Anti-igf-i receptor antibodies, dnas, vectors, host cells and genetic constructs

Abstract

DNAs, vectors, host cells and genetic constructs of antibodies, humanized antibodies, resurfaced antibodies, antibody fragments, derivatized antibodies, and conjugates of these molecules with cytotoxic agents, which specifically bind to and inhibit insulin-like growth factor-I receptor, antagonize the effects of IGF-I and are substantially devoid of agonist activity toward the insulin-like growth factor-I receptor. These molecules can be conjugated to cytotoxic agents for use in the treatment of tumors that express elevated levels of IGF-I receptor, such as breast cancer, colon cancer, lung cancer, ovarian carcinoma, synovial sarcoma and pancreatic cancer. These molecules can also be labeled for in vitro and in vivo diagnostic uses, such as in the diagnosis and imaging of tumors that express elevated levels of IGF-I receptor.

What is claimed is: 
     
         1 . A method for treating a cancer in a subject in need thereof, comprising:
 administering to the subject an anti-IGFI-R antibody or fragment thereof that specifically binds to IGF-IR, wherein said antibody or fragment thereof comprises:
 (a) at least one heavy chain variable region (VH) and at least one light chain variable region (VL), wherein said heavy chain variable region comprises a CDR1 having the amino acid sequence of SEQ ID NO: 1, a CDR2 having the amino acid sequence of either SEQ ID NO:2 or SEQ ID NO:54 and a CDR3 having the amino acid sequence of SEQ ID NO:3, and wherein said light chain variable region comprises a CDR1 having the amino acid sequence of SEQ ID NO: 4, a CDR2 having the amino acid sequence of SEQ ID NO:5 and a CDR3 having the amino acid sequence of SEQ ID NO:6, or 
   (b) at least one heavy chain variable region (VH) and at least one light chain variable region (VL), wherein said heavy chain variable region comprises a CDR1, CDR2 and CDR3 of the antibody produced by mouse hybridoma EM164 (ATCC accession number PTA 4457) and said light chain variable region comprises a CDR1, CDR2 and CDR3 of the antibody produced by mouse hybridoma EM164 (ATCC accession number PTA 4457); and   administering an additional therapeutic agent.   
     
     
         2 . The method of  claim 1 , wherein the framework of the VH region of the anti-IGFI-R antibody is at least 85% or more identical to the framework of the VH region of SEQ ID NO: 13; and wherein the framework of the VL region of the humanized anti-IGFI-R antibody is at least 85% or more identical to the framework of the VL region of SEQ ID NO: 9, 10, 11 or 12. 
     
     
         3 . The method of  claim 2 , wherein the framework of the VH region of the anti-IGFR-I antibody is at least 95% or more identical to the framework of the VH region of SEQ ID NO: 13 and wherein the framework of the VL region of the humanized anti-IGFI-R antibody is at least 95% or more identical to the framework of the VL region of SEQ ID NO: 9, 10, 11 or 12. 
     
     
         4 . The method of  claim 1 , wherein said antibody, or fragment thereof, is a human antibody, a humanized antibody, a resurfaced antibody, a chimeric antibody or an antibody produced by mouse hybridoma EM164 (ATCC accession number PTA 4457). 
     
     
         5 . The method of  claim 1 , wherein said antibody fragment is a Fab, Fab′2, ScFv, Fd or dAb. 
     
     
         6 . The method  claim 1 , wherein the isotype of the anti-IGFI-R is IgG, IgM, IgA, IgD or IgE. 
     
     
         7 . The method of  claim 1 , wherein said additional therapeutic agent is selected from the group consisting of docetaxel, paclitaxel, doxorubicin, epirubicin, cyclophosphamide, trastuzumab, capecitabine, tamoxifen, toremifene, letrozole, anastrozole, fulvestrant, exemestane, goserelin, oxaliplatin, carboplatin, cisplatin, dexamethasone, antide, bevacizumab, 5-fluorouracil, leucovorin, levamisole, irinotecan, etoposide, topotecan, gemcitabine, vinorelbine, estramustine, mitoxantrone, abarelix, zoledronate, streptozocin, rituximab, idarubicin, busulfan, chlorambucil, fludarabine, imatinib, cytarabine, ibritumomab, tositumomab, interferon alpha-2b, melphalam, bortezomib, altretamine, asparaginase, gefitinib, erlonitib, anti-EGF receptor (EGFR) antibody, interferon alpha-2a, vincristine, pamidronate, thalidomide, carmustine, prednisone, erythropoietin, bisphosphonate, antibody conjugate and an epothilone. 
     
     
         8 . The method of  claim 7 , wherein said additional therapeutic agent is an antibody conjugate comprising an anti-EGFR antibody or fragment thereof, wherein said fragment specifically binds to EGFR. 
     
     
         9 . The method of  claim 7 , wherein said additional therapeutic agent is selected from the group consisting of carboplatin, oxaliplatin, cisplatin, paclitaxel, docetaxel, gemcitabine, camptothecin and an anti-EGFR antibody. 
     
     
         10 . The method of  claim 7 , wherein said additional therapeutic agent is selected from the group consisting of bortezomib, melphalan, thalidomide, doxorubicin, cyclophosphamide, interferon alpha-2b, interferon alpha-2a, vincristine, pamidronate, carmustine, zoledronate, and dexamethasone. 
     
     
         11 . The method of  claim 1 , wherein said antibody or fragment thereof is present in a composition, and wherein said composition optionally comprises a pharmaceutically acceptable carrier. 
     
     
         12 . The method of  claim 1 , wherein said antibody or fragment thereof is a conjugate. 
     
     
         13 . The method of  claim 1 , wherein said antibody or fragment thereof is linked to a cytotoxic agent. 
     
     
         14 . The method of  claim 13 , wherein said cytotoxic agent is selected from the group consisting of a maytansinoid, a small drug, a prodrug, a taxoid, CC-1065 and a CC-1065 analog. 
     
     
         15 . The method of  claim 1 , wherein said cancer is a cancer selected from the group consisting of breast cancer, colon cancer, ovarian carcinoma, osteosarcoma, cervical cancer, prostate cancer, lung cancer, synovial carcinoma, pancreatic cancer, melanoma, multiple myeloma, neuroblastoma, and rhabdomyosarcoma. 
     
     
         16 . The method of  claim 1 , wherein said additional therapeutic agent is a cytotoxic agent. 
     
     
         17 . The method of  claim 13 , wherein said administering of said conjugate and said additional therapeutic agent is concurrently or sequentially and in either order. 
     
     
         18 . The method of  claim 1 , wherein the antibody, or fragment thereof, is administered intravenously, intramuscularly, or subcutaneously to the subject. 
     
     
         19 . The method of  claim 1 , wherein the antibody, or fragment thereof, is administered in combination with the additional therapeutic agent.