Methods of treating lymphoma with bispecific antibodies against cd3 and cd20

Abstract

The present invention provides dosing regimens of bispecific antibodies targeting both CD3 and CD20 when used in the treatment of lymphoma, such as B-cell Non-Hodgkin lymphoma (B-NHL).

Description

Abstract This invention provides a dosing regimen for a bispecific antibody targeting both CD3 and CD20 when used to treat lymphomas such as B-cell non-Hodgkin lymphoma (B-NHL).

Claims

Claims1. A method of treating lymphoma, e.g. B-cell Non-Hodgkin lymphoma, such as aggressive or indolent lymphoma in a human subject, the method comprising administering to the subject a bispecific antibody, wherein the bispecific antibody comprises:(i) a first binding arm comprising a first antigen-binding region which binds to human CD3s (epsilon) and comprises a variable heavy chain (VH) region and a variable light chain (VL) region, wherein the VH region comprises the CDR1 , CDR2 and CDR3 sequences that are in the VH region sequence of SEQ ID NO: 6, and the VL region comprises the CDR1, CDR2 and CDR3 sequences that are in the VL region sequence of SEQ ID NO: 7; and(ii) a second binding arm comprising a second antigen-binding region which binds to human CD20 and comprises a VH region and a VL region, wherein the VH region comprises the CDR1, CDR2 and CDR3 sequences that are in the VH region sequence of SEQ ID NO: 13, and the VL region comprises the CDR1, CDR2 and CDR3 sequences that are in the VL region sequence of SEQ ID NO: 14, wherein the bispecific antibody is administered in a 28 day cycle comprising administering a priming dose on day 1 of about 0.05 mg to about 0.35 mg, a first intermediate dose on about day 8 of about 0.6 mg to 5 mg, a second intermediate dose on about day 15 of about 1 mg to about 10 mg, followed by one weekly dose of between about 20-100 mg; or wherein the bispecific antibody is administered in a 35 day cycle comprising administering a priming dose on day 1 of about 0.05 mg to about 0.35 mg, a first intermediate dose on about day 8 of about 0.6 mg to 5 mg, a second intermediate dose on about day 15 of about 1 mg to about 10 mg, followed by at least two weekly doses of between about 20-100 mg.

2. The method of claim 1, wherein the priming dose is about 0.16 mg.

3. The method of claim 1 or claim 2, wherein the first intermediate dose is about 0.6- 1.2 mg.

4. The method of claim 3, wherein the first intermediate dose is about 0.8 mg.

5. The method of any one of claims 1-4, wherein the second intermediate dose is about 3-6 mg.

6. The method of claim 5, wherein the second intermediate dose is 3 mg.

7. The method of claim 5, wherein the second intermediate dose is 6 mg.

8. The method of any one of claims 1-7, wherein the weekly dose is between about 20 to 60 mg.

9. The method of claim 8, wherein the weekly dose is about 24 mg.

10. The method of claim 8, wherein the weekly dose is about 48 mg.

11. The method of any one of claims 1-10, wherein the indolent lymphoma is follicular lymphoma (FL), cutaneous T-cell lymphoma (CTCL), marginal zone lymphoma (MZL), chronic lymphocytic leukemia (CLL) or small cell lymphocytic lymphoma (SLL), and / or wherein the aggressive lymphoma is large B-cell lymphoma (LBCL), such as Diffuse large B-cell lymphoma (DLBCL), high-grade B-cell lymphoma (HGBCL), primary mediastinal large B-cell lymphoma (PMBCL), follicular lymphoma (FL) grade 3B or mantle cell lymphoma (MCL).

12. The method of claim 11, wherein the indolent lymphoma is FL.

13. The method of any one of claims 1-12, wherein the subject has received prior anti-neoplastic therapy.

14. The method of claim 13, wherein the subject has received prior treatment with a CD20 monospecific antibody.

15. The method of any one of claims 1-14, wherein the indolent lymphoma is relapsed or refractory.

16. The method of any one of claims 1-15, wherein the weekly administration is performed at least 4 times.

17. The method of any one of claims 1-16, wherein after the weekly administration, the bispecific antibody is administered once every two weeks.

18. Th method of claim 17, wherein the biweekly administration of the bispecific antibody is performed at least six (6) times.

19. The method of claim 17 or claim 18, wherein after the biweekly administration, the bispecific antibody is administered once every four weeks.

20. The method of any one of claims 1-19, wherein the bispecific antibody is administered subcutaneously.

21. The method of any one of claims 1-20, comprising:(a) a first cycle of 28-days wherein(i) the priming dose of the bispecific antibody is administered on Day 1 ;(ii) the first intermediate dose of the bispecific antibody is administered on Day 8;(iii) the second intermediate dose of the bispecific antibody is administered on Day 15;(iv) a dose of 24 mg of the bispecific antibody is administered on Day 22; and(b) cycles 2-3 each comprising 28 days wherein a dose of 24 mg of the bispecific antibody is administered on Days 1, 8, 15 and 22;(c) cycles 4-9 each comprising 28 days wherein a dose of 24 mg of the bispecific antibody is administered on Days 1 and 15; and(d) further subsequent 28 day cycles, wherein a dose of 24 mg of the bispecific antibody is administered on Day 1.

22. The method of any one of claims 1-20, comprising:(a) a first cycle of 28-days wherein(i) the priming dose of the bispecific antibody is administered on Day 1 ;(ii) the first intermediate dose of the bispecific antibody is administered on Day 8;(iii) the second intermediate dose of the bispecific antibody is administered on Day 15;(iv) a dose of 48 mg of the bispecific antibody is administered on Day 22; and(b) cycles 2-3 each comprising 28 days wherein a dose of 48 mg of the bispecific antibody is administered on Days 1, 8, 15 and 22;(c) cycles 4-9 each comprising 28 days wherein a dose of 48 mg of the bispecific antibody is administered on Days 1 and 15; and(d) further subsequent 28 day cycles, wherein a dose of 48 mg of the bispecific antibody is administered on Day 1.

23. The method of any one of claims 1-20, comprising:(a) a first cycle of 28-days wherein(i) a priming dose of 0.16 mg of the bispecific antibody is administered on Day 1 ;(ii) a first intermediate dose 0.8 mg of the bispecific antibody is administered on Day 8;(iii) a second intermediate dose of 3 mg of the bispecific antibody is administered on Day 15;(iv) a dose of 48 mg of the bispecific antibody is administered on Day 22; and(b) cycles 2-3 each comprising 28 days wherein a dose of 48 mg of the bispecific antibody is administered on Days 1, 8, 15 and 22;(c) cycles 4-9 each comprising 28 days wherein a dose of 48 mg of the bispecific antibody is administered on Days 1 and 15; and(d) further subsequent 28 day cycles, wherein a dose of 48 mg of the bispecific antibody is administered on Day 1.

24. The method of any one of claims 1-20, comprising:(a) a first cycle of 28-days wherein(i) a priming dose of 0.16 mg of the bispecific antibody is administered on Day 1 ;(ii) a first intermediate dose 0.8 mg of the bispecific antibody is administered on Day 8;(iii) a second intermediate dose of 6 mg of the bispecific antibody is administered on Day 15;(iv) a dose of 48 mg of the bispecific antibody is administered on Day 22; and(b) cycles 2-3 each comprising 28 days wherein a dose of 48 mg of the bispecific antibody is administered on Days 1, 8, 15 and 22;(c) cycles 4-9 each comprising 28 days wherein a dose of 48 mg of the bispecific antibody is administered on Days 1 and 15; and(d) further subsequent 28 day cycles, wherein a dose of 48 mg of the bispecific antibody is administered on Day 1.

25. The method of any one of claims 21-24, wherein the indolent lymphoma is FL.

26. The method of any one of claims 1-25, wherein the subject has manageable cytokine release syndrome (CRS) of grade 1 or grade 2 during administration of the bispecific antibody.

27. The method of any one of the preceding claims, wherein the subject does not experience tumor lysis syndrome.

28. The method of any one of the preceding claims, wherein the subject is treated with prophylaxis for CRS.

29. The method of claim 28, wherein the prophylaxis includes the administration of a corticosteroid.

30. The method of claim 29, wherein the corticosteroid is dexamethasone.

31. The method of claim 30, wherein the dexamethasone is administered at a dose of about 2-20 mg.

32. The method of claim 31, wherein the dexamethasone is administered at a dose of about 15 mg.

33. The method of any one of claims 28-32, wherein the prophylaxis is administered at the same day as the bispecific antibody.

34. The method of any one of claims 28-33, wherein the prophylaxis is administered at subsequent days 2-3, and optionally day 4, or at subsequent days 2-4.

35. The method of any one of claims 28-34, wherein when the prophylaxis is administered at the same day as the bispecific antibody, the prophylaxis is administered 30-120 minutes prior to the administration of the bispecific antibody.

36. The method of any one of the preceding claims, wherein the human subject is treated with premedication to reduce reactions to injections.

37. The method of claim 36, wherein the premedication includes the administration of antihistamines.

38. The method of claim 36 or 37, wherein the premedication includes the administration of antipyretics.

39. The method of any one of claims 36-37, wherein the antihistamine is diphenhydramine, e.g., at an intravenous or oral dose 50 mg, or equivalent thereof.

40. The method of claim 38, wherein the antipyretic is acetaminophen, e.g., at an oral dose of 650-1000 mg, or equivalent thereof.

41. The method of any one of claims 36-40, wherein the premedication is administered at the same day as the bispecific antibody.

42. The method of claim 41, wherein the premedication administered 30-120 minutes prior to the administration of the bispecific antibody.

43. The method one of the claims 28-42, wherein the prophylaxis is administered during the first cycle.

44. The method of any one of claims 28-43, wherein the premedication is administered during the first cycle.

45. The method of claims 43 or 44, wherein the prophylaxis is administered during the second cycle when the human subject experiences CRS greater than grade 1 after the fourth administration of the bispecific antibody in cycle 1.

