Elimination of heterogeneous or mixed cell population in tumors
AssigneeImmunoGen, Inc.
InventorsViktor Goldmakher, Robert Lutz, Ravi Chari, Yelena Kovtun, John Lambert, Rita Steeves, Hans Erickson
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Abstract
Methods of killing or inhibiting tumors comprising of heterogeneous or mixed cell populations is described. The killing or inhibition of tumors is achieved by selectively targeting a unique ligand suspected of being expressed on a particular cell population to also kill a cell population lacking the unique ligand. These conjugates have therapeutic use as they are delivered to a specific cell population to kill these cells and the cytotoxic drug is released to kill non-targeted cells, thereby eliminating the tumor.
Claims115
A method of eliminating a heterogeneous or mixed cell population AB, wherein A represents a cell population selectively expressing an ligand and B represents a cell lacking the ligand expressed in A, said method comprising:
- a. targeting a cell-binding agent drug conjugate to the selected cell population A, wherein one or more drugs is covalently linked to the cell-binding agent via a linker comprising a disulfide bond and the cell-binding agent binds to the ligand in the cell population A;
- b. internalization of the cell-binding agent drug conjugate in the cells comprising the cell population A;
- c. cleaving the drug from the conjugate such that the drug undergoes an alkylation step prior to killing the cells in the cell population A;
- and
- d. releasing the alkylated drug from the cell population A to induce killing of cells in the cell population B,
- thereby eliminating the heterogeneous cell population.
A method of eliminating cells in an abnormal cell population, said method comprising:
- a) targeting a cell-binding agent drug conjugate to a selected cell population that expresses a ligand recognized by the cell-binding agent of the conjugate, wherein one or more drugs is covalently linked to the cell-binding agent via a linker comprising a disulfide bond and the cell-binding agent binds to the cells;
- b) conversion of the pro-drug in the conjugate to a cytotoxic drug which further undergoes an alkylation step prior to killing the selected cell population suspected of containing the ligand;
- and
- c) releasing the alkylated cytotoxic drug from the selected cell population to induce killing of another selected cell population suspected of lacking the ligand, thereby eliminating cells in the abnormal cell population.
A method of utilizing a targeted cell population to inhibit or kill non-targeted cells in a heterogeneous or mixed cell population, said method comprising:
- a) targeting a cell-binding agent drug conjugate to the targeted cell population suspected of containing an ligand recognized by the cell-binding agent of the conjugate, wherein one or more drugs is covalently linked to the cell-binding agent via a linker comprising a disulfide bond and the cell-binding agent binds to the cells;
- b) conversion of the pro-drug in the conjugate to a cytotoxic drug in the targeted selected cell population to inhibit or kill the targeted cells;
- and
- c) releasing the cytotoxic drug from the targeted cell population to inhibit or kill the non-targeted cells which lack the ligand in the targeted cell,
- d) thereby inhibit or kill the heterogeneous or mixed cell population, targeted and non-targeted.
A method of killing tumor cells in a tumor comprising a heterogeneous or mixed cell population, said method comprising:
- a) selectively targeting a shed ligand, shed from a selected population of tumor cells suspected of expressing the ligand with a cell-binding agent drug conjugate wherein one or more drugs is covalently linked to the cell-binding agent via a linker comprising a disulfide bond and the cell-binding agent binds to the shed ligand.
- b) conversion of the pro-drug in the conjugate to a cytotoxic drug which further undergoes an alkylation step prior to killing the selected cell population of tumor cells which shed the ligand;
- and
- c) further induce killing of tumor cells which completely lack the ligand, to thereby kill the heterogeneous or mixed cells in the tumor.
A compound of formula:
- MayOCH(Me)N(CH3n)COCH2CH2(CMe2)nSMe
- wherein, n=0 or 1, and May=maytansinoid.
A compound of formula:
- MayOCH(Me)N(CH3n)COCH2CH2(CMe2)nSMe
- wherein, DM1Me:
- n=0;
- DM4Me:
- n=1
An alkylated maytansinoid, wherein the maytansinoid has undergone alkylation at an unreacted thiol group.
Isolated lysine-Nε-SMCC-DM1.
Isolated lysine-Nε-SPDB-DM4.
Isolated S-cysteinyl-DM4.
Isolated S-methyl-DM4.
Dependencies are inferred from the claim text.