WO2004043361A2 - Compositions and methods for the treatment of natural killer cell related diseases - Google Patents

Compositions and methods for the treatment of natural killer cell related diseases Download PDF

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Publication number
WO2004043361A2
WO2004043361A2 PCT/US2003/035268 US0335268W WO2004043361A2 WO 2004043361 A2 WO2004043361 A2 WO 2004043361A2 US 0335268 W US0335268 W US 0335268W WO 2004043361 A2 WO2004043361 A2 WO 2004043361A2
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Prior art keywords
polypeptide
pro
acid sequence
antibody
nucleic acid
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PCT/US2003/035268
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English (en)
French (fr)
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WO2004043361A3 (en
Inventor
Sherman Fong
Kathryn Dennis
Hilary Clark
Henry Chiu
Jill Schoenfeld
P. Mickey Williams
William I. Wood
Thomas D. Wu
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Genentech Inc
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Genentech Inc
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Priority to AU2003295401A priority Critical patent/AU2003295401B2/en
Priority to EP03786587A priority patent/EP1581169A4/en
Priority to US10/533,416 priority patent/US20070037148A1/en
Priority to CA002503748A priority patent/CA2503748A1/en
Priority to JP2004551756A priority patent/JP2006516094A/ja
Publication of WO2004043361A2 publication Critical patent/WO2004043361A2/en
Anticipated expiration legal-status Critical
Publication of WO2004043361A3 publication Critical patent/WO2004043361A3/en
Priority to US12/228,137 priority patent/US20090232802A1/en
Priority to AU2010202969A priority patent/AU2010202969A1/en
Priority to US12/979,877 priority patent/US20110182889A1/en
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Definitions

  • the present invention relates to compositions and methods useful for the diagnosis and treatment of immune related diseases.
  • 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.
  • 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.
  • Immune related diseases could be treated by suppressing the immune response. Using neutralizing antibodies that inhibit molecules having immune stimulatory activity would be beneficial in the treatment of immune-mediated and inflammatory diseases. Molecules which inhibit the immune response can be utilized (proteins directly or via the use of antibody agonists) to inhibit the immune response and thus ameliorate immune related disease.
  • NK cells Natural killer cells are an important effector cell of the innate immune system. They are specialized to effect killing against host cells that have either been infected by viruses, parasites or that have become cancerous. Phenotypically, NK cells are large granular lymphocytes that constitute ⁇ 2 % of the circulating lymphocyte population. They are commonly identified by cell surface expression of CD56 and CD 16. NK cells mature in the bone marrow from a CD34+ precursor cell that they share with T cells. The mature NK cell, shares expression of CD8, cytolytic machinery, and some KIRs, with T cells, but remains distinct from T cells by the lack of CD3 and the T cell receptors.
  • cytotoxic T cells Like cytotoxic T cells, they contain granules filled with pore forming protein, cytotoxins, serine esterases and proteoglycans that mediate lysis of target cells. Both cytotoxic T cells and NK cells kill on contact by binding to their targets and delivering their lethal burst of chemicals that produces holes in the target cell's membrane. Unlike cytotoxic T cells, NK cells do not need to recognize a specific antigen before initiating lysis.
  • NK cell activation can be mediated by growth factors and cytokines such as, IL-2, IL-12 and IL-15 have been shown to mediate proliferative and cytotoxic activities or by a delicate balance between two classes of NK cell receptors, one that activates the cells, and another that inhibits.
  • Killer Ig-like receptors are NK cell receptors that transmit an inhibitory signal if they encounter class I MHC molecules on a cell surface. This is important for killing of both cancerous cells and virally infected cells. Because viruses often suppress class I MHC expression in cells they infect, the virus-infected cell becomes susceptible to killing by NK cells. Likewise, cancer cells have reduced or no class I MHC expression also become susceptible to killing by NK cells.
  • NCRs Natural cytotoxicity receptors
  • the surface density of NCRs correlates with the cytolytic activity of the NK cells, while in other systems killing requires cooperation between NCR, another activating receptor NKG2D and its adaptor polypeptide DAP10.
  • the strength of the stimulatory signals can be influenced by engagement of co-receptors such as 2B4 and NTB-A.
  • the ligands for NCRs and NKG2D, hemoglutanins and MICA, MICB respectively are not expressed by most normal cells, but are induced in most tumor cell lines. Expression of the ligands by tumor cells triggers a dramatic immune response resulting in tumor cell rejection.
  • JAM2 Junctional adhesion molecule 2
  • JAM2 Junctional adhesion molecule 2
  • a DNA microarray experiment comparing differential expression of genes from these three modes of activation versus resting NK cells has the potential to reveal novel genes or novel gene associations with NK cell activity.
  • Therapeutic antibodies, peptides or small molecules could be developed to target specific genes revealed by these microarrays for the treatment of immune mediated inflammatory diseases and malignancies.
  • NK cell mediated disorders there is a great need for additional diagnostic and therapeutic agents capable of detecting the presence of NK cell mediated disorders in a mammal and for effectively reducing these disorders. Accordingly, it is an objective of the present invention to identify polypeptides that are differentially expressed in activated NK cells as compared to resting NK cells, and to use those polypeptides, and their encoding nucleic acids, to produce compositions of matter useful in the therapeutic treatment and diagnostic detection of NK cell mediated disorders in mammals.
  • the present invention concerns compositions and methods useful 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 are a result of stimulation of 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. Alternatively, molecules that suppress the immune response attenuate or reduce the immune response to an antigen ⁇ e.g., neutralizing antibodies) can be used therapeutically where attenuation of the immune response would be beneficial ⁇ e.g., inflammation).
  • the PRO polypeptides, agonists and antagonists thereof are also useful to prepare medicines and medicaments for the treatment of immune-related and inflammatory diseases.
  • such medicines and medicaments comprise a therapeutically effective amount of a PRO polypeptide, agonist or antagonist thereof with a pharmaceutically acceptable carrier.
  • the admixture is sterile.
  • the invention concerns a method of identifying agonists or antagonists to a
  • PRO polypeptide which comprises contacting the PRO polypeptide with a candidate molecule and monitoring a biological activity mediated by said PRO polypeptide.
  • the PRO polypeptide is a native sequence PRO polypeptide.
  • the PRO agonist or antagonist is an anti-PRO antibody.
  • the invention concerns a composition of matter comprising a PRO polypeptide or an agonist or antagonist antibody which binds the polypeptide in admixture with a carrier or excipient. In one aspect, the composition comprises a therapeutically effective amount of the polypeptide or antibody.
  • the composition when the composition comprises 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, (c) increasing the proliferation of NK cells in a mammal in need thereof in response to an antigen, (d) stimulating the activity of NK cells or (e) increasing the vascular permeability.
  • the composition when the composition comprises 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, (c) decreasing the activity of NK cells or (d) decreasing the proliferation of NK cells in a mammal in need thereof in response to an antigen.
  • the composition comprises 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 a method of treating an immune related disorder in a mammal in need thereof, comprising administering to the mammal an effective amount of a PRO polypeptide, an agonist thereof, or an antagonist thereto.
  • the immune related disorder is selected from the group consisting of: systemic lupus erythematosis, rheumatoid arthritis, osteoarthritis, juvenile chronic arthritis, spondyloarthropathies, systemic sclerosis, idiopathic inflammatory myopathies, Sj ⁇ gren's syndrome, systemic vasculitis, sarcoidosis, autoimmune hemolytic anemia, autoimmune thrombocytopenia, tliyroiditis, diabetes mellitus, immune-mediated renal disease, 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,
  • the invention provides an antibody which specifically binds to any of the above or below described polypeptides.
  • the antibody is a monoclonal antibody, humanized antibody, antibody fragment or single-chain antibody.
  • the present invention concerns an isolated antibody which binds a PRO polypeptide.
  • the antibody mimics the activity of a PRO polypeptide (an agonist antibody) or conversely the antibody inhibits or neutralizes the activity of a PRO 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 monoclonal antibody, a single-chain antibody, or an anti-idiotypic antibody.
  • the present invention provides a composition comprising an anti-PRO antibody in admixture with a pharmaceutically acceptable carrier.
  • the composition comprises a therapeutically effective amount of the antibody.
  • the composition is sterile.
  • the composition may be administered in the form of a liquid pharmaceutical formulation, which may be preserved to achieve extended storage stability.
  • the antibody is a monoclonal antibody, an antibody fragment, a humanized antibody, or a single-chain antibody.
  • the invention concerns an article of manufacture, comprising:
  • composition of matter comprising a PRO polypeptide or agonist or antagonist thereof;
  • composition may comprise a therapeutically effective amount of the PRO polypeptide or the agonist or antagonist thereof.
  • 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 PRO 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 or lower expression level in the test sample as compared to the control sample indicates the presence of immune related disease in the mammal from which the test tissue cells were obtained.
  • the present invention concerns a method of diagnosing an immune disease in a mammal, comprising (a) contacting an anti-PRO antibody with a test sample of tissue cells obtained from the mammal, and (b) detecting the formation of a complex between the antibody and a PRO polypeptide, in the test sample; wherein the formation of said complex is indicative of the presence or absence of said disease.
  • the detection may be qualitative or quantitative, and may be performed in comparison with monitoring the complex formation in a control sample of known normal tissue cells of the same cell type. A larger quantity of complexes formed in the test sample indicates the presence or absence of an immune disease in the mammal from which the test tissue cells were obtained.
  • the antibody preferably carries a detectable label.
  • the invention provides a method for determining the presence of a PRO polypeptide in a sample comprising exposing a test sample of cells suspected of containing the PRO polypeptide to an anti-PRO antibody and determining the binding of said antibody to said cell sample.
  • the sample comprises a cell suspected of containing the PRO polypeptide and the antibody binds to the cell.
  • the antibody is preferably detectably labeled and/or bound to a solid support.
  • the present invention concerns an immune-related disease diagnostic kit, comprising an anti-PRO antibody and a carrier in suitable packaging.
  • the kit preferably contains instructions for using the antibody to detect the presence of the PRO polypeptide.
  • the carrier is pharmaceutically acceptable.
  • the present invention concerns a diagnostic kit, containing an anti-PRO antibody in suitable packaging. The kit preferably contains instructions for using the antibody to detect the PRO polypeptide.
  • the invention provides a method of diagnosing an immune-related disease in a mammal which comprises detecting the presence or absence or a PRO polypeptide in a test sample of tissue cells obtained from said mammal, wherein the presence or absence of the PRO polypeptide in said test sample is indicative of the presence of an immune-related disease in said mammal.
  • the present invention concerns a method for identifying an agonist of a PRO polypeptide comprising:
  • the invention concerns a method for identifying a compound capable of inhibiting the activity of a PRO polypeptide comprising contacting a candidate compound with a PRO polypeptide under conditions and for a time sufficient to allow these two components to interact and determining whether the activity of the PRO polypeptide is inhibited.
  • either the candidate compound or the PRO polypeptide is immobilized on a solid support.
  • the non- immobilized component carries a detectable label.
