Compositions and methods for treating pulmonary hypertension
In some aspects, the disclosure relates to GDF/BMP antagonists and methods of using GDF/BMP antagonists to treat, prevent, or reduce the progression rate and/or severity of pulmonary hypertension (PH), particularly treating, preventing or reducing the progression rate and/or severity of one or more PH-associated complications. The disclosure also provides methods of using a GDF/BMP antagonist to treat, prevent, or reduce the progression rate and/or severity of a variety of conditions including, but not limited to, pulmonary vascular remodeling, pulmonary fibrosis, and right ventricular hypertrophy. The disclosure further provides methods of using a GDF/BMP antagonist to reduce right ventricular systolic pressure in a subject in need thereof.
1. A method of treating pulmonary arterial hypertension, comprising administering to a patient in need thereof an effective amount of an ActRIIA 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: 9, wherein the polypeptide binds to activin and/or GDF11.
2. The method of claim 1 , wherein the patient has resting pulmonary arterial pressure (PAP) of at least 25 mm Hg.
3. The method of claim 1 , wherein the method reduces PAP in the patient.
4. The method of claim 1 , wherein the patient has Functional Class II or Class III pulmonary hypertension as recognized by the World Health Organization.
5. The method of claim 4 , wherein the method prevents or delays pulmonary hypertension Functional Class progression.
6. The method of claim 1 , wherein the ActRIIA polypeptide is selected from the group consisting of:
a. 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: 9;
b. a polypeptide comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 10; and
c. a polypeptide comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 11.
7. The method of claim 6 , wherein the polypeptide is a fusion protein further comprising an Fc domain of an immunoglobulin.
8. The method of claim 7 , wherein the Fc domain of the immunoglobulin is an Fc domain of an IgG1 immunoglobulin.
9. The method of claim 1 , wherein the polypeptide comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 32.
10. The method of claim 1 , wherein the polypeptide is part of a homodimer protein complex.
11. The method of claim 1 , wherein the polypeptide is glycosylated.
12. The method of claim 1 , wherein the ActRIIA polypeptide binds to one or more ligands selected from the group consisting of: activin A, activin B, and GDF11.
13. The method of claim 12 , wherein the ActRIIA polypeptide further binds to one or more ligands selected from the group consisting of: BMP10, GDF8, and BMP6.
14. The method of claim 7 , wherein the Fc fusion protein further comprises a linker domain positioned between the ActRIIA polypeptide domain and the Fc domain of the immunoglobulin.
15. The method of claim 14 , wherein the linker domain comprises TGGG (SEQ ID NO: 23).
16. The method of claim 1 , wherein the ActRIIA polypeptide comprises the amino acid sequence of SEQ ID NO: 32.
17. The method of claim 1 , comprising further administering to the patient an additional active agent and/or supportive therapy for treating pulmonary hypertension.
18. The method of claim 17 , wherein the additional active agent and/or supportive therapy for treating pulmonary hypertension is selected from the group consisting of: prostacyclin and derivatives thereof; prostacyclin receptor agonists; endothelin receptor; calcium channel blockers; anticoagulants; diuretics; oxygen therapy; atrial septostomy; pulmonary thromboendarterectomy; phosphodiesterase type 5 inhibitors; activators of soluble guanylate cyclase; ASK-1 inhibitors; NF-κB antagonists; lung and/or heart transplantation.
19. The method of claim 1 , wherein the ActRIIA polypeptide comprises an amino acid sequence that is at least 95% identical to an amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 9, wherein the polypeptide binds to activin and/or GDF11.
20. The method of claim 1 , wherein the ActRIIA polypeptide comprises an amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 9, wherein the polypeptide binds to activin and/or GDF11.
21. The method of claim 1 , wherein the polypeptide is a fusion protein further comprising an Fc domain of an immunoglobulin.
22. The method of claim 21 , wherein the Fc domain of the immunoglobulin is an Fc domain of an IgG1 immunoglobulin.
23. The method of claim 1 , wherein the patient has been treated with one or more vasodilators.
24. The method of claim 1 , wherein the patient has been treated with one or more agents selected from the group consisting of: phosphodiesterase type 5 inhibitors, soluble guanylate cyclase stimulators, prostacyclin receptor agonist, and endothelin receptor antagonists.
25. The method of claim 24 , wherein the one or more agents is selected from the group consisting of: bosentan, sildenafil, beraprost, macitentan, selexipag, epoprostenol, treprostinil, iloprost, ambrisentan, and tadalafil.
26. The method of claim 1 , wherein the method further comprises administration of one or more vasodilators.
27. The method of claim 1 , wherein the method further comprises administration of one or more agents selected from the group consisting of: phosphodiesterase type 5 inhibitors, soluble guanylate cyclase stimulators, prostacyclin receptor agonist, and endothelin receptor antagonists.
28. The method of claim 27 , wherein the one or more agents is selected from the group consisting of: bosentan, sildenafil, beraprost, macitentan, selexipag, epoprostenol, treprostinil, iloprost, ambrisentan, and tadalafil.
29. The method of claim 1 , wherein the ActRIIA 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: 9.
30. The method of claim 1 , wherein the ActRIIA polypeptide is a polypeptide comprising the amino acid sequence corresponding to residues 21-135 of SEQ ID NO: 9.
31. The method of claim 29 , wherein the polypeptide is a fusion protein further comprising an Fc domain of an immunoglobulin.
32. The method of claim 31 , wherein the Fc domain of the immunoglobulin is an Fc domain of an IgG1 immunoglobulin.
33. The method of claim 1 , wherein the ActRIIA polypeptide is a polypeptide comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 10.
34. The method of claim 1 , wherein the ActRIIA polypeptide is a polypeptide comprising the amino acid sequence of SEQ ID NO: 10.
35. The method of claim 33 , wherein the polypeptide is a fusion protein further comprising an Fc domain of an immunoglobulin.
36. The method of claim 35 , wherein the Fc domain of the immunoglobulin is an Fc domain of an IgG1 immunoglobulin.
37. The method of claim 1 , wherein the ActRIIA polypeptide is a polypeptide comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 11.
38. The method of claim 1 , wherein the ActRIIA polypeptide is a polypeptide comprising the amino acid sequence of SEQ ID NO: 11.
39. The method of claim 37 , wherein the polypeptide is a fusion protein further comprising an Fc domain of an immunoglobulin.
40. The method of claim 39 , wherein the Fc domain of the immunoglobulin is an Fc domain of an IgG1 immunoglobulin.
41. The method of claim 1 , wherein the polypeptide comprises an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 32.
42. The method of claim 1 , wherein the polypeptide comprises an amino acid sequence that is at least 99% identical to the amino acid sequence of SEQ ID NO: 32.