Organ-on-Chip Recapitulates Thrombosis Induced by an anti-CD154 Monoclonal Antibody
| Autor: | Geraldine A. Hamilton, Katia Karalis, Jacob P. Fraser, Monicah A. Otieno, Riccardo Barrile, Fang Teng, Mimi Zhou, Donald E. Ingber, Andries D. van der Meer, Justin Nguyen, David Conegliano, Hyoungshin Park, Damir Simic, Abhishek Jain |
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| Přispěvatelé: | Applied Stem Cell Technologies |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
Blood Platelets
0301 basic medicine Endothelium medicine.drug_class CD40 Ligand UT-Hybrid-D Antibodies Monoclonal Humanized Monoclonal antibody Risk Assessment Fibrin Autoimmune Diseases Endothelial activation 03 medical and health sciences 0302 clinical medicine Thrombin Drug Development Lab-On-A-Chip Devices Microchip Analytical Procedures medicine Immunologic Factors Pharmacology (medical) Prospective Studies Receptor Blood Coagulation Retrospective Studies Pharmacology biology business.industry Receptors IgG Endothelial Cells Thrombosis medicine.disease 22/4 OA procedure 030104 developmental biology medicine.anatomical_structure Drug Design 030220 oncology & carcinogenesis Monoclonal biology.protein Cancer research business medicine.drug |
| Zdroj: | Clinical pharmacology & therapeutics, 104(6), 1240-1248. Wiley-Blackwell |
| ISSN: | 0009-9236 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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