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.

1 - 16 . (canceled) 
     
     
         17 . A Ligand-Functional Agent Conjugate having the formula: 
       
         
           
           
               
               
           
         
       
       or a salt thereof, wherein
 L is a monoclonal antibody attached to the remainder of the conjugate via a thioether linkage; 
 D′ is a cytotoxic agent; 
 the subscript p ranges from 1 to 12; 
 —W— is a dipeptide; 
 the subscript w′ is 1; 
 the subscript y′ is 1; 
 —Y— has the 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′; 
         A′ is a Stretcher unit; and 
         the subscript a′ is 0. 
       
     
     
         18 . The Ligand-Functional Agent Conjugate of  claim 17 , wherein p ranges from 1 to 8. 
     
     
         19 . The Ligand-Functional Agent Conjugate of  claim 18 , wherein p is 2, 4, 6, or 8. 
     
     
         20 . The Ligand-Functional Agent Conjugate of  claim 17 , wherein W w′  is —Val-Cit-. 
     
     
         21 . The Ligand-Functional Agent Conjugate of  claim 17 , wherein W w′  is —Val-Ala-. 
     
     
         22 . The Ligand-Functional Agent Conjugate of  claim 17 , wherein W w′  is -Phe-Lys-. 
     
     
         23 . A Drug-Linker Conjugate represented by the formulae: 
       
         
           
           
               
               
           
         
       
       or a salt thereof, wherein:
 BU is —CH 2 NH 2 , —CH 2 CH 2 NH 2 , —CH 2 CH 2 CH 2 NH 2 , or —CH 2 CH 2 CH 2 CH 2 NH 2 ; 
 D is a cytotoxic agent; 
 L 0  is -A a′ -W w′ —Y y′ —; 
 a′, w′, and y′ are each independently 0 or 1; 
 A has the structure 
 
       
         
           
           
               
               
           
         
         wherein R 13  is —C 1 -C 10  alkylene-, —C 3 -C 8 carbocyclo-, -arylene-, —C 1 -C 30 heteroalkylene-, —C 3 -C 8 heterocyclo-, —C 1 -C 10 alkylene-arylene-, -arylene-C 1 -C 10 alkylene-, —C 1 -C 10 alkylene-(C 3 -C 8 -carbocyclo)-, —(C 3 -C 8 -carbocyclo)-C 1 -C 10 alkylene-, —C 1 -C 10 alkylene-(C 3 -C 8  heterocyclo)-, —(C 3 -C 8  heterocycle)-C 1 -C 10  alkylene-, —(CH 2 CH 2 O) 1-10 (—CH 2 ) 1-3 —, or —(CH 2 CH 2 NH) 1-10 (—CH 2 ) 1-3 —; 
         W is represented by -(-AA-) 1-12 -, or (-AA-AA-) 1-6  wherein AA is at each occurrence independently selected from natural or non-natural amino acids; and 
         Y has the 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. 
       
     
     
         24 . The Drug-Linker Conjugate of  claim 23 , wherein A has the structure 
       
         
           
           
               
               
           
         
       
       and R 13  is —C 1 -C 10  alkylene-. 
     
     
         25 . The Drug-Linker Conjugate of  claim 23 , wherein W is represented by (-AA-AA-) 1-6  wherein AA is at each occurrence independently selected from natural amino acids. 
     
     
         26 . The Drug-Linker Conjugate of  claim 25 , wherein W is selected from the group consisting of -Val-Cit-, -Phe-Lys- and -Val-Ala-. 
     
     
         27 . The Drug-Linker Conjugate of  claim 23 , wherein D is selected from the group consisting of:
 (a) antitubulin agents, auristatins, DNA minor groove binders, DNA replication inhibitors, alkylating agents, anthracyclines, antibiotics, antifolates, antimetabolites, chemotherapy sensitizers, duocarmycins, etoposides, fluorinated pyrimidines, ionophores, lexitropsins, nitrosoureas, platinols, pre-forming compounds, purine antimetabolites, puromycins, radiation sensitizers, steroids, taxanes, topoisomerase inhibitors, and vinca alkaloids;   (b) auristatins, camptothecins, duocarmycins, etoposides, maytansines and maytansinoids, taxanes, benzodiazepines, and vinca alkaloids; or   (c) auristatins and pyrrolo[1,4]benzodiazepines (PBDs).   
     
     
         28 . The Drug-Linker Conjugate of  claim 27 , wherein D is selected from the group consisting of AE, AFP, AEB, AEVB, MMAF and MMAE. 
     
     
         29 . The Drug-Linker Conjugate of  claim 28 , wherein D is MMAE. 
     
     
         30 . The Drug-Linker Conjugate of  claim 23 , wherein a′ is 0. 
     
     
         31 . 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 an antibody attached to the remainder of the conjugate via a thioether linkage; 
 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. 
 
     
     
         32 . The method of  claim 31 , wherein p ranges from 1 to 8. 
     
     
         33 . The method of  claim 32 , wherein p is 4. 
     
     
         34 . The method of  claim 31 , wherein D′ is an auristatin selected from the group consisting of AE, AFP, AEB, AEVB, MMAF and MMAE. 
     
     
         35 . The method of  claim 31 , wherein a′ is 0. 
     
     
         36 . The method of  claim 35 , wherein w′ is 1 and W is a dipeptide.