CA2481691A1 - Secreted and transmembrane polypeptides and nucleic acids encoding the same - Google Patents

Abstract

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

Description

SAME
FIELD OF THE INVENTION
The present invention relates generally to the identification and isolation of novel DNA and to the recombinant production of novel polypeptides.
BACKGROUND OF THE INVENTION
Extracellular proteins 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 polypeprides (for instance, mitogenic factors, survival factors, cytotoxic factors, differentiation factors, neuropeptides, and hormones) which are, in turn, received and interpreted by diverse cell receptors or membrane-bound proteins. These secreted polypeptides or signaling molecules normally pass through the cellular secretory pathway to reach their site of IS 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 thromboiytic agents, interferons, interleukins, erythropoietins, colony stimulating factors, and various other cytokines, are secretory proteins.
Their receptors, which are membrane proteins, also have potential as therapeutic or diagnostic agents. Efforts are being undertaken by both industry and academia to identify new, native secreted proteins. Many efforts are focused on the screening of 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. 5,536,537)].
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, bur are not limited to, cytoldne 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 lcinases, enzymes that catalyze that process, can also act as growth factor receptors. Examples include fibroblast growth factor receptor and ". ~~. . ,. ~, . . ~~ 9. .F~~,~.m~<~~.~-..x,.~..~_x ~.._.._-..._.._ . ..__ _ .....

wo omu8 PCT/US00lZ3328 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.
S Efforts are being undertaken by both industry and academia 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.
SUMMARY OF THE INVENTION
In one embodiment, the invention provides an isolated nucleic acid molecule comprising a nucleotide sequence that encodes a PRO golypeptide.
In one aspect, the isolated nucleic acid molecule comprises a nucleotide sequence having at least about 80 % nucleic acid sequence identity, alternatively at least about 8196 nucleic acid sequence identity, alternatively at least about 82% nucleic acid sequence identity, alternatively at least about 83% nucleic acid sequence identity, alternatively at least about 84% nucleic acid sequence identity, alternatively at least about 85% nucleic acid sequence identity, alternatively at least about 86% nucleic acid sequence identity, alternatively at least about 87%
nucleic acid sequence identity, alternatively at least about 88% nucleic acid sequence identity, alternatively at least about 89% nucleic acid sequence identity, alternatively at.least about 90% nucleic acid sequence identity, alternatively at least about 91 % nucleic acid sequence identity, alternatively at least about:92 % nucleic acid sequence identity, alternatively at Least about 93 % nucleic acid sequence identity, alternatively at least about 94 %
nucleic acid sequence identity, alternatively at least about 95 % nucleic acid sequence identity, alternatively at least about 96% nucleic acid sequence identity, alternatively at least about 97% nucleic acid sequence identity, alternatively at least about 98% nucleic acid sequence identity and alternatively at least about 99% nucleic acid sequence identity to (a) a DNA molecule encoding a PRO polypeptide having a full-length amino acid sequence as disclosed herein, an amino acid sequence lacking the signal peptide as disclosed herein, an extracellular domain of a transmembrane protein, with or without the signal peptide, as disclosed herein or any other specifically defined fragment of the full-length amino acid sequence as disclosed herein, or (b) the complement of the DNA molecule of (a).
In other aspects, 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 9Q% 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 %

wo oxnms nucleic acid sequence identity, alternatively at least about 95 9b nucleic acid sequence identity, alternatively at least about 96% nucleic acid sequence identity, ahernatively at least about 97% nucleic acid sequence identity, alternatively at least about 98 %a nucleic acid sequence identity and alternatively at least about 99 ~ nucleic acid sequence identity to (a) a DNA molecule comprising the coding sequence of a full-length PRO polypeptide cDNA
as disclosed herein, the coding sequence of a PRO polypeptide lacking the signal peptide as disclosed herein, the coding sequence of an extracellular domain of a transmembrane PRO
polypeptide, with or without the signal peptide, as disclosed herein or the coding sequence of any other specifically defined fragment of the full-length amino acid sequence as disclosed herein, ar (b) the complement of the DNA
molecule of (a).
In a further aspect, 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 9b 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 853 nucleic acid sequence identity, alternatively at least about 869b nucleic acid sequence identity, alternatively at least about 87 % nucleic acid sequence identity, alternatively at least about 88 % nucleic acid sequence identity, alternatively at least about 89 ~ nucleic acid sequence identity, alternatively at least about 90 ~
nucleic acid sequence identity, alternatively at least about 91 % nucleic acid sequence identity, alternatively at least about 92°~ nucleic acid sequence identity, alternatively at least about 93 % nucleic acid sequence identity, alternatively at least about 94 ~ nucleic acid sequence identity, alternatively at least about 95 % nucleic acid sequence identity, alternatively at least about 96% nucleic acid sequence identity, alternatively at least about 97~
nucleic acid sequence identity, alternatively at least about 98 k nucleic acid sequence identity and alternatively at least about 99'~ nucleic acid sequence identity to (a) a DNA molecule that encodes the same mature polypeptide encoded by any of the human protein cDNAs deposited with the ATCC
as disclosed herein, or (b) the complement of the DNA molecule of (a).
Another aspect the invention provides an isolated nucleic acid molecule comprising a nucleotide sequence encoding a PRO polypeptide which is either transmembrane domain-deleted or transmembrane domain-inactivated, .or is complementary to such encoding nucleotide sequence, wherein the transmembrane domains) 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. Such nucleic acid fragments are usually at least about 20 nucleotides in length, alternatively at least about 30 nucleotides in length, alternatively at least about 40 nucleotides in length, alternatively at least about 50 nucleotides in length, alternatively at least about 60 nucleotides in length, alternatively at least about 70 nucleotides in length, alternatively at least about. 80 nucleotides in , length, alternatively at least about 90 nucleotides in length, alternatively at least about 100 nucleotides in length, alternatively at least about 110 nucleotides in length, alternatively at least about I20 nucleotides in length, alternatively at least about 130 nucleotides in length, alternatively at least about 140 nucleotides in length, ___. _..__ ___..__ _.~.~ ,~.~-::-_..ri . ~.--~-~:..~ . ~_,._~~.~.._. __._ .
.__ WO 01/16318 PCT~S~~~
alternatively at least about 150 nucleotides in length, alternatively at least about 160 nucleotides in length, alternatively at least about 170 nucleotides in length, alternatively at least about 180 nucleotides in length, alternatively at least about 190 nucleotides in length, alternatively at least about 200 nucleotides in length, alternatively at least about 250 nucleotides in length, alternatively at least about 300 nucleotides in length, alternatively at least about 350 nucleotides in length, alternatively at least about 400 nucleotides in length, alternatively at least about 450 nucleotides in length, alternatively at least about 500 nucleotides in length, alternatively at least about 600 nucleotides in length, alternatively at least about 700 nucleotides in length, alternatively at least about 800 nucleotides in length, alternatively at least about 900 nucleotides in length and alternatively at least about 1000 nucleotides in length, wherein in this context the term "about" means the referenced nucleotide sequence length plus or minus 10% of that referenced length. It is noted that 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 polypegtide-encoding nucleotide sequence fragments) 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.
In another embodiment, the invention provides isolated PRO polypeptide encoded by any of the isolated nucleic acid sequences hereinabove identified.
In a certain aspect, 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 8196 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 PRO polypeptide having a full-length amino acid sequence as disclosed herein, an amino acid sequence lacking the signal peptide as disclosed herein, an extracellular domain of a transmembrane protein, with or without the signal peptide, as disclosed herein or any other specifically defined fragment of the full-lengih amino acid. sequence as disclosed herein.
In a further aspect, the invention concerns an isolated PRO polypepiide 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 %

wo oma$ rcTCnrsoon33zs amino acid sequence identity, alternatively at least about 84 qb 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 879'o 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 ab 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 9896 amino acid sequence identity and alternatively at least about 99% amino acid sequence identity to an amino acid sequence encoded by any of the human protein cDNAs deposited with the ATCC as disclosed herein.
In a specific aspect, the invention provides an isolated PRO polypeptide without the N-terminal signal sequence andlor 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 IS 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.
In yet another ernboditnent, the invention concerns agonists and antagonists of a native PRO polypeptide as defined herein. In a particular embodiment, the agonist or antagonist is an anti-PRO antibody or a small molecule.
In a further embodiment, 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. Preferably, the PRO
polypeptide is a native PRO
polypeptide.
In a still further embodiment, 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 wi.h a carrier. Optionally, 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 PR~.
polyPe~tide,_ an agonist or antagonist thereof or an anti-FRO antibody.
In other embodiments of the present invention, the invention provides vectors comprising DNA
encoding any of the herein described polypeptides. Host cell comprising any such vector are also provided.. By wo omems rc'i'nrsoon~zs way of example, 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.
In other embodiments, the invention provides chimeric molecules comprising any of the herein described polypeptides fused to a heterologous poIypeptide or amino acid sequence.
Example of such chimeric molecules comprise any of the herein described polypeptides fused to an egltope tag sequence or a Fc region of an immunoglobulin.
In another embodiment, the invention provides an antibody which binds, preferably specifically, to any of the above or below described polypeptides. Optionally, the antibody is a monoclonal antibody, humanized antibody, antibody fragment or single-chain antibody.
In yet other embodiments, the invention provides oligonucleotide probes useful for isolating genomic and cDNA nucleotide sequences or as antisense probes, wherein those probes may be derived from any of the above or below described nucleotide sequences.
In yet other embodiments, 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.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 shows a nucleotide sequence (SEQ ID NO:1) of a native sequence PR0180 cDNA, wherein SEQ ID NO:1 is a clone designated herein as "DNA26843-1389".
Figure 2 shows the amino acid sequence (SEQ ID N0:2) derived from the coding sequence of SEQ ID
NO:I shown in Figure I.
Figure 3 shows a nucleotide sequence (SEQ ID N0:3) of a native sequence PR0218 cDNA, wherein SEQ ID N0:3 is a clone designated herein as "DNA30867-1335".
Figure 4 shows the amino acid sequence (SEQ ID N0:4) derived from the coding sequence of SEQ ID
N0:3 shown in Figure 3.
Figure 5 shows a nucleotide sequence (SEQ ID N0:5) of a native sequence PR0263 cDNA, wherein SEQ ID N0:5 is a clone designated herein as "DNA34431-I 177".
Figure 6 shows the amino acid sequence (SEQ ID N0:6) derived from~.the coding sequence pf SEQ ID
N0:5 shown in Figure 5.
Figure 7 shows a nucleotide sequence (SEQ ID N0:7) of a native sequence PR0295 cDNA, wherein SEQ ID N0:7 is a clone designated herein as "DNA38268-1188".
Figure 8 shows the amino acid sequence (SEQ ID N0:8) derived from the coding sequence of SEQ ID
N0:7 shown in Figure 7.
Figure 9 shows a nucleotide sequence (SEQ ID N0:9) of a native sequence PR0874 cDNA; wheiein SEQ ID N0:9 is a clone designated herein as "DNA40621-1440".
Figure 10 shows the amino acid sequence (SEQ ID NO:10) derived from the coding sequence of SEQ
ID N0:9 shown in Figure 9.

Figure 11 shows a nucleotide sequence (SEQ ID NO:11) of a native sequence PR0300 cDNA, wherein SEQ ID NO:I 1 is a clone designated herein as "DNA40625-1189".
Figure 12 shows the amino acid sequence (SEQ ID N0:12) derived from the coding sequence of SEQ
ID NO:11 shown in 'Figure 11.
Figure 13 shows a nucleotide sequence (SEQ ID N0:13) of a native sequence PR01864 eDNA, wherein SEQ ID N0:13 is a clone designated herein as "DNA45409-2511".
Figure 14 shows the amino acid sequence (SEQ ID NO:14) derived from the coding sequence of SEQ
ID N0:13 shown in Figure 13.
Figure 15 shows a nucleotide sequence (SEQ ID N0:15) of a native sequence PR01282 cDNA, wherein SEQ ID NO:15 is a clone designated herein as "DNA45495-1550".
1Q Figure I6 shows the amino acid sequence (SEQ ID N0:16) derived from the coding sequence of SEQ
ID NO:15 shown in Figure I5.
Figure 17 shows a nucleotide sequence (SEQ ID N0:17) of a native sequence PR01063 cDNA, wherein SEQ ID NO:17 is a clone designated herein as "DNA49820-1427".
Figure 18 shows the amino acid sequence (SEQ ID N0:18) derived from the coding sequence of SEQ
ID N0:17 shown in Figure 17.
Figure 19 shows a nucleotide sequence (SEQ ID N0:19) of a native sequence PRO
1773 eDNA, wherein SEQ ID N0:19 is a clone designated herein as "DNA56406-1704".
Figure 20 shows the amino acid sequence (SEQ ID N0:20) derived from the coding sequence of SEQ
ID N0:19 shown in Figure i9.
2d Figure 21 shows a nucleotide sequence: (SEQ ID N0:21 ) of a native sequence PRO 1013 cDNA, wherein SEQ ID N0:21 is a clone,designated herein as "DNA56410-1414".
Figure 22 shows the amino acid sequence (SEQ ID N0:22) derived from the coding sequence of SEQ
ID NO:21 shown in Figure 21.
Figure 23 shows a nucleotide sequence (SEQ ID N0:23) of a native sequence PR0937 cDNA, wherein SEQ ID N0:23 is a clone designated herein as "DNAS6436-1448".
Figure 24 shows the amino acid sequence (SEQ ID N0:24) derived from the coding sequence of SEQ
ID N0:23 shown in Figure 23.
Figure 25 shows a nucleotide sequence (SEQ ID N0:25) of a ytative sequence PR0842 cDNA., wherein , SEQ ID N0:25 is a clone designated herein as "DNAS6855-1447".
Figure 26 shows the amino acid sequence (SEQ ID N0:26) derived from the coding sequence of SEQ
ID N0:25 shown in Figure 25.
Figure 27 shows a nucleotide sequence (SEQ ID N0:27) of a native sequence PR01180 cDNA, wherein SEQ ID N0:27 is a clone designated herein as "DNA56860-1510".
Figure 28 shows the amino acid sequence (SEQ ID.N0.28) derived from the coding sequeace of S~Q _ ID N0:27 shown in Figure 27:
Figure 29 shows a nucleotide sequence (SEQ ID N0:29) of a native sequence PR0831 cDNA, wherein SEQ ID N0:29 is a clone designated herein as "DNA56862-1343".

~. . _ ._ xz . =.mex a~ w>n.rN..ax<n. -r~r. . w» ."~,~r-.~. .. ",. .-~. .
......_...
. ...... ,. ,., ... , ~, n, .gym ,-xr,~"~ _.r~.v xnx..~~, r..r ssm.ru...,"..,a.,n x.-"x.m w x,=..rz.~x.,.~r,o~a,~z~.~~"~.m~.... p WO Oi/I63I8 PCT~3~
Figure 30 shows the amino acid sequence (SEQ ID N0:30) derived from the coding sequence of SEQ
ID N0:29 shown in Figure 29.
Figure 31 shows a nucleotide sequence (SEQ ID N0:31 ) of ~ native sequence PRO1115 cDNA, wherein SEQ ID N0:31 is a clone designated herein as "DNA56868-1478".
Figure 32 shows the amino acid sequence (SEQ ID N0:32) derived from the coding sequence of SEQ
ID N0:31 shown in Figure 31.
Figure 33 shows a nucleotide sequence (SEQ ID N0:33) of a native sequence PR01277 cDNA, wherein SEQ ID N0:33 is a clone designated herein as "DNA56869-1545".
Figure 34 shows the amino acid sequence (SEQ ID N0:34) derived from the coding sequence of SEQ
ID N0:33 shown in Figure 33.
Figure 35 shows a nucleotide sequence (SEQ ID N0:35) of a native sequence PR01074 cDNA, wherein SEQ ID N0:35 is a clone designated herein as "DNA57704-1452".
Figure 36 shows the amino acid sequence (SEQ ID N0:36) derived from the coding sequence of SEQ
ID N0:35 shown in Figure 35.
Figure 37 shows a nucleotide sequence (SEQ ID N0:37) of a native sequence PRO
1344 cDNA, wherein SEQ ID N0:37 is a clone designated herein as "DNA58723-1588".
Figure 38 shows the amino acid sequence (SEQ ID N0:38) derived from the coding sequence of SEQ
ID N0:37 shown in Figure 37.
Figure 39 shows a nucl~tide sequence (SEQ ID N0:39) of a native sequence PRO
1136 cDNA, wherein SEQ ID N0:39 is a clone designated herein as "DNA57827-1493".
Figure 40 shows the amino acid sequence (SEQ ID N0:40) derived from the coding sequence of SEQ
ID N0:39 shown in Figure 39.
Figure 41 shows a nucleotide sequence (SEQ ID N0:41 ) of a native sequence PRO
1109 cDNA, wherein SEQ ID N0:41 is a clone designated herein as "DNA58737-1473".
Figure 42 shows the amino acid sequence (SEQ ID N0:42) derived from the coding sequence of SEQ
ID N0:41 shown in Figure 41.
Figure 43 shows a nucleotide sequence (SEQ ID N0:43) of a native sequence PRO
1003 cDNA, wherein SEQ ID N0:43 is a clone designated herein as "DNA58846-1409".
Figuee 44 shows the amino acid sequence (SEQ ID N0:44) derived from the coding sequence of SEQ .
ID N0:43 shown in Figure 43.
Figure 45 shows a nucleotide sequence (SEQ ID N0:45) of a native sequence PRO
1138 cDNA, wherein SEQ ID N0:45 is a clone designated herein as "DNA58850-1495".
Figure 46 shows the amino acid sequence (SEQ ID N0:46) derived from the coding sequence of SEQ
ID N0:45 shown in Figure 45.
Figure 47 shows a nucleotide sequence (SEQ ID N0:47) of a native sequence PR0994 cDNA, wherein SEQ ID NQ:47 is a clone designated herein as "DNA58855-1422".
Figure 48 shows the amino acid sequence (SEQ ID N0:48) derived from the coding sequence of SEQ
ID N0:47 shown in Figure 47.

Figure 49 shows a nucleotide sequence (SEQ ID NO:49) of a native sequence PRO
1069 cDNA, wherein SEQ ID N0:49 is a clone designated herein as "DNA59211-1450".
Figure SO shows the amino acid sequence (SEQ ID NO:SO) derived from the coding sequence of SEQ
ID N0:49 shown in Figure 49.
Figure 51 shows a nucleotide sequence (SEQ ID NO:S 1 ) of a native sequence PRO1411 cDNA, wherein SEQ ID NO:51 is a clone designated herein as "DNAS9212-1627".
Figure 52 shows the amino acid sequence (SEQ ID N0:52) derived from the coding sequence of SEQ
ID NO:SI shown in Figure 51.
Figure S3 shows a nucleotide sequence (SEQ ID NO: S3) of a native sequence PRO
1129 cDNA, wherein SEQ ID N0:53 is a clone designated herein as "DNA592i3-1487"..
IQ Figure 54 shows the amino acid sequence (SEQ ID N0:54) derived from the coding sequence of SEQ
iD N0:53 shown in Figure 53.
Figure SS shows a nucleotide sequence (SEQ ID NO:55) of a native sequence PRO
1027 cDNA, wherein SEQ 1D NO:SS is a clone designated herein as "DNA5960S-1418".
Figure 56 shows the amino acid sequence (SEQ ID N0:56) derived from the coding sequence of SEQ
ID NO:SS shown in Figure 55.
Figure 57 shows a nucleotide sequence (SEQ ID N0:57) of a native sequence PR01106 cDNA, wherein SEQ ID NO:S7 is a clone designated herein as "DNA59609-1470".
Figure 58 shaves the amino acid sequence (SEQ ID NO:SB) derived from the coding sequence of SEQ
ID N0:57 shown in Figure S7:
Figure 59 shows a nucleotide sequence (SEQ ID N0:59) of a native sequence PRO
1291 cDNA, wherein SEQ ID N0:59 is a clone designated herein as "DNA59610-1556".
Figure 60 shows the amino acid sequence (SEQ ID N0:60) derived from the coding sequence of SEQ
ID N0:59 shown in Figure S9.
Figure 61 shows a nucleotide sequence (SEQ ID N0:61) of a native sequence PR03573 cDNA, wherein SEQ ID N0:61 is a clone designated herein as "DNA59837-2545".
Figure 62 shows the amino acid sequence (SEQ ID NO:b2) derived from the coding sequence of SEQ
ID N0:6I shown in Figure 61.
Figure 63 shows a nucleotide sequence (SEQ ID N0:63) of a native sequence PR03566 cDNA, wherein 5EQ ID N0:63 is a clone designated herein as "DNA59844-2542".
Figure 64 shows the amino acid sequence (SEQ ID N0:64) derived from the coding sequence of SEQ
ID NO:63 shown in Figure 63.
Figure 6S shows a nucleotide sequence (SEQ ID N0:65) of a native sequence PRO
1098 eDNA, wherein SEQ ID N0:65 is a clone designated herein as "DNAS9854-1459"_ Figure 66 shows the amino acid sequence (SEQ ID N0:66) derived from the coding sequence of SEQ
ID N0:65 shown in Figure 65.
Figure 67 shows a nucleotide sequence (SEQ ID N0:67) of a native sequence PRO
1158 cDNA, wherein SEQ ID N0:67 is a clone designated herein as "DNA6062S-1507".

_ .. . m ~ .. ..... .. ~" ,w. .~. .~ ~~~5.~.~.N., .. _ _. ..,._... ~.
~~..,~,~r . .. _..

wo omt~ls rcz'msoor~zs Figure 68 shows the amino acid sequence (SEQ ID N0:68) derived from the coding sequence of SEQ
ID N0:67 shown in Figure 67.
Figure 69 shows a nucleotide sequence (SEQ ID N0:69) of a native sequence PROl 124 cDNA, wherein SEQ ID N0:69 is a clone designated herein as "DNA60629-1481 ".
Figure 70 shows the amino acid sequence (SEQ ID N0:70) derived from the coding sequence of SEQ
ID N0:69 shown in Figure 69.
Figure 71 shows a nucleotide sequence (SEQ ID N0:71 ) of a native sequence PROI287 cDNA, wherein SEQ ID N0:7I is a clone designated herein as "DNA6I75S-1554".
Figure 72 shows the amino acid sequence (SEQ ID N0:72) derived from the coding sequence of SEQ
ID N0:71 shown in Figure 71.
Figure 73 shows a nucleotide sequence (SEQ ID N0:73) of a native sequence PROI335 eDNA, wherein SEQ ID N0:73 is a clone designated herein as "DNA62812-1594".
Figure 74 shows the amino acid sequence (SEQ ID N0:74) derived from the coding sequence of SEQ
ID N0:73 shown in Figure 73.
Figure 75 shows a nucleotide sequence (SEQ ID N0:75) of a native sequence PR01315 cDNA, wherein SEQ ID N0:75 is a clone designated herein as "DNA62815-1576".
Figure 76 shows the amino acid sequence (SEQ ID N0:76) derived from the coding sequence of SEQ
ID N0:75 shown in Figure 75.
Figure 77 shows a nucleotide sequence (SEQ ID N0:77) of a native sequence PR01357 eDNA, wherein SEQ ID N0:77 is a clone designated herein as "DNA64881-1602".
Figure 78 shows the amino acid sequence (SEQ ID N0:78) derived from the coding sequence of SEQ
ID N0:77 shown in Figure 77.
Figure 79 shows a nucleotide sequence (SEQ ID N0:79) of a native sequence PRO
1356 cDNA, wherein SEQ ID N0:79 is a clone designated herein as "DNA64886-1601".
Figure 80 shows the amino acid sequence (SEQ ID N0:80) derived from the coding sequence of SEQ
ID N0:79-shown in Figure 79.
Figure 81 shows a nucleotide sequence (SEQ ID N0:81 ) of a native sequence PR01557 cDNA, wherein SEQ ID N0:81 is a clone designated herein as "DNA64902-1667".
Figure 82 shows the amino acid sequence, (SEQ ID N0:82) derived from the coding sequence of SEQ
ID N0:8I shown in Figure 81.
Figure 83 shows a nucleotide sequence (SEQ ID N0:83) of a native sequence PRO
1347 cDNA, wherein SEQ ID N0:83 is a clone designated herein as "DNA649S0-1590".
Figure 84 shows the amino acid sequence (SEQ ID NO:84) derived from the coding sequence of SEQ
ID N0:83 shown in Figure 83.
Figure 85 shows a nucleotide sequence (SEQ ID N0:85) of a native sequence PRO
1302 cDNA, wherein SEQ ID N0:85 is a clone designated herein as "DNA65403-15b5".
Figure 86 shows the amino acid sequence (SEQ ID N0:86) derived from the coding sequence of SEQ
ID N0:85 shown in Figure 85.
lfl Figure 87 shows a nucleotide sequence (SEQ ID N0:87) of a native sequence PR01270 cDNA, wherein SEQ ID N0:87 is a clone designated herein as "DNA66308-1537".
Figure 88 shows the amino acid sequence (SEQ ID N0:88) derived from the coding sequence of SEQ
ID N0:87 shown in Figure 87.
Figure 89 shows a nucleotide sequence (SEQ ID N0:89) of a native sequence PRO
1268 cDNA, wherein SEQ ID N0:89 is a clone designated herein as "DNA66519-1535".
Figure 90 shows the amino acid sequence (SEQ ID N0:90) derived from the coding sequence of SEQ
ID N0:89 shown in Figure 89.
Figure 91 shows a nucleotide sequence (SEQ ID N0:91 ) of a native sequence PRO
1327 cDNA, wherein SEQ ID N0:91 is a clone designated herein as "DNA66521-1583".
IO Figure 92 shows the amino acid sequence (SEQ ID N0:92) derived from the coding sequence of SEQ
ID N0:91 shown in Figure 91.
Figure 93 shows a nucleotide sequence (SEQ ID N0:93) of a native sequence PR01328 cDNA, wherein SEQ ID N0:93 is a clone designated herein as "DNA66658-1584".
Figure 94 shows the amino acid sequence (SEQ ID N0:94) derived from the coding sequence of SEQ
IS ID N0:93 shown in Figure 93.
Figure 95 shows a nucleotide sequence (SEQ ID N0:95) of a native sequence PR01329 cDNA, wherein SEQ ID N0:95 is a clone designated herein as "DNA66660-1585".
Figure 96 shows the amino acid sequence (SEQ ID N0:96) derived from the coding sequence of SEQ
ID N0:95 shown in Figure 95.
20 Figure 97 shows a nucleotide sequence (SEQ ID N0:97) of a native sequence PRO 1340 cDNA, wherein SEQ ID N0:97 is a clone designated herein as "DNA66663-1598".
Figure 98 shows the amino acid sequence (SEQ ID N0:98) derived from the coding sequence of SEQ
ID N0:97 shown in Figure 97.
Figure 99 shows a nucleotide sequence (SEQ ID N0:99) of a native sequence PR01342 cDNA, wherein 25 SEQ ID N0:99 is a clone designated herein as "DNA66674-1599".
Figure 100 shows the amino acid sequence (SEQ ID N0:100) derived from the coding sequence of SEQ
ID N0:99 shown in Figure 99.
Figure 101 shows a nucleotide sequence (SEQ ID NO:101) of a native sequence PR03579 cDNA, wherein SEQ ID NO:101 is a clone designated herein as "DNA68862-2546".
30 Figure 102 shows the amino acid sequence (SEQ ID N0:102) derived from the coding sequence of SEQ
ID NO:IOi shown in Figure 10I.
Figure 103 shows a nucleotide sequence (SEQ ID N0:103) of a native sequence PR01472 cDNA, wherein SEQ ID N0:103 is a clone designated herein as "DNA68866-1644".
Figure 104 shows the amino acid sequence (SEQ ID N0:104) derived from the coding sequence.of SEQ_ 35 ID N0:103 shown in Figure 103.
Figure 105 shows a nucleotide sequence (SEQ ID NO:105) of a native sequence PR01461 cDNA, wherein SEQ ID NO:105 is a clone designated herein as "DNA68871-1638".
Il ..n,.... . .~,~~~1 .w~:~-~.~.~...r_w, -_ ____...__ . __~-.,.~~~~~4. - ._ Figure 106 shows the amino acid sequence (SEQ ID NO: I06) derived from the coding sequence of SEQ
ID N0:105 shown in Figure 105.
Figure 107 shows a nucleotide sequence (SEQ ID N0:107) of a native sequence PR01568 cDNA, wherein SEQ ID N0:107 is a clone designated herein as "DNA68880-1676".
Figure 108 shows the amino acid sequence (SEQ ID N0:108) derived from the coding sequence of SEQ
ID N0:107 shown in Figure 107.
Figure 109 shows a nucleotide sequence (SEQ ID NO:I09) of a native sequence PR01753 cDNA, wherein SEQ ID N0:109 is a clone designated herein as "DNA68883-1691".
Figure 110 shows the amino acid sequence (SEQ ID NO:110) derived from the coding sequence of SEQ
ID N0:109 shown in Figure 109.
Figure 111 shows a nucleotide sequence (SEQ !D NO:111) of a native sequence PR01570 cDNA, wherein SEQ ID NO:111 is a clone designated herein as "DNA68885-1678".
Figure 112 shows the amino acid sequence (SEQ iD N0:112) derived from the coding sequence of SEQ
ID NO:111 shown in Figure 111.
Figure 113 shows a nucleotide sequence (SEQ ID N0:113) of a native sequence PR01446 cDNA, wherein SEQ ID N0:113 is a clone designated herein as "DNA71277-1636".
Figure I 14 shows the amino acid sequence {SEQ ID N0:114) derived from the coding sequence of SEQ
ID N0:113 shown in Figure 1 I3.
Figure I !5 shows a nucleotide sequence (SEQ ID N0:115) of a native sequence PRO1565 cDNA, wherein SEQ ID NO:115 is a clone designated herein as "DNA73727-1673".
Figure 116 shows the amino acid sequence (SEQ ID N0:116) derived from the coding sequence of SEQ
ID NO:115 shown in Figure 115.
Figure 117 shows a nucleotide sequence (SEQ ID NO:117) of a native sequence PR01572 cDNA, wherein SEQ ID N0:117 is a clone designated herein as "DNA73734-1680".
Figure 118 shows the amino acid sequence (SEQ ID N0:118) derived from the coding sequence of SEQ
ID N0:117 shown in Figure 117.
Figure 119 shows a nucleotide sequence {SEQ ID N0:119) of a native sequence PR01573 cDNA, wherein SEQ ID N0:119 is a clone designated herein as "DNA73735-1681".
Figure 120 shows the amino acid sequence {SEQ ID N0:120) derived from the coding sequence of SfiQ
ID N0:119 shown in Figure 119.
Figure 121 shows a nucleotide sequence (SEQ ID N0:121) of a native sequence PR01550 cDNA, wherein SEQ ID N0:12! is a clone designated herein as "DNA76393-l664".
Figure 122 shows the amino acid sequence (SEQ ID N0:122) derived from the coding sequence of SEQ
ID N0:121 shown in Figure 12I.
Figure 123. shows a nucleotide sequence (SEQ ID N0:123):of,a native sequence PR01693 cDNA, wherein SEQ ID NO:I23 is a clone designated herein as "DNA7730!-1708".
Figure 124 shows the amino acid sequence (SEQ ID N0:124) derived from the coding sequence of SEQ
ID N0:123 shown in Figure 123.

WO 01116318 PCTlUS00/23328 Figure 125 shows a nucleotide sequence (SEQ ID N0:125) of a native sequence PR015b6 eDNA, wherein SEQ ID N0:125 is a clone designated herein as "DNA775b8-1626".
Figure 126 shows the amino acid sequence (SEQ ID N0:126) derived from the coding sequence of SEQ
ID N0:125 shown in Figure 125.
Figure 127 shows a nucleotide sequence (SEQ ID N0:127) of a native sequence PR01774 eDNA, wherein SEQ ID N0:127 is a clone designated herein as "DNA77626-1705".
Figure 128 shows the amino acid sequence (SEQ ID N0:128) derived from the coding sequence of SEQ
ID N0:127 shown in Figure 127.
Figure 129 shows a nucleotide sequence (SEQ ID N0:129) of a native sequence PR01928 cDNA, wherein SEQ ID N0:129 is a clone designated herein as "DNA81754-2532".
Figure i 30 shows the amino acid sequence (SEQ ID N0:130) derived from the coding sequence of SEQ
ID N0:129 shown in Figure 129.
Figure 131 shows a nucleotide sequence (SEQ ID N0:131) of a native sequence PR01865 cDNA, wherein SEQ ID N0:131 is a clone designated herein as "DNA8I757-2512".
Figure 132 shows the amino acid sequence (SEQ ID N0:132) derived from the coding sequence of SEQ
ID NO: I31 shown in Figure 131.
Figure 133 shows a nucleotide sequence (SEQ ID NO:I33) of a native sequence PR01925 cDNA, wherein SEQ ID N0:133 is a clone designated herein as "DNA82302-2529".
Figure 134 shows the amino acid sequence (SEQ ID N0:134) derived from the coding sequence of SEQ
ID N0:133 shown in Figure 133.
Figure 135 shows a nucleotide sequence (SEQ ID N0:135) of a native sequence PR01926 cDNA, wherein SEQ ID N0:135 is a clone designated herein as "DNA82340-2530".
Figure 136 shows the amino acid sequence (SEQ ID N0:13b) derived from the coding sequence of SEQ
ID N0:135 shown in Figure 135.
Figure 137 shows a nucleotide sequence (SEQ ID N0:137) of a native sequence PR01801 cDNA, wherein SEQ ID N0:137 is a clone designated herein as "DNA83500-2506".
Figure 138 shows the amino acid sequence (SEQ ID N0:138) derived from the coding sequence of SEQ
ID N0:137 shown in Figure 137.
Figure 139 shows a nucleotide sequence (SEQ ID N0:139) of a native sequence PR04405 cDNA, wherein SEQ ID N0:139 is a clone designated herein as "DNA84920-2614".
Figure 140 shows the amino acid sequence (SEQ ID N0:140) derived from the coding sequence of SEQ
ID N0:139 shown in Figure 139.
Figure 141 shows a nucleotide sequence (SEQ ID N0:141) of a native sequence PR03435 cDNA, wherein SEQ ID N0:141 is a clone designated herein as "DNA850b6-2534".
Figure 142 shows the amino acid sequence (SEQ ID N0:142) derived from the coding sequence of SEQ
ID N0:141 shown in Figure 141. -Figure 143 shows a nucleotide sequence (SEQ ID N0:143) of a native sequence PR03543 cDNA, wherein SEQ ID NO:I43 is a clone designated herein as "DNA8b571-2551".

WO 01/I6318 PG"T/US00/23328 Figure 144 shows the amino acid sequence (SEQ ID N0:144) derived from the coding sequence of SEQ
ID NO:143 shown in Figure 143.
Figure 145 shows a nucleotide sequence (SEQ ID N0:145) of a native sequence PR03443 cDNA, wherein SEQ ID N0:145 is a clone designated herein as "DNA87991-2540".
Figure 146 shows the amino acid sequence (SEQ ID N0:146) derived from the coding sequence of SEQ
ID N0:145 shown in Figure 145.
Figure 147 shows a nucleotide sequence (SEQ ID N0:147) of a native sequence PR03442 cDNA, wherein SEQ ID NO:I47 is a clone designated herein as "DNA92238-2539".
Figure 148 shows the amine acid sequence (SEQ ID NO:148) derived fram the coding sequence of SEQ
ID N0:147 shown in Figure 147.
Figure 149 shows a nucleotide sequence (SEQ ID N0:149) of a native sequence PR05990 cDNA, wherein SEQ ID N0:149 is a clone designated herein as "DNA96042-2682".
Figure 150 shows the amino acid sequence (SEQ ID NO: i50) derived from the coding sequence of SEQ
ID N0:149 shown in Figure 149.
Figure 151 shows a nucleotide sequence (SEQ ID N0:151) of a native sequence PR04342 cDNA, wherein SEQ ID N0:151 is a clone designated herein as "DNA96787-2534".
Figure 152 shows the amino acid sequence (SEQ ID N0:152) derived from the coding sequence of SEQ
ID N0:151 shown in Figure 151.
Figure 153 shows a nucleotide sequence (SEQ ID N0:153) of a native sequence PR010096 cDNA, wherein SEQ ID N0:153 is a clone designated herein as "DNA125185-2806".
Figure 154 shows the amino acid sequence (SEQ ID N0:154) derived from the coding sequence of SEQ
ID N0:153 shown in-Figure 153.
Figure 155 shows a nucleotide sequence {SEQ ID N0:155) of a native sequence PROi0272 cDNA, wherein SEQ ID N0:155 is a clone designated herein as "DNA147531-2821".
Figure 156 shows the amino acid sequence (SEQ ID NO:156) derived from the coding sequence of SEQ
ID N0:155 shown in Figure 155.
Figure 157 shows a nucleotide sequence (SEQ ID NO:157) of a native sequeilce PR05801 cDNA, wherein SEQ ID N0:157 is a clone designated herein as "DNA115291-2681".
Figure 158 shows the amino acid sequence (SEQ ID N0:158) derived from the coding sequence of.SEQ . _ ID N0:157 shown in Figure 157.
Figure 159 shows a nucleotide sequence (SEQ ID N0:159) of a native sequence PR020110 cDNA, wherein SEQ ID N0:159 is a clone designated herein as "DNA166819".
Figure 160 shows the amino acid sequence (SEQ ID N0:160) derived from the coding sequence of SEQ
ID N0:159 shown in Figure 159.
Figure I61 shows a nucleotide sequence (SEQ ID NO:I61) of a native sequence PR020040 cDNA, wherein SEQ ID N0:161 is a clone designated herein as "DNA164625-2890".
Figure 162 shows the amino acid sequence (SEQ ID N0:162) derived from the coding sequence of SEQ
ID N0:161 shown in Figure 161.

. .~ w...._~. _ ..~~.n ,....~~~M.,~~.~~~,. _~;~ _ ~ .r. #~ ~M, ~.~.. a.,_rt AM.~.,x~~. ~~a..~_ _ . _ wo o><n63ig IPCriusoon33z8 Figure 163 shows a nucleotide sequence (SEQ ID N0:163) of a native sequence PR020233 cDNA, wherein SEQ ID N0:163 is a clone designated herein as "DNA165608".
Figure 164 shows the amino acid sequence (SEQ ID N0:164) derived from the coding sequence of SEQ
ID N0:163 shown in Figure 163.
Figure 165 shows a nucleotide sequence (SEQ ID N0:165) of a native sequence PR019670 cDNA, wherein SEQ ID N0:165 is a clone designated herein as "DNA131639-2874".
Figure 166 shows the amino acid sequence (SEQ ID N0:166) derived from the coding sequence of SEQ
ID N0:165 shown in Figure 165.
Figure 167 shows a nucleotide sequence (SEQ ID N0:167) of a native sequence PRO1890 cDNA, wherein SEQ ID N0:167 is a clone designated herein as "DNA79230-2525".
Figure 168 shows the amino acid sequence (SEQ ID N0:168) derived from the coding sequence of SEQ
ID N0:167 shown in Figure 167.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
I. Definitions The terms "PRO polypeptide" and "PRO" as used herein and when immediately followed by a numerical designation refer to various polypeptides, wherein the complete designation (i.e., PROlnumber) refers to specific polypeptide sequences as described herein. The terms "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. The term "PRO polypeptide" refers to each individual PROlnumber 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, composieions containing, treatment of a disease with, etc., pertain to each polypeptide of the invention individually. The term "PRO polypeptide" also includes variants of ehe PRO/number polypeptides disclosed herein.
A "native sequence PRO polypeptide" comprises a polypeptide having the same amino acid sequence as the corresponding PRO golypeptide 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 exiracellular domain sequence), naturally-occurring variant forms (e.g., alternatively spliced forms} and. naturally-occurring allelic variants of the polypeptide.
In various embodiments of the invention, the native sequence .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 WO O1/I63I8 PGT/U500n3328 acid position I in the figures, it is conceivable and possible that other methionine residues located either upstream yr downstream from the amino acid position I in the figures may be employed as the starting amino acid residue for the PRO polypeptides.
The PRO polypeptide "extracellular domain" or "ECD" refers to a form of the PRO polypeptide which is essentially free of the transmembrane and cytoplasmic domains. Ordinarily, a PRO polypeptide ECD will have less than 1 %fl of such transmembrane andlor 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. Optionally, therefore, 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.
The approximate location of the "signal peptides" of the various PRO
polypeptides disclosed herein are shown in the present specification andlor the accompanying figures. It is noted, however, that the C-terminal boundary of a signal peptide may vary, but most likely by no more than about 5 amino acids on either side of the signal peptide C-terminal boundary as initially identified herein, wherein the C-terminal boundary of the signal peptide may be identified pursuant to criteria routinely employed in the art for identifying that type of amino acid sequence element (e:g., NieIsen et al., Prot. Eng. 10:1-6 (1997) and von Heinje et al., Nucl. Acids.
Res. 14:4683-4690 (1986)). Moreover, it is also recognized that, in some cases, 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 809b 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 o: any other fragment of a full-length PRO poiypeptide sequence as disclosed herein. Such PRO
polypeptide variants include, for instance, PRO polypeptides wherein one or more amino acid residues are added, or deleted, at the N- or C-terminus of the full-length native amino acid sequence. Ordinarily, a PRO
polypeptide variant will have at least about 80% amino acid sequence identity, alternatively at least about 81 %
amino acid sequence identity, alternatively at least about 82 k 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 atiouE 85 90 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.°6 amino acid sequence identity, alternatively at least about 90~ amino acid __m~.n...._r._~e~n.~ .F. ~ ;~.n.,.~,~x. _ _,~e~: .:_ ~~.~..~~-~... -~..., .~.ø~,.e.~., _. ..

wo oms3>t$ PCTrasoor~32s sequence identity, alternatively at least about 919 amino acid sequence identity, alternaeively at least about 92 ~
amino acid sequence identity, alternatively at least about 93 '~ amino acid sequence identity, aleematively 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 ideneity, alternatively at least about 97% amino acid sequence identity, alternatively at least about 98 % amino acid sequence identity and alternatively at least about S 99 % amino acid sequence identity to 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 specifically defined fragment of a full-length PRO polypeptide sequence as disclosed herein. Ordinarily, 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 $0 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 ZS 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 ideneity, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity ran 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 aligtunent over the full length of the sequences being compared. For purposes herein, however, 9~ amino acid sequence identity values are generaeed 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 ~mputer 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. TXUS 10087. The ALIGN-2 program is publicly available through Genentech, Ine., South San Francisco, California or may be compiled from the source code provided in Table 1 below. The ALIGN-2 program should be compiled for use on a UNIX operating system, preferably digital UNIX V4.OD. All sequence comparison parameters are set by the ALIGN-2 program and do not vary. -In sieuations where ALIGN-2 is employed for amino acid sequence comparisons, the '&. amino :acid sequenct identity of a given amino acid sequence A to, with, or against a given amino acid sequence B (which can alternaeively be phrased as a given amino acid sequence A that has or comprises a certain 9~ amino acid sequence identity to, with, or against a given amino acid sequence B) is calculated as follows:

*-trademark WO OI/I63I8 PCT/US00~3328 10(f tunes the fraction X/Y
where X is the number of amino acid residues scored as identical matches by the sequence alignment program ALIGN-2 in that program's alignment of A and B, and where Y is the total number of amino acid residues in B. It will be appreciated that where the length of amino acid sequence A is not equal to the length of amino acid sequence B, the % amino acid sequence identity of A to B will not equal the 9'o amino acid sequence identity of B to A. As examples of % amino acid sequence identity calculations using this method, 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 atritno 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 96 amino acid sequence identity values used herein are obtained as described in the immediately preceding paragraph using the ALIGN-2 computer program. However, '~ amino acid sequence identity values may also be obtained as described below by using the WU-BLAST-2 computer program {Altschul et al., Methods in~nz~mologv 266:4b0~80 (1996)). Most of the WU-BLAST-2 search parameters are set to the default values. Those not set to default values, i.e., the adjustable parameters, are set with the following values: overlap span = 1, overlap fraction = 0.125, word threshold (T) = 11, and scoring matrix = BLOSUM62. When WU-BLAST-2 is employed, 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 iatet~est (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. For example, in the statement "a polypeptide comprising as the amino acid sequence A which has or having at least 80% amino acid sequence identity to the amino acid sequence B", the amino acid sequence A is the comparisoa amino acid sequence of interest aad the amino acid sequence B is the amino acid sequence of the PRO polypepdde of interest.
Percent amino acid sequence identity may also be determined using the sequence comparison program NCBI-BLAST2 (Altschul et al., Nucleic Acids Res. 25:3389 3402 (I997)a. 'the NCBI-BLAST2 sequence comparison program may be obtained from the National Institute of Health, Bethesda, MD. NCBI-BLAST2 uses several search parameters, wherein all of those search parameters are set to default values including, for example, unmask =
yes, strand = all, expected occurrences = 10, minimum low complexity length = 15/5, multi-pass e-value =
0.01, constant for mull pass = 25, dropoff for final gapped aligntatxtt = 23 and scoring matrix = BLOSUM62.
~ situations whore NCBI-BLAST2 is-~tnployed for amino acid sequence comparisons, the % amino acid sequence identity of a given amino acid sequence A to, with, or against a given amino acid sequence B
(which can alternatively be phrased as a given amino acid sequence A that has or comprises a certain 'Y amino acid sequence identity to, with, or against a given amino acid sequence B) is calculated as follows:

wo -omus Pc~r~crsourzs~zs 100 times the fraction XIY
where X is the number of amino acid residues scored as identical matches by the sequence alignment program NCBI-BLAST2 in that program's alignment of A and B, and where Y is the total number of amino acid residues in B. It will be appreciated that where the length of amino acid sequence A is not equal to the length of amino acid sequence B, the % amino acid sequence identity of A to B will not equal the % amino acid sequence identity of B to A.
"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.
Ordinarily, 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 sequencx identity, alternatively at least about 9f %
nucleic acid sequence identity, alternatively at least about 9296 nucleic acid sequence identity, alternatively at least about 93 % nucleic acid sequence identity, alternatively at least about 94 % nucleic acid sequence identity, alternatively at least about 95 % nucleic acid sequence identity, alternatively at least about 96 °i; nucleic acid sequence identity, alternatively at least about 97 % nucleic acid sequence identity, alternatively at least about 98 %
nucleic acid sequence identity and alternatively at least about 9996 nucleic acid sequence identity with a nucleic 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 sequence, as disclosed herein or any other fragment of a full-length PRO polypeptide sequence as disclosed herein. Variants do not encompass the native nucleotide sequence.
Ordinarily, PRO variant potynucleotides 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 iS0 nucleotides in length, alternatively at least about 180 nucleotides in length, alternatively at least about 2I0 nucleotides in length, alternatively at least about 240 nucleotides in length, alternatively at least about 270 nucleotides in length, alternatively at least about 30Q
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.

WO 01/16318 PCTlUS00/233Z8 "Percent (°b) nucleic acid sequence identity" with respect to PRO-encoding nucleic acid se~ences 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. For purposes herein, however, % 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 mould be compiled for use on a UNIX operating system, preferably digital UNIX V4.OD.
All sequence comparison parameters are set by the ALIGN-2 program and do not vary.
IS In situations where ALIGN-2 is employed for nucleic acid sequence comparisons, the % nucleic acid sequence identity of a given nucleic acid sequence C to, with, or against a given nucleic acid sequence D (which can alternatively be phrased as a given nucleic acid sequence C that has or comprises a certain % nucleic acid sequence identity to, with, or against a given nucleic-acid sequence D) is calculated as follows:
100 times the fraction WIZ.
where W is the number of nucleotides scored as identical matches by the sequence alignment program ALIGN-2 in that program's alignment of C and D, and where Z is the total number of nucleotides in D. It will be appreciated that where the length of nucleic acid sequence C is not equal to the length of nucleic acid sequence D, the % nucleic acid sequence identity of C to D will not equal the % nucleic acid sequence identity of D to C. As examples of % nucleic acid sequence identity calculations, 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.
Unless specifically stated otherwise, all % nucleic acid sequence identity values used herein are obtained as described in the immediately preceding paragraph using the ALIGN-2 computer program. However, nucleic acid sequence identity values may also be obtained as described below by using the WU-BLAST-2 computer program (Altsdtul et al., Methods in Enzvmolo~y, 26b:460-480 (1996)).
Most of the WU-BLAST-2 search parameters are set to the default values. Those not set to default values, i.e., the adjustable parameters, are set with the following values: overlap span = 1, averlap fraction = 0.125, word threshold (T) _ 11, and _._.... ...w..... ~,~,:~~~H". .... .. ...____ _. _....w- _.~..... ~...".z~.. -._ ~_-._.. _.......
. ~ ._a r~ .~_~ .t~ .~s~,~.~ u.~~:~~P~, WO Q1lI63I8 PCT~USO~~13328 scoring matrix = BLOSUM62. When WU-BLAST-2 is employed, 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 polypepiide-encoding nucleic acid molecule of interest is being compared which S 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. For example, in the statement °ari isolated nucleic acid molecule comprising a nucleic acid sequence A which has or having at last 80l nucleic acid sequence identity to the nucleic acid sequence B", the 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-BLAS'T2 (Altschul en al., nucleic Acids Res. 25:3389-3402 (1997)). The NCBI-BLAST2 sequence comparison program may be obtained from the National Institute of Health, Betltesda, MD. NCBI-BLAST2 uses several search parameters, wherein all of those search parameters are set to default values including, for example, unmask =
yes, strand = all, expected occurrences = 10, minimum low complexity length = 1515, mufti-pass e-value =
0.01, constant for mufti-pass = 25, dropoff for final gapped alignment = 25 and scoring matrix = BLOSUMb2.
In situations where NCBI-BLAST2 is employed for sequence comparisons, the ~
nucleic acid sequence identity of a given nucleic acid sequence C to, with, or against a given nucleic acid sequence D (which can alternatively be phrased as a given nucleic acid sequence C that has or comprises a certain °.b nucleic acid sequence identity to, with, or against a given nucleic acid sequence D) is calculated as follows:
100 times the fraction WlZ
' 25 where W is the number of nucleotides scored as identical matches by the sequence alignment program NCBI-BLAST2 in that program's alignment of C and D, arid where Z is the total number of nucleotides in D. It will be appreciated that where the length of nucleic acid sequence C is not equal to the length of nucleic acid sequence D, the °~ nucleic acid sequence identity of C to D will not equal the 9~ nucleic acid sequence identity of D to C.
In other embodiments, 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 foil-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 thathas been identified and separated andJor 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 enzyme, hormones, and other proteinacoous or non-proteinacoous solutes. In preferred embodiments, the polypeptide will be purified (1) to a degree sufficient to obtain at least 15 residues of N-terminal or internal amino acid ~quence 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 poiypeptide 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 p~lypeptide-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 tlherefore are distinguished from the specific polypeptide-encoding nucleic acid molecule as it exists in natural cells. However, an isolated polypeptide-encoding nucleic acid molecule includes polypeptide-encoding nucleic acid molecules contained in cells that ordinarily express the golypeptide where, for example, the nucleic acid molecule is in a chromosomal location different from that of natural cells.
The term "control sequences" refers to DNA sequences necessary for the expression of an operably linked coding sequence in a particular host organism. The control sequences that are suitable for prokaryotes, for example, include a promoter, optionally an operator sequence, and a ribosome binding site. Eukaryotic cells are known to utilize promoters, polyadenylation signals, and enhancers.
Nucleic acid is "operabiy linked" when it is placed into a functional relationship with another nucleic acid sequence. For example, 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. Generally, "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.
The term "antibody" is used in the broadest sense and specifically covers, for example, single anti-PRO
monoclonal antibodies (including agonist, antagonist, and neutralizing antibodies), anti-PRO antibody compositions with polyepitopic specificity, single chain anti-PRO antibodies, and fragments of anti-PRO
antibodies (see below). The term "monoclonal antibody" as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally-occurring mutations that may be present in minor amounts.
"Stringency" of hybridization reactions is readily determinable by one of ordinary skill in the art; and generally is an empirical calculation dependent upon probe length, washing temperature, and salt concentration.
In general, longer probes require higher temperatures for proper annealing, while shorter probes need lower temperatures. Hybridization generally depends on the ability of denatured DNA
to reanneal when WO OI/I63I8 PCTIUS00l13328 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 Biolo~v, Wiley Interscience S 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 exatriple 0.015 M sodium chloride/0.0015 M sodium citratel0.1 % sodium dodecyl sulfate at 50°C;
(2) employ during hybridization a denaturing agent, *uch as formamide, for example, 50% lulu) formamide with 0.1 % bovine serum albuminl0. l ~ Fico11/0.1 % polyvinylgyrrolidonelSOmM sodium phosphate buffer at pH 6.5 with 750 mM sodium chloride, 75 mM sodium citrate at 42°C; or (3) employ 50~ formamide, 5 x SSC (0.75 M NaCI; 0.075 M
sodium citrate), Sd mM sodium phosphate (pH 6.8), 0.1 '~ sodium pyrophosphate, 5 x Denhardt's solution, sonicated salmon sperm DNA (50 fcg/ml), 0.1 °~ SDS, and 10~ dextran sulfate at 42°C, with washes at 42°C
in 0.2 x SSC (sodium chioride/sodium citrate) and .50 °.6 formamide at SS °C, followed by a high-stringency wash consisting of 0.1 x SSC contatttirtg EDTA at 55°C.
"Moderately stringent conditions" may be identified as described by Sambrook et al., olecular 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. An example of moderately stringent conditions is overnight incubation at 37 °C in a solution 20. comprising: 20 ~ foimamide, 5 x SSC (150 mM NaCI, I5. mM trisodium citrate), SO mM sodium phosphate (pH
7:6), 5 x Denhardt's solution, 1096 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. .
The term "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 ~itopes. Suitable tag polypeptides generally have,at least siic amino acid residues and usually between about 8 and 50 amino acid residues (preferably, between about 10 and 20 amino acid residues).
As used herein, the term "immunoadhesin" designates antibody-like molecules which combine the binding specificity of a heterologous protein (an "adhesin") with the effector functions of immunoglobulin constant domains. Structurally, the immunoadhesins comprise a fusion of an amino acid sequence-wilt the desired binding specificity which is other than the. antigen recognition and binding site of an antibody lie., :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 immunoglobuIin constant domain sequence in the immunoadhesin may be obtained from any *-trademark 23 _.__. . _-_.., .. .. .. ... ._ . .,. ,. ..~ ~ ..* . , ~.. ,. a ~N2 .,.~.,r.
~:~,~~::.~~~,~ ,~..,~~ ~..,~",., ~ -~,. , ~ v..ro.,.=F. ~~.,~,~~~n~~~.~,. . ~
~__...._. __ . -. _..

WO 01/1631$ PCT/US00/23328 immunoglobuiin, 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 forms) 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.
The term "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. Fn a similar manner, the term "agonist" is used in the broadest sense and includes any molecule that mimics a biological activity of a native PRO polypegtide 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 agents) in a continuous mode as opposed to an acute mode, so as to maintain the initial therapeutic effect (activity) for an extended period of time.
"Intermittent" administration is treatment that is not consecutively done without interruption, but rather is cyclic in nature.
"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 {concurrent) and consecutive administration in any order.
"Carriers" as used herein include pharmaceutically acceptable carriers, excipients, or stabilizers which are nontoxic to the cell or mammal being exposed thereto at the dosages and concentrations employed. Often the physiologically acceptable carrier is an aqueous pH buffered solution.
Examples of physiologically acceptable carriers include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid; low molecular weight (less than about 10 residues) polypeptide;
proteins, such as serum albumin, gelatin, or immunoglobuIins; 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-WO 01/I6318 PCT/US00l23328 forming counterions such as sodium; andlor nonionic surfactants such as TWEEN~", polyethylene glycol (PEG), and PLURONICS"".
"Antibody fragments" comprise a portion of an intact antibody, preferably the antigen binding or variable region of the intact antibody. Examples of antibody fragments include Fab, Fab', F(ab')2, and Fv fragments; diabodies; linear antibodies (Zapata et al., Protein Ene. 8(10):
1057-1062 [1995j); single-chain antibody molecules; and multispecific antibodies formed from antibody fragments.
Papain digestion of antibodies produces two identical antigen-binding fragments, called "Fob"
fragments, each with a single antigen-binding site, and a residual "Fc"
fragment, a designation reflecting the ability to crystallize readily. Pegsin treatment yields an F(ab'), fragment that has two antigen-combining sites and is still capable of cross-linking antigen.
"Fv" is the minimum antibody fragment which contains a complete antigen-recognition and -binding site. This region consists of a dimer of one heavy- and one light-chain variable domain in tight, non-covalent association. It is in this configuration that the three CDRs of each variable domain interact to define an antigen-binding site on the surface of the VH-VL dimer. 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 CH1 domain including one or more cysteines from the, antibody hinge region. Fab'-SH is the designation herein for Fab' in which the cysteine residues} of the constant domains bear a free thiol group. F(ab')Z antibody fragments originally were produced as pairs of Fob' fragments which have hinge cysteines between them. Other chemical couplings of antibody fragments are also lrnown.
The ~light chains" of antibodies (immunoglobulins) from any vertebrate species can be assigned to one of two clearly distinct types, called kappa and lambda, based on the amino acid sequences of their constant domains.
Depending on the amino acid sequence of the constant domain of their heavy chains, 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 fut~tter divided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, -IgA, .
and IgA2.
"Single-chain Fv" or "sFv" antibody fragmenes comprise the VH and V~ domains of antibody, wherein these domains are present in a single polypeptide chain. Preferably, the Fv polypeptide further comprises a polypeptide linker between the VH and V~ domains which enables the sFv to form the desired structure for antigen binding. For a review of sFv, see Pluckthun in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds.; Springer-Verlag, New York, pp. 269-315 { 1994).
The term "diabodies" refers to small antibody fragments with two antigen-binding sites, which fragments comprise a heavy-chain variable domain (VH) connected to a light-chain variable domain (V J in the same polypeptide chain (VH-V,~. By using a linker that is too short to allow pairing between the two domains . ~.... _ ._~~z...~ p.dro ,~, ~. ,~~...r~~,_,~~.,.,.~~E~~v_:~,~ x~~ ~~4~~~~
...~._~~ rv.a.~_w____ ____...___ wo oms~ls p~'~s~
on the same chain, the domains are forced to pair with the complementary domains of another chain and create two antigen-binding sites. Diabodies are described more fully in, for example, EP 404,097; WO 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 proteinaceaus or nonproteinaceous solutes. In preferred embodiments, 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 polypegtide or an epitoge 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.
The word "label" when used herein refers to a detectable compound or composition which is conjugated directly or indirectly to the antibody so as to generate a "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.
By "solid phase" is meant a non-aqueous matrix to which the antibody of the present invention can adhere. Examples of solid phases encompassed herein include those formed partially or entirely of glass (e.g., controlled pore glass), polysaccharides (e.g., agatose), polyacrylamides, polystyrene, polyvinyl alcohol and silicones. In certain embodiments, depending on the context, 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 "Iiposome" is a small vesicle composed of various types of lipids, phospholipids andlor surfactant which is useful far delivery of a drug (such as a PRO polypeptide or antibody thereto) to a mammal. The components of the liposome are commonly arranged in a biIayer formation, similar to the lipid arrangement of biological membranes.
A "small molecule" is defined herein to have a molecular weight below about 500 Daltons.

WO O1II6318 PCTlUS00/23328 Ta~ie 1 I*
* C-C increased from 12 to 15 * Z is average of EQ
S * B is average of ND
* match with stop is M; stop-stop =. 0; I (joker) match = 0 */
#defirae M -8 !* value of a match with a stop *I
int _day(26](26] _ {

/* A B C D E F G H I J K L M N O P Q R S T U V W X Y Z */ _ I* A { 2, 0,-2, 0, 0,-4, 1.-1,-1. 0; 1,-2; 1, 0,_M, 1, 0,-2, */ I, 1, 0, 0,-6, 0,-3. 0}, /* B { 0, 3>-4, 3, 2,-5, 0, 1,-2, 0, 0,-3,-2, 2, M,-1, 1, 0, */ 0, 0, 0,-2,-5, 0,-3, 1}, I* C M,-3,-5,-4. 0,-2, 0.-2,-8, 0, 0,-5}, */ {-2,-4,15.-5,-5.-4,-3.-3,-2, 0,-5,-6,-5,-4, /* D _ *I { 0, 3,-5, 4, 3; 6, 1, 1, 2, 0, 0,-4,-3, 2 =M,-I, 2,-1, 0, 0, 0,-2; ?, 0,-4, 2}, /* E M,-1, 2; 1, 0, 0, 0,-2, 7, 0,-4, 3}, *I { 0, 2,-5, 3, 4,-5, 0, 1, 2, 0, 0,-3,-2, 1, I* F ~
*/ M,-5,-5,-4,-3,-3, 0,-1, 0, 0, 7,-5}, {-4,-5,-4,-6,-5. 9; 5,-2, 1, 0,-5, 2, 0,-4, I* G _ *I M,-1,-I,-3, I, 0, 0,-1, 7, 0; 5, 0}.
{ I, 0;-3, 1, 0,-5, 5, 2,-3, 0,-2,-4,-3, 0, J* H _ *I M, 0. 3, 2,-1,-1, 0, 2; 3, 0, 0, 2}, {-1, I; 3, 1, I; 2, 2, 6; 2, 0, 0,-2; 2, 2, /* I ~
*I {-1. 2,-2,-2, 2, I,-3, 2, 5, 0,-2, 2, 2,-2 =M,-2,-2, 2;
1, 0, 0, 4; 5, 0,-1,-2}, l* J { 0, 0. 0> 0, 0, 0, 0, 0, 0. 0, 0, 0, 0, 0, M, 0. 0, 0, */ 0, 0, 0. 0, 0, 0, 0, 0}, I* K {-1, 0,-5, 0, 0,-5,-2, 0,-2, 0, 5; 3, 0, 1, M,-1, 1, 3, */ 0, 0, 0,-2,-3, 0,-4, 0}, /* L {-2,-3,-6.-4,-3, 2,-4,-2, 2, 0; 3, 6, 4; 3, M,-3,-2,-3,-3,-1, *I 0, 2; 2, 0,-1,-2}, !* M {-I,-2,-5,-3,-2, 0.-3,-2, 2, 0, 0, 4, 6,-2 _M,-2,-I, 0,-2,-1, *l 0, 2,-4, 0,-2,-1}, I* N M,-I, 1, 0, 1, 0, 0,-2,-4, 0,-2, 1}, */ { 0, 2,-4, 2, 1,-4, 0, 2, 2, 0, 1,-3,-2, 2, l* O _ *l M =M,_M,_M, 0,_M =M,_M,_M =M,_M ~M,~M,_M =M,~M}.
{
M, M, M _M, M, M, M, M, M, M, l* P r ~/ _ { I,-I,-3 1; I,-5; I, 0,-2, 0,-1; 3,-2; 1,_M, 6, 0, 0, I, 0. 0,-1,-6, 0,-5, 0}, /* Q { 0, I,-5, 2, 2; 5,-1, 3,-2, 0, 1, 2,-1, I, M. 0, 4, I,-1,-1, *I 0,-2,-5; 0,-4, 3}, /* R M, 0, 1, 6, 0; 1, 0, 2, 2, 0,-4, 0}, *I {-2, 0,-4; 1,-1.-4,-3, 2,-2, 0, 3,-3, 0, 0, 3~ /* S _ *l { 1, 0, 0, 0, 0.-3, I,-I,-1, 0, 0,-3,-2, 1 =M, I,-1, 0, 2, 1, 0,-I,-2, 0; 3, 0}, !* T { 1, 0,-2, 0, 0; 3, 0,-1, 0, 0, 0,-1,-1, 0 ~M, 0; 1; 1, *! 1, 3, 0, 0,-5, 0,-3, 0}, l* U M, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0}, *! { 0, 0, 0, 0. 0, 0, 0, 0, 0, 0, 0, 0, 0, O, !* V ~
*I { 0,-2,-2,-2;2; 1,-I,-2, 4, 0; 2, 2, 2,-2 ~M,-1, 2, 2,-1, 0, 0, 4,-6, 0,-2,-2}, !* W {..6,-5.-8.-7,-7, 0,-7,-3; 5, 0; 3, 2,-4,-4 =M,-6; 5> 2;
*! 2; 5. 0,-6,17, 0, 0,-6}.

~S l* X { 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, M, 0, 0, 0, *J 0, 0, 0, 0, 0, 0, 0, 0}, l* Y {-3,-3, 0,-4,-4, 7,-5, 0,-1, 0,-4; 1; 2.-2, IvIrS,-4.-4,-3,3.
*l 0.-2, 0, 0,10,-4}, I* Z M, 0; 3, 0, 0, 0, 0,-2,-6, 0,-4, 4}
*I { 0, 1;-3, 2, 3; 5, 0, 2,-2, 0, 0,-2,-1, i, ~

WO OI/16318 PCT/IJSOOl23328 Table 1 (cony) /*

*/

#include <
stdio.
h >

#include h >
<
ctype.

#defineMAX1MP I * max jumps in a diag *I

#defineMAXGAP I* don't continue to penalize gaps larger than 24 this */

#defineJMPS 1024 I * max jmps in an path *I

#defineMX 4 I* save if there's at least MX-1 bases since last jmp *I

#defineDMAT 3 /* value of matching bases */

#defmeDMIS 0 /* penalty for mismatched bases */

#defineDINSO8 /* penalty for a gap */

#defineDINS11 /* penalty per base *I

1$ #defmePINSO8 I* penalty for a gap */

#definePINS14 /* penalty per residue */

struct jmp {

shortn[MAXJMP];
I* size of jmp (neg for dely) *I

unsigned short x[MAXJMPJ;
/*
base no.
of jmp in seq x *I

}: I* limits seq to 2"16 -1 *I

struct diag {

int score; I * score at last jmp *I

long offset; I * offset of prev block *I

shortijmp; !* current jtnp index */

struct I* list of jmps *I
jmp jp;

j:

3~ struct path {

int, spc; I * number of leading spaces *I

shortn[JMPSJ;1*
size of jmp (gap) *I

int x[JMPSJ;
I * loc of jmp (last elem before gap) *I

3$

char *ofde; I * output file name *I

char *namex[2J;I * seq names: getseqsp *I

char *prog; f* grog name for err msgs *I

char *seqx[2); I* seqs: getseqsp *I

4~ int dmax; I* best diag: nw() *I

int dtnax0; I * final diag *I

int dna; I * set if dna: main() *l int endgaps; I* set if penalizing end gaps *I

int gapx, gapy;I* total gaps in seqs *I

int len0, lent;I* seq lens *I

int ngapx, I * total size of gaps *I
ngapy;

int smax; l* max score: nw() *I

int *xbm; ' l * bitmap for matching *I

long offset; I* current offset in jmp file *l $o structdiag *dx; I* holds diagonals *I

structpath pp[2J; /* holds path for seqs */

char *callocQ, Q, *index(), *strcpyQ;
*malloc char *getseq(), *g callocQ;

$$

Ta.~le 1 (coast') I* Needleman-Wunsch alignment program * usage: props filet filet * where file 1 and filet are two dna or two protein sequences.
$ * The sequences can be in upper- or lower-case an may contain ambiguity * Any lines beginning with '; ' > ' or ' < ' are ignored * Max file length is 65535 (limited by unsigned short x in the jmp struct) * A sequence with 113 or more of its elements ACGTU is assumed to be DNA
* Output is in the file "align.out"
1~
* The program may create a tmp file in Itmp to hold info about traceback.
* Original version developed under BSD 4.3 on a vax 8650 *I
Ifinclude "nw.h"
].$ flinclude "day.h".
static _dbvai(26] = f 1,14,2,I3,0,0,4,11,O,O,i2,0,3,15,0,0,0,5,6,8,8,7,9;0,10,0 static ~pbval[26] _ {
I, 2~(1< <{'D'- A'))~(1 < <('N'-'A')), 4, 8, 16, 32, 64.
128, 256, OxFFFFFFF, 1 < < 10, 1 < < 11, 1 < < 12, 1 < < 13, 1 < < 14, 1«I5, 1«16, 1«17, I«18, 1«19, 1«20, 1«21, 1«22, 2$ 1«23, 1«24, I«25(1«('E'-'A'))~(t«('Q'-'A')) main(ac, av) main int ac;
char *av j ];
prag = avj0];
if (ac 1= 3) {
fprintf(stderr,"usage: ~s filet file2tn", prop);
3$ fprirnf(stderr,"where filet and filet are two dna or two protein sequences.\n");
fprintf(stderr, "The sequences can be in upper- or lower-case\n");
fprintf(stderr,"Any lines beginning with ';' or ' < ' are ignored\n");
fprintf(stderr, "Output is in the file \"align.out\"1n");
exit(1);
) namex[0] = avjl];
rtamex( 1 ] = av[2];
seqx[0] = getseq(namexj0], &len0);
seqxjl] = getseq(namex[1], &lenl);
4$ xbm = (dna)? dbval : pbvat;
endgaps = 0; /* 1 to penalize endgaps */, ofile = "align.out"; l* output file *!
$0 nwp; I* fill in the matrix, get the possible jmps *I
readjmpsQ; I* get the actual jmps *I
printQ; /* print scats, alignment */
cleanup(0); I* unlink any tmp files *l $$ }

wo oWS3ls PC'T/USOOI23328 Table I (eont' ) I* do the alignment, return best score: main() * dna: values in Fitch and Smith, PNAS, 80, 1382-1386, 1983 * pro: PAM 250 values * When scores are equal, we prefer mismatches eo any gap, prefer * a new gap to extending an ongoing gap, and prefer a gap in seqx * to a gap in seq y. .
*I
nw() L1W
{
1~ char *px, *py; /* seqs and ptrs */
int *ndely, *dely; I* keep track of defy *I _ int ndelx, deli; I* keep track of delx */
int *tmp; 1* for swapping row0, rowY *l int mis; I * score for each type *I
int ins0, insl; I* insertion penalties *I
register id; /* diagonalindex *!
register ij; l* jmp index *I
register *col0, *coll; /* score for curr, last row */
register xx, yy; /* index into seqs */
dx = (struts diag *)g calloc("to get diags", len0+lenl +1, sizeof(struct diag));
ndely = (int *)g calloc("to get ndely", lenl +1, sizeof(int));
defy = (int *)g calloc("to get defy", lenl+I, sizeof(int));
col0 = (int *)g calloc("to get col0", lenl + I , sizeof(int));
col l = (int *)g calloc("to get col l ", lenl + 1, sizeof(int));
ins0 !_ (dna)? DINSO : PINSO;
insl = (dna)? DINSl : PINSl;
smax = -10000;
if (endgaps) {
for (col0(Oj = dely(0] _ -ins0, yy = 1; yy < = Ienl; yy++) {
col0[yyj = dely[yy] = cot0(yy-1l - insl;
Y(Yy1 ° YY;
}
col0[0] ~ 0; I* Waterman Bull Math Biol 84 */
else for (yy = 1; yy < = lent; yy++) defy[yy] = -ins0;
/* fill in match matrix *I
for (px = seqx[0], xx = 1; xx < = IenO; px++, xx++} {
4J /* initialize first entry in col if (endgaps) {
;f(~ _= 1) $0 eke coll[O] = deix = -(ins0+insl);
col a [Oj = delx = col0(0) - ins 1;
ndeix = xx;
else {
col l [0j = 0;
deix = -ias0;
ndeIx = 0;

WO O1/I6318 PC"T/USOOlZ3328 ~'ablg,~lsoont') for (py = seqx[Ij, yy = 1; yy < = leni; py++, yy++) {

mis = col0(yy-1];

if (dna) mis +_ (xbm(*px-'A']&xbm[*py-'A'])? DMAT : DMIS;

else mis += day[*px-'A'][*PY'~A']:

/* update penalty for del in x seq;

* favor new del over ongong del * ignore MAXGAP if weighting endgaps *l if (endgaps J ~ ~ely[yyj < MAXGAP) {

if (col0[yy] - ins0 > = dely(yy]) {

defy[yyl = col0[yy] - (ins0+insl);

ndely[YY] = 1;

} else {

dely[yy] -= insl:

ndelyIYYI++:

z0 }

} else {

if (col0(yyj - (ins0+insl) > = defy[yy]) {

dely[yy] = col0[yy] - (ins0+insl);

naelytYYj = 1:

z5 } else ndely[yy] + + :

}

l* update penalty for del in y seq;

30 * favor new del over ongong del *l if (endgags ~ ~ ndelx < MAXGAP) {

if (coll(yy-lj - ins0 > = delx) {

delx = coll[yy-1] -(ins0+insl);

35 ndelx = 1;

} else {

deli -= insl;

ndelx+ +;

}

40 } ~s~ {

if (coll[yy-1] - (ins0-1-insi) > = delx) {

delx = coll[yy-i] - (ins0+insl);

ndelx = 1;

} else ndelx+ +;

}

I* pick the maximum score; we're favoring * mis over any del and delx over defy 50 *l ...nw .. ... . , ~ , . xi.~... . ~. P. . .. xm , ~~~...rc,_~~ ~ ... ~.~~.FMrw:~~,~.
~~:",n.T~.~...~v...._~. .._ _ _. ___ ~~. . ~_~M~...H -_ .-..w.. _ _.

Table 1 (cony) id=xx-yy+leni-I;
If (mis > = delx && mis > = dely(yy]) coll(yy] = mis;
$ ~ else if (delx > = dety[yy)) {
tol l [yy] = delx;
ij = dx[id].ijmp;
if (dx[id).jp.n[fl] && (!dna ) ~ (ndelx > = MAX1MP
&& xx > dx[id].jp.x[ij]-t-MX) ~ ~ mis > dx(id].score+DINSO)) {
dx[id].ijmp++;
if (++ij > = MAXJMP) {
wrieejmps(id); -ij = dx[id).ijmp = 0;
dx[id].offset = offset;
offset + = sizeof(struct jmp) + sizeof(offset);
dx[id].jp.n[ij) = ndelx;
dx[id].jp.x[ij) = xx;
, - dx[id].score = deli;
else {
col l [yy] = dely[yy);
ij = dx[id].ijmp;
2$ if (dx[idj.jp.n[0] && (!dna ~ ~ (ndely[yy] > = MAX1MP
&& xx > dx(id).jp.x[ij)+MX) ~ ~ mis > dx[id].score+DINSO)) {
dx[id].ijmp++;
if (++ij > = MAXJMP) {
writejmps(id);
ij = dx[id).ijmp = U;
dx(id).offset = offset;
offset + = sizeof(struct jmp) + sizeof(offset);
3$ dx(id] :lp~nlijl _ -~ly[YY):
dx[id] jp.x[ij) = xx;
dx[id].score = dely[yy];
if (xx == IenO && yy < lent) {
40 /* last col */
if (endgaps) coll(yy) -= ins0+insl*(lenl-yy);
if (col l [yy] > smax) {
4$ smax = coll[yy];
dmax = id;
...nvW
$d_ f (endgaps && xx < len0) coll[yy-i]-= ins0+insl*(IenO-xx);
if (coil[yy-1) > smax) {
smax = coi 1 [yy-i);
$$ ~x = id;
tmp = col0; col0 = coil; coil = tmp;
(void) free((char *)ndely);
(void) free((char *)dely);
f)~ (void) free((char *xol0);
(void) free((char *xoll );

. . .,.. .. . ~. ,. , . , .. ,, ,"." . ~ ~w~..", . ..,~m ".,«.~ _:~ ~c.~,:, a.v..;.;u~m~P-..-~~.-..~~.~. u..,.~.m ...-,.~ __~-._ __.w...~.".~,w~". ,p . _ r._ ."-h. ........_-.".. __..."_..".,. . ..
t:xp.~rE[~.~~"hv'PmR.~ .. w. K _~.o.vney~m-a..s..

