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Title | Anti-Ebola virus mAb 3A6 protects highly viremic animals from fatal outcome via binding GP in a position elevated from the virion membrane. |
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Journal, issue, pages | Nat Commun, Vol. 16, Issue 1, Page 1293, Year 2025 |
Publish date | Feb 3, 2025 |
![]() | 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 / Erica Ollmann Saphire / ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
PubMed Abstract | Monoclonal antibodies (mAbs) against Ebola virus (EBOV) glycoprotein (GP) are the standard of care for Ebola virus disease (EVD). Anti-GP mAbs targeting the stalk and membrane proximal external ...Monoclonal antibodies (mAbs) against Ebola virus (EBOV) glycoprotein (GP) are the standard of care for Ebola virus disease (EVD). Anti-GP 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 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 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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Methods | EM (subtomogram averaging) |
Resolution | 7.4 - 17.7 Å |
Structure data | ![]() EMDB-45833: KZ52 Fab fragment bound to Ebola GP, subtomogram average from a tight mask ![]() EMDB-45834: KZ52 Fab fragment bound to Ebola GP, subtomogram average from a cylinder mask ![]() EMDB-45835: 3A6 Fab fragment bound to Ebola GP, subtomogram average from a cylinder mask ![]() EMDB-45836: 3A6 and KZ52 Fab fragments bound to Ebola GP, subtomogram average from a tight mask ![]() EMDB-45837: 3A6 and KZ52 Fab fragments bound to Ebola GP, subtomogram average from a cylinder mask |