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The race is on to nail down the cause of the catastrophic immune response of the six seriously-ill drug trial volunteers.

Doctors at Northwick Park Hospital say two men are still critically ill, and that it is too early to comment on their prognosis. Three of the four who have shown signs of recovery are now off organ support.

They were given the drug last Monday and very quickly showed an adverse reaction, with a fellow volunteer who was given a placebo, saying: “They went down like dominoes.”

Questions are now being asked about why potential problems with the drug weren't picked up in animal trials and how it caused the men's inflammatory response.

A TeGenero statement says: “The drug was tested extensively in laboratories and has been tested on rabbits and monkeys. We saw no drug-related adverse events and there were no drug-related deaths.”

However, the company did admit that in monkey trials there was temporary mild swelling of lymph nodes, which are part of the immune system.

TGN1412 was designed to target a subtype of immune cells, regulatory T-cells. In a healthy person these cells act to dampen the function of the other parts of the immune system; they prevent the body attacking itself. Failure of this system at any point, for whatever reason, can lead to auto-immune diseases of the kind TeGenero was hoping to tackle – rheumatoid arthritis, multiple sclerosis and certain leukaemias.

TeGenero's logic is clear: by stimulating the production of more regulatory T-cells, they hoped to supress the immune system and so relieve symptoms.

Instead, TGN1412 super-activated the immune system. The inflammatory swelling that left one victim looking like the “Elephant Man”, according to his girlfriend, is one manifestation of an overactive immune system.

Medical Research Council Technology chief executive Roberto Solari said last week: “Instead of switching on the regulators, we have switched on the activators and super-induced the immune system.”

But considering how the therapy was meant to work, TeGenero provides a seemingly reasonable explanation for the temporary swelling it saw in experimental monkeys. It says it was caused by an accumulation of the extra regulatory T-cell the drug is designed to stimulate. Rather than a side effect, TeGenero says the swelling was a sign of the drug behaving properly.

The TGN1412 protein is designed to activate a receptor on the surface of regulatory T-cells called CD28. The three-dimensional structure of CD28 was worked out by TeGenero, which in turn helped the company develop the drug. It came up with what is known as a monoclonal antibody. This simply means it interacts with a single target receptor. Part of the thinking behind these therapies is that adverse reactions can be avoided by their being specifically tailored for humans.

The CD28 receptor is known to be very well conserved across species; it hasn't changed much through the course of evolution. This makes the response that the human volunteers showed all the more mysterious.

The trial would never have been approved if that kind of reaction had been seen in the monkeys, or even the more distantly-related rabbits. Getting a drug to the human trial stage is very expensive, but starting the trial is even more costly. It can take ten years from the beginning of Phase I trials (as the TGN1412 was) until a drug finally comes to market. A Health Select Committee report puts the cost of that process at $897m.

It's unlikely TeGenero would have bothered if it had big doubts over safety.

Investigations began immediately as the TGN1412 trial was shut down. TeGenero and its testing contractor Parexel are conducting their own examinations. According to the BBC, the Medicines and Healthcare products Regulatory Agency (MHRA), which approved the testing, has seized documents and sealed off offices involved in the trial.

A good possibility is that the drug was too specific. The very fact it was designed for humans could have meant that it wasn't as powerful in the animal subjects. Broader issues about the wisdom of interfering with the immune system in such a high-level way when many reactions are unclear also face the pharmaceutical industry. ®

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