Anti-igf antibodies

Abstract

Antibody molecules, in particular fully human antibodies that bind to human IGF-1 and cross-react with IGF-2 such that binding of IGF-1 and IGF-2 to the IGF-1 receptor is prevented and IGF-1 receptor-mediated signaling is inhibited. The antibodies do not bind to insulin and thus do not affect the mitogenic properties of insulin that are mediated by its binding to the insulin receptors. The antibodies are useful for the treatment of hyperproliferative diseases, in particular cancer.

1 - 18 . (canceled) 
     
     
         19 ) A DNA molecule encoding the variable heavy chain or the variable light chain of an antibody molecule, which
 a) binds to human IGF-1 and IGF-2 such that
 i) binding of IGF-1 and IGF-2 to the IGF-1 receptor is prevented and 
 ii) IGF-1 receptor-mediated signaling is inhibited, 
   b) binds to mouse and rat IGF-1 and IGF-2,   c) does not bind to human insulin;   wherein said antibody molecule is selected from the group comprising
 i) an antibody molecule that has heavy chain CDRs comprising the amino acid sequences of SEQ ID NO:1 (CDR1), SEQ ID NO:2 (CDR2) and SEQ ID NO:3 (CDR3) and that has light chain CDRs comprising the amino acid sequences of SEQ ID NO:4 (CDR1), SEQ ID NO:5 (CDR2) and SEQ ID NO:6 (CDR3); 
 ii) an antibody molecule that has heavy chain CDRs comprising the amino acid sequences of SEQ ID NO:11 (CDR1), SEQ ID NO:12 (CDR2) and SEQ ID NO:13 (CDR3) and that has light chain CDRs comprising the amino acid sequences of SEQ ID NO:14 (CDR1), SEQ ID NO:15 (CDR2) and SEQ ID NO:16 (CDR3); 
 iii) an antibody molecule that has heavy chain CDRs comprising the amino acid sequences of SEQ ID NO:21 (CDR1), SEQ ID NO:22 (CDR2) and SEQ ID NO:23 (CDR3) and that has light chain CDRs comprising the amino acid sequences of SEQ ID NO:24 (CDR1), SEQ ID NO:25 (CDR2) and SEQ ID NO:26 (CDR3), 
   or a fragment or variant thereof.   
     
     
         20 ) The DNA molecule of  claim 19  which has the nucleotide sequence of SEQ ID NO:7, 17 or 27. 
     
     
         21 ) The DNA molecule of  claim 19  which has the nucleotide sequence of SEQ ID NO:9, 19 or 29. 
     
     
         22 ) An expression vector containing a DNA molecule comprising the nucleotide sequence encoding the variable heavy chain and/or the variable light chain of an antibody molecule, which
 a) binds to human IGF-1 and IGF-2 such that
 i) binding of IGF-1 and IGF-2 to the IGF-1 receptor is prevented and 
 ii) IGF-1 receptor-mediated signaling is inhibited, 
   b) binds to mouse and rat IGF-1 and IGF-2,   c) does not bind to human insulin;   wherein said antibody molecule is selected from the group comprising
 i) an antibody molecule that has heavy chain CDRs comprising the amino acid sequences of SEQ ID NO:1 (CDR1), SEQ ID NO:2 (CDR2) and SEQ ID NO:3 (CDR3) and that has light chain CDRs comprising the amino acid sequences of SEQ ID NO:4 (CDR1), SEQ ID NO:5 (CDR2) and SEQ ID NO:6 (CDR3); 
 ii) an antibody molecule that has heavy chain CDRs comprising the amino acid sequences of SEQ ID NO:11 (CDR1), SEQ ID NO:12 (CDR2) and SEQ ID NO:13 (CDR3) and that has light chain CDRs comprising the amino acid sequences of SEQ ID NO:14 (CDR1), SEQ ID NO:15 (CDR2) and SEQ ID NO:16 (CDR3); 
 iii) an antibody molecule that has heavy chain CDRs comprising the amino acid sequences of SEQ ID NO:21 (CDR1), SEQ ID NO:22 (CDR2) and SEQ ID NO:23 (CDR3) and that has light chain CDRs comprising the amino acid sequences of SEQ ID NO:24 (CDR1), SEQ ID NO:25 (CDR2) and SEQ ID NO:26 (CDR3). 
   
     
     
         23 ) The expression vector of  claim 22  containing a DNA molecule comprising the nucleotide sequence of SEQ ID NO:7 and/or SEQ ID NO:9, or comprising the sequence of SEQ ID NO:17 and/or SEQ ID NO:19, or comprising the sequence of SEQ ID NO:27 and/or SEQ ID NO:29. 
     
