Cytotoxic agents comprising new maytansinoids
New thiol and disulfide-containing maytansinoids bearing a mono or di-alkyl substitution on the α-carbon atom bearing the sulfur atom are disclosed. Also disclosed are methods for the synthesis of these new maytansinoids and methods for the linkage of these new maytansinoids to cell-binding agents. The maytansinoid-cell-binding agent conjugates are useful as therapeutic agents, which are delivered specifically to target cells and are cytotoxic. These conjugates display vastly improved therapeutic efficacy in animal tumor models compared to the previously described agents.
1. A method of treating a tumor comprising administering to a subject in need of treatment an effective amount of a maytansinoid-cell-binding agent conjugate or a pharmaceutically acceptable salt or solvate thereof, wherein the maytansinoid-cell-binding agent conjugate comprises at least one maytansinoid linked to the cell-binding agent, wherein the maytansinoid is represented by formula (II-L), (II-D) or (II-D, L):
wherein:
Y 1 represents (CR 7 R 8 ) l (CR 5 R 6 ) m (CR 3 R 4 ) n CR 1 R 2 S—, wherein:
R 1 and R 2 are each independently linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, phenyl or substituted phenyl, and in addition R 2 can be H;
R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently H, linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, phenyl or substituted phenyl;
l, m and n are each independently an integer of from 1 to 5, and in addition n can be 0; and
May represents a maytansinoid which bears the side chain at C-3, C-14 hydroxymethyl, C-15 hydroxy or C-20 desmethyl.
2. The method of claim 1 , wherein R 1 is methyl; R 2 is H; R 5 , R 6 , R 7 and R 8 are each H; l and m are each 1; n is 0.
3. The method of claim 1 , wherein R 1 and R 2 are methyl; R 5 , R 6 , R 7 and R 8 are each H; l and m are 1; n is 0.
4. The method of claim 1 , wherein the maytansinoid is represented by formula (II-L).
5. The method of claim 2 , wherein the maytansinoid is represented by formula (II-L).
6. The method of claim 3 , wherein the maytansinoid is represented by formula (II-L).
7. The method of claim 1 , wherein the cell-binding agent is selected from the group consisting of a humanized or resurfaced MY9 antibody that specifically binds to the CD33 antigen, a humanized or resurfaced anti-B4 antibody that specifically binds to the CD19 antigen and a humanized or resurfaced C242 antibody that specifically binds to the CanAg antigen.
8. The method of claim 1 , wherein the tumor cells are selected from breast cancer cells, prostate cancer cells, ovarian cancer cells, lung cancer cells, colon cancer cells, kidney cancer cells, pancreas cancer cells, and cancer cells of the lymphatic organs.
9. A method of treating a tumor comprising administering to a subject in need of treatment an effective amount of a maytansinoid-cell-binding agent conjugate or a pharmaceutically acceptable salt thereof, wherein the maytansinoid-cell-binding agent conjugate comprises at least one maytansinoid linked to the cell-binding agent, wherein the maytansinoid is represented by formula 4 1 :
wherein:
Y 1 represents (CR 7 R 8 ) l (CR 5 R 6 ) m (CR 3 R 4 ) n CR 1 R 2 S—, wherein:
R 1 and R 2 are each independently linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, phenyl or substituted phenyl, and in addition R 2 can be H;
R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently H, linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, phenyl or substituted phenyl; and
l, m and n are each independently an integer of from 1 to 5, and in addition n can be 0.
10. The method of claim 9 , wherein R 1 is methyl, R 2 is H, R 5 , R 6 , R 7 and R 8 are each H; l and m are each 1; and n is 0.
11. The method of claim 9 , wherein R 1 and R 2 are methyl; R 5 , R 6 , R 7 and R 8 are each H; l and m are 1; and n is 0.
12. The method of claim 9 , wherein the cell-binding agent is selected from the group consisting of a humanized or resurfaced MY9 antibody that specifically binds to the CD33 antigen, a humanized or resurfaced anti-B4 antibody that specifically binds to the CD19 antigen and a humanized or resurfaced C242 antibody that specifically binds to the CanAg antigen.
13. The method of claim 9 , wherein the tumor cells are selected from breast cancer cells, prostate cancer cells, ovarian cancer cells, lung cancer cells, colon cancer cells, kidney cancer cells, pancreas cancer cells, and cancer cells of the lymphatic organs.
