Organ-on-Chip Recapitulates Thrombosis Induced by an anti-CD154 Monoclonal Antibody: Translational Potential of Advanced Microengineered Systems.
Clin Pharmacol Ther
; 104(6): 1240-1248, 2018 12.
Article
in En
| MEDLINE
| ID: mdl-29484632
ABSTRACT
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Autoimmune Diseases
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Thrombosis
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Blood Coagulation
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Drug Design
/
CD40 Ligand
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Microchip Analytical Procedures
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Lab-On-A-Chip Devices
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Antibodies, Monoclonal, Humanized
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Drug Development
/
Immunologic Factors
Type of study:
Etiology_studies
/
Observational_studies
/
Prognostic_studies
Language:
En
Journal:
Clin Pharmacol Ther
Year:
2018
Type:
Article
Affiliation country:
United States