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Proc Natl Acad Sci U S A. 2014 Dec 2;111(48):17182-7. doi: 10.1073/pnas.1414164111. Epub 2014 Nov 17.

Structures of protective antibodies reveal sites of vulnerability on Ebola virus.

Author information

1
Department of Integrative Structural and Computational Biology, Department of Immunology and Microbial Science, and.
2
Department of Immunology and Microbial Science, and.
3
National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB, Canada R3E 3R2;
4
National Institute of Allergy and Infectious Diseases/Integrated Research Facility, National Institutes of Health, Frederick, MD 21702;
5
Mapp Biopharmaceutical, San Diego, CA 92121;
6
National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB, Canada R3E 3R2; Department of Medical Microbiology, University of Manitoba, Winnipeg, MB, Canada R3E 0J9; and Department of Immunology, University of Manitoba, Winnipeg, MB, Canada R3E 0T5.
7
Department of Integrative Structural and Computational Biology, abward@scripps.edu erica@scripps.edu.
8
Department of Immunology and Microbial Science, and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037; abward@scripps.edu erica@scripps.edu.

Abstract

Ebola virus (EBOV) and related filoviruses cause severe hemorrhagic fever, with up to 90% lethality, and no treatments are approved for human use. Multiple recent outbreaks of EBOV and the likelihood of future human exposure highlight the need for pre- and postexposure treatments. Monoclonal antibody (mAb) cocktails are particularly attractive candidates due to their proven postexposure efficacy in nonhuman primate models of EBOV infection. Two candidate cocktails, MB-003 and ZMAb, have been extensively evaluated in both in vitro and in vivo studies. Recently, these two therapeutics have been combined into a new cocktail named ZMapp, which showed increased efficacy and has been given compassionately to some human patients. Epitope information and mechanism of action are currently unknown for most of the component mAbs. Here we provide single-particle EM reconstructions of every mAb in the ZMapp cocktail, as well as additional antibodies from MB-003 and ZMAb. Our results illuminate key and recurring sites of vulnerability on the EBOV glycoprotein and provide a structural rationale for the efficacy of ZMapp. Interestingly, two of its components recognize overlapping epitopes and compete with each other for binding. Going forward, this work now provides a basis for strategic selection of next-generation antibody cocktails against Ebola and related viruses and a model for predicting the impact of ZMapp on potential escape mutations in ongoing or future Ebola outbreaks.

KEYWORDS:

EM; Ebola; ZMapp; antibodies

PMID:
25404321
PMCID:
PMC4260551
DOI:
10.1073/pnas.1414164111
[Indexed for MEDLINE]
Free PMC Article

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