Combination therapies with anti cd40 antibodies

Abstract

The present invention relates to combination therapies for treating a solid tumour in a subject. The combination therapies comprise (a) an antibody, or antigen-binding portion thereof, that specifically binds to CD40, and (b) a further immunotherapeutic agent with efficacy in the treatment of cancer, which agent is not an anti-CD40 antibody or antigen-binding fragment thereof. The invention also relates to a kits and methods of using such therapies.

1 . A combination therapy for use in a method of treating a solid tumour in a subject comprising
 (a) an antibody, or antigen-binding portion thereof, that specifically binds to CD40, and   (b) a further immunotherapeutic agent with efficacy in the treatment of cancer,   wherein the antibody or antigen-binding portion thereof that specifically binds to CD40 comprises light chain CDR sequences of SEQ ID NOs: 1, 2 and 3 and heavy chain CDR sequences of SEQ ID NOs: 4, 5 and 6 and   wherein the further immunotherapeutic agent is an anti-PD-1 antibody which blocks the interaction between PD1 and PD-L1.   
     
     
         2 . The combination therapy according to  claim 1  wherein the combination therapy provides a synergistic benefit in the treatment of a solid tumour in a subject. 
     
     
         3 . The combination therapy according to  claim 1  or  2  wherein the solid tumour is selected from the groups consisting of an adenoma, a blastoma, a carcinoma, a desmoid tumour, a desmopolastic small round cell tumour, an endocrine tumour, a germ cell tumour, a lymphoma, a sarcoma, a Wilms tumour, a lung tumour, a colon tumour, a lymph tumour, a breast tumour and a melanoma. 
     
     
         4 . The combination therapy to any one of the preceding claims wherein the solid tumour is a melanoma. 
     
     
         5 . A combination therapy according to any one of the preceding claims wherein the antibody or antigen-binding portion thereof that specifically binds to CD40 comprises or consists of an intact antibody. 
     
     
         6 . A combination therapy according to any one of  claims 1  to  4  wherein the antibody or antigen-binding portion thereof that specifically binds to CD40 comprises or consists of an antigen-binding fragment selected from the group consisting of: an Fv fragment and a Fab-like fragment. 
     
     
         7 . A combination therapy according to any one of the preceding claims wherein the antibody or antigen-binding portion thereof is human or humanised. 
     
     
         8 . A combination therapy according to any one of the preceding claims, wherein the antibody or antigen-binding portion thereof that specifically binds to CD40 comprises the light chain variable region of SEQ ID NO: 7 and/or the heavy chain variable region of SEQ ID NO: 8. 
     
     
         9 . A combination therapy according to any one of the preceding claims, wherein the antibody or antigen-binding portion thereof that specifically binds to CD40 comprises the light chain constant region of SEQ ID NO: 11 and/or the heavy chain constant region of SEQ ID NO: 12. 
     
     
         10 . A combination therapy according to any one of the preceding claims, wherein the antibody or antigen-binding portion thereof that specifically binds to CD40 comprises or consists of the light chain of SEQ ID NO: 7 plus SEQ ID NO: 11, and/or the heavy chain of SEQ ID NO: 8 plus SEQ ID NO: 12. 
     
     
         11 . A combination therapy according to any one of the preceding claims wherein the anti-PD-1 antibody is selected from the group consisting of Nivolumab, Pembrolizumab, Lambrolizumab, Pidilzumab, and AMP-224. 
     
     
         12 . An antibody, or antigen-binding portion thereof, that specifically binds to CD40 for use in a method of treating a solid tumour,
 wherein the antibody or antigen-binding portion thereof that specifically binds to CD40 comprises light chain CDR sequences of SEQ ID NOs: 1, 2 and 3 and heavy chain CDR sequences of SEQ ID NOs: 4, 5 and 6   and wherein the antibody or antigen-binding portion thereof that specifically binds to CD40 is for use in combination with a further immunotherapeutic agent with efficacy in the treatment of cancer, which agent is an anti-PD-1antibody which blocks the interaction between PD1 and PD-L1.   
     
     
         13 . An antibody, or antigen-binding portion thereof, according to  claim 12  wherein the antibody or antigen-binding portion thereof is as defined in any one of  claims 4  to  0 . 
     
     
         14 . An antibody, or antigen-binding portion thereof, according to  claim 12  or  13  wherein the further immunotherapeutic agent with efficacy in the treatment of cancer is as defined in  claim 11 . 
     
     
         15 . Use of an antibody, or antigen-binding portion thereof, that specifically binds to CD40 in the preparation of a medicament for treating a solid tumour,
 wherein the antibody or antigen-binding portion thereof that specifically binds to CD40 comprises light chain CDR sequences of SEQ ID NOs: 1, 2 and 3 and heavy chain CDR sequences of SEQ ID NOs: 4, 5 and 6   and wherein the antibody or antigen-binding portion thereof that specifically binds to CD40 is for use in combination with a further immunotherapeutic agent with efficacy in the treatment of cancer, which agent is an anti-PD-1 antibody which blocks the interaction between PD1 and PD-L1.   
     
     
         16 . The use according to  claim 15  wherein the antibody or antigen-binding portion thereof is as defined in any one of  claims 4  to  10 . 
     
     
         17 . The use according to  claim 15  or  16  wherein the further immunotherapeutic agent with efficacy in the treatment of cancer is as defined in  claim 11 . 
     
     
         18 . A pharmaceutical composition comprising (a) an antibody, or antigen-binding portion thereof, that specifically binds to CD40, and (b) a further immunotherapeutic agent with efficacy in the treatment of cancer, which agent is an anti-PD-1 antibody which blocks the interaction between PD1 and PD-L1, wherein the antibody or antigen-binding portion thereof that specifically binds to CD40 comprises light chain CDR sequences of SEQ ID NOs: 1, 2 and 3 and heavy chain CDR sequences of SEQ ID NOs: 4, 5 and 6. 
     
     
         19 . A pharmaceutical composition according to  claim 18  wherein the antibody or antigen-binding portion thereof is as defined in any one of  claims 4  to  10 . 
     
     
         20 . A pharmaceutical composition according to  claim 18  or  19  wherein the further immunotherapeutic agent with efficacy in the treatment of cancer is as defined in  claim 11 . 
     
     
         21 . A kit for treating a solid tumour comprising (a) an antibody, or antigen-binding portion thereof, that specifically binds to CD40, and (b) a further immunotherapeutic agent with efficacy in the treatment of cancer, which agent is an anti-PD-1 antibody which blocks the interaction between PD1 and PD-L1, wherein the antibody or antigen-binding portion thereof that specifically binds to CD40 comprises light chain CDR sequences of SEQ ID NOs: 1, 2 and 3 and heavy chain CDR sequences of SEQ ID NOs: 4, 5 and 6. 
     
     
         22 . A kit according to  claim 21  wherein the antibody or antigen-binding portion thereof is as defined in any one of  claims 4  to  10 . 
     
     
         23 . A kit according to  claim 21  or  22  wherein the further immunotherapeutic agent with efficacy in the treatment of cancer is as defined in  claim 11 . 
     
     
         24 . A method for treating a solid tumour in a subject, the method comprising administering to the subject a therapeutically effect amount of (a) administering to the subject a therapeutically effect amount of an antibody, or antigen-binding portion thereof, that specifically binds to CD40, and (b) administering to the subject a therapeutically effect amount of a further immunotherapeutic agent with efficacy in the treatment of cancer, which agent is an anti-PD-1 antibody which blocks the interaction between PD1 and PD-L1, wherein the antibody or antigen-binding portion thereof that specifically binds to CD40 comprises light chain CDR sequences of SEQ ID NOs: 1, 2 and 3 and heavy chain CDR sequences of SEQ ID NOs: 4, 5 and 6. 
     
     
         25 . A method according to  claim 24  wherein the antibody or antigen-binding portion thereof is as defined in any one of  claims 4  to  10 . 
     
     
         26 . A method according to  claim 24  or  25  wherein the further immunotherapeutic agent with efficacy in the treatment of cancer is as defined in  claim 11 . 
     
     
         27 . A method according to any one of  claims 24  to  26  wherein steps (a) and (b) are carried out simultaneously or wherein step (b) is carried out between 24 hours and two weeks after step (a), between 24 hours and one week after step (a), between 24 and 72 hours after step (a), or between 24 and 48 hours after step (a). 
     
     
         28 . A method according to any one of  claims 24  to  27  wherein step (a) comprises local administration of the antibody to the tumour site. 
     
     
         29 . A method according to any one of  claims 24  to  28 , wherein at least 30% of the amount of antibody administered in step (a) is retained at the tumour site at four hours after administration, preferably wherein at least 40% of the said amount is retained at the tumour site at four hours after administration. 
     
     
         30 . A method according to any one of  claims 24  to  29  wherein the additional therapeutic agent of step (b) is formulated as a composition suitable for systemic administration with at least one pharmaceutically acceptable diluent or carrier. 
     
     
         31 . A method according to one of  claims 24  to  30  wherein step (a) is conducted on multiple separate occasions and step (b) is conducted such that exposure of the subject to the additional therapeutic agent is continuous for the duration of the method. 
     
     
         32 . A method according to any one of  claims 24  to  31  wherein the subject is a human.