Anti-CD3 antibodies and methods of use
The invention provides anti-cluster of differentiation 3 (CD3) antibodies and methods of using the same.
1. A method of treating or delaying progression of a B cell proliferative disorder in a subject, the method comprising administering to the subject an effective amount of a bispecific antibody that binds to CD20 and CD3, wherein the bispecific antibody comprises:
(a) an anti-CD20 arm comprising a first binding domain, the first binding domain comprising:
a hypervariable region (HVR)-H1 comprising the amino acid sequence of SEQ ID NO: 157,
an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 158,
an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 159,
an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 160,
an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 161, and
an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 162; and
(b) an anti-CD3 arm comprising a second binding domain, the second binding domain comprising:
an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1,
an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 2,
an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 3,
an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 4,
an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 5, and
an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 6.
2. The method of claim 1 , wherein the first binding domain comprises:
(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: 266; (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: 267; or (c) a VH domain as in (a) and a VL domain as in (b),
and the second binding domain comprises:
(a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 184; (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 185; or (c) a VH domain as in (a) and a VL domain as in (b).
3. The method of claim 1 , wherein the second binding domain binds to a human CD3ε polypeptide or a cynomolgus monkey (cyno) CD3ε polypeptide.
4. The method of claim 1 , wherein the bispecific antibody comprises a substitution mutation in the Fc region that reduces effector function.
5. The method of claim 4 , wherein the substitution mutation is an aglycosylation site mutation.
6. The method of claim 4 , wherein the substitution mutation is at amino acid residue N297, L234, L235, and/or D265 (EU numbering).
7. The method of claim 6 , wherein the substitution mutation is selected from the group consisting of N297G, N297A, L234A, L235A, and D265A.
8. The method of claim 1 , wherein the bispecific antibody is monoclonal, humanized, or chimeric.
9. The method of claim 8 , wherein the bispecific antibody is an antibody fragment that binds CD20 and CD3.
10. The method of claim 8 , wherein the bispecific antibody is a full-length antibody.
11. The method of claim 1 , wherein the B cell proliferative disorder is a B cell lymphoma, B cell leukemia, chronic lymphoid leukemia (CLL), marginal zone lymphoma (MZL), small lymphocytic leukemia (SLL), lymphoplasmacytic lymphoma (LL), Waldenstrom macroglobulinemia (WM), central nervous system lymphoma (CNSL), Burkitt's lymphoma (BL), B-cell prolymphocytic leukemia, Splenic marginal zone lymphoma, Hairy cell leukemia, Splenic lymphoma/leukemia, unclassifiable, Splenic diffuse red pulp small B-cell lymphoma, Hairy cell leukemia variant, Heavy chain diseases, a Heavy chain disease, γ Heavy chain disease, μ Heavy chain disease, Plasma cell myeloma, Solitary plasmacytoma of bone, Extraosseous plasmacytoma, Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma), Nodal marginal zone lymphoma, Pediatric nodal marginal zone lymphoma, Pediatric follicular lymphoma, Primary cutaneous follicle centre lymphoma, T-cell/histiocyte rich large B-cell lymphoma, Primary DLBCL of the CNS, Primary cutaneous DLBCL, leg type, EBV-positive DLBCL of the elderly, DLBCL associated with chronic inflammation, Lymphomatoid granulomatosis, Primary mediastinal (thymic) large B-cell lymphoma, Intravascular large B-cell lymphoma, ALK-positive large B-cell lymphoma, Plasmablastic lymphoma, Large B-cell lymphoma arising in HHV8-associated multicentric Castleman disease, Primary effusion lymphoma: B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma, or B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma.
12. The method of claim 1 , wherein the B cell proliferative disorder is a non-Hodgkin's lymphoma (NHL).
13. The method of claim 1 , further comprising administering to the subject rituximab, obinutuzumab, or an antibody-drug conjugate (ADC).
14. The method of claim 13 , wherein the ADC is an anti-CD79b ADC.
15. The method of claim 1 , further comprising administering to the subject polatuzumab vedotin.
16. The method of claim 1 , wherein the bispecific antibody is administered to the subject in a dosage of about 0.01 mg/kg to about 10 mg/kg.
17. The method of claim 1 , wherein the bispecific antibody is administered subcutaneously, intravenously, intramuscularly, topically, orally, transdermally, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecally, intraventricularly, or intranasally.
18. The method of claim 12 , wherein the NHL is DLBCL, follicular lymphoma (FL), or mantle cell lymphoma (MCL).
19. The method of claim 1 , wherein the bispecific antibody is administered intravenously.
20. The method of claim 1 , wherein the bispecific antibody is administered subcutaneously.
21. A method of treating or delaying progression of a B cell proliferative disorder in a subject, the method comprising administering to the subject an effective amount of a bispecific antibody that binds to CD20 and CD3, wherein the bispecific antibody comprises:
a first binding domain comprising:
(a) a VH domain comprising the amino acid sequence of SEQ ID NO: 266; and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 267, and
a second binding domain comprising:
(a) a VH domain comprising the amino acid sequence of SEQ ID NO: 184; and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 185.
