ZA200208657B - Novel compounds. - Google Patents

Description

x WO 01/81363 PCT/US01/13360

Novel Compounds \ Field of Invention

This invention relates to newly identified polypeptides and polynucleotides ] encoding such polypeptides, to their use in diagnosis and in identifying compounds that may be agonists, antagonists that are potentially useful in therapy, and to production of such polypeptides and polynucleotides. The polynucleotides and polypeptides of the present invention also relate to proteins with signal sequences which allow them to be secreted extracellularly or membrane-associated (hereinafter often referred collectively as secreted proteins or secreted polypeptides).

Background of the Invention

The drug discovery process is currently undergoing a fundamental revolution as it embraces "functional genomics”, that is, high throughput genome- or gene-based biology.

This approach as a means to identify genes and gene products as therapeutic targets is rapidly superseding earlier approaches based on "positional cloning”. A phenotype, that is a biological function or genetic disease, would be identified and this would then be tracked back to the responsible gene, based on its genetic map position.

Functional genomics relies heavily on high-throughput DNA sequencing technologies and the various tools of bioinformatics to identify gene sequences of potential interest from the many molecular biology databases now available. There is a continuing need to identify and characterise further genes and their related polypeptides/proteins, as targets for drug discovery.

Proteins and polypeptides that are naturally secreted into blood, lymph and other body fluids, or secreted into the cellular membrane are of primary interest for pharmaceutical research and development. The reason for this interest is the relative ease to target protein therapeutics into their place of action (body fluids or the cellular membrane).

The natural pathway for protein secretion into extracellular space is the endoplasmic reticulum in eukaryotes and the inner membrane in prokaryotes (Palade, 1975, Science, 189, 347; Milstein, Brownlee, Harrison, and Mathews, 1972, Nature New Biol., 239, 117;

Blobel, and Dobberstein, 1975, J. Cell. Biol., 67, 835). On the other hand, there is no known , natural pathway for exporting a protein from the exterior of the cells into the cytosol (with the exception of pinocytosis, a mechanism of snake venom toxin intrusion into cells).

Therefore targeting protein therapeutics into cells poses extreme difficulties.

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N WO 01/81363 PCT/US01/13360

The secreted and membrane-associated proteins include but are not limited to all peptide hormones and their receptors (including but not limited to insulin, growth hormones, chemokines, cytokines, neuropeptides, integrins, kallikreins, , lamins, melanins, natriuretic hormones, neuropsin, neurotropins, pituitiary hormones, pleiotropins, prostaglandins, secretogranins, selectins, thromboglobulins, . thymosins), the breast and colon cancer gene products, leptin, the obesity gene protein and its receptors, serum albumin, superoxide dismutase, spliceosome proteins, 7TM (transmembrane) proteins also called as G-protein coupled receptors, immunoglobulins, several families of serine proteinases (including but not limited to proteins of the blood coagulation cascade, digestive enzymes), deoxyribonuclease

I, etc.

Therapeutics based on secreted or membrane-associated proteins approved by FDA or foreign agencies include but are not limited to insulin, glucagon, growth hormone, chorionic gonadotropin, follicle stimulating hormone, luteinizing hormone, calcitonin, adrenocorticotropic hormone (ACTH), vasopressin, interleukines, interferones, immunoglobulins, lactoferrin (diverse products marketed by several companies), tissue-type plasminogen activator (Alteplase by Genentech), hyaulorindase (Wydase by Wyeth-Ayerst), dornase alpha (Pulmozyme\ by

Genentech), Chymodiactin (chymopapain by Knoll), alglucerase (Ceredase by

Genzyme), streptokinase (Kabikinase by Pharmacia) (Streptase by Astra), etc. This indicates that secreted and membrane-associated proteins have an established, proven history as therapeutic targets. Clearly, there is a need for identification and characterization of further secreted and membrane-associated proteins which can play a role in preventing, ameliorating or correcting dysfunction or disease, including but not limited to diabetes, breast-, prostate-, colon cancer and other malignant tumors, hyper- and hypotension, obesity, bulimia, anorexia, growth abnormalities, asthma, manic depression, dementia, delirium, mental retardation,

Huntington's disease, Tourette's syndrome, schizophrenia, growth, mental or sexual development disorders, and dysfunctions of the blood cascade system including those leading to stroke. The proteins of the present invention which include the signal sequences are also useful to further elucidate the mechanism of protein transport which at present is not entirely understood, and thus can be used as research tools.

Summary of the Invention

The present invention relates to particular polypeptides and polynucleotides of the genes set forth in Table I, including recombinant materials and methods for their production.

Such polypeptides and polynucleotides are of interest in relation to methods of treatment of certain diseases, including, but not limited to, the diseases set forth in Tables Ill and V, hereinafter referred to as "diseases of the invention". In a further aspect, the invention . relates to methods for identifying agonists and antagonists (e.g., inhibitors) using the materials provided by the invention, and treating conditions associated with imbalance of polypeptides and/or polynucleotides of the genes set forth in Table I with the identified compounds. In still a further aspect, the invention relates to diagnostic assays for detecting diseases associated with inappropriate activity or levels the genes set forth in Table IL.

Another aspect of the invention concerns a polynucleotide comprising any of the nucleotide sequences set forth in the Sequence Listing and a polypeptide comprising a polypeptide encoded by the nucleotide sequence. In another aspect, the invention relates to a polypeptide comprising any of the polypeptide sequences set forth in the Sequence Listing and recombinant materials and methods for their production. Another aspect of the invention relates to methods for using such polypeptides and polynucleotides. Such uses include the treatment of diseases, abnormalities and disorders (hereinafter simply referred to as diseases) caused by abnormal expression, production, function and or metabolism of the genes of this invention, and such diseases are readily apparent by those skilled in the art from the homology to other proteins disclosed for each attached sequence. In still another aspect, the invention relates to methods to identify agonists and antagonists using the materials provided by the invention, and treating conditions associated with the imbalance with the identified compounds. Yet another aspect of the invention relates to diagnostic assays for detecting diseases associated with inappropriate activity or levels of the secreted proteins of the present invention.

Description of the Invention

In a first aspect, the present invention relates to polypeptides the genes set forth in

Table I. Such polypeptides include: (a) an isolated polypeptide encoded by a polynucleotide comprising a sequence set forth in the Sequence Listing, herein when referring to polynucleotides or polypeptides of the

Sequence Listing, a reference is also made to the Sequence Listing referred to in the

Sequence Listing; (b) an isolated polypeptide comprising a polypeptide sequence having at least 95%, 96%, 97%, 98%, or 99% identity to a polypeptide sequence set forth in the Sequence Listing;

(c) an isolated polypeptide comprising a polypeptide sequence set forth in the Sequence

Listing; (d) an isolated polypeptide having at least 95%, 96%, 97%, 98%, or 99% identity to a . polypeptide sequence set forth in the Sequence Listing; (e) apolypeptide sequence set forth in the Sequence Listing; and . (f) an isolated polypeptide having or comprising a polypeptide sequence that has an Identity

Index of 0.95, 0.96, 0.97, 0.98, or 0.99 compared to a polypeptide sequence set forth in the

Sequence Listing; (g) fragments and variants of such polypeptides in (a) to (f).

Polypeptides of the present invention are believed to be members of the gene families set forth in Table IT . They are therefore of therapeutic and diagnostic interest for the reasons set forth in Tables III and V. The biological properties of the polypeptides and polynucleotides of the genes set forth in Table I are hereinafter referred to as "the biological activity" of polypeptides and polynucleotides of the genes set forth in Table 1. Preferably, a polypeptide of the present invention exhibits at least one biological activity of the genes set forth in Table I.

Polypeptides of the present invention also include variants of the aforementioned polypeptides, including all allelic forms and splice variants. Such polypeptides vary from the reference polypeptide by insertions, deletions, and substitutions that may be conservative or non-conservative, or any combination thereof. Particularly preferred variants are those in which several, for instance from 50 to 30, from 30 to 20, from 20 to 10, from 10 to 5, from 5 to 3, from 3 to 2, from 2 to 1 or | amino acids are inserted, substituted, or deleted, in any combination.

Preferred fragments of polypeptides of the present invention include an isolated polypeptide comprising an amino acid sequence having at least 30, 50 or 100 contiguous amino acids from an amino acid sequence set forth in the Sequence Listing, or an isolated polypeptide comprising an amino acid sequence having at least 30, 50 or 100 contiguous amino acids truncated or deleted from an amino acid sequence set forth in the Sequence

Listing. Preferred fragments are biologically active fragments that mediate the biological activity of polypeptides and polynucleotides of the genes set forth in Table I, including those with a similar activity or an improved activity, or with a decreased undesirable activity. Also preferred are those fragments that are antigenic or immunogenic in an animal, } especially in a human.

Fragments of a polypeptide of the invention may be employed for producing the corresponding full-length polypeptide by peptide synthesis; therefore, these variants may be employed as intermediates for producing the full-length polypeptides of the invention. A polypeptide of the present invention may be in the form of the “mature” protein or may be a part of a larger protein such as a precursor or a fusion protein. It is often advantageous to . include an additional amino acid sequence that contains secretory or leader sequences, pro- 5S sequences, sequences that aid in purification, for instance multiple histidine residues, or an i additional sequence for stability during recombinant production.

Polypeptides of the present invention can be prepared in any suitable manner, for instance by isolation form naturally occurring sources, from genetically engineered host cells comprising expression systems (vide infra) or by chemical synthesis, using for instance 10 automated peptide synthesizers, or a combination of such methods. Means for preparing such polypeptides are well understood in the art.

In a further aspect, the present invention relates to polynucleotides of the genes set forth in

Table I. Such polynucleotides include: (a) an isolated polynucleotide comprising a polynucleotide sequence having at least 95%, 15 96%, 97%, 98%, or 99% identity to a polynucleotide sequence set forth in the Sequence

Listing; (b) an isolated polynucleotide comprising a polynucleotide set forth in the Sequence : Listing; (c) an isolated polynucleotide having at least 95%, 96%, 97%, 98%, or 99% identity to a : 20 polynucleotide set forth in the Sequence Listing; (d) an isolated polynucleotide set forth in the Sequence Listing; (e) an isolated polynucleotide comprising a polynucleotide sequence encoding a polypeptide sequence having at least 95%, 96%, 97%, 98%, or 99% identity to a polypeptide sequence set forth in the Sequence Listing; 25 (f) an isolated polynucleotide comprising a polynucleotide sequence encoding a polypeptide set forth in the Sequence Listing; (g) an isolated polynucleotide having a polynucleotide sequence encoding a polypeptide sequence having at least 95%, 96%, 97%, 98%, or 99% identity to a polypeptide sequence set forth in the Sequence Listing; 30 (h) an isolated polynucleotide encoding a polypeptide set forth in the Sequence Listing; (i) an isolated polynucleotide having or comprising a polynucleotide sequence that has an

Identity Index of 0.95, 0.96, 0.97, 0.98, or 0.99 compared to a polynucleotide sequence set forth in the Sequence Listing;

(J) an isolated polynucleotide having or comprising a polynucleotide sequence encoding 2 polypeptide sequence that has an Identity Index of 0.95, 0.96, 0.97, 0.98, or 0.99 compared to a polypeptide sequence set forth in the Sequence Listing; and i polynucleotides that are fragments and variants of the above mentioned polynucleotides or that are complementary to above mentioned polynucleotides, over the entire length thereof. . Preferred fragments of polynucleotides of the present invention include an isolated polynucleotide comprising an nucleotide sequence having at least 15, 30, 50 or 100 contiguous nucleotides from a sequence set forth in the Sequence Listing, or an isolated polynucleotide comprising a sequence having at least 30, 50 or 100 contiguous nucleotides truncated or deleted from a sequence set forth in the Sequence Listing.

