Variants of vascular endothelial growth factor (vegf) receptor and use thereof

Abstract

Novel polypeptides and polynucleotides encoding same are provided. Also provided methods and pharmaceutical compositions which can be used to treat various disorders such as cancer, immunological-related, blood-related and skin-related disorders using the polypeptides and polynucleotides of the present invention. Also provided are methods and kits for diagnosing, determining predisposition and/or prognosis of various disorders using as diagnostic markers the novel polypeptides and polynucleotides of the present invention.

1 . An isolated polypeptide comprising an amino acid sequence set forth in any one of SEQ ID NOs: 1, 2, 5, 6, 9, 10, 13, 14, 17, 18, 54-62, 64, 65, 67, 68, 70, 71, 73, 74, 76, 77, 79, 80, 82, 83, 85, 86, 88, 89, 91, 92, 94, 95, 97, 98, 100, 101, 103, 104, 106, 107, 109, 110, 112, 113, 115, 117, 118, 120, 122, 124, 126, 155, 158, 160, 162, 164, 166, 168, 169, 171, 172, 175, 176, 178, 179, 182, 184, 186, 187, 189, 190, 192, 195, 198, 199, 200, 202, 204, 258, 261-264, 266, 268, 270, 272, 274, 276, 278, 280, 282, 284, 285, 287, 289, 291, 293, 295, 297, 299, 301, 303, 305, 307, 309, 311, 313, 315, 317, 319, 321, 323, 326, 329, 331, 334, 335, 337, 338, 340, 367, 368, 369, 423-426, 495, 496, 531-537, 556, 557, 565, 632-639, 641-643, 645-646, 652-656, 658-674, 696-699, 702, 727-729, 765-767, 816-820, 849, 851-855, 857, 859-861, 898, 899, 900, 927-932, 956-958, 972, 973, 1000-1011, 1043-1047, 1102-1104, 1127-1130, 1144-1146, 1148, 1150, and 1152. 
     
     
         2 . A pharmaceutical composition, comprising a pharmaceutically acceptable diluent, excipient or carrier and an active ingredient, wherein the active ingredient comprises at least one polypeptide according to  claim 1 . 
     
     
         3 . The pharmaceutical composition of  claim 2 , for treating a disease selected from the group consisting of: inflammation, immunologically related and autoimmune disease, infectious disease, metabolic disease, bone disease, cardiovascular related disease gastrointestinal tract resections or disorders, chronic obstructive pulmonary diseases, pulmonary fibrosis, general emphysema, chronic bronchitis, respiratory diseases, macular degeneration, macular oedema, glaucoma, hematopoiesis-related diseases, neurological, respiratory, stomatological, vulnerary, urological, haematological, stomatological, opthalmalogical disorders, hepatic disorders, gastrointestinal disorders, pulmonary disorders, hematopoietic disorders, nervous disorders, psychoneuroendocrine disorders, neurodegenerative disorders, haemostasis, anaemia, Neutropenia, Parkinson's disease, decubitus ulcer, acromegaly, uraemia, growth hormone deficiency, preterm labor, general neuropathy, renal fibrosis, Infant Respiratory Distress Syndrome (IRDS), Rett syndrome, endometriosis and cancer. 
     
     
         4 . The pharmaceutical composition of  claim 3 , wherein said metabolic disease is selected from the group consisting of: hepatic dysfunction, hepatic cirrhosis, diabetic ulcer, hyperlipidaemia, lipodystrophy, obesity, diabetes, diabetes related retinopathy and type II diabetes. 
     
     
         5 . The pharmaceutical composition of  claim 3 , wherein said bone disease is selected from the group consisting of: osteoporosis, degenerative rheumatic and traumatic bone disorders, bone regeneration and musculoskeletal disorders. 
     
