Methods of treatment using CTLA-4 antibodies

1. A method for inducing or enhancing a memory immune response to an antigen in a human patient, which comprises administering to the patient who has developed a primary immune response to the antigen an anti-CTLA-4 antibody such that plasma concentration of the anti-CTLA-4 antibody is maintained above detectable levels for greater than four months, wherein the anti-CTLA-4 antibody comprises a heavy chain variable region that comprises CDR1, CDR2, and CDR3 domains; and a light chain variable region that comprises CDR1, CDR2, and CDR3 domains, wherein the heavy chain variable region CDR1 comprises amino acids having the sequence set forth in SEQ ID NO:3; the heavy chain variable region CDR2 comprises amino acids having the sequence set forth in SEQ ID NO:4; the heavy chain variable region CDR3 comprises amino acids having the sequence set forth in SEQ ID NO:5; the light chain variable region CDR1 comprises amino acids having the sequence set forth in SEQ ID NO:6; the light chain variable region CDR2 comprises amino acids having the sequence set forth in SEQ ID NO:7; and the light chain variable region CDR3 comprises amino acids having the sequence set forth in SEQ ID NO:8.

2. The method of claim 1 , wherein the anti-CTLA-4 antibody is administered multiple times.

3. The method of claim 1 , wherein the anti-CTLA-4 antibody is administered in an amount and at intervals such that the plasma concentration of anti-CTLA-4 antibody in the patient is at least 2 μg/ml for greater than four months.

4. The method of claim 1 , wherein the anti-CTLA-4 antibody is administered in an amount and at intervals such that the plasma concentration of anti-CTLA-4 antibody in the patient is at least 5 μg/ml for greater than four months.

5. The method of claim 1 , wherein the anti-CTLA-4 antibody is administered in an amount and at intervals such that the plasma concentration of anti-CTLA-4 antibody in the patient is at least 10 μg/ml for greater than four months.

6. The method of claim 1 , wherein the antigen is a cancer antigen and the patient has been previously treated with surgery to resect a tumor.

7. The method of claim 1 , wherein the antigen is a cancer antigen and the patient has been previously treated with chemotherapy.

8. The method of claim 1 , wherein the antigen is a cancer antigen and the patient has been previously treated with radiation.

9. The method of claim 6 , wherein the cancer antigen is a melanoma antigen.

10. The method of claim 7 , wherein the cancer antigen is a melanoma antigen.

11. The method of claim 8 , wherein the cancer antigen is a melanoma antigen.

12. The method of claim 1 , wherein the patient is immunocompromised.

13. The method of claim 1 , wherein the anti-CTLA-4 antibody is administered in a single dose.

14. The method of claim 1 , wherein administration of the anti-CTLA-4 antibody does not result in detrimental side-effects.

15. A method for inducing or enhancing a memory immune response to an antigen in a human patient, which comprises administering to the patient an anti-CTLA-4 antibody such that plasma concentration of the anti-CTLA-4 antibody is maintained above detectable levels for greater than four months, wherein the anti-CTLA-4 antibody comprises a heavy chain variable region that comprises CDR1, CDR2, and CDR3 domains; and a light chain variable region that comprises CDR1, CDR2, and CDR3 domains, wherein the heavy chain variable region CDR1 comprises amino acids having the sequence set forth in SEQ ID NO:3; the heavy chain variable region CDR2 comprises amino acids having the sequence set forth in SEQ ID NO:4; the heavy chain variable region CDR3 comprises amino acids having the sequence set forth in SEQ ID NO:5; the light chain variable region CDR1 comprises amino acids having the sequence set forth in SEQ ID NO:6; the light chain variable region CDR2 comprises amino acids having the sequence set forth in SEQ ID NO:7; and the light chain variable region CDR3 comprises amino acids having the sequence set forth in SEQ ID NO:8.

16. The method of claim 15 , wherein the anti-CTLA-4 antibody is administered multiple times.

17. The method of claim 15 , wherein the anti-CTLA-4 antibody is administered in an amount and at intervals such that the plasma concentration of anti-CTLA-4 antibody in the patient is at least 2 μg/ml for greater than four months.

18. The method of claim 15 , wherein the anti-CTLA-4 antibody is administered in an amount and at intervals such that the plasma concentration of anti-CTLA-4 antibody in the patient is at least 5 μg/ml for greater than four months.

19. The method of claim 15 , wherein the anti-CTLA-4 antibody is administered in an amount and at intervals such that the plasma concentration of anti-CTLA-4 antibody in the patient is at least 10 μg/ml for greater than four months.

20. The method of claim 15 , wherein the antigen is a cancer antigen and the patient has been previously treated with surgery to resect a tumor.

21. The method of claim 15 , wherein the antigen is a cancer antigen and the patient has been previously treated with chemotherapy.

22. The method of claim 15 , wherein the antigen is a cancer antigen and the patient has been previously treated with radiation.

