MX2007008691A - Gitr antibodies for the diagnosis of nsclc - Google Patents

Abstract

The present invention provides methods and compositions for detecting, diagnosing, prognosing and monitoring the progress of cancers,e.g.,NSCLC, of epithelial origin,e.g.,lung, ovarian, breast, prostate and colon cancers and malignancies and kits for use in said methods. Further provided are methods for screening to identify agonists and antagonists of antigens associated with these cancers and malignancies.

Description

GITR ANTIBODIES FOR DIAGNOSIS OF NSCLC TECHNICAL FIELD The invention relates to compositions and methods useful in therapeutic, diagnostic and classification methods for human cancers and related malignancies. BACKGROUND Despite numerous advances in medical research, cancer remains the second leading cause of death in the United States. In industrialized nations, approximately one in five people will die of cancer. Traditional modes of clinical care, such as surgical resection, radiotherapy and chemotherapy have a significant failure rate, especially for solid tumors. Failure occurs either because the initial tumor is non-responsive, or due to recurrence due to re-growth at the original site and / or metastasis. Lung cancer is one of the most common malignancies worldwide and is the second leading cause of cancer death in men. See, American Cancer Society, Cancer facts and figures, 1996, Atlanta. Approximately 178,100 new cases of lung cancer were diagnosed in 1997, taking into account 13% of cancer diagnosis. An estimated 160,400 deaths due to lung cancer would occur in 1997 taking into account 29% of all cancer deaths, making lung cancer more deadly than the combination of breast, prostate and colorectal cancers. Jemal, A. et al. (2004) Cancer Statistics 2004, CA: A Cancer Journal for Clinicians 53: 5-26. The one-year survival rates for lung cancer have increased from 32% in 1973 to 41% in 1993, largely due to improvements in surgical techniques. The 5-year survival ratio for all the combined stages is only 14%. The survival rate is 48% for cases detected when the disease is still localized, but only 15% of lung cancers are discovered in the early phase. Among several forms of lung cancer, non-small cell lung cancer (NSCLC) accounts for almost 80% of all new cases of lung cancer each year. Small cell lung cancer is the most malignant and fastest growing form of lung cancer. The primary tumor is usually responsive to chemotherapy, but it is followed by widespread metastasis. The average survival time of the diagnosis is approximately 1 year, a 5-year survival rate of 5%. For patients diagnosed with NSCLC, surgical resection offers the only chance of significant survival. There are five types of non-small cell lung cancer: squamous cell carcinoma, adenocarcinoma, large cell carcinoma, adenosquamous carcinoma and undifferentiated carcinoma. Adenoescamous carcinomas begin in cells that appear flattened when viewed under a microscope. Undifferentiated carcinoma cells do not appear similar to normal cells and multiply in an uncontrollable manner. Squamous cell cancer is the most common type of lung cancer. This develops from the cells that line the airways. Adenocarcinoma develops from glandular or secretory cells that produce mucus (phlegm). Large-cell lung cancer has been named because the cells look large and rounded when viewed under a microscope. Non-small cell cancer is also characterized by four clinical stages. Stage I is very localized cancer without cancer in the lymph nodes. Stage II cancer has spread to the lymph nodes in the upper part of the affected lung. Stage III cancer has spread near where the cancer started. This can be to the chest wall, the covering of the lung (pleura), the middle part of the chest (mediastinum) or other lymph nodes. Stage IV cancer has spread to another part of the body. Several antibody therapies are in development to treat lung cancer. Cetuximab and gifitinib are approved by the U.S. Food and Drug Administration for these cancers. Cetuximab in combination with chemotherapy has provided some benefit to patients with NSCLC but additional experiments are still needed. Kelly, K. and collaborators (2003) Proc. Am. Soc. Clin. Oncol. 22: 644. Therefore, an effective treatment for NSCLC is still required. This invention satisfies this need and provides related advantages as well. DESCRIPTION OF THE INVENTION The present invention provides compositions and methods to aid in the diagnosis of the condition of a cell, to identify and / or distinguish normal and neoplastic cells and to identify potential therapeutic agents to reverse the neoplasia and / or ameliorate the symptoms associated with the presence of neoplastic cells in a subject. Accordingly, the embodiments of the invention are directed to methods for diagnosing the condition of a cell by classifying or detecting the presence of a differentially expressed gene identified in Table 1. In one aspect, the differential expression of the gene is indicative of the neoplastic state of a cell of epithelial origin, for example, non-small cell lung cancer (NSCLC), ovarian, breast, prostate and colon cancers. Expression can be detected by any appropriate method, including, for example, by detecting the amount of mRNA transcribed from the gene or the amount of cDNA produced from the reverse transcription of the mRNA transcribed from the gene or the amount of the polypeptide or protein encoded by the gene. the Gen. These methods can be analyzed on a sample-by-sample basis or can be modified for high-throughput analysis. Additionally, databases containing complete or partial quantitative transcripts or protein sequences isolated from a cell sample can be searched and analyzed for the presence and amount of transcript or gene product expressed. Another aspect of the invention is a classification for identifying therapeutic agents that reverse or treat neoplasia and tumors, wherein the cell and / or tumor is characterized by the differential expression of a polypeptide or protein identified in Table 1. The method comprises putting contact the previously identified cell that possesses this genotype with an effective amount of a potential agent and analyze for the reversal of the neoplastic condition. Further provided are polynucleotides encoding the proteins, fragment (s) thereof or polypeptides shown in Table 1 (also referred to herein as "gene expression product"), the gene delivery vehicles comprising these polynucleotides and host cells that comprise these polynucleotides. The proteins, polypeptides or fragment (s) thereof are also useful for generating antibodies that specifically recognize and bind to these molecules. The antibodies can be polyclonal or monoclonal. These antibodies can be used to isolate protein or polypeptides expressed from the genes encoding the polypeptides and to detect neoplastic cells or tumors. The invention also provides isolated host cells and recombinant host cells that contain a polynucleotide that encodes the polypeptides identified in Table 1 and / or fragment (s) thereof. The cells may be prokaryotic or eukaryotic and by way of example only, may be any of one or more of bacterial, yeast, mammalian, mammalian, human cells and particular subtypes thereof, eg, stem cells, antigen presenting cells (APCs) such as dendritic cells (DCs) or T cells. Table 1 'TNFRSFl 8' AF117297.1 scaly AF241229.1 NSCLC; AF125304.1 cancers AY358877.1 of ovary NM_148901.1 of breast; NM_148902.1 of NM_00 195.2 prostate NP__004186 of colon NP_683699 NT 077913 * the address of the network is = ncbi.nlm.nih.gov/LocusLink/list.cgi. Further provided by this invention is a method for monitoring a cancer in a subject by analyzing, at different times, the expression level of the gene of interest and comparing the expression levels of the gene or to determine whether the expression has increased or decreased, to thereby monitor the cancer in the subject. A device for the use of a method of diagnosis or classification of drugs is also provided herein. The kit comprises at least one agent (e.g., probe, primer or antibody) that detects gene expression and instructions for use. BRIEF DESCRIPTION OF SEQUENCE LISTS As used herein, the term "GITR gene" refers to at least the ORF of a contiguous polynucleotide sequence and which encodes a protein or polypeptide having the biological activity as set forth in the present. LocusLink, supra, reports that the protein encoded by this gene is a member of the TNF receptor superfamily. This receptor has been reported to have increased expression in T cell activation, and is thought to play a key role in the dominant immune self-tolerance maintained by CD25 (+) CD (+) regulatory T cells. Inactivation studies in mice also suggest that the function of this receptor is in the regulation of T cell activation induced by CD3 and programmed cell death. Three alternately spliced transcript variants of this gene encoding different isoforms have been reported. The sequence ID N0.:1 is an example of a GITR polynucleotide sequence, and others are known in the art, examples of which include, but are not limited to the sequences set forth in Table 1, and the sequences encoding the GITR gene expression products as defined herein. Also included within this definition are biologically equivalent sequences such as those sequences that encode the polypeptide of SEQ ID NO: 2 and those that have at least 90% or alternatively, at least 95% sequence homology of a sequence exemplary, such as SEQ ID NO. : 1, and as determined by the percent of the run of identity sequence analysis under error parameters. Also within this definition are the biologically equivalent or polynucleotide genes that are identified by the ability to hybridize under conditions of high stringency to the least strand. This may be desirable for using non-human genes, the polynucleotide sequences of which are known in the art. See, for example, UniGene Cluster Hs.212680. Polynucleotide fragments are also known in the art, and include but are not limited to GenBank Accesses numbers: BI911657.1; AI499936.1; AI214481.1; and AI923712.1. These are particularly useful as probes or primers. As used herein, the term "gene expression product GITR, protein or polypeptide" includes the amino acid sequence of SEQ ID NO. : 2 as well as the transcribed and translated amino acid sequences of the GITR genes identified in the above, without considering the gene expression system, for example, bacterial or other prokaryotic cell, yeast cell, mammalian cell such as simian cell, bovine or human The term includes naturally occurring, isolated polypeptides isolated from tissue samples as well as recombinantly produced proteins and polypeptides. The term also includes polypeptides having the amino acid sequence which are at least 90% or alternatively at least 95% homologous to SEQ ID NO: 2 and which have the biological activity as described herein. Examples of homologous amino acid sequence include but are not limited to polypeptides having the amino acid sequence of SEQ ID NO. : 2 or another GITR gene expression product that has been modified by conservative amino acid substitutions. MODES FOR CARRYING OUT THE INVENTION Throughout this description, several publications, patents and published patent specifications are referenced by an identification appointment. The descriptions of these publications, patents and published patent specifications are incorporated herein by reference in the present description to more fully describe the state of the art to which this invention pertains. Definitions The practice of the present invention will employ, unless otherwise indicated, conventional techniques of immunology, molecular biology, microbiology, cell biology and recombinant DNA which are within the skill of the art. See, for example, Sambrook, Fritsch and Maniatis, MOLECLAR CLONING: A LABORATORY MANUAL, 2nd edition (1989); CURRENT PROTOCOLS IN MOLECULAR BIOLOGY F.M. Auxubel et al., Eds. , (1987); the METHODS IN ENZYMOLOGY series (Academic Press, Inc. (: PCR 2: A PRACTICAL APPROACH (MJ Acpherson, BD Hames and GR Taylor eds. (1995)), Harlow and Lane, eds. (1988) ANTIBODIES, A LABORATORY MANUAL and ANIMAL CELL CULTURE (RI Preshney, ed. (1987)) As used herein, certain terms have the following definite meanings: As used in the specification and claims, the singular form "a", "an" and "the" include plural references unless the context clearly dictates otherwise, For example, the term "a cell" includes a plurality of cells, including mixtures thereof, all numeric designations, eg, pH, temperature , time, concentration and molecular weight, including the intervals, are approximations that are varied (+) or (-) with increments of 0.1 It will be understood, although not ys explicitly stated that all numerical designations are preceded by the term " apr Approximately. " It is also to be understood, although not ys explicitly stated, that the reagents described herein are merely exemplary and that equivalents thereof are known in the art. The terms "polynucleotide" and "oligonucleotide" are used interchangeably and refer to a polymeric form of nucleotides of any length, either deoxyribonucleotides or ribonucleotides or analogs thereof. The polynucleotides can have any three-dimensional structure and can perform any function, known or unknown. The following are non-limiting examples of polynucleotides: a gene or gene fragments (eg, a probe, primer, EST or SAGE tag), exons, introns, messenger RNA (mRNA), RNA interference, ribosomal RNA, ribozymes, cDNA, recombinant polynucleotides, branched polynucleotides, plasmids, vectors, DNA isolated from any sequence, RNA isolated from any sequence, probes and nucleic acid primers. A polynucleotide can comprise modified nucleotides, such as methylated nucleotides and nucleotide analogs. If present, modifications to the nucleotide structure can be imparted before or after polymer assembly. The nucleotide sequence can be interrupted by non-nucleotide components. A polynucleotide can be further modified after polymerization, such as by conjugation with a labeling component. The term also refers to double and single-stranded molecules. Unless otherwise specified or required, any embodiment of this invention that is a polynucleotide encompasses both the double-stranded form and each of the two complementary single-stranded forms known or predicted to constitute the double-stranded form . A polynucleotide is composed of a specific sequence of four nucleotide bases: adenine (A); cytosine (C); guanine (G); thymine (T) and uracil (U) for guanine when the polynucleotide is RNA. Thus, the term "polynucleotide sequence" is the alphabetic representation of a polynucleotide molecule. This alphabetical representation can be entered into databases on a computer that has a central processing unit and is used for bioinformatics applications such as functional genomics and homology search. A "gene" refers to a polynucleotide that contains at least one open reading structure (ORF) that is capable of encoding a particular polypeptide or protein after it is transcribed and translated. Any of the polynucleotide sequences described herein may be used to identify larger fragments or full-length coding sequences of the gene of which they are associated. Methods for isolating larger fragment sequences are known to those skilled in the art. A "gene product" or alternatively a "gene expression product" refers to the amino acid (e.g., peptide or polypeptide) generated when a gene is transcribed and translated. The term "polypeptide" is used interchangeably with the term "protein" and in its broadest sense refers to a compound of two or more subunit amino acids, amino acid analogs or peptidomimetics. The subunits can be linked by peptide bonds. In another embodiment, the subunit can be linked by other links, for example ester, ether, etc. As used herein the term "amino acid" refers to amino acids either natural and / or non-natural or synthetic, which include glycine and both of the optical isomers D and L, amino acid analogs and peptidomimetics. A peptide of three or more amino acids is commonly called an oligopeptide if the peptide chain is short. If the peptide chain is long, the peptide is commonly called a polypeptide or a protein. "Under transcriptional control" is a term well understood in the art and indicates that transcription of a polynucleotide sequence, usually a DNA sequence, depends on being operably linked to an element that contributes to the initiation of, or promotes, transcription. . "Operationally linked" refers to a juxtaposition where the elements are in arrangement that allows them to function.

