Scholarlink

<p>Therapeutic monoclonal antibodies can prevent severe disease in SARS-CoV-2 exposed individuals. However, currently circulating virus variants have evolved to gain significant resistance to nearly all neutralizing human immune system-derived therapeutic monoclonal antibodies that had previously been emergency-authorized for use in the clinic. Here, we describe the discovery of a panel of single-domain antibodies (VHHs) directed against the spike protein S2 subunit that broadly neutralize SARS-CoV-1 and −2 with unusually high potency. One of these VHHs tightly clamps the spike’s monomers at a highly conserved, quaternary epitope in the membrane proximal part of the trimeric Heptad Repeat 2 (HR2) coiled-coil, thereby locking the HR2 in its prefusion conformation. Low dose systemic administration of a VHH-human IgG1 Fc fusion prevented SARS-CoV-2 infection in two animal models. Pseudovirus escape selection experiments demonstrate that the very rare escape variants are rendered almost non-infectious. This VHH-based antibody with a highly potent mechanism of antiviral action forms the basis for a new class of pan-sarbecovirus neutralizing biologics, which are currently under development. In addition, the unique quaternary binding mode of the VHHs to the prefusion HR2 could be exploited for other class I fusion proteins.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Ultrapotent SARS coronavirus-neutralizing single-domain antibodies that clamp the spike at its base

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年5月30日

查看全文
  • Sieglinde De Cae,
  • Inge Van Molle,
  • Loes van Schie,
  • Sophie R. Shoemaker,
  • Julie Deckers,
  • Nincy Debeuf,
  • Sahine Lameire,
  • Wim Nerinckx,
  • Kenny Roose,
  • Daria Fijalkowska,
  • Simon Devos,
  • Anne-Sophie De Smet,
  • Jackeline Cecilia Zavala Marchan,
  • Toon Venneman,
  • Koen Sedeyn,
  • Lejla Mujanovic,
  • Marlies Ballegeer,
  • Manon Vanheerswynghels,
  • Caroline De Wolf,
  • Hans Demol,
  • Jasper Zuallaert,
  • Pieter Vanhaverbeke,
  • Gholamreza Hassanzadeh Ghassabeh,
  • Chiara Lonigro,
  • Viki Bockstal,
  • Manuela Rinaldi,
  • Rana Abdelnabi,
  • Johan Neyts,
  • Susan Marqusee,
  • Bart N. Lambrecht,
  • Nico Callewaert,
  • Han Remaut,
  • Xavier Saelens,
  • Bert Schepens

摘要

Therapeutic monoclonal antibodies can prevent severe disease in SARS-CoV-2 exposed individuals. However, currently circulating virus variants have evolved to gain significant resistance to nearly all neutralizing human immune system-derived therapeutic monoclonal antibodies that had previously been emergency-authorized for use in the clinic. Here, we describe the discovery of a panel of single-domain antibodies (VHHs) directed against the spike protein S2 subunit that broadly neutralize SARS-CoV-1 and −2 with unusually high potency. One of these VHHs tightly clamps the spike’s monomers at a highly conserved, quaternary epitope in the membrane proximal part of the trimeric Heptad Repeat 2 (HR2) coiled-coil, thereby locking the HR2 in its prefusion conformation. Low dose systemic administration of a VHH-human IgG1 Fc fusion prevented SARS-CoV-2 infection in two animal models. Pseudovirus escape selection experiments demonstrate that the very rare escape variants are rendered almost non-infectious. This VHH-based antibody with a highly potent mechanism of antiviral action forms the basis for a new class of pan-sarbecovirus neutralizing biologics, which are currently under development. In addition, the unique quaternary binding mode of the VHHs to the prefusion HR2 could be exploited for other class I fusion proteins.