02483nas a2200493   4500000000100000000000100001008004100002260001200043653003800055653002400093653002200117653002000139653001600159653001600175653002100191653002200212653002400234653002600258653003600284653002400320653001900344653002600363653002000389653001500409100002100424700002800445700002000473700002000493700001600513700001400529700002100543700001800564700001800582700001400600700001800614700002100632700002600653700002200679245014900701300001400850490000800864520110300872022001401975       2018                            d  c2018-1210aAntibodies, Monoclonal, Humanized10aAutoimmune Diseases10aBlood Coagulation10aBlood Platelets10aCD40 Ligand10aDrug Design10aDrug development10aEndothelial Cells10aImmunologic Factors10aLab-On-A-Chip Devices10aMicrochip Analytical Procedures10aProspective Studies10aReceptors, IgG10aRetrospective Studies10aRisk Assessment10aThrombosis1 aRiccardo Barrile1 aAndries D. van der Meer1 aHyoungshin Park1 aJacob P. Fraser1 aDamir Simic1 aFang Teng1 aDavid Conegliano1 aJustin Nguyen1 aAbhishek Jain1 aMimi Zhou1 aKatia Karalis1 aDonald E. Ingber1 aGeraldine A. Hamilton1 aMonicah A. Otieno00aOrgan-on-Chip Recapitulates Thrombosis Induced by an anti-CD154 Monoclonal Antibody: Translational Potential of Advanced Microengineered Systems  a1240-12480 v1043 aClinical 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 complexes in the Chip-effluent in response to Hu5c8 in the presence of soluble CD40L. Importantly, the observed prothrombotic effects were not observed with Hu5c8-IgG2σ designed with an Fc domain that does not bind the 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 systems to better predict human response.  a1532-6535