Novel compounds

FIELD OF THE INVENTION

[0001] 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

[0002] 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.

[0003] 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.

[0004] 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.

[0005] 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, selecting, 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.

[0006] 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, immnunoglobulins, 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

[0007] 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 III 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 I. 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

[0008] In a first aspect, the present invention relates to polypeptides the genes set forth in Table I. Such polypeptides include:

[0009] (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;

[0010] (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;

[0011] (c) an isolated polypeptide comprising a polypeptide sequence set forth in the Sequence Listing;

[0012] (d) an isolated polypeptide having at least 95%, 96%, 97%, 98%, or 99% identity to a polypeptide sequence set forth in the Sequence Listing;

[0013] (e) a polypeptide sequence set forth in the Sequence Listing; and

[0014] (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;

[0015] (g) fragments and variants of such polypeptides in (a) to (f).

[0016] Polypeptides of the present invention are believed to be members of the gene families set forth in Table II . They are therefore of therapeutic and diagnostic interest for the reasons set forth in Tables II 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 I. Preferably, a polypeptide of the present invention exhibits at least one biological activity of the genes set forth in Table I.

[0017] 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 I or 1 amino acids are inserted, substituted, or deleted, in any combination.

[0018] 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.

[0019] 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-sequences, sequences that aid in purification, for instance multiple histidine residues, or an additional sequence for stability during recombinant production.

[0020] 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 automated peptide synthesizers, or a combination of such methods. Means for preparing such polypeptides are well understood in the art.

[0021] In a further aspect, the present invention relates to polynucleotides of the genes set forth in Table I. Such polynucleotides include:

[0022] (a) an isolated polynucleotide comprising a polynucleotide sequence having at least 95%, 96%, 97%, 98%, or 99% identity to a polynucleotide sequence set forth in the Sequence Listing;

[0023] (b) an isolated polynucleotide comprising a polynucleotide set forth in the Sequence Listing;

[0024] (c) an isolated polynucleotide having at least 95%, 96%, 97%, 98%, or 99% identity to a polynucleotide set forth in the Sequence Listing;

[0025] (d) an isolated polynucleotide set forth in the Sequence Listing;

[0026] (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;

[0027] (f) an isolated polynucleotide comprising a polynucleotide sequence encoding a polypeptide set forth in the Sequence Listing;

[0028] (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;

[0029] (h) an isolated polynucleotide encoding a polypeptide set forth in the Sequence Listing;

[0030] (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;

[0031] (j) an isolated polynucleotide having or comprising a polynucleotide sequence encoding 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; and

[0032] polynucleotides that are fragments and variants of the above mentioned polynucleotides or that are complementary to above mentioned polynucleotides, over the entire length thereof.

[0033] 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.

[0034] 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).

[0035] 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 5 to 3, from 3 to 2, from 2 to 1 or 1 amino acid residues are substituted, deleted or added, in any combination.

[0036] 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:

[0037] (a) comprises an RNA transcript of the DNA sequence encoding a polypeptide set forth in the Sequence Listing;

[0038] (b) is a RNA transcript of a DNA sequence encoding a polypeptide set forth in the Sequence Listing;

[0039] (c) comprises an RNA transcript of a DNA sequence set forth in the Sequence Listing; or

[0040] (d) is a RNA transcript of a DNA sequence set forth in the Sequence Listing; and RNA polynucleotides that are complementary thereto.

[0041] The polynucleotide sequences set forth in the Sequence Listing show homology with the polynucleotide sequences set forth in Table H. 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 Listing is 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.

[0042] 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 TV (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.

[0043] 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 is an 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.

[0044] 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.

[0045] 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, 5×SSC (150mM NaCl, 15 mM trisodium citrate), 50 mM sodium phosphate (pH 7.6), 5×Denhardt's solution, 10 % dextran sulfate, and 20 microgram/ml denatured, sheared salmon sperm DNA; followed by washing the filters in 0.1×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.

[0046] 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.

[0047] 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 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.

[0048] 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.

[0049] 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.(ibia). Preferred methods of introducing polynucleotides into 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.

[0050] Representative examples of appropriate hosts include bacterial cells, such as Streptococci, Staphylococci, E. coli, Streptonzyces and Bacillus subtilis cells; fungal cells, such as yeast cells and Aspergillus cells; insect cells such as Drosophila S2 and Spodoptera Sf9 cells; animal cells such as CHO, COS, HeLa, C127, 3T3, BHK, HEK 293 and Bowes melanoma cells; and plant cells.

[0051] 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 et al., (ibid). Appropriate 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.

[0052] 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.

[0053] 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.

[0054] 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.

[0055] 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).

[0056] 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.

[0057] 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.

[0058] Thus in another aspect, the present invention relates to a diagnostic kit comprising:

[0059] (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;

[0060] (b) a nucleotide sequence complementary to that of (a);

[0061] (c) a polypeptide of the present invention, preferably the polypeptide set forth in the Sequence Listing or a fragment thereof; or

[0062] (d) an antibody to a polypeptide of the present invention, preferably to the polypeptide set forth in the Sequence Listing.

[0063] 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.

[0064] 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, Ala., 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/.

[0065] 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.

[0066] 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.

[0067] 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).

[0068] Techniques for the production of single chain antibodies, such as those described in U.S. Pat. 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.

[0069] 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.

[0070] 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.

[0071] 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.

[0072] 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.

[0073] 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).

[0074] 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 et al., J Mol Recognition, 8:52-58 (1995); and K. Johanson et al., J Biol Chem, 270(16):9459-9471 (1995)).

[0075] 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.

[0076] 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, 125I), 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.

[0077] 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.

[0078] 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.

[0079] Screening kits for use in the above described methods form a further aspect of the present invention. Such screening kits comprise:

[0080] (a) a polypeptide of the present invention;

[0081] (b) a recombinant cell expressing a polypeptide of the present invention;

[0082] (c) a cell membrane expressing a polypeptide of the present invention; or

[0083] (d) an antibody to a polypeptide of the present invention;

[0084] which polypeptide is preferably that set forth in the Sequence Listing.

