ACTRII protein for the treatment of pulmonary arterial hypertension (PAH)

Abstract

The present invention provides a pharmaceutical composition for use in a method of treating pulmonary arterial hypertension (PAH). [Solution] A pharmaceutical composition for use in a method for treating pulmonary arterial hypertension (PAH) in a patient in need, comprising an ActRIIA fusion protein, wherein the ActRIIA fusion protein is (i) ActRIIA polypeptide containing a specific amino acid sequence, (ii) Fc domains containing an amino acid sequence that is at least 95% identical to a specific amino acid sequence, (iii) comprising a linker domain located between the ActRIIA polypeptide and the Fc domain, Herein, the ActRIIA fusion protein is administered in a first dose of 0.3 mg / kg and a second dose of 0.7 mg / kg, wherein the second dose is administered after confirming that the patient has an acceptable hemoglobin level and / or platelet count, in a pharmaceutical composition.

Description

Technical Field

[0001] Cross - References to Related Applications This application claims the benefit of priority based on U.S. Provisional Application No. 63 / 042,722, filed on Jun. 23, 2020; No. 63 / 084,409, filed on Sep. 28, 2020; No. 63 / 112,513, filed on Nov. 11, 2020; and No. 6 3 / 188,141, filed on May 13, 2021. The disclosures of the foregoing applications are hereby incorporated herein by reference in their entireties.

Background Art

[0002] Background of the Invention Pulmonary hypertension (PH) is a disease characterized by hypertension in the pulmonary vascular system, including the pulmonary arteries, pulmonary veins, and pulmonary capillaries. Generally, PH is defined as a mean pulmonary artery pressure (mPAP) of ≧ 20 mmHg at rest or ≧ 30 mmHg during exercise [Hill et al., Respiratory Care 54(7):958 - 68 (2009)]. One of the main symptoms of PH is dyspnea or shortness of breath, and other symptoms include fatigue, dizziness, syncope, peripheral edema (swelling of the feet, lower limbs or ankles), blue - tinged lips and skin, chest pain, angina, confusion during exercise, dry cough, elevated pulse, and palpitations. PH can be a severe disease that causes heart failure, which is one of the most common causes of death in people with pulmonary hypertension. Post - operative pulmonary hypertension can make many types of surgical procedures or procedures difficult and presents problems related to high mortality.

[0003] PH has similarities in pathophysiological mechanisms, clinical presentations, and treatment approaches​ They can be grouped based on different symptoms of the shared disease [Simonneau et al., JAC C 54(1):S44-54 (2009)]. The clinical classification of PH was first proposed in 1973. The recently updated clinical classification was approved by the World Health Organization (WHO) in 2018. According to the latest updated clinical classification of PH, there are five main groups of PH: Pulmonary arterial hypertension characterized by pulmonary artery wedge pressure (PAWP) of ≤15 mmHg (Pulmonary arterial hypertension; PAH); PAWP > 15 mmHg PH (pulmonary venous hypertension or congestive heart failure) resulting from left heart disease is characterized by left heart disease. Also known); PH due to lung disease and / or hypoxia; PH due to pulmonary artery occlusion; Furthermore, PH due to unclear and / or multifactorial etiologies [Simonneau et al., JAC C 54(1):S44-54 (2009);Hill et al., Respiratory Care 54(7):958-68 (2009) PAH is a sporadic disease in which there is no family history of PAH and no identified risk factors. AH (IPAH); hereditary PAH; drug and toxin-induced PAH; connective tissue Diseases, HIV infection, portal hypertension, congenital heart disease, schistosomiasis, and chronic hemolytic anemia PAH associated with this condition; further classified into persistent PH in neonates [Simonneau et al.] al., (2019) Eur Respir J: 53:1801913]. Diagnosis of various types of PH is, A series of tests are required.

[0004] Generally, the treatment of PH depends on the cause or classification of PH. PH is known to be caused by certain drugs or medical conditions. When caused by this, it is known as secondary pH, and the treatment is usually Treatment is performed for the underlying disease. Group 2 pulmonary hypertension (e.g., venous hypertension) treatment This is generally done by administering diuretics, beta-blockers and ACE inhibitors, or By repairing or replacing the mitral valve or aortic valve, left ventricular function can be optimized. PAH therapy involves pulmonary vasodilators, digoxin, diuretics, anticoagulants, and oxygen therapy. This includes pulmonary vasodilators, such as those used in the prostacyclin pathway (e.g., intravenous epoprostenol). Prostacy, which includes subcutaneous or intravenous treprostinil and inhaled iloprost. (Clean), nitric oxide pathway (e.g., phosphodi(s) containing sildenafil and tadalafil) Esterase-5 inhibitors) and the endotheline-1 pathway (e.g., oral) Contains endothelin receptor antagonists, including bosentan and oral ambrisentan. Targeting different pathways [Humbert, M. Am. J. Respir. Crit. Care Med. 179] :650-6 (2009); Hill et al., Respiratory Care 54(7):958-68 (2009)]. However Furthermore, current therapies do not result in a cure for PH, and the underlying cause observed in many PH patients is It does not directly address vascular remodeling and vascular muscularization.

[0005] There is a high but unmet need for effective treatments to manage pulmonary hypertension. Therefore, the purpose of this disclosure is to treat, prevent, or slow the progression of pH. Methods to reduce and / or the severity of one or more PH-related complications To treat, prevent, or reduce the rate of progression and / or severity of the disease The goal is to provide a method. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Hill et al., Respiratory Care 54(7):958-68 (2009) [Non-Patent Document 2] Simonneau et al., JACC 54(1):S44-54 (2009) [Non-Patent Document 3] Simonneau et al., (2019) Eur Respir J: 53:1801913 [Non-Patent Document 4] Humbert, M. Am. J. Respir. Crit. Care Med. 179:650-6 (2009) [Overview of the project] [Means for solving the problem]

[0007] Summary of the Invention In certain embodiments, the present disclosure relates to a method for treating pulmonary arterial hypertension (PAH), The step includes administering a therapeutically effective dose of ActRII polypeptide to a patient, wherein the polypeptide However, amino acids 21, 22, 23, 24, 25, 26, 27, 28, and 29 of sequence number 1 also It starts with one of the 30 amino acids, 110, 111, 112, 11 of sequence number 1. 3, 114, 115, 116, 117, 118, 119, 120, 121, 122, 12 3, 124, 125, 126, 127, 128, 129, 130, 131, 132, 13 3, an amino acid sequence ending at either 134 or 135, and at least 75%, 8 0%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 9 The polypeptide contains amino acid sequences that are 8%, 99%, or 100% identical, and the polypeptide is 0.1m The drug is administered within a dosage range of g / kg to 2.0 mg / kg, and polypeptide administration is used to reduce pulmonary vascular resistance. Reduced PVR; increased 6-minute walk distance (6MWD); N-terminal pro-B type natriuretic diuresis. Decreased levels of the peptide (NT-proBNP); recognized by the World Health Organization (WHO) Prevention or reduction of the progression of functional classes of pulmonary hypertension recognized by the WHO; pulmonary hypertension Facilitation or increase of the class of functional decline in hypertension; improvement in right ventricular function; in pulmonary artery pressure Improvement in hemodynamic or functional parameters of mean right atrial pressure; and / or improvement in mean right atrial pressure. The present invention provides a method that brings about one or more of these changes.

[0008] In certain aspects, the disclosure addresses one or more complications of pulmonary arterial hypertension. A method for doing, preventing, or reducing the rate of progression and / or severity thereof. The step includes administering an effective amount of ActRII polypeptide to patients who require it. The polypeptide has amino acids 21, 22, 23, 24, 25, 26, and 27 of SEQ ID NO: 1. Starting with one of 28, 29, or 30, and amino acids 110, 111 of SEQ ID NO: 1 , 112, 113, 114, 115, 116, 117, 118, 119, 120, 121 , 122, 123, 124, 125, 126, 127, 128, 129, 130, 131 , amino acid sequences ending at one of 132, 133, 134, or 135 and less 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96% Contains amino acid sequences that are 97%, 98%, 99%, or 100% identical, and polypeptide The drug is administered within a dosage range of 0.1 mg / kg to 2.0 mg / kg, and polypeptides are administered. However, reduced pulmonary vascular resistance (PVR); increased 6-minute walk distance (6MWD); N-terminal pro-B type Decreased levels of natriuretic peptide (NT-proBNP); World Health Organization (WHO) Prevention or reduction of the progression of the functional class of pulmonary hypertension as recognized by the WHO; Facilitation or increase in the functional regression class of recognized pulmonary hypertension; improvement in right ventricular function; Improvement in pulmonary artery pressure; and / or hemodynamic or functional improvement in mean right atrial pressure A method is provided for bringing about a change in one or more parameters. So, one or more complications of pulmonary arterial hypertension involve smooth muscle and / Alternatively, symptoms may include endothelial cell proliferation, angiogenesis in the pulmonary arteries, dyspnea, chest pain, and pulmonary vascular remodeling. The group is selected from those consisting of right ventricular hypertrophy and pulmonary fibrosis.

[0009] In certain aspects, the disclosure relates to a method for treating pulmonary arterial hypertension (PAH). The step of administering a therapeutically effective dose of ActRII polypeptide to the patient is The polypeptide contains amino acids 21, 22, 23, 24, 25, 26, and 2 of SEQ ID NO: 1. Starting with one of 7, 28, 29, or 30, and amino acids 110, 1 of SEQ ID NO: 1 11, 112, 113, 114, 115, 116, 117, 118, 119, 120, 1 21, 122, 123, 124, 125, 126, 127, 128, 129, 130, 1 Amino acid sequences ending at one of the following: 31, 132, 133, 134, or 135 and At least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, Containing amino acid sequences that are 96%, 97%, 98%, 99%, or 100% identical, the regimen The first period of polypeptide intake was between 0.1 mg / kg and 1.0 mg / kg. A second dose of polypeptide between 0.1 mg / kg and 1.0 mg / kg, including dose 1. The present invention provides a method in which the drug is then administered over a second period. In some embodiments, Lipeptide administration reduces pulmonary vascular resistance (PVR); increases 6-minute walk distance (6MWD). Decreased levels of N-terminal pro-B natriuretic peptide (NT-proBNP); World Conservation Prevention or reduction of progression of functional classes of pulmonary hypertension as recognized by the World Health Organization (WHO). ; Promotion or increase of the regression of the functional class of pulmonary hypertension as recognized by the WHO; right ventricular function Improvement in function; improvement in pulmonary artery pressure; and improvement in mean right atrial pressure; hemodynamics This results in a change in one or more functional parameters. In some embodiments, the Period 1 is at least 3 weeks. In some embodiments, period 2 is at least It is 3 weeks. In some embodiments, the second period is at least 21 weeks. In some embodiments, the second period is at least 45 weeks. The period exceeds the first period. In some embodiments, the second dose exceeds the first dose. In some embodiments, the first dose is in the range of about 0.2 mg / kg to about 0.4 mg / kg. Within this range, a second dose in the range of approximately 0.5 mg / kg to approximately 0.8 mg / kg follows. In this embodiment, the first dose is approximately 0.3 mg / kg, and the second dose is approximately 0.7 mg / kg. The dosage continues.

[0010] In some embodiments, the method reduces PVR in patients. The method involves increasing the PVR in patients by at least 10% (e.g., 10%, 15%, 20%). Reduce by 25%, 30%, 35%, 40%, 45%, or at least 50%. In some embodiments, the method reduces the patient's PVR by at least 20%. The reduction in PVR is a result of the decreased mean pulmonary artery pressure. In some embodiments, the method The method increases the patient's 6-minute walking distance. In some embodiments, the method increases the patient's 6-minute walking distance. The distance should be at least 10 meters (for example, at least 10, 20, 30, 40, 50, 6 0, 70, 80, 90, 100, 125, 150, 175, 200, 250, 300 meters To increase (or more than 400 meters). In some embodiments, the method is used for 6 minutes of patient Increase the walking distance by at least 30 meters. In some embodiments, the method is used to give the patient To reduce NT-proBNP levels in patients. In some embodiments, the method involves reducing NT-proBNP levels in patients. The NT-proBNP level should be at least 10% (e.g., 10%, 15%, 20%). 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, To reduce by 75% or at least 80%. In some embodiments, the method is used in patients The NT-proBNP level is reduced by at least 30%. In some embodiments, the method This reduces the NT-proBNP level to a normal level. In some embodiments, NT -The normal level of proBNP is <100 pg / ml.

[0011] In some embodiments, the method is a class of pulmonary hypertension recognized by the WHO. To prevent or reduce progression. In some embodiments, the method is recognized by the WHO. Preventing the progression of pulmonary hypertension from functional class I to functional class II. or reduce. In some embodiments, the method is a class of functions recognized by the WHO. To prevent the progression of functional class of pulmonary hypertension from Class II to Class III pulmonary hypertension or To reduce. In some embodiments, the method is a Class II function recognized by the WHO. To prevent or reduce the progression of functional class of pulmonary hypertension from class I to class IV. In some embodiments, the method is used to classify the function of pulmonary hypertension as recognized by the WHO. To promote or increase the regression of the spurt. In some embodiments, the method is recognized by the WHO. Promotes a decline in the functional class of pulmonary hypertension from Class IV to Class III. To advance or increase. In some embodiments, the method is a Class I recognized by the WHO. Promotes or increases the regression of pulmonary hypertension function class from Class II to Class II pulmonary hypertension. To cause. In some embodiments, the method is to change from Class II to Class II as recognized by the WHO. It promotes or increases the regression of the functional class of pulmonary hypertension to pulmonary hypertension.

[0012] In some embodiments, the method improves right ventricular function in the patient. The improvement in right ventricular function is due to an increase in the rate of change of right ventricular area. In some embodiments, the right The improvement in ventricular function is due to a reduction in right ventricular hypertrophy. In some embodiments, the right ventricular function is The improvement is due to an increase in the ejection fraction. In some embodiments, the improvement in right ventricular function is also observed. This is due to an increase in the rate of change of right ventricular area and the ejection fraction.

[0013] In some embodiments, the method improves pulmonary artery pressure in the patient. Improvement in pulmonary artery pressure is a reduction in mean pulmonary artery pressure (mPAP). In some embodiments, The method involves reducing mPAP in the patient by at least 10% (e.g., 10%, 15%, 20%). Reduce by %, 25%, 30%, 35%, 40%, 45%, or at least 50%. In one embodiment, the method involves raising the mPAP in the patient to at least 3 mmHg (for example, a small amount). At the very least, reduce it by 3, 5, 7, 10, 12, 15, 20, or 25 mmHg. In some embodiments, the method improves mean right atrial pressure (mRAP) in patients. In this case, the improvement in mRAP is a reduction in mRAP. In some embodiments, the method mRAP in patients should be at least 10% (e.g., 10%, 15%, 20%, 25%) Reduce by 30%, 35%, 40%, 45%, or at least 50%. Some implementations In this case, the method involves increasing mRAP in the patient to at least 1 mmHg (for example, at least 1 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 mmHg ) Reduce.

[0014] In some embodiments, the patient has pulmonary vascular resistance greater than or equal to 3 Wood units. It has PVR. In some embodiments, the patient walks 150 to 550 meters for 6 minutes. It has a distance. In some embodiments, patients have elevated NT-p compared to healthy patients. The patient has a roBNP level of at least 100 pg / mL. In some embodiments, the patient has a roBNP level of at least 100 pg / mL. (For example, 100, 150, 200, 300, 400, 500, 1000, 3000, 5 NT-proB (000, 10,000, 15,000, or 20,000 pg / mL) It has NP levels. In some embodiments, patients have elevated brain activity compared to healthy patients. It has a low level of natriuretic peptide (BNP). In some embodiments, the patient has a low level of At the very least, 100 pg / mL (for example, 100, 150, 200, 300, 400, 500) 1,000, 3,000, 5,000, 10,000, 15,000, or 20,000p The BNP level is (g / mL). In some embodiments, the method involves the patient having a BNP level Set the level to at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%) , 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or less It also reduces the BNP level by 80%. In some embodiments, the method reduces the BNP level to a normal level (i.e., Furthermore, the level is reduced to <100 pg / ml). In some embodiments, the patient is at least Mean pulmonary artery pressure (mPAP) of 20 mmHg; mPAP of at least 25 mmHg; less mPAP of 30 mmHg; mPAP of at least 35 mmHg; mPAP of at least 40 mm mPAP of Hg; mPAP of at least 45 mmHg; and mPAP of at least 50 mmHg The patient has an mPAP selected from the group consisting of mPAPs. In some embodiments, the patient has Mean right atrial pressure (mRAP) of at least 5 mmHg; at least 6 mmHg of mRAP; less mRAP of at least 8 mmHg; mRAP of at least 10 mmHg; mRAP of at least 12 mm mRAP of Hg; mRAP of at least 14 mmHg; and at least 16 mmHg It has an mRAP selected from the group consisting of mRAPs.

[0015] In some embodiments, PAH is idiopathic pulmonary arterial hypertension (PAH). In some embodiments, PAH is hereditary PAH. In some embodiments, PAH is drug-induced or toxin-inducible PAH. In some embodiments, PAH is at least one of the factors in shunt repair. One year later, it was a simple congenital PAH associated with a systemic-to-lung shunt. In this embodiment, the patient, according to the World Health Organization's functional classification system for pulmonary hypertension, The patient has functional class II or class III pulmonary hypertension. In some embodiments, the patient This refers to a Class I, Class II, Class III or function recognized by the World Health Organization. The patient has Class IV pulmonary hypertension. In some embodiments, the patient has pulmonary hypertension. According to the World Health Organization's functional classification system, functions are classified into Class I, Class II, and Class III. or has class IV pulmonary hypertension. In some embodiments, the patient has pulmonary hypertension According to the World Health Organization's functional classification system, the patient has pulmonary hypertension of functional class IV. In some embodiments, the method increases transplant-free survival in patients. The method aims to increase transplant-free survival in patients by at least 10% (e.g., 10%, 15%, 2%). Increase by 0%, 25%, 30%, 35%, 40%, 45%, or at least 50%. In some embodiments, the method reduces right ventricular hypertrophy in patients. The method involves reducing right ventricular hypertrophy in patients by at least 10% (e.g., 10%, 15%, 20%). Reduce by 25%, 30%, 35%, 40%, 45%, or at least 50%. In some embodiments, the method reduces smooth muscle hypertrophy in patients. The method involves reducing smooth muscle hypertrophy in patients by at least 10% (e.g., 10%, 15%, 20%). Reduce by 25%, 30%, 35%, 40%, 45%, or at least 50%. In some embodiments, the method reduces pulmonary arteriole muscularization in patients. The method involves reducing pulmonary arteriole muscle formation in the patient by at least 10% (e.g., 10%, 15%). (Reduce by 20%, 25%, 30%, 35%, 40%, 45%, or at least 50%) ru.

[0016] In some embodiments, the method increases the patient's motor capacity. The method reduces the patient's Borg dyspnea index (BDI). In some embodiments, the method The patient's BDI should be at least 0.5 index points (e.g., at least 0.5, 1, 1). 5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, Reduces by 8.5, 9, 9.5, or 10 exponential points. In some embodiments, patients , having reduced renal function. In some embodiments, the method further improves renal function. In some embodiments, the method delays the clinical progression of pulmonary arterial hypertension. In this case, the method follows the World Health Organization's functional classification system for pulmonary hypertension, and the pulmonary artery To delay the clinical progression of pulmonary arterial hypertension. In some embodiments, the method is used to slow the clinical progression of pulmonary arterial hypertension. Reduce the risk of hospitalization for one or more complications related to the disease. In this case, the method is for pathological conditions of one or more complications associated with pulmonary arterial hypertension. To reduce the risk of the condition. In some embodiments, the method is used to treat the pathological condition in the lungs and / or Increased need for heart transplants; need to initiate rescue therapy with known treatments for PAH; Prostacyclin needs to be increased by at least 10%; atrial septal decompression is necessary; less Both 24-hour PAH-specific hospitalizations and one or more exacerbations of PAH. This includes changes in PAH. In some embodiments, the worsening of PAH is a deterioration in the class of WHO function and This includes a reduction of at least 15% in 6MWD. In some embodiments, the method involves pulmonary arterial lung To reduce the risk of death associated with hypertension. In some embodiments, the method involves pulmonary artery The risk of death associated with pulmonary hypertension should be reduced by at least 10% (e.g., 10%, 15%, 20%). Reduce by %, 25%, 30%, 35%, 40%, 45%, or at least 50%. In one embodiment, the patient has a hemoglobin level >8 and <15 g / dl. In this embodiment, the patient's hemoglobin level is <18 g / dl.

[0017] In some embodiments, the ActRII polypeptide is located at residues 30-110 of SEQ ID NO: 1. Corresponding amino acid sequences and at least 70%, 75%, 80%, 85%, 86%, 87% 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% , containing amino acid sequences that are 98%, 99%, or 100% identical. In some embodiments, ActRII polypeptide has at least 70% and 75% of the amino acid sequence of SEQ ID NO: 2. 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93% , 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical amino acids It contains an acid sequence. In some embodiments, the ActRII polypeptide contains the amino acid sequence of SEQ ID NO: 3. Acid sequence and at least 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89% 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% , or containing an amino acid sequence that is 100% identical. In some embodiments, ActRII Lipeptides are fusion proteins that further contain the Fc domain of immunoglobulins. In this embodiment, the Fc domain of immunoglobulin is the Fc domain of IgG1 immunoglobulin In some embodiments, the Fc fusion protein is ActRII polypeptide. It further includes a linker domain located between the main and the Fc domain of the immunoglobulin. In some embodiments, the linker domain is TGGG (SEQ ID NO: 20), TGGGG ( Sequence ID 18), SGGGG (Sequence ID 19), GGGGS (Sequence ID 22), GGG ( It consists of SEQ ID NO: 16), GGGG (SEQ ID NO: 17), and SGGG (SEQ ID NO: 21). Selected from the group. In some embodiments, the ActRII polypeptide is the one specified in SEQ ID NO: 23 Amino acid sequence and at least 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, It contains amino acid sequences that are 99% or 100% identical. In some embodiments, ActR Polypeptide II has at least 70%, 75%, and 80% of the amino acid sequence of SEQ ID NO: 41. 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94% , containing amino acid sequences that are 95%, 96%, 97%, 98%, 99%, or 100% identical. In some embodiments, the polypeptide corresponds to residues 30-110 of SEQ ID NO: 1. It contains an amino acid sequence that is at least 90% identical to the amino acid sequence. In some embodiments, The lipeptide has an amino acid sequence corresponding to residues 21-135 of SEQ ID NO: 1 and at least 90 Contains % identical amino acid sequences. In some embodiments, the polypeptide is freeze-dried. In some embodiments, the polypeptide is soluble. In some embodiments, Lipeptides are administered to patients using subcutaneous injection. In some embodiments, the polypeptides The drug is administered to the patient every three weeks. In some embodiments, the polypeptide is administered every four weeks. It is administered to the patient. In some embodiments, ActRII polypeptide is administered weekly, every two weeks. It is administered to the patient every 3 weeks or every 4 weeks. In some embodiments, Act RII polypeptide is administered to the patient every three weeks. In some embodiments, the polypeptide Tide is part of a homodimeric protein complex. In some embodiments, polypeptides are involved. It is glycosylated. In some embodiments, the polypeptide is Chinese ham It has a glycosylation pattern that can be obtained by expression in star ovarian cells. In some embodiments, the ActRII polypeptide is composed of activin A, activin B and It binds to one or more ligands selected from the group consisting of GDF11. Morphologically, ActRII polypeptides bind to activin and / or GDF11. In some embodiments, the ActRII polypeptide is BMP10, GDF8 and B It further binds to one or more ligands selected from the group consisting of MP6.

[0018] In some embodiments, ActRII polypeptide is present in doses of 0.1 mg / kg to 2.0 mg / kg. It is administered in doses between kg. In some embodiments, ActRII polypeptide is 0. It is administered at a dose of 3 mg / kg. In some embodiments, ActRII polypeptide is It is administered at a dose of 0.7 mg / kg. In some embodiments, the method involves administering additional active ingredients to the patient. The step includes further administering the agent and / or supportive therapy. In some embodiments, additional The activators and / or supportive therapies include beta-blockers and angiotensin-converting enzyme inhibitors. (ACE inhibitors), angiotensin receptor blockers (ARBs), diuretics, lipid-lowering drugs, Ndoselin blockers, PDE5 inhibitors, prostacyclins, or left ventricular assist devices (LV) Selected from the group consisting of AD). In some embodiments, additional activators and / or supporting agents are selected. Therapies include prostacyclins and their derivatives (e.g., epoprostenol, treph). Rostinil and iloprost); prostacyclin receptor agonists (e.g., se Lexipag; endothelin receptor antagonists (e.g., Therin, Ambrisentan) , macitentan, and bosentan); calcium channel blockers (e.g., amlodipine); (e.g., diltiazem and nifedipine); anticoagulants (e.g., warfarin); diuretics; acids Basic therapy; atrial septal dehiscence surgery; pulmonary thromboendarterectomy; phosphodiesterase type 5 inhibitors (e.g.) , sildenafil and tadalafil); activators of soluble guanylate cyclase (for example) For example, synacigat and riociguat); ASK-1 inhibitors (e.g., CIIA; SCH 79797;GS-4997;MSC2032964A;3H-Naphtho[1,2,3-d e) Quinilin-2,7-dione, NQDI-1;2-thioxothiazolidine, 5-bro Mo-3-(4-oxo-2-thioxo-thiazolidin-5-ylidene)-1,3-dihydr Low-indole-2-on); NF-κB antagonist (e.g., dh404, CDD) O-Epoxide; 2,2-difluoropropionamide; C28-imidazole (CDDO) -Im);2-cyano-3,12-dioxoleane-1,9-diene-28-oic Acid (CDDO); 3-acetyloleanolic acid; 3-trifluoroacetyloleanol Acid (3-Triflouroacetyloleanolic Acid); 28-methyl-3-acetyloleanane; 2 8-Methyl-3-trifluoroacetyloleanane; 28-methyloxyoleanolic acid ;SZC014;SCZ015;SZC017;PEGylated derivative of oleanolic acid;3- O-(beta-D-glucopyranosyl)oleanolic acid; 3-O-[beta-D-gluco Pyranosyl-(1→3)-beta-D-glucopyranosyl]oleanolic acid; 3-O-[ Beta-D-glucopyranosyl-(1→2)-beta-D-glucopyranosyl]oleano Glucolic acid; 3-O-[beta-D-glucopyranosyl-(1→3)-beta-D-glucopy Lanosyl oleanolic acid 28-O-beta-D-glucopyranosyl ester; 3-O- [Beta-D-glucopyranosyl-(1→2)-beta-D-glucopyranosyl]olea 28-O-beta-D-glucopyranosyl ester of 28-O-beta-D-glucopyranosyl ester of 3-O-[aL-rhamno Pyranosyl-(1→3)-beta-D-glucuronopyranosyl]oleanolic acid; 3-O -[alpha-L-rhamnopyranosyl-(1→3)-beta-D-glucuronopyranosyl] 28-O-beta-D-glucopyranosyl oleanolic acid; 28-O-β-D -Glucopyranosyl-oleanolic acid; 3-O-β-D-Glucopyranosyl(1→3)- β-D-glucopyranosideuronic acid (CS1); oleanolic acid 3-O-β-D-gluco Pyranosyl(1→3)-β-D-glucopyranosidouronic acid (CS2); methyl 3,11 -Dioxoolean-12-en-28-oleate (DIOXOL);ZCVI4-2; Benzyl 3-dehydro-oxy-1,2,5-oxadiazolo[3',4':2,3] Leanolate; left ventricular assist device (LVAD), or lung and / or heart transplant. Selected from the following group. In some embodiments, the patient is phosphodiesterase type 5 inhibitor. Agents, soluble guanylate cyclase stimulants, prostacyclin receptor agonists, and Treatment with one or more drugs selected from the group consisting of endothelin receptor antagonists. It is placed there. In some embodiments, one or more drugs are bosentan, sildenaf Filtrate, Beraprost, Macitentan, Selexipag, Epoprostenol, Treprosti Selected from the group consisting of nil, iloprost, ambrisentan, and tadalafil. In some embodiments, the method further comprises administering one or more vasodilators. In this embodiment, the method involves a phosphodiesterase type 5 inhibitor and soluble guanylate cyclamate. X-agonists, prostacyclin receptor agonists, and endothelin receptor antagonists Further includes administration of one or more drugs selected from the group consisting of Str. In this case, one or more drugs are bosentan, sildenafil, beraprost, and mate. Ntan, selexipag, epoprostenol, treprostinil, iloprost, ambu Selected from the group consisting of lysentan and tadalafil. In some embodiments, patient The patient was treated with one or more vasodilators before polypeptide administration. Some implementations In some embodiments, the method further comprises administering one or more vasodilators. One or more vasodilators include prostacyclin, epoprostenol, and sil Selected from the group consisting of denafil. In some embodiments, the vasodilator is prostaglandin. It's Ikurin.

[0019] In some embodiments, the patient is receiving one or more therapies for PAH. In some embodiments, one or more therapies for PAH include prostacyclin and Its derivatives (e.g., epoprostenol, treprostinil, and iloprost); Rostacyclin receptor agonists (e.g., selexipag); endothelin receptor agonists Tagonists (e.g., telin, ambrisentan, macitentan and bosentan); Luxium channel blockers (e.g., amlodipine, diltiazem, and nifedipine; anti Anticoagulants (e.g., warfarin); diuretics; oxygen therapy; atrial septal dehiscence surgery; pulmonary endarterectomy Therapy; phosphodiesterase type 5 inhibitors (e.g., sildenafil and tadalafil); Activators of soluble guanylate cyclase (e.g., synaciguat and riociguat); ASK-1 inhibitors (e.g., CIIA; SCH79797; GS-4997; MSC20) 32964A; 3H-naphtho[1,2,3-de]quinilin-2,7-dione, NQDI -1;2-Thioxo-thiazolidined, 5-Bromo-3-(4-Oxo-2-Thioxo-Thi Azolidined-5-ylidene)-1,3-dihydro-indole-2-one); NF-κB Antagonists (e.g., dh404, CDDO-epoxide; 2,2-difluoropropyl alcohol) Pionamide; C28 imidazole (CDDO-Im); 2-cyano-3,12-dioxy Soolean-1,9-diene-28-euic acid (CDDO); 3-acetyloleanol 3-trifluoroacetyloleanolic acid; 28-methyl-3-acetyloleanolate 28-methyl-3-trifluoroacetyloleanane; 28-methyloxyoleanane Oleanolic acid; SZC014; SCZ015; SZC017; PEGylated derivative of oleanolic acid ;3-O-(beta-D-glucopyranosyl)oleanolic acid;3-O-[beta-D- Glucopyranosyl-(1→3)-beta-D-glucopyranosyl]oleanolic acid;3- O-[beta-D-glucopyranosyl-(1→2)-beta-D-glucopyranosyl]o Leanolic acid; 3-O-[beta-D-glucopyranosyl-(1→3)-beta-D-g 28-O-beta-D-glucopyranosyl oleanolic acid 28-O-beta-D-glucopyranosyl ester;3 -O-[beta-D-glucopyranosyl-(1→2)-beta-D-glucopyranosyl] 28-O-beta-D-glucopyranosyl oleanolic acid; 3-O-[aL- Rhamnopyranosyl-(1→3)-beta-D-glucuronopyranosyl]oleanolic acid; 3-O-[alpha-L-rhamnopyranosyl-(1→3)-beta-D-glucuronopyranosyl-(1→3)-beta-D-glucuronopyranosyl- 28-O-beta-D-glucopyranosyl oleanolic acid [nosyl]; 28-O- β-D-glucopyranosyl-oleanolic acid; 3-O-β-D-glucopyranosyl(1→ 3)-β-D-Glucopyranosideuronic acid (CS1); oleanolic acid 3-O-β-D- Glucopyranosyl(1→3)-β-D-glucopyranosidouronic acid (CS2); methyl3 ,11-Dioxolean-12-ene-28-oleate (DIOXOL);ZCVI4 -2; benzyl 3-dehydro-oxy-1,2,5-oxadiazolo[3',4':2, 3] Oleanolates); left ventricular assist devices (LVADs), or lungs and / or heart The group is selected from those consisting of transplants.

[0020] In certain aspects, this disclosure relates to cardiopulmonary respiration associated with pulmonary arterial hypertension in patients. A method for treating or preventing Delling, comprising an effective dose of ActR to a patient in need. The procedure includes the step of administering polypeptide II to slow cardiac remodeling, and / or The present invention provides a method for reversing cardiac remodeling. In some embodiments, cardiac remodeling Inversion in the ring is a sustained inversion. In some embodiments, cardiopulmonary remodeling This is ventricular remodeling. In some embodiments, ventricular remodeling is left ventricular remodeling. In some embodiments, ventricular remodeling is right ventricular remodeling. In this embodiment, cardiopulmonary remodeling is ventricular dilation.

[0021] In certain embodiments, this disclosure includes a kit comprising lyophilized polypeptides and injection devices. The polypeptide is composed of amino acids 21, 22, 23, 24, 25, and 2 of SEQ ID NO: 1. Starting with one of 6, 27, 28, 29, or 30, and amino acid 1 of SEQ ID NO: 1 10, 111, 112, 113, 114, 115, 116, 117, 118, 119, 1 20, 121, 122, 123, 124, 125, 126, 127, 128, 129, 1 Amino acids ending in any one of the following: 30, 131, 132, 133, 134, or 135 Acid sequence and at least 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89% 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% , or ActRII polypeptide containing an amino acid sequence that is 100% identical, kit Regarding the following. In some embodiments, the polypeptide is related to residues 30-110 of SEQ ID NO: 1 A polypeptide containing an amino acid sequence that is at least 90% identical to the corresponding amino acid sequence. In some embodiments, the polypeptide corresponds to residues 30-110 of SEQ ID NO: 1. It is a polypeptide containing an amino acid sequence that is at least 95% identical to the amino acid sequence. In this embodiment, the polypeptide is an amino acid compound corresponding to residues 30-110 of SEQ ID NO: 1. A polypeptide containing an amino acid sequence that is at least 99% identical to the column. Some implementations In this state, the polypeptide contains the amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1. It is a polypeptide. In some embodiments, the polypeptide is residues 30-1 of SEQ ID NO: 1. It is a polypeptide consisting of an amino acid sequence corresponding to 10. In some embodiments, the polypeptide Butido is at least 90% identical to the amino acid sequence corresponding to residues 21-135 of SEQ ID NO: 1. It is a polypeptide containing a single amino acid sequence. In some embodiments, the polypeptide is The amino acid sequence is at least 95% identical to the amino acid sequence corresponding to residues 21-135 of SEQ ID NO: 1. It is a polypeptide containing an amino acid sequence. In some embodiments, the polypeptide is a polypeptide containing an amino acid sequence number Amino acids that are at least 99% identical to the amino acid sequence corresponding to residues 21-135 of No. 1 It is a polypeptide containing the sequence. In some embodiments, the polypeptide is the remainder of sequence number 1. This polypeptide contains amino acid sequences corresponding to groups 21-135. In some embodiments, Polypeptides consist of amino acid sequences corresponding to residues 21-135 of SEQ ID NO: 1. It is a peptide. In some embodiments, the polypeptide has a small amino acid sequence from SEQ ID NO: 2. It is a polypeptide containing an amino acid sequence that is at least 90% identical. In some embodiments, The polypeptide has an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 2. It is a polypeptide containing columns. In some embodiments, the polypeptide is the ami of SEQ ID NO: 2 It is a polypeptide containing an amino acid sequence that is at least 99% identical to the no-acid sequence. In this embodiment, the polypeptide is a polypeptide comprising the amino acid sequence of SEQ ID NO: 2. In some embodiments, the polypeptide is a polypeptide consisting of the amino acid sequence of SEQ ID NO: 2. In some embodiments, the polypeptide has the amino acid sequence of SEQ ID NO: 3 and at least It is a polypeptide containing amino acid sequences that are 90% identical. In some embodiments, the polypeptide Butido contains an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 3. It is a polypeptide. In some embodiments, the polypeptide is the amino acid sequence of SEQ ID NO: 3. A polypeptide containing an amino acid sequence that is at least 99% identical to that of some embodiments. Therefore, the polypeptide is a polypeptide that contains the amino acid sequence of SEQ ID NO: 3. In this application, the polypeptide is a polypeptide consisting of the amino acid sequence of SEQ ID NO: 3. In some embodiments, the polypeptide is a fusion further comprising the Fc domain of the immunoglobulin. It is a protein. In some embodiments, the Fc domain of immunoglobulin is IgG1 immunoglobulin. This is the Fc domain of epidemic globulin. In some embodiments, the fusion protein is polypept The linker domain, located between the cytoplasmic domain and the Fc domain of immunoglobulin, is further... Included in some embodiments, the linker domain is TGGG (SEQ ID NO: 20), TGG GG (sequence number 18), SGGGG (sequence number 19), GGGGS (sequence number 22), G GG (sequence number 16), GGGG (sequence number 17), and SGGG (sequence number 21) Selected from the following group. In some embodiments, the linker domain is TGGG (sequence number Includes (No. 20). In some embodiments, the ActRII polypeptide is the A of SEQ ID NO. 23. Mino acid sequence and at least 70%, 75%, 80%, 85%, 86%, 87%, 88%, 8 9%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 9 It contains amino acid sequences that are 9% or 100% identical. In some embodiments, ActRI Polypeptide I contains the amino acid sequence of SEQ ID NO: 23. In some embodiments, ActR Polypeptide II consists of the amino acid sequence of SEQ ID NO: 23. In some embodiments, Peptides are part of a homodimeric protein complex. In some embodiments, polypeptides The cytoside is glycosylated. In some embodiments, the polypeptide is activin A One or more ligands selected from the group consisting of activin B and GDF11. It binds to BMP10, GDF8, and BM. In some embodiments, the polypeptides are BMP10, GDF8, and BM Further binding to one or more ligands selected from the group consisting of P6. Morphologically, polypeptides bind to activin and / or GDF11.

