CD10-activated prodrug compounds

• US 6,897,034 B2
• Filed: 06/11/2002
• Issued: 05/24/2005
• 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 E
• Application Number:
  US10/167,627
• Publication Number:
  US 20040087497A1
• Time in Patent Office: 1,078 Days
• Field of Search: 530/329, 530/330, 530/331, 530/344, 530/345, 514/17, 514/18, 435/24
• US Class Current: 435/24
• 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 of designing a prodrug, the method comprising:

(1) providing 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 ammo acid,

AA^P1′

represents any amino acid, and

each AA independently represents an amino acid,

(2) linking the oligopeptide at a first attachment site of the oligopeptide to a stabilizing group that hinders cleavage of the oligopeptide by enzymes present in whole blood, and

(3) directly or indirectly linking the oligopeptide to a therapeutic agent at a second attachment site of the oligopeptide,

wherein steps (2) and (3) may be performed in any order or concurrently and further wherein a conjugate is formed by performance of steps (1) through (3),

(4) testing if the conjugate is cleavable by CD10, and

(5) selecting the conjugate as a prodrug if the conjugate is cleavable by CD10.

2. The method of claim 1 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.

3. The method of claim 1 wherein the first attachment site is the N-terminus of the oligopeptide.

4. The method of claim 1 wherein the second attachment site is the C-terminus of the oligopeptide.

5. The method of claim 1 wherein the first attachment site is the C-terminus of the oligopeptide.

6. The method of claim 1 wherein the second attachment site is the N-terminus of the oligopeptide.

7. The method of claim 1 wherein the conjugate is further tested for cleavage by thimet oligopeptidase (TOP).

8. The method of claim 1, wherein the conjugate is further tested for cleavage by prostate specific antigen (PSA).

9. The method claim 1, wherein the conjugate is further tested for stability in whole blood.

10. The method of claim 1, wherein the conjugate is tested for cleavage by CD10 by incubating the conjugate with porcine kidney CD10.