Devastating effects of a drug which left six healthy young men in intensive care during a disastrous drug trial in London, UK, have been replicated in a test tube.

The preliminary results were presented in London today and form part of an official 600-page scientific report into the horrific trial in March 2006, at Northwick Park Hospital in London (see One drug trial, six men, disaster).

“As far as we can determine, such an incident was entirely unprecedented in the history of clinical trials,” said Gordon Duff of the University of Sheffield, UK, who chairs the expert scientific group which produced the report.

The six trial volunteers suffered multiple organ failure which almost killed them, after receiving injections of the drug TGN1412, a monoclonal antibody designed to calm the immune system. The drug was being trialled as a potential treatment for leukaemia, multiple sclerosis and arthritis.


Cytokine storm

Instead, their immune systems went into overdrive, attacking the men’s internal organs. Their bodies were flooded with signalling molecules called cytokines which mobilise the immune system and trigger widespread inflammation.

Amid this “cytokine storm”, white blood cells that normally tackle infections began multiplying rapidly and attacking the men’s organs instead. All were saved following transfer to the hospital’s intensive care unit.

Since then, researchers have been at a loss to explain how the antibody – manufactured by the now-defunct company TeGenero of Germany – caused such devastating effects in people despite showing no obvious adverse effects when tested beforehand in monkeys and mice.

Tethered effect

The new results presented today suggest that to send immune cells berserk, the antibody has to be tethered to a “surface” in the body rather than be free-floating. The team was only able to replicate the excessive cytokine response in the lab that the patients had experienced by effectively sticking the antibodies to a surface.

In all previous lab tests with the antibody – including those done prior to the trial by TeGenero – the antibody encountered immune cells in solution, which fails to produce the dramatic effect.

“We’ve developed an approach which mimics what was seen in the patients,” says Stephen Inglis, director of the National Institute for Biological Standards and Control in Potters Bar, London, and head of the team which recreated the cytokine storm in a test tube.

“Effectively, we immobilise the antibody in a particular way, and that’s the trick that stimulates the immune response,” says Inglis. “This business of immobilising it is mimicking something in the body,” he added.

“The effect was to cause the human immune cells, particularly CD4 cells, to release large amounts of cytokines and to begin to divide dramatically,” says Inglis.

The result suggests that for the antibody to exert its effect, some form of tethering probably happens in the human body too, perhaps on the surfaces of blood vessels or organs. Further tests are underway to find out more about what TGN1412 binds to, and where in the body.

Unique response

Crucially, the same tethering trick did not work when human cells were replaced with macaque monkey cells, suggesting that the response is unique to humans and explaining why no ill effects were seen in monkeys receiving the antibody.

“We saw no ill effects at all, and nothing that could mirror what was seen in humans,” says Inglis. “The implications are that we need to be careful interpreting [apparently reassuring] toxicological data from primates,” he says.

Inglis said that if the test had been available prior to the disaster, it may have “rung alarm bells” if used with TGN1412. But he stressed that the test resulted from a huge effort to reproduce the effects seen in the patients, with resources not available to TeGenero.

“It’s taken a team of 20 scientists working on this for six months, and a hundred experiments,” says Inglis.

He says that if the test is validated, it might be useful for screening other antibodies and therapies designed to have major effects on the immune system. And the novelty of the reaction could improve our understanding of our uniquely human immune response mechanism.

The Duff report made 22 recommendations for measures to avoid similar disasters in the future as new and more potent “biological” therapies come forward for testing.

They include setting up databases – some available only to regulatory agencies – where companies and academic researchers could share clinical and pre-clinical data on new biological medicines, raising the alarm if they see adverse effects. “We think they should be shared worldwide, at least between regulators,” says Duff.

In trials themselves, the expert panel recommends that doses should be given slowly and to only one volunteer initially, to check for adverse effects before any other volunteers receive it. Clinicians involved in a trial should have some expertise on how the drug should work, and make preparations in advance for what might go wrong, they say.

The report also argues for creation of specialist, accredited centres where such trials should go ahead, with antidotes and intensive care readily available.