[0022] In some embodiments, the kit contains one or more freeze-dried polypeptides. Contains ial. In some embodiments, the kit contains less lyophilized polypeptide. Each includes two vials. In some embodiments, the two vials are the same or different. It may contain a certain amount of lyophilized polypeptide. In some embodiments, the vial is Contains lyophilized polypeptide in amounts between 25 mg and 60 mg. In some embodiments, vial At least one of these contains 60 mg of lyophilized polypeptide. In some embodiments, At least one of the vials contains 45 mg of lyophilized polypeptide. In this application form, at least one vial contains 30 mg of lyophilized polypeptide. In some embodiments, at least one of the vials contains 25 mg of lyophilized polypeptide. It contains. In some embodiments, the first vial contains 45 mg of lyophilized polypeptide. The second vial contains 60 mg of lyophilized polypeptide. In terms of form, the first vial contains 30 mg of lyophilized polypeptide, and the second vial The product contains 60 mg of lyophilized polypeptide. In some embodiments, the first vial The first vial contains 45 mg of lyophilized polypeptide, and the second vial contains 45 mg of lyophilized polypeptide. It contains a dried polypeptide. In some embodiments, the first vial contains 30 mg of lyophilized polypeptide. The second vial contains 45 mg of lyophilized polypeptide. The third vial contains 60 mg of lyophilized polypeptide. In some embodiments, The first vial contains 25 mg of lyophilized polypeptide, and the second vial contains 4 The third vial contains 5 mg of lyophilized polypeptide, and the third vial contains 60 mg of lyophilized polypeptide It contains butylate. In some embodiments, the vials are refrigerated at 2-8°C.

[0023] In some embodiments, the injection device includes a pre-filled syringe. The injection device includes a pumping mechanism. In some embodiments, the pumping mechanism is an electric machine. Includes a mechanical pump assembly. In some embodiments, the pump device is a wearable pump device. In some embodiments, the pre-filled syringe contains the reconstitution solution. In form, the restorative solution contains pharmaceutically acceptable carriers and / or excipients. In terms of administration methods, pharmaceutically acceptable carriers are physiological saline solution, purified water, or sterile water for injection. Selected from. In some embodiments, pharmaceutically acceptable excipients are buffers [e.g., Citric acid (monohydrate) and / or trisodium citrate (dehydrated), surfactant ( For example, polysorbate 80), stabilizers (e.g., sucrose), and cryoprotectants (e.g., For example, selected from sucrose. In some embodiments, the injection device is vial Includes an adapter. In some embodiments, the vial adapter is attached to the vial. This can be done. In some embodiments, the vial adapter is attached to the pre-filled syringe. It can be attached. In some embodiments, the pre-filled syringe and vial are It is attached to both ends of the ear adapter. In some embodiments, the restoration solution is pre-filled. It is transferred from the syringe to the vial. In some embodiments, the lyophilized polypeptide is It is restored to a sterile injection solution. In some embodiments, the lyophilized polypeptide is sterile before use. It is restored to an injectable solution. In some embodiments, the sterile injectable solution is sterile water for injection. In some embodiments, the sterile injection solution is administered parenterally. It is administered by subcutaneous injection. In some embodiments, the sterile injection solution is administered by intradermal injection. It is administered by intramuscular injection. In some embodiments, the sterile injection solution is administered by intramuscular injection. In some embodiments, the sterile injection solution is administered via intravenous injection. In some embodiments, The sterile injection solution is self-administered. In some embodiments, the injection device delivers the sterile injection solution. It is used for administration. In some embodiments, the sterile injection solution contains a therapeutically effective dose. In some embodiments, the therapeutically effective dose includes a dose based on body weight. In some embodiments, The lyophilized polypeptide is administered every three weeks. In some embodiments, the lyophilized polypeptide The peptide is administered every four weeks. In some embodiments, the kit treats PAH. Used for this purpose. In some embodiments, the shelf life of the freeze-dried polypeptide is less These are 1, 3, 6, 9, or 11 months. In some embodiments, freeze-dried polypeptide The validity period of the do is at least 1, 1.5, 2, 2.5, or 3 years. Some implementations In this state, the freeze-dried polypeptide is restored. In some embodiments, the restored polypeptide Petit de has a validity period of at least 2 hours, 3 hours, or 4 hours.

[0024] The patent file contains at least one drawing / photograph created in color. A copy of this patent with drawings (multiple possible) / photographs (multiple possible) is available for payment of the claim and required fees. It will be provided by the government ministry, depending on the payment. [Brief explanation of the drawing]

[0025] [Figure 1] Figure 1 shows the alignment of the extracellular domains of human ActRIIB (SEQ ID NO: 31) and human ActRIIA (SEQ ID NO: 2), which have residues indicated by boxes that are inferred herein to be in direct contact with the ligand, based on synthetic analysis of multiple ActRIIB and ActRIIA crystal structures.

[0026] [Figure 2] Figure 2 shows the multiple sequence alignment of various vertebrate ActRIIA proteins and human ActRIIA (SEQ ID NOs: 6-10 and 36-38).

[0027] [Figure 3] Figure 3 shows the multiple sequence alignment of Fc domains derived from human IgG isotypes using Clustal 2.1. Hinge regions are indicated by dotted underlines. Double underlines indicate positions manipulated in IgG1 Fc (SEQ ID NO: 32) to promote asymmetric chain pairing, as well as examples of corresponding positions for other isotypes IgG2 (SEQ ID NO: 33), IgG3 (SEQ ID NO: 34), and IgG4 (SEQ ID NO: 35).

[0028] [Figure 4] Figures 4A and 4B show the purification of ActRIIA-hFc expressed in CHO cells. The purified protein is visualized as a single, clearly defined peak by a sizing column (Figure 4A), and Coomassi-stained SDS-PAGE (Figure 4B) (left lane: molecular weight standard; right lane: ActRIIA-hFc).

[0029] [Figure 5] Figures 5A and 5B show the binding of ActRIIA-hFc to activin (Figure 5A) and GDF-11 (Figure 5B) as measured by the Biacore® assay.

[0030] [Figure 6] Figure 6 shows the effects of sildenafil and ActRIIA-mFc treatment as mediators on vasomuscularization in a monocothalin rat model of pulmonary arterial hypertension.

[0031] [Figure 7] Figure 7 shows the effects of the vehicle, sildenafil, and ActRIIA-mFc treatment on vasomuscularization in the Sugen hypoxic rat model of pulmonary arterial hypertension.

[0032] [Figure 8A-B]Figures 8A–8D show the changes in pulmonary vascular resistance from baseline to week 24 in a placebo-controlled clinical trial using sotatercept (ActRIIA-hFc polypeptide) in patients with pulmonary arterial hypertension. Figure 8A shows the least squares mean ± SE in the full analysis set. The least squares mean difference in pulmonary vascular resistance compared to placebo was -145.8 dyne-seconds / cm5 (95% CI, -241.0 to -50.6) for sotatercept 0.3 mg / kg and -239.5 dyne-seconds / cm5 (95% CI, -329.3 to -149.7) for sotatercept 0.7 mg / kg. Figure 8B shows the change in pulmonary vascular resistance ± SE between baseline and the end of the placebo-controlled treatment period (week 24) in the full analysis set for the sotatercept 0.3 mg / kg and 0.7 mg / kg groups. Figure 8C shows the effect of sotatercept 0.3 mg / kg on the change in pulmonary vascular resistance from baseline to week 24 in patient subgroups. All data are derived from the full analysis set and compared to placebo using ANOVA with baseline values ​​as a covariance. Figure 8D shows the effect of sotatercept 0.7 mg / kg on the change in pulmonary vascular resistance from baseline to week 24 in patient subgroups. All data are derived from the full analysis set and compared to placebo using ANOVA with baseline values ​​as a covariance. [Figure 8C]Figures 8A–8D show the changes in pulmonary vascular resistance from baseline to week 24 in a placebo-controlled clinical trial using sotatercept (ActRIIA-hFc polypeptide) in patients with pulmonary arterial hypertension. Figure 8A shows the least squares mean ± SE in the full analysis set. The least squares mean difference in pulmonary vascular resistance compared to placebo was -145.8 dyne-seconds / cm5 (95% CI, -241.0 to -50.6) for sotatercept 0.3 mg / kg and -239.5 dyne-seconds / cm5 (95% CI, -329.3 to -149.7) for sotatercept 0.7 mg / kg. Figure 8B shows the change in pulmonary vascular resistance ± SE between baseline and the end of the placebo-controlled treatment period (week 24) in the full analysis set for the sotatercept 0.3 mg / kg and 0.7 mg / kg groups. Figure 8C shows the effect of sotatercept 0.3 mg / kg on the change in pulmonary vascular resistance from baseline to week 24 in patient subgroups. All data are derived from the full analysis set and compared to placebo using ANOVA with baseline values ​​as a covariance. Figure 8D shows the effect of sotatercept 0.7 mg / kg on the change in pulmonary vascular resistance from baseline to week 24 in patient subgroups. All data are derived from the full analysis set and compared to placebo using ANOVA with baseline values ​​as a covariance. [Figure 8D]Figures 8A–8D show the changes in pulmonary vascular resistance from baseline to week 24 in a placebo-controlled clinical trial using sotatercept (ActRIIA-hFc polypeptide) in patients with pulmonary arterial hypertension. Figure 8A shows the least squares mean ± SE in the full analysis set. The least squares mean difference in pulmonary vascular resistance compared to placebo was -145.8 dyne-seconds / cm5 (95% CI, -241.0 to -50.6) for sotatercept 0.3 mg / kg and -239.5 dyne-seconds / cm5 (95% CI, -329.3 to -149.7) for sotatercept 0.7 mg / kg. Figure 8B shows the change in pulmonary vascular resistance ± SE between baseline and the end of the placebo-controlled treatment period (week 24) in the full analysis set for the sotatercept 0.3 mg / kg and 0.7 mg / kg groups. Figure 8C shows the effect of sotatercept 0.3 mg / kg on the change in pulmonary vascular resistance from baseline to week 24 in patient subgroups. All data are derived from the full analysis set and compared to placebo using ANOVA with baseline values ​​as a covariance. Figure 8D shows the effect of sotatercept 0.7 mg / kg on the change in pulmonary vascular resistance from baseline to week 24 in patient subgroups. All data are derived from the full analysis set and compared to placebo using ANOVA with baseline values ​​as a covariance.

[0033] [Figure 9A] Figures 9A and 9B show changes in various parameters from baseline to week 24 in a placebo-controlled clinical trial using sotatercept (ActRIIA-hFc polypeptide) treatment in patients with pulmonary arterial hypertension. Patients were treated with placebo, sotatercept 0.3 mg / kg, or sotatercept 0.7 mg / kg. [Figure 9B]Figures 9A and 9B show changes in various parameters from baseline to week 24 in a placebo-controlled clinical trial using sotatercept (ActRIIA-hFc polypeptide) treatment in patients with pulmonary arterial hypertension. Patients were treated with placebo, sotatercept 0.3 mg / kg, or sotatercept 0.7 mg / kg.

[0034] [Figure 10A] Figures 10A–10C show the change in 6-minute walk distance from baseline to week 24 in a placebo-controlled clinical trial using sotatercept (ActRIIA-hFc polypeptide) in patients with pulmonary arterial hypertension. Figure 10A shows the least squares mean ± SE in the full analysis set. The least squares mean difference in 6-minute walk distance compared to placebo was 29.4 m (95% CI, 3.8 to 55.0) for sotatercept 0.3 mg / kg and 21.4 m (95% CI, -2.8 to 45.7) for sotatercept 0.7 mg / kg. Figure 10B shows the effect of sotatercept 0.3 mg / kg on the change in 6-minute walk distance from baseline to week 24 in a patient subgroup. All data are from the full analysis set and compared to placebo using ANOVA with baseline values ​​as covariances. Figure 10C shows the effect of sotatercept 0.7 mg / kg on the change in 6-minute walk distance from baseline to week 24 in a patient subgroup. All data are from the full analysis set and are compared to placebo using analysis of covariance with baseline values ​​as covariates. [Figure 10B]Figures 10A–10C show the change in 6-minute walk distance from baseline to week 24 in a placebo-controlled clinical trial using sotatercept (ActRIIA-hFc polypeptide) in patients with pulmonary arterial hypertension. Figure 10A shows the least squares mean ± SE in the full analysis set. The least squares mean difference in 6-minute walk distance compared to placebo was 29.4 m (95% CI, 3.8 to 55.0) for sotatercept 0.3 mg / kg and 21.4 m (95% CI, -2.8 to 45.7) for sotatercept 0.7 mg / kg. Figure 10B shows the effect of sotatercept 0.3 mg / kg on the change in 6-minute walk distance from baseline to week 24 in a patient subgroup. All data are from the full analysis set and compared to placebo using ANOVA with baseline values ​​as covariances. Figure 10C shows the effect of sotatercept 0.7 mg / kg on the change in 6-minute walk distance from baseline to week 24 in a patient subgroup. All data are from the full analysis set and are compared to placebo using analysis of covariance with baseline values ​​as covariates. [Figure 10C]Figures 10A–10C show the change in 6-minute walk distance from baseline to week 24 in a placebo-controlled clinical trial using sotatercept (ActRIIA-hFc polypeptide) in patients with pulmonary arterial hypertension. Figure 10A shows the least squares mean ± SE in the full analysis set. The least squares mean difference in 6-minute walk distance compared to placebo was 29.4 m (95% CI, 3.8 to 55.0) for sotatercept 0.3 mg / kg and 21.4 m (95% CI, -2.8 to 45.7) for sotatercept 0.7 mg / kg. Figure 10B shows the effect of sotatercept 0.3 mg / kg on the change in 6-minute walk distance from baseline to week 24 in a patient subgroup. All data are from the full analysis set and compared to placebo using ANOVA with baseline values ​​as covariances. Figure 10C shows the effect of sotatercept 0.7 mg / kg on the change in 6-minute walk distance from baseline to week 24 in a patient subgroup. All data are from the full analysis set and are compared to placebo using analysis of covariance with baseline values ​​as covariates.

[0035] [Figure 11A]Figures 11A–11C show the change in NT-proBNP from baseline to week 24 in a placebo-controlled clinical trial using sotatercept (ActRIIA-hFc polypeptide) in patients with pulmonary arterial hypertension. Figure 11A shows the least squares mean ± SE in the full analysis set. The least squares mean difference in NT-ProBNP compared to placebo was -931.5 pg / mL (95% CI, -1353.24 to -5.0.70) for sotatercept 0.3 mg / kg and -651.0 pg / mL (95% CI, -1043.28 to -258.74) for sotatercept 0.7 mg / kg. Figure 11B shows the effect of sotatercept 0.3 mg / kg on the change in NT-proBNP from baseline to week 24 in patient subgroups. All data are derived from the full analysis set and compared to placebo using analysis of covariance with baseline values ​​as covariances. Figure 11C shows the effect of sotatercept 0.7 mg / kg on the change in NT-proBNP from baseline to week 24 in a patient subgroup. All data are derived from the full analysis set and compared to placebo using analysis of covariance with baseline values ​​as covariances. [Figure 11B]Figures 11A–11C show the change in NT-proBNP from baseline to week 24 in a placebo-controlled clinical trial using sotatercept (ActRIIA-hFc polypeptide) in patients with pulmonary arterial hypertension. Figure 11A shows the least squares mean ± SE in the full analysis set. The least squares mean difference in NT-ProBNP compared to placebo was -931.5 pg / mL (95% CI, -1353.24 to -5.0.70) for sotatercept 0.3 mg / kg and -651.0 pg / mL (95% CI, -1043.28 to -258.74) for sotatercept 0.7 mg / kg. Figure 11B shows the effect of sotatercept 0.3 mg / kg on the change in NT-proBNP from baseline to week 24 in patient subgroups. All data are derived from the full analysis set and compared to placebo using analysis of covariance with baseline values ​​as covariances. Figure 11C shows the effect of sotatercept 0.7 mg / kg on the change in NT-proBNP from baseline to week 24 in a patient subgroup. All data are derived from the full analysis set and compared to placebo using analysis of covariance with baseline values ​​as covariances. [Figure 11C]Figures 11A–11C show the change in NT-proBNP from baseline to week 24 in a placebo-controlled clinical trial using sotatercept (ActRIIA-hFc polypeptide) in patients with pulmonary arterial hypertension. Figure 11A shows the least squares mean ± SE in the full analysis set. The least squares mean difference in NT-ProBNP compared to placebo was -931.5 pg / mL (95% CI, -1353.24 to -5.0.70) for sotatercept 0.3 mg / kg and -651.0 pg / mL (95% CI, -1043.28 to -258.74) for sotatercept 0.7 mg / kg. Figure 11B shows the effect of sotatercept 0.3 mg / kg on the change in NT-proBNP from baseline to week 24 in patient subgroups. All data are derived from the full analysis set and compared to placebo using analysis of covariance with baseline values ​​as covariances. Figure 11C shows the effect of sotatercept 0.7 mg / kg on the change in NT-proBNP from baseline to week 24 in a patient subgroup. All data are derived from the full analysis set and compared to placebo using analysis of covariance with baseline values ​​as covariances.

[0036] [Figure 12]Figure 12 shows the mean changes in echocardiographic parameters from baseline to week 24 during a placebo-controlled clinical trial using sotatercept (ActRIIA-hFc polypeptide) treatment in patients with pulmonary arterial hypertension. Baseline data are mean (SD), and changes are mean LS (SE) derived from an evaluable analysis set. All echocardiographic data were obtained in 2D. TAPSE: tricuspid annular plane systolic excursion; RVFAC: fractional area change. Week 24 includes the end-of-treatment visit if the subject discontinued treatment prior to the week 24 visit. P-values ​​are based on ANCOVA analysis with baseline WHO function class and baseline results as covariates.

[0037] [Figure 13A-C]Figures 13A–13F show that the sotatercept analog RAP-011 (ActRIIA-mFc polypeptide) prevents hypertension (PH) and reduces right ventricular hypertrophy in a mouse model of BMPR2 deficiency. The experimental strategy used to test the prophylactic effect of RAP-011 in mice with Bmpr2 haploinsufficiency is described below. Bmpr2+ / R899X mice were exposed to normobaric hypoxia (FiO2=0.10) and treated twice weekly with either RAP-011 (10 mg / kg, sc) or a medium (PBS) for 5 weeks (Figure 13A). Figure 13B shows right ventricular systolic pressure (RVSP), and Figure 13C shows the Fulton index calculated as the ratio of right ventricular mass (RV) to combined left ventricular and septal mass (LV+S). Data are mean ± SEM (n=7–10 per group). Analysis by one-way ANOVA and Tukey post-hoc test. (Figure 13D shows that amplification of genomic DNA by PCR and direct sequencing confirmed the presence of heterozygous mutations (arrows) in Bmpr2+ / R899X mice (equal peak heights for wild-type and mutant alleles). Figure 13E shows immunoblots of lung homogenates from wild-type and Bmpr2+ / R899X mice analyzed to determine BMPR2 expression. Figure 13F shows quantification of BMPR2 protein expression normalized to GADPH. Data are mean ± SEM (n=5 per group). Analysis by Student's t-test. *P<0.05, ***P<0.001, ****P<0.0001.) [Figure 13D-F]Figures 13A–13F show that the sotatercept analog RAP-011 (ActRIIA-mFc polypeptide) prevents hypertension (PH) and reduces right ventricular hypertrophy in a mouse model of BMPR2 deficiency. The experimental strategy used to test the prophylactic effect of RAP-011 in mice with Bmpr2 haploinsufficiency is described below. Bmpr2+ / R899X mice were exposed to normobaric hypoxia (FiO2=0.10) and treated twice weekly with either RAP-011 (10 mg / kg, sc) or a medium (PBS) for 5 weeks (Figure 13A). Figure 13B shows right ventricular systolic pressure (RVSP), and Figure 13C shows the Fulton index calculated as the ratio of right ventricular mass (RV) to combined left ventricular and septal mass (LV+S). Data are mean ± SEM (n=7–10 per group). Analysis by one-way ANOVA and Tukey post-hoc test. (Figure 13D shows that amplification of genomic DNA by PCR and direct sequencing confirmed the presence of heterozygous mutations (arrows) in Bmpr2+ / R899X mice (equal peak heights for wild-type and mutant alleles). Figure 13E shows immunoblots of lung homogenates from wild-type and Bmpr2+ / R899X mice analyzed to determine BMPR2 expression. Figure 13F shows quantification of BMPR2 protein expression normalized to GADPH. Data are mean ± SEM (n=5 per group). Analysis by Student's t-test. *P<0.05, ***P<0.001, ****P<0.0001.)

[0038] [Figure 14A-C]Figures 14A–14E demonstrate that RAP-011 is effective in combination and monotherapy to reverse pulmonary vascular remodeling in severe experimental PAH. Figure 14A shows the experimental strategy used to test the therapeutic effect of RAP-011 in a Sugen-hypoxic-oxygenous (SuHxNx) rat model of severe PAH. Rats were treated with a single dose of SU5416 (20 mg / kg) on ​​day 0 and exposed to normobaric hypoxia (FiO2=0.10) for 3 weeks, followed by 6 weeks of oxygenous exposure to induce disease progression. The rats were then treated with RAP-011 (2.5 mg / kg, sc, twice weekly), sildenafil (30 mg / kg, po, twice daily), combination therapy with RAP-011 and sildenafil, or a medium (PBS) for 4 weeks, starting 5 weeks after SU5416. Figure 14B shows RVSP, and Figure 14C shows Total Pulmonary Resistance Index (TPRI). Data are mean ± SEM (n=7-14 per group). Figure 14D shows images of representative lung sections stained with hematoxylin and eosin. Scale bar, 200 μm. Figure 14E shows images of lung sections immunostained with antibody against α-smooth muscle actin to illustrate the grade of lung histopathology. Scale bar, 50 μm. Percentage of pulmonary artery vessels classified as Grade 0 (normal, no occlusion), Grade 1 (<50% occlusion), or Grade 2 (>50% occlusion), grouped according to vascular outer diameter. Data are mean ± SEM (n=4 rats per group). Analysis by one-way ANOVA and Tukey post-hoc test; for simplification, only significance for the percentage of Grade 0 vessels is indicated (*P<0.05). [Figure 14D]Figures 14A–14E demonstrate that RAP-011 is effective in combination and monotherapy to reverse pulmonary vascular remodeling in severe experimental PAH. Figure 14A shows the experimental strategy used to test the therapeutic effect of RAP-011 in a Sugen-hypoxic-oxygenous (SuHxNx) rat model of severe PAH. Rats were treated with a single dose of SU5416 (20 mg / kg) on ​​day 0 and exposed to normobaric hypoxia (FiO2=0.10) for 3 weeks, followed by 6 weeks of oxygenous exposure to induce disease progression. The rats were then treated with RAP-011 (2.5 mg / kg, sc, twice weekly), sildenafil (30 mg / kg, po, twice daily), combination therapy with RAP-011 and sildenafil, or a medium (PBS) for 4 weeks, starting 5 weeks after SU5416. Figure 14B shows RVSP, and Figure 14C shows Total Pulmonary Resistance Index (TPRI). Data are mean ± SEM (n=7-14 per group). Figure 14D shows images of representative lung sections stained with hematoxylin and eosin. Scale bar, 200 μm. Figure 14E shows images of lung sections immunostained with antibody against α-smooth muscle actin to illustrate the grade of lung histopathology. Scale bar, 50 μm. Percentage of pulmonary artery vessels classified as Grade 0 (normal, no occlusion), Grade 1 (<50% occlusion), or Grade 2 (>50% occlusion), grouped according to vascular outer diameter. Data are mean ± SEM (n=4 rats per group). Analysis by one-way ANOVA and Tukey post-hoc test; for simplification, only significance for the percentage of Grade 0 vessels is indicated (*P<0.05). [Figure 14E]Figures 14A–14E demonstrate that RAP-011 is effective in combination and monotherapy to reverse pulmonary vascular remodeling in severe experimental PAH. Figure 14A shows the experimental strategy used to test the therapeutic effect of RAP-011 in a Sugen-hypoxic-oxygenous (SuHxNx) rat model of severe PAH. Rats were treated with a single dose of SU5416 (20 mg / kg) on ​​day 0 and exposed to normobaric hypoxia (FiO2=0.10) for 3 weeks, followed by 6 weeks of oxygenous exposure to induce disease progression. The rats were then treated with RAP-011 (2.5 mg / kg, sc, twice weekly), sildenafil (30 mg / kg, po, twice daily), combination therapy with RAP-011 and sildenafil, or a medium (PBS) for 4 weeks, starting 5 weeks after SU5416. Figure 14B shows RVSP, and Figure 14C shows Total Pulmonary Resistance Index (TPRI). Data are mean ± SEM (n=7-14 per group). Figure 14D shows images of representative lung sections stained with hematoxylin and eosin. Scale bar, 200 μm. Figure 14E shows images of lung sections immunostained with antibody against α-smooth muscle actin to illustrate the grade of lung histopathology. Scale bar, 50 μm. Percentage of pulmonary artery vessels classified as Grade 0 (normal, no occlusion), Grade 1 (<50% occlusion), or Grade 2 (>50% occlusion), grouped according to vascular outer diameter. Data are mean ± SEM (n=4 rats per group). Analysis by one-way ANOVA and Tukey post-hoc test; for simplification, only significance for the percentage of Grade 0 vessels is indicated (*P<0.05).

[0039] [Figure 15A-D]Figures 15A–15G show that the simultaneous inhibition of activin, GDF8, and GDF11 contributes to the effect of RAP-011 in vitro and in vivo in the PH model. Figure 15A shows the effect of therapeutic treatment with RAP-011 on lung cell proliferation in the SuHxNx model of severe PAH, measured by the percentage of Ki67-positive cells. Data are mean ± SEM (n=4–5 rats per group). Figure 15B describes the cell culture system used to investigate the antiproliferative effect of sotatercept. Human pulmonary artery smooth muscle cells (PASMCs) were treated in conditioned medium collected from human pulmonary artery endothelial cells (PAECs) in the absence or presence of separate antibodies against activin A and activin B (anti-Act), dual antibodies against GDF8 and GDF11 (anti-GDF), combined anti-Act and anti-GDF, or sotatercept (ACE-011). As shown in Figure 15C, PASMC proliferation was quantified in the bromodeoxyuridine (BrdU) assay. Data are mean ± SEM (n=8 per group). Figure 15D illustrates the experimental strategy used to test the prophylactic effect of multiligand inhibition in a SuHx rat model of PH. Rats were treated with a single dose of SU5416 (20 mg / kg, sc), exposed to normobaric hypoxia (FiO2=0.13), and treated with anti-Act (10 mg / kg + 10 mg / kg), anti-GDF (10 mg / kg), a combination of anti-Act and anti-GDF, or sc twice a week for 4 weeks, starting 1 day after SU5416. Figure 15E shows systolic pulmonary artery pressure (sPAP) in rats treated according to Figure 15D. Figure 15F shows mPAP in rats treated according to Figure 15D. Figure 15G shows the Fulton index in rats treated according to Figure 15D. Data are mean ± SEM (n=5-9 rats per group). Analysis was performed using one-way ANOVA and Tukey post-hoc test (*P<0.05, **P<0.01, ****P<0.0001). [Figure 15E-G]Figures 15A–15G show that the simultaneous inhibition of activin, GDF8, and GDF11 contributes to the effect of RAP-011 in vitro and in vivo in the PH model. Figure 15A shows the effect of therapeutic treatment with RAP-011 on lung cell proliferation in the SuHxNx model of severe PAH, measured by the percentage of Ki67-positive cells. Data are mean ± SEM (n=4–5 rats per group). Figure 15B describes the cell culture system used to investigate the antiproliferative effect of sotatercept. Human pulmonary artery smooth muscle cells (PASMCs) were treated in conditioned medium collected from human pulmonary artery endothelial cells (PAECs) in the absence or presence of separate antibodies against activin A and activin B (anti-Act), dual antibodies against GDF8 and GDF11 (anti-GDF), combined anti-Act and anti-GDF, or sotatercept (ACE-011). As shown in Figure 15C, PASMC proliferation was quantified in the bromodeoxyuridine (BrdU) assay. Data are mean ± SEM (n=8 per group). Figure 15D illustrates the experimental strategy used to test the prophylactic effect of multiligand inhibition in a SuHx rat model of PH. Rats were treated with a single dose of SU5416 (20 mg / kg, sc), exposed to normobaric hypoxia (FiO2=0.13), and treated with anti-Act (10 mg / kg + 10 mg / kg), anti-GDF (10 mg / kg), a combination of anti-Act and anti-GDF, or sc twice a week for 4 weeks, starting 1 day after SU5416. Figure 15E shows systolic pulmonary artery pressure (sPAP) in rats treated according to Figure 15D. Figure 15F shows mPAP in rats treated according to Figure 15D. Figure 15G shows the Fulton index in rats treated according to Figure 15D. Data are mean ± SEM (n=5-9 rats per group). Analysis was performed using one-way ANOVA and Tukey post-hoc test (*P<0.05, **P<0.01, ****P<0.0001).

[0040] [Figure 16A-B]Figures 16A–16K show that therapeutic treatment with RAP-011 instead of sildenafil reduces cardiac hypertrophy, restores septal geometry, and improves right ventricular function in severe experimental PAH. Figure 16A shows the Fulton index in normal or SuHxNx rats as a function of treatment, and Figure 16B shows the cardiac index (CI). Data are mean ± SEM (n=7–13 rats per group). Figure 16C shows representative echocardiographic images obtained in a replicated manner from individual SuHxNx rats before and after therapy. Figure 16D shows pulmonary artery acceleration time (PAAT) in animals treated according to Example 13. Figure 16E shows tricuspid annular systolic displacement (TAPSE) in animals treated according to Example 13. Figure 16F shows right ventricular wall thickness (RVWT) measured in diastole in animals treated according to Example 13. Figure 16G shows the percentage change in right ventricular area (RVFAC) in animals treated according to Example 13. Data are mean ± SEM (n=7–11 rats per group). Figures 16H–16K show the ratio of myosin heavy chain isoform expression (Myh7:Myh6) (Figure 16H) as a function of treatment in the right ventricle of normal or SuHxNx rats, as well as the levels of Nppb (Figure 16I), Inhba (Figure 16J), and Inhbb (Figure 16K) mRNA. Data are mean ± SEM (n=6–11 rats per group). Analysis by one-way ANOVA and Tukey post-hoc test (*P<0.05, **P<0.01, ***P<0.001, ****P<0.0001). [Figure 16C]Figures 16A–16K show that therapeutic treatment with RAP-011 instead of sildenafil reduces cardiac hypertrophy, restores septal geometry, and improves right ventricular function in severe experimental PAH. Figure 16A shows the Fulton index in normal or SuHxNx rats as a function of treatment, and Figure 16B shows the cardiac index (CI). Data are mean ± SEM (n=7–13 rats per group). Figure 16C shows representative echocardiographic images obtained in a replicated manner from individual SuHxNx rats before and after therapy. Figure 16D shows pulmonary artery acceleration time (PAAT) in animals treated according to Example 13. Figure 16E shows tricuspid annular systolic displacement (TAPSE) in animals treated according to Example 13. Figure 16F shows right ventricular wall thickness (RVWT) measured in diastole in animals treated according to Example 13. Figure 16G shows the percentage change in right ventricular area (RVFAC) in animals treated according to Example 13. Data are mean ± SEM (n=7–11 rats per group). Figures 16H–16K show the ratio of myosin heavy chain isoform expression (Myh7:Myh6) (Figure 16H) as a function of treatment in the right ventricle of normal or SuHxNx rats, as well as the levels of Nppb (Figure 16I), Inhba (Figure 16J), and Inhbb (Figure 16K) mRNA. Data are mean ± SEM (n=6–11 rats per group). Analysis by one-way ANOVA and Tukey post-hoc test (*P<0.05, **P<0.01, ***P<0.001, ****P<0.0001). [Figure 16D-G]Figures 16A–16K show that therapeutic treatment with RAP-011 instead of sildenafil reduces cardiac hypertrophy, restores septal geometry, and improves right ventricular function in severe experimental PAH. Figure 16A shows the Fulton index in normal or SuHxNx rats as a function of treatment, and Figure 16B shows the cardiac index (CI). Data are mean ± SEM (n=7–13 rats per group). Figure 16C shows representative echocardiographic images obtained in a replicated manner from individual SuHxNx rats before and after therapy. Figure 16D shows pulmonary artery acceleration time (PAAT) in animals treated according to Example 13. Figure 16E shows tricuspid annular systolic displacement (TAPSE) in animals treated according to Example 13. Figure 16F shows right ventricular wall thickness (RVWT) measured in diastole in animals treated according to Example 13. Figure 16G shows the percentage change in right ventricular area (RVFAC) in animals treated according to Example 13. Data are mean ± SEM (n=7–11 rats per group). Figures 16H–16K show the ratio of myosin heavy chain isoform expression (Myh7:Myh6) (Figure 16H) as a function of treatment in the right ventricle of normal or SuHxNx rats, as well as the levels of Nppb (Figure 16I), Inhba (Figure 16J), and Inhbb (Figure 16K) mRNA. Data are mean ± SEM (n=6–11 rats per group). Analysis by one-way ANOVA and Tukey post-hoc test (*P<0.05, **P<0.01, ***P<0.001, ****P<0.0001). [Figure 16H-K]Figures 16A–16K show that therapeutic treatment with RAP-011 instead of sildenafil reduces cardiac hypertrophy, restores septal geometry, and improves right ventricular function in severe experimental PAH. Figure 16A shows the Fulton index in normal or SuHxNx rats as a function of treatment, and Figure 16B shows the cardiac index (CI). Data are mean ± SEM (n=7–13 rats per group). Figure 16C shows representative echocardiographic images obtained in a replicated manner from individual SuHxNx rats before and after therapy. Figure 16D shows pulmonary artery acceleration time (PAAT) in animals treated according to Example 13. Figure 16E shows tricuspid annular systolic displacement (TAPSE) in animals treated according to Example 13. Figure 16F shows right ventricular wall thickness (RVWT) measured in diastole in animals treated according to Example 13. Figure 16G shows the percentage change in right ventricular area (RVFAC) in animals treated according to Example 13. Data are mean ± SEM (n=7–11 rats per group). Figures 16H–16K show the ratio of myosin heavy chain isoform expression (Myh7:Myh6) (Figure 16H) as a function of treatment in the right ventricle of normal or SuHxNx rats, as well as the levels of Nppb (Figure 16I), Inhba (Figure 16J), and Inhbb (Figure 16K) mRNA. Data are mean ± SEM (n=6–11 rats per group). Analysis by one-way ANOVA and Tukey post-hoc test (*P<0.05, **P<0.01, ***P<0.001, ****P<0.0001).

[0041] [Figure 17A-D]Figures 17A–17I demonstrate that RAP-011 exerts structural and functional cardioprotective effects in a model of right heart failure induced by pressure overload. Figure 17A shows the experimental strategy used to evaluate the potential cardioprotective effects of RAP-011 in a mouse model of sustained pressure overload. Wild-type mice were subjected to pulmonary artery ligation and treated twice a week for three weeks, starting one day after surgery, with either RAP-011 (10 mg / kg, sc) or the medium (PBS). The various parameters measured using the experimental strategy described in Figure 17A are as follows: Fulton index (Figure 17B), right ventricular free wall thickness (RVFWT) (Figure 17C), TAPSE (Figure 17D), myocardial performance index (MPI) (Figure 17E), right ventricular maximum pressure (RVDP) (Figure 17F), and peak percentages of right ventricular pressure elevation (dP / dtmax) and reduction (-dP / dtmin) (Figure 17G). Data are mean ± SEM (n=10-15 mice per group for day 21). Figure 17H ​​shows a representative image of a right ventricular section stained with Masson's trichrome blue to detect fibrosis (scale bar, 20 μm), and Figure 17I shows the quantification of the percentage area occupied by fibrous tissue. Data are mean ± SEM (n=10-15 mice per group). Analysis using one-way ANOVA and Tukey post-hoc test (*p<0.05, **p<0.01, ***p<0.001, ****p<0.0001). [Figure 17E-G]Figures 17A–17I demonstrate that RAP-011 exerts structural and functional cardioprotective effects in a model of right heart failure induced by pressure overload. Figure 17A shows the experimental strategy used to evaluate the potential cardioprotective effects of RAP-011 in a mouse model of sustained pressure overload. Wild-type mice were subjected to pulmonary artery ligation and treated twice a week for three weeks, starting one day after surgery, with either RAP-011 (10 mg / kg, sc) or the medium (PBS). The various parameters measured using the experimental strategy described in Figure 17A are as follows: Fulton index (Figure 17B), right ventricular free wall thickness (RVFWT) (Figure 17C), TAPSE (Figure 17D), myocardial performance index (MPI) (Figure 17E), right ventricular maximum pressure (RVDP) (Figure 17F), and peak percentages of right ventricular pressure elevation (dP / dtmax) and reduction (-dP / dtmin) (Figure 17G). Data are mean ± SEM (n=10-15 mice per group for day 21). Figure 17H ​​shows a representative image of a right ventricular section stained with Masson's trichrome blue to detect fibrosis (scale bar, 20 μm), and Figure 17I shows the quantification of the percentage area occupied by fibrous tissue. Data are mean ± SEM (n=10-15 mice per group). Analysis using one-way ANOVA and Tukey post-hoc test (*p<0.05, **p<0.01, ***p<0.001, ****p<0.0001). [Figure 17H-I]Figures 17A–17I demonstrate that RAP-011 exerts structural and functional cardioprotective effects in a model of right heart failure induced by pressure overload. Figure 17A shows the experimental strategy used to evaluate the potential cardioprotective effects of RAP-011 in a mouse model of sustained pressure overload. Wild-type mice were subjected to pulmonary artery ligation and treated twice a week for three weeks, starting one day after surgery, with either RAP-011 (10 mg / kg, sc) or the medium (PBS). The various parameters measured using the experimental strategy described in Figure 17A are as follows: Fulton index (Figure 17B), right ventricular free wall thickness (RVFWT) (Figure 17C), TAPSE (Figure 17D), myocardial performance index (MPI) (Figure 17E), right ventricular maximum pressure (RVDP) (Figure 17F), and peak percentages of right ventricular pressure elevation (dP / dtmax) and reduction (-dP / dtmin) (Figure 17G). Data are mean ± SEM (n=10-15 mice per group for day 21). Figure 17H ​​shows a representative image of a right ventricular section stained with Masson's trichrome blue to detect fibrosis (scale bar, 20 μm), and Figure 17I shows the quantification of the percentage area occupied by fibrous tissue. Data are mean ± SEM (n=10-15 mice per group). Analysis using one-way ANOVA and Tukey post-hoc test (*p<0.05, **p<0.01, ***p<0.001, ****p<0.0001).

