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WO2000070050A1 - Compositions et procedes de traitement de maladies d'ordre immunologique - Google Patents

Compositions et procedes de traitement de maladies d'ordre immunologique Download PDF

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Publication number
WO2000070050A1
WO2000070050A1 PCT/US2000/007532 US0007532W WO0070050A1 WO 2000070050 A1 WO2000070050 A1 WO 2000070050A1 US 0007532 W US0007532 W US 0007532W WO 0070050 A1 WO0070050 A1 WO 0070050A1
Authority
WO
WIPO (PCT)
Prior art keywords
seq
acid sequence
polypeptide
antibody
pro
Prior art date
Application number
PCT/US2000/007532
Other languages
English (en)
Inventor
Kevin P. Baker
Jian Chen
Napoleone Ferrara
Sherman Fong
Audrey Goddard
Austin L. Gurney
Kenneth J. Hillan
Sophia S. Kuo
Daniel Tumas
Willaim I. Wood
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
Application filed by Genentech, Inc. filed Critical Genentech, Inc.
Priority to AU36326/00A priority Critical patent/AU3632600A/en
Priority to DK00939307T priority patent/DK1212417T3/da
Priority to ES00939307T priority patent/ES2307515T3/es
Priority to EP00939307A priority patent/EP1212417B1/fr
Priority to PT00939307T priority patent/PT1212417E/pt
Priority to AT00939307T priority patent/ATE393825T1/de
Priority to PCT/US2000/013705 priority patent/WO2000073445A2/fr
Priority to CA002376116A priority patent/CA2376116A1/fr
Priority to JP2001500757A priority patent/JP4297317B2/ja
Priority to PCT/US2000/015264 priority patent/WO2000073452A2/fr
Publication of WO2000070050A1 publication Critical patent/WO2000070050A1/fr
Priority to EP00983846A priority patent/EP1250426A2/fr
Priority to EP06000582A priority patent/EP1666495A1/fr
Priority to EP06000589A priority patent/EP1661997A1/fr
Priority to EP06000587A priority patent/EP1690872A3/fr
Priority to CA2709291A priority patent/CA2709291A1/fr
Priority to CA002391455A priority patent/CA2391455A1/fr
Priority to EP10005292A priority patent/EP2228446A1/fr
Priority to CA002490909A priority patent/CA2490909A1/fr
Priority to EP06000585A priority patent/EP1661996A1/fr
Priority to EP06000586A priority patent/EP1688497A1/fr
Priority to CA002490853A priority patent/CA2490853A1/fr
Priority to AU20554/01A priority patent/AU2055401A/en
Priority to CA002491610A priority patent/CA2491610A1/fr
Priority to CA002494705A priority patent/CA2494705A1/fr
Priority to EP06000583A priority patent/EP1686134A3/fr
Priority to EP06000581A priority patent/EP1666494A1/fr
Priority to CA002496312A priority patent/CA2496312A1/fr
Priority to PCT/US2000/032678 priority patent/WO2001040466A2/fr
Priority to EP05025102A priority patent/EP1672070A3/fr
Priority to CA002492070A priority patent/CA2492070A1/fr
Priority to CA002491258A priority patent/CA2491258A1/fr
Priority to CA002492049A priority patent/CA2492049A1/fr
Priority to EP06000588A priority patent/EP1690873A3/fr
Priority to CA002491433A priority patent/CA2491433A1/fr
Priority to EP06000584A priority patent/EP1669371A3/fr
Priority to JP2001542531A priority patent/JP2004522404A/ja
Priority to ES10009491.1T priority patent/ES2458349T3/es
Priority to EP10009490A priority patent/EP2290081A3/fr
Priority to AT07016900T priority patent/ATE519847T1/de
Priority to ES07016902T priority patent/ES2388748T3/es
Priority to AT07016899T priority patent/ATE537258T1/de
Priority to ES07016903T priority patent/ES2380812T3/es
Priority to PT07016900T priority patent/PT1897944E/pt
Priority to PT07016901T priority patent/PT1897945E/pt
Priority to EP07016902A priority patent/EP1897946B1/fr
Priority to DK07016903.2T priority patent/DK1897947T3/da
Priority to EP07016899A priority patent/EP1897943B1/fr
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Priority to ES00989401T priority patent/ES2333772T3/es
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Priority to DK07016900.8T priority patent/DK1897944T3/da
Priority to AT00989401T priority patent/ATE444361T1/de
Priority to PCT/US2000/034956 priority patent/WO2001046420A2/fr
Priority to DK00989401.5T priority patent/DK1240325T3/da
Priority to DE60043069T priority patent/DE60043069D1/de
Priority to CA002391374A priority patent/CA2391374A1/fr
Priority to EP10009491.1A priority patent/EP2258848B1/fr
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Priority to PT07016903T priority patent/PT1897947E/pt
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Priority to EP09009972.2A priority patent/EP2163625B1/fr
Priority to AU25909/01A priority patent/AU2590901A/en
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Priority to US10/063,741 priority patent/US7118887B2/en
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Priority to JP2006000562A priority patent/JP4688682B2/ja
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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
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4702—Regulators; Modulating activity
    • C07K14/4703—Inhibitors; Suppressors
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2799/00—Uses of viruses
    • C12N2799/02—Uses of viruses as vector
    • C12N2799/021—Uses of viruses as vector for the expression of a heterologous nucleic acid
    • C12N2799/026—Uses of viruses as vector for the expression of a heterologous nucleic acid where the vector is derived from a baculovirus
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2799/00—Uses of viruses
    • C12N2799/02—Uses of viruses as vector
    • C12N2799/021—Uses of viruses as vector for the expression of a heterologous nucleic acid
    • C12N2799/027—Uses of viruses as vector for the expression of a heterologous nucleic acid where the vector is derived from a retrovirus
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • Immune related and inflammatory diseases are the manifestation or consequence of fairly complex, often multiple interconnected biological pathways which in normal physiology are critical to respond to insult or injury, initiate repair from insult or injury, and mount innate and acquired defense against foreign organisms Disease or pathology occurs when these normal physiological pathways cause additional insult or injury either as directly related to the intensity of the response, as a consequence of abnormal regulation or excessive stimulation, as a reaction to self, or as a combination of these
  • Intervention at critical points in one or more of these pathways can have an ameliorative or therapeutic effect
  • Therapeutic intervention can occur by either antagonism of a detrimental process/pathway or stimulation of a beneficial process/pathway
  • immune-mediated inflammatory diseases include immune-mediated inflammatory diseases, non-immune-mediated inflammatory diseases, infectious diseases, immunodeficiency diseases, neoplasia, etc.
  • T lymphocytes are an important component of a mammalian immune response T cells recognise antigens which are associated with a self-molecule encoded by genes withm the major histocompatibihty complex (MHC)
  • MHC major histocompatibihty complex
  • the antigen may be displayed together with MHC molecules on the surface of antigen presenting cells, virus infected cells, cancer cells, grafts, etc
  • the T cell system eliminates these altered cells which pose a health threat to the host mammal T cells include helper T cells and cytotoxic
  • Helper T cells proliferate extensively following recognition of an antigen-MHC complex on an antigen presenting cell
  • Helper T cells also secrete a variety of cytokines, I e lymphokines, which play a central role in the activation of B cells, cytotoxic T cells and a variety of other cells which participate in the immune response
  • a central event in both humoral and cell mediated immune responses is the activation and clonal expansion of helper T cells
  • Helper T cell activation is initiate by the interaction of the T cell receptor (TCR) - CD3 complex with an antigen-MHC on the surface of an antigen presenting cell This interaction mediates a cascade of biochemical events that induce the resting helper T cell to enter a cell cycle (the Go to Gl transition) and results m the expression of a high affinit) receptor for IL-2 and sometimes IL-4
  • the activated T cell progresses through the cycle proliferating and differentiating mto memory cells or effector cells
  • T cells In addition to the signals mediated through the TCR, activation of T cells involves additional costimulation induced b> cytokines released by the antigen presenting cell or through interactions with membrane bound molecules on the antigen presenting cell and the T cell
  • the cytokines IL 1 and IL 6 have been shown to provide a costimulatory signal
  • the interaction between the B7 molecule expressed on the surface of an antigen presenting cell and CD28 and CTLA-4 molecules expressed on the T cell surface effect T cell activation
  • Activated T cells express an increased number of cellular adhesion molecules, such as ICAM 1 , integrins, VLA-4, LFA 1 CD56, etc
  • T-cell proliferation m a mixed lymphocyte culture or mixed l>mphocyte reaction (MLR) is an established indication of the ability of a compound to stimulate the immune system In man) immune responses, inflammatory cells infiltrate the site of injury or infection
  • the migrating cells may be neutrophi c, eosinophi c, monocytic or lymphocytic as can be determined b> histologic examination of the affected tissues Current Protocols in Immunology, ed John E Coligan 1994, John Wiley & Sons, Ine
  • Immune related diseases can be treated by suppressing the immune response Using neutralizing antibodies that inhibit molecules having immune stimulatory activity would be beneficial m the treatment of immune-mediated and inflammatory diseases Molecules which inhibit the immune response can be utilized
  • the present invention concerns compositions and methods for the diagnosis and treatment of immune related disease in mammals, including humans
  • the present invention is based on the identification of proteins (including agonist and antagonist antibodies) which either stimulate or inhibit the immune response in mammals
  • Immune related diseases can be treated by suppressing or enhancing the immune response Molecules that enhance the immune response stimulate or potentiate the immune response to an antigen Molecules which stimulate the immune response can be used therapeutically where enhancement of the immune response would be beneficial
  • Such stimulatory molecules can also be inhibited where suppression of the immune response would be of value
  • Neutralizing antibodies are examples of molecules that inhibit molecules having immune stimulatory activity and which would be beneficial in the treatment of immune related and inflammatory diseases Molecules which inhibit the immune response can also be utilized (proteins directly or via the use of antibody agonists) to inhibit the immune response and thus ameliorate immune related disease
  • the proteins of the invention encoded by the genes of the invention are useful for the diagnosis and/or treatment (including prevention) of immune related diseases
  • Antibodies which bind to stimulatory proteins are useful to suppress the immune system and the immune response
  • Antibodies which bind to inhibitory proteins are useful to stimulate the immune system and the immune response
  • the proteins and antibodies of the invention are also useful to prepare medicines and medicaments for the treatment of immune related and inflammatory diseases
  • the present invention concerns an isolated antibody which binds a PRO200. PR0526 PR0719, PR0725. or PRO 1031 pol> peptide
  • the antibod ⁇ mimics the act ⁇ ⁇ r> of a PRO200, PR0526 PR0719, PR0725, or PRO1031 polypeptide (an agonist antibody) or converseh the antibody inhibits or neutralizes the activity of a PRO200, PR0526 PR0719, PR0725, or PRO1031 polypeptide (an antagonist antibody)
  • the antibody is a monoclonal antibody, which preferably has nonhuman complementarity determining region (CDR) residues and human framework region (FR) residues
  • CDR complementarity determining region
  • FR human framework region
  • the antibody may be labeled and may be immobilized on a solid support
  • the antibody is an antibody fragment, a single-chain antibody, or an anti-idiotypic antibody
  • the invention concerns a composition containing a PRO200, PR0526
  • the composition contains a therapeutically effective amount of the peptide or antibody
  • the composition when the composition contains an immune stimulating molecule, the composition is useful for (a) increasing infiltration of inflammatory cells into a tissue of a mammal in need thereof, (b) stimulating or enhancing an immune response in a mammal in need thereof, or
  • the composition when the composition contains an immune inhibiting molecule, the composition is useful for: (a) decreasing infiltration of inflammatory cells into a tissue of a mammal in need thereof, (b) inhibiting or reducing an immune response in a mammal in need thereof, or (c) decreasing the proliferation of T-lymphocytes in a mammal in need thereof m response to an antigen
  • the composition contains a further active ingredient, which may, for example, be a further antibody or a cytotoxic or chemotherapeutic agent
  • the composition is sterile
  • the invention concerns the use of the polypeptides and antibodies of the invention to prepare a composition or medicament which has the uses described above
  • the invention concerns nucleic acid encoding an ant ⁇ -PRO200, PR0526
  • the invention concerns a method for producing such an antibody by culturing a host cell transformed with nucleic acid encoding the antibody under conditions such that the antibody is expressed, and recovering the antibody from the cell culture
  • the invention further concerns antagonists and agonists of a PRO200, PR0526 PR0719, PR0725, or PRO1031 polypeptide that inhibit one or more of the functions or activities of the PRO200, PR0526 PR0719, PR0725, or PRO1031 polypeptide.
  • the invention concerns isolated nucleic acid molecules that hybridize to the complement of the nucleic acid molecules encoding the PRO200, PR0526 PR0719, PR0725. or PRO1031 polypeptides
  • the nucleic acid preferably is DNA, and hybridization preferably occurs under stringent conditions.
  • Such nucleic acid molecules can act as antisense molecules of the amplified genes identified herein, which, in turn, can find use in the modulation of the respective amplified genes, or as antisense primers in amplification reactions
  • sequences can be used as part of ⁇ bozyme and/or triple helix sequence which, in turn, ma> be used in regulation of the amplified genes
  • the invention concerns a method for determining the presence of a PRO200, PR0526 PR0719, PR0725, or PRO 1031 pol) peptide comprising exposing a cell suspected of containing the polypeptide to an ant ⁇ -PRO200, PR0526 PR0719, PR0725, or PRO1031 antibody and determining binding of the antibody to the cell
  • the present invention concerns a method of diagnosing an immune related disease in a mammal, comprising detecting the level of expression of a gene encoding a PRO200, PR0526 PR0719, PR0725, or PRO1031 polypeptide (a) in a test sample of tissue cells obtained from the mammal, and (b) in a control sample of known normal tissue cells of the same cell type, wherein a higher expression level in the test sample indicates the presence of immune related disease m the mammal from which the test tissue cells were obtained
  • the present invention concerns a method of diagnosing an immune disease m a mammal, comprising (a) contacting an ant ⁇ -PRO200, PR0526 PR0719, PR0725, or PRO1031 antibody with a test sample of tissue cells obtained from the mammal , and (b) detecting the formation of a complex between the antibody and the PRO200, PR0526 PR0719, PR0725, or PRO1031 polypeptide in the test sample
  • the detection may be qualitative or quantitative, and may be performed in comparison with monitoring the complex formation in a control sample of known normal tissue cells of the same cell type
  • a larger quantity of complexes formed m the test sample indicates the presence of rumor in the mammal from which the test tissue cells were obtained
  • the antibody preferably carries a detectable label Complex formation can be monitored, for example, by light microscopy, flow cytometry, fluo ⁇ metry, or other techniques known in the art
  • the test sample is usually obtained from an individual suspected of having a deficiency or abnormality of the immune system
  • the present invention concerns a diagnostic kit, containing an anti PRO200, PR0526 PR0719, PR0725, or PRO 1031 antibody and a carrier (e g a buffer) in suitable packaging
  • a carrier e g a buffer
  • the kit preferably contains instructions for using the antibody to detect the PRO200, PR0526 PR0719, PR0725 , or PRO1031 polypeptide
  • the invention concerns an article of manufacture comprising a container, a label on the container, and a composition comprising an active agent contained within the container, wherein the composition is effective for stimulating or inhibiting an immune response in a mammal, the label on the container indicates that the composition can be used to treat an immune related disease, and the active agent in the composition is an agent stimulating or inhibiting the expression and/or activity of the PRO200, PR0526 PR0719,
  • the active agent is a PRO200, PR0526 PR0719, PR0725, or PRO1031 polypeptide or an ant ⁇ -PRO200, PR0526 PR0719, PR0725, or PRO1031 antibody
  • a further embodiment is a method for identifying a compound capable of inhibiting the expression and/or activity of a PRO200, PR0526 PR0719, PR0725, or PRO1031 polypeptide bv contacting a candidate compound with a PRO200 PR0526 PR0719, PR0725 or PRO1031 polypeptide under conditions and for a time sufficient to allow these two components to interact
  • the candidate compound or the PRO200 PR0526 PR0719, PR0725 or PRO 1031 polypeptide is immobilized on a solid support
  • the non immobilized component carries a detectable label
  • 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 comp ⁇ se any of the herein described polypeptides fused to an epitope tag sequence or a Fc region of an immunoglobulin
  • the mvention 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 or as antisense probes, 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% nucleic acid sequence identity, alternatively at least about 81 % nucleic acid sequence identity, alternatively at least about 82% nucleic acid sequence identity, alternatively at least about 83% nucleic acid sequence identity, alternatively at least about 84% nucleic acid sequence identity, alternatively at least about 85% nucleic acid sequence identity, alternatively at least about 86% nucleic acid sequence identity, alternatively at least about 87% nucleic acid sequence identity, alternatively at least about 88% nucleic acid sequence identity, alternatively at least about 89% nucleic acid sequence identity, alternatively at least about 90% nucleic acid sequence identity, alternatively at least about 91 % nucleic acid sequence identity, alternatively at least about 92% nucleic acid sequence identity, alternatively at least about 93 % nucleic acid sequence identity, alternatively at least about 94% nucleic acid sequence identity, alternatively at least about 95 % nucleic acid sequence identity, alternatively at least about
  • the isolated nucleic acid molecule comprises a nucleotide sequence having at least about 80% nucleic acid sequence identity, alternatively at least about 81 % nucleic acid sequence identity alternatively at least about 82% nucleic acid sequence identity , alternative] ⁇ at least about 83 % nucleic acid sequence identity, alternatively at least about 84% nucleic acid sequence ldentin , alternatively at least about
  • nucleic acid sequence identity 85 % nucleic acid sequence identity, alternatively at least about 86% nucleic acid sequence identity, alternatively at least about 87% nucleic acid sequence identity, alternatively at least about 88% nucleic acid sequence identity, alternatively at least about 89% nucleic acid sequence ldentit ⁇ .
  • nucleic acid sequence identity alternatively at least about 90% nucleic acid sequence identity, alternatively at least about 91 % nucleic acid sequence identit ⁇ , alternatively at least about 92% nucleic acid sequence identity, alternatively at least about 93 % nucleic acid sequence identity, alternative!) at least about 94% nucleic acid sequence identity , alternatively at least about 95 % nucleic acid sequence identity, alternatively at least about 96% nucleic acid sequence identity, alternatively at least about 97% nucleic acid sequence identity, alternatively at least about 98% nucleic acid sequence identity and alternatively at least about 99% nucleic acid sequence identity to (a) a DNA molecule comprising the coding sequence of a full length PRO polypeptide cDNA as disclosed herein, the coding sequence of a PRO polypeptide lacking the signal peptide as disclosed herein, the coding sequence of an extracellular domain of a transmembrane PRO polypeptide, with or without the signal peptide, as disclosed herein or the coding sequence of any other specifically defined fragment
  • nucleic acid sequence identity alternatively at least about 89% nucleic acid sequence identity, alternatively at least about 90% nucleic acid sequence identity, alternatively at least about 91 % nucleic acid sequence identity, alternatively at least about 92% nucleic acid sequence identity, alternatively at least about 93% nucleic acid sequence identity, alternatively at least about 94% nucleic acid sequence identity, alternatively at least about 95 % nucleic acid sequence identity, alternatively at least about 96% nucleic acid sequence identity, alternatively at least about 97 % nucleic acid sequence identity, alternatively at least about 98% nucleic acid sequence identity and alternatively at least about 99% nucleic acid sequence identity to (a) a DNA molecule that encodes the same mature polypeptide encoded by any of the human protein cDNAs deposited with the ATCC as disclosed herein, or (b) the complement of the DNA molecule of (a) Another aspect the invention provides an isolated nucleic acid molecule comprising a nucleotide sequence encoding a PRO polypeptide which
  • nucleic acid fragments are usually at least about 20 nucleotides in length, alternatively at least about 30 nucleotides in length, alternatively at least about 40 nucleotides in length, alternatively at least about 50 nucleotides in length, alternatively at least about 60 nucleotides in length, alternatively at least about 70 nucleotides in length, alternatively at least about 80 nucleotides in length, alternatively at least about 90 nucleotides in length, alternativel) at least about 100 nucleotides in length, alternatively at least about 110 nucleotides in length, alternatively at least about 120 nucleotides in
  • 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% amino acid sequence identity , alternatively at least about 81 % amino acid sequence identity, alternatively at least about 82% amino acid sequence identity, alternatively at least about 83 % ammo acid sequence identity, alternatively at least about 84 % amino acid sequence identity, alternatively at least about 85 % amino acid sequence identity , alternatively at least about 86% amino acid sequence identity, alternatively at least about 87% amino acid sequence identity, alternatively at least about 88% amino acid sequence identity alternativel) at least about 89% amino acid sequence identity , alternatively at least about 90% amino acid sequence identity , alternativel) at least about 91 % amino acid sequence identity .
