Monoclonal antibodies (mAbs) with pan-ebolavirus cross-reactivity are highly desirable, but development of such mAbs is limited by a lack of a molecular understanding of cross-reactive epitopes. The antibody ADI-15878 was previously identified from a human survivor of Ebola virus Makona variant (EBOV/Mak) infection. This mAb demonstrated potent neutralizing activity against all known ebolaviruses and provided protection in rodent and ferret models against three ebolavirus species. Here, we describe the unliganded crystal structure of ADI-15878 as well as the cryo-EM structures of ADI-15878 in complex with the EBOV/Mak and Bundibugyo virus (BDBV) glycoproteins (GPs). ADI-15878 binds through an induced-fit mechanism by targeting highly conserved residues in the internal fusion loop (IFL), bridging across GP protomers via the heptad repeat 1 (HR1) region. Our structures provide a more complete description of the ebolavirus immunogenic landscape, as well as a molecular basis for how rare but potent antibodies target conserved filoviral fusion machinery.

中文翻译：

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通过针对糖蛋白融合环的抗体中和埃博拉病毒的结构基础。

具有泛埃博拉病毒交叉反应性的单克隆抗体（mAb）是非常需要的，但是由于缺乏对交叉反应性表位的分子了解，这种mAb的开发受到了限制。抗体ADI-15878先前是从人类埃博拉病毒Makona变体（EBOV / Mak）感染的幸存者中鉴定出来的。该单克隆抗体显示出对所有已知埃博拉病毒的有效中和活性，并在啮齿动物和雪貂模型中提供了针对三种埃博拉病毒物种的保护。在这里，我们描述了与EBOV / Mak和Bundibugyo病毒（BDBV）糖蛋白（GPs）结合的ADI-15878的未配体晶体结构以及ADI-15878的冷冻电磁结构。ADI-15878通过靶向内部融合环（IFL）中高度保守的残基，通过诱导拟合机制结合，通过庚七重复序列1（HR1）区域跨越GP祖细胞。我们的结构为埃博拉病毒的免疫原性景观提供了更完整的描述，并为罕见的但有效的抗体如何靶向保守的丝状病毒融合机制提供了分子基础。