A Human Bi-specific Antibody against Zika Virus with High Therapeutic Potential

Jiaqi Wang, Marco Bardelli, Diego A. Espinosa, Mattia Pedotti, Thiam Seng Ng, Siro Bianchi, Luca Simonelli, Elisa X.Y. Lim, Mathilde Foglierini, Fabrizia Zatta, Stefano Jaconi, Martina Beltramello, Elisabetta Cameroni, Guntur Fibriansah, Jian Shi, Taylor Barca, Isabel Pagani, Alicia Rubio, Vania Broccoli, Elisa VicenziVictoria Graham, Steven Pullan, Stuart Dowall, Roger Hewson, Simon Jurt, Oliver Zerbe, Karin Stettler, Antonio Lanzavecchia, Federica Sallusto, Andrea Cavalli, Eva Harris, Shee Mei Lok, Luca Varani, Davide Corti

Research output: Contribution to journalArticlepeer-review

67 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)229-241.e15
JournalCell
Volume171
Issue number1
DOIs
Publication statusPublished - 21 Sep 2017

Keywords

  • Zika
  • neutralizing antibody
  • serotherapy

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