  • this method comprises the steps of: (a) contacting cells and a test compound to be screened in the presence of a PRO polypeptide under conditions suitable for the induction of a cellular response normally induced by a PRO polypeptide; and
  • the invention provides a method for identifying a compound that inhibits the expression of a PRO polypeptide in cells that normally express the polypeptide, wherein the method comprises contacting the cells with a test compound and determining whether the expression of the PRO polypeptide is inhibited. In a preferred aspect, this method comprises the steps of:
  • the present invention concerns a method for treating an immune-related disorder in a mammal that suffers therefrom comprising administering to the mammal a nucleic acid molecule that codes for either (a) a PRO polypeptide, (b) an agonist of a PRO polypeptide or (c) an antagonist of a PRO polypeptide, wherein said agonist or antagonist may be an anti-PRO antibody.
  • the mammal is human.
  • the nucleic acid is administered via ex vivo gene therapy.
  • the nucleic acid is comprised within a vector, more preferably an adenoviral, adeno-associated viral, lentiviral or retroviral vector.
  • the invention provides a recombinant viral particle comprising a viral vector consisting essentially of a promoter, nucleic acid encoding (a) a PRO polypeptide, (b) an agonist polypeptide of a PRO polypeptide, or (c) an antagonist polypeptide of a PRO polypeptide, and a signal sequence for cellular secretion of the polypeptide, wherein the viral vector is in association with viral structural proteins.
  • the signal sequence is from a mammal, such as from a native PRO polypeptide.
  • the invention concerns an ex vivo producer cell comprising a nucleic acid construct that expresses retroviral structural proteins and also comprises a retroviral vector consisting essentially of a promoter, nucleic acid encoding (a) a PRO polypeptide, (b) an agonist polypeptide of a PRO polypeptide or (c) an antagonist polypeptide of a PRO polypeptide, and a signal sequence for cellular secretion of the polypeptide, wherein said producer cell packages the retroviral vector in association with the structural proteins to produce recombinant retroviral particles.
  • the invention provides a method of increasing the activity of NK cells in a mammal comprising administering to said mammal (a) a PRO polypeptide, (b) an agonist of a PRO polypeptide, or (c) an antagonist of a PRO polypeptide, wherein the activity of NK cells in the mammal is increased.
  • the invention provides a method of decreasing the activity of NK cells in a mammal comprising administering to said mammal (a) a PRO polypeptide, (b) an agonist of a PRO polypeptide, or (c) an antagonist of a PRO polypeptide, wherein the activity of NK cells in the mammal is decreased.
  • the invention provides a method of increasing the proliferation of NK cells in a mammal comprising administering to said mammal (a) a PRO polypeptide, (b) an agonist of a PRO polypeptide, or (c) an antagonist of a PRO polypeptide, wherein the proliferation of NK cells in the mammal is increased.
  • the invention provides a method of decreasing the proliferation of NK cells in a mammal comprising administering to said mammal (a) a PRO polypeptide, (b) an agonist of a PRO polypeptide, or (c) an antagonist of a PRO polypeptide, wherein the proliferation of NK cells in the mammal is decreased.
  • the invention provides vectors comprising DNA encoding any of the herein described polypeptides.
  • Host cell comprising any such vector are also provided.
  • the host cells may be CHO cells, E. coli, or yeast.
  • a process for producing any of the herein described polypeptides is further provided and comprises culturing host cells under conditions suitable for expression of the desired polypeptide and recovering the desired polypeptide from the cell culture.
  • the invention provides chimeric molecules comprising any of the herein described polypeptides fused to a heterologous polypeptide or amino acid sequence.
  • Example of such chimeric molecules comprise any of the herein described polypeptides fused to an epitope tag sequence or a Fc region of an immunoglobulin.
  • the invention provides an antibody which specifically binds to any of the above or below described polypeptides.
  • the antibody is a monoclonal antibody, humanized antibody, antibody fragment or single-chain antibody.
  • the invention provides oligonucleotide probes useful for isolating genomic and cDNA nucleotide sequences 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
  • 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 96% nucleic acid sequence
  • the invention concerns an isolated nucleic acid molecule comprising 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 9
  • Another aspect the invention provides an isolated nucleic acid molecule comprising a nucleotide sequence encoding a PRO polypeptide which is either transmembrane domain-deleted or transmembrane domain-inactivated, or is complementary to such encoding nucleotide sequence, wherein the transmembrane domain(s) of such polypeptide are disclosed herein. Therefore, soluble extracellular domains of the herein described PRO polypeptides are contemplated.
  • Another embodiment is directed to fragments of a PRO polypeptide coding sequence, or the complement thereof, that may find use as, for example, hybridization probes, for encoding fragments of a PRO polypeptide that may optionally encode a polypeptide comprising a binding site for an anti-PRO antibody or as antisense oligonucleotide probes.
  • 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, alternatively at least about 100 nucleotides in length, alternatively at least about 110 nucleotides in length, alternatively at least about 120 nucleotides in length, alternatively at least about 130 nucleotides in length, alternatively at least about 140 nucleotides in length, alternatively at least about 150 nucleotides in length, alternatively at least about 160 nucleotides in length, alternatively at least about 170 nucleotides in length, alternatively at least about 180 nucleotides in length, alternatively at least about 190 nucle
  • novel fragments of a PRO polypeptide-encoding nucleotide sequence may be determined in a routine manner by aligning the PRO polypeptide-encoding nucleotide sequence with other known nucleotide sequences using any of a number of well known sequence alignment programs and determining which PRO polypeptide-encoding nucleotide sequence fragment(s) are novel. All of such PRO polypeptide-encoding nucleotide sequences are contemplated herein. Also contemplated are the PRO polypeptide fragments encoded by these nucleotide molecule fragments, preferably those PRO polypeptide fragments that comprise a binding site for an anti-PRO antibody.
  • the invention provides isolated PRO polypeptide encoded by any of the isolated nucleic acid sequences herein above 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% amino 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, alternatively at least about 89% amino acid sequence identity, alternatively at least about 90% amino acid sequence identity, alternatively at least about 91% amino acid sequence identity, alternatively at least about 92% amino acid sequence identity, alternatively at least about 93% amino acid sequence identity, alternatively at least about 94% amino acid sequence identity, alternatively at least about 95% amino acid sequence identity, alternatively at least about 96% amino acid sequence identity, alternatively at least about 97% amino acid sequence identity, alternatively at least about 98% amino acid sequence identity and alternatively at least about 99%
  • the invention provides an isolated PRO polypeptide without the N-terminal signal sequence and/or the initiating methionine and is encoded by a nucleotide sequence that encodes such an amino acid sequence as herein before described.
  • 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.
  • Another aspect the invention provides an isolated PRO polypeptide which is either transmembrane domain-deleted or transmembrane domain-inactivated.
  • Processes for producing the same are also herein described, wherein those processes comprise culturing a host cell comprising a vector which comprises the appropriate encoding nucleic acid molecule under conditions suitable for expression of the PRO polypeptide and recovering the PRO polypeptide from the cell culture.
  • the invention concerns agonists and antagonists of a native PRO polypeptide as defined herein.
  • the agonist or antagonist is an anti-PRO antibody or a small molecule.
  • the invention concerns a method of identifying agonists or antagonists to a PRO polypeptide which comprise contacting the PRO polypeptide with a candidate molecule and monitoring a biological activity mediated by said PRO polypeptide.
  • the PRO polypeptide is a native PRO polypeptide.
  • the invention concerns a composition of matter comprising a PRO polypeptide, or an agonist or antagonist of a PRO polypeptide as herein described, or an anti-PRO antibody, in combination with a carrier.
  • the carrier is a pharmaceutically acceptable carrier.
  • Another embodiment of the present invention is directed to the use of a PRO polypeptide, or an agonist or antagonist thereof as herein before 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.
  • cDNA sequences which are differentially expressed in activated Natural Killer (NK) cells as compared to normal resting NK cells are individually identified with a specific alphanumerical designation. These cDNA sequences are differentially expressed in NK cells that are specifically treated as described in Example 1 below. If start and/or stop codons have been identified in a cDNA sequence shown in the attached figures, they are shown in bold and underlined font, and the encoded polypeptide is shown in the next consecutive figure.
  • NK Natural Killer
  • FIGS. 1-1477 show the nucleic acids of the invention and their encoded PRO polypeptides. Also included, for convenience is a List of Figures attached hereto as Appendix A, which gives the figure number and the corresponding DNA or PRO number.
  • Figure 2 PR069614 Figure 54A-B: DNA287217, CCND2, 200952-s_at
  • Figure 4 PR071106 Figure 56A-B: DNA226303, HUMRSC289,
  • Figure 7 DNA331286, NP-.006143.1, 35974_at
  • Figure 58A-B DNA331289, ABLMl, 200965 -s.at
  • Figure 13A-B DNA103216, BAA31595.1, 38671-at
  • Figure 64 DNA328391, NP.004408.1, 201041-s_at
  • Figure 15A-B DNA329093, NP-.006631.1, 41220-at
  • Figure 66 DNA287198, NP.006073.1, 201090-x-at
  • Figure 17 DNA326185, NP-073607.2, 45633-at
  • Figure 68 DNA304719, NP.002296.1, 201105-at
  • Figure 20 PR085228 Figure 71: DNA273865, NP_006221.1, 201115_at
  • Figure 22 PR086389
  • Figure 73 DNA326273, NP_001961.1, 201123-s_at
  • Figure 24 PR084223
  • Figure 75 DNA329103, NP-.002112.2, 201137_s_at
  • Figure 26 PR081277
  • Figure 77 DNA329104, NP-.004085.1, 201144-s_at
  • Figure 27 DNA324633, NP-.004125.2, 200692-s.at Figure 78 : PRO69550
  • Figure 28 PR081277
  • Figure 79 DNA151802, NP-.003661.1, 201169-s-at
  • Figure 30 PR02758 Figure 81: DNA151802, BHLHB2, 201170_s_at
  • Figure 32 PR039268 Figure 83A-B: DNA103453, HUME16GEN,
  • Figure 35 DNA324135, NP-.005902.1, 200769-s_at
  • Figure 85 DNA103488, NP-.002583.1, 201202_at
  • Figure 37 DNA324060, NP-.002530.1, 200790-at
  • Figure 87 DNA287173, EN01, 201231-s_at
  • Figure 41 DNA287211, HSPD1, 200807 -s_at
  • Figure 91 DNA270950, NP-.003182.1, 201263-at
  • Figure 43A-B DNA255281, NP-.006380.1
  • Figure 93 DNA328405, NP-.112556.1, 201277-s_at
  • Figure 44 PRO50357
  • Figure 95 DNA328406, NP-.001334.1, 201279-s_at
  • Figure 48 DNA327255, NP-002385.2, 200924-s_at
  • Figure 99 DNA331290, NP.038474.1, 201285-at
  • Figure 50 DNA225878, NP-.004334.1, 200935-at
  • Figure 101 DNA327546, HSTOP2A10, 201292-at
  • Figure 51 PR036341
  • Figure 102 DNA329106, NP-.003013.1, 20131 l-S-at
  • Figure 52A-B DNA287217, NP-.001750.1
  • Figure 103 PRO83360
  • PRO80498 Figure 184 DNA328440, NP-.004517.1, 202107-s_at
  • Figure 214 DNA227921, NP.003789.1, 202468-s_at
  • Figure 267A-B DNA331302, YES1, 202933-s.at
  • Figure 216 DNA329123, NP.002873.1, 202483-s_at
  • Figure 269 DNA329134, BC012085, 202951_at
  • Figure 218A-B DNA103449, NP.008862.1, Figure 271A-B: DNA328473, NP.006473.1,
  • Figure 220A-B DNA103449, SLC2A3, 202499-s_at Figure 273A-B: DNA194837, NP.055714.1,
  • Figure 222 DNA234442, NP.055551.1, 202503 -S-at Figure 274: PRO24100
  • Figure 223 PR038852 Figure 275A-B: DNA194837, RHOBTB3, 202976-s-at
  • Figure 224A-B DNA277809, NP.055582.1, Figure 276: PR024100
  • Figure 226A-B DNA255105, NP.000850.1
  • Figure 279A-B DNA271865, NP.055566.1
  • Figure 228A-B DNA255105, HMGCR, 202540-s.at
  • Figure 281 DNA269918, NP.003633.1, 203138-at
  • Figure 230 DNA275244, DNA275244, 202557 ⁇ t
  • Figure 283A-B DNA331303, NP.003129.1,
  • Figure 231 DNA329979, NP.001062.1, 202589 Jit 203181-x.at
  • Figure 233 DNA274881, NP-001896.1, 202613-at
  • Figure 285 DNA331304, BC015747, 203221_at
  • Figure 235 DNA59763, NP.000192.1, 202637-s.at
  • Figure 287 DNA328294, NP.005068.2, 203222-s_at
  • Figure 236 PRO 160 Figure 288: PR084167
  • Figure 237 DNA59763, ICAMl, 202638-s_at Figure 289A-C: DNA274481, NP-000323.1,
  • Figure 240 PR049244 Figure 291A-C: DNA274481, SCA1, 203232-s_at
  • Figure 244 PR062479
  • Figure 295 DNA327590, NP.003355.1, 203234-at
  • Figure 245 DNA331298, NP.055271.2, 202730-s.at Figure 296: PRO83608
  • Figure 246 PRO81909
  • Figure 297 DNA325507, NP.005842.1, 203252-at
  • Figure 248 PR086397
  • Figure 299 DNA302020, NP.005564.1, 203276-at
  • Figure 250 PRO12082 Figure 301A-B: DNA331305, NP.055716.1, 203286-at
  • Figure 251A-B DNA328464, 977954.20, 202769 -at Figure 302: PRO86400
  • Figure 252 PRO84290 Figure 303: DNA271959, NP.002885.1, 203344-s-at
  • Figure 253 DNA226578, NP_004345.1, 202770-s_at Figure 304: PRO60234
  • Figure 254 PRO37041
  • Figure 305 DNA324514, NP.002349.1, 203362-s.at
  • Figure 256 PR061349
  • Figure 307 DNA325749, NP.003868.1, 203372-s-at
  • Figure 257A-B DNA226364, NP.001612.1, 202820_at Figure 308: PR012839
  • Figure 258 PR036827
  • Figure 309 DNA325749, STATI2, 203373-at
  • Figure 260 PRO 1471
  • Figure 311 DNA329140, NP.476433.1, 203391-at
  • Figure 262 PRO84309
  • Figure 313 DNA323927, NP.005563.1 , 203411 -s_at
  • Figure 263 DNA331300, BINl, 20293 l-x_at Figure 314: PRO80660
  • Figure 315 DNA151037, NP.036461.1, 203414-at Figure 367: PRO82290
  • Figure 316 PR012586
  • Figure 368 DNA325824, NPD02906.1, 204128-s_at
  • Figure 317A-B DNA256807, NP.057339.1, 203420 _at Figure 369: PRO82290
  • Figure 318 PR051738
  • Figure 370 DNA272655, NP-.001818.1, 204170-s_at
  • Figure 319A-B DNA275186, DNA275186, 203432-at Figure 371: PRO60781
  • Figure 320A-B DNA330010, NP.005721.2, Figure 372: DNA226881, NP-.002008.2, 204236-at
  • Figure 321 PR085298 Figure 374A-B: DNA287273, NP.006435.1,
  • Figure 322 DNA331306, NP.001715.1, 203502-at 204240-s.at
  • Figure 324A-B DNA331307, NP.003096.1, 203509-at
  • Figure 376 DNA228132, NP.076995.1, 204256-at
  • Figure 326A-B DNA272399, NP.001197.1
  • Figure 378 DNA273802, NP.066950.1, 204285-s_at
  • Figure 327 PRO60653
  • Figure 380 DNA273802, PMAIP1, 204286-s.at
  • Figure 328A-B DNA272399, BTEB1, 203543-s.at Figure 381: PR061763
  • Figure 329 PRO60653
  • Figure 382 DNA331310, NP.000472.1, 204294-at
  • Figure 331 PR069521
  • Figure 384 DNA150972, NP.005252.1, 204472-at
  • Figure 332A-B DNA331308, BCL2, 203685_at Figure 385: PR012162
  • Figure 333 PRO86402
  • Figure 386A-B DNA331311, NP.056054.1,
  • Figure 334 DNA324183, DPP4, 203716-s-at 204500-s.at
  • Figure 336 DNA196562, HSPCHDP7, 203717-at
  • Figure 388 DNA331312, NP.003600.2, 204504-s-at
  • Figure 340A-B DNA325369, NP.055877.2,
  • Figure 392A-B DNA330054, NP.004746.1
  • Figure 342 DNA275339, NP.005685.1, 203880_at
  • Figure 394 DNA103526, LRMP, 204674-at
  • Figure 344 DNA82376, NP.002407.1, 203915-at Figure 396A-B: DNA331313, 481411.2, 204695 Jit
  • Figure 346 DNA272338, NP.001245.1, 203967-at Figure 398A-B: DNA325192, NP.038203.1,
  • Figure 349 PRO60595
  • Figure 400 DNA330060, NP-.002443.2, 204766-s_at
  • Figure 351 PR059673
  • Figure 402 DNA329154, BC000323, 204767-s_at
  • Figure 353 PRO84780
  • Figure 404 DNA325479, NP-004102.1, 204768-s-at
  • Figure 354 DNA330034, NP_002907.1, 204023-at Figure 405: PR069568
  • Figure 355 PR085319
  • Figure 406 DNA330062, NP.006017.1, 204805-s_at
  • Figure 356 DNA328271, NP_008988.2, 204026-s_at Figure 407: PR085342
  • Figure 359 PRO37200
  • Figure 410 DNA328544, NP-.006673.1, 204834-at
  • Figure 362 DNA216689, NP.002975.1, 204103_at
  • Figure 414 DNA329157, NP-.004271.1, 204905-s-at
  • Figure 364 DNA304489, NP_003495.1, 204126-s.at
  • Figure 416 DNA331095, NP-.005216.1, 204947 -at
  • Figure 366 DNA330037, BC000149, 204127-at Figure 418: DNA325061, NP-.005208.1, 205033-s-at Figure 419: PRO9980 205839-s-at
  • Figure 420 DNA328297, NP-477097.1, 205034-at Figure 475: PRO86408
  • Figure 421 PR059418
  • Figure 476 DNA327651, NP-.005612.1, 205863-at
  • Figure 423 PR081585
  • Figure 478 DNA331320, HSU37122, 205882-x-at
  • Figure 424 DNA331314, NP-.055366.1, 205086-s-at Figure 479: PRO86409
  • Figure 425 PRO86406
  • Figure 480 DNA287318, NP-.002683.1, 205909-at
  • Figure 426 DNA330074, HUMHM145, 205098-at Figure 481: PR069583
  • Figure 428 DNA226177, NP-.001286.1, 205099-s.at Figure 483: PR084793
  • Figure 429 PRO36640
  • Figure 484 DNA329168, CLC, 206207 -at
  • Figure 430 DNA192060, NP-.002974.1, 205114-s_at Figure 485 : PR084794
  • Figure 431 PRO21960 Figure 486: DNA281446, NP-.031394.1, 206220-s-at
  • Figure 433 PRO62760 Figure 488: DNA331321, NP-.057473.1, 206245-s-at
  • Figure 435 PR061515 Figure 490A-B: DNA331322, NP.055523.1,
  • Figure 436 DNA227081, NP-.000390.2, 205249_at 206316-S-at
  • Figure 438A-B DNA188301, NP-.002300.1, 205266_at
