Activin-ACTRII antagonists and uses thereof for treating anemia

Abstract

The present invention provides a method for treating anemia in a subject, anemia requiring RBC transfusion, low-risk or intermediate-risk-1 myelodysplastic syndrome (MDS) and / or non-proliferative chronic myelomonocytic leukemia (CMML) in any mammal, wherein the method comprises administering an activin-ActRII signaling inhibitor to a subject in need of treatment.

Description

[0001] 1. Related Applications

[0002] This application is a divisional application of the Chinese patent application for invention titled "Activin - ActRII Antagonists and Use Thereof in the Treatment of Anemia", with application number 201580075198.2, filed on December 3, 2015.

[0003] This application claims the benefit of the priority of U.S. Provisional Patent Application No. 62 / 086,977, filed on December 3, 2014. This application also claims the benefit of the priority of U.S. Provisional Patent Application No. 62 / 088,478, filed on December 5, 2014; U.S. Provisional Patent Application No. 62 / 153,872, filed on April 28, 2015; U.S. Provisional Patent Application No. 62 / 173,782, filed on June 10, 2015; and U.S. Provisional Patent Application No. 62 / 218,728, filed on September 15, 2015; the entire disclosure of each of which is incorporated herein by reference in its entirety and for all purposes.

[0004] 2. Sequence Listing

[0005] This application is filed together with a computer - readable form (CRF) copy of the sequence listing, the file name of which is "12827_978_228_Sequence_Listing.txt", created on November 19, 2015, with a size of 93,638 bytes, which is identical to the paper copy of the sequence listing, and is incorporated herein by reference in its entirety and for all purposes.

[0006] 3. Field

[0007] Provided herein are methods for the long - term treatment of a subject with (i) anemia; (ii) anemia requiring RBC transfusion; (iii) myelodysplastic syndrome (MDS); and / or (iv) non - proliferative chronic myelomonocytic leukemia (CMML), wherein the method comprises administering an Activin - ActRII signaling inhibitor to a subject in need of long - term treatment. Such an Activin - ActRII signaling inhibitor can be a signal transduction inhibitor of ActRIIA and / or ActRIIB signal transduction. Provided herein are methods for the long - term treatment of a subject with (i) anemia; (ii) anemia requiring red blood cell (RBC) transfusion; (iii) MDS; and / or (iv) non - proliferative CMML, wherein the subject has ring sideroblasts. Background

[0008] Anemia is a decrease in the number of red blood cells in the blood or a hemoglobin level lower than the normal amount. Anemia can also be caused by a reduced oxygen-carrying capacity of hemoglobin. Anemia is the most common blood disorder. Anemia can be caused by ineffective erythropoiesis. Ineffective erythropoiesis exists if active erythropoiesis can occur but mature red blood cells fail to develop at an appropriate rate. The progenitor cells undergo apoptosis before reaching the stage of mature red blood cells. MDS encompasses hematopoietic stem cell disorders characterized by ineffective hematopoiesis. In addition, MDS disorders include those characterized by ring sideroblasts. Ring sideroblasts are abnormal erythroblasts. Moreover, certain somatic mutations associated with MDS cause the formation of ring sideroblasts and ineffective erythropoiesis. Dominant mutations in splicing factor 3B1 (SF3B1) are associated with the formation of ring sideroblasts. Ring sideroblasts are a type of erythroblast in which at least five iron-containing (siderotic) granules cover at least one-third of the nuclear circumference. See, for example, Mufti et al., 2008, Haematologica, 93(11):1712-7. Ring sideroblasts contain iron-loaded mitochondria. The presence of ring sideroblasts can be detected by Prussian blue staining and visual inspection. Ring sideroblasts can be detected in peripheral blood and / or bone marrow smears.

[0009] Two related type II receptors, ActRIIA and ActRIIB, have been identified as type II receptors for activin (Mathews and Vale, 1991, Cell 65:973-982; Attisano et al., 1992, Cell 68:97-108). In addition to activin, ActRIIA and ActRIIB can also interact biochemically with several other TGF-β family proteins, including BMP7, Nodal, GDF8, and GDF11 (Yamashita et al., 1995, J. Cell Biol. 130:217-226; Lee and McPherron, 2001, Proc. Natl. Acad. Sci. 98:9306-9311; Yeo and Whitman, 2001, Mol. Cell 7:949-957; Oh et al., 2002, Genes Dev. 16:2749-54). ALK4 is the major type I receptor for activin, particularly activin A, and ALK-7 can also serve as a receptor for activin, particularly activin B.

[0010] A humanized fusion protein consisting of the extracellular domain (ECD) of activin-receptor type IIA (ActRIIA) and the human IgG1 Fc domain binds to activin-A with high affinity, thereby blocking signal transduction through endogenous ActRIIA-receptors. Activin-A is an erythroid-differentiation factor that affects the late stage of RBC-maturation (Murata M, Onomichi K, Eto Y, Shibai H and Muramatsu M. Expression of erythroid differentiation factor in Chinese hamster ovary cells. Biochem Biophys Res Commun 1988;151:230-5). ActRII signal transduction inhibitors for increasing RBC levels have been described (for example, patent application publication numbers 20110038831, 20100204092, 20100068215, 20100028332, 20100028331 and 20090163417).

[0011] 5. Overview

[0012] Provided herein are methods for treating blood-related disorders in a subject, comprising (a) determining the percentage of erythroblasts that are ring sideroblasts in the subject; and (b) if at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or 20% of the erythroblasts in the subject are ring sideroblasts, administering to the subject a pharmaceutically effective dose of an ActRII signal transduction inhibitor between 0.1 mg / kg and 2.0 mg / kg. In certain embodiments, the blood-related disorder is anemia, myelodysplastic syndrome (MDS) or non-proliferative chronic myelomonocytic leukemia (CMML). In certain embodiments, the percentage of erythroblasts that are ring sideroblasts in the subject is determined at a first time. In certain embodiments, the first time is within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 3 months, 4 months, 5 months or 6 months of administering the pharmaceutically effective dose of the ActRII signal transduction inhibitor to the subject.

[0013] Provided herein are methods for treating a blood-related disorder in a subject, comprising administering an activin receptor type II (ActRII) signal transduction inhibitor to the subject at a pharmaceutically effective dose for a period of time to effect (i) a long-term decrease in the percentage of erythroblasts that are ring sideroblasts in the subject as compared to an initial percentage of erythroblasts that are ring sideroblasts in the subject; and / or (ii) a long-term increase in the hemoglobin level of the subject as compared to the hemoglobin level of the subject for a period of time prior to administering an initial dose of the ActRII signal transduction inhibitor to the subject; wherein the pharmaceutically effective dose is between 0.1 mg / kg and 2.0 mg / kg, and wherein the initial percentage of erythroblasts that are ring sideroblasts in the subject is at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or at least 20%. In certain embodiments, the blood-related disorder is anemia, MDS or non-proliferative CMML. Provided herein are methods for treating anemia in a subject, comprising administering an activin receptor type II (ActRII) signal transduction inhibitor to the subject at a pharmaceutically effective dose for a period of time to effect (i) a long-term decrease in the percentage of erythroblasts that are ring sideroblasts in the subject as compared to an initial percentage of erythroblasts that are ring sideroblasts in the subject; and / or (ii) a long-term increase in the hemoglobin level of the subject as compared to the hemoglobin level of the subject for a period of time prior to administering an initial dose of the ActRII signal transduction inhibitor to the subject; wherein the pharmaceutically effective dose is between 0.1 mg / kg and 2.0 mg / kg, and wherein the initial percentage of erythroblasts that are ring sideroblasts in the subject is at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or at least 20%. In certain embodiments, the subject is a subject in need of RBC transfusion. Provided herein are methods for treating MDS in a subject, comprising administering an ActRII signal transduction inhibitor to the subject at a pharmaceutically effective dose for a period of time to effect (i) a long-term decrease in the percentage of erythroblasts that are ring sideroblasts in the subject as compared to an initial percentage of erythroblasts that are ring sideroblasts in the subject; and / or (ii) a long-term increase in the hemoglobin level of the subject as compared to the hemoglobin level of the subject for a period of time prior to administering an initial dose of the ActRII signal transduction inhibitor to the subject; wherein the pharmaceutically effective dose is between 0.1 mg / kg and 2.0 mg / kg, and wherein the initial percentage of erythroblasts that are ring sideroblasts in the subject is at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or at least 20%.Provided herein are methods for treating non-proliferative CMML in a subject, comprising administering an ActRII signal transduction inhibitor to the subject at a pharmaceutically effective dose and for a period of time to effect (i) a long-term decrease in the percentage of erythroblasts that are ring sideroblasts in the subject as compared to an initial percentage of erythroblasts that are ring sideroblasts in the subject; and / or (ii) a long-term increase in the hemoglobin level of the subject as compared to the hemoglobin level of the subject for a period of time prior to administering an initial dose of the ActRII signal transduction inhibitor to the subject; wherein the pharmaceutically effective dose is between 0.1 mg / kg and 2.0 mg / kg, and wherein the initial percentage of erythroblasts that are ring sideroblasts in the subject is at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or at least 20%.

[0014] In certain embodiments, the time period of administration of the ActRII signal transduction inhibitor is 1, 2, 3, 4, 5, or 6 months. In certain embodiments, the initial percentage of erythroblasts that are ring sideroblasts in the subject is the percentage of erythroblasts that are ring sideroblasts in the subject for a time period prior to administration of the initial dose of the ActRII signal transduction inhibitor to the subject. In certain embodiments, a long-term reduction in the percentage of erythroblasts that are ring sideroblasts in the subject is maintained for at least 1, 2, 3, 4, 5, 6, 12, 18, or 24 months after the time period of administration of the ActRII signal transduction inhibitor. In certain embodiments, the long-term reduction in the percentage of erythroblasts that are ring sideroblasts in the subject is at least 1.5, 2.5, 5.0, 7.5, or 10.0-fold lower than the initial percentage of erythroblasts that are ring sideroblasts in the subject for at least 6, 12, 18, or 24 months after the time period of administration of the ActRII signal transduction inhibitor. In certain embodiments, the initial hemoglobin level of the subject is the hemoglobin level of the subject for a time period prior to administration of the initial dose of the ActRII signal transduction inhibitor to the subject. In certain embodiments, the initial hemoglobin level of the subject is less than about 11 g / dL. In certain embodiments, a long-term increase in the hemoglobin level of the subject is maintained for at least 3, 4, 5, 6, 12, 18, or 24 months after the time period of administration of the ActRII signal transduction inhibitor. In certain embodiments, the long-term increase in the hemoglobin level of the subject is such that the hemoglobin level of the subject is between about 11 g / dL and 18 g / dL for at least 3, 4, 5, 6, 12, 18, or 24 months after the time period of administration of the ActRII signal transduction inhibitor. In certain embodiments, the subject does not require red blood cell transfusions for at least 3, 4, 5, 6, 12, 18, or 24 months after the time period of administration of the ActRII signal transduction inhibitor.

[0015] In certain embodiments, the ActRII signal transduction inhibitor is administered once every three weeks. In certain embodiments, the ActRII signal transduction inhibitor is administered (i) once every 28 days; or (ii) once every 42 days. In certain embodiments, the ActRII signal transduction inhibitor is administered by injection. In certain embodiments, the ActRII signal transduction inhibitor is administered subcutaneously.

[0016] In certain embodiments, the method further comprises determining another percentage of erythroblasts that are ring sideroblasts in the subject at 6, 12, 18, and / or 24 months after a time period of administration of the ActRII signal transduction inhibitor. In certain embodiments, the percentage of erythroblasts that are ring sideroblasts in the subject is determined by Prussian blue staining. In certain embodiments, the method further comprises determining another level of hemoglobin in the subject at 6, 12, 18, and / or 24 months after a time period of administration of the ActRII signal transduction inhibitor.

[0017] Also provided herein is a method for treating a blood-related disorder in a subject, the method comprising: (a) determining a first percentage of erythroblasts that are ring sideroblasts in the subject; and (b) (i) if the first percentage of erythroblasts that are ring sideroblasts in the subject is at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or at least 20%, administering an ActRII signal transduction inhibitor to the subject at a pharmaceutically effective dose between 0.1 mg / kg and 2.0 mg / kg for a short time period, or (ii) if the percentage of erythroblasts that are ring sideroblasts in the subject is less than 10%, administering an ActRII signal transduction inhibitor to the subject at a pharmaceutically effective dose between 0.1 mg / kg and 2.0 mg / kg for a long time period. In certain embodiments, the blood-related disorder is anemia, anemia requiring transfusion, MDS or non-proliferative CMML. Also provided herein is a method for treating anemia in a subject, the method comprising: (a) determining a first percentage of erythroblasts that are ring sideroblasts in the subject; and (b) (i) if the first percentage of erythroblasts that are ring sideroblasts in the subject is at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or at least 20%, administering an ActRII signal transduction inhibitor to the subject at a pharmaceutically effective dose between 0.1 mg / kg and 2.0 mg / kg for a short time period, or (ii) if the percentage of erythroblasts that are ring sideroblasts in the subject is less than 10%, administering an ActRII signal transduction inhibitor to the subject at a pharmaceutically effective dose between 0.1 mg / kg and 2.0 mg / kg for a long time period. In certain embodiments, the subject is a subject requiring transfusion. Also provided herein is a method for treating MDS in a subject, the method comprising: (a) determining a first percentage of erythroblasts that are ring sideroblasts in the subject; and (b) (i) if the first percentage of erythroblasts that are ring sideroblasts in the subject is at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or at least 20%, administering an ActRII signal transduction inhibitor to the subject at a pharmaceutically effective dose between 0.1 mg / kg and 2.0 mg / kg for a short time period, or (ii) if the percentage of erythroblasts that are ring sideroblasts in the subject is less than 10%, administering an ActRII signal transduction inhibitor to the subject at a pharmaceutically effective dose between 0.1 mg / kg and 2.0 mg / kg for a long time period.Also provided herein is a method for treating non-proliferative CMML in a subject, the method comprising: (a) determining a first percentage of erythroblasts that are ring sideroblasts in the subject; and (b) (i) if the first percentage of erythroblasts that are ring sideroblasts in the subject is at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or at least 20%, administering an ActRII signal transduction inhibitor to the subject at a pharmaceutically effective dose between 0.1 mg / kg and 2.0 mg / kg for a short time period, or (ii) if the percentage of erythroblasts that are ring sideroblasts in the subject is less than 10%, administering an ActRII signal transduction inhibitor to the subject at a pharmaceutically effective dose between 0.1 mg / kg and 2.0 mg / kg for a long time period.

[0018] In certain embodiments, in the subject to whom an ActRII signal transduction inhibitor is administered for a short time period, at least 6, 12, 18 or 24 months after the short time period of ActRII signal transduction inhibitor administration, the first percentage of erythroblasts that are ring sideroblasts in the subject is reduced to less than 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or less than 1%. In certain embodiments, the hemoglobin level of the subject is less than about 11 g / dL. In certain embodiments, at least 3, 4, 5, 6, 12, 18 or 24 months after the time period of ActRII signal transduction inhibitor administration, the hemoglobin level of the subject to whom an ActRII signal transduction inhibitor is administered for a short time period is between about 11 g / dL and 18 g / dL. In certain embodiments, the short time period is 1, 2, 3, 4 or 5 months. In certain embodiments, the long time period is at least 6, 12, 18 or 24 months. In certain embodiments, at least 3, 4, 5, 6, 12, 18 or 24 months after the time period of ActRII signal transduction inhibitor administration, the subject does not require red blood cell transfusion.

[0019] In certain embodiments, the ActRII signal transduction inhibitor is administered once every three weeks. In certain embodiments, the ActRII signal transduction inhibitor is administered (i) once every 28 days; or (ii) once every 42 days. In certain embodiments, the ActRII signal transduction inhibitor is administered via injection. In certain embodiments, the ActRII signal transduction inhibitor is administered subcutaneously.

[0020] In certain embodiments, the method further comprises determining a second percentage of erythroblasts that are ring sideroblasts in the subject at 6, 12, 18, and / or 24 months after a time period of administration of an ActRII signal transduction inhibitor. In certain embodiments, the percentage of erythroblasts that are ring sideroblasts in the subject is determined by Prussian blue staining. In certain embodiments, the method further comprises determining the hemoglobin level in the subject at 6, 12, 18, and / or 24 months after a time period of administration of an ActRII signal transduction inhibitor.

[0021] Also provided herein is a method for treating a blood-related disorder in a subject, the method comprising: (a) determining that the subject has: a percentage of erythroblasts that are ring sideroblasts in the subject of at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or at least 20%; (b) administering to the subject an initial dose of an ActRII signaling inhibitor between 0.1 mg / kg and 2.0 mg / kg; (c) determining a second percentage of erythroblasts that are ring sideroblasts in the subject after a period of time; and (d) optionally administering an adjusted dose of an ActRII signaling inhibitor to the subject. In certain embodiments, the blood-related disorder is anemia, anemia requiring transfusion, MDS or non-proliferative CMML. Also provided herein is a method for treating anemia in a subject, the method comprising: (a) determining that the subject has: a percentage of erythroblasts that are ring sideroblasts in the subject of at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or at least 20%; (b) administering to the subject an initial dose of an ActRII signaling inhibitor between 0.1 mg / kg and 2.0 mg / kg; (c) determining a second percentage of erythroblasts that are ring sideroblasts in the subject after a period of time; and (d) optionally administering an adjusted dose of an ActRII signaling inhibitor to the subject. In certain embodiments, the subject is a subject requiring transfusion. Also provided herein is a method for treating MDS in a subject, the method comprising: (a) determining that the subject has: a percentage of erythroblasts that are ring sideroblasts in the subject of at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or at least 20%; (b) administering to the subject an initial dose of an ActRII signaling inhibitor between 0.1 mg / kg and 2.0 mg / kg; (c) determining a second percentage of erythroblasts that are ring sideroblasts in the subject after a period of time; and (d) optionally administering an adjusted dose of an ActRII signaling inhibitor to the subject.Also provided herein is a method for treating a subject with non-proliferative chronic myelomonocytic leukemia (CMML), the method comprising: (a) determining that the subject has: a percentage of erythroblasts that are ring sideroblasts in the subject of at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or at least 20%; (b) administering to the subject an initial dose of an ActRII signal transduction inhibitor between 0.1 mg / kg and 2.0 mg / kg; (c) determining a second percentage of erythroblasts that are ring sideroblasts in the subject after a period of time; and (d) optionally administering an adjusted dose of the ActRII signal transduction inhibitor to the subject.

[0022] In certain embodiments, the period of time is 1, 2, 3, 4, 5 or 6 months. In certain embodiments, the initial dose is administered by injection. In certain embodiments, the initial dose is administered subcutaneously. In certain embodiments, the initial dose is administered once every three weeks. In certain embodiments, the initial dose is administered (i) once every 28 days; or (ii) once every 42 days.

[0023] In certain embodiments, the initial dose is administered to the subject immediately following determination of the first percentage of erythroblasts in the subject that are ring sideroblasts or within at most 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 1 week, 2 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months thereof. In certain embodiments, the adjusted dose is administered to the subject immediately following determination of the second percentage of erythroblasts in the subject that are ring sideroblasts or within at most 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 1 week, 2 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months thereof. In certain embodiments, if the second percentage of erythroblasts in the subject that are ring sideroblasts is at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or at least 20%, the adjusted dose of the ActRII signal transduction inhibitor is greater than the initial dose. In certain embodiments, the adjusted dose is about 0.05 mg / kg, about 0.1 mg / kg, about 0.15 mg / kg, about 0.25 mg / kg, about 0.3 mg / kg, about 0.35 mg / kg, about 0.4 mg / kg, or about 0.5 mg / kg, 0.75 mg / kg, 1.0 mg / kg, 1.33 mg / kg, 1.5 mg / kg, or about 1.75 mg / kg higher than the initial dose. In certain embodiments, the adjusted dose is administered more frequently than the initial dose. In certain embodiments, the adjusted dose is administered every 5, 10, 15, 20, 25, 28, 30, 35, or 40 days. In certain embodiments, the adjusted dose is administered via injection. In certain embodiments, the adjusted dose is administered subcutaneously. In certain embodiments, if the second percentage of erythroblasts in the subject that are ring sideroblasts is less than 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or less than 1%, no adjusted dose is administered to the subject. In certain embodiments, the adjusted dose is administered for at most 1, 2, 3, 4, 5, or 6 months.

[0024] In certain embodiments, at least 3, 4, 5, 6, 12, 18, or 24 months following the time period of administration of the ActRII signal transduction inhibitor, the subject does not require red blood cell transfusions. In certain embodiments, the ActRII signal transduction inhibitor is administered once every three weeks. In certain embodiments, the ActRII signal transduction inhibitor is administered (i) once every 28 days; or (ii) once every 42 days. In certain embodiments, the percentage of erythroblasts in the subject that are ring sideroblasts is determined by Prussian blue staining.

[0025] Also provided herein is a method for treating a blood-related disorder in a subject, the method comprising: (a) determining the percentage of erythroblasts that are ring sideroblasts in the subject; (b) if the percentage of erythroblasts that are ring sideroblasts in the subject is at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or at least 20%, administering an ActRII signal transduction inhibitor to the subject at a pharmaceutically effective dose between 0.1 mg / kg and 2.0 mg / kg; (c) determining the level of hemoglobin in the subject after administering the ActRII signal transduction inhibitor to the subject; and (d) if the level of hemoglobin in the subject is at least 11 g / dL, stopping administering the ActRII signal transduction inhibitor to the subject. In certain embodiments, the blood-related disorder is anemia, anemia requiring blood transfusion, MDS or non-proliferative CMML. Also provided herein is a method for treating anemia in a subject, the method comprising: (a) determining the percentage of erythroblasts that are ring sideroblasts in the subject; (b) if the percentage of erythroblasts that are ring sideroblasts in the subject is at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or at least 20%, administering an ActRII signal transduction inhibitor to the subject at a pharmaceutically effective dose between 0.1 mg / kg and 2.0 mg / kg; (c) determining the level of hemoglobin in the subject after administering the ActRII signal transduction inhibitor to the subject; and (d) if the level of hemoglobin in the subject is at least 11 g / dL, stopping administering the ActRII signal transduction inhibitor to the subject. In certain embodiments, the subject requires RBC transfusion. Also provided herein is a method for treating MDS in a subject, the method comprising: (a) determining the percentage of erythroblasts that are ring sideroblasts in the subject; (b) if the percentage of erythroblasts that are ring sideroblasts in the subject is at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or at least 20%, administering an ActRII signal transduction inhibitor to the subject at a pharmaceutically effective dose between 0.1 mg / kg and 2.0 mg / kg; (c) determining the level of hemoglobin in the subject after administering the ActRII signal transduction inhibitor to the subject; and (d) if the level of hemoglobin in the subject is at least 11 g / dL, stopping administering the ActRII signal transduction inhibitor to the subject.Also provided herein is a method for treating non-proliferative CMML in a subject, the method comprising: (a) determining the percentage of erythroblasts that are ring sideroblasts in the subject; (b) if the percentage of erythroblasts that are ring sideroblasts in the subject is at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or at least 20%, administering an ActRII signal transduction inhibitor to the subject at a pharmaceutically effective dose between 0.1 mg / kg and 2.0 mg / kg; (c) after administering the ActRII signal transduction inhibitor to the subject, determining the level of hemoglobin in the subject; and (d) if the level of hemoglobin in the subject is at least 11 g / dL, stopping administering the ActRII signal transduction inhibitor to the subject.

[0026] In certain embodiments, the ActRII signal transduction inhibitor is administered to the subject once every three weeks. In certain embodiments, the ActRII signal transduction inhibitor is administered (i) once every 28 days; or (ii) once every 42 days. In certain embodiments, the ActRII signal transduction inhibitor is administered via injection. In certain embodiments, the ActRII signal transduction inhibitor is administered subcutaneously.

[0027] In certain embodiments, the level of hemoglobin is determined within 6, 12, 18, and / or 24 months after administering the ActRII signal transduction inhibitor.

[0028] Also provided herein is a method for promoting erythropoiesis in a subject having a blood-related disorder, the method comprising: (a) determining the percentage of erythroblasts that are ring sideroblasts in the subject; (b) administering to the subject a pharmaceutically effective dose of an ActRII signal transduction inhibitor for a first time period; (c) after the first time period, if in step (a) the percentage of erythroblasts that are ring sideroblasts in the subject has exceeded 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or 20%, then reducing the dose of the ActRII signal transduction inhibitor administered to the subject, reducing the frequency of administration of the ActRII signal transduction inhibitor to the subject, or stopping the administration of the ActRII signal transduction inhibitor. In certain embodiments, the blood-related disorder is anemia, anemia requiring transfusion, MDS or non-proliferative CMML. In certain embodiments, the method further comprises (i) monitoring the hematological parameters of the subject during the first time period; and (ii) if the hematological parameters of the subject normalize, then reducing or stopping the administration of the ActRII signal transduction inhibitor to the subject. In certain embodiments, the method further comprises (i) monitoring the hematological parameters of the subject during the first time period; and (ii) if the hematological parameters of the subject normalize, then reducing the dose of the ActRII signal transduction inhibitor administered to the subject. In certain embodiments, the method further comprises (i) monitoring the hematological parameters of the subject during the first time period; and (ii) if the hematological parameters of the subject normalize, then reducing the frequency of administration of the ActRII signal transduction inhibitor to the subject. In certain embodiments, the method further comprises (i) monitoring the hematological parameters of the subject during the first time period; and (ii) if the hematological parameters of the subject normalize, stopping the administration of the ActRII signal transduction inhibitor to the subject. In certain embodiments, the normalized hematological parameters of the subject are the levels of the hematological parameters of a reference population. In certain embodiments, the normalized hematological parameters of the subject are at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% improvement in the hematological parameters of the subject as compared to the hematological parameters of the subject during a time period prior to administering the initial dose of the ActRII signal transduction inhibitor to the subject. In certain embodiments, the time period prior to administering the initial dose of the ActRII signal transduction inhibitor to the subject is at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 3 months, 4 months, 5 months or 6 months. In certain embodiments, the hematological parameters are hemoglobin level, hematocrit, red blood cell count or the percentage of erythroblasts that are ring sideroblasts in the subject.

[0029] In certain embodiments, the ActRII signal transduction inhibitor is administered to the subject once every three weeks. In certain embodiments, the ActRII signal transduction inhibitor is administered (i) once every 28 days; or (ii) once every 42 days. In certain embodiments, the ActRII signal transduction inhibitor is administered via injection. In certain embodiments, the ActRII signal transduction inhibitor is administered subcutaneously.

[0030] In certain embodiments, if at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or 20% of the erythroblasts in the subject are ring sideroblasts, the subject has an increased likelihood of achieving normalization of one or more hematological parameters. In certain embodiments, the hematological parameters are hemoglobin level, hematocrit, red blood cell count or the percentage of erythroblasts in the subject that are ring sideroblasts.

[0031] In certain embodiments, the normalized hematological parameter is the level of the hematological parameter of a reference population. In certain embodiments, the normalized hematological parameter is an improvement of at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% compared to the hematological parameter of the subject for a period of time prior to administration of the initial dose of the ActRII signal transduction inhibitor to the subject. In certain embodiments, the period of time prior to administration of the initial dose of the ActRII signal transduction inhibitor to the subject is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 3 months, 4 months, 5 months or 6 months.

[0032] Provided herein is a method for the long-term treatment of anemia in a subject, comprising administering an activin receptor type II (ActRII) inhibitor to the subject in a pharmaceutically effective dose and for a period of time to achieve (i) a long-term decrease in the ratio of ring sideroblasts to normal erythroblasts in the subject compared to the initial ratio of ring sideroblasts to normal erythroblasts in the subject; and (ii) a long-term increase in the hemoglobin level of the subject compared to the hemoglobin level of the subject prior to administration of the ActRII inhibitor; wherein the pharmaceutically effective dose is between 0.75 mg / kg and 2.0 mg / kg, and wherein the initial ratio of ring sideroblasts to normal erythroblasts in the subject is at least 1:10, at least 1:7 or at least 1:5. In certain embodiments, the subject is a subject in need of a blood transfusion.

[0033] Provided herein are methods for the long-term treatment of low-risk or intermediate-risk-1 myelodysplastic syndrome (MDS) in a subject, comprising administering an activin receptor type II (ActRII) inhibitor to the subject at a pharmaceutically effective dose and for a period of time to effect (i) a long-term decrease in the ratio of ring sideroblasts to normal erythroblasts in the subject compared to the initial ratio of ring sideroblasts to normal erythroblasts in the subject; and (ii) a long-term increase in the hemoglobin level of the subject compared to the hemoglobin level of the subject prior to administering the ActRII inhibitor; wherein the pharmaceutically effective dose is between 0.75 mg / kg and 2.0 mg / kg, and wherein the initial ratio of ring sideroblasts to normal erythroblasts in the subject is at least 1:10, at least 1:7, or at least 1:5.

[0034] Provided herein are methods for the long-term treatment of non-proliferative chronic myelomonocytic leukemia (CMML) in a subject, comprising administering an activin receptor type II (ActRII) inhibitor to the subject at a pharmaceutically effective dose and for a period of time to effect (i) a long-term decrease in the ratio of ring sideroblasts to normal erythroblasts in the subject compared to the initial ratio of ring sideroblasts to normal erythroblasts in the subject; and (ii) a long-term increase in the hemoglobin level of the subject compared to the hemoglobin level of the subject prior to administering the ActRII inhibitor; wherein the pharmaceutically effective dose is between 0.75 mg / kg and 2.0 mg / kg, and wherein the initial ratio of ring sideroblasts to normal erythroblasts in the subject is at least 1:10, at least 1:7, or at least 1:5.

[0035] Also provided herein are methods for increasing the level of neutrophils in a subject, comprising administering to the subject a pharmaceutically effective dose of an activin receptor type II (ActRII) signal transduction inhibitor.

[0036] Also provided herein are methods for increasing the level of platelets in a subject, comprising administering to the subject a pharmaceutically effective dose of an activin receptor type II (ActRII) signal transduction inhibitor.

[0037] In certain embodiments, the ActRII signal transduction inhibitor is a polypeptide comprising an amino acid sequence selected from the following: (a) 90% identical to SEQ ID NO:2; (b) 95% identical to SEQ ID NO:2; (c) 98% identical to SEQ ID NO:2; (d) SEQ ID NO:2; (e) 90% identical to SEQ ID NO:3; (f) 95% identical to SEQ ID NO:3; (g) 98% identical to SEQ ID NO:3; (h) SEQ ID NO:3; (i) 90% identical to SEQ ID NO:6; (j) 95% identical to SEQ ID NO:6; (k) 98% identical to SEQ ID NO:6; (l) SEQ ID NO:6; (m) 90% identical to SEQ ID NO:7; (n) 95% identical to SEQ ID NO:7; (o) 98% identical to SEQ ID NO:7; (p) SEQ ID NO:7; (q) 90% identical to SEQ ID NO:12; (r) 95% identical to SEQ ID NO:12; (s) 98% identical to SEQ ID NO:12; (t) SEQ ID NO:12; (u) 90% identical to SEQ ID NO:17; (v) 95% identical to SEQ ID NO:17; (w) 98% identical to SEQ ID NO:17; (x) SEQ ID NO:17; (y) 90% identical to SEQ ID NO:20; (z) 95% identical to SEQ ID NO:20; (aa) 98% identical to SEQ ID NO:20; (bb) SEQ ID NO:20; (cc) 90% identical to SEQ ID NO:21; (dd) 95% identical to SEQ ID NO:21; (ee) 98% identical to SEQ ID NO:21; (ff) SEQ ID NO:21; (gg) 90% identical to SEQ ID NO:25; (hh) 95% identical to SEQ ID NO:25; (ii) 98% identical to SEQ ID NO:25; and (jj) SEQ ID NO:25.

[0038] In certain embodiments, the ActRII signal transduction inhibitor is an ActRIIA signal transduction inhibitor. In certain embodiments, the ActRIIA signal transduction inhibitor is a polypeptide comprising an amino acid sequence selected from the following: (a) 90% identical to SEQ ID NO:2; (b) 95% identical to SEQ ID NO:2; (c) 98% identical to SEQ ID NO:2; (d) SEQ ID NO:2; (e) 90% identical to SEQ ID NO:3; (f) 95% identical to SEQ ID NO:3; (g) 98% identical to SEQ ID NO:3; (h) SEQ ID NO:3; (i) 90% identical to SEQ ID NO:6; (j) 95% identical to SEQ ID NO:6; (k) 98% identical to SEQ ID NO:6; (l) SEQ ID NO:6; (m) 90% identical to SEQ ID NO:7; (n) 95% identical to SEQ ID NO:7; (o) 98% identical to SEQ ID NO:7; and (p) SEQ ID NO:7.

[0039] In certain embodiments, the ActRII signal transduction inhibitor is a polypeptide comprising the amino acid sequence of SEQ ID NO:7. In certain embodiments, the ActRII signal transduction inhibitor is a humanized fusion protein composed of the extracellular domain of ActRIIA and the human IgG1 Fc domain.

[0040] In certain embodiments, the ActRII signal transduction inhibitor is a signal transduction inhibitor of ActRIIB. In certain embodiments, the ActRIIB signal transduction inhibitor is a polypeptide comprising an amino acid sequence selected from the following: (a) 90% identical to SEQ ID NO:17; (b) 95% identical to SEQ ID NO:17; (c) 98% identical to SEQ ID NO:17; (d) SEQ ID NO:17; (e) 90% identical to SEQ ID NO:20; (f) 95% identical to SEQ ID NO:20; (g) 98% identical to SEQ ID NO:20; (h) SEQ ID NO:20; (i) 90% identical to SEQ ID NO:21; (j) 95% identical to SEQ ID NO:21; (k) 98% identical to SEQ ID NO:21; (l) SEQ ID NO:21; (m) 90% identical to SEQ ID NO:25; (n) 95% identical to SEQ ID NO:25; (o) 98% identical to SEQ ID NO:25; and (p) SEQ ID NO:25.

