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首页> 外文期刊>PLOS Neglected Tropical Diseases >A Novel Universal Neutralizing Monoclonal Antibody against Enterovirus 71 That Targets the Highly Conserved “Knob” Region of VP3 Protein
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A Novel Universal Neutralizing Monoclonal Antibody against Enterovirus 71 That Targets the Highly Conserved “Knob” Region of VP3 Protein

机译：一种针对肠病毒71的新型通用中和单克隆抗体，该抗体靶向VP3蛋白的高度保守的“旋钮”区域

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Hand, foot and mouth disease caused by enterovirus 71(EV71) leads to the majority of neurological complications and death in young children. While putative inactivated vaccines are only now undergoing clinical trials, no specific treatment options exist yet. Ideally, EV71 specific intravenous immunoglobulins could be developed for targeted treatment of severe cases. To date, only a single universally neutralizing monoclonal antibody against a conserved linear epitope of VP1 has been identified. Other enteroviruses have been shown to possess major conformational neutralizing epitopes on both the VP2 and VP3 capsid proteins. Hence, we attempted to isolate such neutralizing antibodies against conformational epitopes for their potential in the treatment of infection as well as differential diagnosis and vaccine optimization. Here we describe a universal neutralizing monoclonal antibody that recognizes a conserved conformational epitope of EV71 which was mapped using escape mutants. Eight escape mutants from different subgenogroups (A, B2, B4, C2, C4) were rescued; they harbored three essential mutations either at amino acid positions 59, 62 or 67 of the VP3 protein which are all situated in the “knob” region. The escape mutant phenotype could be mimicked by incorporating these mutations into reverse genetically engineered viruses showing that P59L, A62D, A62P and E67D abolish both monoclonal antibody binding and neutralization activity. This is the first conformational neutralization epitope mapped on VP3 for EV71.
机译：肠道病毒71（EV71）引起的手足口病导致大多数神经系统并发症和幼儿死亡。尽管推定的灭活疫苗目前仅在临床试验中，但尚无特定的治疗选择。理想情况下，可以开发EV71特异性静脉内免疫球蛋白来靶向治疗严重病例。迄今为止，仅鉴定了针对保守的VP1线性表位的单一通用中和单克隆抗体。已显示其他肠病毒在VP2和VP3衣壳蛋白上均具有主要的构象中和表位。因此，我们试图分离出针对构象表位的中和抗体，以用于其在感染治疗以及鉴别诊断和疫苗优化中的潜力。在这里，我们描述了一种通用的中和单克隆抗体，该抗体可识别使用逃逸突变体作图的EV71保守构象表位。挽救了来自不同亚基因组（A，B2，B4，C2，C4）的八个逃避突变体;他们在VP3蛋白的59、62或67位氨基酸上都携带了三个重要的突变，它们都位于“旋钮”区域。通过将这些突变掺入反向基因工程病毒中，可以模拟逃避突变体的表型，表明P59L，A62D，A62P和E67D消除了单克隆抗体的结合和中和活性。这是映射在EV3的VP3上的第一个构象中和表位。

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