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.

中文翻译：

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具有高治疗潜力的针对寨卡病毒的人类双特异性抗体。

寨卡病毒 (ZIKV) 是一种由蚊子传播的黄病毒，会导致毁灭性的先天性出生缺陷。我们分离出一种人单克隆抗体 (mAb) ZKA190，它能有效交叉中和多谱系 ZIKV 毒株。ZKA190 在体内非常有效地预防 ZIKV 感染小鼠的发病和死亡。NMR 和冷冻电子显微镜显示其与 E 蛋白 DIII 上暴露的表位结合。ZKA190 Fab 结合所有 180 个 E 蛋白拷贝，改变病毒四级排列和表面曲率。然而，在 ZKA190 以及其他中和单克隆抗体存在的情况下，在体外和体内都出现了 ZIKV 逃逸突变体。为了解决这个问题，我们开发了一种双特异性抗体 (FIT-1)，包含 ZKA190 和另一种针对 E 蛋白 DII 的单克隆抗体。除了在体外和体内保持较高的效力外，FIT-1 还能强有力地阻止病毒逃逸，这保证了其作为 ZIKV 免疫疗法的发展。