EP0330201A2
Expired / Lapsed
EP
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Method of enhancing the effect of cytotoxic agents
Assignee: Poniard Pharmaceuticals Inc
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Filing: 1989-02-23
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Granted: —
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Expires: 2009-02-23
Abstract
Abstract The activity of cytotoxic agents on target cells is enhanced through administration of a sensitizing agent to a patient prior to or simultaneously with administration of the cytotoxic agent. One or both of the two types of agents are attached to antibodies specific for the desired target cells, thereby enhancing the cytotoxic effect on target cells compared to non-target cells. The sensitizer and/or the cytotoxic agent may be attached to monoclonal antibodies specific for cancer cells to selectively eradicate the cancer cells while minimizing toxicity toward normal tissues.
Inventors
- 👤 Paul G. Abrams
- 👤 Alton Charles Morgan, Jr.
- 👤 Ananthachari Srinivasan
- 👤 Vivekananda M. Vrudhula
Bibliographic Details
Application Number
—
Jurisdiction
EP
Data Source
google_patents
Last Synchronized
2026-10-24 10:39
CPC Classifications
A; A61; A61K; A61K47/00; A61K47/50; A61K47/51; A61K47/68; A61K47/6889; A61P; A61P35/00
Claims Analysis
Total Claims: 37
Claim 1
Independent Claim
26 words
A conjugate comprising a sensitizing agent bound through a cleavable linker to a targeting protein specific for a target site within a human or mammalian host.
Claim 2
Dependent Claim
26 words
A conjugate comprising a sensitizing agent bound through a cleavable linker to a targeting protein specific for a target site within a human or mammalian host.
Claim 3
Dependent Claim
23 words
The conjugate of Claim 1 wherein the sensitizing agent is a drug which enhances the cytotoxic effect of a cytotoxic drug or radiation.
Claim 4
Dependent Claim
43 words
The conjugate of Claim 3 wherein said sensitizing agent is selected from the group consisting of buthionine sulfoximine, calcium channel blockers, metronidazole, misonidazole, diltiazem, 2-(substituted sulfamyl)-6-nitrobenzoates, 2-(substituted sulfamyl)-6-nitrobenzamides, 2,6-disubstituted derivatives of 3-nitropyrazine, isoindoledione compounds, doxorubicin, bleomycin, cis-diaminodichloro platinum, WR 2721, and derivatives thereof.
Claim 5
Dependent Claim
16 words
The conjugate of Claim 2 wherein the sensitizing agent is a drug that inhibits DNA repair.
Claim 6
Dependent Claim
25 words
The conjugate of Claim 1, 2, 3, or 4 wherein the targeting protein is a monoclonal antibody or a fragment thereof specific for cancer cells.
Claim 7
Dependent Claim
26 words
The conjugate of Claim 1 wherein said targeting protein is an antibody and the conjugate additionally comprises a cytotoxic agent linked to the same antibody molecule.
Claim 8
Independent Claim
104 words
A method of specifically increasing the cytotoxic effect of a cytotoxic agent on target cells compared to non-target cells comprising contacting the target cells and the non-target cells with both a sensitizing agent and a cytotoxic agent wherein at least one of the sensitizing agent or the cytotoxic agent is conjugated to a targeting protein specific for the target cells, and wherein the linkage between the targeting protein and the sensitizing agent or the cytotoxic agent or both is cleavable at the target site when the biological activity of the sensitizing agent or the cytotoxic agent is enhanced by release from the targeting protein.
Claim 9
Independent Claim
104 words
A method of specifically increasing the cytotoxic effect of a cytotoxic agent on target cells compared to non-target cells comprising contacting the target cells and the non-target cells with both a sensitizing agent and a cytotoxic agent wherein at least one of the sensitizing agent or the cytotoxic agent is conjugated to a targeting protein specific for the target cells, and wherein the linkage between the targeting protein and the sensitizing agent or the cytotoxic agent or both is cleavable at the target site when the biological activity of the sensitizing agent or the cytotoxic agent is enhanced by release from the targeting protein.
Claim 10
Dependent Claim
21 words
The method of Claim 7 wherein the targeting protein is a monoclonal antibody or a fragment thereof specific for cancer cells.
Claim 11
Dependent Claim
43 words
The method of Claim 7 wherein the sensitizing agent is selected from the group consisting of buthionine sulfoximine, calcium channel blockers, metronidazole, misonidazole, diltiazem, 2-(substituted sulfamyl)-6-nitrobenzoates, 2-(substituted sulfamyl)-6-nitrobenzamides, 2,6-disubstituted derivatives of 3-nitropyrazine, isoindoledione compounds, doxorubicin, bleomycin, cis-diaminodichloro platinum, WR 2721, and derivatives thereof.
Claim 12
Dependent Claim
33 words
The method of Claim 7 wherein the sensitizing agent is a drug that inhibits DNA repair and the cytotoxic agent is a therapeutic radionuclide attached to an antibody specific for the target cells.
