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Use of a33 antigens and jam-itRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Immunoglobulin, Antiserum, Antibody, Or Antibody Fragment, Except Conjugate Or Complex Of The Same With Nonimmunoglobulin Material, Structurally-modified Antibody, Immunoglobulin, Or Fragment Thereof (e.g., Chimeric, Humanized, Cdr-grafted, Mutated, Etc.)Use of a33 antigens and jam-it description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20070190049, Use of a33 antigens and jam-it. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] The present application is a divisional of application Ser. No. 10/633,008 filed Jul. 31, 2003, which is a continuation in part of application Ser. No. 10/265,542 filed Oct. 3, 2002, now abandoned, which is a continuation in part of PCT international application no. PCT/US00/04414, filed Feb. 22, 2000, as a continuation in part of PCT international application no. PCT/US00/14042, filed May 22, 2000, as a continuation in part of PCT international application no. PCT/US00/32678, filed Dec. 1, 2000, as a continuation in part of U.S. application Ser. No. 09/254,465, filed Mar. 5, 1999, now, U.S. Pat. No. 6,410,708, as a continuation in part of PCT international application no. PCT/US99/05028, filed Mar. 8, 1999, as a continuation in part of U.S. application Ser. No. 09/380,138, filed Aug. 25, 1999, as a continuation in part of U.S. application Ser. No. 09/380,139, filed Aug. 25, 1999, now abandoned, as a continuation in part of PCT international application no. PCT/US98/19330, filed Sep. 16, 1998, and as a continuation in part of U.S. application Ser. No. 09/953,499, filed Sep. 14, 2001, now U.S. Pat. No. 6,838,554, which in turn is a continuation application, claiming priority under 35 U.S.C. .sctn.120 as a continuation of PCT international application no. PCT/US98/24855, filed Nov. 20, 1998. BACKGROUND OF THE INVENTION [0002] 1. Field of the Invention [0003] The present invention relates generally to the identification, isolation and recombinant production of novel DNA and novel polypeptides the presence of which is associated with inflammatory diseases (inflammation associated antigens) and/or cancer, and to compositions and methods for the diagnosis and treatment of conditions characterized by such antigens. [0004] 2. Description of the Related Art [0005] The inflammatory response is complex and is mediated by a variety of signaling molecules produced locally by mast cells, nerve endings, platelets, leukocytes and complement activation. Certain of these signaling molecules cause the endothelial cell lining to become more porous and/or even to express selections which act as cell surface molecules which recognize and attract leukocytes through specific carbohydrate recognition. Stronger leukocyte binding is mediated by integrins, which mediate leukocyte movement through the endothelium. Additional signaling molecules act as chemoattractants, causing the bound leukocytes to crawl towards the source of the attractant. Other signaling molecules produced in the course of an inflammatory response escape into the blood and stimulate the bone marrow to produce more leukocytes and release them into the blood stream. [0006] Inflammation is typically initiated by an antigen, which can be virtually any molecule capable of initiating an immune response. Under normal physiological conditions these are foreign molecules, but molecules, generated by the organism itself can serve as the catalyst as is known to occur in various disease states. [0007] T-cell proliferation in a mixed lymphocyte culture or mixed lymphocyte reaction (MLR) is an established indication of the ability of a compound to stimulate the immune system. In an inflammatory response, the responding leukocytes can be neutrophilic, eosinophilic, monocytic or lymphocytic. Histological examination of the affected tissues provides evidence of an immune stimulating or inhibiting response. See Current Protocols in Immunology, ed. John E. Coligan, 1994, John Wiley and Sons, Inc. [0008] Inflammatory bowel disease (IBD) is a term used to collectively describe gut disorders including both ulcerative colitis (UC) and Crohn's disease, both of which are classified as distinct disorders, but share common features and likely share pathology. The commonality of the diagnostic