     
         6 . The pharmaceutical composition of  claim 3 , wherein said cardiovascular disease is selected from the group consisting of: stroke, heart failure, atherosclerosis, restenosis, ischemia and reperfusion injury, adult respiratory distress syndrome, neutrophil accumulation, chronic obstructive pulmonary disease, thrombosis, haemorrhage, myocardial infarction, inflammation, cerebral ischaemia, pulmonary thrombosis, cerebral thrombosis, ischaemic cardiomyopathy, cerebral myelodysplastic syndrome, coronary artery disease, unstable angina, vascular disorders, peripheral vascular disease, hypertension and/or cardiac insufficiency, haemorrhage, Buerger's syndrome, angioedema, chronic obstructive haemostatic and venostasis. 
     
     
         7 . The pharmaceutical composition of  claim 3 , wherein the disease is inflammation selected from the group consisting of: rheumatoid arthritis, systemic lupus erythromatosis, thrombocytopenia, thrombocytopenic purpura, large granular lymphocyte proliferative disease, bone marrow leucopenia, bone marrow neutropenia, chronic inflammation, ocular inflammation, Granulomatous disease, brain inflammation, airway inflammation, Keratoconjunctivitis, nephritis, graft rejection disease, intestinal inflammation associated with colitis, irritable bowl syndrome, gastrointestinal ulcers, colitis, ulcerative inflammatory bowel disease GI inflammatory/bowel disorders, inflammatory bowel diseases, insulitis and uveitis; or immunologically related and autoimmune disease selected from the group consisting of multiple sclerosis, immunodeficiency, allergies, asthma, psoriasis, atopic dermatitis, allergic contact dermatitis, chronic skin diseases, amyotrophic lateral sclerosis, chemotherapy-induced injury, graft-vs-host diseases, bone marrow transplant rejection, Ankylosing spondylitis, atopic eczema, Pemphigus, Behcet's disease, chronic fatigue syndrome fibromyalgia, chemotherapy-induced injury, myasthenia gravis, glomerulonephritis, pancreatitis, TH2-induced ulcerative colitis, hemorrhagic pancreatitis, allergic retinitis and systemic sclerosis. 
     
     
         8 . The pharmaceutical composition of  claim 3 , wherein the disease is infectious disease and is selected from the group consisting of: fibrosis induced by schistosomiasis, susceptibility to  Leishmania , gram-negative septicemia short-bowel syndrome, fungal diseases, hepatitis B/C, herpes and human papilloma virus, HIV/AIDS infection, coronavirus infection, general infection, hepatitis, herpes simplex virus and varicella zoster virus. 
     
     
         9 . The pharmaceutical composition of  claim 3 , wherein the disease is cancer and is selected from the group consisting of: cancers of various origins, and their metastatic development, epithelial, endothelial, muscle, fibroblast and liver cancers, glioblastomas, melanomas, ovarian, colon, colorectal, prostate, lung, brain, breast, pancreatic, stomach, multiple myeloma, hairy cell leukemia and several lymphomas, renal cell carcinoma, melanoma, hematological malignancies, Hodgkin's disease, non-Hodgkin's lymphoma, hairy cell leukemia, leukaemia, chronic myelogenous, bone cancer, sarcoma, Kaposi's sarcoma, cervical cancer, head and neck cancer, skin cancer, leukaemia, acute myelogenous, leukaemia, lymphoma, basal cell carcinoma, cervical cancer, acute myelogenous, mesothelioma, myeloma, muscle tumors, lymph node tumors, hepatocellular carcinoma, B-cell chronic lymphocytic leukemia, thyroid tumors, bladder tumor, cholangiocarcinoma, malignant ascites, malignant and benign diseases of the biliary tract, cutaneous T cell lymphoma, osteosarcomas, aplastic anaemia and Myelodysplastic syndrome. 
     
     
         10 . An antibody or an antibody fragment which specifically binds the polypeptide according to  claim 1 , wherein the polypeptide is other than a polypeptide having SEQ ID NO:533. 
     
     
         11 . A kit for detecting a disease related to expression of at least one polypeptide according to  claim 1 , comprising the antibody of  claim 10  and at least one reagent for performing an immunoassay. 
     
