Combination of Anti-PD-1 Antibodies and Anti-CD20/Anti-CD3 Antibodies to Treat Cancer

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.

What is claimed is: 
     
         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. 
     
     
         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. 
     
     
         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. 
     
     
         4 . The method of  claim 1 , wherein the bispecific antibody comprises between 0.1-10 mg/kg of the subject's body weight. 
     
     
         5 . The method of  claim 1 , wherein the bispecific antibody comprises 10-8000 micrograms. 
     
     
         6 . The method of  claim 1 , wherein the anti-PD-1 antibody is administered prior to, concurrent with or after the bispecific antibody. 
     
     
         7 . The method of  claim 6 , wherein the anti-PD-1 antibody is administered prior to the bispecific antibody. 
     
     
         8 . The method of  claim 7 , wherein the anti-PD-1 antibody is administered 1 week prior to the bispecific antibody. 
     
     
         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. 
     
     
         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. 
     
     
         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. 
     
     
         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. 
     
     
         13 . The method of  claim 10 , wherein each dose of the bispecific antibody comprises between 10-8000 micrograms. 
     
     
         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. 
     
     
         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. 
     
     
         16 . The method of  claim 15 , wherein each dose of the bispecific antibody is administered 0.5-12 weeks after the immediately preceding dose. 
     
     
         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. 
     
     
         18 . The method of  claim 9 , wherein each dose of the bispecific antibody is split into 2-5 fractions within a dosing period. 
     
     
         19 . The method of  claim 9 , wherein the anti-PD-1 antibody is administered prior to, concurrent with or after the bispecific antibody. 
     
     
         20 . The method of  claim 19 , wherein the anti-PD-1 antibody is administered prior to the bispecific antibody. 
     
     
         21 . The method of  claim 20 , wherein the anti-PD-1 antibody is administered 1 week prior to the bispecific antibody. 
     
     
         22 . The method of  claim 9 , wherein the antibodies are administered intravenously, subcutaneously, or intraperitoneally. 
     
     
         23 . The method of  claim 9 , wherein the tumor comprises a B-cell cancer. 
     
     
         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. 
     
     
         25 . The method of  claim 1 , wherein the subject is resistant or inadequately responsive to, or relapsed after prior therapy. 
     
     
         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. 
     
     
         27 . The method of  claim 26 , wherein tumor growth is delayed by at least 10 days as compared to an untreated subject. 
     
     
         28 . The method of  claim 1 , wherein the tumor growth is inhibited by at least 50% as compared to an untreated subject. 
     
     
         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. 
     
     
         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. 
     
     
         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. 
     
     
         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. 
     
     
         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. 
     
     
         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. 
     
     
         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. 
     
     
         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. 
     
     
         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. 
     
     
         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. 
     
     
         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. 
     
     
         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. 
     
     
         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.