CA2294526A1

CA2294526A1 - 86 human secreted proteins

Info

Publication number: CA2294526A1
Application number: CA002294526A
Authority: CA
Inventors: Paul A. Moore; Yanggu Shi; Craig A. Rosen; Steven M. Ruben; David W. Lafleur; Henrik S. Olsen; Reinhard Ebner; Laurie A. Brewer; Paul Young; John M. Greene; Ann M. Ferrie; Guo-Liang Yu; Jian Ni; Ping Feng
Original assignee: Individual
Current assignee: Human Genome Sciences Inc
Priority date: 1997-06-13
Filing date: 1998-06-11
Publication date: 1998-12-17
Also published as: WO1998056804A1

Abstract

The present invention relates to 86 novel human secreted proteins and isolated nucleic acids containing the coding regions of the genes encoding such proteins. Also provided are vectors, host cells, antibodies, and recombinant methods for producing human secreted proteins. The invention further relates to diagnostic and therapeutic methods useful for diagnosing and treating disorders related to these novel human secreted proteins.

Description

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86 Human Secreted Proteins Field of the Invention This invention relates to newly identified polynucleotides and the polypeptides encoded by these polynucleotides, uses of such polynucleotides and polypeptides, and their production.
Background of the Invention Unlike bacterium, which exist as a single compartment surrounded by a membrane, human cells and other eucaryotes are subdivided by membranes into many functionally distinct compartments. Each membrane-bounded compartment, or organelle, contains different proteins essential for the function of the organelle. The cell uses "sorting signals," which are amino acid motifs located within the protein, to target proteins to particular cellular organelles.
One type of sorting signal, called a signal sequence, a signal peptide, or a leader sequence, directs a class of proteins to an organelle called the endoplasmic reticulum (ER). The ER separates the membrane-bounded proteins from all other types of proteins. Once localized to the ER, both groups of proteins can be further directed to another organelle called the Golgi apparatus. Here, the Golgi distributes the proteins to vesicles, including secretory vesicles, the cell membrane, lysosomes, and the other organelles.
Proteins targeted to the ER by a signal sequence can be released into the extracellular space as a secreted protein. For example, vesicles containing secreted proteins can fuse with the cell membrane and release their contents into the extracellular space - a process called exocytosis. Exocytosis can occur constitutively or after receipt of a triggering signal. In the latter case, the proteins are stored in secretory vesicles (or secretory granules) until exocytosis is triggered. Similarly, proteins residing on the cell membrane can also be secreted into the extracellular space by proteolytic cleavage of a "linker" holding the protein to the membrane.
Despite the great progress made in recent years, only a small number of genes encoding human secreted proteins have been identified. These secreted proteins include the commercially valuable human insulin, interferon, Factor VIII, human growth hormone, tissue plasminogen activator, and erythropoeitin. Thus, in light of the pervasive role of secreted proteins in human physiology, a need exists for identifying and characterizing novel human secreted proteins and the genes that encode them. This knowledge will allow one to detect, to treat, and to prevent medical disorders by using secreted proteins or the genes that encode them.

Summary of the Invention The present invention relates to novel polynucleotides and the encoded polypeptides. Moreover, the present invention relates to vectors, host cells, antibodies, and recombinant methods for producing the polypeptides and polynucleotides.
Also provided are diagnostic methods for detecting disorders related to the polypeptides, and therapeutic methods for treating such disorders. The invention further relates to screening methods for identifying binding partners of the polypeptides.
Detailed Description Definitions The following definitions are provided to facilitate understanding of certain terms used throughout this specification.
In the present invention, "isolated" refers to material removed from its original environment (e.g., the natural environment if it is naturally occurring), and thus is altered "by the hand of man" from its natural state. For example, an isolated polynucleotide could be part of a vector or a composition of matter, or could be contained within a cell, and still be "isolated" because that vector, composition of matter, or particular cell is not the original environment of the polynucleotide.
In the present invention, a "secreted" protein refers to those proteins capable of being directed to the ER, secretory vesicles, or the extracellular space as a result of a signal sequence, as well as those proteins released into the extracellular space without necessarily containing a signal sequence. If the secreted protein is released into the extracellular space, the secreted protein can undergo extracellular processing to produce a "mature" protein. Release into the extracellular space can occur by many mechanisms, including exocytosis and proteolytic cleavage.
As used herein , a "polynucleotide" refers to a molecule having a nucleic acid sequence contained in SEQ ID NO:X or the cDNA contained within the clone deposited with the ATCC. For example, the polynucleotide can contain the nucleotide sequence of the full length cDNA sequence, including the 5' and 3' untranslated sequences, the coding region, with or without the signal sequence, the secreted protein coding region, as well as fragments, epitopes, domains, and variants of the nucleic acid sequence.
Moreover, as used herein, a "polypeptide" refers to a molecule having the translated amino acid sequence generated from the polynucleotide as broadly defined.
In the present invention, the full length sequence identified as SEQ ID NO:X
was often generated by overlapping sequences contained in multiple clones {contig analysis). A representative clone containing all or most of the sequence for SEQ ID
NO:X was deposited with the American Type Culture Collection ("ATCC"). As shown in Table 1, each clone is identified by a cDNA Clone ID (Identifier) and the ATCC Deposit Number. The ATCC is located at 10801 University Boulevard, Manassas, Virginia 20110-2209, USA. The ATCC deposit was made pursuant to the terms of the Budapest Treaty on the international recognition of the deposit of microorganisms for purposes of patent procedure.
A "polynucleotide" of the present invention also includes those polynucleotides capable of hybridizing, under stringent hybridization conditions, to sequences contained in SEQ ID NO:X, the complement thereof, or the cDNA within the clone deposited with the ATCC. "Stringent hybridization conditions" refers to an overnight incubation at 42°
C in a solution comprising 50% formamide, Sx SSC (750 mM NaCI, 75 mM sodium citrate), 50 mM sodium phosphate (pH 7.6), Sx Denhardt's solution, 10% dextran sulfate, and 20 pg/ml denatured, sheared salmon sperm DNA, followed by washing the filters in O.lx SSC at about 65°C.
Also contemplated are nucleic acid molecules that hybridize to the polynucleotides of the present invention at lower stringency hybridization conditions.
Changes in the stringency of hybridization and signal detection are primarily accomplished through the manipulation of formamide concentration (lower percentages of formamide result in lowered stringency); salt conditions, or temperature.
For example, lower stringency conditions include an overnight incubation at 37°C in a solution comprising 6X SSPE (20X SSPE = 3M NaCI; 0.2M NaH~P04; 0.02M EDTA, pH 7.4), 0.5% SDS, 30% formamide, 100 uglml salmon sperm blocking DNA;
followed by washes at 50°C with 1 XSSPE, 0.1 % SDS. In addition, to achieve even lower stringency, washes performed following stringent hybridization can be done at higher salt concentrations (e.g. SX SSC).
Note that variations in the above conditions may be accomplished through the inclusion and/or substitution of alternate blocking reagents used to suppress background in hybridization experiments. Typical blocking reagents include Denhardt's reagent, BLOTTO, heparin, denatured salmon sperm DNA, and commercially available proprietary formulations. The inclusion of specific blocking reagents may require modification of the hybridization conditions described above, due to problems with compatibility.
Of course, a polynucleotide which hybridizes only to polyA+ sequences (such as any 3' terminal polyA+ tract of a cDNA shown in the sequence listing), or to a complementary stretch of T (or U) residues, would not be included in the definition of "polynucleotide," since such a polynucleotide would hybridize to any nucleic acid molecule containing a poly (A) stretch or the complement thereof (e.g., practically any double-stranded cDNA clone).
The polynucleotide of the present invention can be composed of any polyribonucleotide or polydeoxribonucleotide, which may be unmodified RNA or DNA
or modified RNA or DNA. For example, polynucleotides can be composed of single-and double-stranded DNA, DNA that is a mixture of single- and double-stranded regions, single- and double-stranded RNA, and RNA that is mixture of single-and double-stranded regions, hybrid molecules comprising DNA and RNA that may be single-stranded or, more typically, double-stranded or a mixture of single-and double-stranded regions. In addition, the polynucleotide can be composed of triple-stranded regions comprising RNA or DNA or both RNA and DNA. A poIynucleotide may also contain one or more modified bases or DNA or RNA backbones modified for stability or for other reasons. "Modified" bases include, for example, tritylated bases and unusual bases such as inosine. A variety of modifications can be made to DNA
and RNA; thus, "polynucleotide" embraces chemically, enzymatically, or metabolically modified forms.
The polypeptide of the present invention can be composed of amino acids joined to each other by peptide bonds or modified peptide bonds, i.e., peptide isosteres, and may contain amino acids other than the 20 gene-encoded amino acids. The polypeptides may be modified by either natural processes, such as posttranslational processing, or by chemical modification techniques which are well known in the art.
Such modifications are well described in basic texts and in more detailed monographs, as well as in a voluminous research literature. Modifications can occur anywhere in a polypeptide, including the peptide backbone, the amino acid side-chains and the amino or carboxyl termini. It will be appreciated that the same type of modification may be present in the same or varying degrees at several sites in a given polypeptide. Also, a given polypeptide may contain many types of modifications. Polypeptides may be branched , for example, as a result of ubiquitination, and they may be cyclic, with or without branching. Cyclic, branched, and branched cyclic polypeptides may result from posttranslation natural processes or may be made by synthetic methods.
Modifications include acetylation, acylation, ADP-ribosylation, amidation, covalent attachment of flavin, covalent attachment of a heme moiety, covalent attachment of a nucleotide or nucleotide derivative, covalent attachment of a lipid or lipid derivative, covalent attachment of phosphotidylinositol, cross-linking, cyclization, disulfide bond formation, demethylation, formation of covalent cross-/inks, formation of cysteine, formation of pyroglutamate, formylation, gamma-carboxylation, glycosylation, GPI
anchor formation, hydroxylation, iodination, methylation, myristoylation, oxidation, pegylation, proteolytic processing, phosphorylation, prenylation, racemization, selenoylation, sulfation, transfer-RNA mediated addition of amino acids to proteins such as arginylation, and ubiquitination. (See, for instance, PROTEINS -STRUCTURE AND MOLECULAR PROPERTIES, 2nd Ed., T. E. Creighton, W.
H. Freeman and Company, New York (1993); POSTTRANSLATIONAL
COVALENT MODIFICATION OF PROTEINS, B. C. Johnson, Ed., Academic Press, New York, pgs. 1-12 (1983); Seifter et aL, Meth Enzymol 182:626-646 (1990);
Rattan et al., Ann NY Acad Sci 663:48-62 ( 1992).) "SEQ ID NO:X" refers to a polynucleotide sequence while "SEQ ID NO:Y"
refers to a polypeptide sequence, both sequences identified by an integer specified in Table 1.
"A polypeptide having biological activity" refers to polypeptides exhibiting activity similar, but not necessarily identical to> an activity of a polypeptide of the present invention, including mature forms, as measured in a particular biological assay, with or without dose dependency. In the case where dose dependency does exist, it need not be identical to that of the polypeptide, but rather substantially similar to the dose-dependence in a given activity as compared to the polypeptide of the present invention (i.e., the candidate polypeptide will exhibit greater activity or not more than about 25-fold less and, preferably, not more than about tenfold less activity, and most preferably, not more than about three-fold less activity relative to the polypeptide of the present invention.) Poiynucleotides and Po~pegtides of the Invention FEATURES OF PROTEIN ENCODED BY GENE NO: 1 The translation product of this gene shares sequence homology with LIM-homeobox domain proteins, such as T-cell translocation protein, which are thought to be important in development and leukemogenesis. In addition, translation product of this gene shares homology with the human breast tumor autoantigen (See Accession No. gi11914877). In one embodiment the polypeptides of the invention comprise the sequence:
MNGSHKDPLLPFPASARTPSLPPAPPAQAPLPWKPSGFARISPPPPLAILQYRG
KADHGESGQQLAAAPGDGRLPLLEAVRRLRGQDCGPLSALCHGQLLAQPVPQ
VLLLPGAXGDIGTSCYTKSGMILCRNDYIRLFGNSGACSACGQSIPASELVMRA
QGNVYHLKCFTCSTCRNRLVPGDRFHYINGSLFCEHDRPTALINGHLNSLQSN

PLLPDQKVCKVRVMQNACLHLRFVHHRWIPCXFSRQVTFVASTSASSMPLHLL
{SEQ ID N0:211 ); MARTRTPSSPFLLLRELPPSLQLRQPRRPFPGSRAASLAFHRR
RLSQYCNIGEKQTMVNPGSSSQPPPVTAGSLSWKRCAGCGGKIADRFLLYA
(SEQ ID N0:212); LFGNSGACSACGQSIPASELVMRA (SEQ ID N0:213);
HDRPTALINGHLNSLQSNP (SEQ ID N0:214); and/or LVPGDRFHYING (SEQ ID
N0:215 ). Polynucleotide fragments encoding these polypeptide fragments are also encompassed by the invention.
This gene is expressed primarily in fetal brain, osteosarcoma, IL-1/TNF
treated synovial, and estradiol treated endometrial stromal cells, and to a lesser extent in chondrosarcoma, smooth muscle and number of other tissues.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, developmental defects or leukemia. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the hematopoietic system and immune system, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types (e.g., brain and other tissue of the nervous system, bone ceps, synovial tissue, endometrial tissue and other reproductive tissue, cartilage cells, smooth muscle, and blood cells and cells and tissue of the immune system, and cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid or spinal fluid) or another tissue or cell sample or another tissue or cell sample or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid or bodily fluid or bodily fluid from an individual not having the disorder. Preferred epitopes include those comprising a sequence shown in SEQ ID NO. 111 as residues: Met-1 to Cys-9.
The tissue distribution and homology to the LIM-homeodomain containing proteins, such as T-cell translocation factor, indicates that polynucleotides and polypeptides corresponding to this gene are useful for diagnosis and intervention of leukemia and other developmental defects. Because of the importance of the LIM-homeodomain proteins in development and their correlation to number of leukemic diseases, the molecule can be either used as a diagnostic or prognostic indicator for leukemia progression or a therapeutic target. In addition, polynucleotides and polypeptides corresponding to this gene are useful for the detection/treatment of neurodegenerative disease states and behavioral disorders such as Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, schizophrenia, mania, dementia, paranoia, obsessive compulsive disorder, panic disorder, and autism. In addition, the gene or gene product may also play a role in the treatment and/or detection of developmental disorders associated with the developing embryo, sexually-linked disorders, or S disorders of the cardiovascular system. Furthermore, homology to the breast auto-antigen may suggest this gene is useful in the detection, prevention, and or treatment of breast cancer and/or other proliferative disorders.
FEATURES OF PROTEIN ENCODED BY GENE NO: 2 Translation product of gene has homology to a highly conserved member of the human calpain family of proteases, Calpain large subunit 1 gene (See Accession No.T32454). Calpains are thought to play a defining role in protein regulation, particularly during development. One embodiment for this gene is the polypeptide fragments comprising the following amino acid sequence:
MKYMGGCAKVMCKYYVILYQGLEYPLLXSGDPETSPPWILRADCIVLSSRNFH
SNXGRLTINKIYVIGGGKYRGEVTNGAK (SEQ ID N0:216);
MGQSELYSSILRNLGVLFLVYTRGGFLLSPLLHGTLTCAHS (SEQ ID N0:217);
MVLLLLTVASYTVFVVMIGDVLDILFLWNFEYTT'LY (SEQ ID N0:218);
MELYNSLCPICYFSTVLTTTYYIYFVYSQSSXIRMKVP (SEQ ID N0:219);
MQIVIVLYCVRNKDKKKVCTCSVQTQFFFPIFPILGCLNGCRTQE (SEQ ID
N0:220); MKYMGGCAKVMCKYYVILYQGLEYPLLX (SEQ ID N0:221);
LEYPLLXSGDPET SPPWILRADCIVLSSRNFHSNX (SEQ ID N0:222); andlor RNFHSNXGRLTINKIY VIGGGKYRGEVTNGAK (SEQ ID N0:223 ). An additional embodiment is the polynucleotide fragments encoding these polypeptide fragments.
This gene is expressed primarily in caudate nucleus, dermatofibrosarcoma protuberance and apoptotic T-cells, and to a lesser extent in eosinophils, brain and smooth muscle.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, neurodegenerative diseases or immune disorders. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the nervous system or immune system, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types (e.g., skin, T-cells and other blood cells and cells and tissue of the immune system, brain and other tissue of the nervous system, and smooth muscle, and cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid or spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
The tissue distribution in caudate nucleus and apoptic T-cells indicates that polynucleotides and polypeptides corresponding to this gene are useful for detection or intervention of neurodegenerative diseases and behavioral disorders such as Alzheimer's Disease, Parkinson's Disease, Huntington's disease, schizophrenia, mania, dementia, paranoia, obsessive compulsive disorder, panic disorder or immune disorders, because the elevated level of the molecule in cells undergoing cell death may be the cause or consequence of these degenerative conditions. In addition, the gene or gene product may also play a role in the treatment and/or detection of developmental disorders associated with the developing embryo, or disorders of the cardiovascular system.
FEATURES OF PROTEIN ENCODED BY GENE NO: 3 This gene maps to chromosome 15, and therefore, may be used as a marker in linkage analysis for chromosome 15. One embodiment for this gene is the polypeptide fragments comprising the following amino acid sequence: VTNEMSQGRGKYDFY

LSMGAGEVANFAAYAFAPATLVTPLGALSVLVSAILSSYFLNERLNLHGKIGCL
LSILG STVMVIHAPKEEEIETLNE (SEQ ID N0:224);
VTNEMSQGRGKYDFYIGLGLAMSSSIFIGGSFILKKKGLLRLARKGSMRAGQG
GHAYLKEWLWWAGLLSMGAGEVANF (SEQ ID N0:225);
NFAAYAFAPATLVTPLGALSVLVSAILSSY (SEQ ID N0:226 ); and/or ERLNLHGKIGCLLSILGSTVMVIHAPKEEEIETLNE (SEQ ID N0:227). An additional embodiment is the polynucleotide fragments encoding these polypeptide fragments This gene is expressed primarily in colon carcinoma cell line, and to a lesser extent in aorta endothelial cells, T-cells, human erythroleukemia cells (HEL), and stromal cells (TF274).
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, colon carcinoma. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of colon carcinoma tissues, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types (e.g., colon, aorta and other vascular tissue, T-cells and other cells and tissue of the immune system, and stromal cells, and cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid or spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder. Preferred epitopes include those comprising a sequence shown in SEQ ID NO. 113 as residues: Asn-191 to Ser-196, Asn-208 to Gly-214.
The tissue distribution in colon carcinoma indicates that polynucleotides and polypeptides corresponding to this gene are useful for detection and intervention of colon carcinoma and/or other tumors. Additionally the significant presence in T-cell populations may indicate the involvement of the function of the gene product in cancer immunosurveillance. Furthermore, the tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for the diagnosis and treatment of cancer and other proliferative disorders, in general. The expression in hematopoietic cells and tissues indicates that this protein may play a role in the proliferation, differentiation, and/or survival of hematopoietic cell lineages. Thus, this gene may be useful in the treatment of lymphoproliferative disorders, and in the maintenance and differentiation of various hematopoietic lineages from early hematopoietic stem and committed progenitor cells.
FEATURES OF PROTEIN ENCODED BY GENE NO: 4 This gene is expressed primarily in ovary.
Therefore, polynucleotides and poiypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, reproductive or endocrine disorders. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the reproductive or endocrine systems, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types (e.g., ovary and other reproductive tissue, and cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid or spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
Preferred epitopes include those comprising a sequence shown in SEQ ID NO. 114 as residues:

5 Pro-20 to Ser-25.
The tissue distribution in ovary indicates that polynucleotides and polypeptides corresponding to this gene are useful for assessing reproductive dysfunction or endocrine disorders, because factors secreted by ovary may be involved in reproductive processes, and in cases have global hormonal effects.
FEATURES OF PROTEIN ENCODED BY GENE NO: 5 This gene is expressed primarily in tissues in the central nervous system, including pineal gland, frontal cortex, and dura mater, and to a lesser extent in bladder, lung, T-cells and liver.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, neurodegenerative diseases, endocrine disorders, and immune disorders. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the nervous and endocrine systems, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types (e.g., tissue of the nervous system, bladder, lung, liver, and T-cells and other cells and tissues of the immune system, and cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid or spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder. Preferred epitopes include those comprising a sequence shown in SEQ
ID
NO. 115 as residues: Glu-14 to Arg-20.
The primary tissue distribution in the central nerve system indicates that polynucleotides and polypeptides corresponding to this gene are useful for the detection and intervention of neurodegenerative diseases or endocrinedisorders, because extracellular proteins in these tissues may function as a neurotrophic factor, a matrix protein for tissue integrity, a neuroguidance factor or as a hormone.

WO 98/56804 PCT/IlS98112125 FEATURES OF PROTEIN ENCODED BY GENE NO: 6 This gene is expressed primarily in spleen, resting T-cells, colorectal tumor and pancreatic carcinoma, and to a lesser extent in number of tissues including prostate, ' synovial hypoxia, osteosarcoma, ulcerative colitis, myeloid progenitor cells, lung and placenta.
~ Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, inflammation, immunosurveillance of cancers, and immune and gastrointestinal disorders. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly in carcinogenesis or the immune system, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types (e.g., prostate, synovial tissue, bone cells, colon, myeloid progenitor cells, lung, cells and tissue of the immune system, cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid or spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder. Preferred epitopes include those comprising a sequence shown in SEQ ID NO. 116 as residues: Arg-29 to Pro-37, GIn-46 to Val-56.
The primary tissue distribution in lymphatic tissues such as T-cells and spleen, as well as tumors and ulcerative tissues indicates that the protein product of this gene may be involved in the irrimuno response to or immunosurveillance of carcinogenesis and/or inflammatory conditions.
FEATURES OF PROTEIN ENCODED BY GENE NO: 7 The translation product of this gene shares very weak sequence homology with voltage dependent sodium channel protein and Bowman-Birk proteinassse inhibitor which is thought to be important in membrane signaling or extracellular signaling cascades. One embodiment for this gene is the polypeptide fragments comprising the following amino acid sequence: RFKTLMTNKSEQDGDSSKTIEISDMKYHIFQ
(SEQ ID N0:228); and/or LVEGKLFYAHKVLLVTXSNR (SEQ ID N0:229) (See Accession No. gnlIPIDId1020763 (AB000216}). An additional embodiment is the polynucieotide fragments encoding these polypeptide fragments.
This gene is expressed primarily in prostate cancer.

Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, prostate cancer. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of prostate cancer tissue, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types {e.g., prostate and cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid or spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder. Preferred epitopes include those comprising a sequence shown in SEQ
ID
NO. 117 as residues: Glu-30 to Ser-35.
The tissue distribution in the prostate cancer and homology to sodium channel or proteinase inhibitor suggest that polynucleotides and polypeptides corresponding to this gene are useful for the intervention of cancer progression, because the gene product may be involved in multidrug resistance by altering the drug kinetics by serving the function as a channel transporter. Alternatively, the proteinase inhibitor like function may facilitate tumor metastasis. By targeting these functions, either through vaccine or small molecules, therapeutics may be rationally designed to slow the cancer progression.
FEATURES OF PROTEIN ENCODED BY GENE NO: 8 This gene is expressed primarily in ovary and to a lesser extent in the adrenal -gland.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell type{s) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, female infertility and endocrine disorders. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the female reproductive system and the endocrine system, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types (e.g., ovary and other reproductive tissue, and adrenal gland, and cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid or spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
The tissue distribution of this gene in ovary and adrenal gland indicates that polynucleotides and polypeptides corresponding to this gene are useful for treatment/diagnosis of female infertility, endocrine disorders, ovarian function, amenorrhea, ovarian cancer and metabolic disorders.
FEATURES OF PROTEIN ENCODED BY GENE NO: 9 This gene is expressed only in prostate cancer.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types}
present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, prostate disorders including cancer. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the endocrine and male reproductive system, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types (e.g., prostrate and cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid or spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
The tissue distribution of this gene only in prostate cancerous tissue, indicates that polynucleotides and polypeptides corresponding to this gene are useful for the treatment/diagnosis of male infertility, metabolic disorders, and prostate disorders including benign prostate hyperplasia and prostate cancer.
FEATURES OF PROTEIN ENCODED BY GENE NO: 10 This gene is expressed primarily in placenta and to a lesser extent in ovary.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, female infertility, pregnancy disorders, and ovarian cancer.
Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing _ immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the reproductive system, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types (e.g., placenta, and ovary and other reproductive tissue, and cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid or spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder. Preferred epitopes include those comprising a sequence shown in SEQ
ID
NO. 120 as residues: Gln-39 to Gly-73.
The tissue distribution of this gene in placenta and ovary indicates that polynucleotides and polypeptides corresponding to this gene are useful for treatment/diagnosis of female infertility, endocrine disorders, fetal deficiencies, ovarian failure, amenorrhea, and ovarian cancer.
FEATURES OF PROTEIN ENCODED BY GENE NO: 11 Gene shares homology with the gene for the Human 3' apolipoprotein B SAR
element gene Rh32 (See Accession No. T31530).
This gene is expressed primarily in prostate and in the pancreas.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell type{s) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, prostate and pancreatic disorders. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type{s). For a number of disorders of the above tissues or cells, particularly of the endocrine system, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types (e.g., prostate and pancreas, and cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid or spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
The tissue distribution of this gene in prostate and pancrease, indicates that polynucleotides and polypeptides corresponding to this gene are useful for treatment/diagnosis of male infertility, prostate disorders including benign prostate hyperplasia, prostate cancer, pancreatic cancer, type I and type II diabetes and hypoglycemia. Homology to a known human apolipoprotein may suggest this gene is useful for the detection, prevention, or treatment of various metabolic disorders, particularly those secondary to lipoprotein disorders such as atherosclerosis, coronary heart disease, stroke, and hyperlipidemias.
FEATURES OF PROTEIN ENCODED BY GENE NO: 12 5 Gene has homology to conserved Beta-casein, an abundant milk protein (See Accession No.Q37894 ) This gene is expressed primarily in stomach.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a 10 biological sample and for diagnosis of diseases and conditions which include, but are not limited to, disorders of the digestive tract and/or mammary glands.
Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues} or cell type(s). For a number of disorders of the above tissues or cells, particularly of the digestive system 15 and breast, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types (e.g., mammary tissue, and stomach and other gastrointestinal tissue, and cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid or spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
The tissue distribution of this gene indicates a role in the treatmenddiagnosis of digestive disorders including stomach cancer and ulceration. Furthermore, the homology to conserved beta-casein may indicate this gene as having utility in the diagnosis and prevention of mammary gland disorders.
FEATURES OF PROTEIN ENCODED BY GENE NO: 13 This gene is expressed in brain and lung.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, neurodegenerative disease states, behavioral abnormalities and pulmonary disorders. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the immune, nervous, and pulmonary systems, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types (e.g., brain and other tissue of the nervous system, and lung, and cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid or spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for the detection/treatment of neurodegenerative disease states and behavioral disorders such as Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, schizophrenia, mania, dementia, paranoia, obsessive compulsive disorder and panic disorder. In addition it could be used in the detection and treatment of pulmonary disease states such as lung lymphoma or sarcoma formation, pulmonary edema and embolism, bronchitis and cystic fibrosis.
FEATURES OF PROTEIN ENCODED BY GENE NO: 14 This gene is expressed exclusively in T-cells.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, immune disorders. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the immune system, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types (e.g., T-cells and other cells and tissue of the immune system, and cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid or spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for treatment/detection of immune disorders such as arthritis, asthma, immune deficiency diseases such as AIDS, and leukemia.
Additionally, the expression in hematopoietic cells and tissues indicates that this protein may play a role in the proliferation, differentiation, and/or survival of hematopoietic cell lineages. Thus, this gene may be useful in the treatment of lymphoproliferative disorders, and in the maintenance and differentiation of various hematopoietic lineages from early hematopoietic stem and committed progenitor cells.

FEATURES OF PROTEIN ENCODED BY GENE NO: 15 This gene is expressed primarily in T-cells.
- Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissue{s) or cell types}
present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, immune disorders. Similarly, polypeptides and antibodies directed to these poIypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the immune system, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types (e.g., T-cells and other cells and tissue of the immune system, and cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid or spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder. Preferred epitopes include those comprising a sequence shown in SEQ ID NO. 125 as residues: Ala-46 to Asp-51.
The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for the diagnosis and treatment of immune disorders including: leukemias, lymphomas, auto-immunities, immunodeficiencies (e.g. AIDS), immuno-suppressive conditions (transplantation) and hematopoeitic disorders.
FEATURES OF PROTEIN ENCODED BY GENE NO: 16 This gene is expressed primarily in endometrial tumors.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, cancer, particularly endometrial. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the female reproductive system, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types (e.g., endometrial cells and other reproductive cells or tissue, and cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid or spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for the treatment and diagnosis of ovarian and other endometrial cancers, as well as reproductive disfunction, prenatal disorders or fetal deficiencies.
FEATURES OF PROTEIN ENCODED BY GENE NO: 17 This gene is expressed primarily in a variety of osteoclastic cells:
osteoclastoma stromal cells, osteosarcoma, chondrosarcoma and stromal cell culture. To a lesser extent, it is also seen in a variety of fetal and embryonic cell and tissue types.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, bone cancer. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the skeletal and developmental systems, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types (e.g., bone cells, cartilage, and stomal cells, and cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid or spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder. Preferred epitopes include those comprising a sequence shown in SEQ ID NO. 127 as residues: Gln-34 to Gln-41, Asn-76 to Lys-82, Ser-85 to Lys-91.
The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for treatment and detection of a variety disorders and conditions affecting bone and the skeletal system, including:
osteoperosis, fracture, osteosarcoma, osteoclastoma, chondrosarcoma, ossification and osteonecrosis, arthritis, tendonitis, chrondomalacia and inflammation.
FEATURES OF PROTEIN ENCODED BY GENE NO: 18 This gene is expressed primarily in smooth muscle.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, cardiovascular disorders including lymphatic system disorders.
Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the cardiovascular and lymphatic systems, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types (e.g., smooth muscles, and cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid or spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for the diagnosis and treatment of conditions and pathologies of the cardiovascular system: heart disease, restenosis, atherosclerosis, stoke, angina, thrombosis, and wound healing.
FEATURES OF PROTEIN ENCODED BY GENE NO: 19 The translation product of this gene shares sequence homology with 5'-nucleotidase (See Accession No. 2668557) as well as the gene for alpha-1 collagen type X (See Accession No. gbIX673481MMCOL10A ). One embodiment for this gene is the polypeptide fragments comprising the following amino acid sequence:
MAQHFSLAACDV VGFDLDHTLCRYNLPESAPLIYNSFAQFLVKEKGYDKELLN
VTPEDWDFCCKGLALDLEDGNFLKLANNGTVLRASHGTKMMTPEVLAEAYG
KKEWKHFLSDTGMACRSGKYYFYDNYFDLPGALLCARV VDYLTKLNNGQKT
FDFWKDIVAAIQHNYKMSAFKENCGIYFPEIKRDPGRYLHSCPESVKKWLRQL
KNAGKILLLITSSHSDYCRLLCEYILGNDFTDLFDIVITNALKPGFFSHLPSQRPF
RTLENDEEQEALPSLDKPGWYSQGNAVHLYELLKKMTGKPEPKVVYFGDSMH
SDIFPARHYSNWETVLILEELRGDEGTRSQRPEESEPLEKKGKYEGPKAKPLNT
SSKKWGSFFIDSVLGLENTEDSLVYTWSCKRISTYSTIAIPSIEAIAELPLDYKFT
RFSSSNSKTAGYYPNPPLVLSSDETLISK (SEQ ID N0:233); andlor TSSHSDYCRLLCEYILGNDFTDLFDIV (SEQ ID N0:234). An additional embodiment is the polynucleotide fragments encoding these polypeptide fragments.
Additionally, another embodiment for this gene is the polynucleotide fragments comprising the following sequence:
CCTTAAAAGCTGACATTTTATAATTGTGTTGTATAGCAGCAACTATATCCTTC
CAAAAATCAAATGTZTIZTGACCATTGTTCAGTT (SEQ >D N0:230);
CCITAAAAGCT GACATTTTATAATTGTGTTGTATAGCA (SEQ ID N0:231 );

and/or CTTCCAAAAA TCAAATGTTTTTTGACCATTGTTCAGTT (SEQ ID
N0:232). An additional embodiment is the polypeptide fragments encoded by these polynucleotide fragments. This gene maps to chromosome 6, and therefore, may be used as a marker in linkage analysis for chromosome 6.
S This gene is expressed primarily in prostate and smooth muscle.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, prostate cancer and cardiovascular disorders. Similarly, polypeptides 10 and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the prostate and cardiovascular system, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types (e.g., prostate, and smooth muscle, and 15 cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid or spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
The tissue distribution indicates that polynucleotides and polypeptides 20 corresponding to this gene are useful for the treatment and diagnosis of prostate cancer and other disorders. In addition the expression in smooth muscle would suggest a role for this gene product in the treatment and diagnosis of cardiovascular disorders such as hypertension, restenosis, atherosclerosis, stoke, angina, thrombosis, and other aspects of heart disease and respiration.
FEATURES OF PROTEIN ENCODED BY GENE NO: 20 This gene is expressed primarily in endometrial tissue and to a lesser extent in synovium.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, endometrial cancer and arthritis. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunologicaI probes for differential identification of the tissues} or cell type(s). For a number of disorders of the above tissues or cells, particularly of the reproductive and skeletal systems, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types (e.g., endometrial tissue and other reproductive tissue, and synovial tissue, and cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid or spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder. Preferred epitopes include those comprising a sequence shown in SEQ
ID
NO. 130 as residues: Ser-19 to His-24, Pro-36 to Arg-43, Ala-61 to Gly-67, Pro-86 to Ala-95.
The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for the diagnosis and treatment of endometrial cancers, as well as reproductive and developmental disorders (fetal deficiencies and other pre-natal conditions). In addition the expression of this gene product in synovium would suggest a role in the detection and treatment of disorders and conditions affecting the skeletal system, in particular the connective tissues (e.g. arthritis, trauma, tendonitis, chrondomalacia and inflammation).
FEATURES OF PROTEIN ENCODED BY GENE NO: 21 This gene maps to chromosome 6, and therefore, may be used as a marker in linkage analysis for chromosome 6.
This gene is expressed primarily in keratinocytes, fetal tissue (especially fetal brain) and leukocytic cell types and tissues (e.g. B-cell, macrophages, Jurkat T-Cell, T
cell helper cells, spleen, thymus and lymphoma).
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, integument and immune systems, as well as developmental disorders.
Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the skin, immune and central nervous systems, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types (e.g., keratinocytes, brain and other tissue of the nervous system, differentiating tissue, leukocytes and other cells and tissue of the immune system, and cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid or spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.

The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for the diagnosis and treatment of immune disorders including: Ieukemias, lymphomas, auto-immunities, immunodeficiencies (e.g. AIDS), immuno-suppressive conditions (transplantation) and hematopoeitic disorders. Expression in keratinocytes would suggest a role for the gene product in the diagnosis treatment of skin disorders such as cancers (melanomas), eczema, psoriasis, wound healing and grafts. In addition the expression in fetal brain might implicate this gene product in the detection and treatment of developmental and neurodegenerative diseases of the brain and nervous system: behavioral or nervous system disorders, such as depression, schizophrenia, Alzheimer's disease, Parkinson's disease, Huntington's disease, mania, dementia, paranoia, addictive behavior and sleep disorders.
FEATURES OF PROTEIN ENCODED BY GENE NO: 22 Translation product of this gene shares significant homology with the conserved YMEI PROTEIN from Saccharomyces cerevisiae, which is a putative ATP-dependent protease thought to regulate the assembly of key respiratory chains within the mitochondria (See Accession No. P32795). Preferred polypeptide fragments comprise the following an>ino acid sequence:
MKTKNIPEAHQDAFKTGFAEGFLKAQALTQKTNDSLRRTRLILFVLLLFGIYGL
LKNPFLSVRFRTTTGLDSAVDPVQMKNVTFEHVKGVEEAKQELQEVVEFLKNP
QKFTILGGKLPKGILLVGPPGTGKTLLARAVAGEADVPFYYASGSEFDEMFVG
VGASRIRNLFREAKANAPCVIFIDELDSVGGKRIESPMHPYSRQTINQLLAEMD
GFKPNEG V IIIGATNFPEALDNALIRPGRFDMQ VT V PRPD V KGRTEILKW YLNK
IKFDXSVDPEIIARGTVGFSGAELENLVNQAALKAAVDGKEMVTMKELGVFQR
QNSNGA (SEQ ID N0:235); MKTKNIPEAHQDAFKTGFAEG (SEQ ID N0:236);
PVQMKNVTF'EHVKGVEEAKQELQ (SEQ ID N0:237);
SRQTINQLLAEMDGFKPN EGVII (SEQ ID N0:238 ); and/or FSGAELENLVNQAALKAAVDGKEM (SEQ ID N0:239). Also preferred are polynucleotide fragments encoding these polypeptide fragments.
This gene is expressed primarily in T-cells.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, immune and hematopoeitic disorders. Similarly, poIypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the immune and hematopoeitic systems, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types (e.g., T-cells and other cells and tissue of the immune system, and cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid or spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for the diagnosis and treatment of immune disorders including:leukemias, lymphomas, auto-immunities, immunodeficiencies (e.g.
AIDS), immuno-suppressive conditions (transplantation) and hematopoeitic disorders.
Furthermore, the homology of this gene indicates that it may play an important role in disorders affecting metabolism.
FEATURES OF PROTEIN ENCODED BY GENE NO: 23 This gene is expressed primarily in human chronic synovitis.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, synovial and other inflammatory disorders. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the synovial tissue and immune system, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types (e.g., synovial tissue, and cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid or spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
The tissue distribution indicates that the protein product of this gene are useful for study, diagnosis and treatment of inflammatory disorders such as chronic synovitis.
FEATURES OF PROTEIN ENCODED BY GENE NO: 24 This gene is expressed primarily in pituitary, breast cancer, and bone marrow;
and to a lesser extent in breast, prostate, uterine cancer and cerebellum.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, endocrine, reproductive disorders and cancers. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the reproductive, metabolic and endocrine systems, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types (e.g., pituitary, mammary tissue, bone marrow, prostate, reproductive tissue, uterus, and brain and other tissue of the nervous system, and cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid or spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder. Preferred epitopes include those comprising a sequence shown in SEQ
ID
NO. 134 as residues: Asp-32 to Gln-38, Lys-88 to Ile-97.
The tissue distribution indicates that the protein products of this gene are useful for the study, treatment and diagnosis of various endocrine disorders, reproductive diseases and disorders and cancers.
FEATURES OF PROTEIN ENCODED BY GENE NO: 25 The translation product of this gene shares sequence homology with androgen withdrawal apoptosis protein in rat which is thought to be important in programmed cell death. Preferred polypeptides encoded by this gene comprise the following anuno acid sequence:
LPMWQVTAFLDHNIVTAQTTWKGLWMSCVVQSTGHMQCKVYDSVLALSTEV
QAARALTVSAVLLAFVALFVTLAGAQCTTCVAPGPAKARVALTGGVLYLFCGL
LALVPLCWFANIVVREFYDPSVPVSQKYELGAXLYIGWAATALLMVGGCLLCC
GAWVCTGRPDLSFPVKYSAPRRPTATGDYDKKNYV (SEQ ID N0:240). This polypeptide is expected to contain multiple transmembrane domains. The extracellular portion of the polypeptide is expected to comprise residues 1-51 of the foregoing amino acid sequence. Therefore, particularly preferred polypeptides encoded by this gene comprise residues 1-51 of the foregoing amino acid sequence. Polynucleotides encoding the foregoing polypeptides are also provided.
This gene is expressed primarily in human adult pulmonary and brain (striatum) tissue and to a lesser extent in thymus, synovium and testis.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, reproductive, metabolic, and neurodegenerative disorders.
Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the reproductive, 5 nervous, respiratory and metabolic systems expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types (e.g., thymus, synovial tissue, testis and other reproductive tissue, and cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid or spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, 10 relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
The tissue distribution and homology to androgen withdrawal apoptosis rat gene protein indicates that polynucleotides and polypeptides corresponding to this gene are useful for study, diagnosis and treatment of disorders in which the mechanism 15 controlling programmed cell death is instrumental. This could include reproductive, neurodegenerative, and various metabolic disorders and diseases such as cancer.
FEATURES OF PROTEIN ENCODED BY GENE NO: 26 The translation product of this gene shares homology with both ubiquitin and a 20 G-protein coupled receptor TM3 consensus polypeptide (see Genbank accession Nos.
gnIIPIDIe331456 (A3000657) and 850664, respectively). Preferred polypeptides encoded by this gene comprising the following amino acid sequence:
LHYFALSFVLILTEICLVSSGMGF (SEQ ID N0:241);
QLRNGIPPGRKALFCSGKPR LFTLGQGRTCA (SEQ ID N0:242); and/or 25 WSGLWVTTWNGSSGERTPSPWRRK RASQSAGRIASWMSF (SEQ ID N0:243).
An additional embodiment is polynucleotides encoding these polypeptides. This gene maps to chromosome 1, and therefore, may be used as a marker in linkage analysis for chromosome 1.
This gene is expressed primarily in activated T cells and to a lesser extent in CD34 depleted buffy coat.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, immune and hemopoietic disorders. Similarly, poiypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the hemopoietic and immune system, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types (e.g., T-cells and other blood cells and other cells and tissue of the immune system, and cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid or spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder. Preferred epitopes include those comprising a sequence shown in SEQ ID NO. 136 as residues: Thr-15 to His-21, Gly-30 to Lys-39, Arg-113 to Met-118, Arg-178 to Ala-187.
The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for the treatment and diagnosis of hematopoetic related disorders such as anemia, pancytopenia, leukopenia, thrombocytopenia or leukemia since stromal cells are important in the production of cells of hematopoietic lineages. The uses include bone marrow cell ex vivo culture, bone marrow transplantation, bone marrow reconstitution, radiotherapy or chemotherapy of neoplasia. The gene product may also be involved in lymphopoiesis, therefore, it can be used in immune disorders such as infection, inflammation, allergy, immunodeficiency etc. Furthermore, the homology to G-coupled proteins as well as to ubiquitin may implicate this gene as being important in regulation of gene expression and protein sorting - both of which are vital to development and would healing models.
Therefore, the gene may provide utility in the diagnosis, prevention, and/or treatment of various developmental disorders.
FEATURES OF PROTEIN ENCODED BY GENE NO: 27 This gene is expressed primarily in activated T cells and to a lesser extent in fetal kidney.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, immune, developmental and metabolic diseases. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the immune and metabolic systems, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types (e.g., T-cells and other cells and tissue of the immune system, and cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid or spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for the study and treatment of diseases and disorders of the immune, metabolic, and endocrine systems; such as renal diseases and T cell dysfunetions. Since the gene is expressed in cells of lymphoid origin, the natural gene product may be involved in immune functions. Therefore it may be also used as an agent for immunological disorders including arthritis, asthma, immune deficiency diseases such as AIDS, and leukemia.
FEATURES OF PROTEIN ENCODED BY GENE NO: 28 The translation product of this gene shares sequence homology with Cystatin-related epididymal specific protein in mouse which is thought to be important in reproductive system function/regulation (See Genbank accession no.bbsi118813).
Based on the structural similarity between these proteins, the translation product of this clone, hereinafter "Cystatin G", is expected to share biological activities with cystatin related proteins and other cysteine protease inhibitors. Such activities are known in the art and are described elsewhere herein. Preferred polypeptides encoded by this gene comprising the following amino acid sequence:
MPRCRWLSLILLTIPLALVARKDPKKNETGVLRKLKPVNASNANVKQCLWFA
MQEYNKESEDKYVFLVVKT'LQAQLQVTNLLEYLIDVEIARSDCRKPLSTNEICAI
QENSKLKRKLSCSFLVGALPWNGEFTVMEKKCEDA (SEQ ID N0:246);
ARKDPKKNETGVLRKLKPVNASNANVKQCLWFAMQEYNKESEDKYVFLV V K
TLQAQLQVTNLLEYLIDVEIARSDCRKPLSTNEICAIQENSKLKRKLSCSFLVGA
LPWNGEFTVMEKKCEDA (SEQ ID N0:248);
CLWFAMQEYNKESEDKYVFLWKTLQAQLQVTNLLEYLIDVEIARSDCRKPLST
NEICAIQENSKLKRKLSCSFLVGALPWNGEFTVMEKKC (SEQ ID N0:247 );
EYNKESEDKYVFLV (SEQ ID N0:244); and/or IDVEIARSDCRKPL (SEQ ID
N0:245). An additional embodiment is the polynucleotide fragments encoding these polypeptide fragments. Preferred cystatin polypeptide fragments are shown to be active in the following assays: The methods used for active site titration of papaln, titration of the molar enzyme inhibitory concentration in cystatin G preparations, and for deterniination of equilibrium constants for dissociation (Ki) of complexes between cystatin G and cysteine peptidases are described in detail in Hall et al., Biochem. J., 291:123-29 { 1993) and Abrahamson, Methods Enzymol., 244:685-700 ( 1994), both of which are hereby incorporated herein by reference. The enzymes used for equilibrium assays are papain (EC 3.4.22.2; from Sigma, St Louis, MO) and cathepsin B (EC
3.4.22.1; from Calbiochem, La Jolla, CA). The fluorogenic substrate used was Z-Phe-Arg-NHMec ( 10 mM; from Bachem Feinchemikalien, Bubendorf, Switzerland) and the assay buffer was 100 mM Na-phosphate buffer (pH 6.5 and 6.0 for papain and cathepsin B, respectively), containing 1 mM dithiothreitol and 2 mM EDTA.
Steady state velocities are measured and Ki values were calculated according to Henderson, Biochem J., 127:321-333 (1972), incorporated herein by reference. Corrections for substrate competition are made using Km values of 150 =BSM for cathepsins B
(Barrett and Kirschke, Methods Enzymol., 80:535-561 ( 1981 ) and 60 =BSM for papain (Hall et al., Biochem. J., 291:123-29 (1992)), both of which are hereby incorporated herein by reference.
This gene is expressed primarily in human testes.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, reproductive disorders and cancer. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the reproductive system, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types (e.g., testis and other reproductive tissue, and cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid or spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder. Preferred epitopes include those comprising a sequence shown in SEQ ID NO. 138 as residues: Arg-21 to Thr-29.
The tissue distribution and homology to cystatin-related epididymal specific protein-mouse indicates that polynucleotides and polypeptides corresponding to this gene are useful for study, diagnosis and treatment of reproductive diseases and disorders. Cysteine proteinase inhibitors of the cystatin superfamily are ubiquitous in the body and are generally tight-binding inhibitors of papain-like cysteine proteinases, such as cathepsins B, H, L, S, and K (for review, see Ref. 1 ). They should therefore serve a protective function to regulate the activities of such endogenous proteinases, which otherwise may cause uncontrolled proteolysis and tissue damage. Cysteine proteinase activity can normally not be measured in body fluids, but can been detected extracellularly in conditions like endotoxin-induced sepsis (2), metastasizing cancer (3), and at local inflammatory processes in rheumatoid arthritis (4), purulent bronchiectasis (5) and geriodontitis (6), which indicates that a tight cystatin regulation is a necessity in the normal state. A deficiency state in which the levels of the intracellular cystatin, cystatin B, are lowered due to mutations has recently been shown to segregate with a form of progressive myoclonus epilepsy (7), which points to additional specialized functions of cystatins. Moreover, results showing that chicken cystatin inhibits polio virus replication (8), human cystatin C inhibits corona- and herpes simplex virus replication (9,10), and human cystatin A inhibits rhabdovirus-induced apoptosis ( 11 ) in cell-cultures indicates that cystatins play additional roles in the human defense system.
The cystatins constitute a superfamily of evolutionary related proteins, all composed of at least one 100-120 residue domain with conserved sequence motifs (12). The previously well characterized single-domain human members of superfamily could be grouped in two protein families. The Family 1 members, cystatins (or stefins) A and B, contain approximately 100 amino acid residues, lack disulfide bridges, and are not synthesized as preproteins with signal peptides. The Family 2 cystatins (cystatins C> D, S, SN, and SA) are secreted proteins of approx. 120 amino acid residues (Mr 13,000-14,000) and have two characteristic intrachain disulfide bonds. Recently, we identified an additional human cystatin superfamily member by EST1 sequencing in epithelial cell derived cDNA libraries which we named cystatin E ( 13). The same cystatin was independently discovered by differential display experiments as a mRNA species down-regulated in breast tumor tissue, but present in the surrounding epithelium and reported under the name cystatin M ( 14). Cystatin E/M is an atypical, secreted low-Mr cystatin in that it is a glycoprotein and just shows 30-35% sequence identity in alignments with the human Family 2 cystatins, which shows that additional cystatin families are yet to be identified (13). The cystatin E/M gene has been localized to chromosome 2 (15), whereas all human Family 2 cystatin genes are clustered on the short arm of chromosome 20 (16), which further stresses that cystatin E/M is just distantly related to the other secreted human low-Mr cystatins.
FEATURES OF PROTEIN ENCODED BY GENE NO: 29 The translation product of this gene shares sequence homology with the leukocyte-associated Ig-like receptor-I, putative inhibitory receptor which is thought to be important in regulation of various physiological functions (See Accession No.
gi12352941 (AF013249). Preferred polypeptides encoded by this gene comprise the following amino acid sequence:
DSPDTEPGSSAGPTQRPSDNSHNEHAPASQGLKAEHLYILIGVS (SEQ ID
N0:249); HRQNQIKQGPPRSKDEEQKPQQRPDLAVDVLERTADKATVNGL
PEKDRETDTSALAAGSSQEVTYAQLDHWALTQRTARAVSPQSTKPMAESITYAA

VARH (SEQ ID N0:250);
MSPHPTALLGLVLCLAQTIHTQEEDLPRPSISAEPGTVIPLGSHVTFVCRGPVGV
QTFRLERESRSTYNDTEDVSQASPSESEARFRIDSVSEGNAGPYRCIYYKPPKW
SEQSDY (SEQ ID N0:251 ); TALLGLVLCLAQTIHTQE (SEQ )D N0:252);
5 LPRPSISAEPGTVI (SEQ ID N0:253); CRGPVGVQTFRLERE (SEQ ID N0:254);
and/or VLERTADKATVNGLPEKDRETDTSALAAGSS (SEQ ID N0:255).
Additional embodiments of the invention include polynucleotides encoding these polypeptides.
This gene is expressed primarily in macrophages and T-cells and to a lesser 10 extent in human fetal heart.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, developmental, inflammatory, and immune disorders. Similarly.
15 polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues} or cell type(s). For a number of disorders of the above tissues or cells, particularly of the growth and inflammatory systems, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types (e.g., macrophages, T-cells 20 and other cells and tissue of the immune system, heart, and cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid or spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder. Preferred epitopes include those 25 comprising a sequence shown in SEQ ID NO. 139 as residues: His-20 to Arg-28, Glu-61 to Val-74, Ser-78 to Ala-84, Lys-105 to Ser-117.
The tissue distribution and homology to putative inhibitory receptor indicates that polynucleotides and polypeptides corresponding to this gene are useful for the study, diagnosis and treatment of functional disorders of the developing fetal heart;
30 including circulatory and vascular; and inflammatory disorders. In addition expression in macrophages and lymphocytes indicates a role in the treatmenddetection of immune disorders including disorders such as arthritis, asthma, immune deficiency diseases such as AIDS, and leukemia.
FEATURES OF PROTEIN ENCODED BY GENE NO: 30 The translation product of this gene shares sequence homology with erythroid cell specific transcription factor- marine which is thought to be important in normal physiological function of erythroid cells. In addition, the translation product of this gene also shares homology with the conserved 3-phosphoglycerate dehydrogenase gene which is essential component of metabolic biosynthetic pathways. Preferred polypeptides comprise the following amino acid sequence:

TLGILGLGRIGREVATRMQSFGMKTIGYDPIISPEVSASFGVQQLPLEEIWPLCDF
ITVHTPLLPSTTGLLNDNTFAQCKKGVRVVNCARGGIVDEGALLRALQSGQCA
GAALDVFTEEPPRDRALVDHENVISCPHLGASTKEAQSRCGEEIAVQFVDMVK
GKSLTGV VNAQALTSAFSPHTKPWIGLAEALGTLMRAWAGSPKGTIQVTTQGT
SLKNAGNCLSPAVIVGLLKEASKQADVNLVNAKLLVKEAGLNVTTSHSPAAPG
EQGFGECLLAVALAGAPYQAVGLVQGTTPVLQGLNGAVFRPEVPLRRDLPLLL
FRTQTSDPAMLPTMIGLLAEAGVRLLSYQTSLVSDGETWH VMGISSLLPSLEAW
KQHVTEAFQFHF (SEQ ID N0:256); MAFANLRKVLISDSLDPCCRKILQ (SEQ ID
N0:257); GGLQVVEKQNL SKEELIA (SEQ ID N0:258);
MCLARQIPQATASMKDGKWERKKFMGTEL (SEQ ID N0:259);
ALTSAFSPHTKPWIGLAEALGTLMRAWAG (SEQ ID N0:260); and/or EVPLRRDLPLLLFRTQTSDPAMLPTMIGLLAEAGVR (SEQ ID N0:261). Also preferred are polynucleotide fragments encoding these polypeptides. This gene maps to chromosome l, and therefore, may be used as a marker in linkage analysis for chromosome 1.
This gene is expressed primarily in IL-1 induced smooth muscle and fetal kidney and to a lesser extent in myeloid progenitor cell line and bone marrow.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, immune, hemopoietic, and cardiovascular disorders. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the hemopoietic and immune system, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types (e.g., smooth muscle, kidney, myeloid progenitor cells, bone, and cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid or spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder. Preferred epitopes include those comprising a sequence shown in SEQ ID NO. 140 as residues: Met-1 to Asn-7. Met-33 to Lys-42, Asn-I23 to Cys-130, Glu-I69 to Asp-174, Ser-192 to Gly-201, Thr-266 to Asn-273, Pro-318 to Phe-323.
The tissue distribution and homology to erythroid cell specific murine transcription factor indicates that polynucleotides and polypeptides corresponding to this gene are useful for study, diagnosis and treatment of disorders and diseases involving the hemopoietic and immune systems; the maturation of progenitor cells; and the development of various smooth muscle tissues (heart, etc.). In addition, homology to a key biosynthetic protein implicates this the protein product of this gene as being important in metabolism. Therefore, the protein may show utility in the diagnosis, prevention, and/or treatment of metabolic disorders and conditions.
FEATURES OF PROTEIN ENCODED BY GENE NO: 31 This gene is expressed primarily in human adult testes.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, reproductive disorders, particularly of the male genitalia.
Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the reproductive system, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types (e.g., cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid or spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder. Preferred epitopes include those comprising a sequence shown in SEQ ID NO. 141 as residues: Met-I to Pro-8, Ser-to Thr-50.
The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for the study, diagnosis, treatment, and possibly prevention of various male reproductive disorders and diseases including mate impotence, failed lebido and male secondary sex characteristics, infertility, and testicular cancer.
FEATURES OF PROTEIN ENCODED BY GENE NO: 32 This gene is expressed primarily in human adult testis.

Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissue{s) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, reproductive disorders and cancers of the male reproductive system.
Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the reproductive system, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types (e.g., testis and other reproductive tissue, and cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid or spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for the study, diagnosis, treatment, and possibly prevention of various male reproductive disorders and diseases including male impotence, failed lebido and male secondary sex characteristics, infertility, and testicular cancer.
FEATURES OF PROTEIN ENCODED BY GENE NO: 33 The translation product of this gene shares homology to the W09D10.1 protein of Caenorhabditis elegans. In addition, the gene also shares homology with the human protein hRIP, a protein known to be critical for HIV replication (See Accession Nos.gnlIPIDIe 1186472 and W 12713). Preferred polypeptides encoded by this gene comprise the following amino acid sequence:
MDLLGLDAPVACSIANSKTSNTLEKDLDLLASVPSPSSSGSRKVVGSMPTAGSA
GSVPENLNLFPEPGSKSEEIGKKQLSKDSILSLYGSQTXQMPTQAMFMAPAQM
AYPTAYPSFPGVTPPNSIMGSMMPPPVGMVAQPGASGMVAPMAMPAGYMGG
MQASMMGVPNGMMTTQQAGYMAGMAAMPQTVYGVQPAQQLQWNLTQMTQ
QMAGMNFYGANGMMNYGQSMSGGNGQAANQTLSPQMWKFGTRFLANLLLE
EDNKFCADCQSKGPRWASWNIGVFICIRCAXIHRNLGVHISRVKSVNLDQWTQ
VQIQC (SEQ ID N0:267); MQXMGNGKANRLYEAYLPETFRRPQIDPAVEGFIR
DXYE {SEQ ID N0:268); EEDNKFCADCQSKGPRWASWN (SEQ ID N0:263);
GVFICIRCAXIHR NLGVHIS (SEQ ID N0:264); and/or SVNLDQWTQVQIQCMQX
MGNGKA {SEQ ID N0:265). Polynucleotides encoding these polypeptides are also provided.

This gene is expressed primarily in lymphoid tumors.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, immune and inflammatory disorders. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the immune, hematopoietic and inflammatory, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types (e.g., lymphoid tissue and other tissue and cells of the immune system, and cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid or spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder. Preferred epitopes include those comprising a sequence shown in SEQ ID NO. i43 as residues: Cys-21 to Trp-28.
The tissue distribution indicates that the protein products of this gene are useful for study, diagnosis and treatment of various immune disorders and diseases, including self recognition and rejection functions of the immune system, hematopoietic disorders, and inflammatory disorders. Homology to the W09D10.1 of C.elegans and the hRIP
implicates this gene as playing a role as an essential receptor for host-viral interactions including, but not limited to retrovirai infections such as AIDS.
FEATURES OF PROTEIN ENCODED BY GENE NO: 34 The translation product of this gene shares homology to an Arabidopsis thaliana recombination and DNA-damage resistance/repair protein (See Accession No.gi1166694). Preferred polypeptides encoded by this gene comprise the following amino acid sequence:
KYGKVGKCVIFEIPGAPDDEAVRIFLEFERVESAIKAVVDLNGRYFGGRVVKAC
FYNLDKFRVLDLA (SEQ ID N0:269); KAVDLGRYFGGR (SEQ ID N0:270);
and/or EAVRIFFRE (SEQ ID N0:271). Polynucleotides encoding these polypeptides are also provided.
This gene is expressed primarily in ovarian and other cancers.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to. cancer, particularly of the female reproductive system.
Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissue{s) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the reproductive system, expression of this gene at significantly higher or lower levels may be routinely 5 detected in certain tissues and cell types (e.g., ovaries and other reproductive tissue, and cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid or spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the 10 disorder. Preferred epitopes include those comprising a sequence shown in SEQ ID
NO. 144 as residues: Thr-11 to Trp-19, Ala-40 to Gln-47, Lys-58 to Arg-6b, Asp-to Lys-110, Arg-114 to Glu-121.
The tissue distribution in tumors of ovarian origins combined with the homology to a known DNA damage repair enzyme indicates that polynucleotides and 15 polypeptides corresponding to this gene are useful for diagnosis and intervention of tumors. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or immunotherapy targets for the above listed tumors and tissues.
FEATURES OF PROTEIN ENCODED BY GENE NO: 35 20 Translation product of this gene shares homology with human stomatin, intestinal surface antigens, as well as protein F30A 10.5 of Caenorhabditis elegans (See Accession No.gnIIPIDIe276130). Preferred polypeptides encoded by this contig comprise the following amino acid sequence: RMGRFHRILEPGLNILIPVLDRIRYVQ
SLKEIVINVPEQSAVTLDNVTLQ)DGVLYLRIIvIDPYKASYGVEDPEYAVTQLAQT

KESMQMQVEAERRKRATVLESEGTRESAINVAEGKKQAQILASEAEKAEQINQA
AGEASAVLAKAKAKAEAIRIL.AAALTQHNGDAAASLTVAEQYVSAFSKLAKDS
NTILLPSNPGDVTSMVAQAMGVYGALTKAPVPGTPDSLSSGSSRDVQGTDASL
DEELDRVKMS (SEQ ID N0:272); ASYGVEDPEYAVTQLAQTT MRSELGK (SEQ
30 ID N0:273); MQMQVEAERRKRATVLESEGTRESAIN (SEQ ID N0:274);
LTVAEQYVSAFSKLAKDSNTILLPSN (SEQ ID NO:27~), and/or LLGATAPLVSLVPEVAAAVGNAGARGAXHWGPFAEGLSTGFWPRSARASSGL
PRNTVVLFVPQQEAWVVE (SEQ ID N0:276). Polynucleotides encoding these polypeptides are also provided.
35 This gene is expressed primarily in activated T-cells and to a lesser extent in other cell types.

Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types}
present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, immune disorders. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the immune system, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types (e.g., T-cells and other cells and tissue of the immune system, and cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid or spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder. Preferred epitopes include those comprising a sequence shown in SEQ ID NO. 145 as residues: Arg-23 to Pro-33, i5 Pro-184 to Ser-189, Ala-196 to Arg-201, Glu-208 to Ser-213, Glu-230 to Ile-237, Gly-326 to Leu-331, Gly-334 to Gln-340.
The tissue distribution indicates that the protein products of this gene are useful for the treatment and diagnosis of hematopoetic related disorders such as anemia, pancytopenia, leukopenia, thrombocytopenia or leukemia since stromal cells are important in the production of cells of hematopoietic lineages. The uses include bone marrow cell ex vivo culture, bone marrow transplantation, bone marrow reconstitution, radiotherapy or chemotherapy of neoplasia. The gene product may also be involved in lymphopoiesis, therefore, it can be used in immune disorders such as infection, inflammation, allergy, immunodeficiency etc. In addition, the homology to known intestinal antigens may suggest that the protein is important in the diagnosis, treatment, and/or prevention of gastrointestinal disorders.
FEATURES OF PROTEIN ENCODED BY GENE NO: 36 Translation product of this gene has homology to a human estrogen receptor variant from human breast cancer. Preferred polypeptides encoded by this gene comprise the following amino acid sequence: R;MWRNGTHFWECKIVQPLWK
TVWWFPRKLSIELPENLAILIGTYFK (SEQ ID N0:277); andlor LKRHFPKEANK
HVKRCSTSLDIREIQIKIKMRY (SEQ ID N0:278). Polynucleotides encoding these polypeptides are also provided.
This gene is expressed primarily in ulcerative colitis.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, intestinal ulcers, inflammatory conditions and cancers, particular of the breast. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the gastrointestinal system, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types (e.g., colon and other gastrointestinal tissue, and cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid or spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
The tissue distribution in colon and breast origins indicates that polynucleotides and polypeptides corresponding to this gene are useful for diagnosis and intervention of tumors or other conditions within these tissues, in addition to other tumors where expression has been indicated. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or immunotherapy targets for the above listed tumors and tissues.
FEATURES OF PROTEIN ENCODED BY GENE NO: 37 This gene is expressed primarily in epithelial cells.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, cancers and skin disorders, particularly melanoma. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the skin and other epithelia, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types (e.g., cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid or spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder. Preferred epitopes include those comprising a sequence shown in SEQ ID NO. 147 as residues: Met-1 to Tyr-6.
The tissue distribution in epithelial tissue indicates that polynucleotides and polypeptides corresponding to this gene are useful for diagnosis and intervention of tumors of this tissue. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or immunotherapy targets for the above listed tissues.
FEATURES OF PROTEIN ENCODED BY GENE NO: 38 This gene is expressed primarily in adult retina.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, diseases of the eye. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number~of disorders of the above tissues or cells, particularly of the eye, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types (e.g., epithelial cells, and cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid or spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder. Preferred epitopes include those comprising a sequence shown in SEQ
ID
NO. 148 as residues: Cys-14 to Lys-21.
The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for treatment and diagnosis of disorders of the eye.
FEATURES OF PROTEIN ENCODED BY GENE NO: 39 This gene is expressed primarily in bone marrow and fetal liver.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, hemopoietic disorders. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the hemopoietic system, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types (e.g., bone marrow and liver, and cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid or spinal fluid) or another tissue or cell sample taken from an individual having such a disorder. relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for treatment and diagnosis of disorders of the hemopoietic system.
FEATURES OF PROTEIN ENCODED BY GENE NO: 40 This gene is expressed primarily in lymph node, fetal liver and brain.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents far differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, hemopoietic diseases and disorders of the CNS. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the hemopoietic and CNS, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types (e.g., lymphoid tissue and other tissue of the immune system, liver, and brain and other tissue of the nervous system, and cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid or spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
The tissue distribution indicates that the protein products of this gene are useful for the diagnosis and treatment of cancer and other proliferative disorders.
Expression in embryonic tissue and other cellular sources marked by proliferating cells indicates that this protein may play a role in the regulation or cellular division.
Additionally, the expression in hematopoietic cells and tissues indicates that this protein may play a role in the proliferation, differentiation, and/or survival of hematopoietic cell lineages. Thus, this gene may be useful in the treatment of lymphoproliferative disorders, and in the maintenance and differentiation of various hematopoietic lineages from early hematopoietic stem and committed progenitor cells. In addition, polynucleotides and polypeptides corresponding to this gene are useful for the detection/treatment of neurodegenerative disease states and behavioral disorders such as Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, schizophrenia, mania, dementia, paranoia, obsessive compulsive disorder, panic disorder, and autism. In addition, the gene or gene product may also play a role in the treatment and/or detection of developmental disorders associated with the developing embryo, sexually-linked disorders, or disorders of the cardiovascular system.
FEATURES OF PROTEIN ENCODED BY GENE NO: 41 5 The translation product of this gene shares sequence homology with fibropellin and epidermal growth factors which are thought to be important in growth and regeneration of epidermal cells (See Genbank Accession Nos. W 11719 and gil310660).
Preferred polypeptides comprise the following amino acid sequence:
GTRPGESHANDLECSGKGKCTTKPSEATFSCTCEEQYVGTFCEEYDACQRKPC

GFTCQCPEGYFGSACEEKVDPCASSPCQNNGTCYVDGVHFTCNCSPGFTGPTC
AQLIDFCALSPCAHGTCRS VGTSYKCLCDPGYHGLYCEEEYNECLSAPCLNAA
TCRDLVNGYECVCLAEYKGTHCELYKDPCANVSCLNGATCDSDGLNGTCICA
PGFTGEECDIDINECDSNPCHHGGSCLDQPNGYNCHCPHGW VGANCEIHLQW
15 KSGHMAESLTN (SEQ ID N0:279); GKCTTKPSEATFSCTCEEQYVGTFC (SEQ
ID N0:280); CAHG TCRSVGTSYKCLCDPGYH (SEQ ID N0:281); and/or CANVSCLNGATCDSDGLNG TCICAPGFTGEECD (SEQ ID N0:282).
Polynucleotides encoding these polypeptides are also provided.
This gene is expressed primarily in brain and kidney and to a lesser extent in 20 several other tissues and organs.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissue{s) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, disorders of the neural and renal systems, particularly growth disorders 25 such as cancer. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the neural and renal systems, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types (e.g., brain and other 30 tissue of the nervous system, and kidney, and cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid or spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
35 The tissue distribution and homology to epidermal growth factor indicates that polynucleotides and polypeptides corresponding to this gene are useful for diagnosis and treatment of growth disorders especially in the neural and renal systems.
In addition, polynucleotides and polypeptides corresponding to this gene are useful for the detection/treatment of neurodegenerative disease states and behavioral disorders such as Alzheimer's Disease, Parkinson's Disease, Huntirigton's Disease, schizophrenia, mania, dementia, paranoia, obsessive compulsive disorder, panic disorder, and autism.
In addition, the gene or gene product may also play a role in the treatment and/or detection of developmental disorders associated with the developing embryo, sexually-linked disorders, or disorders of the cardiovascular system FEATURES OF PROTEIN ENCODED BY GENE NO: 42 This gene is expressed primarily in brain, kidney and stromal cells.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, disorders of the CNS and hemopoietic system. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the hemopoietic, renal and central nervous system, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types (e.g., brain and other tissue of the nervous system, kidney, and stromal cells, and cancerous and wounded tissues) or bodily fluids (e.g., serum> plasma, urine, synovial fluid or spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder. Preferred epitopes include those comprising a sequence shown in SEQ ID NO. 152 as residues: Lys-71 to Trp-76, Glu-99 to Gly-108, Arg-142 to Ser-149.
The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for the detectionltreatment of neurodegenerative disease states and behavioral disorders such as Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, schizophrenia, mania, dementia, paranoia, obsessive compulsive disorder, panic disorder, and autism. In addition, the gene or gene product may also play a role in the treatment and/or detection of developmental disorders associated with the developing embryo, sexually-linked disorders, or disorders of the cardiovascular system. In addition, polynucleotides and polypeptides corresponding to this gene are useful for the treatment and diagnosis of hematopoetic related disorders such as anemia, pancytopenia, leukopenia> thrombocytopenia or leukemia since stromal cells are important in the production of cells of hematopoietic lineages. The uses include bone marrow cell ex vivo culture, bone marrow transplantation, bone marrow reconstitution, radiotherapy or chemotherapy of neoplasia. The gene product is thought to be involved in lymphopoiesis, therefore, it can be used in immune disorders to modulate infection, inflammation, allergy, immunodeficiency, etc.
FEATURES OF PROTEIN ENCODED BY GENE NO: 43 The preferred polypeptide encoded by this gene comprise the following amino acid sequence: MAQNLKDLAGRLPAGPRGMGTALKLLLGAGAVAYGVRESVFT
VEGGHRAIFFNRIGGVQQDTILAEGLHFRIPWFQYPIIYDIRARPRKISSPTGSKD
IO LQMVNISLRVLSRPNAQELPSMYQRLGLDYEERVLPSIVNEVLKSWAKFNASQ
LITQRAQVSLLIRRELTERAKDFSLILDDVAITELSFSREWAAVEAKQVAQQEAQ
RAQFLVEKAKQEQRQKIVQAEGEAEAAKMLGEALSKNPGYIKLRKIRAAQNIS
KTIATSQNRIYLTADNLVLNLQDESFTRGSDSLIKGKK (SEQ ID N0:283). The gene product above share sequence similarity with prohibitin. Thus> these polypeptides are expected to share biological activities with prohibitin. Such activities are known in the art and discussed elsewhere herein.
This gene is expressed primarily in fetal brain.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, neural diseases. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissue{s) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the nervous system, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types (e.g., brain and other tissue of the nervous system, and cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid or spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder. Preferred epitopes include those comprising a sequence shown in SEQ ID NO. 153 as residues: Ala-8~ to Ser-9I, Pro-93 to Asp-98, Glu-167 to Lys-173, Gln-205 to Ala-210.
The tissue distribution and structural similarity to prohibitin indicates that the protein products of this gene are useful for the detection/treatment of neurodegenerative disease states and behavioral disorders such as Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, schizophrenia, mania, dementia, paranoia, obsessive compulsive disorder, panic disorder, and autism. In addition, the gene or gene product may also play a role in the treatment and/or detection of developmental disorders associated with the developing embryo, sexually-linked disorders, and/or disorders of the cardiovascular system.
FEATURES OF PROTEIN ENCODED BY GENE NO: 44 The translation product of this gene snares sequence homology with the F44G4.1 gene of the c. elegans genome which has no known function (See Accession No.gnIIPIDIe236516). The translation product of this gene also shares sequence homology with the human torsionA and torsionB gene products, a gene candidate for the Torsion Dystonia disease locus (See Accession Nos gi12358279 {AF007871 ) and gi12358281 (AF007872)). One embodiment for this gene is the polypeptide fragments comprising the following amino acid sequence: KALALSFHGWSGTGKNFV (SEQ
ID N0:284); NLIDYFIPFLPLEYRHVRLCAR (SEQ ID N0:285); NLIDYFIPFLPL
EYRHVRLC (SEQ ID N0:286); CHQTLFIFDEAEKLHPGLLEVLGPHL (SEQ ID
N0:287); and/or PEKALALSFHGWSGTGKNFVA (SEQ ID N0:288). An additional embodiment is the polynucleotide fragments encoding these polypeptide fragments.
This gene is expressed primarily in tonsils.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, such as tonsilitis or adnoiditis. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the immune system, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types (e.g., tonsils, and cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid or spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
The tissue distribution and homology to F44G4.1 gene of the c. elegans genome indicates that polynucleotides and polypeptides corresponding to this gene are useful for the treatment and detection of conditions affecting the tonsils.
The tonsils have not been thoroughly studied and the actually function of this organ is not known, but this gene could be used in determining what may trigger tonsillitis.
Especially in children, where the tonsils seem to be most active. Furthermore> due to the homoiogy WO 98156804 PC1'/US98/12125 of this gene, it may display potential utility in the detection, diagnosis, and/or treatment for Torsion Dystonia disease.
FEATURES OF PROTEIN ENCODED BY GENE NO: 45 Has exact sequence homology on the nucleotide level as Human HepG2 3' region cDNA, but the function of this gene is not known.
This gene is expressed primarily in osteoclastoma stromal cells and to a lesser extent in T-cells.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, leukemia and bone disorders. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of l5 the above tissues or cells, particularly of the haemolymphoid system, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types (e.g., bone tissue, and cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid or spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for the diagnosis and treatment of diseases such as leukemia.
FEATURES OF PROTEIN ENCODED BY GENE NO: 46 This gene is expressed primarily in activated monocytes.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissue{s) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, immune disorders, including leukemia and allergies. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the lymphoid system, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types (e.g., hemopoietic cells, bone marrow, and spleen, and cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid or spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
Preferred epitopes include those comprising a sequence shown in SEQ ID NO. 156 as residues:
5 Met-1 to Gly-7.
The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for the treatment in tissue repair and modeling since monocytes engage the synthesis and secretion of many cytokines which are soluble proteins that regulate highly diverse aspects of cellular biology.
Monocytes are 10 also important in the fact that their expression of Major Histocompatibility Factor II
(MHCII) enable them to select and stimulate the appropriate lymphocytes to combat specific antigens in the blood. Since the gene is expressed in cells of lymphoid origin, the natural gene product may be involved in immune functions. Therefore it may be also used as an agent for immunological disorders including arthritis, asthma, immune 15 deficiency diseases such as AIDS, and leukemia.
FEATURES OF PROTEIN ENCODED BY GENE NO: 47 Translation product of this gene has homology to the Na+/H+-exchanging protein: Na+/H+ antiporter in Methanobacterium thermoautotrophicum as well as the 20 Na+/H+ antiporter cdu2' in Clostridium difficile (See Accession Nos.
gi12621849 (AE000854) and piriJC53431JC5343, respectively). Thus, it is likely that this gene has sinular Na+/H+ antiporter activity. One embodiment for this gene are polypeptide fragments comprising the following amino acid sequence:
NLKEKIFISFAWLPKATVQAAIG (SEQ ID N0:289) and/or 25 WLPKATVQAAIGSVALD {SEQ ID N0:290). An additional embodiment is the polynucleotide fragments encoding these polypeptide fragments.
This gene is expressed primarily in osteoclastoma cells.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a 30 biological sample and for diagnosis of diseases and conditions which include, but are not limited to, osteoporosis, leukemia. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the lymphoid and skeletal systems, expression of this 35 gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types (e.g., bone cells, and cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid or spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder. Preferred epitopes include those comprising a sequence shown in SEQ ID NO. 157 as residues: His-35 to Gln-43.
S The tissue distribution predominantly in osteoclastoma cells (the site of hematopoeisis) indicates that polynucleoti-des and polypeptides corresponding to this gene are useful for the diagnosis and treatment of bone related diseases including osteporosis, osteopetrosis and leukemia. Furthermore, its homology to known transporter proteins may suggest the protein is useful in the diagnosis, treatment, and prevention of various developmental and metabolic disorders, particularly those based upon ion and proton transport.
FEATURES OF PROTEIN ENCODED BY GENE NO: 48 This gene is expressed primarily in amygdala and to a lesser extent in amniotic cells.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, depression and other emotional behavioral problems. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the nervous system, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types (e.g., brain and tissues of the nervous system, and tissues of the reproductive system, and cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid, spinal fluid or amniotic fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for the diagnosis and treatment of mental problems associated with emotional behavior and neurodegenerative states such as Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, schizophrenia, mania, dementia, paranoia, obsessive compulsive disorder and panic disorders, and depression. The amygdala processes sensory information and relays this to other areas of the brain including the endocrine and autonomic domains of the hypothalamus and the brain stem. In addition, expression of this protein in amniotic cells suggests that this protein would be useful in the diagnosis, prevention, and/or treatment of various developmental and/or reproductive system disorders.
FEATURES OF PROTEIN ENCODED BY GENE NO: 49 This gene is expressed primarily in stromal cells.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, leukemia and other cancers and disorders deriving from hematopoietic cells. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type{s). For a number of disorders of the above tissues or cells, particularly of the lymphoid system, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types (e.g., haematopoietic tissues, and cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid, spinal fluid, or lymph fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for the treatment and diagnosis of hematopoetic related disorders such as anemia, pancytopenia, leukopenia, thrombocytopenia or leukemia since stromal cells are important in the production of cells of hematopoietic lineages. The uses include bone marrow cell ex vivo culture, bone marrow transplantation, bone marrow reconstitution, radiotherapy or chemotherapy of neoplasia. The gene product may also be involved in lymphopoiesis, therefore, it can be used in immune disorders such as infection, inflammation, allergy, immunodeficiency etc.
FEATURES OF PROTEIN ENCODED BY GENE NO: 50 This gene maps to chromosome 9, and therefore, may be used as a marker in linkage analysis for chromosome 9.
This gene is expressed primarily in tumors, particularly skin and adrenal gland tumors, and to a lesser extent in bone marrow stromal cells and activated T
cells.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, cancer; hematopoietic and immune disorders. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type{s). For a number of disorders of the above tissues or cells, particularly of the skin, adrenal gland, and immune system, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types (e.g., endocrine glands, and cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid or spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
Preferred epitopes include those comprising a sequence shown in SEQ ID NO. 160 as residues:
Glu-I3 to Arg-22, Ser-58 to Trp-63.
The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for the detection and treatment of cancer. Elevated levels of expression of this gene in a variety of tumors suggest that it may play a role in cell proliferation, the induction of angiogenesis, destruction of the basal lamina, or a variety of other physiological processes that support the growth and development of tumors and cancer. Alternatively, its expression in the hematopoietic compartment, particularly in the bone marrow stroma and by activated T cells suggest that it may represent a soluble factor capable of influencing a variety of hematopoietic lineages.
Therefore, this gene product may have commercial utility in the expansion of stem cells and committed progenitors of various blood lineages, and in the differentiation and/or proliferation of blood cells.
FEATURES OF PROTEIN ENCODED BY GENE NO: 51 This gene is expressed primarily in benign human breast tissue.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, breast cancer and other female reproductive disorders.
Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the breast and reproductive tissues, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types (e.g., breast tissue, secretory/ductile organs, and cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid, spinal fluid or milk) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for the treatment and/or diagnosis of breast cancer. Alternately, this protein may play an important role in lactation or represent a critical component secreted into the milk, which may have an important function in the immunoprotection, health, and/or nourishment of the infant upon breastfeeding.
Protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or immunotherapy targets for the above listed tumors and tissues FEATURES OF PROTEIN ENCODED BY GENE NO: 52 Translation product of this gene has homology with the conserved human ring finger proteins (See Accession No.gnIlPIDie351238 (AJ001019)) which are thought to be important in facilitating and regulating signal transduction pathways in eukaryotic cells. One embodiment for this gene is the polypeptide fragments comprising the following amino acid sequence: HDRTMQDIVYKLVPGLQE {SEQ >D N0:291) and/or FASHDRTM QDIVYKLVPGLQEGE (SEQ ID N0:292). An additional embodiment is the polynucleotide fragments encoding these polypeptide fragments.
This gene is expressed primarily in adult whole brain.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, neurodegenerative disorders; Schizophrenia; Alzheimer's;
tumors of a brain or neuronal cell origin. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the CNS and/or peripheral nervous system, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types (e.g., brain and other tissue of the nervous system, and cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid or spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder. Preferred epitopes include those comprising a sequence shown in SEQ ID NO. 162 as residues: Phe-39 to Gly-44.
The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for the detection/treatment of neurodegenerative disease states and behavioral disorders such as Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, schizophrenia, mania, dementia, paranoia, obsessive compulsive disorder and panic disorder. In addition, considering the homology to the conserved ring finger proteins may suggest that the gene or gene product may also play 5 a role in the treatment and/or detection of developmental disorders associated with the developing embryo.
FEATURES OF PROTEIN ENCODED BY GENE NO: 53 Translation product of this gene shares homology with the human conserved 10 Lst-1 gene product, a member of the TNF family of proteins (See Accession No.gil l 127546). One embodiment for this gene is the polypeptide fragments comprising the following amino acid sequence: LVLSLGAWGWPSTCLWW (SEQ ID
N0:293). An additional embodiment is the polynucleotide fragments encoding these polypeptide fragments.
15 This gene is expressed primarily in human 6-week old embryo.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, abnormal cell proliferation; defects in terminal tissue differentiation.
20 Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the embryo, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types (e.g., proliferating and differentiating tissues, 25 and cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid, spinal fluid or amniotic fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
30 The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for the treatment and/or diagnosis of fetal disorders. Alternately, expression within embryonic tissues may reflect a role for this protein in proliferating cells. In such an event, this gene product may be useful in the treatment or diagnosis of abnormal cell proliferation, such as that involved in cancer.
35 Similarly, embryonic development also involves decisions involving cell differentiation and/or apoptosis involved in pattern formation. Thus, this protein may also be involved in apoptosis or tissue differentiation, and could again be useful in cancer therapy.

WO 98156804 PCT/t3S98/12125 FEATURES OF PROTEIN ENCODED BY GENE NO: 54 This gene is expressed primarily in human epithelioid sarcoma.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, epithelial sarcoma; tumors of an epithelial cell origin including the underlying integument. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the skin and epithelial tissue layers, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types (e.g., epithelial cells and tissue, and cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid or spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder. Preferred epitopes include those comprising a sequence shown in SEQ ID NO. 164 as residues: Met-1 to Tyr-6, Thr-24 to Cys-36.
The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for the treatment and/or diagnosis of epithelial cancer. This gene product displays enhanced expression in epithelial cell sarcoma, and thus may be involved in cell proliferation, apoptosis, or in the control of angiogenesis.
FEATURES OF PROTEIN ENCODED BY GENE NO: 55 This gene is expressed primarily in endometrial tumors.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, endometrial cancer including other cancers of the female reproductive system. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the endometrium and reproductive system, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types (e.g., endrometrial tissue as well as other tissues of the female reproductive system, and cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid or spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for diagnosis and treatment of cancers, particularly those of the endometrium and other reproductive organs. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or immunotherapy targets for the above listed tumors and tissues FEATURES OF PROTEIN ENCODED BY GENE NO: 56 This gene is expressed primarily in metastatic melanoma and to a lesser extent in fetal lung.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, cancer of the integument system, particularly melanoma, as well as within the developing pulmonary system. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the skin, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types (e.g., cells capable of forming melanin, epithelia, and lung, and cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid, spinal fluid, or pulmonary surfactant) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder. Preferred epitopes include those comprising a sequence shown in SEQ
ID
NO. 166 as residues: Asp-20 to Lys-25.
The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for diagnosis and treatment of cancer, particularly melanoma and more particularly, metastasizing melanomas. In addition, the tissue distribution also indicates that polynucleotides and polypeptides corresponding to this gene are useful for the diagnosis and treatment of cancer and other proliferative disorders. Expression in embryonic tissue and other cellular sources marked by proliferating cells indicates that this protein may play a role in the regulation or cellular division.

FEATURES OF PROTEIN ENCODED BY GENE NO: 57 This gene is expressed primarily in T-cell lymphoma.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, lymphomas and other immune derived cancers. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the immune system, expression of this gene at significantly higher or lower Levels may be routinely detected in certain tissues and cell types (e.g., T-cells and other cells and tissue of the immune system, and cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid or spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder. Preferred epitopes include those comprising a sequence shown in SEQ
ID
NO. 167 as residues: Met-1 to Asn-7.
The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for diagnosis and treatment of lymomas, particularly T cell lymphomas, and other cancers. In addition, the tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for the diagnosis and treatment of cancer and other proliferative disorders.
Additionally, the expression in hematopoietic cells and tissues indicates that this protein may play a role in the proliferation, differentiation, and/or survival of hematopoietic cell lineages. Thus, this gene may be useful in the treatment of lymphoproliferative disorders, and in the maintenance and differentiation of various hematopoietic Iineages from early hematopoietic stem and committed progenitor cells.
FEATURES OF PROTEIN ENCODED BY GENE NO: 58 This gene maps to chromosome 7, and therefore is useful in linkage analysis as a marker for chromosome 7.
This gene is expressed primarily in brain and to a lesser extent in spinal cord.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, CNS and PNS diseases and disorders. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the nervous system, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types (e.g., brain, spinal cord and other tissue of the nervous system, and cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid or spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
Preferred epitopes include those comprising a sequence shown in SEQ ID NO. 168 as residues:
Tyr-14 to Ala-30.
The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for the detection/treatment of neurodegenerative disease states and behavioral disorders such as Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, schizophrenia, mania, dementia, paranoia, obsessive compulsive disorder, panic disorder, and autism.
FEATURES OF PROTEIN ENCODED BY GENE NO: 59 Translation product of this gene shares homology to the conserved C. elegans protein FER-1 (See Accession No.gil1373333). One embodiment for this gene is the polypeptide fragments comprising the following amino acid sequence:
QGKLQMWVDVFPKSL (SEQ ID N0:294); PPFNITPRKAKKYYLR (SEQ ID
N0:295); KTDVHYRSLDGEGNFNWRF (SEQ ID N0:296); and/or PRLIIQIWDNDKFSLDDY LGFLELDL {SEQ ID N0:297). An additional embodiment is the polynucleotide fragments encoding these polypeptide fragments.
This gene is expressed primarily in synovial fibroblasts and to a lesser extent in synovial hypoxia.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, synovial inflammation and other diseases of the joints.
Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the synovium, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types (e.g., synovial tissue, and cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid or spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for diagnosis and treatment of diseases affecting 5 the synovium of the joints, such as rheumatoid arthritis, osteoarthritis, other inflammatory conditions affecting the joints, as well as in the detection and treatment of disorders and conditions affecting the skeletal system, in particular the connective tissues (e.g. trauma, tendonitis, chrondomalacia and inflammation).
Furthermore, the homology to a conserved C.elegans protein may suggest protein is important in human 10 development and thus is beneficial in the diagnosis, prevention, and treatment of developmental disorders.
FEATURES OF PROTEIN ENCODED BY GENE NO: 60 This gene is expressed primarily in endothelial cells and to a lesser extent in 15 brain.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, inflammation and other disorders of the integument, in addition to 20 neurodegenerative and nervous system disorder, such as stroke. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the endothelial, circulatory, and nervous systems, expression of this gene at significantly higher or 25 lower levels may be routinely detected in certain tissues and cell types (e.g., endothelial cells, and brain and other tissue of the nervous system, and cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid or spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily 30 fluid from an individual not having the disorder. Preferred epitopes include those comprising a sequence shown in SEQ ID NO. 170 as residues: Ser-4 to Gly-13.
The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for diagnosis and treatment of inflammatory diseases primarily mediated through endothelial cells, such as sepsis, inflammatory 35 bowel disease, psoriasis, and Crohn's disease, as well as for stroke.
Alternatively, the tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for the detection/treatment of neurodegenerative disease states and behavioral disorders such as Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, schizophrenia, mania, dementia, paranoia, obsessive compulsive disorder and panic disorder. In addition, the gene or gene product may also play a role in the treatment and/or detection of developmental disorders associated with the developing embryo, or disorders of the cardiovascular system.
FEATURES OF PROTEIN ENCODED BY GENE NO: 61 This gene is expressed primarily in fetal brain.
Therefore, polynucleotides and poIypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, CNS and PNS disorders. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the nervous system, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types (e.g., developing and differentiating tissues, brain and other tissue of the nervous system, and cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid, spinal fluid, or amniotic fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for diagnosis and treatment of neural disorders such as Alzheimer's disease, depression, paranoia, schizophrenia, autism, and particularly developmental brain disorders..
FEATURES OF PROTEIN ENCODED BY GENE NO: 62 Translation product of this gene shares homology with a conserved 4-nitrophenylphosphatase from Schizosaccharomyces pombe (See Accession No.
gi11938421 ). One embodiment for this gene is the polypeptide fragments comprising the following amino acid sequence: AVMIGDDCRDDVGGA (SEQ ID N0:298), andlor ILVKTGKYRASDEEKIN (SEQ ID N0:299}. An additional embodiment is the polynucleotide fragments encoding these polypeptide fragments. This gene maps to chromosome 18, and therefore, may be used as a marker in linkage analysis for chromosome 18.

This gene is expressed primarily in endometrial tumors and to a lesser extent in leukemia and lymphoma.
Therefore, polynucleotides and poIypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, cancer, particularly of the immune and hematopoietic systems.
Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the endometrium and white blood cells, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types (e.g., endrometrial andlor proliferating tissues, and cells and tissue of the immune system, and cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid, spinal fluid, or lymph) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder. Preferred epitopes include those comprising a sequence shown in SEQ
ID
NO. 172 as residues: Val-19 to Cys-24.
The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for detection, diagnosis , and treatment of cancers, particularly those cancers affecting endometrial tissues and the lymphatic system. In addition, the tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for the treatment and diagnosis of hematopoetic related disorders such as anemia, pancytopenia, leukopenia, thrombocytopenia or leukemia since stromal cells are important in the production of cells of hematopoietic lineages. The uses include bone marrow cell ex vivo culture, bone marrow transplantation, bone marrow reconstitution, radiotherapy or chemotherapy of neoplasia. The gene product may also be involved in Iymphopoiesis, therefore, ii can be used in immune disorders such as infection, inflammation, allergy, immunodeficiency etc. Furthermore, homology to a conserved S.pombe protein may suggest protein is important in development. Therefore, protein may be beneficial in the diagnosis, prevention, and treatment of developmental disorders.
FEATURES OF PROTEIN ENCODED BY GENE NO: 63 The translation product of this gene shares sequence homology with ribosomal releasing factor which is thought to be important in protein synthesis.

This gene is expressed primarily in pancreatic tumors, placenta, testis, ovarian cancer, adipocytes, spleen, and fetal liver and heart.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for diagnosis of a number of diseases and conditions such as immune-diseases, cardiovascular and endocrine diseases and others. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the immune system, cardiovascular system, digestive system and reproductive system. expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types (e.g., pancreas, testis and ovary and other reproductive tissue, adipocytes, spleen, liver, and heart, and cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid, spinal fluid, or lymph) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder. Preferred epitopes include those comprising a sequence shown in SEQ ID NO. 173 as residues: Glu-3b to His-4I, Thr-57 to Thr-70, Glu-87 to Met-92, Lys-100 to Lys-105, Ala-197 to Ser-227.
The tissue distribution and homology to ribosomal releasing factor indicates that polynucleotides and polypeptides corresponding to this gene are useful for the treatment and diagnosis of many diseases, especially cancers and immuno-related diseases.
FEATURES OF PROTEIN ENCODED BY GENE NO: 64 The translation product of this gene shares sequence homology with metalloprotease and also with thrombospondin, which is thought to be important in the activation of proteins and the processes of thrombopoiesis and metabolism.
This gene is expressed in many tissues, but especially in bladder, kidney, and ovary.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of thrombopenia, hypertension, and other blood disfunctions. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the immune system, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types (e.g., urogenital, and reproductive tissues, and cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder. Preferred epitopes include those comprising a sequence shown in SEQ
ID
NO. 174 as residues: Gly-8 to Leu-14, Met-18 to Phe-30.
The tissue distribution and homology to thrombospondin indicates that polynucleotides and polypeptides corresponding to this gene are useful for the treatment and diagnosis of a variety of blood-related diseases.
FEATURES OF PROTEIN ENCODED BY GENE NO: 65 This gene is expressed primarily in tonsil, placenta, and fetal tissues.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of many diseases of the immune system.
Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the immune system, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types (e.g., immune and developmental tissues, and cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid, spinal fluid, or amniotic fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for diagnosis and treatment of diseases of the immune system including many cancers such as lymphomas, leukemias, lymphocytomas, and the like.
FEATURES OF PROTEIN ENCODED BY GENE NO: 66 Polypeptides encoded by this gene share reasonable homology to steroid/thyroid hormone orphan nuclear receptor and to several additional orphan nuclear receptors isolated from several different tissues.
This gene is expressed primarily in testis.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of testicular tumors, impotence, and other reproductive disorders. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the reproductive system, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types {e.g., male 5 reproductive tissue, and cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid, spinal fluid, or seminal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
10 The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for the treatment and diagnosis of diseases in the male reproductive system such as tumors of the testis and other reproductive disorders.
FEATURES OF PROTEIN ENCODED BY GENE NO: 67 15 Polypeptides encoded by polynucleotides comprising this gene have a high degree of sequence identity with CTGF-4.
In one embodiment, the polypeptides of the invention comprise the sequence: MDSMPEPASRCLLLLPLLLLLLLLLPAPELGPSQAGAEENDWVRLPSK
CEVCKYVAVELKVKPLRKRQDTEVIGTVYGILDQKASGVKYTKSDLRLIEVTET

TSAEVADLKKQCDVLVEEFEEVIEDWYRNHQEEDLTEFLCANHVLKGKDTSCL
AEQWSGKKGDTAALGGKKSKKKSIRAKAAGGRSSSSKQRKELGGLEGDPSP
EEDEGIQKASPLTHSPPDEL(SEQ ID N0:300). Polynucleotides encoding these polypeptide sequences are also encompassed by the invention.
25 This gene is expressed in many tissues especially including cells in the immune system.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissue{s) or cell type{s) present in a biological sample and for the diagnosis of cancers, immunological disorders, and neural 30 diseases (such as spinocerebellar ataxia, bipolar affective disorder, schizophrenia, and autism), and other diseases featuring anticipation, neurodegeneration, or abnormalities of neurodevelopment. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, 35 particularly of the nerve system, immune system, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types (e.g., immune cells and/or tissue, and cancerous and wounded tissues) or bodily fluids {e.g.> serum, plasma, urine, synovial fluid, spinal fluid, or lymph) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.Preferred epitopes include those comprising a sequence shown in SEQ ID NO. 177 as residues: Ser-3 to Ser-9, Gly-to Val-43, Leu-45 to Gly-51.
FEATURES OF PROTEIN ENCODED BY GENE NO: 68 Polypeptides encoded by polynucleotides comprising this gene contain a zinc finger homology domain. Such motifs are believed to be important for protein interactions, particularly with regard to gene regulation.
This gene is expressed primarily in T cells and the colon and, to a lesser extent, in the testes and placenta.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of many immune and digestive disorders.
Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type{s). For a number of disorders of the above tissues or cells, particularly of the immune and digestive systems, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types (e.g., immune, gastrointestinal, and reproductive system tissues, and cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid, spinal fluid, or seminal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder. Preferred epitopes include those comprising a sequence shown in SEQ ID NO. 178 as residues: Pro-12 to Lys-33, Asn-41 to His-46, Pro-48 to Ser-58, Gly-71 to Asp-78, Ala-94 to Gly-102, Ser-133 to Ser-140, Arg-197 to Lys-202.
The expression of this gene in T-cells indicates a potential role in the treatment and detection of immune disorders such as arthritis, asthma, immune deficiency diseases (such as AIDS), and leukemia. Expression of this gene in the colon indicates a potential role in the treatment and detection of colon disorders such as ulcers and colon cancer in addition to digestive disorders in general.

FEATURES OF PROTEIN ENCODED BY GENE NO: 69 The translation product of this gene shares sequence homology with neuroendocrine protein which is thought to be important in neuronal development and differentiation. A preferred embodiment of this gene comprises the following amino acid sequence: MDGQKKNWKDKVVDLLYWRDIKKTGVVFGASLFLLLSLTVF
SIVSVTAYIALALLSVTISFRIYKGVIQAIQKSDEGHPFRAYLESEVAISEELVQKY
SNSALGHVNCTIKELRRLFLVDDLVDSLKFAVLMWVFTYVGALFNGLTLLILAL
ISLFSVPVIYERHQAQIDHYLGLANKNVKDAMAKIQAKIPGLKRKAE (SEQ ID
N0:301). Particularly preferred are polynucleotides comprising polynucleotides encoding this polypeptide sequence.
This gene is expressed in many different tissues, but primarily in brain, and, to a lesser extent, in fetal tissue, placenta, bone marrow, and stromal cells.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for diagnosis of neurodegenerative diseases and developmental disorders.
Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the nervous system and during development, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types (e.g., neural, developmental, and hemopoietic cells and tissue, and cancerous and wounded tissues) or bodily fluids {e.g., serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder. Preferred epitopes include those comprising a sequence shown in SEQ ID NO. 179 as residues: Gln-47 to Gly-52, Leu-169 to Glu-174.
The predominant tissue distribution in brain and homology to neuroendocrine protein indicates that polynucleotides and polypeptides corresponding to this gene are useful for the diagnosis and treatment of neurodegenerative diseases and behavioral disorders such as Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, schizophrenia, mania, dementia, paranoia, obsessive-compulsive disorder and panic disorder.
FEATURES OF PROTEIN ENCODED BY GENE NO: 70 Polypeptides encoded by polynucleotides comprising this gene share sequence identity with human hepatoma-derived growth factor (WPI 95-069304110). As such, polynucleotides comprising this gene can be used for the recombinant production of the WO 98156804 PCT/US98l12125 protein, which can be used to encourage the growth of various animal cells, and for the purification of receptors. Additional embodiments of the invention comprise the following polypeptide sequences: MAVTLSLLLGGRVCA (SEQ ID N0:302);
PSLAVGSRPGGW RAQALLAGSRTPIPTGSRRNGSCRRWRAP (SEQ ID
N0:303); and/or MAVTLSLLLGGRVCAPSLAVGSRPGGWRAQALLAGSRTPIPTG
SRRNGSCRRWRAP (SEQ ID N0:304). Also contemplated are polynucleotides comprising polynucleotides encoding the aforementioned polypeptide sequences.
This gene is expressed primarily in brain and to a lesser extent in endotheilium, T- cell, and tumors.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of many neurodegenerative diseases (for example, Alzheimer's Disease, ALS, and the like) and cancers (including, but not limited to neuroblastoma, glioblastoma, Schwannoma, astrocytoma, and the like).
Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the nervous system, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types (e.g., neural, and haematopoietic cells and tissue, and cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid, spinal fluid or lymph) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder. Preferred epitopes include those comprising a sequence shown in SEQ
ID
NO. 180 as residues: Pro-4 to Thr-10, Glu-25 to Trp-30, Leu-58 to Leu-69, Arg-82 to Thr-87, Ala-108 to His-115, Ser-124 to Glu-146, Pro-159 to Gly-176, Ser-182 to Glu-187, Leu-189 to Ser-198, Phe-208 to Asn-214.
The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for the treatment and diagnosis of many neurodegenerative diseases and cancers.
FEATURES OF PROTEIN ENCODED BY GENE NO: 71 The translation product of this gene shares sequence homology with acrosin, trypsin, as well as trypsinogen precursor which are thought to be important in cell-cell recognition and proteinase activity for protein cleavage and degradation.
Preferred polynucleotide fragments comprise the following sequence:
GATGTTACACAGCTCTTTAATAATAGTGGCCATAGCTGTAATAACAATGACA

ACAGTAGGTAACGGTAGTCATACCAACAGTAGGGCAGTGCATTTTATATTAC
AACTGGTTTCTTGCTCTAGTAGGCTTGGGGATGGGTGAAGACGGACAGGGC
TGGCGCAGACCCTTTCCTTCTCCTCTCCAGCCCACAGTGATCTGGGCTTTTA
CAGACAGCCTGCTTCCATTCAGTAGTGTGGGAAAGTTCCTTCTTGGCTTAGC
AATACCCCTGAGACCTTGTTCAGTGGGCTGTGTCTCTCCCTGGGATGCTGG
GAGCACCAAGTGTGGCCGAGCTAGGGCTGCTGACTTCCTCTGGGCGCCTCT
GGGCTGCGAGGGTCTCTTATAGGAATTGAGGCCCTTTGCTGCTCCAAGAAA
TGCGAGGCTGTGGGCARAGGGKTGTACCCAAGGGGACTCTTGCTCTGTGT
CTGACTTTGGGGRATCC (SEQ ID N0:305); CACAGCTCTTTAATAATAGTGGC
CATAGCTGTAATAACAATGACA ACAGTAGGTAACG (SEQ ID N0:306);
TGTGTCTCTCCCTGGGATGCTGGGAGCACCAAGTGTGGCCGAGCTAGGGCT
GCTGACTT (SEQ ID N0:307); GCGAGGGTCTCTTATAGGAATTGAGGCCCTT
TGCTGCTCCAAGAAATGCTGAGGCTGTGGGCARAGGGKTGTACCCAAGGG
GACT (SEQ ID N0:308). Also preferred are polypeptide fragments encoded by these polynucleotide fragments.
This gene is expressed primarily in cheek carcinoma and to a lesser extent in uterine and pancreatic cancers.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, cheek cancers or cancers of uterine and pancreatic origins.
Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the neoplastic tissues, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types (e.g., epithelial, endocrine, and reproductive tissues, and cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid, spinal fluid, and saliva) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
The tissue distribution and homology to acrosin and trypsin indicates that polynucleotides and polypeptides corresponding to this gene are useful for diagnosis and intervention of cancers. The homology to acrosin and trypsin may indicate the gene function in tumor metastasis or migration since in both cases cell-cell interaction and extracellular matrix degradation may be involved. The gene product can also be used as a target for cancer immunotherapy or as a diagnostic marker.

FEATURES OF PROTEIN ENCODED BY GENE NO: 72 This gene is expressed primarily in T helper cells I, T-cells stimulated with PHA
for 24 hours, and in a placenta Nb2HP cDNA library.
5 Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of many immunodeficiencies and disorders (especially autoimmune diseases). Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential 10 identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the immune system expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types (e.g., immune, and haematopoietic cells and tissue, and cancerous and wounded tissue) or bodily fluids (e.g., serum, plasma, urine, synovial fluid, spinal fluid and 15 lymph) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for the diagnosis and treatment of autoimmune 20 diseases, immunodeficiencies, and other immune system disorders.
FEATURES OF PROTEIN ENCODED BY GENE NO: 73 This gene is expressed primarily in 7 week old early stage human, human chronic synovitis, and infant brain.
25 Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of chronic synovitis. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders 30 of the above tissues or cells, particularly of the synovium, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types (e.g., developmental, differentiating, and neural tissues, and cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid, spinal fluid, and amniotic fluid) or another tissue or cell sample taken from an individual 35 having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder. Preferred epitopes include those comprising a sequence shown in SEQ
ID
NO. 183 as residues: Ser-44 to Pro-49.
The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for the diagnosis and treatment of chronic synovitis and other disorders of the synovium.
FEATURES OF PROTEIN ENCODED BY GENE NO: 74 Polypeptides encoded by polynucleotides comprising this gene exhibit sequence homology to a number of mucin-like extracellular or cell surface proteins. In one embodiment polypeptides of the invention comprise the following sequence:
MVGPVTLHKKIHTTTVLFIVQIHILLIQAITQAK (SEQ >D N0:309); LQMHLMILQ
MTGLSILALLGKSTTTIVEQKFHNGKNQKSGLKENRDKKKQTRWQSTASQKI
GITEER (SEQ ID N0:310); and/or MVGPVTLHKKIHTTTVLFIVQIHILLIQAITQ
AKLQMHLMILQMTGLSILALLGKSTTTIVEQKFHNGKNQKSGLKENRDKKKQ
TRWQSTASQKIGITEER (SEQ ID N0:311). Polynucleotides encoding the aforementioned polypeptides are also contemplated embodiments of the invention.
This gene is expressed primarily in ovarian cancer, endometrial tumor, B-cell lymphoma, brain-medulloblastoma, hepatocellular tumor, osteosarcoma, and T-and B-cells.
Therefore, polynucleotides and poIypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, Ovarian cancer, endometrial tumor, B-cell lymphoma, brain medulloblastoma, hepatocellular tumor, and osteosarcoma. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunologicai probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the immune system, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types (e.g., brain and other tissue of the nervous system, bone, T-cells and other cells of the immune system, and B cells and other blood cells, and cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid, spinal fluid and lymph) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
Preferred epitopes include those comprising a sequence shown in SEQ ID NO. 184 as residues:
Met-1 to Lys-12, Leu-14 to Asn-35, Arg-42 to Asn-58, Ser-65 to Trp-90, Ser-95 to Asn-129, Phe-136 to Arg-144. Met-159 to Ala-167, Thr-179 to Tyr-187, Pro-190 to Val-20I, Gln-226 to Phe-235, Pro-254 to His-272, Thr-288 to Thr-293, Thr-383 to Ser-391, Asp-398 to Tyr-405, Ile-410 to Asn-416, Ala-449 to Lys-458.
The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for the diagnosis and treatment of ovarian cancer, endometrial tumors, B-cell lymphoma, brain medulloblastoma, hepatocellular tumor, and osteosarcoma.
FEATURES OF PROTEIN ENCODED BY GENE NO: 75 An additional preferred polypeptide sequence derived from the polynucleotide of this contig comprises the following amino acid sequence: MQTCPLVGTLLTRNMDG
YTCAV VTSTSFWIISAWXLWKGSPSTSMPTMPETPLRTLCCTKMPSIFSSLMTD
GRA (SEQ ID N0:312). Polynucleotides encoding these polypeptides are also provided. This polypeptide sequence has sequence homology with a Drosoplnla melanogaster male germ-line specific transcript which encodes a putative protamine IS molecule (see, gi1608696).
This gene is expressed primarily in breast tissue and to a lesser extent in various other fetal and adult cells and tissues, especially those comprising endocrine organs.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, developmental and reproductive defects. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the female reproductive system, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types (e.g., breast and/or other ductile secretory tissues, and cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid, spinal fluid, and milk) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for study and treatment of developmental, reproductive and growth and metabolic disorders.
FEATURES OF PROTEIN ENCODED BY GENE NO: 76 In one embodiment, the polypeptides of the invention comprise the sequence:
MTLIQNCWYSWLFFGFFFHFLRKSISIFSIFLVCFRILALGPTCFLVWF'WKAFFR

HILIFICLSREVFRPRCFLVYFR (SEQ ID N0:313). This polypeptide sequence has sequence homology with the MURF4 protein of Herpetomonas muscarum (S43288).
Such RNA-editing enzymes may be useful as molecular targets in the intervention of the life cycle of trypanosomes and other protozoa. Polynucleotides encoding these polypeptides are also encompassed by the invention.
This gene is expressed primarily in fetal liver and spleen, osteosarcoma and bone marrow.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of liver tumors, osteosarcoma, and other cancers.
Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the immune system, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types (e.g., hepatic, developmental, and differentiating tissue, bone cells, liver and spleen, and cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid, spinal fluid, and lymph) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for diagnosis of cancers such as liver tumor and osteosarcoma.
FEATURES OF PROTEIN ENCODED BY GENE NO: 77 This gene is expressed primarily in T cell lymphoma and monocytes.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of T-cell lymphoma. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the immune system, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types (e.g., immune and hematopoietic cells and tissues, and cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid, spinal fluid, and lymph) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
Preferred epitopes include those comprising a sequence shown in SEQ ID NO. 187 as residues:
Thr-1 to Ser-9.
The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for diagnosis and treatment of T-cell lymphoma.
FEATURES OF PROTEIN ENCODED BY GENE NO: 78 This gene is expressed primarily in tonsils and a bone marrow cell line.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of immunological disorders. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the immune system, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types (e.g., haematopoietic and immune cells and tissues, and cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid, spinal fluid, and lymph) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
The tissue distribution indicates that polynucleotides and poIypeptides corresponding to this gene are useful for the diagnosis and treatment of immunological disorders.
FEATURES OF PROTEIN ENCODED BY GENE NO: 79 In one embodiment, the polypeptides of the invention comprise the sequence:
MGTRAQVTPGRLPIPPPAPGLPFSAXEPLQGQLRRVSSSRGGFPGLALQLLRSE
TVKAYVNNEINILASFF (SEQ ID N0:314) and/or MLVRTRPSQPLPLPGVGLGGP
RSGDPPESTELRKGPGFLA (SEQ ID N0:315). Polynucleotides encoding these polypeptides are also encompassed by the invention.
This gene is expressed primarily in brain, placenta, bone marrow, keratinocyte, fetal liver, and spleen.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of brain and skin related diseases.
Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type{s). For a number of disorders of the above tissues or cells, particularly of the immune and skin system, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types (e.g., neural, reproductive, and hepatic tissues, keratinocytes, and spleen, and cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder. Preferred epitopes include those comprising a 10 sequence shown in SEQ ID NO. 189 as residues: Phe-13 to Leu-18.
The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for the diagnosis and treatment of many brain and skin related diseases.
15 FEATURES OF PROTEIN ENCODED BY GENE NO: 80 The translation product of this gene shares sequence homology with mouse RNA Polymerase I which is thought to be important in gene transcription process.
This gene is expressed primarily in HEL cell line and aorta endothelial cells and to a lesser extent in 3urkat T-cells.
20 Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell type{s) present in a biological sample and for diagnosis and treatment of cancer and autoimmune diseases.
Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell 25 type(s). For a number of disorders of the above tissues or cells, particularly of the immune system, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types (e.g., endothelial, haematopoietic tissues, cardiovascular tissue, and T-cells and other cells of the immune system, and cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial 30 fluid, spinal fluid, and lymph) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder. Preferred epitopes include those comprising a sequence shown in SEQ
ID
NO. 190 as residues: Lys-25 to Arg-32.
35 The tissue distribution and homology to mouse RNA polymerase I indicates that polynucleotides and polypeptides corresponding to this gene are useful for the treatment of immune diseases and cardiovascular diseases.

FEATURES OF PROTEIN ENCODED BY GENE NO: 81 In one embodiment, the polypeptides of the invention comprise the sequence:
MCPVCGRALSSPGSLGRHLLIHSEDQRSNCAVCGARFTSHATFNSEKLPEVLN
MESLPTVHNEGPSSAEGKDIAFSPPVYPAGILLVCNNCAAYRKXLEAQTPSVX
KWALRRQNEPLEVRLQRLERERTAKKSRRDNETPEEREVRRMRDREAKRLQR
MQETDEQRARRLQRDREAMRLKRANETPEKRQARLIREREAKRLKRRLEKMD
MMLRAQFGQDPSAMAALAAEMNFFQLPVSGVELDXQLLGKMAFEEQNSSXLH
(SEQ ID N0:316). This polypeptide shares sequence homology with human trichohylin which is thought to be important in gene regulation. Polynucleotides encoding this polypeptide are also encompassed by the invention.
This gene is expressed primarily in brain tissue and to a lesser extent in apoptopic T-cell and B-cell lymphoma.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis and treatment of growth disorders, neurodegenerative diseases, and endochrine disorders. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the neural and immune systems, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types (e.g., neural tissues, T-cells, B-cells and other cells and tissue of the immune system, and cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid or spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
The tissue distribution and homology to DNA binding protein indicates that polynucleotides and polypeptides corresponding to this gene are useful for the diagnosis and treatment of immune and neurological diseases.
FEATURES OF PROTEIN ENCODED BY GENE NO: 82 In one embodiment, the polypeptides of the invention comprise the sequence:
MDHSHHMGMSYMDSNSTMQPSHHHPTTSASHSHGGGDSSMMMMPMTFYFG
FKNVELLFSGLVINTAGEMAGAFVAVFLLAMFYEGLKIARESLLRKSQVSIRYN
SMPVPGPNGTILMETHKTVGQQMLSFPHLLQTVLHIIQV VISYFLMLIFMTYNG
YLCIAXAAGAGTGYFLFSWKKAVVVDITEHCH (SEQ ID N0:317). This polypeptide is thought to function in mediating the uptake of copper and other metal ions by cells. Polynucleotides encoding this polypeptide are also encompassed by the invention.
This gene is expressed primarily in osteosarcoma and to a lesser extent in T-cell and bone marrow stromaI cell.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for treatment and diagnosis of osteosarcoma and copper and other metal uptake disorders. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the immune system, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types (e.g., hematopoietic tissue and cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid, spinal fluid, and lymph) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder. Preferred epitopes include those comprising a sequence shown in SEQ ID NO. 192 as residues: Ser-24 to Ser-29.
The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for the prevention or treatment of osteosarcoma and copper or other metal uptake disorders.
FEATURES OF PROTEIN ENCODED BY GENE NO: 83 This gene is expressed primarily in skin tumor and to a lesser extent in apoptic T-cell.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types}
present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, skin tumor. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the skin, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types (e.g., epithelial and hematopoietic tissues, and T-cells and other tissue of the immune system, and cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid, and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
Preferred epitopes include those comprising a sequence shown in SEQ ID NO. 193 as residues:
Leu-51 to Gly-77, Ile-117 to Pro-125.
The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for diagnosis the treatment of skin tumor.
FEATURES OF PROTEIN ENCODED BY GENE NO: 84 This gene is expressed primarily in testis.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, infertility and endocrine disorders. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the reproductive system, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types (e.g., reproductive tissue, and cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid, spinal fluid, and seminal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for the treatment of reproductive disease and endocrine disorders.
FEATURES OF PROTEIN ENCODED BY GENE NO: 85 In one embodiment, the polypeptides of the invention comprise the sequence:
MVQPCGACAKTXWKACSSCCSSPCCLQERWPXPXAXCPEXGPSSHPGIQALC
AVAWYLSPSSRLDWSLAPLFVPSLAAGETPLTQPAWALTTNTLGHGQPAQDR
LPALGHCAPISVLGLGSS (SEQ ID N0:318). Polynucleotides encoding this polypeptide sequence are also encompassed by the invention.
This gene is expressed primarily in kidney cortex, frontal cortex, spinal cord and hippocampus.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, kidney fibrosis, schizophrenia and neurological disorders.
Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the neural system, S expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types (e.g., endothelial, neural and endocrine tissue, and cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid or spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
Preferred epitopes include those comprising a sequence shown in SEQ ID NO. 195 as residues:
Cys-27 to Tyr-33, Thr-38 to Gly-43, Leu-125 to Gly-130.
The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for the treatment of neurological disorders and kidney diseases..
FEATURES OF PROTEIN ENCODED BY GENE NO: 86 This gene is expressed primarily in resting T-cell.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissue{s) or cell type{s) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, T-cell related diseases. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the immune system, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues and cell types (e.g., hematopoietic and immune cells and tissues, and cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid, spinal fluid, and lymph) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, {i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder). Preferred epitopes include those comprising a sequence shown in SEQ ID NO. 196 as residues: Thr-54 to Ile-59.
The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for the treatment of immune diseases.

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Table 1 summarizes the information corresponding to each "Gene No." described above. The nucleotide sequence identified as "NT SEQ ID NO:X" was assembled from partially homologous ("overlapping") sequences obtained from the "cDNA clone ID"
identified in Table 1 and, in some cases, from additional related DNA clones.
The 5 overlapping sequences were assembled into a single contiguous sequence of high redundancy (usually three to five overlapping sequences at each nucleotide position), resulting in a final sequence identified as SEQ ID NO:X.
The cDNA Clone ID was deposited on the date and given the corresponding deposit number listed in "ATCC Deposit No:Z and Date." Some of the deposits contain 10 multiple different clones corresponding to the same gene. "Vector" refers to the type of vector contained in the cDNA Clone ID.
"Total NT Seq." refers to the total number of nucleotides in the contig identified by "Gene No." The deposited clone may contain all or most of these sequences, reflected by the nucleotide position indicated as "5' NT of Clone Seq." and the "3' NT
15 of Clone Seq." of SEQ ID NO:X. The nucleotide position of SEQ ID NO:X of the putative start codon (methionine) is identified as "5' NT of Start Codon."
Similarly , the nucleotide position of SEQ ID NO:X of the predicted signal sequence is identified as "5' NT of First AA of Signal Pep."
The translated amino acid sequence, beginning with the methionine, is identified 20 as "AA SEQ ID NO:Y," although other reading frames can also be easily translated using known molecular biology techniques. The polypeptides produced by these alternative open reading frames are specifically contemplated by the present invention.
The first and last amino acid position of SEQ ID NO:Y of the predicted signal peptide is identified as "First AA of Sig Pep" and "Last AA of Sig Pep." The predicted 25 first amino acid position of SEQ ID NO:Y of the secreted portion is identified as "Predicted First AA of Secreted Portion." Finally, the amino acid position of SEQ ID
NO:Y of the last amino acid in the open reading frame is identified as "Last AA of ORF."
SEQ ID NO:X and the translated SEQ ID NO:Y are sufficiently accurate and 30 otherwise suitable for a variety of uses well known in the art and described further below. For instance, SEQ ID NO:X is useful for designing nucleic acid hybridization probes that will detect nucleic acid sequences contained in SEQ ID NO:X or the cDNA
contained in the deposited clone. These probes will also hybridize to nucleic acid molecules in biological samples, thereby enabling a variety of forensic and diagnostic 35 methods of the invention. Similarly, polypeptides identified from SEQ ID
NO:Y may be used to generate antibodies which bind specifically to the secreted proteins encoded by the cDNA clones identified in Table 1.