  • Figure 492 DNA218278, NP-.000408.1, 206341-at
  • Figure 440A-B DNA331315, LRP8, 205282-at
  • Figure 494 DNA329169, NP-.002986.1, 206366-x.at
  • Figure 442 DNA227173, NP-.001456.1, 205285-s_at Figure 496A-B: DNA225567, NP-004659.1, 206522 ⁇ at
  • Figure 444A-B DNA331316, 983055.1, 205296-at
  • Figure 498 DNA227540, NP-.003036.1, 206566_at
  • Figure 446 DNA325568, NP-.001265.1, 205393 -s-at
  • Figure 500 DNA329171, NP-.060246.1, 206583-at
  • Figure 448 DNA325568, CHEK1, 205394_at
  • Figure 502 DNA88374, NP.002095.1, 206666-at
  • Figure 450 DNA328566, NP-.060446.1, 205510-s-at
  • Figure 504 DNA330105, HUMNCAX, 206676_at
  • Figure 452 DNA330085, D86324, 205518-s-at
  • Figure 506 DNA328590, C6orf32, 206707-x-at
  • Figure 454 DNA330086, NP-.079184.1, 205519-at
  • Figure 508 DNA325853, NP-.075387.1, 206958-s-at
  • Figure 456 DNA254810, NP-.056536.1, 205527-s-at
  • Figure 510 DNA35629, NP-.000586.2, 206975-at
  • Figure 458 DNA328567, NP.006797.2, 205548-s-at
  • Figure 512 DNA188346, NP-.001450.1, 206980-s-at
  • Figure 460 DNA329013, NP-.005649.1, 205599-at Figure 514A-B: DNA227659, NP-.000570.1,
  • Figure 461 PRO20128 206991-s.at
  • Figure 462 DNA330088, NP-.003087.1, 205644-s-at Figure 515: PR038122
  • Figure 463 PR061962
  • Figure 516A-B DNA227750, NP-001550.1, 206999_at
  • Figure 465 PRO 12507 Figure 518: DNA188289, NP-.001548.1, 207008-at
  • Figure 468 DNA331318, SLC27A2, 205769Jit Figure 521: PRO51038
  • Figure 469 PR051139
  • Figure 522 DNA227481, VAMP1, 207100-s_at
  • Figure 471 PR02541
  • Figure 524 DNA218655, NP-.000585.1, 207113-s-at
  • Figure 473 PRO24046 Figure 526A-B: DNA327674, NP.002739.1,
  • Figure 474A-B DNA331319, NP..004749.1, 207121-s.at Figure 527: PR083661
  • Figure 582 PR085399
  • Figure 528 DNA331323, NP.001250.1, 207143_at
  • Figure 583 DNA327696, AF228339, 208763 -s-at
  • Figure 530 DNA83048, NP-.001916.1, 207269 -at
  • Figure 585 DNA238565, NP-005907.2, 208795-s-at
  • Figure 532 DNA331324, LTB, 207339-s-at
  • Figure 587 DNA330145, NP-.002788.1, 208799-at
  • Figure 534 DNA226396, NP-.002180.1, 207375-s_at Figure 589: DNA273521, NP-.002070.1, 208813-at
  • Figure 536 DNA329178, BTN3A1, 207485-x-at
  • Figure 591 DNA227874, NP-.003320.1, 208864-s-at
  • Figure 538 DNA304473, NP-.001552.2, 207536-s_at
  • Figure 593 DNA328624, BC003562, 208891-at
  • Figure 540A-B DNA330120, FLJ10971, 207606-s.at
  • Figure 595 DNA331329, DUSP6, 208892-s_at
  • Figure 542 DNA227606, NP-.001872.2, 207630-s-at
  • Figure 597 DNA331330, BC005047, 208893-s-at
  • Figure 546 DNA256401, NP-.004063.1, 207652-s_at
  • Figure 601 DNA226500, NP-.005619.1, 208916-at
  • Figure 548 DNA328763, NP_001219.2, 207686-s-at Figure 603: DNA329552, NP.063948.1, 208925 -at
  • Figure 550 DNA325654, NP-.054752.1, 207761-s-at
  • Figure 605 DNA328629, NP-.006079.1, 208977-x-at
  • Figure 552 DNA329184, CITED2, 207980-s_at Figure 607: DNA330154, HUMPECAM27, 208981-at
  • Figure 553 PRO84807
  • Figure 608 DNA330155, 7692317.2, 208982-at
  • Figure 555 PR037687
  • Figure 610 DNA328631, AK027318, 209006-s-at
  • Figure 556 DNA328610, NP-.112601.2, 208146-s-at Figure 611: PRO84409
  • Figure 560 DNA328611, RASGRP2, 208206-s-at Figure 614: PR084413
  • Figure 561 PR084393
  • Figure 615 DNA274202, NP.006804.1, 209034-at
  • Figure 563 DNA103427, NP-.005239.1, 208438-s-at
  • Figure 617A-C DNA328637, HSA7042, 209053-s_at
  • Figure 565A-C DNA331326, ATM, 208442-s_at
  • Figure 619 DNA327713, BC010653, 209146_at
  • Figure 567 DNA331327, NP_036382.2, 208456-s-at
  • Figure 621A-B DNA328642, AF073310, 209184-s.at
  • Figure 569 DNA331328, NP-.000690.1, 208498-s_at
  • Figure 623 DNA331331, AF161416, 209185-s.at
  • Figure 570 PR02157 Figure 624A-B: DNA328643, HUMHK1A, 209186-at
  • Figure 575 DNA330139, AK022493, 208657-s-at
  • Figure 630 DNA326267, NP-.004861.1, 209208-at
  • Figure 577 DNA304686, NP-002565.1, 208680-at
  • Figure 632 DNA328645, NP-.009006.1, 209216_at
  • Figure 579 DNA287189, NP-.002038.1, 208693-s.at
  • Figure 634 DNA227483, NP.003120.1, 209218-at
  • Figure 638A-B DNA331333, 371440.32, 209240-at
  • Figure 693 DNA330203, NP.003755.1, 210190-at
  • Figure 640 DNA328649, NP.l 16093.1, 209251-x_at
  • Figure 695 DNA331335, AF070576, 210202-s.at
  • Figure 641 PR084424
  • Figure 696 DNA217253, NP.000749.1, 210229 -s.at
  • Figure 642 DNA255255, NP-071437.1, 209267-s.at Figure 697: PR034295
  • Figure 643 PRO50332 Figure 698: DNA328690, NP.524145.1, 210240-s-at
  • Figure 646 DNA269750, RGS16, 209325 -s.at Figure 701: PRO85450
  • Figure 650 DNA330170, AF109161, 209357-at Figure 705: PR086419
  • Figure 651 PRO84807
  • Figure 706 DNA329217, BC003406, 210571-s_at
  • Figure 655 PR081503
  • Figure 710 DNA331337, TNFSF11, 210643-at
  • Figure 656 DNA328663, NP.057157.1, 209524_at Figure 711: PRO206
  • Figure 660A-B DNA328670, BC001618, 209610-s-at Figure 715: PR051556
  • Figure 661 PRO70011
  • Figure 716 DNA331338, AF188298, 210757-x_at
  • Figure 665 PR085434
  • Figure 720A-B DNA330216, NP.006445.1
  • Figure 666 DNA330191, NP-.036249.1, 209715-at 210778-S-at
  • Figure 668 DNA329178, HSU90552, 209770_at
  • Figure 722 DNA188234, NP.000630.1, 210865-at
  • Figure 670 DNA329205, NP-.001343.1, 209782-s.at
  • Figure 724 DNA228132, LCE, 210868-s-at
  • Figure 672 DNA226436, NP-.001772.1, 209795-at
  • Figure 726 DNA238565, MCM7, 210983-s-at
  • Figure 674A-B DNA196499, AB002384, 209829-at
  • Figure 728 DNA326239, NP.006752.1, 210996-s-at
  • Figure 678 DNA331334, AF117233, 209845 ⁇ t
  • Figure 732 DNA288254, NP.006000.2, 211058-x-at
  • Figure 680 DNA273915, NP.036215.1, 209864-at
  • Figure 734 DNA288254, TUBA3, 211072-x-at
  • Figure 682 DNA330198, AB014719, 209871-s.at
  • Figure 736 DNA188234, TNFSF6, 211333-s.at
  • Figure 684 DNA154921, DNA154921, 209967 -s_at
  • Figure 738 DNA331339, B3GALT3, 211379-x-at
  • Figure 686 PR037597
  • Figure 740A-B DNA275066, NP-.000170.1
  • Figure 691A-B DNA328685, NP.127497.1
  • Figure 744 DNA226578, CCNG2, 211559-s_at
  • Figure 748 DNA327760, NP.114430.1, 211685-s.at Figure 802: PRO59330
  • Figure 750 DNA328706, BC021909, 211714-x-at Figure 804: PR083141
  • Figure 751 PRO10347
  • Figure 805 DNA331346, BC011685, 212330-at
  • Figure 752 DNA329225, EVI2B, 211742-s-at Figure 806: PR062868
  • Figure 754 DNA328649, TUBA6, 211750-x_at Figure 808: PR086425
  • Figure 755 PR084424 Figure 809A-B: DNA330216, MAD4, 212346-s.at
  • Figure 760 DNA227173, FYB, 211795-s-at 212406-S.at
  • Figure 762A-B DNA331342, DEFCAP, 211822-s-at
  • Figure 815 DNA330251, NP.059965.1, 212430-at
  • Figure 766 DNA226881,FLI1, 211825 -s.at
  • Figure 819A-B DNA328731, 234169.5, 212500-at
  • Figure 768 DNA226176, CXCR4, 211919-s_at
  • Figure 821 DNA328732, NP.116193.1, 212502-at
  • Figure 770 DNA272286, CAT, 211922-s-at
  • Figure 823 DNA226041, NP.005555.1, 212531-at
  • Figure 772A-B DNA325227, NP.005338.1, 211936-at
  • Figure 825 DNA269882, HSWEEIHU, 212533 -at
  • Figure 774A-B DNA329227, HSRANBP5, Figure 827 A-D: DNA328737, 148650.1, 212560-at
  • Figure 775 PRO82307
  • Figure 829 DNA275100, DNA275100, 212589-at
  • Figure 776A-C DNA331344, 1390535.1, 211986-at
  • Figure 830 DNA331349, BC013106, 212590_at
  • Figure 778 DNA287433, NP.006810.1, 212009 -s-at
  • Figure 832 DNA327776, 1379302.1, 212593-s-at
  • Figure 780 DNA330236, 228447.20, 212071-s_at
  • Figure 834 DNA151487, DNA151487, 212594-at
  • Figure 782A-B DNA150956, BAA06685.1, 212110_at
  • Figure 836 DNA287198, K-ALPHA-1, 212639-x-at
  • Figure 784 DNA330240, CAA52801.1, 212141-at
  • Figure 838 DNA328744, AF318364, 212680-x-at
  • Figure 786 DNA330240, HSP1CDC21, 212142-at Figure 840A-B: DNA331350, NP.060903.2,
  • Figure 787A-B DNA150829, AB014568, 212144-at 212689-s.at
  • Figure 791 PRO84805
  • Figure 844 DNA254940, BAA91770.1, 213008-at
