Claims for Patent: 7,217,796

Summary for Patent: 7,217,796

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. (Maplewood, NJ), 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:	10/443,466
Patent Claims:	1. An isolated antibody that binds to IGFR1 comprising a light chain amino acid sequence which comprises CDR-L1 defined by SEQ ID NO: 8, CDR-L2 defined by SEQ ID NO: 9 and CDR-L3 defined by SEQ ID NO: 10; and a heavy chain amino acid sequence which comprises CDR-H1 defined by SEQ ID NO: 14 or SEQ ID NO: 17, CDR-H2 defined by SEQ ID NO: 15 and CDR-H3 defined by SEQ ID NO: 16. 2. An isolated antibody that binds to IGFR1 comprising a member selected from the group consisting of: (a) a light chain variable region comprising amino acids 20 128 of SEQ ID NO: 2 and a heavy chain variable region comprising amino acids 20 137 of SEQ ID NO: 4; (b) a light chain variable region comprising amino acids 20 128 of SEQ ID NO: 72 and a heavy chain variable region comprising amino acids 20 137 of SEQ ID NO; 45; (c) a light chain variable region comprising amino acids 20 128 of SEQ ID NO: 74 and a heavy chain variable region comprising amino acids 20 137 of SEQ ID NO: 45; (d) a light chain variable region comprising amino acids 20 128 of SEQ ID NO: 76 and a heavy chain variable region comprising amino acids 20 137 of SEQ ID NO: 45; (e) a light chain variable region comprising amino acids 20 128 of SEQ ID NO: 78 and a heavy chain variable region comprising amino acids 20 137 of SEQ ID NO: 45; (f) a light chain variable region comprising amino acids 20 128 of SEQ ID NO: 72 and a heavy chain variable region comprising amino acids 20 137 of SEQ ID NO: 112; (g) a light chain variable region comprising amino acids 20 128 of SEQ ID NO: 74 and a heavy chain variable region comprising amino acids 20 137 of SEQ ID NO: 112; (h) a light chain variable region comprising amino acids 20 128 of SEQ ID NO: 76 and a heavy chain variable region comprising amino acids 20 137 of SEQ ID NO; 112; and (i) a light chain variable region comprising amino acids 20 128 of SEQ ID NO: 78 and a heavy chain variable region comprising amine acids 20 137 of SEQ ID NO: 112. 3. A pharmaceutical composition comprising an antibody of claim 1 and a pharmaceutically acceptable carrier. 4. A method for treating a medical condition in a subject, which medical condition 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 that binds to IGFR1 comprising a light chain amino acid sequence which comprises CDR-L1 defined by SEQ ID NO: 8, CDR-L2 defined by SEQ ID No: 9 and CDR-L3 defined by SEQ ID NO: 10; and a heavy chain amino acid sequence which comprises CDR-H1 defined by SEQ ID NO: 14 or SEQ ID NO: 17, CDR-H2 defined by SEQ ID NO: 15 and CDR-H3 defined by SEQ ID NO: 16. 5. A method for treating a medical condition in a subject wherein the medical condition is selected from the group consisting of acromegaly, bladder cancer, Wilm's cancer, ovarian cancer, pancreatic cancer, benign prostatic hyperplasia, breast cancer, prostate cancer, bone cancer, lung cancer, colorectal cancer, cervical cancer, synovial sarcoma, diarrhea associated with metastatic carcinoid, vasoactive intestinal peptide secreting tumors, gigantism, psoriasis, atherosclerosis, smooth muscle restenosis of blood vessels and inappropriate microvascular proliferation; comprising administering, to the subject, a therapeutically effective dosage of an isolated antibody that binds to IGFR1 comprising a light chain amino acid sequence which comprises CDR-L1 defined by SEQ ID NO: 8, CDR-L2 defined by SEQ ID NO: 9 and CDR-L3 defined by SEQ ID NO: 10, and a heavy chain amino acid sequence which comprises CDR-H1 defined by SEQ ID NO: 14 or SEQ ID NO: 17, CDR-H2 defined by SEQ ID NO: 15 and CDR-H3 defined by SEQ ID NO: 16. 6. The method of claim 5 wherein the antibody is administered to the subject by a parenteral route. 7. The method of claim 5 wherein the antibody is administered to the subject in association with an additional anti-cancer therapeutic agent or anti-cancer therapeutic procedure. 8. The method of claim 7 wherein the anti-cancer, therapeutic procedure is radiation therapy or surgical tumorectomy. 9. An isolated antibody of claim 1 which binds to human IGFR1 comprising a property selected from the group consisting of: (a) Binds to IGFR1 with a K.sub.d of about 8.6.times.10.sup.-10 or a lower number; (b) Has an off rate (K.sub.off) for IGFR1 of about 6.50.times.10.sup.