Agonist antibody to guanylate cyclase receptor NPR1 regulates vascular tone
Michael E. Dunn, Aaron Kithcart, Jee Hae Kim, Andre Jo-Hao Ho, Matthew C. Franklin, Annabel Romero Hernandez, Jan de Hoon, Wouter Botermans, Jonathan Meyer, Ximei Jin, Dongqin Zhang, Justin Torello, Daniel Jasewicz, Vishal Kamat, Elena Garnova, Nina Liu, Michael Rosconi, Hao Pan, Satyajit Karnik, Michael E. Burczynski, Wenjun Zheng, Ashique Rafique, Jonas B. Nielsen, Tanima De, Niek Verweij, Anita Pandit, Adam E. Locke, Naga Chalasani, Olle Melander, Tae‐Hwi Schwantes‐An, Penn Medicine Biobank, Daniel J. Rader, Marylyn D. Ritchie, JoEllen Weaver, Nawar Naseer, Afiya Poindexter, Khadijah Hu-Sain, Gary Herman, Meghan Livingstone, Fred Vadivieso, Stephanie DerOhannessian, Teo Tran, Julia Stephanowski, Monica Zielinski, Ned Haubein, Joseph Dunn, Anurag Verma, Colleen Morse Kripke, Marjorie Risman, Renae Judy, Shefali S. Verma, Yuki Bradford, Scott Dudek, Theodore Drivas, Lance J. Adams, Jackie Blank, Dale Bodian, Derek Boris, Adam Buchanan, David J. Carey, Ryan D. Colonie, F. Daniel Davis, Dustin N. Hartzel, Melissa Kelly, H. Lester Kirchner, Joseph B. Leader, David H. Ledbetter, J. Neil Manus, Christa L. Martin, Raghu P. Metpally, Michelle Meyer, Tooraj Mirshahi, Matthew Oetjens, Thomas Nate Person, Christopher Still, Natasha Strande, Amy Sturm, Jen Wagner, Marc Williams, Goncalo Abecasis, Michael Cantor, Giovanni Coppola, Andrew Deubler, Aris Economides, John D. Overton, Jeffrey G. Reid, Katherine Siminovitch, Alan Shuldiner, Christina Beechert, Caitlin Forsythe, Erin D. Fuller, Zhenhua Gu, Michael Lattari, Alexander Lopez, Maria Sotiropoulos Padilla, Manasi Pradhan, Kia Manoochehri, Thomas D. Schleicher, Louis Widom, Sarah E. Wolf
Abstract
Heart failure is a leading cause of morbidity and mortality1,2. 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 congestion3–8. Recombinant natriuretic peptide infusions were developed to treat heart failure but have been limited by a short duration of effect9,10. 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.