Method of targeting specific cell populations using cell-binding agent maytansinoid conjugates linked via a non-cleavable linker, said conjugates and methods of making said conjugates

Abstract

The present invention discloses a method for targeting maytansinoids to a selected cell population, the method comprising contacting a cell population or tissue suspected of containing the selected cell population with a cell-binding agent maytansinoid conjugate, wherein one or more maytansinoids is covalently linked to the cell-binding agent via a non-cleavable linker and the cell-binding agent binds to cells of the selected cell population.

1 - 375 . (canceled) 
     
     
         376 . A maytansinoid thioether bearing an active succinimidyl or sulfosuccinimidyl ester. 
     
     
         377 . The maytansinoid thioether of  claim 376 , wherein the maytansinoid thioether is obtained by reacting a thiol-containing maytansinoid with a cross-linking reagent. 
     
     
         378 . The maytansinoid thioether of  claim 377 , wherein the thiol-containing maytansinoid is N 2′ -deacetyl-N 2′ -(3-mercapto-1-oxopropyl)-maytansine (DM1) or N 2′ -deacetyl-N 2′ -(4-methyl-4-mercapto-l-oxopentyl)-maytansine (DM4). 
     
     
         379 . The maytansinoid thioether of  claim 378 , wherein the cross-linking reagent is selected from the group consisting of N-succinimidyl 4-(maleimidomethyl)cyclohexanecarboxylate (SMCC), N-succinimidyl-4-(N-maleimidomethyl)-cyclohexane-1-carboxy-(6-amidocaproate) (LC-SMCC), κ-maleimidoundecanoic acid N-succinimidyl ester (KMUA), m-maleimidobenzoyl-N-hydroxysuccinimide ester(MBS), N-(a-maleimidoacetoxy)-succinimide ester (AMAS), succinimidyl-6-(β-maleimidopropionamido)hexanoate (SMPH), N-succinimidyl-4-(iodoacetyl)-aminobenzoate (SIAB), N-succinimdyl iodoacetate (SIA) and N-succinimidyl 3-(bromoacetamido)propionate (SBAP). 
     
     
         380 . The maytansinoid thioether of  claim 379 , wherein the cross-linking reagent is N-succinimidyl 4-(maleimidomethyl)cyclohexanecarboxylate (SMCC). 
     
     
         381 . The compound of  claim 376 , wherein the compound is represented by the formula: 
       
         
           
           
               
               
           
         
       
     
     
         382 . The compound of  claim 376 , wherein the compound is represented by the formula: