Claims for Patent: 7,847,068

Summary for Patent: 7,847,068

Title:	Neutralizing human anti-IGFR antibody
Abstract:	The present invention includes fully human, neutralizing, monoclonal antibodies against human Insulin-like Growth Factor Receptor-I (IGFR1). The antibodies are useful for treating or preventing cancer in a subject. Also included are methods of using and producing the antibodies of the invention.
Inventor(s):	Wang; Yan (Scotch Plains, NJ), Greenberg; Robert (Sparta, NJ), Presta; Leonard (San Francisco, CA), Pachter; Jonathan A. (Setauket, NY), Hailey; Judith (Edison, NJ), Brams; Peter (Sacramento, CA), Williams; Denise (San Jose, CA), Srinivasan; Mohan (Cupertino, CA), Feingersh; Diane (Union City, CA)
Assignee:	Schering Corporation (Kenilworth, NJ)
Application Number:	11/598,520
Patent Claims:	1. An isolated antibody or antigen-binding fragment thereof that binds to IGFR1 comprising a CDR-L1, CDR-L2 and CDR-L3 found in a light chain immunoglobulin variable region which comprises the amino acid sequence set forth in SEQ ID NO: 78; and a CDR-H1, CDR-H2 and CDR-H3 found in a heavy chain immunoglobulin variable region which comprises the amino acid sequence set forth in SEQ ID NO: 45. 2. An isolated antibody or antigen-binding fragment thereof comprising a CDR-H1, CDR-H2 and CDR-H3 found in a heavy chain immunoglobulin encoded by a polynucleotide in plasmid 15H12/19D12 HCA (gamma-1) which is deposited at the American Type Culture Collection under deposit number PTA-5220; and a CDR-L1, CDR-L2 and CDR-L3 found in a light chain immunoglobulin encoded by a polynucleotide in plasmid 15H12/19D12 LCF (kappa) which is deposited at the American Type Culture Collection under deposit number PTA-5216. 3. An isolated antibody or antigen-binding fragment thereof that binds to IGFR1 comprising a heavy chain immunoglobulin variable region comprising amino acids 20-137 of SEQ ID NO: 4, 45 or 112; and one or more members selected from the group consisting of: (a) a light chain immunoglobulin variable region comprising amino acids 20-128 of SEQ ID NO: 2; (b) a light chain immunoglobulin variable region comprising amino acids 20-128 of SEQ ID NO: 72; (c) a light chain immunoglobulin variable region comprising amino acids 20-128 of SEQ ID NO: 74 (d) a light chain immunoglobulin variable region comprising amino acids 20-128 of SEQ ID NO: 76; and (e) a light chain immunoglobulin variable region comprising amino acids 20-128 of SEQ ID NO: 78. 4. The antibody or fragment of claim 1 which is a Fab fragment, a F(ab).sub.2 fragment, an Fv fragment, a single chain Fv fragment, a disulfide stabilized Fv fragment, a chimeric antibody, a bispecific antibody, a polyclonal antibody or a labeled antibody. 5. The antibody or fragment of claim 1 which comprises a heavy chain immunoglobulin comprising amino acids 20-137 of SEQ ID NO: 45; and a light chain immunoglobulin comprising amino acids 20-128 of SEQ ID NO: 78. 6. The antibody or fragment of claim 1 which is a monoclonal antibody. 7. The antibody or fragment of claim 4 wherein said antibody or fragment is labeled and said label is one or more members selected from the group consisting of .sup.99Tc, .sup.90Y, .sup.111In, .sup.32P, .sup.14C, .sup.125, .sup.3H, .sup.131I, .sup.11C, .sup.15O, .sup.13N, .sup.18F, .sup.35S, .sup.51Cr, .sup.57To, .sup.226Ra, .sup.60Co, .sup.59Fe, .sup.57Se, .sup.152Eu, .sup.67CU, .sup.217Ci, .sup.211At, .sup.212Pb, .sup.47Sc, .sup.109Pd, .sup.234Th, .sup.40K, .sup.157Gd, .sup.55Mn, .sup.52Tr, .sup.56Fe, fluorescein label, rhodamine label, isothiocyanate label, phycoerythrin label, phycocyanin label, allophycocyanin label, o-phthaladehyde label, fluorescamine label, .sup.152Eu label, dansyl label, umbelliferone label, luciferin label, luminal label, isoluminal label, aromatic acridinium ester label, imidazole label, acridimium salt label, oxalate ester label, aequorin label, 2,3-dihydrophthalazinedione label, biotin label, avidin labelfluorescein label, rhodamine label, isothiocyanate label, phycoerythrin label, phycocyanin label, allophycocyanin label, o-phthaladehyde label, fluorescamine label, .sup.152Eu label, dansyl label, umbelliferone label, luciferin label, luminal label, isoluminal label, aromatic acridinium ester label, imidazole label, acridimium salt label, oxalate ester label, aequorin label, 2,3-dihydrophthalazinedione label, biotin label, avidin label, diptheria toxin, Pseudomonas aeruginosa exotoxin A chain, ricin A chain, abrin A chain, modeccin A chain, alpha-sarcin, dianthin protein, Phytoiacca americana protein PAPI, Phytoiacca americana protein PAPII, Phytoiacca americana protein PAP-S, momordica charantia inhibitor, curcin, crotin, saponaria officinalis inhibitor, mitogellin, restrictocin, phenomycin, neomycin, polyethylene glycol, monomethoxypolyethylene glycol, 2 kDa polyethylene glycol, 5 kDa polyethylene glycol, 10 kDa polyethylene glycol, 12 kDa polyethylene glycol, 20 kDa polyethylene glycol, 30 kDa polyethylene glycol and 40 kDa polyethylene glycol. 