Building IP: XLRN Patent Application re "METHODS AND COMPOSITIONS FOR TREATING MYELOFIBROSIS" (Luspa | BMY Message Board Posts


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Msg  8172 of 8509  at  10/21/2021 9:24:03 AM  by

JBWIN


Building IP: XLRN Patent Application re "METHODS AND COMPOSITIONS FOR TREATING MYELOFIBROSIS" (Luspatercept + JAK2 inhibitor is in Phase III INDEPENDENCE trial)

United States Patent Application20210322514
Kind CodeA1
Kumar; Ravindra ; et al.October 21, 2021

https://clinicaltrials.gov/ct2/show/NCT04717414?term=Luspatercept+Phase+3&cond=Myelofibrosis&draw=2&rank=1 
 
METHODS AND COMPOSITIONS FOR TREATING MYELOFIBROSIS

Abstract

In part, the present disclosure relates methods for treating, preventing, or reducing the progression rate and/or severity of myelofibrosis or one or more complications of myelofibrosis (extramedullary hematopoiesis, splenomegaly, anemia, and fibrosis). In certain aspects, the disclosure provides ActRIIB antagonists for use in treating, preventing, or reducing the progression rate and/or severity of one or more complications associated with Janus kinase inhibitor therapy in a patient (e.g., anemia).


Inventors:Kumar; Ravindra; (Acton, MA) ; Suragani; Naga Venkata Sai Rajasekhar; (Wrentham, MA)
Applicant:
NameCityStateCountryType

Acceleron Pharma Inc.

Cambridge

MA

US
Family ID:1000005678759
Appl. No.:17/210037
Filed:March 23, 2021

Related U.S. Patent Documents

Application NumberFiling DatePatent Number
15660421Jul 26, 2017
17210037
62367289Jul 27, 2016

Current U.S. Class:1/1
Current CPC Class:A61K 45/06 20130101; A61P 7/00 20180101; A61K 38/179 20130101; C07K 14/71 20130101; C07K 2319/30 20130101; A61P 7/06 20180101; A61K 31/519 20130101; A61K 38/1796 20130101
International Class:A61K 38/17 20060101 A61K038/17; A61P 7/06 20060101 A61P007/06; C07K 14/71 20060101 C07K014/71; A61P 7/00 20060101 A61P007/00; A61K 45/06 20060101 A61K045/06; A61K 31/519 20060101 A61K031/519

Claims



1-2. (canceled)

3. A method for treating myelofibrosis, comprising administering to a patient in need thereof an effective amount of: a) a Janus kinase inhibitor; and b) an ActRIIB polypeptide, and wherein the ActRIIB polypeptide comprises amino acids 20-109 of SEQ ID NO: 1, wherein the polypeptide comprises an E or a D at the position corresponding to position 79 of SEQ ID NO: 1; and wherein the ActRIIB polypeptide inhibits myostatin and/or GDF11 in a cell-based assay.

4. (canceled)

5. The method of claim 3, wherein the method decreases one or more of: bone marrow fibrosis, spleen fibrosis, liver fibrosis, lung fibrosis, and lymph node fibrosis.

6-11. (canceled)

12. The method of claim 3, wherein the method increases red blood cell levels in the patient.

13. The method of claim 3, wherein the method increases hemoglobin levels in the patient.

14. The method of claim 3, wherein the patient has anemia.

15. The method of claim 14, wherein the method treats the anemia.

16. The method of claim 3, wherein the patient has been administered one or more blood cell transfusions prior to the start of ActRIIB polypeptide treatment.

17. The method of claim 3, wherein the patient is blood cell transfusion-dependent.

18. The method of claim 17, wherein the method decreases blood cell transfusion burden.

19. The method of claim 18, wherein the method decreases blood cell transfusion by greater than about 30% for 4 to 8 weeks relative to the equal time prior to the start of the ActRIIB polypeptide treatment.

20-22. (canceled)

23. The method of claim 3 wherein the patient has primary myelofibrosis.

24. The method of claim 3 wherein the patient has post-polycythemia vera myelofibrosis.

25. The method of claim 3 wherein the patient has post-essential thrombocythemia myelofibrosis.

26-31. (canceled)

32. The method of claim 3, wherein the myelofibrosis is associated with one or more mutations in JAK2.

33. The method of claim 32, wherein the JAK2 mutation is JAK2V617F.

34. (canceled)

35. The method of claim 3, wherein the patient has been treated with a Janus kinase inhibitor.

36. The method of claim 3, wherein the patient is intolerant of or has an inadequate response to a Janus kinase inhibitor.

37-42. (canceled)

43. The method of claim 36, 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.

44. The method of claim 43, wherein the Janus kinase inhibitor is ruxolitinib.

45-46. (canceled)

47. The method of claim 3, wherein the patient is further administered hydroxyurea or has previously been treated with hydroxyurea.

48. The method of claim 3, wherein the patient is intolerant of hydroxyurea or has an inadequate response to hydroxyurea.

49-60. (canceled)

61. The method of claim 3, wherein the ActRIIB polypeptide is administered prior to treatment with the Janus kinase inhibitor.

62. The method of claim 3, wherein the ActRIIB polypeptide is administered after treatment with the Janus kinase inhibitor.

63. The method of claim 3, wherein the ActRIIB polypeptide is administered concurrently with the Janus kinase inhibitor.

64-70. (canceled)

71. The method of claim 3, wherein the polypeptide comprises a D at the amino acid position corresponding to position 79 of SEQ ID NO: 1.

72. The method of claim 3, wherein the polypeptide comprises a E at the amino acid position corresponding to position 79 of SEQ ID NO: 1.

73. The method of claim 71, wherein the polypeptide is a fusion protein comprising an immunoglobulin Fc domain.

74. The method of claim 73, wherein the immunoglobulin Fc domain is from an IgG1 Fc domain.

75. (canceled)

76. The method of claim 74, wherein the fusion protein further comprises a linker domain positioned between the ActRIIB domain and the immunoglobulin Fc domain.

77-114. (canceled)

115. The method of claim 3, wherein the ActRIIB polypeptide comprises the amino acid sequence of SEQ ID NO: 53.

116. The method of claim 115, wherein the Janus kinase inhibitor is fedratinib.

117. The method of claim 76, wherein the ActRIIB polypeptide comprises amino acids 25-131 of SEQ ID NO: 1; but wherein the polypeptide comprises an E or a D at the position corresponding to position 79 of SEQ ID NO: 1.

118. The method of claim 3, wherein the patient is receiving blood transfusions.
Description



CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is a continuation of U.S. application Ser. No. 15/660,421, filed Jul. 26, 2017 (now pending) which claims the benefit of priority to U.S. Provisional Application No. 62/367,289 (now expired), filed on Jul. 27, 2016. The specifications of each of the foregoing applications are incorporated by reference in their entirety.

SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Mar. 23, 2021, is named 1848179-111-102_Seq.txt and is 116,114 bytes in size.

BACKGROUND OF THE INVENTION

[0003] Myelofibrosis is a rare disease mainly affecting people of older age. Myelofibrosis is a BCR-ABL1-negative myeloproliferative neoplasm that presents de novo (primary) or may be preceded by polycythemia vera (post-polycythemia vera) or essential thrombocythemia (post-essential thrombocythemia). Clinical features include progressive anemia, marked splenomegaly, fibrosis (e.g., bone marrow fibrosis), constitutional symptoms (e.g., fatigue, night sweats, bone pain, pruritus, and cough), and weight loss [Tefferi A (2000) N Engl J Med 342:1255-1265]. Median survival ranges from less than 2 years to over 15 years based on currently identified prognostic factors. Mutations involving JAK2, MPL, TET2, ASXL1, IDH1/IDH2, CBL, IKZF1, LNK, and EZH2 have been described in patients with myelofibrosis [James C et al. (2005) Nature 434:1144-1148, 2005; Scott L M et al. (2007) N Engl J Med 356:459-468, 2007; Pikman Y et al. (2006) PLoS Med 3:e270; Delhommeau F et al. (2009) N Engl J Med 360:2289-2301; Carbuccia N et al. (2009) Leukemia 23:2183-2186; Green A et al. (2010) N Engl J Med 362:369-370; Tefferi A et al. (2010) Leukemia 24:1302-1309; Grand F H et al. (2009) Blood 113:6182-6192; Jager R et al. (2010) Leukemia 24:1290-1298; Oh S T et al. (2010) Blood 116:988-992; and Ernst T et al., Nat Genet. 42:722-726]. Some mutations occur at high frequency in myelofibrosis (e.g. JAK2 mutations in about 50% patients), and either directly (e.g. JAK2 or MPL mutations) or indirectly (e.g. LNK or CBL mutations) induce JAK-STAT hyperactivation.

[0004] The only cure of myelofibrosis is bone marrow transplantation. However, treatment-related mortality is high, and only a minority of patients qualify for transplantation. Many of other currently available treatments are not effective in reversing the process of myelofibrosis, be it primary or secondary disease. Myelofibrosis treatments include, for example, cyto-reductive therapy (e.g., treatment with hydroxyurea); treatment of anemia with androgens and/or erythropoietin; and splenectomy. These therapies have not demonstrated improvement in survival and are largely seen as palliative [Cervantes F., Myelofibrosis: Biology and treatment options, European Journal of Haematology, 2007, 79 (suppl. 68) 13-17]. More recently, JAK inhibitors have been used to treat myelofibrosis. JAK inhibitors appear to be useful for reducing splenomegaly in myelofibrosis patients, but their effects on the disease are otherwise largely palliative [Gupta et al. (2012) Blood 120:1367-1379]. In particular, JAK inhibitors have little to no effect on many manifestations (complications) of the disease including, for example, cytopenia, transfusion dependence, accelerated or blast phase disease, and fibrosis. Moreover, JAK inhibitors have been shown to induce, or worsen, thrombocytopenia, anemia, and neutropenia in some patients.