  • the invention concerns an isolated PRO polypeptide comprising an amino acid sequence having at least about 80% ammo acid sequence identity, alternatively at least about 81 % amino acid sequence identity, alternatively at least about 82% amino acid sequence identity, alternatively at least about 98 % ammo acid sequence identity, alternatively at least about 99 % amino acid sequence identity to a PRO polypeptide having a full-length amino acid sequence as disclosed herein, an ammo acid sequence lacking the signal peptide as disclosed herein, an extracellular domain of a transmembrane protein, with or without the signal peptide, as disclosed herein or any other specifically defined fragment of the full length amino acid sequence as disclosed herein
  • the invention concerns an isolated PRO polypeptide comprising an amino acid sequence having at least about 80% ammo acid sequence identity, alternatively at least about 81 % amino acid sequence identity, alternatively at least about 82% amino acid sequence identity, alternatively at least about 98 % ammo acid sequence identity and alternatively at least about 99 % amino acid sequence identity to a PRO polypeptid
  • the invention concerns an isolated PRO polypeptide comprising an ammo acid sequence scoring at least about 80% positives, alternatively at least about 81 % positives, alternatively at least about 82% positives, alternatively at least about 83 % positives, alternatively at least about 84% positives, alternatively at least about
  • Another aspect the invention provides an isolated PRO polypeptide which is either transmembrane domain-deleted or transmembrane domam-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 the nucleotide sequence of a cDNA containing a nucleotide sequence encoding native sequence PR0526 (UNQ330), wherein the nucleotide sequence (SEQ ID NO 1) is a clone designated herein as "DNA44184 1319" Also presented in bold font and underlined are the positions of the respective start and stop codons
  • Figure 2 shows the amino acid sequence (SEQ ID NO 2) of a native sequence PR0526 polypeptide as derived from the coding sequence of Figure 1 Also shown are the approximate locations of various other important polypeptide domains if known
  • Figure 3 shows the nucleotide sequence of a cDNA containing a nucleotide sequence encoding native sequence PR0719 (UNQ387), wherein the nucleotide sequence (SEQ ID NO 3) is a clone designated herein as "DNA49646-1327" Also presented in bold font and underlined are the positions of the respective start and stop codons
  • Figure 4 shows the amino acid sequence (SEQ ID NO 4) of a native sequence PR0719 polypeptide as derived from the coding sequence of Figure 3 Also shown are the approximate locations of ⁇ arious other important polypeptide domains if known
  • Figure 5 shows the nucleotide sequence of a cDN A containing a nucleotide sequence encoding nativ e sequence PR0725 (UNQ390), wherein the nucleotide sequence (SEQ ID NO 5) is a clone designated herein as "DNA52758 1399" Also presented in bold font and underlined are the positions of the respective start and stop codons
  • Figure 6 shows the amino acid sequence (SEQ ID NO 6) of a native sequence PR0725 polypeptide as derived from the coding sequence of Figure 5 Also shown are the approximate locations of various other important polypeptide domains if known
  • Figure 7 shows the nucleotide sequence of a cDN A containing a nucleotide sequence encoding native sequence PRO 1031 (UNQ516), wherein the nucleotide sequence (SEQ ID NO 7) is a clone designated herein as "DNA59294-1381 " Also presented in bold font and underlined are the positions of the respective start and stop codons
  • Figure 8 shows the amino acid sequence (SEQ ID NO 8) of a native sequence PRO1031 polypeptide as derived from the coding sequence of Figure 7 Also shown are the approximate locations of various other important polypeptide domains if known
  • Figure 9 shows the nucleotide sequence of a cDNA containing a nucleotide sequence encoding native sequence PRO200 (UNQ174), wherein the nucleotide sequence (SEQ ID NO 9) is a clone designated herein as "DNA29101-1122" Also presented m bold font and underlined are the positions of the respective start and stop codons
  • Figure 10 shows the amino acid sequence (SEQ ID NO 10) of a native sequence PRO200 polypeptide as derived from the coding sequence of Figure 9 Also shown are the approximate locations of various other important polypeptide domains if known
  • immune related disease means a disease in which a component of the immune system of a mammal causes, mediates or otherwise contributes to a morbidity in the mammal Also included are diseases in which stimulation or intervention of the immune response has an ameliorative effect on progression of the disease Included within this term are immune -mediated inflammatory diseases, non-immune-mediated inflammatory diseases, infectious diseases, immunodeficiency diseases, neoplasm, etc
  • T cell mediated disease means a disease in which T cells directly or indirectly mediate or otherwise contribute to a morbidity a mammal
  • the T cell mediated disease may be associated with cell mediated effects, lymphokme mediated effects, etc , and even effects associated with B cells if the B cells are stimulated, for example, by the lymphokmes secreted b) T cells
  • immune-related and inflammatory diseases some of which are lmune or T cell mediated, which can be treated according to the invention include s) stemic lupus erythematosis, rheumatoid arthritis, juvenile chronic arthritis, spondyloarthropathies, systemic sclerosis (scleroderma), idiopathic inflammatory myopathies (dermatomvositis.
  • pol)in)ositis S)ogren's syndrome systemic vascuhtis, sarcoidosis, autoimmune hemolytic anemia (immune pancytopema, paroxysmal nocturnal hemoglobinu ⁇ a), autoimmune thrombocytopenia (idiopathic thrombocytopemc pu ura. immune-mediated thrombocytopenia), thyroiditis (Grave's disease, Hashimoto's thyroiditis.
  • lymphocytic thyroiditis atrophic thyroiditis
  • diabetes melhtus immune-mediated renal disease (glomeruloneph ⁇ tis, tubulomterstitial nephritis), demyelinating diseases of the central and peripheral nervous systems such as multiple sclerosis, idiopathic demyelinating polyneuropathy or Guillain-Barre syndrome, and chronic inflammatory demyelinating polyneuropathy, hepatobiliary diseases such as infectious hepatitis (hepatitis A, B, C, D, E and other non-hepatotropic viruses), autoimmune chronic active hepatitis, primary biliary cirrhosis, granulomatous hepatitis, and sclerosmg cholangitis.
  • infectious hepatitis hepatitis A, B, C, D, E and other non-hepatotropic viruses
  • autoimmune chronic active hepatitis primary biliary cirrhosis
  • inflammatory bowel disease Ulcerative colitis Crohn's disease
  • gluten-sensitive enteropathy and Whipple ' s disease
  • autoimmune or immune-mediated skin diseases including bullous skin diseases, erythema multiforme and contact dermatitis, psoriasis, allergic diseases such as asthma, allergic rhinitis, atopic dermatitis, food hypersensitivity and urticaria, immunologic diseases of the lung such as eosinophihc pneumonias, idiopathic pulmonary fibrosis and hypersensitivity pneumonitis, transplantation associated diseases including graft rejection and graft-versus-host-disease Infectious diseases including viral diseases such as AIDS (HIV infection), hepatitis A, B, C, D, and E. herpes, etc , bacterial infections, fungal infections, protozoal infections and parasitic infections.
  • HIV infection HIV infection
  • hepatitis A, B, C, D, and E. herpes, etc bacterial infections, fungal infections,
  • Treatment is an intervention performed with the intention of preventing the development or altering the pathology of a disorder Accordingly, “treatment” refers to both therapeutic treatment and prophylactic or preventative measures Those in need of treatment include those already with the disorder as well as those in which the disorder is to be prevented.
  • a therapeutic agent may directly decrease or increase the magnitude of response of a component of the immune response, or render the disease more susceptible to treatment by other therapeutic agents, e g.
  • 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.
  • the "pathology" of an immune related disease includes all phenomena that compromise the well-being of the patient This includes, without limitation, abnormal or uncontrollable cell growth, antibody production, auto-antibody production, complement production and activation, interference with the normal functioning of neighboring cells, release of cytokines or other secretory products at abnormal levels, suppression or aggravation of any inflammatory or immunological response, infiltration of lnflammatorv cells (neutrophi c, eosinophihc, monocytic, lymphocytic) into tissue spaces, etc
  • “Mammal” for purposes of treatment refers to any animal classified as a mammal, including humans, domestic and farm animals, and zoo, sports, or pet animals, such as dogs, horses, cats, cows, etc
  • the mammal is human Administration ' in combination with one or more further therapeutic agents includes simultaneous (concurrent) and consecutive administration in any order
  • Carriers' as used herein include pharmaceuticall) 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
  • physiologicall) 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 polyvinylpyrrohdone, ammo acids such as glycine, glutamine, asparagine, arginine or lysine, monosaccharides, disacchandes, 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 nomonic surfactants such as
  • cytotoxic agent refers to a substance that inhibits or prevents the function of cells and/or causes destruction of cells
  • the term is intended to include radioactive isotopes (e g 1131 , 1125, Y90 and Rel86), chemotherapeutic agents, and toxins such as enzymatically active toxins of bacterial, fungal, plant or animal origin, or fragments thereof
  • chemotherapeutic agent' is a chemical compound useful in the treatment of cancer
  • chemotherapeutic agents include ad ⁇ amycin, doxorubicin, epirubicm, 5-fluorourac ⁇ l, cytosine arabmoside ("Ara-C"), cyclophosphamide, thiotepa, busulfan, cytoxin, taxoids, e g pac taxel (Taxol, Bristol Myers Squibb Oncology, Princeton, NJ), and doxetaxel (Taxotere, Rhone-Poulenc Rorer, Antony, Rnace), toxotere, methotrexate, cisplatin, melphalan, vinblastine, bleomycin, etoposide, lfosfamide, mitomycm C, mitoxantrone, vinc ⁇ stine, vinorelbme, carboplatm, temposide, daunomycm, carrm
  • methotrexate 5-fluorourac ⁇ l
  • ara C Further information can be found in The Molecular Basis of Cancer, Mendelsohn and Israel, eds Chapter 1 , entitled “Cell cycle regulation, oncogens, and antineoplastic drugs” by Murakami et al (WB Saunders Philadelphia, 1995), especially p
  • cvtokme is a generic term for proteins released by one cell population which act on another cell as intercellular mediators
  • cytokines are l) mphokmes, monokmes and traditional polypeptide hormones Included among the cytokines are growth hormone such as human growth hormone, N-methionyl human growth hormone, and bovme growth hormone, parathyroid hormone, thyroxine insulin, pro suhn, relaxin, prorelaxin, glycoprotem hormones such as follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH), and lutemizing hormone (LH), hepatic growth factor, fibroblast growth factor, prolactm, placental lactogen tumor necrosis factor and ⁇ , mulle ⁇ an inhibiting substance mouse gonadotropin-associated peptide, inhibin, activm vascular endothehal growth factor, integrin, thrombopoiet (TPO), nerve growth factors such as NGF ⁇ platelet growth factor, transforming growth factors
  • growth hormone such
  • 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)
  • 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
  • the term "PRO polypeptide refers to each individual PRO/number polypeptide disclosed herein All disclosures in this specification which refer to the "PRO polypeptide' refer to each of the polypeptides individually as well as jointly For example, descriptions of the preparation of, purification of derivation of, formation of antibodies to or against, administration of, compositions containing, treatment of a disease with, etc , pertain to each PRO polypeptide of the invention individually
  • PRO polypeptide' also includes variants of the PRO/number polypeptides disclosed herein
  • 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
  • the PRO polypeptide disclosed in the accompanying figures are shown to begin with methionme residues designated herein as amino acid position 1 in the figures, it is conceivable and possible that other methion
  • 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
  • ECD extracellular domain
  • 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
  • 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 b) 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 ammo acids on either side of the transmembrane domain/extracellular domain boundary as identified m 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
  • the approximate location of the "signal peptides" of the various PRO polypeptides disclosed herein are shown m the present specification and/or the accompanying figures It is noted, however, that the C- terminal boundary of a signal peptide may vary, but most likely by no more than about 5 amino acids on either side of the signal peptide C terminal boundary as initially identified herein, wherein the C-terminal boundary of the signal peptide may be identified pursuant to criteria routinely employed in the art for identifying that type of amino acid sequence element (e g , Nielsen et al , Prot Eng 10 1-6 (1997) and von
  • 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% ammo acid sequence identity, alternatively at least about 81 % amino acid sequence identity, alternatively at least about 82% amino acid sequence identity, alternatively at least about 83 % amino acid sequence identity, alternatively at least about 84% ammo acid sequence identity, alternatively at least about 85 % amino acid sequence identity, alternatively at least
  • PRO variant polypeptides are at least about 10 amino acids m length, alternatively at least about 20 ammo acids in length, alternatively at least about 30 amino acids in length, alternatively
  • Percent ( % ) amino acid sequence identity with respect to the PRO polypeptide sequences identified herein is defined as the percentage of ammo 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 ammo 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 Mega gn (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 For purposes herein, however, % 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 1 below The ALIGN-2 sequence comparison computer program was authored by Genentech, Ine
  • ALIGN-2 program is publicly available through Genentech, Ine , South San Francisco, California or may be compiled from the source code provided in Table 1 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
  • the % amino acid sequence identity of a given amino acid sequence A to, with, or against a given ammo acid sequence B (which can criz el) be phrased as a given amino acid sequence A that has or comprises a certain % amino acid sequence identity to with, or against a given ammo acid sequence B) is calculated as follows
  • 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))
  • the % amino acid sequence identity of a given ammo acid sequence A to, with, or against a given amino acid sequence B (which can alternatively be phrased as a given amino acid sequence A that has or comprises a certain % amino acid sequence identity to, with, or against a giv en ammo 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, alternatively at least about 81 % nucleic acid sequence identity, alternatively at least about 82% nucleic acid sequence identity, alternatively at least about 83 % nucleic acid sequence identity, alternatively at least about 84% nucleic acid sequence identity, alternatively at least about 85 % nucleic acid sequence identity, alternatively at least about 86% nucleic acid sequence identity, alternatively at least about 87% nucleic acid sequence identity, alternatively at least about 88% nucleic acid sequence identity, alternatively at least about 89% nucleic acid sequence identity, alternatively at least about 90% nucleic acid sequence identity, alternatively at least about 91 % nucleic acid sequence identity, alternatively at least about
  • nucleic acid sequence identity with a nucleic acid sequence encodmg 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 sequence, as disclosed herein or any other fragment of a full-length PRO polypeptide sequence as disclosed herein
  • Variants do not encompass the native nucleotide sequence
  • PRO variant polynucleotides are at least about 30 nucleotides m length, alternatively at least about 60 nucleotides
  • Percent (%) nucleic acid sequence identity' with respect to PRO-encodmg 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 wa) s that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN or Megahgn (DNASTAR) software For purposes herein, howe er, % 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 1 below The ALIGN 2 sequence comparison computer program was authored by Genentech, Ine and the source code shown Table 1 below has been filed with user documentation in the U S Copyright Office, Washington D C , 20559,
  • 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
  • nucleic acid sequence identity of a given nucleic acid sequence C to, with, or against a given nucleic acid sequence D
  • nucleic acid sequence C (which can alternatively be phrased as a given nucleic acid sequence C that has or comprises a certain % nucleic acid sequence identity to, with, or against a given nucleic acid sequence D) is calculated as follows
  • nucleic acid sequence identity of a given nucleic acid sequence C to, with, or against a given nucleic acid sequence D
  • nucleic acid sequence C (which can alternatively be phrased as a given nucleic acid sequence C that has or comprises a certain % nucleic acid sequence identity to, with, or against a given nucleic acid sequence D) is calculated as follows
  • PRO variant polynucleotides are nucleic acid molecules that encode an active
  • 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 6 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 (l 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 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 6 below) of the amino acid residue of interest
  • % value of positives of a given ammo acid sequence A to, with, or against a given amino acid sequence B is calculated as follows:
  • isolated, when used to describe the various polypeptides disclosed herein, means polypeptide that has been identified and separated and/or recovered from a component of its natural environment Contaminant components of its natural environment are materials that would typically interfere with diagnostic or therapeutic uses for the 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-termmal or internal ammo acid sequence by use of a spinning cup sequenator, or (2) to homogeneity by SDS-PAGE under non-reducing or reducing conditions using Coomassie blue or, preferably, silver stain.
  • Isolated polypeptide includes polypeptide in 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 or other polypeptide encoding nucleic acid is a nucleic acid molecule that is identified and separated trom at least one contaminant nucleic acid molecule with which it is ordinarily associated in the natural source of the polvpeptide-encodmg nucleic acid
  • An isolated pol) pept ⁇ de-encod ⁇ ng nucleic acid molecule is other than in the form or setting in which it is found in nature Isolated polypeptide-encoding nucleic acid molecules therefore are distinguished from the specific polypeptide-encoding nucleic acid molecule as it exists in natural cells
  • an isolated polypeptide- encoding nucleic acid molecule includes polypeptide-encoding nucleic acid molecules contained in cells that ordin
  • control sequences' refers to DNA sequences necessar) tor 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 ⁇ bosome 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
  • a ⁇ bosome 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
  • 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 specificall) 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)
  • the term 'monoclonal antibody' as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, I e , the individual antibodies comprising the population are identical except for possible naturally-occurring mutations that may be present in minor amounts
  • Stringent conditions or “high stringency conditions” . as defined herein, mav be identified by those thaf (1) employ low ionic strength and high temperature for washing, for example 0 015 M sodium chlo ⁇ de/0.0015 M sodium c ⁇ trate/0 1 % sodium dodec)l sulfate at 50°C.
  • a denaturing agent such as formamide, for example, 50% (v/v) formamide with 0 1 % bovine serum albumm/0 1 % F ⁇ coll/0 1 % polyv ⁇ nylp) rrol ⁇ done/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 NaCI, 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.
  • formamide for example, 50% (v/v) formamide with 0 1 % bovine serum albumm/0 1 % F ⁇ coll/0 1 % polyv ⁇ nylp) rrol ⁇ done/50mM sodium phosphate buffer at pH 6 5 with 750
  • dextran sulfate at 42°C. with washes at 42°C in 0 2 x SSC (sodium chloride/sodium citrate) and 50% formamide at 55 °C, followed by a high-stringency wash consisting of 0 1 x SSC containing EDTA at 55 °C
  • Modely stringent conditions may be identified as described by Sambrook et al , Molecular Cloning. A Laboratory Manual. New ork 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 m a solution comp ⁇ sing. 20% formamide.
  • 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
  • immunoadhesin designates antibody-like molecules which combine the binding specificity of a heterologous protein (an “adhesin”) with the effector functions of immunoglobulin constant domains Structurally, the 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
  • Activity refers to form(s) of a PRO polypeptide which retain a biological 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
  • agonist is used in the broadest sense, and includes any molecule that partial] ⁇ or full) blocks, inhibits, or neutralizes a biological activity of a native PRO pol) peptide 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 v ariants 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
  • Antibody fragments comprise a portion of an intact antibody, preferably the antigen binding or variable region of the intact antibody Examples of antibody fragments include Fab, Fab', F
  • Papain digestion ot 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') ⁇ 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 -bmding 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 V H -V L dimer Collectively, the six CDRs confer antigen-binding specificity to the antibody However, even a single variable domain (or half of an Fv comprising onlv three
  • the Fab fragment also contains the constant domain of the light chain and the first constant domain
  • CHI heavy chain Fab fragments differ from Fab' fragments by the addition of a few residues at the carboxy terminus of the heavy chain CH 1 domain including one or more cysteines from the antibody hmge region.
  • Fab'-SH is the designation herein for Fab' in which the cysteine res ⁇ due(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
  • immunoglobulins 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 ot their constant domains Depending on the amino acid sequence of the constant domain of their heavy chains, 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 mto subclasses (isotypes), e g , IgG l , IgG2, IgG3, IgG4 IgA and IgA2
  • Antibodies and fragments thereof in this invention also include ' affinity matured' antibodies in which an antibod) is altered to change the amino acid sequence of one or more of the CDR regions and/or the framework regions to alter the affinity of the antibody or fragment thereof for the antigen to which it binds
  • Affinity maturation may result in an increase or in a decrease m the affinity of the matured antibody for the antigen relative to the starting antibod)
  • the starting antibod ⁇ will be a humanized, human, chimeric or murine antibody and the affinity matured antibody will have a higher affinity than the starting antibody
  • one or more of the amino acid residues in the CDRs or in the framework regions are changed to a different residue using any standard method Suitable methods include point mutations using well known cassette mutagenesis methods (Wells et al 1985, Gene, 34 315) or oligonucleotide mediated mutagenesis methods (Zoller et al , 1987 Nucleic Acids Res , 10 6487-6504)
  • Affinity maturation may also be performed using known selection methods m which man) mutations are produced and mutants having the desired affinity are selected from a pool or library of mutants based on improved affinity for the antigen or ligand
  • Known phage display techniques can be conveniently used in this approach See, for example, U S 5,750,373, U S 5,223,409, etc Human antibodies are also with in the scope of the antibodies of the invention Human antibodies can 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) Boerner et al , J Immunol , 147(1) 86-95 (1991
  • Single-chain Fv or “sFv antibody fragments comprise the V H and V L domains of antibody, wherein these domains are present in a single polypeptide chain
  • the Fv polypeptide further comprises a polypeptide linker between the V H and V L domains which enables the sFv to form the desired structure for antigen binding
  • diabodies refers to small antibody fragments with two antigen-binding sites, which fragments comprise a heavy-chain variable domain (V H ) connected to a light chain variable domain (V L ) in the same polypeptide chain (V H -V L )
  • V H heavy-chain variable domain
  • V L light chain variable domain
  • the domains are forced to pair with the complementary domains of another chain and create two antigen-binding sites
  • Diabodies are described more fully in, for example, EP 404,097, WO 93/1 1 161 , and Hol nger 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 env lronment 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-termmal 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 stam 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” antibod)
  • 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), polysaccha ⁇ des (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, phosphohpids 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
  • a "small molecule” is defined herein to have a molecular weight below about 500 Daltons
  • /* best diag nw() */ int dmaxO, /* final diag */ int dna; /* set if dna: ma ⁇ n() */ int endgaps: /* set if penalizing end gaps */ int gapx, gapy; /* total gaps in seqs */ int lenO, lenl ; /* seq lens */ int ngapx.
