Author:
Joshi Sachindra R.,Liu Jun,Bloom Troy,Karaca Atabay Elif,Kuo Tzu-Hsing,Lee Michael,Belcheva Elitza,Spaits Matthew,Grenha Rosa,Maguire Michelle C.,Frost Jeffrey L.,Wang Kathryn,Briscoe Steven D.,Alexander Mark J.,Herrin Brantley R.,Castonguay Roselyne,Pearsall R. Scott,Andre Patrick,Yu Paul B.,Kumar Ravindra,Li Gang
Abstract
AbstractSotatercept is an activin receptor type IIA-Fc (ActRIIA-Fc) fusion protein that improves cardiopulmonary function in patients with pulmonary arterial hypertension (PAH) by selectively trapping activins and growth differentiation factors. However, the cellular and molecular mechanisms of ActRIIA-Fc action are incompletely understood. Here, we determined through genome-wide expression profiling that inflammatory and immune responses are prominently upregulated in the lungs of a Sugen-hypoxia rat model of severe angio-obliterative PAH, concordant with profiles observed in PAH patients. Therapeutic treatment with ActRIIA-Fc—but not with a vasodilator—strikingly reversed proinflammatory and proliferative gene expression profiles and normalized macrophage infiltration in diseased rodent lungs. Furthermore, ActRIIA-Fc normalized pulmonary macrophage infiltration and corrected cardiopulmonary structure and function in Bmpr2 haploinsufficient mice subjected to hypoxia, a model of heritable PAH. Three high-affinity ligands of ActRIIA-Fc each induced macrophage activation in vitro, and their combined immunoneutralization in PAH rats produced cardiopulmonary benefits comparable to those elicited by ActRIIA-Fc. Our results in complementary experimental and genetic models of PAH reveal therapeutic anti-inflammatory activities of ActRIIA-Fc that, together with its known anti-proliferative effects on vascular cell types, could underlie clinical activity of sotatercept as either monotherapy or add-on to current PAH therapies.
Publisher
Springer Science and Business Media LLC
Cited by
26 articles.
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