Preferred variants of polynucleotides of the present invention include splice variants, allelic variants, and polymorphisms, including polynucleotides having one or more single nucleotide polymorphisms (SNPs).

Polynucleotides of the present invention also include polynucleotides encoding polypeptide variants that comprise an amino acid sequence set forth in the Sequence Listing and in which several, for instance from 50 to 30, from 30 to 20, from 20 to 10, from 10 to 5, from 5to 3, from 3 to 2, from 2 to 1 or 1 amino acid residues are substituted, deleted or added, in any combination.

In a further aspect, the present invention provides polynucleotides that are RNA transcripts of the DNA sequences of the present invention. Accordingly, there is provided an RNA polynucleotide that: (a) comprises an RNA transcript of the DNA sequence encoding a polypeptide set forth in the Sequence Listing; (b) is a RNA transcript of a DNA sequence encoding a polypeptide set forth in the

Sequence Listing; (c) comprises an RNA transcript of a DNA sequence set forth in the Sequence

Listing; or (d) is a RNA transcript of a DNA sequence set forth in the Sequence Listing; and RNA polynucleotides that are complementary thereto.

The polynucleotide sequences set forth in the Sequence Listing show homology with the polynucleotide sequences set forth in Table II. A polynucleotide sequence set forth in the Sequence Listing is a cDNA sequence that encodes a polypeptide set forth in the

Sequence Listing. A polynucleotide sequence encoding a polypeptide set forth in the

Sequence Listing may be identical to a polypeptide encoding a sequence set forth in the

Sequence Listing or it may be a sequence other than a sequence set forth in the Sequence

Listing, which, as a result of the redundancy (degeneracy) of the genetic code, also encodes a polypeptide set forth in the Sequence Listing. A polypeptide of a sequence set forth in the

Sequence Listingis related to other proteins of the gene families set forth in Table II, having . homology and/or structural similarity with the polypeptides set forth in Table II. Preferred polypeptides and polynucleotides of the present invention are expected to have, inter alia, . similar biological functions/properties to their homologous polypeptides and polynucleotides. Furthermore, preferred polypeptides and polynucleotides of the present invention have at least one activity of the genes set forth in Table I.

Polynucleotides of the present invention may be obtained using standard cloning and screening techniques from a cDNA library derived from mRNA from the tissues set forth in Table IV (see for instance, Sambrook et al., Molecular Cloning: A Laboratory

Manual, 2nd Ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (1989)).

Polynucleotides of the invention can also be obtained from natural sources such as genomic

DNA libraries or can be synthesized using well known and commercially available techniques.

When polynucleotides of the present invention are used for the recombinant production of polypeptides of the present invention, the polynucleotide may include the coding sequence for the mature polypeptide, by itself, or the coding sequence for the mature polypeptide in reading frame with other coding sequences, such as those encoding a leader or secretory sequence, a pre-, Or pro- or prepro- protein sequence, or other fusion peptide portions. For example, a marker sequence that facilitates purification of the fused polypeptide can be encoded. In certain preferred embodiments of this aspect of the invention, the marker sequence is a hexa-histidine peptide, as provided in the pQE vector (Qiagen, Inc.) and described in Gentz et al., Proc Natl Acad Sci USA (1989) 86:821-824, or isan HA tag. A polynucleotide may also contain non-coding 5° and 3’ sequences, such as transcribed, non-translated sequences, splicing and polyadenylation signals, ribosome binding sites and sequences that stabilize mRNA.

Polynucleotides that are identical, or have sufficient identity to a polynucleotide sequence set forth in the Sequence Listing, may be used as hybridization probes for cDNA and genomic DNA or as primers for a nucleic acid amplification reaction (for instance,

PCR). Such probes and primers may be used to isolate full-length cDNAs and genomic clones encoding polypeptides of the present invention and to isolate cDNA and genomic clones of other genes (including genes encoding paralogs from human sources and orthologs and paralogs from other species) that have a high sequence similarity to sequences set forth in the Sequence Listing, typically at least 95% identity. Preferred probes and primers will generally comprise at least 15 nucleotides, preferably, at least 30 nucleotides and may have at least 50, if not at least 100 nucleotides. Particularly preferred probes will have between 30 and 50 nucleotides. Particularly preferred primers will have between 20 and 25 nucleotides.

S A polynucleotide encoding a polypeptide of the present invention, including ) homologs from other species, may be obtained by a process comprising the steps of screening a library under stringent hybridization conditions with a labeled probe having a sequence set forth in the Sequence Listing or a fragment thereof, preferably of at least 15 nucleotides; and isolating full-length cDNA and genomic clones containing the polynucleotide sequence set forth in the Sequence Listing. Such hybridization techniques are well known to the skilled artisan. Preferred stringent hybridization conditions include overnight incubation at 42°C in a solution comprising: 50% formamide, 5xSSC (150mM

NaCl, 15mM trisodium citrate), 50 mM sodium phosphate (pH 7.6), 5x Denhardt’s solution, 10 % dextran sulfate, and 20 microgram/ml denatured, sheared salmon sperm DNA; followed by washing the filters in 0.1x SSC at about 65°C. Thus the present invention also includes isolated polynucleotides, preferably with a nucleotide sequence of at least 100, obtained by screening a library under stringent hybridization conditions with a labeled probe having the sequence set forth in the Sequence Listing or a fragment thereof, preferably of at least 15 nucleotides.

The skilled artisan will appreciate that, in many cases, an isolated cDNA sequence will be incomplete, in that the region coding for the polypeptide does not extend all the way through to the 5’ terminus. This is a consequence of reverse transcriptase, an enzyme with inherently low "processivity" (a measure of the ability of the enzyme to remain attached to the template during the polymerisation reaction), failing to complete a DNA copy of the mRNA template during first strand cDNA synthesis.

There are several methods available and well known to those skilled in the art to obtain full-length cDNAs, or extend short cDNAs, for example those based on the method of Rapid Amplification of cDNA ends (RACE) (see, for example, Frohman et al., Proc Nat

Acad Sci USA 85, 8998-9002, 1988). Recent modifications of the technique, exemplified by the Marathon (trade mark) technology (Clontech Laboratories Inc.) for example, have significantly simplified the search for longer cDNAs. In the Marathon (trade mark) technology, cDNAs have been prepared from mRNA extracted from a chosen tissue and an ‘adaptor’ sequence ligated onto each end. Nucleic acid amplification (PCR) is then carried out to amplify the "missing" 5’ end of the cDNA using a combination of gene specific and adaptor specific oligonucleotide primers. The PCR reaction is then repeated using ‘nested’

primers, that is, primers designed to anneal within the amplified product (typically an adapter specific primer that anneals further 3’ in the adaptor sequence and a gene specific primer that anneals further 5° in the known gene sequence). The products of this reaction can then be analyzed by DNA sequencing and a full-length cDNA constructed either by 5S joining the product directly to the existing cDNA to give a complete sequence, or carrying out a separate full-length PCR using the new sequence information for the design of the 5’ primer.

Recombinant polypeptides of the present invention may be prepared by processes well known in the art from genetically engineered host cells comprising expression systems.

Accordingly, in a further aspect, the present invention relates to expression systems comprising a polynucleotide or polynucleotides of the present invention, to host cells which are genetically engineered with such expression systems and to the production of polypeptides of the invention by recombinant techniques. Cell-free translation systems can also be employed to produce such proteins using RNAs derived from the DNA constructs of the present invention.

For recombinant production, host cells can be genetically engineered to incorporate expression systems or portions thereof for polynucleotides of the present invention.

Polynucleotides may be introduced into host cells by methods described in many standard laboratory manuals, such as Davis et al., Basic Methods in Molecular Biology (1986) and

Sambrook et al.(ibid). Preferred methods of introducing polynucleotides mto host cells include, for instance, calcium phosphate transfection, DEAE-dextran mediated transfection, transvection, micro-injection, cationic lipid-mediated transfection, electroporation, transduction, scrape loading, ballistic introduction or infection.

Representative examples of appropriate hosts include bacterial cells, such as

Streptococci, Staphylococci, E. coli, Streptomyces and Bacillus subtilis cells; fungal cells, such as yeast cells and Aspergillus cells; insect cells such as Drosophila S2 and Spodoptera

S19 cells; animal cells such as CHO, COS, Hela, C127, 3T3, BHK, HEK 293 and Bowes melanoma cells; and plant cells.

A great variety of expression systems can be used, for instance, chromosomal, episomal and virus-derived systems, e.g., vectors derived from bacterial plasmids, from bacteriophage, from transposons, from yeast episomes, from insertion elements, from yeast chromosomal elements, from viruses such as baculoviruses, papova viruses, such as SV40, vaccinia viruses, adenoviruses, fowl pox viruses, pseudorabies viruses and retroviruses, and vectors derived from combinations thereof, such as those derived from plasmid and bacteriophage genetic elements, such as cosmids and phagemids. The expression systems may contain control regions that regulate as well as engender expression. Generally, any system or vector that is able to maintain, propagate or express a polynucleotide to produce a polypeptide in a host may be used. The appropriate polynucleotide sequence may be ) inserted into an expression system by any of a variety of well-known and routine techniques, such as, for example, those set forth in Sambrook ez al., (ibid). Appropriate i secretion signals may be incorporated into the desired polypeptide to allow secretion of the translated protein into the lumen of the endoplasmic reticulum, the periplasmic space or the extracellular environment. These signals may be endogenous to the polypeptide or they may be heterologous signals.

If a polypeptide of the present invention is to be expressed for use in screening assays, it is generally preferred that the polypeptide be produced at the surface of the cell.

In this event, the cells may be harvested prior to use in the screening assay. If the polypeptide is secreted into the medium, the medium can be recovered in order to recover and purify the polypeptide. If produced intracellularly, the cells must first be lysed before the polypeptide is recovered.

Polypeptides of the present 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 is employed for purification. Well known techniques for refolding proteins may be employed to regenerate active conformation when the polypeptide is denatured during intracellular synthesis, isolation and/or purification.

Polynucleotides of the present invention may be used as diagnostic reagents, through detecting mutations in the associated gene. Detection of a mutated form of a gene is characterized by the polynucleotides set forth in the Sequence Listing in the cDNA or genomic sequence and which is associated with a dysfunction. Will provide a diagnostic tool that can add to, or define, a diagnosis of a disease, or susceptibility to a disease, which results from under-expression, over-expression or altered spatial or temporal expression of the gene. Individuals carrying mutations in the gene may be detected at the DNA level by a variety of techniques well known in the art.

Nucleic acids for diagnosis may be obtained from a subject's cells, such as from blood, urine, saliva, tissue biopsy or autopsy material. The genomic DNA may be used directly for detection or it may be amplified enzymatically by using PCR, preferably RT-

PCR, or other amplification techniques prior to analysis. RNA or cDNA may also be used in similar fashion. Deletions and insertions can be detected by a change in size of the amplified product in comparison to the normal genotype. Point mutations can be identified by hybridizing amplified DNA to labeled nucleotide sequences of the genes set forth in

Table I. Perfectly matched sequences can be distinguished from mismatched duplexes by

RNase digestion or by differences in melting temperatures. DNA sequence difference may . also be detected by alterations in the electrophoretic mobility of DNA fragments in gels, with or without denaturing agents, or by direct DNA sequencing (see, for instance, Myers et al., Science (1985) 230:1242). Sequence changes at specific locations may also be revealed by nuclease protection assays, such as RNase and S1 protection or the chemical cleavage method (see Cotton et al., Proc Natl Acad Sci USA (1985) 85: 4397-4401).

