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Tragic drug trial spotlights potent molecule

March 17, 2006 By Helen Pearson This article courtesy of Nature News.

Researchers are trying to explain how a prototype drug that manipulates the immune system triggered devastating side effects in a British clinical trial.

The trial shot into headlines earlier this week when all six patients who took an experimental antibody fell rapidly and severely ill. Such an extreme reaction among so many trial participants is extremely rare. The UK medical products regulatory agency swiftly halted the trial and launched an investigation.

It is not clear whether the problem is due to a manufacturing error, contamination or the wrong dosage. It is also possible that this first trial in humans simply shows we are affected by the drug in a way that animals are not.

Extreme response

The drug, an antibody called TGN1412, is being developed by German company TeGenero with the aim of directing the immune system to fight cancer cells, or calm joints inflamed by rheumatoid arthritis. The antibody binds to a receptor molecule called CD28 on the surface of the immune system's infection-fighting T cells.

The immediate focus of researchers is on helping the patients, who are suffering multiple organ failure. But scientists note that the trial illustrates how incredibly potent some immune-altering agents can be. "The immune system is capable of extraordinary power and we must be very careful when we tinker with it," says Louis Weiner who studies immunotherapy at Fox Chase Cancer Center in Philadelphia, Pennsylvania.

Some say that TGN1412, or drugs like it, might still find a use in medicine, if researchers can learn how to harness and direct its power. "Can we get the good without the bad?" asks Carl June of the University of Pennsylvania, who pioneered work on the CD28 molecule.

Critical system

CD28 is a pivotal molecule in the immune system. "So the potential for off-target effects is enormous," says Keith Knutson, an expert in T-cell therapy at the Mayo Clinic in Rochester, Minnesota.

Normally, a T cell needs two incoming signals before it fires up: one from CD28 and a second from a separate T-cell receptor. This double signal is thought to act as a safeguard to ensure that T cells react only to real threats such as toxins or invading pathogens.

The drug TGN1412 overrides this basic control mechanism. When it binds to the CD28 receptor, the T cell becomes active without the need for a signal from the second receptor.

Scientists who work in the field say there are several possible ways that the drug could have triggered multiple organ failure. It may have stimulated T cells so much that they released an overwhelming flood of inflammatory molecules called cytokines. Or perhaps wayward T cells launched an attack on the body's own tissues, ignoring the safety mechanisms that normally keep this in check.

Early trials

A statement from TeGenero expresses the company's concern for the patients and notes that its trial adhered to standard clinical research guidelines. It adds that TGN1412 showed no adverse effects in previous studies with animals.

At least one similar drug has already shown side effects in human trials. Skin rashes and gut reactions have been seen during tests of a drug called anti-CTLA4 antibody. This also boosts the effects of the CD28 receptor, but to a lesser degree than TGN1412.

Scientists have continued to work with anti-CTLA4 antibody and it is now in large-scale clinical trials to treat cancer.

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