A Phase I clinical trial was halted by the Medicines and Healthcare products Regulatory Agency (MHRA, UK) only hours after it began on 13 March 2006, when the six healthy volunteers who were injected intravenously with the drug developed severe clinical symptoms that led to multiple organ failure. Three weeks later, although four of the volunteers have been allowed to go home, one remains in intensive care and another is still in hospital but out of intensive care.

This tragic development has raised many questions, such as what was this new drug? Why did it cause such a violent reaction? And what are the implications for other drugs like it? Some of these questions can be answered quickly and easily, whereas others might take many months (if not longer) to answer.

The drug — TGN1412 — is a CD28-specific superagonist monoclonal antibody developed by TeGenero (Würzburg, Germany) for the treatment of rheumatoid arthritis, multiple sclerosis and leukaemia. The antibody is designed to activate T cells directly, bypassing the normal T-cell activation requirements of signals through both CD28 and the T-cell receptor. In animal tests, TGN1412 activated regulatory T cells — which are a subset of T cells that keep the immune system in check and prevent it from attacking the animal's own tissues — more effectively than other T cells. By preferentially activating this subset of T cells, it was hoped that autoimmunity — which is caused by an immune response to the body's own tissues — could be controlled. So, what happened in these volunteers? As Michael Ehrenstein of University College London, UK, said, “It's possible there was contamination [of the drug]” (NewScientist.com News Service, 17 March 2006); it is also possible that there was a dosing error. However, it seems increasingly probable that “the drug may have caused a super-immune response — sending white blood cells called T cells rampaging through the body destroying its own tissues.” (NewScientist.com News Service, 17 March 2006).

Both the MHRA and the local public prosecutor in Würzburg are investigating the tragic events. However, Thomas Hanke, Chief Scientific Officer of TeGenero, said that the company “observed strict standards for this clinical test” and [in animal studies] “saw no drug related adverse events” (TeGenero, 17 March 2006). In addition, a spokesman for Parexel International (Waltham, Massachusetts, USA) — the medical-research company that was running the trial — said, “We believe that best practices were followed and the appropriate policies and procedures were adhered to.” (Nature, 23 March 2006). So, until we know exactly what went wrong, it seems sensible to adopt the 'softly, softly' approaches suggested by Johannes Löwer, President of the Paul Ehrlich Institute (Langen, Germany): that “research is needed to define better animal models of the human response to CD28 agonists ... [and that] extra precaution [needs to] be taken when antibodies are used to stimulate rather than neutralize components of the immune system” (Science, 24 March 2006).