Combination Therapy for the Treatment of Cancer

Abstract

The present invention is directed to a combination therapy involving the administration of a first molecule that specifically binds to human B7-H3 and a second molecule that that specifically binds to human PD-1 to a subject for the treatment of cancer and/or inflammation. The invention also concerns pharmaceutical compositions that comprise a first molecule that specifically binds to human B7-H3 and a second molecule that specifically binds to human PD-1 that are capable of mediating, and more preferably enhancing, the activation of the immune system against cancer cells that are associated with any of a variety of human cancers. The invention also relates to the use of such pharmaceutical compositions to treat cancer and other diseases in recipient subjects.

1 . A method of treating cancer, comprising administering to a subject in need thereof:
 (a) an anti-B7-H3 antibody or an antigen-binding fragment thereof comprising a variable domain that specifically binds to B7-H3 and comprises:
 (i) the three complementarity determining regions (CDRs) of a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 19; and 
 (ii) the three CDRs of a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 20, 
 wherein said anti-B7-H3 antibody or antigen-binding fragment thereof is administered at a dosage of about 1-15 mg/kg body weight, in combination with 
   (b) pembrolizumab.   
     
     
         2 . (canceled) 
     
     
         3 . (canceled) 
     
     
         4 . (canceled) 
     
     
         5 . The method of  claim 1 , wherein said anti-B7-H3 antibody or antigen-binding fragment thereof comprises an Fc Domain. 
     
     
         6 . The method of  claim 5 , wherein said anti-B7-H3 antibody or antigen-binding fragment thereof comprises a variant Fc Domain having at least one modification in the Fc Domain that enhances ADCC. 
     
     
         7 . (canceled) 
     
     
         8 . (canceled) 
     
     
         9 . The method of  claim 1 , wherein said anti-B7-H3 antibody or antigen-binding fragment thereof is administered at a dosage of about 1-15 mg/kg body weight every three weeks, and said pembrolizumab is administered at a fixed dosage of 200 mg or at a dosage of about 2 mg/kg body weight every three weeks. 
     
     
         10 . (canceled) 
     
     
         11 . (canceled) 
     
     
         12 . The method of  claim 9 , wherein said anti-B7-H3 antibody or antigen-binding fragment thereof is administered at a dosage of about 3 mg/kg body weight, about 10 mg/kg body weight, or about 15 mg/kg body weight every three weeks, and said pembrolizumab is administered at a dosage of about 2 mg/kg body weight every three weeks. 
     
     
         13 . (canceled) 
     
     
         14 . (canceled) 
     
     
         15 . (canceled) 
     
     
         16 . The method of  claim 1 , wherein said pembrolizumab is administered every three weeks. 
     
     
         17 . The method of  claim 1 , wherein said anti-B7-H3 antibody or antigen-binding fragment thereof and said pembrolizumab are administered by IV infusion. 
     
     
         18 . The method of  claim 1 , wherein every three weeks said anti-B7-H3 antibody or antigen-binding fragment thereof and said pembrolizumab are administered within a 48-hour period of each other. 
     
     
         19 . (canceled) 
     
     
         20 . The method of  claim 1 , wherein said cancer is a B7-H3-expressing cancer. 
     
     
         21 . The method of  claim 20 , wherein said B7-H3-expressing cancer is selected from the group consisting of: a squamous cell cancer of the head and neck (SCCHN), a bladder cancer, a breast cancer, a colorectal cancer, a gastric cancer, a glioblastoma, a kidney cancer, a lung cancer, a melanoma, an ovarian cancer, a pancreatic cancer, a pharyngeal cancer, a prostate cancer, a renal cell carcinoma, a small round blue cell tumor, a neuroblastoma, and a rhabdomyosarcoma. 
     
     
         22 . The method of  claim 1 , further comprises the step of administering to said subject a third therapeutic agent selected from the group consisting of an anti-angiogenic agent, an anti-neoplastic agent, a chemotherapeutic agent, and a cytotoxic agent. 
     
     
         23 - 33 . (canceled) 
     
     
         34 . The method of  claim 1 , wherein said anti-B7-H3 antibody or antigen-binding fragment thereof comprises:
 a heavy chain variable domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 20, 27, 28, 29 and 30; and   a light chain variable domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 19, 21, 22, 23, 24, 25 and 26.   
     
     
         35 . The method of  claim 1 , wherein said anti-B7-H3 antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO:39, and a heavy chain comprising the amino acid sequence of SEQ ID NO:40. 
     
     
         36 . The method of  claim 9 , wherein said anti-B7-H3 antibody or antigen-binding fragment thereof is administered at a dosage of about 3 mg/kg body weight, about 10 mg/kg body weight, or about 15 mg/kg body weight every three weeks, and said pembrolizumab is administered at a fixed dosage of 200 mg every three weeks. 
     
     
         37 . The method of  claim 12 , wherein said anti-B7-H3 antibody or antigen-binding fragment thereof is administered at a dosage of about 15 mg/kg body weight every three weeks and said pembrolizumab is administered at a dosage of about 2 mg/kg body weight every three weeks. 
     
     
         38 . The method of  claim 36 , wherein said anti-B7-H3 antibody or antigen-binding fragment thereof is administered at a dosage of about 15 mg/kg body weight every three weeks and said pembrolizumab is administered at a fixed dosage of 200 mg every three weeks. 
     
     
         39 . The method of  claim 21 , wherein said B7-H3-expressing cancer is a squamous cell cancer of the head and neck (SCCHN). 
     
     
         40 . The method of  claim 21 , wherein said B7-H3-expressing cancer is a lung cancer, which is a non-small cell lung cancer (NSCLC). 
     
     
         41 . The method of  claim 6 , wherein said variant Fc Domain comprises any one, any two, any three, any four, or all five of the substitutions L235V, F243L, R292P, Y300L, and P396L, wherein the numbering is according to the Kabat numbering scheme. 
     
     
         42 . The method of  claim 41 , wherein said variant Fc Domain comprises:
 (A) at least one substitution selected from the group consisting of F243L, R292P, Y300L, V305I, and P396L;   (B) at least two substitutions selected from the group consisting of:
 (1) F243L and P396L; 
 (2) F243L and R292P; and 
 (3) R292P and V305I; 
   (C) at least three substitutions selected from the group consisting of:
 (1) F243L, R292P and Y300L; 
 (2) F243L, R292P and V305I; 
 (3) F243L, R292P and P396L; and 
 (4) R292P, V305I and P396L; 
   (D) at least four substitutions selected from the group consisting of:
 (1) F243L, R292P, Y300L and P396L; and 
 (2) F243L, R292P, V305I and P396L; or 
   (E) at least the five substitutions selected from the group consisting of:
 (1) F243L, R292P, Y300L, V305I and P396L; and 
 (2) L235V, F243L, R292P, Y300L and P396L; 
   wherein the numbering is according to the Kabat numbering scheme.