Variant activin receptor polypeptides, alone or in combination with chemotherapy, and uses thereof

• US 9,610,327 B2
• Filed: 12/19/2012
• Issued: 04/04/2017
• 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, Huiquan, Kwak, Keith Soo-Nyung, Zhou, Xiaolan
• Primary Examiner(s): Chandra, Gyan
• Application Number:
  US14/366,978
• Publication Number:
  US 20140348827A1
• Time in Patent Office: 1,567 Days
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/4164 1,3-Diazoles
• CPC Class Codes: A61K 31/513 having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
• CPC Class Codes: A61K 31/655 Azo (—N=N—), diazo (=N2), azoxy (>N—O—N< or N(=O)—N<), azido (—N3) or diazoamino (—N=N—N<) compounds
• CPC Class Codes: A61K 31/7072 having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
• CPC Class Codes: A61K 31/7088 Compounds having three or more nucleosides or nucleotides
• CPC Class Codes: A61K 38/179 for growth factors; for growth regulators
• CPC Class Codes: A61K 39/395 Antibodies agglutinins A61K38/36 ; as drug carriers A61K47/50; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 15/08 for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• 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 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07K 14/71 for growth factors; for growth regulators

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. A method of reducing the size of a gonadal tumor mass in a subject in need of such treatment comprising administering to the subject:

an effective amount of an isolated protein comprising a variant activin IIB receptor polypeptide (vActRIIB) wherein vActRIIB comprises a polypeptide sequence having 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 selected from the group of amino acids consisting of A, W, and Y for E, and wherein the polypeptide is capable of binding myostatin, activin A, or GDF-11; and

a chemotherapeutic agent.

2. The method of claim 1, wherein the tumor mass is an ovarian tumor mass.

3. The method of claim 1, wherein the isolated protein and the chemotherapeutic agent are administered at the same time.

4. The method of claim 1, wherein the isolated protein and the chemotherapeutic agent are each administered at different times.

5. The method of claim 1, wherein the substitution at position 28 of the vActRIIB polypeptide is W.

6. The method of claim 1, wherein the isolated protein further comprises an Fc domain linked to vActRIIB via a linker.

7. The method of claim 6, wherein the sequence of the Fc domain is shown in SEQ ID NO:

80, and wherein the sequence of the linker is shown in SEQ ID NO;

79.

8. The method of claim 1, wherein the isolated protein further comprises an IgG2 Fc domain linked to vActRIIB via a peptide linker.

9. The method of claim 1, wherein the chemotherapeutic agent is a nucleoside analogue, 5-fluorouracil, and/or dacarbazine.

10. A method of treating a gonadal cancer in a subject in need of such treatment comprising administering to the subject:

an effective amount of an isolated protein comprising a variant activin IIB receptor polypeptide (vActRIIB) wherein vActRIIB comprises a polypeptide sequence having 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 selected from the group of amino acids consisting of A, W, and Y for E, and wherein the polypeptide is capable of binding myostatin, activin A, or GDF-11; and

a chemotherapeutic agent.

11. The method of claim 10, wherein the gonadal cancer is ovarian cancer.

12. The method of claim 10, wherein the isolated protein and the chemotherapeutic agent are each administered at different times.

13. The method of claim 10, wherein the isolated protein and the chemotherapeutic agent are administered at the same time.

14. The method of claim 10, wherein the substitution at position 28 of the vActRIIB polypeptide is W.

15. The method of claim 10, wherein the isolated protein further comprises an Fc domain linked to vActRIIB via a linker.

16. The method of claim 15, wherein the sequence of the Fc domain is shown in SEQ ID NO:

80, and wherein the sequence of the linker is shown in SEQ ID NO;

79.

17. The method of claim 10, wherein the isolated protein further comprises an Fc domain linked to vActRIIB via a linker.

18. The method of claim 10, wherein the isolated protein further comprises an IgG2Fc domain linked to vActRIIB via a peptide linker.

19. The method of claim 10, wherein the chemotherapeutic agent is a nucleoside analogue, 5-fluorouracil, and/or dacarbazine.