Extracorporeal human whole blood in motion, as a tool to predict first-infusion reactions and mechanism-of-action of immunotherapeutics

• DOI: 10.1016/j.intimp.2017.10.021
• Publication Date: 2017-10-27T20:31:29Z
• Authors: Erika A.K. Fletcher; Mohamed Eltahir; Frida Lindqvist; Jonas Rieth; Gunilla Törnqvist; Justyna Leja-Jarblad; Sara M. Mangsbo
• Keywords: Models, Molecular; Extracorporeal Circulation; CD3 Complex; Drug-Related Side Effects and Adverse Reactions; Cytokine release assay; Microfluidics; Anti-CD28; Pharmacology and Toxicology; Adaptive Immunity; 03 medical and health sciences; 0302 clinical medicine; Cytokine release syndrome; CD28 Antigens; Immunotoxicity; Humans; Infusions, Intravenous; Alemtuzumab; Anaphylaxis; Immunology in the medical area; Antibodies, Monoclonal; Farmakologi och toxikologi; Prognosis; Immunity, Innate; 3. Good health; OKT3; Immunologi inom det medicinska området; Cytokines; Immunotherapy; CRS

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