ACTRII protein and use in the treatment of postcapillary pulmonary hypertension.

Abstract

In some aspects, the present disclosure relates to compositions and methods comprising ActRII polypeptides for treating, preventing, or reducing the rate of progression and / or severity of postcapillary pulmonary hypertension (PcPH), particularly for treating, preventing, or reducing the rate of progression and / or severity of one or more PcPH-related complications. ActRII polypeptides may include polypeptides including any naturally occurring polypeptide of an ActRII family member, and any variant thereof (including mutants, fragments, fusions, and peptidomimetic forms) that retain useful activity.

Description

[Technical Field]

[0001] Cross-references to related applications This application claims priority from U.S. Provisional Application No. 63 / 016,942, filed on 28 April 2020, and U.S. Provisional Application No. 63 / 159,253, filed on 10 March 2021. The aforementioned applications are incorporated herein by reference. [Background technology]

[0002] Background of the Invention Pulmonary hypertension (PH) is a disease characterized by hypertension of 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, while other symptoms include fatigue, dizziness, syncope, peripheral edema (swelling of the feet, lower extremities, or ankles), bluish lips and skin, chest pain, angina, confusion during exercise, dry cough, increased pulse rate, and palpitations. PH can be a severe disease that leads to heart failure, which is one of the most common causes of death in people with pulmonary hypertension. Postoperative pulmonary hypertension can complicate many types of surgical procedures and present challenges associated with high mortality.

[0003] PH can be grouped based on different manifestations of diseases that share similarities in pathophysiological mechanisms, clinical presentation, and therapeutic approaches [Simonneau et al., JACC 54(1):S44-54 (2009)]. The clinical classification of PH was first proposed in 1973, and the most recently updated clinical classification was approved by the World Health Organization (WHO) in 2018. According to the updated clinical classification of PH, there are five main groups of PH: pulmonary arterial hypertension (PAH) characterized by pulmonary artery wedge pressure (PAWP) of ≤15 mmHg; PH resulting from left heart disease characterized by PAWP >15 mmHg (also known as pulmonary venous hypertension or congestive heart failure); PH resulting from lung disease and / or hypoxia; PH resulting from pulmonary artery occlusion; and PH due to unclear and / or multifactorial mechanisms [Simonneau (2019) Eur Respir J: 53:1801913]. PH resulting from left heart disease is further classified into PH resulting from heart failure with maintained left ventricular ejection fraction; PH resulting from heart failure with reduced left ventricular ejection fraction; valvular heart disease; and congenital / acquired cardiovascular conditions leading to postcapillary PH [Simonneau (2019) Eur Respir J: 53:1801913]. Diagnosis of the various types of PH typically requires a series of tests. Generally, the treatment of pulmonary hypertension (PH) depends on its cause or classification. When PH is caused by a known drug or medical condition, this is known as secondary PH, and its treatment is usually directed towards the underlying disease. Treatment of group 2 pulmonary hypertension (e.g., venous hypertension) generally involves optimizing left ventricular function by administering diuretics, beta-blockers, angiotensin receptor-neprilysin inhibitors (ARNIs), and ACE inhibitors, cardiac resynchronization therapy, or repair or replacement of the mitral or aortic valve. [Prior art documents] [Non-patent literature]

[0004] [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 (2019) Eur Respir J: 53:1801913 [Overview of the project] [Means for solving the problem]

[0005] There is a high and unmet need for effective treatments for pulmonary hypertension. Therefore, the object of this disclosure is to provide methods for treating, preventing, or reducing the rate of progression and / or severity of PH, in particular, methods for treating, preventing, or reducing the rate of progression and / or severity of one or more PH-related complications.

[0006] Summary of the Invention In some embodiments, the present disclosure is a method for treating post-capillary pulmonary hypertension (PcPH), starting with any one of amino acids 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 of SEQ ID NO: 1, and continuing with amino acids 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130 of SEQ ID NO: 1, The present invention provides a method comprising administering an effective amount of polypeptide to a patient in need of it, which contains an amino acid sequence that is at least 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to an amino acid sequence ending at any one of 131, 132, 133, 134, or 135. In some embodiments, the Disclosure relates to a method for treating, preventing, or reducing the rate of progression and / or severity of one or more complications of postcapillary pulmonary hypertension (e.g., WHO Group 2 and / or Group 5 PH), starting with any one of amino acids 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 of SEQ ID NO: 1, and continuing with amino acids 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120 of SEQ ID NO: 1, The present invention provides a method comprising administering an effective amount of polypeptide to a patient in need of it, which contains an amino acid sequence that is at least 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to an amino acid sequence ending at any one of 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, or 135. In some embodiments, one or more complications of postcapillary pulmonary hypertension are selected from the group consisting of proliferation of smooth muscle and / or endothelial cells in the pulmonary arteries, angiogenesis in the pulmonary arteries, dyspnea, chest pain, pulmonary vascular remodeling, right ventricular hypertrophy, left ventricular hypertrophy, left atrial dilation, left ventricular fibrosis, right ventricular fibrosis, and pulmonary fibrosis.In some embodiments, PcPH is isolated postcapillary pulmonary hypertension (IpcPH). In some embodiments, PcPH is a mixed postcapillary and precapillary type of pulmonary hypertension (CpcPH).

[0007] In some embodiments, the patient has group 2 pulmonary hypertension as recognized by the World Health Organization (WHO). In some embodiments, the patient has pulmonary hypertension resulting from heart failure with maintained left ventricular ejection fraction (LVEF). In some embodiments, the patient has pulmonary hypertension resulting from heart failure with reduced left ventricular ejection fraction (LVEF). In some embodiments, the patient has valvular heart disease. In some embodiments, the patient has a congenital / acquired cardiovascular condition leading to postcapillary PH. In some embodiments, the patient has group 5 pulmonary hypertension as recognized by the WHO. In some embodiments, the patient has pulmonary hypertension due to an unclear and / or multifactorial mechanism. In some embodiments, the valvular heart disease is aortic regurgitation. In some embodiments, the valvular heart disease is aortic stenosis. In some embodiments, the valvular heart disease is mitral regurgitation. In some embodiments, the valvular heart disease is mitral stenosis.

[0008] In some embodiments, the patient has an mPAP selected from the group consisting of at least 20 mmHg mean pulmonary artery pressure (mPAP); at least 25 mmHg mPAP; at least 30 mmHg mPAP; at least 35 mmHg mPAP; at least 40 mmHg mPAP; at least 45 mmHg mPAP; and at least 50 mmHg mPAP. In some embodiments, the method reduces the mPAP in the patient. In some embodiments, the method reduces the mPAP in the patient by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or at least 80%). In some embodiments, the method reduces the mPAP in the patient by at least 3 mmHg (e.g., at least 3, 5, 7, 10, 12, 15, 20, or 25 mmHg).

[0009] In some embodiments, the patient has a pulmonary wedge pressure (PAWP) greater than 15 mmHg. In some embodiments, the method reduces the PAWP in the patient. In some embodiments, the method reduces the PAWP in the patient by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or at least 80%). In some embodiments, the patient has a left ventricular end-diastolic pressure (LVEDP) greater than 15 mmHg. In some embodiments, the method reduces the LVEDP in the patient. In some embodiments, the method reduces the LVEDP in the patient by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or at least 50%). In some embodiments, the patient has a diastolic pressure gradient (DPG) less than 7 mmHg. In some embodiments, the patient has a DPG of at least 7 mmHg. In some embodiments, the method reduces the DPG in the patient. In some embodiments, the method reduces the DPG in the patient by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or at least 80%). In some embodiments, the patient has a transpulmonary pressure gradient (TPG) of less than or equal to 12 mmHg. In some embodiments, the patient has a TPG greater than 12 mmHg. In some embodiments, the method reduces the TPG in the patient. In some embodiments, the method reduces the TPG in the patient by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or at least 80%). In some embodiments, the patient has a pulmonary vascular resistance (PVR) greater than or equal to 3 Wood units. In some embodiments, the method reduces the PVR in the patient. In some embodiments, the method reduces the PVR in the patient by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or at least 80%).

[0010] In some embodiments, the method prevents progression from IpcPH to CpcPH. In some embodiments, the method reduces the development of precapillary components of PH. In some embodiments, the patient has a maintained left ventricular ejection fraction. In some embodiments, the maintained left ventricular ejection fraction is greater than 45%. In some embodiments, the patient has a reduced left ventricular ejection fraction. In some embodiments, the reduced left ventricular ejection fraction is less than 45%. In some embodiments, the maintained left ventricular fraction is measured using echocardiography. In some embodiments, the patient has left ventricular diastolic dysfunction. In some embodiments, the patient has left ventricular systolic dysfunction. In some embodiments, the method reduces right ventricular hypertrophy in the patient. In some embodiments, the method reduces right ventricular hypertrophy in the patient by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or at least 80%). In some embodiments, the method reduces left ventricular hypertrophy in the patient. In some embodiments, the method reduces left ventricular hypertrophy in a patient by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or at least 80%). In some embodiments, the method reduces smooth muscle hypertrophy in a patient. In some embodiments, the method reduces smooth muscle hypertrophy in a patient by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or at least 80%). In some embodiments, the method reduces muscularity of the pulmonary arterioles in a patient. In some embodiments, the method reduces the muscularity of the pulmonary arterioles in the patient by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or at least 80%).

[0011] In some embodiments, the patient has a right ventricular systolic pressure (RVSP) greater than 35 mmHg. In some embodiments, the method reduces the RVSP in the patient. In some embodiments, the method reduces the RVSP in the patient by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or at least 50%). In some embodiments, the patient has left ventricular fibrosis. In some embodiments, the method reduces the left ventricular fibrosis in the patient. In some embodiments, the method reduces the left ventricular fibrosis in the patient by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or at least 50%). In some embodiments, the patient has right ventricular fibrosis. In some embodiments, the method reduces the right ventricular fibrosis in the patient. In some embodiments, the method reduces right ventricular fibrosis in a patient by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or at least 50%). In some embodiments, the patient has pulmonary fibrosis. In some embodiments, the method reduces pulmonary fibrosis in a patient. In some embodiments, the method reduces pulmonary fibrosis in a patient by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or at least 50%).

[0012] In some embodiments, the patient has comorbidities selected from the group consisting of systemic hypertension, diabetes mellitus, obesity, coronary artery disease (CAD), heart failure, and anemia. In some embodiments, the method further comprises administering additional activators and / or supportive therapies to the patient. In some embodiments, the additional activators and / or supportive therapies are selected from the group consisting of beta-blockers, angiotensin-converting enzyme inhibitors (ACE inhibitors), angiotensin receptor blockers (ARBs), neprilysin inhibitors, angiotensin receptor-neprilysin inhibitors (ARNIs), mineralocorticoid receptor antagonists (MRAs), hyperpolarization-activated cyclic nucleotide-dependent (HCN) channel blockers, diuretics, lipid-lowering agents, endothelin blockers, PDE5 inhibitors, prostacyclins, cardiac resynchronization therapy, valve replacement, valve repair, implantable cardioverter-defibrillators (ICDs), or left ventricular assist devices (LVADs). In some embodiments, additional activators and / or supportive therapies include: prostacyclins and their derivatives (e.g., epoprostenol, treprostinil, and iloprost); prostacyclin receptor agonists (e.g., selexipag); endothelin receptor antagonists (e.g., therin, ambrisentan, macitentan, and bosentan); calcium channel blockers (e.g., amlodipine, diltiazem, and nifedipine); anticoagulants (e.g., warfarin); diuretics; oxygen therapy; atrial septal dehiscence; pulmonary endarterectomy; phosphodiesterase type 5 inhibitors (e.g., sildenafil and tadalafil); soluble guanylate cyclase Activators (e.g., synaciguat and riociguat); ASK-1 inhibitors (e.g., CIIA; SCH79797; GS-4997; MSC2032964A; 3H-naphtho[1,2,3-de]quinilin-2,7-dione, NQDI-1; 2-thioxo-thiazolidinedione, 5-bromo-3-(4-oxo-2-thioxo-thiazolidinedione-5-ylidene)-1,3-dihydro-indole-2-one); NF-κB antagonists (e.g., dh404, CDDO-epoxide; 2,2-difluoropropionamide; C28-imidazole (CDDO-Im); 2-cyano-3,12-dioxolean-1,9-diene-28-euic acid (CDDO);3-Acetyloleanolic acid; 3-Trifluoro(Triflouro)acetyloleanolic acid; 28-Methyl-3-acetyloleanane; 28-Methyl-3-trifluoroacetyloleanane; 28-Methyloxyoleanolic acid; SZC014; SCZ015; SZC017; PEGylated derivatives 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]oleanolic acid; 3-O-[beta-D-glucopyranosyl-(1→3)-beta-D-glucopyranosyl]oleanolic acid 28-O-beta-D-glucopyranosyl ester; 3-O-[beta-D-glucopyranosyl-(1→2)-beta-D-glucopyranosyl]oleanolic acid 28-O-beta-D-glucopyranosyl ester; 3-O -[aL-rhamnopyranosyl-(1→3)-beta-D-glucuronopyranosyl]oleanolic acid; 3-O-[alpha-L-rhamnopyranosyl-(1→3)-beta-D-glucuronopyranosyl]oleanolic acid 28-O-beta-D-glucopyranosyl ester; 28-O-β-D-glucopyranosyl-oleanolic acid; 3-O-β-D-glucopyranosyl(1→3)-β-D-glucopyranosidouronic acid (CS1); oleanolic acid 3-O-β-D-gluco The following are selected from the group consisting of pyranosyl(1→3)-β-D-glucopyranosideuronic acid (CS2); methyl 3,11-dioxolean-12-ene-28-oleate (DIOXOL); ZCVI4-2; benzyl 3-dehydro-oxy-1,2,5-oxadiazolo[3',4':2,3]oleanolate); eplerenone, spironolactone, ivabradine, implantable cardioverter-defibrillators (ICDs), left ventricular assist devices (LVADs), or lung and / or heart transplants.

[0013] In some embodiments, the patient has elevated brain natriuretic peptide (BNP) levels compared to a healthy patient. In some embodiments, the patient has a BNP level of at least 100 pg / mL (e.g., 100, 150, 200, 300, 400, 500, 1000, 3000, 5000, 10,000, 15,000, or 20,000 pg / mL). In some embodiments, the method reduces the BNP level in the patient by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or at least 80%). In some embodiments, the method reduces the BNP level to a normal level (i.e., <100 pg / mL). In some embodiments, the method reduces the NT-proBNP level in the patient. In some embodiments, the method reduces the NT-proBNP level in the patient by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or at least 80%). In some embodiments, the method reduces the NT-proBNP level in the patient by at least 30%. In some embodiments, the method reduces the NT-proBNP level to a normal level. In some embodiments, a normal level of NT-proBNP is <100 pg / ml. In some embodiments, the method increases the patient's exercise capacity. In some embodiments, the patient has a 6-minute walking distance of 150–400 meters. In some embodiments, the patient has a 6-minute walking distance of 150–550 meters. In some embodiments, the method increases the patient's 6-minute walking distance. In some embodiments, the method increases the patient's 6-minute walking distance by at least 10 meters (for example, more than at least 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, 250, 300, or 400 meters). In some embodiments, the method reduces the patient's Borg dyspnea index (BDI).In some embodiments, the method reduces the patient's BDI by at least 0.5 exponential 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, 8.5, 9, 9.5, or 10 exponential points).

[0014] In some embodiments, the patient has reduced renal function. In some embodiments, the method further improves renal function. In some embodiments, the patient has pulmonary hypertension of function class II or class III according to the World Health Organization's functional classification system for pulmonary hypertension. In some embodiments, the patient has pulmonary hypertension of function class I, class II, class III, or class IV as recognized by the World Health Organization. In some embodiments, the method prevents or delays the progression of the functional class of pulmonary hypertension (e.g., prevents or delays the progression from functional class I to class II, class II to class III, or class III to class IV pulmonary hypertension as recognized by the World Health Organization). In some embodiments, the method facilitates or increases the regression of the functional class of pulmonary hypertension (e.g., facilitates or increases the regression from class IV to class III, class III to class II, or class II to class I pulmonary hypertension as recognized by the World Health Organization). In some embodiments, the patient has pulmonary hypertension of function class II or class III according to the New York Heart Association's functional classification system for pulmonary hypertension. In some embodiments, the patient has pulmonary hypertension of functional class I, class II, class III, or class IV as recognized by the New York Heart Association. In some embodiments, the method prevents or delays the progression of functional class of pulmonary hypertension (e.g., prevents or delays progression from functional class I to class II, class II to class III, or class III to class IV pulmonary hypertension as recognized by the New York Heart Association). In some embodiments, the method facilitates or increases the regression of functional class of pulmonary hypertension (e.g., facilitates or increases the regression from class IV to class III, class III to class II, or class II to class I pulmonary hypertension as recognized by the New York Heart Association). In some embodiments, the method delays the clinical progression of PcPH. In some embodiments, the method delays the clinical progression of PcPH according to the World Health Organization's functional classification system for pulmonary hypertension.In some embodiments, the method delays the clinical progression of PcPH according to the New York Heart Association's functional classification system for pulmonary hypertension. In some embodiments, the method reduces the risk of hospitalization for one or more complications associated with PcPH. In some embodiments, the patient has hemoglobin levels >8 and <15 g / dl.

[0015] In some embodiments, the patient is treated with one or more vasodilators. In some embodiments, the patient is treated with one or more agents selected from the group consisting of phosphodiesterase type 5 inhibitors, soluble guanylate cyclase stimulants, prostacyclin receptor agonists, and endothelin receptor antagonists. In some embodiments, one or more agents are selected from the group consisting of bosentan, sildenafil, beraprost, macitentan, selexipag, epoprostenol, treprostinil, iloprost, ambrisentan, and tadalafil. In some embodiments, the method further comprises the administration of one or more vasodilators. In some embodiments, the method further comprises the administration of one or more agents selected from the group consisting of phosphodiesterase type 5 inhibitors, soluble guanylate cyclase stimulants, prostacyclin receptor agonists, and endothelin receptor antagonists. In some embodiments, one or more agents are selected from the group consisting of bosentan, sildenafil, beraprost, macitentan, selexipag, epoprostenol, treprostinil, iloprost, ambrisentan, and tadalafil.

[0016] In some embodiments, the ActRII polypeptide includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1. In some embodiments, the ActRII polypeptide includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 2. In some embodiments, the ActRII polypeptide comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 3. In some embodiments, the ActRII polypeptide is a fusion protein further comprising the Fc domain of an immunoglobulin. In some embodiments, the Fc domain of the immunoglobulin is the Fc domain of IgG1 immunoglobulin. In some embodiments, the Fc fusion protein further comprises a linker domain located between the ActRII polypeptide domain and the Fc domain of the immunoglobulin. In some embodiments, the linker domain is selected from the group consisting of TGGG (SEQ ID NO: 20), TGGGG (SEQ ID NO: 18), SGGGG (SEQ ID NO: 22), GGGGS (SEQ ID NO: 22), GGG (SEQ ID NO: 16), GGGG (SEQ ID NO: 17), and SGGG (SEQ ID NO: 21). In some embodiments, the ActRII polypeptide includes an amino acid sequence that is at least 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 23. In some embodiments, the polypeptide includes an amino acid sequence that is at least 90% identical to the amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1, and the polypeptide binds to activin and / or GDF11.In some embodiments, the polypeptide comprises an amino acid sequence that is at least 90% identical to the amino acid sequence corresponding to residues 21-135 of SEQ ID NO: 1, and the polypeptide binds to activin and / or GDF11. In some embodiments, the polypeptide is lyophilized. In some embodiments, the polypeptide is soluble. In some embodiments, the polypeptide is administered by subcutaneous injection. In some embodiments, the polypeptide is administered every four weeks. In some embodiments, the polypeptide is part of a homodimeric protein complex. In some embodiments, the polypeptide is glycosylated. In some embodiments, the polypeptide has a glycosylation pattern that can be obtained by expression in Chinese hamster ovary cells. In some embodiments, the ActRII polypeptide binds to one or more ligands selected from the group consisting of activin A, activin B, and GDF11. In some embodiments, the ActRII polypeptide further binds to one or more ligands selected from the group consisting of BMP10, GDF8, and BMP6.

[0017] In certain embodiments, the Disclosure relates to a kit comprising a lyophilized polypeptide and an injection device, wherein the polypeptide begins with any one of amino acids 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 of SEQ ID NO: 1, and continues with amino acids 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125 of SEQ ID NO: 1, The present invention relates to an ActRII polypeptide comprising an amino acid sequence that is at least 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to an amino acid sequence ending at any one of 126, 127, 128, 129, 130, 131, 132, 133, 134, or 135. In some embodiments, the polypeptide is a polypeptide comprising an amino acid sequence that is at least 90% identical to an amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1. In some embodiments, the polypeptide is a polypeptide comprising an amino acid sequence that is at least 95% identical to an amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1. In some embodiments, the polypeptide is a polypeptide comprising an amino acid sequence that is at least 99% identical to an amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1. In some embodiments, the polypeptide is a polypeptide comprising an amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1. In some embodiments, the polypeptide is a polypeptide consisting of an amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1. In some embodiments, the polypeptide is a polypeptide comprising an amino acid sequence that is at least 90% identical to the amino acid sequence corresponding to residues 21-135 of SEQ ID NO: 1. In some embodiments, the polypeptide is a polypeptide comprising an amino acid sequence that is at least 95% identical to the amino acid sequence corresponding to residues 21-135 of SEQ ID NO: 1.

[0018] In some embodiments, the polypeptide is a polypeptide comprising an amino acid sequence that is at least 99% identical to the amino acid sequence corresponding to residues 21-135 of SEQ ID NO: 1. In some embodiments, the polypeptide is a polypeptide comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 2. In some embodiments, the polypeptide is a polypeptide comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 2. In some embodiments, the polypeptide is a polypeptide comprising an amino acid sequence that is at least 99% identical to the amino acid sequence of SEQ ID NO: 2. In some embodiments, the polypeptide is a polypeptide comprising an amino acid sequence that is at least 99% identical to the amino acid sequence of SEQ ID NO: 2. In some embodiments, the polypeptide is a polypeptide comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 2. In some embodiments, the polypeptide is a polypeptide comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 3. In some embodiments, the polypeptide is a polypeptide comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 3. In some embodiments, the polypeptide is a polypeptide comprising an amino acid sequence that is at least 99% identical to the amino acid sequence of SEQ ID NO: 3. In some embodiments, the polypeptide is a polypeptide comprising the amino acid sequence of SEQ ID NO: 3. In some embodiments, the polypeptide is a polypeptide consisting of the amino acid sequence of SEQ ID NO: 3.

[0019] In some embodiments, the polypeptide is a fusion protein further comprising the Fc domain of an immunoglobulin. In some embodiments, the immunoglobulin is the Fc domain of IgG1 immunoglobulin. In some embodiments, the fusion protein further comprises a linker domain located between the polypeptide domain and the Fc domain of the immunoglobulin. In some embodiments, the linker domain is selected from the group consisting of TGGG (SEQ ID NO: 20), TGGGG (SEQ ID NO: 18), SGGGG (SEQ ID NO: 19), GGGGS (SEQ ID NO: 22), GGG (SEQ ID NO: 16), GGGG (SEQ ID NO: 17), and SGGG (SEQ ID NO: 21). In some embodiments, the linker domain includes TGGG (SEQ ID NO: 20). In some embodiments, the ActRII polypeptide comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 23. In some embodiments, the ActRII polypeptide comprises the amino acid sequence of SEQ ID NO: 23. In some embodiments, the ActRII polypeptide consists of the amino acid sequence of SEQ ID NO: 23. In some embodiments, the polypeptide is part of a homodimeric protein complex. In some embodiments, the polypeptide is glycosylated. In some embodiments, the polypeptide binds to one or more ligands selected from the group consisting of activin A, activin B, and GDF11. In some embodiments, the polypeptide further binds to one or more ligands selected from the group consisting of BMP10, GDF8, and BMP6. In some embodiments, the polypeptide binds to activin and / or GDF11.

[0020] In some embodiments, the kit comprises one or more vials containing lyophilized polypeptides. In some embodiments, the injection device comprises a pre-filled syringe. In some embodiments, the injection device comprises a pump device. In some embodiments, the pump device comprises an electromechanical pump assembly. In some embodiments, the pump device is a wearable pump device. In some embodiments, the pre-filled syringe comprises a reconstitution solution. In some embodiments, the reconstitution solution comprises a pharmaceutically acceptable carrier and / or excipient. In some embodiments, the pharmaceutically acceptable carrier is selected from physiological saline solution, purified water, or sterile water for injection. In some embodiments, the pharmaceutically acceptable excipient is selected from buffers [e.g., citric acid (monohydrate) and / or trisodium citrate (dehydrated)], surfactants (e.g., polysorbate 80), stabilizers (e.g., sucrose), and cryoprotectants (e.g., sucrose).

[0021] In some embodiments, the injection device includes a vial adapter. In some embodiments, the vial adapter can be attached to a vial. In some embodiments, the vial adapter can be attached to a pre-filled syringe. In some embodiments, the pre-filled syringe and vial are attached to both ends of the vial adapter. In some embodiments, the reconstitution solution is transferred from the pre-filled syringe to the vial. In some embodiments, the lyophilized polypeptide is reconstituted into a sterile injection solution. In some embodiments, the lyophilized polypeptide is reconstituted into a sterile injection solution before use. In some embodiments, the sterile injection solution is sterile water for injection.

[0022] In some embodiments, the sterile injection solution is administered parenterally. In some embodiments, an injection device is used to administer the sterile injection solution parenterally. In some embodiments, the sterile injection solution is administered via subcutaneous injection. In some embodiments, the sterile injection solution is administered via intradermal injection. In some embodiments, the sterile injection solution is administered via 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 sterile injection solution contains a therapeutically effective dose. In some embodiments, the therapeutically effective dose contains a dose based on body weight. In some embodiments, the lyophilized polypeptide is administered every four weeks.

[0023] In some embodiments, the kit is used to treat postcapillary pulmonary hypertension (PcPH). In some embodiments, PcPH is isolated postcapillary pulmonary hypertension (IpcPH). In some embodiments, PcPH is a mixed postcapillary and precapillary type of PH (CpcPH). In some embodiments, the patient has pulmonary hypertension of group 2 as recognized by the WHO. In some embodiments, the patient has pulmonary hypertension resulting from heart failure with maintained left ventricular ejection fraction (LVEF). In some embodiments, the patient has pulmonary hypertension resulting from heart failure with reduced left ventricular ejection fraction (LVEF). In some embodiments, the patient has valvular heart disease. In some embodiments, the patient has a congenital / acquired cardiovascular condition leading to postcapillary PH. In some embodiments, the patient has pulmonary hypertension of group 5 as recognized by the WHO. In some embodiments, the patient has pulmonary hypertension due to an unclear and / or multifactorial mechanism. In some embodiments, the shelf life of the lyophilized polypeptide is at least 1, 1.5, 2, 2.5, or 3 years. In some embodiments, the freeze-dried polypeptide is restored. In some embodiments, the restored polypeptide has an effective period of at least 2, 3, or 4 hours.

[0024] The patent file contains at least one color drawing / photograph. A copy of the patent containing the color drawing(s) / photograph(s) will be provided by the ministry upon request and payment of the necessary fees. [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 a schematic diagram of a linearized version of the cardiopulmonary circulation and the regions associated with various types of pulmonary hypertension (PH). The differences between precapillary pulmonary hypertension, isolated postcapillary pulmonary hypertension, and mixed postcapillary and precapillary pulmonary hypertension are based on pulmonary hemodynamic parameters and the involvement of various regions of the cardiopulmonary system (anterior and / or postcapillary regions). The abbreviations are as follows: VC - superior vena cava; RA - right atrium; RV - right ventricle; PA - pulmonary artery; PC - pulmonary capillaries; PV - pulmonary ventricles; LA - left atrium; LV - left ventricle; AO - aorta. See, for example, Aras MA, et al. Curr Cardiol Rep. 2019;21(7):62 and Galie N. et al. Eur Heart J. 2018;39(15):1265-1268.

[0031] [Figure 7] Figure 7 shows a schematic diagram of a linearized version of the cardiopulmonary circulation and hemodynamic parameters related to precapillary PH. The abbreviations are as follows: VC - superior vena cava; RA - right atrium; RV - right ventricle; PA - pulmonary artery; PC - pulmonary capillary; PV - pulmonary ventricle; LA - left atrium; LV - left ventricle; AO - aorta; mPAP - mean pulmonary artery pressure; PAWP - pulmonary artery wedge pressure; PVR - pulmonary vascular resistance. Ibid.

[0032] [Figure 8]Figure 8 shows a schematic diagram of a linearized version of the cardiopulmonary circulation and hemodynamic parameters associated with isolated postcapillary pulmonary hypertension (IpcPH). The abbreviations are as follows: VC - superior vena cava; RA - right atrium; RV - right ventricle; PA - pulmonary artery; PC - pulmonary capillary; PV - pulmonary ventricle; LA - left atrium; LV - left ventricle; AO - aorta; mPAP - mean pulmonary artery pressure; PAWP - pulmonary artery wedge pressure; PVR - pulmonary vascular resistance. Ibid.

[0033] [Figure 9] Figure 9 shows a schematic diagram of a linearized version of the cardiopulmonary circulation, as well as hemodynamic parameters related to postcapillary and precapillary mixed pulmonary hypertension (CpcPH). The abbreviations are as follows: VC - superior vena cava; RA - right atrium; RV - right ventricle; PA - pulmonary artery; PC - pulmonary capillary; PV - pulmonary ventricle; LA - left atrium; LV - left ventricle; AO - aorta; mPAP - mean pulmonary artery pressure; PAWP - pulmonary artery wedge pressure; PVR - pulmonary vascular resistance. Ibid.