  • Figure 793 DNA150980, DNA150980, 212281-s.at Figure 846A-B: DNA330275, BAA25487.1, 213045 -at
  • Figure 797 DNA328719, BC012895, 212295-s-at Figure 850A-B: DNA331352, BAA76818.1,
  • Figure 800 PR059425 Figure 852A-B: DNA331353, AB023191, 213092-x-at Figure 853A-C: DNA329244, 979567.11, 213106-at Figure 908: PR086436
  • Figure 854 PR084849
  • Figure 909 DNA326089, NP-.000508.1, 214414-x-at
  • Figure 856 PR084364
  • Figure 911 DNA271374, CHAF1A, 214426-x-at
  • Figure 858 PRO85506
  • Figure 913 DNA327811, SHMT2, 214437-s.at
  • Figure 860 PRO84850
  • Figure 915 DNA331363, AF001383, 214439-x-at
  • Figure 861A-B DNA331354, PPP2R5C, 213305-s-at Figure 916: PR086437
  • Figure 862 PRO86430 Figure 917: DNA150971, NP.002249.1, 214470-at
  • Figure 864A-B DNA331355, AAG24545.1, Figure 919: DNA331364, CREM, 214508-x_at
  • Figure 865 PR086431
  • Figure 921 DNA216515, NP.003166.1, 214567-s-at
  • Figure 869 DNA327795, BC014226, 213457-at
  • Figure 925 DNA330308, 307914.1, 215029-at
  • Figure 870 DNA328766, NP_006077.1, 213476-x_at Figure 926: PR085533
  • Figure 871 PR084514
  • Figure 927 DNA196372, HSBCLXL, 215037-s.at
  • Figure 872 DNA227483, SQLE, 213562-s.at Figure 928: PR024874
  • Figure 875 PR083763
  • Figure 931 DNA330314, 026641.5, 215275-at
  • Figure 879 DNA330293, BC011922, 213666-at Figure 935A-B: DNA331134, NP-003381.1,
  • Figure 880 PRO85520 215711-s.at
  • Figure 882 PR082188 Figure 937A-B: DNA256461, NP.009017.1,
  • Figure 883 DNA328629, TUBB2, 213726-x-at 216228-s.at
  • Figure 887 PRO12082
  • Figure 941 DNA88296, NP-.005733.1, 216640-s-at
  • Figure 888 DNA330295, NP.037515.1, 213951-s-at Figure 942: PR02274
  • Figure 891 PR086433
  • Figure 945A-B DNA66475, NP-.004439.1
  • Figure 892 DNA329136, HSPC111, 214011 -s-at 216836-s.at
  • Figure 896 PR037687
  • Figure 949 DNA331366, HUMGPCR, 217028-at
  • Figure 898 PR083772
  • Figure 951A-B DNA331367, BAA34514.1,
  • Figure 901A-B DNA331359, 332730.12, 214155-s_at
  • Figure 953 DNA331368, NP.112233.1, 217226-s-at
  • Figure 906 PR02398 Figure 958: DNA328303, NP.056525.1, 217807.s-at Figure 907 DNA331362, AF275719, 214359-s-at Figure 959: PR084173
  • Figure 960 DNA227172, NP-066952.1, 217848_s_at Figure 1014: PRO82602
  • Figure 961 PR037635
  • Figure 1015 DNA330381, NP-076958.1, 218741 -at
  • Figure 962 DNA330345, NP-055130.1, 217906-at Figure 1016: PR038668
  • Figure 966 DNA227218, RNASE6PL, 217984-at 218807 -at
  • Figure 968 DNA328831, NP.057329.1, 217989-at
  • Figure 1021 DNA330388, NP_078905.1, 218883-s-at
  • Figure 970 DNA328833, BC018929, 217996-at
  • Figure 1023 DNA331092, NP_078918.2, 218885_s_at
  • Figure 972 DNA328834, AF220656, 217997-at
  • Figure 1025 DNA226633, NP_060376.1, 218886-at
  • Figure 974 PRO61079 Figure 1027: DNA328881, NP_057706.2, 218890-x-at
  • Figure 980 PR085572
  • Figure 1033 DNA329050, NP_057053.1, 218982-s-at
  • Figure 982 PR083799
  • Figure 1035 DNA330391, NP-.076999.1, 219000-s-at
  • Figure 984 PRO83800 Figure 1037: DNA227187, NP.057703.1, 219014-at
  • Figure 986 PR084581
  • Figure 1039 DNA329293, NP-.057136.1, 219037-at
  • Figure 991 DNA331372, FLJ20950, 218298-s-at
  • Figure 1045 DNA329223, NP_037517.1, 219183-s-at
  • Figure 995 DNA328854, NP-056979.1, 218350-s-.at Figure 1049A-B: DNA331376, NP-.079484.1,
  • Figure 998 PR071044
  • Figure 1051 DNA287404, NP.073748.1, 219334-s-at
  • Figure 1000 PR084586
  • Figure 1053 DNA331377, NP_060753.1, 219347-at
  • Figure 1001 DNA327865, NP-.079105.1, 218454-at Figure 1054: PR086448
  • Figure 1002 PRO83806
  • Figure 1055 DNA254518, NP_057354.1, 219371 -_at
  • Figure 1003 DNA329286, NP-.005691.2, 218567 -x-at Figure 1056: PR049625
  • Figure 1004 PR069644
  • Figure 1057 DNA328902, NP-O71750.1, 219452-at
  • Figure 1005A-B DNA273435, NP_057532.1, Figure 1058: PR084623
  • Figure 1007 DNA330377, NP_036577.1, 218638-s_at Figure 1061A-B: DNA227179. NP-.059120.1,
  • Figure 1010 PR071242
  • Figure 1063 DNA329299, NP_004660.1, 219529-at
  • Figure 1012 PRO84880
  • Figure 1065 DNA330410, NP_060925.1, 219555-s-at
  • Figure 1013 DNA326185, FLJ13912, 218719-s_at Figure 1066: PR085618
  • Figure 067 DNA327891, NP-.078909.1, 219563-at Figure 21: PRO85036
  • Figure 068 PR083827
  • Figure 22A-B DNA329314, 1149046.7, 221478_at
  • Figure 070 PR086449
  • Figure 24 DNA227303, NP-.004322.1, 221479 -s-at
  • Figure 072 PRO50332
  • Figure 26 DNA326221. NP-.057179.1, 221521-s.at
  • Figure 076 PRO84640 Figure 30: DNA329318, IRO033793, 221564-at
  • Figure 081 DNA328924, NP-.057150.2, 219933-at Figure 35: DNA330459, NP.060083.1, 221677-s-at
  • Figure 083 DNA330537, NP-.060533.2, 220085-at
  • Figure 37 DNA328961, NP.443112.1, 221756-at
  • Figure 085 DNA227302, NP-.037401.1, 220132-s-at
  • Figure 39 DNA328961, MGC17330, 221757-at
  • Figure 089 DNA330436, NP-.037394.1, 220319-s-at
  • Figure 44 DNA330467, NP-060114.1, 221986-s.at
  • Figure 091 DNA327904, NP-.071419.2, 220330_s_at Figure 46: DNA254739, NP-.068766.1, 221987-s.at
  • Figure 093 DNA331379, PHEMX, 220558-x.at Figure 48: DNA257797, DNA257797, 222036-s_at
  • Figure 094 PRO86450 Figure 49: DNA257798, DNA257798, 222037-at
  • Figure 095 DNA330440, NP-.079098.1, 220591-S-at Figure 50: DNA325648, NP-037409.2, 222077-s-at
  • Figure 097 DNA255734, NP-.057607.1, 220646-s_at Figure 52A-B: DNA331385, AF274889S4,
  • Figure 099A-B DNA327908, MCM10, 220651-s.at Figure 53: DNA331386, HST000012, 222150-s-at
  • Figure 100 PR083843
  • Figure 54A-B DNA331387, NP-.008919.2,
  • Figure 104 DNA288247, NP-.478059.1, 220892-s-at Figure 1 58: DNA325821, BC014334, 222402-at
  • Figure 106 DNA331381, BA108L7.2, 220974-x-at Figure 1 60A-B: DNA256489, NP-079110.1,
  • Figure 109 PR069654 Figure 1 62: DNA304460. BC003048, 222500-at
  • Figure 110 DNA328945, NP_079177.2, 221081-s-at Figure 1 63: PR04984
  • Figure 111 PR084657
  • Figure 1 64 DNA327942, NP-.060596.1, 222642-s.at
  • Figure 112 DNA331382, CISH, 221223-x.at Figure 1 65: PRO83870
  • Figure 115 PR085652
  • Figure 1 68A-B DNA273435, RAMP, 222680-s-at
  • Figure 117 PR084659
  • Figure 1 70 DNA330486, HSM802473, 222692-s_at
  • Figure 118 DNA326507, NP-.112490.2, 221267 -s-at
  • Figure 1 71 DNA331388, NP-.068747.1, 222753.s_at
  • Figure 120 DNA329471, NP-.110387.1, 221417-X Jit Figure 1 73: DNA329335, AK023411, 222843-at Figure 74: PR084919 Figure 1228: PR086458 Figure 75: DNA331389, NP-.071428.2, 222848_at Figure 1229: DNA330552, BC001104, 223984-s-at Figure 76: PR081238 Figure 1230: PR085736 Figure 77: DNA287404, FLJ22833, 222872-x_at Figure 1231: DNA330558, NP.057588.1, 224330-s-at Figure 78: PR069661 Figure 1232: PRO84950 Figure 79: DNA330500, AK022872, 222889 -at Figure 1233: DNA328323, NP-.114148.2, 224428-s-at Figure 80: PR085693 Figure 1234: PR069531 Figure 81A-B: DNA287236, AB024334, 222985
  • Figure 202 PRO52040 Figure 1256: PR023259 Figure 203A-B: DNA257461, MAIL, 223218-s_at Figure 1257A-C: DNA329379, 010205.2, 224847 -at Figure 204: PRO52040 Figure 1258: PR084957 Figure 205: DNA326056, NP-.072088.1, 223264-at Figure 1259: DNA257789, NP-.116219.1, 224903-at Figure 206: PR082491 Figure 1260: PR052338 Figure 207: DNA330518, BC002493, 223274-at Figure 1261: DNA151170, DNA151170, 224989 Jit Figure 208: PRO85708 Figure 1262: PR012626 Figure 209: DNA329355, NP-.150596.1, 223299 Jit Figure 1263A-B: DNA327993, 898436.7, 225133-at Figure 210: PRO50434 Figure 1264: PR081138 Figure 211: DNA227
  • Figure 214 PR049998 Figure 1269: PR084972
  • Figure 215 DNA329456, NP-.057126.1, 223490-s-at Figure 1270: DNA304802, AAH00967.1, 225439-at Figure 216: PRO85023
  • Figure 1271 PR071212 Figure 217: DNA330536, NP_115666.1, 223542-at Figure 1272A-B: DNA330617, 336147.2, 225447 -at Figure 218: PR085722 Figure 1273: PR059923 Figure 219: DNA330537, AF155827, 223556-at Figure 1274: DNA196561.
