNA, both of which methods are based on binding of a polynucleotide to DNA or RNA.
  • the 5 ' coding portion of the polynucleotide sequence, which encodes the mature PRO polypeptides herein is used to design an antisense RNA oligonucleotide of from about 10 to 40 base pairs in length.
  • a DNA oligonucleotide is designed to be complementary to a region of the gene involved in transcription (triple helix - see Lee et al. , Nucl. Acids Res.. 3:173 (1979); Cooney et al., Science, 241 : 456 (1988); Dervan et al. , Science, 251 : 1360 (1991)), thereby preventing transcription and the production of the PRO polypeptide.
  • the antisense RNA oligonucleotide hybridizes to the mRNA in vivo and blocks translation of the mRNA molecule into the PRO polypeptide (antisense - Okano, Neurochem..
  • oligodeoxynucleotides as Antisense Inhibitors of Gene Expression (CRC Press: Boca Raton, FL, 1988).
  • the oligonucleotides described above can also be delivered to cells such that the antisense RNA or DNA may be expressed in vivo to inhibit production of the PRO polypeptide.
  • antisense DNA oligodeoxyribonucleotidesderived from the translation-initiation site, e.g., between about -10 and + 10 positions of the target gene nucleotide sequence, are preferred.
  • Potential antagonists include small molecules that bind to the active site, the receptor binding site, or growth factor or other relevant binding site of the PRO polypeptide, thereby blocking the normal biological activity of the PRO polypeptide.
  • small molecules include, but are not limited to, small peptides or peptide-like molecules, preferably soluble peptides, and synthetic non-peptidyl organic or inorganic compounds.
  • Ribozymes are enzymatic RNA molecules capable of catalyzing the specific cleavage of RNA.
  • Ribozymes act by sequence-specific hybridization to the complementary target RNA, followed by endonucleolytic cleavage. Specific ribozyme cleavage sites within a potential RNA target can be identified by known techniques. For further details see, e.g., Rossi, Current Biology, 4:469-471 (1994), and PCT publication No. WO 97/33551
  • Nucleic acid molecules in triple-helix formation used to inhibit transcription should be single-stranded and composed of deoxynucleotides.
  • the base composition of these oligonucleotides is designed such that it promotes triple-helix formation via Hoogsteen base-pairing rules, which generally require sizeable stretches of purines or pyrimidines on one strand of a duplex.
  • therapeutic indications include disorders associated with the preservation and maintenance of gastrointestinal mucosa and the repair of acute and chronic mucosal lesions (e.g., enterocolitis, Zollinger-Ellison syndrome, gastrointestinal ulceration and congenital microvillus atrophy), skin diseases associated with abnormal keratinocyte differentiation (e.g. , psoriasis, epithelial cancers such as lung squamous cell carcinoma, epidermoid carcinoma of the vulva and gliomas.
  • disorders associated with the preservation and maintenance of gastrointestinal mucosa and the repair of acute and chronic mucosal lesions e.g., enterocolitis, Zollinger-Ellison syndrome, gastrointestinal ulceration and congenital microvillus atrophy
  • skin diseases associated with abnormal keratinocyte differentiation e.g. , psoriasis, epithelial cancers such as lung squamous cell carcinoma, epidermoid carcinoma of the vulva and gliomas.
  • PR0232 polypeptide and nucleic acid encoding it possess sequence homology to a cell surface stem cell antigen and its encoding nucleic acid
  • probes based upon the PR0232 nucleotide sequence may be employed to identify other novel stem cell surface antigen proteins.
  • Soluble forms of the PR0232 polypeptide may be employed as antagonists of membrane bound PR0232 activity both in vitro and in vivo.
  • PR0232 polypeptides may be employed in screening assays designed to identify agonists or antagonists of the native PR0232 polypeptide, wherein such assays may take the form of any conventional cell-type or biochemical binding assay.
  • the PR0232 polypeptide may serve as a molecular marker for the tissues in which the polypeptide is specifically expressed.
  • FGF-8 has been implicated in cellular differentiation and embryogenesis, including the patterning which appears during limb formation. FGF-8 and the PRO 187 molecules of the invention therefore are likely to have potent effects on cell growth and development. Diseases which relate to cellular growth and differentiation are therefore suitable targets for therapeutics based on functionality similar to FGF-8. For example, diseases related to growth or survival of nerve cells including Parkinson's disease, Alzheimer's disease, ALS, neuropathies. Additionally, disease related to uncontrolled cell growth, e.g. , cancer, would also be expected therapeutic targets.
  • PR0265 polypeptides disclosed herein other methods for use with PR0265 are described in U.S. Patent 5,654,270 to Ruoslahti et al.
  • PR0265 can be used in comparison with the fibromodulin disclosed therein to compare its effects on reducing dermal scarring and other properties of the fibromodulin described therein including where it is located and with what it binds and does not.
  • the PR0219 polypeptides of the present invention which play a regulatory role in the blood coagulation cascade may be employed in vivo for therapeutic purposes as well as for in vitro purposes. Those of ordinary skill in the art will well know how to employ PR0219 polypeptides for such uses.
  • PR0246 polypeptides of the present invention which serve as cell surface receptors for one or more viruses will find other uses. For example, extracellular domains derived from these PR0246 polypeptides may be employed therapeutically in vivo for lessening the effects of viral infection. Those PR0246 polypeptides which serves as tumor specific antigens may be exploited as therapeutic targets for anti-tumor drugs, and the like. Those of ordinary skill in the art will well know how to employ PR0246 polypeptides for such uses.
  • Assays in which connective growth factor and other growth factors are usually used should be performed with PR0261.
  • An assay to determine whether TGF beta induces PR0261 , indicating a role in cancer is performed as known in the art. Wound repair and tissue growth assays are also performed with PR0261. The results are applied accordingly.
  • PR0228 polypeptides should be used in assays in which EMR1, CD97 and latrophilin would be used in to determine their relative activities. The results can be applied accordingly. For example, a competitive binding assay with PR0228 and CD97 can be performed with the ligand for CD97, CD55.
  • Native PR0533 is a 216 amino acid polypeptide of which residues 1-22 are the signal sequence.
  • Residues 3 to 216 have a Blast score of 509, corresponding to 53 % homology to fibroblast growth factor.
  • DNA47412 the EST from which PCR oligos were generated to isolate the full length DNA49435-1219, has been observed to map to l lpl5. Sequence homology to the l lpl5 locus would indicate that PR0533 may have utility in the treatment of Usher Syndrome or Atrophia areata.
  • fibroblast growth factors can act upon cells in both a mitogenic and non- mitogenic manner.
  • Non-mitogenic actions of fibroblast growth factors include promotion of cell migration into a wound area (chemotaxis), initiation of new blood vessel formulation (angiogenesis), modulation of nerve regeneration and survival (neurotrophism), modulation of endocrine functions, and stimulation or suppression of specific cellular protein expression, extracellular matrix production and cell survival. Baird, A. & Bohlen, P. , Handbook of Exp. Phrmacol. 95(1): 369-418 (1990). These properties provide a basis for using fibroblast growth factors in therapeutic approaches to accelerate wound healing, nerve repair, collateral blood vessel formation, and the like. For example, fibroblast growth factors, have been suggested to minimize myocardium damage in heart disease and surgery (U.S. P. 4,378,437).
  • PR0245 polypeptide and nucleic acid encoding it possess sequence homology to a transmembrane protein tyrosine kinase protein and its encoding nucleic acid
  • probes based upon the PR0245 nucleotide sequence may be employed to identify other novel transmembrane tyrosine kinase proteins.
  • Soluble forms of the PR0245 polypeptide may be employed as antagonists of membrane bound PR0245 activity both in vitro and in vivo.
  • PR0245 polypeptides may be employed in screening assays designed to identify agonists or antagonists of the native PR0245 polypeptide, wherein such assays may take the form of any conventional cell-type or biochemical binding assay.
  • the PR0245 polypeptide may serve as a molecular marker for the tissues in which the polypeptide is specifically expressed.
  • PRO220, PR0221 and PR0227 all have leucine rich repeats. Additionally, PRO220 and PR0221 have homology to SLIT and leucine rich repeat protein. Therefore, these proteins are useful in assays described in the literature, supra, wherein the SLIT and leucine rich repeat protein are used.
  • PR0227 can be used in an assay to determine the affect of PR0227 on neurodegenerative disease. Additionally, PR0227 has homology to human glycoprotein V. In the case of PR0227, this polypeptide is used in an assay to determine its affect on bleeding, clotting, tissue repair and scarring.
  • the PR0266 polypeptide can be used in assays to determine if it has a role in neurodegenerative diseases or their reversal.
  • PR0269 polypeptides and portions thereof which effect the activity of thrombin may also be useful for in vivo therapeutic purposes, as well as for various in vitro applications.
  • PR0269 polypeptides and portions thereof may have therapeutic use as an antithrombotic agent with reduced risk for hemorrhage as compared with heparin. Peptides having homology to thrombomodulin are particularly desirable.
  • BMP 1 /procollagen C-proteinase (PCP) may also be useful for in vivo therapeutic purposes, as well as for various in vitro applications.
  • PR0287 polypeptides and portions thereof may have therapeutic applications in wound healing and tissue repair.
  • Peptides having homology to procollagen C-proteinase enhancer protein and its precursor may also be used to induce bone and/or cartilage formation and are therefore of particular interest to the scientific and medical communities.
  • Therapeutic indications for PR0214 polypeptides include disorders associated with the preservation and maintenance of gastrointestinal mucosa and the repair of acute and chronic mucosal lesions (e.g., enterocolitis,
  • Zollinger-Ellison syndrome gastrointestinal ulceration and congenital microvillus atrophy
  • skin diseases associated with abnormal keratinocyte differentiation e.g., psoriasis, epithelial cancers such as lung squamous cell carcinoma, epidermoid carcinoma of the vulva and gliomas.
  • mice deficient in members of the TGF- superfamily are reported in Matzuk, Trends in Endocrinol. and Metabol.. ⁇ 120-127 (1995).
  • the PR0317 polypeptide, as well as PR0317-specificantibodies, inhibitors, agonists, receptors, or their analogs, herein are useful in treating PR0317-associated disorders. Hence, for example, they may be employed in modulating endometrial bleeding angiogenesis, and may also have an effect on kidney tissue. Endometrial bleeding can occur in gynecological diseases such as endometrial cancer as abnormal bleeding. Thus, the compositions herein may find use in diagnosing and treating abnormal bleeding conditions in the endometrium, as by reducing or eliminating the need for a hysterectomy.
  • the molecules herein may also find use in angiogenesis applications such as anti-tumor indications for which the antibody against vascular endothelial growth factor is used, or, conversely, ischemic indications for which vascular endothelial growth factor is employed.
  • Bioactive compositions comprising PR0317 or agonists or antagonists thereof may be administered in a suitable therapeutic dose determined by any of several methodologies including clinical studies on mammalian species to determine maximal tolerable dose and on normal human subjects to determine safe dose. Additionally, the bioactive agent may be complexed with a variety of well established compounds or compositions which enhance stability or pharmacological properties such as half-life. It is contemplated that the therapeutic, bioactive composition may be delivered by intravenous infusion into the bloodstream or any other effective means which could be used for treating problems of the kidney, uterus, endometrium, blood vessels, or related tissue, e.g., in the heart or genital tract.
  • Dosages and administration of PR0317, PR0317 agonist, or PR0317 antagonist in a pharmaceutical composition may be determined by one of ordinary skill in the art of clinical pharmacology or pharmacokinetics. See, for example, Mordenti and Rescigno, Pharmaceutical Research. 9: 17-25 (1992); Morenti et al. , Pharmaceutical Research. 8: 1351-1359 (1991); and Mordenti and Chappell, "The use of interspecies scaling in toxicokinetics" in Toxicokinetics and New Drug Development. Yacobi etal. (eds) (Pergamon Press: NY, 1989), pp. 42-96.
  • An effective amount of PR0317, PR0317 agonist, or PR0317 antagonist to be employed therapeutically will depend, for example, upon the therapeutic objectives, the route of administration, and the condition of the mammal. 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 10 ng/kg to up to 100 mg/kg of the mammal's body weight or more per day, preferably about 1 ⁇ g/kg/day to 10 mg/kg/day.
  • the clinician will administer PR0317, PR0317 agonist, or PR0317 antagonist, until a dosage is reached that achieves the desired effect for treatment of the above mentioned disorders.
  • PR0317 or an PR0317 agonist or PR0317 antagonist may be administered alone or in combination with another to achieve the desired pharmacological effect.
  • PR0317 itself, or agonists or antagonists of PR0317 can provide different effects when administered therapeutically.
  • Such compounds for treatment will be formulated in a nontoxic, inert, pharmaceutically acceptable aqueous carrier medium preferably at a pH of about 5 to 8, more preferably 6 to 8, although the pH may vary according to the characteristics of the PR0317, agonist, or antagonist being formulated and the condition to be treated. Characteristics of the treatment compounds include solubility of the molecule, half-life, and antigenicity /immunogenicity; these and other characteristics may aid in defining an effective carrier.
  • PR0317 or PR0317 agonists or PR0317 antagonists may be delivered by known routes of administration including but not limited to topical creams and gels; transmucosal spray and aerosol, transdermal patch and bandage; injectable, intravenous, and lavage formulations; and orally administered liquids and pills, particularly formulated to resist stomach acid and enzymes.
  • routes of administration including but not limited to topical creams and gels; transmucosal spray and aerosol, transdermal patch and bandage; injectable, intravenous, and lavage formulations; and orally administered liquids and pills, particularly formulated to resist stomach acid and enzymes.
  • the particular formulation, exact dosage, and route of administration will be determined by the attending physician and will vary according to each specific situation. Such determinations of administration are made by considering multiple variables such as the condition to be treated, the type of mammal to be treated, the compound to be administered, and the pharmacokinetic profile of the particular treatment compound. Additional factors which may be taken into account include disease state (e.g.
  • Long-acting treatment compound formulations (such as liposomally encapsulated PR0317 or PEGylated PR0317 or PR0317 polymeric microspheres , such as polylactic acid-based microspheres) might be administered every 3 to 4 days, every week, or once every two weeks depending on half-life and clearance rate of the particular treatment compound.
  • Normal dosage amounts may vary from about 10 ng/kg to up to 100 mg/kg of mammal body weight or more per day, preferably about 1 ⁇ g/kg/day to 10 mg/kg/day, depending upon the route of administration.
  • Guidance as to particular dosages and methods of delivery is provided in the literature; see, for example, U.S. 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 the uterus, for example, may necessitate delivery in a manner different from that to another organ or tissue, such as cardiac tissue.
  • microencapsulation of PR0317 is contemplated.
  • Microencapsulation of recombinant proteins for sustained release has been successfully performed with human growth hormone (rhGH), interferon- (rhIFN- ), interleukin-2, and MN rgpl20. Johnson et al , Nat. Med.. 2: 795-799 (1996); Yasuda. Biomed. Ther. , 27: 1221-1223 (1993); Hora etal.
  • conditions or diseases of the uterus, endometrial tissue, or other genital tissues or cardiac tissues may precipitate damage that is treatable with PR0317 or PR0317 agonist where PR0317 expression is reduced in the diseased state; or with antibodies to PR0317 or other PR0317 antagonists where the expression of PR0317 is increased in the diseased state.
  • These conditions or diseases may be specifically diagnosed by the probing tests discussed above for physiologic and pathologic problems which affect the function of the organ.
  • the PR0317, PR0317 agonist, or PR0317 antagonist may be administered to a mammal with another biologically active agent, either separately or in the same formulation to treat a common indication for which they are appropriate.
  • PR0317 can be administered together with EBAF-1 for those indications on which they demonstrate the same qualitative biological effects.
  • EBAF-1 may be administered together with an antagonist to PR0317, such as an anti- PR0317 antibody.
  • PR0317 may be administered together with VEGF for coronary ischemia where such indication is warranted, or with an anti-VEGF for cancer as warranted, or, conversely, an antagonist to PR0317 may be administered with VEGF for coronary ischemia or with anti-VEGF to treat cancer as warranted. These administrations would be in effective amounts for treating such disorders.
  • Native PRO301 (SEQ ID NO: 119) has a Blast score of 246 and 30% homology at residues 24 to 282 of Figure 44 with A33_HUMAN, an A33 antigen precursor.
  • A33 antigen precursor as explained in the Background is a tumor-specific antigen, and as such, is a recognized marker and therapeutic target for the diagnosis and treatment of colon cancer.
