Molecular characterization of the monoclonal antibodies composing ZMAb: a protective cocktail against Ebola virus.
Molecular characterization of the monoclonal antibodies composing ZMAb: a protective cocktail against Ebola virus.
复制标题
组成 ZMAb 的单克隆抗体的分子表征：针对埃博拉病毒的保护性混合物。
DOI：
10.1038/srep06881
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发表时间：
2014-11-06
影响因子：
4.6
通讯作者：
Qiu X
中科院分区：
文献类型：
--
作者：
Audet J;Wong G;Wang H;Lu G;Gao GF;Kobinger G;Qiu X
埃博拉病毒（EBOV）在人类和非人类灵长类动物中引起严重的病毒性出血热，在人类疫情中病死率高达88%。在过去的3年中，单克隆抗体（mAb）鸡尾酒已经证明了作为针对EBOV感染的治疗的高功效。一种这样的混合物是ZMAb，其由三种小鼠抗体1H 3、2G 4和4G 7组成。在这里，我们提出了单克隆抗体1H 3，2G 4和4G 7的表位结合特性。我们发现，这些抗体具有不同的可变区序列，这表明单个mAb不是克隆相关的。发现所有三种抗体都中和EBOV变体Mayinga。此外，2G 4和4G 7显示在体外相互交叉抑制，并在EBOV糖蛋白（GP）上的相同位置，在氨基酸508处选择逃逸突变。1H 3选择EBOV GP上氨基酸273处的逃逸突变体。表面等离子体共振研究表明，所有三种抗体的解离常数都在10−7的量级。结合先前评估其他保护性抗体的结合位点的研究，我们的结果表明，靶向GP 1-GP 2界面和聚糖帽的抗体通常被选为针对EBOV的暴露后干预的有效抗体。
Ebola virus (EBOV) causes severe viral hemorrhagic fever in humans and non-human primates, with a case fatality rate of up to 88% in human outbreaks. Over the past 3 years, monoclonal antibody (mAb) cocktails have demonstrated high efficacy as treatments against EBOV infection. One such cocktail is ZMAb, which consists of three mouse antibodies, 1H3, 2G4, and 4G7. Here, we present the epitope binding properties of mAbs 1H3, 2G4, and 4G7. We showed that these antibodies have different variable region sequences, suggesting that the individual mAbs are not clonally related. All three antibodies were found to neutralize EBOV variant Mayinga. Additionally, 2G4 and 4G7 were shown to cross-inhibit each other in vitro and select for an escape mutation at the same position on the EBOV glycoprotein (GP), at amino acid 508. 1H3 selects an escape mutant at amino acid 273 on EBOV GP. Surface plasmon resonance studies showed that all three antibodies have dissociation constants on the order of 10−7. In combination with previous studies evaluating the binding sites of other protective antibodies, our results suggest that antibodies targeting the GP1-GP2 interface and the glycan cap are often selected as efficacious antibodies for post-exposure interventions against EBOV.