Apr 12, 2006
When Clinical Trials Go Wrong
The journal Nature reports on a novel theory as to why trials of monoclonal antibody drug TGN1412 went badly wrong and left six men critically ill with massive organ failure and inflammation in March.
As Sciencebase has already reported, it seems there is no evidence of drug contamination, dosing problems, meaning the devastating effects were almost certainly caused by TGN1412 itself. So, why didn’t this show up in the preclinical animal trials?
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.
According to a report on the BBC on May 17, http://news.bbc.co.uk/1/hi/health/4989810.stm, a thorough reading of the scientific literature could have predicted roughly what happened in this trial, at least that’s what experts told the BBC.
Dr David Glover, a member of an industry task force set up to investigate how trials of this kind should be carried out in the future, told BBC Radio 4′s Today show, It may be that it was unpredicted by the tests that were done. I believe from the basic science it was predictable.”
Other experts, including monoclonal antibody pioneer rofessor Greg Winter, of the Laboratory of Molecular Biology in Cambridge, suggested that the drug’s developers may have been “lulled into a false sense of security” because the in vivo pre-clinical trials did not reveal anything to adverse in TGN1412 use.
TGN1412 remains one of sciencebase most popular internal search terms this month, with more than 3% of all Google site search queries looking for this doomed monoclonal antibody.
An interesting side-effect associated with this clinical trial is that all the adverse publicity has had a positive effect on raising awareness of clinical trials in general, and more specifically, the potential financial gain for those who take part. It has been widely reported that more people are signing up for clinical trials to help the pay off debts, purchase electronic gadgets (such as laptops) and get a deposit down on their holiday. Of course, such assertions may all be PR puff from the pharma and biotech industry hoping to tame this beast. You never can tell.