An array of oligonucleotides probes comprising polynucleotide sequences or fragments thereof of the genes set forth in Table I can be constructed to conduct efficient screening of e.g., genetic mutations. Such arrays are preferably high density arrays or grids.

Array technology methods are well known and have general applicability and can be used to address a variety of questions in molecular genetics including gene expression, genetic linkage, and genetic variability, see, for example, M. Chee et al., Science, 274, 610-613 (1996) and other references cited therein.

Detection of abnormally decreased or increased levels of polypeptide or mRNA expression may also be used for diagnosing or determining susceptibility of a subject to a disease of the invention. Decreased or increased expression can be measured at the RNA level using any of the methods well known in the art for the quantitation of polynucleotides, such as, for example, nucleic acid amplification, for instance PCR, RT-PCR, RNase protection,

Northern blotting and other hybridization methods. Assay techniques that can be used to determine levels of a protein, such as a polypeptide of the present invention, in a sample derived from a host are well-known to those of skill in the art. Such assay methods include radio-immunoassays, competitive-binding assays, Western Blot analysis and ELISA assays.

Thus in another aspect, the present invention relates to a diagnostic kit comprising: (a) a polynucleotide of the present invention, preferably the nucleotide sequence set forth in the Sequence Listing , or a fragment or an RNA transcript thereof; (b) a nucleotide sequence complementary to that of (a); (c) a polypeptide of the present invention, preferably the polypeptide set forth in the

Sequence Listing or a fragment thereof; or (d) an antibody to a polypeptide of the present invention, preferably to the polypeptide set forth in the Sequence Listing .

It will be appreciated that in any such kit, (a), (b), (c) or (d) may comprise a substantial component. Such a kit will be of use in diagnosing a disease or susceptibility to a disease, particularly diseases of the invention, amongst others.

The polynucleotide sequences of the present invention are valuable for chromosome localisation studies. The sequences set forth in the Sequence Listing are specifically } targeted to, and can hybridize with, a particular location on an individual human chromosome. The mapping of relevant sequences to chromosomes according to the present invention is an important first step in correlating those sequences with gene associated disease. Once a sequence has been mapped to a precise chromosomal location, the physical position of the sequence on the chromosome can be correlated with genetic map data. Such data are found in, for example, V. McKusick, Mendelian Inheritance in Man (available on- line through Johns Hopkins University Welch Medical Library). The relationship between genes and diseases that have been mapped to the same chromosomal region are then identified through linkage analysis (co-inheritance of physically adjacent genes). Precise human chromosomal localisations for a genomic sequence (gene fragment etc.) can be determined using Radiation Hybrid (RH) Mapping (Walter, M. Spillett, D., Thomas, P.,

Weissenbach, J., and Goodfellow, P., (1994) A method for constructing radiation hybrid maps of whole genomes, Nature Genetics 7, 22-28). A number of RH panels are available from Research Genetics (Huntsville, AL, USA) e.g. the GeneBridge4 RH panel (Hum Mol

Genet 1996 Mar;5(3):339-46 A radiation hybrid map of the human genome. Gyapay G,

Schmitt K, Fizames C, Jones H, Vega-Czarny N, Spillett D, Muselet D, Prud’' Homme JF,

Dib C, Auffray C, Morissette J, Weissenbach J, Goodfellow PN). To determine the chromosomal location of a gene using this panel, 93 PCRs are performed using primers designed from the gene of interest on RH DNAs. Each of these DNAs contains random human genomic fragments maintained in a hamster background (human / hamster hybrid cell lines). These PCRs result in 93 scores indicating the presence or absence of the PCR product of the gene of interest. These scores are compared with scores created using PCR products from genomic sequences of known location. This comparison is conducted at http://www.genome.wi.mit.edu/.

The polynucleotide sequences of the present invention are also valuable tools for tissue expression studies. Such studies allow the determination of expression patterns of polynucleotides of the present invention which may give an indication as to the expression patterns of the encoded polypeptides in tissues, by detecting the mRNAs that encode them.

The techniques used are well known in the art and include in situ hydridization techniques to clones arrayed on a grid, such as cDNA microarray hybridization (Schena et al, Science,

270, 467-470, 1995 and Shalon et al, Genome Res, 6, 639-645, 1996) and nucleotide amplification techniques such as PCR. A preferred method uses the TAQMAN (Trade mark) technology available from Perkin Elmer. Results from these studies can provide an indication of the normal function of the polypeptide in the organism. In addition, comparative studies of the normal expression pattern of mRNAs with that of mRNAs } encoded by an alternative form of the same gene (for example, one having an alteration in polypeptide coding potential or a regulatory mutation) can provide valuable insights into the role of the polypeptides of the present invention, or that of inappropriate expression thereof in disease. Such inappropriate expression may be of a temporal, spatial or simply quantitative nature.

A further aspect of the present invention relates to antibodies. The polypeptides of the invention or their fragments, or cells expressing them, can be used as immunogens to produce antibodies that are immunospecific for polypeptides of the present invention. The term “immunospecific” means that the antibodies have substantially greater affinity for the polypeptides of the invention than their affinity for other related polypeptides in the prior art.

Antibodies generated against polypeptides of the present invention may be obtained by administering the polypeptides or epitope-bearing fragments, or cells to an animal, preferably a non-human animal, using routine protocols. For preparation of monoclonal antibodies, any technique which provides antibodies produced by continuous cell line cultures can be used. Examples include the hybridoma technique (Kohler, G. and Milstein,

C., Nature (1975) 256:495-497), the trioma technique, the human B-cell hybridoma technique (Kozbor et al., Immunology Today (1983) 4:72) and the EBV-hybridoma technique (Cole et al., Monoclonal Antibodies and Cancer Therapy, 77-96, Alan R. Liss,

Inc. 1985).

Techniques for the production of single chain antibodies, such as those described in

U.S. Patent No. 4,946,778, can also be adapted to produce single chain antibodies to polypeptides of this invention. Also, transgenic mice, or other organisms, including other mammals, may be used to express humanized antibodies.

The above-described antibodies may be employed to isolate or to identify clones expressing the polypeptide or to purify the polypeptides by affinity chromatography.

Antibodies against polypeptides of the present invention may also be employed to treat diseases of the invention, amongst others.

Polypeptides and polynucleotides of the present invention may also be used as vaccines. Accordingly, in a further aspect, the present invention relates to a method for inducing an immunological response in a mammal that comprises inoculating the mammal with a polypeptide of the present invention, adequate to produce antibody and/or T cell immune response, including, for example, cytokine-producing T cells or cytotoxic T cells, . to protect said animal from disease, whether that disease is already established within the individual or not. An immunological response in a mammal may also be induced by a . method comprises delivering a polypeptide of the present invention via a vector directing expression of the polynucleotide and coding for the polypeptide in vivo in order to induce such an immunological response to produce antibody to protect said animal from diseases of the invention. One way of administering the vector is by accelerating it into the desired cells as a coating on particles or otherwise. Such nucleic acid vector may comprise DNA,

RNA, a modified nucleic acid, or a DNA/RNA hybrid. For use a vaccine, a polypeptide or a nucleic acid vector will be normally provided as a vaccine formulation (composition). The formulation may further comprise a suitable carrier. Since a polypeptide may be broken down in the stomach, it is preferably administered parenterally (for instance, subcutaneous, intra-muscular, intravenous, or intra-dermal injection). Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions that may contain anti-oxidants, buffers, bacteriostats and solutes that render the formulation instonic with the blood of the recipient; and aqueous and non-aqueous sterile suspensions that may include suspending agents or thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampoules and vials and may be stored in a freeze-dried condition requiring only the addition of the sterile liquid carrier immediately prior to use. The vaccine formulation may also include adjuvant systems for enhancing the immunogenicity of the formulation, such as oil-in water systems and other systems known in the art. The dosage will depend on the specific activity of the vaccine and can be readily determined by routine experimentation.

Polypeptides of the present invention have one or more biological functions that are of relevance in one or more disease states, in particular the diseases of the invention hereinbefore mentioned. It is therefore useful to identify compounds that stimulate or inhibit the function or level of the polypeptide. Accordingly, in a further aspect, the present invention provides for a method of screening compounds to identify those that stimulate or inhibit the function or level of the polypeptide. Such methods identify agonists or antagonists that may be employed for therapeutic and prophylactic purposes for such diseases of the invention as hereinbefore mentioned. Compounds may be identified from a variety of sources, for example, cells, cell-free preparations, chemical libraries, collections of chemical compounds, and natural product mixtures. Such agonists or antagonists so-

identified may be natural or modified substrates, ligands, receptors, enzymes, etc., as the case may be, of the polypeptide; a structural or functional mimetic thereof (see Coligan et al., Current Protocols in Immunology 1(2):Chapter 5 (1991)) or a small molecule. Such } small molecules preferably have a molecular weight below 2,000 daltons, more preferably between 300 and 1,000 daltons, and most preferably between 400 and 700 daltons. It is . preferred that these small molecules are organic molecules.

The screening method may simply measure the binding of a candidate compound to the polypeptide, or to cells or membranes bearing the polypeptide, or a fusion protein thereof, by means of a label directly or indirectly associated with the candidate compound.

Alternatively, the screening method may involve measuring or detecting (qualitatively or quantitatively) the competitive binding of a candidate compound to the polypeptide against a labeled competitor (e.g. agonist or antagonist). Further, these screening methods may test whether the candidate compound results in a signal generated by activation or inhibition of the polypeptide, using detection systems appropriate to the cells bearing the polypeptide.

Inhibitors of activation are generally assayed in the presence of a known agonist and the effect on activation by the agonist by the presence of the candidate compound is observed.

Further, the screening methods may simply comprise the steps of mixing a candidate compound with a solution containing a polypeptide of the present invention, to form a mixture, measuring an activity of the genes set forth in Table I in the mixture, and comparing activity of the mixture of the genes set forth in Table I to a control mixture which contains no candidate compound.

Polypeptides of the present invention may be employed in conventional low capacity screening methods and also in high-throughput screening (HTS) formats. Such

HTS formats include not only the well-established use of 96- and, more recently, 384-well micotiter plates but also emerging methods such as the nanowell method described by

Schullek et al, Anal Biochem., 246, 20-29, (1997).

Fusion proteins, such as those made from Fc portion and polypeptide of the genes set forth in Table I, as hereinbefore described, can also be used for high-throughput screening assays to identify antagonists for the polypeptide of the present invention (see D. Bennett er al., J

Mol Recognition, 8:52-58 (1995); and K. Johanson ez al., J Biol Chem, 270(16):9459-9471 (1999).

The polynucleotides, polypeptides and antibodies to the polypeptide of the present invention may also be used to configure screening methods for detecting the effect of added compounds on the production of mRNA and polypeptide in cells. For example, an ELISA assay may be constructed for measuring secreted or cell associated levels of polypeptide using monoclonal and polyclonal antibodies by standard methods known in the art. This can be used to discover agents that may inhibit or enhance the production of polypeptide (also called antagonist or agonist, respectively) from suitably manipulated cells or tissues. ] A polypeptide of the present invention may be used to identify membrane bound or soluble receptors, if any, through standard receptor binding techniques known in the art. . These include, but are not limited to, ligand binding and crosslinking assays in which the polypeptide is labeled with a radioactive isotope (for instance, 125, chemically modified (for instance, biotinylated), or fused to a peptide sequence suitable for detection or purification, and incubated with a source of the putative receptor (cells, cell membranes, cell supernatants, tissue extracts, bodily fluids). Other methods include biophysical techniques such as surface plasmon resonance and spectroscopy. These screening methods may also be used to identify agonists and antagonists of the polypeptide that compete with the binding of the polypeptide to its receptors, if any. Standard methods for conducting such assays are well understood in the art.

