DOSING FOR TREATMENT WITH ANTI-CD20/ANTI-CD3 BISPECIFIC ANTIBODIES

• US 20180134798A1
• Filed: 11/15/2017
• Published: 05/17/2018
• Est. Priority Date: 11/15/2016
• Status: Active Grant

• Current Assignee: Genentech, Inc. (Roche Holding AG)
• Original Assignee: Genentech, Inc. (Roche Holding AG)
• Inventors: CHU, Yu-Waye, HOSSEINI, Iraj, RAMANUJAN, Saroja, GADKAR, Kapil, LI, Chi-Chung
• Granted Patent: US 11,466,094 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 2039/507 Comprising a combination of two or more separate antibodies
• CPC Class Codes: A61K 2039/54 characterised by the route of administration
• CPC Class Codes: A61K 2039/545 characterised by the dose, timing or administration schedule
• CPC Class Codes: A61K 31/573 substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 16/2809 against the T-cell receptor (TcR)-CD3 complex
• CPC Class Codes: C07K 16/2827 against B7 molecules, e.g. CD80, CD86
• CPC Class Codes: C07K 16/2866 against receptors for cytokines, lymphokines, interferons
• CPC Class Codes: C07K 16/2887 against CD20
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/31 multispecific
• CPC Class Codes: C07K 2317/41 Glycosylation, sialylation, or fucosylation

Abstract

The invention provides methods of dosing for the treatment of cancers, such as B cell proliferative disorders, with anti-cluster of differentiation 20 (CD20)/anti-cluster of differentiation 3 (CD3) bispecific antibodies.

Claims

1. A method of treating a subject having a B cell proliferative disorder comprising administering to the subject a bispecific antibody that binds to CD20 and CD3 in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein:

(a) the first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of the bispecific antibody, wherein the C1D1 and the C1D2 are each no greater than the C1D3, and wherein the C1D1 is between about 0.02 mg to about 4.0 mg, the C1D2 is between about 0.05 mg to about 20.0 mg, and the C1D3 is between about 0.2 mg to about 20.0 mg; and

(b) the second dosing cycle comprises a single dose (C2D1) of the bispecific antibody, wherein the C2D1 is equal to or greater than the C1D3 and is between about 0.2 mg to about 20 mg.

2. The method of claim 1, wherein:

(a) the C1D1 is between about 0.4 mg to about 4.0 mg, the C1D2 is between about 1.0 mg to about 20.0 mg, and the C1D3 is between about 3.0 mg to about 20.0 mg; and

(b) the C2D1 is between about 3.0 mg to about 20.0 mg.

3. The method of claim 2, wherein:

(a) the C1D1 is between about 0.8 mg to about 3.0 mg, the C1D2 is between about 1.0 mg to about 6.0 mg, and the C1D3 is between about 3.0 to about 6.0 mg; and

(b) the C2D1 is between about 3.0 to about 6.0 mg.

4. The method of any one of claims 1-3, wherein:

(a) the C1D1 is about 0.8 mg, the C1D2 is about 2.0 mg, and the C1D3 is about 4.2 mg, and the C2D1 is about 4.2 mg;

or

(b) the C1D1 is about 1.0 mg, the C1D2 is about 1.0 mg, and the C1D3 is about 3.0 mg, and the C2D1 is about 3.0 mg;

or

(c) the C1D1 is about 1.0 mg, the C1D2 is about 2.0 mg, and the C1D3 is about 6.0 mg, and the C2D1 is about 6.0 mg;

or

(d) the C1D is about 0.8 mg, the C1D2 is about 2.0 mg, and the C1D3 is about 6.0 mg, and the C2D1 is about 6.0 mg.

5. The method of any one of claims 1-4, wherein the length of the first dosing cycle is 21 days.

6. The method of claim 5, wherein the method comprises administering to the subject the C1D1, the C1D2, and the C1D3 on or about Days 1, 8, and 15, respectively, of the first dosing cycle.

7. The method of any one of claims 1-6, wherein the length of the second dosing cycle is 21 days.

8. The method of claim 7, wherein the method comprises administering to the subject the C2D1 on Day 1 of the second dosing cycle.

9. The method of any one of claims 1-8, wherein the dosing regimen comprises one or more additional dosing cycles.

10. The method of claim 9, wherein the dosing regimen comprises one to six additional dosing cycles.

11. The method of claim 9 or 10, wherein the length of each of the one or more additional dosing cycles is 21 days.

12. The method of any one of claims 9-11, wherein each of the one or more additional dosing cycles comprises a single dose of the bispecific antibody.