[0041] In certain embodiments, the ActRII signal transduction inhibitor is a polypeptide comprising the amino acid sequence of SEQ ID NO:25.

[0042] In certain embodiments, the ActRII signal transduction inhibitor is a humanized fusion protein consisting of the extracellular domain of ActRIIA and the human IgG1 Fc domain.

[0043] In certain embodiments, the subject is a human.

[0044] In certain embodiments, the dosage of the ActRII signal transduction inhibitor is between 0.1 and 2.25 mg / kg. In certain embodiments, the dosage of the ActRII signal transduction inhibitor is between 0.1 and 2.0 mg / kg. In certain embodiments, the dosage of the ActRII signal transduction inhibitor is between 0.7 and 2.0 mg / kg. In certain embodiments, the dosage of the ActRII signal transduction inhibitor is about 0.1 mg / kg, 0.125 mg / kg, 0.3 mg / kg, 0.5 mg / kg, 0.7 mg / kg, 1.0 mg / kg, 1.25 mg / kg, 1.33 mg / kg, 1.5 mg / kg, 1.75 mg / kg, 2.0 mg / kg or 2.25 mg / kg. In certain embodiments, the dosage of the ActRII signal transduction inhibitor is between 0.1 mg / kg and 0.5 mg / kg, between 0.3 mg / kg and 0.7 mg / kg, between 0.5 mg / kg and 1.0 mg / kg, between 0.7 mg / kg and 1.25 mg / kg, between 1.0 mg / kg and 2.0 mg / kg or between 1.5 and 2.25 mg / kg.

[0045] Protocol 1. A method for treating a blood-related disorder in a subject, comprising

[0046] (a) determining the percentage of erythroblasts that are ring sideroblasts in the subject; and

[0047] (b) if at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or 20% of the erythroblasts in the subject are ring sideroblasts, administering to the subject a pharmaceutically effective dose of an ActRII signal transduction inhibitor between 0.1 mg / kg and 2.0 mg / kg.

[0048] Protocol 2. The method according to Protocol 1, wherein the blood-related disorder is anemia, anemia requiring blood transfusion, myelodysplastic syndrome (MDS) or non-proliferative chronic myelomonocytic leukemia (CMML).

[0049] Protocol 3. The method according to Protocol 1 or 2, wherein the percentage of erythroblasts that are ring sideroblasts in the subject is determined at a first time.

[0050] Protocol 4. The method according to Protocol 3, wherein the first time is within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 3 months, 4 months, 5 months or 6 months of administering the pharmaceutically effective dose of the ActRII signal transduction inhibitor to the subject.

[0051] Method 5. A method for treating a blood-related disorder in a subject, comprising administering an activin receptor type II (ActRII) signal transduction inhibitor to the subject at a pharmaceutically effective dose for a period of time to achieve (i) a long-term decrease in the percentage of erythroblasts that are ring sideroblasts in the subject compared to the initial percentage of erythroblasts that are ring sideroblasts in the subject; and / or (ii) a long-term increase in the hemoglobin level of the subject compared to the hemoglobin level of the subject for a period of time prior to administering an initial dose of the ActRII signal transduction inhibitor to the subject; wherein the pharmaceutically effective dose is between 0.1 mg / kg and 2.0 mg / kg, and wherein the initial percentage of erythroblasts that are ring sideroblasts in the subject is at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or at least 20%.

[0052] Method 6. The method of Method 5, wherein the blood-related disorder is anemia, MDS or non-proliferative CMML.

[0053] Method 7. A method for treating anemia in a subject, comprising administering an activin receptor type II (ActRII) signal transduction inhibitor to the subject at a pharmaceutically effective dose for a period of time to achieve (i) a long-term decrease in the percentage of erythroblasts that are ring sideroblasts in the subject compared to the initial percentage of erythroblasts that are ring sideroblasts in the subject; and / or (ii) a long-term increase in the hemoglobin level of the subject compared to the hemoglobin level of the subject for a period of time prior to administering an initial dose of the ActRII signal transduction inhibitor to the subject; wherein the pharmaceutically effective dose is between 0.1 mg / kg and 2.0 mg / kg, and wherein the initial percentage of erythroblasts that are ring sideroblasts in the subject is at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or at least 20%.

[0054] Method 8. The method of Method 7, wherein the subject is a subject in need of RBC transfusion.

[0055] Method 9. A method for treating MDS in a subject, comprising administering an ActRII signal transduction inhibitor to the subject at a pharmaceutically effective dose for a period of time to achieve (i) a long-term decrease in the percentage of erythroblasts that are ring sideroblasts in the subject as compared to the initial percentage of erythroblasts that are ring sideroblasts in the subject; and / or (ii) a long-term increase in the hemoglobin level of the subject as compared to the hemoglobin level of the subject during a period of time prior to administering the initial dose of the ActRII signal transduction inhibitor to the subject; wherein the pharmaceutically effective dose is between 0.1 mg / kg and 2.0 mg / kg, and wherein the initial percentage of erythroblasts that are ring sideroblasts in the subject is at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or at least 20%.

[0056] Method 10. A method for treating non-proliferative CMML in a subject, comprising administering an ActRII signal transduction inhibitor to the subject at a pharmaceutically effective dose for a period of time to achieve (i) a long-term decrease in the percentage of erythroblasts that are ring sideroblasts in the subject as compared to the initial percentage of erythroblasts that are ring sideroblasts in the subject; and / or (ii) a long-term increase in the hemoglobin level of the subject as compared to the hemoglobin level of the subject during a period of time prior to administering the initial dose of the ActRII signal transduction inhibitor to the subject; wherein the pharmaceutically effective dose is between 0.1 mg / kg and 2.0 mg / kg, and wherein the initial percentage of erythroblasts that are ring sideroblasts in the subject is at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or at least 20%.

[0057] Method 11. The method according to any one of Methods 5-10, wherein the period of time for administering the ActRII signal transduction inhibitor is 1, 2, 3, 4, 5 or 6 months.

[0058] Method 12. The method according to any one of Methods 5-11, wherein the initial percentage of erythroblasts that are ring sideroblasts in the subject is the percentage of erythroblasts that are ring sideroblasts in the subject during a period of time prior to administering the initial dose of the ActRII signal transduction inhibitor to the subject.

[0059] Method 13. The method according to any one of Methods 5-12, wherein the long-term decrease in the percentage of erythroblasts that are ring sideroblasts in the subject is maintained for at least 1, 2, 3, 4, 5, 6, 12, 18 or 24 months after the period of time for administering the ActRII signal transduction inhibitor.

[0060] Protocol 14. The method according to any one of Protocols 5-13, wherein the long-term decrease in the percentage of erythroblasts that are ring sideroblasts in the subject is at least 1.5, 2.5, 5.0, 7.5, or 10.0 times lower than the initial percentage of erythroblasts that are ring sideroblasts in the subject, and the duration is at least 6, 12, 18, or 24 months after the time period of administration of the ActRII signal transduction inhibitor.

[0061] Protocol 15. The method according to any one of Protocols 5-14, wherein the initial hemoglobin level of the subject is the hemoglobin level of the subject for a period of time before administering the initial dose of the ActRII signal transduction inhibitor to the subject.

[0062] Protocol 16. The method according to any one of Protocols 5-15, wherein the initial hemoglobin level of the subject is less than about 11 g / dL.

[0063] Protocol 17. The method according to any one of Protocols 5-16, wherein the long-term increase in the hemoglobin level of the subject is maintained for at least 3, 4, 5, 6, 12, 18, or 24 months after the time period of administration of the ActRII signal transduction inhibitor.

[0064] Protocol 18. The method according to any one of Protocols 5-17, wherein the long-term increase in the hemoglobin level of the subject is at least 3, 4, 5, 6, 12, 18, or 24 months after the time period of administration of the ActRII signal transduction inhibitor, and the hemoglobin level of the subject is between about 11 g / dL and 18 g / dL.

[0065] Protocol 19. The method according to any one of Protocols 5-17, wherein the subject does not require red blood cell transfusion for at least 3, 4, 5, 6, 12, 18, or 24 months after the time period of administration of the ActRII signal transduction inhibitor.

[0066] Protocol 20. The method according to any one of the foregoing protocols, wherein the ActRII signal transduction inhibitor is administered once every three weeks.

[0067] Protocol 21. The method according to any one of Protocols 1-19, wherein the ActRII signal transduction inhibitor is administered (i) once every 28 days; or (ii) once every 42 days.

[0068] Protocol 22. The method according to any one of the foregoing protocols, wherein the ActRII signal transduction inhibitor is administered via injection.

[0069] Protocol 23. The method according to Protocol 16, wherein the ActRII signal transduction inhibitor is administered subcutaneously.

[0070] Method 24. The method of any of the foregoing methods, wherein the method further comprises determining, at 6, 12, 18, and / or 24 months after the time period of administration of the ActRII signal transduction inhibitor, another percentage of erythroblasts that are ring sideroblasts in the subject.

[0071] Method 25. The method of any of the foregoing methods, wherein the percentage of erythroblasts that are ring sideroblasts in the subject is determined by Prussian blue staining.

[0072] Method 26. The method of any of the foregoing methods, wherein the method further comprises determining, at 6, 12, 18, and / or 24 months after the time period of administration of the ActRII signal transduction inhibitor, another hemoglobin level in the subject.

[0073] Method 27. A method for treating a blood-related disorder in a subject, wherein the method comprises:

[0074] (a) determining the percentage of erythroblasts that are ring sideroblasts in the subject; and

[0075] (b) (i) if the percentage of erythroblasts that are ring sideroblasts in the subject is at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or at least 20%, administering an ActRII signal transduction inhibitor to the subject at a pharmaceutically effective dose between 0.1 mg / kg and 2.0 mg / kg for a short time period, or (ii) if the percentage of erythroblasts that are ring sideroblasts in the subject is less than 10%, administering an ActRII signal transduction inhibitor to the subject at a pharmaceutically effective dose between 0.1 mg / kg and 2.0 mg / kg for a long time period.

[0076] Method 28. The method of Method 27, wherein the blood-related disorder is anemia, anemia requiring transfusion, MDS, or non-proliferative CMML.

[0077] Method 29. A method for treating anemia in a subject, wherein the method comprises:

[0078] (a) determining a first percentage of erythroblasts that are ring sideroblasts in the subject; and

[0079] (b)(i) If the first percentage of erythroblasts that are ring sideroblasts in the subject is at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or at least 20%, administer an ActRII signal transduction inhibitor to the subject at a pharmaceutically effective dose between 0.1 mg / kg and 2.0 mg / kg for a short time period, or (ii) if the percentage of erythroblasts that are ring sideroblasts in the subject is less than 10%, administer an ActRII signal transduction inhibitor to the subject at a pharmaceutically effective dose between 0.1 mg / kg and 2.0 mg / kg for a long time period.

[0080] Protocol 30. The method of Protocol 29, wherein the subject is a subject in need of a blood transfusion.

[0081] Protocol 31. A method for treating MDS in a subject, wherein the method comprises:

[0082] (a) Determining a first percentage of erythroblasts that are ring sideroblasts in the subject; and

[0083] (b)(i) If the first percentage of erythroblasts that are ring sideroblasts in the subject is at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or at least 20%, administer an ActRII signal transduction inhibitor to the subject at a pharmaceutically effective dose between 0.1 mg / kg and 2.0 mg / kg for a short time period, or (ii) if the percentage of erythroblasts that are ring sideroblasts in the subject is less than 10%, administer an ActRII signal transduction inhibitor to the subject at a pharmaceutically effective dose between 0.1 mg / kg and 2.0 mg / kg for a long time period.

[0084] Protocol 32. A method for treating non-proliferative CMML in a subject, wherein the method comprises:

[0085] (a) Determining a first percentage of erythroblasts that are ring sideroblasts in the subject; and

[0086] (b)(i) If a first percentage of erythroblasts that are ring sideroblasts in the subject is at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or at least 20%, an ActRII signal transduction inhibitor is administered to the subject at a pharmaceutically effective dose between 0.1 mg / kg and 2.0 mg / kg for a short time period, or (ii) if the percentage of erythroblasts that are ring sideroblasts in the subject is less than 10%, an ActRII signal transduction inhibitor is administered to the subject at a pharmaceutically effective dose between 0.1 mg / kg and 2.0 mg / kg for a long time period.

[0087] Protocol 33. The method according to any one of Protocols 27 - 32, wherein at least 6, 12, 18 or 24 months after the short time period of administration of the ActRII signal transduction inhibitor, the first percentage of erythroblasts that are ring sideroblasts in the subject to whom the ActRII signal transduction inhibitor was administered for the short time period is reduced to less than 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or less than 1%.

[0088] Protocol 34. The method according to any one of Protocols 27 - 33, wherein the hemoglobin level of the subject is less than about 11 g / dL.

[0089] Protocol 35. The method according to any one of Protocols 27 - 34, wherein at least 3, 4, 5, 6, 12, 18 or 24 months after the time period of administration of the ActRII signal transduction inhibitor, the hemoglobin level of the subject to whom the ActRII signal transduction inhibitor was administered for a short time period is between about 11 g / dL and 18 g / dL.

[0090] Protocol 36. The method according to any one of Protocols 27 - 35, wherein the short time period is 1, 2, 3, 4 or 5 months.

[0091] Protocol 37. The method according to any one of Protocols 27 - 35, wherein the long time period is at least 6, 12, 18 or 24 months.

[0092] Protocol 38. The method according to any one of Protocols 27 - 36, wherein at least 3, 4, 5, 6, 12, 18 or 24 months after the time period of administration of the ActRII signal transduction inhibitor, the subject does not require red blood cell transfusions.

[0093] Protocol 39. The method according to any one of Protocols 27 - 38, wherein the ActRII signal transduction inhibitor is administered once every three weeks.

[0094] Regimen 40. A method according to any one of regimens 27 - 38, wherein the ActRII signal transduction inhibitor is administered (i) once every 28 days; or (ii) once every 42 days.

[0095] Regimen 41. A method according to any one of regimens 27 - 40, wherein the ActRII signal transduction inhibitor is administered by injection.

[0096] Regimen 42. A method according to Regimen 41, wherein the ActRII signal transduction inhibitor is administered subcutaneously.

[0097] Regimen 43. A method according to any one of regimens 27 - 42, wherein the method further comprises determining a second percentage of erythroblasts that are ring sideroblasts in the subject 6, 12, 18, and / or 24 months after the time period of ActRII signal transduction inhibitor administration.

[0098] Regimen 44. A method according to any one of regimens 27 - 43, wherein the percentage of erythroblasts that are ring sideroblasts in the subject is determined by Prussian blue staining.

[0099] Regimen 45. A method according to any one of regimens 27 - 43, wherein the method further comprises determining the hemoglobin level of the subject 6, 12, 18, and / or 24 months after the time period of ActRII signal transduction inhibitor administration.

[0100] Regimen 46. A method of treating a blood - related disorder in a subject, the method comprising:

[0101] (a) determining that the subject has: a percentage of erythroblasts that are ring sideroblasts in the subject of at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or at least 20%;

[0102] (b) administering to the subject an initial dose of an ActRII signal transduction inhibitor between 0.1 mg / kg and 2.0 mg / kg;

[0103] (c) determining a second percentage of erythroblasts that are ring sideroblasts in the subject after a period of time; and

[0104] (d) optionally administering an adjusted dose of an ActRII signal transduction inhibitor to the subject.

[0105] Regimen 47. The method of Regimen 46, wherein the blood - related disorder is anemia, anemia requiring transfusion, MDS, or non - proliferative CMML.

[0106] Scheme 48. A method for treating anemia in a subject, wherein the method comprises:

[0107] (a) determining that the subject has: a percentage of erythroblasts that are ring sideroblasts in the subject of at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or at least 20%;

[0108] (b) administering to the subject an initial dose of an ActRII signal transduction inhibitor between 0.1 mg / kg and 2.0 mg / kg;

[0109] (c) determining a second percentage of erythroblasts that are ring sideroblasts in the subject after a period of time; and

[0110] (d) optionally administering an adjusted dose of an ActRII signal transduction inhibitor to the subject.

[0111] Scheme 49. The method of Scheme 48, wherein the subject is a subject in need of a blood transfusion.

[0112] Scheme 50. A method for treating MDS in a subject, wherein the method comprises:

[0113] (a) determining that the subject has: a percentage of erythroblasts that are ring sideroblasts in the subject of at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or at least 20%;

[0114] (b) administering to the subject an initial dose of an ActRII signal transduction inhibitor between 0.1 mg / kg and 2.0 mg / kg;

[0115] (c) determining a second percentage of erythroblasts that are ring sideroblasts in the subject after a period of time; and

[0116] (d) optionally administering an adjusted dose of an ActRII signal transduction inhibitor to the subject.

[0117] Scheme 51. A method for treating non-proliferative chronic myelomonocytic leukemia (CMML) in a subject, wherein the method comprises:

[0118] (a) determining that the subject has: a percentage of erythroblasts that are ring sideroblasts in the subject of at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or at least 20%;

[0119] (b) Administer an initial dose of an ActRII signal transduction inhibitor to the subject that is between 0.1 mg / kg and 2.0 mg / kg;

[0120] (c) Determine a second percentage of erythroblasts that are ring sideroblasts in the subject after a period of time; and

[0121] (d) Optionally, administer an adjusted dose of an ActRII signal transduction inhibitor to the subject.

[0122] Protocol 52. The method according to any one of Protocols 46 - 51, wherein the period of time is 1, 2, 3, 4, 5, or 6 months.

[0123] Protocol 53. The method according to any one of Protocols 46 - 52, wherein the initial dose is administered by injection.

[0124] Protocol 54. The method according to Protocol 53, wherein the initial dose is administered subcutaneously.

[0125] Protocol 55. The method according to any one of Protocols 46 - 54, wherein the initial dose is administered once every three weeks.

[0126] Protocol 56. The method according to any one of Protocols 46 - 54, wherein the initial dose is administered (i) once every 28 days; or (ii) once every 42 days.

[0127] Protocol 57. The method according to any one of Protocols 46 - 56, wherein the initial dose is administered to the subject immediately after or within at most 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 1 week, 2 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months after determining the first percentage of erythroblasts that are ring sideroblasts in the subject.

[0128] Protocol 58. The method according to any one of Protocols 46 - 56, wherein the adjusted dose is administered to the subject immediately after or within at most 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 1 week, 2 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months after determining the second percentage of erythroblasts that are ring sideroblasts in the subject.

[0129] Aspect 59. The method according to any one of Aspects 46 - 58, wherein if the second percentage of erythroblasts that are ring sideroblasts in the subject is at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or at least 20%, the adjusted dose of the ActRII signal transduction inhibitor is greater than the initial dose.

[0130] Aspect 60. The method according to Aspect 59, wherein the adjusted dose is about 0.05 mg / kg, about 0.1 mg / kg, about 0.15 mg / kg, about 0.25 mg / kg, about 0.3 mg / kg, about 0.35 mg / kg, about 0.4 mg / kg or about 0.5 mg / kg, 0.75 mg / kg, 1.0 mg / kg, 1.33 mg / kg, 1.5 mg / kg or about 1.75 mg / kg higher than the initial dose.

[0131] Aspect 61. The method according to any one of Aspects 59 or 60, wherein the adjusted dose is administered more frequently than the initial dose.

[0132] Aspect 62. The method according to any one of Aspects 59 - 61, wherein the adjusted dose is administered every 5, 10, 15, 20, 25, 28, 30, 35 or 40 days.

[0133] Aspect 63. The method according to any one of Aspects 46 - 62, wherein the adjusted dose is administered by injection.

[0134] Aspect 64. The method according to Aspect 63, wherein the adjusted dose is administered subcutaneously.

[0135] Aspect 65. The method according to any one of Aspects 46 - 57, wherein if the second percentage of erythroblasts that are ring sideroblasts in the subject is less than 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or less than 1%, the adjusted dose is not administered to the subject.

[0136] Aspect 66. The method according to any one of Aspects 46 - 64, wherein the adjusted dose is administered for at most 1, 2, 3, 4, 5 or 6 months.

[0137] Aspect 67. The method according to any one of Aspects 46 - 66, wherein at least 3, 4, 5, 6, 12, 18 or 24 months after the time period of administration of the ActRII signal transduction inhibitor, the subject does not require red blood cell transfusion.

[0138] Aspect 68. The method according to any one of Aspects 46 - 67, wherein the ActRII signal transduction inhibitor is administered once every three weeks.

[0139] Scheme 69. The method according to any one of Schemes 46-67, wherein the ActRII signal transduction inhibitor is administered (i) once every 28 days; or (ii) once every 42 days.

[0140] Scheme 70. The method according to any one of Schemes 46-69, wherein the percentage of erythroblasts that are ring sideroblasts in the subject is determined by Prussian blue staining.

[0141] Scheme 71. A method for treating a blood-related disorder in a subject, wherein the method comprises:

[0142] (a) determining the percentage of erythroblasts that are ring sideroblasts in the subject;

[0143] (b) if the percentage of erythroblasts that are ring sideroblasts in the subject is at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or at least 20%, administering an ActRII signal transduction inhibitor to the subject at a pharmaceutically effective dose between 0.1 mg / kg and 2.0 mg / kg;

[0144] (c) after administering the ActRII signal transduction inhibitor to the subject, determining the level of hemoglobin in the subject; and

[0145] (d) if the level of hemoglobin in the subject is at least 11 g / dL, stopping administering the ActRII signal transduction inhibitor to the subject.

[0146] Scheme 72. The method according to Scheme 71, wherein the blood-related disorder is anemia, anemia requiring transfusion, MDS or non-proliferative CMML.

[0147] Scheme 73. A method for treating anemia in a subject, wherein the method comprises:

[0148] (a) determining the percentage of erythroblasts that are ring sideroblasts in the subject;

[0149] (b) if the percentage of erythroblasts that are ring sideroblasts in the subject is at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or at least 20%, administering an ActRII signal transduction inhibitor to the subject at a pharmaceutically effective dose between 0.1 mg / kg and 2.0 mg / kg;

[0150] (c) after administering the ActRII signal transduction inhibitor to the subject, determining the level of hemoglobin in the subject; and

[0151] (d) If the level of hemoglobin in the subject is at least 11 g / dL, discontinue administering the ActRII signal transduction inhibitor to the subject.

[0152] Protocol 74. The method of Protocol 73, wherein the subject requires RBC transfusion.

[0153] Protocol 75. A method for treating MDS in a subject, wherein the method comprises:

[0154] (a) Determining the percentage of erythroblasts that are ring sideroblasts in the subject;

[0155] (b) If the percentage of erythroblasts that are ring sideroblasts in the subject is at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or at least 20%, administering an ActRII signal transduction inhibitor to the subject at a pharmaceutically effective dose between 0.1 mg / kg and 2.0 mg / kg;

[0156] (c) After administering the ActRII signal transduction inhibitor to the subject, determining the level of hemoglobin in the subject; and

[0157] (d) If the level of hemoglobin in the subject is at least 11 g / dL, discontinue administering the ActRII signal transduction inhibitor to the subject.

[0158] Protocol 76. A method for treating non-proliferative CMML in a subject, wherein the method comprises:

[0159] (a) Determining the percentage of erythroblasts that are ring sideroblasts in the subject;

[0160] (b) If the percentage of erythroblasts that are ring sideroblasts in the subject is at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or at least 20%, administering an ActRII signal transduction inhibitor to the subject at a pharmaceutically effective dose between 0.1 mg / kg and 2.0 mg / kg;

[0161] (c) After administering the ActRII signal transduction inhibitor to the subject, determining the level of hemoglobin in the subject; and

[0162] (d) If the level of hemoglobin in the subject is at least 11 g / dL, discontinue administering the ActRII signal transduction inhibitor to the subject.

[0163] Aspect 77. The method according to any one of Aspects 71 - 76, wherein the ActRII signal transduction inhibitor is administered to the subject once every three weeks.

[0164] Aspect 78. The method according to any one of Aspects 71 - 76, wherein the ActRII signal transduction inhibitor is administered (i) once every 28 days; or (ii) once every 42 days.

[0165] Aspect 79. The method according to any one of Aspects 27 - 40, wherein the ActRII signal transduction inhibitor is administered by injection.

[0166] Aspect 80. The method according to Aspect 79, wherein the ActRII signal transduction inhibitor is administered subcutaneously.

[0167] Aspect 81. The method according to any one of Aspects 71 - 80, wherein the level of hemoglobin is measured within 6, 12, 18, and / or 24 months after the administration of the ActRII signal transduction inhibitor.

[0168] Aspect 82. A method for promoting erythropoiesis in a subject suffering from a blood - related disorder, the method comprising:

[0169] (a) determining the percentage of erythroblasts that are ring sideroblasts in the subject;

[0170] (b) administering a pharmaceutically effective dose of an ActRII signal transduction inhibitor to the subject for a first time period;

[0171] (c) after the first time period, if in step (a) the percentage of erythroblasts that are ring sideroblasts in the subject has exceeded 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20%, then reducing the dose of the ActRII signal transduction inhibitor administered to the subject, reducing the frequency of administration of the ActRII signal transduction inhibitor to the subject, or stopping the administration of the ActRII signal transduction inhibitor.

[0172] Aspect 83. The method according to Aspect 82, wherein the blood - related disorder is anemia, anemia requiring transfusion, MDS, or non - proliferative CMML.

[0173] Aspect 84. The method according to Aspect 82 or 83, wherein the method further comprises (i) monitoring the hematological parameters of the subject during the first time period; and (ii) if the hematological parameters of the subject have normalized, then reducing or stopping the administration of the ActRII signal transduction inhibitor to the subject.

[0174] Scheme 85. The method according to any one of Schemes 82 - 84, wherein the method further comprises (i) monitoring a hematological parameter of the subject during a first time period; and (ii) reducing the dose of the ActRII signal transduction inhibitor administered to the subject if the hematological parameter of the subject normalizes.

[0175] Scheme 86. The method according to any one of Schemes 82 - 85, wherein the method further comprises (i) monitoring a hematological parameter of the subject during a first time period; and (ii) reducing the frequency of administration of the ActRII signal transduction inhibitor to the subject if the hematological parameter of the subject normalizes.

[0176] Scheme 87. The method according to any one of Schemes 82 - 86, wherein the method further comprises (i) monitoring a hematological parameter of the subject during a first time period; and (ii) stopping the administration of the ActRII signal transduction inhibitor to the subject if the hematological parameter of the subject normalizes.

[0177] Scheme 88. The method according to any one of Schemes 82 - 87, wherein the normalized hematological parameter of the subject is the level of the hematological parameter of a reference population.

[0178] Scheme 89. The method according to any one of Schemes 82 - 87, wherein the normalized hematological parameter of the subject is an improvement in the hematological parameter of the subject of at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% compared to the hematological parameter of the subject during the time period before the initial dose of the ActRII signal transduction inhibitor was administered to the subject.

[0179] Scheme 90. The method according to Scheme 89, wherein the time period before the initial dose of the ActRII signal transduction inhibitor was administered to the subject is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 3 months, 4 months, 5 months or 6 months.

[0180] Scheme 91. The method according to any one of Schemes 82 - 90, wherein the first time period is at least 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 1 year.

[0181] Scheme 92. The method according to any one of Schemes 82 - 91, wherein the hematological parameter is the hemoglobin level, hematocrit, red blood cell count or the percentage of erythroblasts in the subject that are ring sideroblasts.

[0182] Regimen 93. The method of any one of Regimens 82 - 92, wherein the ActRII signal transduction inhibitor is administered to the subject once every three weeks.

[0183] Regimen 94. The method of any one of Regimens 82 - 92, wherein the ActRII signal transduction inhibitor is administered (i) once every 28 days; or (ii) once every 42 days.

[0184] Regimen 95. The method of any one of Regimens 82 - 94, wherein the ActRII signal transduction inhibitor is administered by injection.

[0185] Regimen 96. The method of Regimen 95, wherein the ActRII signal transduction inhibitor is administered subcutaneously.

[0186] Regimen 97. The method of any one of Regimens 82 - 96, wherein the pharmaceutically effective dose of the ActRII signal transduction inhibitor is between 0.1 mg / kg and 2.0 mg / kg.

[0187] Regimen 98. The method of any one of the foregoing regimens, wherein if at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or 20% of the erythroblasts in the subject are ring sideroblasts, the subject has an increased likelihood of achieving normalization of one or more hematological parameters.

[0188] Regimen 99. The method of Regimen 98, wherein the hematological parameter is hemoglobin level, hematocrit, red blood cell count or the percentage of erythroblasts in the subject that are ring sideroblasts.

[0189] Regimen 100. The method of Regimen 98 or 99, wherein the normalized hematological parameter is the level of the hematological parameter of a reference population.

[0190] Regimen 101. The method of any one of Regimens 98 - 100, wherein the normalized hematological parameter is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% improved compared to the hematological parameter of the subject during a time period before the initial dose of the ActRII signal transduction inhibitor is administered to the subject.

[0191] Regimen 102. The method of Regimen 101, wherein the time period before the initial dose of the ActRII signal transduction inhibitor is administered to the subject is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 3 months, 4 months, 5 months or 6 months.

[0192] Scheme 103. A method for increasing the level of neutrophils in a subject, comprising administering to the subject a pharmaceutically effective dose of an activin receptor type II (ActRII) signal transduction inhibitor.

[0193] Scheme 104. The method of Scheme 103, wherein the method is for treating a disease associated with a reduced level of neutrophils.

[0194] Scheme 105. A method for increasing the level of platelets in a subject, comprising administering to the subject a pharmaceutically effective dose of an activin receptor type II (ActRII) signal transduction inhibitor.

[0195] Scheme 106. The method of Scheme 105, wherein the method is for treating a disease associated with a reduced level of platelets.

[0196] Scheme 107. The method of any one of Schemes 103-106, wherein the pharmaceutically effective dose of the ActRII signal transduction inhibitor is between 0.1 mg / kg and 2.0 mg / kg.

[0197] Scheme 108. The method of any one of the foregoing schemes, wherein the ActRII signal transduction inhibitor is a polypeptide comprising an amino acid sequence selected from:

[0198] (a) having 90% identity to SEQ ID NO:2;

[0199] (b) having 95% identity to SEQ ID NO:2;

[0200] (c) having 98% identity to SEQ ID NO:2;

[0201] (d) SEQ ID NO:2;

[0202] (e) having 90% identity to SEQ ID NO:3;

[0203] (f) having 95% identity to SEQ ID NO:3;

[0204] (g) having 98% identity to SEQ ID NO:3;

[0205] (h) SEQ ID NO:3;

[0206] (i) having 90% identity to SEQ ID NO:6;

[0207] (j) having 95% identity to SEQ ID NO:6;

[0208] (k) having 98% identity to SEQ ID NO:6;

[0209] (l) SEQ ID NO:6;

[0210] (m) 90% identical to SEQ ID NO:7;

[0211] (n) 95% identical to SEQ ID NO:7;

[0212] (o) 98% identical to SEQ ID NO:7;

[0213] (p) SEQ ID NO:7;

[0214] (q) 90% identical to SEQ ID NO:12;

[0215] (r) 95% identical to SEQ ID NO:12;

[0216] (s) 98% identical to SEQ ID NO:12;

[0217] (t) SEQ ID NO:12;

[0218] (u) 90% identical to SEQ ID NO:17;

[0219] (v) 95% identical to SEQ ID NO:17;

[0220] (w) 98% identical to SEQ ID NO:17;

[0221] (x) SEQ ID NO:17;

[0222] (y) 90% identical to SEQ ID NO:20;

[0223] (z) 95% identical to SEQ ID NO:20;

[0224] (aa) 98% identical to SEQ ID NO:20;

[0225] (bb) SEQ ID NO:20;

[0226] (cc) 90% identical to SEQ ID NO:21;

[0227] (dd) 95% identical to SEQ ID NO:21;

[0228] (ee) 98% identical to SEQ ID NO:21;

[0229] (ff) SEQ ID NO:21;

[0230] (gg) 90% identical to SEQ ID NO:25;

[0231] (hh) 95% identical to SEQ ID NO:25;

[0232] (ii) 98% identical to SEQ ID NO:25; and

[0233] (jj) SEQ ID NO:25.

[0234] Embodiment 109. The method of any of the preceding embodiments, wherein the ActRII signaling inhibitor is an ActRIIA signaling inhibitor.

[0235] 110. The method of 109, wherein the ActRIIA signaling inhibitor is a polypeptide comprising an amino acid sequence selected from the group consisting of:

[0236] (a) 90% identical to SEQ ID NO: 2;

[0237] (b) 95% identical to SEQ ID NO: 2;

[0238] (c) 98% identical to SEQ ID NO: 2;

[0239] (d) SEQ ID NO: 2;

[0240] (e) 90% identical to SEQ ID NO:3;

[0241] (f) 95% identical to SEQ ID NO:3;

[0242] (g) 98% identical to SEQ ID NO:3;

[0243] (h) SEQ ID NO: 3;

[0244] (i) 90% identical to SEQ ID NO:6;

[0245] (j) 95% identical to SEQ ID NO:6;

[0246] (k) 98% identical to SEQ ID NO:6;

[0247] (1) SEQ ID NO: 6;

[0248] (m) 90% identical to SEQ ID NO:7;

[0249] (n) having 95% identity to SEQ ID NO:7;

[0250] (o) having 98% identity to SEQ ID NO:7; and

[0251] (p) SEQ ID NO:7.

[0252] Aspect 111. The method of any one of the foregoing aspects, wherein the ActRII signal transduction inhibitor is a polypeptide comprising the amino acid sequence of SEQ ID NO:7.

[0253] Aspect 112. The method of any one of Aspects 1 - 106, wherein the ActRII signal transduction inhibitor is a humanized fusion protein consisting of the extracellular domain of ActRIIA and the human IgG1 Fc domain.

[0254] Aspect 113. The method of any one of Aspects 1 - 107, wherein the ActRII signal transduction inhibitor is a signal transduction inhibitor of ActRIIB.