As used herein, the term "comprising" is intended to imply that the compositions and methods include the elements mentioned, but do not exclude others. "Consisting essentially of" when used to define compositions and methods, will mean the exclusion of other elements of some essential meaning to the combination. Thus, a composition consisting essentially of the elements as defined herein will not exclude contaminants of very small amounts of the isolation and purification method and pharmaceutically acceptable carriers, such as phosphate buffered saline, preservatives and the like. "Consisting of" shall mean the exclusion of more minor elements from other ingredients and substantial method steps to administer the compositions of this invention. The modalities defined by each of these transition terms are within the scope of this invention. The term "isolated" means separated from constituents, cellular and otherwise, in which the polynucleotide, peptide, polypeptide, protein, antibody or fragment (s) thereof, are normally associated in nature. In one aspect of this invention, an isolated polynucleotide is separated from the contiguous 3 'and 5' nucleotides with which it is normally associated in its natural native environment, for example, on the chromosome. As is apparent to those skilled in the art, a naturally occurring polynucleotide, peptide, polypeptide, protein, antibody or fragment (s) thereof does not require "isolation" to distinguish it from its naturally occurring counterpart. In addition, a polynucleotide, peptide, polypeptide, protein, antibody or fragment (s) thereof, "concentrated", "separated" or "diluted", is distinguishable from its naturally occurring counterpart in that the concentration of a number of molecules per Volume is greater than "concentrated" or less than "separated" than that of its naturally occurring counterpart. A polynucleotide, peptide, polypeptide or protein, antibody or fragment (s) thereof, which differs from the counterpart that occurs naturally in its primary sequence or, for example, by its glycosylation pattern, needs not to be present in its form isolated since its counterpart that occurs naturally by its primary sequence or, alternatively, by another characteristic such as the pattern of glycos is distinguishable. lation Thus, a polynucleotide that does not occur naturally provides a separate modality of the naturally occurring isolated polynucleotide. A protein produced in a bacterial cell is provided as a separate form of the naturally occurring protein isolated from a prokaryotic cell in which it is produced in nature. "Gene delivery", "gene transfer" and the like as used herein, are terms that refer to the introduction of an exogenous polynucleotide (sometimes referred to as a "transgene" in a host cell, regardless of the method used for the introduction Such methods include a variety of well-known techniques such as vector-molded gene transfer (by, for example, viral infection / transfection or several other protein-based or lipid-based gene delivery complexes) as techniques that facilitate the delivery of "naked" polynucleotides (such as electroporation, "gene gun" delivery, and various other techniques used for the introduction of polynucleotides.) The introduced polynucleotide can be stably or transiently maintained in the host cell. Stable maintenance typically requires that the polynucleotide introduced either contain to an origin of replication compatible with the host cell or integrated into a replicon of the host cell such as an extrachromosomal replicon (eg, a plasmid) or a nuclear or mitochondrial chromosome. A number of vectors are known in the art that are capable of mediating gene transfer in mammalian cells. A "gene delivery vehicle" is defined as any molecule that can carry polynucleotides inserted into a host cell. Examples of gene delivery vehicles are liposomes, biocompatible polymers, including natural polymers and synthetic polymers; lipoproteins; polypeptides; polysaccharides; lipolisaccharides; artificial viral envelopes; recombinant yeast cells, metal particles; and bacteria or viruses, such as baculovirus, adenovirus and retrovirus, bacteriophage, cosmid, plasmid, fungal vectors and other recombination vehicles typically used in the art that have been described for expression in a variety of eukaryotic or prokaryotic hosts and can be used for gene therapy as well as for the expression of simple protein. A "viral vector" is defined as a recombinantly produced virus or viral particle comprising a polynucleotide that is delivered to a host cell, either in vivo, ex vivo or in vitro. Examples of viral vectors include retroviral vectors, adenovirus vectors, adeno-associated virus vectors, alphavirus vectors and the like. Alphavirus vectors, such as vectors based on Semliki Forest virus and vectors based on Sindbis virus, have also been developed for use in gene therapy and immunotherapy. See, Schlesinger and Dubensky (1999) Curr. Opin. Biotechnol. 5: 434-439 and Ying et al. (1999) Nat. Med. (7): 823-827. In aspects where gene transfer is mediated by a retroviral vector, a vector construct refers to the polynucleotide comprising the retroviral genome or part thereof and a therapeutic gene. As used herein, "retroviral-mediated gene transfer" or "retroviral transduction" carries the same meaning and refers to the process by which a gene or nucleic acid sequences are stably transferred into the host cell under the virus that enters the cell and integrates its genome in the genome of the host cell. The virus can enter the host cell via its normal mechanism of infection or be modified such that it binds to a different host cell surface receptor or ligand to enter the cell. As used herein, "retroviral vector" refers to a viral particle capable of introducing exogenous nucleic acid into a cell through a viral or viral-like entry mechanism. Retroviruses carry their genetic information in the form of RNA; however, once the virus infects a cell, RNA is reverse transcribed in the form of DNA that is integrated into the genomic DNA of the infected cell. The integrated DNA form is called a provirus. In aspects where gene transfer is mediated by a viral DNA vector, such as an adenovirus (Ad) or adeno-associated virus (AAV), a vector construct refers to the polynucleotide comprising the viral gonoma or part thereof and a transgen. Adenoviruses (Ads) are a group of relatively well characterized homogenous viruses, which include more than 50 serotypes. See, for example, WO 95/27071. The Ads are easy to grow and do not require integration into the genome of the host cell. Recombinant Ad-derived vectors, particularly those that reduce the potential for recombination and generation of wild type viruses, have also been constructed. See, for example, WO 95/00655 and WO 95/11984. The wild type AAV has high infectivity and specificity to integrate into the genome of the host cell. See, Hermonat and Muzyczka (1984) Proc. Nati Acad. Sci. USA 81: 6466-6470 and Lebkowski et al. (1988) Mol. Cell. Biol. 8: 3988-3996. Vectors that contain both a promoter and a cloning site in which a polynucleotide can be operably linked are well known in the art. Such vectors are capable of transcribing RNA in vitro or in vivo and are commercially available from sources such as Strategene (La Joya, CA) and Promega Biotech (Madison, WI). In order to optimize expression and / or in vitro transcription, it may be necessary to remove, add or alter the 5 'and / or 3' untranslated portions of the clones to eliminate the inappropriate, potential, extra, alternative translation initiation codons or other sequences that may interfere with or reduce expression, either at the level of transcription or translation. Alternatively, consensual ribosome binding sites can be inserted immediately 5 'from the start codon to increase expression. The gene delivery vehicles also include several non-viral vectors, including DNA / liposome complexes, recombinant yeast cells and viral directed protein-DNA complexes. Liposomes that also comprise a targeting antibody or fragment thereof can be used in the methods of this invention. To increase the supply to a cell, the nucleic acid or proteins of this invention can be conjugated to antibodies or binding fragment (s) thereof that bind the cell surface antigens, eg, TCR, CD3 or CD4. A "probe" when used in the context of polynucleotide manipulation refers to an oligonucleotide that is provided as a reagent to detect a target potentially present in a sample of interest by hybridizing to the target. Usually, a probe will comprise a tag or a means by which a tag can be joined, either before or subsequent to the hybridization reaction. Suitable labels include, but are not limited to radioisotopes, fluorochromes, chemiluminescent compounds, dyes and proteins, including enzymes. A "primer" is a short polynucleotide, generally with a free -OH 3 'group that binds to a target or "template" potentially present in a sample of interest by hybridization to the target and, then, the polymerization promotion of a polynucleotide complementary to the target. A "polymerase chain reaction" ("PCR") is a reaction in which replicate copies are made of a target polynucleotide using a "primer pair" or a "set of primers" consisting of an "upstream" primer and a "downstream" primer and a catalyst for polymerization, such as a polymerase DNA and, typically, a thermally stable polymerase enzyme. Methods for PCR are well known in the art, and taught, for example in "PCR: A PRACTICAL APPROACH" (M. Mac Pherson et al., IRL Press at Oxford University Press (1991)). All processes for producing replicated copies of a polynucleotide, such as PCR or gene cloning, are collectively referred to herein as "replication." A primer can also be used as a probe in hybridization reactions, such as Southern or Northern spotting analysis. Sambrook et al., Supra. An expression "database" denotes a set of stored data representing a collection of sequences, which in turn represents a collection of biological reference materials. The term "cDNAs" refers to complementary DNA, that is mRNA molecules present in a cell or organism made in cDNa of an enzyme such as reverse transcriptase. A "cDNA library" is a collection of all the mRNA molecules present in a cell or organism, all changed into cDNA molecules with the enzyme reverse transcriptase, then inserted into "vectors" (other DNA molecules that can continue to replicate afterwards). of the addition of foreign DNA). Exemplary vectors for libraries include bacteriophage (also known as "phage"), viruses that infect bacteria, for example, iambda phage. The library can then be probed for the specific cDNA (and thus mRNA) of interest. As used herein, "expression" refers to a process by which polynucleotides are transcribed into mRNA and / or to the process by which the transcribed mRNA is subsequently translated into peptides, polypeptides or proteins. If the polynucleotide is derived from the genomic DNA, the expression must include the splicing of the mRNA in a eukaryotic cell. "Differentially expressed" as applied to a gene, refers to the differential production of the transcribed and / or translated mRNA of the gene or protein product encoded by the gene. A differentially expressed gene can be overexpressed or underexpressed as compared to the expression level of a normal or control cell. However, as used herein, overexpression is at least 1.25 times or, alternatively, at least 1.5 times or, alternatively, at least 2 times the expression on that detected in the normal counterpart or cell or tissue. healthy. The term "differentially expressed" also refers to nucleotide sequences in a cell or tissue that are expressed where they are silenced in a control cell or not expressed where expressed in a control cell. As used herein, "solid phase support" or "solid support", used interchangeably, is not limited to a specific type of support. Rather a large number of support are available if they are known to one of ordinary skill in the art. Solid phase supports include silica gels, resins, derived plastic films, glass beads, cotton, plastic beads, alumina gels, microarrays and chips. As used herein, "solid support" also includes matrices that present synthetic antigens, cells and liposomes. A suitable solid phase support can be selected based on the desired end use and adaptability for various protocols. For example, for peptide synthesis, the solid phase support can refer to resins such as polystyrenes (e.g., PAM resin obtained from Bachem Inc., Peninsula Laboratories, etc.), POLYHIPE® resin (obtained from Aminotech, Canada) , polyamide resin (obtained from Peninsula Laboratories), polyethylene resin grafted with polyethylene glycol (TentaGel®, Rapp Polymere, Tubingen, Germany) or polydimethacrylamide resin (obtained from Milligen / Biosearch, California). A polynucleotide can also be attached to a solid support for use in high throughput screening assays. PCT WO 97/10365, for example, discloses the construction of high density oligonucleotide chips. See also, US patents Nos. 5,405,783; 5,412,087 and 5,445,934. Using this method, the probes are synthesized on a derived glass surface also known as a chip array. The photoprotected nucleoside phosphoramidites are coupled to the surface of the glass, selectively deprotected by photolysis through a photolithographic screen and reacted with a second protected nucleoside phosphoramidite. The coupling / deprotection process is repeated until the desired probe is completed. "Hybridization" refers to a reaction in which one or more polynucleotides react to form a complex that is stabilized via the hydrogen bonding between the bases of the nucleotide residues. Hydrogen bonding can occur through atson-Crick basement, Hoogstein link, or in any other specific sequence manner. The complex may comprise two strands forming a duplex structure, three or more strands forming a multi-strand complex, an individual self-inhibiting strand or any combination thereof. A hybridization reaction may constitute a step in a more extensive process, such as the initiation of a PCR reaction or the enzymatic cleavage of a polynucleotide by a ribozyme. Hybridization reactions can be performed under conditions of different "severity". In general, a low stringency hybridization reaction is carried out at about 40 ° C in 10X SSC or a solution of equivalent ionic strength / temperature. A hybridization of moderate severity is typically performed at approximately 50 ° C in 6x SSC, and a high stringency hybridization reaction is generally performed at approximately 60 ° C in Ix SSC. When hybridization occurs in an antiparallel configuration between two single-stranded polynucleotides, the reaction is termed "tempered" and those polynucleotides are described as "complementary". A double-stranded polynucleotide can be "complementary" or "homologous" to another polynucleotide, if hybridization can occur between one of the strands of the first nucleotide and the second. "Complementarity" or "homology" (the degree that a polynucleotide is complementary to another) in terms of the proportion of bases in opposite strands that are expected to form the hydrogen bond with each other, in accordance with the rules of base pairing generally accepted A polynucleotide or polynucleotide region (or a polypeptide or polypeptide region) has a certain percentage (eg, 80%, 85%, 90% or 95%) of "sequence identity" to another sequence means that, when aligned, that percentage of bases (or amino acids) are the same in the comparison of the two sequences. This alignment and the percent homology or sequence identity can be determined using software programs known in the art, for example those described in CURRENT PROTOCOLS IN MOLECULAR BIOLOGY (FM Ausubel et al., Eds., 1987) Supplement 30, section 7.7 .18, Table 7.7.1. Preferably error parameters are used for alignment. A referred alignment program is BLAST, using error parameters. In particular, the preferred programs are BLASTN and BLASTP, using the following error parameters: genetic code = standard; filter = none; strand = both; cut = 60; expected = 10; Matrix = BLOSUM62; Descriptions = 50 sequences; classified by = HIGH SCORE; Database = non-redundant, GenBank + EMBL + DDBJ + PDB + GenBank CDS translations + S issProtein + Spupdate + PIR. The details of these programs can be found at the following Internet address: www. ncbi. nlm. nih gov / cgi-bin / BLAST. Hyperplasia is a form of controlled cell proliferation that involves an increase in the number of cells in a tissue or organ, without significant alteration in structure or function. Metaplasia is a form of controlled cell growth in which a completely differentiated type of cell replaces another type of differentiated cell. Metaplasia can occur in cells of epithelial or connective tissue. Atypical metaplasia involves a somewhat disordered metaplastic epithelium. As used in this, the terms "neoplastic cells", "neoplasia", "tumor", "tumor cells", "cancer" and "cancer cells" (used interchangeably) refers to cells that exhibit relatively autonomous growth, so that they exhibit a aberrant growth phenotype characterized by a significant loss of cell proliferation control (ie, deregulated cell division). The neoplastic cells can be malignant or benign. A metastatic cell or tissue means that the cell can invade and destroy neighboring body structures. "Suppression" of tumor growth induced a growth state that is shortened when growth is compared without therapeutic intervention. Tumor cell growth can be estimated by any means known in the art, including, but not limited to, the measurement of tumor size, determination of whether tumor cells are proliferating using a 3 H-thymidine incorporation assay or counting the tumor cells. "Suppression" of tumor cell growth means any or all of the following states: to be slow, slow and stop tumor growth as well as tumor shrinkage. The term "antigen" is well understood in the art and includes substances that are immunogenic. The term as used herein also includes substances that induce non-immune responsiveness or anergy. A "native" or "natural" or "wild-type" antigen is a polypeptide, protein or fragment that contains an epitope and that has been isolated from a natural biological source. This can also specifically bind to an antigen receptor. As used herein, an "antibody" includes complete antibodies and any antigen binding fragment or an individual chain thereof. Thus, the term "antibody" includes any protein or peptide containing molecule comprising at least a portion of an immunoglobulin molecule. Examples of such include, but are not limited to a region of complementarity determination (CDR) of a heavy or light chain or a ligand binding portion thereof, a variable region of heavy chain or light chain, a constant region of heavy chain or light chain, a framework region (FR), or any portion thereof, or at least a portion of a binding protein, any of which can be incorporated into an antibody of the present invention. The antibodies can be polyclonal or monoclonal and can be isolated from any suitable biological source, eg, murine, rat, sheep and canine. Additional sources are identified below. The term "antibody" is further proposed to comprise fragments of digestion, specified portions, derivatives and variants thereof, including antibody mimetics or comprising portions of antibodies that mimic the structure and / or function of an antibody or specified fragment or portion thereof, which includes individual chain antibodies and fragments thereof. Examples of binding fragments within the term "antigen binding portion" of an antibody include a Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CH domains.; an F (ab ') 2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge in the hindered region; an Fd fragment consisting of the VH and CH domains, an Fv fragment consisting of the VL and VH domains of a single arm of an antibody, a dAb fragment (Ward et al. (1989) Nature 341: 544-546), which consists of a VH domain and a region of isolated complementarity determination (CDR). In addition, although the two domains of the Fv, VL and VH fragment are encoded by separate genes, they can be linked, using recombinant methods, by a synthetic linker that allows them to be made as an individual protein chain in which the regions VL and VH are paired to form monovalent molecules (known as single chain Fv (scFv)). Bird et al (1988) Science 242: 423-426 and Huston et al. (1988) Proc. Nati Acad. Sci. USA 85: 5879-5883. Individual chain fragments are also proposed to be understood within the term "fragment of an antibody". Any of the antibody fragments mentioned in the above are obtained using conventional techniques known to those skilled in the art, and the fragments are classified for binding specificity and neutralization activity in the same manner as are intact antibodies.

