Davidson Edgar, Bryan Christopher, Fong Rachel H, Barnes Trevor, Pfaff Jennifer M, Mabila Manu, Rucker Joseph B, Doranz Benjamin J
Integral Molecular, Philadelphia, Pennsylvania, USA.
Integral Molecular, Philadelphia, Pennsylvania, USA
J Virol. 2015 Nov;89(21):10982-92. doi: 10.1128/JVI.01490-15. Epub 2015 Aug 26.
Cocktails of monoclonal antibodies (MAbs) that target the surface glycoprotein (GP) of Ebola virus (EBOV) are effective in nonhuman primate models and have been used under emergency compassionate-treatment protocols in human patients. However, the amino acids that form the detailed binding epitopes for the MAbs in the ZMapp, ZMAb, and the related MB-003 cocktails have yet to be identified. Other binding properties that define how each MAb functionally interacts with GP—such as affinity, epitope conservation, and epitope accessibility—also remain largely unknown. To help define how each MAb interacts with GP, here we used comprehensive alanine-scanning mutagenesis (shotgun mutagenesis), neutralization escape, and whole virion binding to define each MAb's specific epitope, epitope accessibility, epitope conservation, and apparent affinity. Each of the six therapeutic MAbs binds nonidentical epitopes in the GP base, glycan cap, or mucin-like domain. Their apparent affinity, epitope complementarity, and epitope accessibility helps explain why MAbs 4G7 and 13C6 are more protective than 2G4 and 1H3. The mucin-like domain MAbs 6D8 and 13F6 bind with the strongest apparent affinity, helping to explain their effectiveness in vivo despite their inability to neutralize virus.
Ebola virus disease (EVD) can be caused by four different filovirus family members, including Ebola virus (EBOV), which infected 10 times more people in western Africa over the last year than all previous EVD outbreaks combined, with a number of cases distributed across the globe by travelers. Cocktails of inhibitory monoclonal antibodies (MAbs), such as ZMAb, MB-003, and in particular ZMapp, have demonstrated in animal models some of the most significant therapeutic potential for treating EVD, and in 2014, 15 patients were treated with ZMapp or ZMAb under compassionate-use protocols. Here, we have defined the epitope features for the most important therapeutic MAbs against EBOV developed to date. Defining the epitopes and binding characteristics for these MAbs, as well as the commonly used reference MAb KZ52, helps explain their breadth of reactivity against different ebolavirus species, predict viral evasion against these MAbs, and design new cocktails of MAbs with improved complementarity.
靶向埃博拉病毒（EBOV）表面糖蛋白（GP）的单克隆抗体（MAb）鸡尾酒疗法在非人灵长类动物模型中有效，并已在人类患者的紧急同情治疗方案中使用。然而，ZMapp、ZMAb和相关的MB - 003鸡尾酒疗法中，构成MAb详细结合表位的氨基酸尚未确定。定义每个MAb如何与GP功能性相互作用的其他结合特性，如亲和力、表位保守性和表位可及性，在很大程度上也仍然未知。为了帮助确定每个MAb如何与GP相互作用，我们在这里使用了全面的丙氨酸扫描诱变（散弹枪诱变）、中和逃逸和全病毒体结合来确定每个MAb的特异性表位、表位可及性、表位保守性和表观亲和力。六种治疗性MAb中的每一种都结合GP基部、聚糖帽或粘蛋白样结构域中的不同表位。它们的表观亲和力、表位互补性和表位可及性有助于解释为什么MAb 4G7和13C6比2G4和1H3更具保护性。粘蛋白样结构域MAb 6D8和13F6以最强的表观亲和力结合，这有助于解释它们在体内的有效性，尽管它们无法中和病毒。
埃博拉病毒病（EVD）可由四种不同的丝状病毒科成员引起，包括埃博拉病毒（EBOV），去年在西非感染的人数比以往所有EVD疫情的总和多10倍，还有一些病例由旅行者传播到全球各地。抑制性单克隆抗体（MAb）鸡尾酒疗法，如ZMAb、MB - 003，特别是ZMapp，已在动物模型中显示出治疗EVD的一些最显著的治疗潜力，并且在2014年，有15名患者根据同情使用方案接受了ZMapp或ZMAb治疗。在这里，我们已经确定了迄今为止开发的针对EBOV的最重要治疗性MAb的表位特征。确定这些MAb以及常用参考MAb KZ52的表位和结合特性，有助于解释它们对不同埃博拉病毒物种的反应广度，预测病毒对这些MAb的逃逸，并设计具有改进互补性的新MAb鸡尾酒疗法。