Tile 1 (coat' 1 I*
* print() -- only routine visible outside this module * static:
* getmat0 -- trace back best path, count matches: printQ.
* pr align() -- print alignment of described in array p[ ]: print() * dumpblock() -- dump a block of lines with numbers, stars: pr align() * nums() -- put out a number line: durnpblockQ
* pudineQ -- put out a line (name, [num]. seq, [numj): dumpblockQ
* stars() - -put a line of stars: dumpblock0 * stripnameQ -- strip any path and prefix from a seqrtame --*/
1$ #include "nw.h"
#defme SPC 3 #define P LINE 256 /* maximum output line *!
#define P SPC 3 /* space between name or num and seq *!
ZO
extern _day[26][26];
int olen; /* set output line length *!
FILE *fx; /* output file */
25 print() print int lx, ly, firstgap, lastgap; I * overlap *I
if ((fx = fopen(ofile, "w")) _ = 0) {
30 fprintf(stderr,"~s: can°t write ~sln", prog, ofile);
cleanup(I); .
fprintf(fx, " < first sequence: 'Y s (length = ~d}1n", namex(0], len0);
fprintf(fx, " < second sequence: ~s (length = 9&d)~n", namex(lj, Ienl);
3$ oleo = 60;
Ix = len0;
3y = lent;
firstgap = lastgap = 0;
if (dmax < lent - 1) { /* leading gap in x *!
40 PP(Ql.sPc = srstgap = teal - dmax - 1;
ly _-_ pPLO)~~~
}.
else if (dmax > lent - I) { I* leading gap in y */
pp(lj.spc = firstgap = dmax - (lent - 1);
4$ lx -= pp[I].spc;
if (dtnax~ < lett0 - I) { I* trailing gap in x */ ' lastgap = len0 - dmax0 -1;
lx -= lastgap;
$o }
else If (dmax0 > IenO - 1) { /* trailing gap in y */
lastgap = dmax0 - (IenO - 1);
ly -= lastgap;
$$ getmat(Ix, ly, firstgap, lastgap);
pr align();

WO O1lIG318 _ PCT/USOO123328 ~al~le I (cony) i*
* trace back the best path, count matches *I
static getmat(lx, ly, firstgap, lastgap) getltiat int Ix, ly; /* "core" (minus endgaps) */
int 6rstgap, lastgap; I* leading trailing overlap *I
int nm, i0, ii, sizfl, sizl;
char outx(32];
double pct;
register n0, nl;
register char *p0, *p 1;
. I* get totai matches, score */
i0 = il = siz0 = sizl = 0;
p0 = seqx[0] + pp[f].spc;
pl = seqx[1) + pp[0].spc;
n0 = pp[1].spc + 1;
nl = pp[0].spc + 1;
nm = 0;
while ( *p0 && *pf ) {
if (siz0} {
pf++;
nl++;
siz0--;
else if (sizf) {
p0++;
n0++;
sizf-;
else ~
if (xbm[*p0-'A']&xbm[*pl-'A°]) nm++;
if (nID++ _= pp[0].x[iU]) siz0 = pp[0].n[i0++];
if(nl++ _=pp[f].x[i1]) sizl = pp[1).n[if++];
p0++;
pf++
~
I* pct homology:
* if penalizing endgaps, base is the shorter seq * else, knock off overhangs and take shorter core */
if (endgaps) lx = (IenO < lenl)? len0 : lenl; _ else lx. _ (Ix < ly)? lx : ly;
pct = 100.*(douWe)mnl(double)ix;
fprlntf(fx, "fin"), fprintf(fx, "< R6d matches in an overlap of %d: ~.2f percent similarityln", ,~~ (~ _ = 1)~ ". : "es", lx, pct):

. .E. ~u ~ .. ~ ,.:N.aa~u, s~.u~ . ~sa~pzac,~ ,~...,~.~",ww"a~" ,,-,~.. , ~°..~.ucssm....

wo omus rcrwsoor~~zs T_a le 1 (cony) fprintf(fx, "<gaps in first sequence: %d", gapx); ...getiriat ~' (gaPx) 1 (void) sprintf(outx, " (%d % s%s)", agapx, (dna)? "base": "residue", (ngapx = = 1 )? "": "s");
fprintf(fx,"%s", outx);
fprintf{fx, ", gaps in second sequence: % d", gapy);
if (gapY) 1 (void) sprintf(outx, " (%d %s%s)", ngapy, (dna)? "base":"residue", (ngapy == 1)? "":"s");
fprintf(fx,"%s", outx); - -if (dna) fprintf(fx, "1n < score: %d (march = % d, mismaech = % d, gap penalty = %d + % d per base)1n", smax, DMAT, DMIS, DINSO, DINSI);
else fprintf(fx, 0 "1n<score: %d (Dayhoff FAM 250 matrix, gap penalty = %d + %d per residue)1n", smax, PINSO, PINSI);
if (endgaps) fP~(~.
"<endgaps penalized. left endgap: %d %sY6s, right endgap: %d %s%s\n", firstgap, (dna)? "base" : "residue", (firstgap == I)? "" : "s", lastgap, (dna)? "base" : "residue", (lastgap == 1)? " , "s");
else fprintf(fx, "<endgaps not penalizedln"};
) static nm; I* 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]; I* current elem number - for gapping *I
static siz[2];
static char *ps[2]; I * ptr to current element *I
static char *po(2]; /* ptr to next output char slat *1 static char out[2)[P LINE]; I* output line */
static char star[P LINE]; J* set by stars() *I
I*
* print alignment of described in struct.path pp j ]
*!
static .
pr align() Pr_~Iign mt nn; I * char count *I
~t more;
register i;
for (i = 0, Imax = 0; i < 2; i++) {
nn = stripname(namex[i]);
if (nn > lmax) ~x = ~~
nc[i) --- 1; , _ . ..
ni[i] = 1;
sizji] = ijji] -- 0;
ps[i) = seqx[i];
poji] = out[i];

wo oins3i8 pcr~soorr~3zs Table 1 (cony) for (nn = nm = 0, more = 1: more; ) {
for (i = more = 0; i < 2; i++) {
l*
$ * do we have more of this sequence?
*l.
if (! *ps(i]) continue:
1Q more++;
if (pp[iJ.spc) { I* leading space *I
*po(i]++ = , ,;
pp(il.spc_-~
15 ) else if (siz[i]) { /* in a gap *l *po[i]++ _ '-';
siz[i]__;
else { /* we're putting a eq element *I
*Po(i] _ *PSIi];
if (islower(*ps[i])) *ps(i] = toupper(*ps(i]);
25 po(il++:
ps(iJ + +;
I*
* are we at next gap for this seq?
3U *l if (~(i] _= PP(i].x(ij(i]]) {
I*
* we need to merge all gaps * ae this location 35 *l siz[i] = pp(i].n(ij[i]++J;
while (ni(i] _= pp[i].x(ij(i]]) ~(il += pp(i].n(ijCi]++]:
) 4Q ni(i]++;
) ) if (++nn == olen ~ f !more && nn) {
dumpbIockQ;
45 for (i = 0; i < 2; i++) poji] = out(iJ;
j 50 ) l*
* dump a block of lines, including numbers, stars: pr align() *l 55 static d~pblock() dumpbIock register i;
6fl for (i = 0; i < 2; i++) *po(i]_ = '10':

WO 01/16318 Pt'TIUSOOIZ3328 Table I (coot') ...dwnpblock (void) putc('1n', fx);
for (i = 0; i < 2; i++) {
$ if (*out[i] && (*out(i] !_ ' ~ j j *(po(i]) t= ' ')) {
if (i == 0) nums(i);
if (i == 0 && *out[1]) stars();
putline(i);
if (i == 0 && *out[1]) fprintf(fx, star); -if (i == 1) nums(i);
1$ 1 /*
z0 * put out a number line: dumpblock() */
statie nums(ix) nums int ix; /* index in out[] holding seq line */
zs ~
char nline(P LINE];
register i, j;
"Pn. *px. *pY:
30 for (pn = mine, i = 0; i < imax+P 51'C; i++, pn++) *pn = , for (i = nc[ix], py = out[ix]; *py; py++, pn++) {
(*PY = - ' ~ I j *PY = _ ~= ) ak"n ~ n a 9 3$ ~ {
if (i9610 = = 0 ~. ~ (i = = 1 && nc[ix] ! = I )) {
j = (i < 0)? _i : i;
for (px = pn; j; j /= 10, px--) *px = j 9~ 10 + '0';
40 if (i < 0) "px = , eke *pn = ", 4$ i++; ' *pn = '\0';
nc[ix] = i;
$0 for (pn = mine; *pn; pn++) (void) pule(*pn, fx);
(void) putc('\n', fx);
$$ /*
* put out a line (name, (num], seq, [num]): dumpblockQ
*/
static putline(ix) piIthnt' 60 int ix; {

Table 1 {cont'1 ...putline int i;

register char *px;

S

for (px = namex(ix], i = Q; *px && *px !_ :'; px++, i++) (void) pure(*px, fX);

for (; i < Imax+P SPC; i+ +) (void) pure(' ', fx);

/* these count from 1:

* ni(] is current element (from 1) * nc[] is number at start of current line *7 I for (px = out[ix]; *px; px+ +) S

(void) pure(*px&Ox7F, fx);

(void) putc('1n', fx);

~*

* put line of stars (seqs always in out(0]
a out[1]): dumpblockp *~ , static 25 stars() stars int i;

register char *p0, *p 1, cx, *px;

30 if (!*out[0] I ( (*out[0] _ _ ' && *(po[0]) =- ' ') I I

!*out[1] I ( (*out[1] __ ' && *(Po[1]) _- ' ')) retorts;

px = star;

for (i = lmax+P SPC; i; i-) 35 *px++ _ ' ';

for (p0 = out[Oj, pl = out(1]; *p0 && *pl; p0++, pl ++) {

if (isaipha(*p0) && isalpha(*pl)) {

40 if (xbm[*p0-'A']&xbm[*pl-'A']) {

cx = '*';
~

nm -h +;

~ .

else if (!dna && day[*p0-'A'](*pl-'A'] > 0) 45 cx = . , else cx = t else 50 cx ~ ".

*px++ = cx;

*px++ _ '1n';

*px = .10,:

55 ~

Table 1 (cony) I*
* strip path or prefix from pn, return len: pr align() *I
static stripname(pn) stripname char *pn; I* file name (may be path) *I
register char *px, *py;
py = o;
for (px = pn; *px; px++) if (*px = _ ~I~) _ PY=Px+l;
if (py) (void) strcpy(pn, py);
return(strlen(pn));

SS

wo .oin631<$ rrr~usoor~zs Table 1 (cont'1 I*
* cleanup() -- cleanup any tmp file * getseq() -- read in seq, set dna, len, maxlen * g calioc() -- callocQ with error checkin $ * readjmpsQ -- get the good jmps, from tmp file if necessary * writejmpsQ -- write a filled array of jmps to a tmp file: nw() *I
Ifinclude "nw.h"
A'include < syslftle.h >
char *jname = "/tmp/homgXXXXXX"; I * tmp file for jmps *I
FILE *~;
int cleanupQ; I* cleanup tmp file *I
tong IseekO;
I*
* remove any tmp file if we blow *I
cleanup(i) Cleanup int i;
if (fj) (void) unlittk(jname);
exit(i);
j I*
* read, return ptr to seq, set dna, len, maxlen * skip litres starting with ';', ' <', or ' >' * seq in upper or lower case *I
char getseq(file, len) 3$ char *file; I* file name *I
int *len; 1* seq len */
char litre[1024], *pseq;
register char *px, *py;
40 int natgc, tlen;
FILE *fp;
if ((fp = fopen(file,"r")) == U) {
fprintf(stderr," ~ s: can't read ~ s1n", prog, file);
45 exit(1);

tlen = natgc = tl;
while (fgets(line, 1024, fp)) {
if (*line =- ''' ~ ~ *line =- ' <' ~ ~ *tine =- ' >') oontinne;
for (px = line; *px !_ '\n'; px++) if (isupper(*px) ~ ~ islower(*px)) tlen++;

55 if ((pseq = malloc((tansigned)(tlen+6))) _ = 0) {
fprintfistdea:"96s: m~llocQ faired to get 9~d bytes for ~sln", prog, tlen+6, file);
exit( 1 );

fib P~q(~l P~q[11 = P~q[21 = P~9L3) _ '~o';
4(?

WO 01/16318 PCTJUSOOJZ33~8 fable lscont') py = pseq + 4;
*len = tlen;
rewind(fp);
while (fgets(line, 1024, fp)) {
if (*line =- ';' 1 ( *line =- ' <' ~ ~ *line =- ' >') continue;
for (px = line; *px ! _ '\n'; px++) {
if (isupper(*px)) *py++ = *px;
else if (islower(*px)) *py++ = toupper(*px);
if (index("ATGCU",*(py-1))) IS natgc+ +;
I
*py++ _ '\0';
*PY = ~\0';
(void) fclose(tp);
dna = natgc > (tlenJ3);
return(pseq+4);
...getseq I
char g calloc(msg, nx, sz) ~ g-CaIIOC
char *msg; I* program, calling routine */
int nx, sz; J* number and size of elements *J
char *px, *catioc0;
if ((px = calloc((unsigned)nz, (unsigned)sz)) _= 0) {
if (*msg) {
fprintf(stderr, "96s: g call~Q failed ~s (n='~'od, sz=~d)1n", prog, msg, nx, sz);
exit(1);
I
retur<s(px);
I
l*
* get final jmps from dx[} or trap file, set pp[], reset dmax: main() , *, readjmps0 readjmps {
int fd = -1;
int SIZ, 10, 11;
register i, j, xx;
if (fj) {
(void) fciose(fj);
if ((fd = open(jname, O_RDONLY, 0)) < 0) {
fprintf(stderr, "~s: can't open() ~s\n", prog, jname);
cleanup( 1 );

for (i = i0 = il = 0, dmax0 = dmax, zx = len0; ; i++) {
white (1) {
for (j = dxjdmax].ijmp; j > = 0 && dxjdmax].jp.x[j] > = xx; j--) , WO O1/I6318 PCT/US00/~3328 Table I lcont') ...readjmps if (j < 0 && dx[dmax].offset 8c& fj) {
(void) Iseek(fd, dx[dmax].offset, 0); -(void) read(fd, (char *)&dx[dmax].jp, sizeof(struct jmp));
S (void) read(fd, (char *)&dx[dmax].offset, sizeof(dx(dmaxj.offset));
dx[dmax].ijmp = MAXJMP-1;
j else break;
}
if (i > = 3MPS) {
fprintf(stderr, " %s: too many gaps in alignmentln", prog); -cleanup( 1 );
if (j > = o) f siz = dx[dmax].jp.n[j];
xx = dx(dmax].jp.x[j];
dmax += siz;
if (siz < 0) ~ /* gap in second seq */
pp[1].n[il] _ -siz;
xx +, = siz;
!*id=xx-yy+lenl-1 *t pp[1].x[il] = xx - dmax + lent - 1;
2S gapy+ t ;
n&'tPY -= siz;
!* ignore MAXGAP when doing endgaps *!
siz = (-siz < MAXGAP ( ~ endgaps)? -siz : MAXGAP;
11++;
) else if (siz > 0) { /* gap in fcrst seq */
pp(0].n(i0] = siz;
PP[0].x[i0] = xx;
gapx++;
ngapx + = siz;
/* ignore MAXGAP when doing endgaps *!
siz = (siz < MAXGAP I ~ endgaps)? siz : MAXGAP;
i0++;
) else break;

4S J* reverse the order of jmps */

for (j = 0, i0--; j < i0; j + +, i0-) f i = PP[0]-nh]; pp[0]n[1] = PPI01n[i0]; PP[0].nli0] = i;

1 PP(O].xCl]; PP[0]xC)] = PP[O].x[i0]; PP(0]x(i0] = i;

for (j = 0, il--; j < il; j++, il-) {

i = pp[1].n[j]: PP[1].n(j] = PP(1].n[il]; PP[1].n[il] = i;

1 = PP[1].xU]: PP[1].xCi] = PP[11.x[il]; PP[1]-x(il) = i:

5$ if (fd > = 0) (void) ciose(fd);

if(f)y (void) unlink(jname);

offset = 0;

wo om~l8 rc~rmsoon~zs Table 1 (cony) ~*
* write a filled jmp struct offset of the prey one (if any): nwQ
*/
s writejmps(ix) writejmps int ix;
char *mktempQ;
1~ if (!f) ~
if (mktemp(jname) < 0) {
fprintf(stderr, "%s: can't mktempQ Y&s1n", prog, jname); ' cleanup(1);
j is if ((fj = fopen(jname, "w")) _- 0) {
fprintf(stderr, "~s: can't write ~sln", prog, jname);
exit(1);
2~ (void) fwrite((char *~cdx[ix].jp, sizeof(struct jmp), 1, fj);
(void) fwrite((char *~cdx[ix].offset, sizeof(dx[ix].offset), 1, fj);
2s 3s sa ss WO Ol/I631g PCT/USOOI23328 Table 2 PRO XXXXXXXXXXXXXXX (Length = 15 amino acids) Comparison Protein XXXXXYYYYYYY (Length = 12 amino acids) S % amino acid sequence identity =
(the number of identically matching amino acid residues between the two polypeptide sequences as determined by ALIGN-2) divided by (the total number of amino acid residues of the PRO
polypeptide) =
5 divided by 15 = 33.3 %

~..w . , ., .m, . ... ... _ . ~. ... _ . .. _ ,~. . ~:,~ ~~~~m~-.,,,~,wn..,~.
~~,.r..~ . ._.. . _~ .._ __~.~.._..~ .- _ __ ....
,..., , ._.c... ., . .....~mrv~wr. ..ny m.an. . .

WO 01/16318 PCT~~~
Table 3 PRO XXXXXXXXXX (Length = 10 amino acids) Comparison. Protein XXXXXYYYYYYZZYZ (Length = 15 amino acids) % amino acid sequence identity =
(the number of identically matching amino acid residues between the two polypeptide sequences as determined by ALIGN-2) divided by (the total number of amino acid residues of the PRO
polypeptide) _ 5 divided by 10 = 50~

Table 4 PRO-DNA NNNNNNNNNNNNNN (Length = 14 nucleotides) Comparison DNA NNNNNNLLLLLLLLLL (Length = 16 nucleotides) % nucleic acid sequence identity =
(the number of identically matching nucleotides between the two nucleic acid sequences as determined by ALIGN-2) divided by (the total number of nucleotides of the PRO-DNA nucleic acid sequence) _ 6 divided by 14 = 42.9 wo .otn~3ts Pcclrrmsoorz3328 T_ able 5 PRO-DNA NNNNNNNNNNNN (Length = 12 nucleotides) Comparison DNA NNNNLLLVV (Length = 9 nucleotides) % nucleic acid sequence identity =
(the number of identically matching nucleotides between the two nucleic acid sequences as determined by ALIGN-2) divided by (the total number of nucleotides of the PRO-DNA nucleic acid sequence) _ 4 divided by 12 = 33.3 4~

WO O1/I6318 PC'TIUS00/23328 II. Compositions and Methods of the Invention A. Full-Length PRO Polype~tides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PRO polypeptides. In particular, cDNAs encoding various PRO
polypeptides have been identified and isolated, as disclosed in further detail in the Examples below. It is noted S that proteins produced in separate expression rounds may be given different PRO numbers but the UNQ number is unique for any given DNA and the encoded protein, and will not be changed.
However, for sake of simplicity, in the present specification the protein encoded by the full length native nucleic acid molecules disclosed herein as welt as all further native homologues and variants included in the foregoing definition of PRO, will be referred to as "PROlnumber", regardless of their origin or mode of preparation.
As disclosed in the Examples below, various cDNA clones have been deposited with the ATCC. The actual nucleotide sequences of those clones can readily be determined by the skilled artisan by sequencing of the deposited clone using routine methods iti the art. The predicted amino acid sequence can be determined from the nucleotide sequence using routine skill. For the PRO polypeptides and encoding nucleic acids described herein, Applicants have identified what is believed to be the reading frame best identifiable with the sequence information available at the time.
B. PRO Po~~tide 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, andlor by synthesis of the desired PRO polypeptide. Those skilled in the art will appreciate that amino acid changes may alter post-translational processes of the PRO, such as changing the number or position of glycosylation sites or altering the membrane anchoring characteristics.
Variations in the native full-length sequence PRO or in various domains of the PRO described herein, can be made, for example, using any of the techniques and guidelines for conservative and non-conservative mutations set forth, for instance, in U.S. Patent No. 5,364,934. Variations may be a substitution, deletion or insertion of one or more colons encoding the PRO that results in a change in the amino acid sequence of the PRO as compared with the native sequence PRO. Optionally the variation is by substitution of at least one amino acid with any other amino acid in one or more of the domains of the PRO.
Guidance in determining which amino acid residue may be inserted, substituted or deleted without adversely affecting the desired activity may be found by comparing the sequence of the PRO with that of homologous . known protein molecules and minimizing the number of amino acid sequence changes made in regions of high homology. Amino acid substitutions can be the result of replacing one amino acid with another amino acid having similar structural and/or chemical properties, such as the replacement of a leucine with a serine, i.e., conservative amino acid replacements. Insertions or deletions may optionally be in the range of about 1 to 5 amino acids, The vat~iation 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.

WO 01/16318 PC'Ii/US00123328 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 rnay 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.
In particular embodiments, 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.

WO O11I6318 PC'T/US00/23328 Table 6 Original Exemplary Preferred Residue Substitutions Substitutions Ala (A) val; leu; iIe val Arg (R) lys; gln; asn lys Asn (N) gln; his; lys;. erg gln Asp (D) glu glu Cys (C) ser sex IO Gln (Q) asn asn Glu (E) asp asg Gly (G) pro; ale ale His (H) asn; gln; lys; erg erg IIe (I) leu; val; met; ale; phe;

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

met; ale; phe ile Lys (K) erg; gln; asn erg Met (M) leu; phe; ile leu Phe (F) leu; val; ile; ale; tyr leu Pro (P) ale ale Ser (S) thr thr Thr (T) ser ser Trp (W) tyr; phe tyr Tyr (Y) trp; phe; thr; ser phe Val (V) ile; leu; met; phe;

ale; norleucine leu 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 poiypeptide 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 buck of the side chain. Naturally occurring residues are divided into groups based on common side-chain properties:
(1) hydrophobic: norleucine, met, ale, val, leu, ile;
(2) neutral hydrophilic: cys, ser, thr;
(3) acidic: asp, giu;
(4) basic: asn, gin, his, lys, erg;
(5) residues that influence chain orientation: gly, pro; and (6) aromatic: trp, tyr, phe.
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.
The variations can be made using methods known in,the art such as oligonucleotide-mediated {site-directed) mutagenesis, alanine scanning, and PGR mutagenests Site-directed mutagenesis [Carter et al:; ucl:
Acids Res., 1:4331 (1986); Zoller et al., ~IucI. Acids Res., x:64.87 (1987)], cassette mutagenesis (Wells et al., Gene, 34:315 (1985)], restriction selection mutagenesis (Wells et al., Philos. Trans. R. Soc. London SerA, wo .oin6s><s rcrrcrSO°r~~8 X17:415 (1986)] or other known techniques can be performed on the cloned DNA
to produce the PRO variant DNA.
Scanning amino acid analysis can also be employed to identify one or more amino acids along a contiguous sequence. Among the preferred scanning amino acids are relatively small, neutral amino acids. Such amino acids include alanine, glyeine, 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)). AIanine 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 aianine substitution does not yield adequate amounts of variant, an isoteric amino acid can be used.
C. Modifications of PRO
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. Commonly used crosslinking agents include, e.g., l,l-bis(diazoacetyl)-2-phenylethane, glutaraldehyde, N-hydroxysuccinimide esters, for example, esters with 4-azidosalicylie acid, homobifurtetional imidoesters, including disuccinimidyl esters such as 3,3'-dithiobis(succinimidylpropionate), bifunetional maleimides such as bis-N-maleimida-1,8-octane and agents such as methyl-3-[(p-azidophenyl)dithio]propioimidate.
Other modifications include deamidation of glutaminyl and asparaginyl residues to the corresponding glutamyl and aspartyl residues, respectively, hydroxylation of proline and lysine, phosphorylation of hydroxyl groups of seryl or threanyl residues, methylation of the a-amino groups of lysine, arginine, and histidine side chains [T.E. Creighton, Proteins: Structure and Molecular Properties, W.H.
Freeman & Co., San Francisco, pp. 79-86 (1983)], acetylation of the N-terminal amine, and arnidation of any C-terminal carboxyl group.
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 andfor enzymatic means), andfor adding one or more glycosylation sites that are not present in the native sequence PRO. In addition, 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 amin6 acid sequence may optionally be altered through changes at the DNA level, particularly by mutating the DNA
encoding the PRO poIypeptide at preselected bases such that colons are generated that will translate into the w0 o1n631s . iPGTIUS00123328 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 87105330 published l I Sepeember 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 far 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. Bioohvs.; 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.
Enzymol., 138:350 (1987).
Another type of covalent modification of PRO comprises linking the PRO
polypeptide to one of a variety of nonproteinaceous polymers, e.g., polyethylene glycol (PEG), polypropylene glycol, or polyoxyalkylenes, in the manner set forth in U.S. Patent Nos. 4,640,835; 4;496,689; 4,301,144;
4,670,417; 4,791,192 or 4,179,337.
The PRO 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, In one embodiment, 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. Various tag polypeptides and their respective antibodies are well known in the art. Examples include poly-histidine (poly-his) or poly-histidine-glycine (poly-his-gly) tags; the flu HA tag polypeptide and its antibody 12CA5 [Field et al., MoI. Cell. Biol., 8:2159-2165 (1988)]; the c-myc tag and the 8F9, 3C7, 6E10, G4, B7 and 9E10 antibodies thereeo [Evan et al., Molecular and Cellular Biology, 5:3610-3616 (1985)]; and the Herpes Simplex virus glycopmtein D (gD) tag and its antibody [Paborsky et al., Protein Engineering, 3_(6):547-553 (1990)]. Other tag polypeptides include the Flag-peptide [Hopp et al., BioTechnoloQV, _6:1204-1210 (1988)]; the KT3 epitope peptide [Martin et al., Science, x:192-194 (1992)];
an a-tubulin epitope peptide [Skinner et al., J. Biol. Clvem., 266:15163-15166 (1991)]; and the T7 gene 10 protein peptide tag- [Lutz-Freyermuth et al., Proc. Natl. Aced. Sci. USA, 87:6393-6397 (1990)].
In an alternative embodiment, the chimeric molecule may comprise a fusion of the PRO with an immunoglobutin or a particular region of an immunoglobulin. For a bivalent form of the chimeric molecule (also referred to as an "immunoadhesin"), such a fusion could be to the Fc region of an IgG molecule. The Ig fusions preferably include the substitution of a soluble (transmembrane domain deleted or inactivated) form of a PRO
polypeptide in place of at least one variable region within an Ig -molecule.
In a particularly vpreferred-embodiment, the immunoglobulin fusion includes the hinge, CH2 and CH3, or the hinge, CH1, CH2 and CH3 regions of an IgG 1 molecule. For the production of immunoglobulin fusions see also US Patent No. 5,428,130 issued June 27, 1995.

...,.W,, s" nn ~.rc,.<,..,. ..~rre,g.....~..:.%.~ W, .. _..:, ."".mom s:~:..,.,a..upwar- ~., ~vs>~3'i~.#'~;,cx>aaauat'' ocs-F?x~:.'n~-:"'~?"~.r~u~.~w.~asm.:.,;s~., wT~'R~a:w9-~'.;al~p~Rxrmwa ~;mrTaru,.
..».wysa~.~,~p~,.-.,wp,~aw. .,»-_.,. "",.......,."~.-.~.»...a~.

WO 01116318 PG"TIUSQOP~.3328 D. Preparation of PRO
The description below relates primarily to production of PRO by culturing cells transformed or transfected with a vector containing PRO nucleic acid. It is, of course, contemplated that alternative methods, which are well known in the art, may be employed to prepare PRO. For instance, the PRO sequence, or portions thereof, may be produced by direct peptide synthesis using solid-phase techniques [see, e.g., Stewart et al. , Sol id-Phase Peptide Synthesis, W.H. Freeman Co. , San Francisco, CA
( 1969); Merrifield,1. 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.
1. lsolaeion of DNA Encoding PRO
DNA encoding PRO may be obtained from a eDNA library prepared from tissue believed to possess the FRO tnRNA 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 tray also be obtained from a genotnic library or by known synthetic procedures (e.g., automated nucleic acid synthesis).
Libraries can be screened with probes (such as antibodies to the PRO or oligonucleotides of ac least about 20-80 bases) designed to identify the gene of interest or the protein encoded by it. Screening the cDNA
or genotnic library with the selected probe may be conducted using standard procuiures, 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., SCR Primer: A Laboraton~ Manual (Cold Spring Harbor Laboratory Press, 1995)].
The Examples below describe techniques for screening a cDNA library. The oligonucleotide sequences selected as probes should be of sufFcient length and sufficiently unambiguous that false positives are trianitnized.
The oligonupleotide 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 uP-labeled ATP, biotinylation or enzyme labeling. 1-iybridization 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 knows in the alt and as described herein.
Nucleic acid having protein coding-sequence may be obtained by screening selected-eDNA or genoinic 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 tnRNA that may not have been reverse-transcn'bed into cDNA.
x-trademark . S3 -~ .,~M~a.**v ~~m ,.W.~ .~* ~ *...~-~r ~,~-~~~ "~ . aw~..-__. __.._m~h.

2. Selection and Transformation of Host Cells Host cells are transfected or transformed with expression ar cloning vectors described herein for PRO
production and cultured in conventional nutrient media modified as appropriate for inducing promoters, selecting transformants, or amplifying the genes encoding the desired sequences. The culture conditions, such as media, temperature, pH and the like, can be selected by the skilled artisan without undue experimentation. In general, principles, protocols, and practical techniques for maximizing the productivity of cell cultures can be found in Mammalian Cell Biotechnology a Practical Approach, M. Butler, ed. (IRL Press, 1991) and Sambrook et al., supra.
Methods of eukaryotic cell transfection and prokaryotic cell transformation are known to the ordinarily skilled artisan, for example, CaClz, CaP04; liposome-mediated and electroporation. Depending on the host cell used, transformation is performed using standard techniques appropriate to such cells. The calcium treatment employing calcium chloride, as described in Sambrook et al., supra, or electraporation is generally used for prokaryotes. Infection with Agro6acterium tumefaciens is used for transformation of certain plant cells, as described by Shaw et al., Gene, 23:315 (1983) and WO 89/05859 published 29 June 1989. For mammalian cells without such cell walls, the calcium phosphate precipitation method of Graham and van der Eb, Virology, 52:456-457 (1978) can be employed. General aspects of mammalian cell host system transfections have been described in U.S. Patent No. 4,399,216. Transformations into yeast are typically carried out according to the.
method of Van Solingen et al., J. Bact., ,30:946 (1977) and Hsiao et al., Proc. Natl. Acad. Sci. (USA), 76:3829 (1979). However, other methods for introducing DNA into cells, such as by nuclear microinjection;
electroporation, bacterial protoplast fusion wish intact cells, or polycations, e.g., polybrene, polyornithine, may also be used. For various t~hniques for transforming mammalian cells, see Keown et al., Methods in Enz~mol ogy, 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 bur are not limited to cubacteria, 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 KS 772 (ATCC 53,635). Other suitable prokaryotic host cells include Enterobacteriaceae such as Escherachia, e.g., E. coli, Enterabacter, Erwinia, Klebsiella, Proteus, Salmonella, e.g., Salmonella typhimurium, Serratia, e.g., Serratia marcescans, and Shlgella, as well as Bacdlli such as_B.
subtilis and B. licheniformis (e.g., B. licheniformis 41P disclosed in DD
266,710 published 12 April 1989), Pseudomonas such as P. aerugirwsa, and Streptomyces. These examples are illustrative rather than limiting.
Strain W3110 is one particularly preferred host or parent host because it is a common host strain for recombinant DNA product fermentations. Preferably, the host cell secretes minimal amounts of proteolytic enzymes. For example, strain W3110 may be modified to effect a genetic mutation in the genes encoding proteins endogenous to the host, with examples of sucxt hosts including E. coli W3110 strain l A2, which has the complete genotype tonA ; E. toll W3110 strain 9E4, which has the complete genotype torrA ptr3;
E. coli W3110 strain 27C7 (ATCC 55,244), which has the complete genotype tonA ptr3 phoA Ed5 (argF
lac)169 degP ompT kan'; E. toll W3110 strain 37D6, which has the complete genotype tonA ptr3 phoA Ed5 (argF
lac)169 degP ompT rbs7 r.. .. ,. a . « ~;~~~:._ ~,.~.a" ~~ ~ ., ~ .,.- . . » ~. , . .,rc~ ~z ~. ...
.. . .... . ~.~_., u.._..m..~..~.__._..

WO 01/16318 . PCT/IJS001Z3328 ilvG kan ; E. colt W3110 strain 40B4, which is strain 37D6 with a non-kanamycin resistant degP deletion mutation; and an E. colt strain having mutant periplasmic protease disclosed in U. S. Patent No. 4,946,783 issued 7 August 1990. Alternatively, irz vitro methods of cloning, e.g., PCR or other nucleic acid polymerase reactions, are suitable.
In addition to prokaryotes, eukaryotic microbes such as filamentous fungi or yeast are suitable cloning S or expression hosts for PRO-encoding vectors. Saccharomyces cerevisiae is a commonly used lower eukaryotic host microorganism. Others include Schizosaccharomyces pombe (Beach and Nurse, Nature, 290: 140 [1981];
EP 139,383 published 2 May 1985); Ktuyveromyces hosts (U.S. Patent No.
4,943,529; Fleer et al., Bio/Technolo$X, 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.
butgaricus (ATCC 16,045), K.
wickeramii (ATCC 24,178), K. waltii (ATCC 56,500}, K. drosophilarum (ATCC
36,906; Van den Berg et al., BioITechnoloey, 8:135 (1990)}, K. thermotolerans, and K. marxianus; yarrowia (EP 402,226); Pichiapastoris (EP 183,070; Sreekrishna et al., J. Basic Microbiol., 28:265-278 [1988]);
Candida; Trichoderma reesia (EP
244,234); Neurospora crassa (Case et al., Proc. Natl. Acad. Sci. USA, 76:5259-5263 [1979]); Schwanniomyces such as Schwanniomyces occidentatis (EP 394,538 published 31 October 1990);
and filamentous fungi such as, 1S e.g.,Neurospora, Penicillium,Tolypocladium(W091/00357published lOJanuary 1991), andAspergillushosts such as A. nidulans (Ballance et al., Biochem. Bionhy~ Res. Commun., 112:284-289 [1983J; Tilbum et al., Gene, 26:205-221 [1983]; Melton et al., Proc. Natl. Acad. Sci. USA, 81: 1470-1474 [1984]) andA. niger(Kelly and Hynes, M~ BO J., 4:475-479 [/985]): Methylotropic yeasts are suitable herein and include; :but are. not limited to, yeast capable of growth on methanol selected from the genera consisting of Narisenula, Candida;
Ktoeckem, Pichia, Saccharomyces, Torulopsis, and Rhodotorula. A list of specifnc species that are exemplary of this class of yeasts may be found in C. Anthony, The Biochemisuy of Methylotrnnhs, 269 (1982).
Suitable host cells for the expression of glycosylated PRO are derived from multicelluiar organisms.
Examples of invertebrate cells include insect cells such as Drosophila S2 and Spodoptera Sf9, as well as plant cells. Examples of useful mammalian host cell lines include Chinese hamster ovary (CHO) and COS cells.
2S More specific examples include monkey kidney CV 1 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, 36:39 (/977)); Chinese hamster ovary cells/-DHFR (CHO, Urlaub and Chasin, Proc. Natl. Acad.
Sci. SA, 77:4216 (1980)); mouse sertoli cells (TM4, Mather, Biol. Reprod., 23:243-251 (1980}); human lung cells (W138, ATCC CCL 75}; human liver cells (Hep G2, HB 8065); and mouse mammary tumor (MMT
060562, ATCC CCL51). The selection of the appropriate host cell is deemed to be within the skill in the art.
3. Selection and Use of a Replicable Vector 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. Various vectors are.publicly available. .The:yector.
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 sites) using techniques known in the art.
Vector components generally SS

wo .omus PCTlUS00~13328 include, but are not limited to, one or more of a signal sequence, an origin of replication, one or more marker genes, an enhancer element, a promoter, and a transcription termination sequence. Construction of suitable vectors containing one or more of these components employs standard Iigation techniques which are known to the skilled artisan.
The PRO may be produced recombinantly not only directly, but also as a fusion polypeptide with a heterologous polypeptide, which may be a signal sequence or other polypeptide having a specific cleavage site at the N-terminus of the mature protein or polypeptide. In general, 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. For yeast secretion the signal sequence may be, e.g., the yeast invertase leader, alpha factor leader (including 5accharornyces and Ktuyveromyces a-factor leaders, the latter described in U.S. Patent No. 5,010,182), or acid phosphatase leader, the C. albicans glucoamylase leader (EP 362,179 published 4 April 1990), or the signal described in WO
90/13646 published 15 November 1990. In mammalian cell expression, mammalian signal sequences may be used to direct secretion of the protein, such as signal sequences from secreted polypeptides of the same or related species, as well as viral secretory leaders.
Both expression and cloning vectors contain a nucleic acid sequence that enables the vector to replicate in one or more selected host cells. Such sequences are well known for a variety of bacteria, yeast, and viruses.
The origin of replication from the plasmid pBR322 is suitable for most Gram-negative bacteria, the 2P, plasmid -.
origin is suitable for yeast, and various viral origins (SV40, polyoma, aderiovirus, VSV or BPV) are useful for cloning vectors in mammalian cells.
Expression and cloning vectors will typically contain a selection gene, also termed a selectable marker.
Typical selection genes encode proteins that (a) confer resistance to antibiotics or other toxins, e.g., ampicillin, neomycin, methotrexate, or tetracycline, (b) complement auxotrophic deficiencies, or (c) supply critical nutrients not available from complex media, e.g., the gene encoding D-alanine racemase for Bacilli.
An example of suitable selectable markers for mammalian cells are those that enable the identification of cells competent to take up the PRO-encoding nucleic acid, such as DHFR or thymidine kinase. An appropriate host cell when wild-type DHFR is employed is the CHO cell line deficient in DHFR activity, prepared and propagated as described by Urlaub et al., Proc. Natl. Acad. Sci-USA, 77:4216 (1980). A suitable selection gene for use in yeast is the trill gene present in the yeast plasmid YRp7 [Stinchcomb et al., Nature, 282:39 (1979); Kingsman et al., Gene, 7:141 (1979); Tschemper et al., Gene, 10:157 (1980)]. The trill gene provides a selection marker for a mutant strain of yeast lacking the ability to grow in tryptophan, for example, ATCC No. 44076 or PEP4-1 [Jones, Genetics, 85:12 {I977)].
Expression and cloning vectors usually contain a promoter operably linked to the PRO-encoding nucleic acid sequence to direct rnRNA synthesis. Promoters recognized by a variety of potential host cells are well known. Promoters suitable for use with prokaryotic hosts include the ~i-lactamase and lactose promoter systems [Chang et al., ature, 275:615 (1978); Goeddel et al., Nature, 281:544 (1979)],'alkaline phosphatase, a tryptophan (trp) promoter system [Goeddel, Nucleic Acids Res., 8:4057 (1980);
EP 36,776], and hybrid r ,. ". .. . . .. . .~r..-.. ~ ~ ~, .:~.~,~x .., .N .~. ...- ___.~ n,~,~ ..
".~~r ~." ..,~ . .___... _ __ _ _. _ . . ~ ~ ~ , fi," ., m, . _ .. ,. , a, WO U1/I6318 . PCTIUSt10123328 promoters such as the tac promoter [deBoer et al., Proe. Natl. Acad. Sci. USA, 80;21-25 (1983)]. Promoters for use in bacterial systems also will contain a Shine-Dalgarno (S.D.) sequence operably linked to the DNA
encoding PRO.
Examples of 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 S et al., J. Adv. Enz my a Reg_, 7:149 (1968}; Holland, Biochemistrv, 17:4900 (1978)], 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.
Other yeast promoters, which are inducible promoters having the additional advantage of transcription controlled by growth conditions, are the promoter regions for alcohol dehydrogenase 2, isocytochrome C, acid phosphatase, degradative enzymes associated with nitrogen metabolism, metallothionein, glyceraldehyde-3-phosphate dehydrogenase, and enzymes responsible for maltose and galactose utilization. Suitable vectors and promoters for use in yeast expression are fi~rther 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 heteroIogous 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.
Transcription of a DNA encoding the PRO by higher eukaryotes may be increased by inserting an enhaneer sequence into the vector. 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, a-fetoprotein, and insulin).
Typically, however, one will use an enhancer from a eukaryotic cell virus. Examples include the SV40 enhancer on the late side of the replication origin (bp 100-270), the eytomegalovirus early promoter enhancer, the polyoma enhancer on the late side of the replication origin, and adenovirus enhancers. The enhances 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 ineukaryotic host cells (yeast; fungi, insect, plant, animal, human, or nucleated cells from other multicellular organisms) will also contain sequences necessary for the termination of transcription and for stabilizing the mRNA. Such sequences are commonly available from the 5' and, occasionally 3', untranslated regions of eukaryotie or viral DNAs or cDNAs.
These regions contain nucleotide segments transcribed as polyadenylated fragments in the untransiated portion of the mRNA encoding PRO.
Still other methods, vectors, and host cells suitable for adaptation to the synthesis of PRO in recombinant vertebrate cell culture ate described in~Gething et al., ature, 293:620-625 (.1981); Mantel et-al., Nature, 281:40-4b (1979); EP 117,060; and EP 117,058.

wo .olns3ls »crmsoor~~zs 4. Detecitlg c:ene AmplificationlExpression 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, Pry:
Acad. Sci. USA, 77:5201-5205 (1980)], dot blotting (DNA analysis), or in situ hybridization, using an appropriately labeled probe, based on the sequences provided herein.
Alternatively, antibodies may be employed that can recognize specific duplexes, including DNA duplexes, RNA duplexes, and DNA-RNA hybrid duplexes or DNA-protein duplexes. The antibodies in turn may be labeled and the assay may be carried out where the duplex is bound to a surface, so chat upon the formation of duplex on the surface, the presence of antibody bound to the duplex can be detected.
Gene expression, alternatively, may be measured by immunological methods, such as IO immunohistochemical staining of cells oe tissue sections and assay of cell culture or body fluids, to quanzitaie directly the expression of gene product. Antibodies useful for immunohistochemical scairimg and/or assay of sample fluids may be either monoclonal or poIyclonal, 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 4r against exogenous sequence fused to PRO
DNA and encoding a specific IS antibody epitoge.
5. Purification of Polvpeptide Forms of PRO may be recovered from culture medium or from host cetl lysates.
If membrane-bound, , it can be released from the membrane using a suitable detergent solution (e.g.
Triton-X i00) or by enzymatic 20 cleavage. Cells employed in expression of PRO can be disrupted by various physical or chemical means, such as freeze-thaw cycling, sonication, mechanical disruption, or cell lysing agents.
It may be desired to purify PRO from recombinant cell proteins or polypeptides. The following procedures are exemplary of suitable purification procedures: by fractionation on an ion-exchange coh~tnn;
ethanol precipitation; reverse phase. HPLC; chromatography on silica or on a ration-exchange resin such as 25 DEAF; chromatofocusing; SDS-PAGE; ammonium sulfate precipitation; gel falaation using, for example, Sephadex G-75; protein A Sephtarose columns to remove contaminants such as IgG; and metal chelating columns to bind epitope-tagged forms of the PRO. Various methods of proto'tn purification may be employed and such methods are known in the art and described for example is Deutscher, Methods in Enzymologrr, 182 X1990);
Scopes, ~'rotein Purification: Principles and Practice, Springer-Verlag, New York (1982). The purification 30 steps) selected will depend, for example, on the nature of the production process used and the particular PRO
produced.
E. Uses for PRO
Nucleotide sequences (oc their complement) cncodi.~g--PRO have various :
apphcattons in. the art .of 35 molecular biology, including uses as hybridization probes, in chromosome and gene mapping and in the generation of sari-sense RNA and DNA. PRO nucleic acid will also be useful for the preparation of PRO
polypeptides by the recornbinattt techniques described herein.
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_ .__ .._.._._. o-._..__. ~..-,..-.,- _ .._..._.-_ .._ ..._ ..~._. . ,~ ... .. ..._ __ _. - o._.>,a~~,.~:~~~~~-=A .~~~~ r .. ~
~~-.r- _.-~.. ._.

The foil-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 eDNAs (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. Optionally, 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. By way of example, 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'ZP or'SS, 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.
Any EST sequences disclosed in the present application may similarly be employed as probes, using the methods disclosed herein.
Other useful fragments of the PRO nucleic acids include 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, according to the present invention, 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. The ability to derive an antisense or a sense oligonucleotide, based upon a cDNA sequence encoding a given protein is described in, for example, Stein and Cohen (Cancer R_es. 48:2659, 1988) and van der ICrol et al. (BioTechngues 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 ternuination of transcription or translation, or by other z~ans:
The antisense oligonucleotides thus may be used to block expression of PRO
proteins. Antisense or sense otigonucleotides further comprise oligonueleotides having modified sugar-phosphodiester backbones (or other sugar linkages, such as those described in WO 91106629) 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.
Other examples of sense or antisense oligonueleotides include those oligonucleotides which are eovaiently linked to organic moieties, such as those described in WO 90/
10048, and other moieties that increases affinity of the oligonucleotide far a target nucleic acid sequence, such as poly-(L-lysine). Further still, intercalating agents; such as ellipticine, and.alkylating agents or metal complexes may be attached to sense or antisense oligonucleotides to modify binding specificities of the antisense or sense oligonucleotide for the target nucleotide sequence.

.. ~" . ~ ._ ,. n.. r. ~ ,.,. .;~.::..~..~u ~.~.w~._._.. _. _...__ _ _. . _ ..
. ~~ w~, ~~~~.9 ~, . .h WO O1/I6318 PC°T/USOOn3328 Antisense or sense oligonucteotides may be introduced into a cell containing the target nucleic acid sequence by any gene transfer method, including, for example, CaP04-mediated DNA transfection, electroporation, or by using gene transfer vectors such as Epstein-Barr virus.
In a preferred procedure, an antisense or sense oligonucleotide is inserted into a suitable retroviral vector. A cell containing the target nucleic acid sequence is contacted with the recombinant retroviral vector, either in vivo or ex vivo. Suitable retroviral vectors include, but are not limited to, those derived from the murine reti'ovirus M-MuLV, N2 (a retrovirus derived from M-MuLV), or the double copy vectors designated DCTSA, DCTSB and DCTSC (see WO
90/13641).
Sense or antisense oligonucleotides also may be introduced into a cell containing the target nucleotide sequence by formation of a conjugate with a ligand binding molecule, as described in WO 91104753. Suitable Iigand binding molecules include, but are not limited to, cell surface receptors, growth factors, other cytokines, or other ligands that bind to cell surface receptors. Preferably, conjugation of the ligand binding molecule does not substantially interfere with the ability of the ligand binding molecule to bind to its corresponding molecule or receptor, or block entry of the sense or antisense oligonucleotide or its conjugated version into the cell.
Alternatively, a sense or an antisense oligonucleotide may be introduced into a cell containing the target nucleic acid sequence by formation of an oligonucleotide-lipid complex, as described in WO 90/I0448. The sense or antisense aligonucleotide-lipid complex is preferably dissociated within the cell by an endogenous lipase.
Antisense or sense RNA or DNA molecules are generally at least about 5 bases in length, about 10 bases in length, about I5 bases in length, about 20 bases in length, about 25 bases in length, about 30 bases in length, about 35 bases in length, about 40 bases in length, about 45 bases in length, about 50 bases in length, about 55 bases in length, about 60 bases in length, about 65 bases in length, about 70 bases in length, about 75 bases in length, about 80 bases in length, about 85 bases in length, about 90 bases in length, about 95 bases in length, about 100 bases in length, or more.
The probes may also be employed in PCR techniques to generate a pool of sequences for identification of closely related PRO coding sequences.
Nucleotide sequences encoding a PRO can also be used to construct hybridization probes for mapping the gene which encodes that PRO and for the genetic analysis of individuals with genetic disorders. The nucleotide sequences provided herein may be trapped to a chromosome and specific regions of a chromosome using known techniques, such as in situ hybridization, linkage analysis against known chromosomal markers, and hybridizaticn screening with libraries.
When the coding sequences for PRO encode a protein which binds to another protein (example, where the- PRO is a receptor), the PRO can be used in assays to identify the other proteins or molecules involved in the binding interaction. By such methods, inhibitors of the receptor/ligand binding interaction can be identified.
Proteins involved in such binding interactions can also be used to screen for peptide or small molecule inhibitors or agonists of the binding interaction. Also, the receptor PRO can be used to isolate correlative ligand(s).
Screening assays can be designed to find lead compoW ods that mimic the biological activity of a native PRO or a receptor for PRO. Such screening assays will include assays amenable to high-throughput screening of chemical libraries, making them particularly suitable for identifying small molecule drug candidates, Small 6a wo o><ns3>ls rc~rrnrsoor~3is molecules contemplated include synthetic organic or inorganic compounds. The assays can be performed in a variety of formats, including protein-protein binding assays, biochemical screening assays, immunoassays and cell based assays, which are well characterized in the art.
Nucleic acids which encode PRO or its modified forms can also be used to generate either transgenic animals or "knock out" animals which, in turn, are useful in the development and screening of therapeutically useful reagents. A transgenic animal (e.g., a mouse or rat) is an animal having cells that contain a transgene, which transgene was introduced into the animal or an ancestor of the animal at a prenatal, e.g., an embryonic stage. A transgene is a DNA which is integrated into the genome of a cell from which a transgenic animal develops. In one embodiment, cDNA encoding PRO can be used to clone genomic DNA encoding PRO in accordance with established techniques and the genomic sequences used to generate transgenic animals that contain cells which express DNA encoding PRO. Methods for generating transgenic animals, particularly animals such as mice or rats, have become conventional in the art and are described, for example, in U.S. Patent Nos. 4,736,866 and 4,870,009. Typically, particular cells would be targeted for PRO transgene incorporation with tissue-specific enhancers. Transgenic animals that include a copy of a transgene encoding PRO introduced into the germ line of the animal at an embryonic stage can be used to examine the effect of increased expression of DNA encoding PRO. Such animals can be used as tester animals for reagents thought to confer protection from, for example, pathological conditions associated with its overexpression.
In accordance with this facet of the invention, an animal is treated with the reagent and a reduced incidence of the pathological condition, compared to untreated animals bearing the transgene, would indicate a potential therapeutic intervention for the pathological condition.
Alternatively, non-human homologues of PRO can be used to construct a PRO
"knock out" animal which has a defective or altered gene encoding PRO as a result of homologous recombination between the endogenous gene encoding PRO and altered genomic DNA encoding PRO introduced into an embryonic stem cell of the animal. For example, cDNA encoding PRO can be used to clone genomic DNA encoding PRO in accordance with established techniques. A portion of the genomic DNA encoding PRO can be deleted or replaced with another gene, such as a gene encoding a selectable marker. which can be used to monitor integration. Typically, several kilobases of unaltered flanking DNA (both at the 5' and 3' ends) are included in the vector [see e.g., Thomas and Capeechi, Cell, 51:503 (1987) for a description of homologous recombination vectors]. The vector is introduced into an embryonic stem cell line (e.g., by electroporation) and cells in which the introduced DNA has homologously recombined with the endogenous DNA are selected [see e.g., Li et al., CeII, 69:915 (1992}]. The selected cells are then injected into a blastocyst of an animal (e.g., a mouse or rat) to form aggregaeion chimeras [see e.g., Bradley, in Teratocarcinomas arid Embryonic Stem Cells: A Practical Approach, E.1. Robertson, ed. (IRL, Oxford, 1987), pp. I 13-152). A chimeric embryo can then be implanted into a suitable pseudopregnant female foster animal and the embryo brought to term to create a "knock out" animal. Progeny harboring the homologously recombined DNA in their germ cells can-be identified by standard techniques and used to breed animals in which all cells of the animal contain the homologously recombined DNA. Knockout animals can be characterized for instance, for their ability to defend against certain pathological conditions and for their development of pathological conditions due to absence of ._ ... , ,~.s......rfr . o ,~.s.s ~ern...,..--ts~.r--;.....x .. , . ...,..-.".;_"........,..-. ..,~.,....Y~,.. xaa.. ~.amr... ........»~
m.....,~a",.,.....»... ........... _.........._.. .~ _.._._..._..._._-._.._.~____..._.._._., ._ ....... ...
ngee WOOII16318 .CA 02481691 2004-10-25 pcTTnrsoon33Z8 the PRO polypeptide.
Nucleic acid encoding the PRO polypeptides may also be used in gene therapy.
In gene therapy applications, genes are introduced into cells in order to achieve in vivo synthesis of a therapeutically effective genetic product, for example for replacement of a defective gene. "Gene therapy" includes both conventional gene therapy where a lasting effect is achieved by a single treatment, and the administration of gene therapeutic agents, which involves the one time or repeated administration of a therapeutically effective DNA or mRNA.
Antisense RNAs and DNAs can be used as therapeutic agents for blocking the expression of certain genes in viva. It has already been shown that short antisense oligonucleotides can be imported into cells where they act as inhibitors, despite their fow intracellular concentrations caused by their restricted uptake by the cell membrane. (Zamecnik et al., Proc. Natl. Acad. Sci. USA 83:4143-4146 [1986]).
The oligonucleotides can be modified to enhance their uptake, e.g. by substituting their, negatively charged phosphodiester groups by uncharged groups.
There are a variety of techniques available for introducing nucleic acids into viable cells. The techniques vary depending upon whether the nucleic acid is transferred into cultured cells in vitro, or in vivo in the cells of the intended host. Techniques suitable for the transfer of nucleic acid into mammalian cells in vitro include the use of Iiposomes, electroporation, microinjection, cell fusion, DEAE-dextran, the calcium phosphate precipitation method, etc. The currently preferred In vivo gene transfer techniques include transfection with. viral (typically retroviral) vectors and viral coat protein-liposome mediated transfection (Dzau et al., Trends in Biotechnoioay 11, 205-210 (1993]). In some situations it is desirable to provide the nucleic acid source with an agent that targets the target cells, such as an antibody specific for a cell surface membrane protein or the target cell, a ligand for a receptor on the target cell, ete. Where liposomes are employed, proteins which bind to a cell surface rnembt~ne protein associated with endocytosis may be used for targeting andlor to facilitate uptake, e. g. capsid proteins or fragments thereof tropic for a particular cell type, antibodies for proteins which undergo internalization in cycling, proteins that target intracellular localization and enhance intracellular half life.
The technique of receptor-mediated endocytosis is described, for example, by Wu et al., ~ Biol: Chem. 262, 4429-4432 (1987); and Wagner et al., Proc. Nati. Acad. Sci. USA f7, 3410-3414 (1990). For review of gene marking and gene therapy protocols see Anderson et al., S i nce 25b, 808-813 (1992).
The PRO polypeptides described herein may also be employed as molecular weight markers for protein electrophoresis purposes and the isolated nucleic acid sequences may be used for recombinantly expressing those markers.
The nucleic acid molecules encoding the PRO polypeptides or fragments thereof described herein are useful for chromosome identification. In this regard, there exists an ongoing need to identify new chromosome markers, since relatively few chromosome marking reagents, based upon actual sequence data are presently available. Each PRO nucleic acid molecule of the present invention can be used as a chromosome marker.
The PRO polypeptides and nucleic acid molecules of the present invention may also be used diagnostically for tissue typing, wherein the PRO polypegtides of the present invention may be differentially expressed in one tissue as compared to another, preferably in a diseased tissue as compared to a normal tissue of the same tissue type. PRO nucleic acid molecules will find use for generating probes for PCR, Northern k a n .. .. ~ ~ .. . ~ . . n .~ .~ ~,~~ F_~ .~.,x~ yxe,.~~,~~~~
v~"~.o~~.....~~~., w0 Ol/I(f31$ CA 02481691 2004-10-25 PCT/(1500/23328 analysis, Southern analysis and Western analysis.
The PRO polypeptides described herein may also be employed as therapeutic agents. The PRO
polypeptides of the present invention can be formulated according to known methods to prepare pharmaceutically useful compositions, whereby the PRO product hereof is combined in admixture with a pharmaceutically acceptable carrier vehicle. Therapeutic formulations are prepared for storage by mixing the active ingredient having the desired degree of purity with optional physiologically acceptable carriers, excipients or stabilizers (ReminQton's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980)), in the form of lyophilized formulations or aqueous solutions. Acceptable carriers, excipients or stabilizers are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate and other organic acids;
antioxidants including ascorbic acid; low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone, amino acids such as glycine, glutamine, asparagine, arginine or lysine;
monosaccharides, disaccharides and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; and/or nonionic surfactants such as TWEENTM, PLURONICSTM or PEG.
The formulations to be used for in vivo administration must be sterile. This is readily accomplished by filtration through sterile filtration membranes, prior to or following lyophilization and reconstitution.
Therapeutic compositions herein generally are placed into a container having a sterile access port, for example, an intravenous solution bag or via! having a stopper pierceable by a hypodermic injection needle.
The route of administration is in accord with lanown methods, e.g. injection or infusion by intravenous;
intraperitoneal, intracerebraI, intramuscular, intraacular, intraarterial or intralesional routes, topical administration, or by sustained release systems.
Dosages and desired drug concentrations of pharmaceutical compositions of the present invention may vary depending on the particular use envisioned. The determination of the appropriate dosage or route of administration is well within the skill of an ordinary physician. Animal experiments provide reliable guidance for the determination of effective doses for human therapy. Interspecies scaling of effective doses can be performed following the principles laid down by Mordenti,1. and Chappell, W.
"The use of interspecies scaling in toxicokinetics° In Toxicoldnetics and New Drug Development, Yacobi et al., Eds., Pergamon Press, New York 1989, pp. 42-96.
When in vivo administration of a PRO polypeptide or agonist or antagonist thereof is employed, normal dosage amounts may vary from about 10 ng/kg to up to 100 mg/kg of mammal body weight or more per day, preferably about I ~cg/kglday to 10 mglkg/day, depending upon the route of administration. Guidance as to particular dosages and methods of delivery is provided in the literature; see, for example, U.S. Pat. Nos.
4,657,760; 5,206,344; or 5,225,212. It is anticipated that different formulations will be effective for different treatment compounds and different disorders, that administration targeting one organ or t'issue,.for example, may necessitate delivery in a manner different from that to another organ or tissue.
Where sustained-release administration of a PRO polypeptide is desired in a formulation with release characteristics suitable for the treatment of any disease or disorder requiring administration of the PRO

sr.,.v. iM 6'P.,.w.re~,m.W..-~,---.. _....... w ur~rvnan,..nv..'~T~, ~~-~w.............,_ _._.__.. .... .._ _.
.r. _art. v a _u,a .... ,aG....aa~.4,u%-.~'Fa.w ,.x~ Pw . ..n P~.~..~yv,fafiiNA~b2~ y~,Vt~"kNPwv,.~...~P'S'°.., 'W~ dl/16318 CA 02481691 2004-10-25 polypeptide, microeneapsulation of the PRO polypeptide is contemplated.
Microencapsulation of recombinant proteins for sustained release has been successfully performed with human growth hormone (rhGH), interferon-(rhIFN- ), interleukin-2, and MN rgp120. Johnson et ai., Nat. Med., 2:795-799 (1996); Yasuda, Biomed.
Ther. , 27:1221-1223 (1993}; Hora et al., Bio/TechnoloQV. 8:755-758 ( 1990);
Cleland, "Design and Production of Single Immunization Vaccines Using Polylactide Polyglycolide Microsphere Systems," in Vaccine Design:
The Subunit and Adjuvant Approach, Powell and Newrnan, eds, (Plenum Press: New York, 1995), pp. 439-462;
WO 97/03692, WO 96140072, WO 96/07399; and U.S. Pat. No. 5,654,010.
The sustained-release formulations of these proteins were developed using poly-lactic-coglycolic acid (PLGA) polymer due to its biocompatibility and wide range of biodegradable properties. The degradation products of PLGA, lactic and glycolic acids, can be cleared quickly within the human body. Moreover, the degradability of this polymer can be adjusted from months to years depending on its molecular weight and composition. Lewis, "Controlled release of bioactive agents from lactide/glycolide polymer," in: M. Chasin and R. Langer (Eds.), Biodegradable Po~,ymers as Drug Delivery Systems (Marvel Dekker: New York, 1990), pp. 1-41.
This invention encompasses methods of screening compounds to identify those that mimic the PRO
polypeptide (agonists) or prevent the effect of the PRO polypeptide (antagonists). Screening assays for antagonist drug candidates are designed to identify compounds that bind or complex with the PRO polypeptides encoded by the genes identified herein, or otherwise interfere with the interaction of the encoded polypeptides with other cellular proteins. Such screening assays will include assays amenable to high-throughput screening of chemical~libraries, making them particularly suitable for identifying small molecule drug candidates:
The assays can be performed in a variety of formats, including protein-protein binding assays, biochemical screening assays, immunoassays, and cell-based assays, which are well characterized in the art.
All assays for antagonists are common in that they call for contacting the drug candidate with a PRO
polypeptide encoded by a nucleic acid identified herein under conditions and for a time sufficient to allow these two components to interact.
2S In binding assays, the interaction is binding and the complex formed can be isolated or detected in the reaction mixture. In a particular embodiment, the PRO polypeptide encoded by the gene identified herein or the drug candidate is immobilized on a solid phase, e.g., on a micrntiter plate, by covalent or non-covalent attachments. Non-covalent attachment generally is accomplished by coating the solid surface with a solution of the PRO polypeptide and drying. Alternatively, an immobilized antibody, e.g., a monoclonal antibody, specific for the PRO polypeptide to be immobilized can be used to anchor it to a solid surface. The assay is performed by adding the non-immobilized component, which may be labeled by a detectable label, to the immobilized component, e.g., the coated surface containing the anchored component. When the reaction is complete, the non-reacted components are removed, e.g., by washing, and complexes anchored on the solid surface are detected. When the originally non-immobilized component carries a detectable label, the detection of label , immobilized on the surface indicates that complexing occurred. Where the originally non-amtrtob~lized component does not carry a label, complexing can be detected, for example, by using a labeled antibody specifically binding the immobilized complex.

If the candidate compound interacts with but does not bind to a particular PRO
polypeptide encoded by a gene identified herein, its interaction with that polypeptide can be assayed by methods well known for detecting protein-protein interactions. Such assays include traditional approaches, such as, e.g., cross-linking, eo-immunoprecipitation, and co-purification through gradients or chromatographic columns. In addition, protein-protein interactions can be monitored by using a yeast-based genetic system described by Fields and co-workers (Fields and Song, Nature (L.ondonl, 344:245-246 (1989); Chien et al., Proc.
Natl. Acad. Sci. USA, 88:9578-9582 (1991)) as disclosed by Chevray and Nathans, Proc. Natl. Acad. Sci: USA, 89: 5789-5793 (1991). Many transcriptional activators, such as yeast GAL4, consist of two physically discrete modular domains, one acting as the DNA-binding domain, the other ane functioning as the transcription-activation domain. The yeast expression system described in the foregoing publications (generally referred to as the "two-hybrid system") takes advantage of this property, and employs two hybrid proteins, one in which the target protein is fused to the DNA-binding domain of GAL4, and another, in which candidate activating proteins are fused to the activation domain. The expression of a GALL-IacZ reporter gene under control of a GAL4-activated promoter depends on reconstitution of GAL4 activity via protein-protein interaction.
Colonies containing interacting polypeptides are detected with a chanmogenic substrate for (3-galactosidase. A
complete kit (MATCHMAKERTM) for identifying protein-protein interactions between two specific proteins using. the two-hybrid technique is commercially available from Clontech. This system can also be extended to map protein domains involved in specific protein interactions as well as to pinpoint amino acid residues that are crucial for these interactions.
Cotripounds that interfere with the interaction of a gene encoding a PRO
poiypeptide identified herein and other infra- or extracellular components can be tested as follows: usually a reaction mixture is prepared containing the product of the gene and the infra- or extracellular component.under conditions and for a time allowing for the interaction and binding of the two products. To test the ability of a candidate compound to inhibit binding, the reaction is run in the absence and in the presence of the test compound. In addition, a placebo may be added to a third reaction mixture, to serve as positive control. The binding (complex formation) between the test compound and the infra- or extracellular component present in the mixture is monitored as described hereinabove. The formation of a complex in the control reactions) but not in the reaction mixture conta'ming the test compound indicates that the test compound interferes with the interaction of the test compound and its reaction partner:
To assay for antagonists, the PRO polypeptide may be added to a cell along with the compound to be screened for a particular activity and the ability of the compound to inhibit the activity of interest in the presence of the PRO polypeptide indicates that the compound is an antagonist to the PRO
polypepeide. Alternatively, antagonists may be detected by combining the PRO polypeptide and a potential antagonist with membrane-bound PRO polypeptide receptors or recombinant receptors under appropriate conditions for a competitive inhibition assay. The PRO polypeptide can be labeled; such as by radioactivity, such that the number of PR0 polypeptide:
molecules bound to the receptor can be used to determine the effectiveness of the patential antagonist. The gene encoding the receptor can be identified by numerous methods laiown to those of skill in the art, for example, ligand panning and FAGS sorting. Coligan et al., Current Protocols in lmrnun., 1(2): Chapter 5 (1991).
m .._ , r _ .~ , ».4.~~ _~., .~.~.~ ~_~ ~. - ~_-- .. " a- .~ ~ -~=.,~..~~-~.-.-~ -.__..__ . ...._..._._ WO OI/I6318 PCTlUS00/2332~
Preferably, expression cloning is employed wherein polyadenylated RNA is prepared from a cell responsive to the PRO polypeptide and a cDNA library created from this RNA is divided into pools and used to transfect COS
cells or other cells that are not responsive to the PRO polypeptide.
Transfected cells thae are grown on glass slides are exposed to labeled PRO polypeptide. The PRO polypeptide can be labeled by a variety of means including iodination or inclusion of a recognition site for a site-specific protein kinase. Following fixation and incubation, the slides are subjected to autoradiographic analysis. Positive pools are identified and sub-pools are prepared and re-transfected using an interactive sub-pooling and re-screening process, eventually yielding a single clone that encodes the putative receptor. _ As an alternative approach for receptor identification, labeled PRO
polypeptide can be photoaffinity-linked with cell membrane or extract preparations that express the receptor molecule. Cross-linked material is resolved by PAGE and exposed to X-ray film. The labeled complex containing the receptor can be excised, resolved into peptide fragments, and subjected to protein micro-sequencing.
The ariiino acid sequence obtained from micro- sequencing would be used to design a set of degenerate oligonucleotide probes to screen a cDNA
library to identify the gene encoding the putative receptor.
In another assay for antagonists, mammalian cells or a membrane preparation expressing the receptor would be incubated with labeled PRO polygeptide in the presence of the candidate compound. The ability of the compound to enhance or block this interaction could then be measured.
More specific examples of potential antagonists include an oligonucleotide that binds to the fusions of immunoglobulin with PRO poiypeptide, and, in particular, antibodies including, without limitation, poly- and monoclonal antibodies and antibody fragments, single-chain antibodies, anti-idiotypic antibodies, and chimeric or humanized versions of such antibodies or fragments, as well as human antibodies and antibody fragments.
Alternatively, a potential antagonist may be a closely related protein, for example, a mutated form of the PRO
polypeptide that recognizes the receptor but imparts no effect, thereby competitively inhibiting the action of the PRO polypeptide.
Another potential PRO polypeptide antagonist is an antisense RNA or DNA
construct prepared using antisense technology, where, e.g., an antisense RNA or DNA molecule acts to block directly the translation of mRNA by hybridizing to targeted mRNA and preventing protein translation.
Antisense technology can be used to control gene expression through triple-helix formation or antisense DNA or RNA, both of which methods are based on binding of a polynucIeotide to DNA or RNA. For example, the 5 ° coding portion of the polynucleotide sequence, which encodes the mature PRO polypeptides herein, is used to design an antisense RNA
oligonucleotide of from about 10 to 40 base pairs in length. A DNA
oligonucleotide is designed to be complementary to a region of the gene involved in transcription (triple helix -see Lee et al., Nucl. Acids Res., 6:3073 (1979); Cooney et al., Science, 24I: 456 (1988); Dervan et al., Science, 251:1360 (199I)), thereby preventing transcription and the production of the PRO polypeptide. The antisense RNA oligonucleotide hybridizes to the mRNA in. vivo and blocks translation of the-mRNA molecule into.ahe PRO..-p4lypeptide (antisense - Okano, Neurochem., 56:560 (1991); Oligodeoxvnucleotides as Antisense Inhibitors of Gene x ressi n (CRC Press: l3oca Raton, FL, 1988). The oligonucleotides described above can also be delivered to cetls such that the antisense RNA or DNA may be expressed ira vivo to inhibit production of the PRO
6fi ..._..... . . .,... . .. y r ... .~~. ~ ,~_.~.:~~.:~.:..~,ES:~~~~.u .~. «.n w.
.-r. ~ . __._~.___. __..~.n~~~~,..~.. _rt-.~~.-.~____~_~.~ ~__ ___ WO O1/Ib318 PCT/USOOI23328 polypeptide. When antisense DNA is used, oligodeoxyribonucleotides derived from the translation-initiation site, e.g., between about -10 and +IQ positions of the target gene nucleotide sequence, are preferred.
Potential antagonists include small molecules that bind to the active site, the receptor binding site, or growth factor or other relevant binding site of the PRO polypeptide, thereby blocking the normal biological activity of the PRO polypeptide. Examples of small molecules include, but are not limited to, small peptides or peptide-like molecules, preferably soluble peptides, and synthetic non-peptidyl organic or inorganic compounds.
Ribozymes are enzymatic RNA molecules capable of catalyzing the specific cleavage of RNA.
Ribozymes act by sequence-specific hybridization to the complementary target RNA, followed by endonucleolytic cleavage. Specific ribozyrne cleavage sites within a potential RNA target can be identified by known techniques. For further details see, e.g., Rossi, Current Biology, 4:469-471 ( 1994), and PCT publication No. WO 97/33551 (published September I8, 1997).
Nucleic acid molecules in triple-helix formation used to inhibit transcription should be single-stranded and composed of deoxynueleotides. The base composition of these oligonucleotides is designed such that it promotes triple-helix formation via Hoogsteen base-pairing rules, which generally require sizeable stretches of purines or pyrimidines on one strand of a duplex. For further details see, e.g., PCT publication No. WO
97/33551, supra.
These small molecules can be identified by any one or more of the screening assays discussed hereinabove and/or by any other screening techniques well known for those skilled in the art.
Diagnostic and therapeutic uses of the herein disclosed molecules may also be based upon the positive functional assay hits disclosed and described below.
F. Anti-PRO Antibodies The present invention further provides anei-PRO antibodies. Exemplary antibodies include polyclonaI, monoclonal, humanized, bispecific, and heteroconjugate antibodies.
I. Pol~clonal Antibodies The anti-PRO antibodies may eornprise polyclonal antibodies. Methods of preparing polyclonal antibodies are known to the skilled artisan. Polyclonal antibodies can be raised in a mammal, for example, by one or more injections of an immunizing agent and, if desired, an adjuvant.
Typically, the immunizing agent and/or adjuvant will be injected in the mammal by multiple subcutaneous or intraperitoneal injections. The immunizing agent may include the PRO polypeptide or a fusion protein thereaf.
It may be useful to conjugate the immunizing agent eo a protein known to be immunogenic in the mammal being immunized. Examples of such immunogenic proteins include but are not limited to keyhole limpet hemocyanin, serum albumin, bovine thyroglobulin,. and soybean trypsin inhibitor. Examples of adjuvants which maybe employed itlclude Fremtd's complete adjuvant and MPL-TDM adjuvant (monophosphoryl Lipid A, synthetic trehalose dicorynomycolate).
'The immunization protocol may be selected by one skilled in the art without undue experimentation.

WO OIII6318 PCT~~~~
2. Monoclonal Antibodies The anti-PRO antibodies may, alternatively, be monoclonal antibodies.
Monoclonal antibodies may be prepared using hybridoma methods, such as those described by Kohler and Milstein, Nature, 25(:495 (1975).
In a hybridoma method, a mouse, hamster, or other appropriate host animal, is typically immunized with an immunizing agent to elicit lymphocytes that produce or are capable of producing antibodies that will specifically bind to the immunizing agent. Alternatively, the lymphocytes may be immunized in uitro.
The immunizing agent will typically include the PRO polypeptide or a fusion protein thereof.
Generally, either peripheral blood lymphocytes ("PBLs") are used if cells of human origin are desired, or spleen cells or lymph node cells are used if non-human mammalian sources are desired.
The lymphocytes are then fused with an immortalized cell line using a suitable fusing agent, such as polyethylene glycol, io form a hybridoma cell [coding, Monoclonal Antibodies: Princples and Practice, Academic Press, (1986) pp. 59-103j.
Immortalized cell lines are usuatly transformed mammalian cells, particularly myelorna cells of rodent, bovine and human origin. Usually, rat or mouse myeIoma cell lines are employed. The hybridoma cells may be cultured in a suitable culture medium that preferably contains one or more substances that inhibit the growth or survival of the unfused, immortalized cells. For example, if the parental cells lack the enzyme hypoxanthine guanine phosphoribosyl uansferase (HGPRT ar HPRT), the culture medium for the hybridomas typically will include hypoxanthine, aminopterin, and thymidine ("HAT medium"), which substances prevent the growth of HGPRT-deficient cells.
Preferred immortalized cell lines are those that fuse efficiently, support stable high level expression of antibody by the selected antibody-producing cells, and are sensitive to a medial n such as HAT medium. More preferred immortalized cell lines are marine myeloma lines, which can be obtained, for instance, from the Salk Institute Cell Distribution Center, San Diego, California and the American Type Culture Collection, Manassas, Virginia. Human myeloma and mouse-human heteromyeloma cell lines also have been described for the production of human monoclonal antibodies [Kozbor, J. Immunol.,133:3001 ( 1984); Brodeur et al., Monoclonal Antibody Production Techniques a~d~pplieations, Marvel Dekker, Inc., New York, (1987) pp. 51-63j.
The culture medium in which the hybridoma cells are cultured can then be assayed for the presence of monoclonal antibodies directed against PRO. Preferably, the binding specificity of monoclonal antibodies produced by the hybridoma cells is determined by immunoprecipitation or by an in vitro binding assay, such as radioimmunoassay (RIA) or enzyme-linked immunoabsorbent assay (ELISA). Such techniques and assays are known in the art. The binding affinity of the monoclonal antibody can, for example, be determined by the Scatchard analysis of Munson and Pollard, Anal. Biochem., 107:220 (1980).
After the desired hybridoma cells are identified, the clones may be subcloned by limiting dilution procedures and grown by standard methods [coding, su ra . Suitable culture media for this purpose include, for example, Dulbecco's Modified Eagle's Medium and RPMI-1640 medium.
Alternatively, the hybridoma cells may be grown in vivo as ascites in a mammal.
The iiionoclonal antibodies secreted by tFie subclones may be isolated or purified from the culture medium or ascites fluid by conventional immunoglobulin purification procedures such as, for example, protein A-Sepharose, hydroxylapatite chromatography, gel electrophoresis, dialysis, or affinity chromatography.

WO O11I6318 PCT~~~~
The monoclonal antibodies may also be made by recombinant DNA methods, such as those described in U.S. Patent No. 4,816,567. DNA encoding the monoclonal antibodies of the invention canbe readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that are capable of binding specifically to genes encoding the heavy and light chains of murine antibodies). The hybridoma cells of the invention serve as a preferred source of such DNA. Once isolated, the DNA may be placed into expression vectors, which are then transfected into host cells such as simian COS cells, Chinese hamster ovary (CHO) cells, or myeloma cells that do not otherwise produce immunoglobulin protein, to obtain the synthesis of monoclonal antibodies in the recombinant host cells. The DNA also may be modified, for example, by substituting the coding sequence for human heavy and light chain constant domains in place of the homologous murine sequences [U.S. Patent No. 4,816,567; Morrison et al., supra] or by covaiently joining to the immunoglobulin coding sequence all or pan of the coding sequence for a non-immunoglobulin polypeptide. Such a non-immunoglobulin polypeptide can be substituted for the constant domains of an antibody of the invention, or can be substituted for the variable domains of one antigen-combining site of an antibody of the invention to create a chirneric bivalent antibody.
The antibodies may be monovalent antibodies. Methods for preparing monovalent antibodies are well known in the art. For example, one method involves recombinant expression of itnmunoglobulin light chain and modified heavy chain. The heavy chain is truncated generally at any point in the Fc region so as to prevent heavy chain crosslinking. Alternatively, the relevant cysteine residues are substituted with another amino acid residue or are deleted so as to prevent crosslinking.
In vitro methods are also suitable for preparing monovalent antibodies.
Digestion of antibodies-to produce fragments thereof, particularly, Fab fragments, can be accomplished using routine techniques known in the art.
3. Human and Humanized Antibodies The anti-PRO antibodies of the invention may further comprise humanized antibodies or human antibodies. Humanized forms of non-human (e.g:, murine) antibodies are chimeric immunoglobulins, immunoglobulin chains or fragments thereof (such as Fv, Fab, Fab', F(ab')2 or other antigen-binding subsequences of antibodies) which contain minimal sequence derived from non-human immunoglobuIin.
Humanized antibodies include human immunoglobulins .(recipient antibody) in which residues from a complementary determining region (CDR) of the recipient are replaced by residues from a CDR of a non-human species (donor antibody) such as mouse, rat or rabbit having the desired specificity, affinity and capacity. In some instances, Fv framework residues of the human immunoglobulin are replaced by corresponding non-human residues. Humanized antibodies may also comprise residues which are found neither in the recipient antibody nor in the imported CDR or framework sequences. In general, the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the.CDR
regions correspond to those of a non-human immunoglobulin and all or substantially alt of the FR regions are those of a human immunogiobulin consensus sequence. The humanized antibody optimally also will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin [Jones 6g ffO OI/16318 PC'T/US00/23328 et al., Nature, 321:522-525 (1986); Riechtttatm et al., ature, 332:323-329 (1988); and Presta, C
Struct. Biol., _2:593-596 (1992)].
Methods for humanizing non-human antibodies are well laraown in the art.
Generally, a humanized antibody has one or more amino acid residues introduced into it from a source which is non-human. These non-human amino acid residues are often referred to as "import" residues, which are typically taken from an "import"
variable domain. Humanization can be essentially performed following the method of Winter and co-workers [Jones et al., Nature, 'y1-2I,:522-525 (1986); Riechmann et al., Nature, 332:323-327 (1988); Verhoeyen et al., Science, 239:1534-1536 (1988)], by substituting rodent CDRs or CDR sequences for the corresponding sequences of a human antibody. Accordingly, such "humanized" antibodies are chimeric antibodies (U. S. Patent No. 4,816,567), wherein substantially less than an intact human variable domain has been substituted by the corresponding sequence from a non-human species. In gractice, humanized antibodies are typically human antibodies in which some CDR residues and possibly some FR residues are substituted by residues from analogous sites in rodent antibodies.
Human antibodies can also be produced using various techniques known in the art, including phage display libraries [Hoogenboom and Winter, J. Mol. B_iol., 227:381 (1991);
Marks et al., J. ol. Biol., X2:581 (1991)]. The techniques of Cole et al, and Boerner et al. are also available for the preparation of human monoclonal antibodies (Cole et aL,11~(onoclonal Antibodigs and Cancer Therapy, Alan R. Liss, p. 77 (1985) and Boerner et al., J. Immunol., 14711):86-95 (1991)]. Similarly, human antibodies can be made by introducing of human immunoglobulin Loci into transgenic animals, e.g., mice in which the endogenous immunoglobulin genes have been partially or completely inactivated. Upon challenge, human antibody production is observed, ~-which closely resembles that seen in humans in all respects, including gene rearrangement, assembly, and antibody repertoire. This approach is described, for example, in U.S. Patent Nos. 5,545,807; 5,545,806;
5,569,825; 5,625,126; 5,633,425; 5,661,016, and in the following scientific publications: Marks et al., BioITechnoloay I0, 779-783 ( 1992); Lonberg et al. , Nature 368 856-859 ( 1994); Morrison, Nature 368, 812-13 (1994); Fishwild et al., Nature Biotechnology ,~_4, 843-51 (1996); Neuberger, Nature Biotechnology 1_4, 826 (1996); Lonberg and Huszar, Intern. Rev. Imtrtunol. _l~ 65-93 (1995).
The antibodies may also be affinity matured using known selection and/or mutagenesis methods as described above. Preferred affinity matured antibodies have an affinity which is five times, more preferably 10 times, even more preferably 20 or 30 times greater than the starting antibody (generally marine, humanized or human) from which the matured antibody is prepared.
4. Bi~ecific Antibodies Bispecific antibodies are monoclonal, preferably human or humanized, antibodies that have binding specificities for at least two different antigens. In the present case, one of the binding specificities is for the PRO, the other one is for any other antigen, and preferably for a cell-surface protein or recepfor ox receptor subunit.
Methods for making bispecific antibodies are known in the art. Traditionally, the recombinant production of bispecific antibodies is based on the co-expression of two immunogiobulin heavy-chainllight-chain . _ . _T~. .. ~ . ~.w. . ~.~.~.... ~.,.~, . ~. ~-. ~ ~.~ ~~,.~. r ~.~ . "-<..... ~...._~.__ _ -M-..r...-..
~ro. ~, wo olnc>3><s pc'rnJSOOr~Zs pairs, where the two heavy chains have different specificities [Milstein and Cuello, ature, 05:537-539 ( 1983)].
Because of the random assortment of immunoglobulin heavy and light chains, these hybridomas (quadromas) produce a potential mixture of ten different antibody molecules, of which only one has the correct bispecific structure. The purification of the correct molecule is usually accomplished by affinity chromatography steps.
Similar procedures are disclosed in WO 93/08829, published 13 May 1993, and in Traunecker et al., EMBO
J., 10:3655-3659 (1991).
Antibody variable domains with the desired binding specificities (antibody-antigen combining sites) can be fused to immunoglobulin constant domain sequences. The fusion preferably is with an immunoglobulin heavy-chain constant domain, comprising at least part of the hinge, CH2, and CH3 regions. It is preferred to have the first heavy-chain constant region {CH 1 ) containing the site necessary for light-chain binding present in at least one of the fusions. I)NAs encoding the immunoglobulin heavy-chain fusions and, if desired, the immunoglobulin light chain, are inserted into separate expression vectors, and are co-transfected into a suitable host organism. For further details of generating bispecific antibodies see, for example, Suresh et al., Methods in Enzymolo~r, 12 :210 (1986).
According to another approach described in WO 96/27011, the interface between a pair of antibody molecules can be engineered to maximize the percentage of heterodimers which are recovered from recombinant cell culture. The preferred interface comprises at least a part of the CI-13 region of an antibody constant domain.
In this method, one or more small amino acid side chains from the interface of the first antibody molecule are replaced with larger side chains (e.g. tyrosine or tryptophan). Compensatory "cavities" of identical or similar size to the large side chains) are created on the interface of the second antibody molecule by replacing large amino acid side chains with smaller ones (e.g. alanine or threoriine). This provides a mechanism for increasing the yield of the heterodimer over other unwanted end-products such as hornodimers.
Bispecific antibodies can be prepared as full length antibodies or antibody fragments (e.g. F(ab')Z
bispecific antibodies). Techniques for generating bispecific antibodies from antibody fragments have been described in the literature. For example, bispecific antibodies can be prepared can be prepared using chemical linkage. Brennan et al. , Science 229:81 ( 1985) describe a procedure wherein intact antibodies are proteolytically cleaved to generate F(ab')Z fragments. These fragments are reduced in the presence of the dithiol complexing agent sodium arsenite to stabilize vicinal dithiols and prevent intermolecular disulfide formation. The Fab' fragments generated are then converted to thionitrobenzoate (TNB) derivatives.
One of the Fab'-TNB.
derivatives is then reconverted to the Fab'-thiol by reduction with mercaptoethylamine and is mixed with an equimolar amount of the other Fab'-TNB derivative to form the bispeciftc antibody. The bispecific antibodies produced can be used as agents for the selective immobilization of enzymes.
Fab' fragments may be directly recovered from E. roll and chemically coupled eo form bispecific antibodies. Shalaby er al., J. Exp. Med. 175:217-225 (1992) describe the production of a fully humanized bispecifte antibody F(ab')z molecule. :Each Fab' fragment was separately secreted from E. roll and subjected to directed chemical coupling in vitro to form the bispecific antibody. The bispecific antibody thus formed was able to bind to cells overexpressing the ErbB2 receptor and normal human T
cells, as well as trigger the iytic activity of human cytotoxic lymphocytes against human breast tumor targets.