8. The antibody or fragment of claim 2 which is a Fab fragment, a F(ab).sub.2 fragment, an Fv fragment, a single chain Fv fragment, a disulfide stabilized Fv fragment, chimeric antibody, a bispecific antibody, a polyclonal antibody or a labeled antibody. 9. The antibody or fragment of claim 2 which is a monoclonal antibody. 10. The antibody or fragment of claim 8 wherein said antibody or fragment is labeled and said label is one or more members selected from the group consisting of .sup.99Tc, .sup.90y, .sup.111In, .sup.32P, .sup.14C, .sup.125I, .sup.3H, .sup.131I, .sup.11C, .sup.15O, .sup.13N, .sup.18F, .sup.35S, .sup.51Cr, .sup.57To, .sup.226Ra, .sup.60Co, .sup.59Fe, .sup.57Se, .sup.152Eu, .sup.67CU, .sup.217Ci, .sup.211At, .sup.212Pb, .sup.47Sc, .sup.109Pd, .sup.234Th, .sup.40K, .sup.157Gd, .sup.55Mn, .sup.52Tr, .sup.56Fe, fluorescein label, rhodamine label, isothiocyanate label, phycoerythrin label, phycocyanin label, allophycocyanin label, o-phthaladehyde label, fluorescamine label, .sup.152Eu label, dansyl label, umbelliferone label, luciferin label, luminal label, isoluminal label, aromatic acridinium ester label, imidazole label, acridimium salt label, oxalate ester label, aequorin label, 2,3-dihydrophthalazinedione label, biotin label, avidin labelfluorescein label, rhodamine label, isothiocyanate label, phycoerythrin label, phycocyanin label, allophycocyanin label, o-phthaladehyde label, fluorescamine label, .sup.152Eu label, dansyl label, umbelliferone label, luciferin label, luminal label, isoluminal label, aromatic acridinium ester label, imidazole label, acridimium salt label, oxalate ester label, aequorin label, 2,3-dihydrophthalazinedione label, biotin label, avidin label, diptheria toxin, Pseudomonas aeruginosa exotoxin A chain, ricin A chain, abrin A chain, modeccin A chain, alpha-sarcin, dianthin protein, Phytoiacca americana protein PAPI, Phytoiacca americana protein PAPII, Phytoiacca americana protein PAP-S, momordica charantia inhibitor, curcin, crotin, saponaria officinalis inhibitor, mitogellin, restrictocin, phenomycin, neomycin, polyethylene glycol, monomethoxypolyethylene glycol, 2 kDa polyethylene glycol, 5 kDa polyethylene glycol, 10 kDa polyethylene glycol, 12 kDa polyethylene glycol, 20 kDa polyethylene glycol, 30 kDa polyethylene glycol and 40 kDa polyethylene glycol. 11. The antibody or fragment of claim 3 which is a Fab fragment, a F(ab).sub.2 fragment, an Fv fragment, a single chain Fv fragment, a disulfide stabilized Fv fragment, a chimeric antibody, a bispecific antibody or a labeled antibody. 12. The antibody or fragment of claim 11 wherein said antibody or fragment is labeled and said label is one or more members selected from the group consisting of .sup.99Tc, .sup.90Y, .sup.111In, .sup.32P, .sup.14C, .sup.125I, .sup.3H, .sup.131I, .sup.11C, .sup.15O, .sup.13N, .sup.18F, .sup.35S, .sup.51Cr, .sup.57To, .sup.226Ra, .sup.60Co, .sup.59Fe, .sup.57Se, .sup.152Eu, .sup.67CU, .sup.217Ci, .sup.211At, .sup.212Pb, .sup.47Sc, .sup.109Pd, .sup.234Th, .sup.40K, .sup.157Gd, .sup.55Mn, .sup.52Tr, .sup.56Fe, fluorescein label, rhodamine label, isothiocyanate label, phycoerythrin label, phycocyanin label, allophycocyanin label, o-phthaladehyde label, fluorescamine label, .sup.152Eu label, dansyl label, umbelliferone label, luciferin label, luminal label, isoluminal label, aromatic acridinium ester label, imidazole label, acridimium salt label, oxalate ester label, aequorin label, 2,3-dihydrophthalazinedione label, biotin label, avidin labelfluorescein label, rhodamine label, isothiocyanate label, phycoerythrin label, phycocyanin label, allophycocyanin label, o-phthaladehyde label, fluorescamine label, .sup.152Eu label, dansyl label, umbelliferone label, luciferin label, luminal label, isoluminal label, aromatic acridinium ester label, imidazole label, acridimium salt label, oxalate ester label, aequorin label, 2,3-dihydrophthalazinedione label, biotin label, avidin label, diptheria toxin, Pseudomonas aeruginosa exotoxin A chain, ricin A chain, abrin A chain, modeccin A chain, alpha-sarcin, dianthin protein, Phytoiacca americana protein PAPI, Phytoiacca americana protein PAPII, Phytoiacca americana protein PAP-S, momordica charantia inhibitor, curcin, crotin, saponaria officinalis inhibitor, mitogellin, restrictocin, phenomycin, neomycin, polyethylene glycol, monomethoxypolyethylene glycol, 2 kDa polyethylene glycol, 5 kDa polyethylene glycol, 10 kDa polyethylene glycol, 12 kDa polyethylene glycol, 20 kDa polyethylene glycol, 30 kDa polyethylene glycol and 40 kDa polyethylene glycol. 13. A composition comprising the antibody or fragment of claim 1 in association with one or more further anti-cancer therapeutic agents. 14. The composition of claim 13 wherein the further anti-cancer therapeutic agent is one or more members selected from the group consisting of an alkylating agent, an antimetabolite, an anti-tumor antibiotic, a mitotic inhibitor, a chromatin function inhibitor, an anti-angiogenesis agent, an anti-estrogen agent, an anti-androgen agent, a therapeutic antibody and an immunomodulator. 