[0005] Thus, there is a high, unmet need for effective therapies for treating myelofibrosis. Accordingly, it is an object of the present disclosure to provide methods for treating or preventing the myelofibrosis, particularly treating or preventing one or more complication of myelofibrosis.

SUMMARY OF THE INVENTION

[0006] In part, the present disclosure relates to the discovery that an ActRIIB antagonist (inhibitor) can be used to treat myelofibrosis, particularly ameliorating various complications of the disease including, for example, splenomegaly, extramedullary hematopoiesis, and fibrosis. In particular, the data presented herein show that a GDF trap polypeptide decrease splenomegaly, extramedullary hematopoiesis, and fibrosis in a JAK2V617F model of myelofibrosis. Accordingly, in certain aspects, the disclosure relates to compositions and methods for treating myelofibrosis, particularly treating or preventing one or more complications of myelofibrosis (e.g., splenomegaly, extramedullary hematopoiesis, anemia, and fibrosis), by administering to a patient in need thereof an effective amount of one or more ActRIIB antagonists, optionally in combination of one or more other supportive therapies or active agents for treating myelofibrosis. While GDF trap polypeptides may affect myelofibrosis through a mechanism other than ActRIIB antagonism [e.g., inhibition of one or more of GDF11, GDF8, activin B, BMP6, GDF3, and BMP10 may be an indicator of the tendency of an agent to inhibit the activities of a spectrum of additional agents, including, perhaps, other members of the TGF-beta superfamily, and such collective inhibition may lead to the desired effect on, for example, myelofibrosis], the disclosure nonetheless demonstrates that desirable therapeutic agents may be selected on the basis of ActRIIB antagonism. Therefore, while not wishing to be bound to a particular mechanism of action, it is expected that other ActRIIB antagonists [e.g., antagonists of the ActRIIB receptor, antagonists of one or more ActRIIB ligand (e.g., GDF11, GDF8, activin B, BMP6, GDF3, and BMP10), antagonists of one or more type I receptor (e.g., ALK4, ALK5, and/or ALK7), antagonists of one or more co-receptor, and/or antagonists of one or more ActRIIB downstream signaling components (e.g., Smads)], or combination of such antagonists] will useful in the treatment of myelofibrosis, particularly in treating or preventing one or more myelofibrosis complications (e.g., splenomegaly, extramedullary hematopoiesis, anemia, and fibrosis). Such agents are collectively referred to herein as "ActRIIB antagonists" or "ActRIIB inhibitors".

[0007] Accordingly, in certain aspects, the disclosure relates to methods for treating myelofibrosis, comprising administering to a patient in need thereof an effective amount of an ActRIIB antagonist. In some embodiments, the disclosure relates to methods for treating one or more complications of myelofibrosis, comprising administering to a patient in need thereof an effective amount of an ActRIIB antagonist. In certain aspects, the disclosure relates to methods of preventing myelofibrosis, comprising administering to a patient in need thereof an effective amount of an ActRIIB antagonist. In some embodiments, the disclosure relates to methods of preventing one or more complications of myelofibrosis, comprising administering to a patient in need thereof an effective amount of an ActRIIB antagonist. In certain aspects, the disclosure relates to reducing the progression rate of myelofibrosis, comprising administering to a patient in need thereof an effective amount of an ActRIIB antagonist. In some embodiments, the disclosure relates to reducing the progression rate of one or more complications of myelofibrosis, comprising administering to a patient in need thereof an effective amount of an ActRIIB antagonist. In certain aspects, the disclosure relates to methods of reducing severity of myelofibrosis, comprising administering to a patient in need thereof an effective amount of an ActRIIB antagonist. In some embodiments, the disclosure relates to methods of reducing severity of one or more complications of myelofibrosis, comprising administering to a patient in need thereof an effective amount of an ActRIIB antagonist. In certain aspects, the disclosure relates to methods of treating, preventing, or reducing the progression rate and/or severity of myelofibrosis or one or more complications of myelofibrosis, wherein the patient has primary myelofibrosis. In certain aspects, the disclosure relates to methods of treating, preventing, or reducing the progression rate and/or severity of myelofibrosis or one or more complications of myelofibrosis, wherein the patient has post-polycythemia vera myelofibrosis. In certain aspects, the disclosure relates to methods of treating, preventing, or reducing the progression rate and/or severity of myelofibrosis or one or more complications of myelofibrosis, wherein the patient has post-essential thrombocythemia myelofibrosis. In certain aspects, the disclosure relates to methods of treating, preventing, or reducing the progression rate and/or severity of myelofibrosis or one or more complications of myelofibrosis, wherein the patient has low risk myelofibrosis according to the International Prognostic Scoring System (IPSS). In certain aspects, the disclosure relates to methods of treating, preventing, or reducing the progression rate and/or severity of myelofibrosis or one or more complications of myelofibrosis, wherein the patient has intermediate-1 risk myelofibrosis according to the IPSS. In certain aspects, the disclosure relates to methods of treating, preventing, or reducing the progression rate and/or severity of myelofibrosis or one or more complications of myelofibrosis, wherein the patient has intermediate-2 risk myelofibrosis according to the IPSS. In certain aspects, the disclosure relates to methods of treating, preventing, or reducing the progression rate and/or severity of myelofibrosis or one or more complications of myelofibrosis, wherein the patient has high-risk myelofibrosis risk myelofibrosis according to the IPSS. In certain aspects, the disclosure relates to methods of treating, preventing, or reducing the progression rate and/or severity of myelofibrosis or one or more complications of myelofibrosis, wherein the patient has low risk myelofibrosis according to the dynamic IPSS (DIPSS). In certain aspects, the disclosure relates to methods of treating, preventing, or reducing the progression rate and/or severity of myelofibrosis or one or more complications of myelofibrosis, wherein the patient has intermediate-1 risk myelofibrosis according to the DIPSS. In certain aspects, the disclosure relates to methods of treating, preventing, or reducing the progression rate and/or severity of myelofibrosis or one or more complications of myelofibrosis, wherein the patient has intermediate-2 risk myelofibrosis according to the DIPSS. In certain aspects, the disclosure relates to methods of treating, preventing, or reducing the progression rate and/or severity of myelofibrosis or one or more complications of myelofibrosis, wherein the patient has high-risk myelofibrosis risk myelofibrosis according to the DIPSS. In certain aspects, the disclosure relates to methods of treating, preventing, or reducing the progression rate and/or severity of myelofibrosis or one or more complications of myelofibrosis, wherein the patient has low risk myelofibrosis according to the DIPSS-plus. In certain aspects, the disclosure relates to methods of treating, preventing, or reducing the progression rate and/or severity of myelofibrosis or one or more complications of myelofibrosis, wherein the patient has intermediate-1 risk myelofibrosis according to the DIPSS-plus. In certain aspects, the disclosure relates to methods of treating, preventing, or reducing the progression rate and/or severity of myelofibrosis or one or more complications of myelofibrosis, wherein the patient has intermediate-2 risk myelofibrosis according to the DIPSS-plus. In certain aspects, the disclosure relates to methods of treating, preventing, or reducing the progression rate and/or severity of myelofibrosis or one or more complications of myelofibrosis, wherein the patient has high-risk myelofibrosis risk myelofibrosis according to the DIPSS-plus. In certain aspects, an ActRIIB antagonists may be used to prevent or delay risk progression of myelofibrosis in accordance with any of the recognized risk stratification models for myelofibrosis (e.g., IPSS, DIPPS, and DIPPS-plus). For example, in some embodiments, an ActRIIB antagonist may be used to prevent or delay myelofibrosis risk progression from low risk to intermediate-1 risk in accordance with IPSS, DIPPS, or DIPPS-plus. In other embodiments, an ActRIIB antagonist may be used to prevent or delay myelofibrosis risk progression from intermediate-1 risk to intermediate-2 risk in accordance with IPSS, DIPPS, or DIPPS-plus. In still other embodiments, an ActRIIB antagonist may be used to prevent or delay myelofibrosis risk progression from intermediate-2 risk to high risk in accordance with IPSS, DIPPS, or DIPPS-plus. In certain aspects, an ActRIIB antagonists may be used to promote or increase myelofibrosis risk regression in accordance with any of the recognized risk stratification models for myelofibrosis (e.g., IPSS, DIPPS, and DIPPS-plus). For example, in some embodiments, an ActRIIB antagonist may be used to promote or increase myelofibrosis risk regression from high risk to intermediate-2 risk in accordance with IPSS, DIPPS, or DIPPS-plus. In other embodiments, an ActRIIB antagonist may be used to promote or increase myelofibrosis risk regression from intermediate-2 risk to intermediate-1 risk in accordance with IPSS, DIPPS, or DIPPS-plus. In still other embodiments, an ActRIIB antagonist may be used to promote or increase myelofibrosis risk regression from intermediate-1 risk to low risk in accordance with IPSS, DIPPS, or DIPPS-plus. In certain aspects, the disclosure relates to methods of using ActRIIB antagonists to treat, prevent, or reduce the progression rate and/or severity of myelofibrosis or one or more complications of myelofibrosis wherein the patient comprises one or more gene mutations associated with myelofibrosis. For example, in some embodiments, an ActRIIB antagonist may be used to treat, prevent, or reduce the progression rate and/or severity of myelofibrosis or one or more complications of myelofibrosis wherein the myelofibrosis is associated with one or more gene mutations selected from the group consisting of: nullizygosity for JAK2 46/1 haplotype, JAK2V617F, IDH1, IDH2, EZH2, SRSF2, ASXL1, JAK1, JAK2, JAK3, TYK2, MPL, CALR, CALR+ASXL1-, CALR-ASKL1+, CALR+ASKL1+, CALR-ASKL1-, TET2, THPO, and LNK. In some embodiments, an ActRIIB antagonist may be used to treat, prevent, or reduce the progression rate and/or severity of myelofibrosis or one or more complications of myelofibrosis wherein the myelofibrosis is associated with one or more gene mutations in a Janus kinase (JAK) (e.g., JAK1, JAK2, and/or JAK3). In some embodiments, an ActRIIB antagonist may be used to treat, prevent, or reduce the progression rate and/or severity of myelofibrosis or one or more complications of myelofibrosis wherein the myelofibrosis is associated with one or more gene mutations in JAK2. In some embodiments, an ActRIIB antagonist may be used to treat, prevent, or reduce the progression rate and/or severity of myelofibrosis or one or more complications of myelofibrosis wherein the myelofibrosis is associated with a JAK2V617F mutation. In certain aspects, the disclosure relates to methods of using an ActRIIB antagonist to treat, prevent, or reduce the progression rate and/or severity of myelofibrosis or one or more complications of myelofibrosis wherein the myelofibrosis is associated with one or more elevated serum markers selected from the group consisting of: increased serum IL-8 levels, increased serum IL-2R levels, and increased serum free light chain levels. In certain aspects, the disclosure relates to methods of using an ActRIIB antagonist to treat, prevent, or reduce the progression rate and/or severity of myelofibrosis or one or more complications of myelofibrosis wherein the patient has been treated with a Janus kinase inhibitor (e.g., ruxolitinib, fedratinib (SAR302503), monoelotinib (CYT387), pacritinib, lestaurtinib, AZD-1480, BMS-911543, NS-018, LY2784544, SEP-701, XL019, and AT-9283). In some embodiments, an ActRIIB antagonist may be used to treat, prevent, or reduce the progression rate and/or severity of myelofibrosis or one or more complications of myelofibrosis wherein the patient is intolerant of a Janus kinase inhibitor. In some embodiments, an ActRIIB antagonist may be used to treat, prevent, or reduce the progression rate and/or severity of myelofibrosis or one or more complications of myelofibrosis wherein the patient has an inadequate response to a Janus kinase inhibitor. In certain aspects, the disclosure relates to methods of using an ActRIIB antagonist to treat, prevent, or reduce the progression rate and/or severity of myelofibrosis or one or more complications of myelofibrosis wherein the patient has been treated with hydroxyurea. In some embodiments, an ActRIIB antagonist may be used to treat, prevent, or reduce the progression rate and/or severity of myelofibrosis or one or more complications of myelofibrosis wherein the patient is intolerant of hydroxyurea. In some embodiments, an ActRIIB antagonist may be used to treat, prevent, or reduce the progression rate and/or severity of myelofibrosis or one or more complications of myelofibrosis wherein the patient has an inadequate response to hydroxyurea.

