Differential requirements for FcγR engagement by protective antibodies against Ebola virus
Differential requirements for FcγR engagement by protective antibodies against Ebola virus
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DOI：
10.1073/pnas.1911842116
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发表时间：
2019-10-01
影响因子：
11.1
通讯作者：
Ravetch, Jeffrey V.
中科院分区：
文献类型：
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作者：
Bournazos, Stylianos;DiLillo, David J.;Ravetch, Jeffrey V.
埃博拉病毒(EBOV)继续对全球公共卫生构成重大威胁，需要不断制定多种疾病控制战略。到目前为止，许多针对EBOV糖蛋白(GP)的单抗已在动物疾病模型中显示出强大的保护活性，因此有望成为控制EBOV的候选抗体。然而，最近在各种病毒疾病中的工作强调了将Fab中和与Fc效应活性结合起来对有效的抗体介导的保护的重要性。为了确定Fc效应活性对单抗对EBOV gP的保护作用，我们选择了针对具有代表性的保护性表位的抗gp单抗，并在Fc-Gamma R人源化EBOV病小鼠攻击模型中研究了它们对Fc受体(Fc-Gamma R)的体内依赖性。与以前的研究相比，我们发现抗gp单抗在介导其保护活性时对Fc-Gamma R的参与表现出不同的要求，而与它们与病毒膜的距离无关。针对膜近端表位或GP粘蛋白结构域的抗GP单抗不依赖Fc-Fc Gamma R相互作用来赋予活性，而针对GP碗和融合环的抗体需要Fc Gamma R参与才能获得最佳的体内抗病毒活性。这种抗体介导的针对EBOV疾病的保护的复杂性突出了Fc-Gamma R与特定病毒表位结合的结构限制，并对开发具有最佳效力和疗效的基于mAb的免疫疗法具有重要意义。
Ebola virus (EBOV) continues to pose significant threats to global public health, requiring ongoing development of multiple strategies for disease control. To date, numerous monoclonal antibodies (mAbs) that target the EBOV glycoprotein (GP) have demonstrated potent protective activity in animal disease models and are thus promising candidates for the control of EBOV. However, recent work in a variety of virus diseases has highlighted the importance of coupling Fab neutralization with Fc effector activity for effective antibody-mediated protection. To determine the contribution of Fc effector activity to the protective function of mAbs to EBOV GP, we selected anti-GP mAbs targeting representative, protective epitopes and characterized their Fc receptor (Fc gamma R) dependence in vivo in Fc gamma R humanized mouse challenge models of EBOV disease. In contrast to previous studies, we find that anti-GP mAbs exhibited differential requirements for Fc gamma R engagement in mediating their protective activity independent of their distance from the viral membrane. Anti-GP mAbs targeting membrane proximal epitopes or the GP mucin domain do not rely on Fc-Fc gamma R interactions to confer activity, whereas antibodies against the GP chalice bowl and the fusion loop require Fc gamma R engagement for optimal in vivo antiviral activity. This complexity of antibody-mediated protection from EBOV disease highlights the structural constraints of Fc gamma R binding for specific viral epitopes and has important implications for the development of mAb-based immunotherapeutics with optimal potency and efficacy.