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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.

摘要