Sotatercept analog suppresses inflammation to reverse experimental pulmonary arterial hypertension

TL;DR

A drug called sotatercept reduces inflammation and improves lung and heart function in a rat model of pulmonary arterial hypertension.

Contribution

The study reveals that sotatercept's anti-inflammatory effects, in addition to its known anti-proliferative actions, contribute to its therapeutic benefits in PAH.

Findings

ActRIIA-Fc reversed proinflammatory gene expression and macrophage infiltration in PAH rat lungs.

ActRIIA-Fc corrected cardiopulmonary structure and function in a genetic model of heritable PAH.

Neutralizing ActRIIA-Fc ligands produced similar benefits to ActRIIA-Fc treatment in PAH rats.

Abstract

Sotatercept 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.

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