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

Author

Listed:
  • 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
    Galveston National Laboratory)

  • Robin Bombardi

    (Vanderbilt University Medical Center)

  • Sean Hui

    (The Scripps Research Institute)

  • Kai Huang

    (University of Texas Medical Branch
    Galveston National Laboratory)

  • Alexander Bukreyev

    (University of Texas Medical Branch
    Galveston National Laboratory
    University of Texas Medical Branch)

  • James E. Crowe

    (Vanderbilt University Medical Center
    Vanderbilt University Medical Center)

  • Erica Ollmann Saphire

    (The Scripps Research Institute
    The Scripps Research Institute
    La Jolla Institute for Immunology La Jolla)

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.

Suggested Citation

  • 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 Saph, 2019. "Cross-reactive neutralizing human survivor monoclonal antibody BDBV223 targets the ebolavirus stalk," Nature Communications, Nature, vol. 10(1), pages 1-8, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-09732-7
    DOI: 10.1038/s41467-019-09732-7
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    Cited by:

    1. Kemin Tan & Junjian Chen & Yu Kaku & Yi Wang & Luke Donius & Rafiq Ahmad Khan & Xiaolong Li & Hannah Richter & Michael S. Seaman & Thomas Walz & Wonmuk Hwang & Ellis L. Reinherz & Mikyung Kim, 2023. "Inadequate structural constraint on Fab approach rather than paratope elicitation limits HIV-1 MPER vaccine utility," Nature Communications, Nature, vol. 14(1), pages 1-14, December.

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