Monoclonal antibody-induced cytokine-release syndrome

Abstract

Monoclonal antibodies (mAbs) are widely used in anti-inflammatory and tumor therapy. Although effective, mAbs can cause a variety of adverse effects. An important toxicity seen with a few mAbs is cytokine-release syndrome (CRS). These mAbs include: alemtuzumab, muromonab-CD3, rituximab, tosituzumab, CP-870,893, LO-CD2a/BTI-322 and TGN1412. By contrast, over 30 mAbs used clinically are not associated with CRS. In this review, the clinical aspects of CRS, the mAbs associated with CRS, the cytokines involved and putative mechanisms mediating cytokine release will be discussed. This will be followed by a discussion of the poor predictive value of studies in animals and the prospects for creating in vitro screens. Finally, approaches to decreasing the probability of CRS, decreasing the severity or treating CRS, should it occur, will be described.

Is an <i>in vitro</i> whole blood cytokine assay useful to detect the potential risk of severe infusion reaction of monoclonal antibody pharmaceuticals?

“…It was considered preferable to include a low risk reference mAb in the assay for comparison with the test articles. In this study, we used panitumumab, which induced infusion reactions in less than 5% of patients and severe ones in less than 1% (Chung, 2008;Amgen Inc., 2015), both of which values are considered irrelevant to CRS (Bugelski et al, 2009). Panitumumab caused marginal but statistically significant dose-related elevation of IL-8 in the WBCA when compared to that of the PBS control.…”

“…CRS is one of the causes of infusion reaction characterized by a rise in tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ), IL-6, IL-10, IL-2, and IL-8, and it leads to a complex of fatigue, headache, urticaria, pruritus, bronchospasm, dyspnea, sensation of tongue or throat swelling, rhinitis, nausea, vomiting, flushing, fever, chills, tachycardia, asthenia, hypotension, and possibly shock (Bugelski et al, 2009). After TGN1412, an anti-CD28 humanized mAb, caused life-threatening multiple organ failure in all volunteers due to CRS (Suntharalingam et al, 2006), the importance of assessing cytokine release potential prior to entry into clinical studies was stated in the guideline of the European Medicines Agency (EMA, 2007).…”

“…An Fc-mediated function is responsible for the CRS caused by alemtuzumab (Wing et al, 1995;Hansel et al, 2010;Brennan et al, 2010). Panitumumab is an anti-epidermal growth factor receptor (EGFR) mAb (Amgen Inc., 2015) that causes severe infusion reactions in less than 1% of patients, probably due to non-CRS mechanisms (Bugelski et al, 2009). …”

Hurdles of CAR-T cell-based cancer immunotherapy directed against solid tumors

“…There are three potentially key routes contributing to the toxicity of CAR-T cells that must be considered (Table 2). The most common is on-target, on-tumor toxicity relating directly to the effects of binding of the CAR to the cognate antigen resident on the target tumor cell, such as cytokine release syndrome (CRS) and tumor lysis syndrome (Bugelski et al, 2009;Howard et al, 2011). CRS is typified by chills, fevers, and hypotension, but can also result in much more severe life-threatening multiple-organ failure (Brentjens et al, 2010;Maude et al, 2014).…”

Monoclonal Antibodies: An Emerging Class of Therapeutics in Non Small Cell Lung Cancer

“…The tox icity of mAbs is mainly associated with excessive pharmacological activity and/or the presence of the targeted antigen in tissues where the therapeutic effect is useless [20]. Serious adverse effects of mAbs include anaphylaxis, a rare response to the first infusion (IgE-mediated), and the cytokine release syndrome (CRS) or cytokine storm [21].…”