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.
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. This panel is expected to be available in 2018.
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 ImmunotoxicologyDr Anna K. NowocinDr Deepa Rajagopal Diana Corogeanu Elliot Macleod