Claim 13
Dependent Claim
35 words
The method of Claim 9 wherein the sensitizing agent is buthionine sulfoximine and the cytotoxic agent is a drug having cytotoxic activity which is enhanced or restored when the target cell glutathione levels are raised.
Claim 14
Dependent Claim
17 words
The method of Claim 9 wherein the sensitizing agent is misonidazole and the cytotoxic agent is radiation.
Claim 15
Dependent Claim
35 words
The method of Claim 9 wherein the sensitizing agent is WR 2721 or a derivative thereof, and the cytotoxic agent is a radionuclide attached to an antibody or fragment thereof specific for the target cells.
Claim 16
Dependent Claim
22 words
The method of Claim 13 wherein the sensitizing agent is attached to an antibody or fragment thereof specific for the target cells.
Claim 17
Dependent Claim
44 words
The method of Claim 7 wherein the sensitizing agent and the cytotoxic agent are attached to different antibody species wherein each antibody species is reactive with a different epitope on the target site and the patterns of cross-reactivity for each antibody species are non-overlapping.
Claim 18
Independent Claim
51 words
A method of reducing the cytotoxic effect of a cytotoxic agent on non-target cells, comprising contacting the non-target cells with a conjugate comprising a protecting agent attached to a targeting protein that binds to the non-target cells prior to or simultaneously with exposure of the non-target cells to the cytotoxic agent.
Claim 19
Independent Claim
51 words
A method of reducing the cytotoxic effect of a cytotoxic agent on non-target cells, comprising contacting the non-target cells with a conjugate comprising a protecting agent attached to a targeting protein that binds to the non-target cells prior to or simultaneously with exposure of the non-target cells to the cytotoxic agent.
Claim 20
Dependent Claim
23 words
The method of Claim 16 wherein the conjugate comprises a drug designated WR 2721 that has the formula: H₂N-(CH₂)₃-NH-(CH₂)₂-SPO₃H₂ as the protecting agent.
Claim 21
Dependent Claim
20 words
The method of Claim 17 wherein the targeting protein is a monoclonal antibody that binds to bone marrow stem cells.
Claim 22
Dependent Claim
24 words
The method of Claim 17 or 18 wherein the cytotoxic agent is a therapeutic radionuclide attached to an antibody that binds to target cells.
Claim 23
Independent Claim
43 words
A method of reducing the cytotoxic effect of a conjugate comprising a therapeutic radionuclide attached to a targeting protein, on non-target cells, comprising contacting the non-target cells with the drug WR 2721 or a derivative thereof and exposing the cells to the conjugate.
Claim 24
Independent Claim
43 words
A method of reducing the cytotoxic effect of a conjugate comprising a therapeutic radionuclide attached to a targeting protein, on non-target cells, comprising contacting the non-target cells with the drug WR 2721 or a derivative thereof and exposing the cells to the conjugate.
Claim 25
Dependent Claim
23 words
The method of Claim 20 wherein the conjugate comprises a radionuclide metal chelate attached to a monoclonal antibody that binds to cancer cells.
Claim 26
Dependent Claim
25 words
The method of Claim 16 or 20 wherein the non-target cells additionally are contacted with a substance that enhances the proliferation of the non-target cells.
Claim 27
Dependent Claim
17 words
The method of Claim 22 wherein the substance enhances proliferation of non-target cells found in bone marrow.
Claim 28
Dependent Claim
13 words
The method of Claim 23 wherein the substance is a colony stimulating factor.
Claim 29
Dependent Claim
16 words
A conjugate comprising a drug WR 2721 or a derivative thereof bound to a targeting protein.
Claim 30
Dependent Claim
16 words
A conjugate comprising a drug WR 2721 or a derivative thereof bound to a targeting protein.
Claim 31
Dependent Claim
25 words
The conjugate of Claim 25 wherein said conjugate has the formula: wherein R represents one or more optional electron withdrawing groups on the benzene ring.
Claim 32
Dependent Claim
18 words
The conjugate of Claim 25 or 26 wherein the targeting protein is a monoclonal antibody or fragment thereof.
Claim 33
Dependent Claim
15 words
A buthionine sulfoximine derivative for conjugation to a protein, wherein the derivative has the formula:
Claim 34
Dependent Claim
15 words
A buthionine sulfoximine derivative for conjugation to a protein, wherein the derivative has the formula:
Claim 35
Dependent Claim
14 words
A misonidazole dervative for conjugation to a protein, wherein the derivative has the formula:
Claim 36
Dependent Claim
14 words
A misonidazole dervative for conjugation to a protein, wherein the derivative has the formula:
Claim 37
Dependent Claim
41 words
The use of a conjugate in accordance with any one of the claims 1 to 6 and 25 to 27 or of a derivative in accordance with claim 28 or 29 in the manufacture of a medicament for use in therapy.
References Cited (Backward Citations)
No citation records indexed.
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