22. The method of claim 21 , wherein the bispecific antibody comprises a substitution mutation in the Fc region that reduces effector function.
23. The method of claim 22 , wherein the substitution mutation is an aglycosylation site mutation.
24. The method of claim 22 , 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, and D265A.
26. The method of claim 21 , wherein the B cell proliferative disorder is a B cell lymphoma, chronic lymphoid leukemia (CLL), marginal zone lymphoma (MZL), small lymphocytic leukemia (SLL), lymphoplasmacytic lymphoma (LL), Waldenstrom macroglobulinemia (WM), central nervous system lymphoma (CNSL), Burkitt's lymphoma (BL), B-cell prolymphocytic leukemia, Splenic marginal zone lymphoma, Hairy cell leukemia, Splenic lymphoma/leukemia, unclassifiable, Splenic diffuse red pulp small B-cell lymphoma, Hairy cell leukemia variant, Heavy chain diseases, a Heavy chain disease, γ Heavy chain disease, μ Heavy chain disease, Plasma cell myeloma, Solitary plasmacytoma of bone, Extraosseous plasmacytoma, Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma), Nodal marginal zone lymphoma, Pediatric nodal marginal zone lymphoma, Pediatric follicular lymphoma, Primary cutaneous follicle centre lymphoma, T-cell/histiocyte rich large B-cell lymphoma, Primary DLBCL of the CNS, Primary cutaneous DLBCL, leg type, EBV-positive DLBCL of the elderly, DLBCL associated with chronic inflammation, Lymphomatoid granulomatosis, Primary mediastinal (thymic) large B-cell lymphoma, Intravascular large B-cell lymphoma, ALK-positive large B-cell lymphoma, Plasmablastic lymphoma, Large B-cell lymphoma arising in HHV8-associated multicentric Castleman disease, Primary effusion lymphoma: B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma, or B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma.
27. The method of claim 21 , wherein the B cell proliferative disorder is an NHL.
28. The method of claim 27 , wherein the NHL is DLBCL, FL, or MCL.
29. The method of claim 21 , further comprising administering to the subject rituximab, obinutuzumab, or an antibody-drug conjugate (ADC).
30. The method of claim 29 , wherein the ADC is an anti-CD79b ADC.
31. The method of claim 21 , further comprising administering to the subject polatuzumab vedotin.
32. The method of claim 21 , wherein the bispecific antibody is administered to the subject in a dosage of about 0.01 mg/kg to about 10 mg/kg.
33. The method of claim 21 , wherein the bispecific antibody is administered intravenously.
34. The method of claim 21 , wherein the bispecific antibody is administered subcutaneously.
35. A method of treating or delaying progression of an NHL in a subject, the method comprising administering to the subject an effective amount of a bispecific antibody that binds to CD20 and CD3, wherein the bispecific antibody comprises:
(a) an anti-CD20 arm comprising a first binding domain, the first binding domain comprising:
an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 157,
an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 158,
an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 159,
an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 160,
an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 161, and
an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 162; and
(b) an anti-CD3 arm comprising a second binding domain, the second binding domain comprising:
an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1,
an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 2,
an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 3,
an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 4,
an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 5, and
an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 6.
36. The method of claim 35 , wherein the first binding domain comprises:
(a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 266; (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 267; or (c) a VH domain as in (a) and a VL domain as in (b), and
the second binding domain comprises:
(a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 184; (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 185; or (c) a VH domain as in (a) and a VL domain as in (b).
37. The method of claim 35 , wherein the bispecific antibody comprises a substitution mutation in the Fc region that reduces effector function.
38. The method of claim 37 , wherein the substitution mutation is an aglycosylation site mutation.
39. The method of claim 37 , wherein the substitution mutation is at amino acid residue N297, L234, L235, and/or D265 (EU numbering).
40. The method of claim 39 , wherein the substitution mutation is selected from the group consisting of N297G, N297A, L234A, L235A, and D265A.
41. The method of claim 35 , wherein the NHL is DLBCL, FL, or MCL.
42. The method of claim 35 , wherein the NHL is DLBCL.
43. The method of claim 42 , wherein the DLBCL is GCB DLBCL, ABC DLBCL, primary DLBCL of the CNS, primary cutaneous DLBCL, EBV-positive DLBCL of the elderly, or DLBCL associated with chronic inflammation.
44. The method of claim 35 , wherein the NHL is FL.
45. The method of claim 35 , wherein the NHL is MCL.
46. The method of claim 35 , further comprising administering to the subject rituximab, obinutuzumab, or an ADC.
47. The method of claim 46 , wherein the ADC is an anti-CD79b ADC.
48. The method of claim 35 , further comprising administering to the subject polatuzumab vedotin.
49. The method of claim 35 , wherein the bispecific antibody is administered to the subject in a dosage of about 0.01 mg/kg to about 10 mg/kg.
