CD-10 activated prodrug compounds

• US 20050267016A1
• Filed: 12/22/2004
• Published: 12/01/2005
• Est. Priority Date: 06/11/2001
• Status: Active Grant

• 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.
• Granted Patent: US 7,304,032 B2
• Time in Patent Office: Days
• US Class Current: 514/1.300
• 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 compound comprising:

(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, p1 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 compound by enzymes present in whole blood, and

wherein the compound is cleavable by CD10, and

further wherein if the oligopeptide is Leu-Ala-Leu, then the stabilizing group is not succinyl or β

Ala or the therapeutic agent is not one of doxorubicin and daunorubicin,

wherein if the oligopeptide is β

Ala-Leu-Ala-Leu, then the stabilizing group is not succinyl or the therapeutic agent is not one of doxorubicin and daunorubicin,

wherein if the oligopeptide is β

Ala-Leu-Ala-Leu, then the stabilizing group is not glutaryl or the therapeutic agent is not doxorubicin, and

wherein the compound is not selected from the group consisting of Succ-Ala-Leu-Ala-Leu-Dnr, pGlu-Ala-Leu-Ala-Leu-Dox, D-Ala-Leu-Ala-Leu-Dnr, D-Leu-Ala-Leu-Ma-Leu-Dnr, D-Leu-D-Ala-Leu-Ala-Leu-Dnr, Acetyl-His-Ser-Ser-Lys-Leu-Gln-Dox, Morpholinocarbonyl-His-Ser-Ser-Lys-Leu-Gln-Leu-Dox, N-(2-hydroxypropyl)methacrylamide-Gly-Phe-Leu-Gly-Dox, N-glutaryl-(4hydroxyprolyl)-Ala-Ser-cyclohexylglycine-Gln-Ser-Leu-Dox, N-Cbz-Gly-Phe-Ala-Leu-Dox, and N-Cbz-Gly-Phe-Ala-Leu-β

ABC-Dox.

2. The compound of claim 1 where 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^P2-AA^P1′

-(AA)_m.

3. The compound of claim 1 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.

4. The compound of claim 1 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.

5. The compound of claim 1 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, Gly-Trp, Arg-Ile, Arg-Phe, Arg-Val, Ala-Phe, Asp-Phe, Ala-Leu, Gly-Phe, Gly-Leu, 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, and Ser-Leu.

6. The compound of claim 1 wherein the oligopeptide includes a sequence selected from the group consisting of β

Ala-Leu-Ala-Leu, Ile-Ala-Leu, β

Ala-Ile-Ala-Leu, Leu-Ala-Leu, Met-Ala-Leu, and Phe-Ala-Leu.

7. The compound of claim 1 wherein AA^P1′

of the oligopeptide of the formula (AA)_n-AA^P2-AA^P1-AA^P1′

-(AA)_m is a hydrophobic amino acid.

8. The compound of claim 1 wherein AA^P2 of the oligopeptide of the formula (AA)_n-AA^P2-AA^P1-AA^P1′

-(AA)_m is a hydrophobic amino acid.

9. The compound of claim 1 wherein AA^P2 of the oligopeptide of the formula (AA)_n-AA^P2-AA^P1-AA^P1′

-(AA)_m is isoleucine.

10. The compound of claim 1 wherein when m=1, then

(AA)_m represents AA_m=1,

AA_m=1 is linked to AA^P1′

, and

AA_m=1 is a hydrophobic amino acid.

11. The compound of claim 1 wherein when m=2, then

(AA)_m represents AA_m=1-AA_m=2,

AA_m=1 is linked to AA^P1, and

AA_m=1 is a hydrophobic amino acid.

12. The compound of claim 1 wherein when m=3, then

(AA)_m represents AA_m=1-AA_m=2-AA_m=3,

AA_m=1 is linked to AA^P1′

, and

AA_m=1 is a hydrophobic amino acid.