Nevertheless, DNA sequences generated by sequencing reactions can contain sequencing errors. The errors exist as misidentified nucleotides, or as insertions or deletions of nucleotides in the generated DNA sequence. The erroneously inserted or deleted nucleotides cause frame shifts in the reading frames of the predicted amino acid sequence. In these cases, the predicted amino acid sequence diverges from the actual amino acid sequence, even though the generated DNA sequence may be greater than 99.9% identical to the actual DNA sequence (for example, one base insertion or deletion in an open reading frame of over 1000 bases).
Accordingly, for those applications requiring precision in the nucleotide sequence or the amino acid sequence, the present invention provides not only the generated nucleotide sequence identified as SEQ ID NO:X and the predicted translated amino acid sequence identified as SEQ ID NO:Y, but also a sample of plasmid DNA
containing a human cDNA of the invention deposited with the ATCC, as set forth in Table 1. The nucleotide sequence of each deposited clone can readily be determined by sequencing the deposited clone in accordance with known methods. The predicted amino acid sequence can then be verified from such deposits. Moreover, the amino acid sequence of the protein encoded by a particular clone can also be directly determined by peptide sequencing or by expressing the protein in a suitable host cell containing the deposited human cDNA, collecting the protein, and determining its sequence.
The present invention also relates to the genes corresponding to SEQ ID NO:X, SEQ B7 NO:Y, or the deposited clone. The corresponding gene can be isolated in accordance with known methods using the sequence information disclosed herein.
Such methods include preparing probes or primers from the disclosed sequence and identifying or amplifying the corresponding gene from appropriate sources of genomic material.
Also provided in the present invention are species homologs. Species homologs may be isolated and identified by making suitable probes or primers from the sequences provided herein and screening a suitable nucleic acid source for the desired homologue.
The polypeptides of the invention can be prepared in any suitable manner. Such polypeptides include isolated naturally occurring polypeptides, recombinantly produced polypeptides, synthetically produced polypeptides, or polypeptides produced by a combination of these methods. Means for preparing such polypeptides are well understood in the art.
The polypeptides may be in the form of the secreted protein, including the mature form, or may be a part of a larger protein, such as a fusion protein (see below).

It is often advantageous to include an additional amino acid sequence which contains secretory or leader sequences, pro-sequences, sequences which aid in purification , such as multiple histidine residues, or an additional sequence for stability during recombinant production.
The polypeptides of the present invention are preferably provided in an isolated form, and preferably are substantially purified. A recombinantly produced version of a polypeptide, including the secreted polypeptide, can be substantially purified by the one-step method described in Smith and Johnson, Gene 67:31-40 ( 1988).
Polypeptides of the invention also can be purified from natural or recombinant sources using antibodies of the invention raised against the secreted protein in methods which are well known in the art.
Signal Sequences Methods for predicting whether a protein has a signal sequence, as well as the cleavage point for that sequence, are available. For instance, the method of McGeoch, Virus Res. 3:271-286 (1985), uses the information from a short N-terminal charged region and a subsequent uncharged region of the complete (uncleaved) protein.
The method of von Heinje, Nucleic Acids Res. 14:4683-4690 ( 1986) uses the information from the residues surrounding the cleavage site, typically residues -13 to +2, where +1 indicates the amino terminus of the secreted protein. The accuracy of predicting the cleavage points of known mammalian secretory proteins for each of these methods is in the range of 75-80%. (von Heinje, supra.) However, the two methods do not always produce the same predicted cleavage points) for a given protein.
In the present case, the deduced amino acid sequence of the secreted polypeptide was analyzed by a computer program called SignalP (Henrik Nielsen et al., Protein Engineering 10:1-6 (1997)), which predicts the cellular location of a protein based on the amino acid sequence. As part of this computational prediction of localization, the methods of McGeoch and von Heinje are incorporated. The analysis of the amino acid sequences of the secreted proteins described herein by this program provided the results shown in Table 1.
As one of ordinary skill would appreciate, however, cleavage sites sometimes vary from organism to organism and cannot be predicted with absolute certainty.
Accordingly, the present invention provides secreted polypeptides having a sequence shown in SEQ ID NO:Y which have an N-terminus beginning within 5 residues (i.e., +
or - 5 residues) of the predicted cleavage point. Similarly, it is also recognized that in some cases, cleavage of the signal sequence from a secreted protein is not entirely uniform, resulting in more than one secreted species. These polypeptides, and the polynucleotides encoding such polypeptides, are contemplated by the present invention.
Moreover, the signal sequence identified by the above analysis may not necessarily predict the naturally occurring signal sequence. For example, the naturally occurring signal sequence may be further upstream from the predicted signal sequence.
However, it is likely that the predicted signal sequence will be capable of directing the secreted protein to the ER. These polypeptides, and the polynucleotides encoding such polypeptides, are contemplated by the present invention.
Polynucleotide and Poly~eptide Variants "Variant" refers to a polynucleotide or polypeptide differing from the poIynucleotide or polypeptide of the present invention, but retaining essential properties thereof. Generally, variants are overall closely similar, and, in many regions, identical to the polynucleotide or polypeptide of the present invention.
By a polynucleotide having a nucleotide sequence at least, for example, 95%
"identical" to a reference nucleotide sequence of the present invention, it is intended that the nucleotide sequence of the polynucleotide is identical to the reference sequence except that the polynucleotide sequence may include up to five point mutations per each 100 nucleotides of the reference nucleotide sequence encoding the polypeptide.
In other words, to obtain a polynucleotide having a nucleotide sequence at least 95%
identical to a reference nucleotide sequence, up to 5% of the nucleotides in the reference sequence may be deleted or substituted with another nucleotide, or a number of nucleotides up to 5% of the total nucleotides in the reference sequence may be inserted into the reference sequence. The query sequence may be an entire sequence shown inTable 1, the ORF
(open reading frame), or any fragement specified as described herein.
As a practical matter, whether any particular nucleic acid molecule or polypeptide is at least 90%, 95%, 96%, 97%, 98% or 99% identical to a nucleotide sequence of the presence invention can be determined conventionally using known computer programs. A preferred method for determing the best overall match between a query sequence (a sequence of the present invention) and a subject sequence, also referred to as a global sequence alignment, can be determined using the FASTDB
computer program based on the algorithm of Brutlag et al. (Comp. App. Biosci.
( 1990) 6:237-245). In a sequence alignment the query and subject sequences are both DNA
sequences. An RNA sequence can be compared by converting U's to T's. The result of said global sequence alignment is in percent identity. Preferred parameters used in a FASTDB alignment of DNA sequences to calculate percent identiy are:
Matrix=Unitary, k-tuple=4, Mismatch Penalty=l, Joining Penalty=30, Randomization Group Length=0, Cutoff Score=l, Gap Penalty=5, Gap Size Penalty 0.05, Window Size=500 or the lenght of the subject nucleotide sequence, whichever is shorter.
If the subject sequence is shorter than the query sequence because of 5' or 3' deletions, not because of internal deletions, a manual correction must be made to the results. This is becuase the FASTDB program does not account for 5' and 3' truncations of the subject sequence when calculating percent identity. For subject sequences truncated at the 5' or 3' ends, relative to the the query sequence, the percent identity is corrected by calculating the number of bases of the query sequence that are 5' and 3' of the subject sequence, which are not matched/aligned, as a percent of the total bases of the query sequence. Whether a nucleotide is matched/aligned is determined by results of the FASTDB sequence alignment. This percentage is then subtracted from the percent identity, calculated by the above FASTDB program using the specified parameters, to arrive at a final percent identity score. This corrected score is what is used for the purposes of the present invention. Only bases outside the 5' and 3' bases of the subject sequence, as displayed by the FASTDB alignment, which are not matched/aligned with the query sequence, are calculated for the purposes of manually adjusting the percent identity score.
For example, a 90 base subject sequence is aligned to a 100 base query sequence to determine percent identity. The deletions occur at the 5' end of the subject sequence and therefore, the FASTDB alignment does not show a matched/alignement of the first 10 bases at 5' end. The 10 unpaired bases represent 10% of the sequence (number of bases at the 5' and 3' ends not matched/total number of bases in the query sequence) so 10% is subtracted from the percent identity score calculated by the FASTDB program. If the remaining 90 bases were perfectly matched the final percent identity would be 90%. In another example, a 90 base subject sequence is compared with a 100 base query sequence. This time the deletions are internal deletions so that there are no bases on the 5' or 3' of the subject sequence which are not matched/aligned with the query. In this case the percent identity calculated by FASTDB is not manually corrected. Once again, only bases 5' and 3' of the subject sequence which are not matched/aligned with the query sequnce are manually corrected for. No other manual corrections are to made for the purposes of the present invention.
By a polypeptide having an amino acid sequence at least, for example, 95%
"identical" to a query amino acid sequence of the present invention, it is intended that the amino acid sequence of the subject polypeptide is identical to the query sequence except that the subject polypeptide sequence may include up to five amino acid alterations per each 100 amino acids of the query amino acid sequence. In other words, to obtain a polypeptide having an amino acid sequence at least 95% identical to a query amino acid sequence, up to 5% of the amino acid residues in the subject sequence may be inserted, deleted, (indels) or substituted with another amino acid. These alterations of the reference sequence may occur at the amino or carboxy terminal positions of the reference amino acid sequence or anywhere between those terminal positions, 5 interspersed either individually among residues in the reference sequence or in one or more contiguous groups within the reference sequence.
As a practical matter, whether any particular polypeptide is at least 90%, 95%, 96%, 97%, 98% or 99% identical to, for instance, the amino acid sequences shown in Table 1 or to the amino acid sequence encoded by deposited DNA clone can be 10 determined conventionally using known computer programs. A preferred method for determing the best overall match between a query sequence (a sequence of the present invention) and a subject sequence, also referred to as a global sequence alignment, can be determined using the FASTDB computer program based on the algorithm of Brutlag et al. (Comp. App. Biosci. ( 1990) 6:237-245). In a sequence alignment the query and 15 subject sequences are either both nucleotide sequences or both amino acid sequences.
The result of said global sequence alignment is in percent identity. Preferred parameters used in a FASTDB amino acid alignment are: Matrix=PAM 0, k-tuple=2, Mismatch Penalty=1, Joining Penalty=20, Randomization Group Length=0, Cutoff Score=1, Window Size=sequence length, Gap Penalty=5, Gap Size Penalty=0.05, Window 20 Size=500 or the length of the subject amino acid sequence, whichever is shorter.
If the subject sequence is shorter than the query sequence due to N- or C-terminal deletions, not because of internal deletions, a manual correction must be made to the results. This is becuase the FASTDB program does not account for N- and C-terminal truncations of the subject sequence when calculating global percent identity.
25 For subject sequences truncated at the N- and C-termini, relative to the the query sequence, the percent identity is corrected by calculating the number of residues of the query sequence that are N- and C-terminal of the subject sequence, which are not matched/aligned with a corresponding subject residue, as a percent of the total bases of the query sequence. Whether a residue is matched/aligned is determined by results of 30 the FASTDB sequence alignment. This percentage is then subtracted from the percent identity, calculated by the above FASTDB program using the specified parameters, to arrive at a final percent identity score. This final percent identity score is what is used for the purposes of the present invention. Only residues to the N- and C-termini of the subject sequence, which are not matched/aligned with the query sequence, are 35 considered for the purposes of manually adjusting the percent identity score. That is, only query residue positions outside the farthest N- and C-terminal residues of the subject sequence.

For example, a 90 amino acid residue subject sequence is aligned with a 100 residue query sequence to determine percent identity. The deletion occurs at the N-terminus of the subject sequence and therefore, the FASTDB alignment does not show a matching/alignment of the first 10 residues at the N-terminus. The 10 unpaired residues represent 10% of the sequence (number of residues at the N- and C-termini not matched/total number of residues in the query sequence) so 10% is subtracted from the percent identity score calculated by the FASTDB program. If the remaining residues were perfectly matched the final percent identity would be 90%. In another example, a 90 residue subject sequence is compared with a 100 residue query sequence.
This time the deletions are internal deletions so there are no residues at the N- or C-termini of the subject sequence which are not matched/aligned with the query.
In this case the percent identity calculated by FASTDB is not manually corrected. Once again, only residue positions outside the N- and C-terminal ends of the subject sequence, as displayed in the FASTDB alignment, which are not matched/aligned with the query sequnce are manually corrected for. No other manual corrections are to made for the purposes of the present invention.
The variants may contain alterations in the coding regions, non-coding regions, or both. Especially preferred are polynucleotide variants containing alterations which produce silent substitutions, additions, or deletions, but do not alter the properties or activities of the encoded polypeptide. Nucleotide variants produced by silent substitutions due to the degeneracy of the genetic code are preferred.
Moreover, variants in which S-10, 1-5, or 1-2 amino acids are substituted, deleted, or added in any combination are also preferred. Polynucleotide variants can be produced for a variety of reasons, e.g., to optimize codon expression for a particular host (change codons in the human mRNA to those preferred by a bacterial host such as E. coli).
Naturally occurring variants are called "allelic variants," and refer to one of several alternate forms of a gene occupying a given locus on a chromosome of an organism. (Genes II, Lewin, B., ed., John Wiley & Sons, New York (1985).) These allelic variants can vary at either the polynucleotide and/or polypeptide level.
Alternatively, non-naturally occurring variants may be produced by mutagenesis techniques or by direct synthesis.
Using known methods of protein engineering and recombinant DNA
technology, variants may be generated to improve or alter the characteristics of the polypeptides of the present invention. For instance, one or more amino acids can be deleted from the N-terminus or C-terminus of the secreted protein without substantial loss of biological function. The authors of Ron et al., J. Biol. Chem. 268:

(1993}, reported variant KGF proteins having heparin binding activity even after deleting 3, 8, or 27 amino-terminal amino acid residues. Similarly, Interferon gamma exhibited up to ten times higher activity after deleting 8-10 amino acid residues from the carboxy terminus of this protein. (Dobeli et al., J. Biotechnology 7:199-216 (1988).) Moreover, ample evidence demonstrates that variants often retain a biological activity similar to that of the naturally occurring protein. For example, Gayle and coworkers (J. Biol. Chem 268:22105-22111 ( 1993)) conducted extensive mutational analysis of human cytokine IL-la. They used random mutagenesis to generate over 3,500 individual IL-la mutants that averaged 2.5 amino acid changes per variant over the entire length of the molecule. Multiple mutations were examined at every possible amino acid position. The investigators found that "[mJost of the molecule could be altered with little effect on either [binding or biological activity]." (See, Abstract.) In fact, only 23 unique amino acid sequences, out of more than 3,500 nucleotide sequences examined, produced a protein that significantly differed in activity from wild-type.
Furthermore, even if deleting one or more amino acids from the N-terminus or C-terminus of a polypeptide results in modification or loss of one or more biological functions, other biological activities may still be retained. For example, the ability of a deletion variant to induce and/or to bind antibodies which recognize the secreted form will likely be retained when less than the majority of the residues of the secreted form are removed from the N-terminus or C-terminus. Whether a particular polypeptide lacking N- or C-terminal residues of a protein retains such immunogenic activities can readily be determined by routine methods described herein and otherwise known in the art.
Thus, the invention further includes polypeptide variants which show substantial biological activity. Such variants include deletions, insertions, inversions, repeats, and substitutions selected according to general rules known in the art so as have little effect on activity. For example, guidance concerning how to make phenotypically silent amino acid substitutions is provided in Bowie, J. U. et al., Science 247:1306-1310 (1990), wherein the authors indicate that there are two main strategies for studying the tolerance of an amino acid sequence to change.
The first strategy exploits the tolerance of amino acid substitutions by natural selection during the process of evolution. By comparing amino acid sequences in different species, conserved amino acids can be identified. These conserved amino acids are likely important for protein function. In contrast, the amino acid positions where substitutions have been tolerated by natural selection indicates that these positions are not critical for protein function. Thus, positions tolerating amino acid substitution could be modified while still maintaining biological activity of the protein.

The second strategy uses genetic engineering to introduce amino acid changes at specific positions of a cloned gene to identify regions critical for protein function. For example, site directed mutagenesis or alanine-scanning mutagenesis (introduction of single alanine mutations at every residue in the molecule} can be used.
(Cunningham and Wells, Science 244:1081-1085 (1989).) The resulting mutant molecules can then be tested for biological activity.
As the authors state, these two strategies have revealed that proteins are surprisingly tolerant of amino acid substitutions. The authors further indicate which amino acid changes are likely to be permissive at certain amino acid positions in the protein. For example, most buried (within the tertiary structure of the protein) amino acid residues require nonpolar side chains, whereas few features of surface side chains are generally conserved. Moreover, tolerated conservative amino acid substitutions involve replacement of the aliphatic or hydrophobic amino acids Ala, Val, Leu and Ile;
replacement of the hydroxyl residues Ser and Thr; replacement of the acidic residues IS Asp and Glu; replacement of the amide residues Asn and Gln, replacement of the basic residues Lys, Arg, and His; replacement of the aromatic residues Phe, Tyr, and Trp, and replacement of the small-sized amino acids Ala, Ser, Thr, Met, and Gly.
Besides conservative amino acid substitution, variants of the present invention include (i) substitutions with one or more of the non-conserved amino acid residues, where the substituted amino acid residues may or may not be one encoded by the genetic code, or (ii) substitution with one or more of amino acid residues having a substituent group, or (iii) fusion of the mature polypeptide with another compound, such as a compound to increase the stability and/or solubility of the polypeptide (for example, polyethylene glycol), or (iv) fusion of the polypeptide with additional amino acids, such as an IgG Fc fusion region peptide, or leader or secretory sequence, or a sequence facilitating purification. Such variant polypeptides are deemed to be within the scope of those skilled in the art from the teachings herein.
For example, polypeptide variants containing amino acid substitutions of charged amino acids with other charged or neutral amino acids may produce proteins with improved characteristics, such as less aggregation. Aggregation of pharmaceutical formulations both reduces activity and increases clearance due to the aggregate's immunogenic activity. (Pinckard et al., Clin. Exp. Immunol. 2:331-340 ( 1967);
Robbins et al., Diabetes 36: 838-845 (1987); Cleland et al., Crit. Rev.
Therapeutic Drug Carrier Systems 10:307-377 (1993).) Polvnucleotide and Polypeptide Fragments In the present invention, a "polynucleotide fragment" refers to a short polynucleotide having a nucleic acid sequence contained in the deposited clone or shown in SEQ ID NO:X. The short nucleotide fragments are preferably at least about 15 nt, and more preferably at least about 20 nt, still more preferably at least about 30 nt, and even more preferably, at least about 40 nt in length. A fragment "at least 20 nt in length," for example, is intended to include 20 or more contiguous bases from the cDNA sequence contained in the deposited clone or the nucleotide sequence shown in SEQ ID NO:X. These nucleotide fragments are useful as diagnostic probes and primers as discussed herein. Of course, larger fragments (e.g., 50, 150, 500, 600, nucleotides) are preferred.
Moreover, representative examples of polynucleotide fragments of the invention, include, for example, fragments having a sequence from about nucleotide number I -50, 51-100, 101-150, I 51-200, 201-250, 251-300, 301-350, 35 I -400, 450, 451-500, 501-550, 551-600, 651-700, 701-750, 751-800, 800-850, 851-900, 901-950, 951-1000, 1001-1050, 1051-1100, 1101-1150, 1151-1200, 1201-1250, 1251-1300, 1301-1350, 1351-1400, 1401-1450, 1451-1500, 1501-1550, 1551-1600, 1601-1650, 1651-1700, 1701-1750, 1751-1800, 1801-1850, 1851-1900, 1901-1950, 1951-2000, or 2001 to the end of SEQ ID NO:X or the cDNA contained in the deposited clone. In this context "about" includes the particularly recited ranges, larger or smaller by several (5, 4, 3, 2, or 1 ) nucleotides, at either terminus or at both termini.
Preferably, these fragments encode a polypeptide which has biological activity. More preferably, these polynucleotides can be used as probes or primers as discussed herein.
In the present invention, a "polypeptide fragment" refers to a short amino acid sequence contained in SEQ ID NO:Y or encoded by the cDNA contained in the deposited clone. Protein fragments may be "free-standing," or comprised within a larger polypeptide of which the fragment forms a part or region, most preferably as a single continuous region. Representative examples of polypeptide fragments of the invention, include, for example, fragments from about amino acid number I-20, 21-40, 41-60, 61-80, 8 I -100, 102-120, 121-140, 141-160, or 161 to the end of the coding region. Moreover, polypeptide fragments can be about 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, or 150 amino acids in length. In this context "about"
includes the particularly recited ranges, larger or smaller by several (5, 4, 3, 2, or 1 ) amino acids, at either extreme or at both extremes.
Preferred polypeptide fragments include the secreted protein as well as the mature form. Further preferred polypeptide fragments include the secreted protein or the mature form having a continuous series of deleted residues from the amino or the carboxy terminus, or both. For example, any number of amino acids, ranging from 1-60, can be deleted from the amino terminus of either the secreted polypeptide or the mature form. Similarly, any number of amino acids, ranging from 1-30, can be deleted from the carboxy terminus of the secreted protein or mature form. Furthermore, any 5 combination of the above amino and carboxy terminus deletions are preferred.
Similarly, polynucleotide fragments encoding these polypeptide fragments are also preferred.
Particularly, N-terminal deletions of the polypeptide of the present invention can be described by the general formula m-p, where p is the total number of anvno acids in 10 the polypeptide and m is an integer from 2 to (p-1), and where both of these integers (m & p) correspond to the position of the amino acid residue identified in SEQ ID
NO:Y.
Moreover, C-terminal deletions of the polypeptide of the present invention can also be described by the general formula 1-n, where n is an integer from 2 to (p-1), and again where these integers (n & p) correspond to the position of the amino acid residue 15 identified in SEQ ID NO:Y.
The invention also provides polypeptides having one or more amino acids deleted from both the amino and the carboxyl termini, which may be described generally as having residues m-n of SEQ ID NO:Y, where m and n are integers as described above.
20 Also preferred are polypeptide and polynucleotide fragments characterized by structural or functional domains, such as fragments that comprise alpha-helix and alpha-heiix forming regions, beta-sheet and beta-sheet-forming regions, turn and turn-forming regions, coil and coil-forming regions, hydrophilic regions, hydrophobic regions, alpha amphipathic regions, beta amphipathic regions, flexible regions, surface-25 forming regions, substrate binding region, and high antigenic index regions.
Polypeptide fragments of SEQ ID NO:Y falling within conserved domains are specifically contemplated by the present invention. Moreover, polynucleotide fragments encoding these domains are also contemplated.
Other preferred fragments are biologically active fragments. Biologically active 30 fragments are those exhibiting activity similar, but not necessarily identical, to an activity of the polypeptide of the present invention. The biological activity of the fragments may include an improved desired activity, or a decreased undesirable activity.
Epitopes & Antibodies 35 In the present invention, "epitopes" refer to polypeptide fragments having antigenic or immunogenic activity in an animal, especially in a human. A
preferred embodiment of the present invention relates to a polypeptide fragment comprising an 9b epitope, as well as the polynucleotide encoding this fragment. A region of a protein molecule to which an antibody can bind is defined as an "antigenic epitope."
In contrast, an "immunogenic epitope" is defined as a part of a protein that elicits an antibody response. (See, for instance, Geysen et aL, Proc. Natl. Acad. Sci.
USA
81:3998-4002 (1983).) Fragments which function as epitopes may be produced by any conventional means. {See, e.g., Houghten, R. A., Proc. Natl. Acad. Sci. USA 82:5131-5135 (1985) further described in U.S. Patent No. 4,631,211.) In the present invention, antigenic epitopes preferably contain a sequence of at least seven, more preferably at least nine, and most preferably between about 15 to about 30 amino acids. Antigenic epitopes are useful to raise antibodies, including monoclonal antibodies, that specifically bind the epitope. (See, for instance, Wilson et al., Cell 37:767-778 ( 1984); Sutcliffe, J. G. et al., Science 219:660-666 ( 1983).) Similarly, immunogenic epitopes can be used to induce antibodies according to I S methods well known in the art. (See, for instance, Sutcliffe et al., supra; Wilson et al., supra; Chow, M. et al., Proc. Natl. Acad. Sci. USA 82:910-914; and Bittle, F.
J. et al., J. Gen. Virol. 66:2347-2354 (1985).) A preferred immunogenic epitope includes the secreted protein. The immunogenic epitopes may be presented together with a carrier protein, such as an albumin, to an animal system (such as rabbit or mouse) or, if it is long enough (at least about 25 amino acids), without a carrier. However, immunogenic epitopes comprising as few as 8 to 10 amino acids have been shown to be sufficient to raise antibodies capable of binding to, at the very least, linear epitopes in a denatured polypeptide (e.g., in Western blotting.) As used herein, the term "antibody" (Ab) or "monoclonal antibody" {Mab) is meant to include intact molecules as well as antibody fragments (such as, for example, Fab and Flab'}2 fragments) which are capable of specifically binding to protein. Fab and F(ab')2 fragments lack the Fc fragment of intact antibody, clear more rapidly from the circulation, and may have less non-specific tissue binding than an intact antibody.
(Wahl et al., J. Nucl. Med. 24:316-325 ( 1983).) Thus, these fragments are preferred, as welt as the products of a FAB or other immunoglobulin expression library.
Moreover, antibodies of the present invention include chimeric, single chain, and humanized antibodies.
Fusion Proteins Any polypeptide of the present invention can be used to generate fusion proteins. For example, the polypeptide of the present invention, when fused to a second protein. can be used as an antigenic tag. Antibodies raised against the WO 98/56804 PCTlUS98/12125 polypeptide of the present invention can be used to indirectly detect the second protein by binding to the polypeptide. Moreover, because secreted proteins target cellular locations based on trafficking signals, the polypeptides of the present invention can be used as targeting molecules once fused to other proteins.
Examples of domains that can be fused to polypeptides of the present invention include not only heterologous signal sequences, but also other heterologous functional regions. The fusion does not necessarily need to be direct, but may occur through linker sequences.
Moreover, fusion proteins may also be engineered to improve characteristics of the polypeptide of the present invention. For instance, a region of additional amino acids, particularly charged amino acids, may be added to the N-terminus of the polypeptide to improve stability and persistence during purification from the host cell or subsequent handling and storage. Also, peptide moieties may be added to the polypeptide to facilitate purification. Such regions may be removed prior to final preparation of the polypeptide. The addition of peptide moieties to facilitate handling of polypeptides are familiar and routine techniques in the art.
Moreover, polypeptides of the present invention, including fragments, and specifically epitopes, can be combined with parts of the constant domain of immunoglobulins {IgG), resulting in chimeric polypeptides. These fusion proteins facilitate purification and show an increased half life in vivo. One reported example describes chimeric proteins consisting of the first two domains of the human polypeptide and various domains of the constant regions of the heavy or light chains of mammalian immunoglobulins. (EP A 394,827; Traunecker et al., Nature 331:84-86 (1988).) Fusion proteins having disulfide-linked dimeric structures {due to the IgG) can also be more efficient in binding and neutralizing other molecules, than the monomeric secreted protein or protein fragment alone. (Fountoulakis et al., J.
Biochem. 270:3958-3964 (1995).) Similarly, EP-A-O 464 533 (Canadian counterpart 2045869) discloses fusion proteins comprising various portions of constant region of immunoglobulin molecules together with another human protein or part thereof. In many cases, the Fc part in a fusion protein is beneficial in therapy and diagnosis, and thus can result in, for example, improved pharmacokinetic properties. (EP-A 0232 262.) Alternatively, deleting the Fc part after the fusion protein has been expressed, detected, and purified, would be desired. For example, the Fc portion may hinder therapy and diagnosis if the fusion protein is used as an antigen for immunizations. In drug discovery, for example, human proteins, such as hIL-5, have been fused with Fc portions for the purpose of high-throughput screening assays to identify antagonists of hIL-5.
(See, D.

Bennett et al., J. Molecular Recognition 8:52-~8 (1995); K. Johanson et al., J. Biol.
Chem. 270:9459-9471 ( 1995).) Moreover, the polypeptides of the present invention can be fused to marker sequences, such as a peptide which facilitates purification of the fused polypeptide. In preferred embodiments, the marker amino acid sequence is a hexa-histidine peptide, such as the tag provided in a pQE vector (QIAGEN, Inc., 9259 Eton Avenue, Chatsworth, CA, 91311), among others, many of which are commercially available.
As described in Gentz et al., Proc. Natl. Acad. Sci. USA 86:821-824 (1989), for instance, hexa-histidine provides for convenient purification of the fusion protein.
Another peptide tag useful for purification, the "HA" tag, corresponds to an epitope derived from the influenza hemagglutinin protein. (Wilson et al., Cell 37:767 (1984).) Thus, any of these above fusions can be engineered using the polynucleotides or the polypeptides of the present invention.
Vectors. Host Cells and Protein Production The present invention also relates to vectors containing the polynucleotide of the present invention, host cells, and the production of polypeptides by recombinant techniques. The vector may be, for example, a phage, plasmid, viral, or retroviral vector. Retroviral vectors may be replication competent or replication defective. In the latter case, viral propagation generally will occur only in complementing host cells.
The polynucleotides may be joined to a vector containing a selectable marker for propagation in a host. Generally, a plasmid vector is introduced in a precipitate, such as a calcium phosphate precipitate, or in a complex with a charged lipid. If the vector is a virus, it may be packaged in vitro using an appropriate packaging cell line and then transduced into host cells.
The polynucleotide insert should be operatively linked to an appropriate promoter, such as the phage lambda PL promoter, the E. coli lac, trp, phoA and tac promoters, the SV40 early and late promoters and promoters of retroviral LTRs, to name a few. Other suitable promoters will be known to the skilled artisan. The expression constructs will further contain sites for transcription initiation, termination, and, in the transcribed region, a ribosome binding site for translation. The coding portion of the transcripts expressed by the constructs will preferably include a translation initiating codon at the beginning and a termination codon (UAA, UGA or UAG) appropriately positioned at the end of the polypeptide to be translated.
As indicated, the expression vectors will preferably include at least one selectable marker. Such markers include dihydrofolate reductase, 6418 or neomycin resistance for eukaryotic cell culture and tetracycline, kanamycin or ampicillin resistance genes for culturing in E. coli and other bacteria. Representative examples of appropriate hosts include, but are not limited to, bacterial cells, such as E.
coli, Streptomyces and Salmonella typhimurium cells; fungal cells, such as yeast cells; insect cells such as Drosophila S2 and Spodoptera Sf9 cells; animal cells such as CHO, COS, 293, and Bowes melanoma cells; and plant cells. Appropriate culture mediums and conditions for the above-described host cells are known in the art.
Among vectors preferred for use in bacteria include pQE70, pQE60 and pQE-9, available from QIAGEN, Inc.; pBluescript vectors, Phagescript vectors, pNHBA, pNH 16a, pNH 18A, pNH46A, available from Stratagene Cloning Systems, Inc.; and ptrc99a, pKK223-3, pKK233-3, pDR540, pRITS available from Pharmacia Biotech, Inc. Among preferred eukaryotic vectors are pWLNEO, pSV2CAT, pOG44, pXTI
and pSG available from Stratagene; and pSVK3, pBPV, pMSG and pSVL available from Pharmacia. Other suitable vectors will be readily apparent to the skilled artisan.
Introduction of the construct into the host cell can be effected by calcium phosphate transfection, DEAE-dextran mediated transfection, cationic lipid-mediated transfection, electroporation, transduction, infection, or other methods. Such methods are described in many standard laboratory manuals, such as Davis et al., Basic Methods In Molecular Biology ( 1986). It is specifically contemplated that the polypeptides of the present invention may in fact be expressed by a host cell lacking a recombinant vector.
A polypeptide of this invention can be recovered and purified from recombinant cell cultures by well-known methods including ammonium sulfate or ethanol precipitation, acid extraction, anion or cation exchange chromatography, phosphocellulose chromatography, hydrophobic interaction chromatography, affinity chromatography, hydroxylapatite chromatography and lectin chromatography. Most preferably, high performance liquid chromatography ("HPLC") is employed for purification.
Polypeptides of the present invention, and preferably the secreted form, can also be recovered from: products purified from natural sources, including bodily fluids, tissues and cells, whether directly isolated or cultured; products of chemical synthetic procedures; and products produced by recombinant techniques from a prokaryotic or eukaryotic host, including, for example, bacterial, yeast, higher plant, insect, and mammalian cells. Depending upon the host employed in a recombinant production procedure, the polypeptides of the present invention may be glycosylated or may be non-glycosylated. In addition, polypeptides of the invention may also include an initial modified methionine residue, in some cases as a result of host-mediated processes.
Thus, it is well known in the art that the N-terminal methionine encoded by the translation initiation codon generally is removed with high efficiency from any protein after translation in all eukaryotic cells. While the N-terminal methionine on most proteins also is efficiently removed in most prokaryotes, for some proteins, this prokaryotic removal process is inefficient, depending on the nature of the amino acid to which the N-terminal methionine is covalently linked.
S
Uses of the Po~nucleotides Each of the polynucleotides identified herein can be used in numerous ways as reagents. The following description should be considered exemplary and utilizes known techniques.
The polynucleotides of the present invention are useful for chromosome identification. There exists an ongoing need to identify new chromosome markers, since few chromosome marking reagents, based on actual sequence data (repeat polymorphisms), are presently available. Each polynucleotide of the present invention can be used as a chromosome marker.
Briefly, sequences can be mapped to chromosomes by preparing PCR primers (preferably 15-25 bp) from the sequences shown in SEQ ID NO:X. Primers can be selected using computer analysis so that primers do not span more than one predicted exon in the genomic DNA. These primers are then used for PCR screening of somatic cell hybrids containing individual human chromosomes. Only those hybrids containing the human gene corresponding to the SEQ ID NO:X will yield an amplified fragment.
Similarly, somatic hybrids provide a rapid method of PCR mapping the polynucleotides to particular chromosomes. Three or more clones can be assigned per day using a single thermal cycler. Moreover, sublocalization of the polynucleotides can be achieved with panels of specific chromosome fragments. Other gene mapping strategies that can be used include in situ hybridization, prescreening with labeled flow sorted chromosomes, and preselection by hybridization to construct chromosome specific-cDNA libraries.
Precise chromosomal location of the polynucleotides can also be achieved using fluorescence in situ hybridization (FISH) of a metaphase chromosomal spread.
This technique uses polynucleotides as short as 500 or 600 bases; however, polynucleotides 2,000-4,000 by are preferred. For a review of this technique, see Verma et al., "Human Chromosomes: a Manual of Basic Techniques," Pergamon Press, New York ( 1988).
For chromosome mapping, the polynucleotides can be used individually (to mark a single chromosome or a single site on that chromosome) or in panels {for marking multiple sites and/or multiple chromosomes). Preferred polynucleotides correspond to the noncoding regions of the cDNAs because the coding sequences are more likely conserved within gene families, thus increasing the chance of cross hybridization during chromosomal mapping.
Once a polynucleotide has been mapped to a precise chromosomal location, the physical position of the polynucleotide can be used in linkage analysis.
Linkage analysis establishes coinheritance between a chromosomal location and presentation of a particular disease. (Disease mapping data are found, for example, in V.
McKusick, Mendelian Inheritance in Man (available on line through Johns Hopkins University Welch Medical Library) .) Assuming 1 megabase mapping resolution and one gene per 20 kb, a cDNA precisely localized to a chromosomal region associated with the disease could be one of 50-500 potential causative genes.
Thus, once coinheritance is established, differences in the polynucleotide and the corresponding gene between affected and unaffected individuals can be examined.
First, visible structural alterations in the chromosomes, such as deletions or translocations, are examined in chromosome spreads or by PCR. If no structural alterations exist, the presence of point mutations are ascertained. Mutations observed in some or all affected individuals, but not in normal individuals, indicates that the mutation may cause the disease. However, complete sequencing of the polypeptide and the corresponding gene from several normal individuals is required to distinguish the mutation from a polymorphism. If a new polymorphism is identified, this polymorphic polypeptide can be used for further linkage analysis.
Furthermore, increased or decreased expression of the gene in affected individuals as compared to unaffected individuals can be assessed using polynucleotides of the present invention. Any of these alterations (altered expression, chromosomal rearrangement, or mutation) can be used as a diagnostic or prognostic marker.
In addition to the foregoing, a polynucleotide can be used to control gene expression through triple helix formation or antisense DNA or RNA. Both methods rely on binding of the polynucleotide to DNA or RNA. For these techniques, preferred polynucleotides are usually 20 to 40 bases in length and complementary to either the region of the gene involved in transcription (triple helix - see Lee et al., Nucl. Acids Res. 6:3073 ( 1979); Cooney et al., Science 241:456 ( 1988); and Dervan et al., Science 251:1360 ( 1991 ) ) or to the mRNA itself (antisense - Okano, J. Neurochem.
56:560 (1991); Oligodeoxy-nucleotides as Antisense Inhibitors of Gene Expression, CRC
Press, Boca Raton, FL ( 1988).) Triple helix formation optimally results in a shut-off of RNA transcription from DNA, while antisense RNA hybridization blocks translation of an mRNA molecule into polypeptide. Both techniques are effective in model systems, and the information disclosed herein can be used to design antisense or triple helix polynucleotides in an effort to treat disease.
Polynucleotides of the present invention are also useful in gene therapy. One goal of gene therapy is to insert a normal gene into an organism having a defective gene, in an effort to correct the genetic defect. The polynucleotides disclosed in the present invention offer a means of targeting such genetic defects in a highly accurate manner. Another goal is to insert a new gene that was not present in the host genome, thereby producing a new trait in the host cell.
The polynucleotides are also useful for identifying individuals from minute biological samples. The United States military, for example, is considering the use of restriction fragment length polymorphism (RFLP) for identification of its personnel. In this technique, an individual's genomic DNA is digested with one or more restriction enzymes, and probed on a Southern blot to yield unique bands for identifying personnel. This method does not suffer from the current limitations of "Dog Tags"
which can be lost, switched, or stolen, making positive identification difficult. The polynucleotides of the present invention can be used as additional DNA markers for RFLP.
The polynucleotides of the present invention can also be used as an alternative to RFLP, by determining the actual base-by-base DNA sequence of selected portions of an individual's genome. These sequences can be used to prepare PCR primers for amplifying and isolating such selected DNA, which can then be sequenced. Using this technique, individuals can be identified because each individual will have a unique set of DNA sequences. Once an unique ID database is established for an individual, positive identification of that individual, living or dead, can be made from extremely small tissue samples.
Forensic biology also benefits from using DNA-based identification techniques as disclosed herein. DNA sequences taken from very small biological samples such as tissues, e.g., hair or skin, or body fluids, e.g., blood, saliva, semen, etc., can be amplified using PCR. In one prior art technique, gene sequences amplified from polymorphic loci, such as DQa class II HLA gene, are used in forensic biology to identify individuals. (Erlich, H., PCR Technology, Freeman and Co. ( 1992).) Once these specific polymorphic loci are amplified, they are digested with one or more restriction enzymes, yielding an identifying set of bands on a Southern blot probed with DNA corresponding to the DQa class II HLA gene. Similarly, polynucleotides of the present invention can be used as polymorphic markers for forensic purposes.
There is also a need for reagents capable of identifying the source of a particular tissue. Such need arises, for example, in forensics when presented with tissue of unknown origin. Appropriate reagents can comprise, for example, DNA probes or primers specific to particular tissue prepared from the sequences of the present invention. Panels of such reagents can identify tissue by species and/or by organ type.
In a similar fashion, these reagents can be used to screen tissue cultures for contamination.
In the very least, the polynucleotides of the present invention can be used as molecular weight markers on Southern gels, as diagnostic probes for the presence of a specific mRNA in a particular cell type, as a probe to "subtract-out" known sequences in the process of discovering novel polynucleotides, for selecting and making oligomers for attachment to a "gene chip" or other support, to raise anti-DNA antibodies using DNA immunization techniques, and as an antigen to elicit an immune response.
Uses of the PolYpeptides Each of the polypeptides identified herein can be used in numerous ways. The following description should be considered exemplary and utilizes known techniques.
A polypeptide of the present invention can be used to assay protein levels in a biological sample using antibody-based techniques. For example, protein expression in tissues can be studied with classical immunohistological methods. {Jalkanen, M., et al., J. CeII. Biol. 101:976-985 ( 1985); Jalkanen, M., et al., J. Cell . Biol.
105:3087-3096 ( 1987).) Other antibody-based methods useful for detecting protein gene expression include immunoassays, such as the enzyme linked immunosorbent assay (ELISA) and the radioimmunoassay (RIA). Suitable antibody assay labels are known in the art and include enzyme labels, such as, glucose oxidase, and radioisotopes, such as iodine ( I25I, 121I), carbon ( 14C), sulfur (35S), tritium (3H), indium ( 1 l2ln), and technetium (99mTc}, and fluorescent labels, such as fluorescein and rhodamine, and biotin.
In addition to assaying secreted protein levels in a biological sample, proteins can also be detected in vivo by imaging. Antibody labels or markers for in vivo imaging of protein include those detectable by X-radiography, NMR or ESR. For X-radiography, suitable labels include radioisotopes such as barium or cesium, which emit detectable radiation but are not overtly harmful to the subject. Suitable markers for NMR and ESR include those with a detectable characteristic spin, such as deuterium, which may be incorporated into the antibody by labeling of nutrients for the relevant hybridoma.
A protein-specific antibody or antibody fragment which has been labeled with an appropriate detectable imaging moiety, such as a radioisotope (for example, I31I, 1 l2In, 99mTc), a radio-opaque substance. or a material detectable by nuclear magnetic WO 98/56804 PCTlUS98112125 resonance, is introduced (for example, parenterally, subcutaneously, or intraperitoneally) into the mammal. It will be understood in the art that the size of the subject and the imaging system used will determine the quantity of imaging moiety needed to produce diagnostic images. In the case of a radioisotope moiety, for a human subject, the quantity of radioactivity injected will normally range from about 5 to 20 millicuries of 99mTc. The labeled antibody or antibody fragment will then preferentially accumulate at the location of cells which contain the specific protein. In vivo tumor imaging is described in S.W. Burchiel et al., "Immunopharmacokinetics of Radiolabeled Antibodies and Their Fragments." (Chapter I3 in Tumor Imaging:
The Radiochemical Detection of Cancer, S.W. Burchiel and B. A. Rhodes, eds., Masson Publishing Inc. ( 1982).) Thus, the invention provides a diagnostic method of a disorder, which involves (a) assaying the expression of a polypeptide of the present invention in cells or body fluid of an individual; (b) comparing the level of gene expression with a standard gene expression level, whereby an increase or decrease in the assayed polypeptide gene expression level compared to the standard expression level is indicative of a disorder.
Moreover, polypeptides of the present invention can be used to treat disease.
For example, patients can be administered a polypeptide of the present invention in an effort to replace absent or decreased levels of the polypeptide (e.g., insulin), to supplement absent or decreased levels of a different polypeptide (e.g., hemoglobin S
for hemoglobin B), to inhibit the activity of a polypeptide (e.g., an oncogene), to activate the activity of a polypeptide (e.g., by binding to a receptor), to reduce the activity of a membrane bound receptor by competing with it for free ligand (e.g., soluble TNF receptors used in reducing inflammation), or to bring about a desired response (e.g., blood vessel growth).
Similarly, antibodies directed to a polypeptide of the present invention can also be used to treat disease. For example, administration of an antibody directed to a palypeptide of the present invention can bind and reduce overproduction of the polypeptide. Similarly, administration of an antibody can activate the polypeptide, such as by binding to a polypeptide bound to a membrane (receptor).
At the very least, the polypeptides of the present invention can be used as molecular weight markers on SDS-PAGE gels or on molecular sieve gel filtration columns using methods well known to those of skill in the art. Polypeptides can also be used to raise antibodies, which in turn are used to measure protein expression from a recombinant cell, as a way of assessing transformation of the host cell.
Moreover, the polypeptides of the present invention can be used to test the following biological activities.

Biologicat Activities The polynucleotides and polypeptides of the present invention can be used in assays to test for one or more biological activities. If these polynucleotides and polypeptides do exhibit activity in a particular assay, it is likely that these molecules may be involved in the diseases associated with the biological activity. Thus, the polynucleotides and polypeptides could be used to treat the associated disease.
Immune Activity A polypeptide or polynucleotide of the present invention may be useful in treating deficiencies or disorders of the immune system, by activating or inhibiting the proliferation, differentiation, or mobilization {chemotaxis) of immune cells.
Immune cells develop through a process called hematopoiesis, producing myeloid (platelets, red blood cells, neutrophils, and macrophages) and lymphoid (B and T lymphocytes) cells from pluripotent stem cells. The etiology of these immune deficiencies or disorders may be genetic, somatic, such as cancer or some autoimmune disorders, acquired (e.g., by chemotherapy or toxins), or infectious. Moreover, a polynucleotide or polypeptide of the present invention can be used as a marker or detector of a particular immune system disease or disorder.
A polynucleotide or polypeptide of the present invention may be useful in treating or detecting deficiencies or disorders of hematopoietic cells. A
polypeptide or polynucleotide of the present invention could be used to increase differentiation and proliferation of hematopoietic cells, including the pluripotent stem cells, in an effort to treat those disorders associated with a decrease in certain (or many) types hematopoietic cells. Examples of immunologic deficiency syndromes include, but are not limited to:
blood protein disorders (e.g. agammaglobulinemia, dysgammaglobulinemia), ataxia telangiectasia, common variable immunodeficiency, Digeorge Syndrome, HIV
infection, HTLV-BLV infection, leukocyte adhesion deficiency syndrome, lymphopenia, phagocyte bactericidal dysfunction, severe combined immunodeficiency (SCIDs), Wiskott-Aldrich Disorder, anemia, thrombocytopenia, or hemoglobinuria.
Moreover, a polypeptide or polynucleotide of the present invention could also be used to modulate hemostatic (the stopping of bleeding) or thrombolytic activity {clot formation). For example, by increasing hemostatic or thrombolytic activity, a polynucleotide or polypeptide of the present invention could be used to treat blood coagulation disorders (e.g., afibrinogenemia, factor deficiencies), blood platelet disorders (e.g. thrombocytopenia), or wounds resulting from trauma, surgery, or other causes. Alternatively, a polynucleotide or polypeptide of the present invention that can decrease hemostatic or thrombolytic activity could be used to inhibit or dissolve clotting. These molecules could be important in the treatment of heart attacks (infarction), strokes, or scarring.
A polynucleotide or polypeptide of the present invention may also be useful in treating or detecting autoimmune disorders. Many autoimmune disorders result from inappropriate recognition of self as foreign material by immune cells. This inappropriate recognition results in an immune response leading to the destruction of the host tissue. Therefore, the administration of a polypeptide or polynucleotide of the present invention that inhibits an immune response, particularly the proliferation, differentiation, or chemotaxis of T-cells, may be an effective therapy in preventing autoimmune disorders.
Examples of autoimmune disorders that can be treated or detected by the present invention include, but are not limited to: Addison's Disease, hemolytic anemia, antiphospholipid syndrome, rheumatoid arthritis, dermatitis, allergic encephalomyelitis, glomerulonephritis, Goodpasture's Syndrome, Graves' Disease, Multiple Sclerosis, Myasthenia Gravis, Neuritis, Ophthalmia, Bullous Pemphigoid, Pemphigus, Polyendocrinopathies, Purpura, Reiter's Disease, Stiff-Man Syndrome, Autoimmune Thyroiditis, Systemic Lupus Erythematosus, Autoimmune Pulmonary Inflammation, Guillain-Barre Syndrome, insulin dependent diabetes mellitis, and autoimmune inflammatory eye disease.
Similarly, allergic reactions and conditions, such as asthma (particularly allergic asthma) or other respiratory problems, may also be treated by a polypeptide or polynucleotide of the present invention. Moreover, these molecules can be used to treat anaphylaxis, hypersensitivity to an antigenic molecule, or blood group incompatibility.
A polynucleotide or polypeptide of the present invention may also be used to treat and/or prevent organ rejection or graft-versus-host disease (GVHD).
Organ rejection occurs by host immune cell destruction of the transplanted tissue through an immune response. Similarly, an immune response is also involved in GVHD, but, in this case, the foreign transplanted immune cells destroy the host tissues. The administration of a polypeptide or polynucleotide of the present invention that inhibits an immune response, particularly the proliferation, differentiation, or chemotaxis of T-cells, may be an effective therapy in preventing organ rejection or GVHD.
Similarly, a polypeptide or polynucleotide of the present invention may also be used to modulate inflammation. For example, the polypeptide or polynucleotide may inhibit the proliferation and differentiation of cells involved in an inflammatory response. These molecules can be used to treat inflammatory conditions, both chronic and acute conditions, including inflammation associated with infection (e.g..
septic shock, sepsis, or systemic inflammatory response syndrome (SIRS)), ischemia-reperfusion injury, endotoxin lethality, arthritis, complement-mediated hyperacute rejection, nephritis, cytokine or chemokine induced lung injury, inflammatory bowel disease, Crohn's disease, or resulting from over production of cytokines (e.g., TNF or IL-l.) Hyperproliferative Disorders A polypeptide or polynucleotide can be used to treat or detect hyperproliferative disorders, including neoplasms. A polypeptide or polynucleotide of the present invention may inhibit the proliferation of the disorder through direct or indirect interactions. Alternatively, a polypeptide or polynucleotide of the present invention may proliferate other cells which can inhibit the hyperproliferative disorder.
For example, by increasing an immune response, particularly increasing antigenic qualities of the hyperproliferative disorder or by proliferating, differentiating, or mobilizing T-cells, hyperproliferative disorders can be treated. This immune response may be increased by either enhancing an existing immune response, or by initiating a new immune response. Alternatively, decreasing an immune response may also be a method of treating hyperproliferative disorders, such as a chemotherapeutic agent.
Examples of hyperproliferative disorders that can be treated or detected by a polynucleotide or polypeptide of the present invention include, but are not limited to neoplasms located in the: abdomen, bone, breast, digestive system, liver, pancreas, peritoneum, endocrine glands (adrenal, parathyroid, pituitary, testicles, ovary, thymus, thyroid), eye, head and neck, nervous (central and peripheral), lymphatic system, pelvic, skin, soft tissue, spleen, thoracic, and urogenital.
Similarly, other hyperproliferative disorders can also be treated or detected by a polynucleotide or polypeptide of the present invention. Examples of such hyperproliferative disorders include, but are not limited to:
hypergammaglobulinemia, lymphoproliferative disorders, paraproteinemias, purpura, sarcoidosis, Sezary Syndrome, Waldenstron's Macroglobulinemia, Gaucher's Disease, histiocytosis, and any other hyperproliferative disease, besides neoplasia, located in an organ system listed above.
Infectious Disease A polypeptide or polynucleotide of the present invention can be used to treat or detect infectious agents. For example, by increasing the immune response, particularly increasing the proliferation and differentiation of B and/or T cells, infectious diseases may be treated. The immune response may be increased by either enhancing an existing immune response, or by initiating a new immune response. Alternatively, the polypeptide or polynucleotide of the present invention may also directly inhibit the infectious agent, without necessarily eliciting an immune response.
Viruses are one example of an infectious agent that can cause disease or symptoms that can be treated or detected by a polynucleotide or polypeptide of the present invention. Examples of viruses, include, but are not limited to the following DNA and RNA viral families: Arbovirus, Adenoviridae, Arenaviridae, Arterivirus, Birnaviridae, Bunyaviridae, Caliciviridae, Circoviridae, Coronaviridae, Flaviviridae, Hepadnaviridae (Hepatitis), Herpesviridae (such as, Cytomegalovirus, Herpes Simplex, Herpes Zoster), Mononegavirus (e.g., Paramyxoviridae, Morbillivirus, Rhabdoviridae), Orthomyxoviridae (e.g., Influenza), Papovaviridae, Parvoviridae, Picomaviridae, Poxviridae (such as Smallpox or Vaccinia), Reoviridae (e.g., Rotavirus), Retroviridae (HTLV-I, HTLV-II, Lentivirus), and Togaviridae (e.g., Rubivirus). Viruses falling within these families can cause a variety of diseases or symptoms, including, but not limited to: arthritis, bronchiollitis, encephalitis, eye infections (e.g., conjunctivitis, keratitis), chronic fatigue syndrome, hepatitis (A, B, C, E, Chronic Active, Delta), meningitis, opportunistic infections (e.g., AIDS), pneumonia, Burkitt's Lymphoma, chickenpox , hemorrhagic fever, Measles, Mumps, Parainfluenza, Rabies, the common cold, Polio, leukemia, Rubella, sexually transmitted diseases, skin diseases (e.g., Kaposi's, warts), and viremia. A
polypeptide or polynucleotide of the present invention can be used to treat or detect any of these symptoms or diseases.
Similarly, bacterial or fungal agents that can cause disease or symptoms and that can be treated or detected by a polynucleotide or polypeptide of the present invention include, but not limited to, the following Gram-Negative and Gram-positive bacterial families and fungi: Actinomycetales (e.g., Corynebacterium, Mycobacterium, Norcardia), Aspergillosis, Bacillaceae (e.g., Anthrax, Clostridium), Bacteroidaceae, Blastomycosis, Bordetella, Borrelia, Brucellosis, Candidiasis, Campylobacter, Coccidioidomycosis, Cryptococcosis, Dermatocycoses, Enterobacteriaceae {Klebsiella, Salmonella, Serratia, Yersinia}, Erysipelothrix, Helicobacter, Legionellosis, Leptospirosis, Listeria, Mycoplasmatales, Neisseriaceae (e.g., Acinetobacter, Gonorrhea, Menigococcal), Pasteurellacea Infections (e.g., Actinobacillus, Heamophilus, Pasteurella), Pseudomonas, Rickettsiaceae, Chlamydiaceae, Syphilis, and Staphylococcal. These bacterial or fungal families can cause the following diseases or symptoms, including, but not limited to: bacteremia, endocarditis, eye infections (conjunctivitis. tuberculosis, uveitis), gingivitis, opportunistic infections (e.g., AIDS

related infections), paronychia, prosthesis-related infections, Reiter's Disease, respiratory tract infections, such as Whooping Cough or Empyema, sepsis, Lyme Disease, Cat-Scratch Disease, Dysentery, Paratyphoid Fever, food poisoning, Typhoid, pneumonia, Gonorrhea, meningitis, Chlamydia, Syphilis, Diphtheria, Leprosy, Paratuberculosis, Tuberculosis, Lupus, Botulism, gangrene, tetanus, impetigo, Rheumatic Fever, Scarlet Fever, sexually transmitted diseases, skin diseases (e.g., cellulitis, dermatocycoses), toxemia, urinary tract infections, wound infections.
A polypeptide or polynucleotide of the present invention can be used to treat or detect any of these symptoms or diseases.
Moreover, parasitic agents causing disease or symptoms that can be treated or detected by a polynucleotide or polypeptide of the present invention include, but not limited to, the following families: Amebiasis, Babesiosis, Coccidiosis, Cryptosporidiosis, Dientamoebiasis, Dourine, Ectoparasitic, Giardiasis, Helminthiasis, Leishmaniasis, Theileriasis, Toxoplasmosis, Trypanosomiasis, and Trichomonas.
These parasites can cause a variety of diseases or symptoms, including, but not limited to: Scabies, Trombiculiasis, eye infections, intestinal disease (e.g., dysentery, giardiasis), liver disease, lung disease, opportunistic infections (e.g., AIDS
related), Malaria, pregnancy complications, and toxoplasmosis. A polypeptide or polynucleotide of the present invention can be used to treat or detect any of these symptoms or diseases.
Preferably, treatment using a polypeptide or polynucleotide of the present invention could either be by administering an effective amount of a polypeptide to the patient, or by removing cells from the patient, supplying the cells with a polynucleotide of the present invention, and returning the engineered cells to the patient (ex vivo therapy). Moreover, the polypeptide or polynucleotide of the present invention can be used as an antigen in a vaccine to raise an immune response against infectious disease.
Regeneration A polynucleotide or polypeptide of the present invention can be used to differentiate, proliferate, and attract cells, leading to the regeneration of tissues. {See, Science 276:59-87 (1997).) The regeneration of tissues could be used to repair, replace, or protect tissue damaged by congenital defects, trauma (wounds, burns, incisions, or ulcers), age, disease (e.g. osteoporosis, osteocarthritis, periodontal disease, liver failure), surgery, including cosmetic plastic surgery, fibrosis, reperfusion injury, or systemic cytokine damage.
Tissues that could be regenerated using the present invention include organs (e.g., pancreas, liver, intestine, kidney, skin, endothelium), muscle (smooth, skeletal or cardiac), vascular (including vascular endothelium), nervous, hematopoietic, and skeletal {bone, cartilage, tendon, and ligament) tissue. Preferably, regeneration occurs without or decreased scarring. Regeneration also may include angiogenesis.
Moreover, a polynucleotide or polypeptide of the present invention may increase regeneration of tissues difficult to heal. For example, increased tendon/ligament regeneration would quicken recovery time after damage. A polynucleotide or polypeptide of the present invention could also be used prophylactically in an effort to avoid damage. Specific diseases that could be treated include of tendinitis, carpal tunnel syndrome, and other tendon or ligament defects. A further example of tissue regeneration of non-healing wounds includes pressure ulcers, ulcers associated with vascular insufficiency, surgical, and traumatic wounds.
Similarly, nerve and brain tissue could also be regenerated by using a polynucleotide or polypeptide of the present invention to proliferate and differentiate nerve cells. Diseases that could be treated using this method include central and peripheral nervous system diseases, neuropathies, or mechanical and traumatic disorders (e.g., spinal cord disorders, head trauma, cerebrovascular disease, and stoke). Specifically, diseases associated with peripheral nerve injuries, peripheral neuropathy (e.g., resulting from chemotherapy or other medical therapies), localized neuropathies, and central nervous system diseases (e.g., Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and Shy-Drager syndrome), could all be treated using the polynucleotide or polypeptide of the present invention.
Chemotaxis A polynucleotide or polypeptide of the present invention may have chemotaxis activity. A chemotaxic molecule attracts or mobilizes cells (e.g., monocytes, fibroblasts, neutrophils, T-cells, mast cells, eosinophils, epithelial and/or endothelial cells) to a particular site in the body, such as inflammation, infection, or site of hyperproliferation. The mobilized cells can then fight off and/or heal the particular trauma or abnormality.
A polynucleotide or polypeptide of the present invention may increase chemotaxic activity of particular cells. These chemotactic molecules can then be used to treat inflammation, infection, hyperproliferative disorders, or any immune system disorder by increasing the number of cells targeted to a particular location in the body.
For example, chemotaxic molecules can be used to treat wounds and other trauma to tissues by attracting immune cells to the injured location. Chemotactic molecules of the present invention can also attract fibroblasts, which can be used to treat wounds.