[0255] Aspect 114. The method of Aspect 113, wherein the ActRIIB signal transduction inhibitor is a polypeptide comprising an amino acid sequence selected from:

[0256] (a) having 90% identity to SEQ ID NO:17;

[0257] (b) having 95% identity to SEQ ID NO:17;

[0258] (c) having 98% identity to SEQ ID NO:17;

[0259] (d) SEQ ID NO:17;

[0260] (e) having 90% identity to SEQ ID NO:20;

[0261] (f) having 95% identity to SEQ ID NO:20;

[0262] (g) having 98% identity to SEQ ID NO:20;

[0263] (h) SEQ ID NO:20;

[0264] (i) having 90% identity to SEQ ID NO:21;

[0265] (j) having 95% identity to SEQ ID NO:21;

[0266] (k) having 98% identity to SEQ ID NO:21;

[0267] (l) SEQ ID NO:21;

[0268] (m) 90% identical to SEQ ID NO:25;

[0269] (n) 95% identical to SEQ ID NO:25;

[0270] (o) 98% identical to SEQ ID NO:25; and

[0271] (p) SEQ ID NO:25.

[0272] Aspect 115. The method of aspect 114, wherein the ActRII signal transduction inhibitor is a polypeptide comprising the amino acid sequence of SEQ ID NO:25.

[0273] Aspect 116. The method of any one of aspects 1 - 107, wherein the ActRII signal transduction inhibitor is a humanized fusion protein consisting of the extracellular domain of ActRIIB and the human IgG1 Fc domain.

[0274] Aspect 117. The method of any one of the foregoing aspects, wherein the subject is a human. Sequence Listing <110> Cell Genesys, Inc. Exelixis Pharmaceuticals, Inc. <120> Activin - ACTRII Antagonists and Use for the Treatment of Anemia <130> 12827 - 978 - 228 <140> To be assigned <141> On even date herewith <150> 62 / 086,977 <151> 2014 - 12 - 03 <150> 62 / 088,478 <151> 2014 - 12 - 05 <150> 62 / 153,872 <151> 2015 - 04 - 28 <150> 62 / 173,782 <151> 2015 - 06 - 10 <150> 62 / 218,728 <151> 2015 - 09 - 15 <160> 47 <170> FastSEQ for Windows Version 4.0 <210> 1 <211> 513 <212> PRT <213> Homo sapiens <220> <223> Human ActRIIA precursor polypeptide <400> 1 Met Gly Ala Ala Ala Lys Leu Ala Phe Ala Val Phe Leu Ile Ser Cys 1 5 10 15 Ser Ser Gly Ala Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe 20 25 30 Phe Asn Ala Asn Trp Glu Lys Asp Arg Thr Asn Gln Thr Gly Val Glu 35 40 45 Pro Cys Tyr Gly Asp Lys Asp Lys Arg Arg His Cys Phe Ala Thr Trp 50 55 60 Lys Asn Ile Ser Gly Ser Ile Glu Ile Val Lys Gln Gly Cys Trp Leu 65 70 75 80 Asp Asp Ile Asn Cys Tyr Asp Arg Thr Asp Cys Val Glu Lys Lys Asp 85 90 95 Ser Pro Glu Val Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu 100 105 110 Lys Phe Ser Tyr Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser Asn 115 120 125 Pro Val Thr Pro Lys Pro Pro Tyr Tyr Asn Ile Leu Leu Tyr Ser Leu 130 135 140 Val Pro Leu Met Leu Ile Ala Gly Ile Val Ile Cys Ala Phe Trp Val 145 150 155 160 Tyr Arg His His Lys Met Ala Tyr Pro Pro Val Leu Val Pro Thr Gln 165 170 175 Asp Pro Gly Pro Pro Pro Pro Ser Pro Leu Leu Gly Leu Lys Pro Leu 180 185 190 Gln Leu Leu Glu Val Lys Ala Arg Gly Arg Phe Gly Cys Val Trp Lys 195 200 205 Ala Gln Leu Leu Asn Glu Tyr Val Ala Val Lys Ile Phe Pro Ile Gln 210 215 220 Asp Lys Gln Ser Trp Gln Asn Glu Tyr Glu Val Tyr Ser Leu Pro Gly 225 230 235 240 Met Lys His Glu Asn Ile Leu Gln Phe Ile Gly Ala Glu Lys Arg Gly 245 250 255 Thr Ser Val Asp Val Asp Leu Trp Leu Ile Thr Ala Phe His Glu Lys 260 265 270 Gly Ser Leu Ser Asp Phe Leu Lys Ala Asn Val Val Ser Trp Asn Glu 275 280 285 Leu Cys His Ile Ala Glu Thr Met Ala Arg Gly Leu Ala Tyr Leu His 290 295 300 Glu Asp Ile Pro Gly Leu Lys Asp Gly His Lys Pro Ala Ile Ser His 305 310 315 320 Arg Asp Ile Lys Ser Lys Asn Val Leu Leu Lys Asn Asn Leu Thr Ala 325 330 335 Cys Ile Ala Asp Phe Gly Leu Ala Leu Lys Phe Glu Ala Gly Lys Ser 340 345 350 Ala Gly Asp Thr His Gly Gln Val Gly Thr Arg Arg Tyr Met Ala Pro 355 360 365 Glu Val Leu Glu Gly Ala Ile Asn Phe Gln Arg Asp Ala Phe Leu Arg 370 375 380 Ile Asp Met Tyr Ala Met Gly Leu Val Leu Trp Glu Leu Ala Ser Arg 385 390 395 400 Cys Thr Ala Ala Asp Gly Pro Val Asp Glu Tyr Met Leu Pro Phe Glu 405 410 415 Glu Glu Ile Gly Gln His Pro Ser Leu Glu Asp Met Gln Glu Val Val 420 425 430 Val His Lys Lys Lys Arg Pro Val Leu Arg Asp Tyr Trp Gln Lys His 435 440 445 Ala Gly Met Ala Met Leu Cys Glu Thr Ile Glu Glu Cys Trp Asp His 450 455 460 Asp Ala Glu Ala Arg Leu Ser Ala Gly Cys Val Gly Glu Arg Ile Thr 465 470 475 480 Gln Met Gln Arg Leu Thr Asn Ile Ile Thr Thr Glu Asp Ile Val Thr 485 490 495 Val Val Thr Met Val Thr Asn Val Asp Phe Pro Pro Lys Glu Ser Ser 500 505 510 Leu <210> 2 <211> 115 <212> PRT <213> Homo sapiens <220> <223> Human ActRIIA soluble (extracellular), processed polypeptide sequence <400> 2 Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Phe Asn Ala Asn 1 5 10 15 Trp Glu Lys Asp Arg Thr Asn Gln Thr Gly Val Glu Pro Cys Tyr Gly 20 25 30 Asp Lys Asp Lys Arg Arg His Cys Phe Ala Thr Trp Lys Asn Ile Ser 35 40 45 Gly Ser Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Ile Asn 50 55 60 Cys Tyr Asp Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Glu Val 65 70 75 80 Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr 85 90 95 Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser Asn Pro Val Thr Pro 100 105 110 Lys Pro Pro 115 <210> 3 <211> 100 <212> PRT <213> Artificial Sequence <220> <223> Human ActRIIA soluble (extracellular), processed polypeptide sequence with a 15 - amino - acid deletion at the C - terminus <400> 3 Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Phe Asn Ala Asn 1 5 10 15 Trp Glu Lys Asp Arg Thr Asn Gln Thr Gly Val Glu Pro Cys Tyr Gly 20 25 30 Asp Lys Asp Lys Arg Arg His Cys Phe Ala Thr Trp Lys Asn Ile Ser 35 40 45 Gly Ser Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Ile Asn 50 55 60 Cys Tyr Asp Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Glu Val 65 70 75 80 Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr 85 90 95 Phe Pro Glu Met 100 <210> 4 <211> 1542 <212> DNA <213> Homo sapiens <220> <223> Nucleic acid sequence encoding human ActRIIA precursor protein <400> 4 atgggagctg ctgcaaagtt ggcgtttgcc gtctttctta tctcctgttc ttcaggtgct 60 atacttggta gatcagaaac tcaggagtgt cttttcttta atgctaattg ggaaaaagac 120 agaaccaatc aaactggtgt tgaaccgtgt tatggtgaca aagataaacg gcggcattgt 180 tttgctacct ggaagaatat ttctggttcc attgaaatag tgaaacaagg ttgttggctg 240 gatgatatca actgctatga caggactgat tgtgtagaaa aaaaagacag ccctgaagta 300 tatttttgtt gctgtgaggg caatatgtgt aatgaaaagt tttcttattt tccagagatg 360 gaagtcacac agcccacttc aaatccagtt acacctaagc caccctatta caacatcctg 420 ctctattcct tggtgccact tatgttaatt gcggggattg tcatttgtgc attttgggtg 480 tacaggcatc acaagatggc ctaccctcct gtacttgttc caactcaaga cccaggacca 540 cccccacctt ctccattact agggttgaaa ccactgcagt tattagaagt gaaagcaagg 600 ggaagatttg gttgtgtctg gaaagcccag ttgcttaacg aatatgtggc tgtcaaaata 660 tttccaatac aggacaaaca gtcatggcaa aatgaatacg aagtctacag tttgcctgga 720 atgaagcatg agaacatatt acagttcatt ggtgcagaaa aacgaggcac cagtgttgat 780 gtggatcttt ggctgatcac agcatttcat gaaaagggtt cactatcaga ctttcttaag 840 gctaatgtgg tctcttggaa tgaactgtgt catattgcag aaaccatggc tagaggattg 900 gcatatttac atgaggatat acctggccta aaagatggcc acaaacctgc catatctcac 960 agggacatca aaagtaaaaa tgtgctgttg aaaaacaacc tgacagcttg cattgctgac 1020 tttgggttgg ccttaaaatt tgaggctggc aagtctgcag gcgataccca tggacaggtt 1080 ggtacccgga ggtacatggc tccagaggta ttagagggtg ctataaactt cgaaagggat 1140 gcatttttga ggatagatat gtatgccatg ggattagtcc tatgggaact ggcttctcgc 1200 tgtactgctg cagatggacc tgtagatgaa tacatgttgc catttgagga ggaaattggc 1260 cagcatccat ctcttgaaga catgcaggaa gttgttgtgc ataaaaaaaa gaggcctgtt 1320 ttaagagatt attggcagaa acatgctgga atggcaatgc tctgtgaaac cattgaagaa 1380 tgttgggatc acgacgcaga agccaggtta tcagctggat gtgtaggtga aagaattacc 1440 cagatgcaga gactaacaaa tattattacc acagaggaca ttgtaacagt ggtcacaatg 1500 gtgacaaatg ttgactttcc tcccaaagaa tctagtctat ga 1542 <210> 5 <211> 345 <212> DNA <213> Homo sapiens <220> <223> Nucleic acid sequence encoding human ActRIIA soluble (extracellular) polypeptide <400> 5 atacttggta gatcagaaac tcaggagtgt cttttcttta atgctaattg ggaaaaagac 60 agaaccaatc aaactggtgt tgaaccgtgt tatggtgaca aagataaacg gcggcattgt 120 tttgctacct ggaagaatat ttctggttcc attgaaatag tgaaacaagg ttgttggctg 180 gatgatatca actgctatga caggactgat tgtgtagaaa aaaaagacag ccctgaagta 240 tatttttgtt gctgtgaggg caatatgtgt aatgaaaagt tttcttattt tccagagatg 300 gaagtcacac agcccacttc aaatccagtt acacctaagc caccc 345 <210> 6 <211> 228 <212> PRT <213> Artificial Sequence <220> <223> A fusion protein comprising the soluble extracellular domain of ActRIIA fused to an Fc domain <400> 6 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 1 5 10 15 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 20 25 30 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Ala Val Ser His Glu 35 40 45 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 50 55 60 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 65 70 75 80 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 85 90 95 Glu Tyr Lys Cys Lys Ala Val Ser Asn Lys Ala Leu Pro Val Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 130 135 140 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Pro Phe Phe Leu Tyr Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn Ala His Tyr Thr Gln Lys Ser Leu Ser Leu 210 215 220 Ser Pro Gly Lys 225 <210> 7 <211> 344 <212> PRT <213> Artificial Sequence <220> <223> Extracellular domain of human ActRIIA fused with human Fc domain <400> 7 Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Phe Asn Ala Asn 1 5 10 15 Trp Glu Lys Asp Arg Thr Asn Gln Thr Gly Val Glu Pro Cys Tyr Gly 20 25 30 Asp Lys Asp Lys Arg Arg His Cys Phe Ala Thr Trp Lys Asn Ile Ser 35 40 45 Gly Ser Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Ile Asn 50 55 60 Cys Tyr Asp Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Glu Val 65 70 75 80 Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr 85 90 95 Phe Pro Glu Met Glu Val Thr Gln Pro Thr Ser Asn Pro Val Thr Pro 100 105 110 Lys Pro Pro Thr Gly Gly Gly Thr His Thr Cys Pro Pro Cys Pro Ala 115 120 125 Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro 130 135 140 Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val 145 150 155 160 Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val 165 170 175 Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln 180 185 190 Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln 195 200 205 Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala 210 215 220 Leu Pro Val Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro 225 230 235 240 Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr 245 250 255 Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser 260 265 270 Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr 275 280 285 Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr 290 295 300 Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe 305 310 315 320 Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys 325 330 335 Ser Leu Ser Leu Ser Pro Gly Lys 340 <210> 8 <211> 21 <212> PRT <213> Honeybee <220> <223> Leader sequence of honeybee melittin (HBML) <400> 8 Met Lys Phe Leu Val Asn Val Ala Leu Val Phe Met Val Val Tyr Ile 1 5 10 15 Ser Tyr Ile Tyr Ala 20 <210> 9 <211> 22 <212> PRT <213> Artificial sequence <220> <223> Leader sequence of tissue plasminogen activator (TPA) <400> 9 Met Asp Ala Met Lys Arg Gly Leu Cys Cys Val Leu Leu Leu Cys Gly 1 5 10 15 Ala Val Phe Val Ser Pro 20 <210> 10 <211> 20 <212> PRT <213> Artificial sequence <220> <223> Native ActRIIA <400> 10 Met Gly Ala Ala Ala Lys Leu Ala Phe Ala Val Phe Leu Ile Ser Cys 1 5 10 15 Ser Ser Gly Ala 20 <210> 11 <211> 9 <212> PRT <213> Artificial sequence <220> <223> ActRIIA-hFc and ActRIIA-mFc N-terminal sequences <400> 11 Ile Leu Gly Arg Ser Glu Thr Gln Glu 1 5 <210> 12 <211> 329 <212> PRT <213> Artificial sequence <220> <223> ActRIIA-Fc protein with a 15-amino acid deletion at the C-terminus of the extracellular domain of ActRIIA <400> 12 Ile Leu Gly Arg Ser Glu Thr Gln Glu Cys Leu Phe Phe Asn Ala Asn 1 5 10 15 Trp Glu Lys Asp Arg Thr Asn Gln Thr Gly Val Glu Pro Cys Tyr Gly 20 25 30 Asp Lys Asp Lys Arg Arg His Cys Phe Ala Thr Trp Lys Asn Ile Ser 35 40 45 Gly Ser Ile Glu Ile Val Lys Gln Gly Cys Trp Leu Asp Asp Ile Asn 50 55 60 Cys Tyr Asp Arg Thr Asp Cys Val Glu Lys Lys Asp Ser Pro Glu Val 65 70 75 80 Tyr Phe Cys Cys Cys Glu Gly Asn Met Cys Asn Glu Lys Phe Ser Tyr 85 90 95 Phe Pro Glu Met Thr Gly Gly Gly Thr His Thr Cys Pro Pro Cys Pro 100 105 110 Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys 115 120 125 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 130 135 140 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 145 150 155 160 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 165 170 175 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 180 185 190 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 195 200 205 Ala Leu Pro Val Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 210 215 220 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met 225 230 235 240 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 245 250 255 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 260 265 270 Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 275 280 285 Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 290 295 300 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 305 310 315 320 Lys Ser Leu Ser Leu Ser Pro Gly Lys 325 <210> 13 <211> 369 <212> PRT <213> Artificial Sequence <220> <223> Unprocessed ActRIIA-hFc with TPA Leader Sequence <400> 13 Met Asp Ala Met Lys Arg Gly Leu Cys Cys Val Leu Leu Leu Cys Gly 1 5 10 15 Ala Val Phe Val Ser Pro Gly Ala Ala Ile Leu Gly Arg Ser Glu Thr 20 25 30 Gln Glu Cys Leu Phe Phe Asn Ala Asn Trp Glu Lys Asp Arg Thr Asn 35 40 45 Gln Thr Gly Val Glu Pro Cys Tyr Gly Asp Lys Asp Lys Arg Arg His 50 55 60 Cys Phe Ala Thr Trp Lys Asn Ile Ser Gly Ser Ile Glu Ile Val Lys 65 70 75 80 Gln Gly Cys Trp Leu Asp Asp Ile Asn Cys Tyr Asp Arg Thr Asp Cys 85 90 95 Val Glu Lys Lys Asp Ser Pro Glu Val Tyr Phe Cys Cys Cys Glu Gly 100 105 110 Asn Met Cys Asn Glu Lys Phe Ser Tyr Phe Pro Glu Met Glu Val Thr 115 120 125 Gln Pro Thr Ser Asn Pro Val Thr Pro Lys Pro Pro Thr Gly Gly Gly 130 135 140 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 145 150 155 160 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 165 170 175 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 180 185 190 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 195 200 205 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 210 215 220 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 225 230 235 240 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Val Pro Ile Glu Lys 245 250 255 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 260 265 270 Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 275 280 285 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 290 295 300 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 305 310 315 320 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 325 330 335 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 340 345 350 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 355 360 365 Lys <210> 14 <211> 1114 <212> DNA <213> Artificial Sequence <220> <223> Nucleic acid sequence encoding unprocessed ActRIIA-hFc with a TPA leader sequence <400> 14 atggatgcaa tgaagagagg gctctgctgt gtgctgctgc tgtgtggagc agtcttcgtt 60 tcgcccggcg ccgctatact tggtagatca gaaactcagg agtgtctttt tttaatgcta 120 attgggaaaa agacagaacc aatcaaactg gtgttgaacc gtgttatggt gacaaagata 180 aacggcggca ttgttttgct acctggaaga atatttctgg ttccattgaa tagtgaaaca 240 aggttgttgg ctggatgata tcaactgcta tgacaggact gattgtgtag aaaaaaaaga 300 cagccctgaa gtatatttct gttgctgtga gggcaatatg tgtaatgaaa agttttctta 360 ttttccggag atggaagtca cacagcccac ttcaaatcca gttacaccta agccacccac 420 cggtggtgga actcacacat gcccaccgtg cccagcacct gaactcctgg ggggaccgtc 480 agtcttcctc ttccccccaa aacccaagga caccctcatg atctcccgga cccctgaggt 540 cacatgcgtg gtggtggacg tgagccacga agaccctgag gtcaagttca actggtacgt 600 ggacggcgtg gaggtgcata atgccaagac aaagccgcgg gaggagcagt acaacagcac 660 gtaccgtgtg gtcagcgtcc tcaccgtcct gcaccaggac tggctgaatg gcaaggagta 720 caagtgcaag gtctccaaca aagccctccc agtccccatc gagaaaacca tctccaaagc 780 caaagggcag ccccgagaac cacaggtgta caccctgccc ccatcccggg aggagatgac 840 caagaaccag gtcagcctga cctgcctggt caaaggcttc tatcccagcg acatcgccgt 900 ggagtgggag agcaatgggc agccggagaa caactacaag accacgcctc ccgtgctgga 960 ctccgacggc tccttcttcc tctatagcaa gctcaccgtg gacaagagca ggtggcagca 1020 ggggaacgtc ttctcatgct ccgtgatgca tgaggctctg cacaaccact acacgcagaa 1080 gagcctctcc ctgtctccgg gtaaatgaga attc 1114 <210> 15 <211> 106 <212> PRT <213> Artificial Sequence <220> <223> Modified Human ActRIIB Soluble (Extracellular) <400> 15 Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu Arg 1 5 10 15 Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys Arg 20 25 30 Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile Glu Leu 35 40 45 Val Lys Lys Gly Cys Trp Asp Asp Asp Phe Asn Cys Tyr Asp Arg Gln 50 55 60 Glu Cys Val Ala Thr Glu Glu Asn Pro Gln Val Tyr Phe Cys Cys Cys 65 70 75 80 Glu Gly Asn Phe Cys Asn Glu Arg Phe Thr His Leu Pro Glu Ala Gly 85 90 95 Gly Pro Glu Val Thr Tyr Glu Pro Pro Pro 100 105 <210> 16 <211> 512 <212> PRT <213> Homo sapiens <220> <223> Human ActRIIB precursor protein sequence (A64) <400> 16 Met Thr Ala Pro Trp Val Ala Leu Ala Leu Leu Trp Gly Ser Leu Trp 1 5 10 15 Pro Gly Ser Gly Arg Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr 20 25 30 Asn Ala Asn Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg 35 40 45 Cys Glu Gly Glu Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Ala 50 55 60 Asn Ser Ser Gly Thr Ile Glu Leu Val Lys Lys Gly Cys Trp Leu Asp 65 70 75 80 Asp Phe Asn Cys Tyr Asp Arg Gln Glu Cys Val Ala Thr Glu Glu Asn 85 90 95 Pro Gln Val Tyr Phe Cys Cys Cys Glu Gly Asn Phe Cys Asn Glu Arg 100 105 110 Phe Thr His Leu Pro Glu Ala Gly Gly Pro Glu Val Thr Tyr Glu Pro 115 120 125 Pro Pro Thr Ala Pro Thr Leu Leu Thr Val Leu Ala Tyr Ser Leu Leu 130 135 140 Pro Ile Gly Gly Leu Ser Leu Ile Val Leu Leu Ala Phe Trp Met Tyr 145 150 155 160 Arg His Arg Lys Pro Pro Tyr Gly His Val Asp Ile His Glu Asp Pro 165 170 175 Gly Pro Pro Pro Pro Ser Pro Leu Val Gly Leu Lys Pro Leu Gln Leu 180 185 190 Leu Glu Ile Lys Ala Arg Gly Arg Phe Gly Cys Val Trp Lys Ala Gln 195 200 205 Leu Met Asn Asp Phe Val Ala Val Lys Ile Phe Pro Leu Gln Asp Lys 210 215 220 Gln Ser Trp Gln Ser Glu Arg Glu Ile Phe Ser Thr Pro Gly Met Lys 225 230 235 240 His Glu Asn Leu Leu Gln Phe Ile Ala Ala Glu Lys Arg Gly Ser Asn 245 250 255 Leu Glu Val Glu Leu Trp Leu Ile Thr Ala Phe His Asp Lys Gly Ser 260 265 270 Leu Thr Asp Tyr Leu Lys Gly Asn Ile Ile Thr Trp Asn Glu Leu Cys 275 280 285 His Val Ala Glu Thr Met Ser Arg Gly Leu Ser Tyr Leu His Glu Asp 290 295 300 Val Pro Trp Cys Arg Gly Glu Gly His Lys Pro Ser Ile Ala His Arg 305 310 315 320 Asp Phe Lys Ser Lys Asn Val Leu Leu Lys Ser Asp Leu Thr Ala Val 325 330 335 Leu Ala Asp Phe Gly Leu Ala Val Arg Phe Glu Pro Gly Lys Pro Pro 340 345 350 Gly Asp Thr His Gly Gln Val Gly Thr Arg Arg Tyr Met Ala Pro Glu 355 360 365 Val Leu Glu Gly Ala Ile Asn Phe Gln Arg Asp Ala Phe Leu Arg Ile 370 375 380 Asp Met Tyr Ala Met Gly Leu Val Leu Trp Glu Leu Val Ser Arg Cys 385 390 395 400 Lys Ala Ala Asp Gly Pro Val Asp Glu Tyr Met Leu Pro Phe Glu Glu 405 410 415 Glu Ile Gly Gln His Pro Ser Leu Glu Glu Leu Gln Glu Val Val Val 420 425 430 His Lys Lys Met Arg Pro Thr Ile Lys Asp His Trp Leu Lys His Pro 435 440 445 Gly Leu Ala Gln Leu Cys Val Thr Ile Glu Glu Cys Trp Asp His Asp 450 455 460 Ala Glu Ala Arg Leu Ser Ala Gly Cys Val Glu Glu Arg Val Ser Leu 465 470 475 480 Ile Arg Arg Ser Val Asn Gly Thr Thr Ser Asp Cys Leu Val Ser Leu 485 490 495 Val Thr Ser Val Thr Asn Val Asp Leu Pro Pro Lys Glu Ser Ser Ile 500 505 510 <210> 17 <211> 116 <212> PRT <213> Homo sapiens <220> <223> Human ActRIIB soluble (extracellular), processed polypeptide sequence (amino acids 19 - 134 of SEQ ID NO:16) <400> 17 Ser Gly Arg Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala 1 5 10 15 Asn Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu 20 25 30 Gly Glu Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Ala Asn Ser 35 40 45 Ser Gly Thr Ile Glu Leu Val Lys Lys Gly Cys Trp Leu Asp Asp Phe 50 55 60 Asn Cys Tyr Asp Arg Gln Glu Cys Val Ala Thr Glu Glu Asn Pro Gln 65 70 75 80 Val Tyr Phe Cys Cys Cys Glu Gly Asn Phe Cys Asn Glu Arg Phe Thr 85 90 95 His Leu Pro Glu Ala Gly Gly Pro Glu Val Thr Tyr Glu Pro Pro Pro 100 105 110 Thr Ala Pro Thr 115 <210> 18 <211> 101 <212> PRT <213> Artificial Sequence <220> <223> Human ActRIIB soluble (extracellular), processed polypeptide sequence with a 15 - amino acid deletion at the C - terminus (amino acids 19 - 119 of SEQ ID NO:16) <400> 18 Ser Gly Arg Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala 1 5 10 15 Asn Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu 20 25 30 Gly Glu Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Ala Asn Ser 35 40 45 Ser Gly Thr Ile Glu Leu Val Lys Lys Gly Cys Trp Leu Asp Asp Phe 50 55 60 Asn Cys Tyr Asp Arg Gln Glu Cys Val Ala Thr Glu Glu Asn Pro Gln 65 70 75 80 Val Tyr Phe Cys Cys Cys Glu Gly Asn Phe Cys Asn Glu Arg Phe Thr 85 90 95 His Leu Pro Glu Ala 100 <210> 19 <211> 1539 <212> DNA <213> Homo sapiens <220> <223> Nucleic acid sequence encoding the precursor protein of ActRIIB (A64) <400> 19 atgacggcgc cctgggtggc cctcgccctc ctctggggat cgctgtggcc cggctctggg 60 cgtggggagg ctgagacacg ggagtgcatc tactacaacg ccaactggga gctggagcgc 120 accaaccaga gcggcctgga gcgctgcgaa ggcgagcagg acaagcggct gcactgctac 180 gcctcctggg ccaacagctc tggcaccatc gagctcgtga agaagggctg ctggctagat 240 gacttcaact gctacgatag gcaggagtgt gtggccactg aggagaaccc ccaggtgtac 300 ttctgctgct gtgaaggcaa cttctgcaac gagcgcttca ctcatttgcc agaggctggg 360 ggcccggaag tcacgtacga gccacccccg acagccccca ccctgctcac ggtgctggcc 420 tactcactgc tgcccatcgg gggcctttcc ctcatcgtcc tgctggcctt ttggatgtac 480 cggcatcgca agccccccta cggtcatgtg gacatccatg aggaccctgg gcctccacca 540 ccatcccctc tggtgggcct gaagccactg cagctgctgg agatcaaggc tcgggggcgc 600 tttggctgtg tctggaaggc ccagctcatg aatgactttg tagctgtcaa gatcttccca 660 ctccaggaca agcagtcgtg gcagagtgaa cgggagatct tcagcacacc tggcatgaag 720 cacgagaacc tgctacagtt cattgctgcc gagaagcgag gctccaacct cgaagtagag 780 ctgtggctca tcacggcctt ccatgacaag ggctccctca cggattacct caaggggaac 840 atcatcacat ggaacgaact gtgtcatgta gcagagacga tgtcacgagg cctctcatac 900 ctgcatgagg atgtgccctg gtgccgtggc gagggccaca agccgtctat tgcccacagg 960 gactttaaaa gtaagaatgt attgctgaag agcgacctca cagccgtgct ggctgacttt 1020 ggcttggctg ttcgatttga gccagggaaa cctccagggg acacccacgg acaggtaggc 1080 acgagacggt acatggctcc tgaggtgctc gagggagcca tcaacttcca gagagatgcc 1140 ttcctgcgca ttgacatgta tgccatgggg ttggtgctgt gggagcttgt gtctcgctgc 1200 aaggctgcag acggacccgt ggatgagtac atgctgccct ttgaggaaga gattggccag 1260 cacccttcgt tggaggagct gcaggaggtg gtggtgcaca agaagatgag gcccaccatt 1320 aaagatcact ggttgaaaca cccgggcctg gcccagcttt gtgtgaccat cgaggagtgc 1380 tgggaccatg atgcagaggc tcgcttgtcc gcgggctgtg tggaggagcg ggtgtccctg 1440 attcggaggt cggtcaacgg cactacctcg gactgtctcg tttccctggt gacctctgtc 1500 accaatgtgg acctgccccc taaagagtca agcatctaa 1539 <210> 20 <211> 344 <212> PRT <213> Artificial Sequence <220> <223> A fusion protein comprising the soluble extracellular domain of ActRIIB (A64; SEQ ID NO:17) fused to an Fc domain <400> 20 Ser Gly Arg Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala 1 5 10 15 Asn Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu 20 25 30 Gly Glu Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Ala Asn Ser 35 40 45 Ser Gly Thr Ile Glu Leu Val Lys Lys Gly Cys Trp Leu Asp Asp Phe 50 55 60 Asn Cys Tyr Asp Arg Gln Glu Cys Val Ala Thr Glu Glu Asn Pro Gln 65 70 75 80 Val Tyr Phe Cys Cys Cys Glu Gly Asn Phe Cys Asn Glu Arg Phe Thr 85 90 95 His Leu Pro Glu Ala Gly Gly Pro Glu Val Thr Tyr Glu Pro Pro Pro 100 105 110 Thr Ala Pro Thr Gly Gly Gly Thr His Thr Cys Pro Pro Cys Pro Ala 115 120 125 Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro 130 135 140 Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val 145 150 155 160 Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val 165 170 175 Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln 180 185 190 Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln 195 200 205 Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala 210 215 220 Leu Pro Val Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro 225 230 235 240 Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr 245 250 255 Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser 260 265 270 Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr 275 280 285 Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr 290 295 300 Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe 305 310 315 320 Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys 325 330 335 Ser Leu Ser Leu Ser Pro Gly Lys 340 <210> 21 <211> 329 <212> PRT <213> Artificial Sequence <220> <223> Soluble extracellular domain of ActRIIB (A64) fused to the Fc domain and having a 15 amino acid deletion at the C-terminus (SEQ ID NO:18) <400> 21 Ser Gly Arg Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala 1 5 10 15 Asn Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu 20 25 30 Gly Glu Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Ala Asn Ser 35 40 45 Ser Gly Thr Ile Glu Leu Val Lys Lys Gly Cys Trp Leu Asp Asp Phe 50 55 60 Asn Cys Tyr Asp Arg Gln Glu Cys Val Ala Thr Glu Glu Asn Pro Gln 65 70 75 80 Val Tyr Phe Cys Cys Cys Glu Gly Asn Phe Cys Asn Glu Arg Phe Thr 85 90 95 His Leu Pro Glu Ala Gly Gly Gly Thr His Thr Cys Pro Pro Cys Pro 100 105 110 Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys 115 120 125 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 130 135 140 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 145 150 155 160 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 165 170 175 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 180 185 190 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 195 200 205 Ala Leu Pro Val Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 210 215 220 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met 225 230 235 240 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 245 250 255 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 260 265 270 Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 275 280 285 Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 290 295 300 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 305 310 315 320 Lys Ser Leu Ser Leu Ser Pro Gly Lys 325 <210> 22 <211> 105 <212> PRT <213> Artificial Sequence <220> <223> Modified human ActRIIB soluble (extracellular) <400> 22 Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu Arg 1 5 10 15 Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys Arg 20 25 30 Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile Glu Leu 35 40 45 Val Lys Lys Gly Cys Trp Asp Asp Asp Phe Asn Cys Tyr Asp Arg Gln 50 55 60 Glu Cys Val Ala Thr Glu Glu Asn Pro Gln Val Tyr Phe Cys Cys Cys 65 70 75 80 Glu Gly Asn Phe Cys Asn Glu Arg Phe Thr His Leu Pro Glu Ala Gly 85 90 95 Gly Pro Glu Val Thr Tyr Glu Pro Pro 100 105 <210> 23 <211> 107 <212> PRT <213> Artificial sequence <220> <223> Modified human ActRIIB soluble (extracellular) <400> 23 Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu Arg 1 5 10 15 Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys Arg 20 25 30 Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile Glu Leu 35 40 45 Val Lys Lys Gly Cys Trp Asp Asp Asp Phe Asn Cys Tyr Asp Arg Gln 50 55 60 Glu Cys Val Ala Thr Glu Glu Asn Pro Gln Val Tyr Phe Cys Cys Cys 65 70 75 80 Glu Gly Asn Phe Cys Asn Glu Arg Phe Thr His Leu Pro Glu Ala Gly 85 90 95 Gly Pro Glu Val Thr Tyr Glu Pro Pro Pro Thr 100 105 <210> 24 <211> 360 <212> PRT <213> Artificial Sequence <220> <223> Unprocessed ActRIIB-Fc Fusion Protein with Modifications <400> 24 Met Asp Ala Met Lys Arg Gly Leu Cys Cys Val Leu Leu Leu Cys Gly 1 5 10 15 Ala Val Phe Val Ser Pro Gly Ala Ala Glu Thr Arg Glu Cys Ile Tyr 20 25 30 Tyr Asn Ala Asn Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu 35 40 45 Arg Cys Glu Gly Glu Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp 50 55 60 Arg Asn Ser Ser Gly Thr Ile Glu Leu Val Lys Lys Gly Cys Trp Asp 65 70 75 80 Asp Asp Phe Asn Cys Tyr Asp Arg Gln Glu Cys Val Ala Thr Glu Glu 85 90 95 Asn Pro Gln Val Tyr Phe Cys Cys Cys Glu Gly Asn Phe Cys Asn Glu 100 105 110 Arg Phe Thr His Leu Pro Glu Ala Gly Gly Pro Glu Val Thr Tyr Glu 115 120 125 Pro Pro Pro Thr Gly Gly Gly Thr His Thr Cys Pro Pro Cys Pro Ala 130 135 140 Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro 145 150 155 160 Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val 165 170 175 Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val 180 185 190 Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln 195 200 205 Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln 210 215 220 Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala 225 230 235 240 Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro 245 250 255 Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr 260 265 270 Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser 275 280 285 Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr 290 295 300 Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr 305 310 315 320 Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe 325 330 335 Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys 340 345 350 Ser Leu Ser Leu Ser Pro Gly Lys 355 360 <210> 25 <211> 335 <212> PRT <213> Artificial sequence <220> <223> Modified and processed ActRIIB-Fc fusion protein <400> 25 Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu Arg 1 5 10 15 Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys Arg 20 25 30 Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile Glu Leu 35 40 45 Val Lys Lys Gly Cys Trp Asp Asp Asp Phe Asn Cys Tyr Asp Arg Gln 50 55 60 Glu Cys Val Ala Thr Glu Glu Asn Pro Gln Val Tyr Phe Cys Cys Cys 65 70 75 80 Glu Gly Asn Phe Cys Asn Glu Arg Phe Thr His Leu Pro Glu Ala Gly 85 90 95 Gly Pro Glu Val Thr Tyr Glu Pro Pro Pro Thr Gly Gly Gly Thr His 100 105 110 Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val 115 120 125 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 130 135 140 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 145 150 155 160 Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 165 170 175 Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser 180 185 190 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 195 200 205 Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile 210 215 220 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 225 230 235 240 Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 245 250 255 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 260 265 270 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 275 280 285 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 290 295 300 Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 305 310 315 320 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 325 330 335 <210> 26 <211> 115 <212> PRT <213> Artificial Sequence <220> <223> Human ActRIIB Soluble (Extracellular), Processed Polypeptide Sequence (Amino Acids 20 - 134 of SEQ ID NO:16) <400> 26 Gly Arg Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn 1 5 10 15 Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly 20 25 30 Glu Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Ala Asn Ser Ser 35 40 45 Gly Thr Ile Glu Leu Val Lys Lys Gly Cys Trp Leu Asp Asp Phe Asn 50 55 60 Cys Tyr Asp Arg Gln Glu Cys Val Ala Thr Glu Glu Asn Pro Gln Val 65 70 75 80 Tyr Phe Cys Cys Cys Glu Gly Asn Phe Cys Asn Glu Arg Phe Thr His 85 90 95 Leu Pro Glu Ala Gly Gly Pro Glu Val Thr Tyr Glu Pro Pro Pro Thr 100 105 110 Ala Pro Thr 115 <210> 27 <211> 100 <212> PRT <213> Artificial Sequence <220> <223> Human ActRIIB soluble (extracellular), processed polypeptide sequence with a 15 - amino acid deletion at the C - terminus (amino acids 20 - 119 of SEQ ID NO:16) <400> 27 Gly Arg Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn 1 5 10 15 Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly 20 25 30 Glu Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Ala Asn Ser Ser 35 40 45 Gly Thr Ile Glu Leu Val Lys Lys Gly Cys Trp Leu Asp Asp Phe Asn 50 55 60 Cys Tyr Asp Arg Gln Glu Cys Val Ala Thr Glu Glu Asn Pro Gln Val 65 70 75 80 Tyr Phe Cys Cys Cys Glu Gly Asn Phe Cys Asn Glu Arg Phe Thr His 85 90 95 Leu Pro Glu Ala 100 <210> 28 <211> 512 <212> PRT <213> Homo sapiens <220> <223> Human ActRIIB precursor protein sequence (R64) <400> 28 Met Thr Ala Pro Trp Val Ala Leu Ala Leu Leu Trp Gly Ser Leu Trp 1 5 10 15 Pro Gly Ser Gly Arg Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr 20 25 30 Asn Ala Asn Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg 35 40 45 Cys Glu Gly Glu Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg 50 55 60 Asn Ser Ser Gly Thr Ile Glu Leu Val Lys Lys Gly Cys Trp Leu Asp 65 70 75 80 Asp Phe Asn Cys Tyr Asp Arg Gln Glu Cys Val Ala Thr Glu Glu Asn 85 90 95 Pro Gln Val Tyr Phe Cys Cys Cys Glu Gly Asn Phe Cys Asn Glu Arg 100 105 110 Phe Thr His Leu Pro Glu Ala Gly Gly Pro Glu Val Thr Tyr Glu Pro 115 120 125 Pro Pro Thr Ala Pro Thr Leu Leu Thr Val Leu Ala Tyr Ser Leu Leu 130 135 140 Pro Ile Gly Gly Leu Ser Leu Ile Val Leu Leu Ala Phe Trp Met Tyr 145 150 155 160 Arg His Arg Lys Pro Pro Tyr Gly His Val Asp Ile His Glu Asp Pro 165 170 175 Gly Pro Pro Pro Pro Ser Pro Leu Val Gly Leu Lys Pro Leu Gln Leu 180 185 190 Leu Glu Ile Lys Ala Arg Gly Arg Phe Gly Cys Val Trp Lys Ala Gln 195 200 205 Leu Met Asn Asp Phe Val Ala Val Lys Ile Phe Pro Leu Gln Asp Lys 210 215 220 Gln Ser Trp Gln Ser Glu Arg Glu Ile Phe Ser Thr Pro Gly Met Lys 225 230 235 240 His Glu Asn Leu Leu Gln Phe Ile Ala Ala Glu Lys Arg Gly Ser Asn 245 250 255 Leu Glu Val Glu Leu Trp Leu Ile Thr Ala Phe His Asp Lys Gly Ser 260 265 270 Leu Thr Asp Tyr Leu Lys Gly Asn Ile Ile Thr Trp Asn Glu Leu Cys 275 280 285 His Val Ala Glu Thr Met Ser Arg Gly Leu Ser Tyr Leu His Glu Asp 290 295 300 Val Pro Trp Cys Arg Gly Glu Gly His Lys Pro Ser Ile Ala His Arg 305 310 315 320 Asp Phe Lys Ser Lys Asn Val Leu Leu Lys Ser Asp Leu Thr Ala Val 325 330 335 Leu Ala Asp Phe Gly Leu Ala Val Arg Phe Glu Pro Gly Lys Pro Pro 340 345 350 Gly Asp Thr His Gly Gln Val Gly Thr Arg Arg Tyr Met Ala Pro Glu 355 360 365 Val Leu Glu Gly Ala Ile Asn Phe Gln Arg Asp Ala Phe Leu Arg Ile 370 375 380 Asp Met Tyr Ala Met Gly Leu Val Leu Trp Glu Leu Val Ser Arg Cys 385 390 395 400 Lys Ala Ala Asp Gly Pro Val Asp Glu Tyr Met Leu Pro Phe Glu Glu 405 410 415 Glu Ile Gly Gln His Pro Ser Leu Glu Glu Leu Gln Glu Val Val Val 420 425 430 His Lys Lys Met Arg Pro Thr Ile Lys Asp His Trp Leu Lys His Pro 435 440 445 Gly Leu Ala Gln Leu Cys Val Thr Ile Glu Glu Cys Trp Asp His Asp 450 455 460 Ala Glu Ala Arg Leu Ser Ala Gly Cys Val Glu Glu Arg Val Ser Leu 465 470 475 480 Ile Arg Arg Ser Val Asn Gly Thr Thr Ser Asp Cys Leu Val Ser Leu 485 490 495 Val Thr Ser Val Thr Asn Val Asp Leu Pro Pro Lys Glu Ser Ser Ile 500 505 510 <210> 29 <211> 116 <212> PRT <213> Homo sapiens <220> <223> Human ActRIIB soluble (extracellular), processed polypeptide sequence (amino acids 19 - 134 of SEQ ID NO:28) <400> 29 Ser Gly Arg Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala 1 5 10 15 Asn Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu 20 25 30 Gly Glu Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser 35 40 45 Ser Gly Thr Ile Glu Leu Val Lys Lys Gly Cys Trp Leu Asp Asp Phe 50 55 60 Asn Cys Tyr Asp Arg Gln Glu Cys Val Ala Thr Glu Glu Asn Pro Gln 65 70 75 80 Val Tyr Phe Cys Cys Cys Glu Gly Asn Phe Cys Asn Glu Arg Phe Thr 85 90 95 His Leu Pro Glu Ala Gly Gly Pro Glu Val Thr Tyr Glu Pro Pro Pro 100 105 110 Thr Ala Pro Thr 115 <210> 30 <211> 101 <212> PRT <213> Artificial Sequence <220> <223> Human ActRIIB soluble (extracellular), processed polypeptide sequence with a 15 - amino - acid deletion at the C - terminus (amino acids 19 - 119 of SEQ ID NO:28) <400> 30 Ser Gly Arg Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala 1 5 10 15 Asn Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu 20 25 30 Gly Glu Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser 35 40 45 Ser Gly Thr Ile Glu Leu Val Lys Lys Gly Cys Trp Leu Asp Asp Phe 50 55 60 Asn Cys Tyr Asp Arg Gln Glu Cys Val Ala Thr Glu Glu Asn Pro Gln 65 70 75 80 Val Tyr Phe Cys Cys Cys Glu Gly Asn Phe Cys Asn Glu Arg Phe Thr 85 90 95 His Leu Pro Glu Ala 100 <210> 31 <211> 115 <212> PRT <213> Artificial Sequence <220> <223> Human ActRIIB Soluble (Extracellular), Processed Polypeptide Sequence (Amino Acids 20 - 134 of SEQ ID NO:28) <400> 31 Gly Arg Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn 1 5 10 15 Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly 20 25 30 Glu Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser 35 40 45 Gly Thr Ile Glu Leu Val Lys Lys Gly Cys Trp Leu Asp Asp Phe Asn 50 55 60 Cys Tyr Asp Arg Gln Glu Cys Val Ala Thr Glu Glu Asn Pro Gln Val 65 70 75 80 Tyr Phe Cys Cys Cys Glu Gly Asn Phe Cys Asn Glu Arg Phe Thr His 85 90 95 Leu Pro Glu Ala Gly Gly Pro Glu Val Thr Tyr Glu Pro Pro Pro Thr 100 105 110 Ala Pro Thr 115 <210> 32 <211> 100 <212> PRT <213> Artificial Sequence <220> <223> Human ActRIIB soluble (extracellular), processed polypeptide sequence with a 15 - amino acid deletion at the C - terminus (amino acids 20 - 119 of SEQ ID NO:28) <400> 32 Gly Arg Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn 1 5 10 15 Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly 20 25 30 Glu Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser 35 40 45 Gly Thr Ile Glu Leu Val Lys Lys Gly Cys Trp Leu Asp Asp Phe Asn 50 55 60 Cys Tyr Asp Arg Gln Glu Cys Val Ala Thr Glu Glu Asn Pro Gln Val 65 70 75 80 Tyr Phe Cys Cys Cys Glu Gly Asn Phe Cys Asn Glu Arg Phe Thr His 85 90 95 Leu Pro Glu Ala 100 <210> 33 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Human ActRIIB Soluble (Extracellular), Modified Processed Polypeptide <400> 33 Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu Arg 1 5 10 15 Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys Arg 20 25 30 Leu His Cys Tyr Ala Ser Trp Ala Asn Ser Ser Gly Thr Ile Glu Leu 35 40 45 Val Lys Lys Gly Cys Trp Asp Asp Asp Phe Asn Cys Tyr Asp Arg Gln 50 55 60 Glu Cys Val Ala Thr Glu Glu Asn Pro Gln Val Tyr Phe Cys Cys Cys 65 70 75 80 Glu Gly Asn Phe Cys Asn Glu Arg Phe Thr His Leu Pro Glu Ala Gly 85 90 95 Gly Pro Glu Val Thr Tyr Glu Pro Pro Pro Thr 100 105 <210> 34 <211> 360 <212> PRT <213> Artificial Sequence <220> <223> Modified unprocessed ActRIIB-Fc fusion protein <400> 34 Met Asp Ala Met Lys Arg Gly Leu Cys Cys Val Leu Leu Leu Cys Gly 1 5 10 15 Ala Val Phe Val Ser Pro Gly Ala Ala Glu Thr Arg Glu Cys Ile Tyr 20 25 30 Tyr Asn Ala Asn Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu 35 40 45 Arg Cys Glu Gly Glu Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp 50 55 60 Ala Asn Ser Ser Gly Thr Ile Glu Leu Val Lys Lys Gly Cys Trp Asp 65 70 75 80 Asp Asp Phe Asn Cys Tyr Asp Arg Gln Glu Cys Val Ala Thr Glu Glu 85 90 95 Asn Pro Gln Val Tyr Phe Cys Cys Cys Glu Gly Asn Phe Cys Asn Glu 100 105 110 Arg Phe Thr His Leu Pro Glu Ala Gly Gly Pro Glu Val Thr Tyr Glu 115 120 125 Pro Pro Pro Thr Gly Gly Gly Thr His Thr Cys Pro Pro Cys Pro Ala 130 135 140 Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro 145 150 155 160 Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val 165 170 175 Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val 180 185 190 Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln 195 200 205 Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln 210 215 220 Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala 225 230 235 240 Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro 245 250 255 Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr 260 265 270 Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser 275 280 285 Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr 290 295 300 Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr 305 310 315 320 Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe 325 330 335 Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys 340 345 350 Ser Leu Ser Leu Ser Pro Gly Lys 355 360 <210> 35 <211> 335 <212> PRT <213> Artificial Sequence <220> <223> Modified and Processed ActRIIB-Fc Fusion Protein <400> 35 Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu Arg 1 5 10 15 Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys Arg 20 25 30 Leu His Cys Tyr Ala Ser Trp Ala Asn Ser Ser Gly Thr Ile Glu Leu 35 40 45 Val Lys Lys Gly Cys Trp Asp Asp Asp Phe Asn Cys Tyr Asp Arg Gln 50 55 60 Glu Cys Val Ala Thr Glu Glu Asn Pro Gln Val Tyr Phe Cys Cys Cys 65 70 75 80 Glu Gly Asn Phe Cys Asn Glu Arg Phe Thr His Leu Pro Glu Ala Gly 85 90 95 Gly Pro Glu Val Thr Tyr Glu Pro Pro Pro Thr Gly Gly Gly Thr His 100 105 110 Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val 115 120 125 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 130 135 140 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 145 150 155 160 Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 165 170 175 Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser 180 185 190 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 195 200 205 Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile 210 215 220 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 225 230 235 240 Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 245 250 255 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 260 265 270 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 275 280 285 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 290 295 300 Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 305 310 315 320 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 325 330 335 <210> 36 <211> 115 <212> PRT <213> Artificial Sequence <220> <223> Human ActRIIB soluble (extracellular), processed polypeptide sequence with L79D mutation (amino acids 20 - 134 of SEQ ID NO:28) <400> 36 Gly Arg Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn 1 5 10 15 Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly 20 25 30 Glu Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser 35 40 45 Gly Thr Ile Glu Leu Val Lys Lys Gly Cys Trp Asp Asp Asp Phe Asn 50 55 60 Cys Tyr Asp Arg Gln Glu Cys Val Ala Thr Glu Glu Asn Pro Gln Val 65 70 75 80 Tyr Phe Cys Cys Cys Glu Gly Asn Phe Cys Asn Glu Arg Phe Thr His 85 90 95 Leu Pro Glu Ala Gly Gly Pro Glu Val Thr Tyr Glu Pro Pro Pro Thr 100 105 110 Ala Pro Thr 115 <210> 37 <211> 115 <212> PRT <213> Artificial Sequence <220> <223> Human ActRIIB soluble (extracellular), processed polypeptide sequence with L79D mutation (amino acids 20 - 134 of SEQ ID NO:16) <400> 37 Gly Arg Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn 1 5 10 15 Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly 20 25 30 Glu Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Ala Asn Ser Ser 35 40 45 Gly Thr Ile Glu Leu Val Lys Lys Gly Cys Trp Asp Asp Asp Phe Asn 50 55 60 Cys Tyr Asp Arg Gln Glu Cys Val Ala Thr Glu Glu Asn Pro Gln Val 65 70 75 80 Tyr Phe Cys Cys Cys Glu Gly Asn Phe Cys Asn Glu Arg Phe Thr His 85 90 95 Leu Pro Glu Ala Gly Gly Pro Glu Val Thr Tyr Glu Pro Pro Pro Thr 100 105 110 Ala Pro Thr 115 <210> 38 <211> 343 <212> PRT <213> Artificial Sequence <220> <223> Human ActRIIB soluble (extracellular), processed polypeptide sequence (amino acids 20 - 134 of SEQ ID NO:28) fused with an Fc domain via a GGG linker and having an L79D mutation <400> 38 Gly Arg Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn 1 5 10 15 Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly 20 25 30 Glu Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser 35 40 45 Gly Thr Ile Glu Leu Val Lys Lys Gly Cys Trp Asp Asp Asp Phe Asn 50 55 60 Cys Tyr Asp Arg Gln Glu Cys Val Ala Thr Glu Glu Asn Pro Gln Val 65 70 75 80 Tyr Phe Cys Cys Cys Glu Gly Asn Phe Cys Asn Glu Arg Phe Thr His 85 90 95 Leu Pro Glu Ala Gly Gly Pro Glu Val Thr Tyr Glu Pro Pro Pro Thr 100 105 110 Ala Pro Thr Gly Gly Gly Thr His Thr Cys Pro Pro Cys Pro Ala Pro 115 120 125 Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 130 135 140 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 145 150 155 160 Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 165 170 175 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 180 185 190 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 195 200 205 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 210 215 220 Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 225 230 235 240 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys 245 250 255 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 260 265 270 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 275 280 285 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 290 295 300 Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser 305 310 315 320 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 325 330 335 Leu Ser Leu Ser Pro Gly Lys 340 <210> 39 <211> 343 <212> PRT <213> Artificial Sequence <220> <223> Human ActRIIB soluble (extracellular), processed polypeptide sequence fused with Fc domain and having L79D mutation (amino acids 20 - 134 of SEQ ID NO:16) <400> 39 Gly Arg Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn 1 5 10 15 Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly 20 25 30 Glu Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Ala Asn Ser Ser 35 40 45 Gly Thr Ile Glu Leu Val Lys Lys Gly Cys Trp Asp Asp Asp Phe Asn 50 55 60 Cys Tyr Asp Arg Gln Glu Cys Val Ala Thr Glu Glu Asn Pro Gln Val 65 70 75 80 Tyr Phe Cys Cys Cys Glu Gly Asn Phe Cys Asn Glu Arg Phe Thr His 85 90 95 Leu Pro Glu Ala Gly Gly Pro Glu Val Thr Tyr Glu Pro Pro Pro Thr 100 105 110 Ala Pro Thr Gly Gly Gly Thr His Thr Cys Pro Pro Cys Pro Ala Pro 115 120 125 Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 130 135 140 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 145 150 155 160 Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 165 170 175 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 180 185 190 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 195 200 205 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 210 215 220 Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 225 230 235 240 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys 245 250 255 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 260 265 270 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 275 280 285 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 290 295 300 Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser 305 310 315 320 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 325 330 335 Leu Ser Leu Ser Pro Gly Lys 340 <210> 40 <211> 368 <212> PRT <213> Artificial Sequence <220> <223> Human ActRIIB soluble (extracellular), polypeptide sequence fused with Fc domain, having L79D mutation and having processed TPA leader sequence (amino acids 20 - 134 of SEQ ID NO:28) <400> 40 Met Asp Ala Met Lys Arg Gly Leu Cys Cys Val Leu Leu Leu Cys Gly 1 5 10 15 Ala Val Phe Val Ser Pro Gly Ala Ser Gly Arg Gly Glu Ala Glu Thr 20 25 30 Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu Arg Thr Asn 35 40 45 Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys Arg Leu His 50 55 60 Cys Tyr Ala Ser Trp Arg Asn Ser Ser Gly Thr Ile Glu Leu Val Lys 65 70 75 80 Lys Gly Cys Trp Asp Asp Asp Phe Asn Cys Tyr Asp Arg Gln Glu Cys 85 90 95 Val Ala Thr Glu Glu Asn Pro Gln Val Tyr Phe Cys Cys Cys Glu Gly 100 105 110 Asn Phe Cys Asn Glu Arg Phe Thr His Leu Pro Glu Ala Gly Gly Pro 115 120 125 Glu Val Thr Tyr Glu Pro Pro Pro Thr Ala Pro Thr Gly Gly Gly Thr 130 135 140 His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser 145 150 155 160 Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg 165 170 175 Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 180 185 190 Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 195 200 205 Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val 210 215 220 Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 225 230 235 240 Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 245 250 255 Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 260 265 270 Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys 275 280 285 Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 290 295 300 Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 305 310 315 320 Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 325 330 335 Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 340 345 350 Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 355 360 365 <210> 41 <211> 368 <212> PRT <213> Artificial Sequence <220> <223> Soluble (extracellular) human ActRIIB, polypeptide sequence (amino acids 20 - 134 of SEQ ID NO:16) fused to the Fc domain, having the L79D mutation and having a TPA leader sequence <400> 41 Met Asp Ala Met Lys Arg Gly Leu Cys Cys Val Leu Leu Leu Cys Gly 1 5 10 15 Ala Val Phe Val Ser Pro Gly Ala Ser Gly Arg Gly Glu Ala Glu Thr 20 25 30 Arg Glu Cys Ile Tyr Tyr Asn Ala Asn Trp Glu Leu Glu Arg Thr Asn 35 40 45 Gln Ser Gly Leu Glu Arg Cys Glu Gly Glu Gln Asp Lys Arg Leu His 50 55 60 Cys Tyr Ala Ser Trp Ala Asn Ser Ser Gly Thr Ile Glu Leu Val Lys 65 70 75 80 Lys Gly Cys Trp Asp Asp Asp Phe Asn Cys Tyr Asp Arg Gln Glu Cys 85 90 95 Val Ala Thr Glu Glu Asn Pro Gln Val Tyr Phe Cys Cys Cys Glu Gly 100 105 110 Asn Phe Cys Asn Glu Arg Phe Thr His Leu Pro Glu Ala Gly Gly Pro 115 120 125 Glu Val Thr Tyr Glu Pro Pro Pro Thr Ala Pro Thr Gly Gly Gly Thr 130 135 140 His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser 145 150 155 160 Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg 165 170 175 Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 180 185 190 Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 195 200 205 Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val 210 215 220 Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 225 230 235 240 Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 245 250 255 Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 260 265 270 Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys 275 280 285 Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 290 295 300 Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 305 310 315 320 Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 325 330 335 Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 340 345 350 Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 355 360 365 <210> 42 <211> 141 <212> PRT <213> Artificial Sequence <220> <223> Human ActRIIB soluble (extracellular), processed polypeptide sequence with variant C-terminal sequence (disclosed in WO2007 / 053775) <400> 42 Gly Arg Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn 1 5 10 15 Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly 20 25 30 Glu Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser 35 40 45 Gly Thr Ile Glu Leu Val Lys Lys Gly Cys Trp Leu Asp Asp Phe Asn 50 55 60 Cys Tyr Asp Arg Gln Glu Cys Val Ala Thr Glu Glu Asn Pro Gln Val 65 70 75 80 Tyr Phe Cys Cys Cys Glu Gly Asn Phe Cys Asn Glu Arg Phe Thr His 85 90 95 Leu Pro Glu Ala Gly Gly Pro Glu Gly Pro Trp Ala Ser Thr Thr Ile 100 105 110 Pro Ser Gly Gly Pro Glu Ala Thr Ala Ala Ala Gly Asp Gln Gly Ser 115 120 125 Gly Ala Leu Trp Leu Cys Leu Glu Gly Pro Ala His Glu 130 135 140 <210> 43 <211> 141 <212> PRT <213> Artificial Sequence <220> <223> Human ActRIIB Soluble (Extracellular), Processed Polypeptide Sequence with Variant C-Terminal Sequence (Disclosed in WO2007 / 053775) <400> 43 Gly Arg Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn 1 5 10 15 Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly 20 25 30 Glu Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser 35 40 45 Gly Thr Ile Glu Leu Val Lys Lys Gly Cys Trp Asp Asp Asp Phe Asn 50 55 60 Cys Tyr Asp Arg Gln Glu Cys Val Ala Thr Glu Glu Asn Pro Gln Val 65 70 75 80 Tyr Phe Cys Cys Cys Glu Gly Asn Phe Cys Asn Glu Arg Phe Thr His 85 90 95 Leu Pro Glu Ala Gly Gly Pro Glu Gly Pro Trp Ala Ser Thr Thr Ile 100 105 110 Pro Ser Gly Gly Pro Glu Ala Thr Ala Ala Ala Gly Asp Gln Gly Ser 115 120 125 Gly Ala Leu Trp Leu Cys Leu Glu Gly Pro Ala His Glu 130 135 140 <210> 44 <211> 370 <212> PRT <213> Artificial Sequence <220> <223> Human ActRIIB soluble (extracellular), processed polypeptide sequence with variant C-terminal sequence (disclosed in WO2007 / 053775) <400> 44 Gly Arg Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala Asn 1 5 10 15 Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu Gly 20 25 30 Glu Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser Ser 35 40 45 Gly Thr Ile Glu Leu Val Lys Lys Gly Cys Trp Asp Asp Asp Phe Asn 50 55 60 Cys Tyr Asp Arg Gln Glu Cys Val Ala Thr Glu Glu Asn Pro Gln Val 65 70 75 80 Tyr Phe Cys Cys Cys Glu Gly Asn Phe Cys Asn Glu Arg Phe Thr His 85 90 95 Leu Pro Glu Ala Gly Gly Pro Glu Gly Pro Trp Ala Ser Thr Thr Ile 100 105 110 Pro Ser Gly Gly Pro Glu Ala Thr Ala Ala Ala Gly Asp Gln Gly Ser 115 120 125 Gly Ala Leu Trp Leu Cys Leu Glu Gly Pro Ala His Glu Thr Gly Gly 130 135 140 Gly Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 145 150 155 160 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 165 170 175 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 180 185 190 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 195 200 205 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 210 215 220 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 225 230 235 240 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 245 250 255 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 260 265 270 Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu 275 280 285 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 290 295 300 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 305 310 315 320 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 325 330 335 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 340 345 350 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 355 360 365 Gly Lys 370 <210> 45 <211> 1083 <212> DNA <213> Artificial Sequence <220> <223> Nucleic acid sequence encoding SEQ ID NO:24 <400> 45 atggatgcaa tgaagagagg gctctgctgt gtgctgctgc tgtgtggagc agtcttcgtt 60 tcgcccggcg ccgccgaaac ccgcgaatgt atttattaca atgctaattg ggaactcgaa 120 cggacgaacc aatccgggct cgaacggtgt gagggggaac aggataaacg cctccattgc 180 tatgcgtcgt ggaggaactc ctccgggacg attgaactgg tcaagaaagg gtgctgggac 240 gacgatttca attgttatga ccgccaggaa tgtgtcgcga ccgaagagaa tccgcaggtc 300 tatttctgtt gttgcgaggg gaatttctgt aatgaacggt ttacccacct ccccgaagcc 360 ggcgggcccg aggtgaccta tgaacccccg cccaccggtg gtggaactca cacatgccca 420 ccgtgcccag cacctgaact cctgggggga ccgtcagtct tcctcttccc cccaaaaccc 480 aaggacaccc tcatgatctc ccggacccct gaggtcacat gcgtggtggt ggacgtgagc 540 cacgaagacc ctgaggtcaa gttcaactgg tacgtggacg gcgtggaggt gcataatgcc 600 aagacaaagc cgcgggagga gcagtacaac agcacgtacc gtgtggtcag cgtcctcacc 660 gtcctgcacc aggactggct gaatggcaag gagtacaagt gcaaggtctc caacaaagcc 720 ctcccagccc ccatcgagaa aaccatctcc aaagccaaag ggcagccccg agaaccacag 780 gtgtacaccc tgcccccatc ccgggaggag atgaccaaga accaggtcag cctgacctgc 840 ctggtcaaag gcttctatcc cagcgacatc gccgtggagt gggagagcaa tgggcagccg 900 gagaacaact acaagaccac gcctcccgtg ctggactccg acggctcctt cttcctctat 960 agcaagctca ccgtggacaa gagcaggtgg cagcagggga acgtcttctc atgctccgtg 1020 atgcatgagg ctctgcacaa ccactacacg cagaagagcc tctccctgtc cccgggtaaa 1080 tga 1083 <210> 46 <211> 344 <212> PRT <213> Artificial Sequence <220> A fusion protein comprising the soluble extracellular domain of ActRIIB (R64; SEQ ID NO:29) fused to an Fc domain <400> 46 Ser Gly Arg Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala 1 5 10 15 Asn Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu 20 25 30 Gly Glu Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser 35 40 45 Ser Gly Thr Ile Glu Leu Val Lys Lys Gly Cys Trp Leu Asp Asp Phe 50 55 60 Asn Cys Tyr Asp Arg Gln Glu Cys Val Ala Thr Glu Glu Asn Pro Gln 65 70 75 80 Val Tyr Phe Cys Cys Cys Glu Gly Asn Phe Cys Asn Glu Arg Phe Thr 85 90 95 His Leu Pro Glu Ala Gly Gly Pro Glu Val Thr Tyr Glu Pro Pro Pro 100 105 110 Thr Ala Pro Thr Gly Gly Gly Thr His Thr Cys Pro Pro Cys Pro Ala 115 120 125 Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro 130 135 140 Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val 145 150 155 160 Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val 165 170 175 Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln 180 185 190 Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln 195 200 205 Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala 210 215 220 Leu Pro Val Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro 225 230 235 240 Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr 245 250 255 Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser 260 265 270 Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr 275 280 285 Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr 290 295 300 Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe 305 310 315 320 Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys 325 330 335 Ser Leu Ser Leu Ser Pro Gly Lys 340 <210> 47 <211> 329 <212> PRT <213> Artificial Sequence <220> <223> A fusion protein comprising the soluble extracellular domain of ActRIIB (R64) with a C-terminal 15 amino acid deletion (SEQ ID NO:30) fused to an Fc domain <400> 47 Ser Gly Arg Gly Glu Ala Glu Thr Arg Glu Cys Ile Tyr Tyr Asn Ala 1 5 10 15 Asn Trp Glu Leu Glu Arg Thr Asn Gln Ser Gly Leu Glu Arg Cys Glu 20 25 30 Gly Glu Gln Asp Lys Arg Leu His Cys Tyr Ala Ser Trp Arg Asn Ser 35 40 45 Ser Gly Thr Ile Glu Leu Val Lys Lys Gly Cys Trp Leu Asp Asp Phe 50 55 60 Asn Cys Tyr Asp Arg Gln Glu Cys Val Ala Thr Glu Glu Asn Pro Gln 65 70 75 80 Val Tyr Phe Cys Cys Cys Glu Gly Asn Phe Cys Asn Glu Arg Phe Thr 85 90 95 His Leu Pro Glu Ala Gly Gly Gly Thr His Thr Cys Pro Pro Cys Pro 100 105 110 Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys 115 120 125 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 130 135 140 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 145 150 155 160 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 165 170 175 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 180 185 190 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 195 200 205 Ala Leu Pro Val Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 210 215 220 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met 225 230 235 240 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 245 250 255 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 260 265 270 Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 275 280 285 Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 290 295 300 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 305 310 315 320 Lys Ser Leu Ser Leu Ser Pro Gly Lys 325 Brief Description of the Drawings

