Stability-modulating linkers for use with antibody drug conjugates

Abstract

The present invention provides stability-modulated antibody-drug conjugates, stability-modulating linker components used to make these stability-modulated antibody-drug conjugates, therapeutic methods using stability-modulated antibody-drug conjugates, and methods of making stability modulating linkers and stability-modulated antibody-drug conjugates.

1 - 22 . (canceled) 
     
     
         23 . A method of modulating the stability of an antibody drug conjugate of Formula (II): 
       
         
           
           
               
               
           
         
         wherein: 
         M is a stability modulator; 
         P is a peptide sequence which includes one or more glutamine residues; 
         Q is one of said glutamine residues present in P; 
         each E is independently selected from the group consisting of: —C(R 1 ) 2 —, —O—C(R 1 ) 2 —C(R 1 ) 2 — where r is at least 2, and —C(R 1 ) 2 —C(R 1 ) 2 —O— where s is at least 1; 
         each R 1  is independently selected from the group consisting of: H, C 1 -C 6  straight or branched alkyl, C 2 -C 6  straight or branched alkenyl, and C 2 -C 6  straight or branched alkynyl; 
         each X is independently an amino acid, where each amino acid X is the same or is different; 
         each Y is independently an amino acid, where each amino acid Y is the same or is different; 
         each Z is independently a spacer element, where each spacer element is the same or is different; 
         m is 0-5, n is 1-5, p is 0-2, q is 0-10, r is 0-2, and s is 0-2, where q+r+s=2 or more; and 
         D is a cytotoxic agent; 
         said method comprising the steps of: 
         selecting modulator M capable of modulating the extracellular stability of said compound; 
         incorporating said modulator M into said conjugate; and 
         administering said conjugate to a patient. 
       
     
     
         24 . The method of  claim 23  wherein said stability is in vivo stability. 
     
     
         25 . The method of  claim 24 , wherein the ratio of cytotoxic agent released outside of target cells compared to cytotoxic agent released within target cells is increased. 
     
     
         26 . The method of  claim 24 , wherein the ratio of cytotoxic agent released outside of target cells compared to cytotoxic agent released within target cells is decreased. 
     
     
         27 . The method of  claim 24 , wherein the ratio of cytotoxic agent released inside of target cells compared to cytotoxic agent released outside of target cells is increased. 
     
     
         28 . The method of  claim 24 , wherein the ratio of cytotoxic agent released inside of target cells compared to cytotoxic agent released outside of target cells is decreased. 
     
     
         29 . (canceled)