PEPTIDES AND COMPOUNDS THAT BIND TO A RECEPTOR

• US 20070148091A1
• Filed: 12/13/2006
• Published: 06/28/2007
• Est. Priority Date: 06/07/1996
• Status: Active Grant

• Current Assignee: GlaxoSmithKline LLC (GlaxoSmithKline PLC)
• Original Assignee: GlaxoSmithKline LLC (GlaxoSmithKline PLC)
• Inventors: Cwirla, Steven, Dower, William, Mattheakis, Larry, Barrett, Ronald, Wrighton, Nicholas, Duffin, David, Schatz, Peter, Wagstrom, Christopher, Gates, Christian, Haselden, Sherril
• Granted Patent: US 8,227,422 B2
• Time in Patent Office: Days
• US Class Current: 424/1.690
• 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: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: C07K 14/521 Chemokines
• CPC Class Codes: C07K 14/524 Thrombopoietin, i.e. C-MPL ligand
• CPC Class Codes: C07K 7/08 having 12 to 20 amino acids gastrins C07K14/595; somatostatins C07K14/655; melanotropins C07K14/68
• CPC Class Codes: C07K 7/64 Cyclic peptides containing only normal peptide links

Abstract

Described are peptides and peptide mimetics that bind to and activate the thrombopoietin receptor. Such peptides and peptide mimetics are useful in methods for treating hematological disorders and particularly, thrombocytopenia resulting from chemotherapy, radiation therapy, or bone marrow transfusions as well as in diagnostic methods employing labeled peptides and peptide mimetics.

Claims

1. (canceled)

2. (canceled)

3. (canceled)

4. (canceled)

5. (canceled)

6. (canceled)

7. (canceled)

8. (canceled)

9. (canceled)

10. (canceled)

11. (canceled)

12. (canceled)

13. (canceled)

14. (canceled)

15. (canceled)

16. (canceled)

17. (canceled)

18. (canceled)

19. A compound that binds to a thrombopoietin receptor, wherein said compound comprises

X₉X₈GX₁X₂X₃X₄X₅X₆X₇

where X₁ is P;

X₂ is T;

X₃ is L;

X₄ is R;

X₅ is Q;

X₆ is selected from the group consisting of W (Trp), L-Trp, D-Trp, L-1-Nal, D-1-Nal, L-2-Nal, D-2-Nal, L-(Benzothienyl)-alanine, DL-5-Me-Trp, DL-1-Me-Trp, DL-6-F-Trp, DL-5-F-Trp, DL-5-Br-Trp and L-Tic;

X₇ is L;

X₈ is E;

X₉ is I.

20. The compound of claim 19, wherein said compound is covalently attached to a polymer.

21. The compound of claim 20, wherein said polymer has an average molecular weight of between about 500 to about 40,000 daltons.

22. The compound of claim 20, wherein said polymer has an average molecular weight of between about 5,000 to about 20,000 daltons.

23. The compound of claim 20, wherein said polymer has an average molecular weight of about 20,000 daltons.

24. The compound of claim 20, wherein said polymer is selected from the group consisting of polyethylene glycol, polypropylene glycol, polylactic acid and poly glycolic acid.

25. The compound of claim 23, wherein said compound is covalently attached to polyethylene glycol.

26. The compound of claim 25, wherein said polyethylene glycol has an average molecular weight of about 20,000 daltons.

27. A pharmaceutical composition comprising a compound of claim 26 in combination with a pharmaceutically acceptable carrier.

28. A method for treating a patient suffering from a disorder that is susceptible to treatment with a thrombopoietin agonist, comprising administering to the patient a therapeutically effective dose or amount of a compound of claim 26.

29. A method of activating a thrombopoietin receptor in a cell, comprising contacting said cell with an effective amount of a compound which comprises:

X₉X₈GX₁X₂X₃X₄X₅X₆X₇

where X₁ is P;

X₂ is T;

X₃ is L;

X₄ is R;

X₅ is Q;

X₆ is selected from the group consisting of W (Trp), L-Trp, D-Trp, L-1-Nal, D-1-Nal, L-2-Nal, D-2-Nal, L-(Benzothienyl)-alanine, DL-5-Me-Trp, DL-1-Me-Trp, DL-6-F-Trp, DL-5-F-Trp, DL-5-Br-Trp and L-Tic;

X₇ is L;

X₈ is E;

X₉ is I.