[0275] Figure 1 Describe the dosing regimen and study design of Example 2. See Section 8.2. ActRIIA-I refers to an ActRIIA signal transduction inhibitor (SEQ ID NO:7).

[0276] Figure 2 Describe the proportion of subjects with high transfusion burden (HTB) achieving RBC transfusion independence (RBC-TI) of greater than or equal to 56 days; or for subjects with low transfusion burden (LTB), with an increase in mean hemoglobin (Hb) of greater than or equal to 1.5 g / dL during an 8-week transfusion-free period and an RBC-TI of greater than or equal to 56 days. ActRIIA-I refers to an ActRIIA signal transduction inhibitor (SEQ ID NO:7).

[0277] Figure 3 Depict the hemoglobin levels (Hb, g / dL) and the number of RBC transfusion units received by exemplary HTB subjects receiving a 1.0 mg / kg dose of ActRIIA (SEQ ID NO:7).Figure 3 Demonstrate that the exemplary HTB subject achieved an RBC-TI greater than 56 days.

[0278] Figure 4 Demonstrate the maximum duration of the transfusion burden response in HTB responders (n = 19) following treatment with a specified dose of the ActRIIA signal transduction inhibitor (SEQ ID NO:7). ActRIIA-I refers to the ActRIIA signal transduction inhibitor (SEQ ID NO:7).

[0279] Figure 5 Demonstrate the maximum duration of the RBC-TI response in HTB subjects (n = 5) who achieved an RBC-TI greater than or equal to 56 days following treatment with a specified dose of the ActRIIA signal transduction inhibitor (SEQ ID NO:7). ActRIIA-I refers to the ActRIIA signal transduction inhibitor (SEQ ID NO:7).

[0280] Figure 6 Demonstrate the proportion of LTB subjects (n = 9) who achieved an RBC-TI greater than or equal to 56 days and an average Hb increase greater than or equal to 1.5 g / dL following treatment with a specified dose of the ActRIIA signal transduction inhibitor (SEQ ID NO:7). ActRIIA-I refers to the ActRIIA signal transduction inhibitor (SEQ ID NO:7).

