1. A Human Bi-specific Antibody against Zika Virus with High Therapeutic Potential.
- Author
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Wang J, Bardelli M, Espinosa DA, Pedotti M, Ng TS, Bianchi S, Simonelli L, Lim EXY, Foglierini M, Zatta F, Jaconi S, Beltramello M, Cameroni E, Fibriansah G, Shi J, Barca T, Pagani I, Rubio A, Broccoli V, Vicenzi E, Graham V, Pullan S, Dowall S, Hewson R, Jurt S, Zerbe O, Stettler K, Lanzavecchia A, Sallusto F, Cavalli A, Harris E, Lok SM, Varani L, and Corti D
- Subjects
- Amino Acid Sequence, Animals, Antibodies, Monoclonal administration & dosage, Antibodies, Monoclonal chemistry, Antibodies, Neutralizing administration & dosage, Antibodies, Neutralizing chemistry, Antibodies, Viral administration & dosage, Antibodies, Viral chemistry, Cryoelectron Microscopy, Epitopes, Humans, Magnetic Resonance Spectroscopy, Mice, Models, Molecular, Sequence Alignment, Viral Envelope Proteins chemistry, Zika Virus immunology, Antibodies, Monoclonal therapeutic use, Antibodies, Neutralizing therapeutic use, Antibodies, Viral therapeutic use, Zika Virus chemistry, Zika Virus Infection therapy
- Abstract
Zika virus (ZIKV), a mosquito-borne flavivirus, causes devastating congenital birth defects. We isolated a human monoclonal antibody (mAb), ZKA190, that potently cross-neutralizes multi-lineage ZIKV strains. ZKA190 is highly effective in vivo in preventing morbidity and mortality of ZIKV-infected mice. NMR and cryo-electron microscopy show its binding to an exposed epitope on DIII of the E protein. ZKA190 Fab binds all 180 E protein copies, altering the virus quaternary arrangement and surface curvature. However, ZIKV escape mutants emerged in vitro and in vivo in the presence of ZKA190, as well as of other neutralizing mAbs. To counter this problem, we developed a bispecific antibody (FIT-1) comprising ZKA190 and a second mAb specific for DII of E protein. In addition to retaining high in vitro and in vivo potencies, FIT-1 robustly prevented viral escape, warranting its development as a ZIKV immunotherapy., (Crown Copyright © 2017. Published by Elsevier Inc. All rights reserved.)
- Published
- 2017
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