Combination of Anti-PD-1 Antibodies and Anti-CD20/Anti-CD3 Antibodies to Treat Cancer
First Claim
1. A method of treating or inhibiting the growth of a tumor comprising administering to a subject in need thereof a therapeutically effective amount each of (a) an antibody or antigen-binding fragment thereof that specifically binds programmed death 1 (PD-1);
- and (b) a bispecific antibody comprising a first antigen-binding arm that specifically binds CD20 and a second antigen-binding arm that specifically binds CD3.
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Accused Products
Abstract
The present invention provides methods for treating, reducing the severity, or inhibiting the growth of cancer (e.g., a B-cell cancer such as Hodgkin'"'"'s lymphoma or acute lymphoblastic leukemia). The methods of the present invention comprise administering to a subject in need thereof a therapeutically effective amount of an antibody or antigen-binding fragment thereof that specifically binds to programmed death 1 (PD-1) receptor in combination with a therapeutically effective amount of a bispecific antibody that specifically binds to CD20 and CD3.
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Citations
41 Claims
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1. A method of treating or inhibiting the growth of a tumor comprising administering to a subject in need thereof a therapeutically effective amount each of (a) an antibody or antigen-binding fragment thereof that specifically binds programmed death 1 (PD-1);
- and (b) a bispecific antibody comprising a first antigen-binding arm that specifically binds CD20 and a second antigen-binding arm that specifically binds CD3.
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2. The method of claim 1, wherein the anti-PD-1 antibody comprises between 0.1-20 mg/kg of the subject'"'"'s body weight.
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3. The method of claim 2, wherein the anti-PD-1 antibody comprises 0.3, 1, 3 or 10 mg/kg of the subject'"'"'s body weight.
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4. The method of claim 1, wherein the bispecific antibody comprises between 0.1-10 mg/kg of the subject'"'"'s body weight.
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5. The method of claim 1, wherein the bispecific antibody comprises 10-8000 micrograms.
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6. The method of claim 1, wherein the anti-PD-1 antibody is administered prior to, concurrent with or after the bispecific antibody.
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7. The method of claim 6, wherein the anti-PD-1 antibody is administered prior to the bispecific antibody.
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8. The method of claim 7, wherein the anti-PD-1 antibody is administered 1 week prior to the bispecific antibody.
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9. The method of claim 1, wherein one or more doses of the anti-PD-1 antibody are administered in combination with one or more doses of the bispecific antibody.
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10. The method of claim 9, wherein each dose of the anti-PD-1 antibody comprises between 0.1-20 mg/kg of the subject'"'"'s body weight.
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11. The method of claim 10, wherein each dose of the anti-PD-1 antibody comprises 0.3, 1, 3, or 10 mg/kg of the subject'"'"'s body weight.
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12. The method of claim 9, wherein each dose of the bispecific antibody comprises between 0.1-10 mg/kg of the subject'"'"'s body weight.
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13. The method of claim 10, wherein each dose of the bispecific antibody comprises between 10-8000 micrograms.
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14. The method of claim 13, wherein each dose of the anti-PD-1 antibody comprises 1, 3 or 10 mg/kg and each dose of the bispecific antibody comprises 30, 100, 300, 1000 or 2000 micrograms.
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15. The method of claim 9, wherein each dose of the anti-PD-1 antibody is administered 0.5-12 weeks after the immediately preceding dose.
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16. The method of claim 15, wherein each dose of the bispecific antibody is administered 0.5-12 weeks after the immediately preceding dose.
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17. The method of claim 16, wherein each dose of the anti-PD-1 antibody is administered once in two weeks and each dose of the bispecific antibody is administered once a week.
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18. The method of claim 9, wherein each dose of the bispecific antibody is split into 2-5 fractions within a dosing period.
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19. The method of claim 9, wherein the anti-PD-1 antibody is administered prior to, concurrent with or after the bispecific antibody.
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20. The method of claim 19, wherein the anti-PD-1 antibody is administered prior to the bispecific antibody.
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21. The method of claim 20, wherein the anti-PD-1 antibody is administered 1 week prior to the bispecific antibody.
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22. The method of claim 9, wherein the antibodies are administered intravenously, subcutaneously, or intraperitoneally.
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23. The method of claim 9, wherein the tumor comprises a B-cell cancer.
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24. The method of claim 23, wherein the B-cell cancer is selected from the group consisting of Hodgkin'"'"'s lymphoma, non-Hodgkin'"'"'s lymphoma, follicular lymphoma, small lymphocytic lymphoma, lymphoplasmacytoid lymphoma, marginal zone lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, B-cell lymphomas, lymphomatoid granulomatosis, Burkitt'"'"'s lymphoma, acute lymphoblastic leukemia, hairy cell leukemia, and B cell chronic lymphocytic leukemia.
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25. The method of claim 1, wherein the subject is resistant or inadequately responsive to, or relapsed after prior therapy.
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26. The method of claim 1, wherein the treatment produces a therapeutic effect selected from the group consisting of delay in tumor growth, reduction in tumor cell number, tumor regression, increase in survival, partial response, and complete response.
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27. The method of claim 26, wherein tumor growth is delayed by at least 10 days as compared to an untreated subject.
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28. The method of claim 1, wherein the tumor growth is inhibited by at least 50% as compared to an untreated subject.
