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

FcgR 抗体依赖性增强 SARS-CoV-2 感染机制的评估

基本信息

批准号：
10265733
负责人：
Peter Palese
金额：
$ 78.49万
依托单位：
ROCKEFELLER UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-10 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10265733
关键词：
2019-nCoV ACE2 Acute Acute Lung Injury Affinity Animal Disease Models Animal Model Animals Antibodies Antibody Therapy Antibody-Dependent Enhancement Antiviral Agents Binding Biological Biology Biotechnology COVID-19 COVID-19 patient Clinical Trials Coronavirus Dengue Development Disease Disease model Disease susceptibility Engineering Evaluation Exhibits Experimental Models Fc domain Flavivirus Gene Transfer Techniques Generations Hamsters Human IgG1 Immunoglobulin G In Vitro Infection Inflammatory Leukocytes Life Macaca mulatta Mediating Mesocricetus auratus Middle East Respiratory Syndrome Modality Modeling Molecular Monoclonal Antibodies Mouse Strains Mus Pathogenesis Pathogenicity Pathway interactions Pre-Clinical Model Process Proteins Public Health Research Role SARS coronavirus SARS-CoV-2 antibody SARS-CoV-2 immunity SARS-CoV-2 infection Safety Severity of illness Structure Structure of parenchyma of lung Surface System Testing Therapeutic Therapeutic Intervention Vaccination Vaccines Variant clinical development disorder control humanized mouse in vivo in vivo Model in vivo evaluation insight mouse model novel research clinical testing response stem vaccine candidate

项目摘要

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.

抽象的鉴于 SARS-CoV-2 的不受控制的传播以及对公共卫生的破坏性影响，治疗事实上，目前迫切需要采取干预措施来控制疾病。他们的重点是单克隆抗体（mAb）的分离和临床开发，具有强效抗 SARS-CoV-2 的中和活性在过去的几周里，许多中和抗 SARS-CoV- 2 个 mAb 已进入临床测试，代表了控制 COVID-19 的有前途的治疗方式与此同时，几种候选疫苗目前正在进行临床开发或测试，旨在提供治疗疾病的机会。然而，这些方法的一个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- 尽管 ADE 主要针对登革热等黄病毒得到证实，但它并不有效。目前尚不清楚这种现象是否也适用于冠状病毒，例如 SARS-CoV-2。 SARS-CoV 表明针对刺突蛋白的 IgG 抗体可能会促进白细胞和通过过度或不适当的激活前体来引发急性肺损伤，从而调节疾病的严重程度这种致病活性被认为是通过其 Fc 的相互作用介导的。鉴于正在进行的临床开发，FcγR 域在效应白细胞表面表达。对于控制 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 抗体是否具有介导 ADE 的能力，如果有，请确定精确的 FcγR 的分子机制和在此过程中的作用是人类 Fc 功能研究的主要障碍。在体内，人类和其他哺乳动物之间的 FcγR 生物学存在显着的种间差异物种，需要开发新的动物品系来概括人类独特的复杂性为了克服这些限制，拟议的研究旨在开发 FcγR 的结构和功能属性。 SARS-CoV-2感染的新型小鼠品系和仓鼠模型，将用于系统评估一组抗 SARS-CoV-2 mAb 和多克隆 IgG 抗体的体内致病活性通过将具有明确 FcγR 结合谱的 Fc 工程单克隆抗体的能力与 COVID-19 患者进行比较。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-CoV-2 IgG 抗体的活性，表征导致疾病的精确 FcγR 通路发病。