WO 01116318 . PCT/US00123328 Various technique for making and isolating bispeciftcantibody fragments directly from recombinant cell culture have also been described. For example, bispecific antibodies have been produced using leucine zippers.
Kostelny et al., J. Immunol. 148(5):1547-1553 (1992). The leucine zipper peptides from the Fos and Jun proteins were linked to the Fab' portions of two different antibodies by gene fusion. The antibody homodimers were reduced at the hinge region to form monomers and then re-oxidized to form the antibody heterodimers.
This method can also be utilized for the production of antibody homodimers.
The "diabody" technology described by Hollinger et al., Proc. Natl. Acad. Sci. USA 90:6444-6448 (1993) has provided an alternaeive mechanism for making bispecific antibody fragments. The fragments comprise a heavy-chain variable domain (VH) connected to a light-chain variable domain (V J by a linker which is too short to allow pairing between the two domains on the same chain. Accordingly, the VH and V~ domains of one fragment are forced to pair with the complementary VL and VH domains of another fragment, thereby forming two antigen-binding sites. Another strategy for making bispecific antibody fragments by the use of single-chain Fv (sFv) dimers has also been reported. See, Gruber et al., J. Immunol. 152:5368 (1994).
Antibodies with more than two valencies are contemplated. For example, trispeciftc antibodies can be prepared.
Tutt et al., J. Immunol. 147:60 (1991).
Exemplary bispecifte antibodies may bind to two different epitopes on a given PRO polypeptide herein.
Alternatively, an anti-PRO polypeptide arm may be combined with an arm which binds to a triggering molecule on a leukocyte such as a T-cell receptor molecule (e.g. CD2, CD3, CD28, or B7), or Fc receptors for IgG
(FcyR), such as FcyRI (CD64), FcyRII (CD32) and FcyRIIL(CD 16) so as to focus cellular defense mechanisms .. .
to the cell expressing the particular PRO polypeptide. Bispecific antibodies may also be used to localize cytotoxic agents to cells which express a particular PRO polypeptide. These antibodies possess a PRO-binding arm and an arm which binds a cytotoxic agent or a radionuclide chelator, such as EOTUBE, DPTA, DOTA, or TETA. Another bispecific antibody of interest binds the PRO polypeptide and further binds tissue factor (TF).
5. Heterocori u~W ate Antibodies Heteroconjugate antibodies are also within the scope of the present invention.
Heteroconjugate antibodies are composed of two covalently joined antibodies. Such antibodies have, for example, been proposed to target immune system cells to unwanted cells [U.S. Patent No. 4,676,980], and for treatment of HIV infection [WO 91/00360; WO 92/200373; EP 03089]. It is contemplated that the antibodies may be prepared in vitro using .known methods in synthetic protein chemistry, including those involving crosslinking agents. For example, immunotoxins may be constructed using a disulfide exchange reaction or by forming a thioether bond.
Examples of suitable reagents for this purpose include iminothiolate and methyl-4-mercaptobutyrimidate and those disclosed, for example, in U.S. Patent No. 4,b76,980.
6. Effector Function En ineering It may be desirable to modify the antibody of the invention with respect to effector function, so as to enhance, e.g., the effectiveness of the antibody in treating cancer. For example, cysteine residues) may be .~. ,~ _~~..,~~ gar n .~r~s WO O1I163I8 PCTlUS00123328 introduced into the Fc region, thereby allowing interchain disulfide bond formation in this region. The homodimeric antibody thus generated may have improved internalization capability and/or increased complement-mediated cell killing and antibody-dependent cellular cytotoxicity (ADCC). See Caron et al. , J. ExgMed., 176:
1191-1195 (1992) and Shopes, J, Immunol., 148: 2918-2922 (1992). Homodimeric antibodies with enhanced anti-tumor activity may also be prepared using heterobifunctional cross-linkers as described in Wolff et al.
Cancer Research, 53: 2560-2565 ( 1993). Alternatively, an antibody can be engineered that has dual Fe regions and may thereby have enhanced complement lysis and ADCC capabilities. See Stevenson et al., Anti-Cancer Drug Design. 3: 219-230 (1989). -7. Immunocon~u_gates I O The invention also pertains to immunoconjugates comprising an antibody conjugated to a cytotoxic agent such as a chemotherapeutic agent, toxin (e.g., an enzymaticaLLy active toxin of bacterial, fungal, plant, or animal origin, or fragments thereofj, or a radioactive isotope (i.e., a radioconjugate).
Chemotherapeutic agents useful in the generation of such immunoconjugates have been described above.
Enzymatically active toxins and fragments thereof that can be used include diphtheria A chain, nonbinding active fragments of diphtheria toxin, exotoxin A chain (from Pseudorrcortas aeruginosa), ricin A chain, abrin A chain, rnodeccin A chain, alpha-sarcin, Aleurites fordii proteins, dianthin proteins, Phytolaca americana proteins (PAPI, PAPII, and PAP-S), momordica charantia inhibitor, curcin, crodn, sapaonaria officinalis inhibitor, gelonin, mitogellin, restrictocin, phenomycin, enomycin, and the tricothecenes, A variety of radionuclidesare w ~ --available for the production of radioconjugated antibodies. Examples include i'ZBi, "'I, .'j'In, '~Y; and-'~Re.
Conjugates of the antibody and cytotoxic agent are made using a variety of bifunctional protein-coupling agents such as N-succinimidyI-3-(2-pyridyldithiol) propionate (SPDP), iminothiolane (IT), bifunctional derivatives of imidoesters (such as dimethyl adipimidate HCL), active esters (such as disuccinimidyl suberate), aldehydes (such as glutareldehyde), bis-azido compounds (such as bis (p-azidobenzoyl) hexanediamine); bis-diazonium derivatives (such as bis-(p-diazoniumhenzoyl)-ethylenediamine), diisocyanates (such as tolyene 2,6-diisocyanate), and bis-active fluorine compounds (such as 1,S-difluoro-2,4-dinitrnbenzene). For example, a ricin immunotoxin can be prepared as described in Vitetta et al., cience, ~: i098 (198?). Carbon-14-Labeled 1-isothiocyanatobenzyl-3-methyldiethylene triaminepentaacetic acid (M~-DTPA) is an exemplary chelating agent for conjugation of radionucleotide to the antibody. See W094111026.
In another embodiment, the antibody may be conjugated to a "receptor" (such streptavidin) for utilization in tumor pretargeting wherein the antibody-receptor conjugate is administered to the patient, followed by removal of unbound conjugate from the circulation using a clearing agent and then administration of a "ligand" (e.g., avidin) that is conjugated to a cytotoxic agent (e.g., a radionucleotide).
8. Immunoliposomes The antibodies disclosed herein may also be formulated as immunoliposotnes.
Liposomes containing the antibody are prepared by methods known in the art, such as described in Epstein et al., Proc. Natl. Acad.
Sci. USA, 82: 3688 (1985); Hwang et al., Proc. Natl Acad. Sci. USA, 77: 4030 (1980); and U.S. Pat. Nos.

s-~n,x, r. . x .... n , , ...,n. . a~,ap. s.ny,a. ".;.~xu.;"~-,.
~,"nu.<.~~~..u ~, x r n ,,",»."w~~., k, ,.,,~qr,,, ,qyg;.,rcp,~yy_; Fr,. ..
SpnU. ~-au~,h h'F" "~ara wo .olins3is _ Pc'rnrsoor~32s 4,485,045 and 4,544,545. Liposomes with enhanced circulation time are disclosed in U.S. Patent No.
5,013,556.
Particularly useful Iiposomes can be generated by the reverse-phase evaporation method with a lipid composition comprising phosphatidylchoIine, cholesterol, and PEG-derivatized phosphatidylethanolamine (PEG-PE). Liposomes are extruded through filters of defined pore size to yield liposomes with the desired diameter.
Fab' fragments of the antibody of the present invention can be conjugated to the liposomes as described in Martin er al ., J. Biol. Chem., 257: 286-288 (1982) via a disulfide-interchange reaction. A chemotherapeutic agent (such as Doxorubicin) is optionally contained within the liposome. See Gabizon et al. , J. National Cancer Inst., 81(19): 1484 (1989).

9. Pharmaceutical ComQositions of Antibodies Antibodies specifically binding a PRO polypeptide identified herein, as well as other molecules identified by the screening assays disclosed hereinbefore, can be administered for the treatment of various disorders in the form of pharmaceutical compositions.
If the PRO polypeptide is intracellular and whole antibodies are used as inhibitors, internalizing antibodies are preferred. However; lipofections or liposomes can also be used to deliver the antibody, or an antibody fragment, into cells. Where antibody fragments are used, the smallest inhibitory fragment that specifically binds to the binding domain of the target protein is preferred.
For example, based upon the variable-region sequences of an antibody, peptide molecules can be designed that retain the ability to bind the target protein sequence. Such peptides can be synthesized chemically and/or produced by recombinant DNA
technology. See, e.g., Marasco et al., roc. Natl. Acad. Sci. USA., QO_: 7889-7893 (1993). ll~e fanca'lation herein may also contain more than one active compound as necessary for the particular indication being treated, preferably those with complementary activities that do not adversely affect each other. Alternatively, or in addition, the composition may comprise an agent that enhances its function, such as, for example, a eytotoxic agent, cytolcine, chemotherapeutic agent, or growth-inhibitory agent. Such molecules are suitably present in combination in amounts that are effective for the purpose intended.
The active ingredients may also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(methylmethacylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles, and nanocapsules) or in macroemulsions.
Such techniques are dISCIOSed in Rernington's Pharmaceutical Sciences, supra.
The formulations to be used for in vivo administration must be sterile. This is readily accomplished by filtration through sterile filtration membranes.
Sustained-release preparations may be_prepared. Suitable examples of sustained-release preparations include semipenmeable matrices of solid hydrophobic polymers containing the antibody, which matrices are in r5 the form of shaped artioles, c.g., films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels(forexample, poly(2-hydroxyethyl-methacrylate), orpoly(vinylalcohol)), polylactides (U.S.
Pat. No. 3,773,919), copolymers of L-glutamic acid and y ethyl-L-glutamate, non-degradable ethylene-vinyl WO O1/I6318 pCT~s~~~
EXAMPLES
Commercially available reagents referred to in the examples were used according to manufacturer's instructions unless otherwise indicated. The source of those cells identified in the following examples, and throughout the specification, by ATCC accession numbers is the American Type Culture Collection, Mantissas, VA.
EXAMPLE 1: Extracellular Domain Homology Screening, to Identifjr Novel Polypeptides and cDNA Encoding Therefor The extracellular domain (ECD) sequences (including the secretion signal sequence, if any) from about 950 known secreted proteins from the Swiss-Prot public database were used to search EST databases. The EST
databases included public databases (e.g., Dayhoff, GenBank), and proprietary databases (e.g. LIFESEQT"', Incyte Pharmaceuticals, Palo Alto, CA). The search was performed using the computer program BLAST or BLAST-2 (AltschuI et al., Methods in Enzymologx 266:460-480 (1996)) as a comparison of the ECD protein sequences to a 6 frame translation of the EST sequences. Those comparisons with a BLAST score of 70 (or in some cases 90) or greater that did not encode known proteins were clustered and assembled into consensus DNA
sequences with the program "phrap" (Phil Green, University of Washington, Seattle, WA).
Using this extrace11u1ar domain homology screen, consensus DNA sequences were assembled relative to the other identified EST sequences using phrap: In addition, the consensus DNA sequences obtained were often (but not always) extended using repeated cycles of BLAST or BLAST-2 and phrap to extend the conse~us:.; -.
sequence as far as possible using the sources of EST sequences discussed above.
Based upon the consensus sequences obtained as described above, oligonucleotides were then synthesized and used to identify by PCR a cDNA library that contained the sequence of interest and for use.as probes to isolate a clone of the full-length coding sequence for a PR~
polypeptide. Forward and reverse PCR
primers generally range from 20 to 30 nucleotides and are often designed to give a PCR product of about 100-1000 by in length. The probe sequences are typically 40-55 by in length: In some cases, additional oligonucleotides are synthesized when the consensus sequence is greater than about 1-I.Skbp. In order to screen several libraries for a full-length clone, DNA from the libraries was screened by PCR amplification, as per Ausubel et al., Current Protocols in Molecular Bioloev, with the PCR primer pair. A positive library was then used to isolate clones encoding the gene of interest using the probe oligonucleotide and one of the primer pours.
The cDNA libraries used to isolate the cDNA clones were .constructed by standard methods using commercially available reagents such as those from Invitrogen, San Diego, CA.
The cDNA was primed with oIigo dT containing a NotI site, linked with blunt to SaII hemikinased adaptors, cleaved with NotI, sized appropriately by gel electrophoresis, and cloned in a defined orientation into a suitable cloning vector (such as pRKB or pRKD; pRKSB is a precursor of pRKSD that does not contain the Sfil site; see, Holmes et al. , Scien , ~:I278 1280 (1991)) in.the unique Xhol and NotT sites: '.
- >.. -. _ .. . , ~...m _. .... .._...___ ~w..~~ ~,.u~~~;,~..~.:.,«,.~~~.~_.~~.~.. .__.._ _._.... _.___._ wo ovls3l$ Pc~'~SO°~
~_X_AMPLE 2: Isolation of cDNA clones~v Amylase Screening 1. Preparation of olio, dT primed eDNA library mRNA was isolated from a human tissue of interest using reagents and protocols from Invitrogen, San Diego, CA (Fast Track 2). This RNA was used to generate an oligo dT primed cDNA library in the vector pRKS D using reagents and protocols from, Life Technologies, Gaithersburg, MD
(Super Script Plasmid System).
In this procedure, the double stranded cDNA was sized to greater than 1000 hp and the SaII/NotI tinkered eDNA
was cloned into XhoIINotI cleaved vector. pRKSD is a cloning vector that has an sp6 transcription initiation site followed by an SfiI restriction enzyme site preceding the XhoIlNatI cDNA
cloning_sites.
2. Preparation of randomprimed cDNA library A secondary cDNA library was generated in order to preferentially represent the 5' ends of the primary cDNA clones. Sp6 RNA was generated from the primary library (described above), and this, RNA was used to generate a random primed cDNA library in the vector pSST-AMY.O using reagents and protocols from Life Technologies (Super Script Plastnid System, referenced above). In this procedure the double stranded eDNA
was sized to 500-1000 bp, tinkered with blunt to NotI adapters, cleaved with SfiI, and cloned into Sfit/NotI
cleaved vector. pSST-AMY.O is a cloning vector that has a yeast alcohol dehydrogenase promoter preceding the eDNA cloning sites and the mouse amylase sequence (the mature sequence without the secretion signal) followed by the yeast alcohol dehydrogenase terminator, after the cloning sites. Thus, cDNAs cloned into this vector that are fused in frame with amylase sequence will Lead to the secretion of amylase from appropriately' -transferred yeast colonies.
3. Transformation and Detection DNA from the Library described in paragraph 2 above was chilled on ice to which was added electrocampetent DHIOB bacteria (Life Technologies, 20 ml). The bacteria and vector mixture was then electroporated as recommended by the manufacturer. Subsequently, SOC media (Life Teeltnotogies, l ml) was added and the ttitxture was incubated at 37°C for 30 minutes. The iransformants were then plated onto 20 standard i50 mm LB plates containing ampicillin anit incubated for 16 hours (37°C). Positive colonies ere scraped off the plates and the DNA was isolated from the bacterial pellet using standard protocols, e.g. CsCi-gradient. 'Ihe purified DNA was then carried'on to the yeast protocols below.
The yeast methods were divided into three categories:- (I) Transformation of yeast with the plasmidlcDNA combined vector; (2) Detection and isolation of yeast clones secreting amylase; and (3) PCR
amplification of the insert directly from the yeast colony and purification of the DNA for sequencing and further analysis.
The yeast strain used was HD56-SA (ATCC-90785). This strain Itas the following genotype: MAT:.-.
alplia, ,ura3-52,--ieu2-3; Ieu2-112, his3-1~, Itis3-15. MAL'~. SUC+, GAL*.
Preferably, .yeast: muta~c caa'y ~ .
employed that have deficient post-translationat pathways. Snot mutants may have translocation deficient alleles in sec7l, sec72, sec62, with truncated sec7l being most preferred.
Alternatively, antagonists (including anttsetue nucleotides andlor Iigands) which interfere with the normal operation of these genes, other proteins *-trademark wo .oin~ts PCT/US0023328 implicated in this post translation pathway (c.g., SECGIp, SEC72p, SEC62p, SEC63p, TDJIp or SSAIp-4p) or the complex formation of these proteins may also be preferably employed in combination with the amylase-expressing yeast.
Transformation was performed based on the protocol outlined by Gietz et al., Nucf. Acid. Res., 20:1425 (1992). Transformed cells were then inoculated from agar into YEPD
complex media broth (100 ml) and grown overnight at 30°C. The YEPD broth was prepared as described in Kaiser et al., Methods in Yeast Genetics, Cold Spring Harbor Press, Cold Spring Harbor, NY, p. 207 (1994). The overnight culture was then diluted to about 2 x 106 cellslml (approx. ODD=0.1) into fresh YEPD broth (500 ml) and regrown to I x 10' cells/m1 (approx. OD,~=0.4-0.S).
The cells were then harvested and prepared for transformation by transfer into GS3 rotor bottles in a I0 Sorval GS3 rotor at 5,000 rpm for 5 minutes, the supernatant discarded, and then resuspended into sterile water, and centrifuged again in 50 ml falcon tubes at 3,500 rpm in a Beckman GS-6KR
centrifuge. The supernatant was discarded and the cells were subsequently washed with LiAclTE (10 ml, 10 mM Tris-HCl, I mM EDTA
pH 7.5, 100 mM Li200CCHl), and resuspended into LiAc/TE (2.5 ml).
Transformation took place by mixing the prepared cells ( 100 pl) with freshly denatured single stranded salmon testes DNA (Lofstrand Labs, Gaithersburg, MD) and transforming DNA (1 pg, vol. < 10 Fd) in microfuge tubes. The mixture was mixed briefly by vortexing, then 40'~ PEG/TE
(600 ~d, 4096 polyethylene glycol-4000, 10 mM Tris-HCI, 1 mlvt EDTA, I00 mM Lii00CCHj, pH 7.5) was added.
This mixture was gently mixed and incubated at 30°C while agitating for 30 minutes. The cells were then heat shocked.ae 42°C
for 15 minutes, andnhe reaction vessel centrifuged in a mierofuge at 12,000 rpm for 5-10 seconds, decanted and resuspended into TE (500 pl, i0 mM Tris-HCI, 1 mM EDTA pH 7.5) followed by recentrifugation. The cells were then diluted iota TE (1 ml) and aliquots (200 Ed) were spread onto the selective media previously prepared in 150 mm growth plates (VWR).
Alternatively, instead of multiple small reactions, the transformation was gerforraed using a single; large scale reaction, wherein reagent amounts were scaled up accordingly.
2$ The scloctive media ustd was a synthetic complete dextrose agar lacking uracil (SCD-Ura) prepared as described in Kaiser et al., wtetttods in Yeast Gene~'~cs, Cold Spring Harbor Press, Cold Spring Harbor, NY, p.
208-210 (1994). Transfomiants were grown at 30°C for 2-3 days.
The detection of colonies secreting amylase was performed by including red starch in the selective growth media. Starch was coupled to the red dye (Reactive Red-I20, Sigma) as per the procedure described by Biely et aL, Anal. Biochem., 172:176-I79 (1988). The coupled starch was incorporated into the SCD-Ura agar plates at a final concentration of O.IS ~ (w/v), and was buffered with potassium phosphate to a pH of 7.0 (50-100 mM final concentration).
The positive.coloaies were picked and streaked across fresh selective media (onto 150 mm plates) is order to obtaiwwell, isolated and identifiable single colonies, well isolated Single colonies:positive for.amylasc secretion were detected by direcx incorporation of red search into buffered SCD-Ura agar. Positive colonies were determined by their ability to break down starch resulting in a clear halo around the positive colony visualized directly.
*-trademark wo omus rcrms°°rz33~$
4, Isolation of DNA by PC~.~mnlifcation When a positive colony was isolated, a portion of it was picked by a toothpick and diluted into sterile water (30 Vii) in a 96 welt plate. At this time, the positive colonies were either frozen and stored for subsequent analysis or immediately amplified. An aliquot of cells (5 ~d) was used as a template for the PCR reaction in a 25 ~l volume containing: 0.5 gel Klentaq (Clontech, Palo Alto, CA); 4.0 ~,1 10 mM dNTP's (Perkin Elmer-Cetus); 2.5 ~cl Kentaq buffer (Clontech); 0.25 of forward oligo 1; 0.25 ~.1 reverse oligo 2; 12.5 ~.1 distilled water.
The sequence of the forward oligonucleotide 1 was:
5'-TGTAAAACGACGGCCAGTTAAATAGACCTGCAATTATTAATCT-3'-- (SEQ ID N0:169) The sequence of reverse oligonucieotide 2 was:
5'-CAGGAAACAGCTATGACCACCTGCACACCTGCAAATCCATT-3' (SEQ ID N0:170) IO PCR was then performed as follows:
a. Denature 92°C, 5 minutes b. 3 cycles of: Denature 92°C, 30 seconds Anneal ~ 59°C, 30 seconds IS Extend ~ 72°C, 60 seconds c. 3 cycles of: Denature 92°C, 30 seconds Anneal 57°C, 30 seconds Extend 72°C, 60 seconds d. 25 cycles of: Denature 92°.C, 30 seconds Anneal 55°C, 30 seconds Extend 72°C, b0 seconds e. Hold 4°C
The underlined regions of the oligonucleotides annealed to the ADH promoter region and the amylase region, respectively, and amplified a 307 by region from vector ASST-AMY.O
when no insert was present.
Typically, the first 18 nucleotides of the 5' end of these oligonucleotides contained annealing sites for the .sequencing primers. Thus, the total product of the PCR reaction fsiaan an empty vector was 343 bp. However, signal sequence-fused eDNA resulted in considerably longer nucleotide sequences.
Following the PCR, an aliquot of the reaction (S fd) was examined by agarose gel electrophoresis in a 196 agarose gel using a Tris-Borate-EDTA ('TBE) buffering system as described by Sambrook et at., supra.
Clones resulting .in a single strong PCR product larger than .400 by were fittther analyzed by DNA sequencing *.
after purification with a 96 Qiaquiek PCR clean-up column (Qiagen Ine., Chatsworth, CA).
EXAMPLE 3: ~soIation of cDNA Clones Using Sienal Aleorithm Anal,~rsis Various polypeptide-encoding nucleic acid sequences were identified by applying a proprietary signal sequence'findizig algoritlun develojped 6y Cicnetitech, Inc.-(Sauth San F=artcisco, CA) upon ESfs as welt as clustered and assembled EST fragments fmm public (e.g., GenBank) and/or private (LIFESEQ~, htcyte Pharmaceuticals, Inc., Palo Alta, CA) databases. The signal sequence algorithm computes a secretion signal score based on the character of the DNA nucleotides surrounding the first and optionally the second methionine *-trademark WO 01/16318 PCTlLTS00123328 codon(s) (ATG) at the S'-end of the sequence or sequence fragment under consideration. The nucleotides following the first ATG must code for at least 35 unambiguous amino acids without any stop colons. If the first ATG has the required amino acids, the second is not examined. If neither meets the requirement, the candidate sequence is not scored. In order to determine whether the EST sequence contains an authentic signal sequence, the DNA and corresponding amino acid sequences surrounding the ATG colon are scored using a set of seven sensors (evaluation parameters) known to be associated with secretion signals.
Use of this algorithm resulted in the identification of numerous polypeptide-encoding nucleic acid sequences.
EXAMPLE 4: Isolation of cDNA Clones Encoding Human PRO Poly~e~tides Using the techniques described in Examples 1 to 3 above, numerous full-length cDNA clones were identified as encoding PRO poiypeptides as disclosed herein. These cDNAs were then deposited under the terms of the Budapest Treaty with the American Type Culture Collection, 10801 University Blvd., Manassas, VA
20110-2209, USA (ATCC) as shown in Table 7 below.
Table 7 Material ATCC Dep. No. Deposit Date DNA26843-1389 203099 August 4, 1998 DNA30867-1335 209807 April 28, 1998 DNA34431-1177 209399 October 17, 1997 DNA38268-1188 209421 October 28, 1997 DNA40621-1440 209922 June 2, 1998 . _ v..

