Variant activin receptor

• US 10,407,487 B2
• Filed: 09/25/2017
• Issued: 09/10/2019
• Est. Priority Date: 03/06/2007
• Status: Active Grant

• Current Assignee: Amgen Inc.
• Original Assignee: Amgen Inc.
• Inventors: Sun, Jeonghoon, Tam, Lei-Ting Tony, Han, Hui-Quan, Kwak, Keith Soo-Nyung, Zhou, Xiaolan
• Primary Examiner(s): Chandra, Gyan
• Application Number:
  US15/714,726
• Publication Number:
  US 20180072791A1
• Time in Patent Office: 715 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 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/00 Drugs for disorders of the urinary system
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 39/06 Free radical scavengers or antioxidants
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07K 14/71 for growth factors; for growth regulators
• CPC Class Codes: C07K 2319/00 Fusion polypeptide
• CPC Class Codes: C07K 2319/30 : Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto

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.

Claims

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 1, wherein the cachexia is cancer cachexia.