CA2485424A1 - Cytotoxic agents comprising polyethylene glycol-containing taxanes and their therapeutic use - Google Patents

Cytotoxic agents comprising polyethylene glycol-containing taxanes and their therapeutic use Download PDF

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CA2485424A1
CA2485424A1 CA002485424A CA2485424A CA2485424A1 CA 2485424 A1 CA2485424 A1 CA 2485424A1 CA 002485424 A CA002485424 A CA 002485424A CA 2485424 A CA2485424 A CA 2485424A CA 2485424 A1 CA2485424 A1 CA 2485424A1
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cr13r14
och2ch2
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conr12
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CA2485424C (en
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Ravi V. J. Chari
Michael Louis Miller
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Immunogen Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
    • C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6889—Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

A cytotoxic agent comprising one or more polyethylene glycol-containing taxanes linked to a cell binding agent. A therapeutic composition for killin g selected cell populations comprising: (A) a cytotoxic amount of one or more polyethylene glycol-containing 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 polyethylene glycol-containing taxanes linked to a cell binding agent.

Claims (50)

1. A taxane comprising a polyethylene glycol-containing linking group at C-7 or C-10.
2. The taxane of claim 1, wherein the polyethylene glycol-containing linking group comprises a thiol or disulfide as a linking moiety.
3. The taxane of claim 2, wherein the polyethylene glycol-containing linking group is carried on a side chain that is a linear or branched, aromatic or heterocyclic group.
4. The taxane of claim 1, wherein the polyethylene glycol-containing linking group is cleavable.
5. The taxane of claim 1, wherein the polyethylene glycol-containing linking group is acid labile, photolabile, peptidase labile, or esterase labile.
6. The taxane of claim 1, wherein the polyethylene glycol-containing linking group is not cleavable.
7. The taxane of claim 1, wherein the substituent comprising the polyethylene glycol-containing linking group is selected from the group consisting of:
-(CR13R14)l(CH2)m(C R13R14)l(OCH2CH2)nO(C R13R14)l(CH2)m(C R13R14)lSZ, -CO(C R13R14)l(CH2)m(C R13R14)l (OCH2CH2)nO(C R13R14)l(CH2)m(C R13R14)l SZ, -CONR12(C R13R14)l(CH2)m(C R13R14)l(OCH2CH2)nO(C R13R14)l(CH2)m(CR13R14)l SZ, -(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)n OCO(CR13R14)l(CH2)m(CR13R14)lSZ, -(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)n NR12CO(CR13R14)l(CH2)m(CR13R14)lSZ, -(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)n OCONR12(CR13R14)l(CH2)m(CR13R14)lSZ, -CO(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)nOCO(CR13R14)l(CH2)m(CR13R14)l SZ, -CO(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)nNR12CO(CR13R14)l(CH2)m(CR13R14)l SZ, -CO(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)nOCONR12(CR13R14)l(CH2)m(CR13R14)l SZ, -CONR12(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)nOCO(CR13R14)l(CH2)m(CR13R14)l SZ, -CONR12(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)nNR12CO(CR13R14)l(CH2)m(CR13R14)l SZ, -CONR12(CR13R14)l(CH2)m(CR13R14)t(OCH2CH2)n OCONR12(CR13R14)l(CH2)m(CR13R14)l SZ, -CO-morpholino-X(OCH2CH2)n SZ, -CO-piperazino-X(OCH2CH2)n SZ, -CO-piperidino-X(OCH2CH2)n SZ, and -CO-N-methylpiperazino-X(OCH2CH2)n SZ, wherein Z is H or SR, X is a linear alkyl or branched alkyl having 1-10 carbon atoms, R and R12 are the same or different and represent linear alkyl, branched alkyl or cyclic alkyl having 1 to 10 carbon atoms, or simple or substituted aryl having 1 to 10 carbon atoms or heterocyclic, and R12 can in addition be H, R13 and R14 are same or different and represent H or linear alkyl, branched alkyl or cyclic alkyl having 1 to 10 carbon atoms, or aryl, l is 0 or an integer from 1 to 10, m is an integer of 1 to 10, and n is 2 to 1000.