46. The method of any one of claims 43-43, wherein the prophylaxis is continued during a subsequent cycle, when in the last administration of the bispecific antibody of the previous cycle, the human subject experiences CRS greater than grade 1.

47. The method of any one of claims 44-46 , wherein the premedication is optionally administered during the second cycle.

48. The method of claim 47, wherein the premedication is optionally administered during subsequent cycles.

49. The method of any one of the preceding claims, wherein the bispecific antibody comprises: a. a first binding arm comprising a first antigen-binding region binding to human CD3s (epsilon), wherein the first antigen-binding region comprises a heavy chain variable (VH) region CDR1, CDR2, and CDR3 having the sequences as set forth in SEQ ID NOs: 1, 2, and 3, respectively, and a light chain variable (VL) region CDR1, CDR2, and CDR3 having the sequences as set forth in SEQ ID NO: 4, the sequence GTN, and the sequence as set forth in SEQ ID NO: 5, respectively, and b. a second binding arm comprising a second antigen-binding region binding to human CD20, wherein the second antigen-binding region comprises a heavy chain variable (VH) region CDR1, CDR2, and CDR3 having the sequences as set forth in SEQ ID NOs: 8, 9, and 10, respectively, and a light chain variable (VL) region CDR1, CDR2, and CDR3 having the sequences as set forth in SEQ ID NO:11, the sequence DAS, and the sequence as set forth in SEQ ID NO: 12, respectively.

50. The method of any one of the preceding claims, wherein the bispecific antibody comprises: a. a first binding arm comprising a first antigen-binding region binding to human CD3s (epsilon), comprising a variable heavy chain region and a variable light chain region wherein the variable heavy chain region comprises SEQ ID NO: 6; and wherein the variable light chain region comprises SEQ ID NO: 7; and b. a second binding arm comprising a second antigen-binding region binding to human CD20, comprising a variable heavy chain region and a variable light chain region wherein the variable heavy chain region comprises SEQ ID NO: 13; and wherein the variable light chain region comprises SEQ ID NO: 14.

51. The method of any one of the preceding claims, wherein the first binding arm of the bispecific antibody is derived from a humanized antibody, preferably from a full-length IgGI ,A (lambda) antibody.

52. The method of claim 51, wherein the bispecific antibody comprises a X light chain constant region as defined in SEQ ID NO: 22.

53. The method of claim 51, wherein the second binding arm of the bispecific antibody is derived from a human antibody, preferably from a full-length IgGl,K (kappa) antibody.

54. The method of claim 53, wherein the bispecific antibody comprises a K light chain constant region as defined in SEQ ID NO: 23.

55. The method of any one of the preceding claims, wherein the bispecific antibody is a full- length antibody with a human IgGl constant region.

56. The method of any one of the preceding claims, in which the bispecific antibody comprises an inert Fc region.

57. The method of claim 56, wherein the bispecific antibody comprises in the first and second heavy chain at the positions corresponding to positions L234, L235, and D265 in the human IgGl heavy chain of SEQ ID NO: 15 of both the first heavy chain and the second heavy chain, the amino acids F, E, and A, respectively.

58. The method of any one of the preceding claims, wherein the bispecific antibody comprises in the first heavy chain the amino acid L in the position corresponding to F405 in a human IgGl heavy chain of SEQ ID NO: 15, and wherein the second heavy chain comprises the amino acid R in the position corresponding to K409 in a human IgGl heavy chain of SEQ ID NO: 15 is R, or vice versa.

59. The method of any one of the preceding claims, wherein the bispecific antibody comprises in the first and second heavy chain at the positions corresponding to positions L234, L235, and D265 in the human IgGl heavy chain of SEQ ID NO: 15 of both the first heavy chain and the second heavy chain, the amino acids F, E, and A, respectively, and wherein in the first heavy chain the amino acid L in the position corresponding to F405 in a human IgGl heavy chain of SEQ ID NO: 15, and wherein the second heavy chain comprises the amino acid R in the position corresponding to K409 in a human IgGl heavy chain of SEQ ID NO: 15 is R, or vice versa.

60. The method of claim 59, wherein the bispecific antibody comprises constant regions as defined in SEQ ID NOs: 19 and 20.

61. The method of any one of the preceding claims, wherein the bispecific antibody comprises a heavy chain and a light chain as defined in SEQ ID NOs: 24 and 25, respectively, and a heavy chain and a light chain as defined in SEQ ID NOs: 26 and 27.

62. The method of any one of the preceding claims, the bispecific antibody consists of a heavy chain and a light chain as defined in SEQ ID NOs: 24 and 25, respectively, and a heavy chain and a light chain as defined in SEQ ID NOs: 26 and 27.

63. The method of any one of the preceding claims, wherein the bispecific antibody is epcoritamab, or a biosimilar thereof.

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