The term "epitope" means a determinant of a protein capable of binding specifically to an antibody. Epitopes usually consist of chemically active surface groupings of molecules such as amino acids or sugar side chains and usually have specific three-dimensional structural characteristics, as well as specific charge characteristics. The conformational and non-conformational epitopes are distinguished in that the binding of the first but not the last is lost in the presence of denaturing solvents. The term "antibody derivative" is intended to comprise molecules that bind an epitope as defined herein and which are modifications or derivatives of a native monoclonal antibody of this invention. Derivatives include, but are not limited to, for example, biospecific, multispecific, heterospecific, trichispecific, tetraespecific, multiperspecific antibodies, diabodies, chimeric, recombinant and humanized. The term "bispecific molecule" is intended to include any agent, for example, a protein, peptide or protein or peptide complex, having two different binding specificities. The term "multispecific molecule" or "heterospecific molecule" is intended to include any agent, for example a protein, peptide or protein or peptide complex, having more than two different binding specificities. The term "heteroantibodies" refers to two or more antibodies, antibody binding fragments (e.g., Fab), derivatives thereof, or antigen binding regions linked together, at least two of which have different specificities. The term "human antibody" as used herein, is proposed to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. The human antibodies of the invention can include amino acid residues not encoded by human germline immunoglobulin sequences (eg, mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo). However, the term "human antibody" as used herein, is not intended to include antibodies in which CDR sequences derived from the germ line of another mammalian species, such as a mouse, have been grafted onto sequences of human structure. Thus, as used herein, the term "human antibody" refers to an antibody in which substantially every part of the protein (e.g., CDR, structure, CL domain, CH (e.g., CHi, CH2, CH3) ), articulation (VL, VH) is substantially non-immunogenic in humans, with only minor changes or sequence variations, Similarly, antibodies designated primates (monkey, baboon, chimpanzee, etc.), rodent (mouse, rat, rabbit , guinea pigs, hamsters and the like) and other mammals designate such antibodies specific to the species, subgenus, genus, subfamily, family specific.In addition, the chimeric antibodies may include any combination of the foregoing, such changes or variations optionally and Preferably, they retain or reduce immunogenicity in humans or other species relative to unmodified antibodies, Thus, a human antibody is distinct from a chimeric or humanized antibody. It is pointed out that a human antibody can be produced by a non-human animal or prokaryotic or eukaryotic cell that is capable of expressing functionally rearranged human immunoglobulin genes (e.g., heavy chain and / or light chain). In addition, when a human antibody is an individual chain antibody, it can comprise a linker peptide that is not found in native human antibodies. For example, an Fv may comprise a linker peptide, such as two to about eight glycine residues or other amino acid residues, which connects the heavy chain variable region and the variable region of the light chain. Such linker peptides are considered to be of human origin.

As used herein, a human antibody is "derived" from a particular germ line sequence if the antibody is obtained from a system using human immunoglobulin sequence, for example, by immunizing a transgenic mouse carrying human immunoglobulin genes or by classifying a library of human immunoglobulin genes. A human antibody that is "derived from" a human germ line immunoglobulin sequence can be identified as such by comparing the amino acid sequence of the human antibody to the amino acid sequence of the human germ line immunoglobulins. A human antibody typically selected is at least 90% identical in amino acid sequence to an amino acid sequence encoded by a human germline immunoglobulin gene that contains amino acid residues that identify the human antibody as being human when compared to the human antibodies. amino acid sequences of germline immunoglobulin from other species (eg, murine germline sequences). In certain cases, a human antibody can be at least 95%, or even at least 96%, 97%, 98% or 99% identical to the amino acid sequence to the amino acid sequence encoded by the line immunoglobulin gene germinal. Typically, a human antibody derived from a particular human germline sequence will exhibit no more than 10 amino acid differences of the amino acid sequence encoded by the human germline immunoglobulin gene. In certain cases, the human antibody can exhibit no more than 5, or even no more than 4, 3, 2 or 1 amino acid difference of the amino acid sequence encoded by the germline immunoglobulin gene. The terms "monoclonal antibody" or "monoclonal antibody composition" as used herein refers to a preparation of antibody molecules of individual molecular composition. A monoclonal antibody composition exhibits a single binding affinity specificity for a particular epitope. A "human monoclonal antibody" refers to antibodies that exhibit a single binding specificity having variable and constant regions derived from the human germline immunoglobulin sequences. The term "recombinant human antibody", as used herein, includes all human antibodies that are prepared, expressed, created or isolated by recombinant means, such as antibodies isolated from an animal (e.g., a mouse) that is transgenic or transchromosomal for human immunoglobulin genes or a hybridoma prepared therefrom, antibodies isolated from a host cell transformed to express the antibody, for example, from a trans-eome, antibodies isolated from a combinatorial, recombinant human antibody library, and antibodies prepared , expressed, created or isolated by any other means involving the splicing of the human immunoglobulin gene sequence to other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from the human germline immunoglobulin sequences. In certain embodiments, however, such recombinant human antibodies can be subjected to in vitro mutagenesis (or, when a transgenic animal is used for the human Ig sequences, in vivo somatic mutagenesis) and thus the amino acid sequences of the VH and VL regions of the recombinant antibodies are sequences which, while derived from and related to the VH and VL sequences of the human germ line, can not exist naturally within the repertoire of human antibody germ lines in vivo. As used herein, "isotype" refers to the class of antibody (e.g., IgM or IgGl) that is encoded by heavy chain constant region genes. The terms "non-human, transgenic animal" refers to a non-human animal that has a genome comprising one or more heavy and / or light chain human transgenes or transchromosomes (either integrated or not integrated into the animal's natural genomic DNA). ) and that it is capable of expressing completely human antibodies. For example, a transgenic rat can have a human light chain transgene and either a human heavy chain transgene or a human heavy chain transchromosome, such that the rat produces anti-INF-human antibodies. The human heavy chain transgene can be integrated into the chromosomal DNA of the rat, or the human heavy chain transgene can be maintained extrachromosomally. Transgenic and transchromosomal animals are capable of producing multiple isotypes of human monoclonal antibodies to Alpha V (eg, IgG, IgA and / or IgE) by subjecting V-D-J recombination and isotype disruption. A "composition" is also proposed to comprise a combination of active agent and another carrier, e.g., compound or composition, inert (e.g., a detectable agent or brand) or active, such as an adjuvant, diluent, binder, stabilizer, regulatory solutions, salts, lipophilic solvents, preservatives, adjuvants or the like. Carriers also include pharmaceutical excipients and additives, proteins, peptides, amino acids, lipids and carbohydrates (for example, sugars, including monosaccharides, di-, tri-, tetra-, and oligosaccharides).; sugars derivatives such as alditols, aldonic acids, esterified sugars and the like; and polysaccharides or sugar polymers), which may be presented individually or in combination, comprising alone or in combination 1-99.99% by weight or volume. Exemplary protein excipients include serum albumin, such as human serum albumin (HSA), recombinant human albumin (rHA), gelatin, casein and the like. Representative amino acid / antibody components, which may also function in a regulatory capacity, include alanine, glycine, arginine, betaine, histidine, glutamic acid, aspartic acid, cysteine, lysine, leucine, isoleucine, valine, methionine, phenylalanine, aspartame and the similar ones. Carbohydrate excipients are also proposed within the scope of this invention, examples of which include but are not limited to monosaccharides such as fructose, maltose, galactose, glucose, D-mannose, sorbose and the like; disaccharides, such as lactose, sucrose, trehalose, cellobiose and the like; polysaccharides, such as raffinose, melezitose, maltodextrins, dextrans, starches and the like; and alditols, such as mannitol, xylitol, maltitol, lactitol, xylitol sorbitol (glucitol) and myoinositol. The term "carrier" further includes a buffer solution or a pH adjusting agent; typically, the buffer is a salt prepared from an organic acid or base. Representative regulatory solutions include organic acid salts such as citric acid salts, ascorbic acid, gluconic acid, carbonic acid, tartaric acid, succinic acid, acetic acid or italic acid; Tris, tromethamine hydrochloride or phosphate buffer solutions. Additional carriers include polymeric excipients / additives such as polyvinylpyrrolidones, ficolls (a polymeric sugar), dextrates (eg, cyclodextrins, such as 2-hydroxypropyl-, quadrature, -cyclododas) polyethylene glycols, flavoring agents, antimicrobial agents, sweeteners, antioxidants. , antistatic agents, surfactants (for example polysorbates such as "TWEEN 20" and "TWEEN 80"), lipids (for example phospholipids, fatty acids), steroids (for example collesterol) and chelating agents (for example EDTA). As used herein, the term "Pharmaceutically acceptable carrier" encompasses any of the standard pharmaceutical carriers, such as a buffered saline solution of phosphate, water and emulsions, such as an oil / water or water / oil emulsion, and various types of wetting agents. The compositions may also include stabilizers and preservatives and any of the carriers mentioned in the foregoing with the additional proviso that they have been acceptable for in vivo use. For examples of carriers, stabilizers and adjuvants, see Martin REMINGTO 'S PHARM. SCI., 15th Ed. (Mack Publ. Co., Easton (1975) and Williams &Williams, (1995), and in the "PHYSICIAN'S DESK REFERENCE", 52nd ed., Medical Economics, Montvale, .J., (1998). "effective amount" is an amount sufficient to effect beneficial or desired results An effective amount may be administered in one or more administrations, applications or dosages The invention provides an antibody or a variant, derivative or fragment thereof that specifically recognizes and in a epitope on the protein polypeptide expressed by a gene identified in Table 1. In one aspect, the antibodies are isolated.In another aspect, they are combined by a suitable carrier.The antibodies can be polyclonal or monoclonal and can be isolated from any species , murine, rat, simian or can be produced recombinantly and can be isolated.Also provided by this invention are the hybridoma cell lines that produce these monocyte antibodies nales, alone or in combination with a carrier or in culture. Also provided by this invention is a polypeptide comprising an antibody, variant, derivative or fragment thereof, including but not limited to immunoglobulin chains and CDRs. The present invention also provides an anti-idiotypic antibody. An "anti-idiotype antibody" includes any protein or peptide that contains a molecule that comprises at least a portion of an immunoglobulin molecule, such as but not limited to at least one region of complementarity determination (CDR) of a heavy or light chain or a ligand binding portion thereof, a heavy or light chain variable region, a heavy chain or light chain constant region, a framework region, or any portion thereof, that can be incorporated into an antibody of the present invention. An anti-idiotype antibody of the invention can include or be derived from any mammal, such as but not limited to a human, a mouse, a rabbit, a rat, a rodent, a primate and the like. This invention further provides an isolated polynucleotide encoding an antibody of this invention, only in combination with vectors, carriers, carriers, pharmaceutically acceptable diluents and host cells. The present invention further provides, in one aspect, isolated nucleic acid molecules comprising, complementary to, or hybridizing to, a polynucleotide encoding at least one antibody or anti-idiotype antibody of this invention, comprising at least one specified sequence. , domain, portion or variant thereof. The present invention further provides recombinant vectors comprising the nucleotides, host cells containing the nucleic acids and / or recombinant vectors, as well as methods for making and / or using such nucleic acids, vectors and / or host cells. Methods for isolating, replicating and expressing polynucleotides are known in the art and described infra. One or more of the foregoing may also be combined with a carrier, a pharmaceutically acceptable carrier or medical device that is suitable for the use of the antibody related composition in diabetic or therapeutic methods. The carrier can be a liquid phase carrier or solid phase carrier, eg, bead, gel or carrier molecule such as a liposome. The composition may also optionally comprise at least one additional compound, protein or composition. A further example of "carriers" includes therapeutically active agents such as another peptide or protein (e.g., a Fab 'fragment). For example, an antibody of this invention, variant, fragment derivative thereof may be functionally linked (eg, by chemical coupling, genetic fusion, non-covalent association or otherwise) to one or more other molecular entities, such as another antibody (e.g., to produce a bispecific or multispecific antibody), a cytotoxin such as a cell ligand or an antigen. Accordingly, this invention encompasses a large variety of antibody conjugates, bi- and multispecific molecules, and fusion proteins, whether targeting or not targeting the same epitope as the antibodies of this invention. Still further examples of carriers are organic molecules (also called modifying agents) or activating agents, which can be covalently linked, directly or indirectly, to an antibody of this invention. The binding of the molecule can improve the pharmacokinetic properties (for example, increased serum half-life in vivo). Examples of organic molecules include, but are not limited to, a hydrophilic polymer group, a fatty acid group or a fatty acid ester group. As used herein, the term "fatty acid" encompasses monocarboxylic acid and dicarboxylic acid. A "hydrophilic polymer group", as the term is used herein, refers to an organic polymer that is more soluble in water than in octane. Hydrophilic polymers suitable for modifying antibodies of the invention can be linear or branched and include, for example, polyalkane glycols (for example PEG, monomethoxy-polyethylene glycol (mPEG), PPG and the like), carbohydrates (e.g., dextran, cellulose, oligosaccharides, polysaccharides and the like), polymers of hydrophilic amino acids (for example polylysine, polyarginine, polyaspartate and the like), polyalkane oxides (for example, polyethylene oxide, polypropylene oxide and the like) and polyvinyl pyrrolidone. A suitable hydrophilic polymer that modifies the antibody of the invention has a molecular weight of about 800 to about 150,000 Daltons as a separate molecular identity. The hydrophilic polymeric group can be substituted with one to about six alkyl groups, fatty acid or fatty acid ester. Hydrophilic polymers that are substituted with a fatty acid or fatty acid ester group can be prepared by employing suitable methods. For example, a polymer comprising an amine group can be coupled to a carboxylate of the fatty acid or fatty acid ester, and activated carboxylate (eg, activated with N, N-carbonyl diimidazole) on a fatty acid or fatty acid ester it can be coupled to a hydroxyl group on a polymer. The fatty acids and fatty acid esters suitable for modifying the antibodies of the invention may be saturated or may contain one or more units of unsaturation. Examples of such include, but are not limited to n-dodecanoate, n-tetradecanoate, n-octadecanoate, n-eicosanoate, n-docosanoate, n-triacontanoate, n-tetracontanoate, cis-. DELTA .9-octadecanoate, all cis-. DELTA .5, 8, 11, 14-eicosatetraenoate, octanedioic acid, tetradecanedioic acid, octadecanedioic acid, docosanedioic acid, and the like, suitable fatty acid esters include mono-esters of dicarboxylic acids comprising a linear or branched lower alkyl group. The lower alkyl group may comprise from one to about twelve, preferably one to about six carbon atoms. In yet another aspect, the present invention provides a transgenic non-human animal, such as a transgenic mouse (also referred to herein as a "HuMAb mouse"), which expresses a fully human monoclonal antibody that neutralizes at least one protein subtype. similar to an antibody of this invention as defined above. In a particular modality, the transgenic non-human animal in a transgenic mouse having a genome comprising a human heavy chain transgene and a human light chain transgene encoding all or a portion of an anti-alpha V antibody of the invention. Preferably, the transgenic non-human animal, e.g., the transgenic mouse, is capable of producing multiplex isotypes of human monoclonal antibodies to epitope of interest by subjecting V-D-J recombination and isotype disruption. Isotype disruption can occur through, for example, the disruption of classical or non-classical isotype.