[0034] [Figure 10]Figures 10-14 show the therapeutic effects of ActRIIA-mFc in the TAC-PH model based on endpoints for left ventricular function. On day 0, 26 C57 / B6 male mice (10 weeks old) underwent TAC pulmonary hypertension surgery (TAC-PH), and 10 animals of the same age underwent a sham procedure. Two weeks after surgery, the TAC-PH mice were randomized into two groups: i) 14 mice received subcutaneous injections of a medium control (phosphate-buffered saline (PBS)) twice a week for 4 weeks, starting 14 days post-surgery, as the "TAC-PH / PBS" group; and ii) 12 mice received subcutaneous injections of ActRIIA-mFc at a dose of 10 mg / kg twice a week for 4 weeks, starting 14 days post-TAC surgery, as the "TAC-PH / ActRIIA-mFc" group. Figures 10–14 show endpoints for left ventricular function, including changes in cardiac hypertrophy, cardiac weight / body weight (HW / BW) (Figure 10), fractional shorting of LV function parameters (Figure 11), and LV ejection fraction (Figure 12); as well as changes in LV diastolic parameters E / E' [ratio of mitral valve inflow velocity (E) to mitral valve annular velocity (E')] (Figure 13) and isovolumetric relaxation time (IVRT) (Figure 14). Compared to "TAC-PH / PBS" treated mice, "TAC-PH / ActRIIA-mFc" treated mice demonstrated a significant effect of ActRIIA-mFc in reducing cardiac hypertrophy and improving cardiac function. Statistical significance (p-values) are described as *p<0.05, **p<0.01, ***p<0.001, and ****p<0.0001 for comparisons between "sham" and the "TAC-PH / PBS" sample. Statistical significance (p-values) are depicted as #p<0.05, ##p<0.01, ###p<0.001, and ####p<0.0001 for comparisons between "Sham" and sample "TAC-PH / ActRIIA-mFc". Statistical significance (p-values) are depicted as @p<0.05, @@p<0.01, @@@p<0.001, and @@@@p<0.0001 for comparisons between sample "TAC-PH / PBS" and sample "TAC-PH / ActRIIA-mFc". [Figure 11] Same as above. [Figure 12] Same as above. [Figure 13] Same as above. [Figure 14] Same as above.

[0035] [Figure 15]Figures 15-18 show the therapeutic effects of ActRIIA-mFc in the TAC-PH model based on endpoints for right ventricular function. On day 0, 26 C57 / B6 male mice (10 weeks old) underwent TAC pulmonary hypertension surgery (TAC-PH), and 10 animals of the same age underwent a sham procedure. Two weeks after surgery, the TAC-PH mice were randomized into two groups: i) 14 mice received subcutaneous injections of a medium control (phosphate-buffered saline (PBS)) twice a week for 4 weeks, starting 14 days post-surgery, as the "TAC-PH / PBS" group; and ii) 12 mice received subcutaneous injections of ActRIIA-mFc at a dose of 10 mg / kg twice a week for 4 weeks, starting 14 days post-TAC surgery, as the "TAC-PH / ActRIIA-mFc" group. Figures 15–18 show endpoints for right ventricular function, including the RV remodeling parameter right ventricular free wall thickness (RVFWT) (Figure 15), the RV remodeling and functional parameter tricuspid annular plane systolic excursion (TAPSE) (Figure 16), and the RV functional parameters RV stroke work (Figure 17) and RV contractility (dP / dT) (Figure 18). Compared to "TAC-PH / PBS" treated mice, "TAC-PH / ActRIIA-mFc" treated mice demonstrated a significant effect of ActRIIA-mFc on the improvement of right ventricular remodeling and function. Statistical significance (p-values) are described as *p<0.05, **p<0.01, ***p<0.001, and ****p<0.0001 for comparisons between "sham" and the "TAC-PH / PBS" sample. Statistical significance (p-values) are depicted as #p<0.05, ##p<0.01, ###p<0.001, and ####p<0.0001 for comparisons between "Sham" and sample "TAC-PH / ActRIIA-mFc". Statistical significance (p-values) are depicted as @p<0.05, @@p<0.01, @@@p<0.001, and @@@@p<0.0001 for comparisons between sample "TAC-PH / PBS" and sample "TAC-PH / ActRIIA-mFc". [Figure 16] Same as above. [Figure 17]Same as above. [Figure 18] Same as above.

[0036] [Figure 19] Figures 19 and 20 show the therapeutic effects of ActRIIA-mFc in a TAC-PH model based on an endpoint for lung remodeling. On day 0, 26 C57 / B6 male mice (10 weeks old) underwent TAC pulmonary hypertension surgery (TAC-PH), and 10 animals of the same age underwent a sham procedure. Two weeks after surgery, the TAC-PH mice were randomized into two groups: i) 14 mice received subcutaneous injections of a medium control (phosphate-buffered saline (PBS)) twice a week for 4 weeks, starting 14 days post-surgery, as the "TAC-PH / PBS" group; and ii) 12 mice received subcutaneous injections of ActRIIA-mFc at a dose of 10 mg / kg twice a week for 4 weeks, starting 14 days post-TAC surgery, as the "TAC-PH / ActRIIA-mFc" group. Figures 19 and 20 show endpoints for lung remodeling, including the ratio of lung weight to tibia length (LW / TL) (Figure 19) and the percentage of pulmonary fibrosis (Figure 20). Compared to mice treated with "TAC-PH / PBS," mice treated with "TAC-PH / ActRIIA-mFc" demonstrated a significant effect of ActRIIA-mFc on the reduction of lung remodeling and fibrosis. Statistical significance (p-values) are depicted as *p<0.05, **p<0.01, ***p<0.001, and ****p<0.0001 for comparisons between "sham" and the "TAC-PH / PBS" sample. Statistical significance (p-values) are depicted as #p<0.05, ##p<0.01, ###p<0.001, and ####p<0.0001 for comparisons between "sham" and the "TAC-PH / ActRIIA-mFc" sample. Statistical significance (p-values) are described as @p<0.05, @@p<0.01, @@@p<0.001, and @@@@p<0.0001 for comparisons between the "TAC-PH / PBS" and "TAC-PH / ActRIIA-mFc" samples. [Figure 20] Same as above.

[0037] [Figure 21] Figure 21 shows the components of the kit, including lyophilized polypeptide and an injection device. Vial (1) holds lyophilized polypeptide, reconstituted sterile injection solution, or sterile injection solution. A pre-filled syringe (2) containing the reconstitution solution is used to reconstitute the lyophilized polypeptide from (1) into the 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.

[0038] [Figure 22] Figures 22–25 show that treatment with ActRIIA-mFc fusion protein improves diastolic dysfunction in a rat model of left ventricular diastolic dysfunction (also known as HEpEF) group 2 (subgroup 2.2) pulmonary hypertension (PH). The experimental strategy used to test the prophylactic effect of ActRIIA-mFc in a rat model of HEpEF is shown in Figure 22. Figures 23–25 show endpoints for left ventricular function, including left ventricular ejection fraction (Figure 23); LV diastolic parameters E / E' [ratio of mitral valve inflow velocity (E) to mitral valve annular velocity (E')] (Figure 24); and isovolumetric relaxation time (IVRT) (Figure 25). Statistical significance (p-values) are described as *p<0.05, **p<0.01, and ***p<0.001. [Figure 23] Same as above. [Figure 24] Same as above. [Figure 25] Same as above.

[0039] [Figure 26]Figures 26–28 show that treatment with ActRIIA-mFc fusion protein reduces left ventricular remodeling in a rat model of left ventricular diastolic dysfunction (HEpEF) group 2 (subgroup 2.2) pulmonary hypertension (PH). Figures 26–28 show endpoints for left ventricular remodeling, including changes in the ratio of cardiac weight to tibial length (HW / TL) (Figure 26); diastolic interventricular septal dimension (IVSd) (Figure 27); and left ventricular mass (LVM) (Figure 28). Statistical significance (p-values) are described as *p<0.05, **p<0.01, and ***p<0.001. [Figure 27] Same as above. [Figure 28] Same as above.

[0040] [Figure 29] Figures 29–31 show that treatment with ActRIIA-mFc fusion protein reduces right ventricular systolic pressure (RVSP) and improves right ventricular function in a rat model of left ventricular diastolic dysfunction (HEpEF) group 2 (subgroup 2.2) pulmonary hypertension (PH). Figures 29–31 show endpoints for right ventricular function, including changes in right ventricular free wall thickness (Figure 29); pulmonary artery acceleration time (PAAT) (Figure 30); and right ventricular systolic pressure (RVSP) (Figure 31). Statistical significance (p-values) are described as *p<0.05 and **p<0.01. [Figure 30] Same as above. [Figure 31] Same as above.

[0041] [Figure 32] Figures 32–34 show that treatment with ActRIIA-mFc fusion protein significantly reduced fibrosis in the left ventricular lung (LV), rear lung (RV), and lungs in a rat model of left ventricular diastolic dysfunction (also known as HEpEF) group 2 (subgroup 2.2) pulmonary hypertension (PH). Figures 32–34 show the reduction in fibrosis, including changes in left ventricular fibrosis (Figure 32); right ventricular fibrosis (Figure 33); and pulmonary fibrosis (Figure 34). Statistical significance (p-values) are depicted as *p<0.05 and **p<0.01. [Figure 33] Same as above. [Figure 34] Same as above.

[0042] [Figure 35] Figures 35–38 show that treatment with ActRIIA-mFc fusion protein significantly improves hyperglycemia and glucose intolerance in a rat model of left ventricular diastolic dysfunction (also known as HEpEF) group 2 (subgroup 2.2) pulmonary hypertension (PH). Figures 35–38 show endpoints for hyperglycemia and glucose intolerance, including changes in body weight (Figure 35); fasting blood glucose (Figure 36); blood glucose (Figure 37); and glucose / creatine ratio (Figure 38). Statistical significance (p-values) are depicted as *p<0.05, **p<0.01, and ***p<0.001. [Figure 36] Same as above. [Figure 37] Same as above. [Figure 38] Same as above.

[0043] [Figure 39]Figures 39–43 show that treatment with ActRIIA-mFc fusion protein inhibits cardiac remodeling and improves LV function in mouse models of PH (also known as HErEF) group 2 (subgroup 2.1) pulmonary hypertension (PH) and valvular heart disease (subgroup 2.3) with reduced LVEF. The experimental strategy used to test the prophylactic effect of ActRIIA-mFc in a rat model of HErEF is shown in Figure 39. Figures 40–43 show endpoints for left ventricular function, including changes in cardiac hypertrophy, cardiac weight / tibial length (HW / TL) (Figure 41), LV function parameters such as LV ejection fraction (Figure 40), and LV diastolic parameters E / E' [ratio of mitral valve inflow velocity (E) to mitral valve annular velocity (E')] (Figure 42) and isovolumetric relaxation time (IVRT) (Figure 43). Compared to mice treated with "TAC PBS," mice treated with "TAC ActRIIA-mFc" demonstrated a significant effect of ActRIIA-mFc in inhibiting cardiac remodeling and improving LV function. Statistical significance (p-values) are depicted as *p<0.05, **p<0.01, ***p<0.001, and ****p<0.0001 for comparisons between "TAC PBS" and the "TAC ActRIIA-mFc" sample. Statistical significance (p-values) are depicted as #p<0.05, ##p<0.01, ###p<0.001, and ####p<0.0001 for comparisons between "sham" and the "TAC PBS" sample. [Figure 40] Same as above. [Figure 41] Same as above. [Figure 42] Same as above. [Figure 43] Same as above.

[0044] [Figure 44]Figures 44–46 show the therapeutic effects of ActRIIA-mFc in the TAC-PH model based on endpoints for right ventricular function. Figures 44–46 show endpoints for right ventricular function, including right ventricular systolic pressure (RVSP) (Figure 44), right ventricular free wall thickness (RVFWT) (Figure 45), and pulmonary artery acceleration time (PAAT) (Figure 46). Compared to mice treated with "TAC PBS," "TAC ActRIIA-mFc" mice treated with either 3mpk or 10mpk demonstrated a significant effect of ActRIIA-mFc in reducing RVSP and improving RV function. Statistical significance (p-values) are depicted as *p<0.05, **p<0.01, ***p<0.001, and ****p<0.0001 for comparisons between "TAC PBS" and the "TAC ActRIIA-mFc" sample. Statistical significance (p-values) are described as #p<0.05, ##p<0.01, ###p<0.001, and ####p<0.0001 for comparisons between "Sham" and the sample "TAC PBS". [Figure 45] Same as above. [Figure 46] Same as above.

[0045] [Figure 47]Figures 47–49 show the therapeutic effects of ActRIIA-mFc in the TAC-PH model based on endpoints for fibrosis in the left ventricle (LV), right ventricle (RV), and lung. Figures 47–49 show the endpoints for fibrosis in the left ventricle (LV) (Figure 47), right ventricle (RV) (Figure 48), and lung (Figure 49). Compared to mice treated with "TAC PBS," "TAC ActRIIA-mFc" mice treated with either 3mpk or 10mpk demonstrated a significant effect of ActRIIA-mFc in reducing fibrosis in the LV (Figure 47), RV (Figure 48), and lung (Figure 49). Statistical significance (p-values) are depicted as *p<0.05, **p<0.01, ***p<0.001, and ****p<0.0001 for comparisons between "TAC PBS" and the "TAC ActRIIA-mFc" sample. Statistical significance (p-values) are described as #p<0.05, ##p<0.01, ###p<0.001, and ####p<0.0001 for comparisons between "Sham" and the sample "TAC PBS". [Figure 48] Same as above. [Figure 49] Same as above.

[0046] [Figure 50]Figures 50–55 show that treatment with ActRIIA-mFc fusion protein reduces right ventricular systolic pressure (RVSP) and improves cardiopulmonary function in a rat model of left ventricular diastolic dysfunction (also known as HEpEF) group 2 (subgroup 2.2) pulmonary hypertension (PH). The experimental strategy used to test the prophylactic effect of ActRIIA-mFc fusion protein in a rat model of HEpEF is shown in Figure 50. Figures 51–55 show endpoints for right ventricular function, including changes in pulmonary artery acceleration time (PAAT) (Figure 51); right ventricular systolic pressure (RVSP) (Figure 52); right ventricular wall thickness (RVWT) (Figure 53); tricuspid annular systolic displacement (TAPSE) (Figure 54); and the Fulton index (Figure 55), calculated as the ratio of right ventricular mass (RV) to the combined left ventricle and septal mass (LV+S). Statistical significance (p-value) is described as *p<0.05, **p<0.01, ***p<0.001, and ****p<0.0001. [Figure 51] Same as above. [Figure 52] Same as above. [Figure 53] Same as above. [Figure 54] Same as above. [Figure 55] Same as above. [Modes for carrying out the invention]

[0047] Detailed explanation 1. Overview This disclosure relates to compositions and methods for treating postcapillary pulmonary hypertension (e.g., WHO Group 2 and / or Group 5 PH), comprising administering an effective amount of the ActRII polypeptide described herein to a patient in need. In certain embodiments, this disclosure provides a method for treating or preventing postcapillary pulmonary hypertension (PcPH) in an individual in need by administering a therapeutically effective amount of the ActRII polypeptide described herein to the individual. In certain embodiments, this disclosure provides a method for treating or preventing postcapillary and precapillary mixed PH in an individual in need by administering a therapeutically effective amount of the ActRII polypeptide described herein to the individual.

[0048] Pulmonary hypertension resulting from left heart disease (PH-LHD) (also known as WHO Group 2 PH) is a complex pathological phenotype that, if present, can lead to increased susceptibility to adverse events and worse clinical outcomes. Of these patients with PH-LHD, two phenotypes have been described: 1) a group of isolated retrocapillary PH (IpcPH) or “passive” PH, where the increase in pulmonary pressure is reversible and proportional to the increase in left atrial pressure; and 2) a group with a “retrocapillary” component [mixed retrocapillary and precapillary PH (CpcPH)], where the pulmonary hypertension is worse than can be fully explained by the passive increase secondary to the increase in left atrial pressure. CpcPH in this latter group may also have mixed pulmonary vascular remodeling and therefore may exhibit persistent PH after interventions to reduce left-sided filling pressure.

[0049] PH-LHD may be defined as a patient having a pulmonary capillary wedge pressure (PCWP) >15 mmHg and mean pulmonary artery pressure (mPAP) ≥25 mmHg (or, under updated guidelines, mean pulmonary artery pressure (mPAP) ≥20 mmHg). PH-LHD occurs as a result of high left-sided filling pressure, primarily driven by LV diastolic dysfunction, being directly transmitted retrocapillary to the post-capillary pulmonary vessels, thereby retrocapillary to the rest of the pulmonary circulation. In some embodiments, PH-LHD is driven by both systolic and diastolic dysfunction. PH-LHD may be associated with, or caused by, congenital / acquired cardiovascular conditions leading to PH resulting from heart failure with maintained left ventricular ejection fraction (LVEF) [also known as HFpEF], PH resulting from heart failure with reduced LVEF (also known as HFrEF), valvular heart disease, or retrocapillary PH. Compared to PAH, patients with PH-LHD are often older women with a higher prevalence of cardiovascular comorbidities and, though not all, most have characteristics of metabolic syndrome.

[0050] For patients with WHO Group 2 (PH-LHD) and Group 5 pulmonary hypertension (PH), there are no approved specific therapies available beyond the treatment of the underlying condition. Most PH-LHD therapies target the underlying condition (e.g., repair of heart valve disease) rather than specifically treating PH. The lack of specific therapies is particularly problematic because PH-LHD is the most common cause of PH in Western countries, and its presence usually leads to an unfavorable course of the disease. Specifically, the presence of PH-LHD can lead to more severe symptoms of LHD, worse exercise tolerance, and negative impacts on outcomes. Therefore, there is a high unmet need for new treatments for postcapillary pulmonary hypertension (e.g., WHO Group 2 and / or Group 5 PH) that could positively impact a large number of patients.

[0051] The terms used herein generally have their common meanings in the art within the context of this disclosure and in the specific context in which each term is used. Certain terms are discussed below or elsewhere in this specification to provide additional guidance to practitioners when describing the compositions and methods of this disclosure and how they are prepared and used. The scope or meaning of any use of a term will become clear from the specific context in which it is used.

[0052] The term "sequence similarity" refers to the degree of identity or agreement between nucleic acid sequences or amino acid sequences that may or may not share a common evolutionary origin in all their grammatical forms.

[0053] "Sequence identity percentage (%)" is defined as the percentage of amino acid residues (or nucleic acids) in a candidate sequence that are identical to amino acid residues (or nucleic acids) in a reference polypeptide (or nucleotide) sequence, after aligning the sequence with respect to a reference polypeptide (or nucleotide) sequence and, if necessary, introducing gaps to achieve the maximum possible sequence identity percentage, without considering any conservative substitutions as part of the sequence identity. Alignment for the purpose of determining amino acid sequence identity percentage can be achieved in various ways within the scope of the skill of the art, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN, or Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithm necessary to achieve the maximum alignment over the entire length of the sequences being compared. However, for the purposes of this specification, the value of amino acid (nucleic acid) sequence identity % is generated using the sequence comparison computer program ALIGN-2. The ALIGN-2 sequence comparison computer program was created by Genentech, Inc., and its source code, along with user documentation, has been filed with the U.S. Copyright Office, Washington DC, 20559, and is registered under U.S. Copyright Registration No. TXU510087. The ALIGN-2 program is publicly available from Genentech, Inc., South San Francisco, Calif., or may be compiled from the source code. The ALIGN-2 program should be compiled for use on UNIX® operating systems, including Digital UNIX® V4.0D. All sequence comparison parameters are set by the ALIGN-2 program and do not change.

[0054] In all its grammatical forms, "agonize" refers to the process of activating a protein and / or gene (for example, by activating or amplifying the gene expression of that protein, or by inducing an inactive protein to become active), or by increasing the activity of a protein and / or gene.

[0055] "Antagonizing," in all its grammatical forms, refers to the process of inhibiting a protein and / or gene (for example, by inhibiting or reducing the gene expression of that protein, or by inducing an active protein to become inactive), or by reducing the activity of a protein and / or gene.

[0056] When the terms “about” and “approximately” are used in relation to numbers throughout this specification and the claims, they represent an interval of precision that is familiar to and acceptable to those skilled in the art. Generally, such an interval of precision is ±10%. Alternatively, and especially in biological systems, the terms “about” and “approximately” may mean a value that is within one decimal place of a given value, preferably ≤5 times, and more preferably ≤2 times.

[0057] Numerical ranges disclosed herein include numbers that define the range.

[0058] The terms “one (a)” and “one (an)” include multiple referents unless the context in which the terms are used explicitly indicates otherwise. The terms “one (a)” (or “one (an)”), as well as “one or more” and “at least one” can be used interchangeably herein. Furthermore, “and / or” should be considered, when used herein, as a specific disclosure of each of two or more designated characteristics or components, with or without the other. Thus, when the term “and / or” is used herein in phrases such as “A and / or B,” it is intended to include “A and B,” “A or B,” “A” (alone), and “B” (alone). Similarly, when the term "and / or" is used in phrases such as "A, B, and / or C," it is intended to encompass the following aspects: 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).

[0059] Throughout this specification, the word “comprise,” or variations such as “comprises” or “comprising,” will be understood to mean the inclusion of the integer or group of integers mentioned, but not the exclusion of any other integer or group of integers. 2. ActRII polypeptide

[0060] In certain aspects, this disclosure relates to ActRII polypeptides and their use (e.g., to treat, prevent, or reduce the rate of progression and / or severity of postcapillary pulmonary hypertension (PcPH) or one or more complications of PcPH). As used herein, the term “ActRII” refers to the family of type II activin receptors, which include activin receptor type IIA (ActRIIA) and activin receptor type IIB (ActRIIB).

[0061] In certain embodiments, the disclosure relates to an ActRII polypeptide having an amino acid sequence that is at least 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in any one of SEQ ID NOs: 1, 2, 3, 23, 27, 30, and 41. In other embodiments, the disclosure relates to an ActRII polypeptide having an amino acid sequence that is at least 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in any one of SEQ ID NOs: 31, 39, and 40. 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 thereof and / or variants. ActRII polypeptides may originate from any species and may include variants derived from such ActRII proteins by mutagenesis or other modifications. References to ActRII herein are understood to refer to any one of the currently identified forms. Members of the ActRII family are generally transmembrane proteins comprising a ligand-binding extracellular domain containing a cysteine-rich region, a transmembrane domain, and a cytoplasmic domain having putative serine / threonine kinase activity.

[0062] 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 retain useful activity. Examples of such variant ActRII polypeptides are provided throughout this disclosure and 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. The amino acid numbering for all ActRII-related polypeptides described herein is based on the numbering of the human ActRII precursor protein sequence (SEQ ID NO: 1) provided below, unless otherwise specifically specified.

[0063] The standard human ActRII precursor protein sequence is as follows: [ka]

[0064] Signal peptides are indicated by a single underline; extracellular domains are indicated in bold font; and possible endogenous N-linked glycosylation sites are indicated by a double underline.

[0065] The processed (mature) extracellular human ActRII polypeptide sequence is as follows: [ka]

[0066] The C-terminal "tail" of the extracellular domain is indicated by a single underline. Sequences lacking the "tail" (Δ15 sequences) are as follows: [ka]

[0067] The nucleic acid sequence encoding the human ActRII precursor protein is shown below (SEQ ID NO: 4), and corresponds to nucleotides 159-1700 of the Genbank reference sequence NM_001616.4. The signal sequence is underlined. [ka] [ka]

[0068] The nucleic acid sequence encoding the processed soluble (extracellular) human ActRII polypeptide is as follows: [ka]

[0069] ActRII is well conserved among vertebrates, and the large elongation of the extracellular domain is completely conserved. For example, Figure 2 shows the multiple sequence alignment of the human ActRII extracellular domain compared to various ActRII orthologues. Many of the ligands that bind to ActRII are also highly conserved. Therefore, from these alignments, it is possible to predict not only the critical amino acid positions within the ligand-binding domain that are important for normal ActRII-ligand-binding activity, but also amino acid positions that may tolerate substitution without significantly altering normal ActRII-ligand-binding activity. Thus, an active human ActRII variant polypeptide useful according to the methods disclosed herein may contain one or more amino acids at corresponding positions from the ActRII sequence of another vertebrate, or it may contain residues similar to those in the human or other vertebrate sequence.

[0070] Figure 1 illustrates the amino acid sequence alignment of the human ActRIIA extracellular domain and the human ActRIIB extracellular domain. This alignment shows the amino acid residues in both receptors that are thought to be in direct contact with the ActRII ligand. For example, the composite ActRII structure shows that the ActRIIA-ligand binding pocket is partially defined by residues F31, N33, N35, K38 to T41, E47, Y50, K53 to K55, R57, H58, F60, T62, K74, W78 to N83, Y85, R87, E92, and K94 to F101. Conservative mutations are expected to be tolerated at these positions.

[0071] While not limiting, the following examples illustrate this approach to defining active ActRII variants. As illustrated in Figure 2, F13 in the human extracellular domain is Y in the ActRII of Ovis aries (SEQ ID NO: 7), Gallus gallus (SEQ ID NO: 10), Bos Taurus (SEQ ID NO: 36), Tyto alba (SEQ ID NO: 37), and Myotis davidii (SEQ ID NO: 38), indicating that aromatic residues including F, W, and Y are acceptable at this position. Q24 in the human extracellular domain is R in the ActRII of Bos Taurus, indicating that charged residues including D, R, K, H, and E are acceptable at this position. S95 in the human extracellular domain is F in ActRII of Gallus gallus and Tyto alba, indicating that this site can tolerate a wide variety of changes, including polar residues such as E, D, K, R, H, S, T, P, G, and Y, and possibly hydrophobic residues such as L, I, or F. E52 in the human extracellular domain is D in ActRII of Ovis aries, indicating that acidic residues, including D and E, are tolerated at this position. P29 in the human extracellular domain is relatively unconserved, appearing as S in ActRII of Ovis aries and as L in ActRII of Myotis davidii, therefore essentially any amino acid should be tolerated at this position.

[0072] Furthermore, as discussed above, ActRII proteins are characterized in the art in terms of their structural / functional features, particularly with respect to ligand binding [Attisano et al. (1992) Cell 68(1):97-108; Greenwald et al. (1999) Nature Structural Biology 6(1): 18-22; Allendorph et al. (2006) PNAS 103(20: 7643-7648; Thompson et al. (2003) The EMBO Journal 22(7): [1555-1566; and U.S. Patents 7,709,605, 7,612,041, and 7,842,663]. 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 is formed by conserved cysteine ​​residues located in variable positions within the extracellular domains of the respective monomeric receptors [Greenwald et al. (1999) Nat Struct Biol 6:18-22; and Hinck (2012) FEBS Lett 586:1860-1870]. In addition to the teachings herein, these references provide ample guidance on methods for constructing ActRII variants that retain one or more desired activities (e.g., ligand-binding activity).

[0073] For example, defining a known structural motif as the three-finger toxin fold is crucial for ligand binding by type I and type II receptors, and is formed by conserved cysteine ​​residues located in variable positions within the extracellular domains of each monomeric receptor [Greenwald et al. (1999) Nat Struct Biol 6:18-22; and Hinck (2012) FEBS Lett 586:1860-1870]. Therefore, the core ligand-binding domain of human ActRII, bounded by the outermost cysteine ​​of these conserved residues, corresponds to positions 30-110 of SEQ ID NO: 1 (ActRII precursor). Therefore, structurally unordered amino acids adjacent to the core sequences bounded by these cysteines can truncate approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, or 29 residues at the N-terminus and approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 residues at the C-terminus without necessarily altering ligand binding. Exemplary truncations of the ActRII extracellular domain include SEQ ID NOs: 2 and 3.

[0074] Therefore, the general formula of the active moiety of ActRII (e.g., ligand binding) is a polypeptide that contains, essentially consists of, or comprises amino acids 30-110 of SEQ ID NO: 1. Thus, an ActRII polypeptide starts at a residue corresponding to any one of amino acids 21-30 of SEQ ID NO: 1 (e.g., starting at any one of amino acids 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30) and ends at a position corresponding to any one of amino acids 110-135 of SEQ ID NO: 1 (e.g., amino acids 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121 It may contain, may essentially contain, or may be essentially contain, an amino acid sequence that is at least 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a portion of ActRII (ending at any one of 22, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, or 135). Other examples include positions selected from 21-30 of SEQ ID NO: 1 (e.g., starting with any one of amino acids 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30), 22-30 (e.g., starting with any one of amino acids 22, 23, 24, 25, 26, 27, 28, 29, or 30), 23-30 (e.g., starting with any one of amino acids 23, 24, 25, 26, 27, 28, 29, or 30), and 24-30 (e.g., starting with any one of amino acids 24, 25, 26, 27, 28, 29, or 30). Starting from, and ending with any one of the amino acids 111-135 (e.g., 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 135), 112-135 (e.g., amino acids 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133,(ends 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, 133, 134, or 135), 120-135 (for example, amino acids 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130 , ending with one of 131, 132, 133, 134, or 135), 130-135 (for example, ending with one of amino acids 130, 131, 132, 133, 134, or 135), 111-134 (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, 133, or (ends with one of 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, 128, 129, 130, 131, 132, or 133), 111-132 (for example, amino acids 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 12 Examples of constructs include those ending at any one of 1, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, or 132, or 111-131 (for example, ending at any one of 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). Variants within these ranges, in particular, are intended to include, essentially be, or consist of, amino acid sequences having at least 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the corresponding portion of SEQ ID NO: 1. Therefore,In some embodiments, the ActRII polypeptide may, essentially be, or may be, a polypeptide that is at least 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to amino acids 30-110 of SEQ ID NO: 1. If necessary, the ActRII polypeptide may include a polypeptide that is at least 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to amino acids 30-110 of SEQ ID NO: 1 and includes 1, 2, 5, 10, or 15 or fewer conservative amino acid changes in the ligand-binding pocket. ,

[0075] In certain embodiments, this disclosure relates to ActRII polypeptides, including fragments, functional variants, and modified forms thereof, and their uses (e.g., to treat, prevent, or reduce postcapillary pulmonary hypertension). Preferably, the ActRII polypeptide is soluble (e.g., the extracellular domain of ActRII). In some embodiments, the ActRII polypeptide inhibits (e.g., Smad signaling) of one or more GDF / BMP ligands [e.g., GDF11, GDF8, activin A, activin B, GDF3, BMP4, BMP6, BMP10, and / or BMP15]. In some embodiments, the ActRII polypeptide binds to one or more GDF / BMP ligands [e.g., GDF11, GDF8, activin A, activin B, GDF3, BMP4, BMP6, BMP10, and / or BMP15]. In some embodiments, the ActRII polypeptide of this disclosure begins at a residue corresponding to amino acids 21-30 of SEQ ID NO: 1 (for example, starting at any one of amino acids 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30) and ends at a position corresponding to any one of amino acids 110-135 of SEQ ID NO: 1 (for example, amino acids 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, It contains, essentially consists of, or comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a portion of ActRII (ending at any one of 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, or 135). In some embodiments, the ActRII polypeptide comprises, consists of, or is essentially composed of, an amino acid sequence that is at least 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to amino acids 30-110 of SEQ ID NO: 1.In certain embodiments, the ActRII polypeptide comprises, consists of, or is essentially derived from, an amino acid sequence that is at least 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to amino acids 21-135 of SEQ ID NO: 1. In some embodiments, the ActRII polypeptide comprises, consists of, or is essentially derived from, an amino acid sequence that is at least 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 97%, 98%, 99%, or 100% identical to any one of the amino acid sequences of SEQ ID NOs: 1, 2, 3, 23, 27, 30, and 41.