  • Native PRO301 (SEQ ID NO: 119) and A33 HUMAN also show a Blast score of 245 and 30% homology at residues 21 to 282 of Fig. 44 with A33_HUMAN, the variation dependent upon how spaces are inserted into the compared sequences.
  • Native PRO301 (SEQ ID NO: 119) also has a Blast score of 165 and 29% homology at residues 60 to 255 of Fig. 44 with HS46KDA_1, a human coxsackie and adenovirus receptor protein, also known as cell surface protein HCAR. This region of PRO301 also shows a similar Blast score and homology with HSU90716_1. Expression of such proteins is usually associated with viral infection and therapeutics for the prevention of such infection may be accordingly conceived. As mentioned in the Background, the expression of viral receptors is often associated with neoplastic tumors.
  • PR0234 polypeptides of the invention includes treatments associated with leukocyte homing or the interaction between leukocytes and the endothelium during an inflammatory response. Examples include asthma, rheumatoid arthritis, psoriasis and multiple sclerosis.
  • PR0231 polypeptide and nucleic acid encoding it possess sequence homology to a putative acid phosphatase and its encoding nucleic acid
  • probes based upon the PR0231 nucleotide sequence may be employed to identify other novel phosphatase proteins.
  • Soluble forms of the PR0231 polypeptide may be employed as antagonists of membrane bound PR0231 activity both in vitro and in vivo.
  • PR0231 polypeptides may be employed in screening assays designed to identify agonists or antagonists of the native PR0231 polypeptide, wherein such assays may take the form of any conventional cell-type or biochemical binding assay.
  • the PR0231 polypeptide may serve as a molecular marker for the tissues in which the polypeptide is specifically expressed.
  • PR0229 polypeptides can be fused with peptides of interest to determine whether the fusion peptide has an increased half-life over the peptide of interest.
  • the PR0229 polypeptides can be used accordingly to increase the half-life of polypeptides of interest. Portions of PR0229 which cause the increase in half-life are an embodiment of the invention herein.
  • PR0238 can be used in assays which measure its ability to reduce substrates, including oxygen and Aceyl-CoA, and particularly, measure PR0238's ability to produce oxygen free radicals. This is done by using assays which have been previously described. PR0238 can further be used to assay for candidates which block, reduce or reverse its reducing abilities. This is done by performing side by side assays where candidates are added in one assay having PR0238 and a substrate to reduce, and not added in another assay, being the same but for the lack of the presence of the candidate.
  • PR0233 polypeptides and portions thereof which have homology to reductase may also be useful for in vivo therapeutic purposes, as well as for various other applications.
  • the identification of novel reductase proteins and related molecules may be relevant to a number of human disorders such as inflammatory disease, organ failure, atherosclerosis, cardiac injury, infertility, birth defects, premature aging, AIDS, cancer, diabetic complications and mutations in general.
  • 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 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 PR0233.
  • PR0223 polypeptides of the present invention which exhibit serine carboxypeptidease activity may be employed in vivo for therapeutic purposes as well as for in vitro purposes. Those of ordinary skill in the art will well know how to employ PR0223 polypeptides for such uses.
  • PR0235 polypeptides and portions thereof which may be involved in cell adhesion are also useful for in vivo therapeutic purposes, as well as for various in vitro applications.
  • PR0235 polypeptides and portions thereof may have therapeutic applications in disease states which involve cell adhesion. Given the physiological importance of cell adhesion mechanisms in vivo, efforts are currently being under taken to identify new, native proteins which are involved in cell adhesion. Therefore, peptides having homology to plexin are of particular interest to the scientific and medical communities.
  • the PR0236 and PR0262 polypeptides disclosed herein are homologous to various known ⁇ - galactosidase proteins, the PR0236 and PR0262 polypeptides disclosed herein will find use in conjugates of monoclonal antibodies and the polypeptide for specific killing of tumor cells by generation of active drug from a galactosylated prodrug (e.g., the generation of 5-fluorouridine from the prodrug ⁇ -D-galactosyl-5- fluorouridine).
  • the PR0236 and PR0262 polypeptides disclosed herein may also find various uses both in vivo and in vitro, wherein those uses will be similar or identical to uses for which ⁇ -galactosidase proteins are now employed. Those of ordinary skill in the art will well know how to employ PR0236 and PR0262 polypeptides for such uses.
  • PR0239 polypeptides and portions thereof which have homology to densin may also be useful for in vivo therapeutic purposes, as well as for various in vitro applications.
  • PR0239 polypeptides and portions thereof may have therapeutic applications in disease states which involve synaptic mechanisms, regeneration or cell adhesion. Given the physiological importance of synaptic processes, regeneration and cell adhesion mechanisms in vivo, efforts are currently being under taken to identify new, native proteins which are involved in synaptic machinery and cell adhesion. Therefore, peptides having homology to densin are of particular interest to the scientific and medical communities.
  • the PRO260 polypeptides described herein can be used in assays to determine their relation to fucosidase.
  • the PRO260 polypeptides can be used in assays in determining their ability to remove fucose or other sugar residues from proteoglycans.
  • the PRO260 polypeptides can be assayed to determine if they have any functional or locational similarities as fucosidase.
  • the PRO260 polypeptides can then be used to regulate the systems in which they are integral.
  • PR0263 can be used in assays wherein CD44 antigen is generally used to determine PR0263 activity relative to that of CD44. The results can be used accordingly.
  • PRO270 polypeptides and portions thereof which effect reduction-oxidation (redox) state may also be useful for in vivo therapeutic pu ⁇ oses, as well as for various in vitro applications. More specifically, PRO270 polypeptides may affect the expression of a large variety of genes thought to be involved in the pathogenesis of AIDS, cancer, atherosclerosis, diabetic complications and in pathological conditions involving oxidative stress such as stroke and inflammation. In addition, PRO270 polypeptides and portions thereof may affect the expression of a genes which have a role in apoptosis. Therefore, peptides having homology to thioredoxin are particularly desirable to the scientific and medical communities.
  • redox reduction-oxidation
  • PR0272 polypeptides and portions thereof which possess the ability to bind calcium may also have numerous in vivo therapeutic uses, as well as various in vitro applications. Therefore, peptides having homology to reticulocalbin are particularly desirable. Those with ordinary skill in the art will know how to employ PR0272 polypeptides and portions thereof for such pu ⁇ oses.
  • PR0294 polypeptides and portions thereof which have homology to collagen may also be useful for in vivo therapeutic pu ⁇ oses, as well as for various other applications.
  • the identification of novel collagens and collage-like molecules may have relevance to a number of human disorders. Thus, the identification of new collagens and collage-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. Given the large number of uses for collagen, there is substantial interest in polypeptides with homology to the collagen molecule.
  • PR0295 polypeptides and portions thereof which have homology to integrin may also be useful for in vivo therapeutic pu ⁇ oses, as well as for various other applications.
  • the identification of novel integrins and integrin-like molecules may have relevance to a number of human disorders such as modulating the binding or activity of cells of the immune system.
  • the identification of new integrins and integrin-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 PR0295.
  • the peptide can be used in all applications that the known NLRR-1 and NLRR-2 polypeptides are used. The activity can be compared between these peptides and thus applied accordingly.
  • PR0247 polypeptides described herein can be used in assays in which densin is used to determine the activity of PR0247 relative to densin or these other proteins. The results can be used accordingly in diagnostics and/or therapeutic applications with PR0247.
  • PRO302, PRO303, PRO304, PRO307 and PR0343 polypeptides of the present invention which possess protease activity may be employed both in vivo for therapeutic pu ⁇ oses and in vitro.
  • PRO302, PRO303, PRO304, PRO307 and PR0343 polypeptides of the present invention for such pu ⁇ oses.
  • PR0328 polypeptides and portions thereof which have homology to GLIP and CRISP may also be useful for in vivo therapeutic pu ⁇ oses, as well as for various other applications.
  • the identification of novel GLIP and CRISP-like molecules may have relevance to a number of human disorders which involve transcriptional regulation or are over expressed in human tumors.
  • PR0335, PR0331 or PR0326 can also be used in assays where LIG-1 would be used to determine if the same effects are incurred.
  • PR0332 contains GAG repeat (GKEK) at amino acid positions 625-628 in Fig. 108 (SEQ ID NO:310). Slippage in such repeats can be associated with human disease. Accordingly, PR0332 can use useful for the treatment of such disease conditions by gene therapy, i.e. by introduction of a gene containing the correct GKEK sequence motif.
  • GKEK GAG repeat
  • PR0334 uses in assays in which fibrillin or fibulin would be used to determine the relative activity of PR0334 to fibrillin or fibulin.
  • PR0334 can be used in assays which require the mechanisms imparted by epidermal growth factor repeats.
  • Native PR0346 (SEQ ID NO:320) has a Blast score of 230, corresponding to 27% homology between amino acid residues 21 to 343 with residues 35 to 1040 CGM6 HUMAN, a carcinoembryonic antigen cgm6 precursor.
  • This homology region includes nearly all but 2 N-terminal extracellular domain residues, including an immunoglobulin superfamily homology at residues 148 to 339 of PR0346 in addition to several transmembrane residues (340-343).
  • Carcinoembryonic antigen precursor as explained in the Background is a tumor-specific antigen, and as such, is a recognized marker and therapeutic target for the diagnosis and treatment of colon cancer . The expression of tumor-specific antigens is often associated with the progression of neoplastic tissue disorders.
  • Native PR0346 (SEQ ID NO: 320) and P_W06874, a human carcinoembryonic antigen CEA-d have a Blast score of 224 and homology of 28% between residues 2 to 343 and 67 to 342, respectively. This homology includes the entire extracellular domain residues of native PR0346, minus the initiator methionine (residues 2 to 18) as well as several transmembrane residues (340-343).
  • PR0268 polypeptides which have protein disulfide isomerase activity will be useful for many applications where protein disulfide isomerase activity is desirable including, for example, for use in promoting proper disulfide bond formation in recombinantly produced proteins so as to increase the yield of correctly folded protein.
  • protein disulfide isomerase activity is desirable including, for example, for use in promoting proper disulfide bond formation in recombinantly produced proteins so as to increase the yield of correctly folded protein.
  • PR0268 polypeptides for such pu ⁇ oses will readily know how to employ such PR0268 polypeptides for such pu ⁇ oses.
  • PRO330 polypeptides of the present invention which possess biological activity related to that of the prolyl 4-hydroxylase alpha subunit protein may be employed both in vivo for therapeutic pu ⁇ oses and in vitro. Those of ordinary skill in the art will well know how to employ the PRO330 polypeptides of the present invention for such pu ⁇ oses.
  • F. Anti-PRO Antibodies
  • the present invention further provides anti-PRO antibodies.
  • Exemplary antibodies include polyclonal, monoclonal, humanized, bispecific, and heteroconjugate antibodies.
  • the anti-PRO antibodies may comprise polyclonal antibodies. Methods of preparing polyclonal antibodies are known to the skilled artisan. Polyclonal antibodies can be raised in a mammal, for example, by one or more injections of an immunizing agent and, if desired, an adjuvant. Typically, the immunizing agent and/or adjuvant will be injected in the mammal by multiple subcutaneous or intraperitoneal injections.
  • the immunizing agent may include the PRO polypeptide or a fusion protein thereof. It may be useful to conjugate the immunizing agent to a protein known to be immunogenic in the mammal being immunized.
  • immunogenic proteins include but are not limited to keyhole limpet hemocyanin, serum albumin, bovine thyroglobulin, and soybean trypsin inhibitor.
  • adjuvants which may be employed include Freund's complete adjuvant and MPL-TDM adjuvant (monophosphoryl Lipid A, synthetic trehalose dicorynomycolate).
  • the immunization protocol may be selected by one skilled in the art without undue experimentation.
  • the anti-PRO antibodies may, alternatively, be monoclonal antibodies.
  • Monoclonal antibodies may be prepared using hybridoma methods, such as those described by Kohler and Milstein, Nature. 256:495 (1975).
  • 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.
  • the lymphocytes may be immunized in vitro.
  • the immunizing agent will typically include the PRO polypeptide or a fusion protein thereof.
  • PBLs peripheral blood lymphocytes
  • spleen cells or lymph node cells are used if non-human mammalian sources are desired.
  • the lymphocytes are then fused with an immortalized cell line using a suitable fusing agent, such as polyethylene glycol, to form a hybridoma cell [Goding, Monoclonal Antibodies: Principles and Practice. Academic Press, (1986) pp. 59-103].
  • Immortalized cell lines are usually transformed mammalian cells, particularly myeloma cells of rodent, bovine and human origin.
  • 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.
  • a suitable culture medium that preferably contains one or more substances that inhibit the growth or survival of the unfused, immortalized cells.
  • the culture medium for the hybridomas typically will include hypoxanthine, aminopterin, and thymidine (“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 murine myeloma lines, which can be obtained, for instance, from the Salk Institute Cell Distribution Center, San Diego, California and the American Type Culture Collection, Manassas, Virginia. Human myeloma and mouse-human heteromyeloma 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 PRO.
  • the binding specificity of monoclonal antibodies produced by the hybridoma cells is determined by immunoprecipitation or by an in vitro binding assay, such as radioimmunoassay (RIA) or enzyme-linked immunoabsorbent assay (ELISA).
  • RIA radioimmunoassay
  • ELISA enzyme-linked immunoabsorbent assay
  • the binding affinity of the monoclonal antibody can, for example, be determined by the Scatchard analysis of Munson and Pollard, Anal. Biochem.. 107:220 (1980).
  • the clones may be subcloned by limiting dilution procedures and grown by standard methods [Goding, supral . Suitable culture media for this pu ⁇ ose include, for example, Dulbecco's Modified Eagle's Medium and RPMI-1640 medium. Alternatively, the hybridoma cells may be grown in vivo as ascites in a mammal.
  • the monoclonal antibodies 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.
  • the 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 murine antibodies).
  • the hybridoma cells of the invention serve as a preferred source of such DNA.
  • the DNA may be placed into expression vectors, which are then transfected into host cells such as simian COS cells, Chinese hamster ovary (CHO) cells, or myeloma cells that do not otherwise produce immunoglobulin protein, to obtain the synthesis of monoclonal antibodies in the recombinant host cells.
  • the DNA also may be modified, for example, by substituting the coding sequence for human heavy and light chain constant domains in place of the homologous murine sequences [U.S. Patent No. 4,816,567; Morrison et al., supral or by covalently joining to the immunoglobulin coding sequence all or part of the coding sequence for a non-immunoglobulin polypeptide.
  • Such a non-immunoglobulin polypeptide can be substituted for the constant domains of an antibody of the invention, or can be substituted for the variable domains of one antigen-combining site of an antibody of the invention to create a chimeric bivalent antibody.
  • the antibodies may be monovalent antibodies. Methods for preparing monovalent antibodies are well known in the art. For example, one method involves recombinant expression of immunoglobulin light chain and modified heavy chain. The heavy chain is truncated generally at any point in the Fc region so as to prevent heavy chain crosslinking. Alternatively, the relevant cysteine residues are substituted with another amino acid residue or are deleted so as to prevent crosslinking. In 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. 3. Human and Humanized Antibodies
  • the anti-PRO antibodies of the invention may further comprise humanized antibodies or human antibodies.
  • Humanized forms of non-human (e.g., murine) antibodies are chimeric immunoglobulins, immunoglobulin chains or fragments thereof (such as Fv, Fab, Fab' , F(ab') 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.
  • CDR complementary determining region
  • 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.
  • the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin and all or substantially all of the FR regions are those of a human immunoglobulin consensus sequence.
  • the humanized antibody optimally also will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin [Jones et al.. Nature, 321 :522-525 (1986); Riechmannet al. , Nature, 332:323-329 (1988): and Presta, Curr. Op. Struct. Biol.. 2:593-596 (1992)1.
  • a humanized antibody has one or more amino acid residues introduced into it from a source which is non-human. These non- human amino acid residues are often referred to as "import" residues, which are typically taken from an "import” variable domain.
  • Humanization can be essentially performed following the method of Winter and co-workers [Jones et al., Nature. 321:522-525 (1986); Riechmann et al. , Nature, 332:323-327 (1988); Verhoeyen et al., Science, 239: 1534-1536 (1988)], by substituting rodent CDRs or CDR sequences for the corresponding sequences of a human antibody.
  • 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.
