TY - JOUR
KW - Antibodies, Monoclonal, Humanized
KW - Autoimmune Diseases
KW - Blood Coagulation
KW - Blood Platelets
KW - CD40 Ligand
KW - Drug Design
KW - Drug development
KW - Endothelial Cells
KW - Immunologic Factors
KW - Lab-On-A-Chip Devices
KW - Microchip Analytical Procedures
KW - Prospective Studies
KW - Receptors, IgG
KW - Retrospective Studies
KW - Risk Assessment
KW - Thrombosis
AU - Riccardo Barrile
AU - Andries D. van der Meer
AU - Hyoungshin Park
AU - Jacob P. Fraser
AU - Damir Simic
AU - Fang Teng
AU - David Conegliano
AU - Justin Nguyen
AU - Abhishek Jain
AU - Mimi Zhou
AU - Katia Karalis
AU - Donald E. Ingber
AU - Geraldine A. Hamilton
AU - Monicah A. Otieno
AB - 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 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.
BT - Clinical Pharmacology and Therapeutics
DA - 2018-12
DO - 10.1002/cpt.1054
IS - 6
LA - eng
N2 - 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 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.
PY - 2018
SP - 1240
EP - 1248
ST - Organ-on-Chip Recapitulates Thrombosis Induced by an anti-CD154 Monoclonal Antibody
T2 - Clinical Pharmacology and Therapeutics
TI - Organ-on-Chip Recapitulates Thrombosis Induced by an anti-CD154 Monoclonal Antibody: Translational Potential of Advanced Microengineered Systems
VL - 104
SN - 1532-6535
ER -