EP1259614A2 - Secreted and transmembrane polypeptides and nucleic acids encoding the same - Google Patents

Secreted and transmembrane polypeptides and nucleic acids encoding the same

Info

Publication number
EP1259614A2
EP1259614A2 EP01945919A EP01945919A EP1259614A2 EP 1259614 A2 EP1259614 A2 EP 1259614A2 EP 01945919 A EP01945919 A EP 01945919A EP 01945919 A EP01945919 A EP 01945919A EP 1259614 A2 EP1259614 A2 EP 1259614A2
Authority
EP
European Patent Office
Prior art keywords
seq
acid sequence
sequence
shows
amino acid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP01945919A
Other languages
German (de)
English (en)
French (fr)
Inventor
Kevin P. Baker
Jian Chen
Luc Desnoyers
Audrey Goddard
Paul J. Godowski
Austin L. Gurney
James Pan
Victoria Smith
Colin K. Watanabe
William I. Wood
Zemin Zhang
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Genentech Inc
Original Assignee
Genentech Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from PCT/US2000/005601 external-priority patent/WO2000056889A2/en
Priority claimed from PCT/US2000/005841 external-priority patent/WO2000053758A2/en
Priority claimed from PCT/US2000/006884 external-priority patent/WO2001005972A1/en
Priority claimed from PCT/US2000/008439 external-priority patent/WO2000073454A1/en
Priority claimed from PCT/US2000/013705 external-priority patent/WO2000073445A2/en
Priority claimed from PCT/US2000/014042 external-priority patent/WO2000077037A2/en
Priority claimed from PCT/US2000/014941 external-priority patent/WO2000073348A2/en
Priority claimed from PCT/US2000/015264 external-priority patent/WO2000073452A2/en
Priority claimed from PCT/US2000/020710 external-priority patent/WO2001009327A2/en
Priority claimed from PCT/US2000/023328 external-priority patent/WO2001016318A2/en
Priority claimed from PCT/US2000/030952 external-priority patent/WO2001049715A2/en
Priority claimed from PCT/US2000/032678 external-priority patent/WO2001040466A2/en
Priority claimed from PCT/US2000/034956 external-priority patent/WO2001046420A2/en
Application filed by Genentech Inc filed Critical Genentech Inc
Publication of EP1259614A2 publication Critical patent/EP1259614A2/en
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70503—Immunoglobulin superfamily
    • C07K14/70532—B7 molecules, e.g. CD80, CD86
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates generally to the identification and isolation of novel DNA and to the recombinant production of novel polypeptides.
  • Extracellular proteins play important roles in, among other things, the formation, differentiation and maintenance of multicellular organisms.
  • secreted polypeptides or signaling molecules normally pass through the cellular secretory pathway to reach their site of action in the extracellular environment.
  • Secreted proteins have various industrial applications, including as pharmaceuticals, diagnostics, biosensors and bioreactors.
  • Most protein drugs available at present, such as thrombolytic agents, interferons, interleukins, erythropoietins, colony stimulating factors, and various other cytokines, are secretory proteins.
  • Their receptors, which are membrane proteins, also have potential as therapeutic or diagnostic agents.
  • Efforts are being undertaken by both industry and proficient to identify new, native secreted proteins. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel secreted proteins. Examples of screening methods and techniques are described in the literature [see, for example, Klein et al., Proc. Natl. Acad. Sci. 93:7108-7113 (1996); U.S. Patent No. 5,536,637)].
  • Membrane-bound proteins and receptors can play important roles in, among other things, the formation, differentiation and maintenance of multicellular organisms.
  • the fate of many individual cells, e.g. , proliferation, migration, differentiation, or interaction with other cells is typically governed by information received from other cells and/or the immediate environment. This information is often transmitted by secreted polypeptides (for instance, mitogenic factors, survival factors, cytotoxic factors, differentiation factors, neuropeptides, and hormones) which are, in turn, received and interpreted by diverse cell receptors or membrane-bound proteins.
  • Such membrane-bound proteins and cell receptors include, but are not limited to, cytokine receptors, receptor kinases, receptor phosphatases, receptors involved in cell-cell interactions, and cellular adhesin molecules like selectins and integrins. For instance, transduction of signals that regulate cell growth .and differentiation is regulated in part by phosphorylation of various cellular proteins . Protein tyrosine kinases , enzymes that catalyze that process, can also act as growth factor receptors. Examples include fibroblast growth factor receptor and nerve growth factor receptor.
  • Membrane-bound proteins and receptor molecules have various industrial applications, including as pharmaceutical and diagnostic agents.
  • Receptor immunoadhesins for instance, can be employed as therapeutic agents to block receptor-ligand interactions.
  • the membrane-bound proteins can also be employed for screening of potential peptide or small molecule inhibitors of the relevant receptor/ligand interaction.
  • Efforts are being undertaken by both industry .and ME to identify new, native receptor or membrane-bound proteins . Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel receptor or membrane-bound proteins.
  • the invention provides an isolated nucleic acid molecule comprising a nucleotide sequence that encodes a PRO polypeptide.
  • the isolated nucleic acid molecule comprises a nucleotide sequence having at least about 80% nucleic acid sequence identity, alternatively at least about 81% nucleic acid sequence identity, alternatively at least about 82% nucleic acid sequence identity, alternatively at least about 83 % nucleic acid sequence identity, alternatively at least about 84% nucleic acid sequence identity, alternatively at least about 85% nucleic acid sequence identity, alternatively at least about 86% nucleic acid sequence identity, alternatively at least about 87% nucleic acid sequence identity, alternatively at least about 88 % nucleic acid sequence identity, alternatively at least about 89% nucleic acid sequence identity, alternatively at least about 90% nucleic acid sequence identity, alternatively at least about 91% nucleic acid sequence identity, alternatively at least about 92% nucleic acid sequence identity, alternatively at least about 93 % nucleic acid sequence identity, alternatively at least about 94% nucleic acid sequence identity, alternatively at least about 95 % nucleic acid sequence identity, alternatively at least about
  • the isolated nucleic acid molecule comprises a nucleotide sequence having at least about 80% nucleic acid sequence identity, alternatively at least about 81 % nucleic acid sequence identity, alternatively at least about 82% nucleic acid sequence identity, alternatively at least about 83 % nucleic acid sequence identity, alternatively at least about 84% nucleic acid sequence identity, alternatively at least about 85% nucleic acid sequence identity, alternatively at least about 86% nucleic acid sequence identity, alternatively at least about 87% nucleic acid sequence identity, alternatively at least about 88 % nucleic acid sequence identity, alternatively at least about 89% nucleic acid sequence identity, alternatively at least about 90% nucleic acid sequence identity, alternatively at least about 91% nucleic acid sequence identity, alternatively at least about 92% nucleic acid sequence identity, alternatively at least about 93 % nucleic acid sequence identity, alternatively at least about 94% nucleic acid sequence identity, alternatively at least about 95 % nucleic acid sequence identity, alternatively at least about
  • the 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,
  • 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 10 nucleotides in length, alternatively at least about 15 nucleotides in length, alternatively 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 nucleo
  • novel fragments of a PRO polypeptide-encoding nucleotide sequence may be determined in a routine manner by aligning the PRO polypeptide-encoding nucleotide sequence with other known nucleotide sequences using any of a number of well known sequence alignment programs and determining which PRO polypeptide-encoding nucleotide sequence fragment(s) are novel. All of such PRO polypeptide-encoding nucleotide sequences are contemplated herein. Also contemplated are the PRO polypeptide fragments encoded by these nucleotide molecule fragments, preferably those PRO polypeptide fragments that comprise a binding site for an anti-PRO antibody.
  • the invention provides isolated PRO polypeptide encoded by any of the isolated nucleic acid sequences hereinabove identified.
  • the invention concerns an isolated PRO polypeptide, comprising an amino acid sequence having at least about 80% 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 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 at least about
  • the invention provides an isolated PRO polypeptide without the N-terminal signal sequence and/or the initiating methionine and is encoded by a nucleotide sequence that encodes such an amino acid sequence as hereinbefore described.
  • Processes for producing the same are also herein described, wherein those processes comprise 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 antagomst is an anti-PRO antibody or a small molecule.
  • the invention concerns a method of identifying agonists or antagonists to a PRO polypeptide which comprise contacting the PRO polypeptide with a candidate molecule and monitoring a biological activity mediated by said PRO polypeptide.
  • the PRO polypeptide is a native PRO polypeptide.
  • the invention concerns a composition of matter comprising a PRO polypeptide, or an agonist or antagonist of a PRO polypeptide as herein described, or an anti-PRO antibody, in combination with a carrier.
  • the carrier is a pharmaceutically acceptable carrier.
  • Another embodiment of the present invention is directed to the use of a PRO polypeptide, or an agonist or antagonist thereof as hereinbefore described, or an anti-PRO antibody, for the preparation of a medicament useful in the treatment of a condition which is responsive to the PRO polypeptide, an agonist or antagonist thereof or an anti-PRO antibody.
  • 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 binds, preferably specifically, 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 which may be useful for isolating genomic and cDNA nucleotide sequences, measuring or detecting expression of an associated gene or as antisense probes, wherein those probes may be derived from any of the above or below described nucleotide sequences. Preferred probe lengths are described above.
  • the present invention is directed to methods of using the PRO polypeptides of the present invention for a variety of uses based upon the functional biological assay data presented in the Examples below.
  • Figure 1 shows a nucleotide sequence (SEQ ID NO:l) of a native sequence PR0276 cDNA, wherein SEQ ID NO:l is a clone designated herein as "DNA16435-1208".
  • Figure 2 shows the amino acid sequence (SEQ ID NO:2) derived from the coding sequence of SEQ ID NO:2
  • Figure 3 shows a nucleotide sequence (SEQ ID NO:3) of a native sequence PR0284 cDNA, wherein SEQ ID NO:3 is a clone designated herein as "DNA23318-1211".
  • Figure 4 shows the amino acid sequence (SEQ ID NO:4) derived from the coding sequence of SEQ ID NO: 3 shown in Figure 3.
  • Figure 5 shows a nucleotide sequence (SEQ ID NO:5) of a native sequence PRO 193 cDNA, wherein SEQ ID NO:5 is a clone designated herein as "DNA23322-1393".
  • Figure 6 shows the amino acid sequence (SEQ ID NO: 6) derived from the coding sequence of SEQ ID NO: 5 shown in Figure 5.
  • Figure 7 shows a nucleotide sequence (SEQ ID NO:7) of a native sequence PRO190 cDNA, wherein
  • SEQ ID NO:7 is a clone designated herein as "DNA23334-1392".
  • Figure 8 shows the amino acid sequence (SEQ ID NO: 8) derived from the coding sequence of SEQ ID NO: 7 shown in Figure 7.
  • Figure 9 shows a nucleotide sequence (SEQ ID NO:9) of a native sequence PRO180 cDNA, wherein SEQ ID NO:9 is a clone designated herein as "DNA26843-1389" .
  • Figure 10 shows the amino acid sequence (SEQ ID NO: 10) derived from the coding sequence of SEQ ID NQ:9 shown in Figure 9.
  • Figure 11 shows a nucleotide sequence (SEQ ID NO: 11) of a native sequence PR0194 cDNA, wherein SEQ ID NO: 11 is a clone designated herein as "DNA26844-1394".
  • Figure 12 shows the amino acid sequence (SEQ ID NO: 12) derived from the coding sequence of SEQ ID NO: 11 shown in Figure 11.
  • Figure 13 shows a nucleotide sequence (SEQ ID NO: 13) of a native sequence PR0218 cDNA, wherein SEQ ID NO: 13 is a clone designated herein as "DNA30867-1335".
  • Figure 14 shows the amino acid sequence (SEQ ID NO: 14) derived from the coding sequence of SEQ ID NO: 13 shown in Figure 13.
  • Figure 15 shows a nucleotide sequence (SEQ ID NO: 15) of a native sequence PRO260 cDNA, wherein SEQ ID NO:15 is a clone designated herein as "DNA33470-1175".
  • Figure 16 shows the amino acid sequence (SEQ ID NO: 16) derived from the coding sequence of SEQ
  • Figure 17 shows a nucleotide sequence (SEQ ID NO: 17) of a native sequence PR0233 cDNA, wherein SEQ ID NO: 17 is a clone designated herein as "DNA34436-1238".
  • Figure 18 shows the amino acid sequence (SEQ ID NO: 18) derived from the coding sequence of SEQ ID NO: 17 shown in Figure 17.
  • Figure 19 shows a nucleotide sequence (SEQ ID NO: 19) of a native sequence PR0234 cDNA, wherein SEQ ID NO: 19 is a clone designated herein as "DNA35557-1137".
  • Figure 20 shows the amino acid sequence (SEQ ID NO:20) derived from the coding sequence of SEQ ID NO: 19 shown in Figure 19.
  • Figure 21 shows a nucleotide sequence (SEQ ID NO:21) of a native sequence PR0236 cDNA, wherein
  • SEQ ID NO:21 is a clone designated herein as "DNA35599-1168".
  • Figure 22 shows the amino acid sequence (SEQ ID NO:22) derived from the coding sequence of SEQ ID NO:21 shown in Figure 21.
  • Figure 23 shows a nucleotide sequence (SEQ ID NO:23) of a native sequence PR0244 cDNA, wherein SEQ ID NO:23 is a clone designated herein as "DNA35668-1171 " .
  • Figure 24 shows the amino acid sequence (SEQ ID NO: 24) derived from the coding sequence of SEQ ID NO:23 shown in Figure 23.
  • Figure 25 shows a nucleotide sequence (SEQ ID NO:25) of a native sequence PR0262 cDNA, wherein SEQ ID N0:25 is a clone designated herein as "DNA36992-1168".
  • Figure 26 shows the amino acid sequence (SEQ ID NO:26) derived from the coding sequence of SEQ
  • Figure 27 shows a nucleotide sequence (SEQ ID NO:27) of a native sequence PR0271 cDNA, wherein SEQ ID NO:27 is a clone designated herein as "DNA39423-1182".
  • Figure 28 shows the amino acid sequence (SEQ ID NO:28) derived from the coding sequence of SEQ ID NO:27 shown in Figure 27.
  • Figure 29 shows a nucleotide sequence (SEQ ID NO:29) of a native sequence PR0268 cDNA, wherein SEQ ID N0:29 is a clone designated herein as "DNA39427-1179".
  • Figure 30 shows the amino acid sequence (SEQ ID NO:30) derived from the coding sequence of SEQ ID NO:29 shown in Figure 29.
  • Figure 31 shows a nucleotide sequence (SEQ ID NO: 31) of a native sequence PRO270 cDNA, wherein SEQ ID NO:31 is a clone designated herein as "DNA39510-1181".
  • Figure 32 shows the amino acid sequence (SEQ ID NO: 32) derived from the coding sequence of SEQ ID NO:31 shown in Figure 31.
  • Figure 33 shows a nucleotide sequence (SEQ ID NO:33) of a native sequence PR0355 cDNA, wherein SEQ ID NO:33 is a clone designated herein as "DNA39518-1247".
  • Figure 34 shows the amino acid sequence (SEQ ID NO: 34) derived from the coding sequence of SEQ ID NO:33 shown in Figure 33.
  • Figure 35 shows a nucleotide sequence (SEQ ID NO:35) of a native sequence PR0298 cDNA, wherein
  • SEQ ID NO:35 is a clone designated herein as "DNA39975-1210".
  • Figure 36 shows the amino acid sequence (SEQ ID NO:36) derived from the coding sequence of SEQ ID NO:35 shown in Figure 35.
  • Figure 37 shows a nucleotide sequence (SEQ ID NO: 37) of a native sequence PR0299 cDNA, wherein SEQ ID NO:37 is a clone designated herein as "DNA39976-1215" .
  • Figure 38 shows the amino acid sequence (SEQ ID NO:38) derived from the coding sequence of SEQ ID NO: 37 shown in Figure 37.
  • Figure 39 shows a nucleotide sequence (SEQ ID NO:39) of a native sequence PR0296 cDNA, wherein SEQ ID NO:39 is a clone designated herein as "DNA39979-1213".
  • Figure 40 shows the amino acid sequence (SEQ ID NO: 40) derived from the coding sequence of SEQ
  • Figure 41 shows a nucleotide sequence (SEQ ID NO:41) of a native sequence PR0329 cDNA, wherein SEQ ID NO:41 is a clone designated herein as "DNA40594-1233".
  • Figure 42 shows the amino acid sequence (SEQ ID NO: 42) derived from the coding sequence of SEQ ID NO:41 shown in Figure 41.
  • Figure 43 shows a nucleotide sequence (SEQ ID NO:43) of a native sequence PRO330 cDNA, wherein SEQ ID NO:43 is a clone designated herein as "DNA40603-1232".
  • Figure 44 shows the amino acid sequence (SEQ ID NO: 44) derived from the coding sequence of SEQ ID NO: 43 shown in Figure 43.
  • Figure 45 shows a nucleotide sequence (SEQ ID NO:45) of a native sequence PR0294 cDNA, wherein
  • SEQ ID NO:45 is a clone designated herein as "DNA40604-1187".
  • Figure 46 shows the amino acid sequence (SEQ ID NO: 46) derived from the coding sequence of SEQ ID NO: 45 shown in Figure 45.
  • Figure 47 shows a nucleotide sequence (SEQ ID NO:47) of a native sequence PRO300 cDNA, wherein SEQ ID NO:47 is a clone designated herein as "DNA40625-1189".
  • Figure 48 shows the amino acid sequence (SEQ ID NO: 48) derived from the coding sequence of SEQ ID NO:47 shown in Figure 47.
  • Figure 49 shows a nucleotide sequence (SEQ ID NO:49) of a native sequence PRO307 cDNA, wherein SEQ ID NO:49 is a clone designated herein as "DNA41225-1217".
  • Figure 50 shows the amino acid sequence (SEQ ID NO: 50) derived from the coding sequence of SEQ ID NO:49 shown in Figure 49.
  • Figure 51 shows a nucleotide sequence (SEQ ID NO:51) of a native sequence PR0334 cDNA, wherein SEQ ID NO:51 is a clone designated herein as "DNA41379-1236" .
  • Figure 52 shows the amino acid sequence (SEQ ID NO: 52) derived from the coding sequence of SEQ ID NO:51 shown in Figure 51.
  • Figure 53 shows a nucleotide sequence (SEQ ID NO:53) of a native sequence PR0352 cDNA, wherein SEQ ID NO:53 is a clone designated herein as "DNA41386-1316".
  • Figure 54 shows the amino acid sequence (SEQ ID NO: 54) derived from the coding sequence of SEQ
  • Figure 55 shows a nucleotide sequence (SEQ ID NO:55) of a native sequence PRO710 cDNA, wherein SEQ ID NO:55 is a clone designated herein as "DNA44161-1434".
  • Figure 56 shows the amino acid sequence (SEQ ID NO: 56) derived from the coding sequence of SEQ ID NO:55 shown in Figure 55.
  • Figure 57 shows a nucleotide sequence (SEQ ID NO:57) of a native sequence PR0873 cDNA, wherein SEQ ID NO:57 is a clone designated herein as "DNA44179-1362".