     
         12 . The kit of  claim 11 , wherein said immunoassay is selected from the group consisting of: an enzyme linked immunosorbent assay (ELISA), an immunoprecipitation assay, an immunofluorescence analysis, an enzyme immunoassay (EIA), a radioimmunoassay (RIA), FACS, or a Western blot analysis. 
     
     
         13 . A method for detecting a disease related to expression of the polypeptide set forth in any one of SEQ ID NOs: 1, 2, 5, 6, 9, 10, 13, 14, 17, 18, 54-62, 64, 65, 67, 68, 70, 71, 73, 74, 76, 77, 79, 80, 82, 83, 85, 86, 88, 89, 91, 92, 94, 95, 97, 98, 100, 101, 103, 104, 106, 107, 109, 110, 112, 113, 115, 117, 118, 120, 122, 124, 126, 155, 158, 160, 162, 164, 166, 168, 169, 171, 172, 175, 176, 178, 179, 182, 184, 186, 187, 189, 190, 192, 195, 198, 199, 200, 202, 204, 258, 261-264, 266, 268, 270, 272, 274, 276, 278, 280, 282, 284, 285, 287, 289, 291, 293, 295, 297, 299, 301, 303, 305, 307, 309, 311, 313, 315, 317, 319, 321, 323, 326, 329, 331, 334, 335, 337, 338, 340, 367, 368, 369, 423-426, 495, 496, 531-537, 556, 557, 565, 632-639, 641-643, 645-646, 652-656, 658-674, 696-699, 702, 727-729, 765-767, 816-820, 849, 851-855, 857, 859-861, 898, 899, 900, 927-932, 956-958, 972, 973, 1000-1011, 1043-1047, 1102-1104, 1127-1130, 1144-1146, 1148, 1150, and 1152, comprising detecting overexpression of the polypeptide set forth in any one of SEQ ID NOs: 1, 2, 5, 6, 9, 10, 13, 14, 17, 18, 54-62, 64, 65, 67, 68, 70, 71, 73, 74, 76, 77, 79, 80, 82, 83, 85, 86, 88, 89, 91, 92, 94, 95, 97, 98, 100, 101, 103, 104, 106, 107, 109, 110, 112, 113, 115, 117, 118, 120, 122, 124, 126, 155, 158, 160, 162, 164, 166, 168, 169, 171, 172, 175, 176, 178, 179, 182, 184, 186, 187, 189, 190, 192, 195, 198, 199, 200, 202, 204, 258, 261-264, 266, 268, 270, 272, 274, 276, 278, 280, 282, 284, 285, 287, 289, 291, 293, 295, 297, 299, 301, 303, 305, 307, 309, 311, 313, 315, 317, 319, 321, 323, 326, 329, 331, 334, 335, 337, 338, 340, 367, 368, 369, 423-426, 495, 496, 531-537, 556, 557, 565, 632-639, 641-643, 645-646, 652-656, 658-674, 696-699, 702, 727-729, 765-767, 816-820, 849, 851-855, 857, 859-861, 898, 899, 900, 927-932, 956-958, 972, 973, 1000-1011, 1043-1047, 1102-1104, 1127-1130, 1144-1146, 1148, 1150, and 1152 in a sample from a patient. 
     
