Co-Therapy Comprising A Small Molecule CSF-1R Inhibitor And An Agonistic Antibody That Specifically Binds CD40 For The Treatment Of Cancer

Abstract

The present invention is directed to methods for treating cancer, preferably a solid tumor or hematological malignancy, including for example pancreatic cancer, lung cancer (including but not limited to non-small cell lung cancer (NSCLC)), prostate cancer, colorectal cancer, breast cancer, melanoma or non-Hodgkin's lymphoma, comprising administering to a subject in need thereof a therapeutically effective amount of co-therapy comprising, consisting or consisting essentially of (a) a small molecule CSF-1R inhibitor and (b) an agonistic antibody that binds CD40.

We claim: 
     
         1 . A method of treating a cancer comprising administering to a subject in need thereof a therapeutically effective amount of co-therapy comprising (a) a small molecule CSF-1R inhibitor and (b) an agonistic antibody or an antigen-binding fragment thereof that specifically binds CD40. 
     
     
         2 . The method of  claim 1 , wherein the cancer is a solid tumor or a hematological malignancy. 
     
     
         3 . The method of  claim 1 , wherein the cancer is selected from the group consisting of pancreatic cancer, prostate cancer, colorectal cancer, lung cancer, non-Hodgkin's lymphoma, breast cancer and melanoma. 
     
     
         4 . The method of  claim 1 , wherein the cancer is selected from the group consisting of pancreatic cancer, prostate cancer, colorectal cancer and non-small cell lung cancer. 
     
     
         5 . The method of  claim 3 , wherein the prostate cancer is castration resistant prostate cancer. 
     
     
         6 . The method of  claim 3 , wherein the lung cancer is non-small cell lung cancer (NSCLC). 
     
     
         7 . The method of  claim 1 , wherein the subject is resistant or refractory to treatment with a CSF-1R inhibitor. 
     
     
         8 . The method of  claim 1 , wherein the subject is resistant or refractory to treatment with a CD40 agonist. 
     
     
         9 . The method of  claim 1 , wherein the small molecule CSF-1R inhibitor and the agonistic antibody or the antigen-binding fragment thereof that specifically binds CD40 are administered concurrently, sequentially or separately. 
     
     
         10 . The method of  claim 1 , wherein the small molecule CSF-1R inhibitor is administered prior to administration of the agonistic antibody or the antigen-binding fragment thereof that specifically binds CD40 or wherein the small molecule CSF-1R inhibitor is administered prior to and concurrently with administration of the agonistic antibody or the antigen-binding fragment thereof that specifically binds CD40. 
     
     
         11 . The method of  claim 1 , further comprising administering to the subject radiation therapy or at least one additional cancer therapeutic agents. 
     
     
         12 . The method of  claim 11 , wherein the at least one additional cancer therapeutic agent is a standard of care drug for treatment of the cancer. 
     
     
         13 . The method of  claim 1 , wherein the small molecule CSF-1R inhibitor is selected from the group consisting of AB-530, AC-708, AC-710, AC-855, BLZ-3495, DCC-3014, GW-2580, Ilorasertib, Masitinib, Pexidartinib, PLX 5622, PLX FK1, PLX-7486, REDX-05182 and a compound of formula (I) 
       
         
           
           
               
               
           
         
       
       or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof. 
     
     
         14 . The method of  claim 1 , wherein the small molecule CSF-1R inhibitor is selected from the group consisting of PLX-3397, DCC-3014, BLZ-3495 and a compound of formula (I) 
       
         
           
           
               
               
           
         
       
       or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof. 
     
     
         15 . The method of  claim 1 , wherein the small molecule CSF-1R inhibitor is a compound of formula (I) 
       
         
           
           
               
               
           
         
       
       or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof. 
     
     
         16 . The method of  claim 15 , wherein the compound of formula (I) is administered prior to administration of the agonistic antibody or the antigen-binding fragment thereof that specifically binds CD40 or wherein the compound of formula (I) is administered prior to and concurrently with administration of the agonistic antibody or the antigen-binding fragment thereof that specifically binds CD40. 
     
     
         17 . The method of  claim 16 , wherein the compound of formula (I) is administered prior to administration of the agonistic antibody or the antigen-binding fragment thereof that specifically binds CD40. 
     
     
         18 . The method of  claim 17 , wherein the compound of formula (I) is administered daily for between 1 and 30 days prior to administration of the agonistic antibody or the antigen-binding fragment thereof that specifically binds CD40. 
     
     
         19 . The method of  claim 17 , wherein the compound of formula (I) is administered daily for between 7 and 14 days prior to administration of the agonistic antibody or the antigen-binding fragment thereof that specifically binds CD40. 
     
     
         20 . The method of  claim 16 , wherein the compound of formula (I) is administered in an amount in the range of from about 10 mg per day to about 600 mg per day. 
     