  • Figure 58 shows the amino acid sequence (SEQ ID NO:58) derived from the coding sequence of SEQ ID NO:57 shown in Figure 57.
  • Figure 59 shows a nucleotide sequence (SEQ ID NO: 59) of a native sequence PR0354 cDNA, wherein
  • SEQ ID NO:59 is a clone designated herein as "DNA44192-1246".
  • Figure 60 shows the amino acid sequence (SEQ ID NO: 60) derived from the coding sequence of SEQ ID NO:59 shown in Figure 59.
  • Figure 61 shows a nucleotide sequence (SEQ ID NO:61) of a native sequence PR01151 cDNA, wherein SEQ ID NO:61 is a clone designated herein as "DNA44694-1500" .
  • Figure 62 shows the amino acid sequence (SEQ ID NO: 62) derived from the coding sequence of SEQ ID NO:61 shown in Figure 61.
  • Figure 63 shows a nucleotide sequence (SEQ ID NO:63) of a native sequence PR0382 cDNA, wherein SEQ ID NO:63 is a clone designated herein as "DNA45234-1277".
  • Figure 64 shows the amino acid sequence (SEQ ID NO: 64) derived from the coding sequence of SEQ
  • Figure 65 shows a nucleotide sequence (SEQ ID NO : 65) of a native sequence PRO 1864 cDNA, wherein SEQ ID NO:65 is a clone designated herein as "DNA45409-2511".
  • Figure 66 shows the amino acid sequence (SEQ ID NO: 66) derived from the coding sequence of SEQ ID NO:65 shown in Figure 65.
  • Figure 67 shows a nucleotide sequence (SEQ ID NO:67) of a native sequence PR0386 cDNA, wherein SEQ ID NO:67 is a clone designated herein as "DNA45415-1318".
  • Figure 68 shows the amino acid sequence (SEQ ID NO: 68) derived from the coding sequence of SEQ ID NO: 67 shown in Figure 67.
  • Figure 69 shows a nucleotide sequence (SEQ ID NO: 69) of a native sequence PR0541 cDNA, wherein SEQ ID NO:69 is a clone designated herein as "DNA45417-1432".
  • Figure 70 shows the amino acid sequence (SEQ ID NO: 70) derived from the coding sequence of SEQ ID NO: 69 shown in Figure 69.
  • Figure 71 shows a nucleotide sequence (SEQ ID NO:71) of a native sequence PR0852 cDNA, wherein SEQ ID NO:71 is a clone designated herein as "DNA45493-1349".
  • Figure 72 shows the amino acid sequence (SEQ ID NO: 72) derived from the coding sequence of SEQ ID NO:71 shown in Figure 71.
  • Figure 73 shows a nucleotide sequence (SEQ ID NO:73) of a native sequence PRO700 cDNA, wherein
  • SEQ ID NO:73 is a clone designated herein as "DNA46776-1284".
  • Figure 74 shows the amino acid sequence (SEQ ID NO:74) derived from the coding sequence of SEQ ID NO:73 shown in Figure 73.
  • Figures 75A-75B show a nucleotide sequence (SEQ ID NO:75) of a native sequence PRO708 cDNA, wherein SEQ ID NO:75 is a clone designated herein as "DNA48296-1292" .
  • Figure 76 shows the amino acid sequence (SEQ ID NO: 76) derived from the coding sequence of SEQ ID NO:75 shown in Figures 75A-75B.
  • Figure 77 shows a nucleotide sequence (SEQ ID NO:77) of a native sequence PRO707 cDNA, wherein SEQ ID NO:77 is a clone designated herein as "DNA48306-1291".
  • Figure 78 shows the amino acid sequence (SEQ ID NO: 78) derived from the coding sequence of SEQ
  • Figure 79 shows a nucleotide sequence (SEQ ID NO:79) of a native sequence PR0864 cDNA, wherein SEQ ID NO:79 is a clone designated herein as "DNA48328-1355" .
  • Figure 80 shows the amino acid sequence (SEQ ID NO: 80) derived from the coding sequence of SEQ ID NO:79 shown in Figure 79.
  • Figure 81 shows a nucleotide sequence (SEQ ID NO:81) of a native sequence PRO706 cDNA, wherein SEQ ID NO:81 is a clone designated herein as "DNA48329-1290".
  • Figure 82 shows the amino acid sequence (SEQ ID NO: 82) derived from the coding sequence of SEQ ID NO:81 shown in Figure 81.
  • Figure 83 shows a nucleotide sequence (SEQ ID NO:83) of a native sequence PR0732 cDNA, wherein
  • SEQ ID NO:83 is a clone designated herein as "DNA48334-1435".
  • Figure 84 shows the amino acid sequence (SEQ ID NO: 84) derived from the coding sequence of SEQ ID NO:83 shown in Figure 83.
  • Figure 85 shows a nucleotide sequence (SEQ ID NO:85) of a native sequence PR0537 cDNA, wherein SEQ ID NO:85 is a clone designated herein as "DNA49141-1431".
  • Figure 86 shows the amino acid sequence (SEQ ID NO: 86) derived from the coding sequence of SEQ ID NO:85 shown in Figure 85.
  • Figure 87 shows a nucleotide sequence (SEQ ID NO:87) of a native sequence PR0545 cDNA, wherein SEQ ID NO:87 is a clone designated herein as "DNA49624-1279".
  • Figure 88 shows the amino acid sequence (SEQ ID NO: 88) derived from the coding sequence of SEQ ID NO:87 shown in Figure 87.
  • Figure 89 shows a nucleotide sequence (SEQ ID NO:89) of a native sequence PR0718 cDNA, wherein SEQ ID NO:89 is a clone designated herein as "DNA49647-1398".
  • Figure 90 shows the amino acid sequence (SEQ ID NO: 90) derived from the coding sequence of SEQ ID NO:89 shown in Figure 89.
  • Figure 91 shows a nucleotide sequence (SEQ ID NO:91) of a native sequence PR0872 cDNA, wherein SEQ ID NO:91 is a clone designated herein as "DNA49819-1439".
  • Figure 92 shows the amino acid sequence (SEQ ID NO:92) derived from the coding sequence of SEQ
  • Figure 93 shows a nucleotide sequence (SEQ ID NO:93) of a native sequence PRO704 cDNA, wherein SEQ ID NO:93 is a clone designated herein as "DNA50911-1288".
  • Figure 94 shows the amino acid sequence (SEQ ID NO: 94) derived from the coding sequence of SEQ ID NO: 93 shown in Figure 93.
  • Figure 95 shows a nucleotide sequence (SEQ ID NO:95) of a native sequence PRO705 cDNA, wherein SEQ ID NO:95 is a clone designated herein as "DNA50914-1289".
  • Figure 96 shows the amino acid sequence (SEQ ID NO: 96) derived from the coding sequence of SEQ ID NO:95 shown in Figure 95.
  • Figure 97 shows a nucleotide sequence (SEQ ID NO:97) of a native sequence PR0871 cDNA, wherein
  • SEQ ID NO:97 is a clone designated herein as "DNA50919-1361".
  • Figure 98 shows the amino acid sequence (SEQ ID NO: 98) derived from the coding sequence of SEQ ID NO:97 shown in Figure 97.
  • Figure 99 shows a nucleotide sequence (SEQ ID NO: 99) of a native sequence PRO702 cDNA, wherein SEQ ID NO:99 is a clone designated herein as "DNA50980-1286".
  • Figure 100 shows the amino acid sequence (SEQ ID NO: 100) derived from the coding sequence of SEQ ID NO: 99 shown in Figure 99.
  • Figure 101 shows anucleotide sequence (SEQ ID NO: 101) of a native sequence PR0944 cDNA, wherein SEQ ID NO: 101 is a clone designated herein as "DNA52185-1370".
  • Figure 102 shows the amino acid sequence (SEQ ID NO: 102) derived from the coding sequence of SEQ
  • Figure 103 shows anucleotide sequence (SEQ ID NO: 103) of a native sequence PR0739 cDNA, wherein SEQ ID NO: 103 is a clone designated herein as "DNA52756".
  • Figure 104 shows the amino acid sequence (SEQ ID NO: 104) derived from the coding sequence of SEQ ID NO: 103 shown in Figure 103.
  • Figure 105 shows anucleotide sequence (SEQ ID NO: 105) of a native sequence PR0941 cDNA, wherein SEQ ID NO: 105 is a clone designated herein as "DNA53906-1368".
  • Figure 106 shows the amino acid sequence (SEQ ID NO: 106) derived from the coding sequence of SEQ ID NO: 105 shown in Figure 105.
  • Figure 107 shows a nucleotide sequence (SEQ ID NO: 107) of a native sequence PRO1082 cDNA, wherein SEQ ID NO: 107 is a clone designated herein as "DNA53912-1457".
  • Figure 108 shows the amino acid sequence (SEQ ID NO: 108) derived from the coding sequence of SEQ ID NO: 107 shown in Figure 107.
  • Figure 109 shows a nucleotide sequence (SEQ ID NO:109) of a native sequence PR01133 cDNA, wherein SEQ ID NO: 109 is a clone designated herein as "DNA53913-1490".
  • Figure 110 shows the amino acid sequence (SEQ ID NO: 110) derived from the coding sequence of SEQ ID NO: 109 shown in Figure 109.
  • Figure 111 shows a nucleotide sequence (SEQ ID NO: 111) of a native sequence PR0983 cDNA, wherein
  • SEQ ID NO:lll is a clone designated herein as "DNA53977-1371".
  • Figure 112 shows the amino acid sequence (SEQ ID NO: 112) derived from (he coding sequence of SEQ ID NO:lll shown in Figure 111.
  • Figure 113 shows a nucleotide sequence (SEQ ID NO: 113) of a native sequence PR0784 cDNA, wherein SEQ ID NO:113 is a clone designated herein as "DNA53978-1443".
  • Figure 114 shows the amino acid sequence (SEQ ID NO: 114) derived from the coding sequence of SEQ ID NO:113 shown in Figure 113.
  • Figure 115 shows a nucleotide sequence (SEQ ID NO: 115) of a native sequence PR0783 cDNA, wherein SEQ ID NO: 115 is a clone designated herein as "DNA53996-1442".
  • Figure 116 shows the amino acid sequence (SEQ ID NO : 116) derived from the coding sequence of SEQ
  • Figure 117 shows a nucleotide sequence (SEQ ID NO: 117) of a native sequence PRO940 cDNA, wherein SEQ ID NO: 117 is a clone designated herein as "DNA54002-1367".
  • Figure 118 shows the amino acid sequence (SEQ ID NO : 118) derived from the coding sequence of SEQ ID NO: 117 shown in Figure 117.
  • Figure 119 shows a nucleotide sequence (SEQ ID NO: 119) of a native sequence PR0768 cDNA, wherein SEQ ID NO:119 is a clone designated herein as "DNA55737-1345".
  • Figure 120 shows the amino acid sequence (SEQ ID NO: 120) derived from the coding sequence of SEQ ID NO: 119 shown in Figure 119.
  • Figure 121 shows a nucleotide sequence (SEQ ID NO: 121) of a native sequence PRO1079 cDNA, wherein SEQ ID NO: 121 is a clone designated herein as "DNA56050-1455".
  • Figure 122 shows the amino acid sequence (SEQ ID NO: 122) derived from the coding sequence of SEQ ID NO: 121 shown in Figure 121.
  • Figure 123 shows a nucleotide sequence (SEQ ID NO: 123) of a native sequence PRO1078 cDNA, wherein SEQ ID NO:123 is a clone designated herein as "DNA56052-1454".
  • Figure 124 shows the amino acid sequence (SEQ ID NO: 124) derived from the coding sequence of SEQ ID NO : 123 shown in Figure 123.
  • Figure 125 shows a nucleotide sequence (SEQ ID NO: 125) of a native sequence PRO1018 cDNA, wherein SEQ ID NO: 125 is a clone designated herein as "DNA56107-1415".
  • Figure 126 shows the amino acid sequence (SEQ ID NO: 126) derived from the coding sequence of SEQ ID NO: 125 shown in Figure 125.
  • Figure 127 shows anucleotide sequence (SEQ ID NO: 127) of a native sequence PR0793 cDNA, wherein SEQ ID NO:127 is a clone designated herein as "DNA56110-1437".
  • Figure 128 shows the amino acid sequence (SEQ ID NO : 128) derived from the coding sequence of SEQ ID NO: 127 shown in Figure 127.
  • Figure 129 shows a nucleotide sequence (SEQ ID NO: 129) of a native sequence PR01773 cDNA, wherein SEQ ID NO: 129 is a clone designated herein as "DNA56406-1704".
  • Figure 130 shows the amino acid sequence (SEQ ID NO: 130) derived from the coding sequence of SEQ
  • Figure 131 shows a nucleotide sequence (SEQ ID NO: 131) of a native sequence PRO1014 cDNA, wherein SEQ ID NO: 131 is a clone designated herein as "DNA56409-1377".
  • Figure 132 shows the amino acid sequence (SEQ ID NO: 132) derived from the coding sequence of SEQ ID NO: 131 shown in Figure 131.
  • Figure 133 shows a nucleotide sequence (SEQ ID NO: 133) of a native sequence PRO1013 cDNA, wherein SEQ ID NO: 133 is a clone designated herein as "DNA56410-1414".
  • Figure 134 shows the amino acid sequence (SEQ ID NO: 134) derived from the coding sequence of SEQ ID NO: 133 shown in Figure 133.
  • Figure 135 shows a nucleotide sequence (SEQ ID NO : 135) of a native sequence PR0937 cDNA, wherein
  • SEQ ID NO: 135 is a clone designated herein as "DNA56436-1448".
  • Figure 136 shows the amino acid sequence (SEQ ID NO: 136) derived from the coding sequence of SEQ ID NO: 135 shown in Figure 135.
  • Figure 137 shows a nucleotide sequence (SEQ ID NO: 137) of a native sequence PR01477 cDNA, wherein SEQ ID NO: 137 is a clone designated herein as "DNA56529-1647" .
  • Figure 138 shows the amino acid sequence (SEQ ID NO: 138) derived from the coding sequence of SEQ ID NO: 137 shown in Figure 137.
  • Figure 139 shows anucleotide sequence (SEQ ID NO: 139) of a native sequence PR0842 cDNA, wherein SEQ ID N0:139 is a clone designated herein as "DNA56855-1447".
  • Figure 140 shows the amino acid sequence (SEQ ID NO: 140) derived from the coding sequence of SEQ
  • Figure 141 shows anucleotide sequence (SEQ ID NO: 141) of a native sequence PR0839 cDNA, wherein SEQ ID NO:141 is a clone designated herein as "DNA56859-1445".
  • Figure 142 shows the amino acid sequence (SEQ ID NO: 142) derived from the coding sequence of SEQ ID NO: 141 shown in Figure 141.
  • Figure 143 shows a nucleotide sequence (SEQ ID NO: 143) of a native sequence PRO1180 cDNA, wherein SEQ ID NO: 143 is a clone designated herein as "DNA56860-1510".
  • Figure 144 shows the amino acid sequence (SEQ ID NO: 144) derived from the coding sequence of SEQ ID NO: 143 shown in Figure 143.
  • Figure 145 shows a nucleotide sequence (SEQ ID NO: 145) of a native sequence PR01134 cDNA, wherein SEQ ID NO:145 is a clone designated herein as "DNA56865-1491".
  • Figure 146 shows the amino acid sequence (SEQ ID NO: 146) derived from the coding sequence of SEQ ID NO: 145 shown in Figure 145.
  • Figure 147 shows a nucleotide sequence (SEQ ID NO:147) of a native sequence PR01115 cDNA, wherein SEQ ID NO: 147 is a clone designated herein as "DNA56868-1478".
  • Figure 148 shows the amino acid sequence (SEQ ID NO: 148) derived from the coding sequence of SEQ ID NO: 147 shown in Figure 147.
  • Figure 149 shows a nucleotide sequence (SEQ ID NO: 149) of a native sequence PRO 1277 cDNA, wherein SEQ ID NO:149 is a clone designated herein as "DNA56869-1545".
  • Figure 150 shows the amino acid sequence (SEQ ID NO: 150) derived from the coding sequence of SEQ ID NO: 149 shown in Figure 149.
  • Figure 151 shows a nucleotide sequence (SEQ ID NO: 151) of a native sequence PR01135 cDNA, wherein SEQ ID NO:151 is a clone designated herein as "DNA56870-1492".
  • Figure 152 shows the amino acid sequence (SEQ ID NO: 152) derived from the coding sequence of SEQ ID NO:151 shown in Figure 151.
  • Figure 153 shows anucleotide sequence (SEQ ID NO:153) of anative sequence PR0827cDNA, wherein SEQ ID NO: 153 is a clone designated herein as "DNA57039-1402".
  • Figure 154 shows the amino acid sequence (SEQ ID NO: 154) derived from the coding sequence of SEQ
  • Figure 155 shows a nucleotide sequence (SEQ ID NO: 155) of a native sequence PRO1057 cDNA, wherein SEQ ID NO: 155 is a clone designated herein as "DNA57253-1382".
  • Figure 156 shows the amino acid sequence (SEQ ID NO: 156) derived from the coding sequence of SEQ ID NO: 155 shown in Figure 155.
  • Figure 157 shows a nucleotide sequence (SEQ ID NO: 157) of a native sequence PR01113 cDNA, wherein SEQ ID NO: 157 is a clone designated herein as "DNA57254-1477".
  • Figure 158 shows the amino acid sequence (SEQ ID NO: 158) derived from the coding sequence of SEQ ID NO: 157 shown in Figure 157.
  • Figure 159 shows a nucleotide sequence (SEQ ID NO: 159) of a native sequence PRO 1006 cDNA, wherein SEQ ID NO: 159 is a clone designated herein as "DNA57699-1412".
  • Figure 160 shows the amino acid sequence (SEQ ID NO: 160) derived from the coding sequence of SEQ ID NO: 159 shown in Figure 159.
  • Figure 161 shows a nucleotide sequence (SEQ ID NO: 161) of a native sequence PRO1074 cDNA, wherein SEQ ID NO: 161 is a clone designated herein as "DNA57704-1452" .
  • Figure 162 shows the amino acid sequence (SEQ ID NO: 162) derived from the coding sequence of SEQ ID NO:161 shown in Figure 161.
  • Figure 163 shows a nucleotide sequence (SEQ ID NO: 163) of a native sequence PRO1073 cDNA, wherein SEQ ID NO: 163 is a clone designated herein as "DNA57710-1451".
  • Figure 164 shows the amino acid sequence (SEQ ID NO: 164) derived from the coding sequence of SEQ ID NO: 163 shown in Figure 163.
  • Figure 165 shows a nucleotide sequence (SEQ ID NO: 165) of a native sequence PR01136 cDNA, wherein SEQ ID NO:165 is a clone designated herein as "DNA57827-1493".
  • Figure 166 shows the amino acid sequence (SEQ ID NO : 166) derived from the coding sequence of SEQ ID NO: 165 shown in Figure 165.
  • Figure 167 shows a nucleotide sequence (SEQ ID NO: 167) of a native sequence PRO1004 cDNA, wherein SEQ ID NO: 167 is a clone designated herein as "DNA57844-1410".
  • Figure 168 shows the amino acid sequence (SEQ ID NO: 168) derived from the coding sequence of SEQ
  • Figure 169 shows a nucleotide sequence (SEQ ID NO: 169) of a native sequence PR01344 cDNA, wherein SEQ ID NO:169 is a clone designated herein as "DNA58723-1588".
  • Figure 170 shows the amino acid sequence (SEQ ID NO: 170) derived from the coding sequence of SEQ ID NO: 169 shown in Figure 169.
  • Figure 171 shows a nucleotide sequence (SEQ ID NO:171) of a native sequence PRO1110 cDNA, wherein SEQ ID NO: 171 is a clone designated herein as "DNA58727-1474".
  • Figure 172 shows the amino acid sequence (SEQ ID NO: 172) derived from the coding sequence of SEQ ID NO: 171 shown in Figure 171.
  • Figure 173 shows a nucleotide sequence (SEQ ID NO: 173) of a native sequence PR01378 cDNA, wherein SEQ ID NO: 173 is a clone designated herein as "DNA58730-1607".
  • Figure 174 shows the amino acid sequence (SEQ ID NO: 174) derived from the coding sequence of SEQ ID NO: 173 shown in Figure 173.
  • Figure 175 shows a nucleotide sequence (SEQ ID NO: 175) of a native sequence PRO 1481 cDNA, wherein SEQ ID NO: 175 is a clone designated herein as "DNA58732-1650" .
  • Figure 176 shows the amino acid sequence (SEQ ID NO: 176) derived from the coding sequence of SEQ ID NO: 175 shown in Figure 175.
  • Figure 177 shows a nucleotide sequence (SEQ ID NO: 177) of a native sequence PRO1109 cDNA, wherein SEQ ID NO: 177 is a clone designated herein as "DNA58737-1473".
  • Figure 178 shows the amino acid sequence (SEQ ID NO: 178) derived from the coding sequence of SEQ
  • Figure 179 shows a nucleotide sequence (SEQ ID NO: 179) of a native sequence PRO 1383 cDNA, wherein SEQ ID NO: 179 is a clone designated herein as "DNA58743-1609".
  • Figure 180 shows the amino acid sequence (SEQ ID NO: 180) derived from the coding sequence of SEQ ID NO: 179 shown in Figure 179.
  • Figure 181 shows a nucleotide sequence (SEQ ID NO: 181) of a native sequence PRO1072 cDNA, wherein SEQ ID NO:181 is a clone designated herein as "DNA58747-1384".
  • Figure 182 shows the amino acid sequence (SEQ ID NO: 182) derived from the coding sequence of SEQ ID NO: 181 shown in Figure 181.
  • Figure 183 shows a nucleotide sequence (SEQ ID NO: 183) of a native sequence PR01189 cDNA, wherein SEQ ID NO: 183 is a clone designated herein as "DNA58828-1519".
  • Figure 184 shows the amino acid sequence (SEQ ID NO: 184) derived from the coding sequence of SEQ ID NO: 183 shown in Figure 183.
  • Figure 185 shows a nucleotide sequence (SEQ ID NO: 185) of a native sequence PRO 1003 cDNA, wherein SEQ ID NO: 185 is a clone designated herein as "DNA58846-1409".
  • Figure 186 shows the amino acid sequence (SEQ ID NO: 186) derived from the coding sequence of SEQ ID NO: 185 shown in Figure 185.
  • Figure 187 shows a nucleotide sequence (SEQ ID NO:187) of a native sequence PRO1108 cDNA, wherein SEQ ID NO: 187 is a clone designated herein as "DNA58848-1472".
  • Figure 188 shows the amino acid sequence (SEQ ID NO: 188) derived from the coding sequence of SEQ ID NO: 187 shown in Figure 187.
  • Figure 189 shows a nucleotide sequence (SEQ ID NO:189) of a native sequence PROH37 cDNA, wherein SEQ ID NO: 189 is a clone designated herein as "DNA58849-1494" .
  • Figure 190 shows the amino acid sequence (SEQ ID NO: 190) derived from the coding sequence of SEQ ID NO: 189 shown in Figure 189.
  • Figure 191 shows a nucleotide sequence (SEQ ID NO:191) of a native sequence PROH38 cDNA, wherein SEQ ID NO: 191 is a clone designated herein as "DNA58850-1495".
  • Figure 192 shows the amino acid sequence (SEQ ID NO: 192) derived from the coding sequence of SEQ
  • Figure 193 shows a nucleotide sequence (SEQ ID NO: 193) of a native sequence PR01415 cDNA, wherein SEQ ID NO: 193 is a clone designated herein as "DNA58852-1637".
  • Figure 194 shows the amino acid sequence (SEQ ID NO: 194) derived from the coding sequence of SEQ ID NO: 193 shown in Figure 193.
  • Figure 195 shows a nucleotide sequence (SEQ ID NO: 195) of a native sequence PRO1054 cDNA, wherein SEQ ID NO:195 is a clone designated herein as "DNA58853-1423".
  • Figure 196 shows the amino acid sequence (SEQ ID NO: 196) derived from the coding sequence of SEQ ID NO: 195 shown in Figure 195.
  • Figure 197 shows a nucleotide sequence (SEQ ID NO: 197) of a native sequence PR0994 cDNA, wherein
  • SEQ ID N0:197 is a clone designated herein as "DNA58855-1422".
  • Figure 198 shows the amino acid sequence (SEQ ID NO: 198) derived from the coding sequence of SEQ ID NO: 197 shown in Figure 197.
  • Figure 199 shows a nucleotide sequence (SEQ ID NO: 199) of a native sequence PRO 1069 cDNA, wherein SEQ ID NO: 199 is a clone designated herein as "DNA59211-1450" .
  • Figure 200 shows the amino acid sequence (SEQ ID NO: 200) derived from the coding sequence of SEQ ID NO: 199 shown in Figure 199.
  • Figure 201 shows a nucleotide sequence (SEQ ID NO:201) of a native sequence PR01411 cDNA, wherein SEQ ID NO:201 is a clone designated herein as "DNA59212-1627".
  • Figure 202 shows the amino acid sequence (SEQ ID NO: 202) derived from the coding sequence of SEQ ID NO:201 shown in Figure 201.
  • Figure 203 shows a nucleotide sequence (SEQ ID NO:203) of a native sequence PR01129 cDNA, wherein SEQ ID NO:203 is a clone designated herein as "DNA59213-1487".
  • Figure 204 shows the amino acid sequence (SEQ ID NO: 204) derived from the coding sequence of SEQ ID NO:203 shown in Figure 203.
  • Figure 205 shows a nucleotide sequence (SEQ ID NO:205) of a native sequence PR01359 cDNA, wherein SEQ ID NO:205 is a clone designated herein as "DNA59219-1613".
  • Figure 206 shows the amino acid sequence (SEQ ID NO: 206) derived from the coding sequence of SEQ
  • Figure 207 shows a nucleotide sequence (SEQ ID NO:207) of a native sequence PR01139 cDNA, wherein SEQ ID NO:207 is a clone designated herein as "DNA59497-1496".
  • Figure 208 shows the amino acid sequence (SEQ ID NO: 208) derived from the coding sequence of SEQ ID NO:207 shown in Figure 207.
  • Figure 209 shows a nucleotide sequence (SEQ ID NO:209) of a native sequence PRO1065 cDNA, wherein SEQ ID NO:209 is a clone designated herein as "DNA59602-1436".
  • Figure 210 shows the amino acid sequence (SEQ ID NO:210) derived from the coding sequence of SEQ ID NO:209 shown in Figure 209.
  • Figure 211 shows a nucleotide sequence (SEQ ID NO:211) of a native sequence PRO1028 cDNA, wherein SEQ ID NO:211 is a clone designated herein as "DNA59603-1419".
  • Figure 212 shows the amino acid sequence (SEQ ID NO:212) derived from the coding sequence of SEQ ID NO:211 shown in Figure 211.
  • Figure 213 shows a nucleotide sequence (SEQ ID NO:213) of a native sequence PRO1027 cDNA, wherein SEQ ID NO:213 is a clone designated herein as "DNA59605-1418" .
  • Figure 214 shows the amino acid sequence (SEQ ID NO:214) derived from the coding sequence of SEQ ID NO:213 shown in Figure 213.
  • Figure 215 shows a nucleotide sequence (SEQ ID NO:215) of a native sequence PRO1140 cDNA, wherein SEQ ID NO:215 is a clone designated herein as "DNA59607-1497".
  • Figure 216 shows the amino acid sequence (SEQ ID NO:216) derived from the coding sequence of SEQ
  • Figure 217 shows a nucleotide sequence (SEQ ID NO:217) of a native sequence PR01291 cDNA, wherein SEQ ID NO:217 is a clone designated herein as "DNA59610-1556".
  • Figure 218 shows the amino acid sequence (SEQ ID NO:218) derived from the coding sequence of SEQ ID NO:217 shown in Figure 217.
  • Figure 219 shows a nucleotide sequence (SEQ ID NO:219) of a native sequence PRO1105 cDNA, wherein SEQ ID NO:219 is a clone designated herein as "DNA59612-1466".
  • Figure 220 shows the amino acid sequence (SEQ ID NO:220) derived from the coding sequence of SEQ ID NO:219 shown in Figure 219.
  • Figure 221 shows a nucleotide sequence (SEQ ID NO:221) of a native sequence PRO1026 cDNA, wherein SEQ ID NO:221 is a clone designated herein as "DNA59613-1417".
  • Figure 222 shows the amino acid sequence (SEQ ID NO: 222) derived from the coding sequence of SEQ ID NO :221 shown in Figure 221.
  • Figure 223 shows a nucleotide sequence (SEQ ID NO:223) of a native sequence PRO1104 cDNA, wherein SEQ ID NO:223 is a clone designated herein as "DNA59616-1465".
  • Figure 224 shows the amino acid sequence (SEQ ID NO: 224) derived from the coding sequence of SEQ ID NO:223 shown in Figure 223.
  • Figure 225 shows a nucleotide sequence (SEQ ID NO:225) of a native sequence PRO1100 cDNA, wherein SEQ ID NO:225 is a clone designated herein as "DNA59619-1464".
  • Figure 226 shows the amino acid sequence (SEQ ID NO:226) derived from the coding sequence of SEQ ID NO:225 shown in Figure 225.
  • Figure 227 shows a nucleotide sequence (SEQ ID NO:227) of a native sequence PROH41 cDNA, wherein SEQ ID NO:227 is a clone designated herein as "DNA59625-1498".
  • Figure 228 shows the amino acid sequence (SEQ ID NO: 228) derived from the coding sequence of SEQ ID NO:227 shown in Figure 227.
  • Figure 229 shows a nucleotide sequence (SEQ ID NO:229) of a native sequence PR01772 cDNA, wherein SEQ ID N0:229 is a clone designated herein as "DNA59817-1703".
  • Figure 230 shows the amino acid sequence (SEQ ID NO:230) derived from the coding sequence of SEQ
  • Figure 231 shows a nucleotide sequence (SEQ ID NO:231) of a native sequence PRO1064 cDNA, wherein SEQ ID NO:231 is a clone designated herein as "DNA59827-1426".
  • Figure 232 shows the amino acid sequence (SEQ ID NO:232) derived from the coding sequence of SEQ ID NO:231 shown in Figure 231.
  • Figure 233 shows a nucleotide sequence (SEQ ID NO:233) of a native sequence PR01379 cDNA, wherein SEQ ID NO:233 is a clone designated herein as "DNA59828-1608".
  • Figure 234 shows the amino acid sequence (SEQ ID NO: 234) derived from the coding sequence of SEQ ID NO:233 shown in Figure 233.
  • Figure 235 shows a nucleotide sequence (SEQ ID NO:235) of a native sequence PR03573 cDNA, wherein SEQ ID NO:235 is a clone designated herein as "DNA59837-2545".
  • Figure 236 shows the amino acid sequence (SEQ ID NO:236) derived from the coding sequence of SEQ ID NO:235 shown in Figure 235.
  • Figure 237 shows a nucleotide sequence (SEQ ID NO:237) of a native sequence PR03566 cDNA, wherein SEQ ID NO:237 is a clone designated herein as "DNA59844-2542" .
  • Figure 238 shows the amino acid sequence (SEQ ID NO:238) derived from the coding sequence of SEQ ID NO:237 shown in Figure 237.
  • Figure 239 shows a nucleotide sequence (SEQ ID NO:239) of a native sequence PR01156 cDNA, wherein SEQ ID NO:239 is a clone designated herein as "DNA59853-1505 " .
  • Figure 240 shows the amino acid sequence (SEQ ID NO: 240) derived from the coding sequence of SEQ ID NO:239 shown in Figure 239.
  • Figure 241 shows a nucleotide sequence (SEQ ID NO:241) of a native sequence PRO1098 cDNA, wherein SEQ ID NO:241 is a clone designated herein as "DNA59854-1459".
  • Figure 242 shows the amino acid sequence (SEQ ID NO:242) derived from the coding sequence of SEQ ID NO.-241 shown in Figure 241.
  • Figure 243 shows a nucleotide sequence (SEQ ID NO:243) of a native sequence PROH28 cDNA, wherein SEQ ID NO:243 is a clone designated herein as "DNA59855-1485".
  • Figure 244 shows the amino acid sequence (SEQ ID NO:244) derived from the coding sequence of SEQ
  • Figure 245 shows a nucleotide sequence (SEQ ID NO:245) of a native sequence PR01248 cDNA, wherein SEQ ID NO:245 is a clone designated herein as "DNA60278-1530".
  • Figure 246 shows the amino acid sequence (SEQ ID NO:246) derived from the coding sequence of SEQ ID NO:245 shown in Figure 245.
  • Figure 247 shows a nucleotide sequence (SEQ ID NO:247) of a native sequence PR01127 cDNA, wherein SEQ ID NO:247 is a clone designated herein as "DNA60283-1484".
  • Figure 248 shows the amino acid sequence (SEQ ID NO:248) derived from the coding sequence of SEQ ID NO:247 shown in Figure 247.
  • Figure 249 shows a nucleotide sequence (SEQ ID NO:249) of a native sequence PR01316 cDNA, wherein SEQ ID NO:249 is a clone designated herein as "DNA60608-1577".
  • Figure 250 shows the amino acid sequence (SEQ ID NO:250) derived from the coding sequence of SEQ ID NO:249 shown in Figure 249.
  • Figure 251 shows a nucleotide sequence (SEQ ID NO:251) of a native sequence PROH97 cDNA, wherein SEQ ID NO:251 is a clone designated herein as "DNA60611-1524".
  • Figure 252 shows the amino acid sequence (SEQ ID NO:252) derived from the coding sequence of SEQ ID NO-.251 shown in Figure 251.
  • Figure 253 shows a nucleotide sequence (SEQ ID NO:253) of a native sequence PRO 1125 cDNA, wherein SEQ ID NO:253 is a clone designated herein as "DNA60619-1482".
  • Figure 254 shows the amino acid sequence (SEQ ID NO:254) derived from the coding sequence of SEQ
  • Figure 255 shows a nucleotide sequence (SEQ ID NO:255) of a native sequence PR01158 cDNA, wherein SEQ ID NO:255 is a clone designated herein as "DNA60625-1507".
  • Figure 256 shows the amino acid sequence (SEQ ID NO:256) derived from the coding sequence of SEQ ID NO:255 shown in Figure 255.
  • Figure 257 shows a nucleotide sequence (SEQ ID NO:257) of a native sequence PR01124 cDNA, wherein SEQ ID NO:257 is a clone designated herein as "DNA60629-1481".
  • Figure 258 shows the amino acid sequence (SEQ ID NO:258) derived from the coding sequence of SEQ ID NO:257 shown in Figure 257.
  • Figure 259 shows a nucleotide sequence (SEQ ID NO:259) of a native sequence PRO1380 cDNA, wherein SEQ ID NO:259 is a clone designated herein as "DNA60740-1615".
  • Figure 260 shows the amino acid sequence (SEQ ID NO: 260) derived from the coding sequence of SEQ ID NO:259 shown in Figure 259.
  • Figure 261 shows a nucleotide sequence (SEQ ID NO:261) of a native sequence PR01377 cDNA, wherein SEQ ID NO:261 is a clone designated herein as "DNA61608-1606".
  • Figure 262 shows the amino acid sequence (SEQ ID NO: 262) derived from the coding sequence of SEQ ID NO-.261 shown in Figure 261.
  • Figure 263 shows a nucleotide sequence (SEQ ID NO-.263) of a native sequence PR01287 cDNA, wherein SEQ ID N0:263 is a clone designated herein as "DNA61755-1554".
  • Figure 264 shows the amino acid sequence (SEQ ID NO: 264) derived from the coding sequence of SEQ ID NO.-263 shown in Figure 263.
  • Figure 265 shows a nucleotide sequence (SEQ ID NO:265) of a native sequence PR01249 cDNA, wherein SEQ ID NO:265 is a clone designated herein as "DNA62809-1531 " .
  • Figure 266 shows the amino acid sequence (SEQ ID NO:266) derived from the coding sequence of SEQ ID NO:265 shown in Figure 265.
  • Figure 267 shows a nucleotide sequence (SEQ ID NO -.267) of a native sequence PRO 1335 cDN , wherein SEQ ID NO:267 is a clone designated herein as "DNA62812-1594".
  • Figure 268 shows the amino acid sequence (SEQ ID NO:268) derived from the coding sequence of SEQ
  • Figure 269 shows a nucleotide sequence (SEQ ID NO:269) of a native sequence PR03572 cDNA, wherein SEQ ID N0:269 is a clone designated herein as "DNA62813-2544".
  • Figure 270 shows the amino acid sequence (SEQ ID NO: 270) derived from the coding sequence of SEQ ID NO:269 shown in Figure 269.
  • Figure 271 shows a nucleotide sequence (SEQ ID NO:271) of a native sequence PR01599 cDNA, wherein SEQ ID NO:271 is a clone designated herein as "DNA62845-1684".
  • Figure 272 shows the amino acid sequence (SEQ ID NO:272) derived from the coding sequence of SEQ ID NO:271 shown in Figure 271.
  • Figure 273 shows a nucleotide sequence (SEQ ID NO:273) of a native sequence PR01374 cDNA, wherein SEQ ID NO:273 is a clone designated herein as "DNA64849-1604".
  • Figure 274 shows the amino acid sequence (SEQ ID NO: 274) derived from the coding sequence of SEQ ID NO:273 shown in Figure 273.
  • Figure 275 shows a nucleotide sequence (SEQ ID NO:275) of a native sequence PR01345 cDNA, wherein SEQ ID NO:275 is a clone designated herein as "DNA64852-1589".
  • Figure 276 shows the amino acid sequence (SEQ ID NO:276) derived from the coding sequence of SEQ ID NO:275 shown in Figure 275.
  • Figure 277 shows a nucleotide sequence (SEQ ID NO:277) of a native sequence PR01311 cDNA, wherein SEQ ID NO:277 is a clone designated herein as "DNA64863-1573".
  • Figure 278 shows the amino acid sequence (SEQ ID NO:278) derived from the coding sequence of SEQ ID NO:277 shown in Figure 277.
  • Figure 279 shows a nucleotide sequence (SEQ ID NO:279) of a native sequence PR01357 cDNA, wherein SEQ ID NO:279 is a clone designated herein as "DNA64881-1602".
  • Figure 280 shows the amino acid sequence (SEQ ID NO: 280) derived from the coding sequence of SEQ ID NO:279 shown in Figure 279.
  • Figure 281 shows a nucleotide sequence (SEQ ID NO:281) of a native sequence PR01557 cDNA, wherein SEQ ID NO:281 is a clone designated herein as "DNA64902-1667".
  • Figure 282 shows the amino acid sequence (SEQ ID NO:282) derived from the coding sequence of SEQ
  • Figure 283 shows a nucleotide sequence (SEQ ID NO:283) of a native sequence PRO1305 cDNA, wherein SEQ ID NO:283 is a clone designated herein as "DNA64952-1568".
  • Figure 284 shows the .amino acid sequence (SEQ ID NO: 284) derived from the coding sequence of SEQ ID NO:283 shown in Figure 283.
  • Figure 285 shows a nucleotide sequence (SEQ ID NO: 285) of a native sequence PRO 1302 cDNA, wherein SEQ ID NO:285 is a clone designated herein as "DNA65403-1565".
  • Figure 286 shows the amino acid sequence (SEQ ID NO:286) derived from the coding sequence of SEQ ID NO:285 shown in Figure 285.
  • Figure 287 shows a nucleotide sequence (SEQ ID NO:287) of a native sequence PR01266 cDNA, wherein SEQ ID NO:287 is a clone designated herein as "DNA65413-1534".
  • Figure 288 shows the amino acid sequence (SEQ ID NO:288) derived from the coding sequence of SEQ ID NO:287 shown in Figure 287.
  • Figures 289A-289B show a nucleotide sequence (SEQ ID NO:289) of a native sequence PR01336 cDNA, wherein SEQ ID NO:289 is a clone designated herein as "DNA65423-1595" .
  • Figure 290 shows the amino acid sequence (SEQ ID NO:290) derived from the coding sequence of SEQ ID NO:289 shown in Figures 289A-289B.
  • Figure 291 shows a nucleotide sequence (SEQ ID NO:291) of a native sequence PR01278 cDNA, wherein SEQ ID NO:291 is a clone designated herein as "DNA66304-1546".
  • Figure 292 shows the amino acid sequence (SEQ ID NO:292) derived from the coding sequence of SEQ
  • Figure 293 shows a nucleotide sequence (SEQ ID NO:293) of a native sequence PRO 1270 cDNA, wherein SEQ ID NO:293 is a clone designated herein as "DNA66308-1537".
  • Figure 294 shows the amino acid sequence (SEQ ID NO:294) derived from the coding sequence of SEQ ID NO :293 shown in Figure 293.
  • Figure 295 shows a nucleotide sequence (SEQ ID NO:295) of a native sequence PR01298 cDNA, wherein SEQ ID NO:295 is a clone designated herein as "DNA66511-1563".
  • Figure 296 shows the amino acid sequence (SEQ ID NO:296) derived from the coding sequence of SEQ ID NO:295 shown in Figure 295.
  • Figure 297 shows a nucleotide sequence (SEQ ID NO:297) of a native sequence PRO1301 cDNA, wherein SEQ ID NO:297 is a clone designated herein as "DNA66512-1564".
  • Figure 298 shows the amino acid sequence (SEQ ID NO:298) derived from the coding sequence of SEQ ID NO:297 shown in Figure 297.
  • Figure 299 shows a nucleotide sequence (SEQ ID NO:299) of a native sequence PR01268 cDNA, wherein SEQ ID NO:299 is a clone designated herein as "DNA66519-1535".
  • Figure 300 shows the amino acid sequence (SEQ ID NO: 300) derived from the coding sequence of SEQ ID NO:299 shown in Figure 299.
  • Figure 301 shows a nucleotide sequence (SEQ ID NO:301) of a native sequence PR01327 cDNA, wherein SEQ ID NO:301 is a clone designated herein as "DNA66521-1583".
  • Figure 302 shows the amino acid sequence (SEQ ID NO:302) derived from the coding sequence of SEQ ID NO:301 shown in Figure 301.
  • Figure 303 shows a nucleotide sequence (SEQ ID NO:303) of a native sequence PR01328 cDNA, wherein SEQ ID NO:303 is a clone designated herein as "DNA66658-1584".
  • Figure 304 shows the amino acid sequence (SEQ ID NO: 304) derived from the coding sequence of SEQ ID NO:303 shown in Figure 303.
  • Figure 305 shows a nucleotide sequence (SEQ ID NO:305) of a native sequence PR01329 cDNA, wherein SEQ ID NO:305 is a clone designated herein as "DNA66660-1585".
  • Figure 306 shows the amino acid sequence (SEQ ID NO: 306) derived from the coding sequence of SEQ
  • Figure 307 shows a nucleotide sequence (SEQ ID NO:307) of a native sequence PR01339 cDNA, wherein SEQ ID NO:307 is a clone designated herein as "DNA66669-1597".
  • Figure 308 shows the amino acid sequence (SEQ ID NO:308) derived from the coding sequence of SEQ ID NO:307 shown in Figure 307.
  • Figure 309 shows a nucleotide sequence (SEQ ID NO:309) of a native sequence PR01342 cDNA, wherein SEQ ID NO:309 is a clone designated herein as "DNA66674-1599".
  • Figure 310 shows the amino acid sequence (SEQ ID NO:310) derived from the coding sequence of SEQ ID NO:309 shown in Figure 309.
  • Figures 311A-311B show a nucleotide sequence (SEQ ID NO:311) of a native sequence PR01487 cDNA, wherein SEQ ID NO:311 is a clone designated herein as "DNA68836-1656".
  • Figure 312 shows the amino acid sequence (SEQ ID NO:312) derived from the coding sequence of SEQ ID NO:311 shown in Figures 311A-311B.
  • Figure 313 shows a nucleotide sequence (SEQ ID NO:313) of a native sequence PR03579 cDNA, wherein SEQ ID NO:313 is a clone designated herein as "DNA68862-2546".
  • Figure 314 shows the amino acid sequence (SEQ ID NO:314) derived from the coding sequence of SEQ ID NO-.313 shown in Figure 313.
  • Figure 315 shows a nucleotide sequence (SEQ ID NO:315) of a native sequence PR01472 cDNA, wherein SEQ ID NO:315 is a clone designated herein as "DNA68866-1644".
  • Figure 316 shows the amino acid sequence (SEQ ID NO:316) derived from the coding sequence of SEQ ID NO:315 shown in Figure 315.
  • Figure 317 shows a nucleotide sequence (SEQ ID NO:317) of a native sequence PR01385 cDNA, wherein SEQ ID NO:317 is a clone designated herein as "DNA68869-1610" .
  • Figure 318 shows the amino acid sequence (SEQ ID NO:318) derived from the coding sequence of SEQ ID NO:317 shown in Figure 317.
  • Figure 319 shows a nucleotide sequence (SEQ ID NO:319) of a native sequence PR01461 cDNA, wherein SEQ ID NO:319 is a clone designated herein as "DNA68871-1638".
  • Figure 320 shows the amino acid sequence (SEQ ID NO:320) derived from the coding sequence of SEQ
  • Figure 321 shows a nucleotide sequence (SEQ ID NO:321) of a native sequence PR01429 cDNA, wherein SEQ ID NO:321 is a clone designated herein as "DNA68879-1631".
  • Figure 322 shows the amino acid sequence (SEQ ID NO: 322) derived from the coding sequence of SEQ ID NO:321 shown in Figure 321.
  • Figure 323 shows a nucleotide sequence (SEQ ID NO:323) of a native sequence PR01568 cDNA, wherein SEQ ID NO:323 is a clone designated herein as "DNA68880-1676".
  • Figure 324 shows the amino acid sequence (SEQ ID NO: 324) derived from the coding sequence of SEQ ID NO: 323 shown in Figure 323.
  • Figure 325 shows a nucleotide sequence (SEQ ID NO:325) of a native sequence PR01569 cDNA, wherein SEQ ID NO:325 is a clone designated herein as "DNA68882-1677".
  • Figure 326 shows the amino acid sequence (SEQ ID NO: 326) derived from the coding sequence of SEQ ID NO: 325 shown in Figure 325.
  • Figure 327 shows a nucleotide sequence (SEQ ID NO:327) of a native sequence PR01753 cDNA, wherein SEQ ID NO:327 is a clone designated herein as "DNA68883-1691 " .
  • Figure 328 shows the amino acid sequence (SEQ ID NO: 328) derived from the coding sequence of SEQ ID NO:327 shown in Figure 327.
  • Figure 329 shows a nucleotide sequence (SEQ ID NO:329) of a native sequence PRO1570 cDNA, wherein SEQ ID NO:329 is a clone designated herein as "DNA68885-1678".
  • Figure 330 shows the amino acid sequence (SEQ ID NO:330) derived from the coding sequence of SEQ
  • Figure 331 shows a nucleotide sequence (SEQ ID NO:331) of a native sequence PR01559 cDNA, wherein SEQ ID NO: 331 is a clone designated herein as "DNA68886".
  • Figure 332 shows the amino acid sequence (SEQ ID NO: 332) derived from the coding sequence of SEQ ID NO:331 shown in Figure 331.
  • Figure 333 shows a nucleotide sequence (SEQ ID NO:333) of a native sequence PR01486 cDNA, wherein SEQ ID NO:333 is a clone designated herein as "DNA71180-1655".
  • Figure 334 shows the amino acid sequence (SEQ ID NO:334) derived from the coding sequence of SEQ ID NO:333 shown in Figure 333.
  • Figure 335 shows a nucleotide sequence (SEQ ID NO:335) of a native sequence PRO 1433 cDNA, wherein SEQ ID NO: 335 is a clone designated herein as "DNA71184-1634".
  • Figure 336 shows the amino acid sequence (SEQ ID NO:336) derived from the coding sequence of SEQ ID NO:335 shown in Figure 335.
  • Figure 337 shows a nucleotide sequence (SEQ ID NO:337) of a native sequence PRO1490 cDNA, wherein SEQ ID NO:337 is a clone designated herein as "DNA71213-1659".
  • Figure 338 shows the amino acid sequence (SEQ ID NO: 338) derived from the coding sequence of SEQ ID NO:337 shown in Figure 337.
  • Figure 339 shows a nucleotide sequence (SEQ ID NO:339) of a native sequence PR01482 cDNA, wherein SEQ ID NO:339 is a clone designated herein as "DNA71234-1651".
  • Figure 340 shows the amino acid sequence (SEQ ID NO: 340) derived from the coding sequence of SEQ ID NO:339 shown in Figure 339.
  • Figure 341 shows a nucleotide sequence (SEQ ID NO:341) of a native sequence PRO1409 cDNA, wherein SEQ ID NO:341 is a clone designated herein as "DNA71269-1621 " .
  • Figure 342 shows the amino acid sequence (SEQ ID NO: 342) derived from the coding sequence of SEQ ID NO:341 shown in Figure 341.
  • Figure 343 shows a nucleotide sequence (SEQ ID NO:343) of a native sequence PR01446 cDNA, wherein SEQ ID NO:343 is a clone designated herein as "DNA71277-1636".
  • Figure 344 shows the amino acid sequence (SEQ ID NO: 344) derived from the coding sequence of SEQ
  • Figure 345 shows a nucleotide sequence (SEQ ID NO:345) of a native sequence PRO1604 cDNA, wherein SEQ ID NO:345 is a clone designated herein as "DNA71286-1687".
  • Figure 346 shows the amino acid sequence (SEQ ID NO: 346) derived from the coding sequence of SEQ ID NO:345 shown in Figure 345.
  • Figure 347 shows a nucleotide sequence (SEQ ID NO:347) of a native sequence PR01491 cDNA, wherein SEQ ID NO:347 is a clone designated herein as "DNA71883-1660".
  • Figure 348 shows the amino acid sequence (SEQ ID NO: 348) derived from the coding sequence of SEQ ID NO: 347 shown in Figure 347.
  • Figure 349 shows a nucleotide sequence (SEQ ID NO:349) of a native sequence PR01431 cDNA, wherein SEQ ID NO:349 is a clone designated herein as "DNA73401-1633 " .
  • Figure 350 shows the amino acid sequence (SEQ ID NO:350) derived from the coding sequence of SEQ ID NO:349 shown in Figure 349.
  • Figures 351A-351B show a nucleotide sequence (SEQ ID NO:351) of a native sequence PR01563 " cDNA, wherein SEQ ID NO:351 is a clone designated herein as "DNA73492-1671".
  • Figure 352 shows the amino acid sequence (SEQ ID NO:352) derived from the coding sequence of SEQ ID NO:351 shown in Figures 351A-351B.
  • Figure 353 shows a nucleotide sequence (SEQ ID NO:353) of a native sequence PR01571 cDNA, wherein SEQ ID NO:353 is a clone designated herein as "DNA73730-1679".
  • Figure 354 shows the amino acid sequence (SEQ ID NO: 354) derived from the coding sequence of SEQ ID NO:353 shown in Figure 353.
  • Figure 355 shows a nucleotide sequence (SEQ ID NO:355) of a native sequence PR01572 cDNA, wherein SEQ ID NO:355 is a clone designated herein as "DNA73734-1680".
  • Figure 356 shows the amino acid sequence (SEQ ID NO:356) derived from the coding sequence of SEQ ID NO:355 shown in Figure 355.
  • Figure 357 shows a nucleotide sequence (SEQ ID NO:357) of a native sequence PR01573 cDNA, wherein SEQ ID NO:357 is a clone designated herein as "DNA73735-1681".
  • Figure 358 shows the amino acid sequence (SEQ ID NO:358) derived from the coding sequence of SEQ
  • Figure 359 shows a nucleotide sequence (SEQ ID NO:359) of a native sequence PRO1508 cDNA, wherein SEQ ID NO:359 is a clone designated herein as "DNA73742-1662".
  • Figure 360 shows the amino acid sequence (SEQ ID NO:360) derived from the coding sequence of SEQ ID NO:359 shown in Figure 359.
  • Figure 361 shows a nucleotide sequence (SEQ ID NO:361) of a native sequence PR01485 cDNA, wherein SEQ ID NO:361 is a clone designated herein as "DNA73746-1654".
  • Figure 362 shows the amino acid sequence (SEQ ID NO:362) derived from the coding sequence of SEQ ID NO:361 shown in Figure 361.
  • Figure 363 shows a nucleotide sequence (SEQ ID NO:363) of a native sequence PR01564 cDNA, wherein SEQ ID NO:363 is a clone designated herein as "DNA73760-1672".
  • Figure 364 shows the amino acid sequence (SEQ ID NO:364) derived from the coding sequence of SEQ ID NO:363 shown in Figure 363.
  • Figure 365 shows a nucleotide sequence (SEQ ID NO:365) of a native sequence PRO1550 cDNA, wherein SEQ ID NO:365 is a clone designated herein as "DNA76393-1664".
  • Figure 366 shows the amino acid sequence (SEQ ID NO: 366) derived from the coding sequence of SEQ ID NO:365 shown in Figure 365.
  • Figure 367 shows a nucleotide sequence (SEQ ID NO:367) of a native sequence PR01757 cDNA, wherein SEQ ID NO:367 is a clone designated herein as "DNA76398-1699".
  • Figure 368 shows the amino acid sequence (SEQ ID NO:368) derived from the coding sequence of SEQ
  • Figure 369 shows a nucleotide sequence (SEQ ID NO:369) of a native sequence PR01758 cDNA, wherein SEQ ID NO:369 is a clone designated herein as "DNA76399-1700".
  • Figure 370 shows the amino acid sequence (SEQ ID NO: 370) derived from the coding sequence of SEQ ID NO:369 shown in Figure 369.
  • Figure 371 shows a nucleotide sequence (SEQ ID NO:371) of a native sequence PR01781 cDNA, wherein SEQ ID NO:371 is a clone designated herein as "DNA76522-2500”.
  • Figure 372 shows the amino acid sequence (SEQ ID NO: 372) derived from the coding sequence of SEQ ID NO:371 shown in Figure 371.
  • Figure 373 shows a nucleotide sequence (SEQ ID NO:373) of a native sequence PRO1606 cDNA, wherein SEQ ID NO:373 is a clone designated herein as "DNA76533-1689".
  • Figure 374 shows the amino acid sequence (SEQ ID NO: 374) derived from the coding sequence of SEQ ID NO:373 shown in Figure 373.
  • Figure 375 shows a nucleotide sequence (SEQ ID NO:375) of a native sequence PR01784 cDNA, wherein SEQ ID NO:375 is a clone designated herein as "DNA77303-2502".
  • Figure 376 shows the amino acid sequence (SEQ ID NO:376) derived from the coding sequence of SEQ ID NO:375 shown in Figure 375.
  • Figure 377 shows a nucleotide sequence (SEQ ID NO:377) of a native sequence PR01774 cDNA, wherein SEQ ID NO:377 is a clone designated herein as "DNA77626-1705".
  • Figure 378 shows the amino acid sequence (SEQ ID NO:378) derived from the coding sequence of SEQ ID NO:377 shown in Figure 377.
  • Figure 379 shows a nucleotide sequence (SEQ ID NO:379) of a native sequence PRO1605 cDNA, wherein SEQ ID NO:379 is a clone designated herein as "DNA77648-1688" .
  • Figure 380 shows the amino acid sequence (SEQ ID NO:380) derived from the coding sequence of SEQ ID NO:379 shown in Figure 379.
  • Figure 381 shows a nucleotide sequence (SEQ ID NO:381) of a native sequence PR01928 cDNA, wherein SEQ ID NO:381 is a clone designated herein as "DNA81754-2532".
  • Figure 382 shows the amino acid sequence (SEQ ID NO:382) derived from the coding sequence of SEQ
  • Figure 383 shows a nucleotide sequence (SEQ ID NO:383) of a native sequence PR01865 cDNA, wherein SEQ ID NO:383 is a clone designated herein as "DNA81757-2512".
  • Figure 384 shows the amino acid sequence (SEQ ID NO:384) derived from the coding sequence of SEQ ID NO:383 shown in Figure 383.
  • Figure 385 shows a nucleotide sequence (SEQ ID NO:385) of a native sequence PR01925 cDNA, wherein SEQ ID NO:385 is a clone designated herein as "DNA82302-2529".
  • Figure 386 shows the amino acid sequence (SEQ ID NO:386) derived from the coding sequence of SEQ ID NO:385 shown in Figure 385.
  • Figure 387 shows a nucleotide sequence (SEQ ID NO:387) of a native sequence PR01926 cDNA, wherein SEQ ID NO:387 is a clone designated herein as "DNA82340-2530".
  • Figure 388 shows the amino acid sequence (SEQ ID NO:388) derived from the coding sequence of SEQ ID NO:387 shown in Figure 387.
  • Figure 389 shows a nucleotide sequence (SEQ ID NO:389) of a native sequence PRO2630 cDNA, wherein SEQ ID NO:389 is a clone designated herein as "DNA83551".
  • Figure 390 shows the amino acid sequence (SEQ ID NO:390) derived from the coding sequence of SEQ ID NO:389 shown in Figure 389.
