Rational Engineering and Characterization of an mAb that Neutralizes Zika Virus by Targeting a Mutationally Constrained Quaternary Epitope
Name
Rational Engineering and Characterization of an mAb that Neutralizes Zika Virus by Targeting a Mutationally Constrained Quaternary Epitope.pdf
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1.06 MB
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Checksum (MD5)
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Author(s)
Watanabe, Satoru
Chan, Kuan Rong
Huan, Jia
Chionh, Yok Hian
Raguram, Aditya
McBee, Megan
Ong, Eugenia Z.
Gan, Esther S.
Tan, Hwee Cheng
Tyagi, Anu
Date Issued
May 2018
Journal
Cell Host & Microbe
Publisher
Elsevier
Citation
Tharakaraman, Kannan, et al. “Rational Engineering and Characterization of an MAb That Neutralizes Zika Virus by Targeting a Mutationally Constrained Quaternary Epitope.” Cell Host & Microbe, vol. 23, no. 5, May 2018, pp. 618-627.e6.
Version
Author's final manuscript
Abstract
Following the recent emergence of Zika virus (ZIKV), many murine and human neutralizing anti-ZIKV antibodies have been reported. Given the risk of virus escape mutants, engineering antibodies that target mutationally constrained epitopes with therapeutically relevant potencies can be valuable for combating future outbreaks. Here, we applied computational methods to engineer an antibody, ZAb_FLEP, that targets a highly networked and therefore mutationally constrained surface formed by the envelope protein dimer. ZAb_FLEP neutralized a breadth of ZIKV strains and protected mice in distinct in vivo models, including resolving vertical transmission and fetal mortality in infected pregnant mice. Serial passaging of ZIKV in the presence of ZAb_FLEP failed to generate viral escape mutants, suggesting that its epitope is indeed mutationally constrained. A single-particle cryo-EM reconstruction of the Fab-ZIKV complex validated the structural model and revealed insights into ZAb_FLEP's neutralization mechanism. ZAb_FLEP has potential as a therapeutic in future outbreaks. Tharakaraman et al. describe the engineering and validation of a neutralizing anti-Zika antibody (ZAb_FLEP) that targets a mutationally constrained surface epitope formed by the envelope protein. ZAb_FLEP neutralizes ZIKV strains in vitro and protects mice and unborn pups from Zika infection in vivo, indicating its potential as a therapeutic candidate.
MIT Department
Massachusetts Institute of Technology. Department of Biological Engineering
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Creative Commons Attribution-NonCommercial-NoDerivs License
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DOI of Published Version
https://doi.org/10.1016/j.chom.2018.04.004
