Document text
Principal Investigator: Peter Palese
Organization: ROCKEFELLER UNIVERSITY
Fiscal Year: 2020
Award: $654,116
Funding agency: National Institute of Allergy and Infectious Diseases
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.
Terms: <2019 novel coronavirus><2019-nCoV><7S Gamma Globulin><Acute><Acute Lung Injury><Acute Pulmonary Injury><Affinity><Animal Disease Models><Animal Model><Animal Models and Related Studies><Animals><Antibodies><Antibody Therapy><Antibody-Dependent Enhancement><Antiviral Agents><Antiviral Drugs><Antivirals><Binding><Biological><Biology><Biotech><Biotechnology><Blood leukocyte><COVID-19><COVID19><Clinical Evaluation><Clinical Testing><Clinical Treatment Moab><Clinical Trials><Coronaviridae><Coronavirus><Cricetinae><Dengue><Development><Diathesis><Disease><Disease model><Disease susceptibility><Disorder><Engineering><Evaluation><Exhibits><Experimental Models><Fc domain><Flavivirus><Gene Transfer Techniques><Generations><Golden Hamsters><Golden Syrian Hamsters><Group B Arbovirus><Hamsters><Hamsters Mammals><Human><IgG><IgG1><Immunity><Immunoglobulin G><In Vitro><Infection><Inflammatory><Leukocytes><Leukocytes Reticuloendothelial System><Life><Lung Parenchyma><Lung Tissue><M mulatta><M. mulatta><MERS><MERS coronavirus disease><MERS-CoV disease><Macaca mulatta><Marrow leukocyte><Mediating><Mesocricetus auratus><Mice><Mice Mammals><Middle East Respiratory Syndrome><Middle East Respiratory Syndrome CoV disease><Middle East Respiratory Syndrome coronavirus disease><Middle Eastern Respiratory Syndrome><Middle Eastern Respiratory Syndrome CoV disease><Middle Eastern Respiratory Syndrome coronavirus disease><Modality><Modeling><Modern Man><Molecular><Molecular Interaction><Monoclonal Antibodies><Mouse Strains><Murine><Mus><Pathogenesis><Pathogenicity><Pathway interactions><Patients><Pre-Clinical Model><Preclinical Models><Process><Proteins><Public Health><Research><Rhesus Macaque><Rhesus Monkey><Role><SARS Virus><SARS corona virus><SARS coronavirus><SARS-Associated Coronavirus><SARS-CoV><SARS-CoV-2><SARS-CoV2><SARS-Related Coronavirus><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related coronavirus 2><Safety><Severe Acute Respiratory Syndrome Virus><Severe Acute Respiratory Syndrome corona virus><Severe Acute Respiratory Syndrome coronavirus><Severe acute respiratory syndrome coronavirus 2><Severity of illness><Structure><Structure of parenchyma of lung><Surface><Syrian Hamsters><System><Testing><Therapeutic><Therapeutic Intervention><Transgenesis><Vaccination><Vaccines><Variant><Variation><White Blood Cells><White Cell><Wuhan coronavirus><anti-viral agents><anti-viral drugs><anti-virals><antibody based therapies><antibody treatment><antibody-based therapeutics><antibody-based treatment><clinical development><clinical test><corona virus><corona virus disease 2019><coronavirus disease 2019><developmental><disease control><disease severity><disorder control><disorder model><humanized mice><humanized mouse><in vivo><in vivo Model><in vivo evaluation><in vivo testing><insight><intervention therapy><liability to disease><mAbs><model of animal><model organism><mouse model><murine model><novel><pathway><research clinical testing><response><severe acute respiratory syndrome-CoV><social role><stem><vaccine candidate><white blood cell><white blood corpuscle>