  • sequences can be in uppei- or lower-case an may contain ambiguity
  • Max file length is 65535 (limited by unsigned short x in the jmp struct)
  • a sequence with 1/3 or more of its elements ACGTU is assumed to be DNA
  • the program may create a tmp file in /tmp to hold info about traceback
  • static nm matches m core — tor checking */ static lmax, /* lengths of stripped file names */ static ⁇ j[2], /* jmp index for a path */ static nc[2]. /* number at start of current line */ static m[2]. /* current elem number — for gapping */ static s ⁇ z[2], static char *ps[2], /* ptr to current element */ static char *po[2]. /* ptr to next output char slot */ static char oouutt[[22]][[]P_LINE] /* output line */ static char star[P E], /* set by stars() *//
  • *py+ + toupper(*px). if ( ⁇ ndex( ⁇ TGCU”.*(py-l))) natgc + + ,
  • endgaps) 9 -siz MAXGAP ⁇ l + + , ⁇ else if (siz > 0) ⁇ /* gap in first seq */ gapx + + , ngapx + siz
  • the present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PRO polypeptides
  • PRO polypeptides cDNAs encoding various PRO polypeptides have been identified and isolated, as disclosed in further detail in the Examples below
  • 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
  • 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' or "PRO/number , regardless of their origin or mode of preparation
  • the description below relates primarily to production of the PRO polypeptide of the invention by culturing cells transformed or transfected with a vector containing nucleic acid which encodes of the PRO polypeptide of the invention
  • the polypeptide sequence, or portions thereof may be produced by direct peptide synthesis using solid-phase techniques [see, e g , Stewart et al , Solid-Phase Peptide Synthesis W H Freeman Co , San Francisco, CA (1969), Mer ⁇ field, J Am Chem Soc , 85 2149-2154 (1963)]
  • ⁇ ttio 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 polypeptide of the invention may be chemically synthesized separately and
  • 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 Those skilled in the art will appreciate that 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 m 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 tor 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 Optionally the variation is by substitution of at least one amino acid with any other amino acid in one or more ot the domains of the PRO
  • Guidance m 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 ammo 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 leucme with a serine, l e , conservative ammo 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 residue
  • PRO fragments may be prepared by any of a number ot 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 cleav e 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 activ ity with the native PRO polypeptide disclosed herein
  • Substantial modifications in function or lmmunological identity of the PRO polypeptide are accomplished by selecting substimtions 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.
  • Non-conservative substitutions will entail exchanging a member of one of these classes for another class Such substituted residues also may be introduced into the conservative substimtion sites or, moie preferably, into the remaining (non-conserved) sites.
  • Scanning amino acid analysis can also be employed to identify one or more ammo acids along a contiguous sequence
  • preferred scanning ammo acids are relativ el) small neutral amino acids
  • Such amino acids include alanine, glycine, serine, and cysteine Alanme 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.
  • Alanine is also typically preferred because it is the most common ammo 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 lsote ⁇ c 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 ammo acid residues of a PRO polypeptide with an organic de ⁇ vatizing agent that is capable of reacting with selected side chains or the N or C- terminal residues of the PRO
  • De ⁇ vatization with bifunctional agents is useful, for instance, for crosslmking PRO to a water-insoluble support matrix or surface for use m the method for purifying anti PRO antibodies, and vice-versa
  • Commonly used crosslmking agents include, e g , l , l-b ⁇ s(d ⁇ azoacetyl) 2-phenylethane, glutaraldehyde, N hydroxysuccimmide esters, for example, esters with 4-az ⁇ dosal ⁇ cyhc acid, homobifunctional lmidoesters, including disuccimmidyl esters such as 3 , 3 ' d ⁇ th ⁇ ob ⁇ s(succ ⁇ n ⁇ m ⁇ dylprop ⁇ onate) bifunctional maleimides such as b ⁇ s-N-male ⁇ m ⁇ do-l ,8-octane and agents such as methyl-3-[(p-az ⁇ dophenyl)d ⁇ th ⁇ o]prop ⁇ o ⁇ m ⁇ date
  • 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 mav be made for example, by the addition of or substitution b , one or more serine or threonine residues to the native sequence PRO (for O linked glycosylation sites)
  • the PRO ammo acid sequence may optionally be altered through changes at the DNA lev el. 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
  • Removal of carbohydrate moieties present on the PRO polypeptide may be accomplished chemicall ⁇ or enzymatically or by mutational substitution of codons encoding for ammo 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 Biophvs 259 52 ( 1987) and by Edge et al , Anal Biochem .
  • Enzymatic cleavage of carbohydrate moieties on polypeptides can be achieved by the use of a variety of endo- and exo glycosidases as described by Thotakura et al , Meth Enzymol , 138 350 (1987)
  • Another type of covalent modification of PRO comprises linking the PRO polypeptide to one of a variety of nonproteinaceous polymers, e g , polyethylene glycol (PEG), polypropylene glycol, or polyoxyalkylenes, in the manner set forth m U S Patent Nos 4,640,835, 4,496,689, 4,301 , 144, 4,670,417, 4,791 , 192 or 4, 179,337
  • the PRO 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
  • provision of the epitope tag enables the PRO to be readily purified by affimty 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 Examples include poly-histidine (poly-his) or poly-histidme-glycine (poly-his-gly) tags, the flu HA tag polypeptide and its antibody 12CA5 [Field et al , Mol Cell Biol .
  • tag polypeptides include the Flag -peptide [Hopp et al . BioTechnologv, 6 1204-1210 (1988)] the KT3 epitope peptide [Martin et al , Science, 255 192 194 ( 1992)] , an ⁇ -tubu n epitope peptide [Skinner et al , J Biol Chem , 266 15163-15166 (1991 )1, and the T7 gene 10 protein peptide tag [Lutz-Freyermuth et al , Proc Natl Acad Sci USA.
  • 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 lg 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 withm an lg 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), Mer ⁇ field, J Am Chem Soc .
  • 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 cDN A or genomic library with the selected probe may be conducted using standard procedures, such as described in Sambrook et al , Molecular Cloning A Laboratory Manual (New York Cold Spring Harbor Laborator) Press, 1989)
  • An alternative means to isolate the gene encoding PRO is to use PCR methodology [Sambrook et al , supra, Dieffenbach et al , PCR Primer A Laboratory Manual (Cold Spring Harbor Laboratory Press, 1995)]
  • 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 m the art, and include the use of radiolabels like 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 a ⁇ ailable 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 con entional primer extension procedures as described m Sambrook et al , supra, to detect precursors and processing intermediates of mRNA that may not have been reverse transcribed into cDN A
  • 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 culmre 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
  • 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 eubacte ⁇ a 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
  • E coh strain W31 10 ATCC 27,325)
  • K5 772 ATCC 53,635
  • Other suitable prokaryotic host cells include Enterobacteriaceae such as Escheiichta, e g E coli, Entetobacter Erwtnia Klebsiella Proteus. Salmonella, e g Salmonella nphimunum, Serratia, e g , Serratia marcescans, and Shigella, as well as Bacilli such as B subtilis and B lichenifonms (e g .
  • Strain W31 10 is one particularly preferred host or parent host because it is a common host strain for recombinant DNA product fermentations
  • the host cell secretes minimal amounts of proteolytic enzymes
  • strain W31 10 may be modified to effect a genetic mutation m the genes encoding proteins endogenous to the host, with examples of such hosts including E colt W31 10 strain 1A2, which has the complete genotype tonA , E coli W31 10 strain 9E4, which has the complete genotype tonA ptr3, E coli W31 10 strain 27C7 (ATCC 55 244) which has the complete genotype tonA ptr3 phoA El 5 (argF lac) 169 degP ompT kan r , E coli W31 10 strain 37
  • 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 Schizosaccharomyces pombe (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.
  • K lactts such as, e g , K lactts (MW98-8C, CBS683, CBS4574, Louvencourt et al , J Bacteriol , 154(2) 737-742 [1983]), K fragilis (ATCC 12,424), K bulgancus (ATCC 16,045), K mckeramii (ATCC 24, 178), K waltn (ATCC 56,500), K drosophilarum (ATCC 36,906, Van den Berg et al , Bio/Technology.
  • K thermotolerans and K marxianus
  • varrowia EP 402,226)
  • Pichia pastons EP 183,070, Sreekrishna et al , J Basic Microbiol . 28 265-278 [1988]
  • Candida Tnchoderma reesia
  • Neurospora crassa Neurospora crassa (Case et al , Proc Natl Acad Sci USA.
  • Schwanniomvces such as Schwannwmyces occidentahs (EP 394,538 published 31 October 1990)
  • filamentous fungi such as, e g , Neurospora, Penicillium Tolvpocladium (WO 91/00357 published 10 January 1991)
  • Asperg ⁇ lus hosts such as A mdulans (Ballance et al , Biochem Biophys Res Commun . 1 12 284-289 [1983], Tilburn et al , Gene, 26 205 221 [1983], Yelton et al , Proc Natl Acad Sci USA.
  • 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
  • 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 ova ⁇ cells/-DHFR (CHO, Urlaub and Chasm, Proc Natl Acad Sci USA. 77 4216 (1980)), mouse sertoli cells (TM4, Mather, Biol Reprod , 23 243 251 (1980)), human lung cells (W138 ATCC CCL 75). human liver cells (Hep G2, HB 8065), and mouse mammary tumor (MMT 060562, ATCC CCL51) The selection of the appropriate host cell is deemed to be within the skill in the art
  • the nucleic acid (e g , cDNA or genomic DNA) encoding PRO may be inserted into a rephcable vector for cloning (amplification of the DNA) or for expression
  • a rephcable 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
  • DNA is inserted into an appropriate restriction endonuclease s ⁇ te(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 recombmantly 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
  • 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 mvertase leader, alpha factor leader (including Saccharomyces and Kl xveromyces ⁇ -factor leaders, the latter described in U S Patent No 5,010, 182), or acid phosphatase leader, the C albicans glucoamylase leader (EP 362,
  • Both expression and clomng vectors contain a nucleic acid sequence that enables the vector to replicate in one or more selected host cells Such sequences are well known for a variety of bacteria, yeast, and viruses
  • the origin of replication from the plasmid pBR322 is suitable for most Gram-negative bacteria, the 2 ⁇ 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 , ampicilhn, 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
  • An appropriate host cell when wild type DHFR is employed is the CHO cell line deficient in DHFR activity, prepared and propagated as described by Urlaub et al , Proc Natl Acad Sci USA, 77 4216 (1980)
  • a suitable selection gene for use in yeast is the trp ⁇ gene present in the yeast plasmid
  • the trp ⁇ 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 Sh e-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 . 7 149 (1968), Holland, Biochemistry.
  • 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 desc ⁇ bed 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,
  • 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, -fetoprotem, and insulin) Typicalh however, one will use an enhancer from a eukaryotic cell virus Examples include the SV40 enhancer on the late side of the replication origin (bp 100 270), the cytomegalovirus early promoter enhancer, the polyoma enhancer on the late side of the replication origin and adenovirus enhancers
  • the enhancer may be spliced into the vector at a position 5 or 3 to the PRO coding sequence, but is preferably located at a site 5 from the promoter
  • Expression vectors used m eukaryotic host cells m eukaryotic host cells (yeast, fungi, insect, plant, animal human, or
  • Gene expression may be measured in a sample directly, for example, by conv entional 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 Alternatively, antibodies may be employed that can recognize specific duplexes, including DNA duplexes, RNA duplexes, and DNA-RNA hybrid duplexes or DNA protein duplexes The antibodies in turn may be labeled and the assay may be carried out where the duplex is bound to a surface, so that upon the formation of duplex on the surface, the presence of antibody bound to the duplex can be detected
  • Gene expression may be measured by lmmunological methods, such as immunohistochemical staining of cells or tissue sections and assay of cell culmre 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, somcation, mechanical disruption, or cell lysing agents
  • PRO may be desired to purify PRO from recombinant cell proteins or polypeptides
  • the following procedures are exemplary of suitable purification procedures by fractionation on an ⁇ on-e ⁇ change column, ethanol precipitation reverse phase HPLC, chromatography on silica or on a cation exchange resm such as DEAE, chromato focusing, 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 m the art and described for example in Deutscher, Methods in Enzvmologv. 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
  • tissue expressing the PRO polypeptides of the invention can be identified by determining mRNA expression in various human tissues The location of such genes provides information about which tissues are most likely to be affected by the stimulating and inhibiting activities of the PRO polypeptides of the invention The location of a gene in a specific tissue also provides sample tissue for the activity blocking assays discussed below As noted before, gene expression in various tissues may be measured by conventional Southern blotting, Northern blotting to quantitate the transcription of mRNA (Thomas, Proc Natl Acad Sci USA.
  • duplexes including DNA duplexes, RNA duplexes, and DNA-RNA hybrid duplexes or DNA-protein duplexes
  • Gene expression in various tissues may be measured by immunological methods, such as immunohistochemical staining of 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 of a PRO polypeptide of the invention or against a synthetic peptide based on the DNA sequences encoding the PRO polypeptide of the invention or against an exogenous sequence fused to a DNA encoding a PRO polypeptide of the invention and encodmg a specific antibody epitope
  • General techniques for generating antibodies, and special protocols for Northern blotting and in situ hybridization are provided below
  • polypeptides of the invention can be further verified by antibody binding studies, in which the ability of anti PRO antibodies to inhibit the effect of the PRO polypeptides on tissue cells is tested.
  • Exemplary antibodies include polyclonal, monoclonal, humanized bispecific, and heteroconjugate antibodies, the preparation of which will be described hereinbelow
  • Antibody binding studies may be carried out in any known assav method, such as competitive binding assays, direct and indirect sandwich assay s, and immunoprecipitation assays Zola, Monoclonal Antibodies A Manual of Techniques, pp 147-158 (CRC Press, Ine , 1987)
  • the antibodies preferably are lnsolubihzed before or after the competition, so that the standard and analyte that are bound to the antibodies may conveniently be separated from the standard and analyte which remain unbound
  • Sandwich assays involve the use of two antibodies, each capable of binding to a different immunogenic portion, or epitope, of the protein to be detected
  • the test sample analyte is bound by a first antibody which is immobilized on a solid support, and thereafter a second antibodv binds to the analyte, thus forming an insoluble three-part complex
  • the second antibody may itself be labeled with a detectable moiety (direct sandwich assays) or may be measured using an anti-immunoglobulin antibody that is labeled with a detectable moiety (indirect sandwich assa> )
  • sandwich assay is an ELISA assay, in which case the detectable moiety is an enzyme
  • the tissue sample may be fresh or frozen or may be embedded in paraffin and fixed with a preservative such as formalin, for example
  • cells of a cell type known to be involved in a particular immune related disease are transfected with the cDNAs described herein, and the ability of these cDNAs to stimulate or inhibit immune function is analyzed Suitable cells can be transfected with the desired gene, and monitored for immune function activity Such transfected cell lines can then be used to test the ability of poly- or monoclonal antibodies or antibody compositions to inhibit or stimulate immune function, for example to modulate T-cell proliferation or inflammatory cell infiltration
  • Cells transfected with the coding sequences of the genes identified herein can further be used to identify drug candidates for the treatment of immune related diseases
  • transgenic animals in addition, primary cultures derived from transgenic animals (as described below) can be used in the cell-based assays herein, although stable cell lines are preferred Techniques to derive continuous cell lines from transgenic animals are well known in the art (see, e g Small et al , Mol Cell Biol 5, 642-648 [1985])
  • MLR mixed lymphocyte reaction
  • T cells is culmred with allogeneic stimulator cells and the proliferation of T cells is measured by uptake of t ⁇ tiated thymidine
  • This assay is a general measure of T cell reactivity Since the majority of T cells respond to and produce IL-2 upon activation, differences m responsiveness in this assay m part reflect differences in IL-2 production by the responding cells
  • the MLR results can be verified by a standard lymphokme (IL 2) detection assay Current Protocols in Immunology, above, 3 15, 6 3
  • a proliferative T cell response in an MLR assay may be due to direct mitogenic properties of an assayed molecule or to external antigen induced activation Additional verification of the T cell stimulatory activity of the polypeptides of the invention can be obtained by a costimulation assay T cell activation requires an antigen specific signal mediated through the T-cell receptor (TCR) and a costimulatory signal mediated through a second ligand binding interaction, for example, the B7(CD80.
  • TCR T-cell receptor
  • B7(CD80 costimulatory signal
  • CD86 CD86/CD28 binding interaction
  • CD28 crosslmking increases lymphokme secretion by activated T cells
  • T cell activation has both negative and positive controls through the binding of ligands which have a negative or positive effect
  • CD28 and CTLA-4 are related glycoprote s in the lg superfamily which bind to B7 CD28 binding to B7 has a positive costimulation effect of T cell activation, conversely, CTLA 4 binding to B7 has a negative T cell deactivating effect Chambers and Allison, Curr Opin Immunol (1997) 9 396 Schwartz, Cell (1992)
  • the PRO polypeptides of the invention are assayed for T cell costimulatory or inhibitory activity
  • PRO polypeptides of the invention as well as other compounds of the invention, which are stimulators (costimulators) of T cell proliferation and agonists , e g agonist antibodies, thereto as determined by MLR and costimulation assays, for example, are useful m treating immune related diseases characterized by poor, suboptimal or inadequate immune function These diseases are treated by stimulating the proliferation and activation of T cells (and T cell mediated immunity) and enhancing the immune response in a mammal through administration of a stimulatory compound, such as the stimulating polypeptides of the invention
  • the stimulating polypeptide may, for example, be a PRO polypeptide or an agonist antibody therefor Direct use of a stimulating compound as in the invention has been validated in experiments with
  • 4-1BB glycoprotein a member of the tumor necrosis factor receptor family, which binds to a ligand (4- 1 BBL) expressed on primed T cells and signals T cell activation and growth Alderson et al , J Immunol (1994) 24 2219
  • an agonist stimulating compound has also been validated experimentally Activation of 4- IBB by treatment with an agonist ant ⁇ -4-lBB antibody enhances eradication of tumors Hellstrom and
  • An immune stimulating or enhancing effect can also be achieved by antagonizing or blocking the activity of a protein which has been found to be inhibiting in the MLR assay Negating the inhibitory activity of the compound produces a net stimulatory effect
  • Suitable antagonists/blocking compounds are antibodies or fragments thereof which recognize and bind to the inhibitory protein, thereby blocking the effective interaction of the protein with its receptor and inhibiting signaling through the receptor This effect has been validated in experiments using ant ⁇ -CTLA-4 antibodies which enhance T cell proliferation, presumably by removal of the inhibitory signal caused by CTLA 4 binding Walunas et al Immunity (1994) 1 405
  • PRO polypeptides of the invention as well as other compounds of the invention, which are direct inhibitors of T cell proliferation/activation and/or lymphokme secretion, can be directly used to suppress the immune response
  • These compounds are useful to reduce the degree of the immune response and to treat immune related diseases characterized by a hyperactive, superoptimal, or autoimmune response
  • compounds, e g antibodies, which bind to stimulating PRO polypeptides of the invention and block the stimulating effect of these molecules produce a net inhibitory effect and can be used to suppress the T cell mediated immune response by inhibiting T cell proliferation/activation and/or lymphokme secretion Blocking the stimulating effect of the PRO polypeptides suppresses the immune response of the mammal
  • This use has been validated in experiments using an ant ⁇ -IL2 antibody In these experiments, the antibody binds to IL2 and blocks binding of IL2 to its receptor thereby achieving a T cell inhibitory effect
  • results of the cell based in vitro assays can be further verified using in vivo ammal models and assays for T-cell function
  • animal models can be used to further understand the role of the genes identified herein in the development and pathogenesis of immune related disease, and to test the efficacy of candidate therapeutic agents, including antibodies, and other antagomsts of the native polypeptides, including small molecule antagonists
  • the in vivo nature of such models makes them predictive of responses in human patients
  • Animal models of immune related diseases include both non-recombinant and recombinant (transgenic) animals
  • Non-recombinant animal models include, for example, rodent, e g , murine models
  • Such models can be generated by introducing cells into syngeneic mice using standard techniques, e g subcutaneous injection, tail vein injection, spleen implantation, intraperitoneal implantation, implantation under the renal capsule, etc
  • Graft-versus-host disease occurs when immunocompetent cells are transplanted into immunosuppressed or tolerant patients The donor cells recognize and respond to host antigens The response can vary from life threatening severe inflammation to mild cases of diarrhea and weight loss
  • An animal model for skin allograft rejection is a means of testing the ability of T cells to mediate in vivo tissue destruction and a measure of their role in transplant reiection
  • the most common and accepted models use murine tail-skin grafts
  • Skin allograft rejection is mediated by T cells, helper T cells and killer-effector T cells, and not antibodies Auchincloss and Sachs, Fundamental Immunology. 2nd ed W E Paul ed , Raven Press, NY, 1989, 889 992
  • a suitable procedure is described m detail in Current Protocols in Immunology .
  • transplant reiection models which can be used to test the compounds of the invention are the allogeneic heart transplant models described by Tanabe et al , Transplantation (1994) 58 23 and Tinubu et al J Immunol (1994) 4330 4338
  • EAE animal models for delayed type hypersensitivity provides an assay of cell mediated immune function as well Delayed type hypersensitivity reactions are a T cell mediated in ⁇ ⁇ o immune response characterized by inflammation which does not reach a peak until after a period of time has elapsed after challenge with an antigen These reactions also occur in tissue specific autoimmune diseases such as multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE, a model for MS)
  • MS multiple sclerosis
  • EAE experimental autoimmune encephalomyelitis
  • a suitable procedure is described in detail in Current Protocols in Immunology, above, unit 4 5 EAE is a T cell mediated autoimmune disease characterized by T cell and mononuclear cell inflammation and subsequent demyelination of axons m the central nervous system EAE is generally considered to be a relevant animal model for MS in humans Bolton.
