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Dec 22, 2023;

Anti-Ebola virus mAb 3A6 with unprecedented potency protects highly viremic animals from fatal outcome and physically lifts its glycoprotein target from the virion membrane.

Erica Saphire, Zhe Li Salie, Zunlong Ke, Peter Halfmann, Lisa Evans DeWald, Sara McArdle, Ariadna Grinyo, Edgar Davidson, Sharon Schendel, Chitra Hariharan, Michael Norris, Xiaoying Yu, Chakravarthy Chennareddy, Xiaoli Xiong, Megan Heinrich, Michael Holbrook, Benjamin Doranz, Ian Crozier, Kathryn Hastie, Yoshihiro Kawaoka, Luis Branco, Jens Kuhn, John Briggs, Gabriella Worwa, Carl Davis, Rafi Ahmed
Author Information
  1. Erica Saphire: La Jolla Institute for Immunology. ORCID
  2. Zhe Li Salie: Eli Lilly.
  3. Zunlong Ke: Medical Research Council.
  4. Peter Halfmann: University of Wisconsin - Madison. ORCID
  5. Lisa Evans DeWald: Emergent Biosolutions.
  6. Sara McArdle: La Jolla Institute for Immunology. ORCID
  7. Ariadna Grinyo: Integral Molecular.
  8. Edgar Davidson: Integral Molecular.
  9. Sharon Schendel: La Jolla Institute for Immunology. ORCID
  10. Chitra Hariharan: La Jolla Institute for Immunology.
  11. Michael Norris: Univeristy of Toronto Canada.
  12. Xiaoying Yu: La Jolla Institute for Immunology.
  13. Chakravarthy Chennareddy: Emory University.
  14. Xiaoli Xiong: Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences. ORCID
  15. Megan Heinrich: Page 2/29 Zalgen Labs, LLC.
  16. Michael Holbrook: National Institute of Allergy and Infectious Diseases (NIAID) Integrated Research Facility, National Institutes of Health (NIH). ORCID
  17. Benjamin Doranz: Integral Molecular. ORCID
  18. Kathryn Hastie: La Jolla Institute for Immunology.
  19. Yoshihiro Kawaoka: University of Wisconsin-Madison. ORCID
  20. Luis Branco: Zalgen.
  21. Jens Kuhn: National Institutes of Health (NIH). ORCID
  22. John Briggs: Medical Research Council.
  23. Gabriella Worwa: National Institutes of Health.
  24. Carl Davis: Emory University.
  25. Rafi Ahmed: Emory University School of Medicine. ORCID
PMID: 38196595 DOI: 10.21203/rs.3.rs-3722563/v1

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 region (MPER) potently neutralize EBOV . However, their neutralization mechanism is poorly understood because they target a GP epitope that has evaded structural characterization. Moreover, their efficacy has only been evaluated in the mouse model of EVD. Using x-ray crystallography and cryo-electron tomography of 3A6 complexed with its stalk- GP MPER epitope we reveal a novel mechanism in which 3A6 elevates the stalk or stabilizes a conformation of GP that is lifted from the virion membrane. In domestic guinea pig and rhesus monkey EVD models, 3A6 provides therapeutic benefit at high viremia levels, advanced disease stages, and at the lowest dose yet demonstrated for any anti-EBOV mAb-based monotherapy. These findings can guide design of next-generation, highly potent anti-EBOV mAbs.

Keywords

3A6 Animal study EBOV Ebola virus MPER antibody efficacy study mAb membrane proximal external region monoclonal antibody stalk

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Grants

  1. 75N91019D00024/NCI NIH HHS
  2. HHSN272200700016I/NIAID NIH HHS
  3. HHSN261201500003C/NCI NIH HHS
  4. S10 OD012289/NIH HHS
  5. U19 AI142790/NIAID NIH HHS
  6. HHSN261201500003I/NCI NIH HHS
  7. HHSN272201400058C/NIAID NIH HHS
  8. HHSN272201800013C/NIAID NIH HHS
  9. P41 GM103393/NIGMS NIH HHS
Preprint Journal Article
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Word Cloud

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