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London clinical trial disaster: Theory explains why animals didn’t get sick, but people did
A new idea about why the experimental antibody drug TGN1412 had devastating effects on humans that had not been seen in animal tests is put forward in an exclusive special news report by Nature this week.
Last month, the experimental antibody drug TGN1412 put six British men in intensive care. It was announced last week that there is no evidence of contamination in the treatments, meaning the devastating effects were almost certainly caused by TGN1412 itself. Researchers have been left wondering what went wrong, and in particular why the problem did not show up when the drug was tested in monkeys.
Antibodies to be used as drugs are modified to have the same overall structure as a human antibody. The CD28 antibody receptor – which switches on immune cells, and was targeted by TGN1412 – is identical in humans and monkeys, so researchers thought that the drug would have comparable effects in the two species.
But crucially, the antibody’s ‘tail’, at the opposite end of the molecule from the CD28-binding site, may not be the same. Antibody tails are known to undergo a phenomenon called ‘crosslinking’, in which they bind to other antibodies and amplify the immune response. Some researchers believe this could have caused the human volunteers’ immune system to release a massive flood of inflammatory molecules called a ‘cytokine storm’, causing their organs to shut down within hours of taking the drug.
Thomas Hünig, co-founder of the company TeGenero, which developed the drug, told Nature that he agrees this could be what happened. The idea is supported by research on another super-antibody that activates the immune system in a similar way. Early tests in mice triggered an uncontrolled immune response. But tweaks to the antibody’s tail solved the problem, and the drug has now been approved for patients taking immunosuppressive drugs.
Nature’s special report (see press site) contains more details about this idea, as well as other more controversial ideas, and asks what the future is now for the field of super-antibody therapy.
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