Variant activin receptor

Patent metadata

Field	Value
Publication number	US-9809638-B2
Application number	US-201615171944-A
Country	US
Kind code	B2
Filing date	Jun 2, 2016
Priority date	Mar 6, 2007
Publication date	Nov 7, 2017
Grant date	Nov 7, 2017

Abstract

The present invention provides variant activin IIB soluble receptor polypeptides and proteins capable of binding and inhibiting the activities of activin A, myostatin, or GDF-11. The present invention also provides polynucleotides, vectors and host cells capable of producing the variant polypeptides and proteins. Compositions and methods for treating muscle-wasting and other diseases and disorders are also provided.

First claim

The invention claimed is:

1. An isolated protein comprising a variant activin IIB receptor (vActRIIB) polypeptide wherein the polypeptide is selected from the group consisting of:
(a) a polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 18, wherein the polypeptide comprises an amino acid substitution at position 28, wherein the substitution at position 28 is A, W, Y, F, Q, V, I, L, M, K, or H for E;
(b) a polypeptide comprising the amino acid sequence set forth in amino acids 19 through 134 of SEQ ID NO: 18, wherein the polypeptide comprises an amino acid substitution at position 28, wherein the substitution at position 28 is A, W, Y, F, Q, V, I, L, M, K, or H for E;
(c) a polypeptide comprising the amino acid sequence set forth in amino acids 23 through 134 of SEQ ID NO: 18, wherein the polypeptide comprises an amino acid substitution at position 28, wherein the substitution at position 28 is A, W, Y, F, Q, V, I, L, M, K, or H for E;
(d) a polypeptide comprising the amino acid sequence set forth in amino acids 25 through 134 of SEQ ID NO: 18, wherein the polypeptide comprises an amino acid substitution at position 28, wherein the substitution at position 28 is A, W, Y, F, Q, V, I, L, M, K, or H for E; and
(e) a polypeptide having at least 99% identity to any one of (a) through (d), wherein the polypeptide comprises an amino acid substitution at the position corresponding to position 28 of SEQ ID NO:18, wherein the substitution at position 28 is A, W, Y, F, Q, V, I, L, M, K, or H for E, and wherein the polypeptide is capable of binding myostatin, activin A, or GDF-11.

2. The protein of claim 1 , wherein polypeptide is capable of binding to each of myostatin and activin.

3. The protein of claim 1 , wherein the substitution at position 28 of the vActRIIB polypeptide is selected from the group of amino acids consisting of A, W and Y for E.

4. The protein of claim 1 , wherein the substitution at position 28 of the vActRIIB polypeptide is W for E.

5. The protein of claim 1 , wherein the isolated protein further comprises the sequence set forth in SEQ ID NO:79.

6. The protein of claim 1 , wherein the isolated protein further comprises the sequence set forth in SEQ ID NO:80.

7. The protein of claim 1 , wherein the polypeptide sequence has at least 99% identity to the amino acid sequence set forth at amino acids 25 through 134 of SEQ ID NO: 18, and wherein the polypeptide comprises an amino acid substitution at position 28, wherein the substitution at position 28 is A, W, Y, F, Q, V, I, L, M, K, or H for E, and wherein the polypeptide is capable of binding myostatin, activin A, or GDF-11.

8. The protein of claim 1 , wherein the polypeptide sequence has at least 99% identity to the amino acid sequence set forth at amino acids 25 through 134 of SEQ ID NO: 18, wherein the polypeptide comprises an amino acid substitution at position 28, wherein the substitution at position 28 is W for E, and wherein the isolated protein further comprises an Fc domain linked to vActRIIB polypeptide via a linker.

9. The protein of claim 1 , wherein the polypeptide sequence has at least 100% identity to the amino acid sequence set forth at amino acids 25 through 134 of SEQ ID NO: 18, wherein the polypeptide comprises an amino acid substitution at position 28, wherein the substitution at position 28 is W for E, and wherein the isolated protein further comprises a human Fc domain (SEQ ID NO:80) linked to vActRIIB polypeptide via a peptide linker (SEQ ID NO:79).

10. The isolated protein of claim 1 , wherein the polypeptide is fused to at least one heterologous polypeptide.

11. A dimer comprising the protein of claim 1 .

12. A pharmaceutical composition comprising the protein of claim 1 and an excipient.

13. A method for inhibiting myostatin in a subject, comprising administering an effective amount of the protein of claim 1 to the subject.

14. A method for increasing lean muscle mass or increasing the ratio of lean muscle mass to fat mass in a subject, comprising administering an effective amount of the protein of claim 1 to the subject.

15. A method for treating a muscle-wasting disease or a metabolic disorder in a subject, comprising administering an effective amount of the protein of claim 1 to the subject.

16. A method for treating a disease in which activin is over-expressed in a subject, comprising administering an effective amount of the protein of claim 1 to the subject, optionally wherein the disease is cancer.

17. A method of treating cancer in a subject, comprising administering an effective amount of the protein of claim 1 to the subject.

18. The method of claim 17 , wherein the cancer is ovarian cancer.

19. A method of treating cachexia in a subject, comprising administering an effective amount of the protein of claim 1 to the subject.

20. The method of claim 19 , wherein the cachexia is cancer cachexia.

Assignees

• Amgen Inc

Inventors

• Sun Jeonghoon
• Tam Lei-Ting Tony
• Han Hui-Quan
• Kwak Keith Soo-Nyung
• Zhou Xiaolan

Classifications

• A61P3/04

  Anorexiants; Antiobesity agents · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

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

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P31/18

  for HIV · CPC title