  • Contact hypersensitivity is a simple delayed type hypersensitivity in vivo assay of cell mediated immune function
  • cutaneous exposure to exogenous haptens which gives rise to a delayed type hypersensitivity reaction which is measured and quantitated
  • Contact sensitivity involves an initial sensitizing phase followed by an ehcitation phase
  • the ehcitation phase occurs when the T lymphocytes encounter an antigen to which they have had previous contact Swelling and inflammation occur, making this an excellent model of human allergic contact dermatitis
  • a suitable procedure is described in detail in Current Protocols in Immunology, Eds J E Cologan, AM Kruisbeek, DH Marguhes, EM Shevach and Strober, John Wiley & Sons, Ine , 1994, unit 4 2 See also Grabbe and Schwarz, Immun Today
  • An animal model for arthritis is collagen-induced arthritis This model shares clinical, histological and lmmunological characteristics of human autoimmune rheumatoid arthritis and is an acceptable model for human autoimmune arthritis
  • Mouse and rat models are characterized by synovitis, erosion of cartilage and subchondral bone
  • the PRO polypeptides and compounds of the invention can be tested for activity against autoimmune arthritis using the protocols described in Current Protocols in Immunology, above, units 15 5 See also the model using a monoclonal antibody to CD 18 and VLA-4 integrins described in Issekutz et al , Immunology (1996) 88 569
  • the PRO polypeptides and compounds of the invention can be tested on animal models for psoriasis like diseases Evidence suggests a T cell pathogenesis for psoriasis
  • the compounds of the invention can be tested in the scid/scid mouse model described by Schon et al, Nat Med (1997) 3 183, m which the mice demonstrate histopathologic skin lesions resembling psoriasis
  • Another suitable model is the human skin/scid mouse chimera prepared as described by Nickoloff et al, Am J Path (1995) 146 580
  • Recombinant (transgenic) animal models can be engineered by introducing the coding portion of the genes identified herein into the genome of animals of interest, using standard techniques for producing transgenic animals
  • Animals that can serve as a target for transgenic manipulation include, without limitation, mice, rats, rabbits, guinea pigs, sheep, goats, pigs, and non-human primates, e g baboons, chimpanzees and monkeys
  • Techniques known in the art to introduce a transgene into such animals include pronucleic microinjection (Hoppe and Wanger, U S Patent No 4,873, 191), retrovirus mediated gene transfer into germ lines (e g , Van der Putten et al , Proc Natl Acad Sci USA 82, 6148 615 [1985]), gene targeting in embryonic stem cells (Thompson et al , Cell 56, 313-321 [1989]), electroporation of embryos
  • transgenic animals include those that carry the transgene only m part of their cells ("mosaic animals”).
  • the transgene can be integrated either as a single transgene, or in concatamers, e g , head-to-head or head-to-tail tandems Selective introduction of a transgene into a particular cell type is also possible by following, for example, the technique of Lasko et al , Proc Natl Acad Sci USA 89, 6232-636 (1992)
  • transgene m transgenic animals can be monitored by standard techniques For example, Southern blot analysis or PCR amplification can be used to verify the integration of the transgene The level of mRNA expression can then be analyzed using techniques such as in situ hybridization, Northern blot analysis, PCR, or immunocytochemistry
  • the animals may be further examined for signs of immune disease pathology, for example by histological examination to determine infiltration of immune cells into specific tissues
  • Blocking experiments can also be performed in which the transgenic animals are treated with the compounds of the invention to determine the extent of the T cell proliferation stimulation or inhibition of the compounds
  • blocking antibodies which bind to the PRO polypeptide of the invention, prepared as described above, are administered to the animal and the effect on immune function is determined
  • "knock out" animals can be constructed which have a defective or altered gene encoding a polypeptide identified herein, as a result of homologous recombination between the endogenous gene encoding the polypeptide and altered genomic DNA encoding the same polypeptide introduced into an embryonic cell of the animal
  • cDNA encoding a particular polypeptide can be used to clone genomic DNA encoding that polypeptide in accordance with established techniques
  • a portion of the genomic DNA encoding a particular polypeptide can be deleted or replaced with another gene, such as a gene encoding a selectable marker which can be used to monitor integration Typicall , 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 mto an embryonic stem cell line (e g , by electropor
  • 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, Teratocarcmomas and Embryonic Stem Cells A Practical Approach, 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 recombmed 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 recombmed 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 polypeptide
  • the lmmunostimulating PRO polypeptides and compounds of the invention can be used in immunoadjuvant therapy for the treatment of tumors (cancer) It is now well established that T cells recognize human tumor specific antigens
  • tumor antigens encoded by the MAGE, BAGE and GAGE families of genes, are silent in all adult normal tissues, but are expressed in significant amounts in tumors, such as melanomas, lung tumors, head and neck tumors, and bladder carcinomas DeSmet et al, (1996) Proc Natl Acad Sci USA.
  • the stimulatory PRO polypeptides and compounds of the invention can be administered as adjuvants, alone or together with a growth regulating agent, cytotoxic agent or chemotherapeutic agent, to stimulate T cell proliferation/activation and an antitumor response to tumor antigens
  • the growth regulating, cytotoxic, or chemotherapeutic agent may be administered in conventional amounts using known administration regimes lmmunostimulating activity by the PRO polypeptides and compounds of the invention allows reduced amounts of the growth regulating, cytotoxic, or chemotherapeutic agents thereby potentially lowering the toxicity to the patient
  • Screening assays for drug candidates are designed to identify compounds that bind to or complex with the polypeptides encoded by the genes identified herein or a biologically active fragment thereof, 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
  • Small molecules contemplated include synthetic organic or inorganic compounds, including peptides preferably soluble peptides, (poly)pept ⁇ de immunoglobulin fusions, and, in particular, antibodies including, without limitation, poly- and monoclonal antibodies and antibody fragments, single chain antibodies a i ldiotypic antibodies, and chimeric or humanized versions of such antibodies or fragments, as well as human antibodies and antibody fragments
  • 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
  • the candidate compound interacts with but does not bind to a particular protein encoded by a gene identified herein, its interaction with that protein can be assayed by methods well known for detecting protein-protem interactions
  • Such assays include traditional approaches, such as, 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 (1989), Chien et al , Proc Natl Acad Sci USA 88, 9578-9582 (1991)] as disclosed by Chevray and Nathans rProc Natl Acad Sci USA 89, 5789-5793 (1991)]
  • Many transcriptional activators such as yeast GAL4, consist of two physically discrete modular domains, one acting as the DNA-binding domain, while the other one functioning as the transcription activation domain
  • yeast expression system described in the foregoing publications
  • a reaction mixture is usually 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 placebo may be added to a third reaction mixture, 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 above
  • compositions useful m the treatment of immune related diseases include, without limitation, proteins, antibodies, small orgamc molecules, peptides, phosphopeptides, antisense and ⁇ bozyme molecules, triple helix molecules, etc that inhibit or stimulate immune function, for example, T cell proliferation/activation, lymphokme release, or immune cell infiltration
  • antisense RNA and RNA molecules act to directly block the translation of mRNA by hybridizing to targeted mRNA and preventing protein translation
  • oligodeoxy ⁇ bonucleotides derived from the translation initiation site e g between about -10 and + 10 positions of the target gene nucleotide sequence, are preferred
  • 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 ⁇ bozyme 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 (published September 18, 1997)
  • Nucleic acid molecules in triple helix formation used to inhibit transcription should be smgle-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 pu ⁇ nes or py ⁇ midines on one strand of a duplex
  • Hoogsteen base pairing rules which generally require sizeable stretches of pu ⁇ nes or py ⁇ midines on one strand of a duplex
  • the present invention further provides anti-PRO antibodies
  • Exemplary antibodies include polyclonal monoclonal, humanized, bispecific, and heterocon]ugate antibodies
  • Some of the most promising drug candidates according to the present invention are antibodies and antibodv tragments which may inhibit (antagonists) or stimulate (agonists) T cell proliferation, eosmophil infiltration, etc
  • 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 mtrape ⁇ toneal 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 lmmunogenic in the mammal being immunized
  • lmmunogenic proteins include but are not limited to keyhole limpet hemocyanin, serum albumm, bovine thyroglobulm, and soybean trypsm inhibitor
  • adjuvants which may be employed include Freund's complete adjuvant and MPL-TDM ad]uvant (monophosphoryl Lipid A, synthetic trehalose dicorynomycolate)
  • the immunization protocol may be selected by one skilled m the art without undue experimentation.
  • the anti-PRO antibodies may, alternatively, be monoclonal antibodies
  • Monoclonal antibodies may be prepared using hyb ⁇ doma methods, such as those described by Kohler and Milstem, Nature. 256:495 (1975)
  • a hyb ⁇ doma method a mouse, hamster, or other appropriate host animal, is typically immunized with an immunizing agent to elicit lymphocytes that produce or are capable ot 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
  • peripheral blood lymphocytes are used if cells of human origin are desired, or spleen cells or lymph node cells are used if non-human mammalian sources are desired.
  • the lymphocytes are then fused with an immortalized cell line using a suitable fusing agent, such as polyethylene glycol, to form a hyb ⁇ doma 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 Usually, rat or mouse myeloma cell lines are employed
  • the hyb ⁇ doma 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 parental cells lack the enzyme hypoxanthine guanine phospho ⁇ bosyl transferase (HGPRT or HPRT)
  • the culture medium for the hyb ⁇ domas typically will include hypoxanthine.
  • HAT medium aminopte ⁇ n, and thymidme
  • Preferred immortalized cell lines are those that fuse efficiently , support stable high le el 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 m eloma lines, which can be obtained for instance, from the Salk Institute Cell Distribution Center San Diego, California and the American T pe 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
  • the culmre medium m 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 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 b> 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, supra] Suitable culture media for this purpose include for example, Dulbecco's Modified Eagle's Medium and RPMI-1640 medium Alternatively, the hybridoma cells may be grown in vivo as ascites in a mammal
  • the monoclonal antibodies secreted by the subclones may be isolated or purified from the culmre 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 m place of the homologous murine sequences [U S Patent No 4,816,567, Morrison et
  • 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 heavv chain is truncated generally at any point in the Fc region so as to prevent heavy chain crosslinking
  • the relevant cysteine residues are substituted with another ammo acid residue or are deleted so as to prevent crosslmking
  • 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 ot a non human species (donor antibody) such as mouse, rat or rabbit having the desired specificity, affinity and capacity
  • CDR complementary determining region
  • donor antibody such as mouse, rat or rabbit having the desired specificity, affinity and capacity
  • 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
  • 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 Humamzation 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.
  • 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 .
  • human antibodies can be made by introducing of human immunoglobulin loci into transgenic animals, e g mice in which the endogenous immunoglobulin genes hav e been partially or completely inactivated Upon challenge human antibod) 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
  • the antibodies may also be affinity mamred using known selection and/or mutagenesis methods as described above
  • Preferred affinity mamred antibodies have an affinity which is five times more preferably 10 times, even more preferably 20 or 30 times greater than the starting antibody (generally murine, humanized or human) from which the mamred antibody is prepared
  • Bispecific antibodies are monoclonal, preferably human or humanized, antibodies that have binding specificities for at least two different antigens
  • one of the binding specificities is for the PRO
  • the other one is for any other antigen
  • Methods for making 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 [Milste and Cuello, Nature.
  • 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 hmge, CH2 and CH3 regions
  • 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
  • CH 1 first heavy chain constant region
  • 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 ammo 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 cham(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 threonme)
  • Bispecific antibodies can be prepared as full length antibodies or antibody fragments (e g F(ab') ⁇ 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 et al , Science 229 81 (1985) describe a procedure wherein intact antibodies are proteolytically cleaved to generate F(ab'), fragments These fragments are reduced in the presence of the dithiol complexing agent sodium arsemte to stabilize vicinal dithiols and prevent intermolecular disulfide formation The Fab' fragments generated are then converted to thiomtrobenzoate (TNB) derivatives One of the 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
  • 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 Kostelny et al , J Immunol 148(5) 1547 1553 (1992)
  • 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 "diabody " technology described by Holhnger et al , Proc Natl Acad Sci USA 90 6444 6448 (1993) has provided an alternative mechanism for making bispecific antibody fragments
  • 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 render and V I
  • t ⁇ specific antibodies can be prepared Tutt et al , J Immunol 147 60 (1991 ) Exemplary bispecific antibodies may bind to two different epitopes on a given PRO polypeptide herein Alternatively , 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 (CD16) so as to focus cellular defense mechanisms to the cell expressing the particular PRO poly peptide 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
  • 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] It is contemplated that the antibodies may be prepared in vitro using known methods in synthetic protein chemistry including those involving crosshnking agents For example, immunotoxms may be constructed using a disulfide exchange reaction or by forming a thioether bond Examples of suitable reagents for this purpose include lminothiolate and methyl-4- mercaptobuty ⁇ midate and those disclosed, for example, in U S Patent No 4,676,980
  • cysteine res ⁇ due(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 mtemalization capability and/or increased complement-mediated cell killing and antibody-dependent cellular cytotoxicity (ADCC) See Caron et al ,
  • 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 nonbmdmg active fragments of diphtheria toxm exotoxin A chain (from Pseudomonas aeruginosa).
  • ⁇ cin A chain ab ⁇ n A chain modeccin A chain, alpha-sarcm Aleuntes fordu proteins, dianthm proteins PhMolaca americana proteins (PAPI PAPII. and PAP S), momordica charantia inhibitor curcin. crotm, sapaonaria officinahs inhibitor, gelonm, mitogellin.
  • radionuc des are available for the production of radioconjugated antibodies
  • Examples include 212 B ⁇ , n ⁇ I, ' ''In, ⁇ Y, and 186 Re Conjugates of the antibody and cytotoxic agent are made using a variety of bifunctional protein coupling agents such as N-succimmidyl 3 (2-py ⁇ dyld ⁇ th ⁇ ol) propionate (SPDP), lm othiolane (IT), bifunctional derivatives of lmidoesters (such as dimethyl adipimidate HCL), active esters (such as disuccimmidyl suberate), aldehydes (such as glutareldehyde), bis-azido compounds (such as bis (p azidobenzoy 1) hexanediamine), bis diazomum derivatives (such as b ⁇ s-(p-d ⁇ azomumbenzoyl)-
  • SPDP N-succimmidyl 3 (2-py ⁇ dyld ⁇ th ⁇ ol
  • MX-DTPA Carbon- 14-labeled 1 ⁇ soth ⁇ ocyanatobenzyl-3-methyld ⁇ ethylene t ⁇ ammepentaacetic acid
  • the antibody may be conjugated to a ' receptor" (such streptav idin) 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)
  • 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 m 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 ith a lipid composition comprising phosphatidylchohne, 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-mterchange 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)
  • chemotherapeutic agent such as Doxorubicin
  • compositions The active molecules of the invention.
  • PRO polypeptides and antibodies, as well as other molecules identified by the screening assays disclosed above, can be administered for the treatment of immune related diseases, m the form of pharmaceutical compositions
  • Therapeutic formulations of the active molecule, preferably a PRO pol) peptide or anti-PRO antibody of the invention are prepared for storage by mixing the active molecule hav mg the desired degree of purity with optional pharmaceutically 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 and methionme, preservatives (such as octadecyldimethvlbenzyl ammonium chloride, hexamethomum chloride benzalkomum
  • Lipofections or liposomes can also be used to deliver the polypeptide, antibody, or an antibody fragment, into cells Where antibody fragments are used, the smallest inhibitory fragment which specifically binds to the binding domain of the target protein is preferred
  • peptide molecules can be designed which retain the ability to bind the target protein sequence
  • Such peptides can be synthesized chemically and/or produced by recombinant DNA technology (see, e g Marasco et al , Proc Natl Acad Sci USA 90, 7889-7893 [1993])
  • the formulation herein may also contain more than one active polypeptide or compound as necessary for the particular indication being treated, preferably those with complementary activities that do not adversely affect each other Alternatively, or in addition, the composition may comprise a cytotoxic agent, cytokine or growth inhibitory agent Such molecules are suitably present in combination in amounts that are effective for the purpose intended
  • the active molecules may also be entrapped in microcapsules prepared, for example, by coacervation techniques or by mterfacial polymerization, for example hydroxymethylcellulose or gelatm-microcapsules and poly-(methylmethacylate) microcapsules respecm ely , in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions nano-particles and nanocapsules) or in macroemulsions Such techniques are disclosed in Remington's Pharmaceutical Sciences 16th edition, Osol, A Ed (1980)
  • the formulations to be used for in vivo administration must be sterile This is readily accomplished by filtration through sterile filtration membranes
  • Sustained-release preparations may be prepared Suitable examples of sustained-release preparations include semipermeable matrices of solid hy drophobic polymers containing the antibody, which matrices are in the form of shaped articles, e g films, or microcapsules Examples of susta
  • poly(2-hydroxyethyl-methacrylate), or poly(vmy alcohol) poly(2-hydroxyethyl-methacrylate), or poly(vmy alcohol)).
  • polylactides U.S. Pat No 3,773,919
  • copolymers of L-glutamic acid and g ethyl-L-glutamate non-degradable ethylene-vmyl acetate
  • degradable lactic acid glycolic acid copolymers such as the LUPRON DEPOTTM
  • injectable microspheres composed of lactic acid-glycohc acid copolymer and leuprolide acetate
  • polymers such as ethylene-vmyl acetate and lactic acid-glycohc acid enable release of molecules for over 100 days
  • certain hydrogels release proteins for shorter time periods
  • 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 formation through thio-di sulfide 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.
  • PRO polypeptides, antibodies and other active compounds of the present invention may be used to treat various immune related diseases and conditions, such as T cell mediated diseases, including those characterized by infiltration of inflammatory cells mto a tissue, stimulation of T-cell proliferation, inhibition of T-cell proliferation, increased or decreased vascular permeability or the inhibition thereof
  • Exemplary conditions or disorders to be treated with the PRO polypeptides, antibodies and other compounds of the invention include, but are not limited to systemic lupus erythematosis, rheumatoid arthritis, juvenile chronic arthritis, osteoarthritis, spondyloarthropathies, systemic sclerosis (scleroderma), idiopathic inflammatory myopathies (dermatomyositis, polymyositis), Sjogren's syndrome, systemic vascuhtis, sarcoidosis, autoimmune hemolytic anemia (immune pancytopenia, paroxysmal nocturnal hemoglobinu ⁇ a), autoimmune thrombocytopenia (idiopathic thrombocytopenic purpura, immune -mediated thrombocytopenia), thyroiditis (Grave's disease, Hashimoto's thyroiditis, juvenile lymphocytic thyroiditis, atrophic thyroiditis), diabetes mel tus, immune-mediated renal disease (glomeruloneph
  • Rheumatoid arthritis is a chronic systemic autoimmune inflammatory disease that mainly involves the synovial membrane of multiple joints with resultant injury to the articular cartilage
  • the pathogenesis is T lymphocyte dependent and is associated with the production of rheumatoid factors, auto-antibodies directed against self IgG, with the resultant formation of immune complexes that attain high levels in ]omt fluid and blood
  • extra-articular disease also occurs in two major forms.
  • One form is the development of extra-articular lesions with ongoing progressive joint disease and typical lesions of pulmonary fibrosis, vascuhtis, and cutaneous ulcers
  • the second form of extra-articular disease is the so called Felty ' s syndrome which occurs late in the R A disease course , sometimes after joint disease has become quiescent, and involves the presence of neutropenia, thrombocytopenia and splenomegaly.
  • Juvenile chronic arthritis is a chronic idiopathic inflammatory disease which begins often at less than 16 years of age Its phenotype has some similarities to RA, some patients which are rhematoid factor positive are classified as juvenile rheumatoid arthritis The disease is sub-classified mto three major categories: pauciarticular, polya ⁇ icular, and systemic The arthritis can be severe and is typically destructive and leads to joint ankylosis and retarded growth Other manifestations can include chronic anterior uveitis and systemic amyloidosis
  • Spondyloarthropathies are a group of disorders with some common clinical features and the common association with the expression of HLA-B27 gene product
  • the disorders include, ankylosing sponyhtis.