13. The compound of claim 1 wherein the target cell is a tumor or inflammatory cell.

14. The compound of claim 1 wherein the target cell is from tissue selected from the group consisting of B-cell lymphoblastic leukemia, T-cell lymphoblastic leukemia, lymphoma, including B-cell lymphoma and non-Hodgkins'"'"' lymphoma, follicular lymphoma, Burkitt lymphoma, melanoma, ocular melanoma, cutaneous melanoma, colon adenocarcinomas, hepatocellular carcinomas, renal cell carcinoma, ovarian carcinoma, prostate adenocarcinoma, liver carcinoma, transitional cell carcinoma, pancreatic adenocarcinoma, lung carcinoma, breast carcinoma, and colon carcinoma.

15. The compound of claim 1 wherein the CD10 is associated with the target cell or a leukocyte associated with the target cell.

16. The compound of claim 1 wherein the CD10 is present at least during some portion of the target cell life cycle.

17. The compound of claim 1 wherein a CD10 active site is present in the extracellular vicinity of the target cell.

18. The compound of claim 1 wherein CD10 cleaves the linkage between AA^P1 and AA^P1′

of the oligopeptide of the formula (AA)_n-AA^P2-AA^P1-AA^P1′

-(AA)_m.

19. The compound of claim 1 being a prodrug having an active portion, wherein the active portion of the prodrug is more capable of entering the target cell after cleavage by CD10 than prior to cleavage by CD10, the active portion including at least the therapeutic agent.

20. The compound of claim 1 wherein the stabilizing group is a dicarboxylic or higher order carboxylic acid.

21. The compound of claim 1 wherein the stabilizing group is selected from the group consisting of succinic acid, adipic acid, glutaric acid, phthalic acid, diglycolic acid, fumaric acid, naphthalene dicarboxylic acid, pyroglutamic acid, acetic acid, 1-naphthylcarboxylic acid, 2-naphthylcarboxylic acid. 1,8-naphthyl dicarboxylic acid, aconitic acid, carboxycinnamic acid, triazole dicarboxylic acid, gluconic acid, 4-carboxyphenyl boronic acid, isonipecotic acid, nipecotic acid, polyethylene glycolic acid, butane disulfonic acid, and maleic acid.

22. The compound of claim 1 wherein the stabilizing group is a non-genetically encoded amino acid.

23. The compound of claim 1 wherein the stabilizing group is selected from the group consisting of β

-Alanine, Thiazolidine-4-carboxylic acid, 2-Thienylalanine, 2-Naphthylalanine, D-Alanine, D-Leucine, D-Methionine, D-Phenylalanine, 3-Amino-3-phenylpropionic acid, γ

-Aminobutyric acid, 3-Amino-4,4-diphenylbutyric acid, Tetrahydroisoquinoline-3-carboxylic acid, 4-Aminomethylbenzoic acid, and Aminoisobutyric acid.

24. The compound of claim 1 wherein the stabilizing group is one of aspartic acid linked to the oligopeptide at the β

-carboxy group of the aspartic acid and glutamic acid linked to the oligopeptide at the γ

-carboxy group of the glutamic acid.

25. The compound of claim 1 wherein the stabilizing group is negatively charged or neutral.

26. The compound of claim 1 wherein the stabilizing group is selected to reduce interaction between the compound and endothelial cells that line blood vessels when administered intravenously to the patient.

27. The compound of claim 1 wherein the therapeutic agent is selected from the group consisting of Alkylating Agents, Antiproliferative agents, Tubulin Binding agents, Vinca Alkaloids, Enediynes, Podophyllotoxins or Podophyllotoxin derivatives, the Pteridine family of drugs, Taxanes, Anthracyclines, Dolastatins, Topoisomerase inhibitors, Maytansinoids, and Platinum complex chemotherapeutic agents.

28. The compound of claim 1 wherein the therapeutic agent is selected from the group consisting of Doxorubicin, Daunorubicin, Vinblastine, Vincristine, Calicheamicin, Etoposide, Etoposide phosphate, CC-1065, Duocarmycin, KW-2189, Methotrexate, Methopterin, Aminopterin, Dichloromethotrexate, Docetaxel, Paclitaxel, Epithiolone, Combretastatin, Combretastatin A₄ Phosphate, Dolastatin 10, Dolastatin 11, Dolastatin 15, Topotecan, Camptothecin, Mitomycin C, Porfiromycin, 5-Fluorouracil, 6-Mercaptopurine, Fludarabine, Tamoxifen, Cytosine arabinoside, Adenosine arabinoside, Colchicine, Halichondrin B, Cisplatin, Carboplatin, Mitomycin C, Bleomycin, Melphalan, Chloroquine, Cyclosporin A, Maytansine, a derivative of any of the foregoing, and an analog of any of the foregoing.