-5 or a lower number; (c) Has an on rate (K.sub.on) for IGFR1 of about 0.7.times.10.sup.5 or a higher number; (d) Competes with IGF1 for binding to IGFR1; (e) Inhibits autophosphorylation of IGFR1; and (f) Inhibits anchorage-independent growth of a cell expressing IGFR1. 10. An isolated antibody of claim 9 comprising all of said properties. 11. An isolated antibody comprising a light chain variable region comprising amino acids 20 128 of SEQ ID NO: 78 linked to a kappa light chain constant region and a heavy chain variable region comprising amino acids 20 137 of SEQ ID NO: 45 linked to a gamma 1 heavy chain constant region. 12. An isolated antibody comprising: (a) a light chain amino acid sequence which comprises CDR-L1 defined by SEQ ID NO: 8, CDR-L2 defined by SEQ ID NO: 9 and CDR-L3 defined by SEQ ID NO: 10, linked to a kappa light chain constant region; and (b) a heavy chain amino acid sequence which comprises CDR-H1 defined by SEQ ID NO: 14 or SEQ ID NO: 17, CDR-H2 defined by SEQ ID NO: 15 and CDR-H3 defined by SEQ ID NO: 16, linked to a gamma 1 heavy chain constant region. 13. A pharmaceutical composition comprising an isolated antibody comprising a light chain variable region comprising amino acids 20 128 of SEQ ID NO: 78 linked to a kappa light chain constant region and amino acids 20 137 of SEQ ID NO: 45 linked to a gamma 1 heavy chain constant region and a pharmaceutically acceptable carrier. 14. A pharmaceutical composition comprising an antibody of claim 2 and a pharmaceutically acceptable carrier. 15. An antibody of claim 1 which is monoclonal. 16. An antibody of claim 1 which is polyclonal. 17. An antibody of claim 1 which is recombinant. 18. An antibody of claim 2 which is monoclonal. 19. An antibody of claim 2 which is polyclonal. 20. An antibody of claim 2 which is recombinant. 21. An antibody of claim 11 which is monoclonal. 22. An antibody of claim 11 which is polyclonal. 23. An antibody of claim 11 which is recombinant. 24. A composition comprising an isolated antibody of claim 1 and an anti-cancer therapeutic agent. 25. The composition of claim 24 wherein the 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, levamisole in conjunction with 5-fluorouracil, interferon and interleukin-2. 26. The composition of claim 25 wherein the anti-cancer therapeutic agent is paclitaxel. 27. The composition of claim 25 wherein the anti-cancer therapeutic agent is docetaxel. 28. The composition of claim 25 wherein the anti-cancer therapeutic agent is vincristine. 29. The composition of claim 25 wherein the anti-cancer therapeutic agent is vinblastine. 30. The composition of claim 25 wherein the anti-cancer therapeutic agent is doxorubicin. 31. The composition of claim 25 wherein the anti-cancer therapeutic agent is daunorubicin. 32. The composition of claim 25 wherein the anti-cancer therapeutic agent is tamoxifen. 33. A pharmaceutical composition comprising the composition of claim 24 and a pharmaceutically acceptable carrier. 34. A composition comprising an isolated antibody of claim 2 and an anti-cancer therapeutic agent. 35. The composition of claim 34 wherein the 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, levamisole in conjunction with 5-fluorouracil, interferon and interleukin-2. 36. The composition of claim 35 wherein the anti-cancer therapeutic agent is paclitaxel. 37. The composition of claim 35 wherein the anti-cancer therapeutic agent is docetaxel. 38. The composition of claim 35 wherein the anti-cancer therapeutic agent is vincristine. 39. The composition of claim 35 wherein the anti-cancer therapeutic agent is vinblastine. 40. The composition of claim 35 wherein the anti-cancer therapeutic agent is doxorubicin. 41. The composition of claim 35 wherein the anti-cancer therapeutic agent is daunorubicin. 42. The composition of claim 35 wherein the anti-cancer therapeutic agent is tamoxifen. 43. A pharmaceutical composition comprising the composition of claim 34 and a pharmaceutically acceptable carrier. 44. A composition comprising an isolated antibody of claim 11 and an anti-cancer therapeutic agent. 45. The composition of claim 44 wherein the 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, levamisole in conjunction with 5-fluorouracil, interferon and interleukin-2. 46. The composition of claim 45 wherein the anti-cancer therapeutic agent is paclitaxel. 47. The composition of claim 45 wherein the anti-cancer therapeutic agent is docetaxel. 48. The composition of claim 45 wherein the anti-cancer therapeutic agent is vincristine. 49. The composition of claim 45 wherein the anti-cancer therapeutic agent is vinblastine. 