  • Figure 1283 DNA329406, 1503139.10, 225562j ⁇ t
  • Figure 1336 DNA257914, DNA257914, 226743-at
  • Figure 1285 DNA304469, NP_149078.1, 225621 Jit Figure 1338: DNA328038, 216863.2, 226811 -at
  • Figure 1287 DNA331399, 994419.37, 225622-at
  • Figure 1340 DNA328044, 039170.3, 226936-at
  • Figure 1289A-B DNA331400, NP_060910.2, Figure 1342A-B: DNA330705, 198782.1, 227020-at
  • Figure 1290 PR086464 Figure 1344A-B: DNA330706, AF445027, 227027-at
  • Figure 1292 PR02679
  • Figure 1346 DNA331411, 232146.1, 227200 Jit
  • Figure 1295A-B DNA331401, 336865.4, 225700 -at
  • Figure 1350 DNA331412, 1378353.1, 227223-at
  • Figure 1297 DNA304821, BC011254, 225706-at Figure 1352A-B: DNA329442, AH007300S2,
  • Figure 1300 DNA330633, BC003515, 225723 -at Figure 1354: PRO85012
  • Figure 1301 DNA329417, 411336.1, 225842 _at
  • Figure 1355 DNA330718, 025465.3, 227295 -at
  • Figure 1303A-B DNA331402, 197159.1, 225845 Jit Figure 1357A-B: DNA330721, 198680.1, 227350-at
  • Figure 1305 DNA287370, BAB14983.1, 225866J « Figure 1359: DNA226872, NP_001955.1, 227404_s_at
  • Figure 1307A-B DNA331403, TP53INP1, 225912-at
  • Figure 1361 DNA329450, BC017226, 227726_at
  • Figure 1308 PR086467
  • Figure 1362 PRO85018
  • Figure 1309A-B DNA331405, 979005.2, 225956-at
  • Figure 1363 DNA59606, DNA59606, 227803-at
  • Figure 1311 DNA328021, BC004538, 226038-at
  • Figure 1365 DNA329456, RRP40, 227916-x-at
  • Figure 1312A-B DNA329428, 1446144.8, 226218 Jit Figure 1366: PRO85023
  • Figure 1313 PR084999
  • Figure 1367 DNA330745, BC011716, 228069-at
  • Figure 1315 PR023314
  • Figure 1369 DNA329460, BC017117, 228092-at
  • Figure 1316 DNA328028, NP.005773.1, 226319-s-at Figure 1370: PRO85027
  • Figure 1317 PR083945
  • Figure 1371 DNA330436, AF187016, 228098-s.at
  • Figure 1320A-B DNA331406, 399773.27, Figure 1374: PRO85028
  • Figure 1322A-B DNA331407, 198233.1, 226352-at
  • Figure 1377 DNA331414, 1450017.11, 228559-at
  • Figure 1324A-B DNA331409, AB051464, 226370-at
  • Figure 1379 DNA331415, 345279.19, 228788-at
  • Figure 1325A-B DNA330675, 177663.2, 226372-at Figure 1380: PR086479
  • Figure 1326 PR085847
  • Figure 1381 DNA330780, 335374.1, 228955j ⁇ t
  • Figure 1329 DNA331410, HSM802051, 226416-at Figure 1384: PR085948
  • Figure 1331 DNA330679, BC013040, 226456-at Figure 1386: PR085951
  • Figure 1332A-B DNA330680, BC022792, 226481 -at
  • Figure 1387 DNA327307, AF442769, 229215-at
  • Figure 1334 DNA330684, 984114.1, 226548-at Figure 1389: DNA287421, 234832.1, 229437-at Figure 1390: PR069678
  • Figure 1391 DNA330799, 481875.1, 229551-x-at
  • Figure 1435A-C DNA331425, 228001.3, 235116 -at
  • Figure 1393A-B DNA330809, 336997.1, 229844-at Figure 1437: DNA328146, BC019239, 235117 Jit
  • Figure 1397A-B DNA331416, FREQ, 230146-s-at
  • Figure 1441 DNA194081, DNA194081, 235556_at
  • FIG. 1400 PRO88 Figure 1444: PRO86077
  • Figure 1401 DNA330818, 212282.1, 230304-at
  • Figure 1445 DNA330943, 1042935.2, 237009 -at
  • Figure 1403 DNA257756, DNA257756, 230405 -at
  • Figure 1447 DNA331426, 361450.1, 237542-at
  • Figure 1405 PRO85036 Figure 1449: DNA331427, AB052906, 238542-at
  • Figure 1407 PRO86480 Figure 1451: DNA258952, DNA258952, 239901 -at
  • Figure 1408 DNA331418, 7693630.2, 230917-at
  • Figure 1452 DNA328206, 1384214.3, 240277-at
  • Figure 1410A-B DNA287217, DNA287217, Figure 1454: DNA331428, 7692702.1, 241803-s-at
  • Figure 1411 PR036766
  • Figure 1456 DNA329506, NP-387510.1, 241937-s-at
  • Figure 1412 DNA330843, 201388.1, 231832-at Figure 1457: PRO85067
  • Figure 1413 PRO86006
  • Figure 1458 DNA331429, NP-.110403.1, 242020-s-at
  • Figure 1415 PR086482
  • Figure 1460 DNA331030, 407930.2, 242648-at
  • Figure 1416 DNA331420, 029520.1, 232210-at Figure 1461: PR086188
  • Figure 1417 PR086483
  • Figure 1462 DNA331037, 206873.1, 242890 it
  • Figure 1420 DNA328194, 998827.1, 233068-at Figure 1465: PRO85068
  • Figure 1421 PRO84097
  • Figure 1466 DNA331043, 005042.1, 243134-at
  • Figure 1423 PR069661
  • Figure 1468 DNA331053, 243689.1, 243509-at
  • Figure 1425 PR086485
  • Figure 1470 DNA331430, 030957.1, 243808 Jit
  • Figure 1426 DNA331423, AF176071, 233467-s -at Figure 1471: PRO86490
  • Figure 1429 DNA331424, LOCI 12840, 235025 -at
  • Figure 1474 DNA331432, 151634.1, 244035 -at
  • Figure 1431 DNA330888, 7687712.2, 235088j ⁇ t
  • Figure 1476 DNA331433, 020071.1, 244434-at
  • Figure 1432 PR069581 Figure 1477: PR086493
  • Figure 1433 DNA330891, AK027315, 235113 Jit DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS I. Definitions
  • PRO polypeptide and PRO as used herein and when immediately followed by a numerical designation refer to various polypeptides, wherein the complete designation (i.e., PRO/number) refers to specific polypeptide sequences as described herein.
  • the 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.
  • PRO polypeptide refers to each individual PRO/number polypeptide disclosed herein.
  • PRO polypeptide refers 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 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.
  • PRO polypeptide disclosed in the accompanying figures are shown to begin with methionine residues designated herein as amino acid position 1 in the figures, it is conceivable and possible that other methionine residues located either upstream or downstream from the amino acid position 1 in the figures may be employed as the starting amino acid residue for the PRO polypeptides.
  • the PRO polypeptide "extracellular domain" or “ECD” refers to a form of the PRO polypeptide which is essentially free of the transmembrane and cytoplasmic domains. Ordinarily, a PRO polypeptide ECD will have less than 1% of such transmembrane and/or cytoplasmic domains and preferably, will have less than 0.5% of such domains.
  • transmembrane domains identified for the PRO polypeptides of the present invention are identified pursuant to criteria routinely employed in the art for identifying that type of hydrophobic domain.
  • the exact boundaries of a transmembrane domain may vary but most likely by no more than about 5 amino acids at either end of the domain as initially identified herein.
  • an extracellular domain of a PRO polypeptide may contain from about 5 or fewer amino acids on either side of the transmembrane domain/extracellular domain boundary as identified in the Examples or specification and such polypeptides, with or without the associated signal peptide, and nucleic acid encoding them, are contemplated by the present invention.
  • cleavage of a signal sequence from a secreted polypeptide is not entirely uniform, resulting in more than one secreted species.
  • These mature polypeptides, where the signal peptide is cleaved within no more than about 5 amino acids on either side of the C-terminal boundary of the signal peptide as identified herein, and the polynucleotides encoding them, are contemplated by the present invention.
  • PRO polypeptide variant means an active PRO polypeptide as defined above or below having at least about 80% amino acid sequence identity with a full-length native sequence PRO polypeptide sequence as disclosed herein, a PRO polypeptide sequence lacking the signal peptide as disclosed herein, an extracellular domain of a PRO polypeptide, with or without the signal peptide, as disclosed herein or any other fragment of a full-length PRO polypeptide sequence as disclosed herein.
  • Such PRO polypeptide variants include, for instance, PRO polypeptides wherein one or more amino acid residues are added, or deleted, at the N- or C-terminus of the full-length native amino acid sequence.
  • a PRO polypeptide variant will have at least about 80% amino acid sequence identity, 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% 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, alternatively at least about 89% amino acid sequence identity, alternatively at least about 90% amino acid sequence identity, alternatively at least about 91% amino acid sequence identity, alternatively at least about 92% amino acid sequence identity, alternatively at least about 93% amino acid sequence identity, alternatively at least about 94% amino acid sequence identity, alternatively at least about 95% amino acid sequence identity, alternatively at least about 96% amino acid sequence identity, alternatively at least about 97% amino acid sequence identity, alternatively at least about 98% amino acid sequence identity and alternatively at least about 99% amino acid sequence identity to a full-length
  • PRO variant polypeptides are at least about 10 amino acids in length, alternatively at least about 20 amino acids in length, alternatively at least about 30 amino acids in length, alternatively at least about 40 amino acids in length, alternatively at least about 50 amino acids in length, alternatively at least about 60 amino acids in length, alternatively at least about 70 amino acids in length, alternatively at least about 80 amino acids in length, alternatively at least about 90 amino acids in length, alternatively at least about 100 amino acids in length, alternatively at least about 150 amino acids in length, alternatively at least about 200 amino acids in length, alternatively at least about 300 amino acids in length, or more.
  • Percent (%) amino acid sequence identity with respect to the PRO polypeptide sequences identified herein is defined as the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the specific PRO polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared.
  • % amino acid sequence identity values are generated using the sequence comparison computer program ALIGN-2, wherein the complete source code for the ALIGN-2 program is provided in Table 1 below.
  • the ALIGN-2 sequence comparison computer program was authored by Genentech, Inc. and the source code shown in Table 1 below has been filed with user documentation in the U.S. Copyright Office, Washington D.C., 20559, where it is registered under U.S. Copyright Registration No. TXU510087.
  • the ALIGN-2 program is publicly available through Genentech, Inc., South San Francisco, California or may be compiled from the source code provided in Table 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.
  • % amino acid sequence identity of a given amino acid sequence A to, with, or against a given amino acid sequence B is calculated as follows:
  • Tables 2 and 3 demonstrate how to calculate the % amino acid sequence identity of the amino acid sequence designated "Comparison Protein” to the amino acid sequence designated "PRO", wherein “PRO” represents the amino acid sequence of a hypothetical PRO polypeptide of interest, “Comparison Protein” represents the amino acid sequence of a polypeptide against which the "PRO” polypeptide of interest is being compared, and "X, "Y” and “Z” each represent different hypothetical amino acid residues.
  • a % amino acid sequence identity value is determined by dividing (a) the number of matching identical amino acid residues between the amino acid sequence of the PRO polypeptide of interest having a sequence derived from the native PRO polypeptide and the comparison amino acid sequence of interest (i.e., the sequence against which the PRO polypeptide of interest is being compared which may be a PRO variant polypeptide) as determined by WU-BLAST-2 by (b) the total number of amino acid residues of the PRO polypeptide of interest.
  • amino acid sequence A is the comparison amino acid sequence of interest and the amino acid sequence B is the amino acid sequence of the PRO polypeptide of interest.
  • Percent amino acid sequence identity may also be determined using the sequence comparison program NCBI-BLAST2 (Altschul et al., Nucleic Acids Res. 25:3389-3402 (1997)).
  • NCBI-BLAST2 sequence comparison program may be downloaded from http://www.ncbi.nlm.nih.gov or otherwise obtained from the National Institute of Health, Bethesda, MD.
  • % amino acid sequence identity of a given amino acid sequence A to, with, or against a given amino acid sequence B is calculated as follows:
  • PRO variant polynucleotide or "PRO variant nucleic acid sequence” means a nucleic acid molecule which encodes an active PRO polypeptide as defined below and which has at least about 80% nucleic acid sequence identity with a nucleotide acid sequence encoding a full-length native sequence PRO polypeptide sequence as disclosed herein, a full-length native sequence PRO polypeptide sequence lacking the signal peptide as disclosed herein, an extracellular domain of a PRO polypeptide, with or without the signal peptide, as disclosed herein or any other fragment of a full-length PRO polypeptide sequence as disclosed herein.
