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US 2004/0171562 A1Published application
Prodrugs activated by plasmin and their use in cancer chemotherapy
AssigneeMedarex, Inc.
InventorsAndre Trouet, Vincent Dubois, Alexandre Passioukov
Life of this patent
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Abstract
The product of the invention is a modified form of a therapeutic agent and comprises a therapeutic agent, an oligopeptide having a plasmin peptide substrate of 2-4 amino acids and mono- or di-peptide linkage, a stabilizing group and, optionally, a linker group. The prodrug is cleavable by plasmin. Also disclosed are methods of making and using the prodrug compounds.
Claims38
A compound comprising:
- (1) a therapeutic agent capable of entering a target cell;
- (2) an oligopeptide having the formula X-Y, where X is a plasmin peptide substrate of 2-4 amino acids and Y is a peptide comprising 1-2 aliphatic amino acids having large lateral chains;
- (3) a stabilizing group;
- and
- (4) optionally, a linker group not cleavable by plasmin;
- wherein the oligopeptide is directly linked to the stabilizing group at a first attachment site of the oligopeptide and the oligopeptide is directly linked to the therapeutic agent or indirectly linked through the linker group to the therapeutic agent at a second attachment site of the oligopeptide;
- wherein the stabilizing group hinders cleavage of the oligopeptide by enzymes present in whole blood;
- and
- wherein the compound is cleavable by plasmin.
6 more elements
An oligopeptide having the formula (AAx)m-(AAy)n (SEQ ID NO:1) wherein:
- (AAx)m is a plasmin substrate and each AAx independently represents an amino acid;
- each AAY independently represents an aliphatic amino acid having a large lateral chain;
- m is an integer from 2-4;
- and n is an integer from 1-2, said oligopeptide being cleavable by plasmin.
1 more element
A pharmaceutical composition comprising:
- (1) A compound comprising:
- (a) a therapeutic agent capable of entering a target cell;
- (b) an oligopeptide having the formula (AAx)m-(AAy)n (SEQ ID NO:1) wherein:
- (AAx)m is a plasmin substrate and each AAx independently represents an amino acid;
- each AAy independently represents an aliphatic amino acid having a large lateral chain;
- m is an integer from 2-4;
- and n is an integer from 1-2;
- (c) a stabilizing group;
- and
- (d) optionally, a linker group not cleavable by plasmin;
- wherein the oligopeptide is directly linked to the stabilizing group at a first attachment site of the oligopeptide and the oligopeptide is directly linked to the therapeutic agent or indirectly linked through the linker group to the therapeutic agent at a second attachment site of the oligopeptide;
- wherein the stabilizing group hinders cleavage of the oligopeptide by enzymes present in whole blood;
- and
- wherein the compound is cleaved by plasmin under physiological conditions;
- and
- (2) a pharmaceutically acceptable carrier.
13 more elements
A method for treating a patient, the method comprising administering to the patient a compound comprising:
- (1) a therapeutic agent capable of entering a target cell;
- (2) an oligopeptide having the formula (AAx)m(AAy)n (SEQ ID NO:1) wherein:
- (AAx)n is a plasmin substrate and each AAx independently represents an amino acid;
- each AAy independently represents an aliphatic amino acid having a large lateral chain;
- m is an integer from 2-4;
- and n is an integer from 1-2;
- (3) a stabilizing group;
- and
- (4) optionally, a linker group not cleavable by plasmin;
- wherein the oligopeptide is directly linked to the stabilizing group at a first attachment site of the oligopeptide and the oligopeptide is directly linked to the therapeutic agent or indirectly linked through the linker group to the therapeutic agent at a second attachment site of the oligopeptide;
- wherein the stabilizing group hinders cleavage of the oligopeptide by enzymes present in whole blood;
- and
- wherein the compound is cleaved by plasmin under physiological conditions.
10 more elements
A method for decreasing the toxicity of a therapeutic agent wherein the therapeutic agent is intended for administration to a patient, the method comprising:
- covalently forming a prodrug by linking an oligopeptide cleavable by plasmin to a stabilizing group at a first attachment site of the oligopeptide and directly or indirectly linking the therapeutic agent at a second attachment site of the oligopeptide, wherein the oligopeptide has the formula (AAx)m-(AAy)n (SEQ ID NO:1) wherein:
- (AAx)m is a plasmin substrate and each AAx independently represents an amino acid;
- each AAy independently represents an aliphatic amino acid having a large lateral chain;
- m is an integer from 2-4;
- and n is an integer from 1-2, and wherein the compound is cleavable by plasmin, whereby the prodrug provides for decreased toxicity of the therapeutic agent when administered to the patient.
2 more elements
An article of manufacture for diagnosis or conducting assays comprising:
- (1) a compound comprising:
- (a) a marker;
- (b) an oligopeptide having a formula (AAx)m-(AAy)n (SEQ ID NO:1) wherein:
- (AAx)m is a plasmin substrate and each AAx independently represents an amino acid;
- each AAy independently represents an aliphatic amino acid having a large lateral chain;
- m is an integer from 2-4;
- and n is an integer from 1-2;
- (c) a stabilizing group;
- and
- (d) optionally, a linker group not cleavable by plasmin;
- wherein the oligopeptide is directly linked to the stabilizing group at a first attachment site of the oligopeptide and the oligopeptide is directly linked to the therapeutic agent or indirectly linked through the linker group to the therapeutic agent at a second attachment site of the oligopeptide;
- wherein the stabilizing group hinders cleavage of the oligopeptide by enzymes present in whole blood;
- and
- wherein the compound is cleavable by plasmin;
- and
- (2) at least one reagent useful in the detection of the marker.
13 more elements
Dependencies are inferred from the claim text.