Anti-Ebola virus mAb 3A6 protects highly viremic animals from fatal outcome via binding GP(1,2) in a position elevated from the virion membrane

Monoclonal antibodies (mAbs) against Ebola virus (EBOV) glycoprotein (GP<sub>1,2</sub>) are the standard of care for Ebola virus disease (EVD). Anti-GP<sub>1,2</sub> mAbs targeting the stalk and membrane proximal external region (MPER) potently neutralize EBOV in vitro and are protective in a mouse model of EVD. However, their neutralization mechanism is poorly understood because they target a GP<sub>1,2</sub> epitope that has evaded structural characterization. Using X-ray crystallography and cryo-electron tomography of mAb 3A6 complexed with its stalk-MPER epitope, we reveal a previously undescribed mechanism in which 3A6 binds to a conformation of GP<sub>1,2</sub> that is lifted from the virion membrane. We further show that in both domestic guinea pig and rhesus monkey EVD models, 3A6 provides therapeutic benefit at high-viremia advanced disease stages and at the lowest dose yet demonstrated for any anti-EBOV mAb-based monotherapy. The findings reported here can guide design of next-generation highly potent anti-EBOV therapeutics and vaccines.

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Publication Details

Journal
Nature Communications
Published
2025-02-03
DOI
https://doi.org/10.1038/s41467-025-56452-2
Citations
3
Primary Topic
Viral Infections and Outbreaks Research
Type
article
Field-Weighted Citation Impact
4.19

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article

Anti-Ebola virus mAb 3A6 protects highly viremic animals from fatal outcome via binding GP(1,2) in a position elevated from the virion membrane

Michael R. Holbrook, Xiaoli Xiong, Jens H. Kuhn, Rafi Ahmed et al.
3 citations
Nature Communications
Viral Infections and Outbreaks Research
4.19
article

Anti-Ebola virus mAb 3A6 protects highly viremic animals from fatal outcome via binding GP(1,2) in a position elevated from the virion membrane

Michael R. Holbrook, Xiaoli Xiong, Jens H. Kuhn, Rafi Ahmed, John A. G. Briggs, Zhe Salie, Zunlong Ke, Ariadna Grinyo i Escuer, Sharon L. Schendel, Ian Crozier, Sara McArdle, Edgar Davidson, Megan L. Heinrich, Luis M. Branco, Benjamin J. Doranz, Erica Ollmann Saphire, Peter Halfmann, Gabriella Worwa, Yoshihiro Kawaoka, Kathryn M. Hastie, Lisa Evans DeWald, Michael Norris, Carl W. Davis, Chakravarthy Chennareddy, Chitra Hariharan, Xiaoying Yu
article en
3 citations

Abstract

Monoclonal antibodies (mAbs) against Ebola virus (EBOV) glycoprotein (GP<sub>1,2</sub>) are the standard of care for Ebola virus disease (EVD). Anti-GP<sub>1,2</sub> mAbs targeting the stalk and membrane proximal external region (MPER) potently neutralize EBOV in vitro and are protective in a mouse model of EVD. However, their neutralization mechanism is poorly understood because they target a GP<sub>1,2</sub> epitope that has evaded structural characterization. Using X-ray crystallography and cryo-electron tomography of mAb 3A6 complexed with its stalk-MPER epitope, we reveal a previously undescribed mechanism in which 3A6 binds to a conformation of GP<sub>1,2</sub> that is lifted from the virion membrane. We further show that in both domestic guinea pig and rhesus monkey EVD models, 3A6 provides therapeutic benefit at high-viremia advanced disease stages and at the lowest dose yet demonstrated for any anti-EBOV mAb-based monotherapy. The findings reported here can guide design of next-generation highly potent anti-EBOV therapeutics and vaccines.

Nature CommunicationsVol. 16(1)
National Institutes of Health (US), La Jolla Institute for Immunology (US), Emory Healthcare (US), University of Wisconsin–Madison (US), Emory University (US), Tokyo University of Science (JP), Eli Lilly (United States) (US), MRC Laboratory of Molecular Biology (GB), University of Toronto (CA), Guangzhou Institutes of Biomedicine and Health (CN), University of California San Diego (US), National Center for Global Health and Medicine (JP), Arcturus Therapeutics (United States) (US), Vall d'Hebron Hospital Universitari (ES), Frederick National Laboratory for Cancer Research (US), National Institute of Allergy and Infectious Diseases (US), Integral Molecular (United States) (US), Max Planck Institute of Biochemistry (DE), Zalgen (United States) (US), The University of Tokyo (JP), The University of Texas at Austin (US), Medical Research Council (GB)
U.S. Department of Energy, U.S. Department of Health and Human Services, Battelle, Eli Lilly and Company, Emory University, National Center for Global Health and Medicine, Frederick National Laboratory for Cancer Research, European Commission, Chinese Academy of Sciences, University of Toronto, Max-Planck-Gesellschaft, National Institutes of Health, Defense Advanced Research Projects Agency, Office of Science, University of California, San Diego, Medical Research Council, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Institute of Medical Science, University of Tokyo, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, Basic Energy Sciences, Biological and Environmental Research, Argonne National Laboratory, SLAC National Accelerator Laboratory
Good health and well-being
Openalex Percentile: Top 8%
Viral Infections and Outbreaks Research
4.19
DOIOpen Access PDFOpenAlex
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