[0085] It will be appreciated that in any such kit, (a), (b), (c) or (d) may comprise a substantial component.

[0086] Glossary

[0087] The following definitions are provided to facilitate understanding of certain terms used frequently hereinbefore.

[0088] “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.

[0089] “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.

[0090] “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.

[0091] “Secreted protein gene” refers to a polynucleotide comprising any of the attached nucleotide sequences or allelic variants thereof and/or their complements.

[0092] “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 is a mixture of single- and double-stranded regions, single- and double-stranded RNA, and RNA that is mixture of single- and double-stranded regions, hybrid molecules comprising DNA and RNA that may be single-stranded or, more typically, double-stranded or a mixture of single- and double-stranded regions. In addition, “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.

[0093] “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 in a 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 et 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).

[0094] “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.

[0095] “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 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.

[0096] “Allele” refers to one of two or more alternative forms of a gene occurring at a given locus in the genome.

[0097] “Polymorphism” refers to a variation in nucleotide sequence (and encoded polypeptide sequence, if relevant) at a given position in the genome within a population.

[0098] “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.

[0099] “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.

[0100] “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.

[0101] “% 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 over shorter, defined lengths (so-called local alignment), that is more suitable for sequences of unequal length.

[0102] “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.

[0103] 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, Wis., 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.

[0104] 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, 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).

[0105] Preferably, the BLOSUM62 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 acid sequences before comparison.

[0106] 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.

[0107] “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 mutatidis for other values of the Identity Index, for instance 0.96, 0.97, 0.98 and 0.99.

[0108] 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.

[0109] The relationship between the number of nucleotide or amino acid differences and the Identity Index may be expressed in the following equation:

n

a

≦x

a
−(xa·I),

[0110] in which:

[0111] na is the number of nucleotide or amino acid differences,

[0112] xa is the total number of nucleotides or amino acids in a sequence set forth in the Sequence Listing,

[0113] I is the Identity Index,

[0114] · is the symbol for the multiplication operator, and in which any non-integer product of xa and I is rounded down to the nearest integer prior to subtracting it from xa.

[0115] “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 polynucleotide or polypeptide that within the same species which is functionally similar.

[0116] “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 immnunoglobulin 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.

[0117] 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.

1TABLE ICorrespondingGSKNucleic AcidProteinGene NameGene IDSEQ ID NO'sSEQ ID NO'ssbg318680DNase318680SEQ ID NO:1 SEQ ID NO:40sbg237038SA237038SEQ ID NO:2 SEQ ID NO:41SEQ ID NO:3 SEQ ID NO:42sbg340871GPV340871SEQ ID NO:4 SEQ ID NO:43sbg293416HNKS293416SEQ ID NO:5 SEQ ID NO:44SEQ ID NO:6 SEQ ID NO:45sbg257418ZP257418SEQ ID NO:7 SEQ ID NO:46sbg319185CDa319185SEQ ID NO:8 SEQ ID NO:47SEQ ID NO:9 SEQ ID NO:48sbg323307KIAAa323307SEQ ID NO:10SEQ ID NO:49sbg315953GPPa315953SEQ ID NO:11SEQ ID NO:50SEQ ID NO:12SEQ ID NO:51sbg318486ONC318486SEQ ID NO:13SEQ ID NO:52sbg299359LIPO299359SEQ ID NO:14SEQ ID NO:53sbg230022NGa230022SEQ ID NO:15SEQ ID NO:54SEQ ID NO:16SEQ ID NO:55sbg297169BGP297169SEQ ID NO:17SEQ ID NO:56SEQ ID NO:18SEQ ID NO:57sbg253919HSCCAa253919SEQ ID NO:19SEQ ID NO:58SEQ ID NO:20SEQ ID NO:59sbg228137OLF228137SEQ ID NO:21SEQ ID NO:60SEQ ID NO:22SEQ ID NO:61sbg378514Netrin378514SEQ ID NO:23SEQ ID NO:62SEQ ID NO:24SEQ ID NO:63sbg253227.mucous253227SEQ ID NO:25SEQ ID NO:64matrix glycoproteinSEQ ID NO:26SEQ ID NO:65sbg262831SIAa262831SEQ ID NO:27SEQ ID NO:66SEQ ID NO:28SEQ ID NO:67sbg233728LIPASE233728SEQ ID NO:29SEQ ID NO:68sbg400455.CRF400455SEQ ID NO:30SEQ ID NO:69sbg400612KINASEa400612SEQ ID NO:31SEQ ID NO:70sbg381373ACRP381373SEQ ID NO:32SEQ ID NO:71sbg401294MEX-3401294SEQ ID NO:33SEQ ID NO:72SEQ ID NO:34SEQ ID NO:73sbg247722Cadherin247722SEQ ID NO:35SEQ ID NO:74SEQ ID NO:36SEQ ID NO:75sbg391057THIPa391057SEQ ID NO:37SEQ ID NO:76SEQ ID NO:38SEQ ID NO:77sbg378067TGFc378067SEQ ID NO:39SEQ ID NO:78

[0118]

2

TABLE II

Cell

Localization

Gene

Closest Polynuclotide by
Closest Polypeptide by
(by

Name
Gene Family
homology
homology
homology)

sbg318680-
DNase I
GB:AC022471
Human DNase I-like
Secreted

DNase

Sbmitted (4 FEB. 2000)
endonuclease,

by Lita Annenberg Hazen
gi:5803007

Genome Sequencing
Parrish J E,

Center, Cold Spring
Ciccodicola A,

Harbor Laboratory,
Wehhert M, Cox G F,

1 Bungtown Road, Cold
Chen E, and

Spring Harbor, NY 11724,
Nelson D L; 1995;

USA.
Hum. Mol. Genet.