[0042] [Figure 18A-D]Figures 18A–18G demonstrate that the disease reversal effect of RAP-011 persists after discontinuation of treatment in severe experimental PAH. Figure 18A shows the experimental strategy used to test the persistence of the therapeutic effect of RAP-011 in a SuHxNx rat model of severe PAH. Rats were treated with a single dose of SU5416 (20 mg / kg, sc) on day 0, followed by 3 weeks of normobaric hypoxia (FiO2=0.10), and then 10 weeks of normal oxygenation to induce disease progression. The rats were then treated twice a week with RAP-011 (2.5 mg / kg, sc) or a medium (PBS) from week 5 to week 9 after SU5416, with treatment discontinued at week 9 for the remaining 4 weeks. The following parameters were determined as functions of treatment: RVSP (Figure 18B), TPRI (Figure 18C), Fulton index (Figure 18D), CI (Figure 18E), PAAT (Figure 18F), and TAPSE (Figure 18G). Data are mean ± SEM (n=7–13 rats per group). Analysis was performed using one-way ANOVA and Tukey post-hoc test (*P<0.05, **P<0.01, ****P<0.0001). [Figure 18E-G] Figures 18A–18G demonstrate that the disease reversal effect of RAP-011 persists after discontinuation of treatment in severe experimental PAH. Figure 18A shows the experimental strategy used to test the persistence of the therapeutic effect of RAP-011 in a SuHxNx rat model of severe PAH. Rats were treated with a single dose of SU5416 (20 mg / kg, sc) on day 0, followed by 3 weeks of normobaric hypoxia (FiO2=0.10), and then 10 weeks of normal oxygenation to induce disease progression. The rats were then treated twice a week with RAP-011 (2.5 mg / kg, sc) or a medium (PBS) from week 5 to week 9 after SU5416, with treatment discontinued at week 9 for the remaining 4 weeks. The following parameters were determined as functions of treatment: RVSP (Figure 18B), TPRI (Figure 18C), Fulton index (Figure 18D), CI (Figure 18E), PAAT (Figure 18F), and TAPSE (Figure 18G). Data are mean ± SEM (n=7–13 rats per group). Analysis was performed using one-way ANOVA and Tukey post-hoc test (*P<0.05, **P<0.01, ****P<0.0001).

[0043] [Figure 19] Figure 19 shows the components of the kit, including lyophilized polypeptide and an injection device. A vial (1) holds lyophilized polypeptide, reconstituted sterile injection solution, or sterile injection solution. From (1) is a pre-filled syringe (2) containing a reconstitution solution used to reconstitute the lyophilized polypeptide into a sterile injection solution. A vial adapter (3) connects vial (1) to pre-filled syringe (2) by attaching to the vial at one end and to the pre-filled syringe at both ends. A syringe (4) and needle (5) are provided for administering the sterile injection solution. A swab material (6) is provided for sterilizing the individual kit components.

[0044] [Figure 20A-C] Figures 20A–20C show the mean changes in echocardiographic parameters from baseline to week 24 during a placebo-controlled clinical trial using sotatercept (ActRIIA-hFc polypeptide) in patients with pulmonary arterial hypertension. Figure 20A shows the improvement in mean LS (SE) change of right ventricular end-diastolic area (RVEDA) from baseline to week 24. Figure 20B shows the improvement in mean LS (SE) change of right ventricular end-systolic area (RVESA) from baseline to week 24. Figure 20C presents the mean LS and p-value data derived from Figures 20A and 20B in tabular format. Baseline data are mean (SD), and changes are mean LS (SE) derived from the evaluable analysis set. All echocardiographic data were obtained in 2D. Bar graphs represent mean ± standard deviation. †EOP represents data obtained at the end of the placebo-controlled treatment period (week 24). ‡Standard errors are shown in parentheses relative to the overall LS mean. CI: Confidence Interval; EOP: End of Placebo-Controlled Treatment Period; LS: Least Squares; SOC: Standard of Care.

[0045] [Figure 21A-B]Figures 21A and 21B show the mean change in pulmonary artery systolic pressure (PASP) from baseline to week 24, as measured during a placebo-controlled clinical trial using sotatercept (ActRIIA-hFc polypeptide) in patients with pulmonary arterial hypertension. Figure 21A shows the improvement in pulmonary artery systolic pressure (PASP) in patients treated with 0.3 mg / kg sotatercept and standard care (SOC) or 0.7 mg / kg sotatercept and SOC. Figure 21B presents the mean LS and p-value data derived from Figure 21A in tabular format. Baseline data are mean (SD), and change is mean LS (SE) derived from the evaluable analysis set. All echocardiographic data were obtained in 2D. Bar graphs represent mean ± standard deviation. †EOP represents data obtained at the end of the placebo-controlled treatment period (week 24). ‡Standard error is shown in parentheses relative to the overall mean LS. CI: Confidence interval; LS: Least squares.

[0046] [Figure 22A-B] Figures 22A and 22B show the mean change in right ventricular-pulmonary (RV-PA) coupling from baseline to week 24 as measured during a placebo-controlled clinical trial using sotatercept (ActRIIA-hFc polypeptide) treatment in patients with pulmonary arterial hypertension. Figure 22A shows improvement in RV-PA coupling in patients treated with 0.3 mg / kg sotatercept and standard care (SOC) or 0.7 mg / kg sotatercept and SOC. Figure 22B presents the mean LS and p-value data derived from Figure 22A in tabular format. Baseline data are mean (SD), and change is mean LS (SE) derived from the evaluable analysis set. All echocardiographic data were obtained in 2D. Bar graphs represent mean ± standard deviation. †EOP represents data obtained at the end of the placebo-controlled treatment period (week 24). ‡Standard error is shown in parentheses relative to the overall mean LS. §The cutoff value for RV-PA coupling has not been validated in large cohorts. CI: Confidence interval; LS: Least squares; Values ​​in parentheses are relative to the overall LS mean; RV-PA: Right ventricle-pulmonary artery.

[0047] [Figure 23A-C] Figures 23A to 23F show that treatment with ActRIIA-mFc polypeptide prevents PH and reduces right ventricular hypertrophy in a mouse model of BMPR2 haploinsufficiency. The experimental strategy used to test the prophylactic effect of ActRIIA-mFc in a mouse model of Bmpr2 haploinsufficiency is shown in Figure 23A. Twenty-nine Bmpr2+ / R899X mice were randomized into three groups: (i) seven mice were housed under normal oxygen pressure conditions for five weeks, "Nx"; (ii) eleven mice were housed under hypoxic conditions and subcutaneously injected with a medium control (phosphate-buffered saline (PBS)) twice a week for five weeks, "Hx Veh"; and (iii) eleven mice were housed under hypoxic conditions and subcutaneously injected with ActRIIA-mFc at a dose of 10 mg / kg twice a week for five weeks, "Hx ActRIIA-mFc". Figure 23B shows pulmonary artery acceleration time (PAAT), and Figure 23C shows right ventricular systolic pressure (RVSP). Figure 23D shows right ventricular free wall thickness (RVWT), and Figure 23E shows the Fulton index calculated as the ratio of right ventricular weight (RV) to the combined weight of the left ventricle and septum (LV+S) (RV / (LV+S)). Figure 23F shows tricuspid annular systolic displacement (TAPSE). Data are mean ± SEM (n=7-11 per group). Analysis was performed using one-way ANOVA and Tukey post-hoc test. *P<0.05, ***P<0.001, ****P<0.0001. [Figure 23D-F]Figures 23A to 23F show that treatment with ActRIIA-mFc polypeptide prevents PH and reduces right ventricular hypertrophy in a mouse model of BMPR2 haploinsufficiency. The experimental strategy used to test the prophylactic effect of ActRIIA-mFc in a mouse model of Bmpr2 haploinsufficiency is shown in Figure 23A. Twenty-nine Bmpr2+ / R899X mice were randomized into three groups: (i) seven mice were housed under normal oxygen pressure conditions for five weeks, "Nx"; (ii) eleven mice were housed under hypoxic conditions and subcutaneously injected with a medium control (phosphate-buffered saline (PBS)) twice a week for five weeks, "Hx Veh"; and (iii) eleven mice were housed under hypoxic conditions and subcutaneously injected with ActRIIA-mFc at a dose of 10 mg / kg twice a week for five weeks, "Hx ActRIIA-mFc". Figure 23B shows pulmonary artery acceleration time (PAAT), and Figure 23C shows right ventricular systolic pressure (RVSP). Figure 23D shows right ventricular free wall thickness (RVWT), and Figure 23E shows the Fulton index calculated as the ratio of right ventricular weight (RV) to the combined weight of the left ventricle and septum (LV+S) (RV / (LV+S)). Figure 23F shows tricuspid annular systolic displacement (TAPSE). Data are mean ± SEM (n=7-11 per group). Analysis was performed using one-way ANOVA and Tukey post-hoc test. *P<0.05, ***P<0.001, ****P<0.0001.

[0048] [Figure 24A-B]Figures 24A and 24B show that treatment with ActRIIA-mFc polypeptide prevents perivascular inflammation by preventing macrophage infiltration in the lungs. Twenty-nine Bmpr2+ / R899X mice were randomized into three groups: (i) seven mice were housed under normal oxygen pressure conditions for five weeks, designated "Nx"; (ii) eleven mice were housed under hypoxic conditions and subcutaneously injected with a medium control (phosphate-buffered saline (PBS)) twice a week for five weeks, designated "Hx Veh"; and (iii) eleven mice were housed under hypoxic conditions and subcutaneously injected with ActRIIA-mFc at a dose of 10 mg / kg twice a week for five weeks, designated "Hx ActRIIA-mFc". Figure 24A shows postmortem analysis of macrophage infiltration in the lungs by immunohistochemical staining for the macrophage marker F4 / 80. Figure 24B shows the quantification of the percentage of F4 / 80 positive cells in the lungs based on the evaluation of 40 high-magnification fields per animal. Data are mean ± SEM (n=7-11 per group). Analysis by one-way ANOVA and Tukey post-hoc test. *P<0.05, ***P<0.001, ****P<0.0001. [Modes for carrying out the invention]

[0049] Detailed explanation 1. Overview This disclosure relates to pulmonary arterial hypertension (e.g., functional class II or functional class III). A composition for treating ) and for a patient in need thereof, in an effective amount as described herein A method comprising the step of administering an ActRII polypeptide. A specific implementation In this disclosure, the ActRII polyp used herein is used to provide an individual with a therapeutically effective amount of the ActRII polyp used herein. By administering ptide, pulmonary arterial hypertension is treated in individuals who require it. Or provide a method of prevention.

[0050] Pulmonary arterial hypertension [WHO Group 1 PH] is a condition characterized by severe vascular stenosis. and the abnormal proliferation of smooth muscle cells in the pulmonary artery wall, which is characteristic of the pulmonary vascular structure. It is a severe, progressive, and life-threatening disease. Severe vascular stenosis in the lungs is very common. This creates pulmonary artery pressure. Such high pressure forces the heart to pump blood through the lungs for oxygenation. This makes it difficult. The heart struggles to pump against such high pressure, P Patients with AH suffer from extreme shortness of breath. Patients with PAH typically have a significant increase in PVR and This leads to a persistent increase in mPAP, which ultimately results in right ventricular failure and death. Patients diagnosed with PAH have a poor prognosis and similarly impaired quality of life. If the patient has IF, the average life expectancy is 2 to 5 years from the time of diagnosis if left untreated.

[0051] PAH is defined as a mean pulmonary artery pressure (PHA) above 25 mmHg at rest (or according to the latest updated guidelines). A reading above 20 mmHg on the line can be diagnosed based on normal pulmonary artery capillary wedge pressure. PAH can cause shortness of breath, dizziness, fainting, and other symptoms, all of which occur with exertion. It worsens. PAH can be a severe disease accompanied by significantly reduced exercise tolerance and heart failure. The two main types of PAH are idiopathic PAH (e.g., PAH for which the etiology has not been identified). AH) and hereditary PAH (e.g., BMPR2, ALK1, ENG, SMAD9, CA) Includes PAHs associated with mutations in V1, KCNK3, or EIF2AK4. In 70% of familial PAH cases, the mutation is located in the BMPR2 gene. Risk factors for the disease include a family history of PAH, drug and toxin use (e.g., methamphetamine). (or cocaine use), infectious diseases (e.g., HIV infection or schistosomiasis), cirrhosis of the liver, Congenital heart abnormalities, portal hypertension, pulmonary veno-occlusive disease, pulmonary capillary hemangioma, or connective tissue / This includes autoimmune disorders (e.g., scleroderma or lupus). PAH is a calcium channel Long-term responders to pulmonary blockers, clear characteristics of venous / capillary (PVOD / PCH) involvement, It may be associated with persistent PH in neonatal syndromes.

[0052] The terms used herein are generally used within the context of this disclosure and in the respective contexts in which they are used. In a specific context, they have their usual meanings in the art. The terms used hereto describe the compositions and methods of this disclosure, as well as the methods of preparing and using them. To provide additional guidance to the implementer when doing so, see below or elsewhere in this specification. The scope or meaning of any use of a term is not clear from the specific context in which it is used. It will become softer.

[0053] The term "sequence similarity" refers to the fact that all of its grammatical forms share a common evolutionary origin. Identity between nucleic acid sequences or amino acid sequences, which may or may not be present. Alternatively, it refers to the degree of agreement.

[0054] "Sequence identity percentage (%)" is the percentage of the reference polypeptide (or nucleotide) sequence that matches the reference polypeptide (or nucleotide) sequence. In contrast, to align the sequences and, if necessary, achieve the highest possible sequence identity percentage. After introducing a gap, any conservative substitution is not considered part of sequence identity, and the reference point Candidate sequences identical to amino acid residues (or nucleic acids) in a lipeptide (nucleotide) sequence. Defined as the percentage of amino acid residues (or nucleic acids) within the sequence. Alignment for the purpose of determining sex percentage is within the scope of the skills in this art. In various ways, for example, BLAST (Basic Local Alignment S search Tool), BLAST-2, ALIGN, ALIGN-2, Clusta publicly available software such as Omega or Megalign (DNASTAR) This can be achieved using readily available computer software. Those skilled in the art will find that... Any algorithm required to achieve maximum alignment across the entire length of the arrays being compared It is possible to determine the appropriate parameters for aligning the sequence, including the rhythm. In some embodiments, the value of amino acid (nucleic acid) sequence identity % is determined by a sequence comparison computer. - Generated using the ALIGN-2 program. ALIGN-2 sequence comparison computer The developer program was created by Genentech, Inc., and the source code The U.S. Copyright Office, Washington DC, 20559, has a user document It has been submitted together and is registered under U.S. Copyright Registration Number TXU510087. The ALIGN-2 program is developed by Genentech, Inc., South San Is it publicly available from Francisco, Calif., or is the source code available? It may be compiled from there. The ALIGN-2 program is a registered trademark of Digital UNIX. ) For use in UNIX® operating systems, including V4.0D It should be compiled for this purpose. All sequence comparison parameters are ALIGN-2 parameters. It is set by the program and does not change. Other factors used to determine sequence identity or homology. The algorithms include: Clustal Omega (http: / / www.ebi.ac.uk / Tools / msa / clustalo / ), LALIGN (http: / / www.ebi.ac.uk / Tools / psa / lalign / and also http: / / www.ebi.ac.uk / Tools / psa / lalign / nucleotide.html), FASTA (http: / / ww w.ebi.ac.uk / Tools / sss / fasta / ), SIM (http: / / web.expasy.org / sim / ) and EMB OSS Needle (https: / / www.ebi.ac.uk / Tools / psa / emboss_needle / ). In a preferred embodiment, the algorithm used to determine sequence identity is Clustal Omega.

[0055] "Agonize" refers, in all its grammatical forms, to activating a protein and / or gene (e.g., by activating or amplifying the gene expression of the protein or by inducing an inactive protein to become active), or to a process of increasing the activity of a protein and / or gene.

[0056] "Antagonize" refers, in all its grammatical forms, to inhibiting a protein and / or gene (e.g., by inhibiting or decreasing the gene expression of the protein or by inducing an active protein to become inactive), or to a process of decreasing the activity of a protein and / or gene.

[0057] The terms "about" and "approximately" throughout this specification and the claims When used in relation to a value, the interval of precision is known to a person skilled in the art and is acceptable to a person skilled in the art. It represents. Generally, such an accuracy interval is ±10%. Instead, and especially in biological systems In the stem, the terms "about" and "approximately" mean within one decimal place of a given value, preferably. This can mean a value that is ≤5 times, or more preferably, ≤2 times.

[0058] Numerical ranges disclosed herein include numbers that define the range.

[0059] The terms "one (a)" and "one (an)" depend on the context in which these terms are used. Unless explicitly indicated otherwise, it can refer to multiple things. "One (a)" (or "One The term (an)) and the phrases "one or more" and "at least one" The terms used herein may be used interchangeably. Furthermore, "and / or" When used herein, this refers to two or more designated characteristics or components. Each of these should be considered a specific disclosure, with or without the other. Therefore, the term "and / or" is used herein in a manner similar to "A and / or B." When used in a phrase, it means "A and B", "A or B", "A" (alone), and It is intended to include "B" (alone). Similarly, the term "and / or" means When used in phrases such as "A, B, and / or C", the following forms apply: A, B, and C;A, B, or C;A or C;A or B;B or C;A and C;A and B; B and C; A (alone); B (alone); and C (alone) each include This is intended to be the case.

[0060] Throughout this specification, the word "comprise" or "com" is used without exception. Variations such as "prises" or "comprising" are used in language This means the inclusion of the specified integer or group of integers, but excluding any other integer or group of integers. It will be understood that this will not happen.

[0061] 2. ActRII polypeptide In certain aspects, this disclosure relates to ActRII polypeptides and their use (e.g., To treat pulmonary arterial hypertension or one or more complications of pulmonary arterial hypertension, Regarding prevention or reducing the rate of progression and / or severity of the disease. When used in writing, the term "ActRII" refers to the type II activin receptor. This refers to the family of activin receptors, including type IIA (ActRIIA) and A Contains cutibin receptor type IIB (ActRIIB).

[0062] In certain embodiments, this disclosure relates to Sequence IDs 1, 2, 3, 23, 27, 30, and The amino acid sequence shown in any one of the 41 and at least 70%, 75%, 80%, 85% %, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95 They have amino acid sequences that are identical by %, 96%, 97%, 98%, 99%, or 100%. This disclosure relates to the ActRII polypeptide. In other embodiments, this disclosure is shown in SEQ ID NO: 31. The amino acid sequence is at least 70%, 75%, 80%, 85%, 86%, 87%, 88% %, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98 ActRII polypeptides having amino acid sequences that are %, 99%, or 100% identical. Relates to. As used herein, the term "ActRII" refers to the family of activin receptor type IIA (ActRIIA) proteins, the family of activin receptor type IIB (ActRIIB) proteins, or combinations and / or variants thereof. ActRII polypeptides can be derived from any species and can include variants derived from such ActRII proteins by mutagenesis or other modifications. References to ActRII are understood herein to refer to any one of the currently identified forms. Members of the ActRII family generally are transmembrane proteins composed of a ligand-binding extracellular domain that includes a cysteine-rich region, a transmembrane domain, and a cytoplasmic domain having putative serine / threonine kinase activity. The term ActRII polypeptide includes any naturally occurring polypeptide of an ActRII family member and any variant thereof (including mutants, fragments, fusions, and peptidomimetic forms) that retains useful activity. Examples of such variant ActRII polypeptides are provided throughout this disclosure as well as in International Patent Application Publication Nos. WO2006 / 012627, WO2007 / 062188, WO2008 / 097541, WO2010 / 151426, and WO2011 / 020045, which are incorporated herein by reference in their entirety. For all ActRII-related polypeptides described herein, amino acid numbering is provided below as human ActRII unless specifically specified otherwise. 指す。ActRIIポリペプチドは、任意の種に由来し得、突然変異誘発または他の改変によってそのようなActRIIタンパク質から誘導されたバリアントを含み得る。ActRIIへの言及は、本明細書では、現在特定されている形態のうちのいずれか1つへの言及であることが理解される。ActRIIファミリーのメンバーは、一般に、システインリッチ領域を含むリガンド結合細胞外ドメイン、膜貫通ドメイン、および推定セリン / トレオニンキナーゼ活性を有する細胞質ドメインから構成される膜貫通タンパク質である。 Relates to. As used herein, the term "ActRII" refers to the family of activin receptor type IIA (ActRIIA) proteins, the family of activin receptor type IIB (ActRIIB) proteins, or combinations and / or variants thereof. ActRII polypeptides can be derived from any species and can include variants derived from such ActRII proteins by mutagenesis or other modifications. References to ActRII are understood herein to refer to any one of the currently identified forms. Members of the ActRII family generally are transmembrane proteins composed of a ligand-binding extracellular domain that includes a cysteine-rich region, a transmembrane domain, and a cytoplasmic domain having putative serine / threonine kinase activity. The term ActRII polypeptide includes any naturally occurring polypeptide of an ActRII family member and any variant thereof (including mutants, fragments, fusions, and peptidomimetic forms) that retains useful activity. Examples of such variant ActRII polypeptides are provided throughout this disclosure as well as in International Patent Application Publication Nos. WO2006 / 012627, WO2007 / 062188, WO2008 / 097541, WO2010 / 151426, and WO2011 / 020045, which are incorporated herein by reference in their entirety. For all ActRII-related polypeptides described herein, amino acid numbering is provided below as human ActRII unless specifically specified otherwise. Relates to. As used herein, the term "ActRII" refers to the family of activin receptor type IIA (ActRIIA) proteins, the family of activin receptor type IIB (ActRIIB) proteins, or combinations and / or variants thereof. ActRII polypeptides can be derived from any species and can include variants derived from such ActRII proteins by mutagenesis or other modifications. References to ActRII are understood herein to refer to any one of the currently identified forms. Members of the ActRII family generally are transmembrane proteins composed of a ligand-binding extracellular domain that includes a cysteine-rich region, a transmembrane domain, and a cytoplasmic domain having putative serine / threonine kinase activity. The term ActRII polypeptide includes any naturally occurring polypeptide of an ActRII family member and any variant thereof (including mutants, fragments, fusions, and peptidomimetic forms) that retains useful activity. Examples of such variant ActRII polypeptides are provided throughout this disclosure as well as in International Patent Application Publication Nos. WO2006 / 012627, WO2007 / 0i2188, WO2008 / 097541, WO2010 / 151426, and WO2011 / 020045, which are incorporated herein by reference in their entirety. For all ActRII-related polypeptides described herein, amino acid numbering is provided below as human ActRII unless specifically specified otherwise. Relates to. As used herein, the term "ActRII" refers to the family of activin receptor type IIA (ActRIIA) proteins, the family of activin receptor type IIB (ActRIIB) proteins, or combinations and / or variants thereof. ActRII polypeptides can be derived from any species and can include variants derived from such ActRII proteins by mutagenesis or other modifications. References to ActRII are understood herein to refer to any one of the currently identified forms. Members of the ActRII family generally are transmembrane proteins composed of a ligand-binding extracellular domain that includes a cysteine-rich region, a transmembrane domain, and a cytoplasmic domain having putative serine / threonine kinase activity. The term ActRII polypeptide includes any naturally occurring polypeptide of an ActRII family member and any variant thereof (including mutants, fragments, fusions, and peptidomimetic forms) that retains useful activity. Examples of such variant ActRII polypeptides are provided throughout this disclosure as well as in International Patent Application Publication Nos. WO2006 / 012627, WO2007 / 062188, WO2008 / 097541, WO2010 / 151426, and WO2011 / 020045, which are incorporated herein by reference in their entirety. For all ActRII-related polypeptides described herein, amino acid numbering is provided below as human ActRII unless specifically specified otherwise. Relates to. As used herein, the term "ActRII" refers to the family of activin receptor type IIA (ActRIIA) proteins, the family of activin receptor type IIB (ActRIIB) proteins, or combinations and / or variants thereof. ActRII polypeptides can be derived from any species and can include variants derived from such ActRII proteins by mutagenesis or other modifications. References to ActRII are understood herein to refer to any one of the currently identified forms. Members of the ActRII family generally are transmembrane proteins composed of a ligand-binding extracellular domain that includes a cysteine-rich region, a transmembrane domain, and a cytoplasmic domain having putative serine / threonine kinase activity.

[0063] Relates to. As used herein, the term "ActRII" refers to the family of activin receptor type IIA (ActRIIA) proteins, the family of activin receptor type IIB (ActRIIB) proteins, or combinations and / or variants thereof. ActRII polypeptides can be derived from any species and can include variants derived from such ActRII proteins by mutagenesis or other modifications. References to ActRII are understood herein to refer to any one of the currently identified forms. Members of the ActRII family generally are transmembrane proteins composed of a ligand-binding extracellular domain that includes a cysteine-rich region, a transmembrane domain, and a cytoplasmic domain having putative serine / threonine kinase activity. The term ActRII polypeptide includes any naturally occurring polypeptide of an ActRII family member and any variant thereof (including mutants, fragments, fusions, and peptidomimetic forms) that retains useful activity. Examples of such variant ActRII polypeptides are provided throughout this disclosure as well as in International Patent Application Publication Nos. WO2006 / 012627, WO2007 / 062188, WO2008 / 097541, WO2010 / 151426, and WO2011 / 020045, which are incorporated herein by reference in their entirety. For all ActRII-related polypeptides described herein, amino acid numbering is provided below as human ActRII unless specifically specified otherwise. Relates to. As used herein, the term "ActRII" refers to the family of activin receptor type IIA (ActRIIA) proteins, the family of activin receptor type IIB (ActRIIB) proteins, or combinations and / or variants thereof. ActRII polypeptides can be derived from any species and can include variants derived from such ActRII proteins by mutagenesis or other modifications. References to ActRII are understood herein to refer to any one of the currently identified forms. Members of the ActRII family generally are transmembrane proteins composed of a ligand-binding extracellular domain that includes a cysteine-rich region, a transmembrane domain, and a cytoplasmic domain having putative serine / threonine kinase activity. The term ActRII polypeptide includes any naturally occurring polypeptide of an ActRII family member and any variant thereof (including mutants, fragments, fusions, and peptidomimetic forms) that retains useful activity. Examples of such variant ActRII polypeptides are provided throughout this disclosure as well as in International Patent Application Publication Nos. WO2006 / 012627, WO2007 / 062188, WO2008 / 097541, WO2010 / 151426, and WO2011 / 020045, which are incorporated herein by reference in their entirety. For all ActRII-related polypeptides described herein, amino acid numbering is provided below as human ActRII unless specifically specified otherwise. Relates to. As used herein, the term "ActRII" refers to the family of activin receptor type IIA (ActRIIA) proteins, the family of activin receptor type IIB (ActRIIB) proteins, or combinations and / or variants thereof. ActRII polypeptides can be derived from any species and can include variants derived from such ActRII proteins by mutagenesis or other modifications. References to ActRII are understood herein to refer to any one of the currently identified forms. Members of the ActRII family generally are transmembrane proteins composed of a ligand-binding extracellular domain that includes a cysteine-rich region, a transmembrane domain, and a cytoplasmic domain having putative serine / threonine kinase activity. The term ActRII polypeptide includes any naturally occurring polypeptide of an ActRII family member and any variant thereof (including mutants, fragments, fusions, and peptidomimetic forms) that retains useful activity. Examples of such variant ActRII polypeptides are provided throughout this disclosure as well as in International Patent Application Publication Nos. WO2006 / 012627, WO2007 / 062188, WO2008 / 097541, WO2010 / 151426, and WO2011 / 020045, which are incorporated herein by reference in their entirety. For all ActRII-related polypeptides described herein, amino acid numbering is provided below as human ActRII unless specifically specified otherwise. Relates to. As used herein, the term "ActRII" refers to the family of activin receptor type IIA (ActRIIA) proteins, the family of activin receptor type IIB (ActRIIB) proteins, or combinations and / or variants thereof. ActRII polypeptides can be derived from any species and can include variants derived from such ActRII proteins by mutagenesis or other modifications. References to ActRII are understood herein to refer to any one of the currently identified forms. Members of the ActRII family generally are transmembrane proteins composed of a ligand-binding extracellular domain that includes a cysteine-rich region, a transmembrane domain, and a cytoplasmic domain having putative serine / threonine kinase activity. The term ActRII polypeptide includes any naturally occurring polypeptide of an ActRII family member and any variant thereof (including mutants, fragments, fusions, and peptidomimetic forms) that retains useful activity. Examples of such variant ActRII polypeptides are provided throughout this disclosure as well as in International Patent Application Publication Nos. WO2006 / 012627, WO2007 / 062188, WO2008 / 097541, WO2010 / 151426, and WO2011 / 020045, which are incorporated herein by reference in their entirety. For all ActRII-related polypeptides described herein, amino acid numbering is provided below as human ActRII unless specifically specified otherwise. Relates to. As used herein, the term "ActRII" refers to the family of activin receptor type IIA (ActRIIA) proteins, the family of activin receptor type IIB (ActRIIB) proteins, or combinations and / or variants thereof. ActRII polypeptides can be derived from any species and can include variants derived from such ActRII proteins by mutagenesis or other modifications. References to ActRII are understood herein to refer to any one of the currently identified forms. Members of the ActRII family generally are transmembrane proteins composed of a ligand-binding extracellular domain that includes a cysteine-rich region, a transmembrane domain, and a cytoplasmic domain having putative serine / threonine kinase activity. Based on the numbering of the precursor protein sequence (SEQ ID NO: 1).

[0064] The standard human ActRII precursor protein sequence is as follows: [ka]

[0065] Signal peptides are indicated by a single underline; extracellular domains are indicated in bold. Possible endogenous N-linked glycosylation sites are indicated by double underlines.

[0066] The processed (mature) extracellular human ActRII polypeptide sequence is as follows: be: [ka]

[0067] The C-terminal "tail" of the extracellular domain is indicated by a single underline. The "tail" is deleted. The sequence (Δ15 sequence) is as follows: [ka]

[0068] The nucleic acid sequence encoding the human ActRII precursor protein is shown below (SEQ ID NO: 4) Nucleotides 159-1700 of the Genbank reference sequence NM_001616.4 As shown above, the signal sequence is underlined. [ka] [ka]

[0069] Nucleic acid encoding processed soluble (extracellular) human ActRII polypeptide The array is as follows: [ka]

[0070] ActRII is well-conserved among vertebrates, and the large elongation of the extracellular domain is , completely preserved. For example, Figure 2 compares various ActRIIA orthologues. This shows the multiple sequence alignment of the extracellular domain of human ActRIIA. Many of the ligands that bind to them are also highly conserved. Therefore, these alignments Therefore, important ligand-binding domains within ActRII are crucial for normal ActRII-ligand binding activity. In addition to predicting amino acid positions, it also exhibits normal ActRII-ligand binding activity. It is possible to predict amino acid positions that may allow substitution without modification. Therefore, an active human ActRII barrier, useful according to the method disclosed herein. The nucleotide polypeptide has no corresponding position in the ActRII sequence of another vertebrate. It may contain multiple amino acids, or the sequence may be that of a human or other vertebrate. It may also contain residues similar to those of the substance.

[0071] Amino acids of the extracellular domains of human ActRIIA and human ActRIIB The alignment of the acid sequence is shown in Figure 1. This alignment is for ActRII ligand. This shows the amino acid residues in both receptors that are thought to be in direct contact. For example, the complex ActR In structure II, the ActRIIA-ligand binding pocket is partially located at residues F31 and N3 3, N35, K38 to T41, E47, Y50, K53 to K55, R57, H58, F60, T62, K74, W78 to N83, Y85, R87, E92, and K94 We showed that it is defined by F101. Conservative mutations are permitted at these locations. It is expected that this will happen.

[0072] While not intended to be limiting, the following example defines this active ActRII variant. The approach is shown. As illustrated in Figure 2, F13 in the human extracellular domain is Ov is aries (sequence number 7), Gallus gallus (sequence number 10), Bo s Taurus (SEQ ID NO: 36), Tyto alba (SEQ ID NO: 37), and My In ActRIIA of otis davidii (sequence number 38), the values ​​are Y, F, and W. This indicates that aromatic residues containing , and Y are acceptable at this position. Human extracellular domain Q24 in Bos Taurus is R in ActRIIA, and D, R, This indicates that charged residues including K, H, and E are acceptable at this position. (Human extracellular domain) In the context of the S95, the ActR of Gallus gallus and Tyto alba In IIA, it is F, and this region is E, D, K, R, H, S, T, P, G, Y, etc. Allows for a wide variety of changes, including polar residues and possibly hydrophobic residues such as L, I, or F. This indicates that it is acceptable. E52 in the human extracellular domain is A of Ovis aries. In ctRIIA, D is present, and acidic residues including D and E are acceptable at this position. This indicates that P29 in the human extracellular domain is relatively unconserved, and Ov is aries as S in ActRIIA, and Myotis david In ActRIIA of ii, it appears as L, and therefore, essentially any amino acid, This position should be acceptable.

[0073] Furthermore, as discussed above, ActRII proteins have structural / functional characteristics. From this perspective, particularly with respect to ligand binding, it is characterized in the field of [Attisano et al. (1992) Cell 68(1):97-108;Greenwald et al. (1999) Nature Struc tural Biology 6(1): 18-22;Allendorph et al. (2006) PNAS 103(20: 7643-7 648; Thompson et al. (2003) The EMBO Journal 22(7): 1555-1566; and U.S. Patent No. 7,709,605, No. 7,612,041, and No. 7,842, [Issue 663] For example, define a known structural motif as the three-finger toxin fold. This is important for ligand binding by type I and type II receptors, respectively. By conserved cysteine ​​residues located in variable positions within the extracellular domain of the monomeric receptor [Greenwald et al. (1999) Nat Struct Biol 6:18-22; and Hi [nck (2012) FEBS Lett 586:1860-1870]. In addition to the teachings herein, see these references. The present invention relates to ActRI that possess one or more desired activities (e.g., ligand-binding activity). Provide ample guidance on how to construct I variants.

[0074] For example, defining a known structural motif as the three-finger toxin fold is , important for ligand binding by type I and type II receptors, and each monomeric receptor It is formed by conserved cysteine ​​residues located in variable positions within the extracellular domain of the cell. [Greenwald et al. (1999) Nat Struct Biol 6:18-22; and Hinck (2012] [FEBS Lett 586:1860-1870]. Therefore, the outermost layer of these conserved cysteine The core ligand-binding domain of human ActRII, whose boundaries are defined by Sequence ID No. 1 This corresponds to positions 30-110 of the (ActRII precursor). Therefore, these cysteines Amino acids adjacent to the core sequence that defines the boundary are structurally less ordered and are not necessarily ligands. Without changing the bond, approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 at the N-terminus. , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, or 29 residues, and approximately 1, 2, 3, 4, 5, 6 at the C-terminus. 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 2 Residues 1, 22, 23, 24, or 25 can be truncated. Exemplary Ac Examples of truncation of the extracellular domain of tRII include SEQ ID NOs: 2 and 3. .

[0075] Therefore, the general formula for the active portion of ActRII (e.g., ligand binding) is: A poly(1) containing 30-110 amino acids, essentially composed of them, or consisting of them. It is a peptide. Therefore, ActRII polypeptide is, for example, the amino acid of SEQ ID NO: 1. Start with a residue corresponding to any one of amino acids 21-30 (for example, amino acids 21, 22) Start with one of the following numbers: 23, 24, 25, 26, 27, 28, 29, or 30. ), terminates at a position corresponding to any one of amino acids 110-135 of sequence number 1 (e.g. For example, amino acids 110, 111, 112, 113, 114, 115, 116, 117, 1 18, 119, 120, 121, 122, 123, 124, 125, 126, 127, 1 One of the following: 28, 129, 130, 131, 132, 133, 134, or 135 (Ends with) A portion of ActRII and at least 70%, 75%, 80%, 85%, 86% %, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96 It may contain amino acid sequences that are identical by %, 97%, 98%, 99%, or 100%, or It can essentially become, or may become from. Another example is sequence number 1, part 2. 1-30 (for example, amino acids 21, 22, 23, 24, 25, 26, 27, 28, 29, Or start with any one of 30), 22-30 (for example, amino acids 22, 23, (Start with one of the following: 24, 25, 26, 27, 28, 29, or 30), 23 ~30 (for example, amino acids 23, 24, 25, 26, 27, 28, 29, or 30) (Start with one off), 24-30 (for example, amino acids 24, 25, 26, 27, 2) Starting from a position selected from (starting from one of 8, 29, or 30), Column number 1, 111-135 (for example, amino acids 111, 112, 113, 114, 115) , 116, 117, 118, 119, 120, 121, 122, 123, 124, 125 , 126, 127, 128, 129, 130, 131, 132, 133, 134, or (ends with one of 135), 112-135 (for example, amino acids 112, 113) , 114, 115, 116, 117, 118, 119, 120, 121, 122, 123 , 124, 125, 126, 127, 128, 129, 130, 131, 132, 133 , ending with either 134 or 135), 113~135 (for example, amino Acids 113, 114, 115, 116, 117, 118, 119, 120, 121, 122 , 123, 124, 125, 126, 127, 128, 129, 130, 131, 132 (ends with one of 133, 134, or 135), 120-135 (for example) , Amino acids 120, 121, 122, 123, 124, 125, 126, 127, 128 Ends with one of the following: 129, 130, 131, 132, 133, 134, or 135. (to finish), 130-135 (for example, amino acids 130, 131, 132, 133, 134) (ends with either 1, or 135), 111-134 (for example, amino acid 110 , 111, 112, 113, 114, 115, 116, 117, 118, 119, 120 , 121, 122, 123, 124, 125, 126, 127, 128, 129, 130 (ends with one of 131, 132, 133, or 134), 111-133 (For example, amino acids 110, 111, 112, 113, 114, 115, 116, 117) , 118, 119, 120, 121, 122, 123, 124, 125, 126, 127 (Ends with one of the following: 128, 129, 130, 131, 132, or 133) , 111~132 (for example, amino acids 110, 111, 112, 113, 114, 115 , 116, 117, 118, 119, 120, 121, 122, 123, 124, 125 Ends with one of the following: 126, 127, 128, 129, 130, 131, or 132. (to complete), or 111-131 (for example, amino acids 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, or 131 Examples of structures that terminate at a position selected from (terminating at one) are listed. Riant, in particular, the corresponding part of Sequence ID No. 1 and at least 70%, 75%, 80%, 85% %, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95 Amino acid sequences having %, 96%, 97%, 98%, 99%, or 100% identity It is intended to include, essentially become, or consist of. In one embodiment, the ActRII polypeptide has amino acids 30-110 of SEQ ID NO: 1 At least 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90% , 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or It may contain, or essentially be, a polypeptide that is 100% identical to, or It can consist of these. If necessary, the ActRII polypeptide contains amino acid 3 of SEQ ID NO: 1. 0-110 and at least 70%, 75%, 80%, 85%, 86%, 87%, 88%, 8 9%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 9 They are 9% or 100% identical, and in the ligand-binding pockets, 1, 2, 5, 10 or It comprises a polypeptide containing 15 or fewer conservative amino acid changes. In some embodiments, A The ctRII polypeptide is part of a homodimeric protein complex.

