Journal Article

Agonist antibody to guanylate cyclase receptor NPR1 regulates vascular tone

Huang, Tammy, Locke, Adam, Olenchock, Benjamin A., Chalasani, Naga, Rankin, Andrew J., Pandit, Anita, Zheng, Wenjun, Mastaitis, Jason, Schwantes-An, Tae-Hwi, Botermans, Wouter, Lotta, Luca A., Kamat, Vishal, Ho, Andre Jo-Hao, Liu, Nina, Karnik, Satyajit, Nielsen, Jonas B., Jin, Ximei, Musser, Bret J., Rosconi, Michael, Melander, Olle, Murphy, Andrew J., Torello, Justin, Verweij, Niek, Yancopoulos, George D., Morton, Lori, Rafique, Ashique, Dunn, Michael E., de Hoon, Jan, Baras, Aris, Meyer, Jonathan, Pan, Hao, De, Tanima, Devalaraja-Narashimha, Kishor B., Olson, William, Jasewicz, Daniel, Garnova, Elena, Kithcart, Aaron, Franklin, Matthew C., Romero Hernandez, Annabel, Herman, Gary, Burczynski, Michael E., Kim, Jee Hae, Zhang, Dongqin

2024

Overview

Heart failure is a leading cause of morbidity and mortality 1 , 2 . Elevated intracardiac pressures and myocyte stretch in heart failure trigger the release of counter-regulatory natriuretic peptides, which act through their receptor (NPR1) to affect vasodilation, diuresis and natriuresis, lowering venous pressures and relieving venous congestion 3 – 8 . Recombinant natriuretic peptide infusions were developed to treat heart failure but have been limited by a short duration of effect 9 , 10 . Here we report that in a human genetic analysis of over 700,000 individuals, lifelong exposure to coding variants of the NPR1 gene is associated with changes in blood pressure and risk of heart failure. We describe the development of REGN5381, an investigational monoclonal agonist antibody that targets the membrane-bound guanylate cyclase receptor NPR1. REGN5381, an allosteric agonist of NPR1, induces an active-like receptor conformation that results in haemodynamic effects preferentially on venous vasculature, including reductions in systolic blood pressure and venous pressure in animal models. In healthy human volunteers, REGN5381 produced the expected haemodynamic effects, reflecting reductions in venous pressures, without obvious changes in diuresis and natriuresis. These data support the development of REGN5381 for long-lasting and selective lowering of venous pressures that drive symptomatology in patients with heart failure. Durable agonism of NPR1 achieved with a novel investigational monoclonal antibody could mirror the positive hemodynamic changes in blood pressure and heart failure identified in humans with lifelong exposure to NPR1 coding variants.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 38/23 / 631/154/436/108 / 631/154/51/1568 / 64/60 / 82/103 / Adult / Agonists / Allosteric properties / Allosteric Regulation - drug effects / Animal models / Animals / Antibodies / Antibodies, Monoclonal - administration & dosage / Antibodies, Monoclonal - adverse effects / Antibodies, Monoclonal - pharmacokinetics / Antibodies, Monoclonal - pharmacology / Biomarkers / Blood pressure / Blood Pressure - drug effects / Blood Pressure - genetics / Cardiology and Cardiovascular Disease / Clinical Medicine / Conformation / Congestive heart failure / Diuresis / Diuresis - drug effects / Dogs / Failure / Female / Genetic analysis / Guanylate cyclase / Healthy Volunteers / Heart failure / Heart Failure - drug therapy / Heart Failure - physiopathology / Hemodynamics / Hemodynamics - drug effects / Humanities and Social Sciences / Humans / Kardiologi och kardiovaskulära sjukdomar / Klinisk medicin / Ligands / Macaca fascicularis / Male / Medical and Health Sciences / Medicin och hälsovetenskap / Mice / Middle Aged / Monoclonal antibodies / Morbidity / multidisciplinary / Muscle, Smooth, Vascular - drug effects / Myocytes / Natriuresis - drug effects / NPR1 gene / Peptides / Physiology / Pressure effects / Proteins / Receptors / Receptors, Atrial Natriuretic Factor - agonists / Receptors, Atrial Natriuretic Factor - genetics / Receptors, Atrial Natriuretic Factor - metabolism / Science / Science (multidisciplinary) / Vasoconstriction - drug effects / Vasoconstriction - physiology / Vasodilation / Veins - drug effects / Veins - physiology / Young Adult