A catastrophic over-stimulation of the immune system may have caused the horrific reactions suffered by six men taking part in the first human clinical trial of an experimental drug.
An investigation by 麻豆传媒 suggests the drug may have caused a super-immune response 鈥� sending white blood cells called T cells rampaging through the body destroying its own tissues.
Several experts contacted by 麻豆传媒 agree this is the most likely explanation for the terrible incident which put all six men in hospital intensive care in London, UK, with two in a critical condition. The victims, who were healthy, paid volunteers, are said to have suffered multiple organ failure.
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The drug, called TGN1412 and made by German pharmaceutical company TeGenero, works by stimulating T cells, which could help treat leukaemia and auto-immune diseases such as rheumatoid arthritis. But this super-stimulation may have backfired. Indeed, a scientific article, highlighted on TeGenero鈥檚 own website, may have presaged this.
鈥淚ndiscriminate attack鈥�
TGN1412 is a monoclonal antibody but works slightly differently from other similar drugs. It is a 鈥渟uperagonist鈥�, 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.
鈥淔ortunately, 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,鈥� wrote Peter Linsley, from Rosetta Inpharmatics in Seattle, US, in March 2005 in a commentary accompanying a paper in Nature Immunology, which involved TGN1412.
鈥淥ne 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,鈥� says Ken Campbell, clinical information officer at the Leukaemia Research Fund in London, UK. 鈥淭his would be consistent with multiple organ failure.鈥�
An immunologist contacted by 麻豆传媒, but who asked not to be named, says: 鈥淵ou don鈥檛 need to be a rocket scientist to work out what will happen if you non-specifically activate every T cell in the body.鈥�
Regulatory response
Michael Ehrenstein, at University College London, UK, who works on regulatory T cells and rheumatoid arthritis, believes the drug was intended to activate regulatory T cells. This subgroup of T-cells actually suppresses the activation of the immune system and stops it from attacking a person鈥檚 own body. TeGenero states that this is the strategy they hoped would ease the symptoms of rheumatoid arthritis patients.
鈥淚t鈥檚 possible there was contamination鈥� of the drugs the patients received, Ehrenstein notes, but he says it is just as possible that something unexpected happened. 鈥淚nstead of damping down the immune system, it鈥檚 activated it more. That鈥檚 what it looks like to me,鈥� he told 麻豆传媒.
Multiple attempts to contact TeGenero by 麻豆传媒 were unsuccessful. Previous experiments on immuno-deficient rats by the company indicated that the effect of the drug on regulatory T cells was disproportionately greater than on other T cells, leading to a normally functioning immune system. But it is unknown whether TGN1412 had been made more specific to regulatory T cells before the human trials.
Special status
Reports from friends and relatives describe the nightmarish symptoms suffered by the men. One man鈥檚 head was said to have swollen massively and his limbs turned purple. Another was said to resemble the deformed 鈥淓lephant Man鈥�.
TGN1412 was being tested as a treatment for a range of illnesses, including autoimmune diseases, but it had been awarded special status as a possible treatment for a type of leukaemia called B-cell chronic lymphocytic leukaemia (B-CLL).
The drug is a type of monoclonal antibody. Antibodies are produced by the immune system in response to a foreign invader like a bacterium. It recognises the particular invader, or antigen, and neutralises it as well as kick-starting a wider immune response. A monoclonal antibody is one manufactured to be specific for one antigen only. These have been used safely in treatments for a variety of diseases, including lymphoma, experts stress.
Direct stimulation
But TGN1412 differs from other monoclonal antibodies because it is a superagonist 鈥� massively enhancing the body鈥檚 immune response. It works by binding to a molecule, or receptor, on the surface of a T cell called CD28. Normally, binding to CD28 triggers the T cell response, but only when the T cell is also bound by another factor which is specific to the tissue designated for attack.
However, TGN1412 bypasses this so-called 鈥渃o-stimulation鈥�. It binds in a different place on the molecule to natural antibodies and directly causes CD28 to provoke a strong T cell response, without needing the other antigen-specific molecule to bind.
This is what was highlighted by Linsley in his article accompanying the Nature Immunology paper (vol 6, p 271). In that paper, scientists had for the first time managed to crystallise and examine the structure of CD28.
鈥淐ompletely unexpected鈥�
Whatever the cause of the terrible side-effects seen in the UK trial, it is unusual not to have seen anything similar in animal testing, says Campbell: 鈥淐D28 is widely conserved across species. It鈥檚 very, very strange if it does turn out to be some idiosyncratic case in humans,鈥� he told 麻豆传媒.
The company insists animal testing gave no hint of these side effects. 鈥淭hese events were completely unexpected and do not reflect the results we obtained from initial laboratory studies which enabled us to progress investigations into human volunteers鈥�, said CEO Benedikte Hatz, in a statement.
The UK鈥檚 regulatory body, the Medicines and Healthcare products Regulatory Agency, which halted the trial, is currently conducting an investigation which could take weeks to reach a conclusion.