[0076] In certain embodiments, this disclosure includes fragments, functional variants, and modified forms thereof. Contains ActRII polypeptide (e.g., ActRIIA polypeptide, ActRIIB polypeptide) Polypeptides, or combinations thereof, and their use (for example, pulmonary arterial hypertension) Related to treating, preventing, or reducing. Preferably ActRII polypeptide The cytoplasm is soluble (e.g., the extracellular domain of ActRII). In some embodiments, ActRII polypeptide contains one or more GDF / BMP ligands [e.g., G DF11, GDF8, Activin A, Activin B, GDF3, BMP4, BMP6, B Inhibiting MP10 and / or BMP15 (e.g., Smad signaling) In some embodiments, the ActRII polypeptide is one or more GDF / BMP Ligands [e.g., GDF11, GDF8, activin A, activin B, GDF3, B] Combine into MP4, BMP6, BMP10, and / or BMP15. Some implementations In this state, the ActRII polypeptide of this disclosure corresponds to amino acids 21-30 of SEQ ID NO: 1. Start from the residue (for example, amino acids 21, 22, 23, 24, 25, 26, 27, 2 (Starting with one of 8, 29, or 30), amino acids 110-13 of SEQ ID NO: 1 It terminates at a position corresponding to any one of the 5 (for example, amino acids 110, 111, 112) , 113, 114, 115, 116, 117, 118, 119, 120, 121, 122 , 123, 124, 125, 126, 127, 128, 129, 130, 131, 132 (Ending with one of 133, 134, or 135) Part of ActRII and a small At least 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 1 It contains, essentially consists of, or is composed of an amino acid sequence that is 00% identical. In some embodiments, the ActRII polypeptide is amino acids 30-11 of SEQ ID NO: 1. 0 and at least 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 9 0%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, It contains, consists of, or is essentially identical to an amino acid sequence. In a particular embodiment, the ActRII polypeptide is the amino acid of SEQ ID NO: 1. 21-135 and at least 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, It contains, consists of, or is 99% or 100% identical amino acid sequences. Essentially, it becomes. In some embodiments, the ActRII polypeptide is sequence numbers 1, 2 , one of the amino acid sequences 3, 23, 27, 30, and 41 and at least 70% 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92% , 93%, 94%, 95%, 97%, 98%, 99%, or 100% identical amino acids It contains, consists of, or is essentially composed of an acid sequence.

[0077] In some embodiments, the ActRII polypeptide has a small amino acid sequence from SEQ ID NO: 23. At least 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 97%, 98%, 99%, or 100% It contains, consists of, or is essentially a single amino acid sequence. In an alternative embodiment, the ActRII polypeptide (e.g., SEQ ID NO: 23) has a C-terminal ri The lysine may be absent. In some embodiments, ActRII lacks the C-terminal lysine. The polypeptide is sequence number 41. In some embodiments, the ActRII polypeptide is used. This is the amino acid sequence of SEQ ID NO: 41 and at least 70%, 75%, 80%, 85%, and 86% 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 97% , containing or consisting of amino acid sequences that are 98%, 99%, or 100% identical, Or essentially become so. In some embodiments, the patient receives the amino acid combination of SEQ ID NO: 23. Columns and at least 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 9 0%, 91%, 92%, 93%, 94%, 95%, 97%, 98%, 99%, or 10 A contains, consists of, or is essentially derived from an amino acid sequence that is 0% identical. The patient is administered ctRII polypeptide. In some embodiments, the patient is given SEQ ID NO: 41 Mino acid sequence and at least 70%, 75%, 80%, 85%, 86%, 87%, 88%, 8 9%, 90%, 91%, 92%, 93%, 94%, 95%, 97%, 98%, 99%, It contains, consists of, or is essentially identical to an amino acid sequence. The patient is administered the ActRII polypeptide, which becomes SEQ ID NO: The combination of 23 and SEQ ID NO: 41 is administered.

[0078] In certain aspects, this disclosure refers to ActRII polypeptides (e.g., ActRII Regarding polypeptides, ActRIIB polypeptides, or combinations thereof. Partial implementation In terms of form, the ActRII trap of this disclosure is a variant ActRII polypeptide, One or more modified ligand bindings from the corresponding wild-type ActRII polypeptide. ActRII polypeptides (e.g., "wild-type" or unmodified ActRII) are made to be active. One extracellular domain (also called the ligand-binding domain) of the tRII polypeptide or including multiple mutations (e.g., addition, deletion, substitution, and combination thereof of amino acids) ActRII polypeptide variant (for example, ActRIIA polypeptide, Act RIIB polypeptide, or a combination thereof. In preferred embodiments, the present disclosure The riant ActRII polypeptide differs slightly from the corresponding wild-type ActRII polypeptide. It retains at least one similar activity. For example, a preferred ActRII polypeptide is G It binds to DF11 and / or GDF8 and inhibits their function (e.g., antagonistic (To do so). In some embodiments, the ActRII polypeptide of this disclosure is GDF / BMP One or more ligands [e.g., GDF11, GDF8, activin A, activin [B, GDF3, BMP4, BMP6, BMP10, and / or BMP15] It binds to and inhibits one or more ActRII ligands. Therefore, this disclosure relates to one or more ActRII ligands. This provides an ActRII polypeptide having modified binding specificity.

[0079] To explain, activin (activin A or activin B), especially activin A GDF11 and / or G to one or more ActRII-binding ligands such as One or more mutations that increase the selectivity of the modified ligand-binding domain of DF8 Different types may be selected. If necessary, the modified ligand-binding domain will be used with the wild-type ligand. Compared to the ratio for binding domains, at least 2, 5, 10, 20, 50, and 100 times, Or even 1000 times higher, K for activin binding d GDF11 and / or This is about K for GDF8 bonds. d It has a ratio to . Modified ligand as needed. The binding domain has at least 2, 5, 10, and 20 more binding domains compared to the wild-type ligand-binding domain. IC for activin inhibition is 50, 100 times, or even 1000 times higher. 50 IC regarding the inhibition of GDF11 and / or GDF8 50 It has a ratio to [the specified value]. If necessary, the modified ligand-binding domain is used for IC (Impulse Control) for activin inhibition. 50 1 / 2, 1 / 5, 1 / 10, 1 / 20, 1 / 50, 1 / 100, or Furthermore, ICs with a size of less than 1 / 1000th 50 This inhibits GDF11 and / or GDF8.

[0080] In certain embodiments, the present disclosure modifies the glycosylation of a polypeptide. ActRII polypeptide (e.g., ActRIIA polypeptide, ActRIIB polypeptide) The aim is to induce specific mutations in peptides (or combinations thereof). Such mutations are One or more glycosylated sites, such as O-linked or N-linked glycosylated sites, are introduced. Alternatively, it may be selected to be excluded. The asparagine-linked glycosylation recognition site is generally In addition, the tripeptide sequence is specifically recognized by the appropriate cellular glycosylation enzyme. Lagin-X-threonine or asparagine-X-serine (where "X" is any a) It contains (which is a methyl amino acid). The modification also involves adding one or more serine to the polypeptide sequence. Alternatively, it may be prepared by the addition or substitution of threonine residues (O-linked glycan). (Due to the cosylation site) Either the first or third amino acid position of the glycosylation recognition site or various amino acid substitutions or deletions in both (and / or amino acid deletions at the second position) Loss of this result in nonglycosylation of the modified tripeptide sequence. Another way to increase the number of carbohydrate moieties is through the chemical addition of glycosides to polypeptides. or by enzymatic coupling. Depending on the coupling method used, the sugar is (a) a (b) Ruginine and histidine; (c) Free carboxyl group; (c) Cysteine, etc. Free sulfhydryl group; (d) serine, threonine or hydroxyproline Which free hydroxyl group; (e) phenylalanine, tyrosine or tryptophan Aromatic residues such as (f) may be bonded to the amide group of glutamine. The removal of one or more carbohydrate portions present on the ptide can be done chemically and / or fermented. It may be achieved organically. Chemical deglycosylation is, for example, the compound trifluoromethane. This may involve exposure of polypeptides to sulfonic acid or equivalent compounds. With the acid sequence intact, the linked sugar (N-acetylglucosamine or N-acetyl It causes the cleavage of most or all sugars except for galactosamine in polypeptides. The enzymatic cleavage of the carbohydrate portion is described by Thotakura et al. [Meth. Enzymol. (1987)]. As described in [138:350], various endoglycosidases and exoglycosidases This can be achieved by using cosidase. Mammalian, yeast, insect, and plant cells All of these are different glycosylation patterns that can be influenced by the amino acid sequence of the peptide. Since it may be possible to introduce this, the polypeptide sequence may be adapted to the type of expression system used as needed. It may be adjusted accordingly. Generally, the polypeptides of this disclosure for use in humans are HE Mammalian cell lines that provide suitable glycosylation, such as K293 or CHO cell lines. While it may be possible to express the gene using this method, other mammalian cell lines expressing the gene are expected to be equally useful.

[0081] This disclosure relates to mutants, particularly ActRII polypeptides (e.g., ActRII polypeptides). Combinatorial peptides (lipeptides, ActRIIB polypeptides, or combinations thereof) Further attempts are made to create sets of mutants and truncation mutants. The pool of microbial mutants includes functionally active mutants (e.g., GDF / BMP-ligan). It is particularly useful for identifying the ActRII sequence (combinatorial linkage). The purpose of screening the library is, for example, to find altered pharmacokinetics or altered By creating polypeptide variants with modified properties such as ligand binding, It is possible. We offer various screening assays below, and such assays are , can be used to evaluate variants. For example, the ActRII variant is one Alternatively, multiple GDF / BMP ligands [e.g., GDF11, GDF8, activin A] , activin B, GDF3, BMP4, BMP6, BMP10, and / or BMP1 5) Ability to bind to ActRII polypeptide and its heteromultimers, GDF / B The ability to prevent the binding of MP ligands, and / or by GDF / BMP ligands. The ability to interfere with the resulting signaling may be screened.

[0082] ActRII polypeptide (e.g., ActRIIA polypeptide, ActRIIB polypeptide) The activity of the lipeptide (or a combination thereof) or its variant is also cell-based. It may be tested in a sieve or in vivo assay. For example, pulmonary arterial hypertension The effect of ActRII polypeptide on the expression of genes involved in the pathogenesis of hypertension was evaluated. This may be done by adding one or more recombinant ligand proteins as needed [e.g.] GDF11, GDF8, Activin A, Activin B, GDF3, BMP4, BMP 6. This may also be done in the presence of BMP10 and / or BMP15, and the cells are Ac To produce tRII polypeptide and, if necessary, GDF / BMP ligands. It may also be lanced. Similarly, ActRII polypeptide can be used in mice or other It may be administered to animals, and its effect on the pathogenesis of pulmonary arterial hypertension has been recognized in the art. It may be evaluated using known methods. Similarly, ActRII polypeptides The activity of this variant is in blood cell progenitor cells, and in relation to the growth of these cells For any effect, see, for example, the assays described herein and in the art. The SMAD-responsive reporter gene may be tested by a general knowledge assay. Even if used in such cell systems, the effect on downstream signaling can be monitored. good.

[0083] Reference ActRII polypeptide (e.g., ActRIIA polypeptide, ActRII Compared to B polypeptides (or combinations thereof), this results in increased selectivity or generally increased efficacy. It is possible to create combinatorial variants that possess force. When expressed from recombinant DNA constructs, the gene is used in gene therapy protocols. It is possible. Similarly, mutagenesis can induce the corresponding unmodified ActRII polypeptide. This allows for the creation of variants with dramatically different intracellular half-lives. For example, The modified protein may cause proteolysis, destruction, or other damage to the unmodified polypeptide. Otherwise, it will be more stable or less stable to other cellular processes that result in inactivation. It can be either one. Such variants and the genes that encode them By utilizing this, the half-life of polypeptides can be modulated, thereby enabling polypeptide complexes. The level can be changed. For example, a shorter half-life produces a more transient biological effect. It can be made to do so, and if it is part of an inducible expression system, recombinant polypeptide complex within the cell This could allow for tighter control at the systemic level. In Fc fusion proteins, mutations can be controlled by phosphorus. In the Ker (if any) and / or Fc portion, the ActRII polypeptide is generated. The half-life may be changed.

[0084] The combinatorial library contains at least one potential ActRII polypeptide sequence. Degenerate libraries of genes encoding polypeptide libraries that each contain a portion of It may be generated as a Lie. For example, a nucleotide encoding a potential ActRII. A degenerate set of sequences, as individual polypeptides, or instead, as a larger fusion chain To make them expressible as a set of proteins (for example, for phage display), A mixture of synthetic oligonucleotides can be enzymatically ligated into a gene sequence. Cut.

[0085] It is possible to create a library of potential homologs from degenerate oligonucleotide sequences. There are many methods. Chemical synthesis of degenerate gene sequences can be performed using an automated DNA synthesizer. This process is then completed, and the synthetic gene is ligated into a suitable vector for expression. This can be done. The synthesis of degenerate oligonucleotides is well known in the art. [Nara ng, SA (1983) Tetrahedron 39:3;Itakura et al. (1981) Recombinant DNA, Proc. 3rd Cleveland Sympos. Macromolecules, ed. AG Walton, Amsterdam: Elsevier pp273-289;Itakura et al. (1984) Annu. Rev. Biochem. 53:323; Itakura et al. (1984) Science 198:1056; and Ike et al. (1983) Nucleic [Acid Res. 11:477]. Such techniques have been used in the directional evolution of other proteins. [Scott et al., (1990) Science 249:386-390; Roberts et al. (1992 ) PNAS USA 89:2429-2433;Devlin et al. (1990) Science 249: 404-406;Cwi rla et al., (1990) PNAS USA 87: 6378-6382; and U.S. 5,223, [Nos. 409, 5,198,346, and 5,096,815].

[0086] Alternatively, combinatorial libraries can be created using other forms of mutagenesis. This is possible. For example, alanine scanning mutagenesis [Ruf et al. (1994)]. Biochemistry 33:1565-1572;Wang et al. (1994) J. Biol. Chem. 269:3095- 3099;Balint et al. (1993) Gene 137:109-118;Grodberg et al. (1993) Eur J. Biochem. 218:597-601;Nagashima et al. (1993) J. Biol. Chem. 268: 2888-2892; Lowman et al. (1991) Biochemistry 30:10832-10838; and Cunningh am et al. (1989) Science 244:1081-1085], Linker Scanning Mutagenesis [Gustin et al. (1993) Virology 193:653-660; and Brown et al. (1992) Mol. Cell Biol. 12:2644-2652; McKnight et al. (1982) Science 232:316] Therefore, by saturated mutagenesis [Meyers et al., (1986) Science 232:613]; PCR mutagenesis [Leung et al. (1989) Method Cell Mol Biol 1:11-19] Therefore; or random mutagenesis including chemical mutagenesis [Miller et al. (19 92) A Short Course in Bacterial Genetics, CSHL Press, Cold Spring Har Bor, NY; and Greener et al. (1994) Strategies in Mol Biol 7:32-34] By using and screening, for example, the ActRII polypeptide of this disclosure (For example, ActRIIA polypeptide, ActRIIB polypeptide, or a combination thereof) Linker scanning mutations can be created and isolated from the library. Mutagenesis induction, particularly linker scanning mutagenesis in combinatorial settings, is a key aspect of the process. This is an attractive method for identifying the catech (bioactive) form of ActRII polypeptide. ru.

[0087] Combinatorial libraries created by point mutation and truncation In order to screen for gene products, and in that regard, having certain properties This technology is a broad range of techniques for screening cDNA libraries of gene products. It is publicly known in the field. Such techniques generally involve ActRII polypeptides (e.g.) For example, ActRIIA polypeptide, ActRIIB polypeptide, or a combination thereof. Rapid screening of gene libraries created by combinatorial mutagenesis It would be adaptable for screening large gene libraries. The most widely used technique typically involves creating a replicable expression vector into which the gene is replicated. Cloning the vector and then using the resulting vector library to select appropriate cells The conversion and detection of the desired activity is performed by encoding the gene in which the product was detected. Under conditions that facilitate the relatively easy isolation of the gene, combinatorial genes are expressed. This includes the following. Preferred assays include ligands [e.g., GDF11, GDF8, etc.]. Cutivin A, Activin B, GDF3, BMP4, BMP6, BMP10, and / or Examples include BMP15 binding assays and / or ligand-mediated cell signaling assays. It can be done.

[0088] As can be recognized by those skilled in the art, the mutations, variants, or specified herein are not the same as those described herein. Most of the modifications described are at the nucleic acid level, or in some cases, post-translational modifications. They can be produced by chemical synthesis. Such techniques are well known in the art. A portion of this is described herein. In part, this disclosure is provided herein. Guide for creating and using other variant ActRII polypeptides within the range ActRII polypeptides that can be used as a prop (for example, ActRII polypeptides) Functional active portion (fragment) of a lipeptide, ActRIIB polypeptide, or a combination thereof. ) and identify variants.

[0089] In a particular embodiment, the functionally active fragment of the ActRII polypeptide of this disclosure is A Recombinantly produced poly from the corresponding fragment of nucleic acid encoding the ctRII polypeptide It can be obtained by screening peptides. In addition, the fragments are conventional Known techniques in the art, such as Merrifield solid-phase f-Moc or t-Boc chemistry. It can be chemically synthesized using the method. Fragments can be produced (recombinantly or chemically combined). (by composition), test the ActRII receptor and / or one or more ligans [For example, GDF11, GDF8, activin A, activin B, GDF3, BMP4] Antagonists (inhibitors) of BMP6, BMP10, and / or BMP15 These peptidyl fragments that can function in this way can be identified.

[0090] In certain embodiments, the ActRII polypeptide of the present disclosure (e.g., ActRII A polypeptide, ActRII polypeptide, or a combination thereof, is ActRII In addition to any naturally occurring post-translational modifications in the lipeptide, further post-translational modifications are included. It may be. Such modifications are not limited to acetylation, calcification, etc. These include boxylation, glycosylation, phosphorylation, lipidation, and acylation. ActRII polypeptide is made from polyethylene glycol, lipids, polysaccharides or monosaccharides, It may also contain non-amino acid elements such as phosphates. Ligand trap The effect of such non-amino acid elements on polypeptide functionality is also seen in other ActR The II variant may be tested as described herein. When lipeptides are produced in cells by cleaving the nascent form of polypeptides, Post-translational processing is also important for the accurate folding and / or function of proteins. This may be important for different cells (e.g., CHO, HeLa, MDCK, 293, WI3). 8. NIH-3T3, or HEK293) is a specific post-translational activity. It possesses cellular mechanisms and characteristic mechanisms, and accurately modifies ActRII polypeptides. It may be chosen to ensure transformation and processing.

[0091] In certain embodiments, the ActRII polypeptide of this disclosure (e.g., ActRII polypeptide) Lipeptides, ActRIIB polypeptides, or combinations thereof are ActRII polypeptides. At least a portion (domain) of the petit and one or more heterogeneous portions (domains) It contains a fusion protein. Known examples of such fusion domains are limited to It is not a polyhistidine, but rather polyhistidine, Glu-Glu, glutathione S-transfer GST, thioredoxin, protein A, protein G, immunoglobulin heavy chain constant state Examples include Fc region, maltose-binding protein (MBP), or human serum albumin. The fusion domain may be selected to confer the desired properties. For example, some The fusion domain is particularly useful for isolating fusion proteins by affinity chromatography. It is useful for affinity purification purposes. Glutathione, amylase, and Affinity chromatography of nickel or cobalt-conjugated resins, etc. A relevant matrix is ​​used for the fee. Many of such matrices are Pharmacia GST purification system and (HIS6) fusion partner Uses the QIAexpress (trademark) system (Qiagen) in "kit" form. It is possible to use it. Another example is that the fusion domain facilitates the detection of ActRII polypeptides. They may be selected to advance. Examples of such detection domains include various fluorescence Proteins (e.g., GFP) and typically short peptides for which specific antibodies are available. One example is the "epitope tag," which is a sequence. Specific monoclonal antibodies are readily available. Well-known epitope tags that can be used include FLAG and influenza virus hemagglutination. Examples include the HA (HA) and c-myc tags. In some cases, the fused domain is related to The linked proteases partially digest the fusion protein, thereby recombining them. This allows the release of proteins such as factor Xa or thrombin. It has a rotease cleavage site. Subsequently, the released protein is subjected to subsequent chromatography. It can be isolated from the fusion domain by Phi-isolation. Other types may be selected. Fusion domains include multimerization domains (e.g., dimerization, tetramerization), and, for example, immunoglobulins. Functional domains containing constant domains (e.g., Fc domains) derived from epidemic globulin (additional) This includes (conferring biological functions to...).

[0092] In certain embodiments, the ActRII polypeptide of this disclosure (e.g., ActRII polypeptide) Lipeptides, ActRIIB polypeptides, or combinations thereof, are polypeptides that are "safe It contains one or more modifications that can be "stabilized". "Stabilized" means that this This is due to reduced drug breakdown, decreased renal clearance, or other pharmacokinetic effects. Whether or not, any increase in in vitro half-life, serum half-life This also means that, for example, such modifications enhance the shelf life of the polypeptide. To enhance the circulating half-life of plutide and / or reduce the proteolysis of polypeptides. Such stabilizing modifications are not limited to, but include fusion proteins. (For example, a fusion protein containing an ActRII polypeptide domain and a stabilizer domain) (including quality), modification of glycosylation sites (e.g., glycosylation to polypeptides of the present disclosure) This includes the addition of parts, and modification of the carbohydrate portion (for example, from the polypeptide of this disclosure) Examples include the removal of the carbohydrate portion. When used herein, "stabilizer Domaine The term "n" refers to a fusion domain (e.g., immunoglobulin) in the case of fusion proteins. This refers not only to the robulin Fc domain, but also to non-protein modifications such as the carbohydrate portion. Or it may also include non-protein components such as polyethylene glycol. In the application form, the ActRII polypeptide contains heterogeneous domains that stabilize the polypeptide (" Stabilizer domain), preferably, increases the stability of polypeptides in vivo. It is fused with a heterogeneous domain. (e.g., the constant domain of immunoglobulins, the Fc domain) Fusion with [this substance] has been shown to confer desirable pharmacokinetic properties to a wide range of proteins. It is knowledge. Similarly, fusion with human serum albumin can confer desirable properties. ru.

[0093] Native amino acid sequences that can be used for the Fc portion (G1Fc) of human IgG1 An example is shown below (Sequence ID 11). The dotted underline indicates the hinge area, and the solid underline indicates the natural Indicates the location of the existing variant. In part, this disclosure relates to Sequence ID No. 11 and 70% 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92% 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity A polypeptide containing, essentially having, or consisting of an amino acid sequence having Provides cydides. The naturally occurring variant of G1Fc is used in SEQ ID NO: 11. According to the numbering system, this would include E134D and M136L (Unip (See rot P01857). [ka]

[0094] If necessary, the IgG1 Fc domain can be Asp-265, Lysine 322, and A It has one or more mutations in residues such as sn-434. In certain cases, Mutations containing one or more of these mutations (e.g., the Asp-265 mutation) The somatic IgG1 Fc domain is reduced in its ability to reach the Fcγ receptor compared to the wild-type Fc domain. It has the ability to bind. In other cases, one or more of these mutations (e.g., As The mutant Fc domain with the n-434 mutation is the wild-type IgG1 Fc domain. Compared to [another substance], it has increased binding ability to MHC class I-related Fc receptors (FcRNs). .

[0095] Native amino acid sequences that can be used for the Fc portion (G2Fc) of human IgG2 An example is shown below (Sequence ID 12). The dotted underline indicates the hinge region, and the double underline indicates the arrangement. This indicates the location where database inconsistencies exist (according to UniProt P01859). ). In part, this disclosure relates to Sequence ID No. 12 and 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, It contains an amino acid sequence having 97%, 98%, 99%, or 100% identity, or Provides a polypeptide that is essentially derived from or composed of. [ka]

[0096] Here are two examples of amino acid sequences that could be used for the Fc portion (G3Fc) of human IgG3. As shown below, the hinge region in G3Fc can be up to four times longer than in other Fc chains. It contains three identical 15-residue segments that precede a similar 17-residue segment. The first G3Fc sequence shown below (SEQ ID NO: 13) is a single 15-residue segment. While it contains a short hinge region consisting of a , the second G3Fc sequence (SEQ ID NO: 14) Includes the entire hinge region. In each case, the dotted underline indicates the hinge region, and the solid underline indicates the hinge region. The lines indicate locations with naturally occurring variants according to UniProt P01859. In part, this disclosure relates to Sequence IDs 13 and 14 and 70%, 75%, 80%, and 85%. 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95% , containing amino acid sequences having 96%, 97%, 98%, 99%, or 100% identity The present invention provides polypeptides that are essentially derived from or composed of thereof. [ka]

[0097] Naturally occurring variants in G3Fc (e.g., Uniprot P01860) (See reference) When converted to the numbering system used in Sequence ID No. 13 , E68Q, P76L, E79Q, Y81F, D97N, N100D, T124A, S Including 169N, S169del, and F221Y, this disclosure is one of these variations or It provides a fusion protein containing multiple G3Fc domains. In addition, it provides a human immunofusion protein. The globulin IgG3 gene (IGHG3) is characterized by different hinge lengths. It exhibits polymorphism [see Uniprot P01859]. Specifically, Varian WIS lacks most of the V region and all of the CH1 region. This is due to the hinge region. In addition to the normally present 11th position, it has an extra interchain disulfide bond at the 7th position. ZUC lacks most of the V region, all of the CH1 region, and part of the hinge. The OMM may represent an allele or another gamma chain subclass. This disclosure refers to these Further fusion proteins containing a G3Fc domain with one or more variants To provide.

[0098] Native amino acid sequences that can be used for the Fc portion (G4Fc) of human IgG4 An example is shown below (Sequence ID 15). The dotted underline indicates the hinge area. In part, this disclosure is , Sequence ID 15 and 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, Or it contains, or is essentially derived from, an amino acid sequence that has 100% identity, It provides polypeptides consisting of it. [ka]

[0099] Various manipulated mutations in the Fc domain result in the G1Fc sequence (SEQ ID NO: 11). Regarding the similar mutations in G2Fc, G3Fc, and G4Fc presented herein, The difference can be derived from their alignment with G1Fc in Figure 4. Equivalent Due to the hinge length, similar Fc position based on isotype alignment (Figure 4) The positions have different amino acid numbers at array numbers 11, 12, 13, 14, and 15 . If the numbering encompasses the entire IgG1 heavy chain constant domain as in the Uniprot database (consisting of C H 1, hinge, C H 2, and C H 3 regions), it can be understood that a given amino acid position in the immunoglobulin sequence consisting of the hinge, C H 2, and C H 3 regions (e.g., array numbers 11, 12, 13, 14, and 15) is specified by a different number than the same position. For example, the correspondence between the human G1Fc sequence (array number 11), the human IgG 1 heavy chain constant domain (Uniprot P01857), and selected C 3 positions in the human IgG1 heavy chain is as follows. H

[0100]

Table A

[0101] In a single cell line, various methods are known in the art to increase the desired pairing of Fc-containing fusion polypeptide chains to produce preferred asymmetric fusion proteins at an acceptable yield [Klein et al (2012) mAbs 4:653 -​​​​​​​​​​​Pair formation based on supplication can be cited [Ridgway et al (1996) Protein Eng 9:617-6]. 21;Merchant et al (1998) Nat Biotech 16:677-681;Davis et al (2010) P rotein Eng Des Sel 23:195-202;Gunasekaran et al (2010); 285:19637-19646 Wranik et al (2012) J Biol Chem 287:43331-43339; U.S. Patent No. 593244 No. 8; WO1993 / 011162; WO2009 / 089004 and WO201 No. 1 / 034605].

[0102] Different elements of a fusion protein (e.g., immunoglobulin Fc fusion protein) It is understood that they can be arranged in any manner that matches the desired functionality. For example, Act The RII polypeptide domain may be placed at the C-terminus relative to the heterogeneous domain, or Alternatively, the heterogeneous domain can be placed at the C-terminus of the ActRII polypeptide domain. The ActRII polypeptide domain and heterologous domain may be present in the fusion protein. They do not need to be adjacent; an additional domain or amino acid sequence may be present in either domain. It may be included at the C or N terminus, or between domains.

[0103] For example, the ActRII receptor fusion protein has the amino acid sequence shown in formula ABC. It may also contain the ActRII polypeptide domain (for example, ActR (corresponds to IIA polypeptide, ActRIIB polypeptide, or a combination thereof) And the C portion may independently consist of 0, 1, or more than 1 amino acids, A Both parts A and C are heterogeneous with respect to B, if present. The component may be bound to the B portion via a linker sequence. The linker is glycine (for example) (2-10, 2-5, 2-4, 2-3 glycine residues) or glycine and proli The nucleotide-rich sequence may also be, for example, a single sequence of threonine / serine and glycine. , or a repeating sequence of threonine / serine and / or glycine, for example, GGG ( Column number 16), GGGG (sequence number 17), TGGGG (sequence number 18), SGGGG ( Sequence ID 19), TGGG (Sequence ID 20), SGGG (Sequence ID 21), or GG It may contain a singlet or repeat of GGS (SEQ ID NO: 22). In its application form, the ActRII fusion protein contains the amino acid sequence shown in formula ABC. Here, A is the leader (signal) sequence, and B is the ActRII polypeptide. It consists of domains, and C represents in vivo stability, in vivo half-life, and uptake / intake. One of the following: administration, tissue localization or distribution, protein complex formation, and / or purification. It is a polypeptide moiety that enhances one or more molecules. In a particular embodiment, ActRI The I fusion protein contains the amino acid sequence shown in formula ABC, where A is TP A is the reader sequence, B consists of the ActRII receptor polypeptide domain, and C is The immunoglobulin Fc domain is preferred. Preferred fusion proteins are SEQ ID NOs. 23 and 27. It includes the amino acid sequence shown in any one of 30 and 41.

[0104] In a preferred embodiment, ActRII is used according to the method described herein. Lipeptides are isolated polypeptides. When used herein, isolated Proteins or polypeptides are isolated from their natural environment. In some embodiments, the polypeptides of this disclosure are subjected to electrophoresis (e.g., SDS- PAGE, isoelectric focusing (IEF), capillary electrophoresis, or chromatography - Determined by (e.g., ion exchange or reverse-phase HPLC), 95%, 96%, 9 It is purified to a purity of 7%, 98%, or over 99%. The method for evaluating purity is as follows: This is well known in the field of technology [for example, Flatman et al., (2007) J. Chromatogr. B See 848:79-87. In some embodiments, the method described herein is used. The ActRII polypeptide used is a recombinant polypeptide.

[0105] The ActRII polypeptides described herein are produced by various techniques known in the art. For example, the polypeptides of this disclosure are Bodansky, M. Principles of P Peptide Synthesis, Springer Verlag, Berlin (1993) and Grant GA (ed.), Synthetic Peptides: A User's Guide, WH Freeman and Company, New The synthesis is performed using standard protein chemistry techniques, such as those described in York (1992). This is possible. In addition, automated peptide synthesizers are commercially available (for example, Advanc ed ChemTech Model 396;Milligen / Biosearch 9600). Alternatively, the polypeptides of this disclosure may include fragments or variants thereof. As is well known in this field, various expression systems [e.g., E. coli, ci] Using [Yellow hamster ovary (CHO) cells, COS cells, and baculovirus] , may be produced recombinantly. Further embodiments may involve modified or unmodified polymers of the Disclosure. Peptides include, for example, proteases such as trypsin, thermolysin, and chymotrypsin. By using pepsin or pair-forming basic amino acid converting enzyme (PACE), It may also be produced by digestion of recombinantly produced full-length ActRII polypeptide. Computer analysis (commercial software, e.g., MacVector, Omega, (Using PCGene, Molecular Simulation, Inc.) By using this, the protein cleavage site can be identified. Alternatively, such a polypeptide D uses chemical cleavage (e.g., cyanogen bromide, hydroxylamine, etc.) to perform recombinant DNA. It may also be generated from a fully-length ActRII polypeptide that has been prepared in a specific manner.

[0106] 3. Nucleic acid encoding ActRII polypeptide In certain embodiments, the present disclosure relates to fragments, functional variants, and fusion tampers. ActRII polypeptides containing chlorine (e.g., ActRIIA polypeptide, Act Isolated nucleic acids and / or encoding RIIB polypeptides or combinations thereof We provide recombinant nucleic acids.

[0107] When used herein, isolated nucleic acids are isolated from components of their natural environment. This refers to isolated nucleic acid molecules. Isolated nucleic acids are the nucleic acids contained in cells that normally contain nucleic acid molecules. It contains molecules, but nucleic acid molecules stain outside the chromosome or in a different location than their natural chromosomal location. It exists in a physical location.

[0108] In certain embodiments, the nucleic acid encoding the ActRII polypeptide of this disclosure is distributed It is reasonable to include nucleic acids that are any one variant of column number 4, 5, or 28. It is understood that a variant nucleotide sequence contains one or more allele variants. It contains different sequences due to substitutions, additions, or deletions of a number of nucleotides, and therefore, In any one of the following column numbers, 4, 5, or 28, the nucleotide sequence is different from the one specified. Includes a code array.

[0109] In certain embodiments, the ActRII polypeptide of the present disclosure is represented by SEQ ID NOs: 4, 5, and or one of the 28 and at least 70%, 75%, 80%, 85%, 90%, 91% 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% Encoded by identical isolated nucleic acid sequences and / or recombinant nucleic acid sequences. The vendor has sequences complementary to sequence numbers 4, 5, or 28 and at least 70%, 75%, 80% %, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98 Nucleic acid sequences and their variants that are %, 99%, or 100% identical are also within the scope of this disclosure. It will be understood that it is inside. In further embodiments, the nucleic acid sequence of the present disclosure is isolated Can it be recombinant, and / or can it be fused with a heterologous nucleotide sequence? or it could be in a DNA library.

[0110] In other embodiments, the nucleic acids of this disclosure are also specified in SEQ ID NOs: 4, 5, or 28. The nucleotide sequence, the complementary sequence of SEQ ID NOs. 4, 5, or 28, or a fragment thereof. It contains nucleotide sequences that hybridize under highly stringent conditions. As discussed in the text, a person skilled in the art can provide appropriate storage solutions to facilitate DNA hybridization. It will be easy to understand that the lingency conditions can be changed. Those skilled in the art will understand D By changing the appropriate stringency conditions to promote NA hybridization, It will be easy to understand that this is possible. For example, 6.0 × sodium chloride / c at approximately 45°C. Hybridization with sodium enate (SSC), followed by 2. fermentation at 50°C. Washing with 0×SSC can be performed. For example, the salt concentration in the washing step is 50°C. From low stringency of approximately 2.0 × SSC at 50°C to high stringency of approximately 0.2 × SSC at 50°C. It can be selected up to the triingency level. In addition, the temperature during the washing step is room temperature. From low stringing conditions of approximately 22°C to high stringing conditions of approximately 65°C It can be increased by changing both the temperature and the salt, or other variables. The temperature or salt concentration may be kept constant while varying the other parameters. In one embodiment, the present disclosure This involves washing with 6×SSC at room temperature, followed by washing with 2×SSC at room temperature for low stringing This provides nucleic acids that hybridize under sea conditions.

[0111] The nucleic acids shown in SEQ ID NOs: 4, 5, or 28 differ in degeneracy in the genetic code. Isolated nucleic acids are also within the scope of this disclosure. For example, several amino acids, one or more It is specified by a triplet. A codon or synonym that identifies the same amino acid (e.g.) For example, CAU and CAC are synonyms for histidine. It is also possible to induce "silent" mutations that do not affect the no-acid sequence. However, In mammalian cells, DNs can cause changes in the amino acid sequence of the target protein. It is expected that A sequence polymorphisms will exist. Those skilled in the art can code for a specific protein. One or more nucleotides (up to approximately 3-5% of the nucleic acid) These variant forms are the result of naturally occurring allelic variants and exist among individuals of a given species. They will understand that all sorts of such nucleotide variants can exist. The resulting amino acid polymorphisms are within the scope of this disclosure.

