Compositions and methods for treating pulmonary hypertension
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Publication Number
US-12343378-B2
Publication Date
2025-07-01
Expiration Date
Abstract
In some aspects, the disclosure relates to GDF/BMP antagonists and methods of using GDF3/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.
Core Innovation
The document describes soluble ActRIIB extracellular-Fc fusion proteins, including ActRIIB-Fc variants with N/C truncations and specific mutations, and sequence-defined ActRIIB(25-131)-hFc and GDF trap variants such as ActRIIB(L79D 20-134)-hFc and ActRIIB(L79D 25-131)-hFc. The fusion proteins are produced using defined leader/linker designs together with extensive amino-acid and nucleic-acid sequence disclosures, including an Fc-fusion format.
The disclosure addresses inhibiting activin A binding while retaining GDF11 and myostatin activity in the context of ActRIIB-Fc molecules. It reports that L79D/L79E variants yield greatly reduced activin A binding while retaining activity toward GDF11 and GDF8 (myostatin), and it compares binding parameters across ActRIIB-Fc variants including Kd comparisons.
The document further discloses an ALK4:ActRIIB heterodimer concept using separately Fc-fused extracellular domains with asymmetric Fc engineering to guide heterodimer formation. It reports comparative binding and signaling outcomes for these configurations, and it includes in vivo evaluation in monocrotaline and Sugen/hypoxia rat models of pulmonary arterial hypertension.
Claims Coverage
The independent claims are directed to methods of treating pulmonary arterial hypertension. Across the claims, the inventive features center on administering an ActRIIA polypeptide comprising SEQ ID NO: 10 fused to an IgG1 Fc domain with a linker positioned between the domains, with additional claims requiring increased exercise capacity or a linker comprising SEQ ID NO: 23.
ActRIIA-fc fusion protein with linker positioned between domains
A method of treating pulmonary arterial hypertension by administering a fusion protein comprising an ActRIIA polypeptide comprising the amino acid sequence of SEQ ID NO: 10, an Fc domain of an IgG1 immunoglobulin, and a linker domain positioned between the ActRIIA polypeptide and the Fc domain.
ActRIIA-fc fusion protein increases exercise capacity
A method of treating pulmonary arterial hypertension by administering a fusion protein comprising an ActRIIA polypeptide comprising the amino acid sequence of SEQ ID NO: 10, an Fc domain of an IgG1 immunoglobulin, and a linker domain positioned between the ActRIIA polypeptide and the Fc domain, wherein the method increases exercise capacity of the patient.
Defined linker (SEQ ID NO: 23) in ActRIIA-fc fusion for human treatment
A method of treating pulmonary arterial hypertension in a human patient by administering an effective amount of a fusion protein comprising an ActRIIA polypeptide domain comprising the amino acid sequence of SEQ ID NO: 10, an Fc domain of an IgG1 immunoglobulin, and a linker domain comprising the amino acid sequence of SEQ ID NO: 23, wherein the linker domain is positioned between the ActRIIA polypeptide domain and the Fc domain.
The claims cover pulmonary arterial hypertension treatment using an ActRIIA polypeptide comprising SEQ ID NO: 10 fused to an IgG1 Fc domain with a linker positioned between the domains, with further coverage for methods that increase exercise capacity and for human treatment methods requiring a linker comprising SEQ ID NO: 23.
Stated Advantages
Increases exercise capacity of the patient.
Reduces pulmonary arterial pressure by at least 10%.
Improves 6-minute walk distance (6MWD) by at least 10 meters.
Reduces Borg dyspnea index (BDI) by at least 0.5 index points.
Reduces pulmonary vascular resistance in a human patient.
Delays clinical worsening.
Reduces blood pressure.
Reduces cardiac hypertrophy.
Reduces lung weight.
Reduces vascular remodeling/muscularization via histology.
Documented Applications
Treating pulmonary arterial hypertension in a patient by administering an ActRIIA-IgG1 Fc fusion protein with a linker positioned between the ActRIIA polypeptide and the Fc domain.
Treating pulmonary arterial hypertension in a human patient.
Modulating GDF/BMP signaling by inhibiting ligand-receptor binding and downstream Smad signaling.
Treatment of pulmonary arterial hypertension in a patient by administering an ActRIIA-Fc fusion protein with a linker positioned between the ActRIIA polypeptide and the IgG1 Fc domain.
Treatment of pulmonary arterial hypertension in a human patient using an ActRIIA-Fc fusion protein with a linker domain comprising SEQ ID NO: 23 positioned between the ActRIIA domain and the Fc domain.
Treating pulmonary arterial hypertension in a patient in need thereof.
Treating pulmonary arterial hypertension with a fusion protein that increases exercise capacity.
Treating pulmonary arterial hypertension in a human patient using a fusion protein with the linker domain comprising SEQ ID NO: 23.
Treatment applicable to pulmonary hypertension subtypes and patient classifications including World Health Organization Functional Class II or Class III.
PAH subtype coverage including idiopathic, heritable, drug- and/or toxin-induced, pulmonary hypertension associated with connective tissue disease, and pulmonary hypertension associated with congenital systemic-to-pulmonary shunts at least 1 year after shunt repair.
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