Methods of treatment using glycopegylated G-CSF

• US 9,050,304 B2
• Filed: 04/01/2008
• Issued: 06/09/2015
• Est. Priority Date: 04/03/2007
• Status: Expired due to Fees

• Current Assignee: Ratiopharm GmbH (Teva Pharmaceutical Industries Limited)
• Original Assignee: Ratiopharm GmbH (Teva Pharmaceutical Industries Limited)
• Inventors: Zopf, David A., Lubenau, Heinz
• Primary Examiner(s): Gamett, Daniel C
• Application Number:
  US12/594,326
• Publication Number:
  US 20100120666A1
• Time in Patent Office: 2,625 Days
• US Class Current: 1/1
• CPC Class Codes: A61K 38/193 Colony stimulating factors [CSF]
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/04 Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• CPC Class Codes: A61P 7/06 Antianaemics
• 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

The present invention provides a glycopegylated G-CSF that is therapeutically active and which has pharmacokinetic parameters and properties that are improved relative to an identical, or closely analogous, G-CSF peptide that is not glycopegylated. Furthermore, the invention provides methods for mobilizing hematopoiesis in a subject, particularly a subject who has received or will receive radiation or chemotherapy treatment. The methods and compositions of the invention can further be used to prevent, alleviate and treat the myelosuppressive effects such therapies.

Claims

1. A method for increasing stem cell production in a donor, said method comprising administering to said donor an amount of a covalent conjugate between a G-CSF peptide having the amino acid sequence according to SEQ ID NO:

1 and a poly(ethylene glycol) (PEG) group,

wherein said covalent conjugate comprises a structure according to the formula

2. The method according to claim 1, wherein said PEG group has a molecular weight distribution that is essentially homodisperse.

3. The method according to claim 1, wherein q is 0.

4. A method for increasing the number of granulocytes in a subject, wherein said subject is eligible for a bone marrow transplant, said method comprising administering to said subject an amount of a covalent conjugate between a G-CSF peptide having the amino acid sequence according to SEQ ID NO:

1 and a poly(ethylene glycol) (PEG) group,

wherein said covalent conjugate comprises a structure according to the formula

5. The method according to claim 4, wherein q is 0.

6. A method for preventing, treating, and alleviating myelosuppression resulting from a cancer therapy, said method comprising administering to a recipient of said cancer therapy an amount of amount of a covalent conjugate between a G-CSF peptide having the amino acid sequence according to SEQ ID NO:

1 and a poly(ethylene glycol) (PEG) group,

wherein said covalent conjugate comprises a structure according to the formula

7. The method according to claim 6, wherein said cancer therapy comprises a member selected from radiation therapy and chemotherapy.

8. The method according to claim 6, wherein q is 0.

9. A method of treating a condition in a subject in need thereof, said condition characterized by compromised white blood cell production in said subject, said method comprising the step of administering to said subject an amount of a covalent conjugate between a G-CSF peptide having the amino acid sequence according to SEQ ID NO:

1 and a poly(ethylene glycol) (PEG) group,

wherein said covalent conjugate comprises a structure according to the formula

10. The method according to claim 9, wherein said compromised white blood cell production is a result of chemotherapy, radiation therapy, or idiopathic thrombocytopenia purpura.

11. The method according to claim 9, wherein q is 0.

12. A method for the treatment of neutropenia in a mammal comprising administering a pharmaceutically effective amount of a covalent conjugate between a G-CSF peptide having the amino acid sequence according to SEQ ID NO:

1 and a poly(ethylene glycol) (PEG) group,

wherein said covalent conjugate comprises a structure according to the formula

13. The method according to claim 12, wherein q is 0.

14. A method for the treatment of thrombocytopenia in a mammal comprising administering a pharmaceutically effective amount of a covalent conjugate between a G-CSF peptide having the amino acid sequence according to SEQ ID NO:

1 and a poly(ethylene glycol) (PEG) group,

wherein said covalent conjugate comprises a structure according to the formula

15. The method according to claim 14, wherein q is 0.

16. A method for expanding hematopoietic stem cells in culture, said method comprising the step of administering to said stem cells an effective amount of amount of a covalent conjugate between a G-CSF peptide having the amino acid sequence according to SEQ ID NO:

1 and a poly(ethylene glycol) (PEG) group,

wherein said covalent conjugate comprises a structure according to the formula

17. The method according to claim 16, wherein q is 0.

18. A method for increasing hematopoiesis in a subject, said method comprising the step of administering to said subject an effective amount of a covalent conjugate between a G-CSF peptide having the amino acid sequence according to SEQ ID NO:

1 and a poly(ethylene glycol) (PEG) group,

wherein said covalent conjugate comprises a structure according to the formula

19. The method according to claim 18, wherein q is 0.

20. A method for increasing the number of hematopoietic progenitor cells in a subject, said method comprising administering to said subject an effective amount of a covalent conjugate between a G-CSF peptide having the amino acid sequence according to SEQ ID NO:

1 and a poly(ethylene glycol) (PEG) group,

wherein said covalent conjugate comprises a structure according to the formula

21. The method according to claim 20, wherein said hematopoietic progenitor cells are CD34+ cells.

22. The method according to claim 20, wherein q is 0.

23. A method for increasing stem cell production in a donor, said method comprising administering to said donor an effective amount of a covalent conjugate between a G-CSF peptide having the amino acid sequence according to SEQ ID NO:

1 and a poly(ethylene glycol) (PEG) group,

wherein said covalent conjugate comprises a structure according to the formula

24. The method according to claim 23, wherein q is 0.

25. A method for providing stable engraftment of bone marrow, said method comprising:

(a) administering to a donor of said bone marrow an amount of a covalent conjugate between a G-CSF peptide having the amino acid sequence according to SEQ ID NO;

1 and a poly(ethylene glycol) (PEG) group,

wherein said covalent conjugate comprises a structure according to the formula

26. The method according to claim 25, wherein said donor is the same individual as said recipient.

27. The method according to claim 26, wherein said donor is a different individual from said recipient.

28. The method according to claim 25, wherein q is 0.

29. A method for increasing the number of hematopoietic progenitor cells in a subject, said method comprising administering to said subject:

(a) a first composition comprising a compound of formula (I) is 1,1′

-[1,4-phenylene-bis-(methylene)-bis-1,4,8,11-tetraazacyclotetradecane (AMD3100); and

(b) a second composition comprising an amount of a covalent conjugate between a G-CSF peptide having the amino acid sequence according to SEQ ID NO;

1 and a poly(ethylene glycol) (PEG) group,

wherein said covalent conjugate comprises a structure according to the formula

30. The method according to claim 29, wherein said first composition and said second composition are administered sequentially and in any order.

31. The method according to claim 29, wherein said first composition and said second composition are administered simultaneously.

32. The method according to claim 29, wherein said hematopoietic progenitor cells are CD34+ cells.

33. The method according to claim 29, wherein q is 0.

34. A method for increasing stem cell production in a donor, said method comprising administering to said donor an amount of a covalent conjugate between a G-CSF peptide having the amino acid sequence according to SEQ ID NO:

1 and a poly(ethylene glycol) (PEG) group,

wherein said covalent conjugate comprises a structure according to the formula

35. The method according to claim 34, wherein q is 0.

36. A method for increasing stem cell production in a donor, said method comprising administering to said donor an amount of a covalent conjugate between a G-CSF peptide having the amino acid sequence according to SEQ ID NO:

1 and a poly(ethylene glycol) (PEG) group,

wherein said covalent conjugate comprises a structure according to the formula

37. The method according to claim 36, wherein q is 0.