Radioimmunotherapy of lymphoma using anti-CD20 antibodies

• US 5,843,398 A
• Filed: 04/26/1996
• Issued: 12/01/1998
• Est. Priority Date: 09/16/1993
• Status: Expired due to Term

• Current Assignee: GlaxoSmithKline LLC (GlaxoSmithKline PLC), Board of Regents of the University of Michigan (University of Michigan)
• Original Assignee: Coulter Pharmaceutical, Inc. (GlaxoSmithKline PLC), Board of Regents of the University of Michigan (University of Michigan)
• Inventors: Glenn, Stephan D., Kaminski, Mark S., Wahl, Richard L., Butchko, Gregory M.
• Primary Examiner(s): Kight, John
• Assistant Examiner(s): Hartley, Michael G.
• Application Number:
  US08/639,882
• Time in Patent Office: 949 Days
• Field of Search: 424/1.49, 424/1.53, 424/144.1, 424/130.1, 424/179.1, 530/387.7, 530/388.1, 530/391.3
• US Class Current: 424/1.49
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 51/1069 the tumor cell being from blood cells, e.g. the cancer being a myeloma
• CPC Class Codes: C07K 14/52 Cytokines; Lymphokines; Interferons
• CPC Class Codes: C07K 16/22 against growth factors ; against growth regulators
• CPC Class Codes: C07K 16/2887 against CD20
• CPC Class Codes: C07K 2317/73 Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
• CPC Class Codes: C07K 2319/00 Fusion polypeptide
• CPC Class Codes: G01N 33/57426 leukemia

Abstract

Methods for the treatment of lymphoma by administration of a B cell-specific antibody are described. The invention encompasses providing to a patient both unlabeled antibodies and antibodies labeled with a radioisotope. A principal advantage of the method is that tumor responses can be obtained in a radiometric dose range that does not require hematopoietic stem cell replacement as an adjunct therapy.

Claims

1. A method for immunotherapy of B-cell lymphoma, which comprises:

(i) administering to a patient a clearance-rate-determinative amount of an antibody or a Fab, Fab'"'"' or F(ab'"'"')₂ portion thereof trace-labelled with a first radiolabel, which binds to CD20 antigen present on the surface of cells of said B-cell lymphoma;

(ii) determining the clearance rate of the trace-labelled antibody or the Fab, Fab'"'"' or F(ab'"'"')₂ portion thereof of step (i), within the body of the patient;

(iii) administering to the patient an amount of the antibody or the Fab, Fab'"'"' or F(ab'"'"')₂ portion thereof of step (i) in unlabelled form, which binds to CD20 antigen present on the surface of cells of said B-cell lymphoma, said amount effective for blocking non-tumor binding sites for an antibody or a Fab, Fab'"'"' or F(ab'"'"')₂ portion thereof effective for treating B-cell lymphoma, within the body of the patient; and

(iv) administering to the patient a radioimmunotherapeutically effective amount for treating B-cell lymphoma of the antibody or the Fab, Fab'"'"' or F(ab'"'"')₂ portion thereof of step (i), which binds to CD20 antigen present on the surface of cells of said B-cell lymphoma, that is labelled with said first radiolabel or with a different radiolabel, wherein the radioimmunotherapeutically effective amount is based on the clearance rate determined in step (ii).

2. The method of claim 1, further comprising administering multiple doses of unlabelled antibody or a Fab, Fab'"'"' or F(ab'"'"')₂ portion thereof to the patient, 6 to 12 weeks apart, after step (iv).

3. The method of claim 1, further comprising administering multiple doses of a radioimmunotherapeutically effective amount of a radiolabeled antibody or a Fab, Fab'"'"' or F(ab'"'"')₂ portion thereof, 6 to 12 weeks apart, after step (iv).

4. The method of claim 1, wherein said antibody is labelled with a β

^- emitter.

5. The method of claim 4, wherein said antibody is labelled with an isotope selected from the group consisting of ¹³¹ I, ⁹⁰ Y and ¹⁸⁶ Re.

6. The method of claim 1, wherein the radioimmunotherapeutically effective amount of step (iv) provides irradiation at a dose in the range of 10 to 200 cGy to the whole body of said patient.

7. The method of claim 1, wherein the radioimmunotherapeutically effective amount of step (iv) provides irradiation at a dose in the range of 25 to 150 cGy to the whole body of said patient.

8. The method of claim 1, wherein the antibody administered in step (i) is labelled with ⁹⁹ Tc or ¹¹¹ In, and wherein the antibody administered in step (iv) is labelled with an isotope selected from the group consisting of ¹³¹ I, ⁹⁰ Y and ¹⁸⁶ Re.

9. The method of claim 1, wherein an amount of radioactivity between 5 and 250 mCi is administered to the patient in step (iv).

10. The method of claim 1, which further comprises:

removing hematopoietic stem cells from the patient before step (iv), and

replacing the removed hematopoietic stem cells in the patient after step (iv).

11. The method of claim 10, wherein the steps of removing and replacing hematopoietic stem cells comprise removing and replacing bone marrow.

12. The method of claim 10, which further comprises:

treating said removed hematopoietic stem cells to reduce B-cell lymphoma before replacing said hematopoietic stem cells in the patient.

13. The method of claim 1, wherein the step of determining the clearance rate comprises:

imaging the distribution of the trace-labelled antibody or the Fab, Fab'"'"' or F(ab'"'"')₂ portion thereof within the body of the patient at two or more time points.

14. The method of claim 1, wherein the step of determining the clearance rate comprises:

drawing sequential samples from the blood of the patient, and

counting radioactivity levels of said samples.

15. The method of claim 1, wherein the step of determining the clearance rate comprises:

studying the pharmacokinetics of the trace-labelled antibody or the Fab, Fab'"'"' or F(ab'"'"')₂ portion thereof within the body of the patient with a gamma camera or NaI probe.

16. The method of claim 1, wherein the amount of antibody or the Fab, Fab'"'"' or F(ab'"'"')₂ portion thereof administered in step (i) is the same as the amount administered in steps (iii) and (iv).

17. The method of claim 16, wherein the antibody or the Fab, Fab'"'"' or F(ab'"'"')₂ portion thereof of step (i), and the antibody or the Fab, Fab'"'"' or F(ab'"'"')₂ portion thereof of steps (iii) and (iv), are labeled with ¹³¹ I.

18. The method of claim 1, wherein the antibody or the Fab, Fab'"'"' or F(ab'"'"')₂ portion thereof of step (i), and the antibody or the Fab, Fab'"'"' or F(ab'"'"')₂ portion thereof of step (iv) are labeled with ¹³¹ I.

19. The method of claim 6, wherein the amount of antibody or the Fab, Fab'"'"' or F(ab'"'"')₂ portion thereof administered in step (i) is the same as the amount administered in steps (iii) and (iv).

20. The method of claim 6, wherein the antibody or the Fab, Fab'"'"' or F(ab'"'"')₂ portion thereof of step (i), and the antibody or the Fab, Fab'"'"' or F(ab'"'"')₂ portion thereof of step (iv), are labeled with ¹³¹ I.

21. The method of claim 8 wherein the amount of antibody or the Fab, Fab'"'"' or F(ab'"'"')₂ portion thereof administered in step (i) is the same as the amount administered in steps (iii) and (iv).

58. The method of claim 1, further comprising administering multiple doses of trace-labelled antibody or a Fab, Fab'"'"' or F(ab'"'"')₂ portion thereof, 6 to 12 weeks apart, after step (iv).

59. The method of claim 1, wherein the clearance rate is determined in step (ii) from the whole body of the patient.

64. The method of claim 1, wherein the step of determining the clearance rate comprises:

drawing sequential samples from the urine of the patient, and

counting radioactivity levels of said samples.