  • Figure 391 shows a nucleotide sequence (SEQ ID NO:391) of a native sequence PR03443 cDNA, wherein SEQ ID NO:391 is a clone designated herein as "DNA87991-2540".
  • Figure 392 shows the amino acid sequence (SEQ ID NO:392) derived from the coding sequence of SEQ ID NO:391 shown in Figure 391.
  • Figure 393 shows a nucleotide sequence (SEQ ID NO:393) of a native sequence PRO3301 cDNA, wherein SEQ ID NO:393 is a clone designated herein as "DNA88002" .
  • Figure 394 shows the amino acid sequence (SEQ ID NO: 394) derived from the coding sequence of SEQ ID NO:393 shown in Figure 393.
  • Figure 395 shows a nucleotide sequence (SEQ ID NO:395) of a native sequence PR03442 cDNA, wherein SEQ ID NO:395 is a clone designated herein as "DNA92238-2539".
  • Figure 396 shows the amino acid sequence (SEQ ID NO:396) derived from the coding sequence of SEQ
  • Figure 397 shows a nucleotide sequence (SEQ ID NO:397) of a native sequence PR04978 cDNA, wherein SEQ ID NO:397 is a clone designated herein as "DNA95930".
  • Figure 398 shows the amino acid sequence (SEQ ID NO:398) derived from the coding sequence of SEQ ID NO:397 shown in Figure 397.
  • Figure 399 shows a nucleotide sequence (SEQ ID NO:399) of a native sequence PRO5801 cDNA, wherein SEQ ID NO:399 is a clone designated herein as "DNA115291-2681".
  • Figure 400 shows the amino acid sequence (SEQ ID NO: 400) derived from the coding sequence of SEQ ID NO:399 shown in Figure 399.
  • Figure 401 shows a nucleotide sequence (SEQ ID NO:401) of a native sequence PRO19630 cDNA, wherein SEQ ID NO:401 is a clone designated herein as "DNA23336-2861".
  • Figure 402 shows the amino acid sequence (SEQ ID NO: 402) derived from the coding sequence of SEQ ID NO:401 shown in Figure 401.
  • Figure 403 shows a nucleotide sequence (SEQ ID NO:403) of a native sequence PRO203 cDNA, wherein SEQ ID NO:403 is a clone designated herein as "DNA30862-1396" .
  • Figure 404 shows the amino acid sequence (SEQ ID NO: 404) derived from the coding sequence of SEQ ID NO:403 shown in Figure 403.
  • Figure 405 shows anucleotide sequence (SEQ ID NO:405) of anative sequence PRO204 cDNA, wherein SEQ ID NO:405 is a clone designated herein as "DNA30871-1157”.
  • Figure 406 shows the amino acid sequence (SEQ ID NO:406) derived from the coding sequence of SEQ
  • Figure 407 shows a nucleotide sequence (SEQ ID NO:407) of anative sequence PRO210 cDNA, wherein SEQ ID NO:407 is a clone designated herein as "DNA32279-1131".
  • Figure 408 shows the amino acid sequence (SEQ ID NO: 408) derived from the coding sequence of SEQ ID NO:407 shown in Figure 407.
  • Figure 409 shows a nucleotide sequence (SEQ ID NO:409) of a native sequence PR0223 cDNA, wherein SEQ ID NO:409 is a clone designated herein as "DNA33206-1165".
  • Figure 410 shows the amino acid sequence (SEQ ID NO:410) derived from the coding sequence of SEQ ID NO:409 shown in Figure 409.
  • Figure 411 shows anucleotide sequence (SEQ ID NO:411) of anative sequence PR0247 cDNA, wherein SEQ ID N0:411 is a clone designated herein as "DNA35673-1201".
  • Figure 412 shows the amino acid sequence (SEQ ID NO:412) derived from the coding sequence of SEQ ID NO:411 shown in Figure 411.
  • Figure 413 shows a nucleotide sequence (SEQ ID NO:413) of a native sequence PR0358 cDNA, wherein SEQ ID NO:413 is a clone designated herein as "DNA47361-1154-2".
  • Figure 414 shows the amino acid sequence (SEQ ID NO:414) derived from the coding sequence of SEQ ID NO:413 shown in Figure 413.
  • Figure 415 shows anucleotide sequence (SEQ ID NO:415) of anative sequence PR0724 cDNA, wherein
  • SEQ ID NO:415 is a clone designated herein as "DNA49631-1328".
  • Figure 416 shows the amino acid sequence (SEQ ID NO:416) derived from the coding sequence of SEQ ID NO:415 shown in Figure 415.
  • Figure 417 shows anucleotide sequence (SEQ ID NO:417) of anative sequence PR0868 cDNA, wherein SEQ ID NO:417 is a clone designated herein as "DNA52594-1270".
  • Figure 418 shows the amino acid sequence (SEQ ID NO:418) derived from the coding sequence of SEQ ID NO:417 shown in Figure 417.
  • Figure 419 shows a nucleotide sequence (SEQ ID NO:419) of a native sequence PRO740 cDNA, wherein SEQ ID NO:419 is a clone designated herein as "DNA55800-1263".
  • Figure 420 shows the amino acid sequence (SEQ ID NO: 420) derived from the coding sequence of SEQ
  • Figure 421 shows a nucleotide sequence (SEQ ID NO:421) of a native sequence PR01478 cDNA, wherein SEQ ID NO:421 is a clone designated herein as "DNA56531-1648".
  • Figure 422 shows the amino acid sequence (SEQ ID NO: 422) derived from the coding sequence of SEQ ID NO:421 shown in Figure 421.
  • Figure 423 shows anucleotide sequence (SEQ ID NO: 423) of anative sequence PRO 162 cDNA, wherein SEQ ID NO:423 is a clone designated herein as "DNA56965-1356".
  • Figure 424 shows the amino acid sequence (SEQ ID NO: 424) derived from the coding sequence of SEQ ID NO:423 shown in Figure 423.
  • Figure 425 shows anucleotide sequence (SEQ ID NO: 425) of a native sequence PR0828 cDNA, wherein
  • SEQ ID NO:425 is a clone designated herein as "DNA57037-1444".
  • Figure 426 shows the amino acid sequence (SEQ ID NO:426) derived from the coding sequence of SEQ ID NO:425 shown in Figure 425.
  • Figure 427 shows anucleotide sequence (SEQ ID NO:427) of a native sequence PR0819 cDNA, wherein SEQ ID NO:427 is a clone designated herein as "DNA57695-1340" .
  • Figure 428 shows the amino acid sequence (SEQ ID NO: 428) derived from the coding sequence of SEQ ID NO:427 shown in Figure 427.
  • Figure 429 shows anucleotide sequence (SEQ ID NO: 429) of a native sequence PR0813 cDNA, wherein SEQ ID NO:429 is a clone designated herein as "DNA57834-1339".
  • Figure 430 shows the amino acid sequence (SEQ ID NO:430) derived from the coding sequence of SEQ ID NO:429 shown in Figure 429.
  • Figure 431 shows a nucleotide sequence (SEQ ID NO:431) of a native sequence PR01194 cDNA, wherein SEQ ID NO:431 is a clone designated herein as "DNA57841-1522".
  • Figure 432 shows the amino acid sequence (SEQ ID NO:432) derived from the coding sequence of SEQ ID NO: 431 shown in Figure 431.
  • Figure 433 shows anucleotide sequence (SEQ ID NO:433) of a native sequence PR0887 cDNA, wherein SEQ ID NO:433 is a clone designated herein as "DNA58130".
  • Figure 434 shows the amino acid sequence (SEQ ID NO:434) derived from the coding sequence of SEQ
  • Figure 435 shows a nucleotide sequence (SEQ ID NO:435) of a native sequence PRO1071 cDNA, wherein SEQ ID NO:435 is a clone designated herein as "DNA58847-1383".
  • Figure 436 shows the amino acid sequence (SEQ ID NO:436) derived from the coding sequence of SEQ ID NO:435 shown in Figure 435.
  • Figure 437 shows a nucleotide sequence (SEQ ID NO:437) of a native sequence PRO1029 cDNA, wherein SEQ ID NO:437 is a clone designated herein as "DNA59493-1420".
  • Figure 438 shows the amino acid sequence (SEQ ID NO:438) derived from the coding sequence of SEQ ID NO:437 shown in Figure 437.
  • Figure 439 shows a nucleotide sequence (SEQ ID NO:439) of a native sequence PRO1190 cDNA, wherein SEQ ID NO:439 is a clone designated herein as "DNA59586-1520".
  • Figure 440 shows the amino acid sequence (SEQ ID NO: 440) derived from the coding sequence of SEQ ID NO:439 shown in Figure 439.
  • Figure 441 shows a nucleotide sequence (SEQ ID NO:441) of a native sequence PR04334 cDNA, wherein SEQ ID NO:441 is a clone designated herein as "DNA59608-2577".
  • Figure 442 shows the amino acid sequence (SEQ ID NO:442) derived from the coding sequence of SEQ ID NO:441 shown in Figure 441.
  • Figure 443 shows a nucleotide sequence (SEQ ID NO:443) of a native sequence PR01155 cDNA, wherein SEQ ID NO:443 is a clone designated herein as "DNA59849-1504".
  • Figure 444 shows the amino acid sequence (SEQ ID NO: 444) derived from the coding sequence of SEQ
  • Figure 445 shows a nucleotide sequence (SEQ ID NO: 445) of a native sequence PRO 1157 cDNA, wherein SEQ ID NO:445 is a clone designated herein as "DNA60292-1506".
  • Figure 446 shows the amino acid sequence (SEQ ID NO: 446) derived from the coding sequence of SEQ ID NO:445 shown in Figure 445.
  • Figure 447 shows a nucleotide sequence (SEQ ID NO:447) of a native sequence PR01122 cDNA, wherein SEQ ID NO:447 is a clone designated herein as "DNA62377-1381-1".
  • Figure 448 shows the amino acid sequence (SEQ ID NO: 448) derived from the coding sequence of SEQ ID NO:447 shown in Figure 447.
  • Figure 449 shows a nucleotide sequence (SEQ ID NO:449) of a native sequence PR01183 cDNA, wherein SEQ ID NO:449 is a clone designated herein as "DNA62880-1513".
  • Figure 450 shows the amino acid sequence (SEQ ID NO: 450) derived from the coding sequence of SEQ ID NO:449 shown in Figure 449.
  • Figure 451 shows a nucleotide sequence (SEQ ID NO:451) of a native sequence PR01337 cDNA, wherein SEQ ID NO:451 is a clone designated herein as "DNA66672-1586".
  • Figure 452 shows the amino acid sequence (SEQ ID NO: 452) derived from the coding sequence of SEQ ID NO:451 shown in Figure 451.
  • Figure 453 shows a nucleotide sequence (SEQ ID NO:453) of a native sequence PRO1480 cDNA, wherein SEQ ID NO:453 is a clone designated herein as "DNA67962-1649".
  • Figure 454 shows the amino acid sequence (SEQ ID NO:454) derived from the coding sequence of SEQ ID NO:453 shown in Figure 453.
  • Figure 455 shows a nucleotide sequence (SEQ ID NO:455) of a native sequence PR019645 cDNA, wherein SEQ ID NO:455 is a clone designated herein as "DNA69555-2867" .
  • Figure 456 shows the amino acid sequence (SEQ ID NO:456) derived from the coding sequence of SEQ ID NO:455 shown in Figure 455.
  • Figure 457 shows a nucleotide sequence (SEQ ID NO:457) of a native sequence PR09782 cDNA, wherein SEQ ID NO:457 is a clone designated herein as "DNA71162-2764".
  • Figure 458 shows the amino acid sequence (SEQ ID NO:458) derived from the coding sequence of SEQ
  • Figure 459 shows a nucleotide sequence (SEQ ID NO:459) of a native sequence PR01419 cDNA, wherein SEQ ID NO:459 is a clone designated herein as "DNA71290-1630".
  • Figure 460 shows the amino acid sequence (SEQ ID NO: 460) derived from the coding sequence of SEQ ID NO:459 shown in Figure 459.
  • Figure 461 shows a nucleotide sequence (SEQ ID NO:461) of a native sequence PR01575 cDNA, wherein SEQ ID NO-.461 is a clone designated herein as "DNA76401-1683".
  • Figure 462 shows the amino acid sequence (SEQ ID NO:462) derived from the coding sequence of SEQ ID NO:461 shown in Figure 461.
  • Figure 463 shows a nucleotide sequence (SEQ ID NO:463) of a native sequence PR01567 cDNA, wherein SEQ ID NO:463 is a clone designated herein as "DNA76541-1675".
  • Figure 464 shows the amino acid sequence (SEQ ID N0:464) derived from the coding sequence of SEQ ID NO: 463 shown in Figure 463.
  • Figure 465 shows a nucleotide sequence (SEQ ID NO:465) of a native sequence PR01891 cDNA, wherein SEQ ID NO:465 is a clone designated herein as "DNA76788-2526" .
  • Figure 466 shows the amino acid sequence (SEQ ID NO: 466) derived from the coding sequence of SEQ ID NO:465 shown in Figure 465.
  • Figure 467 shows a nucleotide sequence (SEQ ID NO:467) of a native sequence PR01889 cDNA, wherein SEQ ID NO:467 is a clone designated herein as "DNA77623-2524".
  • Figure 468 shows the amino acid sequence (SEQ ID NO:468) derived from the coding sequence of SEQ ID NO:467 shown in Figure 467.
  • Figure 469 shows a nucleotide sequence (SEQ ID NO:469) of a native sequence PR01785 cDNA, wherein SEQ ID NO:469 is a clone designated herein as "DNA80136-2503" .
  • Figure 470 shows the amino acid sequence (SEQ ID NO:470) derived from the coding sequence of SEQ ID NO:469 shown in Figure 469.
  • Figure 471 shows a nucleotide sequence (SEQ ID NO:471) of a native sequence PRO6003 cDNA, wherein SEQ ID NO:471 is a clone designated herein as "DNA83568-2692".
  • Figure 472 shows the amino acid sequence (SEQ ID NO:472) derived from the coding sequence of SEQ
  • Figure 473 shows a nucleotide sequence (SEQ ID NO:473) of a native sequence PR04333 cDNA, wherein SEQ ID NO:473 is a clone designated herein as "DNA84210-2576".
  • Figure 474 shows the amino acid sequence (SEQ ID NO:474) derived from the coding sequence of SEQ ID NO:473 shown in Figure 473.
  • Figure 475 shows a nucleotide sequence (SEQ ID NO:475) of a native sequence PR04356 cDNA, wherein SEQ ID NO:475 is a clone designated herein as "DNA86576-2595".
  • Figure 476 shows the amino acid sequence (SEQ ID NO: 476) derived from the coding sequence of SEQ ID NO:475 shown in Figure 475.
  • Figure 477 shows a nucleotide sequence (SEQ ID NO:477) of a native sequence PR04352 cDNA, wherein SEQ ID NO:477 is a clone designated herein as "DNA87976-2593".
  • Figure 478 shows the amino acid sequence (SEQ ID NO:478) derived from the coding sequence of SEQ ID NO:477 shown in Figure 477.
  • Figure 479 shows a nucleotide sequence (SEQ ID NO:479) of a native sequence PR04354 cDNA, wherein SEQ ID NO:479 is a clone designated herein as "DNA92256-2596".
  • Figure 480 shows the amino acid sequence (SEQ ID NO: 480) derived from the coding sequence of SEQ ID NO:479 shown in Figure 479.
  • Figure 481 shows a nucleotide sequence (SEQ ID NO:481) of a native sequence PR04369 cDNA, wherem SEQ ID NO:481 is a clone designated herein as "DNA92289-2598".
  • Figure 482 shows the amino acid sequence (SEQ ID NO:482) derived from the coding sequence of SEQ
  • Figure 483 shows a nucleotide sequence (SEQ ID NO:483) of a native sequence PRO6030 cDNA, wherein SEQ ID NO:483 is a clone designated herein as "DNA96850-2705".
  • Figure 484 shows the amino acid sequence (SEQ ID NO: 484) derived from the coding sequence of SEQ ID NO:483 shown in Figure 483.
  • Figure 485 shows a nucleotide sequence (SEQ ID NO:485) of a native sequence PR04433 cDNA, wherein SEQ ID NO:485 is a clone designated herein as "DNA96855-2629".
  • Figure 486 shows the amino acid sequence (SEQ ID NO:486) derived from the coding sequence of SEQ ID NO:485 shown in Figure 485.
  • Figure 487 shows a nucleotide sequence (SEQ ID NO:487) of a native sequence PR04424 cDNA, wherein SEQ ID NO:487 is a clone designated herein as "DNA96857-2636".
  • Figure 488 shows the amino acid sequence (SEQ ID NO:488) derived from the coding sequence of SEQ ID NO:487 shown in Figure 487.
  • Figure 489 shows a nucleotide sequence (SEQ ID NO:489) of a native sequence PRO6017 cDNA, wherein SEQ ID NO:489 is a clone designated herein as "DNA96860-2700".
  • Figure 490 shows the amino acid sequence (SEQ ID NO:490) derived from the coding sequence of SEQ ID NO:489 shown in Figure 489.
  • Figure 491 shows a nucleotide sequence (SEQ ID NO:491) of a native sequence PR019563 cDNA, wherein SEQ ID NO:491 is a clone designated herein as "DNA96861-2844".
  • Figure 492 shows the amino acid sequence (SEQ ID NO: 492) derived from the coding sequence of SEQ ID NO:491 shown in Figure 491.
  • Figure 493 shows a nucleotide sequence (SEQ ID NO:493) of a native sequence PRO6015 cDNA, wherein SEQ ID NO:493 is a clone designated herein as "DNA96866-2698".
  • Figure 494 shows the amino acid sequence (SEQ ID NO:494) derived from the coding sequence of SEQ ID NO:493 shown in Figure 493.
  • Figure 495 shows a nucleotide sequence (SEQ ID NO:495) of a native sequence PR05779 cDNA, wherein SEQ ID NO:495 is a clone designated herein as "DNA96870-2676".
  • Figure 496 shows the amino acid sequence (SEQ ID NO: 496) derived from the coding sequence of SEQ
  • Figure 497 shows a nucleotide sequence (SEQ ID NO:497) of a native sequence PR05776 cDNA, wherein SEQ ID NO:497 is a clone designated herein as "DNA96872-2674".
  • Figure 498 shows the amino acid sequence (SEQ ID NO:498) derived from the coding sequence of SEQ ID NO:497 shown in Figure 497.
  • Figure 499 show ' s a nucleotide sequence (SEQ ID NO:499) of a native sequence PRO4430 cDNA, wherein SEQ ID NO: 499 is a clone designated herein as "DNA96878-2626".
  • Figure 500 shows the amino acid sequence (SEQ ID NO: 500) derived from the coding sequence of SEQ ID NO.-499 shown in Figure 499.
  • Figure 501 shows a nucleotide sequence (SEQ ID NO:501) of a native sequence PR04421 cDNA, wherein SEQ ID NO:501 is a clone designated herein as "DNA96879-2619".
  • Figure 502 shows the amino acid sequence (SEQ ID NO: 502) derived from the coding sequence of SEQ ID NO:501 shown in Figure 501.
