Compositions and methods for the depletion of cd137+ cells

Abstract

The invention provides methods of preventing and treating graft-versus-host-disease and autoimmune diseases, such as those arising from transplant therapy, by selective depletion of hematopoietic cells through the use of antibody-drug conjugates and ligand-drug conjugates that specifically bind CD137. The compositions and methods described herein can be used to treat a variety of pathologies, including stem cell disorders and other blood conditions.

1 . (canceled) 
     
     
         2 . A method of depleting a population of CD137 positive cells in a human patient suffering from or at risk for graft-versus-host disease or an autoimmune disease, the method comprising administering to the patient an effective amount of an antibody or antigen-binding fragment thereof capable of binding CD137, wherein the antibody or antigen-binding fragment thereof is conjugated to a cytotoxin via a linker. 
     
     
         3 - 5 . (canceled) 
     
     
         6 . The method of  claim 2 , wherein the antibody or antigen-binding fragment thereof binds human CD137 extracellular domain at an epitope located within amino acid residues 115-156 of SEQ ID NO: 20. 
     
     
         7 - 8 . (canceled) 
     
     
         9 . The method of  claim 2 , wherein the cytotoxin is a microtubule-binding agent or an RNA polymerase inhibitor. 
     
     
         10 . The method of  claim 9 , wherein the microtubule-binding agent is maytansine or a maytansinoid. 
     
     
         11 . (canceled) 
     
     
         12 . The method of  claim 10 , wherein the maytansinoid is selected from the group consisting of DM1, DM3, and DM4, and maytansinol. 
     
     
         13 - 35 . (canceled) 
     
     
         36 . The method of  claim 2 , wherein the autoimmune disease is multiple sclerosis, rheumatoid arthritis, intestinal bowel disease, psoriasis, lupus, or Type 1 diabetes. 
     
     
         37 . The method of  claim 2 , wherein said patient is suffering from a stem cell disorder, a hemoglobinopathy disorder, an immunodeficiency disorder, a metabolic disorder, or a cancer. 
     
     
         38 - 65 . (canceled) 
     
     
         66 . A method of depleting allo-reactive T cells in a human patient who received an allogenic transplant, the method comprising administering an anti-CD137 ADC to the human patient such that allo-reactive T cells are depleted, wherein the ADC comprises an anti-CD137 antibody linked to a cytotoxin. 
     
     
         67 - 71 . (canceled) 
     
     
         72 . The method of  claim 66 , wherein the cytotoxin is an RNA polymerase inhibitor. 
     
     
         73 . The method of  claim 72 , wherein the RNA polymerase inhibitor is an amatoxin. 
     
     
         74 . The method of  claim 73 , wherein the amatoxin is represented by formula (IV) 
       
         
           
           
               
               
           
         
         wherein R 1  is H, OH, OR A , or OR C ; 
         R 2  is H, OH, OR B , or OR C ; 
         R A  and R B , together with the oxygen atoms to which they are bound, combine to form an optionally substituted 5-membered heterocyclolalkyl group; 
         R 3  is H, R C , or R D ; 
         R 4 , R 5 , R 6 , and R 7  are each independently H, OH, OR C , OR D , R C , or R D ; 
         R 8  is OH, NH 2 , OR C , OR D , NHR C , or NR C R D ; 
         R 9  is H, OH, OR C , or OR D ; 
         X is —S—, —S(O)—, or —SO 2 —; 
         R C  is -L-Z; 
         R D  is optionally substituted C 1 -C 6  alkyl, optionally substituted C 1 -C 6  heteroalkyl, optionally substituted C 2 -C 6  alkenyl, optionally substituted C 2 -C 6  heteroalkenyl, optionally substituted C 2 -C 6  alkynyl, optionally substituted C 2 -C 6  heteroalkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; 
         L is optionally substituted C 1 -C 6  alkylene, optionally substituted C 1 -C 6  heteroalkylene, optionally substituted C 2 -C 6  alkenylene, optionally substituted C 2 -C 6  heteroalkenylene, optionally substituted C 2 -C 6  alkynylene, optionally substituted C 2 -C 6  heteroalkynylene, optionally substituted cycloalkylene, optionally substituted heterocycloalkylene, optionally substituted arylene, optionally substituted heteroarylene, or comprises a dipeptide; and 
         Z is a chemical moiety formed from a coupling reaction between a reactive substituent present on L and a reactive substituent present within the antibody or antigen binding fragment thereof, 
         wherein Am comprises exactly one R C  substituent. 
       
     
     
         75 . (canceled) 
     
     
         76 . The method of  claim 72 , wherein the RNA polymerase inhibitor is an amanitin. 
     
     
         77 - 94 . (canceled) 
     
     
         95 . An antibody drug conjugate (ADC) comprising an anti-CD137 antibody conjugated to a cytotoxin via a linker. 
     
     
         96 . The ADC of  claim 95 , wherein the antibody comprises a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 having an amino acid sequence as set forth in SEQ ID NOs: 25, 26, and 27, respectively, and comprising a light chain variable region comprising a CDR1, a CDR2, and a CDR3 having an amino acid sequence as set forth in SEQ ID NOs: 29, 30, and 31, respectively. 
     
     
         97 . (canceled) 
     
     
         98 . The ADC of  claim 96 , wherein the heavy chain variable region comprises an amino acid sequence as set forth in SEQ ID NO: 28 and the light chain variable region comprises an amino acid sequence as set forth in SEQ ID NO: 32. 
     
     
         99 . (canceled) 
     
     
         100 . The ADC of  claim 95 , wherein the cytotoxin is a microtubule-binding agent or an RNA polymerase inhibitor. 
     
     
         101 . The ADC of  claim 100 , wherein the RNA polymerase inhibitor is an amatoxin. 
     
     
         102 . The ADC of  claim 101 , wherein the amatoxin is an amanitin. 
     
     
         103 . (canceled) 
     
     
         104 . A pharmaceutical composition comprising the ADC of  claim 95 , and a pharmaceutically acceptable carrier. 
     
     
         105 - 108 . (canceled) 
     
     
         109 . The method of  claim 2 , wherein the cytotoxin is a pyrrolobenzodiazepine (PBD).