[0112] In certain embodiments, one or more recombinant nucleic acids of the Disclosure are used in the expression construct. The regulatory nucleotide sequence may be operably ligated to the regulatory nucleotide sequence. Generally, it would be suitable for the host cells used for expression. Numerous types of suitable Expression vectors and suitable regulatory sequences are known in the art and can be used in various host cells. It can be used in the following applications. Typically, it involves one or more regulatory nucleotide sequences and This includes, but is not limited to, promoter sequences, leader sequences, or signal sequences. Columns, ribosome binding sites, transcription start sequences and transcription termination sequences, translation start sequences and translation termination sequences. Examples include the bloc sequence, as well as the enhancer sequence or activator sequence. In the field, constitutive or inducible promoters known in this disclosure are intended to A promoter is a naturally occurring promoter, or one or more promoters. It could be any of the hybrid promoters that combine the elements of a promoter. The current construct may be present in cells on episomes such as plasmids, or expressed. The construct may be inserted into the chromosome. In some embodiments, the expression vector is shaped It contains selection marker genes to enable the selection of converted host cells. The marker gene is well known in this field and can be modified depending on the host cell used. It is possible.

[0113] In certain embodiments, the nucleic acids disclosed herein are ActRII polypeptides. (For example, ActRIIA polypeptide, ActRIIB polypeptide, or a combination thereof) A nucleotide sequence that codes for (se) and is operablely linked to at least one regulatory sequence Provided in an expression vector containing the regulatory sequence, which is recognized in the art, Ac It is selected to direct the expression of the tRII polypeptide. Therefore, the regulatory sequence and The term includes promoters, enhancers, and other expression regulatory elements. (Example) The regulatory sequence is described in Goeddel's *Genesis Expression Technology: Methods in Enzymology*. It is described in Academic Press, San Diego, CA (1990). For example, to make it operational. When ligated, one of the many different expression regulatory sequences that control the expression of the DNA sequence is A These vectors are used to express the DNA sequence encoding the ctRII polypeptide. It can be used in such applications. Such useful expression regulatory sequences include, for example, the early expression of SV40. and late promoter, tet promoter, adenovirus or cytomegalovirus Russ's early promoter, RSV promoter, lac system, trp system, TAC or The TRC system, the T7 promoter whose expression is directed by T7 RNA polymerase, The major operator and promoter regions of phage lambda, and the regulation of FD coat proteins. Your domain, promoters of 3-phosphoglycerate kinase or other glycosulfating enzymes, acid phosphate Sphatase promoters, e.g., Pho5, yeast α-conjugation factor promoter, b Polyhedron promoters of culoviruses, as well as prokaryotic or eukaryotic cells, or so Other sequences known to control the gene expression of these viruses, as well as their characteristics Various combinations can be cited. The design of the expression vector involves the selection of the host cells to be transformed and This may depend on factors such as the type of protein that is desired to be expressed. This should be understood. Also, the number of copies of a vector, the ability to control the number of copies, and The expression of any other proteins encoded by vectors, such as antibiotic markers, is also considered. This should be considered.

[0114] Recombinant nucleic acids disclosed herein are cloned genes or portions thereof, and are used in prokaryotic cells. Expression in one or both of the following nuclear cells (yeast, birds, insects, or mammals): It can be produced by ligating it into a suitable vector. Recombinant Act Plasmids and other vectors are used as expression vehicles for the production of RII polypeptides. —For example, suitable vectors include the following types of plasmids: Ec pBR322-derived plasmid, pEMBL, for expression in prokaryotic cells such as oli Plasmid derived from pEX, plasmid derived from pBTac, and plasmid derived from pUC Plasmids are one example.

[0115] Some mammalian expression vectors promote the reproduction of the vector in bacteria using prokaryotes. Both the sequence and one or more eukaryotic transcription units expressed in eukaryotic cells. It contains: pcDNAI / amp, pcDNAI / neo, pRc / CMV, pSV2 gpt, pSV2neo, pSV2-dhfr, pTk2, pRSVneo, pMSG, The vectors derived from pSVT7, pko-neo, and pHyg are transfected into eukaryotic cells. Examples of mammalian expression vectors suitable for expression. Some of these vectors are prokaryotic. To promote replication and drug resistance selection in both cellular and eukaryotic cells, pBR3 Modified by sequences derived from bacterial plasmids such as 22, or by bovine papillomavirus. (BPV-1) or Epstein-Barr virus (pHEBo, derived from pREP and p 205) Viral derivatives such as these are used for transient protein expression in eukaryotic cells. It can be used. Examples of other virus expression systems (including retroviruses) include gene therapy. The following can be found in the description of legal delivery systems: Plasmid preparation and host organism transformation. Various methods used in exchange are well known in the art. Prokaryotic cells and For other suitable expression systems for both eukaryotic and ubiquitous cells, and for general recombination procedures, for example, Molecular Cloning A Laboratory Manual, 3rd Ed., ed. by Sambrook, F. Ritsch and Maniatis (Cold Spring Harbor Laboratory Press, 2001). Partially. In some cases, recombinant polypeptides are expressed using a baculovirus expression system. In some cases, this is desirable. An example of such a baculovirus expression system is pVL-derived baculovirus. Testers (pVL1392, pVL1393, and pVL941, etc.), pAcUW-derived Vectors (such as pAcUW1), and pBlueBac-derived vectors (containing β-gal p Examples include the BlueBac III.

[0116] In a preferred embodiment, the Pcmv-Script vector (Stratagene, L a Jolla, Calif.), pcDNA4 vector (Invitrogen, Ca rlsbad, Calif.) and pCI-neo vectors (Promega, Mad Vectors such as ison (Wisc.) target ActRII poly(CHO) cells Designed for peptide production. As is clear, the gene construct in question is purified. For example, to produce proteins containing fusion proteins or variant proteins. To achieve this, the target ActRII polypeptide is expressed in cells that have been cultured. It can be used to cause the present.

[0117] This disclosure also includes one or more coding sequences of the ActRII polypeptide in question. This relates to host cells transfected with recombinant genes. The host cell is any prokaryotic cell. or it may be a eukaryotic cell. For example, the ActRII polypeptide of this disclosure is E. col Bacterial cells such as i, insect cells (for example, using a baculovirus expression system), yeast, or It is expressed in mammalian cells [e.g., Chinese hamster ovary (CHO) cell line]. Other suitable host cells are known to those skilled in the art.

[0118] Therefore, this disclosure further relates to a method for generating the ActRII polypeptide in question. For example, transfected with an expression vector encoding the ActRII polypeptide. Host cells that have been subjected to the appropriate conditions for inducing the expression of ActRII polypeptide are It can be cultured under the following conditions. Polypeptides are polypeptides in cells and culture media containing polypeptides. It may be secreted and isolated from the mixture. Alternatively, the ActRII polypeptide may be released from the cell The membrane fraction and cells may be retained in quality, or recovered and lysed, as well as single It may be present in the detached protein. Cell cultures include host cells, culture medium, and other by-products. Includes the product. Suitable culture media for cell culture are well known in the art. Tide is used in ion exchange chromatography, gel filtration chromatography, ultrafiltration, and electrochemistry. Immunotherapy using antibodies specific to specific epitopes of ActRII polypeptides, electrophoresis Nity purification and drugs that bind to the domain fused to the ActRII polypeptide Affinity purification method used (for example, using a Protein A column, ActRII-F In the art, for purifying proteins, including (which can purify c-fusion proteins), Using known techniques, it is possible to isolate cells from the cell culture medium, host cells, or both. Yes, it is possible. In some embodiments, the ActRII polypeptide is used to facilitate its purification. It is a fusion protein containing n.

[0119] In some embodiments, purification is performed, for example, in any order of three or more steps. This is achieved by a series of column chromatography steps including: Protein A chromatography Mathography, Q Sepharose chromatography, phenyl Sepharose chromatography Raffy, size exclusion chromatography, and cation exchange chromatography. The process can be completed by viral filtration and buffer exchange. ActRII protein >90%, >95%, >96%, determined by size exclusion chromatography. Purity of >98% or >99%, and >90% as determined by SDS PAGE. It may be purified to a purity of >95%, >96%, >98%, or >99%. The target level is mammalian, especially non-human primates, rodents (mice), and humans. It must be at a level sufficient to achieve the desired results.

[0120] In another embodiment, a purified leader sequence, for example, a recombinant ActRII polypeptide, is used. A fusion encoding the poly-(His) / enterokinase cleavage site sequence at the N-terminus of the desired portion. The gene is Ni 2+ Expression by affinity chromatography using metal resins This may enable the purification of the fusion protein. Then, the purified leader sequence is then processed. The ActRII polypeptide is purified by removal with anterokinase. It is possible. For example, Hochuli et al. (1987) J. Chromatography 411:177; See also Janknecht et al. (1991) PNAS USA 88:8972.

[0121] Techniques for creating fusion genes are well known. Essentially, they involve different polypeptide sequences. The joining of various DNA fragments encoding each other is done with blunt ends or slashes for ligation. Twisted ends, restriction enzyme digestion to provide appropriate ends, and, where appropriate, filling of sticky ends. , alkaline phosphatase treatment to avoid undesirable conjugation, and enzymatic ligation This is carried out according to conventional techniques using auto. In another embodiment, the fusion gene is automated It can be synthesized using conventional techniques, including DNA synthesizers. Alternatively, gene fragments PCR amplification creates an anchor that produces a complementary overhang between two consecutive gene fragments. This can be done using primers, which then generate a chimeric gene sequence. It can be annealed. For example, Current Protocols in Molecular Bio See logy, eds. Ausubel et al., John Wiley & Sons: 1992.

[0122] 4. How to use In part, this disclosure is a method for treating pulmonary arterial hypertension (PAH), and Administer an effective dose of the ActRII polypeptide described herein to patients who require it. The present disclosure relates to a method that includes the step of treating pulmonary arterial hypertension. In some embodiments, the present disclosure relates to pulmonary arterial hypertension. To treat, prevent, or control the progression rate of one or more complications of the disease and / or A method for reducing the severity of the condition, which is used to provide to patients in need of it in an effective amount as described herein. A method is planned that includes the step of administering the ActRII polypeptide. In terms of administration, ActRII polypeptide is administered at a dose of 0.1 mg / kg to 2.0 mg / kg (for example) In some cases, it is administered within a dosage range of 0.3 mg / kg or 0.7 mg / kg. In this state, administration of ActRII polypeptide affects one or more hemodynamic or functional parameters. Changes in pulmonary vascular resistance (e.g., reduction in pulmonary vascular resistance (PVR); 6-minute walk distance (6MWD)) Increase; decrease in N-terminal pro-B natriuretic peptide (NT-proBNP) levels; Prevention of progression of the class of pulmonary hypertension recognized by the World Health Organization (WHO) or Delay; acceleration or increase of the regression of the class of pulmonary hypertension recognized by the WHO; right ventricle It results in improvements in function; and improvements in pulmonary artery pressure.

[0123] These methods are specifically intended for therapeutic and preventive treatment of animals, and more specifically, humans. The terms “subject,” “individual,” or “patient” are used interchangeably throughout this specification. Interchangeable, referring to either humans or non-human animals. These terms include mammals, for example. For example, humans, non-human primates, laboratory animals, domestic animals (including cattle, pigs, camels, etc.), Companion animals (e.g., dogs, cats, and other domesticated animals), and rodents (e.g., Includes mice and rats. In certain embodiments, the patient, subject or individual is human. be.

[0124] Usage of words such as "treatment," "treating," and "relief" In this specification, the term generally refers to obtaining desired pharmacological and / or physiological effects. This means that one or more clinical complications of the condition being treated (e.g., PAH) It can also be used to refer to improving, alleviating, and / or reducing the severity of an illness. It may be used. The effect is to completely or completely stop the onset or recurrence of a disease, condition, or its complications. It may be preventive in the sense of partially delaying, and / or disease or condition To partially or completely cure adverse effects resulting from a condition and / or disease or state. It may be therapeutic in terms of causing [something]. When used herein, "treatment" refers to mammals. , in particular, encompasses any treatment of human diseases or conditions. When used herein, impediments Or, a treatment that "prevents" the condition, in a statistical sample, compared to an untreated control sample, To reduce the appearance of defects or conditions in the placed sample, or compared with an untreated control sample In contrast, it refers to compounds that delay the onset of a disease or condition.

[0125] In general, the treatment or prevention of the diseases or conditions described in this disclosure (e.g., PAH) By administering one or more ActRII polypeptides of this disclosure in an "effective dose," This is achieved. The effective dose of the drug is administered over the required dosage and duration to achieve the desired therapeutic outcome. The term "therapeutic effective dose" of a drug in this disclosure refers to an amount effective to achieve a preventive outcome. The patient's condition, age, sex, and weight, as well as the ability of the drug to induce the desired response in the individual. It can fluctuate depending on factors such as force. The "effective preventive dose" is the required amount and duration of medication. This refers to the amount that is effective in achieving the desired preventive outcome.

[0126] In certain aspects, this disclosure may be used to treat or prevent a disease or condition (e.g., PAH). ActRI in combination with one or more additional activators or other supportive therapies for the purpose of I intend to use polypeptides. When used herein, "in combination with" and "of" Combination, combined with, or joint administration of an additional activator or supportive therapy (For example, the second, third, fourth, etc.) are still effective in the body (for example, multiple Several compounds are effective simultaneously in patients for a certain period of time, and this is because of these compounds Refers to any form of administration (which may include synergistic effects). Efficacy is measured in blood, serum, or plasma. It does not need to correlate with the measurable concentration of the drug. For example, different therapeutic compounds may be manufactured by the same company. In the drug or in separate formulations, simultaneously or sequentially, different schedules It can be administered in liters. Therefore, the subjects receiving such treatment have different activity levels. Benefits can be obtained from the combined effects of agents or therapies. One or more Acs of this disclosure tRII polypeptides can be used with one or more other additional drugs or supportive therapies, such as Honmei It may be administered simultaneously with, before, or after, what is disclosed in the details. Generally, each activator or therapy is determined by the specific drug and / or Or it is administered according to a time schedule. The specific combination used in the regimen is this The compatibility of the disclosed ActRII polypeptide with additional activators or supportive therapies, and / Alternatively, take the desired effect into consideration.

[0127] Overview of the WHO classification The pulmonary arterial hypertension condition treated by the methods described herein is a World Health Organization (WHO) condition. This may include one or more of the conditions recognized by the organization (WHO). For example, See Simonneau (2019) Eur Respir J: 53:1801913.

[0128] [Table 1]

[0129] The clinical purpose of classifying PAH is to categorize the clinical conditions associated with PAH and their pathophysiological mechanisms. Catheterization is performed on specific subgroups according to the symptoms, clinical presentation, hemodynamic characteristics, and treatment strategy. This involves gory classification. This clinical classification is available when new data is available in the above characteristics. This may be updated when additional clinical entities are considered.

[0130] As used herein, the term “pulmonary hemodynamic parameters” refers to the heart and lungs. Refers to any parameter used to describe or evaluate blood flow through the vascular system. (Lungs) Examples of hemodynamic parameters, though not limited to them, include mean pulmonary artery pressure (mPA). P) Diastolic pulmonary artery pressure (dPAP) [also known as pulmonary artery diastolic pressure (PADP)], systolic sPAP (spontaneous pulmonary artery pressure) [also known as pulmonary artery systolic pressure (PASP)], mean right atrial pressure (m RAP), pulmonary capillary wedge pressure (PCWP) [also known as pulmonary artery wedge pressure (PAWP)], lung These include vascular resistance (PVR) and cardiac output (CO).

[0131] Many of the pulmonary hemodynamic parameters listed above are interrelated. For example, PVR is mPAP, PCWP, and CO are related according to the following equation: PVR = (mPAP - PCWP) / CO [in Woods units] PVR is the resistance to flow imposed by the pulmonary vascular system without the influence of left-side filling pressure. Measure. PVR is calculated using the following formula: PVR = TPG × 80 / CO[Unit: dyne-second-cm] -5 ] or PVR=(mPAP -PCWP) × 80 / CO [Unit: dyne-second-cm] -5 ] It can also be measured according to this method.

[0132] In some embodiments, total peripheral resistance (TPR) can be measured using the following equation: Kill: TPR=mPAP / CO

[0133] According to some embodiments, the contribution of the precapillary pulmonary artery to PH is due to elevated PVR. This can be reflected. In some embodiments, a normal PVR is 20-130 dyne-seconds-cm². - 5 Or it is 0.5 to 1.1 wood units. According to some embodiments, the increased PVR is , exceeding 2 wood units, exceeding 2.5 wood units, exceeding 3 wood units, or 3 It can sometimes refer to a PVR exceeding 0.5 wood units.

[0134] As yet another example, mPAP is related to dPAP and sPAP according to the following equation. kerareru: mPAP = (2 / 3)dPAP + (1 / 3)sPAP

[0135] Furthermore, dPAP and sPAP are calculated using the following formula: pulse pressure = sPAP - dPAP It can be used to calculate pulse pressure (mmHg).

[0136] Pulse pressure is calculated using the following formula: Pulmonary artery compliance (mI.mmHg) -1 )=stroke volume / pulse Pressure can be used to calculate pulmonary artery compliance.

[0137] In some embodiments, pulmonary hemodynamic parameters are directly measured during procedures such as right heart catheterization. In other embodiments, pulmonary hemodynamic parameters are determined by magnetic resonance imaging (MRI). Alternatively, it may be estimated and / or evaluated by other techniques such as echocardiography.

[0138] Exemplary pulmonary hemodynamic parameters include mPAP, PAWP, and PVR. Alternatively, multiple pulmonary hemodynamic parameters can be measured using right heart catheterization or echocardiography. pH and PAH can be measured by any appropriate procedure, such as by [method]. Table 2 shows various hemodynamic characteristics.

[0139] [Table 2]

[0140] The clinical classification or hemodynamic characteristics of PAH described herein, and related diagnostic parameters The meter is based on the availability of new or existing data sources, or additional When clinical reality is taken into consideration, it may be updated or changed.

[0141] Characteristics of PAH Pulmonary arterial hypertension (WHO Group 1 PH) is characterized by severe vasoconstriction and pulmonary artery hypertension. Characterized by the abnormal proliferation of smooth muscle cells in the pulmonary vascular system, a severe, progressive life-threatening condition of the pulmonary vascular system. It is a threatening disease. Severe constriction of the blood vessels in the lungs leads to extremely high pulmonary artery pressure. High pressure makes it difficult for the heart to pump blood through to the lungs, where it needs oxygen. In patients with PAH, the heart tries to work hard to pump blood against these high pressures. Therefore, they suffer from extreme shortness of breath. Patients with PAH typically experience a significant increase in PVR. This leads to a persistent increase in mPAP, which ultimately results in right ventricular failure and death. Patients diagnosed with PAH have a poor prognosis, similarly experience impaired quality of life, and require treatment. If not treated, the average life expectancy from the time of diagnosis is 2 to 5 years.

[0142] Various factors, including the proliferation of lung cells (i.e., hyperplasia) that can contribute to vascular remodeling, are involved. It contributes to the pathogenesis of pulmonary hypertension. For example, pulmonary vascular remodeling is involved in the development of pulmonary hypertension. It is mainly caused by the proliferation of arterial endothelial cells and smooth muscle cells in patients. Overexpression of is thought to promote pulmonary hypertension. Furthermore, pulmonary hypertension is associated with the pulmonary artery It has been found that this can result from the overgrowth of smooth cells and lung endothelial cells. Furthermore, Progressive PAH involves muscle formation of the distal pulmonary arterioles, concentric endocardium thickening, and proliferation of endothelial cells. It can be characterized by occlusion of the vascular lumen. Pietra et al., J. Am. Coll. Ca rdiol., 43:255-325 (2004).

[0143] PAH is defined as a resting heart rate above 25 mmHg (or 20 mmHg under the updated guidelines). It can be diagnosed based on mean pulmonary artery pressure (above g) and normal pulmonary artery capillary wedge pressure. PA H can cause shortness of breath, dizziness, fainting, and other symptoms, all of which are caused by exercise. It worsens. PAH can be a severe disease accompanied by significantly reduced exercise tolerance and heart failure. There are two main types of PAH: idiopathic PAH (for example, when a predisposing factor is identified) (Non-PAH) and hereditary PAH (e.g., BMPR2, ALK1, ENG, SMAD9) PAHs associated with mutations in CAV1, KCNK3, or EIF2AK4 It can be cited that in 70% of familial PAH cases, the mutation is located in the BMPR2 gene. Risk factors for the development of PAH include a family history of PAH and the use of drugs and toxins. (e.g., methamphetamine or cocaine use), infection (e.g., HIV infection or resident infection) Blood-suscitation, cirrhosis, congenital heart abnormalities, portal hypertension, pulmonary veno-occlusive disease, pulmonary capillary hemangioma , or connective tissue / autoimmune disorders (e.g., scleroderma or lupus erythematosus). AH is a clear characteristic of calcium channel blockers, involving venous / capillary (PVOD / PCH) pathways. Sex and long-term responders to persistent PH in neonatal syndromes may be related.

[0144] Diagnosis of PAH The diagnosis of PAH, including functional groups, determines whether hemodynamic and other criteria are met. Using a comprehensive review of the set of parameters for this purpose, based on symptoms and health examinations This can be used to make a decision. Some of the criteria that may be considered include the patient's clinical presentation (e.g., , shortness of breath, fatigue, weakness, anguina, fainting, dry cough, exercise-induced nausea, and (Vomiting), electrocardiogram (ECG) results, chest X-ray results, pulmonary function tests, arterial blood gas analysis, echocardiography. Examination results, ventilation / perfusion lung scan results, high-resolution computed tomography results, contrast-enhanced Pewter tomography results, pulmonary angiography results, cardiac magnetic resonance imaging, blood test results (for example) For example, biomarkers such as BNP or NT-proBNP, immunology, abdominal ultrasound, etc. Canine, right heart catheterization (RHC), vascular reactivity, and genetic testing For example, see Galie N., et al Euro Heart J. (2016) 37, 67-119. Please refer to this.

[0145] In some embodiments, biomarkers can be used to aid in the diagnosis of PAH. Yes, it is possible. For example, in some embodiments, the biomarker is a marker of vascular dysfunction. (For example, asymmetric dimethylarginine (ADMA), endothelin-1, angiopo Ethine (angiopoeitin or von Willebrand factor). In some embodiments, Iomarkers are markers of inflammation (C-reactive protein, interleukin-6, keratin). (Mokine). In some embodiments, the biomarker is a marker of myocardial stress [ For example, (atrial natriuretic peptide, brain natriuretic peptide (BNP) / NT -proBNP or troponin]. In some embodiments, the biomarker is low CO and / or markers of tissue hypoxia (e.g., pCO2, uric acid, growth differentiation factor 1) 5 (GDF15 or osteopontin). In some embodiments, the biomarker is These are markers of secondary organ damage (e.g., creatinine or bilirubin). For example, See Galie N., et al Euro Heart J. (2016) 37, 67-119.

[0146] pH measurement In certain aspects, this disclosure relates to the treatment and prevention of pulmonary arterial hypertension (PAH). or a method for reducing the rate of progression and / or severity thereof, which is necessary For patients, an effective amount of ActRII polypeptide (e.g., residues 30-11 of SEQ ID NO: 1) is administered. The steroids administered are amino acid sequences that are at least 90% identical to the amino acid sequence corresponding to 0. This relates to a method including a rap. In some embodiments, the method is used for PAH patients with idiopathic PAH. This relates to treating individuals with hereditary PAH (e.g., BM). In some embodiments, the method involves treating individuals with hereditary PAH (e.g., BM). PR2, ALK-1, ENG, SMAD9, CAV1, and KCNK3 - one or more of these Regarding the treatment of PAH patients with PAH (PAH caused by mutations in the number of individuals). In terms of administration, the method involves treating PAH patients with hereditary PAH caused by unknown mutations. The method relates to having a drug or toxin-inducible PAH. In some embodiments, the method involves having a drug or toxin-inducible PAH. This relates to treating PAH patients. In some embodiments, the method relates to connective tissue disease. This relates to treating PAH patients who have PAH. In some embodiments, the method is Regarding the treatment of PAH patients with HIV-related PAH. Partial implementation Morphologically, the method involves treating PAH patients with PAH associated with portal hypertension. Regarding. In some embodiments, the method relates to PAH patients with schistosomiasis-related PAH. The method relates to treating the following. In some embodiments, the method involves treating the following with a calcium channel blocker. This relates to treating PAH patients who are classified as long-term responders. In some embodiments, The method involves PAH patients with clear characteristics of venous / capillary (PVOD / PCH) involvement. Regarding treatment. In some embodiments, the method relates to persistent pulmonary hypertension in neonatal syndrome. This relates to treating PAH patients with (PH). In some embodiments, the method is Simple congenital systemic-to-lung shunt (simple, c) at least one year after shunt repair. PAH patients with PAH associated with ongenital systemic-to-pulmonary shunts Regarding placement.

[0147] mPAP In certain aspects, this disclosure relates to the treatment and prevention of pulmonary arterial hypertension (PAH). or a method for reducing the rate of progression and / or severity thereof, which is necessary For patients, an effective amount of ActRII polypeptide (e.g., residues 30-11 of SEQ ID NO: 1) is administered. The steroids administered are amino acid sequences that are at least 90% identical to the amino acid sequence corresponding to 0. Including the suppository, the patient has at least 20 mmHg (e.g., 20, 25, 30, 35, 40 A method having a resting mean pulmonary artery pressure (mPAP) of 45 or 50 mmHg In some embodiments, the method involves a patient having a resting mPAP of at least 20 mmHg. Regarding this matter, in some embodiments, the method has a resting mPAP of at least 25 mmHg. This relates to patients. In some embodiments, the method involves a resting mP of at least 30 mmHg. This relates to patients with AP. In some embodiments, the method involves a stable temperature of at least 35 mmHg. This relates to patients with static mPAP. In some embodiments, the method involves at least 40 mm This relates to patients with resting mPAP of Hg. In some embodiments, the method is at least This relates to a patient with a resting mPAP of 45 mmHg. In some embodiments, the method is less This applies to patients with at least 50 mmHg of resting mPAP.

[0148] In some embodiments, this disclosure relates to one or more hemodynamic parameters in PAH patients. The monitor is at a more normal level (for example, normal compared to a healthy person of similar age and sex). A method for adjusting toward an effective amount of ActRII polypeptide (e.g., SEQ ID NO: The amino acid sequence corresponding to residues 30-110 of 1 is at least 90% identical to the amino acid sequence of 1. The present invention relates to a method, which includes administering a column (of the drug) to a patient who needs it. The method relates to improving pulmonary artery pressure in patients. In some embodiments, pulmonary Improvement in pulse pressure is a reduction in mean pulmonary artery pressure (mPAP). In some embodiments, the method is: This relates to reducing mPAP. In some embodiments, the method reduces the patient's mPAP. The method relates to reducing the patient's mP by at least 1 mmHg. In some embodiments, the method relates to reducing the patient's mP The present invention relates to reducing AP by at least 2 mmHg. In some embodiments, the method involves the patient This relates to reducing the mPAP of a person by at least 3 mmHg. In a particular embodiment, The method relates to reducing the patient's mPAP by at least 5 mmHg. In one embodiment, the method relates to reducing the patient's mPAP by at least 7 mmHg. In a particular embodiment, the method reduces the patient's mPAP by at least 10 mmHg. This relates to the following: In a particular embodiment, the method involves reducing the patient's mPAP to at least 12 m This relates to reducing mHg. In certain embodiments, the method reduces the patient's mPAP. The method relates to reducing blood pressure by at least 15 mmHg. In a particular embodiment, the method relates to the patient This relates to reducing the mPAP by at least 20 mmHg. In a particular embodiment, The method relates to reducing the patient's mPAP by at least 25 mmHg.

[0149] In some embodiments, this disclosure relates to one or more hemodynamic parameters in PH patients. To bring the ter to a more normal level (for example, normal compared to a healthy person of similar age and sex) A method for adjusting the amount of ActRII polypeptide (e.g., SEQ ID NO: 1) Amino acid sequences that are at least 90% identical to the amino acid sequences corresponding to residues 30-110 of [the specified amino acid sequence]. The present invention relates to a method, which includes administering a substance to a patient who needs it.In some embodiments, The method involves reducing the patient's mPAP by at least 1% (e.g., at least 1, 5, 10, 15%). 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 8 Regarding reducing by 5, 90, 95, or 100%. In some embodiments, the method This relates to reducing the patient's mPAP by at least 1%. In some embodiments, The law relates to reducing the patient's mPAP by at least 5%. In some embodiments, The method relates to reducing the patient's mPAP by at least 10%. In some embodiments... The method concerns reducing the patient's mPAP by at least 15%. Some implementations The method involves reducing the patient's mPAP by at least 20%. In terms of administration, the method relates to reducing the patient's mPAP by at least 25%. In one embodiment, the method relates to reducing a patient's mPAP by at least 30%. In some embodiments, the method relates to reducing the patient's mPAP by at least 35%. In some embodiments, the method reduces the patient's mPAP by at least 40%. Regarding this, in some embodiments, the method reduces the patient's mPAP by at least 45%. This relates to the following. In some embodiments, the method reduces the patient's mPAP by at least 50%. This relates to reducing the patient's mPAP by at least 55%. In some embodiments, the method reduces the patient's mPAP by at least 55%. Regarding causing the patient's mPAP to decrease by at least 60%. In some embodiments, the method involves reducing the patient's mPAP by at least 60%. The method relates to reducing the patient's mPAP by at least 6 The method relates to reducing by 5%. In some embodiments, the method reduces the patient's mPAP It also relates to reducing by 70%. In some embodiments, the method reduces the patient's mPAP The method relates to reducing the patient's mPAP by at least 75%. In some embodiments, the method involves reducing the patient's mPAP The method relates to reducing by at least 80%. In some embodiments, the method involves the patient's mPA The method relates to reducing P by at least 85%. In some embodiments, the method involves the patient's m The method relates to reducing PAP by at least 90%. In some embodiments, the method involves the patient The method relates to reducing mPAP by at least 95%. In some embodiments, the method is Regarding reducing the patient's mPAP by at least 100%.

[0150] mRAP As PAH progresses, increased pulmonary vascular resistance to blood flow leads to right atrial pressure (RAP) and This leads to an increase in right heart failure. Patients with right heart failure typically have a high right atrial pressure (RAP). and has an increased ratio of pulmonary artery wedge pressure (PAWP). In certain embodiments, the present disclosure is To treat, prevent, or manage the progression of pulmonary arterial hypertension (PAH) and / or if or a method to reduce the severity, wherein an effective amount of ActRII polypeptide (for example, The amino acid sequence corresponding to residues 30-110 of column number 1 is at least 90% identical to the amino acid sequence of the same amino acid sequence. The procedure involves administering a no-acid sequence to a patient who requires it, and the patient has at least 5 mm Hg (for example, at least 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, Rest (16, 17, 18, 18, 20, 21, 22, 23, 24, or 25 mmHg) This invention relates to a method having mean right atrial pressure (mRAP) over time. In some embodiments, the method has less This relates to patients with a resting mRAP of at least 5 mmHg. In some embodiments, the method This relates to patients having a resting mRAP of at least 6 mmHg. In some embodiments, The method relates to patients with a resting mRAP of at least 7 mmHg. Some embodiments The method concerns patients with a resting mRAP of at least 8 mmHg. In terms of the method, the application method relates to patients with a resting mRAP of at least 9 mmHg. In one embodiment, the method relates to a patient having a resting mRAP of at least 10 mmHg. In some embodiments, the method has a resting mRAP of at least 11 mmHg. Regarding the patient. In some embodiments, the method involves a resting mRAP of at least 12 mmHg. This relates to patients having a resting temperature of at least 13 mmHg. In some embodiments, the method involves a resting temperature of at least 13 mmHg. This relates to patients with mRAP. In some embodiments, the method involves at least 14 mmHg This relates to patients with resting mRAP. In some embodiments, the method includes at least 15 This relates to patients with resting mRAP of mmHg. In some embodiments, the method is less This relates to patients with a resting mRAP of 16 mmHg. In some embodiments, the method This relates to patients having a resting mRAP of at least 17 mmHg. In some embodiments, The method concerns patients with a resting mRAP of at least 18 mmHg. In terms of form, the method relates to patients with a resting mRAP of at least 19 mmHg. In one embodiment, the method relates to a patient having a resting mRAP of at least 20 mmHg. In some embodiments, the method has a resting mRAP of at least 21 mmHg. Regarding the patient. In some embodiments, the method involves a resting mRAP of at least 22 mmHg. This relates to patients having a resting temperature of at least 23 mmHg. In some embodiments, the method involves a resting temperature of at least 23 mmHg. This relates to patients with mRAP. In some embodiments, the method involves at least 24 mmHg This relates to patients with resting mRAP. In some embodiments, the method is at least 25 Regarding patients with resting mRAP of mmHg.

[0151] In some embodiments, this disclosure relates to one or more hemodynamic parameters in PAH patients. The monitor is at a more normal level (for example, normal compared to a healthy person of similar age and sex). A method for adjusting toward an effective amount of ActRII polypeptide (e.g., SEQ ID NO: The amino acid sequence corresponding to residues 30-110 of 1 is at least 90% identical to the amino acid sequence of 1. The present invention relates to a method, which includes administering a column (of the drug) to a patient who needs it. The method relates to improving mean right atrial pressure in patients. In some embodiments, Improvement in mean right atrial pressure (mRAP) is achieved by reducing mRAP. In some embodiments, the method is: This relates to reducing mRAP. In some embodiments, the method reduces the patient's mRAP. The method relates to reducing the patient's mR by at least 1 mmHg. In some embodiments, the method involves the patient's mR The present invention relates to reducing AP by at least 2 mmHg. In some embodiments, the method involves the patient The present invention relates to reducing the mRAP of the person by at least 3 mmHg. In some embodiments, The law concerns reducing the patient's mRAP by at least 4 mmHg. In terms of form, the method relates to reducing the patient's mRAP by at least 5 mmHg. In one embodiment, the method relates to reducing the patient's mRAP by at least 6 mmHg. In a particular embodiment, the method reduces the patient's mRAP by at least 7 mmHg. This relates to the process of moving the patient's mRAP to at least 8 mmH The method relates to reducing g. In some embodiments, the method involves reducing the patient's mRAP to at least Regarding reducing by 9 mmHg. In a particular embodiment, the method involves the patient's mRAP The method relates to reducing the blood pressure by at least 10 mmHg. In some embodiments, the method relates to the patient This relates to reducing mRAP by at least 11 mmHg. In a particular embodiment, The method relates to reducing the patient's mRAP by at least 12 mmHg. In terms of administration, the method relates to reducing the patient's mRAP by at least 13 mmHg. In some embodiments, the method reduces the patient's mRAP by at least 14 mmHg. Regarding the following, in a particular embodiment, the method involves moving the patient's mRAP to at least 15 mmH The method relates to reducing g. In some embodiments, the method involves reducing the patient's mRAP to at least The method relates to reducing the patient's mRAP by 16 mmHg. In some embodiments, the method involves reducing the patient's mRAP The method relates to reducing the blood pressure by at least 17 mmHg. In some embodiments, the method relates to the patient The method relates to reducing mRAP by at least 18 mmHg. In some embodiments, This relates to reducing the patient's mRAP by at least 19 mmHg. In terms of morphology, the method relates to reducing the patient's mRAP by at least 20 mmHg.

[0152] In some embodiments, this disclosure relates to one or more hemodynamic parameters in PAH patients. The monitor is at a more normal level (for example, normal compared to a healthy person of similar age and sex). A method for adjusting toward an effective amount of ActRII polypeptide (e.g., SEQ ID NO: The amino acid sequence corresponding to residues 30-110 of 1 is at least 90% identical to the amino acid sequence of 1. The present invention relates to a method, which includes administering a column (of the drug) to a patient who needs it. The method involves increasing the patient's mRAP to at least 1% (e.g., at least 1, 5, 10, 15%). , 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, Regarding reducing by 85, 90, 95, or 100%. In some embodiments, The method relates to reducing the patient's mRAP by at least 1%. In some embodiments, The method relates to reducing the patient's mRAP by at least 5%. In some embodiments, The method relates to reducing the patient's mRAP by at least 10%. Some embodiments The method concerns reducing the patient's mRAP by at least 15%. In terms of morphology, the method relates to reducing the patient's mRAP by at least 20%. In the embodiment, the method relates to reducing the patient's mRAP by at least 25%. In one embodiment, the method relates to reducing the patient's mRAP by at least 30%. In some embodiments, the method relates to reducing the patient's mRAP by at least 35%. In some embodiments, the method reduces the patient's mRAP by at least 40%. Regarding this matter, in some embodiments, the method reduces the patient's mRAP by at least 45%. This relates to the following: In some embodiments, the method reduces the patient's mRAP by at least 50%. This relates to reducing the patient's mRAP by at least 55%. In some embodiments, the method reduces the patient's mRAP by at least 55%. Regarding reducing. In some embodiments, the method involves reducing the patient's mRAP to at least 60 Regarding reducing by %. In some embodiments, the method reduces the patient's mRAP by at least Regarding a 65% reduction. In some embodiments, the method reduces the patient's mRAP Both relate to reducing by 70%. In some embodiments, the method reduces the patient's mRAP The method relates to reducing mRAP by at least 75%. In some embodiments, the method involves the patient's mRAP The method relates to reducing the patient's mR by at least 80%. In some embodiments, the method involves the patient's mR The method relates to reducing AP by at least 85%. In some embodiments, the method relates to the patient The present invention relates to reducing mRAP by at least 90%. In some embodiments, the method involves the patient The method relates to reducing the mRAP of the person by at least 95%. In some embodiments, the method This relates to reducing the patient's mRAP by at least 100%.

