Rational Engineering and Characterization of an mAb that Neutralizes Zika Virus by Targeting a Mutationally Constrained Quaternary Epitope

• Main Authors: Watanabe, Satoru (Author), Chan, Kuan Rong (Author), Huan, Jia (Author), Chionh, Yok Hian (Author), Raguram, Aditya (Author), McBee, Megan (Author), Ong, Eugenia Z. (Author), Gan, Esther S. (Author), Tan, Hwee Cheng (Author), Tyagi, Anu (Author), Bhushan, Shashi (Author), Lescar, Julien (Author), Vasudevan, Subhash G. (Author), Ooi, Eng Eong (Author), Tharakaraman, Kannan (Contributor), Subramanian, Vidya (Contributor), Quinlan, Devin Scott (Contributor), Sasisekharan, Ram (Contributor)
• Other Authors: Massachusetts Institute of Technology. Department of Biological Engineering (Contributor)
• Format: Article
• Language: English
• Published: Elsevier, 2018-10-01T20:04:39Z.
• Subjects: Article
• Online Access: Get fulltext

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.
National Institutes of Health (U.S.) (Award 1R01AI111395)
Singapore. National Research Foundation