  • humanized antibodies are typically human antibodies in which some CDR residues and possibly some FR residues are substituted by residues from analogous sites in rodent antibodies.
  • Human antibodies can also be produced using various techniques known in the art, including phage display libraries [Hoogenboom and Winter, J. Mol. Biol., 227:381 (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 Antibodies and Cancer Therapy. Alan R . Liss , p ..77 ( 1985) and Boerner et al. , J. Immunol., 147(l):86-95 (1991)].
  • human antibodies can be made by introducing of human immunoglobulin loci into transgenic animals, e.g., mice in which the endogenous immunoglobulin genes have been partially or completely inactivated. Upon challenge, human antibody production is observed, which closely resembles that seen in humans in all respects, including gene rearrangement, assembly, and antibody repertoire.
  • transgenic animals e.g., mice in which the endogenous immunoglobulin genes have been partially or completely inactivated.
  • human antibody production is observed, which closely resembles that seen in humans in all respects, including gene rearrangement, assembly, and antibody repertoire.
  • This approach is described, for example, in U.S. Patent Nos. 5,545,807; 5,545,806; 5,569,825; 5,625, 126; 5,633,425; 5,661,016, and in the following scientific publications: Marks et al, Bio/Technology 10, 779-783 (1992): Lonberg etal.
  • Bispecific antibodies are monoclonal, preferably human or humanized, antibodies that have binding specificities for at least two different antigens. In the present case, one of the binding specificities is for the PRO, the other one is for any other antigen, and preferably for a cell-surface protein or receptor or receptor subunit.
  • bispecific antibodies are known in the art. Traditionally, the recombinant production of bispecific antibodies is based on the co-expression of two immunoglobulin heavy-chain/light-chain pairs, where the two heavy chains have different specificities [Milstein and Cuello, Nature. 305:537-539 (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 93/08829, published 13 May 1993, and in Traunecker et al., EMBO , 10:3655-3659 (1991).
  • Antibody variable domains with the desired binding specificities can be fused to immunoglobulin constant domain sequences.
  • the fusion preferably is with an immunoglobulin 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 (CH 1) 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.
  • the interface between a pair of antibody molecules can be engineered to maximize the percentage of heterodimers which are recovered from recombinant cell culture.
  • the preferred interface comprises at least a part of the CH3 region of an antibody constant domain.
  • one or more small amino acid side chains from the interface of the first antibody molecule are replaced with larger side chains (e.g. tyrosine or tryptophan).
  • Compensatory "cavities" of identical or similar size to the large side chain(s) are created on the interface of the second antibody molecule by replacing large amino acid side chains with smaller ones (e.g. alanine or threonine). This provides a mechanism for increasing the yield of the heterodimer over other unwanted end-products such as homodimers.
  • Bispecific antibodies can be prepared as full length antibodies or antibody fragments (e.g. F(ab') 2 bispecific antibodies). Techniques for generating bispecific antibodies from antibody fragments have been described in the literature. For example, bispecific antibodies can be prepared can be prepared using chemical linkage. Brennan etal.. Science 229:81 (1985) describe a procedure wherein intact antibodies are proteolytically cleaved to generate F(ab') 2 fragments. These fragments are reduced in the presence of the dithiol complexing agent sodium arsenite to stabilize vicinal dithiols and prevent intermolecular disulfide formation. The Fab' fragments generated are then converted to thionitrobenzoate (TNB) derivatives.
  • TAB thionitrobenzoate
  • Fab'-TNB derivatives is then reconverted to the Fab'-thiol by reduction with mercaptoethylamine and is mixed with an equimolar amount of the other Fab'-TNB derivative to form the bispecific antibody.
  • the bispecific antibodies produced can be used as agents for the selective immobilization of enzymes.
  • Fab' fragments may be directly recovered from E. coli and chemically coupled to form bispecific antibodies.
  • Shalaby et al J. Exp. Med. 175:217-225 (1992) describe the production of a fully humanized bispecific antibody F(ab'), molecule.
  • Each Fab' fragment was separately secreted from E. coli and subjected to directed chemical coupling in vitro to form the bispecific antibody.
  • the bispecific antibody thus formed was able to bind to cells overexpressing the ErbB2 receptor and normal human T cells, as well as trigger the lytic activity of human cytotoxic lymphocytes against human breast tumor targets.
  • bispecific antibodies have been produced using leucine zippers.
  • the leucine zipper peptides from the Fos and Jun proteins were linked to the Fab' portions of two different antibodies by gene fusion.
  • the antibody homodimers were reduced at the hinge region to form monomers and then re-oxidized to form the antibody heterodimers. This method can also be utilized for the production of antibody homodimers.
  • the fragments comprise a heavy-chain variable domain (V H ) connected to a light-chain variable domain (V L ) by a linker which is too short to allow pairing between the two domains on the same chain. Accordingly, the V H and V L domains of one fragment are forced to pair with the complementary V L and V H domains of another fragment, thereby forming two antigen-binding sites.
  • V H and V L domains of one fragment are forced to pair with the complementary V L and V H domains of another fragment, thereby forming two antigen-binding sites.
  • sFv single-chain Fv
  • Another strategy for making bispecific antibody fragments by the use of single-chain Fv (sFv) dimers has also been reported. See, Gruber et al. , J. Immunol. 152:5368 (1994). Antibodies with more than two valencies are contemplated. For example, trispecific antibodies can be prepared. Tutt et al. , J. Immunol. 147:60 (1991).
  • bispecific antibodies may bind to two different epitopes on a given PRO polypeptide herein.
  • an anti-PRO polypeptide arm may be combined with an arm which binds to a triggering molecule on a leukocyte such as a T-cell receptor molecule (e.g. CD2, CD3, CD28, or B7), or Fc receptors for IgG (Fc ⁇ R), such as Fc ⁇ RI (CD64), Fc ⁇ RII (CD32) and Fc ⁇ RIII (CD 16) so as to focus cellular defense mechanisms to the cell expressing the particular PRO polypeptide.
  • Bispecific antibodies may also be used to localize cytotoxic agents to cells which express a particular PRO polypeptide.
  • These antibodies possess a PRO-binding arm and an arm which binds a cytotoxic agent or a radionuclide chelator, such as EOTUBE, DPTA, DOTA, or TETA.
  • a cytotoxic agent or a radionuclide chelator such as EOTUBE, DPTA, DOTA, or TETA.
  • Another bispecific antibody of interest binds the PRO polypeptide and further binds tissue factor (TF).
  • 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 92/200373; EP 03089].
  • the antibodies may be prepared in vitro using known methods in synthetic protein chemistry, including those involving crosslinking agents.
  • immunotoxins may be constructed using a disulfide exchange reaction or by forming a thioether bond. Examples of suitable reagents for this pu ⁇ ose include iminothiolate and mefhyl-4-mercaptobutyrimidate and those disclosed, for example, in U.S. Patent No. 4,676,980.
  • cysteine residue(s) may be introduced into the Fc region, thereby allowing interchain disulfide bond formation in this region.
  • the homodimeric antibody thus generated may have improved internalization capability and/or increased complement-mediated cell killing and antibody-dependent cellular cytotoxicity (ADCC). See Caron et al , Exp Med. , 176: 1191-1195 (1992) and Shopes, J. Immunol., 148: 2918-2922 (1992).
  • Homodimeric antibodies with enhanced anti-tumor activity may also be prepared using heterobifunctional cross-linkers as described in Wolff et al. Cancer Research. 53: 2560-2565 (1993).
  • an antibody can be engineered that has dual Fc regions and may thereby have enhanced complement lysis and ADCC capabilities. See Stevenson et al. , Anti- Cancer Drug Design, 3: 219-230 (1989).
  • the invention also pertains to immunoconjugates comprising an antibody conjugated to a cytotoxic agent such as a chemotherapeutic agent, toxin (e.g. , an enzymatically active toxin of bacterial, fungal, plant, or animal origin, or fragments thereof), or a radioactive isotope (i.e., a radioconjugate).
  • a cytotoxic agent such as a chemotherapeutic agent, toxin (e.g. , an enzymatically active toxin of bacterial, fungal, plant, or animal origin, or fragments thereof), or a radioactive isotope (i.e., a radioconjugate).
  • Enzymatically active toxins and fragments thereof that can be used include diphtheria A chain, nonbinding active fragments of diphtheria toxin, exotoxin A chain (from Pseudomonas aeruginosa), ricin A chain, abrin A chain, modeccin A chain, alpha-sarcin, Aleurites fordii proteins, dianthin proteins, Phytolaca americana proteins (PAPI, PAPII, and PAP-S), momordica charantia inhibitor, curcin, crotin, sapaonaria officinalis inhibitor, gelonin, mitogellin, restrictocin, phenomycin, enomycin, and the tricothecenes.
  • a variety of radionuclides are available for the production of radioconjugated antibodies. Examples include 212 Bi, 131 I, 131 In, 90 Y, and 186 Re.
  • Conjugates of the antibody and cytotoxic agent are made using a variety of bifunctional protein-coupling agents such as N-succinimidyl-3-(2- ⁇ yridyldithiol) propionate (SPDP), iminothiolane (IT), bifunctional derivatives of imidoesters (such as dimethyl adipimidate HCL), active esters (such as disuccinimidyl suberate), aldehydes (such as glutareldehyde), bis-azido compounds (such as bis (p-azidobenzoyl) hexanediamine), bis- diazonium derivatives (such as bis-(p-diazoniumbenzoyl)-ethylenediamine), diisocyanates (such as tolyene 2,6- diisocyanate), and bis-active fluorine compounds (such as 1 ,5-difluoro-2,4-dinitrobenzene).
  • SPDP N-succinimidyl-3-
  • a ricin immunotoxin can be prepared as described in Vitetta et al. , Science. 238: 1098 (1987).
  • Carbon-14-labeled 1- isothiocyanatobenzyl-3-methyldiethylene triaminepentaacetic acid (MX-DTPA) is an exemplary chelating agent for conjugation of radionucleotide to the antibody. See W094/11026.
  • the antibody may be conjugated to a "receptor” (such streptavidin) for utilization in tumor pretargeting wherein the antibody-receptor conjugate is administered to the patient, followed by removal of unbound conjugate from the circulation using a clearing agent and then administration of a "ligand” (e.g., avidin) that is conjugated to a cytotoxic agent (e.g., a radionucleotide).
  • a "receptor” such streptavidin
  • a ligand e.g., avidin
  • cytotoxic agent e.g., a radionucleotide
  • the antibodies disclosed herein may also be formulated as immunoliposomes.
  • Liposomes containing the antibody are prepared by methods known in the art, such as described in Epstein et al. , Proc. Natl. Acad. Sci. USA, 82: 3688 (1985); Hwang et al, Proc. Natl Acad. Sci. USA. 77: 4030 (1980); and U.S. Pat. Nos. 4,485,045 and 4,544,545. Liposomes with enhanced circulation time are disclosed in U.S. Patent No. 5,013,556.
  • Particularly useful liposomes can be generated by the reverse-phase evaporation method with a lipid composition comprising phosphatidylcholine, cholesterol, and PEG-derivatized phosphatidylethanolamine(PEG- PE). Liposomes are extruded through filters of defined pore size to yield liposomes with the desired diameter.
  • Fab' fragments of the antibody of the present invention can be conjugated to the liposomes as described in Martin et al .. J. Biol. Chem.. 257: 286-288 (1982) via a disulfide-interchange reaction.
  • a chemotherapeutic agent such as Doxorubicin is optionally contained within the liposome. See Gabizon et al. , J. National Cancer Inst.. 81(19): 1484 (1989).
  • Antibodies specifically binding a PRO polypeptide identified herein, as well as other molecules identified by the screening assays disclosed hereinbefore, can be administered for the treatment of various disorders in the form of pharmaceutical compositions. If the PRO polypeptide is intracellular and whole antibodies are used as inhibitors, internalizing antibodies are preferred. However, lipofections or liposomes can also be used to deliver the antibody, or an antibody fragment, into cells. Where antibody fragments are used, the smallest inhibitory fragment that specifically binds to the binding domain of the target protein is preferred . For example , based upon the variable- region sequences of an antibody, peptide molecules can be designed that retain the ability to bind the target protein sequence. Such peptides can be synthesized chemically and/or produced by recombinant DNA technology.
  • the formulation herein may also contain more than one active compound as necessary for the particular indication being treated, preferably those with complementary activities that do not adversely affect each other.
  • the composition may comprise an agent that enhances its function, such as, for example, a cytotoxic agent, cytokine, chemotherapeutic agent, or growth-inhibitory agent.
  • cytotoxic agent such as, for example, a cytotoxic agent, cytokine, chemotherapeutic agent, or growth-inhibitory agent.
  • Such molecules are suitably present in combination in amounts that are effective for the pu ⁇ ose intended.
  • the active ingredients may also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(methylmethacylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles, and nanocapsules) or in macroemulsions.
  • colloidal drug delivery systems for example, liposomes, albumin microspheres, microemulsions, nano-particles, and nanocapsules
  • the formulations to be used for in vivo administration must be sterile. This is readily accomplished by filtration through sterile filtration membranes.
  • Sustained-release preparations may be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the antibody, which matrices are in the form of shaped articles, e.g., films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)), polylactides (U.S. Pat. No.
  • copolymers of L-glutamic acid and ⁇ efhyl-L-glutamate non-degradable ethylene- vinyl acetate
  • degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOT TM (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate)
  • LUPRON DEPOT TM injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate
  • ⁇ oly-D-(-)-3- hydroxybutyric acid While polymers such as ethylene-vinyl acetate and lactic acid-glycolic acid enable release of molecules for over 100 days, certain hydrogels release proteins for shorter time periods.
  • encapsulated antibodies When encapsulated antibodies remain in the body for a long time, they may denature or aggregate as a result of exposure to moismre at 37°C, resulting in a loss of biological activity and possible changes in immunogenicity. Rational strategies can be devised for stabilization depending on the mechanism involved. For example, if the aggregation mechanism is discovered to be intermolecular S-S bond formationthroughthio-disulfide interchange, stabilization may be achieved by modifying sulfhydryl residues, lyophilizing from acidic solutions, controlling moisture content, using appropriate additives, and developing specific polymer matrix compositions.
  • anti-PRO antibodies of the invention have various utilities.
  • anti-PRO antibodies may be used in diagnostic assays for PRO, e.g. , detecting its expression in specific cells, tissues, or serum.
  • diagnostic assay techniques known in the art may be used, such as competitive binding assays, direct or indirect sandwich assays and immunoprecipitation assays conducted in either heterogeneous or homogeneous phases [Zola, Monoclonal Antibodies: A Manual of Techniques. CRC Press, Inc. (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.
  • the detectable moiety may be a radioisotope, such as 3 H, 14 C, 32 P, 35 S, or 125 I, a fluorescent or chemiluminescent compound, such as fluorescein isofhiocyanate, rhodamine, or luciferin, or an enzyme, such as alkaline phosphatase, beta-galactosidase or horseradish peroxidase.
  • a radioisotope such as 3 H, 14 C, 32 P, 35 S, or 125 I
  • a fluorescent or chemiluminescent compound such as fluorescein isofhiocyanate, rhodamine, or luciferin
  • an enzyme such as alkaline phosphatase, beta-galactosidase or horseradish peroxidase.
  • Any method known in the art for conjugating the antibody to the detectable moiety may be employed, including those methods described by Hunter et al. , Nature, 144:945 (1962); Pa
  • Anti-PRO antibodies also are useful for the affinity purification of PRO from recombinant cell culture or natural sources.
  • the antibodies against PRO 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 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, which is bound to the immobilized antibody. Finally, the support is washed with another suitable solvent that will release the PRO from the antibody.
  • EXAMPLE 1 Extracellular Pomain Homology Screening to Identify Novel Polypeptides and cPNA Encoding Therefor
  • the extracellular domain (ECP) 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., Payhoff, GenBank), and proprietary databases (e.g. LIFESEQTM, Incyte Pharmaceuticals, Palo Alto, CA).
  • the search was performed using the computer program BLAST or BLAST2 (Altschul , and Gish , Methods in Enzvmology 266 : 460-80 ( 1996) ; http: //blast.
  • consensus PNA sequences were assembled relative to the other identified EST sequences.
  • consensus PNA 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.
  • oligonucleotides were then synthesized and used to identify by PCR a cPNA library that contained the sequence of interest and for use as probes to isolate 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 bp in length.
  • the probe (.p) sequences are typically 40-55 bp in length.
