ST receptor binding compounds and methods of using the same

• US 7,744,870 B1
• Filed: 11/28/2000
• Issued: 06/29/2010
• Est. Priority Date: 10/26/1993
• Status: Expired due to Term

• Current Assignee: Thomas Jefferson University (Main Line Health System)
• Original Assignee: Thomas Jefferson University (Main Line Health System)
• Inventors: Waldman, Scott A.
• Primary Examiner(s): Helms; Larry R.
• Assistant Examiner(s): Yao; Lei
• Application Number:
  US09/724,983
• Time in Patent Office: 3,500 Days
• Field of Search: 424/130.1, 424/138.1, 424/181.1
• US Class Current: 424/130.1
• CPC Class Codes: A61K 2121/00 Preparations for use in therapy
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 47/6425 the peptide or protein in the drug conjugate being a receptor, e.g. CD4, a cell surface antigen, i.e. not a peptide ligand targeting the antigen, or a cell surface determinant, i.e. a part of the surface of a cell
• CPC Class Codes: A61K 51/08 Peptides, e.g. proteins , carriers being peptides, polyamino acids, proteins
• CPC Class Codes: C07K 14/24 from Enterobacteriaceae (F), e.g. Citrobacter, Serratia, Proteus, Providencia, Morganella, Yersinia
• CPC Class Codes: C07K 7/08 having 12 to 20 amino acids gastrins C07K14/595; somatostatins C07K14/655; melanotropins C07K14/68
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

Conjugated compounds which comprises an ST receptor binding moiety and a radiostable active moiety are disclosed. Pharmaceutical compositions comprising a pharmaceutically acceptable carrier or diluent, and a conjugated compound which comprises an ST receptor binding moiety and a radiostable active moiety or an ST receptor binding moiety and a radioactive, active moiety are disclosed. Methods of treating an individual suspected of suffering from metastasized colorectal cancer comprising the steps of administering to said individual a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent, and a therapeutically effective amount of a conjugated compound which comprises an ST receptor binding moiety and a radiostable active moiety or an ST receptor binding moiety and a radiostable active moiety are disclosed. Methods of radioimaging metastasized colorectal cancer cells comprising the steps of first administering to an individual suspected of having metastasized colorectal cancer cells, a pharmaceutical composition that comprises a pharmaceutically acceptable carrier or diluent, and conjugated compound that comprises an ST receptor binding moiety and a radioactive active moiety wherein the conjugated compound is present in an amount effective for diagnostic use in humans suffering from colorectal cancer and then detecting the localization and accumulation of radioactivity in the individual'"'"'s body are disclosed.

Claims

1. A method of treating an individual suspected of suffering from metastatic colorectal cancer comprising the step of administering to said individual a pharmaceutical composition that comprises:

a) a heat stable enterotoxin (ST) receptor ligand in combination with;

b) an active agent in an amount effective to cause a cytotoxic or cytostatic effect on metastasized colorectal cancer cells without causing lethal side effects on the individual, wherein the active agent causes cell death, inhibits cell division or induces differentiation; and

c) a pharmaceutically acceptable carrier or diluent wherein said ST receptor ligand is an antibody, Fab or F(AB)₂.

2. The method of claim 1 wherein said ST receptor ligand is an antibody.

3. The method of claim 1 wherein said active agent causes cell death.

4. The method of claim 1 wherein said active agent is selected from the group consisting of methotrexate, doxorubicin, daunorubicin, cytosinarabinoside, etoposide, 5-fluorouracil, melphalan, chlorambucil, cis-platin, vindesine, mitomycin, bleomycin, purothionin, macromomycin, 1,4-benzoquinone derivatives, trenimon, ricin, ricin A chain, Pseudomonas exotoxin, diphtheria toxin, Clostridium perfringens phospholipase C, bovine pancreatic ribonuclease, pokeweed antiviral protein, abrin, abrin A chain, cobra venom factor, gelonin, saporin, modeccin, viscumin, volkensin, nitroimidazole, metronidazole and misonidazole.

5. The method of claim 1 wherein said pharmaceutical composition combination is administered intravenously.

6. The method of claim 4 wherein said ST receptor ligand is an antibody.

7. The method of claim 5 wherein said ST receptor ligand is an antibody.

8. The method of claim 1 wherein said ST receptor ligand is a Fab.

9. The method of claim 4 wherein said ST receptor ligand is a Fab.

10. The method of claim 5 wherein said ST receptor ligand is a Fab.

11. The method of claim 1 wherein said ST receptor ligand is a F(ab)₂.

12. The method of claim 4 wherein said ST receptor ligand is a F(ab)₂.

13. The method of claim 5 wherein said ST receptor ligand is a F(ab)₂.

14. The method of claim 3 wherein said ST receptor ligand is an antibody.

15. The method of claim 3 wherein said ST receptor ligand is a F(ab).

16. The method of claim 3 wherein said ST receptor ligand is a F(ab)₂.

17. The method of claim 1 wherein said active agent is a chemotherapeutic agent.

18. The method of claim 1 wherein said active agent is a cytotoxic chemotherapeutic agent.

19. A method of treating an individual suffering from metastatic colorectal cancer comprising the step of administering to said individual an amount of a pharmaceutical composition effective to therapeutically eliminate metastasized colorectal cancer cells, wherein said pharmaceutical compositions comprises:

a) a heat stable enterotoxin (ST) receptor ligand;

b) an active agent, wherein the active agent causes cell death, inhibits cell division or induces differentiation; and

a pharmaceutically acceptable carrier or diluent,

wherein said ST receptor ligand is an antibody, Fab or F(AB)₂.