  • a PRO variant polynucleotide will have at least about 80% nucleic acid sequence identity, 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 96% nucleic acid sequence identity, alternatively at least about 9
  • PRO variant polynucleotides are at least about 30 nucleotides in length, alternatively at least about 60 nucleotides in length, alternatively at least about 90 nucleotides in length, alternatively at least about 120 nucleotides in length, alternatively at least about 150 nucleotides in length, alternatively at least about 180 nucleotides in length, alternatively at least about 210 nucleotides in length, alternatively at least about 240 nucleotides in length, alternatively at least about 270 nucleotides in length, alternatively at least about 300 nucleotides in length, alternatively at least about 450 nucleotides in length, alternatively at least about 600 nucleotides in length, alternatively at least about 900 nucleotides in length, or more.
  • Percent (%) nucleic acid sequence identity with respect to PRO-encoding nucleic acid sequences identified herein is defined as the percentage of nucleotides in a candidate sequence that are identical with the nucleotides in the PRO nucleic acid sequence of interest, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity. Alignment for purposes of determining percent nucleic acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software.
  • % nucleic acid sequence identity values are generated using the sequence comparison computer program ALIGN-2, wherein the complete source code for the ALIGN-2 program is provided in Table 1 below.
  • the ALIGN-2 sequence comparison computer program was authored by Genentech, Inc. and the source code shown in Table 1 below has been filed with user documentation in the U.S. Copyright Office, Washington D.C., 20559, where it is registered under U.S. Copyright Registration No. TXU510087.
  • the ALIGN-2 program is publicly available through Genentech, Inc., South San Francisco, California or may be compiled from the source code provided in Table 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 % nucleic acid sequence identity of a given nucleic acid sequence C to, with, or against a given nucleic acid sequence D is calculated as follows:
  • Tables 4 and 5 demonstrate how to calculate the % nucleic acid sequence identity of the nucleic acid sequence designated "Comparison DNA” to the nucleic acid sequence designated "PRO-DNA”, wherein "PRO-DNA” represents a hypothetical PRO-encoding nucleic acid sequence of interest, “Comparison DNA” represents the nucleotide sequence of a nucleic acid molecule against which the "PRO-DNA” nucleic acid molecule of interest is being compared, and "N", “L” and “V” each represent different hypothetical nucleotides.
  • a % nucleic acid sequence identity value is determined by dividing (a) the number of matching identical nucleotides between the nucleic acid sequence of the PRO polypeptide-encoding nucleic acid molecule of interest having a sequence derived from the native sequence PRO polypeptide-encoding nucleic acid and the comparison nucleic acid molecule of interest (i.e., the sequence against which the PRO polypeptide-encoding nucleic acid molecule of interest is being compared which may be a variant PRO polynucleotide) as determined by WU-BLAST-2 by (b) the total number of nucleotides of the PRO polypeptide-encoding nucleic acid molecule of interest.
  • nucleic acid sequence A is the comparison nucleic acid molecule of interest and the nucleic acid sequence B is the nucleic acid sequence of the PRO polypeptide-encoding nucleic acid molecule of interest.
  • Percent nucleic acid sequence identity may also be determined using the sequence comparison program NCBI-BLAST2 (Altschul et al., Nucleic Acids Res. 25:3389-3402 (1997)).
  • NCBI-BLAST2 sequence comparison program may be downloaded from http://www.ncbi.nlm.nih.gov or otherwise obtained from the National Institute of Health, Bethesda, MD.
  • % nucleic acid sequence identity of a given nucleic acid sequence C 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 polypeptide and which are capable of hybridizing, preferably under stringent hybridization and wash conditions, to nucleotide sequences encoding a full-length PRO polypeptide as disclosed herein.
  • PRO variant polypeptides may be those that are encoded by a PRO variant polynucleotide.
  • 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-terminal or internal amino acid sequence by use of a spinning cup sequenator, or (2) to homogeneity by SDS-PAGE under non-reducing or reducing conditions using Coomassie blue or, preferably, silver stain.
  • Isolated polypeptide includes polypeptide in 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 from at least one contaminant nucleic acid molecule with which it is ordinarily associated in the natural source of the polypeptide-encoding nucleic acid.
  • An isolated polypeptide-encoding 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 ordinarily express the polypeptide where, for example, the nucleic acid molecule is in a chromosomal location different from that of natural cells.
  • control sequences refers to DNA sequences necessary for the expression of an operably linked coding sequence in a particular host organism.
  • the control sequences that are suitable for prokaryotes include a promoter, optionally an operator sequence, and a ribosome binding site.
  • Eukaryotic cells are known to utilize promoters, polyadenylation signals, and enhancers.
  • Nucleic acid is "operably linked” when it is placed into a functional relationship with another nucleic acid sequence.
  • DNA for a presequence or secretory leader is operably linked to DNA for a polypeptide if it is expressed as a preprotein that participates in the secretion of the polypeptide; a promoter or enhancer is operably linked to a coding sequence if it affects the transcription of the sequence; or a ribosome binding site is operably linked to a coding sequence if it is positioned so as to facilitate translation.
  • "operably linked" means that the DNA sequences being linked are contiguous, and, in the case of a secretory leader, contiguous and in reading phase. However, enhancers do not have to be contiguous. Linking is accomplished by ligation at convenient restriction sites. If such sites do not exist, the synthetic oligonucleotide adaptors or linkers are used in accordance with conventional practice.
  • antibody is used in the broadest sense and specifically covers, for example, single anti-
  • PRO monoclonal antibodies including agonist, antagonist, and neutralizing antibodies
  • anti-PRO antibody compositions with polyepitopic specificity single chain anti-PRO antibodies
  • 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.
  • “Stringency” of hybridization reactions is readily determinable by one of ordinary skill in the art, and generally is an empirical calculation dependent upon probe length, washing temperature, and salt concentration. In general, longer probes require higher temperatures for proper annealing, while shorter probes need lower temperatures. Hybridization generally depends on the ability of denatured DNA to reanneal when complementary strands are present in an environment below their melting temperature. The higher the degree of desired homology between the probe and hybridizable sequence, the higher the relative temperature which can be used. As a result, it follows that higher relative temperatures would tend to make the reaction conditions more stringent, while lower temperatures less so. For additional details and explanation of stringency of hybridization reactions, see Ausubel et al., Current Protocols in Molecular Biology. Wiley Interscience Publishers, (1995).
  • “Stringent conditions” or “high stringency conditions”, as defined herein, may be identified by those that: (1) employ low ionic strength and high temperature for washing, for example 0.015 M sodium chloride/0.0015 M sodium citrate/0.1% sodium dodecyl sulfate at 50°C; (2) employ during hybridization a denaturing agent, such as formamide, for example, 50% (v/v) formamide with 0.1% bovine serum albumin/0.1% Ficoll/0.1% polyvinylpyrrolidone/50mM sodium phosphate buffer at pH 6.5 with 750 mM sodium chloride, 75 mM sodium citrate at 42°C; or (3) employ 50% formamide, 5 x SSC (0.75 M NaCl, 0.075 M sodium citrate), 50 mM sodium phosphate (pH 6.8), 0.1% sodium pyrophosphate, 5 x Denhardt's solution, sonicated salmon sperm DNA (50 ⁇ g/ml), 0.1% SDS, and 10% dextran sul
  • Modely stringent conditions may be identified as described by Sambrook et al., Molecular Cloning: A Laboratory Manual. New York: Cold Spring Harbor Press, 1989, and include the use of washing solution and hybridization conditions (e.g., temperature, ionic strength and %SDS) less stringent that those described above.
  • washing solution and hybridization conditions e.g., temperature, ionic strength and %SDS
  • moderately stringent conditions is overnight incubation at 37 C C in a solution comprising: 20% formamide, 5 x SSC (150 mM NaCl, 15 mM trisodium citrate), 50 mM sodium phosphate (pH 7.6), 5 x Denhardt's solution, 10% dextran sulfate, and 20 mg/ml denatured sheared salmon sperm DNA, followed by washing the filters in 1 x SSC at about 37-50°C.
  • the skilled artisan will recognize how to adjust the temperature, ionic strength, etc. as necessary to accommodate factors such as probe length and the like.
  • epitope tagged when used herein refers to a chimeric polypeptide comprising a PRO polypeptide fused to a "tag polypeptide".
  • the tag polypeptide has enough residues to provide an epitope against which an antibody can be made, yet is short enough such that it does not interfere with activity of the polypeptide to which it is fused.
  • the tag polypeptide preferably also is fairly unique so that the antibody does not substantially cross-react with other epitopes.
  • Suitable tag polypeptides generally have at least six amino acid residues and usually between about 8 and 50 amino acid residues (preferably, between about 10 and 20 amino acid residues).
  • immunoadhesin designates antibody-like molecules which combine the binding specificity of a heterologous protein (an “adhesin”) with the effector functions of immunoglobulin constant domains.
  • the immunoadhesins comprise a fusion of an amino acid sequence with the desired binding specificity which is other than the antigen recognition and binding site of an antibody (i.e., is “heterologous"), and an immunoglobulin constant domain sequence.
  • the adhesin part of an immunoadhesin molecule typically is a contiguous amino acid sequence comprising at least the binding site of a receptor or a ligand.
  • the immunoglobulin constant domain sequence in the immunoadhesin may be obtained from any immunoglobulin, such as IgG-1, IgG-2, IgG-3, or IgG-4 subtypes, IgA (including IgA-1 and IgA-2), IgE, IgD or IgM.
  • immunoglobulin such as IgG-1, IgG-2, IgG-3, or IgG-4 subtypes, IgA (including IgA-1 and IgA-2), IgE, IgD or IgM.
  • Active or “activity” for the purposes herein refers to form(s) of a PRO polypeptide which retain a biological and/or an immunological activity of native or naturally-occurring PRO, wherein "biological” activity refers to a biological function (either inhibitory or stimulatory) caused by a native or naturally- occurring PRO other than the ability to induce the production of an antibody against an antigenic epitope possessed by a native or naturally-occurring PRO and an “immunological” activity refers to the ability to induce the production of an antibody against an antigenic epitope possessed by a native or naturally- occurring PRO.
  • antagonist is used in the broadest sense, and includes any molecule that partially or fully blocks, inhibits, or neutralizes a biological activity of a native PRO polypeptide disclosed herein.
  • agonist is used in the broadest sense and includes any molecule that mimics a biological activity of a native PRO polypeptide disclosed herein.
  • Suitable agonist or antagonist molecules specifically include agonist or antagonist antibodies or antibody fragments, fragments or amino acid sequence variants of native PRO polypeptides, peptides, antisense oligonucleotides, small organic molecules, etc.
  • Methods for identifying agonists or antagonists of a PRO polypeptide may comprise contacting a PRO polypeptide with a candidate agonist or antagonist molecule and measuring a detectable change in one or more biological activities normally associated with the PRO polypeptide.
  • Treatment refers to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) the targeted pathologic condition or disorder.
  • Those in need of treatment include those already with the disorder as well as those prone to have the disorder or those in whom the disorder is to be prevented.
  • Chronic administration refers to administration of the agent(s) in a continuous mode as opposed to an acute mode, so as to maintain the initial therapeutic effect (activity) for an extended period of time.
  • Intermittent administration is treatment that is not consecutively done without interruption, but rather is cyclic in nature.