  • Reiter's syndrome reactive arthritis
  • arthritis associated with inflammatory bowel disease spondylitis associated with psoriasis
  • Distinguishing features include sacroileitis with or without spondylitis; inflammatory asymmetric arthritis, association with HLA B27 (a serologically defined allele of the HLA B locus of class I MHC ) ocular inflammation, and absence of autoantibodies associated with other rheumatoid disease
  • the cell most implicated as key to induction of the disease is the CD8 + T lymphocyte, a cell which targets antigen presented by class I MHC molecules CD8" T cells may react against the class I MHC allele HLA B
  • Systemic sclerosis (scleroderma) has an unknown etiology A hallmark of the disease is induration of the skm, likely this is induced by an active inflammatory process Scleroderma can be localized or systemic, vascular lesions are common and endothelial cell injury in the microvasculature is an early and important event in the development of systemic sclerosis, the vascular injury may be immune mediated An immunologic basis is implied by the presence of mononuclear cell infiltrates in the cutaneous lesions and the presence of anti nuclear antibodies many patients ICAM 1 is often upregulated on the cell surface of f ⁇ broblasts in skin lesions suggesting that T cell interaction with these cells may have a role in the pathogenesis of the disease Other organs involved include the gastrointestinal tract smooth muscle atrophy and fibrosis resulting in abnormal pe ⁇ stalsis/motihty, kidney concentric subendothehal intimal proliferation affecting small arcuate and interlobular arteries with resultant reduced renal cortical blood flow, results in
  • Idiopathic inflammatory myopathies including dermatomyositis, polymyositis and others are disorders of chronic muscle inflammation of unknown etiology resulting m muscle weakness Muscle injury/inflammation is often symmetric and progressive Autoantibodies are associated with most forms These myositis-specific autoantibodies are directed against and inhibit the function of components, proteins and RNA's, involved in protein synthesis
  • Sjogren's syndrome is due to immune-mediated inflammation and subsequent functional destruction of the tear glands and salivary glands
  • the disease can be associated with or accompanied by inflammatory connective tissue diseases
  • the disease is associated with autoantibody production agamst Ro and La antigens, both of which are small RNA-protein complexes Lesions result in keratoconjunctivitis sicca, xerostomia, with other manifestations or associations including bilary cirrhosis, peripheral or sensory neuropathy, and palpable purpura
  • Systemic vascuhtis are diseases in which the primary lesion is inflammation and subsequent damage to blood vessels which results ischemia/necrosis/degeneration to tissues supplied by the affected vessels and eventual end organ dysfunction in some cases
  • Vascuhtides can also occur as a secondary lesion or sequelae to other immune-inflammatory mediated diseases such as rheumatoid arthritis, systemic sclerosis, etc , particularly in diseases also associated with the formation of immune complexes Diseases in the primary
  • Sarcoidosis is a condition of unknown etiology which is characterized by the presence of epithehoid granulomas in nearly any tissue in the body, involvement of the lung is most common
  • the pathogenesis involves the persistence of activated macrophages and lymphoid cells at sites of the disease with subsequent chronic sequelae resultant from the release of locally and systemically active products released by these cell types
  • Autoimmune hemolytic anemia including autoimmune hemolytic anemia, immune pancytopenia, and paroxysmal noctural hemoglobinu ⁇ a is a result of production of antibodies that react with antigens expressed on the surface of red blood cells (and in some cases other blood cells including platelets as well) and is a reflection of the removal of those antibody coated cells via complement mediated lysis and/or
  • autoimmune thrombocytopenia including thrombocytopenic purpura
  • immune-mediated thrombocytopenia m other clinical settings
  • platelet destruction/removal occurs as a result of either antibody or complement attaching to platelets and subsequent removal by complement lysis, ADCC or FC-receptor mediated mechanisms
  • Thyroiditis including Grave's disease, Hashimoto's thyroiditis, juvenile lymphocytic thyroiditis, and atrophic thyroiditis, are the result of an autoimmune response against thyroid antigens with production of antibodies that react with proteins present in and often specific for the thyroid gland
  • Experimental models exist including spontaneous models rats (BUF and BB rats) and chickens (obese chicken strain), inducible models immunization of animals with either thyroglobulm, thyroid microsomal antigen (thyroid peroxidase)
  • Type I diabetes melhtus or insulin-dependent diabetes is the autoimmune destruction of pancreatic islet ⁇ cells, this destruction is mediated by auto-antibodies and auto-reactive T cells
  • Antibodies to insulin or the insulin receptor can also produce the phenotype of insulin-non-responsiveness
  • Immune mediated renal diseases including glomeruloneph ⁇ tis and tubulointerstmal nephritis, are the result of antibody or T lymphocyte mediated injury to renal tissue either directly as a result of the production of autoreactive antibodies or T cells against renal antigens or indirectly as a result of the deposition of antibodies and/or immune complexes in the kidney that are reactive against other, non-renal antigens
  • immune mediated diseases that result in the formation of immune-complexes can also induce immune mediated renal disease as an indirect sequelae
  • Both direct and indirect immune mechanisms result in inflammatory response that produces/induces lesion development in renal tissues with resultant organ function impairment and in some cases progression to renal failure
  • Both humoral and cellular immune mechanisms can be involved in the pathogenesis of lesions
  • Demyelinating diseases of the central and peripheral nervous systems including Multiple Sclerosis, idiopathic demyelinating polyneuropathy or Guillain-Barr syndrome, and Chronic Inflammatory Demyelinating Polyneuropathy,
  • Inflammatory and Fibrotic Lung Disease including Eosinophihc Pneumonias, Idiopathic Pulmonar) Fibrosis, and Hypersensitivity Pneumonitis may involve a deregulated immune-inflammatory response Inhibition of that response would be of therapeutic benefit
  • Psoriasis is a T lymphocyte-mediated inflammatory disease Lesions contain infiltrates of T lymphocytes, macrophages and antigen processing cells, and some neutrophils
  • Allergic diseases including asthma, allergic rhinitis, atopic dermatitis, food hypersensitivity; and urticaria are T lymphocyte dependent These diseases are predominantly mediated by T lymphocyte induced inflammation, IgE mediated-inflammation or a combination of both
  • Transplantation associated diseases including Graft reiection and Graft- Versus-Host-Disease (GVHD) are T lymphocyte-dependent, inhibition of T lymphocyte function is ameliorative
  • infectious disease including but not limited to viral infection (including but not limited to AIDS, hepatitis A, B, C, D, Eand herpes) bacterial infection, fungal infections, and protozoal and parasitic infections (molecules (or derivatives/agonists) which stimulate the MLR can be utilized therapeutically to enhance the immune response to infectious agents) , diseases of immunodeficiency (molecules/de ⁇ vatives/agonists) which stimulate the MLR can be utilized therapeutically to enhance the immune response for conditions of inherited, acquired, infectious induced (as in HIV infection), or latrogemc (I e as from chemotherapy) immunodeficiency), and neoplasia
  • PRO polypeptides and compounds of the present invention are administered to a mammal, preferably a human, in accord with known methods, such as intravenous administration as a bolus or by continuous infusion over a period of time, by intramuscular, intraperitoneal, lntracerobrospmal, subcutaneous, intra articular, intrasynovial, mtrathecal, oral, topical, or inhalation (intranasal, intrapulmonary) routes Intravenous or inhaled administration of polypeptides and antibodies is preferred
  • an anti-cancer agent chemotherapeutic agent
  • radiation therapy Preparation and dosmg schedules for such chemotherapeutic agents may be used according to manufacturers instructions or as determined empirically by the skilled practitioner Preparation and dosing schedules for such chemotherapy are also described in Chemotherapy Service Ed , M C Perry, Williams & Wilkins, Baltimore, MD (1992)
  • the chemotherapeutic agent may precede, or follow administration of the immunoadjuvant or may be given simultaneously therewith
  • an anti-oestrogen compound such as tamoxifen or an anti -progesterone such as onap ⁇ stone (see, EP 616812) may be given in dosages known for such molecules
  • the polypeptides of the invention are coadmmistered with a growth inhibitory agent
  • the growth inhibitory agent may be administered first, followed by a PRO polypeptide of the invention
  • simultaneous administration or administration first is also contemplated Suitable dosages for the growth inhibitory agent are those presently used and may be lowered due to the combined action (synergy) of the growth inhibitory agent and the PRO polypeptide of the invention
  • an a PRO polypeptide or compound of the invention will depend on the type of disease to be treated, as defined above, the seventy and course of the disease whether the agent is administered for preventive or therapeutic purposes, previous therapy, the patient's clinical history and response to the compound, and the discretion of the attending physician
  • the compound is suitably administered to the patient at one time or over a series of treatments
  • about 1 ⁇ g/kg to 15 mg/kg (e g 0 l-20mg/kg) of polypeptide or antibody is an initial candidate dosage for administration to the patient, whether, for example, by one or more separate administrations, or by continuous infusion
  • a typical dail) dosage might range from about 1 ⁇ g/kg to 100 mg/kg or more depending on the factors mentioned above
  • the treatment is sustained until a desired suppression of disease symptoms occurs
  • other dosage regimens may be useful The progress of this therapy is easily
  • an article of manufacture containing materials useful for the diagnosis or treatment of the disorders described above comprises a container and a label Suitable containers include, for example, bottles, vials, syringes, and test tubes
  • the containers may be formed from a variety of materials such as glass or plastic
  • the container holds a composition which is effective for diagnosing or treating the condition and may have a sterile access port (for example the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle)
  • the active agent the composition is usually a PRO polypeptide or an antibody of the invention
  • the label on, or associated with, the container indicates that the composition is used for diagnosing or treating the condition of choice
  • the article of manufacture may further comprise a second container comprising a pharmaceutically-acceptable buffer, such as phosphate-buffered saline, Ringer's solution and dextrose solution It may further include other materials desirable from a commercial and user standpoint, including other buffers, dil
  • Cell surface proteins such as proteins which are overexpressed in certain immune related diseases, are excellent targets for drug candidates or disease treatment
  • the same proteins along with secreted proteins encoded by the genes amplified m immune related disease states find additional use in the diagnosis and prognosis of these diseases
  • antibodies directed against the protein products of genes amplified in multiple sclerosis, rheumatoid arthritis, or another immune related disease can be used as diagnostics or prognostics
  • antibodies, including antibody fragments can be used to qualitative!) or quantitatively detect the expression of proteins encoded by amplified or overexpressed genes (' marker gene products")
  • the antibody preferably is equipped with a detectable, e g fluorescent label, and binding can be monitored by light microscopy, flow cytometry, fluo ⁇ metry, or other techniques known m the art These techniques are particularly suitable, if the overexpressed gene encodes a cell surface protein Such binding assays are performed essentially as dec ⁇ bed above
  • In situ detection of antibody binding to the marker gene products can be performed, for example, by lmmunofluorescence or immunoelectron microscopy
  • a histological specimen is removed from the patient, and a labeled antibody is applied to it preferabh by overlaying the antibody on a biological sample
  • This procedure also allows for determining the distribution ot the marker gene product in the tissue examined It will be apparent for those skilled in the art that a wide variety of histological methods are readily available for in situ detection
  • Extracellular domain (ECD) sequences (including the secretion signal, if any) of from about 950 known secreted proteins from the Swiss Prot public protein database were used to search expressed sequence tag (EST) databases
  • the EST databases included public EST databases (e g GenBank) and a proprietary EST DNA database (LIFESEQTM, Incyte Pharmaceuticals, Palo Alto, CA)
  • the search was performed using the computer program BLAST or BLAST2 (Altshul et al , Methods in Enzymology 266 460-480 (1996)) as a comparison of the ECD protein sequences to a 6 frame translation of the EST sequence Those comparisons resulting m a BLAST score of 70 (or in some cases 90) or greater that did not encode known proteins were clustered and assembled into consensus DNA sequences with the program "phrap" (Phil Green, University of Washington.
  • oligonucleotides were synthesized 1) to identify by PCR a cDNA library that contained the sequence of interest and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0526
  • Forward and reverse 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 sequences are typically 40 55 bp in length
  • additional oligonucleotides are synthesized when the consensus sequence is greater than about 1-1 5kbp
  • DNA 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
  • a pair of PCR primers (forward and reverse) were synthesized forward PCR primer 5' TGGCTGCCCTGCAGTACCTCTACC-3 (SEQ ID NO 1 1), and reverse PCR primer 5' CCCTGCAGGTCATTGGCAGCTAGG 3 (SEQ ID NO 12)
  • oligonucleotide hybridization probe was constructed from the consensus sequence which had the following nucleotide sequence hybridization probe
  • PR0526 [herein designated as DNA44184-1319] (SEQ ID NO 1 ) and the derived protein sequence for PR0526
  • DNA44184 1319 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 514-516 and ending at the stop codon at nucleotide positions 1933 1935 (Figure 1 )
  • the predicted polypeptide precursor is 473 amino acids long ( Figure 2)
  • the full length PR0526 protein shown in Figure 2 has an estimated molecular weight of about 50,708 daltons and a pl of about 9 28 Clone DNA44184-1319 has been deposited with the ATCC on March 26. 1998 It is understood that the clone contains the actual sequence, whereas the sequences presented herein are representative based on current sequencing techniques
  • PR0526 is a novel protein which is involved in protein-protem interactions
  • the signal peptide sequence is at about amino acids 1-26
  • a leucine zipper pattern is at about ammo acids 135-156
  • a glycosaminoglycan attachment is at about amino acids 436-439
  • N-glycosy ation sites are at about ammo acids 82-85, 179-182, 237-240 and 423-426.
  • a von Willebrand factor (VWF) type C doma ⁇ n(s) is found at about amino acids 411-425 The skilled artisan can understand which nucleotides correspond to these ammo acids based on the sequences provided herein
  • the extracellular domain (ECD) sequences (including the secretion signal, if any) of from about 950 known secreted proteins from the Swiss-Prot public protein database were used to search expressed sequence tag (EST) databases
  • the EST databases included public EST databases (e g , GenBank) and a proprietary EST DNA database (LIFESEQTM, Incyte Pharmaceuticals, Palo Alto, CA)
  • the search was performed using the computer program BLAST or BLAST2 (Altshul et al , Methods in Enzvmologv 266 460-480 (1996)) as a comparison of the ECD protein sequences to a 6 frame translation of the EST sequence Those comparisons resulting in a BLAST score of 70 (or in some cases 90) or greater that did not encode known proteins were clustered and assembled into consensus DNA sequences with the program "phrap” (Phil Green, University of Washington, Seattle, Washington)
  • DNA44851 A consensus DNA sequence was assembled relative to other EST sequences using phrap This consensus sequence is herein designated DNA44851 Based on the DNA44851 consensus sequence, oligonucleotides were synthesized 1) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR071 Forward and reverse 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 sequences are typically 40-55 bp in length In some cases, additional oligonucleotides are synthesized when the consensus sequence is greater than about 1-1.5kbp.
  • DNA 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
  • a pair of PCR primers (forward and reverse) were synthesized forward PCR nnmer.
  • 5'-GTGAGCATGAGCGAGCCGTCCAC-3 ' (SEQ ID NO- 14) reverse PCR n ⁇ mer 5 '-GCTATTACAACGGTTCTTGCGGCAGC-3 ' (SEQ ID NO- 15)
  • a synthetic oligonucleotide hybridization probe was constructed from the consensus DN A44851 sequence which had the following nucleotide sequence hybridization probe 5'-TTGACTCTCTGGTGAATCAGGACAAGCCGAGTTTTGCCTTCCAG 3 (SEQ ID NO 16)
  • RNA for construction of the cDNA libraries was isolated from human placenta tissue (LIB90)
  • the cDNA libraries used to isolate the cDNA clones were constructed by standard methods using commercially available reagents such as those from Invitrogen, San Diego, CA
  • the cDNA was primed with oligo dT containing a 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 pRKD, pRK5B is a precursor of pRK5D that does not contain the Sfil site see, Holmes et al , Science.
  • a suitable cloning vector such as pRKB or pRKD, pRK5B is a precursor of pRK5D that does not contain the Sfil site see, Holmes et al ,
  • DNA sequencing of the clones isolated as described above gave the full length DNA sequence for PR0719 [herein designated as DNA49646-1327] (SEQ ID NO 3) and the derived protein sequence for
  • DNA49646-1327 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 223-225 and ending at the stop codon at nucleotide positions 1285-1287 ( Figure 3)
  • the predicted polypeptide precursor is 354 amino acids long ( Figure 4)
  • the full-length PR0719 protein shown in Figure 4 has an estimated molecular weight of about 39,362 daltons and a pi of about 8 35
  • Analysis of the full length PR 0719 sequence evidences the presence of a signal peptide from about amino acid 1 to about ammo acid 16, a hpase associated serine containing active site at about amino acid 163 to about ammo acid 172, and two potential N-glycosylation sites from about amino acid 80 to about ammo acid 83 and about amino acid 136 to about amino acid 139
  • Clone DNA49646-1327 has been deposited with ATCC on March
  • PR0719 may be a novel lipoprotein hpase homolog More specifically, an analysis of the Dayhoff database (version 35 45 SwissProt 35) evidenced significant homology between the PR0719 amino acid sequence and the following
  • a secondary cDNA library was generated order to preferentially represent the 5' ends of the primary cDNA clones
  • Sp6 RNA was generated from the primary library and this RNA was used to generate a random primed cDNA library in the vector pSST-AMY 0 using reagents and protocols from Life Technologies (Super Script Plasmid System, referenced above)
  • the double stranded cDNA was sized to 500-1000 bp, hnkered with blunt to Notl adaptors, cleaved with Sfil, and cloned into Sfil/Notl cleaved vector pSST AMY 0 is a cloning vector that has a yeast alcohol dehv drogenase promoter preceding the cDNA cloning sites and the mouse amylase sequence (the mature sequence without the secretion signal) followed by the yeast alcohol dehydrogenase terminator, after the cloning sues
  • cDNAs cloned into this vector
  • DNA from the library described above was chilled on ice to which was added electrocompetent DH10B bacteria (Life Technologies, 20 ml) The bacteria and vector mixture was then electroporated as recommended by the manufacturer Subsequently, SOC media (Life Technologies, 1 ml) was added and the mixture was incubated at 37°C for 30 minutes The transformants were then plated onto 20 standard 150 mm LB plates containing ampicilhn and incubated for 16 hours (37°C) Positive colonies were scraped off the plates and the DNA was isolated from the bacterial pellet using standard protocols, e g CsCl gradient The purified DNA was then carried on to the yeast protocols below
  • the yeast methods were divided into three categories (1 ) Transformation of yeast with the plasmid/cDNA combined vector, (2) Detection and isolation of yeast clones secreting amylase, and (3) PCR amplification of the insert directly from the yeast colony and purification ot the DNA for sequencing and further analysis
  • the yeast strain used was HD56-5A (ATCC 90785) This strain has the following genotype MAT alpha, ura3 52, leu2-3, leu2 1 12, h ⁇ s3-l l , h ⁇ s3 15, MAL + , SUC + , GAL +
  • the selective media used was a synthetic complete dextrose agar lacking uracil (SCD Ura) prepared as described in Kaiser et al , Methods in Yeast Genetics Cold Spring Harbor Press, Cold Spring Harbor, NY, p 208-210 (1994) Transformants were grown at 30°C for 2-3 days
  • the detection of colonies secreting amylase was performed by including red starch m the selective growth media Starch was coupled to the red dye (Reactive Red 120, Sigma) as per the procedure described by Biely et al , Anal Biochem . 172 176-179 (1988) The coupled starch was incorporated mto the red dye (Reactive Red 120, Sigma) as per the procedure described by Biely et al , Anal Biochem . 172 176-179 (1988) The coupled starch was incorporated mto the red starch.
  • the first 18 nucleotides of the 5' end of these oligonucleotides contained annealing sites for the sequencing primers, wherein these sequences may differ depending upon the sequencing primers employed
  • the total product of the PCR reaction from an empty vector was 343 bp
  • signal sequence-fused cDNA resulted in considerably longer nucleotide sequences
  • an aliquot of the reaction (5 ⁇ l) was examined by agarose gel electrophoresis in a 1 % agarose gel using a T ⁇ s-Borate-EDTA (TBE) buffering system as described by Sambrook et al , supra Clones resulting in a single strong PCR product larger than 400 bp were further analyzed by DNA sequencing after
  • oligonucleotide probes were generated and used to screen a human fetal brain (LIB 153) library prepared as described above
  • the cloning vector was pRK5B (pRK5B is a precursor of pRK5D that does not contain the Sfil site, see, Holmes et al , Science, 253 1278-1280 (1991)), and the cDNA size cut was less than 2800 bp PCR primers (forward and reverse) were sy nthesized forward PCR primer 5'-CCAAACTCACCCAGTGAGTGTGAGC 3 (SEQ ID NO 19) reverse PCR primer 5' TGGGAAATCAGGAATGGTGTTCTCC 3' (SEQ ID NO 20) Additionall) a synthetic oligonucleotide hybridization probe was constructed which had the following nucleotide sequence hybridization probe
  • N-glycosylation site from about amino acid 72 to about amino acid 75 and a tyrosine kinase phosphor) lation site from about amino acid 63 to about ammo acid 70 Clone DNA52758 1399 has been deposited with ATCC on April 14, 1998 and is assigned ATCC deposit no 209773
  • the extracellular domain (ECD) sequences (including the secretion signal, if any) of from about 950 known secreted proteins from the Swiss-Prot public protein database were used to search expressed sequence tag (EST) databases
  • the EST databases included public EST databases (e g . GenBank, Merck/Wash U ) and a proprietary EST DNA database (LIFESEQTM, Incyte Pharmaceuticals Palo Alto, CA) The search was performed using the computer program BLAST or BLAST2 (Altshul et al , Methods m Enzvmologv
  • a region having sequence identity with IL-17 is at about amino acids 96 180
  • the corresponding nucleotides can be routinely determined given the sequences provided herein
  • Probes based on an expressed sequence tag (EST) identified from the Incyte Pharmaceuticals database due to homology with VEGF were used to screen a cDNA library derived from the human glioma cell line G61
  • Incyte Clone "INC 1302516' was used to generate the following four probes
  • PRO polypeptides of the invention are active as a stimulator of the proliferation of stimulated T lymphocytes
  • a therapeutic agent may take the form of antagonists of the PRO polypeptide of the invention, for example murine human chimeric, humanized or human antibodies against the polypeptide
  • peripheral blood mononuclear cells are isolated from mammalian individuals, for example a human volunteer, by leukopheresis (one donor will supply stimulator PBMCs, the other donor will supply responder PBMCs) If desired the cells are frozen in fetal bovine serum and DMSO after isolation Frozen cells may be thawed overnight in assay media (37°C, 5 % CO,) and then washed and resuspended to 3xl0 6 cells/ml of assay media (RPMI, 10% fetal bovme serum
  • the stimulator PBMCs are prepared by irradiating the cells (about 3000 Rads)
  • the assay is prepared by plating in triplicate wells a mixture of
  • test sample diluted to 1 % or to 0 1 % , 50 1 of irradiated stimulator cells, and
  • PBMCs are isolated from the spleens of Balb/c mice and C57B6 mice The cells are teased from freshly harvested spleens in assay media (RPMI, 10% fetal bovine serum, 1 % penicillin/streptomycin, 1 % glutamine, 1 % HEPES, 1 % non-essential amino acids, 1 % pyruvate) and the PBMCs are isolated by overlaying these cells over Lympholyte M (Organon Teknika), centrifuging at 2000 r
  • This assay sho s that certain PRO polypeptides of the invention stimulate an immune response and induce inflammation by inducing mononuclear cell, eosmophil and PMN infiltration at the site of injection of the animal Compounds which stimulate an immune response are useful therapeutically where stimulation of an immune response is beneficial
  • This skm vascular permeability assay is conducted as follows Hairless guinea pigs weighing 350 grams or more are anesthetized with ketamme (75-80 mg/Kg) and 5 mg/Kg xylazine intramuscularly (IM)
  • ketamme 75-80 mg/Kg
  • IM intramuscularly
  • a sample of purified PRO polypeptide of the invention or a conditioned media test sample is injected lntradermally onto the backs of the test animals with 100 ⁇ l per injection site It is possible to have about 10-30, preferably about 16-24, inaction sites per animal
  • Each skin injection site is biopsied and fixed in formalin The skins are then prepared for histopathologic evaluation
  • Each site is evaluated for inflammatory cell infiltration into the skin Sites with visible inflammatory cell inflammation are scored as positive Inflammatory cells may be neutrophihc, eosinophihc , monocytic or lymphocytic
  • At least a minimal pe ⁇ vascular infiltrate at the injection site is scored as positve, no infiltrate at the site of injection is scored as negative.
  • the following polypeptides tested positive in this assay PRO200.
  • T cell activation requires a costimulatory signal.
  • One costimulatory signal is generated by the interaction of B7 (CD3) with CD28.
  • B7 CD3
  • 96 well plates are coated with CD3 with or without CD28 and then human peripheral blood lymphocytes followed by a test protein, are added Proliferation of the lymphocytes is determined by t ⁇ tiated thymidine uptake A positive assay indicates that the test protein provided a stimulatory signal for lymphocyte proliferation Material
  • Plates are prepared by coating 96 well flat bottom plates with ant ⁇ -CD3 antibody (Amac) or ant ⁇ -CD28 antibody (Biodesign) or both Hyclone D-PBS without calcium and magnesium Ant ⁇ -CD3 antibody is used at 10 ng/well (50.1 of 200 ng/ml) and ant ⁇ -CD28 antibody at 25 ng/well (50:1 of 0.5 ⁇ g/ml) in 100.1 total volume
  • PBLs are isolated from human donors using standard leukophoresis methods The cell preparations are frozen in 50% fetal bovine serum and 50% DMSO until the assay is conducted
  • Cells are prepared by thawing and washing PBLs in media resuspending PBLs m 25 mis of media and incubating at 37°C, 5 % CO, o ⁇ ernight
  • the coated plate is washed twice with PBS and the PBLs are washed and resuspended to lxlO 6 cells/ml using lOO ⁇ l/well 100 ⁇ l of a test protein or control media are added to the plate making a total volume per well of 200 ⁇ l
  • the plate is incubated for 72 hours
  • the plate is then pulsed for 6 hours with tritiated thymidine (1 mC/well, Amersham) and the PBLs are harvested from the plates and evaluated for uptake of the tritiated thymidine
  • In situ hybridization is a powerful and versatile technique for the detection and localization of nucleic acid sequences within cell or tissue preparations It may be useful, for example, to identify sites of gene expression, analyze the tissue distribution of transcription, identify and localize viral infection, follow changes in specific mRNA synthesis and aid in chromosome mapping
  • In situ hybridization was performed following an optimized version of the protocol by Lu and
  • the tubes were incubated at 37°C for one hour. 1.0 ⁇ l RQ1 DNase were added, followed by incubation at 37°C for 15 minutes. 90 ⁇ l TE (10 mM Tris pH 7.6/lmM EDTA pH 8.0) were added, and the mixture was pipetted onto DE81 paper. The remaining solution was loaded in a M ⁇ crocon-50 ultrafiltration unit, and spun using program 10 (6 minutes). The filtration unit was inverted over a second tube and spun using program 2 (3 minutes). After the final recovery spin, 100 ⁇ l TE were added. 1 ⁇ l of the final product was pipetted on DE81 paper and counted in 6 ml of Biofluor II
  • the probe was run on a TBE/urea gel. 1-3 ⁇ l of the probe or 5 ⁇ l of RNA Mrk III were added to
  • the slides were removed from the freezer, placed on aluminium trays and thawed at room temperature for 5 minutes The trays were placed in 55 °C incubator tor five minutes to reduce condensation The slides were fixed for 10 minutes in 4% paraformaldehyde on ice in the fume hood, and washed in 0.5 x SSC for 5 minutes, at room temperature (25 ml 20 x SSC + 975 ml SQ H,0) After deprotemation in 0 5 ⁇ g/ml proteinase K for 10 minutes at 37°C (12.5 ⁇ l of 10 mg/ml stock in 250 ml prewarmed RNase-free RNAse buffer), the sections were washed in 0.5 x SSC for 10 minutes at room temperature The sections were dehydrated in 70% , 95 % , 100% ethanol, 2 minutes each B Pretreatment of paraffin-embedded sections
  • the slides were deparaffimzed placed in SQ H,0. and rmsed twice in 2 x SSC at room temperature, for 5 minutes each time.
  • the sections were deproteinated in 20 ⁇ g/ml proteinase K (500 ⁇ l of 10 mg/ml in
  • the in situ hybridization method of Example 6 is used to determine gene expression analyze the tissue distribution of transcription, and follow changes in specific mRNA synthesis for the genes/DNAs and the proteins of the invention in diseased tissues isolated from human individuals suffering from a specific disease These results show more specifically where in diseased tissues the genes of the invention are expressed and are more predictive of the particular localization of the therapeutic effect of the inhibitory or stimulatory compounds of the invention (and agonists or antagonists thereof) m a disease Hybridization is performed according to the method of Example 6 using one or more of the following tissue and cell samples
  • lymphocytes and antigen presenting cells dendritic cells, langherhans cells, macrophages and monocytes, NK cells
  • lymphoid tissues normal and reactive lymph node, thymus, Bronchial Associated Lymphoid
  • BALT Mucosal Associated Lymphoid Tissues
  • nucleotide sequence encoding PRO as a hybridization probe DNA comprising the coding sequence of full-length or mature PRO as disclosed herein is employed as a probe to screen for homologous DNAs (such as those encoding naturally occurring variants of PRO) in human tissue cDNA libraries or human tissue genomic libraries
  • Hybridization and washing of filters containing either library DNAs is performed under the following high stringency conditions
  • Hybridization of radiolabeled PRO derived probe to the filters is performed m a solution of 50% formamide, 5x SSC, 0 1 % SDS, 0 1 % sodium pyrophosphate, 50 mM sodium phosphate, pH 6 8, 2x Denhardt's solution, and 10% dextran sulfate at 42°C for 20 hours
  • Washing of the filters is performed in an aqueous solution of 0 lx SSC and 0 1 % SDS at 42°C
  • DNAs having a desired sequence identity with the DNA encoding full-length native sequence PRO can then be identified using standard techniques known in the art
  • This example illustrates preparation of an unglycosylated form of PRO by recombinant expression
  • the DNA sequence encoding PRO is initially amplified using selected PCR primers
  • the primers should contain restriction enzyme sites which correspond to the restriction enzyme sites on the selected expression vector
  • restriction enzyme sites A variety of expression vectors may be employed
  • An example of a suitable vector is pBR322 (derived from E coli, see Bolivar et al , Gene.
  • the vector is digested with restriction enzyme and dephosphorylated
  • the PCR amplified sequences are then ligated mto the vector
  • the vector will preferably include sequences which encode for an antibiotic resistance gene, a trp promoter, a polyhis leader (including the first six STII codons, polyhis sequence, and enterokmase cleavage site), the PRO coding region, lambda transcriptional terminator, and an argU gene
  • the ligation mixture is then used to transform a selected E coli strain using the methods described in Sambrook et al , supra Transformants are identified by their ability to grow on LB plates and antibiotic resistant colonies are then selected Plasmid DNA can be isolated and confirmed by restriction analysis and DNA sequencing
  • Selected clones can be grown overnight in liquid culture medium such as LB broth supplemented with antibiotics
  • the overnight culture may subsequently be used to inoculate a larger scale culture
  • the cells are then grown to a desired optical density, during which the expression promoter is turned on
  • the cells After culturing the cells for several more hours, the cells can be harvested by centrifugation
  • the cell pellet obtained by the centrifugation can be solubilized using various agents known in the art, and the solubihzed PRO protein can then be purified using a metal chelating column under conditions that allow tight binding of the protein
  • PRO may be expressed m E coli in a poly-His tagged form, using the following procedure
  • the DNA encoding PRO is initially amplified using selected PCR primers
  • the primers will contain restriction enzyme sites which correspond to the restriction enzyme sites on the selected expression vector, and other useful sequences providing for efficient and reliable translation initiation, rapid purification on a metal chelation column, and proteolytic removal with enterokmase
  • the PCR-amplified, poly-His tagged sequences are then ligated into an expression vector, which is used to transform an E coli host based on strain 52 (W31 10 fuhA(tonA) Ion galE rpoHts(htpRts) clpP(ladq)
  • Transformants are first grown in LB containing 50 mg/ml carbenicilhn at 30°C with shaking until an O D 600 of 3 5 is reached Cultures are then diluted 50 100 fold into CRAP media (prepared by mixing 3 57 g (NH 4 ),
  • E coli paste from 0 5 to 1 L fermentations (6 10 g pellets) is resuspended in 10 volumes (w/v) in 7 M guanidine, 20 mM T ⁇ s, pH 8 buffer
  • Solid sodium sulfite and sodium tetrathionate is added to make final concentrations of 0 l M and 0 02 M respectively , and the solution is stirred overnight at 4 °C
  • This step results in a denatured protein with all cysteine residues blocked by sulfitohzation
  • the solution is centrifuged at 40,000 rpm in a Beckman Ultracentifuge for 30 m
  • the supernatant is diluted with 3 5 volumes of metal chelate column buffer (6 M guanidine 20 mM Tris, pH 7 4) and filtered through 0 22 micron filters to clarify
  • the clarified extract is loaded onto a 5 ml Qiagen Ni-NTA metal chelate column equilibrated in the metal chelate column buffer The
  • the proteins are refolded by diluting the sample slowly into freshly prepared refolding buffer consisting of 20 mM Tris, pH 8 6, 0 3 M NaCI, 2 5 M urea 5 mM cysteine 20 mM glycine and 1 mM
  • EDTA Refolding volumes are chosen so that the final protein concentration is between 50 to 100 micrograms/ml
  • the refolding solution is stirred gently at 4 °C for 12 36 hours
  • the refolding reaction is quenched by the addition of TFA to a final concentration of 0 4% (pH of approximately 3)
  • the solution is filtered through a 0 22 micron filter and acetonitrile is added to
  • the refolded protein is chromatographed on a Poros Rl/H reversed phase column using a mobile buffer of 0 1 % TFA with elution with a gradient of acetonitrile from 10 to 80% Aliquots of fractions with A280 absorbance are analyzed on SDS polyacrylamide gels and fractions contaming homogeneous refolded protein are pooled Generally the properly refolded species of most proteins are eluted at the lowest concentrations of acetonitrile since those species are the most compact with their hydrophobic interiors shielded from interaction with the reversed phase resm Aggregated species are usually eluted at higher acetonitrile concentrations In addition to resolving misfolded forms of proteins from the desired form, the reversed phase step also removes endotoxm from the samples
  • Proteins are formulated into 20 mM Hepes, pH 6 8 with 0 14 M sodium chloride and 4% mannitol by dialysis or by gel filtration using G25 Superfine (Pharmacia) resins equilibrated in the formulation buffer and sterile filtered Many of the PRO polypeptides disclosed herein were successfully expressed as described above
  • This example illustrates preparation of a potentially glycosylated form of PRO by recombinant expression in mammalian cells
  • the vector, pRK5 (see EP 307,247, published March 15 1989) is employed as the expression vector
  • the PRO DNA is ligated into pRK5 with selected restriction enzymes to allow insertion of the PRO DNA using ligation methods such as described in Sambrook et al , supra
  • the resulting vector is called pRK5-PRO
  • the selected host cells ma) be 293 cells
  • Human 293 cells (ATCC CCL 1573) are grown to confluence in tissue culture plates in medium such as DMEM supplemented with fetal calf serum and optionally, nutrient components and/or antibiotics
  • About 10 ⁇ g pRK5-PRO DNA is mixed with about 1 ⁇ g DNA encoding the VA RNA gene [Thimmappaya et al , Cell, 31 543 (1982)] and dissolved in 500 ⁇ l of 1 mM Tns-HCl, 0 1 mM EDTA, 0 227 M CaCl, To this mixture is added, dropwise, 500 ⁇ l of
  • the culture medium is removed and replaced with culture medium (alone) or culmre medium containing 200 ⁇ Ci/ml ,3 S-cyste ⁇ ne and 200 ⁇ Ci/ml 1S S methionme
  • the conditioned medium is collected, concentrated on a spin filter, and loaded onto a 15 % SDS gel
  • the processed gel may be dried and exposed to film for a selected period of time to reveal the presence of PRO polypeptide
  • the culmres containing transfected cells may undergo further incubation (in serum free medium) and the medium is tested m selected bioassays
  • PRO may be introduced into 293 cells transiently using the dextran sulfate method described by Somparyrac et al , Proc Natl Acad Sci . 12 7575 (1981) 293 cells are grown to maximal density in a spinner flask and 700 ⁇ g pRK5-PRO DNA is added The cells are first concentrated from the spmner flask by centrifugation and washed with PBS The DNA-dextran precipitate is incubated on the cell pellet for four hours The cells are treated with 20% glycerol tor 90 seconds, washed with tissue culture medium, and re-introduced into the spinner flask containing tissue culture medium, 5 ⁇ g/ml bovine insulin and 0 1 ⁇ g/ml bovine transferrin After about four days, the conditioned media is centrifuged and filtered to remove cells and debris The sample containing expressed PRO can then be concentrated and purified by any selected method, such as dialysis and/or column chromatography
  • PRO in another embodiment, can be expressed m CHO cells
  • the pRK5-PRO can be transfected into CHO cells using known reagents such as CaP0 4 or DEAE-dextran
  • the cell cultures can be incubated, and the medium replaced with culmre medium (alone) or medium containing a radiolabel such as 35 S-meth ⁇ onme
  • the culmre medium may be replaced with serum free medium
  • the cultures are incubated for about 6 days, and then the conditioned medium is harvested The medium containing the expressed PRO can then be concentrated and purified by any selected method
  • Epitope tagged PRO may also be expressed in host CHO cells
  • the PRO may be subcloned out of the pRK5 vector
  • the subclone insert can undergo PCR to fuse m frame with a selected epitope tag such as a poly-his tag into a Baculovirus expression vector
  • the poly-his tagged PRO inse ⁇ can then be subcloned into a SV40 driven vector containing a selection marker such as DHFR for selection of stable clones
  • the CHO cells can be transfected (as described above) with the SV40 driven vector Labeling may be performed as described above to verify expression
  • the culmre medium containing the expressed pol) His tagged PRO can then be concentrated and purified by any selected method, such as by Nf + -chelate affinity chromatography
  • PRO may also be expressed in CHO and/or COS cells by a transient expression procedure or in CHO cells by another stable expression procedure Stable expression in CHO cells is performed using the following procedure
  • the proteins are expressed as an IgG construct (immunoadhesin), in which the coding sequences for the soluble forms (e g extracellular domains) of the respective proteins are fused to an IgGl constant region sequence containing the hinge, CH2 and CH2 domains and/or is a poly His tagged form
  • CHO expression vectors are constructed to have compatible restriction sites 5' and 3' of the DNA of interest to allow the convenient shuttling of cDNA s
  • the vector used expression m CHO cells is as described in Lucas et al , Nucl Acids Res 24 9 (1774-1779 (1996), and uses the SV40 early promoter/enhancer to drive expression of the cDNA of interest and dihydrofolate reductase (DHFR) DHFR expression permits selection for stable maintenance of the plasmid following transfection
  • the spinner is sampled, the temperature shifted to 33°C, and 30 mL of 500 g/L glucose and 0 6 mL of 10% antifoam (e g , 35 % polydimethylsiloxane emulsion Dow Corning 365 Medical Grade Emulsion) taken Throughout the production, the pH is adjusted as necessary to keep it at around 7 2 After 10 days, or until the viability dropped below 70% , the cell culmre is harvested by centrifugation and filtering through a 0 22 ⁇ m filter The filtrate was either stored at 4°C or immediately loaded onto columns for purification For the poly-His tagged constructs, the proteins are purified using a Ni-NTA column (Qiagen) Before purification, imidazole is added to the conditioned media to a concentration of 5 mM The conditioned media is pumped onto a 6 ml Ni-NTA column equilibrated in 20 mM Hepes, pH 7 4, buffer containing 0 3 M NaCI and 5
  • Immunoadhesin (Fc containing) constructs are purified from the conditioned media as follow s
  • the conditioned medium is pumped onto a 5 ml Protein A column (Pharmacia) which had been equilibrated in 20 mM Na phosphate buffer, pH 6 8 After loading, the column is washed extensively with equilibration buffer before elution with 100 mM citric acid, pH 3 5
  • the eluted protein is immediately neutralized by collecting 1 ml fractions mto tubes containing 275 ⁇ L of 1 M Tris buffer, pH 9
  • the highly purified protein is subsequently desalted into storage buffer as described above for the poly-His tagged proteins The homogeneity is assessed by SDS polyacry lamide gels and by N terminal ammo acid sequencing by Edman degradation
  • yeast expression vectors are constructed for intracellular production or secretion of PRO from the ADH2/GAPDH promoter DNA encoding PRO and the promoter is inserted into suitable restriction enzyme sites in the selected plasmid to direct intracellular expression of PRO
  • DNA encoding PRO can be cloned into the selected plasmid, together with DNA encoding the ADH2/GAPDH promoter, a native PRO signal peptide or other mammalian signal peptide, or, for example, a yeast alpha factor or mvertase secretory signal/leader sequence, and linker sequences (if needed) for expression of PRO
  • yeast cells such as yeast strain AB1 10
  • yeast supernatants can be analyzed by precipitation with 10% t ⁇ chloroacetic acid and separation by SDS PAGE, followed by staining of the gels with Coomassie Blue stam Recombinant PRO can subsequently be isolated and purified by removing the yeast cells from the fermentation medium by centrifugation and then concentrating the medium using selected cartridge filters
  • the concentrate containing PRO may further be purified using selected column chromatography resins Many of the PRO polypeptides disclosed herein were successfull) expressed as described above EXAMPLE 12 Expression of PRO in Baculovirus Infected Insect Cells
  • sequence coding for PRO is fused upstream of an epitope tag contained within a baculovirus expression vector
  • epitope tags include poly his tags and immunoglobulin tags (like Fc regions of IgG)
  • Plasmids may be employed, including plasmids derived from commercially available plasmids such as pVL1393 (Novagen) Briefly the sequence encoding PRO or the desired portion of the coding sequence of PRO such as the sequence encoding the extracellular domain of a transmembrane protein or the sequence encoding the mature protein if the protein is extracellular is amplified by PCR with primers complementary to the 5 and 3 regions The 5 primer may incorporate flanking (selected) restriction enzyme sites The product is then digested with those selected restriction enzymes and subcloned into the expression vector
  • Recombinant baculovirus is generated by co transfecting the above plasmid and BaculoGoldTM virus DNA (Pharmingen) into Spodopteia frug ⁇ erda ("Sf9 ) cells (ATCC CRL 1711) using lipofectin (commercially available from GIBCO BRL) After 4 5 days of incubation at 28°C the released viruses are harvested and used for further amplifications Viral infection and protein expression are performed as described by O Reilley et al , Baculovirus expression vectors A Laboratory Manual, Oxford Oxford
  • Expressed poly his tagged PRO can then be purified, tor example, by N + -chelate affinity chromatography as follows Extracts are prepared from recombinant virus-infected Sf9 cells as described by Rupert et al , Nature. 362 175-179 (1993) Briefly, Sf9 cells are washed, resuspended in somcation buffer (25 mL Hepes, pH 7 9, 12 5 mM MgCl,, 0 1 mM EDTA, 10% glycerol, 0 1 % NP-40, 0 4 M KC1), and sonicated twice for 20 seconds on ice The sonicates are cleared by centrifugation, and the supernatant is diluted 50 fold in loading buffer (50 mM phosphate, 300 mM NaCI, 10% glycerol, pH 7 8) and filtered through a 0 45 ⁇ m filter A Nf + -NTA agarose column (commercially available from Qiagen)
  • purification of the IgG tagged (or Fc tagged) PRO can be performed using known chromatography techniques, including for instance, Protein A or protein G column chromatography
  • This example illustrates preparation of monoclonal antibodies which can specifically bind PRO
  • Techniques for producing the monoclonal antibodies are known in the art and are described, for instance, in Godmg, supra Immunogens that may be employed include purified PRO, fusion proteins containing PRO, and cells expressing recombinant PRO on the cell surface Selection of the lmmunogen can be made by the skilled artisan without undue experimentation
  • mice such as Balb/c are immunized with the PRO immunogen emulsified in complete Freund's adjuvant and injected subcutaneously or lntrape ⁇ toneally in an amount from 1 -100 micrograms
  • the immunogen is emulsified in MPL-TDM adjuvant (Ribi Immunochemical Research, Hamilton, MT) and injected into the animal's hind foot pads
  • MPL-TDM adjuvant Ribi Immunochemical Research, Hamilton, MT
  • the immunized mice are then boosted 10 to 12 days later with additional immunogen emulsified m the selected adjuvant Thereafter, for several weeks, the mice may also be boosted with additional immunization injections
  • Serum samples may be periodically obtained from the mice by retro orbital bleeding for testing in ELISA assays to detect anti-PRO antibodies After a suitable antibody titer has been detected, the animals "positive" for antibodies can be lmected with a final intravenous injection of PRO Three to four days later, the mice are
  • hybridoma cells which can then be plated m 96 well tissue culmre plates containing HAT (hypoxanthine, aminopte ⁇ n, and thymidine) medium to inhibit proliferation of non-fused cells, myeloma hybrids, and spleen cell hybrids
  • HAT hyperxanthine, aminopte ⁇ n, and thymidine
  • the hybridoma cells will be screened in an ELISA for reactivity against PRO Determination of
  • the positive hybridoma cells can be injected lntrape ⁇ toneally into syngeneic Balb/c mice to produce ascites containing the anti-PRO monoclonal antibodies
  • the hybridoma cells can be grown in tissue culture flasks or roller bottles Purification of the monoclonal antibodies produced in the ascites can be accomplished using ammonium sulfate precipitation, followed by gel exclusion chromatography Alternatively, affinity chromatography based upon binding of antibody to protein A or protein G can be employed
  • Native or recombinant PRO polypeptides may be purified by a variety of standard techniques in the art of protein purification
  • pro-PRO polypeptide, mature PRO polypeptide, or pre-PRO polypeptide is purified by immunoaffimty chromatography using antibodies specific for the PRO polypeptide of interest
  • an immunoaffimty column is constructed by covalently coupling the anti-PRO polypeptide antibody to an activated chromatographic resin
  • Polyclonal immunoglobulins are prepared from immune sera either by precipitation with ammonium sulfate or by purification on immobilized Protein A (Pharmacia LKB Biotechnology, Piscataway, N J ) Likewise monoclonal antibodies are prepared from mouse ascites fluid by ammonium sulfate precipitation or chromatography on immobilized Protein A Partially purified immunoglobulin is covalently attached to a chromatographic resm such as CnBr-activated SEPHAROSETM (Pharmacia LKB Biotechnology ) The antibody is coupled to the resm, the resm is blocked, and the derivative resin is washed according to the manufacturer's instructions Such an lmmunoaffinity column is utilized in the purification of PRO polypeptide by preparing a fraction from cells containing PRO polypeptide in a soluble form This preparation is derived by solubihzation of the whole cell or of a subcellular fraction obtained via differential centrifugation by the addition of detergent or by other methods
  • This invention is particularly useful for screening compounds by using PRO polypeptides or binding fragment thereof in any of a variety of drug screening techniques
  • the PRO polypeptide or fragment employed in such a test may either be free solution, affixed to a solid support, borne on a cell surface, or located mtracellularly
  • One method of drug screening utilizes eukaryotic or prokaryotic host cells which are stably transformed with recombinant nucleic acids expressing the PRO polypeptide or fragment Drugs are screened against such transformed cells in competitive binding assays Such cells, either in viable or fixed form, can be used for standard binding assays One may measure, for example, the formation of complexes between PRO polypeptide or a fragment and the agent being tested Alternatively, one can examine the diminution m complex formation between the PRO polypeptide and its target cell or target receptors caused by the agent being tested
  • the present invention provides methods of screening for drugs or any other agents which can affect a PRO polypeptide associated disease or disorder
  • methods comprise contacting such an agent with an PRO polypeptide or fragment thereof and assaying (I) for the presence of a complex between the agent and the PRO polypeptide or fragment, or (n) for the presence of a complex between the PRO polypeptide or fragment and the cell, by methods well known in the art
  • the PRO polypeptide or fragment is typically labeled After suitable incubation, free PRO polypeptide or fragment is separated from that present in bound form, and the amount of free or uncomplexed label is a measure of the ability of the particular agent to bind to PRO polypeptide or to interfere with the PRO polypeptide/cell complex
  • Another technique for drug screening provides high throughput screening for compounds having suitable binding affinity to a polypeptide and is described in detail WO 84/03564, published on September 13, 1984 Briefly stated, large numbers of different small peptide test compounds are synthesized on a solid substrate such as plastic pms or some other surface As applied to a PRO polypeptide, the peptide test compounds are reacted with PRO polypeptide and washed Bound PRO poly peptide is detected by methods well known in the art Purified PRO polypeptide can also be coated directly onto plates for use m the aforementioned drug screening techniques In addition non neutralizing antibodies can be used to capmre the peptide and immobilize it on the solid support
  • This invention also contemplates the use of competitive drug screening assays in which neutralizing antibodies capable of binding PRO polypeptide specifically compete with a test compound for binding to PRO polypeptide or fragments thereof In this manner, the antibodies can be used to detect the presence of any peptide which shares one or more antigemc determinants with PRO polypeptide
  • the goal of rational drug design is to produce structural analogs of biologically active polypeptide of interest (i e a PRO polypeptide) or of small molecules with which they interact, e g agonists, antagonists, or inhibitors Any of these examples can be used to fashion drugs which are more active or stable forms of the PRO polypeptide or which enhance or interfere with the function of the PRO polypeptide in vivo (c f , Hodgson, Bio/Technology. 9 19 21 (1991))
  • the three-dimensional structure of the PRO polypeptide, or of an PRO polypeptide-inhibitor complex is determined by x ray crystallography, by computer modeling or, most typically, by a combination of the two approaches
  • Both the shape and charges of the PRO polypeptide must be ascertained to elucidate the structure and to determine active s ⁇ te(s) of the molecule
  • useful information regarding the structure of the PRO polypeptide may be gained by modeling based on the structure of homologous proteins
  • relevant structural information is used to design analogous PRO polypeptide-hke molecules or to identify efficient inhibitors
  • Useful examples of rational drug design may include molecules which have improved activity or stability as shown by Braxton and Wells, Biochemistry 31 7796-7801 (1992) or which act as inhibitors, agonists, or antagonists of native peptides as shown by
  • PRO polypeptide may be made available to perform such analytical studies as X-ray crystallography
  • knowledge of the PRO polypeptide amino acid sequence provided herein will provide guidance to those employ mg computer modeling techniques in place of or in addition to x-ray crystallography
  • EXAMPLE 17 Biological activities of PRO1031
  • human foreskin fibroblast cells (ATCC) were cultured in MEM media (10% FBS) with the test protein After incubation for 18 hr at 37°C and 5 % CO, conditioned media were assayed for IL-6 using an ELISA kit (R&D systems)
  • human leukemia monocytic THP-1 cells were cultured in RPMI media (10% FBS) with the test protein After incubation for 18hr at 37°C and 5 % CO, conditioned media were quantitated for TNF using an ELISA assay kit (R&D systems)
  • IL-17 One of the biological activities of IL-17 is the induction of IL 6 release in fibroblast cells ( Yao et al , 1995, J Immunol 155 5483)
  • human foreskin fibroblasts were treated with the protein and assa) ed for IL 6 production
  • PRO1031 failed to stimulate IL-6 secretion in fibroblast cells
  • a human leukemic monocytic cell lme, THP 1 reported to express IL-17 receptor (Yao et al, 1997, Cytokine 9 794), was then used to assay for the stimulation of TNF a release by IL 17 and PRO1031 While IL 17 induced only a low level of TNF in THP-1 cells, PRO 1031 (as an Fc fusion protein) stimulated TNF production in THP 1 cells A control Fc fusion protein had no effect Similar results were obtained with his tagged protein
  • PRO 1031 promotes the release of proinflammatory cytokines
  • Such stimulator proteins are useful in treating immune related diseases characterized by poor or inadequate immune function
  • PRO 1031 may be used in immunoadjuvant therapy
  • An antagonist antibody binding to PRO 1031 will inhibit the proinflammatory action of the protein and is useful in inhibiting the immune resonse
  • Such an antibody is useful to treat, for example, immune mediated diseases such as rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, etc using the compositions and methods of administration described above

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Abstract

L'invention concerne une composition contenant des nouvelles protéines, ainsi que des procédés de diagnostic et de traitement de maladies d'ordre immunologique.