[0281] Figure 7 Demonstrate the maximum duration of the RBC-TI response in LTB subjects (n = 5) who achieved an RBC-TI greater than or equal to 56 days and an average Hb increase greater than or equal to 1.5 g / dL following treatment with a specified dose of ActRIIA (SEQ ID NO:7). ActRIIA-I refers to the ActRIIA signal transduction inhibitor (SEQ ID NO:7).

[0282] Figure 8 Describe the dosing regimen and study design of Example 2. See Section 8.3. BL = baseline. ActRIIB-I refers to the ActRIIB signal transduction inhibitor (SEQ ID NO:25).

[0283] Figure 9 Describe the maximum hemoglobin increase in LTB subjects following treatment with a specified dose of the ActRIIB signal transduction inhibitor (SEQ ID NO:25).

[0284] Figure 10Describe the increase in reticulocytes in LTB subjects after treatment with a specified dose of an ActRIIB signal transduction inhibitor (SEQ ID NO:25).

[0285] Figure 11 Describe the hemoglobin levels of exemplary LTB subjects administered a specified dose of an ActRIIB signal transduction inhibitor (SEQ ID NO:25) according to the specified treatment regimen. BL = baseline.

[0286] Figure 12 Describe the hemoglobin levels of exemplary LTB subjects administered a specified dose of an ActRIIB signal transduction inhibitor (SEQ ID NO:25) according to the specified treatment regimen. BL = baseline.

[0287] Figure 13 Describe the hemoglobin levels of exemplary HTB subjects administered a specified dose of an ActRIIB signal transduction inhibitor (SEQ ID NO:25) according to the specified treatment regimen. BL = baseline.

[0288] Figure 14 Depict the hemoglobin levels (Hb, g / dL) and the number of RBC transfusion units received by exemplary HTB subjects receiving a 1.0 mg / kg dose of ActRIIA-hFc (SEQ ID NO:7). Figure 14 Demonstrate that exemplary HTB subjects achieved an RBC-TI of at least 337 days after initiation of treatment with ActRIIA-hFc (SEQ ID NO:7).

[0289] Figure 15 Depict the hemoglobin levels (Hb, g / dL) and the number of RBC transfusion units received by exemplary LTB subjects receiving a 1.0 mg / kg dose of ActRIIA (SEQ ID NO:7). Figure 15 Demonstrate that exemplary LTB subjects achieved a sustained increase in Hb levels of at least 337 days after initiation of treatment with ActRIIA-hFc (SEQ ID NO:7).

[0290] Figure 16 Depict the transfusion burden for obtaining eligible subjects who are transfusion-independent. Subjects received treatment with ActRIIB-hFc between 0.75 mg / kg and 1.75 mg / kg.

[0291] Figure 17Describe the proportion of subjects achieving red blood cell transfusion independence (RBC-TI) with an average hemoglobin increase equal to or greater than 1.5 g / dL in patients receiving the ActRIIA-hFC fusion (SEQ ID NO:7) during any 8-week period for patients with LTB. The dark grey shading represents patients with HTB, and the light grey shading represents patients with LTB.

[0292] Figure 18 Illustrate the hemoglobin response of an exemplary HTB subject during the 12-month ActRIIA-hFc (SEQ ID NO:7) treatment extension study. The first and last treatment doses are indicated by arrows. Transfusion events are represented by thick lines. Plot the hemoglobin (Hgb) results (g / dL) against time (days).

[0293] Figure 19 Illustrate the hemoglobin response of an exemplary LTB subject during the 12-month ActRIIA-hFc (SEQ ID NO:7) treatment extension study. Plot the mean change in Hgb (g / L) against time (months).

[0294] Figure 20 Illustrate the transfusion independence response observed in six subjects receiving ActRIIA-hFc (SEQ ID NO:7) at doses of 1.0 mg / kg (subjects represented by the bottom four thick lines) and 1.75 mg / kg (subject represented by the top thick line) simultaneously during the 12-month ActRIIA-hFc (SEQ ID NO:7) treatment extension study. Throughout the study, four patients achieved sustained transfusion independence (middle 4 thick lines). One patient achieved transfusion independence approximately 1 month after treatment with ActRIIA-hFc (SEQ ID NO:7) (top thick line). One patient experienced transfusion independence intermittently for approximately 2 months (bottom thick line).

[0295] 7. Detailed description

[0296] 7.1 Summary

[0297] The present invention unexpectedly discovers that the level of ring sideroblasts in patients with blood-related disorders can be used to identify patients who respond to treatment with inhibitors of activin-ActRII signal transduction. Such blood-related disorders can be: (i) anemia; (ii) anemia requiring RBC transfusion; (iii) MDS; and / or (iv) non-proliferative CMML. See Section 7.8. Without being bound by theory, approximately 15% or more ring sideroblasts in erythroblasts in patients with blood-related disorders predict an improved clinical response to inhibitors of activin-ActRII signal transduction in that patient, as compared to patients with the same blood-related disorder but having less than approximately 15% ring sideroblasts in erythroblasts. Such improved clinical responses can be an increased response of hematological parameters such as hemoglobin level, red blood cell level, and hematocrit. Such improved clinical responses may themselves manifest as a lower transfusion burden. In addition, such improved clinical responses can lead to long-term benefits for patients who no longer require continued administration of inhibitors of activin-ActRII signal transduction. In other words, the methods provided herein can lead to an improvement in one or more hematological parameters of a patient over a period of time after the administration of inhibitors of activin-ActRII signal transduction has been stopped.

[0298] Accordingly, provided herein are methods for treating patients with blood-related disorders, wherein the methods comprise: (a) determining the percentage of ring sideroblasts in erythroblasts; and (b) administering an inhibitor of activin-ActRII signal transduction to the patient if approximately 15% or more of the erythroblasts are ring sideroblasts. More specifically, provided herein are methods for treating patients with blood-related disorders, wherein the methods comprise: (a) determining the percentage of ring sideroblasts in erythroblasts of a patient; (b) administering an inhibitor of activin-ActRII signal transduction to the patient; and (c) if at least approximately 15% of the erythroblasts are ring sideroblasts, then (i) reducing the dose of the inhibitor of activin-ActRII signal transduction administered or stopping its administration after a period of time, and / or (ii) reducing the frequency of administration of the inhibitor of activin-ActRII signal transduction after a period of time. A detailed description of these methods can be found in Sections 7.3 and 7.4.

[0299] 7.2 Terms and Abbreviations

[0300] As used herein, "ActRII" refers to activin receptor type II. As used herein, "ActRIIA" refers to activin receptor type IIA. See, e.g., Mathews and Vale, 1991, Cell 65:973-982. GenBank TM GenBank accession number NM_001278579.1 provides an exemplary human ActRIIA nucleic acid sequence. GenBank TM GenBank accession number NP_001265508.1 provides an exemplary human ActRIIA amino acid sequence. As used herein, "ActRIIB" refers to activin receptor type IIB. See, e.g., Attisano et al., 1992, Cell 68:97-108. GenBank TM GenBank accession number NM_001106.3 provides an exemplary human ActRIIB nucleic acid sequence. GenBank TM GenBank accession number NP_001097.2 provides an exemplary human ActRIIB amino acid sequence.

[0301] As used herein, "ActRIIA-mFc" or "mActRIIA-Fc" refers to a murine activin type IIA receptor-IgG1 fusion protein. See, e.g., U.S. Patent No. 8,173,601. As used herein, "mActRIIB-Fc" or "ActRIIB-mFc" refers to a murine activin type IIB receptor-IgG1 fusion protein. See, e.g., U.S. Patent No. 8,173,601. As used herein, "hActRIIA-Fc" or "ActRIIA-hFc" refers to a human activin type IIA receptor-IgG1 fusion protein. See, e.g., U.S. Patent No. 8,173,601. In a particular embodiment, hActRIIA-Fc is sotatercept (SEQ ID NO:7). As used herein, "hActRIIB-Fc" or "ActRIIB-hFc" refers to a human activin type IIB receptor-IgG1 fusion protein. See, e.g., U.S. Patent No. 8,173,601. In a particular embodiment, hActRIIB-Fc is luspatercept (SEQ ID NO:25).

[0302] As used herein, "ALK" refers to anaplastic lymphoma kinase.

[0303] As used herein, "BL" refers to baseline.

[0304] As used herein, "BMP7" refers to bone morphogenetic protein 7.

[0305] As used herein, "CMML" refers to chronic myelomonocytic leukemia.

[0306] As used herein, "DEXA" refers to dual-energy X-ray absorptiometry.

[0307] As used herein, "DNMT3A" refers to DNA (cytosine-5)-methyltransferase 3A. GenBank TM Accession numbers NM_153759.3, NM_022552.4, NM_175629.2, and NM_175630.1 provide exemplary nucleic acid sequences of DNMT3A. GenBank TM Accession numbers NP_715640.2, NP_783329.1, NP_783328.1, and NP_072046.2 provide exemplary amino acid sequences of DNMT3A.

[0308] As used herein, "ECD" refers to extracellular domain.

[0309] As used herein, "EPO" refers to erythropoietin.

[0310] As used herein, "ESA" refers to erythropoiesis-stimulating agent.

[0311] As used herein, "G-CSF" refers to granulocyte colony-stimulating factor.

[0312] As used herein, "GM-CSF" refers to granulocyte macrophage colony-stimulating factor.

[0313] As used herein, "Hb" refers to hemoglobin.

[0314] As used herein, "HBML" refers to honey bee melittin.

[0315] As used herein, "HI-E" refers to erythroid hematological improvement. In certain embodiments, the HI-E is as defined by the IWG. In certain embodiments, the HI-E is as defined by the Revised 2006 IWG. In certain embodiments, HI-E in patients with a low transfusion burden is an increase in hemoglobin concentration of at least 1.5 g / dL in the patient for at least 8 weeks. In certain embodiments, HI-E in patients with a high transfusion burden is a reduction of at least 4 units of RBC transfusions within 8 weeks.

[0316] As used herein, "HTB" refers to high transfusion burden. In certain embodiments, an HTB subject receives greater than or equal to 4 RBC units during an 8-week course of treatment.

[0317] As used herein, "IgG" refers to immunoglobulin G.

[0318] As used herein, "Intermediate-1 (Int-1)" refers to an IPSS score of intermediate 1. See Section 7.8.

[0319] As used herein, "IPSS" refers to the International Prognostic Scoring System. See Section 7.8.

[0320] As used herein, "IWG" refers to the International Working Group. See, e.g., Cheson et al., Blood. 2000 96:3671-3674. In certain embodiments, the IWG refers to the 2006 Revised Standard. See, e.g., Cheson et al., 2006, Blood, 108(2).

[0321] As used herein, "LTB" refers to low transfusion burden. In certain embodiments, an LTB subject receives less than 4 RBC units during an 8-week course of treatment.

[0322] As used herein, "MDS" refers to myelodysplastic syndrome.

[0323] As used herein, "PD" refers to pharmacodynamics.

[0324] As used herein, "PK" refers to pharmacokinetics.

[0325] As used herein, "qCT" refers to quantitative computed tomography.

[0326] As used herein, "RARS" refers to refractory anemia with ring sideroblasts.

[0327] As used herein, "RBC" refers to red blood cell.

[0328] As used herein, "RBC-TI" refers to red blood cell transfusion independent.

[0329] As used herein, "RCMD-RS" refers to refractory cytopenia with multilineage dysplasia with ring sideroblasts.

[0330] As used herein, "RS" refers to ring sideroblast.

[0331] As used herein, "SC" refers to subcutaneous.

[0332] As used herein, "SETBP1" refers to SET binding protein 1. GenBank TM GenBank accession numbers NM_015559.2 and NM_001130110.1 provide exemplary nucleic acid sequences of human SETBP1. TM GenBank accession numbers NP_056374.2 and NP_001123582.1 provide exemplary amino acid sequences of human SETBP1.

[0333] As used herein, "SF3B1" refers to splicing factor 3B1. GenBank TM GenBank accession numbers NM_012433.3, NM_001005523.2 and NM_001308824.1 provide exemplary nucleic acid sequences of human SF3B1. TM GenBank accession numbers NP_001295753.1, NP_001005526.1 and NP_036565.2 provide exemplary amino acid sequences of human SF3B1.

[0334] As used herein, "SPR" refers to surface plasmon resonance.

[0335] As used herein, "SRSF2" refers to serine / arginine-rich splicing factor 2. GenBank TM Accession numbers NM_003016.4 and NM_001195427.1 provide exemplary nucleic acid sequences of human SRSF2. GenBank TM Accession numbers NP_001182356.1 and NP_003007.2 provide exemplary amino acid sequences of human SRSF2.

[0336] As used herein, "TET2" refers to tet methylcytosine dioxygenase 2. GenBank TM Accession numbers NM_001127208.2 and NM_017628.4 provide exemplary nucleic acid sequences of human TET2. GenBank TM Accession numbers NP_001120680.1 and NP_060098.3 provide exemplary amino acid sequences of human TET2.

[0337] As used herein, "TGF" refers to transforming growth factor.

[0338] As used herein, "TPA" refers to tissue plasminogen activator.

[0339] 7.3 Treatment methods

[0340] In certain embodiments, provided herein are methods of treating a subject having a blood-related disorder, wherein the methods comprise (a) determining the percentage of erythroblasts that are ring sideroblasts in the subject; and (b) administering to the subject a pharmaceutically effective dose of an ActRII signaling inhibitor if at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% of the erythroblasts in the subject are ring sideroblasts. In certain embodiments, the inhibitor of ActRII signaling is administered to the subject if at least 15% of the erythroblasts in the subject are ring sideroblasts. In certain embodiments, the percentage of erythroblasts that are ring sideroblasts in the subject is determined at a first time. In certain embodiments, the first time is within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 3 months, 4 months, 5 months, or 6 months of administering to the subject a pharmaceutically effective dose of an ActRII signaling inhibitor. In certain embodiments, the blood-related disorder is a blood-related disorder as described in Section 7.8. In certain embodiments, the subject is a subject as described in Section 7.8. In certain embodiments, the subject has a hemoglobin level of less than 11 g / dL. In certain embodiments, the subject has a reduced hemoglobin level compared to a reference population. In certain embodiments, the reference population is as described in Section 7.10. In certain embodiments, the subject has anemia. In certain embodiments, the subject is a subject in need of RBC transfusion. In certain embodiments, the subject has MDS. In certain embodiments, the subject has non-proliferative CMML. In certain embodiments, if at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% of the erythroblasts in the subject are ring sideroblasts, then the subject has an increased likelihood of achieving normalization of one or more hematological parameters. In certain embodiments, if at least 15% of the erythroblasts in the subject are ring sideroblasts, the subject has an increased likelihood of achieving normalization of one or more hematological parameters. In certain embodiments, the hematological parameter is a hemoglobin level. In certain embodiments, the hematological parameter is a hematocrit. In certain embodiments, the hematological parameter is a red blood cell count. In certain embodiments, the hematological parameter is the percentage of erythroblasts that are ring sideroblasts in the subject. In certain embodiments, the normalized hematological parameter is the level of the hematological parameter of a reference population. In certain embodiments, the reference population is the reference population as described in Section 7.10.In certain embodiments, the normalization of the one or more hematological parameters is an improvement of at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% compared to the hematological parameters of the subject for a period of time prior to administering the initial dose of the ActRII signal transduction inhibitor to the subject. In certain embodiments, the period of time prior to administering the initial dose of the ActRII signal transduction inhibitor to the subject is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 3 months, 4 months, 5 months or 6 months. In certain embodiments, the percentage of erythroblasts that are ring sideroblasts in the subject is determined by the assay described in Section 7.10. In certain embodiments, ring sideroblasts are identified by the assay described in Section 7.10. In certain embodiments, ring sideroblasts are identified by Prussian blue staining. In certain embodiments, erythroblasts are identified by the assay described in Section 7.10. In certain embodiments, the hemoglobin level of the subject is determined by the assay described in Section 7.10. In certain embodiments, the pharmaceutically effective dose is the dose described in Section 7.7. In certain embodiments, the pharmaceutically effective dose is administered at the frequency described in Section 7.7. In certain embodiments, the pharmaceutically effective dose is administered as described in Section 7.7. In certain embodiments, the pharmaceutically effective dose is the initial dose described in Section 7.7. In certain embodiments, the pharmaceutically effective dose is the adjusted dose described in Section 7.7. In certain embodiments, the ActRII signal transduction inhibitor is administered in a composition as described in Section 7.11. In certain embodiments, the composition is administered at the frequency described in Section 7.7. In certain embodiments, the composition is administered as described in Section 7.7. In certain embodiments, the ActRII signal transduction inhibitor is the ActRII signal transduction inhibitor described in Section 7.9. In certain embodiments, the ActRII signal transduction inhibitor is an ActRIIA signal transduction inhibitor. In certain embodiments, the ActRIIA signal transduction inhibitor is administered subcutaneously once every 21 days. In certain embodiments, the ActRII signal transduction inhibitor is ActRIIA-Fc such as ActRIIA-hFc (e.g., SEQ ID NO:7). In certain embodiments, the ActRII signal transduction inhibitor is an ActRIIB signal transduction inhibitor. In certain embodiments, the ActRIIB signal transduction inhibitor is administered subcutaneously once every 21 days.In certain embodiments, the ActRII signal transduction inhibitor is ActRII-Fc such as ActRIIB-hFc (e.g., SEQ ID NO:25).

[0341] In certain embodiments, provided herein are methods of treating a blood-related disorder in a subject, comprising administering an activin receptor type II (ActRII) signal transduction inhibitor to the subject at a pharmaceutically effective dose for a period of time to effect (i) a long-term decrease in the percentage of erythroblasts that are ring sideroblasts in the subject as compared to an initial percentage of erythroblasts that are ring sideroblasts in the subject; and (ii) a long-term increase in the hemoglobin level of the subject as compared to the hemoglobin level of the subject during a period of time prior to administering an initial dose of the ActRII signal transduction inhibitor to the subject; wherein the pharmaceutically effective dose is between 0.1 mg / kg and 2.0 mg / kg, and wherein at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or at least 20% of the erythroblasts in the subject are ring sideroblasts. In certain embodiments, the pharmaceutically effective dose is between 0.75 mg / kg and 2.0 mg / kg. In certain embodiments, the blood-related disorder is a blood-related disorder as described in Section 7.8. In certain embodiments, the subject is a subject as described in Section 7.8. In certain embodiments, 15% of the erythroblasts in the subject are ring sideroblasts. In certain embodiments, the period of time prior to administering an initial dose of the ActRII signal transduction inhibitor to the subject is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 3 months, 4 months, 5 months or 6 months. In certain embodiments, the subject is a subject in need of RBC transfusion. As used herein, "ring sideroblasts" and "ringed sideroblasts" and "RS" may be used interchangeably. In certain embodiments, the ActRII signal transduction inhibitor is administered for up to 1, 2, 3, 4, 5 or 6 months. In certain embodiments, the initial percentage of erythroblasts that are ring sideroblasts in the subject is the percentage of erythroblasts that are ring sideroblasts in the subject during a period of time prior to administering an initial dose of the ActRII signal transduction inhibitor to the subject. In certain embodiments, the period of time prior to administering an initial dose of the ActRII signal transduction inhibitor to the subject is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 3 months, 4 months, 5 months or 6 months. In certain embodiments, the long-term decrease in the percentage of erythroblasts that are ring sideroblasts in the subject is maintained for at least 3, 4, 5, 6, 12, 18 or 24 months after the period of time of administration of the ActRII signal transduction inhibitor.In certain embodiments, a long-term reduction in the percentage of erythroblasts that are ring sideroblasts in the subject is maintained for at least 3, 4, 5, 6, 12, 18, or 24 months after the last dose of the ActRII signal transduction inhibitor is administered and without further administration of the ActRII signal transduction inhibitor. In certain embodiments, the long-term reduction in the percentage of erythroblasts that are ring sideroblasts in the subject is at least 1.5, 2.5, 5.0, 7.5, or 10.0-fold lower than the initial percentage of erythroblasts that are ring sideroblasts in the subject at least 6, 12, 18, or 24 months after the time period of ActRII signal transduction inhibitor administration. In certain embodiments, a long-term increase in the hemoglobin level of the subject is maintained for at least 3, 4, 5, 6, 12, 18, or 24 months after the time period of ActRII signal transduction inhibitor administration. In certain embodiments, the long-term increase in the hemoglobin level of the subject, at least 3, 4, 5, 6, 12, 18, or 24 months after the time period of ActRII signal transduction inhibitor administration, is a hemoglobin level of the subject between about 11 g / dL and 18 g / dL. In certain embodiments, the subject does not require RBC transfusion at least 3, 4, 5, 6, 12, 18, or 24 months after the time period of ActRII signal transduction inhibitor administration. In certain embodiments, the method eliminates the subject's need for RBC transfusion at least 3, 4, 5, 6, 12, 18, or 24 months after administration of the ActRII signal transduction inhibitor. In certain embodiments, the long-term reduction in the percentage of erythroblasts that are ring sideroblasts in the subject is at least 1.5, 2.5, 5.0, 7.5, or 10.0-fold lower than the initial percentage of erythroblasts that are ring sideroblasts in the subject at least 6, 12, 18, or 24 months after the last dose of the ActRII signal transduction inhibitor is administered and without further administration of the ActRII signal transduction inhibitor. In certain embodiments, a long-term increase in the hemoglobin level of the subject is maintained for at least 3, 4, 5, 6, 12, 18, or 24 months after the last dose of the ActRII signal transduction inhibitor is administered and without further administration of the ActRII signal transduction inhibitor. In certain embodiments, the long-term increase in the hemoglobin level of the subject, at least 3, 4, 5, 6, 12, 18, or 24 months after the last dose of the ActRII signal transduction inhibitor is administered and without further administration of the ActRII signal transduction inhibitor, is a hemoglobin level of the subject between about 11 g / dL and 18 g / dL. In certain embodiments, the subject does not require RBC transfusion at least 3, 4, 5, 6, 12, 18, or 24 months after the last dose of the ActRII signal transduction inhibitor is administered and without further administration of the ActRII signal transduction inhibitor.In certain embodiments, at least 3, 4, 5, 6, 12, 18, or 24 months after the last dose of the ActRII signal transduction inhibitor is administered and without further administration of the ActRII signal transduction inhibitor, the method eliminates the subject's need for RBC transfusions.

[0342] In certain embodiments, the method further comprises determining another percentage of erythroblasts that are ring sideroblasts in the subject 6, 12, 18, and / or 24 months after the time period of ActRII signal transduction inhibitor administration. In certain embodiments, the method further comprises determining another hemoglobin level in the subject 6, 12, 18, and / or 24 months after the time period of ActRII signal transduction inhibitor administration.

[0343] In certain embodiments, the percentage of erythroblasts that are ring sideroblasts in the subject is determined by the assay described in Section 7.10. In certain embodiments, ring sideroblasts are identified by the assay described in Section 7.10. In certain embodiments, ring sideroblasts are identified by Prussian blue staining. In certain embodiments, erythroblasts are identified by the assay described in Section 7.10. In certain embodiments, the hemoglobin level of the subject is determined by the assay described in Section 7.10. In certain embodiments, the subject is the subject described in Section 7.8. In certain embodiments, at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or at least 20% of the erythroblasts in the subject are ring sideroblasts. In certain embodiments, the subject is the subject described in Section 7.8. In certain embodiments, at least 15% of the erythroblasts in the subject are ring sideroblasts. In certain embodiments, the hemoglobin level of the subject is less than 11 g / dL. In certain embodiments, the subject has a reduced hemoglobin level compared to a reference population. In certain embodiments, the reference population is as described in Section 7.10. In certain embodiments, the subject has anemia. In certain embodiments, the subject is a subject in need of RBC transfusions. In certain embodiments, the subject has MDS. In certain embodiments, the subject has non-proliferative CMML.

[0344] In certain embodiments, the pharmaceutically effective dose is the dose described in Section 7.7. In certain embodiments, the pharmaceutically effective dose is administered at the frequency described in Section 7.7. In certain embodiments, the pharmaceutically effective dose is administered as described in Section 7.7. In certain embodiments, the pharmaceutically effective dose is an initial dose. In certain embodiments, the initial dose is administered according to the method described in Section 7.4. In certain embodiments, the pharmaceutically effective dose is an adjusted dose. In certain embodiments, the adjusted dose is administered according to the method described in Section 7.4.

[0345] In certain embodiments, the ActRII signal transduction inhibitor is administered in a composition as described in Section 7.11. In certain embodiments, the composition is administered at the frequency described in Section 7.7. In certain embodiments, the composition is administered as described in Section 7.7.

[0346] In certain embodiments, the ActRII signal transduction inhibitor is the ActRII signal transduction inhibitor described in Section 7.9. In certain embodiments, the ActRII signal transduction inhibitor is an ActRIIA signal transduction inhibitor. In certain embodiments, the ActRIIA signal transduction inhibitor is administered subcutaneously once every 21 days. In certain embodiments, the ActRII signal transduction inhibitor is ActRIIA-Fc such as ActRIIA-hFc (e.g., SEQ ID NO:7). In certain embodiments, the ActRII signal transduction inhibitor is an ActRIIB signal transduction inhibitor. In certain embodiments, the ActRIIB signal transduction inhibitor is administered subcutaneously once every 21 days. In certain embodiments, the ActRII signal transduction inhibitor is ActRII-Fc such as ActRIIB-hFc (e.g., SEQ ID NO:25).

[0347] In certain embodiments, provided herein are methods for treating a blood-related disorder in a subject, wherein the methods comprise: (a) determining the percentage of erythroblasts that are ring sideroblasts in the subject; and (b) (i) if the percentage of erythroblasts that are ring sideroblasts in the subject is at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or at least 20%, administering an ActRII signal transduction inhibitor to the subject at a pharmaceutically effective dose between 0.1 mg / kg and 2.0 mg / kg for a short time period, or (ii) if the percentage of erythroblasts that are ring sideroblasts in the subject is less than 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1%, administering an ActRII signal transduction inhibitor to the subject at a pharmaceutically effective dose between 0.1 mg / kg and 2.0 mg / kg for a long time period. In certain embodiments, the blood-related disorder is the blood-related disorder as described in Section 7.8. In certain embodiments, the subject is the subject as described in Section 7.8. In certain embodiments, the pharmaceutically effective dose is between 0.75 mg / kg and 2.0 mg / kg. In certain embodiments, the subject is a subject in need of RBC transfusion. In certain embodiments, the short time period for administering the ActRII signal transduction inhibitor to the subject is 1, 2, 3, 4 or 5 months. In certain embodiments, the long time period for administering the ActRII signal transduction inhibitor to the subject is at least 6, 12, 18 or 24 months. In one specific embodiment, the level of ring sideroblasts is tested at least 0, 3, 4, 5, 6, 12, 28, 24 or 48 months after the last administration of the ActRII signal transduction inhibitor following the short administration time period. In certain embodiments, the ActRII signal transduction inhibitor is the ActRII signal transduction inhibitor as described in Section 7.9. In certain embodiments, the ActRII signal transduction inhibitor is an ActRIIA signal transduction inhibitor. In certain embodiments, the ActRIIA signal transduction inhibitor is administered subcutaneously once every 21 days. In certain embodiments, the ActRII signal transduction inhibitor is ActRIIA-Fc such as ActRIIA-hFc (e.g., SEQ ID NO:7). In certain embodiments, the ActRII signal transduction inhibitor is an ActRIIB signal transduction inhibitor. In certain embodiments, the ActRIIB signal transduction inhibitor is administered subcutaneously once every 21 days. In certain embodiments, the ActRII signal transduction inhibitor is ActRII-Fc such as ActRIIB-hFc (e.g., SEQ ID NO:25).

[0348] In certain embodiments, the method further comprises determining, at 6, 12, 18, and / or 24 months after the time period of ActRII signaling inhibitor administration, another percentage of erythroblasts that are ring sideroblasts in the subject. In certain embodiments, the method further comprises determining, at 6, 12, 18, and / or 24 months after the time period of ActRII signaling inhibitor administration, another hemoglobin level in the subject.

[0349] In certain embodiments, the method further comprises determining, at 6, 12, 18, and / or 24 months after the time period of ActRII signaling inhibitor administration, another percentage of erythroblasts that are ring sideroblasts in the subject. In certain embodiments, the method further comprises determining, at 6, 12, 18, and / or 24 months after the time period of ActRII signaling inhibitor administration, the hemoglobin level in the subject. In certain embodiments, at least 3, 4, 5, 6, 12, 18, or 24 months after ActRII signaling inhibitor administration, the method eliminates the subject's need for red blood cell transfusions. In certain embodiments, at least 3, 4, 5, 6, 12, 18, or 24 months after the last dose of ActRII signaling inhibitor is given and without further administration of ActRII signaling inhibitor, the method eliminates the subject's need for red blood cell transfusions.

[0350] In certain embodiments, the percentage of erythroblasts that are ring sideroblasts in the subject is determined according to the assay described in Section 7.10. In certain embodiments, ring sideroblasts are identified according to the assay described in Section 7.10. In certain embodiments, ring sideroblasts are identified by Prussian blue staining. In certain embodiments, erythroblasts are identified according to the assay described in Section 7.10. In certain embodiments, the hemoglobin level of the subject is determined according to the assay described in Section 7.10. In certain embodiments, the hemoglobin level of the subject is determined according to the assay described in Section 7.10.

[0351] In certain embodiments, the subject is a subject as described in Section 7.8. In certain embodiments, at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or at least 20% of the erythroblasts in the subject are ring sideroblasts. In certain embodiments, at least 15% of the erythroblasts in the subject are ring sideroblasts. In certain embodiments, the hemoglobin level of the subject is less than 11 g / dL. In certain embodiments, the subject has a reduced hemoglobin level compared to a reference population. In certain embodiments, the reference population is as described in Section 7.10. In certain embodiments, the subject has anemia. In certain embodiments, the subject is a subject in need of RBC transfusion. In certain embodiments, the subject has MDS. In certain embodiments, the subject has non-proliferative CMML.

[0352] In certain embodiments, the pharmaceutically effective dose is the dose as described in Section 7.7. In certain embodiments, the pharmaceutically effective dose is administered at the frequency as described in Section 7.7. In certain embodiments, the pharmaceutically effective dose is administered as described in Section 7.7. In certain embodiments, the pharmaceutically effective dose is an initial dose. In certain embodiments, the initial dose is administered according to the method as described in Section 7.4. In certain embodiments, the pharmaceutically effective dose is an adjusted dose. In certain embodiments, the adjusted dose is administered according to the method as described in Section 7.4.

[0353] In certain embodiments, the ActRII signal transduction inhibitor is administered using the composition as described in Section 7.11. In certain embodiments, the composition is administered at the frequency as described in Section 7.7. In certain embodiments, the composition is administered as described in Section 7.7.

[0354] In certain embodiments, the ActRII signal transduction inhibitor is the ActRII signal transduction inhibitor as described in Section 7.9. In certain embodiments, the ActRII signal transduction inhibitor is an ActRIIA signal transduction inhibitor. In certain embodiments, the ActRIIA signal transduction inhibitor is administered subcutaneously once every 21 days. In certain embodiments, the ActRII signal transduction inhibitor is ActRIIA-Fc such as ActRIIA-hFc (e.g., SEQ ID NO:7). In certain embodiments, the ActRII signal transduction inhibitor is an ActRIIB signal transduction inhibitor. In certain embodiments, the ActRIIB signal transduction inhibitor is administered subcutaneously once every 21 days. In certain embodiments, the ActRII signal transduction inhibitor is ActRII-Fc such as ActRIIB-hFc (e.g., SEQ ID NO:25).

[0355] In certain embodiments, provided herein are methods for treating a subject having a blood-related disorder, comprising administering to the subject a pharmaceutically effective dose of an activin receptor type II (ActRII) signaling inhibitor, and wherein the subject expresses SF3B1 comprising one or more mutations. In certain embodiments, the one or more mutations are in non-coding regions. In certain embodiments, the one or more mutations are in coding regions. In certain embodiments, SF3B1 is the SF3B1 protein. In certain embodiments, SF3B1 is the gene encoding SF3B1. In certain embodiments, the subject is a subject as described in Section 7.8. In certain embodiments, the blood-related disorder is a blood-related disorder as described in Section 7.8. In certain embodiments, one or more mutations in SF3B are as described in Section 7.8. In certain embodiments, at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or at least 20% of the erythroblasts in the subject are ring sideroblasts. In certain embodiments, at least 15% of the erythroblasts in the subject are ring sideroblasts. In certain embodiments, the hemoglobin level of the subject is less than 11 g / dL. In certain embodiments, the subject has a reduced hemoglobin level compared to a reference population. In certain embodiments, the reference population is as described in Section 7.10. In certain embodiments, the subject has anemia. In certain embodiments, the subject is a subject in need of RBC transfusion. In certain embodiments, the subject has MDS. In certain embodiments, the subject has non-proliferative CMML. In certain embodiments, the subject being treated according to the methods provided herein has thrombocytopenia. In certain embodiments, the pharmaceutically effective dose is a dose as described in Section 7.7. In certain embodiments, the pharmaceutically effective dose is between 0.1 mg / kg and 2.0 mg / kg of the ActRII signaling inhibitor. In certain embodiments, the pharmaceutically effective dose is between 0.75 mg / kg and 2.0 mg / kg of the ActRII signaling inhibitor. In certain embodiments, the pharmaceutically effective dose is administered at a frequency as described in Section 7.7. In certain embodiments, the pharmaceutically effective dose is administered as described in Section 7.7. In certain embodiments, the pharmaceutically effective dose is an initial dose. In certain embodiments, the initial dose is administered according to the method as described in Section 7.4. In certain embodiments, the pharmaceutically effective dose is an adjusted dose. In certain embodiments, the adjusted dose is administered according to the method as described in Section 7.4. In certain embodiments, the ActRII signaling inhibitor is administered in a composition as described in Section 7.11.In certain embodiments, the composition is administered at the frequency described in Section 7.7. In certain embodiments, the composition is administered as described in Section 7.7. In certain embodiments, the ActRII signal transduction inhibitor is an ActRII signal transduction inhibitor as described in Section 7.9. In certain embodiments, the ActRII signal transduction inhibitor is an ActRIIA signal transduction inhibitor. In certain embodiments, the ActRIIA signal transduction inhibitor is administered subcutaneously once every 21 days. In certain embodiments, the ActRII signal transduction inhibitor is ActRIIA-Fc such as ActRIIA-hFc (e.g., SEQ ID NO:7). In certain embodiments, the ActRII signal transduction inhibitor is an ActRIIB signal transduction inhibitor. In certain embodiments, the ActRIIB signal transduction inhibitor is administered subcutaneously once every 21 days. In certain embodiments, the ActRII signal transduction inhibitor is ActRII-Fc such as ActRIIB-hFc (e.g., SEQ ID NO:25). The subject in need of elevated neutrophil levels can be a subject with ring sideroblasts, anemia, anemia requiring RBC transfusion, non-proliferative CMML, and / or MDS.