50. The composition of claim 45 wherein the anti-cancer therapeutic agent is doxorubicin. 51. The composition of claim 45 wherein the anti-cancer therapeutic agent is daunorubicin. 52. The composition of claim 45 wherein the anti-cancer therapeutic agent is tamoxifen. 53. A pharmaceutical composition comprising the composition of claim 44 and a pharmaceutically acceptable carrier. 54. An isolated antibody comprising a heavy chain encoded by a polynucleotide in plasmid 15H12/19D12 HCA (.gamma.4) which is deposited at the American Type Culture Collection (ATCC) under number PTA-5214; and a light chain encoded by a polynucleotide in plasmid 15H12/19D12 LCF (.kappa.) which is deposited at the American Type Culture Collection (ATCC) under number PTA-5220. 55. A pharmaceutical composition comprising an antibody of claim 54 and a pharmaceutically acceptable carrier. 56. An isolated antibody comprising a heavy chain encoded by a polynucleotide in plasmid 15H12/19D12 HCA (.gamma.1) which is deposited at the American Type culture Collection (ATCC) under number PTA-5216; and a light chain encoded by a polynucleotide in plasmid 15H12/19D12 LCF (.kappa.) which is deposited at the American Type Culture Collection (ATCC) under number PTA-5220. 57. A pharmaceutical composition comprising an antibody of claim 56 and a pharmaceutically acceptable carrier. 58. An isolated antibody, that binds to IGFR1, comprising a light chain amino acid sequence which comprises CDR-L1 defined by SEQ ID NO: 31, CDR-L2 defined by SEQ ID NO: 32 and CDR-L3 defined by SEQ ID NO: 33; and a heavy chain amino acid sequence which comprises CDR-H1 defined by SEQ ID NO; 37 or SEQ ID NO: 70, CDR-H2 defined by SEQ ID NO: 38 and CDR-H3 defined by SEQ ID NO: 39. 59. An isolated antibody, that binds to IGFR1 comprising a light chain variable region comprising amino acids 21 130 of SEQ ID NO: 25 and a heavy chain variable region comprising amino acids 20 140 of SEQ ID NO: 27. 60. The method of claim 5 wherein the condition is colorectal cancer. 61. The method of claim 5 wherein the condition is breast cancer. 62. The method of claim 5 wherein the condition is Wilm's cancer. 63. A method for treating a medical condition in a subject, which medical condition 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 that binds to IGFR1 comprising a member selected from the group consisting of: (a) a light chain variable region comprising amino acids 20 128 of SEQ ID NO: 2 and a heavy chain variable region comprising amino acids 20 137 of SEQ ID NO: 4; (b) a light chain variable region comprising amino acids 20 128 of SEQ ID NO: 72 and a heavy chain variable region comprising amino acids 20 137 of SEQ ID NO: 45; (c) a light chain variable region comprising amino acids 20 128 of SEQ ID NO: 74 and a heavy chain variable region comprising amino acids 20 137 of SEQ ID NO; 45; (d) a light chain variable region comprising amino acids 20 128 of SEQ ID NO: 76 and a heavy chain variable region comprising amino acids 20 137 of SEQ ID NO: 45; (e) a light chain variable region comprising amino acids 20 128 of SEQ ID NO: 78 and a heavy chain variable region comprising amino acids 20 137 of SEQ ID NO: 45; (f) a light chain variable region comprising amino acids 20 128 of SEQ ID NO: 72 and a heavy chain variable region comprising amino acids 20 137 of SEQ ID NO: 112; (g) a light chain variable region comprising amino acids 20 128 of SEQ ID NO: 74 and a heavy chain variable region comprising amino acids 20 137 of SEQ ID NO: 112; (h) a light chain variable region comprising amino acids 20 128 of SEQ ID NO: 76 and a heavy chain variable region comprising amino acids 20 137 of SEQ ID NO: 112; and (i) a light chain variable region comprising amino acids 20 128 of SEQ ID NO: 78 and a heavy chain variable region comprising amino acids 20 137 of SEQ ID NO: 112. 64. A method of treating a medical condition in a subject wherein the medical condition is selected from the group consisting of acromegaly, bladder cancer, Wilm's cancer, ovarian cancer, pancreatic cancer, benign prostatic hyperplasia, breast cancer, prostate cancer, bone cancer, lung cancer, colorectal cancer, cervical cancer, synovial sarcoma, diarrhea associated with metastatic carcinoid, vasoactive intestinal peptide secreting tumors, gigantism, psoriasis, atherosclerosis, smooth muscle restenosis of blood vessels and inappropriate microvascular proliferation comprising administering, to the subject, a therapeutically effective dosage of an isolated antibody that binds to IGFR1 comprising