It is also contemplated that a polynucleotide or polypeptide of the present invention may inhibit chemotactic activity. These molecules could also be used to treat disorders. Thus, a polynucleotide or polypeptide of the present invention could be used as an inhibitor of chemotaxis.
Binding Activity A polypeptide of the present invention may be used to screen for molecules that bind to the polypeptide or for molecules to which the polypeptide binds. The binding of the polypeptide and the molecule may activate (agonist}, increase, inhibit {antagonist), or decrease activity of the polypeptide or the molecule bound.
Examples of such molecules include antibodies, oligonucleotides, proteins (e.g., receptors),or small molecules.
Preferably, the molecule is closely related to the natural ligand of the polypeptide, e.g., a fragment of the ligand, or a natural substrate, a Iigand, a structural or functional mimetic. (See, Coligan et al., Current Protocols in Immunology 1(2):Chapter 5 {1991).) Similarly, the molecule can be closely related to the natural receptor to which the polypeptide binds, or at least, a fragment of the receptor capable of being bound by the polypeptide (e.g., active site). In either case, the molecule can be rationally designed using known techniques.
Preferably, the screening for these molecules involves producing appropriate cells which express the polypeptide, either as a secreted protein or on the cell membrane. Preferred cells include cells from mammals, yeast, Drosophila, or E
coli.
Cells expressing the polypeptide (or cell membrane containing the expressed polypeptide) are then preferably contacted with a test compound potentially containing the molecule to observe binding, stimulation, or inhibition of activity of either the polypeptide or the molecule.
The assay may simply test binding of a candidate compound to the polypeptide, wherein binding is detected by a label, or in an assay involving competition with a labeled competitor. Further, the assay may test whether the candidate compound results in a signal generated by binding to the polypeptide.
Alternatively, the assay can be carried out using cell-free preparations, polypeptide/molecule affixed to a solid support, chemical libraries, or natural product mixtures. The assay may also simply comprise the steps of mixing a candidate compound with a solution containing a polypeptide, measuring polypeptide/molecule activity or binding, and comparing the polypeptide/molecule activity or binding to a standard.

Preferably, an ELISA assay can measure polypeptide level or activity in a sample (e.g., biological sample) using a monoclonal or polyclonal antibody.
The antibody can measure polypeptide level or activity by either binding, directly or indirectly, to the polypeptide or by competing with the polypeptide for a substrate.
All of these above assays can be used as diagnostic or prognostic markers. The molecules discovered using these assays can be used to treat disease or to bring about a particular result in a patient (e.g., blood vessel growth) by activating or inhibiting the polypeptide/molecule. Moreover, the assays can discover agents which may inhibit or enhance the production of the polypeptide from suitably manipulated cells or tissues.
Therefore, the invention includes a method of identifying compounds which bind to a polypeptide of the invention comprising the steps of: (a) incubating a candidate binding compound with a polypeptide of the invention; and (b) determining if binding has occurred. Moreover, the invention includes a method of identifying agonists/antagonists comprising the steps of: (a) incubating a candidate compound with a polypeptide of the invention, (b) assaying a biological activity , and (b}
determining if a biological activity of the polypeptide has been altered.
Other Activities A polypeptide or polynucleotide of the present invention may also increase or decrease the differentiation or proliferation of embryonic stem cells, besides, as discussed above, hematopoietic lineage.
A polypeptide or polynucleotide of the present invention may also be used to modulate mammalian characteristics, such as body height, weight, hair color, eye color, skin, percentage of adipose tissue, pigmentation, size, and shape (e.g., cosmetic surgery). Similarly, a polypeptide or polynucleotide of the present invention may be used to modulate mammalian metabolism affecting catabolism, anabolism, processing, utilization, and storage of energy.
A polypeptide or polynucleotide of the present invention may be used to change a mammal's mental state or physical state by influencing biorhythms, caricadic rhythms, depression (including depressive disorders), tendency for violence, tolerance for pain, reproductive capabilities (preferably by Activin or Inhibin-like activity), hormonal or endocrine levels, appetite, libido, memory, stress, or other cognitive qualities.
A polypeptide or polynucleotide of the present invention may also be used as a food additive or preservative, such as to increase or decrease storage capabilities, fat content, lipid, protein, carbohydrate, vitamins, minerals, cofactors or other nutritional components.

Other Preferred Embodiments Other preferred embodiments of the claimed invention include an isolated nucleic acid molecule comprising a nucleotide sequence which is at least 95%
identical to a sequence of at least about 50 contiguous nucleotides in the nucleotide sequence of SEQ ID NO:X wherein X is any integer as defined in Table 1.
Also preferred is a nucleic acid molecule wherein said sequence of contiguous nucleotides is included in the nucleotide sequence of SEQ ID NO:X in the range of positions beginning with the nucleotide at about the position of the 5' Nucleotide of the Clone Sequence and ending with the nucleotide at about the position of the 3' Nucleotide of the Clone Sequence as defined for SEQ ID NO:X in Table 1.
Also preferred is a nucleic acid molecule wherein said sequence of contiguous nucleotides is included in the nucleotide sequence of SEQ ID NO:X in the range of positions beginning with the nucleotide at about the position of the 5' Nucleotide of the Start Codon and ending with the nucleotide at about the position of the 3' Nucleotide of the Clone Sequence as defined for SEQ ID NO:X in Table 1.
Similarly preferred is a nucleic acid molecule wherein said sequence of contiguous nucleotides is included in the nucleotide sequence of SEQ ID NO:X
in the range of positions beginning with the nucleotide at about the position of the 5' Nucleotide of the First Amino Acid of the Signal Peptide and ending with the nucleotide at about the position of the 3' Nucleotide of the Clone Sequence as defined for SEQ ID
NO:X in Table 1.
Also preferred is an isolated nucleic acid molecule comprising a nucleotide sequence which is at least 95% identical to a sequence of at least about 150 contiguous nucleotides in the nucleotide sequence of SEQ ID NO:X.
Further preferred is an isolated nucleic acid molecule comprising a nucleotide sequence which is at least 95% identical to a sequence of at least about 500 contiguous nucleotides in the nucleotide sequence of SEQ ID NO:X.
A further preferred embodiment is a nucleic acid molecule comprising a nucleotide sequence which is at least 95% identical to the nucleotide sequence of SEQ
ID NO:X beginning with the nucleotide at about the position of the 5' Nucleotide of the First Amino Acid of the Signal Peptide and ending with the nucleotide at about the position of the 3' Nucleotide of the Clone Sequence as defined for SEQ ID NO:X
in Table 1.

WO 98/56804 PCTlUS98/12125 A further preferred embodiment is an isolated nucleic acid molecule comprising a nucleotide sequence which is at least 95% identical to the complete nucleotide sequence of SEQ ID NO:X.
Also preferred is an isolated nucleic acid molecule which hybridizes under S stringent hybridization conditions to a nucleic acid molecule, wherein said nucleic acid molecule which hybridizes does not hybridize under stringent hybridization conditions to a nucleic acid molecule having a nucleotide sequence consisting of only A
residues or of only T residues.
Also preferred is a composition of matter comprising a DNA molecule which comprises a human cDNA clone identified by a cDNA Clone Identifier in Table l, which DNA molecule is contained in the material deposited with the American Type Culture Collection and given the ATCC Deposit Number shown in Table 1 for said cDNA Clone Identifier.
Also preferred is an isolated nucleic acid molecule comprising a nucleotide sequence which is at least 95% identical to a sequence of at least 50 contiguous nucleotides in the nucleotide sequence of a human cDNA clone identified by a cDNA
Clone Identifier in Table 1, which DNA molecule is contained in the deposit given the ATCC Deposit Number shown in Table 1.
Also preferred is an isolated nucleic acid molecule, wherein said sequence of at least 50 contiguous nucleotides is included in the nucleotide sequence of the complete open reading frame sequence encoded by said human cDNA clone.
Also preferred is an isolated nucleic acid molecule comprising a nucleotide sequence which is at least 95% identical to sequence of at least 150 contiguous nucleotides in the nucleotide sequence encoded by said human cDNA clone.
A further preferred embodiment is an isolated nucleic acid molecule comprising a nucleotide sequence which is at least 95% identical to sequence of at least contiguous nucleotides in the nucleotide sequence encoded by said human cDNA
clone.
A further preferred embodiment is an isolated nucleic acid molecule comprising a nucleotide sequence which is at least 95% identical to the complete nucleotide sequence encoded by said human cDNA clone.
A further preferred embodiment is a method for detecting in a biological sample a nucleic acid molecule comprising a nucleotide sequence which is at least 95%
identical to a sequence of at least 50 contiguous nucleotides in a sequence selected from the group consisting of: a nucleotide sequence of SEQ ID NO:X wherein X is any integer as defined in Table 1; and a nucleotide sequence encoded by a human cDNA clone identified by a cDNA Clone Identifier in Table 1 and contained in the deposit with the ATCC Deposit Number shown for said cDNA clone in Table 1; which method comprises a step of comparing a nucleotide sequence of at least one nucleic acid molecule in said sample with a sequence selected from said group and determining whether the sequence of said nucleic acid molecule in said sample is at least 95%
identical to said selected sequence.
Also preferred is the above method wherein said step of comparing sequences comprises determining the extent of nucleic acid hybridization between nucleic acid molecules in said sample and a nucleic acid molecule comprising said sequence selected from said group. Similarly, also preferred is the above method wherein said step of comparing sequences is performed by comparing the nucleotide sequence determined from a nucleic acid molecule in said sample with said sequence selected from said group. The nucleic acid molecules can comprise DNA molecules or RNA molecules.
A further preferred embodiment is a method for identifying the species, tissue or cell type of a biological sample which method comprises a step of detecting nucleic acid molecules in said sample, if any, comprising a nucleotide sequence that is at least 95%
identical to a sequence of at least 50 contiguous nucleotides in a sequence selected from the group consisting of: a nucleotide sequence of SEQ ID NO:X wherein X is any integer as defined in Table 1; and a nucleotide sequence encoded by a human cDNA
clone identified by a cDNA Clone Identifier in Table 1 and contained in the deposit with the ATCC Deposit Number shown for said cDNA clone in Table 1.
The method for identifying the species, tissue or cell type of a biological sample can comprise a step of detecting nucleic acid molecules comprising a nucleotide sequence in a panel of at least two nucleotide sequences, wherein at least one sequence in said panel is at least 95% identical to a sequence of at least 50 contiguous nucleotides in a sequence selected from said group.
Also preferred is a method for diagnosing in a subject a pathological condition associated with abnormai structure or expression of a gene encoding a secreted protein identified in Table I, which method comprises a step of detecting in a biological sample obtained from said subject nucleic acid molecules, if any, comprising a nucleotide sequence that is at /east 95% identical to a sequence of at least 50 contiguous nucleotides in a sequence selected from the group consisting of: a nucleotide sequence of SEQ ID NO:X wherein X is any integer as defined in Table 1; and a nucleotide sequence encoded by a human cDNA clone identified by a cDNA Clone Identifier in Table 1 and contained in the deposit with the ATCC Deposit Number shown for said cDNA clone in Table 1.
The method for diagnosing a pathological condition can comprise a step of detecting nucleic acid molecules comprising a nucleotide sequence in a panel of at least two nucleotide sequences, wherein at least one sequence in said panel is at least 95%

WO 98!56804 PCT/US98/12125 identical to a sequence of at least 50 contiguous nucleotides in a sequence selected from said group.
Also preferred is a composition of matter comprising isolated nucleic acid molecules wherein the nucleotide sequences of said nucleic acid molecules comprise a panel of at least two nucleotide sequences, wherein at least one sequence in said panel is at least 95% identical to a sequence of at least 50 contiguous nucleotides in a sequence selected from the group consisting of: a nucleotide sequence of SEQ ID NO:X
wherein X is any integer as defined in Table 1; and a nucleotide sequence encoded by a human cDNA clone identified by a cDNA Clone Identifier in Table 1 and contained in the deposit with the ATCC Deposit Number shown for said cDNA clone in Table 1. The nucleic acid molecules can comprise DNA molecules or RNA molecules.
Also preferred is an isolated polypeptide comprising an amino acid sequence at least 90% identical to a sequence of at least about 10 contiguous amino acids in the amino acid sequence of SEQ ID NO:Y wherein Y is any integer as defined in Table 1.
Also preferred is a polypeptide, wherein said sequence of contiguous amino acids is included in the amino acid sequence of SEQ ID NO:Y in the range of positions beginning with the residue at about the position of the First Amino Acid of the Secreted Portion and ending with the residue at about the Last Amino Acid of the Open Reading Frame as set forth for SEQ ID NO:Y in Table 1.
Also preferred is an isolated polypeptide comprising an amino acid sequence at least 95% identical to a sequence of at least about 30 contiguous amino acids in the amino acid sequence of SEQ ID NO:Y.
Further preferred is an isolated polypeptide comprising an amino acid sequence at least 95% identical to a sequence of at least about 100 contiguous amino acids in the amino acid sequence of SEQ ID NO:Y.
Further preferred is an isolated polypeptide comprising an amino acid sequence at least 95% identical to the complete amino acid sequence of SEQ ID NO:Y.
Further preferred is an isolated polypeptide comprising an amino acid sequence at least 90% identical to a sequence of at least about 10 contiguous amino acids in the complete amino acid sequence of a secreted protein encoded by a human cDNA
clone identified by a cDNA Clone Identifier in Table I and contained in the deposit with the ATCC Deposit Number shown for said cDNA clone in Table 1.
Also preferred is a polypeptide wherein said sequence of contiguous amino acids is included in the amino acid sequence of a secreted portion of the secreted protein encoded by a human cDNA clone identified by a cDNA Clone Identifier in Table l and contained in the deposit with the ATCC Deposit Number shown for said cDNA
clone in Table 1.

Also preferred is an isolated polypeptide comprising an amino acid sequence at least 95% identical to a sequence of at least about 30 contiguous amino acids in the amino acid sequence of the secreted portion of the protein encoded by a human cDNA
clone identified by a cDNA Clone Identifier in Table 1 and contained in the deposit with the ATCC Deposit Number shown for said cDNA clone in Table 1.
Also preferred is an isolated polypeptide comprising an amino acid sequence at least 95% identical to a sequence of at least about 100 contiguous amino acids in the amino acid sequence of the secreted portion of the protein encoded by a human cDNA
clone identified by a cDNA Clone Identifier in Table I and contained in the deposit with the ATCC Deposit Number shown for said cDNA clone in Table 1.
Also preferred is an isolated polypeptide comprising an amino acid sequence at least 95% identical to the amino acid sequence of the secreted portion of the protein encoded by a human cDNA clone identified by a cDNA Clone Identifier in Table 1 and contained in the deposit with the ATCC Deposit Number shown for said cDNA
clone in Table 1.
Further preferred is an isolated antibody which binds specifically to a polypeptide comprising an amino acid sequence that is at least 90% identical to a sequence of at least 10 contiguous amino acids in a sequence selected from the group consisting of: an amino acid sequence of SEQ ID NO:Y wherein Y is any integer as defined in Table 1; and a complete amino acid sequence of a protein encoded by a human cDNA clone identified by a cDNA Clone Identifier in Table 1 and contained in the deposit with the ATCC Deposit Number shown for said cDNA clone in Table 1.
Further preferred is a method for detecting in a biological sample a polypeptide comprising an amino acid sequence which is at least 90% identical to a sequence of at least 10 contiguous amino acids in a sequence selected from the group consisting of: an amino acid sequence of SEQ ID NO:Y wherein Y is any integer as defined in Table 1;
and a complete amino acid sequence of a protein encoded by a human cDNA clone identified by a cDNA Clone Identifier in Table 1 and contained in the deposit with the ATCC Deposit Number shown for said cDNA clone in Table 1; which method comprises a step of comparing an amino acid sequence of at least one polypeptide molecule in said sample with a sequence selected from said group and determining whether the sequence of said polypeptide molecule in said sample is at least 90%
identical to said sequence of at least 10 contiguous amino acids.
Also preferred is the above method wherein said step of comparing an amino acid sequence of at least one polypeptide molecule in said sample with a sequence selected from said group comprises deternzining the extent of specific binding of polypeptides in said sample to an antibody which binds specifically to a polypeptide comprising an amino acid sequence that is at least 90% identical to a sequence of at least contiguous amino acids in a sequence selected from the group consisting of: an amino acid sequence of SEQ ID NO:Y wherein Y is any integer as defined in Table 1;
and a complete amino acid sequence of a protein encoded by a human cDNA clone 5 identified by a cDNA Clone Identifier in Table l and contained in the deposit with the ATCC Deposit Number shown for said cDNA clone in Table 1.
Also preferred is the above method wherein said step of comparing sequences is performed by comparing the amino acid sequence determined from a polypeptide molecule in said sample with said sequence selected from said group.
10 Also preferred is a method for identifying the species, tissue or cell type of a biological sample which method comprises a step of detecting polypeptide molecules in said sample, if any, comprising an amino acid sequence that is at least 90%
identical to a sequence of at least 10 contiguous amino acids in a sequence selected from the group consisting of: an amino acid sequence of SEQ ID NO:Y wherein Y is any integer as defined in Table 1; and a complete amino acid sequence of a secreted protein encoded by a human cDNA clone identified by a cDNA Clone Identifier in Table l and contained in the deposit with the ATCC Deposit Number shown for said cDNA clone in Table I .
Also preferred is the above method for identifying the species, tissue or cell type of a biological sample, which method comprises a step of detecting polypeptide molecules comprising an amino acid sequence in a panel of at least two amino acid sequences, wherein at least one sequence in said panel is at least 90%
identical to a sequence of at least 10 contiguous amino acids in a sequence selected from the above group.
Also preferred is a method for diagnosing in a subject a pathological condition associated with abnormal structure or expression of a gene encoding a secreted protein identified in Table 1, which method comprises a step of detecting in a biological sample obtained from said subject polypeptide molecules comprising an amino acid sequence in a panel of at least two amino acid sequences, wherein at least one sequence in said panel is at least 90% identical to a sequence of at least 10 contiguous amino acids in a sequence selected from the group consisting of: an amino acid sequence of SEQ
ID
NO:Y wherein Y is any integer as defined in Table l; and a complete amino acid sequence of a secreted protein encoded by a human cDNA clone identified by a cDNA
Clone Identifier in Table l and contained in the deposit with the ATCC Deposit Number shown for said cDNA clone in Table 1.
In any of these methods, the step of detecting said polypeptide molecules includes using an antibody.

Also preferred is an isolated nucleic acid molecule comprising a nucleotide sequence which is at least 95% identical to a nucleotide sequence encoding a polypeptide wherein said polypeptide comprises an amino acid sequence that is at least 90% identical to a sequence of at least 10 contiguous amino acids in a sequence selected from the group consisting of: an amino acid sequence of SEQ ID NO:Y wherein Y
is any integer as defined in Table 1; and a complete amino acid sequence of a secreted protein encoded by a human cDNA clone identified by a cDNA Clone Identifier in Table 1 and contained in the deposit with the ATCC Deposit Number shown for said cDNA
clone in Table 1.
Also preferred is an isolated nucleic acid molecule, wherein said nucleotide sequence encoding a polypeptide has been optimized for expression of said polypeptide in a prokaryotic host.
Also preferred is an isolated nucleic acid molecule, wherein said polypeptide comprises an amino acid sequence selected from the group consisting of: an amino acid sequence of SEQ ID NO:Y wherein Y is any integer as defined in Table l; and a complete amino acid sequence of a secreted protein encoded by a human cDNA
clone identified by a cDNA Clone Identifier in Table 1 and contained in the deposit with the ATCC Deposit Number shown for said cDNA clone in Table 1.
Further preferred is a method of making a recombinant vector comprising inserting any of the above isolated nucleic acid molecule into a vector. Also preferred is the recombinant vector produced by this method. Also preferred is a method of making a recombinant host cell comprising introducing the vector into a host cell, as well as the recombinant host cell produced by this method.
Also preferred is a method of making an isolated polypeptide comprising culturing this recombinant host cell under conditions such that said polypeptide is expressed and recovering said polypeptide. Also preferred is this method of making an isolated polypeptide, wherein said recombinant host cell is a eukaryotic cell and said polypeptide is a secreted portion of a human secreted protein comprising an amino acid sequence selected from the group consisting of: an amino acid sequence of SEQ
ID
NO:Y beginning with the residue at the position of the First Amino Acid of the Secreted Portion of SEQ ID NO:Y wherein Y is an integer set forth in Table 1 and said position of the First Amino Acid of the Secreted Portion of SEQ ID NO:Y is defined in Table 1;
and an amino acid sequence of a secreted portion of a protein encoded by a human cDNA clone identified by a cDNA Clone Identifier in Table 1 and contained in the deposit with the ATCC Deposit Number shown for said cDNA clone in Table 1. The isolated polypeptide produced by this method is also preferred.

Also preferred is a method of treatment of an individual in need of an increased level of a secreted protein activity, which method comprises administering to such an individual a pharmaceutical composition comprising an amount of an isolated polypeptide, polynucleotide, or antibody of the claimed invention effective to increase the level of said protein activity in said individual.
Having generally described the invention, the same will be more readily understood by reference to the following examples, which are provided by way of illustration and are not intended as limiting.
Examples Example 1: Isolation of a Selected cDNA Clone From the Deposited Sample Each cDNA clone in a cited ATCC deposit is contained in a plasmid vector.
Table I identifies the vectors used to construct the cDNA library from which each clone was isolated. In many cases, the vector used to construct the library is a phage vector from which a plasmid has been excised. The table immediately below correlates the related plasmid for each phage vector used in constructing the cDNA library.
For example, where a particular clone is identified in Table 1 as being isolated in the vector "Lambda Zap," the corresponding deposited clone is in "pBluescript."
Vector Used to Construct Library Corresponding Deposited Plasmid Lambda Zap pBluescript (pBS) Uni-Zap XR pBluescript (pBS) Zap Express pBK

Iafmid BA plafmid BA

pSportl pSport2 pCMVSport 2.0 pCMVSport 2.0 pCMVSport 3.0 pCMVSport 3.0 pCR2.1 pCR2.1 Vectors Lambda Zap (U.S. Patent Nos. 5,128>256 and 5,286,636), Uni-Zap XR (U.S. Patent Nos. 5,128, 256 and 5,286,636), Zap Express (U.S. Patent Nos.
5,128,256 and 5,286,636), pBluescript (pBS) (Short, J. M. et al., Nucleic Acids Res.
26:7583-7600 {1988); Alting-Mees, M. A. and Short, J. M., Nucleic Acids Res.
17:9494 ( 1989)) and pBK (Alting-Mees, M. A. et al., Strategies 5:58-6I ( 1992)) are commercially available from Stratagene Cloning Systems, Inc., I 1011 N. Torrey Pines Road, La Jolla, CA, 92037. pBS contains an ampiciIlin resistance gene and pBK
contains a neomycin resistance gene. Both can be transformed into E. coli strain XL-1 Blue, also available from Stratagene. pBS comes in 4 forms SK+, SK-, KS+ and KS.
The S and K refers to the orientation of the polylinker to the T7 and T3 primer sequences which flank the polylinker region ("S" is for SacI and "K" is for KpnI which are the first sites on each respective end of the linker). "+" or "-" refer to the orientation of the f 1 origin of replication ("ori"), such that in one orientation, single stranded rescue initiated from the f 1 on generates sense strand DNA and in the other, antisense.
Vectors pSportl, pCMVSport 2.0 and pCMVSport 3.0, were obtained from Life Technologies, Inc., P. O. Box 6009, Gaithersburg, MD 20897. All Sport vectors contain an ampicillin resistance gene and may be transformed into E. coli strain DH l OB, also available from Life Technologies. (See, for instance, Glvber, C.
E., et al., Focus 15:59 ( 1993).) Vector lafmid BA (Bento Soares, Columbia University, NY) contains an ampicillin resistance gene and can be transformed into E. coli strain XL-1 Blue. Vector pCR°2.1, which is available from Invitrogen, 1600 Faraday Avenue, Carlsbad, CA 92008, contains an ampicillin resistance gene and may be transformed into E. coli strain DHIOB, available from Life Technologies. (See, for instance, Clark, J. M., Nuc. Acids Res. 16:9677-9686 ( 1988) and Mead, D. et al., BioITechnology 9:
( 1991 ).) Preferably, a polynucleotide of the present invention does not comprise the phage vector sequences identified for the particular clone in Table 1, as well as the corresponding plasmid vector sequences designated above.
The deposited material in the sample assigned the ATCC Deposit Number cited in Table 1 for any given cDNA clone also may contain one or more additional plasmids, each comprising a cDNA clone different from that given clone. Thus, deposits sharing the same ATCC Deposit Number contain at least a plasmid for each cDNA clone identified in Table 1. Typically, each ATCC deposit sample cited in Table 1 comprises a mixture of approximately equal amounts (by weight) of about 50 plasmid DNAs, each containing a different cDNA clone; but such a deposit sample may include plasmids for more or less than 50 cDNA clones, up to about 500 cDNA clones.
Two approaches can be used to isolate a particular clone from the deposited sample of plasmid DNAs cited for that clone in Table 1. First, a plasmid is directly isolated by screening the clones using a polynucleotide probe corresponding to SEQ ID
NO:X.
Particularly, a specific polynucleotide with 30-40 nucleotides is synthesized using an Applied Biosystems DNA synthesizer according to the sequence reported.
The oligonucleotide is labeled, for instance, with 3'P-y ATP using T4 polynucleotide kinase and purified according to routine methods. (E.g., Maniatis et al., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Press, Cold Spring, NY ( 1982).) The plasmid mixture is transformed into a suitable host, as indicated above (such as XL-1 Blue (Stratagene)) using techniques known to those of skill in the art, such as those provided by the vector supplier or in related publications or patents cited above.
The transformants are plated on 1.5% agar plates (containing the appropriate selection agent, e.g., ampicillin) to a density of about 150 transformants (colonies) per plate.
These plates are screened using Nylon membranes according to routine methods for bacterial colony screening (e.g., Sambrook et al., Molecular Cloning: A
Laboratory Manual, 2nd Edit., ( 1989), Cold Spring Harbor Laboratory Press, pages 1.93 to 1.104), or other techniques known to those of skill in the art.
Alternatively, two primers of 17-20 nucleotides derived from both ends of the SEQ ID NO:X (i.e., within the region of SEQ ID NO:X bounded by the 5' NT and the 3' NT of the clone defined in Table 1 ) are synthesized and used to amplify the desired cDNA using the deposited cDNA plasmid as a template. The polymerase chain reaction is carried out under routine conditions, for instance, in 25 ~1 of reaction mixture with 0.5 ug of the above cDNA template. A convenient reaction mixture is 1.5-5 mM
MgCI" 0.01 % (w/v} gelatin, 20 ~,M each of dATP, dCTP, dGTP, dTTP, 25 pmol of each primer and 0.25 Unit of Taq polymerase. Thirty five cycles of PCR
(denaturation at 94°C for I min; annealing at 55°C for 1 min; elongation at 72°C for 1 min) are performed with a Perkin-Elmer Cetus automated thermal cycler. The amplified product is analyzed by agarose gel electrophoresis and the DNA band with expected molecular weight is excised and purified. The PCR product is verified to be the selected sequence by subcloning and sequencing the DNA product.
Several methods are available for the identification of the 5' or 3' non-coding portions of a gene which may not be present in the deposited clone. These methods include but are not limited to, filter probing, clone enrichment using specific probes, and protocols similar or identical to 5' and 3' "RACE" protocols which are well known in the art. For instance, a method similar to 5' RACE is available for generating the missing 5' end of a desired full-length transcript. (Fromont-Racine et al., Nucleic Acids Res. 21(7):1b83-1684 (1993).) Briefly, a specific RNA oligonucleotide is ligated to the 5' ends of a population of RNA presumably containing full-length gene RNA transcripts. A primer set containing a primer specific to the ligated RNA oligonucleotide and a primer specific to a known sequence of the gene of interest is used to PCR amplify the 5' portion of the desired full-length gene. This amplified product may then be sequenced and used to generate the full length gene.

This above method starts with total RNA isolated from the desired source, although poly-A+ RNA can be used. The RNA preparation can then be treated with phosphatase if necessary to eliminate 5' phosphate groups on degraded or damaged RNA which may interfere with the later RNA ligase step. The phosphatase should then be inactivated and the RNA treated with tobacco acid pyrophosphatase in order to remove the cap structure present at the 5' ends of messenger RNAs. This reaction leaves a 5' phosphate group at the 5' end of the cap cleaved RNA which can then be ligated to an RNA oligonucleotide using T4 RNA ligase.
This modified RNA preparation is used as a template for first strand cDNA
synthesis using a gene specific oligonucleotide. The first strand synthesis reaction is used as a template for PCR amplification of the desired S' end using a primer specific to the ligated RNA oligonucleotide and a primer specific to the known sequence of the gene of interest. The resultant product is then sequenced and analyzed to confirm that the 5' end sequence belongs to the desired gene.
Example 2: Isolation of Genomic Clones Corresponding to a Polynucleotide A human genomic PI library (Genomic Systems, Inc.) is screened by PCR
using primers selected for the eDNA sequence corresponding to SEQ ID NO:X., according to the method described in Example 1. {See also, Sambrook.) Example 3: Tissue Distribution of Polypeptide Tissue distribution of mRNA expression of polynucleotides of the present invention is determined using protocols for Northern blot analysis, described by, among others, Sambrook et al. For example, a cDNA probe produced by the method described in Example 1 is labeled with P3z using the rediprimeTM DNA labeling system (Amersham Life Science), according to manufacturer's instructions. After labeling, the probe is purified using CHROMA SPIN-100TM column (Clontech Laboratories, Inc.), according to manufacturer's protocol number PT1200-1. The purified labeled probe is then used to examine various human tissues for mRNA expression.
Multiple Tissue Northern (MTN) blots containing various human tissues (H) or human immune system tissues (IM) (Clontech) are examined with the labeled probe using ExpressHybTM hybridization solution (Clontech) according to manufacturer's protocol number PTI 190-1. Following hybridization and washing, the blots are mounted and exposed to film at -70°C overnight, and the films developed according to standard procedures.

Example 4: Chromosomal Mapping of the Polynucleotides An oligonucleotide primer set is designed according to the sequence at the 5' end of SEQ ID NO:X. This primer preferably spans about 100 nucleotides. This primer set is then used in a polymerase chain reaction under the following set of conditions : 30 seconds, 95°C; 1 minute, 56°C; 1 minute, 70°C. This cycle is repeated 32 times followed by one 5 minute cycle at 70°C. Human, mouse, and hamster DNA
is used as template in addition to a somatic cell hybrid panel containing individual chromosomes or chromosome fragments (Bios, Inc). The reactions is analyzed on IO either 8% polyacrylamide gels or 3.5 % agarose gels. Chromosome mapping is determined by the presence of an approximately 100 by PCR fragment in the particular somatic cell hybrid.
Example S: Bacterial Expression of a Polxpeptide A polynucleotide encoding a polypeptide of the present invention is amplified using PCR oligonucleotide primers corresponding to the 5' and 3' ends of the DNA
sequence, as outlined in Example 1, to synthesize insertion fragments. The primers used to amplify the cDNA insert should preferably contain restriction sites, such as BamHI and XbaI, at the 5' end of the primers in order to clone the amplified product into the expression vector. For example, BamHI and XbaI correspond to the restriction enzyme sites on the bacterial expression vector pQE-9. (Qiagen, Inc., Chatsworth, CA). This plasmid vector encodes antibiotic resistance (Ampr), a bacterial origin of replication (ori), an IPTG-regulatable promoter/operator (P/O), a ribosome binding site (RBS), a 6-histidine tag (6-His), and restriction enzyme cloning sites.
The pQE-9 vector is digested with BamHI and XbaI and the amplified fragment is ligated into the pQE-9 vector maintaining the reading frame initiated at the bacterial RBS. The ligation nvxture is then used to transform the E. coli strain M
lS/rep4 (Qiagen, Inc.) which contains multiple copies of the plasmid pREP4, which expresses the lacI repressor and also confers kanamycin resistance (Kanr). Transformants are identified by their ability to grow on LB plates and ampicillin/kanamycin resistant colonies are selected. Plasmid DNA is isolated and confirmed by restriction analysis.
Clones containing the desired constructs are grown overnight (O/N) in liquid culture in LB media supplemented with both Amp ( 100 ug/ml) and Kan (25 ug/ml).
The O/N culture is used to inoculate a large culture at a ratio of 1:100 to 1:250. The cells are grown to an optical density 600 (O.D.~°°) of between 0.4 and 0.6. IPTG

(Isopropyl-B-D-thiogalacto pyranoside) is then added to a final concentration of 1 mM.
IPTG induces by inactivating the lacI repressor, clearing the P/O leading to increased gene expression.
Cells are grown for an extra 3 to 4 hours. Cells are then harvested by centrifugation {20 mins at 6000Xg). The cell pellet is solubilized in the chaotropic agent 6 Molar Guanidine HCl by stirring for 3-4 hours at 4°C. The cell debris is removed by centrifugation, and the supernatant containing the polypeptide is loaded onto a nickel-nitrilo-tri-acetic acid ("Ni-NTA") affinity resin column {available from QIAGEN, Inc., supra}. Proteins with a 6 x His tag bind to the Ni-NTA resin with high affinity and can be purified in a simple one-step procedure (for details see:
The QIAexpressionist (1995) QIAGEN, Inc., supra).
Briefly, the supernatant is loaded onto the column in 6 M guanidine-HCI, pH 8, the column is first washed with 10 volumes of 6 M guanidine-HCI, pH 8, then washed with 10 volumes of 6 M guanidine-HCl pH 6, and finally the polypeptide is eluted with 6 M guanidine-HCI, pH 5.
The purified protein is then renatured by dialyzing it against phosphate-buffered saline (PBS) or 50 mM Na-acetate, pH 6 buffer plus 200 mM NaCI. Alternatively, the protein can be successfully refolded while immobilized on the Ni-NTA column.
The recommended conditions are as follows: renature using a linear 6M-1M urea gradient in 500 mM NaCI, 20% glycerol, 20 mM Tris/HCl pH 7.4, containing protease inhibitors.
The renaturation should be performed over a period of 1.5 hours or more. After renaturation the proteins are eluted by the addition of 250 mM immidazole.
Immidazole is removed by a final dialyzing step against PBS or 50 mM sodium acetate pH 6 buffer plus 200 mM NaCI. The purified protein is stored at 4° C or frozen at -80° C.
In addition to the above expression vector, the present invention further includes an expression vector comprising phage operator and promoter elements operatively linked to a polynucleotide of the present invention, called pHE4a. (ATCC
Accession Number 209b45, deposited on February 25, 1998.) This vector contains: 1) a neomycinphosphotransferase gene as a selection marker, 2) an E. coli origin of replication, 3) a T5 phage promoter sequence, 4) two lac operator sequences, 5) a Shine-Delgarno sequence, and 6) the lactose operon repressor gene (lacIq). The origin of replication (oriC) is derived from pUCl9 (LTI, Gaithersburg, MD). The promoter sequence and operator sequences are made synthetically.
DNA can be inserted into the pHEa by restricting the vector with NdeI and XbaI, BamHI, XhoI, or Asp718, running the restricted product on a gel, and isolating the larger fragment (the stuffer fragment should be about 310 base pairs). The DNA

insert is generated according to the PCR protocol described in Example 1, using PCR
primers having restriction sites for NdeI (5' primer) and XbaI, BamHI, XhoI, or Asp718 {3' primer). The PCR insert is gel purified and restricted with compatible enzymes. The insert and vector are ligated according to standard protocols.
The engineered vector could easily be substituted in the above protocol to express protein in a bacterial system.
Example 6: Purification of a Polypeptide from an Inclusion Body The following alternative method can be used to purify a polypeptide expressed in E coli when it is present in the form of inclusion bodies. Unless otherwise specified, all of the following steps are conducted at 4-10°C.
Upon completion of the production phase of the E. toll fermentation, the cell culture is cooled to 4-10°C and the cells harvested by continuous centrifugation at 15,000 rpm (Heraeus Sepatech). On the basis of the expected yield of protein per unit weight of cell paste and the amount of purified protein required, an appropriate amount of cell paste, by weight, is suspended in a buffer solution containing 100 mM
Tris, 50 mM EDTA, pH 7.4. The cells are dispersed to a homogeneous suspension using a high shear mixer.
The cells are then lysed by passing the solution through a microfluidizer (Microfuidics, Corp. or APV Gaulin, Inc.) twice at 4000-6000 psi. The homogenate is then mixed with NaCI solution to a final concentration of 0.5 M NaCI, followed by centrifugation at 7000 xg for 15 min. The resultant pellet is washed again using 0.5M
NaCI, 100 mM Tris, 50 mM EDTA, pH 7.4.
The resulting washed inclusion bodies are solubilized with 1.5 M guanidine hydrochloride (GuHCI) for 2-4 hours. After 7000 xg centrifugation for 15 min., the pellet is discarded and the polypeptide containing supernatant is incubated at 4°C
overnight to allow further GuHCI extraction.
Following high speed centrifugation (30,000 xg) to remove insoluble particles, the GuHCI solubilized protein is refolded by quickly mixing the GuHCI extract with 20 volumes of buffer containing 50 mM sodium, pH 4.5, 150 mM NaCI, 2 mM EDTA by vigorous stirring. The refolded diluted protein solution is kept at 4°C
without mixing for 12 hours prior to further purification steps.
To clarify the refolded polypeptide solution, a previously prepared tangential filtration unit equipped with 0.16 p.m membrane filter with appropriate surface area (e.g., Filtron)> equilibrated with 40 mM sodium acetate, pH 6.0 is employed.
The filtered sample is loaded onto a cation exchange resin (e.g., Poros HS-50, Perseptive Biosystems). The column is washed with 40 mM sodium acetate, pH 6.0 and eluted with 250 mM, 500 mM, 1000 mM, and 1500 mM NaCI in the same buffer, in a stepwise manner. The absorbance at 280 nm of the effluent is continuously monitored.
Fractions are collected and further analyzed by SDS-PAGE.
Fractions containing the polypeptide are then pooled and mixed with 4 volumes of water. The diluted sample is then loaded onto a previously prepared set of tandem columns of strong anion (Poros HQ-50, Perseptive Biosystems) and weak anion (Poros CM-20, Perseptive Biosystems) exchange resins. The columns are equilibrated with 40 mM sodium acetate, pH 6Ø Both columns are washed with 40 mM sodium acetate, pH 6.0, 200 mM NaCI. The CM-20 column is then eluted using a 10 column volume linear gradient ranging from 0.2 M NaCI, 50 mM sodium acetate, pH 6.0 to 1.0 M NaCI, 50 mM sodium acetate, pH 6.5. Fractions are collected under constant AZBo monitoring of the effluent. Fractions containing the polypeptide (determined, for instance, by 16% SDS-PAGE) are then pooled.
The resultant polypeptide should exhibit greater than 95% purity after the above refolding and purification steps. No major contaminant bands should be observed from Commassie blue stained 16% SDS-PAGE gel when 5 ~tg of purified protein is loaded.
The purified protein can also be tested for endotoxin/LPS contamination, and typically the LPS content is less than 0.1 ng/ml according to LAL assays.
Example 7: Cloning and Expression of a Polypeptide in a Bacutovirus Expression System In this example, the plasmid shuttle vector pA2 is used to insert a polynucleotide into a baculovirus to express a polypeptide. This expression vector contains the strong polyhedrin promoter of the Autographa californica nuclear polyhedrosis virus (AcMNPV) followed by convenient restriction sites such as BamHI, Xba I and Asp718. The polyadenylation site of the simian virus 40 ("SV40") is used for efficient polyadenylation. For easy selection of recombinant virus, the plasmid contains the beta-galactosidase gene from E. coli under control of a weak Drosophila promoter in the same orientation, followed by the polyadenylation signal of the polyhedrin gene. The inserted genes are flanked on both sides by viral sequences for cell-mediated homologous recombination with wild-type viral DNA to generate a viable virus that express the cloned polynucleotide.

Many other baculovirus vectors can be used in place of the vector above, such as pAc373, pVL941, and pAcIMI, as one skilled in the art would readily appreciate, as long as the construct provides appropriately located signals for transcription, translation, secretion and the like, including a signal peptide and an in-frame AUG as required. Such vectors are described, for instance, in Luckow et al., Virology 170:3I-39 ( 1989).
Specifically, the cDNA sequence contained in the deposited clone, including the AUG initiation codon and the naturally associated leader sequence identified in Table 1, is amplified using the PCR protocol described in Example 1. If the naturally occurring signal sequence is used to produce the secreted protein, the pA2 vector does not need a second signal peptide. Alternatively, the vector can be modified (pA2 GP) to include a baculovirus leader sequence, using the standard methods described in Summers et al., "A Manual of Methods for Baculovirus Vectors and Insect Cell Culture Procedures,"
Texas Agricultural Experimental Station Bulletin No. 1555 ( 1987).
The amplified fragment is isolated from a 1 % agarose gel using a commercially available kit ("Geneclean," BIO 101 Inc., La Jolla, Ca.). The fragment then is digested with appropriate restriction enzymes and again purified on a 1 % agarose gel.
The plasmid is digested with the corresponding restriction enzymes and optionally, can be dephosphorylated using calf intestinal phosphatase, using routine procedures known in the art. The DNA is then isolated from a 1 % agarose gel using a commercially available kit ("Geneclean" BIO 101 Inc., La Jolla, Ca.).
The fragment and the dephosphorylated plasmid are ligated together with T4 DNA ligase. E. coli HB101 or other suitable E. coli hosts such as XL-1 Blue (Stratagene Cloning Systems, La Jolla, CA) cells are transformed with the ligation mixture and spread on culture plates. Bacteria containing the plasmid are identified by digesting DNA from individual colonies and analyzing the digestion product by gel electrophoresis. The sequence of the cloned fragment is confirmed by DNA
sequencing.
Five p,g of a plasmid containing the polynucleotide is co-transfected with 1.0 p.g of a commercially available linearized baculovirus DNA ("BaculoGoldTM
baculovirus DNA", Pharmingen, San Diego, CA), using the lipofection method described by Felgner et al., Proc. Natl. Acad. Sci. USA 84:7413-7417 (1987). One p,g of BaculoGoldTM virus DNA and 5 p.g of the plasmid are mixed in a sterile well of a microtiter plate containing 50 ~tl of serum-free Grace's medium (Life Technologies Inc., Gaithersburg, MD). Afterwards, 10 ~tl Lipofectin plus 90 pl Grace's medium are added, mixed and incubated for 15 minutes at room temperature. Then the transfection mixture is added drop-wise to Sf9 insect cells (ATCC CRL 1711 ) seeded in a 35 mm tissue culture plate with 1 ml Grace's medium without serum. The plate is then incubated for 5 hours at 27° C. The transfection solution is then removed from the plate and I ml of Grace's insect medium supplemented with 10% fetal calf serum is added.
Cultivation is then continued at 27° C for four days.
After four days the supernatant is collected and a plaque assay is performed, as described by Summers and Smith, supra. An agarose gel with "Blue Gal" (Life Technologies Inc., Gaithersburg) is used to allow easy identification and isolation of gal-expressing clones, which produce blue-stained plaques. (A detailed description of a "plaque assay" of this type can also be found in the user's guide for insect cell culture and baculovirology distributed by Life Technologies Inc., Gaithersburg, page 9-10.) After appropriate incubation, blue stained plaques are picked with the tip of a micropipettor (e.g., Eppendorf). The agar containing the recombinant viruses is then resuspended in a microcentrifuge tube containing 200 p.l of Grace's medium and the suspension containing the recombinant baculovirus is used to infect Sf9 cells seeded in 35 mm dishes. Four days later the supernatants of these culture dishes are harvested and then they are stored at 4° C.
To verify the expression of the polypeptide, Sf9 cells are grown in Grace's medium supplemented with 10% heat-inactivated FBS. The cells are infected with the recombinant baculovirus containing the polynucleotide at a multiplicity of infection ("MOI") of about 2. If radiolabeled proteins are desired, 6 hours later the medium is removed and is replaced with SF900 II medium minus methionine and cysteine (available from Life Technologies Inc., Rockville, MD). After 42 hours, 5 pCi of 3'S-methionine and 5 ~tCi 35S-cysteine (available from Amersham) are added. The cells are further incubated for 16 hours and then are harvested by centrifugation. The proteins in the supernatant as well as the intracellular proteins are analyzed by SDS-PAGE
followed by autoradiography (if radiolabeled).
Microsequencing of the amino acid sequence of the amino terminus of purified protein may be used to determine the amino terminal sequence of the produced protein.
Example 8: Expression of a Potypeptide in Mammalian Cells The polypeptide of the present invention can be expressed in a mammalian cell.
A typical mammalian expression vector contains a promoter element, which mediates WO 98156804 PCTlUS98l12125 13~
the initiation of transcription of mRNA, a protein coding sequence, and signals required for the termination of transcription and polyadenylation of the transcript.
Additional elements include enhancers, Kozak sequences and intervening sequences flanked by donor and acceptor sites for RNA splicing. Highly efficient transcription is achieved with the early and late promoters from SV40, the long terminal repeats (LTRs) from Retroviruses, e.g., RSV, HTLVI, HIVI and the early promoter of the cytomegalovirus (CMV). However, cellular elements can also be used (e.g., the human actin promoter).
Suitable expression vectors for use in practicing the present invention include, for example, vectors such as pSVL and pMSG {Pharmacia, Uppsala, Sweden), pRSVcat (ATCC 37152), pSV2dhfr (ATCC 37146), pBCI2MI (ATCC 67109), pCMVSport 2.0, and pCMVSport 3Ø Mammalian host cells that could be used include, human Hela, 293, H9 and Jurkat cells, mouse NIH3T3 and C127 cells, Cos 1, Cos 7 and CV 1, quail QC 1-3 cells, mouse L cells and Chinese hamster ovary (CHO) cells.
Alternatively, the polypeptide can be expressed in stable cell lines containing the polynucleotide integrated into a chromosome. The co-transfection with a selectable marker such as dhfr, gpt, neomycin, hygromycin allows the identification and isolation of the transfected cells.
The transfected gene can also be amplified to express large amounts of the encoded protein. The DHFR (dihydrofolate reductase) marker is useful in developing cell lines that carry several hundred or even several thousand copies of the gene of interest. (See, e.g., Alt, F. W., et al., J. Biol. Chem. 253:1357-1370 (1978);
Hamlin, J. L. and Ma, C., Biochem. et Biophys. Acta, 1097:107-143 (i990); Page, M. J.
and Sydenham, M. A., Biotechnology 9:64-68 (1991).) Another useful selection marker is the enzyme glutamine synthase (GS) (Murphy et al., Biochem J. 227:277-279 ( 1991 );
Bebbington et aL, BiolTechnology 10:169-175 ( 1992). Using these markers, the mammalian cells are grown in selective medium and the cells with the highest resistance are selected. These cell lines contain the amplified genes) integrated into a chromosome. Chinese hamster ovary (CHO) and NSO cells are often used for the production of proteins.
Derivatives of the plasmid pSV2-dhfr (ATCC Accession No. 37146), the expression vectors pC4 (ATCC Accession No. 209646) and pC6 (ATCC Accession No.209647) contain the strong promoter (LTR) of the Rous Sarcoma Virus (Cullen et al., Molecular and Cellular Biology, 438-447 (March, 1985)) plus a fragment of the CMV-enhancer (Boshart et al., Cell 41:521-530 (1985).) Multiple cloning sites, e.g., with the restriction enzyme cleavage sites BamHI, Xbal and Asp718, facilitate the cloning of the gene of interest. The vectors also contain the 3' intron, the polyadenylation and termination signal of the rat preproinsulin gene, and the mouse DHFR gene under control of the SV40 early promoter.
Specifically, the plasmid pC6, for example, is digested with appropriate restriction enzymes and then dephosphorylated using calf intestinal phosphates by procedures known in the art. The vector is then isolated from a 1 % agarose gel.
- A polynucleotide of the present invention is amplified according to the protocol outlined in Example 1. If the naturally occurring signal sequence is used to produce the secreted protein, the vector does not need a second signal peptide.
Alternatively, if the naturally occurring signal sequence is not used, the vector can be modified to include a heterologous signal sequence. (See, e.g., WO 96!34891.) The amplified fragment is isolated from a 1 % agarose gel using a commercially available kit ("Geneclean," BIO 101 Inc., La Jolla, Ca.). The fragment then is digested with appropriate restriction enzymes and again purified on a 1 % agarose gel.
The amplified fragment is then digested with the same restriction enzyme and purified on a I % agarose gel. The isolated fragment and the dephosphorylated vector are then ligated with T4 DNA ligase. E. coli HB 101 or XL-1 Blue cells are then transformed and bacteria are identified that contain the fragment inserted into plasmid pCb using, for instance, restriction enzyme analysis.
Chinese hamster ovary cells lacking an active DHFR gene is used for transfection. Five ug of the expression plasmid pC6 is cotransfected with 0.5 ~tg of the plasmid pSVneo using lipofectin (Felgner et al., supra). The plasmid pSV2-neo contains a dominant selectable marker, the neo gene from Tn5 encoding an enzyme that confers resistance to a group of antibiotics including 6418. The cells are seeded in alpha minus MEM supplemented with 1 mg/ml 6418. After 2 days, the cells are trypsinized and seeded in hybridoma cloning plates (Greiner, Germany) in alpha minus MEM supplemented with 10, 25, or 50 ng/ml of metothrexate plus I mg/ml 6418.
After about IO-14 days single clones are trypsinized and then seeded in 6-well petri dishes or 10 ml flasks using different concentrations of methotrexate (50 nM, 100 nM, 200 nM, 400 nM, 80(? nM). Clones growing at the highest concentrations of methotrexate are then transferred to new 6-well plates containing even higher concentrations of methotrexate ( 1 p.M, 2 p.M, 5 pM, 10 mM, 20 mM). The same procedure is repeated until clones are obtained which grow at a concentration of 100 -200 u.M. Expression of the desired gene product is analyzed, for instance, by SDS-PAGE and Western blot or by reversed phase HPLC analysis.

Example 9: Protein Fusions The polypeptides of the present invention are preferably fused to other proteins.
These fusion proteins can be used for a variety of applications. For example, fusion of the present polypeptides to His-tag, HA-tag, protein A, IgG domains, and maltose binding protein facilitates purification. (See Example 5; see also EP A
394,827;
Traunecker, et al., Nature 331:84-86 (1988).) Similarly, fusion to IgG-l, IgG-3, and albumin increases the halflife time in vivo. Nuclear localization signals fused to the polypeptides of the present invention can target the protein to a specific subcellular localization, while covalent heterodimer or homodimers can increase or decrease the activity of a fusion protein. Fusion proteins can also create chimeric molecules having more than one function. Finally, fusion proteins can increase solubility andlor stability of the fused protein compared to the non-fused protein. All of the types of fusion proteins described above can be made by modifying the following protocol, which outlines the fusion of a polypeptide to an IgG molecule, or the protocol described in Example 5.
Briefly, the human Fc portion of the IgG molecule can be PCR amplified, using primers that span the 5' and 3' ends of the sequence described below. These primers also should have convenient restriction enzyme sites that will facilitate cloning into an expression vector, preferably a mammalian expression vector.
For example, if pC4 (Accession No. 209646) is used, the human Fc portion can be ligated into the BamHI cloning site. Note that the 3' BamHI site should be destroyed. Next, the vector containing the human Fc portion is re-restricted with BamHI, linearizing the vector, and a polynucleotide of the present invention, isolated by the PCR protocol described in Example 1, is ligated into this BamHI site.
Note that the polynucleotide is cloned without a stop codon, otherwise a fusion protein will not be produced.
If the naturally occurring signal sequence is used to produce the secreted protein, pC4 does not need a second signal peptide. Alternatively, if the naturally occurring signal sequence is not used, the vector can be modified to include a heterologous signal sequence. (See, e.g., WO 96/34891.) Human IgG Fc region:
GGGATCCGGAGCCCAAATCTTCTGACAAAACTCACACATGCCCACCGTGCC
CAGCACCTGAATTCGAGGGTGCACCGTCAGTCTTCCTCTTCCCCCCAAAACC
CAAGGACACCCTCATGATCTCCCGGACTCCTGAGGTCACATGCGTGGTGGT
GGACGTAAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACG
GCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAAC

AGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTG
AATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAACCCCC
ATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGT
GTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCT
GACCTGCCTGGTCAAAGGCTTCTATCCAAGCGACATCGCCGTGGAGTGGGA
GAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGG
ACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCA
GGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGC
ACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAATGAGTGC
GACGGCCGCGACTCTAGAGGAT (SEQ ID NO:1) Example 10: Production of an Antibody from a Poly~eptide The antibodies of the present invention can be prepared by a variety of methods.
(See, Current Protocols, Chapter 2.) For example, cells expressing a polypeptide of the present invention is administered to an animal to induce the production of sera containing polyclonal antibodies. In a preferred method, a preparation of the secreted protein is prepared and purified to render it substantially free of natural contaminants.
Such a preparation is then introduced into an animal in order to produce polyclonal antisera of greater specific activity.
In the most preferred method, the antibodies of the present invention are monoclonal antibodies (or protein binding fragments thereof). Such monoclonal antibodies can be prepared using hybridoma technology. (Kohler et al., Nature 256:495 ( 1975); Kohler et al., Eur. J. Immunol. 6:511 ( / 976); Kohler et al., Eur. J.
Immunol. 6:292 ( 1976); Hammerling et al., in: Monoclonal Antibodies and T-Cell Hybridomas, Elsevier, N.Y., pp. 563-681 ( / 981 ).) In general, such procedures involve immunizing an animal (preferably a mouse) with polypeptide or, more preferably, with a secreted polypeptide-expressing cell. Such cells may be cultured in any suitable tissue culture medium; however, it is preferable to culture cells in Earle's modified Eagle's medium supplemented with 10°lo fetal bovine serum (inactivated at about 56°C), and supplemented with about 10 g/1 of nonessential amino acids, about 1,000 U/ml of penicillin, and about 100 p.g/ml of streptomycin.
The splenocytes of such mice are extracted and fused with a suitable myeloma cell line. Any suitable myeloma cell line may be employed in accordance with the present invention; however, it is preferable to employ the parent myeloma cell line (SP20), available from the ATCC. After fusion, the resulting hybridoma cells are selectively maintained in HAT medium, and then cloned by limiting dilution as WO 98/56804 PCTlUS98/12125 i34 described by Wands et al. (Gastroenterology 80:225-232 (1981).) The hybridoma cells obtained through such a selection are then assayed to identify clones which secrete antibodies capable of binding the poiypeptide.
Alternatively, additional antibodies capable of binding to the polypeptide can be produced in a two-step procedure using anti-idiotypic antibodies. Such a method makes use of the fact that antibodies are themselves antigens, and therefore, it is possible to obtain an antibody which binds to a second antibody. In accordance with this method, protein specific antibodies are used to immunize an animal, preferably a mouse. The splenocytes of such an animal are then used to produce hybridoma cells, and the hybridoma cells are screened to identify clones which produce an antibody whose ability to bind to the protein-specific antibody can be blocked by the polypeptide.
Such antibodies comprise anti-idiotypic antibodies to the protein-specific antibody and can be used to immunize an animal to induce formation of further protein-specific antibodies.
It will be appreciated that Fab and F(ab')2 and other fragments of the antibodies of the present invention may be used according to the methods disclosed herein. Such fragments are typically produced by proteolytic cleavage, using enzymes such as papain (to produce Fab fragments) or pepsin (to produce F{ab')2 fragments).
Alternatively, secreted protein-binding fragments can be produced through the application of recombinant DNA technology or through synthetic chemistry.
For in vivo use of antibodies in humans, it may be preferable to use "humanized" chimerie monoclonal antibodies. Such antibodies can be produced using genetic constructs derived from hybridoma cells producing the monoclonal antibodies described above. Methods for producing chimeric antibodies are known in the art.
(See, for review, Morrison, Science 229:1202 (1985); Oi et al., BioTechniques 4:214 ( 1986); Cabilly et al., U.S. Patent No. 4,816,567; Taniguchi et al., EP
171496;
Morrison et al., EP 173494; Neuberger et al., WO 8601533; Robinson et al., WO
8702671; Boulianne et al., Nature 312:643 ( 1984}; Neuberger et al., Nature 314:268 (1985).) Example 11: Production Of Secreted Protein For High-Throughput Screening Assays The following protocol produces a supernatant containing a polypeptide to be tested. This supernatant can then be used in the Screening Assays described in Examples 13-20.
First, dilute Poly-D-Lysine (644 587 Boehringer-Mannheim) stock solution (lmg/ml in PBS) 1:20 in PBS (w/o calcium or magnesium 17-516F Biowhittaker) for a working solution of SOug/ml. Add 200 ul of this solution to each well (24 well plates) and incubate at RT for 20 minutes. Be sure to distribute the solution over each well (note: a 12-channel pipetter may be used with tips on every other channel).
Aspirate off the Poly-D-Lysine solution and rinse with lml PBS {Phosphate Buffered Saline).
The PBS should remain in the well until just prior to plating the cells and plates may be poly-lysine coated in advance for up to two weeks.
Plate 293T cells (do not carry cells past P+20) at 2 x 105 cells/well in .Sml DMEM(Dulbecco's Modified Eagle Medium)(with 4.5 G/L glucose and L-glutamine (12-604F Biowhittaker))/10% heat inactivated FBS(14-503F Biowhittaker)/lx Penstrep( 17-602E Biowhittaker). Let the cells grow overnight.
The next day, mix together in a sterile solution basin: 300 ul Lipofectamine ( 18324-012 GibcoBRL) and Sml Optimem I (31985070 GibcoBRL)/96-well plate.
With a small volume mufti-channel pipetter, aliquot approximately tug of an expression vector containing a polynucleotide insert, produced by the methods described in Examples 8 or 9, into an appropriately labeled 96-well round bottom plate.
With a mufti-channel pipetter, add SOuI of the Lipofectamine/Optimem I mixture to each well.
Pipette up and down gently to mix. Incubate at RT 15-45 minutes. After about minutes, use a mufti-channel pipetter to add 150u1 Optimem I to each well. As a control, one plate of vector DNA lacking an insert should be transfected with each set of transfections.
Preferably, the transfection should be performed by tag-teaming the following tasks. By tag-teaming, hands on time is cut in half, and the cells do not spend too much time on PBS. First, person A aspirates off the media from four 24-well plates of cells, and then person B rinses each well with .5-Iml PBS. Person A then aspirates off PBS rinse, and person B, using a12-channel pipetter with tips on every other channel, adds the 200u1 of DNA/Lipofectamine/Optimem I complex to the odd wells first, then to the even wells, to each row on the 24-well plates. Incubate at 37°C for 6 hours.
While cells are incubating, prepare appropriate media, either 1 %BSA in DMEM
with 1 x penstrep, or CHO-5 media ( 116.b mg/L of CaCl2 (anhyd); 0.00130 mg/L
CuS04-SHZO; 0.050 mg/L of Fe(NO;)~ 9H,0; 0.417 mg/L of FeSOa 7Hz0; 311.80 mg/L of Kcl; 28.64 mg/L of MgClz; 48.84 mg/L of MgS04; 6995.50 mg/L of NaCI;
2400.0 mg/L of NaHC03; 62.50 mg/L of NaH~POa-H20; 71.02 mg/L of Na,HP04;
.4320 mg/L of ZnS04 7H~0; .002 mg/L of Arachidonic Acid ; 1.022 mg/L of Cholesterol; .070 mg/L of DL-alpha-Tocopherol-Acetate; 0.0520 mg/L of Linoleic Acid; 0.010 mg/L of Linolenic Acid; 0.010 mg/L of Myristic Acid; 0.010 mg/L of Oleic Acid; 0.010 mg/L of Palmitric Acid; 0.010 mg/L of Palmitic Acid; 100 mg/L of 13b Pluronic F-68; 0.010 mg/L of Stearic Acid; 2.20 mg/L of Tween 80; 4551 mg/L of D-Glucose; 130.85 mg/ml of L- Alanine; 147.50 mg/ml of L-Arginine-HCL; 7.50 mg/mI
of L-Asparagine-H,O; 6.65 mg/ml of L-Aspartic Acid; 29.56 mg/ml of L-Cystine-2HCL-H~O; 31.29 mg/ml of L-Cystine-2HCL; 7.35 mg/ml of L-Glutamic Acid; 365.0 mg/ml of L-Glutamine; 18.75 mg/ml of Glycine; 52.48 mg/ml of L-Histidine-HCL-H20; 106.97 mg/ml of L-Isoleucine; 111.45 mg/ml of L-Leucine; 163.75 mg/ml of L-Lysine HCL; 32.34 mg/ml of L-Methionine; 68.48 mglml of L-Phenylalainine; 40.0 mg/ml of L-Proline; 26.25 mg/ml of L-Serine; 101.05 mg/ml of L-Threonine;
19.22 mg/ml of L-Tryptophan; 91.79 mg/ml of L-Tryrosine-2Na-2H~0; 99.65 mg/ml of L-Valine; 0.0035 mg/L of Biotin; 3.24 mg/L of D-Ca Pantothenate; 11.78 mg/L of Choline Chloride; 4.65 mglL of Folic Acid; 15.60 mg/L of i-Inositol; 3.02 mg/L
of Niacinamide; 3.00 mg/L of Pyridoxal HCL; 0.031 mg/L of Pyridoxine HCL; 0.319 mglL of Riboflavin; 3.17 mg/L of Thiamine HCL; 0.365 mg/L of Thymidine; and 0.680 mg/L of Vitamin B,~; 25 mM of HEPES Buffer; 2.39 mg/L of Na Hypoxanthine;
0.105 mg/L of Lipoic Acid; 0.081 mglL of Sodium Putrescine-2HCL; 55.0 mg/L of Sodium Pyruvate; 0.0067 mglL of Sodium Selenite; 20uM of Ethanolamine; 0.122 mg/L of Ferric Citrate; 41.70 mg/L of Methyl-B-Cyclodextrin complexed with Linoleic Acid; 33.33 mg/L of Methyl-B-Cyclodextrin complexed with Oleic Acid; and 10 mg/L
of Methyl-B-Cyclodextrin complexed with Retinal) with 2mm glutamine and lx penstrep. (BSA (81-068-3 Bayer) 100gm dissolved in IL DMEM for a 10% BSA stock solution). Filter the media and collect 50 ul for endotoxin assay in l5ml polystyrene conical.
The transfection reaction is terminated, preferably by tag-teaming, at the end of the incubation period. Person A aspirates off the transfection media, while person B
adds l.5ml appropriate media to each well. Incubate at 37°C for 45 or 72 hours depending on the media used: 1 %BSA for 45 hours or CHO-5 for 72 hours.
On day four, using a 300u1 multichannel pipetter, aliquot 600u1 in one 1 ml deep well plate and the remaining supernatant into a 2m1 deep well. The supernatants from each well can then be used in the assays described in Examples 13-20.
It is specifically understood that when activity is obtained in any of the assays described below using a supernatant, the activity originates from either the polypeptide directly (e.g., as a secreted protein) or by the polypeptide inducing expression of other proteins, which are then secreted into the supernatant. Thus, the invention further provides a method of identifying the protein in the supernatant characterized by an activity in a particular assay.

