CD-10 activated prodrug compounds

• US 7,304,032 B2
• Filed: 12/22/2004
• Issued: 12/04/2007
• Est. Priority Date: 06/11/2001
• Status: Expired due to Term

• Current Assignee: ER Squibb & Sons LLC (Bristol-Myers Squibb Company)
• Original Assignee: Medarex Incorporated (Bristol-Myers Squibb Company)
• Inventors: Pan, Chin, Gangwar, Sanjeev, Bebbington, Christopher R., Pickford, Lesley B., Nieder, Matthew H., Cardarelli, Pina M.
• Primary Examiner(s): Russel; Jeffrey Edwin
• Application Number:
  US11/022,341
• Publication Number:
  US 20050267016A1
• Time in Patent Office: 1,077 Days
• Field of Search: None
• US Class Current: 514/1.3
• CPC Class Codes: A61K 47/65 Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C12Q 1/37 involving peptidase or proteinase
• CPC Class Codes: G01N 2333/70596 Molecules with a "CD"-designation not provided for elsewhere in G01N2333/705
• CPC Class Codes: G01N 2500/00 Screening for compounds of potential therapeutic value
• CPC Class Codes: G01N 33/57492 involving compounds localized on the membrane of tumor or cancer cells

Abstract

The compounds of the invention are modified forms of therapeutic agents. A typical prodrug compound of the invention comprises a therapeutic agent, an oligopeptide, a stabilizing group and, optionally, a linker group. The prodrug is cleavable by the CD10 enzyme. Methods of treatment using the prodrug and methods of designing a prodrug are also disclosed.

Claims

1. A method for treating a tumor comprising contacting the tumor with a therapeutically effective amount of a CD10 cleavable prodrug, wherein said tumor is comprised of one or more target cells which express CD10 for at least a portion of the target cell life cycle, wherein said tumor is selected from the group consisting of B-cell lymphoma, follicular lymphoma, Burkitt lymphoma, and non-Hodgkins'"'"' lymphoma.

2. The method of claim 1 wherein the CD10 cleavable prodrug comprises:

(1) a therapeutic agent capable of entering a target cell,

(2) an oligopeptide of the formula (AA)_n—

AA^P2—

AA^P1—

AA^P1′

—

(AA)_m,

wherein;

n and m are integers,

AA^P2 represents any amino acid,

AA^P1 represents any amino acid,

AA^P1′

represents any amino acid, and

each AA independently represents an amino acid,

(3) a stabilizing group, and

(4) optionally, a linker group,

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 prodrug by enzymes present in whole blood.

3. The method of claim 2 wherein n is 0 to 3, m is 0 to 3, and m+n is no more than 3 of the oligopeptide of the formula (AA)_n—

AA^P2—

AA^P1—

AA^P1′

—

(AA)_m.

4. The method of claim 2 wherein AA^P1 of the oligopeptide of the formula (AA)_n—

AA^P2—

AA^P1—

AA^P1′

—

(AA)_m is selected from the group consisting of arginine, alanine, glycine, leucine, methionine, proline, phenylalanine, tyrosine, glutamine, valine, and serine.

5. The method of claim 2 wherein AA^P1′

of the oligopeptide of the formula (AA)_n—

AA^P2—

AA^p1—

AA^P1′

—

(AA)_m is selected from the group consisting of leucine, isoleucine, phenylalanine, valine, tyrosine, and proline.

6. The method of claim 2 wherein the prodrug is administered intravenously to a subject having said tumor.

7. The method of claim 2 wherein the prodrug is resistant to cleavage by TOP.

8. The method of claim 2 wherein AA^P1—

AA^P1′

of the oligopeptide of the formula (AA)_n—

AA^P2—

AA^P1—

AA^P1′

—

(AA)_m is selected from the group consisting of Arg-Leu, Arg-Ile, Arg-Phe, Arg-Val, Ala-Phe, Ala-Leu, Gly-Phe, Leu-Phe, Leu-Tyr, Met-Leu, Pro-Phe, Pro-Tyr, Pro-Leu, Phe-Leu, Phe-Phe, Tyr-Ile, Tyr-Pro, Tyr-Leu, Gln-Phe, Val-Tyr, Val-Phe, Gly-Trp, Asp-Phe, and Ser-Leu.

9. The method of claim 2 wherein AA² of the oligopeptide of the formula (AA)_n—

AA^P2—

AA^P1—

AA^P1′

—

(AA)_m is a hydrophobic amino acid.

10. The method of claim 2 wherein AA^P2 of the oligopeptide of the formula (AA)_n—

AA^P2—

AA^P1—

AA^P1′

—

(AA)_m is isoleucine.