29. The compound of claim 1 wherein the therapeutic agent has an intracellular active site.

31. The compound of claim 1 wherein the oligopeptide sequence is indirectly linked to the therapeutic agent at the second attachment site of the oligopeptide via a linker group, the linker group selected from the group consisting of amino caproic acid, a hydrazide group, an ester group, an ether group, and a sulphydryl group.

32. The compound of claim 1 wherein the compound is selected from the group consisting of Suc-Ile-Ala-Leu-Dox, Suc-β

Ala-Rle-Ala-Leu-Dox, Suc-Met-Ala-Leu-Dox, and Suc-Phe-Ala-Leu-Dox.

33. The compound of claim 1 wherein the compound is resistant to cleavage by TOP.

34. The compound of claim 1 wherein the compound is resistant to cleavage by PSA.

30. The compound of claim I wherein the oligopeptide is directly linked to the therapeutic agent.

35. A conjugate comprising 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, and

wherein the oligopeptide is cleavable by CD10.

36. The conjugate of claim 35 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.

37. The conjugate of claim 35 wherein the oligopeptide is linked to a stabilizing group.

38. The conjugate of claim 35 wherein the oligopeptide is linked to a therapeutic agent.

39. The conjugate of claim 38 wherein the oligopeptide is selected from the group consisting of β

Ala-Leu-Ala-Leu, Ile-Ala-Leu, β

Ala-Ile-Ala-Leu, Leu-Ala-Leu, Met-Ala-Leu, Arg-Leu, Gly-Trp, Arg-Ile, Arg-Phe, Arg-Val, Ala-Phe, Asp-Phe, Ala-Leu, Gly-Phe, Gly-Leu, 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, and Ser-Leu.

40. The conjugate of claim 38 wherein the oligopeptide is further linked to a stabilizing group and the oligopeptide is selected from the group consisting of β

Ala-Leu-Ala-Leu, Ile-Ala-Leu, β

Ala-Ile-Ala-Leu, Leu-Ala-Leu, Met-Ala-Leu, Arg-Leu, Gly-Trp, Arg-Ile, Arg-Phe, Arg-Val, Ala-Phe, Asp-Phe, Ala-Leu, Gly-Phe, Gly-Leu, 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, and Ser-Leu.

41. The conjugate of claim 38 wherein if the oligopeptide is Leu-Ala-Leu, then the stabilizing group is not succinyl or β

Ala or the therapeutic agent is not one of doxorubicin and daunorubicin,

wherein if the oligopeptide is β

Ala-Leu-Ala-Leu, then the stabilizing group is not succinyl or the therapeutic agent is not one of doxorubicin and daunorubicin,

wherein if the oligopeptide is β

Ala-Leu-Ala-Leu, then the stabilizing group is not glutaryl or the therapeutic agent is not doxorubicin, and

wherein the compound is not selected from the group consisting of Succ-Ala-Leu-Ala-Leu-Dnr, pGlu-Ala-Leu-Ala-Leu-Dox, D-Ala-Leu-Ala-Leu-Dnr, D-Leu-Ala-Leu-Ala-Leu-Dnr, D-Leu-D-Ala-Leu-Ala-Leu-Dnr, Acetyl-His-Ser-Ser-Lys-Leu-Gln-Dox, Morpholinocarbonyl-His-Ser-Ser-Lys-Leu-Gln-Leu-Dox, N-(2-hydroxypropyl)methacrylamide-Gly-Phe-Leu-Gly-Dox, N-glutaryl-(4-hydroxyprolyl) -Ala-Ser-cyclohexylglycine-Gln-Ser-Leu-Dox, N-Cbz-Gly-Phe-Ala-Leu-Dox, and N-Cbz-Gly-Phe-Ala-Leu-β

ABC-Dox.

42. A conjugate comprising 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, and

wherein the oligopeptide is cleavable by a thermolysin-like enzyme.

