Co-stimulators of drug-trial disaster identified
14.05.2012 - German researchers found a potential co-factor that triggered the cytokine storm, which led to hospitalisation of six volunteers treated with TGN1412.
Langen – A team of German researchers from the Paul-Ehrlich-Institut (PEI) has identified an important mechanism that can explain how immunotherapy drug TGN1412 might have triggered the catastrophic immune reaction responsible for the 2006 Northwick Park trial. The drug-trial disaster left six healthy volunteers hospitalised. The team, led by Zoe Waibler, reports that TGN1412-mediated T cell proliferation and cytokine release triggered by the superagonistic CD28-specific antibody, requires an interaction of an inducible co-stimulator on T cells (ICOS) with its ligand on endothelial cells (LICOS). The team reports in the journal Blood. "We found that co-stimulatory ICOS-LICOS interaction between T cells and endothelial cells is critically involved in TGN1412-mediated effects."
The Phase I clinical trial of TGN1412 took place at an independent clinical trials unit at Northwick Park and St Mark's Hospital, London, on 13 March 2006. TGN1412 was intended for the treatment of leukaemia, multiple sclerosis and rheumatoid arthritis. Eight volunteers were given the drug or a placebo by intravenous infusion, with an interval of about 10 minutes between patients. Within minutes of the last patient being administered the drug, the first began to complain of headache, followed by fever and pain. The five other patients to receive TGN1412, as opposed to the placebo, became seriously ill soon afterwards. All six male volunteers experienced cytokine release syndrome (cytokine storms) with effects similar to those of people suffering a severe allergic reaction. Each of the men was hospitalised for several weeks, with the worst affected requiring hospital treatment for four months. The drug developing company, TeGenero Immuno Therapeutics from Germany, entered into insolvency proceedings later in 2006. It assets were sold to German-Russian Theramab LLC, which develops TGN1412 under the new name TAB08 as therapy for B-cell chronic lymphocytic leukaemia and rheumatoid arthritis.