Examples of antagonists of polypeptides of the present invention include antibodies or, in some cases, oligonucleotides or proteins that are closely related to the ligands, substrates, receptors, enzymes, etc., as the case may be, of the polypeptide, e.g., a fragment of the ligands, substrates, receptors, enzymes, etc.; or a small molecule that bind to the polypeptide of the present invention but do not elicit a response, so that the activity of the polypeptide is prevented.

Screening methods may also involve the use of transgenic technology and the genes set forth in Table I. The art of constructing transgenic animals is well established. For example, the genes set forth in Table I may be introduced through microinjection into the male pronucleus of fertilized oocytes, retroviral transfer into pre- or post-implantation embryos, or injection of genetically modified, such as by electroporation, embryonic stem cells into host blastocysts. Particularly useful transgenic animals are so-called "knock-in" animals in which an animal gene is replaced by the human equivalent within the genome of that animal. Knock-in transgenic animals are useful in the drug discovery process, for target validation, where the compound is specific for the human target. Other useful transgenic animals are so-called "knock-out" animals in which the expression of the animal ortholog of a polypeptide of the present invention and encoded by an endogenous DNA sequence in a cell is partially or completely annulled. The gene knock-out may be targeted to specific cells or tissues, may occur only in certain cells or tissues as a consequence of the limitations of the technology, or may occur in all, or substantially all, cells in the animal. Transgenic animal technology also offers a whole animal expression-cloning system in which introduced genes are expressed to give large amounts of polypeptides of the present invention

Screening kits for use in the above described methods form a further aspect of the present invention. Such screening kits comprise: (a) a polypeptide of the present invention; . (b) a recombinant cell expressing a polypeptide of the present invention; (c) a cell membrane expressing a polypeptide of the present invention; or (d) an antibody to a polypeptide of the present invention; which polypeptide is preferably that set forth in the Sequence Listing.

It will be appreciated that in any such kit, (a), (b), (c) or (d) may comprise a substantial component.

Glossary

The following definitions are provided to facilitate understanding of certain terms used frequently hereinbefore. “Antibodies” as used herein includes polyclonal and monoclonal antibodies, chimeric, single chain, and humanized antibodies, as well as Fab fragments, including the products of an

Fab or other immunoglobulin expression library. "Isolated" means altered "by the hand of man" from its natural state, i.e., if it occurs in nature, it has been changed or removed from its original environment, or both. For example, a polynucleotide or a polypeptide naturally present in a living organism is not “isolated,” but the same polynucleotide or polypeptide separated from the coexisting materials of its natural state is "isolated", as the term is employed herein. Moreover, a polynucleotide or polypeptide that is introduced into an organism by transformation, genetic manipulation or by any other recombinant method is "isolated" even if it is still present in said organism, which organism may be living or non-living. "Secreted protein activity or secreted polypeptide activity” or “biological activity of the secreted protein or secreted polypeptide” refers to the metabolic or physiologic function of said secreted protein including similar activities or improved activities or these activities with decreased undesirable side-effects. Also included are antigenic and immunogenic activities of said secreted protein. "Secreted protein gene” refers to a polynucleotide comprising any of the attached nucleotide sequences or allelic variants thereof and/or their complements.

“Polynucleotide” generally refers to any polyribonucleotide (RNA) or polydeoxribonucleotide (DNA), which may be unmodified or modified RNA or DNA. “Polynucleotides” include, without limitation, single- and double-stranded DNA, DNA that ) 1s 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, “polynucleotide” refers to triple- stranded regions comprising RNA or DNA or both RNA and DNA. The term "polynucleotide" also includes DNAs or RNAs containing one or more modified bases and

DNAs or RNAs with 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 may be made to DNA and RNA; thus, “polynucleotide” embraces chemically, enzymatically or metabolically modified forms of polynucleotides as typically found in nature, as well as the chemical forms of DNA and RNA characteristic of viruses and cells. “Polynucleotide” also embraces relatively short polynucleotides, often referred to as oligonucleotides. . “Polypeptide” refers to any polypeptide comprising two or more amino acids joined to each other by peptide bonds or modified peptide bonds, i.e., peptide isosteres. “Polypeptide” refers to both short chains, commonly referred to as peptides, oligopeptides or oligomers, and to longer chains, generally referred to as proteins. Polypeptides may contain amino acids other than the 20 gene-encoded amino acids. “Polypeptides” include amino acid sequences modified either by natural processes, such as post-translational processing, or by chemical modification techniques that are well known in the art. Such modifications are well described in basic texts and in more detailed monographs, as well as ina voluminous research literature. Modifications may 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 to 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 as a result of ubiquitination, and they may be cyclic, with or without branching. Cyclic, branched and branched cyclic polypeptides may result from post-translation natural processes or may be made by synthetic methods. Modifications include acetylation, acylation, ADP- ribosylation, amidation, biotinylation, 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- links, formation of cystine, formation of pyroglutamate, formylation, gamma-carboxylation, glycosylation, GPI anchor formation, hydroxylation, iodination, methylation, myristoylation, oxidation, 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; Wold, F., Post-translational Protein Modifications: Perspectives and Prospects, 1-12, in Post-translational Covalent Modification of Proteins, B. C. Johnson, Ed., Academic Press,

New York, 1983; Seifter ef al., “Analysis for protein modifications and nonprotein cofactors”, Meth Enzymol, 182, 626-646, 1990, and Rattan et al., “Protein Synthesis: Post- translational Modifications and Aging”, Ann NY Acad Sci, 663, 48-62, 1992). "Fragment" of a polypeptide sequence refers to a polypeptide sequence that is shorter than the reference sequence but that retains essentially the same biological function or activity as the reference polypeptide. "Fragment" of a polynucleotide sequence refers to a polynucleotide sequence that is shorter than the reference sequence set forth in the Sequence

Listing. "Variant" refers to a polynucleotide or polypeptide that differs from a reference polynucleotide or polypeptide, but retains the essential properties thereof. A typical variant of a polynucleotide differs in nucleotide sequence from the reference polynucleotide.

Changes in the nucleotide sequence of the variant may or may not alter the amino acid sequence of a polypeptide encoded by the reference polynucleotide. Nucleotide changes may result in amino acid substitutions, additions, deletions, fusions and truncations in the polypeptide encoded by the reference sequence, as discussed below. A typical variant of a polypeptide differs in amino acid sequence from the reference polypeptide. Generally, alterations are limited so that the sequences of the reference polypeptide and the variant are closely similar overall and, in many regions, identical. A variant and reference polypeptide may differ in amino acid sequence by one or more substitutions, insertions, deletions in any combination. A substituted or inserted amino acid residue may or may not be one encoded by the genetic code. Typical conservative substitutions include Gly, Ala; Val, Ile, Leu; Asp,

Glu; Asn, Gln; Ser, Thr; Lys, Arg; and Phe and Tyr. A variant of a polynucleotide or polypeptide may be naturally occurring such as an allele, or it may be a variant that is not known to occur naturally. Non-naturally occurring variants of polynucleotides and polypeptides may be made by mutagenesis techniques or by direct synthesis. Also included as variants are polypeptides having one or more post-translational modifications, for v WO 01/81363 PCT/US01/13360 instance glycosylation, phosphorylation, methylation, ADP ribosylation and the like.

Embodiments include methylation of the N-terminal amino acid, phosphorylations of serines and threonines and modification of C-terminal glycines. . "Allele" refers to one of two or more alternative forms of a gene occurring at a given locus in the genome. . "Polymorphism" refers to a variation in nucleotide sequence (and encoded polypeptide sequence, if relevant) at a given position in the genome within a population. "Single Nucleotide Polymorphism" (SNP) refers to the occurrence of nucleotide variability at a single nucleotide position in the genome, within a population. An SNP may occur within a gene or within intergenic regions of the genome. SNPs can be assayed using

Allele Specific Amplification (ASA). For the process at least 3 primers are required. A common primer is used in reverse complement to the polymorphism being assayed. This common primer can be between 50 and 1500 bps from the polymorphic base. The other two (or more) primers are identical to each other except that the final 3’ base wobbles to match one of the two (or more) alleles that make up the polymorphism. Two (or more) PCR reactions are then conducted on sample DNA, each using the common primer and one of the

Allele Specific Primers. "Splice Variant” as used herein refers to cDNA molecules produced from RNA molecules initially transcribed from the same genomic DNA sequence but which have undergone alternative RNA splicing. Alternative RNA splicing occurs when a primary

RNA transcript undergoes splicing, generally for the removal of introns, which results in the production of more than one mRNA molecule each of that may encode different amino acid sequences. The term splice variant also refers to the proteins encoded by the above cDNA molecules. "Identity" reflects a relationship between two or more polypeptide sequences or two or more polynucleotide sequences, determined by comparing the sequences. In general, identity refers to an exact nucleotide to nucleotide or amino acid to amino acid correspondence of the two polynucleotide or two polypeptide sequences, respectively, over the length of the sequences being compared. "% Identity" - For sequences where there is not an exact correspondence, a "% identity" may be determined. In general, the two sequences to be compared are aligned to give a maximum correlation between the sequences. This may include inserting "gaps" in either one or both sequences, to enhance the degree of alignment. A % identity may be determined over the whole length of each of the sequences being compared (so-called global alignment), that is particularly suitable for sequences of the same or very similar length, or 20 /i over shorter, defined lengths (so-called local alignment), that is more suitable for sequences of unequal length. "Similarity" is a further, more sophisticated measure of the relationship between ) two polypeptide sequences. In general, "similarity" means a comparison between the amino acids of two polypeptide chains, on a residue by residue basis, taking into account not only . exact correspondences between a between pairs of residues, one from each of the sequences being compared (as for identity) but also, where there is not an exact correspondence, whether, on an evolutionary basis, one residue is a likely substitute for the other. This likelihood has an associated "score" from which the "% similarity” of the two sequences can then be determined.

Methods for comparing the identity and similarity of two or more sequences are well known in the art. Thus for instance, programs available in the Wisconsin Sequence

Analysis Package, version 9.1 (Devereux J et al, Nucleic Acids Res, 12, 387-395, 1984, available from Genetics Computer Group, Madison, Wisconsin, USA), for example the programs BESTFIT and GAP, may be used to determine the % identity between two polynucleotides and the % identity and the % similarity between two polypeptide sequences.

BESTFIT uses the "local homology" algorithm of Smith and Waterman (J Mol Biol, 147,195-197, 1981, Advances in Applied Mathematics, 2, 482-489, 1981) and finds the best single region of similarity between two sequences. BESTFIT is more suited to comparing two polynucleotide or two polypeptide sequences that are dissimilar in length, the program assuming that the shorter sequence represents a portion of the longer. In comparison, GAP aligns two sequences, finding a "maximum similarity", according to the algorithm of

Neddleman and Wunsch (J Mol Biol, 48, 443-453, 1970). GAP is more suited to comparing sequences that are approximately the same length and an alignment is expected over the entire length. Preferably, the parameters "Gap Weight" and "Length Weight" used in each program are 50 and 3, for polynucleotide sequences and 12 and 4 for polypeptide sequences, respectively. Preferably, % identities and similarities are determined when the two sequences being compared are optimally aligned.

