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

• Published in: Nature communications Vol. 16; no. 1; pp. 1293 - 12
• Main Authors: Hastie, Kathryn M., Salie, Zhe Li, Ke, Zunlong, Halfmann, Peter J., DeWald, Lisa Evans, McArdle, Sara, Grinyó, Ariadna, Davidson, Edgar, Schendel, Sharon L., Hariharan, Chitra, Norris, Michael J., Yu, Xiaoying, Chennareddy, Chakravarthy, Xiong, Xiaoli, Heinrich, Megan, Holbrook, Michael R., Doranz, Benjamin, Crozier, Ian, Kawaoka, Yoshihiro, Branco, Luis M., Kuhn, Jens H., Briggs, John A. G., Worwa, Gabriella, Davis, Carl W., Ahmed, Rafi, Saphire, Erica Ollmann
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 03.02.2025; Nature Publishing Group; Nature Portfolio
• Subjects: 147/28; 631/250; 631/326/596; 631/535; 82/80; Animal models; Animals; Antibodies, Monoclonal - immunology; Antibodies, Monoclonal - pharmacology; Antibodies, Monoclonal - therapeutic use; Antibodies, Neutralizing - immunology; Antibodies, Viral - immunology; Conformation; Cryoelectron Microscopy; Crystallography; Crystallography, X-Ray; Disease Models, Animal; Ebola virus; Ebolavirus; Ebolavirus - drug effects; Ebolavirus - immunology; Epitopes; Epitopes - immunology; Female; Glycoproteins; Guinea Pigs; Hemorrhagic Fever, Ebola - immunology; Hemorrhagic Fever, Ebola - prevention & control; Hemorrhagic Fever, Ebola - virology; Humanities and Social Sciences; Humans; Macaca mulatta; Membranes; Mice; Monoclonal antibodies; multidisciplinary; Neutralization; Science; Science (multidisciplinary); Structural analysis; Tomography; Viral diseases; Viral Envelope Proteins - chemistry; Viral Envelope Proteins - immunology; Viral Envelope Proteins - metabolism; Viremia; Viremia - immunology; Viremia - prevention & control; Virion - immunology; Virion - metabolism; Virions; Viruses; X-ray crystallography
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-025-56452-2

Monoclonal antibodies (mAbs) against Ebola virus (EBOV) glycoprotein (GP 1,2 ) are the standard of care for Ebola virus disease (EVD). Anti-GP 1,2 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 GP 1,2 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 GP 1,2 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. Here, combining X-ray crystallography, cryo-electron tomography and animal studies, the authors show that the monoclonal antibody against Ebola virus glycoprotein (GP1,2) 3A6 exerts protection via binds to a conformation of GP1,2 that is lifted from the virion membrane, providing insights into the mechanism of action with implications for the design of anti-Ebola therapeutics.