     
         14 . A method of detecting a disease related to expression of a polypeptide comprising the amino acid sequence set forth in any one of SEQ ID NOs: 1, 2, 5, 6, 9, 10, 13, 14, 17, 18, 54-62, 64, 65, 67, 68, 70, 71, 73, 74, 76, 77, 79, 80, 82, 83, 85, 86, 88, 89, 91, 92, 94, 95, 97, 98, 100, 101, 103, 104, 106, 107, 109, 110, 112, 113, 115, 117, 118, 120, 122, 124, 126, 155, 158, 160, 162, 164, 166, 168, 169, 171, 172, 175, 176, 178, 179, 182, 184, 186, 187, 189, 190, 192, 195, 198, 199, 200, 202, 204, 258, 261-264, 266, 268, 270, 272, 274, 276, 278, 280, 282, 284, 285, 287, 289, 291, 293, 295, 297, 299, 301, 303, 305, 307, 309, 311, 313, 315, 317, 319, 321, 323, 326, 329, 331, 334, 335, 337, 338, 340, 367, 368, 369, 423-426, 495, 496, 531-537, 556, 557, 565, 632-639, 641-643, 645-646, 652-656, 658-674, 696-699, 702, 727-729, 765-767, 816-820, 849, 851-855, 857, 859-861, 898, 899, 900, 927-932, 956-958, 972, 973, 1000-1011, 1043-1047, 1102-1104, 1127-1130, 1144-1146, 1148, 1150, and 1152, comprising detecting binding of the antibody according to  claim 10  to said polypeptide in a sample from a patient. 
     
     
         15 . The method of  claim 14 , wherein the disease is selected from the group consisting of: inflammation, immunologically related and autoimmune disease, infectious disease, metabolic disease, bone disease, cardiovascular related disease gastrointestinal tract resections or disorders, chronic obstructive pulmonary diseases, pulmonary fibrosis, general emphysema, chronic bronchitis, respiratory diseases, macular degeneration, macular oedema, glaucoma, hematopoiesis-related diseases, neurological, respiratory, stomatological, vulnerary, urological, haematological, stomatological, opthalmalogical disorders, hepatic disorders, gastrointestinal disorders, pulmonary disorders, hematopoietic disorders, nervous disorders, psychoneuroendocrine disorders, neurodegenerative disorders, haemostasis, anaemia, Neutropenia, Parkinson's disease, decubitus ulcer, acromegaly, uraemia, growth hormone deficiency, preterm labor, general neuropathy, renal fibrosis, Infant Respiratory Distress Syndrome (IRDS), Rett syndrome, endometriosis and cancer. 
     
     
         16 . The method of  claim 15 , wherein said metabolic disease is selected from the group consisting of: hepatic dysfunction, hepatic cirrhosis, diabetic ulcer, hyperlipidaemia, lipodystrophy, obesity, diabetes, diabetes related retinopathy and type II diabetes. 
     
     
         17 . The method of  claim 15 , wherein said bone disease is selected from the group consisting of: osteoporosis, degenerative rheumatic and traumatic bone disorders, bone regeneration and musculoskeletal disorders. 
     
     
         18 . The method of  claim 15 , wherein said cardiovascular disease is selected from the group consisting of: stroke, heart failure, atherosclerosis, restenosis, ischemia and reperfusion injury, adult respiratory distress syndrome, neutrophil accumulation, chronic obstructive pulmonary disease, thrombosis, haemorrhage, myocardial infarction, inflammation, cerebral ischaemia, pulmonary thrombosis, cerebral thrombosis, ischaemic cardiomyopathy, cerebral myelodysplastic syndrome, coronary artery disease, unstable angina, vascular disorders, peripheral vascular disease, hypertension and/or cardiac insufficiency, haemorrhage, Buerger's syndrome, angioedema, chronic obstructive haemostatic and venostasis. 
     
     
         19 . The method of  claim 15 , wherein the disease is inflammation selected from the group consisting of: rheumatoid arthritis, systemic lupus erythromatosis, thrombocytopenia, thrombocytopenic purpura, large granular lymphocyte proliferative disease, bone marrow leucopenia, bone marrow neutropenia, chronic inflammation, ocular inflammation, Granulomatous disease, brain inflammation, airway inflammation, Keratoconjunctivitis, nephritis, graft rejection disease, intestinal inflammation associated with colitis, irritable bowl syndrome, gastrointestinal ulcers, colitis, ulcerative inflammatory bowel disease GI inflammatory/bowel disorders, inflammatory bowel diseases, insulitis and uveitis; or immunologically related and autoimmune disease and selected from the group consisting of multiple sclerosis, immunodeficiency, allergies, asthma, psoriasis, atopic dermatitis, allergic contact dermatitis, chronic skin diseases, amyotrophic lateral sclerosis, chemotherapy-induced injury, graft-vs-host diseases, bone marrow transplant rejection, Ankylosing spondylitis, atopic eczema, Pemphigus, Behcet's disease, chronic fatigue syndrome fibromyalgia, chemotherapy-induced injury, myasthenia gravis, glomerulonephritis, pancreatitis, TH2-induced ulcerative colitis, hemorrhagic pancreatitis, allergic retinitis and systemic sclerosis. 
     
