Title: Rational Engineering and Characterization of an mAb that Neutralizes Zika Virus by Targeting a Mutationally Constrained Quaternary Epitope.
Authors: Tharakaraman, Kannan; Watanabe, Satoru; Chan, Kuan Rong; Huan, Jia; Subramanian, Vidya; Chionh, Yok Hian; Raguram, Aditya; Quinlan, Devin; McBee, Megan; Ong, Eugenia Z; Gan, Esther S; Tan, Hwee Cheng; Tyagi, Anu; Bhushan, Shashi; Lescar, Julien; Vasudevan, Subhash G; Ooi, Eng Eong; Sasisekharan, Ram
Published In Cell Host Microbe, (2018 05 09)
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.
PubMed ID: 29746833
MeSH Terms: Animals; Antibodies, Monoclonal/administration & dosage; Antibodies, Monoclonal/immunology; Antibodies, Monoclonal/therapeutic use; Antibodies, Neutralizing/administration & dosage; Antibodies, Neutralizing/immunology*; Antibodies, Neutralizing/therapeutic use; Antibodies, Viral/administration & dosage; Antibodies, Viral/chemistry*; Antibodies, Viral/immunology*; Antibodies, Viral/therapeutic use; Dengue Virus/immunology; Disease Models, Animal; Epitopes/chemistry; Epitopes/genetics; Epitopes/immunology*; Female; Male; Mice; Models, Molecular; Neutralization Tests/methods; Pregnancy; Protein Engineering*; Protein Structure, Quaternary; Treatment Outcome; Viral Envelope Proteins/chemistry; Viral Envelope Proteins/genetics; Viral Envelope Proteins/immunology; Viremia/drug therapy; Zika Virus Infection/drug therapy; Zika Virus Infection/immunology*; Zika Virus Infection/virology; Zika Virus/genetics*; Zika Virus/immunology*