15. The composition of claim 13 wherein the further anti-cancer therapeutic agent is one or more members selected from the group consisting of mechlorethamine, cyclophosphamide, ifosfamide, phenylalanine mustard, melphalen, chlorambucol, uracil mustard, estramustine, thiotepa, busulfan, lomustine, carmustine, streptozocin, dacarbazine, cis-platinum, carboplatin, altretamine, methotrexate, 5-fluoruracil, floxuridine, 5-fluorodeoxyuridine, capecitabine, fludarabine, cytosine arabinoside, 6-mercaptopurine, 6-thioguanine, gemcitabine, cladribine, deoxycoformycin, pentostatin, doxorubicin, daunorubicin, idarubicin, valrubicin, mitoxantrone, dactinomycin, mithramycin, plicamycin, mitomycin C, bleomycin, procarbazine, paclitaxel, docetaxel, vinblastine, vincristine, vinorelbine, topotecan, irinotecan, etoposide, teniposide, razoxin, marimastat, COL-3, neovastat, BMS-275291, thalidomide, squalamine, endostatin, SU5416, SU6668, interferon-alpha, EMD121974, interleukin-12, IM862, angiostatin, vitaxin, tamoxifen, toremifene, raloxifene, droloxifene, iodoxyfene, anastrozole, letrozole, exemestane, flutamide, nilutamide, bicalutamide, sprironolactone, cyproterone acetate, finasteride, cimitidine, trastuzumab, rituximab, denileukin diftitox, interferon and interleukin-2 and levamisole in conjunction with 5-fluorouracil. 16. The composition of claim 15 wherein the further anti-cancer therapeutic agent is irinotecan, docetaxel, paclitaxel, cyclophosphamide, tamoxifen or anastrazole. 17. A pharmaceutical composition comprising the antibody or fragment of claim 1 and a pharmaceutically acceptable carrier. 18. A composition comprising the antibody or fragment of claim 2 in association with one or more further anti-cancer therapeutic agents. 19. The composition of claim 18 wherein the further anti-cancer therapeutic agent is one or more members selected from the group consisting of an alkylating agent, an antimetabolite, an anti-tumor antibiotic, a mitotic inhibitor, a chromatin function inhibitor, an anti-angiogenesis agent, an anti-estrogen agent, an anti-androgen agent, a therapeutic antibody and an immunomodulator. 20. The composition of claim 18 wherein the further anti-cancer therapeutic agent is one or more members selected from the group consisting of mechlorethamine, cyclophosphamide, ifosfamide, phenylalanine mustard, melphalen, chlorambucol, uracil mustard, estramustine, thiotepa, busulfan, lomustine, carmustine, streptozocin, dacarbazine, cis-platinum, carboplatin, altretamine, methotrexate, 5-fluoruracil, floxuridine, 5-fluorodeoxyuridine, capecitabine, fludarabine, cytosine arabinoside, 6-mercaptopurine, 6-thioguanine, gemcitabine, cladribine, deoxycoformycin, pentostatin, doxorubicin, daunorubicin, idarubicin, valrubicin, mitoxantrone, dactinomycin, mithramycin, plicamycin, mitomycin C, bleomycin, procarbazine, paclitaxel, docetaxel, vinblastine, vincristine, vinorelbine, topotecan, irinotecan, etoposide, teniposide, razoxin, marimastat, COL-3, neovastat, BMS-275291, thalidomide, squalamine, endostatin, SU5416, SU6668, interferon-alpha, EMD121974, interleukin-12,IM862, angiostatin, vitaxin, tamoxifen, toremifene, raloxifene, droloxifene, iodoxyfene, anastrozole, letrozole, exemestane, flutamide, nilutamide, bicalutamide, sprironolactone, cyproterone acetate, finasteride, cimitidine, trastuzumab, rituximab, denileukin diftitox, interferon and interleukin-2 and levamisole in conjunction with 5-fluorouracil. 21. The composition of claim 20 wherein the further anti-cancer therapeutic agent is irinotecan, docetaxel, paclitaxel, cyclophosphamide, tamoxifen or anastrazole. 22. A pharmaceutical composition comprising the antibody or fragment of claim 2 and a pharmaceutically acceptable carrier. 23. A composition comprising the antibody or fragment of claim 3 in association with one or more further anti-cancer therapeutic agents. 24. The composition of claim 23 wherein the further anti-cancer therapeutic agent is one or more members selected from the group consisting of an alkylating agent, an antimetabolite, an anti-tumor antibiotic, a mitotic inhibitor, a chromatin function inhibitor, an anti-angiogenesis agent, an anti-estrogen agent, an anti-androgen agent, a therapeutic antibody and an immunomodulator. 25. The composition of claim 23 wherein the further anti-cancer therapeutic agent is one or more members selected from the group consisting of mechlorethamine, cyclophosphamide, ifosfamide, phenylalanine mustard, melphalen, chlorambucol, uracil mustard, estramustine, thiotepa, busulfan, lomustine, carmustine, streptozocin, dacarbazine, cis-platinum, carboplatin, altretamine, methotrexate, 5-fluoruracil, floxuridine, 5-fluorodeoxyuridine, capecitabine, fludarabine, cytosine arabinoside, 6-mercaptopurine, 6-thioguanine, gemcitabine, cladribine, deoxycoformycin, pentostatin, doxorubicin, daunorubicin, idarubicin, valrubicin, mitoxantrone, dactinomycin, mithramycin, plicamycin, mitomycin C, bleomycin, procarbazine, paclitaxel, docetaxel, vinblastine, vincristine, vinorelbine, topotecan, irinotecan, etoposide, teniposide, razoxin, marimastat, COL-3, neovastat, BMS-275291, thalidomide, squalamine, endostatin, SU5416, SU6668, interferon-alpha, EMD121974, interleukin-12, IM862, angiostatin, vitaxin, tamoxifen, toremifene, raloxifene, droloxifene, iodoxyfene, anastrozole, letrozole, exemestane, flutamide, nilutamide, bicalutamide, sprironolactone, cyproterone acetate, finasteride, cimitidine, trastuzumab, rituximab, denileukin diftitox, interferon and interleukin-2 and levamisole in conjunction with 5-fluorouracil. 