[0076] In some embodiments, the ActRII polypeptide contains, consists of, or is essentially composed of, an amino acid sequence that is at least 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 23. In some alternative embodiments, the ActRII polypeptide (e.g., SEQ ID NO: 23) may lack a C-terminal lysine. In some embodiments, the ActRII polypeptide lacking a C-terminal lysine is SEQ ID NO: 41. In some embodiments, the ActRII polypeptide contains, consists of, or is essentially derived from an amino acid sequence that is at least 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 41. In some embodiments, the patient is administered an ActRII polypeptide that contains, consists of, or is essentially derived from an amino acid sequence that is at least 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 23. In some embodiments, the patient is administered an ActRII polypeptide that contains, consists of, or is essentially derived from an amino acid sequence that is at least 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 41. In some embodiments, the patient is administered a combination of SEQ ID NO: 23 and SEQ ID NO: 41.

[0077] In certain embodiments, this disclosure relates to ActRII polypeptides. In some embodiments, the ActRII traps of this disclosure are variant ActRII polypeptides (e.g., ActRIIA polypeptide, ActRIIB polypeptide, or a combination thereof) that include one or more mutations (e.g., addition, deletion, substitution, and combination thereof) in the extracellular domain (also referred to as the ligand-binding domain) of an ActRII polypeptide (e.g., “wild-type” or unmodified ActRII polypeptide) such that the variant ActRII polypeptide has one or more modified ligand-binding activities from the corresponding wild-type ActRII polypeptide. In preferred embodiments, the variant ActRII polypeptide of this disclosure retains at least one similar activity to the corresponding wild-type ActRII polypeptide. For example, the preferred ActRII polypeptide binds to GDF11 and / or GDF8 and inhibits its function (e.g., antagonistizes it). In some embodiments, the ActRII polypeptides of this disclosure further bind to and inhibit one or more ligands of GDF / BMP [e.g., GDF11, GDF8, activin A, activin B, GDF3, BMP4, BMP6, BMP10, and / or BMP15]. Accordingly, this disclosure provides ActRII polypeptides having modified binding specificity to one or more ActRII ligands.

[0078] To illustrate, one or more mutations may be selected to increase the selectivity of the modified ligand-binding domains of GDF11 and / or GDF8 for one or more ActRII-binding ligands, particularly activin (activin A or activin B), such as activin A. If necessary, the modified ligand-binding domains may have a K+ ratio of at least 2, 5, 10, 20, 50, 100, or even 1000 times higher for activin binding compared to the wild-type ligand-binding domain. d K for GDF11 and / or GDF8 bond dIt has a ratio to . If necessary, the modified ligand-binding domain has an IC50 ratio of at least 2, 5, 10, 20, 50, 100 times, or even 1000 times, higher IC50 ratio for activin inhibition compared to the wild-type ligand-binding domain. 50 IC regarding the inhibition of GDF11 and / or GDF8 50 It has a ratio to . If necessary, the modified ligand-binding domain has IC for activin inhibition. 50 ICs that are 1 / 2, 1 / 5, 1 / 10, 1 / 20, 1 / 50, 1 / 100, or even less than 1 / 1000 of that. 50 This inhibits GDF11 and / or GDF8.

[0079] In certain embodiments, this disclosure intends to introduce specific mutations of ActRII polypeptides to alter the glycosylation of the polypeptide. Such mutations may be selected to introduce or eliminate one or more glycosylation sites, such as O-linked or N-linked glycosylation sites. Asparagine-linked glycosylation recognition sites generally include asparagine-X-threonine or asparagine-X-serine (where "X" is any amino acid) of a tripeptide sequence that is specifically recognized by a suitable cellular glycosylation enzyme. The modification may also be made by adding or substituting one or more serine or threonine residues into the polypeptide sequence (for O-linked glycosylation sites). Various amino acid substitutions or deletions at one or both of the first or third amino acid positions of the glycosylation recognition site (and / or amino acid deletions at the second position) result in nonglycosylation in the modified tripeptide sequence. Another means of increasing the number of carbohydrate moieties in the polypeptide is by chemical or enzymatic coupling of glycosides to the polypeptide. Depending on the coupling mechanism used, the sugars may be (a) arginine and histidine; (b) a free carboxyl group; (c) a free sulfhydryl group, such as that of cysteine; (d) a free hydroxyl group, such as that of serine, threonine, or hydroxyproline; (e) an aromatic residue, such as that of phenylalanine, tyrosine, or tryptophan; or (f) an amide group of glutamine. Removal of one or more carbohydrate moieties present on the polypeptide may be achieved chemically and / or enzymatically. Chemical deglycosylation may involve, for example, exposure of the polypeptide to the compound trifluoromethanesulfonic acid or an equivalent compound. This process results in the cleavage of most or all sugars except the linked sugar (N-acetylglucosamine or N-acetylgalactosamine), while keeping the amino acid sequence intact. Enzymatic cleavage of the carbohydrate moiety in polypeptides can be achieved by the use of various endoglycosidases and exoglycosidases, as described by Thotakura et al. [Meth. Enzymol. (1987) 138:350].Since mammalian, yeast, insect, and plant cells can all introduce different glycosylation patterns that can be influenced by the amino acid sequence of the peptide, the polypeptide sequence may be adjusted as needed depending on the type of expression system used. Generally, polypeptides of this disclosure for use in humans may be expressed in mammalian cell lines that provide suitable glycosylation, such as HEK293 or CHO cell lines, but other mammalian expression cell lines are expected to be equally useful.

[0080] This disclosure further intends to describe methods for constructing mutants, in particular combinatorial mutants and truncation mutants of ActRII polypeptides. A pool of combinatorial mutants is particularly useful for identifying functionally active (e.g., GDF / BMP ligand-binding) ActRII sequences. The objective of screening such combinatorial libraries may be to construct polypeptide variants having altered properties, such as altered pharmacokinetics or altered ligand binding. Various screening assays are provided below, and such assays may be used to evaluate variants. For example, ActRII variants may be screened for their ability to bind to one or more GDF / BMP ligands [e.g., GDF11, GDF8, activin A, activin B, GDF3, BMP4, BMP6, BMP10, and / or BMP15], their ability to prevent the binding of GDF / BMP ligands to ActRII polypeptides and their heteromultimers, and / or their ability to interfere with signaling induced by GDF / BMP ligands.

[0081] The activity of ActRII polypeptide or its variants may also be tested in cell-based assays or in vivo assays. For example, the effect of ActRII polypeptide on the expression of genes involved in the pathogenesis of PcPH may be evaluated. This may be done in the presence of one or more recombinant ligand proteins [e.g., GDF11, GDF8, activin A, activin B, GDF3, BMP4, BMP6, BMP10, and / or BMP15] as needed, and cells may be transfected to produce ActRII polypeptide and, if necessary, GDF / BMP ligands. Similarly, ActRII polypeptide may be administered to mice or other animals, and its effect on PcPH pathogenesis may be evaluated using methods recognized in the art. Likewise, the activity of ActRII polypeptide or its variants may be tested in hematopoietic progenitor cells for any effect on the growth of these cells, for example, by assays described herein and assays of general knowledge in the art. SMAD-responsive reporter genes may be used in such cell lines to monitor their effect on downstream signaling.

[0082] Combinatorial variants can be created that exhibit increased selectivity or generally increased potency compared to the reference ActRII polypeptide. Such variants can be used in gene therapy protocols when expressed from recombinant DNA constructs. Similarly, mutagenesis can produce variants with dramatically different intracellular half-lives from the corresponding unmodified ActRII polypeptide. For example, the modified protein can be made either more stable or more unstable to proteolysis, or other cellular processes that would otherwise lead to the destruction or inactivation of the unmodified polypeptide. Such variants and the genes encoding them can be used to modulate the polypeptide complex levels by modulating the polypeptide half-life. For example, a shorter half-life can produce more transient biological effects and, when part of an inducible expression system, may allow for tighter control of the intracellular recombinant polypeptide complex levels. In Fc fusion proteins, mutations may be introduced in the linker (if any) and / or the Fc moiety to alter the ActRII polypeptide half-life.

[0083] The combinatorial library may be generated as a degenerate library of genes encoding a library of polypeptides, each containing at least a portion of the potential ActRII polypeptide sequence. For example, a mixture of synthetic oligonucleotides can be enzymatically ligated to the gene sequence so that the degenerate set of nucleotide sequences encoding the potential ActRII can be expressed as individual polypeptides, or instead as a larger set of fusion proteins (e.g., for phage display).

[0084] There are many methods for creating libraries of potential homologs from degenerate oligonucleotide sequences. The chemical synthesis of degenerate gene sequences can be performed in automated DNA synthesizers, and the synthesized genes can then be ligated into appropriate vectors for expression. The synthesis of degenerate oligonucleotides is well known in the art. [Narang, 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; Cwirla et al., (1990) PNAS USA 87: 6378-6382; and U.S. Patents 5,223,409, 5,198,346 and 5,096,815].

[0085] Alternatively, combinatorial libraries can be created using other forms of mutagenesis. 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 Cunningham et al. (1989) Science 244:1081-1085], linker scanning mutagenesis [Gustin et al. (1993) ActRII polypeptides of this disclosure can be prepared and isolated from a library, for example, by screening using Virology 193:653-660; and Brown et al. (1992) Mol. Cell Biol. 12:2644-2652; McKnight et al. (1982) Science 232:316], saturated mutagenesis [Meyers et al., (1986) Science 232:613], PCR mutagenesis [Leung et al. (1989) Method Cell Mol Biol 1:11-19], or random mutagenesis including chemical mutagenesis [Miller et al. (1992) A Short Course in Bacterial Genetics, CSHL Press, Cold Spring Harbor, NY; and Greener et al. (1994) Strategies in Mol Biol 7:32-34].Linker scanning mutagenesis, particularly in combinatorial settings, is an attractive method for identifying truncated (bioactive) forms of ActRII polypeptides.

[0086] A wide range of techniques are known in the art for screening gene products of combinatorial libraries prepared by point mutation and truncation, and for screening cDNA libraries of gene products having certain properties. Such techniques would generally be adaptable for rapid screening of gene libraries prepared by combinatorial mutagenesis of ActRII polypeptides. The most widely used techniques for screening large gene libraries typically involve cloning the gene library into a replicable expression vector, transforming suitable cells with the library of the resulting vector, and expressing the combinatorial gene under conditions where the detection of desired activity facilitates the relatively easy isolation of the vector encoding the gene from which the product was detected. Preferred assays include ligand [e.g., GDF11, GDF8, activin A, activin B, GDF3, BMP4, BMP6, BMP10, and / or BMP15] binding assays and / or ligand-mediated cell signaling assays.

[0087] As will be recognized by those skilled in the art, most of the mutations, variants, or modifications described herein can be produced at the nucleic acid level, or in some cases, by post-translational modification or chemical synthesis. Such techniques are well known in the art, and some are described herein. In part, this disclosure identifies functionally active moieties (fragments) and variants of ActRII polypeptides that can be used as guidance for producing and using other variant ActRII polypeptides within the scope of this disclosure provided herein.

[0088] In certain embodiments, functionally active fragments of the ActRII polypeptide of this disclosure can be obtained by screening polypeptides recombinantly produced from corresponding fragments of nucleic acids encoding the ActRII polypeptide. In addition, fragments can be chemically synthesized using techniques known in the art, such as conventional Merrifield solid-phase f-Moc or t-Boc chemistry. The fragments can be generated (recombinantly or chemically synthesized) and tested to identify their peptidyl fragments that can function as antagonists (inhibitors) of the ActRII receptor and / or one or more ligands [e.g., GDF11, GDF8, activin A, activin B, GDF3, BMP4, BMP6, BMP10, and / or BMP15].

[0089] In certain embodiments, the ActRII polypeptides of this disclosure may further include post-translational modifications in addition to any post-translational modifications naturally present in the ActRII polypeptide. Such modifications include, but are not limited to, acetylation, carboxylation, glycosylation, phosphorylation, lipidation, and acylation. As a result, the ActRII polypeptides may contain non-amino acid elements such as polyethylene glycol, lipids, polysaccharides or monosaccharides, and phosphates. The effect of such non-amino acid elements on the functionality of the ligand-trap polypeptide may be tested as described herein for other ActRII variants. If the polypeptides of this disclosure are produced in cells by cleaving the nascent form of the polypeptide, post-translational processing may also be important for the correct folding and / or function of the protein. Different cells (e.g., CHO, HeLa, MDCK, 293, WI38, NIH-3T3, or HEK293) have specific cellular mechanisms and characteristic mechanisms for such post-translational activity and may be selected to ensure the correct modification and processing of the ActRII polypeptide.

[0090] In certain embodiments, the ActRII polypeptides of this disclosure include fusion proteins having at least a portion (domain) of an ActRII polypeptide and one or more heterologous portions (domains). Well-known examples of such fusion domains include, but are not limited to, polyhistidine, Glu-Glu, glutathione S-transferase (GST), thioredoxin, protein A, protein G, immunoglobulin heavy chain constant region (Fc), maltose-binding protein (MBP), or human serum albumin. The fusion domains may be selected to confer desired properties. For example, some fusion domains are particularly useful for the isolation of fusion proteins by affinity chromatography. For the purpose of affinity purification, relevant matrices for affinity chromatography are used, such as resins conjugated with glutathione, amylase, and nickel or cobalt. Many of such matrices are available in “kit” form, such as the QIAexpress™ system (Qiagen), which is useful with the Pharmacia GST purification system and (HIS6) fusion partner. In another example, the fusion domain may be selected to facilitate the detection of ActRII polypeptides. Examples of such detection domains include various fluorescent proteins (e.g., GFP) and “epitope tags,” which are usually short peptide sequences for which specific antibodies are available. Well-known epitope tags for which specific monoclonal antibodies are readily available include FLAG, influenza virus hemagglutinin (HA), and the c-myc tag. In some cases, the fusion domain has a protease cleavage site, such as for factor Xa or thrombin, which allows the relevant protease to partially digest the fusion protein, thereby releasing the recombinant protein from them. The released protein can then be isolated from the fusion domain by subsequent chromatographic separation.Other types of fusion domains that may be selected include multimerizing (e.g., dimerizing, tetramerizing) domains, and functional domains (which confer additional biological function) including, for example, a constant domain derived from immunoglobulin (e.g., an Fc domain).

[0091] In certain embodiments, the ActRII polypeptide of the present disclosure contains one or more modifications that can “stabilize” the polypeptide. “Stabilizing” means any modification that increases the in vitro half-life, serum half-life, whether this is due to reduced drug breakdown, reduced renal clearance, or other pharmacokinetic effects. For example, such modifications enhance the shelf life of the polypeptide, enhance the circulating half-life of the polypeptide, and / or reduce the proteolysis of the polypeptide. Such stabilizing modifications include, but are not limited to, fusion proteins (e.g., fusion proteins comprising an ActRII polypeptide domain and a stabilizer domain), modifications of glycosylation sites (e.g., adding a glycosylation site to the polypeptide of the present disclosure), and modifications of carbohydrate moieties (e.g., removing a carbohydrate moiety from the polypeptide of the present disclosure). As used herein, the term “stabilizer domain” refers not only to a fusion domain (e.g., an immunoglobulin Fc domain) as in the case of a fusion protein, but also to non-proteinogenic modifications such as carbohydrate moieties, or non-proteinogenic moieties such as polyethylene glycol. In certain preferred embodiments, the ActRII polypeptide is fused with a heterogeneous domain that stabilizes the polypeptide ("stabilizer" domain), preferably a heterogeneous domain that increases the polypeptide's stability in vivo. Fusion with the constant domain of immunoglobulins (e.g., the Fc domain) is known to confer desirable pharmacokinetic properties to a wide range of proteins. Similarly, fusion with human serum albumin can confer desirable properties.

[0092] An example of a native amino acid sequence that may be used for the Fc portion (G1Fc) of human IgG1 is shown below (SEQ ID NO: 11). Dotted underlines indicate hinge regions, and solid underlines indicate positions with naturally occurring variants. In part, this disclosure provides polypeptides containing, essentially derived from, or comprising amino acid sequences having 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with SEQ ID NO: 11. Naturally occurring variants of G1Fc would include E134D and M136L, according to the numbering system used in SEQ ID NO: 11 (see Uniprot P01857). [ka]

[0093] If necessary, the IgG1 Fc domain may have one or more mutations in residues such as Asp-265, lysine 322, and Asn-434. In certain cases, mutant IgG1 Fc domains with one or more of these mutations (e.g., the Asp-265 mutation) have reduced binding ability to Fcγ receptors compared to wild-type Fc domains. In other cases, mutant Fc domains with one or more of these mutations (e.g., the Asn-434 mutation) have increased binding ability to MHC class I-associated Fc receptors (FcRNs) compared to wild-type IgG1 Fc domains.

[0094] An example of a native amino acid sequence that may be used for the Fc portion (G2Fc) of human IgG2 is shown below (SEQ ID NO: 12). Dotted underlines indicate hinge regions, and double underlines indicate locations in the sequence where database discrepancies exist (according to UniProt P01859). In part, this disclosure provides polypeptides comprising, essentially derived from, or consisting of amino acid sequences having 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with SEQ ID NO: 12. [ka] [ka]

[0095] Two examples of amino acid sequences that may be used for the Fc portion (G3Fc) of human IgG3 are shown below. The hinge region in G3Fc can be up to four times longer than in other Fc chains and contains three identical 15-residue segments preceded by a similar 17-residue segment. The first G3Fc sequence shown below (SEQ ID NO: 13) contains a short hinge region consisting of a single 15-residue segment, while the second G3Fc sequence (SEQ ID NO: 14) contains a full-length hinge region. In each case, the dotted underline indicates the hinge region, and the solid underline indicates the position with a naturally occurring variant according to UniProt P01859. In part, the present disclosure provides polypeptides comprising, essentially, or consisting of amino acid sequences having 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with SEQ ID NOs: 13 and 14. [ka]

[0096] Naturally occurring variants in G3Fc (see, e.g., Uniprot P01860) include E68Q, P76L, E79Q, Y81F, D97N, N100D, T124A, S169N, S169del, and F221Y when converted to the numbering system used in Sequence ID No. 13, and this disclosure provides fusion proteins containing a G3Fc domain containing one or more of these variant forms. In addition, the human immunoglobulin IgG3 gene (IGHG3) exhibits structural polymorphisms characterized by different hinge lengths [see Uniprot P01859]. Specifically, variant WIS lacks most of the V region and all of the CH1 region. It has an extra interchain disulfide bond at position 7 in addition to the normally present position 11 in the hinge region. Variant ZUC lacks most of the V region, all of the CH1 region, and part of the hinge. The variant OMM may represent an allele or another gamma chain subclass. This disclosure provides further fusion proteins containing a G3Fc domain containing one or more of these variants.

[0097] An example of a native amino acid sequence that may be used for the Fc portion (G4Fc) of human IgG4 is shown below (SEQ ID NO: 15). The dotted underline indicates the hinge region. In part, the present disclosure provides polypeptides comprising, essentially, or consisting of an amino acid sequence having 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with SEQ ID NO: 15. [ka]

[0098] Various engineered mutations in the Fc domain are presented herein with respect to the G1Fc sequence (SEQ ID NO: 11), and similar mutations in G2Fc, G3Fc, and G4Fc can be derived from their alignment with G1Fc in FIG. 4. Due to unequal hinge lengths, similar Fc positions based on the isotype alignment (FIG. 4) have different amino acid numbers in SEQ ID NOs: 11, 12, 13, 14, and 15. It can also be understood that a given amino acid position in an immunoglobulin sequence consisting of the hinge, C H 1, hinge, C H 2 and C H 3 regions (when encompassing the entire IgG1 heavy chain constant domain as in the Uniprot database) (i.e., consisting of the hinge, C H 2 and C H 3 regions) may be specified by different numbers than the same position. For example, the correspondence between the human G1Fc sequence (SEQ ID NO: 11), the human IgG1 heavy chain constant domain (Uniprot P01857), and selected C H 3 positions in the human IgG1 heavy chain is as follows.

Table 5

[0099] Various methods are known in the art for increasing the desired pairing of Fc-containing fusion polypeptide chains in single-cell systems to produce preferred asymmetric fusion proteins in acceptable yields [Klein et al (2012) mAbs 4:653-663; and Spiess et al (2015) Molecular Immunology 67(2A): 95-106]. Methods for obtaining desired pairing of Fc-containing chains include, but are not limited to, charge-based pairing (electrostatic steering), "knob-into-hole" stereopairing, seedbody pairing, and leucine zipper-based pairing [Ridgway et al (1996) Protein Eng 9:617-621; Merchant et al (1998) Nat Biotech 16:677-681; Davis et al (2010) Protein Eng Des Sel 23:195-202; Gunasekaran et al (2010); 285:19637-19646; Wranik et al (2012) J Biol Chem [287:43331-43339; US Patent No. 5932448; WO1993 / 011162; WO2009 / 089004 and WO2011 / 034605].

[0100] It is understood that the different elements of a fusion protein (e.g., an immunoglobulin Fc fusion protein) can be arranged in any manner that matches the desired functionality. For example, the ActRII polypeptide domain may be placed C-terminus relative to the heterologous domain, or the heterologous domain may be placed C-terminus relative to the ActRII polypeptide domain. The ActRII polypeptide domain and the heterologous domain do not need to be adjacent in the fusion protein, and additional domains or amino acid sequences may be included C-terminus or N-terminus of either domain, or between the domains.

[0101] For example, an ActRII receptor fusion protein may contain the amino acid sequence shown in formula ABC. The B portion corresponds to the ActRII polypeptide domain. The A and C portions may independently consist of 0, 1, or more than 1 amino acids, and both A and C portions, if present, are heterogeneous to B. The A and / or C portions may be bound to the B portion via a linker sequence. The linker may be rich in glycine (e.g., 2-10, 2-5, 2-4, or 2-3 glycine residues) or glycine and proline residues, and may contain, for example, a single sequence of threonine / serine and glycine, or a repeat sequence of threonine / serine and / or glycine, such as a singlet or repeat of GGG (SEQ ID NO: 16), GGGG (SEQ ID NO: 17), TGGGG (SEQ ID NO: 18), SGGGG (SEQ ID NO: 19), TGGG (SEQ ID NO: 20), SGGG (SEQ ID NO: 21), or GGGGS (SEQ ID NO: 22). In certain embodiments, the ActRII fusion protein comprises the amino acid sequence shown in formula ABC, where A is a leader (signal) sequence, B is the ActRII polypeptide domain, and C is a polypeptide moiety that enhances one or more of the following: in vivo stability, in vivo half-life, uptake / administration, tissue localization or distribution, protein complex formation, and / or purification. In certain embodiments, the ActRII fusion protein comprises the amino acid sequence shown in formula ABC, where A is the TPA leader sequence, B is the ActRII receptor polypeptide domain, and C is the immunoglobulin Fc domain. Preferred fusion proteins comprise the amino acid sequence shown in any one of SEQ ID NOs: 23, 27, 30, and 41.

[0102] In preferred embodiments, the ActRII polypeptide used according to the methods described herein is an isolated polypeptide. As used herein, an isolated protein or polypeptide is one that has been isolated from its natural environment. In some embodiments, the polypeptides of this disclosure are purified to a purity of 95%, 96%, 97%, 98%, or greater than 99%, as determined, for example, by electrophoresis (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatography (e.g., ion exchange or reverse-phase HPLC). Methods for evaluating purity are well known in the art [see, for example, Flatman et al., (2007) J. Chromatogr. B 848:79-87]. In some embodiments, the ActRII polypeptide used according to the methods described herein is a recombinant polypeptide.

[0103] The ActRII polypeptides of this disclosure can be produced by various techniques known in the art. For example, the polypeptides of this disclosure can be synthesized using standard protein chemistry techniques such as those described in Bodansky, M. Principles of Peptide Synthesis, Springer Verlag, Berlin (1993) and Grant GA (ed.), Synthetic Peptides: A User's Guide, WH Freeman and Company, New York (1992). In addition, automated peptide synthesizers are commercially available (e.g., Advanced ChemTech Model 396; Milligen / Biosearch 9600). Alternatively, the polypeptides of this disclosure, including their fragments or variants, may be recombinantly produced using various expression systems [e.g., E. coli, Chinese hamster ovary (CHO) cells, COS cells, baculovirus], as is well known in the art. In further embodiments, modified or unmodified polypeptides of the present disclosure may be produced by digestion of recombinantly produced full-length ActRII polypeptides, for example, by using proteases such as trypsin, thermolysin, chymotrypsin, pepsin, or pair-forming basic amino acid converting enzymes (PACE). Protein cleavage sites can be identified using computer analysis (using commercially available software, e.g., MacVector, Omega, PCGene, Molecular Simulation, Inc.). Alternatively, such polypeptides may be produced from recombinantly produced full-length ActRII polypeptides using chemical cleavage (e.g., cyanogen bromide, hydroxylamine, etc.). 3. Nucleic acid encoding ActRII polypeptide

[0104] In certain embodiments, the disclosure provides isolated nucleic acids and / or recombinant nucleic acids encoding ActRII polypeptides (including fragments, functional variants, and fusion proteins thereof).

[0105] As used herein, isolated nucleic acids refer to nucleic acid molecules separated from components of their natural environment. Isolated nucleic acids include nucleic acid molecules contained in cells that normally contain nucleic acid molecules, but the nucleic acid molecules are located outside of chromosomes or in chromosomal locations different from their natural chromosomal locations.

[0106] In certain embodiments, it is understood that the nucleic acid encoding the ActRII polypeptide of the present disclosure comprises a nucleic acid that is any one variant of SEQ ID NO: 4, 5, or 28. The variant nucleotide sequence comprises a sequence that differs due to the substitution, addition, or deletion of one or more nucleotides, including the allele variant, and therefore comprises a coding sequence that is different from the nucleotide sequence specified in any one of SEQ ID NO: 4, 5, or 28.

[0107] In certain embodiments, the ActRII polypeptides of the Disclosure are encoded by isolated nucleic acid sequences and / or recombinant nucleic acid sequences that are at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to any one of SEQ ID NOs: 4, 5, or 28. Those skilled in the art will understand that nucleic acid sequences and variants thereof that are at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to sequences complementary to SEQ ID NOs: 4, 5, or 28 are also within the scope of the Disclosure. In further embodiments, the nucleic acid sequences of the Disclosure may be isolated, recombinant, and / or fused with heterologous nucleotide sequences, or present in a DNA library.

[0108] In other embodiments, the nucleic acids of the Disclosure also include nucleotide sequences that hybridize under highly stringent conditions with a nucleotide sequence specified in SEQ ID NO: 4, 5, or 28, a complementary sequence of SEQ ID NO: 4, 5, or 28, or a fragment thereof. As discussed above, those skilled in the art will readily understand that the appropriate stringency conditions that promote DNA hybridization can be varied. For example, hybridization can be performed with 6.0 × sodium chloride / sodium citrate (SSC) at about 45°C, followed by washing with 2.0 × SSC at 50°C. For example, the salt concentration in the washing step can be selected from low stringency of about 2.0 × SSC at 50°C to high stringency of about 0.2 × SSC at 50°C. In addition, the temperature in the washing step can be increased from low stringency conditions of about 22°C (room temperature) to high stringency conditions of about 65°C. Both temperature and salt concentration may be varied, or the temperature or salt concentration may be kept constant while other variables are varied. In one embodiment, the disclosure provides nucleic acids that hybridize under low stringency conditions of washing with 6×SSC at room temperature followed by 2×SSC at room temperature.

[0109] Isolated nucleic acids that differ from those shown in Sequence ID No. 4, 5, or 28 in terms of degeneracy in the genetic code are also within the scope of this disclosure. For example, some amino acids are designated by one or more triplets. Codons or synonyms that identify the same amino acid (e.g., CAU and CAC are synonyms for histidine) may result in “silent” mutations that do not affect the amino acid sequence of the protein. However, it is expected that in mammalian cells there will be DNA sequence polymorphisms that result in changes in the amino acid sequence of the protein in question. Those skilled in the art will understand that these variant forms in one or more nucleotides (up to about 3-5% of nucleotides) of the nucleic acid encoding a particular protein may exist among individuals of a given species due to naturally occurring allelic variant forms. All such nucleotide variant forms and the resulting amino acid polymorphisms are within the scope of this disclosure.

[0110] In certain embodiments, the recombinant nucleic acids of this disclosure may be operably ligated to one or more regulatory nucleotide sequences in an expression construct. The regulatory nucleotide sequences will generally be appropriate for the host cell used for expression. Numerous types of appropriate expression vectors and suitable regulatory sequences are known in the art and can be used in various host cells. Typically, one or more regulatory nucleotide sequences may include, but are not limited to, promoter sequences, leader or signal sequences, ribosome binding sites, transcription start and termination sequences, translation start and termination sequences, and enhancer or activator sequences. Constitutive or inducible promoters known in the art are intended by this disclosure. The promoter may be a naturally occurring promoter or a hybrid promoter combining elements of one or more promoters. The expression construct may be present in the cell on an episome such as a plasmid, or the expression construct may be inserted into a chromosome. In some embodiments, the expression vector contains a selection marker gene to allow selection of transformed host cells. Selection marker genes are well known in the art and can be modified depending on the host cell used.

[0111] In certain embodiments, the nucleic acids disclosed herein are provided in expression vectors comprising a nucleotide sequence encoding an ActRII polypeptide and operably ligated to at least one regulatory sequence. The regulatory sequence is recognized in the art and selected to direct the expression of the ActRII polypeptide. Thus, the term regulatory sequence includes promoters, enhancers, and other expression regulatory elements. Exemplary regulatory sequences are described in Goeddel; Gene Expression Technology: Methods in Enzymology, Academic Press, San Diego, CA (1990). For example, any of the wide variety of expression regulatory sequences that control the expression of a DNA sequence when operably ligated may be used in these vectors to express the DNA sequence encoding the ActRII polypeptide. Such useful expression regulatory sequences include, for example, the early and late promoters of SV40, the tet promoter, the pre-early promoters of adenoviruses or cytomegaloviruses, the RSV promoter, the lac system, the trp system, the TAC or TRC system, the T7 promoter whose expression is directed by T7 RNA polymerase, the major operator and promoter regions of phage lambda, the regulatory regions of fd coat proteins, promoters of 3-phosphoglycerate kinase or other glycoseptic enzymes, promoters of acid phosphatases, such as Pho5, the yeast α-conjugation factor promoter, the polyhedron promoter of baculovirus systems, and other sequences known to regulate the expression of genes in prokaryotic or eukaryotic cells, or their viruses, as well as various combinations thereof. It should be understood that the design of expression vectors may depend on factors such as the selection of the host cell to be transformed and / or the type of protein to be expressed. The copy number of the vector, its ability to control copy number, and the expression of any other proteins encoded by the vector, such as antibiotic markers, should also be considered.