  • additional oligonucleotides are synthesized when the consensus sequence is greater than about 1 - 1.5kbp.
  • PNA from the libraries was screened by PCR amplification, as per Ausubel et al. , Current Protocols in Molecular Biology, 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 cPNA libraries used to isolate the cPNA clones were constructed by standard methods using commercially available reagents such as those from Invitrogen, San Piego, CA.
  • the cPNA was primed with oligo dT containing a Notl site, linked with blunt to Sail 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 pRKP; pRK5B is a precursor of pRK5P that does not contain the Sfil site; see, Holmes et al. , Science, 253: 1278-1280 (1991)) in the unique Xhol and Notl sites.
  • a suitable cloning vector such as pRKB or pRKP; pRK5B is a precursor of pRK5P that does not contain the Sfil site; see, Holmes e
  • oligonucleotides were synthesized and used to identify by PCR a cDNA library that contained the sequences of interest and for use as probes to isolate a clone of the full-length coding sequence for the PR0211 and PR0217 polypeptides.
  • the libraries used to isolate DNA32292-1131 and DNA33094-1131 were fetal lung libraries.
  • cDNA clones were sequenced in their entirety. The entire nucleotide sequences of PR0211
  • the predicted polypeptides are 353 and 379 amino acid in length, respectively, with respective molecular weights of approximately 38,190 and 41 ,520 daltons.
  • the oligonucleotide sequences used in the above procedures were the following:

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Abstract

L'invention concerne des polypeptides et des molécules d'acides nucléiques codant pour ces polypeptides. L'invention concerne également des vecteurs et des cellules hôtes comprenant ces séquences d'acides nucléiques, des molécules de polypeptides chimériques où les polypeptides selon l'invention sont fusionnés à des séquences de polypeptides hétérologues. L'invention concerne en outre des anticorps qui se lient aux polypeptides selon l'invention ainsi que des procédés de production des polypeptides selon l'invention.
PCT/US1999/021090 1994-09-08 1999-09-15 Polypeptides secretes et transmembranaires et acides nucleiques codant pour ces polypeptides WO2000015796A2 (fr)

Priority Applications (804)

Application Number Priority Date Filing Date Title
JP2000570323A JP2004507201A (ja) 1998-09-16 1999-09-15 分泌及び膜貫通ポリペプチドとそれをコードしている核酸
MXPA01002592A MXPA01002592A (es) 1998-09-16 1999-09-15 Polipeptidos de transmembrana y secretados y acidos nucleicos que codifican los mismos.
KR1020017003385A KR20010087359A (ko) 1998-09-16 1999-09-15 분비 및 막횡단 폴리펩티드, 및 이를 코딩하는 핵산
AU59229/99A AU5922999A (en) 1998-09-16 1999-09-15 Secreted and transmembrane polypeptides and nucleic acids encoding the same
IL14153599A IL141535A0 (en) 1998-09-16 1999-09-15 Secreted and transmembrane polypeptides and nucleic acids encoding the same
EP99946924A EP1114152A2 (fr) 1998-09-16 1999-09-15 Polypeptides secretes et transmembranaires et acides nucleiques codant pour ces polypeptides
CA002343577A CA2343577A1 (fr) 1998-09-16 1999-09-15 Polypeptides secretes et transmembranaires et acides nucleiques codant pour ces polypeptides
AU17471/00A AU1747100A (en) 1999-09-13 1999-11-29 Promotion or inhibition of angiogenesis and cardiovascularization
PCT/US1999/028214 WO2001019987A1 (fr) 1999-09-13 1999-11-29 Promotion ou inhibition de l'angiogenese et de la vascularisation cardiaque
PCT/US1999/028313 WO2000032221A2 (fr) 1998-12-01 1999-11-30 Promotion et inhibition de l'angiogenese et de la vascularisation cardiaque
AU17482/00A AU771751C (en) 1998-12-01 1999-11-30 Promotion or inhibition of angiogenesis and cardiovascularization
CA002347835A CA2347835A1 (fr) 1998-12-01 1999-11-30 Promotion et inhibition de l'angiogenese et de la vascularisation cardiaque
CA002503475A CA2503475A1 (fr) 1998-12-01 1999-11-30 Promotion et inhibition de l'angiogenese et de la vascularisation cardiaque
EP06014175A EP1734051A3 (fr) 1998-12-01 1999-11-30 Composition et procédés de diagnostic de tumeurs
IL14274299A IL142742A0 (en) 1998-12-01 1999-11-30 Promotion or inhibition of angiogenesis and cardiovascularization
NZ535590A NZ535590A (en) 1998-12-01 1999-11-30 Promotion or inhibition of angiogenesis and cardiovascularization
EP99960624A EP1135485B1 (fr) 1998-12-01 1999-11-30 Promotion et inhibition de l'angiogenese et de la vascularisation cardiaque
KR10-2001-7006818A KR100529270B1 (ko) 1998-12-01 1999-11-30 혈관신생 및 심혈관형성의 촉진 또는 억제
MXPA01005169A MXPA01005169A (es) 1998-12-01 1999-11-30 Promocion o inhibicion deangiogenesis y cardiovascularizacion.
AT99960624T ATE458050T1 (de) 1998-12-01 1999-11-30 Promotion oder inhibition von angiogenese und kardiovaskularisation
JP2000584912A JP3695642B2 (ja) 1998-12-01 1999-11-30 血管形成及び心臓血管新生の促進又は阻害
MXPA01006330A MXPA01006330A (es) 1998-12-22 1999-12-02 Metodos y composiciones para inhibir el crecimiento de celulas neoplasticas.
CA002353799A CA2353799A1 (fr) 1998-12-22 1999-12-02 Methodes permettant d'inhiber la croissance de cellules neoplasiques
AU17498/00A AU1749800A (en) 1999-03-12 1999-12-02 Methods and compositions for inhibiting neoplastic cell growth
ES04007617T ES2281704T3 (es) 1998-12-22 1999-12-02 Procedimientos y compuestos para inhibir el crecimiento de celulas neoplasicas.
DK04007617T DK1484338T3 (da) 1998-12-22 1999-12-02 Fremgangsmåder og sammensætninger til inhibition af neoplastisk cellevækst
DE69940964T DE69940964D1 (de) 1998-12-22 1999-12-02 Verfahren und Zusammensetzungen zur Hemmung des neoplastischen Zellenwachstums
EP99960644A EP1141284A2 (fr) 1998-12-22 1999-12-02 Methodes permettant d'inhiber la croissance de cellules neoplasiques
AT04007617T ATE353339T1 (de) 1998-12-22 1999-12-02 Verfahren und zusammensetzung zur hemmung des neoplastischen zellwachstums
KR10-2001-7007850A KR100499600B1 (ko) 1998-12-22 1999-12-02 신생 세포 성장을 억제하기 위한 방법 및 조성물
EP09004092A EP2075335A3 (fr) 1998-12-22 1999-12-02 Procédés et compositions d'inhibition de la croissance de cellules néoplasiques
DE69935085T DE69935085T2 (de) 1998-12-22 1999-12-02 Verfahren und Zusammensetzung zur Hemmung des neoplastischen Zellwachstums
EP07001711A EP1820859B9 (fr) 1998-12-22 1999-12-02 Procédés et compositions d'inhibition de la croissance de cellules néoplasiques
IL14303199A IL143031A0 (en) 1998-12-22 1999-12-02 Methods and compositions for inhibiting neoplastic cell growth
ES07001711T ES2327785T3 (es) 1998-12-22 1999-12-02 Procedimientos y compuestos para inhibir el crecimiento de celulas neoplasticas.
PCT/US1999/028565 WO2000037638A2 (fr) 1998-12-22 1999-12-02 Methodes permettant d'inhiber la croissance de cellules neoplasiques
PT04007617T PT1484338E (pt) 1998-12-22 1999-12-02 Métodos e composições para inibição do crescimento de células neoplásicas.
PCT/US1999/028564 WO2000055319A1 (fr) 1999-03-12 1999-12-02 Procedes et compositions pour inhiber la croissance des cellules neoplasiques
AT07001711T ATE432987T1 (de) 1998-12-22 1999-12-02 Verfahren und zusammensetzungen zur hemmung des neoplastischen zellenwachstums
AU17499/00A AU768230B2 (en) 1998-12-22 1999-12-02 Methods and compositions for inhibiting neoplastic cell growth
JP2000589692A JP3993746B2 (ja) 1998-12-22 1999-12-02 腫瘍性細胞成長阻害のための組成物及び方法
CA002450402A CA2450402A1 (fr) 1998-12-22 1999-12-02 Methodes et compositions permettant d'inhiber la croissance de cellules cancereuses avec la pro224
EP04007617A EP1484338B1 (fr) 1998-12-22 1999-12-02 Méthode et composition pour l'inhibition de la croissance des cellules néoplastiques
EP99966374A EP1141289A2 (fr) 1998-12-22 1999-12-16 Compositions et methodes de traitement d'une tumeur
KR1020017007877A KR20010102960A (ko) 1998-12-22 1999-12-16 종양 치료용 조성물 및 방법
CA002353775A CA2353775A1 (fr) 1998-12-22 1999-12-16 Compositions et methodes de traitement d'une tumeur
IL14321299A IL143212A0 (en) 1998-12-22 1999-12-16 Compositions and methods for the treatment of tumor
MXPA01006345A MXPA01006345A (es) 1998-12-22 1999-12-16 Composiciones y metodos para el tratamiento de un tumor.
AU21928/00A AU2192800A (en) 1998-12-22 1999-12-16 Compositions and methods for the treatment of tumor
JP2000589694A JP2003524390A (ja) 1998-12-22 1999-12-16 腫瘍治療のための組成物及び方法
PCT/US1999/030095 WO2000037640A2 (fr) 1998-12-22 1999-12-16 Compositions et methodes de traitement d'une tumeur
PCT/US1999/030911 WO2000075316A1 (fr) 1999-06-02 1999-12-20 Procedes et compositions pour l'inhibition de la croissance de cellules neoplastiques
AU23907/00A AU2390700A (en) 1999-07-20 1999-12-20 Polypeptidic compositions and methods for the treatment of tumors
AU22153/00A AU2215300A (en) 1999-06-02 1999-12-20 Methods and compositions for inhibiting neoplastic cell growth
PCT/US1999/030999 WO2001005836A1 (fr) 1999-07-20 1999-12-20 Compositions polypeptidiques et methodes de traitement des tumeurs
AU26008/00A AU2600800A (en) 1999-03-08 2000-01-05 Promotion or inhibition of angiogenesis and cardiovascularization
PCT/US2000/000219 WO2000053753A2 (fr) 1999-03-08 2000-01-05 Activation ou inhibition de l'angiogenese et de la cardiovascularisation
AT05018353T ATE422536T1 (de) 1999-03-08 2000-02-11 Zusammensetzungen und methoden zur diagnose von tumoren
ES05018354T ES2290834T3 (es) 1999-03-08 2000-02-11 Secuencias de genes amplificados en tumores y sus usos diagnosticos.
PT05018355T PT1623989E (pt) 1999-03-08 2000-02-11 ''composições e métodos para o diagnóstico de tumores''
PT05018357T PT1626058E (pt) 1999-03-08 2000-02-11 Composições e métodos para o diagnóstico de tumores
EP05018358A EP1623990B1 (fr) 1999-03-08 2000-02-11 Compositions et procédures pour le traitement de tumeurs
EP00907270A EP1173563A1 (fr) 1999-03-08 2000-02-11 Compositions et procedes destines au traitement de tumeur
DK05018358T DK1623990T3 (da) 1999-03-08 2000-02-11 Sammensætninger og fremgangsmåder til tumorbehandling
CA002365610A CA2365610A1 (fr) 1999-03-08 2000-02-11 Compositions et procedes destines au traitement de tumeur
DK05018354T DK1632499T3 (da) 1999-03-08 2000-02-11 Gensekvenser amplificeret i tumorer og diagnistiske anvendelser deraf
EP05018354A EP1632499B9 (fr) 1999-03-08 2000-02-11 Séquences des gènes amplifiés dans des tumeurs et leurs utilisations diagnostiques
DK05018356T DK1607402T3 (da) 1999-03-08 2000-02-11 Sammensætninger og fremgangsmåder til tumorbehandling
CA002479498A CA2479498A1 (fr) 1999-03-08 2000-02-11 Compositions et procedes destines au traitement de tumeur
AT05018355T ATE364628T1 (de) 1999-03-08 2000-02-11 Verfahren und zusammensetzungen zur diagnose von tumoren
EP05018355A EP1623989B1 (fr) 1999-03-08 2000-02-11 Compositions et méthodes de diagnostique de tumeurs
ES05018356T ES2279473T3 (es) 1999-03-08 2000-02-11 Procedimiento de diagnosis de tumores.
ES05018353T ES2321954T3 (es) 1999-03-08 2000-02-11 Composiciones y procedimientos para el diagnostico de tumores.
AT05018354T ATE363489T1 (de) 1999-03-08 2000-02-11 In tumoren vervielfältigte gensequenzen und deren diagnostische verwendungen
EP05018356A EP1607402B1 (fr) 1999-03-08 2000-02-11 Méthode de diagnostic de tumeurs
DK05018355T DK1623989T3 (da) 1999-03-08 2000-02-11 Sammensætninger og fremgangsmåder til diagnosticering af tumorer
PT05018356T PT1607402E (pt) 1999-03-08 2000-02-11 Método para o diagnóstico de tumores
JP2001553947A JP2004520003A (ja) 1999-03-08 2000-02-11 腫瘍治療のための組成物及び方法
AT05018357T ATE377025T1 (de) 1999-03-08 2000-02-11 Zusammensetzungen und verfahren zur diagnose von tumoren
KR10-2001-7011391A KR100512819B1 (ko) 1999-03-08 2000-02-11 종양 치료용 조성물 및 방법
CA002479511A CA2479511A1 (fr) 1999-03-08 2000-02-11 Compositions et procedes destines au traitement de tumeur
ES05018358T ES2298896T3 (es) 1999-03-08 2000-02-11 Composiciones y procedimientos para el tratamiento de tumores.
PT05018354T PT1632499E (pt) 1999-03-08 2000-02-11 Dispositivo de detecção de impacto para automóveis.
DK05018357T DK1626058T3 (da) 1999-03-08 2000-02-11 Sammensætninger og fremgangsmåder til diagnosticering af tumor
CA002479476A CA2479476C (fr) 1999-03-08 2000-02-11 Compositions et procedes destines au traitement de tumeur
ES05018355T ES2289630T3 (es) 1999-03-08 2000-02-11 Composiciones y procedimientos para el diagnostico de tumores.
PT05018358T PT1623990E (pt) 1999-03-08 2000-02-11 Composições e métodos para o tratamento de tumores
EP05018357A EP1626058B1 (fr) 1999-03-08 2000-02-11 Compositions et méthodes pour le diagnostique de tumeurs
EP05018353A EP1626084B1 (fr) 1999-03-08 2000-02-11 Compositions et méthodes pour le diagnostic de tumeurs
AT05018356T ATE348108T1 (de) 1999-03-08 2000-02-11 Methode zum nachweis von tumoren
AU28794/00A AU756400B2 (en) 1999-03-08 2000-02-11 Compositions and methods for the treatment of tumor
AT05018358T ATE380195T1 (de) 1999-03-08 2000-02-11 Zusammensetzungen und verfahren zur behandlung von tumoren
PCT/US2000/003565 WO2001053486A1 (fr) 1999-03-08 2000-02-11 Compositions et procedes destines au traitement de tumeur
CA002479494A CA2479494C (fr) 1999-03-08 2000-02-11 Compositions et methodes associees au gene pro5725 et son application aux diagnostics d'une tumeur broncho-pulmonaire et d'une tumeur du colon
ES05018357T ES2296029T3 (es) 1999-03-08 2000-02-11 Composiciones y procedimientos para el diagnostico de tumores.