Other programs for determining identity and/or similarity between sequences are also known in the art, for instance the BLAST family of programs (Altschul S F et al, J Mol

Biol, 215, 403-410, 1990, Altschul S F et al, Nucleic Acids Res., 25:389-3402, 1997, available from the National Center for Biotechnology Information (NCBI), Bethesda,

Maryland, USA and accessible through the home page of the NCBI at www.ncbi.nlm.nih.gov) and FASTA (Pearson W R, Methods in Enzymology, 183, 63-99, 21 o

1990; Pearson W R and Lipman D J, Proc Nat Acad Sci USA, 85, 2444-2448,1988, available as part of the Wisconsin Sequence Analysis Package).

Preferably, the BLOSUMG62 amino acid substitution matrix (Henikoff S and

Henikoff J G, Proc. Nat. Acad Sci. USA, 89, 10915-10919, 1992) is used in polypeptide sequence comparisons including where nucleotide sequences are first translated into amino i acid sequences before comparison.

Preferably, the program BESTFIT is used to determine the % identity of a query polynucleotide or a polypeptide sequence with respect to a reference polynucleotide or a polypeptide sequence, the query and the reference sequence being optimally aligned and the parameters of the program set at the default value, as hereinbefore described. "Identity Index" is a measure of sequence relatedness which may be used to compare a candidate sequence (polynucleotide or polypeptide) and a reference sequence.

Thus, for instance, a candidate polynucleotide sequence having, for example, an Identity

Index of 0.95 compared to a reference polynucleotide sequence is identical to the reference sequence except that the candidate polynucleotide sequence may include on average up to five differences per each 100 nucleotides of the reference sequence. Such differences are selected from the group consisting of at least one nucleotide deletion, substitution, including transition and transversion, or insertion. These differences may occur at the 5’ or 3’ terminal positions of the reference polynucleotide sequence or anywhere between these terminal | positions, interspersed either individually among the nucleotides in the reference sequence or in one or more contiguous groups within the reference sequence. In other words, to obtain a polynucleotide sequence having an Identity Index of 0.95 compared to a reference polynucleotide sequence, an average of up to 5 in every 100 of the nucleotides of the in the reference sequence may be deleted, substituted or inserted, or any combination thereof, as hereinbefore described. The same applies mutatis mutandis for other values of the Identity

Index, for instance 0.96, 0.97, 0.98 and 0.99.

Similarly, for a polypeptide, a candidate polypeptide sequence having, for example, an Identity Index of 0.95 compared to a reference polypeptide sequence is identical to the reference sequence except that the polypeptide sequence may include an average of up to five differences per each 100 amino acids of the reference sequence. Such differences are selected from the group consisting of at least one amino acid deletion, substitution, including conservative and non-conservative substitution, or insertion. These differences may occur at the amino- or carboxy-terminal positions of the reference polypeptide sequence or anywhere between these terminal positions, interspersed either individually among the amino acids in the reference sequence or in one or more contiguous groups within the reference sequence. In other words, to obtain a polypeptide sequence having an

Identity Index of 0.95 compared to a reference polypeptide sequence, an average of up to 5 in every 100 of the amino acids in the reference sequence may be deleted, substituted or } inserted, or any combination thereof, as hereinbefore described. The same applies mutatis mutandis for other values of the Identity Index, for instance 0.96, 0.97, 0.98 and 0.99. . The relationship between the number of nucleotide or amino acid differences and the Identity Index may be expressed in the following equation: ny $X,-(xpeD, in which: ng, is the number of nucleotide or amino acid differences,

X, is the total number of nucleotides or amino acids in a sequence set forth in the

Sequence Listing, 1 is the Identity Index, - » is the symbol for the multiplication operator, and in which any non-integer product of x, and I is rounded down to the nearest integer prior to subtracting it from x. "Homolog" is a generic term used in the art to indicate a polynucleotide or polypeptide sequence possessing a high degree of sequence relatedness to a reference sequence. Such relatedness may be quantified by determining the degree of identity and/or similarity between the two sequences as hereinbefore defined. Falling within this generic term are the terms "ortholog", and "paralog". "Ortholog" refers to a polynucleotide or polypeptide that is the functional equivalent of the polynucleotide or polypeptide in another species. "Paralog” refers to a polynucleotideor polypeptide that within the same species which is functionally similar. "Fusion protein” refers to a protein encoded by two, often unrelated, fused genes or fragments thereof. In one example, EP-A-0 464 533-A discloses fusion proteins comprising various portions of constant region of immunoglobulin molecules together with another human protein or part thereof. In many cases, employing an immunoglobulin Fc region as a part of a fusion protein is advantageous for use in therapy and diagnosis resulting in, for example, improved pharmacokinetic properties [see, e.g., EP-A 0232 262]. On the other hand, for some uses it would be desirable to be able to delete the Fc part after the fusion protein has been expressed, detected and purified. ) All publications and references, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference in their entirety as if each individual publication or reference were specifically and individually indicated to be incorporated by reference herein as being fully set forth. Any patent application to which this application claims priority is also incorporated by reference herein in its entirety in the manner described above for publications and references.

Table I.

GSK Nucleic Acid Corresponding Protein : Gene Name Gene ID SEQ ID NO’s SEQ ID NO’s

SEQ ID NO:3 SEQ ID NO:42

SEQ ID NO:6 SEQ ID NO:45

SEQ ID NO:9 SEQ ID NO:48

SEQ ID NO:12 SEQ ID NO:51

SEQ ID NO:16 SEQ ID NO:55 sbg297169BGP 297169 SEQ ID NO:17 SEQ ID NO:56

I i FT sbg253919HSCCAa 253919 SEQ ID NO:19 SEQ ID NO:58

SEQ ID NO:20 SEQ ID NO:59

SEQ ID NO:22 SEQ ID NO:61

SEQ ID NO:24 SEQ ID NO:63 matrix glycoprotein SEQ ID NO:26 SEQ ID NO:65

SEQ ID NO:28 SEQ ID NO:67

SEQ ID NO:34 SEQ ID NO:73

SEQ ID NO:36 SEQ ID NO:75

SEQ ID NO:38 SEQ ID NO:77

Table II

Gene Gene Family | Closest Polynuclotide by | Closest Polypeptide by | Cell

Name homology homology Localization (by

EN SE el __| homology) } sbg318680- | DNase I GB:AC022471 Human DNase I-like Secreted

DNase Sbmitted (04-FEB-2000) endonuclease, by Lita Annenberg Hazen g1:5803007

Genome Sequencing Parrish JE, Ciccodicola

Center, Cold Spring A, Wehhert M, Cox

Harbor Laboratory, 1 GF, Chen E, and

Bungtown Road, Cold Nelson DL; 1995;

Spring Harbor, NY 11724, | Hum. Mol. Genet.

USA. 4:1557-1564. sbg237038- | SA protein GB:AC023292 Human SA gene, Secreted

SA Submitted (11-FEB-2000) | £i:2988399 by Whitehead Loftus,B.J. et al.

Institute/MIT Center for Genomics 60 (3), 295-

Genome Research, 320 308 (1999)

Charles Street, Cambridge,

MA 02141, USA. sbg340871- | Platelet GB:AC025389 Rat platelet Secreted

GPV glycoprotein Submitted (08-MAR-2000) | glycoprotein V (GPV) (GPV) by Whitehead precursor, gi:6980974

Institute/MIT Center for Ravanat C, Morales M,

Genome Research, 320 Azorsa DO, Moog S,

Charles Street, Cambridge, | Schuhler S, Grunert P,

MA 02141, USA. Loew D, Van

Dorsselaer A, Cazenave

JP, Lanza F; 1997;

Blood 89:3253-62. sbg293416- | HNK-1 JGLLLNL-R_241B6 Human GalNAc 4- Secreted

HNKS sulfotransfera | Joint Genome Institute, sulfotransferase, se Department of Energy, USA | gi:11990885 Okuda, T.,

Mita,S., Yamauchi,S.,

Fukuta,M., Nakano H.,

Sawada, T. and

Habuchi,O. J. Biol.

Chem. 275 (51), 40605- 40613 (2000) sbg257418- | Zona GB:AP000777 Mouse zona pellucida Secreted

VAY pellucida Submitted (25-NOV-1999) { glycoprotein, protein to the g1:6677653

DDBJ/EMBL/GenBank Epifano,O., Liang, L.F., databases. Masahira Familari,M., Moos,M.C.

Hattori, The Institute of Jr. and Dean,J.; 1995;

Physical and Chemical Development 121:1947-

Research (RIKEN), 1956.

Genomic Sciences Center (GSC); Kitasato Univ. 1- : 15-1 Kitasato, Sagamihara,

Kanagawa 228-8555,

Japan.

Table II (cont).

Gene Gene Family | Closest Polynuclotide by | Closest Polypeptide by | Cell (by oo 1 _homology) sbg319185- | Leukocyte GB:AC024004 Human leukocyte Secreted

CDa differentiatio | Submitted (20-FEB-2000) differentiation antigen n antigen by Whitehead Institute/MIT | CD84 isoform CD84s,

Center for Genome 21:6650112

Research, 320 Charles Submitted (20-

Street, Cambridge, MA MAR-1998) by Servei 02141, USA d’Immunologia,

Hospital Clinic,

Villarroel 170,

Barcelona 08036, Spain sbg32330 | Slit-like GB:AL160156, Human unnamed Secreted 7-KiIAAa Submitted (10-MAR-2000) | protein, gi:10439289 by Sanger Centre, Hinxton, | Submitted (29-AUG-

Cambridgeshire, CB10 2000) by Sumio 1SA, UK. Sugano, Institute of

Medical Science,

University of Tokyo,

Laboratory of Genome

Structure Analysis,

Human Genome

Center; Shirokane-dai, 4-6-1, Minato-ku,

Tokyo 108-8639, Japan sbg31595 | Granulocyte | GB:AC011666 Human hypothetical Secreted 3-GPPa peptide A Submitted (09-OCT-1999) | protein SBBI67, by Department Of £i:9966869

Chemistry And Submitted (08-MAR-

Biochemistry, 2000) by Department of

The University Of Immunology, Second

Oklahoma, 620 Parrington | Military Medical

Oval, Room 208, Norman, | University & Shanghai

OK 73019, USA Brilliance

Biotechnology Institute, 800 Xiangyin Rd.,

Shanghai 200433, P.R.

China sbg31848 | Oncotrophobl | GB:AC022045 Canine 5T4 tumour- Secreted 6-ONC ast Submitted (25-JAN-2000) | associated antigen’ glycoprotein | by tehead Institute/MIT geneseqp:Y94351

Center for Genome Submitted by

Research, 320 Charles OXFORD

Street, Cambridge, MA BIOMEDICA UK LTD 02141, USA. Publication number and date: W0O200029428-

A2, 25-MAY-00

Table II (cont).