[0008] As described herein myelofibrosis is a clonal neoplastic disorder of hematopoiesis that is associated with various clinical complications that may manifest during disease progression in a patient. The examples of the disclosure demonstrate that an ActRIIB antagonist may be used to mitigate a number of these clinical complications, indicating that an ActRIIB antagonist may be used to more broadly treat various complications myelofibrosis as opposed to many of the current myelofibrosis therapies, which only treat one or a limited number of complications of the disease. Therefore, in some embodiments, an ActRIIB antagonist may be used to treat, prevent, or reduce the progression rate and/or severity of ineffective hematopoiesis in a patient with myelofibrosis. In certain aspects, an ActRIIB antagonist may be used to treat, prevent, or reduce the progression rate and/or severity of extramedullary hematopoiesis in a patient with myelofibrosis. For example, an ActRIIB antagonist may be used to treat, prevent, or reduce the progression rate and/or severity of extramedullary hematopoiesis in the spleen (splenic extramedullary hematopoiesis) in a patient with myelofibrosis. In other embodiments, an ActRIIB antagonist may be used to treat, prevent, or reduce the progression rate and/or severity of extramedullary hematopoiesis in the liver (hepatic extramedullary hematopoiesis) in a patient with myelofibrosis. In even other embodiments, an ActRIIB antagonist may be used to treat, prevent, or reduce the progression rate and/or severity of extramedullary hematopoiesis in the lung (pulmonary extramedullary hematopoiesis) in a patient with myelofibrosis. In still other embodiments, an ActRIIB antagonist may be used to treat, prevent, or reduce the progression rate and/or severity of extramedullary hematopoiesis in the lymph nodes (lymphatic extramedullary hematopoiesis) in a patient with myelofibrosis. In certain aspects, an ActRIIB antagonist may be used to treat, prevent, or reduce the progression rate and/or severity of inflammation and/or enlargement (size) of an organ or tissue in a myelofibrosis patient. In some embodiments, an ActRIIB antagonist may be used to treat, prevent, or reduce the progression rate and/or severity of inflammation and/or enlargement (size) in the spleen of a patient with myelofibrosis. In some embodiments, an ActRIIB antagonist may be used to treat, prevent, or reduce the progression rate and/or severity of inflammation and/or enlargement (size) in the liver of a patient with myelofibrosis. In some embodiments, an ActRIIB antagonist may be used to treat, prevent, or reduce the progression rate and/or severity of inflammation and/or enlargement (size) in the lung(s) of a patient with myelofibrosis. In some embodiments, an ActRIIB antagonist may be used to treat, prevent, or reduce the progression rate and/or severity of inflammation and/or enlargement (size) in the lymph node(s) of a patient with myelofibrosis. In some embodiments, an ActRIIB antagonist may be used to treat, prevent, or reduce the progression rate and/or severity of splenomegaly in a patient with myelofibrosis. In some embodiments, an ActRIIB antagonist may be used to treat, prevent, or reduce the progression rate and/or severity of hepatomegaly in a patient with myelofibrosis. In certain aspects, an ActRIIB antagonist may be used to treat, prevent, or reduce the progression rate and/or severity of fibrosis in a patient with myelofibrosis. In some embodiments, an ActRIIB antagonist may be used to treat, prevent, or reduce the progression rate and/or severity of bone marrow fibrosis in a patient with myelofibrosis. In some embodiments, an ActRIIB antagonist may be used to treat, prevent, or reduce the progression rate and/or severity of spleen fibrosis in a patient with myelofibrosis. In some embodiments, an ActRIIB antagonist may be used to treat, prevent, or reduce the progression rate and/or severity of liver fibrosis in a patient with myelofibrosis. In some embodiments, an ActRIIB antagonist may be used to treat, prevent, or reduce the progression rate and/or severity of lung fibrosis in a patient with myelofibrosis. In some embodiments, an ActRIIB antagonist may be used to treat, prevent, or reduce the progression rate and/or severity of lymph node fibrosis in a patient with myelofibrosis. In certain aspects, an ActRIIB antagonist may be used to treat, prevent, or reduce the progression rate and/or severity of osteosclerosis in a patient with myelofibrosis. In certain aspects, an ActRIIB antagonist may be used to treat, prevent, or reduce the progression rate and/or severity of osteomyelofibrosis. In certain aspects, an ActRIIB antagonist may be used to treat, prevent, or reduce the progression rate and/or severity of one or more blood-related complications of myelofibrosis. In some embodiments, an ActRIIB antagonist may be used to treat, prevent, or reduce the progression rate and/or severity of anemia in a patient with myelofibrosis. In some embodiments, an ActRIIB antagonist may be used to treat, prevent, or reduce the progression rate and/or severity of thrombocytopenia in a patient with myelofibrosis. In some embodiments, an ActRIIB antagonist may be used to treat, prevent, or reduce the progression rate and/or severity of pancytopenia in a patient with myelofibrosis. In some embodiments, an ActRIIB antagonist may be used to treat, prevent, or reduce the progression rate and/or severity of poikilocytosis in a patient with myelofibrosis. In some embodiments, an ActRIIB antagonist may be used to treat, prevent, or reduce the progression rate and/or severity of bleeding in a patient with myelofibrosis. In certain aspects, an ActRIIB antagonist may be used to treat, prevent, or reduce the progression rate and/or severity of one or more constitutional symptoms of myelofibrosis (e.g., fatigue, pruritus, weight loss, night sweats, fever, abdominal pain or discomfort, paresthesia, and early satiety). In certain aspects, an ActRIIB antagonist may be used to treat, prevent, or reduce the progression rate and/or severity of pain in a tissue and/or organ in a patient with myelofibrosis. In some embodiments, an ActRIIB antagonist may be used to treat, prevent, or reduce the progression rate and/or severity of bone pain in a patient with myelofibrosis. In some embodiments, an ActRIIB antagonist may be used to treat, prevent, or reduce the progression rate and/or severity of arthralgia in a patient with myelofibrosis. In some embodiments, an ActRIIB antagonist may be used to treat, prevent, or reduce the progression rate and/or severity of myalgia in a patient with myelofibrosis. In certain aspects, an ActRIIB antagonist may be used to treat, prevent, or reduce the progression rate and/or severity of cachexia in a patient with myelofibrosis. In certain aspects, disclosure relates to increasing red blood cell levels in a myelofibrosis patient by administering an effective amount of an ActRIIB antagonist. In certain aspects, disclosure relates to increasing hemoglobin levels in a myelofibrosis patient by administering an effective amount of an ActRIIB antagonist. In certain aspects, a myelofibrosis patient to be treated in accordance with the methods described herein has anemia. In some embodiments, ActRIIB antagonist may be used to treat, prevent, or reduce the progression rate and/or severity of anemia in a patient with myelofibrosis. In certain aspects, the disclosure relate to methods using an ActRIIB antagonists to treat, prevent, or reduce the progression rate and/or severity of myelofibrosis or a complication of myelofibrosis in patient that has been administered one or more blood cell transfusions (whole or red blood cell transfusions). In some embodiments, the disclosure relate to methods using an ActRIIB antagonists to treat, prevent, or reduce the progression rate and/or severity of myelofibrosis or a complication of myelofibrosis in patient that is blood cell transfusion-dependent. In certain aspects, an ActRIIB antagonist may be used to decrease blood cell transfusion burden in a patient with myelofibrosis. For example, an ActRIIB antagonist may be used to decrease blood cell transfusion by greater than about 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% for 4 to 8 weeks relative to the equal time prior to the start of the ActRIIB antagonist treatment. In some embodiments, an ActRIIB antagonist may be used to decrease blood cell transfusion by greater than about 50% for 4 to 8 weeks relative to the equal time prior to the start of the ActRIIB antagonist treatment in a patient with myelofibrosis. In certain aspects, an ActRIIB antagonist may be used to decrease iron overload in a patient with myelofibrosis. For example, an ActRIIB antagonist may be used to decrease iron overload in an organ or tissue in a patient with myelofibrosis. In some embodiments, an ActRIIB antagonist may be used to decrease iron overload in the spleen of a patient with myelofibrosis. In some embodiments, an ActRIIB antagonist may be used to decrease iron overload in the liver of a patient with myelofibrosis. In some embodiments, an ActRIIB antagonist may be used to decrease iron overload in the heart of a patient with myelofibrosis.