DNA40625-1189 209788 , April 2L, 1998 DNA45409-2S 203579 January 12, 1999 DNA4549S-1550 203156 August 25, 1998 DNA49820-1427 209932 June 2, 1998 DNA56406-1704 203478 November 17, 1998 DNASb410-1414 209923 June 2, 1998 DNA56436-1448 209902 May 27, 1998 DNA56855-1447 203004 June 23, 1998 DNA56860-1510 209952 June 9, 1998 DNA56862-1343 203174 September 1, 1998 DNAS6868-1478 203024 June 23, 1998 DNAS6869-1S4S 203161 August 2S, 1998 DNA57704-1452 209953 June 9, 1998 DNAS8723-1588 203133 August 18, 1998 DNA5782?-1493 203045 July 1, 1998 DNA58737-1473 203136 August 18, 1998 DNA58846-1409 209957 June 9, 1998 DNA58850-1495 209956 June 9, 1998 DNA58855-1422 203018 June 23, 1998 DNA59211-1450 209960 June 9, 1998 DNA59212-1627 203245 September 9, 1998 DNA59213-1487 209959 June 9, 1998 DNA59605-1418 203005 June 23~ 1998 DNA59609-1470 209963 June 9, 1998 DNA59610-1556 209990 June 16, 1998 DNA59837-2545 203658 February 9, 1999 DNA59844-2542 203650 February 9, 1999 DNAS9854-1459 209974 June 16, 1998 "...". .,..., .".":u....,..,.. ,..,.~~> t-~,.,x«mds:~;: ,~. .".~;~~~rm.
~~~x~a~~..:m~surra~aw .:~-_-....~u,..~.:"w..~: ,..."M ....,...._ .. .. ..
_..._......._._-..~."~,..»"...""".x,~,....o""....n, .~.,,..-:_.,..
_...m.~"...M ...,.....w....;..,...,.,.

wo oin63><s Table 7 tcont') DNA60625-1507 209975 June 16, 1998 DNA60629-1481 209979 June 16, 1998 DNA61755-1554 20311'2 August 11, 1998 DNA62812-1594 203248 September 9, 1998 DNA62815-1576 203247 September 9, 1998 DNA64881-1602 203240 September 9, 1998 DNA64886-1601 203241 September 9, 1998 DNA64902-i667 203317 October 6, 1998 DNA64950-1590 203224 September 15, 1998 DNA65403-1565 203230 September 15, 1998 DNA66308-1537 203159 August 25, 1998 DNA66519-1535 203236 September 15, 1998 DNA66521-1583 203225 September 15, 1998 DNA66658-1584 203229 September 15, 1998 DNA66660-1585 203279 September 22, 1998 DNA66663-1598 203268 September 22, 1998 DNA66674-1599 203281 September 22, 1998 DNA68862-2546 203652 February 9, 1999 DNA68866-1644 203283 September 22, 1998 DNA68871-1638 203280 September 22, 1998 DNA68880-1676 203319 October 6, 1998 DNA68883-1691 203535 December 15, 1998 DNA68885-1678 203311 October 6, 1998 DNA71277-1636 203285 September 22, 1998 , DNA73727-1673 - 203459 November 3, 1998 DNA73734-1680 203363 October 20, 1998 DNA73735-1681 203356 October 20, 1998 DNA76393-1664 203323 October 6, 1998 DNA77301-1708 203407 October 27, 1998 DNA77568-1626 203134 August 18, 1998 DNA77626-1705 203536 December 15, 1998 DNA81754-2532 203542 December 15, 1998 DNA81757-2512 203543 ~ December I5, 1998 DNA82302-2529 203534 December 15, 1998 DNA82340-2530 203547 December 22, 1998 DNA83500-2506 203391 October 29, 1998 DNA84920-2614 203966 Apri127, 1999 DNA85066-2534 203588 January 12, 1999 DNA86571-2551 203660 February 9, 1999 DNA87991-2540 203656 February 9, 1999 DNA92238-2539 203602 January 20, 1999 DNA96042-2682 PTA-382 July 20, 1999 DNA96787-2534 203589 January 12, 1999 DNA12S185-2806 PTA-1031 December 7, 1999 DNA147531-2821 PTA-1185 3anuary I1, 2000 DNA115291-2681 PTA-202 June 8, 1999 DNA164625-28890PTA-I53S March 2I, 2000 DNA131639-2874 PTA-1784 April 25, 2000 DNA79230-2525 203549 December 22, 1998 These deposits were made under the provisions of the Budapest Treaty on the International Recognition of the Deposit of Microorganisms for the Purpose of Patent Procedure and the Regulations thereunder (Budapest Treaty). This assures maintenance of a viable culture of the deposit for 30 years from the date of deposit. The _. . . , a.... ,r * .oNB'~s : . dY..,.wC v "xa~ri.~sro-V~~Sac,~:~Y~,v?e ., y , ~~wn . ~u ' "'A .:.~4F~5YC~:"Y'.H~~~.~' '~-rw ~ "%~~""~, "~' WO 01/16318 PCT/US001?3328 deposits will be made available by ATCC under the tectns of the Budapest Treaty, and subject to ut xgree»nt between Genentech, lnc. and ATCC, which assures permanent and unrestricted availability of the googeny of the culture of the deposit to the public upon issuance of the pertinent U.S.
patent or upon laying open to the public of any U.S, or foreign patent application, whichever comes first, and assures availability of the progeny to one determined by the U.S. Commissioner of Patents and Trademarks The assignee of the gresent application has agreed that if a culture of the materials on deposit should die or be lost or destroyed when cultivated under suitable conditions, the materials will be promptly replaced on notification with another of the same. Availability of the deposited material is not to be construed as a license IO to practice the invention in contravention of the rights granted under the authority of any government in accordance with its patent laws.
EXAMPLE 5: Use of PRO as a hvbridization probe The following method describes use of a nucleotide sequence encoding PRO as a hybridization probe.
DNA comprising the coding sequence of full-length or mature PRO as disclosed herein is employed as a probe to screen for homologous DNAs (such as those encoding naturally-occurring variants of PRO) in human .
tissue cDNA libraries or human tissue genomic libraries.
Hybridization and washing of filters coruaining either library DNAs is performed under the following high stringency conditions. Hybridization of radiolabeled PRO-derived probe to the filters is performed in a:
solution of 50~ forznatmide, Sx SSC, 0.19o SDS, 0.1 % sodium pyrophosphate, 50 mM sodium phosphate, pH
6.8, 2x Denhardt's solution, and 10 96 dextran sulfate ax 42°C for 20 hours. Washing of the filters is performed in an aqueous solution of 0.1x. SSC and 0. I ~ SDS at 42°C.
DNAs having a desired sequence identity with the DNA encoding full-length native sequence PRO can then be identified using standard techniques known in the art.
EXAMPLE 6: Expression of PRO~n E. anti This example illustrates preparation of an unglycosylated form of PRO by recomb'mant expression in E. colt.
The DNA sequence etxodimg PRO is initially amplified using selected PCR
primers. The primers should contain restriction enzyme sites which correspond to the restriction enzyme sites on the selected expression vector. A variety of expression vectors may be employed. An example of a suitable .vector is pBR322 (derived from E. colt; see Bolivar et al., Gene, 2:95 (1977)) which contains genes for ampicillin and tetracycline resistance. The vector is digested with restriction enzyme and dephosphorylated. The PCR
amplified sequences are Cheat Iigated into the vector. The vectpr will preferably include sequences which encode for an antibiotic resistance gene, a trp promoter, a polyhis leader (including the first six STII codoas, polyhis sequence, and enterokinase cleavage site), the PRO coding region, lambda transcriptional terminator, and an argU gene.

....~."......,.. ,.....", ,.., .m< .-~,. ,~ u.." .k., -. ,.~ ."."~t.~"..~..>."
.,~ .x~..ec~~uro-~

WO 01116318 PCTlUS00/23328 The ligation mixture is then used to transform a selected E. coli strain using the methods described in Sambrook et al. , supra. Transformants are identified by their ability to grow on LB plates and antibiotic resistant colonies are then selected. Plasmid DNA can be isolated and confirmed by restriction analysis and DNA
sequencing.
Selected clones can be grown overnight in liquid culture medium such as LB
broth supplemented with antibiotics. The overnight culture may subsequently be used to inoculate a larger scale culture. The cells are then grown to a desired optical density, during which the expression promoter is turned on.
After culturing the cells for several more hours, the cells can be harvested by centrifugation. The cell pellet obtained by the centrifugation can be solubilized using various agents known in the art, and the solubilized PRO protein can then be purified using a metal chelating column under conditions that allow eight binding of the protein.
PRO may be expressed in E, coli in a poly-His tagged form, using the following procedure. The DNA
encoding PRO is initially amplified using selected PCR primers. The primers will contain restriction enryme sites which correspond to the restriction enzyme sites on the selected expression vector, and other useful sequences providing for efficient and reliable translation initiation, rapid purification on a metal chelation column, and proteolyric removal with enterokinase. The PCR-amplified, poly-His tagged sequences are then ligated into an expression vector, which is used to transform an E. toll host based on strain 52 (W3110 fuhA(tonA) lop galE rpoHts(htpRts) clpP(IacIq): Transformants are first grown in LB containing 50 mg/ml' carbenicilIin at 30°C with shaking until an O.D.b00 of 3-5 is reached.
Cultures are then diluted 50-100 fold into CRAP media (prepared by mixing 3.57 g (NH4)2S04, 0.71 g sodium cierate~2H20, 1.07 g KCI, 5.36 g Difco yeast extract, 5.36 g Sheffield hycase SF in 500 mL water, as well as 110 mM
MPOS, pH 7.3, 0.5596 (w/v) glucose and 7 mM MgS04) and grown for approximately 20-30 hours at 30°C
with shaking. Samples are removed to verify expression by SDS-PAGE analysis, and the bulk culture is centrifuged to pellet the cells. Cell pellets are frozen until purification and refolding.
E. toll paste.from 0,5 to 1 L fermentations (6-10 g pellets) is resuspended in 10 volumes (wlv) in 7 M
2S guanidine, 20 mM Tris, pH 8 buffer. Solid sodium sulfite and sodium tetrathionate is added to make final concentrations of O.1M and 0.02 M, respectively, and the solution is stirred overnight at 4°C. This step results in a denatured protein with all cysteine residues blocked by sulfitolization.
The solution is centrifuged at 40,000 rpm in a Beckman Ultracentifuge for 30 min. The supernatant is diluted with 3-5 volumes of metal chelat~
column buffer (6 M guanidine, 20 rnM Tris, pH 7.4) and filtered through 0.22 micron filters to clarify. The clarified extract is loaded onto a 5 ml Qiagen Ni-NTA metal chelate column equilibrated in the metal chelate column buffer. The column is washed with additional buffer containing 50 mM
imidazole (Calbiochem, Utrol grade), pH 7.4. The protein is eluted with buffer containing 250 mM imidazole.
Fractions containing the desired protein are pooled and stored at 4°C. Protein concentration is estimated by its absorbance at 280 nm using the calculated extinetioti coeffic'cent baseii ozi its amino acid sequence.
The proteins are refolded by diluting the sample slowly into freshly prepared refolding buffer consisting of: 20 mM Tris, pH 8.6, 0.3 M NaCI, 2.5 M urea, 5 mM cyseeine, 20 mM glycine and I mM EDTA.
Refolding volumes are chosen so that the final protein concentration is between 50 to 100 microgramslml. The WO O1lI6318 pCT~~0~3~
refolding solution is stirred gently at 4 °C for 12-36 hours. The refolding reaction is quenched by the addition of TFA to a final concentration of 0.4'~ (pH of approximately 3). Before further purification of the protein, the solution is filtered through a 0.22 micron filter and acetonitrile is added to 2-I0~ final concentration. The refolded protein is chromatographed on a Poros RIlH reversed phase column using a mobile buffer of 0.I ~
TFA with elution with a gradient of acetonitrite from 10 to 80% . Aliquots of fractions with A280 absorhance are analyzed on SDS polyacrylamide gels and fractions containing homogeneous refolded protein are pooled.
Generally, the properly refolded species of most proteins are eluted at the lowest concentrations of acetonitrilc since those species are the most compact with their hydrophobic interiors shielded fram interaction with the reversed phase resin. ,Aggregated species are usually eluted at higher acetonitrile concentrations. In addition to resolving misfolded forms of proteins from the desired form, the reversed phase step also removes endotoxin from the samples.
Fractions containing the desired folded PRO polypeptide are pooled and the acetonitrile removed using a gentle stream of nitrogen directed at the solution. Proteins are formulated into 20 mM Hepes, pH 5.8 with 0.14 M sodium chloride and 4 ~ mannitol by dialysis or by get filtration using G25 Superfine (Pharmacia) resins equilibrated in the formulation buffer and sterile filtered.
IS Many of the PRO polypeptides disclosed herein were successfully expressed as described above.
EXAMPLE 7: ExQzession of PRO in mammaIiari cells This example illustrates preparation of a potentially glycosylated form of PRO
by i~ecotribiiiaiit expression in mammalian cells.
The vector, pRICS (see EP 307,247, published March 15, 1989), is employed as the expression vector.
Optionally, the PRO DNA is Iigated into pRICS with selected restriction enzymes to allow insertion of the PRO
DNA using tigation methods such as described in Sambrook et aL, supra. The resulting vector is called pRICS-PRO.
In one embodiment, the selected host cells may be 293 cells. Human 293 cells (ATCC CCL 1523) are grown to confluence is tissue culture plates in medium such as DMEM
supplemented with fetal calf serum and optionally, nutrient components and/or antibiotics. About 10 ~:g pRKS-PRO DNA
is mixed with about 1 P,g DNA encoding the VA RNA gene [Thimmappaya et al., Cell, X1_:543 (1982)] and dissolved in 500 Ecl of 1 mM
Tcis-HCI, 0.1 mM EDTA, 0.227 M CaCI~. To this mixture is added, drapwise, 500 ~d of 50 mM -HBPES (pH
7.35), 280 mM NaCt, 1.5 mM NaPO,, and a precipitate is allowed to form for 10 minutes at 25°C. The precipitate is suspended and added to the 293 cells and allowed to settle for about four hours at 37°C. The culture medium is aspirated off and 2 mI of 209 glycerol in PBS is added for 30 seconds. The 293 cells are then washed with serum free medium, fresh medium is added and the cells are incubated for about S days.
Approximately 24 hours after the transfections, the culture medium is removed and replaced with culture medium (alone) or culture medium containing 200 ~cCalml ~S-cysteine and 20Q
~cCi/mLuS-methzonine~ 'After a 12 hour incubation, the conditioned medium is collected, concentrated on a spin fitter, and loaded onto a 15 ~O
SDS gel. The processed gel may be dried and exposed to film for a selected period of time to reveal the presence of PRO polypeptide. The cultures containing transfected cells may undergo further incubation (in *-trademark $4 ,. ..,. " d .. ".. a....s,. n ..:",w~_ n~- .s .w. Wr .r....,~na ..~cs;rs»s ~e"~a~~-'~~'~,:w~'*;a~~°T"~-'""°"~"~"...~.b.«..,~...,.-n..--~, -~m~. ~°~----"' serum free medium) and the medium is tested in selected bioassays.
In an alternative technique, PRO may be introduced into 293 cells transiently using the dextran sulfate method described by Somparyracet al., Proc. Natl. Acad.,Sci., 12:7575 (1981).
293 cells are grown to maximal density in a spinner flask and 700 p.g pRKS-PRO DNA is added. The cells are first concentrated from the spinner flask by centrifugation and washed with PBS. The DNA-dextran precipitate is incubated on the cell pellet for four hours. The cells are treated with 209b glycerol for 90 seconds, washed with tissue culture medium, and re-introduced into the spinner flask containing tissue culture medium, S p.g/ml bovine insulin and 0.1 ~cg/ml bovine transferrin. After about four days, the conditioned media is centrifuged and filtered to remove cells and debris. The sample containing expressed PRO can then be concentrated and purified by any selected method, such as dialysis and/or column chromatography.
In another embodiment, PRO can be expressed in CHO cells. The ARKS-PRO can be transfected into CHO cells using known reagents such as CaPO,, or DEAF-dextran. As described above, the cell cultures can be incubated, and the medium replaced with culture medium (alone) or medium containing a radiolabel such as 3sS-methionine. After determining the presence of PRO polypeptide, the culture medium may be replaced with serum free medium. Preferably, the cultures are incubated for about 6 days, and then the conditioned medium is harvested. The medium containing the expressed PRO can then be concentrated and purified by any selected method.
Epitope-tagged PRO may also be expressed in host CHO cells. The PRO may be subcloned out of the pRKS vector. The subclone insert can undergo PCR to fuse in frame with a selected epitope tag such as a poly-his tag into a Baculovirus expression vector. The poly-his tagged PRO insert can then be subeioned into a SV40 driven vector containing a selection marker such as DHFR for selection of stable clones. Finally, the CHO cells can be transfected (as described above) with the SV40 driven vector. Labeling may be performed, as described above, to verify expression. The culture medium containing the expressed poly-His tagged PRO can then be concentrated and purified by any selected method, such as by Ni2+-chelate affinity chromatography.
PRO may also be expressed in CHO and/or COS cells by a transient expression procedure or in CHO
cells by another stable expression procedure.
Stable expression in CHO cells is performed using the following procedure. The proteins are expressed as an IgG construct (immunoadhesin), in which the coding sequences for the soluble forms (e.g. extracellular domains) of the respective proteins are fused to an IgG l constant region sequence containing the hinge; . CH2 and CH2 domains andlor is a poly-His tagged form.
Following PCR amplification, the respective DNAs are subcloned in a CHO
expression vector using standard techniques as described in Ausubel et al., Current Protocols of Molecular Biolo~y, Unit 3.16, John Wiiey and Sons (1997). CHO expression vectors are constructed to have compatible restriction sites S' and 3' of the DNA of interest to allow the convenient shuttling of eDNA's. The vector used expression in CHO cells is as described in Lucas et al., Nucl. Acids Res. 24:9 (1774-1779 (1996), and uses the SV40 early promoter/enhancer to drive expression of the cDNA of interest and dihydrofolate reductase (DHFR). DHFR
expression permits selection for stable maintenance of the plasmid following transfection.
_...._. .,~, _ _ .,_~.ee_ .. Y~. . ... _9_~ ~..~..~~.. ~;~,~.~,~~~:",.,~",.~.-...a.-_-.--.--_._ .._._ WO O1/I6318 . PCT/USOOIZ3328 Twelve micrograms of the desired plasmid DNA is introduced into approximately 10 million CHO cells using commercially available transfection reagents Superfect' (Quiagen), Dosper° or Fugene' (Boehringer Mannheim). The cells are grown as described in Lucas et al., supra.
Approximately 3 x 10-' cells are frozen in an ampule for further growth and production as described below.
The ampules containing the plasmid DNA are thawed by placement into water bath and mixed by vortexing. The contents are pipetted into a centrifuge tube containing 10 mLs of media and centrifuged at 1000 rpm for 5 minutes. The supernatant is aspirated and the cells are resuspended in 10 mL of selective media (0.2 ~m filtered PS20 with 5~ 0.2 gem diafiltered fetal bovine serum). The cells are then aiiquoted into a 100 mL
spinner containing 90 mL of selective media. After I-2 days, the cells are transferred into a 250 mL spinner filled with 150 mL selective growth medium and incubated at 37°C. After another 2-3 days, 250 mL, 500 mL
and 2000 mL spinners are seeded with 3 x 105 cells/mL. The cell media is exchanged with fresh media by centrifugation and resuspension in production medium. Although any suitable CHO media may be employed, a production medium described in U.S. Patent No. 5,122,469, issued June 16, 1992 may actually be used. A
3L production spinner is seeded at 1.2 x 106 cells/mL. On day 0, the cell number pH ie determined. On day 1, the spinner is sampled and sparging with filtered air is commenced. On day 2, the spinner is sampled, the temperature shifted to 33°C, and 30 mL of 500 g/L glucose and 0.6 mL of 10°k antifoam (e.g., 3596 polydimethylsiloxane emulsion, Dow Corning 365 Medical Grade Emulsion) taken.
Throughout the production, the pH is adjusted as necessary to keep it at around 7.2. After 10 days, or until the viability dropped below 70 ~ , the cell culture is harvested by centrifugation and filtering through a 0.22 ~m filter. .The filtrate was either stored at 4°C or immediately loaded onto columns for purification.
For the poly-His tagged constructs, the proteins are purified using a Ni-NTA
column (Qiagen). Before purification, imidazole is added to the conditioned media to a concentration of 5 mM. The conditioned media is pumped onto a 6 ml Ni-NT'A column equilibrated in 20 mM Hepes, pH 7.4, buffer containing 0.3 M NaCI
and 5 mM imidazole at a flow rate of 4-5 ml/min. at 4°C. After loading, the column is washed with additional equilibration buffer and the protein eluted with equilibration buffer containing 0.25 M imidazole. The highly purified protein is subsequently desalted into a storage buffer containing 10 mM Hepes, 0.14 M NaC1 and 49b rnannitol, pH 6.8, with a 25 ml G25 Superfine (Pharmacia) column and stored at -80°C.
Imrnunoadhesin (Fc-containing) constructs are purified from the conditioned media as follows. The conditioned medium is pumped onto a 5 ml Protein A column (Pharmacia) which had been equilibrated in 20 mM Na phosphate buffer, pH 6.8. After loading, the column is washed extensively with equilibration buffer before elution with I00 mM citric acid, pH 3.5. The eluted protein is immediately neutralized by collecting 1 mI fractions into tubes containing 275 uL of 1 M Tris buffer, pH 9. The highly purified protein is subsequently desalted into storage huffer as described above for the poly-His tagged proteins. The homogeneity is assessed by SDS polyacrylamide gels and by N-terminal amino acid sequencing by Edman degradation.
Many of the PRO polypeptides disclosed herein were successfully expressed as described above. , $6 r..... , , ,u._..,.,x ,vcw-.,-..~.,.. .~, :mmu-. w.r...:. ~.. ,...,..m.
".,..,.. ,. ,. »., _,.,.,,:qH..~.y~yyp,s~aa~dum,~. ~tu's~agerz-.~-,~ww.N'~.,w :a~cmxa, .~'',xc~ .....~",.,..~..n..".,-..e....,...<....,...... ...,-.~«..,.....o-.",."."....»,.,~...

EXAMPLE 8: Expression of PRO in Yeast The following method describes recombinant expression of PRO in yeast.
First, yeast expression vectors are constructed for intracellular production or secretion of PRO from the ADH2/GAPDH promoter. DNA encoding PRO and the promoter is inserted into suitable restriction enzyme sites in the selected plasmid to direct intracellular expression of PRO. For secretion, DNA encoding PRO can be cloned into the selected plasmid, together with DNA encoding the ADH2IGAPDH
promoter, a native PRO
signal peptide or other mammalian signal peptide, or, for example, a yeast alpha-factor or invertase secretory signal/leader sequence, and linker sequences (if needed) for expression of PRO.
Yeast cells, such as yeast straia AB 110, can then be transformed with the expression plasmids described above and cultured in selected fermentation media. The transformed yeast supernatants can be analyzed by 10' precipitation with 10 % trichloroacetic acid and separation by SDS-PAGE, followed by staining of the gels with Coomassie Blue stain.
Recombinant PRO can subsequently be isolated and purified by removing the yeast cells from the fermentation medium by centrifugation and then concentrating the medium using selected cartridge filters. The concentrate containing PRO may further be purified using selected column chromatography resins.
Many of the PRO polypeptides disclosed herein were successfully expressed as described above.
EXAMPLE 9: Expression of PRO in Baculovirus-Infected Insect Cells The following method describes recombinant expression of PRO in Baculovirus-infected insect cells. .
The sequence coding for PRO is fused upstream of an epitope tag contained within a baculovirus expression vector. Such epitope tags include poly-his tags and immunoglobulin tags (like Fc regions of IgG).
A variety.of plasmids may be employed, including plasmids derived from commercially available plasmids such as pVL1393 (Novagen). Briefly, the sequence encoding PRO or the desired portion of the coding sequence of PRO such as the sequence encoding the extracellular domain of a transmembrane protein or the sequence encoding the mature protein if the protein is extracellular is amplified by PCR with primers complementary to the 5' and 3' regions. The 5' primer may incorporate flanking (selected) restriction enzyme sites. The product is then digested with those selected restriction enzymes and subcloned into the expression vector.
Recombinant baculovirus is generated by co-transfecting the above plasmid and BaculoGoldT"" virus DNA (Pharmingen) into Spodoptera frugiperda ("SP9") cells (ATCC CRL 1711) using lipofectin (commercially available from GIBCO-BRL}. After 4 - 5 days of incubation at 28°C, the released viruses are harvested and used for further amplifications. Viral infection and protein expression are performed as described by O'Reilley et al., Baculovirus ex~,ression vectors. A Laboratory Manual, Oxford: Oxford University Press ( 1994).
Expressed poly-his tagged PRO can then be purified, for example, by Ni2+-chelate affinity chromatography as follows. Extracts are prepared from recombinant virus-infected Sf9 cells as described by Rupert et al., Nature, X62:175-179 (1993). Briefly, Sf9 cells are washed, resuspended in sonication buffer (25 mL Hepes, pH 7.9; 12.5 mM MgGh; 0.1 mM EDTA; l0qb glycerol; 0.1 R& NP-40; 0.4 M KCl), and sonicated twice for 20 seconds on ice. The sonicates are cleared by centrifugation, and the supernatant is diluted 50-fold in loading buffer (50 mM phosphate, 300 mM NaCI, 109b glycerol, pH 7.8) and filtered through a 0.45 ~cm WO 0111631$ PCT/USOOI233Z8 filter. A Niz+-NTA agarose column {commercially available from Qiagen) is prepared with a bed volume of 5 mL, washed with 25 mL of water and equilibrated with 25 mL of loading buffer.
The filtered cell extract is loaded onto the column at 0.5 mL per minute. The column is washed to baseline Az~ with loading buffer, at which point fraction collection is started. Next, the column is washed with a secondary wash buffer (50 mM
phosphate; 300 mM NaCI, 10% glycerol, pH 6.0), which elutes nonspecifically bound protein. After reaching AZ~ baseline again, the column is developed with a 0 to 500 mM lmidazole gradient in the secondary wash buffer. One mL fractions are collected and analyzed by SDS-FAGS and silver staining or Western blot with Ni2+-NTA-conjugated to alkaline phosphatase (Qiagen). Fractions containing the eluted His,o-tagged PRO are pooled and dialyzed against loading buffer.
Alternatively, purification of the IgG tagged (or Fc tagged) PRO can be performed using known chromatography techniques, including for instance, Protein A or protein G
column chromatography.
Many of the PRO polypeptides disclosed herein were successfully expressed as described above.
EXAMPLE 10: Preparation of Antibodies that Bind PRO
This example illustrates preparation of monoclonal antibodies which can specifically bind PRO.
Techniques for producing the moitoclonai antibodies are known in the art and are described, for instance, in Goding, a ra. Immunagens that may be employed include purified PRO, fusion proteins containing PRO, and cells expressing recombinant PRO on the cell surface. Selection of the immunogen can be made by the skilled artisan without undue experimentation.
Mice, such as Balblc, are immunized with the PRO immunogen emulsified in complefe Freund's adjuvant and injected subeutaneously or intraperitoneally in an amount from 1-I00 micrograms. Alternatively, the immunogen is emulsified in MPL-TDM adjuvant (Ribi Immunochemical Research, Hamilton, MT) and injected into the animal's hind foot pads. The immunized mice are then boosted 10 to I2 days later with additional immunogen emulsified in the selected adjuvant. Thereafter, for several weeks, the mice may also be boosted with additional immunization injections. Serum samples may be periodically obtained from the mice by retro-orbital bleeding for testing in ELISA assays to detect anti-PRO
antibodies.
After a suitable antibody titer has been detected, the animals "positive" for antibodies can be injected with a final intravenous injection of PRO. Three to four days later, the mice are sacrificed and the spleen cells .
are harvested. The spleen cells are then fused (using 3596 polyethylene glycol) to a selected murine myeloma cell line such as P3X63AgU.l, available from ATCC, No. CRL 1597. The fitsions generate hybridoma cells which can then be plated in 96 well tissue culture plates containing HAT
(hypoxanthine, aminopterin, and thymidine) medium to inhibit proliferation of non-fused cells, myeloma hybrids, and spleen cell hybrids.
The hybridoma cells will be screened in an ELISA for reactivity against PRO.
Determination of "positive" hybridoma cells secreting the desired monoclonal antibodies against PRO is within the skill in the art.
The positive h~bridoma cells can be injected intraperitoneally into syngeneic:
Balb/c mice to produce _ , ascites containing the anti-PRO monoclonal antibodies. Alternatively, the hybridoma cells can be grown in tissue culture flasks or roller bottles. Purification of the monoclonal antibodies produced in the ascites can be accomplished using ammonium sulfate precipitation, followed by gel exclusion chromatography. Alternatively, affinity chromatography based upon binding of antibody to protein A or protein G can be employed.
EXAMPLE 1 l: Purification of PRO Polypentides Usin~S,pecific Antibodies Native or recombinant PRO polypeptides may be purified by a variety of standard techniques in the art of protein purification. For example, pro-PRO polypeptide, mature PRO
polypeptide, or pre-PRO polypeptide is purified by immunaaffinity chromatography using antibodies specific for the PRO polygeptide of interest. In general, an immunoaffinity column is constructed by covalently coupling the anti-PRO polypeptide antibody to an activated chromatographic resin.
Polyclonal immunoglobulins are prepared from immune sera either by precipitation with ammonium sulfate ar by purification on immobilized Protein A (Pharmacia LKB
Biotechnology, Piscataway, N.1.).
Likewise, monoclonal antibodies are prepared from mouse ascites fluid by ammonium sulfate precipitation or chromatography on immobilized Protein A. Partially purified immunogIobulin is covalently attached to a chromatographic resin such as CnBr-activated SEPHAROSET"' (Pharmacia LKB
Biotechnology). The antibody is coupled to the resin, the resin is blocked, and the derivative resin is washed according to the manufacturer's inStruCti0IlS.
Such an immunoafftnity column is utilized in the purification of PRO
polypeptide by preparing a fraction from cells containing PRO polypeptide in a soluble form. This preparation is derived by solubilization of the whole cell or of a subcellular fraction obtained via differential centrifugation by the addition of detergent or by other methods well known in the art. Alternatively, soluble PRO polypeptide containing a signal sequence may be secreted in useful quantity into the medium in which the cells are grown.
A soluble PRO polypeptide-containing preparation is passed over the immunoaffinity column, and the column is washed under conditions that allow the preferential absorbance of PRO polypeptide (e.g., high ionic strength buffers in the presence of detergent). Then, the column is eluted under conditions that disrupt antibody/PRO polypeptide binding (e. g. , a low pH buffer such as approximately pH 2-3, or a high concentration of a chaotrope such as urea or thiocyanate ion), and PRO polypeptide is collected.
EXAMPLE 12: Drug_Screenin~
This invention is particularly useful for screening compounds by using PRO
polypeptides or binding fragment thereof in any of a variety of drug screening techniques. The PRO
polypeptide or fragment employed in such a test may either be free in solution, affixed to a solid support, borne on a cell surface, or located intracellularly. One method of drug screening utilizes eukaryotic or prokaryotic host cells which are stably transformed with recombinant nucleic acids expressing the PRO polypeptide or fragment. Drugs are screened against such transformed cells in competitive binding assays. Such cells, either in viable or fixed form, can be used for standard binding assays. One may measure, for example, the formation of complexes between PRO
polypeptide or a fragment and the agent being tested: Alternatively; one can examine the diminution in complex:
formation between the PRO polypeptide and its target cell or target receptors caused by the agent being tested.
Thus, the present invention provides methods of screening for drugs or any other agents which can affect a PRO polypeptide-associated disease or disorder. These methods comprise contacting such an agent with .., , . , ,., a . . "~" . _ . ~... . , . w. . ~~..r ~~ .~~,, ._~ ~ , a_~."~ ~, A,,. ~ .,w~._.~..~.. .m___.~_._~_ _. . __ . ... _.. .. _ ...

WO O1/I6318 PCT/US00l23328 an PRO polypeptide or fragment thereof and assaying (I) for the presence of a complex between the agent and the PRO polypeptide or fragment, or (ii) for the presence of a complex between the PRO polypeptide or fragment and the cell, by methods well known in the art. In such competitive binding assays, the PRO polypeptide or fragment is typically labeled. After suitable incubation, free PRO polypeptide or fragment is separated from that present in bound form, and the amount of free or uncomplexed label is a measure of the ability of the particular agent to bind to PRO polypeptide or to interfere with the PRO polypeptide/cell complex.
Another technique for drug screening provides high throughput screening for compounds having suitable binding affinity to a polypeptide and is described in detail in WO 84103564, published on September 13, 1984.
Briefly stated, large numbers of different small peptide test compounds are synthesized on a solid substrate, such as plastic pins or some other surface. As applied to a PRO polypeptide, the peptide test compounds are reacted with PRO polypeptide and washed. Bound PRO polypeptide is detected by methods well known in the art.
Purified PRO polypeptide can also be coated directly onto plates for use in the aforementioned drug screening techniques. In addition, non-neutralizing antibodies can be used to capture the peptide and immobilize it on the solid support.
This invention also contemplates the use of competitive drug screening assays in which neutralizing antibodies capable of binding PRO polypeptide specifically compete with a test compound for binding to PRO
polypeptide or fragments thereof. In this manner, the antibodies can be used to detect the presence of any peptide which shares one or more antigenic determinants with PRO polypeptide.
EXAMPLE 13: Rational Drug Design The goal of rational drug design is to produce structural analogs of biologically active polypeptide of interest (i.e., a PR4 polypeptide) or of small molecules with which they interact, e.g., agonists, antagonists, or inhibitors. Any of these examples can be used to fashion drugs which are more active or stable forms of the PRO polypeptide or which enhance or interfere with the function of the PRO
polypeptide in vivo (cf., Hodgson, Bio/Technolozv, Q: 19-21 {1991)).
In one approach, the three-dimensional structure of the PRO polypeptide, or of an PRO
polypeptide-inhibitor complex, is determined by x-ray crystallography, by computer modeling or, most typically, by a combination of the two approaches. Both the shape and charges of the PRO
polypeptide must be ascertained to elucidate the structure and to determine active sites) of the molecule.
Less ofteil, useful information regarding the structure of the PRO polypeptide may be gained by modeling based on the structure of homologous proteins.
In both cases, relevant structural information is used to design analogous PRO
polypeptide-like molecules or to identify efficient inhibitors. Useful examples of rational drug design may include molecules which have improved activity or stability as shown by Braxton and Wells, Biochemistry. 31:7796-7801 (1992) or which act as inhibitors, agonists, or antagonists of native peptides as shown by Athauda et al. , J. Biochem. , ,113:742-746 (1993).
It is also possible to isolate a target-specific antibody, selected by functional assay, as described above, and then to solve its crystal structure. This approach, in principle, yields a pharmacore upon which subsequent drug design can be based. It is possible to bypass protein crystallography altogether by generating anti-idiotypic ~,~.~ . - ~~...,~_._. T. ~, _ _______.__ ~__~ _.___ .__~ .,.

WO .01/16318 PCTlUSa0l233Z8 antibodies (anti-ids) to a functional, pharmacologically active antibody. As a mirror image of a mirror image, the binding site of the anti-ids would be expected to be an analog of the original receptor. The anti-id could then be used to identify and isolate peptides from banks of chemically or biologically produced peptides. The isolated peptides would then act as the pharmacore.
By virtue of the present invention, sufficient amounts of the PRO poiypeptide may be made available to perform such analytical studies as X-ray crystallography. In addition, knowledge of the PRO polypeptide amino acid sequence provided herein will provide guidance to those employing computer modeling techniques in place of or in addition to x-ray crystallography. __ EXAMPLE 14: Pericyte c-Fos Induction (Assay This assay shows that certain polypeptides of the invention act to induce the expression of c-fos in pericyte cells and, therefore, are useful not only as diagnostic markers for particular types of pericyte-associated tumors but also for giving rise to antagonists which would be expected to be useful for the therapeutic treatment of pericyte-associated tumors. Induction of c-fos expression in pericytes is also indicative of the induction of angiogenesis and, as such, PRO polypeptides capable of inducing the expression of c-fos would be expected to be useful for the treatment of conditions where induced angiogenesis would be beneficial including, for example, wound healing, and the like. Specifically, on day 1, pericytes are received from VEC Technologies and all but 5 ml of media is removed from flask. On day 2; the pericytes are trypsinized;
washed, spun and then plated onto 96 well plates. On day 7, the media is removed and the pericytes are created with 100 ld of PRO polypeptide test samples and controls (positive control = DME+5 % serum +/- PDGF at 500 ng/ml; negative control =
protein 32). Replicates are averaged and SD/CV are determined. Fold increase over Protein 32 (buffer control) value indicated by chemiluminescence units (RLU) luminometer reading verses frequency is plotted on a histogram. Two-fold above Protein 32 value is considered positive for the assay. ASY Matrix: Growth media = low glucose DMEM = 20% FBS + IX pen strep + IX fungizone. Assay Media = low glucose DMEM
+5 % FBS.
The following polypeptides tested positive in this assay: PR01347 and PR01340.
EXAMPLE 15: Ability of PRO Polypeytides to Stimulate the Release of Proteoal~cans from Cartilage (Assay 2~
The ability of various PRO polypeptides to stimulate the release of proteoglycans from cartilage tissue was tested as follows.
The metacarphophalangeal joint of 4-6 month old pigs was aseptically dissected; and articular cartilage was removed by free hand slicing being careful to avoid the underlying bone.
The cartilage was minced and cultured in bulk for 24 hours in a humidified atmosphere of 95 % air, 5 % COz in serum free (SF) media (DMElFI2 1:1) woth 0.1 °& BSA and 100U1m1 penicillin and 100~cg/m1 streptomycin. After washing three-v- ;=. _-times, approximately 100 mg of articular cartilage was aliquoted into micronics tubes and incubated for an additional 24 hours in the above SF media. PRO polypeptides were then added at 1 % either alone or in combination with 18 ng/ml interleukin-I a, a known stimulator'of proteogIycan release from cartilage tissue.

WO 01116318 PCTIUS00l23328 The supernatant was then harvested and assayed for the amount of proteoglycans using the 1,9-dimethyl-methylene blue (DMB) colorimeiric assay (Farndale and Buttle, Biochem.
Biophys. Acta 883:173-177 (1985)).
A positive result in this assay indicates that the test polypeptide will find use, for example, in the treatment of sports-related joint problems, articular cartilage defects, osteoarthritis or rheumatoid arthritis.
When various PRO polypeptides were tested in the above assay, the polypeptides demonstrated a marked ability to stimulate release of proteoglycans from cartilage tissue both basally and after stimulation with interleukin-1 a and at 24 and 72 hours after treatment, thereby indicating that these PRO polypeptides are useful for stimulating proteoglycan release from cartilage tissue. As such, these PRO
polypeptides are useful for the treatment of sports-related joint problems, articular cartilage defects, osteoarthritis or rheumatoid arthritis. The polypeptides testing positive in this assay are: PRO 1565, PR01693, PRO1801 and PR010096.
EXAMPLE 16: Detection of Polypeptides That Affect Glucose or FFA Uptake in Skeletal Muscle (Assay 1061 This assay is designed to determine whether PRO polypeptides show the ability to affect glucose or FFA
uptake by skeletal muscle cells. PRO polypeptides testing positive in this assay would be expected to be useful for the therapeutic treatment of disorders where either the stimulation or inhibition of glucose uptake by skeletal muscle would be beneficial including, for example, diabetes or hyper- or hypo-insulinemia.
In a 96 well format, PRO polypeptides to be assayed are added to primary rat differentiated skeletal muscle, and allowed to incubate overnight. Then fresh media with the PRO
polypeptide and +/- insulin are added to the wells. The sample media is then monitored to determine glucose and FFA uptake by the keletal muscle cells. The insulin will stimulate glucose and FFA uptake by the skeletal muscle, and insulin in media without the PRO polypeptide is used as a positive control, and a limit for scoring. As the PRO polypeptide being tested may either stimulate or inhibit glucose and FFA uptake, results are scored as posirive in the assay if greater than 1.5 'times or less than 0.5 times the insulin control.
The following PRO polypeptides tested positive as either stimulators or inhibitors of glucose andlor-FFA
uptake in this assay: PR04405.
EXAMPLE 17: Identification of PRO Polyp~tides ,Stimulate TNF-a Release In Human Blood (Assay i28) This assay shows that certain PRO polypeptides of the present invention act to stimulate the release of TNF-oc in human blood. PRO polypeptides testing positive in this assay are useful for, among other things, research purposes where stimulation of the release of TNF-a would be desired and for the therapeutic treatment of conditions wherein enhanced TNF-a release would be beneficial.
Specifically, 200 ~cl of human blood .
supplemented with SOmM Hepes buffer (pH 7.2) is aliquotted per well in a 96 well test plate. To each well is then added 300.1 of either the test PRO polypeptide in 50 mM Hepes buffer (at various concentrations) or 50 mM Hepes buffer alone (negative control) and the plates are incubated at 37°C for 6 hours. The samples are then centrifuged and SOlcl of plasma is collected from each well and tested for the presence of TNF-a by ELISA
assay. A positive in the assay is a higher amount of TNF-a in the PRO
polypeptide treated samples as compared to the negative control samples.

WO OI/I6318 PG"T/USOO~L3328 The following PRO polypeptides tested positive in this assay: PR0263. PR0295, PR012$2, PR01063, PROI356, PR03543, and PR05990.
EXAMPLE 18: Tumor Versus Normal Differential Tissue Expression Distribution Oligonucleotide probes were constructed from some of the PRO polypeptide-encoding nucleotide sequences shown in the accompanying figures for use in quantitative PCR
amplification reactions. The oligonucleotide probes were chosen so as to give an approximately 200-600 base pair amplified fragment from the 3' end of its associated template in a standard PCR reaction. The oligonucleotide probes were employed in standard quantitative PCR amplification reactions with cDNA libraries isolated from different human tumor and normal human tissue samples and analyzed by agarose gel electrophoresis so as to obtain a..quantitative determination of the level of expression of the PRO polypeptide-encoding nucleic acid in the various tumor and normal tissues tested. . ø-actin was used as a control to assure that equivalent amounts of nucleic acid was used in each reaction. Identification of the differential expression of the PRO
polypeptide-encoding nucleic acid in one or more tumor tissues as compared to one or more normal tissues of the same tissue type renders the molecule useful diagnostically for the determination of the presence or absence of tumor in a subject suspected of possessing a tumor as well as therapeutically as a target for the treatment of a tumor in a subject possessing such a tumor. These assays provided the following results.
lecule is more highly expressed in: as compared to:
DNA26843-1389 normal lung lung tumor rectum tumor normal rectum DNA30867-1335 normal kidney kidney tumor DNA40621-1440 normal lung lung tumor DNA40625-1189 normal lung lung tumor DNA45409-2511 melanoma tumor normal skin DNA56406-1704 kidney tumor normal kidney normal skin melanoma tumor DNA56410-1414 normal stomach stomach tumor DNA56436-1448 normal skin melanoma tumor DNA56855-1447 normal esophagus esophageal tumor rectum tumor normal rectum DNA56860-1510 normal kidney kidney tumor rectum tumor normal rectum DNA56862-1343 kidney tumor normal kidney normal lung lung tumor WO O1/163I8 PC"T/US00/23328 Molecule is more highly expressedas mpared to:
in:

DNA56868-1478 normal stomach stomach tumor normal lung lung tumor DNA56869-1545 normal esophagus esophageal rumor normal skin melanoma tumor DNA57704-1452 normal stomach stomach tumor rectum tumor normal rectum DNA58723-1588 normal stomach stomach tumor kidney tumor normal kidney _ normal skin melanoma tumor DNA57827-1493 normal stomach stomach tumor IS normal skin melanoma tumor DNA58737-1473 esophageal tumor normal esophagus normal stomach stomach tumor DNA58846-1409 lung tumor normal lung DNA58850-1495 esophageal tumor normal esophagus kidney tumor normal kidney DNA58855-1422 normal stomach stomach tumor rectum tumor - normal rectum DNA59211-1450 normal kidney kidney rumor DNA59212-1627 normal skin melanoma tumor DNA59213-1487 normal stomach stomach tumor normal skin melanoma tumor DNA59605-1418 melanoma tumor normal skin DNA59609-1470 esophageal tumor normal esophagus DNA59610-155b esophageal tsunor normal esophagus lung tumor normal lung normal skin melanoma tumor DNA59837-2545 normal skin melanoma tumor DNA59844-2542 normal skin melanoma tumor esophageal tumor normal esophagus DNA59854-1459 normal esophagus esophageal tumor stomach tumor normal stomach normal lung lung tumor DNA60625=1507 normal lung lung tumor DNA60629-1481 normal esophagus esophageal tumor normal rectum rectum tumor omns o rcrmsoor~za w olecule is more highly expressed as comgared to:
in:

DNA6175S-1554 normal stomach stomach tumor kidney tumor normal kidney DNA62812-1594 normal stomach stomach tumor normal lung lung tumor normal rectum rectum tumor normal skin melanoma tumor DNA62815-1576 esophageal tumor normal esophagus DNA64881-1602 normal stomach stomach tumor normal lung lung tumor DNA64902-1667 esophageal tumor normal esophagus kidney tumor normal kidney DNA65403-1565 normal esophagus esophageal tumor DNA66308-1537 normal lung lung tumor DNA665I9-1535 kidney tumor normal kidney DNA66521-1583 normal esophagus esophageal tumor normal stomach stomach tumor normal lung lung tumor normal rectum rectum tumor normal skin melanoma tumor DNA66658-1584 normal lung lung tumor melanoma tumor normal skin DNA66660-1585 lung tumor normal lung DNA66674-1599 kidney tumor normal kidney normal lung lung tumor DNA68862-2546 melanoma tumor normal skin DNA68866-1644 normal stomach stomach tumor DNA68871-1638 lung tumor normal lung narmal skin melanoma tumor DNA68880-1676 normal lung lung tumor normal skin melanoma tumor DNA68883-1691 esophageal tumor normal esophagus DNA6888S-1678 lung tumor normal lung DNA71277-1636 normal stomach stomach tumor DNA73734-1680 normal lung lung tumor WO OI/I63I8 PCTIUS00~3328 ecule is more highl~expressed in: as comvared to:
DNA73735-1681 esophageal tumor normal esophagus normal kidney kidney tumor lung tumor normal lung normal skin melanoma tumor DNA76393-1664 esophageal tumor normal esophagus stomach tumor normal stomach lung tumor normal lung rectum tumor normal rectum DNA77568-1626 normal stomach stomach tumor -iung tumor normal lung DNA77626-1705 normal rectum rectum tumor DNA81754-2532 . normal skin melanoma tumor DNA81757-2512 esophageal tumor normal esophagus normal stomach stomach tumor melanoma tumor normal skin DNA82302-2529 normal stomach stomach tumor normal lung lung tumor DNA82340-2530 normal esophagus esophageal tumor DNA85066-2534 lung tumor n~rmal lung normal skin melanoma tumor DNA87991-2540 esophageal tumor normal esophagus DNA92238-2539 normal skin melanoma tumor DNA96787-2534 normal kidney kidney tumor EXAMPLE 19: Identificatio;~of Recep orlLig_and Interaction, In this assay, various PRO polypeptides are tested for ability to bind to a panel of potential receptor or ligand molecules for the purpose of identifying receptor/ligand interactions.
The identification of a ligand for a known receptor, a receptor for a known ligand or a navel receptor/ligand pair is useful for a variety of indications including, for example, targeting bioactive molecules (linked to the ligand or receptor) to a cell known to express the receptor or ligand, use of the receptor or ligand as a reagent to detect the presence of the ligand or receptor in a composition suspected of containing the same, wherein the composition may comprise cells suspected of expressing the ligand or receptor, modulating the growth of or another biological or immunological activity of a cell known to express or respond to the receptor or ligand, modulating the immune response of cells or toward cells that express the receptor or ligand, allowing the preparaion of agonists, antagonists and/or antibodies directed against the receptor or ligand which will modulate the grgwth :of or a. : - .
biological or immunological activity of a cell expressing the receptor or ligand, and various other indications which will be readily apparent to the ordinarily skilled artisan.
9b ~... . ...""., t~.x .~..~, ~ a.~r, . n~,~~ ~AU.~~~~N4~,~;u~~.~~.~.:~ ~ _.e,~~
.n "~, .~~rv.~ ~....~_... .~.,w~~ ~_~~.~L .~ ~... ~e_.~,~~e.. .~~w~~«m..~

WO OI/I6318 .PCT/US00~23328 The assay is performed as follows. A PRO polypeptide of the present invention suspected of being a tigand for a receptor is expressed as a fusion protein containing the Fe domain of human IgG (an immunoadhesin). Receptor-ligand binding is detected by allowing interaction of the immunoadhesin polypeptide with cells (e.g. Cos cells) expressing candidate PRO polypeptide receptors and visualization of bound immunoadhesin with fluorescent reagents directed toward the Fc fusion domain and examination by microscope.
Cells expressing candidate receptors are produced by transient transfection, in parallel, of defined subsets of a library of cDNA expression vectors encoding PRO polypeptides that may function as receptor molecules. Cells are then incubated for 1 hour iri the presence of the PRO polypeptide immunoadhesin being tested for possible receptor binding. The cells are then washed and fixed with paraformaldehyde.
The cel Is are then incubated with fluorescent conjugated antibody directed against the Fe portion of the PRO
polypeptide immunoadhesin (e.g.
FITC conjugated goat anti-human-Fc antibody). The cells are then washed again and examined by microscope.
A positive interaction is judged by the presence of fluorescent labeling of cells transfected with cDNA encoding a particular PRO polypeptide receptor or pool of receptors and an absence of similar fluorescent labeling of similarly prepared cells that have been transfected with other cDNA or pools of cDNA. If a defined pool of cDNA expression vectors is judged to be positive for interaction with a PRO
polypeptide immunoadhesin, the individual eDNA species that comprise the pool are tested individually (the pool is "broken down") to determine the specific cDNA that encodes a receptor able to interact with the PRO
polypeptide immunoadhesin.
In another embodiment of this assay; an epitope-tagged potential ligand PRO
polypeptide (e.g. 8 histidine "His" tag) is allowed to interact with a panel of potential receptor PRO polypeptide molecules that have been expressed as fusions with the Fc domain of human IgG (immunoadhesins).
Following a i hour co=incubation with the epitope tagged PRO polypeptide, the candidate receptors are each immunoprecipitated with protein A beads and the beads are washed. Potential ligand interaction is determined by western blot analysis of the immunoprecipitated complexes with antibody directed towards the epitope tag. An interaction is judged to occur if a band of the anticipated molecular weight of the epitope tagged pratein is observed in the western blot analysis with a candidate receptor, but is not observed to occur with the other members of the panel of potential receptors.
Using these assays, the following receptor/ligand interactions have been herein identified:
(1) PR010272 binds to PR0580i.
(2) PR020110 binds to the human IL-17 receptor (Yao et al., Cytokine 9( 11 ):794-800 ( i 997); also herein designated as PROl) and to PR020040.
(3) PR010096 binds to PR020233.
(4) PR019670 binds to PRO1890.
The foregoing written specification is considered to be sufficient to enable one skilled in the art to practice the invention. The present invention is not to be limited in scope by the construct deposited, since the deposited embodiment is intended as a single illustration of certain aspects of the invention and any constructs that are functionally equivalent are within the scope of this invention. The deposit of material herein does not constitute an admission that the written description herein contained is inadequate to enable the practice of any aspect of the invention, including the best mode thereof, nor is it to be construed as limiting the scope of the claims to the specific illustrations that it represents. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description and fall within the scope of the appended claims.

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' PCT-u500-23328_Sequence Sequence Listing <110> Genentech, Inc.
Eaton,Dan L.
Filvaroff,Ellen Gerritsen,Mary E.
Goddard,Audrey Go.dowski,Paui J.
Grimaldi,Christopher ~.
Gurney,Austin L.
watanabe,Colin K.
wood,william I.
<120> SECRETED AND TRANSMEMBRANE PO.LYPEPTID'ES AND NUCLEIC
ACIDS ENCODING THE SAME
<130> P3230R1PCT
<140> PCT/US00/23328 <141> 2000-08-24 <150> PCT/US99/20111 <151> 1999-09-01 <150> PCT/US99/21090 <151> 1999-09-15 <150> uS 60/169,495 <151> 1999-12-07 <150> U5 60/170,262 <151> 1999-12-09 <150> US 60/175,481 <151> 2000-01-11 <150> PCT/US00/04341 <I51> 2000-02-18 <150> PCT/US00/04342 <151> 2000-02-18 <150> PCT/US00/04414 <151> 2000-02-22 <150> PCT/US00/05601 <151> 2000-03-O1 <150> US 60/187,202 <151> 2000-03-03 <150> US 60/191,007 <151> 2000-03-21 <150> PCT/U500/08439 <151> 2000-03-30 <150> US 60/199,397 <151> 2000-04-25 <150> PCT/US00/14042 <151> 2000-05-22 PCT-u500-23328_5equence <150> u5 60/209,832 <151> 2000-06-05 <160> 170 <210> 1 <211> 1173 <212> DNA
<213> Homo Sapien <400> 1 ggggcttcgg cgccagcggc cagcgctagt cggtctggta aggatttaca 50 aaaggtgcag gtatgagcag gtctgaagac taacattttg tgaagttgta 100 aaacagaaaa cctgttagaa atgtggtggt ttcagcaagg cctcagtttc 150 cttccttcag cccttgtaat ttggacatct gctgctttca tattttcata 200 cattactgca gtaacactcc accatataga cccggcttta ccttatatca 250 gtgacactgg tacagtagct ccagaaaaat gcttatttgg ggcaatgcta 300 aatattgcgg cagttttatg cattgctacc atttatgttc gttataagca 350 agttcatgct ctgagtcctg aagagaacgt tatcatcaaa ttaaacaagg 400 ctggccttgt acttggaata ctgagttgtt taggactttc tattgtggca 450 aacttccaga aaacaaccct ttttgctgca catgtaagtg gagctgtgct 500 tacctttggt atgggctcat tatatatgtt tgttcagacc atcctttcct 550 accaaatgca gcccaaaatc catggcaaac aagtcttctg gatcagactg 600 ttgttggtta tctggtgtgg agtaagtgca cttagcatgc tgacttgctc 650 atcagttttg cacagtggca attttgggac tgatttagaa cagaaactcc 700 attggaaccc cgaggacaaa ggttatgtgc ttcacatgat cactactgca 750 gcagaatggt ctatgtcatt ttccttcttt ggttttttcc tgacttacat 800 tcgtgatttt cagaaaattt ctttacgggt ggaagccaat ttacatggat 850 taaccctcta tgacactgca ccttgcccta ttaacaatga acgaacacgg 900 ctactttcca gagatatttg atgaaaggat aaaatatttc tgtaatgatt 950 atgattctca gggattgggg aaaggttcac agaagttgct tattcttctc 1000 tgaaattttc aaccacttaa tcaaggctga cagtaacact gatgaatgct 1050 gataatcagg aaacatgaaa gaagccattt gatagattat tctaaaggat 1100 atcatcaaga agactattaa aaacacctat gcctatactt ttttatctca 1150 gaaaataaag tcaaaagact atg 1173 <210> 2 <211> 266 <212> PRT

PCT-US00-23328_Seguence <213> Homo Sapien <400> 2 Met Trp Trp Phe Gin Gln Gly Leu Ser Phe Leu Pro Ser Ala Leu 1 5 10 . 15 Val Ile Trp Thr Ser Ala Ala Phe Ile Phe Ser Tyr Ile Thr Ala Va1 Thr Leu His His Ile Asp Pro Ala Leu Pro Tyr Ile Ser Asp 3 5 40 =45 Thr Gly Thr Val Ala Pro Glu Lys Cys Leu Phe Gly Ala Met Lew Asn Ile Ala Ala Val Leu Cys Ile Ala Thr Ile Tyr Val Arg Tyr Lys Gln Val His Aia Leu Ser Pro Glu Glu Asn Val Ile Ile Lys Leu Asn Lys Ala Gly Leu Val Leu Gly Ile Leu Ser Cys Leu Gly Leu Ser Ile Val Ala Asn Phe Gln Lys Thr Thr Leu Phe Ala Ala His Val Ser Gly Ala Val Leu Thr Phe Gly Met Gly Ser Leu Tyr Met Phe Val Gln Thr Ile Leu Ser Tyr Gln Met Gln Pro Lys Ile His Gly Lys Gln Val Phe Trp Ile Arg Leu Leu Leu Val Ile Trp Cys Gly Val Ser Aha Leu Ser Met Leu Thr Cys Ser Ser Val Leu His Ser Gly Asn Phe Gly Thr Asp Leu Glu Gln Lys Leu His Trp Asn Pro Glu Asp Lys Gly Tyr Val Leu His Met Ile Thr Thr Ala Ala Glu Trp Ser Met Ser Phe Ser Phe Phe Gly Phe Phe Leu Thr Tyr Ile Arg Asp 230 Gln Lys Ile Ser 235 Arg val Glu Ala 240 Leu His Gly Leu Thr Leu Tyr Asp Thr Ala Pro Cys Pro Ile Asn Asn Glu Arg Thr Arg Leu Leu ser Arg Asp Ile <210> 3 .
<211> 2037 <212> DNA ..
<213> Homo Sapien <440> 3 .

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PcT-u500-23328_Sequence cggacgcgtg ggcggacgcg tgggggagag ccgcagtccc ggctgcagca 50 cctgggagaa ggcagaccgt gtgagggggc ctgtggcccc agcgtgctgt 100 ggcctcgggg agtgggaagt ggaggcagga gccttcctta cacttcgcca 150 tgagtttcct catcgactcc agcatcatga ttacctccca gatactattt 200 tttggatttg ggtggctttt cttcatgcgc caattgttta aagactatga 250 gatacgtcag tatgttgtac aggtgatctt ctccgtgacg tttgcatttt 300 cttgcaccat gtttgagctc atcatctttg aaatcttagg agtattgaat 350 agcagctccc gttattttca ctggaaaatg aacctgtgtg taattctgct 400 gatcctggtt ttcatggtgc ctttttacat tggctatttt attgtgagca 450 atatccgact actgcataaa caacgactgc ttttttcctg tctcttatgg 500 ctgaccttta tgtatttctt ctggaaacta ggagatccct ttcccattct 550 cagcccaaaa catgggatct tatccataga acagctcatc agccgggttg 600 gtgtgattgg agtgactctc atggctcttc tttctggatt tggtgctgtc 650 aactgcccat acacttacat gtcttacttc ctcaggaatg tgactgacac 700 ggatattcta gccctggaac ggcgactgct gcaaaccatg gatatgatca 750 taagcaaaaa gaaaaggatg gcaatggcac ggagaacaat gttccagaag 800 ggggaagtgc ataacaaacc atcaggtttc tggggaatga taaaaagtgt 850 taccacttca gcatcaggaa gtgaaaatct tactcttatt caacaggaag 900 tggatgcttt ggaagaatta agcaggcagc tttttctgga aacagctgat 950 ctatatgcta ccaaggagag aatagaatac tccaaaacct tcaaggggaa 1000 atattttaat tttcttggtt actttttctc tatttactgt gtttggaaaa 1050 ttttcatggc taccatcaat attgtttttg atcgagttgg gaaaacggat 1100 cctgtcacaa gaggcattga gatcactgtg aattatctgg gaatccaatt 1150 tgatgtgaag ttttggtccc aacacatttc cttcattctt gttggaataa 1200 tcatcgtcac atccatcaga ggattgctga tcactcttar_ caagttcttt 1250 tatgccatct ctagcagtaa gtcctccaat gtcattgtcc tgctattagc 1300 acagataatg ggcatgtact ttgtctcctc tgtgctgctg atccgaatga 1350 gtatgccttt agaataccgc accataatca ctgaagtcct tggagaactg 1400 cagttcaact tctatcaccg ttggtttgat gtgatcttcc tggtcagcgc 1450 tctctctagc atactcttcc tctatttggc tcacaaacag gcaccagaga 1500 agcaaatggc accttgaact taagcctact acagactgtt agaggccagt 1550 PCT-US00-23328_Sequence ggtttcaaaa tttagatata agagggggga aaaatggaac cagggcctga 1600 cattttataa acaaacaaaa tgctatggta gcatttttca ccttcatagc 1650 atactccttc cccgtcaggt gatactatga ccatgagtag catcagccag 1700 aacatgagag ggagaactaa ctcaagacaa tactcagcag agagcatccc 1750 gtgtggatat gaggctggtg tagaggcgga gaggagccaa gaaactaaag 1800 gtgaaaaata cactggaact ctggggcaag acatgtctat ggtagctgag 1850 ccaaacacgt aggatttccg ttttaaggtt cacatggaaa aggttatagc 1900 tttgccttga gattgactca ttaaaatcag agactgtaac aaaaaaaaaa 1950 aaaaaaaaaa agggcggccg cgactctaga gtcgacctgc agaagcttgg 2000 ccgccatggc ccaacttgtt tattgcagct tataatg 2037 <210> 4 <211> 455 <212> PRT
<213> Homo Sapien <400> 4 Met Ser Phe Leu Ile Asp Ser Ser Ile Met Ile Thr Ser Gln Ile Leu Phe Phe Gly Phe Gly Trp Leu Phe Phe Met Arg Gln Leu Phe Lys Asp Tyr Glu Ile.Arg Gln Tyr Val Val Gln Val Ile Phe Ser Val Thr Phe Ala Phe Ser Cys Thr Met Phe Glu Leu Ile Ile Phe Glu Ile Leu Gly Val Leu Asn Ser Ser Ser Arg Tyr Phe His Trp Lys Met Asn Leu Cys Val Ile Leu Leu Ile Leu Val Phe Met Val Pro Phe Tyr Ile Gly Tyr Phe Ile Val Ser Asn Ile Arg Leu Leu His Lys Gln Arg Leu Leu Phe Ser Cys Leu Leu Trp Leu Thr Phe Met Tyr Phe Phe Trp Lys Leu Gly Asp Pro Phe Pro Ile Leu Ser Pro Lys His Gly Ile Leu Ser Ile Glu Gln Leu Ile Ser Arg Val Gly Val Ile Gly Val Thr Leu Met Ala Leu Leu Ser Gly Phe Gly Ala Val Asn Cys Pro Tyr Thr Tyr Met Ser Tyr Phe Leu Arg Asn Val Thr Asp Thr asp Ile Leu Ala Leu Glu Arg Arg Leu Leu Gln PCT-uS00-23328 Sequence Thr Met Asp Met Ile Ile Ser Lys Lys Lys Arg Met Ala Met Ala Arg Arg Thr Met Phe Gln Lys Gly Glu Val His Asn Lys Pro Ser Gly Phe Trp Gly Met Iie Lys Ser Val Thr Thr Ser Ala Ser Gly Ser Glu Asn Leu Thr Leu Iie Gln Gln Glu Val Asp Ala Leu Glu G1u Leu Ser Arg Gin Leu Phe Leu Glu Thr Ala Asp Leu Tyr Ala Thr Lys Glu Arg Ile Glu Tyr Ser Lys Thr Phe Lys Gly Lys Tyr Phe Asn Phe Leu Gly Tyr Phe Phe Ser Ile Tyr Cys Val Trp Lys Ile Phe Met Ala Thr Ile Asn Ile val Phe asp Arg Val Gly Lys Thr Asp Pro Val Thr Arg Gly Ile Glu Ile Thr Val Asn Tyr Leu Gly Ile Gln Phe Asp Val Lys Phe Trp Ser Gln His Ile Ser Phe Ile Leu Val Gly Ile Iie Ile Val Thr Ser Ile Arg Gly Leu Leu Iie Thr Leu Thr Lys Phe Phe Tyr Ala Ile Ser Ser Ser Lys Ser Ser Asn Val Ile Vai Leu Leu Leu Ala Gin Ile Met Gly Met Tyr Phe Val Ser Ser Vai Leu Le.u Ile Arg Met Ser Met Pro Leu Glu Tyr Arg Thr Ile Ile Thr G1u Val Leu Gly Glu Leu Gln Phe Asn Phe Tyr His Arg Trp Phe Asp Val Ile Phe Leua Val Ser Ala Leu 425 430 ' 435 Ser Ser Ile Leu Phe Leu Tyr Leu Ala His Lys Gln Ala Pro Glu Lys Gln Met Ala Pro <210> 5 <211> 2372 <212> DNA . .
<213> Homo Sapien <400> 5 agcagggaaa tccggatgtc tcggttatga agtggagcag tgagtgtgag 50 PCT-uS00-23328_Sequence cctcaacata gttccagaac tctccatccg gactagttat tgagcatctg 100 cctctcatat caccagtggc catctgaggt gtttccctgg ctctgaaggg 150 gtaggcacga tggccaggtg cttcagcctg gtgttgcttc tcacttccat 200 ctggaccacg aggctcctgg tccaaggctc tttgcgtgca gaagagcttt 250 ccatccaggt gtcatgcaga attatgggga tcacccttgt gagcaaaaag 300 gcgaaccagc agctgaattt cacagaagct aaggaggcct gtaggctgct 350 gggactaagt ttggccggca aggaccaagt tgaaacagcc ttgaaagcta 400 gctttgaaac ttgcagctat ggctgggttg gagatggatt cgtggtcatc 450 tctaggatta gcccaaaccc caagtgtggg aaaaatgggg tgggtgtcct 500 gatttggaag gttccagtga gccgacagtt tgcagcctat tgttacaact 550 catctgatac ttggactaac tcgtgcattc cagaaattat caccaccaaa 600 gatcccatat tcaacactca aactgcaaca caaacaacag aatttattgt 650 cagtgacagt acctactcgg tggcatcccc ttactctaca atacctgccc 700 ctactactac tcctcctgct ccagcttcca cttctattcc acggagaaaa 750 aaattgattt gtgtcacaga agtttttatg gaaactagca ccatgtctac 800 agaaactgaa ccatttgttg aaaataaagc agcattcaag aatgaagctg 850 ctgggtttgg aggtgtcccc acggctctgc tagtgcttgc tctcctcttc 900 tttggtgctg cagctggtct tggattttgc tatgtcaaaa ggtatgtgaa 950 ggccttccct tttacaaaca agaatcagca gaaggaaatg atcgaaacca 1000 aagtagtaaa ggaggagaag gccaatgata gcaaccctaa tgaggaatca 1050 aagaaaactg ataaaaaccc agaagagtcc aagagtccaa gcaaaactac 1100 cgtgcgatgc ctggaagctg aagtttagat gagacagaaa tgaggagaca 1150 cacctgaggc tggtttcttt catgctcctt accctgcccc agctggggaa 1200 atcaaaaggg ccaaagaacc aaagaagaaa gtccaccctt ggttcctaac 1250 tggaatcagc tcaggactgc cattggacta tggagtgcac caaagagaat 1300 gcccttctcc ttattgtaac cctgtctgga tcctatcctc ctacctccaa 1350 agcttcccac ggcctttcta gcctggctat gtcctaataa. tatcccactg 1400 ggagaaagga gttttgcaaa gtgcaaggac ctaaaacatc tcatcagtat 1450 ccagtggtaa aaaggcctcc tggctgtctg aggctaggtg ggttgaaagc 1500 caaggagtca ctgagaccaa ggctttctct actgattccg cagctcagac 1550 cctttcttca gctctgaaag agaaacacgt atcccacctg acatgtcctt 1600 PCT-uS00-23328_sequence ctgagcccgg taagagcaaa agaatggcag aaaagtttag cccctgaaag 1650 ccatggagat tctcataact tgagacctaa tctctgtaaa gctaaaataa 1700 agaaatagaa caaggctgag gatacgacag tacactgtca gcagggactg 1750 taaacacaga cagggtcaaa gtgttttctc tgaacacatt gagttggaat 1800 cactgtttag aacacacaca cttacttttt ctggtctcta ccactgctga 1850 tattttctct aggaaatata cttttacaag taacaaaaat aaaaactctt 1900 ataaatttct atttttatct gagttacaga aatgattact aaggaagatt 1950 actcagtaat ttgtttaaaa agtaataaaa ttcaacaaac atttgctgaa 2000 tagctactat atgtcaagtg ctgtgcaagg tattacactc tgtaattgaa 2050 tattattcct caaaaaattg cacatagtag aacgctatct gggaagctat 2100 ttttttcagt tttgatattt ctagcttatc tacttccaaa ctaattttta 2150 tttttgctga gactaatctt attcattttc tctaatatgg caaccattat 2200 aaccttaatt tattattaac atacctaaga agtacattgt tacctctata 2250 taccaaagca cattttaaaa gtgccattaa caaatgtatc actagccctc 2300 ctttttccaa caagaaggga ctgagagatg cagaaatatt tgtgacaaaa 2350 aattaaagca tttagaaaac tt 2372 <210> 6 <211> 322 <212> PRT
<213> Homo Sapien <400> '6 Met Ala Arg Cys Phe Ser Leu Val Leu Leu Leu Thr Ser Ile Trp Thr Thr Arg Leu Leu Vai Gln Gly Ser Leu Arg Ala Glu Glu Leu Ser Ile Gln Val Ser Cys Arg Ile Met Gly Ile Thr Leu Val Ser Lys Lys Ala Asn Gln Gln Leu Asn Phe Thr Glu Ala Lys Glu Ala Cys Arg Leu Leu Gly Leu Ser Leu Ala Giy Lys Asp Gln Val G1a Thr Ala Leu Lys Ala Ser Phe Glu Thr Cys Ser Tyr Gly Trp Val Gly Asp Gly Phe Val Vai Ile Ser Arg Ile Ser Pro Asn Pro Lys Cys Gly Lys Asn Giy Vai Gly Val Leu Ile Trp Lys Val Pro Val PCT-u500-23328_sequence Ser Arg Gln Phe Ala Ala Tyr Cys Tyr Asn Ser Ser Asp Thr Trp Thr Asn Ser Cys Ile Pro G1u Ile Ile Thr Thr Lys Asp Pro Ile Phe Asn Thr Gln Thr Ala Thr Gln Thr Thr Glu Phe Ile Va1 5er Asp Ser Thr Tyr Ser Val Ala Ser Pro Tyr Ser Thr Iie Pro ala Pro Thr Thr Thr Pro Pro Ala Pro Ala Ser Thr Ser Ile Pro Arg Arg Lys Lys Leu Ile Cys Val Thr Glu Val Phe Met Glu Thr Ser Thr Met Ser Thr Glu Thr Glu Pro Phe Val Glu Asn Lys Ala Ala Phe Lys Asn Glu Ala Ala Gly Phe Gly Gly Val Pro Thr Ala Leu Leu Val Leu Ala Leu Leu Phe Phe Gly Ala Ala A1a Gly Leu Gly Phe Cys Tyr Val Lys Arg Tyr Val Lys Ala Phe Pro Phe Thr Asn Lys Asn Gln Gln Lys Glu Met Ile Glu Thr Lys Val Val Lys Glu Glu Lys Ala Asn Asp Ser Asn Pro Asn Glu Glu Ser Lys Lys Thr Asp Lys Asn Pro Glu Glu Ser Lys 5er Pro 5er Lys Thr Thr Val Arg Cys Leu Glu Ala Glu val <210> 7 <211> 2586 <212> DNA
<213> Homo Sapien <400> 7 cgccgcgctc ccgcacccgc ggcccgccca ccgcgccgct cccgcatctg 50 cacccgcagc ccggcggcct eccggcggga gcgagcagat ccagtccggc 100 ccgcagcgca actcggtcca gtcggggcgg cggctgcggg cgcagagcgg 150 agatgcagcg gcttggggcc accctgctgt gcctgctgct ggcggcggcg 200 gtccccacgg cccccgcgcc cgctccgacg gcgacctcgg ctccagtcaa 250 gcccggcccg gctctcagct acccgcagga ggaggccacc ctcaatgaga 300 tgttccgcga ggttgaggaa ctgatggagg acacgcagca caaattgcgc 350 PCT-0500-23328_5equence agcgcggtgg aagagatgga ggcagaagaa gctgctgcta aagcatcatc 400 agaagtgaac ctggcaaact tacctcccag ctatcacaat gagaccaaca 450 cagacacgaa ggttggaaat aataccatcc atgtgcaccg agaaattcac 500 aagataacca acaaccagac tggacaaatg gtcttttcag agacagttat 550 cacatctgtg ggagacgaag aaggcagaag gagccacgag tgcatcatcg 600 acgaggactg tgggcccagc atgtactgcc agtttgccag cttccagtac 650 acctgccagc catgccgggg ccagaggatg ctctgcaccc gggacagtga 700 gtgctgtgga gaccagctgt gtgtctgggg tcactgcacc aaaatggcca 750 ccaggggcag caatgggacc atctgtgaca accagaggga ctgccagccg 800 gggctgtgct gtgccttcca gagaggcctg ctgttccctg tgtgcacacc 850 cctgcccgtg gagggcgagc tttgccatga ccccgccagc cggcttctgg 900 acctcatcac ctgggagcta gagcctgatg gagccttgga ccgatgccct 950 tgtgccagtg gcctcctctg ccagccccac agccacagcc.tggtgtatgt 1000 gtgcaagccg accttcgtgg ggagccgtga ccaagatggg gagatcctgc 1050 tgcccagaga ggtccccgat gagtatgaag ttggcagctt catggaggag 1100 gtgcgccagg agctggagga cctggagagg agcctgactg aagagatggc 1150 gctgggggag cctgcggctg ccgccgctgc actgctggga ggggaagaga 1200 tttagatctg gaccaggctg tgggtagatg tgeaatagaa atagctaatt 1250 tatttcccca ggtgtgtgct ttaggcgtgg gctgaccagg cttcttccta 1300 catcttcttc ccagtaagtt tcccctctgg cttgacagca tgaggtgttg 1350 tgcatttgtt cagctccccc aggctgttct ccaggcttca cagtctggtg 1400 cttgggagag tcaggcaggg ttaaactgca ggagcagttt gccacccctg 1450 tccagattat tggctgcttt gcctctacca gttggcagac agccgtttgt 1500 tctacatggc tttgataatt gtttgagggg aggagatgga aacaatgtgg 1550 agtctccctc tgattggttt tggggaaatg tggagaagag tgccctgctt 1600 tgcaaacatc aacctggcaa aaatgcaaca aatgaatttt ccacgcagtt 1650 ctttccatgg gcataggtaa gctgtgcctt cagctgttgc agatgaaatg 1700 ttctgttcac cctgcattac atgtgtttat tcatccagca gtgttgctca 1750 gcteetaeet ctgtgeeagg geageatttt eatatecaag atcaattcce 1800 tctctcagca cagcctgggg agggggtcat tgttctcctc gtccatcagg 1850 gatctcagag gctcagagac tgcaagctgc ttgcccaagt cacacagcta 1900 PCT-0500-23328_Sequence gtgaagacca gagcagtttc atctggttgt gactctaagc tcagtgctct 1950 ctccactacc ccacaccagc cttggtgcca ccaaaagtgc tccccaaaag 2000 gaaggagaat gggatttttc ttgaggcatg cacatctgga attaaggtca 2050 aactaattct cacatccctc taaaagtaaa ctactgttag gaacagcagt 2100 gttctcacag tgtggggcag ccgtccttct aatgaagaca atgatattga 2150 cactgtccct ctttggcagt tgcattagta actttgaaag gtatatgact 2200 gagcgtagca tacaggttaa cctgcagaaa cagtacttag gtaattgtag 2250 ggcgaggatt ataaatgaaa tttgcaaaat cacttagcag caactgaaga 2300 caattatcaa ccacgtggag aaaatcaaac cgagcagggc tgtgtgaaac 2350 atggttgtaa tatgcgactg cgaacactga actctacg~cc actccacaaa 2400 tgatgttttc aggtgtcatg gactgttgcc accatgtatt catccagagt 2450 tcttaaagtt taaagttgca catgattgta taagcatgct ttctttgagt 2500 tttaaattat gtataaacat aagttgcatt tagaaatcaa gcataaatca 2550 cttcaactgc aaaaaaaaaa aaaaaaaaaa aaaaaa 2586 <210> 8 <211> 350 , <212> PRT _;
<213> Homo Sapien ~ w <400> 8 Met Gln Arg Leu Gly Ala Thr Leu Leu Cys Leu Leu Leu Ala Ala Ala Val Pro Thr Ala Pro Ala Pro Ala Pro Thr Ala Thr Ser Ala 20 25 ~ 30 Pro Val Lys Pro Gly Pro Ala Leu Ser Tyr Pro Gln Glu Glu Ala Thr Leu Asn Glu Met Phe Arg Glu Vah Glu Glu Leu Met Glu Asp Thr Gln His Lys Leu Arg Ser Ala Val Glu Glu Met Glu Ala Glu Glu Ala Ala Ala Lys Aia Ser Ser Glu val Asn Leu Ala Asn Leu Pro Pro Ser Tyr His Asn Glu Thr Asn Thr Asp Thr Lys Val Gly Asn Asn Thr Ile His Val His Arg Glu Ile His Lys Ile Thr Asn 110 lI5 120 Asn Gln Thr Gly Gln Met Val Phe Ser Glu Thr Val Ile Thr Ser Val Gly Asp Glu Glu Gly Arg Arg Ser His Glu Cys Ile Ile Asp Page I1 PCT-u500-23328_Sequence Glu Asp Cys Gly Pro Ser Met Tyr Cys Gln Phe Ala Ser Phe Gln Tyr Thr Cys Gln Pro Cys Arg Gly Gln Arg Met Leu Cys Thr Arg Asp Ser Glu Cys Cys Gly Asp Gln Leu Cys va.l Trp Gly His Cys Thr Lys Met Ala Thr Arg Gly Ser Asn Gly Thr Ile Cys Asp Asn Gln Arg Asp Cys Gln Pro Gly Leu Cys Cys Ala Phe Gln Arg Gly Leu Leu Phe Pro Val Cys Thr Pro Leu Pro Val Glu Gly Glu Leu Cys His Asp Pro Ala Ser Arg Leu Leu Asp Leu Ile Thr Trp Glu Leu Giu Pro Asp Gly Ala Leu Asp Arg Cys Pro Cys Ala Ser Gly Leu Leu Cys Gln Pro His Ser His Ser Leu Val Tyr Val Cys Lys Pro Thr Phe val Gly Ser Arg Asp Gln asp Gly Glu Ile Leu Leu Pro Arg Glu Val Pro Asp Glu Tyr Glu Val Gly Ser Phe Met Glu Glu Val Arg Gln Glu Leu Glu Asp Leu Glu Arg Ser Leu Thr Glu Glu Met Ala Leu Gly Glu Pro Ala Ala Ala Ala Ala Ala Leu Leu Gly Gly Glu Glu Ile <210> 9 <211> 1395 <212> DNA
<213> Homo Sapien <400> 9 cggacgcgtg ggcggacgcg tgggggctgt gagaaagtgc caataaatac 50 atcatgcaac cccacggccc accttgtgaa ctcctcgtgc ccagggctga 100 tgtgcgtctt ccagggctac tcatccaaag gcctaatcca acgttctgtc 150 ttcaatctgc aaatctatgg ggtcctgggg ctcttctgga cccttaactg 200 ggtactggcc ctgggccaat gcgtcctcgc tggagccttt gcctccttct 250 actgggcctt ccacaagccc caggacatcc ctaccttccc cttaatctct 300 gccttcatcc gcacactccg ttaccacact gggtcattgg catttggagc 350 Page 12 .
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PCT-US00-23328_Sequ ence cctcatcctg _acccttgtgr_ agatagcccg ggtcatcttc~ gagtatattg 400 accacaagct cagaggagtg cagaaccctg tagcccgctg catcatgtgc 450 tgtttcaagt gctgcctctg gtgtctggaa aaatttatca agttcctaaa 500 ccgcaatgca tacatcatga tcgccatcta cgggaagaat ttctgtgtct 550 cagccaaaaa tgcgttcatg ctactcatgc gaaacattgt cagggtggtc 600 gtcctggaca aagtcacaga cctgctgctg ttctttggga agctgctggt 650 ggtcggaggc gtgggggtcc tgtccttctt ttttttctcc ggtcgcatcc 700 cggggctggg taaagacttt aagagccccc acctcaacta ttactggctg 750 cccatcatga cctceatcct gggggcctat gtcatcgcc<~ gcggcttctt 800 cagcgttttc ggcatgtgtg tggacacgct cttcctctgc ttcctggaag 850 acctggagcg gaacaacggc tccctggacc ggccctacta catgtccaag 900 agccttctaa agattctggg caagaagaac gaggcgcccc cggacaacaa 950 gaagaggaag aagtgacagc tccggccctg atccaggact gcaccccacc 1000 cccaccgtcc agccatccaa cctcacttcg ccttacaggt ctccattttg 1050 tggtaaaaaa aggttttagg ccaggcgccg tggctcacge ctgtaatcca 1100 acactttgag aggctgaggc gggcggatca cctgagtcag gagttcgaga 1150 ccagcctggc caacatggtg aaacctccgt ctctattaaa aatacaaaaa 1200 ttagccgaga gtggtggcat gcacctgtca tcccagctac tcgggaggct 1250 gaggcaggag aatcgcttga acccgggagg cagaggttgc agtgagccga 1300 gatcgcgcca ctgcactcca acctgggtga cagactctgt ctccaaaaca 1350 aaacaaacaa acaaaaagat tttattaaag atattttgtt aactc 1395 <210> 10 <211> 321 <212> PRT
<213> Homo Sapien <400> 10 Arg Thr Arg Gly Arg Thr Arg Gly Gly Cys Glu Lys Val Pro Ile Asn Thr Ser Cys Asn Pro Thr Ala His.Leu va.l Asn Ser Ser Cys Pro Gly Leu Met Cys val Phe Gln Gly Tyr Ser Ser Lys Gly Leu Ile Gln Arg Ser val Phe Asn Leu G1n Ile Tyr Gly val Leu Gly Leu Phe Trp Thr Leu Asn Trp val Leu Ala Leu Gly Gln Cys val PcT-US00-23328_Sequence Leu Aia Gly Ala Phe Aia Ser Phe Tyr Trp Ala Phe His Lys Pro Gln Asp Iie Pro Thr Phe Pro Leu Ile Ser Ala Phe Ile Arg Thr Leu Arg Tyr His Thr Gly Ser Leu Ala Phe Gly Ala Leu Ile Leu Thr Leu Val Gln Ile Ala Arg Val Ile Leu Glu Tyr Ile Asp His Lys Leu Arg Gly Val Gln Asn Pro Val Ala Arg Cys Ile Met Cys Cys Phe Lys Cys Cys Leu Trp Cys Leu GluWys Phe Ile Lys Phe Leu Asn Arg Asn Ala Tyr Ile Met Ile Ala Ile Tyr Gly Lys Asn Phe Cys Val Ser Ala Lys Asn Ala Phe Met Leu Leu Met Arg Asn Ile Val Arg Val Vai Vai Leu.ASp Lys Vai Thr Asp Leu Leu Leu Phe Phe Gly Lys Leu Leu Val Vai Gly Gly Val Gly Val Leu Ser Phe Phe Phe Phe Ser Gly Arg Iie Pro Gly Leu Gly Lys Asp Phe Lys Ser Pro His Leu Asn Tyr Tyr Trp Leu Pro Ile Met Thr Ser Ile Leu Gly Ala Tyr wal Ile Ala Ser Gly Phe Phe Ser Val Phe Gly Met Cys Val Asp Thr Leu Phe Leu Cys Phe Leu Glu Asp Leu Glu Arg Asn Asn Gly Ser Leu Asp Arg Pro Tyr Tyr Met Ser Lys Ser Leu Leu Lys Ile Leu Gly Lys Lys Asn Glu Ala Pro Pro Asp Asn Lys Lys Arg Lys Lys 3zo <210> 11 <211> 1901 <212> DNA
<213> Homo Sapien <400> 11 gccccgcgcc cggcgccggg cgcccgaagc cgggagcca.c cgccatgggg 50 gcctgcctgg gagcctgctc cctgctcagc tgcgcgtcct gcctctgcgg 100 PcT-US00-23328_Sequence ctctgccccc tgcatcctgt gcagctgctg ccccgccagc cgcaactcca 150 ccgtgagccg cctcatcttc acgttcttcc tcttcctggg ggtgctggtg 200 tccatcatta tgctgagccc gggcgtggag agtcagctct acaagctgcc 250 ctgggtgtgt gaggaggggg ccgggatccc caccgtcctg cagggccaca 300 tcgactgtgg ctccctgctt ggctaccgcg ctgtctaccg catgtgcttc 350 gccacggcgg ccttcttctt cttctttttc accctgctca tgctctgcgt 400 gagcagcagc cgggaccccc gggctgccat ccagaatggg ttttggttct 450 ttaagttcct gatcctggtg ggcctcaccg tgggtgcctt ctacatccct 500 gacggctcct tcaccaacat ctggttctac ttcggcgtcg tgggctcctt 550 cctcttcatc ctcatccagc tggtgctgct catcgacttt gcgcactcct 600 ggaaccagcg gtggctgggc aaggccgagg agtgcgattc ccgtgcctgg 650 tacgcaggcc tcttcttctt cactctcctc ttctacttgc tgtcgatcgc 700 ggccgtggcg ctgatgttca tgtactacac tgagcccagc ggctgccacg 750 agggcaaggt cttcatcagc ctcaacctca ccttctgtgt ctgcgtgtcc 800 atcgctgctg tcctgcccaa ggtccaggac gcccagccca actcgggtct 850 gctgcaggcc tcggtcatca ccctctacac catgtttgtc acctggtcag 900 ccctatccag tatccctgaa cagaaatgca acccccattt gccaacccag 950 ctgggcaacg agacagttgt ggcaggcccc gagggctatg agacccagtg 1000 gtgggatgcc ccgagcattg tgggcctcat catcttcctc ctgtgcaccc 1050 tcttcatcag tctgcgctcc tcagaccacc ggcaggtgaa.cagcctgatg 1100 cagaccgagg agtgcccacc tatgctagac gccacacagc agcagcagca 1150 gcaggtggca gcctgtgagg gccgggcctt tgacaacgag caggacggcg 1200 tcacctacag ctactccttc ttccacttct gcctggtgct ggcctcactg 1250 , cacgtcatga tgacgctcac caactggtac aagcccggtg agacccggaa 1300 gatgatcagc acgtggaccg ccgtgtgggt gaagatctgt gccagctggg 1350 cagggctgct cctctacctg tggaccctgg tagccccact cctcctgcgc 1400 aaccgcgact tcagctgagg cagcctcaca gcctgccatc tggtgcctcc 1450 tgccacctgg tgcctctcgg ctcggtgaca gccaacctgc cccctcccca 1500 caccaatcag ccaggctgag cccccacccc tgccccagct ccaggacctg 1550 cccctgagcc gggccttcta gtcgtagtgc cttcagggtc cgaggagcat 1600 PCT-US00-23328_sequence caggctcctg cagagcccca tccecccgcc acacccacac ggtggagctg 1650 cctcttcctt cccctcctcc ctgttgccca tactcagcat ctcggatgaa 1700 agggctccct tgtcctcagg ctccacggga gcggggctgc: tggagagagc 1750 ggggaactcc caccacagtg gggcatccgg cactgaagcc ctggtgttcc 1800 tggtcacgtc ccccagggga ccctgccccc ttcctggact tcgtgcctta 1850 ctgagtctct aagacttttt ctaataaaca agccagtgcg tgtaaaaaaa 19D0 a . 1901 <210>12 <211>457 <212>PRT

<213>Homo Sapien <400>12 Met GlyAlaCysLeu GlyAlaCys SerLeuLeu SerCysAla Ser Cys LeuCysGlySer AlaProCys IieLeuCys SerCysCys Pro Ala SerArgAsnSer 'ThrValSer ArgLeuTle PheThrPhe Phe Leu PheLeuGlyVal LeuValSer IleIleMet LeuSerPro Gly val GluSerGlnLeu TyrLysLeu ProTrpVal CysGluGlu Gly 65 70 75.

Ala GlyIleProThr ValLeuGln GlyHisIl~eAspCysGly Ser Leu LeuGlyTyrArg AlaValTyr ArgMetCys PheAlaThr Ala Ala PhePhePhePhe PhePheThr LeuLeuMet LeuCysVal Ser Ser SerArgAspPro ArgAlaAla IleGlnAsn GlyPheTrp Phe Phe Ly5PheL2UIle LeUValGly LeUThrVal GlyAlaPhe Tyr Ile ProAspGlySer PheThrAsn IleTrpPhe TyrPheGly Val Val GlySerPheLeu PheIleLeu IleGlnLeu ValLeuLeu Ile Asp PheAlaHisSer TrpAsnGln ArgTrpLeu GlyLysAla Glu Glu CysAspSerArg AlaTrpTyr AlaGlyLeu PhePhePhe Thr PcT-US00-23328_sequence Leu Leu Phe Tyr Leu Leu Ser Ile Ala Ala Val Ala Leu Met Phe Met Tyr Tyr Thr Glu Pro Ser Gly Cys His Glu Gly Lys Val Phe Ile Ser Leu Asn Leu Thr Phe Cys Val Cys Val Ser Ile Ala Ala Val Leu Pro Lys Val Gln Asp Ala Gln Pro Asn ser Gly Leu Leu Gln Ala Ser Val Ile Thr Leu Tyr Thr Met Phe Val Thr Trp Ser Ala Leu Ser Ser Ile Pro Glu Gln Lys Cys Asn Pro His Leu Pro Thr Gln Leu Gly Asn Glu Thr Val Val Ala Gly Pro Glu Gly Tyr Glu Thr Gln Trp Trp Asp Ala Pro Ser Ile Vai Giy Leu Ile Ile Phe Leu Leu Cys Thr Leu Phe Ile Ser Leu Arg Ser Ser asp His Arg Gln Val Asn Ser Leu Met Gln Thr Glu Glu Cys Pro Pro Met Leu Asp Ala Thr Gln Gln Gln Gln Gln Gln Val Ala Ala Cys Glu Gly Arg Ala Phe Asp Asn Glu Gin Asp Gly Val Thr Tyr Ser Tyr ser Phe Phe His Phe Cys Leu Val Leu Ala Seer Leu His Val Met Met Thr Leu Thr Asn Trp Tyr Lys Pro Gly Glu Thr Arg Lys Met Ile Ser Thr Trp Thr Ala Val Trp Val Lys Ile Cys Ala Ser Trp Ala Gly Leu Leu Leu Tyr Leu Trp Thr Leu Val Ala Pro Leu Leu Leu Arg Asn Arg Asp Phe Ser <210> 13 <211> 1572 <z12> DNA
<213> Homo sapien <400> 13 cgggccagcc tggggcggcc ggccaggaac cacccgttaa ggtgtcttct 50 ctttagggat ggtgaggttg gaaaaagact cctgtaaccc tcctccagga 100 tgaaccacct gccagaagac atggagaacg ctctcaccgg gagccagagc 150 PCT-uS00-23328_Sequence tcccatgctt ctctgcgcaa tatccattcc atcaacccca cacaactcat 200 ggccaggatt gagtcctatg aaggaaggga aaagaaaggc atatctgatg 250 tcaggaggac tttctgtttg tttgtcacct ttgacctctt attcgtaaca 300 ttactgtgga taatagagtt aaatgtgaat ggaggcattg agaacacatt 350 agagaaggag gtgatgcagt atgactacta ttcttcatat tttgatatat 400 ttcttctggc agtttttcga tttaaagtgt taatacttgc atatgctgtg 450 tgcagactgc gccattggtg ggcaatagcg ttgacaacgg cagtgaccag 500 tgccttttta ctagcaaaag tgatcctttc gaagcttttc tctcaagggg 550 cttttggcta tgtgctgccc atcatttcat tcatccttgc ctggattgag 600 acgtggttcc tggatttcaa agtgttacct caagaagcag aagaagaaaa 650 cagactcctg atagttcagg atgcttcaga gagggcagca cttatacctg 700 gtggtctttc tgatggtcag ttttattccc ctcctgaatc cgaagcagga 750 tctgaagaag ctgaagaaaa acaggacagt gagaaaccac ttttagaact 800 atgagtacta cttttgttaa atgtgaaaaa ccctcacaga aagtcatcga 850 ggcaaaaaga ggcaggcagt ggagtctccc tgtcgacagt aaagttgaaa 900 tggtgacgtc cactgctggc tttattgaac agctaataaa gatttattta 950 ttgtaatacc tcacaaacgt tgtaccatat ccatgcacat ttagttgcct 1000 gcctgtggct ggtaaggtaa tgtcatgatt catcctctct tcagtgagac 1050 tgagcctgat gtgttaacaa ataggtgaag aaagtcttgt gctgtattcc 1100 taatcaaaag acttaatata ttgaagtaac acttttttag taagcaagat 1150 acctttttat ttcaattcac agaatggaat ttttttgttt catgtctcag 1200 atttattttg tatttctttt ttaacactct acatttccct tgttttttaa 1250 ctcatgcaca tgtgctcttt gtacagtttt aaaaagtgta ataaaatctg 1300 acatgtcaat gtggctagtt ttatttttct tgttttgcat tatgtgtatg 1350 gcctgaagtg ttggacttgc aaaaggggaa gaaaggaatt gcgaatacat 1400 gtaaaatgtc accagacatt tgtattattt ttatcatgaa atcatgtttt 1450 tctctgattg ttctgaaatg ttctaaatac tcttattttg aatgcacaaa 1500 atgacttaaa ccattcatat catgtttcct ttgcgttcag ccaatttcaa 1550 ttaaaatgaa ctaaattaaa as 1572 <210> 14 <211> 234 <212> PRT
<213> Homo Sapien ,~_4~ .:,~.,"
. .,. ..._n . o a ...~" evzar,~emt~,x ..-...a..o-~x,~aw~us:.. ", ~,rraxiv ,~
M. cr~..z»~.": ~~awAYaxA',:~s<~pmR;w~:,~:~w~a~a, u~~w..F.~..,. .."~"."»n.~ -.
m... ~.~,..."».~ <.,..,.~. ,~.~."".",-.,.~,..z.....~,,.,~.P..
..~,.""",..,~,.""""....,.._.n."......_.._.._..e,.

PCT-uS00-23328_Sequence <400> 14 Met Asn His Leu Pro Glu Asp Met Glu Asn Ala Leu Thr Gly Ser Gln Ser Ser His Ala Ser Leu Arg Asn Ile His Ser Ile Asn Pro Thr Gln Leu Met Ala Arg Ile Glu Ser Tyr Glu Gly Arg Glu Lys Lys Gly Ile Ser Asp Val Arg Arg Thr Phe Cys Leu Phe Val Thr Phe Asp Leu Leu Phe Val Thr Leu Leu Trp I7e Ile Glu Leu Asn Val Asn Gly Gly Ile Glu Asn Thr Leu Glu Lys Glu Val Met Gln Tyr Asp Tyr Tyr Ser Ser Tyr Phe Asp Ile Phe Leu Leu Ala Val Phe Arg Phe Lys Val Leu Ile Leu Ala Tyr Ala Val Cys Arg Leu Arg His Trp Trp Ala Ile Aia Leu Thr Thr Ala Val Thr Ser Ala 12 S 130 13 5.
Phe Leu Leu Ala Lys Val Ile Leu Ser Lys Leu Phe Ser Gln Gly Ala Phe Gly Tyr Val Leu Pro Ile Ile Ser Phe Ile Leu Ala Trp Ile Glu Thr Trp Phe Leu Asp Phe Lys Val Leu Pro Gln Glu Ala 170 175 lso Glu Glu Glu Asn Arg Leu Leu Ile val Gln Asp Ala Ser Glu Arg Ala Ala Leu Ile Pro Gly Gly~Leu Ser Asp G1y Gln Phe Tyr Ser Pro Pro Glu Ser Giu Ala Gly Ser Glu Glu Ala Glu Glu Lys Gln Asp Ser Glu Lys Pro Leu Leu Glu Leu <210> 15 <211> 2768 <212> DNA
<213> Homo Sapien <400> 15 actcgaacgc agttgcttcg ggacccagga ccccctcggg cccgacccgc 50 caggaaagac tgaggccgcg gcctgccccg cccggctccc tgcgccgccg 100 ccgcctcccg ggacagaaga tgtgctccag ggtccctctg ctgctgccgc 150 tgctcctget actggcectg gggectgggg tgeagggetg cccatecgge 200 Pc'r-u500-23328_Sequence tgccagtgca gccagccaca gacagtcttc tgcactgccc gccaggggac 250 cacggtgccc cgagacgtgc cacccgacac ggtggggctg tacgtctttg 300 agaacggcat caccatgctc gacgcaggca gctttgccgg cctgccgggc 350 ctgcagctcc tggacctgtc acagaaccag atcgccagcc tgcccagcgg 400 ggtcttccag ccactcgcca acctcagcaa cctggacctg acggccaaca 450 ggctgcatga aatcaccaat gagaccttcc gtggcctgcg gcgcctcgag 590 cgcctctacc tgggcaagaa ccgcatccgc cacatccagc ctggtgcctt 550 cgacacgctc gaccgcctcc tggagctcaa gctgcaggac aacgagctgc 600 gggcactgcc cccgctgcgc ctgccccgcc tgctgctgct ggacctcagc 650 cacaacagcc tcctggccct g.gagcccggc atcctggaca ctgccaacgt 700 ggaggcgctg cggctggctg gtctggggct gcagcagctg gacgaggggc 750 tcttcagccg cttgcgcaac ctccacgacc tggatgtgtc cgacaaccag 800 ctggagcgag tgccacctgt gatccgaggc ctccggggcc tgacgcgcct 850 gcggctggcc ggcaacaccc gcattgccca gctgcggccc gaggacctgg 900 ccggcctggc tgccctgcag gagctggatg tgagcaacca aagcctgcag 950 gccctgcctg gcgacctctc gggcctcttc ccccgcctgc ggctgctggc 1000 agctgcccgc aaccccttca actgcgtgtg ccccctgac~c tggtttggcc 1050 cctgggtgcg cgagagccac gtcacactgg ccagccctga ggagacgcgc 1100 tgccacttcc cgcccaagaa cgctggccgg ctgctcctgg agcttgacta 1150 cgccgacttt ggctgcccag ccaccaccac cacagccaca gtgcccacca 1200 egaggcecgt ggtgegggag eeeaeageet.tgtcttetag cttggctcet 1250 acctggctta gccccacagc gccggccact gaggccccca gcccgccctc 1300 cactgcccca ccgactgtag ggcctgtccc ccagccccag gactgcccac 1350 cgtccacctg cctcaatggg ggcacatgcc acctggggac acggcaccac 1400 ctggcgtgct tgtgccccga aggcttcacg ggcctgtact gtgagagcca 1450 gatggggcag gggacacggc ccagccctac accagtcacg ccgaggccac 1500 cacggtccct gaccctgggc atcgagccgg tgagccccac ctccctgcgc 1550 gtggggctgc agcgctacct ccaggggagc tccgtgcac~c tcaggagcct 1600 ccgtctcacc tatcgcaacc tatcgggccc tgataagcgg ctggtgacgc 1650 tgcgactgcc tgcctcgctc gctgagtaca cggtcaccr_a gctgcggccc 1700 aacgccactt actccgtctg tgtcatgcct tfggggcccg ggcgggtgcc 1750 ggagggcgag gaggcctgcg gggaggccca tacaccccca gccgtccact 1800 ".~ ~ , .~s"~v,.~~,~,~~ ., ~, r~,~~ a~~~.~.~~.~~~ ,"$~~~ 7~~~w FY,~"~
...~~~~F.,_.~~.ea. ~~, ,~ ~ xw~,~~.~

PCT-u500-23328_5equence ccaaccacgc cccagtcacc caggcccgcg agggcaacct gccgctcctc 1850 attgcgcccg ccctggccgc ggtgctcctg gccgcgctgg ctgcggtggg 1900 ggcagcctac tgtgtgcggc gggggcgggc catggcagc<~ gcggctcagg 1950 acaaagggca ggtggggcca ggggctgggc ccctggaact ggagggagtg 2000 aaggtcccct tggagccagg cccgaaggca acagagggcg gtggagaggc 2050 cctgcccagc gggtctgagt gtgaggtgcc actcatgggc ttcccagggc 2100 ctggcctcca gtcacccctc cacgcaaagc cetacatcta agccagagag 2150 agacagggca gctggggccg ggctctcagc cagtgagatg gccagccccc 2200 tcctgctgcc acaccacgta agttctcagt cccaacctcg gggatgtgtg 2250 cagacagggc tgtgtgacca cagctgggcc ctgttccctc tggacctcgg 2300 tctcctcatc tgtgagatgc tgtggcccag ctgacgagcc ~taacgtccc 2350 cagaaccgag tgcctatgag gacagtgtcc gccctgccct~ccgcaacgtg 2400 cagtccctgg gcacggcggg ccctgccatg tgctggtaac gcatgcctgg 2450 gtcctgctgg gctctcccac tccaggcgga ccctgggggc cagtgaagga 2500 agctcccgga aagagcagag ggagagcggg taggcggctg tgtgactcta 2550 gtcttggccc caggaagcga aggaacaaaa gaaactggaa aggaagatgc 2600 tttaggaaca tgttttgctt ttttaaaata tatatattta taagagatcc 2650 tttcccattt attctgggaa gatgtttttc aaactcagag acaaggactt 2700 tggtttttgt aagacaaacg atgatatgaa ggccttttgt aagaaaaaat 2750 aaaagatgaa gtgtgaaa 2768 <210> 16 <211> 673 <212> PRT
<213> Homo Sapien <400> 16 Met Cys Ser Arg Val Pro Leu i.eu Leu Pro Leu Leu Leu Leu Leu I 5 10 15 w Ala Leu Gly Pro Gly Vai Gin Giy Cys Pro Ser Giy Cys Gln Cys ser Gln Pro Gln Thr val Phe Cys Thr Ala Arg Gln Gly Thr Thr val Pro Arg Asp val Pro Pro Asp Thr Val Giy Leu Tyr Val Phe Glu ASn Gly Ile Thr Met Leu Asp A7a Gly Ser Phe Ala Gly Leu Pro Gly Leu Gln Leu Leu Asp Leu Ser Gln Asn Gln Ile Ala Ser PCT-uS00-23328_Sequence Leu Pro Ser Gly va7 Phe Gln Pro Leu Ala Asn Leu Ser Asn Leu Asp Leu Thr Ala Asn Arg Leu His Glu Ile Thr Asn Glu Thr Phe Arg Gly Leu Arg Arg Leu Glu Arg Leu Tyr Leu Gly Lys Asn Arg Tle Arg His Ile Gln Pro Gly Ala Phe Asp Thr Leu ASp Arg Leu Leu Glu Leu Lys Leu Gln Asp Asn Glu Leu Arg Ala Leu Pro Pro Leu Arg Leu Pro Arg Leu Leu Leu Leu Asp Leu Ser His Asn Ser Leu Leu Ala Leu Glu Pro Gly Ile Leu Asp Thr Ala Asn Val Glu Ala Leu Arg Leu Ala Gly Leu Gly Leu Gln Gln Leu Asp Glu Gly Leu Phe Ser Arg Leu Arg Asn Leu His Asp Leu Asp Val Ser Asp Asn Gln Leu Glu Arg Val Pro Pro Val Ile Arg Giy Leu Arg Gly Leu Thr Arg Leu Arg Leu Ala Gly Asn Thr Arg Ile Ala Gln Leu Arg Pro Glu Asp Leu Ala Gly Leu Ala Ala Leu Gln Glu Leu Asp Val Ser Asn Leu Ser Leu Gln Ala Leu Pro Gly Asp Leu Ser Gly Leu Phe Pro Arg Leu Arg Leu Leu Ala Ala Ala Arg Asn Pro Phe Asn Cys Val Cys Pro Leu ser Trp Phe Gly Pro Trp Val Arg Glu Ser His Val Thr Leu Ala Ser Pro Glu Glu Thr Arg Cys His Phe Pro Pro Lys Asn Ala Gly Arg Leu Leu Leu Glu Leu Asp Tyr Ala Asp Phe Gly Cys Pro Ala Thr Thr Thr Thr Ala Thr Val Pro Thr Thr Arg Pro Val Val Arg Glu Pro Thr Ala Leu Ser Ser Ser Leu Ala Pro Thr Trp Leu Ser Pro Thr Ala Pro Ala Thr Glu Ala Pro Ser Pro Pro Ser Thr Ala Pro Pro Thr Val Gly Pro Val Pro Gln .".." . , . ,. xe w: n ~",n:..:.~au _,u..v.awma~ntaw.~ r ..~... :~urwm.. v~:-,."~.>..~~~nrzwaeu,~~~.P. M..:~,ny~.~,:c~;~ia~e~aua, ,~"~r,~.~q-,~,r~.,.~~"~
~;,~Un.~".""~e",..."~.~Hw,~F.~.x".:..,,.. ~....~,..-".,..."...,.-.~....,~...m....~.A"~

PCT-US00-23328_Sequence Pro Gln Asp Cys Pro Pro Ser Thr Cys Leu Asn Gly Gly Thr Cys His Leu Gly Thr Arg His His Leu Ala Cys Leu Cys Pro Glu Gly Phe Thr Gly Leu Tyr Cys Glu Ser Gln Met Gly Gln Gly Thr Arg Pro Ser Pro Thr Pro Val Thr Pro Arg Pro Pro Arg Ser Leu Thr Leu Gly Ile Glu Pro Val 5er Pro Thr Ser Leu Arg Val Gly Leu Gln Arg Tyr Leu Gln Gly Ser Ser Val Gln Leu Arg Ser Leu Arg Leu Thr Tyr Arg Asn Leu Ser Gly Pro Asp Lys Arg Leu Val Thr Leu Arg Leu Pro Ala Ser Leu Ala Glu Tyr Thr Val Thr Gln Leu Arg Pro Asn Ala Thr Tyr Ser Val Cys Val Met Pro Leu Gly Pro Gly Arg Val Pro Glu Gly Glu Glu Ala Cys Gly Glu Ala His Thr Pro Pro Ala Val His Ser Asn His Ala Pro Val Thr Gln Ala Arg Glu Gly Asn Leu Pro Leu Leu Ile Ala Pro Ala Leu Ala Ala Va7 Leu Leu Ala Ala Leu Ala Ala Val Gly Ala Ala Tyr Cys Val Arg Arg Gly Arg Ala Met Ala Ala Ala Ala Gln Asp Lys Gly Gln Val Gly Pro Gly Ala Gly Pro Leu Glu Leu Glu Gly Val Lys Val Pro Leu Glu Pro Gly Pro Lys Ala Thr Glu Gly Gly G1y Glu Ala Leu Pro Ser Gly Ser Glu Cys Glu Val Pro Leu Met Gly Phe Pro Gly Pro Gly Leu Gln Ser Pro Leu His Ala Lys Pro Tyr Ile <210> 17 <211> 1672 <212> DNA
<213> Homo Sapien , ~.
<400> 17 gcagcggcga ggcggcggtg gtggctgagt ccgtggtggc agaggcgaag SO

....~--~------PCT-uS00-23328_Sequence gcgacagctc atgcgggtcc ggatagggct gacgctgctg ctgtgtgcgg 100 tgctgctgag cttggcctcg gcgtcctcgg atgaagaagg cagccaggat 150 gaatccttag attccaagac tactttgaca tcagatgagt cagtaaagga 200 ccatactact gcaggcagag tagttgctgg tcaaatattt cttgattcag 250 aagaatctga attagaatcc tctattcaag aagaggaaga cagcctcaag 300 agccaagagg gggaaagtgt cacagaagat atcagctttc tagagtctcc 350 aaatccagaa aacaaggact atgaagagcc aaagaaagt;a cggaaaccag 400 ctttgaccgc cattgaaggc acagcacatg gggagccctg ccacttccct 450 tttcttttcc tagataagga gtatgatgaa tgtacatcag atgggaggga 500 agatggcaga ctgtggtgtg ctacaaccta tgactacaa;a gcagatgaaa 550 agtggggctt ttgtgaaact gaagaagagg ctgctaaga~g acggcagatg 600 caggaagcag aaatgatgta tcaaactgga atgaaaatcc ttaatggaag 650 caataagaaa agccaaaaaa gagaagcata tcggtatctc caaaaggcag 700 caagcatgaa ccataccaaa gccctggaga gagtgtcat~a tgctctttta 750 tttggtgatt acttgccaca gaatatccag gcagcgaga~g agatgtttga 800 gaagctgact gaggaaggct ctcccaaggg acagactgct cttggctttc 8SO
tgtatgcctc tggacttggt gttaattcaa gtcaggcaaa ggctcttgta 900 tattatacat ttggagctct tgggggcaat ctaatagccc acatggtttt 950 ggtaagtaga ctttagtgga aggctaataa tattaacatc agaagaattt 1000 gtggtttata gcggccacaa ctttttcagc tttcatgatc cagatttgct 1050 tgtattaaga ccaaatattc agttgaactt ccttcaaatt cttgttaatg 1100 gatataacac atggaatcta catgtaaatg aaagttggtg gagtccacaa 1150 tttttcttta aaatgattag tttggctgat tgcccctaaa aagagagatc 1200 tgataaatgg ctctttttaa attttctctg agttggaatt gtcagaatca 1250 ttttttacat tagattatca taattttaaa aatttttctt tagtttttca 1300 aaattttgta aatggtggct atagaaaaac aacatgaaat attatacaat 1350 attttgcaac aatgccctaa gaattgttaa aattcatgga gttatttgtg 1400 cagaatgact ccagagagct ctactttctg ttttttactt ttcatgattg 1450 gctgtcttcc catttattct ggtcatttat tgctagtgac actgtgcctg 1500 cttccagtag tctcattttc cctattttgc taatttgtta ctttttcttt 1550-gctaatttgg aagattaact catttttaat aaaattatgt etaagattaa 1600 ~..,.~w.>~~-~ ~ ~. ~ n~v. m ~ ~ =fr._ ~~ ._ ,.~~~, , ~ a _.-.. ~ ~.~w~.,.
.. .- . ._ . . . .., .~t r _,.." .. .»~,.', - a "n~.,.,.a..xza.... .m :..as~a rsr s.,:.t.,w.H.-s .,....». a ,J~T.C.3y&~n~~s~MST s.

Pcr-US00-23328_Sequence aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 1650 aaaaaaaaaa aaaaaaaaaa as 1672 <210> 18 <211> 301 <212> PRT
<213> Homo Sapien <400> 18 Met Arg Val Arg Ile Gly Leu Thr Leu Leu Leu Cys Ala Val Leu Leu Ser Leu~ Ala Ser Ala Ser Ser Asp Glu Glu Gly Ser Gln Asp Glu Ser Leu Asp Ser Lys Thr Thr Leu Thr Ser Asp Glu Ser Val Lys Asp His Thr Thr Ala Gly Arg Val Val Ala Gly Gln Ile Phe Leu Asp Ser Glu Glu Ser Glu Leu Glu Ser Ser Ile Gln Glu Glu Glu Asp Ser Leu Lys Ser Gln Glu Gly Glu Ser Val Thr Glu Asp Ile Ser Phe Leu Glu Ser Pro Asn Pro Glu Asn Lys Asp Tyr Glu Glu Pro Lys Lys Val Arg Lys Pro Ala Leu Thr Ala Ile Glu Gly Thr Ala His Gly Glu Pro Cys His Phe Pro Phe Leu Phe Leu Asp Lys Glu Tyr Asp Glu Cys Thr Ser Asp G1y Arg Glu asp Gly Arg Leu Trp Cys Ala Thr Thr Tyr Asp Tyr Lys Ala Asp Glu Lys Trp Gly Phe Cys Glu Thr Glu Glu Glu Ala Ala Lys Arg Arg Gln Met Gln Glu Ala Glu Met Met Tyr Gln Thr Gly Met Lys Ile Leu Asn Gly Ser Asn Lys Lys 5er Gln Lys Arg Glu Ala Tyr Arg Tyr Leu zoo 205 210 Gln Lys Ala Ala Ser Met Asn His Thr Lys Ala Leu Glu Arg Val Ser Tyr,Ala Leu Leu Phe Gly Asp Tyr Leu Pro Gln Asn Ile Gln Ala Ala Arg Glu Met Phe Glu Lys Leu Thr Glu Glu Gly Ser Pro Lys Gly Gln Thr 26~ Leu Gly Phe Leu 2 5 Ala Ser Gly Leu 2~0 F a . ~.. ~.-~,. ...~.,Y~. ~..,,~~-~~...~~~~~~.H. ~3~~~~~.~~m~~~~~
~..~«.~.,~,..~ ~,~ ~ -,e= ~,..- .~w~~

PCT-u500-23328_Sequence Val Asn Ser Ser Gln Ala Lys Ala Leu val Tyr Tyr Thr Phe Gly Ala Leu Gly Gly Asn Leu Iie Ala His Met val Leu val Ser Arg Leu <210> 19 -<211> 1508 <212> DNA
<213> Homo Sapien <400> 19 aattcagatt ttaagcccat tctgcagtgg aatttcatga actagcaaga 50 ggacaccatc ttcttgtatt atacaagaaa ggagtgtacc tatcacacac 100 agggggaaaa atgctctttt gggtgctagg cctcctaatc ctctgtggtt 150 ttctgtggac tcgtaaagga aaactaaaga ttgaagacat cactgataag 200 tacattttta tcactggatg tgactcgggc tttggaaact tggcagccag 250 aacttttgat aaaaagggat ttcatgtaat cgctgcctgt ctgactgaat 300 caggatcaac agctttaaag gcagaaacct cagagagact tcgtactgtg 350 cttctggatg tgaccgaccc agagaatgtc aagaggactg cccagtgggt 400 gaagaaccaa gttggggaga aaggtctctg gggtctgatc aataatgctg 450 gtgttcccgg cgtgctggct cccactgact ggctgacact agaggactac 500 agagaaccta ttgaagtgaa cctgtttgga ctcatcagtg tgacactaaa 550 tatgcttcct ttggtcaaga aagctcaagg gagagttatt aatgtctcca 600 gtgttggagg tcgccttgca atcgttggag ggggctatac tccatccaaa 650 tatgcagtgg aaggtttcaa tgacagctta agacgggaca. tgaaagcttt 700 tggtgtgcac gtctcatgca ttgaaccagg attgttcaaa acaaacttgg 750 cagatccagt aaaggtaatt gaaaaaaaac tcgccatttg ggagcagctg 800 tctccagaca tcaaacaaca atatggagaa ggttacattg aaaaaagtct 850 agacaaactg aaaggcaata aatcctatgt gaacatggac ctctctccgg 900 tggtagagtg catggaccac gctctaacaa gtctcttccc taagactcat 950 tatgccgctg gaaaagatgc caaaattttc tggatacctc tgtctcacat 1000 gccagcagct ttgcaagact ttttattgtt gaaacagaaa gcagagctgg 1050 ctaatcccaa ggcagtgtga ctcagctaac cacaaatgtc tcctccaggc 1100 tatgaaattg gccgatttca agaacacatc tccttttcaa ccccattcct 1150 tatetgctee aaeetggaet eatttagate gtgettattt ggattgeaaa 1200 ,. ..~ . nm ,~, "., , x <,..» . a ~,. __ a a. a.i:atllW0.hb'K>.a.....n..~d4'A2aAaY,'~W..~.u. ~,s.anw.mrv rn m x.~,v..,~Fm,euanatn atsaga.uuwaawaarc~.",~.n.wu~..mxra..-,.,m,,m..~erm,...mww..,~.."4 ~..,......."M.,~.-PCT-0500-23328_Sequence agggagtccc accatcgctg gtggtatccc agggtccctg etcaagtttt 1250 _ctttgaaaag gagggctgga atggtacatc acataggcaa gtcctgccct 1300 gtatttaggc tttgcctgct tggtgtgatg taagggaaat tgaaagactt 1350 gcccattcaa aatgatcttt accgtggcct gccccatgct tatggtcccc 1400 agcatttaca gtaacttgtg aatgttaagt atcatctctt atctaaatat 1450 taaaagataa gtcaacccaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 1500 aaaaaaaa 1508 <210> 20 <211> 319 <212> PRT
<213> Homo Sapien <400> 20 Met Leu Phe Trp Val Leu Gly Leu Leu Ile Leu Cys Gly Phe Leu Trp Thr Arg Lys Gly Lys Leu Lys Ile Glu Asp Ile Thr Asp Lys Tyr Ile Phe Ile Thr Gly Cys Asp Ser Gly Phe Gly Asn Leu Ala Ala Arg Thr Phe Asp Lys Lys Gly Phe His Val Ile Ala Ala Cys Leu Thr Glu Ser Gly Ser Thr Ala Leu Lys Ala Glu Thr Ser Glu Arg Leu Arg Thr Vai Leu Leu Asp Val Thr Asp Pro Glu Asn Val Lys Arg Thr Ala Gln Trp val Lys Asn Gln Val Gly Glu Lys Gly Leu Trp Gly Leu Ile Asn Asn Ala Gly val Pro Gly val Leu Ala Pro Thr Asp Trp Leu Thr Leu Glu Asp Tyr Arg Glu Pro Ile Glu vat Asn Leu Phe Gly Leu Ile ser val Thr Leu Asn Met Leu Pro Leu val Lys Lys Ala Gln Gly Arg val I1e Asn Val 5er ser val Gly Gly Arg Leu ala Ile val Gly Gly G1y Tyr Thr Pro Ser Lys Tyr Ala Val Glu Gly Phe Asn Asp Ser Leu Arg Arg Asp Met Lys 185 ' 190 19.5 Ala Phe Gly Val His val Ser Cys Ile Glu Pro Gly Leu Phe Lys PCT-u500-23328_Sequence Thr Asn Leu Ala Asp Pro Val Lys Val Ile Glu Lys Lys Leu Ala Ile Trp Glu Gln Leu Ser Pro Asp Ile Lys G7n Gln Tyr Gly Glu Gly Tyr Ile Glu Lys Ser Leu Asp Lys Leu Lys Gly Asn Lys Ser Tyr Val Asn Met Asp Leu Ser Pro Val Val Glu Cys Met Asp His Ala Leu Thr Ser Leu Phe Pro Lys Thr His Tyr Ala Ala G7y Lys Asp Ala Lys Ile Phe Trp Ile Pro Leu Ser His Met Pro Ala Ala Leu Gln Asp Phe Leu Leu Leu Lys Gln Lys Ala Glu Leu Ala Asn Pro Lys Ala Val <210> 21 <211> 1849 <212> DNA
<213> Homo Sapien <400> 21 ctgaggcggc ggtagcatgg agggggagag tacgtcggcg gtgctctcgg 50 gctttgtgct cggcgcactc gctttccagc acctcaacac ggactcggac 100 acggaaggtt ttcttcttgg ggaagtaaaa ggtgaagcca agaacagcat 150 tactgattcc caaatggatg atgttgaagt tgtttataca attgacattc 200 agaaatatat tccatgctat cagcttttta gcttttataa ttcttcaggc 250 gaagtaaatg agcaagcact gaagaaaata ttatcaaatg tcaaaaagaa 300 tgtggtaggt tggtacaaat tccgtcgtca ttcagatcag atcatgacgt 350 ttagagagag gctgcttcac aaaaacttgc aggagcattt ttcaaaccaa 400 gaccttgttt ttctgctatt aacaccaagt ataataacag aaagctgctc 450 tactcatcga ctggaacatt ccttatataa acctcaaaaa ggactttttc 500 acagggtacc tttagtggtt gccaatctgg gcatgtctga acaactgggt 550 tataaaactg tatcaggttc ctgtatgtcc actggtttta gccgagcagt 600 acaaacacac agctctaaat tttttgaaga agatggatcc ttaaaggagg 650 tacataagat aaatgaaatg tatgcttcat tacaagagga attaaagagt 700 atatgcaaaa aagtggaaga cagtgaacaa gcagtagata aactagtaaa 750 ggatgtaaac agattaaaac gagaaattga gaaaaggaga ggagcacaga 800 ttcaggcagc aagagagaag aacatccaaa aagaccctca ggagaacatt 850 PCT-uS00-23328_Sequence tttctttgtc aggcattacg gacctttttt ccaaattctg aatttcttca 900 ttcatgtgtt atgtctttaa aaaatagaca tgtttctaaa agtagctgta 950 actacaacca ccatctcgat gtagtagaca atctgacctt aatggtagaa 1000 cacactgaca ttcctgaagc tagtccagct agtacaccac aaatcattaa 1050 gcataaagcc ttagacttag atgacagatg gcaattcaag agatctcggt 1100 tgttagatac acaagacaaa cgatctaaag caaatactgg tagtagtaac 1150 caagataaag catccaaaat gagcagccca gaaacagatg aagaaattga 1200 aaagatgaag ggttttggtg aatattcacg gtctcctaca ttttgatcct 1250 tttaacctta caaggagatt tttttatttg gctgatgggt aaagccaaac 1300 atttctattg tttttactat gttgagctac ttgcagtaag ttcatttgtt 1350 tttactatgt tcacctgttt gcagtaatac acagataact cttagtgcat 1400 ttacttcaca aagtactttt tcaaacatca gatgctttta tttccaaacc 1450 tttttttcac ctttcactaa gttgttgagg ggaaggctta cacagacaca 1500 ttctttagaa ttggaaaagt gagaccaggc acagtggctc acacctgtaa 1550 tcccagcact tagggaagac aagtcaggag gattgattga agctaggagt 1600 tagagaccag.cctgggcaac gtattgagac catgtctatt aaaaaataaa 1650 atggaaaagc aagaatagcc ttattttcaa aatatggaaa gaaatttata 1700 tgaaaattta tctgagtcat taaaattctc cttaagtgat acttttttag 1750 aagtacatta tggctagagt tgccagataa aatgctggat atcatgcaat 1800 aaatttgcaa aacatcatct aaaatttaaa aaaaaaaaaa aaaaaaaaa 1849 <210> 22 <211> 409 <212> PRT
<213> Homo Sapien <400> 22 Met Glu Gly Glu Ser Thr Ser Ala 1/al Leu Ser Gly Phe Val Leu Gly Ala Leu Ala Phe Gln His Leu Asn Thr Asp Ser ASp Thr Glu Gly Phe Leu Leu Gly Glu val Lys Gly Glu Ala Lys Asn Ser zle Thr Asp Ser Gln Met Asp Asp Val Glu val va'I Tyr Thr zle Asp zle Gin Lys Tyr zle Pro cys Tyr Gin Leu Phe ser Phe Tyr Asn Ser Ser Gly Glu Val Asn Giu Gln Ala Leu Lys Lys Ile Leu Ser PCT-u500-23328_Sequence Asn Val Lys Lys Asn Val Val Gly Trp Tyr Lys Phe Arg Arg His Ser Asp Gln Ile Met Thr Phe Arg Glu Arg Leu Leu His Lys Asn Leu Gln Glu His Phe Ser Asn Gln Asp Leu Val Phe Leu Leu Leu 125 130 i35 Thr Pro Ser Ile Ile Thr Glu Ser Cys Ser Thr His Arg Leu Glu His Ser Leu Tyr Lys Pro Gln Ly5 Gly Leu Phe His Arg Val Pro Leu Val Val Ala Asn Leu Gly Met Ser Glu Gln Leu Gly Tyr Lys Thr Val Ser Gly Ser Cys Met Ser Thr Gly Phe Ser Arg Ala Val Gln Thr His Ser Ser Lys Phe Phe Glu Glu Asp Gly Ser Leu Lys Glu Val His Lys Ile Asn Glu Met Tyr Ala Ser Leu Gln Glu Glu Leu Lys Ser Ile Cys Lys Lys Val Glu Asp Ser Glu Gln Ala val Asp Lys Leu Val Lys Asp Val Asn Arg Leu Lys Arg Glu Ile Glu Lys Arg Arg Gly Ala Gln Ile Gln Ala Ala Arg Glu Lys Asn Ile Gln Lys asp Pro Gln Glu Asn Ile Phe Leu Cys Gln Ala Leu Arg Thr Phe Phe Pro Asn Ser Glu Phe Leu His Ser Cys Val Met Ser Leu Lys Asn Arg His Val Ser Lys Ser Ser Cys Asn Tyr Asn His His Leu Asp Val val Asp Asn Leu Thr Leu Met val Glu His Thr Asp Ile Pro Glu Ala Ser Pro Ala Ser Thr Pro Gln zle Ile Lys His Lys Ala Leu Asp Leu Asp Asp Arg Trp Gln Phe Lys Arg Ser 350 355 3b0 Arg Leu Leu Asp Thr Gln Asp Lys Arg Ser Lys Ala Asn Thr Gly Ser Ser ASn Gln Asp Lys Ala Ser Lys Met Ser Ser Pro Glu Thr Asp Glu Glu Ile Glu Lys Met Lys Gly Phe Gly Glu Tyr Ser Arg r- .. ....v,-,"vum,.. -r., .. ." q,~pmxAY?fi,..,~-,wFnsp~
~,~~~.yn.°.erx,.etrR.~x~x5.n,-..x:ro..<wnw.,mo...nnvrzruw~w.vsmxuw~rnr-xwf~~~.ra~~~.m-mmHe~,a,smrawtG.rss.
._ , x.M ..nhTr.-a..~..2., s,. ".. rr Wa>s~ .WY'tt'fi~,5'Nn4 ~xY~.A.fy~;-e:-W."'>~S"!'~sl~..'a' ~~

PCT-uS00-23328_Sequence Ser Pro Thr Phe <210> 23 <21I> 2651 <212> t~NA
<213> Homo Sapien <400> 23 -ggcacagccg cgcggcggag ggcagagtca gccgagccga gtccagccgg 50 acgagcggac cagcgcaggg cagcccaagc agcgcgcagc gaacgcccgc 100 cgccgcccac accctctgcg gtccccgcgg cgcctgccac ccttccctcc 150 ttccccgcgt ccccgcctcg ccggccagtc agcttgccgg gttcgctgcc 200 ccgcgaaacc ccgaggtcac cagcccgcgc ctctgcttcc ctgggccgcg 250 cgccgcctcc acgccctcct tctcccctgg cccggcgcct ggcaccgggg 300 accgttgcct gacgcgaggc ccagctctac ttttcgcccc gcgtctcctc 350 cgcctgctcg cctcttccac caactccaac tccttctccc tccagctcca 400 ctcgctagtc cccgactccg ccagccctcg gcccgctgcc gtagcgccgc 450 ttcccgtccg gtcccaaagg tgggaacgcg tccgccccgg cccgcaccat 500 ggcacggttc ggcttgcccg cgcttctctg caccctggca gtgctcagcg 550 w ccgcgctgct ggctgccgag ctcaagtcga aaagttgctc ggaagtgcga 600 egtctttaeg tgtccaaagg etteaacaag aacgatgccc ecctceacga 650 gatcaacggt gatcatttga agatctgtcc ccagggttct acctgctgct 700 ctcaagagat ggaggagaag tacagcctgc aaagtaaaga tgatttcaaa 750 agtgtggtca gcgaacagtg caatcatttg caagctgtct ttgcttcacg 800 ttacaagaag tttgatgaat tcttcaaaga actacttgaa aatgcagaga 850 aatccctgaa tgatatgttt gtgaagacat atggccattt atacatgcaa 900 aattctgagc tatttaaaga tctcttcgta gagttgaaac gttactacgt 950 ggtgggaaat gtgaacctgg aagaaatgct aaatgacttc tgggctcgcc 1000 tcctggagcg gatgttccgc ctggtgaact cccagtacca ctttacagat 1050 gagtatctgg aatgtgtgag caagtatacg gagcagctga agcccttcgg 1100 agatgtccct cgcaaattga agctccaggt tactcgtgct tttgtagcag 1150 cccgtacttt cgctcaaggc ttagcggttg cgggagatgt cgtgagcaag 1200 gtctccgtgg taaaccccac agcccagtgt acccatgccc tgttgaagat 1250 gatctactgc tcccactgcc ggggtctcgt gactgtgaag ccatgttaca 1300 .... , n ~ .. ., _ . ,~ . ~yaz~ ~.~. .~. aa,~ n ~. . . ,,~ , ~ . .. . , .
~x,~z ,. .
~unnw . nc~a~nuzerz»n..,a:~~-~4~~N»-r_c",r~rzxm~nrr .~ rorvm,,~,- x,.-"we"c,~...e~.s~.,.wvuro~w"~.~.,m~..w~w":""m,.ww,zocs _,a, ~ ~a~~~~~

PCr-u500-23328_sequence actactgctc aaacatcatg agaggctgtt tggccaacca aggggatctc 1350 gattttgaat ggaacaattt catagatgct atgctgatgg tggcagagag 1400 gctagagggt cctttcaaca ttgaatcggt catggatccc atcgatgtga 1450 agatttctga tgctattatg aacatgcagg ataatagtgt tcaagtgtct 1500 cagaaggttt tccagggatg tggacccccc aagcccctcc cagctggacg 1550 aatttctcgt tccatctctg aaagtgcctt cagtgctcgc ttcagaccac 1600 atcaccccga ggaacgccca accacagcag ctggcactag tttggaccga 1650 ctggttactg atgtcaagga gaaactgaaa caggccaaga aattctggtc 1700 ctcccttccg agcaacgttt gcaacgatga gaggatggct gcaggaaacg 1750 gcaatgagga tgactgttgg aatgggaaag gcaaaagcag gtacctgttt 1800 gcagtgacag gaaatggatt agccaaccag ggcaacaacc cagaggtcca 1850 ggttgacacc agcaaaccag acatactgat ccttcgtcaa atcatggctc 1900 ttcgagtgat gaccagcaag atgaagaatg catacaatgg gaacgacgtg 1950 gacttctttg atatcagtga tgaaagtagt ggagaaggaa gtggaagtgg 2000 ctgtgagtat eagcagtgce etteagagtt tgaetaeaat gccactgace 2050 atgctgggaa gagtgccaat gagaaagccg acagtgctgg tgtccgtcct 2100 ggggcacagg cctacctcct cactgtcttc tgcatcttgt tcctggttat 2150 gcagagagag tggagataat tctcaaactc tgagaaaaag tgttcatcaa 2200 aaagttaaaa ggcaccagtt atcacttttc taccatccta gtgactttgc 2250 tttttaaatg aatggacaac aatgtacagt ttttactatg tggccactgg 2300 tttaagaagt gctgactttg ttttctcatt cagttttggg aggaaaaggg 2350 actgtgcatt gagttggttc ctgctccccc aaaccatgtt aaacgtggct 2400 aacagtgtag gtacagaact atagttagtt gtgcatttgt gattttatca 2450 ctctattatt tgtttgtatg tttttttctc atttcgtttg tgggtttttt 2500 tttccaactg tgatctcgcc ttgtttctta caagcaaacc agggtccctt 2550 cttggcacgt aacatgtacg tatttctgaa atattaaata gctgtacaga 2600 agcaggtttt atttatcatg ttatcttatt aaaagaaaaa gcccaaaaag 2650 c 2651 <210> 24 <211> 556 <212> PRT
<213> Homo sapien <400> 24 Met Ala Arg Phe Gly Leu Pro Ala Leu Leu cys Thr Leu Ala Val v n..._ .. , . . ~ . n n"xo-~~>. r ,..m,n..-_ wnw..~,~. _ ~-.~.aunv.».rzr.. ~, W~=»~~...~urv-,dc ,aa,.~:~awar~.,TU ~.:~~~xxw.~v~."~"s,v~; ms~ ,.~..". .
w,."."".., ..,..........,..,.,.M ,..,-....>. ."..~..,"~,,~,.~.~n.~.w-.
.~n.,an"..,~.,:~.~.:,._,~.,.....~,.~.~:~..~ .m ""e~.~.

PCT-uS00-23328_Sequence LeuSerAlaAla LeuLeuAla AlaGlu LeuLysSer LysSerCys SerGluValArg ArgLeuTyr ValSer LysGlyPhe AsnLysAsn AspAlaProLeu HisGluI1e AsnGly AspHisLeu LysIleCys ProGlnGlySer ThrCysCys SerGln GluMetGlu GluLysTyr SerLeuGlnSer LysAspAsp PheLys SerValVal SerGluGln CysAsnHisLeu GlnAlaVal PheAla SerArgTyr LysLysPhe AspGluPhePhe LysGluLe,uLeuGlu AsnAlaGlu LysSerLeu AsnAspMetPhe ValLysThr TyrGly HisLeuTyr MetGlnAsn SerGluLeuPhe LysAspLeu PheYal GluLeuLys ArgTyrTyr ValValGlyAsn ValAsnLeu GluGlu MetLeuAsn AspPheTrp AlaArgLeuLeu GluArgMet PheArg LeuValAsn SerGlnTyr HisPheThrAsp GluTyrLeu GluCy5 YalSerLys TyrThrGlu GlnLeuLysPro PheGlyAsp ValPro ArgLysLeu LysLeuGln ValThrArgAla PheYalAla AlaArg ThrPheAla GlnGlyteu 215 220 22s AlaYalAlaGly AspYalYal SerLys ValSerYal YalAsnPro .

ThrAlaGlnCys ThrHisAla LeuLeu LysMetIle TyrCysSer HisCysArgGly LeuValThr ValLys ProCysTyr AsnTyrCys SerAsnIleMet ArgGlyCys LeuAla AsnGlnGly AspLeuAsp PheGluTrpAsn AsnPheIle AspAla MetLeuMet ValAlaGlu ArgLeuGluGly ProPheAsn IleGlu SerYalMet AspProale AspValLysIle SerAspAla IleMet AsnMetGln AspAsnSer Pag e PCT-u500-23328_Sequence Val Gln Val Ser Gln Lys Val Phe Gln Gly Cys Gly Pro Pro Lys Pro Leu Pro Ala Gly Arg Ile Ser Arg Ser Ile Ser Glu Ser Ala Phe Ser Ala Arg Phe Arg Pro His His Pro Glu Glu Arg Pro Thr Thr Ala Ala G1y Thr Ser Leu Asp Arg Leu Val Thr Asp Val Lys G1u Lys Leu Lys G1n Ala Lys Lys Phe Trp Ser Ser Leu Pro Ser Asn Va1 Cys Asn Asp Glu Arg Met Ala Ala Gly Asn Gly Asn Glu 410 ~ 415 420 ASp Asp Cys Trp Asn Gly Lys Gly Lys Ser Arg Tyr Leu Phe Ala .425 430 435 val Thr Gly Asn G1y Leu Ala Asn Gln Gly ASn Asn Pro Glu val Gln val Asp Thr Ser Lys Pro Asp Ile Leu Ile Leu Arg Gln Ile Met Ala Leu Arg Val Met Thr Ser Lys Met Lys Asn Ala Tyr Asn Gly Asn Asp Val Asp Phe Phe Asp Ile Ser Asp Glu Ser Ser Gly Glu Gly Ser Gly Ser Gly Cys Glu Tyr Gln Gln Cys Pro Ser Glu Phe Asp Tyr Asn Ala Thr Asp His Ala Gly Lys Ser Ala Asn Glu Lys Ala Asp Ser 530 Gly val Arg Pro 535 Ala Gln Ala Tyr 5~0 Leu Thr val Phe Cys Ile Leu Phe Leu Val Met Gln Arg Glu Trp 545 550 ~ 555 Arg <210> 25 <211> 870 <212> DNA
<213> Homo Sapien <400> 25 ctcgccctca aatgggaacg ctggcctggg actaaagcat agaccaccag 50 gctgagtatc ctgacctgag tcatccccag ggatcaggag cctccagcag 100 ggaaccttcc attatattct tcaagcaact tacagctgca ccgacagttg 150 cgatgaaagt tctaatctct tccctcctcc tgttgctgcc actaatgctg 200 PCT-uS00-23328_Sequence atgtccatgg tctctagcag cctgaatcca ggggtcgcca gaggccacag 250 ggaccgaggc caggcttcta ggagatggct ccaggaaggc ggccaagaat 300 gtgagtgcaa agattggttc ctgagagccc cgagaagaaa attcatgaca 350 gtgtctgggc tgccaaagaa gcagtgcccc tgtgatcatt tcaagggcaa 400 tgtgaagaaa acaagacacc aaaggcacca cagaaagcca aacaagcatt 450 ccagagcctg ccagcaattt ctcaaacaat gtcagctaag aagctttgct 500 ctgcctttgt aggagctctg agcgcccact cttccaatta aacattctca 550 gccaagaaga cagtgagcac acctaccaga cactcttctt ctcccacctc 600 actctcccac tgtacccacc cctaaatcat tccagtgctc tcaaaaagca 650 tgtttttcaa gatcattttg tttgttgctc tctctagtgt cttcttctct 700 cgtcagtctt agcctgtgcc ctccccttac ccaggcttag gcttaattac 750 ctgaaagatt ccaggaaact gtagcttcct agctagtgte atttaacctt 800 aaatgcaatc aggaaagtag caaacagaag tcaataaata tttttaaatg 850 tcaaaaaaaa aaaaaaaaaa 870 <210> 26 <211> 119 <212> PRT
<213> Homo sapien <400> 26 Met Lys Val Leu Ile Ser Ser Leu Leu Leu Leu Leu Pro Leu Met Leu Met Ser Met val ser ser ser Leu Asn Pro Gly val Ala Arg Gly His Arg Asp Arg Gly Gln Ala Ser Arg Arg Trp Leu Gln Glu Gly Gly Gln Glu Cys Glu Cys Lys Asp Trp Phe Leu Arg Ala Pro Arg Arg Lys Phe Met Thr val Ser Gly Leu Pro Lys Lys Gln Cys Pro Cys Asp His Phe Lys Gly Asn val Lys Lys Thr Arg His Gln Arg His His Arg Lys Pro Asn Lys His Ser Arg Ala Cys Gln Gln Phe Leu Lys Gln Cys Gln Leu Arg Ser Phe Ala Leu Pro Leu <210> 27 ~ , <211> 1371 <212> DNA
<213> Homo sapien x, ...,..k. a . °'y'.'.a,~"W A'S;:F,.. ..~3~~s."r... ~'.,wq.....

PCT-u500-23328_Sequence <400> 27 ggacgccagc gcctgcagag gctgagcagg gaaaaagcr_a gtgccccagc 50 ggaagcacag ctcagagctg gtctgccatg gacatcctgg tcccactcct 100 gcagctgctg gtgctgcttc ttaccctgcc cctgcacctc atggctctgc 150 tgggctgctg gcagcccctg tgcaaaagct acttccccta cctgatggcc 200 gtgctgactc ccaagagcaa ccgcaagatg gagagcaaga aacgggagct 250 cttcagccag ataaaggggc ttacaggagc ctccgggaaa gtggccctac 300 tggagctggg ctgtggaacc ggagccaact ttcagttcta cccaccgggc 350 tgcagggtca cctgcctaga cccaaatccc cactttgaga agttcctgac 400 aaagagca~g gctgagaaca ggcacctcca atatgagcgg tttgtggtgg 450 ctcctggaga ggacatgaga cagctggctg atggctccat ggatgtggtg 500 gtctgcactc tggtgctgtg ctctgtgcag agcccaagga aggtcctgca 550 ggaggtccgg agagtactga gaccgggagg tgtgctcttt ttctgggagc 600 atgtggcaga accatatgga agetgggcct tcatgtggca gcaagttttc 650 gagcccacct ggaaacacat tggggatggc tgctgcctca ccagagagac 700 ctggaaggat cttgagaacg cccagttctc cgaaatccaa atggaacgac 750 agccccctcc cttgaagtgg ctacctgttg ggccccacat catgggaaag 800 gctgtcaaac aatctttccc aagctccaag gcactcattt gctccttccc 850 cagcctccaa ttagaacaag ccacccacca gcctatctat cttccactga 900 gagggaccta gcagaatgag agaagacatt catgtaccac ctactagtcc 950 ctctctcccc aacctctgcc agggcaatct ctaacttcaa tcccgccttc 1000 gacagtgaaa aagctctact tctacgctga cccagggagg aaacactagg 1050 accctgttgt atcctcaact gcaagtttct ggactagtct cccaacgttt 1100 gcctcccaat gttgtccctt tccttcgttc ccatggtaaa gctcctctcg 1150 ctttcctcct gaggctacac ccatgcgtct ctaggaactg gtcacaaaag 1200 tcatggtgcc tgcatccctg ccaagccccc ctgaccctct ctccccacta 1250 ccaccttctt cctgagctgg gggcaccagg gagaatcaga gatgctgggg 1300 atgccagagc aagactcaaa gaggcagagg ttttgttctc aaatattttt 1350 taataaatag acgaaaccac g 1371 <210> 28 <211> 277 _ <212> PRT
<213> Homo Sapien .,a t,..~,~.,~.T.~.ur-= _~. ~.a.ar .~m~..._ ~ .. cKe,Yers~.,a~.1 .,. . .. . .
. _ ~=a......~~-n..~...,~.,... ."~.,~.,..,~._~uwda~..r PCT-0500-23328_Sequence <400>

Met AspIleLeu VaiProLeu LeuGlnLeu LeuVal LeuLeuLeu Thr LeuProLeu HisLeuMet AlaLeuLeu GlyCys TrpGlnPro Leu CysLysSer TyrPhePro TyrLeuMet AlaVal LeuThrPro Lys SerAsnArg LysMetGlu SerLysLys ArgGlu LeuPheSer 50 55 ~ 60 Gln IleLysGly LeuThrGly AlaSerGly LysVal AlaLeuLeu Glu LeuGlyCys GlyThrGly AlaAsnPhe GlnPhe TyrProPro Gly CysArgVal ThrCysLeu AspProAsn ProHis PheGluLys Phe LeuThrLys SerMetAla GluAsnArg HisLeu GlnTyrGlu Arg PheValVal AlaProGly GluAspMet ArgGln LeuAlaAsp Gly SerMetAsp ValValVal CysThrLeu ValLeu CysSerVal Gln SerProArg LysValLeu GlnGluVal ArgArg ValLeuArg Pro GlyGlyVal LeuPhePhe TrpGluHis ValAla GluProTyr Gly SerTrpAla PheMetTrp GlnGlnVal PheG1u ProThrTrp Lys HisIieGly AspGlyCys CysLeuThr ArgGlu ThrTrpLys 200 20.5 210 Asp LeuGluAsn AlaGlnPhe SerGluIle GlnMet GluArgGln Pro ProProLeu LysTrpLeu ProValGly ProHis IleMetGly 230 235 ~ 240 Lys AlaValLys GlnSerPhe ProSerSer LysAla LeuIleCys Ser PheProSer LeuGlnLeu GluGlnAla ThrHis GlnProIle Tyr LeuProLeu ArgGlyThr <210>29 <211>494 <212>DNA

<213>Homo Sapien PCT-u500-Z3328_se:quence <400> 29 caatgtttgc ctatccacct cccccaagcc cctttaccta tgctgctgct 50 aacgctgctg ctgctgctgc tgctgcttaa aggctcatgc ttggagtggg 100 gactggtcgg tgcccagaaa gtctcttctg ccactgacgc ccccatcagg 150 gattgggcct tctttccccc ttcctttctg tgtctcctgc ctcatcggcc 200 tgccatgacc tgcagccaag cccagccccg tggggaaggg gagaaagtgg 250 gggatggcta agaaagctgg gagataggga acagaagagg gtagtgggtg 300 ggctaggggg gctgccttat ttaaagtggt tgtttatgat tcttatacta 350 atttatacaa agatattaag gccctgttca ttaagaaatt gttcccttcc 400 cctgtgttca atgtttgtaa agattgttct gtgtaaatat gtctttataa 450 taaacagtta aaagctgaaa aaaaaaaaaa aaaaaaaaaa aaaa 494 <210> 30 <211> 73 <212> PRT
<213> Homo Sapien <400> 30 Met Leu Leu Leu Thr Leu Leu Leu Leu Leu Leu Leu Leu Lys Gly Ser Cys Leu Glu Trp Gly Leu Val Gly Ala Gln Lys Val Ser Ser Ala Thr Asp Ala Pro Ile Arg Asp Trp Ala Phe Phe Pro Pro Ser Phe Leu Cys Leu Leu Pro His Arg Pro Ala Met Thr Cys Ser Gln Ala G1n Pro Arg Gly Glu Gly Glu Lys Val Gly Asp Gly <210> 31 <211> 1660 <212> DNA
<213> Homo Sapien <400> 31 gtttgaattc cttcaactat acccacagtc caaaagcaga ctcactgtgt -50 cccaggctac cagttcctcc aagcaagtca tttcccttat ttaaccgatg 100 tgtccctcaa acacctgagt gctactccct atttgcatct gttttgataa 150 atgatgttga caccctccac cgaattctaa gtggaatca~t gtcgggaaga 200 gatacaatcc ttggcctgtg tatcctcgca ttagccttgt ctttggccat 250 gatgtttacc ttcagattca tcaccaccct tctggttcac: attttcattt 300 cattggttat tttgggattg ttgtttgtct gcggtgtttt atggtggctg 350 tattatgact ataccaacga cctcagcata gaattggaca cagaaaggga 400 PcT-u500-23328_Sequence aaatatgaag tgcgtgctgg ggtttgctat cgtatccac:a ggcatcacgg 450 cagtgctgct cgtcttgatt tttgttctca gaaagagaat aaaattgaca 500 gttgagcttt tccaaatcac aaataaagcc atcagcagtg ctcccttcct 550 gctgttccag ccactgtgga catttgccat cctcattttc ttctgggtcc 600 tctgggtggc tgtgctgctg agcctgggaa ctgcaggagc tgcccaggtt 650 atggaaggcg gccaagtgga atataagccc ctttcgggca ttcggtacat 700 gtggtcgtac catttaattg gcctcatctg gactagtgaa ttcatccttg 750 cgtgccagca aatgactat;a gctggggcag tggttacttg ttatttcaac 800 agaagtaaaa atgatcctc.c tgatcatccc atcctttcgt ctctctccat 850 tctcttcttc taccatcaag gaaccgttgt gaaagggtca tttttaatct 900 ctgtggtgag gattccgaga atcattgtca tgtacatgca aaacgcactg 950 aaagaacagc agcatggtgc attgtccagg tacctgttcc gatgctgcta 1000 ctgctgtttc tggtgtcttg acaaatacct gctccatctc aaccagaatg 1050 catatactac aactgctatt aatgggacag atttctgtac atcagcaaaa 1100 gatgcattca aaatcttgtc caagaactca agtcacttta catctattaa 1150 ctgctttgga gacttcataa tttttctagg aaaggtgtt~a gtggtgtgtt 1200 tcactgtttt tggaggactc atggctttta actacaatcg ggcattccag 1250 gtgtgggcag tccctctgtt attggtagct ttttttgcct acttagtagc 1300 ccatagtttt ttatctgtgt ttgaaactgt gctggatgca cttttcctgt 1350 gttttgctgt tgatctggaa acaaatgatg gatcgtcaga aaagccctac 1400 tttatggatc aagaatttct gagtttcgta aaaaggagca acaaattaaa 1450 caatgcaagg gcacagcagg acaagcactc attaaggaai: gaggagggaa 1500 cagaactcca ggccattgtg agatagatac ccatttaggt atctgtacct 1550 ggaaaacatt tccttctaag agccatttac agaatagaag atgagaccac 1600 tagagaaaag ttagtgaatt tttttttaaa agacctaata aaccctattc 1650 ttcctcaaaa 1660 <210> 32 <211> 445 <212> PRT , <213> Homo Sapien <400> 32 ..
Met Ser Gly Arg Asp Thr Ile Leu Gly Leu Cys Ile .Leu Ala Leu Ala Leu Ser Leu Ala Met Met Phe Thr Phe Arg Phe Ile Thr Thr PCT-uS00-23328_Sequence Leu Leu Val His Ile Phe Ile Ser Leu Val Ile Leu Gly Leu Leu 35 ~ 40 45 Phe Val Cys Gly Val Leu Trp Trp Leu Tyr Tyr Asp Tyr Thr Asn Asp Leu Ser Ile Glu Leu Asp Thr Glu Arg Glu Asn Met Lys Cys Val Leu Gly Phe Ala Ile Val Ser Thr Gly Ile Thr Ala Val Leu Leu Val Leu Ile Phe Val Leu Arg Lys Arg Ile Lys Leu Thr Val Glu Leu Phe Gln Ile Thr Asn Lys Ala Ile Ser Ser Ala Pro Phe Leu Leu Phe Gln Pro Leu Trp Thr Phe Ala Ile Leu Ile Phe Phe Trp Val Leu Trp Val Ala Val Leu Leu Ser Leu Gly Thr Ala Gly Ala Ala Gln Val Met Glu Gly Gly Gln Val Glu Tyr Lys Pro Leu Ser Gly Ile Arg Tyr Met Trp Ser Tyr His Leu Ile Gly Leu Ile Trp Thr Ser Glu Phe Ile Leu Ala Cys Gln Gln Met Thr I12 Ala Gly Ala val Val Thr Cys Tyr Phe Asn Arg Ser Lys Asn Asp Pro Pro Asp His Pro Ile Leu Ser Ser Leu Ser Ile Leu Phe Phe Tyr His Gln Gly Thr Val Val Lys Gly ser Phe Leu Ile Ser val Val Arg Ile Pro Arg Ile Ile Val Met Tyr Met Gln Asn Ala Leu Lys Glu Gln Gln His Gly Ala Leu Ser Arg Tyr Leu Phe Arg Cys Cys Tyr Cys Cys Phe Trp Cys Leu Asp Lys Tyr Leu Leu His Leu Asn G1n Asn Ala Tyr Thr Thr Thr Ala Ile Asn Gly Thr Asp Phe Cys Thr Ser Ala Lys Asp Ala Phe Lys Ile Leu Ser Lys Asn Ser Ser His Phe Thr Ser Ile Asn Cys Phe Gly Asp Phe: I1e Ile Phe Leu Gly Lys Val Leu Val Val Cys Phe Thr Vai Phe Gly Gly Leu Met PCT-0500-23328_Sequence Ala Phe Asn Tyr Asn Arg Ala Phe Gln Val Trp Ala Val Pro Leu Leu Leu Val Ala Phe Phe Ala Tyr Leu Val Ala His Ser Phe Leu Ser Val Phe Glu Thr Val Leu Asp Ala Leu Phe Leu Cys Phe Ala Val Asp Leu Glu Thr Asn Asp Gly Ser Ser Glu Lys Pro Tyr Phe Met Asp Gln Glu Phe Leu Ser Phe Val Lys Arg Ser Asn Lys Leu Asn Asn Ala Arg Ala Gln Gln Asp Lys His Ser Leu Arg Asn Glu Glu Gly Thr Glu Leu Gln Ala Ile Val Arg <210> 33 <211> 2773 <212> DNA
<213> Homo sapien <400> 33 gttcgattag ctcctctgag aagaagagaa aaggttcttg gacctctccc SO
tgtttcttcc ttagaataa~t ttgtatggga tttgtgatgc aggaaagcct 100 aagggaaaaa gaatattcat tctgtgtggt gaaaattttt tgaaaaaaaa 150 attgccttct tcaaacaagg gtgtcattct gatatttatg aggactgttg 200 ttctcactat gaaggcatct gttattgaaa tgttccttgt tttgctggtg- 250 actggagtac attcaaaca<~ agaaacggca aagaagatt<~. aaaggcccaa 300 gttcactgtg cctcagatca actgcgatgt caaagccgga aagatcatcg 350 atcctgagtt cattgtgaaa tgtccagcag gatgccaaga ccccaaatac 400 catgtttatg gcactgacgt gtatgcatcc tactccagtg tgtgtggcgc 450 tgccgtacac agtggtgtgc ttgataattc aggagggaaa atacttgttc 500 ggaaggttgc tggacagtct ggttacaaag ggagttattc caacggtgtc 550 caatcgttat ccctaccacg atggagagaa tcctttatcg tcttagaaag 600 taaacccaaa aagggtgtaa cctacccatc agctcttaca tactcatcat 650 cgaaaagtcc agctgcccaa gcaggtgaga ccacaaaagc: ctatcagagg 700 ccacctattc cagggacaac tgcacagccg gtcactctga tgcagcttct 750 "_, ggctgtcact gtagctgtgg ccacccccac caccttgcca aggccatccc 800 , cttctgctgc ttctaccacc: agcatcccca gaccacaatc: agtgggccac 850 u~~~.

PCT-uS00-23328_Sequence aggagccagg agatggatct ctggtccact gccacctaca caagcagcca 900 aaacaggccc agagctgatc caggtatcca aaggcaagat ccttcaggag 950 ctgccttcca gaaacctgtt ggagcggatg tcagcctggg acttgttcca 1000 aaagaagaat tgagcacaca gtctttggag ccagtatccc tgggagatcc 1050 aaactgcaaa attgacttgt cgtttttaat tgatgggagc accagcattg 1100 gcaaacggcg attccgaatc cagaagcagc tcctggctga tgttgcccaa 1150 gctcttgaca ttggccctgc cggtccactg atgggtgttg tccagtatgg 1200 agacaaccct gctactcact ttaacctcaa gacacacacg aattctcgag 1250 atctgaagac agccatagag aaaattactc agagaggagg actttctaat 1300 gtaggtcggg ccatctcctt tgtgaccaag aacttctttt ccaaagccaa 1350 tggaaacaga agcggggctc ccaatgtggt ggtggtgatg gtggatggct 1400 ggcccacgga caaagtggag gaggcttcaa gacttgcgag agagtcagga 1450 atcaacattt tcttcatcac cattgaaggt gctgctgaaa atgagaagca 1500 gtatgtggtg gagcccaact ttgcaaacaa ggccgtgtgc agaacaaacg 1550 gcttctactc gctccacgtg cagagctggt ttggcctcca caagaccctg 1600 cagcctctgg tgaagcgggt ctgcgacact gaccgcctgg cctgcagcaa 1650.
gacctgcttg aactcggctg acattggctt cgtcatcgac ggctccagca 1700 gtgtggggac gggcaacttc cgcaccgtcc tccagtttgt gaccaacctc 1750 accaaagagt ttgagatttc cgacacggac acgcgcatcg gggccgtgca 1800 gtacacctac gaacagcggc tggagtttgg gttcgacaag tacagcagca 1850 agcctgacat cctcaacgcc atcaagaggg tgggctactg gagtggtggc 1900 accagcacgg gggctgccat caacttcgcc ctggagcagc tcttcaagaa 1950 gtccaagccc aacaagagga agttaatgat cctcatcacc gacgggaggt 2000 cctacgacga cgtccggatc ccagccatgg ctgcccatct gaagggagtg 2050 atcacctatg cgataggcgt tgcctgggct gcccaagagg agctagaagt 2100 cattgccact caccccgcca gagaccactc cttctttgtg gacgagtttg 2150 acaacctcca tcagtatgtc cccaggatca tccagaacat ttgtacagag 2200 ttcaactcac agcctcggaa ctgaattcag agcaggcaga~ gcaccagcaa 2250 gtgctgcttt actaactgac gtgttggacc accccaccgc: ttaatggggc 2300 acgcacggtg catcaagtct tgggcagggc atggagaaac: aaatgtcttg 2350 ttattattct ttgccatcat gctttttcat attccaaaac: ttggagttac 2400 aaagatgatc acaaacgtat agaatgagcc aaaaggctac atcatgttga 2450 ,,.,. ...,.,.,m. .~~.,.,~:..~..-~.-~.a,H.,. ,. ,.~.-.."".",~F,..-..,..-era,~..~..~..;~,riwaw.r»ro;r<"ss~:~a:.~...~~~.~n...w~..,~.._z.:.~s..-~x~.~,.1,~.:x,a~wxarae~.,~~.~,."a~,.~~...;""~,.:,~,o,.~,~,".~.,:~"~.~"~a~;

