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 HER2-positive cancer in a subject, the method comprising administering to the subject an effective amount of a bispecific antibody that binds to HER2 and CD3, wherein the bispecific antibody comprises
(a) an anti-HER2 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: 169,
an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 170,
an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 171,
an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 172,
an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 173, and
an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 174; 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: 270; (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: 271; 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 5 , wherein the aglycosylation site mutation is at amino acid residue N297, L234, L235, and/or D265 (EU numbering).
7. The method of claim 6 , wherein the aglycosylation site 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 HER2 and CD3.
10. The method of claim 9 , wherein the antibody fragment is a Fab, Fab′-SH, Fv, scFv, or (Fab′) 2 fragment.
11. The method of claim 8 , wherein the bispecific antibody is a full-length antibody.
12. The method of claim 1 , wherein the HER2-positive cancer is a HER2-positive breast cancer or a HER2-positive gastric cancer.
13. The method of claim 1 , further comprising administering to the subject a PD-1 axis binding antagonist and/or an additional therapeutic agent.
14. The method of claim 13 , wherein the PD-1 axis binding antagonist and/or additional therapeutic agent is administered prior to, or concurrently with, the administration of the bispecific antibody.
15. The method of claim 13 , wherein the PD-1 axis binding antagonist and/or additional therapeutic agent is administered subsequent to the administration of the bispecific antibody.
16. The method of claim 13 , wherein the PD-1 axis binding antagonist is a PD-L1 binding antagonist, a PD-1 binding antagonist, or a PD-L2 binding antagonist.
17. The method of claim 16 , wherein the PD-1 axis binding antagonist is a PD-L1 binding antagonist, and wherein the PD-L1 binding antagonist is MPDL3280A, MDX-1105, or MED14736.
18. The method of claim 17 , wherein the PD-L1 binding antagonist is MPDL3280A.
19. The method of claim 16 , wherein the PD-1 axis binding antagonist is a PD-1 binding antagonist, and wherein the PD-1 binding antagonist is MDX-1106 (nivolumab), MK-3475 (lambrolizumab), or AMP-224.
20. The method of claim 16 , wherein the PD-1 axis binding antagonist is a PD-L2 binding antagonist, and wherein the PD-L2 binding antagonist is an antibody or an immunoadhesin.
21. The method of claim 1 , further comprising administering to the subject a glucocorticoid or an antibody-drug conjugate (ADC).
22. 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.
23. The method of claim 1 , wherein the bispecific antibody is administered intravenously, subcutaneously, intramuscularly, topically, orally, transdermally, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecally, intraventricularly, or intranasally.
24. The method of claim 23 , wherein the bispecific antibody is administered intravenously.
25. A method of enhancing immune function in a subject having a HER2-positive cancer, the method comprising administering to the subject an effective amount of a bispecific antibody that binds to HER2 and CD3, wherein the bispecific antibody comprises
(a) an anti-HER2 arm comprising a first binding domain, the first binding domain comprising:
an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 169,
an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 170,
an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 171,
an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 172,
an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 173, and
an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 174; 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.
26. The method of claim 25 , 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: 270; (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 271; 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).
27. The method of claim 25 , wherein the second binding domain binds to a human CD3ε polypeptide or a cyno CD3ε polypeptide.
28. The method of claim 25 , wherein the bispecific antibody comprises a substitution mutation in the Fc region that reduces effector function.
29. The method of claim 28 , wherein the substitution mutation is an aglycosylation site mutation.
30. The method of claim 29 , wherein the aglycosylation site mutation is at amino acid residue N297, L234, L235, and/or D265 (EU numbering).
31. The method of claim 30 , wherein the aglycosylation site mutation is selected from the group consisting of N297G, N297A, L234A, L235A, and D265A.
32. The method of claim 25 , wherein the bispecific antibody is monoclonal, humanized, or chimeric.
33. The method of claim 32 , wherein the bispecific antibody is an antibody fragment that binds HER2 and CD3.
34. The method of claim 33 , wherein the antibody fragment is a Fab, Fab′-SH, Fv, scFv, or (Fab′) 2 fragment.
35. The method of claim 32 , wherein the bispecific antibody is a full-length antibody.
36. The method of claim 25 , wherein the HER2-positive cancer is a HER2-positive breast cancer or a HER2-positive gastric cancer.
37. The method of claim 25 , further comprising administering to the subject a PD-1 axis binding antagonist and/or an additional therapeutic agent.
38. The method of claim 37 , wherein the PD-1 axis binding antagonist and/or additional therapeutic agent is administered prior to, or concurrently with, the administration of the bispecific antibody.
39. The method of claim 37 , wherein the PD-1 axis binding antagonist and/or additional therapeutic agent is administered subsequent to the administration of the bispecific antibody.
40. The method of claim 37 , wherein the PD-1 axis binding antagonist is a PD-L1 binding antagonist, a PD-1 binding antagonist, or a PD-L2 binding antagonist.
41. The method of claim 40 , wherein the PD-1 axis binding antagonist is a PD-L1 binding antagonist, wherein the PD-L1 binding antagonist is MPDL3280A, MDX-1105, or MED14736.
42. The method of claim 41 , wherein the PD-L1 binding antagonist is MPDL3280A.
43. The method of claim 40 , wherein the PD-1 axis binding antagonist is a PD-1 binding antagonist, wherein the PD-1 binding antagonist is MDX-1106 (nivolumab), MK-3475 (lambrolizumab), or AMP-224.
44. The method of claim 42 , wherein the PD-1 axis binding antagonist is a PD-L2 binding antagonist, wherein the PD-L2 binding antagonist is an antibody or an immunoadhesin.
45. The method of claim 25 , further comprising administering to the subject a glucocorticoid or an ADC.
46. The method of claim 25 , wherein the bispecific antibody is administered to the subject in a dosage of about 0.01 mg/kg to about 10 mg/kg.
47. The method of claim 25 , wherein the bispecific antibody is administered intravenously, subcutaneously, intramuscularly, topically, orally, transdermally, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecally, intraventricularly, or intranasally.
48. The method of claim 47 , wherein the bispecific antibody is administered intravenously.
49. The method of claim 1 , further comprising administering to the subject one or more additional therapeutic agents that target the HER pathway.
50. The method of claim 49 , wherein the one or more additional therapeutic agents that target the HER pathway is selected from trastuzumab, T-DM1, and pertuzumab.
51. The method of claim 50 , wherein the one or more additional therapeutic agents that target the HER pathway is trastuzumab.
52. The method of claim 25 , further comprising administering to the subject one or more additional therapeutic agents that target the HER pathway.
53. The method of claim 52 , wherein the one or more additional therapeutic agents that target the HER pathway is selected from trastuzumab, T-DM1, or pertuzumab.
54. The method of claim 53 , wherein the one or more additional therapeutic agents that target the HER pathway is trastuzumab.
55. The method of claim 2 , wherein the first binding domain comprises:
a VH domain comprising the amino acid sequence of SEQ ID NO: 270 and a VL domain comprising the amino acid sequence of SEQ ID NO: 271; and
the second binding domain comprises:
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.
56. The method of claim 26 , wherein the first binding domain comprises:
a VH domain comprising the amino acid sequence of SEQ ID NO: 270 and a VL domain comprising the amino acid sequence of SEQ ID NO: 271; and
the second binding domain comprises:
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.