Cytotoxic agents comprising new maytansinoids (dm4)

Abstract

New thiol and disulfide-containing maytansinoids bearing a mono or di-alkyl substitution on the α-carbon atom bearing the sulfur atom are disclosed. Also disclosed are methods for the synthesis of these new maytansinoids and methods for the linkage of these new maytansinoids to cell-binding agents. The maytansinoid-cell-binding agent conjugates are useful as therapeutic agents, which are delivered specifically to target cells and are cytotoxic. These conjugates display vastly improved therapeutic efficacy in animal tumor models compared to the previously described agents.

1 - 98 . (canceled) 
     
     
         99 . A maytansinoid-cell-binding agent conjugate comprising at least one maytansinoid linked to a cell-binding agent, wherein the maytansinoid is represented by the following formula: 
       
         
           
           
               
               
           
         
         wherein the cell-binding agent is an antibody. 
       
     
     
         100 . The conjugates of  claim 99 , wherein the antibody is a monoclonal antibody. 
     
     
         101 . The conjugate of  claim 99 , wherein the antibody is a resurfaced antibody. 
     
     
         102 . The conjugate of  claim 99 , wherein the antibody is a humanized antibody. 
     
     
         103 . The conjugate of  claim 99 , wherein the antibody is a human monoclonal antibody. 
     
     
         104 . The conjugate of  claim 99 , wherein the conjugate is a disulfide-linked antibody-maytansinoid conjugate. 
     
     
         105 . The conjugate of  claim 99 , wherein an average of 1-10 maytansinoid molecules is bound per antibody. 
     
     
         106 . A method of treating a tumor comprising administering to a subject in need of treatment an effective amount of a maytansinoid-cell-binding agent conjugate or a pharmaceutically acceptable salt thereof, wherein the maytanisinoid-cell-binding agent conjugate comprising at least one maytansinoid linked to a cell-binding agent, wherein the maytansinoid is represented by the following formula: 
       
         
           
           
               
               
           
         
         wherein the cell-binding agent is an antibody. 
       
     
     
         107 . The method of  claim 106 , wherein the antibody is a monoclonal antibody. 
     
     
         108 . The method of  claim 106 , wherein the antibody is a resurfaced antibody. 
     
     
         109 . The method of  claim 106 , wherein the antibody is a humanized antibody. 
     
     
         110 . The method of  claim 106 , wherein the antibody is a human monoclonal antibody. 
     
     
         111 . The method of  claim 106 , wherein the conjugate is a disulfide-linked antibody-maytansinoid conjugate. 
     
     
         112 . The method of  claim 106 , wherein an average of 1-10 maytansinoid molecules is bound per antibody.