     
         24 ) The expression vector of  claim 22 , comprising, in addition, a DNA molecule encoding the constant heavy chain and/or the constant light chain, respectively, linked to the DNA molecule encoding the variable heavy chain and/or the variable light chain, respectively. 
     
     
         25 ) A host cell carrying one or more expression vectors of  claim 22 . 
     
     
         26 ) The host cell of  claim 25 , which is a mammalian cell. 
     
     
         27 ) A method for producing an antibody, comprising transfecting a mammalian host cell with one or more vectors of  claim 22 , cultivating the host cell and recovering and purifying the antibody. 
     
     
         28 ) A method for producing an antibody, comprising obtaining a mammalian host cell comprising one or more vectors of  claim 22 , and cultivating the host cell. 
     
     
         29 ) The method according to  claim 28 , further comprising recovering and purifying the antibody. 
     
     
         30 . (canceled) 
     
     
         31 ) A method of treating a cancerous disease selected from cancers of the hematopoietic system including leukemias, lymphomas and myelomas, cancers of the gastrointestinal tract including esophageal, gastric, colorectal, pancreatic, liver and gall bladder cancer and bile duct cancer, in particular hepatocellular carcinoma; kidney, prostate and bladder cancer; gynecological cancers including breast, ovarian, cervical and endometrial cancer; skin and head and neck cancers including malignant melanomas; pediatric cancers like Wilms' tumour, neuroblastoma and Ewing's sarcoma; brain cancers like glioblastoma; sarcomas like osteosarcoma, soft tissue sarcoma, rhabdomyosarcoma, hemangiosarcoma; lung cancer, in particular non-small cell lung cancer; mesothelioma and thyroid cancer comprising administering to a patient an antibody molecule, which
 a) binds to human IGF-1 and IGF-2 such that
 i) binding of IGF-1 and IGF-2 to the IGF-1 receptor is prevented and 
 ii) IGF-1 receptor-mediated signaling is inhibited, 
   b) binds to mouse and rat IGF-1 and IGF-2,   c) does not bind to human insulin;   wherein said antibody molecule is selected from the group comprising
 i) an antibody molecule that has heavy chain CDRs comprising the amino acid sequences of SEQ ID NO:1 (CDR1), SEQ ID NO:2 (CDR2) and SEQ ID NO:3 (CDR3) and that has light chain CDRs comprising the amino acid sequences of SEQ ID NO:4 (CDR1), SEQ ID NO:5 (CDR2) and SEQ ID NO:6 (CDR3); 
 ii) an antibody molecule that has heavy chain CDRs comprising the amino acid sequences of SEQ ID NO:11 (CDR1), SEQ ID NO:12 (CDR2) and SEQ ID NO:13 (CDR3) and that has light chain CDRs comprising the amino acid sequences of SEQ ID NO:14 (CDR1), SEQ ID NO:15 (CDR2) and SEQ ID NO:16 (CDR3); 
 iii) an antibody molecule that has heavy chain CDRs comprising the amino acid sequences of SEQ ID NO:21 (CDR1), SEQ ID NO:22 (CDR2) and SEQ ID NO:23 (CDR3) and that has light chain CDRs comprising the amino acid sequences of SEQ ID NO:24 (CDR1), SEQ ID NO:25 (CDR2) and SEQ ID NO:26 (CDR3). 
   
     
     
         32 ) The method of  claim 31 , wherein the antibody is to be used in combination with platinum-based chemotherapy, in particular paclitaxel/carboplatin or gemcitabine/cisplatin platinum doublet therapy, sorafenib, or a compound selected from the group of inhibitors of EGFR, VEGF, HER2-neu, AuroraB, Plk1, PI3 kinase, or mTor. 
     