PCT-uS00-23328_Sequence gggtgctgga gattttacat tttgacaatt gttttcaaaa taaatgttcg 2500 gaatacagtg cagcccttac gacaggctta cgtagagctt ttgtgagatt 2550 tttaagttgt tatttctgat ttgaactctg taaccctcag caagtttcat 2600 ttttgtcatg acaatgtagg aattgctgaa ttaaatgtta agaaggatga 2650 aaaataaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 2700 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 2750 aaaaaaaaaa aaaaaaaaaa aag 2773 <210> 34 <211> 678 <212> PRT
<213> Homo Sapien <400> 34 Met Arg Thr val val Leu Thr Met Ly5 Ala Ser val Ile Glu Met Phe Leu Val Leu Leu val Thr Gly val His Ser Asn Lys Glu Thr Ala Lys Lys Ile Lys Arg Pr0 Lys Phe Thr Val Pro Gln Ile Asn Cys asp val Lys Ala Gly Lys Ile Ile Asp Pro Glu Phe Ile val Lys Cys Pro Ala Gly Cys Gln asp Pro Lys Tyr His val Tyr Gly Thr Asp Val Tyr Ala Ser Tyr Ser Ser val Cys Gly Ala Ala Val His Ser Gly val Leu Asp Asn Ser Gly Gly Lys Ile Leu val Arg Lys Val Ala Gly Gln Ser Gly Tyr Lys Gly Ser Tyr Ser Asn Gly Val Gln Ser Leu Ser Leu Pro Arg Trp Arg Glu Ser Phe Ile Val Leu Glu Ser Lys Pro Lys Lys Gly Val Thr Tyr Pro 5er Ala Leu Thr Tyr Ser Ser Ser Lys Ser Pro Ala Ala Gln Ala Gly Glu Thr Thr LyS Ala Tyr Gln Arg Pro Pro Ile Pro Gly Thr Thr Ala Gln Pro Val Thr Leu Met Gln Leu Leu Ala Val Thr Val Ala Val Ala Thr Pro Thr Thr Leu Pro Arg Pro Ser Pro .Ser Ala Ala Ser Thr PCT-u540-23328_Sequence Thr Ser Ile Pro Arg Pro Gln Ser Val Gly His Arg Ser Gln Glu Met Asp Leu Trp Ser Thr Ala Thr Tyr Thr Ser Ser Gln Asn Arg Pro Arg Ala Asp Pro Gly Ile Gln Arg Gln Asp Pro Ser G1y Ala Ala Phe Gln Lys Pro Val Gly Ala Asp Val Ser Leu Gly Leu Val Pro Lys Glu Glu Leu Ser Thr Gln Ser Leu Glu Pro Val Ser Leu Gly Asp Pro Asn Cys Lys Ile Asp Leu Ser Phe Leu Ile Asp Gly Ser Thr Ser Ile Gly Lys Arg Arg Phe Arg Ile Gln Lys Gln Leu Leu Ala Asp Val Ala Gln Ala Leu Asp Ile Gly Pro Ala Gly Pro Leu Met Gly Val Val Gln Tyr Gly Asp Asn Pro Ala Thr His Phe 335 ~ 340 345 Asn Leu Lys Thr His Thr Asn Ser Arg Asp Leu Lys Thr Ala I1e Glu Lys Ile Thr Gln Arg Gly Gly Leu Ser Asn Val Gly Arg Ala Ile Ser Phe Val Thr Lys Asn Phe Phe Ser Lys Ala Asn Gly Asn Arg Ser Gly Ala Pro Asn Val Val Val Val Met Val Asp Gly Trp Pro Thr Asp Lys Val Glu Glu Ala Ser Arg Leu Ala Arg Glu Ser G1y Ile Asn Ile Phe Phe Ile Thr Ile Glu Gly Ala Ala Glu Asn Glu Lys Gln 'fyr Val Val Glu Pro Asn Phe Ala Asn Lys Ala Va1 Cys Arg Thr Asn Gly Phe Tyr Ser Leu His Val Gln Ser Trp Phe Gly Leu His Lys Thr Leu Gln Pro Leu Val Ly:~ Arg Val Cys Asp Thr Asp Arg Leu Ala c~ys Ser Lys Thr Cys Leu Asn Ser Ala Asp Ile Gly Phe Val Ile Asp Gly Ser Ser Ser Vaf Gly Thr Gly Asn Phe Arg Thr Val Leu Gln Phe Val Thr Asn Leu Thr Lys Glu Phe .. .. » .i », a'1'.dt.fe..mrc. ..vM...x,rxwr.Mwn.. wwr,...~.»nmm-z.
vrinwei.»tm."WS,u~F=~kTS.,y=~.~tYU'fi~.m~~~;.u,~.;nm,~ninW.smv~s~:.»mmsucm~-.afmv~c.r..~e.."..mamaa, amr .n.w..~.w..,.mwvmm_-.-rntrin ..rsa..",xvaAmm.~.a~~wa. rnn .n.".ne,:.. ~.wvr..w...~wasn~vwe PCT-u500-23328_Sequence Glu Ile Ser Asp Thr Asp Thr Arg Ile Gly Ala Val Gln Tyr Thr Tyr Glu Gln Arg Leu Glu Phe Giy Phe Asp Lys Tyr Ser Ser Lys Pro Asp Ile Leu Asn Ala Ile Lys Arg Val Gly Tyr Trp Ser Gly Gly Thr Ser Thr Giy Aia Ala Ile Asn Phe Ala Leu Glu Gln Leu Phe Lys Lys Ser Lys Pro Asn Lys Arg Lys Leu Met Ile Leu Ile Thr Asp Giy Arg Ser Tyr Asp Asp Val Arg Ile Pro Ala Met Ala Ala His Leu Lys Gly Val Ile Thr Tyr Aia Iie Gly Val Ala Trp Ala Ala Gln Giu Glu Leu Glu Val Ile Ala Thr His Pro Ala Arg Asp His Ser Phe Phe Val Asp Glu Phe Asp Asn Leu His Gln Tyr Val Pro Arg Ile Ile Gln Asn Ile Cys Thr Glu Phe Asn Ser Gln Pro Arg Asn _ .
<210> 35 <211> 2095 <212> DNA
<213> Homo Sapien <400> 35 ccgagcacag gagattgcct gcgtttagga ggtggctgcg ttgtgggaaa 50 agctatcaag gaagaaattg ccaaaccatg tctttttttc tgttttcaga 100 gtagttcaca acagatctga gtgttttaat taagcatgga atacagaaaa 150 caacaaaaaa cttaagcttt aatttcatct ggaattccac agttttctta 200 gctccctgga cccggttgac ctgttggctc ttcccgctgg ctgctctatc 250 acgtggtgct ctccgactac tcaccccgag tgtaaagaac cttcggctcg 300 cgtgcttctg agctgctgtg gatggcctcg gctctctgga ctgtccttcc 350 gagtaggatg tcactgagat ccctcaaatg gagcctcctg ctgctgtcac 400 tcctgagttt ctttgtgatg tggtacctca gccttcccca ctacaatgtg 450 atagaacgcg tgaactggat gtacttctat gagtatgagc cgatttacag 500 -acaagacttt cacttcacac ttcgagagca ttcaaactgc tctcatcaaa 550 atccatttct ggtcattetg gtgacctccc acccttcaga. tgtgaaagcc 600 PCT-US00-23328_sequence aggcaggcca ttagagttac ttggggtgaa aaaaagtcta ggtggggata 650 tgaggttctt acatttttct tattaggcca agaggctgaa aaggaagaca 700 aaatgttggc attgtcctta gaggatgaac accttcttta tggtgacata 750 atccgacaag attttttaga cacatataat aacctgacct tgaaaaccat 800 tatggcattc aggtgggtaa ctgagttttg ccccaatgcc aagtacgtaa 850 tgaagacaga cactgatgtt ttcatcaata ctggcaattt agtgaagtat 9DO
cttttaaacc taaaccactc agagaagttt ttcacaggtt atcctctaat 950 tgataattat tcctatagag gattttacca aaaaacccat atttcttacc 1000 aggagtatcc tttcaaggt:g ttccctccat actgcagtgg gttgggttat 1050 ataatgtcca gagatttggt gccaaggatc tatgaaatga tgggtcacgt 1100 aaaacccatc aagtttgaag atgtttatgt cgggatctgt ttgaatttat 1150 taaaagtgaa cattcatatt ccagaagaca caaatctttt ctttctatat 1200 agaatccatt tggatgtctg tcaactgaga cgtgtgattg cagcccatgg 1250 cttttcttcc aaggagatca tcactttttg gcaggtcatg ctaaggaaca 1300 ccacatgcca ttattaactt cacattctac aaaaagccta gaaggacagg 1350 ataccttgtg gaaagtgtta aataaagtag gtactgtgga aaattcatgg 1400 ggaggtcagt gtgctggctt acactgaact gaaactcat~g aaaaacccag 1450 actggagact ggagggttac acttgtgatt tattagtcag gcccttcaaa 1500 gatgatatgt ggaggaatta aatataaagg aattggagg~t ttttgctaaa 1550 gaaattaata ggaccaaaca atttggacat gtcattctgt agactagaat 1600 ttcttaaaag ggtgttactg agttataagc tcactaggct gtaaaaacaa 1650 aacaatgtag agttttattt attgaacaat gtagtcactt gaaggttttg 1700 tgtatatctt atgtggatta ccaatttaaa aatatatgta gttctgtgtc 1750 aaaaaacttc ttcactgaag ttatactgaa caaaatttta cctgtttttg 1800 gtcatttata aagtacttca agatgttgca gtatttcaca gttattatta 1850 tttaaaatta cttcaacttt gtgtttttaa atgttttgac gatttcaata 1900 caagataaaa aggatagtga atcattcttt acatgcaaac attttccagt 1950 tacttaactg atcagtttat tattgataca tcactccatt aatgtaaagt 2000 cataggtcat tattgcatat cagtaatctc ttggactttg ttaaatattt 2050 tactgtggta atatagagaa gaattaaagc aagaaaatct gaaaa 2095 <210w 36 <211> 331 <212> PRT

PCT-u500-23328_Sequence <213> Homo Sapien <400> 36 Met Ala Ser Ala Leu Trp Thr Val Leu Pro Ser Arg Met Ser Leu a s to is Arg Ser Leu Lys Trp Ser Leu Leu Leu Leu Ser Leu teu Ser Phe zo 25 30 Phe Val Met Trp Tyr Leu 5er Leu Pro His Tyr Asn Val Ile Glu 35 40 =45 Arg Val Asn Trp Met Tyr Phe Tyr Glu Tyr Glu Pro Ile Tyr Arg Gln Asp Phe His Phe Thr Leu Arg Glu His Ser Asn Cys Ser His Gln Asn Pro Phe Leu Val Ile Leu Val Thr Ser His Pro Ser Asp Val Lys Ala Arg Gln Ala ale Arg Val Thr Trp Gly Glu Lys Lys Ser Trp Trp Gly Tyr Glu Val Leu Thr Phe Phe Leu Leu Gly Gln Glu Ala Glu Lys Glu Asp Lys Met Leu Ala Leu Ser Leu Glu Asp Glu His Leu Leu Tyr Gly Asp Ile Ile Arg Gln Asp Phe Leu Asp Thr Tyr Asn Asn Leu Thr Leu Lys Thr Ile Met Ala Phe Arg Trp Val Thr Glu Phe Cys Pro Asn Ala Lys Tyr Val Met Lys Thr Asp Thr Asp Val Phe Ile Asn Thr Gly Asn Leu Val Lys Tyr Leu Leu Asn Leu Asn His Ser Glu Lys Phe Phe Thr Gly Tyr Pro Leu Ile Asp Asn Tyr Ser Tyr Arg Gly Phe Tyr Gln Lys Thr His Ile Ser 215 . 220 225 Tyr Gln Glu Tyr Pro Phe Lys Val Phe Pro Pro Tyr Cys Ser Gly Leu Gly Tyr Ile Met Ser Arg Asp Leu Val Pro Arg zle Tyr Glu Met Met Gly His Val Lys Pro Ile Lys Phe Glu Asp Val Tyr Val Gly Ile Cys Leu Asn Leu Leu Lys Val Asn Ile His Ile Pro Glu Asp Thr Asn Leu Phe Phe Leu Tyr Arg Ile His Leu ASp Val Cys PCT-u500-23328_Sequence Gln Leu Arg Arg Val Ile Ala Ala His Gly Phe Ser Ser Lys Glu Ile Ile Thr Phe Trp Gln Val Met Leu Arg Asn Thr Thr Cys His Tyr <210> 37 <211> 2846 <212> DNA
<213> Homo Sapien <400> 37 cgctcgggca ccagccgcgg caaggatgga gctgggttgc tggacgcagt 50 tggggctcac ttttcttcag ctccttctca tctcgtcctt gccaagagag 100 tacacagtca ttaatgaagc ctgccctgga gcagagtgga atatcatgtg 150 tcgggagtgc tgtgaatatg atcagattga gtgcgtctgc cccggaaaga 200 gggaagtcgt gggttatacc atcccttgct gcaggaatga ggagaatgag 250 tgtgactcct gcctgatcca cceaggttgt accatctttg aaaactgcaa 300 gagctgccga aatggctcat gggggggtac cttggatgac ttctatgtga 350 aggggttcta ctgtgcagag tgccgagcag gctggtacgg aggagactgc 400 atgcgatgtg gccaggttct gcga.gcccca aagggtcaga ttttgttgga 450 aagctatccc ctaaatgctc actgtgaatg gaccattcat gctaaacctg 500 ggtttgtcat ccaactaaga tttgtcatgt tgagtctgga gtttgactac 550 atgtgccagt atgactatgt tgaggttcgt gatggagaca accgcgatgg 600 ccagatcatc aagcgtgtct gtggcaacga gcggccagct cctatccaga 650 gcataggatc ctcactccac gtcctcttcc actccgatgg ctccaagaat 700 tttgacggtt tccatgccat ttatgaggag atcacagcat gctcctcatc 750 cccttgtttc catgacggca cgtgcgtcct tgacaaggct ggatcttaca 800 agtgtgcctg cttggcaggc tatactgggc agcgctgtga aaatctcctt 850 gaagaaagaa actgctcaga ccctgggggc ccagtcaatg ggtaccagaa 900 aataacaggg ggccctgggc ttatcaacgg acgccatgct aaaattggca 950 ccgtggtgtc tttcttttgt aacaactcct atgttcttag tggcaatgag 1000 aaaagaactt gccagcagaa tggagagtgg tcagggaaac agcccatctg 1050 cataaaagcc tgccgagaac caaagatttc agacctggtc~ agaaggagag 1100 ttcttccgat gcaggttcag tcaagggaga caccattaca ccagctatac 1150 tcagcggcct tcagcaagca gaaactgcag agtgccccta ccaagaagcc 1200 i PCT-uS00-23328_Sequence agcccttccc tttggagatc tgcccatggg ataccaacat ctgcataccc 1250 agctccagta tgagtgcatc tcacccttct accgccgcct gggcagcagc 1300 aggaggacat gtctgaggac tgggaagtgg agtgggcggg caccatcctg 1350 catccctatc tgcgggaaaa ttgagaacat cactgctcca aagacccaag 1400 ggttgcgctg gccgtggcag gcagccatct acaggaggac cagcggggtg 1450 catgacggca gcctacacaa gggagcgtgg ttcctagt<a gcagcggtgc 1500 cctggtgaat gagcgcactg tggtggtggc tgcccactgt gttactgacc 1550 tggggaaggt caccatgatc aagacagcag acctgaaagt tgttttgggg 1600 aaattctacc gggatgatga ccgggatgag aagaccatcc agagcctaca 1650 gatttctgct atcattctgc atcccaacta tgaccccatc ctgcttgatg 1700 ctgacatcgc catcctgaag ctcctagaca aggcccgtat eagcacccga 1750 gtccagccca tctgcctcgc tgecagtcgg gatctcagc:a cttccttcca 1800 ggagtcccac atcactgtgg ctggctggaa tgtcctggca gacgtgagga 1850 gccctggctt caagaacgac acactgcgct ctggggtggt cagtgtggtg 1900 gactcgctgc tgtgtgagga gcagcatgag gaccatggca tcccagtgag 1950 tgtcactgat aacatgttct gtgccagctg ggaacccact gccccttctg 2000 atatctgcac tgcagagaca ggaggcatcg cggctgtgtc cttcccggga 2050 cgagcatctc ctgagccacg ctggcatctg atgggactgg tcagctggag 2100 ctatgataaa acatgcagcc acaggctctc cactgccttc accaaggtgc 2150 tgccttttaa agactggatt gaaagaaata tgaaatgaac catgctcatg 2200 cactccttga gaagtgtttc tgtatatccg tctgtacgtg tgtcattgcg 2250 tgaagcagtg tgggcctgaa gtgtgatttg gcctgtgaac ttggctgtgc 2300 cagggcttct gacttcaggg acaaaactca gtgaagggtg agtagacctc 2350 cattgctggt aggctgatgc cgcgtccact actaggaca~g ccaattggaa 2400 gatgccaggg cttgcaagaa gtaagtttct tcaaagaaga ccatatacaa 2450 aacctctcca ctccactgac ctggtggtct tccccaactt tcagttatac 2500 gaatgccatc agcttgacca gggaagatct gggcttcatg aggccccttt 2550 tgaggctctc aagttctaga gagctgcctg tgggacagcc cagggcagca 2600 gagctgggat gtggtgcatg cctttgtgta catggccaca gtacagtctg 2650 gtccttttcc ttccccatct cttgtacaca ttttaataaa ataagggttg 2700 gcttctgaac tacaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 2750 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 2800 ,a ~ ~.,aa . , :,""r~n N _:~:.as .,.. "wmy,...-a..-ur..n,. ..,....~,noc, ....;~xxxrx,~ ~x~=snz~-ax g-:°.x'arc~~:--a~a~:.-,.~,."~ . ~., ~~" a~.
,.«~,= cur. ~~mnxaz~u~~.n,.":~s.-az~m.. ,s,~w.,~sr.~,.~nm PCT-uS00-23328_Sequence aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaa.a aaaaaa 2846 <210> 38 <211> 720 <212> PRT
<213> Homo Sapien <400> 38 Met Glu Leu Gly Cys Trp Thr Gln Leu Gly Leu Thr Phe Leu Gln 1 5 10 '15 Leu Leu Leu Ile Ser Ser Leu Pro Arg Glu Tyr Thr Val Ile Asn Glu Ala Cys Pro Gly Ala Glu Trp Asn Ile Met Cys Arg Glu Cys Cys Glu Tyr Asp Gln Ile Glu Cys Val Cys Pro Gly Lys Arg Glu Val Val Gly Tyr Thr Ile pro cys Cys Arg Asn Glu Glu Asn Glu Cys Asp Ser Cys Leu Ile His Pro Gly Cys Thr Ile Phe Glu Asn Cys Lys Ser Cys Arg Asn Gly Se_r Trp Gly Gly Thr Leu Asp Asp Phe Tyr Val Lys Gly Phe Tyr Cys Ala Glu Cys Arg Ala Gly Trp Tyr Gly Gly Asp Cys Met Arg Cys Gly Gln Val Leu Arg Ala Pro Lys Gly Gln Ile Leu E_2u Glu Ser Tyr Pro Leu Asn Ala His Cys Glu Trp Thr Ile His Ala Lys Pro Gly Phe Vall Ile Gln Leu Arg Phe Val Met Leu Ser Leu Glu Phe Asp Tyr Met Cys Gln Tyr Asp Tyr Val Glu Val i$g Asp Gly Asp Asn Arg Asp Gly Gln Ile Ile Lys Arg Val Cys Gly Asn Glu Arg Pro Ala Pro Ile Gln Ser Ile Gly Ser Ser Leu His Vai Leu Phe His Ser Asp Gly Ser Lys Asn Phe Asp Gly Phe His Ala Ile Tyr Glu Glu Ile. Thr Ala Cys Ser Ser Ser Pro Cys Phe 6-lis ASp Gly Thr Cys Val Leu Asp Lys Ala Gly Ser Tyr Lys Cys A,la Cys Leu Ala Gly Tyr Thr Gly Gln Arg Page SO
a, .,.., .o .. ......a a='r°t~~FI'~x.-~<-~2.~ u. a sa"rc,m~a~-~was3wrs.:.,. fi..~.:a5~.amp'am~ca9Wnt.e~:~-.~~.,w~~.-.".. . ..-..,.~., .......,..,~....v..,., ,ww ~r...:.F..n.mw..mxr~o.,.~.,.:,vrr~".;.~..
mrvnmmu~»:..,~..,m., ..,_".~enrr~.wr .~m~.rw-m,rx~a.,.a PCT-u500-23328_Sequence Cys GluAsn LeuLeuGlu GluArgAsn CysSer AspProGly Gly Pro VaiAsn GlyTyrGln LysIleThr GlyGly ProGlyLeu Ile ASn GlyArg HisAlaLys IleGlyThr ValVal SerPhePhe Cys Asn AsnSer TyrValLeu SerGlyAsn GluLys ArgThrCys Gln Gln AsnGly GluTrpSer GlyLysGln ProIle CysIleLys Ala Cys ArgGlu ProLysIle $erAspLeu ValArg ArgArgVal Leu Pro MetGln ValGlnSer ArgGluThr ProLeu HisGlnLeu Tyr Ser AlaAla PheSerLys GlnLysLeu GlnSer AlaProThr Lys Lys ProAla LeuProPhe GlyAspLeu ProMet GlyTyrGln His Leu HisThr GlnLeuGln TyrGluCys IleSer ProPheTyr Arg Arg LeuGly SerSerArg ArgThrCys LeuArg ThrGlyLys Trp ~, Ser GlyArg AlaProSer CysIlePro IieCys GlyLysIle Glu Asn IleThr AlaProLys ThrGlnGly LeuArg TrpProTrp Gln Ala AlaIle TyrArgArg ThrSerGly ValHis AspGlySer Leu His LysGly AlaTrpPhe LeuValCys SerGly AlaLeuVal Asn Glu ArgThr ValValVal AlaAlaHis CysVal ThrAspLeu Gly Lys ValThr MetIlet_ysThrAlaAsp LeuLys ValValLeu Gly Lys PheTyr ArgAspAsp AspArgAsp GluLys ThrIleGln Ser 530. 535 540 Leu GlnIle SerA1aIle IleLeuHis ProAsn TyrAspPro Ile Leu LeuAsp AlaAspIle AlaIleLeu LysLeu LeuAspLys Ala Arg IleSer ThrArgVal GlnProIle CysLeu AlaAlaSer Arg Page S1 PCT-uS00-23328_Sequence Asp Leu Ser Thr Ser Phe Gln Glu Ser His Ile Thr Val Ala Gly Trp Asn Val Leu Ala Asp Val Arg Ser Pro Gly Phe Lys Asn Asp Thr Leu Arg Ser Gly Val Val Ser Val Val Asp Ser Leu Leu Cys Glu Glu Gln His Glu Asp His Gly Ile Pro Val Ser Val Thr Asp 635 640 f545 Asn Met Phe Cys Ala Ser Trp Glu Pro Thr Ala Pro Ser asp Ile Cys Thr Ala Glu Thr Gly Gly Ile Ala Ala Val Ser Phe Pro Gly Arg Ala Ser Pro Glu Pro Arg Trp His Leu Met Gly Leu Val Ser Trp Ser Tyr Asp Lys Thr Cys Ser His Arg Leu Ser Thr Ala Phe Thr Lys Val Leu Pro Phe Lys Asp Trp Ile Glu Arg Asn Met Lys <210> 39 <211> 2571 <212> DNA
<213> Homo Sapien <400> 39 ggttcctaca tcctctcatc tgagaatcag agagcataat cttcttacgg 50 gcccgtgatt tattaacgtg gcttaatctg aaggttctc~a gtcaaattct 100 ttgtgatcta ctgattgtgg gggcatggca aggtttgctt aaaggagctt 150 ggctggtttg ggcccttgta gctgacagaa ggtggccagg gagaatgcag 200 cacactgctc ggagaatgaa ggcgcttctg ttgctggtct tgccttggct 250 cagtcctgct aactacattg acaatgtggg caacctgcac ttcctgtatt 300 cagaactctg taaaggtgce tcccactacg gcctgaccaa agataggaag 350 aggcgctcac aagatggctg tccagacggc tgtgcgagcc tcacagccac 400 ggctccctcc ccagaggttt ctgcagctgc caccatctcc ttaatgacag 450 acgagcctgg cctagacaac cctgcctacg tgtcctcggc agaggacggg 500 cagccagcaa tcagcccagt: ggactctggc cggagcaacc: gaactagggc 550 acggcccttt gagagatcca ctattagaag cagatcattt aaaaaaataa 600 atcgagcttt gagtgttctt cgaaggacaa agagcgggag tgcagttgcc 650 aaccatgccg accagggcag ggaaaattct gaaaacacca ctgcccctga 700 agtctttcca aggttgtacc acctgattcc agatggtgaa attaccagca 750 PCT-0500-23328_Sequence tcaagatcaa tcgagtagat cccagtgaaa gcctctctat taggctggtg 800 ggaggtagcg aaaccccact ggtccatatc attatccaac acatttatcg 850 tgatggggtg atcgccagag acggccggct actgccagga gacatcattc 900 taaaggtcaa cgggatggac atcagcaatg tccctcacaa ctacgctgtg 950 cgtctcctgc ggcagccctg ccaggtgctg tggctgactg tgatgcgtga 1000 acagaagttc cgcagcagga acaatggaca ggccccggat gcctacagac 1050 cccgagatga cagctttcat gtgattctca acaaaagtag ccccgaggag 1100 cagcttggaa taaaactggt gcgcaaggtg gatgagcct:g gggttttcat 1150 cttcaatgtg ctggatggcg gtgtggcata tcgacatggt cagcttgagg 1200 agaatgaccg tgtgttage:c atcaatggac atgatcttc:g atatggcagc 1250 ccagaaagtg cggctcatct gattcaggcc agtgaaaga.c gtgttcacct 1300 cgtcgtgtcc cgccaggtt:c ggcagcggag ccctgacatc tttcaggaag 1350 ccggctggaa cagcaatggc agctggtccc cagggccagg ggagaggagc 1400 aacactccca agcccctcca tcctacaatt acttgtcatg agaaggtggt 1450 aaatatccaa aaagaccccg gtgaatctct cggcatgacc gtcgcagggg 1500 gagcatcaca tagagaatgg gatttgccta tctatgtcat cagtgttgag 1550 cccggaggag tcataagcag agatggaaga ataaaaacag gtgacatttt 1600 gttgaatgtg gatggggtcg aactgacaga ggtcagccgg agtgaggcag 1650 tggcattatt gaaaagaaca tcatcctcga tagtactcaa agctttggaa 1700 gtcaaagagt atgagcccca ggaagactgc agcagcccag cagccctgga 1750 ctccaaccac aacatggccc cacccagtga ctggtcccca tcctgggtca 1800 tgtggctgga attaccacgg tgcttgtata actgtaaaga tattgtatta 1850 cgaagaaaca cagctggaag tctgggcttc tgcattgtag gaggttatga 1900 agaatacaat ggaaacaaac cttttttcat caaatccatt gttgaaggaa 1950 caccagcata caatgatgga agaattagat gtggtgatat tcttcttgct 2000 gtcaatggta gaagtacatc aggaatgata catgcttgct tggcaagact 2050 gctgaaagaa cttaaaggaa gaattactct aactattgtt tcttggcctg 2100 gcactttttt atagaatcaa tgatgggtca gaggaaaaca gaaaaatcac 2150 aaataggcta agaagttgaa acactatatt tatcttgtca gtttttatat 2200 ttaaagaaag aatacattgt aaaaatgtca ggaaaagtat gatcatctaa 2250 tgaaagccag ttacacctca gaaaatatga ttccaaaaaa attaaaacta 2300 ctagtttttt ttcagtgtgg aggatttctc attactctac aacattgttt 2350 Page 53 _ PCT-US00-23328_Sequence atattttttc tattcaataa aaagccctaa aacaactaaa atgattgatt 2400 tgtatacccc actgaattca agctgattta aatttaaaat ttggtatatg 2450 ctgaagtctg ccaagggtac attatggcca tttttaattt acagctaaaa 2500 tattttttaa aatgcattgc tgagaaacgt tgctttcatc aaacaagaat 2550 aaatattttt cagaagttaa a 2571 <210> 40 <211> 632 <212> PRT
<213> Homo Sapien <400> 40 Met Lys Ala Leu Leu Leu Leu Val Leu Pro Trp Leu Ser Pro A1a Asn Tyr Ile Asp Asn Val Gly Asn Leu His Plle Leu Tyr Ser Glu Leu cys Lys Gly Ala Ser His Tyr Gly Leu Thr Lys Asp Arg Lys Arg Arg Ser Gln Asp Gly cys Pro Asp Gly Cars Ala Ser Leu Thr Ala Thr Ala Pro Ser Pro Glu Val Ser Ala Alla Ala Thr Ile Ser Leu Met Thr Asp Glu Pro Gly Leu Asp Asn Pro Ala Tyr Val Ser Ser Ala Glu Asp G1y Gln Pro Ala Ile Ser Pro val Asp Ser Gly Arg Ser Asn Arg Thr Arg Ala Arg Pro Phe Glu Arg Ser Thr Ile Arg ser Arg Ser Phe Lys Lys Ile Asn Arg Ala Leu ser Va1 Leu 125 130 ~ 135 Arg Arg Thr Lys Ser Gly Ser Ala Val Ala Asn His Ala Asp Gln Gly Arg Glu Asn Ser Glu Asn Thr Thr Ala Pro Glu Val Phe Pro Arg Leu Tyr His Leu Ile Pro Asp Gly Glu Ile Thr Ser Ile Lys Ile Asn Arg Val Asp Pro Ser Glu Ser Leu Ser Ile Arg Leu Val Gly Gly Ser Glu Thr Pro Leu Val His Ile Ile Ile Gln His Ile Tyr Arg Asp Gly Val Ile Ala Arg Asp Gly Arg Leu Leu Pro Gly Asp Ile Ile Leu Lys val Asn Gly Met Asp Ile Ser Asn Val Pro PCT-US00-23328_Sequence His Asn Tyr Ala Val Arg Leu Leu Arg Gln Pro Cys Gln Val Leu Trp Leu Thr Val Met Arg Glu Gln Lys Phe p,rg Ser Arg Asn Asn Gly Gln Ala Pro Asp Ala Tyr Arg Pro Arg Asp Asp Ser Phe His Val Ile Leu Asn Lys Ser Ser Pro Glu Glu Gln Leu Gly Ile Lys Leu Val Arg Lys Val Asp Glu Pro Gly Val Phe Ile Phe Asn Val Leu Asp Gly Gly Va1 Ala Tyr Arg His Gly G~ln Leu Glu Glu Asn Asp Arg Val Leu Ala Ile Asn Gly His Asp Leu Arg Tyr Gly Ser Pro Glu Ser Ala Ala His Leu Ile Gln Ala Ser Glu Arg Arg Val His Leu Val Val Ser Arg Gln Val Arg Gln Arg Ser Pro Asp Ile Phe Gln Glu Ala Gly Trp Asn Ser Asn Gly Ser Trp 5er Pro Gly Pro Gly Glu Arg Ser Asn Thr Pro Lys Pro Leu His Pro Thr Ile Thr Cys His Glu Lys Val Val Asn Ile Gln Lys Asp Pro Gly Glu Ser Leu Gly Met Thr Val Ala Gly Gly Ala Ser His Arg Glu Trp Asp Leu Pro Ile Tyr Val Ile Ser Val Glu Pro Gly Gly Val Ile Ser Arg Asp Gly Arg Ile Lys Thr Gly Asp Ile Leu Leu Asn Val Asp Gly Val Glu Leu Thr Glu Val Ser Arg Ser Glu Ala Val Ala Leu Leu Lys Arg Thr Ser Ser Ser Ile Val Leu Lys Ala Leu Glu Val Lys Glu Tyr Glu Pro Gln Glu Asp Cys Ser Ser Pro Ala Ala Leu Asp Ser Asn His Asn Met Ala Pro Pro Ser Asp Trp Ser Pro Ser Trp Val Met Trp Leu Glu Leu Pro Arg Cys Leu Tyr Asn Cys Lys Asp Ile Val Leu Arg Arg Asn Thr Ala Gly Ser Leu Gly Phe Page S5 . -,~~ ~ ",-.~..~. .., _m._ ..... w .. .... _... _. .... . _... _ _ .. ...
....._ PCT-US00-23328_sequence Cys Ile Va7 Gly Gly Tyr Glu Glu Tyr Asn Gly Asn Lys Pro Phe Phe Ile Lys 5er I12 Val Glu Gly Thr Pro Ala Tyr Asn Asp Gly Arg Ile Arg Cys Gly Asp Ile Leu Leu Ala val Asn Gly Arg Ser Thr Ser Gly Met Ile His Ala Cys Leu Ala Arg Leu Leu Lys Glu Leu Lys Gly Arg Ile Thr Leu Thr Ile Val ser Trp Pro Gly Thr Phe Leu <210> 41 <211> 1964 <212> DNA
<213> Homo sapien <400> 41 , accaggcatt gtatcttcag ttgtcatcaa gttcgcaatc agattggaaa 50 agctcaactt gaagctttct tgcctgcagt gaagcagag!a gatagatatt 100 attcacgtaa taaaaaacat gggcttcaac ctgactttcc acctttccta 150 caaattccga ttactgttgc tgttgacttt gtgcctgaca gtggttgggt 200 gggccaccag taactacttc gtgggtgcca ttcaagagat tcctaaagca 250 aaggagttca tggctaatta ccataagacc ctcattttgg ggaagggaaa 300 aactctgact aatgaagcat ccacgaagaa ggtagaactt gacaactgtc 350 cttctgtgtc tccttacctc agaggccaga gcaagctcat tttcaaacca 400 gatctcactt tggaagaggt acaggcagaa aatcccaaag tgtccagagg 450 ccggtatcgc cctcaggaat gtaaagcttt acagagggtc gccatcctcg 500 ttccccaccg gaacagagag aaacacctga tgtacctgct ggaacatctg 550 catcccttcc tgcagaggca gcagctggat tatggcatct acgtcatcca 600 ccaggctgaa ggtaaaaagt ttaatcgagc caaactcttg aatgtgggct 650 atctagaagc cctcaaggaa gaaaattggg actgctttat attccacgat 700 gtggacctgg tacccgagaa tgactttaac ctttacaag~t gtgaggagca 750 teeeaageat ctggtggttg geaggaaeag eaetgggtac aggttaegtt 800 acagtggata ttttgggggt gttactgccc taagcagaga gcagtttttc 850 aaggtgaatg gattctctaa caactactgg ggatggggag gcgaagacga 900 tgacctcaga ctcagggttg agctccaaag aatgaaaatr_ tcccggcccc 950 ," ..,._,.,~,. _», _.,:."~sxk,.s~mrnwr ~ xf"~,-~_ha xw:~,~a.m~Efia.sh,,.
"..a»..,..,._._...... ...."",v"""", " "~~~,,~,, ~. """, m.,M,~., ,~.....,...._ _.T...._ _ PCT-0500-23328_Sequence tgcctgaagt gggtaaatat acaatggtct tccacactag agacaaaggc 1000 aatgaggtga acgcagaacg gatgaagctc ttacaccaag tgtcacgagt 1050 ctggagaaca gatgggttga gtagttgttc ttataaatta gtatctgtgg 1100 aacacaatcc tttatatatc aacatcacag tggatttctg gtttggtgca 1150 tgaccctgga tcttttggtg atgtttggaa gaactgattc tttgtttgca 1200 ataattttgg cctagagact tcaaatagta gcacacatta agaacctgtt 1250 acagctcatt gttgagctga atttttcctt tttgtatttt cttagcagag 1300 ctcctggtga tgtagagtat aaaacagttg taacaagaca gctttcttag 1350 tcattttgat catgagggtt aaatattgta atatggatac ttgaaggact 1400 ttatataaaa ggatgactca aaggataaaa tgaacgctat ttgaggactc 1450 tggttgaagg agatttattt aaatttgaag taatatatta tgggataaaa 1500 ggccacagga aataagactg ctgaatgtct gagagaacca gagttgttct 1550 cgtccaaggt agaaaggtac gaagatacaa tactgttata catttatcct 1600 gtacaatcat ctgtgaagtg gtggtgtcag gtgagaaggc gtccacaaaa 1650 gaggggagaa aaggcgacga atcaggacac agtgaacttg ggaatgaaga 1700 ggtagcagga gggtggagtg tcggctgcaa aggcagcagt agctgagctg 1750 gttgcaggtg ctgatagcct tcaggggagg acctgccca.g gtatgccttc 1800 cagtgatgcc caccagagaa tacattctct attagttttt aaagagtttt 1850 tgtaaaatga ttttgtacaa gtaggatatg aattagcagt ttacaagttt 1900 acatattaac taataataaa tatgtctatc aaatacctct gtagtaaaat 1950 gtgaaaaagc aaaa 1964 <210> 42 <211> 344 <212> PRT
<213> Homo 5apien <400> 42 Met Gly Phe Asn Leu Thr Phe His Leu Ser Tyr Ly5 Phe Arg Leu Leu Leu Leu Leu Thr Leu Cys Leu Thr Val Val Gly Trp Ala Thr Ser Asn Tyr Phe Val Gly A7a I12 Gln Glu Ile Pro Lys Ala Lys Glu Phe Met Ala Asn Phe His Lys Thr Leu IIE~ Leu Gly Lys Gly Lys Thr Leu Thr Asn Glu Ala Ser Thr Lys Lys Val Glu Leu Asp -.. ~_ ~-r.._-._ PCT-uS00-23328_Sequence Asn Cys Pro ser val Ser Pro Tyr Leu Arg Gly Gln Ser Lys Leu Ile Phe Lys Pro Asp Leu Thr Leu Glu Glu Val Gln Ala Glu Asn Pro Lys Val 5er Arg Gly Arg Tyr Arg Pro Gln Glu Cys Lys Ala Leu Gln Arg Val Ala Ile Leu Val Pro His Arg Asn Arg Glu Lys His Leu Met Tyr Leu Leu Glu His Leu His Pro Phe Leu Gln Arg Gln Gln Leu Asp Tyr Gly Ile Tyr Val Ile His Gln Ala Glu Gly Lys Lys Phe Asn Arg Ala Lys Leu Leu Asn Val Gly Tyr Leu Glu Ala Leu Lys Glu Glu Asn Trp Asp Cys Phe I1e Phe His Asp Val Asp Leu Val Pro Glu Asn Asp Phe Asn Leu Tyr Lys Cys Glu Glu 20o zo5 210 His Pro Lys His Leu Val Val Gly Arg Asn Ser Thr Gly Tyr Arg Leu Arg Tyr Ser Gly Tyr Phe Gly Gly Val Thr Ala Leu Ser Arg Glu Gln Phe Fhe Lys Val Asn Gly Phe Ser Asn Asn Tyr Trp Gly Trp Gly Gly Glu Asp Asp Asp Leu Arg Leu Arg Val Glu Leu Gln Arg Met Lys Ile Ser Arg Pro Leu Pro Glu Va~i Gly Lys Tyr Thr Met Val Phe His Thr Arg Asp Lys Gly Asn Glu Val Asn Ala Glu Arg Met Lys Leu Leu His Gln Val Ser Arg Val Trp Arg Thr Asp Gly Leu Ser Ser Cys 5er Tyr Lys Leu Val Ser Val Glu His Asn Pro Leu Tyr Ile Asn Ile Thr Val Asp Phe Trp Phe Gly Ala <210> 43~
<211> 485 <21z> DNA
<213> Homo Sapien <400> 43 gctcaagacc cagcagtggg acagccagac agacggcacg atggcactga 50 _.,...,. . " . .r,.., "~ .~.. , . ,. _.. a ..~.~.,~ H,,.~,~"~..~~~..
",".~,.~.~~,~~,~-..~.:,~ ._wa .."...~.. . _ ..___,_,.._Y_..M.._.... 7. ..

PCT-u500-23328_Sequence gctcccagat ctgggccgct tgcctcctgc tcctcctcct cctcgccagc 100 ctgaccagtg gctctgtttt cccacaacag acgggacaac ttgcagagct 150 gcaaccccag gacagagctg gagccagggc cagctggatg cccatgttcc 200 agaggcgaag gaggcgagac acccacttcc ccatctgc~at tttctgctgc 250 ggctgctgtc atcgatcaaa gtgtgggatg tgctgcaaga ~cgtagaacct 300 acctgccctg cccccgtccc ctcccttcct tatttattcc tgctgcccca 350 gaacataggt cttggaataa aatggctggt tcttttgttt tccaaaaaaa 400 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 450 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaa 485 <210> 44 <211> 84 <212> PRT
<213> Homo Sapien <400> 44 Met Ala Leu Ser Ser Gln Ile Trp Ala Ala Cys Leu Leu Leu Leu Leu Leu Leu Ala Ser Leu Thr Ser Gly Ser Val Phe Pro Gln G1n Thr Gly Gln Leu Ala Glu Leu Gln Pro Gln Asp Arg Ala Gly Ala Arg Ala Ser Trp Met Pro Met Phe Gln Arg Arg Arg Arg Arg Asp Thr His Phe Pro Ile Cys Ile Phe Cys Cys Gly Cys Cys His Arg Ser Lys Cys Gly Met Cys Cys Lys Thr <210> 45 <211> 1076 <212> DNA
<213> Homo Sapien <400> 45 gtggcttcat ttcagtggct gacttccaga gagcaatatg gctggttccc 50 caacatgcct caccctcatc tatatccttt_ggcagctcac agggtcagca 100 gcctctggac ccgtgaaaga gctggtcggt tccgttggtg gggccgtgac 150 tttccccctg aagtccaaag taaagcaagt tgactctat~t gtctggacct 200 tcaacacaac ccctcttgtc accatacagc cagaaggggg cactatcata 250 gtgacccaaa atcgtaatag ggagagagta gacttcccag atggaggcta 300 ctccctgaag ctcagcaaac tgaagaagaa tgactcaggg atctactatg 350 tggggatata cagctcatca ctccagcagc cctccaccca ggagtacgtg 400 PCT-uS00-23328_Sequence ctgcatgtct acgagcacct gtcaaagcct aaagtcacca tgggtctgca 450 gagcaataag aatggcacct gtgtgaccaa tctgacatgc tgcatggaac 500 atggggaaga ggatgtgatt tatacctgga aggccctggg gcaagcagcc 550 aatgagtccc ataatgggtc catcctcccc atctcctgga gatggggaga 600 aagtgatatg accttcatct gcgttgccag gaaccctgt c agcagaaact 650 tctcaagccc catccttgcc aggaagctct gtgaaggtgc tgctgatgac 700 ccagattcct ccatggtcct cctgtgtctc ctgttggtg c ccctcctgct 750 cagtctcttt gtactggggc tatttctttg gtttctgaag agagagagac 800 aagaagagta cattgaagag aagaagagag tggacatttg tcgggaaact 850 cctaacatat gcccccattc tggagagaac acagagtacg acacaatccc 900 tcaeactaat agaacaatce taaaggaaga tccagcaaat acggtttact 950 ccactgtgga aataccgaaa aagatggaaa atccccactc actgctcacg 1000 atgccagaca caccaaggct atttgcctat gagaatgtta tctagacagc 1050 agtgcactcc cctaagtctc tgctca 1076 <210> 46 <211> 335 <212> PRT
<213> Homo Sapien <400> 46 Met Ala Gly Ser Pro Thr Cys Leu Thr Leu Ile Tyr Ile Leu Trp Gln Leu Thr Gly Ser Ala Ala Ser Gly Pro Val Lys Glu Leu Val Gly Ser Val Gly Gly Ala Val Thr Phe Pro Leu Lys Ser Lys Val Lys Gln Val Asp Ser Ile Val Trp Thr Phe Asn Thr Thr Pro Leu Val Thr Ile Gln Pro Glu Gly Gly Thr Ile Ile Val Thr Gln Asn Arg Asn Arg Glu Arg Val Asp Phe Pro Asp Gly GIy Tyr Ser Leu Lys Leu Ser Lys Leu Lys Lys Asn Asp Ser Gly Ile Tyr Tyr val Gly Ile Tyr Ser Ser Ser Leu Gln Gln Pro Ser Thr Gln Glu Tyr Val Leu.His Val Tyr Glu His Leu Ser Lys Pro Lys Val Thr Met Gly Leu Gln Ser Asn Lys Asn Gly Thr Cys Val Thr Asn Leu Thr .. ...._ .. ...:. _r_-~ _,~~:;:;,~.,,.~,,~,~. ___._~___._~.__«._n.~~...~~-~ _ -~.._--PCT-uS00-23328_Sequence Cys Cys Met Glu His Gly Glu Glu Asp Val Ile Tyr Thr Trp Lys Ala Leu Gly Gln Ala Ala Asn Glu Ser His Asn Gly Ser Ile Leu Pro Ile Ser Trp Arg Trp Gly Glu Ser Asp Met Thr Phe Ile Cys Val Ala Arg Asn Pro Val Ser Arg Asn Phe Ser Ser Pro Ile Leu Ala Arg Lys Leu Cys Glu Gly Ala Ala Asp Asp Pro Asp Ser Ser Met Val~Leu Leu Cys Leu Leu Leu Val Pro Leu Leu Leu Ser Leu Phe Val Leu Gly Leu Phe Leu Trp Phe Leu Lys Arg Glu Arg Gln Glu Glu Tyr Ile Glu Glu Lys Lys Arg Val Asp Ile Cys Arg Glu Thr Pro Asn Ile Cys Pro His Ser Gly Glu Asn Thr Glu Tyr Asp Thr Ile Pro His Thr Asn Arg Thr Ile Leu Lys Glu Asp Pro Ala Asn Thr Val Tyr Ser Thr Va7 Glu Ile Pro Lys Lys Met Glu Asn Pro His Ser Leu Leu Thr Met Pro Asp Thr Pro Arg Leu Phe Ala Tyr Glu Asn Val Ile <210> 47 <211> 766 <212> DNA
<213> Homo Sapien <400> 47 ggctcgagcg tttctgagcc aggggtgacc atgacctgct gcgaaggatg 50 gacatcctgc aatggattca gcctgctggt tctactgctg ttaggagtag 100 ttctcaatgc gatacctcta attgtcagct tagttgagga agaccaattt 150 tctcaaaacc ccatctcttg ctttgagtgg tggttcccag gaattatagg 200 agcaggtctg atggccattr~ cagcaacaac aatgtccttg acagcaagaa 250 aaagagcgtg ctgcaacaar_ agaactggaa tgtttctttc atcatttttc 300 agtgtgatca cagtcattgg tgctctgtat tgcatgctga tatccatcca 350 ggctctctta aaaggtcctr_ tcatgtgtaa ttctccaagc: aacagtaatg 400 PCT-uS00-23328_Sequence ccaattgtga attttcatag aaaaacatca gtgacattca tccagaatcc 450 ttcaacttgc agtggttttt caatgactct tgtgcacctc ctactggttt S00 caataaaccc accagtaacg acaccatggc gagtggctgg agagcatcta 550 gtttccactt cgattctgaa gaaaacaaac ataggcttat ccacttctca 600 gtatttttag gtctattgct tgttggaatt ctggaggtcc tgtttgggct 650 cagtcagata gtcatcggtt tccttggctg tctgtgtgga gtctctaagc 700 gaagaagtca aattgtgtag tttaatggga ataaaatgta agtatcagta 750 gtttgaaaaa aaaaaa 766 <210> 48 <211> 229 <212> PRT
<213> Homo Sapien <400> 48 Met Thr Cys Cys Glu Gly Trp Thr Ser Cys Asn Gly Phe Ser Leu Leu Val Leu Leu Leu Leu Gly Val Val Leu Asn Ala Ile Pro Leu Ile Val Ser Leu val Glu Glu Asp Gln Phe Ser G1n Asn Pro Ile Ser Cys Phe Glu Trp Trp Phe Pro Gly Ile Ile Gly Ala Gly Leu Met Ala Ile Pro Ala Thr Thr Met Ser Leu Thr Ala Arg Lys Arg Ala Cys Cys Asn Asn Arg Thr Gly Met Phe Leu Ser Ser Phe Phe Ser Val Ile Thr Val Ile Gly Ala Leu Tyr Cys Met Leu Ile Ser Ile Gln Ala Leu Leu Lys Gly Pro Leu Met Cys Asn Ser Pro Ser Asn Ser Asn Ala Asn Cys Glu Phe Ser Leu Lys Asn Ile Ser Asp Ile His Pro Glu Ser Phe Asn Leu Gln Trp Phe Phe Asn Asp Ser Cys Ala Pro Pro Thr Gly Phe Asn Lys Pro Thr Ser Asn Asp Thr Met Ala Ser Gly Trp Arg Ala Ser Ser Phe His Phe Asp Ser Glu Glu Asn Lys His Arg L.eu Ile His Phe Ser Val Phe Leu Gly Leu Leu Leu Val Gly Ile Leu Glu Val Leu Phe Gly Leu Ser Gln Ile PCT-US00-23328_Sequence Val Ile Gly Phe Leu G1y Cys Leu Cys Gly Val Ser Lys Arg Arg Ser Gln Ile Val <210> 49 <211> 636 <212> DNA
<213> Homo Sapien -<400> 49 atccgttctc tgcgctgcca gctcaggtga gccctcgcca aggtgacctc 50 gcaggacact ggtgaaggag cagtgaggaa cctgcagagt cacacagttg 100 ctgaccaatt gagctgtgag cctggagcag atccgtgggc tgcagacccc 150 cgccccagtg cctctccccc tgcagccctg cccctcgaac tgtgacatgg 200 agagagtgac cctggccctt ctcctactgg caggcctgac tgccttggaa 250 gccaatgacc catttgccaa taaagacgat cccttctact atgactggaa 300 aaacctgcag ctgagcggac tgatctgcgg agggctcctg gccattgctg 350 ggatcgcggc agttctgagt ggcaaatgca aatacaagag cagccagaag 400 cagcacagtc ctgtacctga gaaggccatc ccactcatca ctccaggctc 450 tgccactact tgctgagcac aggactggcc tccagggatg gcctgaagcc S00 taacactggc ccccagcacc tcctcccctg ggaggcctt:a tcctcaagga 550 aggacttctc tccaagggca ggctgttagg cccctttct:g atcaggaggc 600 ttctttatga attaaactcg ccccaccacc ccctca 636 <210> 50 <211> 89 <2I2> PRT
<213> Homo Sapien <400> 50 Met Glu Arg Val Thr Leu Ala Leu Leu Leu Leu Ala Gly Leu Thr Ala Leu Glu Ala Asn Asp Pro Phe Ala Asn Lys Asp Asp Pro Phe Tyr Tyr Asp Trp Lys Asn Leu Gln Leu Ser Gly Leu Ile Cys Gly Gly Leu Leu Ala Ile Ala Gly Ile Ala Ala Val Leu Ser Gly Lys Cys Lys Tyr Lys Ser. Ser Gln Lys Gln His Ser Pro Val Pro Glu Lys Ala Ile Pro Leu Ile Thr Pro Gly Ser Ala Thr Thr Cys PCT-u500-23328_Sequence <210> 51 <211> 1734 <21b DNA
<213> Homo sapien <400> 51 gtggactctg agaagcccag gcagttgagg acaggagaga gaaggctgca SO
gacccagagg gagggaggac agggagtcgg aaggaggagg acagaggagg 100 gcacagagac gcagagcaag ggcggcaagg aggagaccct ggtgggagga I50 agacactctg gagagagagg gggctgggca gagatgaagt tccaggggcc 200 cctggcctgc ctcctgctgg ccctctgcct gggcagtggg gaggctggcc 250 ccctgcagag cggagaggaa agcactggga caaatattgg ggaggccctt 300 ggacatggcc tgggagacgc cctgagcgaa ggggtgggaa aggccattgg 350 caaagaggcc ggaggggcag ctggctctaa agtcagtgag gcccttggcc 400 aagggaccag agaagcagtt ggcactggag tcaggcaggt tccaggcttt 450 ggcgcagcag atgctttggg caacagggtc ggggaagcag cccatgctct 500 gggaaacact gggcacgaga ttggcagaca ggcagaagat gtcattcgac 550 acggagcaga tgctgtccgc ggctcctggc agggggtgcc tggccacagt 600 ggtgcttggg aaacttctgg aggccatggc atctttggc;t ctcaaggtgg 650 ccttggaggc cagggccagg gcaatcctgg aggtctggg~g actccgtggg 700 tccacggata ccccggaaac tcagcaggca gctttggaat gaatcctcag 750 ggagctccct ggggtcaagg aggcaatgga gggccaccaa actttgggac 800 caacactcag ggagctgtgg cccagcctgg ctatggttca gtgagagcca 850 gcaaccagaa tgaagggtgc acgaatcccc caccatctgg ctcaggtgga 900 ggctccagca actctggggg aggcagcggc tcacagtcgg gcagcagtgg 950 cagtggcagc aatggtgaca acaacaatgg cagcagcagt ggtggcagca 1000 gcagtggcag cagcagtggc agcagcagtg gcggcagcag tggcggcagc 1050 agtggtggca gcagtggcaa cagtggtggc agcagaggtg acagcggcag 1100 tgagtcctcc. tggggatcca gcaccggctc ctcctccggc aaccacggtg 1150 ggagcggcgg aggaaatgga cataaacccg ggtgtgaaaa gccagggaat 1200 gaagcccgcg ggagcgggga atctgggatt cagggcttca gaggacaggg 1250 agtttccagc aacatgaggg aaataagcaa agagggcaat cgcctccttg 1300 gaggctctgg agacaattat cgggggcaag ggtcgagctg gggcagtgga 1350 ggaggtgacg ctgttggtgg agtcaatact gtgaactctg agacgtctcc 1400 tgggatgttt aactttgaca ctttctggaa gaattttaaa tccaagctgg 1450 .,. ,.,...,. v. "v~., ~ :.~,.", ....,t.. "~ .~. . ,r... ,~""..n..~-...,~., .~-~ , a.~. .sax.~.::.30.~;,":~,~wr.~~~:~~:w~,:...-,,»~~_~~,~~ s,"",..z,.~,m~.
~...A~".....~,.. ......~,.~",",..,.o."~,~w.~", r,",.....>M...~..._~.~,.""._ ..._ ......_-_.~.~...~,_~.w PCT-u500-23328_Sequence gtttcatcaa ctgggatgcc ataaacaagg accagagaag ctctcgcatc 1500 ccgtgacctc cagacaagga gccaccagat tggatgggag cccccacact 1550 ccctccttaa aacaccaccc tctcatcact aatctcagcc cttgcccttg 1600 aaataaacct tagctgcccc acaaaaaaaa aaaaaaaaaa aaaaaaaaaa 1650 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 1700 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaa 1734 <210> 52 <211> 440 <212> PRT
<213> Homo Sapien <400> 52 Met Lys Phe Gln Gly Pro Leu Ala Cys Leu Leu Leu Ala Leu Cys Leu Gly Ser Gly Glu Ala Gly Pro Leu Gln Ser Gly Glu Glu Ser Thr Gly Thr Asn Ile Gly Glu Ala Leu Gly His Gly Leu Gly Asp Ala Leu Ser Glu Gly val Gly Lys Ala Ile Gly Lys Glu Ala Gly Gly Ala Ala Gly Ser Lys val Ser Glu Ala Leu Gly Gln Gly Thr Arg Glu Ala Val Gly Thr Gly Val Arg Gln va~l Pro Gly Phe Gly Ala Ala Asp Ala Leu Gly Asn Arg Val Gly Glu Ala Ala His Ala Leu Gly Asn Thr Gly His Glu Ile Gly Arg Gln Ala Glu Asp val Ile Arg His Gly Ala Asp Ala val Arg Gly Ser Trp Gln Gly val Pro Gly His Ser Gly Ala Trp Glu Thr Ser Gly Gly His Gly Ile Phe Gly Ser Gln Gly Gly Leu Gly Gly Gln Gly Gln Gly Asn Pro Gly Gly Leu Gly Thr Pro Trp val His Gly Tyr Pro Gly Asn Ser Ala Gly Ser Phe Gly Met Asn Pro Gln Gly Ala Pro Trp Gly G1n Gly Gly Asn Gly Gly Pro Pro Asn Phe G1y Thr Asn Thr Gln Gly Ala val Ala Gln Pro Gly Tyr G1y Ser vat Arg Ala Ser Asn Gln PCT-u500-23328_sequence Asn Glu Gly Cys Thr Asn Pro Pro Pro Ser Gly Ser Gly Gly Gly ser Ser Asn Ser Gly Gly Gly Ser Gly Ser Gln Ser Gly ser ser Gly Ser Gly Ser Asn Gly Asp Asn Asn Asn Giy ser Ser Ser Gly G1y Ser Ser ser Gly Ser Ser Ser Gly Ser ser Ser Gly Gly Ser ser Gly Gly Ser 5er Gly Gly Ser Ser Gly Asn Ser Gly Gly Ser Arg Gly Asp ser Gly Ser Glu Ser Ser Trp Gly Ser Ser Thr Gly Ser Ser Ser Giy Asn His Giy Gly ser Gly Gly Gly Asn Giy His ~ys Pro Gly Cys Glu Lys Pro Giy Asn Glu Ala Arg Gly Ser Gly Glu Ser Gly Ile Gln Gly Phe Arg Gly Gln Gly Val Ser Ser Asn stet Arg Glu Ile Ser Lys Glu Gly Asn Arg Leu Leu Gly Gly Ser Gly ASp Asn Tyr Arg Gly Gln Gly Ser Ser Trp Gly Ser Gly Gly Gly Asp Aia vat Gly Giy val Asn Thr val Asn ser Giu Thr Ser Pro Giy Met Phe Asn.Phe Asp Thr Phe Trp Lys Asn Phe Lys Ser Lys Leu Giy Phe Ile Asn Trp Asp Ala Ile Asn Lys Asp Gln Arg Ser Ser Arg Ile Pro <210> 53 <211> 1676 <212> DNA
<213> Homo sapien <400> 53 ggagaagagg ttgtgtggga caagctgctc ccgacagaag gatgtcgctg 50 ctgagcctgc cctggctggg cctcagaccg gtggcaatgt ccccatggct 100 actcctgctg ctggttgtgg gctcctggct actcgcccgc atcctggctt 150 ggacctatgc cttctataac aactgccgcc ggctccagtg tttcccacag 200 cccccaaaac ggaactggtt ttggggtcac ctgggcctga tcactcctac 250 agaggagggc ttgaaggact cgacccagat gtcggccacc tattcccagg 300 PcT-u500-23328_seguence gctttacggt atggctgggt cccatcatcc ccttcatcgt tttatgccac 350 cctgacacca tccggtctat caccaatgcc tcagctgcca ttgcacccaa 400 ggataatctc ttcatcaggt tcctgaagcc ctggctggga gaagggatac 450 tgctgagtgg cggtgacaag tggagccgcc accgtcggat gctgacgccc 500 gccttccatt tcaacatcct gaagtcctat ataacgatct tcaacaagag 550 tgcaaacatc atgcttgaca agtggcagca cctggcctca gagggcagca 600 gtcgtctgga catgtttgag cacatcagcc tcatgacctt ggacagtcta 650 cagaaatgca tcttcagctt tgacagccat tgtcaggaga ggcccagtga 700 atatattgcc accatcttgg agctcagtgc ccttgtagag aaaagaagcc 750 agcatatcct ccagcacatg gactttctgt attacctctc ccatgacggg 800 cggcgcttcc acagggcctg ccgcctggtg catgacttca cagacgctgt 850 catccgggag cggcgtcgca ccctccccac tcagggtatt gatgattttt 900 tcaaagacaa agccaagtcc aagactttgg atttcattga tgtgcttctg 950 ctgagcaagg atgaagatgg gaaggcattg tcagatgagg atataagagc 1000 agaggctgac accttcatgt ttggaggcca tgacaccacg gccagtggcc 1050 tctcctgggt cctgtacaac cttgcgaggc acccagaata ccaggagcgc 1100 tgccgacagg aggtgcaaga gcttctgaag gaccgcgatc ctaaagagat 1150 tgaatgggac gacctggccc agctgccctt cctgaccatg tgcgtgaagg 1200 agagcctgag gttacatccc ccagctccct tcatctcccg atgctgcacc 1250 caggacattg ttctcccaga tggccgagtc atccccaaag gcattacctg 1300 cctcatcgat attatagggg tccatcacaa cccaactgtg tggccggatc 1350 ctgaggtcta cgaccccttc cgctttgacc cagagaacag caaggggagg 1400 tcacctctgg cttttattcc tttctccgca gggcccagga actgcatcgg 1450 gcaggcgttc gccatggcgg agatgaaagt ggtcctggcg ttgatgctgc 1500 tgcacttccg gttcctgcca gaccacactg agccccgcag gaagctggaa 1550 ttgatcatgc gcgccgaggg cgggctttgg ctgcgggtgg agcccctgaa 1600 tgtaggcttg cagtgacttt ctgacccatc cacctgtttt tttgcagatt 1650 gtcatgaata aaacggtgct gtcaaa 1676 <210> 54 <211> 524 <212> PRT
<213> Homo Sapien <400> 54 PCT-u500-23328_Sequence Met Ser Leu Leu Ser Leu Pro Trp Leu Gly Leu Arg Pro Val Ala Met Ser Pro Trp Leu Leu Leu Leu Leu Val Val Gly Ser Trp Leu Leu Ala Arg Ile Leu Ala Trp Thr Tyr Ala Phe Tyr Asn Asn cys Arg Arg Leu Gln Cys Phe Pro Gln Pro Pro Lys Arg Asn Trp Phe Trp Gly His Leu Gly Leu Ile Thr Pro Thr Glu Glu Gly Leu Lys Asp Ser Thr Gln Met Ser Ala Thr Tyr Ser Gln Gly Phe Thr Val Trp Leu Gly.Pro zle Ile Pro Phe Ile val Leu Cys His Pro Asp Thr Ile Arg Ser Ile Thr Asn Ala Ser Ala Ala Ile Ala Pro Lys Asp Asn Leu Phe Ile Arg Phe Leu Lys Pro Trp Leu Gly Glu Gly Ile Leu Leu Ser Gly Gly Asp Lys Trp Ser Arg His Arg Arg Met Leu Thr Pro Ala Phe His Phe Asn Ile Leu Lys Ser Tyr Ile Thr 155 160 ~ 165 Ile Phe Asn Lys Ser Ala Asn Ile Met Leu Asp Lys Trp Gln His Leu Ala Ser Glu Gly Ser ser Arg Leu Asp Met Phe Glu His Ile Ser Leu Met Thr Leu Asp S.er Leu Gln Lys Cys I1e Phe Ser Phe Asp Ser His Cys Gln Glu Arg Pro Ser Glu Tyr Ile Ala Thr Ile Leu Glu Leu Ser Ala Leu Val Glu Lys Arg Ser Gln His Ile Leu Gln His Met Asp Phe Leu Tyr Tyr Leu Ser His Asp Gly Arg Arg Phe His Arg Ala Cys Arg Leu Val His Asp Phe Thr Asp Ala V,al Ile Arg Glu Arg Arg Arg Thr Leu Pro Thr Gln Gly Ile Asp Asp Phe Phe Lys Asp Lys Ala Lys Ser Lys Thr Leu Asp Phe Ile Asp Val Leu Leu Leu Ser Lys Asp Glu Asp Gly Lys Ala Leu Ser Asp PCT-u500-23328_sequence Glu ASp Ile Arg Ala Glu Ala Asp Thr Phe Met Phe Gly Gly His Asp Thr Thr Ala ser Gly Leu Ser Trp Val Leu Tyr Asn Leu Ala Arg His Pro Glu Tyr Gln Glu Arg Cys Arg Gln Glu val Gln Glu Leu Leu Lys Asp Arg Asp Pro Lys Glu Ile Glu Trp Asp Asp Leu Ala Gln Leu Pro Phe Leu Thr Met Cys Val Lys Glu Ser Leu Arg Leu His Pro Pro Ala Pro Phe Ile ser Arg Cys Cys Thr Gln Asp Ile Val Leu Pro Asp Gly Arg Val Ile Pro Lys Gly Iie Thr Cys Leu Ile Asp Ile Ile Gly Val His His Asn Pro Thr Val Trp Pro 425 ~ 430 435 Asp Pro Glu val Tyr Asp Pro Phe Arg Phe asp Pro Glu Asn ser Lys Gly Arg Ser Pro Leu Ala Phe Ile Pro Phe ser Ala Gly Pro Arg Asn Cys Ile Gly Gln Ala Phe Ala Met Ala Glu Met Lys Val Val Leu Ala Leu Met Leu Leu His Phe Arg Phe Leu Pro Asp His Thr Glu Pro Arg Arg Lys Leu Glu Leu Ile Met Arg Ala Glu G1y Gly Leu Trp Leu Arg Val Glu Pro Leu Asn Val Gly Leu Gln <210> 55 <211> 644 <212> DNA
<213> Homo sapien <400> 55 atcgcatcaa ttgggagtac catcttcctc atgggaccag tgaaacagct SO
gaagcgaatg tttgagccta ctcgtttgat tgcaactatc atggtgctgt 100 tgtgttttgc acttaccctg tgttctgcct tttggtggca taacaaggga 150 cttgcactta tcttctgcat tttgcagtct ttggcattga cgtggtacag 200 cctttccttc ataccatttg caagggatgc tgtgaagaag tgttttgccg 250 tgtgtcttgc ataattcatg gccagtttta tgaagctttg gaaggcacta 300 tggacagaag ctggtggaca gttttgtaac tatcttcgaa acctctgtct 350 tacagacatg tgccttttat cttgcagcaa tgtgttgctt: gtgattcgaa 400 PCT-uS00-23328_Sequence catttgaggg ttacttttgg aagcaacaat acattctcga acctgaatgt 450 cagtagcaca ggatgagaag tgggttctgt atcttgtgga gtggaatctt 500 cctcatgtac ctgtttcctc tctggatgtt gtcccactga attcccatga 550 atacaaacct attcagcaac agcaaaaaaa aaaaaaaaaa aaaaaaaaaa 600 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaa 644 <210> 56 <211> 77 <212> PRT
<213> Homo Sapien <400> 56 Met Gly Pro Val Lys Gln Leu Lys Arg Met Phe Glu Pro Thr Arg 1 s to 15 Leu Ile Ala Thr Ile Met Val Leu Leu Cys Phe Ala Leu Thr Leu Cys Ser Ala Phe Trp Trp His Asn Lys Gly Leu Ala Leu Ile Phe Cys Ile Leu Gln Ser Leu Ala Leu Thr Trp Tyr Ser Leu Ser Phe Ile Pro Phe Ala Arg Asp Ala Val Lys Lys Cys Phe Ala Val Cys Leu Ala <210> 57 <2I1> 3334 <212> DNA
<213> Homo Sapien <400> 57 cggctcgagc tcgagccgaa tcggctcgag gggcagtgga gcacccagca 50 ggccgccaac atgctctgtc tgtgcctgta cgtgccggtc atcggggaag 100 cccagaccga gttccagtac tttgagtcga aggggctccc tgccgagctg 150 aagtccattt tcaagctcag tgtcttcatc ccctcccagg aattctccac 2-00 ctaccgccag tggaagcaga aaattgtaca agctggagat aaggaccttg 250 atgggcagct agactttgaa gaatttgtcc attatctcca agatcatgag 300 aagaagctga ggctggtgtt taagattttg gacaaaaaga atgatggacg 350 cattgacgcg caggagatca tgcagtccct gcgggacttg ggagtcaaga 400 tatctgaaca gcaggcagaa aaaattctca agagcatgga taaaaacggc 450 acgatgacca tcgactggaa cgagtggaga gactaccacc tcctccaccc 500 - -cgtggaaaac atccccgaga tcatcctcta ctggaagcat tccacgatct 550 PCT-US00-23328_5equence ttgatgtggg tgagaatcta acggtcccgg atgagttcac agtggaggag 600 aggcagacgg ggatgtggtg gagacacctg gtggcaggag gtggggcagg 650 ggccgtatcc agaacctgca cggcccccct ggacaggctc aaggtgctca 700 tgcaggtcca tgcctcccgc agcaacaaca tgggcatcgt tggtggcttc 750 actcagatga ttcgagaagg aggggccagg tcactctgge ggggcaatgg 800 catcaacgtc ctcaaaattg cccccgaatc agccatcaaa ttcatggcct 85-0 atgagcagat caagcgcctt gttggtagtg accaggagac tctgaggatt 900 cacgagaggc ttgtggcagg gtccttggca ggggccatcg cccagagcag 950 catctaccca atggaggtcc tgaagacccg gatggcgctg cggaagacag 1000 gccagtactc aggaatgctg gactgcgcca ggaggatcct ggccagagag 1050 ggggtggccg ccttctacaa aggctatgtc cccaacatgc tgggcatcat 1100 cccctatgcc ggcatcgacc ttgcagtcta cgagacgctc aagaatgcct 1150 ggctgcagca ctatgcagtg aacagcgcgg accccggcgt gtttgtgctc 1200 ctggcctgtg gcaccatgtc cagtacctgt ggccagctgg ccagctaccc 1250 cctggcccta gtcaggaccc ggatgcaggc gcaagcctct attgagggcg 1300 ctccggaggt gaccatgagc agcctcttca aacatatcct gcggaccgag 1350 ggggccttcg ggctgtacag ggggctggcc cccaacttca tgaaggtcat 1400 cccagctgtg agcatcagct acgtggtcta cgagaacctg aagatcaccc 1450 tgggcgtgca gtcgcggtga cggggggagg gccgcccggc agtggactcg T500 ctgatcctgg gccgcagcct ggggtgtgca gccatctcat tctgtgaatg 1550 tgccaacact aagctgtctc gagccaagct gtgaaaaccc tagacgcacc 1600 cgcagggagg gtggggagag ctggcaggcc cagggcttgt cctgctgacc 1650 ccagcagacc ctcctgttgg ttccagcgaa gaccacaggc attccttagg 1700 gtccagggtc agcaggctcc gggctcacat gtgtaaggac aggacatttt 1750 ctgcagtgcc tgccaatagt gagcttggag cctggaggcc ggcttagttc 1800 -ttccatttca cccttgcagc cagctgttgg ccacggcccc tgccctctgg 1850 tctgccgtgc atctccctgt gccctcttgc tgcctgcctg tctgctgagg 1900 taaggtggga ggagggctac agcccacatc ccaccccctc gtccaatccc 1950 ataatccatg atgaaaggtg aggtcacgtg gcctcccagg cctgacttcc 2000 caacctacag cattgacgcc aacttggctg tgaaggaaga ggaaaggatc 2050 tggccttgtg gtcactggca tctgagccct.gctgatggct ggggctctcg 2100 ggcatgcttg ggagtgcagg gggctcgggc tgcctggcct ggctgcacag 2150 .... . . . . . .., . ~., .r . .... . . ~ _"~~w. "~ ~. ~-~zu.~~ z ,_.M. _ . _-.. T ,._.a__ _ . _.....__._..~,. w~..~ m..._ _ .

PCT-u500-23328_Sequence aaggcaagtg ctggggctca tggtgctctg agctggcctg gaccctgtca 2200 ggatgggccc cacctcagaa ccaaactcac tgtccccact gtggcatgag 2250 ggcagtggag caccatgttt gagggcgaag ggcagagcgt ttgtgtgttc 2300 tggggaggga aggaaaaggt gttggaggcc ttaattatgg actgttggga 2350 aaagggtttt gtccagaagg acaagccgga caaatgagcg acttctgtgc 2400 ttccagagga agacgaggga gcaggagctt ggctgactgc tcagagtctg 2450 ttctgacgcc ctgggggttc ctgtccaacc ccagcagggg cgcagcggga 2500 ccagccccac attccacttg tgtcactgct tggaacctat ttattttgta 2550 tttatttgaa cagagttatg tcctaactat ttttatagat ttgtttaatt 2600 aatagcttgt cattttcaag ttcatttttt attcatattt atgttcatgg 2650 ttgattgtac cttcccaagc ccgcccagtg ggatgggagg aggaggagaa 2700 ggggggcctt gggccgctgc agtcacatct gtccagagaa attccttttg 2750 ggactggagg cagaaaagcg gccagaaggc agcagccctg gctcctttcc 2800 tttggcaggt tggggaaggg cttgccccca gccttaggat ttcagggttt 2850 gactgggggc gtggagagag agggaggaac ctcaataacc ttgaaggtgg 2900 aatccagtta tttcctgcgc tgcgagggtt tctttatttc actcttttct 2950 gaatgtcaag gcagtgaggt gcctctcact gtgaatttgt ggtgggcggg 3000 ggctggagga gagggtgggg ggctggctcc gtccctccca gccttctgct 3050 gcccttgctt aacaatgccg gccaactggc gacctcacgg ttgcacttcc 3100 attccaccag aatgacctga tgaggaaatc ttcaatagga tgcaaagatc 3150 aatgcaaaaa ttgttatata tgaacatata actggagtcg tcaaaaagca 3200 aattaagaaa gaattggacg ttagaagttg tcatttaaag cagccttcta 3250 ataaagttgt ttcaaagctg aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 3300 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaa 3334 <210> 58 <211> 469 <212> PRT
<213> Homo sapien <400> 58 Met Leu Cys Leu Cys Leu Tyr Val Pro Val Ile Gly GTu Ala Gln Thr Glu Phe Gln Tyr Phe Glu Ser Lys Gly Leu Pro Ala Glu Leu Lys Ser Ile Phe Lys Leu Ser val Phe Ile Pro Ser Gln Glu Phe ...~,. , .~,.~-~A . _ao.~,n, , . ~ _ri, .~U.~,. ~~, ,.. _ .~a%~,r~:~~~,.~~.
_~~~.. -~___.. ._. uwh.."~. .~ .r ..~" ~ K .~m~w_._ ~_.. ___...

PCT-uS00-23328_Sequence Ser Thr Tyr Arg Gln Trp Lys Gln Lys Tle val Gln Ala Gly Asp Lys Asp Leu Asp Gly Gln Leu Asp Phe Glu Glu Phe Val His Tyr Leu Gln Asp His Glu Lys Lys Leu Arg Leu Val Phe Lys Ile Leu Asp Lys Lys Asn ASp Gly Arg Ile Asp Ala Gin Glu Ile Met Gln Ser Leu Arg Asp Leu Gly Val Lys Ile Ser Glu Gln Gln Ala Glu Lys Ile Leu Lys Ser Met Asp Lys Asn Gly Thr Met Thr Ile Asp Trp Asn Glu Trp Arg Asp Tyr His Leu Leu His Pro Val Glu Asn 140 145 15p Ile Pro Glu Ile Ile Leu Tyr Trp Lys His Ser Thr Ile Phe Asp Val Gly Glu Asn Leu Thr Val Pro Asp Glu Phe Thr Val Glu Glu Arg Gln Thr Gly Met Trp Trp Arg His Leu Val Ala Gly Gly Gly Ala Gly Ala Val Ser Arg Thr Cys Thr Ala Pro Leu Asp Arg Leu Lys Val Leu Met Gln Val His Ala Ser Arg Ser Asn Asn Met Gly Ile Val Gly Gly Phe Thr Gln Met.Ile Arg Glu Gly Gly Ala Arg Ser Leu Trp Arg Gly Asn Gly Ile Asn Val Leu Lys Ile Ala Pro Glu Ser Ala Ile Lys Phe Met Ala Tyr Glu Gl~n Ile Lys Arg Leu Val Gly Ser Asp Gln Glu Thr Leu Arg Ile His Glu Arg Leu Val Ala Gly Ser Leu Ala Gly Ala Ile Ala Gln Ser Ser Ile Tyr Pro Met Glu Val Leu Lys Thr Arg Met Ala Leu Arg Lys Thr Gly Gln Tyr Ser Gly Met Leu Asp Cys Ala Arg Arg Ile Leu Ala Arg Glu Gly Val Ala Ala Phe Tyr Lys Gly Tyr Val Pro Asn Met Leu Gly Ile Ile Pro Tyr Ala Gly Ile Asp Leu Ala Val Tyr Glu Thr Leu _~~T4_ pa" ~...... ~.~a,~~.x ~ .~n~.~ ,4 ~,~~.~~~ ~~,~a .~~~~-~M~,~gN--.._ ._ __ _....__ ... ,. _ .A_....ri_._.____ _ PCT-US00-23328_Sequence Lys Asn Ala Trp Leu Gln His Tyr Ala Val Asn Ser Ala Asp Pro Gly Val Phe Val Leu Leu Ala Cys Gly Thr Met Ser Ser Thr Cys Gly Gln Leu Ala Ser Tyr Pro Leu Ala Leu Val Arg Thr Arg Met Gln Ala Gln Ala Ser Ile Glu Gly Ala Pro Glu Val Thr Met Ser 41.0 415 420 Ser Leu Phe Lys His Ile Leu Arg Thr Glu Gly Ala Phe Gly Leu Tyr Arg Gly Leu Ala Pro Asn Phe Met Lys Val Ile Pro Ala Val Ser Ile Ser Tyr l/al Val Tyr Glu Asn Leu Lys Ile Thr Leu Gly Val Gln Ser Arg <210> 59 <211> 1658 <212> DNA ~ ' <213> Homo Sapien <400> 59 _ ggaaggcagc ggcagctcca ctcagccagt acccagatac gctgggaacc SO
ttccccagcc atggcttccc tggggcagat cctcttctgg agcataatta 100 gcatcatcat tattctggct ggagcaattg cactcatcat tggctttggt 150 atttcaggga gacactccat cacagtcact actgtcgcct cagctgggaa 200 cattggggag gatggaatcc tgagctgcac ttttgaacct gacatcaaac 250 tttctgatat cgtgatacaa tggctgaagg aaggtgtttt aggcttggtc 300 catgagttca aagaaggcaa agatgagctg tcggagcagg atgaaatgtt~350 cagaggccgg acagcagtgt ttgctgatca agtgatagtt ggcaatgcct 400 ctttgcggct gaaaaacgtg caactcacag atgctggcac ctacaaatgt 450 tatatcatca cttctaaagg caaggggaat gctaaccttg agtataaaac S00 tggagccttc agcatgccgg aagtgaatgt ggactataat gccagctcag 550 ~agaccttgcg gtgtgaggct ccccgatggt tcccccagcc cacagtggtc 600 tgggcatccc aagttgacca gggagccaac ttctcggaag tctccaatac 650 cagctttgag ctgaactctg agaatgtgac catgaaggtt gtgtctgtgc 700 tctacaatgt tacgatcaac aacacatact cctgtatgat tgaaaatgac 750 attgccaaag caacagggga tatcaaagtg aeagaatcgg agatcaaaag 800 gcggagtcac ctacagctgc taaactcaaa ggcttctctg tgtgtctctt 850 PCT-u500-23328_Sequence ctttctttgc catcagctgg gcacttctgc ctctcagccc ttacctgatg 900 ctaaaataat gtgccttggc cacaaaaaag catgcaaagt cattgttaca 950 acagggatct acagaactat ttcaccacca gatatgacct agttttatat 1000 ttctgggagg aaatgaattc atatctagaa gtctggagtg agcaaacaag 1050 agcaagaaac aaaaagaagc caaaagcaga aggctccaat atgaacaaga 1100 taaatctatc ttcaaagaca tattagaagt tgggaaaata attcatgtga 1150 actagacaag tgtgttaaga gtgataagta aaatgcacgt ggagacaagt 1200 gcatccccag atctcaggga cctccccctg cctgtcacct ggggagtgag 1250 aggacaggat agtgcatgtt ctttgtctct gaatttttag ttatatgtgc 1300 tgtaatgttg ctctgaggaa gcccctggaa agtctatccc aacatatcca 1350 catcttatat tccacaaatt aagctgtagt atgtacccta agacgctgct 1400 aattgactgc cacttcgcaa -ctcaggggcg gctgcatttt agtaatgggt 1450 caaatgattc actttttatg atgcttccaa aggtgccttg gcttctcttc 1500 ccaactgaca aatgccaaag ttgagaaaaa tgatcataat tttagcataa 1550 acagagcagt cggggacacc gattttataa ataaactgag caccttcttt 1600 ttaaacaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 1650 aaaaaaaa 1658 <210> 60 <211> 282 <212> PRT
<213> Homo Sapien <400> 60 Met Ala Ser Leu Gly Gln Ile Leu Phe Trp Ser~ Ile Ile Ser Ile Ile Ile Ile Leu Ala Giy AIa I1e Ala Leu Ile I1e Gly Phe Gly Ile Ser Gly Arg His Ser Ile Thr val Thr Thr val Ala Ser Ala Gly Asn Ile Gly Glu Asp Gly Ile teu Ser cys Thr Phe Glu Pro Asp Ile Lys Leu Ser Asp Ile val Ile Gln Trp Leu Lys Glu Gly Val Leu Gly Leu Val His Glu Phe Lys Glu Gly Lys Asp Glu Leu Ser Glu G1n Asp GTu Met Phe Arg Gly Arg Thr Ala Val Phe A1a Asp Gln Val Ile val Gly Asn Ala Ser Leu Arg Leu Lys Asn Val PCT-uS00-23328_Sequence Gln Leu Thr Asp Ala Gly Thr Tyr Lys Cys Tyr Ile Ile Thr Ser Lys Gly Lys Gly Asn Ala Asn Leu Glu Tyr Lys Thr Gly Ala Phe 140 145. 150 Ser Met Pro Glu Val Asn Val Asp Tyr Asn Ala Ser Ser Glu Thr Leu Arg Cys Glu Ala Pro Arg Trp Phe Pro Gln Pro Thr Val Val Trp Ala Ser Gln Vai Asp Gln Gly Ala Asn Phe Ser Glu Val Ser Asn Thr Ser Phe Glu Leu Asn Ser Glu Asn Val Thr Met Lys Val Val Ser Val Leu Tyr Asn Val Thr Ile Asn Asn Thr Tyr Ser Cys Met Ile Glu Asn Asp Ile Ala Lys Ala Thr Gly Asp Ile Lys Val Thr Glu Ser Giu Ile Lys Arg Arg Ser His Leu Gln Leu Leu Asn Ser Lys Ala Ser Leu Cys Val Ser Ser Phe Phe Ala Ile Ser Trp Ala Leu Leu Pro Leu Ser Pro Tyr Leu Met Leu Lys <210> 61 <211> 1617 <212> DNA
<213> Homo Sapien <400> 61 tgacgtcaga atcaccatgg ccagctatcc ttaccggcag ggctgcccag 50 gagctgcagg acaagcacca ggagcccctc cgggtagcta ctaccctgga 100 ccccccaata gtggagggca gtatggtagt gggctacccc ctggtggtgg 150 ttatgggggt cctgcccctg gagggcctta tggaccacca gctggtggag 200 ggccctatgg acaccccaat cctgggatgt tcccctctgg aactccagga 250 ggaccatatg gcggtgcagc tcccgggggc ccctatggtc agccacctcc 300 aagttcctac ggtgcccagc agcctgggct ttatggacag ggtggcgccc 350 ctcccaatgt ggatcctgag gcctactcct ggttccagtc ggtggactca 400 gatcacagtg gctatatctc catgaaggag ctaaagcagg ccctggtcaa 450 ctgcaattgg tcttcattca atgatgagac ctgcctcatg atgataaaca S00 .
tgtttgacaa gaccaagtca ggccgcatcg atgtctacgg cttctcagcc 550 .. . , . _... . ,..,. ,., a,~.,r _ ro.xomppp,~.: .." "whm.~kuxR
.;",S.g4.7~4'k~., u... !~avpyqor.v-rav,~.. n,.e..w..:,a,....... .. . .._......

PCT-us00-23328_Sequence ctgtggaaat tcatccagca gtggaagaac ctcttccagc agtatgaccg 600 ggaccgctcg ggctccatta gctacacaga gctgcagcaa gctctgtccc 650 aaatgggcta caacctgagc ccccagttca cccagcttct ggtctcccgc 700 tactgcccac gctctgccaa tcctgccatg cagcttgacc gcttcatcca 750 ggtgtgcacc cagctgcagg tgctgacaga ggccttccgg gagaaggaca 800 cagctgtaca aggcaacatc cggctcagct tcgaggactt cgtcaccatg 850 acagcttctc ggatgctatg acccaaccat ctgtggagag tggagtgcac 900 cagggacctt tcctggcttc ttagagtgag agaagtatgt ggacatctct 950 tcttttcctg tccctctaga agaacattct cccttgcttg atgcaacact 1000 gttccaaaag agggtggaga gtcctgcatc atagccacca aatagtgagg 1050 accggggctg aggccacaca gataggggcc tgatggagga gaggatagaa 1100 gttgaatgtc ctgatggcca tgagcagttg agtggcacag cctggcacca 1150 ggagcaggtc cttgtaatgg agttagtgtc.cagtcagctc~ agctccaccc 1200 tgatgccagt ggtgagtgtt catcggcctg ttaccgttag tacctgtgtt 1250 ccctcaccag gccatcctgt caaacgagcc cattttctcc aaagtggaat 1300 ctgaccaagc atgagagaga tctgtctatg ggaccagtgg cttggattct 1350 gccacaccca taaatccttg tgtgttaact tctagctgcc tggggctggc 1400 cctgetcaga caaatctgct ccctgggcat ctttggccag gcttctgccc 1450 cctgcagctg ggacccctca cttgcctgcc atgctctgct cggcttcagt 1500 ctccaggaga cagtggtcac ctctccctgc caatactttt tttaatttgc 1550 attttttttc atttggggcc aaaagtccag tgaaattgta agcttcaata 1600 aaaggatgaa actctga 1617 <210> 62 <211> 284 <212> PRT
<213> Homo Sapien <400> 62 Met Ala Ser Tyr Pro Tyr Arg Gln Gly Cys Pro Gly Ala Ala Gly Gln Ala Pro Gly Ala Pro Pro Gly Ser Tyr Tyr Pro Gly Pro Pro Asn Ser Gly Gly Gln Tyr Gly Ser Gly Leu Pro Pro Gly Gly Gly Tyr Gly Gly Pro Ala Pro Gly Gly Pro Tyr Gly Pro Pro Ala Gly Gly Gly Pro Tyr Gly t~tis Pro Asn Pro Gly Met Phe Pro Ser Gly . ". ~.re r. . , ~ ~;~ .~~~~ ., mu.u~~ ~.. . e.r,F~~..~ ~~ ~r.:~x~A~.
,~~~W,~mwx,. .~~~ w.,a.e_ ~r ..~ ~~x~~., ~_. ~ ,. ~...r.~.~..n..~~..~
~N

PCT-uS00-23328 Sequence Thr Pro Gly Gly Pro Tyr Gly Gly Ala Ala Pro Gly Gly Pro Tyr Gly Gln Pro Pro Pro Ser Ser Tyr Gly Ala Gln Gln Pro Gly Leu Tyr Gly Gln Gly Gly Ala Pro Pro Asn Val Asp Pro Glu Ala Tyr Ser Trp Phe Gln Ser val Asp Ser Asp His Ser Gly Tyr Ile Ser Met Lys Glu Leu Lys Gln Ala Leu val Asn Cys Asn Trp Ser Ser Phe Asn Asp Glu Thr Cys Leu Met Met Ile Asn Met Phe Asp Lys Thr Lys Ser Gly Arg Ile Asp Val Tyr Gly Phe Ser Ala Leu Trp Lys Phe Ile Gln Gln Trp Lys Asn Leu Phe Gln Gln Tyr Asp Arg Asp Arg Ser Gly Ser Ile Ser Tyr Thr Glu Leu Gln Gln Ala Leu Ser Gln Met Gly Tyr Asn Leu Ser Pro Gln Phe Thr Gln Leu Leu 215 220 . 225 val Ser Arg Tyr Cys Pro Arg Ser Ala Asn Pro Ala Met Gln Leu Asp Arg Phe Ile Gln val Cys Thr Gln Leu Gln val Leu Thr Glu Ala Phe Arg Glu Lys Asp Thr Ala val Gln Gly Asn Ile Arg Leu Ser Phe Glu Asp Phe val Thr Met Thr Ala Ser Arg Met Leu <210> 63 <211> 1234 <212> DNA
<213> Homo Sapien <400> 63 caggatgcag ggccgcgtgg cagggagctg cgctcctctg ggcctgctcc 50 tggtctgtct tcatctccca ggcctctttg cccggagca.t cggtgttgtg 100 gaggagaaag tttcccaaaa cttcgggacc aacttgcctc agctcggaca 150 accttcctcc actggcccct ctaactctga acatccgca.g cccgctctgg 200 accctaggtc taatgacttg gcaagggttc ctctgaagct cagegtgcct 250 ccatcagatg gcttcccacc tgcaggaggt tctgcagtgc agaggtggcc 300 tccatcgtgg gggctgcctg ccatggattc ctggccccct gaggatcctt 350 PCT-0500-23328_Sequence ggcagatgat ggctgctgcg gctgaggacc gcctggggga agcgctgcct 400 gaagaactct cttacctctc cagtgctgcg gccctcgctc cgggcagtgg 450 ccctttgcct ggggagtctt ctcccgatgc cacaggcctc tcacctgagg 500 cttcactcct ccaccaggac tcggagtcca gacgactgcc ccgttctaat SSO
tcactgggag ccgggggaaa aatcctttcc caacgccctc cctggtctct 600 catccacagg gttctgcctg atcacccctg gggtaccctg aatcccagtg 650 tgtcctgggg aggtggaggc cctgggactg gttggggaa.c.gaggcccatg 700 ccacaccctg agggaatctg gggtatcaat aatcaacccc caggtaccag 750 ctggggaaat attaatcggt atccaggagg cagctgggga aatattaatc 800 ggtatccagg aggcagctgg gggaatatta atcggtatcc aggaggcagc 850 tgggggaata ttcatctata cceaggtatc aataacccat ttcctcctgg 900 agttctccgc cctcctggct cttcttggaa catcccagc,t ggcttcccta 950 atcctccaag ccctaggttg cagtggggct agagcacgat agagggaaac 1000 ccaacattgg gagttagagt cctgctcccg ccccttgct:g tgtgggctca 1050 atccaggccc tgttaacatg tttccagcac tatccccact tttcagtgcc 1100 tcccctgctc atctccaata aaataaaagc acttatgaaa aaaaaaaaaa 1150 aaaaaaaaaa.aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 1200 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaa 1234 <210> 64 <211> 325 <212> PRT
<213> Homo Sapien <400> 64 Met Gln Gly Arg Val Ala Gly Ser Cys Ala Pro Leu Gly Leu Leu Leu Val Cys Leu His Leu Pro Gly Leu Phe Ala Arg Ser Ile Gly 20 25 ~ 30 Val val Glu Glu Lys Val Ser Gln Asn Phe Glly Thr Asn Leu Pro Gln Leu Gly Gln Pro Ser Ser Thr Gly Pro Ser Asn Ser Glu His Pro Gln Pro Ala Leu Asp Pro Arg Ser Asn Asp Leu Ala Arg Val Pro Leu Lys Leu Ser Val Pro Pro Ser Asp Gly Phe Pro Pro Ala Gly Gly Ser Ala Val Gln Arg Trp Pro Pro Ser Trp Gly Leu Pro ..

PCT-uS00-23328_Sequence Ala Met Asp Ser Trp Pro Pro Glu Asp Pro Trp Gln Met Met Ala Ala Ala Ala Glu Asp Arg Leu Gly Glu Ala Leu Pro Glu Glu Leu Ser Tyr Leu Ser Ser Ala Ala Ala Leu Ala Pro Gly Ser Gly Pro Leu Pro Gly Glu Ser Ser Pro Asp Ala Thr Gly Leu Ser Pro Glu Ala Ser Leu Leu His Gln Asp Ser Glu Ser Arg Arg Leu Pr.o Arg Ser Asn Ser Leu Gly Ala Gly Gly Lys Ile Leu Ser Gln Arg Pro Pro Trp Ser Leu Ile His Arg Val Leu Pro Asp His Pro Trp Gly Thr Leu Asn Pro Ser Val Ser Trp Gly Gly Gly Gly Pro Gly Thr Gly Trp Gly Thr Arg Pro Met Pro His Pro Glu Gly Ile Trp Gly Ile Asn Asn Gln Pro Pro Gly Thr Ser Trp Gly Asn Ile Asn Arg Tyr Pro Gly Gly Ser Trp Gly Asn Ile Asn Arg Tyr Pro Gly Gly Ser Trp Gly Asn Ile.Asn Arg Tyr Pro Gly Gly Ser Trp Gly Asn Ile His Leu Tyr Pro Gly Ile Asn Asn Pro Phe Pro Pro Gly Val Leu Arg Pro Pro Gly Ser Ser Trp Asn Ile Pro Ala Gly Phe Pro Asn Pro Pro Ser Pro Arg Leu Gln Trp Gly <210> 65 <211> 422 <212> DNA
<213> Homo Sapien <400> 65 aaggagaggc caccgggact tcagtgtctc ctccatccca ggagcgcagt 50 ggccactatg gggtctgggc tgccccttgt cctcctcttg accctccttg 100 gcagctcaca tggaacaggg ccgggtatga ctttgcaact gaagctgaag 150 gagtcttttc tgacaaattc ctcctatgag tcc~ge~tcc tggaattgct 200 tgaaaagctc tgcctcctcc tccatctccc ttcagggacc agcgtcaccc 250 tccaccatgc aagatctcaa caccatgttg tctgcaacac atgacagcca 300 PCT-us00-2 3328_Seq~ence ttgaagcctg tgtccttctt ggcccgggct tttgggccgg ggatgcagga 350 ggcaggcccc gaccctgttt ttcagcaggc ccccaccctc ctgagtggca 400 ataaataaaa ttcggtatgc tg 422 <210> 66 <2I1> 7&
<212> PRT
<213> Homo Sapien <400> 66 Met Gly Ser Gly Leu Pro Leu Val Leu Leu Leu Thr Leu Leu Gly Ser Ser His Gly Thr Gly Pro Gly Met Thr Leu Gln Leu Lys Leu Lys Glu Ser Phe Leu Thr Asn Ser Ser Tyr Glu Ser Ser Phe Leu Glu Leu Leu Glu Lys Leu Cys Leu Leu Leu His Leu Pro Ser Gly Thr ser val Thr Leu His His A1a Arg Ser Glin His His val val Cys Asn Thr <210> 67 <211> 744 <212> oNA
<213> Homo Sapien <400> 67 acggaccgag ggttcgaggg agggacacgg accaggaacc tgagctaggt 50 caaagacgcc cgggccaggt gccccgtcgc aggtgcccct ggccggagat 100 gcggtaggag gggcgagcgc gagaagcccc ttcctcggcg ctgccaaccc 150 gccacccagc ccatggcgaa ccccgggctg gggctgcttc tggcgctggg 200 cctgccgttc ctgctggccc gctggggccg agcctggggg caaatacaga 250 ccacttctgc aaatgagaat agcactgttt tgccttcatc caccagctcc 300 agctccgatg gcaacctgcg tccggaagcc atcactgcta tcatcgtggt 350 cttctccctc ttggctgcct tgctcctggc tgtggggctg gcactgttgg 400 tgcggaagct tcgggagaag cggcagacgg agggcaccta ccggcccagt 450 agcgaggagc agttctccca tgcagccgag gcccgggccc ctcaggactc 500 caaggagacg gtgcagggct gcctgcccat ctaggtcccc tctcctgcat 550 ctgtctccct tcattgctgt gtgaccttgg ggaaaggcag tgccctctct 600 gggcagtcag atccacccag tgcttaatag cagggaagaa ggtacttcaa 6S0 PCT-US00-23328_Sequence agactctgcc cctgaggtca agagaggatg gggctattca cttttatata 700 tttatataaa attagtagtg agatgtaaaa aaaaaaaaaa aaaa 744 <210> 68 <211> 123 <212> PRT