a member selected from the group consisting of: (a) a light chain variable region comprising amino acids 20 128 of SEQ ID NO: 2 and a heavy chain variable region comprising amino acids 20 137 of SEQ ID NO: 4; (b) a light chain variable region comprising amino acids 20 128 of SEQ ID NO: 72 and a heavy chain variable region comprising amino acids 20 137 of SEQ ID NO: 45; (c) a light chain variable region comprising amino acids 20 128 of SEQ ID NO: 74 and a heavy chain variable region comprising amino acids 20 137 of SEQ ID NO: 45; (d) a light chain variable region comprising amino acids 20 128 of SEQ ID NO: 76 and a heavy chain variable region comprising amino acids 20 137 of SEQ ID NO: 45; (e) a light chain variable region comprising amino acids 20 128 of SEQ ID NO: 78 and a heavy chain variable region comprising amino acids 20 137 of SEQ ID NO: 45; (f) a light chain variable region comprising amino acids 20 128 of SEQ ID NO: 72 and a heavy chain variable region comprising amino acids 20 137 of SEQ ID NO: 112; (g) a light chain variable region comprising amino acids 20 128 of SEQ ID NO: 74 and a heavy chain variable region comprising amino acids 20 137 of SEQ ID NO: 112; (h) a light chain variable region comprising amino acids 20 128 of SEQ ID NO: 76 and a heavy chain variable region comprising amino acids 20 137 of SEQ ID NO: 112; and (i) a light chain variable region comprising amino acids 20 128 of SEQ ID NO: 78 and a heavy chain variable region comprising amino acids 20 137 of SEQ ID NO: 112. 65. The method of claim 64 wherein the antibody is administered to the subject by a parenteral route. 66. The method of claim 64 wherein the antibody is administered to the subject in association with an additional anti-cancer therapeutic agent or anti-cancer therapeutic procedure. 67. The method of claim 66 wherein the anti-cancer, therapeutic procedure is radiation therapy or surgical tumorectomy. 68. The method of claim 64 wherein the condition is colorectal cancer. 69. The method of claim 64 wherein the condition is breast cancer. 70. The method of claim 64 wherein the condition is Wilm's cancer. 71. A method for treating a medical condition in a subject, which medical condition 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 comprising a light chain variable region comprising amino acids 20 128 of SEQ ID NO: 78 linked to a kappa light chain constant region and a heavy chain variable region comprising amino acids 20 137 of SEQ ID NO: 45 linked to a gamma 1 heavy chain constant region. 72. A method of treating a medical condition in a subject wherein the medical condition is selected from the group consisting of acromegaly, bladder Cancer, Wilm's cancer, ovarian cancer, pancreatic cancer, benign prostatic hyperplasia, breast cancer, prostate cancer, bone cancer, lung cancer, colorectal cancer, cervical cancer, synovial sarcoma, diarrhea associated with metastatic carcinoid, vasoactive intestinal peptide secreting tumors, gigantism, psoriasis, atherosclerosis, smooth muscle restenosis of blood vessels and inappropriate microvascular proliferation; comprising administering, to the subject, a therapeutically effective dosage of an isolated antibody comprising a light chain variable region comprising amino acids 20 128 of SEQ ID NO: 78 linked to a kappa light chain constant region and a heavy chain variable region comprising amino acids 20 137 of SEQ ID NO: 45 linked to a gamma 1 heavy chain constant region. 73. The method of claim 72 wherein the antibody is administered to the subject by a parenteral route. 74. The method of claim 72 wherein the antibody is administered to the subject in association with an additional anti-cancer therapeutic agent or anti-cancer therapeutic procedure. 75. The method of claim 74 wherein the anti-cancer, therapeutic procedure is radiation therapy or surgical tumorectomy. 76. The method of claim 72 wherein the cancer is colorectal cancer. 77. The method of claim 72 wherein the cancer is breast cancer. 78. The method of claim 72 wherein the cancer is Wilm's cancer. 79. The method of claim 5 wherein the subject is human. 80. The method of claim 64 wherein the subject is human. 81. The method of claim 72 wherein the subject is human.

Details for Patent 7,217,796

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	RITUXAN	rituximab	Injection	103705	11/26/1997		2022-05-24
Idec Pharmaceuticals Corp.	RITUXAN	rituximab	Injection	103737	02/19/2002		2022-05-24
Eisai, Incorporated	ONTAK	denileukin diftitox	Injection	103767	02/05/1999		2022-05-24