TALK about medical disasters and landmark tragedies come to mind: birth defects caused by thalidomide, deaths caused by the painkillers Opren (Oraflex) and Vioxx, and the demise of teenager Jesse Gelsinger during a gene therapy trial. It seems likely we can now add to this list TGN1412, the experimental drug that was given to six healthy young men in the UK last week which sent their immune systems into sudden frenzy (see 鈥淥ne drug, six men, disaster鈥︹��).
What caused these reactions is still being investigated: was it overdose, contamination or the drug itself? There are strong suspicions among immunologists that the drug was to blame. It is a powerful antibody which works by binding to the immune system鈥檚 T-cells, causing them to activate and multiply rapidly.
In animal experiments, TeGenero, the company behind TGN1412, found that the drug has two apparently contradictory effects. In rodents with poor immune function it increased T-cell activity and numbers. Yet it also suppressed the immune systems of rats and monkeys, because it preferentially boosted 鈥渞egulatory鈥� T-cells, a subset that suppresses the activity of other T-cells. Which way would the drug behave in humans? On the strength of its preclinical work 鈥� in animals and in vitro 鈥� the company reckoned that it would dampen down T-cells. It seems likely that this reckoning was badly mistaken.
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For everyone working on drugs that act directly on immune cells, and for the agencies that check the safety of experimental drugs, this case should ring alarm bells. The immune system is a moving target: our understanding of it changes constantly. Regulatory T-cells themselves were discovered a decade ago, and in recent years have changed our view of the immune system from something that 鈥渄oes nothing until provoked鈥� to a system that 鈥渘eeds to be constantly held back鈥�.
Given our imperfect knowledge of immune function, researchers must test not only how they think a drug works, but also actively rule out worst-case scenarios. Though TeGenero appears to have carried out all the preclinical tests that would normally be expected, that testing regime now seems inadequate.
A test for extreme overstimulation of the immune system may be hard to devise. There is no certainty that administering 鈥渕icro鈥� doses of the drug would have signalled danger, but if the drug鈥檚 mode of action is found to be at fault then tests of this kind must be a priority for safety agencies.
Other antibodies that regulate immunity are on their way. They have already proved successful against cancer and diabetes, and hold promise for other disorders. Let us hope this tragedy tells us more about safely manipulating the immune system. Then, at least the suffering of the six test subjects will not have been for nothing.