8. A compound of formula (I):
wherein:
R1 is H, an electron withdrawing group, or an electron donating group;
42~

R1' and R1" are the same or different and are H, an electron withdrawing group, or an electron donating group;
R2 is -(CR13R14)l(CH2)m(C R13R14)l(OCH2CH2)n O(C R13R14)l(CH2)m(C R13R14)l SZ, -CO(C R13R14)l(CH2)m(C R13R14)l(OCH2CH2)n O(C R13R14)l(CH2)m(C R13R14)l SZ, -CONR12(C R13R14)l(CH2)m(C R13R14)l(OCH2CH2)n O(C R13R14)(CH2)m(CR13R14)l SZ, -(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)n OCO(CR13R14)l(CH2)m(CR13R14)l SZ, -(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)n NR12CO(CR13R14)l(CH2)m(CR13R14)l SZ, -(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)n OCONR12(CR13R14)l(CH2)m(CR13R14)l SZ, -CO(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)n OCO(CR13R14)l(CH2)m(CR13R14)l SZ, -CO(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)n NR12CO(CR13R14)l(CH2)m(CR13R14)l SZ, -CO(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)n OCONR12(CR13R14)l(CH2)m(CR13R14)l SZ, -CONR12(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)n OCO(CR13R14)l(CH2)m(CR13R14)l SZ, -CONR12(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)n NR12CO(CR13R14)l(CH2)m(CR13R14)l SZ, -CONR12(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)n OCONR12(CR13R14)l(CH2)m(CR13R14)l SZ, -CO-morpholino-X(OCH2CH2)n SZ, -CO-piperazino-X(OCH2CH2)n SZ, -CO-piperidino-X(OCH2CH2)n SZ, and -CO-N-methylpiperazino-X(OCH2CH2)n SZ, wherein Z is H or SR, X is a linear alkyl or branched alkyl having 1-10 carbon atoms, R and R12 are the same or different and represent linear alkyl, branched alkyl or cyclic alkyl having 1 to 10 carbon atoms, or simple or substituted aryl having 1 to 10 carbon atoms or heterocyclic, and R12 can in addition be H, R13 and R14 are same or different and represent H or linear alkyl, branched alkyl or cyclic alkyl having 1 to 10 carbon atoms, or aryl, 1 is 0 or an integer from 1 to 10, m is an integer of 1 to 10, and n is 2 to 1000;
R3 is aryl, or is linear, branched or cyclic alkyl having 1 to 10 carbon atoms;
R4 is -OC(CH3)3 or -C6H5; and R5 is H, a heterocyclic, a linear, branched, or cyclic ester or ether having from 1 to 10 carbon atoms or a carbamate of formula -CNR10R11, wherein R10 and R11 are the same or different and are H, linear, branched, or cyclic alkyl having 1 to 10 atoms or simple or substituted aryl having 1 to 10 carbon atoms.
9. A compound of formula (I):
wherein:
R1 is H, an electron withdrawing group, or an electron donating group;
R1' and R1" are the same or different and are H, an electron withdrawing group, or an electron donating group;
R2 is H, a heterocyclic, a linear, branched, or cyclic ester or ether having from 1 to 10 carbon atoms or a carbamate of the formula -CNR10R11, wherein R10 and R11 are the same or different and are H, linear, branched, or cyclic alkyl having 1 to 10 atoms or simple or substituted aryl having 1 to 10 carbon atoms;
R3 is aryl, or is linear, branched or cyclic alkyl having 1 to 10 carbon atoms;