13. The method of claim 12, wherein the method comprises administering to the subject the single dose of the one or more additional dosing cycles on Day 1, of the one or more additional dosing cycles.

14. The method of any one of claims 1-13, wherein the bispecific antibody comprises an anti-CD20 arm comprising a first binding domain comprising the following six hypervariable regions (HVRs):

(a) an HVR-H1 comprising the amino acid sequence of GYTFTSYNMH (SEQ ID NO;

     1);

(b) an HVR-H2 comprising the amino acid sequence of AIYPGNGDTSYNQKFKG (SEQ ID NO;

     2);

(c) an HVR-H3 comprising the amino acid sequence of VVYYSNSYWYFDV (SEQ ID NO;

3);

(d) an HVR-L1 comprising the amino acid sequence of RASSSVSYMH (SEQ ID NO;

     4);

(e) an HVR-L2 comprising the amino acid sequence of APSNLAS (SEQ ID NO;

     5); and

(f) an HVR-L3 comprising the amino acid sequence of QQWSFNPPT (SEQ ID NO;

     6).

15. The method of any one of claims 1-14, wherein the bispecific antibody comprises an anti-CD20 arm comprising a first binding domain comprising (a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:

7;

(b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO;

8;

or (c) a VH domain as in (a) and a VL domain as in (b).

16. The method of claim 15, wherein the first binding domain comprises a VH domain comprising an amino acid sequence of SEQ ID NO:

7 and a VL domain comprising an amino acid sequence of SEQ ID NO;

8.

17. The method of any one of claims 1-16, wherein the bispecific antibody comprises an anti-CD3 arm comprising a second binding domain comprising the following six HVRs:

(a) an HVR-H1 comprising the amino acid sequence of NYYIH (SEQ ID NO;

     9);

(b) an HVR-H2 comprising the amino acid sequence of WIYPGDGNTKYNEKFKG (SEQ ID NO;

     10);

(c) an HVR-H3 comprising the amino acid sequence of DSYSNYYFDY (SEQ ID NO;

     11);

(d) an HVR-L1 comprising the amino acid sequence of KSSQSLLNSRTRKNYLA (SEQ ID NO;

     12);

(e) an HVR-L2 comprising the amino acid sequence of WASTRES (SEQ ID NO;

     13); and

(f) an HVR-L3 comprising the amino acid sequence of TQSFILRT (SEQ ID NO;

     14).

18. The method of any one of claims 1-17, wherein the bispecific antibody comprises an anti-CD3 arm comprising a second binding domain comprising (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:

15;

(b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO;

16;

or (c) a VH domain as in (a) and a VL domain as in (b).

19. The method of claim 18, wherein the second binding domain comprises a VH domain comprising an amino acid sequence of SEQ ID NO:

15 and a VL domain comprising an amino acid sequence of SEQ ID NO;

16.

20. The method of any one of claims 1-19, wherein the bispecific antibody comprises an aglycosylation site mutation.

21. The method of claim 20, wherein the aglycosylation site mutation reduces effector function of the bispecific antibody.

22. The method of claim 20 or 21, wherein the aglycosylation site mutation is a substitution mutation.

23. The method of claim 22, wherein the bispecific antibody comprises a substitution mutation in the Fc region that reduces effector function.

24. The method of claim 23, wherein the substitution mutation is at amino acid residue N297, L234, L235, and/or D265 (EU numbering).

25. The method of claim 24, wherein the substitution mutation is selected from the group consisting of N297G, N297A, L234A, L235A, D265A, and P329G.

26. The method of claim 24 or 25, wherein the substitution mutation is at amino acid residue N297.

27. The method of claim 26, wherein the substitution mutation is N297A.

28. The method of any one of claims 1-27, wherein the bispecific antibody is a monoclonal antibody.

29. The method of any one of claims 1-28, wherein the bispecific antibody is a humanized antibody.

30. The method of any one of claims 1-29, wherein the bispecific antibody is a chimeric antibody.

31. The method of any one of claims 1-30, wherein the bispecific antibody is an antibody fragment that binds CD20 and CD3.

32. The method of claim 31, wherein the antibody fragment is selected from the group consisting of Fab, Fab′

-SH, Fv, scFv, and (Fab′

)₂ fragments.

33. The method of any one of claims 1-30, wherein the bispecific antibody is a full-length antibody.

34. The method of any one of claims 1-30 and 33, wherein the bispecific antibody is an IgG antibody.

35. The method of claim 34, wherein the IgG antibody is an IgG₁ antibody.

36. The method of any one of claims 1-35, wherein the bispecific antibody comprises one or more heavy chain constant domains, wherein the one or more heavy chain constant domains are selected from a first CH1 (CH1₁) domain, a first CH2 (CH2₁) domain, a first CH3 (CH3₁) domain, a second CH1 (CH1₂) domain, second CH2 (CH2₂) domain, and a second CH3 (CH3₂) domain.