4: 1557-1564.

sbg237038-
SA protein
GB:AC023292
Human SA gene,
Secreted

SA

Submitted (11 FEB. 2000)
gi:2988399

by Whitehead
Loftus, B. J. et al.

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

Genome Research,
308 (1999)

320 Charles Street,

Cambridge, MA 02141,

USA.

sbg340871-
Platelet
GB:AC025389
Rat platelet
Secreted

GPV
glycoprotein
Submitted (8 MAR. 2000)
glycoprotein V (GPV)

(GPV)
by Whitebead
precursor, gi:6980974

Institute/MIT Center for
Ravanat C, Morales M,

Genome Research,
Azorsa D O, Moog S,

320 Charles Street,
Schuhler S, Grunert P,

Cambridge, MA 02141,
Loew D, Van Dorsselaer A,

USA.
Cazenave J P,

Lanza F; 1997;

Blood 89: 3253-62.

sbg293416-
HNK-1
JGI:LLNL-R_241B6
Human GalNAc 4-
Secreted

HNKS
sulfotransferase
Joint Genome Institute,
sulfotransferase,

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

ZP
pellucida
Submitted (25 NOV. 1999)
glycoprotein,

protein
to the
gi: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.

sbg319185-
Leukocyte
GB:AC024004
Human leukocyte
Secreted

CDa
differentiation
Submitted (20 FEB. 2000)
differentiation antigen

antigen
by Whitehead Institute/MIT
CD84 isoform CD84s,

Center for Genome
gi:6650112

Research, 320 Charles
Submitted

Street, Cambridge, MA
(20 MAR. 1998) by Servei

02141, USA
d'Immunologia,

Hospital Clinic,

Villarroel 170,

Barcelona 08036, Spain

sbg323307-
Slit-like
GB:AL160156,
Human unnamed
Secreted

KIAAa

Submitted (10 MAR. 2000)
protein, gi:10439289

by Sanger Centre, Hinxton,
Submitted (29 AUG. 2000)

Cambridgeshire, CB10
by Sumio Sugano,

1SA, UK.
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

sbg315953-
Granulocyte
GB:AC011666
Human hypothetical
Secreted

GPPa
peptide A
Submitted (9 OCT. 1999)
protein SBBI67,

by Department Of
gi:9966869

Chemistry And
Submitted (8 MAR. 2000)

Biochemistry,
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

sbg318486-
Oncotrophoblast
GB:AC022045
Canine 5T4 tumour-
Secreted

ONC
glycoprotein
Submitted (25 JAN. 2000)
associated antigen'

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: WO200029428-

A2, 25 May 2000

sbg299359-
Lipocalin
SC:AL139041
Mouse major urinary
Secreted

LIPO

Submitted (16 NOV. 2000)
protein (MUP) 4,

by Sanger Centre, Hinxton,
gi:6678968

Cambridgeshire, CB10
Shahan K, Gilmartin M, and

1SA, UK
Derman E; 1987;

Mol Cell Biol 7: 1938-

1946.

sbg230022-
Plasmacytoma-
GB:AC066608
Rat neural cell adhesion
Membrane-

NGa
associated
GB:AC022002
protein BIG-2
bound

neuronal
Submitted
precursor, gi:1016012

glycoprotein
(25 APR. 2000) and
Yoshihara, Y.,

(24 JAN. 2000) by
Kawasaki, M.,

Human Genomic Center,
Tamada, A., Nagata, S.,

Institute of Genetics,
Kagamiyama, H. and

Chinese Academy of
Mori, K. J. Neurobiol.

Sciences, Datun Road,
28 (1), 51-69 (1995)

Beijing, Beijing 100101,

P.R. China

sbg297169-
Biliary
JGI: CITB-
Mouse biliary
Secreted

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.

sbg253919-
Human
GB:AC019355
Human
Secreted

HSCCAa
squamous cell
Submitted (2 JAN. 2000)
squamous cell

carcinoma
by Whitehead
carcinoma antigen 2

antigen
Institute/MIT Center for
(SCCA-2) (LEUPIN).

(SCCA)
Genome Research,
gi:1710877.

320 Charles Street,
Schneider, S. S.,

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

USA
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).

sbg228137-
Olfactomedin-
GB:AC022606
Rat neuronal
Secreted

OLF
related
Submitted
olfactomedin-related

protein
(6 FEB. 2000) by Whitehead
protein precursor,

Institute/MIT Center for
gi:3024210

Genome Research,
Danielson, P. E., Forss-

320 Charles Street,
Petter, S.,

Cambridge, MA 02141,
Battenberg, E. L.,

USA
deLecea, L.,

Bloom, F. E., and

Sutcliffe, J. G., 1994,

J. Neurosci. Res. 38:

468-478.

sbg378514-
Netrin
SC:BA5N16
Mouse Netrin-G1a
Secreted

Netrin
precursor
Submitted (9 APR. 2001)
protein

by Sanger Centre, Hinxton,
gi:9909148

Cambridgeshire, CB10
Nakashiba, T., Ikeda, T.,

1SA, UK.
Nishimura, S.,

Tashiro, K., Honjo, T.,

Culotti, J. G. and

Itohara, S. J. Neurosci.

20 (17), 6540-6550

(2000)

sbg253227.
Extracellular
GB:AC011647
Human colon specific
Secreted

mucous
mucous
Submitted (8 OCT. 1999)
protein,

matrix
matrix
by Whitehead
geneseqp:Y54368

glycoprotein
glycoprotein
Institute/MIT Center for
Submitted by

(EMMG)
Genome Research,
DIADEXUS LLC

320 Charles Street,
Publication number and

Cambridge, MA 02141, USA
date: WO9960161-A1,

25 NOV. 1999

sbg262831-
Sialoadhesin
JGI: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 (1 OCT. 1999)
precursor, gi:126318

by Whitehead
Lowe M E,

Institute/MIT Center for
Rosenblum J L, and

Genome Research,
Strauss A W;

320 Charles Street,
1989; J Biol Chem

Cambridge, MA 02141, USA.
264: 20042-8.

sbg400455.-
C1q-related
GB:AC024339
Mouse Gliacolin,
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,
Nagata, K. J. Biol.

