Enhancing FcγR-mediated antibody effector function during persistent viral infection

Persistent viral infections can interfere with Fc gamma R-mediated antibody effector functions by excessive immune complex (IC) formation, resulting in resistance to therapeutic Fc gamma R-dependent antibodies. We and others have previously demonstrated that mice persistently infected with lymphocytic choriomeningitis virus (LCMV) are resistant to a wide range of depleting antibodies due to excessive IC formation. Here, we dissect the mechanisms by which two depleting antibodies overcome the obstacle of endogenous ICs and achieve efficient target cell depletion in persistently infected mice. Efficient antibody-mediated depletion during persistent LCMV infection required increased levels of antibody bound to target cells or use of afucosylated antibodies with increased affinity for Fc gamma Rs. Antibodies targeting the highly expressed CD90 antigen or overexpressed human CD20 efficiently depleted their target cells in naive and persistently infected mice, whereas antibodies directed against less abundant antigens failed to deplete their target cells during persistent LCMV infection. In addition, we demonstrate the superior activity of afucosylated antibodies in the presence of endogenous ICs. We generated afucosylated antibodies directed against CD4 and CD8 alpha, which, in contrast to their parental fucosylated versions, efficiently depleted their respective target cells in persistently infected mice. Efficient antibody-mediated depletion can thus be achieved if therapeutic antibodies can outcompete endogenous ICs for access to Fc gamma Rs either by targeting highly expressed antigens or by increased affinity for Fc gamma Rs. Our findings have implications for the optimization of therapeutic antibodies and provide strategies to allow efficient Fc gamma R engagement in the presence of competing endogenous ICs in persistent viral infections, autoimmune diseases, and cancer.