R4 is -OC(CH3)3 or -C6H5; and R5 is -(CR13R14)l(CH2)m(C R13R14)l(OCH2CH2)n O(C R13R14)l(CH2)m(C R13R14)l SZ, -CO(C R13R14)OCH2)m(C R13R14)l(OCH2CH2)n O(C R13R14)l(CH2)m(C R13R14)l SZ, -CONR12(C R13R14)l(CH2)m(C R13R14)l(OCH2CH2)n O(C R13R14)l(CH2)m(CR13R14)l SZ, -(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)n OCO(CR13R14)l(CH2)m(CR13R14)l SZ, -(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)n NR12CO(CR13R14)l(CH2)m(CR13R14)l SZ, -(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)n OCONR12(CR13R14)l(CH2)m(CR13R14)l SZ, -CO(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)n OCO(CR13R14)l(CH2)m(CR13R14)l SZ, -CO(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)n NR12CO(CR13R14)l(CH2)m(CR13R14)l SZ, -CO(CR13R14)t(CH2)m(CR13R14)l(OCH2CH2)n OCONR12(CR13R14)l(CH2)m(CR13R14)l SZ, -CONR12(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)n OCO(CR13R14)l(CH2)m(CR13R14)l SZ, -CONR12(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)n NR12CO(CR13R14)l(CH2)m(CR13R14)l SZ, -CONR12(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)n OCONR12(CR13R14)l(CH2)m(CR13R14)l SZ, -CO-morpholino-X(OCH2CH2)n SZ, -CO-piperazino-X(OCH2CH2)n SZ, -CO-piperidino-X(OCH2CH2)n SZ, and -CO-N-methylpiperazino-X(OCH2CH2)n SZ, wherein Z is H or SR, X is a linear alkyl or branched alkyl having 1-10 carbon atoms, R and R12 are the same or different and represent linear alkyl, branched alkyl or cyclic alkyl having 1 to 10 carbon atoms, or simple or substituted aryl having 1 to
10 carbon atoms or heterocyclic, and R12 can in addition be H, R13 and R14 are same or different and represent H or linear alkyl, branched alkyl or cyclic alkyl having 1 to 10 carbon atoms, or aryl, 1 is 0 or an integer from 1 to 10, m is an integer of 1 to 10, and n is 2 to 1000.
10. The compound of claim 8 or 9, wherein R1 is H, F, NO2, CN, Cl, CHF2, CF3, -OCH3, -OCH2CH3, -NR6R7, or -OR8.
11. The compound of claim 8 or 9, wherein R1 is OMe, OEt, Cl, F, NO2, or CF3.
12. The compound of claim 8 or 9, wherein R1 is in the meta position, R1' is OMe, and R1" is H.
13. The compound of claim 8 or 9, wherein R1' and R1" are the same or different and are H, F, NO2, CN, Cl, CHF2, CF3, -OCH3, OCH2CH3, -NR6R7, or -OR8, wherein:
R6 and R7 are the same or different and are each H, linear, branched, or cyclic alkyl groups having 1 to 10 carbon atoms, or simple or substituted aryl having 1 to 10 carbon atoms, and R8 is linear, branched or cyclic alkyl having 1 to 10 carbon atoms.
14. The compound of claim 13, wherein R6 and R7 are same or different and are each H, or are alkyl or aryl having 1 to 4 carbon atoms.
15. The compound of claim 13, wherein -NR6R7 is dimethyl amino, diethyl amino, dipropyl amino, or dibutyl amino, where the butyl moiety is any of primary, secondary, tertiary or isobutyl..
16. The compound of claim 8 or 9, wherein R3 is -CH2CH(CH3)2 or -CH=C(CH3)2.
17. The compound of claim 8 or 9, wherein R4 is -OC(CH3)3 or -C6H5.
18. The compound of claim 8, wherein R5 is H, -COCH3, -COCH2CH3 and -COCH2CH2CH3.
19. The compound of claim 9, wherein R2 is H, -COCH3, -COCH2CH3 and -COCH2CH2CH3.
20. The compound of claim 8, wherein R5 is H, or -CONHCH2CH3, -CONHCH2CH2CH3, -CO-morpholino, -CO-piperazino, -CO-piperidino, or -CO-N-methylpiperazino.
21. The compound of claim 9, wherein R2 is H, or -CONHCH2CH3, -CONHCH2CH2CH3, -CO-morpholino, -CO-piperazino, -CO-piperidino, or -CO-N-methylpiperazino.
22. A cytotoxic agent comprising one or more taxanes linked to a cell binding agent through a polyethylene glycol-containing linking group at C-7 or C-10 of at least one of the taxanes.
23. The cytotoxic agent of claim 22, wherein the polyethylene glycol-containing linking group comprises a thiol or disulfide as the linking moiety.
24. The cytotoxic agent of claim 22, wherein the polyethylene glycol-containing linking group is carried on a side chain that is a linear or branched, aromatic or heterocyclic group.
25. The cytotoxic agent of claim 22, wherein at least one of the taxanes is linked to the cell binding agent through a cleavable linking group.
