Radioimmunoconjugates and checkpoint inhibitor combination therapy

Abstract

Combination therapies comprising administering radioimmunoconjugates and one or more checkpoint inhibitors.

1 . A method of inducing an immune response to a tumor in a mammal, said method comprising:
 (i) administering to the mammal a radioimmunoconjugate, wherein the mammal has received or is receiving one or more checkpoint inhibitors;   (ii) administering to the mammal one or more checkpoint inhibitors, wherein the mammal has received or is receiving a radioimmunoconjugate; or   (iii) administering the mammal one or more checkpoint inhibitors at the same time as administering the mammal a radioimmunoconjugate.   
     
     
         2 . The method of  claim 1 , said method comprising administering to a mammal one or more checkpoint inhibitors, wherein the mammal has received or is receiving a radioimmunoconjugate. 
     
     
         3 . The method of  claim 1  or  2 , wherein the one or more checkpoint inhibitors 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 IGF-1R 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 one or more checkpoint inhibitors comprise a PD-1 inhibitor. 
     
     
         18 . The method of  claim 17 , wherein the PD-1 inhibitor is an antibody. 
     
     
         19 . The method of any one of  claims 1 - 18 , wherein the one or more checkpoint inhibitors comprise an CTLA-4 inhibitor. 
     
     
         20 . The method of  claim 19 , wherein the CTLA-4 inhibitor is antibody. 
     
     
         21 . The method of any one of  claims 1 - 16 , wherein the one or more checkpoint inhibitors comprises both a PD-1 inhibitor and a CTLA-4 inhibitor. 
     
     
         22 . The method of any one of  claims 1 - 21 , wherein the mammal is a human. 
     
     
         23 . The method of any one of  claims 1 - 22 , wherein the mammal is diagnosed with cancer. 
     
     
         24 . The method of  claim 23 , 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. 
     
     
         25 . The method of any one of  claims 1 - 24 , wherein mammal has at least one solid tumor. 
     
     
         26 . The method of any one of  claims 1 - 25 , wherein said administering results in a therapeutic effect. 
     
     
         27 . The method of  claim 26 , wherein the targeting moiety is capable of binding to a tumor-associated antigen, and said therapeutic effect comprises an increase in T cells specific for the tumor-associated antigen. 
     
     
         28 . The method of  claim 27 , wherein said increase in T cells occurs in the tumor. 
     
     
         29 . The method of  claim 27  or  28 , wherein said increase in the T cells in the tumor is relative to T cells in the spleen. 
     
     
         30 . The method of  claim 27 ,  28 , or  29 , wherein said administering results in at least 15% of the total T cell population in a sample from the mammal being specific for the tumor-associated antigen. 
     
     
         31 . The method of  claim 30 , wherein said administering results in at least 20% of the total T cell population in a sample from the mammal being specific for the tumor-associated antigen. 
     
     
         32 . The method of  claim 31 , wherein said administering results in at least 25% of the total T cell population in a sample from the mammal being specific for the tumor-associated antigen. 
     
     
         33 . The method of  claim 32 , wherein said administering results in at least 30% of the total T cell population in a sample from the mammal being specific for the tumor-associated antigen. 
     
     
         34 . The method of  claim 33 , wherein said administering results in at least 35% of the total T cell population in a sample from the mammal being specific for the tumor-associated antigen. 
     
     
         35 . The method of  claim 34 , wherein said administering results in at least 40% of the total T cell population in a sample from the mammal being specific for the tumor-associated antigen. 
     
     
         36 . The method of  claim 35 , wherein said administering results in at least 45% of the total T cell population in a sample from the mammal being specific for the tumor-associated antigen. 
     
     
         37 . The method of  claim 36 , wherein said administering results in at least 50% of the total T cell population in a sample from the mammal being specific for the tumor-associated antigen. 
     
     
         38 . The method of  claim 37 , wherein said administering results in at least 55% of the total T cell population in a sample from the mammal being specific for the tumor-associated antigen. 
     
     
         39 . The method of  claim 38 , wherein said administering results in at least 60% of the total T cell population in a sample from the mammal being specific for the tumor-associated antigen. 
     
     
         40 . The method of  claim 40 , wherein said administering results in at least 65% of the total T cell population in a sample from the mammal being specific for the tumor-associated antigen. 
     
     
         41 . The method of  claim 41 , wherein said administering results in at least 70% of the total T cell population in a sample from the mammal being specific for the tumor-associated antigen. 
     
     
         42 . The method of any one of  claims 30 - 41 , wherein the sample is a tumor sample. 
     
     
         43 . The method of any one of  claims 26 - 42 , wherein said therapeutic effect comprises a decrease in tumor volume, a stable tumor volume, or a reduced rate of increase in tumor volume. 
     
     
         44 . The method of any one of  claims 26 - 43 , wherein said therapeutic effect comprises a decreased incidence of recurrence or metastasis.