11. The method of claim 2 wherein the prodrug is selected from the group consisting of Suc-β

Ala-Leu-Ala-Leu-Dox SEQ ID NO;

41, Suc-Ile-Ala-Leu-Dox SEQ ID NO;

42, Suc-β

Ala-Ile-Ala-Leu-Dox SEQ ID NO;

39, Suc-Leu-Ala-Leu-Dox SEQ ID NO;

45, and Suc-Met-Ala-Leu-Dox SEQ ID NO;

73.

12. A method for treating a tumor comprising contacting the tumor with a therapeutically effective amount of a CD10 cleavable prodrug, wherein said tumor is comprised of one or more target cells which express CD10 for at least a portion of the target cell life cycle, wherein said tumor is selected from the group consisting of ocular melanoma and cutaneous melanoma.

13. The method of claim 12 wherein the CD10 cleavable prodrug comprises:

(1) a therapeutic agent capable of entering a target cell,

(2) an oligopeptide of the formula (AA)_n—

AA^P2—

AA^P1—

AA^P1′

—

(AA)_m,

wherein;

n and m are integers,

AA^P2 represents any amino acid,

AA^P1 represents any amino acid,

AA^P1′

represents any amino acid, and

each AA independently represents an amino acid,

(3) a stabilizing group, and

(4) optionally, a linker group,

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 prodrug by enzymes present in whole blood.

14. The method of claim 13 wherein n is 0 to 3, m is 0 to 3, and m+n is no more than 3 of the oligopeptide of the formula (AA)_n—

AA^P2—

AA^P1—

AA^P1′

—

(AA)_m.

15. The method of claim 13 wherein AA^P1 of the oligopeptide of the formula (AA)_n—

AA^P2—

AA^P1—

AA^P1′

—

(AA)_m is selected from the group consisting of arginine, alanine, glycine, leucine, methionine, proline, phenylalanine, tyrosine, glutamine, valine, and serine.

16. The method of claim 13 wherein AA^P1′

of the oligopeptide of the formula (AA)_n—

AA^P2—

AA^P1—

AA^P1′

—

(AA)_m is selected from the group consisting of leucine, isoleucine, phenylalanine, valine, tyrosine, and proline.

17. The method of claim 12 wherein the prodrug is administered intravenously to a subject having said tumor.

18. The method of claim 12 wherein the prodrug is resistant to cleavage by TOP.

19. The method of claim 13 wherein AA^P1—

AA^P1′

of the oligopeptide of the formula (AA)_n—

AA^P2—

AA^P1—

AA^P1′

—

(AA)_m is selected from the group consisting of Arg-Leu, Arg-Ile, Arg-Phe, Arg-Val, Ala-Phe, Ala-Leu, Gly-Phe, Leu-Phe, Leu-Tyr, Met-Leu, Pro-Phe, Pro-Tyr, Pro-Leu, Phe-Leu, Phe-Phe, Tyr-Ile, Tyr-Pro, Tyr-Leu, Gln-Phe, Val-Tyr, Val-Phe, Gly-Trp, Asp-Phe, and Ser-Leu.

20. The method of claim 13 wherein AA^P2 of the oligopeptide of the formula (AA)_n—

AA^P2—

AA^P1—

AA^P1′

—

(AA)_m is a hydrophobic amino acid.

21. The method of claim 13 wherein AA^P2 of the oligopeptide of the formula (AA)_n—

AA^P2—

AA^P1—

AA^P1′

—

(AA)_m is isoleucine.

22. The method of claim 13 wherein the prodrug is selected from the group consisting of Suc-β

Ala-Leu-Ala-Leu-Dox SEQ ID NO;

41, Suc-Ile-Ala-Leu-Dox SEQ ID NO;

42, Suc-β

Ala-Ile-Ala-Leu-Dox SEQ ID NO;

39, Suc-Leu-Ala-Leu-Dox SEQ ID NO;

45, and Suc-Met-Ala-Leu-Dox SEQ ID NO;

73.

23. A method for treating a tumor comprising contacting the tumor with a therapeutically effective amount of a CD10 cleavable prodrug, wherein said tumor is comprised of one or more target cells which express CD10 for at least a portion of the target cell life cycle, wherein the CD10 cleavable prodrug comprises:

(1) a therapeutic agent capable of entering a target cell,

(2) an oligopeptide of the formula (AA)_n—

AA^P2—

AA^P1—

AA^P1′

—

(AA)_m,

wherein;

n and m are integers,

AA^P2 represents isoleucine,

AA^P1 represents any amino acid,

AA^P1′

represents any amino acid, and

each AA independently represents an amino acid,

(3) a stabilizing group, and

(4) optionally, a linker group,

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 prodrug by enzymes present in whole blood.