Example 12: Construction of GAS Reporter Construct One signal transduction pathway involved in the differentiation and proliferation of cells is called the Jaks-STATs pathway. Activated proteins in the Jaks-STATs pathway bind to gamma activation site "GAS" elements or interferon-sensitive responsive element ("ISRE"), located in the promoter of many genes. The binding of a protein to these elements alter the expression of the associated gene.
GAS and ISRE elements are recognized by a class of transcription factors called Signal Transducers and Activators of Transcription, or "STATs." There are six members of the STATs family. Statl and Stat3 are present in many cell types, as is Stat2 (as response to IFN-alpha is widespread). Stat4 is more restricted and is not in many cell types though it has been found in T helper class I, cells after treatment with IL-12. StatS was originally called mammary growth factor, but has been found at higher concentrations in other cells including myeloid cells. It can be activated in tissue culture cells by many cytokines.
The STATs are activated to translocate from the cytoplasm to the nucleus upon tyrosine phosphorylation by a set of kinases known as the Janus Kinase ("Jaks") family. Jaks represent a distinct family of soluble tyrosine kinases and include Tyk2, Jakl, Jak2, and Jak3. These kinases display significant sequence similarity and are generally catalytically inactive in resting cells.
The Jaks are activated by a wide range of receptors summarized in the Table below. (Adapted from review by Schidler and Darnell, Ann. Rev. Biochem. 64:621-(1995).) A cytokine receptor family, capable of activating Jaks, is divided into two groups: (a) Class I includes receptors for IL-2, IL-3, IL-4, IL-6> 1L-7, IL-9, IL-11, IL-12, IL-15, Epo, PRL, GH, G-CSF, GM-CSF, LIF, CNTF, and thrombopoietin; and (b) Class 2 includes IFN-a, IFN-g, and IL-10. The Class 1 receptors share a conserved cysteine motif (a set of four conserved cysteines and one tryptophan) and a WSXWS motif (a membrane proxial region encoding Trp-Ser-Xxx-Trp-Ser (SEQ ID
N0:2)).
Thus, on binding of a ligand to a receptor, Jaks are activated, which in turn activate STATs, which then translocate and bind to GAS elements. This entire process is encompassed in the Jaks-STATs signal transduction pathway.
Therefore, activation of the Jaks-STATs pathway, reflected by the binding of the GAS or the ISRE element, can be used to indicate proteins involved in the proliferation and differentiation of cells. For example, growth factors and cytokines are known to activate the Jaks-STATs pathway. (See Table below.) Thus, by using GAS
elements linked to reporter molecules, activators of the Jaks-STATs pathway can be identified.

JAKs STATS GASfelements) or ISRE

Ligand t~k2Jak1 Jak2 Jak3 IFN family IFN-aB + + - - 1,2,3 ISRE

IFN-g + + - 1 GAS (IRF 1 >Lys6>IFP) Il-10 + ? ? - 1,3 gp 130 familX

IL-6 (Pleiotrohic)+ + + ? 1,3 GAS (IRFI>Lys6>IFP) Il-11(Pleiotrohic)? + ? ? 1,3 OnM(Pleiotrohic)? + + ? 1, 3 LIF(Pleiotrohic)? + + ? 1, 3 CNTF(Pleiotrohic)-/+ + + ? 1,3 G-CSF(Pleiotrohic)~ + ~ ~ 1,3 IL-12(Pleiotrohic)+ - + + 1,3 g-C familX

IL-2 (lymphocytes)- + - + 1,3,5 GAS

IL-4 (lymph/myeloid)- + - + 6 GAS {IRFI = IFP Ly6)(IgH) IL-7 (lymphocytes)- + - + 5 GAS

IL-9 (lymphocytes)- + - + 5 GAS

IL-13 (lymphocyte)- + ? ? 6 GAS

IL-15 ? + ? + 5 GAS

gp140 familX

IL-3 (myeloid) - - + - 5 GAS {IRF1>IFPLy6) IL-5 (myeloid) - - + - 5 GAS

GM-CSF (myeloid)- - + - 5 GAS

Growth hormone farnilv GH ? - + - 5 PRL ? +/- + - 1,3,5 EPO ? - + - 5 GAS(B-CAS>IRF1=IFPLy6) Receptor Tyrosine Kinases EGF ? + + - 1, 3 GAS (IRF 1 ) PDGF ? + + - 1,3 CSF-1 ? + + - I,3 GAS (not IRFI) To construct a synthetic GAS containing promoter element, which is used in the Biological Assays described in Examples 13-14, a PCR based strategy is employed to generate a GAS-SV40 promoter sequence. The 5' primer contains four tandem copies of the GAS binding site found in the IRF1 promoter and previously demonstrated to bind STATs upon induction with a range of cytokines (Rothman et al., Immunity 1:457-468 ( 1994).), although other GAS or ISRE elements can be used instead.
The 5' primer also contains l8bp of sequence complementary to the SV40 early promoter sequence and is flanked with an XhoI site. The sequence of the 5' primer is:
5':GCGCCTCGAGATTTCCCCGAAATCTAGATTTCCCCGAAATGATTTCCCCG
AAATGATTTCCCCGAAATATCTGCCATCTCAATTAG:3' (SEQ ID N0:3}
The downstream primer is complementary to the SV40 promoter and is flanked with a Hind III site: 5':GCGGCAAGCTTTTTGCAAAGCCTAGGC:3' (SEQ ID
N0:4) PCR amplification is performed using the SV40 promoter template present in the B-gal:promoter plasmid obtained from Clontech. The resulting PCR fragment is digested with XhoI/Hind III and subcloned into BLSK2-. (Stratagene.}
Sequencing with forward and reverse primers confirms that the insert contains the following sequence:
5' : CTCGAGATTTCCCCGAAATCTAGATTTCCCCGAAATGATTTCCCCGAAATG
ATTTCCCCGAAATATCTGCCATCTCAATTAGTCAGCAACCATAGTCCCGCCC
CTAACTCCGCCCATCCCGCCCCTAACTCCGCCCAGTTCCGCCCATTCTCCGC
CCCATGGCTGACTAATTTTTTTTATTTATGCAGAGGCCGAGGCCGCCTCGGC
CTCTGAGCTATTCCAGAAGTAGTGAGGAGGCTTTTTTGGAGGCCTAGGCTTT
TGCAAAAAGCTT:3' (SEQ ID NO:S) With this GAS promoter element linked to the SV40 promoter, a GAS:SEAP2 reporter construct is next engineered. Here, the reporter molecule is a secreted alkaline phosphatase, or "SEAP." Clearly, however, any reporter molecule can be instead of SEAP, in this or in any of the other Examples. Well known reporter molecules that can be used instead of SEAP include chloramphenicol acetyltransferase (CAT), luciferase, alkaline phosphatase, B-galactosidase, green fluorescent protein (GFP), or any protein detectable by an antibody.
The above sequence confirmed synthetic GAS-SV40 promoter element is subcloned into the pSEAP-Promoter vector obtained from Clontech using HindIII
and XhoI, effectively replacing the SV40 promoter with the amplified GAS:SV40 promoter element, to create the GAS-SEAP vector. However, this vector does not contain a neomycin resistance gene, and therefore, is not preferred for mammalian expression systems.

WO 98!56804 PCT/US98I12125 Thus, in order to generate mammalian stable cell lines expressing the GAS-SEAP reporter, the GAS-SEAP cassette is removed from the GAS-SEAP vector using SaII and NotI, and inserted into a backbone vector containing the neomycin resistance gene, such as pGFP-I (Clontech), using these restriction sites in the multiple cloning site, to create the GAS-SEAP/Neo vector. Once this vector is transfected into mammalian cells, this vector can then be used as a reporter molecule for GAS
binding as described in Examples 13-14.
Other constructs can be made using the above description and replacing GAS
with a different promoter sequence. For example, construction of reporter molecules containing NFK-B and EGR promoter sequences are described in Examples I S and 16.
However, many other promoters can be substituted using the protocols described in these Examples. For instance, SRE, IL-2, NFAT, or Osteocalcin promoters can be substituted, alone or in combination (e.g., GAS/NF-KB/EGR, GAS/NF-KB, Il-2INFAT, or NF-KB/GAS). Similarly, other cell lines can be used to test reporter construct activity, such as HELA (epithelial), HUVEC (endothelial), Reh (B-cell), Saos-2 (osteoblast), HUVAC (aortic), or Cardiomyocyte.
Example 13: High-Throughput Screening Assay for T-cell Activity The following protocol is used to assess T-cell activity by identifying factors, such as growth factors and cytokines, that may proliferate or differentiate T-cells. T-cell activity is assessed using the GAS/SEAP/Neo construct produced in Example 12.
Thus, factors that increase SEAP activity indicate the ability to activate the Jaks-STATS
signal transduction pathway. The T-cell used in this assay is Jurkat T-cells (ATCC
Accession No. TIB-152), although Molt-3 cells {ATCC Accession No. CRL-1552) and Molt-4 cells (ATCC Accession No. CRL-1582) cells can also be used.
Jurkat T-cells are lymphoblastic CD4+ Th 1 helper cells. In order to generate stable cell lines, approximately 2 million Jurkat cells are transfected with the GAS-SEAP/neo vector using DMRIE-C (Life Technologies)(transfection procedure described below). The transfected cells are seeded to a density of approximately 20,000 cells per well and transfectants resistant to 1 mg/ml genticin selected. Resistant colonies are expanded and then tested for their response to increasing concentrations of interferon gamma. The dose response of a selected clone is demonstrated.
Specifically, the following protocol will yield sufficient cells for 75 wells containing 200 ul of cells. Thus, it is either scaled up, or performed in multiple to generate sufficient cells for multiple 96 well plates. Jurkat cells are maintained in RPMI
+ 10% serum with 1 %Pen-Strep. Combine 2.5 mls of OPTI-MEM (Life Technologies) with 10 ug of plasmid DNA in a T25 flask. Add 2.5 ml OPTI-MEM containing 50 ul of DMRIE-C and incubate at room temperature for 15-45 minx.
During the incubation period, count cell concentration, spin down the required number of cells ( 10' per transfection), and resuspend in OPTI-MEM to a final concentration of 10' cells/ml. Then add 1 ml of 1 x 10' cells in OPT/-MEM to T25 flask and incubate at 37°C for 6 hrs. After the incubation, add 10 ml of RPMI
+ 15% serum.
The Jurkat:GAS-SEAP stable reporter lines are maintained in RPM/ + 10%
serum, 1 mg/ml Genticin, and 1 % Pen-Strep. These cells are treated with supernatants containing a polypeptide as produced by the protocol described in Example 11.
On the day of treatment with the supernatant, the cells should be washed and resuspended in fresh RPMI + 10% serum to a density of 500,000 cells per ml.
The exact number of cells required will depend on the number of supernatants being screened. For one 96 well plate, approximately 10 million cells (for 10 plates, 100 million cells) are required.
Transfer the cells to a triangular reservoir boat, in order to dispense the cells into a 96 well dish, using a 12 channel pipette. Using a 12 channel pipette, transfer 200 ul of cells into each well (therefore adding 100, 000 cells per well).
After all the plates have been seeded, 50 ul of the supernatants are transferred directly from the 96 well plate containing the supernatants into each well using a 12 channel pipette. In addition, a dose of exogenous interferon gamma {0.1, 1.0, 10 ng) is added to wells H9, H 10, and H 11 to serve as additional positive controls for the assay.
The 96 well dishes containing Jurkat cells treated with supernatants are placed in an incubator for 48 hrs (note: this time is variable between 48-72 hrs). 35 ul samples from each well are then transferred to an opaque 96 well plate using a 12 channel pipette. The opaque plates should be covered (using sellophene covers) and stored at -20oC until SEAP assays are performed according to Example 17. The plates containing the remaining treated cells are placed at 4oC and serve as a source of material for repeating the assay on a specific well if desired.
As a positive control, 100 Unit/ml interferon gamma can be used which is known to activate 3urkat T cells. Over 30 fold induction is typically observed in the positive control wells.

WO 98/5b804 PCT/US98/12125 Example 14: High-Throughput Screening Assay Identifying Myeloid Activity The following protocol is used to assess myeloid activity by identifying factors, such as growth factors and cytokines, that may proliferate or differentiate myeloid cells.
Myeloid cell activity is assessed using the GAS/SEAP/Neo construct produced in Example 12. Thus, factors that increase SEAP activity indicate the ability to activate the Jaks-STATS signal transduction pathway. The myeloid cell used in this assay is U937, a pre-monocyte cell line, although TF-l, HL60, or KGI can be used.
To transiently transfect U937 cells with the GAS/SEAP/Neo construct produced in Example 12, a DEAE-Dextran method (Kharbanda et. al., I994, Cell Growth &
Differentiation, 5:259-265) is used. First, harvest 2xI0e7 U937 cells and wash with PBS. The U937 cells are usually grown in RPMI 1640 medium containing 10% heat-inactivated fetal bovine serum (FBS) supplemented with 100 units/ml penicillin and 100 mg/ml streptomycin.
Next, suspend the cells in 1 ml of 20 mM Tris-HCl (pH 7.4) buffer containing 0.5 mg/ml DEAE-Dextran, 8 ug GAS-SEAP2 plasmid DNA, 140 mM NaCI, 5 mM
KCI, 375 uM Na2HP04.7H20, 1 mM MgCl2, and 675 uM CaCl2. Incubate at 37oC
for 45 min.
Wash the cells with RPMI 1640 medium containing 10% FBS and then resuspend in 10 ml complete medium and incubate at 37oC for 36 hr The GAS-SEAP/LT937 stable cells are obtained by growing the cells in 400 ug/mI 6418. The 6418-free medium is used for routine growth but every one to two months, the cells should be re-grown in 400 ug/ml 6418 for couple of passages.
These cells are tested by harvesting 1x10 cells (this is enough for ten 96-well plates assay) and wash with PBS. Suspend the cells in 200 ml above described growth medium, with a final density of Sx 105 cells/ml. Plate 20(? ul cells per well in the 96-well plate (or 1 x 105 cells/well).
Add 50 ul of the supernatant prepared by the protocol described in Example 11.
Incubate at 37oC for 48 to 72 hr. As a positive control, 100 Unit/ml interferon gamma can be used which is known to activate U937 cells. Over 30 fold induction is typically observed in the positive control wells. SEAP assay the supernatant according to the protocol described in Example 17.

Example 15: High-Throughput Screening Assay Identif~n$ Neuronal Activity.
When cells undergo differentiation and proliferation, a group of genes are activated through many different signal transduction pathways. One of these genes, EGR 1 (early growth response gene 1 ), is induced in various tissues and cell types upon activation. The promoter of EGR1 is responsible for such induction. Using the promoter linked to reporter molecules, activation of cells can be assessed.
Particularly, the following protocol is used to assess neuronal activity in PC

cell lines. PC 12 cells (rat phenochromocytoma cells) are known to proliferate and/or differentiate by activation with a number of mitogens, such as TPA
(tetradecanoyl phorbol acetate), NGF {nerve growth factor), and EGF (epidermal growth factor). The EGR 1 gene expression is activated during this treatment. Thus, by stably transfecting PC 12 cells with a construct containing an EGR promoter linked to SEAP
reporter, activation of PC 12 cells can be assessed.
The EGR/SEAP reporter construct can be assembled by the following protocol.
The EGR-1 promoter sequence (-633 to +1)(Sakamoto K et al., Oncogene 6:867-871 ( 1991 )) can be PCR amplified from human genomic DNA using the following primers:
5' GCGCTCGAGGGATGACAGCGATAGAACCCCGG -3' (SEQ ID N0:6) 5' GCGAAGCTTCGCGACTCCCCGGATCCGCCTC-3' (SEQ ID N0:7) Using the GAS:SEAP/Neo vector produced in Example 12, EGR1 amplified product can then be inserted into this vector. Linearize the GAS:SEAP/Neo vector using restriction enzymes XhoI/HindIII, removing the GAS/SV40 stuffer.
Restrict the EGR 1 amplified product with these same enzymes. Ligate the vector and the EGR

promoter.
To prepare 96 well-plates for cell culture, two mls of a coating solution ( 1:30 dilution of collagen type I (Upstate Biotech Inc. Cat#08-115) in 30% ethanol (filter sterilized)) is added per one 10 cm plate or 50 ml per well of the 96-well plate, and allowed to air dry for 2 hr.
PC12 cells are routinely grown in RPMI-1640 medium (Bio Whittaker) containing 10% horse serum (JRH BIOSCIENCES, Cat. # 12449-78P), 5% heat-inactivated fetal bovine serum (FBS) supplemented with 100 units/ml penicillin and 100 ug/ml streptomycin on a precoated 10 cm tissue culture dish. One to four split is done every three to four days. Cells are removed from the plates by scraping and resuspended with pipetting up and down for more than 15 times.
Transfect the EGR/SEAP/Neo construct into PC12 using the Lipofectamine protocol described in Example 11. EGR-SEAP/PC12 stable cells are obtained by growing the cells in 300 uglml 6418. The 6418-free medium is used for routine growth but every one to two months, the cells should be re-grown in 300 uglml for couple of passages.
To assay for neuronal activity, a 10 cm plate with cells around 70 to 80%
confluent is screened by removing the old medium. Wash the cells once with PBS
(Phosphate buffered saline). Then starve the cells in low serum medium (RPMI-containing 1% horse serum and 0.5% FBS with antibiotics) overnight.
The next morning, remove the medium and wash the cells with PBS. Scrape off the cells from the plate, suspend the cells well in 2 ml low serum medium.
Count the cell number and add more low serum medium to reach final cell density as Sx105 cells/ml.
Add 200 ul of the cell suspension to each well of 96-well plate (equivalent to 1 x 105 cells/well). Add 50 ul supernatant produced by Example 11, 37oC for 48 to 72 hr. As a positive control, a growth factor known to activate PC 12 cells through EGR
can be used, such as 50 ng/ul of Neuronal Growth Factor (NGF). Over fifty-fold induction of SEAP is typically seen in the positive control wells. SEAP assay the supernatant according to Example 17.
Example 16: High-Throyghput Screening Assay for T-cell Activity NF-tcB (Nuclear Factor xB) is a transcription factor activated by a wide variety of agents including the inflammatory cytokines IL-1 and TNF, CD30 and CD40, lymphotoxin-alpha and lymphotoxin-beta, by exposure to LPS or thrombin, and by expression of certain viral gene products. As a transcription factor, NF-xB
regulates the expression of genes involved in immune cell activation, control of apoptosis (NF-oB appears to shield cells from apoptosis), B and T-cell development, anti-viral and antimicrobial responses, and multiple stress responses.
In non-stimulated conditions, NF- tcB is retained in the cytoplasm with I-oB
(Inhibitor xB). However, upon stimulation, I- tcB is phosphorylated and degraded, causing NF- tcB to shuttle to the nucleus, thereby activating transcription of target genes. Target genes activated by NF- oB include IL-2, IL-6, GM-CSF, ICAM-1 and class 1 MHC.
Due to its central role and ability to respond to a range of stimuli, reporter constructs utilizing the NF-oB promoter element are used to screen the supernatants produced in Example 11. Activators or inhibitors of NF-kB would be useful in treating diseases. For example, inhibitors of NF-1cB could be used to treat those diseases related to the acute or chronic activation of NF-kB, such as rheumatoid arthritis.
To construct a vector containing the NF-xB promoter element, a PCR based strategy is employed. The upstream primer contains four tandem copies of the NF-1cB
binding site (GGGGACTTTCCC) (SEQ ID N0:8), 18 by of sequence complementary to the 5' end of the SV40 early promoter sequence, and is flanked with an XhoI
site:
S':GCGGCCTCGAGGGGACTTTCCCGGGGACTTTCCGGGGACTTTCCGGGAC
TTTCCATCCTGCCATCTCAATTAG:3' (SEQ ID N0:9) The downstream primer is complementary to the 3' end of the SV40 promoter and is flanked with a Hind III site:
5':GCGGCAAGCTTTTTGCAAAGCCTAGGC:3' (SEQ ID N0:4) PCR amplification is performed using the SV40 promoter template present in the pB-gal:promoter plasmid obtained from Clontech. The resulting PCR fragment is digested with XhoI and Hind III and subcloned into BLS K2-. (Stratagene) Sequencing with the T7 and T3 primers confirms the insert contains the following sequence:
5':CTCGAGGGGACTTTCCCGGGGACTTTCCGGGGACTTTCCGGGACTTTCC
ATCTGCCATCTCAATTAGTCAGCAACCATAGTCCCGCCCCTAACTCCGCCCA
TCCCGCCCCTAACTCCGCCCAGTTCCGCCCATTCTCCGCCCCATGGCTGACT
AATI'ITI'TTTATTTATGCAGAGGCCGAGGCCGCCTCGGCCTCTGAGCTATTC
CAGAAGTAGTGAGGAGGCTI")'TT'TGGAGGCCTAGGCTTTTGCAAAAAGCTT:
3' (SEQ ID NO:10) Next, replace the SV40 minimal promoter element present in the pSEAP2-promoter plasmid (Clontech) with this NF-tcB/SV40 fragment using Xhol and HindIII.
However, this vector does not contain a neomycin resistance gene, and therefore, is not preferred for mammalian expression systems.
In order to generate stable mammalian cell lines, the NF-xB/SV40lSEAP
cassette is removed from the above NF-oB/SEAP vector using restriction enzymes SaII
and NotI, and inserted into a vector containing neomycin resistance.
Particularly, the ' NF-xB/SV40/SEAP cassette was inserted into pGFP-1 (Clontech), replacing the GFP
gene, after restricting pGFP-I with SaII and NotI.

Once NF-ICB/SV40/SEAPINeo vector is created, stable Jurkat T-cells are created and maintained according to the protocol described in Example 13.
Similarly, the method for assaying supernatants with these stable Jurkat T-cells is also described in Example 13. As a positive control, exogenous TNF alpha (0.1,1, 10 ng) is added to wells H9, H10, and H11, with a 5-10 fold activation typically observed.
Example 17: Assay for SEAP Activity As a reporter molecule for the assays described in Examples 13-16, SEAP
activity is assayed using the Tropix Phospho-light Kit (Cat. BP-400) according to the following general procedure. The Tropix Phospho-light Kit supplies the Dilution, Assay, and Reaction Buffers used below.
Prime a dispenser with the 2.Sx Dilution Buffer and dispense 15 ~tl of 2.Sx dilution buffer into Optiplates containing 35 ~tl of a supernatant. Seal the plates with a plastic sealer and incubate at 65°C for 30 min. Separate the Optiplates to avoid uneven heating.
Cool the samples to room temperature for 15 minutes. Empty the dispenser and prime with the Assay Buffer. Add 50 p,l Assay Buffer and incubate at room temperature 5 min. Empty the dispenser and prime with the Reaction Buffer (see the table below). Add 50 ~1 Reaction Buffer and incubate at room temperature for minutes. Since the intensity of the chemiluminescent signal is time dependent, and it takes about 10 minutes to read 5 plates on luminometer, one should treat 5 plates at each time and start the second set 10 minutes later.
Read the relative light unit in the luminometer. Set HI2 as blank, and print the results. An increase in chemiluminescence indicates reporter activity.
Reaction Buffer Formulation:
# of platesRxn buffer diluent CSPD (ml) (ml) I 1 65 3.25 12 70 3.5 13 75 3.75 15 85 4.25 16 90 4.5 17 95 4.75 19 105 5.25 20 110 5.5 21 I 15 5.75 23 125 6.25 24 130 b.5 ' 25 135 6.75 27 145 7.25 28 150 7.5 29 155 7,75 3 I 165 8.25 32 170 8.5 33 175 8.75 35 185 9.25 36 I90 9.5 37 I95 9.75 39 205 10.25 40 2 I 0 I 0.5 41 215 10.75 43 225 11.25 44 230 1 1.5 45 235 I 1,75 47 245 12.25 48 250 12.5 49 255 12,75 Example 1$: High-Throughput Screening Assay Identi~in~ Changes in Small Molecule Concentration and Membrane Permeability Binding of a ligand to a receptor is known to alter intracellular levels of small molecules, such as calcium, potassium, sodium, and pH, as well as alter membrane potential. These alterations can be measured in an assay to identify supernatants which bind to receptors of a particular cell. Although the following protocol describes an assay for calcium, this protocol can easily be modified to detect changes in potassium, sodium, pH, membrane potential, or any other small molecule which is detectable by a fluorescent probe.
The following assay uses Fluorometric Imaging Plate Reader ("FLIPR") to measure changes in fluorescent molecules (Molecular Probes) that bind small molecules. Clearly, any fluorescent molecule detecting a small molecule can be used - instead of the calcium fluorescent molecule, fluo-3, used here.
For adherent cells, seed the cells at 10,000 -20,000 cells/well in a Co-star black 96-well plate with clear bottom. The plate is incubated in a CO~ incubator for 20 hours.
The adherent cells are washed two times in Biotek washer with 200 ul of HBSS
- (Hank's Balanced Salt Solution) leaving 100 ul of buffer after the final wash.

A stock solution of 1 mg/ml fluo-3 is made in 10% pluronic acid DMSO. To load the cells with fluo-3, 50 ul of 12 ug/ml fluo-3 is added to each well.
The plate is incubated at 37°C in a CO, incubator for 60 min. The plate is washed four times in the Biotek washer with HBSS leaving 100 ul of buffer.
S For non-adherent cells, the cells are spun down from culture media. Cells are re-suspended to 2-5x106 cells/ml with HBSS in a 50-ml conical tube. 4 ul of 1 mg/ml fluo-3 solution in 10% pluronic acid DMSO is added to each ml of cell suspension.
The tube is then placed in a 37°C water bath for 30-60 min. The cells are washed twice with HBSS, resuspended to 1x106 cells/ml, and dispensed into a microplate, 100 ul/well. The plate is centrifuged at 1000 rpm for 5 min. The plate is then washed once in Denley CellWash with 200 ul, followed by an aspiration step to 100 ul final volume.
For a non-cell based assay, each well contains a fluorescent molecule, such as fluo-3. The supernatant is added to the well, and a change in fluorescence is detected.
To measure the fluorescence of intracellular calcium, the FLIPR is set for the following parameters: (1) System gain is 300-800 mW; (2) Exposure time is 0.4 second; (3) Camera F/stop is F/2; (4) Excitation is 488 nm; (5) Emission is 530 nm; and (6) Sample addition is 50 ul. Increased emission at 530 nm indicates an extracellular signaling event which has resulted in an increase in the intracellular Ca'~'-~
concentration.
Exam~le19: High-Throughout Screening Assay Identifvin~ Tyrosine Kinase Activity The Protein Tyrosine Kinases (PTK) represent a diverse group of transmembrane and cytoplasmic kinases. Within the Receptor Protein Tyrosine Kinase RPTK) group are receptors for a range of mitogenic and metabolic growth factors including the PDGF, FGF, EGF, NGF, HGF and Insulin receptor subfamilies. In addition there are a large family of RPTKs for which the corresponding ligand is unknown. Ligands for RPTKs include mainly secreted small proteins, but also membrane-bound and extracellular matrix proteins.
Activation of RPTK by iigands involves ligand-mediated receptor dimerization, resulting in transphosphorylation of the receptor subunits and activation of the cytoplasmic tyrosine kinases. The cytoplasmic tyrosine kinases include receptor associated tyrosine kinases of the src-family (e.g., src, yes, lck, lyn, fyn) and non-receptor linked and cytosolic protein tyrosine kinases, such as the Jak family, members of which mediate signal transduction triggered by the cytokine superfamily of receptors (e.g., the Interleukins, Interferons, GM-CSF, and Leptin).

Because of the wide range of known factors capable of stimulating tyrosine kinase activity, the identification of novel human secreted proteins capable of activating tyrosine kinase signal transduction pathways are of interest. Therefore, the following protocol is designed to identify those novel human secreted proteins capable of activating the tyrosine kinase signal transduction pathways.
Seed target cells (e.g., primary keratinocytes) at a density of approximately 25,000 cells per well in a 96 well Loprodyne Silent Screen Plates purchased from Nalge Nunc (Naperville, IL). The plates are sterilized with two 30 minute rinses with 100% ethanol, rinsed with water and dried overnight. Some plates are coated for 2 hr with 100 ml of cell culture grade type I collagen (50 mglml), gelatin (2%) or polylysine (50 mg/ml), all of which can be purchased from Sigma Chemicals (St. Louis, MO) or 10% Matrigel purchased from Becton Dickinson (Bedford,MA), or calf serum, rinsed with PBS and stored at 4oC. Cell growth on these plates is assayed by seeding 5,000 cells/well in growth medium and indirect quantitation of cell number through use of alamarBlue as described by the manufacturer Alamar Biosciences, Inc.
(Sacramento, CA) after 48 hr. Falcon plate covers #3071 from Becton Dickinson (Bedford,MA) are used to cover the Loprodyne Silent Screen Plates. Falcon Microtest III cell culture plates can also be used in some proliferation experiments.
To prepare extracts, A431 cells are seeded onto the nylon membranes of Loprodyne plates (20,000/200m1/well) and cultured overnight in complete medium.
Cells are quiesced by incubation in serum-free basal medium for 24 hr. After 5-minutes treatment with EGF (60ng/ml) or 50 ul of the supernatant produced in Example 11, the medium was removed and 100 ml of extraction buffer ((20 mM HEPES pH

7.5, 0.15 M NaCI, 1 % Triton X-100, 0.1 % SDS, 2 mM Na3V04, 2 mM Na4P2O7 and a cocktail of protease inhibitors (# 1836170) obtained from Boeheringer Mannheim (Indianapolis, IN) is added to each well and the plate is shaken on a rotating shaker for 5 minutes at 4oC. The plate is then placed in a vacuum transfer manifold and the extract filtered through the 0.45 mm membrane bottoms of each well using house vacuum.
Extracts are collected in a 96-well catch/assay plate in the bottom of the vacuum manifold and immediately placed on ice. To obtain extracts clarified by centrifugation, the content of each well, after detergent solubilization for 5 minutes, is removed and _ centrifuged for 15 minutes at 4oC at 16,000 x g.
Test the filtered extracts for levels of tyrosine kinase activity. Although many . methods of detecting tyrosine kinase activity are known, one method is described here.
Generally, the tyrosine kinase activity of a supernatant is evaluated by determining its ability to phosphorylate a tyrosine residue on a specific substrate (a biotinylated peptide). Biotinylated peptides that can be used for this purpose include PSK1 (corresponding to amino acids 6-20 of the cell division kinase cdc2-p34) and PSK2 (corresponding to amino acids 1-17 of gastrin). Both peptides are substrates for a range of tyrosine kinases and are available from Boehringer Mannheim.
The tyrosine kinase reaction is set up by adding the following components in order. First, add 10u1 of 5uM Biotinylated Peptide, then 10u1 ATP/Mg2+ (5mM
ATP/50mM MgCl2), then 10u1 of 5x Assay Buffer (40mM imidazole hydrochloride, pH7.3, 40 mM beta-glycerophosphate, 1mM EGTA, 100mM MgCl2, 5 mM MnCl2, 0.5 mg/ml BSA), then Sul of Sodium Vanadate(1mM), and then 5u1 of water. Mix the components gently and preincubate the reaction mix at 30oC for 2 min. Initial the reaction by adding 10u1 of the control enzyme or the filtered supernatant.
The tyrosine kinase assay reaction is then terminated by adding 10 ul of 120mm EDTA and place the reactions on ice.
Tyrosine kinase activity is determined by transferring 50 ul aliquot of reaction mixture to a microtiter plate (MTP) module and incubating at 37oC for 20 min.
This allows the streptavadin coated 96 well plate to associate with the biotinylated peptide.
Wash the MTP module with 300u1/well of PBS four times. Next add 75 ul of anti-phospotyrosine antibody conjugated to horse radish peroxidase(anti-P-Tyr-POD{0.5u/m1)) to each well and incubate at 37oC for one hour. Wash the well as above.
Next add I OOuI of peroxidase substrate solution (Boehringer Mannheim) and incubate at room temperature for at least 5 rains (up to 30 min). Measure the absorbance of the sample at 405 nm by using ELISA reader. The level of bound peroxidase activity is quantitated using an ELISA reader and reflects the level of tyrosine kinase activity.
Example 20: High-Throughput Screening Assay Identifying Phosphorylation Activitx As a potential alternative and/or compliment to the assay of protein tyrosine kinase activity described in Example 19, an assay which detects activation (phosphorylation) of major intracellular signal transduction intermediates can also be used. For example, as described below one particular assay can detect tyrosine phosphorylation of the Erk-1 and Erk-2 kinases. However, phosphorylation of other molecules, such as Raf, JNK, p38 MAP, Map kinase kinase (MEK), MEK kinase, Src, Muscle specific kinase (MUSK), IRAK, Tec, and Janus, as well as any other phosphoserine, phosphotyrosine, or phosphothreonine molecule, can be detected by substituting these molecules for Erk-1 or Erk-2 in the following assay.
Specifically, assay plates are made by coating the wells of a 96-well ELISA
plate with O.lml of protein G (lug/ml) for 2 hr at room temp, (RT). The plates are then rinsed with PBS and blocked with 3% BSA/PBS for I hr at RT. The protein G
plates are then treated with 2 commercial monoclonal antibodies (100ng/well) against Erk-1 and Erk-2 ( 1 hr at RT) (Santa Cruz Biotechnology). (To detect other molecules, this step can easily be modified by substituting a monoclonal antibody detecting any of the above described molecules.) After 3-5 rinses with PBS, the plates are stored at 4oC
until use.
A431 cells are seeded at 20,OOO/well in a 96-well Loprodyne filterplate and cultured overnight in growth medium. The cells are then starved for 48 hr in basal medium (DMEM) and then treated with EGF (6nglwell) or 50 uI of the supernatants obtained in Example 11 for 5-20 minutes. The cells are then solubilized and extracts filtered directly into the assay plate.
After incubation with the extract for 1 hr at RT, the wells are again rinsed.
As a positive control, a commercial preparation of MAP kinase ( l Ong/well) is used in place of A431 extract. Plates are then treated with a commercial polyclonal (rabbit) antibody ( l ug/ml) which specifically recognizes the phosphorylated epitope of the Erk-1 and Erk-2 kinases ( 1 hr at RT). This antibody is biotinylated by standard procedures. The bound polyclonal antibody is then quantitated by successive incubations with Europium-streptavidin and Europium fluorescence enhancing reagent in the Wallac DELFIA instrument (time-resolved fluorescence). An increased fluorescent signal over background indicates a phosphorylation.
Example 21: Method of Determining Alterations in a Gene Corresponding to a Polvnucleotide RNA isolated from entire families or individual patients presenting with a phenotype of interest (such as a disease) is be isolated. cDNA is then generated from these RNA samples using protocols known in the art. (See, Sambrook.) The cDNA
is then used as a template for PCR, employing primers surrounding regions of interest in SEQ ID NO:X. Suggested PCR conditions consist of 35 cycles at 95°C
for 30 seconds; 60-120 seconds at 52-58°C; and 60-120 seconds at 70°C, using buffer solutions described in Sidransky, D., et al., Science 252:706 ( 1991 ).
PCR products are then sequenced using primers labeled at their 5' end with T4 polynucleotide kinase, employing SequiTherm Polymerase. (Epicentre Technologies).

The intron-exon borders of selected exons is also determined and genomic PCR
products analyzed to confirm the results. PCR products harboring suspected mutations is then cloned and sequenced to validate the results of the direct sequencing.
PCR products is cloned into T-tailed vectors as described in Holton, T.A. and Graham, M.W., Nucleic Acids Research, 19:1156 (1991) and sequenced with T7 polymerase (United States Biochemical). Affected individuals are identified by mutations not present in unaffected individuals.
Genomic rearrangements are also observed as a method of determining alterations in a gene corresponding to a polynucleotide. Genomic clones isolated according to Example 2 are nick-translated with digoxigenindeoxy-uridine 5'-triphosphate (Boehringer Manheim), and FISH performed as described in Johnson, Cg. et al., Methods Cell Biol. 35:73-99 (1991). Hybridization with the labeled probe is carried out using a vast excess of human cot-1 DNA for specific hybridization to the corresponding genomic locus.
Chromosomes are counterstained with 4,6-diamino-2-phenylidole and propidium iodide, producing a combination of C- and R-bands. Aligned images for precise mapping are obtained using a triple-band filter set (Chroma Technology, Brattleboro, VT) in combination with a cooled charge-coupled device camera (Photometrics, Tucson, AZ) and variable excitation wavelength filters.
(Johnson, Cv.
et al., Genet. Anal. Tech. Appl., 8:75 (1991).) Image collection, analysis and chromosomal fractional length measurements are performed using the ISee Graphical Program System. {Inovision Corporation, Durham, NC.) Chromosome alterations of the genomic region hybridized by the probe are identified as insertions, deletions, and translocations. These alterations are used as a diagnostic marker for an associated disease.
Example 22: Method of Detecting Abnormal Levels of a Polype,~tide in a Biological Sample A polypeptide of the present invention can be detected in a biological sample, and if an increased or decreased level of the polypeptide is detected, this polypeptide is a marker for a particular phenotype., Methods of detection are numerous, and thus, it is understood that one skilled in the art can modify the following assay to fit their particular needs.
For example, antibody-sandwich ELISAs are used to detect polypeptides in a sample, preferably a biological sample. Wells of a microtiter plate are coated with specific antibodies, at a final concentration of 0.2 to 10 ug/ml. The antibodies are either monoclonal or polyclonal and are produced by the method described in Example 10.

The wells are blocked so that non-specific binding of the polypeptide to the well is reduced.
The coated wells are then incubated for > 2 hours at RT with a sample containing the polypeptide. Preferably, serial dilutions of the sample should be used to validate results. The plates are then washed three times with deionized or distilled water to remove unbounded polypeptide.
Next, 50 ul of specific antibody-alkaline phosphatase conjugate, at a concentration of 25-400 ng, is added and incubated for 2 hours at room temperature.
The plates are again washed three times with deionized or distilled water to remove IO unbounded conjugate.
Add 75 ul of 4-methylumbelliferyl phosphate {MUP) or p-nitrophenyl phosphate (NPP) substrate solution to each well and incubate 1 hour at room temperature. Measure the reaction by a microtiter plate reader. Prepare a standard curve, using serial dilutions of a control sample, and plot polypeptide concentration on the X-axis (log scale) and fluorescence or absorbance of the Y-axis (linear scale).
Interpolate the concentration of the polypeptide in the sample using the standard curve.
Example 23: Formulating a Polypeptide The secreted polypeptide composition will be formulated and dosed in a fashion consistent with good medical practice, taking into account the clinical condition of the individual patient (especially the side effects of treatment with the secreted polypeptide alone), the site of delivery, the method of administration, the scheduling of administration, and other factors known to practitioners. The "effective amount" for purposes herein is thus determined by such considerations.
As a general proposition, the total pharmaceutically effective amount of secreted polypeptide administered parenterally per dose will be in the range of about 1 ~tglkg/day to 10 mglkg/day of patient body weight, although, as noted above, this will be subject to therapeutic discretion. More preferably, this dose is at least 0.01 mg/kg/day, and most preferably for humans between about 0.01 and 1 mg/kg/day for the hormone.
If given continuously, the secreted polypeptide is typically administered at a dose rate of about 1 ~g/kg/hour to about 50 p,g/kg/hour, either by 1-4 injections per day or by continuous subcutaneous infusions, for example, using a mini-pump. An intravenous - bag solution may also be employed. The length of treatment needed to observe changes and the interval following treatment for responses to occur appears to vary depending on the desired effect.
Pharmaceutical compositions containing the secreted protein of the invention are administered orally, rectally, parenterally, intracistemally, intravaginally, intraperitoneally, topically (as by powders, ointments, gels, drops or transdermal patch), bucally, or as an oral or nasal spray. "Pharmaceutically acceptable Garner" refers to a non-toxic solid, semisolid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. The term "parenteraI" as used herein refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion.
The secreted polypeptide is also suitably administered by sustained-release systems. Suitable examples of sustained-release compositions include semi-permeable polymer matrices in the form of shaped articles, e.g., films, or mirocapsules.
Sustained-release matrices include polylactides (U.S. Pat. No. 3,773,919, EP
58,481 ), copolymers of L-glutamic acid and gamma-ethyl-L-glutamate (Sidman, U. et al., Biopolymers 22:547-556 (1983)), poly (2- hydroxyethyl methacrylate) (R. Langer et al., J. Biomed. Mater. Res. 15:167-277 ( 1981 ), and R. Langer, Chem. Tech.
12:98-105 (1982)), ethylene vinyl acetate {R. Langer et al.) or poly-D- (-)-3-hydroxybutyric acid (EP 133,988). Sustained-release compositions also include liposomally entrapped polypeptides. Liposomes containing the secreted polypeptide are prepared by methods known per se: DE 3,218,121; Epstein et al., Proc. Natl. Acad. Sci. USA 82:3688-{ 1985); Hwang et al., Proc. Natl. Acad. Sci. USA 77:4030-4034 ( 1980); EP
52,322;
EP 36,676; EP 88,046; EP 143,949; EP 142,641; Japanese Pat. Appl. 83-118008;
U.S. Pat. Nos. 4,485,045 and 4,544,545; and EP 102,324. Ordinarily, the liposomes are of the small (about 200-800 Angstroms) unilameilar type in which the lipid content is greater than about 30 mol. percent cholesterol, the selected proportion being adjusted for the optimal secreted polypeptide therapy.
For parenteral administration, in one embodiment, the secreted polypeptide is formulated generally by mixing it at the desired degree of purity, in a unit dosage injectable form (solution, suspension, or emulsion), with a pharmaceutically acceptable carrier, i.e., one that is non-toxic to recipients at the dosages and concentrations employed and is compatible with other ingredients of the formulation. For example, the formulation preferably does not include oxidizing agents and other compounds that are known to be deleterious to polypeptides.
Generally, the formulations are prepared by contacting the polypeptide uniformly and intimately with liquid carriers or finely divided solid Garners or both.
Then, if necessary, the product is shaped into the desired formulation.
Preferably the carrier is a parenteral carrier, more preferably a solution that is isotonic with the blood of the recipient. Examples of such carrier vehicles include water, saline, Ringer's solution, and dextrose solution. Non-aqueous vehicles such as fixed oils and ethyl oleate are also useful herein, as well as liposomes.

The carrier suitably contains minor amounts of additives such as substances that enhance isotonicity and chemical stability. Such materials are non-toxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, succinate, acetic acid, and other organic acids or their salts;
antioxidants such as ascorbic acid; low molecular weight (less than about ten residues) polypeptides, e.g., polyarginine or tripeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids, such as giycine, glutamic acid, aspartic acid, or arginine; monosaccharides, disaccharides, and other carbohydrates including cellulose or its derivatives, glucose, manose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; counterions such as sodium; and/or nonionic surfactants such as polysorbates, poloxamers, or PEG.
The secreted polypeptide is typically formulated in such vehicles at a concentration of about 0.1 mg/ml to 100 mg/ml, preferably 1-10 mglml, at a pH
of about 3 to 8. It will be understood that the use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of polypeptide salts.
Any polypeptide to be used for therapeutic administration can be sterile.
Sterility is readily accomplished by filtration through sterile filtration membranes (e.g., 0.2 micron membranes). Therapeutic polypeptide compositions generally are placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle.
Polypeptides ordinarily will be stored in unit or mufti-dose containers, for example, sealed ampoules or vials, as an aqueous solution or as a lyophilized formulation for reconstitution. As an example of a lyophilized formulation, 10-ml vials are failed with 5 ml of sterile-filtered 1% (w/v) aqueous polypeptide solution, and the resulting mixture is lyophilized. The infusion solution is prepared by reconstituting the lyophilized polypeptide using bacteriostatic Water-for-Injection.
The invention also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention. Associated with such containers) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of ' manufacture, use or sale for human administration. In addition, the polypeptides of the present invention may be employed in conjunction with other therapeutic compounds.

WO 98156804 PCTlUS98/12125 Example 24: Method of Treating Decreased Levels of the Polvpeptide It will be appreciated that conditions caused by a decrease in the standard or normal expression level of a secreted protein in an individual can be treated by administering the polypeptide of the present invention, preferably in the secreted form.
Thus, the invention also provides a method of treatment of an individual in need of an increased level of the polypeptide comprising administering to such an individual a pharmaceutical composition comprising an amount of the polypeptide to increase the activity level of the polypeptide in such an individual.
For example, a patient with decreased levels of a polypeptide receives a daily dose 0.1-100 ug/kg of the polypeptide for six consecutive days. Preferably, the polypeptide is in the secreted form. The exact details of the dosing scheme, based on administration and formulation, are provided in Example 23.
Example 2~: Method of Treating Increased Levels of the Polvuentide Antisense technology is used to inhibit production of a polypeptide of the present invention. This technology is one example of a method of decreasing levels of a polypeptide, preferably a secreted form, due to a variety of etiologies, such as cancer.
For example, a patient diagnosed with abnormally increased levels of a polypeptide is administered intravenously antisense polynucleotides at 0.5, 1.0, 1.5, 2.0 and 3.0 mg/kg day for 21 days. This treatment is repeated after a 7-day rest period if the treatment was well tolerated. The formulation of the antisense polynucleotide is provided in Example 23.
Example 26: Method of Treatment Using Gene Therapy One method of gene therapy transplants fibroblasts, which are capable of expressing a polypeptide, onto a patient. Generally, fibroblasts are obtained from a subject by skin biopsy. The resulting tissue is placed in tissue-culture medium and separated into small pieces. Small chunks of the tissue are placed on a wet surface of a tissue culture flask, approximately ten pieces are placed in each flask. The flask is turned upside down, closed tight and left at room temperature over night.
After 24 ' hours at room temperature, the flask is inverted and the chunks of tissue remain fixed to the bottom of the flask and fresh media (e.g., Ham's F12 media, with 10°lo FBS, penicillin and streptomycin) is added. The flasks are then incubated at 37°C for approximately one week.

At this time, fresh media is added and subsequently changed every several days After an additional two weeks in culture, a monolayer of fibroblasts emerge.
The monolayer is trypsinized and scaled into larger flasks.
. pMV-7 (Kirschmeier, P.T. et al., DNA, 7:219-25 (1988)), flanked by the long terminal repeats of the Moloney marine sarcoma virus, is digested with EcoRI
and . HindIII and subsequently treated with calf intestinal phosphatase. The linear vector is fractionated on agarose gel and purified, using glass beads.
The cDNA encoding a polypeptide of the present invention can be amplified using PCR primers which correspond to the 5' and 3' end sequences respectively as set forth in Example 1. Preferably, the 5' primer contains an EcoRI site and the 3' primer includes a HindIII site. Equal quantities of the Moloney marine sarcoma virus linear backbone and the amplified EcoRI and HindIII fragment are added together, in the presence of T4 DNA ligase. The resulting mixture is maintained under conditions appropriate for ligation of the two fragments. The ligation mixture is then used to transform bacteria HB 101, which are then plated onto agar containing kanamycin for the purpose of confirming that the vector has the gene of interest properly inserted.
The amphotropic pA317 or GP+aml2 packaging cells are grown in tissue culture to confluent density in Dulbecco's Modified Eagles Medium (DMEM) with 10%
calf serum (CS), penicillin and streptomycin. The MSV vector containing the gene is then added to the media and the packaging cells transduced with the vector.
The packaging cells now produce infectious viral particles containing the gene (the packaging cells are now referred to as producer cells).
Fresh media is added to the transduced producer cells, and subsequently, the media is harvested from a 10 cm plate of confluent producer cells. The spent media, containing the infectious viral particles, is filtered through a millipore filter to remove detached producer cells and this media is then used to infect fibroblast cells. Media is removed from a sub-confluent plate of fibroblasts and quickly replaced with the media from the producer cells. This media is removed and replaced with fresh media.
If the titer of virus is high, then virtually all fibroblasts will be infected and no selection is required. If the titer is very low, then it is necessary to use a retroviral vector that has a selectable marker, such as neo or his. Once the fibroblasts have been efficiently infected, the fibroblasts are analyzed to determine whether protein is produced.
The engineered fibroblasts are then transplanted onto the host, either alone or after having been grown to confluence on cytodex 3 microcarrier beads.

Example 27: Method of Treatment Using Gene Thera-,pv - In Vivo Another aspect of the present invention is using in vivo gene therapy methods to treat disorders, diseases and conditions. The gene therapy method relates to the introduction of naked nucleic acid (DNA, RNA, and antisense DNA or RNA) sequences into an animal to increase or decrease the expression of the polypeptide of the present invention. A polynucleotide of the present invention may be operatively linked to a promoter or any other genetic elements necessary for the expression of the encoded polypeptide by the target tissue.
Such gene therapy and delivery techniques and methods are known in the art, see, for example, W090111092, W098/11779; U.S. Patent NO. 5693622, 5705151, 5580859; Tabata H. et al. (1997) Cardiovasc. Res. 35(3):470-479, Chao J et al. (1997) Pharmacol. Res. 35(6):517-522, Wolff J.A. (1997) Neuromuscul. Disord. 7(5):314-3 I 8, Schwartz B. et al. ( 1996) Gene Ther.
3(5):405-41 I, Tsurumi Y. et al. {1996) Circulation 94(12):3281-3290 (incorporated herein by reference}.
The polynucleotide constructs of the present invention may be delivered by any method that delivers injectable materials to the cells of an animal, such as, injection into the interstitial space of tissues (heart, muscle, skin, lung, liver, intestine and the like). These polynucleotide constructs can be delivered in a pharmaceutically acceptable liquid or aqueous carrier.
The term "naked" polynucleotide, DNA or RNA, refers to sequences that are free from any delivery vehicle that acts to assist, promote, or facilitate entry into the cell, including viral sequences, viral particles, liposome formulations, Iipofectin or precipitating agents and the like. However, the polynucleotides may also be delivered in liposome formulations (such as those taught in Felgner P.L. et al. (1995) Ann. NY Acad. Sci. 772:126-139 and Abdallah B. et al. ( 1995) Biol. Cell 85( 1 ):1-7) which can be prepared by methods well known to those skilled in the art.
The polynucleotide vector constructs of the present invention used in the gene therapy method are preferably constructs that will not integrate into the host genome nor will they contain sequences that allow for replication. Any strong promoter known to those skilled in the art can be used for driving the expression of DNA. Unlike other gene therapies techniques, one major advantage of introducing naked nucleic acid sequences into target cells is the transitory nature of the polynucleotide synthesis in the cells. Studies have shown that non-replicating DNA sequences can be introduced into cells to provide production of the desired polypeptide for periods of up to six months.

t59 The polynucleotide construct of the present invention can be delivered to the interstitial space of tissues within the an animal, including of muscle, skin, brain, lung, liver, spleen, bone marrow, thymus, heart, lymph, blood, bone, cartilage, pancreas, kidney, gall bladder, stomach, intestine, testis, ovary, uterus, rectum, nervous system, eye, gland, and connective tissue.
Interstitial space of the tissues comprises the intercellular fluid, mucopolysaccharide matrix among the reticular fibers of organ tissues, elastic fibers in the walls of vessels or chambers, collagen fibers of fibrous tissues, or that same matrix within connective tissue ensheathing muscle cells or in the lacunae of bone. It is similarly the space occupied by the plasma of the circulation and the lymph fluid of the lymphatic channels. Delivery to the interstitial space of muscle tissue is preferred for the reasons discussed below. They may be conveniently delivered by injection into the tissues comprising these cells. They are preferably delivered to and expressed in persistent, non-dividing cells which are differentiated, although delivery and expression may be achieved in non-differentiated or less completely differentiated cells, such as, for example, stem cells of blood or skin fibroblasts. In vivo muscle cells are particularly competent in their ability to take up and express polynucleotides.
For the naked polynucleotide injection, an effective dosage amount of DNA or RNA will be in the range of from about 0.05 g/kg body weight to about 50 mg/kg body weight. Preferably the dosage will be from about 0.005 mglkg to about 20 mglkg and more preferably from about 0.05 mg/kg to about 5 mg/kg.
Of course, as the artisan of ordinary skill will appreciate, this dosage will vary according to the tissue site of injection. The appropriate and effective dosage of nucleic acid sequence can readily be determined by those of ordinary skill in the art and may depend on the condition being treated and the route of administration. The preferred route of administration is by the parenteral route of injection into the interstitial space of tissues. However, other parenteral routes may also be used, such as, inhalation of an aerosol formulation particularly for delivery to lungs or bronchial tissues, throat or mucous membranes of the nose.
In addition, naked polynucleotide constructs can be delivered to arteries during angioplasty by the catheter used in the procedure.
The dose response effects of injected polynucleotide in muscle in vivo is determined as follows. Suitable template DNA for production of mRNA coding for the polypeptide of the present invention is prepared in accordance with a standard recombinant DNA methodology. The template DNA, which may be ' either circular or linear, is either used as naked DNA or complexed with liposomes. The quadriceps muscles of mice are then injected with various amounts of the template DNA.
Five to six week old female and male Balb/C mice are anesthetized by intraperitoneal injection with 0.3 ml of 2.5% Avertin. A 1.5 cm incision is made on the anterior thigh, and the quadriceps muscle is directly visualized. The template DNA is injected in 0.1 ml of carrier in a 1 cc syringe through a 27 gauge needle over one minute, approximately 0.5 cm from the distal insertion site of the muscle into the knee and about 0.2 cm deep. A suture is placed over the injection site for future localization, and the skin is closed with stainless steel clips.
After an appropriate incubation time (e.g., 7 days) muscle extracts are prepared by excising the entire quadriceps. Every fifth 15 um cross-section of the individual quadriceps muscles is histochemicalIy stained for protein expression. A time course for protein expression may be done in a similar fashion except that quadriceps from different mice are harvested at different times. Persistence of DNA in muscle following injection may be determined by Southern blot analysis after preparing total cellular DNA
and HIRT supernatants from injected and control mice. The results of the above experimentation in mice can be use to extrapolate proper dosages and other treatment parameters in humans and other animals using naked DNA of the present invention.
It will be clear that the invention may be practiced otherwise than as particularly described in the foregoing description and examples. Numerous modifications and variations of the present invention are possible in light of the above teachings and, therefore, are within the scope of the appended claims.
The entire disclosure of each document cited (including patents, patent applications, journal articles, abstracts, laboratory manuals, books, or other disclosures) in the Background of the Invention, Detailed Description, and Examples is hereby incorporated herein by reference.

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(viii) ATTORNEY/AGENT INFORMATION:.
(A) NAME: A. Anders Brookes (B) REGISTRATION NUMBER: 36,373 (C) REFERENCE/DOCKET NUMBER: PZ008PCT
(vi) TELECOMMUNICATION INFORMATION:
IS (A) TELEPHONE: (301) 309-8504 (B) TELEFAX: (301) 309-8439 (2) INFORMATION FOR SEQ ID NO: 1:

(i) SEQUENCE CHARACTERISTICS:

2J~(A) LENGTH: 733 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear 3O (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 2:

CCAGCACCTG

ACCCTCATGA

GACCCTGAGG

AAGCCGCGGG

CACCAGGACT

ACCCCCATCG

ACCCTGCCCC

AAAGGCTTCT

AACTACAAGA

CTCACCGTGG

GAGGCTCTGC

CGACGGCCGC

WO 98/5b804 PCT/US98/12125 ' (2) INFORMATION FOR SEQ ID NO: 2:
S (i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 5 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear IO (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 2:
Trp Ser Xaa Trp Ser IS
(2) INFORMATION FOR SEQ ID NO: 3:
2O (i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 86 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double iD) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 3:
GCGCCTCGAG ATTTCCCCGA AATCTAGATT TCCCCGAAAT GATTTCCCCG AAATvATTTC 60 3S (2) INFORMATION FOR SEQ ID NO: 4:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 27 base pairs (B) TYPE: nucleic acid 40 (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 4:

SO (2) INFORMATION FOR SEQ ID NO: 5:
(i) SEQUENCE CHARACTERISTICS:
(A> LENGTH: 271 base pairs (B) TYPE: nucleic acid SS (C) STRANDEDNESS: double ' (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 5:
C)O CTCGAGATTT CCCCGAAATC TAGATTTCCC CGAAATGATT TCCCCGAAAT GATTTCCCCG 60 GCCCCTAACT CCGCCCAGTT CCGCCCATTC TCCGCCCCAT GGCTGACTAA TTTTrTTTAT 180 S

(2) INFORMATION FOR SEQ ID NO: 6:
IS (i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 32 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 6:

{2) INFORMATION FOR SEQ ID NO: 7:
3O (i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 31 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 7:

{2) INFORMATION FOR SEQ ID NO: 8:
(i) SEQUENCE CHARACTERISTICS:
{A) LENGTH: 12 base pairs {B) TYPE: nucleic acid (C) STRANDEDNESS: double S0 (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: B:

SS
(2) INFORMATION FOR SEQ ID NO. 9:

(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 73 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double S (D) TOPOLOGY: linear ' (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 9.