[0356] 7.3.1 Genetic Markers

[0357] In certain embodiments, provided herein are methods for treating a subject having a blood-related disorder, comprising administering to the subject a pharmaceutically effective dose of an activin receptor type II (ActRII) signaling inhibitor, and wherein the subject expresses SF3B1 comprising one or more mutations. In certain embodiments, the one or more mutations are in non-coding regions. In certain embodiments, the one or more mutations are in coding regions. In certain embodiments, SF3B1 is the SF3B1 protein. In certain embodiments, SF3B1 is the gene encoding SF3B1. In certain embodiments, the subject is the subject described in Section 7.8. In certain embodiments, the blood-related disorder is the blood-related disorder described in Section 7.8. In certain embodiments, one or more mutations in SF3B1 are as described in Section 7.8. In certain embodiments, at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or at least 20% of the erythroblasts in the subject are ring sideroblasts. In certain embodiments, at least 15% of the erythroblasts in the subject are ring sideroblasts. In certain embodiments, the hemoglobin level of the subject is less than 11 g / dL. In certain embodiments, the subject has a reduced hemoglobin level compared to a reference population. In certain embodiments, the reference population is as described in Section 7.10. In certain embodiments, the subject has anemia. In certain embodiments, the subject is a subject in need of RBC transfusion. In certain embodiments, the subject has MDS. In certain embodiments, the subject has non-proliferative CMML. In certain embodiments, the subject being treated according to the methods provided herein has thrombocytopenia. In certain embodiments, the pharmaceutically effective dose is the dose described in Section 7.7. In certain embodiments, the pharmaceutically effective dose is between 0.1 mg / kg and 2.0 mg / kg of the ActRII signaling inhibitor. In certain embodiments, the pharmaceutically effective dose is between 0.75 mg / kg and 2.0 mg / kg of the ActRII signaling inhibitor. In certain embodiments, the pharmaceutically effective dose is administered at the frequency described in Section 7.7. In certain embodiments, the pharmaceutically effective dose is administered as described in Section 7.7. In certain embodiments, the pharmaceutically effective dose is an initial dose. In certain embodiments, the initial dose is administered according to the method described in Section 7.4. In certain embodiments, the pharmaceutically effective dose is an adjusted dose. In certain embodiments, the adjusted dose is administered according to the method described in Section 7.4. In certain embodiments, the ActRII signaling inhibitor is administered in a composition as described in Section 7.11.In certain embodiments, the composition is administered at the frequency described in Section 7.7. In certain embodiments, the composition is administered as described in Section 7.7. In certain embodiments, the ActRII signal transduction inhibitor is an ActRII signal transduction inhibitor as described in Section 7.9. In certain embodiments, the ActRII signal transduction inhibitor is an ActRIIA signal transduction inhibitor. In certain embodiments, the ActRIIA signal transduction inhibitor is administered subcutaneously once every 21 days. In certain embodiments, the ActRII signal transduction inhibitor is ActRIIA-Fc such as ActRIIA-hFc (e.g., SEQ ID NO:7). In certain embodiments, the ActRII signal transduction inhibitor is an ActRIIB signal transduction inhibitor. In certain embodiments, the ActRIIB signal transduction inhibitor is administered subcutaneously once every 21 days. In certain embodiments, the ActRII signal transduction inhibitor is ActRII-Fc such as ActRIIB-hFc (e.g., SEQ ID NO:25). The subject in need of elevated neutrophil levels can be a subject with ring sideroblasts, anemia, anemia requiring RBC transfusion, non-proliferative CMML, and / or MDS.

[0358] 7.4 Adjusted Administration Methods

[0359] In certain embodiments, provided herein are methods of treating a blood-related disorder in a subject, the method comprising: (a) determining that at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or at least 20% of the erythroblasts in the subject are ring sideroblasts; (b) administering to the subject an initial dose of an ActRII signaling inhibitor between 0.1 mg / kg and 2.0 mg / kg; (c) after a period of time, determining a second percentage of the erythroblasts in the subject that are ring sideroblasts; and (d) optionally administering an adjusted dose of the ActRII signaling inhibitor to the subject. In certain embodiments, the blood-related disorder is the blood-related disorder as described in Section 7.8. In certain embodiments, the subject is the subject as described in Section 7.8. In certain embodiments, the initial dose is between 0.75 mg / kg and 2.0 mg / kg. In certain embodiments, the subject is a subject in need of RBC transfusion. In certain embodiments, the initial dose is administered to the subject immediately after or within at most 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 1 week, 2 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months of determining the first percentage of the erythroblasts in the subject that are ring sideroblasts. In certain embodiments, the period of time between administering the initial dose to the subject and determining the second percentage of the erythroblasts in the subject that are ring sideroblasts is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 1 week, 2 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months. In certain embodiments, the adjusted dose is administered to the subject immediately after or within at most 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 1 week, 2 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months of determining the second percentage of the erythroblasts in the subject that are ring sideroblasts. In certain embodiments, if the second percentage of the erythroblasts in the subject that are ring sideroblasts is at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or at least 20%, then the adjusted dose of the ActRII signaling inhibitor is less than the initial dose. In certain embodiments, the second percentage of the erythroblasts in the subject that are ring sideroblasts is at least 15%.In certain embodiments, if the second percentage of erythroblasts that are ring sideroblasts in the subject is less than 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1%, an adjusted dose is not administered to the subject. In certain embodiments, at least 3, 4, 5, 6, 12, 18, or 24 months after administration of the ActRII signal transduction inhibitor, the method eliminates the subject's need for red blood cell transfusions.

[0360] In certain embodiments, the subject is a subject as described in Section 7.8. In certain embodiments, at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or at least 20% of the erythroblasts in the subject are ring sideroblasts. In certain embodiments, at least 15% of the erythroblasts in the subject are ring sideroblasts. In certain embodiments, the hemoglobin level of the subject is less than 11 g / dL. In certain embodiments, the subject has a reduced hemoglobin level compared to a reference population. In certain embodiments, the reference population is as described in Section 7.10. In certain embodiments, the subject has anemia. In certain embodiments, the subject is a subject in need of RBC transfusion. In certain embodiments, the subject has MDS. In certain embodiments, the subject has non-proliferative CMML. In certain embodiments, the pharmaceutically effective dose is the initial dose as described in Section 7.7. In certain embodiments, the dose is the adjusted dose as described in Section 7.7. In certain embodiments, the pharmaceutically effective dose is the adjusted dose. In certain embodiments, the pharmaceutically effective dose is administered at the frequency as described in Section 7.7. In certain embodiments, the pharmaceutically effective dose is administered as described in Section 7.7. In certain embodiments, the ActRII signal transduction inhibitor is administered using the composition as described in Section 7.11. In certain embodiments, the composition is administered at the frequency as described in Section 7.7. In certain embodiments, the composition is administered as described in Section 7.7. In certain embodiments, the ActRII signal transduction inhibitor is the ActRII signal transduction inhibitor as described in Section 7.9. In certain embodiments, the ActRII signal transduction inhibitor is an ActRIIA signal transduction inhibitor. In certain embodiments, the ActRIIA signal transduction inhibitor is administered subcutaneously once every 21 days. In certain embodiments, the ActRII signal transduction inhibitor is ActRIIA-Fc such as ActRIIA-hFc (e.g., SEQ ID NO:7). In certain embodiments, the ActRII signal transduction inhibitor is an ActRIIB signal transduction inhibitor. In certain embodiments, the ActRIIB signal transduction inhibitor is administered subcutaneously once every 21 days. In certain embodiments, the ActRII signal transduction inhibitor is ActRII-Fc such as ActRIIB-hFc (e.g., SEQ ID NO:25).

[0361] In certain embodiments, provided herein are methods for promoting erythropoiesis in a subject having a blood-related disorder, the methods comprising: (a) determining the percentage of erythroblasts that are ring sideroblasts in the subject; (b) administering to the subject a pharmaceutically effective dose of an ActRII signaling inhibitor for a first time period; and (c) after the first time period, if in step (a) the percentage of erythroblasts that are ring sideroblasts in the subject has exceeded 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20%, then reducing the dose of the ActRII signaling inhibitor administered to the subject, reducing the frequency of administration of the ActRII signaling inhibitor to the subject, or stopping the administration of the ActRII signaling inhibitor. In certain embodiments, the methods further comprise (i) monitoring the hematological parameters of the subject during the first time period; and (ii) if the hematological parameters of the subject have normalized, e.g., if the hematological parameters of the subject are at least at the level of the hematological parameters of a reference population, then reducing (e.g., reducing the dose or reducing the frequency) or stopping the administration of the ActRII signaling inhibitor to the subject. In certain embodiments, the reference population is the reference population as described in Section 7.10. In certain embodiments, the methods further comprise (i) monitoring the hematological parameters of the subject during the first time period; and (ii) if the hematological parameters of the subject have normalized, e.g., if the hematological parameters of the subject are improved by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% compared to the hematological parameters of the subject during a second time period, then reducing (e.g., reducing the dose or reducing the frequency) or stopping the administration of the ActRII signaling inhibitor to the subject, wherein the second time period is the time period prior to administering an initial dose of the ActRII signaling inhibitor to the subject. In certain embodiments, the first time period is at least 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 1 year. In certain embodiments, the second time period is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 3 months, 4 months, 5 months, or 6 months. In certain embodiments, the hematological parameter is a hemoglobin level. In certain embodiments, the hematological parameter is a hematocrit. In certain embodiments, the hematological parameter is an erythrocyte count. In certain embodiments, the hematological parameter is the percentage of erythroblasts that are ring sideroblasts in the subject. In certain embodiments, the reduced dose of the ActRII signaling inhibitor is the dose as described in Section 7.7.In certain embodiments, the reduced dosing frequency of the ActRII signal transduction inhibitor is the frequency described in Section 7.7. In certain embodiments, the blood-related disorder is the blood-related disorder described in Section 7.8. In certain embodiments, the subject is the subject described in Section 7.8. In certain embodiments, the pharmaceutically effective dose is the initial dose described in Section 7.7. In certain embodiments, the dose is the adjusted dose described in Section 7.7. In certain embodiments, the pharmaceutically effective dose is the adjusted dose. In certain embodiments, the pharmaceutically effective dose is administered at the frequency described in Section 7.7. In certain embodiments, the pharmaceutically effective dose is administered as described in Section 7.7. In certain embodiments, the ActRII signal transduction inhibitor is administered in a composition as described in Section 7.11. In certain embodiments, the composition is administered at the frequency described in Section 7.7. In certain embodiments, the composition is administered as described in Section 7.7. In certain embodiments, the ActRII signal transduction inhibitor is the ActRII signal transduction inhibitor described in Section 7.9. In certain embodiments, the ActRII signal transduction inhibitor is an ActRIIA signal transduction inhibitor. In certain embodiments, the ActRIIA signal transduction inhibitor is administered subcutaneously once every 21 days. In certain embodiments, the ActRII signal transduction inhibitor is ActRIIA-Fc such as ActRIIA-hFc (e.g., SEQ ID NO:7). In certain embodiments, the ActRII signal transduction inhibitor is an ActRIIB signal transduction inhibitor. In certain embodiments, the ActRIIB signal transduction inhibitor is administered subcutaneously once every 21 days. In certain embodiments, the ActRII signal transduction inhibitor is ActRII-Fc such as ActRIIB-hFc (e.g., SEQ ID NO:25).

[0362] 7.5 Methods for Increasing Neutrophil Levels

[0363] In certain embodiments, provided herein are methods for increasing the level of neutrophils in a subject in need thereof, comprising administering to the subject a pharmaceutically effective dose of an activin receptor type II (ActRII) signal transduction inhibitor. In certain embodiments, the neutrophil level is the absolute neutrophil count. In certain embodiments, the level of neutrophils in the subject is increased by at least 0.1x10 9 / L, 0.5x10 9 / L, 1.0x10 9 / L, 5x10 9 / L, 1.0x10 10 / L, 5x10 10 / L or 1.0x10 11 / L. In certain embodiments, the level of neutrophils in the subject is increased by at least 1.2-fold, 1.3-fold, 1.4-fold, 1.5-fold, 2-fold, 2.5-fold, 3-fold, 3.5-fold, 4-fold, 4.5-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, or 10-fold compared to the level of neutrophils in the subject during a period of time prior to administering the initial dose of the ActRII signal transduction inhibitor to the subject. In certain embodiments, the level of neutrophils in the subject is increased by at most 1.2-fold, 1.3-fold, 1.4-fold, 1.5-fold, 2-fold, 2.5-fold, 3-fold, 3.5-fold, 4-fold, 4.5-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, or 10-fold compared to the level of neutrophils in the subject during a period of time prior to administering the initial dose of the ActRII signal transduction inhibitor to the subject. In certain embodiments, the level of neutrophils in the subject is increased at least 1, 2, 3, 4, 5, or 6 months after administering a pharmaceutically effective dose of the ActRII signal transduction inhibitor to the subject. In certain embodiments, the level of neutrophils in the subject is increased at least 1, 2, 3, 4, 5, or 6 months after stopping administration of a pharmaceutically effective dose of the ActRII signal transduction inhibitor to the subject. See also Section 7.4. In certain embodiments, the period of time prior to administering the initial dose of the ActRII signal transduction inhibitor to the subject is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 3 months, 4 months, 5 months, or 6 months. In certain embodiments, the neutrophil level is measured as described in Section 7.10. In certain embodiments, the absolute neutrophil count is measured as described in Section 7.10. In certain embodiments, the subject is the subject as described in Section 7.8. In certain embodiments, at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or at least 20% of the erythroblasts in the subject are ring sideroblasts. In certain embodiments, at least 15% of the erythroblasts in the subject are ring sideroblasts. In certain embodiments, the hemoglobin level of the subject is less than 11 g / dL. In certain embodiments, the subject has a reduced hemoglobin level compared to a reference population. In certain embodiments, the reference population is as described in Section 7.10. In certain embodiments, the subject has anemia. In certain embodiments, the subject is a subject in need of RBC transfusion. In certain embodiments, the subject has MDS. In certain embodiments, the subject has non-proliferative CMML. In certain embodiments, the subject being treated according to the methods provided herein has thrombocytopenia. In certain embodiments, the pharmaceutically effective dose is the dose as described in Section 7.7.In certain embodiments, the pharmaceutically effective dose is administered at the frequency described in Section 7.7. In certain embodiments, the pharmaceutically effective dose is administered as described in Section 7.7. In certain embodiments, the pharmaceutically effective dose is an initial dose. In certain embodiments, the initial dose is administered according to the method described in Section 7.4. In certain embodiments, the pharmaceutically effective dose is an adjusted dose. In certain embodiments, the adjusted dose is administered according to the method described in Section 7.4. In certain embodiments, the ActRII signal transduction inhibitor is administered in a composition as described in Section 7.11. In certain embodiments, the composition is administered at the frequency described in Section 7.7. In certain embodiments, the composition is administered as described in Section 7.7. In certain embodiments, the ActRII signal transduction inhibitor is the ActRII signal transduction inhibitor described in Section 7.9. In certain embodiments, the ActRII signal transduction inhibitor is an ActRIIA signal transduction inhibitor. In certain embodiments, the ActRIIA signal transduction inhibitor is administered subcutaneously once every 21 days. In certain embodiments, the ActRII signal transduction inhibitor is ActRIIA-Fc such as ActRIIA-hFc (e.g., SEQ ID NO:7). In certain embodiments, the ActRII signal transduction inhibitor is an ActRIIB signal transduction inhibitor. In certain embodiments, the ActRIIB signal transduction inhibitor is administered subcutaneously once every 21 days. In certain embodiments, the ActRII signal transduction inhibitor is ActRII-Fc such as ActRIIB-hFc (e.g., SEQ ID NO:25). Subjects in need of increased neutrophil levels can be subjects with ring sideroblasts, anemia, anemia requiring RBC transfusion, non-proliferative CMML, and / or MDS.

[0364] 7.6 Methods for Increasing Platelet Levels

[0365] In certain embodiments, provided herein are methods for increasing the platelet levels of a subject in need of increased platelet levels, comprising administering a pharmaceutically effective dose of an activin receptor type II (ActRII) signal transduction inhibitor to the subject. In certain embodiments, the platelet levels of the subject are increased by at least 1x10 10 / L, 3x10 10 / L, 5x10 10 / L, 1x10 11 / L, 5x10 11 / L or at least 1 x 10 12 / L. In certain embodiments, the level of platelets in the subject is increased by at least 1.2-fold, 1.3-fold, 1.4-fold, 1.5-fold, 2-fold, 2.5-fold, 3-fold, 3.5-fold, 4-fold, 4.5-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold or 10-fold compared to the level of platelets in the subject during a period of time prior to administering an initial dose of an ActRII signal transduction inhibitor to the subject. In certain embodiments, the level of platelets in the subject is increased by at most 1.2-fold, 1.3-fold, 1.4-fold, 1.5-fold, 2-fold, 2.5-fold, 3-fold, 3.5-fold, 4-fold, 4.5-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold or 10-fold compared to the level of platelets in the subject during a period of time prior to administering an initial dose of an ActRII signal transduction inhibitor to the subject. In certain embodiments, the period of time prior to administering an initial dose of an ActRII signal transduction inhibitor to the subject is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 3 months, 4 months, 5 months or 6 months. In certain embodiments, the level of platelets in the subject is increased at least 1, 2, 3, 4, 5 or 6 months after administering a pharmaceutically effective dose of an ActRII signal transduction inhibitor to the subject. In certain embodiments, the level of neutrophils in the subject is increased at least 1, 2, 3, 4, 5 or 6 months after stopping administration of a pharmaceutically effective dose of an ActRII signal transduction inhibitor to the subject. See also Section 7.4. In certain embodiments, the platelet level is measured as described in Section 7.10.

[0366] In certain embodiments, the subject is a subject as described in Section 7.8. In certain embodiments, at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or at least 20% of the erythroblasts in the subject are ring sideroblasts. In certain embodiments, at least 15% of the erythroblasts in the subject are ring sideroblasts. In certain embodiments, the hemoglobin level of the subject is less than 11 g / dL. In certain embodiments, the subject has a reduced hemoglobin level compared to a reference population. In certain embodiments, the reference population is as described in Section 7.10. In certain embodiments, the subject has anemia. In certain embodiments, the subject is a subject in need of RBC transfusion. In certain embodiments, the subject has MDS. In certain embodiments, the subject has non-proliferative CMML. In certain embodiments, the subject being treated according to the methods provided herein has neutropenia.

[0367] In certain embodiments, the pharmaceutically effective dose is the dose described in Section 7.7. In certain embodiments, the pharmaceutically effective dose is administered at the frequency described in Section 7.7. In certain embodiments, the pharmaceutically effective dose is administered as described in Section 7.7. In certain embodiments, the pharmaceutically effective dose is an initial dose. In certain embodiments, the initial dose is administered according to the method described in Section 7.4. In certain embodiments, the pharmaceutically effective dose is an adjusted dose. In certain embodiments, the adjusted dose is administered according to the method described in Section 7.4.

[0368] In certain embodiments, the ActRII signal transduction inhibitor is administered in a composition as described in Section 7.11. In certain embodiments, the composition is administered at the frequency described in Section 7.7. In certain embodiments, the composition is administered as described in Section 7.7.

[0369] In certain embodiments, the ActRII signal transduction inhibitor is the ActRII signal transduction inhibitor described in Section 7.9. In certain embodiments, the ActRII signal transduction inhibitor is an ActRIIA signal transduction inhibitor. In certain embodiments, the ActRIIA signal transduction inhibitor is administered subcutaneously once every 21 days. In certain embodiments, the ActRII signal transduction inhibitor is ActRIIA-Fc such as ActRIIA-hFc (e.g., SEQ ID NO:7). In certain embodiments, the ActRII signal transduction inhibitor is an ActRIIB signal transduction inhibitor. In certain embodiments, the ActRIIB signal transduction inhibitor is administered subcutaneously once every 21 days. In certain embodiments, the ActRII signal transduction inhibitor is ActRII-Fc such as ActRIIB-hFc (e.g., SEQ ID NO:25).

[0370] The subject in need of increased neutrophil levels can be a subject having ring sideroblasts, anemia, anemia requiring RBC transfusion, non-proliferative CMML, and / or MDS.

[0371] 7.7 Dose

[0372] Provided herein are methods for treating a subject having a blood-related disorder (e.g., anemia, anemia requiring RBC transfusion, MDS, and / or non-proliferative CMML), wherein the methods comprise administering to the subject in need of treatment a pharmaceutically effective dose of a signal transduction inhibitor of ActRII (see Section 7.9). In certain embodiments, the ActRII signal transduction inhibitor is a signal transduction inhibitor of ActRIIA as set forth in Section 7.9.1. In other embodiments, the ActRII signal transduction inhibitor is a signal transduction inhibitor of ActRIIB as set forth in Section 7.9.2. In certain embodiments, the ActRII signal transduction inhibitor is a combination of an ActRIIA signal transduction inhibitor and an ActRIIB signal transduction inhibitor. In certain embodiments, the ActRII signal transduction inhibitor is SEQ ID NO:7. In certain embodiments, the ActRII signal transduction inhibitor is SEQ ID NO:25.

[0373] The doses provided herein can be used for the treatment of blood-related diseases such as, for example, anemia, anemia requiring RBC transfusion, MDS, and / or non-proliferative CMML. In certain embodiments, the dose is a pharmaceutically effective dose.

[0374] In certain embodiments, the pharmaceutically effective dose of the ActRII signal transduction inhibitor is a dose sufficient to alleviate one or more symptoms of anemia. In certain embodiments, the pharmaceutically effective dose of the ActRII signal transduction inhibitor is a dose sufficient to prevent at least one symptom of anemia from worsening. Non-limiting examples of symptoms of anemia include fatigue, loss of energy, rapid heartbeat, shortness of breath, headache, difficulty concentrating, dizziness, pale skin, leg cramps, and insomnia.

[0375] In certain embodiments, the pharmaceutically effective dose of the ActRII signal transduction inhibitor is a dose sufficient to alleviate one or more symptoms of non-proliferative CMML. In certain embodiments, the pharmaceutically effective dose of the ActRII signal transduction inhibitor is a dose sufficient to prevent one or more symptoms of non-proliferative CMML from worsening. Non-limiting examples of CMML symptoms include splenomegaly, hepatomegaly, anemia, fatigue, shortness of breath, leukopenia, frequent infections, thrombocytopenia, easy bruising or bleeding, fever, weight loss, pale skin, and loss of appetite.

[0376] In certain embodiments, a pharmaceutically effective dose of the ActRII signal transduction inhibitor is a dose sufficient to alleviate one or more symptoms of MDS. In certain embodiments, a pharmaceutically effective dose of the ActRII signal transduction inhibitor is a dose sufficient to prevent one or more symptoms of MDS from worsening. Non-limiting examples of MDS symptoms include anemia, shortness of breath, fatigue, pale skin, leukopenia, frequent infections, neutropenia, thrombocytopenia, easy bruising or bleeding, weight loss, fever, loss of appetite, weakness, and bone pain.

[0377] In certain embodiments, the ActRII signal transduction inhibitor is administered at intervals and in amounts sufficient to achieve a serum concentration of 0.2 micrograms / kg or greater, e.g., a serum level of 1 microgram / kg or 2 micrograms / kg or greater. A dosing regimen can be designed to achieve a serum concentration between 0.2 and 15 micrograms / kg and optionally between 1 and 5 micrograms / kg. In humans, a serum level of 0.2 micrograms / kg can be achieved with a single dose of 0.1 mg / kg or greater, and a serum level of 1 microgram / kg can be achieved with a single dose of 0.3 mg / kg or greater. The observed serum half-life of the molecule is between about 20 and 30 days, significantly longer than most Fc fusion proteins, and thus a continuously effective serum level can be achieved, for example, by administering 0.2 - 0.4 mg / kg on a once-weekly or once-every-two-weeks basis, or higher doses with longer intervals between administrations can be used. For example, doses of 1 - 3 mg / kg can be used on a once-monthly or once-every-two-months basis, and the effect on bone may be sufficiently long-lasting such that dosing once every 3, 4, 5, 6, 9, 12 months or more months may be required. The serum level of the ActRII signal transduction inhibitor can be measured by any means known to the person skilled in the art. For example, the serum level of the ActRII signal transduction inhibitor can be determined using an antibody against the ActRII signal transduction inhibitor, e.g., by ELISA. In a specific embodiment, the methods provided herein can also achieve a significant effect on bone density and bone strength.

[0378] In certain embodiments, the dosage of the ActRII signal transduction inhibitor is about 0.1 mg / kg, about 0.3 mg / kg, about 0.5 mg / kg, 0.75 mg / kg, about 1.0 mg / kg, about 1.25 mg / kg, about 1.5 mg / kg, about 1.75 mg / kg, about 2.0 mg / kg or about 2.25 mg / kg. In certain embodiments, the dosage of the ActRII signal transduction inhibitor is between 0.1 mg / kg and 2.25 mg / kg. In certain embodiments, the dosage of the ActRII signal transduction inhibitor is between 0.1 mg / kg and 1 mg / kg. In certain embodiments, the dosage of the ActRII signal transduction inhibitor is between 0.3 mg / kg and 1.25 mg / kg. In certain embodiments, the dosage of the ActRII signal transduction inhibitor is between 0.5 mg / kg and 1.5 mg / kg. In certain embodiments, the dosage of the ActRII signal transduction inhibitor is between 0.1 mg / kg and 2.0 mg / kg. In certain embodiments, the dosage of the ActRII signal transduction inhibitor is between 0.75 mg / kg and 1.0 mg / kg, between 1.0 mg / kg and 1.25 mg / kg, between 1.25 mg / kg and 1.5 mg / kg, between 1.5 mg / kg and 1.75 mg / kg or between 1.75 mg / kg and 2.0 mg / kg. In certain embodiments, the dosage of the ActRII signal transduction inhibitor is a pharmaceutically effective dosage. When used in combination with the dosages provided herein (e.g., the dosage of the ActRII signal transduction inhibitor or the dosage of the second active agent), the word "about" means any value within 1%, 5% or 10% of the recited value.

[0379] In certain embodiments, the dose of the ActRII signal transduction inhibitor is a pharmaceutically effective dose. In certain embodiments, the pharmaceutically effective dose of the ActRII signal transduction inhibitor is about 0.1 mg / kg, about 0.3 mg / kg, about 0.5 mg / kg, 0.75 mg / kg, about 1.0 mg / kg, about 1.25 mg / kg, about 1.5 mg / kg, about 1.75 mg / kg, about 2.0 mg / kg, or about 2.25 mg / kg. In certain embodiments, the pharmaceutically effective dose of the ActRII signal transduction inhibitor is between 0.1 mg / kg and 2.25 mg / kg. In certain embodiments, the pharmaceutically effective dose of the ActRII signal transduction inhibitor is between 0.1 mg / kg and 1 mg / kg. In certain embodiments, the pharmaceutically effective dose of the ActRII signal transduction inhibitor is between 0.3 mg / kg and 1.25 mg / kg. In certain embodiments, the pharmaceutically effective dose of the ActRII signal transduction inhibitor is between 0.5 mg / kg and 1.5 mg / kg. In certain embodiments, the pharmaceutically effective dose of the ActRII signal transduction inhibitor is between 0.1 mg / kg and 2.0 mg / kg. In certain embodiments, the pharmaceutically effective dose of the ActRII signal transduction inhibitor is between 0.75 mg / kg and 1.0 mg / kg, between 1.0 mg / kg and 1.25 mg / kg, between 1.25 mg / kg and 1.5 mg / kg, between 1.5 mg / kg and 1.75 mg / kg, or between 1.75 mg / kg and 2.0 mg / kg.

[0380] In certain embodiments, the dose of the ActRII signal transduction inhibitor is an initial dose. In certain embodiments, the initial dose of the ActRII signal transduction inhibitor is about 0.1 mg / kg, about 0.3 mg / kg, about 0.5 mg / kg, 0.75 mg / kg, about 1.0 mg / kg, about 1.25 mg / kg, about 1.5 mg / kg, about 1.75 mg / kg, about 2.0 mg / kg, or about 2.25 mg / kg. In certain embodiments, the initial dose of the ActRII signal transduction inhibitor is between 0.1 mg / kg and 2.25 mg / kg. In certain embodiments, the initial dose of the ActRII signal transduction inhibitor is between 0.1 mg / kg and 1 mg / kg. In certain embodiments, the initial dose of the ActRII signal transduction inhibitor is between 0.3 mg / kg and 1.25 mg / kg. In certain embodiments, the initial dose of the ActRII signal transduction inhibitor is between 0.5 mg / kg and 1.5 mg / kg. In certain embodiments, the initial dose of the ActRII signal transduction inhibitor is between 0.1 mg / kg and 2.0 mg / kg. In certain embodiments, the initial dose of the ActRII signal transduction inhibitor is between 0.75 mg / kg and 1.0 mg / kg, between 1.0 mg / kg and 1.25 mg / kg, between 1.25 mg / kg and 1.5 mg / kg, between 1.5 mg / kg and 1.75 mg / kg, or between 1.75 mg / kg and 2.0 mg / kg. In certain embodiments, the initial dose of the ActRII signal transduction inhibitor is administered (i) once every 28 days; or (ii) once every 42 days. In certain embodiments, the initial dose of the ActRII signal transduction inhibitor is administered once every three weeks.

[0381] In certain embodiments, the dose is an adjusted dose. In certain embodiments, the adjusted dose of the ActRII signal transduction inhibitor is about 0.1 mg / kg, about 0.3 mg / kg, about 0.5 mg / kg, 0.75 mg / kg, about 1.0 mg / kg, about 1.25 mg / kg, about 1.5 mg / kg, about 1.75 mg / kg, about 2.0 mg / kg, or about 2.25 mg / kg. In certain embodiments, the adjusted dose of the ActRII signal transduction inhibitor is between 0.1 mg / kg and 2.25 mg / kg. In certain embodiments, the adjusted dose of the ActRII signal transduction inhibitor is between 0.1 mg / kg and 1 mg / kg. In certain embodiments, the adjusted dose of the ActRII signal transduction inhibitor is between 0.3 mg / kg and 1.25 mg / kg. In certain embodiments, the adjusted dose of the ActRII signal transduction inhibitor is between 0.5 mg / kg and 1.5 mg / kg. In certain embodiments, the adjusted dose of the ActRII signal transduction inhibitor is between 0.1 mg / kg and 2.0 mg / kg. In certain embodiments, the adjusted dose of the ActRII signal transduction inhibitor is between 0.75 mg / kg and 1.0 mg / kg, between 1.0 mg / kg and 1.25 mg / kg, between 1.25 mg / kg and 1.5 mg / kg, between 1.5 mg / kg and 1.75 mg / kg, or between 1.75 mg / kg and 2.0 mg / kg. In certain embodiments, the adjusted dose of the ActRII signal transduction inhibitor is administered (i) once every 28 days; or (ii) once every 42 days. In certain embodiments, the adjusted dose of the ActRII signal transduction inhibitor is administered once every three weeks.

[0382] In certain embodiments, the adjusted dose of the ActRII signal transduction inhibitor is greater than the initial dose. In certain embodiments, the adjusted dose of the ActRII signal transduction inhibitor is about 2.5 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, or about 35 mg higher than the initial dose of the ActRII signal transduction inhibitor, or about 0.05 mg / kg, about 0.1 mg / kg, about 0.15 mg / kg, about 0.25 mg / kg, about 0.3 mg / kg, about 0.35 mg / kg, about 0.4 mg / kg, or about 0.5 mg / kg higher than the initial dose of the ActRII signal transduction inhibitor. In certain embodiments, the adjusted dose of the ActRII signal transduction inhibitor is administered more frequently than the initial dose of the ActRII signal transduction inhibitor. In certain embodiments, the adjusted dose of the ActRII signal transduction inhibitor is administered every 5, 10, 15, 20, 25, 28, 30, 35, or 40 days. In certain embodiments, the adjusted dose of the ActRII signal transduction inhibitor is administered every 1 week or 2 weeks.

[0383] In certain embodiments, the adjusted dose of the ActRII signal transduction inhibitor is less than the initial dose. In certain embodiments, the adjusted dose of the ActRII signal transduction inhibitor is about 2.5 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, or about 35 mg lower than the initial dose of the ActRII signal transduction inhibitor, or about 0.05 mg / kg, about 0.1 mg / kg, about 0.15 mg / kg, about 0.25 mg / kg, about 0.3 mg / kg, about 0.35 mg / kg, about 0.4 mg / kg, or about 0.5 mg / kg lower than the initial dose of the ActRII signal transduction inhibitor. In certain embodiments, the adjusted dose of the ActRII signal transduction inhibitor is administered less frequently than the initial dose of the ActRII signal transduction inhibitor. In certain embodiments, the adjusted dose of the ActRII signal transduction inhibitor is administered every 30, 35, 40, 42, 50, 60, 70, 80, or 90 days. In certain embodiments, the adjusted dose of the ActRII signal transduction inhibitor is administered every 4, 5, 6, 7, or 8 weeks.

