US Edition Scientists believe they have discovered why a group of men were left seriously ill when they took an experimental drug that was harmless to animals in previous tests.
The severe inflammatory reaction suffered by volunteers in a drug trial at Northwick Park Hospital in north London could only occur in immune system cells that had “memories” of previous infections, and not in animals born in sterile laboratories, researchers said.
Six men suffered multiple organ failure in March 2006 after being given TGN1412, an experimental drug designed to treat rheumatoid arthritis, leukaemia and multiple sclerosis.
While other antibody therapies such as Herceptin for breast cancer have been developed to suppress immune responses, scientists at German biotech company TeGenero designed the new drug to stimulate an increased immune reaction.
Tests of TGN1412 on mice, rats and monkeys failed to show toxic responses, leading to the Medicines and Healthcare products Regulatory Agency (MHRA) giving the go-ahead for human trials.
Dr Federica Marelli-Berg, of the Department of Immunology at Imperial College London, presented the findings of research suggesting why the “inexperienced” immune systems of laboratory animals did not react to the drug.
Speaking at the Club de la Transplantation conference near Paris yesterday, Dr Marelli-Berg said: “Experimental animals kept in clinical conditions are never subjected to infections in the way that human and animal immune systems outside the lab are.”
White blood cells called T-cells play a crucial role in the immune system’s response to infections or other attacks.
Experiments carried out by Dr Marelli-Berg and colleagues showed that in normal animals stimulating a molecule called CD28 on T-cells caused them to move from the blood stream into the healthy kidney, the heart and the gut, causing significant tissue damage.
However the same tests on laboratory animals did not provoke any immune system reaction.Dr Marelli-Berg said that adult human T-cells have a form of “memory” activated by infections, illnesses and vaccines that lead them to go under attack when there is a perceived threat.
TGN1412 was designed to stimulate just such a reaction through the stimulation of CD28 molecules.
Dr Marelli-Berg, whose research was funded by the British Heart Foundation (BHF), added: “The drug TGN1412 appeared to be relatively safe when it was tested in animal models.However, when the drug was tested on human volunteers, some experienced very severe side-effects.
“Our research suggests that this is because the human subjects’ memory T-cells lost their sense of direction and started migrating into several areas of the body where they were not supposed to go, and caused damage.
“This is backed by the fact we know the bodies of the human volunteers in the TGN1412 trial were depleted of white blood cells for a long time afterwards.”
Prof Jeremy Pearson, associate medical director at the BHF, said: “These findings could help to explain the serious problems which were encountered during the Northwick Park clinical trial.”
Dr Marelli-Berg’s study is due to be published in the scientific journal Blood later this year.