A novel agonist antibody to membrane-bound guanylate cyclase receptor, natriuretic peptide receptor 1, induces sustained vasodilation

Heart failure (HF) is a leading cause of morbidity and mortality. Elevated intracardiac pressures and myocyte stretch in HF triggers release of counter-regulatory natriuretic peptides (NPs), which act via their receptor (NPR1) to affect vasodilation and natriuresis, lowering venous pressures and relieving venous congestion. Recombinant NP infusions were developed to treat HF but have been limited by a short duration of effect. Here, we report that, in a human genetic analysis of over 700,000 individuals, lifelong exposure to coding variants in the NPR1 gene are associated with changes in blood pressure (BP) and risk of HF. We then describe the development of an NPR1-agonist antibody, REGN5381, a novel investigational monoclonal agonist antibody targeting a membrane-bound guanylate cyclase receptor. REGN5381, an allosteric agonist of NPR1, induces an active-like receptor conformation resulting in hemodynamic effects preferentially on venous vasculature, including reductions in systolic BP and venous pressure in animal models. In healthy human volunteers, REGN5381 produced the expected hemodynamic effects, reflecting reductions in venous pressures. These data support the development of REGN5381 for long-lasting and selective lowering of venous pressures that drive symptomatology in patients with HF.