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Updated: Jun 13, 2025

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Agonist antibody to guanylate cyclase receptor NPR1 regulates vascular tone

Michael E Dunn1, Aaron Kithcart2, Jee Hae Kim2

  • 1Regeneron Pharmaceuticals, Tarrytown, NY, USA. michael.dunn@regeneron.com.

Nature
|September 11, 2024
PubMed

Insights

Genetic variants in the natriuretic peptide receptor 1 (NPR1) gene influence heart failure risk. A new antibody, REGN5381, selectively lowers venous pressure, offering a potential new treatment for heart failure patients.

Area of Science:

  • Cardiovascular Medicine
  • Pharmacology
  • Genetics

Background:

  • Heart failure is a major cause of illness and death.
  • Natriuretic peptides and their receptor (NPR1) play a role in regulating blood pressure and fluid balance.
  • Existing treatments using natriuretic peptides have limitations due to short duration of effect.

Purpose of the Study:

  • To investigate the association between genetic variants of the NPR1 gene and heart failure risk.
  • To develop and evaluate a novel therapeutic agent targeting the NPR1 receptor for heart failure treatment.

Main Methods:

  • Human genetic analysis of over 700,000 individuals.
  • Development of REGN5381, a monoclonal agonist antibody targeting the NPR1 receptor.
  • Assessment of REGN5381's hemodynamic effects in animal models and healthy human volunteers.

Main Results:

  • Lifelong exposure to NPR1 gene variants is linked to altered blood pressure and heart failure risk.
  • REGN5381 demonstrated preferential reduction of venous pressure and systolic blood pressure in animal models.
  • In humans, REGN5381 induced expected hemodynamic effects, reducing venous pressure without significant changes in diuresis or natriuresis.

Conclusions:

  • Genetic insights into NPR1 function provide a basis for novel heart failure therapies.
  • REGN5381 shows promise as a long-lasting therapeutic agent for selectively lowering venous pressure in heart failure.
  • Further development of REGN5381 is supported for managing heart failure symptoms driven by elevated venous pressures.

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