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Intravenous immunoglobulin (IVIG) administered at high doses is used to treat a wide array of autoimmune diseases. Studies in murine models have identified that the anti-inflammatory activity of IVIG is dependent on sialylation of the N-linked glycan on the CH2 domain of immunoglobulin G (IgG), the type I IgG inhibitory Fc receptor FcγRIIB, and the type II Fc receptor dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN). We hypothesized that DC-SIGN, a C-type lectin, may directly interact with glycans on FcγRIIB, augmenting its ability to bind sialylated IgG. We found that Fc-engineering sialylated IgG1 to enhance its affinity for FcγRIIB resulted in a molecule that was more potent than IVIG in reducing the inflammatory sequelae of antibody or T cell-mediated autoimmune diseases, providing the basis for a class of potent anti-inflammatory therapeutics.
Jones et al. (Thu,) studied this question.