PCT/US2000/007532 1997-03-31 2000-03-21 Compositions et procedes de traitement de maladies d'ordre immunologique WO2000070050A1 (fr)

Priority Applications (479)

Application Number Priority Date Filing Date Title
AU36326/00A AU3632600A (en) 1999-05-14 2000-03-21 Compositions and methods for the treatment of immune related diseases
DK00939307T DK1212417T3 (da) 1999-06-02 2000-05-17 Fremmelse eller inhibering af angiogenese og vaskularisering
ES00939307T ES2307515T3 (es) 1999-06-02 2000-05-17 Activacion o inhibicion de la angiogenesis y la cardiovascularizacion.
EP00939307A EP1212417B1 (fr) 1999-06-02 2000-05-17 Activation ou inhibition de l'angiogenèse et de la cardiovascularisation
PT00939307T PT1212417E (pt) 1999-06-02 2000-05-17 Promoção ou inibição de angiogénese e cardiovascularização
AT00939307T ATE393825T1 (de) 1999-06-02 2000-05-17 Stimulierung oder hemmung von angiogenese und herzvaskularisierung
PCT/US2000/013705 WO2000073445A2 (fr) 1999-06-02 2000-05-17 Promotion ou inhibition de l'angiogenese et de la cardiovascularisation
CA002376116A CA2376116A1 (fr) 1999-06-02 2000-05-17 Promotion ou inhibition de l'angiogenese et de la cardiovascularisation
JP2001500757A JP4297317B2 (ja) 1999-06-02 2000-05-17 血管形成及び心臓血管新生の促進又は阻害
PCT/US2000/015264 WO2000073452A2 (fr) 1999-06-02 2000-06-02 Compositions et methodes de traitement de maladies liees a l'immunite
EP00983846A EP1250426A2 (fr) 1999-12-01 2000-12-01 Polypeptides transmembranaires et secretes et les acides nucleiques codant ceux-ci
EP06000582A EP1666495A1 (fr) 1999-12-01 2000-12-01 Polypeptides secretés et transmembranaires et acides nucléiques les codant
EP06000589A EP1661997A1 (fr) 1999-12-01 2000-12-01 Polypeptides sécrétés et transmembranaires ainsi que les acides nucléiques codant pour ceux-ci
EP06000587A EP1690872A3 (fr) 1999-12-01 2000-12-01 Composition et procédés de diagnostic de tumeurs
CA2709291A CA2709291A1 (fr) 1999-12-01 2000-12-01 Polypeptides secretes et transmembranaires et acides nucleiques codant ces polypeptides
CA002391455A CA2391455A1 (fr) 1999-12-01 2000-12-01 Polypeptides secretes et transmembranaires et acides nucleiques codant ces polypeptides
EP10005292A EP2228446A1 (fr) 1999-12-01 2000-12-01 Polypeptides secrétés et transmembranaires et acides nucléiques codant pour ceux-ci
CA002490909A CA2490909A1 (fr) 1999-12-01 2000-12-01 Polypeptides secretes et transmembranaires et acides nucleiques codant ces polypeptides
EP06000585A EP1661996A1 (fr) 1999-12-01 2000-12-01 Polypeptides sécrétés et transmembranaires ainsi que les acides nucléiques codant pour ceux-ci
EP06000586A EP1688497A1 (fr) 1999-12-01 2000-12-01 Polypeptides sécrétés et transmembranaires ainsi que les acides nucléiques codant pour ceux-ci
CA002490853A CA2490853A1 (fr) 1999-12-01 2000-12-01 Polypeptides secretes et transmembranaires et acides nucleiques codant ces polypeptides
AU20554/01A AU2055401A (en) 1999-12-01 2000-12-01 Secreted and transmembrane polypeptides and nucleic acids encoding the same
CA002491610A CA2491610A1 (fr) 1999-12-01 2000-12-01 Polypeptides secretes et transmembranaires et acides nucleiques codant ces polypeptides
CA002494705A CA2494705A1 (fr) 1999-12-01 2000-12-01 Polypeptides secretes et transmembranaires et acides nucleiques codant ces polypeptides
EP06000583A EP1686134A3 (fr) 1999-12-01 2000-12-01 Polypeptides transmembranaires et secrétés et les acides nucléiques codant ceux-ci
EP06000581A EP1666494A1 (fr) 1999-12-01 2000-12-01 Polypeptides secretés et transmembranaires et acides nucléiques les codant
CA002496312A CA2496312A1 (fr) 1999-12-01 2000-12-01 Polypeptides du type pro4799, marqueurs de tumeurs du colon, et acides nucleiques codant lesdits polypeptides
PCT/US2000/032678 WO2001040466A2 (fr) 1999-12-01 2000-12-01 Polypeptides secretes et transmembranaires et acides nucleiques codant ces polypeptides
EP05025102A EP1672070A3 (fr) 1999-12-01 2000-12-01 Polypeptides secrétés et transmembranaires et acides nucléiques codant pour ceux-ci
CA002492070A CA2492070A1 (fr) 1999-12-01 2000-12-01 Polypeptides pro4329 marqueurs de tumeurs du poumon et acides nucleiques codant lesdits polypeptides
CA002491258A CA2491258A1 (fr) 1999-12-01 2000-12-01 polypeptides transmembranaires et secretes et acides nucleiques codant ces polypeptides
CA002492049A CA2492049A1 (fr) 1999-12-01 2000-12-01 Polypeptides secretes et transmembranaires et acides nucleiques codant ces polypeptides
EP06000588A EP1690873A3 (fr) 1999-12-01 2000-12-01 Composition et procédés de diagnostic de tumeurs
CA002491433A CA2491433A1 (fr) 1999-12-01 2000-12-01 Polypeptides secretes et transmembranaires et acides nucleiques codant ces polypeptides
EP06000584A EP1669371A3 (fr) 1999-12-01 2000-12-01 Composition et procédés de diagnostic de tumeurs
JP2001542531A JP2004522404A (ja) 1999-12-01 2000-12-01 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
ES10009491.1T ES2458349T3 (es) 1999-12-23 2000-12-20 Polipéptidos homólogos IL-17 y usos terapéuticos de los mismos
EP10009490A EP2290081A3 (fr) 1999-12-23 2000-12-20 Polypeptides allogéniques IL-17 et utilisations thérapeutiques
AT07016900T ATE519847T1 (de) 1999-12-23 2000-12-20 Il-17-homologe polypeptide und ihre therapeutische verwendung
ES07016902T ES2388748T3 (es) 1999-12-23 2000-12-20 Polipéptidos homólogos a IL-17 y usos terapéuticos de los mismos
AT07016899T ATE537258T1 (de) 1999-12-23 2000-12-20 Il-17-homologe polypeptide und ihre therapeutische verwendung
ES07016903T ES2380812T3 (es) 1999-12-23 2000-12-20 Polipéptidos homólogos a IL-17 y usos terapéuticos de los mismos
PT07016900T PT1897944E (pt) 1999-12-23 2000-12-20 Polipéptidos homólogos de il-17 e suas utilizações terapêuticas
PT07016901T PT1897945E (pt) 1999-12-23 2000-12-20 Polipéptidos homólogos de il-17 e suas utilizações terapêuticas
EP07016902A EP1897946B1 (fr) 1999-12-23 2000-12-20 Polypeptides allogéniques IL-17 et utilisations thérapeutiques
DK07016903.2T DK1897947T3 (da) 1999-12-23 2000-12-20 IL-17-homologe polypeptider og terapeutiske anvendelser deraf
EP07016899A EP1897943B1 (fr) 1999-12-23 2000-12-20 Polypeptides allogéniques IL-17 et utilisations thérapeutiques
EP07016900A EP1897944B1 (fr) 1999-12-23 2000-12-20 Polypeptides allogéniques IL-17 et utilisations thérapeutiques
ES00989401T ES2333772T3 (es) 1999-12-23 2000-12-20 Polipeptidos homologos de il-17 y il-17r y sus utilizaciones terapeuticas.
EP07016903A EP1897947B1 (fr) 1999-12-23 2000-12-20 Polypeptides allogéniques IL-17 et utilisations thérapeutiques
DK07016900.8T DK1897944T3 (da) 1999-12-23 2000-12-20 IL-17 homologe polypeptider og terapeutisk anvendelse deraf
AT00989401T ATE444361T1 (de) 1999-12-23 2000-12-20 Il-17 und il-17r homologe polypeptide und deren therapeutische verwendungen
PCT/US2000/034956 WO2001046420A2 (fr) 1999-12-23 2000-12-20 Polypeptides homologues de l'il-17 et leurs utilisations therapeutiques
DK00989401.5T DK1240325T3 (da) 1999-12-23 2000-12-20 IL-17 og IL-17R homologe polypeptider og terapeutisk anvendelse deraf
DE60043069T DE60043069D1 (de) 1999-12-23 2000-12-20 Il-17 und il-17r homologe polypeptide und deren therapeutische verwendungen
CA002391374A CA2391374A1 (fr) 1999-12-23 2000-12-20 Polypeptides homologues de l'il-17 et leurs utilisations therapeutiques
EP10009491.1A EP2258848B1 (fr) 1999-12-23 2000-12-20 Polypeptides allogéniques IL-17 et utilisations thérapeutiques
ES07016899T ES2379101T3 (es) 1999-12-23 2000-12-20 Polipéptidos homólogos IL-17 y usos terapéuticos de los mismos
EP07016901A EP1897945B1 (fr) 1999-12-23 2000-12-20 Polypeptides allogéniques IL-17 et utilisations thérapeutiques
DK07016901.6T DK1897945T3 (da) 1999-12-23 2000-12-20 IL-17 homologe polypeptider og terapeutiske anvendelser deraf.
