biostudies-literatureUnknown120(15)Izadi AAntibodies play a central role in the immune defense against SARS-CoV-2. Emerging evidence has shown that nonneutralizing antibodies are important for immune defense through Fc-mediated effector functions. Antibody subclass is known to affect downstream Fc function. However, whether the antibody subclass plays a role in anti-SARS-CoV-2 immunity remains unclear. Here, we subclass-switched eight human IgG1 anti-spike monoclonal antibodies (mAbs) to the IgG3 subclass by exchanging their constant domains. The IgG3 mAbs exhibited altered avidities to the spike protein and more potent Fc-mediated phagocytosis and complement activation than their IgG1 counterparts. Moreover, combining mAbs into oligoclonal cocktails led to enhanced Fc- and complement receptor-mediated phagocytosis, superior to evProceedings of the National Academy of Sciences of the United States of Americae2217590120https://www.ebi.ac.uk/biostudies/studies/S-EPMC10104557biostudies-literatureSubclass-switched anti-spike IgG3 oligoclonal cocktails strongly enhance Fc-mediated opsonization.PMC10104557Ohlin MLarsson OElder EAppelberg SIzadi AWrighton SWendel-Hansen VBahnan WValsjo MGodzwon MOlofsson BHailu ASchmidt TNordenfelt PSoderlund-Strand AfalseSubclass-switched anti-spike IgG3 oligoclonal cocktails strongly enhance Fc-mediated opsonization.Antibodies play a central role in the immune defense against SARS-CoV-2. Emerging evidence has shown that nonneutralizing antibodies are important for immune defense through Fc-mediated effector functions. Antibody subclass is known to affect downstream Fc function. However, whether the antibody subclass plays a role in anti-SARS-CoV-2 immunity remains unclear. Here, we subclass-switched eight human IgG1 anti-spike monoclonal antibodies (mAbs) to the IgG3 subclass by exchanging their constant domains. The IgG3 mAbs exhibited altered avidities to the spike protein and more potent Fc-mediated phagocytosis and complement activation than their IgG1 counterparts. Moreover, combining mAbs into oligoclonal cocktails led to enhanced Fc- and complement receptor-mediated phagocytosis, superior to ev2023-01-01T00:00:00Z2023 Apr2025-04-21T21:57:18.56Z2025-04-05T18:29:01.506ZS-EPMC101045573701119710.1073/pnas.2217590120