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Cell. 2017 Sep 21;171(1):229-241.e15. doi: 10.1016/j.cell.2017.09.002.

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

Author information

1
Program in Emerging Infectious Diseases, Duke-National University of Singapore Medical School, Singapore 169857, Singapore; Centre for BioImaging Sciences, National University of Singapore, Singapore 117557, Singapore.
2
Insitute for Research in Biomedicine, Università della Svizzera italiana, Via Vincenzo Vela 6, 6500 Bellinzona, Switzerland.
3
Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, 185 Li Ka Shing Center, 1951 Oxford Street, Berkeley, California, 94720-3370, USA.
4
Humabs BioMed SA a subsidiary of Vir Biotechnology, Inc., Via Mirasole 1, 6500 Bellinzona, Switzerland.
5
Centre for BioImaging Sciences, National University of Singapore, Singapore 117557, Singapore; CryoEM unit, Department of Biological Sciences, National University of Singapore, Singapore 117557.
6
Viral Pathogens and Biosafety Unit, San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milan, Italy.
7
Viral Pathogens and Biosafety Unit, San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milan, Italy; CNR-Institute of Neuroscience, Via Vanvitelli 32, 20129, Milan, Italy.
8
National Infection Service, Public Health England, Porton Down, Salisbury, Wiltshire, UK.
9
Department of Chemistry, University of Zurich, Zurich, Switzerland.
10
Program in Emerging Infectious Diseases, Duke-National University of Singapore Medical School, Singapore 169857, Singapore; Centre for BioImaging Sciences, National University of Singapore, Singapore 117557, Singapore. Electronic address: sheemei.lok@duke-nus.edu.sg.
11
Insitute for Research in Biomedicine, Università della Svizzera italiana, Via Vincenzo Vela 6, 6500 Bellinzona, Switzerland. Electronic address: luca.varani@irb.usi.ch.
12
Humabs BioMed SA a subsidiary of Vir Biotechnology, Inc., Via Mirasole 1, 6500 Bellinzona, Switzerland. Electronic address: davide.corti@humabs.ch.

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.

KEYWORDS:

Zika; neutralizing antibody; serotherapy

PMID:
28938115
PMCID:
PMC5673489
DOI:
10.1016/j.cell.2017.09.002
[Indexed for MEDLINE]
Free PMC Article

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