[0009] In any of the methods described herein, a myelofibrosis patient may further be administered one or more additional active agents and/or supportive therapies (in addition to administration of one or more ActRIIB antagonists) for treating, preventing, or reducing, the progression rate and/or severity of myelofibrosis or one or more complications of myelofibrosis. For example, in some embodiments, a patient may be further administered one or more supportive therapies or active agents is selected from the group consisting of: blood transfusion (whole blood or red blood cell transfusion), iron chelators (e.g., deferoxamine, deferiprone and deferasirox), corticosteroids, prednisone, ESAs (e.g., erythropoietin, epoetin alfa, epoetin beta, darbepoetin alfa, and methoxy polyethylene glycol-epoetin beta), androgens, danazol, thalidomide, lenalidomide, a cytoreductive agent, hydroxyurea, busulfan, melphalm, cladribine, splenectomy, radiotherapy, aspirin, pomalidonmide, Janus kinase inhibitors, mTOR inhibitors (e.g., rapamycin, sirolimus, deforolimus, everolimus, temsirolimus, NVP-BEZ235, BGT226, SF1126, PK1-587, INK128, AZD8055, and AZD2014), and histone deacetylase inhibitors (e.g., givinostat, panobinostat, and pracinostat). In certain aspects, the disclosure relates to methods for treating, preventing, or reducing the progression rate and/or severity of myelofibrosis or one or more complications of myelofibrosis, comprising administering to a patient in need thereof: a) a Janus kinase inhibitor; and b) an ActRIIB antagonists, wherein the Janus kinase inhibitor and ActRIIB antagonist are administered in an effective amount. In some embodiments, an ActRIIB antagonist is administered prior to treatment with the Janus kinase inhibitor. In other embodiments, an ActRIIB antagonist is administered after treatment with the Janus kinase inhibitor. In even other embodiments, an ActRIIB antagonist is administered concurrently with the Janus kinase inhibitor. Janus kinase inhibitors to be used in accordance with the methods described herein may be an agent that inhibits one or more Janus kinases selected from the group consisting of: JAK1, JAK2, and JAK3. For example, a Janus kinase inhibitor may be an agent that inhibits signaling of one or more of JAK1, JAK2, and JAK3 in a cell-based assay. In some embodiments, a Janus kinase inhibitor to be used in accordance with the methods described herein 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. In some preferred embodiments, a Janus kinase inhibitor to be used in accordance with the methods described herein is ruxolitinib.

[0010] Janus kinase inhibitors (e.g., ruxolitinib) have been approved for treatment of a variety of disorders including, for example, myelofibrosis. In addition, there are a number of other clinical investigations ongoing to determine the efficacy of Janus kinase inhibitors to treat various other diseases. A common adverse side-effect of Janus kinase inhibitor therapy is anemia. While blood cell transfusion and EPO receptor activator therapy may be used treated anemia in patients treated with a Janus kinase inhibitor, these anemia therapies also are associated with adverse effects in patients (e.g., promoting or increasing iron overload, inadequate response to EPO, and EPO intolerance). Therefore, there is a need in the art for alternative methods of increasing red blood cell/hemoglobin levels and treating anemia in patients treated with a Janus kinase inhibitor. In part, the present disclosure relates to the discovery that an ActRIIB antagonist (inhibitor) can be used to increase red blood cell and hemoglobin levels in patients treated with a Janus kinase inhibitor. Accordingly, in certain aspects, the disclosure relates to compositions and methods for increasing red blood cell/hemoglobin levels and treating or preventing anemia in a patient treated with a Janus kinase inhibitor by administering to a patient in need thereof an effective amount of one or more ActRIIB antagonists, optionally in combination of one or more other supportive therapies or active agents for treating anemia. While GDF trap polypeptides may affect red blood cell and/or hemoglobin levels through a mechanism other than ActRIIB antagonism [e.g., inhibition of one or more of GDF11, GDF8, activin B, BMP6, GDF3, and BMP10 may be an indicator of the tendency of an agent to inhibit the activities of a spectrum of additional agents, including, perhaps, other members of the TGF-beta superfamily, and such collective inhibition may lead to the desired effect on, for example, red blood cell levels and/or hemoglobin levels in patients treated with a Janus kinase inhibitor], the disclosure nonetheless demonstrates that desirable therapeutic agents may be selected on the basis of ActRIIB antagonism. Therefore, while not wishing to be bound to a particular mechanism of action, it is expected that other ActRIIB antagonists [e.g., antagonists of the ActRIIB receptor, antagonists of one or more ActRIIB ligand (e.g., GDF11, GDF8, activin B, BMP6, GDF3, and BMP10), antagonists of one or more type I receptor (e.g., ALK4, ALK5, and/or ALK7), antagonists of one or more co-receptor, and/or antagonists of one or more ActRIIB downstream signaling components (e.g., Smads)], or combination of such antagonists] will useful in the treatment of patients treated with a Janus kinase, particularly in treating or preventing one or more complications associated with Janus kinase therapy (e.g., anemia, thrombocytopenia, and/or neutropenia). Such agents are collectively referred to herein as "ActRIIB antagonists" or "ActRIIB inhibitors".

[0011] In certain aspects, the disclosure relate to methods for increasing red blood cell levels and/or hemoglobin levels in a patient treated with a Janus kinase inhibitor by administering to a patient in need thereof an effective amount of an ActRIIB antagonist. In some embodiments, ActRIIB antagonists may be used to treat or prevent anemia in a patient treated with a Janus kinase inhibitor. In some embodiments, a patient treated with a Janus kinase inhibitor may have been administered one or more blood cell transfusions prior to the start of ActRIIB antagonist treatment. In some embodiments, a patient treated with a Janus kinase inhibitor is blood cell transfusion-dependent. In certain aspects, the disclosure relate to methods of using an ActRIIB antagonist to decrease blood cell transfusion burden in a patient treated with a Janus kinase inhibitor. For example, an ActRIIB antagonist may be used to decrease blood cell transfusion by greater than about 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% for 4 to 8 weeks relative to the equal time prior to the start of the ActRIIB antagonists treatment in a patient treated with a Janus kinase inhibitor. In some embodiments, an ActRIIB antagonist may be used to decrease blood cell transfusion by greater than about 50% for 4 to 8 weeks relative to the equal time prior to the start of the ActRIIB antagonists treatment in a patient treated with a Janus kinase inhibitor. In certain aspects, the disclosure relates to methods of using an ActRIIB antagonist to decrease iron overload in a patient treated with a Janus kinase inhibitor. In some embodiment, ActRIIB antagonists may be used to decrease iron content in the liver of a patient treated with a Janus kinase inhibitor. In some embodiment, ActRIIB antagonists may be used to decrease iron content in the spleen of a patient treated with a Janus kinase inhibitor. In some embodiment, ActRIIB antagonists may be used to decrease iron content in the heart of a patient treated with a Janus kinase inhibitor. In some embodiments, the ActRIIB antagonist is administered prior to treatment with the Janus kinase inhibitor. In other embodiments, the ActRIIB antagonist is administered after treatment with the Janus kinase inhibitor. In still other embodiments, the ActRIIB antagonist is administered concurrently with the Janus kinase inhibitor. In certain aspects, a patient treated with a Janus kinase inhibitor has been treated with an agent that inhibitor inhibits one or more of Janus kinases selected from the group consisting of: JAK1, JAK2, and JAK3. In some embodiments, the Janus kinase inhibitor inhibits signaling of one or more of JAK1, JAK2, and JAK3 in a cell-based assay. For example, a patient may be treated with one or more Janus kinase inhibitors 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. In some embodiments, a patient may be treated with ruxolitinib.

