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Agonist antibody to guanylate cyclase receptor NPR1 regulates vascular tone

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2024年9月11日

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  • Michael E. Dunn,
  • Aaron Kithcart,
  • Jee Hae Kim,
  • Andre Jo-Hao Ho,
  • Matthew C. Franklin,
  • Annabel Romero Hernandez,
  • Jan de 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,
  • Daniel J. Rader,
  • Marylyn D. Ritchie,
  • JoEllen Weaver,
  • Nawar Naseer,
  • Afiya Poindexter,
  • Khadijah Hu-Sain,
  • Yi-An Ko,
  • Meghan Livingstone,
  • Fred Vadivieso,
  • Stephanie DerOhannessian,
  • Teo Tran,
  • Julia Stephanowski,
  • Monica Zielinski,
  • Ned Haubein,
  • Joseph Dunn,
  • Anurag Verma,
  • Colleen Morse Kripke,
  • Marjorie Risman,
  • Renae Judy,
  • Shefali S. Verma,
  • Yuki Bradford,
  • Scott Dudek,
  • Theodore Drivas,
  • Lance J. Adams,
  • Jackie Blank,
  • Dale Bodian,
  • Derek Boris,
  • Adam Buchanan,
  • David J. Carey,
  • Ryan D. Colonie,
  • F. Daniel Davis,
  • Dustin N. Hartzel,
  • Melissa Kelly,
  • H. Lester Kirchner,
  • Joseph B. Leader,
  • David H. Ledbetter,
  • J. Neil Manus,
  • Christa L. Martin,
  • Raghu P. Metpally,
  • Michelle Meyer,
  • Tooraj Mirshahi,
  • Matthew Oetjens,
  • Thomas Nate Person,
  • Christopher Still,
  • Natasha Strande,
  • Amy Sturm,
  • Jen Wagner,
  • Marc Williams,
  • Goncalo Abecasis,
  • Michael Cantor,
  • Giovanni Coppola,
  • Andrew Deubler,
  • Aris Economides,
  • John D. Overton,
  • Jeffrey G. Reid,
  • Katherine Siminovitch,
  • Alan Shuldiner,
  • Christina Beechert,
  • Caitlin Forsythe,
  • Erin D. Fuller,
  • Zhenhua Gu,
  • Michael Lattari,
  • Alexander Lopez,
  • Maria Sotiropoulos Padilla,
  • Manasi Pradhan,
  • Kia Manoochehri,
  • Thomas D. Schleicher,
  • Louis Widom,
  • Sarah E. Wolf,
  • Ricardo H. Ulloa,
  • Amelia Averitt,
  • Nilanjana Banerjee,
  • Dadong Li,
  • Sameer Malhotra,
  • Deepika Sharma,
  • Jeffrey C. Staples,
  • Xiaodong Bai,
  • Suganthi Balasubramanian,
  • Suying Bao,
  • Boris Boutkov,
  • Siying Chen,
  • Gisu Eom,
  • Lukas Habegger,
  • Alicia Hawes,
  • Shareef Khalid,
  • Olga Krasheninina,
  • Rouel Lanche,
  • Adam J. Mansfield,
  • Evan K. Maxwell,
  • George Mitra,
  • Mona Nafde,
  • Sean O’Keeffe,
  • Max Orelus,
  • Razvan Panea,
  • Tommy Polanco,
  • Ayesha Rasool,
  • William Salerno,
  • Kathie Sun,
  • Joshua Backman,
  • Amy Damask,
  • Lee Dobbyn,
  • Manuel Allen Revez Ferreira,
  • Arkopravo Ghosh,
  • Christopher Gillies,
  • Lauren Gurski,
  • Eric Jorgenson,
  • Hyun Min Kang,
  • Michael Kessler,
  • Jack Kosmicki,
  • Alexander Li,
  • Nan Lin,
  • Daren Liu,
  • Jonathan Marchini,
  • Anthony Marcketta,
  • Joelle Mbatchou,
  • Arden Moscati,
  • Charles Paulding,
  • Carlo Sidore,
  • Eli Stahl,
  • Kyoko Watanabe,
  • Bin Ye,
  • Blair Zhang,
  • Andrey Ziyatdinov,
  • Ariane Ayer,
  • Aysegul Guvenek,
  • George Hindy,
  • Jan Freudenberg,
  • Jonas Bovijn,
  • Kavita Praveen,
  • Manav Kapoor,
  • Mary Haas,
  • Moeen Riaz,
  • Olukayode Sosina,
  • Parsa Akbari,
  • Priyanka Nakka,
  • Sahar Gelfman,
  • Sujit Gokhale,
  • Veera Rajagopal,
  • Gannie Tzoneva,
  • Juan Rodriguez-Flores,
  • Esteban Chen,
  • Marcus B. Jones,
  • Michelle G. LeBlanc,
  • Jason Mighty,
  • Lyndon J. Mitnaul,
  • Nirupama Nishtala,
  • Nadia Rana,
  • Jaimee Hernandez,
  • Jennifer Rico Varela,
  • 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,
  • Lori Morton

摘要

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.