14. A method for inducing cell death in selected cell populations comprising contacting target cells or tissue containing target cells with an effective amount of a maytansinoid-cell-binding agent conjugate, or a salt thereof, wherein the maytansinoid-cell-binding agent conjugate comprises at least one maytansinoid linked to the
cell-binding agent, wherein the maytansinoid is represented by formula (II-L), (II-D) or (II-D, L):
wherein:
Y 1 represents (CR 7 R 8 ) l (CR 5 R 6 ) m (CR 3 R 4 ) n CR 1 R 2 S—, wherein:
R 1 and R 2 are each independently linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, phenyl or substituted phenyl, and in addition R 2 can be H;
R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently H, linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, phenyl or substituted phenyl;
l, m and n are each independently an integer of from 1 to 5, and in addition n can be 0; and
May represents a maytansinoid which bears the side chain at C-3, C-14 hydroxymethyl, C-15 hydroxy or C-20 desmethyl.
15. The method of claim 14 , wherein R 1 is methyl; R 2 is H; R 5 , R 6 , R 7 and R 8 are each H; l and m are each 1; n is 0.
16. The method of claim 14 , wherein R 1 and R 2 are methyl; R 5 , R 6 , R 7 and R 8 are each H; l and m are 1; n is 0.
17. The method of claim 14 , wherein the maytansinoid is represented by formula (II-L).
18. The method of claim 15 , wherein the maytansinoid is represented by formula (II-L).
19. The method of claim 16 , wherein the maytansinoid is represented by formula (II-L).
20. The method of claim 1 , wherein the cell-binding agent is selected from the group consisting of a humanized or resurfaced MY9 antibody that specifically binds to the CD33 antigen, a humanized or resurfaced anti-B4 antibody that specifically binds to the CD19 antigen and a humanized or resurfaced C242 antibody that specifically binds to the CanAg antigen.
21. The method of claim 1 , wherein the tumor cells are selected from breast cancer cells, prostate cancer cells, ovarian cancer cells, lung cancer cells, colon cancer cells, kidney cancer cells, pancreas cancer cells, and cancer cells of the lymphatic organs.
22. A method for inducing cell death in selected cell populations comprising contacting target cells or tissue containing target cells with an effective amount of a maytansinoid-cell-binding agent conjugate, or a salt thereof, wherein the maytansinoid-cell-binding agent conjugate comprises at least one maytansinoid linked to the cell-binding agent, wherein the maytansinoid is represented by formula 4 1 :
wherein:
Y 1 represents (CR 7 R 8 ) l (CR 5 R 6 ) m (CR 3 R 4 ) n CR 1 R 2 S—, wherein:
R 1 and R 2 are each independently linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, phenyl or substituted phenyl, and in addition R 2 can be H;
R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently H, linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, phenyl or substituted phenyl; and
l, m and n are each independently an integer of from 1 to 5, and in addition n can be 0.
23. The method of claim 22 , wherein R 1 is methyl; R 2 is H; R 5 , R 6 , R 7 and R 8 are each H; l and m are each 1; and n is 0.
24. The method of claim 22 , wherein R 1 and R 2 are methyl; R 5 , R 6 , R 7 and R 8 are each H; l and m are 1; and n is 0.
25. The method of claim 9 , wherein the cell-binding agent is selected from the group consisting of a humanized or resurfaced MY9 antibody that specifically binds to the CD33 antigen, a humanized or resurfaced anti-B4 antibody that specifically binds to the CD19 antigen and a humanized or resurfaced C242 antibody that specifically binds to the CanAg antigen.
26. The method of claim 9 , wherein the tumor cells are selected from breast cancer cells, prostate cancer cells, ovarian cancer cells, lung cancer cells, colon cancer cells, kidney cancer cells, pancreas cancer cells, and cancer cells of the lymphatic organs.
27. A method of treating a tumor comprising administering to a subject in need of treatment an effective amount of a maytansinoid-cell-binding agent conjugate or a pharmaceutically acceptable salt thereof, wherein the maytansinoid-cell-binding agent conjugate is represented by the following formula:
wherein w is 1-10.
28. The method of claim 27 , wherein the method is for treating non-Hodgkin's lymphoma or chronic lymphoblastic leukemia.
29. The method of claim 28 , wherein the method is for treating non-Hodgkin's lymphoma.
30. The method of claim 27 , wherein the antibody is a humanized or resurfaced anti-B4 antibody that specifically binds to the CD19 antigen.