  • Figure 503 shows a nucleotide sequence (SEQ ID NO: 503) of a native sequence PR04499 cDNA, wherein SEQ ID NO:503 is a clone designated herein as "DNA96889-2641 " .
  • Figure 504 shows the amino acid sequence (SEQ ID NO:504) derived from the coding sequence of SEQ ID NO:503 shown in Figure 503.
  • Figure 505 shows a nucleotide sequence (SEQ ID NO:505) of a native sequence PR04423 cDNA, wherein SEQ ID NO:505 is a clone designated herein as "DNA96893-2621".
  • Figure 506 shows the amino acid sequence (SEQ ID NO: 506) derived from the coding sequence of SEQ ID NO:505 shown in Figure 505.
  • Figure 507 shows a nucleotide sequence (SEQ ID NO:507) of a native sequence PR05998 cDNA, wherein SEQ ID NO:507 is a clone designated herein as "DNA96897-2688".
  • Figure 508 shows the amino acid sequence (SEQ ID NO: 508) derived from the coding sequence of SEQ ID NO:507 shown in Figure 507.
  • Figure 509 shows a nucleotide sequence (SEQ ID NO:509) of a native sequence PRO4501 cDNA, wherein SEQ ID NO:509 is a clone designated herein as "DNA98564-2643".
  • Figure 510 shows the amino acid sequence (SEQ ID NO:510) derived from the coding sequence of SEQ
  • Figure 511 shows a nucleotide sequence (SEQ ID NO:511) of a native sequence PRO6240 cDNA, wherein SEQ ID NO:511 is a clone designated herein as "DNA107443-2718".
  • Figure 512 shows the amino acid sequence (SEQ ID NO:512) derived from the coding sequence of SEQ ID NO:511 shown in Figure 511.
  • Figure 513 shows a nucleotide sequence (SEQ ID NO:513) of a native sequence PR06245 cDNA, wherein SEQ ID NO:513 is a clone designated herein as "DNA107786-2723".
  • Figure 514 shows the amino acid sequence (SEQ ID NO:514) derived from the coding sequence of SEQ ID NO:513 shown in Figure 513.
  • Figure 515 shows a nucleotide sequence (SEQ ID NO:515) of a native sequence PR06175 cDNA, wherein SEQ ID NO:515 is a clone designated herein as "DNA108682-2712".
  • Figure 516 shows the amino acid sequence (SEQ ID NO:516) derived from the coding sequence of SEQ ID NO:515 shown in Figure 515.
  • Figure 517 shows a nucleotide sequence (SEQ ID NO:517) of a native sequence PR09742 cDNA, wherein SEQ ID NO:517 is a clone designated herein as "DNA108684-2761 " .
  • Figure 518 shows the amino acid sequence (SEQ ID NO:518) derived from the coding sequence of SEQ ID NO:517 shown in Figure 517.
  • Figure 519 shows a nucleotide sequence (SEQ ID NO:519) of a native sequence PR07179 cDNA, wherein SEQ ID NO:519 is a clone designated herein as "DNA108701-2749".
  • Figure 520 shows the amino acid sequence (SEQ ID NO: 520) derived from the coding sequence of SEQ
  • Figure 521 shows a nucleotide sequence (SEQ ID NO:521) of a native sequence PR06239 cDNA, wherein SEQ ID NO:521 is a clone designated herein as "DNA108720-2717".
  • Figure 522 shows the amino acid sequence (SEQ ID NO: 522) derived from the coding sequence of SEQ ID NO:521 shown in Figure 521.
  • Figure 523 shows a nucleotide sequence (SEQ ID NO: 523) of a native sequence PR06493 cDNA, wherein SEQ ID NO:523 is a clone designated herein as "DNA108726-2729".
  • Figure 524 shows the amino acid sequence (SEQ ID NO: 524) derived from the coding sequence of SEQ ID NO: 523 shown in Figure 523.
  • Figures 525A-525B show a nucleotide sequence (SEQ ID NO: 525) of a native sequence PR09741 cDNA, wherein SEQ ID NO:525 is a clone designated herein as "DNA108728-2760".
  • Figure 526 shows the amino acid sequence (SEQ ID NO: 526) derived from the coding sequence of SEQ ID NO:525 shown in Figures 525A-525B.
  • Figure 527 shows a nucleotide sequence (SEQ ID NO:527) of a native sequence PR09822 cDNA, wherein SEQ ID NO:527 is a clone designated herein as "DNA108738-2767".
  • Figure 528 shows the amino acid sequence (SEQ ID NO: 528) derived from the coding sequence of SEQ ID NO:527 shown in Figure 527.
  • Figure 529 shows a nucleotide sequence (SEQ ID NO: 529) of a native sequence PR06244 cDNA, wherein SEQ ID NO:529 is a clone designated herein as "DNA108743-2722".
  • Figure 530 shows the amino acid sequence (SEQ ID NO: 530) derived from the coding sequence of SEQ ID NO:529 shown in Figure 529.
  • Figure 531 shows a nucleotide sequence (SEQ ID NO: 531) of a native sequence PRO9740 cDNA, wherein SEQ ID NO:531 is a clone designated herein as "DNA108758-2759".
  • Figure 532 shows the amino acid sequence (SEQ ID NO: 532) derived from the coding sequence of SEQ ID NO:531 shown in Figure 531.
  • Figure 533 shows a nucleotide sequence (SEQ ID NO: 533) of a native sequence PR09739 cDNA, wherein SEQ ID NO:533 is a clone designated herein as "DNA108765-2758".
  • Figure 534 shows the amino acid sequence (SEQ ID NO: 534) derived from the coding sequence of SEQ
  • Figure 535 shows a nucleotide sequence (SEQ ID NO:535) of a native sequence PR07177 cDNA, wherein SEQ ID NO:535 is a clone designated herein as "DNA108783-2747".
  • Figure 536 shows the amino acid sequence (SEQ ID NO: 536) derived from the coding sequence of SEQ ID NO:535 shown in Figure 535.
  • Figure 537 shows a nucleotide sequence (SEQ ID NO:537) of a native sequence PR07178 cDNA, wherein SEQ ID NO:537 is a clone designated herein as "DNA108789-2748".
  • Figure 538 shows the amino acid sequence (SEQ ID NO:538) derived from the coding sequence of SEQ ID NO:537 shown in Figure 537.
  • Figure 539 shows a nucleotide sequence (SEQ ID NO:539) of a native sequence PR06246 cDNA, wherein SEQ ID NO:539 is a clone designated herein as "DNA108806-2724".
  • Figure 540 shows the amino acid sequence (SEQ ID NO: 540) derived from the coding sequence of SEQ ID NO:539 shown in Figure 539.
  • Figure 541 shows a nucleotide sequence (SEQ ID NO:541) of a native sequence PR06241 cDNA, wherein SEQ ID NO:541 is a clone designated herein as "DNA108936-2719".
  • Figure 542 shows the amino acid sequence (SEQ ID NO: 542) derived from the coding sequence of SEQ ID NO:541 shown in Figure 541.
  • Figure 543 shows a nucleotide sequence (SEQ ID NO:543) of a native sequence PR09835 cDNA, wherein SEQ ID NO:543 is a clone designated herein as "DNA119510-2771".
  • Figure 544 shows the amino acid sequence (SEQ ID NO: 544) derived from the coding sequence of SEQ ID NO:543 shown in Figure 543.
  • Figure 545 shows a nucleotide sequence (SEQ ID NO:545) of a native sequence PR09857 cDNA, wherein SEQ ID NO:545 is a clone designated herein as "DNA119517-2778".
  • Figure 546 shows the amino acid sequence (SEQ ID NO: 546) derived from the coding sequence of SEQ ID NO: 545 shown in Figure 545.
  • Figure 547 shows a nucleotide sequence (SEQ ID NO:547) of a native sequence PR07436 cDNA, wherein SEQ ID NO:547 is a clone designated herein as "DNA119535-2756".
  • Figure 548 shows the amino acid sequence (SEQ ID NO:548) derived from the coding sequence of SEQ
  • Figure 549 shows a nucleotide sequence (SEQ ID NO:549) of a native sequence PR09856 cDNA, wherein SEQ ID NO:549 is a clone designated herein as "DNA119537-2777".
  • Figure 550 shows the amino acid sequence (SEQ ID NO: 550) derived from the coding sequence of SEQ ID NO:549 shown in Figure 549.
  • Figure 551 shows a nucleotide sequence (SEQ ID NO:551) of a native sequence PRO19605 cDNA, wherein SEQ ID NO:551 is a clone designated herein as "DNA119714-2851".
  • Figure 552 shows the amino acid sequence (SEQ ID NO: 552) derived from the coding sequence of SEQ ID NO: 551 shown in Figure 551.
  • Figure 553 shows a nucleotide sequence (SEQ ID NO:553) of a native sequence PR09859 cDNA, wherein SEQ ID NO:553 is a clone designated herein as "DNA125170-2780".
  • Figure 554 shows the amino acid sequence (SEQ ID NO: 554) derived from the coding sequence of SEQ ID NO:553 shown in Figure 553.
  • Figure 555 shows a nucleotide sequence (SEQ ID NO:555) of a native sequence PRO12970 cDNA, wherein SEQ ID NO:555 is a clone designated herein as "DNA129594-2841".
  • Figure 556 shows the amino acid sequence (SEQ ID NO: 556) derived from the coding sequence of SEQ • ID NO: 555 shown in Figure 555.
  • Figure 557 shows a nucleotide sequence (SEQ ID NO:557) of a native sequence PR019626 cDNA, wherein SEQ ID NO:557 is a clone designated herein as "DNA129793-2857".
  • Figure 558 shows the amino acid sequence (SEQ ID NO:558) derived from the coding sequence of SEQ
  • Figure 559 shows a nucleotide sequence (SEQ ID NO:559) of a native sequence PR09833 cDNA, wherein SEQ ID NO:559 is a clone designated herein as "DNA130809-2769".
  • Figure 560 shows the amino acid sequence (SEQ ID NO: 560) derived from the coding sequence of SEQ ID NO:559 shown in Figure 559.
  • Figure 561 shows a nucleotide sequence (SEQ ID NO:561) of a native sequence PRO19670 cDNA, wherein SEQ ID NO:561 is a clone designated herein as "DNA131639-2874".
  • Figure 562 shows the amino acid sequence (SEQ ID NO: 562) derived from the coding sequence of SEQ ID NO:561 shown in Figure 561.
  • Figure 563 shows a nucleotide sequence (SEQ ID NO: 563) of a native sequence PRO 19624 cDNA, wherein SEQ ID NO:563 is a clone designated herein as "DNA131649-2855".
  • Figure 564 shows the amino acid sequence (SEQ ID NO: 564) derived from the coding sequence of SEQ ID NO:563 shown in Figure 563.
  • Figure 565 shows a nucleotide sequence (SEQ ID NO:565) of a native sequence PRO19680 cDNA, wherein SEQ ID NO:565 is a clone designated herein as "DNA131652-2876".
  • Figure 566 shows the amino acid sequence (SEQ ID NO:566) derived from the coding sequence of SEQ ID NO: 565 shown in Figure 565.
  • Figure 567 shows a nucleotide sequence (SEQ ID NO:567) of a native sequence PR019675 cDNA, wherein SEQ ID NO:567 is a clone designated herein as "DNA131658-2875".
  • Figure 568 shows the amino acid sequence (SEQ ID NO: 568) derived from the coding sequence of SEQ ID NO: 567 shown in Figure 567.
  • Figure 569 shows a nucleotide sequence (SEQ ID NO:569) of a native sequence PR09834 cDNA, wherein SEQ ID NO:569 is a clone designated herein as "DNA132162-2770".
  • Figure 570 shows the amino acid sequence (SEQ ID NO: 570) derived from the coding sequence of SEQ ID NO:569 shown in Figure 569.
  • Figure 571 shows a nucleotide sequence (SEQ ID NO:571) of a native sequence PR09744 cDNA, wherein SEQ ID NO:571 is a clone designated herein as "DNA136110-2763".
  • Figure 572 shows the amino acid sequence (SEQ ID NO: 572) derived from the coding sequence of SEQ
  • Figure 573 shows a nucleotide sequence (SEQ ID NO:573) of a native sequence PR019644 cDNA, wherein SEQ ID NO:573 is a clone designated herein as "DNA139592-2866".
  • Figure 574 shows the amino acid sequence (SEQ ID NO: 574) derived from the coding sequence of SEQ ID NO:573 shown in Figure 573.
  • Figure 575 shows a nucleotide sequence (SEQ ID NO:575) of a native sequence PR019625 cDNA, wherein SEQ ID NO:575 is a clone designated herein as "DNA139608-2856".
  • Figure 576 shows the amino acid sequence (SEQ ID NO: 576) derived from the coding sequence of SEQ ID NO:575 shown in Figure 575.
  • Figure 577 shows a nucleotide sequence (SEQ ID NO:577) of a native sequence PR019597 cDNA, wherein SEQ ID NO:577 is a clone designated herein as "DNA143292-2848".
  • Figure 578 shows the amino acid sequence (SEQ ID NO: 578) derived from the coding sequence of SEQ ID NO:577 shown in Figure 577.
  • Figure 579 shows a nucleotide sequence (SEQ ID NO:579) of a native sequence PRO16090 cDNA, wherein SEQ ID NO:579 is a clone designated herein as "DNA144844-2843 " .
  • Figure 580 shows the amino acid sequence (SEQ ID NO:580) derived from the coding sequence of SEQ ID NO:579 shown in Figure 579.
  • Figure 581 shows a nucleotide sequence (SEQ ID NO:581) of a native sequence PR019576 cDNA, wherein SEQ ID NO:581 is a clone designated herein as "DNA144857-2845".
  • Figure 582 shows the amino acid sequence (SEQ ID NO:582) derived from the coding sequence of SEQ ID NO:581 shown in Figure 581.
  • Figure 583 shows a nucleotide sequence (SEQ ID NO:583) of a native sequence PR019646 cDNA, wherein SEQ ID NO:583 is a clone designated herein as "DNA145841-2868" .
  • Figure 584 shows the amino acid sequence (SEQ ID NO:584) derived from the coding sequence of SEQ ID NO: 583 shown in Figure 583.
  • Figure 585 shows a nucleotide sequence (SEQ ID NO:585) of a native sequence PR019814 cDNA, wherein SEQ ID NO:585 is a clone designated herein as "DNA148004-2882".
  • Figure 586 shows the amino acid sequence (SEQ ID NO:586) derived from the coding sequence of SEQ
  • Figure 587 shows a nucleotide sequence (SEQ ID NO:587) of a native sequence PR019669 cDNA, wherein SEQ ID NO:587 is a clone designated herein as "DNA149893-2873".
  • Figure 588 shows the .amino acid sequence (SEQ ID NO:588) derived from the coding sequence of SEQ ID NO:587 shown in Figure 587.
  • Figure 589 shows a nucleotide sequence (SEQ ID NO:589) of a native sequence PR019818 cDNA, wherein SEQ ID NO:589 is a clone designated herein as "DNA149930-2884".
  • Figure 590 shows the amino acid sequence (SEQ ID NO: 590) derived from the coding sequence of SEQ ID NO:589 shown in Figure 589.
  • Figure 591 shows a nucleotide sequence (SEQ ID NO:591) of a native sequence PRO20088 cDNA, wherein SEQ ID NO:591 is a clone designated herein as "DNA150157-2898".
  • Figure 592 shows the amino acid sequence (SEQ ID NO: 592) derived from the coding sequence of SEQ ID NO:591 shown in Figure 591.
  • Figure 593 shows a nucleotide sequence (SEQ ID NO:593) of a native sequence PRO16089 cDNA, wherein SEQ ID NO:593 is a clone designated herein as "DNA 150163-2842" .
  • Figure 594 shows the amino acid sequence (SEQ ID NO: 594) derived from the coding sequence of SEQ ID NO:593 shown in Figure 593.
  • Figure 595 shows a nucleotide sequence (SEQ ID NO:595) of a native sequence PRO20025 cDNA, wherein SEQ ID NO:595 is a clone designated herein as "DNA153579-2894".
  • Figure 596 shows the amino acid sequence (SEQ ID NO:596) derived from the coding sequence of SEQ
  • Figure 597 shows a nucleotide sequence (SEQ ID NO: 597) of a native sequence PRO20040 cDNA, wherein SEQ ID NO:597 is a clone designated herein as "DNA 164625-2890".
  • Figure 598 shows the amino acid sequence (SEQ ID NO:598) derived from the coding sequence of SEQ ID NO:597 shown in Figure 597.
  • Figure 599 shows anucleotide sequence (SEQ ID NO:599) of anative sequence PR0791 cDNA, wherein SEQ ID NO:599 is a clone designated herein as "DNA57838-1337".
  • Figure 600 shows the amino acid sequence (SEQ ID NO: 600) derived from the coding sequence of SEQ ID NO:599 shown in Figure 599.
  • Figure 601 shows a nucleotide sequence (SEQ ID NO:601) of a native sequence PR01131 cDNA, wherein SEQ ID NO:601 is a clone designated herein as "DNA59777-1480".
  • Figure 602 shows the amino acid sequence (SEQ ID NO: 602) derived from the coding sequence of SEQ ID NO:601 shown in Figure 601.
  • Figure 603 shows a nucleotide sequence (SEQ ID NO:603) of a native sequence PR01343 cDNA, wherein SEQ ID NO: 603 is a clone designated herein as "DNA66675-1587".
  • Figure 604 shows the amino acid sequence (SEQ ID NO: 604) derived from the coding sequence of SEQ ID NO:603 shown in Figure 603.
  • Figure 605 shows a nucleotide sequence (SEQ ID NO:605) of a native sequence PRO1760 cDNA, wherein SEQ ID NO:605 is a clone designated herein as "DNA76532-1702".
  • Figure 606 shows the amino acid sequence (SEQ ID NO: 606) derived from the coding sequence of SEQ ID NO:605 shown in Figure 605.
  • Figure 607 shows a nucleotide sequence (SEQ ID NO: 607) of a native sequence PRO6029 cDNA, wherein SEQ ID NO:607 is a clone designated herein as "DNA 105849-2704" .
  • Figure 608 shows the amino acid sequence (SEQ ID NO: 608) derived from the coding sequence of SEQ ID NO:607 shown in Figure 607.
  • Figure 609 shows a nucleotide sequence (SEQ ID NO: 609) of a native sequence PRO 1801 cDNA, wherein SEQ ID NO:609 is a clone designated herein as "DNA83500-2506".
  • Figure 610 shows the amino acid sequence (SEQ ID NO:610) derived from the coding sequence of SEQ
  • PRO polypeptide and "PRO” as used herein and when immediately followed by a numerical designation refer to various polypeptides, wherein the complete designation (i.e. , PRO/number) refers to specific polypeptide sequences as described herein.
  • PRO/number polypeptide and “PRO/number” wherein the term “number” is provided as an actual numerical designation as used herein encompass native sequence polypeptides and polypeptide variants (which are further defined herein) .
  • the PRO polypeptides described herein may be isolated from a variety of sources, such as from human tissue types or from another source, or prepared by recombinant or synthetic methods.
  • PRO polypeptide refers to each individual PRO/number polypeptide disclosed herein. All disclosures in this specification which refer to the "PRO polypeptide” refer to each of the polypeptides individually as well as jointly. For example, descriptions of the preparation of, purification of, derivation of, formation of antibodies to or against, administration of, compositions containing, treatment of a disease with, etc., pertain to each 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. However, while the PRO polypeptide disclosed in the accompanying figures are shown to begin with methionine residues designated herein as amino acid position 1 in the figures, it is conceivable and possible that other methionine residues located either upstream or downstream from the amino acid position 1 in the figures may be employed as the starting amino acid residue for the PRO polypeptides.
  • the PRO polypeptide "extracellular domain” or “ECD” refers to a form of the PRO polypeptide which is essentially free of the tr.ansmembrane and cytoplasmic domains. Ordinarily, a PRO polypeptide ECD will have less than 1 % of such transmembrane and/or cytoplasmic domains and preferably, will have less than 0.5 % of such domains. It will be understood that any transmembrane domains identified for the PRO polypeptides of the present invention are identified pursuant to criteria routinely employed in the art for identifying that type of hydrophobic domain. The exact boundaries of a transmembrane domain may vary but most likely by no more than about 5 amino acids at either end of the domain as initially identified herein.
  • an extracellular domain of a PRO polypeptide may contain from about 5 or fewer amino acids on either side of the transmembrane domain extracellular domain boundary as identified in the Examples or specification and such polypeptides, with or without the associated signal peptide, and nucleic acid encoding them, are comtemplated by the present invention.
  • cleavage of a signal sequence from a secreted polypeptide is not entirely uniform, resulting in more than one secreted species.
  • These mature polypeptides, where the signal peptide is cleaved within no more than about 5 amino acids on either side of the C-terminal boundary of the signal peptide as identified herein, and the polynucleotides encoding them, are contemplated by the present invention.
  • PRO polypeptide variant means an active PRO polypeptide as defined above or below having at least about 80% amino acid sequence identity with a full-length native sequence PRO polypeptide sequence as disclosed herein, a PRO polypeptide sequence lacking the signal peptide as disclosed herein, an extracellular domain of a PRO polypeptide, with or without the signal peptide, as disclosed herein or any other fragment of a full-length PRO polypeptide sequence as disclosed herein.
  • Such PRO polypeptide variants include, for instance, PRO polypeptides wherein one or more amino acid residues are added, or deleted, at the N- or C-terminus of the full- length native amino acid sequence.
  • a PRO polypeptide variant will have at least about 80% amino acid sequence identity, 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
  • 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. Unless specifically stated otherwise, all % amino acid sequence identity values used herein are obtained as described in the immediately preceding paragraph using the ALIGN-2 computer program.
  • 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 dete ⁇ nined using the sequence comparison program
  • NCBI-BLAST2 (Altschul et al., Nucleic Acids Res. 25:3389-3402 (1997)).
  • the 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 at least about
  • 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 withpolyepitopic specificity, single chain anti-PRO antibodies, and fragments of anti-PRO antibodies (see below).
  • monoclonal antibody refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e. , the individual antibodies comprising the population are identical except for possible naturally-occurring mutations that may be present in minor amounts.
  • “Stringency” of hybridization reactions is readily determinable by one of ordinary skill in the art, and generally is an empirical calculation dependent upon probe length, washing temperature, and salt concentration. In general, longer probes require higher temperatures for proper annealing, while shorter probes need lower temperatures. Hybridization generally depends on the ability of denatured DNA to reanneal when complementary strands are present in an environment below their melting temperature. The higher the degree of desired homology between the probe and hybridizable sequence, the higher the relative temperature which can be used. As a result, it follows that higher relative temperatures would tend to make the reaction conditions more stringent, while lower temperatures less so. For additional details and explanation of stringency of hybridization reactions, see Ausubel et al., Current Protocols in Molecular Biology. Wiley Interscience Publishers, (1995).
  • Stringent conditions or “high stringency conditions” , as defined herein, may be identified by those that: (1) employ low ionic strength and high temperature for washing, for example 0.015 M sodium chloride/0.0015 M sodium citrate/0.1 % sodium dodecyl sulfate at 50°C; (2) employ during hybridization a denaturing agent, such as formamide, for example, 50% (v/v) formamide with 0.1% bovine serum albumin/0.1% Ficoll/0.1% 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%
  • Moderately 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.
  • moderately stringent conditions is overnight incubation at 37°C in a solution comprising: 20% formamide, 5 x SSC (150 mM NaCl, 15 mM trisodium citrate), 50 mM sodium phosphate (pH 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. Collectively, the six CDRs confer antigen-binding specificity to the antibody. However, even a single variable domain (or half of an Fv comprising only three CDRs specific for an antigen) has the ability to recognize and bind antigen, although at a lower affinity than the entire binding site.
  • 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 CH 1 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.
  • Single-chain Fv or “sFv” antibody fragments comprise the V H and V L domains of antibody, wherein these domains are present in a single polypeptide chain.
  • the Fv polypeptide further comprises a polypeptide linker between the V H and V L domains which enables the sFv to form the desired structure for antigen binding.
  • diabodies refers to small antibody fragments with two antigen-binding sites, which fragments comprise a heavy-chain variable domain (V H ) coimected to a light-chain variable domain (V L ) in the same polypeptide chain (V H -V L ).
  • V H heavy-chain variable domain
  • V L light-chain variable domain
  • the domains are forced to pair with the complementary domains of another chain and create two antigen-binding sites.
  • Diabodies are described more fully in, for example, EP 404,097; WO 93/11161; 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.
  • a drug such as a PRO polypeptide or antibody thereto
  • the components of the liposome are commonly arranged in a bilayer formation, similar to the lipid arrangement of biological membranes.
  • a "small molecule” is defined herein to have a molecular weight below about 500 Daltons.
  • an “effective amount” of a polypeptide disclosed herein or an agonist or antagonist thereof is an amount sufficient to carry out a specifically stated purpose.
  • An “effective amount” may be determined empirically and in a routine manner, in relation to the stated purpose. Table 1
  • filel and file2 are two dna or two protein sequences.
  • Max file length is 65535 (limited by unsigned short x in the jmp struct)
  • a sequence with 1/3 or more of its elements ACGTU is assumed to be DNA
  • the program may create a tmp file in /tmp to hold info about traceback.
  • dumpblockO * putline() put out a line (name, [num.], seq, [num]): dumpblockO
  • static nm matches in core — for checking */ static lmax; /* lengths of stripped file names */ static ij[2]; /* jmp index for a path */ static nc[2]; /* number at start of current line */ static ni[2]; /* current elem number — for gapping */ static siz[2]; static char *ps[2]; /* ptr to current element */ static char *po[2]; /* ptr to next output char slot */ static char oouutt[[22]][[lP_LINE]; /* output line */ static char star[P ] ⁇ ]; /* set by stars() *//
  • *po[i] *ps[i]; if (islower(*ps[i]))
  • *ps[i] toupper(*ps[i]); po[i]+ + ; ps[i] + +;
  • *py+ + *px; else if (islower(*px))
  • *py+ + tou ⁇ per(*px); if (index("ATGCU",*(py-l))) natgc+ + ; ⁇ ⁇
  • the present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PRO polypeptides.
  • cDNAs encoding various PRO polypeptides have been identified and isolated, as disclosed in further detail in the Examples below. It is noted that proteins produced in separate expression rounds may be given different PRO numbers but the UNQ number is unique for any given DNA and the encoded protein, and will not be changed.
  • PRO/number the protein encoded by the full length native nucleic acid molecules disclosed herein as well as all further native homologues and variants included in the foregoing definition of PRO, will be referred to as "PRO/number", regardless of their origin or mode of preparation.
  • PRO Polypeptide Variants In addition to the full-length native sequence PRO polypeptides described herein, it is contemplated that
  • PRO variants can be prepared.
  • PRO variants can be prepared by introducing appropriate nucleotide changes into the PRO DNA, and/or by synthesis of the desired PRO polypeptide.
  • amino acid changes may alter post-translational processes of the PRO, such as changing the number or position of glycosylation sites or altering the membrane anchoring characteristics.
  • Variations in the native full-length sequence PRO or in v. rious domains of the PRO described herein can be made, for example, using any of the techniques and guidelines for conservative and non-conservative mutations set forth, for instance, in U.S. Patent No. 5,364,934.
  • Variations may be a substitution, deletion or insertion of one or more codons encoding the PRO that results in a change in the amino acid sequence of the PRO as compared with the native sequence PRO.
  • the variation is by substitution of at least one amino acid with any other amino acid in one or more of the domains of the PRO .
  • Guidance in determining which amino acid residue may be inserted, substituted or deleted without adversely affecting the desired activity may be found by comparing the sequence of the PRO with that of homologous known protein molecules and minimizing the number of amino acid sequence changes made in regions of high homology.
  • Amino acid substitutions can be the result of replacing one amino acid with another amino acid having similar structural and/or chemical properties, such as the replacement of a leucine with a serine, i.e.
  • Insertions or deletions may optionally be in the range of about 1 to 5 amino acids. The variation allowed may be determined by systematically making insertions , deletions or substitutions of amino acids in the sequence and testing the resulting variants for activity exhibited by the full-length or mature native sequence.
  • PRO polypeptide fragments are provided herein. Such fragments may be truncated at the N-terminus or C-terminus, or may lack internal residues, for example, when compared with a full length native protein. Certain fragments lack amino acid residues that are not essential for a desired biological activity of the PRO polypeptide.
  • PRO fragments may be prepared by any of a number of conventional techniques. Desired peptide fragments may be chemically synthesized. An alternative approach involves generating PRO fragments by enzymatic digestion, e.g., by treating the protein with an enzyme known to cleave proteins at sites defined by particular amino acid residues, or by digesting the DNA with suitable restriction enzymes and isolating the desired fragment. Yet another suitable technique involves isolating and amplifying a DNA fragment encoding a desired polypeptide fragment, by polymerase chain reaction (PCR). Oligonucleotides that define the desired termini of the DNA fragment are employed at the 5' and 3' primers in the PCR. Preferably, PRO polypeptide fragments share at least one biological and/or immunological activity with the native PRO polypeptide disclosed herein.
  • PCR polymerase chain reaction
  • conservative substitutions of interest are shown in Table 6 under the heading of preferred substitutions. If such substitutions result in a change in biological activity, then more substantial changes, denominated exemplary substitutions in Table 6, or as further described below in reference to amino acid classes, are introduced and the products screened.
  • Substantial modifications in function or immunological identity of the PRO polypeptide are accomplished by selecting substitutions that differ significantly in their effect on maintaining (a) the structure of the polypeptide backbone in the area of the substitution, for example, as a sheet or helical conformation, (b) the charge or hydrophobicity of the molecule at the target site, or (c) the bulk of the side chain.
  • Naturally occurring residues are divided into groups based on common side-chain properties: (1) hydrophobic: norleucine, met, ala, val, leu, ile;
  • Non-conservative substitutions will entail exchanging a member of one of these classes for another class. Such substituted residues also may be introduced into the conservative substitution sites or, more preferably, into the remaining (non-conserved) sites.
  • Scanning amino acid analysis can also be employed to identify one or more amino acids along a contiguous sequence.
  • preferred scanning amino acids are relatively small, neutral amino acids.
  • amino acids include alanine, glycine, serine, and cysteine.
  • Alanine is typically a preferred scanning amino acid among this group because it eliminates the side-chain beyond the beta-carbon and is less likely to alter the main- chain conformation of the variant [Cunningham and Wells, Science. 244: 1081-1085 (1989)].
  • Alanine is also typically preferred because it is the most common amino acid. Further, it is frequently found in both buried and exposed positions [Creighton, The Proteins. (W.H. Freeman & Co., N.Y.); Chothia, J. Mol. Biol.. 150:1 (1976)]. If alanine substitution does not yield adequate amounts of variant, an isoteric amino acid can be used.
  • Covalent modifications of PRO are included within the scope of this invention.
  • One type of covalent modification includes reacting targeted amino acid residues of a PRO polypeptide with an organic derivatizing agent that is capable of reacting with selected side chains or the N- or C- terminal residues of the PRO.
  • Derivatization with bifunctional agents is useful, for instance, for crosslinking PRO to a water-insoluble support matrix or surface for use in the method for purifying anti-PRO antibodies, and vice-versa.
  • crosslinking agents include, e.g., l,l-bis(diazoacetyl)-2-phenylefhane, glutaraldehyde, N-hydroxysuccinimide esters, for example, esters with 4-azidosalicylic acid, homobifunctional imidoesters, including disuccinimidyl esters such as 3,3'-ditluobis(succinimidylpropionate), bifunctional maleimides such as bis-N-maleimido-l,8-octane and agents such as methyl-3-[(p-azidophenyl)dithio]propioimidate.
  • Another type of covalent modification of the PRO polypeptide included within the scope of this invention comprises altering the native glycosylation pattern of the polypeptide.
  • "Altering the native glycosylation pattern” is intended for purposes herein to mean deleting one or more carbohydrate moieties found in native sequence PRO (either by removing the underlying glycosylation site or by deleting the glycosylation by chemical and/or enzymatic means), and/or adding one or more glycosylation sites that are not present in the native sequence PRO.
  • the phrase includes qualitative changes in the glycosylation of the native proteins, involving a change in the nature and proportions of the various carbohydrate moieties present.
  • Addition of glycosylation sites to the PRO polypeptide may be accomplished by altering the amino acid sequence.
  • the alteration may be made, for example, by the addition of, or substitution by, one or more serine or threonine residues to the native sequence PRO (for O-linked glycosylation sites).
  • the PRO amino acid sequence may optionally be altered through changes at the DNA level, particularly by mutating the DNA encoding the PRO polypeptide at preselected bases such that codons are generated that will translate into the desired amino acids.
  • Another means of increasing the number of carbohydrate moieties on the PRO polypeptide is by chemical or enzymatic coupling of glycosides to the polypeptide. Such methods are described in the art, e.g., in WO 87/05330 published 11 September 1987, and in Aplin and Wriston, CRC Crit. Rev. Biochem.. pp. 259-306 (1981).
  • Removal of carbohydrate moieties present on the PRO polypeptide may be accomplished chemically or enzymatically or by mutational substitution of codons encoding for amino acid residues that serve as targets for glycosylation.
  • Chemical deglycosylation techniques are known in the art and described, for instance, by Hakimuddin, et al., Arch. Biochem. Biophys., 259:52 (1987) and by Edge et al., Anal. Biochem.. 118: 131 (1981).
  • Enzymatic cleavage of carbohydrate moieties on polypeptides can be achieved by the use of a variety of endo- and exo-glycosidases as described by Thotakura et al., Meth. EnzvmoL. 138:350 (1987).
  • PRO polypeptide comprises linking the PRO polypeptide to one of a variety of nonproteinaceous polymers, e.g., polyethylene glycol (PEG), polypropylene glycol, or polyoxyalkylenes, in the manner set forth in U.S. Patent Nos. 4,640,835; 4,496,689; 4,301,144; 4,670,417; 4,791,192 or 4,179,337.
  • PEG polyethylene glycol
  • the PRO of the present invention may also be modified in a way to form a chimeric molecule comprising
  • PRO fused to another, heterologous polypeptide or amino acid sequence.
  • such a chimeric molecule comprises a fusion of the PRO with a tag polypeptide which provides an epitope to which an anti-tag antibody can selectively bind.
  • the epitope tag is generally placed at the amino- or carboxyl- terminus of the PRO. The presence of such epitope-tagged forms of the PRO can be detected using an antibody against the tag polypeptide. Also, provision of the epitope tag enables the PRO to be readily purified by affinity purification using an anti-tag antibody or another type of affinity matrix that binds to the epitope tag.
  • tag polypeptides and their respective antibodies are well known in the art.
  • poly-histidine poly-his
  • poly-histidine-glycine poly-his-gly
  • flu HA tag polypeptide and its antibody 12CA5 [Field et al. , Mol. Cell. Biol.. 8:2159-2165 (1988)]
  • c-myc tag and the 8F9, 3C7, 6E10, G4, B7 and 9E10 antibodies thereto [Evan et al., Molecular and Cellular Biology. 5:3610-3616 (1985)]
  • the flu HA tag polypeptide and its antibody 12CA5 [Field et al. , Mol. Cell. Biol.. 8:2159-2165 (1988)]
  • c-myc tag and the 8F9, 3C7, 6E10, G4, B7 and 9E10 antibodies thereto [Evan et al., Molecular and Cellular Biology. 5:3610-3616 (1985)]
  • the flu HA tag polypeptide and its antibody 12CA5 [Field et
  • tag polypeptides include the Flag-peptide [Hopp et al. , BioTechnology, 6: 1204-1210 (1988)] ; the KT3 epitope peptide [Martin et al., Science, 255:192-194 (1992)]; an ⁇ -tubulin epitope peptide [Skinner et al., J. Biol. Chem.. 266:15163-15166 (1991)]; and the T7 gene 10 protein peptide tag [Lutz-Freyermuth et al., Proc. Natl. Acad. Sci. USA. 87:6393-6397 (1990)].
  • the chimeric molecule may comprise a fusion of the PRO with an immunoglobulin or a particular region of an immunoglobulin.
  • an immunoglobulin also referred to as an ''immunoadhesin
  • a fusion could be to the Fc region of an IgG molecule.
  • the Ig fusions preferably include the substitution of a soluble (tr ⁇ smembrane domain deleted or inactivated) form of a PRO polypeptide in place of at least one variable region within an Ig molecule.
  • the immunoglobulin fusion includes the hinge, CH2 and CH3, or the hinge, CHI, CH2 and CH3 regions of an IgGl molecule.
  • PRO sequence or portions thereof, may be produced by direct peptide synthesis using solid-phase techniques [see, e.g. , Stewart et al. , Solid- Phase Peptide Synthesis. W.H. Freeman Co., San Francisco, CA (1969); Merrifield, J. Am. Chem. Soc. 85:2149-2154 (1963)]. In vitro protein synthesis may be performed using manual techniques or by automation.
  • Automated synthesis may be accomplished, for instance, using an Applied Biosystems Peptide Synthesizer (Foster City, CA) using manufacturer's instructions.
  • Various portions of the PRO may be chemically synthesized separately and combined using chemical or enzymatic methods to produce the full-length PRO.
  • DNA encoding PRO may be obtained from a cDNA library prepared from tissue believed to possess the PRO mRNA and to express it at a detectable level. Accordingly, human PRO DNA can be conveniently obtained from a cDNA library prepared from human tissue, such as described in the Examples.
  • the PRO-encoding gene may also be obtained from a genomic library or by known synthetic procedures (e.g., automated nucleic acid synthesis).
  • Probes such as antibodies to the PRO or oligonucleotides of at least about 20-80 bases
  • Screening the cDNA or genomic library with the selected probe may be conducted using standard procedures, such as described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989).
  • An alternative means to isolate the gene encoding PRO is to use PCR methodology [Sambrook et al., supra: Dieffenbach et al. , PCR Primer: A Laboratory Manual (Cold Spring Harbor Laboratory Press * , 1995)] .
  • the oligonucleotide sequences selected as probes should be of sufficient length and sufficiently unambiguous that false positives are minimized.
  • the oligonucleotide is preferably labeled such that it can be detected upon hybridization to DNA in the library being screened. Methods of labeling are well known in the art, and include the use of radiolabels like 32 P-labeled ATP, biotinylation or enzyme labeling. Hybridization conditions, including moderate stringency and high stringency, are provided in Sambrook et al., supra.
  • Sequences identified in such library screening methods can be compared and aligned to other known sequences deposited and available in public databases such as GenBank or other private sequence databases. Sequence identity (at either the amino acid or nucleotide level) within defined regions of the molecule or across the full-length sequence can be determined using methods known in the art and as described herein. Nucleic acid having protein coding sequence may be obtained by screening selected cDNA or genomic libraries using the deduced amino acid sequence disclosed herein for the first time, and, if necessary, using conventional primer extension procedures as described in Sambrook et al., supra, to detect precursors and processing intermediates of mRNA that may not have been reverse-transcribed into cDNA.
  • Host cells are transfected or transformed with expression or cloning vectors described herein for PRO production and cultured in conventions nutrient media modified as appropriate for inducing promoters, selecting transformants, or amplifying the genes encoding the desired sequences.
  • the culture conditions such as media, temperature, pH and the like, can be selected by the skilled artisan without undue experimentation. In general, principles, protocols, and practical techniques for maximizing the productivity of cell cultures can be found in Mammalian Cell Biotechnology: a Practical Approach. M. Butler, ed. (IRL Press, 1991) and Sambrook et al., supra.
  • Methods of eukaryotic cell transfection and prokaryotic cell transformation are known to the ordinarily skilled artisan, for example, CaCl 2 , CaP0 4 , liposome-mediated and electroporation.
  • transformation is performed using standard techniques appropriate to such cells.
  • the calcium treatment employing calcium chloride, as described in Sambrook et al., supra, or electroporation is generally used for prokaryotes.
  • Infection with Agrobacterium tumefatiens is used for transformation of certain plant cells, as described by Shaw et al., Gene, 23:315 (1983) and WO 89/05859 published 29 June 1989.
  • polybrene polyornithine
  • polybrene polyornithine
  • transforming mammalian cells see Keown et al., Methods in Enzymology, 185:527-537 (1990) and Mansour et al., Nature, 336:348-352 (1988).
  • Suitable host cells for cloning or expressing the DNA in the vectors herein include prokaryote, yeast, or higher eukaryote cells.
  • Suitable prokaryotes include but are not limited to eubacteria, such as Gram-negative or Gram-positive organisms, for example, Enterobacteriaceae such as E. coli.
  • Various E. coli strains are publicly available, such as E. coli K12 strain MM294 (ATCC 31,446); E. coli X1776 (ATCC 31,537); E. coli strain W3110 (ATCC 27,325) and K5 772 (ATCC 53,635).
  • suitable prokaryotic host cells include Enterobacteriaceae such as Escherichia, e.g., E. coli, Enterobacter, Erwinia, Klebsiella, Proteus, Salmonella, e.g., Salmonella typhimurium, Serratia, e.g., Serratia marcescans, and Shigella, as well as Bacilli such as B. subtilis and B. licheniformis (e.g., B. Mcheniformis 41P disclosed in DD 266,710 published 12 April 1989), Pseudomonas such as P. aeruginosa, and Streptomyces. These examples are illustrative rather than limiting.
  • Strain W3110 is one particularly preferred host or parent host because it is a common host strain for recombinant DNA product fermentations.
  • the host cell secretes minimal amounts of proteolytic enzymes.
  • strain W3110 may be modified to effect a genetic mutation in the genes encoding proteins endogenous to the host, with examples of such hosts including E. coli W3110 strain 1A2, which has the complete genotype tonA ; E. coli W3110 strain 9E4, which has the complete genotype tonA ptr3; E. coli W3110 strain 27C7 (ATCC 55,244), which has the complete genotype tonAptr3phoA E15 (argF-lac)169 degP ompTkan r ; E.
  • E. coli W3110 strain 37D6 which has the complete genotype tonA ptr3 phoA E15 (argF-lac)169 degP ompT rbs7 ilvG kan r ; E. coli W3110 strain 40B4, which is strain 37D6 with a non-kanamycin resistant degP deletion mutation; and an E. coli strain having mutant periplasmic protease disclosed in U.S. Patent No. 4,946,783 issued 7 August 1990.
  • in vitro methods of cloning e.g., PCR or other nucleic acid polymerase reactions, are suitable.
  • eukaryotic microbes such as filamentous fungi or yeast are suitable cloning or expression hosts for PRO-encoding vectors.
  • Saccharomyces cerevisiae is a commonly used lower eukaryotic host microorganism.
  • Others include Schizosaccharomycespom.be (Beach and Nurse, Nature. 290: 140 [1981]; EP 139,383 published 2 May 1985); Kluyveromyces hosts (U.S. Patent No. 4,943,529; Fleer et al., Bio/Technology. 9:968-975 (1991)) such as, e.g., K.
  • lactis (MW98-8C, CBS683, CBS4574; Louvencourt et al., J. Bacteriol.. 154(2):737-742 [1983]), K. fragilis (ATCC 12,424), K. bulgaricus (ATCC 16,045), K. wickeramii (ATCC 24,178), K. waltii (ATCC 56,500), K. drosophilarum (ATCC 36,906; Van den Berg et al., Bio/Technology, 8:135 (1990)), K. thermotolerans, and K. marxianus; yarrowia (EP 402,226); Pichia pastoris (EP 183,070; Sreekrishna et al., J.
  • Candida Trichoderma reesia (EP 244,234); Neurospora crassa (Case et al., Proc. Natl. Acad. Sci. USA, 76:5259-5263 [1979]); Schwanniomyces such as Schwanniomyces occidentalis (EP 394,538 published 31 October 1990); and filamentous fungi such as, e.g., Neurospora, Penicillium, Tolypocladium (WO 91/00357 published 10 January 1991), and Aspergillus hosts such as A. nidulans (Ballance et al., Biochem. Biophys. Res. Commun..
  • Methylotropic yeasts are suitable herein and include, but are not limited to, yeast capable of growth on methanol selected from the genera consisting of Hansenula, Candida, Kloeckera, Pichia, Saccharomyces, Torulopsis, and Rhodotorula. A list of specific species that are exemplary of this class of yeasts may be found in C. Anthony, The Biochemistry of Mefhylotrophs. 269 (1982).
  • Suitable host cells for the expression of glycosylated PRO are derived from multicellular organisms.
  • invertebrate cells include insect cells such as Drosophila S2 and Spodoptera Sf9, as well as plant cells.
  • useful mammalian host cell lines include Chinese hamster ovary (CHO) and COS cells. More specific examples include monkey kidney CV1 line transformed by SV40 (COS-7, ATCC CRL 1651); human embryonic kidney line (293 or 293 cells subcloned for growth in suspension culture, Graham et al. , J. Gen Virol.. 36:59 (1977)); Chinese hamster ovary cells/-DHFR (CHO, Urlaub and Chasin, Proc. Natl. Acad. Sci. USA.
  • mice sertoli cells TM4, Mather, Biol. Reprod..23:243-251 (1980)
  • human lung cells W138, ATCC CCL 75
  • human liver cells Hep G2, HB 8065
  • mouse mammary tumor MMT 060562, ATCC CCL51. The selection of the appropriate host cell is deemed to be within the skill in the art.
  • the nucleic acid (e.g., cDNA or genomic DNA) encoding PRO may be inserted into a replicable vector for cloning (amplification of the DNA) or for expression.
  • a replicable vector for cloning (amplification of the DNA) or for expression.
  • the vector may, for example, be in the form of a plasmid, cosmid, viral particle, or phage.
  • the appropriate nucleic acid sequence may be inserted into the vector by a variety of procedures. In general, DNA is inserted into an appropriate restriction endonuclease site(s) using techniques known in the art.
  • Vector components generally include, but are not limited to, one or more of a signal sequence, an origin of replication, one or more marker genes, an enhancer element, a promoter, and a transcription termination sequence.
  • the PRO may be produced recombinantly not only directly, but also as a fusion polypeptide with a heterologous polypeptide, which may be a signal sequence or other polypeptide having a specific cleavage site at the N-terminus of the mature protein or polypeptide.
  • a heterologous polypeptide which may be a signal sequence or other polypeptide having a specific cleavage site at the N-terminus of the mature protein or polypeptide.
  • the signal sequence may be a component of the vector, or it may be a part of the PRO-encoding DNA that is inserted into the vector.
  • the signal sequence may be a prokaryotic signal sequence selected, for example, from the group of the alkaline phosphatase, penicillinase, lpp, or heat-stable enterotoxin II leaders.
  • the signal sequence may be, e.g. , the yeast invertase leader, alpha factor leader (including Saccharomyces and Kluyveromyces ⁇ -factor leaders, the latter described in U.S. Patent No. 5,010,182), or acid phosphatase leader, the C. albicans glucoamylase leader (EP 362,179 published 4 April 1990), or the signal described in WO 90/13646 published 15 November 1990.
  • mammalian signal sequences may be used to direct secretion of the protein, such as signal sequences from secreted polypeptides of the same or related species, as well as viral secretory leaders.
  • Both expression and cloning vectors contain a nucleic acid sequence that enables the vector to replicate in one or more selected host cells. Such sequences are well known for a variety of bacteria, yeast, and viruses.
  • the origin of replication from the plasmid pBR322 is suitable for most Gram-negative bacteria, the 2 ⁇ plasmid origin is suitable for yeast, and various viral origins (SV40, polyoma, adenovirus, VSV or BPV) are useful for cloning vectors in mammalian cells.
  • Selection genes will typically contain a selection gene, also termed a selectable marker.
  • Typical selection genes encode proteins that (a) confer resistance to antibiotics or other toxins, e.g., ampicillin, neomycin, methotrexate, or tetracycline, (b) complement auxotrophic deficiencies, or (c) supply critical nutrients not available from complex media, e.g., the gene encoding D-alanine racemase for Bacilli.
  • suitable selectable markers for mammalian cells are those that enable the identification of cells competent to take up the PRO-encoding nucleic acid, such as DHFR or thymidine kinase.
  • DHFR DHFR activity
  • yeast plasmid YRp7 yeast plasmid YRp7
  • the trpl gene provides a selection marker for a mutant strain of yeast lacking the ability to grow in tryptophan, for example, ATCC No. 44076 or PEP4-1 [Jones, Genetics. 85:12 (1977)].
  • Expression and cloning vectors usually contain a promoter operably linked to the PRO-encoding nucleic acid sequence to direct mRNA synthesis. Promoters recognized by a variety of potential host cells are well known. Promoters suitable for use with prokaryotic hosts include the ⁇ -lactamase and lactose promoter systems [Chang et al., Nature, 275:615 (1978); Goeddel et al., Nature.
  • Suitable promoting sequences for use with yeast hosts include the promoters for 3- phosphoglycerate kinase [Hitzeman et al., J. Biol. Chem.. 255:2073 (1980)] or other glycolytic enzymes [Hess et al., J. Adv. Enzyme Reg., 7:149 (1968); Holland, Biochemistry.
  • enolase such as enolase, glyceraldehyde-3-phosphate dehydrogenase, hexokinase, pyruvate decarboxylase, phosphofructokinase, glucose-6- phosphate isomerase, 3-phosphoglycerate mutase, pyruvate kinase, triosephosphate isomerase, phosphoglucose isomerase, and glucokinase.
  • enolase such as enolase, glyceraldehyde-3-phosphate dehydrogenase, hexokinase, pyruvate decarboxylase, phosphofructokinase, glucose-6- phosphate isomerase, 3-phosphoglycerate mutase, pyruvate kinase, triosephosphate isomerase, phosphoglucose isomerase, and glucokinase.
  • yeast promoters which are inducible promoters having the additional advantage of transcription controlled by growth conditions, are the promoter regions for alcohol dehydrogenase 2, isocytochrome C, acid phosphatase, degradative enzymes associated with nitrogen metabolism, metallothionein, glyceraldehyde-3- phosphate dehydrogenase, and enzymes responsible for maltose and galactose utilization. Suitable vectors and promoters for use in yeast expression are further described in EP 73,657.
  • PRO transcription from vectors in mammalian host cells is controlled, for example, by promoters obtained from the genomes of viruses such as polyoma virus, fowlpox virus (UK 2,211,504 published 5 July 1989), adenovirus (such as Adenovirus 2), bovine papilloma virus, avian sarcoma virus, cytomegalovirus, a retrovirus, hepatitis-B virus and Simian Virus 40 (SV40), from heterologous mammalian promoters, e.g., the actin promoter or an immunoglobulin promoter, and from heat-shock promoters, provided such promoters are compatible with the host cell systems.
  • viruses such as polyoma virus, fowlpox virus (UK 2,211,504 published 5 July 1989), adenovirus (such as Adenovirus 2), bovine papilloma virus, avian sarcoma virus, cytomegalovirus, a retrovirus, he
  • Enhancers are cis-acting elements of DNA, usually about from 10 to 300 bp, that act on a promoter to increase its transcription.
  • Many enhancer sequences are now known from mammalian genes (globin, elastase, albumin, ⁇ -fetoprotein, and insulin). Typically, however, one will use an enhancer from a eukaryotic cell virus.
  • Examples include the SV40 enhancer on the late side of the replication origin (bp 100- 270), the cytomegalovirus early promoter enhancer, the polyoma enhancer on the late side of the replication origin, and adenovirus enhancers.
  • the enhancer may be spliced into the vector at a position 5' or 3' to the PRO coding sequence, but is preferably located at a site 5' from the promoter.
  • Expression vectors used in eukaryotic host cells will also contain sequences necessary for the termination of transcription and for stabilizing the mRNA. Such sequences are commonly available from the 5' and, occasionally 3', untranslated regions of eukaryotic or viral DNAs or cDNAs. These regions contain nucleotide segments transcribed as polyadenylated fragments in the untranslated portion of the mRNA encoding PRO.
  • Gene amplification and/or expression may be measured in a sample directly, for example, by conventional Southern blotting, Northern blotting to quantitate the transcription of mRNA [Thomas, Proc. Natl. Acad. Sci. USA. 77:5201-5205 (1980)], dot blotting (DNA analysis), or in situ hybridization, using an appropriately labeled probe, based on the sequences provided herein.
  • antibodies may be employed that can recognize specific duplexes, including DNA duplexes, RNA duplexes, and DNA-RNA hybrid duplexes or DNA-protein duplexes. The antibodies in turn may be labeled and the assay may be carried out where the duplex is bound to a surface, so that upon the formation of duplex on the surface, the presence of antibody bound to the duplex can be detected.
  • Gene expression may be measured by immunological methods, such as immunohistochemical staining of cells or tissue sections and assay of cell culture or body fluids, to quantitate directly the expression of gene product.
  • Antibodies useful for immunohistochemical staining and/or assay of sample fluids may be either monoclonal or polyclonal, and may be prepared in any mammal. Conveniently, the antibodies may be prepared against a native sequence PRO polypeptide or against a synthetic peptide based on the DNA sequences provided herein or against exogenous sequence fused to PRO DNA and encoding a specific antibody epitope.
  • PRO may be recovered from culture medium or from host cell lysates. If membrane-bound, it can be released from the membrane using a suitable detergent solution (e.g. Triton-X 100) or by enzymatic cleavage. Cells employed in expression of PRO can be disrupted by various physical or chemical means, such as freeze-fhaw cycling, sonication, mechanical disruption, or cell lysing agents.
  • a suitable detergent solution e.g. Triton-X 100
  • Cells employed in expression of PRO can be disrupted by various physical or chemical means, such as freeze-fhaw cycling, sonication, mechanical disruption, or cell lysing agents.
  • the following procedures are exemplary of suitable purification procedures : by fractionation on an ion-exchange column; ethanol precipitation; reverse phase HPLC; chromatography on silica or on a cation-exchange resin such as DEAE; chromatofocusing; SDS-PAGE; ammonium sulfate precipitation; gel filtration using, for example, SephadexG-75; protein A Sepharose columns to remove contaminants such as IgG; and metal chelating columns to bind epitope- tagged forms of the PRO .
  • PRO Nucleotide sequences (or their complement) encoding PRO have various applications in the art of molecular biology, including uses as hybridization probes, in chromosome and gene mapping and in the generation of anti-sense RNA and DNA.
  • PRO nucleic acid will also be useful for the preparation of PRO polypeptides by the recombinant techniques described herein.
  • the full-length native sequence PRO gene, or portions thereof, may be used as hybridization probes for a cDNA library to isolate the full-length PRO cDNA or to isolate still other cDNAs (for instance, those encoding naturally-occurring variants of PRO or PRO from other species) which have a desired sequence identity to the native PRO sequence disclosed herein.
  • the length of the probes will be about 20 to about 50 bases.
  • the hybridization probes may be derived from at least partially novel regions of the full length native nucleotide sequence wherein those regions may be determined without undue experimentation or from genomic sequences including promoters, enhancer elements and introns of native sequence PRO.
  • a screening method will comprise isolating the coding region of the PRO gene using the known DNA sequence to synthesize a selected probe of about 40 bases.
  • Hybridization probes may be labeled by a variety of labels, including radionucleotides such as 32 P or 35 S, or enzymatic labels such as alkaline phosphatase coupled to the probe via avidin/biotin coupling systems. Labeled probes having a sequence complementary to that of the PRO gene of the present invention can be used to screen libraries of human cDNA, genomic DNA or mRNA to determine which members of such libraries the probe hybridizes to. Hybridization techniques are described in further detail in the Examples below.
  • antisense or sense oligonucleotides comprising a singe-stranded nucleic acid sequence (either RNA or DNA) capable of binding to target PRO mRNA (sense) or PRO DNA (antisense) sequences.
  • Antisense or sense oligonucleotides comprise a fragment of the coding region of PRO DNA. Such a fragment generally comprises at least about 14 nucleotides, preferably from about 14 to 30 nucleotides.
  • Stein and Cohen Cancer Res. 48:2659, 1988
  • van der Krol et al. BioTechniques 6:958, 1988.
  • binding of antisense or sense oligonucleotides to target nucleic acid sequences results in the formation of duplexes that block transcription or translation of the target sequence by one of several means, including enhanced degradation of the duplexes, premature termination of transcription or translation, or by other means.
  • the antisense oligonucleotides thus may be used to block expression of PRO proteins.
  • Antisense or sense oligonucleotides further comprise oligonucleotides having modified sugar-phosphodiester backbones (or other sugar linkages, such as those described in WO 91/06629) and wherein such sugar linkages are resistant to endogenous nucleases.
  • Such oligonucleotides with resistant sugar linkages are stable in vivo (i.e., capable of resisting enzymatic degradation) but retain sequence specificity to be able to bind to target nucleotide sequences.

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PCT/US2000/013705 WO2000073445A2 (en) 1999-06-02 2000-05-17 Interleukin-1-receptor associated kinase-3 (irak3)
PCT/US2000/014042 WO2000077037A2 (en) 1999-06-15 2000-05-22 Secreted and transmembrane polypeptides and nucleic acids encoding the same
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PCT/US2000/014941 WO2000073348A2 (en) 1999-06-02 2000-05-30 Methods and compositions for inhibiting neoplastic cell growth
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