Cross-reactive neutralizing human survivor monoclonal antibody BDBV223 targets the ebolavirus stalk

Liam B. King, Brandyn R. West, Crystal L. Moyer, Pavlo Gilchuk, Andrew Flyak, Philipp A. Ilinykh, Robin Bombardi, Sean Hui, Kai Huang, Alexander Bukreyev, James E. Crowe and Erica Ollmann Saphire ()
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Liam B. King: The Scripps Research Institute
Brandyn R. West: The Scripps Research Institute
Crystal L. Moyer: The Scripps Research Institute
Pavlo Gilchuk: Vanderbilt University Medical Center
Andrew Flyak: Vanderbilt University Medical Center
Philipp A. Ilinykh: University of Texas Medical Branch
Robin Bombardi: Vanderbilt University Medical Center
Sean Hui: The Scripps Research Institute
Kai Huang: University of Texas Medical Branch
Alexander Bukreyev: University of Texas Medical Branch
James E. Crowe: Vanderbilt University Medical Center
Erica Ollmann Saphire: The Scripps Research Institute

Nature Communications, 2019, vol. 10, issue 1, 1-8

Abstract: Abstract Three Ebolavirus genus viruses cause lethal disease and lack targeted therapeutics: Ebola virus, Sudan virus and Bundibugyo virus. Monoclonal antibody (mAb) cocktails against the surface glycoprotein (GP) present a potential therapeutic strategy. Here we report two crystal structures of the antibody BDBV223, alone and complexed with its GP2 stalk epitope, an interesting site for therapeutic/vaccine design due to its high sequence conservation among ebolaviruses. BDBV223, identified in a human survivor of Bundibugyo virus disease, neutralizes both Bundibugyo virus and Ebola virus, but not Sudan virus. Importantly, the structure suggests that BDBV223 binding interferes with both the trimeric bundle assembly of GP and the viral membrane by stabilizing a conformation in which the monomers are separated by GP lifting or bending. Targeted mutagenesis of BDBV223 to enhance SUDV GP recognition indicates that additional determinants of antibody binding likely lie outside the visualized interactions, and perhaps involve quaternary assembly or membrane-interacting regions.

Date: 2019
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DOI: 10.1038/s41467-019-09732-7

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