Gene Gene Family | Closest Polynuciotide by | Closest Polypeptide by | Cell (by

I | homology) . sbg29935 ! Lipocalin SC:AL139041 Mouse major urinary Secreted 9-LIPO Submitted (16-NOV-2000) | protein (MUP) 4, by Sanger Centre, Hinxton, | 21:6678968

Cambridgeshire, CB10 Shahan K, Gilmartin M, 1SA, UK and Derman E; 1987;

Mol Cell Biol 7:1938- 1946. sbg23002 | Plasmacytoma | GB:AC066608 Rat neural cell adhesion | Membrane- 2-NGa -associated GB:AC022002 protein BIG-2 bound neuronal Submitted (25-APR-2000) | precursor, gi :1016012 glycoprotein and (24-JAN-2000) by Yoshihara,Y.,

Human Genomic Center, Kawasaki,M.,

Institute of Genetics, Tamada,A., Nagata,S.,

Chinese Academy of Kagamiyama,H. and

Sciences, Datun Road, Mori, K. J. Neurobiol.

Beijing, Beijing 100101, 28 (1), 51-69 (1995)

P.R.China sbg29716 | Biliary JGI: CITB- Mouse biliary Secreted 9-BGP glycoprotien | E1_2616J11 glycoprotein (BGP), (BGP) Submitted by gi:312584

Joint Genome Institute, McCuaig K,

Department of Energy, Rosenberg M,

USA Nedellec P, Turbide C, and Beauchemin N; 1993; Gene 127:173- 83. sbg25391 | Human GB:AC019355 Human Secreted 9- squamous cell | Submitted (02-JAN-2000) | squamous cell

HSCCAa | carcinoma by Whitehead carcinoma antigen 2 antigen Institute/MIT Center for (SCCA-2) (LEUPIN). (SCCA) Genome Research, 320 gi:1710877.

Charles Street, Cambridge, | Schneider,S.S.,

MA 02141, USA Schick,C., Fish, K.E.,

Miller,E., Pena,J.C.,

Treter,S.D., Hui,S.M. and Silverman,G.A,

Proc. Natl. Acad. Sci.

U.S.A. 92 (8), 3147- 3151 (1995). sbg22813 | Olfactomedin GB:AC022606 Rat neuronal Secreted 7-OLF related Submitted (06- olfactomedin-related protein FEB-2000) by Whitehead | protein precursor,

Institute/MIT Center for 2i:3024210

Genome Research, 320 Danieison,P.E., Forss-

Charles Street, Cambridge, | Petter,S., : MA 02141, USA Battenberg,E.L., deLecea,L.,

Bloom,F.E., and . Sutcliffe, J.G., 1994, J.

Neurosci. Res. 38:468- 478.

Table II (cont).

Gene Gene Family | Closest Polynuclotide by | Closest Polypeptide by | Cell

Name homology homology Localization (by — — ) | homology) , sbg378514- | Netrin SC:BA5SN16 Mouse Netrin-Gla Secreted

Netrin precursor Submitted (09-APR-2001) | protein by Sanger Centre, Hinxton, | gi:9909148

Cambridgeshire, CB10 Nakashiba,T., Ikeda, T., 1SA, UK. Nishimura,S.,

Tashiro,K., Honjo, T.,

Culotti,].G. and

Itohara,S. J. Neurosci. (17), 6540-6550 (2000) sbg253227. | Extracellular | GB:ACO011647 Human colon specific Secreted mucous mucous Submitted (08-OCT-1999) | protein, matrix matrix by Whitehead geneseqp:Y54368 glycoprotei | glycoprotein | Institute/MIT Center for Submitted by n (EMMG) Genome Research, 320 DIADEXUS LLC

Charles Street, Cambridge, { Publication number and

MA 02141, USA date: WO9960161-A1, 25-NOV-99 sbg262831- | Sialoadhesin JGL:.CITB- Human sialic acid Secreted

SiAa E1_3073N11 binding

Found at Joint immunoglobulin-like

Genome Institute lectin 8 long splice variant, gi: 9837433

Foussias,G.,

Yousef, G.M. and

Diamandis,E.P.

Biochem. Biophys. Res.

Commun. 278 (3), 775- 781 (2000) sbg233728- | Pancreatic GB:AC011098 Human pancreatic lipase | Secreted

LIPASE lipase Submitted (01-OCT-1999) | precursor, gi:126318 by Whitehead Lowe ME, Rosenblum

Institute/MIT Center for JL, and Strauss AW;

Genome Research, 320 1989; J Biol Chem

Charles Street, Cambridge, | 264:20042-8.

MA 02141, USA. sbgd00455. | Clg-related | GB:AC024339 MouseGliacolin, Secreted -CRF factor (CRF) | Submitted (28-FEB-2000) | gi:10566471 by Whitehead Koide,T., Aso,A.,

Institute/MIT Center for Yorihuzi,T. and

Genome Research, 320 Nagata, K. J. Biol.

Charles Street, Cambridge, | Chem. 275 (36), 27957-

MA 02141, USA 27963 (2000)

Table II (cont).

Gene Gene Closest Polynuclotide by | Closest Polypeptide by | Cell (by oo oo _ I NE | homology) _ . sbgd00612- | Protein GB:AP0O01615 Murine protein Secreted

KINASEa | kinase Submitted (04-APR-2000) | kinase/ankyrin to the homologue, . DDBI/EMBL/GenBank geneseqp:Y76079 databases. Nobuyoshi Submitted by

Shimizu, Keio University, GENESIS RES & DEV

School of CORP LTD

Medicine, Publication

Molecular Biology; 35 number and date:

Shinanomachi, Shinjuku- WO09955865-A1 ku, Tokyo 160-8582, Japan | 04-NOV-99 sbg381373- | Adipocyte JGLRPCI-11_161M6 Human adipocyte Secreted

ACRP complement | Found at Joint Genome Complement-Related -related Institute, Department of Protein (ACRP30R2), protein Energy, USA geneseqp:Y44487. (ACRP30) Submitted by

SMITHEKLINE

BEECHAM CORP

Publication number and date:

W09964629-A1, 16-

DEC-99 sbg401294- | MEX- GB:AC026956 Caenorhabditis Cyto

MEX-3 3(1AP) Submitted (25-MAR-2000) | elegans solic (RNA- by Whitehead Institute/ MEX.-3, gi:1644450 binding

MIT Center for Genome Draper,B.W., protein)

Research, 320 Charles Mello,C.C.,

Street, Cambridge, MA Bowerman,B., : 02141, USA Hardin,J. and

Priess,I.R. Cell 87 (2), 205-216 (1996) sbg247722- | OB- GB:AL132780 Human OB-cadherin- | Secreted

Cadherin Cadherin Submitted (02-NOV-1999) | 1, gi:1377894 by Genoscope - Centre Okazaki, M.,

National de Sequencage : Takeshita,S.,

BP 191 91006 EVRY Kawai,S., Kikuno,R., cedex - FRANCE Tsujimura,A.,

Kudo, A. and

Amann,E.

J. Biol. Chem. 269 (16), 12092-12098

Table II (cont).

Gene Gene Family | Closest Polynuclotide by | Closest Polypeptide Cell

Name homology by homology Localization (by

I | homology) . sbg391057- | Thyroid SC:AL158153, Human TANGO 239, Secreted

THIPa hormone SC:AL392044 geneseqp:B01432 induced Submitted (22-MAR-2001) | Submitted by protein and (02-MAR-2001) by MILLENNIUM : Sanger Centre, Hinxton, PHARM INC

Cambridgeshire, CB10 Publication 1SA, UK. number and date:

W0200039284-A1, 06-JUL-00 sbg378067- | TGF beta SC:AL162502 Human persephin Secreted

TGFc (transforming | Submitted (06-APR-2001) | growth factor, growth factor | by Sanger Centre, Hinxton, | geneseqp:Y 16714 beta) Cambridgeshire, CB10 Submitted by UNIV 1SA, UK. WASHINGTON

Publication number and date:

W09914235-A1 25-MAR-99

Table II.

Name | 000000000 sbg318680- | An embodiment of the invention is the use of sbg318680- Cancer, infection,

DNase Dnase to treat respiratory diseases and target parasites or autoimmune disorder, cancer cells as a chromosome degrading agent to cause death | hematopoietic disorder, of those cells. Close homologues of sbg318680-DNase are wound healing

DNases. DNase can be used to treat respiratory diseases, disorders, inflammation : such as pneumonia, cystic fibrosis and asthma, by reducing and respiratory diseases viscosity of bronchopulmonary secretions (MacConnachie

AM; 1999; Intensive Crit Care Nurs 14:101-2). sbg237038- | An embodiment of the invention is the use of sbg237038SA | Cancer, infection,

SA in blood pressure control. A close homologue of autoimmune disorder, sbg237038SA is the rat SA gene. The SA gene is expressed | hematopoietic disorder, at higher levels in the kidney of genetically hypertensive rats | wound healing (Yang T, Hassan SA, Singh I, Smart A, Brosius FC, disorders, inflammation,

Holzman LB, Schnermann JB, Briggs JP; 1996; and hypertension

Hypertension 27:541-51). sbg340871- | An embodiment of the invention is the use of sbg340871- Cancer, infection,

GPV GPV in hemostasis and platelet aggregation. A close autoimmune disorder, homologue of sbg340871-GPV is platelet glycoprotein (GP) | hematopoietic disorder,

Vv. wound healing

Platelet glycoprotein (GP) V is a major surface protein which | disorders, inflammation, is cleaved by thrombin during platelet activation, and and Bernard-Soulier associates with GPIb-IX complex to form GPIb-V-IX, a disease receptor for von Willebrand factor and thrombin. Its functional role in hemostasis is possibly related to thrombin- induced platelet aggregation (Ravanat C, Morales M, Azorsa

DO, Moog S, Schuhler S, Grunert P, Loew D, Van

Dorsselaer A, Cazenave JP, Lanza F; 1997; Blood 89:3253- 62). sbg293416- | An embodiment of the invention is the use of sbg293416- Cancer, infection,

HNKS HNKS in cell interactions and the development of the autoimmune disorder, nervous system. Close homologues of sbg293416-HNKS hematopoietic disorder, are sulfotransferases. Sulfotransferases are considered to be | wound healing key enzymes in the biosynthesis of the HNK-1 carbohydrate | disorders, inflammation, epitope, which is expressed on several neural adhesion and peripheral glycoproteins and as a glycolipid, and is involved in cell neuropathies interactions (Bakker,H., Friedmann,I., Oka,S., Kawasaki, T.,

Nifant’ev,N., Schachner,M. and Mantei,N., 1997, J. Biol.

Chem. 272:29942-29946). The HNK-1 epitope is spatially and temporally regulated during the development of the nervous system. The biological function of the HNK-1 sulfotransferase may be related to the development of the nervous system, and also may be involved in the preferential reinervation of muscle nerves by motor axons after lesion (Jungalwala FB, 1994, Neurochem Res 19:945-57).

Table III (cont).