[0112] The recombinant nucleic acids of this disclosure can be produced by ligating a cloned gene or a portion thereof into a vector suitable for expression in prokaryotic cells, eukaryotic cells (yeast, birds, insects, or mammals), or both. Expression vehicles for the production of recombinant ActRII polypeptides include plasmids and other vectors. For example, suitable vectors include the following types of plasmids for expression in prokaryotic cells such as E. coli: pBR322-derived plasmids, pEMBL-derived plasmids, pEX-derived plasmids, pBTac-derived plasmids, and pUC-derived plasmids.

[0113] Some mammalian expression vectors contain both prokaryotic sequences to promote vector reproduction in bacteria and one or more eukaryotic transcription units expressed in eukaryotic cells. Vectors derived from pcDNAI / amp, pcDNAI / neo, pRc / CMV, pSV2gpt, pSV2neo, pSV2-dhfr, pTk2, pRSVneo, pMSG, pSVT7, pko-neo, and pHyg are examples of mammalian expression vectors suitable for eukaryotic cell transfection. Some of these vectors are modified with bacterial plasmid-derived sequences, such as pBR322, to promote replication and drug resistance selection in both prokaryotic and eukaryotic cells. Alternatively, viral derivatives such as bovine papillomavirus (BPV-1) or Epstein-Barr virus (pHEBo, derived from pREP, and p205) can be used for transient protein expression in eukaryotic cells. Examples of other viral (including retrovirus) expression systems can be found below in the description of gene therapy delivery systems. Various methods used in plasmid preparation and host organism transformation are well known in the art. For other suitable expression systems for both prokaryotic and eukaryotic cells, and for general recombination procedures, see, for example, Molecular Cloning: A Laboratory Manual, 3rd Ed., ed. by Sambrook, Fritsch and Maniatis (Cold Spring Harbor Laboratory Press, 2001). In some cases, it may be desirable to express recombinant polypeptides using baculovirus expression systems. Examples of such baculovirus expression systems include pVL-derived vectors (e.g., pVL1392, pVL1393 and pVL941), pAcUW-derived vectors (e.g., pAcUWl), and pBlueBac-derived vectors (e.g., β-gal-containing pBlueBac III).

[0114] In preferred embodiments, vectors such as Pcmv-Script vectors (Stratagene, La Jolla, Calif.), pcDNA4 vectors (Invitrogen, Carlsbad, Calif.), and pCI-neo vectors (Promega, Madison, Wisc.) are designed for the production of the target ActRII polypeptide in CHO cells. As is evident, the target gene construct can be used to induce the expression of the target ActRII polypeptide in cells grown in culture, for example, to produce a protein containing a fusion protein or a variant protein, for purification purposes.

[0115] This disclosure also relates to host cells transfected with recombinant genes containing one or more coding sequences of the ActRII polypeptide in question. The host cells may be any prokaryotic or eukaryotic cells. For example, the ActRII polypeptides of this disclosure may be expressed in bacterial cells such as E. coli, insect cells (e.g., using a baculovirus expression system), yeast, or mammalian cells [e.g., Chinese hamster ovary (CHO) cell line]. Other suitable host cells are known to those skilled in the art.

[0116] Accordingly, this disclosure further relates to methods for generating the ActRII polypeptide of interest. For example, host cells transfected with an expression vector encoding the ActRII polypeptide can be cultured under suitable conditions capable of inducing the expression of the ActRII polypeptide. The polypeptide may be secreted and isolated from a mixture of cells and culture medium containing the polypeptide. Alternatively, the ActRII polypeptide may be retained in the cytoplasm, or may be recovered and lysed in membrane fractions and cells, as well as in isolated proteins. The cell culture comprises host cells, culture medium, and other by-products. Suitable culture media for cell culture are well known in the art. The polypeptide of interest can be isolated from cell culture medium, host cells, or both using techniques known in the art for purifying proteins, including ion exchange chromatography, gel filtration chromatography, ultrafiltration, electrophoresis, immunoaffinity purification using antibodies specific to a particular epitope of the ActRII polypeptide, and affinity purification using a drug that binds to the domain fused to the ActRII polypeptide (for example, the ActRII-Fc fusion protein can be purified using a protein A column). In some embodiments, the ActRII polypeptide is a fusion protein containing a domain that facilitates its purification.

[0117] In some embodiments, purification is achieved by a series of column chromatography steps, for example, comprising three or more of the following in any order: protein A chromatography, Q Sepharose chromatography, phenyl Sepharose chromatography, size exclusion chromatography, and cation exchange chromatography. Purification can be completed by viral filtration and buffer exchange. ActRII proteins may be purified to purities of >90%, >95%, >96%, >98%, or >99% as determined by size exclusion chromatography, and to purities of >90%, >95%, >96%, >98%, or >99% as determined by SDS PAGE. The target level of purity must be sufficient to achieve the desired results in mammalian systems, particularly in non-human primates, rodents (mice), and humans.

[0118] In another embodiment, a fusion gene encoding a purified leader sequence, for example, a poly-(His) / enterokinase cleavage site sequence at the N-terminus of a desired portion of a recombinant ActRII polypeptide, is Ni 2+ Affinity chromatography using a metal resin may enable the purification of the expressed fusion protein. The purified leader sequence can then be removed by subsequent treatment with enterokinase to provide a purified ActRII polypeptide. See, for example, Hochuli et al. (1987) J. Chromatography 411:177; and Janknecht et al. (1991) PNAS USA 88:8972.

[0119] Techniques for constructing fusion genes are well known. Essentially, the conjugation of various DNA fragments encoding different polypeptide sequences is carried out according to conventional techniques using blunt or twisted ends for ligation, restriction enzyme digestion to provide suitable ends, sticky end filling where appropriate, alkaline phosphatase treatment to avoid undesirable conjugations, and enzymatic ligation. In another embodiment, fusion genes can be synthesized by conventional techniques including automated DNA synthesizers. Alternatively, PCR amplification of gene fragments can be performed using anchor primers that create complementary overhangs between two consecutive gene fragments, which can then be annealed to generate a chimeric gene sequence. See, for example, Current Protocols in Molecular Biology, eds. Ausubel et al., John Wiley & Sons: 1992. 4. How to use

[0120] In part, this disclosure relates to a method for treating postcapillary pulmonary hypertension (PcPH) (e.g., WHO Group 2 and / or Group 5 PH), comprising administering an effective amount of the ActRII polypeptide described herein to a patient in need. In some embodiments, PcPH is a postcapillary and precapillary mixed type of PH. In certain embodiments, this disclosure provides a method for treating or prophylactically treating postcapillary pulmonary hypertension (PcPH) in an individual in need by administering a therapeutically effective amount of the ActRII polypeptide described herein to the individual. These methods are particularly intended for therapeutic and prophylactic treatment of animals, more particularly humans. The terms “subject,” “individual” or “patient” are interchangeable throughout this specification and refer to either human or non-human animals. These terms include mammals, e.g., humans, non-human primates, laboratory animals, domesticated animals (including cattle, pigs, camels, etc.), companion animals (e.g., dogs, cats, other domesticated animals, etc.), and rodents (e.g., mice and rats). In certain embodiments, the patient, subject, or individual is human.

[0121] The terms “treatment,” “treating,” and “relieving” are used herein to generally mean obtaining a desired pharmacological and / or physiological effect, and may also be used to mean improving, reducing, and / or decreasing the severity of one or more clinical complications of the treated condition (e.g., WHO Group 2 and / or Group 5 PH). The effect may be prophylactic in that it completely or partially delays the onset or recurrence of the disease, condition, or its complications, and / or therapeutic in that it partially or completely cures the disease or condition and / or adverse effects resulting from the disease or condition. “Treatment,” as used herein, encompasses any treatment of a disease or condition in a mammal, particularly a human. As used herein, a “preventive” therapeutic agent of a disorder or condition means a compound that, in a statistical sample, reduces the occurrence of the disorder or condition in a treated sample compared to an untreated control sample, or delays the onset of the disease or condition compared to an untreated control sample.

[0122] Generally, the treatment or prevention of the diseases or conditions described in this disclosure (e.g., WHO Group 2 and / or Group 5 PH) is achieved by administering one or more ActRII polypeptides of this disclosure in an “effective dose.” An effective dose of a drug refers to the amount effective to achieve the desired therapeutic or preventive outcome over the required dosage and duration. The “therapeutic effective dose” of a drug in this disclosure may vary depending on factors such as the individual’s condition, age, sex, and weight, as well as the drug’s ability to induce the desired response in the individual. A “preventive effective dose” refers to the amount effective to achieve the desired preventive outcome over the required dosage and duration.

[0123] In certain embodiments, this disclosure envisions the use of ActRII polypeptides in combination with one or more additional activators or other supportive therapies to treat or prevent a disease or condition (e.g., WHO Group 2 and / or Group 5 PH). As used herein, “in combination with,” “combined with,” “in combination with,” or “joint” administration refers to any form of administration in which the additional activator or supportive therapy (e.g., second, third, fourth, etc.) remains effective in the body (e.g., multiple compounds are effective simultaneously in the patient for a period of time, which may include a synergistic effect of these compounds). Efficacy does not have to correlate with a measurable concentration of the drug in blood, serum, or plasma. For example, different therapeutic compounds may be administered in the same formulation or in separate formulations, concurrently or sequentially, on different schedules. Thus, subjects receiving such treatment may benefit from the combined effects of different activators or therapies. One or more ActRII polypeptides of this disclosure may be administered concurrently with, before, or after, one or more additional agents or supportive therapies, such as those disclosed herein. Generally, each activator or therapy is administered in a dose and / or time schedule determined for the specific agent. The specific combination used in the regimen takes into account the compatibility of the ActRII polypeptides of this disclosure with the additional activators or supportive therapies, and / or the desired effect. Overview of the WHO classification

[0124] The pulmonary hypertension conditions treated by the methods described herein may include one or more of the conditions recognized in accordance with the World Health Organization (WHO). See, for example, Simonneau (2019) Eur Respir J: 53:1801913. Table 1: Clinical classification of pulmonary hypertension [Table 1-1] [Table 1-2]

[0125] The clinical purpose of the classification of PH is to categorize clinical conditions associated with PH into five groups according to their pathophysiological mechanisms, clinical presentation, hemodynamic characteristics, and treatment strategies. This clinical classification may be updated as new data becomes available on the above characteristics or when additional clinical entities are considered.

[0126] Pulmonary hypertension (PH) was previously classified as primary PH or secondary PH. The term primary pulmonary hypertension is now replaced by idiopathic PAH or familial PAH, depending on the presence or absence of genetic information, and the term secondary pulmonary hypertension is no longer used.

[0127] As used herein, the term “pulmonary hemodynamic parameters” refers to any parameters used to describe or assess blood flow through the cardiac and pulmonary vascular systems. Examples of pulmonary hemodynamic parameters include, but are not limited to, mean pulmonary artery pressure (mPAP), diastolic pulmonary artery pressure (dPAP) [also known as pulmonary artery diastolic pressure (PADP)], systolic pulmonary artery pressure (sPAP) [also known as pulmonary artery systolic pressure (PASP)], mean right atrial pressure (mRAP), pulmonary capillary wedge pressure (PCWP) [also known as pulmonary artery wedge pressure (PAWP)], left ventricular end-diastolic pressure (LVEDP), diastolic pressure gradient (DPG) [also known as diastolic pressure difference (DPD)], left atrial pressure (LAP), transpulmonary pressure gradient (TPG), pulmonary vascular resistance (PVR), and cardiac output (CO).

[0128] Many of the pulmonary hemodynamic parameters listed above are interrelated. For example, PCWP is often used as a more convenient and less invasive approximation of LAP.

[0129] As another example, PVR is given by the following formula: PVR = (mPAP - PCWP) / CO [Wood units] Accordingly, it relates to mPAP, PCWP, and CO.

[0130] PVR measures the resistance to flow imposed by the pulmonary vascular system without the influence of left-sided filling pressure. 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.

[0131] In some embodiments, the total PVR is given by the following formula: TPR=mPAP / CO It can be measured using [this method].

[0132] According to some embodiments, the contribution of the precapillary pulmonary artery to PH may be reflected by an elevated PVR. 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, an increased PVR may refer to a PVR greater than 2 wood units, greater than 2.5 wood units, greater than 3 wood units, or greater than 3.5 wood units.

[0133] As yet another example, TPG is the difference between mPAP and left atrial pressure (PLA; pulmonary capillary wedge pressure: usually estimated by PCWP), as shown by the following formula: TPG = mPAP - PCWP.

[0134] TPG is influenced by all determinants of mPAP, including flow, resistance, and left ventricular filling pressure. The contribution of the anterior capillary pulmonary artery to PH may be affected by the increased transpulmonary pressure gradient (TPG). According to some embodiments, an increased TPG may refer to mPAP-PCWP exceeding 12–15 mmHg.

[0135] DPG (defined as diastolic PAP – mean PAWP) appears to be the best approach to the features needed to determine pulmonary vascular disease. In some embodiments, DPG is synonymous with diastolic pressure difference (DPD). In normal subjects, DPG is generally in the range of 1–3 mmHg, and in patients evaluated for cardiac disease (excluding shunts), DPG remains ≤5 mmHg in most cases.

[0136] As a further example, mPAP is related to dPAP and sPAP according to the following formula: mPAP = (2 / 3)dPAP + (1 / 3)sPAP.

[0137] Furthermore, dPAP and sPAP can be used to calculate pulse pressure (mmHg) using the following formula: pulse pressure = sPAP - dPAP.

[0138] 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. In some embodiments, pulmonary hemodynamic parameters are measured directly, such as during right heart catheterization. In other embodiments, pulmonary hemodynamic parameters are estimated and / or evaluated by other techniques such as magnetic resonance imaging (MRI) or echocardiography.

[0139] Exemplary pulmonary hemodynamic parameters include mPAP, PAWP, TPG, DPG, and PVR. One or more pulmonary hemodynamic parameters may be measured by any appropriate procedure, for example, by right heart catheterization or echocardiography. The various hemodynamic types of PH are shown in Table 2, along with their corresponding clinical classifications (Table 1). Table 2. Types of hemodynamics in pulmonary hypertension (PH) [Table 2]

[0140] The type of PH and the differences between precapillary pulmonary hypertension and postcapillary pulmonary hypertension are based on pulmonary hemodynamic parameters. As used herein, the term “precapillary pulmonary hypertension” includes WHO clinical groups 1, 3, 4, and 5. Generally, precapillary pulmonary hypertension is characterized using the pulmonary hemodynamic parameters shown in Table 2 (i.e., mPAP > 20 mmHg, or in some embodiments, mPAP > 25 mmHg). As used herein, the term “postcapillary pulmonary hypertension” (PcPH) includes both isolated postcapillary pulmonary hypertension (IpcPH) and mixed precapillary and postcapillary pulmonary hypertension (CpcPH), both of which are within WHO clinical groups 2 and 5. In some embodiments, IpcPH is characterized using the pulmonary hemodynamic parameters shown in Table 2 (i.e., one or more of the following pulmonary hemodynamic parameters: mPAP > 20 mmHg, PAWP > 15 mmHg, PVR < 3 Wood units, and / or DPG < 7 mmHg). In some embodiments, CpcPH is characterized using the pulmonary hemodynamic parameters shown in Table 2 (i.e., one or more of the following pulmonary hemodynamic parameters: mPAP > 20 mmHg, PAWP > 15 mmHg, PVR ≥ 3 Wood units, and / or DPG ≥ 7 mmHg). In some embodiments, CpcPH is characterized as including one or more of the following hemodynamic parameters: mPAP ≥ 25 mmHg; PAWP > 15 mmHg; and PVR > 3 WU.

[0141] The clinical classifications or hemodynamic types of PH and associated diagnostic parameters described herein may be updated or changed based on the availability of new or existing data sources, or when additional clinical entities are considered. Characteristics of pH

[0142] The diagnosis of PH, including the WHO PH class and functional group, can be determined based on symptoms and health examination using a comprehensive review of a set of parameters to determine whether hemodynamic and other criteria are met. 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 gases, echocardiogram results, ventilation / perfusion lung scan results, high-resolution computed tomography results, contrast-enhanced computed tomography results, pulmonary angiography results, magnetic resonance imaging, blood tests (e.g., biomarkers such as BNP or NT-proBNP), immunology, abdominal ultrasound scan, right heart catheterization (RHC), vascular reactivity, and genetic testing. See, for example, Galie N., et al Euro Heart J. (2016) 37, 67-119.

[0143] In some embodiments, biomarkers may be used to determine the diagnosis of PH. For example, in some embodiments, the biomarker is a marker of vascular dysfunction (e.g., asymmetric dimethylarginine (ADMA), endothelin-1, angiopoietin, or von Willebrand factor). In some embodiments, the biomarker is a marker of inflammation (C-reactive protein, interleukin-6, chemokine). In some embodiments, the biomarker is a marker of myocardial stress (e.g., atrial natriuretic peptide, brain natriuretic peptide (BNP) / NT-proBNP, or troponin). In some embodiments, the biomarker is a marker of low CO and / or tissue hypoxia (e.g., pCO2, uric acid, growth differentiation factor 15 (GDF15), or osteopontin). In some embodiments, the biomarker is a marker of secondary organ injury (e.g., creatinine, or bilirubin). For example, see Galie N., et al Euro Heart J. (2016) 37, 67-119. Group 1 PH

[0144] Pulmonary arterial hypertension (PH, Group 1 according to the WHO) is a severe, progressive, and life-threatening disease of the pulmonary vascular system characterized by severe vasoconstriction and abnormal proliferation of smooth muscle cells in the walls of the pulmonary arteries. Severe constriction of the pulmonary blood vessels results in extremely high pulmonary artery pressure. These high pressures make it difficult for the heart to pump blood through the lungs to supply oxygen. Patients with PAH suffer from extreme shortness of breath as the heart tries to pump blood against these high pressures. Patients with PAH typically develop a marked increase in PVR and a persistent increase in mPAP, which ultimately leads to right ventricular failure and death. Patients diagnosed with PAH have a poor prognosis, as well as a impaired quality of life, with an average life expectancy of 2 to 5 years from the time of diagnosis if left untreated.

[0145] Various factors contribute to the pathogenesis of pulmonary hypertension, including the proliferation of lung cells (i.e., hyperplasia) that can contribute to vascular remodeling. For example, pulmonary vascular remodeling is primarily caused by the proliferation of arterial endothelial cells and smooth muscle cells in patients with pulmonary hypertension. Overexpression of various cytokines is thought to promote pulmonary hypertension. Furthermore, it has been found that pulmonary hypertension can arise from the overproliferation of pulmonary artery smooth cells and pulmonary endothelial cells. Moreover, progressive PAH can be characterized by muscularization of distal pulmonary arterioles, concentric endocardium thickening, and occlusion of vascular lumen due to endothelial cell proliferation. Pietra et al., J. Am. Coll. Cardiol., 43:255-325 (2004).

[0146] PAH can be diagnosed based on mean pulmonary artery pressure above 25 mmHg at rest (or above 20 mmHg under updated guidelines) and normal pulmonary artery capillary wedge pressure. PAH can result in shortness of breath, dizziness, syncope, and other symptoms, all of which worsen with exercise. PAH can be a severe disorder accompanied by significantly reduced exercise tolerance and heart failure. There are two main types of PAH: idiopathic PAH (e.g., PAH with no identified predisposition) and hereditary PAH (e.g., PAH associated with mutations in BMPR2, ALK1, ENG, SMAD9, CAV1, KCNK3, or EIF2AK4). In 70% of cases of familial PAH, the mutation is located in the BMPR2 gene. Risk factors for the development of PAH include a family history of PAH, drug and toxin use (e.g., methamphetamine or cocaine use), infection (e.g., HIV infection or schistosomiasis), cirrhosis, congenital cardiac anomalies, portal hypertension, pulmonary veno-occlusive disease, pulmonary capillary hemangioma, or connective tissue / autoimmune disorders (e.g., scleroderma or lupus erythematosus). PAH may be associated with calcium channel blockers, the apparent venous / capillary (PVOD / PCH) involvement, and long-term responders to persistent PH in neonatal syndromes. Group 2 PH

[0147] Pulmonary hypertension due to left heart disease (PH-LHD) (WHO Group 2 PH) is a complex pathological phenotype that, if present, can lead to increased susceptibility to adverse events and worse clinical outcomes. PH-LHD may be defined as a patient having a pulmonary capillary wedge pressure (PCWP) >15 mmHg and mean pulmonary artery pressure (mPAP) ≥25 mmHg (or, under updated guidelines, ≥20 mmHg). PH-LHD occurs as a result of high left-sided filling pressure, primarily driven by LV diastolic function, being directly transmitted retrocapillary to the post-capillary pulmonary vessels, thereby retrocapillary to the rest of the pulmonary circulation. PH-LHD may be associated with, or may be caused by, congenital / acquired cardiovascular conditions leading to PH due to heart failure with maintained left ventricular ejection fraction (LVEF) [also known as HFpEF], PH due to heart failure with reduced LVEF (also known as HFrEF), valvular heart disease (VHD), or retrocapillary PH. Compared to PAH, patients with PH-LHD often have a higher prevalence of cardiovascular comorbidities and are mostly, though not all, older women with metabolic syndrome characteristics.

[0148] Valvular heart disease (VHD) associated with pulmonary hypertension can arise from multiple mechanisms, including increased pulmonary blood flow (PVR), pulmonary venous pressure (RPR), or pulmonary venous pressure (RV). Chronic elevation of PAP frequently leads to PV pressure overload and subsequent RV failure. Clinical signs and symptoms of left-sided VHD with PH include orthopnea and paroxysmal nocturnal dyspnea. In the advanced stages of the disease, signs of RV failure, including peripheral edema, ascites, and fainting, are frequently observed. There are four subtypes of valvular heart disease, including mitral stenosis, mitral regurgitation, aortic stenosis, and aortic regurgitation.

[0149] Mitral stenosis occurs when the mitral valve of the heart narrows due to hardening or scarring of the valve, or partial fusion of the valve flaps. This results in the valve not opening to its full potential, leading to insufficient blood flow and potentially backflow of blood into the lungs. If left untreated, mitral stenosis can lead to serious cardiac complications. Common causes of mitral stenosis include rheumatic heart disease, radiation therapy, and mitral annular calcification. Typical interventions for mitral stenosis include vavuloplasty, commissurrotomy, and surgical valve replacement.

[0150] Mitral regurgitation (also known as mitral valve insufficiency) occurs when the flap (lobule) of the mitral valve does not close properly, allowing blood to flow backward into the heart. As a result, blood cannot pass through the heart or efficiently move to other parts of the body, leading to fatigue or shortness of breath. In addition, reduced flow increases pressure in the left atrium and pulmonary vascular system. In moderate to severe cases, surgery may be recommended to repair or replace the damaged valve. If left untreated, severe mitral regurgitation can lead to heart failure or serious cardiac problems. Common causes of mitral regurgitation include mitral valve prolapse and degenerative mitral valve diseases such as mitral annular calcification. Typical interventions for mitral regurgitation include transcatheter mitral valve repair, surgical repair, or replacement.

[0151] In aortic stenosis, the aortic valve does not open completely. This reduces blood flow from the heart. As the aortic valve narrows further, pressure increases inside the left ventricle. This thickens the left ventricle, reducing blood flow and potentially causing chest pain. As the pressure continues to rise, blood can backflow into the lungs, causing shortness of breath. Severe forms of aortic stenosis can prevent sufficient blood from reaching the brain and other parts of the body. Common causes of aortic stenosis include calcification of the aortic valve or the presence of a bicuspid aortic valve. Typical interventions include transcatheter aortic valve replacement (percutaneous valve replacement) and surgical valve replacement.

[0152] Aortic regurgitation (also known as aortic valve insufficiency) occurs when the aortic valve cannot close completely. The valve leaks, resulting in reduced blood flow. As a result, the heart has to work harder to compensate for the reduced blood flow, and becomes weakened over time. For this reason, the amount of blood flowing from the heart to other parts of the body is reduced. Common causes of aortic regurgitation include dilation of the aortic root and the presence of a bicuspid aortic valve.

[0153] Among these patients with PH-LHD, two phenotypes have been described: 1) a group of isolated postcapillary PH (IpcPH) or “passive” PH, where the increase in pulmonary pressure is reversible and proportional to the increase in left atrial pressure; and 2) a group with an additional “precapillary” component [postcapillary and precapillary mixed PH (CpcPH)]. CpcPH in this latter group may also have mixed pulmonary vascular remodeling and therefore may exhibit persistent PH after interventions to reduce left-sided filling pressure.

[0154] In some embodiments, combinations of mPAP, PAWP, PVR, or DPG may be used to define different subtypes of PH-LHD, namely IpcPH and CpcPH (see, for example, Table 2). In some embodiments, patients with CpcPH are characterized as having a TPG > 12–15 mmHg and a PVR > 2.5–3 Wood units (WU). In some embodiments, CpcPH is distinguished from IpcPH using DPG. In some embodiments, patients with CpcPH have a DPG ≥ 7 mmHg. In some embodiments, patients with IpcPH have a DPG < 7 mmHg.

[0155] In some embodiments, combinations of DPG and PVR may be used to define different types of PH-LHD. For example, in some embodiments, IpcPH patients have DPG < 7 mmHg and / or PVR ≤ 3 WU. In some embodiments, CpcPH patients have DPG ≥ 7 mmHg and / or PVR > 3 WU.

[0156] The clinical or hemodynamic classifications and associated diagnostic parameters described herein may be updated as new data become available or as additional clinical entities are considered. For example, at the 5th World Symposium on Pulmonary Hypertension (WSPH), a new term was approved to distinguish IpcPH from CpcPH based on the diastolic pressure difference / gap (DPG) between dPAP and PAWP. However, this definition was found to be too restrictive and open to interpretation, leading to controversy over whether DPG predicts outcomes in patients with group 2 PH. Therefore, at the 6th WSPH, pulmonary vascular resistance (PVR) was subsequently reintroduced to better reflect the right ventricular influence on patient outcomes. See, for example, Vachiery JL, et al. Eur Respir J 2019 Jan 24;53(1).

[0157] Therapies for treating PH-LHD primarily involve addressing underlying conditions (i.e., COPD, sleep apnea syndrome, CTEPH) before considering specific measures to treat PH itself. Some therapies include repair of heart valve disease (if indicated). Nonspecific vasodilators such as nitrates and hydralazine may also be used. In some embodiments, LVADs may be used to reduce pulmonary pressure. The lack of a specific therapy is particularly problematic because PH-LHD is the most common cause of PH in Western countries, and its presence usually leads to an unfavorable course of the disease. Specifically, the presence of PH-LHD can result in more severe symptoms of LHD, worse exercise tolerance, and negative impacts on outcomes. Group 3 PH

[0158] Pulmonary hypertension resulting from lung disease and / or hypoxia (WHO Group 3 PH) refers to a form of pulmonary hypertension resulting from lung disease or chronic hypoxia. This form of PH is also known as "hypoxic PH" or "hypoxic pulmonary hypertension." Hypoxic PH may be associated with or caused by chronic obstructive pulmonary disease (e.g., emphysema), interstitial lung disease, sleep-disordered breathing (e.g., sleep apnea), lung disease (e.g., pulmonary fibrosis), impaired alveolar ventilation, chronic exposure to high altitude, or developmental abnormalities. Group 4 PH

[0159] Pulmonary hypertension resulting from pulmonary artery occlusion (WHO Group 4 PH) is a form of pulmonary hypertension associated with chronic arterial occlusion (e.g., blood coagulation). Multiple pathophysiological mechanisms may drive the development of Group 4 PH, including chronic thromboembolic PH, sarcoma (high or moderate grade) or angiosarcoma, other malignancies (e.g., renal cancer, uterine cancer, germ cell tumors of the testis, or other tumors), non-malignancies (e.g., uterine leiomyoma), arteritis without connective tissue disease, congenital pulmonary stenosis, or parasitic infections (e.g., hydatid cystitis).

[0160] Various pulmonary hemodynamic parameters are associated with group 4 PH. For example, in patients with PH due to pulmonary occlusion, patients with severe PH (>40 mmHg) often have a significant increase in PVR (around 10 WU), and more often these patients may have mild PH (mPAP 20-30 mmHg) associated with a lower PVR, although it generally remains >3 WU. See, for example, Simonneau (2019) Eur Respir J: 53:1801913. In these different chronic lung diseases, even a moderate increase in mPAP (20-29 mmHg) may be associated with a poor prognosis. Furthermore, in chronic thromboembolic PH, patients may have severe precapillary PH with an mPAP of approximately 47 mmHg and an average PVR of approximately 8.9 WU. Ibid. In this situation, even in patients with mild mPAP elevation (20-24 mmHg), the PVR is generally >3 WU. Group 5 PH

[0161] Pulmonary hypertension due to unclear and / or multifactorial mechanisms (PH in WHO Group 5) is a group that includes less studied forms of PH compared to other groups. However, many forms of PH currently represent a large portion of the PH burden in Group 5. Diseases within PH in Group 5 are characterized by the absence of a single identified key mechanism driving the development of PH. There may be many pathophysiological mechanisms driving the development of PH, including hematological disorders (e.g., chronic hemolytic anemia or myeloproliferative disorders), systemic and metabolic disorders (e.g., pulmonary Langerhans cell histioproliferative disorder, Gaucher disease, glycogen storage disease, neurofibromatosis, or sarcoidosis), others (e.g., chronic renal failure with or without hemodialysis or fibrous mediastinitis), or complex congenital heart disease. pH measurement

[0162] In certain embodiments, the Disclosure relates to a method for treating, preventing, or reducing the rate and / or severity of progression of PcPH (e.g., treating, preventing, or reducing the rate and / or severity of progression of one or more complications of post-capillary pulmonary hypertension of WHO group 2 and / or group 5 PH), comprising administering an effective amount of ActRII polypeptide (e.g., an amino acid sequence that is at least 90% identical to the amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1) to a patient in need. In some embodiments, the method relates to treating a PcPH patient having IpcPH. In some embodiments, the method relates to treating a PcPH patient having CpcPH. In some embodiments, the method relates to treating a PcPH patient having pulmonary hypertension due to left heart disease (PH-LHD). In some embodiments, the method relates to treating a PcPH patient having group 2 PH as classified by the WHO. In some embodiments, the method relates to treating a PcPH patient having pulmonary hypertension due to heart failure with maintained LVEF (HFpEF). In some embodiments, the method relates to treating patients with PcPH who have pulmonary hypertension due to heart failure with reduced LVEF (HFrEF). In some embodiments, the method relates to treating patients with PcPH who have valvular heart disease. In some embodiments, valvular heart disease is aortic regurgitation. In some embodiments, valvular heart disease is aortic stenosis. In some embodiments, valvular heart disease is mitral valve disease. In some embodiments, valvular heart disease is mitral regurgitation. In some embodiments, valvular heart disease is mitral stenosis. In some embodiments, the method relates to treating patients with CpcPH who have PH due to valvular heart disease. In some embodiments, the method relates to treating patients with IpcPH who have PH due to valvular heart disease. In some embodiments, the method relates to treating patients with PcPH who have a congenital / acquired cardiovascular condition leading to postcapillary PH. In some embodiments, the method relates to treating patients with PcPH who have pulmonary hypertension due to unclear and / or multifactorial mechanisms.In some embodiments, the method relates to treating PcPH patients with group 5 PH as classified by the WHO.

