Monomethylvaline compounds capable of conjugation to ligands

Abstract

Auristatin peptides, including MeVal-Val-Dil-Dap-Norephedrine (MMAE) and MeVal-Val-Dil-Dap-Phe (MMAF), were prepared and attached to Ligands through various linkers, including maleimidocaproyl-val-cit-PAB. The resulting ligand drug conjugates were active in vitro and in vivo.

1 . An antibody-drug conjugate compound comprising an antibody covalently attached to one or more drug moieties, the compound having Formula Ic:
   Ab A a -W w —Y y -D) p   Ic
   or a pharmaceutically acceptable salt or solvate thereof, wherein:   Ab is an antibody which binds to the polypeptide of SEQ ID NO:3,   A is a Stretcher unit,   a is 0 or 1,   each W is independently an Amino Acid unit,   w is an integer ranging from 0 to 12,   Y is a Spacer unit, and   y is 0, 1 or 2,   p ranges from 1 to 20, and   D is a drug moiety of Formula D E :   
       
         
           
           
               
               
           
         
         wherein the wavy line of D E  indicates the covalent attachment site to A, W, or Y, and independently at each location: 
         R 2  is selected from H and C 1 -C 8  alkyl; 
         R 3  is selected from H, C 1 -C 8  alkyl, C 3 -C 8  carbocycle, aryl, C 1 -C 8  alkyl-aryl, C 1 -C 8  alkyl-(C 3 -C 8  carbocycle), C 3 -C 8  heterocycle and C 1 -C 8  alkyl-(C 3 -C 8  heterocycle); 
         R 4  is selected from H, C 1 -C 8  alkyl, C 3 -C 8  carbocycle, aryl, C 1 -C 8  alkyl-aryl, C 1 -C 8  alkyl-(C 3 -C 8  carbocycle), C 3 -C 8  heterocycle and C 1 -C 8  alkyl-(C 3 -C 8  heterocycle); 
         R 5  is selected from H and methyl; 
         or R 4  and R 5  jointly form a carbocyclic ring and have the formula —(CR a R b ) n — wherein R a  and R b  are independently selected from H, C 1 -C 8  alkyl and C 3 -C 8  carbocycle and n is selected from 2, 3, 4, 5 and 6; 
         R 6  is selected from H and C 1 -C 8  alkyl; 
         R 7  is selected from H, C 1 -C 8  alkyl, C 3 -C 8  carbocycle, aryl, C 1 -C 8  alkyl-aryl, C 1 -C 8  alkyl-(C 3 -C 8  carbocycle), C 3 -C 8  heterocycle and C 1 -C 8  alkyl-(C 3 -C 8  heterocycle); 
         each R 8  is independently selected from H, OH, C 1 -C 8  alkyl, C 3 -C 8  carbocycle and O-(C 1 -C 8  alkyl); 
         R 9  is selected from H and C 1 -C 8  alkyl; and 
         R 18  is selected from —C(R 8 ) 2 —C(R 8 ) 2 —aryl, —C(R 8 ) 2 —C(R 8 ) 2 —(C 3 -C 8  heterocycle), and —C(R 8 ) 2 —C(R 8 ) 2 —(C 3 -C 8  carbocycle). 
       
     
     
         2 . The antibody-drug conjugate compound of  claim 1 , wherein the antibody is attached to the drug moiety through a cysteine residue of the antibody. 
     
     
         3 . The antibody-drug conjugate compound of  claim 1 , wherein p is 1 to 4. 
     
     
         4 . The antibody-drug conjugate compound of  claim 1 , wherein p is 2 to 8. 
     
     
         5 . The antibody-drug conjugate compound of  claim 1 , wherein p is 2 to 5. 
     
     
         6 . The antibody-drug conjugate compound of  claim 1 , having the formula: 
       
         
           
           
               
               
           
         
       
     
     
         7 . The antibody-drug conjugate compound of  claim 6  having the formula: 
       
         
           
           
               
               
           
         
         wherein w and y are each 0. 
       