<213> Homo Sapien <400> 68 Met Ala Asn Pro Gly Leu Gly Leu Leu Leu Ala Leu Gly Leu Pro Phe Leu Leu Ala Arg Trp Gly Arg Ala Trp Gly Gln Ile Gln Thr Thr Ser Ala Asn Glu Asn Ser Thr Val Leu Pro Ser Ser Thr Ser ser Ser Ser Asp Gly Asn Leu Arg Pro Glu Ala Ile Thr Ala Ile Ile Val Val Phe Ser Leu Leu Ala Ala Leu Leu Leu Ala Val Gly Leu Ala Leu Leu Val Arg Lys Leu Arg Glu Lys Arg Gln Thr Glu Gly Thr Tyr Arg Pro Ser Ser Glu Glu Gln Phe Ser His Ala Ala Glu Ala Arg Ala Pro Gln Asp Ser Lys Glu Thr Val Gln Gly cys Leu Pro Ile <210> 69 <211> 3265 <212> DNA
<213> Homo Sapien <400> 69 gccaggaata actagagagg aacaatgggg ttattcagag gttttgtttt 50 cctcttagtt ctgtgcctgc tgcaccagtc aaatacttcc ttcattaagc 100 tgaataataa tggctttgaa gatattgtca ttgttataga tcctagtgtg 150 ccagaagatg aaaaaataat tgaacaaata gaggatatgg tgactacagc 200 ttctacgtac ctgtttgaag ccacagaaaa aagatttttt ttcaaaaatg 250 tatctatatt aattcctgag aattggaagg aaaatcctca gtacaaaagg 300 ccaaaacatg aaaaccataa acatgctgat gttatagttg caccacctac 350 actcccaggt agagatgaac catacaccaa gcagttcaca gaatgtggag 400 agaaaggcga atacattcac ttcacccctg accttctact tggaaaaaaa 450 caaaatgaat atggaccacc aggcaaactg tttgtccatg agtgggctca 500 PCT-US00-23328_Seguence cctccggtgg ggagtgtttg atgagtacaa tgaagatcag cctttctacc 550 gtgctaagtc aaaaaaaatc gaagcaacaa ggtgttccgc aggtatctct 600 ggtagaaata gagtttataa gtgtcaagga ggcagctgtc ttagtagagc 650 atgcagaatt gattctacaa caaaactgta tggaaaagat tgtcaattct 700 ttcctgataa agtacaaaca gaaaaagcat ccataatgtt tatgcaaagt 750 attgattctg ttgttgaatt ttgtaacgaa aaaacccata atcaagaagc 800 tccaagccta caaaacataa agtgcaattt tagaagtaca tgggaggtga 850 ttagcaattc tgaggatttt aaaaacacca tacccatggt gacaccacct 900 cctccacctg tcttctcatt gctgaagatc agtcaaagaa ttgtgtgctt 950 agttcttgat aagtctggaa gcatgggggg taaggaccgc ctaaatcgaa 1000 tgaatcaagc agcaaaacat ttcctgctgc agactgttga aaatggatcc 2050 tgggtgggga tggttcactt tgatagtact gccactattg taaataagct 1140 aatccaaata aaaagcagtg atgaaagaaa cacactcatg gcaggattac 1150 ctacatatcc tctgggagga acttccatct gctctggaat taaatatgca 1200 tttcaggtga ttggagagct acattcccaa ctcgatggat ccgaagtact 1250 gctgctgact gatggggagg ataacactgc aagttcttgt attgatgaag 1300 tgaaacaaag tggggccatt gttcatttta ttgctttggg aagagctgct 1350 gatgaagcag taatagagat gagcaagata acaggaggaa gtcattttta 1400 tgtttcagat gaagctcaga acaatggcct cattgatgct tttggggctc 1450 ttacatcagg aaatactgat ctctcccaga agtcccttca gctcgaaagt 1500 aagggattaa cactgaatag taatgcctgg atgaacgaca ctgtcataat 1550 tgatagtaca gtgggaaagg acacgttctt tctcatcaca tggaacagtc 1600 tgcctcccag tatttctctc tgggatccca gtggaacaat aatggaaaat 1650 ttcacagtgg atgcaacttc caaaatggcc tatctcagta ttccaggaac 1700 tgcaaaggtg ggcacttggg catacaatct tcaagccaaa gcgaacccag 1750 aaacattaac tattacagta acttctcgag cagcaaattc ttctgtgcct 1800 ccaatcacag tgaatgctaa aatgaataag gacgtaaaca gtttccccag 1850 cccaatgatt gtttacgcag aaattctaca aggatatgta cctgttcttg 2900 gagccaatgt gactgctttc attgaatcac agaatggaca tacagaagtt 1950.
ttggaacttt tggataatgg tgcaggcgct gattctttca agaatgatgg 2000 agtctactcc aggtatttta cagcatatac agaaaatggc agatatagct 2050 taaaagttcg ggctcatgga ggagcaaaca ctgccaggct aaaattacgg 2100 PCT-U500-23328_Sequence cctccactga atagagccgc gtacatacca ggctgggtag tgaacgggga 2150 aattgaagca aacccgccaa gacctgaaat tgatgaggat actcagacca 2200 ccttggagga tttcagccga acagcatccg gaggtgcata tgtggtatca 2250 caagtcccaa gccttccctt gcctgaccaa tacccaccaa gtcaaatcac 2300 agaccttgat gccacagttc atgaggataa gattattctt acatggacag 2350 caccaggaga taattttgat gttggaaaag ttcaacgtta tatcataaga 2400 ataagtgcaa gtattcttga tctaagagac agttttgatg atgctcttca 2450 agtaaatact actgatctgt caccaaagga ggccaactc:c aaggaaagct 2500 ttgcatttaa accagaaaat atctcagaag aaaatgcaac ccacatattt 2550 attgccatta aaagtataga taaaagcaat ttgacatcaa aagtatccaa 2600 cattgcacaa gtaactttgt ttatccctca agcaaatcct gatgacattg 2650 atcctacacc tactcctact cctactccta ctcctgataa aagtcataat 2700 tctggagtta atatttctac gctggtattg tctgtgattg ggtctgttgt 2750 aattgttaac tttattttaa gtaccaccat ttgaacctta acgaagaaaa 2800 aaatcttcaa gtagacctag aagagagttt taaaaaacaa aacaatgtaa 2850 gtaaaggata tttctgaatc ttaaaattca tcccatgtgt gatcataaac 2900 tcataaaaat aattttaaga tgtcggaaaa ggatactttg attaaataaa 2950 aacactcatg gatatgtaaa aactgtcaag attaaaattt aatagtttca 3000 tttatttgtt attttatttg taagaaatag tgatgaacaa agatcctttt 3050 tcatactgat acctggttgt atattatttg atgcaacagt tttctgaaat 3100 gatatttcaa attgcatcaa gaaattaaaa tcatctatct gagtagtcaa 3150 aatacaagta aaggagagca aataaacaac atttggaaaa aaaaaaaaaa 3200 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 3250 aaaaaaaaaa aaaaa 3265 <210> 70 <211> 919 <212> PRT
<2I3> Homo Sapien <400> 70 Met Gly Leu Phe Arg Gly Phe val Phe Leu Leu val Leu cys Leu Leu His Gln Ser Asn Thr Ser Phe Ile Lys Leu Asn Asn Asn Gly _ zo i5 30 Phe Glu Asp Ile Val Ile val Ile Asp Pro Ser Val Pro Glu Asp PCT-u500-23328 Sequence Glu Lys Ile Ile Glu Gln Ile Glu Asp Met Val Thr Thr Ala Ser Thr Tyr Leu Phe Glu Ala Thr Glu Lys Arg Phe Phe Phe Lys Asn val Ser Ile Leu Ile Pro Glu Asn Trp Lys G1u Asn Pro Gln Tyr Lys Arg Pro Lys His Glu Asn His Lys His Aia Asp Val Ile Val Ala Pro Pro Thr Leu Pro Gly Arg Asp Glu Pro Tyr Thr Lys Gln Phe Thr Glu Cys Gly Glu Lys Gly Glu Tyr Ile His Phe Thr Pro Asp Leu Leu Leu Gly Lys Lys Gln Asn Glu Tyr Gly Pro Pro Gly Lys Leu Phe val His Glu Trp Ala His Leu Arg Trp Gly val Phe Asp Glu Tyr Asn Glu Asp Gln Pro Phe Tyr Arg Ala Lys Ser Lys Lys Ile Glu Ala Thr Arg Cys Ser Ala Gly Ile Ser Gly Arg Asn Arg val Tyr Lys Cys Gln Gly Gly Ser Cys Leu Ser Arg Ala Cys Arg Ile Asp Ser Thr Thr Lys Leu Tyr Gly Lys Asp Cys Gln Phe Phe Pro ASp Lys Val Gln Thr Glu Lys Ala Ser I12 Met Phe Met Gln Ser Ile Asp Ser Val Val Glu Phe Cys Asn Glu Lys Thr His Asri Gln Glu Ala Pro Ser Leu Gln Asn Ile Lys Cys Asn Phe Arg Ser Thr Trp Glu Val Ile Ser Asn Ser Glu Asp Phe Lys Asn Thr Ile Pro Met Val Thr Pro Pro Pro Pro Pro Val Phe Ser teu Leu Lys Ile Ser Gln Arg Ile val Cys Leu val Leu Asp Lys ser Gly Ser Met Gly Gly Lys Asp Arg Leu Asn Arg Met Asn Gln Ala Ala Lys His Phe Leu Leu Gln '~hr val Glu Asn Gly Ser Trp val Gly Met val His Phe Asp ser Thr Ala Thr Ile val Asn Lys Leu Ile PCT-u500-23328_Sequence Gln Ile Lys Ser Ser Asp Glu Arg Asn Thr Leu Met Ala Gly Leu Pro Thr Tyr Pro Leu Gly Gly Thr Ser Ile Cys Ser Gly Ile Lys Tyr Ala Phe Gln Val Ile Gly Glu Leu His Ser Gln Leu Asp Gly Ser G1u Va1 Leu Leu Leu Thr Asp Gly Glu Asp Asn Thr Ala Ser Ser Cys Ile Asp Glu Val Lys Gln Ser Gly Ala Ile Val His Phe Ile Ala Leu Gly Arg Ala Ala Asp Glu Ala Val Ile Glu Met Ser Lys Ile Thr Gly Gly Ser His Phe Tyr Val Ser Asp Glu Ala Gln Asn Asn Gly Leu Ile Asp Ala Phe Gly Ala Leu Thr Ser Gly Asn Thr Asp Leu Ser Gln Lys Ser Leu Gln Leu Glu Ser Lys Gly Leu Thr Leu Asn Ser Asn Ala Trp Met Asn Asp Thr val Ile Ile Asp Ser Thr Val Gly Lys ASp Thr Phe Phe Leu Ile Thr Trp Asn Ser Leu Pro Pro Ser Ile Ser Leu Trp Asp Pro Ser Gly Thr Ile Met Glu Asn Phe Thr Val Asp Aia Thr Ser Lys Met Ala Tyr Leu Ser Ile Pro Gly Thr Ala Lys Val Gly Thr Trp Ala Tyr Asn Leu Gln Ala Lys Ala Asn Pro Glu Thr Leu Thr Ile Thr val Thr Ser Arg Ala Ala Asn Ser ser val Pro Pro Ile Thr va.l Asn Ala Lys Met Asn Lys Asp Val Asn Ser Phe Pro Ser Pro Met Ile Val Tyr Ala Glu Ile Leu Gln Gly Tyr Val Pro Val Leu Gly Ala Asn Val Thr 620 ~ 625 630 Ala Phe Ile Glu Ser Gln Asn Gly His Thr Glu Val Leu Glu Leu Leu Asp Asn Gly Ala Gly Ala ASp Ser Phe Lys Asn Asp Gly val Tyr Ser Arg Tyr Phe Thr Ala Tyr Thr Glu Asn Gly Arg 'ryr ser PCT-uS00-23328_Sequence Leu Lys Val Arg Ala His Gly Gly Ala Asn Thr Ala Arg Leu Lys Leu Arg Pro Pro Leu Asn Arg Ala Ala Tyr Ile Pro Gly Trp Val Val Asn Gly Glu Ile Glu Ala Asn Pro Pro Arg Pro Glu Ile Asp Glu Asp Thr Gln Thr Thr Leu Glu Asp Phe Ser Arg Thr Ala Ser Gly Gly Ala Phe Val Val Ser Gln Val Pro Ser Leu Pro Leu Pro Asp Gln Tyr Pro Pro Ser Gln Ile Thr Asp Leu Asp Ala Thr Val His Glu Asp Lys Ile Ile Leu Thr Trp Thr Ala Pro Gly Asp Asn Phe Asp Val Gly Lys Val Gln Arg Tyr Ile Ile Arg Ile Ser Ala ser Ile Leu Asp Leu Arg Asp Ser Phe Asp App Ala Leu Gln Val Asn Thr Thr Asp Leu Ser Pro Lys Glu Ala Asn Ser Lys Glu Ser Phe Ala Phe Lys Pro Glu Asn Ile Ser Glu Glu Asn Ala Thr His Ile Phe Ile Ala Ile Lys ser Ile Asp Lys Ser Asn Leu Thr Ser Lys Val Ser Asn Ile Ala Gln Val Thr Leu Phe Ile Pro Gln Ala Asn Pro Asp Asp Ile Asp Pro Thr Pro Thr Pr~ Thr Pro Thr Pro Thr Pro Asp Lys ser His Asn 5er Gly Val Asn Ile Ser Thr Leu val Leu Ser val I1e Gly ser val val Ile val Asn Phe Ile Leu Ser Thr Thr Ile <210> 71 <211> 3877 <212> DNA
<213> Homo Sapien <400> 71 ctccttaggt ggaaaccctg ggagtagagt actgacagca aagaccggga 50 aagaccatac gtccccgggc aggggtgaca acaggtgtca tctttttgat 100 ctcgtgtgtg gctgccttcc tatttcaagg aaagacgcca aggtaatttt 150 PcT-u500-23328_Sequence gacccagagg agcaatgatg tagccacctc ctaaccttcc cttcttgaac 200 ccccagttat gccaggattt actagagagt gtcaactcaa ccagcaagcg 250 gctccttcgg cttaacttgt ggttggagga gagaaccttt gtggggctgc 300 gttctcttag cagtgctcag aagtgacttg cctgagggtg gaccagaaga 350 aaggaaaggt cccctcttgc tgttggctgc acatcaggaa ggctgtgatg 400 ggaatgaagg tgaaaacttg gagatttcac ttcagtcatt gcttctgcct 450 gcaagatcat cctttaaaag tagagaagct gctctgtgtg gtggttaact 500 ccaagaggca gaactcgttc tagaaggaaa tggatgcaag cagctccggg 550 ggccccaaac gcatgcttcc tgtggtctag cccagggaag cccttccgtg 600 ggggccccgg ctttgaggga tgccaccggt tctggacgca tggctgattc 650 ctgaatgatg atggttcgcc gggggctgct tgcgtggatt tcccgggtgg 700 tggttttgct ggtgctcctc tgctgtgcta tctctgtcct gtacatgttg 750 gcctgcaccc caaaaggtga cgaggagcag ctggcactgc ccagggccaa 800 cagccccacg gggaaggagg ggtaccaggc cgtccttcag gagtgggagg 850 agcagcaccg caactacgtg agcagcctga agcggcagat cgcacagctc 900 aaggaggagc tgcaggagag gagtgagcag ctcaggaatg ggcagtacca 950 agccagcgat gctgctggcc tgggtctgga caggagcccc ccagagaaaa 1000 cccaggccga cctcctggec ttcctgcact cgcaggtgga caaggcagag 1050 gtgaatgctg gcgtcaagct ggccacagag tatgcagcag tgcctttcga 1100 tagctttact ctacagaagg tgtaccagct ggagactggc cttacccgcc 1150 accccgagga gaagcctgtg aggaaggaca agcgggatga gttggtggaa 1200 gccattgaat cagccttgga gaccctgaac aatcctgcag agaacagccc 1250 caatcaccgt ccttacacgg cctctgattt catagaaggg atctaccgaa 1300 cagaaaggga caaagggaca ttgtatgagc tcaccttcaa aggggaccac 1350 aaacacgaat tcaaacggct catcttattt cgaccattca gccccatcat 1400 gaaagtgaaa aatgaaaagc tcaacatggc caacacgctt atcaatgtta 1450 tcgtgcctct agcaaaaagg gtggacaagt tccggcagtt catgcagaat 1500 ttcagggaga tgtgcattga gcaggatggg agagtccatc tcactgttgt 1550 ttactttggg aaagaagaaa taaatgaagt caaaggaata cttgaaaaca 1600 cttccaaagc tgccaacttc aggaacttta ccttcatcCa gctgaatgga 1650 gaattttctc ggggaaaggg acttgatgtt ggagcccgct tctggaaggg 1700 PCT-US00-23328_Sequence aagcaacgtc cttctctttt tctgtgatgt ggacatctac ttcacatctg 1750 aattcctcaa tacgtgtagg ctgaatacac agccagggaa gaaggtattt 1800 tatccagttc ttttcagtca gtacaatcct ggcataatat acggccacca 1850 tgatgcagtc cctcccttgg aacagcagct ggtcataaag aaggaaactg 1900 gattttggag agactttgga tttgggatga cgtgtcagta tcggtcagac 1950 ttcatcaata taggtgggtt tgatctggac atcaaaggct ggggcggaga 2600 ggatgtgcac ctttatcgca agtatctcca cagcaacctc atagtggtac 2050 ggacgcctgt gcgaggactc ttccacctct ggcatgagaa gcgctgcatg 2100 gacgagctga cccccgagca gtacaagatg tgcatgcagt ccaaggccat 2150 gaacgaggca tcccacggcc agctgggcat gctggtgttc aggcacgaga 2200 tagaggctca ccttcgcaaa cagaaacaga agacaagtag caaaaaaaca 2250 tgaactccca gagaaggatt gtgggagaca ctttttcttt ccttttgcaa 2300 ttactgaaag tggctgcaac agagaaaaga cttccataaa ggacgacaaa 2350 agaattggac tgatgggtca gagatgagaa agcctccgat ttctctctgt 2400 tgggcttttt acaacagaaa tcaaaatctc cgctttgcct gcaaaagtaa 2450 cccagttgca ccctgtgaag tgtctgacaa aggcagaat:g cttgtgagat 2500 tataagccta atggtgtgga ggttttgatg gtgtttacaa tacactgaga 2550 cctgttgttt tgtgtgctca ttgaaatatt catgatttaa gagcagtttt 2600 gtaaaaaatt cattagcatg aaaggcaagc atatttctcc tcatatgaat 2650 gagcctatca gcagggctct agtttctagg aatgctaaaa tatcagaagg 2700 ~caggagagga gataggctta ttatgatact agtgagtaca ttaagtaaaa 2750 taaaatggac cagaaaagaa aagaaaccat aaatatcgl:g tcatattttc 2800 cccaagatta accaaaaata atctgcttat ctttttggtt gtccttttaa 2850 ctgtctccgt ttttttettt tatttaaaaa tgcacttttt ttcccttgtg 2900 agttatagtc tgcttattta attaccactt tgcaagcctt acaagagagc 2950 acaagttggc ctacattttt atatttttta agaagatact ttgagatgca 3000 ttatgagaac tttcagttca aagcatcaaa ttgatgccat atccaaggac 3050 atgccaaatg ctgattctgt caggcactga atgtcaggca ttgagacata 3100 gggaaggaat ggtttgtact aatacagacg tacagatact ttctctgaag 3150 agtattttcg aagaggagca actgaacact ggaggaaaag aaaatgacac 3200 tttctgcttt acagaaaagg aaactcattc agactggtga tatcgtgatg 3250 tacctaaaag tcagaaacca cattttctcc tcagaagtag ggaccgcttt 3300 PcT-0500-23328_Sequence Gln gtt taaataaacc aaagtatacc gtgtgaaccaaacaatctct3350 aca gggtgctcct cctggcttct ggcttccataagaagaaatg3400 ~eu 510 ata tatatatata tatatatatt gtgaaagatcaatccatctg3450 ~ln cta gtgggatgga agtttttgct acatgttatccaccccaggc3500 aag taactgaatt attttttaaa ttaagcagttctactcaatc3550 tgc ttctgaaaat tgcattttat taccatttcaaactattttt3600 aaa tacagttaac atagagtggt ttcttcattcatgtgaaaat3650 cag caccagatgc atgagctaat tatctctttgagtccttgct3700 get cacagtaaac tcattgttta aaagcttcaagaacattcaa3750 gtg tgttaaaaaa tgcattgtat tgatttgtactggtagttta3800 taa ttaaaacaca ggccatgaat ggaaggtggtattgcacagc3850 ata tgatttgtgg atatgaa 3877 )0 2 r ;p ono S api en )0 Met Val Arg Arg Gly Leu Leu Ile Ser Val Ala Trp Arg .0 5 10 15 )0 Lew Leu Vai Leu Leu Cys Cys Ser Val Tyr Ala Ile Leu e0 Ala Cys Thr Pro Lys Gly Asp Gln Leu Leu Glu Glu Ala i0 ~ 35 40 45 ;0 Ala Asn Ser Pro Thr Gly Lys Tyr Gln Val Glu Giy Ala ~0 Glu Trp Glu Glu Gln His Arg Val Ser Leu Asn Tyr Ser ,0 65 70 75 r0 Gin Ile Aia Gln Leu Lys Glu Gln Glu Ser Glu Leu Arg ,0 .

Leu Arg Asn Gly Gln Tyr Gln Asp Ala Gly Ala Ser Ala ~0 95 100 lp5 0 Leu Asp Arg Ser Pro Pro Glu Gln Ala Leu Lys Thr Asp Phe Leu His Ser Gln Val Asp Glu Val Ala Lys Ala Asn Lys Leu Ala Thr Glu Tyr Ala Pro Phe Ser Ala Val Asp 14o i4s lso Leu Gln Lys Vai Tyr Gln Leu Gly Leu Arg Glu Thr Thr ., .... . . . ..m. _ . ..._.. . ",. « ~....r,~,~.~..~ .4 ~~.~ ,y.~,..~;~,~- ~
_.,. _ .... __ ~. . . ... ..~ __ ... _...

PCT-u500-23328_Sequence His Pro Glu Glu Lys Pro Val Arg Lys Asp Lys Arg Asp Glu Leu val Glu Ala Ile Glu Ser Ala Leu Glu Thr Leu Asn Asn Pro A1a Glu Asn Ser Pro Asn His Arg Pro Tyr Thr Ala Ser Asp Phe Ile Glu Gly I1e Tyr Arg Thr Glu Arg Asp Lys Gly Thr Leu Tyr-Glu Leu Thr Phe Lys Gly Asp His Lys His Glu Phe Lys Arg Leu Ile Leu Phe Arg Pro Phe Ser Pro Ile Met Lys Val Lys Asn Glu Lys Leu Asn Met Ala Asn Thr Leu Ile Asn Vai Ile Val Pro Leu Ala Lys Arg Val Asp Lys Phe Arg Gln Phe Met Gln Asn Phe Arg Glu Met Cys Ile Glu Gln Asp Gly Arg Val His Leu Thr Val Val Tyr Phe Gly Lys Glu.Glu Ile Asn Glu Val Lys Gly Ile Leu Glu Asn Thr Ser Lys Ala Ala Asn Phe Arg Asn Phe Thr Phe Ile Gln Leu Asn Gly G1u Phe Ser Arg Gly Lys Gly Leu Asp val Gly Ala Arg Phe Trp Lys Gly Ser Asn Val Leu Leu Phe Phe:Cys Asp Val Asp Ile Tyr Phe Thr Ser Glu Phe Leu Asn Thr Cys Arg Leu Asn Thr Gln Pro Gly Lys Lys Val Phe Tyr Pro Val Leu Phe Ser Gln Tyr Asn Pro Gly Ile Ile Tyr Gly His His Asp Ala Val Pro Pro Leu Glu Gln Gln Leu Val Ile Lys Lys Glu Thr Gly Phe Trp Arg Asp Phe Gly Phe Gly Met Thr Cys Gln Tyr Arg Ser Asp Phe Ile Asn Ile Gly Gly Phe Asp Leu Asp IIe Lys G1y Trp Gly Gly Glu Asp Val His Leu Tyr Arg Lys Tyr Leu His Ser Asn Leu Ile Val Val Arg Thr Pro Val Arg Gly Leu Phe His Leu Trp His Glu Lys Arg PCT-US00-23328_Sequence Cys Met Asp Glu Leu Thr Pro Glu Gln Tyr Lys Met Cys Met Gln Ser Lys Ala Met Asn Glu Ala Ser His Gly Glr Leu Gly Met Leu Val Phe Arg His Glu Ile Glu Ala His Leu Arg Lys Gln Lys Gln Lys Thr Ser Ser Lys Lys Thr _ <210> 73 <211> 1701 <212> DNA
<213> Homo Sapien <220>
<221> unsure <222> 1528 <223> unknown base <400> 73 gagactgcag agggagataa agagagaggg caaagaggca gcaagagatt 50 tgtcctgggg atccagaaac ccatgatacc ctactgaaca ccgaateccc 100 tggaagccca cagagacaga gacagcaaga gaagcagaga taaatacact 150 cacgccagga gctcgctcgc tctctctctc tctctctcac tcctccctcc 200 ctctctctct gcctgtccta gtcctctagt cctcaaattc ccagtcccct 250 gcaccccttc ctgggacact atgttgttct ccgccctcct gctggaggtg 300 atttggatcc tggctgcaga tgggggtcaa cactggacgt atgagggccc 350 acatggtcag gaccattggc cagcctctta ccctgagtgt ggaaacaatg 400 cccagtcgcc catcgatatt cagacagaca gtgtgacatt tgaccctgat 450 ttgcctgctc tgcagcccca cggatatgac cagcctggca ccgagccttt 500 ggacctgcac aacaatggcc acacagtgca actctctctg ccctctaccc 550 tgtatctggg tggacttccc cgaaaatatg tagctgccca gctccacctg 600 cactggggtc agaaaggatc cccagggggg tcagaacacc agatcaacag 650 tgaagccaca tttgcagagc tccacattgt acattatgac tctgattcct 700 atgacagctt gagtgaggct. gctgagaggc ctcagggcct ggctgtcctg 750 ggcatcctaa ttgaggtggg tgagactaag aatatagctt atgaacacat 800 tctgagtcac ttgcatgaag tcaggcataa agatcagaag acctcagtgc 850 ctcccttcaa cctaagagag ctgctcccca aacagctggg gcagtaettc 900 cgctacaatg gctcgctcac aactccccct tgctaccaga gtgtgctctg 950 gacagttttt tatagaaggt cccagatttc aatggaacag ctggaaaagc 1000 PCT-u500-23328_Sequence ttcaggggac attgttctcc acagaagagg agccctcta.a gcttctggta 1050 cagaactacc gagcccttca gcctctcaat cagcgcatgg tctttgcttc 1100 tttcatccaa gcaggatcct cgtataccac aggtgaaatg ctgagtctag 1150 gtgtaggaat cttggttggc tgtctctgcc ttctcctggc tgtttatttc 1200 attgctagaa agattcggaa gaagaggctg gaaaaccgaa agagtgtggt 1250 cttcacctca gcacaagcca cgactgaggc ataaattcct tctcagatac 1300 catggatgtg gatgacttcc cttcatgcct atcaggaagc ctctaaaatg 1350 gggtgtagga tctggccaga aacactgtag gagtagtaag cagatgtcct 1400 ccttcccctg gacatctctt agagaggaat ggacccaggc tgtcattcca 1450 ggaagaactg cagagccttc agcctctcca aacatgtagg aggaaatgag 1500 gaaatcgctg tgttgttaat gcagaganca aactctgttt agttgcaggg 1550 gaagtttggg atatacccca aagtcctcta ccccctcact tttatggccc 1600 tttccctaga tatactgcgg gatctctcct taggataaag agttgctgtt 1650 gaagttgtat atttttgatc aatatatttg gaaattaaag tttctgactt 1700 t 1701 <210> 74 <211> 337 <212> PRT
<213> Homo Sapien <400> 74 Met Leu Phe Ser Ala Leu Leu Leu Glu val Ile Trp Ile Leu Ala Ala Asp Gly Gly Gln His Trp Thr Tyr Glu Gly Pro His Gly Gln Asp His Trp Pro Ala Ser Tyr Pro Glu cys Gly Asn Asn Ala Gln ser Pro Ile Asp Ile Gln Thr Asp Ser val Thr Phe Asp Pro Asp Leu Pro Ala Leu Gln Pro His Gly Tyr Asp Gln Pro Gly Thr Glu Pro Leu Asp Leu His Asn Asn Gly His Thr Val Gln Leu Ser Leu Pro Ser Thr Leu Tyr Leu Gly Gly Leu Pro Arg Lys Tyr Val Ala Ala Gln Leu His Leu His Trp Gly Gln Lys G1y Ser Pro Gly Gly .

Ser Glu His Gln Ile Asn Ser Glu Ala Thr Phe Ala Glu teu His 125 i30 135 PCT-u500-23328_Sequence Ile Val His Tyr Asp Ser Asp Ser Tyr Asp Ser Leu Ser Glu Ala Ala Glu Arg Pro Gln Gly Leu Ala Val Leu Gly Ile Leu Ile Glu Val Gly Glu Thr Lys Asn Ile Ala Tyr Glu His Ile Leu Ser His Leu His Glu Val Arg His Lys Asp Gln Lys Thr Ser Val Pro Pro Phe Asn Leu Arg Glu Leu Leu Pro Lys Gln Leu Gly Gln Tyr Phe Arg Tyr Asn Gly Ser Leu Thr Thr Pro Pro Cys Tyr Gln Ser Val Leu Trp Thr Val Phe Tyr Arg Arg ser Gln Ile Ser Met Glu Gln Leu Glu Lys Leu Gln Gly Thr Leu Phe Ser Thr Glu Glu Glu Pro Ser Lys Leu Leu Val Gln Asn Tyr Arg Ala Leu Gln Pro Leu Asn Gln Arg Met Val Phe Ala Ser Phe Ile Gln Ala Gly Ser ser Tyr 275 280 ~ 285 Thr Thr Gly Glu Met Leu Ser Leu Gly Val Gly Iie Leu Val Gly Cys Leu Cys Leu Leu Leu Ala Val Tyr Phe Ile Ala Arg Lys Ile Arg Lys Lys Arg Leu Glu Asn Arg Lys Ser Val Val Phe Thr Ser Ala Gln Ala Thr Thr Glu Ala <210> 75 <211> 1743 <212> DNA
<213> Homo Sapien <400> 75 tgccgctgcc gccgctgctg ctgttgctcc tggcggcgcc ttggggacgg 50 gcagttccct gtgtctctgg tggtttgcct aaacctgcaa acatcacctt 100 cttatccatc aacatgaaga atgtcctaca atggactcca ccagagggtc 150 ttcaaggagt taaagttact tacactgtgc agtatttcat cacaaattgg 200 cccaccagag gtggcactga ctacagatga gaagtccatt tctgttgtcc 250 tgacagctcc agagaagtgg aagagaaatc cagaagacct tcctgtttcc 300 atgcaacaaa tatactccaa tctgaagtat aacgtgtctg tgttgaatac 350 PCr-u500-23328_sequence taaatcaaac agaacgtggt cccagtgtgt gaccaaccac acgctggtgc 400 tcacctggct ggagccgaac actctttact gcgtacacgt ggagtccttc 450 gtcccagggc cccctcgccg tgctcagcct tctgagaagc agtgtgccag 500 gactttgaaa gatcaatcat cagagttcaa ggctaaaatc atcttctggt 550 atgttttgcc catatctatt accgtgtttc ttttttctgt gatgggctat 600 tccatctacc gatatatcca cgttggcaaa gagaaacacc cagcaaattt 650 gattttgatt tatggaaatg aatttgacaa aagattcttt gtgcctgctg 700 aaaaaatcgt gattaacttt atcaccctca atatctcgga tgattctaaa 750 atttctcatc aggatatgag tttactggga aaaagcagtg atgtatccag 800 ccttaatgat cctcagccca gcgggaacct gaggccccct caggaggaag 850 aggaggtgaa acatttaggg tatgcttcgc atttgatgga aattttttgt 900 gactctgaag aaaacacgga aggtacttct ctcacccagc aagagtccct 950 cagcagaaca atacccccgg ataaaacagt cattgaatat gaatatgatg 1000 tcagaaccac tgacatttgt gcggggcctg aagagcagga gctcagtttg 1050 caggaggagg tgtccacaca aggaacatta ttggagtcgc aggcagcgtt 1100 ggcagtcttg ggcccgcaaa cgttacagta ctcatacacc cctcagctcc 1150 aagacttaga ccccctggcg caggagcaca cagactcgga ggaggggccg 1200 gaggaagagc catcgacgac cctggtcgac tgggatcecc aaactggcag 1250 gctgtgtatt ccttcgctgt ccagcttcga ccaggattc,a gagggctgcg 1300 agccttctga gggggatggg ctcggagagg agggtcttct atctagactc 1350 tatgaggagc cggctccaga caggccacca ggagaaaatg aaacctatct 1400 catgcaattc atggaggaat gggggttata tgtgcagatg gaaaactgat 1450 gccaacactt ccttttgcct tttgtttcct gtgcaaacaa gtgagtcacc 1500 cctttgatcc cagccataaa gtacctggga tgaaagaagt tttttccagt 1550 ttgtcagtgt ctgtgagaat tacttatttc ttttctctat tctcatagca 1600 cgtgtgtgat tggttcatgc atgtaggtct cttaacaatg atggtgggcc 1650 tctggagtcc aggggctggc cggttgttct atgcagagaa agcagtcaat 1700 aaatgtttgc cagactgggt gcagaattta ttcaggtggg tgt 1743 <210> 76 <211> 442 <212> PRT ;_':
<213> Homo Sapien <400> 76 Met Ser Tyr Asn Gly ~eu His Gln Arg Val Phe Lys Glu Leu Lys _.... _. "".". ...,.. ..., .._ ,. ... ".... , ..-~>,PZe7Wa,~a,x.,.r o,.n.~aC.~R:us...FY"~5zr.~.wra~6~NPz:.,a-,.m-au-say..._~.~..",...~......~..,_.~._-... ...._. ._.,.. _m.m" .,....""a..,M",.,,.~
T,..,..b,.".~...~~....--.._., ~ ....._..

PCT-u500-23328_Sequence Leu Leu Thr Leu Cys Ser Ile Ser Ser Gln Ile Gly Pro Pro Glu Val Ala Leu Thr Thr Asp Glu Lys Ser Ile Ser Val Val Leu Thr Ala Pro Glu Lys Trp Lys Arg Asn Pro Glu Asp Leu Pro Val Ser Met Gln Gln Ile Tyr Ser Asn Leu Lys Tyr Asn Val Ser Val Leu Asn Thr Lys Ser Asn Arg Thr Trp Ser Gln Cys Val Thr Asn His Thr Leu Va7 Leu Thr Trp Leu Glu Pro Asn Thr Leu Tyr Cys Val His Val Glu Ser Phe Val Pro Gly Pro Pro Arg Arg Ala Gln Pro Ser Glu Lys Gln Cys Ala Arg Thr Leu Lys Asp Gln Ser Ser Glu Phe Lys Ala Lys Ile Ile Phe Trp Tyr Val Leu Pro I1a Ser Ile Thr Val Phe Leu Phe Ser Val Met Gly Tyr Ser Ile Tyr Arg Tyr Ile His Val Gly Lys Glu Lys His Pro Ala Asn Leu Ile Leu Ile Tyr Gly Asn Glu Phe Asp Lys Arg Phe Phe Val Pro Ala Glu Lys Iie Vai Ile Asn Phe Ile Thr Leu Asn Ile Ser Asp Asp Ser Lys Ile Ser His Gln Asp Met Ser Leu Leu Gly Lys Ser Ser Asp Val Ser Ser Leu Asn Asp Pro Gln Pro Ser Gly Asn Leu Arg Pro Pro Gln Glu Glu Glu Glu Val Ly5 His Leu G1y Tyc° Ala Ser His Leu Met Glu Ile Phe Cys Asp Ser Glu Glu Asn Thr Glu Gly Thr Ser Leu Thr Gln Gln Giu Ser Leu Ser Arg Thr Ile Pro Pro Asp Lys Thr Val Lle Glu Tyr Glu Tyr Asp Val Arg Thr Thr Asp Ile Cys Ala Gly Pro Glu Glu Gln Glu Leu Ser Leu Gln Glu Glu Val Ser Thr Gln Gly Thr Leu Leu Giu Ser Gln Ala Ala Leu Ala Val Leu . .. .. _ ..,. ,~ ~. ~...... a V ,.,~ .. . .ro uM~ r." ..,,~~ ro ".,~~~.~,,,~xi. ~~"~,t,~.,ri _,~ ~ tT ~ ,~ , ~ ~.~.u,~" ~.~,w. ~_..__. _. _. _ PCT-u500-23328_sequence Gly Pro Gln Thr Leu Gln Tyr Ser Tyr Thr Pro Gln Leu Gln Asp Leu Asp Pro Leu Ala Gln Glu His Thr Asp Ser Glu Glu Gly Pro Glu Glu Glu Pro Ser Thr Thr Leu Val Asp Trp Asp Pro Gln Thr Gly Arg Leu Cys Ile Pro Ser Leu Ser Ser Phe Asp Gln Asp Ser Glu Gly Cys Glu Pro Ser Glu Gly Asp Gly Leu Gly Glu Glu Gly Leu Leu Ser Arg Leu Tyr Glu Glu Pro Ala Pro Asp Arg Pro Pro Gly Glu Asn Glu Thr Tyr Leu Met Gln Phe Met Glu Glu Trp Gly Leu Tyr val Gln Met Glu Asn <210> 77 <211> 1636 <212> DNA
<213> Homo Sapien <400> 77 gaggagcggg ccgaggactc cagcgtgccc aggtctggca tcctgcactt 50 gctgccctct gacacctggg aagatggccg gcccgtggac cttcaccctt 100 ctctgtggtt tgctggcagc caccttgatc caagccaccc tcagtcccac 150 tgcagttctc atcctcggce caaaagtcat caaagaaaag ctgacacagg 200 agctgaagga ccacaacgcc accagcatcc tgcagcagct gccgctgctc 250 agtgccatgc gggaaaagcc agccggaggc atccctgtgc tgggcagcct 300 ggtgaacacc gtcctgaagc acatcatctg gctgaaggtc atcacagcta 350 acatcctcca gctgcaggtg aagccctcgg ccaatgacca ggagetgcta 400 gtcaagatcc ccctggacat ggtggctgga ttcaacacgc ccctggtcaa 450 gaccatcgtg gagttccaca tgacgactga ggcccaagcc accatccgca 500 tggacaccag tgcaagtggc cccacccgcc tggtcctcag tgactgtgcc 550 accagccatg ggagcctgcg catecaactg ctgtataagc tctccttcct 600 ggtgaacgcc ttagctaagc aggtcatgaa cctcctagtg ccatccctgc 650 ccaatctagt gaaaaaccag ctgtgtcccg tgatcgaggc ttccttcaat 700 ggcatgtatg cagacctcct gcagctggtg aaggtgccca tttccctcag 750 cattgaccgt ctggagtttg accttctgta tcctgccatc aagggtgaca 800 Pc~r-u500-23328_5equence ccattcagct ctacctgggg gccaagttgt tggactcaca gggaaaggtg 850 accaagtggt tcaataactc tgcagcttcc ctgacaatgc ccaccctgga 900 caacatcccg ttcagcctca tcgtgagtca ggacgtggtg aaagctgcag 950 tggctgctgt gctctctcca gaagaattca tggtcctgtt ggactctgtg 1000 cttcctgaga gtgcccatcg gctgaagtca agcatcgggc tgatcaatga 1050 aaaggctgca gataagctgg gatctaccca gatcgtgaag atcctaactc 1100 aggacactcc cgagtttttt atagaccaag gccatgccaa ggtggcccaa 1150 ctgatcgtgc tggaagtgtt tccctccagt gaagccctcc gccctttgtt 1200 caccctgggc atcgaagcca gctcggaagc tcagttttac accaaaggtg 1250 accaacttat actcaacttg aataacatca gctctgatcg gatccagctg 1300 atgaactctg ggattggctg gttccaacct gatgttctga aaaacatcat 1350 cactgagatc atccactcca tcctgctgcc gaaccagaat ggcaaattaa 1400 gatctggggt cccagtgtca ttggtgaagg ccttgggatt cgaggcagct 1450 gagtcctcac tgaccaagga tgcccttgtg cttactccag cctccttgtg 1500 gaaacccagc tctcctgtct cccagtgaag acttggatgg cagccatcag 1550 ggaaggctgg gtcccagctg ggaigtatggg tgtgagctct atagaccatc 1600 cctctctgca atcaataaac acttgcctgt gaaaaa 1636 <210> 78 <211> 484 <212> PRT
<213> Homo Sapien <400> 78 Met Ala Gly Pro Trp Thr Phe Thr Leu Leu cys Gly Leu Leu Ala Ala Thr Leu Ile Gln Ala Thr Leu Ser Pro Thr Ala Val Leu Ile 2o zs 30 Leu Gly Pro Lys Val Tie Lys Glu Lys Leu Thr Gln Glu Leu Lys Asp His Asn Ala Thr Ser Ile Leu Gln Gln Leu Pro Leu Leu Ser Ala Met Arg Glu Lys Pro Ala Gly Gly Ile Pro Val Leu Gly Ser Leu Val Asn Thr Val Leu Lys His Ile Ile Trp Leu Lys Val Ile Thr Ala Asn Ile Leu GIn Leu Gln Val eys Pro Ser Ala Asn Asp Gln Glu Leu Leu Val Lys Ile Pro Leu Asp Met Val Ala Gly Phe ", ~.v . ~..... , .. " roRrRe .,".~~ a_ve~"~v~yY~C;c . Y9~'~-°~~."wW -:~~yw. «~....._._.,.. ,..

PCT-u500-23328_Sequence Asn Thr Pro Leu Val Lys Thr Ile Val Glu Phe His Met Thr Thr Glu Ala Gln Ala Thr Ile Arg Met Asp Thr Ser Ala Ser Gly Pro Thr Arg Leu Val Leu Ser Asp Cys Ala Thr Ser His Gly Ser Leu Arg Ile Gln Leu Leu Tyr Lys Leu Ser Phe Leu Val A5n Ala Leu Aia Lys Gln Val Met Asn Leu Leu Val Pro Ser Leu Pro Asn Leu Val Lys Asn Gln Leu Cys Pro Val Ile Glu Ala Ser Phe Asn Gly Met Tyr Ala Asp Leu Leu Gln Leu Val Lys Val Pro Ile Ser Leu Ser Ile Asp Arg Leu Glu Phe Asp Leu Leu Tyr Pro Ala Ile Lys Gly Asp Thr Ile Gln Leu Tyr Leu Gly Ala Lys Leu Leu Asp Ser Gln Gly Lys Val Thr Lys Trp Phe Asn Asn Ser Ala Ala Ser Leu Thr Met Pro Thr Leu Asp Asn Ile Pro Phe Ser Leu Ile Val Ser Gln Asp Val Val Lys Ala Ala Val Ala Ala val Leu Ser Pro Glu Giu Phe Met Val Leu Leu Asp Ser Val Leu Pro Glu Ser Ala His Arg Leu Lys Ser Ser Ile Giy Leu Iie Asn Giu Lys Ala Ala Asp Lys Leu Gly Ser Thr Gln Ile Val Lys Ile Leu Thr Gln Asp Thr Pro Glu Phe Phe Ile Asp Gln Giy His Ala Lye val Ala Gln Leu Ile Val Leu Glu Val Phe Pro Ser ser Glu Ala Leu Arg Pro Leu Phe Thr Leu Gly Ile Glu Ala Ser Ser Glu Ala Gln Phe Tyr Thr Lys Giy Asp Gln Leu Ile Leu Asn Leu Asn Asn Ile Ser Ser Asp Arg Ile Gln Leu Met Asn 5er Gly Ile Giy Trp Phe Gln Pro Asp Val Leu Lys Asn Iie Ile Thr Glu Ile Ile His 5er Ile Leu Leu PCT-u500-23328_Sequence Pro Asn Gln Asn Gly Lys Leu Arg Ser Gly Val Pro Val Ser Leu val Lys Ala Leu Gly Phe Glu Ala Ala Glu Ser Ser Leu Thr Lys Asp Ala Leu val Leu Thr Pro Ala ser Leu Trp Lys Pro Ser Ser Pro Val Ser Gln <210> 79 <211> 1475 <212> DNA
<213> Homo Sapien <400> 79 gagagaagtc agcctggcag agagactctg aaatgaggga ttagaggtgt SO
tcaaggagca agagcttcag cctgaagaca agggagcagt ccctgaagac 100 gcttctactg agaggtctgc catggcctct cttggcctc:c aacttgtggg 150 ctacatccta ggccttctgg ggcttttggg cacactggtt gccatgctgc 200 tccccagctg gaaaacaagt tcttatgtcg gtgccagca.t tgtgacagca 250 gttggcttct ccaagggcct ctggatggaa tgtgccacac acagcacagg 300 catcacccag tgtgacatct atagcaccct tctgggcctg cccgctgaca 350 tccaggctgc ccaggccatg atggtgacat ccagtgcaat ctcctccctg 400 gcctgcatta tctctgtggt gggcatgaga tgcacagtct tctgccagga 450 atcccgagcc aaagacagag tggcggtagc aggtggagtc tttttcatcc 500 ttggaggcct cctgggattc attcctgttg cctggaatct tcatgggatc 550 ctacgggact tctactcacc actggtgcct gacagcatga aatttgagat 600 tggagaggct ctttacttgg gcattatttc ttccctgttc tccctgatag 650 ctggaatcat cctctgcttt tcctgctcat cccagagaaa tcgctccaac 700 tactacgatg cctaccaagc ccaacctctt gccacaagga gctctccaag 750 gcctggtcaa cctcccaaag tcaagagtga gttcaattcc tacagcctga 800 cagggtatgt gtgaagaacc aggggccaga gctggggggt ggctgggtct 850 gtgaaaaaca gtggacagca ccccgagggc cacaggtgag ggacactacc 900 actggatcgt gtcagaaggt gctgctgagg atagactgac tttggccatt 950 ggattgagca aaggcagaaa tgggggctag tgtaacagca tgcaggttga 1000 attgccaagg atgctcgcca tgccagcctt tctgttttcc tcaccttgct 1050 gctcccctgc cctaagtccc caaccctcaa cttgaaaccc cattccctta 1100 PCT-0500-23328_Sequence agccaggact cagaggatcc ctttgccctc tggtttacct gggactccat 1150 ccccaaaccc actaatcaca tcccactgac tgaccctctg tgatcaaaga 1200 ccctctctct ggctgaggtt ggctcttagc tcattgctgg ggatgggaag 1250 gagaagcagt ggcttttgtg ggcattgctc taacctactt ctcaagcttc 1300 cctccaaaga aactgattgg ccctggaacc tccatcccac tcttgttatg 1350 actccacagt gtccagacta atttgtgcat gaactgaaat aaaaccatcc 1400 tacggtatcc agggaacaga aagcaggatg caggatggga ggacaggaag 1450 gcagcctggg acatttaaaa aaata 1475 <210> 80 <211> 230 <212> PRT
<213> Homo Sapien <400> 80 Met Ala Ser Leu Gly Leu Gln Leu Val Gly Tyr Ile Leu Gly Leu Leu Gly Leu Leu Gly Thr Leu Val Ala Met Leu Leu Pro Ser Trp Lys Thr Ser Ser Tyr Val Gly Ala Ser Ile Val Thr Ala Val Gly Phe Ser Lys Gly Leu Trp Met Glu Cys Ala Thr His Ser Thr Gly 50 s5 so Ile Thr Gln Cys Asp Ile Tyr Ser Thr Leu Leu Gly Leu Pro Ala Asp Ile Gln Ala Ala Gln Ala Met Met Va7 Thr Ser Ser Ala Ile Ser 5er Leu A'la Cys Iie Ile Ser Val Val Gly Met Arg Cys Thr Val Phe Cys Gln Glu Ser Arg Ala Lys Asp Arg val Ala Val Ala Gly Gly Val Phe Phe Ile LeU Gly Gly L2U LeU Gly Phe I12 Pr0 Val Ala Trp Asn Leu His Gly Ile Leu Arg Asp Phe Tyr Ser Pro Leu Val Pro Asp Ser Met Lys Phe Glu Ile Gly Glu Ala Leu Tyr teu Gly Ile Ile Ser Ser Leu Phe Ser Leu Ile Ala Gly Ile Ile Leu Cys Phe Ser Cys Ser Ser Gln Arg Asn Arg Ser Asn Tyr Tyr Asp Ala Tyr Gln Ala Gln Pro Leu Ala Thr Arg Ser Ser Pro Arg PCT-u500-23328_Sequence Pro Gly Gln Pro Pro Lys Val Lys Ser Glu Phe Asn Ser Tyr Ser Leu Thr Gly Tyr Val <210> 81 <211> 1732 <212> DNA -<213> Homo Sapien <400> 81 cccacgcgtc cgcgcctctc ccttctgctg gaccttcctt cgtctctcca 50 tctctccctc ctttccccgc gttctctttc cacctttctc ttcttcccac 100 cttagacctc ccttcctgcc ctcctttcct gcccaccgct gcttcctggc 150 ccttctccga ccccgctcta gcagcagacc tcctggggtc tgtgggttga 200 tctgtggccc ctgtgcctcc gtgtcctttt cgtctccctt cctcccgact 250 ccgctcccgg accagcggcc tgaccctggg gaaaggatgg ttcccgaggt 300 gagggtcctc tcctccttgc tgggactcgc gctgctctgg ttccccctgg 350 actcccacgc tcgagcccgc ccagacatgt tctgcctttt ccatgggaag~.400 agatactccc ccggcgagag ctggcacccc tacttggagc cacaaggcct~450 gatgtactgc ctgcgctgta cctgctcaga gggcgcccat gtgagttgtt 500 accgecteca etgteegect gtccaetgee eccagcctgt gacggagcea 550 cagcaatgct gtcccaagtg tgtggaacct cacactccct ctggactccg 600 ggccccacca aagtcctgcc agcacaacgg gaccatgtac caacacggag 650 agatcttcag tgcccatgag ctgttcccct cccgcctgcc caaccagtgt 700 gtcctctgca gctgcacaga gggccagatc tactgcggcc tcacaacctg 750 ccccgaacca ggctgcccag cacccctccc actgccagac tcctgctgcc 800 aagcctgcaa agatgaggca agtgagcaat cggatgaaga ggacagtgtg 850 cagtcgctcc atggggtgag acatcctcag gatccatgtt ccagtgatgc 900 tgggagaaag agaggcccgg gcaccccagc ccccactggc ctcagcgccc 950 ctctgagctt catccctcgc cacttcagac ccaagggagc aggcagcaca 1000 actgtcaaga tcgtcctgaa ggagaaacat aagaaagcct gtgtgcatgg 1050 cgggaagacg tactcccacg gggaggtgtg gcacccggcc ttccgtgcct 1100 tcggcccctt gccctgcatc ctatgcacct gtgaggatgg ccgccaggac 1150 tgccagcgtg tgacctgtcc caccgagtac ccctgccgtc accccgagaa 1200 agtggctggg aagtgctgca agatttgccc agaggacaaa gcagaccctg 1250 Page I02 PCT-u500-23328'Sequence gccacagtga gatcagttct accaggtgtc ccaaggcacc gggccgggtc 1300 ctcgtccaca catcggtatc cccaagccca gacaacctgc gtcgctttgc 1350 cctggaacac gaggcctcgg acttggtgga gatctacctc tggaagctgg 1400 taaaagatga ggaaactgag gctcagagag gtgaagtacc tggcccaagg 1450 ccacacagcc agaatcttcc acttgactca gatcaagaaa gtcaggaagc 1500 aagacttcca gaaagaggca cagcacttcc gactgctcgc tggcccccac 1550 gaaggtcact ggaacgtctt cctagcccag accctggagc tgaaggtcac 1600 ggccagtcca gacaaagtga ccaagacata acaaagacct aacagttgca 1650 gatatgagct gtataattgt tgttattata tattaataaa taagaagttg 1700 cattaccctc aaaaaaaaaa aaaaaaaaaa as 1732 <210> 82 <211> 451 <212> PRT
<213> Homo Sapien <400> 82 Met Val Pro Glu Val Arg Val Leu Ser Ser Leu Leu Gly Leu Ala Leu Leu Trp Phe Pro Leu Asp Ser His Ala Arg Ala Arg Pro Asp zo z5 Met Phe Cys Leu Phe His Gly Lys Arg Tyr Ser Pro Gly Glu Ser Trp His Pro Tyr Leu Glu Pro Gln Gly Leu Met Tyr Cys Leu Arg Cys Thr Cys Ser Glu Gly Ala His Val Ser Cys Tyr Arg Leu His Cys Pro Pro Val His Cys Pro Gln Pro Val Thr Glu Pro Gln Gln Cys Cys Pro Lys Cys Val Glu Pro His Thr Pro Ser Gly Leu Arg Ala Pro Pro Lys Ser Cys Gln His Asn Gly Thr Met Tyr Gln His Gly Glu Ile Phe Ser Ala His Glu Leu Phe Pro Ser Arg Leu Pro Asn Gln Cys Val Leu Cys Ser Cys Thr Glu Gly Gln Ile Tyr Cys Gly Leu Thr Thr Cys Pro Glu Pro Gly Cys Pro Ala Pro Leu Pro Leu Pro Asp Ser Cys Cys Gln Ala Cys Lys Asp G1u Ala Ser Glu ~.____4._.. .. -_u -.~." ~ __.r~.~ M~_ ~ _«_~.~ .~~~ ~.,~.~ _ ~ -r~..-..~--~.
~ ~_ . ___ _____.-_. ~ ___ ____ _ PCT-US00-23328_Sequence Gln Ser Asp Glu Glu Asp Ser Val Gln Ser Leu His Gly Val Arg His Pro Gin Asp Pro Cys Ser Ser Asp Ala Gly Arg Lys Arg Gly Pro Gly Thr Pro Ala Pro Thr Gly Leu Ser Ala Pro Leu Ser Phe Ile Pro Arg His Phe Arg Pro Lys Gly Ala Gly Ser Thr Thr Va1 Lys Ile Val Leu Lys Glu Lys His Lys Lys Ala Cys Val His Gly Gly Lys Thr Tyr Ser His Gly Glu Val Trp His Pro Ala Phe Arg Ala Phe Gly Pro Leu Pro Cys Ile Leu Cys Thr Cys Glu Asp Gly 275 28o zs5 Arg Gln Asp Cys Gln Arg Val Thr Cys Pro .Thr Glu Tyr Pro Cys Arg His Pro Glu Lys Val Ala Gly Lys Cys Cys Lys Ile Cys Pro Glu Asp Lys Ala Asp Pro Gly His Ser Glu Ile Ser Ser Thr Arg Cys Pro Lys Ala Pro Gly Arg Val Leu Val His Thr Ser Val Ser Pro Ser Pro Asp Asn Leu Arg Arg Phe Ala Leu Glu His Glu Ala Ser Asp Leu Val Giu Ile Tyr Leu Trp Lys Leu Val Lys Asp Glu 365 ~ 370 375 Glu Thr Glu Ala Gln Arg Gly Glu Val Pro Giy Pro Arg Pro His Ser Gln Asn Leu Pro Leu Asp Ser Asp Gln Glu Ser Gln Glu Ala Arg Leu Pro Glu Arg Gly Thr Ala Leu Pro Thr Ala Arg Trp Pro Pro Arg Arg Ser Leu Glu Arg Leu Pro Ser Pro Asp Pro Gly Ala Glu Gly His Gly Gln Ser Arg Gln Ser Asp Gln Asp Ile Thr Lys 440 445 _ 450 Thr <210> 83 <211> 2052 <2I2> DNA
<213> Homo Sapien <400> 83 PCT-u500-23328_sequence gacagctgtg tctcgatgga gtagactctc agaacagcgc agtttgccct 50 ccgctcacgc agagcctctc cgtggcttcc gcaccttgag cattaggcca 100 gttctcctct tctctctaat ccatccgtca cctctcctgt catccgtttc 150 catgccgtga ggtccattca cagaacacat ccatggctct catgctcagt 200 ttggttctga gtctcctcaa gctgggatca gggcagtggc aggtgtttgg 250 gccagacaag cctgtccagg ccttggtggg ggaggacgca gcattctcct 300 gtttcctgtc tcctaagacc aatgcagagg ccatggaagt gcggttcttc 350 aggggccagt tctctagcgt ggtccacctc tacagggacg ggaaggacca 400 gccatttatg cagatgccac agtatcaagg caggacaaaa ctggtgaagg 450 attctattgc ggaggggcgc atctctctga ggctggaaaa cattactgtg 500 ttggatgctg gcctctatgg gtgcaggatt agttcccagt cttactacca 550 gaaggccatc tgggagctac aggtgtcagc actgggctca gttcctctca 600 tttccatcac gggatatgtt gatagagaca tccagctact ctgtcagtcc 650 tcgggctggt tcccccggcc cacagcgaag tggaaaggtc cacaaggaca 700 ggatttgtcc acagactcca ggacaaacag agacatgcat ggcctgtttg 750 atgtggagat ctctctgacc gtccaagaga acgccgggag catatcctgt 800 tccatgcggc atgctcatct gagccgagag gtggaatcca gggtacagat 850 aggagatacc tttttcgagc ctatatcgtg gcacctggct accaaagtac 900 tgggaatact ctgctgtggc ctattttttg gcattgttgg actgaagatt 950 ttcttctcca aattccagtg gaaaatccag gcggaactgg actggagaag 1000 aaagcacgga caggcagaat tgagagacgc ccggaaacac gcagtggagg 1050 tgactctgga tccagagacg gctcacccga agctctgcgt ttctgatctg 1100 aaaactgtaa cccatagaaa agctccccag gaggtgcctc actctgagaa 1150 gagatttaca aggaagagtg tggtggcttc tcagagtttc caagcaggga 1200 aacattactg ggaggtggac ggaggacaca ataaaaggtg gcgcgtggga 1250 gtgtgccggg atgatgtgga caggaggaag gagtacgtga ctttgtctcc 1300 cgatcatggg tactgggtcc tcagactgaa tggagaacat ttgtatttca 1350 cattaaatcc ccgttttatc agcgtcttcc ccaggacccc acctacaaaa 1400 ataggggtct tcctggacta tgagtgtggg accatctcct tcttcaacat 1450 aaatgaccag tcccttattt ata~cctgac atgtcggttt gaaggcttat 1500 w tgaggcccta cattgagtat ccgtcctata atgagcaaaa tggaactccc 1550 atagtcatct gcccagtcac ccaggaatca gagaaagagg cctcttggca 1600 ~~;~x~a~.~ ~.~. . ~ ..mm.~.~. «~W..masK".~ ~ ~.,~~,....~rs..~.r5_ ~.~...~-.__ ~._.._.w.._..~....~.~.~.~~.., PCT-uS00-23328_Sequence aagggcctct gcaatcccag agacaagcaa cagtgagtcc tcctcacagg 1650 caaccacgcc cttcctcccc aggggtgaaa tgtaggatga atcacatccc 1700 acattcttct ttagggatat taaggtctct ctcccagatc caaagtcccg 1750 cagcagccgg ccaaggtggc ttccagatga agggggactg gcctgtccac 1800 atgggagtca ggtgtcatgg ctgccctgag ctgggaggga agaaggctga 1850 cattacattt agtttgctct cactccatct ggctaagtga tcttgaaata 1900 ccacctctca ggtgaagaac cgtcaggaat tcccatctca caggctgtgg 1950 tgtagattaa gtagacaagg aatgtgaata atgcttagat cttattgatg 2000 acagagtgta tcctaatggt ttgttcatta tattacactt tcagtaaaaa 2050 as 2052 <210> 84 <211> 500 <212> PRT
<213> Homo Sapien <400> 84 Met Ala Leu Met Leu Ser Leu Val Leu Ser Leu Leu Lys Leu Gly Ser Gly Gln Trp Gln Val Phe Gly Pro Asp Lys Pro Val'Gln Ala Leu Val Gly Glu Asp Ala Ala Phe Ser Cys Phe Leu Ser Pro Lys Thr Asn Ala Glu Ala Met Glu Val Arg Phe Phe Arg Gly Gln Phe Ser Ser Vai Val His Leu Tyr Arg Asp Gly Lys Asp Gln Pro Phe Met Gln Met Pro G80n Tyr Gln Gly Arg T85 Lys Leu Val Lys A9o Ser Ile Ala Glu Gly Arg Ile Ser Leu Arg Leu Glu Asn Ile Thr Val Leu Asp Ala Gly Leu Tyr Gly Cys Arg Ile Ser Ser Gln Ser Tyr, Tyr Gln Lys Ala Ile Trp Glu Leu Gln Val Ser Ala Leu Gly 125 130 . 135 ser val Pro ~eu Ile Ser Ile Thr Gly Tyr Val Asp arg Asp Ile Gln Leu Leu Cys Gln Ser Ser Gly Trp Phe Pro Arg Pro Thr Ala iss lso ls5 Lys Trp Lys Gly Pro Gln Gly Gln Asp Leu Ser Thr Asp Ser Arg PCT-uS00-23328_Sequence ThrAsnArg AspMetHis GlyLeu PheAspVal GluIleSer Leu ThrValG1n GluAsnAla GlySer IleSerCys SerMetArg His AlaHisLeu SerArgGlu ValGlu SerArgVal GlnIleGly Asp ThrPhePhe GluProIle SerTrp HisLeuA1a ThrLysVal Leu GlyIleLeu CysCysGly LeuPhe PheGlyIle ValGlyLeu Lys IlePhePhe SerLysPhe GlnTrp LysIleGln AlaGluLeu Asp TrpArgArg LysHisGly GlnAla GluLeuArg AspAlaArg Lys HisAlaVal GluValThr LeuAsp ProGluThr AlaHisPro Lys LeuCysval SerAspLeu LysThr ValThrHis ArgLysAla Pro GlnGluVal ProHisSer GluLys ArgPheThr ArgLysSer Val val Ala Ser Gln Ser Phe Gln Ala Gly Lys His Tyr Trp Glu val Asp Gly Gly His Asn Lys Arg Trp Arg Val Gly Val Cys Arg Asp 350 , 355 360 Asp Val Asp Arg Arg Lys Glu Tyr Val Thr Len Ser Pro Asp His Gly Tyr Trp Val Leu Arg Leu Asn Gly Glu His Leu Tyr Phe Thr Leu Asn Pro Arg Phe Ile Ser val Phe Pro Arg Thr Pro Pro Thr 39s 400 405 Lys Ile Gly Val Phe Leu Asp Tyr Glu Cys Gly Thr Ile Ser Phe Phe Asn Ile Asn Asp Gln Ser Leu Ile Tyr Thr Leu Thr Cys Arg 425 430 435 .
Phe Glu Gly Leu Leu Arg Pro Tyr Ile Glu Tyr Pro Ser Tyr Asn Glu Gin Asn Gly Thr Pro Ile Val Ile Cys Pro Val Thr Gln Glu Ser Glu Lys Glu Ala Ser Trp Gln Arg Ala Ser Ala Ile Pro Glu Thr Ser Asn Ser Glu Ser Ser Ser Gln Ala Thr Thr Pro Phe Leu _.............. . ..... .. __ ___r.~., .~,.,..»....~..~,Rax~.~,...~awc.;aa~::a,~»_a,.~..."",. ".~"~.~..-....~a,.,<.~-=a-..,....._~..-..-...r.-__.__a._.___..__....

PCT-uS00-23328_Seguence Pro Arg Gly Glu Met <210> 85 <211> 1665 <212> DNA
<213> Homo sapien <400> 85 aacagacgtt ccctcgcggc cctggcacct ctaaccccag acatgctgct 50 gctgctgctg cccctgctct gggggaggga gagggcggaa ggacagacaa 100 gtaaactgct gacgatgcag agttccgtga cggtgcagga aggcctgtgt 150 gtccatgtgc cctgctcctt ctcctacccc tcgcatggct ggatttaccc 200 tggcccagta gttcatggct actggttccg ggaaggggcc aatacagacc 250 aggatgctcc agtggccaca aacaacccag ctcgggcagt gtgggaggag 300 actcgggacc gattccacct ccttggggac ccacatacca agaattgcac 350 cctgagcatc agagatgcca gaagaagtga tgcggggaga tacttctttc 400 gtatggagaa aggaagtata aaatggaatt ataaacatca ccggctctct 450 gtgaatgtga cagccttgac ccacaggccc aacatcctca tcccaggcac 500 cctggagtcc ggctgccccc agaatctgac ctgctctgtg ccctgggcct 550 gtgagcaggg gacaccccct atgatctcct ggatagggac ctccgtgtcc 600 cccctggacc cctccaccac ccgctcctcg gtgctcaccc tcatcccaca 650 gccccaggac catggcacca gcctcacctg tcaggtgacc ttccctgggg 700 ccagcgtgac cacgaacaag accgtccatc tcaacgtgtr_ ctacccgcct 750 cagaacttga ccatgactgt cttccaagga gacggcacag tatccacagt 800 cttgggaaat ggctcatctc tgtcactccc agagggccag tctctgcgcc 850.
tggtctgtgc agttgatgca gttgacagca atccccctgc caggctgagc 900 ctgagctgga gaggcctgac cctgtgcccc tcacagccct caaacccggg 950 ggtgctggag ctgccttggg tgcacctgag ggatgcagct gaattcacct 1000 gcagagctca gaaccctctc ggctctcagc aggtctacct gaacgtctcc 1050 ctgcagagca aagccacatc aggagtgact cagggggtgg tcgggggagc 1100 tggagccaca gccctggtct tcctgtcctt ctgcgtcatc ttcgttgtag 1150 tgaggtcctg caggaagaaa tcggcaaggc cagcagcggg cgtgggagat 1200 acgggcatag aggatgcaaa cgctgtcagg ggttcagcct ctcaggggcc 1250 ectgactgaa ccttgggcag aagacagtcc cccagaccag cctcccccag 1300 cttctgcccg ctcctcagtg ggggaaggag agctccagta tgcatccctc 1350 .,."... ...,.. . , ....» . _.".., » .,.... . ._ . ..... ~ .. ~,~ ~y>..,"~ ,~, _ .".~,",. u,~ T . n~. ..._ __ _..__,~ .. . _M.... .__ . _ _._ ._ _. ..._.

PCT-0500-23328_Sequence agcttccaga tggtgaagcc ttgggactcg cggggacagg aggccactga 1400 caccgagtac tcggagatca agatccacag atgagaaact gcagagactc 1450 accctgattg agggatcaca gcccctccag gcaagggaga agtcagaggc 1500 tgattcttgt agaattaaca gccctcaacg tgatgagcta tgataacact 1550 atgaattatg tgcagagtga aaagcacaca ggctttagag tcaaagtatc 1600 tcaaacctga atccacactg tgccctccct tttatttttt taactaaaag 1650 acagacaaat tccta 1665 <210> 86 <211> 463 <212> PRT
<213> Homo Sapien <400> 86 Met Leu Leu Leu Leu Leu Fro Leu Leu Trp Gly Arg Glu Arg Ala Glu Gly Gln Thr Ser Lys Leu Leu Thr Met Gln Ser Ser Val Thr Val Gln Glu Gly Leu Cys val His val Pro Cys Ser Phe Ser Tyr Pro Ser His Gly Trp Ile Tyr Pro Gly Pro Val Val His Gly Tyr Trp Phe Arg Glu Gly Ala Asn Thr Asp Gln Asp Ala Pro Val Ala Thr Asn Asn Pro Ala Arg Aia Val Trp Glu Glu Thr Arg Asp Arg Phe His Leu Leu Gly Asp Pro His Thr Lys Asn Cys Thr Leu Ser ile Arg Asp Ala Arg Arg Ser Asp Ala Gly Arg Tyr Phe Phe Arg Met Glu Lys Gly Ser Ile Lys Trp Asn Tyr Lys His His Arg Leu Ser Vai Asn Val Thr Ala Leu Thr His Arg Pro Asn Ile Leu Ile Pro Gly Thr Leu Glu Ser Gly Cys Pro Gln Asn Leu Thr Cys Ser Val Pro Trp Ala Cys Glu Gln Gly Thr Pro Pro Met Ile_Ser Trp Ile Gly Thr Ser Val Ser Pro Leu Asp Pro Ser Thr Thr Arg ser Ser Val Leu Thr LQU Ile Pro G1n Pro Gln Asp His Gly Thr Ser Leu Thr Cys Gln Val Thr Phe Pro Gly Ala Ser Val Thr Thr Asn PCT-uS00-23328_Sequence Lys Thr Val His Leu Asn Val Ser Tyr Pro Pro Gln Asn Leu Thr Met Thr Val Phe Gln Gly Asp Gly Thr Val Ser Thr Val Leu Gly 245 z50 255 Asn Gly Ser Ser Leu Ser Leu Pro Glu Gly Gln Ser Leu Arg Leu Val Cys Ala Val Asp Ala Val Asp Ser Asn Pro Pro Ala Arg Leu Ser Leu Ser Trp Arg Gly Leu Thr Leu Cys Pro Ser Gln Pro Ser Asn Pro Gly Val Leu Glu Leu Pro Trp Val His Leu Arg Asp Ala Ala Glu Phe Thr Cys Arg Ala Gln Asn Pro Leu Gly Ser Gln Gln Val Tyr Leu Asn Val Ser Leu Gln Ser Lys Ala Thr Ser Gly Val Thr Gln Gly Val Val Gly Gly ATa Gly Ala Thr Ala Leu Val Phe Leu Ser Phe Cys Val Ile Phe Val Val Val Arg Ser Cys Arg Lys Lys Ser Ala Arg Pro Ala Ala Gly Val Gly Asp Thr Gly Ile Glu Asp Ala Asn Ala Val Arg Gly Ser Ala Ser Gln Gly Pro Leu Thr Glu Pro Trp Ala Glu Asp Ser Pro Pro Asp Gln Pro Pro Pro Ala Ser Ala Arg Ser Ser Val Gly Glu Gly Glu Leu Gln Tyr Ala Ser Leu Ser Phe Gln Met Val Lys Pro Trp Asp Ser Arg Gly Gln Glu Ala Thr Asp Thr Glu Tyr Ser Glu Ile Lys Ile His Arg.

<210> 87 <2I1> 1176 <212> DNA
<213> Homo Sapien <400> 87 agaaagctgc actctgttga gctccagggc gcagtggagg gagggagtga 50 aggagctctc tgtacccaag gaaagtgcag ctgagactca gacaagatta 100 caatgaacca actcagcttc ctgctgtttc tcatagcgac caccagagga 150 tggagtacag atgaggctaa tacttacttc aaggaatgga. cctgttcttc 200 .. _.... ._. ., ..zn,. W .~~~ ~~N~~~~~._~. .,~N. .. . .. __._. ..

PCT-0500-23328_sequence gtctccatct ctgcccagaa gctgcaagga aatcaaagac gaatgtccta 250 gtgcatttga tggcctgtat tttctccgca ctgagaatgg tgttatctac 300 cagaccttct gtgacatgac ctctgggggt ggcggctgga ccctggtggc 350 cagcgtgcat gagaatgaca tgcgtgggaa gtgcacggtg ggcgatcgct 400 ggtccagtca gcagggcagc aaagcagact acccagaggg ggacggcaac 450 tgggccaact acaacacctt tggatctgca gaggcggcca cgagcgatga 500 ctacaagaac cctggctact acgacatcca ggccaaggac ctgggcatct 550 ggcacgtgcc caataagtcc cccatgcagc actggagaaa cagctccctg 600 ctgaggtacc gcacggacac tggcttcctc cagacactgg gacataatct 650 gtttggcatc taccagaaat atccagtgaa atatggagaa ggaaagtgtt 700 ggactgacaa cggcccggtg atccctgtgg tctatgattt tggcgacgcc 750 cagaaaacag catcttatta ctcaecctat ggccagcggg aattcactgc 800 gggatttgtt cagttcaggg tatttaataa cgagagagca gccaacgcct 850 tgtgtgctgg' aatgagggtc accggatgta acactgagca tcactgcatt 900 ggtggaggag gatactttcc agaggccagt ccccagcagt gtggagattt 950 ttctggtttt gattggagtg gatatggaac tcatgttggt tacagcagca 1000 gccgtgagat aactgaggca gctgtgcttc tattctatcg ttgagagttt 1050 tgtgggaggg aacccagacc tctcctccca accatgagat cccaaggatg 1100 gagaacaact tacccagtag ctagaatgtt aatggcagaa gagaaaacaa 1150 taaatcatat tgactcaaga aaaaaa 1176 <210> 88 <211> 313 <212> PRT
<213> Homo Sapien <400> 88 Met Asn Gln Leu Ser Phe Leu Leu Phe Leu Ile Ala Thr Thr Arg Gly Trp Ser Thr Asp Glu Ala Asn Thr Tyr Phe Lys Glu Trp Thr Cys Ser Ser Ser Pro Ser Leu Pro Arg Ser Cys Lys Glu Ile Lys Asp Glu Cys Pro Ser Ala Phe Asp Gly Leu Tyr Phe Ueu Arg Thr Giu Asn Gly Val Ile Tyr Gin Thr Phe Cys Asp Met Thr Ser Gly ..

Gly Gly Gly Trp Thr Leu Val Ala Ser val His Glu Asn Asp Met PCT-US00-23328_Seguence Arg Gly Lys Cys Thr Val Gly Asp Arg Trp Ser Ser Gln G.ln Gly Ser Lys Ala ASp Tyr Pro Glu Gly Asp Gly Asn Trp Ala Asn Tyr Asn Thr Phe Gly Ser Ala Glu Ala Ala Thr Ser Asp Asp Tyr Lys Asn Pro Gly Tyr Tyr Asp Ile Gln Ala Lys Asp Leu Gly Ile Trp His Val Pro Asn Lys Ser Pro Met Gln His Trp Arg Asn Ser Ser Leu Leu Arg Tyr Arg Thr Asp Thr Gly Phe Leu Gln Thr Leu Gly His Asn Leu Phe Gly Ile Tyr Gln Lys Tyr Pro Val Lys Tyr Gly Glu Gly Lys Cys Trp Thr Asp Asn Gly Pro Val Ile Pro Val Val 200 205 z1o Tyr Asp Phe Giy Asp Ala Gln Lys Thr Ala Ser Tyr Tyr Ser Pro Tyr Gly Gln Arg Glu Phe Thr Ala Gly Phe Val Gln Phe Arg Val Phe Asn Asn Glu Arg Ala Ala Asn Ala Leu cys Ala Gly Met Arg Val Thr Gly Cys Asn Thr Glu His His Cys Ile Gly Gly Gly Gly Tyr Phe Pro Glu Ala Ser Pro Gln Gln Cys Gly Asp Phe Ser Gly Phe Asp Trp Ser Gly Tyr Gly Thr His val Gly Tyr Ser Ser Ser Arg Glu Ile Thr Glu Ala Ala Val Leu Leu Phe Tyr Arg <210> 89 <211> 759 <212> DNA
<213> Homo Sapien <400> 89 ctagatttgt cggcttgcgg ggagacttca ggagtcgctg tctctgaact 50 tccagcctca gagaccgccg cccttgtccc cgagggccat: gggccgggtc 100 tcagggcttg tgccctctcg cttcctgacg ctcctggcgc atctggtggt 150 cgtcatcacc ttattctggt cccgggacag caacatacag gcctgcctgc 200 ctctcacgtt cacccccgag gagtatgaca agcaggacat tcagctggtg 250 Page lI2 -PCT-US00-23328_Sequence gccgcgctct ctgtcaccct gggcctcttt gcagtggagc tggccggttt 300 cctctcagga gtctccatgt tcaacagcac ccagagcctc atctccattg 350 gggctcactg tagtgcatcc gtggccctgt ccttcttcat attcgagcgt 400 tgggagtgca ctacgtattg gtacattttt gtcttctgca gtgcccttcc 450 agctgtcact gaaatggctt tattcgtcac cgtctttggg ctgaaaaaga 500 aacccttctg attaccttca tgacgggaac ctaaggacga agcctacagg 5~0 ggcaagggcc gcttcgtatt cctggaagaa ggaaggcata ggcttcggtt 600 ttcccctcgg aaactgettc tgctggagga tatgtgttgg aataattacg 650 tcttgagtct gggattatcc gcattgtatt tagtgctttg taataaaata 700 tgttttgtag taacattaag acttatatac agttttaggg gacaattaaa 750 aaaaaaaaa 759 <210> 90 <211> 140 <212> PRT
<213> Homo Sapien <400> 90 Met Gly Arg Val Ser Gly Leu Val Pro Ser Arg Phe Leu Thr Leu Leu Ala His Leu Val Val Val Ile Thr Leu Phe Trp Ser Arg Asp Ser Asn Ile Gln Ala Cys Leu Pro Leu Thr Phe Thr Pro G1u Glu Tyr Asp Ly.s Gln Asp Ile Gln Leu Val Ala Ala Leu Ser Val Thr Leu Gly Leu Phe Ala Val Glu Leu Ala Gly Phe Leu Ser Gly Val Ser Met Phe Asn Ser Thr Gln Ser Leu Ile Ser Ile Gly Ala His Cys Ser Ala Ser Val Ala Leu Ser Phe Phe Ile Phe Glu Arg Trp Glu Cys Thr Thr Tyr Trp Tyr Ile Phe Val Phe cys Ser Ala Leu Pro Ala Val Thr Glu Met Ala Leu Phe val Thr Val Phe Gly Leu Lys Lys Lys Pro Phe <210> 91 <211> 1871 <212> DNA
<213> Homo sapien PCT-uS00-23328_Sequence <400> 91 ctgggacccc gaaaagagaa ggggagagcg aggggacgag agcggaggag 50 gaagatgcaa ctgactcgct gctgcttcgt gttcctggtg cagggtagcc 100 tctatctggt catctgtggc caggatgatg gtcctcccgg ctcagaggac 150 cctgagcgtg atgaccacga gggccagccc cggccccggg tgcctcggaa 200 gcggggccac atctcaccta agtcccgccc catggccaat tccactctcc 250 tagggctgct ggccccgcct ggggaggctt ggggcattct tgggcagccc 300 cccaaccgcc cgaaccacag ccccccaccc tcagccaar~g tgaagaaaat 350 ctttggctgg ggcgacttct actccaacat caagacggtg gccctgaacc 400 tgctcgtcac agggaagatt gtggaccatg gcaatgggac cttcagcgtc 450 cacttccaac acaatgccac aggccaggga aacatctcca tcagcctcgt 500 gccccccagt aaagctgtag agttccacca ggaacagcag atcttcatcg 550 aagccaaggc ctccaaaatc ttcaactgcc ggatggagtg ggagaaggta 600 gaacggggcc gccggacctc gctttgcacc cacgacccag ccaagatctg 650 ctcccgagac cacgctcaga gctcagccac ctggagctgc tcccagccct 700 tcaaagtcgt ctgtgtctac atcgccttct acagcacgga ctatcggctg 750 gtccagaagg tgtgcccaga ttacaactac catagtgata ccccctacta 800 cccatctggg tgacccgggg caggccacag aggccaggcc agggctggaa 850 ggacaggcct gcccatgcag gagaccatct ggacaccggg cagggaaggg 900 gttgggcctc aggcagggag gggggtggag acgaggagat gccaagtggg 950 gccagggcca agtctcaagt ggcagagaaa gggtcccaag tgctggtccc 1000 aacctgaagc tgtggagtga ctagatcaca ggagcactgg aggaggagtg 1050 ggctctctgt gcagcctcac agggctttgc cacggagcca cagagagatg 1100 ctgggtcccc gaggcctgtg ggcaggccga tcagtgtggc cccagatcaa 1150 gtcatgggag gaagctaagc ccttggttct tgccatcctg aggaaagata 1200 gcaacaggga gggggagatt tcatcagtgt ggacagcctg tcaacttagg 1250 atggatggct gagagggctt cctaggagcc agtcagcagg gtggggtggg 1300 gccagaggag ctctccagcc ctgcctagtg ggcgccctga gccccttgtc 1350 gtgtgctgag catggcatga ggctgaagtg gcaaccctgg ggtctttgat 1400 gtcttgacag attgaccatc tgtctccagc caggccaccc ctttccaaaa 1450 ttccctcttc tgccagtact ccccctgtac cacccattgc tgatggcaca 1500 ...._ .-cccatcctta agctaagaca ggacgattgt ggtcctccca cactaaggcc 1550 Page I14 ._. aye, , ~>.<_ xa,a..ys~~iq--nAxo~~..2i~~?T~?.c~.=-y"~, . _ .~;:~..c.~.~-~.r-"r.~.~.».. _-~.m.".~..~a~. "~". ~._,_ -.._.

PCT-uS00-23328_5equence acagcccatc cgcgtgctgt gtgtccctct tccaccccaa cccctgctgg 1600 ctcctctggg agcatccatg tcccggagag gggtccctca acagtcagcc 1650 tcacctgtca gaccggggtt ctcccggatc tggatggcgc cgcectctca 1700 gcagcgggca cgggtggggc ggggccgggc cgcagagcat gtgctggatc 1750 tgttctgtgt gtctgtctgt gggtgggggg aggggaggga agtcttgtga 1800 aaccgctgat tgctgacttt tgtgtgaaga atcgtgttct tggagcagga 1850 aataaagctt gccccggggc a 1871 <210> 92 <211> 252 <212> PRT
<213> Homo Sapien <400> 92 Met Gln Leu Thr Arg Cys Cys Phe val Phe Leu val Gln Gly Ser Leu Tyr Leu val Ile Cys Gly Gln Asp Asp Gly Pro Pro Gly Ser Glu Asp Pro G1U A3g Asp Asp His Glu G~y~ Gln Pro Arg Pro A~g val, Pro Arg Lys Arg Gly His Ile ser Pro Lys ser Arg Pro Met Ala Asn Ser Thr Leu Leu Gly Leu Leu Ala Pro Pro Gly Glu Ala Trp G1y Ile Leu Gly Gln Pro Pro Asn Arg Pr0 Asn His Ser Pro Pro Pro Ser Ala Lys vah Lys Lys Ile Phe Gly Trp Gly Asp Phe Tyr Ser Asn Ile Lys Thr val Ala Leu Asn Leu Leu val Thr Gly Lys Ile Val Asp His Gly Asn Gly Thr Phe Ser val His Phe Gln His Asn_ Ala Thr Gly Gln Gly Asn Ile Ser Ile Ser Leu val Pro Pro Ser Lys Ala val Glu Phe His Gln Glu Gln Gln Ile Phe Ile Glu Ala Lys Ala Ser Lys Ile Phe Asn Cys Arg Met Glu Trp Glu Lys val Glu Arg Gly Arg Arg Thr Ser Leu Cys Thr His Asp Pro Ala Lys I1a Cys Ser Arg Asp His Ala Gln 5er Ser Ala Thr Trp Ser Cys Ser Gln Pro Phe Lys vai val Cys val Tyr Ile Ala Phe ..... ...~.. _......,. ..~._ n wu,m....h.me ~.~.A".
,.';tYkM.xfyfiepuSRd7Mk4~?~"'~'~.~m..,x"m....,.... M,..,.e,.~.."". ~ ,~~m..-..... .............

PCT-uS00-23328_Sequence Tyr Ser Thr Asp Tyr Arg Leu val Gln Lys val Cys Pro Asp Tyr Asn Tyr His Ser Asp Thr Pro Tyr Tyr Pro Ser Gly <210> 93 <211> 902 <212> oNA _ <213> Homo Sapien <400> 93 cggtggccat gactgcggcc gtgttcttcg gctgcgcctt cattgccttc 50 gggcctgcgc tcgcccttta tgtcttcacc atcgccatcg agccgttgcg 100 tatcatcttc ctcatcgccg gagctttctt ctggttggtg tctctactga 150 tttcgtccct tgtttggttc atggcaagag tcattattga caacaaagat 200 ggaccaacac agaaatatct gctgatcttt ggagcgtttg tctctgtcta 250 tatccaagaa atgttccgat ttgcatatta taaactctta aaaaaagcca 300 gtgaaggttt gaagagtata aacccaggtg agacagcacc ctctatgcga 350 ctgctggcct atgtttctgg cttgggcttt ggaatcatga gtggagtatt 400 ttcctttgtg aataccctat ctgactcctt ggggccaggc acagtgggca 450 ttcatggaga ttctcctcaa ttcttccttt attcagcttt catgacgctg 500 gtcattatct tgctgcatgt attctggggc attgtatttt ttgatggctg 550 tgagaagaaa aagtggggca tcctccttat cgttctcctg acccacctgc 600 tggtgtc~gc ccagaccttc ataagttctt attatggaat aaacctggcg 650 tcagcattta taatcctggt gctcatgggc acctgggcat tcttagctgc 700 gggaggcagc tgccgaagcc tgaaactctg cctgctctgc caagacaaga 750 actttcttct ttacaaecag cgctccagat aacctcaggg aaccagcact 800 tcccaaaccg cagactacat ctttagagga agcacaactg tgcctttttc 850 tgaaaatccc tttttctggt ggaattgaga aagaaataaa actatgcaga 900 to 902 <210> 94 <211> 257 <212> PRT
<213> Homo Sapien <400> 94 Met Thr Ala Ala Val Phe Phe Gly Cys Ala Phe Ile Ala Phe Gly Pro Ala Leu Ala Leu Tyr val Phe Thr Ile Ala Ile Glu Pro Leu PCT-u500-23328_sequence Arg Ile Iie Phe Leu Ile Ala Gly Ala Phe Phe Trp Leu Val Ser Leu Leu Ile Ser Ser Leu Val Trp Phe Met Ala Arg Val Ile Ile Asp Asn Lys Asp Gly Pro Thr Gln Lys Tyr Leu Leu Ile Phe Gly Ala Phe Val Ser Val Tyr Ile Gin Glu Met Phe Arg Phe Ala Tyr Tyr Lys Leu Leu Lys Lys Ala Ser Glu Gly Leu Lys Ser Ile Asn Pro Gly Glu Thr Ala Pro Ser Met Arg Leu Leu Ala Tyr Val Ser Gly Leu Giy Phe Gly Ile Met Ser Gly Vai Phe Ser Phe Val Asn Thr Leu Ser Asp Ser Leu Gly Pro Gly Thr val Gly Ile His Gly Asp Ser Pro Gln Phe Phe Leu Tyr Ser Ala Phe Met Thr Leu Val Ile Ile Leu Leu His Val Phe Trp Gly Ile Val Phe Phe Asp Gly Cys Glu Lys Lys Lys Trp Gly Ile Leu Leu Ile Val Leu Leu Thr His Leu Leu Val Ser Ala Gln Thr Phe Tle Ser Ser Tyr Tyr Gly Ile Asn Leu Ala Ser Ala Phe Ile IIe Leu Val Leu Met Gly Thr Trp Ala Phe Leu Ala Ala Gly Gly Ser Cys Arg Ser Leu Lys Leu Cys Leu Leu Cys Gln Asp Lys Asn Phe Leu Leu Tyr Asn Gln Arg Ser Arg <210> 95 <211> 107 3 <212> DNA
<213> Homo Sapien _ <400> 95 aatttttcac.cagagtaaac ttgagaaacc aactggacct tgagtattgt SO
acattttgcc tcgtggaccc aaaggtagca atctgaaaca tgaggagtac 100 gattctactg ttttgtcttc taggatcaac tcggtcatta ccacagctca 150 aacctgcttt gggactccct cccacaaaac tggctccgga tcagggaaca 200 PCT-uS00-23328_Sequence ctaccaaacc aacagcagtc aaatcaggtc tttccttctt taagtctgat 250 accattaaca cagatgctca cactggggcc agatctgcat ctgttaaatc 300 ctgctgcagg aatgacacct ggtacccaga cccacccatt gaccctggga 350 gggttgaatg tacaacagca actgcaccca catgtgttac caatttttgt 400 cacacaactt ggagcccagg gcactatcct aagctcagag gaattgccac 450 aaatcttcac gagcctcatc atccattcct tgttcccggg aggcatcctg 500 cccaccagtc aggcaggggc taatccagat .gtccaggatg gaagccttcc 550 , agcaggagga gcaggtgtaa atcctgccac ccagggaacc ccagcaggcc 600 gcctcccaac tcccagtggc acagatgacg actttgcagt gaccacccct 650 gcaggcatcc aaaggagcac acatgccatc gaggaagcca ccacagaatc 700 agcaaatgga attcagtaag ctgtttcaaa ttttttcaa:c taagctgcct 750 cgaatttggt gatacatgtg aatctttatc attgattata ttatggaata 800 gattgagaca cattggatag tcttagaaga aattaattct taatttacct 850 gaaaatattc ttgaaatttc agaaaatatg ttctatgtag agaatcccaa 900 cttttaaaaa caataattca atggataaat ctgtctttga aatataacat 950 tatgctgcct ggatgatatg catattaaaa catatttgga aaactggaaa 1000 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 1050 aaaaaaaaaa aaaaaaaaaa aaa 1073 <210> 96 <211> 209 <212> PRT
<213> Homo Sapien .
<400> 96 Met Arg Ser Thr Ile Leu Leu Phe Cys Leu Leu Gly Ser Thr Arg Ser Leu Pro Gln Leu Lys Pro Ala Leu Gly Leu Pro Pro Thr Lys Leu Ala Pro Asp Gin Gly Thr Leu Pro Asn Gln Gln Gln Ser Asn 35 40 . 4S
Gln Val Phe Pro Ser Leu Ser Leu Ile Pro Leu Thr Gln Met Leu Thr Leu Gly Pro Asp Leu His Leu Leu Asn.Pro Ala Ala Gly Met Thr Pro Gly Thr Gln Thr His Pro Leu Thr Leu Gly Gly Leu Asn Val Gln Gln Gln Leu His Pro His Val Leu Pro Ile Phe Val Thr PCT-0500-23328_Sequence Gln Leu Gly Ala Gln Gly Thr Ile Leu Ser Ser Glu Glu Leu Pro Gln Ile Phe Thr Ser Leu Ile Ile His Ser Leu Phe Pro Gly Gly Ile Leu Pro Thr Ser Gln Ala Gly Ala Asn Pro Asp Val Gln Asp Gly Ser Leu Pro Ala Gly Gly Ala Gly Val Asn Pro Ala Thr Gln Gly Thr Pro Ala Gly Arg Leu Pro Thr Pro Ser Giy Thr Asp Asp Asp Phe Ala Val Thr Thr Pro Ala Gly Ile Gln Arg Ser Thr His Ala Ile Glu Glu Ala Thr Thr Glu Ser Ala Asn Giy Ile Gln <210> 97 <211> 2848 <212> DNA
<213> Homo Sapien <400> 97 gctcaagtgc cctgccttgc cccacccagc ccagcctggc cagagccccc 50 tggagaagga gctctcttct tgcttggcag ctggaccaag ggagccagtc 100 ttgggcgctg gagggcctgt cctgaccatg gtccctgcct ggctgtggct 150 gctttgtgtc tccgtccccc aggctctccc caaggcccag cctgcagagc 200 tgtctgtgga agttccagaa aactatggtg gaaatttccc tttatacctg 250 accaagttgc cgctgccccg tgagggggct gaaggccaga tcgtgctgtc 300 aggggactca ggcaaggcaa ctgagggccc atttgctatg gatccagatt 350 ctggcttcct gctggtgacc agggccctgg accgagagga gcaggcagag 400 taccagctac aggtcaccct ggagatgcag gatggacatg tcttgtgggg 450 tccacagcct gtgcttgtgc acgtgaagga tgagaatgac caggtgcccc 500 atttctctca agccatctac agagctcggc tgagccgggg taccaggcct 550 ggeatceeet teetettcet tgaggcttea gaeegggatg ageeaggcae 600 agccaactcg gatcttcgat tccacatcct gagccaggct ccagcccagc 650 cttccccaga catgttccag ctggagcctc ggctgggggc tctggccctc 700 agccccaagg ggagcaccag ccttgaccac gccctggaga ggacctacca 750 gctgttggta caggtcaagg acatgggtga ccaggcctca ggccaccagg 800 ccactgccac cgtggaagtc tecatcatag agagcacctg ggtgtcccta 850 gagcctatcc acctggcaga gaatctcaaa gtcctatacc cgcaccacat 900 _ *~ ~~. ~:. ~~.~d~. ~ . ,~ .~ m. r...r..a.w... w... _.... .
... _. ,_ v.. ~-. ...vk,~e~":...,-s,n. -~ ~ _.~m~...-~.r:.._,~ma..s.,.~....srm~,*,~r~a,.-;sue.. n,as.~.~:;"~° -.....

PCT-US00-23328_sequence ggcccaggta cactggagtg ggggtgatgt gcactatcac ctggagagcc 950 atcccccggg accctttgaa gtgaatgcag agggaaacct ctacgtgacc 1000 agagagctgg acagagaagc ccaggctgag tacctgctcc aggtgcgggc 1050 tcagaattcc catggcgagg actatgcggc ccctctggag ctgcacgtgc 1100 tggtgatgga tgagaatgac aaegtgeeta tetgecetec eegtgaeece 1150 acagtcagca tccctgagct cagtccacca ggtactgaag tgactagact 1200 gtcagcagag gatgcagatg cccccggctc ccccaattcc cacgttgtgt 1250 atcagctcct gagccctgag cctgaggatg gggtagaggg gagagccttc 1300 caggtggacc ccacttcagg cagtgtgacg ctgggggtgc tcccactccg 1350 agcaggccag aacatcctgc ttctggtgct ggccatggac ctggcaggcg 1400 cagagggtgg cttcagcagc acgtgtgaag tcgaagtcgc agtcacagat 1450 atcaatgatc acgcccctga gttcatcact tcccagattg ggcctataag 1500 cctccctgag gatgtggagc ccgggactct ggtggccatg ctaacagcca 1550 ttgatgctga cctcgagccc gccttccgcc tcatggattt tgccattgag 1600 aggggagaca cagaagggac ttttggcctg gattgggagc cagactctgg 1650 gcatgttaga ctcagactct gcaagaacct cagttatgag gcagctccaa 1700 gtcatgaggt ggtggtggtg gtgcagagtg tggcgaagct ggtggggcca 1750 ggcecaggcc ctggagceae egceaeggtg aetgtgctag tggagagagt 1800 gatgccaccc cccaagttgg accaggagag ctacgaggcc agtgtcccca 1850 tcagtgcccc agccggctct ttcctgctga ccatccagcc ctccgacccc 1900 atcagecgaa cectcaggtt ctccctagtc aatgactcag agggctggct 1950 ctgcattgag aaattctccg gggaggtgca caccgcccag tccctgcagg 2000 gcgcccagcc tggggacacc tacacggtgc ttgtggaggc ccaggataca 2050 gccctgactc ttgcccctgt gccctcccaa tacctctgca caccccgcca 2100 agaccatggc ttgatcgtga gtggacccag caaggacccc gatctggcca 2150 gtgggcacgg tccctacagc ttcacccttg gtcccaaccc cacggtgcaa 2200 cgggattggc gcctccagac tctcaatggt tcccatgcct acctcacctt 2250 ggccctgcat tgggtggagc cacgtgaaca cataatcccc gtggtggtca 2300 gccacaatgc ccagatgtgg cagctcctgg ttcgagtgat cgtgtgtcgc 2350 tgcaacgtgg aggggcagtg catgcgcaag gtgggccgca tgaagggcat 240~
gcccacgaag ctgtcggcag tgggcatcct tgtaggcacc ctggtagcaa 2450 taggaatctt cctcatcctc attttcaccc actggaccat gtcaaggaag 2500 PCT-uSOU-23328-Sequence aaggacccgg atcaaccagc agacagcgtg cccctgaagg cgactgtctg 2550 aatggcccag gcagctctag ctgggagctt ggcctctggc tccatctgag 2600 tcccctggga gagagcccag cacccaagat ccagcagggg acaggacaga 2650 gtagaagccc ctccatctgc cctggggtgg aggcaccatc accatcacca 2700 ggcatgtctg cagagcctgg acaccaactt tatggactgc ccatgggagt 2750 gctccaaatg tcagggtgtt tgcccaataa taaagcccca gagaactggg 2800 ctgggcccta tgggaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaag 2848 <210> 98 <211> 807 <212> PRT