[0163] In some embodiments, this disclosure relates to methods for treating, preventing, or reducing the rate of progression and / or severity of pulmonary hypertension in a particular combination of patient populations. Each of the patient populations described herein can be combined and rearranged accordingly. For example, in some embodiments, the method relates to treating CpcPH patients with heart failure-induced PH (HFpEF) with maintained LVEF. In some embodiments, the method relates to treating CpcPH patients with heart failure-induced PH (HFrEF) with reduced LVEF. In some embodiments, the method relates to treating CpcPH patients with PH due to valvular heart disease. In some embodiments, the method relates to treating IpcPH patients with heart failure-induced PH (HFpEF) with maintained LVEF. In some embodiments, the method relates to treating IpcPH patients with heart failure-induced PH (HFrEF) with reduced LVEF. In some embodiments, the method relates to treating IpcPH patients with PH due to valvular heart disease.

[0164] In some embodiments, the method relates to patients with pulmonary hypertension due to unclear and / or multifactorial mechanisms. In some embodiments, the method relates to patients with hematological disorders (e.g., chronic hemolytic anemia and myeloproliferative disorders). In some embodiments, the method relates to patients with systemic and / or metabolic disorders (e.g., pulmonary Langerhans cell histiocytosis, Gaucher disease, glycogen storage disease, neurofibromatosis, and sarcoidosis). In some embodiments, the method relates to patients with other disorders due to unclear and / or multifactorial mechanisms (e.g., chronic renal failure with or without hemodialysis and fibrous mediastinitis). In some embodiments, the method relates to patients with complex congenital heart disease. mPAP

[0165] In certain embodiments, the Disclosure relates to a method for treating, preventing, or reducing the rate and / or severity of progression of PcPH (e.g., treating, preventing, or reducing the rate and / or severity of progression of one or more complications of PcPH of WHO Group 2 and / or Group 5 PH), comprising administering an effective amount of ActRII polypeptide (e.g., an amino acid sequence that is at least 90% identical to the amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1) to a patient in need thereof, wherein the patient has a resting mean pulmonary artery pressure (mPAP) of at least 20 mmHg (e.g., 20, 25, 30, 35, 40, 45, or 50 mmHg). As used herein, the terms “mean pulmonary arterial pressure” and “mean pulmonary artery pressure” are used interchangeably. In some embodiments, the method relates to a patient having a resting mPAP of at least 20 mmHg. In some embodiments, the method relates to a patient having a resting mPAP of at least 25 mmHg. In some embodiments, the method relates to a patient having a resting mPAP of at least 30 mmHg. In some embodiments, the method relates to a patient having a resting mPAP of at least 35 mmHg. In some embodiments, the method relates to a patient having a resting mPAP of at least 40 mmHg. In some embodiments, the method relates to a patient having a resting mPAP of at least 45 mmHg. In some embodiments, the method relates to a patient having a resting mPAP of at least 50 mmHg.

[0166] In some embodiments, the present disclosure relates to a method for adjusting one or more hemodynamic parameters in a patient with PcPH to a more normal level (e.g., normal compared to a healthy person of similar age and sex), comprising administering an effective amount of ActRII polypeptide (e.g., an amino acid sequence that is at least 90% identical to the amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1) to the patient in need. In some embodiments, the method relates to improving pulmonary artery pressure in the patient. In some embodiments, improvement of pulmonary artery pressure is a reduction in mean pulmonary artery pressure (mPAP). In some embodiments, the method relates to reducing mPAP. In some embodiments, the method relates to reducing the patient's mPAP by at least 1 mmHg. In some embodiments, the method relates to reducing the patient's mPAP by at least 2 mmHg. In some embodiments, the method relates to reducing the patient's mPAP by at least 3 mmHg. In certain embodiments, the method relates to reducing the patient's mPAP by at least 5 mmHg. In certain embodiments, the method relates to reducing the patient's mPAP by at least 7 mmHg. In certain embodiments, the method relates to reducing a patient's mPAP by at least 10 mmHg. In certain embodiments, the method relates to reducing a patient's mPAP by at least 12 mmHg. In certain embodiments, the method relates to reducing a patient's mPAP by at least 15 mmHg. In certain embodiments, the method relates to reducing a patient's mPAP by at least 20 mmHg. In certain embodiments, the method relates to reducing a patient's mPAP by at least 25 mmHg.

[0167] In some embodiments, the present disclosure relates to a method for adjusting one or more hemodynamic parameters in a PcPH patient toward a more normal level (e.g., normal compared to a healthy person of similar age and sex), comprising administering an effective amount of ActRII polypeptide (e.g., an amino acid sequence that is at least 90% identical to the amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1) to the patient in need. In some embodiments, the method relates to reducing the patient's mPAP by at least 1% (e.g., 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100%). In some embodiments, the method relates to reducing the patient's mPAP by at least 1%. In some embodiments, the method 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 relates to reducing the patient's mPAP by at least 15%. In some embodiments, the method relates to reducing the patient's mPAP by at least 20%. In some embodiments, the method relates to reducing the patient's mPAP by at least 25%. In some embodiments, the method relates to reducing the 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 relates to reducing the patient's mPAP by at least 40%. In some embodiments, the method relates to reducing the patient's mPAP by at least 45%. In some embodiments, the method relates to reducing the patient's mPAP by at least 50%. In some embodiments, the method relates to reducing the patient's mPAP by at least 55%. In some embodiments, the method relates to reducing the patient's mPAP by at least 60%. In some embodiments, the method relates to reducing the patient's mPAP by at least 65%. In some embodiments, the method relates to reducing the patient's mPAP by at least 70%. In some embodiments, the method relates to reducing the patient's mPAP by at least 75%.In some embodiments, the method relates to reducing the patient's mPAP by at least 80%. In some embodiments, the method relates to reducing the patient's mPAP by at least 85%. In some embodiments, the method relates to reducing the patient's mPAP by at least 90%. In some embodiments, the method relates to reducing the patient's mPAP by at least 95%. In some embodiments, the method relates to reducing the patient's mPAP by at least 100%. mRAP

[0168] In some patients, increased pulmonary vascular resistance to blood flow leads to increased right atrial pressure (RAP) and right heart failure. Patients with right heart failure typically have an increased ratio of RAP to pulmonary artery wedge pressure (PAWP). In certain embodiments, the Disclosure relates to a method for treating, preventing, or reducing the rate and / or severity of progression of PcPH (e.g., treating, preventing, or reducing the rate and / or severity of progression of one or more complications of PcPH of WHO Group 2 and / or Group 5 PH), comprising administering an effective amount of ActRII polypeptide (e.g., an amino acid sequence that is at least 90% identical to the amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1) to a patient in need thereof, wherein the patient has a mean resting right atrial pressure (mRAP) of at least 5 mmHg (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 18, 20, 21, 22, 23, 24, or 25 mmHg). In some embodiments, the method relates to a patient having a resting mRAP of at least 5 mmHg. In some embodiments, the method relates to a patient having a resting mRAP of at least 6 mmHg. In some embodiments, the method relates to a patient having a resting mRAP of at least 7 mmHg. In some embodiments, the method relates to a patient having a resting mRAP of at least 8 mmHg. In some embodiments, the method relates to a patient having a resting mRAP of at least 9 mmHg. In some embodiments, the method relates to a patient having a resting mRAP of at least 10 mmHg. In some embodiments, the method relates to a patient having a resting mRAP of at least 11 mmHg. In some embodiments, the method relates to a patient having a resting mRAP of at least 12 mmHg. In some embodiments, the method relates to a patient having a resting mRAP of at least 13 mmHg. In some embodiments, the method relates to a patient having a resting mRAP of at least 14 mmHg. In some embodiments, the method relates to a patient having a resting mRAP of at least 15 mmHg. In some embodiments, the method relates to a patient having a resting mRAP of at least 16 mmHg.In some embodiments, the method relates to a patient having a resting mRAP of at least 17 mmHg. In some embodiments, the method relates to a patient having a resting mRAP of at least 18 mmHg. In some embodiments, the method relates to a patient having a resting mRAP of at least 19 mmHg. In some embodiments, the method relates to a patient having a resting mRAP of at least 20 mmHg. In some embodiments, the method relates to a patient having a resting mRAP of at least 21 mmHg. In some embodiments, the method relates to a patient having a resting mRAP of at least 22 mmHg. In some embodiments, the method relates to a patient having a resting mRAP of at least 23 mmHg. In some embodiments, the method relates to a patient having a resting mRAP of at least 24 mmHg. In some embodiments, the method relates to a patient having a resting mRAP of at least 25 mmHg.

[0169] In some embodiments, the present disclosure relates to a method for adjusting one or more hemodynamic parameters in a patient with PcPH to a more normal level (e.g., normal compared to a healthy person of similar age and sex), comprising administering an effective amount of ActRII polypeptide (e.g., an amino acid sequence that is at least 90% identical to the amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1) to the patient in need. In some embodiments, the method relates to improving mean right atrial pressure in the patient. In some embodiments, improvement of mean right atrial pressure (mRAP) is a reduction of mRAP. In some embodiments, the method relates to reducing mRAP. In some embodiments, the method relates to reducing the patient's mRAP by at least 1 mmHg. In some embodiments, the method relates to reducing the patient's mRAP by at least 2 mmHg. In some embodiments, the method relates to reducing the patient's mRAP by at least 3 mmHg. In some embodiments, the method relates to reducing the patient's mRAP by at least 4 mmHg. In certain embodiments, the method relates to reducing the patient's mRAP by at least 5 mmHg. In some embodiments, the method relates to reducing the patient's mRAP by at least 6 mmHg. In certain embodiments, the method relates to reducing the patient's mRAP by at least 7 mmHg. In some embodiments, the method relates to reducing the patient's mRAP by at least 8 mmHg. In some embodiments, the method relates to reducing the patient's mRAP by at least 9 mmHg. In certain embodiments, the method relates to reducing the patient's mRAP by at least 10 mmHg. In some embodiments, the method relates to reducing the patient's mRAP by at least 11 mmHg. In certain embodiments, the method relates to reducing the patient's mRAP by at least 12 mmHg. In some embodiments, the method relates to reducing the patient's mRAP by at least 13 mmHg. In some embodiments, the method relates to reducing the patient's mRAP by at least 14 mmHg. In certain embodiments, the method relates to reducing the patient's mRAP by at least 15 mmHg.In some embodiments, the method relates to reducing the patient's mRAP by at least 16 mmHg. In some embodiments, the method relates to reducing the patient's mRAP by at least 17 mmHg. In some embodiments, the method relates to reducing the patient's mRAP by at least 18 mmHg. In some embodiments, the method relates to reducing the patient's mRAP by at least 19 mmHg. In a particular embodiment, the method relates to reducing the patient's mRAP by at least 20 mmHg.

[0170] In some embodiments, the present disclosure relates to a method for adjusting one or more hemodynamic parameters in a PcPH patient toward a more normal level (e.g., normal compared to a healthy person of similar age and sex), comprising administering an effective amount of ActRII polypeptide (e.g., an amino acid sequence that is at least 90% identical to the amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1) to the patient in need. In some embodiments, the method relates to reducing the patient's mRAP by at least 1% (e.g., 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 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%. In some embodiments, the method relates to reducing the patient's mRAP by at least 15%. In some embodiments, the method relates to reducing the patient's mRAP by at least 20%. In some embodiments, the method relates to reducing the patient's mRAP by at least 25%. In some embodiments, 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 relates to reducing the patient's mRAP by at least 40%. In some embodiments, the method relates to reducing the patient's mRAP by at least 45%. In some embodiments, the method relates to reducing the patient's mRAP by at least 50%. In some embodiments, the method relates to reducing the patient's mRAP by at least 55%. In some embodiments, the method relates to reducing the patient's mRAP by at least 60%. In some embodiments, the method relates to reducing the patient's mRAP by at least 65%. In some embodiments, the method relates to reducing the patient's mRAP by at least 70%. In some embodiments, the method relates to reducing the patient's mRAP by at least 75%.In some embodiments, the method relates to reducing the patient's mRAP by at least 80%. In some embodiments, the method relates to reducing the patient's mRAP by at least 85%. In some embodiments, the method relates to reducing the patient's mRAP by at least 90%. In some embodiments, the method relates to reducing the patient's mRAP by at least 95%. In some embodiments, the method relates to reducing the patient's mRAP by at least 100%. PVR

[0171] In certain embodiments, the Disclosure relates to a method for treating, preventing, or reducing the rate and / or severity of progression of PcPH (e.g., treating, preventing, or reducing the rate and / or severity of progression of one or more complications of PcPH of WHO Group 2 and / or Group 5 PH), comprising administering an effective amount of ActRII polypeptide (e.g., an amino acid sequence that is at least 90% identical to the amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1) to a patient in need thereof, wherein the patient has a pulmonary vascular resistance (PVR) of at least 2.5 Wood units (e.g., 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or 20 Wood units). In some embodiments, the method relates to a patient having a PVR of at least 2.5 Wood units. In some embodiments, the method relates to a patient having a PVR of at least 3 Wood units. In some embodiments, the method relates to a patient having a PVR of at least 4 Wood units. In some embodiments, the method relates to a patient having a PVR of at least 5 Wood units. In some embodiments, the method relates to a patient having a PVR of at least 6 wood units. In some embodiments, the method relates to a patient having a PVR of at least 7 wood units. In some embodiments, the method relates to a patient having a PVR of at least 8 wood units. In some embodiments, the method relates to a patient having a PVR of at least 9 wood units. In some embodiments, the method relates to a patient having a PVR of at least 10 wood units. In some embodiments, the method relates to a patient having a PVR of at least 12 wood units. In some embodiments, the method relates to a patient having a PVR of at least 14 wood units. In some embodiments, the method relates to a patient having a PVR of at least 16 wood units. In some embodiments, the method relates to a patient having a PVR of at least 18 wood units. In some embodiments, the method relates to a patient having a PVR of at least 20 wood units.

[0172] In some embodiments, the present disclosure relates to a method for adjusting one or more hemodynamic parameters in a PcPH patient toward a more normal level (e.g., normal compared to a healthy person of similar age and sex), comprising administering an effective amount of ActRII polypeptide (e.g., an amino acid sequence that is at least 90% identical to the amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1) to the patient in need. In some embodiments, the method relates to reducing the patient's PVR. In some embodiments, the reduction of the patient's PVR is a result of a decrease in the patient's mean pulmonary artery pressure (mPAP). In some embodiments, the method relates to reducing the patient's PVR by at least 0.5 Wood units. In some embodiments, the method relates to reducing the patient's PVR by at least 1 Wood unit. In some embodiments, the method relates to reducing the patient's PVR by at least 2 Wood units. In some embodiments, the method relates to reducing the patient's PVR by at least 4 Wood units. In some embodiments, the method relates to reducing the patient's PVR by at least 6 Wood units. In some embodiments, the method relates to reducing the patient's PVR by at least 8 Wood units. In some embodiments, the method relates to reducing the patient's PVR by at least 10 Wood units.

[0173] In some embodiments, the present disclosure relates to a method for adjusting one or more hemodynamic parameters in a PcPH patient toward a more normal level (e.g., normal compared to a healthy person of similar age and sex), comprising administering an effective amount of ActRII polypeptide (e.g., an amino acid sequence that is at least 90% identical to the amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1) to the patient in need. In some embodiments, the method relates to reducing the patient's PVR. In some embodiments, the reduction in the patient's PVR is a result of a reduction in the patient's mean pulmonary artery pressure (mPAP). In some embodiments, the method relates to reducing the patient's PVR by at least 1% (e.g., 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%). In some embodiments, the method relates to reducing the patient's PVR by at least 1%. In some embodiments, the method relates to reducing the patient's PVR by at least 5%. In some embodiments, the method relates to reducing the patient's PVR by at least 10%. In some embodiments, the method 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%. In some embodiments, the method relates to reducing the patient's PVR by at least 35%. In some embodiments, the method relates to reducing the patient's PVR by at least 40%. In some embodiments, the method relates to reducing the patient's PVR by at least 45%. In some embodiments, the method 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 some embodiments, the method relates to reducing the patient's PVR by at least 60%. In some embodiments, the method relates to reducing the 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 relates to reducing the patient's PVR by at least 85%. In some embodiments, the method relates to reducing the patient's PVR by at least 90%. In some embodiments, the method relates to reducing the patient's PVR by at least 95%. In some embodiments, the method relates to reducing the patient's PVR by at least 100%. PAWP

[0174] In certain embodiments, the Disclosure relates to a method for treating, preventing, or reducing the rate and / or severity of progression of PcPH (e.g., treating, preventing, or reducing the rate and / or severity of progression of one or more complications of PcPH of WHO Group 2 and / or Group 5 PH), comprising administering an effective amount of ActRII polypeptide (e.g., an amino acid sequence that is at least 90% identical to the amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1) to a patient in need thereof, wherein the patient has a pulmonary artery wedge pressure (PAWP) of at least 12 mmHg (e.g., 12, 15, 20, 25, 30, 35, 40, 45, or 50 mmHg). In some embodiments, the method relates to a patient having a PAWP of at least 15 mmHg. In some embodiments, the method relates to a patient having a PAWP of at least 20 mmHg. In some embodiments, the method relates to a patient having a PAWP of at least 25 mmHg. In some embodiments, the method relates to a patient having a PAWP of at least 30 mmHg. In some embodiments, the method relates to a patient having PAWP of at least 35 mmHg. In some embodiments, the method relates to a patient having PAWP of at least 40 mmHg. In some embodiments, the method relates to a patient having PAWP of at least 45 mmHg. In some embodiments, the method relates to a patient having PAWP of at least 50 mmHg. In some embodiments, the method relates to a patient having PCWP of 15 to 30 mmHg.

[0175] In some embodiments, the present disclosure relates to a method for adjusting one or more hemodynamic parameters in a PcPH patient to a more normal level (e.g., normal compared to a healthy person of similar age and sex), comprising administering an effective amount of ActRII polypeptide (e.g., an amino acid sequence that is at least 90% identical to the amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1) to the patient in need. In some embodiments, the method relates to reducing the patient's PAWP by at least 1 mmHg. In some embodiments, the method relates to reducing the patient's PAWP by at least 2 mmHg. In some embodiments, the method relates to reducing the patient's PAWP by at least 4 mmHg. In some embodiments, the method relates to reducing the patient's PAWP by at least 6 mmHg. In some embodiments, the method relates to reducing the patient's PAWP by at least 10 mmHg. In some embodiments, the method relates to reducing the patient's PAWP by at least 15 mmHg. In some embodiments, the method relates to reducing the patient's PAWP by at least 20 mmHg. In some embodiments, the method relates to reducing the patient's PAWP by at least 25 mmHg. In some embodiments, the method relates to reducing the patient's PAWP by at least 30 mmHg.

[0176] In some embodiments, the present disclosure relates to a method for adjusting one or more hemodynamic parameters in a PcPH patient toward a more normal level (e.g., normal compared to a healthy person of similar age and sex), comprising administering an effective amount of ActRII polypeptide (e.g., an amino acid sequence that is at least 90% identical to the amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1) to the patient in need. In some embodiments, the method relates to reducing the patient's PAWP by at least 1% (e.g., 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100%). In some embodiments, the method relates to reducing the patient's PAWP by at least 1%. In some embodiments, the method relates to reducing the patient's PAWP by at least 5%. In some embodiments, the method relates to reducing the patient's PAWP by at least 10%. In some embodiments, the method relates to reducing the patient's PAWP by at least 15%. In some embodiments, the method relates to reducing the patient's PAWP by at least 20%. In some embodiments, the method relates to reducing the patient's PAWP by at least 25%. In some embodiments, the method relates to reducing the patient's PAWP by at least 30%. In some embodiments, the method relates to reducing the patient's PAWP by at least 35%. In some embodiments, the method relates to reducing the patient's PAWP by at least 40%. In some embodiments, the method relates to reducing the patient's PAWP by at least 45%. In some embodiments, the method relates to reducing the patient's PAWP by at least 50%. In some embodiments, the method relates to reducing the patient's PAWP by at least 55%. In some embodiments, the method relates to reducing the patient's PAWP by at least 60%. In some embodiments, the method relates to reducing the patient's PAWP by at least 65%. In some embodiments, the method relates to reducing the patient's PAWP by at least 70%. In some embodiments, the method relates to reducing the patient's PAWP by at least 75%.In some embodiments, the method relates to reducing the patient's PAWP by at least 80%. In some embodiments, the method relates to reducing the patient's PAWP by at least 85%. In some embodiments, the method relates to reducing the patient's PAWP by at least 90%. In some embodiments, the method relates to reducing the patient's PAWP by at least 95%. In some embodiments, the method relates to reducing the patient's PAWP by at least 100%. LVEDP

[0177] In certain embodiments, the Disclosure relates to a method for treating, preventing, or reducing the rate and / or severity of progression of PcPH (e.g., treating, preventing, or reducing the rate and / or severity of progression of one or more complications of PcPH of WHO Group 2 and / or Group 5 PH), comprising administering an effective amount of ActRII polypeptide (e.g., an amino acid sequence that is at least 90% identical to the amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1) to a patient in need thereof, wherein the patient has a left ventricular end-diastolic pressure (LVEDP) of at least 12 mmHg (e.g., 12, 15, 20, 25, 30, 35, 40, 45, or 50 mmHg). In some embodiments, the method relates to a patient having an LVEDP of at least 15 mmHg. In some embodiments, the method relates to a patient having an LVEDP of at least 20 mmHg. In some embodiments, the method relates to a patient having an LVEDP of at least 25 mmHg. In some embodiments, the method relates to a patient having at least 30 mmHg of LVEDP. In some embodiments, the method relates to a patient having at least 35 mmHg of LVEDP. In some embodiments, the method relates to a patient having at least 40 mmHg of LVEDP. In some embodiments, the method relates to a patient having at least 45 mmHg of LVEDP. In some embodiments, the method relates to a patient having at least 50 mmHg of LVEDP.

[0178] In some embodiments, the present disclosure relates to a method for adjusting one or more hemodynamic parameters in a PcPH patient toward a more normal level (e.g., normal compared to a healthy person of similar age and sex), comprising administering an effective amount of ActRII polypeptide (e.g., an amino acid sequence that is at least 90% identical to the amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1) to the patient in need. In some embodiments, the method relates to reducing the patient's LVEDP by at least 1 mmHg. In some embodiments, the method relates to reducing the patient's LVEDP by at least 2 mmHg. In some embodiments, the method relates to reducing the patient's LVEDP by at least 4 mmHg. In some embodiments, the method relates to reducing the patient's LVEDP by at least 6 mmHg. In some embodiments, the method relates to reducing the patient's LVEDP by at least 10 mmHg. In some embodiments, the method relates to reducing the patient's LVEDP by at least 15 mmHg. In some embodiments, the method relates to reducing the patient's LVEDP by at least 20 mmHg. In some embodiments, the method relates to reducing the patient's LVEDP by at least 25 mmHg. In some embodiments, the method relates to reducing a patient's LVEDP by at least 30 mmHg.

[0179] In some embodiments, the present disclosure relates to a method for adjusting one or more hemodynamic parameters in a PcPH patient toward a more normal level (e.g., normal compared to a healthy person of similar age and sex), comprising administering an effective amount of ActRII polypeptide (e.g., an amino acid sequence that is at least 90% identical to the amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1) to the patient in need. In some embodiments, the method relates to reducing the patient's LVEDP by at least 1% (e.g., 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100%). In some embodiments, the method relates to reducing the patient's LVEDP by at least 1%. In some embodiments, the method relates to reducing the patient's LVEDP by at least 5%. In some embodiments, the method relates to reducing the patient's LVEDP by at least 10%. In some embodiments, the method relates to reducing the patient's LVEDP by at least 15%. In some embodiments, the method relates to reducing the patient's LVEDP by at least 20%. In some embodiments, the method relates to reducing the patient's LVEDP by at least 25%. In some embodiments, the method relates to reducing the patient's LVEDP by at least 30%. In some embodiments, the method relates to reducing the patient's LVEDP by at least 35%. In some embodiments, the method relates to reducing the patient's LVEDP by at least 40%. In some embodiments, the method relates to reducing the patient's LVEDP by at least 45%. In some embodiments, the method relates to reducing the patient's LVEDP by at least 50%. In some embodiments, the method relates to reducing the patient's LVEDP by at least 55%. In some embodiments, the method relates to reducing the patient's LVEDP by at least 60%. In some embodiments, the method relates to reducing the patient's LVEDP by at least 65%. In some embodiments, the method relates to reducing a patient's LVEDP by at least 70%. In some embodiments, the method relates to reducing a patient's LVEDP by at least 75%. In some embodiments, the method relates to reducing a patient's LVEDP by at least 80%. In some embodiments, the method relates to reducing a patient's LVEDP by at least 85%. In some embodiments, the method relates to reducing a patient's LVEDP by at least 90%. In some embodiments, the method relates to reducing a patient's LVEDP by at least 95%. In some embodiments, the method relates to reducing a patient's LVEDP by at least 100%. DPG

[0180] In certain embodiments, the Disclosure relates to a method for treating, preventing, or reducing the rate and / or severity of progression of PcPH (e.g., treating, preventing, or reducing the rate and / or severity of progression of one or more complications of PcPH of WHO Group 2 and / or Group 5 PH), comprising administering an effective amount of ActRII polypeptide (e.g., an amino acid sequence that is at least 90% identical to the amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1) to a patient in need thereof, wherein the patient has a resting diastolic pressure gradient (DPG) of at least 5 mmHg (e.g., 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, or 45 mmHg). In some embodiments, the method relates to a patient having a DPG of at least 5 mmHg. In some embodiments, the method relates to a patient having a DPG of at least 6 mmHg. In some embodiments, the method relates to a patient having a DPG of at least 7 mmHg. In some embodiments, the method relates to a patient having at least 8 mmHg of DPG. In some embodiments, the method relates to a patient having at least 9 mmHg of DPG. In some embodiments, the method relates to a patient having at least 10 mmHg of DPG. In some embodiments, the method relates to a patient having at least 15 mmHg of DPG. In some embodiments, the method relates to a patient having at least 20 mmHg of DPG. In some embodiments, the method relates to a patient having at least 25 mmHg of DPG. In some embodiments, the method relates to a patient having at least 30 mmHg of DPG. In some embodiments, the method relates to a patient having at least 35 mmHg of DPG. In some embodiments, the method relates to a patient having at least 40 mmHg of DPG. In some embodiments, the method relates to a patient having at least 45 mmHg of DPG.

[0181] In some embodiments, the present disclosure relates to a method for adjusting one or more hemodynamic parameters in a PcPH patient to a more normal level (e.g., normal compared to a healthy person of similar age and sex), comprising administering an effective amount of ActRII polypeptide (e.g., an amino acid sequence that is at least 90% identical to the amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1) to the patient in need. In some embodiments, the method relates to reducing the patient's DPG by at least 1 mmHg. In some embodiments, the method relates to reducing the patient's DPG by at least 2 mmHg. In some embodiments, the method relates to reducing the patient's DPG by at least 4 mmHg. In some embodiments, the method relates to reducing the patient's DPG by at least 6 mmHg. In some embodiments, the method relates to reducing the patient's DPG by at least 10 mmHg. In some embodiments, the method relates to reducing the patient's DPG by at least 15 mmHg. In some embodiments, the method relates to reducing the patient's DPG by at least 20 mmHg. In some embodiments, the method relates to reducing the patient's DPG by at least 25 mmHg. In some embodiments, the method relates to reducing the patient's DPG by at least 30 mmHg.

[0182] In some embodiments, the present disclosure relates to a method for adjusting one or more hemodynamic parameters in a PcPH patient toward a more normal level (e.g., normal compared to a healthy person of similar age and sex), comprising administering an effective amount of ActRII polypeptide (e.g., an amino acid sequence that is at least 90% identical to the amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1) to the patient in need. In some embodiments, the method relates to reducing the patient's DPG by at least 1% (e.g., 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100%). In some embodiments, the method relates to reducing the patient's DPG by at least 1%. In some embodiments, the method relates to reducing the patient's DPG by at least 5%. In some embodiments, the method relates to reducing the patient's DPG by at least 10%. In some embodiments, the method relates to reducing the patient's DPG by at least 15%. In some embodiments, the method relates to reducing the patient's DPG by at least 20%. In some embodiments, the method relates to reducing the patient's DPG by at least 25%. In some embodiments, the method relates to reducing the patient's DPG by at least 30%. In some embodiments, the method relates to reducing the patient's DPG by at least 35%. In some embodiments, the method relates to reducing the patient's DPG by at least 40%. In some embodiments, the method relates to reducing the patient's DPG by at least 45%. In some embodiments, the method relates to reducing the patient's DPG by at least 50%. In some embodiments, the method relates to reducing the patient's DPG by at least 55%. In some embodiments, the method relates to reducing the patient's DPG by at least 60%. In some embodiments, the method relates to reducing the patient's DPG by at least 65%. In some embodiments, the method relates to reducing the patient's DPG by at least 70%. In some embodiments, the method relates to reducing the patient's DPG by at least 75%. In some embodiments, the method relates to reducing the patient's DPG by at least 80%.In some embodiments, the method relates to reducing the patient's DPG by at least 85%. In some embodiments, the method relates to reducing the patient's DPG by at least 90%. In some embodiments, the method relates to reducing the patient's DPG by at least 95%. In some embodiments, the method relates to reducing the patient's DPG by at least 100%. TPG

[0183] In certain embodiments, the Disclosure relates to a method for treating, preventing, or reducing the rate and / or severity of progression of PcPH (e.g., treating, preventing, or reducing the rate and / or severity of progression of one or more complications of PcPH of WHO Group 2 and / or Group 5 PH), comprising administering an effective amount of ActRII polypeptide (e.g., an amino acid sequence that is at least 90% identical to the amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1) to a patient in need thereof, wherein the patient has a transpulmonary pressure gradient (TPG) of at least 10 mmHg (e.g., 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, or 50 mmHg). In some embodiments, the method relates to a patient having a TPG of at least 10 mmHg. In some embodiments, the method relates to a patient having a TPG of at least 11 mmHg. In some embodiments, the method relates to a patient having a TPG of at least 12 mmHg. In some embodiments, the method relates to a patient having a TPG of at least 13 mmHg. In some embodiments, the method relates to a patient having a TPG of at least 14 mmHg. In some embodiments, the method relates to a patient having a TPG of at least 15 mmHg. In some embodiments, the method relates to a patient having a TPG of at least 20 mmHg. In some embodiments, the method relates to a patient having a TPG of at least 25 mmHg. In some embodiments, the method relates to a patient having a TPG of at least 30 mmHg. In some embodiments, the method relates to a patient having a TPG of at least 35 mmHg. In some embodiments, the method relates to a patient having a TPG of at least 40 mmHg. In some embodiments, the method relates to a patient having a TPG of at least 45 mmHg. In some embodiments, the method relates to a patient having a TPG of at least 50 mmHg.

