Ebolaviruses cause a severe and often fatal illness with the potential for global spread. Monoclonal antibody-based treatments that have become available recently have a narrow therapeutic spectrum and are ineffective against ebolaviruses other than Ebola virus (EBOV), including medically important Bundibugyo (BDBV) and Sudan (SUDV) viruses. Here, we report the development of a therapeutic cocktail comprising two broadly neutralizing human antibodies, rEBOV-515 and rEBOV-442, that recognize non-overlapping sites on the ebolavirus glycoprotein (GP). Antibodies in the cocktail exhibited synergistic neutralizing activity, resisted viral escape, and possessed differing requirements for their Fc-regions for optimal in vivo activities. The cocktail protected non-human primates from ebolavirus disease caused by EBOV, BDBV, or SUDV with high therapeutic effectiveness. High-resolution structures of the cocktail antibodies in complex with GP revealed the molecular determinants for neutralization breadth and potency. This study provides advanced preclinical data to support clinical development of this cocktail for pan-ebolavirus therapy.

埃博拉病毒会导致严重且通常是致命的疾病，并有可能在全球传播。最近出现的基于单克隆抗体的治疗具有狭窄的治疗范围，并且对埃博拉病毒 (EBOV) 以外的埃博拉病毒无效，包括医学上重要的本迪布焦 (BDBV) 和苏丹 (SUDV) 病毒。在这里，我们报告了一种治疗混合物的开发，该混合物包含两种广泛中和的人类抗体 rEBOV-515 和 rEBOV-442，它们识别埃博拉病毒糖蛋白 (GP) 上的非重叠位点。鸡尾酒中的抗体表现出协同中和活性，抵抗病毒逃逸，并且对其 Fc 区具有不同的要求，以实现最佳的体内活动。该混合物保护非人类灵长类动物免受由 EBOV、BDBV 或 SUDV 引起的埃博拉病毒病，具有很高的治疗效果。与 GP 复合的鸡尾酒抗体的高分辨率结构揭示了中和广度和效力的分子决定因素。这项研究提供了先进的临床前数据，以支持这种用于泛埃博拉病毒治疗的鸡尾酒的临床开发。