HS135: Novel Activin & GDF Ligand Trap for the Treatment of Pulmonary Hypertension (PH)

Abstract

<b>Background:</b> Vascular remodeling in PH is associated with increased Activin and growth differentiation factor (GDF) signaling. This is coupled with reduced bone morphogenetic protein (BMP) signaling, causing an imbalance of growth-promoting vs. -inhibiting effects. Thus, targeting of pro-proliferative Activins and GDFs has been proposed as a potentially disease modifying strategy to treat PH. <b>Aims and objectives:</b> HS135 is a novel Activin-receptor (ActR) based fusion protein designed to sequester Activins and GDFs with best-in-class potency without affecting hematological parameters that limit dosing of other Activin ligand traps such as ActRIIA-Fc. <b>Methods:</b> HS135 candidates were discovered using computational modelling, rational design and cell-based screening assays. Single doses of HS135 and ActRIIA-Fc were administered to wild type (wt) mice and hematological parameters were assessed after 4 days. Pharmacodynamic response to treatment was assessed by ELISA and PCR in serum and lung tissue. <b>Results:</b> In reporter assays and primary arterial smooth muscle cells, HS135 more potently blocked pro-proliferative ligands than ActRIIA-Fc. In wt mice, a single administration of ActRIIA-Fc led to robust increases in red blood cells, hemoglobin and hematocrit whereas HS135 did not. A single dose of HS135 led to greater reductions in mRNA expression of pro-proliferative ligands and downstream effectors in mouse lung tissue compared to ActRIIA-Fc. <b>Conclusion:</b> The design of HS135 achieved best-in-class potency against pro-proliferative Activins and GDFs without affecting hematological parameters&nbsp;which may limit dosing of other ActR-based ligand traps. Further evaluation of HS135 in disease models of PH is warranted.