Accordingly, in another embodiment, the invention provides isolated cells derived or isolated from a transgenic non-human animal as described above, for example, a transgenic mouse, which expresses human antibodies. The B cells isolated can then be immortalized by fusion to an immortalized cell to provide a source (eg, hybridoma) of human antibodies. These hybridomas are also included within the scope of the invention. The present invention further provides at least one method or composition of antibody, for diagnosing a cancer of epithelial origin, for example, non-small cell lung cancer (NSCLC), ovarian, cancer, prostate or colon cancer, in a cell, tissue, organ, animal or patient and / or prior to, subsequent to, or during a related condition, as is known in the art and / or as described herein, they are also used to forecast or monitor the progression of the disease. Also provided is a composition containing at least one antibody of this invention, variant, derivative or fragment thereof, suitable for administration in an amount effective to modulate or ameliorate the symptoms associated with cancers of epithelial origin, eg, cancer of non-small cell lung (NSCLC), ovarian, breast, prostate and colon cancer, or treating at least one cancer of that class. The compositions include, for example, pharmaceutical and diagnostic compositions / kits, comprising a pharmaceutically acceptable carrier and at least one antibody of this invention, variant, derivative or fragment thereof. As mentioned in the above, the composition may further comprise additional antibodies or therapeutic agents which, in combination, provide multiple therapies adapted to provide the maximum therapeutic benefit. Alternatively, a composition of this invention can be co-administered with other therapeutic or cytotoxic agents, either linked or not linked to these or administered in the same dosage. They may be coadministered simultaneously with such agents (eg, in a single composition or separately) or may be administered before and after the administration of such agents. Such agents may include corticosteroids, non-spheroidal immune suppressors, anti-malarials, and non-spheroidal anti-inflammatory drugs. The compositions can be combined with alternative therapies such as the administration of corticosteroids, non-steroidal anti-malarial immunosuppressants and non-spheroidal anti-inflammatory drugs. The methods of this invention can be practiced either in vitro or in vivo. When practiced in vitro, the methods require contact of the cells with (e.g., administration or delivery to the cells) of one or more antibodies and / or related therapeutic compositions, derivatives, etc., which contains the antibodies as is described in the above. The antibodies and compositions can be delivered by any suitable means and with any suitable formulation. Accordingly, a formulation comprising an antibody of this invention is further provided herein. The formulation may further comprise one or more preservatives or stabilizers such as phenol, m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, phenylmercuric nitrite, phenoxyethanol, formaldehyde, chlorobutanol, magnesium chloride (eg, hexahydrates) , alkyl parabens (methyl, ethyl, propyl, butyl and the like), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate and thimerosal, or mixtures thereof in an aqueous diluent. Any suitable concentration or mixture can be used as is known in the art, such as 0.001-5%, or any interval or value therein, such as, but not limited to, 0.001, 0.003, 0.005, 0.009, 0.01., 0.02, 0.03, 0.05, 0.09, 0.1, 0.2, 0.3, 0.4. , 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9 , 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.3, 4.5, 4.6, 4.7, 4.8, 4.9, or any interval or value in them. Non-limiting examples include, not conservative, 0.1 -2% m-cresol (eg, 0.2, 0.3, 0.4, 0.5, 0.9, 1.0%), 0.1-3% benzyl alcohol (eg, 0.5, 0.9, 1.1 ., 1.5, 1.9, 2.0, 2.5%), 0.001-0.5% thimerosal (eg, 0.005, 0.01), 0.001-2.0% phenol (eg, 0.05, 0.25, 0.28, 0.5, 0.9, 1.0%) , 0.0005-1.0% alkylparaben (s) (eg, 0.00075, 0.0009, 0.001, 0.002, 0.005, 0.0075, 0.009, 0.01, 0.02, 0.05, 0.075, 0.09, 0.1, 0.2, 0.3, 0.5, 0.75, 0.9, and 1.0%). As mentioned in the above, the invention provides a manufacturing article, comprising packaging material and at least one vial comprising a solution of at least one antibody as of this invention with the prescribed regulatory and / or preservative solutions, optionally in an aqueous diluent, wherein a packaging material comprises a label indicating that such a solution can be maintained for a period of 1, 2, 3, 4, 5, 6, 9, 12, 18, 20, 24, 30 , 36, 40, 48, 54, 60, 66, 72 hours or more. The invention further comprises in article of manufacture, which comprises packaging material, a first vial comprising at least one lyophilized antibody of this invention and a second vial comprising an aqueous diluent of prescribed buffer or preservative, wherein the material of Packaging comprises a label that instructs a patient to reconstitute the antibody in the aqueous diluent to form a solution that can be maintained for a period of twenty-four hours or larger. The antibody range includes amounts that result in reconstitution, if in a wet / dry system, concentrations of about 1.0 g / ml to about 1000 mg / ml, although lower and higher concentrations are operable and dependent on the delivery vehicle proposed, for example, solution formulations will differ from the transdermal patch, pulmonary, transmucosal or osmotic or micro pump methods. The formulations of the present invention can be prepared by a process comprising mixing at least one antibody of this invention and a preservative selected from the group consisting of phenol, m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol , alkyl paraben, (methyl, ethyl, propyl, butyl and the like), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate and thimerosal or mixtures thereof in an aqueous diluent. The mixing of the antibody and preservative in an aqueous diluent is carried out using conventional dissolution and mixing procedures. For example, a measured amount of at least one antibody in the regulated solution is combined with the desired preservative in a regulated solution in amounts sufficient to provide the antibody and preservative in the desired concentrations. The variation of this process is guided by one of ordinary skill in the art, for example, the order in which the components are added, if additional additives are used, the temperature and the pH at which the formulation is prepared, all are factors that can be optimized for the concentration and means of administration used. The compositions and formulations can be provided to patients as clear solutions or as double-flasks comprising a vial of lyophilized antibody which is reconstituted with a second vial containing aqueous diluent. Either a single solution vial or double vial requiring reconstitution can be reused multiple times and may be sufficient for one or multiple patient treatment cycles and thus provides a more convenient treatment regimen than currently available. The recognized devices comprising these individual vial systems include those pen-injector devices for the supply of solution such as BD Pens, BD Autojectore, Huma ect. RTM. 'NovoPen. RTM. , B- D.RTM.Pen, AutoPen. RTM. , and OptiPen. RTM. , GenotropinPen. RTM. , Genotronorm Pen.RTM., Humatro Pen.RTM., Reco-Pen. RTM. , Roferon Pen.RTM., Bio ector. RT , iject.RTM., J-tip Needle-Free In ector. RT , Intraject. RTM. , Medi-Ject.RTM., For example, how it is made and developed by Becton Dickensen (Franklin Lakes, NJ Available at bectondickenson.com), Disetronic (Burgdorf, Switzerland available at disetronic.com; Bioject, Portland, Oregon (available bioject.com); National Medical Products, est Medical (Peterborough, UK available at weston-medical.com), Medi-Ject Corp (Minneapolis, Minn., Available at mediject.com). ANTIBODIES The antibodies of this invention are monoclonal antibodies, although in certain aspects, polyclonal antibodies can be used. They may also be functional fragments, antibody derivatives or antibody variants. They can be chimerical, humanized or totally human. A functional fragment of an antibody that includes, but is not limited to, Fab, Fab ', Fab2, Fab'2, and individual chain variable regions. The antibodies can be produced in cell culture, in phage, or in several animals, including but not limited to cows, rabbits, goats, mice, rats, hamsters, guinea pigs, sheep, dogs, cats, monkeys, chimpanzees, apes, etc. While the fragment or derivative retains binding specificity or neutralization ability as the antibodies of this invention may be used. The antibodies can be tested for binding specificity by comparing the binding to the appropriate antigen to bind the irrelevant antigen or mixture of antigens under a given set of conditions. If the antibody binds the appropriate antigen at least 2, 5, 7, and preferably 10 times more than the irrelevant antigen or mixtures of antigens then it is considered to be specific. Specific assays, eg, ELISA, to determine specificity are known in the art. Antibodies are also characterized by their ability to specifically recognize and bind an epitope of interest. The monoclonal antibodies of the invention can be generated using conventional hybridoma techniques known in the art and well described in the literature. For example, a hybridoma is produced by fusing a suitable immortal cell line (e.g., a myeloma cell line, such as, but not limited to, Sp2 / 0, Sp2 / 0-AG14, NSO, NS1, NS2, AE - 1, L.5,> 243, P3X63Ag8.653, Sp2 SA3, Sp2 MA I, Sp2 SS1, Sp2 SA5, U397, LA 144, ACT IV, MOLT4, DA-I, JURKA, W EH I, K -562, COS, RAJI, NIH 3T3, HL-60, MLA 144, NAMAIWA, NEURO 2A, CHO, PerC.6, YB2 / 0) or the like, or heteromyelomas, fusion products thereof, or any cell or fusion cell derived therefrom, or any other suitable cell line as is known in the art (see, for example, www.atcc.org, www.lifetech.com., and the like), with cells that produce antibody , such, but not limited to, isolated or cloned spleen cells, peripheral bleeding, lymph, amygdala or other immune cells or cells containing B cell, or any other cells expressing constant or variable heavy or light chain or structure ao CDR sequences, either as endogenous or heterologous nucleic acid, as recombinant or · endogenous, viral, bacterial, algal, prokaryotic, amphibian, insect, reptile, fish, mammal, rodent, equine, bovine, caprine, sheep, primate, eukaryotic, DNA, genomic, cDNA, rDNA, mitochondrial DNA or RNA, chloroplast DNA or RNA, hnRNA, mRNA, tRNA, single or double stranded, hybridized and the like or any combination thereof. The antibody producing cells can also be from the peripheral blood, or preferably the spleen or lymph node, of human or other animals, of humans or other suitable animals that have been immunized with the antigen of interest. Any other suitable host cell can also be used to express heterologous or endogenous nucleic acid encoding an antibody, specified fragment or variant thereof, of the present invention. The fused cells (hybridomas) or recombinant cells can be isolated using selective culture conditions or other suitable known methods, and can be cloned by limiting cell dilution or classification, or other known methods. Other suitable methods for producing or isolating antibodies of the necessary specificity can be used, including, but not limited to, methods that select recombinant antibody from a protein peptide library (eg, but not limited to, a bacteriophage, ribosome, oligonucleotide). , RNA, cDNA, or similar, display library; for example, as it is available from several commercial vendors such as Cambridge Antibody Technologies (Cambridgeshire, UK), MorphoSys (Martinsreid / Planegg, Del.), Biovation (Aberdeen, Scotland, UK) Biolnvent (Lund, Sweden), using methods known in the art, see U.S. Patent Nos. 4,704,692; 5,723,323; 5, 763.192; 5,814,476; 5, 817,483; 5,824,514; 5,976,862. Alternative methods depend on the immunization of transgenic animals (eg, SCID mice, Nguyen et al., (1977) Microbiol, Immunol., 41: 901-907 (1997), Sandhu et al., (1996) Crit. Rev. Biotechnol. 16: 95-118; Eren et al (1998) Immunol. 93: 154-161 which are capable of producing a repertoire of human antibodies, as is known in the art and / or as described herein. but they are not limited to, ribosome display (Hanes et al. (1997) Proc. Nati, Acad. Sci. USA, 94: 4937-4942; Hanes et al., (1998) Proc. Nati. Acad. Sci. USA, 95 : 14130-14135), technologies that produce single cell antibody (eg, selected lymphocyte antibody method ("SLA") (US Patent No. 5,627,052, in et al. (1987) J. Immunol., 17: 887-892; Babcook et al., Proc. Nati, Acad. Sci. USA (1996) 93: 7843-78 8), gel microdroplet and flow cytometry (Powell et al. (1990) Biotechnol. 8: 333-337; One Cell Systems, (Cambridge, Mass.); Gray et al. (1995) J. Imm. Meth. 182: 155-163; Kenny and collaborators. (1995) Bio / Technol. 13: 787-790); B cell selection (Steenba kkers et al. (1994) Molec. Biol. Reports 19: 125-134 (1994).) Antibody variants of the present invention can also be prepared using a polynucleotide encoding an antibody of this invention. to a suitable host such as to provide such transgenic animals or mammals, goats, cows, horses, sheep, and the like that produce such antibodies in their milk.These methods are known in the art and are described by way of example in US Pat. 5,827,690, 5,849,992, 4,873,316, 5,849,992, 5,994,616, 5,565,362, and 5,304,489 The term "antibody variant" includes post-translational modification to the linear polypeptide sequence of the antibody or fragment, for example, US Patent No. 6,602,684 Bl. discloses a method for the generation of modified glycol forms of antibody, including complete fragment antibody molecules antibodies or fusion proteins that include an Fe equivalent region of an immunoglobulin, which has increased Fe-mediated cellular toxicity, and the glycoproteins thus generated. Antibody variants can also be prepared by supplying a polynucleotide of this invention to provide transgenic plants and cells of cultured plants (for example, but not limited to tobacco, corn and duckweed) that produce such antibodies, specified portions or variants in the plant parts or in cells cultured therefrom. For example, Cramer et al. (1999) Curr. Top. Microbol. Immunol. 240: 95-118 and references cited therein, describes the production of transgenic tobacco leaves that express large amounts of recombinant proteins, for example, using an inducible promoter. Transgenic corn has been used to express mammalian protein at commercial production levels, with equivalent biological activities those produced in another recombinant system or purified from natural sources. See, for example, Hood et al., Ad. Exp. Med. Biol. (1999) 464: 127-147 and references cited therein. Antibody variants have also been produced in large amounts from seeds of transgenic plants that include antibody fragments, such as individual antibodies (scFv's), including tobacco seeds and potato tubers. See, for example, Conrad et al. (1998) Plant Mol. Biol. 38: 101-109 and the reference cited therein. A) Yes, the antibodies of the present invention can also be produced using transgenic plants, according to known methods. Antibody derivatives can be produced, for example, by adding exogenous sequences to modify the immunogenicity or reducing or increasing or modifying the bond, affinity, proportion, out of proportion, avidity, specificity, half-life or any other suitable characteristic. Generally, part or all of the sequence of non-human or human CDRs are maintained while the non-human sequences of the variable and constant regions are replaced with human or other amino acids. In general, CDR residues are directly and more substantially involved in influencing the antigen binding. Humanization or engineering of antibodies of the present invention can be performed using any known method, but not limited to those described in U.S. Patent Nos. 5,723,323, 5,976,862, 5,824,514, 5,817,483, 5,814,476, 5,763,192, 5,723,323, 5,766,886, 5,714,352, 6,204,023, 6,180,370, 5,693,762, 5,530,101, 5,585,089, 5,225,539; and 4,816,567. Techniques for making partially or completely human antibodies are known in the art and any such techniques can be used. According to one embodiment, the fully human antibody sequences are made in a transgenic mouse that is designed to express human heavy and light chain antibody genes. Multiple strains of such transgenic mice have been made that can produce different kinds of antibody. B-cell transgenic mice that are producing a desirable antibody can be fused to make hybridoma cell lines for the continuous production of the desired antibody. (See, for example, Russel, ND et al. (2000) Infection and Immunity April 2000: 1820-1826; Gallo, ML et al. (2000) European J. of Immun. 30: 534-540; Green, LL (1999) J. of Immun. Methods 231: 11-23; Yang, XD et al. (1999A) J. of Leukocyte Biology 66: 401-410; Yang, XD (1999B) Cancer Research 59 (6): 1236-1243; Jakobovits, A. (1998) Advanced Drug Delivery Reviews 31: 33-42; Green, L. and Jakobovits, A. (1998) J. Exp. Med. 188 (3): 483-495; Jakobovits, A. (1998) Exp. Opinion Invest. Drugs 7 (4): 607-614; Tsuda, H. et al. (1997) Genomics 42: 413-421; Sherman-Gold, R. (1997). Genetic Engineering News 17 (14); Méndez, M. and collaborators. (1997) Nature Genetics 15: 146-156; Jakobovits, A. (1996) WEIR'S HANDBOOK OF EXPERIMENTAL IMMUNOLOGY, THE INTEGRATED IMMUNE SYSTEM VOL. IV, 194.1-194.7; Jakobovits, A. (1995) Current Opinion in Biotechnology 6: 561-566; Mendez, M. et al. (1995) Genomics 26: 294-307; Jakobovits, A. (1994) Current Biology 4 (8): 761-763; Arbones, M. et al. (1994) Immunity 1 (): 247-260; Jakobovits, A. (1993) Nature 362 (6417): 255-258; Jakobovits, A. and collaborators (1993) Proc. Nati Acad. Sci. USA 90 (6): 2551-2555; Kucherlapati, and collaborators U.S. Patent No. 6, 075, 181.) Human monoclonal antibodies can also be produced by a hybridoma that includes a B cell obtained from a transgenic human animal, eg, transgenic mouse, having a gene comprising a chain transgene. heavy human and a light chain transgene fused to an immortalized cell. The antibodies of this invention can also be modified to create chimeric antibodies. Chimeric antibodies are those in which the various domains of the heavy and light chains of the antibodies are encoded by DNA of more than one species. See, for example, US Patent No. 4,816,567.