[0012] In certain aspects, an ActRIIB antagonist, or combination of antagonists, to be used in accordance with methods and uses described herein is an agent that inhibits at least GDF11 (e.g., a GDF11 antagonist). Effects on GDF11 inhibition may be determined, for example, using a cell-based assay including those described herein (e.g., a Smad signaling reporter assay). Therefore, in some embodiments, an ActRIIB antagonist, or combination of antagonists, of the disclosure may bind to at least GDF11. Ligand binding activity may be determined, for example, using a binding affinity assay including those described herein. In some embodiments, an ActRIIB antagonist, or combination of antagonists, of the disclosure binds to at least GDF11 with a K.sub.D of at least 1.times.10.sup.-7M (e.g., at least 1.times.10.sup.-8M, at least 1.times.10.sup.-9M, at least 1.times.10.sup.-10 M, at least 1.times.10.sup.11M, or at least 1.times.10.sup.12M). As described herein, various ActRIIB antagonists that inhibit GDF11 can be used in accordance with the methods and uses described herein including, for example, ligand traps (e.g., ActRIIB polypeptides, GDF Traps, follistatin polypeptides, and FLRG polypeptides), antibodies, small molecules, nucleotide sequences, and combinations thereof. In certain embodiments, an ActRIIB antagonist, or combination of antagonists, that inhibits GDF11 may further inhibit one or more of: activin (e.g., activin A, activin B, activin AB, activin C, activin AC, activin BC, activin E, activin AE, and/or activin BE), GDF8, GDF3, BMP6, BMP10, ActRIIB, ALK4, ALK5, and ALK7.

[0013] In certain aspects, an ActRIIB antagonist, or combination of antagonists, to be used in accordance with methods and uses described herein is an agent that inhibits at least GDF8 (e.g., a GDF8 antagonist). Effects on GDF8 inhibition may be determined, for example, using a cell-based assay including those described herein (e.g., a Smad signaling reporter assay). Therefore, in some embodiments, an ActRIIB antagonist, or combination of antagonists, of the disclosure may bind to at least GDF8. Ligand binding activity may be determined, for example, using a binding affinity assay including those described herein. In some embodiments, an ActRIIB antagonist, or combination of antagonists, of the disclosure binds to at least GDF8 with a K.sub.D of at least 1.times.10.sup.-7 M (e.g., at least 1.times.10.sup.-8 M, at least 1.times.10.sup.-9 M, at least 1.times.10.sup.10 M, at least 1.times.10.sup.11 M, or at least 1.times.10.sup.12 M). As described herein, various ActRIIB antagonists that inhibit GDF8 can be used in accordance with the methods and uses described herein including, for example, ligand traps (e.g., ActRIIB polypeptides, GDF Traps, follistatin polypeptides, and FLRG polypeptides), antibodies, small molecules, nucleotide sequences, and combinations thereof. In certain embodiments, an ActRIIB antagonist, or combination of antagonists, that inhibits GDF8 may further inhibit one or more of: activin (e.g., activin A, activin B, activin AB, activin C, activin AC, activin BC, activin E, activin AE, and/or activin BE), GDF11, GDF3, BMP6, BMP10, ActRIIB, ALK4, ALK5, and ALK7.

[0014] In certain aspects, an ActRIIB antagonist, or combination of antagonists, to be used in accordance with methods and uses described herein is an agent that inhibits at least GDF3 (e.g., a GDF3 antagonist). Effects on GDF3 inhibition may be determined, for example, using a cell-based assay including those described herein (e.g., a Smad signaling reporter assay). Therefore, in some embodiments, an ActRIIB antagonist, or combination of antagonists, of the disclosure may bind to at least GDF3. Ligand binding activity may be determined, for example, using a binding affinity assay including those described herein. In some embodiments, an ActRIIB antagonist, or combination of antagonists, of the disclosure binds to at least GDF3 with a K.sub.D of at least 1.times.10.sup.-7 M (e.g., at least 1.times.10.sup.-8 M, at least 1.times.10.sup.-9 M, at least 1.times.10.sup.-10 M, at least 1.times.10.sup.11 M, or at least 1.times.10.sup.-12M). As described herein, various ActRIIB antagonists that inhibit GDF3 can be used in accordance with the methods and uses described herein including, for example, ligand traps (e.g., ActRIIB polypeptides, GDF Traps, follistatin polypeptides, and FLRG polypeptides), antibodies, small molecules, nucleotide sequences, and combinations thereof. In certain embodiments, an ActRIIB antagonist, or combination of antagonists, that inhibits GDF3 may further inhibit one or more of: activin (e.g., activin A, activin B, activin AB, activin C, activin AC, activin BC, activin E, activin AE, and/or activin BE), GDF8, GDF11, BMP6, BMP10, ActRIIB, ALK4, ALK5, and ALK7.

[0015] In certain aspects, an ActRIIB antagonist, or combination of antagonists, to be used in accordance with methods and uses described herein is an agent that inhibits at least BMP6 (e.g., a BMP6 antagonist). Effects on BMP6 inhibition may be determined, for example, using a cell-based assay including those described herein (e.g., a Smad signaling reporter assay). Therefore, in some embodiments, an ActRIIB antagonist, or combination of antagonists, of the disclosure may bind to at least BMP6. Ligand binding activity may be determined, for example, using a binding affinity assay including those described herein. In some embodiments, an ActRIIB antagonist, or combination of antagonists, of the disclosure binds to at least BMP6 with a K.sub.D of at least 1.times.10.sup.-7M (e.g., at least 1.times.10.sup.-8M, at least 1.times.10.sup.-9M, at least 1.times.10.sup.-10 M, at least 1.times.10-.sup.11 M, or at least 1.times.10.sup.-12M). As described herein, various ActRIIB antagonists that inhibit BMP6 can be used in accordance with the methods and uses described herein including, for example, ligand traps (e.g., ActRIIB polypeptides, GDF Traps, follistatin polypeptides, and FLRG polypeptides), antibodies, small molecules, nucleotide sequences, and combinations thereof. In certain embodiments, an ActRIIB antagonist, or combination of antagonists, that inhibits BMP6 may further inhibit one or more of: activin (e.g., activin A, activin B, activin AB, activin C, activin AC, activin BC, activin E, activin AE, and/or activin BE), GDF8, GDF3, GDF11, BMP10, ActRIIB, ALK4, ALK5, and ALK7.

[0016] In certain aspects, an ActRIIB antagonist, or combination of antagonists, to be used in accordance with methods and uses described herein is an agent that inhibits at least BMP10 (e.g., a BMP10 antagonist). Effects on BMP10 inhibition may be determined, for example, using a cell-based assay including those described herein (e.g., a Smad signaling reporter assay). Therefore, in some embodiments, an ActRIIB antagonist, or combination of antagonists, of the disclosure may bind to at least BMP10. Ligand binding activity may be determined, for example, using a binding affinity assay including those described herein. In some embodiments, an ActRIIB antagonist, or combination of antagonists, of the disclosure binds to at least BMP10 with a K.sub.D of at least 1.times.10.sup.-7 M (e.g., at least 1.times.10.sup.-8 M, at least 1.times.10.sup.-9 M, at least 1.times.10.sup.-10 M, at least 1.times.10.sup.-11 M, or at least 1.times.10.sup.-12 M). As described herein, various ActRIIB antagonists that inhibit BMP10 can be used in accordance with the methods and uses described herein including, for example, ligand traps (e.g., ActRIIB polypeptides, GDF Traps, follistatin polypeptides, and FLRG polypeptides), antibodies, small molecules, nucleotide sequences, and combinations thereof. In certain embodiments, an ActRIIB antagonist, or combination of antagonists, that inhibits BMP10 may further inhibit one or more of: activin (e.g., activin A, activin B, activin AB, activin C, activin AC, activin BC, activin E, activin AE, and/or activin BE), GDF8, GDF3, GDF11, BMP6, ActRIIB, ALK4, ALK5, and ALK7.

[0017] In certain aspects, an ActRIIB antagonist, or combination of antagonists, to be used in accordance with methods and uses described herein is an agent that inhibits at least activin (e.g., activin A, activin B, activin AB, activin C, activin AC, activin BC, activin E, activin AE, and/or activin BE) (e.g., an activin antagonist). Effects on activin inhibition may be determined, for example, using a cell-based assay including those described herein (e.g., a Smad signaling reporter assay). Therefore, in some embodiments, an ActRIIB antagonist, or combination of antagonists, of the disclosure may bind to at least activin. Ligand binding activity may be determined, for example, using a binding affinity assay including those described herein. In some embodiments, an ActRIIB antagonist, or combination of antagonists, of the disclosure binds to at least activin with a K.sub.D of at least 1.times.10.sup.-7 M (e.g., at least 1.times.10.sup.-8M, at least 1.times.10.sup.-9 M, at least 1.times.10.sup.-10 M, at least 1.times.10.sup.-11M, or at least 1.times.10.sup.-12 M). As described herein, various ActRIIB antagonists that inhibit activin can be used in accordance with the methods and uses described herein including, for example, ligand traps (e.g., ActRIIB polypeptides, GDF Traps, follistatin polypeptides, and FLRG polypeptides), antibodies, small molecules, nucleotide sequences, and combinations thereof. In certain embodiments, an ActRIIB antagonist, or combination of antagonists, that inhibits activin may further inhibit one or more of: GDF8, GDF3, GDF11, BMP6, BMP10, ActRIIB, ALK4, ALK5, and ALK7. In certain preferred embodiments, an ActRIIB antagonist, or combination of antagonists, to be used in accordance with methods and uses described herein is an agent that inhibits at least activin B. In some embodiments, an ActRIIB antagonist, or combination of antagonists, to be used in accordance with methods and uses described herein does not substantially bind to activin A (e.g., binds to activin A with a K.sub.D higher than 1.times.10.sup.-7M or has relatively modest binding, e.g., about 1.times.10.sup.-8 M or about 1.times.10.sup.-9M) and/or inhibit activin A activity. In certain preferred embodiments, an ActRIIB antagonist, or combination of antagonists, to be used in accordance with methods and uses described herein is an agent that inhibits at least activin B but does not substantially bind to activin A (e.g., binds to activin A with a K.sub.D higher than 1.times.10.sup.-7M or has relatively modest binding, e.g., about 1.times.10.sup.-8M or about 1.times.10.sup.-9M) and/or inhibit activin A activity.