     
         33 . (canceled) 
     
     
         34 ) A pharmaceutical composition comprising an antibody molecule, which
 a) binds to human IGF-1 and IGF-2 such that
 i) binding of IGF-1 and IGF-2 to the IGF-1 receptor is prevented and 
 ii) IGF-1 receptor-mediated signaling is inhibited, 
   b) binds to mouse and rat IGF-1 and IGF-2,   c) does not bind to human insulin;   wherein said antibody molecule is selected from the group comprising
 i) an antibody molecule that has heavy chain CDRs comprising the amino acid sequences of SEQ ID NO:1 (CDR1), SEQ ID NO:2 (CDR2) and SEQ ID NO:3 (CDR3) and that has light chain CDRs comprising the amino acid sequences of SEQ ID NO:4 (CDR1), SEQ ID NO:5 (CDR2) and SEQ ID NO:6 (CDR3); 
 ii) an antibody molecule that has heavy chain CDRs comprising the amino acid sequences of SEQ ID NO:11 (CDR1), SEQ ID NO:12 (CDR2) and SEQ ID NO:13 (CDR3) and that has light chain CDRs comprising the amino acid sequences of SEQ ID NO:14 (CDR1), SEQ ID NO:15 (CDR2) and SEQ ID NO:16 (CDR3); 
 iii) an antibody molecule that has heavy chain CDRs comprising the amino acid sequences of SEQ ID NO:21 (CDR1), SEQ ID NO:22 (CDR2) and SEQ ID NO:23 (CDR3) and that has light chain CDRs comprising the amino acid sequences of SEQ ID NO:24 (CDR1), SEQ ID NO:25 (CDR2) and SEQ ID NO:26 (CDR3) 
   and a pharmaceutically acceptable carrier, further comprising one or more additional therapeutic agents selected from   a) DNA damaging agents,   b) therapeutically active compounds that inhibit signal transduction pathways or mitotic checkpoints in cancer cells,   c) antidiabetics.   
     
     
         35 ) The pharmaceutical composition of  claim 34 , wherein said one or more compounds b) is selected from the group of inhibitors of EGFR, VEGF, HER2-neu, AuroraB, Plk1, PI3 kinase, or mTor. 
     
     
         36 ) A pharmaceutical composition comprising an antibody molecule, which
 a) binds to human IGF-1 and IGF-2 such that
 i) binding of IGF-1 and IGF-2 to the IGF-1 receptor is prevented and 
 ii) IGF-1 receptor-mediated signaling is inhibited, 
   b) binds to mouse and rat IGF-1 and IGF-2,   c) does not bind to human insulin;   wherein said antibody molecule is selected from the group comprising
 i) an antibody molecule that has heavy chain CDRs comprising the amino acid sequences of SEQ ID NO:1 (CDR1), SEQ ID NO:2 (CDR2) and SEQ ID NO:3 (CDR3) and that has light chain CDRs comprising the amino acid sequences of SEQ ID NO:4 (CDR1), SEQ ID NO:5 (CDR2) and SEQ ID NO:6 (CDR3); 
 ii) an antibody molecule that has heavy chain CDRs comprising the amino acid sequences of SEQ ID NO:11 (CDR1), SEQ ID NO:12 (CDR2) and SEQ ID NO:13 (CDR3) and that has light chain CDRs comprising the amino acid sequences of SEQ ID NO:14 (CDR1), SEQ ID NO:15 (CDR2) and SEQ ID NO:16 (CDR3); 
 iii) an antibody molecule that has heavy chain CDRs comprising the amino acid sequences of SEQ ID NO:21 (CDR1), SEQ ID NO:22 (CDR2) and SEQ ID NO:23 (CDR3) and that has light chain CDRs comprising the amino acid sequences of SEQ ID NO:24 (CDR1), SEQ ID NO:25 (CDR2) and SEQ ID NO:26 (CDR3) 
   and a pharmaceutically acceptable carrier for the treatment of a cancerous disease selected from cancers of the hematopoietic system including leukemias, lymphomas and myelomas, cancers of the gastrointestinal tract including esophageal, gastric, colorectal, pancreatic, liver and gall bladder cancer and bile duct cancer, in particular hepatocellular carcinoma; kidney, prostate and bladder cancer; gynecological cancers including breast, ovarian, cervical and endometrial cancer; skin and head and neck cancers including malignant melanomas; pediatric cancers like Wilms' tumour, neuroblastoma and Ewing's sarcoma; brain cancers like glioblastoma; sarcomas like osteosarcoma, soft tissue sarcoma, rhabdomyosarcoma, hemangiosarcoma; lung cancer, in particular non-small cell lung cancer; mesothelioma and thyroid cancer.   
     
     
         37 ) The pharmaceutical composition of  claim 36 , to be further used in combination with platinum-based chemotherapy, in particular paclitaxel/carboplatin or gemcitabine/cisplatin platinum doublet therapy, sorafenib, or a compound selected from the group of inhibitors of EGFR, VEGF, HER2-neu, AuroraB, Plk1, PI3 kinase, or mTor. 
     