[0384] In certain embodiments, the dose of the ActRII signal transduction inhibitor is administered by injection. In certain embodiments, the dose of the ActRII signal transduction inhibitor is administered once every 28 days or once every 42 days. In certain embodiments, the dose of the ActRII signal transduction inhibitor is administered once every 21 days. In certain embodiments, the ActRII signal transduction inhibitor is SEQ ID NO:7.

[0385] In certain embodiments, the dose of the ActRII signal transduction inhibitor is administered via injection. In certain embodiments, the dose of the ActRII signal transduction inhibitor is administered subcutaneously. In certain embodiments, the dose of the ActRII signal transduction inhibitor is administered once every three weeks. In certain embodiments, the ActRII signal transduction inhibitor is SEQ ID NO:25.

[0386] In certain embodiments, the dose of the ActRII signal transduction inhibitor administered to the subject according to the methods provided herein is sufficient to reduce the percentage of erythroblasts that are ring sideroblasts in the subject by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or at least 100% compared to the percentage of erythroblasts that are ring sideroblasts in the subject during a period of time prior to administering the initial dose of the ActRII signal transduction inhibitor to the subject. In certain embodiments, the dose of the ActRII signal transduction inhibitor administered to the subject according to the methods provided herein is sufficient to reduce the percentage of erythroblasts that are ring sideroblasts in the subject by at most 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or at most 100% compared to the percentage of erythroblasts that are ring sideroblasts in the subject during a period of time prior to administering the initial dose of the ActRII signal transduction inhibitor to the subject. In certain embodiments, the period of time prior to administering the ActRII signal transduction inhibitor to the subject is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 3 months, 4 months, 5 months or 6 months. In certain embodiments, at least 3, 4, 5, 6, 12, 18, 24 or 48 months after administration of the ActRII signal transduction inhibitor, the dose of the ActRII signal transduction inhibitor administered to the subject according to the methods provided herein is sufficient to reduce the percentage of erythroblasts that are ring sideroblasts in the subject. In certain embodiments, indefinitely after administration of the ActRII signal transduction inhibitor, the dose of the ActRII signal transduction inhibitor administered to the subject according to the methods provided herein is sufficient to reduce the percentage of erythroblasts that are ring sideroblasts in the subject. In certain embodiments, the dose is between 0.1 mg / kg and 2.0 mg / kg. In certain embodiments, the dose is between 0.75 mg / kg and 2.0 mg / kg. In certain embodiments, the percentage of erythroblasts that are ring sideroblasts in the subject is determined by the assay described in Section 7.10.In certain embodiments, the dose of the ActRII signal transduction inhibitor administered to a subject according to the methods provided herein is sufficient to reduce the level of the subject's ring sideroblasts by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or at least 100% compared to the level of the subject's ring sideroblasts during a period of time prior to administration of an initial dose of the ActRII signal transduction inhibitor to the subject. In certain embodiments, the dose of the ActRII signal transduction inhibitor administered to a subject according to the methods provided herein is sufficient to reduce the level of the subject's ring sideroblasts by at most 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or at most 100% compared to the level of the subject's ring sideroblasts during a period of time prior to administration of an initial dose of the ActRII signal transduction inhibitor to the subject. In certain embodiments, the period of time prior to administration of an initial dose of the ActRII signal transduction inhibitor to the subject is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 3 months, 4 months, 5 months or 6 months. In certain embodiments, at least 3, 4, 5, 6, 12, 18, 24 or 48 months after administration of the ActRII signal transduction inhibitor, the dose of the ActRII signal transduction inhibitor administered to a subject according to the methods provided herein is sufficient to reduce the level of the subject's ring sideroblasts. In certain embodiments, indefinitely after administration of the ActRII signal transduction inhibitor, the dose of the ActRII signal transduction inhibitor administered to a subject according to the methods provided herein is sufficient to reduce the level of the subject's ring sideroblasts. In certain embodiments, the dose is between 0.1 mg / kg and 2.0 mg / kg. In certain embodiments, the dose is between 0.75 mg / kg and 2.0 mg / kg. In certain embodiments, the level of the subject's ring sideroblasts is determined according to the assay described in Section 7.10.

[0387] In certain embodiments, the dose of the ActRII signal transduction inhibitor administered to the subject according to the methods provided herein is sufficient to increase the level of hemoglobin in the subject by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 300%, 400%, or at least 500% compared to the level of hemoglobin in the subject during a period of time prior to administering the initial dose of the ActRII signal transduction inhibitor to the subject. In certain embodiments, the dose of the ActRII signal transduction inhibitor administered to the subject according to the methods provided herein is sufficient to increase the level of hemoglobin in the subject by at most 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 300%, 400%, or at most 500% compared to the level of hemoglobin in the subject during a period of time prior to administering the initial dose of the ActRII signal transduction inhibitor to the subject. In certain embodiments, the dose of the ActRII signal transduction inhibitor administered to the subject according to the methods provided herein is sufficient to increase the level of hemoglobin in the subject by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, or at least 60% compared to the level of hemoglobin in the subject during a period of time prior to administering the initial dose of the ActRII signal transduction inhibitor to the subject. In certain embodiments, the dose of the ActRII signal transduction inhibitor administered to the subject according to the methods provided herein is sufficient to increase the level of hemoglobin in the subject by at most 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, or at most 60% compared to the level of hemoglobin in the subject during a period of time prior to administering the initial dose of the ActRII signal transduction inhibitor to the subject.In certain embodiments, the dose of the ActRII signal transduction inhibitor administered to the subject according to the methods provided herein is sufficient to increase the level of hemoglobin by at least 0.5 g / dL, 1.0 g / dL, 1.1 g / dL, 1.3 g / dL, 1.5 g / dL, 1.8 g / dL, 2.0 g / dL, 2.2 g / dL, 2.4 g / dL, 2.6 g / dL, 2.8 g / dL, 3.0 g / dL, 3.2 g / dL, 3.4 g / dL, 3.6 g / dL, 3.8 g / dL, 4.0 g / dL, 4.2 g / dL, 4.4 g / dL, or at least 4.6 g / dL as compared to the level of hemoglobin of the subject during a period of time prior to administering the initial dose of the ActRII signal transduction inhibitor to the subject. In certain embodiments, the dose of the ActRII signal transduction inhibitor administered to the subject according to the methods provided herein is sufficient to increase the level of hemoglobin by at most 0.5 g / dL, 1.0 g / dL, 1.1 g / dL, 1.3 g / dL, 1.5 g / dL, 1.8 g / dL, 2.0 g / dL, 2.2 g / dL, 2.4 g / dL, 2.6 g / dL, 2.8 g / dL, 3.0 g / dL, 3.2 g / dL, 3.4 g / dL, 3.6 g / dL, 3.8 g / dL, 4.0 g / dL, 4.2 g / dL, 4.4 g / dL, or at most 4.6 g / dL as compared to the level of hemoglobin of the subject during a period of time prior to administering the initial dose of the ActRII signal transduction inhibitor to the subject. In certain embodiments, the period of time prior to administering the initial dose of the ActRII signal transduction inhibitor to the subject is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 3 months, 4 months, 5 months, or 6 months. In certain embodiments, at least 3, 4, 5, 6, 12, 18, 24, or 48 months after administration of the ActRII signal transduction inhibitor, the dose of the ActRII signal transduction inhibitor administered to the subject according to the methods provided herein is sufficient to increase the level of hemoglobin of the subject. In certain embodiments, indefinitely after administration of the ActRII signal transduction inhibitor, the dose of the ActRII signal transduction inhibitor administered to the subject according to the methods provided herein is sufficient to increase the level of hemoglobin of the subject. In certain embodiments, the dose is between 0.1 mg / kg and 2.0 mg / kg. In certain embodiments, the dose is between 0.75 mg / kg and 2.0 mg / kg.

[0388] In certain embodiments, the dose of the ActRII signal transduction inhibitor administered to the subject according to the methods provided herein is sufficient to increase the level of reticulocytes in the subject by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100% compared to the level of reticulocytes in the subject for a period of time prior to administration of the initial dose of the ActRII signal transduction inhibitor to the subject. In certain embodiments, the dose of the ActRII signal transduction inhibitor administered to the subject according to the methods provided herein is sufficient to increase the level of reticulocytes in the subject by at most 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or at most 100%, 150%, 200%, 300%, 400% or at most 500% compared to the level of reticulocytes in the subject for a period of time prior to administration of the initial dose of the ActRII signal transduction inhibitor to the subject. In certain embodiments, the period of time prior to administration of the initial dose of the ActRII signal transduction inhibitor to the subject is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 3 months, 4 months, 5 months or 6 months. In certain embodiments, at least 3, 4, 5, 6, 12, 18, 24 or 48 months after administration of the ActRII signal transduction inhibitor, the dose of the ActRII signal transduction inhibitor administered to the subject according to the methods provided herein is sufficient to increase the level of reticulocytes in the subject. In certain embodiments, indefinitely after administration of the ActRII signal transduction inhibitor, the dose of the ActRII signal transduction inhibitor administered to the subject according to the methods provided herein is sufficient to increase the level of reticulocytes in the subject. In certain embodiments, the dose is between 0.1 mg / kg and 2.0 mg / kg. In certain embodiments, the dose is between 0.75 mg / kg and 2.0 mg / kg.

[0389] In certain embodiments, the dose of the ActRII signal transduction inhibitor administered to a subject according to the methods provided herein is sufficient to reduce the subject's red blood cell transfusion dependence as compared to the red blood cell transfusion dependence during a time period prior to administration of an initial dose of the ActRII signal transduction inhibitor to the subject. In certain embodiments, the dose of the ActRII signal transduction inhibitor administered to a subject according to the methods provided herein is sufficient to reduce the frequency of red blood cell transfusion in the subject as compared to the frequency of red blood cell transfusion in the subject during a period of time prior to administration of an initial dose of the ActRII signal transduction inhibitor to the subject. In certain embodiments, the dose of the ActRII signal transduction inhibitor administered to a subject being treated according to the methods provided herein is sufficient to reduce red blood cell transfusion by at least 30%, 40%, 50%, 60%, 70%, 80%, 90% or by at least 100%. In certain embodiments, the dose of the ActRII signal transduction inhibitor administered to a subject being treated according to the methods provided herein is sufficient to reduce red blood cell transfusion by at most 30%, 40%, 50%, 60%, 70%, 80%, 90% or by at most 100%. In certain embodiments, the dose of the ActRII signal transduction inhibitor administered to a subject being treated according to the methods provided herein is sufficient to reduce the units of red blood cell transfusion in the subject by at least 4, 5, 6, 7, 8, 9, 11, 12 or 13 units as compared to the units of red blood cell transfusion in the subject during a period of time prior to administration of an initial dose of the ActRII signal transduction inhibitor to the subject. In certain embodiments, the time period prior to administration of an initial dose of the ActRII signal transduction inhibitor to the subject is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 3 months, 4 months, 5 months or 6 months. In certain embodiments, the dose of the ActRII signal transduction inhibitor administered to a subject being treated according to the methods provided herein is sufficient to reduce the frequency of red blood cell transfusion by at least 30%, 40%, 50%, 60%, 70%, 80%, 90% or by 100%. In certain embodiments, the dose of the ActRII signal transduction inhibitor administered to a subject being treated according to the methods provided herein is sufficient to reduce the frequency of red blood cell transfusion by at most 30%, 40%, 50%, 60%, 70%, 80%, 90% or by 100%. In certain embodiments, at least 3, 4, 5, 6, 12, 18, 24 or 48 months after administration of the ActRII signal transduction inhibitor, the dose of the ActRII signal transduction inhibitor administered to a subject according to the methods provided herein is sufficient to eliminate the subject's need for red blood cell transfusion.In certain embodiments, following administration of the ActRII signal transduction inhibitor indefinitely, the dose of the ActRII signal transduction inhibitor administered to a subject according to the methods provided herein is sufficient to obviate the subject's need for red blood cell transfusions. In certain embodiments, the dose is between 0.1 mg / kg and 2.0 mg / kg. In certain embodiments, the dose is between 0.75 mg / kg and 2.0 mg / kg. In certain embodiments, 1 RBC unit refers to approximately 150 mL, 200 mL, 250 mL, 300 mL, 350 mL, 100 - 200 mL, 150 - 250 mL, 200 - 300 mL, or 250 - 350 mL of RBCs.

[0390] In certain embodiments, the dose of the ActRII signal transduction inhibitor administered to the subject according to the methods provided herein is sufficient to reduce the transfusion burden of the subject by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or at least 100% compared to the transfusion burden of the subject during a period of time prior to administration of an initial dose of the ActRII signal transduction inhibitor to the subject. In certain embodiments, the dose of the ActRII signal transduction inhibitor administered to the subject according to the methods provided herein is sufficient to reduce the transfusion burden of the subject by at most 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or at most 100% compared to the transfusion burden of the subject during a period of time prior to administration of an initial dose of the ActRII signal transduction inhibitor to the subject. In certain embodiments, the dose of the ActRII signal transduction inhibitor administered to the subject according to the methods provided herein is sufficient to reduce the transfusion burden of the subject by at least 33% compared to the transfusion burden of the subject during a period of time prior to administration of an initial dose of the ActRII signal transduction inhibitor to the subject. In certain embodiments, the dose of the ActRII signal transduction inhibitor administered to the subject according to the methods provided herein is sufficient to reduce the transfusion burden of the subject by at least 50% compared to the transfusion burden of the subject during a period of time prior to administration of an initial dose of the ActRII signal transduction inhibitor to the subject. In certain embodiments, the period of time prior to administration of an initial dose of the ActRII signal transduction inhibitor to the subject is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 3 months, 4 months, 5 months or 6 months. In certain embodiments, at least 3, 4, 5, 6, 12, 18, 24 or 48 months after administration of the ActRII signal transduction inhibitor, the dose of the ActRII signal transduction inhibitor administered to the subject according to the methods provided herein is sufficient to reduce the transfusion burden of the subject. In certain embodiments, indefinitely after administration of the ActRII signal transduction inhibitor, the dose of the ActRII signal transduction inhibitor administered to the subject according to the methods provided herein is sufficient to reduce the transfusion burden of the subject. In certain embodiments, the dose is between 0.1 mg / kg and 2.0 mg / kg. In certain embodiments, the dose is between 0.75 mg / kg and 2.0 mg / kg.

[0391] In certain embodiments, the dose of the ActRII signal transduction inhibitor administered to the subject according to the methods provided herein is sufficient to reduce the iron chelation therapy (e.g., dose or frequency) of the subject by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or at least 100% compared to the iron chelation therapy (e.g., dose or frequency) of the subject for a period of time prior to administration of the initial dose of the ActRII signal transduction inhibitor to the subject. In certain embodiments, the dose of the ActRII signal transduction inhibitor administered to the subject according to the methods provided herein is sufficient to reduce the iron chelation therapy (e.g., dose or frequency) of the subject by at most 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or at most 100% compared to the iron chelation therapy (e.g., dose or frequency) of the subject for a period of time prior to administration of the initial dose of the ActRII signal transduction inhibitor to the subject. In certain embodiments, the period of time prior to administration of the initial dose of the ActRII signal transduction inhibitor to the subject is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 3 months, 4 months, 5 months or 6 months. In certain embodiments, at least 3, 4, 5, 6, 12, 18, 24 or 48 months after administration of the ActRII signal transduction inhibitor, the dose of the ActRII signal transduction inhibitor administered to the subject according to the methods provided herein is sufficient to reduce the iron chelation therapy (e.g., dose or frequency) of the subject. In certain embodiments, indefinitely after administration of the ActRII signal transduction inhibitor, the dose of the ActRII signal transduction inhibitor administered to the subject according to the methods provided herein is sufficient to reduce the iron chelation therapy (e.g., dose or frequency) of the subject. In certain embodiments, the dose is between 0.1 mg / kg and 2.0 mg / kg. In certain embodiments, the dose is between 0.75 mg / kg and 2.0 mg / kg.

[0392] In certain embodiments, the dose of the ActRII signal transduction inhibitor administered to the subject according to the methods provided herein is sufficient to reduce the serum ferritin level of the subject by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or at least 50% compared to the serum ferritin level of the subject during a period of time prior to administration of an initial dose of the ActRII signal transduction inhibitor to the subject. In certain embodiments, the dose of the ActRII signal transduction inhibitor administered to the subject according to the methods provided herein is sufficient to reduce the serum ferritin level of the subject by at most 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% compared to the serum ferritin level of the subject during a period of time prior to administration of an initial dose of the ActRII signal transduction inhibitor to the subject. In certain embodiments, the period of time prior to administration of an initial dose of the ActRII signal transduction inhibitor to the subject is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 3 months, 4 months, 5 months, or 6 months. In certain embodiments, at least 3, 4, 5, 6, 12, 18, 24, or 48 months after administration of the ActRII signal transduction inhibitor, the dose of the ActRII signal transduction inhibitor administered to the subject according to the methods provided herein is sufficient to reduce the serum ferritin level of the subject. In certain embodiments, indefinitely after administration of the ActRII signal transduction inhibitor, the dose of the ActRII signal transduction inhibitor administered to the subject according to the methods provided herein is sufficient to reduce the serum ferritin level of the subject. In certain embodiments, the dose is between 0.1 mg / kg and 2.0 mg / kg. In certain embodiments, the dose is between 0.75 mg / kg and 2.0 mg / kg.

[0393] In certain embodiments, compared to the improvement in erythroid hematology of the subject over a period of time prior to administration of an initial dose of an ActRII signal transduction inhibitor to the subject, the dose of the ActRII signal transduction inhibitor administered to the subject according to the methods provided herein is sufficient to result in an improvement in erythroid hematology of the subject of at least 1.5 g / dL, 1.8 g / dL, 2.0 g / dL, 2.2 g / dL, 2.4 g / dL, 2.6 g / dL, 2.8 g / dL, 3.0 g / dL, 3.2 g / dL, 3.4 g / dL, 3.6 g / dL, 3.8 g / dL, or at least 4.0 g / dL. In certain embodiments, the period of time prior to administration of an initial dose of an ActRII signal transduction inhibitor to the subject is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 3 months, 4 months, 5 months, or 6 months. In certain embodiments, at least 3, 4, 5, 6, 12, 18, 24, or 48 months after administration of the ActRII signal transduction inhibitor, the dose of the ActRII signal transduction inhibitor administered to the subject according to the methods provided herein is sufficient to result in an improvement in erythroid hematology of the subject. In certain embodiments, indefinitely after administration of the ActRII signal transduction inhibitor, the dose of the ActRII signal transduction inhibitor administered to the subject according to the methods provided herein is sufficient to result in an improvement in erythroid hematology of the subject. In certain embodiments, the improvement in erythroid hematology in a patient with a low transfusion burden is an increase in the hemoglobin concentration of the patient of at least 1.5 g / dL for at least 8 weeks. In certain embodiments, the improvement in erythroid hematology in a patient with a high transfusion burden is a reduction in RBC transfusions of at least 4 units within 8 weeks. In certain embodiments, the dose is between 0.1 mg / kg and 2.0 mg / kg. In certain embodiments, the dose is between 0.75 mg / kg and 2.0 mg / kg.

[0394] In certain embodiments, the dose of the ActRII signal transduction inhibitor administered to a subject according to the methods provided herein is sufficient to increase the level of neutrophils in the subject by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 300%, 400%, or at least 500% compared to the level of neutrophils in the subject for a period of time prior to administering an initial dose of the ActRII signal transduction inhibitor to the subject. In certain embodiments, the dose of the ActRII signal transduction inhibitor administered to a subject according to the methods provided herein is sufficient to increase the level of neutrophils in the subject by at most 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 300%, 400%, or at most 500% compared to the level of neutrophils in the subject for a period of time prior to administering the ActRII signal transduction inhibitor. In certain embodiments, the dose of the ActRII signal transduction inhibitor administered to a subject according to the methods provided herein is sufficient to increase the level of neutrophils by at least 0.1x10 9 / L, 0.5x10 9 / L, 1.0x10 9 / L, 5x10 9 / L, 1.0x10 10 / L, 5x10 10 / L, or 1.0x10 11 / L. In certain embodiments, the time period before administering the initial dose of the ActRII signal transduction inhibitor to the subject is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 3 months, 4 months, 5 months, or 6 months. In certain embodiments, at least 3, 4, 5, 6, 12, 18, 24, or 48 months after administration of the ActRII signal transduction inhibitor, the dose of the ActRII signal transduction inhibitor administered to the subject according to the methods provided herein is sufficient to increase the level of neutrophils in the subject. In certain embodiments, indefinitely after administration of the ActRII signal transduction inhibitor, the dose of the ActRII signal transduction inhibitor administered to the subject according to the methods provided herein is sufficient to increase the level of neutrophils in the subject. In certain embodiments, the dose is between 0.1 mg / kg and 2.0 mg / kg. In certain embodiments, the dose is between 0.75 mg / kg and 2.0 mg / kg.

[0395] In certain embodiments, compared to the level of platelets in the subject during a period of time before administering the initial dose of the ActRII signal transduction inhibitor to the subject, the dose of the ActRII signal transduction inhibitor administered to the subject according to the methods provided herein is sufficient to increase the level of platelets in the subject by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 300%, 400%, or up to 500%. In certain embodiments, compared to the level of platelets in the subject during a period of time before administering the initial dose of the ActRII signal transduction inhibitor to the subject, the dose of the ActRII signal transduction inhibitor administered to the subject according to the methods provided herein is sufficient to increase the level of platelets in the subject by up to 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 300%, 400%, or up to 500%. In certain embodiments, compared to the level of platelets in the subject during a period of time before administering the initial dose of the ActRII signal transduction inhibitor to the subject, the dose of the ActRII signal transduction inhibitor administered to the subject according to the methods provided herein is sufficient to increase the platelet level by at least 1x10 10 / L, 3x10 10 / L, 5x10 10 / L, 1x1011 / L, 5 x 10 11 / L or at least 1 x 10 12 / L. In certain embodiments, the time period prior to administering the initial dose of the ActRII signal transduction inhibitor to the subject is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 3 months, 4 months, 5 months, or 6 months. In certain embodiments, at least 3, 4, 5, 6, 12, 18, 24, or 48 months after administration of the ActRII signal transduction inhibitor, the dose of the ActRII signal transduction inhibitor administered to the subject according to the methods provided herein is sufficient to increase the level of platelets in the subject. In certain embodiments, indefinitely after administration of the ActRII signal transduction inhibitor, the dose of the ActRII signal transduction inhibitor administered to the subject according to the methods provided herein is sufficient to increase the level of platelets in the subject. In certain embodiments, the dose is between 0.1 mg / kg and 2.0 mg / kg. In certain embodiments, the dose is between 0.75 mg / kg and 2.0 mg / kg.

[0396] When used in combination with a dose provided herein (e.g., a dose of an ActRII signal transduction inhibitor or a second active agent), the word "about" refers to any value within 1%, 5%, or 10% of the recited value.

[0397] In certain embodiments, the ActRII signal transduction inhibitor as described herein is administered subcutaneously or intravenously. In certain embodiments, the ActRII signal transduction inhibitor as described herein is administered subcutaneously once every three weeks. In certain embodiments, ActRIIA-hFC (SEQ ID NO:7; also known as sotatercept) is administered subcutaneously to a subject being treated according to the methods provided herein once every three weeks. In certain embodiments, ActRIIB-hFC (SEQ ID NO:25; also known as luspatercept) is administered subcutaneously to a subject being treated according to the methods provided herein once every three weeks.

[0398] 7.8 Patient Population

[0399] The subject to be treated according to the methods described herein can be any mammal (such as rodents and primates, and in a preferred embodiment, a human). In certain embodiments, the subject is a human. In certain embodiments, the methods described herein can be used to treat anemia, anemia requiring RBC transfusion, MDS, and / or non-proliferative CMML in any mammal (such as rodents and primates, and in a preferred embodiment, a human subject). In certain embodiments, the methods described herein can be used to increase the level of neutrophils in any mammal (such as rodents and primates, and in a preferred embodiment, a human subject). In certain embodiments, the methods described herein can be used to increase the level of platelets in any mammal (such as rodents and primates, and in a preferred embodiment, a human subject).

[0400] In certain embodiments, the percentage of erythroblasts that are ring sideroblasts in the subject to be treated according to the methods provided herein is at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or at least 20%. In certain embodiments, the percentage of erythroblasts that are ring sideroblasts in the subject to be treated according to the methods provided herein is at least 15%. In certain embodiments, the percentage of erythroblasts that are ring sideroblasts in the subject to be treated according to the methods provided herein is about 15%. In certain embodiments, the percentage of erythroblasts that are ring sideroblasts in the subject to be treated according to the methods provided herein is between about 10% and 20%. In certain embodiments, the percentage of erythroblasts that are ring sideroblasts in the subject to be treated according to the methods provided herein is between about 12% and 17%. In certain embodiments, the subject to be treated according to the methods provided herein has a ratio of ring sideroblasts to normal erythroblasts of at least 1:10, at least 1:7 or at least 1:5.

[0401] In certain embodiments, the subject to be treated according to the methods provided herein has a blood-related disorder. In certain embodiments, the blood-related disorder is anemia. In certain embodiments, the blood-related disorder is anemia requiring transfusion. In certain embodiments, the blood-related disorder is MDS. In certain embodiments, the blood-related disorder is non-proliferative CMML.

[0402] In certain embodiments, a subject being treated according to the methods provided herein has been diagnosed with anemia. In some aspects, the Hb level of the anemic subject is less than or equal to 9.0 g / dL. In some aspects, prior to treatment according to the methods provided herein, the anemic subject requires 2 or more units of RBC transfusions within 84 days. In certain embodiments, the subject has a high transfusion burden (HTB). An HTB subject requires at least 4 units of RBC transfusions every 56 days. In certain embodiments, the subject has a low transfusion burden (LTB). An LTB subject requires less than 4 units of RBC transfusions every 56 days. In certain embodiments, the subject is a subject in need of RBC transfusions. In certain embodiments, a subject being treated according to the methods provided herein has sideroblastic anemia, such as, for example, X-linked sideroblastic anemia, autosomal recessive pyridoxine-refractory sideroblastic anemia, X-linked sideroblastic anemia and spinocerebellar ataxia, myopathy, lactic acidosis and sideroblastic anemia, myopathy, lactic acidosis and sideroblastic anemia, thiamine-responsive megaloblastic anemia, pearson marrow-pancreas syndrome, refractory anemia with ring sideroblasts, refractory anemia with ring sideroblasts and marked thrombocytosis, and alcohol-induced and drug-induced sideroblastic anemia. In certain embodiments, a subject being treated according to the methods provided herein has been diagnosed with anemia and at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or at least 20% of the erythroblasts in the subject are ring sideroblasts. In certain embodiments, at least 15% of the erythroblasts in the subject are ring sideroblasts.

[0403] In certain embodiments, a subject being treated according to the methods provided herein has been diagnosed with MDS as defined by IPSS. In certain embodiments, a subject being treated according to the methods provided herein has been diagnosed with MDS as defined by IPSS and at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or at least 20% of the erythroblasts in the subject are ring sideroblasts. In certain embodiments, at least 15% of the erythroblasts in the subject are ring sideroblasts.

[0404] IPSS refers to the International Prognostic Scoring System, which is used to assess prognosis in myelodysplastic syndromes. See, e.g., Greenberg et al., Blood, 1997; 89(6):2079-2088, and Erratum in Blood, 1998; 91:1100. The IPSS uses a standard scoring system to characterize the outcomes of myelodysplastic syndrome patients as low-risk (0 points; median survival of 5.7 years), intermediate-1 (0.5 - 1 point; median survival of 3.5 years); intermediate-2 (1.5 - 2.0 points; median survival of 1.2 years); or high-risk (2.5 - 3.5 points; median survival of 0.4 years). This scoring system assesses (i) the percentage of bone marrow blasts in the subject; (ii) the karyotype of the subject; and (iii) cytopenia in the subject (defined as a hemoglobin concentration less than 10 g / dL, an absolute neutrophil count less than 1,800 / μL, and a platelet count less than 100,000 / μL).

[0405] In certain embodiments, a subject being treated according to the methods provided herein has been diagnosed with MDS as defined by IPSS-R. In certain embodiments, a subject being treated according to the methods provided herein has been diagnosed with MDS as defined by IPSS-R and at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or at least 20% of the erythroblasts in the subject are ring sideroblasts. In certain embodiments, at least 15% of the erythroblasts in the subject are ring sideroblasts.

[0406] The IPSS-R refers to the International Prognostic Scoring System-Revised, which is used to evaluate prognosis in myelodysplastic syndromes. See, e.g., Greenberg et al., Blood, 2012; 120(12):2454-2465; and Erratum in Blood, 1998; 91:1100. The IPSS-R uses a standard scoring system to characterize the outcomes of myelodysplastic syndrome patients as very low risk (less than or equal to 1.5 points; median survival of 8.8 years), low risk (greater than 1.5 points, less than or equal to 3 points; median survival of 5.3 years); intermediate risk (greater than 3 points, less than or equal to 4.5 points; median survival of 3 years); high risk (greater than 4.5 points, less than or equal to 6 points; median survival of 1.6 years); or very high risk (greater than 6 points; median survival of 0.8 years). This scoring system specifically evaluates: (i) the percentage of bone marrow blasts in the subject; (ii) the karyotype of the subject; and (iii) cytopenia in the subject (defined as a hemoglobin concentration less than 10 g / dL, an absolute neutrophil count less than 1,800 / μL, and a platelet count less than 100,000 / μL).

[0407] In certain embodiments, the subject being treated according to the methods provided herein has been diagnosed with non-proliferative CMML. In certain embodiments, the subject being treated according to the methods provided herein has been diagnosed with non-proliferative CMML and at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or at least 20% of the erythroblasts in the subject are ring sideroblasts.

[0408] In certain embodiments, a subject being treated according to the methods provided herein has MDS. In certain embodiments, the MDS is low-risk MDS as defined by IPSS. In certain embodiments, the MDS is intermediate-1 risk MDS as defined by IPSS. In certain embodiments, the MDS is intermediate-2 risk MDS as defined by IPSS. In certain embodiments, the MDS is high-risk MDS as defined by IPSS. In certain embodiments, the MDS is very low-risk MDS as defined by IPSS-R. In certain embodiments, the MDS is low-risk MDS as defined by IPSS-R. In certain embodiments, the MDS is intermediate risk MDS as defined by IPSS-R. In certain embodiments, the MDS is high-risk MDS as defined by IPSS-R. In certain embodiments, the MDS is very high-risk MDS as defined by IPSS-R. In certain embodiments, a subject being treated according to the methods provided herein (i) has MDS and (ii) has RARS. In certain embodiments, a subject being treated according to the methods provided herein (i) has MDS and (ii) has RCMD-RS. In certain embodiments, a subject being treated according to the methods provided herein (i) has MDS, (ii) has RARS, and (iii) has RCMD-RS. In certain embodiments, a subject being treated according to the methods provided herein (i) has MDS, and (ii) at least 15% of the erythroblasts in the subject are ring sideroblasts. In certain embodiments, a subject being treated according to the methods provided herein (i) has MDS, (ii) has RARS, and (iii) at least 15% of the erythroblasts in the subject are ring sideroblasts. In certain embodiments, a subject being treated according to the methods provided herein (i) has MDS, (ii) has RCMD-RS, and (iii) at least 15% of the erythroblasts in the subject are ring sideroblasts. In certain embodiments, a subject being treated according to the methods provided herein (i) has MDS, (ii) has RARS, (iii) has RCMD-RS, and (iv) at least 15% of the erythroblasts in the subject are ring sideroblasts. In certain embodiments, a subject being treated according to the methods provided herein (i) has MDS, (ii) has RARS, and (iii) expresses SF3B1 having one or more mutations. In certain embodiments, a subject being treated according to the methods provided herein (i) has MDS, (ii) has RCMD-RS, and (iii) expresses SF3B1 having one or more mutations. In certain embodiments, a subject being treated according to the methods provided herein (i) has MDS, (ii) has RARS, (iii) has RCMD-RS, and (iv) expresses SF3B1 having one or more mutations.In certain embodiments, a subject being treated according to the methods provided herein (i) has MDS, (ii) at least 15% of the erythroblasts in the subject are ring sideroblasts, and (iii) expresses SF3B1 having one or more mutations. In certain embodiments, a subject being treated according to the methods provided herein (i) has MDS, (ii) has RARS, (iii) at least 15% of the erythroblasts in the subject are ring sideroblasts, and (iv) expresses SF3B1 having one or more mutations. In certain embodiments, a subject being treated according to the methods provided herein (i) has MDS, (ii) has RCMD-RS, (iii) at least 15% of the erythroblasts in the subject are ring sideroblasts, and (iv) expresses SF3B1 having one or more mutations. In certain embodiments, a subject being treated according to the methods provided herein (i) has MDS, (ii) has RARS, (iii) has RCMD-RS, (iv) at least 15% of the erythroblasts in the subject are ring sideroblasts, and (v) expresses SF3B1 having one or more mutations.