43. The conjugate of claim 42 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.

44. The conjugate of claim 42 wherein the oligopeptide is linked to a stabilizing group.

45. The conjugate of claim 42 wherein the oligopeptide is linked to a therapeutic agent.

46. A pharmaceutical composition comprising:

(1) a compound comprising;

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

(b) 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,

(c) a stabilizing group, and

(d) optionally, a linker group not cleavable by CD10,

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 compound by enzymes present in whole blood, and

wherein the compound is cleavable by CD10, and

(2) a pharmaceutically acceptable carrier.

47. The pharmaceutical composition of claim 46 wherein n is 0 to 3, m is 0 to 3, and m+n is no more than 3 in the oligopeptide of the formula (AA)_n-AA^P2-AA^P1-AA^P1′

-(AA)_m of the compound.

48. The pharmaceutical composition of claim 46 wherein if the oligopeptide is Leu-Ala-Leu, then the stabilizing group is not succinyl or β

Ala or the therapeutic agent is not one of doxorubicin and daunorubicin,

wherein if the oligopeptide is β

Ala-Leu-Ala-Leu, then the stabilizing group is not succinyl or the therapeutic agent is not one of doxorubicin and daunorubicin,

wherein if the oligopeptide is β

Ala-Leu-Ala-Leu, then the stabilizing group is not glutaryl or the therapeutic agent is not doxorubicin, and

wherein the compound is not selected from the group consisting of Succ-Ala-Leu-Ala-Leu-Dnr, pGlu-Ala-Leu-Ala-Leu-Dox, D-Ala-Leu-Ala-Leu-Dnr, D-Leu-Ala-Leu-Ala-Leu-Dnr, D-Leu-D-Ala-Leu-Ala-Leu-Dnr, Acetyl-His-Ser-Ser-Lys-Leu-Gln-Dox, Morpholinocaibonyl-His-Ser-Ser-Lys-Leu-Gln-Leu-Dox, N-(2-hydroxypropyl)methacrylamide-Gly-Phe-Leu-Gly-Dox, N-glutaryl-(4-hydroxyprolyl)-Ala-Ser-cyclohexylglycine-Gln-Ser-Leu-Dox, N-Cbz-Gly-Phe-Ala-Leu-Dox, and N-Cbz-Gly-Phe-Ala-Leu-β

ABC-Dox.

49. A method for treatment of a disorder having CD10-associated target cells, the method comprising:

administering to a patient a therapeutically effective amount of a compound comprising;

(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 not cleavable by CD10,

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 compound by enzymes present in whole blood, and

wherein the compound is cleavable by CD10.

50. The method of claim 49 wherein n is 0 to 3, m is 0 to 3, and m+n is no more than 3 in the oligopeptide of the formula (AA)_n-AA^P2-AA^P1-AA^P1′

-(AA)_m of the compound.

51. The method of claim 49 wherein the compound is administered intravenously.

52. The method of claim 49 wherein the patient is treated for a medical condition selected from the group consisting of cancer, neoplastic diseases, tumors, inflammatory diseases, and infectious diseases.

53. The method of claim 49 wherein the compound is resistant to cleavage by TOP.

54. The method of claim 49 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.

55. The method of claim 49 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.

56. The method of claim 49 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, Gly-Leu, 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-Trip, Asp-Phe, and Ser-Leu.

57. The method of claim 49 wherein AA^P2 of the oligopeptide of the formula (AA)_n-AA^P2-AA^P1-AA^P1′

-(AA)_m is a hydrophobic amino acid.

58. The method of claim 49 wherein AA^P2 of the oligopeptide of the formula (AA)_n-AA^P2-AA^P1-AA^P1′

-(AA)_m is isoleucine.

59. The method of claim 49 wherein the compound is selected from the group consisting of Suc-β

Ala-Leu-Ala-Leu-Dox, Suc-Ile-Ala-Leu-Dox, Suc-β

Ala-Ule-Ala-Leu-Dox, Suc-Leu-Ala-Leu-Dox, Suc-Met-Ala-Leu-Dox, and Suc-Phe-Ala-Leu-Dox.

60. A method for treating a tumor comprising administering a CD10 cleavable prodrug to the tumor.

61. The method of claim 60 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;

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.

62. The method of claim 61 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.

63. The method of claim 61 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.

64. The method of claim 61 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.

65. A method of treating prostate cancer in a patient comprising administering a prodrug cleavable by CD10 to the patient.

