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

摘要 鉴于SARS-CoV-2的不受控制的传播和对公共卫生的破坏性影响， 迫切需要采取干预措施来控制疾病。事实上，一些生物技术和学术团体目前正在 他们的工作重点是分离和临床开发单克隆抗体（mAb）， 对SARS-CoV-2的中和活性。在过去的几周里，一些中和抗SARS-CoV- 2种mAb已进入临床测试，代表了控制COVID-19的有希望的治疗方式 疾病与此同时，几种候选疫苗目前正在临床开发或测试中，旨在提供 对SARS-CoV-2的终身免疫。然而，这些方法的主要安全问题是 抗病毒IgG抗体增强而不是控制感染的潜力;这种现象称为抗体- 依赖性增强（ADE）。虽然ADE主要被证明是黄病毒，如登革热， 目前尚不清楚这种现象是否也延伸到冠状病毒，如SARS-CoV-2。以往的研究对 SARS-CoV表明，针对刺突蛋白的IgG抗体可能促进白细胞的感染， 通过过度或不适当地激活肺组织中的促炎因子， 炎症通路。这种致病活性被认为是通过它们的Fc Fcγ R在效应白细胞表面表达。鉴于目前的临床研究 为了控制SARS-CoV-2感染，基于抗体的治疗和疫苗的努力，重要的是评估 抗SARS-CoV-2抗体是否具有介导ADE的能力，如果是， 分子机制和FcγRs在这一过程中的作用。人类Fc功能研究中的一个主要障碍 在体内，人类和其他哺乳动物之间FcγR生物学的实质性种间差异 物种，有必要开发新的动物品系，重现人类独特的复杂性， FcγR结构和功能属性。为了克服这些局限性，拟议的研究旨在开发 新的SARS-CoV-2感染小鼠品系和仓鼠模型，将用于系统地评估 一组抗SARS-CoV-2单克隆抗体和多克隆IgG抗体体内致病活性 新冠肺炎患者。通过比较具有确定FcγR结合谱的Fc工程化mAb与 SARS-CoV-2感染介导的ADE，拟议的研究将为体内ADE提供新的见解 抗SARS-CoV-2 IgG抗体的活性，表征导致疾病的精确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.