20. The method of claim 19 wherein said ST receptor ligand is an antibody.

21. The method of claim 19 wherein said active agent causes cell death.

22. The method of claim 19 wherein said active agent is selected from the group consisting of methotrexate, doxorubicin, daunorubicin, cytosinarabinoside, etoposide, 5-fluorouracil, melphalan, chlorambucil, cis-platin, vindesine, mitomycin, bleomycin, purothionin, macromomycin, 1,4-benzoquinone derivatives, trenimon, ricin, ricin A chain, Pseudomonas exotoxin, diphtheria toxin, Clostridium perfringens phospholipase C, bovine pancreatic ribonuclease, pokeweed antiviral protein, abrin, abrin A chain, cobra venom factor, gelonin, saporin, modeccin, viscumin, volkensin, nitroimidazole, metronidazole and misonidazole.

23. The method of claim 19 wherein said pharmaceutical composition is administered intravenously.

24. The method of claim 22 wherein said ST receptor ligand is an antibody.

25. The method of claim 23 wherein said ST receptor ligand is an antibody.

26. The method of claim 19 wherein said ST receptor ligand is a Fab.

27. The method of claim 22 wherein said ST receptor ligand is a Fab.

28. The method of claim 23 wherein said ST receptor ligand is a Fab.

29. The method of claim 19 wherein said ST receptor ligand is a F(ab)₂.

30. The method of claim 23 wherein said ST receptor ligand is a F(ab)₂.

31. The method of claim 23 wherein said ST receptor ligand is a F(ab)₂.

32. The method of claim 21 wherein said ST receptor ligand is an antibody.

33. The method of claim 21 wherein said ST receptor ligand is a Fab.

34. The method of claim 21 wherein said ST receptor ligand is a F(ab)₂.

35. The method of claim 19 wherein said active agent is a chemotherapeutic agent.

36. The method of claim 19 wherein said active agent is a cytotoxic chemotherapeutic agent.

37. A method of treating an individual suffering from metastatic colorectal cancer comprising the step of administering to said individual a conjugated compound in an amount effective to cause a cytotoxic or cytostatic effect on metastasized colorectal cancer cells without causing lethal side effects on the individual, wherein said conjugated compound comprises

a) a heat stable enterotoxin (ST) receptor binding moiety which is an antibody or a fragment thereof;

b) an active moiety which is an active agent that causes cell death, inhibits cell division or induces differentiation.

38. The method of claim 37 wherein said ST receptor binding moiety is an antibody.

39. The method of claim 37 wherein said ST receptor binding moiety is a FAb.

40. The method of claim 37 wherein said ST receptor binding moiety is an F(Ab)₂.

41. The method of claim 37 wherein said active moiety is an active agent that causes cell death.

42. The method of claim 37 wherein said active moiety is a chemotherapeutic agent.

43. The method of claim 37 wherein said active moiety is a cytotoxic chemotherapeutic agent.

44. The method of claim 37 wherein said active moiety is selected from the group consisting of methotrexate, doxorubicin, daunorubicin, cytosinarabinoside, etoposide, 5-fluorouracil, melphalan, chlorambucil, cis-platin, vindesine, mitomycin, bleomycin, purothionin, macromomycin, 1,4-benzoquinone derivatives, trenimon, ricin, ricin A chain, Pseudomonas exotoxin, diphtheria toxin, Clostridium perfringens phospholipase C, bovine pancreatic ribonuclease, pokeweed antiviral protein, abrin, abrin A chain, cobra venom factor, gelonin, saporin, modeccin, viscumin, volkensin, nitroimidazole, metronidazole and misonidazole.

45. The method of claim 37 wherein said conjugated compound is administered intravenously.

46. A method of treating an individual suspected of suffering from metastatic colorectal cancer or suffering from metastatic colorectal cancer comprising administering to said individual a heat stable enterotoxin (ST) receptor ligand in combination with an active agent in an amount effective to cause a cytotoxic or cytostatic effect on metastasized colorectal cancer cells without causing lethal side effects on the individual,

wherein the active agent causes cell death, inhibits cell division or induces differentiation;

and

wherein said ST receptor ligand is an antibody, Fab or F(AB)₂.