     
         21 . The method of  claim 16 , wherein the compound of formula (I) is administered in an amount in the range of from about 50 mg per day to about 300 mg per day 
     
     
         22 . The method of  claim 16 , wherein the compound of formula (I) is administered in an amount in the range of from about 100 mg per day to about 200 mg per day 
     
     
         23 . The method of  claim 16 , wherein the compound of formula (I) is administered daily for between 7 and 14 days prior to administration of the agonistic antibody or the antigen-binding fragment thereof that specifically binds CD40, and then further administered concurrently with administration of the agonistic antibody or the antigen-binding fragment thereof that specifically binds CD40. 
     
     
         24 . The method of  claim 16 , wherein the agonistic antibody or the antigen-binding fragment thereof that specifically binds CD40 is administered between about once a week and about once every three months, in an amount in the range of from about 1 mg/kg to about 100 mg/kg. 
     
     
         25 . The method of  claim 16 , wherein the agonistic antibody or the antigen-binding fragment thereof that specifically binds CD40 is administered once a week or once a month in an amount in the range of from about 1 mg/kg to about 50 mg/kg. 
     
     
         26 . The method of  claim 16 , wherein the agonistic antibody or the antigen-binding fragment thereof binds CD40 within CD40 residues 24-59 of SEQ ID NO: 1. 
     
     
         27 . The method of  claim 26 , wherein the agonistic antibody or the antigen-binding fragment thereof comprises a heavy chain variable region 1 (HCDR1), a HCDR2, a HCDR3, a light chain complementarity determining region 1 (LCDR1), a LCDR2 and a LCDR3 of SEQ ID NOs:
 a) 2, 3, 4, 5, 6 and 7, respectively;   b) 2, 3, 4, 13, 6 and 20 respectively;   c) 2, 3, 4, 14, 18 and 21, respectively;   d) 2, 12, 4, 13, 6 and 20, respectively; or   e) 2, 3, 4, 5, 6 and 25, respectively.   
     
     
         28 . The method of  claim 26 , wherein the agonistic antibody or the antigen-binding fragment thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL) of SEQ ID NOs:
 a) 8 and 9, respectively;   b) 8 and 27, respectively;   c) 8 and 28, respectively;   d) 26 and 27, respectively; or   e) 8 and 33, respectively.   
     
     
         29 . The method of  claim 26 , wherein the agonistic antibody comprises a heavy chain (HC) of SEQ ID NO: 10 and a light chain (LC) of SEQ ID NO: 11. 
     
     
         30 . The method of  claim 1 , wherein the agonistic antibody or the antigen-binding fragment thereof binds CD40 within CD40 residues 46-64 and 75-76 of SEQ ID NO: 1. 
     
     
         31 . The method of  claim 30 , wherein the agonistic antibody or the antigen-binding fragment thereof comprises
 a) the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 34, 35, 36, 37, 38 and 39, respectively;   b) the VH and the VL of SEQ ID NOs: 40 and 41, respectively; and/or   C) the HC and the LC of SEQ ID NOs: 48 and 49, respectively.   
     
     
         32 . The method of  claim 1 , wherein the agonistic antibody or the antigen-binding fragment thereof comprises
 a) the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 2, 3, 4, 15, 6 and 22, respectively; and/or   b) the VH and the VL of SEQ ID NOs: 8 and 29, respectively.   
     
     
         33 . The method of any of the  claims 1 - 25 , wherein the agonistic antibody or the antigen-binding fragment thereof comprises
 a) the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 2, 3, 4, 16, 19 and 23, respectively; and/or   b) the VH and the VL of SEQ ID NOs: 8 and 30, respectively.   
     
     
         34 . The method of  claim 1 , wherein the agonistic antibody or the antigen-binding fragment thereof comprises
 a) the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 2, 3, 4, 17, 6 and 24, respectively; and/or   b) the VH and the VL of SEQ ID NOs: 8 and 31, respectively.   
     
     
         35 . The method of  claim 1 , wherein the agonistic antibody or the antigen-binding fragment thereof comprises
 a) the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 2, 3, 4, 5, 6 and 20, respectively; and/or   b) the VH and the VL of SEQ ID NOs: 8 and 32, respectively.   
     
     
         36 . The method of  claim 1 , wherein the agonistic antibody or the antigen-binding fragment thereof comprises the VH and the VL of
 a) SEQ ID NOs: 42 and 43, respectively;   b) SEQ ID NOs: 44 and 45, respectively; or   c) SEQ ID NOs: 46 and 47, respectively.   
     
     
         37 . The method of  claim 1 , wherein the antibody is an IgG1, an IgG2, an IgG3 or an IgG4 isotype. 
     
     
         38 . The method of  claim 37 , wherein the antibody comprises at least one mutation in an Fc region. 
     
     
         39 . The method of  claim 38 , wherein the at least one mutation enhances binding of the antibody to FcγRIIb. 
     
     
         40 . The method of  claim 39 , wherein the at least one mutation in the Fc region is a S267E mutation, a S267E/I332E mutation, a S267E/L328F mutation, a G236D/S267E mutation or a E233D/G237D/H268D/P271G/A330R/P238D mutation, residue numbering according to the EU Index.