Antibody-drug conjugates and methods

Abstract

The present invention relates to antibody-drug conjugate compounds of Formula I: Ab-(L-D) p   I where one or more maytansinoid drug moieties (D) are covalently linked by L to an antibody (Ab) which binds to an ErbB receptor, or which binds to one or more tumor-associated antigens or cell-surface receptors. These compounds may be used in methods of diagnosis or treatment of cancer, and other diseases and disorders.

We claim: 
     
         1 . Trastuzumab-SMCC having the structure: 
       
         
           
           
               
               
           
         
         wherein Tr is trastuzumab. 
       
     
     
         2 . Trastuzumab-SMCC of  claim 1  prepared by the process of derivatizing trastuzumab with succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate. 
     
     
         3 . Trastuzumab-SMCC of  claim 2  wherein 20 mg/mL of trastuzumab in 50 mM potassium phosphate/50 mM sodium chloride/2 mM EDTA, pH 6.5 is treated with 7.5 to 10 molar equivalents of SMCC in 20 mM in DMSO or DMA (dimethylacetamide) to form a reaction mixture containing trastuzumab-SMCC. 
     
     
         4 . Trastuzumab-SMCC of  claim 3  wherein the reaction mixture containing trastuzumab-SMCC is filtered through a Sephadex G25 column. 
     
     
         5 . A process to prepare trastuzumab-SMCC having the structure: 
       
         
           
           
               
               
           
         
         wherein Tr is trastuzumab, comprising derivatizing trastuzumab with succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate. 
       
     
     
         6 . The process of  claim 5  wherein 20 mg/mL of trastuzumab in 50 mM potassium phosphate/50 mM sodium chloride/2 mM EDTA, pH 6.5 is treated with 7.5 to 10 molar equivalents of SMCC in 20 mM in DMSO or DMA (dimethylacetamide) to form a reaction mixture containing trastuzumab-SMCC. 
     
     
         7 . The process of  claim 6  wherein the reaction mixture containing trastuzumab-SMCC is filtered through a Sephadex G25 column.