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 represented by the following formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein R is H or Me; and w is 1-10. 
       
     
     
         100 . The conjugate of  claim 99 , wherein R is Me. 
     
     
         101 . The conjugate of  claim 100 , wherein the antibody is a humanized or resurfaced MY9 antibody that specifically binds to the CD33 antigen, a humanized or resurfaced anti-B4 antibody that specifically binds to the CD19 antigen, or a humanized or resurfaced C242 antibody that specifically binds to the CanAg antigen. 
     
     
         102 . A pharmaceutical composition comprising an effective amount of a maytansinoid-cell-binding-agent conjugate or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient, wherein the conjugate is represented by the following formula: 
       
         
           
           
               
               
           
         
         wherein R is H or Me; and w is 1-10. 
       
     
     
         103 . The pharmaceutical composition of  claim 102 , wherein R is Me. 
     
     
         104 . The pharmaceutical composition of  claim 103 , wherein the antibody is a humanized or resurfaced MY9 antibody that specifically binds to the CD33 antigen, a humanized or resurfaced anti-B4 antibody that specifically binds to the CD19 antigen, or a humanized or resurfaced C242 antibody that specifically binds to the CanAg antigen. 
     
     
         105 . A method of treating a cancer comprising administering to a subject in need of the treatment an effective amount of a maytansinoid-cell-binding-agent conjugate or a pharmaceutically acceptable salt thereof, wherein the conjugate is represented by the following formula: 
       
         
           
           
               
               
           
         
         wherein R is H or Me; and w is 1-10. 
       
     
     
         106 . The method of  claim 105 , wherein R is Me. 
     
     
         107 . The method of  claim 106 , wherein the antibody is a humanized or resurfaced MY9 antibody that specifically binds to the CD33 antigen, a humanized or resurfaced anti-B4 antibody that specifically binds to the CD19 antigen, or a humanized or resurfaced C242 antibody that specifically binds to the CanAg antigen. 
     
     
         108 . The method of  claim 105 , wherein the cancer is selected from breast cancer, prostate cancer, ovarian cancer, lung cancer, colon cancer, kidney cancer, pancreas cancer and cancer of the lymphatic organs. 
     
     
         109 . The method of  claim 105 , wherein the method is for treating non-Hodgkin's lymphoma or chronic lymphoblastic leukemia. 
     
     
         110 . The method of  claim 105 , wherein the method is for treating non-Hodgkin's lymphoma.