23. The method of claim 20 , wherein the cancer antigen is a melanoma antigen.

24. The method of claim 21 , wherein the cancer antigen is a melanoma antigen.

25. The method of claim 22 , wherein the cancer antigen is a melanoma antigen.

26. The method of claim 15 , wherein the patient is immunocompromised.

27. The method of claim 15 , wherein the anti-CTLA-4 antibody is administered in a single dose.

28. The method of claim 15 , wherein administration of the anti-CTLA-4 antibody does not result in detrimental side-effects.

29. A method for treating cancer in a human patient, which comprises administering to the patient an anti-CTLA-4 antibody such that plasma concentration of the anti-CTLA-4 antibody is maintained above detectable levels for greater than four months, wherein the anti-CTLA-4 antibody comprises a heavy chain variable region that comprises CDR1, CDR2, and CDR3 domains; and a light chain variable region that comprises CDR1, CDR2, and CDR3 domains, wherein the heavy chain variable region CDR1 comprises amino acids having the sequence set forth in SEQ ID NO:3; the heavy chain variable region CDR2 comprises amino acids having the sequence set forth in SEQ ID NO:4; the heavy chain variable region CDR3 comprises amino acids having the sequence set forth in SEQ ID NO:5; the light chain variable region CDR1 comprises amino acids having the sequence set forth in SEQ ID NO:6; the light chain variable region CDR2 comprises amino acids having the sequence set forth in SEQ ID NO:7; and the light chain variable region CDR3 comprises amino acids having the sequence set forth in SEQ ID NO:8.

30. The method of claim 29 , wherein the anti-CTLA-4 antibody is administered multiple times.

31. The method of claim 29 , wherein the anti-CTLA-4 antibody is administered in an amount and at intervals such that the plasma concentration of anti-CTLA-4 antibody in the patient is at least 2 μg/ml for greater than four months.

32. The method of claim 29 , wherein the anti-CTLA-4 antibody is administered in an amount and at intervals such that the plasma concentration of anti-CTLA-4 antibody in the patient is at least 5 μg/ml for greater than four months.

33. The method of claim 29 , wherein the anti-CTLA-4 antibody is administered in an amount and at intervals such that the plasma concentration of anti-CTLA-4 antibody in the patient is at least 10 μg/ml for greater than four months.

34. The method of claim 29 , wherein the patient is immunocompromised.

35. The method of claim 29 , wherein the anti-CTLA-4 antibody is administered in a single dose.

36. The method of claim 29 , wherein administration of the anti-CTLA-4 antibody does not result in detrimental side-effects.

37. The method of claim 29 , wherein the cancer is melanoma.

38. The method of claim 29 , wherein the patient has been previously treated with surgery to resect a tumor.

39. The method of claim 29 , wherein the patient has been previously treated with chemotherapy.

40. The method of claim 29 , wherein the patient has been previously treated with radiation.

41. The method of claim 1 , wherein the anti-CTLA-4 antibody comprises a heavy chain variable region comprising amino acids comprising the sequence set forth in SEQ ID NO:9; and a light chain variable region comprising amino acids comprising the sequence set forth in SEQ ID NO:10.

42. The method of claim 15 , wherein the anti-CTLA-4 antibody comprises a heavy chain variable region comprising amino acids comprising the sequence set forth in SEQ ID NO:9; and a light chain variable region comprising amino acids comprising the sequence set forth in SEQ ID NO:10.

43. The method of claim 29 , wherein the anti-CTLA-4 antibody comprises a heavy chain variable region comprising amino acids comprising the sequence set forth in SEQ ID NO:9; and a light chain variable region comprising amino acids comprising the sequence set forth in SEQ ID NO:10.

44. A method for inducing or enhancing a memory immune response to an antigen in a human patient, which comprises administering to the patient who has developed a primary immune response to the antigen an anti-CTLA-4 antibody such that plasma concentration of the anti-CTLA-4 antibody is maintained above detectable levels for greater than four months, wherein the anti-CTLA-4 antibody comprises a heavy chain variable region that comprises CDR1, CDR2, and CDR3 domains; and a light chain variable region that comprises CDR1, CDR2, and CDR3 domains, wherein the heavy chain variable region CDR3 comprises amino acids having the sequence set forth in SEQ ID NO:5 and the light chain variable region CDR3 comprises amino acids having the sequence set forth in SEQ ID NO:8.

45. The method of claim 44 , wherein the heavy chain variable region CDR2 of the anti-CTLA-4 antibody comprises amino acids having the sequence set forth in SEQ ID NO:4 and the light chain variable region CDR2 of the anti-CTLA-4 antibody comprises amino acids having the sequence set forth in SEQ ID NO:7.

46. The method of claim 44 or 45 , wherein the heavy chain variable region CDR1 of the anti-CTLA-4 antibody comprises amino acids having the sequence set forth in SEQ ID NO:3 and the light chain variable region CDR1 of the anti-CTLA-4 antibody comprises amino acids having the sequence set forth in SEQ ID NO:6.