26. The composition of claim 25 wherein the further anti-cancer therapeutic agent is irinotecan, docetaxel, paclitaxel, cyclophosphamide, tamoxifen or anastrazole. 27. A pharmaceutical composition comprising the antibody or fragment of claim 3 and a pharmaceutically acceptable carrier. 28. A method for treating cancer in a mammalian subject, which cancer is mediated by elevated expression or activity of Insulin-like Growth Factor Receptor 1, comprising administering, to the subject, a therapeutically effective dosage of an isolated antibody or antigen-binding fragment thereof of claim 1. 29. The method of claim 28 wherein the cancer is colorectal cancer. 30. The method of claim 29 wherein the subject is administered the antibody or fragment in association with one or more further anti-cancer therapeutic agents. 31. The method of claim 30 wherein the further anti-cancer therapeutic agent is one or more members selected from the group consisting of an alkylating agent, an antimetabolite, an anti-tumor antibiotic, a mitotic inhibitor, a chromatin function inhibitor, an anti-angiogenesis agent, an anti-estrogen agent, an anti-androgen agent, a therapeutic antibody and an immunomodulator. 32. The method of claim 30 wherein the further anti-cancer therapeutic agent is one or more members selected from the group consisting of mechlorethamine, cyclophosphamide, ifosfamide, phenylalanine mustard, melphalen, chlorambucol, uracil mustard, estramustine, thiotepa, busulfan, lomustine, carmustine, streptozocin, dacarbazine, cis-platinum, carboplatin, altretamine, methotrexate, 5-fluoruracil, floxuridine, 5-fluorodeoxyuridine, capecitabine, fludarabine, cytosine arabinoside, 6-mercaptopurine, 6-thioguanine, gemcitabine, cladribine, deoxycoformycin, pentostatin, doxorubicin, daunorubicin, idarubicin, valrubicin, mitoxantrone, dactinomycin, mithramycin, plicamycin, mitomycin C, bleomycin, procarbazine, paclitaxel, docetaxel, vinblastine, vincristine, vinorelbine, topotecan, irinotecan, etoposide, teniposide, razoxin, marimastat, COL-3, neovastat, BMS-275291, thalidomide, squalamine, endostatin, SU5416, SU6668, interferon-alpha, EMD121974, interleukin-12, IM862, angiostatin, vitaxin, tamoxifen, toremifene, raloxifene, droloxifene, iodoxyfene, anastrozole, letrozole, exemestane, flutamide, nilutamide, bicalutamide, sprironolactone, cyproterone acetate, finasteride, cimitidine, trastuzumab, rituximab, denileukin diftitox, interferon and interleukin-2 and levamisole in conjunction with 5-fluorouracil. 33. The method of claim 32 wherein the further anti-cancer therapeutic agent is irinotecan, docetaxel, paclitaxel, cyclophosphamide, tamoxifen or anastrazole. 34. A method for treating cancer in a mammalian subject, which cancer is mediated by elevated expression or activity of Insulin-like Growth Factor Receptor 1, comprising administering, to the subject, a therapeutically effective dosage of an isolated antibody or antigen-binding fragment thereof of claim 2. 35. The method of claim 34 wherein the cancer is colorectal cancer. 36. The method of claim 35 wherein the subject is administered the antibody or fragment in association with one or more further anti-cancer therapeutic agents. 37. The method of claim 36 wherein the further anti-cancer therapeutic agent is one or more members selected from the group consisting of an alkylating agent, an antimetabolite, an anti-tumor antibiotic, a mitotic inhibitor, a chromatin function inhibitor, an anti-angiogenesis agent, an anti-estrogen agent, an anti-androgen agent, a therapeutic antibody and an immunomodulator. 38. The method of claim 36 wherein the further anti-cancer therapeutic agent is one or more members selected from the group consisting of mechlorethamine, cyclophosphamide, ifosfamide, phenylalanine mustard, melphalen, chlorambucol, uracil mustard, estramustine, thiotepa, busulfan, lomustine, carmustine, streptozocin, dacarbazine, cis-platinum, carboplatin, altretamine, methotrexate, 5-fluoruracil, floxuridine, 5-fluorodeoxyuridine, capecitabine, fludarabine, cytosine arabinoside, 6-mercaptopurine, 6-thioguanine, gemcitabine, cladribine, deoxycoformycin, pentostatin, doxorubicin, daunorubicin, idarubicin, valrubicin, mitoxantrone, dactinomycin, mithramycin, plicamycin, mitomycin C, bleomycin, procarbazine, paclitaxel, docetaxel, vinblastine, vincristine, vinorelbine, topotecan, irinotecan, etoposide, teniposide, razoxin, marimastat, COL-3, neovastat, BMS-275291, thalidomide, squalamine, endostatin, SU5416, SU6668, interferon-alpha, EMD121974, interleukin-12,IM862, angiostatin, vitaxin, tamoxifen, toremifene, raloxifene, droloxifene, iodoxyfene, anastrozole, letrozole, exemestane, flutamide, nilutamide, bicalutamide, sprironolactone, cyproterone acetate, finasteride, cimitidine, trastuzumab, rituximab, denileukin diftitox, interferon and interleukin-2 and levamisole in conjunction with 5-fluorouracil. 