320 Charles Street,
Chem. 275 (36), 27957-

Cambridge, MA 02141, USA
27963 (2000)

sbg400612-
Protein
GB:AP001615
Murine protein
Secreted

KINASEa
kinase
Submitted (4 APR. 2000)
kinase/ankyrin

to the
homologue,

DDBJ/EMBL/GenBank
geneseqp:Y76079

databases. Nobuyoshi
Submitted by

Shimizu, Keio University,
GENESIS RES & DEV

School of
CORP LTD

Medicine,
Publication

Molecular Biology;
number and date:

35 Shinanomachi, Shinjuku-
WO9955865-A1

ku, Tokyo 160-8582, Japan
4 NOV. 1999

sbg381373-
Adipocyte
JGI:RPCI-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

SMITHKLINE

BEECHAM CORP

Publication num-

ber and date:

WO9964629-A1,

16 DEC. 1999

sbg401294-
MEX-
GB:AC026956
Caenorhabditis
Cytosolic

MEX-3
3(IAP)
Submitted (25 MAR. 2000)
elegans
(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, J. R. Cell 87 (2),

205-216 (1996)

sbg247722-
OB-
GB:AL132780
Human OB-cadherin-
Secreted

Cadherin
Cadherin
Submitted (2 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

(1994)

sbg391057-
Thyroid
SC:AL158153,
Human TANGO 239,
Secreted

THIPa
hormone
SC:AL392044
geneseqp:B01432

induced
Submitted
Submitted by

protein
(22 MAR. 2001) and
MILLENNIUM

(2 MAR. 2001) by
PHARM INC

Sanger Centre, Hinxton,
Publication

Cambridgeshire, CB10
number and date:

1SA, UK.
WO200039284-A1,

6 JUL. 2000

sbg378067-
TGF beta
SC:AL162502
Human persephin
Secreted

TGFc
(transforming
Submitted (6 APR. 2001)
growth factor,

growth factor
by Sanger Centre, Hinxton,
geneseqp:Y16714

beta)
Cambridgeshire, CB10
Submitted by UNIV

1SA, UK.
WASHINGTON

Publication

number and date:

WO9914235-A1

25 MAR. 1999

[0119]

3

TABLE III

Gene

Name
Uses
Associated Diseases

sbg318680-
An embodiment of the invention
Cancer, infection,

DNase
is the use of sbg318680-Dnase to
autoimmune disorder,

treat respiratory diseases and
hematopoietic dis-

target parasites or cancer cells
order, wound healing

as a chromosome degrading agent
disorders, inflamma-

to cause death of those cells.
tion and respiratory

Close homologues of sbg318680-
diseases

DNase are DNases. DNase can be

used to treat respiratory diseases,

such as pneumonia, cystic fibro-

sis and asthma, by reducing viscos-

ity of bronchopulmonary secretions

(MacConnachie A M; 1999; Inten-

sive Crit Care Nurs 14: 101-2).

sbg237038-
An embodiment of the invention is
Cancer, infection,

SA
the use of sbg237038SA in blood
autoimmune disorder,

pressure control. A close homo-
hematopoietic dis-

logue of sbg237038SA is the rat
order, wound healing

SA gene. The SA gene is ex-
disorders, inflamma-

pressed at higher levels in the
tion, and hypertension

kidney of genetically hypertensive

rats (Yang T, Hassan S A, Singh I,

Smart A, Brosius F C,

Holzman L B, Schnermann J B,

Briggs J P; 1996; Hypertension 27:

541-51).

sbg340871-
An embodiment of the invention
Cancer, infection,

GPV
is the use of sbg340871-GPV in
autoimmune disorder,

hemostasis and platelet aggrega-
hematopoietic dis-

tion. A close homologue of
order, wound healing

sbg340871-GPV is platelet
disorders, inflamma-

glycoprotein (GP) V.
tion, and Bernard-

Platelet glycoprotein (GP) V
Soulier disease

is a major surface protein which

is cleaved by thrombin during

platelet activation, and associ-

ates with GPIb-IX complex to

form GPIb-V-IX, a receptor

for von Willebrand factor and

thrombin. Its functional role in

hemostasis is possibly related to

thrombin-induced platelet aggrega-

tion (Ravanat C, Morales M,

Azorsa D O, Moog S, Schuhler S,

Grunert P, Loew D,

Van Dorsselaer A,

Cazenave J P, Lanza F; 1997;

Blood 89: 3253-62).

sbg293416-
An embodiment of the invention is
Cancer, infection,

HNKS
the use of sbg293416-HNKS in
autoimmune disorder,

cell interactions and the develop-
hematopoietic dis-

ment of the nervous system. Close
order, wound healing

homologues of sbg293416-HNKS
disorders, inflamma-

are sulfotransferases. Sulfo-
tion, and peripheral

transferases are considered to be
neuropathies

key enzymes in the biosynthesis of

the HNK-1 carbohydrate epitope,

which is expressed on several

neural adhesion glycoproteins and

as a glycolipid, and is involved

in cell 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 sulfotrans-

ferase 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 F B,

1994, Neurochem Res 19: 945-

57).

sbg257418-
An embodiment of the invention is
Infertility

ZP
the use of sbg257418ZP in fer-

tilization. A close homologue of

sbg257418ZP is zona pellucida.

Zona pellucida protein is an extra-

cellular matrix that surrounds

growing oocytes, ovulated

eggs, and early embryos and it is

critically involved in fertilization

(Epifano, O., 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
Cancer, autoimmune

CDa
the use of sbg319185CDa, a se-
disorders, wound

creted protein, in the diag-
healing disorders,

nosis and treatment of can-
infections and

cer and autoimmune disorders.
hematopoietic dis-

Close homologues of
orders

sbg319185CDa are leukocyte

differentiation antigen CD84

isoforms.