[0153] PVR In certain aspects, this disclosure relates to treating, preventing, or accelerating PAH. A method for reducing the severity of an effective amount of ActRII polypeptide ( For example, the amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1 is at least 90% identical. This involves administering an amino acid sequence (which is such that the patient has a small amount of amino acids) to patients who need it, and the patient has a small amount of amino acids. Each in 2.5 wood units (for example, at least 2.5, 3, 4, 5, 6, 7, 8, 9, 10 Having a pulmonary vascular resistance (PVR) of 12, 14, 16, 18, or 20 Wood units, Regarding the method, in some embodiments, the method has a PVR of at least 2.5 wood units. Regarding patients who... In some embodiments, the method has at least 3 Wood units of PVR Regarding patients. In some embodiments, the method has at least 4 wood units of PVR. Regarding patients. In some embodiments, the method has at least 5 wood units of PVR. Regarding patients. In some embodiments, the method has at least 6 wood units of PVR. Regarding patients who... In some embodiments, the method has at least 7 wood units of PVR Regarding patients. In some embodiments, the method has at least 8 wood units of PVR. Regarding patients who... In some embodiments, the method has at least 9 wood units of PVR Regarding patients who... In some embodiments, the method involves a PVR of at least 10 wood units Regarding patients having. In some embodiments, the method involves at least 12 wood units of PVR This relates to patients having the following characteristics: In some embodiments, the method involves at least 14 wood units of PV This relates to patients with R. In some embodiments, the method involves at least 16 Wood units of P This relates to patients with VR. In some embodiments, the method involves at least 18 wood units This relates to patients with PVR. In some embodiments, the method involves at least 20 wood units. Regarding patients with PVR.

[0154] In some embodiments, this disclosure relates to one or more hemodynamic parameters in PAH patients. The monitor is at a more normal level (for example, normal compared to a healthy person of similar age and sex). A method of adjusting for this, and for patients who need it, an effective amount of ActRII poly Peptides (for example, amino acid sequences corresponding to residues 30-110 of SEQ ID NO: 1 and at least The present invention relates to a method comprising the step of administering an amino acid sequence that is 90% identical. In this context, the method relates to reducing the patient's PVR. In some embodiments, the patient The reduction in PVR is a result of a decrease in the patient's mean pulmonary artery pressure (mPAP). In some embodiments The method concerns reducing the patient's PVR by at least 0.5 Wood units. In one embodiment, the method relates to reducing the patient's PVR by at least 1 Wood unit. In some embodiments, the method reduces the patient's PVR by at least 2 Wood units. This relates to reducing the patient's PVR by at least 4 Wood units. In some embodiments, the method reduces the patient's PVR by at least 4 Wood units. Regarding reducing. In some embodiments, the method involves reducing the patient's PVR by at least 6. This relates to reducing the PVR by units. In some embodiments, the method reduces the patient's PVR It also relates to reducing by 8 Wood units. In some embodiments, the method is to reduce the patient's PVR Regarding reducing the amount by at least 10 wood units.

[0155] In some embodiments, this disclosure relates to one or more hemodynamic parameters in PAH patients. The monitor is at a more normal level (for example, normal compared to a healthy person of similar age and sex). A method of adjusting for this, and for patients who need it, an effective amount of ActRII poly Peptides (for example, amino acid sequences corresponding to residues 30-110 of SEQ ID NO: 1 and at least The present invention relates to a method comprising the step of administering an amino acid sequence that is 90% identical. In this case, the method involves reducing the patient's PVR by at least 1% (e.g., at least 1, 5, 10, 1). 5, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80 Regarding reducing by 85, 90, 95, or 100%. In some embodiments, The law relates to reducing the patient's PVR. In some embodiments, the reduction of the patient's PVR The small difference is a result of the patient's mean pulmonary artery pressure (mPAP). In some embodiments, the method This relates to reducing the patient's PVR by at least 1%. In some embodiments, the method This relates to reducing the patient's PVR by at least 5%. In some embodiments, the method This relates to reducing the patient's PVR by at least 10%. In some embodiments, The law relates to reducing the patient's PVR by at least 15%. In some embodiments, The method relates to reducing the patient's PVR by at least 20%. In some embodiments, The method relates to reducing the patient's PVR by at least 25%. In some embodiments The method relates to reducing the patient's PVR by at least 30%. Some embodiments The method concerns reducing the patient's PVR by at least 35%. Some implementations The method involves reducing the patient's PVR by at least 40%. In terms of form, the method relates to reducing the patient's PVR by at least 45%. In terms of administration methods, the approach relates to reducing the patient's PVR by at least 50%. In some embodiments, the method relates to reducing the patient's PVR by at least 55%. In one embodiment, the method relates to reducing the patient's PVR by at least 60%. In one embodiment, the method relates to reducing a patient's PVR by at least 65%. In some embodiments, the method relates to reducing the patient's PVR by at least 70%. In some embodiments, the method relates to reducing the patient's PVR by at least 75%. In some embodiments, the method relates to reducing the patient's PVR by at least 80%. In some embodiments, the method reduces the patient's PVR by at least 85%. Regarding this, in some embodiments, the method reduces the patient's PVR by at least 90%. Regarding this matter, in some embodiments, the method reduces the patient's PVR by at least 95%. This relates to the following. In some embodiments, the method reduces the patient's PVR by at least 100%. Regarding the act of doing something.

[0156] In some embodiments, PVR is used to enable patients to use ActRII poly(P) as disclosed herein. Tested after a 4-week treatment using the peptide. In some embodiments, PVR This refers to a patient undergoing an 8-week treatment using the ActRII polypeptide disclosed herein. It is tested after the procedure. In some embodiments, the PVR is disclosed herein The test will be conducted after a 12-week treatment using the ActRII polypeptide. In some embodiments, PVR is used to allow a patient to use the ActRII polyp disclosed herein. It is tested after a 16-week treatment using ptide. In some embodiments, PVR This refers to a 20-week period in which the patient utilizes the ActRII polypeptide disclosed herein. Tested after treatment. In some embodiments, PVR is disclosed herein The test will be conducted after a 22-week treatment using ActRII polypeptide. In some embodiments, PVR is used to enable the patient to use ActRII poly(P) as disclosed herein. It is tested after a 24-week treatment using the peptide. In some embodiments, PV R refers to a 26-week period during which the patient utilized the ActRII polypeptide disclosed herein. It is tested after the procedure. In some embodiments, the PVR is performed on the patient as described herein. The study was conducted after a 28-week treatment using the ActRII polypeptide shown. In some embodiments, PVR is used to enable the patient to use ActRII as disclosed herein. The test will be conducted after a 48-week treatment using lipeptides.

[0157] BNP Both BNP and NT-proBNP are atrium and cardiac due to increased intracardiac pressure. It is a marker of ventricular distension. The New York Heart Association (NYHA) uses a marker based on the severity of symptoms. We developed a four-stage functional classification system for congestive heart failure (CHF). The measured concentrations of circulating BNP and NT-proBNP are based on the NYHA classification. It has been demonstrated that this increases with the severity of CHF. In certain aspects, this disclosure, To treat, prevent, or reduce the rate of progression and / or severity of PAH. A method comprising an effective amount of ActRII polypeptide (e.g., residues 30-1 of SEQ ID NO: 1). (An amino acid sequence that is at least 90% identical to the amino acid sequence corresponding to 10) This includes administering the drug to patients who require it, and the patient receiving at least 100 pg / mL (for example, a small amount). Even without that, 100, 150, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 3000, 5000, 10,000, 15,000, or 20,0 A method relating to a brain natriuretic peptide (BNP) level of 00 pg / mL In some embodiments, the method has a BNP level of at least 100 pg / mL. Regarding the patient. In some embodiments, the method involves a BNP level of at least 150 pg / mL. This relates to patients having the condition. In some embodiments, the method involves at least 200 pg / mL This relates to patients with BNP levels. In some embodiments, the method is at least 300p This relates to patients having BNP levels of g / mL. In some embodiments, the method is at least This also relates to patients with a BNP level of 400 pg / mL. In some embodiments, the method , relating to patients having a BNP level of at least 500 pg / mL. In some embodiments The method relates to patients with a BNP level of at least 600 pg / mL. In the embodiment, the method relates to patients having a BNP level of at least 700 pg / mL. In some embodiments, the method has a BNP level of at least 800 pg / mL. Regarding the patient. In some embodiments, the method involves a BNP level of at least 900 pg / mL. This relates to patients with the condition. In some embodiments, the method involves at least 1000 pg / mL This relates to patients having BNP levels. In some embodiments, the method involves at least 300 This relates to patients with a BNP level of 0 pg / mL. In some embodiments, the method is less This relates to patients having a BNP level of at least 5000 pg / mL. In some embodiments, The method concerns patients with BNP levels of at least 10,000 pg / mL. In one embodiment, the method is used for patients having a BNP level of at least 15,000 pg / mL. Regarding the person. In some embodiments, the method involves at least 20,000 pg / mL of BNP. Regarding patients having a level. In some embodiments, the method is compared to a healthy patient. Regarding the management of patients with elevated BNP levels.

[0158] In some embodiments, this disclosure relates to one or more hemodynamic parameters in PAH patients. The monitor is at a more normal level (for example, normal compared to a healthy person of similar age and sex). A method of adjusting for this, and for patients who need it, an effective amount of ActRII poly Peptides (for example, amino acid sequences corresponding to residues 30-110 of SEQ ID NO: 1 and at least The present invention relates to a method comprising the step of administering an amino acid sequence that is 90% identical. In this case, the method relates to reducing the patient's BNP level by at least 10 pg / mL. In some embodiments, the method reduces the patient's BNP level by at least 50 pg / mL. Regarding causing a patient's BNP level to be at least 1 This relates to reducing the BNP level of the patient by 0.00 pg / mL. In some embodiments, the method involves reducing the BNP level of the patient. The method relates to reducing the bell by at least 200 pg / mL. In some embodiments, the method This relates to reducing the patient's BNP level by at least 300 pg / mL. In one embodiment, the method reduces the patient's BNP level by at least 400 pg / mL. This relates to the following. In some embodiments, the method involves raising the patient's BNP level to at least 500 pg The method relates to reducing the patient's BNP level by / mL. In some embodiments, the method reduces the patient's BNP level. The method relates to reducing the level by at least 600 pg / mL. In some embodiments, the method relates to the patient This relates to reducing the BNP level by at least 700 pg / mL. Some embodiments The method involves reducing the patient's BNP level by at least 800 pg / mL. In some embodiments, the method reduces the patient's BNP level by at least 900 pg / mL. Regarding reducing. In some embodiments, the method reduces the patient's BNP level to at least This relates to reducing the BN by 1000 pg / mL. In some embodiments, the method involves the patient's BN This relates to reducing the P level by at least 5000 pg / mL. In some embodiments, The method concerns reducing the patient's BNP levels to normal levels. Some implementations Morphologically, a normal level corresponds to a level of <100 pg / mL.

[0159] In some embodiments, the method involves reducing the patient's BNP by at least 5% (e.g., at least 5%) , 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, Regarding reductions of 75%, 80%, 85%, 90%, 95%, or 100%. Partial implementation In terms of form, the method relates to reducing the patient's BNP by at least 5%. Some implementations In terms of form, the method relates to reducing the patient's BNP by at least 10%. In terms of administration, the method relates to reducing the patient's BNP by at least 15%. In some embodiments, the method relates to reducing a patient's BNP by at least 20%. In one embodiment, the method relates to reducing a patient's BNP by at least 25%. In one embodiment, the method relates to reducing a patient's BNP by at least 30%. In some embodiments, the method relates to reducing the patient's BNP by at least 35%. In some embodiments, the method relates to reducing the patient's BNP by at least 40%. In some embodiments, the method relates to reducing the patient's BNP by at least 45%. In some embodiments, the method aims to reduce the patient's BNP by at least 50%. Regarding this, in some embodiments, the method reduces the patient's BNP by at least 55%. Regarding this matter, in some embodiments, the method reduces the patient's BNP by at least 60%. This relates to the following. In some embodiments, the method reduces the patient's BNP by at least 65%. Regarding this matter, in some embodiments, the method reduces the patient's BNP by at least 70%. This relates to reducing the patient's BNP by at least 75%. In some embodiments, the method reduces the patient's BNP by at least 75%. This relates to reducing the patient's BNP by at least 80%. In some embodiments, the method reduces the patient's BNP by at least 80%. Regarding causing this, in some embodiments, the method reduces the patient's BNP by at least 85%. Regarding reducing. In some embodiments, the method reduces the patient's BNP by at least 90%. The method relates to reducing the patient's BNP by at least 95%. The method relates to reducing by %. In some embodiments, the method involves reducing the patient's BNP by at least 1 Regarding reducing by 00%.

[0160] NT-proBNP In certain aspects, this disclosure relates to treating, preventing, or accelerating PAH. A method to reduce the severity of and / or to an effective dose of A to a patient who needs it. ctRII polypeptide (for example, amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1) The step includes administering an amino acid sequence that is at least 90% identical to the sequence, and the patient is less At least 100 pg / mL (for example, at least 100, 150, 200, 300, 40 0, 500, 600, 700, 800, 900, 1000, 3000, 5000, 10 (000, 15,000, 20,000, 25,000 or 30,000 pg / mL) This invention relates to a method having NT-proBNP levels. In some embodiments, the method has a small This concerns patients with an NT-proBNP level of at least 100 pg / mL. Morphologically, the method involves patients with an NT-proBNP level of at least 150 pg / mL. Regarding the person. In some embodiments, the method involves at least 200 pg / mL of NT-pro This relates to patients with BNP levels. In some embodiments, the method is at least 300p This relates to patients having NT-proBNP levels of g / mL. In some embodiments, the method This relates to patients with an NT-proBNP level of at least 400 pg / mL. In one embodiment, the method involves achieving an NT-proBNP level of at least 500 pg / mL. Regarding patients having the following: In some embodiments, the method involves at least 600 pg / mL of NT - relating to patients having proBNP levels. In some embodiments, the method is at least This relates to patients with an NT-proBNP level of 700 pg / mL. In some embodiments, The method involves patients with an NT-proBNP level of at least 800 pg / mL. In some embodiments, the method involves at least 900 pg / mL of NT-proBNP. This relates to patients having a level. In some embodiments, the method involves at least 1000 pg / This relates to patients having an NT-proBNP level of mL. In some embodiments, the method is This applies to patients with NT-proBNP levels of at least 3000 pg / mL. In this embodiment, the method provides an NT-proBNP level of at least 5000 pg / mL. Regarding patients having the condition. In some embodiments, the method involves at least 10,000 pg / mL This relates to patients having NT-proBNP levels. In some embodiments, the method is less This applies to patients with NT-proBNP levels of at least 15,000 pg / mL. In this embodiment, the method involves at least 20,000 pg / mL of NT-proBNP level This relates to patients having the condition. In some embodiments, the method involves administering at least 25,000 pg / This relates to patients having an NT-proBNP level of mL. In some embodiments, the method is This applies to patients with NT-proBNP levels of at least 30,000 pg / mL. In some embodiments, the method compares elevated NT-proBNP levels in healthy patients. Regarding the treatment of patients with [unspecified condition].

[0161] In some embodiments, this disclosure relates to one or more hemodynamic parameters in PAH patients. The monitor is at a more normal level (for example, normal compared to a healthy person of similar age and sex). A method of adjusting for this, and for patients who need it, an effective amount of ActRII poly Peptides (for example, amino acid sequences corresponding to residues 30-110 of SEQ ID NO: 1 and at least The present invention relates to a method comprising the step of administering an amino acid sequence that is 90% identical. In this context, the method concerns reducing the patient's NT-proBNP levels. In terms of administration methods, the approach involves reducing the patient's NT-proBNP level by at least 10 pg / mL. Regarding causing a patient's NT-proBNP level The method relates to reducing by at least 50 pg / mL. In some embodiments, the method relates to the patient This relates to reducing NT-proBNP levels by at least 100 pg / mL. In one embodiment, the method involves raising the patient's NT-proBNP level to at least 200 pg / The method relates to reducing the patient's NT-proBNP by mL. In some embodiments, the method relates to reducing the patient's NT-proBNP by mL. The method relates to reducing the level by at least 300 pg / mL. In some embodiments, The law requires a reduction of at least 400 pg / mL in the patient's NT-proBNP level. Regarding this, in some embodiments, the method raises the patient's NT-proBNP level to at least 5 This relates to reducing the patient's NT-p Regarding reducing roBNP levels by at least 600 pg / mL. Some implementations In this case, the method involves reducing the patient's NT-proBNP level by at least 700 pg / mL. This relates to reducing the patient's NT-proBNP level. In some embodiments, the method reduces the patient's NT-proBNP level. The method relates to reducing the level by at least 800 pg / mL. In some embodiments, the method relates to the patient Regarding reducing NT-proBNP levels by at least 900 pg / mL. In one embodiment, the method involves raising the patient's NT-proBNP level to at least 1000 pg The method relates to reducing the patient's NT-proBN This relates to reducing the P level by at least 5000 pg / mL. In some embodiments, The method involves reducing the patient's NT-proBNP level by at least 10,000 pg / mL. This relates to reducing the patient's NT-proBNP level. In some embodiments, the method reduces the patient's NT-proBNP level. The method relates to reducing the level by at least 15,000 pg / mL. In some embodiments, the method To reduce the patient's NT-proBNP level by at least 20,000 pg / mL. Regarding this, in some embodiments, the method reduces the patient's NT-proBNP level to at least Regarding a reduction of 25,000 pg / mL.

[0162] In some embodiments, the method reduces the patient's NT-proBNP levels to normal levels. Regarding reducing and maintaining their normal NT-proBNP levels. In some embodiments, this disclosure relates to one or more hemodynamic parameters in PAH patients. Maintain the hormone at a normal level (for example, normal compared to a healthy person of similar age and sex). A method comprising an effective amount of ActRII polypeptide (for example, residue 30 of SEQ ID NO: 1) (An amino acid sequence that is at least 90% identical to the amino acid sequence corresponding to ~110) The present invention relates to a method, which includes administering to patients who require it. In some embodiments, the method is Regarding maintaining patients' NT-proBNP levels at normal levels. Some implementations In this case, the method is to maintain the patient's NT-proBNP level at less than 100 pg / mL. This relates to the following. In some embodiments, the method involves raising the patient's NT-proBNP level to 200p Regarding maintaining a level below g / mL. In some embodiments, the method involves the patient's NT-pr This relates to maintaining oBNP levels below 300 pg / mL. In some embodiments, The method involves maintaining the patient's NT-proBNP level below 400 pg / mL. ru.

[0163] In some embodiments, the method involves reducing the patient's NT-proBNP to at least 5% (e.g., At least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, Regarding reducing by 65, 70, 75, 80, 85, 90, 95, or 100%) In some embodiments, the method reduces the patient's NT-proBNP by at least 5%. This relates to the following. In some embodiments, the method involves reducing the patient's NT-proBNP by at least 1 The method relates to reducing the patient's NT-proBNP by 0%. In some embodiments, the method involves reducing the patient's NT-proBNP by 0%. The method relates to reducing the patient's NT by at least 15%. In some embodiments, the method involves the patient's NT. -Related to reducing proBNP by at least 20%. In some embodiments, the method This relates to reducing patients' NT-proBNP levels by at least 25%. Some implementations Morphologically, the method relates to reducing the patient's NT-proBNP by at least 30%. In some embodiments, the method reduces the patient's NT-proBNP by at least 35%. Regarding reducing the patient's NT-proBNP. In some embodiments, the method reduces the patient's NT-proBNP. It also relates to reducing by 40%. In some embodiments, the method involves the patient's NT-proB The method relates to reducing NP by at least 45%. In some embodiments, the method relates to the patient The present invention relates to reducing NT-proBNP by at least 50%. In some embodiments, The method concerns reducing the patient's NT-proBNP by at least 55%. In one embodiment, the method reduces the patient's NT-proBNP by at least 60%. Regarding this, in some embodiments, the method reduces the patient's NT-proBNP by at least 65%. Regarding reducing. In some embodiments, the method reduces the patient's NT-proBNP. The method relates to reducing by at least 70%. In some embodiments, the method involves reducing the patient's NT-pr The present invention relates to reducing oBNP by at least 75%. In some embodiments, the method involves the patient The present invention relates to reducing the NT-proBNP of the subject by at least 80%. In some embodiments, The method relates to reducing the patient's NT-proBNP by at least 85%. In one embodiment, the method reduces the patient's NT-proBNP by at least 90%. This relates to the following. In some embodiments, the method involves reducing the patient's NT-proBNP to at least 95%. Regarding reducing by %. In some embodiments, the method involves reducing the patient's NT-proBNP The method relates to reducing the patient's NT by at least 100%. In some embodiments, the method involves the patient's NT. -Related to reducing proBNP levels to normal levels. In some embodiments, The normal level of NT-proBNP is <100 pg / ml. In some embodiments The method involves reducing the patient's NT-proBNP level to less than 300 ng / L. Regarding.

[0164] smooth muscle hypertrophy In certain aspects, this disclosure relates to treating, preventing, or accelerating PAH. A method to reduce the severity of and / or to an effective dose of A to a patient who needs it. ctRII polypeptide (for example, amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1) The step includes administering an amino acid sequence that is at least 90% identical to the sequence, and the patient is able to This disclosure relates to a method for having smooth muscle hypertrophy. In some embodiments, this disclosure relates to a patient with PAH. One or more parameters are set to a more normal level (for example, similar age and gender). A method of adjusting towards normal (compared to a healthy person), and for patients who need it, The effective ActRII polypeptide (for example, the residues corresponding to residues 30-110 of SEQ ID NO: 1) A method comprising the step of administering an amino acid sequence that is at least 90% identical to the amino acid sequence. Regarding. In some embodiments, the method relates to reducing smooth muscle hypertrophy in patients. In some embodiments, the method reduces the patient's smooth muscle hypertrophy by at least 1% (e.g., less than 1%). Kutomo 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, Regarding reducing by 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, the method relates to reducing the patient's smooth muscle hypertrophy by at least 1%. In some embodiments, the method reduces the patient's smooth muscle hypertrophy by at least 5%. Regarding this matter, in some embodiments, the method reduces the patient's smooth muscle hypertrophy by at least 10%. This relates to the following: In some embodiments, the method reduces the patient's smooth muscle hypertrophy by at least 15%. The method relates to causing smooth muscle hypertrophy in patients at least 20 Regarding a % reduction. In some embodiments, the method reduces the patient's smooth muscle hypertrophy. It also relates to reducing by 25%. In some embodiments, the method reduces the smooth muscle hypertrophy in patients. The method relates to reducing by at least 30%. In some embodiments, the method involves the patient's smooth muscle mass The method relates to reducing the size by at least 35%. In some embodiments, the method involves the patient's level The present invention relates to reducing smooth muscle hypertrophy by at least 40%. In some embodiments, the method is used to treat the patient The present invention relates to reducing smooth muscle hypertrophy in individuals by at least 45%. In some embodiments, the method This relates to reducing smooth muscle hypertrophy in patients by at least 50%. In some embodiments, The method relates to reducing smooth muscle hypertrophy in patients by at least 55%. Some implementations The method concerns reducing smooth muscle hypertrophy in patients by at least 60%. In one embodiment, the method relates to reducing a patient's smooth muscle hypertrophy by at least 65%. In some embodiments, the method relates to reducing the patient's smooth muscle hypertrophy by at least 70%. In some embodiments, the method reduces the patient's smooth muscle hypertrophy by at least 75%. In some embodiments, the method reduces the patient's smooth muscle hypertrophy by at least 80%. Regarding the reduction of smooth muscle hypertrophy in patients by at least 85%. In some embodiments, the method reduces smooth muscle hypertrophy in patients by at least 85%. Regarding reducing. In some embodiments, the method reduces the smooth muscle hypertrophy of the patient to at least Regarding reducing by 90%. In some embodiments, the method reduces the smooth muscle hypertrophy in the patient. The method relates to reducing by at least 95%. In some embodiments, the method relates to the smooth muscle hypertrophy of patients. Regarding reducing it by at least 100%.

[0165] Pulmonary arteriole muscularization In certain aspects, this disclosure relates to treating, preventing, or accelerating PAH. A method to reduce the severity of (an effective amount of ActRII polypeptide) (For example, the amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1 is at least 90% identical.) This involves administering a specific amino acid sequence to patients who require it, and the patient's condition is increasing. The present disclosure relates to a method having muscular pulmonary arterioles. In some embodiments, the present disclosure relates to PAH One or more parameters in a patient are at a more normal level (for example, similar age). A method of adjusting to normal (compared to a healthy person of the same sex), with an effective amount of ActR II polypeptide (for example, the amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1 and a small amount This includes administering an amino acid sequence (which is at least 90% identical) to patients who require it. Regarding the method, in some embodiments, the method reduces the muscularity of the pulmonary arterioles in the patient. Regarding causing this. In some embodiments, the method reduces the muscularity of the patient's pulmonary arterioles. Also 1% (for example, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 5 Reduce by 5, 60, 65, 70, 75, 80, 85, 90, 95, or 100% The method relates to reducing the muscularity of the patient's pulmonary arterioles by at least 1%. Regarding reducing. In some embodiments, the method reduces the muscularity of the patient's pulmonary arterioles. Both relate to a 5% reduction. In some embodiments, the method involves the muscle of the patient's pulmonary arterioles. The method relates to reducing quality by at least 10%. In some embodiments, the method involves the patient's lungs. The method relates to reducing the muscularity of arterioles by at least 15%. In some embodiments, the method This relates to reducing the muscularity of the patient's pulmonary arterioles by at least 20%. Some implementations The method involves reducing the muscularity of the patient's pulmonary arterioles by at least 25%. In some embodiments, the method reduces the muscularity of the patient's pulmonary arterioles by at least 30%. The method relates to the following: In some embodiments, the method reduces the muscularity of the patient's pulmonary arterioles by at least 35% Regarding reduction. In some embodiments, the method reduces the muscularity of the patient's pulmonary arterioles. The method relates to reducing by at least 40%. In some embodiments, the method involves the patient's pulmonary arterioles The method relates to reducing muscle mass by at least 45%. In some embodiments, the method involves the patient This relates to reducing the muscularity of the pulmonary arterioles by at least 50%. In some embodiments, The method involves reducing the muscularity of the patient's pulmonary arterioles by at least 55%. In terms of administration, the method involves reducing the muscularity of the patient's pulmonary arterioles by at least 60%. In some embodiments, the method reduces the muscularity of the patient's pulmonary arterioles by at least 65%. The method relates to the following: In some embodiments, the method involves the muscular tissue of the patient's pulmonary arterioles being reduced to at least 7 Regarding reducing by 0%. In some embodiments, the method involves the muscular tissue of the patient's pulmonary arterioles The method relates to reducing by at least 75%. In some embodiments, the method relates to the patient's pulmonary fibrillation The method relates to reducing the muscularity of the pulse by at least 80%. In some embodiments, the method is This relates to reducing the muscularity of the patient's pulmonary arterioles by at least 85%. In some embodiments, The method involves reducing the muscularity of the patient's pulmonary arterioles by at least 90%. In this embodiment, the method reduces the muscularity of the patient's pulmonary arterioles by at least 95%. Regarding this, in some embodiments, the method reduces the muscularity of the patient's pulmonary arterioles by at least 100%. Regarding reducing.

[0166] Percentage of hospitalizations In certain aspects, this disclosure relates to treating, preventing, or accelerating PAH. A method to reduce the severity of and / or to an effective dose of A to a patient who needs it. ctRII polypeptide (for example, amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1) The step includes administering an amino acid sequence that is at least 90% identical to the sequence, and the patient's hospitalization. The rate should be at least 1% (for example, at least 1%, 2%, 3%, 4%, 5%, 10%, 15%). %, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65 Reduce by %, 70%, 75%, 80%, 85%, 90%, 95%, or 100%) Regarding the law. In some embodiments, the method reduces the rate of hospitalization of patients by at least 1%. Regarding this matter, in some embodiments, the method reduces the patient hospitalization rate by at least 2%. This relates to reducing the hospitalization rate of patients by at least 3%. This relates to reducing the rate of hospitalization among patients by at least 4%. In some embodiments, the method reduces the rate of hospitalization among patients by at least 4%. Regarding causing this, in some embodiments, the method reduces the patient hospitalization rate by at least 5%. Regarding reducing. In some embodiments, the method reduces the patient hospitalization rate to at least 10 The method relates to reducing by %. In some embodiments, the method reduces the patient hospitalization rate by at least The method relates to reducing by 15%. In some embodiments, the method reduces the rate of hospitalization of patients. The method relates to reducing both by 20%. In some embodiments, the method reduces the rate of hospitalization of patients. The method relates to reducing by at least 25%. In some embodiments, the method relates to the patient hospitalization rate. The method relates to reducing by at least 30%. In some embodiments, the method involves the patient's hospitalization. The method relates to reducing the percentage by at least 35%. In some embodiments, the method relates to the patient The present invention relates to reducing the hospitalization rate by at least 40%. In some embodiments, the method involves the patient The invention relates to reducing the hospitalization rate of patients by at least 45%. In some embodiments, the method The invention relates to reducing the hospitalization rate of patients by at least 50%. In some embodiments, The law relates to reducing the rate of hospitalization for patients by at least 55%. In some embodiments, The method relates to reducing the hospitalization rate of patients by at least 60%. Some embodiments The method concerns reducing the hospitalization rate of patients by at least 65%. In terms of form, the method relates to reducing the hospitalization rate of patients by at least 70%. In one embodiment, the method relates to reducing the patient hospitalization rate by at least 75%. In one embodiment of the part, the method relates to reducing the hospitalization rate of patients by at least 80%. In some embodiments, the method relates to reducing the patient hospitalization rate by at least 85%. In some embodiments, the method reduces the rate of patient hospitalization by at least 90%. Regarding this matter, in some embodiments, the method reduces the patient hospitalization rate by at least 95%. This relates to the following: In some embodiments, the method reduces the patient hospitalization rate by at least 100%. The method relates to causing one or more PAHs. In some embodiments, the method relates to one or more PAHs. Reduce the risk of hospitalization due to complications.

[0167] Quality of Life In certain aspects, this disclosure relates to treating, preventing, or accelerating PAH. A method to reduce the severity of and / or to an effective dose of A to a patient who needs it. ctRII polypeptide (for example, amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1) The step includes administering an amino acid sequence that is at least 90% identical to the sequence, and the patient's quorum Life of life reduced by at least 1% (for example, at least 1%, 2%, 3%, 4%, 5%) 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55% (60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%) This relates to methods for increasing the patient's quality of life. In some embodiments, the methods increase the patient's quality of life. The method relates to increasing by at least 1%. In some embodiments, the method relates to the quality of the patient The method relates to increasing the lifespan by at least 2%. In some embodiments, the method Regarding increasing the patient's quality of life by at least 3%. Some implementations In this context, the method aims to increase the patient's quality of life by at least 4%. In some embodiments, the method increases the patient's quality of life by at least 5%. Regarding the matter, in some embodiments, the method reduces the patient's quality of life. It also relates to increasing by 10%. In some embodiments, the method relates to the patient's quality of The method relates to increasing life by at least 15%. In some embodiments, the method relates to the patient Regarding increasing the quality of life by at least 20%. In some embodiments The method concerns increasing the patient's quality of life by at least 25%. In some embodiments, the method increases the patient's quality of life by at least 30%. Regarding the matter, in some embodiments, the method reduces the patient's quality of life. It also relates to increasing by 35%. In some embodiments, the method relates to the patient's quality of The method relates to increasing life by at least 40%. In some embodiments, the method involves the patient Regarding increasing the quality of life by at least 45%. In some embodiments The method concerns increasing the patient's quality of life by at least 50%. In some embodiments, the method increases the patient's quality of life by at least 55%. Regarding the matter, in some embodiments, the method reduces the patient's quality of life. It also relates to increasing by 60%. In some embodiments, the method relates to the patient's quality of The method relates to increasing life by at least 65%. In some embodiments, the method involves the patient Regarding increasing the quality of life by at least 70%. In some embodiments The method concerns increasing the patient's quality of life by at least 75%. In some embodiments, the method increases the patient's quality of life by at least 80%. Regarding the matter, in some embodiments, the method reduces the patient's quality of life. It also relates to increasing it by 85%. In some embodiments, the method is related to the patient's quality of The method relates to increasing life by at least 90%. In some embodiments, the method involves the patient Regarding increasing the quality of life by at least 95%. In some embodiments The method is related to increasing the patient's quality of life by at least 100%. .

[0168] In some embodiments, the patient's quality of life is affected by the outcome of Cambridge pulmonary hypertension. Measured using a view (CAMPHOR). In some embodiments, patient quality Life is measured using PAH-SYMPACT®. In terms of treatment methods, the patient's quality of life is measured by the Medical Outcomes Survey Short Form 36 (SF). It is measured using -36). In some embodiments, the patient's quality of life is Measured using Euro Quality of Life (EuroQol). Some embodiments So, the patient's quality of life is measured in EuroQuality of Life - 5 Dimensions. (EQ-5D) is used for measurement. In some embodiments, the patient's quality of light is measured. The F is Euro Quality of Life - 5 Dimension 5 Level (EQ-5D-5L) It is measured using [unclear text]. In some embodiments, the patient's quality of life is measured using [unclear text]. It is measured using the KCCQ (Kidney Cardiomyopathy Questionnaire).

[0169] ejection fraction In certain aspects, this disclosure relates to treating, preventing, or accelerating PAH. A method to reduce the severity of and / or to an effective dose of A to a patient who needs it. ctRII polypeptide (for example, amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1) The step includes administering an amino acid sequence that is at least 90% identical to the sequence, and the patient is 1 Less than 0% (for example, 10, 15, 20, 25, 30, 35, 40, 45, 50 or 55) The present invention relates to a method having an ejection fraction of less than 10%. In some embodiments, the method has an ejection fraction of less than 10%. This relates to patients with a full ejection fraction. In some embodiments, the method is used for patients with an ejection fraction of less than 15%. Regarding patients having: In some embodiments, the method is used for patients having an ejection fraction of less than 20%. Regarding. In some embodiments, the method relates to patients having an ejection fraction of less than 25%. In some embodiments, the method relates to patients having an ejection fraction of less than 30%. The method relates to patients with an ejection fraction of less than 35%. In some embodiments, the method is This relates to patients with an ejection fraction of less than 40%. In some embodiments, the method is for patients with less than 45% This relates to patients with an ejection fraction. In some embodiments, the method is for patients with an ejection fraction of less than 50%. Regarding patients. In some embodiments, the method relates to patients with an ejection fraction of less than 55%. In some embodiments, the ejection fraction is the right ventricular ejection fraction. In some embodiments, the ejection fraction is This is the left ventricular ejection fraction. In some embodiments, the ejection fraction is measured using echocardiography. In some embodiments, the patient has a maintained left ventricular ejection fraction.

[0170] In some embodiments, this disclosure relates to one or more hemodynamic parameters in PAH patients. A method of adjusting the motor towards a more normal level (for example, >50% ejection fraction). , an effective amount of ActRII polypeptide (for example, corresponding to residues 30-110 of SEQ ID NO: 1) (An amino acid sequence that is at least 90% identical to the amino acid sequence used) for patients who need it. The present invention relates to a method, which includes administering to a patient. In some embodiments, the method reduces the patient's ejection fraction. The method relates to increasing the patient's ejection fraction by at least 1%. In some embodiments, the method reduces the patient's ejection fraction. The method relates to increasing the patient's ejection fraction by at least 5%. In some embodiments, the method reduces the patient's ejection fraction. The method relates to increasing the patient's ejection fraction by at least 10%. In some embodiments, the method relates to increasing the patient's ejection fraction The method relates to increasing by at least 15%. In some embodiments, the method relates to the patient's ejection fraction The method relates to increasing by at least 20%. In some embodiments, the method involves the ejection of the patient The method relates to increasing the rate by at least 25%. In some embodiments, the method involves the patient The method relates to increasing the output rate by at least 30%. In some embodiments, the method relates to the patient The method relates to increasing the ejection fraction by at least 35%. In some embodiments, the method relates to the patient The present invention relates to increasing the ejection rate by at least 40%. In some embodiments, the method involves the patient The present invention relates to increasing the ejection rate of the person by at least 45%. In some embodiments, the method is The invention relates to increasing the patient's ejection fraction by at least 50%. In some embodiments, the method The method relates to increasing the patient's ejection fraction by at least 55%. In some embodiments, the method This relates to increasing the patient's ejection fraction by at least 60%. In some embodiments, The law relates to increasing the patient's ejection fraction by at least 65%. In some embodiments, The method relates to increasing the patient's ejection fraction by at least 70%. In some embodiments, The method relates to increasing the patient's ejection fraction by at least 75%. In some embodiments The method relates to increasing the patient's ejection fraction by at least 80%. Some embodiments The method, then, concerns increasing the patient's ejection fraction by at least 85%. Some implementations In this context, the method relates to increasing the patient's ejection fraction by at least 90%. Some implementations In terms of form, the method relates to increasing the patient's ejection fraction by at least 95%. In terms of application, the method relates to increasing the patient's ejection fraction by at least 100%.

[0171] Right ventricular function In certain aspects, this disclosure relates to methods for improving or maintaining right ventricular function in PAH. If available, an effective amount of ActRII polypeptide (for example, sequence number) should be given to patients who need it. Amino acids that are at least 90% identical to the amino acid sequence corresponding to residues 30-110 of No. 1 The present invention relates to a method that includes the step of administering a sequence of drugs. Improving or maintaining right ventricular function is a common goal for many heart It can be evaluated by echocardiographic measurements. Such as for evaluating right ventricular function. One quantitative approach is to measure the tricuspid annular systolic displacement (TAPSE). PSE is the systolic phase of the lateral tricuspid valve annulus towards the apex. By measuring the level of displacement, RV contraction function is estimated. Other echocardiographic measurements that can be used to assess retention and / or improvement include the right ventricular plane. Product ratio change (RVFAC), right ventricular end-diastolic area (RVEDA), right ventricular end-systolic area (RVE) SA), right ventricular ejection fraction (RVEF), right ventricle-pulmonary artery (RV-PA) coupling, pulmonary artery This includes, but is not limited to, pulse-systolic pressure (PASP), tricuspid regurgitation velocity (TRV), and right ventricular hypertrophy. It is not determined.