_ 10 CCATCI'CAAT TAG 73 (2) INFORMATION FOR SEQ ID NO: 10:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 256 base pairs 20 (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 10:

CTCGAGGGGA CT'T'CCCCGGG GACTTTCCGG GGACTTTCCG GGACT2'I'CCA TCTGCCATCT 60 3O CAGTTCCGCC CATTCTCCGC CCCATGGCTG ACTAATTTTT TTTA'I"I'I'ATG CAGAGGCCGA 180 GGCCGCCTCG GCCTCTGAGC TATTCCAGAA GTAGTGAGGA GGCTTTTT'I'G GAGGCCTAGG 240 (2) INFORMATION FOR SEQ ID NO: 11:

(i) SEQUENCE CHARACTERISTICS:

(A1 LENGTH: 1220 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double 4S (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 11:

. CATGAATGGC TCGCACAAGG ACCCCCTCCT CCCCTZTCCT GCTTCTGCGA60 GAACTCCCTC

GCTTCGCTCG

CATTT'CACCG CCGCCGCCTC TCGCAATATT GCAATATAGG 180 GGAAAAGCAG ACCATGGTGA

TGGAAGCGGT

GACAGCTATT

TATTTGGAAA

TCATGAGGGC

ATCGCCTGGT

ATAGACCTAC

CAGACCAGAA

lO

GGTCTvCTAA AAGGTCAGAG TAATGCAGAA TGCGTGCCTT CATCTCAGAT720 TTGTTCATCA

CAGG'IGGATC CCATGTKTCT TCAGTAGACA AGTCACCTTT 780 GTAGCTAGCA CCAGTGCCAG

TGGTGTATTA

CTCATTAACA

ATTCTATTTG

CCATGAGATA

TCTCTGTAAA

CATGGCAAAG

P~AAAAAAAAA GAATGAAAAA AP~AAAAAAA P~AAAAAAAAA 1200 AAAAAAAAAA CTCGAGGGGG

(2) INFORMATION FOR SEQ ID NO: 12:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 1939 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double 4OtD) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 12:

CTTGTTGATG

CAGTATCAAT

TGTATAATCT

SOATTTTGTCCT AACAATTACA AATATATrTT TTATTTCAGA TTRTATATAT240 TCCTACCAGA

CATTGACATT

AAATTTTrAT GGACACATAA TAACTGTACA TATATATGGG GTAGAATGTG360 ATGTTTTAAT

SS

TTTCTGTAGG

TATTGTTAAC

ACATCCGTTA

ACATGTACAG

CATGACATTT

S

TGTGCAAAGG

TGATGTGCAA ATACTA'IGTC ATTTTATATC AGGGACTTGA 780 GTATCCTTTG TTAYCCTCAG

CTATCCTCAC

ATAGGTGGTG

CATYCTTAGA

TCCTTTATTA

GAAAAGCGTC

GCTAATGGTC

TGTCTTGGAT

CAATGGAAGC

TCATGAGGCA

TTAMTTGGGA

CAAAGCAGAG

TTGGGAGCAA CAGATGC'I'AA AGAGTAGTTG CTGTAGTTCC 1500 TCTTTGGGTC GTAGGAGCAG

CTGGGTGAAC

TAAGTAAATA

AGAGCTATAA

AATATTTATG

TTATTGTTTS

TACACATTGA

GTAAGCAAAA

SO
(2) INFORMATION FOR SEQ ID NO: 13:
SS (i) SEQUENCE CHARACTERISTICS:
' (A) LENGTH: 2602 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 13:

TAATCCTCAG

GCTCGTT~vGC

TTGGTTTGAA

ATGTGATTCA

CAGGAACTCC TTAAGTAACA AACGAAATGA GCCAGGGGCG 'PGGAAAATAT300 GACTTC?'ATA

ATTTTGAAAA

GGTC,GCCATG

GGTGAGGTGG

GGAGCTCTCA

AATCTTCATG

CATGCTCCAA

Z.SAGGAAGAGGA GATTGAGACT TTAAATGAAA TGTCTCACAA GCTAGGTGAT720 CCAGGTTT'IG

GTGGGTCCTC

GGCGCGTTTT

GGGAAGCCTG

GTGAGCACAC

ACTCCAATAT

AAGGAGTGGC

ATCATTGTGG

CTGCCTGTGT

GAAGTTCTTA

AATGTCTCCC

ATCTGTGATT

CCTCAAATAA

SO

ATTACTTTTC

CGATTTCTAT

AGCCGAATGC

ACTAATGACA GTTTTAAGTC TATGAAAATG CrTTATTTTT TCATTGGTGA1680 TGAAAGTCTG

TTTTTATTTT

AAAAGTGGCT

' CCTGTTTGTT TGAT~vATGAT TGGTTTTATT TTTGAAATAT 1860 TTATTAAGGG AAAACTAAGT

CACCCCAAGG

ATTCGATGGC

GGGTTTATTC

TCAGCTCi"IG

ACAGCTCTGG

~S GAAATAGAAG ACTAGGGTTG TTTCTTAAAT TTAGCTCATG TTATAATAAA2220 AAGTTGAAAT

ATAGAATATG

ATTTTGGTTT

CAGAAAAGGT

CTCATAACCA

GGTGATGGGG

CCCAGTGGTV

(2) INFORMATION FOR SEQ ID NO: 14:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 808 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIP'I'ION: SEQ ID N0: 14:

CATTTGGATG

TTACAGATAT GZGZGTTCCT GGAGCCCAGG GCCAAGCCCT CCCT~GGGGA120 CTTGGATTGG

TGATCTCTCT CCI"I'GGCCCC AACCTGACAT CTTTTCTTGT 180 CCTTTTAGGA ATGTCTGATG

TGAGAAGGAA

TCAGATAGGT

TTAGCCTCTT

TGGGAAAGGG

TCCTCTACTA

ATGAGAATGC AAAATGTTGA ACAACTGTAA AATGTTT'1'CA 540 CCCTGCTTTT AGACATAAAG

TGGCTCCAGA

ATGTATACTC

S

AACAGGCAAA

AAAAAAAAAA

AAAAAAAAAA AAAAAAAAAA cccccccc sob IS (2) INFORMATION FOR SEQ ID N0: 15:
(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 864 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 15:

'IGCCCCAGAC

TACCTCTGTC

CCTGTTGCCC

TTAGGTTTCT

AAGGTCTGGA

GACATCACTA

CAAGTTGCTA

GCACTTTCTA

AGGGGTACTA

TAGGTGTGTC

CATGCTAAAA

CATTAGCTTT

CTGTTCAGTT

AAAAAAAAAA

SS
(2) INFORMATION FOR SEQ ID NO: 16:
60 (i) sEQuENCE cxARACTERISTICS:

(A) LENGTH: 2361 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 16:

TTGATACTCT

AAACTTTAAC

CCTGCGTATG

TGGATCCAAT

IS

GTATGTTTTG

AGAGGAGGAA

TTTGTTGCCT

TrAATCTCAG

ACTGTTTTTT

AAACGGGACA

GAAACTAGCA

'I'TGAGGGCTG

TTCCATTCAC

ACCTCCAAAA

CACATATGTT GGAAATCGCT TTTGCTvGTG CAAAGTATAT TAATGAGCAG900 GAATACATAC

AGCTTGGTAT

TAGAACGTTT

GCTGCGATAA ATCTTTTGGA T2'TZ'i'GTGTT TTTCTAATGA 1080 GAATACTGTT TTTCATTACC

GATTACATAG

GTTGGCTCAT

AAGTGTACTT

GTTTTTAAAG

CTATCCTuCC

TGGTGCTTGA

TAAGTGGCCT

AGAAAGCCCA

CCGTAGCAAA

ATCATTTTGT

TGGTGGTTTT

S

AACTGACTAG

CTTACAAATA

ACAAAATGTG

TTTAAAATGT

AAGATGTvAG

GGAAAAGTAA

GATTATATTC

ATGTCCTTGT

AGGCTC'IGTT TTAAGAAAAC AATATGTGGG AAATGATTTA 2280 ATTTTTCCTA TTGCTCTTCC

TTGTGGAAAA TAAAGTGTTT TGTTTTTTTC TGTTTTGTAA F,AAAAAAAAA2340 AAAAAAAAAA

P~AAAAAAAAA AAGAANGAGA A 2361 (2) INFORMATION FOR SEQ ID N0: 17:

(i) SEQUENCE CHARACTERISTICS:

(A} LENGTH: 803 base pairs 3S (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 17:

CAGCTvCCCA CAAGGTGGGC TCCTGGGGGA GGGTCATCCC TCTGAGAAGA60 GGGCGGCACC

GTCTTGCTGC

4S TGTCCCCATC CTGTTCTGAT TTATTuGTCA TTAGTGTCTT GAACCTGGAG180 CAAAGGAGAC

AAAGCAAGGT GGGTTTTGAA CCTTI'I'ACTT CACCACTGTG 240 TGGCGNATGG CACCATCTGT

TCCTAAAATA

SO

GCCCAATTCT

GACTCTTCAT

GAACACCACC

GTGGGGCGAG

Z'GGGGCTCTG CTGCAATGTG ACTGCAGTCT GAGGGGCAGA 600 RGCTGCAGGK TACAGCCCCA

S TAAAAC'.AGCT TTCCTTCCAC CAAAAAAAAA AAAAAAAAAC TCGAGGGGGG GCCCGGTACC 780 ' lO
(2) INFORMATION FOR SEQ ID NO: 18:

(i) SEQUENCE CHARACTERISTICS:

IS (A) LENGTH: 1794 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear 2O (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 18:

TTC'TTTTTTG TTCATGGGAC ATGGTACCTA AGCAAATAGG AGTTGGGTTT 60 GGTTTTTCTC

AATGACAATA

GTTTTAATGT

CCATCTCTCC

ACCCTGTTTA

GTATTCT"TT GTGCATTTGG TTTGTTGGTT AGCCGACTGT CTTGAAACTA 360 TTCATTTTGC

CTGTCTCTGT

AGTCAATGGC

ACTTAACTCA

GCATATTAGG

TGTACTGTTG

TTTAAAGAGC

TTTTTTTTTA

ACCAGTGTTT

ATAGCAT~TG

TAACATTTCA

CAAGACAAGC

SS

AATATATATA

AAGAAAATTT

AAAATATAAC

TGAAAAGAAG

GATGATTTGT

S

GATTCCTTGG

AACAGGCTGA

ATAATCAAGA

GGCATTGTGA

ATGCAGTATA

AAGGTTGGTG AAG'IGTAATA TAATTGTGTA AACAAATCCT 1680 GTTAATAGAG AGATGTACAG

GGTTAAAAAA

p~AAAAAAAAA AAYTCGGGGC CAGTTCCCCC CCGGCTATTT 1794 TAAAAGGNAA AAAG

ZS (2) INFORMATION FOR SEQ ID NO: 19:
(i} SEQUENCE CHARACTERISTICS:

(A) LENGTH: 1037 base pairs (B) TYPE: nucleic acid 3O (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 19:

GAGTGCAGTG

TGCYTCAGCY

TTGTATTTTA

CTCAGGCAAT

CACCCAGCCA

4S AGCTGTACTT TTT'ITI'TTTT TTTTAAAGCT TCAAACCTTC 360 AATATTTCAT TAAGAGTTAC

AGTTT~vGTTT CAGTCATTCK GAGGRAAATT AAGGAAGGGG 420 CTTGGCCCAW ACCTGGTAAA

GAGTGCTTTT

SO

CACAATTTGT

AGGTGGATAG

WACAGAACTA

ATGTTTTCAG

ATTTAAAGGG

CACATTTGTG

ATTGACAGGG

GCAAAACACC

CTTTATGATG

(2) INFORMATION FOR SEQ ID NO: 20:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 1309 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 20:

CCCGAAATGA

TTCTAGAAAC

TGTGGTTCAG

CCCCTGAGCA

ACGATGGCCG

AAATGTAAGA

GCCCTTGTTA

GAAGACAGTT TTGCCTTTTC AATCTCATAG CAAGGAACTC AAGTCTGA'IG480 CTTCAAAAAG

AAAGGTGGGG

AACCTTTCCC

ACCCACTGCC

TTT'GCTGGGA GCAGAAGCCC ATAGCAACAA GTGACCTGCC 720 CCTCAGACTC AAGATCCCAG

AGGGTCGAAC

CCATGTGTCC

GGTCCCCACA

TTGTAGTGTG

SS

AGCTAGCAGG

ATGATAGGTT

(2) INFORMATION FOR SEQ ID NO: 21:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 1081 base pairs IS (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 21:

GTGCTTTTAA TCTCAAAA?T

AAGCAGTCAA ATTAAGTAGA

AATAGAAAAT AAACTAAACC

GACCAAAATA TTTAAAATGC

ACAATGCTTT TAACTTAAAT GTGCTAACCC TGTTrCTGTC 300 TGTTTTGTGC TGTACCTTTT

TAACCAATGA GACTACAGGC

AACTTAAATA TATTTTGTTT

ATGGGCAACG ATTATCTTGG

ATGAATTTTG TAATATCCTC

TAAATTGTAT TTCAACAATT

ATGTAGAGAG TTTATATGCA

CGACTATTTT GCCATGGAGA

TTAACCTTAA GTTATTTTTC

ACTTCCAATG AGATAAAATA

TTTACTATTA TGCTTATrAG AACAAAAGGT GTTTAAGGAT 900 GAACTAAATA TTTTAATTGA

SO

TATTTACATC CAGAGTCATA

GTATACTATT GTTTTAATAT

S AATCAGGATT TTCCATATTN

(2} INFORMATION FOR SEQ ID NO: 22:

(i) SEQUENCE CHARACTERISTICS:

tA) LENGTH: 807 base pairs ' (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear IO (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 22:

CTCTTCTCTG

AGAAGAGTTA

IS

GAGGGAATGC

A.1ATCAAGAC CACAAGGAGA TAACAATTTG AGCCTATTGA 240 CAAAAGTTCA GAAGTCTAAT

GGTGGGAGTA

ACATTTGCAT

TGTGTTCTTG

GCCAATGAGA

TAGTGAGATC

CTGTTGAGTA

TTGTvCCTTG

TTTGTTGTCC

CATAATAGTT CT2"~ITZTAA ACTTTCCTCA ATTACACAAT 780 TTGATCTTGT TCCTACCAGT

ACCN'ITGCTG GTACAACCTT AAACZGG 807 (2) INFORMATION FOR SEQ ID NO: 23:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 632 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D} TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 23:

GAAGAAAGAA TGTTvCTTTT CCTCACTGTA ATTAATTTTA TGGCTCTTGC GAAGATGAAT 240 t78 ATT'TGTGAAA

AAAATTGCCT

TAAAAGAGAC

TTTTATCAAC

TGTAACATGT

to TGAGAATATC

(2) INFORMATION FOR SEQ ID NO: 24:

2O (i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 1358 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 24:

TAAAAATAAC

GAAGGGAGGT

ACTCTAAGAA

ATTTRGATAA

CACAAGTATT

GAGAGAAATC

TCTACTACTT

CMTACMTTGA

CTTTAATTCT

GARCCTTAGT

GAGGTTTATA

TGTACCTATA

AATAATGCAG

GAGATCTCCC

SS

TAGAAATTCG

AGTATGCACA

GGTTTGCCCA

TAGGACTCCA TCAGGGTCCA CCAACACAGA CfTACAGCAA AAATTGGAAG 1080 GCTCTTTTCT

CAAAACACGT

CTGTCAAATA

ATAAATCTTG TATTCACTZ'G GGCATGTATG TTTATTATTG GATCTCTAAA 1260 ATATGCTTCA

TATGATGGGT

(2) INFORMATION FOR SEQ ID NO: 25:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 1376 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear ?S (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 25:

TGGTCAGGAG

TTTCCTGTCC

TGAAGGGTGT

GGATTGGTCA

AAGAAGATAT

TATACTGTAT

CTTGGACCAA

AGTCAATTAA

TATvGACACA AATGACATGT GGTTAATGAT GAGAAAAGCT TACAAATACG540 CCTTTGAWAA

CTATCATTGA

TAGGCCACAC

TAAGTGTAGA

SO

AACAGGGAGG

' GATGATTTGG AAGATATCTG AAGATAAACA GCTAGCAGTT TGCCTGAAAT840 ATGCTGGAGT

AATCTGTTGG

GCTGTTGTTC

TGA'IGTATGG

TCTTACCTCC

TTTGTATAGG

ATGTTTCTTT

TACATTTTTA

AAAAAAAAAA F~AAAAAAAAA AAA~AP~AAA ~~1AAAAAAAA 1320 AAAAAAAAAA P,APAA

lO

~ P~AAAAAAAAA AAAAAAAAAA AAAAAAAAAA AAAAAAAAAA 1376 AAAAAA

IS

(2) INFORMATION FOR SEQ ID NO: 26:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 2923 base pairs 2O (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 26:

CCTGCTATAC

AGCGATGCCC

GAKGAGCAGC

TCTCGTCGCA

GACGACTGGT

CCTGCCTTCT

TAATTTTAAG

CAAGTCAACA

AGCTGGGATG

CCAAAGCAGA

TTCAACTACA

GTTCTAAAAC

SO GGGGAG'1GGT CTGAATGAAC ACAGCTGACC CCTTTCCCGC 780 GCACTGAAAG GGCAGAGTAG

GTGGGCCTGC

TCAAGCCTCT

SS

AAAGAATGTC TCACCTCCTC TGCCCAAAAA TGATGCCTTT CTGTAGGCTG9b0 GTGTTGTTGC

CCACCTCTAG

ACTATCr_CTG

f AGCCTGAAGA CTTGGAGCTG

TTAAGGATGC TGAGGCCTAG

TGACATAGCT AGAGCGCAGA

AATGGGCACC TvCTGGAGTC

ACCATAGGTT GGGGTCCCAG

TCAGACCTTC ATAGCCTCTC

ACATAGCCTT GGGACCAGCC

IS

GGCAGCTTTG ACAGGTGCTG

AATTTAAACA AAGATTCTGC

CAGTACCTGC CTGGGGGTGG

GGCTCCAGGT CCTGTTTCCA

CCTCCCTTCC CGCTTTTCCC

TCAGCTCTAG CCAACAGTGA

TATGCTGAAA TCGGCTTCTG

CAGGATCTGT CCCTACCCAG

GCCCTCCGGC TTGAGGAGAG

CGCTTCTCCT CTGCCTTCTT

AGCATGCCGT CTTGCTGTGG

TGTCTCTGGC ACAGGACI"I'G

CCACCTTGTT TCCCAGCCTG

GGTCGTTGAA GGCGCCTGGG

GGTTCTCCCA AATAGGAGAC

ACTAAATTAC CCCCATCCTC

TCTGCTCTGA CCTTGAAGGG

SO GGCGGTGTTG GCCTGGCTTC TGGAATvGAC TGAGTCCATC 2580 GTGGAAAGGG CTGGGGGCAG

AGATCATTAG CTCAGTGACC

GTTTGGTAAT GATCrGCAAG

SS

TAAAATCTAT GCAGCCAAGC

CTCGGGGGGC CGGGGACCCA

CCAAAAAAAA AAAAAAAAAA

S
(2} INFORMATION FOR SEQ ID NO: 27:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 775 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear IS (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 27:

GAACTAGTGN ATCCCCCGGG C'IGCAGGAAT TCGGCACGAG 60 CCCRACCCSC ACCACCACCA

AAACACCGCC

AGAAAAGTCT

CACCTTCATC

TGCGTCTAGG

CTGTCATTTT

ATGTGTCCCG

ATATTTGCAG

CAAACGCTGG

ATCAGGCCTT

GACATGTCAT

TGTGTAACAA

ACCGT

(2) INFORMATION FOR SEQ ID NO: 28:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 534 base pairs SO (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 28:
SS

CAGGGGTvGT GGSCTCACCC CACCTCCAGG CAMCCACAAG AATATAAAAT CTTGTACAAR 120 C)O GATGTCGATA TTACTATTGS CATTCCCAAG TGCACCTGCA CCT'GTAGTAT CAGGTGGTTT 180 AAATCCCAGT

ATCAATTATT

S

CAGGGAMCTC

ACCAAGGTTA

.. ~O AGAACTACTG GTTTAATGGG AAAATATTTT TTTCCNGTGC TTGAATAATA480 CTGGTTTTAT

AAAA

(2) INFORMATION FOR SEQ ID NO: 29:

(i) SEQUENCE CHARACTERISTICS:

20 (A) LENGTH: 1827 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double iD) TOPOLOGY: linear ZS (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 29:

GCCAGCTCCT TGCACCCTTC

CTCAGCACTT CTCCCTGGCC

GTCGCTACAA CCTGCCCGAG

TTAAGGAGAA AGGGTACGAT

GTTGCAAAGG TTTGGCATTG

GCACTGTTCT CAGGGCAAGC

CATGGCACCA AGATGA~GAC TCCAGAGGTG CTGGCAGAGG 420 CATATGGCAA GAAAGAGTGG

GAAAGTATTA CTTTTACGAC

TGGTGGACTA TTTAACAAAA

TAGTTGCTGC TATACAACAC

ATTTTCCAGA AATAAAAAGA

AAAAATGGCT TCGACAGCTA

SO

ACAGTGATTA CTGTAGACTT

TTGACATTGT GATTACAAAT

GACCTTTCCG GACACTCGAG

CTGGCTGGTA CTCCCAAGGG

GCAAACCTGA ACCCAAGGTT

TAGTAATTGG

GAGACAGTCC TCATCCTvGA AGAACTCAGA GGGGATGAAG GCACGAGGAG1140 TCAGAGGCCT

AAAACCTTTA

ACTGGAAAAT

CAGCACTATT

TACAAGATTC

CTTATCAAGT

AGACCCATAT

GGAACAAGTT

ATCTTGATGT

TTATTGGATA

ACTCACACGG

GTGTGGTTCC

CTTGGGGCCT NTTGGGCTT'G GGCCTTT 1827 (2) INFORMATION FOR SEQ ID NO: 30:

(i) SEQUENCE CHARACTERISTICS:

3S (A) LENGTH: 1479 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear 4O (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 30:

CTACCTCACT

CCAGNTGGGT

GGCGGCTTTC

CCGTGGCGCT

TTCTCGCTCT

AGATGCTCGG

AGAGAGAATG

SS

CATGTGGCCA

CCAGTGTAGC

TCACCTCCTG

TGCTGGGACC

TGCCCACCTC

S

CCAC~GCCCC CTCAGCACAC ACACAGTCCC CAGGCGGCCT AGGGGCCAAG780 GCTGGGGCGG

GGAGAGGCAG

TAGTGAGCTG

CTGGCCAACA

CCTGCCGGGC

CCTGCCAGCA

GCCCAGCTCA

TCCACGTTGT

CATTTCCCTT

GCCCTTCACC

ACTTTGCTGT

ATATTATCCA

3S (2) INFORMATION FOR SEQ ID NO: 31:

(i) SEQUENCE CHARACTERISTICS:

tA) LENGTH: 987 base pairs (B) TYPE: nucleic acid 40 (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 31:

GCTTGCGCTC

TTTCTGGACT

GTTTGGCTTT

SO

GGCTACACAG CACrGGTTGT TTCTGGTGGG ATCGTTGGCT ATGTAAAAAC240 AGGCAGCGTG

CCGTCCCTGG CZC,CAGGGCT GCTCZ"tCGGC AGTCTAGCCG 300 GCCTGGGTGC TTACCAGCTG

TTTTGTTGGT

AATTGCAGGT

GCCAGTTZGC TGA'~GGCCGC CAAAGTTGGA GTTCGTATGT 480 TGATGACATC TGATTAGCAG

ACTATTTTCA

AAAAAAAAAA

S GACACCAAAT TTGGCGGAGG G~GTC,GAP~AAT CAGTTGTTAC 660 CATTATAACC CTACAGAGGT

GTATATTGAT

GTTGACATTG

CTCTTGAGAG

AATTATGTTA

AAAAAAAAAA

AAAAAAAAAA F~~ ANANAAA 987 (2) INFORMATION FOR SEQ ID NO: 32:

(i) SEQUENCE CHARACTERISTICS:

2S (A) LENGTH: 2933 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 32:

ATTCGTGAAG

CATGAAAACC

AGGTTTTCTG

TCTGATTCTC

ATCTGTCCGC

AAATGTCACC

TGTTGAATTC

AATTCTTTTA

AGAAGCTGAT

TGTGGGAGCC

TATATTTATT

ATATTCAAGG

SS

AGGAGTTATC

TCCTGGTCGT

AATTTTGAAA

CAGAAATTAT AGCTCGAGGT

ACCAGGCTGC ATTAAAAGCA

GAGTTTTCCA AAGACAAAAT

AAAAACAAAA CCATCACAGC

AAAGATGCAA TGCCTATCAA

CAAAGCTACA ATCATGCCAC GGGGGCCAAC ACTTvGNACA 1260 TGTGTCCCTG TTACCTGAGA

AATGGATGTT AGTATGGGAG

IS

GAAGAG'I'GGC AGAGGAGCTT ATATTTGGAA CCGACCATAT 1380 TACAACAGGT GCTTCCAGTG

CAAATTTGGA ATGAGTv~AAA

TCCAGAAACC CAATCTGCCA

ACGAGCAAAA CATATC'rTGA

ATTGACCTAT GAGACTTTGG

ATuCCAAAGA GATTCAAATT GTTCTTGAGG GGAAAAAGTT 1680 GGAAGTGAGA TGATAACTCT

GTAGCATTGC AGTAGTCTAC

GAAGGGTGTG AAATGCTTTG

TTATGACACC TATTGCAAAT

TATCAGGATT GAAAACAGCT

TAATGATTTT ATGTTTGGTT

ATATACATCA GTGGAAACTT

TATTTTTTAA TCTAAATGTA

AGGGAATATA GCCTTTTGGC

AGGCTGAGGC GGGTGGATTG

GAAACGCTGT YTCTACTAAA

AATCCCAGCA CTTTTCAGAG

CAGCCTGGCC AACATGGTGA

GGTGGCAGGT GCTTATAATC

CTGGGAGATG GAGGTTGCAG

GAGCAAGACT CTGCCTCAAA

GGTGTGGGGT GCATGCCTGG

GO AATCCCAGCT AC'TIGAGAGG CTGAGGCACG AGAATTGCTT 2700 GAACCCAGGA GGTGGAGGTT

S

(2) INFORMATION FOR SEQ ID NO: 33:

IS (i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 1366 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D} TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 33:

CAGCAAGTTC

2S TTGGCATGGC AGGTGTT?'CT GAAATATCAG TGTGTTTTTY 120 TTTGCTTTCT TTGTTTTCCT

TTTGTGCAGG

GAAGAGGGGG

CACGGACATG

ATAGCAGGCA

3S CTCACCCAGC T~.~ATAACTCA AGTTCCAAAT GGACCACAGC 420 TGAGTTGTAG GGGATGTGTG

TCTCAACAGG

ATTTCTTCCT

TTTGAGATGT G~L:AAGGAGAT GACTCCATCC ATGACTTGGC 600 CATTCGAGCT

AATGTTCCTC

CCTACATTTC

TCAGAYTT~G

AGACCAAGAA

AAATTGGAGG

TWATTTTAAG

GGCTCCTCGT

TCAGGAGTTC

WO 9815680a PCT/US98112125 S TTGAACCTGG GAGGCAGAGA CTGCAGTGAG CTGAGATCGT GCCACTACAC TCCAGCCI'GG 1320 (2) INFORMATION FOR SEQ ID NO: 34:

(i) SEQUENCE CHARACTERISTICS:

IS (A) LENGTH: 667 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 34:

ACCGAAGACT

CGGCTACCTG

TGAGCAGGCA

CCGCGGCATG

GGTGACGGTG

TCAGGACAGA GGG'IGTTZ'GT GGTGAAGAGG CAGAACCGAG 360 GTCGGGAGCC CATTGATGTC

CTGTGATGAG

TCGCCCACCT

GGAGAACAAG

TGATGTTCTC

C:F~RMMNIAAAA AAAAAAAAAA AAAAAAAAAA AAAAAAAAAA 660 AAAAAAAAAA AAAAAAAAAA

(2) INFORMATION FOR SEQ ID NO: 35:
SO
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 1710 base pairs ~. (B) TYPE: nucleic acid (C) STRANDEDNESS: double SS (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 35:

' 60 CTGAACTGGG CCCCCAAGGA

TGAAGATTGA GAGCTGCCAG

S AGGCTCTGTG ATTGGCTvCG GCACGATGAC CCGCGCACGG 240 ATTGGCTGCT TCGGGCCGGG

AAGAGGGTAC CCCCCGGCAG

AAACGGACTG GGGCCAAGAG

CGCCGCGCAG CACGGCCTTG

GGGGTTCTGC GGGCCTTCGG GTvCGCGTCT CGCCTCTAGC 480 CATGGGGTCC GCAGCGTTGG

TCTGATCCTG GCGTGCGGGC

CGTGACGGCG CAGACCACCT

GCACATGCAG TGCAAAGTGT

GCGGGCGCTC ACCGTGAGCG

GGGCGCGCAG TGCACCACCT

GGGAGGCGTG CTCTACCTGT

CAACATTGTC GTCCGCGAGT

GGGCGCANGC TGTACATCGG

TTGTGCTGCG GCGCCTGGGT

TCAGCGCCGC GGCGGCCCAC

CGCTGGGCAC GGCCGGGCCC

C'ICCTGCCAG CCACGCCTGC GAGGCGTTGG ATAAGCCTGG 1200 GGAKCCCCGC ATGGACCGCG

TCCGGCTCTG CGCCCCGACG

TTCTCCTGCC ACTAGCCCGG

CGCGGCGCTG TTTCCATAGG

GACGCTGGGG GTCTTGGCTG

CGGATGCAGA GCCCAGGGCC

CAGGCCCGAG CCCAGGGACC

_ CCCCAGGCAA GGCTTGTGGG

ATCTGCTTAG TAAATGGTTT

G0 (2) INFORMATION FOR SEQ ID NO: 36:

(i) SEQUENCE CHARACTERISTICS:

. (A) LENGTH: 1096 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 36:

lO GGCCAGTGGG CAGGGTCACA GGGCAAGGTC CCGCGGGCCG 60 CTGGGTGCGG CGACTTCCGT

AGTGTGGGCT GGGCCGCAGA

GCTCCTTATG TCACATTCCC

TGGTrCATCA GGGGAAAGGA

CGGGAGGATC GCAAGCTGGA

AAGGACAAGC TAGAATTT'GC

TAATGGAGGA CACAGGGCCC

TTGACAGAGC CCCAGAACCC

ACATCTAATT GGCTTTGTTG CTI'ATTCTGG CCCTTCCCAC 540 ACCACACAGC CACACAAATA

GAGGGGCCAG TGAAGAGGAA

CTGAGTTTAC TGGTGCACTG

C'IGGGAGGAG AGTTATGAGA TGAACATTGG CTGTCAATCT 720 CTGTGGGCAG GCGGTTTGGC

CTCTAGTGGG AATGGCTGGG ATTTGGGCGT 'IGCCTTTAGG 780 AGGGATACCT GCATGTCTAG

TTCCAGTCTG CACTGGAAAG AATTCAAATA 'IGCACCTGGC 840 TCCCTTCACT ATTTTGCCCT

TCAGGAATGG GATTCCCCCA

TCACTTTGGG GCAGGGACGA

TCTACCCCCA TCACTGTATA

AAAAAAAAAA AAAAAAAAAA

JO
(2) INFORMATION FOR SEQ ID NO: 37:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 2279 base pairs 55 (B) TYPE: nucleic acid ~ (C> STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 37:
' 60 WO 98156804 PCT/US98l12125 TGGCCGTGGG

CGGAGATTGA

ACTCGGACGA

AGTACGCGGT

CCGACAACGC

CCGACATTGA

AGGTGCGGCT

TGCAGGTGAC

GCeAGAGAAC AGGCGGAAGG TTCTGGGCAA GGCCCTGGGC CTCATTCGCT600 TCCCGCTCAT

ACCGCGAGGT

CATTGACCGG

GGT'GGAGAGT

GCGCATCTTC

GT~vG'I~GGAT TTGGGCTGTA TGGATCCATC CACGGGCCCA 900 CCGACTACCA AGTGAACATC

CTTCAGCTGC

GCTGCCCAAC

CACCAAAGGC

CACCTTTTGC

CGAGGTCATC

AGCCGCAGCC

AGTGTCCCCC

CCCTGTGTTC

GTGGCCAGGC

CCAGGGCCCA

GCGGGCGTCC

TGCTAGGAGC

S CTTTTGTTCC

CAAGCCCAGC

GGATTCAGTG

GTTTGCAGTG

CTCCCTGGAC

S GGCCCTCGCG GTCCCTGCAG CCCAAGATvG GACTCAGACC CTGTGCCCCA1980 GAGCTCCCCT

CGCCTGTACA

TACTGTTGCC CTAGCCCACC TGGTu~CCGTG GGAGCCACCC 2100 CCAGGTGCTG GGGCACAGCC

lO

GACTCCTGGA

CCCCAGATGA

AAAACTCGA

ZO (2) INFORMATION FOR SEQ ID NO: 38:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 745 base pairs (B) TYPE: nucleic acid ZS (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 38:

GACGCTAACA

CCACCCCATC

TCTTGCCCAA

CCTGGCCCTG

GTGGCCAGGA AAGACCCAAA AAAGAATGAG ACGGGGGTGC TvAGGAAATT300 AAAACCCGTC

AGAATACAAC

CCAGCTTCAG

GTCACAAATC TTCT~GAATA CCTTATTGAT GTAGAAATTG CCCGCAGCGA480 TTGCAGAAAG

AGGAAATTAA

ATGGAGAAAA

CTACTTTATC

CATGAAAATG AAGCAA'IGGT CAGGTGGGAG GCTCTTCCCA 720 ATGTvCTTTC TTCAAAAAAA

AAAAAAAAAA P,AAAAAAAAA CTCGA 745 (2) INFORMATION FOR SEQ ID NO: 39:

(i) SEQUENCE CHARACTERISTICS:

!A) LENGTH: 1718 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double S (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 39:

CTGCAGAGTT

GCCATGTCTC

CACACGCAGG

CCCCTGGGGA

CTGGAGAGGG

TCTGAGTCAG

CGCTGCATCT

TGAAAGAAAC

CCACGCAGAG

AAGCTGAGCA

TCCTGGTCCT

AGGACGAGGA

CAGCAGACAA

CCCTGGCTGC

CACAGAGGAC

CGTATGCAGC

CGTTGCCAGA CAC'IGACCCC ATACCCACCT GGCCTCTGCA 1020 CCTGAGGGTA GAAAGTCACT

CTAGGAAAAG CCTGAAGCAG CCATrTGGAA GGCTTCCTGT TGGATTCCTC1080 TTCATCTAGA

4S AAGCCAGCCA GGCAGCTGTC C'IGGAGACAA GAGCTGGAGA 1140 CTGGAGGTTT CTAACCAGCA

TGGACAGACT

GTI~CTCAGT TATTTCCAGA GACCCAGCTA CAGTTCCCTG GCTGTTTCTA1260 GAGACCCAGC

s0 TTI'ATTCACC TGACTGTTTC CAGAGACCCA GCTAAAGTCA 1320 CCTGCCTGTT CTAAAGGCCC

AGCTACAGCC AATCAGCCGA TTrCCTGAGC AGTGATGCCA CCTCCAAGCT1380 TGTCCTAGGT

SS GT~2GTG AACCTCCAGT GACCCCAGAG ACTTTGCTGT AATTATCTGC1440 CCTGCTGACC

TAATtTrGAA

GGCC2'CACAT CTGGCAGCCC CAGGCCTGGT CCTGGG1GCA TAGGTCTCTC GGACCCACTC 1620 TC'I'GCCTTCA CAGTIGTTCA AAGCTGAGTG AGGGAAACAG GACCTACGAA AAAAAAAAAA 1680 IO (2) INFORMATION FOR SEQ ID NO: 40:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 1966 base pairs (B) TYPE: nucleic acid IS (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 40:

GGGGAGCGGG

TCTTGGCTTA

TTTGCAAATC

TTGCAAGATG

GAGGGC'IGCA GGTGGTGGAA AAGCAGAACC TTAGCAAAGA 300 GGAGCTGATA GCGGACTGCA

TCATCAACGC

TGGATCTGGA

GGCCGCAACA AC;GAAGGGCA TCTTGGTTAT GAACACCCCC 480 AATGGGAACA GCCTCAGTGC

AGGCGACGGC

TGAATGGAAA

GGATGCAGTC

CGGCCTCCIT

TGGTGTTCAG CAGCZGCCCC TGGAGGAGAT CTGGCCTCTC 'IGTGATTTCA780 TCACTGTGCA

CACTCCT~TC CTGCCCTCCA CGACAGGCTT GCTGAATGAC AACACCTTTG840 CCCAGTGCAA

GCGCCCTGCT

CGGAAGAGCC

GCCACGGGAC CGGGCCTTGG TGGACCATGA GAA'1GTCATC 1020 AGCTGTCCCC ACCZGGGTGC

TCGTGGACAT

SS

GTGCCTTCTC

TGCGAGCCTG

E)O GGCTGGGTCC CCCAAAGGGA CCATCCAGGT GATAACACAG GGAACATCCC1260 TGAAGAATGC

CCAAGCAGGC

GGATGTGAAC TTvGTGAACG CTAAGCTGCT GGTGAAAGAG GCTGGCCTCA1380 ATGTCACCAC

S

TGGCCGT~vGC

CTGTACTGCA

lO GGGGCTCAAT GGAGCTGTCT TCAGGCCAGA AGTGCCTCTC CGCAGGGACC1560 TGCCCCTGCT

GCCTCCTGGC

GGGAGACCTG

AGCATGTGAC

CTGGC;GCTTT

TTGGGCTGAA

ATAACCGTCT

(2) INFORMATION FOR SEQ ID NO: 41:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 972 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double 3S (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 41:

TuCATCCTGG

ACCCTGTvCA GGTGAAGATG TCCCGACCCA CGCATACTCC TCTTTCGCCT220 GCCACCATTT

GCCGCCACCG

GACAAATCCC

AACTACACCG

ACAACCTGCC

SO

GAGCGGGCCT

CCACCACCCT

AGGTCTGAGC

TGTTGGACGA

CCTCCCAGCC

TCCCACTCAG

TGAAGCGGCA

CCACCTTGAG

GATGTGGGGT

G'IGGGGC'.AGG GCA'IGGAGGG AGAGGAATAA AGAGAAACAG AGTCCAGGAA960 P~AAAAAAAAA

IO

IS
(2) INFORMATION FOR SEQ ID NO: 42:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 1536 base pairs 2O (S) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 42:

GTATGTCCTT GTGTGTACCC

GTCTAATCCA GGTGGATCAG

3O GAGGTGCTTT GTGGTTT'1"IT TGCAAAGAAA TGAAGTCT'GG 180 CAAGCAAACA ATGATTAAAC

GTGGGTGTGC ATTCTTGAAT

TCTT'CTAAAT ACTCTCTTTC

CAGCTTTTCT CTCTCCTCTC

CCTCTTTCTT AGATCTTTAT

CCATTGCATC CCCTACCCGA

AGAAATCCTC CZ'CCCTTASA

TAATCCTTGT CCCTGTTACA

CTATTTTCCA TCT'CTCCTAA

ATTGATGTTT TTTGGAGGCT

GCTCTATTTG TTAAACAATG

GAGGGCTTTG TTCCGCTTTT TTTTTTTTTT TTWT"TCNn'AA 840 CCTGAGCTTT CTGCCCACCC

TTGGTGAGAA GAGTCACTTC

SS

AGAAACATGG GTGCAGTGTA

AAGGAGGCAG CTCYTCGGGG

YTCCCAGGGA CCCCAGAGTG

CTTT'I'CTCAG

GTGTTNTGGA

S

CAGAGACCCA

TCCACATGTA

GTCTCTTAAG

TCACCAGTTT

TATCTCCTCT

(2) INFORMATION FOR SEQ ID NO: 43:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 2541 base pairs 2 (B) TYPE: nucleic acid S

(C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 43:

TTTTGTGCAG

ATCTGCATTC

TCAGTTAACC

GGAAAGGCAA

GACCCAGCTG

AGTCTGGGAC

ACCAGTTCCA

AAAAGAAGAC

TTTGTTGGGC

CCTAGAGAAG

SO

AAAGGTTGTA

CCTGTTTCCG

CTCCATTCTT

TCACTGTATG GATCCCAGAC GCYTC'.AAATG CCTACTCAAG 840 CAATGTTCAT GGCTCCCGCT

TAACAGCATA

AGCCAGGAGC TTCTGGGATG

GT'rGCCCCCA TGGCCA'i'GCC TGCAGGCTAT ATGGGTGGCA 1020 TGCAGGCATC AATGATGGGT

TGGCAGGCAT GGCAGCTATG

' CCCCAGACTG TGTATGGGGT CCAGCCAGCT CAGCAGCTGC 1140 AATGGAACCT TACTCAGATG

GCATGATGAA CTATGGACAG

TCAGTCCTCA GATGTGGAAA

CTCGCTCTCC CCTTTCCACA

GTTTGGTTTA GAAATTGCTC

AATAAGTCAT TTuGGGTTTG GCATCCTGCC CAGCCACTTC 1440 CCAAACATGA AGACCTCTCT

CCTCCCCAGT CCTCTCCTGG

TGTGGGAGAA GTGTGCACAC

CTATATGTGT TAATAAGCTG

ATTTATGGGA ATGAAGCAAG

TTTGACCCTA GCCCTGGGGT

TCTCTTCGCC CTGAGTTGCT

CTTTATTAGC ACCAAAGACT

TCCCCCCTGC CTTCAGTAGG

ATGCAGAGCT TAACGTGTAC

TGCTIGTGTG T"T'GCGTGAG TGTGTGTGTG TGTATGAGTG 2100 TGTGTTCCGC CTCCCACCCT

TAGGTTTACA ACAGAGAGGA

TGGTTTAAAA AACGCCATGT

CTGATCACTC TTTCATGCCT

GTGTATCCAG GGTGCTCTGT TT'CCCCACCG TTCCCAGGTG 2340 TACGAGGCAG AGGGCCGGGA

CAGACAAGAA AACTTTGCTT

SO

TTCTCCTGTG TATGTGTAAA

AAAAAAAAAA AAAAAAAAAA

SS F~AAAAAAAAA AAAAAACTCG A 2541 C70 (2) INFORMATION FOR SEQ ID NO: 44:

ti) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 2418 base pairs tB) TYPE: nucleic acid tC) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 44:

lO CCCACGCGTC CGCCCACGCG TCCGCCCACG CGTCCGCCCA CGCGTCCGGG60 ACTCAGCGAA

CGCCCGGCTC

ATTAAACTGA

AAACAGAAGG

CAGCTCTCAC

TTGACCTGAA

GCGAGGTGGC TCCTCAGATG ACCGGCAAAT 'IGTGGACACT 420 CCACCGCATG TAGCAGCTGG

CCTTAGCTGA

CAAAGAGAGG

GAAAAAAGGC

TCTGATGAAG

CGGACTGCCA TTGCCCCACC

AAGAGGACTC

AGGAACAAGA

GGGGCACGGT

GGAAGCATGA

GCAAGATCAT

GAGGGAAAGG

CAGGGGGACA

CAGGCCGTCC

GGCTCATCTT

GGTGAGAGAC

GAGCATGAAG

AGGTCGTCTC

CAGATTGTTT

GTTGGTGTTT

WO 98/Sb804 PCT/US98I12125 AGAGACAAAC

CTTCCTTTGC

TAAAGAAAGA AGAAAACTTT TCTGGCAGCC CCGTTCATGC ACAGCTTAGG1?40 GATACATCAC

TACTTAAGTG

ATGAAGACTT

TGTGTGATAT

T'IGAAATTCC TGGTGCCCCT GATGATGAAG CAGTACGGAT 1980 ATTTTTAGAA TTTGAGAGAG

IS

TTGAATCAGC AATTAAAGCG GTTGTTGACT TGAATGGGAG GTATZ'TTGGT2040 GGACGGGTGG

Ti:AAAGCATG TTTCTACAAT TTGGACAAAT TCAGGGTCTT 2100 GGATTTGGCA GAACAAGTTT

GCAGGCTGAG

TTGGAAGGAC

ATAGTATAAA

TTTTATTATT

GCTTCAATGA

3S (2) INFORMP.TION FOR SEQ ID NO: 45:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 1337 base pairs (B) TYPE: nucleic acid 40 (C) STRANDEDNESS: double (D) TOPOLCh~"Y: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 45:

CTuCGGCGGT GGGAAATGCT GGCGCGCGCG GCGCGGGGCA CTGGGGCCCT TTTGCTGAGG 120 JO

CCTGAATGCC

CCTCCGTTAT

GCAGGTGGAG

GTCGGCCATC

AAAGGCTGAA

GGCTAAAGCT

AGCAGCTTCA

CTCCAACACT

CATGGGTGTA

CAGTGGGAGC

AGTCAAGATG

TTTCCTGATT

CTTTAGTCGT

GTP_ATAAACT CACCAGTGGC AAACCAAAAA AAAAAAAAAA AAAAAAAAAA1320 AAAAAAAAAA

~~~1.~AAAAAAA AAAAI~INN

(2) INFORMATION FOR SEQ ID NO: 46:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 1276 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 46:

ACTTCCAATT

ATTCTGTTGT

CTGARTTCAR

SO GTCCTGGTAT CTCARTCTTT ACTGTGARTC 'ITCAAATGAC ATAAGAATGA240 CAGAAMTTGT

GTGTCTTCTT

TACTACCTGA

SS

TG'IGGCCAAT TGGACTAAAA CCAATAACCA TTAAGGAAWA AATSSACTWA420 ACCACAAGCA

GCCAACAAGC

ATCAAAATGA

ACATTAACAT

AATAGTGCAG

S

ACCAGAGAAC

TYCTAACAGA

AAAACAACTC

GGGAATATTA

AGCCTCAGAA

CCATTATATG

GCTTAGGGCT

GGTGAAAAAT

ATTGAATTGT

CTGTTTTTTA

(2) INFORMATION FOR SEQ ID NO: 47:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 1282 base pairs 3S tB) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 47:

TGGTAGAACT

GCTT'I'CCAAG AATGCTGTCA CTGCTATAGT TTTTAATGCT 120 TCAAATCTCA ACTCNCTCCC

GTTTTYTCTT

CAATTGTTTA

CTATTTATGC

SO

TTTATAAAAA

ATATATGGAT

ATGGAGGAGA

CCATCTCCAA

ACACTATTTC

AATGAATTWA

TGGAAGTWAC

ACTATGGAAT

AGGAAACTTA

ATGATTTCAA

GCTAGGTGCA

TCAGGAGTTC

AAATTTAACT

GGNGAATTGC

NTCCAGCCTG

AGAANGGAAG

(2) INFORMATION FOR SEQ ID NO: 48:

3O (i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 645 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 48:

TGGCAGATTC

GATACTTAAA

ATTGGCATTA

TTGTGCAGCC

ACTCACAGAC

TGAGCCTAGG

GTGAAAAAGT

GATCACTTAA

CCTGGATGAC

SS

CAAAATTCTA

AAAAAAAAAA AAAAAAAAAA F,AAAAAAAAA F~~AAAAAAAA 645 AAAAA

" (2) INFORMATION FOR SEQ ID NO: 49:

S (i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 1495 base pairs (B) TYPE: nucleic acid (C) STRANDEI7NESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 49:

CTGATTCCAG

AATTTCACTT

CTTTTGTTAT

TTGGATGGCA

ACAGCATCCT

TAAAACTGCT

AACATTTTGG

ATAGCAATTC

TGCTTMCATT

CYTTCYTTKT

TTCTTAAGST WT'PTTTCAGT AGCAAACAAG GCTGTTTTCA 660 TCAATACCCA CATTCCCAYT

3S CRGKRRGRMM ATYTAGTYTT YTCCCAGKTT AAKTGKGRGR KGGRKGAAAA?20 TRATKTCKGG

TTCCACTTTA

GCTTTTCAAC

TGGGTCTAAT

TACTYCCTAA TTTAAAACAC GTATTTT'I'TT AAATAGCATG 960 TTTATTTTCA AATATDATAT

ATATAATGTT

CAAAW~TKAG AGGTAAGGAC TTYCCTTTCT GTCTYCTTAA CACTTWAGTA1080 AATRATTNGA

GAAGGGCTTT

TTTTTTTAAG

TTCCAGGATG

TTAAAATATA

GTAATCCTAG

CCAGCCTGGG

CCAAACGGTG NAACCCTGTT TTTACTNAAA TACCCAAAAA F~P.AAAAAAAA AAAAA 1495 S
(2) INFORMATION FOR SEQ ID NO: 50:

(i) SEQUFI3CE CHARACTERISTICS:

(A) LENGTH: 1630 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 50:

TTAGTATTGC

TATTGTCTTA

2O ATGGGGGTCT TTT'AATGACC AGAAGTTCTT AGTTTTAAAA TAGTCCAGTT180 TATCCATTTT

AAGGTCACAA

GCAGCTCATC

TCATATGGAT

ATTTGGACTG

CTCACAGYTC

AGGACCCACT

TTGTGNT'I'CA TAGATGTCAC CTTCTTGCTG TGTCCCAGTG 600 GTGRAAGGGG CAAACTAGCT

CCCTAATGAT

ATTTGGGGGA

GCTGCCTTCA

TGTCCTACTT

CATCTTAATT

CAGGCTGGAG

TGCAGAGGTA CAGTATTGGC TCACTGCAAC CTCI'GTCCCC AGGCTTAAGC1020 AATTCTCATG

TTCTTTCTTT

GCTAAGATTT

CCAGTuCTGA ATAGGAGTGA TGACAGTGGG CACCCTTGTC TTTCTCCCAA1200 CCTCAGAGGG

SS

CTAGCGGCTT

TTTCCAAATA

C)OCTTTTTCCAT TGAGTT'T'I"I~' TACTTTAACC GTCATATTGC 1380 CAAAAGTCTG CATTTGTTAT

S

CCAAAAAAAA F,AP~AA ACTCGAGGGG GGCCCGGTAC CCAAATCGCC GGGTAGTGAT1620 IS (2) INFORMATION FOR SEQ ID N0: 51:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 2420 base pairs (B) TYPE: nucleic acid (c) sTRArmEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 51:

TCAGGGGGAC

TTTTGTGAAT

GGTCAGCACG

ATGCACCACG

TACTTTCTGT

TAT'IGATGCA

TACTGGAGAG

AGCAACATGC

ATCTGCTTGT

CTGCTATGTG

CTGTGCCCAG

CGTGGGCACC

GGAATATAAT

TAATGGCTAT

GGATCCCTGC

TGGCACGTGC

ATGTGACAGT

CTSCCACTGC

AGCCCTCTGC

CAGCCGCATT

CAGCATCGAC

GAAATCCCGG

TGACAAACCC

TTTCAAAAAG

IS ATGAGATACT ACACTCATTT AAATATTTTT AAGAAANlI'AA 1560 AAAGCTTAAG AAATTTAAAA

CAGCTTTTAG

TTTAATGTAC

TAGACACTAT

GGAGAAGTTT

TAACGTAGCA

TCGTTTTGTG

TTGCCTTATT

GAAACATTCT

TTCGAGTTTG TTTZ'I'GTCAT TTTCGTAACA GTCGTCGAAC 2100 TAGGCCTCAA AAACATACGT

TCTTTAAAAA

TTGCTAAGAG

AGTGCAGCTT

TATITATCTC CAGGATGTTT TTGTu~GCTGT ATTTGATTGA 2340 TATGTGCTTC TTCTGATTCT

TGCTAATTTC CAACCATATT GAATAAATGT GATCAAGTCA P~AAAAAAAAA2400 F~AAAAAAAAA

SO (2) INFORMATION FOR SEQ ID NO: 52:
(i) SEQUENCE CHARACTERISTICS:
(A} LENGTH: 1172 base pairs (B) TYPE: nucleic acid SS (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 52:
6O AAAATTATTC TGTACCATCA CAGCTTTTCA CAACGATGGC AAGCCTTATG TCTT~vGGAGC 60 GTGTGTCTCT

CCTGGGGTGG

S

CAACCCTCAT

AATCAGAAAT

TATCTTTTGT

TSTTCATGAA

TGCTGCTCAG

GCAGAAAGAT

GCTCCAAGAA CCAACACTAT CAATGTCTT'I' GCAAATCCTC 600 ACAGGATTCC TGTGGGTCCA

CCAGCTGCCC

CTCCTAACTC

GGGGCCAGGG

TCTTTGTTCT

CTCTGTATCT

CTACATTCCT

ACTGGTGTCT

GTCTGTTTAG

CTACAAGAAA

(2) INFORMATION FOR SEQ ID NO: 53:
4S (i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 1589 base pairs fB) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear SO
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 53:

GATCAGACAT GGCCCAGAAC TTGAAGGACT Tv~GCGGGACG GCTGCCCGCC GGGCCCCGGG 240 GGTGTGCGCG

ATCGGTGGAG

TTCCAGTACC

GGCTCCAAAG

CAGGAGCTTC

TCCATTGTCA

ACGAGG'IGCT CAAGAGTGTG GTGGCCAAGT TCAATGCCTC ACAGCTGATC660 ACCCAGCGGG

TTCAGCCTCA

GCTGCTGTAG

GAAAAAGCAA

GCCAAGATGC

CGAGCAGCCC

GCTGACAACC

ATCAAGGGTA

CTTCTCCAGT

CATGCGATGG

CTAGCCCCTT

CAGTGCGTGA

GATAAACACC

TCACGTGTTC

TGGGTCTGTC

GGGAAGCAAG

SO (2) INFORMATION FOR SEQ ID NO: 54:
( i ) SEQiJENCE CHARACTERI STICS
(A) LENGTH: 2074 base pairs (B) TYPE: nucleic acid 55 (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUE~1CE DESCRIPTION: SEQ ID NO: 54:

YTCCTGCTGC

ACCGACGAGC

S

AGGGCGGCGG

GACGACTGTG

TTGGGCCAGC

CCTAGAGGGG

CGGCTGCATG

IS

GAGACGCCCC

AAGAACTTCG

TGTGTCAGGA

AAGGAGCAGC

ATCTTCGATG

GAACGCCGGG

AGTAATCTCA

TCCCGGGAAG

ACCATAGACA

ATCCCCTTCC

AGCCAGGAGC

GTCCCCAAGG

4O AGGAACAACT CTTTT'CTTCC CAGGGCTGCA AGTCTATTTC CCAGAGGATT1260 AACTACTTCC

CAGGACCCTG

GGACCTGTAG GAGCACCCCG T'ITGGGACTG TGAGGTGTTT GAGGGTGTGG1380 ACTGGCATCC

TAGAAGCCAA

GCCAATCCTT TTTCTT2'I"I'T TTGGAGGTCC CACCGAGATA 1500 GATAGGAACT TGGATTGCTG

GCATTCCAAA

GGAGCTCAGC

GCTCTTCTGC

- SS

AAGGAAGAGC TTGGGT~TTA GGCCTCAGAG GCTGTAGGGT CCTTGGGTTA1740 CAGAGCCGGG

GAGAACGAAG TTCTG'IGACC CAGGGGTGGA GAATACACTC TAGGTTTGCG1800 GGCTGGTGGG

GO CTT'I'CAAATT GGTACTTCCA GAGGAAAGCC AAGCTGCTTC 1860 TGTTGTGAGC GAATCAGCCA

WO 98156804 PCTlUS98/12125 CAGGTCAGTG

TCAAAGACAA

S

TTTGATTTTC

CTAAAAAAAA A,AAAAAP.AAA AAAAAAAAAA TTNC 2074 (2) INFORMATION FOR SEQ ID NO: 55:

IS (i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 1483 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 55:

AAATCGCTTG

TGCAGGCASC

AGAACATTGG

AATCACAGCT

TAGTAAACTC

TGGAGACTCA

TATATCTTAG

GTTTCTATTT

GATCATGAAA

GTTCATGCTG

ATTTTTCTAT

4S CTCTCACTTC TCAGGGATGA AATTCTTTTT CAAAG'I~TTG AAGTTCCTTG720 CAACTTAGCC

AATTACTGCA

TTAATTATTT

SO

AATATTCTCT

CATTCTTTCC

TCTACAGATT

AAAAAAAACA

CTGTACTACC

TGAGATTGTT

(2) INFORMATION FOR SEQ ID NO: 56:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 1123 base pairs 2~ (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xil SEQUENCE DESCRIPTION: SEQ ID NO: 56:

CAAAAATAAT AATAGTCATC ACATTTGTAT AGCACTGGGT CATT'TTTCCC60 AAGACCATTT

AGTTAC'T'fGA CCTCAGCTGT TGTCCAGCTT CCAGTCTTGG 120 GGTAATGGCA GCTTAATAAT

3O C~GAAAATTG CCAAGAGAAA GATGTGGAAG GATGAAATGG AGGCAACATG180 AAT'I"i'CTGTC

ATATCTTCTG

GTAGCTTTTC

CATTTCTGTC

ACCTATTTTA TT'I"I'GTTGTA GCACCCATAA TAGATCAGCT 420 GTCACAGCCA CAAATCTCTG

GGTTATAGTC

CTGGCTTCTT GAGAGC'ITGT CTGGAGGTTG TAGCAGGGGA GCACAGCTAG540 TCATATACCC

GAGCTTGCAG

CTT'~GGGAGG GACGCACATG GAGTGGTGAG GGAGGAAGGG GACACCCGCC660 TAGCCAGCCA

AGATCGCCCT

AGAAACTGTA

GCACTCATGT

CATCTACTAT

ATGCCATGCA TTGTGC'I'GAG TATCCATGAT GCTCAGGTGA 960 ACGGGACATG GTCCTGTAAA

TTGAGGCAAG

CCTTCACGAT

(2) INFORMATION FOR SEQ ID NO: 57:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 1239 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) OPOLOGY: linear IS (xi) SEQUENCE DESCRIPTION: SEQ ID NO. 57:

TAACTTAAAA

TGCAATAGGA

CTATGGAATG

AAGTCTGCTT

AGATGAAGAA

GAACATAATG

TTTAGAAAGC TGCTACTTTT TTCAAGATGC ATATTGAAAT ATGTNAWGTr420 TAAGCTTAAA

CTNGCTCTTT

TTTTTCAAAC

TACTACCACA

ATTGCCCTAA

CTTTTAACTT TCACAGTTTC C'IGATTCATA TTTGCCCAGG CTCTGATGCC720 TTGAATTGGT

TCTCTCATTA

CCCTTACTAC

ATGAAGTATC

GCCCCCTAGC

CTAAGGAGTG

TCCCATTTCT

ATTAGGGTAA

TCTATTTCTG

t (2) INFORMATION FOR SEQ ID NO: 58:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 803 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear I0 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 58:

TGCCAGGACC

TYTGACGACG

CCCCAGACGC

A~.AATGCCCG TGACCAGTGG CTGCAGGATG CCTTCCACAT CAGCCTCTGA240 AGGGCTGGGG

AGCCCTCAGA

GGCATGTATT

ACTGGGGCGG

GCATCTAGGG TACAGCCTCT GCTCATvGCA CTGGGCCTCC AGTTCTTCCA480 CATGTGTGCA

CCTTCCGCTT

TTTGTTGCTA

TGCCCTGGAA

CCGTGCTGGA

TCAGCGTCAA

p~ ~AATT 803 (2) INFORMATION FOR SEQ ID NO: 59:
4S (i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 995 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 59:

TTTAACTTTT TT'M"I'TTCCA CCTACAGCAG CTGTTTTTAC CCTGTGGTCA GTCAGGTACT 18O

AATGTCTCCT

TTTAAAATGG

GTAACTCCAC

CATCATGTGA

TTAAAAAAAT

TGATGCAGAA

GCTGTAAAAC

TTTACTTCTT

CCGTCTGTT'C

ATGCCTGAGG

TTCTTTAGGA

ATTTAATAAA

(2) INFORMATION FOR SEQ ID NO: 60:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 966 base pairs (B) TYPE: nucleic acid (c) sTRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 60:

TGCCAAGTTT

CACTTTGTTA

AGCAAGAGGA

AGACATTTGA

GAAATTCTTT

TTCTGTATGT

E)OATTAGCTGTG TCTGTCTATG ATGCAAGTAA CTCTCCTCCT ATTTGGGGGA660 TAGTTCAGAG

WO 98/56804 PCTlUS98112125 S

TCTGTGTGAA TAAATGTAAG ACGGTGAAAA AAAAAP.AAAA AAA AAAAAAAAAA960 (2) INFORMATION FOR SEQ ID NO: 61:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 262 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear ZS (xi) SEQUENCE DESCRIPTION: SEQ ID N0: 61:

(2) INFORMATION FOR SEQ ID NO: 62:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 753 base pairs (B) TYPE: nucleic acid 4S (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 62:
SO GGCACAGGTT CTTTTGCCAG TCA'IGACAGA ACCATGCAAG ATATTGTTTA CAAATTGGTA 60 ' SS

E)O TATGGATCGC ATGTTTAGCA CATGGGAMCC CCAGGGNTCA ACGCAGCTCC TGCCCCTCCC 360 CCTCATCCCA

GCTGGTGTTT

S

ACCAAGTAGT

ACAAATACCC TvAAAGTGGA AATCGGTTGC TTGGGGATCG CTCAGCTGAA600 AGCTCCCCCA

AAGCCCAAGG

CTCCATCCAN

IS

(2) INFORMATION FOR SEQ ID NO: 63:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 739 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double 25 (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 63:

GAATCAAGTT

ATGATTTATA GAGGATTCAG CTvGAATACC TTGTGGGTGC TGGCTGAGGG120 TGGCAAAACG

GGGTTGGCCT

GAAGCTGCAA

TGGCCTTGGC

ATGTCAGACT

CATTCTCATT

ACAGGAAGCT

GGTCTTCAAA

TGACTCTGGG

GCTCTATT'TT

GGGT'IGAGGG TCCTTCCTCC TAACTTGGTG AATCTGAATT TCCATCAGTC720 ACTTACTGAG

(2) INFORMATION FOR SEQ ID NO: 64:
6O (i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 476 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 64:

GAATZ'CGGCA CGAGAGGACA TGGATTATGG GTACTACTCA GCAGGCCAGT60 TTTTACTCCA

CTTCTGAGAA

GCTCTTCTTT

CTGAGTGTAC

IS

CTGCTTNCTT

CCTCACCACC

AGGCAGGTGT

ATGACC

(2) INFORMATION FOR SEQ ID NO: 65:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 754 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 65:

TTTCTAATGC

AGACAAATTA

GAGTAGAAAA

CACTCAACTG

4S AGCCTCCCTT CCTACTAAGA ATvGAATAGT GTTGCTTATA GGGGTGTTGG300 TCCAAGTATC

TAATCTTATG

ATTTTGAAAC

TCGCCTGAAC

TCAGTGTTAT

AAAAGTCAGG

AAAATTTAAC ACCCAGTTCC ATTTTTC'sAAC CCATCCTGAA 660 ATTCCAGGTG TTCATTCCAT

P~AA

(2) INFORMATION FOR SEQ ID NO: 66:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 1890 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 66:

IS

TTGGCATTAC

TTTGTTATGT TGT'IGATGGG CAGAAACCCA AGGKGGGGTT TTKTTGAGCA120 TAAACACAAG

GTATATAGTA

ATTATCTTTA

TGGATTCAMC

ACTGTTCTGT

GTTTTGATTA

GCTGATGTAA

AGTTGTGGAG

TGCATGATAG

GGGGGCGAAC

TGCTGTTTAC

AAAACCATAG

TCTACAGCAA

GACAGTTGTA

TTTTATCACC

AAAAGGCATT TTAATTTTGC ACACTTTAGA WTTCI'TACAA TGTGTAATTG1020 ACTGCTAGTT

TGAGTGTAAT

ACAGATGCAC AAGTvACTGG TTGATAATGG AATGAGACCC CTTATAAGAA1140 AGACATACAG

GCCTCTTATA

TATTTGAGCT

CAAGACAGCC

AGAGAGTTAG

CAAAGGGAGT

ATCTCTACAG

S

CTTGTTAAGT TTCWACCCGT C'I'rTGGGTGA CTGAAAAATT 1560 CAAATGTAAA GATGTGGCAA

TTTTCCTAAA

' IO TATCCAACCA TTTAGTCTTT CATAAGCTTT TAATTCCACT AGCCTCACTT1680 TCTGAGATTG

GAGTATAATG

ACCTTCTTTA

AGCTAGGTGT G'M'TGTCCTT TATTAAAGTC AGTTTGACCC 1860 AGCCTGTACA ACATTGCAAG

(2) INFORMATION FOR SEQ ID NO: 67:

ZS (i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 1614 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 67:

AAATAAGACN TCI"ITGAGCA GCGATTGCTG GATCATTGAT 60 C'IGTTTGAGG AATGTCTGAC

GGAGAGCCCC

AGGGCACGGG

GGCCTGGAAG

TCAGCAAAAC

CTCCAAGGTC

TGCATTGGGT

AACATCAGAC

GGAGAAAGCA

SO

AAAGTAATGA

CCAAAACTGA

TACAGTGAAA CAATTAAGGT GAGCAAATAG TTTTRACTTT TCTTTTTT'I'T 780 TTTAAGTTTC

GGCAAAACTG

ATATTATCTG

CCATGCCTGA

TCTCTCATTC

ATTTTTAATG

CATAGACGCA

TACGCATGAT

TAATTTAAAT

CCATGGTGTA

TAATTTTTAC

GGTGTTGGGA

TTTGCTGGAC

GTTT

3O (2) INFORMATION FOR SEQ ID NO: 68:
(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 596 base pairs (B) TYPE: nucleic acid 35 . (c) sTRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 68:

TATTCAGTTT

TCTGCTCTCC

ACTCCTGCAA

CTGTGGTTTT

TGCATTAAGC

TATATGTGGA

CAGGTTCTAA ACTCTATATA TACATATATA TATATATATC TATATA'FCTA420 TATACGTAAT

ATTTCTGAGA

GACTATGTAA

ACTCGA

(2) INFORMATION FOR SEQ ID NO: 69:

S (i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 1524 base pairs - (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear , 10 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 69:

TTCCAGCCCA

IS ACATTTCCCA GGGAAAACTT CAGATGTGGG TGGATGT'I"II' 120 CCCCAAGAGT TTGGGGCCAC

CGTGTGATCA

GAAATGAGTG

ACAGATGTCC

CCGTTTGACT

AGTATTGACC

GACAAGTTTT

CTCTGGATGA CTACTTGGGT TTCCTAGAAC TTGACT~CG TCACACGATC540 ATTCCTGCAA

AACCCCCTTA

AAGCCAAGAC AGCCTCCCTC TTTGAGCAGA AGTCCA'IGAA AGGAT~vGTGG660 CCATGCTACG

GAAATCCTCA

AACATGAACC

AACCCAT'GCA

TTGCTGTTCC

TATTTGTCAA

AGTCATCCAG

CTGAGACCAC

GGTCTTAGTC

ATTAAAAGTT

TGGTTCCATT

AAATTGCTAA

ATCAACTGAA

' AGAGCTGTGC ATTATAAAAT CAGTTAGAAT AGTTAGAACA ATTCTTATTT1440 ATGCCCACAA

CCATTGCTAT A?'TT'I'GTATG GATGTCATAA AAGTCTATTT AACCTCTGTA ATGAAACTAA 1500 (2) INFORMATION FOR SEQ ID NO: 70:

lO (i) SEQUENCE CHARACTERISTICS:

(A} LENGTH: 819 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear ixi) SEQUENCE DESCRIPTION: SEQ ID NO: 70:

CAGGGGNTGG

GACGGAGACC

GTTACAATAA

ACACCCCTCC

CGCTCAGCGT

GGTCTCAGGC

3O CCACAGACGT TCCAGAGGAG GAGGGTGACA TTTTTACTCC CTT'II'TGGGG420 CTAACCATTT

GCGAGGGGCG

GGTTTCTGTT

TACCTCTTGT

AAGAACTAAA

ATTACTGATT

TATTTTTTGA

(2) INFORMATION FOR SEQ ID NO: 71:

(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 1442 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 71:

b0 CTGTACTTGT

CTGACATTTG

TTG'I~CGTGT

CTTCTCTAAC

TTTCTATTAG

. 10 TTCTCTACTT

TCTGGAAAAG

~S TTCTATTTCA CAGGCTTTAA TCTCTCCTAG AGTAGTTAGC ACTCTTTTGT540 GGCTTTGTGT

ACACGTCCAT

ATAAATTCAG

TTCCATACAG

CCAGTGAAAG

TTTCTTTGTT

AGTGGAAAAC

CCACTATTTT

TTTTTTCCTC TGTTTTTATT

TCATTCTGTC

AATCCTGTGA

GATAACTCAA

ATGGACAGAG

TAAGTTTAGA

CATGGATGCC

4S TTGTV1TI'AACA CATTTCACCT TT(:TGGTAAA AAAAAAAAAA 1440 AAAAAAAAAA AAAAAAACTC

SO
(2) INFORMATION FOR SEQ ID N0: 72:
(i) SEQUENCE CHARACTERISTICS:
SS (A) LENGTH: 1223 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear C)O (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 72:

GGGGCTCAAG

A~1GTCGGCAT GCTGGGCATC TTAGTAAAGA CTGGGAAATA TCGAGCATCA120 GATGAAGAAA

S

GACCACATTC

AGCTTCTTAT

GTCAGTGCTG

GAATTGCGGC

TAGCCAGTAA GCCTTGCTAA TCTCTTTTAT TTTGTAACTG AAGAT~vAGAC420 CCAAAGAAAG

TGGGGCTGTG

GGC,GAAAAGC TACTACAGGG AAGAGTGTTC TCTGCTGTCT CTTCACTGGA540 AAACAGGGAG

2O GGGGGATTTC AGACTuTGAA GAAAGTTGAA TGGT~vGTTTT TAAATTATAA600 AGTAATGTAT

CATCAGATGT

GTGGTACAGT

CACGGGTGAC

ATTTTAATTT

GTGTAACAGT

TTTAATTAGA

CAT~TTATTA ACAGGAACAG TGCAGAAACT AGAATCAAGC CTTATAATAT1020 CTTATAGACC

AGATTCATTA

CCAGCCTTTA

4O AGCACTGGGT ACTACAGCCG TAAAAGGAAA TCCCGCCTvG TAGCCAGGGA1200 TATNCCTCCC

(2) INFORMATION FOR SEQ ID NO: 73:
{i) SEQUENCE CHARACTERISTICS:
SO (A) LENGTH: 1814 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double {D) TOPOLOGY: linear SS (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 73:

TACACTGAAG

TGTACCAGTC

AACCAGAGTG

TGAAGAAATG

AAGGACCTCA

TTTAAACCAG

CAGCTTCCCA

GAACCCAGAA

CAGAGAAATG

GAAGGTTCGC

CACCATTAGG

GGACAGGCAT

CAATACTCCA

CTCCCCCATC

AGCCTTCCAG

GGGTGGCTCT

CAGAAAWrAC TTGCTGCTGG CAAAAGGCCT GTACTCAGGC ATTTGCTTTG1140 ACTTGATGTT

TAGGAGTCTC

TTCACCTGTG

AAATTGGAAG

TGAGGATCTG

TATGTGAGGC ACCCATAACA GTAGT'TTTGC CTGTGAGTCG TCTTCACACA1440 TGCTGTTTTC

CAGGCCTTGT

CCCTCATTAC

TTGCACTTAA

AGTCATATGT

TTTTCTTTCT

SS AGTCTTAACA CTCCCTTTCT AATNCATTTC CACTNrIGTA NTGTTCTCAA1800 CATTACTTGG

b0 (2) INFORMATION FOR SEQ ID NO: 74.

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 4712 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear IO (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 74:

CATGGTACGC CTvCAGGTAC CGGTCCGGAA TTCCCGGGTC GACCCACGCG60 TCCGCCCAYG

GGACGGAGAG

AGAGGGGCGC

TCTTGTCCCA

GGAAGAAAAA

GCTTCGGCTG

ACAATCCAGA

CCGTGCGCTG

GTTCGGAAGG

GAGCTTTGGG

CGCACTCGGG

CCCGGGACAC

GCTGCGGCCC

ATCCGGGTCC

CGTGAATGGC

CTTCTACCTG

CKCCACCGCC

GAATCGGCAG

TGGGAAAGCG

GTGGTCGCCG

AAGAAAGAAG

GTCGATGGCA

GGCAGCCAGA

GATCTTGGTC

E)OATCCACGATG AACAGAAGGG GCCGGAAGTG ACCTCCAATG CTGCCCTCAC1500 TCTGCGGAAC

GCACTATGAC

TACTCTTGGG

S

AGAAGATGAT

CATGCCACAT

' IO GATGATGCAA AGCAGTGTGC CAGCCTTAAT GGTGTGAACC AGGATTCCCA1800 CATGATGGCG

CTACATGATT

GAATCCCATA

CCAGTTTACA

CTTGTGGTGT

GGCGGATGGC

AACCGACAGA

GGGAGACTGT

CCCAGTCCCA

TAACCTTGAG

ACACAACGAG

GTACGCTGGC

CTACTTCTTC

CTCTGTCTGT

AAAGAAGTTT

AGGATCAGTT

CACCAACATC

TGCCATCAAA

AGAGCAAGAC

GGAAAGAATT

GGGCAATGCC

TTTCAATGCT

GTCATGTGAA

' SS

TGCTTCCGAG

CTGCCCCCAG

C)O TGGCAGCTGG GGGAGTGGTC ATCATGTTCT AAGACCTGTG GGAP.GGGTTA3300 CAAAAAAAGA

TGATCCTTTA

AGTGGTTTAA

AAAGCAAGAA

AAGGTGGGAT

GCAAAT2'TGA

AAAGCCCCGG

ACAAAGCAAT

IS

AATACTTAGT

A't'CATGGGGG TTGGGAAATG AAAAGTAGGA GAAAAGTGAG 3840 ATTTTACTAA GACCTGTTTT

GACCAGCACT

GAATTAAAAC

ATGGCTTCCT

GAAAAAACAA

TGAAGCATTA

CCTTTCTTTC

TCTCATGAAA

TGTAGAACAG

CTGCTGAGGG

GTCTGTTCAG

ACTATAAATT

AGTTAGTAAT

AAACTTTTAA

ATTATATCGC TTTTGTGGAA GTvCATATAA AATAGAGTAT TTATACAATA4680 TATGTTACTA

JO
(2) INFORMATION FOR SEQ ID NO: 75:
SS (i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 1885 base pairs (B) TYPE: nucleic acid !C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0: 75:
ATGCCARGAA GACTGATvGA GCAGGCTTGC AATATTAAAG TNCCAACCAA60 GAAGCTGAAG

S AAATWfGAGA AAGAATATCC AGACAATGCG AGAGAGTCAG CTGCAACAGG120 AAGACCCAAT

GGATAGATAC AAGTTTvTAT ATTTGTAGGT AACTCCAGCT GTTGCATTTA180 TACTGGGAAT

CTTCATAAGA AGCTGAGAGA AAGAGAGGGG AAAAAGAAAG TvGCTTTCTA240 CTTTCAAAAA

ATCCACAAAG

ACTTZ'rAGCA GGTGAACTGT TCCAAGACTG ACACAAGGAT GTTTCAAACT360 TGCCTCTGTC

ACAAAGGTAT

TTATGAACAA

TTTAATACGT

ATGCAAAGTT

CTTCAACATG

ATATCAATAC

TCTCCTGCCA

AGAAATGGAC TGTGTGGCAT TATTAATTAA ATCACCCACA TTGG.~ATGAC840 TTCCACTTTT

GTAACTAGAG TTAT~TZTAT GTGGTCAGAG CTGGACATAG GCAGCATAGT900 CACACAGAAC

ATGGKGGGAG

3S TATGTAGGTT TKGTAGTCAG ACAGACCKGA ACTCAAATCT TGYTCATTT'I'1020 TTAGAGCACA

GGATT'TGGAY TCCAAATTGA GGGTTTTAAT CCCCATGCCA CCATTCAGCA1080 TCTTCGACTA

TGATGGATTG

TCAATAAATG

ATAATGCCAC

CAAGTATTGC

AAATCCCACA

TACTTCTATA GCAGATAACT ATTAACAGAT AAT"T'I"I'GRA 1440 CTAATTTCAC CACCAACATT

AGAAAGGCTT

TTTGCTAATA

AGTGCTTTAA

ATTGAAC'~"I'G

ATAGTAAGAT

AAAAAAAAAA AAAAAAAAAA AAAAA 1s85 IO (2) INFORMATION FOR SEQ ID NO: 76:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 890 base pairs (B) TYPE: nucleic acid IS (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0: 76:

ATCAGCAGAG

AACCCAGAGG

GCGACCCTCA

CACCCCACCG

CAGCCATGGC

ACAGAAGGGT

CCTGGGCTGA

GCCACAGCCC

CTGGCTCATG GSACCATCCT CACATCCTCT GAATCCACAT TCTCCTCTvA540 ATCTCCCGCC

TGGTAACCCA

CCTGTGGTCA

CTGCCTACCA

AATAATACAT

GGGCCACACC

TGTAAAAAP.A F~AAAAAAAAA AAAAAAAAAA AAAAAAAAAA 890 F~AAAAAAAAA

SO
(2) INFORMATION FOR SEQ ID NO: 77:
SS (i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 1657 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 77:

ACCCAGGCCC

GCCTCCGTTA

TTACTGGCCA

GCCTATTGGC

GAGGAGGGCG

CGGAAGCGGC

TTAGGGTCCG

GGCCCGGCCG GGCATGGATT CAATGCCI'GA GCCCGCGTCC 480 CGCTGTCTTC TGCTTCTTCC

GCCAGGCCGG

GCGGTTAATC

AGGAGAGGAC

ACAACCTGGT

ACACAAAGGG GTCAAGGTGG TGATGGACAT CCCCTATGAG CTGT~vGAACG780 AGACTTCTGC

AGGAGGTGAT

GCGCCAACCA

AGAAGGGAGA

AGGCAGCAGG

CGGCAGGAGT AGCAiCAGCA AACAAAGGAA GGAGCTGGGT GGCCTTGAGG1080 GAGACCCCAG

CCCCTGATGA

TGAGGAGTCA

TTGCCTTGGC

CCGTCATGGG

GTTCAGGCAG

AGGTGTCAGA

CAGTCCTCCC

CAACAGGGTA CTAGGACTGC AGCCCCCTGT AGCTCCTCTC ZGCM'ACCCC1560 TCCTGTGGAC

' SS ACCMGCACT CTGCCTGGCC CTTCCCAGAG CCCAAAGAGT AAAAATGTTC1620 TGGTTCTGAW

F~1AAAAAAAA F~~AAAAAAAA CCCCGGGGGG GGCCCGT 1657 (2) INFORMATION FOR SEQ ID NO: 78:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 2015 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear lO (xi} SEQUENCE DESCRIPTION: SEQ ID NO: 78:

GAAGGGCTGG

TTCTGGTCAT

TTTAAGGGCC

TGAGGATGCC

TCATTCTGGA

AAGCTCCAGA

CTTACGGGGT

AGATCATGGT

TCTTCCATAT

TCTTGGAATT

TTTTCTAAGA

GAAAGGTCCT CAAAGATTCA GTGTC',CTTGG TTACTGGTAT 720 TCTTAGCAGG ATCTTCTGTT

TTTAAATCCT

AGACTTCATT

TTTCATCATG

ATACTACCGA

ACT'I'TI'GTTC CCATACCAGT TTGGTTTCGC TACCTTATAA 1020 GCTATGGGGA RTTTGGTMAC

AAAACTTTTG

TTGTGAAGAG

TGTGATTTCA

ATATTAAGTT

TACTGATAAG

TAGAATGTAG

WO 98/Sb804 PCT/US98/12125 AAAATATATA

ACAGGTAACT

S

TGAAATTAGA

ATAAAGAATA

AGCATTGACT

TTTAAATGAA

TTACTGAGGA

GAAAATAAAT

GATTTAAATT CAAAAAP~AA AAAAAANTNA CTCGA 2015 (2) INFORMATION FOR SEQ ID NO: 79:

2S (i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 1213 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 79:

TCAGGTGACT

GAAACGGGTA

TGCATAATTA

AAAATTGGAA

TGGTGTTTGG

TAACAGCCTA

GTGTGATCCA

CTGAAGTTGC

TGAACTGCAC

SO

TGAAGT2'tGC

AGTGTTGATG TGGGTATTTA CCTATGTTGG ZGCCTTGI"rT AATGGTCTGA660 CACTACTGAT

AGGCACAGAT

AAATCCAAGC

TAGTAGGAGT

GAACGAACCT

CATGCACTGT

ATTGTAAGCT

TGGTGGAATA

AAGTTGCAGA

1~

GATGGTGGAG CTAGAAAAAA P~AAAAAAAAA ANCTYGAGAC TAGCGGCACG1200 AGGGGGGGCC

(2) INFORMATION FOR SEQ ID NO: 80:

2O (i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 1391 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 80:

AGTCTCTTGC

GGGTGGCGGG

AGGAACGGGA

GCTGCAGGAG GTGGAGAGCA CCCTGAAACG ACACiAAACAA 240 GCAATCCGAT TCCAGAAAAT

AAGCCATGGA

GGTTGGCTGA

TTTTACCCAC

TTGCCCACTC

GCCACTCTGT

ATCACAGCAC

GAAGGAAGGG

CACCCCTAGG

GAACTGGCAG

CAGATAACTT

SS

ACTTCCTGTA

TGGGCAAGTA

GAATAGGAAG

ACTTCCTGTG

GTAGTvCTCC CAGTCTGACC TCTGTAGACC TTCAGTACTC ACTCTTCTTG1140 CTTAGGCTCT

GATACTTGCA

CTTGATCAGT

AAATAAAGTA

AAATGTAGCA F~~AAP~A AAAAAAAACN CGGGGGGGGC CCGTCCCATT1380 GCCCAAAAGG

IS

(2) INFORMATION FOR SEQ ID NO: 81:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 1008 base pairs (B) TYPE: nucleic acid (C} STRANDEDNESS: double 2S (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 81:

TCAGGCCCAT

TCATTGGATG

CGTCAGTCCA

TCACCGAGAA

ACAGTGGTGG

GGGGCTATGG

TCAACTGGAT

TGGGAGCCGC

AAGAGTCCCC

GGCCTCAATT

CTAGCTCGGC

SO

GGTCTCAGGG

CTGTCTTGTA

GCCCTGTCCG

AATGCACTGC

CTATGGCCAC

S
(2) INFORMATION FOR SEQ ID N0: 82:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 1261 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 82:

ATATTTGGGG

CATATTCTGT

CTGGCCATTC

GTGATAGGCA

TTACTCTTTT

CAAA'IGCATT ATTCTACCCC TCAACCTAYA TCCAATCATT 360 AGAACTATAC CTGACTGGAG

AACATTAAGC

CTGTACATTT

GAATCTACAG

TGCTATTATA

TATGCATTCT

AAAAATACAC

CTGATAAATG

CTCTAATAGA TATGCTATTT TGTCCTGTAT TGCTTGTTTT ACAGTATv~GT840 GCATGTTGTT

AATTAAAATT

CTTATTCATA

TCTCGTCTTC

GCCAGAATAC

TTTGATTTGA

P,AAAAAAAAA

AAAAAAAAAA F~AAAAAAAAA AAAAAAAAAA AAAAAAAAAA 2260 F~1~.AAAAAAAA AAAGGGCGGC

C

(2) INFORMATION FOR SEQ ID NO: 83:

S (i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 1045 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear . 10 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 83:

AATATGATCC

ACTGGCTCCC

CAGCCCTGGC

GCCAGCGGGT

ACATCTAGGC

TTCTACGACA

CCTGGGCAGG

CAGGCAAGGG

GTACGGC'~GGG CCGGCTTGGC TGGGTGGGGA CCTCAAGTCT 540 GAGGGTGAGG ATGGCTGAAT

GCCAGACCCT

GGCAGGGGTG

GCTGTTGCCA

CATGAATAAT

AGAGCTACCT

CGGCAGGAGG

AAATACGCAC

GCATCACACT

SO
- (2) INFORMATION FOR SEQ ID NO: 84:
(i) SEQUENCE CHARACTERISTICS:
SS (A) LENGTH: 2877 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear GO (xi) SEQUENCE DESCRIPTION: 5EQ ID NO: 84:

ATTACAGAAG

ACCAAATAAA

TCACAGTAAG

GCCAAe'~AATG TGCATACTCA CAGAGTTAGA GAGAGGGATG 290 GTGGGACCAG TTACTCTCCA

IO CAAGAAAATT CACACAACCA CAGTvCTCTT CATAGTTCAA ATTCACATTC300 TTCTAATCCA

CTGGTCTGAG

TTCACAATGG

IS

CAAGATGGCA

AACAGCCACT

TTTGCTCCCA

GCCAAGAGCA

TCATCCAACT

CCAGCCAAAG

CACATCTTCT

CGTATCACAT

TGCACCTCCA

TCCCTTACTT

GCAGCTTAAT

GACACAAGCC

CAACATAACG

TCAGTCTCCG

AATAAGCACA

TTCATCACAG

CCAAAGGTTA GTACrCCAGT AGTTAAGCAA GGACCAGTGT CACAGTCAGC1440 CACACAGCAG

TCTTCAGCGC

TAGTAATGCA

ATTAACGCCT

GCCTGCAGAT

AACTATTCAC

ATGTGAAATT

WO 98156804 PCT/US98l12125 AGGAACTTGA

ACATGGTTTT

S

ATTTAAGTAG

TGAGAGTCAA

' IO TTCAGGGGAA AGATACAAGA TTGATTTGTA AAACCCTTGA AATGTAGATT2100 TCTTGTAGAT

GTATCCTTCA CGTTGTAAAT ATGT'TrIrGTA GAGTGAAGCC 2160 ATGGGAAGCC ATGTGTAACA

CTTTTACATG

IS

TAAACCTGTC TGCAAAATTA GCTTTTTTAA P,AAAAAAAAA 2280 AAAAAAATTG GGGGGGTTAA

TTTATCATTC AGAAATCTTG CAT'I'I"rCAAA AATTCAGTGC 2340 AAGCGCCAGG CGATTTGTGT

2O CTAAGGATAC GATT~.CIGAAC CATATGGGCA GTGTACAAAA 2400 TATGAAACAA CTGTTTCCAC

GTTTTTCATT

AAGGCTCCTC

TTCATTCCTG

TAAATTATTG

CATGTGTGCT

TGTGGGAGGG

CATGTTAAAA

GCGTGGG

(2) INFORMATION FOR SEQ ID NO: 85:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 1367 base pairs 4S (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 85:
AATCATGAGC CTCCAGAAGA GACAGATGGC CCACCAGGAG CTGTTGCTCT GGT'IGCCTTC 60 C'IGCAGGCCT TGGAGAAGGA GGTCGCCATA ATCGTTGACC AGAGAGCCTG GNAACTTGCA 120 GCAGACACCT AGATTTGACC ACCTGGTGGC CATAGAGCGT GCCGGAAGP.G CTGCZGATGG 300 TTGACGATCT

ATGGAGGCAA

ACGGGGATGT

ACTGGGGAGG

GTCAGTACCT

AGGCCCTCCC

GTCGGTCATT AAGGAAGAAA AAATvCTGGG CATCTTGGTG CAGCACAAAG720 TCCGGAGTGG

MCCACGCCGA

'IGTTCCGTGT

GCTTCTGGCG

GGCCTGGGAA

ACTGCAT~vCC CACTTTCTGG GAGGGGTTAG TGCAGGTGCC GTGGACAAAG1020 GACAACATTT

AACCCTCCTT

GACAGTTACT

CATTCCCAGG

TTTCTGTTAC

AAAATTTCAG

(2) INFORMATION FOR SEQ ID N0: 86:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 1009 base pairs (B) TYPE: nucleic acid 4S (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 86:

SS

TGTGGTCCAA

AACTT'I"IGAC

TAACATTTTT

GTGTGTGTGT

' 10 GTGTGTATGT ATGTATAGGT CGGGGAGAGG ATAGTGGTGG GAACAGACAA660 ATAAGGAAGC

TTAAGAGCAG

TGTAAATGCT

IS

TGACTCTTTT

GTTTACTTTT

CACAATGTAC

ATTAAATCAT TATTACATGC TTAAAAAAAA P~AAAAAAAAA 1009 AAAACTCGA

(2) INFORMATION FOR SEQ ID NO: 87:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 1367 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear 3S (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 87:

AGTTATAAAA

AAGAAAGAAT

GAGGGATGTT

GATAAGATTT

TCAAGTTGTC

AAAAATCAAG

ATTGAGTTAC

AGCCTCATCT

TAGC,CAAGAA

' SS ATTAAAGCTA TTCAACTCCT CAAGGCCCAG GGACTATTGC GGAAGAGGTG600 GGCGCGTAAG

TTZ'CTTGAAG CATTAACCAA CTCCTTCATA AAGGTTATAA AAGGCTTATG780 GRAGTTATAT

AAATGTGATT

TCTCTCAAAG

ATAAATGACT

TGTATTTGAC

TCCTTTAAGA

AAAAATTATA

TATGTTA'ITG GTGTATGTTC CAAAATTATG TGAAACTCCT ATAATTCTAA TATAACTTAG 1260 (2) INFORMATION FOR SEQ ID NO: 88:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 1088 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 88:

ATATGCCAGG

CTTCCCTGAT

GAGCATACAG

GATAGCCATT

TTCAAAGGGG

CTCMZT'i'AGC GCACTTGGCG CTTAAGAATT TGAGATCAGT 360 AAGTGTGATG GTCCTAATCT

TTTTTTTTTT

CATTACATAC

TTAGGGCGTG

ATAAGAAAAA ATGGAAGTTA AP~AAAAAWAA AAATCCAAGA ATGGGCTvCT 900 TGTTGCAGTA

S

TCTGTTTTCT

(2) INFORMATION FOR SEQ ID NO: 89:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 1861 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear ?.S (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 89:

CCTGAAGTGG

CAGCTGAAGC

TTCTCTCTCT

CCCCACCCCT

TGAGCGGCGT

CTT'.CIGGGGG TGAGGGAGCT TGGGTAGATG AGGCTCCTGG 360 CTGAGCCCTC CCTGTGGTGA

GACCCTGGGT

ACTTCACCCA

ACTTAAGCCA

GTGCATGGCC

GATTCCYTTG

CGACATAGTA

SO

AGCAGAACAC

ACAACATTTG

TGTGTGTGGA

GATGTTAAGA GCCTCACAAG GAAACTC,GGT TATTGGAGGC 960 CAAGGCGGCT TACAGTTCTC

ATAGCAGATA

CATACCCAAA

CCTCCATGGG

ACAGTTTCAG

ACCCTTCTGA

GTTGGCCCTG GAGTGGCTCA SGGGCAGAGA AGGGTAGCCC TGGGGCTvGG1320 GGAGGGATTG

CCAAGCCCAG

GCCGGACCAT

CAGGACCCGA

GTCTGGGCTT GGGTCCCCCT GCTGCTCTGC CCGTGACCCT TGGGGATuGG1560 TTGATGCGAG

TGGTGGGTCC

GGGTCTGGTC

AATATGTTTG

GCAGGCCGGC

AGGATTGCAA

A 7.861 (i) INFORMATION FOR SEQ ID NO: 90:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 1259 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 90:

TGGAGGAAAT

TGACTTTCCC

GAATTTCCGT

AATTGACGCA

GGCTGTGGAG

TCACCGTCTG

SS

AGGAGATGAA

TCGGAACCCC

AGGCTGATCZ' AGCTGCGGCC

ATCATGCCAA

GTTTTCACCA GT'GGCAACAG CCAGTTACAG GYTCCTGCCA GACATCACCC720 TGCTTGAGCC

TTATTGAGGT

ATACCTTCAG

GGGTTCGAGA

TGGTGAGTGA

ATGCGGTTCA

ACTGACCCAC

TTCTGGGACA

TTTTACGCCT

AAAACTCGA

(2) INFORMATION FOR SEQ ID NO: 91:

(i) SEQUENCE CHARACTERISTICS:

(A) LINGTH: 1566 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double 3 S (D> TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 91:

CTTGGCAGTC

GTTCTGCACC

CTTCCCACAC

CAGAACAGCC

CTGACCCCTT

GCAGTTGATT

SO

GTGTCCTGTC

CCACTCGGAG

' SS GACCAGCGAT CTAACTGTGC TGTGTGTGGA GCCCGGTTCA CCAGCCATGC540 CACTTTTAAC

CAATGAGGGT

TGCTGGAATT

CTvCTTGTGT GCAACAACTG TGCTGCCTAC CGTAAAMTGC TGGAAGCCCA720 GACTCCCAGT

GCAGCGGCTG

GGAGCGGGAG

GTvAGGCGCA TGAGGGACCG TGAAGCCAAG CGCTTGCAGC GCATGCAGGA900 GACAGACGAG

GGCCAATGAA

IO

GCTCAAGAGG

TTCTGCCATG

GGAGTTGGAC

GCACTGAACC

CCACAGCCAC

CAGGCCTGGG

GGGTCAGGAG

TGGCCTCCCC

CATGAAGTTG

GGr',GTTTTTT

TGGGGG

(2) INFORMATION FOR SEQ ID NO: 92:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 1593 base pairs 40 (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 92:

AAGTvGAGGG

GTGCTAGTGG

AAAAATGGAT

ACCTTCTCAC

CATGATGATG

SS

CGGTTTGGTG

AGCAATGTTC

CAGCATTCGC

ACACAAAACT

CATCATCCAG

CCTCTGCATT

GGCAGTGGTA

TATCGATTGC

CTTCTTGCTC

GYTCAAACAG

TTTCTAATAA

GCTvAGATTC CCATTTCTCT TAAGGAGAAG CCACCCATGA GATGTCTTTT1020 CCTTCTCCAT

TCAATGACTT

GGTTTTTTCC

CCTGGGTCAG TGA'I'GGAAAG GGGTTAACTT CAGCCAGGAT 1200 TGATGGCAGC TGAGGGAAAT

CAGGGCCGGA

TGGATCACCT

3O GAGGACAGGA GTTCGAGACC AGTCTGGCCA ACA'I'GGGGAA 1380 ACCCCGTCTC TACTAAAAAT

GAAGGCTGAG

GGCGCCATTG

AAAATANTCG

(2) INFORMATION FOR SEQ ID NO: 93:
(i} SEQUENCE CHARACTERISTICS:
(A) LENGTH: 970 base pairs (B) TYPE: nucleic acid - (C) STRANDEDNESS: double (D) TOPOLOGY: linear SO
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 93:
CTCG'1GCCGA ATTCGGCACG AGGTGCCCAG GCTCTCAGGG CAGAGGGTCC AGTGTGATCA 60 GGAAAAWGGC AGAGGGTGAA GATGGGGTGT CTGGTTTGGG GACCATCCTG GCCCCCCTI'G 180 TCAGACTGGC C'IGTGTCCTG GCTCCTCTTA CCACCTCTTC CAGAGGTTGT CACCTGCAGC 480 CTGGGGTGGC

IO

CCCTTGGTGG

GCGTATGATA

CCTTGGGAGG

ACATGGTGAA

CTGTAATCCC

GGCTACAACG

AGCCGAGATT GCACCACTGC ACTCCAGCCT GATCCGTCTC P~AAAAAAAAA960 F,F~AAAAAAAA

2S AAAAACTCGA g70 30 (2) INFORMATION FOR SEQ ID NO: 94:
(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 934 base pairs (B) TYPE: nucleic acid 3 (C) STRANDEDNESS: double S

(D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 94:

GTATCAGGAA

TAAGTGAAGA

AGAATTTCAT

CATGACCTTG

TTCTTGCATG

ATAACTACAC

TAATGAARTA

TTTCTGTGTG

SS

TAAGACATAT

SAGTCTCATT

AAAAAGGATC

IS (2) INFORMATION FOR SEQ ID NO: 95:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 1392 base pairs (B) TYPE: nucleic acid 20 (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 95:

CCACCTGGTG

CCTGGAGGAG

GCAGGCGGAG

GAGCCCCCTG

CAGGTGGCTG AAAATGTGTC CTTTGTGGAG GAGTACAGGT GGC'IGGCCTA300 YGTCCTCCTG

3S C'IGCTCCTGG AGCTGCT~vGT CTGCCTCTTC ACCCTCCTNG 360 GCCTGGCGAA CAGAGCAAGT

TGGGGCTCCA

CCAGACCCT?' AGCTATTATC

TCCCAGCGAG

CCTCAGTTCC

GAAGGAAATT

TCCACCAGTT GGTGGCACTG CTACACTvCC GCAGCCTGCA CAAGGACTAT780 GGTGCAGCCC

SO

TTCTCCCTGC

GCCCTCTTCC

CTCCTCCCGG

GACCCCACTA

ACCCAGCCTG CCTGGGCTCT GACCACTAAC ACTCT'I'GGCC 1080 ATGGACAGCC TGCACAGGAC

GAGTAGCTGA

CCTCGCACCC

GACATGAGTC

CTCGTGGCAC

AAAAAAAAAA

(2) INFORMATION FOR SEQ ID NO: 96:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 1963 base pairs 2G (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 96:

ATGCAAATTA

ATTTTACTGA

CGGAACCTCA

TAGAGCAGAG

GTCAGAGTTG

GACTAGTTTA

AATTTGGTGT

TGATATACCT

GAGACAACAC

GTTCGGACTC

AAACAACCTC

ATGGGTCAGG

GGAGGGACAA

CACTCYGTTT

CYTGGAGAWT YCTCCTuAAA AAGTCACATG TTATTTCTTC TCACCTCCAT900 TGGCAAAAAA

SS

AATGCATTCA

ATGCCAACAT

C)OGCATCCCTAA CAACCCAGTG CTGTCACCCT CCAAACTTTT TATGTCTTGC1080 AAAGTATTAG

GACATCTCCT

TGCTTTTGGG

S

ATNATAGGGT

GAGGTGGGGT

GGGACCCAGG

GTTAGAATTA

GCTTTGGAGC

AAGACTGACY

GTCTGCTYCC

ATTCCACAAG

GCTCATCATM

TCTTGGTATA

GAGAAAGGAG AAATvCTTAG AGCCACCATC AGGACAGTTG GGATGAAAGT1860 TGGGTATAGG

TTTAATTACT

3S (2) INFORMATION FOR SEQ ID NO: 97:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 1052 base pairs (B) TYPE: nucleic acid 40 (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQLTET~ICE DESCRIPTION: SEQ ID NO: 97:

ACCACAAYCT

ACATAACATA

AGTTWATTTC

SO

AATTTATAGA

ACTTTCCCAA

TCAGCACTAT

TGACATTTTG GACCARATAG TTCTGTV~fI'GT KAAAGGCKGT 420 CTTTGCACTG TAGAATGTTT

ATACTGGTAG

ACCTTTCCAG

CCCAAATGGT

CCTTCCCTTA

TTGAAGGKTT

CAAGCCTGTA

lO

TTCGhCACCA

CCTGGCATGG

GCTTGAACCC

GCAACATAGC

AAGACTCTGT CAAAAAAAP.A AAAAAAACTC GA 1052 (2) INFORMATION FOR SEQ ID NO: 98:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 929 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double 3O (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 98:

GAATATGTGG

AGCCTTCTCA

GAAGATAAAC

GATGCTGATG

ATGACTTATC

AATGGACTGA

TTTGGGCATA

TGAGAAGTGG

GTAGTAGTAA

CACTGGTATA

TTTAAAACAC

SS

GCAAATAAAC

TATTAATAAA TATTATATGT GATAAATTCT AAATTATGAA CATTAGAAAT7gp CTGTGGGGCA

GO CATAT~TG CTGATTGGTT AAAAAATTTT AACAGGTCTT TAGCGTTCTA840 AGATATGCAA

S
(2) INFORMATION FOR SEQ ID NO: 99:

Z

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 359 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double 15 (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 99:

CCAGTCTGCA

CCTTTGTGCT

AAGGAAAGCA

ATGTGCCTCG

GAAAAACCTG

GGGGCCCGG

(2) INFORMATION FOR SEQ ID NO: 100:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 952 base pairs (B) TYPE: nucleic acid tC) STRANDEDNESS: double 4O (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0: 100:

CAGCTCAGGG CGCC2~GCCCA CGTCGTCTGC CGGCGGTGCG CCGCGGGCGT CCCTCGCGTC 180 SS

C)O GAGCGGTTTG CAGTGTCCGT TCTCATCCAC CTGATGGGCC CAGATAAAGG CCCCCGCTGT 540 WO 98/56804 PCT/(JS98/12125 AGACCCTGTG

TCCAGGAGCA

S

CACCCCCAGG

GTTTCTGCCC

CCTCAGACCA

p~F~AAAAAAAA

TT

(2) INFORMATION FOR SEQ ID NO: 101:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 1545 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double 2S (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 101:

TGAAGCAAGT

CAAGATCATG

CCTGAGCACT

CGACGCCACA

CCCATCCATA

CGTGTGGCCA

TATGATGCAC

TTCAGAACAG

4S ACGTAGAGAG ATGAAGGCTT GTGGAGGAAA AGATGGTGAG AGACrI'GGGC540 AGAAAATGAG

GCCATATAGT

TCCCTTTTGC

SO

CCT'I"1'CAGTA TAGATG'IGAT TTCTGATTCT CTTACAGATT 720 GTTIGCTTTG CGAGATCTGA

CATTTAATTT' TAGCATTTTA

AAGAAGAAAA

CTTTTC2GGC AGCCCCGTTC A'IGCACAGCT TAGGATACAT CACGAGCCTG960 ACAGATGCAT

AAAGTGGTCT

TGAAACCAAG

TTCCTGGTGC

CCCTGA'IGAT GAAGCAGTAC GGATATTTTT AGAATTTGAG 12D0 AGAGTTGAAT CAGCAATTAA

CATGTTTCTA

AAGAACTAGA

AGGAAAAAGG

IS TCACAGCCTC CAT'GGCTGTT GCATACCAAG ACTCTTGGAA 1440 GGACTTCTAA GATATATGTT

GATTGATCCC TT'I'TS"rATTT TGTGGTTTTT TAATATAGTA 1500 TAAAAAT'CCT TTTAAAAAAA

(2) INFORMATION FOR SEQ ID NO: 102:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 1322 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0: 102:

GGCGGTGGGA

CTCTACTGGC

GGTACTGTTC

4O GTGCCGCAGC AGGAGGCCTG GGTv~GTGGAG CGAATGGGCC 240 GATTCCACCG GATCCTGGAG

CCTGGT'1'T'GA ACATCCTCAT CCCTGTGTTA GACCGGATCC 300 GATATGTGCA GAGTCTCAAG

AACTCTGCAA

CGGTGTGGAG

GCTCGGCAAA

TGTGGATGCC

CAAGGATATC

GCGGCGGAAA

SS

GGCAGAAGGG

AAATCAGGCA

TATTCGAATC

TGTGGCCGAG

ACTGCCCTCC

S

AGCCCTCACC

AGATGTCCAG

GTGGAGCTGG

TCTAGCTTCC

AAACTCACCA

GTGGCAAACC AAAAAAAAAA P~~AAAAAAAA AAAAAAAAAA 1320 p~AAAAAAAAA AAAAAAAAAN

NN

(2) INFORMATION FOR SEQ ID N0: 103:
2S (i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 276 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 103:

{2) INFORMATION FOR SEQ ID N0: 104:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 381 base pairs SO (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 104:
SS

ATTAATGTAG GTTGCCGTGG TGAAAATAGT TTGAAATACT TCACAGTAAC AGTTTTFC'IGC 240 S

(2) INFORMATION FOR SEQ ID NO: 105:

IS (i) SEQUENCE CHARACTERISTICS:

fA) LENGTH: 638 base pairs fB) TYPE: nucleic acid fC) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 105:

CTGATTCCAG

2S AGAGCTAAAG CCGATGGTAG G'IGGAGATGA RGARGTGGCC GCCCTCCAAG120 AATTTCACTT

CTTTTGTTAT

TTGGATGGCA

CAGCATCCTC

AAAACTGCTG

3S TTvCTCTTGT TTCCTTTTTA ACTGTCAGTG TTTGGCTTTC ATCAGACTGA420 ACATTTTGGT

GCAATTCCTT

CATTGCTGTC

TTTTTTTTNT

f2) INFORMATION FOR SEQ ID NO: 106:
SO (i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 2246 base pairs ~ (B) TYPE: nucleic acid (C) STRANDEDNESS: double ( D ) TOPC?LOGY : 1 inear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 106:

GAGCTGTATT

TGGTTATACT

AAATGGAGCA

CTTCGGATCT

CGGCACCTGC

GCCGACCTGT

CCGCAGCGTG

IS

TGAGGAGGAA

CCTCGTTAAT

GTACAAGGAT

CCTGAA'PGGC

AAATGAATGT

TTATAACTGC

GAAGTCCGGG

CATTvGAGCC

CCGCATCAGC

CGCATTGAAT ACCAGGGTTC TTCCAGGCCA GCC'rATGAGG AGTTCTACAA1140 CTGCCGCAGC

TvGAAAGAAA

TCCTGATGAC

ATTATTTTTC

GCTTAAGAAA

TTTTCTGCAG

ACGATGTTTT

AATGTACCTT CAGCTCTCTA AAC~TGTGC TTCTACTAGT GTGTGCTCTT1560 TTCACTGTAG

TAATCAAGGA

AACCACGTAA

GAAATGTTCG

TTAGCCTTTG

CTTTGTGGAA

GCCTCAAAAA

S

AAAAAAAAAA

AAAAAP.AATT ACTCGGTCGC AAGGGA 2246 (2) INFORMATION FOR SEQ ID NO: 107:

(i) SEQUENCE CHARACTERISTICS:

20 (A) LENGTH: 1105 base pairs (BI TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear ZS (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 107:

CTTTGCCTCA

AGAGCAGTCT

CAAGTTTACT

TTTATTTTGC

TCCAAGTTAT

AATGGCTCTG

AGCAACAGCA

CATACCCATA

AGAACAGCCA

AAATAATACA

CGCTTGCTGG

TAGGTvCTGT ACCAGACTCT TTGTAATCTG CCTTAGKTCA GRGAAGAACA720 AGCCATTACC

SO

ACTCTGCAGG

GCTGGCCTAG

GCTTGAGGCC

AAATTTAAAA

AGGCAGGAAG

S
(2) INFORMATION FOR SEQ ID N0: 108:
IO (i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 505 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 108:

ACCNTCACTA

TGGATCCCCC

GGCCAACCCT

CAGCCTTGCG GTuGGGCCCG AAGCATCTTC CCTTCCGCTT GGCGTCTCTG240 GGATTGGGAT

CTGGCTCAGG

ACCCGTCCCA

TTAGGGGCCG

GTCTCCAGGG CGCGTAGATA AATAAATACA CTCAGCGTCA P~AAAAAAAAA480 AAAAAAAAAA

AAAAAAAAAA P~AAAAAAAAA CTCGA 505 (2) INFORMATION FOR SEQ ID NO: 109:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 1380 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double 4S (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 109:

GGTTGCCTTC

SO

GAACTTGCAC

CCCGATATTA

TGGGGACCCG

TGCTGATGGC

AATTACTACA ATGCAAGGAA GATGAACATC AAGCACTT~vG TTGACCCCAT360 TGACGATCTT

TGGAGGCAAC

CGGGRATGTC

CTGGGGAGGC

TCAGTACCTG

GGCCCTCCCG

CCGGAGTGGC

CCACGCCGAG

GTTCCGTGTG

CTTCTGGCGA

GCCTGGGAAA

CTGCATGCCC ACTTTC~ AGGGGTTAGT GCAGGTGCCG TGGACAAAGG1020 ACAACATTTC

ACCCTCCTTC

ACAGTTACTT

ATTCCCAGGC

TTCTGTTACT

AAATTTCAGA

AATAAACAAC TCTTAAGTTT TP~1AAAAAAA F,~~ AAAAAAAAAA1380 GGGCGGCCGC

(2) INFORMATION FOR SEQ ID NO: 110:
4O (i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 646 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 110:
CAGATGCCAG GGACT'IGGNC TTCCCCCGGT TGAACCACAG GTTCCAAGAA ACCTGCAGGG 60 SS

TGGTGGCCTG AGCGGGGCCA TGGTGARGAC ACCCTTGGTG GCTTGTCCCA CATCAAGC'IG 360 S

(2} INFORMATION FOR SEQ ID NO: 111:
IS {i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 32 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 111:
Met Asp Ser Tyr Trp His Ser Arg Cys Leu Lys Cys Ser Cys Cys Gln Ala Xaa Trp Ala Thr Ser Ala Arg Pro Val Thr Pro Lys Val Ala Xaa f2) INFORMATION FOR SEQ ID NO: 112:
(i) SEQUENCE CHARACTERISTICS:
3S (A) LENGTH: 36 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 1I2:
4~ Ile Tyr Ser Ser Gly Tyr Phe Gln Ile Tyr Asn Met Leu Leu Leu Thr Ile Leu Ile Leu Leu Cys Asn Arg Thr Pro Glu Leu Ile Pro Gly Phe Tyr Ile Arg Xaa (2) INFORMATION FOR SEQ ID NO: 113:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 220 amino acids SS (B) TYPE: amino acid (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 113:
Met Ser His Lys Leu Gly Asp Pro Gly Phe Val Val Phe Ala Thr Leu Val Val Ile Val Ala Leu Ile Leu Ile Phe Val Val Gly Pro Arg His S Gly Gln Thr Asn Ile Leu Val Tyr Ile Thr Ile Cys Ser Val Ile Gly Ala Phe Ser Val Ser Cys Val Lys Gly Leu Gly Ile Ala Ile Lys Glu Leu Phe Ala Gly Lys Pro Val Leu Arg His Pro Leu Ala Trp Ile Leu Leu Leu Ser Leu Ile Val Cys Val Ser Thr Gln Ile Asn Tyr Leu Asn Arg Ala Leu Asp Ile Phe Asn Thr Ser Ile Val Thr Pro Ile Tyr Tyr Val Phe Phe Thr Thr Ser Val Leu Thr Cys Ser Ala Ile Leu Phe Lys Glu Trp Gln Asp Met Pro Val Asp Asp Val Ile Gly Thr Leu Ser Gly Phe Phe Thr Ile Ile Val Gly Ile Phe Leu Leu His Ala Phe Lys Asp Val Ser Phe Ser Leu Ala Ser Leu Pro Val Ser Phe Arg Lys Asp Glu Lys Ala Met Asn Gly Asn Leu Ser Asn Met Tyr Glu Val Leu Asn Asn 3S Asn Glu Glu Ser Leu Thr Cys Gly Ile Glu Gln His Thr Gly Glu Asn Val Ser Arg Arg Asn Gly Asn Leu Thr Ala Phe Xaa (2) INFORMATION FOR SEQ ID NO: 114:
4S (i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 32 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 114:
SO
Met Thr Ile Trp Glu Arg Lys Tyr Ile Trp Met Leu Gln Ile Cys Val ~ 1 5 10 15 Phe Leu Glu Pro Arg Ala Lys Pro Ser Leu Gly Asp Leu Asp Trp Xaa (2) INFORMATION FOR SEQ ID NO: 115.
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 27 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 115:
Met Leu Thr Phe Leu Leu Phe Ile Pro Val Ala Pro Thr Glu Thr Ser Gln Lys Asn Arg Ser Val Phe Leu Pro Pro Xaa (21 INFORMATION FOR SEQ ID NO: 116:
2O (i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 132 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 116:
Met Leu Phe Val Phe Cys Cys Thr Val Phe Phe Val Cys Leu Phe Val Tyr Leu Val Gly Phe Leu Glu Arg Glu Ile Trp Lys Arg Asp Ile His Lys Ser Tyr Thr Pro Thr Phe Pro Phe Tyr His Asp Ile Gln Glu Glu 35 Thr Ser Arg Ala Lys Asn Gly Val Lys Lys Gly Ser Met Ala Gly Thr Ser Lys Glu Leu Arg Ala Val Ala Leu Lys Asn Tyr Phe Phe Tyr Tyr Tyr Phe Glu Ser Met Glu Val Phe His Ser Leu Gly Lys Gly Gly Lys Ser Ala Phe Ile Phe Ile Gln Ser Tyr Leu Ile Thr Ser Lys Thr His Met Leu Glu Ile Ala Phe Ala Gly Ala Lys Tyr Ile Asn Glu Gln Glu Tyr Ile His Xaa SS (2) INFORMATION FOR SEQ ID NO: 117:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 65 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 117:
Met Trp Tyr Phe Met Ser Leu Ile Ser Met Val Leu Leu Leu Ser Pro S
Ser Cys Ser Asp Leu Leu Val Ile Ser Val Leu Asn Leu Glu Gln Arg Arg Gln Ser Lys Val Gly Phe Glu Pro Phe Thr Ser Pro Leu Cys Gly Xaa Trp His His Leu Ser Pro Asp Arg Leu Pro Gln Asp Gly Thr Phe 1 S xaa 20 (2) INFORMATION FOR SEQ ID NO: 1i8:
ii) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 9 amino acids (B) TYPE: amino acid 2S (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 118:
Leu Leu Leu Phe Cys Ile Leu Gly Xaa (2) INFORMATION FOR SEQ ID NO: 119:
3S (i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 50 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 119:
Met Gly Val Leu Phe Val Pro Gln Glu Thr Ser Xaa Lys Val Xaa Xaa Asp Ile Xaa Gly Leu Ser Gln Phe Val Met Gly Glu Lys Arg Thr Thr Ser Ile Arg Gly Ile Gln Ala Arg Tyr Gln Val Asp Arg Gly Leu Glu S0 Tyr Cars SS (2) INFORMATION FOR SEQ ID NO: 120:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 76 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 120:
Met Leu Leu Leu Leu Leu Leu Leu Leu Leu Leu Leu_Trp Thr Cps Gln Lys Ala Leu Val Arg Arg Gln Phe Cys Leu Phe Asn Leu Ile Ala Arg Asn Ser Ser Leu Met Leu Gln Lys Asp Glu Lys Lys Gly Lys Lys Arg Asp Asn Ser Gln Ala Gln Arg Glu Lys Lys Gly Gly Gly Lys Glu Pro Gln Gly Asp Leu Gln Glu Arg Pro Gly Pro Gly Xaa ZO (2) INFORMATION FOR SEQ ID NO: 121:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 27 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 121:
