ANALOGUES OF HEPCIDIN MIMETICS WITH IMPROVED IN VIVO HALF LIVES

• US 20190002503A1
• Filed: 12/29/2016
• Published: 01/03/2019
• Est. Priority Date: 12/30/2015
• Status: Abandoned Application

• Current Assignee: Protagonist Therapeutics, Inc.
• Original Assignee: Protagonist Therapeutics, Inc.
• Inventors: Bourne, Gregory Thomas, Smythe, Mark Leslie, Frederick, Brian Troy, Bhandari, Ashok
• Application Number:
  US16/067,568
• Publication Number:
  US 20190002503A1
• Time in Patent Office: Days
• 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 3/02 Nutrients, e.g. vitamins, minerals
• CPC Class Codes: C07K 14/00 Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
• CPC Class Codes: C07K 14/575 Hormones derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin C07K14/665, e.g. corticotropin C07K14/695
• CPC Class Codes: C07K 7/08 having 12 to 20 amino acids gastrins C07K14/595; somatostatins C07K14/655; melanotropins C07K14/68

Abstract

The present invention provides hepcidin analogues with improved in vivo half-lives, and related pharmaceutical compositions and methods of use thereof.

Claims

1. A hepcidin analogue comprising a polypeptide sequence of Formula (I):

X—

Y 

 

(I)

or a pharmaceutically acceptable salt or solvate thereof, wherein;

X is a peptide sequence having the formula Xa;

2. The hepcidin analogue of claim 1, comprising one of more of the following:

X1 is Asp;

X4 is Phe or Dpa;

X7 is Ile, Leu, Val, nLeu, or Lys;

X7 is Ile or Lys;

X8 is Lys or Arg;

Y1 is Pro or hPro;

Y1 is Pro;

Y2 is Arg or Lys;

Y2 is Arg;

Y3 is Ser;

Y4 is Lys, Arg or His;

Y4 is Lys;

or

Y5 is Gly or Sar.

3. The hepcidin analogue of claim 1, wherein:

X1 is Asp;

X4 is Phe or Dpa;

X7 is Ile, Leu, Val, nLeu, or Lys;

X8 is Lys or Arg;

Y1 is Pro or hPro;

Y2 is Arg or Lys;

Y3 is Ser;

Y4 is Lys, Arg or His; and

Y5 is Gly or Sar.

4. The hepcidin analogue of claim 3, wherein:

X7 is Ile or Lys;

Y1 is Pro;

Y2 is Arg; and

Y4 is Lys.

5. The hepcidin analogue of any one of claims 1-4, comprising a structure of Formula II:

R¹—

X-L-Y—

R² 

 

(II)

or a pharmaceutically acceptable salt or solvate thereof, wherein;

R¹ is hydrogen, a C1-C6 alkyl, a C6-C12 aryl, a C6-C12 aryl C1-C6 alkyl, or a C1-C20 alkanoyl, and including PEGylated versions alone or as spacers of any of the foregoing;

R² is OH or NH₂;

X is a peptide sequence having the formula Xa;

L is absent, a bond, or a linker moiety; and

Y is absent or present;

provided that if Y is present, Y is a peptide having the formula Ya.

6. The hepcidin analogue of any one of claims 1-5, wherein X or Y further comprise one to three additional amino acids at the N-terminus or C-terminus.

7. The hepcidin analogue of any one of claims 1-6, wherein Y is present.

8. The hepcidin analogue of claim 7, comprising a disulfide bond between X6 and Y6.

9. The hepcidin analogue of claim 7 or claim 8, wherein L is a bond.

10. The hepcidin analogue of any one of claims 7-9, comprising a half-life extension moiety conjugated to a Lys at X8 or X10.

11. The hepcidin analogue of any one of claims 1-10, wherein the hepcidin analogue comprises one of the following structures:

12. The hepcidin analogue of any one of claims 1-6, wherein Y is absent.

13. The hepcidin analogue of claim 12, wherein X10 is absent.

14. A dimer comprising two hepcidin analogues of claim 12 or claim 13, wherein the two polypeptide sequence of Formula I or two structures of Formula II are dimerized via a linker moiety.