AU28839/00A AU2883900A (en) 1999-07-07 2000-02-22 Secreted and transmembrane polypeptides and nucleic acids encoding the same
PCT/US2000/004414 WO2001004311A1 (fr) 1999-07-07 2000-02-22 Polypeptides secretes et transmembranaires et acides nucleiques codant pour ces polypeptides
EP00912015A EP1159419A1 (fr) 1999-03-08 2000-02-24 Activation et inhibition de l'angiogenese et de la cardiovascularisation
KR1020017011378A KR100553300B1 (ko) 1999-03-08 2000-02-24 혈관신생 및 심혈관형성의 촉진 또는 억제 방법
PCT/US2000/005004 WO2000053757A2 (fr) 1999-03-08 2000-02-24 Activation et inhibition de l'angiogenese et de la cardiovascularisation
AU33816/00A AU768694B2 (en) 1999-03-08 2000-02-24 Promotion or inhibition of angiogenesis and cardiovascularization
JP2000603378A JP2003531811A (ja) 1999-03-08 2000-02-24 血管形成及び心臓血管新生の促進又は阻害
KR1020017011378D KR20010104373A (ko) 1999-03-08 2000-02-24 혈관신생 및 심혈관형성의 촉진 또는 억제 방법
CA002361849A CA2361849A1 (fr) 1999-03-08 2000-02-24 Activation et inhibition de l'angiogenese et de la cardiovascularisation
CA002362427A CA2362427A1 (fr) 1999-03-08 2000-03-02 Compositions et methodes de traitement des maladies immunitaires
JP2000603379A JP2004516227A (ja) 1999-03-08 2000-03-02 免疫関連疾患を治療するための組成物と方法
KR1020017011406A KR20010103046A (ko) 1999-03-08 2000-03-02 면역 관련 질환 치료용 조성물 및 치료 방법
EP00913764A EP1220905A2 (fr) 1999-03-08 2000-03-02 Compositions et methodes pour le traitement de maladies immunitaires
PCT/US2000/005841 WO2000053758A2 (fr) 1999-03-08 2000-03-02 Compositions et methodes de traitement des maladies immunitaires
AU35144/00A AU3514400A (en) 1999-03-08 2000-03-02 Compositions and methods for the treatment of immune related diseases
PCT/US2000/006471 WO2001018210A1 (fr) 1999-09-08 2000-03-09 Acides nucleiques et polypeptides du facteur 19 de croissance du fibroblaste, et procedes d'utilisation dans le traitement de l'obesite
SI200030879T SI1214409T1 (sl) 1999-09-08 2000-03-09 Nukleinske kisline in polipeptidi fibroblastnega rastnega faktorja-19 (FGF-19) in postopki za uporabo za zdravljenje debelosti
MXPA02002491A MXPA02002491A (es) 1999-09-08 2000-03-09 Acidos nucleicos y polipeptidos del factor 19 de crecimiento de fibroblastos y metodos de uso para tratamiento de la obesidad.
KR1020027003131A KR20020059591A (ko) 1997-10-27 2000-03-09 섬유모세포 성장 인자-19 (ｆｇｆ-19) 핵산 및폴리펩티드, 및 비만 치료를 위한 사용 방법
ES00917878T ES2264929T3 (es) 1999-09-08 2000-03-09 Acidos nucleicos y polipeptidos del factor 19 de crecimiento fibroblastico (fgf-19) y procedimientos de utilizacion para el tratamiento de la obesidad.
JP2001521746A JP2004500037A (ja) 1999-09-08 2000-03-09 繊維芽細胞成長因子−１９（ｆｇｆ−１９）核酸及びポリペプチド並びに肥満の治療のための利用の方法
DE60028054T DE60028054T2 (de) 1999-09-08 2000-03-09 Fibroblasten-wachstumsfaktor-19 (fgf-19) nukleinsäure und polypeptide und verfahren zu deren verwendung für behandlung von fettleibigkeit
AU38784/00A AU783117B2 (en) 1999-09-08 2000-03-09 Fibroblast growth factor-19 (FGF-19) nucleic acids and polypeptides and methods of use for the treatment of obesity
PT00917878T PT1214409E (pt) 1999-09-08 2000-03-09 Acidos nucleicos e polipeptidos do factor de crescimento de fibroblastos-19 (fgf-19) e metodos de utilizacao para o tratamento de obesidade
DK00917878T DK1214409T3 (da) 1999-09-08 2000-03-09 Fibroblast vækstfaktor-19 (FGF-19) nucleinsyrer og polypeptider samt anvendelsesmetoder til behandling af fedme
AT00917878T ATE326532T1 (de) 1999-09-08 2000-03-09 Fibroblasten-wachstumsfaktor-19 (fgf-19) nukleinsäure und polypeptide und verfahren zu deren verwendung für behandlung von fettleibigkeit
CA002384089A CA2384089A1 (fr) 1999-09-08 2000-03-09 Acides nucleiques et polypeptides du facteur 19 de croissance du fibroblaste, et procedes d'utilisation dans le traitement de l'obesite
EP00917878A EP1214409B1 (fr) 1999-09-08 2000-03-09 Acides nucleiques et polypeptides du facteur 19 de croissance du fibroblaste, et procedes d'utilisation dans le traitement de l'obesite
IL14818800A IL148188A0 (en) 1999-09-08 2000-03-09 Fibroblast growth factor-19 (fgf-19) nucleic acids and polypeptides and methods of use for the treatment of obesity
CN00815274A CN1387570A (zh) 1999-09-08 2000-03-09 成纤维细胞生长因子－19(fgf－19)的核酸和多肽以及用于治疗肥胖的方法
CNA2004100465359A CN1560249A (zh) 1999-09-08 2000-03-09 成纤维细胞生长因子-19（fgf-19）的核酸和多肽以及用于治疗肥胖的方法
EP00916675A EP1210418B1 (fr) 1999-06-02 2000-03-30 Polypeptides secretes et transmembranaires ainsi que les acides nucleiques codant pour ceux-ci
JP2001500766A JP2004522402A (ja) 1999-06-02 2000-03-30 同一のものをコードする分泌及び膜貫通ポリペプチドと核酸
AT00916675T ATE478145T1 (de) 1999-06-02 2000-03-30 Sekretierte und transmembran polypeptide und dafür kodierende nukleinsäuren
PCT/US2000/008439 WO2000073454A1 (fr) 1999-06-02 2000-03-30 Polypeptides transmembranaires secretes et acides nucleiques codants pour ceux-ci
CA002383254A CA2383254A1 (fr) 1999-06-02 2000-03-30 Polypeptides transmembranaires secretes et acides nucleiques codants pour ceux-ci
AU37743/00A AU3774300A (en) 1999-06-02 2000-03-30 Secreted and transmembrane polypeptides and nucleic acids encoding the same
DE60044849T DE60044849D1 (de) 1999-06-02 2000-03-30 Sekretierte und transmembran polypeptide und dafür kodierende nukleinsäuren
EP07025116A EP1953173B1 (fr) 1999-06-15 2000-05-22 Polypeptides sécrétés et transmembranaires, et acides nucléiques les codant
EP00936172A EP1208195A2 (fr) 1999-06-15 2000-05-22 Polypeptides secretes et transmembranaires et acides nucleiques codant pour ceux-ci
AT07025116T ATE449109T1 (de) 1999-06-15 2000-05-22 Sekretierte und transmembran-polypeptide sowie nukleinsäuren zu deren kodierung
AU51527/00A AU5152700A (en) 1999-06-15 2000-05-22 Secreted and transmembrane polypeptides and nucleic acids encoding the same
DE60043367T DE60043367D1 (de) 1999-06-15 2000-05-22 Sekretierte und Transmembran-Polypeptide sowie Nukleinsäuren zu deren Kodierung
PCT/US2000/014042 WO2000077037A2 (fr) 1999-06-15 2000-05-22 Polypeptides secretes et transmembranaires et acides nucleiques les codant
JP2001503894A JP2003529324A (ja) 1999-06-15 2000-05-22 分泌及び膜貫通ポリペプチドとそれをコードする核酸
EP07025118A EP1956030B1 (fr) 1999-06-15 2000-05-22 Polypeptides sécrétés et transmembranaires, et acides nucléiques les codant
CA2372511A CA2372511C (fr) 1999-06-15 2000-05-22 Polypeptides secretes et transmembranaires et acides nucleiques les codant
EP07025117A EP1978029A3 (fr) 1999-06-15 2000-05-22 Polypeptides sécrétés et transmembranaires, et acides nucléiques les codant
DE60043322T DE60043322D1 (de) 1999-06-15 2000-05-22 Sekretierte und Transmembran-Polypeptide sowie Nukleinsäuren zu deren Kodierung
AT07025118T ATE448246T1 (de) 1999-06-15 2000-05-22 Sekretierte und transmembran-polypeptide sowie nukleinsäuren zu deren kodierung
PCT/US2000/015264 WO2000073452A2 (fr) 1999-06-02 2000-06-02 Compositions et methodes de traitement de maladies liees a l'immunite
AU54601/00A AU5460100A (en) 1999-06-02 2000-06-02 Compositions and methods for the treatment of immune related diseases
PCT/US2000/020710 WO2001009327A2 (fr) 1999-07-28 2000-07-28 Procede de prevention de la deterioration ou de la mort des cellules de la retine et de traitement des troubles oculaires
AU63910/00A AU6391000A (en) 1999-07-28 2000-07-28 Method of preventing the injury or death of retinal cells and treating ocular diseases
EP05019539A EP1623993A3 (fr) 1999-09-01 2000-08-24 Protéines sécrétées et transmembranaire et acides nucléiques les codant
CA002645727A CA2645727A1 (fr) 1999-09-01 2000-08-24 Polypeptides secretes et transmembranaires et acides nucleiques codant pour ceux-ci
JP2001520864A JP3951035B2 (ja) 1999-09-01 2000-08-24 分泌及び膜貫通ポリペプチドとそれをコードしている核酸
ES05019537T ES2341257T3 (es) 1999-09-01 2000-08-24 Polipeptidos secretados y transmembrana y acidos nucleicos que los codifican.
PCT/US2000/023328 WO2001016318A2 (fr) 1999-09-01 2000-08-24 Polypeptides secretes et transmembranaires et acides nucleiques codant pour ceux-ci
AU75730/00A AU7573000A (en) 1999-09-01 2000-08-24 Secreted and transmembrane polypeptides and nucleic acids encoding the same
EP07019808A EP1892249A1 (fr) 1999-09-01 2000-08-24 Polypeptides sécrétés et transmembranaires, et acides nucléiques les codant
EP00964919A EP1208202A2 (fr) 1999-09-01 2000-08-24 Polypeptides secretes et transmembranaires et acides nucleiques codant pour ceux-ci
AT05019537T ATE459645T1 (de) 1999-09-01 2000-08-24 Ausgeschiedene polypeptide und transmembranpolypeptide und dafür kodierende nukleinsäuren
EP05019538A EP1623992A3 (fr) 1999-09-01 2000-08-24 Polypeptides sécrétés et transmembranaires ainsi que les acides nucléiques codant pour ceux-ci
EP05019540A EP1621620A3 (fr) 1999-09-01 2000-08-24 Polypeptides sécrétés et transmembranaires ainsi que les acides nucléiques codant pour ceux-ci
EP05019536A EP1623991A3 (fr) 1999-09-01 2000-08-24 Polypeptides sécrétés et transmembranaires ainsi que les acides nucléiques codant pour ceux-ci
CA002380355A CA2380355A1 (fr) 1999-09-01 2000-08-24 Polypeptides secretes et transmembranaires et acides nucleiques codant pour ceux-ci
EP05019537A EP1637541B1 (fr) 1999-09-01 2000-08-24 Polypeptides sécrétés et transmembranaires ainsi que les acides nucléiques codant pour ceux-ci
DE60043951T DE60043951D1 (de) 1999-09-01 2000-08-24 Ausgeschiedene Polypeptide und Transmembranpolypeptide und dafür kodierende Nukleinsäuren
US09/767,609 US20020042367A1 (en) 1997-11-25 2001-01-22 Fibroblast growth factor-19 (FGF-19) nucleic acids and polypeptides and methods of use for the treatment of obesity and related disorders
US09/828,366 US20020010137A1 (en) 1997-09-18 2001-04-05 Methods and compositions for inhibiting neoplastic cell growth
US09/866,028 US6642360B2 (en) 1997-12-03 2001-05-25 Secreted polypeptides that stimulate release of proteoglycans from cartilage
US09/902,713 US20030082541A1 (en) 1997-09-17 2001-07-10 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/902,572 US20030108983A1 (en) 1997-09-17 2001-07-10 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/902,692 US20030054400A1 (en) 1997-09-17 2001-07-10 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/902,759 US20030077654A1 (en) 1997-09-17 2001-07-10 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/902,853 US20020192659A1 (en) 1997-09-17 2001-07-10 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/902,634 US20030082540A1 (en) 1997-09-17 2001-07-10 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/902,615 US20030092002A1 (en) 1997-09-17 2001-07-10 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/902,736 US20030049676A1 (en) 1997-09-17 2001-07-10 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/902,979 US20030113718A1 (en) 1997-09-17 2001-07-10 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/902,903 US20030044839A1 (en) 1997-09-17 2001-07-10 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/903,520 US20030054401A1 (en) 1997-09-17 2001-07-11 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/903,823 US20030104381A1 (en) 1997-09-17 2001-07-11 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/903,806 US20030130489A1 (en) 1997-09-17 2001-07-11 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/903,925 US20030096233A1 (en) 1997-09-17 2001-07-11 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/904,119 US20030049621A1 (en) 1997-09-17 2001-07-11 Secreted and transmembrane polypeptides and nucleic acids enconding the same
US09/903,943 US20030054349A1 (en) 1997-09-17 2001-07-11 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/903,749 US7147853B2 (en) 1997-09-17 2001-07-11 Anti-pro211 polypeptide antibodies
US09/903,640 US7208308B2 (en) 1997-09-17 2001-07-11 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/903,786 US20030044793A1 (en) 1997-09-17 2001-07-11 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/903,562 US6965015B2 (en) 1997-09-17 2001-07-11 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/904,011 US20030003530A1 (en) 1997-09-17 2001-07-11 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/903,603 US20030148419A1 (en) 1997-09-17 2001-07-11 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/904,877 US20030186358A1 (en) 1997-09-17 2001-07-12 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/904,992 US20030135025A1 (en) 1997-09-17 2001-07-12 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/905,125 US6664376B2 (en) 1997-09-17 2001-07-12 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/904,786 US7557192B2 (en) 1997-09-17 2001-07-12 Anti-PRO335 antibodies
US09/904,766 US20030152999A1 (en) 1997-09-17 2001-07-12 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/905,088 US20030073077A1 (en) 1997-09-17 2001-07-12 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/905,291 US20020160374A1 (en) 1997-09-17 2001-07-12 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/904,859 US20030036060A1 (en) 1997-09-17 2001-07-12 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/904,938 US20030211569A1 (en) 1997-09-17 2001-07-12 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/905,056 US20030054441A1 (en) 1997-09-17 2001-07-12 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/905,381 US6818746B2 (en) 1997-09-17 2001-07-13 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/904,485 US20030064367A1 (en) 1997-09-17 2001-07-13 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/905,075 US7169906B2 (en) 1997-09-17 2001-07-13 PRO211 polypeptides
US09/905,348 US20030064923A1 (en) 1997-09-17 2001-07-13 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/904,532 US7151160B2 (en) 1997-09-17 2001-07-13 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/904,820 US20030036094A1 (en) 1997-09-17 2001-07-13 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/904,462 US6878807B2 (en) 1997-09-17 2001-07-13 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/904,838 US20030148370A1 (en) 1997-09-17 2001-07-13 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/904,553 US20030059828A1 (en) 1997-09-17 2001-07-13 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/904,920 US6806352B2 (en) 1997-09-17 2001-07-13 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/905,449 US6965011B2 (en) 1997-09-17 2001-07-13 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/904,956 US20030049622A1 (en) 1995-12-01 2001-07-14 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/906,742 US20030023054A1 (en) 1997-09-17 2001-07-16 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/906,760 US20030096340A1 (en) 1997-09-17 2001-07-16 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/906,646 US6852848B2 (en) 1997-09-17 2001-07-16 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/906,722 US6946262B2 (en) 1997-09-17 2001-07-16 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/906,618 US6828146B2 (en) 1997-09-17 2001-07-16 Nucleic acid encoding PRO229 polypeptides
US09/906,815 US7094567B2 (en) 1997-09-17 2001-07-16 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/906,777 US20030148371A1 (en) 1997-09-17 2001-07-16 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/906,838 US7070979B2 (en) 1997-09-17 2001-07-16 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/906,700 US6723535B2 (en) 1997-09-17 2001-07-16 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/907,794 US6635468B2 (en) 1997-09-17 2001-07-17 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/907,925 US20030054352A1 (en) 1997-09-17 2001-07-17 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/907,613 US20030027145A1 (en) 1997-09-17 2001-07-17 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/907,728 US20030190611A1 (en) 1997-09-17 2001-07-17 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/907,575 US20030073079A1 (en) 1997-09-17 2001-07-17 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/907,824 US20020197671A1 (en) 1997-09-17 2001-07-17 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/907,841 US7033825B2 (en) 1997-09-17 2001-07-17 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/907,979 US20030082542A1 (en) 1994-09-08 2001-07-17 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/907,652 US20030104469A1 (en) 1997-09-17 2001-07-17 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/908,093 US20030017498A1 (en) 1997-09-17 2001-07-17 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/907,942 US7087738B2 (en) 1997-09-17 2001-07-17 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/909,204 US20030036061A1 (en) 1997-09-17 2001-07-18 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/909,064 US6818449B2 (en) 1997-09-17 2001-07-18 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/909,088 US20020146709A1 (en) 1997-09-17 2001-07-18 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/908,576 US20040005553A1 (en) 1997-09-17 2001-07-18 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/909,320 US7074592B2 (en) 1997-09-17 2001-07-18 Secreted and transmembrane polypeptides nucleic acid encoding
US09/924,647 US20020155543A1 (en) 1997-11-25 2001-08-07 Fibroblast growth factor-19 (FGF-19) nucleic acids and polypeptides and methods of use for the treatment of obesity and related disorders
US09/941,992 US20030082546A1 (en) 1996-11-06 2001-08-28 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/944,413 US20020156004A1 (en) 1998-09-16 2001-08-30 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/944,403 US20020165143A1 (en) 1997-12-03 2001-08-30 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/943,851 US20020150976A1 (en) 1997-12-03 2001-08-30 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/944,432 US20020142419A1 (en) 1998-09-16 2001-08-30 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/943,762 US20020142958A1 (en) 1998-09-16 2001-08-30 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/944,457 US6734288B2 (en) 1997-12-03 2001-08-30 Antibodies against a secreted polypeptide that stimulates release of proteoglycans from cartilage
