Anti-igf-i receptor antibodies

Abstract

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, prostate cancer 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.

1 . A composition comprising an isolated antibody or fragment thereof, wherein said antibody or said fragment comprises at least one heavy chain variable region and at least one light chain variable region, wherein said heavy chain variable region comprises three complementarity-determining regions comprising the amino acid sequences of SEQ ID NOS:1-3, and wherein said light chain variable region comprises three complementarity-determining regions comprising the amino acid sequences of SEQ ID NOS:4-6, and wherein said antibody or said fragment specifically binds to IGF-IR; and
 a therapeutic agent.   
     
     
         2 . A composition comprising an antibody or fragment thereof, wherein said antibody or said fragment comprises a heavy chain variable region and a light chain variable region, wherein said heavy chain variable region comprises the amino acid sequence of SEQ ID NO:7, and wherein said light chain variable region comprises three complementarity determining regions having the amino acid sequence of SEQ ID NOs:4-6; and a therapeutic agent; wherein said antibody or said fragment specifically binds IGF-IR. 
     
     
         3 . A composition comprising an antibody or fragment thereof, wherein said antibody or said fragment comprises a heavy chain variable region and a light chain variable region, wherein said light chain variable region comprises the amino acid sequence of SEQ ID NO:8, and wherein said heavy chain variable region comprises three complementarity determining regions having the amino acid sequence of SEQ ID NOs:1-3; and a therapeutic agent; wherein said antibody or said fragment specifically binds IGR-IR. 
     
     
         4 . A composition comprising an antibody or fragment thereof, wherein said antibody or said fragment comprises a heavy chain variable region and a light chain variable region, and wherein said antibody or said fragment specifically binds IGR-IR, wherein said light chain region comprises the amino acid sequence selected from the group consisting of:
 SEQ ID NO:9;   SEQ ID NO:10;   SEQ ID NO:11; and   SEQ ID NO:12; and   wherein said heavy chain variable region comprises three complementarity determining regions having the amino acid sequence of SEQ ID NO:1-3; and   wherein said composition further comprises a therapeutic agent.   
     
     
         5 . A composition comprising an antibody or fragment thereof, wherein said antibody or said fragment specifically binds IGF-IR, wherein said antibody comprises a heavy chain variable region and a light chain variable region, wherein said heavy chain variable region comprises the amino acid sequence of SEQ ID NO:13, and wherein said light chain variable region comprises three complementarity determining regions having the amino acid sequence of SEQ ID NOs:4-6; and a therapeutic agent. 
     
     
         6 . A composition comprising the antibody or fragment thereof of  claim 1 , comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:13. 
     
     
         7 . A composition comprising the antibody or antibody fragment of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         8 . A composition comprising a conjugate comprising the antibody or antibody fragment of  claim 1  linked to a cytotoxic agent. 
     
     
         9 . The composition of  claim 1 , wherein said therapeutic agent is selected from the group consisting of bortezomib, melphalan, thalidomide, doxorubicin, cyclophosphamide, interferon alpha-2b, interferon alpha-2a, vincristine, pamidronate, carmustine, predisone, zoledronate, erythropoietin, bisphosphonate and dexamethasone. 
     
     
         10 . The composition of  claim 1 , wherein said antibody or said fragment is selected from the group consisting of:
 (i) a resurfaced antibody or epitope binding fragment thereof;   (ii) a human antibody or epitope binding fragment thereof;   (iii) a humanized antibody or epitope binding fragment thereof; and   (iv) an antibody produced by mouse hybridoma EM164 (ATCC accession number PTA 4457) or epitope binding fragment thereof.   
     
     
         11 . The composition of  claim 1 , wherein the antibody or antibody fragment has at least one property selected from the group consisting of:
 a) inhibits cellular function of a IGF-IR without activating said IGF-IR; and   b) inhibits tumor cell growth in the presence of serum by at least 80%.   
     
     
         12 . The composition of any one of  claim 1 ,  2  or  3 - 5 , wherein said 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 antibody, thalidomide, carmustine, predisone, interferon alpha-2a, vincristine, pamidronate, erythropoietin, bisphosphonate and an epothilone. 
     
     
         13 . The composition of any one of  claim 1 ,  2  or  3 - 5 , wherein said therapeutic agent is selected from the group consisting of carboplatin, oxaliplatin, cisplatin, paclitaxel, docetaxel, gemcitabine, and camptothecin. 
     
     
         14 . The composition of any one of  claim 1 ,  2  or  3 - 5 , wherein said therapeutic agent is selected from the group consisting of bortezomib, melphalan, thalidomide, doxorubicin, cyclophosphamide, interferon alpha-2b, interferon alpha-2a, vincristine, pamidronate, carmustine, predisone, zoledronate, erythropoietin, bisphosphonate and dexamethasone. 
     
     
         15 . A composition comprising an antibody or antibody fragment, wherein said antibody or said fragment specifically binds IGF-IR, and wherein said antibody comprises a heavy chain variable region and a light chain variable region, wherein said heavy chain variable region comprises heavy chain complementarity-determining regions comprising the amino acid sequences of SEQ ID NOs:1-3, and wherein said light chain variable region comprises complementarity-determining regions comprising the amino acid sequences of SEQ ID NOs:4-6; and wherein said light chain variable region comprises the amino acid sequence of SEQ ID NO:8; and
 a therapeutic agent.   
     
