Now Available: A Comparison of In Vitro and In Vivo Biomarker Response After Treatment with an Anti-CD3 monoclonal Antibody

Sep 05 2012

Cytokine release syndrome is a potential adverse effect attributed to cellular release of pro-inflammatory cytokines that occurs on initial and sometimes subsequent intravenous infusion of some types of protein biotherapeutics. For this reason, generalized systemic inflammation, whether caused by some biologics due to target activation, as an off-target secondary event or indirectly as a result of tissue damage, has become a growing concern in the pharmaceutical industry. Measurement of biomarkers of inflammation has been shown to be a useful component of non-clinical testing approaches to identify compounds that have the potential to modulate the immune system.

Study Design

Charles River has validated several assays intended to analyze markers of the inflammatory response in serum and/or plasma. An in vivo study in which animals were stimulated with an anti-CD3 mAb was initiated to demonstrate the sensitivity of the validated method, to characterize the range and dynamics of inflammatory responses after treatment, and to verify if modulation of inflammatory markers can be adequately monitored. Additionally, assays were developed to identify the potential of compounds to induce cytokine release in vitro. The development of reliable in vitro assays capable of predicting in vivo cytokine release could help reduce study costs and the number of animals used for drug screening purposes.

Study Findings

The sensitivity of the assays was shown to be appropriate to measure in vivo changes in inflammation markers. In vitro stimulation may be predictive of the intensity of cytokine release, but in vivo and in vitro stimulation differ in the magnitude and occurrence of cytokine release. Therefore, in vitro cytokine release assays are best used for hazard identification and not for risk quantitation. With the current assays, it is not possible to define a threshold or exposure level in which cytokine release may be of concern, thus underlying the importance of a suitable in vivo model of stimulation.