Cytotoxic agents comprising taxanes and their therapeutic use
A cytotoxic agent comprising one or more taxanes linked to a cell binding agent. A therapeutic composition for killing selected cell populations comprising: (A) a cytotoxic amount of one or more taxanes covalently bonded to a cell binding agent through a linking group, and (B) a pharmaceutically acceptable carrier, diluent or excipient. A method for killing selected cell populations comprising contacting target cells or tissue containing target cells with an effective amount of a cytotoxic agent comprising one or more taxanes linked to a cell binding agent. Novel sulfur-containing taxanes.
1. A method of inducing cell death in selected cell populations comprising contacting target cells or tissue containing target cells with an effective amount of a cytotoxic agent, wherein the target cells are cancer cells that express a marker that binds to the cell binding agent and wherein the cytotoxic agent comprises one or more taxanes covalently bonded to a cell binding agent through a linking group, wherein at least one of said taxanes is a compound represented by formula (I):
wherein:
R 1 and R 1 ′ are the same or different and are H, —F, —NO 2 , —CN, Cl, —CHF 2 , —CF 3 , —NR 7 R 8 , or —OR 9 , wherein R 7 and R 8 are the same or different and are linear alkyl having 1 to 10 carbon atoms, branched or cyclic alkyl having 3 to 10 carbon atoms, or simple or substituted phenyl or naphthyl, and R 9 is linear alkyl having 1 to 10 carbon atoms, or branched or cyclic alkyl having 3 to 10 carbon atoms;
R 1 ″ is H;
R 2 is —(CH 2 ) n SZ, —CO(CH 2 ) n SZ, —(CH 2 ) n CH(CH 3 )SZ, —CO(CH 2 ) n CH(CH 3 )SZ, —(CH 2 ) n C(CH 3 ) 2 SZ, —CO(CH 2 ) n C(CH 3 ) 2 SZ, —CONR 12 (CH 2 ) n SZ, —CONR 12 (CH 2 ) n CH(CH 3 )SZ, —CONR 12 (CH 2 ) n C(CH 3 ) 2 SZ, —CO-morpholino-XSZ, —CO-piperazino-XSZ, —CO-piperidino-XSZ, or —CO—N-methylpiperazino-XSZ,
wherein Z is H or SR, wherein R and R 12 are the same or different and are linear alkyl having 1 to 10 carbon atoms, branched or cyclic alkyl having 3 to 10 carbon atoms, or simple or substituted phenyl, naphthyl or heterocyclic, and R 12 in addition can be H, X is linear alkyl having 1-10 carbon atoms or branched alkyl having 3-10 carbon atoms, and n is an integer of 1 to 10;
R 3 is —CH═C(CH 3 ) 2 ;
R 4 is —OC(CH 3 ) 3 or phenyl;
R 5 together with the oxygen atom at the C-7 position forms a linear ether having from 1 to 10 carbon atoms, or a branched or cyclic ether having from 3 to 10 carbon atoms; and
R 6 is H.
2. The method of claim 1 , wherein the cell binding agent is selected from the group consisting of antibodies, an antigen specific antibody fragment, interferons, lymphokines, hormones, vitamins, growth factors, colony stimulating factors, and nutrient-transport molecules.
3. The method of claim 2 , wherein the cell binding agent is an antibody or an antigen specific antibody fragment thereof.
4. The method of claim 2 , wherein the cell binding agent is a monoclonal antibody or an antigen specific antibody fragment thereof.
5. The method of claim 4 , wherein the cell binding agent is specific for Common Acute Lymphoblastic Leukemia Antigen (CALLA) or CD19 antigen.
6. The method of claim 4 , wherein the monoclonal antibody is monoclonal antibody J5 or an anti-B4 monoclonal antibody.
7. The method of claim 4 , wherein the antigen specific antibody fragment is selected from the group consisting of sFV, Fab, Fab′, and F(ab′) 2 .
8. The method of claim 2 , wherein the cell binding agent is an interferon.
9. The method of claim 8 , wherein the interferon is interferon α, interferon β or interferon γ.
10. The method of claim 2 , wherein the cell binding agent is a lymphokine.
11. The method of claim 10 , wherein the lymphokine is IL-2, IL-3, IL-4 or IL-6.
12. The method of claim 2 , wherein the cell binding agent is a hormone.
13. The method of claim 12 , wherein the hormone is insulin, thyrotropin releasing hormones (TRH), thyroid stimulating hormone (TSH), melanocyte-stimulating hormone (MSH), or a steroid hormone.
14. The method of claim 13 , wherein the steroid hormones are androgens, androgen analogues, estrogens or estrogen analogues.
15. The method of claim 13 , wherein the steroid hormones are estradiol or androstenediol.
16. The method of claim 2 , wherein the cell binding agent is a vitamin.
17. The method of claim 16 , wherein the vitamin is folic acid.
18. The method of claim 2 , wherein the cell binding agent is a growth factor.
19. The method of claim 18 , wherein the growth factor is epidermal growth factor (EGF) or transforming growth factor α (TGF-α).
20. The method of claim 2 , wherein the cell binding agent is a colony stimulating factor.
21. The method of claim 20 , wherein the colony stimulating factor is G-CSF, M-CSF or GM-CSF.
22. The method of claim 2 , wherein the cell binding agent is a nutrient-transport molecule.
23. The method of claim 22 , wherein the nutrient-transport molecule is a transferrin.
24. The method of claim 1 , wherein the cancer cells are solid tumor cells.
25. The method of claim 1 , wherein the target cells are lung, breast, colon, prostate, kidney, pancreas, ovary, or lymphatic cancer cells.