From Alex Corbishley
Andy Coghlan suggested that a possible explanation for the tragic ill effects of TGN1412 might have been an accidental “overdose” (25 March, p 10). Has anyone considered the possibility that the investigators may have inadvertently “underdosed” the volunteers?
It was hoped that TGN1412 would work by binding to the CD28 receptor of regulatory T-cells and activating them to dampen down the immune response. But if it has a stronger affinity for the CD28 receptor of “conventional” T-cells than for that of regulatory T-cells, a low dose may be enough to stimulate the former but not to stimulate the protective regulatory T-cells, resulting in the disastrous effects seen. I note that the investigators administered just 0.2 per cent of the dose considered safe in animal experiments.
The same effect could appear if there were a subtle difference between the messenger systems that convey the message from the CD28 receptor into the regulatory and “conventional” T-cells.
Cambridge, UK
