Methods for treating Janus kinase-associated disorders by administering soluble transforming growth factor beta type II receptor

9,884,900

15/228956

August 04, 2016

In part, the present disclosure relates methods for treating, preventing, or reducing the severity of a myeloproliferative disorder (e.g., polycythemia vera, essential thrombocythemia, and myelofibrosis) or one or more complications of a myeloproliferative disorder. The present disclosure further relates methods for treating, preventing, or reducing the severity of a Janus kinase-associated disorder or one or more complications of a Janus kinase-associated disorder. In certain aspects the disclosure provides TβRII antagonists for treating, preventing, or reducing the severity of a myeloproliferative disorder (e.g., polycythemia vera, essential thrombocythemia, and myelofibrosis) or a Janus kinase-associated disorder or one or more complications of a myeloproliferative disorder or a Janus kinase-associated disorder.

Acceleron Pharma Inc. (Cambridge, MA, US)

ACCELERON PHARMA INC. (Cambridge, MA, US)

1. A method for treating a Janus kinase-associated disorder, comprising administering to a patient in need thereof an effective amount of a soluble transforming growth factor beta type II receptor (TβRII), wherein the disorder is associated with elevated kinase activity of JAK2 as compared to healthy patients of the same age and sex, and wherein the patient is being treated with or has been treated with a Janus kinase inhibitor.

2. A method for treating a Janus kinase-associated disorder comprising administering to a patient in need thereof: i) a soluble transforming growth factor beta type II receptor (TβRII) and ii) a Janus kinase inhibitor, wherein the soluble TβRII receptor and Janus kinase inhibitor are administered in an effective amount, wherein the disorder is associated with elevated kinase activity of JAK2 as compared to healthy patients of the same age and sex.

3. The method of claim 1 , wherein the soluble TβRII receptor inhibits the activity of transforming growth factor beta type I (TGFβ1) and transforming growth factor beta type 3 (TGFβ3).

4. The method of claim 1 , wherein the soluble TβRII receptor is an Fc fusion protein.

5. The method of claim 4 , wherein the TβRII-Fc fusion protein comprises the amino acid sequence of SEQ ID NO: 103.

6. The method of claim 1 , wherein the patient has a disorder associated with a gain-of-function Janus kinase mutation.

7. The method of claim 1 , wherein the patient has a disorder associated with a gain-of-function mutation in JAK2.

8. The method of claim 1 , wherein the patient has a disorder associated with constitutive kinase activity of JAK2.

9. The method of claim 7 , wherein the patient has a JAK2V617F-associated disorder.

10. The method of claim 1 , wherein the patient has myelofibrosis.

11. The method of claim 10 , wherein the patient has primary myelofibrosis.

12. The method of claim 10 , wherein the patient has post-polycythemia vera myelofibrosis.

13. The method of claim 10 , wherein the patient has post-essential thrombocythemia myelofibrosis.

14. The method of claim 1 , wherein the patient has polycythemia vera.

15. The method of claim 1 , wherein the patient has essential thrombocythemia.

16. The method of claim 1 , wherein the patient is intolerant or refractory to treatment with a Janus kinase inhibitor.

17. The method of claim 1 , wherein the Janus kinase inhibitor inhibits at least JAK2.

18. The method of claim 1 , wherein the Janus kinase inhibitor is selected from the group consisting of: ruxolitinib, fedratinib (SAR302503), monoelotinib (CYT387), pacritinib, lestaurtinib, AZD-1480, BMS-911543, NS-018, LY2784544, SEP-701, XL019, and AT-9283.

19. The method of claim 18 , wherein the Janus kinase inhibitor is ruxolitinib.

20. The method of claim 4 or 5 , wherein the soluble TβRII receptor comprises one or more modified amino acid residues selected from: a glycosylated amino acid, a PEGylated amino acid, a farnesylated amino acid, an acetylated amino acid, a biotinylated amino acid, an amino acid conjugated to a lipid moiety, and an amino acid conjugated to an organic derivatizing agent.

21. The method of claim 20 , wherein the soluble TβRII receptor is glycosylated.

22. The method of claim 21 , wherein the soluble TβRII receptor is glycosylated and has a glycosylation pattern obtainable from expression in a CHO cell.

23. The method of claim 4 or 5 , wherein the soluble TβRII receptor binds to TGFβ1.

24. The method of claim 4 or 5 , wherein the soluble TβRII receptor binds to TGFβ3.

25. The method of claim 4 or 5 , wherein the soluble TβRII receptor binds to TGFβ1 and TGFβ3.

26. The method of claim 4 or 5 , wherein the soluble TβRII receptor is isolated.

27. The method of claim 4 or 5 , wherein the soluble TβRII receptor is recombinant.

28. The method of claim 4 or 5 , wherein the fusion protein is a homodimer.

29. The method of claim 4 , wherein the TβRII amino acid sequence consists of an amino acid sequence that is at least 95% identical to SEQ ID NO: 13; wherein the fusion polypeptide does not include a signal sequence and does not include the amino acids corresponding to amino acids 185-592 of SEQ ID NO: 6.

30. The method of claim 29 , wherein the TβRII amino acid sequence consists of the amino acid sequence of SEQ ID NO: 13.

31. The method of claim 29 , wherein the TβRII-Fc fusion protein comprises a heterologous amino acid sequence comprising the amino acid sequence of SEQ ID NO: 21.

32. The method of claim 31 , wherein the TβRII-Fc fusion protein comprises a heterologous amino acid sequence joined to the TβRII polypeptide by a linker.

33. The method of claim 32 , wherein the TβRII-Fc fusion protein binds to TGFβ1 or TGFβ3.

34. The method of claim 32 , wherein the TβRII-Fc fusion protein binds to TGFβ1 and TGFβ3.

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