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：
10202128
负责人：
Peter Palese
金额：
$ 65.41万
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/10202128
关键词：
2019-nCoV 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 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 Immunity 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 Patients Pre-Clinical Model Process Proteins Public Health Research Role SARS coronavirus 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不受控制的传播以及对公共卫生的毁灭性影响，治疗迫切需要进行疾病控制的干预措施。确实，目前有几个生物技术和学术团体将他们的精力集中在具有强大的单克隆抗体（mAb）的隔离和临床发展上对SARS-COV-2的中和活性。在过去的几周中，许多中和抗Sars-Cov- 2个mAB进入了临床测试，代表了COVID-19的有希望的治疗方式疾病。同时，目前正在临床开发或测试中几个候选疫苗，旨在提供终身对SARS-COV-2的免疫力。但是，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；一种称为抗体的现象依赖增强（ADE）。尽管ADE主要是针对登革热的黄病毒的证明尚不清楚这种现象是否也延伸到冠状病毒，例如SARS-COV-2。先前的研究 SARS-COV表明针对峰值蛋白的IgG抗体可能促进白细胞感染和通过过量或不适当的激活来调节疾病的严重程度炎症途径。提出这种致病活性是通过FC的相互作用介导的在效应子白细胞表面表达的FcγR的结构域。考虑到正在进行的临床发展基于抗体的治疗和疫苗控制SARS-COV-2感染的努力，评估很重要抗SARS-COV-2抗体是否具有介导ADE的能力，如果是，请确定精度分子机制和FcγR在此过程中的作用。人类FC功能研究的主要障碍体内是人与其他哺乳动物之间的FcγR生物学的大量种间差异物种，开发新型动物菌株的发展所必需的物种，这些动物菌株概括了人类的独特复杂性 FcγR结构和功能属性。为了克服这些局限性，拟议的研究旨在发展 SARS-COV-2感染的新型小鼠菌株和仓鼠模型，该模型将用于系统评估从回收的抗SARS-COV-2 mAb和多克隆IgG抗体的体内病原活性 Covid-19患者。通过比较具有定义的FcγR结合曲线的FC工程MAB的能力与介导SARS-COV-2感染的ADE，拟议的研究将提供对体内ADE的新见解抗SARS-COV-2 IgG抗体的活性，表征有助于疾病的精确FcγR途径发病。