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

Nature, 2024, vol. 633, issue 8030, 654-661

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41586-024-07903-1

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