[0018] In certain aspects, an ActRIIB antagonist, or combination of antagonists, to be used in accordance with methods and uses described herein is an agent that inhibits at least ActRIIB (e.g., an ActRIIB antagonist). Effects on ActRIIB inhibition may be determined, for example, using a cell-based assay including those described herein (e.g., a Smad signaling reporter assay). Therefore, in some embodiments, an ActRIIB antagonist, or combination of antagonists, of the disclosure may bind to at least ActRIIB Ligand binding activity may be determined, for example, using a binding affinity assay including those described herein. In some embodiments, an ActRIIB antagonist, or combination of antagonists, of the disclosure binds to at least ActRIIB with a K.sub.D of at least 1.times.10.sup.-7M (e.g., at least 1.times.10.sup.-8 M, at least 1.times.10.sup.-9M, at least 1.times.10.sup.-10 M, at least 1.times.10.sup.-11M, or at least 1.times.10.sup.12M). As described herein, various ActRIIB antagonists that inhibit ActRIIB can be used in accordance with the methods and uses described herein including, for example, ligand traps (e.g., ActRIIB polypeptides, GDF Traps, follistatin polypeptides, and FLRG polypeptides), antibodies, small molecules, nucleotide sequences, and combinations thereof. In certain embodiments, an ActRIIB antagonist, or combination of antagonists, that inhibits ActRIIB may further inhibit one or more of: activin (e.g., activin A, activin B, activin AB, activin C, activin AC, activin BC, activin E, activin AE, and/or activin BE), GDF8, GDF3, GDF11, BMP6, BMP10, ALK4, ALK5, and ALK7.

[0019] In certain aspects, an ActRIIB antagonist, or combination of antagonists, to be used in accordance with methods and uses described herein is an agent that inhibits at least ALK4 (e.g., an ALK4 antagonist). Effects on ALK4 inhibition may be determined, for example, using a cell-based assay including those described herein (e.g., a Smad signaling reporter assay). Therefore, in some embodiments, an ActRIIB antagonist, or combination of antagonists, of the disclosure may bind to at least ALK4. Ligand binding activity may be determined, for example, using a binding affinity assay including those described herein. In some embodiments, an ActRIIB antagonist, or combination of antagonists, of the disclosure binds to at least ALK4 with a K.sub.D of at least 1.times.10.sup.-7M (e.g., at least 1.times.10.sup.-8M, at least 1.times.10.sup.-9M, at least 1.times.10.sup.-10 M, at least 1.times.10.sup.-11M, or at least 1.times.10.sup.-12M). As described herein, various ActRIIB antagonists that inhibit ALK4 can be used in accordance with the methods and uses described herein including, for example, ligand traps (e.g., ActRIIB polypeptides, GDF Traps, follistatin polypeptides, and FLRG polypeptides), antibodies, small molecules, nucleotide sequences, and combinations thereof. In certain embodiments, an ActRIIB antagonist, or combination of antagonists, that inhibits ALK4 may further inhibit one or more of: activin (e.g., activin A, activin B, activin AB, activin C, activin AC, activin BC, activin E, activin AE, and/or activin BE), GDF8, GDF3, GDF11, BMP6, BMP10, ActRIIB, ALK5, and ALK7.

[0020] In certain aspects, an ActRIIB antagonist, or combination of antagonists, to be used in accordance with methods and uses described herein is an agent that inhibits at least ALK5 (e.g., an ALK5 antagonist). Effects on ALK5 inhibition may be determined, for example, using a cell-based assay including those described herein (e.g., a Smad signaling reporter assay). Therefore, in some embodiments, an ActRIIB antagonists, or combination of antagonist, of the disclosure may bind to at least ALK5. Ligand binding activity may be determined, for example, using a binding affinity assay including those described herein. In some embodiments, an ActRIIB antagonist, or combination of antagonists, of the disclosure binds to at least ALK5 with a K.sub.D of at least 1.times.10.sup.-7M (e.g., at least 1.times.10.sup.-8M, at least 1.times.10.sup.-9M, at least 1.times.10.sup.-10 M, at least 1.times.10.sup.-11M, or at least 1.times.10.sup.-12M). As described herein, various ActRIIB antagonists that inhibit ALK5 can be used in accordance with the methods and uses described herein including, for example, ligand traps (e.g., ActRIIB polypeptides, GDF Traps, follistatin polypeptides, and FLRG polypeptides), antibodies, small molecules, nucleotide sequences, and combinations thereof. In certain embodiments, an ActRIIB antagonist, or combination of antagonists, that inhibits ALK5 may further inhibit one or more of: activin (e.g., activin A, activin B, activin AB, activin C, activin AC, activin BC, activin E, activin AE, and/or activin BE), GDF8, GDF3, GDF11, BMP6, BMP10, ActRIIB, ALK4, and ALK7.

[0021] In certain aspects, an ActRIIB antagonist, or combination of antagonists, to be used in accordance with methods and uses described herein is an agent that inhibits at least ALK7 (e.g., an ALK7 antagonist). Effects on ALK7 inhibition may be determined, for example, using a cell-based assay including those described herein (e.g., a Smad signaling reporter assay). Therefore, in some embodiments, an ActRIIB antagonist, or combination of antagonists, of the disclosure may bind to at least ALK7. Ligand binding activity may be determined, for example, using a binding affinity assay including those described herein. In some embodiments, an ActRIIB antagonist, or combination of antagonists, of the disclosure binds to at least ALK7 with a K.sub.D of at least 1.times.10.sup.-7M (e.g., at least 1.times.10.sup.-8M, at least 1.times.10.sup.-9M, at least 1.times.10.sup.-10 M, at least 1.times.10.sup.-11M, or at least 1.times.10.sup.-12M). As described herein, various ActRIIB antagonists that inhibit ALK7 can be used in accordance with the methods and uses described herein including, for example, ligand traps (e.g., ActRIIB polypeptides, GDF Traps, follistatin polypeptides, and FLRG polypeptides), antibodies, small molecules, nucleotide sequences, and combinations thereof. In certain embodiments, an ActRIIB antagonist, or combination of antagonists, that inhibits ALK7 may further inhibit one or more of: activin (e.g., activin A, activin B, activin AB, activin C, activin AC, activin BC, activin E, activin AE, and/or activin BE), GDF8, GDF3, GDF11, BMP6, BMP10, ActRIIB, ALK5, and ALK4.

[0022] In part, the disclosure relates to ActRIIB antagonists that are ActRIIB polypeptides. The term "ActRIIB polypeptide" collectively refers to naturally occurring ActRIIB polypeptides as well as truncations and variants thereof such as those described herein (e.g., GDF trap polypeptides). Preferably ActRIIB polypeptides comprise, consist essentially of, or consist of a ligand-binding domain of an ActRIIB polypeptide or modified (variant) form thereof. For example, in some embodiments, an ActRIIB polypeptide comprises, consists essentially of, or consists of an ActRIIB ligand-binding domain of an ActRIIB polypeptide, for example, a portion of the ActRIIB extracellular domain. Preferably, ActRIIB polypeptides to be used in accordance with the methods described herein are soluble polypeptides.

