NEW drugs such as the one used in the Northwick Park Hospital trial may be intrinsically unsafe for human beings because of an immune system quirk, research suggests.

Scientists have identified a mechanism designed to prevent the immune system overreacting that is present in apes but not in humans.

The finding, published yesterday, may explain why animal tests uncovered no adverse reaction to TGN1412, a monoclonal antibody that caused multiple organ failure in six volunteers at Northwick Park.

Scientists at the University of California, San Diego, have found a difference between human and chimpanzee immune cells that may explain why the reaction to TGN1412 did not happen when monkeys were given a higher dose. It may account for why humans are affected by immune-related diseases, such as Aids and rheumatoid arthritis, which have little impact on apes. The researchers have found a molecule expressed in non-human primate T-cells — which help to organise the immune system — that is absent in humans. These molecules, called siglecs, appear to act as “brakes” on immune system behaviour.

The study, published in Proceedings of the National Academy of Sciences, could be particularly relevant to new monoclonal antibodies.

Most monoclonal antibodies, such as the anti-cancer drugs Herceptin and Avastin, work by blocking certain processes in the immune system, but some are agonists, including TGN1412, which excite a greater immunological response to defeat disease. Some scientists have expressed concerns about the latter approach and over the potential knock-on effects of such heightened activity.

A report by Britain’s drugs regulator found no evidence of human error, contamination or failure to follow protocols in the Northwick Park trails. An inquiry has been started by the Government.

The American scientists said that siglecs appeared to regulate T-cell activity in chimpanzees by binding to sialic acids, the complex sugars found on the outside of cells. This restricted the degree of signalling from the T-cell receptor, which normally triggers the response of T-cells in the immune system.

Ajit Varki, professor of medicine and cellular and molecular medicine at the University of California, who led the study, said that the finding in chimpanzees, bonobos and gorillas could be significant. “Siglecs can slow down the activation of an immune cell upon stimulation,” Professor Varki said. “During human evolution, we seem to have shut off these brakes on our T-cells, allowing them to become hyperactive.”

He added that the study could explain the reactions at Northwick Park. “The absence of natural restrictions on activation, such as that provided by siglecs, could have predicted this striking disparity between humans and nonhuman primates,” Professor Varki said, adding that the human volunteers could have experienced rapid activation of T-cells and a resulting cytokine storm — a potentially fatal chain reaction in the immune system.

The research team asked for TGN1412 from TeGenero, its German manufacturer, to test it on chimpanzee blood, but the company declined.

Professor Varki said that siglecs could also account for the rarity of other T-cell mediated diseases in apes, including bronchial asthma, rheumatoid arthritis and type 1 diabetes.

The research team said that the reason for the humanspecific evolutionary loss of siglecs is unknown. British experts said that the research offered an insight into immune behaviour, but added that more evidence was needed before it could be directly related to the TGN1412 trial.

David Glover, the former chief medical officer at Cambridge Antibody Technology Group, said: “It is an explanation for why potency of a drug may differ between monkeys and humans. But it is only one of many possible issues at stake [in the TGN1412 case].”

Explore UK News

• Crime News

• Education News

• Health News

• Scotland News

Times Recommends

• Postmen: We bind the nation together
• Tewkesbury: when the memories flood back
• Cast Offs actress: I’m happy that my face fits