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Anti-Ebola virus mAb 3A6 protects highly viremic animals from fatal outcome via binding GP(1,2) in a position elevated from the virion membrane

Author

Listed:
  • Kathryn M. Hastie

    (La Jolla Institute for Immunology)

  • Zhe Li Salie

    (La Jolla Institute for Immunology
    Eli Lilly)

  • Zunlong Ke

    (Medical Research Council Laboratory of Molecular Biology
    Martinsried
    the University of Texas at Austin)

  • Peter J. Halfmann

    (University of Wisconsin)

  • Lisa Evans DeWald

    (Fort Detrick)

  • Sara McArdle

    (La Jolla)

  • Ariadna Grinyó

    (Integral Molecular
    Hospital del Mar Research Institute)

  • Edgar Davidson

    (Integral Molecular)

  • Sharon L. Schendel

    (La Jolla Institute for Immunology)

  • Chitra Hariharan

    (La Jolla Institute for Immunology)

  • Michael J. Norris

    (La Jolla Institute for Immunology
    University of Toronto)

  • Xiaoying Yu

    (La Jolla Institute for Immunology
    Arcturus Therapeutics)

  • Chakravarthy Chennareddy

    (Emory Vaccine Center)

  • Xiaoli Xiong

    (Medical Research Council Laboratory of Molecular Biology
    Science Park)

  • Megan Heinrich

    (Zalgen Labs LLC)

  • Michael R. Holbrook

    (Fort Detrick)

  • Benjamin Doranz

    (Integral Molecular)

  • Ian Crozier

    (Frederick National Laboratory for Cancer Research)

  • Yoshihiro Kawaoka

    (University of Wisconsin
    University of Tokyo
    National Center for Global Health and Medicine Research Institute
    University of Tokyo)

  • Luis M. Branco

    (Zalgen Labs LLC)

  • Jens H. Kuhn

    (Fort Detrick)

  • John A. G. Briggs

    (Medical Research Council Laboratory of Molecular Biology
    Martinsried)

  • Gabriella Worwa

    (Fort Detrick)

  • Carl W. Davis

    (Emory Vaccine Center)

  • Rafi Ahmed

    (Emory Vaccine Center)

  • Erica Ollmann Saphire

    (La Jolla Institute for Immunology
    University of California San Diego)

Abstract

Monoclonal antibodies (mAbs) against Ebola virus (EBOV) glycoprotein (GP1,2) are the standard of care for Ebola virus disease (EVD). Anti-GP1,2 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 GP1,2 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 GP1,2 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.

Suggested Citation

  • 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 & Xia, 2025. "Anti-Ebola virus mAb 3A6 protects highly viremic animals from fatal outcome via binding GP(1,2) in a position elevated from the virion membrane," Nature Communications, Nature, vol. 16(1), pages 1-12, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56452-2
    DOI: 10.1038/s41467-025-56452-2
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    References listed on IDEAS

    as
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