US09/943,664 US20040091972A1 (en) 1997-12-03 2001-08-30 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/943,780 US20030096742A1 (en) 1997-12-03 2001-08-30 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/944,396 US20020132981A1 (en) 1997-12-03 2001-08-30 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/944,449 US20020102647A1 (en) 1997-12-03 2001-08-30 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/944,896 US7189566B2 (en) 1997-12-03 2001-08-31 PRO347 nucleic acids
US09/944,862 US20020115145A1 (en) 1997-12-03 2001-08-31 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/944,884 US7018837B2 (en) 1997-12-03 2001-08-31 Nucleic acids encoding secreted polypeptides that stimulate release of proteoglycans from cartilage
US09/945,015 US20020132768A1 (en) 1997-12-03 2001-08-31 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/944,654 US20020142959A1 (en) 1998-09-16 2001-08-31 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/944,929 US7550573B2 (en) 1997-12-03 2001-08-31 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/945,584 US6908993B2 (en) 1997-12-03 2001-08-31 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/944,944 US6929947B2 (en) 1997-12-03 2001-08-31 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/944,852 US20030083479A1 (en) 1997-12-03 2001-08-31 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/945,587 US6936254B2 (en) 1997-12-03 2001-08-31 Method of inducing fetal hemoglobin synthesis
US09/944,907 US20020198147A1 (en) 1997-12-03 2001-08-31 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/990,442 US20020132252A1 (en) 1997-06-16 2001-11-14 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/993,687 US20020198149A1 (en) 1997-06-16 2001-11-14 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/990,443 US20030054987A1 (en) 1997-06-16 2001-11-14 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/990,726 US20030054359A1 (en) 1997-06-16 2001-11-14 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/992,521 US20030083461A1 (en) 1997-06-16 2001-11-14 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/990,444 US6930170B2 (en) 1997-06-16 2001-11-14 PRO1184 polypeptides
US09/991,854 US20030059780A1 (en) 1997-06-16 2001-11-14 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/990,711 US20030032023A1 (en) 1997-06-16 2001-11-14 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/993,748 US20030069403A1 (en) 1997-06-16 2001-11-14 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/990,456 US20020137890A1 (en) 1997-03-31 2001-11-14 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/993,583 US7074897B2 (en) 1997-06-16 2001-11-14 Pro943 polypeptides
US09/993,469 US20030068623A1 (en) 1997-06-16 2001-11-14 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/992,598 US6956108B2 (en) 1997-06-16 2001-11-14 PRO1184 antibodies
US09/990,427 US20030073809A1 (en) 1997-06-16 2001-11-14 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/990,562 US20030027985A1 (en) 1997-06-16 2001-11-14 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/991,073 US20020127576A1 (en) 1997-06-16 2001-11-14 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/991,163 US20020132253A1 (en) 1997-06-16 2001-11-14 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/990,440 US20030060407A1 (en) 1997-06-16 2001-11-14 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/990,436 US20020198148A1 (en) 1997-06-16 2001-11-14 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/990,438 US20030027754A1 (en) 1997-06-16 2001-11-14 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/993,667 US20030022187A1 (en) 1997-06-16 2001-11-14 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/997,384 US7119177B2 (en) 1997-06-16 2001-11-15 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/998,041 US7309775B2 (en) 1997-06-16 2001-11-15 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/997,428 US20030027162A1 (en) 1997-06-16 2001-11-15 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/998,156 US20030044806A1 (en) 1997-06-16 2001-11-15 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/997,585 US7166282B2 (en) 1997-06-16 2001-11-15 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/997,614 US20030124531A1 (en) 1997-06-16 2001-11-15 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/997,683 US20030059783A1 (en) 1997-06-16 2001-11-15 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/997,440 US20030059833A1 (en) 1997-06-16 2001-11-15 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/997,666 US7244816B2 (en) 1997-06-16 2001-11-15 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/997,641 US7112656B2 (en) 1997-06-16 2001-11-15 PRO1312 polypeptides
US09/997,628 US20030059782A1 (en) 1997-06-16 2001-11-15 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/997,601 US7189814B2 (en) 1997-06-16 2001-11-15 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/997,349 US7034106B2 (en) 1997-06-16 2001-11-15 Pro1159 polypeptides
US09/997,666 US20030027163A1 (en) 1997-06-16 2001-11-15 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/997,384 US20030087305A1 (en) 1997-06-16 2001-11-15 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/997,529 US20030134284A1 (en) 1997-06-16 2001-11-15 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/002,796 US20030032057A1 (en) 1997-08-26 2001-11-15 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/997,573 US20030049682A1 (en) 1997-06-16 2001-11-15 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/997,542 US20030068647A1 (en) 1997-06-16 2001-11-15 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/997,601 US20030054404A1 (en) 1997-06-16 2001-11-15 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/997,585 US20030119055A1 (en) 1997-06-16 2001-11-15 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/997,857 US20030064375A1 (en) 1997-06-16 2001-11-15 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/997,333 US6953836B2 (en) 1997-06-16 2001-11-15 PRO844 polypeptides
US09/998,041 US20030119001A1 (en) 1997-06-16 2001-11-15 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/997,559 US20030054403A1 (en) 1997-06-16 2001-11-15 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/997,641 US20030224358A1 (en) 1997-06-16 2001-11-15 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/997,514 US7019116B2 (en) 1997-06-16 2001-11-15 PRO 1387 polypeptides
US09/997,653 US7034122B2 (en) 1997-06-16 2001-11-15 Antibodies to PRO1159 polypeptides
US09/997,529 US7309761B2 (en) 1997-06-16 2001-11-15 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/991,172 US20030050457A1 (en) 1997-06-16 2001-11-16 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/990,437 US20030045463A1 (en) 1997-06-16 2001-11-16 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/990,441 US7041804B2 (en) 1997-06-16 2001-11-16 Antibodies to PRO1387 polypeptides
US09/991,150 US20030194760A1 (en) 1997-06-16 2001-11-16 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/991,181 US6913919B2 (en) 1997-06-16 2001-11-16 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/991,157 US7101687B2 (en) 1997-06-16 2001-11-16 Nucleic acids encoding PRO943
US09/989,735 US6972185B2 (en) 1997-06-16 2001-11-19 Nucleic acids encoding PRO844 polypeptides
US09/989,727 US20020072497A1 (en) 1997-06-16 2001-11-19 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/989,722 US20020072067A1 (en) 1997-06-16 2001-11-19 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/989,862 US20030130182A1 (en) 1997-11-05 2001-11-19 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/989,732 US7037679B2 (en) 1997-06-16 2001-11-19 Nucleic acids encoding PRO1184 polypeptides
US09/989,279 US7083978B2 (en) 1997-06-16 2001-11-19 Nucleic acid encoding PRO1111 polypeptides
US09/989,723 US20020072092A1 (en) 1997-06-16 2001-11-19 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/989,328 US7056736B2 (en) 1997-06-16 2001-11-19 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/989,726 US7018811B2 (en) 1997-06-16 2001-11-19 Nucleic acids encoding PRO189 polypeptides
US09/989,734 US7491529B2 (en) 1997-06-16 2001-11-19 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/989,729 US20030059831A1 (en) 1997-06-16 2001-11-19 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/989,721 US20020142961A1 (en) 1997-06-16 2001-11-19 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/989,728 US7029873B2 (en) 1997-06-16 2001-11-20 Nucleic acids to PRO1387 polypeptides
US09/989,293 US7034136B2 (en) 1997-06-16 2001-11-20 Nucleic acids encoding PRO1159 polypeptides
US09/989,731 US20020103125A1 (en) 1997-06-16 2001-11-20 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/989,725 US20030139329A1 (en) 1997-06-16 2001-11-20 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/989,730 US7157247B2 (en) 1997-06-16 2001-11-20 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/989,724 US7060812B2 (en) 1997-06-16 2001-11-20 PRO1312 nucleic acids
US10/006,867 US7160985B2 (en) 1997-10-29 2001-12-06 Pro180 polypeptide
US10/028,072 US20030004311A1 (en) 1997-06-18 2001-12-19 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/052,586 US20020127584A1 (en) 1997-09-18 2002-01-15 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/066,500 US20020177165A1 (en) 1997-08-26 2002-02-01 Secreted and transmembrane polypeptides and nucleic acids encoding
US10/066,269 US20030040014A1 (en) 1997-08-26 2002-02-01 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/066,193 US20030044902A1 (en) 1997-08-26 2002-02-01 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/066,494 US20030032063A1 (en) 1997-08-26 2002-02-01 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/066,273 US7317092B2 (en) 1997-08-26 2002-02-01 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/066,198 US20030170721A1 (en) 1997-08-26 2002-02-01 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/066,203 US20030180796A1 (en) 1997-08-26 2002-02-01 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/066,211 US20030044844A1 (en) 1997-08-26 2002-02-01 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/081,056 US20040043927A1 (en) 1997-09-19 2002-02-20 Compositions and methods for the diagnosis and treatment of disorders involving angiogenesis
US10/119,480 US20040087769A1 (en) 1998-09-10 2002-04-09 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/121,045 US20030073210A1 (en) 1997-03-31 2002-04-11 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/121,042 US20030096386A1 (en) 1997-03-31 2002-04-11 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/121,059 US20030190721A1 (en) 1997-03-31 2002-04-11 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/121,046 US20030194791A1 (en) 1997-03-31 2002-04-11 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/121,040 US20030082759A1 (en) 1997-03-31 2002-04-11 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/121,047 US20030077778A1 (en) 1997-03-31 2002-04-11 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/121,044 US20030190717A1 (en) 1997-03-31 2002-04-11 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/121,041 US20030077776A1 (en) 1997-03-31 2002-04-11 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/121,051 US20030092147A1 (en) 1997-03-31 2002-04-11 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/121,061 US20030082761A1 (en) 1997-03-31 2002-04-12 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/121,043 US7220831B2 (en) 1997-03-31 2002-04-12 PRO235 polypeptides
US10/121,060 US20030190722A1 (en) 1997-03-31 2002-04-12 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/121,056 US20030082760A1 (en) 1997-03-31 2002-04-12 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/121,054 US20030199054A1 (en) 1997-03-31 2002-04-12 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/121,053 US20030199053A1 (en) 1997-03-31 2002-04-12 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/121,062 US20030077779A1 (en) 1997-03-31 2002-04-12 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/121,048 US20030199051A1 (en) 1997-03-31 2002-04-12 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/121,050 US20030054516A1 (en) 1997-03-31 2002-04-12 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/121,052 US20030199052A1 (en) 1997-03-31 2002-04-12 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/121,057 US20030190719A1 (en) 1997-03-31 2002-04-12 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/121,063 US20030199055A1 (en) 1997-03-31 2002-04-12 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/121,055 US20030190718A1 (en) 1997-03-31 2002-04-12 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/121,049 US20030022239A1 (en) 1997-06-18 2002-04-12 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/121,058 US20030190720A1 (en) 1997-03-31 2002-04-12 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/123,155 US20030068794A1 (en) 1997-03-31 2002-04-15 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/123,771 US20030199060A1 (en) 1997-03-31 2002-04-15 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/123,156 US20030194792A1 (en) 1997-03-31 2002-04-15 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/123,235 US20030082762A1 (en) 1997-03-31 2002-04-15 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/123,214 US7343721B2 (en) 1997-03-31 2002-04-15 PRO4406 polypeptide
US10/123,213 US7193048B2 (en) 1997-03-31 2002-04-15 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/123,157 US20030190725A1 (en) 1997-03-31 2002-04-15 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/123,236 US20030068795A1 (en) 1997-03-31 2002-04-15 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/123,322 US20030199059A1 (en) 1997-03-31 2002-04-15 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/123,213 US20030199057A1 (en) 1997-03-31 2002-04-15 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/123,212 US7276577B2 (en) 1997-03-31 2002-04-15 PRO1866 polypeptides
US10/123,291 US20030199058A1 (en) 1997-03-31 2002-04-15 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/123,215 US7291329B2 (en) 1997-03-31 2002-04-15 Antibodies against PRO4406
US10/123,292 US20030073211A1 (en) 1997-03-31 2002-04-15 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/123,262 US20030049816A1 (en) 1997-03-31 2002-04-15 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/123,261 US20030068796A1 (en) 1997-03-31 2002-04-15 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/123,108 US7635478B2 (en) 1997-03-31 2002-04-15 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/123,154 US20030190724A1 (en) 1997-03-31 2002-04-15 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/123,109 US20030190723A1 (en) 1997-03-31 2002-04-15 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/123,902 US20030077781A1 (en) 1997-03-31 2002-04-16 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/123,905 US7285625B2 (en) 1997-06-18 2002-04-16 PRO536 polypeptides
US10/123,908 US7335728B2 (en) 1997-03-31 2002-04-16 PRO1310 polypeptides
US10/123,909 US7193049B2 (en) 1997-03-31 2002-04-16 PRO862 polypeptides
US10/123,907 US7084258B2 (en) 1997-03-31 2002-04-16 Antibodies against the PRO862 polypeptides
US10/123,905 US20030087344A1 (en) 1997-06-18 2002-04-16 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/123,910 US7329404B2 (en) 1997-03-31 2002-04-16 Antibodies against PRO1310
US10/123,913 US20030203462A1 (en) 1997-03-31 2002-04-16 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/123,911 US7408032B2 (en) 1997-03-31 2002-04-16 PRO1188 polypeptides
US10/123,912 US20030100087A1 (en) 1997-03-31 2002-04-16 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/123,906 US20030190726A1 (en) 1997-03-31 2002-04-16 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/123,903 US20030073212A1 (en) 1997-03-31 2002-04-16 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/123,904 US20030022328A1 (en) 1997-03-31 2002-04-16 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/124,824 US20030077659A1 (en) 1997-03-31 2002-04-17 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/125,166 US20030039648A1 (en) 1998-09-16 2002-04-17 Compositions and methods for the diagnosis and treatment of tumor
US10/124,822 US7109305B2 (en) 1997-03-31 2002-04-17 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/124,816 US20030190728A1 (en) 1997-03-31 2002-04-17 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/124,814 US7105335B2 (en) 1997-03-31 2002-04-17 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/124,821 US20030199023A1 (en) 1997-03-31 2002-04-17 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/124,823 US20030199062A1 (en) 1997-03-31 2002-04-17 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/125,795 US7304131B2 (en) 1997-03-31 2002-04-17 PRO1483 polypeptides
US10/124,820 US20030190729A1 (en) 1997-03-31 2002-04-17 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/125,805 US20030194794A1 (en) 1997-03-31 2002-04-17 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/124,817 US20030077786A1 (en) 1997-03-31 2002-04-17 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/124,813 US7312307B2 (en) 1997-03-31 2002-04-17 PRO1056 polypeptides
US10/124,819 US7285626B2 (en) 1997-03-31 2002-04-17 PRO1076 polypeptides
US10/125,704 US7357926B2 (en) 1997-03-31 2002-04-17 Antibodies against PRO1879 and the use thereof
US10/124,818 US20030082763A1 (en) 1997-03-31 2002-04-17 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/125,924 US7342097B2 (en) 1997-03-31 2002-04-19 PRO1309 polypeptides
US10/125,931 US20030199063A1 (en) 1997-03-31 2002-04-19 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/125,922 US7309762B2 (en) 1997-03-31 2002-04-19 PRO1360 polypeptides
US10/125,927 US20030190731A1 (en) 1997-03-31 2002-04-19 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/125,932 US7317079B2 (en) 1997-03-31 2002-04-19 PRO812 polypeptides
US10/127,831 US20030082689A1 (en) 1997-03-31 2002-04-22 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/128,689 US20030087365A1 (en) 1997-03-31 2002-04-23 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/131,825 US7282566B2 (en) 1997-03-31 2002-04-24 PRO1779 polypeptide