CD84's are members of the

immunoglobulin superfamily,

show high homology with several

molecules belonging to the CD2

family of differentiation anti-

gens and is proposed to be useful

in the diagnosis and treatment of

cancer and autoimmune disorders

(Palou E, Pirotto F, Sole J,

Freed J H, Peral B, Vilardell C,

Vilella R, Vives J, Gaya A.

Genomic characterization of

CD84 reveals the existence of

five isoforms differing in their

cytoplasmic domains. Tissue Anti-

gens February 2000; 55 (2):

118-27)).

sbg323307-
An embodiment of the invention is
Cancer, autoimmune

KIAAa
the use of sbg323307-KIAAa, a
disorders, infec-

secreted protein, to regulate cell
tions, wound healing

signaling, motility, and nucleic
disorders and

acid management. A close homo-
hematopoietic dis-

logue of sbg323307-KIAAa is
orders

human KIAA0918 protein. Human

KIAA0918 protein, a slit-like

protein is functionally related to

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)).

sbg315953-
An embodiment of the invention is
Infections, cancer,

GPPa
the use of sbg315953GPPa, a se-
autoimmune

creted protein, to treat disorders
disorders, wounder

associated with lipopolysaccha-
healing disorders and

rides. A close homologue to
hematopoietic

sbg315953GPPa is Bovine granu-
disorders.

locyte peptide A precursor. Bovine

granulocyte peptide A precursors

are used in human and veterinary

medicine, particularly to treat

disorders associated with lipopoly-

saccharides, e.g. sepsis and endo-

toxaemia (1. Selsted M E, Bovine

granulocyte peptide A precursor

(antimicrobial BGP-A). Accession

Number W23722, Publication Date

21 AUG. 1997. 2. Yount N Y,

Yuan J, Tarver A, Castro T,

Diamond G, Tran P A, Levy J N,

McCullough C, Cullor J S,

Bevins C L, Selsted M E.

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 10 Sep. 1999;

274 (37): 26249-58)).

sbg318486-
An embodiment of the invention is
Cancer, infection,

ONC
the use of sbg318486ONC in the
autoimmune disorder,

growth and invasion events of
hematopoietic

trophoblast and tumor cells.
disorder, wound

A close homologue to
healing disorders, and

sbg318486ONC is oncotrophoblast
inflammation

glycoproteins. It has been shown

that oncotrophoblast protein was

expressed by tumor cells with

metastatic spread, suggesting a

role in 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
Cancer, infection,

LIPO
is the use of sbg299359LIPO in
autoimmune disorder,

sperm maturation, taste recog-
hematopoietic

nition, and transportation of
disorder, wound

some molecules across the blood
healing disorders, and

brain barrier. A close homologue
inflammation

to sbg299359LIPO is Lipocalin.

Lipocalins transport small

hydrophobic molecules such as

steroids, bilins, retinoids, and

lipids, and they have various

effects on a number of tissues.

It has been shown that lipocalins

are involved in sperm maturation,

taste recognition, and transporta-

tion of some molecules across the

blood brain barrier

(Newcomer M. E.; 1993; Struc-

ture 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)

sbg230022-
An embodiment of the invention is
Cancer, infections,

NGa
the use of sbg230022Nga in the
autoimmune

formation and maintenance of
disorders, wound

neuron type-specific networks in
healing disorders and

the brain. Close homologues to
hematopoietic

sbg230022Nga are mouse plasma-
disorders

cytoma-associated neuronal

glycoprotein and rat BIG-1 protein.

Mouse plasmacytoma-associated

neuronal glycoprotein, is ec-

topically activated by intracister-

nal A-type particle long terminal

repeats in murine plasmacytomas.

Rat BIG-1 protein, is a TAG-1/F3-

related member of the immuno-

globulin superfamily with neurite

outgrowth-promoting activity and

involved in the formation and

maintenance of neuron type-

specific networks in the brain

(1. Connelly M A, Grady R C,

Mushinski J F, Marcu K B.

PANG, a gene encoding a

neuronal glycoprotein, is

ectopically activated by intra-

cisternal A-type particle long

terminal repeats in murine plasma-

cytomas. Proc Natl Acad Sci USA

15 Feb. 1994; 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 August 1994;

13 (2): 415-26).

sbg297169-
An embodiment of the invention is
Cancer, infection,

BGP
the use of sbg297169BGP in re-
autoimmune disorder,

newal and/or differentiation of
hematopoietic

epithelial cells. A close homologue
disorder, wound

to sbg297169BGP is BGP protein.
healing disorders,

BGP proteins are expressed at the
inflammation

cell surface and function in vitro

as cell adhesion molecules. The

expression of the many BGP

isoforms at the surface of

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).

sbg253919-
An embodiment of the invention
Cancers, such as

HSCCAa
is the use of sbg253919-HSCCAa
squamous cell

for treatment of cancer or
carcinomas

psoriasis or in development of

more aggressive squamous cell

carcinomas. Close homologues of

sbg253919-HSCCAa are

Psoriastatin type II and a human

leupin precursor. Psoriastatin

type II, is claimed to modulate

activity of psoriastatin

type I and II genes, e.g. using

(ant) agonists, useful for treat-

ment of cancer or psoriasis. The

other, a human leupin precursor,

contains a tandem duplication of

the human squamous cell carci-

noma antigen gene playing a causal

role in development of more ag-

gressive squamous cell carcinomas

(1. Goetinck P F, Hibino T,

Takahashi T and Baciu P C.

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, pub-

lication date 24 APR. 1997.

