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.
| Original language | English |
|---|---|
| Pages (from-to) | 1240-1248 |
| Number of pages | 9 |
| Journal | Clinical pharmacology & therapeutics |
| Volume | 104 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - Dec 2018 |
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Keywords
- UT-Hybrid-D
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Organ-on-Chip Recapitulates Thrombosis Induced by an anti-CD154 Monoclonal Antibody : Translational Potential of Advanced Microengineered Systems. / Barrile, Riccardo (Corresponding Author); van der Meer, Andries D.; Park, Hyoungshin; Fraser, Jacob P.; Simic, Damir; Teng, Fang; Conegliano, David; Nguyen, Justin; Jain, Abhishek; Zhou, Mimi; Karalis, Katia; Ingber, Donald E.; Hamilton, Geraldine A.; Otieno, Monicah A.
In: Clinical pharmacology & therapeutics, Vol. 104, No. 6, 12.2018, p. 1240-1248.Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - Organ-on-Chip Recapitulates Thrombosis Induced by an anti-CD154 Monoclonal Antibody
T2 - Translational Potential of Advanced Microengineered Systems
AU - Barrile, Riccardo
AU - van der Meer, Andries D.
AU - Park, Hyoungshin
AU - Fraser, Jacob P.
AU - Simic, Damir
AU - Teng, Fang
AU - Conegliano, David
AU - Nguyen, Justin
AU - Jain, Abhishek
AU - Zhou, Mimi
AU - Karalis, Katia
AU - Ingber, Donald E.
AU - Hamilton, Geraldine A.
AU - Otieno, Monicah A.
N1 - Wiley deal
PY - 2018/12
Y1 - 2018/12
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.
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.
KW - UT-Hybrid-D
UR - http://www.scopus.com/inward/record.url?scp=85046131849&partnerID=8YFLogxK
U2 - 10.1002/cpt.1054
DO - 10.1002/cpt.1054
M3 - Article
AN - SCOPUS:85046131849
VL - 104
SP - 1240
EP - 1248
JO - Clinical pharmacology & therapeutics
JF - Clinical pharmacology & therapeutics
SN - 0009-9236
IS - 6
ER -