[0184] In some embodiments, the present disclosure relates to a method for adjusting one or more hemodynamic parameters in a PcPH patient toward a more normal level (e.g., normal compared to a healthy person of similar age and sex), comprising administering an effective amount of ActRII polypeptide (e.g., an amino acid sequence that is at least 90% identical to the amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1) to the patient in need. In some embodiments, the method relates to reducing the patient's TPG by at least 1 mmHg. In some embodiments, the method relates to reducing the patient's TPG by at least 2 mmHg. In some embodiments, the method relates to reducing the patient's TPG by at least 4 mmHg. In some embodiments, the method relates to reducing the patient's TPG by at least 6 mmHg. In some embodiments, the method relates to reducing the patient's TPG by at least 10 mmHg. In some embodiments, the method relates to reducing the patient's TPG by at least 15 mmHg. In some embodiments, the method relates to reducing the patient's TPG by at least 20 mmHg. In some embodiments, the method relates to reducing the patient's TPG by at least 25 mmHg. In some embodiments, the method relates to reducing the patient's TPG by at least 30 mmHg. In some embodiments, the method relates to reducing the patient's TPG by at least 40 mmHg.

[0185] In some embodiments, the present disclosure is a method for adjusting one or more hemodynamic parameters in a PcPH patient to a more normal level (e.g., normal compared to a healthy person of similar age and sex), comprising administering an effective amount of ActRII polypeptide (e.g., an amino acid sequence that is at least 90% identical to the amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1) to the patient in need. The present invention relates to a method, which includes giving a patient a TPG. In some embodiments, the method relates to reducing a patient's TPG by at least 1% (e.g., 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100%). In some embodiments, the method relates to reducing a patient's TPG by at least 1%. In some embodiments, the method relates to reducing a patient's TPG by at least 5%. In some embodiments, the method relates to reducing a patient's TPG by at least 10%. In some embodiments, the method relates to reducing a patient's TPG by at least 15%. In some embodiments, the method relates to reducing a patient's TPG by at least 20%. In some embodiments, the method relates to reducing a patient's TPG by at least 25%. In some embodiments, the method relates to reducing a patient's TPG by at least 30%. In some embodiments, the method relates to reducing a patient's TPG by at least 35%. In some embodiments, the method relates to reducing a patient's TPG by at least 40%. In some embodiments, the method relates to reducing the patient's TPG by at least 45%. In some embodiments, the method relates to reducing the patient's TPG by at least 50%. In some embodiments, the method relates to reducing the patient's TPG by at least 55%. In some embodiments, the method relates to reducing the patient's TPG by at least 60%. In some embodiments, the method relates to reducing the patient's TPG by at least 65%. In some embodiments, the method relates to reducing the patient's TPG by at least 70%. In some embodiments, the method relates to reducing the patient's TPG by at least 75%. In some embodiments, the method relates to reducing the patient's TPG by at least 80%. In some embodiments, the method relates to reducing the patient's TPG by at least 85%. In some embodiments, the method relates to reducing the patient's TPG by at least 90%. In some embodiments, the method relates to reducing the patient's TPG by at least 95%. In some embodiments, the method relates to reducing the patient's TPG by at least 100%. BNP

[0186] Both BNP and NT-proBNP are markers of atrial and ventricular distension resulting from increased intracardiac pressure. The New York Heart Association (NYHA) has developed a four-stage functional classification system for congestive heart failure (CHF) based on the severity of symptoms. Studies have demonstrated that measured concentrations of circulating BNP and NT-proBNP increase with the severity of CHF based on the NYHA classification. In certain aspects, the Disclosure relates to a method for treating, preventing, or reducing the rate and / or severity of progression of PcPH (e.g., treating, preventing, or reducing the rate and / or severity of progression of one or more complications of PcPH of WHO Group 2 and / or Group 5 PH), comprising administering an effective amount of ActRII polypeptide (e.g., an amino acid sequence that is at least 90% identical to the amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1) to a patient in need thereof, wherein the patient has a brain natriuretic peptide (BNP) level of at least 100 pg / mL (e.g., 100, 150, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 3000, 5000, 10,000, 15,000, or 20,000 pg / mL). In some embodiments, the method relates to a patient having a BNP level of at least 100 pg / mL. In some embodiments, the method relates to a patient having a BNP level of at least 150 pg / mL. In some embodiments, the method relates to a patient having a BNP level of at least 200 pg / mL. In some embodiments, the method relates to a patient having a BNP level of at least 300 pg / mL. In some embodiments, the method relates to a patient having a BNP level of at least 400 pg / mL. In some embodiments, the method relates to a patient having a BNP level of at least 500 pg / mL. In some embodiments, the method relates to a patient having a BNP level of at least 600 pg / mL. In some embodiments, the method relates to a patient having a BNP level of at least 700 pg / mL. In some embodiments, the method relates to a patient having a BNP level of at least 800 pg / mL.In some embodiments, the method relates to a patient having a BNP level of at least 900 pg / mL. In some embodiments, the method relates to a patient having a BNP level of at least 1000 pg / mL. In some embodiments, the method relates to a patient having a BNP level of at least 5000 pg / mL. In some embodiments, the method relates to a patient having a BNP level of at least 10,000 pg / mL. In some embodiments, the method relates to a patient having a BNP level of at least 15,000 pg / mL. In some embodiments, the method relates to a patient having a BNP level of at least 20,000 pg / mL. In some embodiments, the method relates to the treatment of a patient having elevated BNP levels compared to a healthy patient.

[0187] In some embodiments, the present disclosure is a method of adjusting one or more hemodynamic parameters in a patient with PcPH towards more normal levels (e.g., normal as compared to healthy individuals of similar age and gender), the method comprising administering to a patient in need thereof an effective amount of an ActRII polypeptide (e.g., an amino acid sequence that is at least 90% identical to the amino acid sequence corresponding to residues 30 - 110 of SEQ ID NO: 1). In some embodiments, the method relates to reducing the BNP level in the patient by at least 10 pg / mL. In some embodiments, the method relates to reducing the BNP level in the patient by at least 50 pg / mL. In some embodiments, the method relates to reducing the BNP level in the patient by at least 100 pg / mL. In some embodiments, the method relates to reducing the BNP level in the patient by at least 200 pg / mL. In some embodiments, the method relates to reducing the BNP level in the patient by at least 300 pg / mL. In some embodiments, the method relates to reducing the BNP level in the patient by at least 400 pg / mL. In some embodiments, the method relates to reducing the BNP level in the patient by at least 500 pg / mL. In some embodiments, the method relates to reducing the BNP level in the patient by at least 600 pg / mL. In some embodiments, the method relates to reducing the BNP level in the patient by at least 700 pg / mL. In some embodiments, the method relates to reducing the BNP level in the patient by at least 800 pg / mL. In some embodiments, the method relates to reducing the BNP level in the patient by at least 900 pg / mL. In some embodiments, the method relates to reducing the BNP level in the patient by at least 1000 pg / mL. In some embodiments, the method relates to reducing the BNP level in the patient by at least 5000 pg / mL. In some embodiments, the method relates to reducing the BNP level in the patient to a normal level. In some embodiments, the normal level corresponds to a level of <100 pg / mL.

[0188] In some embodiments, the method relates to reducing a patient's BNP by at least 5% (e.g., 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100%). In some embodiments, the method relates to reducing a patient's BNP by at least 5%. In some embodiments, the method relates to reducing a patient's BNP by at least 10%. In some embodiments, the method relates to reducing a patient's BNP by at least 15%. In some embodiments, the method relates to reducing a patient's BNP by at least 20%. In some embodiments, the method relates to reducing a patient's BNP by at least 25%. In some embodiments, the method relates to reducing a patient's BNP by at least 30%. In some embodiments, the method relates to reducing a patient's BNP by at least 35%. In some embodiments, the method relates to reducing a patient's BNP by at least 40%. In some embodiments, the method relates to reducing a patient's BNP by at least 45%. In some embodiments, the method relates to reducing a patient's BNP by at least 50%. In some embodiments, the method relates to reducing a patient's BNP by at least 55%. In some embodiments, the method relates to reducing a patient's BNP by at least 60%. In some embodiments, the method relates to reducing a patient's BNP by at least 65%. In some embodiments, the method relates to reducing a patient's BNP by at least 70%. In some embodiments, the method relates to reducing a patient's BNP by at least 75%. In some embodiments, the method relates to reducing a patient's BNP by at least 80%. In some embodiments, the method relates to reducing a patient's BNP by at least 85%. In some embodiments, the method relates to reducing a patient's BNP by at least 90%. In some embodiments, the method relates to reducing a patient's BNP by at least 95%. In some embodiments, the method relates to reducing a patient's BNP by at least 100%. NT-proBNP

[0189] In certain aspects, the Disclosure relates to a method for treating, preventing, or reducing the rate and / or severity of progression of PcPH (e.g., treating, preventing, or reducing the rate and / or severity of progression of one or more complications of PcPH of WHO Group 2 and / or Group 5 PH), comprising administering an effective amount of ActRII polypeptide (e.g., an amino acid sequence that is at least 90% identical to the amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1) to a patient in need thereof, wherein the patient has an NT-proBNP level of at least 100 pg / mL (e.g., 100, 150, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 3000, 5000, 10,000, 15,000, 20,000, 25,000, or 30,000 pg / mL). In some embodiments, the method relates to a patient having an NT-proBNP level of at least 100 pg / mL. In some embodiments, the method relates to a patient having an NT-proBNP level of at least 150 pg / mL. In some embodiments, the method relates to a patient having an NT-proBNP level of at least 200 pg / mL. In some embodiments, the method relates to a patient having an NT-proBNP level of at least 300 pg / mL. In some embodiments, the method relates to a patient having an NT-proBNP level of at least 400 pg / mL. In some embodiments, the method relates to a patient having an NT-proBNP level of at least 500 pg / mL. In some embodiments, the method relates to a patient having an NT-proBNP level of at least 600 pg / mL. In some embodiments, the method relates to a patient having an NT-proBNP level of at least 700 pg / mL. In some embodiments, the method relates to a patient having an NT-proBNP level of at least 800 pg / mL. In some embodiments, the method relates to a patient having an NT-proBNP level of at least 900 pg / mL. In some embodiments, the method relates to patients having an NT-proBNP level of at least 1000 pg / mL. In some embodiments, the method relates to patients having an NT-proBNP level of at least 5000 pg / mL.In some embodiments, the method relates to a patient having an NT-proBNP level of at least 10,000 pg / mL. In some embodiments, the method relates to a patient having an NT-proBNP level of at least 15,000 pg / mL. In some embodiments, the method relates to a patient having an NT-proBNP level of at least 20,000 pg / mL. In some embodiments, the method relates to a patient having an NT-proBNP level of at least 25,000 pg / mL. In some embodiments, the method relates to a patient having an NT-proBNP level of at least 30,000 pg / mL. In some embodiments, the method relates to the treatment of a patient having elevated NT-proBNP levels compared to a healthy patient.

[0190] In some embodiments, the present disclosure relates to a method for adjusting one or more hemodynamic parameters in a PcPH patient toward a more normal level (e.g., normal compared to a healthy person of similar age and sex), comprising administering an effective amount of ActRII polypeptide (e.g., an amino acid sequence that is at least 90% identical to the amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1) to the patient in need. In some embodiments, the method relates to reducing the patient's NT-proBNP level. In some embodiments, the method relates to reducing the patient's NT-proBNP level by at least 10 pg / mL. In some embodiments, the method relates to reducing the patient's NT-proBNP level by at least 50 pg / mL. In some embodiments, the method relates to reducing the patient's NT-proBNP level by at least 100 pg / mL. In some embodiments, the method relates to reducing the patient's NT-proBNP level by at least 200 pg / mL. In some embodiments, the method relates to reducing the patient's NT-proBNP level by at least 300 pg / mL. In some embodiments, the method relates to reducing the patient's NT-proBNP level by at least 400 pg / mL. In some embodiments, the method relates to reducing the patient's NT-proBNP level by at least 500 pg / mL. In some embodiments, the method relates to reducing the patient's NT-proBNP level by at least 600 pg / mL. In some embodiments, the method relates to reducing the patient's NT-proBNP level by at least 700 pg / mL. In some embodiments, the method relates to reducing the patient's NT-proBNP level by at least 800 pg / mL. In some embodiments, the method relates to reducing the patient's NT-proBNP level by at least 900 pg / mL. In some embodiments, the method relates to reducing the patient's NT-proBNP level by at least 1000 pg / mL. In some embodiments, the method relates to reducing the patient's NT-proBNP level by at least 5000 pg / mL.In some embodiments, the method relates to reducing the patient's NT-proBNP level by at least 10,000 pg / mL. In some embodiments, the method relates to reducing the patient's NT-proBNP level by at least 15,000 pg / mL. In some embodiments, the method relates to reducing the patient's NT-proBNP level by at least 20,000 pg / mL. In some embodiments, the method relates to reducing the patient's NT-proBNP level by at least 25,000 pg / mL.

[0191] In some embodiments, the method relates to reducing a patient's NT-proBNP levels to normal levels and maintaining their normal NT-proBNP levels. In some embodiments, the disclosure relates to a method for maintaining one or more hemodynamic parameters in a PcPH patient at normal levels (e.g., normal compared to a healthy person of similar age and sex), comprising administering an effective amount of ActRII polypeptide (e.g., an amino acid sequence that is at least 90% identical to the amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1) to the patient in need. In some embodiments, the method relates to maintaining a patient's NT-proBNP levels at normal levels. In some embodiments, the method relates to maintaining a patient's NT-proBNP levels below 100 pg / mL. In some embodiments, the method relates to maintaining a patient's NT-proBNP levels below 200 pg / mL. In some embodiments, the method relates to maintaining a patient's NT-proBNP levels below 300 pg / mL. In some embodiments, the method relates to maintaining a patient's NT-proBNP levels below 400 pg / mL.

[0192] In some embodiments, the method relates to reducing a patient's NT-proBNP by at least 5% (e.g., 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100%). In some embodiments, the method relates to reducing a patient's NT-proBNP by at least 5%. In some embodiments, the method relates to reducing a patient's NT-proBNP by at least 10%. In some embodiments, the method relates to reducing a patient's NT-proBNP by at least 15%. In some embodiments, the method relates to reducing a patient's NT-proBNP by at least 20%. In some embodiments, the method relates to reducing a patient's NT-proBNP by at least 25%. In some embodiments, the method relates to reducing a patient's NT-proBNP by at least 30%. In some embodiments, the method relates to reducing a patient's NT-proBNP by at least 35%. In some embodiments, the method relates to reducing a patient's NT-proBNP by at least 40%. In some embodiments, the method relates to reducing the patient's NT-proBNP by at least 45%. In some embodiments, the method relates to reducing the patient's NT-proBNP by at least 50%. In some embodiments, the method relates to reducing the patient's NT-proBNP by at least 55%. In some embodiments, the method relates to reducing the patient's NT-proBNP by at least 60%. In some embodiments, the method relates to reducing the patient's NT-proBNP by at least 65%. In some embodiments, the method relates to reducing the patient's NT-proBNP by at least 70%. In some embodiments, the method relates to reducing the patient's NT-proBNP by at least 75%. In some embodiments, the method relates to reducing the patient's NT-proBNP by at least 80%. In some embodiments, the method relates to reducing the patient's NT-proBNP by at least 85%. In some embodiments, the method relates to reducing the patient's NT-proBNP by at least 90%.In some embodiments, the method relates to reducing the patient's NT-proBNP by at least 95%. In some embodiments, the method relates to reducing the patient's NT-proBNP by at least 100%. In some embodiments, the method relates to reducing the patient's NT-proBNP level to a normal level. In some embodiments, a normal level of NT-proBNP is <100 pg / ml. In some embodiments, the method relates to reducing the patient's NT-proBNP level to less than 300 ng / L. smooth muscle hypertrophy

[0193] In certain embodiments, the Disclosure relates to a method for treating, preventing, or reducing the rate and / or severity of progression of PcPH (e.g., treating, preventing, or reducing the rate and / or severity of progression of PcPH of WHO Group 2 and / or Group 5 PH), comprising administering an effective amount of ActRII polypeptide (e.g., an amino acid sequence that is at least 90% identical to the amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1) to a patient in need, wherein the patient has smooth muscle hypertrophy. In some embodiments, the Disclosure relates to a method for adjusting one or more parameters in a PcPH patient toward a more normal level (e.g., normal compared to a healthy person of similar age and sex), comprising administering an effective amount of ActRII polypeptide (e.g., an amino acid sequence that is at least 90% identical to the amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1) to a patient in need. In some embodiments, the method relates to reducing smooth muscle hypertrophy in a patient. In some embodiments, the method relates to reducing the patient's smooth muscle hypertrophy by at least 1% (e.g., 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 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 relates to reducing the patient's smooth muscle hypertrophy by at least 5%. In some embodiments, the method relates to reducing the patient's smooth muscle hypertrophy by at least 10%. In some embodiments, the method relates to reducing the patient's smooth muscle hypertrophy by at least 15%. In some embodiments, the method relates to reducing the patient's smooth muscle hypertrophy by at least 20%. In some embodiments, the method relates to reducing the patient's smooth muscle hypertrophy by at least 25%. In some embodiments, the method relates to reducing the patient's smooth muscle hypertrophy by at least 30%. In some embodiments, the method relates to reducing the patient's smooth muscle hypertrophy by at least 35%. In some embodiments, the method relates to reducing smooth muscle hypertrophy in a patient by at least 40%.In some embodiments, the method relates to reducing the patient's smooth muscle hypertrophy by at least 45%. In some embodiments, the method relates to reducing the patient's smooth muscle hypertrophy by at least 50%. In some embodiments, the method relates to reducing the patient's smooth muscle hypertrophy by at least 55%. In some embodiments, the method relates to reducing the patient's smooth muscle hypertrophy by at least 60%. In some embodiments, the method relates to reducing the 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 relates to reducing the patient's smooth muscle hypertrophy by at least 75%. In some embodiments, the method relates to reducing the patient's smooth muscle hypertrophy by at least 80%. In some embodiments, the method relates to reducing the patient's smooth muscle hypertrophy by at least 85%. In some embodiments, the method relates to reducing the patient's smooth muscle hypertrophy by at least 90%. In some embodiments, the method relates to reducing the patient's smooth muscle hypertrophy by at least 95%. In some embodiments, the method relates to reducing the patient's smooth muscle hypertrophy by at least 100%. Muscular pulmonary arterioles

[0194] In certain embodiments, the Disclosure relates to a method for treating, preventing, or reducing the rate and / or severity of progression of PcPH (e.g., treating, preventing, or reducing the rate and / or severity of progression of PcPH of WHO Group 2 and / or Group 5 PH), comprising administering an effective amount of ActRII polypeptide (e.g., an amino acid sequence that is at least 90% identical to the amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1) to a patient in need, wherein the patient has increased pulmonary arteriole muscularity. In some embodiments, the Disclosure relates to a method for adjusting one or more parameters in a PcPH patient toward a more normal level (e.g., normal compared to a healthy person of similar age and sex), comprising administering an effective amount of ActRII polypeptide (e.g., an amino acid sequence that is at least 90% identical to the amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1) to a patient in need. In some embodiments, the method relates to reducing pulmonary arteriole muscularity in a patient. In some embodiments, the method relates to reducing the muscularity of the patient's pulmonary arterioles by at least 1% (e.g., 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100%). In some embodiments, the method relates to reducing the muscularity of the patient's pulmonary arterioles by at least 1%. In some embodiments, the method relates to reducing the muscularity of the patient's pulmonary arterioles by at least 5%. In some embodiments, the method relates to reducing the muscularity of the patient's pulmonary arterioles by at least 10%. In some embodiments, the method relates to reducing the muscularity of the patient's pulmonary arterioles by at least 15%. In some embodiments, the method relates to reducing the muscularity of the patient's pulmonary arterioles by at least 20%. In some embodiments, the method relates to reducing the muscularity of the patient's pulmonary arterioles by at least 25%. In some embodiments, the method relates to reducing the muscularity of the patient's pulmonary arterioles by at least 30%. In some embodiments, the method relates to reducing the muscularity of the patient's pulmonary arterioles by at least 35%.In some embodiments, the method relates to reducing the muscularity of the patient's pulmonary arterioles by at least 40%. In some embodiments, the method relates to reducing the muscularity of the patient's pulmonary arterioles by at least 45%. In some embodiments, the method relates to reducing the muscularity of the patient's pulmonary arterioles by at least 50%. In some embodiments, the method relates to reducing the muscularity of the patient's pulmonary arterioles by at least 55%. In some embodiments, the method relates to reducing the muscularity of the patient's pulmonary arterioles by at least 60%. In some embodiments, the method relates to reducing the muscularity of the patient's pulmonary arterioles by at least 65%. In some embodiments, the method relates to reducing the muscularity of the patient's pulmonary arterioles by at least 70%. In some embodiments, the method relates to reducing the muscularity of the patient's pulmonary arterioles by at least 75%. In some embodiments, the method relates to reducing the muscularity of the patient's pulmonary arterioles by at least 80%. In some embodiments, the method relates to reducing the muscularity of the patient's pulmonary arterioles by at least 85%. In some embodiments, the method relates to reducing the muscularity of the patient's pulmonary arterioles by at least 90%. In some embodiments, the method relates to reducing the muscularity of the patient's pulmonary arterioles by at least 95%. In some embodiments, the method relates to reducing the muscularity of the patient's pulmonary arterioles by at least 100%. Percentage of hospitalizations

[0195] In certain embodiments, the Disclosure relates to a method for treating, preventing, or reducing the rate and / or severity of progression of PcPH (e.g., treating, preventing, or reducing the rate and / or severity of progression of one or more complications of PcPH of WHO Group 2 and / or Group 5 PH), comprising administering an effective amount of ActRII polypeptide (e.g., an amino acid sequence that is at least 90% identical to the amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1) to a patient in need thereof, wherein the method reduces the patient hospitalization rate by at least 1% (e.g., 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%). In some embodiments, the method relates to reducing the patient hospitalization rate by at least 1%. In some embodiments, the method relates to reducing the patient hospitalization rate by at least 2%. In some embodiments, the method relates to reducing the patient hospitalization rate by at least 3%. In some embodiments, the method relates to reducing the patient hospitalization rate by at least 4%. In some embodiments, the method relates to reducing the patient hospitalization rate by at least 5%. In some embodiments, the method relates to reducing the patient hospitalization rate by at least 10%. In some embodiments, the method relates to reducing the patient hospitalization rate by at least 15%. In some embodiments, the method relates to reducing the patient hospitalization rate by at least 20%. In some embodiments, the method relates to reducing the patient hospitalization rate by at least 25%. In some embodiments, the method relates to reducing the patient hospitalization rate by at least 30%. In some embodiments, the method relates to reducing the patient hospitalization rate by at least 35%. In some embodiments, the method relates to reducing the patient hospitalization rate by at least 40%. In some embodiments, the method relates to reducing the patient hospitalization rate by at least 45%. In some embodiments, the method relates to reducing the patient hospitalization rate by at least 50%. In some embodiments, the method relates to reducing the patient hospitalization rate by at least 55%.In some embodiments, the method relates to reducing the patient hospitalization rate by at least 60%. In some embodiments, the method relates to reducing the patient hospitalization rate by at least 65%. In some embodiments, the method relates to reducing the patient hospitalization rate by at least 70%. In some embodiments, the method relates to reducing the patient hospitalization rate by at least 75%. In some embodiments, the method relates to reducing the patient hospitalization rate 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 relates to reducing the patient hospitalization rate by at least 90%. In some embodiments, the method relates to reducing the patient hospitalization rate by at least 95%. In some embodiments, the method relates to reducing the patient hospitalization rate by at least 100%. In some embodiments, the method reduces the risk of hospitalization for one or more complications associated with PCPH. Quality of Life

[0196] In certain embodiments, the Disclosure relates to a method for treating, preventing, or reducing the rate and / or severity of progression of PcPH (e.g., treating, preventing, or reducing the rate and / or severity of progression of one or more complications of PcPH of WHO Group 2 and / or Group 5 PH), comprising administering an effective amount of ActRII polypeptide (e.g., an amino acid sequence that is at least 90% identical to the amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1) to a patient in need thereof, wherein the method increases the patient's quality of life by at least 1% (e.g., 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%). In some embodiments, the method relates to increasing the patient's quality of life by at least 1%. In some embodiments, the method relates to increasing the patient's quality of life by at least 2%. In some embodiments, the method relates to increasing the patient's quality of life by at least 3%. In some embodiments, the method relates to increasing the patient's quality of life by at least 4%. In some embodiments, the method relates to increasing the patient's quality of life by at least 5%. In some embodiments, the method relates to increasing the patient's quality of life by at least 10%. In some embodiments, the method relates to increasing the patient's quality of life by at least 15%. In some embodiments, the method relates to increasing the patient's quality of life by at least 20%. In some embodiments, the method relates to increasing the patient's quality of life by at least 25%. In some embodiments, the method relates to increasing the patient's quality of life by at least 30%. In some embodiments, the method relates to increasing the patient's quality of life by at least 35%. In some embodiments, the method relates to increasing the patient's quality of life by at least 40%. In some embodiments, the method relates to increasing the patient's quality of life by at least 45%.In some embodiments, the method relates to increasing the patient's quality of life by at least 50%. In some embodiments, the method relates to increasing the patient's quality of life by at least 55%. In some embodiments, the method relates to increasing the patient's quality of life by at least 60%. In some embodiments, the method relates to increasing the patient's quality of life by at least 65%. In some embodiments, the method relates to increasing the patient's quality of life by at least 70%. In some embodiments, the method relates to increasing the patient's quality of life by at least 75%. In some embodiments, the method relates to increasing the patient's quality of life by at least 80%. In some embodiments, the method relates to increasing the patient's quality of life by at least 85%. In some embodiments, the method relates to increasing the patient's quality of life by at least 90%. In some embodiments, the method relates to increasing the patient's quality of life by at least 95%. In some embodiments, the method relates to increasing the patient's quality of life by at least 100%.

[0197] In some embodiments, the patient's quality of life is measured using the Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR). In some embodiments, the patient's quality of life is measured using PAH-SYMPACT®. In some embodiments, the patient's quality of life is measured using the Medical Outcome Survey Short Form 36 (SF-36). In some embodiments, the patient's quality of life is measured using EuroQol. In some embodiments, the patient's quality of life is measured using EuroQol-5 Dimension (EQ-5D). In some embodiments, the patient's quality of life is measured using EuroQol-5 Dimension 5 Level (EQ-5D-5L). In some embodiments, the patient's quality of life is measured using the Kansas City Cardiomyopathy Questionnaire (KCCQ). Extensions

[0198] In certain embodiments, the Disclosure relates to a method for treating, preventing, or reducing the rate and / or severity of progression of PcPH (e.g., treating, preventing, or reducing the rate and / or severity of progression of one or more complications of PcPH of WHO Group 2 and / or Group 5 PH), comprising administering an effective amount of ActRII polypeptide (e.g., an amino acid sequence that is at least 90% identical to the amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1) to a patient in need thereof, wherein the method increases the patient's LV-expanding capacity by at least 5% (e.g., 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100%). In some embodiments, the method relates to increasing the patient's LV-expanding capacity by at least 5%. In some embodiments, the method relates to increasing the patient's LV-expanding capacity by at least 10%. In some embodiments, the method relates to increasing the patient's LV-expanding capacity by at least 15%. In some embodiments, the method relates to increasing the patient's LV expansion capacity by at least 20%. In some embodiments, the method relates to increasing the patient's LV expansion capacity by at least 25%. In some embodiments, the method relates to increasing the patient's LV expansion capacity by at least 30%. In some embodiments, the method relates to increasing the patient's LV expansion capacity by at least 35%. In some embodiments, the method relates to increasing the patient's LV expansion capacity by at least 40%. In some embodiments, the method relates to increasing the patient's LV expansion capacity by at least 45%. In some embodiments, the method relates to increasing the patient's LV expansion capacity by at least 50%. In some embodiments, the method relates to increasing the patient's LV expansion capacity by at least 55%. In some embodiments, the method relates to increasing the patient's LV expansion capacity by at least 60%. In some embodiments, the method relates to increasing the patient's LV expansion capacity by at least 65%. In some embodiments, the method relates to increasing the patient's LV expansion capacity by at least 70%. In some embodiments, the method relates to increasing the patient's LV expansion capacity by at least 75%.In some embodiments, the method relates to increasing the patient's LV expansion capacity by at least 80%. In some embodiments, the method relates to increasing the patient's LV expansion capacity by at least 85%. In some embodiments, the method relates to increasing the patient's LV expansion capacity by at least 90%. In some embodiments, the method relates to increasing the patient's LV expansion capacity by at least 95%. In some embodiments, the method relates to increasing the patient's LV expansion capacity by at least 100%. ejection fraction

[0199] In certain embodiments, the Disclosure relates to a method for treating, preventing, or reducing the rate and / or severity of progression of PcPH (e.g., treating, preventing, or reducing the rate and / or severity of progression of one or more complications of PcPH of WHO Group 2 and / or Group 5 PH), comprising administering an effective amount of ActRII polypeptide (e.g., an amino acid sequence that is at least 90% identical to the amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1) to a patient in need thereof, wherein the patient has an ejection fraction of less than 10% (e.g., 10, 15, 20, 25, 30, 35, 40, or 45%). In some embodiments, the method relates to a patient having an ejection fraction of less than 10%. In some embodiments, the method relates to a patient having an ejection fraction of less than 15%. In some embodiments, the method relates to a patient having an ejection fraction of less than 20%. In some embodiments, the method relates to a patient having an ejection fraction of less than 25%. In some embodiments, the method relates to a patient having an ejection fraction of less than 30%. In some embodiments, the method relates to patients with an ejection fraction of less than 35%. In some embodiments, the method relates to patients with an ejection fraction of less than 40%. In some embodiments, the method relates to patients with an ejection fraction of less than 45%. In some embodiments, the method relates to patients with an ejection fraction of less than 50%. In some embodiments, the method relates to patients with an ejection fraction of less than 55%.