Gene Uses Associated Diseases sbg257418- | An embodiment of the invention is the use of sbg257418ZP | Infertility zp in fertilization. A close homologue of sbg257418ZP is zona : pellucida. Zona pellucida protein is an extracellular matrix that surrounds growing oocytes, ovulated eggs, and early embryos and it is critically involved in fertilization (Epifano,0., Liang, L..F., Familari,M., Moos,M.C. Jr. and ’ Dean,J.; 1995; Development 121:1947-1956). The zona pellucida also provides a post-fertilization block to polyspermy and protects the growing embryo as it passes down the oviduct (Rankin T, and Dean J; 1996; Mol Hum

Reprod 2:889-94). sbg319185- | An embodiment of the invention is the use of Cancer, autoimmune

CDa sbg319185CDa, a secreted protein, in the diagnosis and disorders, wound treatment of cancer and autoimmune disorders. Close healing disorders, homologues of sbg319185CDa are leukocyte differentiation infections and antigen CD84 isoforms. hematopoietic disorders

CD84’s are members of the immunoglobulin superfamily, show high homology with several molecules belonging to the

CD2 family of differentiation antigens and is proposed to be useful in the diagnosis and treatment of cancer and autoimmune disorders (Palou E, Pirotto F, Sole J, Freed JH,

Peral B, Vilardell C, VilellaR, Vives J, Gaya A. Genomic characterization of CD84 reveals the existence of five isoforms differing in their cytoplasmic domains. Tissue Antigens 2000

Feb;55(2):118-27)). sbg323307- | An embodiment of the invention is the use of sbg323307- Cancer, autoimmune

KIAAa KIA Aa, a secreted protein, to regulate cell signaling, motility, disorders, infections, and nucleic acid management. A close homologue of wound healing sbg323307-KIAAa is human KIAAQ0918 protein. Human disorders and

KIAAQ918 protein, a slit-like protein is functionally related to | hematopoietic disorders cell signaling/communication, cell structure/motility and nucleic acid management (Nagase, T., Ishikawa K_,

Suyama,M., Kikuno,R., Hirosawa,M., Miyajima,N.,

Tanaka,A., Kotani, H., Nomura,N. and Ohara,O. KIAA0918 protein [Homo sapiens], DNA Res. 5 (6), 355-364 (1998)).

Table III (cont).

Uses Associated Diseases — a4 sbg315953- | An embodiment of the invention is the use of Infections, cancer,

GPPa sbg315953GPPa, a secreted protein, to treat disorders autoimmune associated with lipopolysaccharides. A close homologue to disorders. wounder sbg315953GPPa is Bovine granulocyte peptide A precursor. healing disorders and

Bovine granulocyte peptide A precursors are used in human hematopoietic and veterinary medicine, particularly to treat disorders disorders. ’ associated with lipopolysaccharides, e.g. sepsis and endotoxaemia (1. Selsted ME, Bovine granulocyte peptide A precursor (antimicrobial BGP-A). Accession Number W23722,

Publication Date 21-AUG-97. 2. Yount NY, Yuan J, Tarver A,

Castro T, Diamond G, Tran PA, Levy JN, McCullough C,

Cullor JS, Bevins CL, Selsted ME. Cloning and expression of bovine neutrophil beta-defensins. Biosynthetic profile during neutrophilic maturation and localization of mature peptide to novel cytoplasmic dense granules. J Biol Chem 1999 Sep 10;274(37):26249-58)). sbg318486- | An embodiment of the invention is the use of Cancer, infection,

ONC sbg3184860NC in the growth and invasion events of autoimmune disorder, trophoblast and tumor cells. A close homologue to hematopoietic sbg3184860NC is oncotrophoblast glycoproteins. It has disorder, wound been shown that oncotrophoblast protein was expressed by healing disorders, and tumor cells with metastatic spread, suggesting a role in inflammation invasion during cancer (King, K.W., Sheppard,F.C.,

Westwater,C., Stern,P.L. and Myers, K.A.; 1999; Biochim.

Biophys. Acta 1445, 257-270). sbg299359- | An embodiment of the invention is the use of Cancer, infection,

LIPO sbg299359LIPO in sperm maturation, taste recognition, and | autoimmune disorder, transportation of some molecules across the blood brain hematopoietic barrier. A close homologue to sbg299359LIPO is Lipocalin. | disorder, wound

Lipocalins transport small hydrophobic molecules such as healing disorders, and steroids, bilins, retinoids, and lipids, and they have various inflammation effects on a number of tissues. It has been shown that lipocalins are involved in sperm maturation, taste recognition, and transportation of some molecules across the blood brain barrier (Newcomer M.E.; 1993; Structure 1:7- 18; Achen M.G., Harms P.J., Thomas T., Richardson S.J.,

Wettenhall R.E.H., Schreiber G.; 1992; J. Biol. Chem. 267:23170-23174)

Table III (cont).

Gene Uses Associated Diseases

FI Ee ial sbg230022- | An embodiment of the invention is the use of sbg230022Nga | Cancer, infections,

NGa in the formation and maintenance of neuron type-specific autoimmune . networks in the brain. Close homologues to sbg230022Nga disorders. wound are mouse plasmacytoma-associated neuronal glycoprotein and | healing disorders and rat BIG-1 protein. Mouse plasmacytoma-associated neuronal hematopoietic glycoprotein, is ectopically activated by intracisternal A-type disorders particle long terminal repeats in murine plasmacytomas. Rat

BIG-1 protein, is a TAG-1/F3-related member of the immunoglobulin superfamily with neurite outgrowth- promoting activity and involved in the formation and maintenance of neuron type-specific networks in the brain (1.

Connelly MA, Grady RC, Mushinski JF, Marcu KB. PANG, a gene encoding a neuronal glycoprotein, is ectopically activated by intracisternal A-type particle long terminal repeats in murine plasmacytomas. Proc Natl Acad Sci U S A 1994 Feb 15;91(4):1337-41 2. Yoshihara Y, Kawasaki M, Tani A,

Tamada A, Nagata S, Kagamiyama H, Mori K. BIG-1: a new

TAG-1/F3-related member of the immunoglobulin superfamily with neurite outgrowth-promoting activity. Neuron 1994

Aug;13(2):415-26). sbg297169- | An embodiment of the invention is the use of Cancer, infection,

BGP sbg297169BGP in renewal and/or differentiation of autoimmune disorder, epithelial cells. A close homologue to sbg297169BGP is hematopoietic

BGP protein. BGP proteins are expressed at the cell surface | disorder, wound and function in vitro as cell adhesion molecules. The healing disorders, expression of the many BGP isoforms at the surface of inflammation epithelial cells, such as the colon, suggests that these proteins play a major role in renewal and/or differentiation of their epithelia (McCuaig K, Rosenberg M, Nedellec P,

Turbide C, and Beauchemin N; 1993; Gene 127:173-83).

Table II (cont).

Gene Uses Associated Diseases sbg253919- | An embodiment of the invention is the use of sbg253919- Cancers, such as

HSCCAa HSCCAa for treatment of cancer or psoriasis or in squamous cell . development of more aggressive squamous cell carcinomas. carcinomas

Close homologues of sbg253919-HSCCAa are Psoriastatin type II and a human leupin precursor. Psoriastatin type II, is

A claimed to modulate activity of psoriastatin type I and II genes, e.g. using (ant)agonists, useful for treatment of cancer or psoriasis. The other, a human leupin precursor, contains a tandem duplication of the human squamous cell carcinoma antigen gene playing a causal role in development of more aggressive squamous cell carcinomas (1. Goetinck PF, Hibino

T, Takahashi T and Baciu PC. Modulating cell proliferation or apoptosis - by modulating activity of psoriastatin type I and II genes, e.g. using (ant) agonists, useful for treatment of cancer or psoriasis. Accession Number W15242, publication date 24-

APR-97. 2. Schneider SS, Schick C, Fish KE, Miller E, Pena

JC, Treter SD, Hui SM, Silverman GA. A serine proteinase inhibitor locus at 1821.3 contains a tandem duplication of the human squamous cell carcinoma antigen gene. Proc Natl Acad

Sci US A 1995 Apr 11;92(8):3147-51. 3. Barnes RC, Worrall

DM. Identification of a novel human serpin gene; cloning sequencing and expression of leupin. FEBS Lett 1995 Oct 2; 373 (1): 61-5). sbg228137- | An embodiment of the invention is the use of sbg2281370LF Cancer, infection,

OLF in functinal roles in chemoreception and in the central nervous | autoimmune system. A close homologue to sbg2281370LF is disorder, olfactomedin. hematopoietic

Olfactomedin is a glycoprotein, and reacts with proteins of disorder, wound olfactory cilia. It was originally discovered at the mucociliary healing disorders, surface of the amphibian olfactory neuroepithelium and inflammation, and subsequently found throughout the mammalian brain nervous system (Danielson, P.E., Forss-Petter,S., Battenberg, E.L., deLecea,L., disorders

Bloom,F.E., and Sutcliffe,].G., 1994, J. Neurosci. Res. 38:468-478). Its noticeable deposition at the chemosensory surface of the olfactory neuroepithelium suggest a role for this protein in chemoreception (Snyder DA, Rivers AM, Yokoe H,

Menco BP, and Anholt RR, 1991, Biochemistry 30:9143-53).

The widespread occurrence of olfactomedin among : mammalians in the brains also suggests its new functions in the central nervous system (Karavanich CA, and Anbolt RR, 1998,

Mol Biol Evol 15:718-26).

Table III (cont).

Gene Uses Associated Diseases

Noe Cree sbg378514- | An embodiment of the invention is the use of sbg378514- Cancer, infection,

Netrin Netrin in roles of the central nervous system. autoimmune disorder, . A close homologue to shg378514-Netrin is Netrin. hematopoietic

Netrins possess commissural axon outgrowth-promoting disorder, wound activity, and control guidance of CNS commissural axons healing disorders, ] and peripheral motor axons (Serafini T, Kennedy TE, Galko inflammation,

M]J, Mirzayan C, Jessell TM, and Tessier-Lavigne M; and nervous system 1994; Cell 78:409-24). Diffusible and substrate-bound cues, | disorder including netrins and their receptors, can guide axonal pathway choice via attractive and repulsive signals (Tear G; 1908; Essays Biochem 33:1-13). sbg253227. | An embodiment of the invention is the use of sbg253227.- | Hematopoietic mucous mucous matrix glycoprotein for the treatment of disorder, wound matrix gastrointestinal disorders and cancer. Close homologues of | healing disorder, viral glycoprotein | shg253227.mucous matrix glycoprotein have been used in and bacterial combination for treatment of infections associated with infection, cancer,

EMMG. EMMG is useful for the treatment of autoimmune diseases gastrointestinal disorders and cancer, ¢.g. dysphagia, Neurological abdominal angina, pancreatitis, colonic carcinoma, Crohn's | disorders, disease and the Mallory-Weiss syndrome (US5929033-A, gastrointestinal

CORLEY NC, TANG YT, Submitted by INCYTE PHARM | disorders,dysphagia,

INC. Reference number, WPI; 09-420518/36, 1999). abdominal angina, pancreatitis, colonic carcinoma, Crohn’s disease and the

Mallory-Weiss syndrome. sbg262831- | An embodiment of the invention is the use of Cancer, autoimmune

SIAa sbg262831SIAa to mediate sialic acid-dependent ligand disorders, infection, recognition and to function as an inhibitory receptor in wound healing human natural killer cells. disorders, and

A close homologue of sbg262831SIAa is human QA79 hematopoietic membrane protein. QA79 belongs to the sialoadhesin disorders. family and is proposed to mediate sialic acid-dependent ligand recognition and to function as an inhibitory receptor in human natural killer cells (FFalco,M., Biassoni,R.,

Bottino,C., Vitale,M., Sivori,S., Augugliaro,R., Moretta,L. and Moretta,A. Identification and molecular cloning of p75/AIRM1, a novel member of the sialoadhesin family that functions as an inhibitory receptor in human natural killer cells. J Exp Med 1999 Sep 20;190(6):793-802).

Table ITI (cont).

