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, Erica Ollmann Saphire

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number1788
JournalNature communications
Volume10
Issue number1
DOIs
StatePublished - Dec 1 2019

Fingerprint

Ebolavirus
viruses
antibodies
Viruses
Monoclonal Antibodies
Membrane Glycoproteins
Sudan
Antibodies
Virus Diseases
Mutagenesis
Epitopes
Therapeutics
Vaccines
vaccines
membranes
Membranes
mutagenesis
determinants
bundles
Conformations

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

King, L. B., West, B. R., Moyer, C. L., Gilchuk, P., Flyak, A., Ilinykh, P. A., ... Saphire, E. O. (2019). Cross-reactive neutralizing human survivor monoclonal antibody BDBV223 targets the ebolavirus stalk. Nature communications, 10(1), [1788]. https://doi.org/10.1038/s41467-019-09732-7

Cross-reactive neutralizing human survivor monoclonal antibody BDBV223 targets the ebolavirus stalk. / King, Liam B.; West, Brandyn R.; Moyer, Crystal L.; Gilchuk, Pavlo; Flyak, Andrew; Ilinykh, Philipp A.; Bombardi, Robin; Hui, Sean; Huang, Kai; Bukreyev, Alexander; Crowe, James E.; Saphire, Erica Ollmann.

In: Nature communications, Vol. 10, No. 1, 1788, 01.12.2019.

Research output: Contribution to journalArticle

King, LB, West, BR, Moyer, CL, Gilchuk, P, Flyak, A, Ilinykh, PA, Bombardi, R, Hui, S, Huang, K, Bukreyev, A, Crowe, JE & Saphire, EO 2019, 'Cross-reactive neutralizing human survivor monoclonal antibody BDBV223 targets the ebolavirus stalk', Nature communications, vol. 10, no. 1, 1788. https://doi.org/10.1038/s41467-019-09732-7
King, Liam B. ; West, Brandyn R. ; Moyer, Crystal L. ; Gilchuk, Pavlo ; Flyak, Andrew ; Ilinykh, Philipp A. ; Bombardi, Robin ; Hui, Sean ; Huang, Kai ; Bukreyev, Alexander ; Crowe, James E. ; Saphire, Erica Ollmann. / Cross-reactive neutralizing human survivor monoclonal antibody BDBV223 targets the ebolavirus stalk. In: Nature communications. 2019 ; Vol. 10, No. 1.
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