Self-stabilizing linker conjugates

Abstract

The present invention provides Ligand-Drug Conjugates, Drug-Linkers, Linkers, and Ligand-Linker Conjugates comprising a self-stabilizing linker assembly component.

What is claimed is: 
     
         1 . A method of treating cancer, an autoimmune disease or an infectious disease that expresses a target antigen comprising administering a Ligand-Functional Agent Conjugate having the formula: 
       
         
           
           
               
               
           
         
         or a salt thereof, wherein 
         L is a Ligand unit directly attached to the succinimide ring of the Functional Agent Conjugate via a thioether linkage, wherein the Ligand is a monoclonal antibody that specifically binds to the target antigen; 
         D′ is a Drug unit; 
         the subscript p ranges from 1 to 20; 
         —W— is an optional Cleavable unit, 
         the subscript w′ is 0 or 1; 
         —Y— is an optional Spacer unit, 
         the subscript y′ is 0 or 1; 
         A′ is an optional Stretcher unit; and 
         the subscript a′ is 0 or 1. 
       
     
     
         2 . The method of  claim 1  wherein p is 1 to 12. 
     
     
         3 . The method of  claim 1  wherein p is 1 to 8. 
     
     
         4 . The method of  claim 1  wherein p is 1 to 8. 
     
     
         5 . The method of  claim 1  wherein D′ is a cytotoxic agent. 
     
     
         6 . The method of  claim 1  wherein D′ is an auristatin selected from the group consisting of AE, AFP, AEB, AEVB, MMAF and MMAE. 
     
     
         7 . The method of  claim 1  wherein W w′  is selected from the group consisting of Val-Cit, Phe-Lys and Val-Ala. 
     
     
         8 . The method of  claim 1  wherein Y y′  is a PAB unit. 
     
     
         9 . The method of  claim 8  wherein the PAB unit has a structure of: 
       
         
           
           
               
               
           
         
         wherein the wavy line adjacent to the nitrogen atom indicates covalent binding of that nitrogen atom to W and the # adjacent to the carbonyl indicates covalent binding of its carbon atom to D′. 
       
     
     
         10 . The method of  claim 1  wherein the subscript a′ is 0; W w′  is Val-Cit; and Y y′  is PAB. 
     
     
         11 . The method of  claim 1  wherein the subscript a′ is 0; W w′  is Val-Cit; Y y′  is PAB; and D′ is a cytotoxic agent. 
     
     
         12 . The method of  claim 1  wherein the subscript a′ is 0; W w′  is Val-Cit; Y y′  is PAB; D′ is a cytotoxic agent; and p is 1 to 8. 
     
     
         13 . The method of  claim 1  wherein D′ is MMAE. 
     
     
         14 . The method of  claim 1  wherein the subscript a′ is 0; W w , is Val-Cit; Y y′  is PAB; and D′ is MMAE. 
     
     
         15 . The method of  claim 1  wherein the Ligand-Functional Agent Conjugate has the structure of: 
       
         
           
           
               
               
           
         
       
       or the structure wherein the succinimide ring is hydrolyzed, or a salt thereof, wherein
 mAb is a monoclonal antibody and S is a sulfur atom from the monoclonal antibody. 
 
     
     
         16 . The method of  claim 15 , wherein the subscript p is about 4.