Neutralizing human anti-IGFR antibody

• US 7,217,796 B2
• Filed: 05/22/2003
• Issued: 05/15/2007
• Est. Priority Date: 05/24/2002
• Status: Expired due to Fees

• Current Assignee: Merck Sharp & Dohme Corporation (Merck & Co., Inc.)
• Original Assignee: Schering Corporation (Merck & Co., Inc.)
• Inventors: Greenberg, Robert, Srinivasan, Mohan, Wang, Yan, Brams, Peter, Williams, Denise, Presta, Leonard, Hailey, Judith, Feingersh, Diane, Pachter, Jonathan A.
• Primary Examiner(s): Huff; Sheela
• Assistant Examiner(s): Tungaturthi; Parithosh K.
• Application Number:
  US10/443,466
• Publication Number:
  US 20040018191A1
• Time in Patent Office: 1,454 Days
• Field of Search: 530/387.3, 530/350, 530/380, 530/385, 530/387.1, 530/387.7, 530/388.1, 530/388.15, 530/388.24, 424/134.1, 424/135.1, 424/141.1, 424/142.1, 424/155.1, 424/174.1, 435/7.9, 435/188, 435/320.1
• US Class Current: 530/387.3
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/12 Antidiarrhoeals
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07K 16/2863 against receptors for growth factors, growth regulators
• CPC Class Codes: C07K 16/2869 against hormone receptors for antibodies against neuromediator receptors C07K16/286
• CPC Class Codes: C07K 2317/21 from primates, e.g. man
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/56 variable (Fv) region, i.e. VH and/or VL
• CPC Class Codes: C07K 2317/565 Complementarity determining region [CDR]
• CPC Class Codes: C07K 2317/73 Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
• CPC Class Codes: C07K 2317/76 Antagonist effect on antigen, e.g. neutralization or inhibition of binding

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.

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.

3. A pharmaceutical composition comprising an antibody of claim 1 and a pharmaceutically acceptable carrier.

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_d of about 8.6×

10<sup>−

10</sup> or a lower number;

(b) Has an off rate (K_off) for IGFR1 of about 6.50×

10<sup>−

5</sup> or a lower number;

(c) Has an on rate (K_on) for IGFR1 of about 0.7×

10⁵ 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.

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.

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.

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.

14. A pharmaceutical composition comprising an antibody of claim 2 and a pharmaceutically acceptable carrier.

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.

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.

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.

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.

79. The method of claim 5 wherein the subject is human.

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.

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.

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.

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.

54. An isolated antibody comprising a heavy chain encoded by a polynucleotide in plasmid 15H12/19D12 HCA (γ

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 (κ

) 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 (γ

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 (κ

) 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.

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.

80. The method of claim 64 wherein the subject is human.

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.

81. The method of claim 72 wherein the subject is human.