Immunotoxicology

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).

TGN1412

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. 

What we do 

• investigate adverse drug responses in patients and provide advice to regulators and pharmaceutical companies, such as with TGN1412
• determine the mechanisms of pro-inflammatory mediator release from immune cells following exposure to different biological medicines – such as immunotherapies and vaccines
• develop novel assays for predicting adverse responses to biological medicines through the induction of immune responses
• develop reference standards for harmonisation of immunotoxicity assays across platforms 

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

Control

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 

Standardisation

To harmonize the field of immunotoxicology evaluation, we have developed a panel of validated reference reagents for cross-platform comparison of cytokine release data. This panel (NIBSC code: 19/156) consists of three isotype controls plus three positive controls (human anti-CD52, mouse anti-CD3 and human superagonistic anti-CD28 mAb ) with different mechanisms of action and inducing cytokine release from different type of immune cells. 

Research

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.