39. The method of claim 38 wherein the further anti-cancer therapeutic agent is irinotecan, docetaxel, paclitaxel, cyclophosphamide, tamoxifen or anastrazole. 40. A method for treating cancer in a mammalian subject, which cancer is mediated by elevated expression or activity of Insulin-like Growth Factor Receptor 1, comprising administering, to the subject, a therapeutically effective dosage of an isolated antibody or antigen-binding fragment thereof of claim 3. 41. The method of claim 40 wherein the cancer is colorectal cancer. 42. The method of claim 41 wherein the subject is administered the antibody or fragment in association with one or more further anti-cancer therapeutic agents. 43. The method of claim 42 wherein the further anti-cancer therapeutic agent is one or more members selected from the group consisting of an alkylating agent, an antimetabolite, an anti-tumor antibiotic, a mitotic inhibitor, a chromatin function inhibitor, an anti-angiogenesis agent, an anti-estrogen agent, an anti-androgen agent, a therapeutic antibody and an immunomodulator. 44. The method of claim 42 wherein the further anti-cancer therapeutic agent is one or more members selected from the group consisting of mechlorethamine, cyclophosphamide, ifosfamide, phenylalanine mustard, melphalen, chlorambucol, uracil mustard, estramustine, thiotepa, busulfan, lomustine, carmustine, streptozocin, dacarbazine, cis-platinum, carboplatin, altretamine, methotrexate, 5-fluoruracil, floxuridine, 5-fluorodeoxyuridine, capecitabine, fludarabine, cytosine arabinoside, 6-mercaptopurine, 6-thioguanine, gemcitabine, cladribine, deoxycoformycin, pentostatin, doxorubicin, daunorubicin, idarubicin, valrubicin, mitoxantrone, dactinomycin, mithramycin, plicamycin, mitomycin C, bleomycin, procarbazine, paclitaxel, docetaxel, vinblastine, vincristine, vinorelbine, topotecan, irinotecan, etoposide, teniposide, razoxin, marimastat, COL-3, neovastat, BMS-275291, thalidomide, squalamine, endostatin, SU5416, SU6668, interferon-alpha, EMD121974, interleukin-12, IM862, angiostatin, vitaxin, tamoxifen, toremifene, raloxifene, droloxifene, iodoxyfene, anastrozole, letrozole, exemestane, flutamide, nilutamide, bicalutamide, sprironolactone, cyproterone acetate, finasteride, cimitidine, trastuzumab, rituximab, denileukin diftitox, interferon and interleukin-2 and levamisole in conjunction with 5-fluorouracil. 45. The method of claim 44 wherein the further anti-cancer therapeutic agent is irinotecan, docetaxel, paclitaxel, cyclophosphamide, tamoxifen or anastrazole. 46. An isolated antibody or antigen-binding fragment thereof that binds to IGFR1 comprising a light chain amino acid sequence which comprises CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 8, CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 9 and CDR-L3comprising the amino acid sequence set forth in SEQ ID NO: 10; and a heavy chain amino acid sequence which comprises CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 14 or SEQ ID NO: 17, CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 15 and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 16. 47. The antibody or fragment of claim 46 which is a Fab fragment, a F(ab).sub.2 fragment, an Fv fragment, a single chain Fv fragment, a disulfide stabilized Fv fragment, a chimeric antibody, a bispecific antibody, or a labeled antibody. 48. A composition comprising the antibody or fragment of claim 46 in association with one or more further anti-cancer therapeutic agents. 49. The composition of claim 48 wherein the further anti-cancer therapeutic agent is one or more members selected from the group consisting of an alkylating agent, an antimetabolite, an anti-tumor antibiotic, a mitotic inhibitor, a chromatin function inhibitor, an anti-angiogenesis agent, an anti-estrogen agent, an anti-androgen agent, a therapeutic antibody and an immunomodulator. 50. The composition of claim 48 wherein the further anti-cancer therapeutic agent is one or more members selected from the group consisting of mechlorethamine, cyclophosphamide, ifosfamide, phenylalanine mustard, melphalen, chlorambucol, uracil mustard, estramustine, thiotepa, busulfan, lomustine, carmustine, streptozocin, dacarbazine, cis-platinum, carboplatin, altretamine, methotrexate, 5-fluoruracil, floxuridine, 5-fluorodeoxyuridine, capecitabine, fludarabine, cytosine arabinoside, 6-mercaptopurine, 6-thioguanine, gemcitabine, cladribine, deoxycoformycin, pentostatin, doxorubicin, daunorubicin, idarubicin, valrubicin, mitoxantrone, dactinomycin, mithramycin, plicamycin, mitomycin C, bleomycin, procarbazine, paclitaxel, docetaxel, vinblastine, vincristine, vinorelbine, topotecan, irinotecan, etoposide, teniposide, razoxin, marimastat, COL-3, neovastat, BMS-275291, thalidomide, squalamine, endostatin, SU5416, SU6668, interferon-alpha, EMD121974, interleukin-12, IM862, angiostatin, vitaxin, tamoxifen, toremifene, raloxifene, droloxifene, iodoxyfene, anastrozole, letrozole, exemestane, flutamide, nilutamide, bicalutamide, sprironolactone, cyproterone acetate, finasteride, cimitidine, trastuzumab, rituximab, denileukin diftitox, interferon and interleukin-2 and levamisole in conjunction with 5-fluorouracil. 