The term "antibody derivative" also includes "diabodies" which are small antibody fragments with two antigen binding sites, wherein the fragments comprise a heavy chain variable domain (VH) connected to a light chain variable domain (VL) ) in the same polypeptide chain (VH VL). (See, for example, EP 404,097, WO 93/11161, and Hollinger et al., (1993) Proc. Nati, Acad. Sci. USA 90: 6444-64 8.). By using a linker that is too short to allow pairing between the two domains on the same chain, the domains are made to pair with the complementary domains of another chain and create two antigen binding sites. (See also US Patent No. 6,632,926 to Chen et al. Which discloses antibody variants having one or more amino acids inserted in a hypervariable region of the parent antibody and a binding affinity for a target antigen that is at least about twice as much. stronger than the binding affinity of the parent antibody to the antigen). The term "antibody derivative" further includes "linear antibodies." The procedure for doing this is known in the art and described in Zapata et al. (1995) Protein Eng. 8 (10): 1057-1062. Briefly, as these antibodies comprise a pair of tandem Fd segments (VH -CH 1 -VH -CH1) that form a pair of antigen binding regions. Linear antibodies can be biespeci or monospecific. The antibodies of this invention can be recovered and purified from recombinant cell cultures by known methods including, but not limited to, protein A purification, ammonium sulfate or ethanol precipitation, acid extraction, anionic or cation exchange chromatography. , phosphocellulose chromatography, hydrophobic interaction chromatography, affinity chromatography, hydroxylapatite chromatography and lectin chromatography. High performance liquid chromatography ("HPLC") can also be used for purification. The antibodies of the present invention include naturally purified products, products of synthetic chemical processes, and products known by techniques from a eukaryotic host, including, for example, yeast, higher plant, insect and mammalian cells, or alternatively from prokaryotic cells as described in the above. In some aspects of this invention, it will be useful to therapeutically detectably label the antibody. Methods for conjugating antibodies to these agents are known in the art. For the purpose of illustration only, the antibodies can be labeled with a detectable portion such as a radioactive atom, a chromophore, a fluorophore or the like. Such labeled antibodies can be used for diagnostic techniques, either in vivo, or in an isolated test sample. The antibodies can also be conjugated, for example, to a pharmaceutical agent, such as a chemotherapeutic drug or a toxin. They can bind to a cytokine, a ligand, to another antibody. Suitable agents for coupling antibodies to achieve an anti-tumor effect include cytokines, such as interleukin-2 (IL-2) and Tumor Necrosis Factor (TNF).; photosensitizers, for use in photodynamic therapy, including aluminum phthalocyanine tetrasulfonate (III), hematoporphyrin, and phthalocyanine, radionuclides, such as iodine-131 (131I), yttrium-90 (90Y), bismuth-212 (212Bi) , bismuth-213 (213Bi), technetium-99m (99mTc), rhenium-186 (186Re), and rhenium-188 (188Re); antibiotics, such as doxorubicin, adriamycin, daunorubicin, methotrexate, daunomycin, neocarzinostatin and carboplatin; bacterial, plant, and other toxins, such as diphtheria toxin, pseudomonas A exotoxins, staphylococcal A enterotoxins, ricin A abrin-A toxin (deglycosylated ricin A and native ricin A), TGF-alpha toxin, Chinese cobra cytotoxin (naja naja atra), and geloninas (a plant toxin); ribosome inactivation proteins of plants, bacteria and fungi, such as restrictocin (a ribosome inactivation protein produced by Aspergillus restrictus), saporin (a ribosome inactivation protein of Saponaria officinalis), and RNase; tyrosine kinase inhibitors; ly207702 (a diffused purine nucleoside); liposomes containing anti-cystic agents (eg, antisense oligonucleotides, plasmids encoding methotrexate toxins, etc.); and other antibodies or antibody fragments, such as F (ab). With respect to preparations containing antibodies covalently linked to organic molecules, they can be prepared using suitable methods, such as by reaction with one or more modifying agents. Examples of such include modification and activation groups. A "modification agents" the term is used herein, refers to a suitable organic group (e.g., hydrophilic polymer, a fatty acid such as a fatty acid ether) that comprises an activating group. Specific examples of this are provided supra. An "activation group" is a chemical functional group that can, under appropriate conditions, react with a second chemical group to thereby form a covalent bond between the modifying people and the second chemical group. Examples of such are electrophilic groups, tosylate, mesylate, halo (chlorine, bromine, fluorine, iodine), N-hydroxysuccinimidyl esters (NHS), and the like. Activation groups that can react with thiols include, for example, maleimide, iodoacetyl, acryloyl, pyridyl disulfide, 5-thiol-2-nitrobenzoic thiol (TNB-thiol), and the like. An aldehyde functional group can be coupled to molecules containing amine or hydrazide, and an azide group can react with a trivalent phosphorus group to form phosphoramidate or phosphorimide bonds. Suitable methods for introducing activation groups into molecules are well known in the art (see for example, Hermanson, G. T., BIOCONJUGATE TECHNIQUES, Academic Press: San Diego, Calif. (1996)). An activation group can be directly organic bound (eg, hydrophilic polymer, fatty acid, fatty acid ester), through a linker portion, for example, a divalent C1-C12 group wherein one or more carbon atoms they can be replaced by a heteroatom such as oxygen, nitrogen or sulfur. Suitable linker moieties include, for example, tetraethylene glycol. Modifying agents comprising a linker portion can be produced, for example, by reacting a mono-Boc-alkyldiamine (eg, mono-Boc-ethylenediamine, mono-Boc-diaminohexane) with a fatty acid in the presence of -ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC) to form an amide bond between the free amine and the fatty acid carboxylate. The Boc protecting group can be removed from the product by treatment with trifluoroacetic acid (TFA) to expose a primary amine that can be coupled to another carboxylate as described, or it can be reacted with maleic anhydride and the resulting product cyclized to produce an activated maleimide derivative of the fatty acid. The modified antibodies of the invention can be produced by reacting a human antibody or antigen acid fragment with a modifying agent. For example, the organic portions can be bound to the antibody in a non-site-specific manner by employing an amine reactive modifying agent, for example, an NHS ester of PEG. The modified human antibodies or antigen binding fragments can also be prepared by reducing the disulfide acid (eg, intrachain disulfide bonds) of an antibody or antigen binding fragment. The antibody or reduced antigen binding fragment can then be reacted with a thiol-reactive modification agent to produce the modified antibody of the invention. Modified human antibodies and antigen binding fragments comprising an organic portion that is linked to the specific sites of an antibody of the present invention can be prepared using suitable methods, such as reverse proteolysis. See generally, Hermanson, G. T. , BIOCONJUGATE TECHNIQUES, Academic Press: San Diego, Calif. (nineteen ninety six) . POLYINUCLEOTIDES AND POLYPEPTIDES Polynucleotides, polypeptides and fragment (s) thereof, can be obtained by using the proportional sequence information in Table 1 (and the sequence listing infra) and chemical synthesis using a commercially available automated peptide synthesizer such , those manufactured by Perkin Elmer / Applied Biosystems, Inc., Model 430A or 431A, Foster City, CA, USA. The synthesized protein or polypeptides can be precipitated and further purified, for example, by high performance liquid chromatography (HPLC). Accordingly, this invention also provides a process for chemically synthesizing the proteins of this invention by providing the sequence of the protein and reagents, such as amino acids and enzymes and which together link the amino acids in the proper orientation and the linear sequence. Alternatively, proteins and polypeptides can be obtained by well-known recombinant methods as described herein using the host cells and vector systems as described herein. The host cell can be prokaryotic or eukaryotic. The host cell systems are described supra. METHODS OF DIAGNOSIS As mentioned in the above, this invention provides various methods to aid in the diagnosis of the state of a cell characterized by normal cell growth in the form of, for example, malignancy, hyperplasia or metaplasia. The methods are particularly routine to aid in the diagnosis of cancers of epithelial origin, for example, non-small cell lung cancer (NSCLC), ovarian cancer, cancer, prostate and colon cancer. The neoplastic state of a cell can be determined by noting whether the growth of the cell is not governed by the usual limitation of normal growth. For the purposes of this invention, the term also includes genotypic changes that occur prior to the detection of this growth in the form of a tumor and are causative of these phenotypic changes. The phenotypic changes associated with the neoplastic state of a cell (a set of in vitro characteristics associated with a tumorigenic ability in vivo) include a more rounded cell morphology, looser substrate binding, loss of contact inhibition, loss of dependence on walking, release of proteases such as plasminogen activator, increased sugar transport, decreased serum requirement, expression of fetal antigens and the like. (See, and collaborators. (1978) GENERAL VIROLOGY, 3d edition, 436-446 (John Wiley &Sons, New York)). Accordingly, one embodiment is a method for diagnosing the condition of a cell by classifying the presence of a differentially expressed polynucleotide or polypeptide, isolated from a sample that contains or is suspected of containing cells that express the gene, in which The differential expression of the gene is indicative of the neoplastic state of the cell. As shown below, the gene is expressed more in a cancer or tumor cell, where the cell is one or more of the lung, ovary or prostate, as compared to a normal or healthy counterpart cell or tissue. Detection can be done by any suitable method including, for example, detection of the amount of mRNA transcribed from the gene or the amount of cDNA produced from the reverse transcription of the mRNA transcribed from the gene or the amount of the protein polypeptide encoded by the gene , the waves for each of these methods are provided by reverse translation of the peptides identified in Table 1 and using the polynucleotides encoding the peptides. These methods can be performed on a sample using the sample base or modified for high-throughput analysis. Additionally, databases containing complete or partial quantitative transcripts or protein sequences isolated from a cell sample can be searched and analyzed for the presence and amount of transcript or gene product expressed. In one aspect, the database contains at least one of the sequences shown in Table 1 and / or the polynucleotide encoding it. For the purpose of illustration only, gene expression is determined by noting the amount (if any, for example, altered) of the expression of the gene in the test system at the level of an mRNA transcribed from the gene of interest. In a separate embodiment, increasing the level of the polypeptide or protein encoded by the gene of interest is indicative of the presence of the neoplastic condition of the cell. The method can be used to help in the diagnosis of lung, ovarian or prostate cancer. Thus, by detecting this genotype before tumor growth, a predisposition to cancer can be predicted and / or early diagnosis and treatment can be provided. The samples of cells or tissue used for this invention comprise body fluid, solid tissue samples, tissue cultures or cells derived therefrom, the progeny thereof and sections or slides prepared from these sources, or any other samples that they may contain a cell having a gene described herein. In one embodiment, the sample comprises cells prepared from a tissue of a subject, e.g., lung or tissue that may contain a metastasis.