[0172] TAP SE The tricuspid annular systolic displacement (TAPSE) can be obtained using echocardiography. It represents a measure of the long-term function of the RV. TAPSE is a parameter that estimates the overall contractile function of the RV. It has been previously shown to have a good correlation with the meter. <17mm TAPSE is R This suggests a high degree of systolic dysfunction in the right ventricle (V) in some embodiments. Improvement or maintenance of function is measured as an increase in TAPSE. In some embodiments, right PAH patients with improved or maintained ventricular function have a TAPSE of 20mm to 28mm. In some embodiments, PAH patients with improved or maintained right ventricular function have at least It has a 20 mm TAPSE. In some embodiments, it improves or maintains right ventricular function. PAH patients have a TAPSE of at least 22 mm. In some embodiments, the right ventricle PAH patients with improved or maintained function have a TAPSE of at least 24 mm. In some embodiments, PAH patients with improved or maintained right ventricular function have at least two It has a 6 mm tapse. In some embodiments, it improves or maintains right ventricular function. PAH patients have a TAPSE of at least 28 mm. In some embodiments, TAP SE is measured using echocardiography.

[0173] In some embodiments, PAH patients with improved or maintained right ventricular function have a 16mm-3 It has a TAPSE between 0 mm. In some embodiments, it has improved or maintained right ventricular function. PAH patients have a TAPSE between 18 mm and 28 mm. In some embodiments, PAH patients with improved or maintained right ventricular function should have at least 18 mm of TAPSE. It has. In some embodiments, TAPSE is measured using echocardiography.

[0174] PASP In certain aspects, this disclosure relates to the treatment and prevention of pulmonary arterial hypertension (PAH). or a method for reducing the rate of progression and / or severity thereof, wherein an effective amount of Ac tRII polypeptide (for example, the amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1) To administer an amino acid sequence that is at least 90% identical to that of the patient in need. This includes, and the patient has a blood pressure of at least 30 mmHg (for example, at least 30, 35, 40, 45 Pulmonary artery systolic pressure (PA) of 50, 55, 60, 65, 70, 75, or 80 mmHg The present invention relates to a method having SP. This relates to patients with PASP. In some embodiments, the method is at least 35 mmH The method relates to a patient having PASP g. In some embodiments, the method is at least 40 mm This relates to patients with Hg PASP. In some embodiments, the method involves at least 45m This relates to patients with mHg PASP. In some embodiments, the method is at least 50 This relates to patients with PASP in mmHg. In some embodiments, the method is at least 5 This relates to a patient with PASP of 5 mmHg. In some embodiments, the method is at least This relates to a patient with PASP of 60 mmHg. In some embodiments, the method is at least This also relates to patients with PASP of 65 mmHg. In some embodiments, the method is less This relates to patients with PASP of 70 mmHg. In some embodiments, the method is less This relates to patients with PASP of at least 75 mmHg. In some embodiments, the method is less This relates to patients with PASP of at least 80 mmHg. In some embodiments, PASP This is the resting PASP. In some embodiments, PASP is the tricuspid valve regurgitation velocity (TRV). ) and right arterial (RA) pressure are used to determine the PASP. In some embodiments, the PASP is determined using The following formula: PASP=TRV 2 ×4 + RA pressure It is determined using

[0175] TRV has been shown to correlate with resting and exercise-induced PASP. Right ventricle and right The pressure difference between the clusters is given by a modified Bernoulli equation (Δp=4V). 2 It can be calculated using ). ru.

[0176] In some embodiments, this disclosure relates to one or more hemodynamic parameters in PAH patients. The monitor is at a more normal level (for example, normal compared to a healthy person of similar age and sex). A method for adjusting toward an effective amount of ActRII polypeptide (e.g., SEQ ID NO: The amino acid sequence corresponding to residues 30-110 of 1 is at least 90% identical to the amino acid sequence of 1. The present invention relates to a method, which includes administering a column (of the drug) to a patient who needs it. The method relates to improving pulmonary artery systolic pressure (PASP) in patients. In some embodiments, the method relates to reducing PASP. The patient's PASP is at least 1 mmHg (for example, at least 1, 2, 3, 5, 7, Regarding the reduction of 10, 12, 15, 20, 25, 30, or 35 mmHg. In some embodiments, the method aims to reduce the patient's PASP by at least 2 mmHg. Regarding this, in some embodiments, the method reduces the patient's PASP by at least 3 mmHg. Regarding the following: In a particular embodiment, the method involves moving the patient's PASP to at least 5 mm This relates to reducing Hg. In a particular embodiment, the method reduces the patient's PASP. The method relates to reducing the patient's P by at least 7 mmHg. In a particular embodiment, the method relates to reducing the patient's P This relates to reducing ASP by at least 10 mmHg. In a particular embodiment, The law concerns reducing the patient's PASP by at least 12 mmHg. In terms of administration, the method relates to reducing the patient's PASP by at least 15 mmHg. In a particular embodiment, the method reduces the patient's PASP by at least 20 mmHg. Regarding the following: In a particular embodiment, the method involves the patient's PASP at least 25m This relates to reducing mHg. In certain embodiments, the method reduces the patient's PASP. The method relates to reducing blood pressure by at least 30 mmHg. In a particular embodiment, the method relates to the patient Regarding reducing the PASP by at least 35 mmHg.

[0177] In some embodiments, this disclosure relates to one or more hemodynamic parameters in PH patients. The test results were at a more normal level (for example, normal compared to a healthy person of similar age and sex). A method of adjusting for this, and for patients who need it, an effective amount of ActRII polyp Plitter (for example, the amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1 and at least 9 The present invention relates to a method comprising the step of administering an amino acid sequence that is 0% identical. So, the method is to reduce the patient's PASP by at least 1% (for example, at least 1, 5, 10, 1) 5, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80 Regarding reducing by 85, 90, 95, or 100%. In some embodiments, The law relates to reducing the patient's PASP by at least 1%. In some embodiments, The method relates to reducing the patient's PASP by at least 5%. In some embodiments, The method relates to reducing the patient's PASP by at least 10%. Some embodiments The method concerns reducing the patient's PASP by at least 15%. In terms of form, the method relates to reducing the patient's PASP by at least 20%. In one embodiment, the method relates to reducing the patient's PASP by at least 25%. In one embodiment, the method relates to reducing the patient's PASP by at least 30%. In some embodiments, the method relates to reducing the patient's PASP by at least 35%. In some embodiments, the method reduces the patient's PASP by at least 40%. Regarding this matter, in some embodiments, the method reduces the patient's PASP by at least 45%. Regarding this matter, in some embodiments, the method reduces the patient's PASP by at least 50%. This relates to reducing the patient's PASP by at least 55%. In some embodiments, the method reduces the patient's PASP by at least 55%. Regarding reducing. In some embodiments, the method involves reducing the patient's PASP by at least 60 Regarding reducing by %. In some embodiments, the method reduces the patient's PASP by at least Regarding a 65% reduction. In some embodiments, the method reduces the patient's PASP. The method relates to reducing both by 70%. In some embodiments, the method reduces the patient's PASP The method relates to reducing PASP by at least 75%. In some embodiments, the method involves the patient's PASP. The method relates to reducing the patient's PA by at least 80%. In some embodiments, the method involves the patient's PA The method relates to reducing SP by at least 85%. In some embodiments, the method relates to the patient The present invention relates to reducing PASP by at least 90%. In some embodiments, the method involves the patient The method relates to reducing the PASP of the person by at least 95%. In some embodiments, the method , regarding reducing patients' PASP by at least 100%.

[0178] RV-PA coupling Right ventricular dysfunction is a central feature of PAH and a major factor affecting the prognosis. The energy transfer between contractility and atrial afterload is called coupling. Right ventricle (RV) The specific energy transfer between the right ventricle and the pulmonary artery is the right ventricle-pulmonary artery (RV-PA) coupling. This is referred to as [the term]. In some embodiments, right ventricular dysfunction occurs due to a decrease in RV-PA coupling. The RV-PA coupling is non-invasively estimated as the ratio of TAPSE / PASP values. It is possible. In some embodiments, TAPSE / PA ≥ 0.31 mm / mmHg The SP ratio may be associated with a better prognosis and may reduce the risk of clinical deterioration. In some embodiments, the improvement in the RV-PA coupling is due to the improvement in the PASP. So, the calculation of RV-PA coupling involves three parameters (for example, TRV, RAP) It depends on the pair of results (and TAPSE).

[0179] In certain aspects, this disclosure relates to the treatment and prevention of pulmonary arterial hypertension (PAH). or a method for reducing the rate of progression and / or severity thereof, wherein an effective amount of Ac tRII polypeptide (for example, the amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1) To administer an amino acid sequence that is at least 90% identical to that of the patient in need. This includes patients with a blood glucose level of less than 0.31 mmHg (for example, at least 0.3, 0.25, Having a TAPSE / PASP ratio of 0.2, 0.15, or 0.1 mm / mmHg, Regarding the method, in some embodiments, the method involves a TAPSE of less than 0.31 mm / mmHg. This relates to patients with a PASP ratio of 0.3 mm / mmH. In some embodiments, the method is 0.3 mm / mmH This relates to patients having a TAPSE / PASP ratio of less than g. In some embodiments, the method is Regarding patients with a TAPSE / PASP ratio of less than 0.25 mm / mmHg. In terms of administration method, the procedure is performed on patients with a TAPSE / PASP ratio of less than 0.2 mm / mmHg. Regarding the following: In some embodiments, the method involves TAPSE / P below 0.15 mm / mmHg. This relates to patients with an ASP ratio of 0.1 mm / mmHg. In some embodiments, the method is used for patients with an ASP ratio of 0.1 mm / mmHg. This relates to patients with a normal TAPSE / PASP ratio. In some embodiments, the method is normal Compared to patients with a normal TAPSE / PASP ratio, patients with a reduced TAPSE / PASP ratio To relate to.

[0180] In some embodiments, this disclosure relates to one or more hemodynamic parameters in PAH patients. The monitor is at a more normal level (for example, normal compared to a healthy person of similar age and sex). A method for adjusting toward an effective amount of ActRII polypeptide (e.g., SEQ ID NO: The amino acid sequence corresponding to residues 30-110 of 1 is at least 90% identical to the amino acid sequence of 1. The present invention relates to a method, which includes administering a column (of the drug) to a patient who needs it. The methods relate to improving or maintaining right ventricular function in patients. In the embodiment, PAH patients with improved or maintained right ventricular function had a blood pressure of 0.3 mmHg Ultra-high (e.g., 0.31, 0.32, 0.33, 0.34, or 0.35 mm / mmHg) It has a TAPSE / PASP ratio of (extremely high). In some embodiments, it improves or maintains right ventricular function. PAH patients with this condition have a TAPSE / PASP ratio greater than 0.31 mm / mmHg. In some embodiments, PAH patients with improved or maintained right ventricular function have a 0.32 mm It has a TAPSE / PASP ratio greater than / mmHg. In some embodiments, it improves right ventricular function. PAH patients with or maintaining a TAPSE / PASP ratio greater than 0.33 mmHg It has. In some embodiments, PAH patients with improved or maintained right ventricular function are 0. It has a TAPSE / PASP ratio of over 34 mm / mmHg. In some embodiments, the right ventricular unit PAH patients with improved or maintained function, TAPSE / P It has an ASP ratio. In some embodiments, improvement in right ventricular function is due to the TAPSE / PASP ratio. It is an increase. In some embodiments, the method increases the TAPSE / PASP ratio. Regarding this, in some embodiments, the method aims to reduce the patient's TAPSE / PASP ratio to at least 0. The method relates to increasing the patient's TA by 0.5 mmHg. In some embodiments, the method involves the patient's TA Regarding increasing the PSE / PASP ratio by at least 0.07 mm / mmHg. In this embodiment, the method involves setting the patient's TAPSE / PASP ratio to at least 0.10 mm / m This relates to increasing mHg. In some embodiments, the method involves the patient TAPSE / PA This relates to increasing the SP ratio by at least 0.12 mm / mmHg. In some embodiments, The method involves increasing the patient's TAPSE / PASP ratio by at least 0.15 mm / mmHg. Regarding the reduction of the patient's TAPSE / PASP ratio. In some embodiments, the method reduces the patient's TAPSE / PASP ratio. The method relates to increasing the value by at least 0.18 mm / mmHg. In some embodiments, the method is Regarding increasing the patient's TAPSE / PASP ratio by at least 0.20 mm / mmHg do.

[0181] In some embodiments, this disclosure relates to one or more hemodynamic parameters in PAH patients. The monitor is at a more normal level (for example, normal compared to a healthy person of similar age and sex). A method for adjusting toward an effective amount of ActRII polypeptide (e.g., SEQ ID NO: The amino acid sequence corresponding to residues 30-110 of 1 is at least 90% identical to the amino acid sequence of 1. The present invention relates to a method, which includes administering a column (of the drug) to a patient who needs it. The method involves increasing the patient's TAPSE / PASP ratio to at least 1% (e.g., at least 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70 Regarding increasing by 75, 80, 85, 90, 95, or 100%. Some actual In terms of administration, the method aims to increase the patient's TAPSE / PASP ratio by at least 5%. Regarding this, in some embodiments, the method involves increasing the patient's TAPSE / PASP ratio to at least 10 Regarding increasing by %. In some embodiments, the method involves the patient's TAPSE / PASP The method relates to increasing the ratio by at least 15%. In some embodiments, the method involves the patient's T This relates to increasing the APSE / PASP ratio by at least 20%. In some embodiments, The method involves increasing the patient's TAPSE / PASP ratio by at least 25%. In some embodiments, the method increases the patient's TAPSE / PASP ratio by at least 30%. Regarding the reduction of the patient's TAPSE / PASP ratio. In some embodiments, the method reduces the patient's TAPSE / PASP ratio. The method relates to increasing the patient's TAPSE by at least 35%. In some embodiments, the method involves the patient's TAPSE The method relates to increasing the / PASP ratio by at least 40%. In some embodiments, the method Regarding increasing the patient's TAPSE / PASP ratio by at least 45%. In terms of administration, the method involves increasing the patient's TAPSE / PASP ratio by at least 50%. Regarding this, in some embodiments, the method involves increasing the patient's TAPSE / PASP ratio to at least 5 Regarding increasing by 5%. In some embodiments, the method involves the patient's TAPSE / PAS The method relates to increasing the P ratio by at least 60%. In some embodiments, the method relates to the patient This relates to increasing the TAPSE / PASP ratio by at least 65% in some embodiments. The method relates to increasing the patient's TAPSE / PASP ratio by at least 70%. In some embodiments, the method increases the patient's TAPSE / PASP ratio by at least 75%. Regarding causing this. In some embodiments, the method reduces the patient's TAPSE / PASP ratio. The method relates to increasing the patient's TAPS by at least 80%. In some embodiments, the method involves the patient's TAPS The method relates to increasing the E / PASP ratio by at least 85%. In some embodiments, the method This relates to increasing the patient's TAPSE / PASP ratio by at least 90%. In the embodiment, the method increases the patient's TAPSE / PASP ratio by at least 95%. In some embodiments, the method involves reducing the patient's TAPSE / PASP ratio to at least Regarding increasing it by 100%.

[0182] RVFAC, RVEDA, and RVESA The rate of change in right ventricular area (RVFAC) is a non-invasive quantitative measure of right ventricular function. This can be calculated using the formula [(RVEDA-RVESA) / RVEDA]×100. Yes, it is possible. In some embodiments, RVFAC is measured using echocardiography. In this embodiment, normal RVFAC is approximately 47.5 ± 8.6% in males and approximately in females. The figure is 50.9 ± 8.0%. For example, Kou S, et al. European Heart Journal - See Cardiovascular Imaging. 2014 Jun 1;15(6):680-90. (Partial implementation) Morphologically, PAH patients have a decrease in RVFAC.

[0183] In certain aspects, this disclosure relates to the treatment and prevention of pulmonary arterial hypertension (PAH). or a method for reducing the rate of progression and / or severity thereof, wherein an effective amount of Ac tRII polypeptide (for example, the amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1) To administer an amino acid sequence that is at least 90% identical to that of the patient in need. Including patients with less than 20% (e.g., less than 20, 25, 30, 35, or 40%) This relates to a method having RVFAC. In some embodiments, the method has less than 25% RVF This relates to patients with AC. In some embodiments, the method has less than 30% RVFAC. Regarding patients who have less than 35% RVFAC. In some embodiments, the method is used for patients who have less than 35% RVFAC. Regarding. In some embodiments, the method relates to patients having less than 40% RVFAC. .

[0184] In some embodiments, this disclosure relates to one or more hemodynamic parameters in PAH patients. The monitor is at a more normal level (for example, normal compared to a healthy person of similar age and sex). A method for adjusting toward an effective amount of ActRII polypeptide (e.g., SEQ ID NO: The amino acid sequence corresponding to residues 30-110 of 1 is at least 90% identical to the amino acid sequence of 1. The present invention relates to a method, which includes administering a column (of the drug) to a patient who needs it. The methods relate to improving or maintaining right ventricular function in patients. In the embodiment, improvement or maintenance of right ventricular function occurs when the rate of change of right ventricular area (RVFAC) increases. This is due to the fact that, in some embodiments, PAH patients with improved or maintained right ventricular function are 32- It has RVFAC between 56%. In some embodiments, it has improved or maintained right ventricular function. PAH patients have at least 32% RVFAC. In some embodiments, the right ventricle PAH patients with improved or maintained function have at least 34% RVFAC. In some embodiments, PAH patients with improved or maintained right ventricular function are at least 35 It has % RVFAC. In some embodiments, it has PA which improves or maintains right ventricular function. Patient H has at least 36% RVFAC. In some embodiments, right ventricular function is improved. PAH patients with good or maintained condition have at least 38% RVFAC. In terms of treatment methods, PAH patients with improved or maintained right ventricular function had at least 40% RV In some embodiments, PAH patients with improved or maintained right ventricular function have FAC. , having at least 42% RVFAC. In some embodiments, improvement of right ventricular function or PAH patients with maintenance have at least 44% RVFAC. In some embodiments PAH patients with improved or maintained right ventricular function have at least 46% RVFAC. In some embodiments, PAH patients with improved or maintained right ventricular function are less Both have 48% RVFAC. In some embodiments, there is improvement or maintenance of right ventricular function. PAH patients have at least 50% RVFAC. In some embodiments, the right ventricle PAH patients with improved or maintained function have at least 52% RVFAC. In some embodiments, PAH patients with improved or maintained right ventricular function are at least 54 It has % RVFAC. In some embodiments, it has PA which improves or maintains right ventricular function. Patient H has at least 56% RVFAC.

[0185] In some embodiments, this disclosure relates to one or more echocardiographic parameters in PAH patients. The monitor is at a more normal level (for example, normal compared to a healthy person of similar age and sex). A method for adjusting toward an effective amount of ActRII polypeptide (e.g., SEQ ID NO: The amino acid sequence corresponding to residues 30-110 of 1 is at least 90% identical to the amino acid sequence of 1. The present invention relates to a method, which includes administering a column (of the drug) to a patient who needs it. The method involves reducing the patient's RVEDA to at least 1% (e.g., at least 1, 2, 3, 4, To reduce by 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or 20% Regarding. In some embodiments, the method increases the patient's RVFAC by at least 2%. Regarding the following, in some embodiments, the method increases the patient's RVFAC by at least 3%. This relates to increasing the patient's RVFAC by at least 4%. In some embodiments, the method increases the patient's RVFAC by at least 4%. Regarding causing the patient's RVFAC to decrease by at least 5%. In some embodiments, the method involves reducing the patient's RVFAC by at least 5%. Regarding increasing. In some embodiments, the method involves increasing the patient's RVFAC at least Regarding increasing by 6%. In some embodiments, the method reduces the patient's RVFAC. Both relate to increasing by 7%. In some embodiments, the method reduces the patient's RVFAC The method relates to increasing it by at least 8%. In some embodiments, the method involves the patient's RVFAC The method relates to increasing the patient's RVF by at least 9%. In some embodiments, the method involves increasing the patient's RVF The method relates to increasing AC by at least 10%. In some embodiments, the method relates to the patient The method relates to increasing RVFAC by at least 12%. In some embodiments, the method is The present invention relates to increasing the patient's RVFAC by at least 14%. In some embodiments, The law concerns increasing the patient's RVFAC by at least 16% in some embodiments. The method concerns increasing the patient's RVFAC by at least 18%. Some implementations In terms of form, the method relates to increasing the patient's RVFAC by at least 20%.

[0186] In some embodiments, the improvement in right ventricular function is due to an increase in ejection fraction. The improvement in right ventricular function is attributed to an increase in ejection fraction and an increase in the patient's RVFAC.

[0187] Right ventricular end-diastolic area (RVEDA) can be measured using echocardiography. A normal RVEDA is approximately 18.2 ± 4.3 cm in males. 2 Approximately 14.8±3 for women. 0.5cm 2 For example, Kou S, et al. European Heart Journal - Cardiov See ascular Imaging. 2014 Jun 1;15(6):680-90.

[0188] In certain aspects, this disclosure relates to the treatment and prevention of pulmonary arterial hypertension (PAH). or a method for reducing the rate of progression and / or severity thereof, wherein an effective amount of Ac tRII polypeptide (for example, the amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1) To administer an amino acid sequence that is at least 90% identical to that of the patient in need. This includes, and the patient is at least 22 cm 2 (For example, at least 22, 24, 26, 28, 30, 32, or 34 cm 2 The present invention relates to a method having RVEDA of some embodiments. So, the method is at least 24cm 2 Regarding patients with RVEDA. Some implementations In this case, the method is at least 26 cm 2 Regarding patients with RVEDA. Partial implementation In terms of form, the method is at least 28 cm 2 Regarding patients with RVEDA. Some actual In terms of application method, the method is at least 30 cm 2Regarding patients with RVEDA. Some In the embodiment, the method is at least 32 cm 2 Regarding patients with RVEDA. In this embodiment, the method is at least 34 cm 2 Regarding patients with RVEDA. In one embodiment of the part, the method has increased RVEDA compared to normal RVEDA. Regarding patients.

[0189] In some embodiments, this disclosure relates to one or more hemodynamic parameters in PAH patients. The monitor is at a more normal level (for example, normal compared to a healthy person of similar age and sex). A method of adjusting for this, and for patients who need it, an effective amount of ActRII poly Peptides (for example, amino acid sequences corresponding to residues 30-110 of SEQ ID NO: 1 and at least The present invention relates to a method comprising the step of administering an amino acid sequence that is 90% identical. In this context, the method relates to improving or maintaining right ventricular function in patients. In one embodiment, PAH patients with improved or maintained right ventricular function have a 14-22 cm 2 It has RVEDA. In some embodiments, improvement in right ventricular function is achieved by reducing RVEDA. In some embodiments, the method relates to reducing RVEDA. In this case, the method involves inserting the patient's RVEDA at least 1 cm 2 Regarding reduction. In one embodiment, the method involves moving the patient's RVEDA to at least 2 cm 2 Regarding reduction In some embodiments, the method involves moving the patient's RVEDA to at least 3 cm. 2 To reduce In some embodiments, the method involves moving the patient's RVEDA to at least 4 cm. 2 reduction Regarding causing the patient to RVEDA at least 5c m 2 Regarding reduction. In some embodiments, the method reduces the patient's RVEDA Both are 6cm 2 Regarding reduction. In some embodiments, the method involves the patient's RVEDA at least 7cm 2 Regarding reduction. In some embodiments, the method involves the patient's R VEDA at least 8cm 2 Regarding reduction. In some embodiments, the method is The patient's RVEDA should be at least 9 cm 2 Regarding reduction. In some embodiments, The method involves placing the patient's RVEDA at least 10 cm 2 Regarding reduction.

[0190] In some embodiments, this disclosure relates to one or more echocardiographic parameters in PAH patients. The monitor is at a more normal level (for example, normal compared to a healthy person of similar age and sex). A method for adjusting toward an effective amount of ActRII polypeptide (e.g., SEQ ID NO: The amino acid sequence corresponding to residues 30-110 of 1 is at least 90% identical to the amino acid sequence of 1. The present invention relates to a method, which includes administering a column (of the drug) to a patient who needs it. The method involves reducing the patient's RVEDA to at least 1% (e.g., at least 1, 5, 10, 1) Regarding reducing by 5, 20, 25, 30, 35, or 40%. Some embodiments The method concerns reducing patients' RVEDA by at least 5%. Some implementations In terms of form, the method relates to reducing the patient's RVEDA by at least 10%. In one embodiment, the method relates to reducing the patient's RVEDA by at least 15%. In some embodiments, the method reduces the patient's RVEDA by at least 20%. Regarding this, in some embodiments, the method reduces the patient's RVEDA by at least 25%. This relates to the following: In some embodiments, the method reduces the patient's RVEDA by at least 30%. Regarding causing the patient to have at least 35 RVEDA Regarding a % reduction. In some embodiments, the method reduces the patient's RVEDA It also relates to reducing it by 40%.

[0191] The right ventricular end-systolic area (RVESA) can be measured using echocardiography. A normal RVESA in males is approximately 9.6 ± 2.8 cm. 2 For women, approximately 7.3 ± 2.3 cm 2 For example, Kou S, et al. European Heart Journal - Cardiovascu See lar Imaging. 2014 Jun 1;15(6):680-90.

[0192] In certain aspects, this disclosure relates to the treatment and prevention of pulmonary arterial hypertension (PAH). or a method for reducing the rate of progression and / or severity thereof, wherein an effective amount of Ac tRII polypeptide (for example, the amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1) To administer an amino acid sequence that is at least 90% identical to that of the patient in need. This includes, and the patient is at least 12 cm 2 (For example, at least 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, or 32 cm 2 A method having RVESA of ) Regarding the method, in some embodiments, the method is at least 14 cm 2Patients with RVESA Regarding the person. In some embodiments, the method is at least 16 cm 2 RVESA has Regarding the patient. In some embodiments, the method is at least 18 cm 2 It has RVESA Regarding patients. In some embodiments, the method is at least 20 cm 2 RVESA has Regarding patients. In some embodiments, the method is at least 22 cm 2 RVESA Regarding patients having. In some embodiments, the method is at least 24 cm 2 RVESA This relates to patients having the following characteristics. In some embodiments, the method is at least 26 cm 2 RVES This relates to a patient having A. In some embodiments, the method is at least 28 cm 2 RVE This relates to patients with SA. In some embodiments, the method is at least 30 cm 2 RV This relates to patients with ESA. In some embodiments, the method is at least 32 cm 2 R This relates to patients with VESA. In some embodiments, the method compares with a normal VESA. And, regarding patients with increased RVESA.

[0193] In some embodiments, this disclosure relates to one or more hemodynamic parameters in PAH patients. The monitor is at a more normal level (for example, normal compared to a healthy person of similar age and sex). A method for adjusting toward an effective amount of ActRII polypeptide (e.g., SEQ ID NO: The amino acid sequence corresponding to residues 30-110 of 1 is at least 90% identical to the amino acid sequence of 1. The present invention relates to a method, which includes administering a column (of the drug) to a patient who needs it. The methods relate to improving or maintaining right ventricular function in patients. In the embodiment, PAH patients with improved or maintained right ventricular function are 7-20 cm 2 RV It has ESA. In some embodiments, improvement in right ventricular function is due to a reduction in RVESA. In some embodiments, the method relates to reducing RVESA. The method involves inserting the patient's RVESA at least 1 cm 2 Regarding reduction. Partial implementation Morphologically, the method involves inserting the patient's RVESA at least 2 cm. 2 Regarding reduction. In one embodiment, the method involves moving the patient's RVESA to at least 3 cm 2 Regarding reduction In some embodiments, the method involves moving the patient's RVESA to at least 4 cm. 2 Reduce Regarding this matter, in some embodiments, the method involves moving the patient's RVESA to at least 5 cm. 2 low Regarding reducing. In some embodiments, the method involves reducing the patient's RVESA by at least 6 cm 2 Regarding reduction. In some embodiments, the method reduces the patient's RVESA. at least 7cm 2 Regarding reduction. In some embodiments, the method involves the patient's RVES A to at least 8cm 2 The method relates to reducing. In some embodiments, the method relates to the patient RVESA at least 9cm 2 Regarding reduction. In some embodiments, the method , the patient's RVESA at least 10 cm 2 Regarding reduction.

[0194] In some embodiments, this disclosure relates to one or more echocardiographic parameters in PAH patients. The monitor is at a more normal level (for example, normal compared to a healthy person of similar age and sex). A method for adjusting toward an effective amount of ActRII polypeptide (e.g., SEQ ID NO: The amino acid sequence corresponding to residues 30-110 of 1 is at least 90% identical to the amino acid sequence of 1. The present invention relates to a method, which includes administering a column (of the drug) to a patient who needs it. The method involves reducing the patient's RVESA by at least 1% (e.g., at least 1, 2, 3, 4) Regarding reducing by 5, 10, 15, 20, 25, 30, 35, or 40%. In one embodiment, the method relates to reducing the patient's RVESA by at least 2%. In some embodiments, the method relates to reducing the patient's RVESA by at least 3%. In some embodiments, the method reduces the patient's RVESA by at least 4%. Regarding this matter, in some embodiments, the method reduces the patient's RVESA by at least 5%. This relates to the following: In some embodiments, the method reduces the patient's RVESA by at least 10%. The method relates to causing the patient's RVESA to decrease by at least 15 Regarding a % reduction. In some embodiments, the method reduces the patient's RVESA It also relates to reducing by 20%. In some embodiments, the method reduces the patient's RVESA The method relates to reducing by at least 25%. In some embodiments, the method involves the patient's RVES The method relates to reducing A by at least 30%. In some embodiments, the method relates to the patient's R The present invention relates to reducing VESA by at least 35%. In some embodiments, the method is used to treat patients Regarding reducing the RVESA of individuals by at least 40%.

[0195] RVEF Right ventricular ejection fraction (RVEF) is a comprehensive measure of the systolic performance of the RV. RVEF is the end-diastolic volume of the RV. It can be calculated using RVEDV (Revolutionary Volume Elevated Volume) and RV End-Contraction Volume (RVESV). Specifically, RVEF is given by the following formula: RVEF(%)=((RVEDV-RVESV) / It can be calculated using RVEDV) × 100. A normal RVEF is approximately, The percentage is 56-65% for all sexes and 60-71% for women. For example, Lang RM, J Am Soc Echoc See ardiogr. 2015;28(1):1-39.e14. In some embodiments, RVEF is the heart It is measured using ultrasound. In some embodiments, this disclosure relates to PAH patients. One or more hemodynamic parameters are brought to a more normal level (e.g., similar age and A method of adjusting to normal (compared to a healthy person of the same sex), with an effective dose of ActRII Polypeptides (for example, amino acid sequences corresponding to residues 30-110 of SEQ ID NO: 1 and less This includes administering an amino acid sequence (which is 90% identical) to patients who require it. Regarding the method, in some embodiments, the method aims to improve right ventricular function in patients. This relates to maintenance. In some embodiments, PA has the effect of improving or maintaining right ventricular function. Patient H has RVEF of 45-71%. In some embodiments, there is improvement in right ventricular function. PAH patients with maintenance have a 45% RVEF. In some embodiments, the right ventricular function PAH patients with improved or maintained function have a 50% RVEF. (Some embodiments) Therefore, PAH patients with improved or maintained right ventricular function have a 55% RVEF. In one embodiment, PAH patients with improved or maintained right ventricular function had a 60% RVEF. In some embodiments, PAH patients with improved or maintained right ventricular function are 65 It has % RVEF. In some embodiments, PAH has improved or maintained right ventricular function. The patient has a 70% RVEF.

[0196] In some embodiments, this disclosure relates to one or more echocardiographic parameters in PAH patients. The monitor is at a more normal level (for example, normal compared to a healthy person of similar age and sex). A method for adjusting toward an effective amount of ActRII polypeptide (e.g., SEQ ID NO: The amino acid sequence corresponding to residues 30-110 of 1 is at least 90% identical to the amino acid sequence of 1. The present invention relates to a method, which includes administering a column (of the drug) to a patient who needs it. The method relates to increasing the patient's RVEF by at least 2%. Some embodiments The method concerns increasing the patient's RVEF by at least 3%. Some implementations The method involves increasing the patient's RVEF by at least 4%. In terms of form, the method relates to increasing the patient's RVEF by at least 5%. In terms of administration, the method relates to increasing the patient's RVEF by at least 6%. In some embodiments, the method relates to increasing the patient's RVEF by at least 7%. In one embodiment, the method relates to increasing the patient's RVEF by at least 8%. In one embodiment, the method relates to increasing the patient's RVEF by at least 9%. In some embodiments, the method relates to increasing the patient's RVEF by at least 10%. In some embodiments, the method increases the patient's RVEF by at least 11%. Regarding this, in some embodiments, the method increases the patient's RVEF by at least 12%. Regarding the following, in some embodiments, the method increases the patient's RVEF by at least 13% This relates to increasing the patient's RVEF by at least 14%. In some embodiments, the method increases the patient's RVEF by at least 14%. Regarding causing the patient's RVEF to increase by at least 15%. In some embodiments, the method involves reducing the p...

Claims

1. A method for treating pulmonary arterial hypertension (PAH), comprising a therapeutically effective dose of ActRII The step of administering a lipeptide to a patient, wherein the polypeptide is the amino of SEQ ID NO: 1 Any one of acids 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 Starting from there, amino acids 110, 111, 112, 113, 114, 115, 1 of sequence number 1 １６、１１７、１１８、１１９、１２０、１２１、１２２、１２３、１２４、１２５、１ 26, 127, 128, 129, 130, 131, 132, 133, 134 or 135 Amino acid sequences ending with one of the following and at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 10 The polypeptide contains 0% identical amino acid sequences, and the polypeptide is present in a concentration of 0.1 mg / kg to 2.0 mg. The dosage range is g / kg, and the administration of the polypeptide is a. Reduction of pulmonary vascular resistance (PVR); b. Increase in 6-minute walk distance (6 MWD); c. Decreased levels of N-terminal pro-B natriuretic peptide (NT-proBNP); d. Prediction of progression of functional classes of pulmonary hypertension as recognized by the World Health Organization (WHO) Prevention or reduction; e. Facilitation or increase of the regression of the functional class of pulmonary hypertension as recognized by the WHO; f. Improvement in right ventricular function; g. Improvement in pulmonary artery pressure; and h. Improvement in mean right atrial pressure A method for causing a change in one or more of the hemodynamic or functional parameters.

2. To treat, prevent, or manage one or more complications of pulmonary arterial hypertension. A method for reducing the speed and / or severity, in an effective amount for patients who need it. The step includes administering the ActRII polypeptide, wherein the polypeptide is SEQ ID NO: 1 amino acid 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 Start with any one of them, amino acids 110, 111, 112, 113, 114 of SEQ ID NO: 1, １１５、１１６、１１７、１１８、１１９、１２０、１２１、１２２、１２３、１２４、 125, 126, 127, 128, 129, 130, 131, 132, 133, 134 or an amino acid sequence ending with any one of 135 and at least 75%, 80%, 85% 、９０％、９１％、９２％、９３％、９４％、９５％、９６％、９７％、９８％、９９％ Alternatively, it may contain an amino acid sequence that is 100% identical, and the polypeptide may be present in a concentration of 0.1 mg / kg. The dosage range is ~2.0 mg / kg, and the administration of the polypeptide is a. Reduction of pulmonary vascular resistance (PVR); b. Increase in 6-minute walk distance (6 MWD); c. Decreased levels of N-terminal pro-B natriuretic peptide (NT-proBNP); d. Prediction of progression of functional classes of pulmonary hypertension as recognized by the World Health Organization (WHO) Prevention or reduction; e. Facilitation or increase of the regression of the functional class of pulmonary hypertension as recognized by the WHO; f. Improvement in right ventricular function; g. Improvement in pulmonary artery pressure; and h. Improvement in mean right atrial pressure A method for causing a change in one or more of the hemodynamic or functional parameters.

3. One or more of the above complications of pulmonary arterial hypertension involve smooth muscle and / Alternatively, symptoms may include endothelial cell proliferation, angiogenesis in the pulmonary arteries, dyspnea, chest pain, and pulmonary vascular remodeling. The method according to claim 2, selected from the group consisting of right ventricular hypertrophy and pulmonary fibrosis.

4. A method for treating pulmonary arterial hypertension (PAH), comprising a therapeutically effective dose of ActRII The regimen includes administering a lipeptide to a patient, wherein the polypeptide is sequence Amino acids 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 of number 1 Start with any one of the amino acids 110, 111, 112, 113, and 11 of SEQ ID NO:

1. ４、１１５、１１６、１１７、１１８、１１９、１２０、１２１、１２２、１２３、１２ ４、１２５、１２６、１２７、１２８、１２９、１３０、１３１、１３２、１３３、１３ Amino acid sequences ending with either 4 or 135 and at least 75%, 80%, 8 ５％、９０％、９１％、９２％、９３％、９４％、９５％、９６％、９７％、９８％、９ The regimen comprises amino acid sequences that are 9% or 100% identical, and the regimen is maintained over a first period of time. The first dose of the polypeptide is between 0.1 mg / kg and 1.0 mg / kg, A second dose of the polypeptide between 1 mg / kg and 1.0 mg / kg is subsequently administered. A method involving administration over a period of two.

5. The administration of the polypeptide mentioned above a. Reduction of pulmonary vascular resistance (PVR); b. Increase in 6-minute walk distance (6 MWD); c. Decreased levels of N-terminal pro-B natriuretic peptide (NT-proBNP); d. Prediction of progression of functional classes of pulmonary hypertension as recognized by the World Health Organization (WHO) Prevention or reduction; e. Facilitation or increase of the regression of the functional class of pulmonary hypertension as recognized by the WHO; f. Improvement in right ventricular function; g. Improvement in pulmonary artery pressure; and h. Improvement in mean right atrial pressure Claim 4, which results in a change in one or more of the hemodynamic or functional parameters. Methods used.

6. The method according to any one of claims 1 to 5, which reduces the PVR in the patient. Law.

7. The PVR in the aforementioned patient was reduced to at least 10% (for example, 10%, 15%, 20%). Claims to reduce by 25%, 30%, 35%, 40%, 45%, or at least 50% The method described in any one of items 1 to 6.

8. The patient’s PVR is reduced by at least 20%, as described in any one of claims 1 to 7. Method of loading.

9. Any of claims 4 to 8, the reduction in PVR is a result of a decrease in mean pulmonary artery pressure. The method described in item 1.

