Methods for treating myeloproliferative disorders

Abstract

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 - 262 . (canceled) 
     
     
         263 . A method for treating, preventing, or reducing the progression rate or severity of myelofibrosis in a patient in need thereof, comprising administering an effective amount of a transforming growth factor beta type II receptor (TβRII) antagonist, wherein the TβRII antagonist is a fusion protein comprising:
 (a) a TβRII polypeptide comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 13; 
 (b) a linker; and 
 (c) an immunoglobulin Fc domain, 
 
       and wherein the patient is being treated with a Janus kinase inhibitor. 
     
     
         264 . The method of  claim 263 , wherein the patient is intolerant or refractory to treatment with a Janus kinase inhibitor. 
     
     
         265 . The method of  claim 263 , wherein the method further comprises administering to a patient in need thereof a Janus kinase inhibitor, wherein the Janus kinase inhibitor is administered in an effective amount. 
     
     
         266 . The method of  claim 263 , wherein the TβRII antagonist inhibits TGFβ1 and TGFβ3. 
     
     
         267 . The method of  claim 263 , wherein the TβRII antagonist comprises an amino acid sequence that is 90%, 91%, 92%, 93%, 94% 95%, 96%, 97%, 98%, 99%, or 100% identical to any one of SEQ ID NOs: 19, 20 and 21. 
     
     
         268 . The method of  claim 263 , wherein the TβRII antagonist comprises a first amino acid sequence from the extracellular domain of TβRII and an immunoglobulin Fc amino acid sequence, wherein the first amino acid sequence comprises an amino acid sequence at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical to the amino acid sequence of SEQ ID NO: 13. 
     
     
         269 . The method of  claim 268 , wherein the first amino acid sequence comprises the amino acid sequence of SEQ ID NO: 13. 
     
     
         270 . The method of  claim 263 , wherein the linker is positioned between the first polypeptide and the immunoglobulin Fc domain. 
     
     
         271 . The method of  claim 263 , wherein the fusion protein comprises an amino acid sequence that is at least 90%, 95%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 103. 
     
     
         272 . The method of  claim 263 , wherein the patient has a disorder associated with a gain-of-function mutation in JAK2. 
     
     
         273 . The method of  claim 263 , wherein the patient has a disorder associated with elevated or constitutive kinase activity of JAK2, preferably wherein the elevated kinase activity of JAK2 is as compared to healthy patients of the same age and sex. 
     
     
         274 . The method of  claim 263 , wherein the patient has a JAK2V617F-associated disorder. 
     
     
         275 . The method of  claim 263 , wherein the patient has primary myelofibrosis, post-polycythemia vera myelofibrosis or post essential thrombocythemia myelofibrosis. 
     
     
         276 . The method of  claim 275 , wherein the patient has primary myelofibrosis. 
     
     
         277 . The method of  claim 263 , 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. 
     
     
         278 . The method of  claim 277 , wherein the Janus kinase inhibitor is ruxolitinib or fedratinib. .