In the assay for an alteration in the level of mRNA, the nucleic acid contained in the aforementioned samples is first extracted according to standard methods in the art. For example, the mRNA can be isolated using various lithic enzymes or chemical solutions according to the procedures set forth in Sambrook et al. (1989) supra or can be extracted by nucleic acid binding resins following the accompanying instructions provided by the manufacturers. The mRNA of a gene contained in the extracted nucleic acid sample is then detected by hybridization (e.g., Northern blot analysis) t / o amplification procedure according to methods well known in the art or based on the methods identified in the present. Nucleic acid molecules having at least 10 nucleotides and exhibiting complementarity or sequence homology to at least one polynucleotide encoding a peptide identified in Table 1 are used as hybridization probes, it is known in the art that probes " perfectly matched "is not needed for a specific hybridization. Minor changes in probe sequence achieved by underwriting, deletion insertion of a smaller number of bases does not affect the hybridization specificity. In general, as much as 20% mismatch of base pairs (when aligned optimally) can be tolerated. Preferably, a probe useful for detecting mRNA is at least about 80% identical to the homologous region of comparable size contained in the genes or polynucleotides encoding the peptides identified in Table 1. In one aspect, the probe is 85% identical to the corresponding polynucleotide sequence after alignment of the homologous region or, alternatively, exhibits 90% identity. These probes can be used in radioassays (eg, Southern and Northern spotting analysis) to detect, predict, diagnose or monitor various neoplastic states resulting from the differential expression of a polynucleotide of interest. The total size of the fragment, as well as the size of the complementary stretches, will depend on the proposed use the application of the acid segment of the particular nucleic acid. Smaller fragments derived from known sequences generally find use in hybridization modalities, wherein the length of the complementary region may be varied, such as between about 10 and about 100 nucleotides or even full length according to the complementary sequences that you want to detect. In one aspect, nucleotide probes that have complementary sequences on stretches greater than about 10 nucleotides in length are used to increase the stability and selectivity of the hybrid and, thereby, improve the specificity of the particular hybrid molecules obtained. Alternatively, nucleic acid molecules can be designed having complementary stretches of gene of greater than about 25 or alternatively more than about 50 nucleotides in length or even longer where desired. Such fragments can be easily prepared by, for example, directly synthesizing the fragment by chemical means, by application of the nucleic acid reproduction technology, such as PCR ™ technology with two priming oligonucleotides as described in the North American Patent. No. 4,603,102 or by introducing selected sequences into recombinant vectors for recombinant production. In one aspect, a probe is from about 50 to about 75, nucleotides or, alternatively, from about 50 to about 100 nucleotides in length. These probes can be designed from the sequence of full-length genes. In certain embodiments, it will be advantageous to employ nucleic acid sequences as described herein in combination with an appropriate medium, such as a tag, to detect hybridization and therefore complementary sequences. A wide variety of suitable indicator means are known in the art, and including fluorescent, radioactive, enzymatic or other ligands, such as avidin / biotin, which are capable of giving a detectable signal. A fluorescent tag or an enzyme tag, such as loop, alkaline phosphatase or peroxidase, may be employed in place of radioactive reagents or other environmentally undesirable reagents. In the case of enzyme label the calorimetric indicator substrates are known which can be used to provide a visible medium to the human eye or spectrophotometrically, to identify the specific hybridization with the complementary nucleic acid-containing samples. Hybridization reactions can be performed under conditions of different "severity". Relevant conditions include temperature, ionic strength, incubation time, the presence of additional solutes to the reaction mixture such as formamide and the washing procedure. The conditions of higher severity are those conditions, such as the higher temperature and lower concentration of sodium ion, which requires higher minimal complementarity between the hybridization elements so that a stable hybridization complex is formed. The conditions that increase the severity of a hybridization reaction are well known and published in the art. See, for example, Sambrook et al. (1989) supra. The nucleotide probes of the present invention can also be used as dryers and the detection of genes or gene transcripts that are differentially expressed in certain tissues of the body. Additionally, a digger useful for detecting the differentially expressed mRNA mentioned in the above is at least about 80% identical to the homologous region of comparable size contained in the briefly identified sequences encoding the peptides identified in Table 1. For the purpose of this invention "amplification" means any method that employs a digger-dependent polymerase capable of replicating an objective sequence with reasonable fidelity. The amplification can be carried out by natural or recombinant DNA polymerases such as T7 DNA polymerase, full fragment of E. coli DNA polymerase and reverse transcriptase. A known amplification method is PCR, acPherson and collaborators, PCR: A PRACTICAL APPROACH, (IRL Press at Oxford University Press (1991)). However, the PCR condition used for each application reaction is empirically determined. A number of parameters influence the success of a reaction. Among these is the tempering temperature and time, the extension time, Mg2 + ATP concentration, pH and the relative concentration of diggers, templates and deoxyribonucleotides. After amplification, the resulting DNA fragments can be detected by agarose gel electrophoresis followed by visualization with staining of ethidium bromide and ultraviolet illumination. A specific amplification of differentially expressed genes of interest can be verified by demonstrating that the amplified DNA gene has the predicted size, exhibits the predicted restriction digestion pattern and / or hybrid to the correct cloned DNA sequence. The probes can also be attached to a solid support for use in high throughput screening assays using methods known in the art. PCT WO 97/10365 and U.S. Patent Nos. 5,405,783; 5,412,087 and 5,445,934; for example, it discloses the construction of high density oligonucleotide chips that may contain one or more of the sequences disclosed herein. Using the methods disclosed in U.S. Patent Nos. 5,405,783; 5,412,087 and 5,445,934; The probes of this invention are synthesized on a surface of derived glass. The photoprotected nucleoside phosphoramidites are coupled to the glass surface, selectively deprotected by photolysis through photolithographic screen and reacted with a second protected nucleoside phosphoramidite. The coupling / deprotection process is repeated until the desired probe is completed.

The level of expression of a gene can also be determined through exposure of a nucleic acid sample to a probe-modified chip. The extracted nucleic acid is labeled, for example, with a fluorescent label, preferably during an amplification step. Hybridization of the labeled sample is carried out at an appropriate severity level. The degree of probe-nucleic acid hybridization is measured quantitatively using a stop device, such as a confocal microscope. See, US Pat. Nos. 5,578,832 and 5,631, 734. The measurement obtained correlates directly with the level of gene expression. Probes and arrays of high density oligonucleotide probes also provide an effective means to monitor the expression of the gene of interest. They are also useful for classifying compositions that up-regulate or down-regulate the expression of the gene of interest. In another embodiment, the methods of this invention are used to monitor the expression of the gene of interest that specifically hybridizes to the probes of this invention in response to defined stimuli, such as an exposure of a cell or subject to a drug. In one embodiment, the hybridized nucleic acids are detected by detecting one or more tags linked to the sample nucleic acids. The marks can be incorporated by any of a number of means known to those of skill in the art. However, in one aspect the label is incorporated simultaneously during the amplification step in the preparation of the sample nucleic acid. Thus, for example, the polymerase chain reaction (PCR) with labeled primers or labeled nucleotides will provide a marked amplification product. In a separate embodiment, the transcription amplification, as described above, using a labeled nucleotide (e.g., UTP and / or fluorescein-labeled CTP) incorporates a tag in the transcribed nucleic acids. Alternatively, a tag can be added directly to the original nucleic acid sample (eg, mRNA, polyA, mRNA, cDNA, etc.) -or to the amplification product after the amplification is complete. The means for attaching labels to nucleic acids are known to those skilled in the art and include, for example, nick translation or end-labeling (eg, with a labeled RNA) by nucleic acid kinase and subsequent binding. (ligation) of a nucleic acid linker that binds the sample nucleic acid to a tag (eg, a fluorophore). Detectable labels suitable for use in the present invention include any composition detectable by spectroscopic, photochemical, biochemical, immunochemical, electrical, optical or chemical means. The labels are used in the present invention which include biotin for staining with labeled streptavidin conjugate, magnetic beads (e.g., Dynabeads ™) fluorescent dyes (e.g. fluorocein, Texas red, rhodamine, green fluorescent protein and the like), radiolabels (for example H, 125I, 35S, 14C or 32P), enzymes (for example horseradish peroxidase, alkaline phosphatase and others commonly used in an ELISA) and colorimetric labels such as colloidal gold or glass beads or colored plastic beads ( for example, polystyrene, polypropylene, latex, etc.). Patents that teach the use of such trademarks include U.S. Patent Nos. 3,817,837; 3,850,752; 3,939,350; 3,996,345; 4,277,437; 4,275,149 and 4,366,241. The means for detecting such marks are known to those skilled in the art. Thus, for example, radiolabels can be detected using photographic or scintillation film counters, fluorescent markers can be detected using a photodetector to detect the emitted light. Enzymatic labels are typically detected by providing the enzyme with a substrate and by detecting the reaction product produced by the action of the enzyme on the substrate and colorimetric labels are detected by simply visualizing the colored mark.