Met His Asn Ala Phe Asn Leu Asn Val Leu Thr Leu Phe Leu Ser Val Leu Cys Cys Thr Phe Ser Asp Ser Glu Leu Xaa (2) INFORMATION FOR SEQ ID NO: 222:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 24 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 122:
Met Ser Trp Leu Phe Leu Leu Phe Ala Leu Leu Cys Lys Phe Gln His Lys Leu Xaa Phe His Asn Ile Xaa (2) INFORMATION FOR SEQ ID NO: 123.
(i) SEQUENCE CHARACTERISTICS:
55 (A) LENGTH: 22 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 123:
60 Met Leu Leu Phe Leu Thr Val Ile Asn Phe Met Ala Leu Ala Lys Met Asn Phe Cps Gly Asp Xaa (2) INFORMATION FOR SEQ ID NO: 124.
10 (i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 55 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 124:
Met Val Xaa Asn Leu Gln Val Ile Ser Ile Trp Xaa Xaa Ser Thr Thr Cys Phe Tyr Ala Cys Ile Trp Xaa Gln Gly Cys Leu Met Leu Arg Xaa Phe Xaa Thr Leu Asn Asn Val Thr Arg Leu Pro Ser Ser Gln Lys Pro Ile Lys Cys Tyr Leu Leu Xaa (2) INFORMATION FOR SEQ ID NO: 125:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 318 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 125:
Met Leu Ser Glu Ser Ser Ser Phe Leu Lys Gly Val Met Leu Gly Ser Ile Phe Cps Ala Leu Ile Thr Met Leu Gly His Ile Arg Ile Gly His Gly Asn Arg Met His His His Glu His His His Leu Gln Ala Pro Asn Lys Glu Asp Ile Leu Lys Ile Ser Glu Asp Glu Arg Met Glu Leu Ser SO Lys Ser Phe Arg Val Tyr Cys Ile Ile Leu Val Lys Pro Lys Asp Val Ser Leu Trp Ala Ala Val Lys Glu Thr Trp Thr Lys His Cys Asp Lys Ala Glu Phe Phe Ser Ser Glu Asn Val Lys Val Phe Glu Ser Ile Asn Met Asp Thr Asn Asp Met Trp Leu Met Met Arg Lys Ala Tyr Lys Tyr Ala Phe Xaa Lys Tyr Arg Asp Gln Tyr Asn Trp Phe Phe Leu Ala Arg Jr Pro Thr Thr Phe Ala Ile Ile Glu Asn Leu Lys Tyr Phe Leu Leu Lys Lys Asp Pro Ser Gln Pro Phe Tyr Leu Gly His Thr Ile Lys Ser Gly Asp Leu Glu Tyr Val Gly Met Glu Gly Gly Ile Val Leu Ser Val Glu Ser Met Lys Arg Leu Asn Ser Leu Leu Asn Ile Pro Glu Lys Cps Pro 1$ 195 200 205 Glu Gln Gly Gly Met Ile Trp Lys Iie Ser Glu Asp Lys Gln Leu Ala Val Cys Leu Lys Tyr Ala Gly Val Phe Ala Glu Asn Ala Glu Asp Ala Asp Gly Lys Asp Val Phe Asn Thr Lys Ser Val Gly Leu Ser Ile Lys Glu Ala Met Thr Tyr His Pro Asn Gln Val Val Glu Gly Cys Cys Ser Asp Met Ala Val Thr Phe Asn Gly Leu Thr Pro Asn Gln Met His Val Met Met Tyr Gly Val Tyr Arg Leu Arg Ala Phe Gly His Ile Phe Asn Asp Ala Leu VaI Phe Leu Pro Pro Asn Gly Ser Asp Asn Asp 4O (2) INFORMATION FOR SEQ ID NO: 126:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 59 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 126:
Met Thr Txp Pro Pro Ser Cys Leu Val Ala Leu Leu Leu Ser Thr Val Thr Gln Lys Met Thr Pro Leu Asn Leu Met Arg Thr Thr Gly Pro Ile Asn Ser Phe Cys Leu Leu Pro Thr Phe Phe Phe Phe Pro Ser Tyr Leu 35 40 ' 45 Pro Ser Leu Met Pro Thr Pro Thr Asp Pro Xaa (2) INFORMATION FOR SEQ ID NO: 127:
(i) SEQUENCE CHARACTERISTICS:
S (A) LENGTH: 99 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 127:
Ile Leu Phe Ser Phe Leu Ile Pro Ser Asn Leu Ser Phe Ser Pro Val Ile Phe Phe Leu Cys Gly Pro Phe Lys Val Val Ile Ile Cys Thr Glu Leu Gln Asn Val Ser Arg Ser Pro Gln Thr Thr Leu Ala Thr Val Tyr Cys Asn Lys Ile Thr Ser Tyr Ile Cys Arg Asn Ser Phe G1y Val Ile Leu Phe Phe Pro Leu Asn Ile Tyr Asn Trp Thr Asn Ala Gly Lys Lys ZS Lys Lys Met Val Ser Lys Lys Pro Lys Ile Lys Phe Arg Gly His Gln Ala Phe Xaa (2) INFORMATION FOR SEQ ID NO: 128:
3S (i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 29 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 128:
Met Ser Ile Leu Leu Leu Xaa Phe Pro Ser Ala Pro Ala Pro Val Val Ser Gly Gly Leu Gln Pro Trp Leu His Ser Cys Ile Xaa (2) INFORMATION FOR SEQ ID NO: 129:
SO
(i) SEQUENCE CHARACTERISTICS:
~ (A) LENGTH: 22 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear SS (xi) SEQUENCE DESCRIPTION: SEQ ID N0: 129:
Met Gly Thr Ser Leu Asn Leu Gln Ile Met Ala Leu Phe Ser Gly Gln 60 Ala Met Ala Pro Arg Xaa S (2) INFORMATION FOR SEQ ID NO: 130:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 112 amino acids (B) TYPE: amino acid 10 (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 130:
Met Leu Trp Leu Pro Leu Leu Ala Ala Leu Ser Pro Ser Pro Pro Gly Val Ser Ser Glu Glu Glu Gln His Trp Ser Gln Ala Glu Ala Leu Pro Cys Trp Asp Pro Gly Ser Glu Ser Ser Pro Arg Ile Pro Gly Cys Arg Glu Leu Gln Ser Cys Pro Pro Pro Thr Ala Pro Ser Ala His Thr Gln 2S Ser Pro Gly Gly Leu Gly Ala Lys Ala Gly Ala Ala Leu Val Pro Phe 65 70 ~5 80 Pro Gly Pro Ser Phe Pro Thr Ser Lys Pro Lys Lys Gly Glu Ala Gly Ala Pro Val Pro Gln Pro His Ser Ala Leu Thr Val Pro Ser Ser Xaa (2) INFORMATION FOR SEQ ID NO: 131:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 114 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear 4S (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 131:
Met Glu Lys Pro Leu Phe Pro Leu Val Pro Leu His Trp Phe Gly Phe SO Gly Tyr Thr Ala Leu Val Val Ser Gly Gly Ile Val Gly Tyr Val Lys Thr Gly Ser Val Pro Ser Leu Ala Ala Gly Leu Leu Phe Gly Ser Leu SS
Ala Gly Leu Gly Ala Tyr Gln Leu Tyr Gln Asp Pro Arg Asn Val Trp Gly Phe Leu Ala Ala Thr Ser Val Thr Phe Val Gly Val Met Gly Met s5 ~o ~s eo Arg Ser Tyr Tyr Tyr Gly Lys Phe Met Pro Val Gly Leu Ile Ala Gly Ala Ser Leu Leu Met Ala Ala Lys Val Gly Val Arg Met Leu Met Thr Ser Asp (2) INFORMATION FOR SEQ ID N0: 132:
IS (i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 22 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0: 132:
Met Ile Thr Leu Leu Ile Trp Met Leu Ala Gly Phe Ile Ala Arg Ile Xaa Val Ala Leu Gln Xaa ao (2) INFORMATION FOR SEQ ID NO: 133:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 52 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear 3S (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 133:
Met Ala Gly Val Ser Glu Ile Ser Val Cys Phe Xaa Leu Leu Ser Leu Phe Ser Leu Phe Cys Ser Phe Tyr Phe Pro Lys Gln Ala Thr Pro Lys Arg Asp Leu Phe Val Gln Glu Ser Gly Lys Gly Lys Arg Asn Thr Glu Ser Trp Glu Xaa ' (2) INFORMATION FOR SEQ ID N0: 134:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 99 amino acids SS (B) TYPE: amino acid (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 134:
Met Thr Ser Ala Leu Thr Gln Gly Leu Glu Arg Ile Pro Asp Gln Leu I 5 to i5 Gly Tyr Leu Val Leu Ser Glu Gly Ala Val Leu Ala Ser Ser Gly Asp Leu Glu Asn Asp Giu Gin Ala Ala Ser Ala Ile Ser Glu Leu Val Ser Thr Ala Gds Giy Phe Arg Leu His Arg Gly Met Asn Val Pro Phe Lys Arg Leu Ser Val Val Phe Gly GIu His Thr Leu Leu Val Thr Val Ser Gly Gln Arg Val Phe Val Val Lys Arg Gln Asn Arg Gly Arg Glu Pro Ile Asp Val (2) INFORMATION FOR SEQ ID NO: 135:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 176 amino acids (B) TYPE: amino acid {D) TOPOLOGY: linear {xi) SEQUENCE DESCRIPTION: SEQ ID NO: 135:
Met Gly Ser Ala Ala Leu Glu Ile Leu Gly Leu Val Leu Cys Leu Val Gly Trp Gly Gly Leu Ile Leu Ala Cys Gly Leu Pro Met Trp Gin Val Thr Ala Phe Leu Asp His Asn Ile Val Thr Ala Gln Thr Thr Trp Lys Gly Leu Trp Met Ser Cys Val Val Gln Ser Thr Gly His Met Gln Cys Lys Val Tyr Asp Ser Val Leu Ala Leu Ser Thr Glu Val Gln Ala Ala Arg Ala Leu Thr Val Ser Ala Val Leu Leu Ala Phe Val Ala Leu Phe Val Thr Leu Ala Gly Ala Gln Cys Thr Thr Cys Val Ala Pro Gly Pro JO
Ala Lys Ala Arg Val Ala Leu Thr Gly Gly Val Leu Tyr Leu Phe Gys Gly Leu Leu Ala Leu Val Pro Leu Cys Trp Phe Ala Asn Ile Val Val Arg Glu Phe Tyr Asp Pro Ser Val Pro Val Ser Gln Lys Tyr Glu Leu Gly Ala Xaa Cys Thr Ser Ala Gly Arg Pro Pro Arg Cars Ser Trp Xaa {2) INFORMATION FOR SEQ ID NO: 136:
lO (i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 187 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 136:
Met Val Leu Leu Trp Val Val Thr Cys Pro Ala Thr Met Leu Thr Glu Pro Gln Asn Pro His Leu Ile Gly Phe Val Ala Tyr Ser Gly Pro Ser His Thr Thr Gln Pro His Lys Tyr Trp Leu Leu Leu Asp Gly Gln Ala ?5 Asp Pro Ala Ala Ala Glu Gly Pro Val Lys Arg Lys Ala Ala Ser Val Val Trp Trp Pro Gln Ala Leu Arg His Leu Ser Leu Leu Val His ~."ys Trp Glu Glu Ser Tyr Glu Met Asn Ile Gly Cys Gln Ser Leu Trp Ala Gly Gly Leu Ala Ser Ser Gly Asn Gly Trp Asp Leu Gly Val Ala Phe loo los 110 Arg Arg Asp Thr Gars Met Ser Ser Ser Ser Leu His Txp Lys Glu Phe Lys Tyr Ala Pro Gly Ser Leu His Tyr Phe Ala Leu Ser Phe Val Leu Ile Leu Thr Glu Ile Cys Leu Val Ser Ser Gly Met Gly Phe Pro Gln Glu Gly Lys His Phe Ser Val Leu Gly Ser Pro Asp Cys Ser Leu Trp Gly Arg Asp Glu His Val Pro Arg Glu Phe Ala (2) INFORMATION FOR SEQ ID NO: 137:
SS
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 288 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear 6O (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 137:

Met Pro Ala His Arg Phe Val Leu Ala Val Gly Ser Ala Val Phe Asn Ala Met Phe Asn Gly Gly Met Ala Thr Thr Ser Thr Glu Ile Glu Leu Pro Asp Val Glu Pro Ala Ala Phe Leu Ala Leu Leu Lys Phe Leu Tyr Ser Asp Glu Val Gln Ile Gly Pro Glu Thr Val Met Thr Thr Xaa Tyr Thr Ala Lys Lys Tyr Ala Val Pro Ala Leu Glu Ala His Cys Val Glu Phe Leu Lys Lys Asn Leu Arg Ala Asp Asn Ala Phe Met Leu Leu Thr Gln Ala Arg Leu Phe Asp Glu Pro Gln Leu Ala Ser Leu Cys Leu Glu Asn Ile Asp Lys Asn Thr Ala Asp Ala Ile Thr Ala Glu Gly Phe Thr Asp Ile Asp Leu Asp Thr Leu Val Ala Val Leu Glu Arg Asp Thr Leu Gly Ile Arg Glu Val Arg Leu Phe Asn Ala Val Val Arg Trp Ser Glu Ala Glu Cys Gln Arg Gln Gln Leu Gln Val Thr Pro Glu Asn Arg Arg Lys Val Leu Gly Lys Ala Leu Gly Leu IIe Arg Phe Pro Leu Met Thr Ile Glu Glu Phe Ala Ala Gly Pro Ala Gln Ser Gly Ile Leu Val Asp Arg Glu Val Val Ser Leu Phe Cys Thr Ser Pro Ser Thr Pro Ser His Glu Trp Ser Ser Leu Thr Gly Pro Ala Ala Ala Cys Val Gly Arg Ser Ala Ala Ser Thr Ala Ser Ser Arg Trp Arg Val Ala Gly Ala Thr Xaa JO Gly Pro VaI Thr Ala Ser Gly Ser Gln Ser Thr Ser Ala Ser Ser Trp Trp Asp Leu Gly Cys Met Asp Pro Ser Thr Gly Pro Pro Thr Thr Lys (2) INFORMATION FOR SEQ ID NO: 138:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 114 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 138:
Met Pro Arg Cys Arg Trp Leu Ser Leu Ile Leu Leu Thr Ile Pro Leu Ala Leu Val Ala Arg Lys Asp Pro Lys Lys Asn Glu Thr Gly Val Leu IS Arg LysLeuLysProVal AlaPhe CysGln Gly Ser Asn Xaa Arg Ser Val XaaGlyPheAlaMet GluTyr LysGlu Glu Asp Gln Asn Ser Lys Tyr ValPheLeuValVal ThrLeu AlaGln Gln Val Lys Gln Leu Thr Asn LeuLeuGluTyrLeu AspVal IleAla Ser Asp Ile Glu Arg Cps 2rJ 85 90 95 Arg LysProLeuSerThr GluIle ProPhe Xaa Thr Asn Ala Lys Pro Ser Xaa (2) INFORMATION FOR SEQ ID NO: 139:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 120 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 139:
Met Ser Pro His Pro Thr Ala Leu Leu Gly Leu Val Leu Cys Leu Ala Gln Thr Ile His Thr Gln Glu Glu Asp Leu Pro Arg Pro Ser Ile Ser Ala Glu Pro Gly Thr Val Ile Pro Leu Gly Ser His Val Thr Phe Val ' Cps Arg Gly Pro Val Gly Val Gln Thr Phe Arg Leu Glu Arg Glu Ser Arg Ser Thr Tyr Asn Asp Thr Glu Asp Val Ser Gln Ala Ser Pro Ser Glu Ser Glu Ala Arg Phe Arg Ile Asp Ser Val Ser Glu Gly Asn Ala Gly Pro Tyr Arg Cys Ile Tyr Tyr Lys Pro Pro Lys Trp Ser Glu Gln Ser Asp Tyr Trp Ser Cys Trp Xaa (2) INFORMATION FOR SEQ ID NO: 140:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 438 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear IS (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 140:
Met Asn Thr Pro Asn Gly Asn Ser Leu Ser Ala Ala Glu Leu Thr Cys 2O Gly Met Ile Met Cys Leu Ala Arg Gln Ile Pro Gln Ala Thr Ala Ser Met Lys Asp Gly Lys Trp Glu Arg Lys Lys Phe Met Gly Thr Glu Leu Asn Gly Lys Thr Leu Gly Ile Leu Gly Leu Gly Arg Ile Gly Arg Glu Val Ala Thr Arg Met Gln Ser Phe Gly Met Lys Thr Ile Gly Tyr Asp Pro Ile Ile Ser Pro Glu Val Ser Ala Ser Phe Gly Val Gln Gln Leu 3S Pro Leu Glu Glu Ile Trp Pro Leu Cys Asp Phe Ile Thr Val His Thr Pro Leu Leu Pro Ser Thr Thr Gly Leu Leu Asn Asp Asn Thr Phe Ala Gln Cys Lys Lys Gly Val Arg Val Val Asn Cys Ala Arg Gly Gly Ile Val Asp Glu Gly Ala Leu Leu Arg Ala Leu Gln Ser Gly Gln Cys Ala Gly Ala Ala Leu Asp Val Phe Thr Glu Glu Pro Pro Arg Asp Arg Ala SO Leu Val Asp His Glu Asn Val Ile Ser Cys Pro His Leu Gly Ala Ser Thr Lys Glu Ala Gln Ser Arg Cys Gly Glu Glu Ile Ala Val Gln Phe SS
Val Asp Met Val Lys Gly Lys Ser Leu Thr Gly Val Val Asn Ala Gln Ala Leu Thr Ser Ala Phe Ser Pro His Thr Lys Pro Trp Ile Gly Leu Ala Glu Ala Leu Gly Thr Leu Met Arg Ala Trp Ala Gly Ser Pro Lys Gly Thr Ile Gln Val Ile Thr Gln Gly Thr Ser Leu Lys Asn Ala Gly Asn Cys Leu Ser Pro Ala Val Ile Val Gly Leu Leu Lys Glu Ala Ser Lys Gln Ala Asp Val Asn Leu Val Asn Ala Lys Leu Leu Val Lys Glu Ala Gly Leu Asn Val Thr Thr Ser His Ser Pro Ala Ala Pro Gly Glu Gln Gly Phe Gly Glu Cys Leu Leu Ala Val Ala Leu Ala Gly Ala Pro 2~ Tyr Gln Ala Val Gly Leu Val Gln Gly Thr Thr Pro Val Leu Gln Gly Leu Asn Gly Ala Val Phe Arg Pro Glu Val Pro Leu Arg Arg Asp Leu Pro Leu Leu Leu Phe Arg Thr Gln Thr Ser Asp Pro Ala Met Leu Pro Thr Met Ile Gly Leu Leu Ala Glu Ala Gly Val Arg Leu Leu Ser Tyr 3d 385 390 395 400 Gln Thr Ser Leu Val Ser Asp Gly Glu Thr Trp His Val Met Gly Ile Ser Ser Leu Leu Pro Ser Leu Glu Ala Trp Lys Gln His Val Thr Glu Ala Phe Gln Phe His Phe (2) INFORMATION FOR SEQ ID NO: 141:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 264 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 141:
Met Ser Arg Pro Thr His Thr Pro Leu Ser Pro Ala Thr Ile Ser Pro Thr Ile Thr Val Ala Val Phe Phe Ala Val Phe Val Ala Ala Ala Ala Ala Thr Ala Val Val Ala Val Ala Ala Ala Thr Thr Ser Ser Gly Arg Arg Thr Xaa Asp Lys Ser Pro Ile Ala Thr Gln Ser Ser Val Thr His Ile Ala Ala Lys Arg Cys His Asn Tyr Thr Glu Cys Leu Ser Leu Ile Arg Xaa Thr Arg Ile Pro Thr Trp Xaa Xaa Xaa Thr Thr Cys Pro Ser Arg Ile Pro Ser Thr His Val Ala Ala Gly Ala Gly Phe Ile Arg Glu Arg Ala Cys Leu Gln Cys Gly Ala Val Gly Pro Pro Gly Cys Ile Leu IS Ala Ser Leu Pro Pro Pro Ser Leu Tyr Leu Ser Pro Glu Leu Arg Cys ME~t Pro Lys Arg Val Glu Ala Arg Ser Glu Leu Arg Leu Cys Pro Pro i45 150 155 160 Gly Val Xaa Xaa (2) INFORMATION FOR SEQ ID NO: 142:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 73 amino acids 3O (B) TYPE: amino acid (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 142:
Met Gln Arg Trp Val Cys Ile Leu Glu Phe Lys Glu Asn Leu Phe Gln Ile Pro Ser Ser Leu Val Ala Leu Leu Asn Thr Leu Phe Leu Asp Ile Leu His Pro Gln Asn Ser Leu Ser Pro His Gly Ser Phe Ser Leu Ser Ser Leu Ser Phe Pro Pro Leu Pro Val Ser Ser Leu Gln Pro Phe Leu Phe Leu Arg Ser Leu Leu Cys Arg Xaa (2) INFORMATION FOR SEQ ID NO: 143:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 123 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 143:
Phe Gly Thr Arg Phe Leu Ala Asn Leu Leu Leu Glu Glu Asp Asn Lys WO 98/5b804 PCT/US98/12125 Phe Cys Ala Asp Cys Gln Ser Lys Gly Pro Arg Tip Ala Ser Trp Asn S Ile Gly Val Phe Ile Cys Ile Arg Cys Ala Xaa Ile His Arg Asn Leu Gly Val His Ile Ser Arg Val Lys Ser Val Asn Leu Asp Gln Trp Thr 1~
Gln Val Gln Ile Gln Cys Met Gln Xaa Met Gly Asn Gly Lys Ala Asn Arg Leu Tyr G1u Ala Tyr Leu Pro Glu Thr Phe Arg Arg Pro Gln Ile Asp Pro Ala Val Glu Gly Phe Ile Arg Asp Xaa Tyr Glu Lys Lys Lys Tyr Met Asp Arg Ser Leu Gly His Gln Gds Leu ZS (2) INFORMATION FOR SEQ ID NO: 144:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 138 amino acids (B) TYPE: amino acid 3~ (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 144:
Met Ser Leu Tyr Asp Asp Leu Gly Val Glu Thr Ser Asp Ser Lys Thr Glu Gly Trp Ser Lys Asn Phe Lys Leu Leu Gln Ser Gln Leu Gln Val Lys Lys Ala Ala Leu Thr Gln Ala Lys Ser Gln Arg Thr Lys Gln Ser Thr Val Leu Ala Pro Val Ile Asp Leu Lys Arg Gly Gly Ser Ser Asp 4S Asp Arg Gln Ile Val Asp Thr Pro Pro His Val Ala Ala Gly Leu Lys Asp Pro Val Pro Ser Gly Phe Ser Ala Gly Glu Val Leu Ile Pro Leu Ala Asp Glu Tyr Asp Pro Met Phe Pro Asn Asp Tyr Glu Lys Val Val Lys Arg Ala Lys Arg Gly Thr Thr Glu Thr Ala Gly Val Xaa Lys Thr Lys Gly Asn Arg Arg Lys Gly Lys Lys Ala (2) INFORMATION FOR SEQ ID NO: 145:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 356 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 145:
Met Leu Ala Arg Ala Ala Arg Gly Thr Gly Ala Leu Leu Leu Arg Gly Ser Leu Leu Ala Ser Gly Arg Ala Pro Arg Arg Ala Ser Ser Gly Leu Pro Arg Asn Thr Val Val Leu Phe Val Pro Gln Gln Glu Ala Trp Val Val Glu Arg Met Gly Arg Phe His Arg Ile Leu Glu Pro Gly Leu Asn Ile Leu Ile Pro Val Leu Asp Arg Ile Arg Tyr Val Gln Ser Leu Lys Glu Ile Val Ile Asn Val Pro Glu Gln Ser Ala Val Thr Leu Asp Asn Val Thr Leu Gln Ile Asp Gly Val Leu Tyr Leu Arg Ile Met Asp Pro Tyr Lys Ala Ser Tyr Gly Val Glu Asp Pro Glu Tyr Ala Val Thr Gln Leu Ala Gln Thr Thr Met Arg Ser Glu Leu Gly Lys Leu Ser Leu Asp Lys Val Phe Arg Glu Arg Glu Ser Leu Asn Ala Ser Ile Val Asp Ala Ile Asn Gln Ala Ala Asp Cys Trp Gly Ile Arg Cys Leu Arg Tyr Glu Ile Lys Asp Ile His Val Pro Pro Arg Val Lys Glu Ser Met Gln Met Gln Val Glu Ala Glu Arg Arg Lys Arg Ala Thr Val Leu Glu Ser Glu Gly Thr Arg Glu Ser Ala Ile Asn Val Ala Glu Gly Lys Lys Gln Ala Gln Ile Leu Ala Ser Glu Ala Glu Lys Ala Glu Gln Ile Asn Gln Ala Ala Gly Glu Ala Ser Ala Val Leu Ala Lys Ala Lys Ala Lys Ala Glu Ala Ile Arg Ile Leu Ala Ala Ala Leu Thr Gln His Asn Gly Asp Ala Ala Ala Ser Leu Thr Val Ala Glu Gln Tyr Val Ser Ala Phe Ser Lys Leu Aia Lys Asp Ser Asn Thr Ile Leu Leu Pro Ser Asn Pro Gly Asp Val Thr Ser Met Val Ala Gln Ala Met Gly Val Tyr Gly Ala Leu Thr Lys Ala Pro Val Pro Gly Thr Pro Asp Ser Leu Ser Ser Gly Ser Ser Arg Asp Val Gln Gly Thr Asp Ala Ser Leu Asp Glu Glu Leu Asp Arg Val Lys Met Ser (2) INFORMATION FOR SEQ ID NO: 146:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 40 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 146:
Met Tyr Ile Leu Leu Phe Trp Gly Gly Xaa Phe His Arg Cys Leu Ser Xaa Leu Phe Asp Pro Glu Leu Xaa Ser Xaa Pro Gly Ile Ser Xaa Phe Thr Val Xaa Leu Gln Met Thr Xaa 4O (2) INFORMATION FOR SEQ ID NO: 147:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 71 amino acids (B) TYPE: amino acid 4S (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 147:
Met Pro Ser Pro Lys Tyr Cys Met His Thr Asn Asp Val Gln Ser Val Glu Tyr Asn Gly Asp Thr Leu Phe Gln Lys Leu Ser Ser Ser Xaa Leu ' 20 25 30 Ser Phe Lys Ser Ile His Ile Tyr Pro Asn Glu Xaa Lys Thr Cys Xaa Xaa Ile Phe Ile Ser Lys Val Tyr Met Ile Ser Lys Thr Trp Lys Xaa Pro Arg Phe Thr Ser Xaa Gly WO 98/Sb804 PCT/US98/12125 s5 70 S (2) INFORMATION FOR SEQ ID NO: 148:
(i} SEQUENCE CHARACTERISTICS:
(A) LENGTH: 33 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 148:
Met Asn Phe Val Leu Phe Phe Ile Gly Ile Asn Val Gly Cys Arg Gly Glu Asn Ser Leu Lys Tyr Phe Thr Val Thr Val Leu Cys Ser Pro Arg ASP
(2) INFORMATION FOR SEQ ID NO: 149:

(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 78 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 149:
Met Lys Glu Ala Gly Lys Gly Gly Val Ala Asp Ser Arg Glu Leu Lys Pro Met Val Gly Gly Asp Glu Glu Val Ala Ala Leu Gln Glu Phe His Phe His Phe Leu Ser Leu Ser Val Phe Thr Asp Cys Thr Ser Ser Gly Glu Ala Phe Val Ile Cys Ile Thr Gln Thr Cys Cys Ser Phe Cys Leu 55 s0 Cys Ala Tyr Pro Ser Leu Gly Txp Gln Asn Ser Cys His Asn (2) INFORMATION FOR SEQ ID N0: 150:
SO
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 32 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear SS (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 150:
Met Phe Ser Ser Lys Ser Leu Leu Val Leu Pro Phe Cys Phe Arg Ser Ala Ala His Leu Glu Leu Ser Val Trp Cys Val Cys Gly Val Arg Xaa (2) INFORMATION FOR SEQ ID N0: 151:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 464 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 151:
l5 Met Leu Ala Leu Gly Asn Asn His Phe Ile Gly Phe Val Asn Asp Ser Val Thr Lys Ser Ile Val Ala Leu Arg Leu Thr Leu Val Val Lys Val Ser Thr Xaa Pro Gly Glu Ser His Ala Asn Asp Leu Glu Cys Ser Gly Lys Gly Lys Cys Thr Thr Lys Pro Ser Glu Ala Thr Phe Ser Cys Thr Cys Glu Glu Gln Tyr Val Gly Thr Phe Cys Glu Glu Tyr Asp Ala Cys Gln Arg Lys Pro Cys Gln Asn Asn Ala Ser Cys Ile Asp Ala Asn Glu Lys Gln Asp Gly Ser Asn Phe Thr Cys Val Cys Leu Pro Gly Tyr Thr 100 105 llo Gly Glu Leu Cys Gln Ser Lys Ile Asp Tyr Cys Ile Leu Asp Pro Cys Arg Asn Gly Ala Thr Cys Ile Ser Ser Leu Ser Gly Phe Thr Cps Gln Cys Pro Glu Gly Tyr Phe Gly Ser Ala Cys Glu Glu Lys Val Asp Pro 145 150 i55 160 Gys Ala Ser Ser Pro Cps Gln Asn Asn Gly Thr Cars Tyr Val Asp Gly Val His Phe Thr CSrs Asn Cys Ser Pro Gly Phe Thr Gly Pro Thr Cys lso lss 190 Ala Gln Leu Ile Asp Phe Cys Ala Leu Ser Pro Cys Ala His Gly Thr Cys Arg Ser Val Gly Thr Ser Tyr Lys Cys Leu Cys Asp Pro Gly Tyr His Gly Leu Tyr Cps Glu Glu Glu Tyr Asn Glu Cys Leu Ser Ala Pro Cys Leu Asn Ala Ala Thr Cys Arg Asp Leu Val Asn Gly Tyr Glu Cps Val Cps Leu Ala Glu Tyr Lys Gly Thr His Cys Glu Leu Tyr Lys Asp Pro Cys Ala Asn Val Ser Cys Leu Asn Gly Ala Thr Cys Asp Ser Asp Gly Leu Asn Gly Thr Cps Ile Cys Ala Pro Gly Phe Thr Gly Glu Glu Cys Asp Ile Asp Ile Asn Glu Cys Asp Ser Asn Pro Cys His His Gly Gly Ser Cys Leu Asp Gln Pro Asn Gly Tyr Asn Xaa His Cys Pro His Gly Trp Val Gly Ala Asn Cys Glu Ile His Leu Gln Trp Lys Ser Gly His Met Ala Glu Ser Leu Thr Asn Met Pro Arg His Ser Leu Tyr Ile Ile Ile Gly Ala Leu Cys Val Ala Phe Ile Leu Met Leu Ile Ile Leu Ile Val Gly Ile Cys Arg Ile Ser Arg Ile Glu Tyr Gln Gly Ser Ser Arg Pro Ala Tyr Xaa Glu Phe Tyr Asn Cys Arg Ser Ile Asp Ser Glu Phe Ser Asn Ala Ile Ala Ser Ile Arg His Ala Arg Phe Gly Lys Lys Ser Arg Pro Ala Met Tyr Asp Val Ser Pro Ile Ala Tyr Glu Asp Tyr Ser Pro Asp Asp Lys Pro Leu Val Thr Leu Ile Lys Thr Lys Asp Leu (2) INFORMATION FOR SEQ ID NO: 152:
SO (i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 151 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 152:
Met His His Gln Met Thr Arg Thr Thr Leu Met Thr Lys Gln His Glu Leu Gly Gly Leu Leu Ala Leu Val Gln Asn Cys Gln Ser Glu Met Asn Ile Lys Asp Ser Arg Ala Val Gly Leu Ser Val Lys Arg Leu Cys Ile Ser Phe Val Asp Glu Phe Cys Glu Arg Thr Glu Arg Pro Leu Tyr Leu Ala Gln Gly Leu Phe Met Lys Arg Glu Thr Tyr Trp Glu VaI Gln Asp Ser Gly Ile Ser Pro Leu Leu Leu Leu Leu Ser Thr Ala Leu Asp Cys Ser Pro Glu Ala Glu Thr Arg Gln Ser Pro Gly Gly Arg Lys Met Leu Gln Glu Pro Thr Leu Ser Met Ser Leu Gln Ile Leu Thr Gly Phe Leu 2~ Trp Val Gln Leu Trp Asn Trp Glu Thr Phe Leu Arg Ile Arg Thr His Ser Thr Asp Ala Ser Cys Pro (2) INFORMATION FOR SEQ ID NO: 153:
3O (i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 299 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 153:
Met Ala Gln Asn Leu Lys Asp Leu Ala Gly Arg Leu Pro Ala Gly Pro Arg Gly Met Gly Thr Ala Leu Lys Leu Leu Leu Gly Ala Gly Ala Val Ala Tyr Gly Val Arg Glu Ser Val Phe Thr Val Glu Gly Gly His Arg Ala Ile Phe Phe Asn Arg Ile Gly Gly Val Gln Gln Asp Thr Ile Leu Ala Glu Gly Leu His Phe Arg Ile Pro Trp Phe Gln Tyr Pro Ile Ile s5 70 75 ao Tyr Asp Ile Arg Ala Arg Pro Arg Lys Ile Ser Ser Pro Thr G1y Ser Lys Asp Leu Gln Met Val Asn Ile Ser Leu Arg Val Leu Ser Arg Pro Asn Ala Gln Glu Leu Pro Ser Met Tyr Gln Arg Leu Gly Leu Asp Tyr Glu Glu Arg Val Leu Pro Ser Ile Val Asn Glu Val Leu Lys Ser Val Val Ala Lys Phe Asn Ala Ser Gln Leu Ile Thr Gln Arg Ala Gln Val Ser Leu Leu Ile Arg Arg Glu Leu Thr Glu Arg Ala Lys Asp Phe Ser Leu Ile Leu Asp Asp Val Ala Ile Thr Glu Leu Ser Phe Ser Arg Glu Tyr Thr Ala Ala Val Glu Ala Lys Gln Val Ala Gln Gln Glu Ala Gln IS Arg Ala Xaa Phe Leu Val Glu Lys Ala Lys Gln Glu Gln Arg Gln Lys Ile Val Gln Ala Glu Gly Glu Ala Glu Ala Ala Lys Met Leu Gly Glu Ala Leu Ser Lys Asn Pro Gly Tyr Ile Lys Leu Arg Lys Ile Arg Ala Ala Gln Asn Ile Ser Lys Thr Ile Ala Thr Ser Gln Asn Arg I1e Tyr Leu Thr Ala Asp Asn Leu Val Leu Asn Leu Gln Asp Glu Ser Phe Thr Arg Gly Ser Asp Ser Leu Ile Lys Gly Lys Lys 3S {2) INFORMATION FOR SEQ ID NO: 154:
(i} SEQUENCE CHARACTERISTICS:
(A) LENGTH: 398 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 154:
Met Leu Arg Gly Pro Trp Arg Gln Leu Trp Leu Phe Xaa Leu Leu Leu Leu Pro Gly Ala Pro Glu Pro Arg Gly Ala Ser Arg Pro Trp Glu Gly Thr Asp Glu Pro Gly Ser Ala Trp Ala Trp Pro Gly Phe Gln Arg Leu Gln Glu Gln Leu Arg Ala Ala Gly Ala Leu Ser Lys Arg Tyr Trp Thr SJr Leu Phe Ser Cys Gln Val Tip Pro Asp Asp Cys Asp Glu Asp Glu Glu Ala Ala Thr Gly Pro Leu Gly Trp Arg Leu Pro Leu Leu Gly Gln Arg i Tyr Leu Asp Leu Leu Thr Thr Trp Tyr Cys Ser Phe Lys Asp Cys Cys Pro Arg Gly Asp Cys Arg Ile Ser Asn Asn Phe Thr Gly Leu Glu Trp $ 115 120 125 Asp Leu Asn Val Arg Leu His Gly Gln His Leu Val Gln Gln Leu Val 1~ Leu Arg Thr Val Arg Gly Tyr Leu Glu Thr Pro Gln Pro Glu Lys Ala 145 150 155 i60 Leu Ala Leu Ser Phe His Gly Trp Ser Gly Thr Gly Lys Asn Phe Val 1$
Ala Arg Met Leu Val Glu Asn Leu Tyr Arg Asp Gly Leu Met Ser Asp Cys Val Arg Met Phe Ile Ala Thr Phe His Phe Pro His Pro Lys Tyr Val Asp Leu Tyr Lys Glu Gln Leu Met Ser Gln Ile Arg Glu Thr Gln 25 Gln Leu Cys His Gln Thr Leu Phe Ile Phe Asp Glu Ala Glu Lys Leu His Pro Gly Leu Leu Glu Val Leu Gly Pro His Leu Glu Arg Arg Ala Pro Xaa Gly His Arg Ala Glu Ser Pro Trp Thr Ile Phe Leu Phe Leu Ser Asn Leu Arg Gly Asp Ile Ile Asn Glu Val Val Leu Lys Leu Leu Lys Ala Gly Trp Ser Arg Glu Glu Ile Thr Met Glu His Leu Glu Pro 4~ His Leu Gln Ala Glu Ile Val Glu Thr Ile Asp Asn Gly Phe Gly His Ser Arg Leu Val Lys Glu Asn Leu Ile Asp Tyr Phe Ile Pro Phe Leu Pro Leu Glu Tyr Arg His Val Arg Leu Cys Ala Arg Asp Ala Phe Leu Ser Gln Glu Leu Leu Tyr Lys Glu Glu Thr Leu Asp Glu Ile Ala Gln J~ 355 360 365 Met Met Val Tyr Val Pro Lys Glu Glu Gln Leu Phe Ser Ser Gln Gly Cars Lys Ser Ile Ser Gln Arg Ile Asn Tyr Phe Leu Ser Xaa C)U (2? INFORMATION FOR SEQ ID NO: 155:

(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 83 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 155:
Met Ala Phe Thr Leu Tyr Ser Leu Leu Gln Ala Xaa Leu Leu Cys Val Asn Ala Ile Ala Val Leu His Glu Glu Arg Phe Leu Lys Asn Ile Gly Trp Gly Thr Asp Gln Gly Ile Gly Gly Phe Gly Glu Glu Pro Gly Ile Lys Ser Gln Leu Met Asn Leu Ile Arg Ser Val Arg Thr Val Met Arg 20 Val Pro Leu Ile Ile Val Asn Ser Ile Ala Ile Val Leu Leu Leu Leu Phe Gly Xaa (2) INFORMATION FOR SEQ ID NO: 156:
3O (i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 50 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 156:
Met Ala Pro Arg Asn Gln Gly Ser Phe Ser Phe Gly Asn Phe Met Leu Phe Leu Val Leu Ile Glu Arg Arg Tyr Leu Pro Phe Leu Ser Pro Ile Leu Phe Cys Cys Ser Thr His Asn Arg Ser Ala Val Thr Ala Thr Asn Leu xaa SO (2) INFORMATION FOR SEQ ID NO: 157:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 51 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 157:
Met Asp Val Leu Thr Val Ala Phe Leu Ser Ile Leu Ile Thr Ala Pro i Ile Gly Ser Leu Leu Ile Gly Leu Leu Gly Pro Arg Leu Leu Gln Lys Val Glu His Gln Asn Lys Asp Glu Glu Val Gln Gly Glu Thr Ser Val Gln Val Xaa IG
(2) INFORMATION FOR SEQ ID NO: 158:
(i) SEQUENCE CHARACTERISTICS:
IS (A) LENGTH: 17 amino acids IB) TYPE: amino acid (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 158:
2G Pro Asn Ser Phe Ser Cys Leu Gly Leu Ala Gly Thr Gly Ala Gly Ile Xaa (2) INFORMATION FOR SEQ ID NO: 159:
3O (i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 53 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 159:

Met Gly Arg Tyr His Phe Val Phe Leu Thr Phe Phe Phe Ser Thr Tyr Ser Ser Cys Phe Tyr Pro Val Val Ser Gln Val Leu Tyr Leu Val Cys Ser Cys Thr Ala Asp Arg Pro Leu Met Ala Pro Val Gly Ser Cys Leu 4S Gly Gly Arg Asn Xaa SG (2) INFORMATION FOR SEQ ID NO: 160:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 64 amino acids (B) TYPE: amino acid S S (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 160:
Met Phe Val Thr Leu Ser Ile Leu Asn Ile Thr Ile Glu Lys Asp Lys Ser Thr Asn Arg Phe Arg Asp Val Phe Leu Gln His Ile Leu Val Ile Leu Met Pro Ser Leu Thr Tyr Cys Leu Ile Gly Gln His Leu Cys Ser Phe Thr Arg Tyr Val Ser Leu Cys Tyr Ser Arg Cys His Ser Trp Xaa IS (2) INFORMATION FOR SEQ ID NO: 162:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 33 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 161:
Met Ser Ile Cys Pro Leu Leu Val Met Leu Ile Leu Ile Thr Trp Val Arg Cps Pro Val Ser Pro Val Tyr Arg Tyr Cys Phe Ser Phe Cys Asn Xaa (2) INFORMATION FOR SEQ ID NO: 162:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 95 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear 4O (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 162:
Met Gln Asp Ile Val Tyr Lys Leu Val Pro Gly Leu Gln Glu Gly Glu Cys LeL~ Thr Val Leu Leu Ile Pro Glu Val Pro Ala Trp Pro Leu Gln Pro Leu Leu Ser Trp Lys Phe Gly Ser Arg Met Gly Gly Pro Phe Pro JO
Phe Gly Arg Ile Thr Val Phe Ser Ser Leu Leu Ser Ala Gln Leu His Leu Leu Gly Trp Ser Leu Leu Ser Ser Lys Met Arg Xaa His Leu Phe Thr Pro Tyr Val Tyr Ser Phe Ser Lys Tyr Gly Ser His Val Xaa i (2) INFORMATION FOR SEQ ID NO: 163:
(i) SEQUENCE CHARACTERISTICS:
iA) LENGTH: 58 amino acids (B) TYPE: amino acid (D) 'I1DPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0: 163:
Met Lys Val Leu Ala Thr Ser Phe Val Leu Gly Ser Leu Gly Leu Ala Phe Tyr Leu Pro Leu Val Val Thr Thr Pro Lys Thr Leu Ala Ile Pro Xaa Glu Ala Ala Arg Ser Cys Gly Glu Ser Tyr His Gin Cys His Asn Leu Tyr Cys His Leu Trp Pro Trp Leu Xaa 2~ 50 55 (2) INFORMATION FOR SEQ ID NO: 164:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 44 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 164:
Met Asp Tyr Gly Tyr Tyr Ser Ala Gly Gln Phe Leu Leu His Leu Phe Leu Ala Asp Leu Thr Gln Ala Thr Thr Gln Gln Lys Thr Asn Thr Ser Glu Asn Gly Cys Lys Phe Val Cys Ala Val Phe Xaa (2) INFORMATION FOR SEQ ID NO: 165:
4S (i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 18 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 165:
Gly Ile Val Leu Leu Ile Gly Val Leu Val Gln Val Ser Ala Val Asp Asp Xaa (2) INFORMATION FOR SEQ ID NO: 166:

(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 30 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear S (xi) SEQUENCE DESCRIPTION: SEQ ID N0: 166:
Met Gly Asn Ala Phe Glu Val Thr Gly Leu Met Leu Ala Leu Leu Cys Tyr Val Val Asp Gly Gln Lys Pro Lys Xaa Gly Phe Xaa Xaa IS (2) INFORMATION FOR SEQ ID NO: 167:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 37 amino acids (B) TYPE: amino acid 20 (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 167:
Met Ser His Glu Lys Ser Asn Glu Leu Val Leu Leu Ile VaI Thr Val Met Arg Ser Leu Thr Tyr Asn Ile Ala Val Val AIa Ala Trp Phe Asn Gly Cys Ile Arg Xaa (2) INFORMATION FOR SEQ ID NO: 168.

(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 40 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 168:
Met Tyr Leu Leu Tyr Leu Pro Ser Ala Leu Leu Pro Pro Tyr Pro Thr 4S Cys Pro Tyr Glu His Gly Ser Pro Trp Pro His Thr Pro Ala Lys Leu Leu Cys Cars Phe Ala Phe Leu Xaa (2) INFORMATION FOR SEQ ID NO: 169:
S 5 (i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 47 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 169:

i Met Lys Phe Ile Val Trp Arg Arg Phe Lys Trp Val Ile Ile Gly Leu Leu Phe Leu Leu Ile Leu Leu Leu Phe Val Ala Val Leu Leu Tyr Ser Leu Pro Asn Tyr Leu Ser Met Lys Ile Val Lys Pro Asn Val Xaa IG
(2) INFORMATION FOR SEQ ID NO: 170:
(i) SEQUENCE CHARACTERISTICS:
IS (A) LENGTH: 34 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 170:
2G Ile Glu Trp Ser Gly Tyr Asn Lys Pro Glu Arg Lys Gly Pro Leu Ala Leu Phe Leu Val Phe Leu Phe Leu Asp Thr Pro Pro Leu G1n Gly Asp Leu Xaa (2) INFORMATION FOR SEQ ID NO: 171:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 5 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 171:
Met Ser Leu Leu Xaa (2) INFORMATION FOR SEQ ID N0: 172:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 25 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear JG (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 172:
- Met Gln Leu Leu Ile Val Trp Asn Glu Ser Leu Thr Asn Ser Val Pro Ala Ser Val Asp Thr Ser Gln Cys Xaa C)O (2) INFORMATION FOR SEQ ID NO: 173:

(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 262 amino acids _ (B) TYPE: amino acid (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0: 173:
Met Ala Leu Gly Leu Lys Cys Phe Arg Met Val His Pro Thr Phe Arg Asn Tyr Leu AIa Ala Ser Ile Arg Pro Val Ser Glu Val Thr Leu Lys Thr Val His Glu Arg Gln His Gly His Arg Gln Tyr Met Ala Tyr Ser Ala Val Pro Val Arg His Phe Ala Thr Lys Lys Ala Lys Ala Lys Gly 20 Lys Gly Gln Ser Gln Thr Arg Val Asn Ile Asn Ala Ala Leu Val Glu Asp Ile Ile Asn Leu Glu Glu Val Asn Glu Glu Met Lys Ser Val Ile Glu Ala Leu Lys Asp Asn Phe Asn Lys Thr Leu Asn Ile Arg Thr Ser Pro Gly Ser Leu Asp Lys Ile Ala Val Val Thr Ala Asp Gly Lys Leu Ala Leu Asn Gln Ile Ser Gln Ile Ser Met Lys Ser Pro Gln Leu Ile 130 i35 140 Leu Val Asn Met Ala Ser Phe Pro Glu Cys Thr Ala Ala Ala Ile Lys Ala Ile Arg Glu Ser Gly Met Asn Leu Asn Pro Glu Val Glu Gly Thr Leu Ile Arg Val Pro Ile Pro Gln Val Thr Arg Glu His Arg Glu Met Leu Val Lys Leu Ala Lys Gln Asn Thr Asn Lys Ala Lys Asp Ser Leu Arg Lys Val Arg Thr Asn Ser Met Asn Lys Leu Lys Lys Ser Lys Asp Thr Val Ser Glu Asp Thr Ile Arg Leu Ile Glu Lys Gln Ile Ser Gln Met Ala Asp Asp Thr Val Ala Glu Leu Asp Arg His Leu Ala Val Lys Thr Lys Glu Leu Leu Gly (2) INFORMATION FOR SEQ ID NO: 174:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 967 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 174:
Met Gln Arg Ala Val Pro Glu Gly Phe Gly Arg Arg Lys Leu Gly Ser Asp Met Gly Asn Ala Glu Arg Ala Pro Gly Ser Arg Ser Phe Gly Pro IS Val Pro Thr Leu Leu Leu Leu Xaa Ala Ala Leu Leu Xaa Val Ser Asp Ala Leu Gly Arg Pro Ser Glu Glu Asp Glu Glu Leu Val Val Pro Glu Leu Glu Arg Ala Pro Gly His Gly Thr Thr Arg Leu Arg Leu His Ala Phe Asp Gln Gln Leu Asp Leu Glu Leu Arg Pro Asp Ser Ser Phe Leu Ala Pro Gly Phe Thr Leu Gln Asn Val Gly Arg Lys Ser Gly Ser Glu Thr Pro Leu Pro Glu Thr Asp Leu Ala His Cys Phe Tyr Ser Gly Thr Val Asn Gly Asp Pro Ser Ser Ala Ala Ala Leu Ser Leu Cys Glu Gly Val Arg Gly Ala Phe Tyr Leu Leu Gly Glu Ala Tyr Phe Ile Gln Pro Leu Pro Ala Ala Ser Glu Arg Leu Xaa Thr Ala Ala Pro Gly Glu Lys Pro Pro Ala Pro Leu Gln Phe His Leu Leu Arg Arg Asn Arg Gln Gly Asp Val Gly Gly Thr Cys Gly Val Val Asp Asp Glu Pro Arg Pro Thr Gly Lys Ala Glu Thr Glu Asp Glu Asp Glu Gly Thr Glu Gly Glu Asp Glu Gly Pro Gln Trp Ser Pro Gln Asp Pro Ala Leu Gln Gly Val Gly Gln Pro Thr Gly Thr Gly Ser Ile Arg Lys Lys Arg Phe Val Ser Ser 5Jr 245 250 255 His Arg Tyr Val Glu Thr Met Leu Val Ala Asp Gln Ser Met Ala Glu Phe His Gly Ser Gly Leu Lys His Tyr Leu Leu Thr Leu Phe Ser Val Ala Ala Arg Leu Xaa Lys His Pro Xaa Ile Arg Asn Ser Val Ser Leu Val Val Val Lys Ile Leu Val Ile His Asp Glu Gln Lys Gly Pro Glu Va1 Thr Ser Asn Ala Ala Leu Thr Leu Arg Asn Phe Cys Asn Trp Gln Lys Gln His Asn Pro Pro Ser Asp Arg Asp Ala Glu His Tyr Asp Thr IS Ala Ile Leu Phe Thr Arg Gln Asp Leu Cys Gly Ser Gln Thr Cys Asp Thr Leu Gly Met Ala Asp Val Gly Thr Val Cys Asp Pro Ser Arg Ser Cys Ser Val Ile Glu Asp Asp Gly Leu Gln Ala Ala Phe Thr Thr Ala His Glu Leu Gly His Val Phe Asn Met Pro His Asp Asp Ala Lys Gln Cys Ala Ser Leu Asn Gly Val Asn Gln Asp Ser His Met Met Ala Ser Met Leu Ser Asn Leu Asp His Ser Gln Pro Trp Ser Pro Cys Ser Ala Tyr Met Ile Thr Ser Phe Leu Asp Asn Gly His Gly Glu Cys Leu Met Asp Lys Pro Gln Asn Pro Ile Gln Leu Pro Gly Asp Leu Pro Gly Thr Ser Tyr Asp Ala Asn Arg Gln Cys Gln Phe Thr Phe Gly Glu Asp Ser Lys His Cys Pro Asp Ala Ala Ser Thr Cps Ser Thr Leu Trp Cys Thr Gly Thr Ser Gly Gly Val Leu Val Cars Gln Thr Lys His Phe Pro Trp Ala Asp Gly Thr Ser Cys Gly Glu Gly Lys Trp Cys I1e Asn Gly Lys Cys Val Xaa Lys Thr Asp Arg Lys His Phe Asp Thr Pro Phe His Gly Ser Trp Gly Met Trp Gly Pro Trp Gly Asp Cys Ser Arg Thr Cys Gly Gly Gly Val Gln Tyr Thr Met Arg Glu Cars Asp Asn Pro Val Pro Lys Asn Gly G1y Lys Tyr Cys Glu Gly Lys Arg Val Arg Tyr Arg Ser Cys i WO 98156804 PCT/US98/12~25 ~ Asn Leu Glu Asp Cys Pro Asp Asn Asn Gly Lys Thr Phe Arg Glu Glu Gln Cys Glu Ala His Asn Glu Phe Ser Lys Ala Ser Phe Gly Ser Gly Pro Ala Val Glu Trp Ile Pro Lys Tyr Ala Gly Val Ser Pro Lys Asp Arg Cys Lys Leu Ile Cys Gln Ala Lys Gly Ile Gly Tyr Phe Phe Val IS Leu Gln Pro Lys Val Val Asp Gly Thr Pro Cys Ser Pro Asp Ser Thr Ser Val Cys Val Gln Gly Gln Cys Val Lys Ala Gly Cys Asp Arg Ile Ile Asp Ser Lys Lys Lys Phe Asp Lys Cys Gly Val Cys Gly Gly Asn Gly Ser Thr Cys Lys Lys Ile Ser Gly Ser Val Thr Ser Ala Lys Pro Gly Tyr His Asp Ile Ile Thr Ile Pro Thr Gly Ala Thr Asn Ile Glu Val Lys Gln Arg Asn Gln Arg Gly Ser Arg Asn Asn Gly Ser Phe Leu Ala Ile Lys Ala Ala Asp Gly Thr Asn Gly Asp Tyr Ile Leu Tyr Thr Leu Ser Thr Leu Glu Gln Asp Ile Gly Val Val Met Tyr Lys Leu Arg Tyr Ser Gly Ser Ser Ala Ala Leu Arg Ser Phe Glu Arg Ile Ser Pro Leu Lys Glu Pro Leu Thr Ile Gln Val Gly Asn Val Leu Thr Ala Leu Arg Pro Lys Ile Lys Tyr Thr Tyr Lys Lys Lys Phe Val Lys Glu Ser Phe Asn Ala Ile Pro Thr Phe Ser Ile Glu Glu Ala Trp Val Trp Gly Glu Cys Ser Lys Ser Cys Glu Leu Arg Arg Leu Gly Trp Gln Val Glu Cys Arg Asp Ile Asn Gly Gln Pro Cys Ala Lys Ala Ser Glu Glu Val Lys Pro Ala Ser Thr Arg Pro Cys Pro Cys Pro Ala Asp His Gln Trp Gln Leu Gly Glu Trp Ser Ser Cys Cys Gly Lys Ser Lys Thr Gly Tyr Lys Lys Arg Ser Leu Lys Cys Leu Ser His Asp Gly Gly Val Leu Ser His Glu Ser Cys Asp Pro Leu Lys Lys Pro Lys His Phe Ile Asp Phe Cys Thr Met Ala Glu Cys Ser lO 965 (2) INFORMATION FOR SEQ ID NO: 175:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 19 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear ZO (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 175:
Met Leu Lys Ile Pro Thr His Leu Glu Gly Lys Ile Lys Ile Thr Lys Val Tyr Xaa 3O (2) INFORMATION FOR SEQ ID NO: 176:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 205 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID N0: 176:
Met Tyr Glu Thr Met Lys Leu Asp Ala Cys Xaa His Gln Gln Arg Pro Thr Leu Gln Ala Gly Pro Lys Leu Leu Thr Leu Ala Pro Arg Glu Glu Pro Arg Gly Gln Ser Gly Arg Gly Ser Glu Leu Thr Ala Arg Gln Arg His Ser Thr Gly Asp Pro Gln Gly Glu Gln Ala Leu Pro Arg Ala Gly Cys Val Thr Gly Pro Pro Ala Thr Pro His Arg Pro Ser Glu Pro Gln Leu Leu Arg Thr His Pro Asp Ala Arg Pro Lys Ser Ala Met Ala Gln Thr Phe Val His GIn Gly Pro Val Ala Leu Gln Gln Leu Thr Thr Asn Arg Arg Val Glu Thr Ser Met Ser Ser Asp Gly His Gly Gln Asn Pro DE11JIANDES OU BRI=1IETS VOLUI1111NEUX

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Claims

What Is Claimed Is:

1. An isolated nucleic acid molecule comprising a polynucleotide having a nucleotide sequence at least 95% identical to a sequence selected from the group consisting of:
(a) a polynucleotide fragment of SEQ ID NO:X or a polynucleotide fragment of the cDNA sequence included in ATCC Deposit No:Z, which is hybridizable to SEQ
ID
NO:X;
(b) a polynucleotide encoding a polypeptide fragment of SEQ ID NO:Y or a polypeptide fragment encoded by the cDNA sequence included in ATCC Deposit No:Z, which is hybridizable to SEQ ID NO:X;
(c) a polynucleotide encoding a polypeptide domain of SEQ ID NO:Y or a polypeptide domain encoded by the cDNA sequence included in ATCC Deposit No:Z, which is hybridizable to SEQ ID NO:X;
(d) a polynucleotide encoding a polypeptide epitope of SEQ ID NO:Y or a polypeptide epitope encoded by the cDNA sequence included in ATCC Deposit No:Z, which is hybridizable to SEQ ID NO:X;
(e) a polynucleotide encoding a polypeptide of SEQ ID NO:Y or the cDNA
sequence included in ATCC Deposit No:Z, which is hybridizable to SEQ ID NO:X, having biological activity;
(f) a polynucleotide which is a variant of SEQ ID NO:X;
(g) a polynucleotide which is an allelic variant of SEQ ID NO:X;
(h) a polynucleotide which encodes a species homologue of the SEQ ID NO:Y;
(i) a polynucleotide capable of hybridizing under stringent conditions to any one of the polynucleotides specified in (a)-(h), wherein said polynucleotide does not hybridize under stringent conditions to a nucleic acid molecule having a nucleotide sequence of only A residues or of only T residues.

2. The isolated nucleic acid molecule of claim 1, wherein the polynucleotide fragment comprises a nucleotide sequence encoding a secreted protein.

3. The isolated nucleic acid molecule of claim 1, wherein the polynucleotide fragment comprises a nucleotide sequence encoding the sequence identified as SEQ ID NO:Y or the polypeptide encoded by the cDNA sequence included in ATCC Deposit No:Z, which is hybridizable to SEQ ID NO:X.

4. The isolated nucleic acid molecule of claim l, wherein the polynucleotide fragment comprises the entire nucleotide sequence of SEQ ID
NO:X or the cDNA sequence included in ATCC Deposit No:Z, which is hybridizable to SEQ
ID
NO:X.

5. The isolated nucleic acid molecule of claim 2, wherein the nucleotide sequence comprises sequential nucleotide deletions from either the C-terminus or the N-terminus.

6. The isolated nucleic acid molecule of claim 3, wherein the nucleotide sequence comprises sequential nucleotide deletions from either the C-terminus or the N-terminus.

7. A recombinant vector comprising the isolated nucleic acid molecule of claim 1.

8. A method of making a recombinant host cell comprising the isolated nucleic acid molecule of claim 1.

9. A recombinant host cell produced by the method of claim 8.

10. The recombinant host cell of claim 9 comprising vector sequences.

11. An isolated polypeptide comprising an amino acid sequence at least 95%
identical to a sequence selected from the group consisting of:
(a) a polypeptide fragment of SEQ ID NO:Y or the encoded sequence included in ATCC Deposit No:Z;
(b) a polypeptide fragment of SEQ ID NO:Y or the encoded sequence included in ATCC Deposit No:Z, having biological activity;
(c) a polypeptide domain of SEQ ID NO:Y or the encoded sequence included in ATCC Deposit No:Z;
(d) a polypeptide epitope of SEQ ID NO:Y or the encoded sequence included in ATCC Deposit No:Z;
(e) a secreted form of SEQ ID NO:Y or the encoded sequence included in ATCC Deposit No:Z;
(f) a full length protein of SEQ ID NO:Y or the encoded sequence included in ATCC Deposit No:Z;

(g) a variant of SEQ ID NO:Y;
(h) an allelic variant of SEQ ID NO:Y; or (i) a species homologue of the SEQ ID NO:Y.

12. The isolated polypeptide of claim 11, wherein the secreted form or the full length protein comprises sequential amino acid deletions from either the C-terminus or the N-terminus.

13. An isolated antibody that binds specifically to the isolated polypeptide of claim 11.

14. A recombinant host cell that expresses the isolated polypeptide of claim 11.

15. A method of making an isolated polypeptide comprising:
(a) culturing the recombinant host cell of claim 14 under conditions such that said polypeptide is expressed; and (b) recovering said polypeptide.

16. The polypeptide produced by claim 15.

17. A method for preventing, treating, or ameliorating a medical condition, comprising administering to a mammalian subject a therapeutically effective amount of the polypeptide of claim 11 or the polynucleotide of claim 1.

18. A method of diagnosing a pathological condition or a susceptibility to a pathological condition in a subject comprising:
(a) determining the presence or absence of a mutation in the polynucleotide of claim 1; and (b) diagnosing a pathological condition or a susceptibility to a pathological condition based on the presence or absence of said mutation.

19. A method of diagnosing a pathological condition or a susceptibility to a pathological condition in a subject comprising:
(a) determining the presence or amount of expression of the polypeptide of claim 11 in a biological sample; and (b) diagnosing a pathological condition or a susceptibility to a pathological condition based on the presence or amount of expression of the polypeptide.

20. A method for identifying a binding partner to the polypeptide of claim 11 comprising:
(a) contacting the polypeptide of claim 11 with a binding partner; and (b) determining whether the binding partner effects an activity of the polypeptide.

21. The gene corresponding to the cDNA sequence of SEQ ID NO:Y.

22. A method of identifying an activity in a biological assay, wherein the method comprises:
(a) expressing SEQ ID NO:X in a cell;
(b) isolating the supernatant;
(c) detecting an activity in a biological assay; and (d) identifying the protein in the supernatant having the activity.

23. The product produced by the method of claim 22.