Pan-ebolavirus and Pan-filovirus Mouse Monoclonal Antibodies: Protection against Ebola and Sudan Viruses
Pan-ebolavirus and Pan-filovirus Mouse Monoclonal Antibodies: Protection against Ebola and Sudan Viruses
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DOI：
10.1128/jvi.02171-15
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发表时间：
2016-01-01
影响因子：
5.4
通讯作者：
Aman, M. Javad
中科院分区：
文献类型：
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作者：
Holtsberg, Frederick W.;Shulenin, Sergey;Aman, M. Javad
2014-2015年西非史无前例的埃博拉病毒病(EVD)疫情突显了对抗丝状病毒的有效疗法的必要性。单抗(MAb)鸡尾酒已显示出作为EVD治疗的巨大潜力；然而，现有的保护性单抗是病毒物种特异性的。在这里，我们报告了泛埃博拉病毒和泛丝状病毒抗体的发展，这些抗体是通过用丝状病毒糖蛋白反复免疫小鼠而产生的，这些糖蛋白被设计成驱动B细胞对保守表位的反应。多种泛埃博拉病毒抗体被鉴定出来，它们对埃博拉病毒、苏丹病毒、本迪布乔病毒和莱斯顿病毒产生反应。还鉴定了一种与所有丝状病毒糖蛋白的受体结合区发生反应的泛丝状病毒抗体。几种单抗，包括一种新的抗体鸡尾酒，暴露后的显著效力被证明。我们首次报道了用单一抗体交叉中和和体内保护两种高度分化的丝状病毒物种，即埃博拉病毒和苏丹病毒。竞争研究表明，该抗体针对一个先前未被识别的保守中和表位，该表位涉及葡聚糖帽。机制研究表明，除了中和作用外，先天免疫细胞效应器功能可能在抗体的抗病毒活性中发挥作用。我们的发现进一步表明，关键的新表位可用于设计有效的鸡尾酒，以广泛保护多种丝状病毒物种。
The unprecedented 2014-2015 Ebola virus disease (EVD) outbreak in West Africa has highlighted the need for effective therapeutics against filoviruses. Monoclonal antibody (MAb) cocktails have shown great potential as EVD therapeutics; however, the existing protective MAbs are virus species specific. Here we report the development of pan-ebolavirus and pan-filovirus antibodies generated by repeated immunization of mice with filovirus glycoproteins engineered to drive the B cell responses toward conserved epitopes. Multiple pan-ebolavirus antibodies were identified that react to the Ebola, Sudan, Bundibugyo, and Reston viruses. A pan-filovirus antibody that was reactive to the receptor binding regions of all filovirus glycoproteins was also identified. Significant postexposure efficacy of several MAbs, including a novel antibody cocktail, was demonstrated. For the first time, we report cross-neutralization and in vivo protection against two highly divergent filovirus species, i.e., Ebola virus and Sudan virus, with a single antibody. Competition studies indicate that this antibody targets a previously unrecognized conserved neutralizing epitope that involves the glycan cap. Mechanistic studies indicated that, besides neutralization, innate immune cell effector functions may play a role in the antiviral activity of the antibodies. Our findings further suggest critical novel epitopes that can be utilized to design effective cocktails for broad protection against multiple filovirus species.