US10/131,823 US7304132B2 (en) 1997-03-31 2002-04-24 PRO1693 polypeptides
US10/131,817 US7291701B2 (en) 1997-03-31 2002-04-24 PRO1777 polypeptides
US10/137,868 US20030082764A1 (en) 1997-03-31 2002-05-03 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/137,865 US20030032155A1 (en) 1997-03-31 2002-05-03 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/137,867 US20030207349A1 (en) 1997-03-31 2002-05-03 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/140,470 US20030022331A1 (en) 1997-03-31 2002-05-06 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/140,474 US20030032156A1 (en) 1997-03-31 2002-05-06 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/140,020 US20030207415A1 (en) 1997-03-31 2002-05-06 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/139,963 US7288625B2 (en) 1997-03-31 2002-05-06 PRO4395 polypeptides
US10/140,024 US20040058424A1 (en) 1997-03-31 2002-05-06 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/140,023 US20030207416A1 (en) 1997-03-31 2002-05-06 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/139,980 US7247710B2 (en) 1997-03-31 2002-05-06 PRO4395 antibodies
US10/140,928 US20030068798A1 (en) 1997-03-31 2002-05-07 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/140,865 US20030207420A1 (en) 1997-03-31 2002-05-07 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,651 US7193057B2 (en) 1997-10-29 2002-05-07 Antibodies to a polypeptide encoded by a nucleic acid underexpressed in rectal tumor
US10/140,805 US20030207417A1 (en) 1997-03-31 2002-05-07 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/140,860 US7307151B2 (en) 1997-03-31 2002-05-07 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/140,864 US20030207419A1 (en) 1997-03-31 2002-05-07 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/140,925 US20030073215A1 (en) 1997-03-31 2002-05-07 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/140,808 US7425621B2 (en) 1997-03-31 2002-05-07 Antibodies against the PRO4401 polypeptide
US10/140,921 US7317080B2 (en) 1997-03-31 2002-05-07 PRO4303 polypeptides
US10/140,809 US20030207418A1 (en) 1997-03-31 2002-05-07 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/141,701 US20030207421A1 (en) 1997-03-31 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/141,755 US7297764B2 (en) 1997-03-31 2002-05-08 PRO4318 polypeptides
US10/141,756 US7488586B2 (en) 1997-03-31 2002-05-08 PRO4409 polypeptides
US10/141,760 US7342104B2 (en) 1997-03-31 2002-05-08 Antibodies against the PRO4320 polypeptide
US10/141,754 US7361732B2 (en) 1997-03-31 2002-05-08 PRO4400 polypeptides
US10/143,114 US20030036180A1 (en) 1997-03-31 2002-05-09 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/142,425 US20030207424A1 (en) 1997-03-31 2002-05-09 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/142,417 US7304133B2 (en) 1997-03-31 2002-05-09 PRO4389 polypeptides
US10/143,113 US7329730B2 (en) 1997-03-31 2002-05-09 PRO4348 polypeptides
US10/142,430 US7309766B2 (en) 1997-03-31 2002-05-09 PRO5774 polypeptides
US10/142,423 US20030049817A1 (en) 1997-03-31 2002-05-10 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/142,431 US7285629B2 (en) 1997-03-31 2002-05-10 Pro5005 polypeptides
US10/143,032 US7408033B2 (en) 1997-03-31 2002-05-10 PRO5995 polypeptides
US10/142,419 US7153941B2 (en) 1997-03-31 2002-05-10 Antibodies that bind PRO4994 polypeptides
US10/146,792 US20030207428A1 (en) 1997-03-31 2002-05-15 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/146,730 US20030207427A1 (en) 1997-03-31 2002-05-15 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/147,528 US20030219885A1 (en) 1997-03-31 2002-05-16 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/147,492 US20030082765A1 (en) 1997-03-31 2002-05-17 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/147,536 US20040077064A1 (en) 1997-03-31 2002-05-17 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/147,519 US20030077791A1 (en) 1997-03-31 2002-05-17 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/152,395 US7189534B2 (en) 1997-03-31 2002-05-21 PRO4320 polynucleotide
US10/153,934 US20030129695A1 (en) 1997-03-31 2002-05-22 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/156,843 US20030207805A1 (en) 1997-06-18 2002-05-28 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/157,782 US20030077792A1 (en) 1997-03-31 2002-05-29 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/157,786 US20030208055A1 (en) 1997-03-31 2002-05-29 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/160,498 US20030073216A1 (en) 1997-03-31 2002-05-30 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/158,791 US20030207429A1 (en) 1997-03-31 2002-05-30 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/158,782 US20030082766A1 (en) 1997-03-31 2002-05-30 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/173,693 US20030073169A1 (en) 1997-09-18 2002-06-17 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/173,701 US20030104538A1 (en) 1997-09-18 2002-06-17 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/173,690 US20030166105A1 (en) 1997-09-18 2002-06-17 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/173,707 US20030166110A1 (en) 1997-09-18 2002-06-17 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/173,694 US20030166107A1 (en) 1997-09-18 2002-06-17 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/173,704 US20030170795A1 (en) 1997-09-18 2002-06-17 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/173,697 US20030032102A1 (en) 1997-09-18 2002-06-17 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/173,691 US20030166106A1 (en) 1997-09-18 2002-06-17 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/173,702 US20030170793A1 (en) 1997-09-18 2002-06-17 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/173,696 US20030082767A1 (en) 1997-09-18 2002-06-17 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/173,689 US20030166104A1 (en) 1997-09-18 2002-06-17 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/173,700 US20030027262A1 (en) 1997-09-18 2002-06-17 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/173,706 US20030022293A1 (en) 1997-09-18 2002-06-17 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/173,695 US20030032101A1 (en) 1997-09-18 2002-06-17 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/173,703 US20030170794A1 (en) 1997-09-18 2002-06-17 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/173,692 US20030166188A1 (en) 1997-09-18 2002-06-17 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/173,705 US20030032103A1 (en) 1997-09-18 2002-06-17 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/173,699 US20030166109A1 (en) 1997-09-18 2002-06-17 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/173,698 US20030166108A1 (en) 1997-09-18 2002-06-17 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/174,585 US20030032105A1 (en) 1997-09-18 2002-06-18 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/174,579 US20030027264A1 (en) 1997-09-18 2002-06-18 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/174,570 US20030211572A1 (en) 1997-09-18 2002-06-18 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/174,581 US7153939B2 (en) 1997-09-18 2002-06-18 PRO354 antibodies
US10/174,591 US20030166115A1 (en) 1997-09-18 2002-06-18 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/174,583 US7211645B2 (en) 1997-09-18 2002-06-18 PRO268 polypeptides
US10/174,574 US20030170796A1 (en) 1997-09-18 2002-06-18 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/174,590 US20030008352A1 (en) 1997-09-18 2002-06-18 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/174,586 US20030032106A1 (en) 1997-09-18 2002-06-18 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/174,587 US20030166113A1 (en) 1997-09-18 2002-06-18 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/174,569 US20030166111A1 (en) 1997-09-18 2002-06-18 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/174,588 US20030027266A1 (en) 1997-09-18 2002-06-18 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/174,572 US20030027263A1 (en) 1997-09-18 2002-06-18 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/174,578 US20030073170A1 (en) 1997-09-18 2002-06-18 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/174,582 US20030027265A1 (en) 1997-09-18 2002-06-18 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/174,589 US20030166114A1 (en) 1997-09-18 2002-06-18 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/174,576 US7125962B2 (en) 1997-09-18 2002-06-18 Anti-Pro268 antibodies
US10/175,742 US20030166118A1 (en) 1997-09-18 2002-06-19 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/175,736 US20030166117A1 (en) 1997-09-18 2002-06-19 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/175,746 US20030027270A1 (en) 1997-09-18 2002-06-19 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/175,741 US20030073171A1 (en) 1997-09-18 2002-06-19 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/175,744 US20030166119A1 (en) 1997-09-18 2002-06-19 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/175,750 US20030073172A1 (en) 1997-09-18 2002-06-19 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/175,738 US20030022294A1 (en) 1997-09-18 2002-06-19 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/175,739 US20030027267A1 (en) 1997-09-18 2002-06-19 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/175,743 US20030027269A1 (en) 1997-09-18 2002-06-19 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/175,752 US20030022295A1 (en) 1997-09-18 2002-06-19 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/175,753 US20030077732A1 (en) 1997-09-18 2002-06-19 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/175,754 US20030166123A1 (en) 1997-09-18 2002-06-19 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/175,749 US20050196832A1 (en) 1997-09-18 2002-06-19 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/175,745 US20030166120A1 (en) 1997-09-18 2002-06-19 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/175,748 US20030166121A1 (en) 1997-09-18 2002-06-19 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/175,747 US20030032107A1 (en) 1997-09-18 2002-06-19 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/175,735 US20030082715A1 (en) 1997-09-18 2002-06-19 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/175,751 US20030166122A1 (en) 1997-09-18 2002-06-19 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/176,490 US20030170798A1 (en) 1997-09-18 2002-06-20 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/176,981 US20030170800A1 (en) 1997-09-18 2002-06-20 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/176,749 US20030017542A1 (en) 1997-09-18 2002-06-20 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/176,746 US20030068680A1 (en) 1997-09-18 2002-06-20 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/176,753 US20030044917A1 (en) 1997-09-18 2002-06-20 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/176,759 US20030166128A1 (en) 1997-09-18 2002-06-20 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/176,491 US20030087373A1 (en) 1997-09-18 2002-06-20 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/176,993 US20030027280A1 (en) 1997-09-18 2002-06-20 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/176,747 US20030027273A1 (en) 1997-09-18 2002-06-20 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/176,479 US20030040054A1 (en) 1997-09-18 2002-06-20 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/176,920 US20030166129A1 (en) 1997-09-18 2002-06-20 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/176,483 US20030017541A1 (en) 1997-09-18 2002-06-20 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/176,911 US20030032113A1 (en) 1997-09-18 2002-06-20 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/176,487 US20030032110A1 (en) 1997-09-18 2002-06-20 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/176,921 US20030027276A1 (en) 1997-09-18 2002-06-20 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/176,482 US20030022296A1 (en) 1997-09-18 2002-06-20 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/176,917 US20030044918A1 (en) 1997-09-18 2002-06-20 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/176,485 US20030032109A1 (en) 1997-09-18 2002-06-20 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/176,918 US7495083B2 (en) 1997-09-18 2002-06-20 PRO940 antibodies
US10/176,988 US20030170802A1 (en) 1997-09-18 2002-06-20 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/176,484 US20030059876A9 (en) 1997-09-18 2002-06-20 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/176,757 US7317082B2 (en) 1997-09-18 2002-06-20 PRO1018 polypeptides
US10/176,493 US20030032111A1 (en) 1997-09-18 2002-06-20 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/176,989 US20030170803A1 (en) 1997-09-18 2002-06-20 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/176,919 US20030032114A1 (en) 1997-09-18 2002-06-20 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/176,754 US7709602B2 (en) 1997-09-18 2002-06-20 PRO1078 polypeptides
US10/176,914 US20030017543A1 (en) 1997-09-18 2002-06-20 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/176,913 US20030022298A1 (en) 1997-09-15 2002-06-20 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/176,752 US20030170799A1 (en) 1997-09-18 2002-06-21 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/176,922 US20030166130A1 (en) 1997-09-18 2002-06-21 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/176,924 US20030166131A1 (en) 1997-09-18 2002-06-21 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/176,760 US7339033B2 (en) 1998-06-26 2002-06-21 Pro1481
US10/176,982 US20030044919A1 (en) 1997-09-18 2002-06-21 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/176,758 US20030008353A1 (en) 1997-09-18 2002-06-21 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/176,991 US20030027324A1 (en) 1997-09-18 2002-06-21 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/176,748 US20030040055A1 (en) 1997-09-18 2002-06-21 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/176,986 US20030073173A1 (en) 1997-09-18 2002-06-21 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/176,987 US20030027278A1 (en) 1997-09-18 2002-06-21 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/176,750 US20030027274A1 (en) 1997-09-18 2002-06-21 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/176,983 US20030170801A1 (en) 1997-09-18 2002-06-21 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/176,985 US20030027277A1 (en) 1997-09-18 2002-06-21 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/176,756 US20030032112A1 (en) 1997-09-18 2002-06-21 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/176,480 US20030166124A1 (en) 1997-09-18 2002-06-21 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/176,925 US20030032115A1 (en) 1997-09-18 2002-06-21 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/176,486 US7354999B2 (en) 1997-09-18 2002-06-21 PRO1481 polypeptides
US10/176,979 US20030087374A1 (en) 1997-09-18 2002-06-21 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/176,481 US20030032108A1 (en) 1997-09-18 2002-06-21 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/176,923 US20030068681A1 (en) 1997-09-18 2002-06-21 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/176,492 US20030027272A1 (en) 1997-09-18 2002-06-21 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/176,992 US20030027279A1 (en) 1997-09-18 2002-06-21 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/176,755 US20030166127A1 (en) 1997-09-18 2002-06-21 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/176,751 US20030036117A1 (en) 1997-09-18 2002-06-21 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/176,488 US20030027271A1 (en) 1997-09-18 2002-06-21 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/176,489 US20030166125A1 (en) 1997-09-18 2002-06-21 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/176,978 US20030032116A1 (en) 1997-09-18 2002-06-21 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/176,916 US20030040056A1 (en) 1997-09-18 2002-06-21 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/176,915 US20030017544A1 (en) 1997-09-18 2002-06-21 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/179,506 US20030044920A1 (en) 1997-09-18 2002-06-24 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/179,511 US20030104539A1 (en) 1997-09-18 2002-06-24 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/179,507 US20030040057A1 (en) 1997-09-18 2002-06-24 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/179,525 US20030040060A1 (en) 1997-09-18 2002-06-24 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/179,521 US20030170806A1 (en) 1997-09-18 2002-06-24 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/179,513 US20030044921A1 (en) 1997-09-18 2002-06-24 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/179,518 US20030104540A1 (en) 1997-09-18 2002-06-24 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/179,516 US20030040058A1 (en) 1997-09-18 2002-06-24 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/179,523 US20030215909A1 (en) 1997-09-18 2002-06-24 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/179,519 US7339024B2 (en) 1997-09-18 2002-06-24 PRO1772 polypeptides
