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Poster

Development of an Autologous Physiologically Relevant Human 3D Vessel-on-a-Chip Cytokine Release Assay System to Predict the Safety of Novel Biologics

November 28, 2021
BSI Congress 2021 -- Following the failure to predict the cytokine release syndrome (CRS) induced by TGN1412 in 2006, the need for improved predictive preclinical in vitro safety assessments has become a priority and a regulatory expectation. Current in vitro assays using Peripheral Blood Mononuclear Cells (PBMCs) and Whole Blood (WB) utilise standard formats of antibody presentation (dry coat, wet coat or liquid phase). While these are biologically simple to run, they do not accurately reflect human in vivo physiology, and the limitations of toxicology models are well documented. Efforts have therefore been made to address this, for example through the development of a co-culture assay using Human Umbilical Vein Endothelial Cells (HUVECs) with PBMCs or WB, designed to mimic the vascular environment. While this is more physiologically relevant than standard assays, the heterologous approach results in higher basal levels of pro-inflammatory cytokines as previously described in the literature (Reed et al., 2015), which ultimately reduces assay sensitivity. This study therefore looked to advance the assay further by developing a human fully autologous co-culture system using Blood Outgrowth Endothelial Cells (BOECs) derived from adult peripheral blood, which can be co-cultured with PBMCs or WB from the same donor.