Abstract 4365558: The Impact of an Investigational First-In-Class Fully Human Natriuretic Peptide Receptor 1-Blocking Monoclonal Antibody REGN7544 on Systolic Blood Pressure and Hypovolemic and Hypotensive Disorders in Mice

Abstract

Introduction: Natriuretic peptide receptor 1 (NPR1) activation by atrial and brain natriuretic peptides (ANPs and BNPs) reduces BP through vasorelaxation and decreased intravascular volume. Blocking NPR1 to counteract the effects of ANPs and BNPs is expected to raise BP. Hypothesis: We hypothesized that the human monoclonal NPR1-blocking antibody REGN7544 raises BP, possibly via inhibition of vasorelaxation and increased intravascular volume. Methods: REGN7544, developed using VelocImmune ® technology, was assessed for binding kinetics, NPR1 inhibition, and structural basis of inhibition. Pharmacodynamics were assessed in telemetered normotensive and hypotensive (ANP overexpression by hydrodynamic DNA delivery) humanized-NPR1 ( NPR1 hu/hu ) mice and normotensive cynomolgus monkeys. Vessel reactivity assays were performed using mesenteric vessels isolated from NPR1 hu/hu mice to determine functional effect of NPR1 blockade on ANP-induced vasorelaxation. Reversal of the REGN7544 effect on BP in NPR1 hu/hu mice was performed using SOC BP-lowering agents. Results: REGN7544 binds to human and monkey NPR1, independent of ANP/BNP, with subnanomolar affinity. Ligand-induced NPR1 activation was noncompetitively inhibited by REGN7544. Dose-dependent SBP increased in normotensive NPR1 hu/hu mice after one dose of REGN7544; a high dose achieved a 10–15 mmHg rise for up to 28 d with no further increase following repeat dosing. SBP increased by 30–40 mmHg in hypotensive NPR1 hu/hu mice. A dose-dependent and persistent SBP increase was observed in monkeys following a single high dose of REGN7544, causing a 15–20 mmHg rise for up to 28 d, along with a transient N-terminal pro-ANP increase and hematocrit decrease (suggesting hemodilution). REGN7544 significantly inhibited ANP-induced relaxation of precontracted mesenteric vessels isolated from NPR1 hu/hu mice confirming direct modulation of vascular tone. The BP increase caused by REGN7544 in NPR1 hu/hu mice was reversed by SOC BP-lowering agents, indicating a specific reversal agent would not be required. Conclusions: These data demonstrated that the high-affinity NPR1-blocking antibody REGN7544 increased SBP in normotensive and hypotensive NPR1 hu/hu mice and normotensive monkeys, possibly via inhibited vasorelaxation and altered blood volume. REGN7544 has potential to be a selective and long-acting treatment for hypervolemic and hypotensive disorders, including postural orthostatic tachycardia syndrome and sepsis-induced hypotension.