Anti-Ebola virus mAb 3A6 protects highly viremic animals from fatal outcome via binding GP<sub>(1,2)</sub> in a position elevated from the virion membrane.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 39900911.
- Also identified by DOI 10.1038/s41467-025-56452-2 and PMC identifier 11791206.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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.
Medical subject headings
- Antibodies, Monoclonal
- Ebolavirus
- Hemorrhagic Fever, Ebola
- Virion
- Antibodies, Viral
- Viral Envelope Proteins
- Viremia