ActRIIB proteins and variants and uses therefore relating to utrophin induction for muscular dystrophy therapy

• US 9,617,319 B2
• Filed: 04/16/2014
• Issued: 04/11/2017
• Est. Priority Date: 11/17/2009
• Status: Active Grant

• Current Assignee: Acceleron Pharma Inc. (Merck & Co., Inc.)
• Original Assignee: Acceleron Pharma Inc. (Merck & Co., Inc.)
• Inventors: Seehra, Jasbir, Lachey, Jennifer
• Primary Examiner(s): Saoud, Christine J
• Assistant Examiner(s): LOCKARD, JON MCCLELLAND
• Application Number:
  US14/254,560
• Publication Number:
  US 20150023970A1
• Time in Patent Office: 1,091 Days
• Field of Search: None
• CPC Class Codes: A61K 38/1709 from mammals
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: C07K 14/4707 Muscular dystrophy
• CPC Class Codes: C07K 14/4708 Duchenne dystrophy
• CPC Class Codes: C07K 16/26 against hormones ; against hormone releasing or inhibiting factors
• CPC Class Codes: C07K 16/2869 against hormone receptors for antibodies against neuromediator receptors C07K16/286
• CPC Class Codes: C07K 2317/76 Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Abstract

In certain aspects, the present invention provides compositions and methods for inducing utrophin expression in muscle with an ActRIIB protein as therapy for muscular dystrophy. The present invention also provides methods of screening compounds that modulate activity of an ActRIIB protein and/or an ActRIIB ligand.

Claims

1. A method for treating a Duchenne muscular dystrophy (DMD) or Becker muscular dystrophy (BMD) patient that has an elevated level of serum creatine kinase, the method comprising administering to the patient an amount of a polypeptide comprising an amino acid sequence that is at least 90% identical to the sequence of amino acids 29-109 of SEQ ID NO:

2.

2. The method of claim 1, wherein the patient has DMD.

3. The method of claim 1, wherein the patient has BMD.

4. The method of claim 1, wherein administration of the polypeptide increases sarcolemmal strength of muscle fibers in the patient.

5. The method of claim 1, wherein utrophin expression is increased in the patient'"'"'s skeletal or cardiac muscle.

6. The method of claim 1, wherein the serum creatine kinase is serum creatine kinase isoform MM (CK-MM).

7. The method of claim 1, wherein the method further comprises evaluating the level of serum creatine kinase and selecting a dose level or frequency for administering the polypeptide based on the evaluated level of serum creatine kinase.

8. The method of claim 7, wherein the serum creatine kinase is serum creatine kinase isoform MM (CK-MM).

9. The method of claim 1, wherein the polypeptide comprises an amino acid sequence that is at least 95% identical to the sequence of amino acids 29-109 of SEQ ID NO:

2.

10. The method of claim 1, wherein the polypeptide comprises an amino acid sequence that is at least 97% identical to the sequence of amino acids 29-109 of SEQ ID NO:

2.

11. The method of claim 1, wherein the polypeptide comprises an amino acid sequence that is at least 90% identical to the sequence of amino acids 25-131 of SEQ ID NO:

2.

12. The method of claim 11, wherein the polypeptide has an acidic amino acid at the position corresponding to position 79 of SEQ ID NO:

2.

13. The method of claim 12, wherein the polypeptide has an aspartic acid at the position corresponding to position 79 of SEQ ID NO:

2.

14. The method of claim 1, wherein the polypeptide comprises an amino acid sequence that is at least 95% identical to the sequence of amino acids 25-131 of SEQ ID NO:

2.

15. The method of claim 1, wherein the polypeptide comprises an amino acid sequence that is at least 97% identical to the sequence of amino acids 25-131 of SEQ ID NO:

2.

16. The method of claim 1, wherein the polypeptide has an acidic amino acid at the position corresponding to position 79 of SEQ ID NO:

2.

17. The method of claim 16, wherein the polypeptide has an aspartic acid at the position corresponding to position 79 of SEQ ID NO:

2.

18. The method of claim 1, wherein the polypeptide binds to GDF8.

19. The method of claim 1, wherein the polypeptide binds to GDF11.

20. The method of claim 1, wherein the polypeptide binds to activin A.

21. The method of claim 1, wherein the polypeptide comprises a heterologous portion.

22. The method of claim 21, wherein the polypeptide comprises a glycine linker.

23. The method of claim 21, wherein the heterologous portion is an Fc domain.

24. The method of claim 21, wherein the polypeptide is part of a dimer.