As described in more detail WO 97/10365, the tag can be added to the target nucleic acid (s) (sample) before or after hybridization. These are detectable labels that are directly linked to or incorporated into the target nucleic acid (sample) prior to hybridization. In contrast, "indirect markers" join the hybrid duplex after hybridization. Frequently, the indirect label binds to a binding moiety that has bound to the target nucleic acid prior to hybridization. Thus, for example, the target nucleic acid can be biotinylated prior to hybridization. After hybridization, an avidin-conjugated fluorophore will bind to the hybrid duplex carrying biotin providing a label that is readily detected. For a detailed review of nucleic acid labeling methods and detection of labeled hybridized nucleic acids; see LABORATORY TECHNIQUES IN BIOCHEMISTRY AND MOLECULAR BIOLOGY, Vol.24: Hybridization with Nucleic Acid Probes, P. Tijssen, ed. Elsevier, N. Y. (1993). The nucleic acid sample can also be modified prior to hybridization to the high density probe array in order to reduce the complexity of the sample so as to decrease the background signal and improve the sensitivity of the measurement using methods known in the art. technique, for example, the methods disclosed in WO 97/10365. The results of the chip test are typically analyzed using a computer software program. See, for example, EP 0717 113 A2 and O 95/20681. The hybridization data is read in the program, which calculates the level of expression of the targeted gene (s) ie the genes identified in Table 1. This figure is compared against the existing data sets of levels of gene expression for sick and healthy individuals. A coloration between the data obtained and that of a group of sick individuals indicates the beginning of a disease in the present patient. Also within the scope of these applications is a useful database for the detection of neoplastic lung tissue comprising one or more of the sequences, polynucleotides encoding the peptides, or portions thereof, of the peptides listed in Table 1 These polynucleotide sequences are stored in a digital storage medium such that a data processing system for the standardized representation of the genes identifies a lung cancer cell that is compiled. The data processing system is useful for analyzing gene expression between two cells to the first one to select a cell that is suspected to be of a neoplastic phenotype or genotype and then to isolate the polynucleotides from the cell. The isolated polynucleotides are then sequenced. The sequences of the sample are compared to the sequence (s) present in the database using the homology search techniques described above. In one aspect, greater than 90% is selected or, alternatively, greater than 95% is selected or, alternatively, greater than or equal to 97% sequence identity is selected, between the test sequence and at least one sequence, or polynucleotide encoding it, identified in Table 1 or its complement, is a positive indication that the polynucleotide is isolated from a lung, prostate or ovarian cancer cell as defined above. Alternatively, a sample can be compared against a database. Briefly, multiple RNAs are isolated from cell or tissue samples using methods known in the art and described for example, in Sambrook et al. (1989) supra. Optionally, gene transcripts can be converted to cDNA. A sampling of the gene transcripts is subjected to the specific sequence analysis is quantified. These abundances of gene transcript sequence are compared against abundances of sequences of reference databases that include normal data sets for sick and healthy patients. The patient has the disease (s) with which the patient data set most closely correlates that includes the overexpression of the transcripts identified herein. The differential expression of the gene of interest can also be determined by examining the protein product. A variety of techniques are available in the art for protein analysis. They include but are not limited to radioimmunoassays, ELISA (enzyme-linked immunoradiometric assays), "intercalation" immunoassays, immunoradiometric assays, in situ immunoassays (using, for example, colloidal gold, enzyme or radioisotope labels), western stain analysis, immunoprecipitation assays, immunofluorescent assays and PAGE-SDS. A means for determining the level of protein involves (a) providing a biological sample containing polypeptides and (b) measuring the amount of any immunospecific binding that occurs between an antibody reactive to the expression pct of a gene of interest and a component in the sample, in which the amount of immunospecific binding indicates the level of the expressed proteins. Antibodies that specifically recognize and bind to the protein pcts of these genes are required for these immunoassays. These can be purchased from commercial vendors or regenerated and classified using methods well known in the art.

See, Harlow and Lane (1988) supra and Sambrook et al. (1989) supra. Alternatively, polyclonal or monoclonal antibodies that specifically recognize and bind the protein product of a gene of interest can be made and isolated using known methods. In the diagnosis of malignancy, hyperplasia or metaplasia characterized by differential gene expression, typically conducts a comparative analysis of the subject and appropriate controls. Preferably, a diagnostic test includes a control sample derived from a subject (then in the present "positive control"), which exhibits the predicted change in the expression of the gene of interest and the clinical characteristics of the malignancy or metaplasia of interest. . Alternatively, a diagnosis also includes a control sample derived from a subject (then in the present "negative control"), which lacks the clinical characteristics of the neoplastic state and whose level of expression of the gene in question is within a normal range. A positive correlation between the subject and the positive control with respect to the identified alterations indicates the presence of or a predisposition to the disease. A lack of correlation between the subject and the negative control confirms the diagnosis. In a preferred embodiment, the method is used to diagnose cancers of epithelial origin, e.g., lung, ovarian or prostate, based on a differential expression of the gene of interest. CLASSIFICATION TESTS The present invention also provides a classification for identifying guide compounds, drugs, therapeutic biological substances and methods for reversing the neoplastic condition of the cells or selectively inhibiting the proliferation growth of the cells described in the above. In one aspect, the identical classification guides or biological agents that are useful for the treatment of malignancy, hyperplasia or metaplasia characterized by the differential expression of the gene of interest. Thus, to practice the in vitro method, it is first provided in suitable cell cultures or tissue cultures. The cell can be a cultured cell or a genetically modified cell that differentially expresses the gene of interest associated with a neoplastic cell. Alternatively, the cells may be from a tissue biopsy. The cells are cultured under conditions (temperature, growth or culture medium and gas (C02)) and for an appropriate amount of time to reach exponential proliferation without density-dependent restrictions. It is also desirable to maintain an additional separate cell culture; one that does not receive the agent that is tested as a control. As is clear to one skilled in the art, the method can be modified for high throughput analysis and suitable cells can be grown on microtiter plates and several agents can be analyzed at the same time by noting genotypic changes, phenotype changes and / or cell death. When the agent is a composition other than a DNA or RNA nucleic acid molecule, suitable conditions comprise adding directly to the cell culture or adding to the culture medium for addition. As is evident to those skilled in the art, an "effective" amount must be added which can be clinically determined. The classification involves contacting the agent with a test cell characterized by differential expression of the gene of interest and then analyzing the cell for the level of the expression gene of interest. In some aspects, it may be necessary to determine the gene level of the expression of interest before the assay. This provides a baseline for comparing expression after administration of the agent to the cell culture. In another embodiment, the test cell is a cultured cell of an established cell line that differentially expresses a gene of interest. An agent is a possible therapeutic agent if the gene expression is returned (reduced or increased) even if it is present in a cell in a normal or non-neoplastic state, or the cell selectively dies, or exhibits reduced growth rate. In still another aspect, the sample of test cells or tissues is isolated from the subject to be treated and one or more potential agents are classified to determine the optimal therapeutic treatment and / or course of treatment for that individual patient. For the purposes of this invention, an "agent" is proposed to include, but is not limited to, a biological or chemical compound such as an organic or inorganic molecule, simple or complex, a peptide, a protein or an oligonucleotide. A vast array of compound can be synthesized, for example oligomers, such as oligopeptides and oligonucleotides and synthetic organic compounds based on various core structures; these compounds are also included in the term "agent". In addition, various natural sources can provide compounds for classification, such as plant or animal extracts and the like. It should be understood, although it is not always explicitly stated that the agent is used only in combination with another agent, which has the same or different biological activity as the agents identified by the inventive classification. Agents and methods are also proposed to be combined with other therapies. As used herein, the term "reversion of the neoplastic state of the cells" is proposed to include apoptosis, necrosis or any other means to prevent cell division, reduced tumorigenicity, loss of. pharmaceutical resistance, maturation, differentiation or reversal of the neoplastic phenotypes as described herein. As mentioned in the above, lung cells that have differential expression of a gene of interest that results in the neoplastic state are treated appropriately by this method. These cells can be identified by any method known in the art that allows the identification of the differential expression of the gene. When the agent is a nucleic acid, it can be added to the cell cultures by methods known in the art, including, but not limited to, calcium phosphate precipitation, microinjection or electroporation. Alternatively or additionally, the nucleic acid can be incorporated into an expression or insertion vector for incorporation into the cells. Vectors that contain both a promoter and a cloning site in which a polynucleotide can be operatively linked are well known in the art and briefly described infra. The polynucleotides are inserted into vector genomes using methods well known in the art. For example, the insert and vector DNA can be contacted, under suitable conditions, with a restriction enzyme to create complementary ends on each molecule that can be paired together and linked together with a ligase. Alternatively, synthetic nucleic acid linkers can be ligated to the terminal portions of the restricted polynucleotide. These synthetic linkers contain nucleic acid sequences that correspond to a particular restriction site in the vector DNA. Additionally, an oligonucleotide containing a stop codon and an appropriate restriction site can be ligated for insertion into a vector that contains, for example, some or all of the following: a selectable marker gene, such as the neomycin gene, for selection of stable or transient transfectants of mammalian cells; enhancer / promoter sequences of the early human CMV immediate gene for high levels of transcription; transcription termination and signal processing of SV40 RNA for mRNA stability; origins of replication SV40 polyoma and C01E1 for appropriate episomal replication; versatile multiple cloning sites; and RNA promoters T7 and SP6 for in vitro transcription of sense and antisense RNA. Other means are well known and available in the art. It can be determined whether the objective of the method, ie the reversion of the neoplastic state of the cell, has been achieved by a reduction of cell division, cell differentiation or analysis for a reduction in gene overexpression. Cell differentiation can be monitored by histological methods or by monitoring for the presence or loss of certain markers on the cell surface, which can be associated with an undifferentiated phenotype, for example, the expression of the gene of interest. The equipment containing the agents and instructions necessary to perform the classification and the in vitro method as described herein are also claimed. When the subject is an animal such as a rat or mouse, the method provides a convenient animal model system that can be used before the clinical trial of the therapeutic agent or alternatively, for the optimization of the guide. In this system, a candidate agent is a potential drug if gene expression is returned to a normal level or if symptoms associated or correlated with the presence of cells containing differential expression of a gene of interest are lessened, each as compared with the untreated animal that has the pathological cells. It may also be useful to have a negative control group separated from cells or animals that are healthy and untreated, which provide a basis for comparison. THERAPEUTIC METHODS The therapeutic agents provided by this invention, include, but are not limited to small molecules, polynucleotides, peptides, antibodies, antigen-presenting cells and include immune effector cells that specifically recognize and lyse cells expressing the gene of interest. It can be determined whether a patient subject will be beneficially treated by the use of agents by classifying one or more of the agents against tumor cells isolated from the subject or patient using methods known in the art. Additional methods are provided. In one embodiment, the therapeutic agent is administered at an effective amount to treat cancer of epithelial origin, for example, lung, ovarian, breast, prostate, and colon cancers. The therapeutic agents of the invention can also be used to prevent the progression of a pre-neoplastic or non-malignant state in a neoplastic or malignant state. Various delivery systems are known and can be used to administer a therapeutic agent of the invention, for example, encapsulation in liposomes, microparticles, microcapsules, expression by recombinant cells, receptor-mediated endocytosis. { See, for example, Wu and Wu (1987) J. Biol. Chem. 262: 4 29-32), construction of a therapeutic nucleic acid, part of a retroviral vector or other vector, etc. Methods of delivery include, but are not limited to, intra-muscular, intra-muscular, intravenous, intranasal and oral routes. In a specific embodiment, it may be desirable to administer the pharmaceutical compositions of the invention locally to the area and need for treatment; this can be achieved by, for example, and not by way of limitation, the local infusion during surgery, or by injection or by means of a catheter. The agents identified herein as effective for their intended purpose may be administered to subjects or individuals susceptible to or at risk of developing a disease correlated with the deferential expression of the gene of interest. When the agent is administered in a subject such as a mouse, a rat or a human patient, the agent can be added to a pharmaceutically acceptable carrier and systemically or topically administered to the subject. In one aspect, to determine patients who can be beneficially treated as a tumor sample is removed from the patient and the cells are analyzed for differential expression of the gene of interest. Therapeutic quantities can be empirically determined and will vary with the pathology that is treated, the subject being treated and the efficacy and toxixity of the agent. When supplied to an animal, the method is useful to further confirm the efficacy of the agent. As an example of an animal model, groups of nude mice (Balb / c NCR nu / nu females, Simonsen, Gilroy, CA) each are subcutaneously immaculate with about 105 to about 109 hyperproluxferative, cancer or target cells as it is defined in the present. When the tumor is established, people are administered, for example, by subcutaneous injection around the tumor. Tumor measurements to determine tumor size reduction are made in two dimensions using venier calibrators twice a week. Other animal models can also be employed as appropriate. In vivo administration can be effected in one dose, continuously or intermittently throughout the course of treatment. Methods for determining the most effective means and dosage of administration are well known to those skilled in the art and will vary with the composition used for the therapy, the purpose of the therapy, the target cell being treated and the subject being treated. Single or multiple administrations can be carried out at the dose level and pattern that is selected by the treating physician. Suitable dosage formulations and methods of administering the agents can be found below. The agents and compositions of the present invention can be used in the manufacture of medicaments and for the treatment of hands and other animals by administration according to conventional procedures, such as an active ingredient in pharmaceutical compositions. The pharmaceutical compositions can be administered orally, intranasally, parenterally, or by inhalation therapy, and can take the form of tablets, pills, granules, capsules, pills, ampules, suppositories or aerosol form. They can also take the form of suspensions, solutions and emulsions of the active ingredient in aqueous or non-aqueous diluents, syrups, granules or powder. In addition to an agent of the present invention, the pharmaceutical compositions may also contain other pharmaceutically active compounds or a plurality of composition of the invention. More particularly, an agent of the present invention is also referred to herein, the active ingredient can be administered for therapy by any suitable route including oral, rectal, nasal, topical (including transgenic, aerosol, buccal and sublingual) administration , vaginal, parental (including subcutaneous, intramuscular, intravenous and intradermal) and pulmonary.

