Radioimmunoconjugates and dna damage and repair inhibitor combination therapy

Abstract

Combination therapies comprising administering radioimmunoconjugates and DNA damage response inhibitors.

1 . A method for treating or ameliorating cancer, said method comprising:
 (i) administering to a mammal a radioimmunoconjugate, wherein the mammal has received or is receiving a DNA damage response inhibitor (DDRi);   (ii) administering to a mammal a DDRi, wherein the mammal has received or is receiving a radioimmunoconjugate; or   (iii) administering to the mammal a DDRi at the same time as administering the mammal a radioimmunoconjugate.   
     
     
         2 . The method of  claim 1 , said method comprising administering to a mammal a DDRi, wherein the mammal has received or is receiving a radioimmunoconjugate. 
     
     
         3 . The method of  claim 1  or  2 , wherein the DDRi is administered in a lower effective dose. 
     
     
         4 . The method of any one of  claims 1 - 3 , wherein the radioimmunoconjugate is administered in a lower effective dose. 
     
     
         5 . The method of  claim 1 , wherein the radioimmunoconjugate comprises (i) a targeting moiety, (ii) a linker, and (iii) a chelating moiety or a metal complex of a chelating moiety. 
     
     
         6 . The method of  claim 5 , wherein the targeting moiety is capable of binding to a tumor-associated antigen. 
     
     
         7 . The method of  claim 6 , wherein the tumor-associated antigen is a tumor-specific antigen. 
     
     
         8 . The method of  claim 6  or  7 , wherein the targeting moiety is an antibody or an antigen-binding fragment thereof. 
     
     
         9 . The method of  claim 8 , wherein the antibody or antigen-binding fragment thereof is an IGF1-R antibody or an antigen-binding fragment thereof. 
     
     
         10 . The method of  claim 8 , wherein the antibody or antigen-binding fragment thereof is an endosialin (TEM-1) antibody or an antigen-binding fragment thereof. 
     
     
         11 . The method of any one of  claims 5 - 10 , wherein the radioimmunoconjugate comprises a metal complex of a chelating moiety. 
     
     
         12 . The method of  claim 11 , wherein the metal complex comprises a radionuclide. 
     
     
         13 . The method of  claim 12 , wherein the radionuclide is an alpha emitter. 
     
     
         14 . The method of  claim 13 , wherein the radionuclide is an alpha emitter selected from the group consisting of Astatine-211 ( 211 At), Bismuth-212 ( 212 Bi), Bismuth-213 ( 213 Bi), Actinium-225 ( 225 Ac), Radium-223 ( 223 Ra), Lead-212 ( 212 Pb), Thorium-227 ( 227 Th), and Terbium-149 ( 149 Tb). 
     
     
         15 . The method of  claim 14 , wherein the radionuclide is  225 Ac. 
     
     
         16 . The method of any one of  claims 5 - 15 , wherein the radioimmunoconjugate comprises the following structure: 
       
         
           
           
               
               
           
         
       
       wherein B is the targeting moiety. 
     
     
         17 . The method of any one of  claims 1 - 16 , wherein the DDRi is a PARP inhibitor. 
     
     
         18 . The method of  claim 17 , wherein the PARP inhibitor is a small molecule PARP inhibitor. 
     
     
         19 . The method of  claim 18 , wherein the small molecule PARP inhibitor is selected from the group consisting of niparib, niraparib, olaparib, talazoparib, pamiparib, rucaparib (camsylate), and veliparib, or an analog thereof. 
     
     
         20 . The method of  claim 19 , wherein the small molecule PARP inhibitor is olaparib or an analog thereof. 
     
     
         21 . The method of any one of  claims 1 - 16 , wherein the DDRi is an ATR inhibitor. 
     
     
         22 . The method of  claim 21 , wherein the ATR inhibitor is a small molecule ATR inhibitor. 
     
     
         23 . The method of  claim 22 , wherein the small molecule ATR inhibitor is selected from the group consisting of AZ20, AZD0156, AZD1390, AZD6738, BAY-1895344, EPT-46464, M3541, M4344, M6620 (formerly known as VE-922 or VX-970), NU6027, VE-821, or an analog thereof. 
     
     
         24 . The method of  claim 23 , wherein the ATR inhibitor is BAY-1895344 or an analog thereof. 
     
     
         25 . The method of any one of  claims 1 - 16 , wherein the DDRi is a WEE1 inhibitor, a Chk1 inhibitor, or a Chk2 inhibitor. 
     
     
         26 . The method of any one of  claims 1 - 16 , wherein the DDRi is a DNA-protein kinase (DNA-PK) inhibitor. 
     
     
         27 . The method of any one of  claims 1 - 26 , wherein the mammal is a human. 
     
     
         28 . The method of any one of  claims 1 - 27 , wherein the mammal is diagnosed with cancer. 
     
     
         29 . The method of any one of  claims 1 - 28 , wherein the cancer is selected from the group comprising: breast cancer, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, head and neck cancer, prostate cancer, colorectal cancer, sarcoma, adrenocortical carcinoma, neuroendocrine cancer, Ewing's Sarcoma, multiple myeloma, or acute myeloid leukemia. 
     
     
         30 . The method of any one of  claims 1 - 29 , wherein the mammal has at least one solid tumor. 
     
     
         31 . The method of any one of  claims 1 - 30 , wherein said administering results in a therapeutic effect. 
     
     
         32 . The method of  claim 31 , wherein said therapeutic effect comprises a decrease in tumor volume, a stable tumor volume, or a reduced rate of increase in tumor volume. 
     
     
         33 . The method of  claim 31  or  32 , wherein said therapeutic effect comprises a decreased incidence of recurrence or metastasis.