66. The method of claim 65 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 ammo 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.

67. The method of claim 66 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.

68. The method of claim 66 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, Gly-Trp, Arg-Ile, Arg-Phe, Arg-Val, Ala-Phe, ASP-Phe, Ala-Leu, Gly-Phe, Gly-Leu, 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, and Ser-Leu.

69. 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 amino 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 lining 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.

70. The method of claim 69 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.

71. The method of claim 69 wherein the first attachment site is the N-terminus of the oligopeptide.

72. The method of claim 69 wherein the second attachment site is the C-terminus of the oligopeptide.

73. The method of claim 69 wherein the first attachment site is the C-terminus of the oligopeptide.

74. The method of claim 69 wherein the second attachment site is the N-terminus of the oligopeptide.

75. A prodrug designed by the method of claim 69.

76. A method of screening to identify an oligopeptide useful for designing a prodrug, the method comprising:

(1) providing an oligopeptide of the formula (AA_n-AA^P2AA^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, and

(2) testing if the oligopeptide is cleavable by CD10,

wherein cleavability by CD10 is indicative of the oligopeptide as a candidate for designing a prodrug.

77. A method for decreasing 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 CD10 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, the prodrug being cleavable by CD10, whereby the prodrug provides for decreased toxicity of the therapeutic agent when administered to the patient.

78. The method of claim 77 wherein the prodrug allows for administration of an increased dosage of the therapeutic agent in prodrug form to the patient relative to the dosage of the therapeutic agent in unconjugated form.

79. The method of claim 77 wherein the oligopeptide cleavable by CD10 is 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.

80. The method of claim 79 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.

81. A method for treating a disorder in a patient, the method comprising:

detecting CD10 associated with a target cell, and

administering a CD10 cleavable prodrug to the patient if CD10 is associated with the target cell.

82. The method of claim 81 wherein the disorder is selected from the group consisting of B-cell lymphoblastic leukemia, T-cell lymphoblastic leukemia, lymphoma, including B-cell lymphoma and non-Hodgkins'"'"' lymphoma, follicular lymphoma, Burkitt lymphoma, melanoma, ocular melanoma, cutaneous melanoma, colon adenocarcinomas, hepatocellular carcinomas, renal cell carcinoma, ovarian carcinoma, prostate adenocarcinoma, liver carcinoma, transitional cell carcinoma, pancreatic adenocarcinoma, lung carcinoma, breast carcinoma, and colon carcinoma.

83. The method of claim 81 wherein the detecting step comprises:

obtaining a sample of tissue,

combining the sample with a CD10-specific antibody, and

determining binding of the CD10-specific antibody to the sample.

84. The method of claim 81 wherein the CD10 cleavable prodrug comprises a compound having:

(1) a therapeutic agent capable of entering the 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, and

wherein the stabilizing group hinders cleavage of the compound by enzymes present in whole blood.

85. The method of claim 84 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.

86. The method of claim 84 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, Gly-Leu, 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.

87. An article of manufacture for diagnosis or assay comprising:

(1) a compound comprising;

(a) a marker,

(b) 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,

(c) a stabilizing group, and

(d) optionally, a linker group not cleavable by CD10,

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 compound by enzymes present in whole blood, and

wherein the compound is cleavable by CD10,

(2) optionally at least one reagent useful in the detection of said marker.

88. In a method of making a prodrug, a method of removing free therapeutic agent comprising:

(1) coupling an optionally protected stabilizing group-oligopeptide conjugate with the free therapeutic agent, wherein the optionally protected stabilizing group-oligopeptide conjugate includes an oligopeptide of the formula (AA)_n-AA^P2-AA^P1-AA^P1′

-(AA)_m, wherein;

n and m are integers,

AA^P2represents any amino acid,

AA^P1 represents any amino acid,

AA^P1′

represents any amino acid, and

each AA independently represents an amino acid.

(2) contacting the reactants of step (1) with a polymeric resin to bind free therapeutic agent remaining after step (1) to form a therapeutic agent-polymeric resin complex, and

(3) removing the therapeutic agent-polymeric resin complex, wherein the polymeric resin is polystyrene methylisocyanate or polystyrene sulfonyl chloride.