[0200] In certain embodiments, the Disclosure relates to a method for treating, preventing, or reducing the rate and / or severity of progression of PcPH (e.g., treating, preventing, or reducing the rate and / or severity of progression of one or more complications of PcPH of WHO Group 2 and / or Group 5 PH), comprising administering an effective amount of ActRII polypeptide (e.g., an amino acid sequence at least 90% identical to the amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1) to a patient in need thereof, wherein the patient has an ejection fraction of at least 35% (e.g., 35, 40, 45, 50, or 55%). In some embodiments, the method relates to a patient having an ejection fraction of at least 35%. In some embodiments, the method relates to a patient having an ejection fraction of at least 40%. In some embodiments, the method relates to a patient having an ejection fraction of at least 45%. In some embodiments, the method relates to a patient having an ejection fraction of at least 50%. In some embodiments, the method relates to a patient having an ejection fraction of at least 55%. In some embodiments, the ejection fraction is the right ventricular ejection fraction. In some embodiments, the ejection fraction is the left ventricular ejection fraction (LVEF). In some embodiments, the ejection fraction is measured using echocardiography. In some embodiments, the patient has a maintained left ventricular ejection fraction.

[0201] In some embodiments, the present disclosure relates to a method for adjusting one or more hemodynamic parameters in a PcPH patient toward a more normal level (e.g., >50% ejection fraction), comprising administering an effective amount of ActRII polypeptide (e.g., an amino acid sequence that is at least 90% identical to the amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1) to the patient in need. In some embodiments, the method relates to increasing the patient's ejection fraction by at least 1%. In some embodiments, the method relates to increasing the patient's ejection fraction by at least 5%. In some embodiments, 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 by at least 15%. In some embodiments, the method relates to increasing the patient's ejection fraction by at least 20%. In some embodiments, the method relates to increasing the patient's ejection fraction by at least 25%. In some embodiments, the method relates to increasing the patient's ejection fraction by at least 30%. In some embodiments, the method relates to increasing the patient's ejection fraction by at least 35%. In some embodiments, the method relates to increasing the patient's ejection fraction by at least 40%. In some embodiments, the method relates to increasing the patient ejection fraction by at least 45%. In some embodiments, the method relates to increasing the patient ejection fraction by at least 50%. In some embodiments, the method relates to increasing the patient ejection fraction by at least 55%. In some embodiments, the method relates to increasing the patient ejection fraction by at least 60%. In some embodiments, the method relates to increasing the patient ejection fraction by at least 65%. In some embodiments, the method relates to increasing the patient ejection fraction by at least 70%. In some embodiments, the method relates to increasing the patient ejection fraction by at least 75%. In some embodiments, the method relates to increasing the patient ejection fraction by at least 80%. In some embodiments, the method relates to increasing the patient ejection fraction by at least 85%. In some embodiments, the method relates to increasing the patient ejection fraction by at least 90%. In some embodiments, the method relates to increasing the patient ejection fraction by at least 95%.In some embodiments, the method relates to increasing the patient's ejection fraction by at least 100%. ventricular function

[0202] In certain embodiments, the disclosure relates to a method for improving or maintaining ventricular function (e.g., left ventricular function or right ventricular function) in PcPH, comprising administering an effective amount of ActRII polypeptide (e.g., an amino acid sequence that is at least 90% identical to the amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1) to a patient in need. Echocardiography is a useful non-invasive screening tool for determining the severity of pulmonary hypertension in a patient. Improvement or maintenance of ventricular function (e.g., left ventricular function or right ventricular function) can be assessed by a number of echocardiographic measurements. One such quantitative approach for assessing ventricular function is the measurement of tricuspid annular systolic displacement (TAPSE). TAPSE estimates the systolic function of the RV by measuring the level of systolic displacement of the lateral tricuspid annulus toward its highest point. Other echocardiographic measurements that may be used to assess the maintenance and / or improvement of ventricular function include, but are not limited to, percentage change in right ventricular area (RVFAC), right ventricular end-diastolic area (RVEDA), right ventricular end-systolic area (RVESA), right ventricular free wall thickness (RVFWT), right ventricular ejection fraction (RVEF), right ventricular-pulmonary (RV-PA) coupling, pulmonary systolic pressure (PASP), right ventricular systolic pressure (RVSP), pulmonary acceleration time (PAAT), tricuspid regurgitation velocity (TRV), left ventricular hypertrophy, and right ventricular hypertrophy. TAP SE

[0203] The tricuspid annular systolic displacement (TAPSE) can be obtained using echocardiography and represents a measure of long-term RV function. TAPSE has previously been shown to correlate well with parameters that estimate overall RV systolic function. A TAPSE of <17 mm suggests high RV systolic dysfunction. In some embodiments, improvement or maintenance of right ventricular function in PcPH patients is measured as an increase in TAPSE. In some embodiments, PcPH patients with improved or maintained right ventricular function have a TAPSE of 20 mm to 28 mm. In some embodiments, PcPH patients with improved or maintained right ventricular function have a TAPSE of at least 20 mm. In some embodiments, PcPH patients with improved or maintained right ventricular function have a TAPSE of at least 22 mm. In some embodiments, PcPH patients with improved or maintained right ventricular function have a TAPSE of at least 24 mm. In some embodiments, PcPH patients with improved or maintained right ventricular function have a TAPSE of at least 26 mm. In some embodiments, PcPH patients with improved or maintained right ventricular function have a TAPSE of at least 28 mm. In some embodiments, TAPSE is measured using echocardiography.

[0204] In some embodiments, PcPH patients with improved or maintained right ventricular function have a TAPSE between 16 mm and 30 mm. In some embodiments, PcPH patients with improved or maintained right ventricular function have a TAPSE between 18 mm and 28 mm. In some embodiments, PcPH patients with improved or maintained right ventricular function have a TAPSE of at least 18 mm. In some embodiments, TAPSE is measured using echocardiography. PASP and RVSP

[0205] In certain embodiments, the present disclosure provides a method of treating, preventing, or reducing the rate of progression and / or severity of PcPH, comprising administering to a patient in need thereof an effective amount of an ActRII polypeptide (e.g., an amino acid sequence that is at least 90% identical to the amino acid sequence corresponding to residues 30 to 110 of SEQ ID NO: 1), wherein the patient has a pulmonary artery systolic pressure (PASP) of at least 30 mmHg (e.g., 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, or 80 mmHg). In some embodiments, the method relates to patients having a PASP of at least 30 mmHg. In some embodiments, the method relates to patients having a PASP of at least 35 mmHg. In some embodiments, the method relates to patients having a PASP of at least 40 mmHg. In some embodiments, the method relates to patients having a PASP of at least 45 mmHg. In some embodiments, the method relates to patients having a PASP of at least 50 mmHg. In some embodiments, the method relates to patients having a PASP of at least 55 mmHg. In some embodiments, the method relates to patients having a PASP of at least 60 mmHg. In some embodiments, the method relates to patients having a PASP of at least 65 mmHg. In some embodiments, the method relates to patients having a PASP of at least 70 mmHg. In some embodiments, the method relates to patients having a PASP of at least 75 mmHg. In some embodiments, the method relates to patients having a PASP of at least 80 mmHg. In some embodiments, the PASP is the resting PASP. In some embodiments, the PASP is determined using the tricuspid regurgitation velocity (TRV) and the right atrial (RA) pressure. In some embodiments, the PASP is determined using the following formula: PASP = TRV 2 × 4 + RA pressure and is determined using the following formula:

[0206] TRV has been shown to correlate with PASP at rest and with exercise. The pressure gradient between the right ventricle and the right atrium can be calculated using the modified Bernoulli equation (Δp = 4V 2 ).

[0207] In some embodiments, right ventricular systolic pressure (RVSP) is equal to PASP. In some embodiments, RVSP is measured in the absence of right ventricular outflow tract obstruction. In some embodiments, RVSP is given by the following formula: RVSP=4V 2 +RAP It is determined using

[0208] In the above formula, V represents the peak tricuspid regurgitation jet velocity, and RAP is the mean right atrial pressure. RVSP is frequently used to estimate PASP.

[0209] In some embodiments, the present disclosure relates to a method for adjusting one or more hemodynamic parameters in a patient with PcPH to a more normal level (e.g., normal compared to a healthy person of similar age and sex), comprising administering an effective amount of ActRII polypeptide (e.g., an amino acid sequence that is at least 90% identical to the amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1) to the patient in need. In some embodiments, the method relates to improving pulmonary artery systolic pressure (PASP) in the patient. In some embodiments, the method relates to reducing PASP. In some embodiments, the method relates to reducing the patient's PASP by at least 1 mmHg (e.g., 1, 2, 3, 5, 7, 10, 12, 15, 20, 25, 30, or 35 mmHg). In some embodiments, the method relates to reducing the patient's PASP by at least 2 mmHg. In some embodiments, the method relates to reducing the patient's PASP by at least 3 mmHg. In certain embodiments, the method relates to reducing the patient's PASP by at least 5 mmHg. In certain embodiments, the method relates to reducing the patient's PASP by at least 7 mmHg. In certain embodiments, the method relates to reducing the patient's PASP by at least 10 mmHg. In certain embodiments, the method relates to reducing the patient's PASP by at least 12 mmHg. In certain embodiments, the method relates to reducing the patient's PASP by at least 15 mmHg. In certain embodiments, the method relates to reducing the patient's PASP by at least 20 mmHg. In certain embodiments, the method relates to reducing the patient's PASP by at least 25 mmHg. In certain embodiments, the method relates to reducing the patient's PASP by at least 30 mmHg. In certain embodiments, the method relates to reducing the patient's PASP by at least 35 mmHg.

[0210] In some embodiments, the present disclosure relates to a method for adjusting one or more hemodynamic parameters in a PcPH patient to a more normal level (e.g., normal compared to a healthy person of similar age and sex), comprising administering an effective amount of ActRII polypeptide (e.g., an amino acid sequence that is at least 90% identical to the amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1) to the patient in need. In some embodiments, the method relates to reducing the patient's PASP by at least 1% (e.g., 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100%). In some embodiments, the method 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%. In some embodiments, the method relates to reducing the patient's PASP by at least 15%. In some embodiments, the method relates to reducing the patient's PASP by at least 20%. In some embodiments, the method relates to reducing the patient's PASP by at least 25%. In some embodiments, 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 relates to reducing the patient's PASP by at least 40%. In some embodiments, the method relates to reducing the patient's PASP by at least 45%. In some embodiments, the method relates to reducing the patient's PASP by at least 50%. In some embodiments, the method relates to reducing the patient's PASP by at least 55%. In some embodiments, the method relates to reducing the patient's PASP by at least 60%. In some embodiments, the method relates to reducing the patient's PASP by at least 65%. In some embodiments, the method relates to reducing the patient's PASP by at least 70%. In some embodiments, the method relates to reducing the patient's PASP by at least 75%.In some embodiments, the method relates to reducing the patient's PASP by at least 80%. In some embodiments, the method relates to reducing the patient's PASP by at least 85%. In some embodiments, the method relates to reducing the patient's PASP by at least 90%. In some embodiments, the method relates to reducing the patient's PASP by at least 95%. In some embodiments, the method relates to reducing the patient's PASP by at least 100%.

[0211] In some embodiments, the present disclosure relates to a method for adjusting one or more hemodynamic parameters in a patient with PcPH to a more normal level (e.g., normal compared to a healthy person of similar age and sex), comprising administering an effective amount of ActRII polypeptide (e.g., an amino acid sequence that is at least 90% identical to the amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1) to the patient in need. In some embodiments, the method relates to improving the right ventricular systolic pressure (RVSP) in the patient. In some embodiments, the method relates to reducing the RVSP. In some embodiments, the method relates to reducing the patient's RVSP by at least 1 mmHg (e.g., 1, 2, 3, 5, 7, 10, 12, 15, 20, 25, 30, or 35 mmHg). In some embodiments, the method relates to reducing the patient's RVSP by at least 2 mmHg. In some embodiments, the method relates to reducing the patient's RVSP by at least 3 mmHg. In certain embodiments, the method relates to reducing the patient's RVSP by at least 5 mmHg. In certain embodiments, the method relates to reducing the patient's RVSP by at least 7 mmHg. In certain embodiments, the method relates to reducing the patient's RVSP by at least 10 mmHg. In certain embodiments, the method relates to reducing the patient's RVSP by at least 12 mmHg. In certain embodiments, the method relates to reducing the patient's RVSP by at least 15 mmHg. In certain embodiments, the method relates to reducing the patient's RVSP by at least 20 mmHg. In certain embodiments, the method relates to reducing the patient's RVSP by at least 25 mmHg. In certain embodiments, the method relates to reducing the patient's RVSP by at least 30 mmHg. In certain embodiments, the method relates to reducing the patient's RVSP by at least 35 mmHg.

[0212] In some embodiments, the present disclosure relates to a method for adjusting one or more hemodynamic parameters in a PcPH patient to a more normal level (e.g., normal compared to a healthy person of similar age and sex), comprising administering an effective amount of ActRII polypeptide (e.g., an amino acid sequence that is at least 90% identical to the amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1) to the patient in need. In some embodiments, the method relates to reducing the patient's RVSP by at least 1% (e.g., 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100%). In some embodiments, the method relates to reducing the patient's RVSP by at least 5%. In some embodiments, the method relates to reducing the patient's RVSP by at least 10%. In some embodiments, the method relates to reducing the patient's RVSP by at least 15%. In some embodiments, the method relates to reducing the patient's RVSP by at least 20%. In some embodiments, the method relates to reducing the patient's RVSP by at least 25%. In some embodiments, the method relates to reducing the patient's RVSP by at least 30%. In some embodiments, the method relates to reducing the patient's RVSP by at least 35%. In some embodiments, the method relates to reducing the patient's RVSP by at least 40%. In some embodiments, the method relates to reducing the patient's RVSP by at least 45%. In some embodiments, the method relates to reducing the patient's RVSP by at least 50%. In some embodiments, the method relates to reducing the patient's RVSP by at least 55%. In some embodiments, the method relates to reducing the patient's RVSP by at least 60%. In some embodiments, the method relates to reducing the patient's RVSP by at least 65%. In some embodiments, the method relates to reducing the patient's RVSP by at least 70%. In some embodiments, the method relates to reducing the patient's RVSP by at least 75%. In some embodiments, the method relates to reducing the patient's RVSP by at least 80%. In some embodiments, the method relates to reducing the patient's RVSP by at least 85%. In some embodiments, the method relates to reducing the patient's RVSP by at least 90%. In some embodiments, the method relates to reducing the patient's RVSP by at least 95%. In some embodiments, the method relates to reducing the patient's RVSP by at least 100%. RV-PA coupling

[0213] Right ventricular dysfunction can occur in PcPH and is a factor affecting prognosis. The energy transfer between ventricular contractility and atrial afterload is called coupling. The specific energy transfer between the right ventricle (RV) and the pulmonary artery is called right ventricular-pulmonary (RV-PA) coupling. In some embodiments, right ventricular dysfunction is attributable to a decrease in RV-PA coupling. RV-PA coupling can be non-invasively estimated as the ratio of TAPSE / PASP values. In some embodiments, a TAPSE / PASP ratio of ≥0.31 mm / mmHg may be associated with a better prognosis and may reduce the risk of clinical deterioration. In some embodiments, improvement in RV-PA coupling is attributable to improvement in PASP. In some embodiments, the calculation of RV-PA coupling depends on the result of a pair of three parameters (e.g., TRV, RAP, and TAPSE).

[0214] In certain embodiments, the Disclosure relates to a method for treating, preventing, or reducing the rate and / or severity of PcPH, comprising administering an effective amount of ActRII polypeptide (e.g., an amino acid sequence at least 90% identical to the amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1) to a patient in need thereof, wherein the patient has a TAPSE / PASP ratio of less than 0.31 mm / mmHg (e.g., 0.3, 0.25, 0.2, 0.15, or 0.1 mm / mmHg). In some embodiments, the method relates to a patient having a TAPSE / PASP ratio of less than 0.31 mm / mmHg. In some embodiments, the method relates to a patient having a TAPSE / PASP ratio of less than 0.3 mm / mmHg. In some embodiments, the method relates to a patient having a TAPSE / PASP ratio of less than 0.3 mm / mmHg. In some embodiments, the method relates to a patient having a TAPSE / PASP ratio of less than 0.25 mm / mmHg. In some embodiments, the method relates to a patient having a TAPSE / PASP ratio of less than 0.2 mm / mmHg. In some embodiments, the method relates to patients having a TAPSE / PASP ratio of less than 0.15 mm / mmHg. In some embodiments, the method relates to patients having a TAPSE / PASP ratio of less than 0.1 mm / mmHg. In some embodiments, the method relates to patients having a reduced TAPSE / PASP ratio compared to a normal TAPSE / PASP ratio.

[0215] In some embodiments, the disclosure relates to a method for adjusting one or more hemodynamic parameters in a patient with PcPH to a more normal level (e.g., normal compared to a healthy person of similar age and sex), comprising administering an effective amount of ActRII polypeptide (e.g., an amino acid sequence that is at least 90% identical to the amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1) to the patient in need. In some embodiments, the method relates to improving or maintaining right ventricular function in the patient. In some embodiments, a PcPH patient with improved or maintained right ventricular function has a TAPSE / PASP ratio greater than 0.3 mm / mmHg (e.g., greater than 0.31, 0.32, 0.33, 0.34, or 0.35 mm / mmHg). In some embodiments, a PcPH patient with improved or maintained right ventricular function has a TAPSE / PASP ratio greater than 0.31 mm / mmHg. In some embodiments, a PcPH patient with improved or maintained right ventricular function has a TAPSE / PASP ratio greater than 0.32 mm / mmHg. In some embodiments, PcPH patients with improved or maintained right ventricular function have a TAPSE / PASP ratio greater than 0.33 mm / mmHg. In some embodiments, PcPH patients with improved or maintained right ventricular function have a TAPSE / PASP ratio greater than 0.34 mm / mmHg. In some embodiments, PcPH patients with improved or maintained right ventricular function have a TAPSE / PASP ratio greater than 0.35 mm / mmHg. In some embodiments, improved right ventricular function is an increase in the TAPSE / PASP ratio. In some embodiments, the method relates to increasing the TAPSE / PASP ratio. In some embodiments, the method relates to increasing the patient's TAPSE / PASP ratio by at least 0.05 mm / mmHg. In some embodiments, the method relates to increasing the patient's TAPSE / PASP ratio by at least 0.07 mm / mmHg. In some embodiments, the method relates to increasing the patient's TAPSE / PASP ratio by at least 0.10 mm / mmHg. In some embodiments, the method relates to increasing the patient's TAPSE / PASP ratio by at least 0.12 mm / mmHg.In some embodiments, the method relates to increasing the patient's TAPSE / PASP ratio by at least 0.15 mm / mmHg. In some embodiments, the method relates to increasing the patient's TAPSE / PASP ratio by at least 0.18 mm / mmHg. In some embodiments, the method relates to increasing the patient's TAPSE / PASP ratio by at least 0.20 mm / mmHg.

[0216] In some embodiments, the present disclosure relates to a method for adjusting one or more hemodynamic parameters in a PcPH patient toward a more normal level (e.g., normal compared to a healthy person of similar age and sex), comprising administering an effective amount of ActRII polypeptide (e.g., an amino acid sequence that is at least 90% identical to the amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1) to the patient in need. In some embodiments, the method relates to increasing the patient's TAPSE / PASP ratio by at least 1% (e.g., 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100%). In some embodiments, the method relates to increasing the patient's TAPSE / PASP ratio by at least 5%. In some embodiments, the method relates to increasing the patient's TAPSE / PASP ratio by at least 10%. In some embodiments, the method relates to increasing the patient's TAPSE / PASP ratio by at least 15%. In some embodiments, the method relates to increasing the patient's TAPSE / PASP ratio by at least 20%. In some embodiments, the method relates to increasing the patient's TAPSE / PASP ratio by at least 25%. In some embodiments, the method relates to increasing the patient's TAPSE / PASP ratio by at least 30%. In some embodiments, the method relates to increasing the patient's TAPSE / PASP ratio by at least 35%. In some embodiments, the method relates to increasing the patient's TAPSE / PASP ratio by at least 40%. In some embodiments, the method relates to increasing the patient's TAPSE / PASP ratio by at least 45%. In some embodiments, the method relates to increasing the patient's TAPSE / PASP ratio by at least 50%. In some embodiments, the method relates to increasing the patient's TAPSE / PASP ratio by at least 55%. In some embodiments, the method relates to increasing the patient's TAPSE / PASP ratio by at least 60%. In some embodiments, the method relates to increasing the patient's 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 relates to increasing the patient's TAPSE / PASP ratio by at least 75%. In some embodiments, the method relates to increasing the patient's TAPSE / PASP ratio by at least 80%. In some embodiments, the method relates to increasing the patient's TAPSE / PASP ratio by at least 85%. In some embodiments, the method relates to increasing the patient's TAPSE / PASP ratio by at least 90%. In some embodiments, the method relates to increasing the patient's TAPSE / PASP ratio by at least 100%. RVFAC, RVEDA, and RVESA

[0217] The percentage change in right ventricular area (RVFAC) is a non-invasive quantitative measure of right ventricular function. RVFAC can be calculated using the formula [(RVEDA-RVESA) / RVEDA]×100. In some embodiments, RVFAC is measured using echocardiography. In some embodiments, a normal RVFAC is approximately 47.5±8.6% in men and approximately 50.9±8.0% in women. See, for example, Kou S, et al. European Heart Journal - Cardiovascular Imaging. 2014 Jun 1;15(6):680-90. In some embodiments, patients with PcPH have a reduced RVFAC.

[0218] In certain embodiments, the Disclosure relates to a method for treating, preventing, or reducing the rate and / or severity of progression of PcPH (e.g., treating, preventing, or reducing the rate and / or severity of progression of one or more complications of PcPH of WHO Group 2 and / or Group 5 PH), comprising administering an effective amount of ActRII polypeptide (e.g., an amino acid sequence that is at least 90% identical to the amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1) to a patient in need thereof, wherein the patient has less than 20% (e.g., 20, 25, 30, 35, or 40%) of RVFAC. In some embodiments, the method relates to a patient with less than 25% RVFAC. In some embodiments, the method relates to a patient with less than 30% RVFAC. In some embodiments, the method relates to a patient with less than 35% RVFAC. In some embodiments, the method relates to a patient with less than 40% RVFAC.

[0219] In some embodiments, the disclosure relates to a method for adjusting one or more hemodynamic parameters in a patient with PcPH to a more normal level (e.g., normal compared to a healthy person of similar age and sex), comprising administering an effective amount of ActRII polypeptide (e.g., an amino acid sequence that is at least 90% identical to the amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1) to the patient in need. In some embodiments, the method relates to improving or maintaining right ventricular function in the patient. In some embodiments, the improvement or maintenance of right ventricular function is attributable to an increase in the rate of change of right ventricular area (RVFAC). In some embodiments, a PcPH patient with improved or maintained right ventricular function has an RVFAC between 32 and 56%. In some embodiments, a PcPH patient with improved or maintained right ventricular function has an RVFAC of at least 32%. In some embodiments, a PcPH patient with improved or maintained right ventricular function has an RVFAC of at least 34%. In some embodiments, a PcPH patient with improved or maintained right ventricular function has an RVFAC of at least 35%. In some embodiments, PcPH patients with improved or maintained right ventricular function have at least 36% RVFAC. In some embodiments, PcPH patients with improved or maintained right ventricular function have at least 38% RVFAC. In some embodiments, PcPH patients with improved or maintained right ventricular function have at least 40% RVFAC. In some embodiments, PcPH patients with improved or maintained right ventricular function have at least 42% RVFAC. In some embodiments, PcPH patients with improved or maintained right ventricular function have at least 44% RVFAC. In some embodiments, PcPH patients with improved or maintained right ventricular function have at least 46% RVFAC. In some embodiments, PcPH patients with improved or maintained right ventricular function have at least 48% RVFAC. In some embodiments, PcPH patients with improved or maintained right ventricular function have at least 50% RVFAC. In some embodiments, PcPH patients with improved or maintained right ventricular function have at least 52% RVFAC.In some embodiments, PcPH patients with improved or maintained right ventricular function have at least 54% RVFAC. In some embodiments, PcPH patients with improved or maintained right ventricular function have at least 56% RVFAC.

[0220] In some embodiments, the present disclosure relates to a method for adjusting one or more echocardiographic parameters in a PcPH patient to a more normal level (e.g., normal compared to a healthy person of similar age and sex), comprising administering an effective amount of ActRII polypeptide (e.g., an amino acid sequence that is at least 90% identical to the amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1) to the patient in need. In some embodiments, the method relates to reducing the patient's RVEDA by at least 1% (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or 20%). In some embodiments, the method relates to increasing the patient's RVFAC by at least 2%. In some embodiments, the method relates to increasing the patient's RVFAC by at least 3%. In some embodiments, the method relates to increasing the patient's RVFAC by at least 4%. In some embodiments, the method relates to increasing the patient's RVFAC by at least 5%. In some embodiments, the method relates to increasing the patient's RVFAC by at least 6%. In some embodiments, the method relates to increasing the patient's RVFAC by at least 7%. In some embodiments, the method relates to increasing the patient's RVFAC by at least 8%. In some embodiments, the method relates to increasing the patient's RVFAC by at least 9%. In some embodiments, the method relates to increasing the patient's RVFAC by at least 10%. In some embodiments, the method relates to increasing the patient's RVFAC by at least 12%. In some embodiments, the method relates to increasing the patient's RVFAC by at least 14%. In some embodiments, the method relates to increasing the patient's RVFAC by at least 16%. In some embodiments, the method relates to increasing the patient's RVFAC by at least 18%. In some embodiments, the method relates to increasing the patient's RVFAC by at least 20%.

[0221] In some embodiments, the improvement in right ventricular function is due to an increase in ejection fraction. In some embodiments, the improvement in right ventricular function is due to an increase in ejection fraction and an increase in the patient's RVFAC.

[0222] Right ventricular end-diastolic area (RVEDA) can be measured using echocardiography. In some embodiments, normal RVEDA is approximately 18.2 ± 4.3 cm² in males. 2 Approximately 14.8 ± 3.5 cm for women. 2 For example, see Kou S, et al. European Heart Journal - Cardiovascular Imaging. 2014 Jun 1;15(6):680-90.

[0223] In certain embodiments, the Disclosure provides a method for treating, preventing, or reducing the rate and / or severity of PcPH, comprising administering an effective amount of ActRII polypeptide (for example, an amino acid sequence that is at least 90% identical to the amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1) to a patient in need thereof, wherein the patient has at least 22 cm 2 (For example, 22, 24, 26, 28, 30, 32, or 34 cm) 2 The present invention relates to a method having RVEDA. In some embodiments, the method has at least 24 cm 2 This relates to patients having RVEDA. In some embodiments, the method is at least 26 cm 2 This relates to patients having RVEDA. In some embodiments, the method is at least 28 cm 2 This relates to patients having RVEDA. In some embodiments, the method is at least 30 cm 2 This relates to patients having RVEDA. In some embodiments, the method is at least 32 cm 2 This relates to patients having RVEDA. In some embodiments, the method is at least 34 cm 2 This relates to patients having RVEDA. In some embodiments, the method relates to patients having elevated RVEDA compared to normal RVEDA.

[0224] In some embodiments, the disclosure relates to a method for adjusting one or more hemodynamic parameters in a patient with PcPH to a more normal level (e.g., normal compared to a healthy person of similar age and sex), comprising administering an effective amount of ActRII polypeptide (e.g., an amino acid sequence that is at least 90% identical to the amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1) to the patient in need. In some embodiments, the method relates to improving or maintaining right ventricular function in the patient. In some embodiments, the patient having improved or maintained right ventricular function is 14-22 cm 2 The RVEDA is present. In some embodiments, improvement in right ventricular function is due to a reduction in RVEDA. In some embodiments, the method relates to reducing RVEDA. In some embodiments, the method reduces the patient's RVEDA to at least 1 cm. 2 Regarding reduction. In some embodiments, the method involves moving the patient's RVEDA to at least 2 cm 2 Regarding reduction. In some embodiments, the method involves reducing the patient's RVEDA to at least 3 cm. 2 Regarding reduction. In some embodiments, the method involves reducing the patient's RVEDA to at least 4 cm. 2 Regarding reduction. In some embodiments, the method involves reducing the patient's RVEDA to at least 5 cm. 2 Regarding reduction. In some embodiments, the method involves reducing the patient's RVEDA to at least 6 cm. 2 Regarding reduction. In some embodiments, the method involves reducing the patient's RVEDA to at least 7 cm. 2 Regarding reduction. In some embodiments, the method involves reducing the patient's RVEDA to at least 8 cm. 2 Regarding reduction. In some embodiments, the method involves reducing the patient's RVEDA to at least 9 cm. 2 The method relates to reducing the patient's RVEDA at least 10 cm. 2 Regarding reduction.

[0225] In some embodiments, the present disclosure relates to a method for adjusting one or more echocardiographic parameters in a PcPH patient to a more normal level (e.g., normal compared to a healthy person of similar age and sex), comprising administering an effective amount of ActRII polypeptide (e.g., an amino acid sequence that is at least 90% identical to the amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1) to the patient in need. In some embodiments, the method relates to reducing the patient's RVEDA by at least 1% (e.g., 1, 5, 10, 15, 20, 25, 30, 35, or 40%). In some embodiments, the method relates to reducing the patient's RVEDA by at least 5%. In some embodiments, the method relates to reducing the patient's RVEDA by at least 10%. In some embodiments, the method relates to reducing the patient's RVEDA by at least 15%. In some embodiments, the method relates to reducing the patient's RVEDA by at least 20%. In some embodiments, the method relates to reducing the patient's RVEDA by at least 25%. In some embodiments, the method relates to reducing the patient's RVEDA by at least 30%. In some embodiments, the method relates to reducing a patient's RVEDA by at least 35%. In some embodiments, the method relates to reducing a patient's RVEDA by at least 40%.

