“A pronounced T-cell activation and expansion mediated by CD28-SuperMABÂ® in animal models is accompanied by the expression of anti-inflammatory cytokines, like IL-10, rather than by the toxic cytokine storm of pro-inflammatory mediators induced by other agents that address the TCR complex.”
To put it another way Tegenero thought that TGN1412 (CD28-SuperMABÂ®) avoided a producing a toxic reaction that other agents working on the same part of the immune system did produce. It may be, and there are other explanations still to be eliminated, that when moved into human subjects this toxic reaction manifested itself – leading to the appalling consequences for the volunteers.
Nature outlines the possible way in which this occurred:
Normally, a T cell needs two incoming signals before it fires up: one from CD28 and a second from a separate T-cell receptor. This double signal is thought to act as a safeguard to ensure that T cells react only to real threats such as toxins or invading pathogens.
The drug TGN1412 overrides this basic control mechanism. When it binds to the CD28 receptor, the T cell becomes active without the need for a signal from the second receptor.
Scientists who work in the field say there are several possible ways that the drug could have triggered multiple organ failure. It may have stimulated T cells so much that they released an overwhelming flood of inflammatory molecules called cytokines. Or perhaps wayward T cells launched an attack on the body’s own tissues, ignoring the safety mechanisms that normally keep this in check.
I would also commend this article to you from New Scientist:
TGN1412 is a monoclonal antibody but works slightly differently from other similar drugs. It is a â€œsuperagonistâ€, causing a far greater immune cell response. It also does not require a second, specific trigger to kick-start this response, as do other monoclonal antibodies affecting the same T cell receptor.
â€œFortunately, this [super-stimulation] does not occur naturally, because T cells activated in this way would lack any antigenic specificity and could indiscriminately attack normal tissues,â€ wrote Peter Linsley, from Rosetta Inpharmatics in Seattle, US, in March 2005 in a commentary accompanying a paper in Nature Immunology, which involved TGN1412.
â€œOne could certainly say that, based on what [TeGenero] has already said about TGN1412, the most plausible explanation would be the triggering of a non-specific activation of natural killer T cells leading to indiscriminate cell destruction,” says Ken Campbell, clinical information officer at the Leukaemia Research Fund in London, UK. “This would be consistent with multiple organ failure.â€
An immunologist contacted by New Scientist, but who asked not to be named, says: â€œYou donâ€™t need to be a rocket scientist to work out what will happen if you non-specifically activate every T cell in the body.â€
Some of the other concerns are addressed in this Guardian article and The Daily Telegraph; animal testing in primates and mice showed no safety concerns, the drug was prepared by Boehringer Ingelheim, and the dosage was one five-hundredth of the dose used in monkeys – which is considered a large safety margin. The Times reports on the debate being expressed about the simultaneous dosing of multiple subjects, although The Daily Telegraph reports that the MHRA are saying they gave permission for the human tests to go ahead without significant time lags between the first volunteer receiving his dose and the others because of the lack of toxicity in pre-clinical trials.
The Daily Telegraph, who seem to have had the best lay reporting on this subject, also cover the potential mechanism of this reaction, and outlined a concern about animal testing in this field, expressed by Camilo Colaco, the chief scientific officer of the Cambridgshirespecialist immunology company Immunobiology Ltd.
“The more we learn about the immune system, the more we realise that the mouse is not a good model for humans. This mismatch may be a particular problem with CD28, where there is little or no cross reactivity between a human antibody and the mouse immune system.”
The eventual human cost is still to be settled, but this report has at least some good news from one of the four who was not as severely effected – he is well enough to watch television. The last word goes to Raste Khan, who was fortunate enough to be given placebo, and watched the reaction skip him:
“They took blood samples from everybody. Then they dosed people at two-minute intervals. Roughly five minutes after everyone had been given the drug, the first person who was given the drug started to shake. He took his top off, he looked like he was burning up, and rubbed his head.
“Several minutes later, it missed me and went to the third person. He started doing similar things but he vomited on several occasions. He came back to consciousness but was hyperventilating. He looked like he was in the worst pain.
“Then No 4 went through similar symptoms. He took several steps and collapsed. He said, â€˜I canâ€™t control myself. I need to use the toilet.â€™ After that it was like a vomiting bath or something. Nurses had a big black liner for them to vomit in. People were fainting and coming back to consciousness. The gentleman on my left was screaming, saying his back was hurting. It was horrible.
“I feel guilty that I had the placebo. It was like Russian roulette. I was doing it for the money. But Â£2,000 is not worth your life.”
Incidently, Mr Khan’s report would seem to be at odds with the statement in this news report that “The protocol indicated that the dosing of subjects was to be staggered over an overall two-hour period.”. From his testimony it would appear that everybody would have received the drug (or placebo) within 16 minutes, with the first side effects starting roughly 21 minutes after the start of the process. It will be interesting to see if any investigation concludes that sticking to the “overall two-hour” might have avoided effects in at least some of these individuals.