Orthoebolavirus is a genus of hazardous pathogens that has caused over 30 outbreaks. However, currently approved therapies are limited in scope, as they are only effective against the Ebola virus and lack cross-protection against other orthoebolaviruses. Here, we demonstrate that a previously isolated human-derived antibody, 2G1, can recognize the glycoprotein (GP) of every orthoebolavirus species. The cryo-electron microscopy structure of 2G1 Fab in complex with the GPΔMucin trimer reveals that 2G1 binds a quaternary pocket formed by three subunits from two GP protomers. 2G1 recognizes highly conserved epitopes among filoviruses and achieves neutralization by blocking GP proteolysis. We designed an efficient mRNA module capable of producing test antibodies at expression levels exceeding 1500 ng/mL in vitro. The lipid nanoparticle (LNP)-encapsulated mRNA-2G1 exhibited potent neutralizing activities against the HIV-pseudotyped Ebola and Sudan viruses that were 19.8 and 12.5 times that of IgG format, respectively. In mice, the antibodies encoded by the mRNA-2G1-LNP peaked within 24 h, effectively blocking the invasion of pseudoviruses with no apparent liver toxicity. This study suggests that the 2G1 antibody and its mRNA formulation represent promising candidate interventions for orthoebolavirus disease, and it provides an efficient mRNA framework applicable to antibody-based therapies.

中文翻译：

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由 mRNA 编码的泛正直埃博拉病毒中和抗体可有效预防病毒感染。


正埃博拉病毒是一种危险病原体，已引起 30 多次疫情。然而，目前批准的疗法范围有限，因为它们仅对埃博拉病毒有效，而缺乏对其他正直埃博拉病毒的交叉保护。在这里，我们证明了先前分离的人类来源抗体 2G1 可以识别每种正直埃博拉病毒物种的糖蛋白 （GP）。2G1 Fab 与 GPΔMucin 三聚体复合物的冷冻电子显微镜结构显示，2G1 结合由两个 GP 原生异构体的三个亚基形成的四元口袋。2G1 可识别丝状病毒中高度保守的表位，并通过阻断 GP 蛋白水解实现中和。我们设计了一种高效的 mRNA 模块，能够在体外产生表达水平超过 1500 ng/mL 的测试抗体。脂质纳米颗粒 （LNP） 封装的 mRNA-2G1 对 HIV 假型埃博拉病毒和苏丹病毒表现出强大的中和活性，分别是 IgG 形式的 19.8 倍和 12.5 倍。在小鼠中，mRNA-2G1-LNP 编码的抗体在 24 小时内达到峰值，有效阻断了假病毒的入侵，无明显的肝毒性。这项研究表明，2G1 抗体及其 mRNA 制剂代表了正肠病毒病的有前途的候选干预措施，并提供了适用于基于抗体的疗法的有效 mRNA 框架。