PT00989401T PT1240325E (pt) 1999-12-23 2000-12-20 Polipéptidos homólogos de il-17 e il-17r e suas utilizações terapêuticas
US09/747,259 US6569645B2 (en) 1999-05-14 2000-12-20 IL-17 homologous polypeptides and therapeutic uses thereof
ES09009972.2T ES2506665T3 (es) 1999-12-23 2000-12-20 Polipéptidos homólogos IL-17 e IL-17R y usos terapéuticos de los mismos
AT07016901T ATE541930T1 (de) 1999-12-23 2000-12-20 Il-17-homologe polypeptide und ihre therapeutische verwendung
PT07016903T PT1897947E (pt) 1999-12-23 2000-12-20 Polipéptidos homólogos de il-17 e suas utilizações terapêuticas
JP2001546918A JP2003527104A (ja) 1999-12-23 2000-12-20 Ｉｌ−１７相同的ポリペプチドとその治療上の用途
ES07016901T ES2380958T3 (es) 1999-12-23 2000-12-20 Polipéptidos homólogos IL-17 y utilizaciones terapéuticas de los mismos
EP00989401A EP1240325B1 (fr) 1999-12-23 2000-12-20 Polypeptides homologues de l'il-17 et de l'il-17r et leurs utilisations therapeutiques
EP09009972.2A EP2163625B1 (fr) 1999-12-23 2000-12-20 Polypeptides homologues IL-17 et IL-17R et utilisations thérapeutiques
AU25909/01A AU2590901A (en) 1999-12-23 2000-12-20 Il-17 homologous polypeptides and therapeutic uses thereof
AT07016903T ATE541931T1 (de) 1999-12-23 2000-12-20 Il-17-homologe polypeptide und ihre therapeutische verwendung
US09/816,744 US6579520B2 (en) 1998-05-15 2001-03-22 IL-17 related mammalian cytokine polypeptides (IL-17E)
US09/874,503 US20020177188A1 (en) 1998-05-15 2001-06-05 IL-17 homologous polypeptides and therapeutic uses thereof
US09/908,827 US20030054442A1 (en) 1998-05-15 2001-07-18 IL-17 homologous polypeptides and therapeutic uses thereof
US09/918,585 US20030060406A1 (en) 1997-10-17 2001-07-30 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/978,191 US20030050239A1 (en) 1997-10-17 2001-10-15 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/978,295 US20020156006A1 (en) 1997-10-17 2001-10-15 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/978,194 US20030195333A1 (en) 1997-10-17 2001-10-15 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/978,188 US20030139328A1 (en) 1997-10-17 2001-10-15 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/978,299 US20030199435A1 (en) 1997-10-17 2001-10-15 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/978,189 US6972325B2 (en) 1997-10-17 2001-10-15 PRO273 polypeptides
US09/978,193 US20030073624A1 (en) 1997-10-17 2001-10-15 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/978,192 US20020177553A1 (en) 1997-10-17 2001-10-15 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/978,298 US20030134785A1 (en) 1997-10-17 2001-10-15 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/978,564 US7195760B2 (en) 1997-10-17 2001-10-16 Anti-pro363 antibodies
US09/978,681 US20030195148A1 (en) 1997-10-17 2001-10-16 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/978,403 US20030050240A1 (en) 1997-10-17 2001-10-16 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/978,802 US20030199674A1 (en) 1997-10-17 2001-10-16 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/978,544 US20030199436A1 (en) 1997-10-17 2001-10-16 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/978,423 US20030069178A1 (en) 1997-10-17 2001-10-16 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/978,697 US20020169284A1 (en) 1997-10-17 2001-10-16 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/978,643 US20030104998A1 (en) 1997-10-17 2001-10-16 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/978,665 US7294700B2 (en) 1997-10-17 2001-10-16 Anti-PRO846 antibodies
US09/978,757 US20030083248A1 (en) 1997-10-17 2001-10-16 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/978,375 US7196165B2 (en) 1997-10-17 2001-10-16 PRO363 polypeptides
US09/978,824 US20050124789A9 (en) 1997-10-17 2001-10-16 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/981,915 US20030054986A1 (en) 1997-10-17 2001-10-16 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/981,915 US7285623B2 (en) 1997-10-17 2001-10-16 PRO337 polypeptides
US09/978,585 US20030049633A1 (en) 1997-10-17 2001-10-16 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/978,824 US20030055216A1 (en) 1997-10-17 2001-10-17 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/210,028 US20030203446A1 (en) 1998-10-07 2001-10-18 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/152,388 US20040223964A1 (en) 1998-03-17 2001-10-18 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/164,749 US20040029218A1 (en) 1998-10-07 2001-10-19 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/165,067 US7279553B2 (en) 1998-05-13 2001-10-19 PRO1083 polypeptides
US10/145,017 US20030186365A1 (en) 1998-03-26 2001-10-19 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/164,929 US20030194781A1 (en) 1998-03-30 2001-10-19 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/145,089 US7208575B2 (en) 1998-10-07 2001-10-19 PRO531 polypeptides
US10/164,728 US20030186368A1 (en) 1998-05-13 2001-10-19 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/165,036 US20050227342A1 (en) 1998-10-07 2001-10-19 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/164,829 US20030194780A1 (en) 1998-04-29 2001-10-19 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/165,247 US7112657B2 (en) 1998-10-07 2001-10-19 PRO697 polypeptides
US10/166,709 US20030104536A1 (en) 1998-10-07 2001-10-19 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/162,521 US7067628B2 (en) 1998-03-17 2001-10-19 PRO788 polypeptides
US10/160,502 US7220835B2 (en) 1998-07-30 2001-10-19 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/143,029 US7105640B2 (en) 1997-10-17 2001-10-19 Anti-pro792 antibodies
US10/145,124 US20030190701A1 (en) 1998-04-30 2001-10-19 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/013,922 US20030195345A1 (en) 1997-10-17 2001-10-21 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/999,829 US20030195344A1 (en) 1997-10-17 2001-10-24 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/017,085 US6974696B2 (en) 1997-10-17 2001-10-24 PRO853 nucleic acids
US09/999,832 US7132283B2 (en) 1997-10-17 2001-10-24 PRO273 polypeptides
US10/017,081 US20030049684A1 (en) 1997-10-17 2001-10-24 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/017,083 US20030148376A1 (en) 1997-10-17 2001-10-24 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/999,834 US20030064407A1 (en) 1997-10-17 2001-10-24 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/999,832 US20020192706A1 (en) 1997-10-17 2001-10-24 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/020,445 US20030198994A1 (en) 1997-10-17 2001-10-24 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/002,967 US20030148373A1 (en) 1997-10-17 2001-10-24 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/017,084 US20030203402A1 (en) 1997-10-17 2001-10-24 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/999,833 US6916648B2 (en) 1997-10-17 2001-10-24 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/999,830 US20030077700A1 (en) 1997-10-17 2001-10-24 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/017,086 US7122375B2 (en) 1997-10-17 2001-10-24 PRO274 nucleic acids
US10/013,917 US7029874B2 (en) 1998-03-17 2001-10-25 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/013,925 US7037710B2 (en) 1997-10-17 2001-10-25 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/013,920 US20040006219A1 (en) 1997-10-17 2001-10-25 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/013,921 US20030068648A1 (en) 1997-10-17 2001-10-25 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/013,926 US7074593B2 (en) 1998-04-01 2001-10-25 PRO 703 nucleic acids
US10/016,177 US20030073131A1 (en) 1997-10-17 2001-10-25 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/013,923 US7169912B2 (en) 1997-10-17 2001-10-25 PRO1017 nucleic acids
US10/013,928 US20030215905A1 (en) 1998-10-07 2001-10-25 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/013,927 US7189529B2 (en) 1997-10-17 2001-10-25 PRO792 nucleic acids
US10/013,929 US7019124B2 (en) 1997-10-17 2001-10-25 PRO788 nucleic acids
US10/013,918 US20030211091A1 (en) 1997-10-17 2001-10-25 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/000,157 US20020182673A1 (en) 1998-05-15 2001-10-30 IL-17 homologous polypedies and therapeutic uses thereof
US09/990,456 US20020137890A1 (en) 1997-03-31 2001-11-14 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US09/978,187 US20030096744A1 (en) 1997-10-17 2002-01-28 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
US10/121,047 US20030077778A1 (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
US10/121,044 US20030190717A1 (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
US10/121,041 US20030077776A1 (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
US10/121,059 US20030190721A1 (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
US10/121,057 US20030190719A1 (en) 1997-03-31 2002-04-12 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
US10/121,058 US20030190720A1 (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
US10/121,043 US7220831B2 (en) 1997-03-31 2002-04-12 PRO235 polypeptides
US10/121,063 US20030199055A1 (en) 1997-03-31 2002-04-12 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/121,060 US20030190722A1 (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
US10/121,053 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
US10/121,055 US20030190718A1 (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
US10/121,052 US20030199052A1 (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
US10/123,215 US7291329B2 (en) 1997-03-31 2002-04-15 Antibodies against PRO4406
US10/123,109 US20030190723A1 (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
US10/123,157 US20030190725A1 (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
US10/123,292 US20030073211A1 (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
US10/123,771 US20030199060A1 (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 US7193048B2 (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
US10/123,214 US7343721B2 (en) 1997-03-31 2002-04-15 PRO4406 polypeptide
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
US10/123,154 US20030190724A1 (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
US10/123,213 US20030199057A1 (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
US10/123,155 US20030068794A1 (en) 1997-03-31 2002-04-15 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/123,908 US7335728B2 (en) 1997-03-31 2002-04-16 PRO1310 polypeptides
US10/123,911 US7408032B2 (en) 1997-03-31 2002-04-16 PRO1188 polypeptides
US10/123,909 US7193049B2 (en) 1997-03-31 2002-04-16 PRO862 polypeptides
US10/123,903 US20030073212A1 (en) 1997-03-31 2002-04-16 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/123,912 US20030100087A1 (en) 1997-03-31 2002-04-16 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/123,913 US20030203462A1 (en) 1997-03-31 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
US10/123,907 US7084258B2 (en) 1997-03-31 2002-04-16 Antibodies against the PRO862 polypeptides
US10/123,905 US7285625B2 (en) 1997-06-18 2002-04-16 PRO536 polypeptides
US10/123,906 US20030190726A1 (en) 1997-03-31 2002-04-16 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/123,905 US20030087344A1 (en) 1997-06-18 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
US10/123,902 US20030077781A1 (en) 1997-03-31 2002-04-16 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
US10/124,822 US7109305B2 (en) 1997-03-31 2002-04-17 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/124,818 US20030082763A1 (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
US10/124,813 US7312307B2 (en) 1997-03-31 2002-04-17 PRO1056 polypeptides
US10/124,820 US20030190729A1 (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
US10/124,823 US20030199062A1 (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
US10/125,704 US7357926B2 (en) 1997-03-31 2002-04-17 Antibodies against PRO1879 and the use thereof
US10/124,824 US20030077659A1 (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
US10/124,819 US7285626B2 (en) 1997-03-31 2002-04-17 PRO1076 polypeptides
US10/125,932 US7317079B2 (en) 1997-03-31 2002-04-19 PRO812 polypeptides
US10/125,922 US7309762B2 (en) 1997-03-31 2002-04-19 PRO1360 polypeptides
US10/125,924 US7342097B2 (en) 1997-03-31 2002-04-19 PRO1309 polypeptides
US10/125,927 US20030190731A1 (en) 1997-03-31 2002-04-19 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/125,931 US20030199063A1 (en) 1997-03-31 2002-04-19 Secreted and transmembrane polypeptides and nucleic acids encoding the same
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
US10/131,823 US7304132B2 (en) 1997-03-31 2002-04-24 PRO1693 polypeptides
US10/131,817 US7291701B2 (en) 1997-03-31 2002-04-24 PRO1777 polypeptides
US10/131,825 US7282566B2 (en) 1997-03-31 2002-04-24 PRO1779 polypeptide
US10/063,521 US20030190669A1 (en) 1998-12-30 2002-05-01 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,520 US20030187196A1 (en) 1998-12-30 2002-05-01 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,510 US7109292B2 (en) 1999-03-08 2002-05-01 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,519 US20030009013A1 (en) 1998-12-30 2002-05-01 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,517 US7232889B2 (en) 1999-03-08 2002-05-01 PRO300 antibodies
US10/063,518 US7465785B2 (en) 1999-03-08 2002-05-01 Polypeptide encoded by a nucleic acid over-expressed in melanoma
US10/063,527 US20030181637A1 (en) 1998-12-30 2002-05-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,548 US7232892B2 (en) 1999-03-08 2002-05-02 Antibodies to a polypeptide encoded by a nucleic acid differentailly expressed in stomach, lung and melanoma tumor
US10/063,532 US7202336B2 (en) 1999-03-08 2002-05-02 Polypeptide encoded by a nucleic acid overexpressed in kidney tumor and underexpressed in lung tumor
US10/063,564 US20030180794A1 (en) 1998-12-30 2002-05-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,563 US20030060602A1 (en) 1998-12-30 2002-05-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,570 US7507404B2 (en) 1999-03-08 2002-05-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,565 US20030180904A1 (en) 1998-12-30 2002-05-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,553 US20030045684A1 (en) 1998-12-30 2002-05-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,547 US20020182638A1 (en) 1998-12-30 2002-05-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,555 US20030065143A1 (en) 1998-12-30 2002-05-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,567 US20030069394A1 (en) 1998-12-30 2002-05-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,536 US7259238B2 (en) 1999-03-08 2002-05-02 Polypeptide encoded by a nucleic acid under-expressed in stomach and lung tumor
US10/063,540 US7193061B2 (en) 1999-03-08 2002-05-02 Antibodies to a polypeptide encoded by a nucleic acid underexpressed in esophageal tumor and melanoma
US10/063,569 US20030018168A1 (en) 1998-12-30 2002-05-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,554 US7223841B2 (en) 1999-03-08 2002-05-02 PR0994 antibodies
US10/063,568 US20030181668A1 (en) 1998-12-30 2002-05-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,560 US7232882B2 (en) 1999-03-08 2002-05-02 Polypeptide uder-expressed in melanoma
US10/063,541 US20030060601A1 (en) 1998-12-30 2002-05-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,523 US7220830B2 (en) 1999-03-08 2002-05-02 Polypeptide underexpressed in stomach tumors
US10/063,547 US7294690B2 (en) 1999-03-08 2002-05-02 Polypeptides encoded by a nucleic acid differentially expressed in lung tumor
US10/063,549 US7253256B2 (en) 1999-03-08 2002-05-02 Polypeptides encoded by a nucleic acid are expressed in esophageal and kidney tumor
US10/063,530 US7193059B2 (en) 1999-03-08 2002-05-02 Antibodies that recognize a polypeptide overexpressed in rectal tumors
US10/063,546 US7435798B2 (en) 1999-03-08 2002-05-02 Antibodies to a polypeptide encoded by a nucleic acid overexpressed in normal stomach, normal skin and kidney tumor
US10/063,526 US20030171550A1 (en) 1998-12-30 2002-05-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,540 US20030181667A1 (en) 1998-12-30 2002-05-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,569 US7378491B2 (en) 1999-03-08 2002-05-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,524 US20030027992A1 (en) 1998-12-30 2002-05-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,548 US20030187228A1 (en) 1998-12-30 2002-05-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,553 US7235630B2 (en) 1999-03-08 2002-05-02 PRO994 polypeptides
US10/063,538 US7253255B2 (en) 1999-03-08 2002-05-02 Polypeptide encoded by a nucleic acid underexpressed in esophageal tumor and melanoma
US10/063,536 US20030181696A1 (en) 1998-12-30 2002-05-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,525 US20030036634A1 (en) 1998-12-30 2002-05-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,545 US20020183505A1 (en) 1998-12-30 2002-05-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,561 US7271247B2 (en) 1999-03-08 2002-05-02 Antibodies to a polypeptide encoded by a nucleic acid differentially expressed in melanoma
US10/063,534 US7193060B2 (en) 1999-03-08 2002-05-02 Antibodies to a polypeptides encoded by a nucleic acid overexpressed in kidney tumor and underexpressed in lung tumor
US10/063,562 US20030181697A1 (en) 1998-12-30 2002-05-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,523 US20030181636A1 (en) 1998-12-30 2002-05-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,528 US20030181666A1 (en) 1998-12-30 2002-05-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,544 US20030027212A1 (en) 1998-12-30 2002-05-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,551 US7214777B2 (en) 1999-03-08 2002-05-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,566 US20030073821A1 (en) 1998-12-30 2002-05-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,545 US7256261B2 (en) 1999-03-08 2002-05-02 Polypeptides encoded by a nucleic acid over expressed in normal stomach normal skin and kidney tumor
US10/063,551 US20020183494A1 (en) 1998-12-30 2002-05-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,537 US7276586B2 (en) 1999-03-08 2002-05-02 Antibodies to a polypeptide encoded by a nucleic acid under-expressed in stomach and lung tumor
US10/063,524 US7205391B2 (en) 1999-03-08 2002-05-02 Antibodies to a polypeptide suppressed in stomach tumors
US10/063,592 US7220841B2 (en) 1998-10-27 2002-05-03 Antibody to PRO1557 polypeptide encoded by a nucleic acid highly expressed in esophageal and kidney tumors
US10/063,581 US7189803B2 (en) 1999-03-08 2002-05-03 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,602 US7230082B2 (en) 1999-03-08 2002-05-03 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,579 US20030181638A1 (en) 1998-12-30 2002-05-03 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,616 US7358339B2 (en) 1999-03-08 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
US10/063,587 US7244428B2 (en) 1998-09-10 2002-05-03 PRO1357 antibodies
US10/063,611 US20030181677A1 (en) 1998-12-30 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
US10/063,578 US7417125B2 (en) 1999-03-08 2002-05-03 Antibodies that bind a PRO1158 polypeptide
US10/063,607 US7345145B2 (en) 1999-03-08 2002-05-03 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,611 US7378501B2 (en) 1999-03-08 2002-05-03 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,597 US7227000B2 (en) 1999-03-08 2002-05-03 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,598 US7223838B2 (en) 1999-03-08 2002-05-03 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,618 US7468424B2 (en) 1999-03-08 2002-05-03 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/137,868 US20030082764A1 (en) 1997-03-31 2002-05-03 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,588 US20030130483A1 (en) 1998-12-30 2002-05-03 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,617 US7423119B2 (en) 1999-03-08 2002-05-03 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,606 US20030181675A1 (en) 1998-12-30 2002-05-03 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,596 US7285624B2 (en) 1999-03-08 2002-05-03 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,583 US7189804B2 (en) 1999-03-08 2002-05-03 PRO1335 polypeptides
US10/063,610 US7371814B2 (en) 1999-03-08 2002-05-03 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,591 US7196174B2 (en) 1998-10-27 2002-05-03 PRO1557 polypeptide encoded by a nucleic acid highly expressed in esophageal and kidney tumors
US10/063,604 US7390876B2 (en) 1999-03-08 2002-05-03 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,610 US20030180907A1 (en) 1998-12-30 2002-05-03 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,577 US7423130B2 (en) 1999-03-08 2002-05-03 PRO1158 polypeptides
US10/063,592 US20030181672A1 (en) 1998-12-30 2002-05-03 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,589 US20030181641A1 (en) 1998-12-30 2002-05-03 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,609 US7402661B2 (en) 1998-10-06 2002-05-03 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,593 US7189805B2 (en) 1999-03-08 2002-05-03 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,582 US7205389B2 (en) 1999-03-08 2002-05-03 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,600 US7230076B2 (en) 1999-03-08 2002-05-03 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,614 US7393931B2 (en) 1999-03-08 2002-05-03 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,612 US7399828B2 (en) 1998-09-24 2002-05-03 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,615 US7405269B2 (en) 1998-10-08 2002-05-03 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,591 US20030180906A1 (en) 1998-12-30 2002-05-03 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
US10/140,470 US20030022331A1 (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
US10/140,023 US20030207416A1 (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
US10/140,024 US20040058424A1 (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
US10/063,649 US20030181652A1 (en) 1998-12-30 2002-05-07 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,664 US7256262B2 (en) 1999-03-08 2002-05-07 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/140,928 US20030068798A1 (en) 1997-03-31 2002-05-07 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,662 US20030180795A1 (en) 1998-12-30 2002-05-07 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,677 US20030187242A1 (en) 1998-12-30 2002-05-07 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,654 US7202337B2 (en) 1999-03-08 2002-05-07 Polypeptide encoded by a nucleic acid overexpressed in esophageal tumor, normal stomach and melanoma
US10/063,652 US7230077B2 (en) 1999-03-08 2002-05-07 Polypeptide encoded by a nucleic acid underexpressed in melanoma
US10/063,660 US7189822B2 (en) 1999-03-08 2002-05-07 Antibodies to a polypeptide encoded by a nucleic acid underexpressed in stomach and lung tumor
US10/063,647 US20030187197A1 (en) 1998-12-30 2002-05-07 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,644 US7196167B2 (en) 1998-10-20 2002-05-07 Polypeptide underexpressed in lung tumor
US10/063,657 US7193063B2 (en) 1999-03-08 2002-05-07 Antibodies to a polypeptide encoded by a nucleic acid overexpressed in esophageal tumor, normal stomach and melanoma
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
US10/063,666 US7411037B2 (en) 1999-03-08 2002-05-07 Polypeptides encoded by a nucleic acid underexpressed in melanoma
US10/063,642 US20030181650A1 (en) 1998-12-30 2002-05-07 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,647 US7193046B2 (en) 1998-10-20 2002-05-07 Polypeptide encoded by a nucleic acid overexpressed in esophageal and lung tumor, and underexpressesd in kidney tumor and melanoma
US10/063,650 US7217787B2 (en) 1999-03-08 2002-05-07 Polypeptide encoded by a nucleic acid underexpressed in rectal tumor
US10/140,921 US7317080B2 (en) 1997-03-31 2002-05-07 PRO4303 polypeptides
US10/063,668 US20030191290A1 (en) 1998-12-30 2002-05-07 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,646 US7189821B2 (en) 1998-10-20 2002-05-07 Antibodies to a polypeptide encoded by a nucleic acid underexpressed in lung tumor
US10/063,661 US7193047B2 (en) 1999-03-08 2002-05-07 Polypeptide encoded by a nucleic acid underexpressed in esophageal tumor
US10/063,659 US7186801B2 (en) 1999-03-08 2002-05-07 Polypeptide encoded by a nucleic acid underexpressed in stomach tumor and lung tumor
US10/140,864 US20030207419A1 (en) 1997-03-31 2002-05-07 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,643 US20030181680A1 (en) 1998-12-30 2002-05-07 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,665 US7427664B2 (en) 1999-03-08 2002-05-07 Antibodies to polypeptides that stimulate TNF-α release
US10/063,673 US20030180908A1 (en) 1998-12-30 2002-05-07 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,640 US7354997B2 (en) 1999-03-08 2002-05-07 Polypeptide encoded by a nucleic acid underexpressed in stomach tumor
US10/140,808 US7425621B2 (en) 1997-03-31 2002-05-07 Antibodies against the PRO4401 polypeptide
US10/063,639 US7081520B2 (en) 1998-10-08 2002-05-07 Anti-pro 1570 antibodies
US10/063,674 US20030180841A1 (en) 1998-12-30 2002-05-07 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,672 US20030181700A1 (en) 1998-12-30 2002-05-07 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,671 US20030180840A1 (en) 1998-12-30 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
US10/140,865 US20030207420A1 (en) 1997-03-31 2002-05-07 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,676 US20030180843A1 (en) 1998-12-30 2002-05-07 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,648 US7193062B2 (en) 1998-10-20 2002-05-07 Antibodies to a polypeptide encoded by a nucleic acid over expressed in esoprageal and lung tumor, and under expressed in kidney tumor and melanoma
US10/063,669 US20030180838A1 (en) 1998-12-30 2002-05-07 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/140,809 US20030207418A1 (en) 1997-03-31 2002-05-07 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,670 US20030180839A1 (en) 1998-12-30 2002-05-07 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,638 US7101970B2 (en) 1999-03-08 2002-05-07 PRO1570 polypeptides
US10/063,644 US20030181651A1 (en) 1998-12-30 2002-05-07 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,675 US20030180842A1 (en) 1998-12-30 2002-05-07 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,646 US20030181681A1 (en) 1998-12-30 2002-05-07 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,653 US7238787B2 (en) 1999-03-08 2002-05-07 Antibodies to a polypeptide encoded by a nucleic acid underexpressed in melanoma
US10/141,701 US20030207421A1 (en) 1997-03-31 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/141,760 US7342104B2 (en) 1997-03-31 2002-05-08 Antibodies against the PRO4320 polypeptide
US10/063,724 US20030180856A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,707 US20030180853A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,723 US20030181703A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,714 US20030180913A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,731 US20030180921A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,718 US20030190698A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,702 US7193074B2 (en) 1999-03-08 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,727 US20030180857A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,722 US20030180918A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,685 US20030180909A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,734 US20030180859A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,709 US7189564B2 (en) 1999-03-08 2002-05-08 PRO1335 nucleic acids
US10/141,754 US7361732B2 (en) 1997-03-31 2002-05-08 PRO4400 polypeptides
US10/063,721 US20030181702A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,720 US20030180917A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,686 US20030180844A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,705 US7220850B2 (en) 1999-03-08 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,693 US20030180847A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,735 US20030138882A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,692 US20030180846A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,726 US20030180919A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,744 US20030180863A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,717 US20030180916A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,684 US20030186407A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,689 US20030180845A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,694 US20030180848A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/141,756 US7488586B2 (en) 1997-03-31 2002-05-08 PRO4409 polypeptides
US10/063,703 US7189563B2 (en) 1999-03-08 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,716 US20030180915A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,712 US20030180912A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,688 US20030186408A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,713 US20030180855A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,728 US20030180920A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,732 US20030180922A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,711 US20030180911A1 (en) 1998-12-30 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
US10/063,698 US20030180849A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,699 US20030180850A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
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JP2014243369A JP2015077137A (ja) 1999-12-23 2014-12-01 Ｉｌ−１７相同的ポリペプチドとその治療上の用途
US14/581,971 US20150266953A1 (en) 1998-05-15 2014-12-23 Il-17 homologous polypeptides and therapeutic uses thereof
JP2015187174A JP2016047051A (ja) 1999-12-23 2015-09-24 Ｉｌ−１７相同的ポリペプチドとその治療上の用途

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US09/747,259 Continuation-In-Part US6569645B2 (en) 1997-03-31 2000-12-20 IL-17 homologous polypeptides and therapeutic uses thereof
US10/081,056 Continuation US20040043927A1 (en) 1997-09-19 2002-02-20 Compositions and methods for the diagnosis and treatment of disorders involving angiogenesis
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WO2001046420A3 (fr) * 1999-12-23 2002-05-10 Genentech Inc Polypeptides homologues de l'il-17 et leurs utilisations therapeutiques
JP2016047051A (ja) * 1999-12-23 2016-04-07 ジェネンテック， インコーポレイテッド Ｉｌ−１７相同的ポリペプチドとその治療上の用途
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US7491512B2 (en) 1999-12-23 2009-02-17 Genentech, Inc. Nucleic acids encoding receptor for IL-17 homologous polypeptides and uses thereof
US8034342B2 (en) 2000-01-11 2011-10-11 Genentech, Inc. Pharmaceutical compositions, kits, and therapeutic uses of antagonist antibodies to IL-17E
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EA008480B1 (ru) * 2000-01-12 2007-06-29 Йейл Юниверсити Выделенный полинуклеотид (варианты), содержащий его вектор и клетка-хозяин, кодируемый им полипептид рецептора nogo, уменьшающий опосредованное этим рецептором ингибирование роста аксонов (варианты), выделенное антитело и фармацевтическая композиция на их основе
US7119165B2 (en) 2000-01-12 2006-10-10 Yale University Nogo receptor-mediated blockade of axonal growth
WO2001051520A3 (fr) * 2000-01-12 2002-04-18 Univ Yale Blocage de la croissance axonale a mediation assuree par le recepteur de nogo
US8338132B2 (en) 2000-03-21 2012-12-25 Genentech, Inc. Nucleic acids encoding receptor for IL-17 homologous polypeptides and therapeutic uses thereof
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