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<p>Cross-reactive antibodies targeting multiple epitopes have been identified in Sarbecoviruses, but the precise molecular mechanism(s) behind the crossreactivity remain poorly understood. Here, we isolate 3D1, a broadly neutralizing antibody (bnAb) derived from a human combinatorial antibody library targeting the conserved HR1 domain. 3D1 uniquely recognizes a β-turn fold comprising a 6-mer peptide (pep<sup>DVVNQN/Q</sup>) that forms during a pre-hairpin transition state, occurring exclusively before membrane fusion during viral infection. 3D1 effectively neutralizes a wide range of live SARS-CoV-2 wild-type strains except for Omicron, which evades neutralization due to a detrimental point mutation (Q954H). Notably, this cryptic epitope reveals a signature motif that extends throughout the core region of coronaviruses and is also present in various RNA viruses, including HIV and Marburgvirus. 3D1 functions as a natural or background antibody capable of binding to a diverse array of non-self antigens. 3D1’s cross-reactivity underscores the effectiveness of the library approach, which encompasses the entire antibody repertoire.</p>

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A broadly neutralizing antibody recognizes a unique epitope with a signature motif common across coronaviruses

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月15日

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  • Lei Yan,
  • Fulian Wang,
  • Michelle Hill,
  • Juliane Brun,
  • Ze Liang,
  • Xinyu Shi,
  • Liangminghui Zhang,
  • Xiuxiu He,
  • Yu Li,
  • Qianping Huang,
  • Xuxue Dong,
  • Huanzhen Liu,
  • Yi Zhang,
  • Lili Liu,
  • Raymond A. Dwek,
  • Nicole Zitzmann,
  • Aibin Liang,
  • Guang Yang

摘要

Cross-reactive antibodies targeting multiple epitopes have been identified in Sarbecoviruses, but the precise molecular mechanism(s) behind the crossreactivity remain poorly understood. Here, we isolate 3D1, a broadly neutralizing antibody (bnAb) derived from a human combinatorial antibody library targeting the conserved HR1 domain. 3D1 uniquely recognizes a β-turn fold comprising a 6-mer peptide (pepDVVNQN/Q) that forms during a pre-hairpin transition state, occurring exclusively before membrane fusion during viral infection. 3D1 effectively neutralizes a wide range of live SARS-CoV-2 wild-type strains except for Omicron, which evades neutralization due to a detrimental point mutation (Q954H). Notably, this cryptic epitope reveals a signature motif that extends throughout the core region of coronaviruses and is also present in various RNA viruses, including HIV and Marburgvirus. 3D1 functions as a natural or background antibody capable of binding to a diverse array of non-self antigens. 3D1’s cross-reactivity underscores the effectiveness of the library approach, which encompasses the entire antibody repertoire.