Abstract
The risk for adverse immune-mediated reactions, associated with the administration of certain immunotherapeutic agents, should be mitigated early. Infusion reactions to monoclonal antibodies and other biopharmaceuticals, known as cytokine release syndrome, can arise from the release of cytokines via the drug target cell, as well as the recruitment of immune effector cells. While several in vitro cytokine release assays have been proposed up to date, many of them lack important blood components, required for this response to occur. The blood endothelial cell chamber model is an in vitro assay, composed of freshly drawn human whole blood and cultured human primary endothelial cells. Herein, its potential to study the compatibility of immunotherapeutics with the human immune system was studied by evaluating three commercially available monoclonal antibodies and bacterial endotoxin lipopolysaccharide. We demonstrate that the anti-CD28 antibody TGN1412 displayed an adaptive cytokine release profile and a distinct IL-2 response, accompanied with increased CD3+ cell recruitment. Alemtuzumab exhibited a clear cytokine response with a mixed adaptive/innate source (IFNγ, TNFα and IL-6). Its immunosuppressive nature is observed in depleted CD3+ cells. Cetuximab, associated with low infusion reactions, showed a very low or absent stimulatory effect on proinflammatory cytokines. In contrast, bacterial endotoxin demonstrated a clear innate cytokine response, defined by TNFα, IL-6 and IL-1β release, accompanied with a strong recruitment of CD14+CD16+ cells. Therefore, the blood endothelial cell chamber model is presented as a valuable in vitro tool to investigate therapeutic monoclonal antibodies with respect to cytokine release and vascular immune cell recruitment.
Highlights
Intravenous administration of immunotherapeutics may result in immune-related adverse events
As presented in a survey by Finco et al in 2014, cytokine release assays frequently utilised in the pharmaceutical industry, contracted research organisations or academia, apply therapeutic monoclonal antibodies (mAbs) either in solution phase or in solid phase [25]
High density cultures of T cells or peripheral blood mononuclear cells (PBMCs) were proven as an elegant strategy to simulate the “lymph node like” state, which could elicit a full T cell response and cytokine release [20]
Summary
Intravenous administration of immunotherapeutics may result in immune-related adverse events. CRS results in a systemic release of several inflammatory mediators, which set off a cascade of cytokines It normally follows a similar profile and timing of events, starting with the release of tumour necrosis factor alpha (TNFα) and interleukin 8 (IL-8), followed by interleukin 6 (IL-6) and interleukin 10 (IL-10) and in some cases, interleukin 2 (IL-2) [1,2,3]. That became evident in a clinical trial, where the administration of an anti-CD28 antibody (TGN1412) caused a nearly fatal systemic inflammatory response in six healthy volunteers [2] This incident was neither predicted by the available in vitro preclinical assays, nor by the examined animal models [7,8], demonstrating the need for novel in vitro cytokine release assays for therapeutic mAbs
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