26. The cytotoxic agent of claim 25, wherein the cleavable linking group is acid labile, photolabile, peptidase labile or esterase labile.
27. The cytotoxic agent of claim 22, wherein at least one of the taxanes is linked to the cell binding agent through a non-cleavable linking group.
28. The cytotoxic agent of claim 22, wherein the substituent comprising the polyethylene glycol-containing linking group is selected from the group consisting of:

-(CR13R14)l(CH2)m(C R13R14)l(OCH2CH2)n O(C R13R14)l(CH2)m(C R13R14)l SZ, -CO(C R13R14)l(CH2)m(C R13R14)l(OCH2CH2)n O(C R13R14)l(CH2)m(C R13R14)l SZ, -CONR12(C R13R14)l(CH1)m(C R13R14)l(OCH2CH2)n O(C R13R14)l(CH2)m(CR13R14)l SZ, -(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)n OCO(CR13R14)l(CH2)m(CR13R14)l SZ, -(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)n NR12CO(CR13R14)l(CH2)m(CR13R14)l SZ, -(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)n OCONR12(CR13R14)l(CH2)m(CR13R14)l SZ, -CO(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)n OCO(CR13R14)l(CH2)m(CR13R14)l SZ, -CO(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)n NR12CO(CR13R14)l(CH2)m(CR13R14)l SZ, -CO(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)n OCONR12(CR13R14)l(CH2)m(CR13R14)l SZ, -CONR12(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)n OCO(CR13R14)l(CH2)m(CR13R14)l SZ, -CONR12(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)n NR12CO(CR13R14)l(CH2)m(CR13R14)l SZ, -CONR12(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)n OCONR12(CR13R14)l(CH2)m(CR13R14)l SZ, -CO-morpholino-X(OCH2CH2)n SZ, -CO-piperazino-X(OCH2CH2)n SZ, -CO-piperidino-X(OCH2CH2)n SZ, and -CO-N-methylpiperazino-X(OCH2CH2)n SZ, wherein Z is H or SR, X is a linear alkyl or branched alkyl having 1-10 carbon atoms, R and R12 are the same or different and represent linear alkyl, branched alkyl or cyclic alkyl having 1 to 10 carbon atoms, or simple or substituted aryl having 1 to 10 carbon atoms or heterocyclic, and R12 can in addition be H, R13 and R14 are same or different and represent H or linear alkyl, branched alkyl or cyclic alkyl having 1 to 10 carbon atoms, or aryl, l is 0 or an integer from 1 to 10, m is an integer of 1 to 10, and n is 2 to 1000.
29. The cytotoxic agent of claim 22, wherein the cell binding agent is an antibody or an antibody fragment.
30. The cytotoxic agent of claim 22, wherein the cell binding agent is an antibody, a single chain antibody or a binding fragment of an antibody or single chain antibody.
31. The cytotoxic agent of claim 22, wherein the cell binding agent is a monoclonal antibody, a single chain monoclonal antibody or a binding fragment of a single chain monoclonal antibody a monoclonal antibody which is or is not humanized or resurfaced or chimeric.
32. The cytotoxic agent of claim 31, wherein the cell binding agent binds specifically to the CD33 antigen.
33. The cytotoxic agent of claim 31, wherein the cell binding agent binds specially to the CD56 antigen.
34. The cytotoxic agent of claim 22, wherein the cell binding agent is an interferon, a lymphokine, a hormone, a vitamin, a growth factor, a colony-stimulating factor, or transferrin.
35. The cytotoxic agent of claim 22, wherein the cell binding agent is epidermal growth factor, transforming growth factor, vascular endothelial growth factor, fibroblast growth factor, insulin like growth factor 1 and 2, platelet derived growth factor, melanocyte stimulating hormone, thyroid stimulating hormone, somatostatin, estrogen, estrogen analogue, androgen, androgen analogue, or folate.
36. A therapeutic composition comprising:
(A) An effective amount of a cytotoxic agent comprising one or more taxanes linked to a cell binding agent through a polyethylene glycol-containing linking group at C-7 or C-10 of at least one of the taxanes; and (B) A pharmaceutically acceptable carrier, diluent, or excipient.
37. The therapeutic composition of claim 36, wherein the polyethylene glycol-containing linking group comprises a thiol or disulfide as the linking moiety.
