METHODS OF TREATMENT USING ANTI-ErbB ANTIBODY-MAYTANSINOID CONJUGATES

Abstract

The application concerns methods of treatment using anti-ErbB receptor antibody-maytansinoid conjugates, and articles of manufacture suitable for use in such methods. In particular, the invention concerns ErbB receptor-directed cancer therapies, using anti-ErbB receptor antibody-maytansinoid conjugates.

1 . A composition of matter comprising an anti-ErbB2 antibody covalently linked to a maytansinoid by succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC), wherein the anti-ErbB2 antibody is a humanized or human antibody. 
     
     
         2 . The composition of  claim 1 , wherein the anti-ErbB2 antibody binds essentially the same epitope as monoclonal antibody 4D5. 
     
     
         3 . The composition of  claim 1 , wherein the anti-ErbB2 antibody is a humanized form of murine monoclonal antibody 4D5. 
     
     
         4 . The composition of  claim 3 , wherein the humanized antibody is huMAb4D5-8 (HERCEPTIN®). 
     
     
         5 . The composition of  claim 1 , wherein the composition has a growth inhibitory effect on SK-BR3 cells in vitro. 
     
     
         6 . The composition of  claim 5 , wherein the growth inhibitory effect comprises a significant inhibition of the in vitro growth of SK-BR3 cells at concentrations greater than or equal to about 0.01 μg/mL. 
     
     
         7 . The composition of  claim 1 , wherein the composition has anti-tumor activity in a mouse tumor model that overexpresses HER2 and does not respond to HERCEPTIN®. 
     
     
         8 . The composition of  claim 1  wherein the anti-ErbB2 antibody is an antigen binding fragment selected from the group consisting of a Fab, Fab′, F(ab′) 2 , F v  fragment, diabody, linear antibody, and single chain antibody. 
     
     
         9 . The composition of  claim 1 , wherein the maytansinoid is selected from the group consisting of maytansine, maytansinol and a maytansinol ester. 
     
     
         10 . The composition of  claim 9 , wherein the maytansinoid is DM1 having the structure 
       
         
           
           
               
               
           
         
       
     
     
         11 . The composition of  claim 1  comprising from about 1 to about 10 maytansinoid molecules per antibody molecule. 
     
     
         12 . The composition of  claim 1  comprising from about 3 to about 5 maytansinoid molecules per antibody molecule. 
     
     
         13 . A pharmaceutical composition comprising the composition of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         14 . A composition comprising huMAb4D5-8 (HERCEPTIN®) conjugated to DM1 by succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC), wherein DM1 has the structure 
       
         
           
           
               
               
           
         
       
     
     
         15 . The composition of  claim 14  comprising from about 1 to about 10 maytansinoid molecules per antibody molecule. 
     
     
         16 . The composition of  claim 14  comprising from about 3 to about 5 maytansinoid molecules per antibody molecule. 
     
     
         17 . A pharmaceutical composition comprising the composition of  claim 14  and a pharmaceutically acceptable carrier. 
     
     
         18 . The composition of  claim 1 , wherein said SMCC linker is covalently linked to a lysine residue of said anti-ErbB2 antibody. 
     
     
         19 . The composition of  claim 14 , wherein the SMCC is covalently linked to a lysine residue of huMAb4D5-8 (HERCEPTIN®), wherein the lysine residue is selected from lysine 13 in the light chain, lysine 32 in the heavy chain, lysine 26 in both Fab fragments, and lysine 38 in the Fc fragment of huMAb4D5-8 (HERCEPTIN®). 
     
     
         20 . An immunoconjugate comprising an anti-ErbB2 antibody conjugated to a maytansinoid, wherein the antibody is huMAb4D5-8. 
     
     
         21 . The immunoconjugate of  claim 20 , wherein the maytansinoid is DM1 having the structure: 
       
         
           
           
               
               
           
         
       
       and wherein the antibody is chemically linked to the maytansinoid via a disulfide or thioether group at “R” shown in the structure. 
     
     
         22 . The immunoconjugate of  claim 20 , wherein the immunoconjugate comprises from 3 to 5 maytansinoid molecules per antibody molecule. 
     
     
         23 . The immunoconjugate of  claim 20  or  claim 21 , wherein the antibody and the maytansinoid are conjugated by a chemical linker selected from N-succinimidyl-3-(2-pyridyldithio)propionate (SPDP), N-succinimidyl-4-(2-pyridylthio)pentanoate (SPP) and succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC). 
     
     
         24 . A pharmaceutical composition comprising an immunoconjugate of any of  claims 20  to  22 , and a pharmaceutically acceptable carrier.