<213> Homo Sapien <400> 98 Met Val Pro Ala Trp Leu Trp Leu Leu Cys Val Ser val Pro Gln Ala Leu Pro Lys Ala Gln Pro Ala Glu Leu Ser Vai Glu val Pro Glu Asn Tyr Gly Gly Asn Phe Pro Leu Tyr Leu Thr Lys Leu Pro Leu Pro Arg Glu Gly Ala Glu Gly Gln Ile Val Leu Ser Gly Asp Ser Gly Lys Ala Thr Glu Gly Pro Phe Ala Met Asp Pro Asp Ser Gly Phe Leu Leu Val Thr Arg Ala Leu ASp Arg Glu Glu Gln Ala Glu Tyr Gln Leu Gln Val Thr Leu Glu Met Gln Asp Gly His val Leu Trp Gly Pro Gln Pro Val Leu Val His Val Lys Asp Glu Asn Asp Gln Val Pro His Phe Ser Gln Ala Ile Tyr Arg Ala Arg Leu Ser Arg Gly Thr Arg Pro Gly Ile Pro Phe Leu Phe Leu Glu Ala Ser Asp Arg Asp Glu Pro Gly Thr Ala Asn Ser Asp Leu Arg Phe His Ile Leu Ser Gln Ala Pro Ala Gln Pro Ser Pro Asp Met Phe Gln Leu Glu Pro Arg.Leu Gly Ala Leu Ala Leu Ser Pro Lys Gly Ser Thr Ser Leu Asp His Ala Leu Glu Arg Thr Tyr Ghn Leu Leu x . _,.~. ~,. ~w_ .».~. .. ~~,<. ~. u~~ , ~. ~~w.W ~ . .,,a"~~."~~ _,. ~ . ..
. .. __ __ _ ..... _. _ ._ __,..~ .__..~.___..._ ._ .. _ PCT-US00-23328_Sequence Val Gln Val Lys Asp Met Gly Asp Gln Ala Ser Gly His Gln Ala Thr Ala Thr Va1 Glu Val Ser Ile Ile Glu Ser Thr Trp val Ser Leu Glu Pro Ile His Leu Ala Glu Asn Leu Lys Val Leu Tyr Pro His His Met Ala Gln Val His Trp Ser Gly Gly Asp Val His Tyr His Leu Glu Ser His Pro Pro Gly Pro Phe Glu Val Asn Ala Glu z75 z8o z85 Gly Asn Leu Tyr Val Thr Arg Glu Leu Asp Arg Glu Ala Gln Ala Glu Tyr Leu Leu Gln Val Arg Ala Gln Asn Ser His Gly Glu Asp Tyr Ala Ala Pro Leu Glu Leu His Val Leu Val Met Asp Glu Asn Asp Asn Val Pro Ile Cys Pro Pro Arg Asp Pro Thr val Ser.Ile Pro Glu Leu Ser Pro Pro Gly Thr Glu Val Thr Arg Leu Ser Ala Glu Asp Ala Asp Ala Pro Gly ser Pro Asn Ser His Val Val Tyr Gln Leu Leu Ser Pro Glu Pro Glu Asp Gly Val Glu Gly Arg Ala Phe Gln Val Asp Pro Thr Ser Gly Ser Val Thr Leu Gly Val Leu Pro Leu Arg Ala Gly Gln Asn Ile Leu Leu Leu Val Leu Ala Met Asp Leu Ala Gly Ala Glu Gly Gly Phe Ser Ser Thr Cys Glu Val G'lu Val Ala Val Thr Asp Ile Asn Asp His Ala Pro Glu Phe Ile Thr Ser Gln Ile Gly Pro Ile Ser Leu Pro Glu Asp Val Glu Pro Gly Thr Leu Val Ala Met Leu Thr Ala Ile Asp Ala Asp Leu Glu Pro Ala Phe Arg Leu Met Asp Phe Ala Ile Glu Arg Gly Asp Thr Glu Gly Thr Phe Gly Leu Asp Trp,Glu Pro Asp Ser Gly His Val Arg Leu Arg Leu ~ys Lys Asn Leu Ser Tyr Glu Ala Ala Pro Ser PCT-US00-23328_Sequence His Glu Val Val Val Val Val Gln Ser Val Ala Lys Leu Val Gly Pro Gly Pro Gly Pro Gly Ala Thr Ala Thr Val Thr Val Leu Val Glu Arg Val Met Pro Pro Pro Lys Leu Asp Gln Glu Ser Tyr Glu Ala Ser Val Pro Iie Ser Ala Pro Ala Gly Ser Phe Leu Leu Thr Ile Gln Pro Ser Asp Pro Ile Ser Arg Thr Leu Arg Phe Ser Leu Val Asn Asp Ser Glu Gly Trp Leu Cys Ile Glu Lys Phe Ser Gly Glu Val His Thr Ala Gln Ser Leu Gln Gly Ala Gln Pro Gly Asp Thr Tyr Thr Val Leu Val Glu Ala Gln Asp Thr Ala Leu Thr Leu Ala Pro Val Pro Ser Gln Tyr Leu Cys Thr Pro Arg Gln Asp His Gly Leu Ile Va1 Ser Gly Pro Ser Lys Asp Pro Asp Leu Ala Ser Gly His Gly Pro Tyr Ser Phe Thr Leu Gly Pro Asn Pro Thr Val Gln Arg Asp Trp Arg Leu Gln Thr Leu Asn Gly ser His Ala Tyr Leu Thr Leu Ala Leu His Trp Val Glu Pro Arg Glu His Ile Ile Pro Val Val Val Ser His Asn Ala Gln Met Trp Gln Leu Leu Val Arg Val Ile Val Cys Arg Cys Asn Val Glu Gly Gln Cys Met Arg Lys Val Gly Arg Met Lys Gly Met Pro Thr Lys Leu Ser Ala Val Gly Ile Leu Val Gly Thr Leu Val Ala Ile Gly Ile Phe Leu zle Leu Ile Phe Thr His Trp Thr Met Ser Arg Lys Lys Asp Pro Asp Gln Pro Ala Asp Ser Val Pro Leu Lys Ala Thr Val <210> 99 <211> 2436 <y <212> DNA
<213> Homo Sapien <400> 99 PCT-US00-23328_Sequence ggctgaccgt gctacattgc ctggaggaag cctaaggaac ccaggcatcc 50 agctgcccac gcctgagtcc aagattcttc ccaggaacac aaacgtagga 100 gacccacgct cctggaagca ccagccttta tctcttcacc ttcaagtccc 150 ctttctcaag aatcctctgt tctttgccct ctaaagtctt ggtacatcta 200 ggacccaggc atcttgcttt ccagccacaa agagacagat gaagatgcag 250 aaaggaaatg ttctccttat gtttggtcta ctattgcatt tagaagctgc 3~0 aacaaattcc aatgagacta gcacctctgc caacactgga tccagtgtga 350 tctccagtgg agccagcaca gccaccaact ctgggtccag tgtgacctcc 400 agtggggtca gcacagccac catctcaggg tccagcgtga cctccaatgg 450 ggtcagcata gtcaccaact ctgagttcca tacaacctcc agtgggatca 500 gcacagccac caactctgag ttcagcacag cgtccagtgg gatcagcata 550 gccaccaact ctgagtccag cacaacctcc agtggggcca gcacagccac 600 caactctgag tccagcacac cctccagtgg ggccagcaca gtcaccaact 650 ctgggtccag tgtgacctcc agtggagcca gcactgccac caactctgag 700 tccagcacag tgtccagtag ggccagcact gccaccaact ctgagtctag 750 cacactctcc agtggggcca gcacagccac caactctgac tccagcacaa 800 cctccagtgg ggctagcaca gccaccaact ctgagtccag cacaacctcc 850 agtggggcca gcacagccac caactctgag tccagcacag tgtccagtag 900 ggccagcact gccaccaact ctgagtccag cacaacctcc agtggggcca 950 gcacagccac caactctgag tccagaacga cctccaatgg ggctggcaca 1000 gccaccaact ctgagtccag cacgacctcc agtggggcca gcacagccac 1050 caactctgac tccagcacag tgtccagtgg ggccagcact gccaccaact 1100 ctgagtccag cacgacctcc agtggggcca gcacagccac caactctgag 1150 tccagcacga cctccagtgg ggctagcaca gccaccaact ctgactccag 1200 cacaacctcc agtggggccg gcacagccac caactctgag tccagcacag 1250 tgtccagtgg gatcagcaca gtcaccaatt ctgagtccag cacaccctcc 1300 agtggggcca acacagccac caactctgag tccagtacga cctccagtgg 1350 ggccaacaca gccaccaact ctgagtccag cacagtgtcc agtggggcca 1400 gcactgccac caactctgag tccagcacaa cctccagtgg ggtcagcaca 1450 gccaccaact ctgagtccag cacaacctcc ag~ggggcta gcacagccac 1500 caactctgac tccagcacaa cctccagtga ggccagcaca gccaccaact 1550 ctgagtctag cacagtgtcc agtgggatca gcacagtcac caattctgag 1600 PCT-uS00-23328_Sequence tccagcacaa cctccagtgg ggccaacaca gccaccaact ctgggtccag 1650 tgtgacctct gcaggctctg gaacagcagc tctgactgga atgcacacaa 1700 cttcccatag tgcatctact gcagtgagtg aggcaaagcc tggtgggtcc 1750 ctggtgccgt gggaaatctt cctcatcacc ctggtctcgg ttgtggcggc 1800 cgtggggctc tttgctgggc tcttcttctg tgtgagaaac agcctgtccc 1850 tgagaaacac ctttaacaca gctgtctacc accctcatgg cctcaaccat 1900 ggccttggtc caggccctgg agggaatcat ggagcccccc acaggcccag 1950 gtggagtcct aactggttct ggaggagacc agtatcatcg atagccatgg 2000 agatgagcgg gaggaacagc gggccctgag cagccccgga agcaagtgcc 2050 gcattcttca ggaaggaaga gacctgggca cccaagacct ggtttccttt 2100 cattcatccc aggagacccc tcccagcttt gtttgagatc ctgaaaatct 2150 tgaagaaggt attcctcacc tttcttgcct ttaccagaca ctggaaagag 2200 aatactatat tgctcattta gctaagaaat aaatacatct catctaacac 2250 acacgacaaa gagaagctgt gcttgccccg gggtgggtat ctagctctga 2300 ~gatgaactca gttataggag aaaacctcca tgctggactc catctggcat 2350 tcaaaatctc cacagtaaaa tccaaagacc tcaaaaaaaa aaaaaaaaaa 2400 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaa 2436 <210> 100 <211> 596 <212> PRT
<213> Homo Sapien <400> 100 Met Lys Met Gln Lys Gly Asn val Leu Leu Met Phe Gly Leu Leu Leu His Leu Glu Ala Ala Thr Asn Ser Asn G1u Thr Ser Thr Ser Ala Asn Thr Gly Ser Ser val Ile Ser Ser Gly Ala Ser Thr Ala Thr Asn Ser Gly Ser Ser val Thr Ser Ser Gly val Ser Thr Ala Thr Ile Ser Gly Ser ser val Thr Ser Asn Gly val Ser zle val Thr Asn Ser Glu Phe His Thr Thr Ser Ser Gly Ile Ser Thr Ala Thr Asn Ser Glu Phe Ser Thr Ala Ser Ser Gly Ile 5er Ile Ala Thr Asn Ser Glu Ser Ser Thr Thr Ser Ser Gly Ala Ser Thr Ala Page 125 .

PCT-uS00-23328_Sequence Thr Asn Ser Glu Ser Ser Thr Pro Ser Ser Gly Ala Ser Thr Val Thr Asn Ser Gly Ser ser val Thr Ser Ser Gly Ala ser Thr Ala Thr Asn Ser Glu Ser Ser Thr val Ser Ser Arg Ala Ser Thr Ala Thr Asn Ser Glu Ser Ser Thr Leu Ser Ser Gly Ala Ser Thr Ala Thr Asn Ser Asp Ser Ser Thr Thr Ser Ser Gly Ala Ser Thr Ala Thr Asn Ser Glu Ser Ser Thr Thr Ser Ser Gly Ala Ser Thr Ala Thr Asn Ser Glu Ser Ser Thr val Ser Ser Arg Ala Ser Thr Ala Thr Asn Ser Glu Ser Ser Thr Thr Ser Ser Gly Ala Ser Thr Ala Thr Asn Ser Glu Ser Arg Thr Thr Ser Asn Gly Ala Gly Thr Ala Thr Asn Ser Glu Ser Ser Thr Thr Ser Ser Gly Ala Ser Thr Ala Thr Asn Ser Asp Ser Ser Thr val Ser Ser Gly Ala Ser Thr Ala Thr Asn Ser Glu Ser Ser Thr Thr Ser Ser Gly Ala Ser Thr Ala Thr Asn Ser Glu Ser Ser Thr Thr Ser Ser Gly Ala Ser Thr Ala . 305 310 315 Thr Asn Ser Asp Ser Ser Thr Thr Ser Ser Gly Ala Giy Thr Ala Thr Asn Ser Glu Ser Ser Thr val Ser Ser Gly Ile Ser Thr val Thr Asn Ser Glu Ser 5er Thr Pro Ser Ser Gly Ala Asn Thr Ala 350 355 ~ 360 Thr Asn Ser Glu Ser Ser Thr Thr Ser Ser Gly Ala Asn Thr Ala Thr Asn Ser Glu Ser Ser Thr val Ser Ser Gly Ala Ser Thr Ala Thr Asn Ser Glu Ser Ser Thr Thr Ser Ser Gly Val Ser Thr Ala Thr Asn Ser Glu Ser Ser Thr Thr Ser Ser Gly Ala Ser Thr Ala Thr Asn Ser Asp Ser Ser Thr Thr Ser Ser Glu Ala Ser Thr Ala PCT-US00-23328_Sequence Thr Asn Ser Glu Ser Ser Thr Val Ser Ser Gly Ile Ser Thr Val Thr Asn Ser Glu Ser Ser Thr Thr Ser Ser Gly Ala Asn Thr Ala Thr Asn Ser Gly Ser Ser Val Thr Ser Ala G~ly Ser Gly Thr Ala Ala Leu Thr Gly Met His Thr Thr Ser His Ser Ala Ser Thr Aia Val Ser Glu Ala Lys Pro Gly Gly Ser Leu Val Pro Trp Glu Ile Phe Leu Ile Thr Leu Val Ser Val Val Ala Ala Val Gly Leu Phe 53.5 520 525 Ala Gly Leu Phe Phe Cys Val Arg Asn Ser Leu Ser Leu Arg Asn Thr Phe Asn Thr Ala Val Tyr His Pro His Gly Leu Asn His Gly Leu Gly Pro Gly Pro Gly Gly Asn His Gly Ala Pro His Arg Pro Arg Trp Ser Pro Asn Trp Phe Trp Arg Arg Pro Val Ser Ser Ile Ala Met Glu Met Ser Gly Arg Asn 5er Gly Pro <210> 101 <211> 1728 <212> DNA
<213> Homo Sapien <400> 101 ggccggacgc ctccgcgtta cgggatgaat taacggcggg ttccgcacgg SO
aggttgtgac ccctacggag ccccagcttg cccacgcacc ccactcggcg 100 tcgcgcggcg tgccctgctt gtcacaggtg ggaggctgga actatcaggc 150 tgaaaaacag agtgggtact ctcttctggg aagctggcaa caaatggatg 200 atgtgatata tgcattccag gggaagggaa attgtggtge ttctgaacee 250 atggtcaatt aacgaggcag tttctagcta ctgcacgtac ttcataaagc 300 aggactctaa aagctttgga atcatggtgt catggaaagg gatttacttt 350 atactgactc tgttttgggg aagctttttt ggaagcattt tcatgctgag 400 tcccttttta cctttgatgt ttgtaaaccc atcttggtat cgctggatca 4S0 acaaccgcct tgtggcaaca tggctcaccc tacctgtggc: attattggag 500 accatgtttg gtgtaaaagt gattataact ggggatgcat ttgttcctgg 550 PCT-uS00-23328_Sequence agaaagaagt gtcattatca tgaaccatcg gacaagaatg gactggatgt 600 tcctgtggaa ttgcctgatg cgatatagct acctcagatt ggagaaaatt 650 tgcctcaaag cgagtctcaa aggtgttcct ggatttggtt gggccatgca 700 ggctgctgcc tatatcttca ttcataggaa atggaaggat gacaagagcc 750 atttcgaaga catgattgat tacttttgtg atattcacga accacttcaa 800 ctcctcatat tcccagaagg gactgatctc acagaaaaca gc_~agtctcg 850 w4 aagtaatgca tttgctgaaa aaaatggact tcagaaatat gaatatgttt 900 tacatccaag aactacaggc tttacttttg tggtagaccg tctaagagaa 950 ggtaagaacc ttgatgctgt ccatgatatc actgtggcgt atcctcacaa 1000 cattcctcaa tcagagaagc acctcctcca aggagacttt cccagggaaa 1050 tccactttca cgtccaccgg tatccaatag acaccctccc cacatccaag 1100 gaggaccttc aactctggtg ccacaaacgg tgggaagaga aagaagagag 1150 gctgcgttcc ttctatcaag gggagaagaa tttttatttt accggacaga 1200 gtgtcattcc accttgcaag tctgaactca gggtccttgt ggtcaaattg 1250 ctctctatac tgtattggac cctgttcagc cctgcaatgt gcctactcat 1300 atatttgtac agtcttgtta agtggtattt tataatcacc attgtaatct 1350 ttgtgctgca agagagaata tttggtggac tggagatcat agaacttgca 1400 tgttaccgac ttttacacaa acagccacat ttaaattcaa agaaaaatga 1450 gtaagattat aaggtttgcc atgtgaaaac ctagagcata ttttggaaat 1500 gttctaaacc tttctaagct cagatgcatt tttgcatgac tatgtcgaat 1550 atttcttact gccatcatta tttgttaaag atattttgca cttaattttg 1600 tgggaaaaat attgctacaa ttttttttaa tctctgaatg taatttcgat 1650 actgtgtaca tagcagggag tgatcggggt gaaataactt gggccagaat 1700 attattaaac aateatcagg cttttaaa 1728 <210> 102 <211> 414 <212> PRT
<213> Homo Sapien <400> 102 Met His Ser Arg Gly Arg Glu Ile Val Val Leu Leu Asn Pro Trp Ser Ile Asn Glu Ala vat Ser Ser Tyr Cys Thr Tyr Phe Ile ~ys Gln Asp Ser Lys Ser Phe Gly Ile Met val Ser Trp Lys Gly Ile PCT-u500-23328~Seguence Tyr Phe Ile Leu Thr Leu Phe Trp Gly Ser Phe Phe Gly Ser Ile Phe Met Leu Ser Pro Phe Leu Pro Leu Met Phe Val Asn Pro Ser Trp Tyr Arg Trp Ile Asn Asn Arg Leu Val Ala Thr Trp Leu Thr 80 $5 90 Leu Pro Val Ala Leu Leu Glu Thr Met Phe Gly Val Lys Val Ile Ile Thr Gly Asp Ala Phe Val Pro Gly Glu Arg Ser val Ile Ile Met Asn His Arg Thr Arg Met Asp Trp Met Phe Leu Trp Asn Cys Leu Met Arg Tyr Ser Tyr Leu Arg Leu Glu Lys Ile Cys Leu Lys 140 . 145 150 Ala Ser Leu Lys Gly Val Pro Gly Phe Gly Trp Ala Met Gln Ala Ala Ala Tyr Ile Phe Ile His Arg Lys Trp Lys asp Asp Lys Ser His Phe Glu Asp Met Ile Asp Tyr Phe Cys Asp Ile His Glu Pro Leu Gln Leu Leu Ile Phe Pro Glu Gly Thr Asp Leu Thr Glu Asn Ser Lys Ser Arg Ser Asn Ala Phe Ala Glu Lys Asn Gly Leu Gln Lys Tyr Glu Tyr Val Leu His Pro Arg Thr Thr Gly Phe Thr Phe Val Val Asp Arg Leu Arg Glu Gly Ly5 Asn Leu Asp Ala Val His Asp Ile Thr Val Ala Tyr Pro His Asn Ile Pro Gln Ser Glu Lys His Leu Leu Gln Gly Asp Phe Pro Arg Glu Ile His Phe His Val His Arg Tyr Pro Ile Asp Thr Leu Pro Thr Ser Lys Glu Asp Leu Gln Leu Trp Cys His Lys Arg Trp Glu Glu Lys Glu Glu Arg Leu Arg Ser Phe Tyr Gln Gly Glu Lys Asn Phe Tyr Phe Thr Gly Gln Ser Val Ile Pro Pro Cys Lys Ser Glu Leu Arg Va1 Leu Val Val ,.

Lys Leu Leu Ser Ile Leu Tyr Trp Thr Leu Phe Ser Pro Ala Met PCT-US00-23328_Sequence Cys Leu Leu Ile Tyr Leu Tyr Ser Leu Val Lys Trp Tyr Phe Ile Ile Thr Ile Val Ile Phe Val Leu Gln Glu Arg Ile Phe Gly Gly Leu Glu Iie Ile Glu Leu Ala Cys Tyr Arg Leu Leu His Lys Gln Pro His Leu Asn Ser Lys Lys Asn Glu <210> 103 <211> 2403 <212> DNA
<213> Homo Sapien <400> 103 cggctcgagc ggctcgagtg aagagcctct ccacggctcc tgcgcctgag 50 acagctggcc tgacctccaa atcatccatc cacccctgct gtcatctgtt 100 ttcatagtgt gagatcaacc cacaggaata tccatggctt ttgtgctcat 150 tttggttctc agtttetacg agctggtgtc aggacagtgg caagtcactg 200 gaccgggcaa gtttgtccag gccttggtgg gggaggacgc cgtgttctcc 250 tgctccctct ttcctgagac cagtgcagag gctatggaag tgcggttctt 300 caggaatcag ttccatgctg tggtccacct ctacagagat ggggaagact 350 gggaatctaa gcagatgcca cagtatcgag ggagaactga gtttgtgaag 400 gactccattg caggggggcg tgtctctcta aggctaaaaa acatcactcc 450 ctcggacatc ggcctgtatg ggtgctggtt cagttcccag atttacgatg 500 aggaggccac ctgggagctg cgggtggcag cactgggctc acttcctctc 550 atttccatcg tgggatatgt tgacggaggt atccagttac tctgcctgtc 600 ctcaggctgg ttcccccagc ccacagccaa gtggaaaggt ccacaaggac 650 aggatttgtc ttcagactcc agagcaaatg cagatgggta cagcctgtat 700 gatgtggaga tctccattat agtccaggaa aatgctggga gcatattgtg 750 ttccatccac cttgctgagc agagtcatga ggtggaatcc aaggtattga 800 taggagagac gtttttccag ccctcacctt ggcgcctggc ttctatttta 850 ctcgggttac tctgtggtgc tctgtgtggt gttgtcatgg ggatgataat 900 tgttttcttc aaatccaaag ggaaaatcca ggcggaactg gactggagaa 950 gaaagcacgg acaggcagaa ttgagagacg cccggaaaca cgcagtggag 1000 gtgactctgg atccagagac ggctcacccg aagctctgcg tttctgatct 1050 gaaaactgta acccatagaa aagctcccca ggaggtgcct cactctgaga 1100 agagatttac aaggaagagt gtggtggctt ctcagggttt ccaagcaggg 1150 PCT-u500-23328_Seguence agacattact gggaggtgga cgtgggacaa aatgtagggt ggtatgtggg 1200 agtgtgtcgg gatgacgtag acagggggaa gaacaatgtg actttgtctc 1250 ccaacaatgg gtattgggtc ctcagactga caacagaaca tttgtatttc 1300 acattcaatc cccattttat cagcctcccc cccagcaccc ctcctacacg 1350 agtaggggtc ttcctggact atgagggtgg gaccatctcc ttcttcaata 1400 caaatgacca gtcccttatt tataccctgc tgacatgtca gtttgaaggc 1450 ttgttgagac cctatatcca gcatgcgatg tatgacgagg aaaaggggac 1500 tcccatattc atatgtccag tgtcctgggg atgagacaga gaagaccctg 1550 cttaaagggc cccacaccac agacccagac acagccaagg gagagtgctc 1600 ccgacaggtg gccccagctt cctctccgga gcctgcgcac agagagtcac 1650 gccccccact ctcctttagg gagctgaggt tcttctgccc tgagccctgc 1700 agcagcggca gtcacagctt ccagatgagg ggggattggc ctgaccctgt 1750 gggagtcaga agccatggct gccctgaagt ggggacggaa tagactcaca 1800 ttaggtttag tttgtgaaaa ctccatccag ctaagcgatc ttgaacaagt 1850 cacaacctcc caggctcctc atttgctagt cacggacagt gattcctgcc 1900 tcacaggtga agattaaaga gacaacgaat gtgaatcatg cttgcaggtt 1950 tgagggcaca gtgtttgcta atgatgtgtt tttatattat acattttccc 2000 accataaact ctgtttgctt atficcacatt aatttacttt tctctatacc 2050 aaatcaccca tggaatagtt attgaacacc tgctttgtga ggctcaaaga 2100 ataaagagga ggtaggattt ttcactgatt ctataagccc agcattacct 2150 gataccaaaa ccaggcaaag aaaacagaag aagaggaagg aaaactacag 2200 gtccatatcc ctcattaaca cagacacaaa aattctaaat aaaattttaa 2250 caaattaaac taaacaatat atttaaagat gatatataac tactcagtgt 2300 ggtttgtccc acaaatgcag agttggttta atatttaaat atcaaccagt 2350 gtaattcagc acattaataa agtaaaaaag aaaaccataa aaaaaaaaaa 2400 aaa 2403 <210> 104 <211> 466 <212> PRT
<213> Homo Sapien <400> 104 Met Ala Phe Val Leu Ile Leu Val Leu Ser Phe Tyr Glu Leu Val Ser Gly Gln Trp Gln Val Thr Gly Pro Gly Lys Phe Val Gin Ala PCT-uS00-23328_Sequence Leu Val Gly Glu Asp Ala Val Phe Ser Cys Ser Leu Phe Pro Glu Thr Ser Ala Glu Ala Met Glu Val Arg Phe Phe Arg Asn Gln Phe His Ala Val Val His Leu Tyr Arg Asp Gly Glu Asp Trp Glu Ser 65 70 _ 75 Lys Gln Met Pro Gln Tyr Arg Gly Arg Thr Glu Phe Val Lys Asp Ser Ile Ala Gly Gly Arg Val Ser Leu Arg Leu Lys Asn Ile Thr Pro Ser Asp Ile Gly Leu Tyr Gly Cys Trp Phe Ser ser Gln Ile Tyr Asp Glu Glu Ala Thr Trp Glu Leu Arg Val Ala Ala Leu Gly Ser Leu Pro Leu Ile Ser Ile Vai Gly Tyr Val Asp Gly Gly Ile Gln Leu Leu Cys Leu Ser Ser Gly Trp Phe Pro Gln Pro Thr Ala Lys Trp Lys Gly Pro Gln G1y Gln Asp Leu Ser Ser Asp Ser Arg Ala Asn A1a Asp Gly Tyr Ser Leu Tyr Asp Vai Glu Ile Ser Ile Ile Val Gin Glu Asn Ala Gly Ser Ile Leu Cys Ser Ile His Leu Ala Glu Gln Ser His GTu Val Glu Ser Lys Vai Leu Ile Gly Glu 215 220. 225 Thr Phe Phe Gln Pro Ser Pro Trp Arg Leu Ala Ser Iie Leu Lea Gly Leu Leu Cys Gly Ala Leu Cys Giy Val Vai Met Giy Met Ile Ile Val Phe Phe Lys Ser Lys Gly Lys Ile Gln Ala Glu Leu Asp Trp Arg Arg Lys His G1y Gln Ala Glu Leu Arg Asp Ala Arg Lys His Ala Val Glu Val Thr Leu Asp Pro Glu Thr Ala His Pro Lys Leu Cys Val Ser Asp Leu Lys Thr Val Thr His Arg Lys Ala Pro Gln Glu Val Pro His Ser Glu Lys Arg Phe Thr Arg Lys Ser Val Val Ala 5er Gln Giy Phe Gin Ala Gly Arg His Tyr Trp Glu Val PCT-u500-23328_Sequence Asp val Gly Gln Asn Val Gly Trp Tyr Val Gly Val Cys Arg Asp Asp Val Asp Arg Gly Lys Asn Asn Val Thr Leu Ser Pro Asn Asn Gly Tyr Trp Val Leu Arg Leu Thr Thr Glu His Leu Tyr Phe Thr Phe Asn Pro His Phe Ile Ser Leu Pro Pro Ser Thr Pro Pro Thr Arg Val Gly Val Phe Leu Asp Tyr Glu Gly Gly Thr Ile Ser Phe Phe Asn Thr Asn Asp Gln Ser Leu Ile Tyr Thr Leu Leu Thr Cys Gln Phe Glu Gly Leu Leu Arg Pro Tyr Tle Gln His Ala Met Tyr asp Glu Glu Lys Gly Thr Pro Ile Phe Ile Cys Pro Val ser Trp Gly <210> 105 -<211> 2103 <212> DNA
<213> Homo sapien <400> 105 ccttcacagg actcttcatt gctggttggc aatgatgtat cggccagatg SO
tggtgagggc taggaaaaga gtttgttggg aaccctgggt tatcggcctc 100 gtcatcttca tatccctgat tgtcctggca gtgtgcattg gactcactgt 150 tcattatgtg agatataatc aaaagaagac ctacaattac tatagcacat 200 tgtcatttac aactgacaaa ctatatgctg agtttggcag agaggcttct 250 aacaatttta cagaaatgag ceagagactt gaateaatgg tgaaaaatge 300 attttataaa tctccattaa gggaagaatt tgtcaagtct caggttatca 350 agttcagtca acagaagcat ggagtgttgg ctcatatgct gttgatttgt 400 agatttcact ctactgagga tcctgaaact gtagataaaa ttgttcaact 450 tgttttacat gaaaagctgc aagatgctgt aggaccccct aaagtagatc 500 ctcactcagt taaaattaaa aaaatcaaca agacagaaac agacagctat 550 ctaaaccatt gctgcggaac acgaagaagt aaaactctag gtcagagtct 600 caggatcgtt ggtgggacag aagtagaaga gggtgaatgg ccctggcagg 650 ctagcctgca gtgggatggg agtcatcgct gtggagcaac cttaattaat 700 PCT-u500-23328_Sequence gccacatggc ttgtgagtgc tgctcactgt tttacaacat ataagaaccc 750 tgccagatgg actgcttcct ttggagtaac aataaaacct tcgaaaatga 800 aacggggtct ccggagaata attgtccatg aaaaatacaa acacccatca 850 catgactatg atatttctct tgcagagctt tctagccctg ttccctacac 900 aaatgcagta catagagttt gtctccctga tgcatcctat gagtttcaac 950 caggtgatgt gatgtttgtg acaggatttg gagcactgaa aaatgatggt 1000 tacagtcaaa atcatcttcg acaagcacag gtgactctca tagacgctac 1050 aacttgcaat gaacctcaag cttacaatga cgccataact cctagaatgt 1100 tatgtgctgg ctccttagaa ggaaaaacag atgcatgcca gggtgactct 1150 ggaggaccac tggttagttc agatgctaga gatatctggt accttgctgg 1200 aatagtgagc tggggagatg aatgtgcgaa acccaacaag cctggtgttt 1250 atactagagt tacggccttg cgggactgga ttacttcaaa aactggtatc 1300 taagagacaa aagcctcatg gaacagataa catttttttt tgttttttgg 1350 gtgtggaggc catttttaga gatacagaat tggagaagac ttgcaaaaca 1400 gctagatttg actgatctca ataaactgtt tgcttgatgc atgtattttc 1450 ttcccagctc tgttccgcac gtaagcatcc tgcttctgcc agatcaactc 1500 tgtcatctgt gagcaatagt tgaaacttta tgtacataga gaaatagata 1550 atacaatatt acattacagc ctgtattcat ttgttctcta gaagttttgt 1600 cagaattttg acttgttgac ataaatttgt aatgcatata tacaatttga 1650 agcactcctt ttcttcagtt cctcagctcc tctcatttca gcaaatatcc 1700 attttcaagg tgcagaacaa ggagtgaaag aaaatataag aagaaaaaaa 1750 tcccctacat tttattggca cagaaaagta ttaggtgttt ttcttagtgg 1800 aatattagaa atgatcatat tcattatgaa aggtcaagca aagacagcag 1850 aataccaatc acttcatcat ttaggaagta tgggaactaa gttaaggaag 1900 tccagaaaga agccaagata tatccttatt ttcatttcca aacaactact 1950 atgataaatg tgaagaagat tctgtttttt tgtgacctat aataattata 2000 caaacttcat gcaatgtact tgttctaagc aaattaaagc aaatatttat 2050 ttaacattgt tactgaggat gtcaacatat aacaataaaa tataaatcac 2100 cca 2103 <210> 106 <211> 423 <212> PRT
<213> Homo Sapien ' PCT-u500-23328_Sequence <400> 106 Mei MetTyrArgPr5 AspVal ValArgAi ArgLys ArgValC
a O i5 Trp, GluProTrpVal IleGly Leu.ValIle PheIle SerLeuIle Val LeuAlaValCys IleGly LeuThrVal HisTyr ValArgTyr Asn GlnLysLysThr TyrAsn TyrTyrSer ThrLeu SerPheThr Thr AspLysLeuTyr AlaGlu PheGlyArg GluAla SerAsnAsn Phe ThrGluMetSer GlnArg LeuGluSer MetVal LysAsnAla Phe TyrLysSerPro LeuArg GluGluPhe ValLys SerGlnVal Ile LysPheSerGln GlnLys HisGlyval LeuAla HisMetLeu Leu IleCysArgPhe HisSer ThrGluAsp ProGlu ThrValAsp Lys IleValGlnLeu ValLeu HisGluLys LeuGln AspAlaVal Gly ProProLysVal AspPro HisSerVal LysIle LysLysIle ' 155 160 165 Asn Lys Thr Glu Thr Asp Ser Tyr Leu Asn His Cys Cys Gly Thr Arg Arg Ser Lys Thr Leu Gly Gln Ser Leu Arg Ile Val Gly Gly 1$5 190 ~ 195 Thr Glu Va1 Glu Glu Gly Glu Trp Pro Trp Gln Ala Ser Leu Gln Trp Asp Gly Ser His Arg Cys Gly Ala Thr Leu Ile Asn Ala Thr Trp Leu Val Ser Ala Ala His Cys Phe Thr Thr Tyr Lys Asn Pro Ala Arg Trp Thr Ala Ser Phe Gly Val Thr Ile Lys Pro Ser Lys Met Lys Arg Gly Leu Arg Arg I12 Ile Val His Glu Lys Tyr Lys His Pro Ser His Asp Tyr Asp Ile Ser Leu Ala Glu Leu Ser Ser Pro Val Pro Tyr Thr Asn Ala Val His Arg Val Cys Leu Pro Asp Ala Ser Tyr Glu Phe Gln Pro Giy Asp Val Met Phe Val Thr Gly PCT-uS00-23328_Sequence Phe Gly Ala Leu Lys Asn Asp Gly Tyr Ser Gln A,sn His Leu Arg Gln Ala Gln Val Thr Leu Ile Asp Ala Thr Thr Cys Asn.Glu Pro Gln Ala Tyr Asn Asp Ala Ile Thr Pro Arg Met Leu Cys Ala Gly Ser Leu Glu Gly Lys Thr Asp Ala Cys Gln Gly Asp Ser Gly Gly Pro Leu val ser Ser Asp Ala Arg Asp Ile Trp Tyr Leu Ala Gly Ile Val Ser Trp Gly Asp Glu Cys Ala Lys Pro Asn Lys Pro Gly Val Tyr Thr Arg Vai Thr Ala Leu Arg Asp Trp Ile Thr Ser Lys Thr Gly Ile <210> 107 <21I> 2397 <212> DNA
<213> Homo Sapien <400> 107 agagaaagaa gcgtctccag ctgaagccaa tgcagccctc cggctctccg 50 cgaagaagtt ccctgccccg atgagccccc gccgtgcgtc cccgactatc 100 cccaggcggg cgtggggcac cgggcccagc gccgacgatc gctgccgttt 150 tgcccttggg agtaggatgt ggtgaaagga tggggcttct cccttacggg 200 gctcacaatg gccagagaag attccgtgaa gtgtctgcgc tgcctgctct 250 acgccctcaa tctgctcttt tggttaatgt ccatcagtgt gttggcagtt 300 tctgcttgga tgagggacta cctaaataat gttctcactt taactgcaga 350 aacgagggta gaggaagcag tcattttgac ttactttcct gtggttcatc 400 cggtcatgat tgctgtttgc tgtttcctta tcattgtggg gatgttagga 450 tattgtggaa cggtgaaaag aaatctgttg cttcttgcat ggtactttgg 500 aagtttgctt gtcattttct gtgtagaact ggcttgtggc gtttggacat 550 atgaacagga acttatggtt ccagtacaat ggtcagatat ggtcactttg 600 aaagccagga tgacaaatta tggattacct agatatcggt ggcttactca 650 tgcttggaat ttttttcaga gagagtttaa gtgctgtgga gtagtatatt 700 tcactgactg gttggaaatg acagagatgg actggccccc agattcctgc 750 tgtgttagag aattcccagg atgttccaaa caggcccacc aggaagatct 800 PCT-u500-23328_sequence cagtgacctt tatcaagagg gttgtgggaa gaaaatgtat tcctttttga 850 gaggaaccaa acaactgcag gtgctgaggt ttctgggaat ctccattggg 900 gtgacacaaa tcctggccat gattctcacc attactctgc tctgggctct 950 gtattatgat agaagggagc ctgggacaga ccaaatgatg tccttgaaga 1000 atgacaactc tcagcacctg tcatgtccct cagtagaact gttgaaacca 1050 agcctgtcaa gaatctttga acacacatcc atggcaaaca gctttaatac 1100 acactttgag atggaggagt tataaaaaga aatgtcacag aagaaaacca 1150 caaacttgtt ttattggact tgtgaatttt tgagtacata ctatgtgttt 1200 cagaaatatg tagaaataaa aatgttgcca taaaataaca cctaagcata 1250 tactattcta tgctttaaaa tgaggatgga aaagtttcat gtcataagtc 1300 accacctgga caataattga tgcccttaaa atgctgaag~ cagatgtcat 1350 acccactgtg tagcctgtgt atgactttta ctgaacacag ttatgttttg 1400 aggcagcatg gtttgattag catttccgca tccatgcaa~ cgagtcacat 1450 atggtgggac tggagccata gtaaaggttg atttacttct accaactagt 1500 atataaagta ctaattaaat gctaacatag gaagttagaa aatactaata 1550 acttttatta ctcagcgatc tattcttctg atgctaaata aattatatat 1600 cagaaaactt tcaatattgg tgactaccta aatgtgattt ttgctggtta 1650 ctaaaatatt cttaccactt aaaagagcaa gctaacacat tgtcttaagc 1700 tgatcaggga ttttttgtat ataagtctgt gttaaatctg tataattcag 1750 tcgatttcag ttctgataat gttaagaata accattatga aaaggaaaat 1800 ttgtcctgta tagcatcatt atttttagcc tttcctgtta ataaagcttt 1850 actattctgt cctgggctta tattacacat ataactgtta tttaaatact 1900 taaccactaa ttttgaaaat taccagtgtg atacatagga atcattattc 1950 agaatgtagt ctggtcttta ggaagtatta ataagaaaat ttgcacataa 2000 cttagttgat tcagaaagga cttgtatgct gtttttctcc caaatgaaga 2050 ctctttttga cactaaacac tttttaaaaa gcttatcttt gccttctcca 2100 aacaagaagc aatagtctcc aagtcaatat aaattctaca gaaaatagtg 2150 ttctttttct ccagaaaaat gcttgtgaga atcattaaaa catgtgacaa 2200 tttagagatt ctttgtttta tttcactgat taatatactg tggcaaatta 2250 cacagattat taaatttttt tacaagagta tagtatattt atttgaaatg 2300 ggaaaagtgc attttactgt attttgtgta ttttgtttat ttctcagaat 2350 atggaaagaa aattaaaatg tgtcaataaa tattttctag agagtaa 2397 .... _. ,. ...,..__ V ....._"., ,.. ye r . ~..vdMtdk~3~~ ~-?n R ~ ~ t~n ~ ,-.-.., w . .. _~ ..__...,. , ...",..wa"",K. ~ ~y,.~.y. .
~'M1~~~iy~,wn~~.~nwvww~.,.. r~.ennn...~. -- . . ..... . .._..

PCT-uS00-23328_Sequence <210> 108 <211> 305 <212> PRT
<213> Homo Sapien <400> 108 Met Ala Arg Glu Asp Ser Val Lys Cys Leu Arg Cys Leu Leu Tyr Ala Leu Asn Leu Leu Phe Trp Leu Met Ser Ile Ser Val Leu ala Val Ser Ala Trp Met Arg Asp Tyr Leu Asn Asn Val Leu Thr Leu Thr Ala Glu Thr Arg Val Glu Glu Ala Val Ile Leu Thr Tyr Phe Pro Val Val His Pro Val Met Ile Ala Val Cys Cys Phe Leu Ile Ile Val Gly Met Leu Gly Tyr Cys Gly Thr Vai Lys Arg Asn Leu Leu Leu Leu Ala Trp Tyr Phe Gly Ser Leu Leu Vai Ile Phe Cys Val Glu Leu Ala Cys Gly Val Trp Thr Tyr Glu Gln Glu Leu Met Val Pro Val Gln Trp Ser Asp Met Val Thr Leu Lys Ala Arg Met Thr Asn Tyr Gly Leu Pro Arg Tyr Arg Trp Leu Thr His A1a Trp 140 i45 150 Asn Phe Phe Gln Arg Glu Phe Lys Cys Cys Gly Val Val Tyr Phe Thr Asp Trp Leu Glu Met Thr Glu Met Asp Trp Pro Pro Asp Ser Cys Cys Val Arg Glu Phe Pro Gly Cys Ser Lys Gln Ala His Gln Glu Asp Leu Ser Asp Leu Tyr Gln Glu Gly Cys Gly Lys Lys Met Tyr Ser Phe Leu Arg Gly Thr Lys Gln Leu Gln Val Leu Arg Phe Leu Gly Ile Ser Iie Gly Val Thr Gln Ile Leu Ala Met Ile Leu Thr Ile Thr Leu Leu Trp Ala Leu Tyr Tyr Asp Arg Arg Glu Pro Gly Thr Asp Gln Met Met Ser Leu LyS Asn Asp ASn Ser Gln His Leu Ser Cys Pro Ser Val Glu Leu Leu Lys Pro Ser Leu Ser Arg PCT-us00-23328_Sequence Ile Phe Glu His Thr Ser Met Ala Asn Ser Phe Asn Thr His Phe Glu Met Glu Glu Leu <210> 109 <211> 2339 <212> DNA
<213> Homo Sapien <400> 109 ccaaggccag agctgtggac accttatccc actcatcctc atcctcttcc 50 tctgataaag cccctaccag tgctgataaa gtctttctcg tgagagccta 100 gaggccttaa aaaaaaaagt gcttgaaaga gaaggggaca aaggaacacc 150 agtattaaga ggattttcca gtgtttctgg cagttggtcc agaaggatgc 200 ctccattcct gcttctcacc tgcctcttca tcacaggcac ctccgtgtca 250 cccgtggccc tagatccttg ttctgcttac atcagcctga atgagccctg 300 gaggaacact gaccaccagt tggatgagtc tcaaggtcct cctctatgtg 350 acaaccatgt gaatggggag tggtaccact tcacgggcat ggcgggagat 400 gccatgccta ccttctgcat accagaaaac cactgtggaa cccacgcacc 450 tgtctggctc aatggcagcc accccctaga aggcgacggc attgtgcaac 500 gccaggcttg tgccagcttc aatgggaact gctgtctctg gaacaccacg 550 gtggaagtca aggcttgccc tggaggctac tatgtgtatc gtctgaccaa 600 gcccagcgtc tgcttccacg tctactgtgg tcatttttat gacatctgcg 650 acgaggactg ccatggcagc tgctcagata ccagcgagtg cacatgcgct 700 ccaggaactg tgctaggccc tgacaggcag acatgctttg atgaaaatga 750 atgtgagcaa aacaacggtg gctgcagtga gatctgtgtg aacctcaaaa 800 actcctaccg ctgtgagtgt ggggttggcc gtgtgctaag aagtgatggc 850 aagacttgtg aagacgttga aggatgccac aataacaatg gtggctgcag 900 ccactcttgc cttggatctg agaaaggcta ccagtgtgaa tgtccccggg 950 gcctggtgct gtctgaggat aaccacactt gccaagtccc tgtgttgtgc 1000 aaatcaaatg ccattgaagt gaacatcccc agggagctgg ttggtggcct 1050 ggagctcttc ctgaccaaca cctcctgccg aggagtgtcc aacggcaccc 1100 atgtcaacat cctcttctct ctcaagacat gtggtacagt ggtcgatgtg 1150 gtgaatgaea agattgtggc cagcaacetc gtgacaggtc tacccaagca 1200 gaccccgggg agcagcgggg acttcatcat ccgaaccagc aagctgctga 1250 PCT-u500-23328_Sequence tcccggtgac ctgcgagttt ccacgcctgt acaccatttc tgaaggatac 1300 gttcccaacc ttcgaaactc cccactggaa atcatgagcc gaaatcatgg 1350 gatcttccca ttcactctgg agatcttcaa ggacaatgag tttgaagagc 1400 cttaccggga agctctgccc accctcaagc ttcgtgactc cctctacttt 1450 ggcattgagc ccgtggtgca cgtgagcggc ttggaaagct tggtggagag 1500 ctgctttgcc acccccacct ccaagatcga cgaggtcctg aaatactacc 1S~50 tcatccggga tggctgtgtt tcagatgact cggtaaagca gtacacatcc 1600 cgggatcacc tagcaaagca cttccaggtc cctgtcttca agtttgtggg 1650 caaagaccac aaggaagtgt ttctgcactg ccgggttctt gtctgtggag 1700 tgttggacga gcgttcccgc tgtgcccagg gttgccaccg gcgaatgcgt 1750 cgtggggcag gaggagagga ctcagccggt ctacagggcc agacgctaac 1800 aggcggcccg atccgcatcg actgggagga ctagttcgta gccatacctc 1850 gagtccctgc attggacggc tctgctcttt ggagcttctc cccccaccgc 1900 cctctaagaa catctgccaa cagctgggtt cagacttcac actgtgagtt 1950 cagactccca gcaccaactc actctgattc tggtccattc agtgggcaca 2000 ggtcacagca ctgctgaaca atgtggcctg ggtggggttt catctttcta 2050 gggttgaaaa ctaaactgtc cacccagaaa gacactcacc ccatttccct 2100 catttctttc ctacacttaa atacctcgtg tatggtgcaa tcagaccaca 2150 aaatcagaag ctgggtataa tatttcaagt tacaaaccct agaaaaatta 2200 aacagttact gaaattatga cttaaatacc caatgactcc ttaaatatgt 2250 aaattatagt tataccttga aatttcaatt caaatgcaga ctaattatag 2300 ggaatttgga agtgtatcaa taaaacagta tataatttt 2339 <210> 110 <211> 545 <212> PRT
<213> Homo Sapien <400> 110 Met Pro Pro Phe Leu Leu Leu Thr Cys Leu Phe Ile Thr Gly Thr ser val Ser Pro val Ala Leu Asp Pro Cys Ser° Ala Tyr Ile ser Leu Asn Glu Pro Trp Arg Asn Thr Asp His Gln Leu Asp Glu Ser Gln Gly Pro Pro Leu Cys ASp Asn His Val Asn Gly Glu Trp Tyr His Phe Thr Gly Met Ala Gly Asp Ala Met PrO Thr Phe Cys Ile A ..sit. S . >'°° W.

PCT-US00-23328_Sequence Pro Glu Asn His Cys Giy Thr His Ala Pro Val Trp Leu Asn Gly Ser His Pro Leu Glu Gly Asp Gly Ile Val G1n Arg Gln Ala Cys Ala Ser Phe Asn Gly Asn Cys Cys Leu Trp Asn Thr Thr Val Glu Val Lys Ala Cys Pro Gly Gly Tyr Tyr Val Tyr Arg Leu Thr Lys Pro Ser Val Cys Phe His Val Tyr Cys Gly His Phe Tyr Asp Ile Cys Asp Glu Asp Cys His Gly Ser Cys Ser Asp Thr Ser Glu Cys Thr Cys Ala Pro Gly Thr Val Leu Gly Pro Asp Arg Gln Thr Cys Phe Asp Glu Asn Glu Cys Glu Gln Asn Asn Gly Gly Cys Ser Glu Iie Cys Val Asn Leu Lys Asn Ser Tyr Arg Cys Glu Cys Gly Val Gly Arg Val Leu Arg Ser Asp Gly Lys Thr Cys Glu Asp Val Glu 215 zzo 225 Gly Cys His Asn Asn Asn Gly Gly Cys Ser His Ser Cys Leu Gly Ser Glu Lys G1y Tyr Gln Cys Glu Cys Pro Arg Gly Leu Val Leu Ser Glu Asp Asn His Thr Cys Gln Val Pro Val Leu Cys Lys Ser Asn Ala Ile Glu Val Asn Ile Pro Arg Glu Leu Val Gly Gly Leu Glu Leu Phe Leu Thr Asn Thr Ser Cys Arg Gly Val Ser Asn Gly Thr His Val Asn Ile Leu Phe Ser Leu Lys Thr Cys Gly Thr Val Val Asp Val Val Asn Asp Lys Ile Val Ala Ser Asn Leu Val Thr Gly Leu Pro Lys Gln Thr Pro Gly Ser Ser Gly Asp Phe Ile Ile Arg Thr Ser Lys Leu Leu Ile Pro Val Thr Cys Glu Phe Pro Arg Leu Tyr Thr Ile Ser Glu Gly Tyr Val Pro Asn Leu Arg Asn Ser Pro Leu Glu Ile htet Ser Arg Asn His Gly Iie Phe Pro Phe Thr Page I41 PCT-uS00-23328_Sequence Leu Glu Ile Phe Lys Asp Asn Glu Phe Glu Glu Pro Tyr Arg Glu Ala Leu Pro Thr Leu Lys Leu Arg Asp Ser Leu Tyr Phe Gly Ile Glu Pro Val VaT His Val Ser Gly Leu Glu Ser Leu Val Glu Ser Cys Phe Ala Thr Pro Thr Ser Lys Ile Asp Glu Val Leu Lys Tyr Tyr Leu Ile Arg Asp Gly Cys Val Ser Asp Asp Ser val Lys Gln Tyr Thr Ser Arg Asp His Leu Ala Lys His Phe Gln Val Pro Val Phe Lys Phe Val Gly Lys Asp His Lys Glu Val Phe Leu His Cys Arg Val Leu Val Cys Gly Val Leu Asp Glu Arg Ser Arg Cys Ala Gln Gly Cys His Arg Arg Net Arg Arg Gly Ala Gly Gly Glu Asp Ser Ala Gly Leu Gln Gly Gln Thr Leu Thr Gly Gly Pro Ile Arg Ile Asp Trp Glu Asp <210> 111 <211> 2053 <212> DNA
<Z13> Homo Sapien <400> 111 gagagaggca gcagcttgct cagcggacaa ggatgctggg cgtgagggac 50 caaggcctgc cctgcactcg ggcctcctcc agccagtgcit gaccagggac 100 ttctgacctg ctggccagcc aggacctgtg tggggaggcc ctcctgctgc 150 cttggggtga caatctcagc tccaggctac agggagaccg ggaggatcac 200 agagccagca tgttacagga tcctgacagt gatcaacctc tgaacagcct 250 cgatgtcaaa cccctgcgca aaccccgtat ccccatggag accttcagaa 300 aggtggggat ccccatcatc atagcactac tgagcctggc gagtatcatc 350 attgtggttg tcctcatcaa ggtgattctg gataaatact acttcctctg 400 cgggcagcct ctccacttca tcccgaggaa gcagctgtgt gacggagagc 450 tggactgtcc cttgggggag gacgaggagc actgtgtcaa gagcttcccc 500 gaagggcctg cagtggcagt ccgcctctcc aaggaccgat ccacactgca 550 PCT-u500-23328_5equence ggtgctggac tcggccacag ggaactggtt ctctgcctgt ttcgacaact 600 tcacagaagc tctcgctgag acagcctgta ggcagatggg ctacagcaga 650 gctgtggaga ttggcccaga ccaggatctg gatgttgttg aaatcacaga 700 aaacagccag gagcttcgca tgcggaactc aagtgggccc tgtctctcag 750 gctccctggt ctccctgcac tgtcttgcct gtgggaagag cctgaagacc 800 ccccgtgtgg tgggtgggga ggaggcctct gtggattctt ggccttggca 85-0 ggtcagcatc cagtacgaca aacagcacgt ctgtggaggg agcatcctgg 900 acccccactg ggtcctcacg gcagcccact gcttcaggaa acataccgat 950 gtgttcaact ggaaggtgcg ggcaggctca gacaaactgg gcagcttccc 1000 atccctggct gtggccaaga tcatcatcat tgaattcaac cccatgtacc 1050 ccaaagacaa tgacatcgcc ctcatgaagc tgcagttccc actcactttc 1100 tcaggcacag tcaggcccat ctgtctgccc ttctttgatg aggagctcac 1150 tccagccacc ccactctgga tcattggatg gggctttacg aagcagaatg 1200 gagggaagat gtctgacata ctgctgcagg cgtcagtcca ggtcattgac 1250 agcacacggt gcaatgcaga cgatgcgtac cagggggaag tcaccgagaa 1300 gatgatgtgt gcaggcatcc cggaaggggg tgtggacacc tgccagggtg 1350 acagtggtgg gcccctgatg taccaatctg accagtggca tgtggtgggc 1400 atcgttagct ggggctatgg ctgcgggggc ccgagcaccc caggagtata 1450 caccaaggtc tcagcctatc tcaactggat ctacaatgtc tggaaggctg 1500 agctgtaatg ctgctgcccc tttgcagtgc tgggagccgc ttccttcctg 1550 ccctgcccac ctggggatcc cccaaagtca gacacagagc aagagtcccc 1600 ttgggtacac ccctctgccc acagcctcag catttcttgg agcagcaaag 1650 ggcctcaatt cctgtaagag accctcgcag cccagaggcg cccagaggaa 1700 gtcagcagcc ctagctcggc cacacttggt gctcccagca tcccagggag 1750 agacacagcc cactgaacaa ggtctcaggg gtattgctaa gccaagaagg 1800 aactttccca cactactgaa tggaagcagg ctgtcttgta aaagcccaga 1850 tcactgtggg ctggagagga gaaggaaagg gtctgcgcca gccctgtccg 1900 tcttcaccca tccccaagcc tactagagca agaaaccagt tgtaatataa 1950 aatgcactgc cctactgttg gtatgactac cgttacctac tgttgtcatt 2000 gttattacag ctatggccac tattattaaa gagctgtgta acatctctgg 2050 caaaaaaaaa aaa 2063 <210> 112 PCT-uS00-23328_Sequence <211> 432 <212> PRT
<213> Homo Sapien <400> 112 Met Leu Gln Asp Pro Asp Ser Asp Gln Pro Leu Asn Ser Leu Asp Val Lys Pro Leu Arg Lys Pro Arg Ile Pro Met Glu Thr Phe Arg Lys Val Gly Ile Pro Ile Ile Ile Ala Leu Leu Ser Leu Ala Ser Ile Ile Ile Val Val Val Leu Ile Lys Val Ile Leu Asp Lys Tyr Tyr Phe Leu Cys Gly Gln Pro Leu His Phe Ile Pro Arg Lys Gln Leu Cys Asp Gly Glu Leu Asp Cys Pro Leu Gly Glu Asp Glu Glu His Cys Val Lys Ser Phe Pro Glu Gly Pro Ala Val Ala Val Arg Leu Ser Lys Asp Arg Ser Thr Leu Gln Val Leu Asp Ser Ala Thr Gly Asn Trp Phe Ser Ala Cys Phe Asp Asn Phe Thr Glu Ala Leu 12 5 130 13 5' Ala Glu Thr Ala cys Arg Gln Met Gly Tyr ser Arg Ala Val Glu Ile Gly Pro Asp Gln Asp Leu Asp Val Val Glu Ile Thr Glu Asn Ser Gln Glu Leu Arg Met Arg Asn Ser Ser Gly Pro Cys Leu Ser Gly Ser Leu Val Ser Leu His Cys Leu Ala Cys Gly Lys Ser Leu Lys Thr Pro Arg Val Val Gly Gly Glu Glu Ala Ser Val Asp Ser Trp Pro Trp Gln Val Ser Ile Gln Tyr Asp Lys Gln His Val Cys Gly Gly Ser Ile Leu Asp Pro His Trp Val Leu Thr Ala Ala His Cys Phe Arg LyS His Thr Asp Val Phe Asn Trp Lys Val Arg Ala Gly Ser Asp Lys Leu Gly Ser Phe Pro Ser Leu Ala Val Ala Lys Ile Ile Ile Ile Glu Phe Asn Pro Met Tyr Pro Lys Asp Asn Asp Ile Ala Leu Met Lys Leu Gln Phe Pro Leu Thr Phe Ser Gly Thr PCT-0500-2332$ Sequence ValArgPro IleCysLeu ProPhe PheAspGlu GluLeuThr Pro AlaThrPro Leu3z~Ile I12Gly TrpGlyPhe ThrLysGln Asn GlyGlyLys MetSerAsp IleLeu LeuGlnAla SerValGln Val IleAspSer ThrArgCys AsnAla AspAspAla TyrGlnGly Glu valThrGlu LysMetMet CysAla GlyIlePro GluGlyGly Val AspThrCys GlnGlyAsp SerGly GlyProLeu MetTyrGln Ser AspGlnTrp HisValVal GlyIle ValSerTrp GlyTyrGly Cys GlyGlyPro SerThrPro GlyVal TyrThrLys ValSerAla Tyr LeuAsnTrp I12TyrAsn ValTrp LysAlaGlu Leu <210> 113 <211> 1768 ' <212> DNA
<213> Homo Sapien <400> 113 ggctggactg gaactcctgg tcccaagtga tccacccgcc tcagcctccc 50 aaggtgctgt gattataggt gtaagccacc gtgtctggcc tctgaacaac 100 tttttcagca actaaaaaag ccacaggagt tgaactgcta ggattctgac 150 tatgctgtgg tggctagtgc tcctactcct acctacatta aaatctgttt 200 tttgttctct tgtaaetagc ctttaccttc ctaacacaga ggatctgtca 250 ctgtggctct ggcccaaacc tgaccttcac tctggaacga gaacagaggt 300 ttctacccac accgtcccct cgaagccggg gacagcctca ccttgctggc 350 ctctcgctgg agcagtgccc tcaecaactg tctcacgtct ggaggcactg 400 actcgggcag tgcaggtagc tgagcctctt ggtagctgcg gctttcaagg 450 tgggccttgc cctggccgta gaagggattg acaagcccga agatttcata S00 ggcgatggct cccactgccc aggcatcagc cttgctgtag tcaatcactg 550 ccctggggcc aggacgggcc gtggacacct gctcagaagc agtgggtgag 600 acatcacgct gcccgcccat ctaacctttt catgtcctgc acatcacctg 650 atccatgggc taatctgaac tctgtcccaa ggaacccaga gcttgagtga 700 PCT-U500-23328_Sequence gctgtggctc agacccagaa ggggtctgct tagaccacct ggtttatgtg 750 acaggacttg cattctcctg gaacatgagg gaacgccgga ggaaagcaaa 800 gtggcaggga aggaacttgt gccaaattat gggtcagaaa agatggaggt 850 gttgggttat cacaaggcat cgagtctcct gcattcagtg gacatgtggg 900 ggaagggctg ccgatggcgc atgacacact cgggactcac ctctggggcc 950 atcagacagc cgtttccgcc ccgatccacg taccagctgc tgaagggcaa 1000 ctgcaggccg atgctctcat cagccaggca gcagccaaaa tctgcgatca 1050 ccagccaggg gcagccgtct gggaaggagc aagcaaagtg accatttctc 1100 ctcccctcct tccctctgag aggccctcct atgtecctac taaagccacc 1150 agcaagacat agctgacagg ggctaatggc tcagtgttgg cccaggaggt 1200 cagcaaggcc tgagagctga tcagaagggc ctgctgtgcg aacacggaaa 1250 tgcctccagt aagcacaggc tgcaaaatcc ccaggcaaag gactgtgtgg 1.300 ctcaatttaa atcatgttct agtaattgga gctgtcccca agaccaaagg 1350 agctagagct tggttcaaat gatctccaag ggcccttata ccccaggaga 1400 ctttgatttg aatttgaaac cccaaatcca aacctaagaa ccaggtgcat 1450 taagaatcag ttattgccgg gtgtggtggc ctgtaatgcc aacattttgg 1500 gaggccgagg cgggtagatc acctgaggtc aggagttcaa gaccagcctg 1550 gccaacatgg tgaaacccct gtctctacta aaaatacaaa aaaactagcc 1600 aggcatggtg gtgtgtgcct gtatcccagc tactcgggag gctgagacag 1650 gagaattact tgaacctggg aggtgaagga ggctgagaca ggagaatcac 1700 tteagcetga geaacaeagc gagaetctgt etcagaaaaa ataaaaaaag 1750 aattatggtt atttgtaa 1768 <210> 114 <211> 109 <212> PRT
<213> Homo Sapien <400> 114 Met Leu Trp Trp Leu Val Leu Leu Leu Leu Pro Thr Leu Lys Ser Val Phe Cys Ser Leu Val Thr Ser Leu Tyr Leu Pro Asn Thr Glu Asp Leu Ser Leu Trp l.eu Trp Pro Lys Pro Asp Leu His Ser Gly Thr Arg Thr Glu Va1 Ser Thr His Thr Val Pro Ser Lys Pro Gly Thr Ala Ser Pro Cys Trp Pro Leu Ala Gly Ala Val Pro Ser Pro PCT-uS00-23328_Sequence Thr val Ser Arg ~eu Glu Ala ~eu Thr Arg Ala val Gln val Ala Glu Pro Leu Gly Ser Cys Gly Phe Gln Gly Gly Pro Cys Pro Gly g5 100 105 Arg Arg Arg Asp <210> 115 <211> 1197 <212> DNA
<213> Homo Sapien <400> 115 cagcagtggt ctctcagtcc tctcaaagca aggaaagagt actgtgtgct 50 gagagaccat ggcaaagaat cctccagaga attgtgaaga ctgtcacatt 100 ctaaatgcag aagcttttaa atccaagaaa atatgtaaat cacttaagat 150 ttgtggactg gtgtttggta tcctggccct aactctaatt gtcctgtttt 200 gggggagcaa gcacttctgg ccggaggtac ccaaaaaagc ctatgacatg 250 gagcacactt tctacagcaa tggagagaag aagaagattt acatggaaat 300 tgatcctgtg accagaactg aaatattcag aagcggaaat ggcactgatg 350 aaacattgga agtgcacgac tttaaaaacg gatacactgg catctacttc 400 gtgggtcttc aaaaatgttt tatcaaaact cagattaaag tgattcctga 450 attttctgaa ccagaagagg aaatagatga gaatgaagaa attaccacaa 500 ctttctttga acagtcagtg atttgggtcc cagcagaaaa gcctattgaa 550 aaccgagatt ttcttaaaaa ttccaaaatt ctggagattt gtgataacgt 600 gaccatgtat tggatcaatc ccactctaat atcagtttct gagttacaag 650 actttgagga ggagggagaa gatcttcact ttcctgccaa cgaaaaaaaa 700 gggattgaac aaaatgaaca gtgggtggtc cctcaagtga aagtagagaa 750 gacccgtcac gccagacaag caagtgagga agaacttcca ataaatgact 800.
atactgaaaa tggaatagaa tttgatccca tgctggatga gagaggttat 850 tgttgtattt actgccgtcg aggcaaccgc tattgccgcc gcgtctgtga 900 acctttacta ggctactacc catatccata ctgctaccaa. ggaggacgag 950 tcatctgtcg tgtcatcatg ccttgtaact ggtgggtggc ccgcatgctg 1000 gggagggtct aataggaggt ttgagctcaa atgcttaaac tgctggcaac 1050 atataataaa tgcatgctat tcaatgaatt tctgcctatg aggcatctgg 1100 cccctggtag ccagctctcc agaattactt gtaggtaatt cctctcttca 1150 PCT-0500-23328 Sequence tgttctaata aacttctaca ttatcaccaa aaaaaaaaaa aaaaaaa 1197 <210> 116 <211> 317 <212> PRT
<213> Homo Sapien <400> 116 Met Ala Lys Asn Pro Pro Glu Asn Cys Glu Asp Cys His Ile Leu Asn Ala Glu Ala Phe Lys Ser Lys Lys Ile Cys Lys Ser Leu Lys Ile Cys Gly Leu Val Phe Gly Ile Leu Ala Leu Thr Leu Ile Val Leu Phe Trp Gly Ser Lys His Phe Trp Pro Glu Val Pro Lys Lys Ala Tyr Asp Met Glu His Thr Phe Tyr Ser Asn Gly Glu Lys Lys Lys Ile Tyr Met Glu Ile Asp Pro Val Thr Arg Thr Glu Ile Phe Arg Ser Gly Asn Gly Thr Asp Glu Thr Leu Glu Val His Asp Phe Lys Asn Gly Tyr Thr Gly Ile Tyr Phe Val Gly Leu Gln Ly5 Cy5 Phe Ile Lys Thr Gln Ile Lys Val Ile Pro Glu Phe Ser Glu Pro Glu Glu Glu Ile Asp Glu Asn Glu Glu Ile Thr Thr Thr Phe Phe Glu Gln Ser Val Ile Trp Val Pro Ala Glu Lys Pro Ile Glu Asn Arg Asp Phe Leu Lys Asn Ser Lys Ile Leu Glu Ile Cys Asp Asn Val Thr Met Tyr Trp Ile Asn Pro Thr Leu I1<~ Ser Val Ser Glu Leu Gln Asp Phe Glu Giu Glu Gly Glu Asp Leu His Phe Pro Ala Asn Glu Lys Lys Gly Ile Glu Gln Asn Glu Gln Trp Val Val Pro Gln Val Lys Val Glu Lys Thr Arg His Ala Arg Gln Aia Ser Glu Glu Glu Leu Pro Ile Asn Asp Tyr Thr Glu Asn Gly Ile Glu Phe Asp Pro Met Leu Asp Glu Arg Gly Tyr Cys Cys Ile Tyr Cys Arg Arg Gly Asn Arg Tyr Cys Arg Arg val Cys Glu Pro Leu Leu Gly PCT-0500-23328_Sequence Tyr Tyr Pro Tyr Pro Tyr Cys Tyr Gln Gly Gly Arg Val Ile Cys Arg Val Ile Met Pro Cys Asn Trp Trp Val Ala Arg Met Leu Gly Arg val <210> 117 <211> 2121 <212> DNA
<213> Homo Sapien <400> 117 gagctcccct caggagcgcg ttagcttcac accttcggca gcaggagggc 50 ggcagcttct cgcaggcggc agggcgggcg gccaggatca tgtccaccac 100 cacatgccaa gtggtggcgt tectcctgtc catcctgggg ctggccggct 150 gcatcgcggc caccgggatg gacatgtgga gcacccagga cctgtacgac 200 aaccccgtca cctccgtgtt ccagtacgaa gggctctgga ggagctgcgt 250 gaggcagagt tcaggcttca ccgaatgcag gccctatttc accatcctgg 300 gacttccagc catgctgcag gcagtgcgag ccctgatgat cgtaggcatc 350 gtcctgggtg ccattggcct cctggtatcc atctttgccc tgaaatgcat 400 ccgcattggc agcatggagg actctgccaa agccaacatg acactgacct 450 ccgggatcat gttcattgtc tcaggtcttt gtgcaattgc tggagtgtct 500 gtgtttgcca acatgctggt gactaacttc tggatgtcca cagctaacat 550 gtacaccggc atgggtggga tggtgcagac tgttcagacc aggtacacat 600 ttggtgcggc tctgttcgtg ggctgggtcg ctggaggcct cacactaatt 650 gggggtgtga tgatgtgcat cgcctgccgg ggcctggcac cagaagaaac 700 caactacaaa gccgtttctt atcatgcctc aggccacagt gttgcctaca 750 agcctggagg cttcaaggcc agcactggct ttgggtccaa caccaaaaac 800 aagaagatat acgatggagg tgcccgcaca gaggacgagg tacaatctta 850 tccttccaag cacgactatg tgtaatgctc taagacctct cagcacgggc 900 ggaagaaact cccggagagc tcacccaaaa aacaaggag<~ tcccatctag 950 atttcttctt gcttttgact cacagctgga agttagaaaa gcctcgattt 1000 catctttgga gaggccaaat ggtcttagcc tcagtctctg tctctaaata 1050 ttccaccata aaacagctga gttatttatg aattagaggc tatagctcac 1100 attttcaatc ctctatttct ttttttaaat ataactttct actctgatga 1150 PCT-uS00-23328_Sequence gagaatgtgg ttttaatctc tctctcacat tttgatgatt tagacagact 1200 ccccctcttc ctcctagtca ataaacccat tgatgatcta tttcccagct 1250 tatccccaag aaaacttttg aaaggaaaga gtagacccaa agatgttatt 1300 ttctgctgtt tgaattttgt ctccccaccc ccaacttggc tagtaataaa 1350 cacttactga agaagaagca ataagagaaa gatatttgta atctctccag 1400 cccatgatct cggttttctt acactgtgat cttaaaagtt accaaaccaa 1450 agtcattttc agtttgaggc aaccaaacct ttctactgct gttgacatct 1500 tcttattaca gcaacaccat tctaggagtt tcctgagctc tccactggag 1550 tcctctttct gtcgcgggtc agaaattgtc cctagatgaa tgagaaaatt 1600 atttttttta atttaagtcc taaatatagt taaaataaat aatgttttag 1650 taaaatgata cactatctct gtgaaatagc ctcaccccta catgtggata 1700 gaaggaaatg aaaaaataat tgctttgaca ttgtctata.t ggtactttgt 1750 aaagtcatgc ttaagtacaa attccatgaa aagctcaca.c ctgtaatcct 1800 agcactttgg gaggctgagg aggaaggatc acttgagccc agaagttcga 1850 gactagcctg ggcaacatgg agaagccctg tctctacaaa atacagagag 1900 aaaaaatcag ccagtcatgg tggcatacac ctgtagtccc agcattccgg 1950 gaggctgagg tgggaggatc acttgagccc agggaggttg gggctgcagt 2000 gagccatgat cacaccactg cactccagcc aggtgacata gcgagatcct 2050 gtctaaaaaa ataaaaaata aataatggaa cacagcaagt cctaggaagt 2100 aggttaaaac taattcttta a 2121 <210> 118 <211.~ 261 <212> PRT
<213> Homo Sapien <400> 118 Met Ser Thr Thr Thr Cys Gln~Va1 Val Ala Phe Leu Leu Ser Ile Leu Gly Leu Ala Gly Cys Ile Ala Ala Thr Gly Met Asp Met Trp Ser Thr Gln Asp Leu Tyr Asp Asn Pro Val Thr Ser Val Phe Gln Tyr Glu Gly Leu Trp Arg Ser Cys val Arg Gln ser ser Gly Phe Thr Glu Cys Arg Pro Tyr Phe Thr Ile Leu Gly Leu Pro Ala Met 65 70 ~ 75 Leu Gln Ala Val A8~ Ala Leu Met Ile V85 Gl~r Ile Val Leu G90y PCT-u500-23328_Seguence Ala Ile Gly Leu Leu Val Ser Ile Phe Ala Leu Lys Cys Ile Arg Ile Gly Ser Met G1u Asp Ser Ala Lys Ala Asn Met Thr Leu Thr Ser Gly Ile Met Phe Ile Val Ser Gly Leu Cys Ala Ile Ala Gly Val Ser val Phe Ala Asn Met Leu val Thr Asn Phe Trp Met her Thr A1a Asn Met Tyr Thr Gly Met Gly Gly Met Val Gln Thr Val Gln Thr Arg Tyr Thr Phe Gly Ala Ala Leu Phe Val Gly Trp Val Ala Gly Gly Leu Thr Leu Ile G1y Gly Va1 Met Met Cys Ile Ala Cys Arg Gly Leu Ala Pro Glu Glu Thr Asn Tyr Lys Ala Val Ser 200 205 2i0 Tyr His Ala Ser Gly His 5er Val Ala Tyr Lys Pro Gly Gly Phe Lys Ala ser Thr Gly Phe Gly Ser Asn Thr Lys Asn Lys Lys Ile Tyr Asp Gly Gly Ala Arg Thr Glu ASp Glu Val Gln Ser Tyr Pro Ser Lys His Asp Tyr Val <210> 119 <211> 2010 <212> DNA
<213> Homo Sapien <400> 119 ggaaaaactg ttctcttctg tggcacagag aaccctgctt caaagcagaa 50 gtagcagttc cggagtccag ctggctaaaa ctcatcccag aggataatgg 100 caacccatgc cttagaaatc gctgggctgt ttcttggtgg tgttggaatg 150 gtgggcacag tggctgtcac tgtcatgcct cagtggagag tgtcggcctt 200 cattgaaaac aacatcgtgg tttttgaaaa cttctgggaa ggactgtgga 250 tgaattgcgt gaggcaggct aacatcagga tgcagtgcaa aatctatgat 300 tccctgctgg ctctttctcc ggacctacag gcagccagag gactgatgtg 350 tgctgcttcc gtgatgtcct tcttggcttt catgatggcc atccttggca 400 tgaaatgcac caggtgcacg ggggacaatg agaaggtgaa ggctcacatt 450 ctgctgacgg ctggaatcat cttcatcatc acgggcatgg tggtgctcat 500 PCT-US00-23328_Sequence ccctgtgagc tgggttgcca atgccatcat cagagatttc tataactcaa 550 tagtgaatgt tgcccaaaaa cgtgagcttg gagaagctct ctacttagga 600 tggaccacgg cactggtgct gattgttgga ggagctctgt tctgctgcgt 650 tttttgttgc aacgaaaaga gcagtagcta cagatactc:g ataccttccc 700 atcgcacaac ccaaaaaagt tatcacaccg gaaagaagtc accgagcgtc 750 tactccagaa gtcagtatgt gtagttgtgt atgttttttt aactttacta 800 taaagccatg caaatgacaa aaatctatat tactttctca aaatggaccc 850 caaagaaact ttgatttact gttcttaact gcctaatctt aattacagga 900 actgtgcatc agctatttat gattctataa gctatttcag cagaatgaga 950 tattaaaccc aatgctttga ttgttctaga aagtatagta atttgttttc 1000 taaggtggtt caagcatcta ctctttttat catttacttc aaaatgacat 1050 tgctaaagac tgcattattt tactactgta atttctccac gacatagcat 1100 tatgtacata gatgagtgta acatttatat ctcacataga gacatgctta 1150 tatggtttta tttaaaatga aatgccagtc cattacactg aataaataga 1200 actcaactat tgcttttcag ggaaatcatg gatagggttg aagaaggtta 1250 ctattaattg tttaaaaaca gcttagggat taatgtcctc catttataat 1300 gaagattaaa atgaaggctt taatcagcat tgtaaaggaa attgaatggc 1350 tttctgatat gctgtttttt agcctaggag ttagaaatcc taacttcttt 1400 atcctcttct cccagaggct ttttttttct tgtgtattaa attaacattt 1450 ttaaaacgca gatattttgt caaggggctt tgcattcaaa ctgcttttcc 1500 agggctatac tcagaagaaa gataaaagtg tgatctaaga aaaagtgatg 1550 gttttaggaa agtgaaaata tttttgtttt tgtatttgaa gaagaatgat 1600 gcattttgac aagaaatcat atatgtatgg atatatttta ataagtattt 1650 gagtacagac tttgaggttt catcaatata aataaaagag cagaaaaata 1700 tgtcttggtt ttcatttgct taccaaaaaa acaacaacaa aaaaagttgt 1750 cctttgagaa cttcacctgc tcctatgtgg gtacctgagt caaaattgtc 1800 atttttgttc tgtgaaaaat aaatttcctt cttgtaccat ttctgtttag 1850 ttttactaaa atctgtaaat actgtatttt tctgtttatt ccaaatttga 1900 tgaaactgac aatccaattt gaaagtttgt gtcgacgtct gtctagctta 1950 aatgaatgtg ttctatttgc tttatacatt tatattaata aattgtacat 2000 ttttctaatt 2010 <210> 120 PCT-0500-23328_Seguence <211> 225 <212> PRT
<213> Homo Sapien <400> 120 Met Ala Thr His Ala Leu Glu I12 Ala Gly Leu Phe Leu Gly Gly val Gly Met val Gly Thr val Ala val Thr val Met Pro Gln Trp Arg val Ser Ala Phe Ile Glu Asn Asn Ile val val Phe Glu Asn Phe Trp Glu Gly Leu Trp Met Asn Cys val Arg Gln Ala Asn Ile Arg Met Gln Cys Lys Ile Tyr Asp Ser Leu Leu Ala Leu Ser Pro Asp Leu Gln Ala Ala Arg Gly Leu Met Cys Ala Ala Ser val Met Ser Phe Leu Ala Phe Met Met Ala Ile Leu Gly Met Lys Cys Thr Arg Cys Thr Gly Asp Asn Glu Lys val Lys Ala His Ile Leu Leu Thr Ala Gly Ile Ile Phe Ile Ile Thr Giy Met val val Leu Ile Pro val Ser Trp val Ala Asn Ala Ile Ile Arg Asp Phe Tyr Asn Ser Ile val Asn val Ala Gln Lys Arg Glu Leu Gly Glu Ala Leu Tyr Leu Gly Trp Thr Thr Ala Leu val Leu Ile val Gly Gly Ala I7o 175 180 Leu Phe Cys Cys val Phe Cys Cys Asn Glu Lys Ser Ser Ser Tyr Arg Tyr Ser Ile Pro Ser His Arg Thr Thr Gln Lys Ser Tyr His Thr Gly Lys Lys Ser Pro Ser val Tyr Ser Ar~g Ser Gln Tyr val 215 220 . 225.
<210> 121 <211> 1257 <212> ~NA
<213> Homo Sapien <400> 121 ggagagaggc gcgcgggtga aaggcgcatt gatgcagcct gcggcggcct SO
cggagcgcgg cggagceaga cgctgaccac gttcctctcc tcggtctcct 100 ccgcctccag ctccgcgctg cccggcagcc gggagccatg cgaccccagg 150 gccccgccgc ctccccgcag cggctccgcg gcctcctgct gctcctgctg 200 ,.... oN,_ _~. . ~,.. " ~r ~~.~7.P~v~.~.a_~,~.~~~k..e..___ _ _ _ __.

PCT-U500-23328_Sequence ctgcagctgc ccgcgccgtc gagcgcctct gagatcccca aggggaagca 250 aaaggcgcag ctccggcaga gggaggtggt ggacctgtat.aatggaatgt 300 gcttacaagg gccagcagga gtgcctggtc gagacgggag ccctggggcc 350 aatgttattc cgggtacacc tgggatccca ggtcgggatg gattcaaagg 400 agaaaagggg gaatgtctga gggaaagctt tgaggagtcc tggacaccca 450 actacaagca gtgttcatgg agttcattga attatggcat agatcttggg 500 aaaattgcgg agtgtacatt tacaaagatg cgttcaaata gtgctctaag 550 agttttgttc agtggctcac ttcggctaaa atgcagaaat gcatgctgtc 600 agcgttggta tttcacattc aatggagctg aatgttcagg acctcttccc 650 attgaagcta taatttattt ggaccaagga agccctgaaa tgaattcaac 700 aattaatatt catcgcactt cttctgtgga aggactttgt gaaggaattg 750 gtgctggatt agtggatgtt gctatctggg ttggcactt:g ttcagattac 800 ccaaaaggag atgcttctac tggatggaat tcagtttctc gcatcattat 850 tgaagaacta ccaaaataaa tgctttaatt ttcatttgct acctcttttt 900 ttattatgcc ttggaatggt tcacttaaat gacattttaa ataagtttat 950 gtatacatct gaatgaaaag caaagctaaa tatgtttaca gaccaaagtg 1000 tgatttcaca ctgtttttaa atctagcatt attcatttt:g cttcaatcaa 1050 aagtggtttc aatatttttt ttagttggtt agaatacttt cttcatagtc 1100 acattctctc aacctataat ttggaatatt gttgtggtct tttgtttttt 1150 ctcttagtat agcattttta aaaaaatata aaagctacca atctttgtac 1200 aatttgtaaa tgttaagaat tttttttata tctgttaaat aaaaattatt 1250 tccaaca 1257 <210> 122 <211> 243 <212> PRT
<213> Homo Sapien <400> 122 Met Arg Pro Gln Gly Pro Ala Ala Ser Pro Gln Arg Leu Arg Gly Leu Leu Leu Leu Leu Leu Leu Gln Leu Pro Ala Pro Ser Ser Ala ser Glu Ile Pro Lys Gly Lys Gln Lys Ala Gln Leu Arg Gln Arg Glu val Val Asp Leu Tyr Asn Gly Met Cys Leu Gln Gly Pro Ala PCT-US00-23328_Sequence Gly Val Pro Gly Arg Asp Gly Ser Pro Gly Ala Asn Val Ile Pro Gly Thr Pro Gly Ile Pro Gly Arg Asp Gly Ph~e Lys Gly Glu Lys Gly Glu Cys Leu Arg Glu Ser Phe Glu Glu 5er Trp Thr Pro Asn Tyr Lys Gln Cys Ser Trp Ser Ser Leu Asn Tyr Gly Ile Asp Leu Gly Lys Ile Ala Glu Cys Thr Phe Thr Lys Met Arg Ser Asn Ser Ala Leu Arg Val Leu Phe Ser Gly Ser Leu Arg Leu Lys Cys Arg Asn Ala Cys Cys Gln Arg Trp Tyr Phe Thr Phe Asn Gly Ala Glu Cys Ser Gly Pro Leu Pro Ile Glu Ala Ile Ile Tyr Leu Asp Gln Gly Ser Pro Glu Met Asn Ser Thr IIe ASn Ile His Arg Thr Ser Ser val Glu Gly Leu Cys Glu Gly Ile Gly Ala Gly Leu val Asp Val Ala Ile Trp Val Gly Thr Cys Ser Asp Tyr Pro Lys Gly Asp z15 z2o 225 Ala Ser Thr Gly Trp Asn Ser Val Ser Arg Ile I12 Ile Glu Glu Leu Pro Lys <210> 123 <211> 2379 <212> flNA
<213> Homo Sapien <400> 123 gctgagcgtg tgcgcggtac ggggctctcc tgccttctgg gctccaacgc 50 agctctgtgg ctgaactggg tgctcatcac gggaactgct gggctatgga 100 atacagatgt ggcagctcag gtagceccaa attgcctgga agaatacatc 150 atgtttttcg ataagaagaa attgtaggat ccagtttttt ttttaaccgc 200 cccctcccca ccccccaaaa aaactgtaaa gatgcaaaaa cgtaatatcc 250 atgaagatcc tattacctag gaagattttg atgttttgct gcgaatgcgg 300 tgttgggatt tatttgttct tggagtgttc tgcgtggctg gcaaagaata 350 atgttccaaa atcggtccat ctcccaaggg gtccaatttt tcttcctggg 400 tgtcagcgag ccctgactca etacagtgca gctgacaggg gctgtcatgc 450 PcT-U500-23328_Sequence aactggcccc taagccaaag caaaagacct aaggacgacc tttgaacaat 500 acaaaggatg ggtttcaatg taattaggct actgagcgga tcagctgtag 550 cactggttat agcccccact gtcttactga caatgctttc ttctgccgaa 600 cgaggatgcc ctaagggctg taggtgtgaa ggcaaaatg.g tatattgtga 650 atctcagaaa ttacaggaga taccctcaag tatatctgct ggttgcttag 700 gtttgtccct tcgctataac agccttcaaa aacttaagta taatcaattt 7~0 aaagggctca accagctcac ctggctatac cttgaccata accatatcag 800 caatattgac gaaaatgctt ttaatggaat acgcagactc aaagagctga 850 ttcttagttc caatagaatc tcctattttc ttaacaatac cttcagacct 900 gtgacaaatt tacggaactt ggatctgtcc tataatcagc tgcattctct 950 gggatctgaa cagtttcggg gcttgcggaa gctgctgagt ttacatttac 1000 ggtctaactc cctgagaacc atccctgtgc gaatattcca agactgccgc 1050 aacctggaac ttttggacct gggatataac cggatccgaa gtttagccag 1100 gaatgtcttt gctggcatga tcagactcaa agaacttcac ctggagcaca 110 atcaattttc caagctcaac ctggcccttt ttccaaggtt ggtcagcctt 1200 cagaaccttt acttgcagtg gaataaaatc agtgtcatag gacagaccat 1250 gtcctggacc tggagctcct tacaaaggct tgatttatca ggcaatgaga 1300 tcgaagcttt cagtggaccc agtgttttcc agtgtgtccc gaatctgcag 1350 cgcctcaacc tggattccaa caagctcaca tttattggtc aagagatttt 1400 ggattcttgg atatccctca atgacatcag tcttgctggg aatatatggg 1450 aatgcagcag aaatatttgc tcc.cttgtaa actggctgaa aagttttaaa 1500 ggtctaaggg agaatacaat tatctgtgcc agtcccaaag agctgcaagg 1550 agtaaatgtg atcgatgcag tgaagaacta cagcatctgt ggcaaaagta 1600 ctacagagag gtttgatctg gccagggctc tcccaaagcc gacgtttaag 1650 cccaagctcc ccaggccgaa gcatgagagc aaaccccctt tgcccccgac 1700 ggtgggagcc acagagcccg gcccagagac cgatgctgac gccgagcaca 1750 tctctttcca taaaatcatc gcgggcagcg tggcgctttt cctgtccgtg 1800 ctcgtcatcc tgctggttat ctacgtgtca tggaagcggt accctgcgag 1850 catgaagcag ctgcagcagc gctccctcat gcgaaggcac aggaaaaaga 1900 aaagacagtc cctaaagcaa atgactccca gcacccagga attttatgta 1950 gattataaac ccaccaacac ggagaccagc gagatgctgc tgaatgggac 2000 gggaccctgc acctataaca aatcgggctc cagggagtgt gaggtatgaa 2050 PCT-US00-23328_Sequence ccattgtgat aaaaagagct cttaaaagct gggaaataag tggtgcttta 2100 ttgaactctg gtgactatca agggaacgcg atgccccccc tccccttccc 2150 tctccctctc actttggtgg caagatcctt ccttgtccgt tttagtgcat 2200 tcataatact ggtcattttc ctctcataca taatcaaccc attgaaattt 2250 aaataccaca atcaatgtga agcttgaact ccggtttaat ataataccta 2300 ttgtataaga ccctttactg attccattaa tgtcgcattt gttttaagat 2350 aaaacttctt tcataggtaa aaaaaaaaa 2379 <210> 124 <211> 513 <212> PRT
<213> Homo Sapien <400> 124 Met Gly Phe Asn Val Ile Arg Leu Leu Ser Gly Ser Ala Val Ala Leu Val Ile Ala Pro Thr Val Leu Leu Thr Met Leu Ser Ser Ala Glu Arg Gly Cys Pro Lys Gly Cys Arg Cys Glu Gly Lys Met Val Tyr Cys Glu Ser Gln Lys Leu Gln Glu Ile Pro Ser Ser Ile Ser Ala Gly Cys Leu Gly Leu Ser Leu Arg Tyr Asn Ser Leu Gln Lys Leu Lys Tyr Asn Gln Phe Lys Gly Leu Asn Gln Leu Thr Trp Leu Tyr Leu Asp His Asn His Ile Ser Asn Ile Asp Glu Asn Ala Phe Asn Gly Iie Arg Arg Leu Lys Glu Leu Ile Leu 5er Ser Asn Arg Ile Ser Tyr Phe Leu Asn Asn Thr Phe Arg Pro Val Thr Asn Leu Arg Asn Leu Asp Leu Ser Tyr Asn Gln Leu His Ser Leu Gly Ser Glu Gin Phe Arg Gly Leu Arg Lys Leu Leu Ser Leu His Leu Arg Ser Asn Ser Leu Arg Thr Ile Pro val Arg Ile Phe Gln Asp Cys Arg Asn Leu Glu Leu Leu Asp Leu Gly Tyr Asn Arg Ile Arg Ser Leu Ala Arg Asn Val Phe Ala Gly Met Ile Ar°g Leu Lys Glu Leu PCT-0500-23328_Sequence His Leu Glu His Asn Gln Phe Ser Lys Leu Asn Leu Ala Leu Phe ' 215 220 225 Pro Arg Leu Val Ser Leu Gln Asn Leu Tyr Leu Gln Trp Asn Lys Ile Ser Val Ile Gly Gln Thr Met Ser Trp Thr Trp Ser Ser Leu Gln Arg Leu Asp Leu Ser Gly Asn Glu Ile Glu Ala Phe Ser Gly Pro Ser Val Phe Gln Cys Val Pro Asn Leu Gln Arg Leu Asn Leu Asp Ser Asn Lys Leu Thr Phe Ile Gly Gln Glu Ile Leu Asp Ser Trp Ile Ser Leu Asn asp Ile Ser Leu Ala Gly Asn Ile Trp Glu Cys Ser Arg Asn Ile Cys Ser Leu Val Asn Trp Leu Ly5 Ser Phe Lys Gly Leu Arg Glu Asn Thr Ile Ile Cys Ala Ser Pro Lys Glu Leu Gln Gly Val Asn Val Ile Asp Ala Val Lys Asn Tyr Ser Ile Cys Gly Lys Ser Thr Thr Glu Arg Phe Asp Leu Ala Arg Ala Leu Pro Lys Pro Thr Phe Lys Pro Lys Leu Pro Arg Pro Lys His Glu Ser Lys Pro Pro Leu Pro Pro Thr Val Gly Ala Thr Glu Pro Giy Pro Glu Thr Asp A1a Asp Ala Glu His I1e Ser Phe His Lys Ile Ile Ala Gly ser val Ala Leu Phe Leu Ser val Leu Val Ile Leu Leu Val Ile Tyr Val Ser Trp Lys Arg Tyr Pro Ala Ser Met Lys Gln Leu Gin Gln Arg Ser Leu Met Arg Arg His Arg Lys Lys Lys Arg Gln Ser Leu Lys Gln Met Thr Pra Ser Thr Gln Glu Phe Tyr Val Asp Tyr Lys Pro Thr Asn Thr Glu Thr Ser Glu Met Leu Leu Asn Gly Thr Gly Pro Cys Thr Tyr Asn Lys Ser Gly Ser Arg Glu Cys Glu Val

Claims (17)

1. Isolated nucleic acid having at least 80% nucleic acid sequence identity to a nucleotide sequence that encodes the amino acid sequence shown in Figure 102 (SEQ
ID NO:102).

2.Isolated nucleic acid having at least 80% nucleic acid sequence identity to the nucleotide sequence shown in Figure 101 (SEQ ID NO:101).

3. Isolated nucleic acid having at least 80% nucleic acid sequence identity to the full-length coding sequence of the nucleotide sequence shown in Figure 101 (SEQ ID
NO:101).

4. A vector comprising the nucleic acid of Claim 1.

5. The vector of Claim 4 operably linked to control sequences recognized by a host cell transformed with the vector.

6. A host cell comprising the vector of Claim 4.

7. The host cell of Claim 6, wherein said cell is a CHO cell.

8. The host cell of Claim 6, wherein said cell is an E. coli.

9. The host cell of Claim 6, wherein said cell is a yeast cell.

10. A process for producing a PRO polypeptides comprising culturing the host cell of Claim 7 under conditions suitable for expression of said PRO polypeptide and recovering said PRO polypeptide from the cell culture.

11. An isolated polypeptide having at least 80 % amino acid sequence identity to the amino acid sequence shown in Figure 102 (SEQ ID NO:102).

12. A chimeric molecule comprising a polypeptide according to Claim 11 fused to a heterologous amino acid sequence.

13. The chimeric molecule of Claim 12, wherein said heterologous amino acid sequence is an epitope tag sequence.

14. The chimeric molecule of Claim 12, wherein said heterologous amino acid sequence is a Fc region of an immunoglobulin

15. A polyclonal antibody which specifically binds to a polypeptide according to Claim 11.

16. Isolated nucleic acid having at least 80 % nucleic acid sequence identity to:
(a) a nucleotide sequence encoding the polypeptide shown in Figure 102 (SEQ ID
NO:102), lacking its associated signal peptide;
(b) a nucleotide sequence encoding an extracellular domain of the polypeptide shown in Figure 102 (SEQ ID NO:102), with its associated signal peptide; or (c) a nucleotide sequence encoding an extracellular domain of the polypeptide shown in Figure 102 (SEQ ID NO:102), lacking its associated signal peptide.

17. An isolated polypeptide having at least 80% amino acid sequence identity to:
(a) an amino acid sequence of the polypeptide shown in Figure 102 (SEQ ID
NO:102), lacking its associated signal peptide;
(b) an amino acid sequence of an extracellular domain of the polypeptide shown in Figure 102 (SEQ ID NO:102), with its associated signal peptide; or (c) an amino acid sequence of an extracellular domain of the polypeptide shown in Figure 102 (SEQ ID NO:102), lacking its associated signal peptide.