Compositions comprising natriuretic peptides and methods of use thereof

Patent metadata

Field	Value
Publication number	US-9266939-B2
Application number	US-201113336651-A
Country	US
Kind code	B2
Filing date	Dec 23, 2011
Priority date	Dec 27, 2010
Publication date	Feb 23, 2016
Grant date	Feb 23, 2016

Abstract

The present invention provides methods, compositions, and kits for the treatment of disorders associated with overactivation of FGFR3, such as achondroplasia; bone or cartilage disorders; or vascular smooth muscle disorders, or for the elongation of bone. In some embodiments, the present invention provides polypeptides having a natriuretic peptide fused to an Fc domain of an immunoglobulin. Such polypeptides can be administered to subjects, e.g., subcutaneously, to treat a disorder associated with overactivation of FGFR3, a bone or cartilage disorder, or a vascular smooth muscle disorder, or to elongate bone. The invention also features nucleic acid molecules encoding such polypeptides and the use of the nucleic acid molecules for treating disorders associated with overactivation of FGFR3, bone or cartilage disorders, or vascular smooth muscle disorders, or for elongating bone.

First claim

What is claimed is:

1. An isolated polypeptide comprising the structure X-Fc-Y-NP-Z or the structure X-NP-Y-Fc-Z, wherein NP is a natriuretic peptide that is an agonist of natriuretic peptide receptor B (NPR-B), wherein said NP comprises the structure: [N-terminal extension]-[short segment]-[ring domain]-[C-terminal extension], wherein each of said N-terminal extension, short segment, and C-terminal extension is, independently, absent or is an amino acid sequence of at least one amino acid, and wherein said NP comprises amino acids 6-22 of SEQ ID NO: 126, wherein the amino-acid at position 17 is not Met, and wherein:
(i) each of X and Z is, independently, absent or is an amino acid sequence of at least one amino acid; and
(ii) the amino acid sequence of Y comprises [(Gly) 4 (Ser)] n (Gly) p or (Gly) p [(Ser)(Gly) 4 ] n , wherein n is between 1and 10 and p is between 0 and 4, or wherein the amino acid sequence of Y comprises the amino acid sequence of any one of SEQ ID NOs: 304-313, 322-333, or 337-389.

2. The isolated polypeptide of claim 1 , wherein said polypeptide comprises the structure X-Fc-Y-NP-Z.

3. The isolated polypeptide of claim 1 , wherein said NP comprises the sequence of any one of SEQ ID NOs: 1156-1159 and 1163-1168.

4. The isolated polypeptide of claim 3 , wherein said NP comprises the sequence of SEQ ID NO: 1156 or 1157.

5. The isolated polypeptide of claim 4 , wherein said NP comprises the sequence of SEQ ID NO: 1157.

6. The isolated polypeptide of claim 1 , wherein said ring domain comprises the amino acid sequence of SEQ ID NO: 6, amino acids 11-27 of SEQ ID NO: 30, or SEQ ID NO: 95.

7. The isolated polypeptide of claim 1 , wherein the amino acid sequence of said short segment consists of amino acids 1-5 of SEQ ID NO: 4.

8. The isolated polypeptide of claim 1 , wherein the amino acid sequence of said short segment consists of amino acids 1-5, 2-5, 3-5, 4-5, or 5 of SEQ ID NO: 4, amino acids 1-10 of SEQ ID NO: 17, amino acids 1-5 of SEQ ID NO: 19, amino acids 1-3 of SEQ ID NO: 20, amino acids 1-5 of SEQ ID NO: 21, or amino acids 1-6 of SEQ ID NO: 29.

9. The isolated polypeptide of claim 1 , wherein the amino acid sequence of said N-terminal extension comprises KGANKK (SEQ ID NO: 314) or KGANQK (SEQ ID NO: 315).

10. The isolated polypeptide of claim 1 , wherein said C-terminal extension comprises the amino acid sequence of SEQ ID NO: 118.

11. The isolated polypeptide of claim 10 , wherein said C-terminal extension comprises the amino acid sequence of SEQ ID NO: 117 or comprises amino acids 23-37 selected from any one of SEQ ID NOs: 101-116.

12. The isolated polypeptide of claim 1 , wherein said NP is selective for NPR-B over NPR-A, wherein the EC 50(NPR-A) /EC 50(NPR-B) ratio for said NP, as determined in an in vivo pharmacokinetic assay, is at least 30.

13. The isolated polypeptide of claim 1 , wherein said Fc comprises a C H2 domain, a C H3 domain, and a hinge region.

14. The isolated polypeptide of claim 13 , wherein said Fc is a constant domain of an immunoglobulin selected from the group consisting of IgG-1, IgG-2, IgG-3, IgG-3 and IgG-4.