37. The method of claim 36, wherein at least one of the one or more heavy chain constant domains is paired with another heavy chain constant domain.

38. The method of claim 36 or 37, wherein the CH3₁ and CH3₂ domains each comprise a protuberance or cavity, and wherein the protuberance or cavity in the CH3₁ domain is positionable in the cavity or protuberance, respectively, in the CH3₂ domain.

39. The method of claim 38, wherein the CH3₁ and CH3₂ domains meet at an interface between the protuberance and cavity.

40. The method of any one of claims 36-39, wherein the CH2₁ and CH2₂ domains each comprise a protuberance or cavity, and wherein the protuberance or cavity in the CH2₁ domain is positionable in the cavity or protuberance, respectively, in the CH2₂ domain.

41. The method of claim 40, wherein the CH2₁ and CH2₂ domains meet at an interface between said protuberance and cavity.

42. The method of any one of claims 1-41, wherein the bispecific antibody is administered to the subject as a monotherapy.

43. The method of any one of claims 1-41, wherein the bispecific antibody is administered to the subject as a combination therapy.

44. The method of claim 43, wherein the bispecific antibody is administered to the subject concurrently with an additional therapeutic agent.

45. The method of claim 43, wherein the bispecific antibody is administered to the subject prior to the administration of an additional therapeutic agent.

46. The method of claim 44 or 45, wherein the additional therapeutic agent is atezolizumab.

47. The method of claim 13, further comprising administering to the subject a first dose of atezolizumab concurrently with the C2D1 of the bispecific antibody on Day 1 of the second dosing cycle.

48. The method of claim 47, further comprising administering to the subject atezolizumab concurrently with the single dose of the bispecific antibody of the one or more additional dosing cycles on Day 1 of the one or more additional dosing cycles.

49. The method of claim 48, wherein atezolizumab is only administered to the subject concurrently with the bispecific antibody.

50. The method of any one of claims 46-49, wherein each dose of atezolizumab is about 1200 mg.

51. The method of claim 43, wherein the bispecific antibody is administered to the subject subsequent to the administration of an additional therapeutic agent.

52. The method of claim 51, wherein the additional therapeutic agent is obinutuzumab (GAZYVA®

).

53. The method of claim 51, wherein the additional therapeutic agent is tocilizumab.

54. The method of any one of claims 1-53, wherein the B cell proliferative disorder is a non-Hodgkin'"'"'s lymphoma (NHL) or a chronic lymphoid leukemia (CLL).

55. The method of claim 54, wherein the NI-HL is a diffuse-large B cell lymphoma (DLBCL), a primary mediastinal (thymic) large B cell lymphoma (PMLBCL), or a follicular lymphoma (FL).

56. The method of claim 55, wherein the DLBCL is a relapsed or refractory DLBCL.

57. The method of any one of claims 1-56, wherein the administering is by intravenous infusion.

58. The method of any one of claims 1-56, wherein the administering is administering subcutaneously.

59. The method of any one of claims 1-53, wherein the subject has a cytokine release syndrome (CRS) event, and the method further comprising treating the symptoms of the CRS event while suspending treatment with the bispecific antibody.

60. The method of claim 59, wherein the method further comprising administering to the subject an effective amount of tocilizumab to treat the CRS event.

61. The method of claim 60, wherein tocilizumab is administered intravenously to the subject as a single dose of about 8 mg/kg.

62. The method of claim 61, wherein the CRS event does not resolve or worsens within 24 hours of treating the symptoms of the CRS event, the method further comprising administering to the subject one or more additional doses of tocilizumab to manage the CRS event.

63. The method of claim 62, wherein the one or more additional doses of tocilizumab is administered intravenously to the subject at a dose of about 8 mg/kg.

64. The method of claim 62 or 63, further comprising administering to the subject an effective amount of a corticosteroid.

65. The method of claim 64, wherein the corticosteroid is administered intravenously to the subject.

66. The method of claim 64 or 65, wherein the corticosteroid is methylprednisolone.

67. The method of claim 66, wherein methylprednisolone is administered at a dose of about 2 mg/kg per day.

68. The method of claim 64 or 65, wherein the corticosteroid is dexamethasone.

69. The method of claim 68, wherein dexamethasone is administered at a dose of about 10 mg.