Evaluation of the FcgR mechanisms in the antibody-dependent enhancement of SARS-CoV-2 infection

摘要 鉴于SARS-CoV-2的失控传播和对公众健康的破坏性影响，治疗性的 疾病控制迫切需要干预措施。事实上，几个生物技术和学术团体目前正在 致力于高效单抗的分离和临床研究 抗SARS-CoV-2的中和活性。在过去的几周里，一些中和的抗SARS冠状病毒- 目前已有2株单抗进入临床试验，有望成为新冠肺炎的有效治疗手段。 疾病。与此同时，几种候选疫苗目前正在进行临床开发或测试，旨在提供 对SARS-CoV-2的终身免疫力。然而，这些方法的一个主要安全问题是 抗病毒抗体增强而不是控制感染的潜力；这种现象被称为抗体- 依赖性增强(ADE)。虽然ADE主要被证明是针对黄病毒，如登革热，但它 目前尚不清楚这种现象是否也延伸到冠状病毒，如SARS-CoV-2。以前的研究关于 SARS冠状病毒提示，抗Spike蛋白的抗体可能促进白细胞和 通过过度或不适当地激活前体通过触发急性肺损伤来调节疾病的严重程度 炎症途径。这种致病活性被认为是通过它们的Fc相互作用来调节的。 效应器白细胞表面表达Fc-γ受体结构域。考虑到正在进行的临床开发 控制SARS-CoV-2感染的基于抗体的疗法和疫苗的努力，重要的是评估 抗SARS-CoV-2抗体是否有能力介导ADE，如果有，确定准确的 FcγRs在这一过程中的分子机制和作用。人类Fc功能研究中的一个主要障碍 在活体内是人类和其他哺乳动物在FcγR生物学上的实质性物种间差异 物种，需要开发新的动物品系来概括人类独特的复杂性 FCγR结构和功能属性。为了克服这些限制，拟议的研究旨在开发 新的SARS-CoV-2感染小鼠和仓鼠模型，将用于系统评估 一组抗SARS-CoV-2单抗和回收多克隆抗体的体内致病活性 新冠肺炎患者。通过将FC工程mAb的容量与定义的FCγR绑定配置文件进行比较， 介导SARS-CoV-2感染的ADE，拟议的研究将为体内ADE提供新的见解 抗SARS冠状病毒2Ig G抗体的活性，表征与疾病有关的FcγR途径 发病机制。

Abstract Given the uncontrolled spread of SARS-CoV-2 and the devastating impact on public health, therapeutic interventions are urgently needed for disease control. Indeed, several biotech and academic groups are currently focusing their efforts on the isolation and clinical development of monoclonal antibodies (mAbs) with potent neutralizing activity against SARS-CoV-2. During the past few weeks, a number of neutralizing anti-SARS-CoV- 2 mAbs have entered clinical testing, representing promising therapeutic modalities for the control of COVID-19 disease. In parallel, several vaccine candidates are currently in clinical development or testing, aiming to provide life-long immunity against SARS-CoV-2. However, a major safety concern for these approaches has been the potential of antiviral IgG antibodies to enhance, rather than control, infection; a phenomenon termed as antibody- dependent enhancement (ADE). Although ADE has been primarily demonstrated for flaviviruses, like dengue, it is unknown whether this phenomenon also extends to coronaviruses, like SARS-CoV-2. Previous studies on SARS-CoV suggest that IgG antibodies against the Spike protein may promote infection of leukocytes and modulate disease severity by triggering acute lung injury through excessive or inappropriate activation of pro- inflammatory pathways. This pathogenic activity is proposed to be mediated through the interaction of their Fc domains with FcγRs expressed on the surface of effector leukocytes. Given the ongoing clinical development efforts for antibody-based therapeutics and vaccines to control SARS-CoV-2 infection, it is important to assess whether anti-SARS-CoV-2 antibodies have the capacity to mediate ADE and if so, determine the precise molecular mechanisms and the role of FcγRs in this process. A major obstacle in the study of human Fc function in vivo is the substantial interspecies differences in the FcγR biology between humans and other mammalian species, necessitating the development of novel animal strains that recapitulate the unique complexity of human FcγR structural and functional attributes. To overcome these limitations, the proposed studies aim to develop novel mouse strains and hamster models of SARS-CoV-2 infection, which will be used to systematically evaluate the in vivo pathogenic activity of a panel of anti-SARS-CoV-2 mAbs and polyclonal IgG antibodies from recovered COVID-19 patients. By comparing the capacity of Fc-engineered mAbs with defined FcγR binding profile to mediate ADE of SARS-CoV-2 infection, the proposed studies will provide novel insights into the in vivo ADE activity of anti-SARS-CoV-2 IgG antibodies, characterizing the precise FcγR pathways that contribute to disease pathogenesis.