[0023] In certain aspects, the disclosure relates compositions comprising an ActRIIB polypeptide and uses thereof. For example, in some embodiments, an ActRIIB polypeptide of the disclosure comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the sequence of amino acids 29-109 of SEQ ID NO: 1. In some embodiments, an ActRIIB polypeptide may comprise an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the sequence of amino acids 29-109 of SEQ ID NO: 1, wherein the ActRIIB polypeptide comprises an acidic amino acid [naturally occurring (E or D) or artificial acidic amino acid] at position 79 with respect to SEQ ID NO: 1. In other embodiments, an ActRIIB polypeptide may comprise an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the sequence of amino acids 25-131 of SEQ ID NO: 1. In some embodiments, an ActRIIB polypeptide may comprise an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the sequence of amino acids 25-131 of SEQ ID NO: 1, wherein the ActRIIB polypeptide comprises an acidic amino acid at position 79 with respect to SEQ ID NO: 1. In other embodiments, an ActRIIB polypeptide may comprise an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 1. In some embodiments, an ActRIIB polypeptide may comprise an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 1, wherein the ActRIIB polypeptide comprises an acidic amino acid at position 79 with respect to SEQ ID NO: 1. In even other embodiments, an ActRIIB polypeptide may comprise an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 2. In other embodiments, an ActRIIB polypeptide may comprise an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 2, wherein the ActRIIB polypeptide comprises an acidic amino acid at position 79 with respect to SEQ ID NO: 1. In still other embodiments, an ActRIIB polypeptide may comprise an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 3. In other, an ActRIIB polypeptide may comprise an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 3, wherein the ActRIIB polypeptide comprises an acidic amino acid at position 79 with respect to SEQ ID NO: 1. In other embodiments, an ActRIIB polypeptide may comprise an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 4. In some embodiments, an ActRIIB polypeptide may comprise an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 4, wherein the ActRIIB polypeptide comprises an acidic amino acid at position 79 with respect to SEQ ID NO: 4. In other embodiments, an ActRIIB polypeptide may comprise an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 5. In some embodiments, an ActRIIB polypeptide may comprise an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 5, wherein the ActRIIB polypeptide comprises an acidic amino acid at position 79 with respect to SEQ ID NO: 4. In other embodiments, an ActRIIB polypeptide may comprise an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 6. In some embodiments, an ActRIIB polypeptide may comprise an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 6, wherein the ActRIIB polypeptide comprises an acidic amino acid at position 79 with respect to SEQ ID NO: 4. In still even other embodiments, an ActRIIB polypeptide may comprise an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 24. In still even other embodiments, an ActRIIB polypeptide may comprise an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 25. In still even other embodiments, an ActRIIB polypeptide may comprise an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 28. In still even other embodiments, an ActRIIB polypeptide may comprise an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 29. In some embodiments, an ActRIIB polypeptide may comprise an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 29, wherein the ActRIIB polypeptide comprises an acidic amino acid at position 79 with respect to SEQ ID NO: 1. In still even other embodiments, an ActRIIB polypeptide may comprise an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 30. In some embodiments, an ActRIIB polypeptide may comprise an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 30, wherein the ActRIIB polypeptide comprises an acidic amino acid at position 79 with respect to SEQ ID NO: 1. In still even other embodiments, an ActRIIB polypeptide may comprise an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 31. In some embodiments, an ActRIIB polypeptide may comprise an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 31, wherein the ActRIIB polypeptide comprises an acidic amino acid at position 79 with respect to SEQ ID NO: 1. In still even other embodiments, an ActRIIB polypeptide may comprise an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 45. In some embodiments, an ActRIIB polypeptide may comprise an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 45, wherein the ActRIIB polypeptide comprises an acidic amino acid at position 79 with respect to SEQ ID NO: 1. In still even other embodiments, an ActRIIB polypeptide may comprise an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 50. In some embodiments, an ActRIIB polypeptide may comprise an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 50, wherein the ActRIIB polypeptide comprises an acidic amino acid at position 79 with respect to SEQ ID NO: 1. In still even other embodiments, an ActRIIB polypeptide may comprise an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 53. In some embodiments, an ActRIIB polypeptide may comprise an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 53, wherein the ActRIIB polypeptide comprises an acidic amino acid at position 79 with respect to SEQ ID NO: 1. In still even other embodiments, an ActRIIB polypeptide may comprise an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 54. In some embodiments, an ActRIIB polypeptide may comprise an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 54, wherein the ActRIIB polypeptide comprises an acidic amino acid at position 79 with respect to SEQ ID NO: 1. In still even other embodiments, an ActRIIB polypeptide may comprise an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 58. In certain embodiments, ActRIIB polypeptides to be used in accordance with the methods and uses described herein do not comprise an acidic amino acid at the position corresponding to L79 of SEQ ID NO: 1.

[0024] As described herein, ActRIIB polypeptides and variants thereof (GDF traps) may be homomultimers, for example, homodimer, homotrimers, homotetramers, homopentamers, and higher order homomultimer complexes. In certain preferred embodiments, ActRIIB polypeptides and variants thereof are homodimers. In certain embodiments, ActRII polypeptide dimers described herein comprise an first ActRIIB polypeptide covalently, or non-covalently, associated with an second ActRIIB polypeptide wherein the first polypeptide comprises an ActRIIB domain and an amino acid sequence of a first member (or second member) of an interaction pair (e.g., a constant domain of an immunoglobulin) and the second polypeptide comprises an ActRIIB polypeptide and an amino acid sequence of a second member (or first member) of the interaction pair.

[0025] In certain aspects, ActRIIB polypeptides, including variants thereof (e.g., GDF traps), may be fusion proteins. For example, in some embodiments, an ActRIIB polypeptide may be a fusion protein comprising an ActRIIB polypeptide domain and one or more heterologous (non-ActRIIB) polypeptide domains. In some embodiments, an ActRIIB polypeptide may be a fusion protein that has, as one domain, an amino acid sequence derived from an ActRIIB polypeptide (e.g., a ligand-binding domain of an ActRIIB receptor or a variant thereof) and one or more heterologous domains that provide a desirable property, such as improved pharmacokinetics, easier purification, targeting to particular tissues, etc. For example, a domain of a fusion protein may enhance one or more of in vivo stability, in vivo half-life, uptake/administration, tissue localization or distribution, formation of protein complexes, multimerization of the fusion protein, and/or purification. Optionally, an ActRIIB polypeptide domain of a fusion protein is connected directly (fused) to one or more heterologous polypeptide domains, or an intervening sequence, such as a linker, may be positioned between the amino acid sequence of the ActRIIB polypeptide and the amino acid sequence of the one or more heterologous domains. In certain embodiments, an ActRIIB fusion protein comprises a relatively unstructured linker positioned between the heterologous domain and the ActRIIB domain. This unstructured linker may correspond to the roughly 15 amino acid unstructured region at the C-terminal end of the extracellular domain of ActRIIB (the "tail"), or it may be an artificial sequence of between 3 and 15, 20, 30, 50 or more amino acids that are relatively free of secondary structure. A linker may be rich in glycine and proline residues and may, for example, contain repeating sequences of threonine/serine and glycines. Examples of linkers include, but are not limited to, the sequences TGGG (SEQ ID NO: 18), SGGG (SEQ ID NO: 19), TGGGG (SEQ ID NO: 16), SGGGG (SEQ ID NO: 17), GGGGS (SEQ ID NO: 20), GGGG (SEQ ID NO: 15), and GGG (SEQ ID NO: 14). In some embodiments, ActRIIB fusion proteins may comprise a constant domain of an immunoglobulin, including, for example, the Fc portion of an immunoglobulin. For example, an amino acid sequence that is derived from an Fc domain of an IgG (IgG1, IgG2, IgG3, or IgG4), IgA (IgA1 or IgA2), IgE, or IgM immunoglobulin. For example, am Fc portion of an immunoglobulin domain may comprise, consist essentially of, or consist of an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to any one of SEQ ID NOs: 9-13. Such immunoglobulin domains may comprise one or more amino acid modifications (e.g., deletions, additions, and/or substitutions) that confer an altered Fc activity, e.g., decrease of one or more Fc effector functions. In some embodiment, an ActRIIB fusion protein comprises an amino acid sequence as set forth in the formula A-B-C. For example, the B portion is an N- and C-terminally truncated ActRIIB polypeptide as described herein. The A and C portions may be independently zero, one, or more than one amino acids, and both A and C portions are heterologous to B. The A and/or C portions may be attached to the B portion via a linker sequence. In certain embodiments, an ActRIIB fusion protein comprises a leader sequence. The leader sequence may be a native ActRIIB leader sequence or a heterologous leader sequence. In certain embodiments, the leader sequence is a tissue plasminogen activator (TPA) leader sequence.

[0026] An ActRIIB polypeptide, including variants thereof (e.g., GDF traps), may comprise a purification subsequence, such as an epitope tag, a FLAG tag, a polyhistidine sequence, and a GST fusion. Optionally, an ActRIIB polypeptide 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, and/or an amino acid conjugated to a lipid moiety. ActRIIB polypeptides may comprise at least one N-linked sugar, and may include two, three or more N-linked sugars. Such polypeptides may also comprise O-linked sugars. In general, it is preferable that ActRIIB polypeptides be expressed in a mammalian cell line that mediates suitably natural glycosylation of the polypeptide so as to diminish the likelihood of an unfavorable immune response in a patient. ActRIIB polypeptides may be produced in a variety of cell lines that glycosylate the protein in a manner that is suitable for patient use, including engineered insect or yeast cells, and mammalian cells such as COS cells, CHO cells, HEK cells and NSO cells. In some embodiments, an ActRIIB polypeptide is glycosylated and has a glycosylation pattern obtainable from a Chinese hamster ovary cell line. In some embodiments, ActRIIB polypeptides of the disclosure exhibit a serum half-life of at least 4, 6, 12, 24, 36, 48, or 72 hours in a mammal (e.g., a mouse or a human). Optionally, ActRIIB may exhibit a serum half-life of at least 6, 8, 10, 12, 14, 20, 25, or 30 days in a mammal (e.g., a mouse or a human).

[0027] In certain aspects, the disclosure provides pharmaceutical preparations comprising one or more ActRIIB antagonists of the present disclosure and a pharmaceutically acceptable carrier. A pharmaceutical preparation may also comprise one or more additional active agents such as a compound that is used to treat myelofibrosis, particularly treating or preventing one or more complications of myelofibrosis (e.g., splenomegaly, extramedullary hematopoiesis, anemia, and fibrosis), and/or a patient treated with a Janus kinase inhibitor. In general pharmaceutical preparation will preferably be pyrogen-free (meaning pyrogen free to the extent required by regulations governing the quality of products for therapeutic use).