50. The method of claim 35 , wherein the bispecific antibody is administered intravenously.
51. The method of claim 35 , wherein the bispecific antibody is administered subcutaneously.
52. A method of treating or delaying progression of an NHL in a subject, the method comprising administering to the subject an effective amount of a bispecific antibody, wherein the bispecific antibody comprises:
a first binding domain comprising:
(a) a VH domain comprising the amino acid sequence of SEQ ID NO: 266; and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 267, and
a second binding domain comprising:
(a) a VH domain comprising the amino acid sequence of SEQ ID NO: 184; and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 185.
53. The method of claim 52 , wherein the bispecific antibody comprises a substitution mutation in the Fc region that reduces effector function.
54. The method of claim 53 , wherein the substitution mutation is an aglycosylation site mutation.
55. The method of claim 53 , wherein the substitution mutation is at amino acid residue N297, L234, L235, and/or D265 (EU numbering).
56. The method of claim 55 , wherein the substitution mutation is selected from the group consisting of N297G, N297A, L234A, L235A, and D265A.
57. The method of claim 52 , wherein the NHL is DLBCL, FL, or MCL.
58. The method of claim 52 , wherein the NHL is DLBCL.
59. The method of claim 58 , wherein the DLBCL is GCB DLBCL, ABC DLBCL, primary DLBCL of the CNS, primary cutaneous DLBCL, EBV-positive DLBCL of the elderly, or DLBCL associated with chronic inflammation.
60. The method of claim 52 , wherein the NHL is FL.
61. The method of claim 52 , wherein the NHL is MCL.
62. The method of claim 52 , further comprising administering to the subject rituximab, obinutuzumab, or an ADC.
63. The method of claim 62 , wherein the ADC is an anti-CD79b ADC.
64. The method of claim 52 , further comprising administering to the subject polatuzumab vedotin.
65. The method of claim 52 , wherein the bispecific antibody is administered to the subject in a dosage of about 0.01 mg/kg to about 10 mg/kg.
66. The method of claim 52 , wherein the bispecific antibody is administered intravenously.
67. The method of claim 52 , wherein the bispecific antibody is administered subcutaneously.
68. A method of treating or delaying progression of a B cell proliferative disorder in a subject, the method comprising administering to the subject an effective amount of a bispecific antibody that binds to CD20 and CD3, wherein the bispecific antibody comprises:
(a) an anti-CD20 arm comprising a VH domain comprising the amino acid sequence of SEQ ID NO: 266 and a VL domain comprising the amino acid sequence of SEQ ID NO: 267; and
(b) an anti-CD3 arm comprising a VH domain comprising the amino acid sequence of SEQ ID NO: 184 and a VL domain comprising the amino acid sequence of SEQ ID NO: 185; and
wherein (a) the anti-CD20 arm further comprises T366W and N297G substitution mutations and (b) the anti-CD3 arm further comprises T366S, L368A, Y407V, and N297G substitution mutations.
69. A method of treating or delaying progression of an NHL in a subject, the method comprising administering to the subject an effective amount of a bispecific antibody that binds to CD20 and CD3, wherein the bispecific antibody comprises:
(a) an anti-CD20 arm comprising a VH domain comprising the amino acid sequence of SEQ ID NO: 266 and a VL domain comprising the amino acid sequence of SEQ ID NO: 267; and
(b) an anti-CD3 arm comprising a VH domain comprising the amino acid sequence of SEQ ID NO: 184 and a VL domain comprising the amino acid sequence of SEQ ID NO: 185; and
wherein (a) the anti-CD20 arm further comprises T366W and N297G substitution mutations and (b) the anti-CD3 arm further comprises T366S, L368A, Y407V, and N297G substitution mutations.
70. The method of claim 69 , wherein the NHL is DLBCL.
71. The method of claim 70 , wherein the DLBCL is GCB DLBCL, ABC DLBCL, primary DLBCL of the CNS, primary cutaneous DLBCL, EBV-positive DLBCL of the elderly, or DLBCL associated with chronic inflammation.
72. The method of claim 69 , wherein the NHL is FL.
73. The method of claim 69 , wherein the NHL is MCL.
74. The method of claim 68 or 69 , further comprising administering to the subject rituximab, obinutuzumab, or an ADC.
75. The method of claim 74 , wherein the ADC is an anti-CD79b ADC.
76. The method of claim 68 or 69 , further comprising administering to the subject polatuzumab vedotin.
77. The method of claim 68 or 69 , wherein the bispecific antibody is administered to the subject in a dosage of about 0.01 mg/kg to about 10 mg/kg.
78. The method of claim 68 or 69 , wherein the bispecific antibody is administered intravenously.
79. The method of claim 68 or 69 , wherein the bispecific antibody is administered subcutaneously.