51. The composition of claim 50 wherein the further anti-cancer therapeutic agent is irinotecan, docetaxel, paclitaxel, cyclophosphamide, tamoxifen or anastrazole. 52. A pharmaceutical composition comprising the antibody or fragment of claim 46 and a pharmaceutically acceptable carrier. 53. A method for treating cancer in a mammalian subject, which cancer is mediated by elevated expression or activity of Insulin-like Growth Factor Receptor 1, comprising administering, to the subject, a therapeutically effective dosage of an isolated antibody or antigen-binding fragment thereof of claim 46. 54. The method of claim 53 wherein the cancer is colorectal cancer. 55. The method of claim 54 wherein the subject is administered the antibody or fragment in association with one or more further anti-cancer therapeutic agents. 56. The method of claim 55 wherein the further anti-cancer therapeutic agent is one or more members selected from the group consisting of an alkylating agent, an antimetabolite, an anti-tumor antibiotic, a mitotic inhibitor, a chromatin function inhibitor, an anti-angiogenesis agent, an anti-estrogen agent, an anti-androgen agent, a therapeutic antibody and an immunomodulator. 57. The method of claim 55 wherein the further anti-cancer therapeutic agent is one or more members selected from the group consisting of mechlorethamine, cyclophosphamide, ifosfamide, phenylalanine mustard, melphalen, chlorambucol, uracil mustard, estramustine, thiotepa, busulfan, lomustine, carmustine, streptozocin, dacarbazine, cis-platinum, carboplatin, altretamine, methotrexate, 5-fluoruracil, floxuridine, 5-fluorodeoxyuridine, capecitabine, fludarabine, cytosine arabinoside, 6-mercaptopurine, 6-thioguanine, gemcitabine, cladribine, deoxycoformycin, pentostatin, doxorubicin, daunorubicin, idarubicin, valrubicin, mitoxantrone, dactinomycin, mithramycin, plicamycin, mitomycin C, bleomycin, procarbazine, paclitaxel, docetaxel, vinblastine, vincristine, vinorelbine, topotecan, irinotecan, etoposide, teniposide, razoxin, marimastat, COL-3, neovastat, BMS-275291, thalidomide, squalamine, endostatin, SU5416, SU6668, interferon-alpha, EMD121974, interleukin-12, IM862, angiostatin, vitaxin, tamoxifen, toremifene, raloxifene, droloxifene, iodoxyfene, anastrozole, letrozole, exemestane, flutamide, nilutamide, bicalutamide, sprironolactone, cyproterone acetate, finasteride, cimitidine, trastuzumab, rituximab, denileukin diftitox, interferon and interleukin-2 and levamisole in conjunction with 5-fluorouracil. 58. The method of claim 57 wherein the further anti-cancer therapeutic agent is irinotecan, docetaxel, paclitaxel, cyclophosphamide, tamoxifen or anastrazole. 59. The antibody or fragment of claim 5 which is a monoclonal antibody. 60. The antibody or fragment of claim 5 which is a recombinant antibody. 61. The antibody or fragment of claim 5 which is an antibody. 62. A pharmaceutical composition comprising the monoclonal antibody of claim 59 and a pharmaceutically acceptable carrier. 63. The pharmaceutical composition of claim 62 wherein the pharmaceutically acceptable carrier comprises water, buffer and a sugar. 64. A composition comprising the monoclonal antibody of claim 59 in association with one or more further anti-cancer therapeutic agents. 65. The composition of claim 64 wherein the further anti-cancer therapeutic agent is one or more members selected from the group consisting of an alkylating agent, an antimetabolite, an anti-tumor antibiotic, a mitotic inhibitor, a chromatin function inhibitor, an anti-angiogenesis agent, an anti-estrogen agent, an anti-androgen agent, a therapeutic antibody and an immunomodulator. 66. The composition of claim 64 wherein the further anti-cancer therapeutic agent is one or more members selected from the group consisting of mechlorethamine, cyclophosphamide, ifosfamide, phenylalanine mustard, melphalen, chlorambucol, uracil mustard, estramustine, thiotepa, busulfan, lomustine, carmustine, streptozocin, dacarbazine, cis-platinum, carboplatin, altretamine, methotrexate, 5-fluoruracil, floxuridine, 5-fluorodeoxyuridine, capecitabine, fludarabine, cytosine arabinoside, 6-mercaptopurine, 6-thioguanine, gemcitabine, cladribine, deoxycoformycin, pentostatin, doxorubicin, daunorubicin, idarubicin, valrubicin, mitoxantrone, dactinomycin, mithramycin, plicamycin, mitomycin C, bleomycin, procarbazine, paclitaxel, docetaxel, vinblastine, vincristine, vinorelbine, topotecan, irinotecan, etoposide, teniposide, razoxin, marimastat, COL-3, neovastat, BMS-275291, thalidomide, squalamine, endostatin, SU5416, SU6668, interferon-alpha, EMD121974, interleukin-12, IM862, angiostatin, vitaxin, tamoxifen, toremifene, raloxifene, droloxifene, iodoxyfene, anastrozole, letrozole, exemestane, flutamide, nilutamide, bicalutamide, sprironolactone, cyproterone acetate, finasteride, cimitidine, trastuzumab, rituximab, denileukin diftitox, interferon and interleukin-2 and levamisole in conjunction with 5-fluorouracil. 