Published in: Clinical Pharmacology & Therapeutics
Clinical development of Hu5c8, a monoclonal antibody against CD40L intended for treatment of autoimmune disorders, was terminated due to unexpected thrombotic complications. These life‐threatening side‐effects were not discovered during preclinical testing due to the lack of predictive models. In the present study, we describe the development of a microengineered system lined by human endothelium perfused with human whole blood, a ‘Vessel‐Chip’. The Vessel‐Chip allowed us to evaluate key parameters in thrombosis, such as endothelial activation, platelet adhesion, platelet aggregation, fibrin clot formation, and thrombin anti‐thrombin (TAT) complexes in the Chip‐effluent in response to Hu5c8 in the presence of soluble CD40L. Importantly, the observed pro‐thrombotic effects were not observed with Hu5c8‐IgG2σ designed with a Fc domain that does not bind FcγRIIa receptor, suggesting that this approach may have a low potential risk for thrombosis. Our results demonstrate the translational potential of Organs‐on‐Chips, as advanced microengineered system to better predict human response. This article is protected by copyright. All rights reserved.