22. A method for immunotherapy of a neoplasm of B cell lineage, which comprises:

(i) administering to a patient a clearance-rate-determinative amount of an antibody or a Fab, Fab'"'"' or (Fab'"'"')₂ portion thereof which binds to CD20 antigen present on the surface of cells of B-cell lineage that is a trace-labelled with a first radiolabel;

(ii) determining the clearance rate of the trace-labelled antibody or the Fab, Fab'"'"' or F(ab'"'"')₂ portion thereof within the body of the patient;

(iii) administering to the patient an amount of the antibody or the Fab, Fab'"'"' or F(ab'"'"')₂ portion thereof of step (i) in unlabelled form, said amount being effective for blocking non-specific binding sites for an antibody or a Fab, Fab'"'"', or F(ab'"'"')₂ portion thereof effective for treating said neoplasm of B-cell lineage within the body of the patient; and

(iv) administering to the patient a radioimmunotherapeutically effective amount for treating said neoplasm of B-cell lineage of the antibody or the Fab, Fab'"'"' or F(ab'"'"')₂ portion thereof of step (i), which binds to CD20 antigen present on the surface of said cells of B-cell lineage, that is labelled with said first radiolabel or with a different radiolabel, wherein the radioimmunotherapeutically effective amount is based on the clearance rate determined in step (ii).

23. The method of claim 22, which further comprises:

removing hematopoietic stem cells from the patient before step (iv), and

replacing the removed hematopoietic stem cells in the patient after step (iv).

24. The method of claim 23 wherein the steps of removing and replacing hematopoietic stem cells comprise removing and replacing bone marrow.

25. The method of claim 23, which further comprises:

treating said removed hematopoietic stem cells to reduce neoplasm of B cell lineage before replacing said hematopoietic stem cells in the patient.

26. The method of claim 22, wherein the step of determining the clearance rate comprises:

imaging the distribution of the trace-labelled antibody or the Fab, Fab'"'"' or F(ab'"'"')₂ portion thereof within the body of the patient at two or more time points.

27. The method of claim 22, wherein the step of determining the clearance rate comprises:

drawing sequential samples from the blood of the patient, and

counting radioactivity levels of said samples.

28. The method of claim 22, wherein the step of determining the clearance rate comprises:

studying the pharmacokinetics of the trace-labelled antibody or the Fab, Fab'"'"' or F(ab'"'"')₂ portion thereof within the body of the patient with a gamma camera or Nal probe.

29. The method of claim 22, wherein the amount of antibody or the Fab, Fab'"'"' or F(ab'"'"')₂ portion thereof administered in step (i) is the same as the amount administered in each of steps (iii) and (iv).

60. The method of claim 22, wherein the clearance rate is determined in step (ii) from the whole body of the patient.

30. A method for immunotherapy of B-cell lymphoma, which comprises:

(i) administering to a patient a clearance-rate-determinative amount of an antibody or a Fab, Fab'"'"' or F(ab'"'"')₂ portion thereof which binds to CD20 antigen present on the surface of cells of said B-cell lymphoma that is trace-labelled with a radiolabel;

(ii) determining the clearance rate of the trace-labelled antibody or the Fab, Fab'"'"' or F(ab'"'"')₂ portion thereof of step (i), within the body of the patient;

(iii) administering to the patient an amount of the antibody or the Fab, Fab'"'"' or F(ab'"'"')₂ portion thereof of step (i) in unlabelled form, which binds to CD20 antigen present on the surface of cells of said B-cell lymphoma, said amount being effective for blocking non-tumor binding sites for an antibody or a Fab, Fab'"'"' or F(ab'"'"')₂ portion thereof effective for treating B-cell lymphoma within the body of the patient; and

(iv) administering to the patient a radioimmunotherapeutically effective amount for treating B-cell lymphoma of the labelled antibody or the Fab, Fab'"'"' or F(ab'"'"')₂ portion thereof of step (i), which binds to CD20 antigen present on the surface of cells of said B-cell lymphoma, wherein the radioimmunotherapeutically effective amount is based on the clearance rate determined in step (ii).

31. The method of claim 30, which further comprises:

removing hematopoietic stem cells from the patient before step (iv), and

replacing the removed hematopoietic stem cells in the patient after step (iv).

32. The method of claim 31, wherein the steps of removing and replacing hematopoietic stem cells comprise removing and replacing bone marrow.

33. The method of claim 31, which further comprises:

treating said removed hematopoietic stem cells to reduce B-cell lymphoma before replacing said hematopoietic stem cells in the patient.

34. The method of claim 30, wherein the step of determining the clearance rate comprises:

imaging the distribution of the trace-labelled antibody or the Fab, Fab'"'"' or F(ab'"'"')₂ portion thereof within the body of the patient at two or more time points.

35. The method of claim 30, wherein the step of determining the clearance rate comprises:

drawing sequential samples from the blood of the patient, and

counting radioactivity levels of said samples.

36. The method of claim 30, wherein the step of determining the clearance rate comprises:

studying the pharmacokinetics of the trace-labelled antibody or the Fab, Fab'"'"' or F(ab'"'"')₂ portion thereof within the body of the patient with a gamma camera or NaI probe.

37. The method of claim 30, wherein the amount of antibody or the Fab, Fab'"'"' or F(ab'"'"')₂ portion thereof administered in step (i) is the same as the amount administered in each of steps (iii) and (iv).

61. The method of claim 30, wherein the clearance rate is determined in step (ii) from the whole body of the patient.

38. A method for immunotherapy of B-cell lymphoma, which comprises:

(i) administering to a patient an effective amount of unlabelled antibody or a Fab, Fab'"'"' or F(ab'"'"')₂ portion thereof which binds to CD20 antigen present on the surface of cells of said B-cell lymphoma, said amount effective for blocking non-tumor binding sites for an antibody or a Fab, Fab'"'"' or F(ab'"'"')₂ portion thereof within the body of said patient;

(ii) administering a clearance-rate-determinative amount of the antibody or the Fab, Fab'"'"' or F(ab'"'"')₂ portion thereof of step (i), which binds to CD20 antigen present on the surface of cells of said B-cell lymphoma, that is trace-labelled with a first radiolabel;

(iii) determining the clearance rate of the trace-labelled antibody or the Fab, Fab'"'"' or F(ab'"'"')₂ portion thereof of step (ii), within the body of the patient;

(iv) administering to the patient an amount of the unlabelled antibody or the Fab, Fab'"'"' or F(ab'"'"')₂ portion thereof which binds to CD20 antigen present on the surface of cells of said B-cell lymphoma, said amount effective for blocking non-tumor binding sites for an antibody or a Fab, Fab'"'"' or F(ab'"'"')₂ portion thereof effective for treating B-cell lymphoma within the body of the patient; and

(v) administering to the patient a radioimmunotherapeutically effective amount for treating B-cell lymphoma of the antibody or the Fab, Fab'"'"', F(ab'"'"')₂ portion thereof of step (ii) which binds to CD20 antigen present on the surface of cells of said B-cell lymphoma, that is labelled with said first radiolabel or with a different radiolabel, wherein the radioimmunotherapeutically effective amount is based on the clearance rate determined in step (iii).

39. The method of claim 38, which further comprises:

removing hematopoietic stem cells from the patient before step (v), and

replacing the removed hematopoietic stem cells in the patient after step (v).

40. The method of claim 39, wherein the steps of removing and replacing hematopoietic stem cells comprise removing and replacing bone marrow.

41. The method of claim 39, which further comprises:

treating said removed hematopoietic stem cells to reduce B-cell lymphoma before replacing said hematopoietic stem cells in the patient.

42. The method of claim 38, wherein the step of determining the clearance rate comprises:

imaging the distribution of the trace-labelled antibody or the Fab, Fab'"'"' or F(ab'"'"')₂ portion thereof within the body of the patient at two or more time points.

43. The method of claim 38, wherein the step of determining the clearance rate comprises:

drawing sequential samples from the blood of the patient, and

counting radioactivity levels of said samples.

44. The method of claim 39, wherein the step of determining the clearance rate comprises:

studying the pharmacokinetics of the trace-labelled antibody or the Fab, Fab'"'"' or F(ab'"'"')₂ portion thereof within the body of the patient with a gamma camera or NaI probe.

45. The method of claim 38, wherein the amount of antibody or Fab, Fab'"'"' or F(ab'"'"')₂ portion thereof administered in step (ii) is the same as the amount administered in step (iv).