15. The dimer of claim 14, wherein the linker moiety is bound to the C-terminus of each hepcidin analogue.

16. The dimer of claim 14 or claim 15, wherein the half-life extension moiety is conjugated to the linker moiety.

17. The hepcidin analogue of any one of claims 1-13 or the dimer of any one of claims 14-16, wherein the linker moiety is selected from IsoGlu, Dapa, PEGn where n=1 to 25, PEG11(40 atoms), OEG, IsoGlu-Ahx, IsoGlu-OEG-OEG, IsoGlu-PEG5, IsoGlu-PEGn where n=1 to 25 β

Ala-PEG2, and β

Ala-PEG11(40 atoms).

18. The hepcidin analogue or dimer of any one of claims 1-17, wherein the half-life extension moiety is selected from C12 (Lauric acid), C14 (Mysteric acid), C16 (Palmitic acid), C18 (Stearic acid, C20, C12 diacid, C14 diacid, C16 diacid, C18 diacid, C20 diacid, biotin, and isovaleric acid.

19. The hepcidin analogue or dimer of any one of claims 1-18, wherein the half-life extension moiety is attached to a linker moiety that is attached to the peptide.

20. The hepcidin analogue or dimer of any one of claims 1-19, wherein the half-life extension moiety increases the molecular weight of the hepcidin analogue by about 50 D to about 2 KD.

21. The hepcidin analogue or dimer of any one of claims 1-20, wherein the half-life extension moiety increases serum half-life, enhances solubility, and/or improves bioavailability of the hepcidin analogue.

22. The hepcidin analogue or dimer of any one of claims 1-21, comprising an isovaleric acid moiety conjugated to the N-terminal Asp residue.

23. The hepcidin analogue or dimer of any one of claims 1-22, comprising an amidated C-terminal residue.

24. The hepcidin analogue or dimer of any one of claims 1-23, comprises the sequence:

25. The hepcidin analogue or dimer of any one of claims 1-23, comprising the sequence:

26. A polynucleotide encoding a peptide of the hepcidin analogue of any one of claims 1-25.

27. A vector comprising the polynucleotide of claim 26.

28. A pharmaceutical composition comprising the hepcidin analogue or dimer of any one of claims 1-25, the polynucleotide of claim 26, or the vector of claim 27, and a pharmaceutically acceptable carrier, excipient or vehicle.

29. A method of binding a ferroportin or inducing ferroportin internalization and degradation, comprising contacting the ferroportin with at least one hepcidin analogue or dimer of any one of claims 1-25 or a composition of claim 28.

30. A method for treating a disease of iron metabolism in a subject in need thereof comprising providing to the subject an effective amount of the pharmaceutical composition of claim 28.

31. The method of claim 30, wherein the pharmaceutical composition is provided to the subject by an oral, intravenous, peritoneal, intradermal, subcutaneous, intramuscular, intrathecal, inhalation, vaporization, nebulization, sublingual, buccal, parenteral, rectal, vaginal, or topical route of administration.

32. The method of claim 31, wherein the pharmaceutical composition is provided to the subject by an oral or subcutaneous route of administration.

33. The method of any one of claims 30-32, wherein the disease of iron metabolism is an iron overload disease.

34. The method of any one of claims 30-33, wherein the pharmaceutical composition is provided to the subject at most twice daily, at most once daily, at most once every two days, at most once a week, or at most once a month.

35. The method of any one of claims 30-34, wherein the hepcidin analogue is provided to the subject at a dosage of about 1 mg to about 100 mg.

36. A device comprising the pharmaceutical composition of claim 28, for delivery of the hepcidin analogue to a subject, optionally orally or subcutaneously.

37. A kit comprising the pharmaceutical composition of claim 28, packaged with a reagent, a device, or an instructional material, or a combination thereof.