[0226] The right ventricular end-systolic area (RVESA) can be measured using echocardiography. In some embodiments, a normal RVESA is approximately 9.6 ± 2.8 cm² in males. 2 Approximately 7.3 ± 2.3 cm for women. 2 For example, see Kou S, et al. European Heart Journal - Cardiovascular Imaging. 2014 Jun 1;15(6):680-90.

[0227] In certain embodiments, the Disclosure provides a method for treating, preventing, or reducing the rate and / or severity of PcPH, comprising administering an effective amount of ActRII polypeptide (for example, an amino acid sequence that is at least 90% identical to the amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1) to a patient in need thereof, wherein the patient has at least 12 cm 2 (For example, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, or 32 cm) 2 The present invention relates to a method having RVESA of ) 2 This relates to patients with RVESA. In some embodiments, the method is at least 16 cm 2 This relates to patients having RVESA. In some embodiments, the method is at least 18 cm 2 This relates to patients having RVESA. In some embodiments, the method is at least 20 cm 2 This relates to patients having RVESA. In some embodiments, the method is at least 22 cm 2 This relates to patients having RVESA. In some embodiments, the method is at least 24 cm 2 This relates to patients having RVESA. In some embodiments, the method is at least 26 cm 2 This relates to patients having RVESA. In some embodiments, the method is at least 28 cm 2 This relates to patients having RVESA. In some embodiments, the method is at least 30 cm 2 This relates to patients having RVESA. In some embodiments, the method is at least 32 cm 2 This relates to patients having RVESA. In some embodiments, the method relates to patients having increased RVESA compared to normal RVESA.

[0228] In some embodiments, the present disclosure relates to a method for adjusting one or more hemodynamic parameters in a patient with PcPH to a more normal level (e.g., normal compared to a healthy person of similar age and sex), comprising administering an effective amount of ActRII polypeptide (e.g., an amino acid sequence that is at least 90% identical to the amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1) to the patient in need. In some embodiments, the method relates to improving or maintaining right ventricular function in the patient. In some embodiments, the patient having improved or maintained right ventricular function is 7-20 cm 2 The patient has a RVESA of at least 1 cm. In some embodiments, improvement in right ventricular function is due to a reduction in RVESA. In some embodiments, the method relates to reducing RVESA. In some embodiments, the method relates to reducing the patient's RVESA by at least 1 cm. 2 Regarding reduction. In some embodiments, the method involves reducing the patient's RVESA by at least 2 cm. 2 Regarding reduction. In some embodiments, the method involves reducing the patient's RVESA by at least 3 cm. 2 Regarding reduction. In some embodiments, the method involves reducing the patient's RVESA by at least 4 cm. 2 Regarding reduction. In some embodiments, the method involves reducing the patient's RVESA by at least 5 cm. 2 Regarding reduction. In some embodiments, the method involves reducing the patient's RVESA to at least 6 cm. 2 Regarding reduction. In some embodiments, the method involves reducing the patient's RVESA by at least 7 cm. 2 Regarding reduction. In some embodiments, the method involves reducing the patient's RVESA by at least 8 cm. 2 Regarding reduction. In some embodiments, the method involves reducing the patient's RVESA to at least 9 cm. 2 The method relates to reducing the patient's RVESA by at least 10 cm. 2 Regarding reduction.

[0229] In some embodiments, the Disclosure relates to a method for adjusting one or more echocardiographic parameters in a PcPH patient to a more normal level (e.g., normal compared to a healthy person of similar age and sex), comprising administering an effective amount of ActRII polypeptide (e.g., an amino acid sequence that is at least 90% identical to the amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1) to the patient in need. In some embodiments, the method relates to reducing the patient's RVESA by at least 1% (e.g., 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, or 40%). In some embodiments, 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 relates to reducing the patient's RVESA by at least 4%. In some embodiments, the method relates to reducing the patient's RVESA by at least 5%. In some embodiments, the method relates to reducing the patient's RVESA by at least 10%. In some embodiments, the method relates to reducing the patient's RVESA by at least 15%. In some embodiments, the method relates to reducing a patient's RVESA by at least 20%. In some embodiments, the method relates to reducing a patient's RVESA by at least 25%. In some embodiments, the method relates to reducing a patient's RVESA by at least 30%. In some embodiments, the method relates to reducing a patient's RVESA by at least 35%. In some embodiments, the method relates to reducing a patient's RVESA by at least 40%. RVFWT

[0230] In patients with pulmonary hypertension, the right ventricle expands in response to increased PAP and right ventricular remodeling. As the disease progresses, right ventricular hypertrophy develops, resulting in increased right ventricular free wall thickness. In some embodiments, right ventricular free wall thickness (RVFWT) can be measured using echocardiography. In some embodiments, normal RVFWT is approximately 0.22–0.42 cm in females and approximately 0.24–0.42 cm in males. See, for example, Lang RM, J Am Soc Echocardiogr. 2015;28(1):1-39.e14.

[0231] In certain embodiments, the Disclosure relates to a method for treating, preventing, or reducing the rate and / or severity of progression of PcPH (e.g., treating, preventing, or reducing the rate and / or severity of progression of one or more complications of PcPH of WHO Group 2 and / or Group 5 PH), comprising administering an effective amount of ActRII polypeptide (e.g., an amino acid sequence that is at least 90% identical to the amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1) to a patient in need thereof, wherein the patient has an RVFWT of at least 0.42 cm (e.g., 0.42, 0.44, 0.46, 0.48, 0.50, 0.52, 0.54, 0.56, 0.58, or 0.60 cm). In some embodiments, the method relates to a patient having an RVFWT of at least 0.44 cm. In some embodiments, the method relates to a patient having an RVFWT of at least 0.46 cm. In some embodiments, the method relates to a patient having an RVFWT of at least 0.48 cm. In some embodiments, the method relates to a patient having an RVFWT of at least 0.50 cm. In some embodiments, the method relates to a patient having an RVFWT of at least 0.52 cm. In some embodiments, the method relates to a patient having an RVFWT of at least 0.54 cm. In some embodiments, the method relates to a patient having an RVFWT of at least 0.56 cm. In some embodiments, the method relates to a patient having an RVFWT of at least 0.58 cm. In some embodiments, the method relates to a patient having an RVFWT of at least 0.60 cm. In some embodiments, the method relates to a patient having an increased RVFWT compared to a normal RVFWT.

[0232] In some embodiments, the present disclosure relates to a method for adjusting one or more hemodynamic parameters in a PcPH patient toward a more normal level (e.g., normal compared to a healthy person of similar age and sex), comprising administering an effective amount of ActRII polypeptide (e.g., an amino acid sequence that is at least 90% identical to the amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1) to the patient in need. In some embodiments, the method relates to improving or maintaining right ventricular function in the patient. In some embodiments, the patient having improved or maintained right ventricular function has an RVFWT between 0.22 and 0.42 cm. In some embodiments, the improvement in right ventricular function is a reduction in RVFWT. In some embodiments, the method relates to reducing RVFWT. In some embodiments, the method relates to reducing the patient's RVFWT by at least 0.05 cm (e.g., 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, or 0.4 cm). In some embodiments, the method relates to reducing the patient's RVFWT by at least 0.1 cm. In some embodiments, the method relates to reducing the patient's RVFWT by at least 0.15 cm. In some embodiments, the method relates to reducing the patient's RVFWT by at least 0.2 cm. In some embodiments, the method relates to reducing the patient's RVFWT by at least 0.25 cm. In some embodiments, the method relates to reducing the patient's RVFWT by at least 0.3 cm. In some embodiments, the method relates to reducing the patient's RVFWT by at least 0.35 cm. In some embodiments, the method relates to reducing the patient's RVFWT by at least 0.4 cm.

[0233] In some embodiments, the present disclosure relates to a method for adjusting the RVFWT in a PcPH patient toward a more normal level (e.g., normal compared to a healthy person of similar age and sex), comprising administering an effective amount of ActRII polypeptide (e.g., an amino acid sequence that is at least 90% identical to the amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1) to the patient in need. In some embodiments, the method relates to reducing the patient's RVFWT by at least 1% (e.g., 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, or 75%). In some embodiments, the method relates to reducing the patient's RVFWT by at least 5%. In some embodiments, the method relates to reducing the patient's RVFWT by at least 10%. In some embodiments, the method relates to reducing the patient's RVFWT by at least 15%. In some embodiments, the method relates to reducing the patient's RVFWT by at least 20%. In some embodiments, the method relates to reducing the patient's RVFWT by at least 25%. In some embodiments, the method relates to reducing the patient's RVFWT by at least 30%. In some embodiments, the method relates to reducing the patient's RVFWT by at least 35%. In some embodiments, the method relates to reducing the patient's RVFWT by at least 40%. In some embodiments, the method relates to reducing the patient's RVFWT by at least 45%. In some embodiments, the method relates to reducing the patient's RVFWT by at least 50%. In some embodiments, the method relates to reducing the patient's RVFWT by at least 55%. In some embodiments, the method relates to reducing the patient's RVFWT by at least 60%. In some embodiments, the method relates to reducing the patient's RVFWT by at least 65%. In some embodiments, the method relates to reducing the patient's RVFWT by at least 70%. In some embodiments, the method relates to reducing the patient's RVFWT by at least 75%. RVEF

[0234] Right ventricular ejection fraction (RVEF) is a comprehensive measure of the systolic performance of the right ventricular cavity (RV). RVEF can be calculated using the RV end-diastolic volume (RVEDV) and RV end-systolic volume (RVESV). Specifically, RVEF can be calculated using the following formula: RVEF(%) = ((RVEDV - RVESV) / ​​RVEDV) × 100. Normal RVEF is approximately 56–65% in men and 60–71% in women. See, for example, Lang RM, J Am Soc Echocardiogr. 2015;28(1):1-39.e14. In some embodiments, RVEF is measured using echocardiography. In some embodiments, the disclosure relates to a method for adjusting one or more hemodynamic parameters in a patient with PcPH to a more normal level (e.g., normal compared to a healthy person of similar age and sex), comprising administering an effective amount of ActRII polypeptide (e.g., an amino acid sequence that is at least 90% identical to the amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1) to the patient in need. In some embodiments, the method relates to improving or maintaining right ventricular function in the patient. In some embodiments, the patient with improved or maintained right ventricular function has an RVEF of 45-71%. In some embodiments, the patient with improved or maintained right ventricular function has an RVEF of at least 45%. In some embodiments, the patient with improved or maintained right ventricular function has an RVEF of at least 50%. In some embodiments, the patient with improved or maintained right ventricular function has an RVEF of at least 55%. In some embodiments, the patient with improved or maintained right ventricular function has an RVEF of at least 60%. In some embodiments, the patient with improved or maintained right ventricular function has an RVEF of at least 65%. In some embodiments, patients with improved or maintained right ventricular function have at least 70% RVEF.

[0235] In some embodiments, the present disclosure relates to a method for adjusting one or more echocardiographic parameters in a PcPH patient to a more normal level (e.g., normal compared to a healthy person of similar age and sex), comprising administering an effective amount of ActRII polypeptide (e.g., an amino acid sequence that is at least 90% identical to the amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1) to the patient in need. In some embodiments, the method relates to increasing the patient's RVEF by at least 2%. In some embodiments, the method relates to increasing the patient's RVEF by at least 3%. In some embodiments, the method relates to increasing the patient's RVEF by at least 4%. In some embodiments, the method relates to increasing the patient's RVEF by at least 5%. In some embodiments, 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 some embodiments, the method relates to increasing the patient's RVEF by at least 8%. In some embodiments, 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 relates to increasing the patient's RVEF by at least 11%. In some embodiments, the method relates to increasing the patient's RVEF by at least 12%. In some embodiments, the method relates to increasing the patient's RVEF by at least 13%. In some embodiments, the method relates to increasing the patient's RVEF by at least 14%. In some embodiments, the method relates to increasing the patient's RVEF by at least 15%. right ventricular hypertrophy

[0236] In certain embodiments, improvement in right ventricular function is measured as a reduction in right ventricular hypertrophy. In some embodiments, right ventricular hypertrophy is measured using the Fulton index (RV / (LV+S)).

[0237] In certain embodiments, the Disclosure relates to a method for treating, preventing, or reducing the rate and / or severity of progression of PcPH (e.g., treating, preventing, or reducing the rate and / or severity of progression of PcPH of WHO Group 2 and / or Group 5 PH), comprising administering an effective amount of ActRII polypeptide (e.g., an amino acid sequence that is at least 90% identical to the amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1) to a patient in need, wherein the patient has right ventricular hypertrophy. In some embodiments, the Disclosure relates to a method for adjusting one or more parameters in a PcPH patient to a more normal level (e.g., normal compared to a healthy person of similar age and sex), comprising administering an effective amount of ActRII polypeptide (e.g., an amino acid sequence that is at least 90% identical to the amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1) to a patient in need. In some embodiments, right ventricular hypertrophy is measured using the Fulton index (RV / (LV+S)). In some embodiments, the method relates to reducing a patient's right ventricular hypertrophy by at least 1% (e.g., 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100%). In some embodiments, the method relates to reducing a patient's right ventricular hypertrophy by at least 1%. In some embodiments, the method relates to reducing a patient's right ventricular hypertrophy by at least 5%. In some embodiments, the method relates to reducing a patient's right ventricular hypertrophy by at least 10%. In some embodiments, the method relates to reducing a patient's right ventricular hypertrophy by at least 15%. In some embodiments, the method relates to reducing a patient's right ventricular hypertrophy by at least 20%. In some embodiments, the method relates to reducing a patient's right ventricular hypertrophy by at least 25%. In some embodiments, the method relates to reducing a patient's right ventricular hypertrophy by at least 30%. In some embodiments, the method relates to reducing a patient's right ventricular hypertrophy by at least 35%. In some embodiments, the method relates to reducing the patient's right ventricular hypertrophy by at least 40%.In some embodiments, the method relates to reducing the patient's right ventricular hypertrophy by at least 45%. In some embodiments, the method relates to reducing the patient's right ventricular hypertrophy by at least 50%. In some embodiments, the method relates to reducing the patient's right ventricular hypertrophy by at least 55%. In some embodiments, the method relates to reducing the patient's right ventricular hypertrophy by at least 60%. In some embodiments, the method relates to reducing the patient's right ventricular hypertrophy by at least 65%. In some embodiments, the method relates to reducing the patient's right ventricular hypertrophy by at least 70%. In some embodiments, the method relates to reducing the patient's right ventricular hypertrophy by at least 75%. In some embodiments, the method relates to reducing the patient's right ventricular hypertrophy by at least 80%. In some embodiments, the method relates to reducing the patient's right ventricular hypertrophy by at least 85%. In some embodiments, the method relates to reducing the patient's right ventricular hypertrophy by at least 90%. In some embodiments, the method relates to reducing the patient's right ventricular hypertrophy by at least 95%. In some embodiments, the method relates to reducing the patient's right ventricular hypertrophy by at least 100%. left ventricular hypertrophy

[0238] In certain embodiments, the Disclosure relates to a method for treating, preventing, or reducing the rate and / or severity of progression of PcPH (e.g., treating, preventing, or reducing the rate and / or severity of progression of one or more complications of PcPH of WHO Group 2 and / or Group 5 PH), comprising administering an effective amount of ActRII polypeptide (e.g., an amino acid sequence that is at least 90% identical to the amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1) to a patient in need, wherein the patient has left ventricular hypertrophy. In some embodiments, the Disclosure relates to a method for adjusting one or more parameters in a PcPH patient to a more normal level (e.g., normal compared to a healthy person of similar age and sex), comprising administering an effective amount of ActRII polypeptide (e.g., an amino acid sequence that is at least 90% identical to the amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1) to a patient in need. In some embodiments, the method relates to reducing a patient's left ventricular hypertrophy by at least 1% (e.g., 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100%). In some embodiments, the method relates to reducing a patient's left ventricular hypertrophy by at least 1%. In some embodiments, the method relates to reducing a patient's left ventricular hypertrophy by at least 5%. In some embodiments, the method relates to reducing a patient's left ventricular hypertrophy by at least 10%. In some embodiments, the method relates to reducing a patient's left ventricular hypertrophy by at least 15%. In some embodiments, the method relates to reducing a patient's left ventricular hypertrophy by at least 20%. In some embodiments, the method relates to reducing a patient's left ventricular hypertrophy by at least 25%. In some embodiments, the method relates to reducing a patient's left ventricular hypertrophy by at least 30%. In some embodiments, the method relates to reducing a patient's left ventricular hypertrophy by at least 35%. In some embodiments, the method relates to reducing the patient's left ventricular hypertrophy by at least 40%. In some embodiments, the method relates to reducing the patient's left ventricular hypertrophy by at least 45%.In some embodiments, the method relates to reducing the patient's left ventricular hypertrophy by at least 50%. In some embodiments, the method relates to reducing the patient's left ventricular hypertrophy by at least 55%. In some embodiments, the method relates to reducing the patient's left ventricular hypertrophy by at least 60%. In some embodiments, the method relates to reducing the patient's left ventricular hypertrophy by at least 65%. In some embodiments, the method relates to reducing the patient's left ventricular hypertrophy by at least 70%. In some embodiments, the method relates to reducing the patient's left ventricular hypertrophy by at least 75%. In some embodiments, the method relates to reducing the patient's left ventricular hypertrophy by at least 80%. In some embodiments, the method relates to reducing the patient's left ventricular hypertrophy by at least 85%. In some embodiments, the method relates to reducing the patient's left ventricular hypertrophy by at least 90%. In some embodiments, the method relates to reducing the patient's left ventricular hypertrophy by at least 95%. In some embodiments, the method relates to reducing the patient's left ventricular hypertrophy by at least 100%. cardiac output

[0239] Cardiac output is the volume of blood the heart pumps out per minute. Cardiac output is calculated by multiplying the stroke volume by the heart rate. Generally, a normal resting cardiac output is approximately 4–8 L / min. The cardiac index (CI) is an assessment of cardiac output based on the patient's size. To determine the CI, the cardiac output is divided by the person's body surface area (BSA). The normal range for CI is 2.5–4 L / min / m². 2 Cardiac output can decrease by almost 40% without deviating from the normal limit, approximately 2.5 L / min / m². 2A low cardiac index (CIND) of less than 1 usually indicates cardiovascular disturbance. The CIND can be calculated using cardiac output (e.g., CIND = cardiac output / body surface area). Stroke volume can also be calculated using cardiac output (e.g., stroke volume = CO / heart rate). In certain embodiments, the Disclosure relates to a method for treating, preventing, or reducing the rate and / or severity of progression of PcPH (e.g., treating, preventing, or reducing the rate and / or severity of progression of one or more complications of PcPH in WHO Group 2 and / or Group 5 PH), comprising administering to a patient in need an effective amount of ActRII polypeptide (e.g., an amino acid sequence that is at least 90% identical to the amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1), thereby increasing the patient's cardiac output by at least 5% (e.g., 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 100%). In some embodiments, the method relates to increasing the patient's cardiac output by at least 5%. In some embodiments, the method relates to increasing the patient's cardiac output by at least 10%. In some embodiments, the method relates to increasing the patient's cardiac output by at least 15%. In some embodiments, the method relates to increasing the patient's cardiac output by at least 20%. In some embodiments, the method relates to increasing the patient's cardiac output by at least 25%. In some embodiments, the method relates to increasing the patient's cardiac output by at least 30%. In some embodiments, the method relates to increasing the patient's cardiac output by at least 35%. In some embodiments, the method relates to increasing the patient's cardiac output by at least 40%. In some embodiments, the method relates to increasing the patient's cardiac output by at least 45%. In some embodiments, the method relates to increasing the patient's cardiac output by at least 50%. In some embodiments, the method relates to increasing the patient's cardiac output by at least 55%. In some embodiments, the method relates to increasing the patient's cardiac output by at least 60%. In some embodiments, the method relates to increasing the patient's cardiac output by at least 65%.In some embodiments, the method relates to increasing the patient's cardiac output by at least 70%. In some embodiments, the method relates to increasing the patient's cardiac output by at least 75%. In some embodiments, the method relates to increasing the patient's cardiac output by at least 80%. In some embodiments, the method relates to increasing the patient's cardiac output by at least 85%. In some embodiments, the method relates to increasing the patient's cardiac output by at least 90%. In some embodiments, the method relates to increasing the patient's cardiac output by at least 95%. In some embodiments, the method relates to increasing the patient's cardiac output by at least 100%. In some embodiments, the method relates to increasing the patient's cardiac index to at least 4.2 L / min / m. 2 The method relates to increasing the cardiac output to at least 4 L / min. In some embodiments, the cardiac index is measured at rest. In some embodiments, the method relates to increasing the patient's cardiac output to at least 4 L / min. In some embodiments, cardiac output is measured at rest. In some embodiments, cardiac output is measured using a right heart catheter. In some embodiments, cardiac output is measured by thermodilution. In some embodiments, cardiac output is measured using the Fick method. Progression from IpcPH to CpcPH

[0240] The primary mechanism underlying PcPH (e.g., WHO Group 2 and / or Group 5 PH) is elevated left-sided filling pressure (i.e., left atrial pressure). Sustained elevation of left atrial pressure can lead to passive pulmonary venous congestion accompanied by increased pulmonary pressure. In some patients, the propagation of venous congestion to the pulmonary capillaries results in leakage and damage, ultimately leading to the creation of obstructive vascular impairment where higher pulmonary pressure is required to maintain forward flow. This is sometimes referred to as the development of the “pre-capillary” component of PH. In certain embodiments, the Disclosure relates to a method for treating, preventing, or reducing the rate and / or severity of progression of PcPH (e.g., treating, preventing, or reducing the rate and / or severity of progression of one or more complications of PcPH in WHO Group 2 and / or Group 5 PH), comprising administering to a patient in need an effective amount of ActRII polypeptide (e.g., an amino acid sequence that is at least 90% identical to the amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1), thereby reducing the occurrence of precapillary components of PH by at least 1% (e.g., 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%). In some embodiments, the method relates to reducing the occurrence of precapillary components of PH in a patient by at least 1%. In some embodiments, the method relates to reducing the occurrence of precapillary components of PH in patients by at least 2%. In some embodiments, the method relates to reducing the occurrence of precapillary components of PH in patients by at least 3%. In some embodiments, the method relates to reducing the occurrence of precapillary components of PH in patients by at least 4%. In some embodiments, the method relates to reducing the occurrence of precapillary components of PH in patients by at least 5%. In some embodiments, the method relates to reducing the occurrence of precapillary components of PH in patients by at least 10%.In some embodiments, the method relates to reducing the occurrence of precapillary PH components in patients by at least 15%. In some embodiments, the method relates to reducing the occurrence of precapillary PH components in patients by at least 20%. In some embodiments, the method relates to reducing the occurrence of precapillary PH components in patients by at least 25%. In some embodiments, the method relates to reducing the occurrence of precapillary PH components in patients by at least 30%. In some embodiments, the method relates to reducing the occurrence of precapillary PH components in patients by at least 35%. In some embodiments, the method relates to reducing the occurrence of precapillary PH components in patients by at least 40%. In some embodiments, the method relates to reducing the occurrence of precapillary PH components in patients by at least 45%. In some embodiments, the method relates to reducing the occurrence of precapillary PH components in patients by at least 50%. In some embodiments, the method relates to reducing the occurrence of precapillary PH components in patients by at least 55%. In some embodiments, the method relates to reducing the occurrence of precapillary PH components in patients by at least 60%. In some embodiments, the method relates to reducing the occurrence of precapillary PH components in patients by at least 65%. In some embodiments, the method relates to reducing the occurrence of precapillary PH components in patients by at least 70%. In some embodiments, the method relates to reducing the occurrence of precapillary PH components in patients by at least 75%. In some embodiments, the method relates to reducing the occurrence of precapillary PH components in patients by at least 80%. In some embodiments, the method relates to reducing the occurrence of precapillary PH components in patients by at least 85%. In some embodiments, the method relates to reducing the occurrence of precapillary PH components in patients by at least 90%. In some embodiments, the method relates to reducing the occurrence of precapillary PH components in patients by at least 95%. In some embodiments, the method relates to reducing the occurrence of precapillary PH components in patients by at least 100%.

[0241] In some embodiments, it has been shown that sustained left atrial pressure in IpcPH leads to the development of CpcPH. In certain aspects, the Disclosure relates to a method for treating, preventing, or reducing the rate and / or severity of progression of PcPH (e.g., treating, preventing, or reducing the rate and / or severity of progression of one or more complications of PcPH in WHO Group 2 and / or Group 5 PH), comprising administering to a patient in need an effective amount of ActRII polypeptide (e.g., an amino acid sequence that is at least 90% identical to the amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1), thereby reducing the progression from IpcPH to CpcPH in the patient by at least 1% (e.g., 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%). In some embodiments, the method relates to reducing the progression from IpcPH to CpcPH in patients by at least 1%. In some embodiments, the method relates to reducing the progression from IpcPH to CpcPH in patients by at least 2%. In some embodiments, the method relates to reducing the progression from IpcPH to CpcPH in patients by at least 3%. In some embodiments, the method relates to reducing the progression from IpcPH to CpcPH in patients by at least 4%. In some embodiments, the method relates to reducing the progression from IpcPH to CpcPH in patients by at least 5%. In some embodiments, the method relates to reducing the progression from IpcPH to CpcPH in patients by at least 10%. In some embodiments, the method relates to reducing the progression from IpcPH to CpcPH in patients by at least 15%. In some embodiments, the method relates to reducing the progression from IpcPH to CpcPH in patients by at least 20%. In some embodiments, the method relates to reducing the progression from IpcPH to CpcPH in patients by at least 25%. In some embodiments, the method relates to reducing the progression from IpcPH to CpcPH in patients by at least 30%.In some embodiments, the method relates to reducing the progression from IpcPH to CpcPH in patients by at least 35%. In some embodiments, the method relates to reducing the progression from IpcPH to CpcPH in patients by at least 40%. In some embodiments, the method relates to reducing the progression from IpcPH to CpcPH in patients by at least 45%. In some embodiments, the method relates to reducing the progression from IpcPH to CpcPH in patients by at least 50%. In some embodiments, the method relates to reducing the progression from IpcPH to CpcPH in patients by at least 55%. In some embodiments, the method relates to reducing the progression from IpcPH to CpcPH in patients by at least 60%. In some embodiments, the method relates to reducing the progression from IpcPH to CpcPH in patients by at least 65%. In some embodiments, the method relates to reducing the progression from IpcPH to CpcPH in patients by at least 70%. In some embodiments, the method relates to reducing the progression from IpcPH to CpcPH in patients by at least 75%. In some embodiments, the method relates to reducing the progression from IpcPH to CpcPH in patients by at least 80%. In some embodiments, the method relates to reducing the progression from IpcPH to CpcPH in patients by at least 85%. In some embodiments, the method relates to reducing the progression from IpcPH to CpcPH in patients by at least 90%. In some embodiments, the method relates to reducing the progression from IpcPH to CpcPH in patients by at least 95%. In some embodiments, the method relates to reducing the progression from IpcPH to CpcPH in patients by at least 100%. Motor skills (6MWD and BDI)

[0242] In certain embodiments, the disclosure relates to a method for increasing exercise capacity in patients with PcPH (e.g., WHO Group 2 and / or Group 5 PH), comprising administering an effective amount of ActRII polypeptide (e.g., an amino acid sequence at least 90% identical to the amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 1) to patients in need. Any suitable measure of exercise capacity can be used. For example, exe...

Claims

1. A pharmaceutical composition for the treatment of precapillary and postcapillary mixed pulmonary hypertension (CpcPH) resulting from heart failure with maintained ejection fraction (HFpEF) in patients in need, comprising an effective amount of a fusion protein, the fusion protein being (i) ACTRII polypeptide containing the amino acid sequence of SEQ ID NO: 2, (ii) Fc domain which is at least 95% identical to the amino acid sequence of Sequence ID No. 32, (iii) A linker domain located between the ActRII polypeptide domain and the Fc domain, Pharmaceutical composition.

2. The pharmaceutical composition according to claim 1, wherein the patient has a pulmonary vascular resistance (PVR) greater than 2 Wood units.

3. The pharmaceutical composition according to claim 1, wherein the Fc domain is at least 99% identical to the amino acid sequence of SEQ ID NO:

32.

4. The pharmaceutical composition according to claim 3, wherein the Fc domain comprises the amino acid sequence of SEQ ID NO:

32.

5. The pharmaceutical composition according to claim 3, wherein the linker domain is selected from the group consisting of TGGG (SEQ ID NO: 20), TGGGGG (SEQ ID NO: 18), SGGGG (SEQ ID NO: 19), GGGGS (SEQ ID NO: 22), GGG (SEQ ID NO: 16), GGGG (SEQ ID NO: 17), and SGGG (SEQ ID NO: 21).

6. The pharmaceutical composition according to claim 5, wherein the linker domain includes Sequence ID No.

20.

7. The pharmaceutical composition according to claim 6, wherein the fusion protein comprises an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 23 or SEQ ID NO:

41.

8. The pharmaceutical composition according to claim 7, wherein the fusion protein comprises an amino acid sequence that is at least 99% identical to the amino acid sequence of SEQ ID NO:

23.

9. The pharmaceutical composition according to claim 8, wherein the fusion protein comprises the amino acid sequence of SEQ ID NO:

23.

10. The pharmaceutical composition according to claim 8, wherein the fusion protein comprises an amino acid sequence that is at least 99% identical to the amino acid sequence of SEQ ID NO:

41.

11. The pharmaceutical composition according to claim 10, wherein the fusion protein comprises the amino acid sequence of SEQ ID NO:

41.

12. The pharmaceutical composition according to claim 1, wherein the patient has group 2 pulmonary hypertension as recognized by the World Health Organization (WHO).

13. The pharmaceutical composition according to claim 1, wherein the patient has a pulmonary vascular resistance (PVR) greater than or equal to 3 Wood units.

14. The pharmaceutical composition according to claim 13, which reduces the PVR in the patient.

15. The pharmaceutical composition according to claim 14, which reduces the PVR in the patient by at least 10%.

16. The pharmaceutical composition according to claim 1, wherein the patient has a maintained left ventricular ejection fraction.

17. The pharmaceutical composition according to claim 16, wherein the maintained left ventricular ejection fraction is greater than 45%.

18. The pharmaceutical composition according to claim 1, which increases the six-minute walking distance of the patient.

19. The pharmaceutical composition according to claim 18, which increases the patient's walking distance in six minutes by at least 10 meters.

20. The pharmaceutical composition according to claim 1, which delays the clinical progression of PCPH.

21. The pharmaceutical composition according to claim 20, which delays the clinical progression of PcPH according to the World Health Organization's functional classification system for pulmonary hypertension.

22. The pharmaceutical composition according to claim 21, which delays the clinical progression of PcPH according to the New York Heart Association's functional classification system for pulmonary hypertension.

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