Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA.
Department of Pathology, University of Texas Medical Branch at Galveston, Galveston, TX, USA; Galveston National Laboratory, Galveston, TX, USA.
Immunity. 2021 Apr 13;54(4):815-828.e5. doi: 10.1016/j.immuni.2021.03.009.
Protective Ebola virus (EBOV) antibodies have neutralizing activity and induction of antibody constant domain (Fc)-mediated innate immune effector functions. Efforts to enhance Fc effector functionality often focus on maximizing antibody-dependent cellular cytotoxicity, yet distinct combinations of functions could be critical for antibody-mediated protection. As neutralizing antibodies have been cloned from EBOV disease survivors, we sought to identify survivor Fc effector profiles to help guide Fc optimization strategies. Survivors developed a range of functional antibody responses, and we therefore applied a rapid, high-throughput Fc engineering platform to define the most protective profiles. We generated a library of Fc variants with identical antigen-binding fragments (Fabs) from an EBOV neutralizing antibody. Fc variants with antibody-mediated complement deposition and moderate natural killer (NK) cell activity demonstrated complete protective activity in a stringent in vivo mouse model. Our findings highlight the importance of specific effector functions in antibody-mediated protection, and the experimental platform presents a generalizable resource for identifying correlates of immunity to guide therapeutic antibody design.
保护性埃博拉病毒 (EBOV) 抗体具有中和活性，并诱导抗体恒定区 (Fc) 介导的先天免疫效应功能。增强 Fc 效应功能的努力通常侧重于最大限度地提高抗体依赖性细胞毒性，然而，对于抗体介导的保护作用，不同的功能组合可能是至关重要的。由于已经从埃博拉病毒病幸存者中克隆出了中和抗体，因此我们试图确定幸存者的 Fc 效应功能谱，以帮助指导 Fc 优化策略。幸存者发展出了一系列功能性抗体反应，因此我们应用了一种快速、高通量的 Fc 工程平台来定义最具保护作用的功能谱。我们从一种埃博拉病毒中和抗体中生成了具有相同抗原结合片段 (Fab) 的 Fc 变体文库。具有抗体介导的补体沉积和适度自然杀伤 (NK) 细胞活性的 Fc 变体在严格的体内小鼠模型中表现出完全的保护活性。我们的研究结果强调了特定效应功能在抗体介导的保护中的重要性，并且该实验平台为鉴定免疫相关性提供了一种普遍适用的资源，以指导治疗性抗体设计。