46. The method of claim 45, wherein the antibody or the Fab, Fab'"'"' or F(ab'"'"')₂ portion thereof of step (ii), and the antibody or the Fab, Fab'"'"' or F(ab'"'"')₂ portion thereof of step (iv), are labelled with ¹³¹ I.

47. The method of claim 38, wherein the antibody or the Fab, Fab'"'"' or F(ab'"'"')₂ portion thereof of step (ii), and the antibody or the Fab, Fab'"'"' or F(ab'"'"')₂ portion thereof of step (v), are labeled with ¹³¹ I.

62. The method of claim 38, wherein the clearance rate is determined in step (iii) from the whole body of the patient.

48. A method for immunotherapy of B-cell lymphoma, which comprises:

(i) administering to a patient a first amount of an unlabelled antibody or a Fab, Fab'"'"' or F(ab'"'"')₂ portion thereof which binds to CD20 antigen present on the surface of cells of said B-cell lymphoma, said first amount effective for blocking non-tumor binding sites for an antibody or a Fab, Fab'"'"' or F(ab'"'"')₂ portion thereof within the body of the patient;

(ii) administering to a patient a clearance-rate-determinative amount of the antibody or the Fab, Fab'"'"' or F(ab'"'"')₂ portion thereof of step (i), which is trace-labelled with a first radiolabel;

(iii) determining the clearance rate of the trace-labelled antibody or the Fab, Fab'"'"' or F(ab'"'"')₂ portion thereof of step (ii) within the body of the patient;

(iv) administering to the patient a second amount of the unlabelled antibody or the Fab, Fab'"'"' or F(ab'"'"')₂ portion thereof, as was used in step (i), said second amount effective for blocking non-tumor binding sites for an antibody or a Fab, Fab'"'"' or F(ab'"'"')₂ portion thereof within the body of the patient; and

(v) administering to the patient a radioimmunotherapeutically effective amount for treating B-cell lymphoma of the antibody or the Fab, Fab'"'"' or F(ab'"'"')₂ portion thereof of step (ii), which binds to CD20 antigen present on the surface of cells of said B-cell lymphoma, that is labelled with said first radiolabel or with a different radiolabel, wherein the radioimmunotherapeutically effective amount is based on the clearance rate determined in step (iii).

49. The method of claim 48, which further comprises:

removing hematopoietic stem cells from the patient before step (v), and

replacing the removed hematopoietic stem cells in the patient after step (v).

50. The method of claim 49, wherein the steps of removing and replacing hematopoietic stem cells comprise removing and replacing bone marrow.

51. The method of claim 49, which further comprises:

treating said removed hematopoietic stem cells to reduce B-cell lymphoma before replacing said hematopoietic stem cells in the patient.

52. The method of claim 48, wherein the step of determining the clearance rate comprises:

imaging the distribution of the trace-labelled antibody or the Fab, Fab'"'"' or F(ab'"'"')₂ portion thereof within the body of the patient at two or more time points.

53. The method of claim 48, wherein the step of determining the clearance rate comprises:

drawing sequential samples from the blood of the patient, and

counting radioactivity levels of said samples.

54. The method of claim 48, wherein the step of determining the clearance rate comprises:

studying the pharmacokinetics of the trace-labelled antibody or the Fab, Fab'"'"' or F(ab'"'"')₂ portion thereof within the body of the patient with a gamma camera or NaI probe.

55. The method of claim 48, wherein the amount of antibody or the Fab, Fab'"'"' or F(ab'"'"')₂ portion thereof administered in step (ii) is the same as the amount administered in step (iv).

56. The method of claim 55, wherein the antibody or the Fab, Fab'"'"' or F(ab'"'"')₂ portion thereof of step (ii), and the antibody or the Fab, Fab'"'"' or F(ab'"'"')₂ portion thereof of step (iv), are labelled with ¹³¹ I.

57. The method of claim 48, wherein the antibody or the Fab, Fab'"'"' or F(ab'"'"')₂ portion thereof of step (ii), and the antibody or the Fab, Fab'"'"' or F(ab'"'"')₂ portion thereof of step (v), are labelled with ¹³¹ I.

63. The method of claim 48, wherein the clearance rate is determined in step (iii) from the whole body of the patient.