2. Schneider S S, Schick C,

Fish K E, Miller E, Pena J C,

Treter S D, Hui S M,

Silverman G A. A serine protein-

ase inhibitor locus at 18q21.3

contains a tandem duplication of

the human squamous cell carci-

noma antigen gene. Proc Natl Acad

Sci USA 11 Apr. 1995; 92 (8):

3147-51. 3. Barnes R C,

Worrall D M. Identification of a

novel human serpin gene; cloning

sequencing and expression of

leupin. FEBS Lett 2 Oct. 1995;

373 (1): 61-5).

sbg228137-
An embodiment of the invention is
Cancer, infection,

OLF
the use of sbg228137OLF in func-
autoimmune

tinal roles in chemoreception and
disorder,

in the central nervous system.
hematopoietic

A close homologue to
disorder, wound

sbg228137OLF is olfactomedin.
healing disorders,

Olfactomedin is a glyco-
inflammation, and

protein, and reacts with proteins
nervous system

of olfactory cilia. It was originally
disorders

discovered at the mucociliary sur-

face of the amphibian olfactory

neuroepithelium and subsequently

found throughout the mammalian

brain (Danielson, P. E., Forss-

Petter, S., Battenberg, E. L.,

deLecea, L., Bloom, F. E., and

Sutcliffe, J. G., 1994, J. Neurosci.

Res. 38: 468-478). Its noticeable

deposition at the chemosensory

surface of the olfactory neuro-

epithelium suggest a role for this

protein in chemoreception

(Snyder D A, Rivers A M,

Yokoe H, Menco B P, and

Anholt R R, 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 C A, and Anholt R R,

1998, Mol Biol Evol 15: 718-26).

sbg378514-
An embodiment of the invention
Cancer, infection,

Netrin
is the use of sbg378514-Netrin in
autoimmnune disorder,

roles of the central nervous
hematopoietic

system.
disorder, wound

A close homologue to sbg378514-
healing disorders,

Netrin is Netrin. Netrins possess
inflammation, and

commissural axon outgrowth-
nervous system

promoting activity, and control
disorder

guidance of CNS commissural

axons and peripheral motor axons

(Serafini T, Kennedy T E,

Galko M J, Mirzayan C,

Jessell T M, and Tessier-

Lavigne M; 1994; Cell 78: 409-

24). Diffusible and substrate-bound

cues, including netrins and their

receptors, can guide axonal

pathway choice via attractive and

repulsive signals (Tear G; 1998;

Essays Biochem 33: 1-13).

sbg253227.
An embodiment of the invention is
Hematopoietic

mucous
the use of sbg253227.-mucous
disorder, wound

matrix
matrix glycoprotein for the treat-
healing disorder,

glycoprotein
ment of gastrointestinal.dis-
viral and bacterial

orders and cancer. Close homo-
infection, cancer,

logues of sbg253227.mucous
autoimmune diseases

matrix glycoprotein have been
Neurological

used in combination for treatment
disorders,

of infections associated with
gastrointestinal

EMMG. EMMG is useful for the
disorders, dysphagia,

treatment of gastrointestinal
abdominal angina,

disorders and cancer, e.g.
pancreatitis, colonic

dysphagia, abdominal angina,
carcinoma, Crohn's

pancreatitis, colonic carcinoma,
disease and the

Crohn's disease and the
Mallory-Weiss

Mallory-Weiss syndrome
syndrome.

(US5929033-A, CORLEY N C,

TANG Y T, Submitted by

INCYTE PHARM INC. Reference

number, WPI; 99-429518/36,

1999).

sbg262831-
An embodiment of the invention is
Cancer, autoimmune

SIAa
the use of sbg262831SIAa to
disorders, infection,

mediate sialic acid-dependent
wound healing

ligand recognition and to func-
disorders, and

tion as an inhibitory receptor
hematopoietic

in human natural killer cells.
disorders.

A close homologue of

sbg262831SIAa is human QA79

membrane protein. QA79 belongs

to the sialoadhesin family and

is proposed to mediate sialic acid-

dependent ligand recognition and

to function as an inhibitory recep-

tor in human natural killer cells

(Falco, 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 func-

tions as an inhibitory receptor

in human natural killer cells.

J Exp Med 20 Sep 1999; 190 (6):

793-802).

sbg233728-
An embodiment of the invention
Cancer, infection,

LIPASE
is the use of sbg233728LIPASE to
autoimmune

treat pancreatitis via replacement
disorder,

therapy. A close homologue of
hematopoietic

sbg233728-LIPASE is pancreatic
disorder, wound

lipase. Pancreatic lipase can be
healing disorders,

used as replacement enzymes for
inflammation, and

patients with chronic pancreatitis.
pancreatitis.

Pancreatic lipase hydrolyzes

dietary long chain triacylglycerol

to free fatty acids and monoacyl-

glycerols in the intestinal lumen

(Lowe M E, Rosenblum J L, and

Strauss A W; 1989; J Biol Chem

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 treat-

ment method for pancreatic

steatorrhea. (Nakamura T,

Takeuchi T, and Tando Y; 1998;

Pancreas 16: 329-36).

sbg400455.-
An embodiment of the invention is
Hematopoietic

CRF
the use of sbg400455.CRF in the
disorder, wound

areas of the nervous system
healing disorder,

involved in motor function,
viral and bacterial

such as the Purkinje cells of
infection, cancer,

the cerebellum, the accessory
autoimmune

olivary nucleus, the pons, and
diseases, energy

the red nucleus. Close homo-
homeostasis

logues of sbg400455.CRF
disorder and

include CRF transcripts. CRF
obesity

transcripts are most abundant

in areas of the nervous sys-

tem and have been used to develop

products for modulating energy

balance or insulin production

in mammals ((W09639429-A2)

Schere, P. E.; Submitted by

Whithead Institute of Biomedical

Research; Berube N G,

Swanson X H, Bertram M J,

Kittle J D, Didenko V,

Baskin D S, Smith J R and

Pereira-Smith O M.,

Brain Res. Mol. Brain Res. 63 (2),

233-240 (1999)).