15. The isolated polypeptide of claim 13 , wherein said Fc comprises the amino acid sequence of SEQ ID NO: 401.

16. The isolated polypeptide of claim 14 , wherein said immunoglobulin is IgG-1.

17. The isolated polypeptide of claim 13 , wherein the amino acid sequence of said Fc comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 401.

18. The isolated polypeptide of claim 13 , wherein the amino acid sequence of said Fc consists of SEQ ID NO: 401.

19. The isolated polypeptide of claim 1 , wherein the amino acid sequence of Y comprises the sequence of SEQ ID NO: 1206.

20. The isolated polypeptide of claim 1 , wherein X, Y, or Z comprises a bone-targeting moiety.

21. The isolated polypeptide of claim 20 , wherein said bone-targeting moiety comprises six consecutive acidic residues.

22. The isolated polypeptide of claim 21 , wherein said bone-targeting moiety comprises ten consecutive acidic residues.

23. The isolated polypeptide of claim 21 , wherein said acidic residues are aspartic acid or glutamic acid.

24. The isolated polypeptide of claim 23 , wherein said bone-targeting moiety comprises E 6 , E 10 , D 6 , or D 10 .

25. The isolated polypeptide of claim 1 , wherein X, Y, or Z comprises a cathepsin cleavage sequence.

26. The isolated polypeptide of claim 25 , wherein said cathepsin cleavage sequence comprises a cathepsin K cleavage sequence.

27. The isolated polypeptide of claim 25 , wherein said cathepsin cleavage sequence is HGPQG (SEQ ID NO: 374) or HKLRG (SEQ ID NO: 375).

28. The isolated polypeptide of claim 1 , wherein said polypeptide comprises the amino acid sequence of any one of SEQ ID NOs: 501-608.

29. The isolated polypeptide of claim 28 , wherein said polypeptide comprises the amino acid sequence of any one of SEQ ID NO: 572, SEQ ID NO: 502, SEQ ID NO: 504, SEQ ID NO: 506, SEQ ID NO: 512, SEQ ID NO: 514, SEQ ID NO: 516, SEQ ID NO: 560, SEQ ID NO: 562, SEQ ID NO: 564, SEQ ID NO: 574, SEQ ID NO: 576, SEQ ID NO: 584, SEQ ID NO: 586, SEQ ID NO: 588, SEQ ID NO: 596, SEQ ID NO: 598, SEQ ID NO: 600, or SEQ ID NO: 608.

30. The isolated polypeptide of claim 29 , wherein said polypeptide comprises a bone-targeting moiety.

31. The isolated polypeptide of claim 30 , wherein said bone-targeting moiety comprises E 6 , E 10 , D 6 , or D 10 .

32. The isolated polypeptide of claim 1 , wherein the amino acid sequence of said polypeptide comprises the amino acid sequence of SEQ ID NO: 512.

33. The isolated polypeptide of claim 32 , wherein the amino acid sequence of said polypeptide consists of the amino acid sequence of SEQ ID NO: 512.

34. The isolated polypeptide of claim 1 , wherein the amino acid sequence of said polypeptide comprises the amino acid sequence of SEQ ID NO: 554.

35. The isolated polypeptide of claim 34 , wherein the amino acid sequence of said polypeptide consists of the amino acid sequence of SEQ ID NO: 554.

36. The isolated polypeptide of claim 1 , wherein the amino acid sequence of said polypeptide comprises the amino acid sequence of SEQ ID NO: 572.

37. The isolated polypeptide of claim 36 , wherein the amino acid sequence of said polypeptide consists of the amino acid sequence of SEQ ID NO: 572.

38. The isolated polypeptide of claim 1 , wherein said polypeptide is glycosylated.

39. The isolated polypeptide of claim 1 , wherein said polypeptide is pegylated.

40. The isolated polypeptide of claim 1 , comprising a bone-targeting moiety.

41. The isolated polypeptide of claim 40 , wherein said bone-targeting moiety comprises E 6 , E 10 , D 6 , or D 10 .

42. A pharmaceutical composition comprising:
(a) the isolated polypeptide of claim 1 ; and
(b) a pharmaceutically acceptable excipient.

43. A kit comprising:
(a) the pharmaceutical composition of claim 42 ; and
(b) instructions for administering said pharmaceutical composition to a subject to treat a disorder associated with overactivation of FGFR3, a bone or cartilage disorder, or a hypertensive di

Assignees

• Crine Philippe
• Joubert Simon
• Parat Marie
• Alexion Pharma Inc

Inventors

• Crine Philippe
• Joubert Simon
• Parat Marie

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P9/04

  Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P9/12

  Antihypertensives · CPC title