It will also be appreciated that the preferred route will vary with the condition and age of the recipient and the illness being treated. Ideally, the agent should be administered to achieve peak concentrations of the active compound at sites of the disease. This can be achieved, for example, by intravenous injection of the agent, optionally in saline or orally administered, for example, as a tablet, capsule or syrup containing active ingredient. Desirable levels of the agent in the blood can be maintained by continuous infusion to provide a therapeutic amount of the active ingredient within the diseased tissue. The use of operative combinations is contemplated to provide therapeutic combinations that require a total and inferior dosage of each component antiviral agent that may be required when each individual therapeutic compound or drug is used alone, in order to thereby reduce the adverse effects. While it is possible for the agent that has been administered alone, it is preferable to present it as a pharmaceutical formulation comprising at least one active ingredient, as defined above, together with one or more pharmaceutically acceptable carriers therefor and optionally other therapeutic agents. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harm the patient. The formulations include those for oral, rectal, nasal, topical (including transdermal, buccal and sublingual), vaginal, parenteral (including subcutaneous, intramuscular, intravenous and intradermal) and pulmonary administration. The formulations can conveniently be presented in unit dosage form and can be prepared by any of the methods well known in the pharmacy art. Such methods include the step of arriving at an association of the active ingredient with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing the association of the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product. Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, wafers or tablets, each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution and suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient can also be presented as a bolus, electuary or paste. A tablet can be made by composition or molding, optionally with one or more additional ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder (e.g., povidone, gelatin, hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrants (for example, sodium starch glycolate, crosslinked polydone, cross-linked sodium carboxymethyl cellulose) active agent on the dispersing surface. The molded tablets can be made to the mouldable in a suitable machine to a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or labeled and may be formulated to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropyl cellulose in varying proportions to provide the desired release profile. The tablets may optionally be provided with an enteric coating, to provide release in portions of the intestine other than the stomach. Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored base, usually sucrose and acacia or tragacanth.; pills comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and buccal washes comprising the active ingredient in a suitable liquid carrier. Pharmaceutical compositions for topical administration according to the present invention may be formulated as an ointment, cream, suspension, lotion, powder, solution, paste, gel, spray, aerosol or oil. Alternatively, a formulation may comprise a patch or a dressing such as an adhesive plaster bandage impregnated with active ingredients and optionally one or more excipients or diluents. If desired, the aqueous phase of the cream phase may include, for example, at least about 30% w / w of a polyhydric alcohol, ie, an alcohol having two or more hydroxyl groups such as propylene glycol, butane- 1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol and mixtures thereof. Topical formulations may desirably include a compound that increases the absorption or penetration of the agent through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogues. The oily phase of the emulsions of this invention may be constituted of different known in a known manner. While this phase may merely comprise an emulsifier (otherwise known as an emulsifier), it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier (s) with or without stabilizer (s) constitute the so-called emulsifying wax, and the wax together with the oil and / or fat constitute the so-called emulsifying ointment base which forms the oily dispersed phase of the emulsion. the cream formulations. Emulsifiers and emulsion stabilizers suitable for use in the formulation of the present invention include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulfate. The choice of oils or fats suitable for the formulation is based on achieving the desired cosmetic properties, since the solubility of the active compound in most oils has probably been used in pharmaceutical emulsion formulations are very low. Thus, the cream should preferably be a non-greasy, non-washable and washable product with adequate consistency to prevent leakage of the tubes or other containers. The straight or branched chain mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, palmotate 2 -ethylhexyl or a mixture of branched chain esters known as Crodamol CAP can be used, the last three being the preferred esters. These can be used alone or in combination depending on the required properties. Alternatively, high melting lipids such as white soft paraffin and / or liquid paraffin and other mineral oils may be used. Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved and suspended in a suitable carrier, especially an aqueous solvent for the agent. Formulations for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate. Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing other than the agent, such carriers as are known in the art to be appropriate.

Formulations suitable for nasal administration wherein the carrier is a solid, include a coarse powder having a particle size, for example, in the range of about 20 to about 500 microns which is administered in the manner in which it is taken aspiration, that is, by rapid inhalation through the nasal passage from a container of dust held close to the nose. Suitable formulations wherein the carrier is a liquid for administration, for example, nasal spray, nasal drops or by aerosol delivery by nebulizer, include aqueous or oily solutions of the agent. Formulations suitable for parenteral administration include sterile, isotonic, aqueous and non-aqueous injection solutions which may contain antioxidants, buffer solutions, bacteriostats and solutes which transform the isotonic solution with the blood of the proposed recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents, thickening agents and liposomes or other microparticulate systems which are designed to direct the compound to the blood components or one or more organs. The formulations may be presented in unit dose or multi-dose sealed containers, for example, ampoules and flasks, and may be stored in a freeze-dried condition (used) that requires only the addition of the sterile liquid carrier, for example water. for injections, immediately before use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules and tablets of the kind previously described. Preferred unit dosage formulations are those containing a daily dose or unit, daily sub-dose, as mentioned hereinabove, or an appropriate fraction thereof, of an agent. TRANSGENIC ANIMALS In another aspect, the gene of interest can be used to generate models of transgenic animals. In recent years, geneticists have succeeded in creating transgenic animals, such as mice, by manipulating genes from developing embryos and introducing foreign genes into these embryos. Once these genes have been integrated into the genome of the recipient embryo, the resulting embryos or adult animals can be analyzed to determine the function of the gene. Mutant animals are produced to understand the function of known genes in vivo and to create animal models of human diseases. (See, for example Chisaka et al. (1992) 355: 516-520; Joyner et al. (1992) in POSTIMPLANTATION DEVELOPMENT IN THE MOUSE (Chadwick and Marsh, eds., John Wiley &Sons, United Kingdora) pp: 277- 297; Dorin et al. (1992) Nature 359: 211-215 US Patents Nos. 5,464,764 and 5,487,992 describe a type of transgenic animal in which the gene of interest is deleted or mutated sufficiently to disrupt its function. , U.S. Patent Nos. 5,631,153 and 5,627,059.) These "inactivated" animals, made by taking advantage of the phenomena of homologous recombination, can be used to study the function of a particular gene sequence in vivo.The sequence of written polynucleotides in the present it is useful in the preparation of animal models of lung cancer EXPERIMENTAL METHODS Experiment No. 1: Expression Analysis Non-small cell lung cancer globally represents a huge unmet medical need. Fresh non-necrotic NSCLC tumor tissue and the corresponding normal tissue from individual patients free of infectious disease were obtained. Fresh tissue samples were of at least 1.5 grams of tissue in less than 24 hours after surgery sent on wet ice. Before the analysis, the tissue was estimated by a pathologist for the percent of tumor content, stage of the tumor and histological type. All tissues received were stage I, II or Illa primary lung cancer where surgery is the first treatment or primary treatment. At tissue reception, the tissue samples were shredded with crossed scalpels. The comminuted tissues were treated with collagenase and elastase until suspensions of single cells were obtained. Single cell suspensions were washed several times and the red blood cells were lysed. The white blood cells were removed by exposing the CD64, CD45 and CD14 antibody cell suspension in magnetic beads. The epithelial cells were isolated using an antibody to BerEP4 linked to magnetic beads. The endothelial cells were isolated using an antibody to CD31 bound to a magnetic bead. The RNA was prepared from the epithelial cell and the endothelial cell samples immediately. The quality of RNA from epithelial and endothelial cells was estimated globally and by the expression of specific markers for cell types. Cytokeratin 18, von Illebrand factor, EF1, P1H12, hevina and cytokeratin 8 were used as markers to determine whether the collected RNA represented a population of relatively pure epithelial cell or endothelial cells. After the quality estimation of the RNAs, 4 samples of squamous carcinoma, 2 samples of simple adenocarcinoma and 3 samples of normal lung tissue were of sufficient quantity and quality for the SAGE analysis. LongSAGE ™ was performed on the 9 RNA samples at a depth of approximately 50,000 fragments for each library using the methods disclosed in Nature Biotechnology (2002) 20: 508-512. An in-depth bioinformatics analysis was carried out to characterize the SAGE data based on the increased information of the RNAs across tumor types and on squamous cell carcinoma and adenocarcinoma compared to normal lung cells. The focus for potential antibody therapeutic targets was on proteins expressed on the plasma membrane. GITR, a protein related to TNFR induced by glucocorticoid, is known to be expressed by activated T cells and Treg cells. GITR is also known as the activation-inducible TNFR family receptor (AITR) and the tumor necrosis factor receptor superfamily, member 18 (TNFRSF-18) (Stephens, GL et al. (2004) J. Immunol., 173: 5008 -5020 and Nocentini, G. and collaborators (1997) PNAS 94: 6216-6221). The ligand GITR binds to GITR and activates the activation of NF-Kappa B through TRAF2. The interaction of the ligand GITR-GITR interrupts the activation of TCR-CD3 - induced apoptosis in cells and can be involved in the survival of the cell. The ligand GITR is also known as AITRL, GITRL, TL6 and hGIRTL. GITR is a transmembrane protein of 228 amino acids that is suggested to be similar to 4-1BB and CD27. The GITR protein has a signal sequence of 19 amino acids, an extracellular region of 134 amino acids with three portions rich in cysteine, a transmembrane segment of 23 amino acids and a cytoplasmic domain of 52 amino acids. The GITR ligand is expressed by endothelial cells (including HUVEC), Bl lymphocytes, mature and immature dendritic cells, and macrophages (Stephens, G. et al. (2004) supra.). GITR is involved in the interactions between T lymphocytes and endothelial cells and the regulation of cell death mediated by the T cell receptor. GITR mediates the activation of NF-kappaB via the TRAF2 pathway / NIK pathway. GITR binds factor-1 associated with the TNF receptor (TRAF1), TRAF2 and TRAF3 but not TRAF5 and TRAF6 (Nocentini, G. et al. (1997) supra.). GITR is expressed on CD4 + CD25 + T cells and after the interaction with GITRL down regulates the T-regulatory suppressor activity. The direction of GITR on tumor cells and the depletion of CD4 + CD25 + T cells potentiates the efficacy of active tumor-specific therapy (Kohm, A.P. and collaborators (2004) J. Immunol. 1 2: 686-4690 and Shimizu, J. et al. (2002) Nature Immunol. 3: 135-142). RT-PCR of tissue RNA in volume of 55 lung tumors and 18 normal lung tissues indicated that the 2-fold increased levels of GITR RNA in 76% of tumors compared with normal tissues. Through RT-PCR, GITR has very minimal expression in a variety of normal tissues including breast, prostate, brain, heart, kidney, liver, salivary gland, spleen, stomach, thymus and uterus. RT-PCR of tissue-volume RNA from a variety of corresponding normal tumors and tissues indicated increased levels of _ >; 2 times of GITR RNA in 50% of ovarian cancers (n = 40), 25% of melanoma (n = 22), 50% of prostate cancers (n = 24), 20% of colon cancers (n = 26), and 66% of breast cancers (n = 23). Immunohistochemistry was performed on samples of non-small human lung cancer embedded in paraffin, fixed in formalin. The antibodies used were anti-GITR (Research Systems, BA689), anti-RDCl (Lifescience, RDC1-LP1439). CD31 (DAKO, M0823), anti-alpha smooth muscle actin (DAKO, M0851), anti-epithelial membrane antigen (DAKO, M0804) and broad spectrum cytokeratin (DAKO, Z0622). Overall, there was strong GITR reactivity on tumor cells from both adenocarcinoma and squamous cell carcinoma of the lung. There was also a strong reactivity in infiltrating cells within the tumor steroid of both adenocarcinoma and squamous cell carcinoma of the lung. There was strong reactivity of RDC1 on tumor cells from both adenocarcinoma and squamous cell carcinoma of the lung. There was moderate RDC1 reactivity on endothelial cells and pericitis / smooth muscle cells associated with tumor vasculature. By means of fluorescence activated cytometry (FACS), the NCI-H358 and NCI-H1436 cell lines have very good GITR expression, and NCI-H1299, NCI-H522, NCI-H23 and NCI-647 have good GITR expression. By FACS the expression of GITR on activated PBMC and activated CD3 + T cells is much lower than what is expression on the lines of non-small cell lung cancer cells. Experiment No. 2: Functional Bioassays After generation, the antibody panel is classified using cell-based assays to identify those that neutralize the function of the target protein and reverse the malignant phenotype using methods known in the art. For the purpose of illustration, such methods are described in: Stanton, C.A. et al. (2004) Blood 103 (2): 601-606 and Malinda, K.M. et al. (1999) Exp. Cell Res. 250: 168-173 (migration assay); paragraphs [0210] to [0226] of U.S. Patent Publication No. 2004 / 0253708A1 (apoptosis); I 10 paragraphs [0183] to [0194] of U.S. Patent Publication No. 2004 / 0258685A1 (inhibition, anti proliferation, blocking and epitope binding assays); Stanton, C.A. et al. (2004) supra (proliferation and cytotoxicity assays); Manches, O. et al. (2003) Blood 101 (3): 9 9-954 (apoptosis, phagositosis and ADCC assays) and paragraphs [0066] of U.S. Patent Publication No. 2004 / 0228859A1 (CDC assay). Experiment No. 3: Efficacy In vivo Antibodies possessing the necessary bioactivity as described for example, in Experiment No. 2, then further classified for efficacy in vivo using a syngeneic tumor model or xenograft tumor model of human tumor. Such assays and models are known to those skilled in the art. For the purpose of illustration, such methods are described in Tumor Models in Cancer Research, Teicher, B.A. Ed. in the Cancer Drug Discovery and Development series, Humana Press, 2004 and Lev. A. and collaborators (2004) PNAS 101 (2): 9051-9056. Although the above experiments and the detailed description are described in reference to the use against NSCLC, it should be apparent to those skilled in the art that the methods and compositions of this invention are relevant to the other cancers identified in Table 1. Thus, this invention provides methods and compositions for II 1 diagnose and predict these malignancies too. It is to be understood that while the invention is described in conjunction with the foregoing embodiments, that the foregoing description and the following examples are intended to illustrate and not to limit the scope of the invention. Other aspects, advantages or modifications within the scope of the invention will be apparent to those skilled in the art to which the invention pertains.

Claims (10)

1. I 12 CLAIMS 1. A method for diagnosing or predicting a cancer selected from the group consisting of non-small cell lung cancer (NSCLC), ovarian, breast, prostate and colon cancer, characterized in that it comprises detecting the level of expression of a gene or gene product identified in Table 1 or fragment thereof in a subject, wherein an overexpression of the gene or gene product is a diagnosis or positive prognosis predictive of cancer in the subject.
2. 2. The method of compliance with the claim 1, characterized in that the level of expression of the gene or gene product or fragment thereof is determined immunochemically.
3. 3. The method of compliance with the claim 2, characterized in that the level of expression of the gene or gene product or fragment thereof is determined immunochemically by an antibody.
4. 4. The method according to claim 1, characterized in that the level of expression of the gene or gene product or fragment thereof is determined immunochemically by a monoclonal antibody, variant or derivative thereof.
5. The method according to claim 1 , characterized in that the level of expression of the gene or gene product or fragment thereof is determined by an antibody selected from the group consisting of a monoclonal antibody, a polyclonal antibody, an antibody variant, an antibody derivative, a humanized antibody and an antibody fragment.
6. 6. The method according to claim 1, characterized in that the level of expression of the gene or gene product is determined by detecting the amount of polynucleotide. The method according to claim 1, characterized in that the detection is performed on a suitable sample isolated from the subject. The method according to claim 7, characterized in that the suitable sample is preserved tissue sample, a tissue biopsy sample or a body fluid sample. The method according to claim 7, characterized in that the suitable sample is a body fluid sample selected from the group consisting of urine, blood and serum. The method according to claim 6, characterized in that the polynucleotide is selected from the group consisting of mRNA and cDNA.