Immunoglobulin GM (γ marker) and FcγR genotypes interact to contribute to the magnitude of ADCC against SARS CoV-2 S-transfected cells

Immunoglobulin GM (γ marker) and KM (κ marker) allotypes have been shown to be associated with antibody responses to several viruses, but their role in immunity to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-the causative agent of Coronavirus disease 2019 (COVID-19)-has not been investigated. The aim of the present investigation was to determine the contribution of GM, KM, and FcγR genotypes to the magnitude of humoral immunity to SARS-CoV-2 and to the antibody-dependent cell-mediated cytotoxicity (ADCC) of SARS CoV-2 S-transfected cells. ADCC is a major host immunosurveillance mechanism against viruses and the leading mechanism underlying the clinical efficacy of therapeutic monoclonal antibodies. We genotyped 124 unvaccinated people for several GM, KM, and FcγR alleles, measured IgG antibodies to the receptor-binding domain of the spike protein (S-RBD) of SARS CoV-2, and quantitated the level of ADCC against SARS CoV-2 S-transfected cells. None of the associations between genotypes and antibody levels were statistically significant, potentially a reflection of relatively small sample sizes. However, we found a significant interactive effect of GM and FcγRIIIa valine (V)/phenylalanine (F) genotypes on the ADCC of SARS CoV-2 S-transfected cells. In the FcγRIIIa F/F group, the mean ADCC value was significantly (p = 0.03) lower among those with GM 17/17 (mean = 45.2) when compared to those with GM 3/3 (mean = 60.2). In the FcγRIIIa V/V group, the mean ADCC value was not significantly (p = 0.68) lower among those with GM 17/17 (mean = 52.5) when compared to those with GM 3/3 (mean = 55.4). These results may help devise potent immunotherapy against emerging SARS CoV-2 variants.