Structural principles underlying the composition of protective antiviral monoclonal antibody (mAb) cocktails are poorly defined. Here, we exploited antibody cooperativity to develop a therapeutic mAb cocktail against Ebola virus. We systematically analyzed the antibody repertoire in human survivors and identified a pair of potently neutralizing mAbs that cooperatively bound to the ebolavirus glycoprotein (GP). High-resolution structures revealed that in a two-antibody cocktail, molecular mimicry was a major feature of mAb-GP interactions. Broadly neutralizing mAb rEBOV-520 targeted a conserved epitope on the GP base region. mAb rEBOV-548 bound to a glycan cap epitope, possessed neutralizing and Fc-mediated effector function activities, and potentiated neutralization by rEBOV-520. Remodeling of the glycan cap structures by the cocktail enabled enhanced GP binding and virus neutralization. The cocktail demonstrated resistance to virus escape and protected non-human primates (NHPs) against Ebola virus disease. These data illuminate structural principles of antibody cooperativity with implications for development of antiviral immunotherapeutics.

中文翻译：

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对治疗性抗体混合物的分析揭示了合作和广泛埃博拉病毒中和的决定因素。

保护性抗病毒单克隆抗体 (mAb) 混合物组成的结构原理尚不清楚。在这里，我们利用抗体协同作用开发了一种针对埃博拉病毒的治疗性 mAb 混合物。我们系统地分析了人类幸存者的抗体库，并确定了一对协同结合埃博拉病毒糖蛋白 (GP) 的强效中和单克隆抗体。高分辨率结构显示，在双抗体混合物中，分子模拟是 mAb-GP 相互作用的主要特征。广泛中和的 mAb rEBOV-520 靶向 GP 碱基区域上的保守表位。mAb rEBOV-548 与聚糖帽表位结合，具有中和和 Fc 介导的效应子功能活性，并通过 rEBOV-520 增强中和作用。通过混合物重塑聚糖帽结构可以增强 GP 结合和病毒中和作用。该鸡尾酒表现出对病毒逃逸的抵抗力，并保护非人类灵长类动物 (NHP) 免受埃博拉病毒病的侵害。这些数据阐明了抗体协同作用的结构原理，对开发抗病毒免疫疗法具有重要意义。