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

Abstract

SUMMARY 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.

A Combination of Two Human Monoclonal Antibodies Prevents Zika Virus Escape Mutations in Non-human Primates

“…Indeed, resistant viral variants arise in antibody-containing cell cultures infected with DENV (Lin et al, 1994; Lok et al, 2001; Zou et al, 2012), WNV (Beasley and Barrett, 2002; Chambers et al, 1998), YFV (Daffis et al, 2005), Japanese encephalitis virus (Shimoda et al, 2013), tick-borne encephalitis virus (Holzmann et al, 1989), and ZIKV (Wang et al, 2017a). Resistance to monoclonal antibodies has also been docu mented in mice challenged with WNV (Sapkal et al, 2011) and rhesus macaques challenged with high doses of DENV (Lai et al, 2007; Magnani et al, 2017a).…”

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

“…Such an approach may be highly desired, for instance, in order to target highly conserved regions of the E-protein assembly and therefore minimize the chance that the virus will escape the neutralizing antibody response. Indeed, a previous study isolated escape viruses to anti-ZIKV monoclonal antibody therapy by using an in vivo animal model and by means of serially passaging the virus in cell culture (Wang et al, 2017). Additionally, since these outbreaks are sporadic and short-lived, obtaining affinity matured antibodies from the peripheral blood mononuclear cells of ZIKV-infected individuals can be challenging.…”

Therapeutic and protective efficacy of a dengue antibody against Zika infection in rhesus monkeys

“…The potency of B10 and apparent relatively high bar to escape raise the possibility of antibody monotherapy, which would be logistically far simpler than the development of antibody cocktails 12 or bi-specific antibodies 9 . The structure of B10 remains to be determined, but the related cross-reactive DENV/ZIKV EDE1-specific mAb C8 binds a conserved quaternary site at the interface between the two Env subunits in the dimer at the interaction site of prM 16 , which may explain its high bar to escape.…”