Uses Associated

Name | — | Diseases _ sbg?233728- | An embodiment of the invention is the use of Cancer, infection,

LIPASE sbg233728 LIPASE to treat pancreatitis via replacement autoimmune . therapy. A close homologue of sbg233728-LIPASE is disorder, pancreatic lipase. Pancreatic lipase can be used as replacement | hematopoietic enzymes for patients with chronic pancreatitis. Pancreatic disorder, wound

R lipase hydrolyzes dietary long chain triacylglycerol to free fatty | healing disorders, acids and monoacylglycerols in the intestinal lumen (Lowe inflammation, and

ME, Rosenblum JL, and Strauss AW; 1989; J Biol Chem pancreatitis. 264:20042-8). Pancreatic steatorrhea and pancreatic diabetes are the dominant symptoms of patients in a certain stage of chronic pancreatitis. In this stage, the nutritional state is greatly disturbed and hypoglycemia and labile infection are involved. Pancreatic enzyme replacement therapy is the principal treatment method for pancreatic steatorrhea. (Nakamura T, Takeuchi T, and Tando Y; 1998; Pancreas 16:329-36). sbgd00455. | An embodiment of the invention is the use of sbgd00455.CRF | Hematopoietic -CRF in the areas of the nervous system involved in motor function, disorder, wound such as the Purkinje cells of the cerebellum, the accessory healing disorder, olivary nucleus, the pons, and the red nucleus. Close viral and bacterial homologues of sbg400455.CRF include CRF transcripts. CRF | infection, cancer, transcripts are most abundant in areas of the nervous system autoimmune and have been used to develop products for modulating energy | diseases, energy balance or insulin production in mammals ((W09639429-A2) homeostasis

Schere, P.E.; Submitted by Whithead Institute of Biomedical disorder and

Research; Berube NG, Swanson XH, Bertram MJ, Kittle JD, obesity

Didenko V, Baskin DS,Smith JR and Pereira-Smith OM.,

Brain Res. Mol. Brain Res. 63 (2), 233-240 (1999)). sbgd00612- | An embodiment of the invention is the use of sbg400612- Cancer, wound

KINASEa KINASEa in the treatment of inflarnmation, cancer, neurological | healing disorders, diseases, growth and developmental defects, skin wounds, and autoimmune hair follicle disorders. A close homologue of sbg400612- disorders,

KINASEa is murine protein kinase/ ankyrin homologue. Murine | hematopoietic protein kinase/ ankyrin homologue can stimulate the growth and | disorders and motility of keratinocytes, inhibit the growth of cancer cells, infection modulate angiogenesis and tumour vascularisation, modulate skin inflammation and epithelial cell growth and inhibit binding of

HIV-1 to leukocytes. Murine protein kinase/ ankyrin homologue can also be used to treat inflammation, cancer, neurological diseases, growth and developmental defects, skin wounds, and hair follicle disorders (Kumble A, Murison JG, Onrust R,

Sleeman M, Strachan L and Watson JD. Novel polynucleotides useful for the treatment of various conditions including wounds and cancer. Accession Number: Y76079 Publication Date: 04-

NOV-99).

Table III (cont).

Gene Uses Associated Diseases sbg381373- | An embodiment of the invention is the use of sbg381373- Cancer, infection,

ACRP ACRP in the complex balanced system of energy autoimmune disorder, . homeostasis involving food intake, carbohydrate hematopoietic disorder, catabolism, and lipid catabolism. A close homologue of wound healing sbg381373-ACRP is ACRP30 protein. ACRP30 protein disorders, may be a factor that participates in the complex balanced inflammation, obesity, ) system of energy homeostasis involving food intake, and diabetes carbohydrate catabolism, and lipid catabolism. ACRP30 is structurally similar to complement factor Clq, and it forms large homo-oligomers that undergo a series of post- translational modifications (Scherer PE, Williams S,

Fogliano M, Baldini G, Lodish HF; 1995; J Biol Chem 270:26746-9). sbgd01294- | An embodiment of the invention is the use of sbgd01294- Hematopoietic

MEX-3 MEX.-3 to develop products for diagnosis and therapy of disorder, wound disease states such as tumor formation, apoptosis regulation | healing disorder, viral in cells to reduce or increase apoptosis and for and bacterial infection, pharmacological screening. cancer, tumor formation, autoimmune diseases, inhibition of apoptosis sbg247722- | An embodiment of the invention is the use of sbg247722- Hematopoietic

Cadherin Cadherin for treatment and diagnosis of bone metabolic disorder, wound diseases. A close homologue of sbg247722-Cadherin is healing disorder, viral cadherin, a Ca2+ dependent cell adhesion protein. and bacterial infection, cancer, autoimmune diseases, energy homeostasis disorder } and bone metabolic disease sbg391057- | An embodiment of the invention is the use of sbg391057- Autoimmune disorders,

THIPa THIPa in controlling thyroid hormone synthesis. A close wound healing homologue of sbg391057-THIPa is xenopus laevis thyroid disorders, cancer, hormone-induced protein. Xenopus laevis thyroid hormone- | infection and induced protein has been implicated in controlling thyroid hematopoietic disorders hormone synthesis in Xenopus tadpoles and provided insights into the biology of metamorphosis (Brown,D.D.,

Wang,Z., Furlow,J.D., Kanamori,A., Schwartzman, R.A,

Remo,B.F. and Pinder, A. The thyroid hormone-induced tail resorption program during Xenopus laevis metamorphosis.

Proc Natl Acad Sci U S A 1996 Mar 5;93(5):1924-9).

Table III (cont).

Gene Uses Associated Diseases sbg378067- | An embodiment of the invention is the Cancer, infection, autoimmune disorder,

TGFc use of sbg378067-TGFc in cellular hematopoietic disorder, wound healing . growth control in the etiology of cancer | disorder, inflammation, preventing or and cell differentiation and development. | treating cellular degeneration or

The sbg378067-TGFc protein contains a | insufficiency, e.g. neuronal close approximation of the prosite degeneration resulting from peripheral ‘ consensus pattern (PDOC00223) for neuropathy, amyotrophic lateral

TGF-beta family members. TGF-beta sclerosis, Alzheimer’s disease, proteins have been known to be involved | Parkinson's disease, Huntington's in growth control and hence the etiology | disease, ischemic stroke, acute brain of cancer (Anticancer Res 1999 Nov- injury, acute spinal cord injury, nervous

Dec; 19(6A):4791-807), cell system tumours, multiple sclerosis, or differentiation and development. A infection (viral, bacterial, fungal,

TGF-beta signaling pathway constitutes | parasitic), hematopoietic cell a tumor suppressor path (Cytokine degeneration or insufficiency resulting

Growth Factor Rev 2000 Apr 1;11(1- from eosinopenia, anemias, 2):159-168). A close homologue of thrombocytopenia, or stem-cell §bg378067-TGFc is TGF-beta protein. insufficiences, cardiac muscle : degeneration or insufficiency resulting from cardiomyopathy or congestive heart failure, peripheral nerve trauma or injury, exposure lo neurotoxins, metabolic diseases such as diabetes or renal dysfunctions and damage caused by infectious agents

Table IV. Quantitative, Tissue-specific mRNA expression detected using SybrMan

Quantitative, tissue-specific, nRNA expression patterns of the genes were measured using SYBR-

Green Quantitative PCR (Applied Biosystems, Foster City, CA; see Schmittgen T.D. et al.,

Analytical Biochemistry 285:194-204, 2000) and human cDNAs prepared from various human } 5 tissues. Gene-specific PCR primers were designed using the first nucleic acid sequence listed in the

Sequence List for each gene. Results are presented as the number of copies of each specific gene’s mRNA detected in Ing mRNA pool from each tissue. Two replicate mRNA measurements were made from each tissue RNA. ) Tissue-Specific mRNA Expression

Gene Name (copies per ng mRNA; avg. + range for 2 data points per tissue)

Lung | Liver | Kid- Skele- Splee Pla- [Testis muscl ph

SSO FS SS — — Sy US WA NUS NN 4029 sbg293416- 553% | 65+1 27+4 38+1 1089 [3 [0

CDa 140 31 30 64 158 31 sbg323307- 20318 | 633+ | 1269+ | 151 | 13625 | 2626 | 1400% 632+ | 196+

Erle Ral

ONC

LIPO 95 13

Table IV (cont.)

Tissue-Specific mRNA Expression

Brain | Heart | Lung | Liver | Kid- Skele- | Intes- | Spleen | Pla- [Testis ’ ney tal tine lymph | centa , } | | muscle

NGa 112 2 7 16 63 7 17 2

BGP 29 8 5 11 1 3 32

HSCCAa 9

OLF 138 12 sbg253227. | 50 11+1 | 21+1 | O+1 28+2 10 13+2 | 2443 2624 | 118+ mucous 1 matrix glycoprotein

SIAa 6 97

LIPASE

CRF 257 14 54 14 147 32 1 59 8

KINASEa 87 2 10

ACRP 40

Sis |)

Cadherin 18 +22 +62 12 52 +47 167 +263 | £30

THIPa +30 +84 1 90 172 +86 23 +32 +174

TGFc 28 4

Table V. Additional diseases based on mRNA expression in specific tissues

Tissue Additional Diseases

El

Brain Neurological and psychiatric diseases, including Alzheimers, parasupranuclear . palsey. Huntington's discase, myotonic dystrophy, anorexia, depression, schizophrenia, headache, amnesias, anxiety disorders, sleep disorders, multiple sclerosis . . Heart Cardiovascular diseases, including congestive heart failure, dilated cardiomyopathy, cardiac arrhythmias, Hodgson’s Disease, myocardial infarction, cardiac arrhythmias

Lung Respiratory diseases, including asthma, Chronic Obstructive Pulmonary Disease,

Tora om tron, spr dios nirome.

Liver Dyslipidemia, hypercholesterolemia, hypertriglyceridemia, cirrhosis, hepatic

SEE

Mellitis, impaired glucose tolerance cystinuria, Fancont’s Syndrome, glomerulonephritis, renal cell carcinoma, renovascular hypertension malignant hyperthermia, paramyotonia congenita, myotonia congenita

Obstruction, Tropical Sprue, Pseudomembranous Enterocolitis

Spleen/lymph Lymphangiectasia, hypersplenism, angiomas, ankylosing spondylitis, Hodgkin's ete sactoiobtoras. maioon hom osm atts

Testis Testicular cancer, male reproductive diseases, including low testosterone and male

Em ——— 42 oo i

Claims (7)

What is claimed is:

1. An isolated polypeptide selected from the group consisting of: . (a) an isolated polypeptide encoded by a polynucleotide comprising a sequence set forth in Table]; . (b) an isolated polypeptide comprising a polypeptide sequence set forth in Table I; and (c) a polypeptide sequence of a gene set forth in Table I.

2. An isolated polynucleotide selected from the group consisting of: (a) an isolated polynucleotide comprising a polynucleotide sequence set forth in Table I; (b) an isolated polynucleotide of a gene set forth in Table I; (c) an isolated polynucleotide comprising a polynucleotide sequence encoding a polypeptide set forth in Table I; (d) an isolated polynucleotide encoding a polypeptide set forth in Table I; (e) a polynucleotide which is an RNA equivalent of the polynucleotide of (a) to (d); or a polynucleotide sequence complementary to said isolated polynucleotide.

3. An expression vector comprising a polynucleotide capable of producing a polypeptide of claim 1 when said expression vector is present in a compatible host cell.

4. A process for producing a recombinant host cell which comprises the step of introducing an expression vector comprising a polynucleotide capable of producing a polypeptide of claim 1 into a cell such that the host cell, under appropriate culture conditions, produces said polypeptide.

5. A recombinant host cell produced by the process of claim 4.

6. A membrane of a recombinant host cell of claim 5 expressing said polypeptide.

7. A process for producing a polypeptide which comprises culturing a host cell of claim 5 under conditions sufficient for the production of said polypeptide and recovering said polypeptide from the culture.