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, wherein:
 the radioimmnoconjugate has the structure of Formula I-b-1, or a pharmaceutically acceptable salt thereof: 
                     
 wherein
 A is a metal complex of a chelating moiety, 
 wherein said chelating moiety is selected from the group consisting of DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), DOTMA (1R,4R,7R,10R)-α, α′, α′′ a‴-tetramethyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, DOTAM (1,4,7,10-tetrakis(carbamoylmethyl)-1,4,7,10-tetraazacyclododecane), DO3AM-acetic acid (2-(4,7,10-tris(2-amino-2-oxoethyl)-l,4,7,10-tetraazacyclododecan-l-yl)acetic acid), DOTP (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetra(methylene phosphonic acid)), DOTA-4AMP (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakis(acetamido-methylenephosphonic acid), NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid), and HP-D03A (hydroxypropyltetraazacyclododecanetriacetic acid), 
 wherein the metal of said metal complex is a radionuclide selected from the group consisting of  47 Sc,  55 Co,  60 Cu,  61 Cu,  62 Cu,  64 Cu,  67 Cu,  66 Ga,  67 Ga,  68 Ga,  82 Rb,  86 Y,  87 Y,  89 Zr,  90 Y,  97 Ru,  99 Tc,  99m Tc,  105 Rh,  109 Pd,  111 In,  117m Sn,  149 Pm,  149 Tb,  153 Sm,  166 Ho,  177 Lu ,   186 Re,  188 Re,  198 Au,  199 Au,  201 Tl,  203 Pb,  211 At,  212 Pb,  212 Bi,  213 Bi,  223 Ra,  225 Ac,  227 Th, and  229 Th; 
 L 1  is optionally substituted C 1 -C 6  alkyl or optionally substituted C 1 -C 6  heteroalkyl; 
 L 2  has the structure of Formula II: 
                     
 wherein 
 X 1  is C═ O (NR 1 ) or NR 1 , in which R 1  is H or optionally substituted C 1 — 
 C 6 alkylor optionally substituted C 1 -C 6  heteroalkyl, optionally substituted aryl or heteroaryl; 
 L 3 is optionally substituted C 1 -C 50  alkyl or optionally substituted C 1 -C 50  heteroakyl; and 
 Z 1  is CH 2,  C═O, C═S, OC═O,NR 1 C═O, or NR 1 , in which R 1  is hydrogen, optionally substituted C 1 -C 6  alkyl, or pyrrolide-2,5-dione, and 
 B is a human or humanized IgG antibody or an antigen-binding fragment thereof. 
 
   
     
     
         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 the radioimmunoconjugate. 
     
     
         3 . The method of  claim 1 , wherein the one or more checkpoint inhibitors or the radioimmunoconjugate is administered in a lower effective dose. 
     
     
         4 - 5 . (canceled) 
     
     
         6 . The method of  claim 1 , wherein the human or humanized IgG antibody or antigen-binding fragment thereof is capable of binding to a tumor-associated antigen. 
     
     
         7 - 8 . (canceled) 
     
     
         9 . The method of claim  8 , wherein the human or humanized IgG antibody or antigen-binding fragment thereof is an IGF-1R antibody or an antigen-binding fragment thereof. 
     
     
         10 - 12 . (canceled) 
     
     
         13 . The method of  claim 1 , 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  claim 1 , wherein the radioimmunoconjugate comprises the following structure: 
       
         
           
           
               
               
           
         
       
       wherein B is the targeting moiety. 
     
     
         17 . The method of  claim 1 ,wherein the one or more checkpoint inhibitors comprise a PD-1 inhibitor. 
     
     
         18 . (canceled) 
     
     
         19 . The method of  claim 1 ,wherein the one or more checkpoint inhibitors comprise an CTLA-4 inhibitor. 
     
     
         20 . (canceled) 
     
     
         21 . The method of  claim 1 , wherein the one or more checkpoint inhibitors comprises both a PD-1 inhibitor and a CTLA-4 inhibitor. 
     
     
         22 . The method of  claim 1 , wherein the mammal is a human. 
     
     
         23 . The method of  claim 1 , 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 . (canceled) 
     
     
         26 . The method of  claim 1 , 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 - 29 . (canceled) 
     
     
         30 . The method of  claim 27 , 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 - 41 . (canceled) 
     
     
         42 . The method of  claim 30 , wherein the sample is a tumor sample. 
     
     
         43 . The method of  claim 26 , wherein said therapeutic effect comprises (a) a decrease in tumor volume, a stable tumor volume, or a reduced rate of increase in tumor volume or (b) a decreased incidence of recurrence or metastasis. 
     
     
         44 . (canceled)