sbg400612-
An embodiment of the invention
Cancer, wound

KINASEa
is the use of sbg400612-KINASEa
healing disorders,

in the treatment of inflammation,
autoimmune

cancer, neurological diseases,
disorders,

growth and developmental defects,
hematopoietic

skin wounds, and hair follicle
disorders and

disorders. A close homologue of
infection

sbg400612-KINASEa is murine

protein kinase/ankyrin homo-

logue. Murine protein kinase/

ankyrin homologue can stimulate

the growth and motility of

keratinocytes, inhibit the

growth of cancer cells,

modulate angiogenesis and

tumour vascularisation,

modulate skin inflamma-

tion and epithelial cell

growth and inhibit binding of

HIV-1 to leukocytes. Murine

protein kinase/ankyrin homologue

can also be used to treat in-

flammation, cancer, neurological

diseases, growth and develop-

mental defects, skin wounds, and

hair follicle disorders (Kumble A,

Murison J G, Onrust R,

Sleeman M, Strachan L and

Watson J D. Novel polynucleotides

useful for the treatment of various

conditions including wounds and

cancer. Accession Number:

Y76079 Publication Date:

4 NOV. 1999).

sbg381373-
An embodiment of the invention
Cancer, infection,

ACRP
is the use of sbg381373-ACRP in
autoimmune disorder,

the complex balanced system of
hematopoietic dis-

energy homeostasis involving
order, wound healing

food intake, carbohydrate
disorders,

catabolism, and lipid catabo-
inflammation, obesi-

lism. A close homologue of
ty, and diabetes

sbg381373-ACRP is ACRP30

protein. ACRP30 protein may

be a factor that participates

in the complex balanced system

of energy homeostasis involving

food intake, carbohydrate cata-

bolism, and lipid catabolism.

ACRP30 is structurally similar

to complement factor C1q, and it

forms large homo-oligomers that

undergo a series of post-transla-

tional modifications (Scherer P E,

Williams S, Fogliano M,

Baldini G, Lodish H F; 1995;

J Biol Chem 270: 26746-9).

sbg401294-
An embodiment of the invention
Hematopoietic

MEX-3
is the use of sbg401294-MEX-3
disorder, wound

to develop products for
healing disorder,

diagnosis and therapy of
viral and bacterial

disease states such as tumor
infection, cancer,

formation, apoptosis regulation
tumor formation,

in cells to reduce or increase
autoimmune diseases,

apoptosis and for pharmacological
inhibition of apoptosis

screening.

sbg247722-
An embodiment of the invention is
Hematopoietic

Cadherin
the use of sbg247722-Cadherin for
disorder, wound

treatment and diagnosis of bone
healing disorder,

metabolic diseases. A close homo-
viral and bacterial

logue of sbg247722-Cadherin is
infection, cancer,

cadherin, a Ca2+ dependent cell
autoimmune

adhesion protein.
diseases, energy

homeostasis dis-

order and bone

metabolic disease

sbg391057-
An embodiment of the invention is
Autoimmune dis-

THIPa
the use of sbg391057-THIPa in
orders, wound healing

controlling thyroid hormone
disorders, cancer,

synthesis. A close homologue of
infection and

sbg391057-THIPa is xenopus
hematopoietic dis-

laevis thyroid hormone-induced
orders

protein. Xenopus laevis thyroid

hormone-induced protein has been

implicated in controlling thyroid

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 USA

5 Mar 1996; 93 (5): 1924-9).

sbg378067-
An embodiment of the invention is
Cancer, infection,

TGFc
the use of sbg378067-TGFc in
autoimmune disorder,

cellular growth control in the
hematopoietic dis-

etiology of cancer and cell
order, wound healing

differentiation and development.
disorder, inflamma-

The sbg378067-TGFc protein con-
tion, preventing or

tains a close approximation of
treating cellular

the prosite consensus pattern
degeneration or in-

(PDOC00223) for TGF-beta family
sufficiency, e.g.

members. TGF-beta proteins have
neuronal degeneration

been known to be involved in
resulting from pe-

growth control and hence the
ripheral neuropathy,

etiology of cancer (Anticancer
amyotrophic lateral

Res November-December 1999;
sclerosis, Alzheimer's

19 (6A): 4791-807), cell
disease, Parkinson's

differentiation and development.
disease, Huntington's

A TGF-beta signaling pathway
disease, ischemic

constitutes a tumor suppressor
stroke, acute brain

path (Cytokine Growth Factor
injury, acute spinal

Rev 1 Apr. 2000; 11 (1-2):
cord injury, nervous

159-168). A close homo-
system tumours, multi-

logue of sbg378O67-TGFc is
ple sclerosis, or infec-

TGF-beta protein.
tion (viral, bacterial,

fungal, parasitic),

hematopoietic cell de-

generation or insuf-

ficiency resulting from

eosinopenia, anemias,

thrombocytopenia, or

stem-cell insuffi-

ciences, cardiac mus-

cle degeneration or

insufficiency resulting

from cardiomy-

opathy or congestive

heart failure, periph-

eral nerve trauma or

injury, exposure to

neurotoxins, metabolic

diseases such as

diabetes or renal

dysfunctions and

damage caused by

infectious agents

[0120]

4

TABLE IV

Quantitative, Tissue-specific mRNA expression detected using SybrMan

Quantitative, tissue-specific, mRNA 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

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 1 ng mRNA pool from each tissue. Two replicate mRNA measurements were

made from each tissue RNA.