[0409] In certain embodiments, the subject being treated according to the methods provided herein has non-proliferative CMML. In certain embodiments, the subject being treated according to the methods provided herein (i) has non-proliferative CMML and (ii) has RARS. In certain embodiments, the subject being treated according to the methods provided herein (i) has non-proliferative CMML and (ii) has RCMD-RS. In certain embodiments, the subject being treated according to the methods provided herein (i) has non-proliferative CMML, (ii) has RARS, and (iii) has RCMD-RS. In certain embodiments, the subject being treated according to the methods provided herein (i) has non-proliferative CMML, and (ii) at least 15% of the erythroblasts in the subject are ring sideroblasts. In certain embodiments, the subject being treated according to the methods provided herein (i) has non-proliferative CMML, (ii) has RARS, and (iii) at least 15% of the erythroblasts in the subject are ring sideroblasts. In certain embodiments, the subject being treated according to the methods provided herein (i) has non-proliferative CMML, (ii) has RCMD-RS, and (iii) at least 15% of the erythroblasts in the subject are ring sideroblasts. In certain embodiments, the subject being treated according to the methods provided herein (i) has non-proliferative CMML, (ii) has RARS, (iii) has RCMD-RS, and (iv) at least 15% of the erythroblasts in the subject are ring sideroblasts. In certain embodiments, the subject being treated according to the methods provided herein (i) has non-proliferative CMML, and (ii) expresses SF3B1 having one or more mutations. In certain embodiments, the subject being treated according to the methods provided herein (i) has non-proliferative CMML, (ii) has RARS, and (iii) expresses SF3B1 having one or more mutations. In certain embodiments, the subject being treated according to the methods provided herein (i) has non-proliferative CMML, (ii) has RCMD-RS, and (iii) expresses SF3B1 having one or more mutations. In certain embodiments, the subject being treated according to the methods provided herein (i) has non-proliferative CMML, (ii) has RARS, (iii) has RCMD-RS, and (iv) expresses SF3B1 having one or more mutations. In certain embodiments, the subject being treated according to the methods provided herein (i) has non-proliferative CMML, (ii) at least 15% of the erythroblasts in the subject are ring sideroblasts, and (iii) expresses SF3B1 having one or more mutations.In certain embodiments, a subject being treated according to the methods provided herein (i) has non-proliferative CMML, (ii) has RARS, (iii) has at least 15% of erythroblasts in the subject being ring sideroblasts, and (iv) expresses SF3B1 having one or more mutations. In certain embodiments, a subject being treated according to the methods provided herein (i) has non-proliferative CMML, (ii) has RCMD-RS, (iii) has at least 15% of erythroblasts in the subject being ring sideroblasts, and (iv) expresses SF3B1 having one or more mutations. In certain embodiments, a subject being treated according to the methods provided herein has (i) non-proliferative CMML, (ii) RARS, (iii) RCMD-RS, (iv) has at least 15% of erythroblasts in the subject being ring sideroblasts, and (v) expresses SF3B1 having one or more mutations.

[0410] In certain embodiments, a subject being treated according to the methods provided herein expresses a gene having a mutation associated with ineffective erythropoiesis. In certain embodiments, a subject being treated according to the methods provided herein expresses one or more splice factor genes that comprise one or more mutations. In a specific embodiment, a subject being treated according to the methods provided herein expresses SF3B1 having one or more mutations. In certain embodiments, the one or more mutations are in non-coding regions. In certain embodiments, SF3B1 is the gene encoding SB3B1. In certain embodiments, the one or more mutations are in coding regions. In certain embodiments, SF3B1 is the SF3B1 protein. In certain embodiments, one or more mutations in the SF3B1 protein are selected from the group consisting of E622D, R625C, H662Q, H662D, K66N, K666T, K666Q, K666E, A672D, K700E, I704N. In certain embodiments, a subject being treated according to the methods provided herein expresses an SF3B1 protein having the mutation E622D. In certain embodiments, a subject being treated according to the methods provided herein expresses an SF3B1 protein having the mutation R625C. In certain embodiments, a subject being treated according to the methods provided herein expresses an SF3B1 protein having the mutation H662Q. In certain embodiments, a subject being treated according to the methods provided herein expresses an SF3B1 protein having the mutation H662D. In certain embodiments, a subject being treated according to the methods provided herein expresses an SF3B1 protein having the mutation K66N. In certain embodiments, a subject being treated according to the methods provided herein expresses an SF3B1 protein having the mutation K666T. In certain embodiments, a subject being treated according to the methods provided herein expresses an SF3B1 protein having the mutation K666Q. In certain embodiments, a subject being treated according to the methods provided herein expresses an SF3B1 protein having the mutation K666E. In certain embodiments, a subject being treated according to the methods provided herein expresses an SF3B1 protein having the mutation A672D. In certain embodiments, a subject being treated according to the methods provided herein expresses an SF3B1 having the mutation K700E. In certain embodiments, a subject being treated according to the methods provided herein expresses an SF3B1 protein having the mutation I704N. In a specific embodiment, a subject being treated according to the methods provided herein expresses SRSF2 having one or more mutations. In a specific embodiment, a subject being treated according to the methods provided herein expresses DNMT3A having one or more mutations. In a specific embodiment, a subject being treated according to the methods provided herein expresses TET2 having one or more mutations.In a specific embodiment, the subject being treated according to the methods provided herein expresses SETBP1 having one or more mutations.

[0411] In certain embodiments, the subject being treated according to the methods provided herein has thrombocytopenia. In certain embodiments, the subject being treated according to the methods provided herein has less than 1 x 10 11 platelets per liter. In certain embodiments, the subject being treated according to the methods provided herein has neutropenia. In certain embodiments, the absolute neutrophil count of the subject being treated according to the methods provided herein is less than 1 x 10 9 / liter.

[0412] In certain embodiments, the subject being treated according to the methods provided herein has less than 13,000 white blood cells / μL, less than 12,000 white blood cells / μL, less than 11,000 white blood cells / μL, less than 10,000 white blood cells / μL, less than 7,500 white blood cells / μL or less than 500 white blood cells / μL.

[0413] In certain embodiments, the hemoglobin level of the subject being treated according to the methods provided herein is less than 10 g / dL, 9 g / dL, 8 g / dL or 7 g / dL. In certain embodiments, the hemoglobin level of the subject being treated according to the methods provided herein is between 7 g / dL and 7.5 g / dL, between 7.5 g / dL and 8 g / dL, between 8 g / dL and 8.5 g / dL, between 8.5 g / dL and 9.0 g / dL, between 9.0 g / dL and 9.5 g / dL or between 9.5 g / dL and 10.0 g / dL.

[0414] In certain embodiments, the subject being treated according to the methods provided herein has a low transfusion burden. In certain embodiments, the subject with a low transfusion burden being treated according to the methods provided herein requires at most 0, 1, 2 or 3 units of red blood cells every 8 weeks. In certain embodiments, the subject being treated according to the methods provided herein has a high transfusion burden. In certain embodiments, the subject with a high transfusion burden being treated according to the methods provided herein requires at least 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 units of red blood cells every 8 weeks.

[0415] In certain embodiments, the subject being treated according to the methods provided herein does not respond, lacks response or has a low response rate to one or more ESAs.

[0416] In certain embodiments, a subject being treated according to the methods provided herein has previously received one or more ESA treatments or is currently undergoing one or more ESA treatments. In certain embodiments, a subject being treated according to the methods provided herein has previously received a hypomethylating agent treatment. In certain embodiments, a subject being treated according to the methods provided herein has previously received lenalidomide treatment. In certain embodiments, a subject being treated according to the methods provided herein has not previously received azacitidine, decitabine, an ESA, G-CSF, GM-CSF, or lenalidomide treatment. In certain embodiments, a subject being treated according to the methods provided herein is non-responsive to treatment with one or more ESAs. In certain embodiments, a subject being treated according to the methods provided herein is refractory to treatment with one or more ESAs. In certain embodiments, a subject being treated according to the methods provided herein becomes refractory to treatment with one or more ESAs. In certain embodiments, a subject being treated according to the methods provided herein is refractory to a previous treatment with an ESA. In certain embodiments, a subject refractory to a previous treatment with an ESA has documented non-responsiveness or a response that is no longer maintained to a previous ESA-containing regimen (either as a single agent or in combination with other drugs (e.g., in combination with G-CSF)); the ESA regimen must have been either (a) recombinant human erythropoietin at greater than 40,000 IU / week for at least 8 doses, or an equivalent regimen, or (b) darbepoetin alpha at greater than 500 μg every three weeks for at least 4 doses, or an equivalent regimen. In certain embodiments, a subject being treated according to the methods provided herein is intolerant to a previous ESA treatment. In certain embodiments, a subject intolerant to a previous ESA treatment has documented discontinuation of a previous ESA-containing regimen (either as a single agent or in combination with other drugs (e.g., in combination with G-CSF)) at any time after the introduction due to intolerance or an adverse event. In certain embodiments, a subject being treated according to the methods provided herein is ESA-ineligible. In certain embodiments, an ESA-ineligible subject has a low response rate to ESA, based on endogenous serum erythropoietin levels greater than 200 U / L for subjects who have not previously received ESA treatment.

[0417] In certain embodiments, the subject being treated according to the methods described herein can be of any age. In certain embodiments, the subject being treated according to the methods described herein is less than 18 years of age. In one specific embodiment, the subject being treated according to the methods described herein is less than 13 years of age. In another specific embodiment, the subject being treated according to the methods described herein is less than 12 years of age, less than 11 years of age, less than 10 years of age, less than 9 years of age, less than 8 years of age, less than 7 years of age, less than 6 years of age, or less than 5 years of age. In another specific embodiment, the subject being treated according to the methods described herein is 1 - 3 years of age, 3 - 5 years of age, 5 - 7 years of age, 7 - 9 years of age, 9 - 11 years of age, 11 - 13 years of age, 13 - 15 years of age, 15 - 20 years of age, 20 - 25 years of age, 25 - 30 years of age, or greater than 30 years of age. In another specific embodiment, the subject being treated according to the methods described herein is 30 - 35 years of age, 35 - 40 years of age, 40 - 45 years of age, 45 - 50 years of age, 50 - 55 years of age, 55 - 60 years of age, or greater than 60 years of age. In another specific embodiment, the subject being treated according to the methods described herein is 60 - 65 years of age, 65 - 70 years of age, 70 - 75 years of age, 75 - 80 years of age, or greater than 80 years of age.

[0418] In certain embodiments, the subject being treated according to the methods described herein has MDS. In certain embodiments, the subject being treated according to the methods described herein has MDS and has intact chromosome 5q. In certain embodiments, the subject being treated according to the methods provided herein has MDS, has intact chromosome 5q, and has no documented failure of treatment with lenalidomide. In certain embodiments, the subject being treated according to the methods provided herein has MDS, has intact chromosome 5q, and has a documented failure of treatment with lenalidomide. In certain embodiments, the subject being treated according to the methods described herein has MDS with del(5q). MDS with del(5q) includes a deletion of the long arm of chromosome 5 which, among other things, is characterized by macrocytic anemia with oval macrocytes, normal to slightly decreased white blood cell count, normal to elevated platelet count, and less than 5% blasts in the bone marrow and blood. In certain embodiments, the subject being treated according to the methods provided herein has MDS with del(5q) and has no documented failure of treatment with lenalidomide. In certain embodiments, the subject being treated according to the methods provided herein has MDS with del(5q) and has a documented failure of treatment with lenalidomide. In certain embodiments, failure of treatment with lenalidomide includes lack of response to lenalidomide, no response to lenalidomide after 4 months of treatment with lenalidomide, intolerance to treatment with lenalidomide, or inoperability of treatment with lenalidomide due to cytopenia.

[0419] In certain embodiments, the subject being treated according to the methods provided herein has less than 5% blasts in the bone marrow and blood.

[0420] In certain embodiments, the EPO serum concentration of the subject being treated according to the methods provided herein is greater than 500 mIU / mL. In certain embodiments, the EPO serum concentration of the subject being treated according to the methods provided herein is greater than 200 mIU / mL.

[0421] 7.9 Signal transduction inhibitors of the ActRII receptor

[0422] Inhibitors of the ActRII receptor covered herein include ActRIIA signal transduction inhibitors and ActRIIB signal transduction inhibitors (see below). In certain embodiments, the ActRII receptor signal transduction inhibitor specifically refers to ActRIIA. In other embodiments, the ActRII receptor signal transduction inhibitor specifically refers to ActRIIB. In certain embodiments, the ActRII receptor signal transduction inhibitor preferentially inhibits ActRIIA. In other embodiments, the ActRII receptor signal transduction inhibitor preferentially inhibits ActRIIB. In certain embodiments, the ActRII receptor signal transduction inhibitor inhibits both ActRIIA and ActRIIB.

[0423] In certain embodiments, the signal transduction inhibitor of the ActRII receptor can be a polypeptide comprising the activin-binding domain of ActRII. Without being bound by theory, such polypeptides comprising the activin-binding domain chelate activin and thus prevent activin signal transduction. These polypeptides comprising the activin-binding domain can comprise all or a portion of the extracellular domain of the ActRII receptor (i.e., all or a portion of the extracellular domain of ActRIIA or all or a portion of the extracellular domain of ActRIIB). In a specific embodiment, the extracellular domain of the ActRII receptor is soluble.

[0424] In certain embodiments, the polypeptide comprising the activin-binding domain is linked to the Fc portion of an antibody (i.e., a conjugate comprising the polypeptide comprising the activin-binding domain of the ActRII receptor and the Fc portion of an antibody is produced). Without being bound by theory, the antibody portion confers increased stability to the conjugate. In certain embodiments, the activin-binding domain is linked to the Fc portion of the antibody via a linker (e.g., a peptide linker).

[0425] Signal transduction inhibitors of ActRII receptors for the compositions and methods described herein include molecules that directly or indirectly inhibit ActRIIA and / or ActRIIB, either extracellularly or intracellularly. In some embodiments, the signal transduction inhibitors of ActRIIA and / or ActRIIB for the compositions and methods described herein inhibit ActRIIA and / or ActRIIB through interaction with the receptor itself. In other embodiments, the signal transduction inhibitors of ActRIIA and / or ActRIIB for the compositions and methods described herein inhibit ActRIIA and / or ActRIIB through interaction with ActRIIA and / or ActRIIB ligands (such as activin).

[0426] 7.9.1 Signal transduction inhibitors of ActRIIA

[0427] As used herein, the term "ActRIIA" refers to a family of activin receptor type IIa (ActRIIA) proteins from any species and variants derived from such ActRIIA proteins by mutagenesis or other modifications. Reference to ActRIIA herein is understood to refer to any currently identified form. Members of the ActRIIA family are generally transmembrane proteins with predicted serine / threonine kinase activity, consisting of a ligand-binding extracellular domain with a cysteine-rich region, a transmembrane domain, and a cytoplasmic domain.

[0428] ActRIIA signal transduction inhibitors to be used in the compositions and methods described herein include, but are not limited to, activin-binding soluble ActRIIA polypeptides; antibodies that bind to activin (especially activin A or B subunits, also known as βA or βB) and disrupt ActRIIA binding; antibodies that bind to ActRIIA and disrupt activin binding; non-antibody proteins selected for activin or ActRIIA binding (for examples of such proteins and methods for the design and selection of such inhibitors see, for example, WO / 2002 / 088171, WO / 2006 / 055689, WO / 2002 / 032925, WO / 2005 / 037989, US 2003 / 0133939, and US 2005 / 0238646, each of which is incorporated herein by reference in its entirety); and random peptides selected for activin or ActRIIA binding, which may be conjugated to an Fc domain.

[0429] In certain embodiments, two or more different proteins (or other moieties) having activin or ActRIIA binding activity, particularly activin binders that separately block type I (e.g., soluble type I activin receptor) and type II (e.g., soluble type II activin receptor) binding sites, can be linked together to produce bifunctional or multifunctional binding molecules that inhibit ActRIIA and can thus be used in the compositions and methods described herein. In certain embodiments, antagonists of the activin-ActRIIA signal transduction axis that inhibit ActRIIA include nucleic acid aptamers, small molecules, and other agents for the compositions and methods described herein.

[0430] (a) An ActRIIA signal transduction inhibitor comprising an ActRIIA polypeptide

[0431] The term "ActRIIA polypeptide" includes any naturally occurring polypeptide comprising a member of the ActRIIA family and any variant thereof (including mutant, fragment, fusion, and peptidomimetic forms) that retains a beneficial activity. For example, ActRIIA polypeptides include polypeptides having a sequence derived from any known ActRIIA sequence that has at least about 80% identity, and optionally at least 85%, 90%, 95%, 97%, 98%, 99% or greater identity to the sequence of an ActRIIA polypeptide. For example, an ActRIIA polypeptide can bind and inhibit the function of an ActRIIA protein and / or activin. ActRIIB polypeptides can be selected for their ability to promote bone growth and bone mineralization. Examples of ActRIIA polypeptides include the human ActRIIA precursor polypeptide (SEQ ID NO:1) and soluble human ActRIIA polypeptides (e.g., SEQ ID NO:2, 3, 7, and 12). With respect to the ActRIIA precursor polypeptide depicted by SEQ ID NO:1 with respect to its amino acid sequence, the signal peptide of the human ActRIIA precursor polypeptide is at amino acid positions 1 to 20; the extracellular domain is at amino acid positions 21 to 135; the N-linked glycosylation sites of the human ActRIIA precursor polypeptide (SEQ ID NO:1) are at amino acid positions 43 and 56 of SEQ ID NO:1. The nucleic acid sequence encoding the human ActRIIB precursor polypeptide of SEQ ID NO:1 is disclosed as SEQ ID NO:4 (nucleotides 164-1705 of Genbank entry NM_001616). The nucleic acid sequence encoding the soluble human ActRIIA polypeptide of SEQ ID NO:2 is disclosed as SEQ ID NO:5. See Table 21 for a description of the sequences.

[0432] In certain embodiments, the ActRIIA polypeptide for use in the compositions and methods described herein is a soluble ActRIIA polypeptide. The extracellular domain of the ActRIIA protein can bind activin and is generally soluble, and thus can be referred to as a soluble activin-binding ActRIIA polypeptide. Thus, as used herein, the term "soluble ActRIIA polypeptide" generally refers to a polypeptide comprising the extracellular domain of the ActRIIA protein, including the extracellular domain of any naturally occurring ActRIIA protein and any variants thereof (including mutants, fragments, and peptidomimetic forms). Soluble ActRIIA polypeptides can bind activin; however, wild-type ActRIIA protein does not exhibit significant selectivity for activin relative to its binding to GDF8 / 11. By conjugating the ActRIIA protein with a second activin-selective binder, additive specificity for activin can be conferred on the native or altered ActRIIA protein. Examples of soluble activin-binding ActRIIA polypeptides include the soluble polypeptides illustrated in SEQ ID NOs: 2, 3, 7, 12, and 13. Other examples of soluble activin-binding ActRIIA polypeptides contain a signal sequence other than the extracellular domain of the ActRIIA protein, such as the melittin leader sequence (SEQ ID NO: 8), the tissue plasminogen activator (TPA) leader sequence (SEQ ID NO: 9), or the native ActRIIA leader sequence (SEQ ID NO: 10). The ActRIIA-hFc polypeptide illustrated in SEQ ID NO: 13 uses the TPA leader sequence.

[0433] In certain embodiments, the signal transduction inhibitor of ActRIIA for use in the compositions and methods described herein comprises a conjugate / fusion protein comprising the activin-binding domain of ActRIIA linked to the Fc portion of an antibody. In certain embodiments, the activin-binding domain is linked to the Fc portion of the antibody by a linker (e.g., a peptide linker). Optionally, the Fc domain has one or more mutations at residues such as Asp-265, Lysine 322, and Asn-434. In some cases, the mutant Fc domain having one or more of these mutations (e.g., the Asp-265 mutation) has a reduced ability to bind to Fcγ receptors relative to the wild-type Fc domain. In other cases, the mutant Fc domain having one or more of these mutations (e.g., the Asn-434 mutation) has an increased ability to bind to the major histocompatibility complex class I-related Fc-receptor (FcRN) relative to the wild-type Fc domain. Exemplary fusion proteins comprising the soluble extracellular domain of ActRIIA fused to an Fc domain are shown in SEQ ID NOs: 6, 7, 12, and 13.

[0434] In one specific embodiment, the ActRIIA signal transduction inhibitor for the compositions and methods described herein comprises the extracellular domain of ActRIIA or a portion thereof linked to the Fc portion of an antibody, wherein the ActRIIA signal transduction inhibitor comprises an amino acid sequence having at least 75% identity to an amino acid sequence selected from SEQ ID NOs: 6, 7, 12, and 13. In another specific embodiment, the ActRIIA signal transduction inhibitor for the compositions and methods described herein comprises the extracellular domain of ActRIIA or a portion thereof linked to the Fc portion of an antibody, wherein the ActRIIA signal transduction inhibitor comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity to an amino acid sequence selected from SEQ ID NOs: 6, 7, 12, and 13.

[0435] In certain embodiments, the signal transduction inhibitor of ActRIIA for the compositions and methods described herein comprises a truncated form of the extracellular domain of ActRIIA. The truncation can be located at the carboxyl terminus and / or the amino terminus of the ActRIIA polypeptide. In certain embodiments, relative to the extracellular domain of the mature ActRIIA polypeptide, the truncation can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 amino acids in length. In certain embodiments, the truncation can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 N-terminal amino acids of the extracellular domain of the mature ActRIIA polypeptide. In certain embodiments, the truncation can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 C-terminal amino acids of the extracellular domain of the mature ActRIIA polypeptide. For example, truncated forms of ActRIIA include polypeptides having amino acids 20-119, 20-128, 20-129, 20-130, 20-131, 20-132, 20-133, 20-134, 20-131, 21-131, 22-131, 23-131, 24-131, and 25-131, wherein the amino acid positions refer to the amino acid positions in SEQ ID NO: 1.

[0436] In certain embodiments, the signal transduction inhibitor of ActRIIA for use in the compositions and methods described herein comprises the extracellular domain of ActRIIA having one or more amino acid substitutions. In certain embodiments, the signal transduction inhibitor of ActRIIA for use in the compositions and methods described herein comprises a truncated form of the ActRIIA extracellular domain that also carries amino acid substitutions.

[0437] In one specific embodiment, the ActRIIA signal transduction inhibitor to be used in the compositions and methods described herein is a fusion protein between the extracellular domain of the human ActRIIA receptor and the Fc portion of IgG1. In another specific embodiment, the ActRIIA signal transduction inhibitor to be used in the compositions and methods described herein is a fusion protein between the truncated extracellular domain of the human ActRIIA receptor and the Fc portion of IgG1. In another specific embodiment, the ActRIIA signal transduction inhibitor to be used in the compositions and methods described herein is a fusion protein between the truncated extracellular domain of the human ActRIIA receptor and the Fc portion of IgG1, wherein the truncated extracellular domain of the human ActRIIA receptor has one or more amino acid substitutions.

[0438] Functional active fragments of the ActRIIA polypeptide can be obtained, for example, by screening polypeptides recombinantly produced from the corresponding fragments of the nucleic acid encoding the ActRIIA polypeptide. Additionally, techniques known in the art, such as conventional Merrifield solid-phase f-Moc or t-Boc chemistry, can be employed to chemically synthesize the fragments. The fragments can be produced (recombinantly or by chemical synthesis) and tested to identify those peptidyl fragments that can act as antagonists (inhibitors) of the ActRIIA protein or activin-mediated signal transduction.

[0439] Additionally, functional active variants of the ActRIIA polypeptide can be obtained, for example, by screening a library of modified polypeptides recombinantly produced from the corresponding mutagenized nucleic acid encoding the ActRIIA polypeptide. Variants can be produced and tested to identify those that can act as antagonists (inhibitors) of the ActRIIA protein or activin-mediated signal transduction. In certain embodiments, the functional variants of the ActRIIA polypeptide comprise an amino acid sequence having at least 75% identity to an amino acid sequence selected from SEQ ID NO:2 or 3. In certain cases, the functional variants have an amino acid sequence having at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identity to an amino acid sequence selected from SEQ ID NO:2 or 3.

[0440] Functional variants can be generated, for example, by modifying the structure of the ActRIIA polypeptide for such purposes as improving therapeutic efficacy or stability (e.g., in vitro shelf life and in vivo resistance to proteolytic degradation). Such modified ActRIIA polypeptides can be considered functional equivalents of the naturally occurring ActRIIA polypeptide when they retain activin binding. Modified ActRIIA polypeptides can also be generated, for example, by amino acid substitution, deletion, or addition. For example, it is reasonable to expect that single substitutions of leucine with isoleucine or valine, aspartic acid with glutamic acid, threonine with serine, or similar substitutions of one amino acid with another structurally related amino acid (e.g., conservative mutations) will not have a major effect on the biological activity of the resulting molecule. Conservative substitutions are those that occur within a class of amino acids that are related in their side chains. By assessing the ability of variant ActRIIA polypeptides to elicit a response in cells in a manner similar to the wild-type ActRIIA polypeptide, it can be readily determined whether changes in the amino acid sequence of the ActRIIA polypeptide result in the production of functional homologs.

[0441] In certain embodiments, provided herein are specific mutations of the ActRIIA polypeptide that can alter the glycosylation of the polypeptide. Such mutations can be selected to introduce or eliminate one or more glycosylation sites, such as O-linked or N-linked glycosylation sites. The asparagine-linked glycosylation recognition site generally comprises the tripeptide sequence asparagine-X-threonine (or asparagine-like-X-serine), where "X" is any amino acid, which is specifically recognized by the appropriate cellular glycosylation enzymes. Alterations can also be made by adding one or more serine or threonine residues to the sequence of the wild-type ActRIIA polypeptide or substituting (for O-linked glycosylation sites) one or more serine or threonine residues. A variety of amino acid substitutions or deletions of one or both of the first or third amino acid positions of the glycosylation recognition site (and / or an amino acid deletion at the second position) result in non-glycosylation on the modified tripeptide sequence. Another way to increase the number of sugar moieties on the ActRIIA polypeptide is by chemical or enzymatic coupling of a glycoside to the ActRIIA polypeptide. Depending on the coupling mode employed, the sugar can be linked to: (a) arginine and histidine; (b) a free carboxyl group; (c) a free sulfhydryl group, such as the free sulfhydryl of cysteine; (d) a free hydroxyl group, such as the free hydroxyl of serine, threonine, or hydroxyproline; (e) an aromatic residue, such as the aromatic residue of phenylalanine, tyrosine, or tryptophan; or (f) the amide group of glutamine. These methods are described in WO 87 / 05330, published Sep. 11, 1987, and Aplin and Wriston (1981) CRC Crit. Rev. Biochem., pp. 259-306, which are incorporated herein by reference. Removal of one or more sugar moieties present on the ActRIIA polypeptide can be accomplished by chemical and / or enzymatic methods. Chemical deglycosylation can include, for example, exposing the ActRIIA polypeptide to the compound trifluoromethanesulfonic acid or an equivalent compound. Such treatment results in cleavage of most or all of the sugars except the sugars linked to the amino acid sequence (N-acetylglucosamine or N-acetylgalactosamine), while leaving the amino acid sequence intact. Chemical deglycosylation is further described in Hakimuddin et al. (1987) Arch. Biochem. Biophys. 259:52 and Edge et al. (1981) Anal. Biochem. 118:131. Enzymatic cleavage of the sugar moieties on the ActRIIA polypeptide can be achieved by using various endo- and exo-glycosidases described in Thotakura et al. (1987) Meth. Enzymol. 138:350. Where appropriate, the sequence of the ActRIIA polypeptide can be adjusted according to the type of expression system used, since mammalian, yeast, insect, and plant cells can all introduce different glycosylation patterns that can be affected by the amino acid sequence of the peptide.In general, ActRIIA protein for human use will be expressed in mammalian cell lines that provide correct glycosylation, such as HEK293 or CHO cell lines, although other expression systems such as other mammalian expression cell lines, yeast cell lines with engineered glycosylation enzymes, and insect cells are also expected to be useful.

[0442] Also provided herein are methods for generating mutants of the ActRIIA polypeptide, particularly groups of combinatorial mutants and truncated mutants; combinatorial mutant pools can be particularly useful for identifying functional variant sequences. The purpose of screening such combinatorial libraries can be to generate, for example, ActRIIA polypeptide variants that can act as agonists or antagonists or have new activities together. Various screening assays are provided below, which can be used to evaluate the variants. For example, ActRIIA polypeptide variants can be screened for their ability to bind to an ActRIIA ligand, prevent binding of an ActRIIA ligand to the ActRIIA polypeptide, or interfere with signal transduction induced by an ActRIIA ligand.

[0443] Variants of combinatorial origin can be generated that have generally increased selectivity or potency compared to the naturally occurring ActRIIA polypeptide. Similarly, mutagenesis can generate variants with significantly different intracellular half-lives compared to the corresponding wild-type ActRIIA polypeptide. For example, the altered protein can be made more or less stable to proteolytic degradation or to other cellular processes that cause the destruction or otherwise inactivation of the native ActRIIA polypeptide. Such variants and their encoding genes can be used to alter ActRIIA polypeptide levels by modulating the half-life of the ActRIIA polypeptide. For example, a short half-life can produce a more transient biological effect and can more tightly control the level of recombinant ActRIIA polypeptide in an object. In an Fc fusion protein, mutations can be made in the linker (if any) and / or the Fc portion to alter the protein's half-life.

[0444] Combinatorial libraries can be generated from degenerate libraries of genes encoding polypeptide libraries, each of which includes at least a portion of a potential ActRIIA polypeptide sequence. For example, a mixture of synthetic oligonucleotides can be enzymatically ligated to a gene sequence such that a degenerate set of potential ActRIIA polypeptide nucleotide sequences can be expres...

Claims

1. Use of an activin receptor type II (ActRII) signal transduction inhibitor in the preparation of a medicament for treating anemia requiring blood transfusion in a subject, wherein the medicament is prepared to be administered at a dose of the ActRII signal transduction inhibitor between 0.1 mg / kg and 2.0 mg / kg, wherein an initial percentage of erythroblasts that are ring sideroblasts in the subject is at least 15%, and wherein the ActRII signal transduction inhibitor is a polypeptide comprising: (i) a fragment of the extracellular domain of ActRIIB, wherein the fragment consists of the amino acid sequence of SEQ ID NO:23; (ii) a linker; and (iii) the Fc of IgG.

2. The use according to claim 1, wherein the medicament is administered to the subject to achieve (i) a long-term decrease in the percentage of erythroblasts that are ring sideroblasts in the subject compared to the initial percentage of erythroblasts that are ring sideroblasts in the subject; and / or (ii) a long-term increase in the hemoglobin level of the subject compared to the initial hemoglobin level of the subject before the initial dose of the ActRII signal transduction inhibitor is to be administered to the subject.

3. The use according to claim 1, wherein the ActRII signal transduction inhibitor is to be administered to the subject for 1, 2, 3, 4, 5 or 6 months.

4. The use according to claim 3, wherein at least 1, 2, 3, 4, 5, 6, 12, 18 or 24 months after administration of the ActRII signal transduction inhibitor to the subject, a long-term decrease in the percentage of erythroblasts that are ring sideroblasts in the subject is maintained.

5. The use according to claim 2, wherein the long-term decrease in the percentage of erythroblasts that are ring sideroblasts in the subject is at least 1.5, 2.5, 5.0, 7.5 or 10.0 times lower than the initial percentage of erythroblasts that are ring sideroblasts in the subject.

6. The use according to claim 2, wherein the initial hemoglobin level of the subject is less than 11 g / dL.

7. The use according to claim 2, wherein at least 3, 4, 5, 6, 12, 18 or 24 months after administration of the ActRII signal transduction inhibitor to the subject, a long-term increase in the hemoglobin level of the subject is maintained.

8. The use according to claim 7, wherein the long-term increase in the hemoglobin level of the subject is such that at least 3, 4, 5, 6, 12, 18 or 24 months after administration of the ActRII signal transduction inhibitor to the subject, the hemoglobin level of the subject is between 11 g / dL and 18 g / dL.

9. The use according to claim 1, wherein at least 3, 4, 5, 6, 12, 18 or 24 months after administration of the ActRII signal transduction inhibitor to the subject, the subject does not require red blood cell transfusion.

10. The use according to any one of claims 1-9, wherein the ActRII signal transduction inhibitor is to be administered to the subject once every three weeks.

11. The use according to any one of claims 1-9, wherein the ActRII signal transduction inhibitor is to be administered to the subject (i) once every 28 days; or (ii) once every 42 days.

12. The use according to claim 10, wherein the ActRII signal transduction inhibitor is to be administered to the subject by injection.

13. The use according to claim 12, wherein the ActRII signal transduction inhibitor is to be administered subcutaneously to the subject.

14. Use according to any one of claims 1-9, wherein the use further comprises determining, at 6, 12, 18 and / or 24 months after administering an ActRII signal transduction inhibitor to the subject, another percentage of erythroblasts that are ring sideroblasts in the subject.

15. Use according to claim 13, wherein administering an ActRII signal transduction inhibitor to the subject promotes erythropoiesis in the subject.

16. Use according to claim 13, wherein administering an ActRII signal transduction inhibitor to the subject increases the level of neutrophils in the subject, and a pharmaceutically effective dose of the activin receptor type II (ActRII) signal transduction inhibitor will be administered.

17. Use according to any one of claims 1-9, wherein the ActRII signal transduction inhibitor is a polypeptide comprising the amino acid sequence of SEQ ID NO:

25.

18. Use according to claim 10, wherein the ActRII signal transduction inhibitor is a polypeptide comprising the amino acid sequence of SEQ ID NO:

25.

19. Use according to claim 13, wherein the ActRII signal transduction inhibitor is a polypeptide comprising the amino acid sequence of SEQ ID NO:

25.

20. Use according to any one of claims 1-9, wherein the subject is a human.

21. Use according to claim 18, wherein the subject is a human.

22. Use according to claim 19, wherein the subject is a human.

23. Use according to any one of claims 1-9, wherein the drug is administered to the subject at a dose of 0.75 mg / kg to 1.75 mg / kg.

24. Use according to claim 10, wherein the drug is administered to the subject at a dose of 0.75 mg / kg to 1.75 mg / kg.

25. Use according to claim 21, wherein the drug is administered to the subject at a dose of 0.75 mg / kg to 1.75 mg / kg.

26. Use according to claim 22, wherein the drug is administered to the subject at a dose of 0.75 mg / kg to 1.75 mg / kg.

27. Use according to claim 23, wherein the drug is administered to the subject at a dose of 1 mg / kg.

28. Use according to claim 24, wherein the drug is administered to the subject at a dose of 1 mg / kg.

29. Use according to claim 25, wherein the drug is administered to the subject at a dose of 1 mg / kg.

30. Use according to claim 26, wherein the drug is administered to the subject at a dose of 1 mg / kg.

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