47. A method for treating cancer in a human patient, which comprises administering to the patient an anti-CTLA-4 antibody such that plasma concentration of the anti-CTLA-4 antibody is maintained above detectable levels for greater than four months, wherein the anti-CTLA-4 antibody comprises a heavy chain variable region that comprises CDR1, CDR2, and CDR3 domains; and a light chain variable region that comprises CDR1, CDR2, and CDR3 domains, wherein the heavy chain variable region CDR3 comprises amino acids having the sequence set forth in SEQ ID NO:5 and the light chain variable region CDR3 comprises amino acids having the sequence set forth in SEQ ID NO:8.

48. The method of claim 47 , wherein the heavy chain variable region CDR2 of the anti-CTLA-4 antibody comprises amino acids having the sequence set forth in SEQ ID NO:4 and the light chain variable region CDR2 of the anti-CTLA-4 antibody comprises amino acids having the sequence set forth in SEQ ID NO:7.

49. The method of claim 47 or 48 , wherein the heavy chain variable region CDR1 of the anti-CTLA-4 antibody comprises amino acids having the sequence set forth in SEQ ID NO:3 and the light chain variable region CDR1 of the anti-CTLA-4 antibody comprises amino acids having the sequence set forth in SEQ ID NO:6.

50. The method of claim 44 , wherein the anti-CTLA-4 antibody comprises a heavy chain variable region comprising amino acids comprising the sequence set forth in SEQ ID NO:9; and a light chain variable region comprising amino acids comprising the sequence set forth in SEQ ID NO:10.

51. The method of claim 47 , wherein the anti-CTLA-4 antibody comprises a heavy chain variable region comprising amino acids comprising the sequence set forth in SEQ ID NO:9; and a light chain variable region comprising amino acids comprising the sequence set forth in SEQ ID NO:10.

52. The method of claim 44 , wherein the anti-CTLA-4 antibody is administered multiple times.

53. The method of claim 44 , wherein the anti-CTLA-4 antibody is administered in an amount and at intervals such that the plasma concentration of the anti-CTLA-4 antibody in the patient is at least 2 μg/ml for greater than four months.

54. The method of claim 44 , wherein the anti-CTLA-4 antibody is administered in an amount and at intervals such that the plasma concentration of anti-CTLA-4 antibody in the patient is at least 5 μg/ml for greater than four months.

55. The method of claim 44 , wherein the anti-CTLA-4 antibody is administered in an amount and at intervals such that the plasma concentration of anti-CTLA-4 antibody in the patient is at least 10 μg/ml for greater than four months.

56. The method of claim 44 , wherein the antigen is a cancer antigen and the patient has been previously treated with surgery to resect a tumor.

57. The method of claim 44 , wherein the antigen is a cancer antigen and the patient has been previously treated with chemotherapy.

58. The method of claim 44 , wherein the antigen is a cancer antigen and the patient has been previously treated with radiation.

59. The method of claim 56 , wherein the cancer antigen is a melanoma antigen.

60. The method of claim 57 , wherein the cancer antigen is a melanoma antigen.

61. The method of claim 58 , wherein the cancer antigen is a melanoma antigen.

62. The method of claim 54 , wherein the patient is immunocompromised.

63. The method of claim 44 , wherein the anti-CTLA-4 antibody is administered in a single dose.

64. The method of claim 44 , wherein administration of the anti-CTLA-4 antibody does not result in detrimental side-effects.

65. The method of claim 47 , wherein the anti-CTLA-4 antibody is administered multiple times.

66. The method of claim 47 , wherein the anti-CTLA-4 antibody is administered in an amount and at intervals such that the plasma concentration of anti-CTLA-4 antibody in the patient is at least 2 μg/ml for greater than four months.

67. The method of claim 47 , wherein the anti-CTLA-4 antibody is administered in an amount and at intervals such that the plasma concentration of anti-CTLA-4 antibody in the patient is at least 5 μg/ml for greater than four months.

68. The method of claim 47 , wherein the anti-CTLA-4 antibody is administered in an amount and at intervals such that the plasma concentration of anti-CTLA-4 antibody in the patient is at least 10 μg/ml for greater than four months.

69. The method of claim 47 , wherein the patient is immunocompromised.

70. The method of claim 47 , wherein the anti-CTLA-4 antibody is administered in a single dose.

71. The method of claim 47 , wherein administration of the anti-CTLA-4 antibody does not result in detrimental side-effects.

72. The method of claim 47 , wherein the cancer is melanoma.

73. The method of claim 47 , wherein the patient has been previously treated with surgery to resect a tumor.

74. The method of claim 47 , wherein the patient has been previously treated with chemotherapy.

75. The method of claim 47 , wherein the patient has been previously treated with radiation.