Cross-linkers and their uses

Abstract

Charged or pro-charged cross-linking moieties and conjugates of cell binding agents and drugs comprising the charged or pro-charged cross-linking moieties and method of making the same.

1 - 26 . (canceled) 
     
     
         27 . A method of treating cancer cells expressing a folate receptor in a patient in need of treatment comprising administering to the patient a therapeutically effective amount of a cell-binding agent-drug conjugate of formula (II) 
       
         
           
           
               
               
           
         
         wherein: 
         CB represents a cell-binding agent; 
         D represents the drug linked to the cell-binding agent by a disulfide, thioether, thioester, peptide, hydrazone, ester, ether, carbamate, or amide bond; 
         R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10  are the same or different and are H, linear alkyl having from 1-6 carbon atoms, branched or cyclic alkyl having from 3 to 6 carbon atoms, linear, branched or cyclic alkenyl or alkynyl having from 2 to 6 carbon atoms, a charged substituent selected from anions selected from SO 3   − , X—SO 3   − , OPO 3   2− , X—OPO 3   2− , PO 3   2− , X—PO 3   2− , CO 2   − , and cations selected from a nitrogen containing heterocycle, N + R 11 R 12 R 13  and X—N + R 11 R 12 R 13 , or a phenyl; wherein: 
         R 11 , R 12 , and R 13  are the same or different and are H, linear alkyl having from 1 to 6 carbon atoms, branched or cyclic alkyl having from 3 to 6 carbon atoms and X represents phenyl or a linear alkyl from 1 to 6 carbon atoms, or branched or cyclic alkyl having from 3 to 6 carbon atoms; 
         l, m and n are 0 or an integer from 1 to 4; 
         A is a phenyl or substituted phenyl, wherein the substituent is a linear alkyl having from 1 to 6 carbon atoms, or a branched or cyclic alkyl having from 3 to 6 carbon atoms, or a charged substituent selected from anions selected from SO 3   − , X—SO 3   − , OPO 3   2− , X—OPO 3   2− , PO 3   2− , X—PO 3   2− , CO 2   − , and cations selected from a nitrogen containing heterocycle, N + R 11 R 12 R 13  and X—N + R 11 R 12 R 13 , wherein X has the same definition as above, and wherein g is 0 or 1; 
         Z is absent, a polyethyleneoxy unit of formula (OCH 2 CH 2 ) p , wherein p is 0 or an integer from 2 to about 1000, or a F1-E1-P-E2-F2 unit in which E1 and E2 are the same or different and are C═O, O, or NR 14 , wherein R 14  is H, a linear alkyl having from 1-6 carbon atoms, a branched or cyclic alkyl having from 3 to 6 carbon atoms, a linear, branched or cyclic alkenyl or alkynyl having from 2 to 6 carbon atoms; P is a peptide unit between 2 and 20 amino acids in length, wherein E1 or E2 can be linked to the peptide through the terminal nitrogen, terminal carbon or through a side chain of one of the amino acids of the peptide; and F1 and F2 are the same or different and are an optional polyethyleneoxy unit of formula (OCH 2 CH 2 ) p , wherein p is 0 or an integer from 2 to about 1000, provided that when Z is not F1-E1-P-E2-F2, at least one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10  is a charged substituent or when g is 1, at least one of A, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10  is a charged substituent; 
         Y represents a carbonyl, thioether, amide, disulfide, or hydrazone group; and 
         q represents an integer from 1 to 20. 
       
     
     
         28 . The method of  claim 27 , wherein the method is for treating ovarian cancer. 
     
     
         29 . The method of  claim 28 , wherein one of R 1 , R 2 , R 3 , R 4 , R 9 , and R 10  is a charged substituent selected from SO 3   − , X—SO 3   − , OPO 3   2− , X—OPO 3   2− , N + R 11 R 12 R 13  and X—N + R 11 R 12 R 13 , and the rest are H; l, g and m are each 0; and n is 1. 
     
     
         30 . The method of  claim 28 , wherein one of R 1 , R 2 , R 3 , R 4 , R 9 , and R 10  is SO 3   −  or X—SO 3   − , the rest are H; l, g and m are each 0; and n is 1. 
     
     
         31 . The method of  claim 28 , wherein the cell-binding agent is an antibody or an antibody fragment that binds to a target cell. 
     
     
         32 . The method of  claim 31 , wherein the cell-binding agent is a resurfaced antibody, a resurfaced single chain antibody, or a resurfaced antibody fragment thereof. 
     
     
         33 . The method of  claim 31 , wherein the cell-binding agent is a monoclonal antibody, a single chain monoclonal antibody, or a monoclonal antibody fragment thereof. 
     
     
         34 . The method of  claim 31 , wherein the cell-binding agent is a human antibody, a humanized antibody or a resurfaced antibody, a humanized single chain antibody, or a humanized antibody fragment thereof. 
     
     
         35 . The method of  claim 31 , wherein the cell-binding agent is a chimeric antibody, a chimeric antibody fragment, a domain antibody, or a domain antibody fragment thereof. 
     
     
         36 . The method of  claim 28 , wherein the conjugate is represented by the following formula: 
       
         
           
           
               
               
           
         
       
       wherein CB′-NH— represents the cell-binding agent linked to Y; and D′-S—S— represents the cytotoxic drug linked to the cell-binding agent by a disulfide bond. 
     
     
         37 . The method of  claim 36 , wherein the cytotoxic agent is a maytansinoid. 
     
     
         38 . The method of  claim 36 , wherein the cytotoxic agent is DM4 and the conjugate is represented by the following formula: 
       
         
           
           
               
               
           
         
       
     
     
         39 . The method of  claim 38 , wherein the cell-binding agent is an antibody that binds to a folate receptor. 
     
     
         40 . The method of  claim 39 , wherein the folate receptor is FOLR1 (folate receptor 1).