     
         16 . A composition comprising an antibody or antibody fragment, wherein said antibody or said fragment comprises at least one heavy chain variable region and at least one light chain variable region, wherein said heavy chain variable region comprises three complementarity-determining regions comprising the amino acid sequences of SEQ ID NOS:1-3, and wherein said light chain variable region comprises three complementarity-determining regions comprising the amino acid sequences of SEQ ID NOS:4-6, respectively, and wherein said heavy chain variable region comprises SEQ ID NO:7; and wherein said antibody or said fragment specifically binds IGF-IR; and
 a therapeutic agent.   
     
     
         17 . A composition comprising a murine antibody EM164 corresponding to ATCC deposit number PTA-4457 or a fragment thereof that specifically binds to an insulin-like growth factor-I receptor, wherein said antibody or fragment is an antagonist of said receptor and is devoid of agonist activity toward said receptor; and
 a therapeutic agent.   
     
     
         18 . A composition comprising a humanized or resurfaced antibody EM164 corresponding to ATCC deposit number PTA-4457 or a fragment thereof that specifically binds to an insulin-like growth factor-I receptor, wherein said antibody or fragment is an antagonist of said receptor and is devoid of agonist activity toward said receptor; and
 a therapeutic agent.   
     
     
         19 . A method for inhibiting the growth of a cancer cell comprising contacting said cell with the composition of  claim 1 . 
     
     
         20 . A method for treating a patient having a cancer comprising administering to said patient an effective amount of the composition of  claim 1 . 
     
     
         21 . A composition comprising a diagnostic reagent comprising the composition of  claim 7 , wherein said antibody or antibody fragment is labeled with a detectable moiety. 
     
     
         22 . The composition of  claim 8 , 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. 
     
     
         23 . A pharmaceutical composition comprising the conjugate of  claim 8  and a pharmaceutically acceptable carrier. 
     
     
         24 . A method for treating a patient having a cancer comprising administering to said patient an effective amount of the conjugate of  claim 8 . 
     
     
         25 . The composition of  claim 11 , wherein the antibody or antibody fragment has all of said properties. 
     
     
         26 . The method of  claim 19 , 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. 
     
     
         27 . The method of  claim 19 , wherein said cell is contacted with said antibody or said fragment and said therapeutic agent concurrently. 
     
     
         28 . The method of  claim 19 , wherein said cell is contacted with said antibody or said fragment and said therapeutic agent sequentially and in either order. 
     
     
         29 . The method of  claim 19  or  32 , wherein said 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 antibody, thalidomide, carmustine, predisone, interferon alpha-2a, vincristine, pamidronate, erythropoietin, bisphosphonate and an epothilone. 
     
     
         30 . The method of  claim 19  or  32 , wherein said therapeutic agent is selected from the group consisting of carboplatin, oxaliplatin, cisplatin, paclitaxel, docetaxel, gemcitabine, and camptothecin. 
     
     
         31 . The method of  claim 19  or  32 , wherein said therapeutic agent is selected from the group consisting of bortezomib, melphalan, thalidomide, doxorubicin, cyclophosphamide, interferon alpha-2b, interferon alpha-2a, vincristine, pamidronate, carmustine, prednisone, zoledronate, erythropoietin, bisphosphonate and dexamethasone. 
     
     
         32 . The method of  claim 20  further comprising administering to said patient a therapeutic agent. 
     
     
         33 . The method of  claim 20 , wherein said antibody or said fragment and said second therapeutic agent are administered concurrently. 
     
     
         34 . The method of  claim 20 , wherein said antibody or said fragment and said therapeutic agent are administered sequentially and in either order. 
     
     
         35 . The method of treatment of  claim 20 , 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 and pancreatic cancer. 
     
     
         36 . The method according to  claim 20 , wherein said effective amount of the composition of  claim 1  comprises about 1 mg/square meter to about 2000 mg/square meter of said antibody or fragment thereof, and about 10 mg/square meter to about 2000 mg/square meter of said therapeutic agent. 
     
     
         37 . The method according to  claim 20 , wherein said effective amount of the composition of  claim 1  comprises about 10 mg/square meter to about 1000 mg/square meter of said antibody or fragment thereof, and about 50 mg/square meter to about 1000 mg/square meter of said therapeutic agent. 
     
     
         38 . The composition of  claim 21 , wherein said detectable moiety is selected from the group consisting of a radiolabel, a fluorophore, a chromophore, an imaging agent and a metal ion. 
     
     
         39 . A method for diagnosing a subject suspect of having a cancer, said method comprising:
 administering to said subject the composition of  claim 21 ; and   detecting the distribution of said reagent within said subject.   
     
     
         40 . The method of  claim 32 , wherein said therapeutic agent is a cytotoxic agent. 
     
     
         41 . The method of diagnosis of  claim 39 , 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 and pancreatic cancer.