Antibody Treatment of Ebola and Sudan Virus Infection via a Uniquely Exposed Epitope within the Glycoprotein Receptor-Binding Site.
Antibody Treatment of Ebola and Sudan Virus Infection via a Uniquely Exposed Epitope within the Glycoprotein Receptor-Binding Site.
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DOI：
10.1016/j.celrep.2016.04.026
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发表时间：
2016-05-17
期刊：
影响因子：
8.8
通讯作者：
Aman MJ
中科院分区：
文献类型：
--
作者：
Howell KA;Qiu X;Brannan JM;Bryan C;Davidson E;Holtsberg FW;Wec AZ;Shulenin S;Biggins JE;Douglas R;Enterlein SG;Turner HL;Pallesen J;Murin CD;He S;Kroeker A;Vu H;Herbert AS;Fusco ML;Nyakatura EK;Lai JR;Keck ZY;Foung SKH;Saphire EO;Zeitlin L;Ward AB;Chandran K;Doranz BJ;Kobinger GP;Dye JM;Aman MJ
以前识别埃博拉病毒糖蛋白受体结合位点(RBS)的交叉中和抗体的努力一直没有成功，主要是因为RBS被封闭在病毒表面。我们报告了一种针对RBS内独特暴露的表位的单抗(FVM04)；交叉中和埃博拉病毒(EBOV)、苏丹病毒(SUDV)，以及较小程度的本迪布乔病毒；并在小鼠和豚鼠中显示出对EBOV和SUDV的保护作用。抗体鸡尾酒ZMapp™对埃博拉病毒(扎伊尔)非常有效，但不交叉中和其他埃博拉病毒。通过用FVM04替换ZMapp的一个™组件，我们保留了抗埃博拉病毒的效果，同时将保护范围扩展到SUDV，从而产生了交叉保护抗体鸡尾酒。此外，我们报告了埃博拉病毒糖蛋白碱基上的几个突变，这些突变增强了FVM04和其他交叉反应抗体的结合。这些发现对泛埃博拉病毒疫苗的开发和定义具有广泛保护性的抗体鸡尾酒具有重要意义。Howell等人。检查与埃博拉病毒受体结合部位结合的单抗FVM04，发现FVM04对EBOV和SUDV具有保护作用。当与两个ZMapp™组分结合时，抗体鸡尾酒保留了与ZMapp™类似的EBOV保护，并扩展了对SUDV的保护。描述了增强交叉中和表位暴露的特定糖蛋白突变。
Previous efforts to identify cross-neutralizing antibodies to the receptor-binding site (RBS) of ebolavirus glycoproteins have been unsuccessful, largely because the RBS is occluded on the viral surface. We report a monoclonal antibody (FVM04) that targets a uniquely exposed epitope within the RBS; cross-neutralizes Ebola (EBOV), Sudan (SUDV), and, to a lesser extent, Bundibugyo viruses; and shows protection against EBOV and SUDV in mice and guinea pigs. The antibody cocktail ZMapp™ is remarkably effective against EBOV (Zaire) but does not cross-neutralize other ebolaviruses. By replacing one of the ZMapp™ components with FVM04, we retained the anti-EBOV efficacy while extending the breadth of protection to SUDV, thereby generating a cross-protective antibody cocktail. In addition, we report several mutations at the base of the ebolavirus glycoprotein that enhance the binding of FVM04 and other cross-reactive antibodies. These findings have important implications for pan-ebolavirus vaccine development and defining broadly protective antibody cocktails. Howell et al. examine a mAb, FVM04, that binds the ebolavirus receptor-binding site and find that FVM04 protects against EBOV and SUDV. When combined with two ZMapp™ components, the antibody cocktail retains EBOV protection similar to that of ZMapp™ and extends protection against SUDV. Specific glycoprotein mutations that enhance the exposure of cross-neutralizing epitopes are described.