Isoquinolidinobenzodiazepine (iqb)-1(chloromethyl)-2,3-dihydro-1h-benzo[e]indole (cbi) dimers

Abstract

Provided herein are isoquinolidinobenzodiazepine (IQB)-1(chloromethyl)-2,3-dihydro-1H-benzo[e]indole (CBI) dimers, antibody-drug conjugates comprising them and methods of use for killing cells and treating disease.

What is claimed is: 
     
         1 . An antibody-drug conjugate having a structure of Formula II: 
       
         
           
           
               
               
           
         
         wherein:
    is an antibody or antibody fragment; 
 
         W—R M  is a linking moiety formed by W and R x , wherein W is a moiety attached a natural or unnatural amino acid residue of the antibody/antibody fragment and R x  is a succinimidyl, maleimidyl, cylooctynyl, aminooxy, bisulfonyl, sulfonyl, or isothiocyanate moiety, such that W—R M  is a disulfide, a thiolated succinimidyl, an amino substituted succinimidyl, a (cyclooctyl)-1, 4 triazolyl, oxime substituted N-glycan, oxime, a substituted bis-sulfopropyl, a sulfonamidyl, an amide, or a thiocarbamate moiety; 
         L is a Linker L, wherein the Linker L is a bond or is a moiety having 1-200 nonhydrogen atoms selected from C, N, O, S, or halogen, and optionally incorporates ether, oxo, carboxamidyl, urethanyl, amino acid, heterocyclic, aromatic or heteroaromatic moieties; 
         IQB-CBI is a compound having a structure of Formula I: 
       
       
         
           
           
               
               
           
         
         wherein:
 the dotted bond shown between —C(R a )— and —N(R b )— is independently a single bond or a double bond;
 when a double bond is present between —C(R a )— and —N(R b )—, the —C(R a )— is olefinic and has a substituent R a , and R b  of the —N(R b )— is not present; 
 when a single bond is present between —C(R a )— and —N(R b )—, the —C(R a )— is saturated and has a hydrogen substituent in addition to the R a  substituent and R b  of the —N(R b )— is present; 
 
 R a  is independently H, or OH; 
 if present, R b  is H or is a bond to the Linker L; 
 R 2  is selected from H, OH, C 1 -C 10  alkyl, C 2 -C 10  alkenyl or C 2 -C 10  alkynyl; 
 R 3 , R 3′ , R 4 , R 4′ , R 6′  and R 6  are each independently selected from H, OH, C 1 -C 10  alkyl, C 2 -C 10  alkenyl or C 2 -C 10  alkynyl, or, if Y is N, is not present; 
 each of R 5  or R 5′  is independently NH 2 , CO 2 H, H, OH, C 1 -C 10  alkyl, C 2 -C 10  alkenyl, C 2 -C 10  alkynyl, is a bond to the Linker L, or, if Y is N, is not present; 
 R 7  is H; 
 G′-Rb′ is selected from OH, O-L, NH 2 , or NH-L, wherein L is the Linker L; 
 each Y is, independently, N or C; 
 each D is, independently, (CH 2 ) n  where n=0-4, provided that at least one D is (CH 2 ) n  where n=1-4; 
 X1 is a spacer selected from the group consisting of the following: 
 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein at least one of R b , R 5 , R 5′  and G-R b′  is a bond linked to Linker L or comprises Linker L; and wherein the IQB-CBI compound has S,S stereochemistry. 
       
     
     
         2 . The antibody-drug conjugate of  claim 1 , wherein the antibody is a cysteine substituted antibody. 
     
     
         3 . The antibody-drug conjugate of  claim 1 , wherein the antibody specifically binds a cancer marker. 
     
     
         4 . The antibody-drug conjugate of  claim 1 , wherein the antibody or antibody fragment is anti-IL1RAP or anti-CLL1. 
     
     
         5 . The antibody-drug conjugate according to  claim 1 , wherein L is a linker having the structure:
   —Y L —X AA -PEG-,
   wherein:
 Y L  is a spacer molecule that links an amino acid unit of XAA to the IQB unit; 
 X AA  is an amino acid sequence having from 1 to 12 amino acids; 
 PEG is a polyethyleneglycol moiety having the structure —(CH 2 CH 2 O) x —, wherein x is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15. 
   
     
     
         6 . The antibody-drug conjugate according to  claim 5 , wherein X AA  is a dipeptide. 
     
     
         7 . The antibody-drug conjugate according to  claim 1 , wherein R M  is a linking group having the structure: 
       
         
           
           
               
               
           
         
       
       wherein: Z is selected from the group consisting of —C1-C10 alkylene-, —C3-C8 cycloalkyl-, —O—(C1-C8 alkyl)-, —(CH 2 CH 2 O) r —, and —(CH 2 CH 2 O) r —CH 2 —; and r is an integer ranging from 1-10. 
     
     
         8 . The antibody-drug conjugate according to  claim 1 , wherein R M  has a structure selected from the group consisting of the following: 
       
         
           
           
               
               
           
         
       
     
     
         9 . The antibody-drug conjugate according to  claim 1 , wherein L is a linker comprising polyethylene glycol and 1-10 amino acids.