     
     
         8 . The antibody-drug conjugate compound of  claim 6 , having the formula: 
       
         
           
           
               
               
           
         
       
     
     
         9 . The antibody-drug conjugate compound of  claim 8  having the formula: 
       
         
           
           
               
               
           
         
       
     
     
         10 . The antibody-drug conjugate compound of  claim 9  having the formula: 
       
         
           
           
               
               
           
         
       
     
     
         11 . The antibody-drug conjugate compound of  claim 1 , wherein w is an integer ranging from 2 to 12. 
     
     
         12 . The antibody-drug conjugate compound of  claim 11 , wherein w is 2. 
     
     
         13 . The antibody-drug conjugate compound of  claim 12  wherein W w  is -valine-citrulline-. 
     
     
         14 . The antibody-drug conjugate compound of  claim 1  wherein A is maleimidocaproyl and a is 1. 
     
     
         15 . The antibody-drug conjugate compound of  claim 1  wherein Y is PAB and y is 1. 
     
     
         16 . The antibody-drug conjugate compound of  claim 1 , wherein D has the formula: 
       
         
           
           
               
               
           
         
       
     
     
         17 . The antibody-drug conjugate compound of  claim 1 , wherein the antibody binds to a portion of the polypeptide of SEQ ID NO:3 that is expressed on the cell surface. 
     
     
         18 . The antibody-drug conjugate compound of  claim 17 , wherein the antibody is a humanized antibody. 
     
     
         19 . The antibody-drug conjugate compound of  claim 1 , wherein the antibody is a monoclonal antibody. 
     
     
         20 . The antibody-drug conjugate compound of  claim 1 , wherein the antibody is a chimeric antibody. 
     
     
         21 . The antibody-drug conjugate compound of  claim 1 , wherein the antibody is a humanized antibody. 
     
     
         22 . The antibody-drug conjugate compound of  claim 1 , wherein the antibody is a Fab fragment. 
     
     
         23 . The antibody-drug conjugate compound of  claim 1 , having the formula: 
       
         
           
           
               
               
           
         
         wherein Val is valine, and Cit is citrulline. 
       
     
     
         24 . The antibody-drug conjugate compound of  claim 23 , wherein the antibody binds to a portion of the polypeptide of SEQ ID NO:3 that is expressed on the cell surface. 
     
     
         25 . The antibody-drug conjugate compound of  claim 24 , wherein the antibody is a humanized antibody. 
     
     
         26 . The antibody-drug conjugate compound of  claim 24 , wherein p is 1 to 4. 
     
     
         27 . A pharmaceutical composition comprising an effective amount of the antibody-drug conjugate compound of  claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent, carrier or excipient. 
     
     
         28 . The pharmaceutical composition of  claim 27  further comprising a therapeutically effective amount of a chemotherapeutic agent selected from a tubulin-forming inhibitor, a topoisomerase inhibitor, a DNA binder, and gemcitabine. 
     
     
         29 . A pharmaceutical composition comprising an effective amount of the antibody-drug conjugate compound of  claim 24 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent, carrier or excipient. 
     
     
         30 . The pharmaceutical composition of  claim 29  further comprising a therapeutically effective amount of a chemotherapeutic agent selected from a tubulin-forming inhibitor, a topoisomerase inhibitor, a DNA binder, and gemcitabine. 
     
     
         31 . An article of manufacture comprising:
 an antibody drug conjugate compound of  claim 1 ; a container; and   a package insert or label indicating that the compound can be used to treat cancer characterized by the expression of SEQ ID NO:3 or a portion thereof expressed on the cell surface.   
     
     
         32 . An article of manufacture comprising:
 an antibody drug conjugate compound of  claim 24 ;   a container; and   a package insert or label indicating that the compound can be used to treat cancer characterized by the expression of SEQ ID NO:3 or a portion thereof expressed on the cell surface.