criteria can make it difficult to precisely determine which of the two disorders a patient has; however the type and location of the lesion in each are typically different. UC lesions are characteristically a superficial ulcer of the mucosa and appear in the colon, proximal to the rectum. CD lesions are characteristically extensive linear fissures, and can appear anywhere in the bowel, occasionally involving the stomach, esophagus and duodenum. [0009] Conventional treatments for IBD usually involve the administration of anti-inflammatory or immunosuppressive agents, such as sulfasalazine, corticosteroids, 6-mercaptopurine/azathoprine, or cyclosporine all of which only bring partial relief to the afflicted patient. However when anti-inflammatory/immunosuppresive therapies fail, colectomies are the last line of defense. Surgery is required for about 30% of CD patients within the first year after diagnosis, with the likelihood for operative procedure increasing about 5% annually thereafter. Unfortunately, CD also has a high rate of reoccurrence as about 5% of patients require subsequent surgery after the initial year. UC patients further have a substantially increased risk of developing colorectal cancer. Presumably this is due to the recurrent cycles of injury to the epithelium, followed by regrowth, which continually increases the risk of neoplastic transformation. [0010] A recently discovered member of the immunoglobulin superfamily known as Junctional Adhesion Molecule (JAM) has been identified to be selectively concentrated at intercellular junctions of endothelial and epithelial cells of different origins. Martin-Padura, I. et al., J Cell Biol. 142(1): 117-27 (1998). JAM is a type I integral membrane protein with two extracellular, intrachain disulfide loops of the V-type. JAM bears substantial homology to A33 antigen (FIG. 1 or FIG. 18). A monoclonal antibody directed to JAM was found to inhibit spontaneous and chemokine-induced monocyte transmigration through an endothelial cell monolayer in vitro. Martin-Padura, supra. It has been recently discovered that JAM expression is increased in the colon of CRF2-4-/-mice with colitis. CRF 2-4-/-(IL-10R subunit knockout mice) develop a spontaneous colitis mediated by lymphocytes, monocytes and neutrophils. Several of the animals also developed colon adenocarcinoma. As a result, it is likely that the polypeptides disclosed herein are expressed in elevated levels in or otherwise associated with human diseases such as inflammatory bowel disease, other inflammatory diseases of the gut as well as colorectal carcinoma. [0011] JAM and the polypeptides disclosed herein bear significant homology to A33 antigen, a known colorectal cancer-associated marker. The A33 antigen is expressed in more than 90% of primary or metastatic colon cancers as well as normal colon epithelium. In carcinomas originating from the colonic mucosa, the A33 antigen is expressed homogeneously in more than 95% of all cases. The A33 antigen, however, has not been detected in a wide range of other normal tissues, i.e., its expression appears to be organ specific. Therefore, the A33 antigen appears to play an important role in the induction of colorectal cancer. [0012] Since colon cancer is a widespread disease, early diagnosis and treatment is an important medical goal. Diagnosis and treatment of colon cancer can be implemented using monoclonal antibodies (mAbs) specific therefore having fluorescent, nuclear magnetic or radioactive tags. Radioactive gene, toxins and/or drug tagged mAbs can be used for treatment in situ with minimal patient description. mAbs can also be used to diagnose during the diagnosis and treatment of colon cancers. For example, when the serum levels of the A33 antigen are elevated in a patient, a drop of the levels after surgery would indicate the tumor resection was successful. On the other hand, a subsequent rise in serum A33 antigen levels after surgery would indicate that metastases of the original tumor may have formed or that new primary tumors may have appeared. [0013] Such monoclonal antibodies can be used in lieu of, or in conjunction with surgery and/or other chemotherapies. For example, preclinical analysis and localization studies in patients infected with colorectal carcinoma with a mAb to A33 are described in Welt et al., J, Clin. Oncol. 