     
         20 . The method of  claim 15 , wherein the disease is infectious disease and is selected from the group consisting of: fibrosis induced by schistosomiasis, susceptibility to  Leishmania , gram-negative septicemia short-bowel syndrome, fungal diseases, hepatitis B/C, herpes and human papilloma virus, HIV/AIDS infection, coronavirus infection, general infection, hepatitis, herpes simplex virus and varicella zoster virus. 
     
     
         21 . The method of  claim 15 , wherein the disease is cancer and is selected from the group consisting of: cancers of various origins, and their metastatic development, epithelial, endothelial, muscle, fibroblast and liver cancers, glioblastomas, melanomas, ovarian, colon, colorectal, prostate, lung, brain, breast, pancreatic, stomach, multiple myeloma, hairy cell leukemia and several lymphomas, renal cell carcinoma, melanoma, hematological malignancies, Hodgkin's disease, non-Hodgkin's lymphoma, hairy cell leukemia, leukaemia, chronic myelogenous, bone cancer, sarcoma, Kaposi's sarcoma, cervical cancer, head and neck cancer, skin cancer, leukaemia, acute myelogenous, leukaemia, lymphoma, basal cell carcinoma, cervical cancer, acute myelogenous, mesothelioma, myeloma, muscle tumors, lymph node tumors, hepatocellular carcinoma, B-cell chronic lymphocytic leukemia, thyroid tumors, bladder tumor, cholangiocarcinoma, malignant ascites, malignant and benign diseases of the biliary tract, cutaneous T cell lymphoma, osteosarcomas, aplastic anaemia and Myelodysplastic syndrome. 
     
     
         22 . A method for screening for a disease, diagnosing the disease, monitoring the disease progression, treatment efficacy or relapse of the disease, or selecting a therapy for the disease, wherein said disease is related to expression of the polypeptide set forth in anyone of SEQ ID NOs: 1, 2, 5, 6, 9, 10, 13, 14, 17, 18, 54-62, 64, 65, 67, 68, 70, 71, 73, 74, 76, 77, 79, 80, 82, 83, 85, 86, 88, 89, 91, 92, 94, 95, 97, 98, 100, 101, 103, 104, 106, 107, 109, 110, 112, 113, 115, 117, 118, 120, 122, 124, 126, 155, 158, 160, 162, 164, 166, 168, 169, 171, 172, 175, 176, 178, 179, 182, 184, 186, 187, 189, 190, 192, 195, 198, 199, 200, 202, 204, 258, 261-264, 266, 268, 270, 272, 274, 276, 278, 280, 282, 284, 285, 287, 289, 291, 293, 295, 297, 299, 301, 303, 305, 307, 309, 311, 313, 315, 317, 319, 321, 323, 326, 329, 331, 334, 335, 337, 338, 340, 367, 368, 369, 423-426, 495, 496, 531-537, 556, 557, 565, 632-639, 641-643, 645-646, 652-656, 658-674, 696-699, 702, 727-729, 765-767, 816-820, 849, 851-855, 857, 859-861, 898, 899, 900, 927-932, 956-958, 972, 973, 1000-1011, 1043-1047, 1102-1104, 1127-1130, 1144-1146, 1148, 1150, and 1152, comprising detecting binding of the antibody of  claim 10  to said polypeptide in a sample from a patient.