Biological medicines can potentially cause adverse drug reactions related to immunosuppression, immunostimulation and hypersensitivity.
These include cytokine release-associated acute reactions involving the production of pro-inflammatory cytokines. The clinical manifestations can range from flu-like reactions to more severe cytokine release syndromes (CRS).
In 2006 a severe CRS was observed during the clinical trial of the therapeutic anti-CD28 monoclonal antibody (mAb) TGN1412 – developed to treat B cell leukaemia and autoimmune diseases.
We were involved in testing trial materials and understanding why pre-clinical safety testing failed to predict the adverse effects observed in humans.
Our findings have been used to develop improved pre-clinical testing methods for biological medicines. Find out more in research published in the Journal of Immunology.
Although severe incidences like this are rare, correctly predicting the cytokine-releasing potential of new biotherapeutics is a major safety concern.
Disseminated intravascular coagulation experienced by a volunteer during the 2006 TGN1412 clinical trial.
Use of intracellular cytokine staining to study the different mechanisms of cytokine release by therapeutic mAbs – Identification of immune cell subpopulation involvement in IFNγ production
We provide contract pre-clinical safety testing of biological medicines and vaccines. We use state-of-the-art in vitro cytokine release assays considered to reflect the ‘cytokine storm’ that occurred during the phase I clinical trial of TGN1412.Find out more about NIBSC control testing. Contact us: Sandrine.Vessillier@nibsc.org
To harmonize the field of immunotoxicology evaluation, we are developing a panel of validated reference reagents for cross-platform comparison of cytokine release data. This panel will consist of one representative immunotherapeutic antibody each with low (alemtuzumab), moderate (muromonab-CD3) and high (TGN1412) immunostimulatory quality plus the corresponding isotype controls.
Our comparative study of cytokine release assays highlighted the strengths and weaknesses of different protocols used in pre-clinical studies. We found that a “one size fits all” approach for the pre-clinical safety testing of biotherapeutics isn’t suitable and recommend a tiered approach to detect multiple mechanisms of cytokine release.
We showed that the presence of red blood cells hampers the induction of T cell-derived cytokines and recommend using isolated white blood cells for evaluation of cytokine release by T cells.
However whole blood cell assays are more predictive for evaluation of non-T cell-derived cytokines.
Glycophorin A (GYPA), the main protein on erythrocytes inhibited TGN1412-induced cytokine release: Cytokine release after red blood cell (RBC) depletion (RBC depleted) in presence of glycophorin A (+ GYPA) or whole blood (+ WB)
Dr Sandra Diebold, Section leader Dr Sandrine Vessillier, Head of ImmunotoxicologyDeepa Rajagopal Elliot Macleod