8: 1894-1906 (1990) and Welt et al., J Clin. Oncol. 12: 1561-1571 (1994), while U.S. Pat. No. 4,579,827 and U.S. Ser. No. 424,991 (E.P. 199,141) are directed to the therapeutic administration of monoclonal antibodies, the latter of which relates to the application of anti-A33 mAb. SUMMARY OF THE INVENTION [0014] In one aspect, the present invention concerns a method of treating an inflammatory disorder in a mammal, comprising administering to the mammal a therapeutically effective amount of an antagonist of a native sequence STIgMA polypeptide. [0015] In one embodiment, the STIgMA polypeptide is selected from the group consisting of polypeptides of SEQ ID NOS: 2, 32, 33, and 34. [0016] In another embodiment, the antagonist is an antibody, such as a monoclonal antibody, which may have non-human complementarity determining region (CDR) residues and contains human framework region (FR) residues. [0017] In a further embodiment, the antagonist is an immunoadhesin, which comprises a STIgMA extracellular domain sequence fused to an immunoglobulin constant region sequence. [0018] In another embodiment, the inflammatory disorder is selected from the group consisting of: inflammatory bowel disease; systemic lupus erythematosus; rheumatoid arthritis; juvenile chronic arthritis; spondyloarthropathies; systemic sclerosis, for example, scleroderma; idiopathic inflammatory myopathies for example, dermatomyositis, polymyositis; Sjogren's syndrome; systemic vaculitis; sarcoidosis; autoimmune hemolytic anemia for example, immune pancytopenia, paroxysmal nocturnal hemoglobinuria; autoimmune thrombocytopenia, for example, idiopathic thrombocytopenic purpura, immune-mediated thrombocytopenia; thyroiditis, for example, Grave's disease, Hashimoto's thyroiditis, juvenile lymphocytic thyroiditis, atrophic thyroiditis; diabetes mellitus, immune-mediated renal disease, for example, glomerulonephritis, tubulointerstitial nephritis; demyelinating diseases of the central and peripheral nervous systems such as multiple sclerosis, idiopathic polyneuropathy; hepatobiliary diseases such as infectious hepatitis such as hepatitis A, B, C, D, E and other nonhepatotropic viruses; autoimmune chronic active hepatitis; primary biliary cirrhosis; granulomatous hepatitis; and sclerosing cholangitis; inflammatory and fibrotic lung diseases (e.g., cystic fibrosis); gluten-sensitive enteropathy; Whipple's disease; autoimmune or immune-mediated skin diseases including bullous skin diseases, erythema multiforme and contact dermatitis, psoriasis; allergic diseases of the lung such as eosinophilic pneumonia, idiopathic pulmonary fibrosis and hypersensitivity pneumonitis, transplantation associated diseases including graft rejection and graft-versus host disease. [0019] In a different aspect, the invention concerns a method of diagnosing an inflammatory disorder in a mammal, said method comprising detecting the level of expression of a gene encoding a STIgMA polypeptide (a) in a test sample of cells obtained from said mammal, and (b) in a control sample of known normal cells of the same cell type, wherein a higher level of expression of said gene in the test sample as compared to the control sample is indicative of the presence of an immune related disorder in the mammal from which the test tissue cells were obtained. [0020] In a further aspect, the invention concerns a method of diagnosing an inflammatory disorder in a mammal, said method comprising (a) contacting an anti-STIgMA antibody with a test sample of cells obtained from said mammal, and (b) detecting the formation of a complex between the antibody and STIgMA polypeptide in the test sample, wherein formation of said complex is indicative of the presence of an inflammatory disorder in said mammal. [0021] The invention further concerns an isolated antibody which specifically binds a STIgMA polypeptide. [0022] In a different aspect, the invention concerns an isolated nucleic acid molecule comprising a nucleotide sequence encoding a polypeptide having at least about 80%, or at least about 85% or at least about 90% or at least about 95% or at least about 99% sequence identity with the amino acid sequence of amino acids 21 to 276 of SEQ ID NO: 32, or amino acids 21 to 182 of SEQ ID NO: 33, or amino acids 21 to 180 of SEQ ID NO: 34. 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