Abstract
Abstract While monoclonal antibodies (mAb), such as αCD20, have significantly improved patient outcomes for B cell malignancies, patient responses vary and drug resistance can occur. One proposed limitation is the reduction of innate immune effector functions such as antibody dependent cellular phagocytosis (ADCP) – the principal cytotoxic mechanism for many mAb-based therapeutics. ADCP is mediated by Fcγ Receptor- and complement-dependent pathways (FcγR-ADCP and cADCP, respectively). However, our lab has shown that the capacity of macrophages (Mϕ) to engulf mAb opsonized targets is finite and after brief period of engorgement, Mϕ enter a phase of negligible phagocytic activity termed hypophagia. We have previously described the mechanisms that negatively regulate FcγR-ADCP, but complement-induced hypophagia is less understood. To begin to characterize complement-induced exhaustion, we used live cell imaging to measure mAb opsonized thymocyte engulfment by primary mouse Mϕ in the presence absence of complement. Preliminary data suggest that cADCP kinetics and cytotoxic capacities are distinct from FcγR-ADCP; however, both lead to a hypophagic state that impinges on future target cell clearance. Furthermore, Mϕ refractory to additional FcγR-ADCP still phagocytose through complement receptors up until the cADCP pathway also becomes exhausted. Published data from our lab also show that FcγR driven hypophagia involves surface receptor downregulation, but interestingly, there is no reduction in complement receptor surface levels following cADCP-induced hypophagia. Therefore, a better understanding of cADCP and the mechanistic overlap with FcγR-ADCP is critical to optimizing mAb therapy by minimizing immune cell exhaustion. Supported by grants from NIH (T32 AI007496, 26A1)
Published Version
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