Cross-linkers and their uses
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. A compound of formula (IV):
wherein:
Y′ represents a functional group that enables reaction with a cell-binding agent;
D represents a cytotoxic drug linked to the cell-binding agent by a disulfide, thioether, thioester, peptide, hydrazone, ester, ether, carbamate, or amide bond;
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;
R 11 , R 12 , and R 13 are the same or different and are linear alkyl having from 1 to 6 carbon atoms, or branched or cyclic alkyl having from 3 to 6 carbon atoms and X represents phenyl or a linear alkyl having from 1 to 6 carbon atoms, or branched or cyclic alkyl having from 3 to 6 carbon atoms;
l and m are each 0;
n is 1; and
Z is absent; or a polyethyleneoxy unit of formula (OCH 2 CH 2 ) p , wherein p is an integer from 2 to about 1000.
2. The compound of claim 1 , wherein the cytotoxic drug is a maytansinoid.
3. The compound of claim 2 , wherein the cytotoxic drug is DM1 or DM4.
4. The compound of claim 2 , wherein the cytotoxic drug is DM4.
5. The compound of claim 4 , wherein Y′ is an amine reactive functional group selected from the group consisting of N-hydroxysuccinmide ester, p-nitrophenyl ester, dinitrophenyl ester, and pentafluorophenyl ester.
6. The compound of claim 5 , wherein R 1 , R 2 , R 3 , R 4 , R 9 , and R 10 is SO 3 − or X—SO 3 − , and the rest are H; and Y′ is a maleimido or a N-hydroxysuccinimide ester.
7. The compound of claim 6 , wherein Y′ is N-hydroxysuccinimide ester.
8. The compound of claim 1 , wherein the compound is represented by the following formula: