Agonist antibody to guanylate cyclase receptor NPR1 regulates vascular tone

Affiliations

• Regeneron Pharmaceuticals, Tarrytown, NY, USA. michael.dunn@regeneron.com.
• Regeneron Pharmaceuticals, Tarrytown, NY, USA.
• Center for Clinical Pharmacology, University Hospitals Leuven, Leuven, Belgium.
• Regeneron Genetics Center, Regeneron Pharmaceuticals, Tarrytown, NY, USA.
• Indiana University School of Medicine & Indiana University Health, Indianapolis, IN, USA.
• The Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden.
• Department of Emergency and Internal Medicine, Skåne University Hospital, Malmö, Sweden.
• Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.

PMID:  39261724  DOI: 10.1038/s41586-024-07903-1

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.

心力衰竭是多种疾病的发病和死亡的主要原因之一。在心力衰竭中，升高的心内压和心肌细胞拉伸会触发对抗调节性利钠肽的释放，这些肽通过其受体（NPR1）发挥作用，影响血管扩张、利尿和排钠，从而降低静脉压并缓解静脉淤血。重组利钠肽的注射被开发用于治疗心力衰竭，但其作用时间较短。我们在此报告了一项针对超过70万人的人类基因分析，结果显示，NPR1基因编码变异的终生暴露与血压变化和心力衰竭风险相关。我们描述了REGN5381的开发，这是一种针对膜结合鸟苷酸环化酶受体NPR1的研究性单克隆激动抗体。REGN5381是一种NPR1的变构激动剂，可诱导受体呈现类似活性的构象，从而对静脉血管系统产生血流动力学效应，包括在动物模型中降低收缩压和静脉压。在健康志愿者中，REGN5381产生了预期的血流动力学效应，表现为静脉压降低，而没有明显的利尿和排钠变化。这些数据支持开发REGN5381，用于长期且选择性地降低心力衰竭患者症状背后的静脉压。