38. The therapeutic composition of claim 36, wherein the polyethylene glycol-containing linking group is carried on a side chain that is a linear or branched, aromatic or heterocyclic group.
39. The therapeutic composition of claim 36, wherein at least one of the taxanes is linked to the cell binding agent through a cleavable linking group.
40. The therapeutic composition of claim 39, wherein the cleavable linking group is acid labile, photolabile, peptidase labile or esterase labile.
41. The therapeutic composition of claim 36, wherein at least one of the taxanes is linked to the cell binding agent through a non-cleavable linking group.
42. The therapeutic composition of claim 36, wherein the substituent comprising the polyethylene glycol-containing linking group is selected from the group consisting of:
-(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)n O(CR13R14)l(CH2)m(CR13R14)l SZ, -CO(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)n O(CR13R14)l(CH2)m(CR13R14)l SZ, -CONR12(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)n O(CR13R14)l(CH2)m(CR13R14)l SZ, -(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)n OCO(CR13R14)l(CH2)m(CR13R14)l SZ, -(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)n NR12CO(CR13R14)l(CH2)m(CR13R14)l SZ, -(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)n OCONR12(CR13R14)l(CH2)m(CR13R14)l SZ, -CO(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)n OCO(CR13R14)l(CH2)m(CR13R14)l SZ, -CO(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)n NR12CO(CR13R14)l(CH2)m(CR13R14)l SZ, -CO(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)n OCONR12(CR13R14)l(CH2)m(CR13R14)l SZ, -CONR12(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)n OCO(CR13R14)l(CH2)m(CR13R14)l SZ
-CONR12(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)n NR12CO(CR13R14)l(CH2)m(CR13R14)l SZ, -CONR12(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)n OCONR12(CR13R14)l(CH2)m(CR13R14)l SZ, -CO-morpholino-X(OCH2CH2)n SZ, -CO-piperazino-X(OCH2CH2)n SZ, -CO-piperidino-X(OCH2CH2)n SZ, and -CO-N-methylpiperazino-X(OCH2CH2)n SZ, wherein Z is H or SR, X is a linear alkyl or branched alkyl having 1-10 carbon atoms, R and R12 are the same or different and represent linear alkyl, branched alkyl or cyclic alkyl having 1 to 10 carbon atoms, or simple or substituted aryl having 1 to 10 carbon atoms or heterocyclic, and R12 can in addition be H, R13 and R14 are same or different and represent H or linear alkyl, branched alkyl or cyclic alkyl having 1 to 10 carbon atoms, or aryl, l is 0 or an integer from 1 to 10, m is an integer of 1 to 10, and n is 2 to 1000.
43. The therapeutic composition of claim 36 or 37, wherein the cell binding agent is an antibody or an antibody fragment.
44. The therapeutic composition of any one of claims 36, 37, 38 or 42, wherein the cell binding agent is an antibody, a single chain antibody or a binding fragment of an antibody or single chain antibody.
45. The therapeutic composition of any one of claims 36, 37, 38 or 42, wherein the cell binding agent is a monoclonal antibody, a single chain monoclonal antibody or a binding fragment of a single chain monoclonal antibody a monoclonal antibody which is or is not humanized or resurfaced or chimeric?.
46. The therapeutic composition of claim 45, wherein the cell binding agent binds specifically to the CD33 antigen.
47. The therapeutic composition of claim 45, wherein the cell binding agent binds specifically to the CD 19 antigen.
48. The therapeutic composition of any one of claims 36, 37, 38 or 42, wherein the cell binding agent is an interferon, a lymphokine, a hormone, a vitamin, a growth factor, a colony-stimulating factor, or transferrin.
49. The therapeutic composition of any one of claims 36, 37, 38 or 42, wherein the cell binding agent is epidermal growth factor, , transforming growth factor, vascular endothelial growth factor, fibroblast growth factor, insulin like growth factor 1 and 2, platelet derived growth factor, somatostatin, melanocyte stimulating hormone, thyroid stimulating hormone, estrogen, estrogen analogue, androgen, androgen analogue, or folate.
50. A method of killing selected cell populations comprising contacting target cells or tissue containing target cells with a cytotoxic amount of the cytotoxic agent of any one of claims 22 to 35.
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