In particular they assumed that their superagonistic monoclonal antibody, designed to bind specifically to human CD28, would cause the same degree of activation and proliferation in macaque lymphocytes as it did in human lymphocytes. Had they done adequate in vitro comparisons of TGN1412 in human and macaque lymphocytes before starting pre-clinical testing they would have found that TGN1412 did not stimulate proliferation in macaque lymphocytes while it induced strong proliferation in human lymphocytes.

Knowing that TGN1412 did not have the same effect on monkeys at a cellular level as it had on humans would have ensured that TeGenero looked at alternative strategies for in vivo pre-clinical testing. Animal testing would still be necessary though, since TeGenero believed the induction of lymphocyte proliferation and cytokine release that their in vitro tests had demonstrated was exactly what they wanted to see happen. It was necessary to determine what the effect of this stimulation would be on the whole organism.

This problem of how to adequately test “human specific” monoclonal antibodies before human trials has been successfully addressed by the use of surrogate antibodies and transgenic animals in the development of other drugs (e.g. Infliximab and Keliximab). In future these may well replace testing on monkeys for most evaluation of monoclonal antibodies.

He discussed how the Agency’s radiation scientists rapidly developed a mass urine testing process, supplied and co-ordinated teams to monitor a wide range of locations, and deployed scientific expertise in the public health investigation.

A possible reason why the Northwick Park clinical trial of the drug TGN1412 caused multiple organ failure in human volunteers could be down to previous infection or illness. The Imperial reserachers suggest that stimulating the molecule CD28 on cells that mediate the immune response, known as T cells, (which is what TGN-1412 was designed to do) can have an adverse effect if these immune cells have been activated and altered by infection or illness in the past.

The scientists found that when they artificially stimulated CD28 on these previously activated ‘memory’ T cells, this caused the cells to migrate from the blood stream into organs where there was no infection, causing significant tissue damage. CD28 is an important molecule for activating T cell responses and the TGN1412 drug tested on the human volunteers strongly activates CD28.

More details appear online at IC soon.

Perhaps the most interesting and potentially controversial is that “some drugs may be best given to people who are already ill” rather than testing cutting edge therapeutic approaches on healthy volunteers. This is something that many people with terminal and chronic diseases with little to lose and all to gain may welcome.

“THE ELEPHANT Man drug trials scandal is all but forgotten. Yet for one 20-year-old the nightmare goes on. He has lost his girlfriend, is ravaged by gangrene and could be dead within a year.
On Thursday, Ryan Wilson will go to hospital to have the third and fourth fingers of his left hand amputated at the second knuckle.

They are blackened and shrivelled through blood poisoning, and he does not dare get them damp because wet gangrene, unlike dry gangrene, spreads and he doesn’t want to lose his whole hand. ”

http://www.news.com.au/heraldsun/story/0,,20739759-663,00.html

They confirmed that the volunteers received several injections of the drug in a short space of time, even though the drug had not been tested on people before. Ill effects were apparent within an hour to and hour and a half and all six volunteers were transferred to Northwick Park and St. Mark’s Hospital in London. Hospitals that saved the mens’ lives.

The NEJM report says that the men appear to have recovered.

However, a subsequent development suggests that one of the men has developed cancer, which is rather ironic given that TGN1412 was being developed as a treatment for leukemia.

Paraxel, the company carrying out the trial, denies any wrongdoing.

The UK’s Medicines and Healthcare products Regulatory Agency (MHRA) has tightened the regulations on future trials involving similar products to the monoclonal antibody TGN1412 given the seriously adverse reaction seen in this trial.

In its preliminary report, the MHRA said, it “has found no evidence to suggest that there was any problem with the manufacturing of the product which was given to the trial volunteers – it appears not to have been contaminated, or to have contained anything other than the correct ingredients. Neither have we found anything in the way the trial was run which contributed to the adverse reactions experienced by the volunteers – it was run according to the agreed protocol, and the correct dose of the product was given to the patients.”