     
         38 ) A method for treating a patient suffering from a cancerous disease selected from cancers of the hematopoietic system including leukemias, lymphomas and myelomas, cancers of the gastrointestinal tract including esophageal, gastric, colorectal, pancreatic, liver and gall bladder cancer and bile duct cancer, in particular hepatocellular carcinoma; kidney, prostate and bladder cancer; gynecological cancers including breast, ovarian, cervical and endometrial cancer; skin and head and neck cancers including malignant melanomas; pediatric cancers like Wilms' tumour, neuroblastoma and Ewing's sarcoma; brain cancers like glioblastoma; sarcomas like osteosarcoma, soft tissue sarcoma, rhabdomyosarcoma, hemangiosarcoma; lung cancer, in particular non-small cell lung cancer; mesothelioma and thyroid cancer, comprising administering to said patient an effective amount of a pharmaceutical composition comprising an antibody molecule, which
 a) binds to human IGF-1 and IGF-2 such that
 i) binding of IGF-1 and IGF-2 to the IGF-1 receptor is prevented and 
 ii) IGF-1 receptor-mediated signaling is inhibited, 
   b) binds to mouse and rat IGF-1 and IGF-2,   c) does not bind to human insulin;   wherein said antibody molecule is selected from the group comprising
 i) an antibody molecule that has heavy chain CDRs comprising the amino acid sequences of SEQ ID NO:1 (CDR1), SEQ ID NO:2 (CDR2) and SEQ ID NO:3 (CDR3) and that has light chain CDRs comprising the amino acid sequences of SEQ ID NO:4 (CDR1), SEQ ID NO:5 (CDR2) and SEQ ID NO:6 (CDR3); 
 ii) an antibody molecule that has heavy chain CDRs comprising the amino acid sequences of SEQ ID NO:11 (CDR1), SEQ ID NO:12 (CDR2) and SEQ ID NO:13 (CDR3) and that has light chain CDRs comprising the amino acid sequences of SEQ ID NO:14 (CDR1), SEQ ID NO:15 (CDR2) and SEQ ID NO:16 (CDR3); 
 iii) an antibody molecule that has heavy chain CDRs comprising the amino acid sequences of SEQ ID NO:21 (CDR1), SEQ ID NO:22 (CDR2) and SEQ ID NO:23 (CDR3) and that has light chain CDRs comprising the amino acid sequences of SEQ ID NO:24 (CDR1), SEQ ID NO:25 (CDR2) and SEQ ID NO:26 (CDR3) 
   and a pharmaceutically acceptable carrier.   
     
     
         39 ) The method of  claim 38 , wherein additionally an effective amount of paclitaxel/carboplatin or gemcitabine/cisplatin, sorafenib, or a compound selected from the group of inhibitors of EGFR, VEGF, HER2-neu, AuroraB, Plk1, PI3 kinase or mTor is administered to the patient. 
     
     
         40 ) A method for inhibiting the binding of IGF-1 and IGF-2 to the IGF-1 receptor in a mammalian cell, comprising administering to said cell an antibody molecule which
 a) binds to human IGF-1 and IGF-2 such that
 i) binding of IGF-1 and IGF-2 to the IGF-1 receptor is prevented and 
 ii) IGF-1 receptor-mediated signaling is inhibited, 
   b) binds to mouse and rat IGF-1 and IGF-2,   c) does not bind to human insulin;   wherein said antibody molecule is selected from the group comprising
 i) an antibody molecule that has heavy chain CDRs comprising the amino acid sequences of SEQ ID NO:1 (CDR1), SEQ ID NO:2 (CDR2) and SEQ ID NO:3 (CDR3) and that has light chain CDRs comprising the amino acid sequences of SEQ ID NO:4 (CDR1), SEQ ID NO:5 (CDR2) and SEQ ID NO:6 (CDR3); 
 ii) an antibody molecule that has heavy chain CDRs comprising the amino acid sequences of SEQ ID NO:11 (CDR1), SEQ ID NO:12 (CDR2) and SEQ ID NO:13 (CDR3) and that has light chain CDRs comprising the amino acid sequences of SEQ ID NO:14 (CDR1), SEQ ID NO:15 (CDR2) and SEQ ID NO:16 (CDR3); 
 iii) an antibody molecule that has heavy chain CDRs comprising the amino acid sequences of SEQ ID NO:21 (CDR1), SEQ ID NO:22 (CDR2) and SEQ ID NO:23 (CDR3) and that has light chain CDRs comprising the amino acid sequences of SEQ ID NO:24 (CDR1), SEQ ID NO:25 (CDR2) and SEQ ID NO:26 (CDR3), 
   whereby signaling mediated by the IGF-1 receptor and proliferation and anti-apoptosis mediated by IGF-1 and IGF-2 are inhibited.   
     
