Agonist antibody to guanylate cyclase receptor NPR1 regulates vascular tone
Dunn, M.E. ; Melander, O. LU
and Morton, L.
(2024)
In Nature
633(8030).
p.654-661
- 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... (More)
- 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. © The Author(s) 2024. (Less)
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- author
- Dunn, M.E.
; Melander, O.
LU
and Morton, L.
- author collaboration
- organization
- publishing date
- 2024
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Adult, Allosteric Regulation, Animals, Antibodies, Monoclonal, Blood Pressure, Diuresis, Female, Healthy Volunteers, Heart Failure, Hemodynamics, Humans, Male, Mice, Middle Aged, Natriuresis, Receptors, Atrial Natriuretic Factor, atrial natriuretic factor, drug derivative, guanylate cyclase, atrial natriuretic factor receptor, monoclonal antibody, natriuretic peptide receptor A, animal, antibody, blood, genetic analysis, health risk, morbidity, peptide, adult, animal experiment, Article, blood pressure, blood vessel tone, C57BL 6 mouse, controlled study, diuresis, double blind procedure, drug development, female, flow cytometry, heart failure, HEK293 cell line, hemodynamics, human, human cell, human experiment, male, mortality, natriuresis, nonhuman, normal human, randomized controlled trial, single drug dose, symptomatology, systolic blood pressure, vasodilatation, allosterism, drug effect, drug therapy, genetics, metabolism, middle aged, mouse, pathophysiology
- in
- Nature
- volume
- 633
- issue
- 8030
- pages
- 8 pages
- publisher
- Nature Publishing Group
- external identifiers
-
- scopus:85204342310
- pmid:39261724
- ISSN
- 0028-0836
- DOI
- 10.1038/s41586-024-07903-1
- language
- English
- LU publication?
- yes
- id
- e18009f7-5c01-4604-8606-b7f945eb2894
- date added to LUP
- 2024-12-12 14:04:10
- date last changed
- 2025-06-27 06:47:52
@article{e18009f7-5c01-4604-8606-b7f945eb2894,
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. © The Author(s) 2024.}},
author = {{Dunn, M.E. and Melander, O. and Morton, L.}},
issn = {{0028-0836}},
keywords = {{Adult; Allosteric Regulation; Animals; Antibodies, Monoclonal; Blood Pressure; Diuresis; Female; Healthy Volunteers; Heart Failure; Hemodynamics; Humans; Male; Mice; Middle Aged; Natriuresis; Receptors, Atrial Natriuretic Factor; atrial natriuretic factor; drug derivative; guanylate cyclase; atrial natriuretic factor receptor; monoclonal antibody; natriuretic peptide receptor A; animal; antibody; blood; genetic analysis; health risk; morbidity; peptide; adult; animal experiment; Article; blood pressure; blood vessel tone; C57BL 6 mouse; controlled study; diuresis; double blind procedure; drug development; female; flow cytometry; heart failure; HEK293 cell line; hemodynamics; human; human cell; human experiment; male; mortality; natriuresis; nonhuman; normal human; randomized controlled trial; single drug dose; symptomatology; systolic blood pressure; vasodilatation; allosterism; drug effect; drug therapy; genetics; metabolism; middle aged; mouse; pathophysiology}},
language = {{eng}},
number = {{8030}},
pages = {{654--661}},
publisher = {{Nature Publishing Group}},
series = {{Nature}},
title = {{Agonist antibody to guanylate cyclase receptor NPR1 regulates vascular tone}},
url = {{http://dx.doi.org/10.1038/s41586-024-07903-1}},
doi = {{10.1038/s41586-024-07903-1}},
volume = {{633}},
year = {{2024}},
}