[0028] In certain instances, when administering an ActRIIB antagonist, or combination of antagonists, of the disclosure to disorders or conditions described herein, it may be desirable to monitor the effects on red blood cells during administration of the ActRIIB antagonist, or to determine or adjust the dosing of the ActRIIB antagonist, in order to reduce undesired effects on red blood cells. For example, increases in red blood cell levels, hemoglobin levels, or hematocrit levels may cause undesirable increases in blood pressure.

[0029] In certain aspects, the ActRIIB antagonist is an antibody, or combination of antibodies. In some embodiments, the antibody binds to at least ActRIIB In certain embodiments an antibody that binds to ActRIIB inhibits ActRIIB signaling, optionally as measured in a cell-based assay such as those described herein. In certain embodiments, an antibody that binds to ActRIIB inhibits one or more TGF-beta superfamily ligands, TGF-beta superfamily type I receptors, or TGF-beta superfamily co-receptors from binding to ActRIIB In certain embodiments an antibody that binds to ActRIIB inhibits one or more TGF-beta superfamily ligands from binding to ActRIIB selected from the group consisting of: activin (e.g., activin A, activin B, activin C, activin AB, activin AC, activin BC, activin E, activin AE, and activin BE), GDF8, GDF11, GDF3, BMP6, BMP10, BMP9, and BMP5. In some embodiments, an antibody binds to at least GDF11. In certain embodiments, an antibody that binds to GDF11 inhibits ActRIIB signaling, optionally as measured in a cell-based assay such as those described herein. In certain embodiments, an antibody that binds to GDF11 inhibits GDF11-ActRIIB binding. In some embodiments, an antibody binds to at least GDF8. In certain embodiments, an antibody that binds to GDF8 inhibits ActRIIB signaling, optionally as measured in a cell-based assay such as those described herein. In certain embodiments, an antibody that binds to GDF8 inhibits GDF8-ActRIIB binding. In some embodiments, an antibody binds to at least BMP6. In certain embodiments, an antibody that binds to BMP6 inhibits ActRIIB signaling, optionally as measured in a cell-based assay such as those described herein. In certain embodiments, an antibody that binds to BMP6 inhibits BMP6-ActRIIB binding. In some embodiments, an antibody binds to BMP10. In certain embodiments, an antibody that binds to at least BMP10 inhibits ActRIIB signaling, optionally as measured in a cell-based assay such as those described herein. In certain embodiments, an antibody that binds to BMP10 inhibits BMP10-ActRIIB binding. In some embodiments, the antibody binds to at least GDF3. In certain embodiments, an antibody that binds to GDF3 inhibits ActRIIB signaling, optionally as measured in a cell-based assay such as those described herein. In certain embodiments, an antibody that binds to GDF3 inhibits GDF3-ActRIIB binding. In some embodiments, the antibody binds to at least activin (e.g. activin A, activin B, activin C, activin AB, activin AC, activin BC, activin E, activin AE, and activin BE). In certain embodiments, an antibody that binds to activin (e.g. activin A, activin B, activin C, activin AB, activin AC, activin BC, activin E, activin AE, and activin BE) inhibits ActRIIB signaling, optionally as measured in a cell-based assay such as those described herein. In certain embodiments, an antibody that binds to activin (e.g. activin A, activin B, activin C, activin AB, activin AC, activin BC, activin E, activin AE, and activin BE) inhibits activin-ActRIIB binding. In some embodiments, the antibody binds to activin B. In certain embodiments, an antibody that binds to activin B inhibits ActRIIB signaling, optionally as measured in a cell-based assay such as those described herein. In certain embodiments, an antibody that binds to activin B inhibits activin B-ActRIIB binding. In some embodiments, the antibody is a multispecific antibody, or combination of multispecific antibodies that binds to one or more of ActRIIB, GDF11, GDF8, activin A, activin B, BMP6, and BMP10. In some embodiments, an antibody binds to at least ALK4. In certain embodiments, an antibody that binds to ALK4 inhibits ALK4 signaling, optionally as measured in a cell-based assay such as those described herein. In certain embodiments, an antibody that binds to ALK4 inhibits one or more ActRIIB ligands, type II receptors, or co-receptors from binding to ALK4. In certain embodiments an antibody that binds to ALK4 inhibits one or more ActRIIB ligands from binding to ALK4 selected from the group consisting of: activin (e.g., activin A, activin B, activin C, activin AB, activin AC, activin BC, activin E, activin AE, and activin BE), GDF8, GDF11, BMP6, BMP10, and GDF3. In some embodiments, the antibody binds to at least ALK5. In certain embodiments, an antibody that binds to ALK5 inhibits ALK5 signaling, optionally as measured in a cell-based assay such as those described herein. In certain embodiments, an antibody that binds to ALK5 inhibits one or more ActRIIB ligands, type II receptors, or co-receptors from binding to ALK5. In certain embodiments an antibody that binds to ALK5 inhibits one or more ActRIIB ligands from binding to ALK5 selected from the group consisting of: activin (e.g., activin A, activin B, activin C, activin AB, activin AC, activin BC, activin E, activin AE, and activin BE), GDF8, GDF11, BMP6, BMP10, and GDF3. In some embodiments, the antibody binds to at least ALK7. In certain embodiments, an antibody that binds to ALK7 inhibits ALK7 signaling, optionally as measured in a cell-based assay such as those described herein. In certain embodiments, an antibody that binds to ALK7 inhibits one or more ActRIIB ligands, type II receptors, or co-receptors from binding to ALK7. In certain embodiments an antibody that binds to ALK7 inhibits one or more ActRIIB ligands from binding to ALK7 selected from the group consisting of: activin (e.g., activin A, activin B, activin C, activin AB, activin AC, activin BC, activin E, activin AE, and activin BE), GDF8, GDF11, BMP6, BMP10, and GDF3. In some embodiments, the antibody binds to at least GDF11. In certain aspects the multispecific antibody, or a combination of multispecific antibodies, inhibits signaling in a cell-based assay of one or more of: ActRIIB, GDF11, GDF8, activin A, activin B, GDF3, BMP6, and BMP10. In some embodiments, antibody is a chimeric antibody, a humanized antibody, or a human antibody. In some embodiments, the antibody is a single-chain antibody, an F(ab').sub.2 fragment, a single-chain diabody, a tandem single-chain Fv fragment, a tandem single-chain diabody, a or a fusion protein comprising a single-chain diabody and at least a portion of an immunoglobulin heavy-chain constant region.

[0030] In certain aspects, the ActRIIB antagonist is a small molecule inhibitor or combination of small molecule inhibitors. In some embodiments, the small molecule inhibitor is an inhibitor of at least ActRIIB In some embodiments, the small molecule inhibitor is an inhibitor of at least ALK4. In some embodiments, the small molecule inhibitor is an inhibitor of at least ALK5. In some embodiments, the small molecule inhibitor is an inhibitor of at least ALK7. In some embodiments, the small molecule inhibitor is an inhibitor of at least GDF11. In some embodiments, the small molecule inhibitor is an inhibitor of at least GDF8. In some embodiments, the small molecule inhibitor is an inhibitor of at least BMP6. In some embodiments, the small molecule inhibitor is an inhibitor of at least BMP10. In some embodiments, the small molecule inhibitor is an inhibitor of at least GDF3. In some embodiments, the small molecule inhibitor is an inhibitor of at least activin (e.g. activin A, activin B, activin C, activin AB, activin AC, activin BC, activin E, activin AE, and activin BE). In some embodiments, the small molecule inhibitor is an inhibitor of at least activin B.

[0031] In certain aspects, the ActRIIB antagonist is a nucleic acid inhibitor or combination of nucleic acid inhibitors. In some embodiments, the nucleic acid inhibitor is an inhibitor of at least ActRIIB In some embodiments, the nucleic acid inhibitor is an inhibitor of at least ALK4. In some embodiments, the nucleic acid inhibitor is an inhibitor of at least ALK5. In some embodiments, the nucleic acid inhibitor is an inhibitor of at least ALK7. In some embodiments, the nucleic acid inhibitor is an inhibitor of at least GDF11. In some embodiments, the nucleic acid inhibitor is an inhibitor of at least GDF8. In some embodiments, the nucleic acid inhibitor is an inhibitor of at least BMP6. In some embodiments, the nucleic acid inhibitor is an inhibitor of at least BMP10. In some embodiments, the nucleic acid inhibitor is an inhibitor of at least GDF3. In some embodiments, the nucleic acid inhibitor is an inhibitor of at least activin (e.g. activin A, activin B, activin C, activin AB, activin AC, activin BC, activin E, activin AE, and activin BE). In some embodiments, the nucleic acid inhibitor is an inhibitor of at least activin B.

[0032] In certain aspects, the ActRIIB antagonist is a follistatin polypeptide. In some embodiments, the follistatin polypeptide comprises an amino acid sequence that is at least 70%, 75% 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 63. In some embodiments, the follistatin polypeptide comprises an amino acid sequence that is at least 70%, 75% 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 64. In some embodiments, the follistatin polypeptide comprises an amino acid sequence that is at least 70%, 75% 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 65. In some embodiments, the follistatin polypeptide comprises an amino acid sequence that is at least 70%, 75% 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 66. In some embodiments, the follistatin polypeptide comprises an amino acid sequence that is at least 70%, 75% 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 67.

[0033] In certain aspects, the ActRIIB antagonist is a FLRG polypeptide. In some embodiments, the FLRG polypeptide comprises an amino acid sequence that is at least 70%, 75% 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 68.


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