Tissue-Specific mRNA Expression

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

Skeletal

Spleen/

Gene Name
Brain
Heart
Lung
Liver
Kidney
muscle
Intestine
lymph
Placenta
Testis

sbg237038SA
14 ± 1
27 ± 1
39 ± 1
14 ± 0
18 ± 1
12 ± 0
21 ± 3
45 ± 2
19 ± 3
40 ± 9

sbg340871-
0 ± 0
200 ± 46
363 ± 10
−9 ± 6
33 ± 13
93 ± 17
74 ± 9
305 ± 9
2902 ± 114
36 ± 4

GPV

sbg293416-
553 ± 15
65 ± 1
39 ± 4
27 ± 4
39 ± 1
38 ± 1
53 ± 4
225 ± 9
43 ± 0
108 ± 9

HNKS

sbg257418ZP
37 ± 3
28 ± 6
6 ± 0
−12 ± 3
−4 ± 2
19 ± 7
15 ± 2
5 ± 2
10 ± 2
605 ± 10

sbg319185-
54 ± 5
113 ± 3
696 ± 140
95 ± 37
317 ± 31
708 ± 30
540 ± 64
5987 ± 158
326 ± 2
258 ± 31

CDa

sbg323307-
293 ± 8
633 ± 15
1269 ± 58
15 ± 1
136 ± 5
26 ± 6
1400 ± 91
33 ± 12
632 ± 12
196 ± 10

KIAAa

sbg315953-
232 ± 31
16 ± 0
54 ± 2
1 ± 6
14 ± 7
4 ± 8
15 ± 3
99 ± 4
61 ± 7
126 ± 6

GPPa

sbg318486-
52 ± 7
3 ± 2
8 ± 0
4 ± 0
4 ± 2
2 ± 1
6 ± 2
1 ± 7
4 ± 1
122 ± 9

ONC

sbg299359-
1701 ± 95
39 ± 0
60 ± 14
21 ± 1
135 ± 13
41 ± 3
49 ± 2
26 ± 7
40 ± 5
138 ± 2

LIPO

sbg230022-
3443 ± 112
684 ± 2
386 ± 7
712 ± 16
1956 ± 63
36 ± 0
588 ± 7
1293 ± 17
43 ± 7
358 ± 2

NGa

sbg297169-
417 ± 29
141 ± 8
236 ± 5
170 ± 11
322 ± 0
74 ± 4
231 ± 1
370 ± 0
223 ± 3
968 ± 32

BGP

sbg253919-
−5 ± 1
1 ± 1
2 ± 1
−14 ± 2
−10 ± 0
−4 ± 3
0 ± 1
6 ± 1
4 ± 3
119 ± 9

HSCCAa

sbg228137-
5174 ± 138
58 ± 4
99 ± 5
9 ± 3
63 ± 7
167 ± 12
98 ± 0
719 ± 9
32 ± 8
67 ± 4

OLF

sbg253227.
5 ± 0
11 ± 1
21 ± 1
0 ± 1
28 ± 2
1 ± 0
13 ± 2
24 ± 3
26 ± 4
118 ± 1

mucous

matrix

glycoprotein

sbg262831-
9 ± 1
6 ± 1
59 ± 1
59 ± 1
5 ± 0
−4 ± 2
134 ± 6
2657 ± 97
45 ± 4
25 ± 0

SIAa

sbg233728-
2 ± 1
6 ± 1
4 ± 2
6 ± 2
1 ± 0
4 ± 0
1 ± 3
1 ± 2
3 ± 2
28 ± 3

LIPASE

sbg400455.-
8735 ± 257
345 ± 14
434 ± 54
191 ± 14
4038 ± 147
705 ± 32
379 ± 1
847 ± 59
434 ± 8
97 ± 8

CRF

sbg400612-
10 ± 0
24 ± 4
276 ± 87
145 ± 2
431 ± 10
7 ± 0
59 ± 5
23 ± 4
82 ± 9
34 ± 3

KINASEa

sbg381373-
112 ± 40
11 ± 3
15 ± 5
14 ± 5
10 ± 2
11 ± 8
14 ± 4
−3 ± 8
6 ± 2
11 ± 8

ACRP

sbg401294-
49 ± 8
39 ± 2
122 ± 1
35 ± 9
151 ± 8
6 ± 5
16 ± 1
15 ± 3
71 ± 8
683 ± 56

MEX-3

sbg247722-
2626 ± 18
1140 ± 22
1733 ± 62
78 ± 4
2007 ± 12
213 ± 52
1175 ± 47
1701 ± 167
3487 ± 263
1814 ± 30

Cadherin

sbg391057-
332 ± 3
3010 ± 30
8567 ± 84
136 ± 1
1013 ± 90
1499 ± 172
2469 ± 86
3512 ± 23
1393 ± 32
2408 ±

THIPa

174

sbg378067-
33 ± 8
58 ± 6
52 ± 4
3 ± 1
48 ± 1
49 ± 22
21 ± 4
116 ± 28
74 ± 24
59 ± 4

TGFc

[0121]

5

TABLE V

Additional diseases based on mRNA expression in specific tissues

Tissue

Expression
Additional Diseases

Brain
Neurological and psychiatric diseases, including

Alzheimers, parasupranuclear palsey, Huntington's

disease, 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 Ob-

structive Pulmonary Disease, cystic fibrosis, acute

bronchitis, adult respiratory distress syndrome

Liver
Dyslipidemia, hypercholesterolemia, hypertriglyc-

eridemia, cirrhosis, hepatic encephalopathy, fatty

hepatocirrhosis, viral and nonviral hepatitis, Type II

Diabetes Mellitis, impaired glucose tolerance

Kidney
Renal diseases, including acute and chronic renal failure,

acute tubular necrosis, cystinuria, Fanconi's Syndrome,

glomerulonephritis, renal cell carcinoma, renovascular

hypertension

Skeletal muscle
Eulenburg's Disease, hypoglycemia, obesity, tendinitis,

periodic paralyses, malignant hyperthermia, paramyoto-

nia congenita, myotonia congenita

Intestine
Gastrointestinal diseases, including Myotonia congenita,

Ileus, Intestinal Obstruction, Tropical Sprue, Pseudo-

membranous Enterocolitis

Spleen/lymph
Lymphangiectasia, hypersplenism, angiomas, ankylosing

spondylitis, Hodgkin's Disease, macroglobulinemia,

malignant lymphomas, rheumatoid arthritis

Placenta
Choriocarcinoma, hydatidiform mole, placenta previa

Testis
Testicular cancer, male reproductive diseases, including

low testosterone and male infertility

Pancreas
Diabetic ketoacidosis, Type 1 & 2 diabetes, obesity,

impaired glucose tolerance

[0122]

Novel compounds

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