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

AbstractGiven the uncontrolled spread of SARS-CoV-2 and the devastating impact on public health, therapeuticinterventions are urgently needed for disease control. Indeed, several biotech and academic groups are currentlyfocusing their efforts on the isolation and clinical development of monoclonal antibodies (mAbs) with potentneutralizing 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-19disease. In parallel, several vaccine candidates are currently in clinical development or testing, aiming to providelife-long immunity against SARS-CoV-2. However, a major safety concern for these approaches has been thepotential 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, itis unknown whether this phenomenon also extends to coronaviruses, like SARS-CoV-2. Previous studies onSARS-CoV suggest that IgG antibodies against the Spike protein may promote infection of leukocytes andmodulate 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 Fcdomains with FcγRs expressed on the surface of effector leukocytes. Given the ongoing clinical developmentefforts for antibody-based therapeutics and vaccines to control SARS-CoV-2 infection, it is important to assesswhether anti-SARS-CoV-2 antibodies have the capacity to mediate ADE and if so, determine the precisemolecular mechanisms and the role of FcγRs in this process. A major obstacle in the study of human Fc functionin vivo is the substantial interspecies differences in the FcγR biology between humans and other mammalianspecies, necessitating the development of novel animal strains that recapitulate the unique complexity of humanFcγR structural and functional attributes. To overcome these limitations, the proposed studies aim to developnovel mouse strains and hamster models of SARS-CoV-2 infection, which will be used to systematically evaluatethe in vivo pathogenic activity of a panel of anti-SARS-CoV-2 mAbs and polyclonal IgG antibodies from recoveredCOVID-19 patients. By comparing the capacity of Fc-engineered mAbs with defined FcγR binding profile tomediate ADE of SARS-CoV-2 infection, the proposed studies will provide novel insights into the in vivo ADEactivity of anti-SARS-CoV-2 IgG antibodies, characterizing the precise FcγR pathways that contribute to diseasepathogenesis.