Research ArticleANTIBODIES

Enhancing FcγR-mediated antibody effector function during persistent viral infection

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Science Immunology  21 Sep 2018:
Vol. 3, Issue 27, eaao3125
DOI: 10.1126/sciimmunol.aao3125

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Giving antibodies a boost

Persistent immune activation during chronic infections is often associated with increased generation and deposition of immune complexes. The actions of antibody-based drugs can therefore be severely impaired in individuals with chronic infections. Using lymphocytic choriomeningitis virus (LCMV) as a model of chronic infection, Wieland et al. have examined how to enhance antibody functions in this setting. They found that the ability of antibodies to deplete target cells is dependent on antigen expression levels. Further, they also found that afucosylation of antibodies directed against CD4 and CD8α enhanced the ability of these antibodies to deplete CD4+ and CD8+ T cells in mice persistently infected with LCMV. Whether afucosylation can be universally used to enhance antibody functions during chronic infections remains to be seen.

Abstract

Persistent viral infections can interfere with FcγR-mediated antibody effector functions by excessive immune complex (IC) formation, resulting in resistance to therapeutic FcγR-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 FcγRs. Antibodies targeting the highly expressed CD90 antigen or overexpressed human CD20 efficiently depleted their target cells in naïve 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 CD8α, 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 FcγRs either by targeting highly expressed antigens or by increased affinity for FcγRs. Our findings have implications for the optimization of therapeutic antibodies and provide strategies to allow efficient FcγR engagement in the presence of competing endogenous ICs in persistent viral infections, autoimmune diseases, and cancer.

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