67. The composition of claim 66 wherein the further anti-cancer therapeutic agent is irinotecan. 68. The composition of claim 66 wherein the further anti-cancer therapeutic agent is docetaxel. 69. The composition of claim 66 wherein the further anti-cancer therapeutic agent is paclitaxel. 70. The composition of claim 66 wherein the further anti-cancer therapeutic agent is cyclophosphamide. 71. The composition of claim 66 wherein the further anti-cancer therapeutic agent is tamoxifen. 72. The composition of claim 66 wherein the further anti-cancer therapeutic agent is anastrazole. 73. A method for treating cancer in a human subject, which cancer is mediated by elevated expression or activity of Insulin-like Growth Factor Receptor 1, comprising administering, to the subject, a therapeutically effective dosage of the monoclonal antibody of claim 59. 74. The method of claim 73 wherein the cancer is colorectal cancer. 75. The method of claim 74 wherein the light chain immunoglobulin variable region is linked to a kappa immunoglobulin constant region; wherein the heavy chain immunoglobulin variable region is linked to a gamma-1 immunoglobulin constant region; wherein the antibody is in a pharmaceutical composition comprising a pharmaceutically acceptable carrier comprising water, buffer and a sugar; and wherein the antibody is administered to the subject parenterally. 76. The method of claim 74 wherein the subject is administered said monoclonal antibody in association with one or more anti-cancer therapeutic agents selected from the group consisting of mechlorethamine, cyclophosphamide, ifosfamide, phenylalanine mustard, melphalen, chlorambucol, uracil mustard, estramustine, thiotepa, busulfan, lomustine, carmustine, streptozocin, dacarbazine, cis-platinum, carboplatin, altretamine, methotrexate, 5-fluoruracil, floxuridine, 5-fluorodeoxyuridine, capecitabine, fludarabine, cytosine arabinoside, 6-mercaptopurine , 6-thioguanine, gemcitabine, cladribine, deoxycoformycin, pentostatin, doxorubicin, daunorubicin, idarubicin, valrubicin, mitoxantrone, dactinomycin, mithramycin, plicamycin, mitomycin C, bleomycin, procarbazine, paclitaxel, docetaxel, vinblastine, vincristine, vinorelbine, topotecan, irinotecan, etoposide, teniposide, razoxin, marimastat, COL-3, neovastat, BMS-275291, thalidomide, squalamine, endostatin, SU5416, SU6668, interferon-alpha, EMD121974, interleukin-12,1M862, angiostatin, vitaxin, tamoxifen, toremifene, raloxifene, droloxifene, iodoxyfene, anastrozole, letrozole, exemestane, flutamide, nilutamide, bicalutamide, sprironolactone, cyproterone acetate, finasteride, cimitidine, trastuzumab, rituximab, denileukin diftitox, interferon and interleukin-2 and levamisole in conjunction with 5-fluorouracil. 77. The method of claim 76 wherein the anti-cancer therapeutic agent is cyclophosphamide; wherein the light chain immunoglobulin variable region is linked to a kappa immunoglobulin constant region; wherein the heavy chain immunoglobulin variable region is linked to a gamma-1 immunoglobulin constant region; wherein the antibody is in a pharmaceutical composition comprising a pharmaceutically acceptable carrier comprising water, buffer and a sugar; and wherein the monoclonal antibody is administered to the subject parenterally. 78. The method of claim 76 wherein the anti-cancer therapeutic agent is paclitaxel; wherein the light chain immunoglobulin variable region is linked to a kappa immunoglobulin constant region; wherein the heavy chain immunoglobulin variable region is linked to a gamma-1 immunoglobulin constant region; wherein the antibody is in a pharmaceutical composition comprising a pharmaceutically acceptable carrier comprising water, buffer and a sugar; and wherein the monoclonal antibody is administered to the subject parenterally. 79. The method of claim 76 wherein the anti-cancer therapeutic agent is docetaxel; wherein the light chain immunoglobulin variable region is linked to a kappa immunoglobulin constant region; wherein the heavy chain immunoglobulin variable region is linked to a gamma-1 immunoglobulin constant region; wherein the antibody is in a pharmaceutical composition comprising a pharmaceutically acceptable carrier comprising water, buffer and a sugar; and wherein the monoclonal antibody is administered to the subject parenterally. 80. The method of claim 76 wherein the anti-cancer therapeutic agent is irinotecan; wherein the light chain immunoglobulin variable region is linked to a kappa immunoglobulin constant region; wherein the heavy chain immunoglobulin variable region is linked to a gamma-1 immunoglobulin constant region; wherein the antibody is in a pharmaceutical composition comprising a pharmaceutically acceptable carrier comprising water, buffer and a sugar; and wherein the monoclonal antibody is administered to the subject parenterally. 