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29. The method of claim 9, wherein the tumor growth is inhibited by at least 50% as compared to a subject administered with either antibody as monotherapy.
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30. The method of claim 20, wherein the tumor growth is inhibited by at least 50% as compared to a subject administered a bispecific anti-CD20/anti-CD3 antibody prior to an anti-PD-1 antibody.
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31. The method of claim 9 further comprising administering to the subject a third therapeutic agent or therapy, wherein the third therapeutic agent or therapy is selected from the group consisting of radiation, surgery, a chemotherapeutic agent, a cancer vaccine, a PD-L1 inhibitor, a LAG-3 inhibitor, a CTLA-4 inhibitor, a TIM3 inhibitor, a BTLA inhibitor, a TIGIT inhibitor, a CD47 inhibitor, an indoleamine-2,3-dioxygenase (IDO) inhibitor, a vascular endothelial growth factor (VEGF) antagonist, an angiopoietin-2 (Ang2) inhibitor, a transforming growth factor beta (TGFβ
- ) inhibitor, an epidermal growth factor receptor (EGFR) inhibitor, an antibody to a tumor-specific antigen, Bacillus Calmette-Guerin vaccine, granulocyte-macrophage colony-stimulating factor, a cytotoxin, an interleukin 6 receptor (IL-6R) inhibitor, an interleukin 4 receptor (IL-4R) inhibitor, an IL-10 inhibitor, IL-2, IL-7, IL-21, IL-15, an antibody-drug conjugate, an anti-inflammatory drug, and a dietary supplement.
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32. The method of claim 9, wherein the anti-PD-1 antibody or antigen-binding fragment thereof comprises the heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3) of a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO:
- 1 and three light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3) of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO;
2.
- 1 and three light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3) of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO;
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33. The method of claim 32, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO:
- 3;
HCDR2 comprises the amino acid sequence of SEQ ID NO;
4;
HCDR3 comprises the amino acid sequence of SEQ ID NO;
5;
LCDR1 comprises the amino acid sequence of SEQ ID NO;
6;
LCDR2 comprises the amino acid sequence of SEQ ID NO;
7; and
LCDR3 comprises the amino acid sequence of SEQ ID NO;
8.
- 3;
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34. The method of claim 33, wherein the HCVR comprises the amino acid sequence of SEQ ID NO:
- 1 and the LCVR comprises the amino acid sequence of SEQ ID NO;
2.
- 1 and the LCVR comprises the amino acid sequence of SEQ ID NO;
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35. The method of claim 34, wherein the anti-PD-1 antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:
- 9 and a light chain comprising the amino acid sequence of SEQ ID NO;
10.
- 9 and a light chain comprising the amino acid sequence of SEQ ID NO;
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36. The method of claim 9, wherein the first antigen-binding arm of the bispecific antibody comprises three heavy chain CDRs (A-HCDR1, A-HCDR2 and A-HCDR3) of a heavy chain variable region (A-HCVR) comprising the amino acid sequence of SEQ ID NO:
- 11 and three light chain CDRs (LCDR1, LCDR2 and LCDR3) of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO;
12.
- 11 and three light chain CDRs (LCDR1, LCDR2 and LCDR3) of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO;
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37. The method of claim 36, wherein A-HCDR1 comprises the amino acid sequence of SEQ ID NO:
- 14;
A-HCDR2 comprises the amino acid sequence of SEQ ID NO;
15;
A-HCDR3 comprises the amino acid sequence of SEQ ID NO;
16;
LCDR1 comprises the amino acid sequence of SEQ ID NO;
17;
LCDR2 comprises the amino acid sequence of SEQ ID NO;
18; and
LCDR3 comprises the amino acid sequence of SEQ ID NO;
19.
- 14;
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38. The method of claim 37, wherein the A-HCVR comprises the amino acid sequence of SEQ ID NO:
- 11 and the LCVR comprises the amino acid sequence of SEQ ID NO;
12.
- 11 and the LCVR comprises the amino acid sequence of SEQ ID NO;
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39. The method of claim 9, wherein the second antigen-binding arm of the bispecific antibody comprises three heavy chain CDRs (B-HCDR1, B-HCDR2 and B-HCDR3) of a heavy chain variable region (B-HCVR) comprising the amino acid sequence of SEQ ID NO:
- 13 and three light chain CDRs (LCDR1, LCDR2 and LCDR3) of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO;
12.
- 13 and three light chain CDRs (LCDR1, LCDR2 and LCDR3) of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO;
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40. The method of claim 39, wherein B-HCDR1 comprises the amino acid sequence of SEQ ID NO:
- 20;
B-HCDR2 comprises the amino acid sequence of SEQ ID NO;
21;
B-HCDR3 comprises the amino acid sequence of SEQ ID NO;
22;
LCDR1 comprises the amino acid sequence of SEQ ID NO;
17;
LCDR2 comprises the amino acid sequence of SEQ ID NO;
18; and
LCDR3 comprises the amino acid sequence of SEQ ID NO;
19.
- 20;
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41. The method of claim 40, wherein the B-HCVR comprises the amino acid sequence of SEQ ID NO:
- 13 and the LCVR comprises the amino acid sequence of SEQ ID NO;
12.
- 13 and the LCVR comprises the amino acid sequence of SEQ ID NO;
Specification