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Peer-reviewedCC BY-NC-ND 4.0Cell Reports Medicine

Structural basis for broad orthopoxvirus neutralization by two antibodies targeting distinct L1R epitopes

  • Li Chen1,2
  • Guanying Zhang2
  • Haotian Lin2
  • Yue Zhang2
  • Jingfei Li2
  • Linfeng Shu2
  • Xiaolin Wang2
  • Ruihua Li2
  • Fangxin Zhao2
  • Xiaofan Zhao2
  • Yilong Yang2
  • Zhang Zhang2
5 more authors
  • Jun Zhang2
  • Congwen Wei2
  • Xiangyang Chi2
  • Xiaodong Zai2
  • Junjie Xu1,2
  1. 1School of Medicine, Zhejiang University, Hangzhou 310058, China
  2. 2National Key Laboratory of Advanced Biotechnology, Academy of Military Medical Sciences, Beijing 100071, China
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Abstract

The 2022 mpox outbreak highlights the persistent threat posed by the mpox virus (MPXV) and related orthopoxviruses (OPXVs). Yet, approved antibody-based therapeutics for OPXVs are lacking. Here, we present two broadly neutralizing monoclonal antibodies (mAbs), G4 and B9, that target the MPXV M1R protein, homologous to L1R in other OPXVs. Both mAbs demonstrate cross-reactive binding and robust neutralization against multiple pathogenic OPXVs. Notably, G4 exhibits exceptional potency, neutralizing mature virions of VACV with an IC50 of 37.93 pM, whereas B9 has an IC50 of 41.13 nM. Cryo-electron microscopy analysis reveals that G4 and B9 target distinct epitopes on M1R. G4 recognizes a conventional conformational epitope but overcomes neutralization escape associated with the Asp35 residue, whereas B9 binds to an epitope on the lateral β-sheets of M1R. Our findings provide two promising candidates with complementary neutralization profiles for the development of broad-spectrum prophylactic and therapeutic interventions against OPXV infections.

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Cite

BibTeXRIS
BibTeX
@article{chen2026structural,
  title = {{Structural basis for broad orthopoxvirus neutralization by two antibodies targeting distinct L1R epitopes}},
  author = {Li Chen and Guanying Zhang and Haotian Lin and Yue Zhang and Jingfei Li and Linfeng Shu and Xiaolin Wang and Ruihua Li and Fangxin Zhao and Xiaofan Zhao and Yilong Yang and Zhang Zhang and Jun Zhang and Congwen Wei and Xiangyang Chi and Xiaodong Zai and Junjie Xu},
  journal = {Cell Reports Medicine},
  year = {2026},
  month = sep,
  doi = {10.1016/j.xcrm.2026.103077},
  url = {https://doi.org/10.1016/j.xcrm.2026.103077},
  note = {CC BY-NC-ND 4.0},
}
RIS
TY  - JOUR
TI  - Structural basis for broad orthopoxvirus neutralization by two antibodies targeting distinct L1R epitopes
AU  - Li Chen
AU  - Guanying Zhang
AU  - Haotian Lin
AU  - Yue Zhang
AU  - Jingfei Li
AU  - Linfeng Shu
AU  - Xiaolin Wang
AU  - Ruihua Li
AU  - Fangxin Zhao
AU  - Xiaofan Zhao
AU  - Yilong Yang
AU  - Zhang Zhang
AU  - Jun Zhang
AU  - Congwen Wei
AU  - Xiangyang Chi
AU  - Xiaodong Zai
AU  - Junjie Xu
PY  - 2026
DA  - 2026/09/28
JO  - Cell Reports Medicine
DO  - 10.1016/j.xcrm.2026.103077
UR  - https://doi.org/10.1016/j.xcrm.2026.103077
AB  - The 2022 mpox outbreak highlights the persistent threat posed by the mpox virus (MPXV) and related orthopoxviruses (OPXVs). Yet, approved antibody-based therapeutics for OPXVs are lacking. Here, we present two broadly neutralizing monoclonal antibodies (mAbs), G4 and B9, that target the MPXV M1R protein, homologous to L1R in other OPXVs. Both mAbs demonstrate cross-reactive binding and robust neutralization against multiple pathogenic OPXVs. Notably, G4 exhibits exceptional potency, neutralizing mature virions of VACV with an IC50 of 37.93 pM, whereas B9 has an IC50 of 41.13 nM. Cryo-electron microscopy analysis reveals that G4 and B9 target distinct epitopes on M1R. G4 recognizes a conventional conformational epitope but overcomes neutralization escape associated with the Asp35 residue, whereas B9 binds to an epitope on the lateral β-sheets of M1R. Our findings provide two promising candidates with complementary neutralization profiles for the development of broad-spectrum prophylactic and therapeutic interventions against OPXV infections.
SN  - 2666-3791
ER  -