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Extracorporeal human whole blood in motion, as a tool to predict first-infusion reactions and mechanism-of-action of immunotherapeutics
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab. Immuneed AB, Uppsala.
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
Immuneed AB, Uppsala.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
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2018 (English)In: International Immunopharmacology, ISSN 1567-5769, E-ISSN 1878-1705, Vol. 54, p. 1-11Article in journal (Refereed) Published
Abstract [en]

First infusion reactions along with severe anaphylactic responses can occur as a result of systemic administration of therapeutic antibodies. The underlying mechanisms by which monoclonal antibodies induce cytokine release syndrome (CRS) can involve direct agonistic effects via the drug target, or a combination of target-engagement along with innate receptor interactions. Despite the wide variety of pathways and cells that can play a role in CRS, many currently used assays are devoid of one or more components that must be present for these responses to occur. One assay that has not been assessed for its capacity to predict CRS is the modified Chandler loop model. Herein we evaluate a plethora of commercially available monoclonal antibodies to evaluate the modified Chandler loop model's potential in CRS prediction. We demonstrate that in a 4-hour loop assay, both the superagonistic antibodies, anti-CD3 (OKT3) and anti-CD28 (ANC28.1), display a clear cytokine response with a mixed adaptive/innate cytokine source. OKT3 induce TNFα and IFN-γ release in 20 out of 23 donors tested, whereas ANC28.1 induce TNF-α, IL-2 and IFN-γ release in all donors tested (n = 18–22). On the other hand, non-agonistic antibodies associated with no or low infusion reactions in the clinic, namely cetuximab and natalizumab, neither induce cytokine release nor cause false positive responses. A TGN1412-like antibody also display a clear cytokine release with an adaptive cytokine profile (IFN-γ and IL-2) and all donors (n = 9) induce a distinct IL-2 response. Additionally, the value of an intact complement system in the assay is highlighted by the possibility to dissect out the mechanism-of-action of alemtuzumab and rituximab. The loop assay can either complement lymph node-like assays or stand-alone to investigate drug/blood interactions during preclinical development, or for individual safety screening prior to first-in-man clinical trial.

Place, publisher, year, edition, pages
2018. Vol. 54, p. 1-11
Keywords [en]
Cytokine release syndrome, CRS, Immunotoxicity, Cytokine release assay, Anti-CD28, Alemtuzumab, OKT3
National Category
Immunology in the medical area Pharmacology and Toxicology
Identifiers
URN: urn:nbn:se:uu:diva-346359DOI: 10.1016/j.intimp.2017.10.021ISI: 000423887900001PubMedID: 29100032OAI: oai:DiVA.org:uu-346359DiVA, id: diva2:1191146
Funder
Swedish Research Council, K2013-79X-22263-01-2Swedish Society for Medical Research (SSMF)Available from: 2018-03-16 Created: 2018-03-16 Last updated: 2018-03-16Bibliographically approved

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Fletcher, Erika A. K.Eltahir, MohamedLeja-Jarblad, JustynaMangsbo, Sara
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