30. A method according to claim 29 wherein said cells comprise human megakaryocytes, platelets or CD34+ cells.

31. A method according to claim 29 wherein said cells comprise TPO-dependent cells.

32. A method of treating thrombocytopenia in a subject, comprising:

(a) obtaining a population of said subject'"'"'s cells comprising megakaryocyte precursor cells;

(b) treating said cells according to the method of claim 29;

and (c) administering said treated cells to said subject, to increase the number of megakaryocytes present in said subject compared to that which would occur without such treatment.

33. A method according to claim 32 wherein said thrombocytopenia is due to chemotherapy.

34. A method according to claim 32 where said population of cells is obtained prior to chemotherapy.

35. A method according to claim 32 wherein said thrombocytopenia is due to radiation therapy.

36. A method according to claim 35 where said population of cells is obtained prior to said radiation therapy.

37. A method of treating a patient suffering from thrombocytopenia, comprising administering to said patient a therapeutically effective dose of a compound which comprises:

X₉X₈GX₁X₂X₃X₄X₅X₆X₇

where X₁ is P;

X₂ is T;

X₃ is L;

X₄ is R;

X₅ is Q;

X₆ is selected from the group consisting of W (Trp), L-Trp, D-Trp, L-1-Nal, D-1-Nal, L-2-Nal, D-2-Nal, L-(Benzothienyl)-alanine, DL-5-Me-Trp, DL-1-Me-Trp, DL-6-F-Trp, DL-5-F-Trp, DL-5-Br-Trp and L-Tic;

X₇ is L;

X₈ is E;

X₉ is I.

38. A method according to claim 37 wherein said thrombocytopenia is due to chemotherapy or radiation therapy.

39. A method according to claim 37 wherein a TPO antagonist is administered to said patient prior to said chemotherapy or radiation therapy.

40. A method according to claim 37 wherein said thrombocytopenia is due to bone marrow transfusion.

41. A method of prophylactically treating a patient at risk of thrombocytopenia, comprising administering to said patient a prophylactically effective amount of a compound:

X₉X₈GX₁X₂X₃X₄X₅X₆X₇

where X₁ is P;

X₂ is T;

X₃ is L;

X₄ is R;

X₅ is Q;

X₆ is selected from the group consisting of W (Trp), L-Trp, D-Trp, L-1-Nal, D-1-Nal, L-2-Nal, D-2-Nal, L-(Benzothienyl)-alanine, DL-5-Me-Trp, DL-1-Me-Trp, DL-6-F-Trp, DL-5-F-Trp, DL-5-Br-Trp and L-Tic;

X₇ is L;

X₈ is E;

I₉ is I.

42. A method according to claim 41 where said compound is administered prior to bone marrow transplantation, chemotherapy or radiation therapy.

43. A compound that binds to thrombopoietin receptor, said compound having:

(i) a molecular weight of less than about 8000 daltons, and (ii) a binding affinity to thrombopoietin receptor as expressed by an IC₅₀ of no more than about 100 μ

M, wherein said compound comprises the following sequence of amino acids;

X₉X₈GX₁X₂X₃X₄X₅X₆X₇

where X₁ is P;

X₂ is T;

X₃ is L;

X₄ is R;

X₅ is Q;

X₆ is selected from the group consisting of W (Trp), L-Trp, D-Trp, L-1-Nal, D-1-Nal, L-2-Nal, D-2-Nal, L-(Benzothienyl)-alanine, DL-5-Me-Trp, DL-1-Me-Trp, DL-6-F-Trp, DL-5-F-Trp, DL-5-Br-Trp and L-Tic;

X₇ is L;

X₈ is E;

I₉ is I.

44. The compound of claim 43, wherein said sequence of amino acids is cyclized.

45. The compound of claim 43, wherein said sequence of amino acids is dimerized.

46. The compound of claim 45, wherein each of the dimeric subunits of said compound is covalently attached to a polymer.

47. The compound of claim 46, wherein said polymer has an average molecular weight of between about 500 to about 40,000 daltons.

48. The compound of claim 46, wherein said polymer has an average molecular weight of between about 5,000 to about 20,000 daltons.

49. The compound of claim 46, wherein said polymer is selected from the group consisting of polyethylene glycol, polypropylene glycol, polylactic acid and poly glycolic acid.

50. The compound of claim 49, wherein each of the dimeric subunits of said compound is covalently attached to polyethylene glycol.

51. The compound of claim 50, wherein said polyethlyene glycol has a molecular weight of about 20,000 daltons.

52. A pharmaceutical composition comprising a compound of claim 51 in combination with a pharmaceutically acceptable carrier.