10. The method according to any one of claims 1 to 9, which increases the 6-minute walking distance of the patient. 。

11. The patient's walking distance in 6 minutes should be at least 10 meters (for example, at least 10, 20 、３０、４０、５０、６０、７０、８０、９０、１００、１２５、１５０、１７５、２０ Claims 1 to 10 increase (0, 250, 300 meters, or more than 400 meters) The method described in any one of the items.

12. The patient's walking distance in 6 minutes is increased by at least 30 meters, according to claims 1 to 11. The method described in any one of the items.

13. Any of claims 1 to 12, which reduces the NT-proBNP level in the patient. The method described in item 1.

14. The NT-proBNP level in the aforementioned patient was reduced to at least 10% (for example, 10%, 1%). ５％、２０％、２５％、３０％、３５％、４０％、４５％、５０％、５５％、６０％、６ Any of claims 1 to 13, which reduces by 5%, 70%, 75%, or at least 80% The method described in item 1.

15. Claim 1, which reduces the NT-proBNP level in the patient by at least 30%. The method described in any one of items 14 to 14.

16. Any one of claims 1 to 15, which reduces the NT-proBNP level to a normal level. The method described in item 1.

17. Claim 16 states that the normal level of NT-proBNP is <100 pg / ml. Method of loading.

18. To prevent or reduce the progression of functional classes of pulmonary hypertension as recognized by the WHO, The method according to any one of claims 1 to 17.

19. Pulmonary hypertension from Class I to Class II as recognized by the WHO The following is a method for preventing or reducing the progression of a class of functions, as described in any one of claims 1 to 18. The method.

20. Pulmonary hypertension from Class II to Class III as recognized by the WHO A method to prevent or reduce the progression of a functional class of pressure, according to any one of claims 1 to 18. Method of description.

21. Pulmonary hypertension from Class III to Class IV of function as recognized by the WHO A method to prevent or reduce the progression of a functional class of pressure, according to any one of claims 1 to 18. Method of description.

22. It promotes or increases the decline in the functional class of pulmonary hypertension as recognized by the WHO. The method according to any one of claims 1 to 17.

23. Pulmonary hypertension from Class IV to Class III as recognized by the WHO Any one of claims 1 to 17 and 22 promotes or increases the regression of the functional class The method described in section [section number].

24. Pulmonary hypertension from Class III to Class II as recognized by the WHO Any one of claims 1 to 17 and 22 promotes or increases the regression of the functional class The method described in section [section number].

25. The function of pulmonary hypertension from Class II to Class I recognized by the WHO To promote or increase the decline of the class, according to any one of claims 1 to 17 and 22 Method of description.

26. A method according to any one of claims 1 to 25, which improves right ventricular function in the aforementioned patient. 。

27. The improvement in right ventricular function is due to an increase in the rate of change of right ventricular area, as described in claim 26. method.

28. The method according to claim 26, wherein the improvement in right ventricular function is due to a reduction in right ventricular hypertrophy.

29. The method according to claim 26, wherein the improvement in right ventricular function is due to an increase in the ejection fraction. 。

30. The aforementioned improvement in right ventricular function is due to an increase in the rate of change of right ventricular area and the ejection fraction. The method described in item 26.

31. The method according to any one of claims 1 to 30, which improves the pulmonary artery pressure in the patient. method.

32. Claim 3, the improvement in pulmonary artery pressure is a reduction in mean pulmonary artery pressure (mPAP). The method described in 1.

33. The mPAP in the aforementioned patient was reduced by at least 10% (for example, 10%, 15%, 20%) Reduce the bill by 25%, 30%, 35%, 40%, 45%, or at least 50%. The method described in item 32.

34. In the aforementioned patient, the mPAP was at least 3 mmHg (for example, at least 3, 5, The method according to claim 32, which reduces (7, 10, 12, 15, 20, or 25 mmHg) 。

35. Any of claims 1 to 34, which improves the mean right atrial pressure (mRAP) in the patient. The method described in item 1.

36. The improvement in the mRAP is a reduction in the mRAP, as described in claim 35. Law.

37. The mRAP in the aforementioned patient was reduced to at least 10% (for example, 10%, 15%, 20%) Reduce the bill by 25%, 30%, 35%, 40%, 45%, or at least 50%. The method described in item 36.

38. The mRAP in the aforementioned patient was at least 1 mmHg (for example, at least 1, 2, Reduction of 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 mmHg The method according to claim 35, which causes

39. The patient has a pulmonary vascular resistance (PVR) greater than or equal to 3 Wood units. The method according to any one of claims 1 to 38.

40. The patient has a walking distance of 150 to 500 meters in 6 minutes, according to claims 1 to 39. The method described in any one of the items.

41. If the aforementioned patient has elevated NT-proBNP levels compared to a healthy patient, The method described in any one of the requests 1 to 40.

42. The patient has a blood alcohol content of at least 100 pg / mL (for example, 100, 150, 200, 300) , 400, 500, 1000, 3000, 5000, 10,000, 15,000 or The method according to claim 41, having an NT-proBNP level of 20,000 pg / mL Law.

43. The aforementioned patients showed elevated brain natriuretic peptide (BNP) levels compared to healthy patients. The method according to any one of claims 1 to 42, comprising a bell.

44. The patient has a blood alcohol content of at least 100 pg / mL (for example, 100, 150, 200, 300) , 400, 500, 1000, 3000, 5000, 10,000, 15,000 or The method according to claim 43, having a BNP level of 20,000 pg / mL.

45. The BNP level in the aforementioned patient was reduced by at least 10% (for example, 10%, 15%, 20%). 、２５％、３０％、３５％、４０％、４５％、５０％、５５％、６０％、６５％、７０％ , reducing by 75% or at least 80%, as per claim 43 or claim 44 Law.

46. Claims to reduce BNP levels to normal levels (i.e., <100 pg / ml). The method described in any one of items 43 to 45.

47. The aforementioned patient, a. Mean pulmonary artery pressure (mPAP) of at least 20 mmHg; b. mPAP of at least 25 mmHg; c. mPAP of at least 30 mmHg; d. mPAP of at least 35 mmHg; e. mPAP of at least 40 mmHg; f. mPAP of at least 45 mmHg; and g. mPAP of at least 50 mmHg The mPAP selected from the group consisting of, according to any one of claims 1 to 46 method.

48. The aforementioned patient, a. Mean right atrial pressure (mRAP) of at least 5 mmHg; b. mRAP of at least 6 mmHg; c. mRAP of at least 8 mmHg; d. mRAP of at least 10 mmHg; e. mRAP of at least 12 mmHg; f. mRAP of at least 14 mmHg; and g. mRAP of at least 16 mmHg The mRAP selected from the group consisting of any one of claims 1 to 46, according to any one of claims 1 to 46. method.

49. The PAH is idiopathic pulmonary arterial hypertension (PAH), according to any of claims 1 to 48. The method described in any one of the items.

50. The method according to any one of claims 1 to 48, wherein the PAH is a hereditary PAH.

51. Any one of claims 1 to 48, wherein the PAH is a drug or toxin-inducing PAH. Methods used.

52. The aforementioned PAH occurred at least one year after shunt repair, and was a simple congenital systemic to pulmonary The method according to any one of claims 1 to 48, wherein the PAH is related to a shunt.

53. According to the World Health Organization's functional classification system for pulmonary hypertension, the aforementioned patient has a functional class A person having pulmonary hypertension of class II or class III, according to any one of claims 1 to 52 Method of description.

54. According to the World Health Organization's functional classification system for pulmonary hypertension, the aforementioned patient has a functional class Claim 1, having pulmonary hypertension of class I, class II, class III, or class IV The method described in any one of items 52.

55. According to the World Health Organization's functional classification system for pulmonary hypertension, the aforementioned patient has a functional class The method according to any one of claims 1 to 52, for a patient with pulmonary hypertension of Lass IV.

56. The method according to any one of claims 1 to 55, which increases transplant-free survival in the patient. method.

57. The transplant-free survival rate in the aforementioned patients should be at least 10% (for example, 10%, 15%, 20%). Claims to increase by 25%, 30%, 35%, 40%, 45%, or at least 50% The method described in 56.

58. The method according to any one of claims 1 to 57, which reduces right ventricular hypertrophy in the aforementioned patient. Law.

59. The right ventricular hypertrophy in the aforementioned patients was reduced by at least 10% (for example, 10%, 15%, 20%, 2%). Claim 5 reduces by 5%, 30%, 35%, 40%, 45%, or at least 50%. The method described in 8.

60. The method for reducing smooth muscle hypertrophy in the patient, according to any one of claims 1 to 59. method.

61. The smooth muscle hypertrophy in the aforementioned patients was reduced by at least 10% (for example, 10%, 15%, 20%). Claims to reduce by 25%, 30%, 35%, 40%, 45%, or at least 50% The method described in 60.

62. The method of reducing pulmonary arteriole muscle formation in the patient, as described in any one of claims 1 to 61. Method of loading.

63. The pulmonary arteriole muscle transformation in the aforementioned patients was reduced by at least 10% (for example, 10%, 15%, 20%). Reduce by %, 25%, 30%, 35%, 40%, 45%, or at least 50%. The method described in item 62.

64. The method according to any one of claims 1 to 63, for increasing the motor capacity of the patient.

65. Any one of claims 1 to 64, which reduces the Borg dyspnea index (BDI) of the patient. The method described in item 1.

66. The BDI of the aforementioned patient should be at least 0.5 index points (for example, at least 0.5, 1, １．５、２、２．５、３、３．５、４、４．５、５、５．５、６、６．５、７、７．５、 The method according to claim 65, which reduces by 8, 8.5, 9, 9.5, or 10 exponential points. 。

67. The method according to any one of claims 1 to 66, wherein the patient has reduced renal function. 。

68. The method according to any one of claims 1 to 67, for further improving kidney function.

69. Delaying the clinical progression of pulmonary arterial hypertension, as described in any one of claims 1 to 68 The method.

70. According to the World Health Organization's functional classification system for pulmonary hypertension, pulmonary arterial hypertension is classified as follows: The method according to claim 69, which delays clinical deterioration.

71. Reduce the risk of hospitalization for one or more complications associated with pulmonary arterial hypertension. The method according to any one of claims 1 to 70.

72. Reduce the risk of pathological conditions for one or more complications associated with pulmonary arterial hypertension. The method according to any one of claims 1 to 71, which reduces

73. The aforementioned pathological condition, a. The increasing need for lung and / or heart transplants; b. The need to initiate rescue therapy with known treatments for PAH; c. Prostacyclin levels need to be increased by at least 10%; d. The necessity of atrial septal dehiscence surgery; e. PAH-specific hospitalization for at least 24 hours; and f. Worsening of PAH The method according to claim 72, comprising one or more of the following variations.

74. The aforementioned deterioration of PAH is a deterioration in the class of WHO functioning and at least 15% of 6 MWD The method according to claim 73, including a reduction.

75. Any of claims 1 to 75 that reduces the risk of death associated with pulmonary arterial hypertension. The method described in item 1.

76. The risk of death associated with pulmonary arterial hypertension is reduced by at least 10% (e.g., 10%, 1%). (Reduction of 5%, 20%, 25%, 30%, 35%, 40%, 45%, or at least 50%) The method according to claim 75, which causes to happen.

77. Claims 1 to 7, wherein the patient has a hemoglobin level >8 and <15 g / dl The method described in any one of item 6.

78. Any of claims 1 to 76, wherein the patient's hemoglobin level is <18 g / dl The method described in item 1.

79. ActRII polypeptide has amino acids corresponding to residues 30-110 of SEQ ID NO: 1 Columns and at least 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 9 0%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, The amino acid sequence comprising any one of claims 1 to 78, or the amino acid sequence comprising 100% identical amino acids. method.

80. ActRII polypeptide has at least 70% and 75% of the amino acid sequence of SEQ ID NO:

2. 、８０％、８５％、８６％、８７％、８８％、８９％、９０％、９１％、９２％、９３％ , 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical amino acids The method according to any one of claims 1 to 78, comprising an acid sequence.

81. ActRII polypeptide has at least 70% and 75% of the amino acid sequence of SEQ ID NO:

3. 、８０％、８５％、８６％、８７％、８８％、８９％、９０％、９１％、９２％、９３％ , 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical amino acids The method according to any one of claims 1 to 78, comprising an acid sequence.

82. The ActRII polypeptide further comprises a fusion molecule containing the Fc domain of an immunoglobulin. The method according to any one of claims 79 to 81, wherein the material is protein.

83. The Fc domain of the immunoglobulin is the Fc domain of the IgG1 immunoglobulin. A method according to claim 82.

84. The Fc fusion protein comprises an ActRII polypeptide domain and the immunoglobulin. Claim 82 further includes a linker domain located between the Fc domain and the Fc domain, or The method described in 83.

85. The linker domains are TGGG (SEQ ID NO: 20), TGGGGG (SEQ ID NO: 18), SGGGG (Sequence ID 22), GGGGS (Sequence ID 22), GGG (Sequence ID 16), Selected from the group consisting of GGGG (SEQ ID NO: 17) and SGGG (SEQ ID NO: 21). The method according to claim 84.

86. The ActRII polypeptide has at least 70% of the amino acid sequence of SEQ ID NO:

23. ７５％、８０％、８５％、８６％、８７％、８８％、８９％、９０％、９１％、９２％、 They are 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical. The method according to any one of claims 1 to 85, comprising an amino acid sequence.

87. The ActRII polypeptide has at least 70% of the amino acid sequence of SEQ ID NO:

41. ７５％、８０％、８５％、８６％、８７％、８８％、８９％、９０％、９１％、９２％、 A is identical to 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%. The method according to any one of claims 1 to 87, comprising a mino acid sequence.

88. The polypeptide has an amino acid sequence that is less than the amino acid sequence corresponding to residues 30-110 of SEQ ID NO:

1. The method according to any one of claims 1 to 79, which includes an amino acid sequence that is 90% identical to both. Law.

89. The polypeptide has an amino acid sequence that is less than the amino acid sequence corresponding to residues 21-135 of SEQ ID NO:

1. The method according to any one of claims 1 to 79, which includes an amino acid sequence that is 90% identical to both. Law.

90. The polypeptide is freeze-dried, according to any one of claims 1 to 89. method.

91. The method according to any one of claims 1 to 90, wherein the polypeptide is soluble.

92. The polypeptide is administered to the patient by subcutaneous injection, according to claims 1 to 91. The method described in any one of the items.

93. The polypeptide is administered to the patient every three weeks, as in any one of claims 1 to 92. The method described in item 1.

94. The polypeptide is administered to the patient every four weeks, as in any one of claims 1 to 92. The method described in item 1.

95. The polypeptide is part of a homodimeric protein complex, according to claims 1 to 94. The method described in any one of the items.

96. The polypeptide is glycosylated, as described in any one of claims 1 to 95. Method of loading.

97. The polypeptide is obtained by expression in Chinese hamster ovary cells. The method according to any one of claims 1 to 96, having a glycosylation pattern that allows for such a glycosylation. 。

98. The ActRII polypeptide is derived from activin A, activin B, and GDF11. Any one of claims 1 to 97, which binds to one or more ligands selected from the group. The method described in item 1.

99. The ActRII polypeptide binds to activin and / or GDF11. The method according to any one of claims 1 to 97.

100. The ActRII polypeptide is a group consisting of BMP10, GDF8, and BMP6. The method described in claim 98 or 99, further binding to one or more ligands selected from thereto. The method.

101. The ActRII polypeptide is administered in doses between 0.1 mg / kg and 2.0 mg / kg. The method according to any one of claims 1 to 100, administered to the patient.

102. Claim 1, wherein the ActRII polypeptide is administered at a dose of 0.3 mg / kg. The method described in any one of items 101.

103. Claim 1, wherein the ActRII polypeptide is administered at a dose of 0.7 mg / kg. The method described in any one of items 101.

104. The procedure further includes administering additional activators and / or supportive therapies to the patient. The method described in any one of the requests 1 to 103.

105. The aforementioned additional activators and / or supportive therapies include beta-blockers, angiotensin converters, and other similar agents. Enzyme inhibitors (ACE inhibitors), angiotensin receptor blockers (ARBs), diuretics, lipids Depressants, endothelin blockers, PDE5 inhibitors, prostacyclins, or left ventricular assist devices. The method according to claim 104, selected from the group consisting of chairs (LVAD).

106. The aforementioned additional activators and / or supportive therapies include prostacyclin and its derivatives ( For example, epoprostenol, treprostinil and iloprost); prostacyclin Phosphate receptor agonists (e.g., selexipag); endothelin receptor antagonists ( For example, thelin, ambrisentan, macitentan, and bosentan; Cium channel blockers (e.g., amlodipine, diltiazem, and nifedipine; anticoagulants) Solidifying agents (e.g., warfarin); diuretics; oxygen therapy; atrial septal dehiscence surgery; pulmonary endarterectomy ; Phosphodiesterase type 5 inhibitors (e.g., sildenafil and tadalafil); OK Activators of soluble guanylate cyclase (e.g., synaciguat and riociguat); A SK-1 inhibitors (e.g., CIIA; SCH79797; GS-4997; MSC203) 2964A; 3H-naphtho[1,2,3-de]quiniline-2,7-diode NQDI-1; 2-thioxo-thiazolidined, 5-bromo-3-(4-oxo-2- Thioxo-thiazolidined-5-ylidene)-1,3-dihydro-indole-2-one) NF-κB antagonist (e.g., dh404, CDDO-epoxide; 2,2-di Fluoropropionamide; C28 imidazole (CDDO-Im); 2-cyano-3, 12-Dioxolean-1,9-diene-28-euic acid (CDDO); 3-acetyl Oleanolic acid; 3-trifluoroacetyloleanolic acid; 28-methyl Tyl-3-acetyloleanane; 28-methyl-3-trifluoroacetyloleanane; 28-methyloxyoleanolic acid; SZC014; SCZ015; SZC017; ole PEG-modified derivative of anolic acid; 3-O-(beta-D-glucopyranosyl)oleanol Acid; 3-O-[beta-D-glucopyranosyl-(1→3)-beta-D-glucopyrano [Syl]oleanolic acid; 3-O-[beta-D-glucopyranosyl-(1→2)-beta -D-glucopyranosyl]oleanolic acid; 3-O-[beta-D-glucopyranosyl- (1→3)-beta-D-glucopyranosyl]oleanolic acid 28-O-beta-D-g Lucopyranosyl ester; 3-O-[beta-D-glucopyranosyl-(1→2)- ester; 3-O-[beta-D-glucopyranosyl-(1→2)-beta-D-glucopyranosyl-(1 28-O-beta-D-glucopyranosyl oleanolic acid Stel; 3-O-[a-L-rhamnopyranosyl-(1→3)-beta-D-glucuronopyl Lanosyl oleanolic acid; 3-O-[alpha-L-rhamnopyranosyl-(1→3)- Beta-D-glucuronopyranosyl oleanolic acid 28-O-beta-D-glucopyranosyl Nosyl ester; 28-O-β-D-glucopyranosyl oleanolic acid; 3-O-β- D-glucopyranosyl(1→3)-β-D-glucopyranosidouronic acid (CS1); ole Anolic acid 3-O-β-D-glucopyranosyl(1→3)-β-D-glucopyranosidole Ronic acid (CS2); methyl 3,11-dioxolean-12-ene-28-oleate ( olate) (DIOXOL); ZCVI ４ -2; benzyl 3-dehydro-oxy -1,2,5-Oxadiazolo[3',4':2,3]oleanolate); Left ventricular assist device A claim is made from a group consisting of a chair (LVAD), or a lung and / or heart transplant. The method described in item 104.

107. The aforementioned patient received a phosphodiesterase type 5 inhibitor, a soluble guanylate cyclase stimulant, It consists of a prostacyclin receptor agonist and an endothelin receptor antagonist. Treated with one or more drugs selected from the group, any one of claims 1 to 103 The method described in section [section number].

108. The one or more of the above drugs are bosentan, sildenafil, beraprost, maciten Tan, selexipag, epoprostenol, treprostinil, iloprost, ambry The method according to claim 107, selected from the group consisting of sentan and tadalafil.

109. Phosphodiesterase type 5 inhibitors, soluble guanylate cyclase stimulants, prostaglandins Selected from a group consisting of clin receptor agonists and endothelin receptor antagonists. The following is a further comprising the administration of one or more drugs as described in any one of claims 1 to 108. Method of loading.

110. The one or more of the above drugs are bosentan, sildenafil, beraprost, maciten Tan, selexipag, epoprostenol, treprostinil, iloprost, ambry The method according to claim 109, selected from the group consisting of sentan and tadalafil.

111. The patient was treated with one or more vasodilators prior to the administration of the polypeptide. The method according to any one of claims 1 to 110.

112. Any one of claims 1 to 111 further comprises the administration of one or more vasodilators. Methods used.

113. The one or more vasodilators include prostacyclin, epoprostenol, and The method according to claim 111 or 112, selected from the group consisting of sildenafil.

114. The method according to claim 113, wherein the vasodilator is prostacyclin.

115. Claims 1 to 114, wherein the patient is receiving one or more therapies for PAH. The method described in any one of the items.

116. One or more therapies for PAH include prostacyclin and its derivatives ( For example, epoprostenol, treprostinil and iloprost); prostacyclin Phosphate receptor agonists (e.g., selexipag); endothelin receptor antagonists ( For example, telin, ambrisentan, macitentan and bosentan); calcium tea Nell-blockers (e.g., amlodipine, diltiazem, and nifedipine); anticoagulants (e.g.) (e.g., warfarin); diuretics; oxygen therapy; atrial septal dehiscence; pulmonary thromboendarterectomy; phosphodiolus Esterase type 5 inhibitors (e.g., sildenafil and tadalafil); soluble guani Acid cyclase activators (e.g., synaciguat and riociguat); ASK-1 inhibitors Harmful agents (e.g., CIIA; SCH79797; GS-4997; MSC2032964A) ;3H-naphtho[1,2,3-de]quinilin-2,7-dione,NQDI-1; 2-Chi Oxo-thiazolidinedione, 5-bromo-3-(4-oxo-2-thioxo-thiazolidinedione) 5-Iridene)-1,3-dihydro-indole-2-one); NF-κB antagonist (For example, dh404, CDDO-epoxide; 2,2-difluoropropionamide) ;C28 imidazole (CDDO-Im);2-cyano-3,12-dioxolean- 1,9-Diene-28-Eucic acid (CDDO); 3-Acetyloleanolic acid; 3- Lifluoroacetyloleanolic acid; 28-methyl-3-acetyloleanane; 28-Me Tyl-3-trifluoroacetyloleanane; 28-methyloxyoleanolic acid; SZ C014; SCZ015; SZC017; PEG derivative of oleanolic acid; 3-O-( Beta-D-glucopyranosyl)oleanolic acid; 3-O-[beta-D-glucopyranosyl] [sil-(1→3)-beta-D-glucopyranosyl]oleanolic acid; 3-O-[beta -D-glucopyranosyl-(1→2)-beta-D-glucopyranosyl]oleanolic acid ;3-O-[beta-D-glucopyranosyl-(1→3)-beta-D-glucopyranosyl 28-O-beta-D-glucopyranosyl oleanolic acid; 3-O-[beta [T-D-glucopyranosyl-(1→2)-beta-D-glucopyranosyl]oleanol Acid 28-O-beta-D-glucopyranosyl ester; 3-O-[a-L-rhamnopyrano [sil-(1→3)-beta-D-glucuronopyranosyl]oleanolic acid; 3-O-[a Rufa-L-Rhamnopyranosyl-(1→3)-Beta-D-Glucronopyranosyl]Ole 28-O-beta-D-glucopyranosyl anolate; 28-O-β-D-glu Copiranosyl oleanolic acid; 3-O-β-D-glucopyranosyl(1→3)-β-D -Glucopyranosideuronic acid (CS1); oleanolic acid 3-O-β-D-glucopyrano Syl(1→3)-β-D-glucopyranosidouronic acid (CS2); methyl 3,11-diol Kisoolean-12-ene-28-oleate (DIOXOL); ZCVI ４ -2; Benji 3-dehydro-oxy-1,2,5-oxadiazolo[3',4':2,3]oleano (Rate); left ventricular assist device (LVAD), or lung and / or heart transplant. The method according to claim 115, selected from the group.

117. The ActRII polypeptide is used weekly, every two weeks, every three weeks, and every four weeks. The patient is administered according to a schedule selected from the following groups, according to claims 1 to 116. The method described in either of the above terms.

118. Claim 102, wherein the ActRII polypeptide is administered to the patient every three weeks. Or the method according to claim 103.

119. Persons who treat or prevent cardiopulmonary remodeling associated with pulmonary arterial hypertension in patients. The law is to administer an effective amount of ActRII polypeptide to patients who need it. Includes a spool, slows down cardiac remodeling, and / or reverses cardiac remodeling. A method.

120. The method according to claim 119, wherein the reversal of cardiac remodeling is a sustained reversal.

121. Claim 119 or Claim 120, wherein the cardiopulmonary remodeling is ventricular remodeling. Methods used.

122. The method according to claim 121, wherein the ventricular remodeling is left ventricular remodeling.

123. The method according to claim 121, wherein the ventricular remodeling is right ventricular remodeling.

124. The cardiopulmonary remodeling is ventricular dilation, according to any one of claims 119 to 123. Method of description.

125. The method according to claim 4, wherein the first period is at least three weeks.

126. The method according to claim 4, wherein the second period is at least three weeks.

127. The method according to claim 4, wherein the second period is at least 21 weeks.

128. The method according to claim 4, wherein the second period is at least 45 weeks.

129. The method according to claim 4, wherein the second period exceeds the first period.

130. The method according to claim 4, wherein the second dose exceeds the first dose.

131. The first dose is in the range of approximately 0.2 mg / kg to approximately 0.4 mg / kg, and approximately 0. Claim 4, wherein a second dose in the range of 5 mg / kg to approximately 0.8 mg / kg is followed. Method of description.

132. The first dose is approximately 0.3 mg / kg, and the second dose is approximately 0.7 mg / kg. The method according to claim 4, which follows.

133. A kit comprising a lyophilized polypeptide and an injection device, wherein the polypeptide is , amino acids 21, 22, 23, 24, 25, 26, 27, 28, 29 of sequence number 1, also It starts with one of the 30 amino acids, and amino acids 110, 111, 112, and 11 of SEQ ID NO:

1. ３、１１４、１１５、１１６、１１７、１１８、１１９、１２０、１２１、１２２、１２ ３、１２４、１２５、１２６、１２７、１２８、１２９、１３０、１３１、１３２、１３ 3. Amino acid sequences ending with one of 134 or 135, and at least 70% ７５％、８０％、８５％、８６％、８７％、８８％、８９％、９０％、９１％、９２％、 They are 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical. A kit containing an ActRII polypeptide with an amino acid sequence.

134. The polypeptide has an amino acid sequence that is less than the amino acid sequence corresponding to residues 30-110 of SEQ ID NO:

1. The polypeptide according to claim 133, which contains amino acid sequences that are 90% identical. .

135. The polypeptide has an amino acid sequence that is less than the amino acid sequence corresponding to residues 30-110 of SEQ ID NO:

1. Claim 133 or 13 is a polypeptide containing amino acid sequences that are 95% identical. The kit described in item 4.

136. The polypeptide has an amino acid sequence that is less than the amino acid sequence corresponding to residues 30-110 of SEQ ID NO:

1. Claims 133 to 135 are polypeptides containing amino acid sequences that are 99% identical. A kit as described in any one of the items.

137. The polypeptide contains an amino acid sequence corresponding to residues 30 to 110 of SEQ ID NO:

1. A kit according to any one of claims 133 to 136, wherein the kit is a lipeptide.

138. The polypeptide consists of an amino acid sequence corresponding to residues 30 to 110 of SEQ ID NO:

1. A kit according to any one of claims 133 to 137, wherein the kit is a polypeptide.

139. The polypeptide has an amino acid sequence that is less than the amino acid sequence corresponding to residues 21-135 of SEQ ID NO:

1. The polypeptide according to claim 133, which contains amino acid sequences that are 90% identical. .

140. The polypeptide has an amino acid sequence that is less than the amino acid sequence corresponding to residues 21-135 of SEQ ID NO:

1. Claim 133 or Claim, which is a polypeptide containing an amino acid sequence that is 95% identical to both. The kit described in item 139.

141. The polypeptide has an amino acid sequence that is less than the amino acid sequence corresponding to residues 21-135 of SEQ ID NO:

1. Claims 133, 139, both are polypeptides containing amino acid sequences that are 99% identical. Or a kit as described in any one of paragraphs 140.

142. The polypeptide contains an amino acid sequence corresponding to residues 21-135 of SEQ ID NO:

1. A kit according to any one of claims 133 or 139 to 141, which is a lipeptide. 。

143. The polypeptide consists of an amino acid sequence corresponding to residues 21 to 135 of SEQ ID NO:

1. A polypeptide, the kit according to any one of claims 133 or 139 to 142 to.

144. The polypeptide is at least 90% identical to the amino acid sequence of SEQ ID NO:

2. The kit according to claim 133, wherein the polypeptide contains an acid sequence.

145. The polypeptide is at least 95% identical to the amino acid sequence of SEQ ID NO:

2. The kit according to claim 133 or claim 144, wherein the polypeptide contains an acid sequence.

146. The polypeptide is at least 99% identical to the amino acid sequence of SEQ ID NO:

2. Any one of claims 133, 144, or 145, which is a polypeptide containing an acid sequence. The kit described above.

147. Claim 1, wherein the polypeptide is a polypeptide comprising the amino acid sequence of SEQ ID NO: 2 A kit as described in any one of paragraphs 33 or 144 to 146.

148. The claim states that the polypeptide is a polypeptide comprising the amino acid sequence of SEQ ID NO:

2. A kit as described in any one of paragraphs 133 or 144 to 147.

149. The polypeptide is at least 90% identical to the amino acid sequence of SEQ ID NO:

3. The kit according to claim 133, wherein the polypeptide contains an acid sequence.

150. The polypeptide is at least 95% identical to the amino acid sequence of SEQ ID NO:

3. The kit according to claim 133 or claim 149, wherein the polypeptide contains an acid sequence.

151. The polypeptide is at least 99% identical to the amino acid sequence of SEQ ID NO:

3. Any one of claims 133, 149, or 150, which is a polypeptide containing an acid sequence. The kit described above.

152. Claim 1, wherein the polypeptide is a polypeptide comprising the amino acid sequence of SEQ ID NO: 3 A kit as described in any one of paragraphs 33 or 149 to 151.

153. The claim states that the polypeptide is a polypeptide comprising the amino acid sequence of SEQ ID NO:

3. A kit as described in any one of paragraphs 133 or 149 to 152.

154. The polypeptide is a fusion protein further comprising the Fc domain of an immunoglobulin. a kit according to any one of claims 133 to 153.

155. The Fc domain of the immunoglobulin is the Fc domain of the IgG1 immunoglobulin. A kit according to claim 154.

156. The fusion protein comprises a polypeptide domain and the Fc domain of the immunoglobulin. Claim 154 or claim 155 further includes a linker domain located between the and The kit as described.

157. The linker domains are TGGG (SEQ ID NO: 20), TGGGGG (SEQ ID NO: 18), SGGGG (Sequence ID 19), GGGGS (Sequence ID 22), GGG (Sequence ID 16), Selected from the group consisting of GGGG (SEQ ID NO: 17) and SGGG (SEQ ID NO: 21). , the kit according to claim 156.

158. Claim 156 or claim that the linker domain includes TGGG (SEQ ID NO: 20) The kit described in item 157.

159. The ActRII polypeptide has at least 70% of the amino acid sequence of SEQ ID NO:

23. ７５％、８０％、８５％、８６％、８７％、８８％、８９％、９０％、９１％、９２％、 They are 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical. A kit according to any one of claims 133 to 158, comprising an amino acid sequence.

160. Claim 133, wherein the ActRII polypeptide comprises the amino acid sequence of SEQ ID NO:

23. A kit as described in any one of items 159 to 159.

161. Claim 13, wherein the ActRII polypeptide consists of the amino acid sequence of SEQ ID NO: 23 A kit as described in any one of items 3 to 160.

162. Claims 133 to 1, wherein the polypeptide is part of a homodimeric protein complex. A kit as described in any one of item 61.

163. The polypeptide is glycosylated, any one of claims 133 to 162 The kit described in the section.

164. The polypeptide is selected from the group consisting of activin A, activin B, and GDF11. A ligand that binds to one or more selected ligands, any one of claims 133 to 163 The kit described in the section.

165. The polypeptide is selected from the group consisting of BMP10, GDF8, and BMP6. The kit according to claim 164, further comprising binding to one or more ligands.

166. Claim 133, wherein the polypeptide is bound to activin and / or GDF11. A kit as described in any one of items 163.

167. Claim 133 comprises one or more vials containing the freeze-dried polypeptide. A kit as described in any one of items 166.

168. Claim 133 comprises at least two vials containing the lyophilized polypeptide. A kit as described in any one of items 167.

169. The two vials contain the same or different amounts of the lyophilized polypeptide. A kit according to any one of claims 133 to 168, which can do the following.

170. Claim that the vial contains the lyophilized polypeptide in an amount between 25 mg and 60 mg. The kit described in 167.

171. Claims that at least one of the vials contains 60 mg of lyophilized polypeptide The kit described in item 167.

172. Claims that at least one of the vials contains 45 mg of lyophilized polypeptide The kit described in item 167.

173. Claim that at least one of the vials contains 30 mg of lyophilized polypeptide The kit described in item 167.

174. Claims that at least one of the vials contains 25 mg of lyophilized polypeptide The kit described in item 167.

175. The first vial contains 45 mg of lyophilized polypeptide, and the second vial contains 6 The kit according to claim 167, comprising 0 mg of lyophilized polypeptide.

176. The first vial contains 30 mg of lyophilized polypeptide, and the second vial contains 6 The kit according to claim 167, comprising 0 mg of lyophilized polypeptide.

177. The first vial contains 45 mg of lyophilized polypeptide, and the second vial contains 4 The kit according to claim 167, comprising 5 mg of lyophilized polypeptide.

178. The first vial contains 30 mg of lyophilized polypeptide, and the second vial contains 4 The third vial contains 5 mg of lyophilized polypeptide, and the third vial contains 60 mg of lyophilized polypeptide The kit according to claim 167, comprising butylate.

179. The first vial contains 25 mg of lyophilized polypeptide, and the second vial contains 4 The third vial contains 5 mg of lyophilized polypeptide, and the third vial contains 60 mg of lyophilized polypeptide The kit according to claim 167, comprising butylate.

180. The vial is refrigerated at 2 to 8°C, as described in any one of claims 135 to 179. A kit containing [something].

181. The injection device includes a pre-filled syringe, as per any of claims 133 to 180. The kit described in item 1.

182. The injection device includes a pump device, as described in any one of claims 133 to 181. A kit containing [something].

183. The kit according to claim 182, wherein the pump device includes an electromechanical pump assembly.

184. The pump device is a wearable pump device, as described in claim 182 or 183. The kit.

185. The kit according to claim 181, wherein the pre-filled syringe contains a reconstitution solution.

186. Claim 185, wherein the restorative solution comprises a pharmaceutically acceptable carrier and / or excipient. The kit described above.

187. The pharmaceutically acceptable carrier is derived from physiological saline solution, purified water, and sterile water for injection. A kit according to claim 186, selected from the group.

188. The aforementioned pharmaceutically acceptable excipients include buffering agents [e.g., citric acid (monohydrate) and / or...] [or trisodium citrate (dehydrated)], surfactant (e.g., polysorbate 80), A stabilizer (e.g., sucrose) and a cryoprotectant (e.g., sucrose) are selected. The kit according to claim 186.

189. The injection device includes a vial adapter, any one of claims 133 to 188. The kit described in item 1.

190. The vial adapter can be attached to a vial, as described in claim 189. The kit.

191. The vial adapter can be attached to a pre-filled syringe, claim The kit according to claim 189 or 190.

192. The pre-filled syringe and the vial are attached to both ends of the vial adapter. The kit described in claim 191, which is attached.

193. Claim 19, the reconstitution solution is transferred from the pre-filled syringe to the vial. The kit described in item 2.

194. Claims 133 to 193, wherein the freeze-dried polypeptide is restored to a sterile injection solution. The kit described above.

195. Claim 133, wherein the lyophilized polypeptide is restored to a sterile injection solution before use. The kit described in section 194.

196. The kit according to claim 194 or claim 195, wherein the restoration solution includes sterile water for injection. to.

197. The sterile injection solution is administered parenterally, according to any one of claims 194 to 196. The kit as described.

198. Any of claims 194 to 196, wherein the sterile injection solution is administered by subcutaneous injection. The kit described in item 1.

199. Any of claims 194 to 196, wherein the sterile injection solution is administered via intradermal injection. The kit described in item 1.

200. The sterile injection solution is administered via intramuscular injection, as per any one of claims 194 to 196. The kit described in item 1.

201. The sterile injection solution is administered via intravenous injection, as per any one of claims 194 to 196. The kit described in item 1.

202. The sterile injection solution is self-administered, as described in any one of claims 194 to 196. kit.

203. The injection device is used for administering the sterile injection solution, according to claims 194 to 201. A kit as described in any one of the items.

204. The sterile injection solution comprises a therapeutically effective dose as described in any one of claims 194 to 203. A kit containing [something].

205. The kit according to claim 204, wherein the therapeutically effective dose includes a dose based on body weight.

206. The sterile injection solution is administered every three weeks, according to any one of claims 133 to 205. The kit described above.

207. The sterile injection solution is administered every four weeks, according to any one of claims 133 to 205. The kit described above.

208. A kit according to any one of claims 133 to 207, used for the treatment of PAH.

209. The shelf life of the freeze-dried polypeptide is at least 1, 3, 6, 9, or 11 months. The kit according to any one of claims 133 to 208.

210. The shelf life of the freeze-dried polypeptide is at least 1, 1.5, 2, 2.5, or 3 A kit according to any one of claims 133 to 208, which is for one year.

211. The freeze-dried polypeptide is restored, any one of claims 133 to 210 The kit described in the section.

212. The restored polypeptide is allowed to remain for at least two hours, at least three hours, and at least The kit according to claim 211, which has an effective period selected from the group consisting of 4 hours.

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