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Nat Struct Mol Biol. 2019 Mar;26(3):204-212. doi: 10.1038/s41594-019-0191-4. Epub 2019 Mar 4.

Structural basis of broad ebolavirus neutralization by a human survivor antibody.

Author information

1
Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, USA.
2
Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA.
3
Adimab LLC, Lebanon, NH, USA.
4
Mapp Biopharmaceutical, San Diego, CA, USA.
5
Department of Pathology, University of Texas Medical Branch, Galveston, TX, USA.
6
Galveston National Laboratory, University of Texas Medical Branch, Galveston, TX, USA.
7
Division of Virology, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, MD, USA.
8
Integrated Biotherapeutics, Rockville, MD, USA.
9
Department of Immunology and Microbiology, University of Texas Medical Branch, Galveston, TX, USA.
10
Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA. kartik.chandran@einstein.yu.edu.
11
Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, USA. erica@scripps.edu.
12
Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA, USA. erica@scripps.edu.

Abstract

The structural features that govern broad-spectrum activity of broadly neutralizing anti-ebolavirus antibodies (Abs) outside of the internal fusion loop epitope are currently unknown. Here we describe the structure of a broadly neutralizing human monoclonal Ab (mAb), ADI-15946, which was identified in a human survivor of the 2013-2016 outbreak. The crystal structure of ADI-15946 in complex with cleaved Ebola virus glycoprotein (EBOV GPCL) reveals that binding of the mAb structurally mimics the conserved interaction between the EBOV GP core and its glycan cap β17-β18 loop to inhibit infection. Both endosomal proteolysis of EBOV GP and binding of mAb FVM09 displace this loop, thereby increasing exposure of ADI-15946's conserved epitope and enhancing neutralization. Our work also mapped the paratope of ADI-15946, thereby explaining reduced activity against Sudan virus, which enabled rational, structure-guided engineering to enhance binding and neutralization of Sudan virus while retaining the parental activity against EBOV and Bundibugyo virus.

PMID:
30833785
PMCID:
PMC6402988
[Available on 2019-09-04]
DOI:
10.1038/s41594-019-0191-4

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