  • “Mammal” for purposes of treatment refers to any animal classified as a mammal, including humans, domestic and farm animals, and zoo, sports, or pet animals, such as dogs, cats, cattle, horses, sheep, pigs, goats, rabbits, etc. Preferably, the mammal is human.
  • Administration "in combination with" one or more further therapeutic agents includes simultaneous
  • Carriers as used herein include pharmaceutically acceptable carriers, excipients, or stabilizers which are nontoxic to the cell or mammal being exposed thereto at the dosages and concentrations employed. Often the physiologically acceptable carrier is an aqueous pH buffered solution.
  • physiologically acceptable carriers include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid; low molecular weight (less than about 10 residues) polypeptide; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; and/or nonionic surfactants such as TWEENTM, polyethylene glycol (PEG), and PLURONICSTM.
  • buffers such as phosphate, citrate, and other organic acids
  • antioxidants including ascorbic acid
  • proteins such as serum albumin,
  • Antibody fragments comprise a portion of an intact antibody, preferably the antigen binding or variable region of the intact antibody.
  • antibody fragments include Fab, Fab', F(ab') 2 , and Fv fragments; diabodies; linear antibodies (Zapata et al., Protein Eng. 8(10): 1057-1062 [1995]); single-chain antibody molecules; and multispecific antibodies formed from antibody fragments.
  • Papain digestion of antibodies produces two identical antigen-binding fragments, called "Fab” fragments, each with a single antigen-binding site, and a residual "Fc” fragment, a designation reflecting the ability to crystallize readily.
  • Pepsin treatment yields an F(ab') 2 fragment that has two antigen-combining sites and is still capable of cross-linking antigen.
  • Fv is the minimum antibody fragment which contains a complete antigen-recognition and - binding site. This region consists of a dimer of one heavy- and one light-chain variable domain in tight, non- covalent association. It is in this configuration that the three CDRs of each variable domain interact to define an antigen-binding site on the surface of the V H -V L dimer.
  • the six CDRs confer antigen- binding specificity to the antibody.
  • a single variable domain or half of an Fv comprising only three CDRs specific for an antigen has the ability to recognize and bind antigen, although at a lower affinity than the entire binding site.
  • the Fab fragment also contains the constant domain of the light chain and the first constant domain (CHI) of the heavy chain.
  • Fab fragments differ from Fab' fragments by the addition of a few residues at the carboxy terminus of the heavy chain CHI domain including one or more cysteines from the antibody hinge region.
  • Fab'-SH is the designation herein for Fab' in which the cysteine residue(s) of the constant domains bear a free thiol group.
  • F(ab') 2 antibody fragments originally were produced as pairs of Fab' fragments which have hinge cysteines between them. Other chemical couplings of antibody fragments are also known.
  • the "light chains" of antibodies (immunoglobulins) from any vertebrate species can be assigned to one of two clearly distinct types, called kappa and lambda, based on the amino acid sequences of their constant domains.
  • immunoglobulins can be assigned to different classes. There are five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgGl, IgG2, IgG3, IgG4, IgA, and IgA2.
  • immunoglobulins There are five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgGl, IgG2, IgG3, IgG4, IgA, and IgA2.
  • Single-chain Fv or “sFv” antibody fragments comprise the 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.
  • a polypeptide linker between the V H and V L domains which enables the sFv to form the desired structure for antigen binding.
  • Diabodies are described more fully in, for example, EP 404,097; WO 93/11161; and Hollinger et al., Proc. Natl. Acad. Sci. USA. 90:6444-6448 (1993).
  • an “isolated” antibody is one which has been identified and separated and/or recovered from a component of its natural environment. Contaminant components of its natural environment are materials which would interfere with diagnostic or therapeutic uses for the antibody, and may include enzymes, hormones, and other proteinaceous or nonproteinaceous solutes.
  • the antibody will be purified (1) to greater than 95% by weight of antibody as determined by the Lowry method, and most preferably more than 99% by weight, (2) to a degree sufficient to obtain at least 15 residues of N-terminal or internal amino acid sequence by use of a spinning cup sequenator, or (3) to homogeneity by SDS-PAGE under reducing or nonreducing conditions using Coomassie blue or, preferably, silver stain.
  • Isolated antibody includes the antibody in situ within recombinant cells since at least one component of the antibody's natural environment will not be present. Ordinarily, however, isolated antibody will be prepared by at least one purification step.
  • an antibody that "specifically binds to” or is “specific for” a particular polypeptide or an epitope on a particular polypeptide is one that binds to that particular polypeptide or epitope on a particular polypeptide without substantially binding to any other polypeptide or polypeptide epitope.
  • label when used herein refers to a detectable compound or composition which is conjugated directly or indirectly to the antibody so as to generate a "labeled" antibody.
  • the label may be detectable by itself (e.g. radioisotope labels or fluorescent labels) or, in the case of an enzymatic label, may catalyze chemical alteration of a substrate compound or composition which is detectable.
  • solid phase is meant a non-aqueous matrix to which the antibody of the present invention can adhere.
  • solid phases encompassed herein include those formed partially or entirely of glass (e.g., controlled pore glass), polysaccharides (e.g., agarose), polyacrylamides, polystyrene, polyvinyl alcohol and silicones.
  • the solid phase can comprise the well of an assay plate; in others it is a purification column (e.g., an affinity chromatography column). This term also includes a discontinuous solid phase of discrete particles, such as those described in U.S. Patent No. 4,275,149.
  • a “liposome” is a small vesicle composed of various types of lipids, phospholipids and/or surfactant which is useful for delivery of a drug (such as a PRO polypeptide or antibody thereto) to a mammal.
  • 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.
  • 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, neoplasia, etc.
  • Natural Killer cell mediated disease means a disease in which NK cells directly or indirectly mediate or otherwise contribute to a morbidity in a mammal.
  • the NK cell mediated disease may be associated with cell mediated effects, lymphokine mediated effects, etc., and even effects associated with other immune cells if the cells are involved.
  • immune-related and inflammatory diseases examples include systemic lupus erythematosis, rheumatoid arthritis, juvenile chronic arthritis, spondyloarthropathies, systemic sclerosis (scleroderma), idiopathic inflammatory myopathies (dermatomyositis, polymyositis), Sj ⁇ gren's syndrome, systemic vasculitis, sarcoidosis, autoimmune hemolytic anemia (immune pancytopenia, paroxysmal nocturnal hemoglobinuria), autoimmune thrombocytopenia (idiopathic thrombocytopenic purpura, immune-mediated tlirombocytopenia), thyroiditis (Grave's disease, Hashimoto's thyroiditis, juvenile lymphocytic thyroiditis, atrophic thyroiditis), diabetes mellitus, immune-mediated renal disease (glomerulonephritis, tubulointerstitial
  • an “effective amount” is a concentration or amount of a PRO polypeptide and/or agonist/antagonist which results in achieving a particular stated purpose.
  • An “effective amount” of a PRO polypeptide or agonist or antagonist thereof may be determined empirically.
  • a “therapeutically effective amount” is a concentration or amount of a PRO polypeptide and/or agonist/antagonist which is effective for achieving a stated therapeutic effect. This amount may also be determined empirically.
  • 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., I 131 , I 125 , Y 90 and Re 186 ), chemotherapeutic agents, and toxins such as enzymatically active toxins of bacterial, fungal, plant or animal origin, or fragments thereof.
  • a "chemotherapeutic agent” is a chemical compound useful in the treatment of cancer.
  • chemotherapeutic agents include adriamycin, doxorubicin, epirubicin, 5-fluorouracil, cytosine arabinoside ("Ara-C"), cyclophosphamide, thiotepa, busulfan, cytoxin, taxoids, e.g., paclitaxel (Taxol, Bristol-Myers Squibb Oncology, Princeton, NJ), and doxetaxel (Taxotere, Rh ⁇ ne-Poulenc Rorer, Antony, France), toxotere, mefhotrexate, cisplatin, melphalan, vinblastine, bleomycin, etoposide, ifosfamide, mitomycin C, mitoxantrone, vincristine, vinorelbine, carboplatin, teniposide, daunomycin, carminomycin, aminopterin, dactinomycin, mitomycins,
  • a “growth inhibitory agent” when used herein refers to a compound or composition which inhibits growth of a cell, especially cancer cell overexpressing any of the genes identified herein, either in vitro or in vivo.
  • the growth inhibitory agent is one which significantly reduces the percentage of cells overexpressing such genes in S phase.
  • growth inhibitory agents include agents that block cell cycle progression (at a place other than S phase), such as agents that induce Gl arrest and M-phase arrest.
  • Classical M-phase blockers include the vincas (vincristine and vinblastine), taxol, and topo II inhibitors such as doxorubicin, epirubicin, daunorabicin, etoposide, and bleomycin.
  • DNA alkylating agents such as tamoxifen, prednisone, dacarbazine, mechlorethamine, cisplatin, methofrexate, 5-fluorouracil, and 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. 13.
  • cytokine is a generic term for proteins released by one cell population which act on another cell as intercellular mediators.
  • cytokines are lymphokines, monokines, and traditional polypeptide hormones. Included among the cytokines are growth hormone such as human growth hormone, N-methionyl human growth hormone, and bovine growth hormone; parathyroid hormone; thyroxine; insulin; proinsulin; relaxin; prorelaxin; glycoprotein hormones such as follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH), and luteinizing hormone (LH); hepatic growth factor; fibroblast growth factor; prolactin; placental lactogen; tumor necrosis factor- ⁇ and - ⁇ ; mullerian-inhibiting substance; mouse gonadotropin-associated peptide; inhibin; activin; vascular endothelial growth factor; integrin; thrombopoietin (TPO); nerve growth factors such as NGF- ⁇ ; platelet-growth factor;
  • immunoadhesin designates antibody-like molecules which combine the binding specificity of a heterologous protein (an “adhesin”) with the effector functions of immunoglobulin constant domains.
  • the immunoadhesins comprise a fusion of an amino acid sequence with the desired binding specificity which is other than the antigen recognition and binding site of an antibody ⁇ i.e., is “heterologous"), and an immunoglobulin constant domain sequence.
  • the adhesin part of an immunoadhesin molecule typically is a contiguous amino acid sequence comprising at least the binding site of a receptor or a ligand.
  • the immunoglobulin constant domain sequence in the immunoadhesin may be obtained from any immunoglobulin, such as IgG-1, IgG-2, IgG-3, or IgG-4 subtypes, IgA (including IgA-1 and IgA-2), IgE, IgD or IgM.
  • immunoglobulin such as IgG-1, IgG-2, IgG-3, or IgG-4 subtypes, IgA (including IgA-1 and IgA-2), IgE, IgD or IgM.
  • Needleman-Wunsch alignment program usage progs filel file2 where filel and file2 are two dna or two protein sequences. The sequences can be in upper- or lower-case an may contain ambiguity Any lines beginning with ';', '>' or ' ⁇ ' are ignored 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 Output is in the file "align.out"
  • the program may create a tmp file in /tmp to hold info about traceback.
  • *ps[i] toupper(*ps[i]); po[i]++; ps[i]++;

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