US10/179,514 US20030044922A1 (en) 1997-09-18 2002-06-24 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/179,510 US20030032117A1 (en) 1997-09-18 2002-06-24 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/179,526 US20030100061A1 (en) 1998-06-26 2002-06-24 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/179,517 US20030170805A1 (en) 1997-09-18 2002-06-24 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/179,508 US20030166133A1 (en) 1997-09-18 2002-06-24 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/179,520 US20030096353A1 (en) 1997-09-18 2002-06-24 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/179,512 US20030166134A1 (en) 1997-09-18 2002-06-24 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/179,509 US20030207392A1 (en) 1997-09-18 2002-06-24 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/179,515 US20030166135A1 (en) 1997-09-18 2002-06-24 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/179,522 US20030044923A1 (en) 1997-09-18 2002-06-24 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/180,546 US20030032120A1 (en) 1997-09-18 2002-06-25 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/180,555 US20030032123A1 (en) 1997-09-18 2002-06-25 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/180,554 US20050202526A1 (en) 1997-09-18 2002-06-25 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/180,547 US20030032121A1 (en) 1997-09-18 2002-06-25 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/180,549 US20030032122A1 (en) 1997-09-18 2002-06-25 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/180,550 US20030064440A1 (en) 1997-09-18 2002-06-25 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/180,552 US7348415B2 (en) 1997-09-18 2002-06-25 PRO1316 antibodies
US10/180,541 US20030036120A1 (en) 1997-09-18 2002-06-25 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/180,556 US7355000B2 (en) 1997-09-18 2002-06-25 PRO1380 polypeptides
US10/180,560 US20030044925A1 (en) 1997-09-18 2002-06-25 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/180,540 US20030040061A1 (en) 1997-09-18 2002-06-25 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/180,548 US7696319B2 (en) 1997-09-18 2002-06-25 PRO1772 antibodies
US10/180,542 US20030036121A1 (en) 1998-06-26 2002-06-25 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/180,544 US20030032119A1 (en) 1998-06-26 2002-06-25 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/180,559 US20030032124A1 (en) 1997-09-18 2002-06-25 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/180,553 US7365156B2 (en) 1997-09-18 2002-06-25 PRO1316 polypeptides
US10/180,557 US20030022301A1 (en) 1997-09-18 2002-06-25 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/180,551 US20030036123A1 (en) 1997-09-18 2002-06-25 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/180,545 US20030040062A1 (en) 1997-09-18 2002-06-25 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/180,543 US20030032118A1 (en) 1997-09-18 2002-06-25 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/183,001 US7084255B2 (en) 1997-09-18 2002-06-26 PRO1278 polypeptides
US10/183,011 US20030068682A1 (en) 1998-06-26 2002-06-26 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/183,008 US20030040064A1 (en) 1997-09-18 2002-06-26 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/183,005 US7317093B2 (en) 1997-09-18 2002-06-26 PRO1339 antibodies
US10/183,018 US20030104541A1 (en) 1997-09-18 2002-06-26 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/183,006 US7297776B2 (en) 1997-09-18 2002-06-26 PRO1374 antibodies
US10/183,017 US20030040065A1 (en) 1997-09-18 2002-06-26 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/183,016 US20030082717A1 (en) 1997-09-18 2002-06-26 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/183,002 US20030054454A1 (en) 1997-09-18 2002-06-26 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/183,015 US20030044926A1 (en) 1997-09-18 2002-06-26 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/183,019 US7425605B2 (en) 1997-09-18 2002-06-26 PRO1486 polypeptides
US10/183,014 US20030064441A1 (en) 1997-09-18 2002-06-26 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/181,000 US7319137B2 (en) 1997-09-18 2002-06-26 PRO1339 polypeptides
US10/183,013 US7309769B2 (en) 1997-09-18 2002-06-26 PRO1487 polypeptides
US10/180,999 US7297767B2 (en) 1997-09-18 2002-06-26 PRO1374 polypeptides
US10/183,010 US20030032126A1 (en) 1997-09-18 2002-06-26 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/183,012 US7718770B2 (en) 1997-09-18 2002-06-26 PRO1305-polypeptides
US10/180,998 US7087421B2 (en) 1997-09-18 2002-06-26 Pro1278 polypeptides
US10/183,003 US20030082716A1 (en) 1997-09-18 2002-06-26 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/183,009 US7339034B2 (en) 1997-09-18 2002-06-26 PRO1305 antibodies
US10/184,619 US20030049738A1 (en) 1997-09-18 2002-06-27 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/184,652 US20030032134A1 (en) 1997-09-18 2002-06-27 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/184,631 US20030036134A1 (en) 1997-09-18 2002-06-27 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/184,654 US7378486B2 (en) 1997-09-18 2002-06-27 PRO1482 antibodies
US10/184,614 US20030032128A1 (en) 1997-09-18 2002-06-27 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/184,630 US20030036133A1 (en) 1997-09-18 2002-06-27 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/184,618 US7393917B2 (en) 1997-09-18 2002-06-27 PRO1482 polypeptides
US10/184,612 US20030036127A1 (en) 1997-09-18 2002-06-27 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/184,613 US20030119105A1 (en) 1997-09-18 2002-06-27 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/184,633 US20030068683A1 (en) 1997-09-18 2002-06-27 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/184,651 US7291704B2 (en) 1997-09-18 2002-06-27 PRO1758 polypeptides
US10/184,642 US7332573B2 (en) 1997-09-18 2002-06-27 PRO1571 polypeptides
US10/184,616 US20030036128A1 (en) 1997-09-18 2002-06-27 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/184,628 US7309770B2 (en) 1997-09-18 2002-06-27 PRO1757 polypeptides
US10/184,627 US20030040070A1 (en) 1997-09-18 2002-06-27 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/184,641 US20030073174A1 (en) 1997-09-18 2002-06-27 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/184,640 US7271250B2 (en) 1998-06-26 2002-06-27 PRO1757 antibodies
US10/184,627 US7282569B2 (en) 1997-09-18 2002-06-27 PRO1508 antibodies
US10/184,630 US7304143B2 (en) 1997-09-18 2002-06-27 PRO1571 antibodies
US10/184,615 US20030044927A1 (en) 1997-09-18 2002-06-27 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/184,638 US20030054456A1 (en) 1997-09-18 2002-06-27 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/184,624 US20030104542A1 (en) 1997-09-18 2002-06-28 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/184,644 US20030044930A1 (en) 1997-09-18 2002-06-28 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/184,657 US20030104543A1 (en) 1997-09-18 2002-06-28 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/184,632 US20030036135A1 (en) 1997-09-18 2002-06-28 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/184,655 US20030040073A1 (en) 1997-09-18 2002-06-28 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/184,636 US20030036136A1 (en) 1997-09-18 2002-06-28 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/184,617 US20030036129A1 (en) 1997-09-18 2002-06-28 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/184,625 US20030040068A1 (en) 1997-09-18 2002-06-28 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/184,646 US20030032132A1 (en) 1997-09-18 2002-06-28 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/184,623 US20030032129A1 (en) 1997-09-18 2002-06-28 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/184,637 US20030032131A1 (en) 1997-09-18 2002-06-28 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/184,645 US7291718B2 (en) 1998-06-26 2002-06-28 PRO1758 antibodies
US10/184,635 US20030032130A1 (en) 1997-09-18 2002-06-28 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/184,634 US20030068684A1 (en) 1998-06-26 2002-06-28 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/184,629 US20030036132A1 (en) 1997-09-18 2002-06-28 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/184,658 US20030027281A1 (en) 1998-06-26 2002-06-28 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/184,643 US20030044929A1 (en) 1997-09-18 2002-06-28 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/184,656 US20030044931A1 (en) 1997-09-18 2002-06-28 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/184,626 US20030040069A1 (en) 1997-09-18 2002-06-28 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/184,621 US20030054455A1 (en) 1998-06-26 2002-06-28 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/184,647 US20030032133A1 (en) 1997-09-18 2002-06-28 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/184,650 US20030036138A1 (en) 1997-09-18 2002-06-28 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/184,620 US20030044928A1 (en) 1997-09-18 2002-06-28 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/184,622 US20030036130A1 (en) 1997-09-18 2002-06-29 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/187,747 US7291707B2 (en) 1997-09-18 2002-07-01 PRO1337 polypeptides
US10/187,594 US7294335B2 (en) 1998-06-26 2002-07-01 PRO19645 antibodies
US10/187,601 US7291705B2 (en) 1997-09-18 2002-07-01 PRO19645 polypeptides
US10/187,884 US20030036155A1 (en) 1997-09-18 2002-07-01 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/187,739 US7291706B2 (en) 1998-06-26 2002-07-01 PRO4352 polypeptides
US10/187,598 US20030036142A1 (en) 1997-09-18 2002-07-01 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/187,588 US7351795B2 (en) 1998-06-26 2002-07-01 PRO19563 polypeptides
US10/187,887 US7285645B2 (en) 1997-09-18 2002-07-01 PRO4356 antibodies
US10/187,597 US20030036141A1 (en) 1997-09-18 2002-07-01 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/187,886 US7291708B2 (en) 1997-09-18 2002-07-01 PRO1785 polypeptides
US10/187,746 US20030036149A1 (en) 1997-09-18 2002-07-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/187,600 US20030036143A1 (en) 1997-09-18 2002-07-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/187,757 US7276578B2 (en) 1997-09-18 2002-07-02 PRO4334 polypeptides
US10/187,753 US20030036152A1 (en) 1997-09-18 2002-07-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/187,596 US20030032136A1 (en) 1997-09-18 2002-07-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/187,745 US7250490B2 (en) 1997-09-18 2002-07-02 PRO1480 polypeptides
US10/188,770 US7358340B2 (en) 1997-09-18 2002-07-02 PRO19563 antibodies
US10/188,769 US20030036157A1 (en) 1997-09-18 2002-07-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/188,781 US20030036160A1 (en) 1997-09-18 2002-07-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/188,774 US20030040074A1 (en) 1997-09-18 2002-07-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/187,741 US20030036147A1 (en) 1997-09-18 2002-07-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/187,754 US20030036153A1 (en) 1997-09-18 2002-07-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/187,751 US20030036151A1 (en) 1997-09-18 2002-07-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/188,767 US7312310B2 (en) 1997-09-18 2002-07-02 PRO6015 polypeptides
US10/187,603 US20030036146A1 (en) 1998-06-26 2002-07-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/187,743 US20030036148A1 (en) 1997-09-18 2002-07-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/188,773 US20030036159A1 (en) 1997-09-18 2002-07-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/187,602 US20030036145A1 (en) 1997-09-18 2002-07-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/187,885 US20030032138A1 (en) 1998-06-24 2002-07-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/188,780 US7268217B2 (en) 1998-06-26 2002-07-02 PRO4421 polypeptides
US10/188,766 US7351804B2 (en) 1998-06-26 2002-07-02 Antibodies against PRO4421
US10/188,775 US20030040075A1 (en) 1997-09-18 2002-07-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/187,747 US20030036150A1 (en) 1997-09-18 2002-07-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/192,010 US20030044932A1 (en) 1997-09-18 2002-07-09 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/194,361 US20030036161A1 (en) 1998-06-26 2002-07-12 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/194,461 US20030054459A1 (en) 1998-06-26 2002-07-12 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/194,365 US7381791B2 (en) 1998-06-26 2002-07-12 PRO9739 polypeptides
US10/194,423 US7339025B2 (en) 1998-06-26 2002-07-12 PRO6246 polypeptides
US10/194,462 US7388073B2 (en) 1998-06-26 2002-07-12 PRO9835 polypeptides
US10/195,894 US20030043176A1 (en) 1998-06-26 2002-07-15 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/195,892 US7385033B2 (en) 1998-06-26 2002-07-15 PRO12970 polypeptides
US10/195,902 US20030038826A1 (en) 1998-06-26 2002-07-15 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/195,897 US20030036164A1 (en) 1997-09-18 2002-07-15 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/195,893 US20030206188A1 (en) 1998-06-26 2002-07-15 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/195,889 US7534856B2 (en) 1998-06-26 2002-07-15 PRO19624 antibodies
US10/195,883 US20060073544A1 (en) 1998-06-26 2002-07-15 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/195,901 US20030036165A1 (en) 1998-06-26 2002-07-15 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/195,888 US20060073545A1 (en) 1998-06-26 2002-07-15 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/196,745 US7423120B2 (en) 1997-09-18 2002-07-16 PRO19814 polypeptides
US10/196,760 US7408034B2 (en) 1998-06-26 2002-07-16 PRO20025 polypeptides
US10/196,762 US20030040078A1 (en) 1998-06-26 2002-07-16 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/196,759 US20030071835A1 (en) 1998-06-26 2002-07-16 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/196,756 US7304145B2 (en) 1998-06-26 2002-07-16 PRO19646 antibodies
US10/196,743 US20030038827A1 (en) 1998-06-26 2002-07-16 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/198,768 US20030049756A1 (en) 1998-06-26 2002-07-19 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/199,462 US20030054468A1 (en) 1998-06-26 2002-07-19 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/199,316 US20030068726A1 (en) 1998-06-26 2002-07-19 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/199,464 US20030032140A1 (en) 1997-09-18 2002-07-19 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/205,904 US20030073813A1 (en) 1998-06-26 2002-07-25 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/226,739 US7390879B2 (en) 1999-06-15 2002-08-23 Secreted and transmembrane polypeptides and nucleic acids encoding the same
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US10/299,937 US20030185846A1 (en) 1998-09-16 2002-11-18 Secreted and transmembrane polypeptides and nucleic acids encoding the same
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US10/336,979 US20050026243A1 (en) 1997-11-25 2003-01-02 Fibroblast growth factor-19 (FGF-19) nucleic acids and polypeptides and methods of use for the treatment of obesity and related disorders
AU2003200731A AU2003200731C1 (en) 1999-03-08 2003-02-25 Compositions and methods for the treatment of tumor
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US10/429,667 US20030207401A1 (en) 1997-12-03 2003-05-01 Secreted and transmembrane polypeptides and nucleic acids encoding the same
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US11/518,609 US20070077623A1 (en) 1997-09-17 2006-09-07 Secreted and transmembrane polypeptides and nucleic acids encoding the same
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IL186154A IL186154A0 (en) 1998-12-22 2007-09-20 Methods and compositions for inhibiting neoplastic cell growth
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PCT/US1999/005028 Continuation-In-Part WO1999046281A2 (fr) 1996-11-06 1999-03-08 Nouveaux polypeptides et acides nucleiques les codant
PCT/US1999/012252 Continuation-In-Part WO1999063088A2 (fr) 1996-11-06 1999-06-02 Proteines membranaires et acides nucleiques codant ces proteines
PCT/US1999/012252 Continuation WO1999063088A2 (fr) 1996-11-06 1999-06-02 Proteines membranaires et acides nucleiques codant ces proteines
PCT/US1999/020944 Continuation-In-Part WO2000015792A2 (fr) 1994-09-08 1999-09-13 Promotion ou inhibition d'angiogenese et de cardiovascularisation
PCT/US1999/021194 Continuation WO2000017353A1 (fr) 1997-10-29 1999-09-15 Ucp4

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US09/284,663 Continuation US20020012961A1 (en) 1997-08-26 1998-11-25 Fibroblast growth factor- 19
PCT/US1999/021547 Continuation-In-Part WO2000015797A2 (fr) 1994-09-08 1999-09-15 Compositions et methodes de traitement des maladies relatives au syteme immunitaire
US40329699A Continuation-In-Part 1996-11-06 1999-10-18
US40329799A Continuation 1997-08-26 1999-10-18
US42384499A A-371-Of-International 1996-11-06 1999-11-12
PCT/US1999/028214 Continuation-In-Part WO2001019987A1 (fr) 1994-09-08 1999-11-29 Promotion ou inhibition de l'angiogenese et de la vascularisation cardiaque
PCT/US1999/028313 Continuation-In-Part WO2000032221A2 (fr) 1994-09-08 1999-11-30 Promotion et inhibition de l'angiogenese et de la vascularisation cardiaque
PCT/US1999/028409 Continuation WO2000032778A2 (fr) 1997-03-31 1999-11-30 Methodes et compositions permettant d'inhiber la croissance de cellules neoplasiques
PCT/US2000/004341 Continuation-In-Part WO2000053756A2 (fr) 1996-11-06 2000-02-18 Polypeptides secretes et transmembranaires et acides nucleiques codant ces polypeptides
US52234200A Continuation-In-Part 1997-08-26 2000-03-09
US66461000A Continuation 1996-11-06 2000-09-18
US09/866,028 Continuation US6642360B2 (en) 1996-11-06 2001-05-25 Secreted polypeptides that stimulate release of proteoglycans from cartilage
US09/903,749 Continuation US7147853B2 (en) 1997-09-17 2001-07-11 Anti-pro211 polypeptide antibodies
US09/944,862 Continuation US20020115145A1 (en) 1997-12-03 2001-08-31 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/081,056 Continuation US20040043927A1 (en) 1997-09-19 2002-02-20 Compositions and methods for the diagnosis and treatment of disorders involving angiogenesis
US10/119,480 Continuation US20040087769A1 (en) 1998-09-10 2002-04-09 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/125,166 Continuation-In-Part US20030039648A1 (en) 1997-10-28 2002-04-17 Compositions and methods for the diagnosis and treatment of tumor
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