Method for treating myelofibrosis comprising administering a transforming growth factor beta type II receptor antagonist
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.
1. A method for treating myelofibrosis, comprising administering to a patient in need thereof an effective amount of a transforming growth factor beta type II receptor (TβRII) antagonist, wherein the patient is also being treated with ruxolitinib.
2. The method of claim 1 , wherein the TβRII antagonist inhibits TGFβ1 and TGFβ3.
3. The method of claim 1 , wherein the TβRII antagonist is an Fc fusion protein.
4. The method of claim 3 , wherein the TβRII-Fc fusion protein comprises the amino acid sequence of SEQ ID NO: 103.
5. The method of claim 1 , wherein the myelofibrosis is associated with a gain-of-function Janus kinase mutation.
6. The method of claim 1 , wherein the myelofibrosis is associated with a gain-of-function mutation in JAK2.
7. The method of claim 1 , wherein the myelofibrosis is associated with constitutive kinase activity of JAK2.
8. The method of claim 6 , wherein the patient has a JAK2V617F-associated myelofibrosis.
9. The method of claim 1 , wherein the patient has primary myelofibrosis.
10. The method of claim 1 , wherein the patient has post-polycythemia vera myelofibrosis.
11. The method of claim 1 , wherein the patient has post-essential thrombocythemia myelofibrosis.
12. The method of claim 1 , wherein the patient is intolerant or refractory to treatment with ruxolitinib.
13. The method of claim 3 , wherein the fusion protein 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.
14. The method of claim 13 , wherein the fusion protein is glycosylated.
15. The method of claim 14 , wherein the fusion protein is glycosylated and has a glycosylation pattern obtainable from expression in a CHO cell.
16. The method of claim 3 , wherein the fusion protein binds to TGFβ1.
17. The method of claim 3 , wherein the fusion protein binds to TGFβ3.
18. The method of claim 3 , wherein the fusion protein binds to TGFβ1 and TGFβ3.
19. The method of claim 3 , wherein the fusion protein is isolated.
20. The method of claim 3 , wherein the fusion protein is recombinant.
21. The method of claim 3 , wherein the fusion protein is a homodimer.
22. The method of claim 3 , wherein the Fc fusion protein comprises a TβRII extracellular domain (ECD), wherein the amino acid sequence of the ECD consists of an amino acid sequence that is at least 95% identical to SEQ ID NO: 13; and wherein the fusion protein does not include a signal sequence and does not include the amino acids corresponding to amino acids 185-592 of SEQ ID NO: 6.
23. The method of claim 22 , wherein the TβRII ECD amino acid sequence consists of the amino acid sequence of SEQ ID NO: 13.
24. The method of claim 22 , wherein the TβRII-Fc fusion protein comprises a heterologous amino acid sequence comprising the amino acid sequence of SEQ ID NO: 21.
25. The method of claim 24 , wherein the TβRII-Fc fusion protein comprises a heterologous amino acid sequence joined to the TβRII ECD by a linker.
26. The method of claim 25 , wherein the TβRII-Fc fusion protein binds to TGFβ1 or TGFβ3.
27. The method of claim 25 , wherein the TβRII-Fc fusion protein binds to TGFβ1 and TGFβ3.