Division of HIV/AIDS and Sex-transmitted Virus Vaccines, National Institutes for Food and Drug Control, Beijing 100050, China.
Division of Animal Model Research, Institute for Laboratory Animal Resources, National Institutes for Food and Drug Control, Beijing 100050, China.
Sci Rep. 2017 Mar 30;7:45552. doi: 10.1038/srep45552.
Passive immunotherapy with monoclonal antibodies (mAbs) is an efficacious treatment for Ebola virus (EBOV) infections in animal models and humans. Understanding what constitutes a protective response is critical for the development of novel therapeutic strategies. We generated an EBOV-glycoprotein-pseudotyped Human immunodeficiency virus to develop sensitive neutralizing and antibody-dependent cellular cytotoxicity (ADCC) assays as well as a bioluminescent-imaging-based mouse infection model that does not require biosafety level 4 containment. The in vivo treatment efficiencies of three novel anti-EBOV mAbs at 12 h post-infection correlated with their in vitro anti-EBOV ADCC activities, without neutralizing activity. When they were treated with these mAbs, natural killer cell (NK)-deficient mice had lower viral clearance than WT mice, indicating that the anti-EBOV mechanism of the ADCC activity of these mAbs is predominantly mediated by NK cells. One potent anti-EBOV mAb (M318) displayed unprecedented neutralizing and ADCC activities (neutralization IC, 0.018 μg/ml; ADCC EC, 0.095 μg/ml). These results have important implications for the efficacy of antiviral drugs and vaccines as well as for pathogenicity studies of EBOV.
被动免疫疗法使用单克隆抗体（mAbs）是治疗埃博拉病毒（EBOV）感染的有效方法，在动物模型和人类中都有疗效。了解什么是保护性反应对于开发新的治疗策略至关重要。我们生成了一种 EBOV-糖蛋白假型 HIV 来开发敏感的中和和抗体依赖性细胞毒性（ADCC）测定法，以及一种基于生物发光成像的不需要生物安全 4 级防护的小鼠感染模型。三种新型抗 EBOV mAbs 在感染后 12 小时的体内治疗效率与它们的体外抗 EBOV ADCC 活性相关，而与中和活性无关。当用这些 mAbs 治疗时，自然杀伤细胞（NK）缺陷型小鼠的病毒清除率低于 WT 小鼠，表明这些 mAbs 的 ADCC 活性的抗 EBOV 机制主要由 NK 细胞介导。一种强效的抗 EBOV mAb（M318）显示出前所未有的中和和 ADCC 活性（中和 IC50，0.018μg/ml；ADCC EC50，0.095μg/ml）。这些结果对抗病毒药物和疫苗的疗效以及 EBOV 的致病性研究具有重要意义。
