Organ-on-Chip Recapitulates Thrombosis Induced by an anti-CD154 Monoclonal Antibody: Translational Potential of Advanced Microengineered Systems

Riccardo Barrile (Corresponding Author), Andries D. van der Meer, Hyoungshin Park, Jacob P. Fraser, Damir Simic, Fang Teng, David Conegliano, Justin Nguyen, Abhishek Jain, Mimi Zhou, Katia Karalis, Donald E. Ingber, Geraldine A. Hamilton, Monicah A. Otieno

Research output: Contribution to journalArticleAcademicpeer-review

13 Citations (Scopus)

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 languageEnglish
Pages (from-to)1240-1248
Number of pages9
JournalClinical pharmacology & therapeutics
Volume104
Issue number6
DOIs
Publication statusPublished - Dec 2018

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CD40 Ligand
Thrombosis
Monoclonal Antibodies
Thrombin
Platelet Activation
Fibrin
Platelet Aggregation
Endothelium
Blood Vessels
Immunoglobulin G

Keywords

  • UT-Hybrid-D

Cite this

Barrile, Riccardo ; 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. / Organ-on-Chip Recapitulates Thrombosis Induced by an anti-CD154 Monoclonal Antibody : Translational Potential of Advanced Microengineered Systems. In: Clinical pharmacology & therapeutics. 2018 ; Vol. 104, No. 6. pp. 1240-1248.
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Barrile, R, van der Meer, AD, Park, H, Fraser, JP, Simic, D, Teng, F, Conegliano, D, Nguyen, J, Jain, A, Zhou, M, Karalis, K, Ingber, DE, Hamilton, GA & Otieno, MA 2018, 'Organ-on-Chip Recapitulates Thrombosis Induced by an anti-CD154 Monoclonal Antibody: Translational Potential of Advanced Microengineered Systems' Clinical pharmacology & therapeutics, vol. 104, no. 6, pp. 1240-1248. https://doi.org/10.1002/cpt.1054

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 journalArticleAcademicpeer-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

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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.

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U2 - 10.1002/cpt.1054

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M3 - Article

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SP - 1240

EP - 1248

JO - Clinical pharmacology & therapeutics

JF - Clinical pharmacology & therapeutics

SN - 0009-9236

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