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

Kathryn M. Hastie, Zhe Li Salie, Zunlong Ke, Peter J. Halfmann, Lisa Evans DeWald, Sara McArdle, Ariadna Grinyó, Edgar Davidson, Sharon L. Schendel, Chitra Hariharan, Michael J. Norris, Xiaoying Yu, Chakravarthy Chennareddy, Xiaoli Xiong, Megan Heinrich, Michael R. Holbrook, Benjamin Doranz, Ian Crozier, Yoshihiro Kawaoka, Luis M. Branco, Jens H. Kuhn (), John A. G. Briggs (), Gabriella Worwa (), Carl W. Davis (), Rafi Ahmed () and Erica Ollmann Saphire ()
Additional contact information
Kathryn M. Hastie: La Jolla Institute for Immunology
Zhe Li Salie: La Jolla Institute for Immunology
Zunlong Ke: Medical Research Council Laboratory of Molecular Biology
Peter J. Halfmann: University of Wisconsin
Lisa Evans DeWald: Fort Detrick
Sara McArdle: La Jolla
Ariadna Grinyó: Integral Molecular
Edgar Davidson: Integral Molecular
Sharon L. Schendel: La Jolla Institute for Immunology
Chitra Hariharan: La Jolla Institute for Immunology
Michael J. Norris: La Jolla Institute for Immunology
Xiaoying Yu: La Jolla Institute for Immunology
Chakravarthy Chennareddy: Emory Vaccine Center
Xiaoli Xiong: Medical Research Council Laboratory of Molecular Biology
Megan Heinrich: Zalgen Labs LLC
Michael R. Holbrook: Fort Detrick
Benjamin Doranz: Integral Molecular
Ian Crozier: Frederick National Laboratory for Cancer Research
Yoshihiro Kawaoka: University of Wisconsin
Luis M. Branco: Zalgen Labs LLC
Jens H. Kuhn: Fort Detrick
John A. G. Briggs: Medical Research Council Laboratory of Molecular Biology
Gabriella Worwa: Fort Detrick
Carl W. Davis: Emory Vaccine Center
Rafi Ahmed: Emory Vaccine Center
Erica Ollmann Saphire: La Jolla Institute for Immunology

Nature Communications, 2025, vol. 16, issue 1, 1-12

Abstract: Abstract Monoclonal antibodies (mAbs) against Ebola virus (EBOV) glycoprotein (GP1,2) are the standard of care for Ebola virus disease (EVD). Anti-GP1,2 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 GP1,2 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 GP1,2 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.

Date: 2025
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DOI: 10.1038/s41467-025-56452-2

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