     
         41 ) A method for inhibiting the binding of IGF-2 to the insulin receptor IR-A in a mammalian cell, comprising administering to said cell an antibody molecule which
 a) binds to human IGF-1 and IGF-2 such that
 i) binding of IGF-1 and IGF-2 to the IGF-1 receptor is prevented and 
 ii) IGF-1 receptor-mediated signaling is inhibited, 
   b) binds to mouse and rat IGF-1 and IGF-2,   c) does not bind to human insulin;   wherein said antibody molecule is selected from the group comprising
 i) an antibody molecule that has heavy chain CDRs comprising the amino acid sequences of SEQ ID NO:1 (CDR1), SEQ ID NO:2 (CDR2) and SEQ ID NO:3 (CDR3) and that has light chain CDRs comprising the amino acid sequences of SEQ ID NO:4 (CDR1), SEQ ID NO:5 (CDR2) and SEQ ID NO:6 (CDR3); 
 ii) an antibody molecule that has heavy chain CDRs comprising the amino acid sequences of SEQ ID NO:11 (CDR1), SEQ ID NO:12 (CDR2) and SEQ ID NO:13 (CDR3) and that has light chain CDRs comprising the amino acid sequences of SEQ ID NO:14 (CDR1), SEQ ID NO:15 (CDR2) and SEQ ID NO:16 (CDR3); 
 iii) an antibody molecule that has heavy chain CDRs comprising the amino acid sequences of SEQ ID NO:21 (CDR1), SEQ ID NO:22 (CDR2) and SEQ ID NO:23 (CDR3) and that has light chain CDRs comprising the amino acid sequences of SEQ ID NO:24 (CDR1), SEQ ID NO:25 (CDR2) and SEQ ID NO:26 (CDR3), 
   whereby signaling mediated by the insulin receptor IR-A is inhibited and whereby proliferation and anti-apoptosis mediated by IGF-2 is inhibited.   
     
     
         42 ) The method of  claim 40 , wherein said administering is done in vitro. 
     
     
         43 ) A method for monitoring the effectiveness of a treatment of a cancer patient with an antibody molecule that binds to IGF-1 and IGF-2, wherein said method comprises
 (a) measuring, in a biological sample of said patient, the level of total IGF-1,   (b) administering to said patient said anti-IGF antibody molecule,   (c) measuring, in a biological sample of said patient, the level of total IGF-1, wherein the amount of increase in the level of total IGF-1, compared with the level of total IGF-1 measured in step (a), indicates to which extent the patient responds to the treatment with said anti-IGF antibody molecule.   
     
     
         44 ) The method of  claim 43 , wherein said antibody molecule is an antibody molecule which
 a) binds to human IGF-1 and IGF-2 such that
 i) binding of IGF-1 and IGF-2 to the IGF-1 receptor is prevented and 
 ii) IGF-1 receptor-mediated signaling is inhibited, 
   b) binds to mouse and rat IGF-1 and IGF-2,   c) does not bind to human insulin;   wherein said antibody molecule is selected from the group comprising
 i) an antibody molecule that has heavy chain CDRs comprising the amino acid sequences of SEQ ID NO:1 (CDR1), SEQ ID NO:2 (CDR2) and SEQ ID NO:3 (CDR3) and that has light chain CDRs comprising the amino acid sequences of SEQ ID NO:4 (CDR1), SEQ ID NO:5 (CDR2) and SEQ ID NO:6 (CDR3); 
 ii) an antibody molecule that has heavy chain CDRs comprising the amino acid sequences of SEQ ID NO:11 (CDR1), SEQ ID NO:12 (CDR2) and SEQ ID NO:13 (CDR3) and that has light chain CDRs comprising the amino acid sequences of SEQ ID NO:14 (CDR1), SEQ ID NO:15 (CDR2) and SEQ ID NO:16 (CDR3); 
 iii) an antibody molecule that has heavy chain CDRs comprising the amino acid sequences of SEQ ID NO:21 (CDR1), SEQ ID NO:22 (CDR2) and SEQ ID NO:23 (CDR3) and that has light chain CDRs comprising the amino acid sequences of SEQ ID NO:24 (CDR1), SEQ ID NO:25 (CDR2) and SEQ ID NO:26 (CDR3). 
   
     
     
         45 - 47 . (canceled)