Proposed mechanism of off-target toxicity for antibody–drug conjugates driven by mannose receptor uptake

Antibody–drug conjugates (ADCs) are developed with the goal of increasing compound therapeutic index by specific and targeted delivery of a toxic payload to the site of action while considerably reducing damage to normal tissues. Yet, off-target hepatic toxicities have been reported for several ADC. Locations of these off-target toxicities coincide with the reported locations of cell surface mannose receptor (MR). The relative proportion of agalactosylated glycans on the Fc domain (G0F vs. G1F and G2F components) in monoclonal antibody (mAb)–based biotherapeutics is closer to some disease state IgG rather than to a normal serum-derived immunoglobulin. The lack of the terminal galactose on a G0F glycan creates an opportunity for the mAb to interact with soluble and cell surface MRs. MR is a known multi-domain lectin that specifically binds and internalizes glycoproteins and immune complexes with relatively high G0F content and has been found on the surface of various cell types, including immune cells of myeloid lineage, endothelial cells, and hepatic and splenic sinusoids. In this review paper it is proposed that the mechanism of the off-target toxicities for ADC biotherapeutics is at least in part driven by the carbohydrates, specifically agalactosylated glycans, such as G0F, their interactions with MR and resulting glycan-derived cellular uptake of ADCs. Several case studies are reviewed presenting corroborating information.