81. The method of claim 76 wherein the anti-cancer therapeutic agent is anastrazole; wherein the light chain immunoglobulin variable region is linked to a kappa immunoglobulin constant region; wherein the heavy chain immunoglobulin variable region is linked to a gamma-1 immunoglobulin constant region; wherein the antibody is in a pharmaceutical composition comprising a pharmaceutically acceptable carrier comprising water, buffer and a sugar; and wherein the monoclonal antibody is administered to the subject parenterally. 82. The method of claim 76 wherein the anti-cancer therapeutic agent is tamoxifen; wherein the light chain immunoglobulin variable region is linked to a kappa immunoglobulin constant region; wherein the heavy chain immunoglobulin variable region is linked to a gamma-1 immunoglobulin constant region; wherein the antibody is in a pharmaceutical composition comprising a pharmaceutically acceptable carrier comprising water, buffer and a sugar; and wherein the monoclonal antibody is administered to the subject parenterally. 83. A complex comprising the antibody or fragment of claim 1 bound to IGFR1. 84. The pharmaceutical composition of claim 63 wherein the light chain immunoglobulin variable region is linked to a kappa immunoglobulin constant region and the heavy chain immunoglobulin variable region is linked to a gamma-1 immunoglobulin constant region. 85. The pharmaceutical composition of claim 84 in a hypodermic needle. 86. The antibody of claim 61 which is a bispecific antibody. 87. The method of claim 74 wherein the patient also suffers from inappropriate microvascular proliferation. 88. The composition of claim 64 wherein the antibody is in a pharmaceutical composition comprising a pharmaceutically acceptable carrier comprising water, buffer and a sugar; and wherein the further anti-cancer therapeutic agent is formulated in a separate composition. 89. The composition of claim 65 wherein the antibody is in a pharmaceutical composition comprising a pharmaceutically acceptable carrier comprising water, buffer and a sugar; and wherein the further anti-cancer therapeutic agent is formulated in a separate composition. 90. The composition of claim 66 wherein the antibody is in a pharmaceutical composition comprising a pharmaceutically acceptable carrier comprising water, buffer and a sugar; and wherein the further anti-cancer therapeutic agent is formulated in a separate composition. 91. The composition of claim 67 wherein the antibody is in a pharmaceutical composition comprising a pharmaceutically acceptable carrier comprising water, buffer and a sugar; and wherein the irinotecan is formulated in a separate composition. 92. The composition of claim 68 wherein the antibody is in a pharmaceutical composition comprising a pharmaceutically acceptable carrier comprising water, buffer and a sugar; and wherein the docetaxel is formulated in a separate composition. 93. The composition of claim 69 wherein the antibody is in a pharmaceutical composition comprising a pharmaceutically acceptable carrier comprising water, buffer and a sugar; and wherein the paclitaxel is formulated in a separate composition. 94. The composition of claim 70 wherein the antibody is in a pharmaceutical composition comprising a pharmaceutically acceptable carrier comprising water, buffer and a sugar; and wherein the cyclophosphamide is formulated in a separate composition. 95. The composition of claim 71 wherein the antibody is in a pharmaceutical composition comprising a pharmaceutically acceptable carrier comprising water, buffer and a sugar; and wherein the tamoxifen is formulated in a separate composition. 96. The composition of claim 72 wherein the antibody is in a pharmaceutical composition comprising a pharmaceutically acceptable carrier comprising water, buffer and a sugar; and wherein the anastrazole is formulated in a separate composition. 97. The method of claim 75 wherein the antibody is administered to the subject intravenously. 98. The method of claim 73 wherein the antibody is formulated in a pharmaceutical composition comprising a pharmaceutically acceptable carrier comprising water, sugar and buffer; wherein the antibody in the pharmaceutical composition is administered to the subject parenterally; wherein the light chain immunoglobulin variable region is linked to a kappa immunoglobulin constant region; and wherein the heavy chain immunoglobulin variable region is linked to a gamma-1 immunoglobulin constant region. 99. The method of claim 73 wherein the subject also undergoes surgical tumorectomy or anti-cancer radiation therapy.

Details for Patent 7,847,068

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	RITUXAN	rituximab	Injection	103705	11/26/1997		2022-05-24
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